Heterocyclic substituted pyrazine derivative as well as preparation method and medical application thereof

Abstract

The invention provides a heterocyclic ring substituted pyrazine derivative. The heterocyclic substituted pyrazine derivative has a structure as shown in a formula I. The heterocycle substituted pyrazine derivative disclosed by the invention has an excellent protection effect on cerebral cortex neuronal cells, and has a remarkable inhibition effect on alpha-syn aggregation and an excellent anti-oxidation effect. Therefore, the heterocyclic substituted pyrazine derivative disclosed by the invention can be used as a medicine for preventing and treating nerve injury, degenerative diseases and ischemic diseases.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a heterocyclic substituted pyrazine derivative, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Neuroprotective agents are a class of drugs that protect the nervous system by reducing nerve cell damage, slowing disease progression, or promoting repair. They play a crucial role in the treatment of various neurological diseases, such as stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Based on their mechanisms and pathways of action, neuroprotective agents exhibit various effects, including anti-excitotoxicity, anti-oxidative stress, inhibition of neuroinflammation, inhibition of apoptosis, improvement of mitochondrial function, promotion of neurotrophic factors, stabilization of calcium ion levels, and inhibition of abnormal protein aggregation. Neuroprotection holds immense potential in the treatment of neurological diseases and is an important strategy for treating neurological disorders with complex mechanisms. In recent years, with a deeper understanding of disease mechanisms, multi-target neuroprotective agents have been found to have multiple pathways of action, affecting various targets, slowing disease progression, and repairing nerve damage, thus occupying an important position in the treatment of neurological diseases.

[0003] Tetramethylpyrazine (TMP) is one of the active ingredients in the traditional Chinese medicine Ligusticum chuanxiong. Pharmacological studies have shown that tetramethylpyrazine has the effects of scavenging free radicals, inhibiting platelet aggregation, antagonizing calcium ions, and promoting endothelial cell repair. Its therapeutic effects on cardiovascular and cerebrovascular diseases are related to its antioxidant, anti-inflammatory, and calcium homeostasis effects. Developing drugs with cardiovascular and neuroprotective properties using tetramethylpyrazine as a lead compound is currently a research hotspot. The applicant previously developed a drug (CN202311219043.4) of tetramethylpyrazine coupled with benzofuranone / indanone, which exhibits good neuroprotective and brain injury protection effects. Based on in-depth research into its pharmacological properties, the applicant has developed more heterocyclic substituted pyrazine derivatives with excellent activity, leading to this invention. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a heterocyclic substituted pyrazine derivative, which is a novel neuroprotective agent. The compound has excellent protective effects on cerebral cortical neurons and can be applied to the prevention and treatment of neurological diseases, such as stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

[0005] In a first aspect, the present invention provides a heterocyclic substituted pyrazine derivative or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof, said heterocyclic substituted pyrazine derivative having the structure shown in Formula I:

[0006]

[0007] Where R is selected from any one of equations a, b, c, and d;

[0008] R1 and R2 are each independently selected from any one of C1-C10 alkyl and halo-C1-C10 alkyl groups;

[0009] R3 is selected from C1-C10 alkyl, halo-C1-C10 alkyl. Any one of them; Ra is selected from C1-C10 alkyl and halo-C1-C10 alkyl;

[0010] X is selected from -O- and -NR 01 -、-CR 02 R 03 Any one of the following; R 01 Selected from hydrogen, C1-6 alkyl, and C3-8 cycloalkyl; R 02 R 03 Each is independently selected from hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or R 02 R 03 Together with the carbon atom it is attached to, they form a C3-8 cycloalkyl group;

[0011] R4, R6, R8, and R9 are each independently selected from any one of hydrogen, C1-C10 alkyl, halogenated C1-C10 alkyl, and C3-8 cycloalkyl.

[0012] R5, R7, R 10 Each is independently selected from any one of halogen, C1-C10 alkyl, halogenated C1-C10 alkyl, C1-C10 alkoxy, halogenated C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C1-C10 acyloxy, and C3-8 cycloalkyl;

[0013] m, n, and p are each independently selected from 1 or 2. When m is 2, each R5 can be the same or different; when n is 2, each R7 can be the same or different; when p is 2, each R... 10 They can be the same or different.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising at least one of the heterocyclic substituted pyrazine derivatives or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof.

[0015] In another aspect, the present invention provides the use of the aforementioned heterocyclic substituted pyrazine derivatives or pharmaceutically acceptable salts, prodrugs, solvates, and stereoisomers thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments.

[0016] In another aspect, the present invention provides a method for preparing the aforementioned heterocyclic substituted pyrazine derivative.

[0017] This invention provides a heterocyclic substituted pyrazine derivative, which has the following advantages:

[0018] 1) The heterocyclic substituted pyrazine derivatives of the present invention have excellent protective effects on cerebral cortical neurons. In particular, when tetramethylpyrazine is coupled to the 2-position of benzofuranone to form a Z-type structure in which tetramethylpyrazine is spatially closer to the oxygen atom at the 1-position of benzofuranone, the derivative has excellent brain injury protection, providing better protection against deep brain injury even at low concentrations. This effect is significantly better than the E-type derivative of CN202311219043.4.

[0019] 2) The heterocyclic substituted pyrazine derivatives of the present invention have a significant inhibitory effect on the aggregation of α-syn.

[0020] 3) The heterocyclic substituted pyrazine derivatives of the present invention also have excellent antioxidant effects.

[0021] The heterocyclic substituted pyrazine derivatives of the present invention can be used as preventive and therapeutic drugs for the prevention and treatment of nerve damage, degenerative diseases and ischemic diseases. Attached Figure Description

[0022] Figure 1 The results are from the single-crystal diffraction analysis of compound 1.

[0023] Figure 2 The results are from the single-crystal diffraction analysis of compound 15.

[0024] Figure 3 The protective effect of compounds 1, 2, 3, 5, 15-20, 22 and the positive control edaravone against neuronal damage;

[0025] Figure 4 The protective effects of compounds 23-25, 29-32, and 35-39 against nerve cell damage;

[0026] Figure 5 The protective effects of compounds 40-42, 45-46, 50, 56, 59, 62, and 70 against nerve cell damage;

[0027] Figure 6 The antioxidant activities of compounds 1, 3, 4, 6, 9, and 10 are described.

[0028] Figure 3-5 middle, * P<0.05, ** P<0.01, *** P < 0.001 vs OGD / R;## P<0.01 vs OGD / R ### P < 0.001 vs OGD / R; Figure 6 middle, * P<0.05, ** P<0.01, *** P < 0.001 vs model; ## P<0.01 vs model. Detailed Implementation

[0029] definition

[0030] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0031] In this invention, the term "alkyl" whether used alone or as a substituent includes both straight-chain and branched chains. Alkyl groups preferably contain 1-10 carbon atoms, more preferably 1-6 carbon atoms, and even more preferably 1-4 carbon atoms. Examples of alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., but are not limited thereto.

[0032] In this invention, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon group, whether used alone or as a substituent. The cycloalkyl group preferably contains 3-12 carbon atoms, more preferably 3-8 carbon atoms, and even more preferably 3-6 carbon atoms. Examples of cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., but are not limited thereto.

[0033] In this invention, the term "pharmaceutically acceptable salt" is described in Berge, et al., "Pharmaceutically Acceptable Salts", J. Pharm. Sci., 66, 1-19 (1977), which refers to salts that are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. The compounds described in this invention may have acidic, basic, or amphoteric groups. Typical pharmaceutically acceptable salts include those prepared by reacting the compounds of this invention with acids, such as: hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, octanoate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, citric acid, maleic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, mandelate, pyruvate, stearate, ascorbate, and salicylate. When the compounds of the present invention contain acidic groups, their pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as salts formed with ammonia, alkylamines, hydroxyalkylamines, amino acids, N-methylglucosamine, etc.

[0034] In this invention, the term "prodrug" refers to a compound that is metabolized in vivo and converted into its original active compound. Typically, a prodrug is an inactive substance, or one with less activity than the active parent compound, but it provides convenience in handling, administration, or improvement of metabolic properties.

[0035] In this invention, the term "solvent" refers to a combination or complex of a compound with one or more solvent molecules. Examples of solvents that form solvates include, but are not limited to, water (also referred to as hydrate in this case), ethanol, methanol, isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine, but are not limited thereto.

[0036] In this invention, the compounds can exist as isomers and mixtures thereof; for example, tautomers, optical isomers, enantiomers, and diastereomers. The compounds can, for example, contain asymmetric carbon atoms, and therefore can exist as enantiomers or diastereomers and mixtures thereof, for example, as racemates. The compounds can exist in (R)-, (S)-, or (R, S)- configurations, preferably in the (R)- or (S)- configuration at specific positions in the compound.

[0037] A heterocyclic substituted pyrazine derivative, or a pharmaceutically acceptable salt, prodrug, solvate, or stereoisomer thereof, is provided, wherein the heterocyclic substituted pyrazine derivative has the structure shown in Formula I:

[0038]

[0039]

[0040] Where R is selected from any one of equations a, b, and c;

[0041] R1 and R2 are each independently selected from any one of C1-C10 alkyl and halo-C1-C10 alkyl groups;

[0042] R3 is selected from C1-C10 alkyl, halo-C1-C10 alkyl. Any one of them; Ra is selected from C1-C10 alkyl and halo-C1-C10 alkyl;

[0043] X is selected from -O- and -NR 01 -、-CR 02 R 03 Any one of the following; R 01 Selected from hydrogen, C1-6 alkyl, and C3-8 cycloalkyl; R 02 R 03 Each is independently selected from hydrogen, halogen, C1-6 alkyl, C3-8 cycloalkyl, or R 02 R 03 Together with the carbon atom it is attached to, they form a C3-8 cycloalkyl group;

[0044] R4, R6, R8, and R9 are each independently selected from any one of hydrogen, C1-C10 alkyl, halogenated C1-C10 alkyl, and C3-8 cycloalkyl.

[0045] R5, R7, R 10 Each is independently selected from any one of halogen, C1-C10 alkyl, halogenated C1-C10 alkyl, C1-C10 alkoxy, halogenated C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C1-C10 acyloxy, and C3-8 cycloalkyl;

[0046] m, n, and p are each independently selected from 1 or 2. When m is 2, each R5 can be the same or different; when n is 2, each R7 can be the same or different; when p is 2, each R... 10 They can be the same or different.

[0047] In one embodiment, the heterocyclic substituted pyrazine derivative has the structure shown in Formula I-1, Formula I-2, Formula I-3, or Formula I-4:

[0048]

[0049] In one embodiment, R1 and R2 are each independently selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and trifluoromethyl. Preferably, R1 and R2 are selected from methyl.

