A pyrazinamide compound and its preparation method and application

Abstract

The present invention discloses a pyrazinamide compound, which is a compound having a structure as represented by general formula (I) or a tautomer, enantiomer, diastereomer, racemate, metabolite or metabolic precursor of the compound, or a pharmaceutically acceptable salt, ester, prodrug of the compound, or a hydrate of the compound; #imgabs0# The present invention also discloses a method for preparing the above-mentioned pyrazinamide compound and its use in preparing a medicament for preventing and treating diseases related to GPR52.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a pyrazinamide compound and a preparation method thereof, and application thereof in preparing drugs for preventing and treating GPR52-related diseases. Background Art

[0002] 1. Structural characteristics of GPR52

[0003] GPR52 is a member of the GPCR family, the largest class of membrane protein receptors in eukaryotes, with over 800 members. GPCRs consist of seven transmembrane proteins and are widely distributed in organs and tissues such as the central nervous system, immune system, cardiovascular system, and retina. They are responsible for intracellular and intercellular communication and, consequently, participate in the regulation of physiological and pathological states in the human body. Dysfunction of GPCRs can lead to a variety of diseases, including cancer, central nervous system (CNS) disorders, metabolic disorders, inflammation, infection, and immune diseases. Therefore, GPCRs have long been a focus of drug development. Currently, over 30% of marketed drugs target GPCRs. However, only 108 unique GPCRs are targeted by these drugs, leaving 56% of non-sensory GPCRs untargeted, some of which are known as orphan GPCR receptors (oGPCRs). Although the endogenous ligands for oGPCRs are unknown, research has revealed that oGPCRs play an essential role in important physiological processes in human life and are closely associated with the development and progression of many human diseases.

[0004] GPR52 is a typical oGPCR. In 1999, Sawzdargo et al. first identified and cloned GPR52, which consists of 361 amino acids and belongs to the class A GPCR family. The GPR52 gene (UniProKB ID: Q9YAT5) is located on human chromosome 1q24, with a single exon encoding a 361-amino acid, 7-TM-spanning protein. GPR52 comprises an extracellular N-terminal domain (amino acid residues 1-39), seven canonical TM domains (TM1-TM7), three extracellular loops (ECLs), three intracellular loops (ICLs), and a C-terminal helix (H8, amino acid residues 327-361). Recently, high-resolution crystal structures of human GPR52 were published in three states: ligand-free, Gs-coupled autoactivation, and the synthetic agonist C17-bound state. To stabilize GPR52 for crystallography, the ligand-free crystal structure was determined using seven mutation-modified GPR52s and two ICL3-fusion protein partners, rubredoxin and flavoxin. The conformations of the two GPR52 structures were remarkably similar, indicating that the ICL3 fusion protein does not alter crystal packing or modify the receptor's conformation. Notably, the ECL2 domain of GPR52 occupies and forms multiple interactions with the orthosteric binding pocket, and this ECL2 interaction plays a key role in both basal and agonist activation of the receptor, as demonstrated by mutagenesis and cell-based functional assays. Furthermore, GPR52 can couple to the Gs protein and form a stable, active, monodisperse GPR52-G protein complex, without the need for agonist activation.

[0005] 2. GPR52 and disease treatment

[0006] GPR52 is highly expressed in the brain, particularly in the striatum. In 2014, Komatsu et al., through detailed histological studies and analysis of GPR52 knockout and transgenic mice, found that GPR52 has the potential to serve as a drug target for schizophrenia. Studies on GPR52 have revealed that GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1 / N-methyl-D-aspartate (NMDA) receptors through intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to become a new class of antipsychotic drugs. Interestingly, GPR52 exhibits a unique expression pattern, being expressed in virtually all D2-expressing mononuclear cells in the basal ganglia and abundantly expressed in D1-expressing neurons in the medial prefrontal cortex. This raises the possibility that activation of GPR52 could ameliorate the positive symptoms of schizophrenia by antagonizing the activity of Gi / o-coupled D2 receptors in striatal monolayers and by enhancing the NMDA receptor activity of protein kinase A (PKA) in prefrontal cortical neurons via D1 receptor-NMDA signaling. Recent reports provide additional evidence for this hypothesis.