[0050] In one embodiment, R3 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, ... Ra is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferably, R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0051] In one implementation, X is selected from -O-, -NR 01 -、-CR 02 R 03 Any one of the following; R 01 Selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, R 02 R 03 It is selected from any one of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or R5 and R6 together with the carbon atom they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] Preferably, in formula a, X is selected from -O-, -NR. 01 -、-CR 02 R 03 any one of -, R 01 Selected from any one of hydrogen, methyl, ethyl, isopropyl, and tert-butyl, R 02 R 03 X is selected from hydrogen. In formula b, X is selected from -O-, -NR. 01 any one of -, R 01 It is selected from any one of hydrogen, methyl, ethyl, isopropyl, and tert-butyl.

[0053] In one embodiment, R4 and R6 are each independently selected from hydrogen, methyl, ethyl, and trifluoromethyl. Preferably, R4 and R6 are selected from hydrogen.

[0054] In one embodiment, R8 and R9 are each independently selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and trifluoromethyl. Preferably, R8 is selected from any one of methyl and cyclopropyl; and R9 is selected from hydrogen.

[0055] In one implementation scheme, R5, R7, R 10 Each of the following is independently selected from any one of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, butoxy, halogen-substituted methoxy, halogen-substituted ethoxy, halogen-substituted propoxy, halogen-substituted butoxy, methoxycarbonyl, ethoxycarbonyl, formyloxy, acetoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably, R5, R7, and R... 10 Each is independently selected from fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, and -O(CH2). s F、-O(CH2) s Any one of Cl, and s is selected from 1, 2, 3 or 4.

[0056] Preferably, the heterocyclic substituted pyrazine derivative is selected from:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063] In another aspect, the present invention provides a pharmaceutical composition comprising at least one of the heterocyclic substituted pyrazine derivatives or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof.

[0064] In one embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient.

[0065] As used in this invention, "pharmaceuticalally acceptable excipient" means a pharmaceutically acceptable material, mixture, or solvent related to the consistency of the dosage form or pharmaceutical composition. Each excipient, when mixed, must be compatible with the other components of the pharmaceutical composition to avoid interactions that would significantly reduce the efficacy of the compounds disclosed in this invention when administered to a patient, and interactions that would lead to pharmaceutically unacceptable pharmaceutical compositions. Furthermore, each excipient must be pharmaceutically acceptable, for example, having sufficiently high purity. Suitable excipients are well known to those skilled in the art and include the following types: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients can provide more than one function and offer alternative functions, depending on how much of that excipient is present in the formulation and what other excipients are present in the formulation.

[0066] Depending on the therapeutic purpose, pharmaceutical compositions can be formulated into various types of dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions). Furthermore, they can also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0067] To form a pharmaceutical composition in tablet form, any excipient known and widely used in the art can be used. Examples include carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silica; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyvinyl sorbitol, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated oil; adsorption promoters such as quaternary ammonium base and sodium lauryl sulfate; wetting agents such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silica; and lubricants such as pure talc, stearates, boric acid powder, and polyethylene glycol. It can also be made into sugar-coated tablets, gelatin-coated tablets, sausage-coated tablets, coated tablets, double-layered tablets and multilayered tablets by selecting common coating materials as needed.

[0068] To form a pharmaceutical composition in pellet form, any excipient known and widely used in the art may be used, such as carriers, like lactose, starch, coconut oil, hardened vegetable oil, kaolin, and talc; binders, like gum arabic, tragacanth, gelatin, and ethanol; and disintegrants, like agar and kelp powder.

[0069] The pharmaceutical compositions provided by this invention can be formulated for single-dose or multiple-dose administration. For an individual weighing approximately 50-70 kg, the pharmaceutical compositions disclosed herein may be in unit dose form containing approximately 1-1000 mg, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 1-50 mg of active ingredient. The therapeutically effective amount of the compound or pharmaceutical composition depends on the individual's species, weight, age, individual condition, the disease being treated, or its severity. A physician, clinician, or veterinarian with common skills can readily determine the effective amount of each active ingredient required for the prevention, treatment, or inhibition of disease progression. In one embodiment, the therapeutically effective dose of the compound disclosed herein is approximately 0.1 mg to approximately 2,000 mg per day. The pharmaceutical composition shall provide a dose of the compound of approximately 0.1 mg to approximately 2,000 mg.

[0070] In another aspect, the present invention provides the use of the aforementioned heterocyclic substituted pyrazine derivatives or pharmaceutically acceptable salts, prodrugs, solvates, and stereoisomers thereof, or the aforementioned pharmaceutical compositions, in the preparation of medicaments.

[0071] The compounds of this invention exhibit excellent protective effects on cerebral cortical neurons, particularly under hypoxic and hypoglycemic conditions. They also possess preferred α-synuclein aggregation inhibition effects and good antioxidant activity. Therefore, these compounds can be used to prepare neuroprotective agents, platelet aggregation inhibitors, free radical scavenging drugs, vasodilators, or antioxidants. These compounds can prevent and treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease; they can prevent and treat ischemic diseases, such as myocardial ischemia and stroke; and they can also prevent and treat multiple sclerosis. Furthermore, these compounds can be used in the treatment of stroke rehabilitation.

[0072] Therefore, the medicament of the present invention can be used to prevent or treat diseases of the nervous system or ischemic diseases. Preferably, the diseases of the nervous system include neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as multiple sclerosis; the ischemic diseases include myocardial ischemia and stroke.

[0073] The drug of this invention can also be used for related treatments during the rehabilitation period of stroke.

[0074] The following will describe preferred embodiments of the invention in detail. These embodiments are provided to better illustrate the invention and are not intended to limit the invention to these examples. Non-essential improvements and adjustments to the embodiments based on the invention's description still fall within the scope of the invention.

[0075] Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions.

[0076] Example 1: Preparation of Compound 1

[0077]

[0078] Step a:

[0079]

[0080] 3,6-Dimethyl-2,5-dialdehyde pyrazine (1 g, 6 mmol) was dissolved in toluene (10 mL), followed by the addition of ethylene glycol (0.53 g, 8.5 mmol) and p-toluenesulfonic acid (15 mg). The reaction was carried out at 80 °C for 3 h, and the reaction was monitored by TLC. After the reaction was complete, the toluene was removed by rotary evaporation, diluted with water, and extracted twice with an equal volume of ethyl acetate. The extract was dried over anhydrous sodium sulfate and then evaporated to dryness. The product was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 15:1) to give 0.83 g of the dioxopentacyclic compound of pyrazinaldehyde, with a yield of 66.5%.

[0081] Step b:

[0082]

[0083] 1 g (6.6 mmol) of 6-fluoro-3-benzofuranone and 1.36 g (6.6 mmol) of the dioxinaldehyde conjugate were added to a reaction flask and dissolved in 10 mL of dichloromethane. Then, 2.68 g of activated alumina was added, and the reaction was carried out at room temperature for 24 h. The reaction was monitored by TLC until complete. The activated alumina was removed by filtration, and the solution was evaporated to dryness. The solution was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 8:1) to give 1.22 g of pure benzofuranone substituted with the dioxinaldehyde conjugate, in 54.3% yield.

[0084] Step c:

[0085]

[0086] A benzofuranone substituted with a dioxinaldehyde conjugate (400 mg, 1.17 mmol) was added to a reaction flask, followed by 20 mL of tetrahydrofuran. The mixture was shaken to dissolve completely, and then 20 mL of water was added and stirred until homogeneous. Finally, 5 mL of 37% hydrochloric acid aqueous solution was added. The mixture was stirred overnight at room temperature, and the reaction was monitored by TLC. After the reaction was complete, excess solvent was removed by rotary evaporation, and the mixture was diluted with 80 mL of ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 6:1) to give 298 mg of pure furanone and pyrazinaldehyde conjugate, in 85.6% yield.

[0087] Step d:

[0088]

[0089] The furanone and pyrazinaldehyde conjugate (500 mg, 1.67 mmol), tert-butylhydroxylamine hydrochloride (210.7 mg, 1.67 mmol), and dichloromethane (5 mL) were added sequentially to a reaction flask. The mixture was shaken to dissolve the compounds completely, and then tetrahydropyrrole (0.16 mL) was added dropwise. The reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC. After the reaction was complete, excess solvent was removed by rotary evaporation to obtain the crude product. Purification by silica gel column chromatography (eluting solvent: ethyl acetate: petroleum ether = 3:1) yielded 380 mg of pure compound 1, with a yield of 61.7%.

[0090] 1 H NMR (400MHz, Chloroform-d) δ7.87 (s, 1H), 7.80 (dd, J = 8.5, 5.6 Hz, 1H), 7.04 (dd, J = 8.6, 2. 1Hz,1H),7.00(s,1H),6.95(td,J=8.7,2.1Hz,1H),2.68(s,3H),2.60(s,3H),1.65(s,9H). 13 C NMR(101MHz,Chloroform-d)δ183.46,168.69(d,J=259.0Hz),168.61(d,J=14.7Hz),151.48,150.33,149.88,144.51,143.28,127.87,126 .88(d,J=11.7Hz),117.72(d,J=1.9Hz),112.49(d,J=24.0Hz),106.84,101.61(d,J=26.8Hz),71.95,28.35,22.04,21.64.HRMS-ESI[M+H] + m / z calcd for C 20H 21 FN3O3 370.1567,found,370.1557.

[0091] The single-crystal diffraction structure of compound 1 is shown in the figure. Figure 1 As shown. Its cell parameters are a = 19.7790(3) Å, b = 7.0997(1) Å, c = 21.0832(3) Å, a = 90°, β = 105.069(2)° and γ = 90°, cell volume = 2858.80(8) Å, space group is P21 / c, and Z value is 12.

[0092] Examples 12-14: Preparation of compounds 12-14

[0093] Following the method of Example 1, 6-fluoro-3-benzofuranone was replaced with the corresponding raw material to obtain compound 2-14.

[0094] The characterization results of compound 2-14 are as follows:

[0095] Compound 2: 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.72(d,J=8.2Hz,1H),7.37(s,1H),7 .21(dd,J=8.2,1.7Hz,1H),7.02(s,1H),2.67(s,3H),2.60(s,3H),1.64(s,9H). 13 C NMR(101MHz,Chloroform-d)δ183.82,167.42,151.50,150.38,149.59,144.48,143.70,143.29 ,127.86,125.68,124.85,119.71,114.26,107.24,71.95,28.34,22.03,21.64.HRMS-ESI[M+H] + m / z calcd for C 20 H 21 ClN3O3 386.1271,found,1264.

[0096] Compound 3: 1 H NMR (400MHz, Chloroform-d) δ8.17 (s, 1H), 7.90-7.83 (m, 2H), 7.81 (t, J = 2.3Hz, 1H),7.72(d,J=8.0Hz,1H),4.37(s,2H),2.73(s,3H),2.58(s,3H),1.65(s,9H). 1313C NMR (101 MHz, Chloroform-d) δ 193.53, 154.57, 151.17, 151.12, 146.64, 142.98, 140.98, 138.20, 131.40 (q, J = 3.3 Hz), 130.35 (q, J = 33.0 Hz), 128.16, 127.23, 126.73, 123.96 (d, J = 272.5 Hz), 121.77 (q, J = 3.7 Hz), 71.87, 33.86, 28.34, 22.13, 21.33. HRMS-ESI [M+H] + m / z calcd for C 22 H 23 F3N3O2 418.1742, found, 418.1731。

[0097] Compound 4: 1 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.60 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 2.68 (s, 3H), 2.60 (s, 3H), 1.64 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 184.06, 165.51, 151.52, 150.48, 149.57, 144.44, 143.34, 137.35, 129.64, 127.86, 124.48, 122.20, 114.99, 107.38, 71.96, 28.33, 22.03, 21.63. HRMS-ESI [M+H] + m / z calcd for C 20 H 21 ClN3O3 386.1271, found, 386.1263。

[0098] Compound 5: 1 1H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.44 (dd, J = 6.6, 2.7 Hz, 1H), 7.38 (td, J = 8.6, 2.8 Hz, 1H), 7.31 (dd, J = 9.0, 3.7 Hz, 1H), 7.02 (s, 1H), 2.68 (s, 3H), 2.61 (s, 3H), 1.64 (s, 9H). 1313C NMR (101 MHz, Chloroform-d) δ 183.57 (d, J = 3.3 Hz), 162.19, 159.13, 156.70, 150.36, 149.09 (d, J = 41.0 Hz), 143.40, 142.14, 126.74, 123.86 (d, J = 25.8 Hz), 120.57 (d, J = 8.2 Hz), 113.74 (d, J = 7.8 Hz), 109.35 (d, J = 24.3 Hz), 106.11, 70.81, 27.20, 20.91, 20.51. HRMS-ESI [M+H] + m / z calcd for C 20 H 21 FN3O3 370.1567, found, 370.1552。

[0099] Compound 6: 1 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.74 (d, J = 10.0 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.33 (td, J = 8.6, 2.5 Hz, 1H), 4.27 (d, J = 12.5 Hz, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). HRMS-ESI [M+H] + m / z calcd for C 21 H 23 FN3O2 368.1774, found, 368.1768。

[0100] Compound 7: 1 1H NMR (400 MHz, Chloroform-d) δ 7.90 (dd, J = 8.4, 5.4 Hz, 1H), 7.86 (s, 1H), 7.73 (t, J = 2.3 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 4.28 (s, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). 1313C NMR (101 MHz, Chloroform-d) δ 192.92, 167.36 (d, J = 256.4 Hz), 154.37 (d, J = 10.3 Hz), 151.02, 150.90, 146.92, 142.68, 141.65, 134.32 (d, J = 1.7 Hz), 128.17, 126.95 (d, J = 10.4 Hz), 125.55, 115.85 (d, J = 23.7 Hz), 113.22 (d, J = 22.5 Hz), 71.80, 33.71, 28.33, 22.11, 21.34. HRMS-ESI [M+H] + m / z calcd for C 21 H 23 FN3O2 368.1774, found, 368.1769。

[0101] Compound 8: 1 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 9.8 Hz, 2H), 7.69 (t, J = 2.0 Hz, 1H), 7.02 (s, 1H), 6.97 (dd, J = 8.5, 2.0 Hz, 1H), 4.86 (t, 1H), 4.74 (t, 1H), 4.36 (t, 1H), 4.29 (t, 1H), 4.23 (s, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 192.93, 164.40, 154.47, 150.91, 150.70, 147.32, 142.67, 142.35, 131.85, 128.29, 126.54, 124.56, 115.93, 110.34, 81.70 (d, J = 171.5 Hz), 71.74, 67.53 (d, J = 20.6 Hz), 33.80, 28.33, 22.13, 21.37. HRMS-ESI [M+H] + m / z calcd for C 23 H 27 FN3O3 412.2036, found, 412.2031。

[0102] Compound 9: 11H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 6.94 (s, 1H), 6.81 - 6.77 (m, 2H), 4.86 (t, 1H), 4.74 (t, 1H), 4.35 (t, 1H), 4.28 (t, 1H), 2.67 (s, 3H), 2.60 (s, 3H), 1.64 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 182.10, 168.50, 165.45, 150.19, 149.42, 149.00, 143.84, 141.77, 126.86, 125.19, 113.57, 111.83, 104.50, 96.77, 80.26 (d, J = 172.1 Hz), 70.73, 66.83 (d, J = 20.5 Hz), 27.20, 20.91, 20.53. HRMS-ESI [M + H] + m / z calcd for C 22 H 24 FN3O4 414.1784, found, 414.1824。

[0103] Compound 10: 1 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 9.5 Hz, 2H), 7.69 (t, J = 2.2 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.95 (dd, J = 8.5, 2.3 Hz, 1H), 4.34 (t, J = 5.9 Hz, 2H), 4.24 (s, 2H), 3.86 (t, J = 5.8 Hz, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 191.77, 163.01, 153.34, 149.77, 149.56, 146.15, 141.48, 141.22, 130.77, 127.13, 125.42, 123.46, 114.76, 109.23, 70.59, 67.18, 40.52, 32.67, 27.19, 20.99, 20.24. HRMS-ESI [M + H] + m / z calcd for C 23 H 27 ClN3O3 428.1741, found, 428.1740。

[0104] Compound 11: 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 6.95 (s, 1H), 6.78 (dt, J = 4.5, 2.4 Hz, 2H), 4.39 (t, J = 6.2 Hz, 1H), 4.33 (t, J = 5.7 Hz, 1H), 3.86 (t, J = 5.7 Hz, 1H), 3.68 (t, J = 6.1 Hz, 1H), 2.67 (s, 3H), 2.61 (s, 3H), 1.65 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 183.23, 169.61, 166.32, 166.20, 151.35, 150.53, 150.16, 144.96, 142.93, 127.97, 126.37, 112.86, 105.68, 98.01, 71.87, 68.52, 28.34, 22.06, 21.68. HRMS-ESI [M+H] + m / z calcd for C 22 H 25 ClN3O4 430.1534, found, 430.1532。

[0105] Compound 12: 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.74 (t, J = 2.1 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 5.9 Hz, 1H), 4.33 (dt, J = 23.5, 5.9 Hz, 2H), 4.22 (d, 2H), 3.76 (dt, J = 71.3, 5.9 Hz, 2H), 2.72 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ

[0106] 194.50, 158.10, 151.02, 150.85, 147.11, 145.07, 142.78, 142.58, 139.05, 128.20, 127.53, 125.61, 124.94, 106.73, 71.79, 68.43, 41.95, 33.04, 28.34, 22.1, 21.38. HRMS-ESI [M+H] + m / z calcd for C 23 H27 ClN3O3 428.1741, found, 428.1727。

[0107] Compound 13: 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.74 (t, J = 2.2 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.28 (dd, 1H), 4.85 (t, 2H), 4.73 (t, 2H), 4.22 (d, 2H), 2.72 (s, 3H), 2.57 (s, 3H), 1.65 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 193.40, 157.15, 149.87, 149.69, 145.97, 143.86, 141.66, 141.42, 137.87, 127.06, 126.35, 124.42, 123.89, 105.31, 80.73 (d, J = 171.0 Hz), 70.64, 66.39 (d, J = 20.3 Hz), 31.88, 27.19, 20.97, 20.23. HRMS-ESI [M+H] + m / z calcd for C 23 H 27 FN3O3 412.2036, found, 412.2021。<000057%5>

[0108] Compound 14: 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.74 (dd, J = 8.6, 1.9 Hz, 1H), 4.21 (t, J = 6.1 Hz, 2H), 3.86 (t, J = 5.9 Hz, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 2.08 (p, J = 6.0 Hz, 2H), 1.65 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 183.26, 169.81, !67.33, 151.34, 150.71, 150.13, 145.10, 142.82, 128.07, 126.19, 114.20, 113.05, 105.40, 97.73, 71.87, 66.20, 59.51, 31.81, 28.34, 22.05, 21.68. HRMS-ESI [M+H]+ m / z calcd for C 23 H 28 N3O5 426.2029,found,426.2011.

[0109] Example 15: Preparation of Compound 15

[0110]

[0111] Step a:

[0112] Under nitrogen protection, 2-bromo-3,5,6-trimethylpyrazine (1 g, 5 mmol), ethynyltrimethylsilane (736 mg, 7.5 mmol), Pd(PPh3)4 (144 mg, 0.125 mmol), and CuI (46 mg, 0.25 mmol) were added to DMF (30 mL), along with a few drops of triethylamine. The mixture was heated to 85 °C and stirred for 12 h. The reaction was monitored by TLC. After the reaction was complete, DMF was removed by rotary evaporation to obtain the crude product. The crude product was dissolved in dry THF (30 mL), cooled to 0 °C, and a 1 M TBAF solution in THF (7.5 mL, 7.5 mmol) was slowly added. The resulting solution was stirred at 0 °C for 0.5 h, followed by the addition of a saturated NH4Cl solution to quench the reaction. After removing THF by rotary evaporation, the mixture was extracted with ethyl acetate. The organic phase was washed once with water and once with saturated brine. Then, it was dried with anhydrous sodium sulfate and the ethyl acetate was removed by rotary evaporation to obtain 606 mg of 2-vinyl-3,5,6-trimethylpyrazine, with a yield of 83%.

[0113] Step b:

[0114] Under nitrogen protection, 2-vinyl-3,5,6-trimethylpyrazine (438 mg, 3 mmol) was dissolved in THF (50 mL). The solution was cooled to -40 °C using an ethanol bath with stirring. Butyllithium (192 mg, 3 mmol) was slowly added dropwise, and the reaction was allowed to proceed for 0.5 h. Then, a THF solution of 4-fluoro-2-hydroxybenzaldehyde (420 mg, 3 mmol) was slowly added dropwise, and the reaction was maintained at this temperature for 3 h. The reaction was monitored by TLC. After the reaction was complete, a saturated solution of NH4Cl was added to quench the reaction. THF was removed by rotary evaporation, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate was removed under reduced pressure. Recrystallization from anhydrous ethanol yielded 643 mg of 5-fluoro-2-(1-hydroxy-3-(3,5,6-trimethylpyrazin-2-yl)prop-2-yn-1-yl)phenol, with a yield of 75%.