[0007] Studies have shown that compared to GPR52 wild-type mice, GPR52 knockout mice have lower expression of D2R mRNA and enkephalin in the striatum, suggesting that GPR52 deficiency enhances D2R signaling in the basal ganglia and reduces striatal neuronal activity. Using histological methods in genetically manipulated mouse models, studies have shown that transgenic mice overexpressing GPR52 exhibit antipsychotic-like behaviors, while GPR52 knockout mice display behaviors associated with psychosis. Furthermore, activation of GPR52 with alternative agonists increased cAMP levels in vitro and exhibited antipsychotic-like activity, suppressing amphetamine- or methamphetamine-induced motor hyperactivity. Furthermore, studies of field excitatory postsynaptic potentials (fEPSPs) following GPR52 agonist treatment at synaptic sites in rat cortical slices demonstrated a dose-dependent potentiation effect. Furthermore, in a rat social recognition model, GPR52 agonist activation significantly enhanced episodic memory, suggesting that targeting GPR52 could ameliorate cognitive impairments associated with psychiatric disorders. In light of the above circumstances, GPR52 has become a new promising target for the treatment of psychiatric disorders such as schizophrenia and substance use disorders.

[0008] GPR52 agonists

[0009] The discovery of GPR52-targeted drugs for neuropsychiatric disorders is gaining increasing attention. Researchers have made significant progress in neurological drug research, particularly in the development of small molecule agonists. Currently, one small molecule agonist has entered Phase I clinical trials, and three more are in preclinical studies, with clinical trials expected to begin soon.

[0010] Abnormal inactivation of GPR52 is closely linked to the development and progression of numerous diseases, including schizophrenia, psychotic disorders, and cognitive impairment. Current small-molecule GPR52 agonists suffer from poor water solubility, poor pharmacokinetic properties, and limited ability to cross the blood-brain barrier. Furthermore, the activity and potency of current GPR52 agonists are low, with most compounds exhibiting pEC50 values ​​in the nanomolar or even micromolar range, falling short of ideal activity levels. This, in turn, limits their potential for drug development. As drugs that must cross the blood-brain barrier, GPR52 agonists have higher requirements for in vivo pharmacokinetic and physicochemical properties (LogP between 2 and 5; molecular weight typically less than 450 Da; and the majority of them are neutral or weakly basic molecules with a pKa between 7.5 and 10.5) than conventional drugs. Summary of the Invention

[0011] The purpose of the present invention is to solve the problem in the prior art that GPR52 agonists are difficult to penetrate the blood-brain barrier and have poor bioavailability, and to provide a pyrazinamide compound and a preparation method and application thereof.

[0012] To solve the above technical problems, the technical solution adopted by the present invention is as follows: a pyrazinamide compound having a structure as represented by general formula (I) or a tautomer, enantiomer, diastereomer, racemate, metabolite or metabolic precursor of the compound, or a pharmaceutically acceptable salt, ester, prodrug of the compound, or a hydrate of the compound;

[0013]

[0014] Wherein, L is selected from One of the following;

[0015] wherein X is selected from one of O, NH, and S;

[0016] n represents 1, 2;

[0017] Z is selected from one of nitrogen atom and CH;

[0018] R 1Selected from substituted or unsubstituted C1-C4 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C4 alkoxy, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkenyl, C2-C4 alkynyl and phenyl; the substitution in the substituted or unsubstituted C1-C4 alkyl refers to substitution with one or more substituents selected from the following: halogen, cyano, nitro, hydroxy, amino;

[0019] Q is selected from substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaromatic ring, substituted or unsubstituted aromatic ring; the substitution in the substituted or unsubstituted heterocycle, heteroaromatic ring, and aromatic ring refers to substitution with one or more substituents selected from the following: substituted or unsubstituted C1-C4 alkyl, halogen, cyano, nitro, hydroxy, amino, C1-C4 alkoxy, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkenyl, C2-C4 alkynyl, and phenyl; the substitution in the substituted or unsubstituted C1-C4 alkyl refers to substitution with one or more substituents selected from the following: halogen, cyano, nitro, hydroxy, and amino;