[0115] Step c:

[0116] Under nitrogen protection, 5-fluoro-2-(1-hydroxy-3-(3,5,6-trimethylpyrazin-2-yl)prop-2-yn-1-yl)phenol from the previous step was completely dissolved in anhydrous toluene (40 ml), potassium carbonate powder (830 mg) was added, and the mixture was stirred thoroughly before adding lead nitrate crystals (2 g). The mixture was heated to reflux for 3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled to room temperature and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, and toluene was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:10) to give 582 mg of compound 15, with a yield of 91%.

[0117] 1 H NMR(400MHz,Chloroform-d)δ7.88(dd,J=8.5,5.7Hz,1H),7.13-7.05(m,1H),7 .03(s,1H),6.99(td,J=8.8,2.0Hz,1H),2.75(s,3H),2.68(s,3H),2.64(s,3H). 13 C NMR (101 MHz, Chloroform-d)δ

[0118] 183.48,168.60(d,J=258.4Hz),168.50(d,J=14.7Hz),151.65,150.94,150.32,149.22,142.53,126.83(d,J=11.8H z),117.83(d,J=1.9Hz),112.39(d,J=24.0Hz),107.56,101.52(d,J=26.7Hz),22.18,22.11,21.59.HRMS-ESI[M+H] + m / z calcd forC 16 H 14 FN2O2 285.1039,found,285.1021.

[0119] The single-crystal structure diagram of compound 15 is shown below. Figure 2 As shown, its cell parameters are: a = 22.3986(9) Å, b = 7.9356(3) Å, c = 22.0610(16) Å, a = 90°, β = 107.317(2)° and γ = 90°, cell volume = 3743.7(3) Å, space group is C2 / c, and Z value is 62.

[0120] Examples 16-20: Preparation of compounds 16-20

[0121] Following the method of Example 15, 4-fluoro-2-hydroxybenzaldehyde was replaced with the corresponding raw material to obtain compounds 16-20.

[0122] The characterization results of compounds 16-20 are as follows:

[0123] Compound 16: 1 H NMR (400MHz, Chloroform-d) δ7.81(d,J=8.4Hz,1H),7.42(d,J=1.5Hz,1H),7.26(dd,J=8.2,1.7Hz,1H),7.11(s,1H),2.75(s,3H),2.68(s,3H),2.62(s,3H). 13 C NMR(101MHz,Chloroform-d)δ183.82,167.32,151.71,151.02,150.32,148.93,143.50 ,142.49,125.65,124.73,119.84,114.19,108.00,22.21,22.10,21.60.HRMS-ESI[M+H] + m / z calcd for C 16 H 14 ClN2O2 301.0744,found,301.0727.

[0124] Compound 17: 1 H NMR (600MHz, Chloroform-d) δ7.85 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.8, 2.1 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.13 (s, 1H), 2.74 (s, 3H), 2.66 (s, 2H), 2.59 (s, 3H).

[0125] Compound 18: 1 H NMR(600MHz,Chloroform-d)δ7.53(dd,J=6.6,2.8Hz,1H),7.46(td,J=8.7,2.8Hz,1 H),7.36(dd,J=8.9,3.6Hz,1H),7.13(s,1H),2.72(s,3H),2.63(s,3H),2.57(s,3H).

[0126] Compound 19: 1H NMR(400MHz,Chloroform-d)δ7.63(td,J=8.3,5.5Hz,1H),7.14(d,J=8.3Hz,1 H),7.02(s,1H),6.85(t,J=8.3Hz,1H),2.65(s,3H),2.61(s,3H),2.55(s,3H).

[0127] Compound 20: 1 H NMR (400MHz, Chloroform-d) δ 8.16 (s, 1H), 7.75 (d, J = 8.2Hz, 1H), 7.42 (d, J = 8.3Hz, 1H), 6.95 (s, 1H), 2.46 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H).

[0128] Example 21: Preparation of compound 21

[0129]

[0130] Add 5-fluoroindole-2-one (500 mg, 3.3 mmol), then add 3,5,6-trimethyl-pyrazine-2-carboxaldehyde (500 mg, 3.3 mmol), dissolve in methanol (10 mL), add a methanol solution of sodium hydroxide, and react overnight at room temperature. Detect the reaction by TLC. After the reaction is complete, evaporate to dryness, and purify by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 2:1) to give 680 mg of pure product, yield 72.7%.

[0131] 1 H NMR(400MHz, DMSO-d6)δ8.62(dd,J=10.4,2.8Hz,1H),7.67(s,1H),7.13(td,J=8.8,2.8Hz,1H), 6.83(dd,J=8.5,4.7Hz,1H),3.34(s,3H),2.63(s,3H),2.58(s,3H),2.52(s,3H).HRMS-ESI[M+H] + m / z calcd for C 16 H 15 FN3O 284.1199,found,284.1180.

[0132] Example 22: Preparation of compound 22

[0133] Following the method of Example 21, 5-fluoroindole-2-one was replaced with the corresponding starting material to obtain compound 22.

[0134] The characterization results of compound 22 are as follows:

[0135] Compound 22: 1 H NMR(400MHz,Chloroform-d)δ9.41(s,1H),7.90(s,1H),7.19(td,J=8.2,5.2Hz,1H),6.72( d,J=7.7Hz,1H),6.60-6.52(m,1H),2.57(s,3H),2.52(s,3H),2.50(s,3H).HRMS-ESI[M+H] + m / zcalcd for C 16 H 15 FN3O 284.1199,found,284.1181.

[0136] Example 23: Preparation of compound 23

[0137]

[0138] Compound 21 was prepared according to the method of Example 21. Then, compound 21 (130 mg, 0.46 mmol) was dissolved in dichloromethane (1 mL) with iodomethane (0.07 mL), followed by the addition of potassium carbonate (126 mg). The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was quenched in ice water, extracted with ethyl acetate, washed several times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness. Purification by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 3:1) yielded 120 mg of the pure product, with a yield of 89.4%.

[0139] 1 H NMR(400MHz,Chloroform-d)δ8.60(dd,J=10.0,2.7Hz,1H),7.93(s,1H),7.04(td,J=8.6,2.7Hz,1H ),6.73(dd,J=8.5,4.3Hz,1H),3.28(s,3H),2.73(s,3H),2.67(s,3H),2.60(s,3H).HRMS-ESI[M+H] + m / z calcd for C 17 H 17 FN3O 298.1356,found,298.1345.

[0140] Examples 24-28: Preparation of compounds 24-28

[0141] Following the method of Example 23, 5-fluoroindole-2-one was replaced with the corresponding starting material to obtain compounds 24-28.

[0142] The characterization results of compounds 24-28 are as follows:

[0143] Compound 24: HRMS-ESI[M+H] + m / z calcd for C 17 H 17 FN3O 298.1356,found,298.1344.

[0144] Compound 25: HRMS-ESI[M+H] + m / z calcd for C 16 H 15 FN3O 284.1199,found,284.1189.

[0145] Compound 26: HRMS-ESI[M+H] + m / z calcd for C 16 H 15 FN3O 284.1199,found,284.1188.

[0146] Compound 27: HRMS-ESI[M+H] + m / z calcd for C 17 H 17 FN3O 298.1356,found,298.1352.

[0147] Compound 28: 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=7.4Hz,1H),7.79(s,1H),7.27(dd,J=11.7,8.3Hz,1H),7.03 (td,J=8.1,4.9Hz,1H),3.40(d,J=3.1Hz,3H),2.63(s,3H),2.59(s,3H),2.54(s,3H).HRMS-ESI[M+H] + m / z calcd for C 17 H 17 FN3O 298.1356,found,298.1352.

[0148] Example 29: Preparation of compound 29

[0149]

[0150] Step a:

[0151]

[0152] Aqueous potassium permanganate was added dropwise to tetramethylpyrazine (2 g, 14.7 mmol) over 60 min. The reaction was carried out at 35 °C for 24 h, and TLC was used to check for complete reaction. After the reaction was complete, the mixture was filtered, extracted with ethyl acetate, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 2-3, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. Silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 4:1) yielded 1.4 g of pure pyrazinic acid, 57.6%.

[0153] Step b:

[0154]

[0155] Pyrazinic acid (166 mg, 1 mmol) was dissolved in ethanol (1.7 mL), and sulfuric acid (0.075 mL) was added dropwise. The mixture was refluxed for 24 h, and the reaction was monitored by TLC. After the reaction was complete, the ethanol was removed under reduced pressure, water was added, and the pH was adjusted to 9 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 6:1) to give 180 mg of pure pyrazinic acid, with a yield of 95.4%.

[0156] Step c:

[0157]

[0158] Add 1.5 g of NaH to a flask, add 15 mL of tetrahydrofuran under ice bath conditions, and protect with nitrogen. Then dissolve 3.3 g of acetone in 30 mL of tetrahydrofuran and add it to the flask. Stir for 2 h. Dissolve 5 g (25.8 mmol) of pyrazine ester in 50 mL of tetrahydrofuran and add it to the flask. Heat the reaction mixture to reflux (70 °C) overnight. Monitor the reaction by TLC. After the reaction is complete, quench the reaction mixture with aqueous hydrochloric acid, extract the aqueous layer with dichloromethane, wash the organic phase with brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 5:1) to give 3.57 g of pure pyrazinedione, yield 67.2%.

[0159] Step d:

[0160]

[0161] p-Fluorophenylhydrazine hydrochloride (2 g, 12.3 mmol) and pyrazinidine (1.5 g, 7.3 mmol) were dissolved in ethanol (3 mL) and stirred overnight. The reaction was monitored by TLC using pure dichloromethane. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate, drying, and rotary evaporation. Purification by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1) yielded 1.45 g of compound 29, in 67.1% yield.

[0162] 1 H NMR(400MHz,Chloroform-d)δ7.19-7.13(m,2H),6.95(t,J=8.6Hz,2H),6.38(s,1H),2.54(s,3H),2.47(s,3H),2.40(s,3H),2.19(s,3H).HRMS-ESI[M+H] + m / z calcdfor C 17 H 18 FN4 297.1515,found,297.1496.

[0163] Examples 30-42: Preparation of compounds 30-42 and 70

[0164] Following the method of Example 29, hydrochloric acid p-fluorophenylhydrazine was replaced with the corresponding raw materials to obtain compounds 30-42 and 70.

[0165] The characterization results of compounds 30-42 and 70 are as follows:

[0166] Compound 30: 1 H NMR (400MHz, Chloroform-d) δ7.19-7.12(m,2H),6.95(t,J=8.6Hz,2H),6.37(s,1H),2.52(s,3H),2.47(s,3H),2.39(s,3H),2.17(s,3H). 13 C NMR(101MHz,Chloroform-d)δ162.62,160.16,151.70,149.78,149.36,149.04,141.34,140.65, 136.45 (d, J = 3.0Hz), 125.71 (d, J = 8.5Hz), 115.99, 115.76, 109.30, 22.02, 21.65, 21.34, 13.69.

[0167] Compound 31: 1 H NMR(400MHz,Chloroform-d)δ7.14(ddd,J=10.1,7.0,1.9Hz,1H),7.03(q,J=8.9Hz,1H), 6.86(d,J=7.7Hz,1H),6.38(s,1H),2.55(s,3H),2.48(s,3H),2.39(s,3H),2.23(s,3H). 1313C NMR (101 MHz, Chloroform-d) δ 151.93, 150.18, 149.60, 148.97, 141.03, 140.60, 136.66 (dd, J = 8.1, 3.5 Hz), 119.84 (dd, J = 6.3, 3.7 Hz), 117.45, 113.79, 113.59, 109.84, 22.02, 21.67, 21.37, 13.69. HRMS-ESI [M+H] + m / z calcd for C 17 H 17 F2N4 315.1241, found, 315.1397。

[0168] Compound 32: 1 1H NMR (400 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.39 - 7.29 (m, 2H), 6.41 (s, 1H), 2.52 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ

[0169] 151.89, 150.33, 149.47, 148.97, 140.98, 140.60 (d, J = 2.0 Hz), 131.38 (q, J = 33.33 Hz), 129.95 (q, J = 213.11 Hz), 129.49, 126.81, 123.50 (q, J = 3.7 Hz), 122.43 (q, J = 273.71 Hz), 121.05 (q, J = 3.9 Hz), 109.92, 21.93, 21.47, 21.35, 13.69. HRMS-ESI [M+H] + m / z calcd for C 18 H 18 F3N4 347.1484, found, 347.1473。

[0170] Compound 33: 1 1H NMR (400 MHz, Chloroform-d) δ 7.62 (d, J = 7.9 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.46 (dd, J = 14.3, 7.1 Hz, 2H), 6.44 (s, 1H), 2.54 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H), 2.13 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 150.13, 148.88, 148.46, 148.27, 141.64, 140.18, 138.69 (d, J = 1.7 Hz), 131.71, 131.37, 128.60, 127.34 (q, J = 31.31 Hz), 126.76 (q, J = 4.8 Hz), 122.98 (q, J = 274.72 Hz), 108.08, 21.89, 21.59, 20.92, 13.62. HRMS-ESI [M+H] + m / z calcd for C 18 H 18 F3N4 347.1484, found, 347.1484。

[0171] Compound 34: 1 1H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.35 (s, 1H), 2.53 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H), 1.25 (s, 10H). 13 13C NMR (101 MHz, Chloroform-d) δ 151.40, 150.08, 149.56, 149.25, 149.10, 141.89, 140.53, 137.70, 125.93, 123.16, 109.12, 34.62, 31.36, 21.98, 21.66, 21.21, 13.69. HRMS-ESI [M+H] + m / z calcd for C 21 H 27 N4 335.2236, found, 335.2232。

[0172] Compound 35: 1 1H NMR (400 MHz, Chloroform-d) δ 7.19 (td, J = 8.2, 6.3 Hz, 1H), 7.00 (dt, J = 9.8, 2.2 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.38 (s, 1H), 2.55 (s, 3H), 2.49 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 162.72, 160.27, 150.62, 149.04, 148.40, 147.83, 140.21, 139.46, 129.06 (d, J = 9.1 Hz), 118.01 (d, J = 3.2 Hz), 112.78 (d, J = 21.1 Hz), 110.12 (d, J = 25.0 Hz), 108.77, 20.81, 20.50, 20.06, 12.55. HRMS-ESI [M+H] + m / z calcd for C 17 H 18 FN4 297.1515, found, 297.1527。

[0173] Compound 36: 1 1H NMR (400 MHz, Chloroform-d) δ 7.46 (td, J = 7.7, 1.7 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.13 (t, J = 7.3 Hz, 1H), 6.95 (ddd, J = 9.8, 8.3, 1.2 Hz, 1H), 6.42 (s, 1H), 2.46 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 156.13, 153.64, 149.74, 148.87, 147.58, 147.43, 140.71, 139.67, 128.24 (d, J = 7.8 Hz), 127.47, 123.32 (d, J = 3.9 Hz), 115.06 (d, J = 20.0 Hz), 107.42, 20.72, 20.55, 20.16, 12.62. HRMS-ESI [M+H] + m / z calcd for C 17 H 18 FN4 297.1515, found, 297.1510。

[0174] Compound 37: 1 1H NMR (400 MHz, Chloroform-d) δ 6.74 (dd, J = 8.0, 2.2 Hz, 2H), 6.66 (tt, J = 8.3, 2.1 Hz, 1H), 6.38 (s, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.38 (s, 3H), 2.23 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ

[0175] 162.86 (d, J = 14.2 Hz), 160.39 (d, J = 14.2 Hz), 151.02, 149.43, 148.51, 147.90, 141.01 (t, J = 12.7 Hz), 139.73, 139.55, 109.33, 105.81 (d, J = 28.8 Hz), 105.81 (d, J = 11.5 Hz), 101.15 (t, J = 25.4 Hz), 20.90, 20.50, 20.16, 12.54. HRMS-ESI [M+H] + m / z calcd for C 17 H 17 F2N4 315.1421, found, 315.1413。

[0176] Compound 38: 1 H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.26 (m, 1H), 7.24 - 7.19 (m, 1H), 7.17 - 7.11 (m, 1H), 6.75 (d, J = 0.9 Hz, 1H), 2.80 (s, 3H), 2.56 (s, 3H), 2.54 (s, 3H), 2.30 (dd, J = 2.2, 0.8 Hz, 3H).

[0177] Compound 39: 1 H NMR (400 MHz, Chloroform-d) δ 7.31 - 7.26 (m, 1H), 7.00 - 6.87 (m, 2H), 6.44 (s, 1H), 2.49 (s, 3H), 2.48 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 158.25 (dd, J = 244.2, 2.6 Hz), 152.06 (dd, J = 246.9, 3.1 Hz), 151.03, 150.42, 148.72, 148.49, 141.79 (d), 140.49 (d, J = 1.4 Hz), 129.56 (dd, J = 14.0, 10.7 Hz), 116.82 (dd, J = 23.0, 9.2 Hz), 115.68 (dd, J = 23.9, 7.8 Hz), 115.51 (d, J = 26.0 Hz), 108.94, 21.89, 21.83, 21.29, 13.74. HRMS-ESI [M+H] + m / z calcd for C 17 H 17F2N4 315.1421,found,315.1416.

[0178] Compound 40: 1 H NMR (400MHz, Chloroform-d) δ7.52(d,J=8.4Hz,2H),7.29(d,J=8.3Hz,2H),6.41(s,1H),2.55(s,3H),2.47(s,3H),2.41(s,3H),2.20(s,3H). 13 C NMR(101MHz,Chloroform-d)δ152.01,150.63,149.64,148.97,142.96,141.21,140.71,128.73(q,J=32.8Hz ),126.25(q,J=3.7Hz),123.93(d,J=272.0Hz),123.49,110.37,22.03,21.64,21.28,13.73.HRMS-ESI[M+H] + m / z calcd for C 18 H 18 F3N4347.1484,found,347.1478.

[0179] Compound 41: 1 H NMR (400MHz, Chloroform-d) δ7.06(s,4H),6.35(s,1H),2.58(q,J=7.6Hz,2H),2.53(s,3H),2.50(s,3H),2.39(s,3H),2.09(s,3H),1.17(t,J=7.6Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ150.26,148.39,148.12,147.96,142.08,140.74,139.42,1 36.81,127.27,122.49,107.95,27.29,20.82,20.53,20.06,14.39,12.56.HRMS-ESI[M+H] + m / z calcd for C 13 H 29 N4 307.1923,found,307.1916.

[0180] Compound 42: 1H NMR(400MHz,Chloroform-d)δ7.08(s,4H),6.35(s,1H),2.84(p,J=6.9Hz,1H), 2.53(s,3H),2.50(s,3H),2.39(s,3H),2.09(s,3H),1.19(s,3H),1.17(s,3H). 13 C NMR(101MHz,Chloroform-d)δ150.24,148.40,148.13,147.94,139.39,136.87,125.86,122.46,107.96,32.62,22.87,20.06,12.56.HRMS-ESI[M+H] + m / z calcd forC 20 H 25 N4 321.2079,found,321.2076.

[0181] Compound 70: 1 H NMR(400MHz,Chloroform-d)δ7.44-7.39(m,2H),7.02-6.96(m,2H),6.71(s,1H), 3.86(s,3H),2.83(s,3H),2.55(s,3H),2.54(s,3H),2.36(s,3H).HRMS-ESI[M+H] + m / z calcd for C 19 H 22 N3O 308.1763,found,309.1715.

[0182] Examples 43 and 44:

[0183]

[0184] Steps a and b are the same as in Example 29.

[0185] Step c:

[0186]

[0187] Add 1.5 g of NaH to a flask, add 15 mL of tetrahydrofuran under ice bath conditions, and protect with nitrogen. Then dissolve 3.3 g (39.3 mmol) of cyclopropyl methyl ketone in 30 mL of tetrahydrofuran and add it to the flask. Stir for 2 h. Dissolve 5 g (25.8 mmol) of pyrazine ester in 50 mL of tetrahydrofuran and add it to the flask. Heat the reaction mixture to reflux (70 °C) overnight. Monitor the reaction by TLC. After the reaction is complete, quench the reaction mixture with aqueous hydrochloric acid, extract the aqueous layer with dichloromethane, wash the organic phase with brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and perform silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 5:1) to give 3.08 g of pure product, yield 51.5%.

[0188] Step d:

[0189]

[0190] tert-Butylphenylhydrazine hydrochloride (2 g, 10 mmol) and pyrazinidine (1.5 g, 6.5 mmol) were dissolved in ethanol (3 mL) and stirred overnight. The reaction was monitored by TLC using pure dichloromethane. After the reaction was complete, water was added to quench the reaction, followed by extraction with ethyl acetate, drying, and rotary evaporation. The mixture was then purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1) to give 0.6 g of pure compound 43 (yield 25.6%) and 0.49 g of compound 44 (yield 21.2%).

[0191] Compound 43: 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.5Hz,2H),7.49(d,J=8.5Hz,2H),6.53(s,1H),2.85(s, 3H), 2.54 (d, J = 5.0Hz, 6H), 1.91-1.85 (m, 1H), 1.36 (s, 9H), 1.05-1.01 (m, 2H), 0.90-0.87 (m, 2H). 13 C NMR(101MHz,Chloroform-d)δ150.90,150.56,149.34,148.45,148.20,146.57,143.14,137 .75,126.00,124.24,103.55,34.80,31.49,23.38,21.83,21.79,9.16,8.06.HRMS-ESI[M+H] + m / z calcd for C 23 H 29 N4361.2392,found,361.2391.