[0020] W is selected from substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaromatic ring, substituted or unsubstituted aromatic ring; the substitution in the substituted or unsubstituted heterocycle, heteroaromatic ring and aromatic ring refers to substitution with one or more substituents selected from the following: substituted or unsubstituted C1-C4 alkyl, halogen, cyano, nitro, hydroxyl, amino, C1-C4 alkoxy, C2-C4 alkylcarbonyl, C2-C4 alkoxycarbonyl, C2-C4 alkenyl, C2-C4 alkynyl and phenyl; the substitution in the substituted or unsubstituted C1-C4 alkyl refers to substitution with one or more substituents selected from the following: halogen, cyano, nitro, hydroxyl and amino.

[0021] Preferably, the compound represented by the general formula (I) is selected from:

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028] The above-mentioned pyrazinamide compounds can be prepared by the following three methods:

[0029] The present invention provides a method for preparing the above-mentioned pyrazinamide compound.

[0030]

[0031] The route looks like this:

[0032] PPh3 is triphenylphosphine, DEAD is diethyl azodicarboxylate, TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, EtOH is ethanol, LiOH is lithium hydroxide, THF is tetrahydrofuran, H2O is water, EDCI is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and DMAP is 4-dimethylaminopyridine;

[0033] The preparation method comprises the following steps:

[0034] (1) D1 (1 eq), D2 (1 eq) and triphenylphosphine (2 eq) were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes; then diethyl azodicarboxylate (2 eq) was added; after stirring at room temperature for 8 hours, the solvent was evaporated and the mixture was dissolved in dichloromethane, and trifluoroacetic acid was added. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain D3;

[0035] (2) D3 (1.5 eq-2 eq) and D4 (1 eq) were dissolved in ethanol, triethylamine (2 eq) was added at room temperature, and the temperature was gradually raised to 78°C for reaction overnight; after the reaction was completed and cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and D5 was separated by column chromatography;

[0036] (3) D5 (1 eq) was dissolved in a 1:1 mixed solvent of tetrahydrofuran and water, and lithium hydroxide (6 eq) was added at room temperature, and stirred at room temperature overnight; after the reaction was completed, the mixture was adjusted to pH <5 with 1N hydrochloric acid solution, and dichloromethane was added for extraction and the organic phase was separated; the solvent was evaporated to obtain D6;

[0037] (4) D6 (1 eq), W-NH2 (1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq), and 4-dimethylaminopyridine (0.5 eq) were dissolved in dichloromethane and stirred at room temperature for 10 minutes. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was separated by column chromatography to obtain I.

[0038] The present invention also provides a second method for preparing the above-mentioned pyrazinamide compounds. The reaction scheme of the pyrazinamide compounds is as follows:

[0039]

[0040] The preparation method comprises the following steps:

[0041] PPh3 is triphenylphosphine, DEAD is diethyl azodicarboxylate, TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, EtOH is ethanol, THF is tetrahydrofuran, EDCI is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and DMAP is 4-dimethylaminopyridine;

[0042] (1) E1 (1 eq), E2 (1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq), and 4-dimethylaminopyridine (0.5 eq) were dissolved in dichloromethane and stirred at room temperature for 10 minutes; after stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and E3 was separated by column chromatography;

[0043] (2) E3 (1.5 eq-2 eq) and E4 (1 eq) were dissolved in ethanol, triethylamine (2 eq) was added at room temperature, and the temperature was gradually raised to 78°C for reaction overnight; after the reaction was completed and cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and E5 was separated by column chromatography;

[0044] (3) E5 (1 eq), E6 (1 eq), and triphenylphosphine (2 eq) were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes. Then, diethyl azodicarboxylate (2 eq) was added. After stirring at room temperature for 8 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain II.