[0192] Compound 44:1 H NMR(400MHz,Chloroform-d)δ7.30-7.25(m,2H),7.14-7.09(m,2H),6.25(s,1H),2.56(s,3H),2. 54(s,3H),2.11-2.04(m,4H),1.28(s,9H),0.99(ddd,J=8.4,6.4,4.2Hz,2H),0.89-0.84(m,2H). 13 C NMR(101MHz,Chloroform-d)δ155.99,151.40,150.03,149.23,149.14,141.89,140.38,137 .70,125.94,123.15,105.75,34.61,31.36,21.98,21.66,21.19,9.30,8.12.HRMS-ESI[M+H] + m / z calcd for C 23 H 29 N4 361.2392,found,361.2383.

[0193] Examples 45-70: Preparation of compounds 45-69

[0194] Following the methods of Examples 43 and 44, hydrochloric acid p-fluorophenylhydrazine was replaced with the corresponding raw materials to obtain compounds 45-69.

[0195] The characterization results of compounds 45-69 are as follows:

[0196] Compound 45: 1 H NMR (400MHz, Chloroform-d) δ7.39 (dd, J=8.2, 2.3Hz, 2H), 6.81 (tt, J=8.8, 2.3Hz, 1H), 6.63 (s, 1H), 2.8 5(s,3H),2.54(s,6H),1.90(tt,J=8.4,5.3Hz,1H),1.15-1.07(m,2H),0.95-0.90(m,2H).HRMS-ESI[M+H] + m / z calcd for C 19 H 19 F2N4341.1578,found,341.1575.

[0197] Compound 46: 11H NMR (400 MHz, Chloroform-d) δ 6.77 - 6.70 (m, 2H), 6.64 (tt, J = 8.8, 2.3 Hz, 1H), 6.24 (s, 1H), 2.55 (s, 3H), 2.48 (s, 3H), 2.20 (s, 3H), 2.02 (tt, J = 8.4, 5.0 Hz, 1H), 0.98 (ddd, J = 8.4, 6.6, 4.2 Hz, 2H), 0.86 - 0.81 (m, 2H). HRMS-ESI [M+H] + m / z calcd for C 19 H 19 F2N4 341.1578, found, 341.1571。

[0198] Compound 47: 1 1H NMR (400 MHz, Chloroform-d) δ 7.31 (ddd, J = 8.5, 5.8, 3.1 Hz, 1H), 7.22 (td, J = 9.2, 4.8 Hz, 1H), 7.14 (ddt, J = 9.2, 7.0, 3.5 Hz, 1H), 6.53 (s, 1H), 2.80 (s, 3H), 2.54 (d, J = 3.6 Hz, 6H), 1.74 - 1.65 (m, 1H), 0.97 - 0.90 (m, 2H), 0.78 (dt, J = 6.9, 4.6 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ

[0199] 157.18 (dd, J = 244.9, 2.7 Hz), 152.11 (dd, J = 248.8, 3.1 Hz), 151.11, 148.67, 147.46, 147.14, 141.54, 127.59 (dd, J = 23.7, 13.4 Hz), 116.42 (dd, J = 22.8, 9.2 Hz), 115.68 (dd, J = 23.8, 7.8 Hz), 115.14, 114.89, 102.46, 22.02, 20.71, 20.62, 7.11, 5.59 (d, J = 4.4 Hz). HRMS-ESI [M+H] + m / z calcd for C 19 H 19 F2N4 341.1578, found, 341.1572。

[0200] Compound 48: 11H NMR (400 MHz, Chloroform-d) δ 7.30 (ddd, J = 8.7, 5.8, 3.1 Hz, 1H), 7.00 - 6.86 (m, 2H), 6.31 (s, 1H), 2.50 (s, 6H), 2.27 (s, 3H), 2.04 (tt, J = 8.5, 5.0 Hz, 1H), 1.00 (ddd, J = 8.4, 6.5, 4.2 Hz, 2H), 0.85 (dd, J = 4.9, 2.2 Hz, 2H). HRMS-ESI [M+H] + m / z calcd for C 19 H 19 F2N4 341.1578, found, 341.1578。

[0201] Compound 49: 1 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 6.64 (s, 1H), 2.85 (s, 3H), 2.55 (s, 6H), 1.89 (tt, J = 8.4, 5.3 Hz, 1H), 1.08 (ddd, J = 8.3, 6.5, 4.3 Hz, 2H), 0.92 (dt, J = 6.7, 4.5 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 150.80, 148.67, 147.49, 147.07, 145.54, 141.93, 141.38, 127.91 (q, J = 32.8 Hz), 125.19 (q, J = 3.7 Hz), 122.96, 122.88 (q, J = 273.11 Hz), 104.31, 22.26, 20.71, 20.63, 8.01, 7.14. HRMS-ESI [M+H] + m / z calcd for C 20 H 20 F3N4 373.1640, found, 373.1637。

[0202] Compound 50: 1 1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.27 (s, 1H), 2.55 (s, 3H), 2.47 (s, 3H), 2.16 (s, 3H), 2.05 (ddd, J = 13.4, 8.5, 5.0 Hz, 1H), 1.03 - 0.96 (m, 2H), 0.87 - 0.82 (m, 2H).13 C NMR (101 MHz, Chloroform-d) δ 155.90, 150.86, 148.47, 147.84, 141.79, 140.07, 139.42, 127.47 (q, J = 32.9 Hz), 125.08 (q, J = 3.7 Hz), 122.78 (q, J = 272.1 Hz), 122.25, 105.92, 20.88, 20.49, 20.11, 8.14, 7.12. HRMS-ESI [M+H] + m / z calcd for C 20 H 20 F3N4 373.1640, found, 373.1661。

[0203] Compound 51: 1 H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.97 (td, J = 4.8, 4.2, 2.1 Hz, 1H), 7.63 (d, J = 5.2 Hz, 2H), 6.62 (s, 1H), 2.86 (s, 3H), 2.55 (d, J = 2.3 Hz, 6H), 1.85 (tt, J = 8.2, 5.1 Hz, 1H), 1.11 - 1.04 (m, 2H), 0.94 - 0.90 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 156.77, 151.91, 149.42, 149.00, 140.95, 140.55, 140.48, 131.32 (q, J = 32.8 Hz), 129.45, 126.71, 123.56 (q, J = 272.5 Hz), 123.39 (q, J = 3.7 Hz), 120.97 (q, J = 3.9 Hz), 106.59, 21.93, 21.45, 21.32, 9.25, 8.21。

[0204] Compound 52: 1 H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.37 - 7.28 (m, 2H), 6.27 (s, 1H), 2.52 (s, 3H), 2.43 (s, 3H), 2.19 (s, 3H), 2.04 (ddd, J = 13.4, 8.5, 5.0 Hz, 1H), 1.02 - 0.95 (m, 2H), 0.87 - 0.81 (m, 2H). 13C NMR(101MHz,Chloroform-d)δ150.65,148.66,147.50,147.07,145.47,141.44,139.55,130.45(q,J=32.9Hz),12 8.63, 126.22, 122.70 (q), 122.65 (q, J = 272.5Hz), 119.92 (q, J = 3.9Hz), 104.13, 22.21, 20.71, 20.63, 7.92, 7.02.

[0205] Compound 53: 1 H NMR(400MHz,Chloroform-d)δ7.63-7.58(m,2H),7.30(d,J=8.4Hz,2H),6.53(s,1H),2.85(s,3H),2.71(q,J=7.6Hz,2H) ,2.54(d,J=3.6Hz,6H),1.89-1.81(m,1H),1.28(t,J=7.6Hz,3H),1.01(ddd,J=8.3,6.5,4.3Hz,2H),0.90-0.85(m,2H). 13 CNMR(101MHz,Chloroform-d)δ150.83,149.25,148.53,148.11,146.56,143.76, 143.21,138.00,128.47,124.67,103.63,28.63,23.31,21.78,15.71,9.08,8.02.

[0206] Compound 54: 1 H NMR(400MHz,Chloroform-d)δ7.05(s,4H),6.20(s,1H),2.77-2.52(m,5H),2.51(s,3H),2.49(s ,3H),2.04-2.00(m,1H),1.15(t,J=7.6Hz,3H),0.95(dt,J=7.1,2.3Hz,2H),0.83-0.80(m,2H). 13 C NMR(101MHz,Chloroform-d)δ155.94,151.39,149.18,149.11,143.12,141.82,140. 38,137.91,128.37,123.57,105.60,28.39,21.93,21.62,21.15,15.51,9.27,8.09.

[0207] Compound 55: 1H NMR(400MHz,Chloroform-d)δ7.63(d,J=7.8Hz,1H),7.55-7.49(m,1H),7.48-7.41(m,2H),6.32(s,1H),2.52 (s,3H),2.42(s,3H),2.14(s,3H),2.03(ddd,J=13.4,8.5,5.0Hz,1H),1.01-0.94(m,2H),0.88-0.82(m,2H). 13 C NMR(101MHz,Chloroform-d)δ154.32,149.14,147.46,147.25,140.40,139.14,137.55,130.66,130.24,127.5 2,126.33(q,J=31.3Hz),125.80(q,J=4.8Hz),121.93(q,J=273.7Hz),104.08,20.79,20.56,19.91,8.11,7.16.

[0208] Compound 56: 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,2H),6.53(s,1H),2.96(dq,J=13.8,6.9Hz,1H),2.85(s,3H ),2.54(s,3H),2.53(s,3H),1.86(ddd,J=13.5,8.4,5.2Hz,1H),1.29(s,3H),1.28(s,3H),1.04-0.98(m,2H),0.91-0.85(m,2H). 13 C NMR(101MHz,Chloroform-d)δ149.72,148.14,147.29,147.16,147.00,145.39,141.9 9,136.90,125.89,123.47,102.39,32.79,22.97,22.22,20.66,7.97.HRMS-ESI[M+H] + m / z calcd for C 22 H 27 N4 347.2236,found,347.2236.

[0209] Compound 57: 11H NMR (400 MHz, Chloroform-d) δ 7.06 (s, 4H), 6.20 (s, 1H), 2.81 (hept, J = 6.9 Hz, 1H), 2.50 (s, 3H), 2.48 (s, 3H), 2.06 - 1.98 (m, 4H), 1.16 (s, 3H), 1.15 (s, 3H), 0.93 (ddd, J = 8.4, 6.5, 4.2 Hz, 2H), 0.84 - 0.79 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 155.86, 151.37, 149.10, 149.07, 147.68, 141.74, 140.35, 137.98, 126.91, 123.49, 105.63, 33.68, 23.94, 21.94, 21.58, 21.16, 9.30 - 9.18 (m), 8.05. HRMS-ESI [M + H] + m / z calcd for C 22 H 27 N4 347.2236, found, 347.2232。

[0210] Compound 58: 1 1H NMR (400 MHz, Chloroform-d) δ 7.54 (td, J = 7.8, 1.8 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.30 - 7.21 (m, 2H), 6.49 (s, 1H), 2.78 (s, 3H), 2.53 (s, 3H), 2.51 (s, 3H), 1.66 (tq, J = 8.7, 5.2 Hz, 1H), 0.92 - 0.86 (m, 2H), 0.78 - 0.73 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 157.28, 154.77, 150.64, 148.46, 147.37 (d, J = 4.8 Hz), 147.15, 141.84, 129.21 (d, J = 7.7 Hz), 128.21, 126.88 (d, J = 12.1 Hz), 123.51 (d, J = 4.0 Hz), 115.62 (d, J = 19.9 Hz), 101.94, 22.03, 20.72, 20.64, 7.07, 5.63 (d, J = 3.7 Hz). HRMS-ESI [M + H] + m / z calcd for C 19 H 20 FN4 323.1672, found, 323.1672。

[0211] Compound 59: 1 H NMR (400MHz, Chloroform-d) δ7.48(td,J=7.7,1.8Hz,1H),7.23(ddd,J=8.1,4.8,1.8Hz,1H),7.14(t,J=7.2Hz,1H),6.95(ddd,J=9.9,8 .3,1.3Hz,1H),6.28(s,1H),2.47(s,3H),2.41(s,3H),2.27(s,3H),2.05(tt,J=8.5,5.0Hz,1H),1.01-0.95(m,2H),0.86-0.81(m,2H). 13 C NMR(101MHz,Chloroform-d)δ157.23,156.50,154.73,150.88,148.74,148.57,141.70,140.85,129.34(d,J=7.7 Hz),128.66,124.50(d,J=3.8Hz),116.21(d,J=20.0Hz),105.19,21.87,21.67,21.32,9.34,8.22.HRMS-ESI[M+H] + m / z calcd for C 19 H 20 FN4 323.1672,found,323.1674.

[0212] Compound 60: 1 H NMR(400MHz,Chloroform-d)δ7.54(q,J=8.3Hz,1H),7.01(t,J=8.6Hz,2H),6.50(s,1H),2.78(s ,3H),2.53(d,J=5.5Hz,6H),1.62(dt,J=8.6,4.9Hz,1H),0.96-0.87(m,2H),0.79-0.73(m,2H). 1313C NMR (101 MHz, Chloroform-d) δ 161.53 (dd, J = 263.61, 241.39 Hz), 156.38 (dd, J = 255.4, 12.6 Hz), 150.77, 148.57, 147.46, 147.44, 147.10, 141.71, 129.19 (d, J = 10.1 Hz), 123.35 (dd, J = 12.5, 4.0 Hz), 110.77 (dd, J = 22.5, 3.9 Hz), 103.97 (dd, J = 26.3, 23.7 Hz), 102.13, 21.97, 20.70, 20.63, 6.98, 5.55, 5.52. HRMS-ESI [M+H] + m / z calcd for C 19 H 20 F2N4 341.1578, found, 341.1582。

[0213] Compound 61: 1 1H NMR (400 MHz, Chloroform-d) δ 7.47 (td, J = 8.7, 5.9 Hz, 1H), 6.93 - 6.85 (m, 1H), 6.72 (ddd, J = 10.2, 8.5, 2.7 Hz, 1H), 6.28 (s, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.27 (s, 3H), 2.04 (tt, J = 8.4, 5.0 Hz, 1H), 1.01 - 0.95 (m, 2H), 0.86 - 0.80 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 160.86 (dd, J = 250.4, 11.1 Hz), 155.41, 155.26 (dd, J = 253.8, 12.5 Hz), 149.86, 147.64, 147.45, 140.53, 139.39, 128.64 (dd, J = 10.0, 1.5 Hz), 124.14 (dd, J = 12.0, 4.0 Hz), 110.42 (dd, J = 22.4, 3.8 Hz), 104.10, 103.31 (dd, J = 26.4, 23.9 Hz), 20.72, 20.62, 20.19, 8.16, 7.09。

[0214] Compound 62: 11H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 9.9 Hz, 1H), 7.44 (q, J = 8.1 Hz, 1H), 7.07 (td, J = 8.3, 2.2 Hz, 1H), 6.59 (s, 1H), 2.85 (s, 3H), 2.54 (s, 3H), 2.53 (s, 3H), 1.88 (tt, J = 8.3, 5.2 Hz, 1H), 1.09 - 1.03 (m, 2H), 0.93 - 0.86 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 162.88, 160.43, 150.37, 148.55, 147.23 (d, J = 30.3 Hz), 145.43, 141.50, 140.50 (d, J = 10.1 Hz), 129.12 (d, J = 9.1 Hz), 118.61 (d, J = 3.1 Hz), 113.04 (d, J = 21.1 Hz), 110.62 (d, J = 24.9 Hz), 103.75, 22.27, 20.72, 20.62, 7.96, 7.05. HRMS-ESI [M+H] + m / z calcd for C 19 H 20 FN4 323.1672, found, 323.1649。

[0215] Compound 63: 1 1H NMR (400 MHz, Chloroform-d) δ 7.16 (td, J = 8.2, 6.3 Hz, 1H), 6.99 (dt, J = 9.9, 2.2 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.23 (s, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 2.13 (s, 3H), 2.03 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 0.99 - 0.94 (m, 2H), 0.85 - 0.80 (m, 2H). 1313C NMR (101 MHz, Chloroform-d) δ 163.83, 161.38, 156.57, 151.85, 149.23 (d, J = 30.3 Hz), 141.53 (d, J = 10.2 Hz), 141.25, 140.51, 130.13 (d, J = 9.1 Hz), 119.00 (d, J = 3.1 Hz), 113.78 (d, J = 21.2 Hz), 111.14 (d, J = 25.0 Hz), 106.53, 22.01, 21.61, 21.23, 9.24, 8.17。

[0216] Compound 64: 1 1H NMR (400 MHz, Chloroform-d) δ 7.67 (ddt, J = 8.2, 5.5, 2.7 Hz, 2H), 7.22 - 7.14 (m, 2H), 6.54 (s, 1H), 2.84 (s, 3H), 2.54 (d, J = 2.2 Hz, 6H), 1.81 (tt, J = 8.4, 5.2 Hz, 1H), 1.05 - 0.99 (m, 2H), 0.90 - 0.84 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 161.78 (d, J = 247.3 Hz), 151.12, 149.47, 148.68, 148.05, 146.64, 142.99, 136.41 (d, J = 3.0 Hz), 126.47 (d, J = 8.6 Hz), 115.98 (d, J = 22.9 Hz), 104.13, 23.25, 21.79, 9.02, 7.93. HRMS-ESI [M+H] + m / z calcd for C 19 H 20 FN4 323.1672, found, 323.1669。

[0217] Compound 65: 1 1H NMR (400 MHz, Chloroform-d) δ 7.15 (ddt, J = 8.2, 5.6, 2.8 Hz, 2H), 6.97 - 6.90 (m, 2H), 6.23 (s, 1H), 2.52 (s, 3H), 2.47 (s, 3H), 2.15 (s, 3H), 2.04 (tt, J = 8.4, 5.0 Hz, 1H), 0.97 (ddd, J = 8.4, 6.5, 4.2 Hz, 2H), 0.85 - 0.80 (m, 2H). 13C NMR(101MHz,Chloroform-d)δ162.59,160.13,156.24,151.65,149.21(d,J=38.3Hz),141.39,140.47,13 6.45 (d, J = 3.0Hz), 125.68 (d, J = 8.5Hz), 115.87 (d, J = 22.9Hz), 105.93, 21.97, 21.64, 21.28, 9.27, 8.17.

[0218] Compound 66: HRMS-ESI[M+H] + m / z calcd for C 19 H 20 F2N4 341.1578,found,341.1577.

[0219] Compound 67: 1 H NMR(400MHz,Chloroform-d)δ7.13(ddd,J=11.1,7.0,2.6Hz,1H),7.01(q,J=8.8Hz,1H),6.86-6.79(m,1H),6.23(s,1 H),2.53(s,3H),2.46(s,3H),2.19(s,3H),2.02(ddd,J=13.4,8.5,5.0Hz,1H),1.01-0.94(m,2H),0.85-0.79(m,2H). 13 C NMR(101MHz,Chloroform-d)δ155.45,150.83,149.66(dd,J=83.7,13.1Hz),148.37,147.89,147.18(dd,J=83.1,13.1Hz),139.83,139.34,135.50( dd,J=8.1,3.3Hz),118.57(dd,J=6.4,3.6Hz),116.16(d,J=18.4Hz),112. 47(d,J=20.4Hz),105.38,20.87,20.49,20.19,8.09,7.08.HRMS-ESI[M+H] + m / z calcd for C 19 H 20 F2N4 341.1578,found,341.1583.

[0220] Compound 68: 1H NMR(400MHz,Chloroform-d)δ7.62-7.56(m,2H),7.02-6.96(m,2H),6.50(s,1H),3.85(s,3H),2.83( s,3H),2.54(s,3H),2.53(s,3H),1.80(tt,J=8.4,5.2Hz,1H),1.02-0.96(m,2H),0.87-0.82(m,2H). 13 C NMR(101MHz,Chloroform-d)δ158.93,150.67,149.27,148.51,148.08,146.59,143. 21,133.47,126.22,114.17,103.42,55.66,23.28,21.78,8.94,7.86.HRMS-ESI[M+H] + m / z calcd for C 20 H 23 N4O335.1872, found, 335.1867.

[0221] Compound 69: 1 H NMR(400MHz,Chloroform-d)δ7.11-7.06(m,2H),6.77-6.72(m,2H),6.19(s,1H),3.74(s,3H),2.51( s,3H),2.49(s,3H),2.09(s,3H),2.04(tt,J=8.4,5.1Hz,1H),0.99-0.92(m,2H),0.85-0.79(m,2H). 13 C NMR(101MHz,Chloroform-d)δ158.47,155.82,151.41,149.22,149.15,141.78,1 40.46,133.53,125.26,114.13,105.29,55.53,21.96,21.68,21.24,9.30,8.11.

[0222] Activity Test 1: Protective Effect on Primary Neurons in the Rat Brain

[0223] Primary cortical neurons from rats around day 7 were selected for an in vitro oxygen-glucose deprivation / reoxygenation (OGD / R) model. 1.5 × 10⁻⁶ neurons were used. 5Cells were seeded at a density of [insert cell density here] / mL in 96-well plates and cultured in DMEM medium containing 10% FBS, 5% CO2, at 37°C for 24 h. The control group continued routine culture, while the model and drug-treated groups were used to prepare the OGD / R model: First, the medium was replaced with glucose-free DMEM medium, and 1% serum was added to maintain basal cell viability. The drug-treated groups were added with the corresponding drug concentrations, and the cells were cultured in a tri-gas incubator containing 5% CO2, 94% N2, and 1% O2 for 24 h to complete the hypoxia process. Then, the cell medium was replaced with complete DMEM medium containing 10% FBS, and the cells were cultured in a 5% CO2 incubator for 24 h to complete the reoxygenation process. After incubation, 10 μL of CCK8 was added to each well and incubated for 1 h, and OD450 was measured using a microplate reader. Results are expressed as mean ± SD. Statistical differences between groups were analyzed using one-way ANOVA and Sidak's test, with a p-value less than 0.05 considered statistically significant. Formula: Survival rate = (OD value of experimental group / OD value of control group) × 100%. Results are as follows: Figure 3-5 As shown.

[0224] Activity Test 2: Inhibition of α-syn aggregation

[0225] 1. Expression of α-syn

[0226] DH5α competent cells were infected with the α-syn(PT7-7) plasmid. The competent cells were then transferred to sterile, antibiotic-free LB liquid medium and incubated at 37°C with shaking for 45 min. The cultured competent cells infused with the plasmid were then spread onto LB solid medium and incubated overnight at 37°C. The next day, single colonies were picked and inoculated into 5 ml of sterile LB liquid medium containing 30 μg / ml carbenicillin, and incubated overnight at 37°C with shaking for 180 rpm. DNA was then extracted using a micro-prep DNA kit, and its concentration was determined using a micro spectrophotometer. The extracted DNA was then added to BL21(DE3) competent cells, and the above steps were repeated until single colonies were picked and inoculated into 5 ml of sterile LB liquid medium containing 30 μg / ml carbenicillin, and incubated at 37°C with shaking for 180 rpm until the OD value reached 0.6–0.8. Take 500 μl of bacterial culture, add 500 μl (40%) of glycerol, and freeze at -80°C.

[0227] 2. Extraction and purification of α-syn

[0228] Dissolve 16g of LB broth powder in 800ml of ultrapure water, autoclave, and cool before use. Using a 10μl pipette tip, pick up glycerol bacteria frozen at -80℃ and add them to 8ml of sterile LB broth medium, then add carbenicillin to a concentration of 30μg / ml. Incubate at 37℃ and 180rpm in a constant temperature shaking incubator. After 4 hours, measure the OD value of A600 using a micro spectrophotometer. When the OD value of *E. coli* is approximately 1, add 8ml of bacterial culture to 800ml of LB broth, then add 800μl of carbenicillin and continue culturing until the OD value reaches 0.8. Add 100μM IPTG and incubate overnight on a shaker to induce *E. coli* expression.

[0229] Centrifuge the overnight induced bacterial culture at 3500g for 20 min, discard the supernatant and collect the precipitate. Resuspend the precipitate in 3.35 ml of 1×TEN buffer per 100 ml of bacterial culture. Heat in a water bath to boiling for 10 min, cool to room temperature, and centrifuge at 10000 rpm for 15 min at 4°C, collecting the supernatant. Add 1% (M / V) streptomycin sulfate and 15% (V / V) glacial acetic acid to the collected supernatant. Mix well and collect the supernatant at 10000 rpm for 15 min. Transfer the supernatant to an equal volume of saturated ammonium sulfate solution. Mix well and incubate at 4°C for 30 min to precipitate the protein. Then centrifuge at 10000 rpm for 15 min at 4°C, discard the supernatant and collect the precipitate. Wash the precipitated protein with semi-saturated ammonium sulfate solution at 10000 rpm for 15 min at 4°C, collecting the precipitate. Finally, the protein precipitate was washed three times with equal volumes of 100 mM ammonium acetate and anhydrous ethanol. The resulting precipitate was dissolved in 0.1 M PBS to obtain crude α-syn protein. After purification, the protein concentration was determined by BCA assay using a C18 column. Store at -80°C.

[0230] 3. Preparation of α-syn aggregated samples

[0231] α-syn protein of known concentration was removed from a -80°C freezer and diluted to 40 μM with PBS. The solution was then thoroughly mixed by pipetting and filtered through a 0.22 μM filter. The blank control group was treated with the corresponding volume of DMSO, while the drug-treated group was treated with the stock solution of the compound to achieve a final concentration of 25 μM. Three replicates were performed for each concentration of each compound.

[0232] 4. Thiamine T (ThT) fluorescence detection method

[0233] A 20 mM ThT stock solution was prepared using DMSO. After incubation with the A-Syn protein solution, ThT solution was added to the protein solution to a final concentration of 20 μM. The mixture was thoroughly mixed and then subjected to fluorescence intensity detection using a microplate reader. The excitation wavelength was 450 nm, and the emission wavelength was 482 nm. Results are expressed as mean ± SD. Statistical differences between groups were assessed using one-way ANOVA and Sidak's test. A p-value less than 0.05 was considered statistically significant. Formula: Inhibition rate = (1 - OD value of experimental group / OD value of control group) × 100%.

[0234] Table 1: Activity of compounds in inhibiting α-syn aggregation

[0235]

[0236] Experimental data are expressed as the mean ± standard deviation of three independent experiments.

[0237] Activity Test 3: Antioxidant Effect

[0238] The antioxidant effects of compounds were studied using PC12 cells. Experimental groups and procedures: Blank control group: Cells were cultured in fresh medium for 4 hours, then treated with serum-free medium for 6 hours. Tert-butyl peroxide group: Cells were cultured in fresh medium for 4 hours, then treated with serum-free medium to a final concentration of 90 μM for 6 hours. Drug-treated groups: Cells were treated with medium containing five concentrations (1.8, 3.75, 7.5, 15, 30 μM) of the drug for 4 hours, then treated with serum-free medium to a final concentration of 90 μM tert-butyl peroxide for 6 hours. After incubation, 10 μL of CCK8 was added to each well and incubated for 1 hour. OD450 was measured using a microplate reader. Results are expressed as mean ± SD. Statistical differences between groups were assessed using one-way ANOVA and Sidak's test; a p-value less than 0.05 was considered statistically significant. Formula: Cell viability = (Experimental group OD value / Control group OD value) × 100%. The results are as follows Figure 6 As shown.

[0239] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A heterocyclic substituted pyrazine derivative or a pharmaceutically acceptable salt, prodrug, solvate, or stereoisomer thereof, said heterocyclic substituted pyrazine derivative having the structure shown in Formula I: wherein, R is selected from any one of equations a, b, c, and d; R1 and R2 are each independently selected from any one of C1-C10 alkyl and halo-C1-C10 alkyl groups; R3is selected from the group consisting of C1-C10alkyl, haloC1-C10alkyl, Ra is selected from the group consisting of C1-C10alkyl, haloC1-C10alkyl; X is selected from -0-, -NR 01 -, -CR 02 R 03 -; R 01 is selected from hydrogen, Ci-6alkyl, C3-8cycloalkyl; R 02 , R 03 are each independently selected from hydrogen, halogen, Ci-6alkyl, C3-8cycloalkyl, or R 02 , R 03 together with the carbon atom to which they are attached form a C3-8cycloalkyl group; R4, R6, R8, and R9 are each independently selected from any one of hydrogen, C1-C10 alkyl, halogenated C1-C10 alkyl, and C3-8 cycloalkyl. R5, R7, R 10 each independently is selected from any one of halogen, C1-C10alkyl, haloC1-C10alkyl, C1-C10alkoxy, haloC1-C10alkoxy, C1-C10alkoxycarbonyl, C1-C10acyloxy, C3-8cycloalkyl; m, n, p are each independently selected from 1 or 2, when m is 2, each R5may be the same or different; when n is 2, each R7may be the same or; when p is 2, each R 10 may be the same or different.

2. The heterocyclic-substituted pyrazine derivative according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof, characterized in that, The heterocyclic substituted pyrazine derivatives have the structures shown in Formula I-1, Formula I-2, Formula I-3 or Formula I-4:

3. The heterocyclic-substituted pyrazine derivative or its pharmaceutically acceptable salt, prodrug, solvate and stereoisomer according to claim 1 or 2, characterized by, R1, R2are each independently selected from any one of methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, trifluoromethyl; preferably, R1, R2are selected from methyl; R3are each independently selected from any one of methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, trifluoromethyl, Ra is selected from any one of methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl.

4. The heterocyclic-substituted pyrazine derivative or its pharmaceutically acceptable salt, prodrug, solvate and stereoisomer according to claim 1 or 2, characterized by, X is selected from -0-, -NR 01 -, -CR 02 R 03 -; R 01 is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, R 02 , R 03 is selected from any one of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or R5, R6together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

5. The heterocyclic-substituted pyrazine derivative according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof, characterized in that, R4, R6are each independently selected from any one of hydrogen, methyl, ethyl, trifluoromethyl; R8, R9are each independently selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl; R5, R7, R 10 each independently selected from any one of fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, propoxy, butoxy, halogen-substituted methoxy, halogen-substituted ethoxy, halogen-substituted propoxy, halogen-substituted butoxy, methoxycarbonyl, ethoxycarbonyl, methacryloyloxy, acryloyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

6. The heterocyclic-substituted pyrazine derivative according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, solvate, and stereoisomer thereof, characterized by, The heterocyclic substituted pyrazine derivatives are selected from:

7. A pharmaceutical composition comprising at least one heterocyclic substituted pyrazine derivative according to any one of claims 1-6, or a pharmaceutically acceptable salt, prodrug, solvate, or stereoisomer thereof.

8. The use of the heterocyclic substituted pyrazine derivatives according to any one of claims 1-6, or pharmaceutically acceptable salts, prodrugs, solvates, and stereoisomers thereof, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for the prevention or treatment of diseases of the nervous system or ischemic diseases.

9. Use according to claim 8, characterized in that, The diseases of the nervous system include neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as multiple sclerosis; the ischemic diseases include myocardial ischemia and stroke.

10. The use of the heterocyclic substituted pyrazine derivatives according to any one of claims 1-6, or pharmaceutically acceptable salts, prodrugs, solvates, and stereoisomers thereof, or the pharmaceutical compositions according to claim 7, in the preparation of neuroprotective agents, platelet aggregation inhibitors, free radical scavenging drugs, vasodilators, or antioxidant drugs.

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