[0045] The present invention also provides a third method for preparing the above-mentioned pyrazinamide compound, characterized in that the reaction scheme of the pyrazinamide compound is as follows:

[0046]

[0047] Wherein, G is hydroxy or bromine;

[0048] TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, and EtOH is ethanol;

[0049] The preparation method comprises the following steps:

[0050] (1) F2 was synthesized from F1 according to the following method: i) F1 (1 eq), F2 (1 eq), and triphenylphosphine (2 eq) were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes; then diethyl azodicarboxylate (2 eq) was added; after stirring at room temperature for 8 hours; ii) F1 (1 eq), F2 (1 eq), and cesium carbonate (3 eq) were dissolved in N,N-dimethylformamide and stirred under reflux for 12 hours; iii) F1 (1 eq), F2 ( 1eq), cesium carbonate (2eq), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1eq), and palladium acetate (0.05eq) were added to dioxane, and the mixture was refluxed at 100°C overnight; after evaporating the solvent, the mixture was dissolved in dichloromethane, and trifluoroacetic acid was added. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain F3;

[0051] (2) F3 (1.5 eq-2 eq) and E3 (1 eq) were dissolved in ethanol, triethylamine (2 eq) was added at room temperature, and the temperature was gradually raised to 78°C for overnight reaction. After the reaction was completed and the mixture was cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and III was separated by column chromatography.

[0052] The present invention provides use of the above-mentioned pyrazinamide compounds as highly selective GPR52 agonists.

[0053] The present invention also provides the use of the above-mentioned pyrazinamide compounds in the preparation of drugs for preventing and treating diseases related to GPR52.

[0054] Preferably, the GPR52-related diseases include neurodegenerative diseases, and the neurodegenerative diseases include schizophrenia, cognitive impairment, depression, Parkinson's disease, Alzheimer's disease, and muscular dystrophy.

[0055] The present invention also provides a pharmaceutical composition comprising the above-mentioned pyrazinamide compound.

[0056] The beneficial effects of the present invention are as follows: The present invention provides a pyrazinamide compound, which has extremely strong agonist activity and agonist effect on GPR52; and in terms of pharmacokinetic performance, the compound has suitable physical and chemical properties, so it can be well absorbed in the body, exhibits very high bioavailability, can pass through the blood-brain barrier, is suitable for use as a GPR52 agonist, and has good application prospects in the preparation of drugs for preventing and treating diseases related to GPR52. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 is the HPLC spectrum of compound S13. DETAILED DESCRIPTION

[0058] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0059] 1 H-NMR was measured using a Varian Mercury AMX300 instrument; all solvents were redistilled before use, and the anhydrous solvents used were dried according to standard methods; unless otherwise stated, all reactions were carried out under nitrogen protection and monitored by TLC, and post-treatment was performed by washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate; products were purified using silica gel (200-300 mesh) column chromatography, unless otherwise stated; the silica gel (200-300 mesh) was produced by Qingdao Ocean Chemical Plant, and the GF254 thin-layer silica gel plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd.

[0060] Example 1 Synthesis of Compound S1

[0061]

[0062] D1 (1 eq), D2 (1 eq), and triphenylphosphine (2 eq) were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes. Diethyl azodicarboxylate (2 eq) was then added. After stirring at room temperature for 8 hours, the solvent was evaporated and the mixture was dissolved in dichloromethane. Trifluoroacetic acid was added and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain D3. 1 H NMR (400MHz, Chloroform-d) δ7.00–6.93(m,2H),6.80(dt,J=10.0,2.4Hz,1H),4.69(tt,J=5.2,2.7Hz,1H),3.44–3.23(m,4H),2.29–2.09(m,4H).

[0063] Dissolve D3 (1.5eq-2eq) and D4 (1eq) in ethanol, add triethylamine (2eq) at room temperature, gradually raise the temperature to 78°C and react overnight; after the reaction is completed and cooled to room temperature, add saturated ammonium chloride solution to the mixture, add dichloromethane for extraction and separate the organic phase. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated. D5 is separated by column chromatography. 1 H NMR(400MHz,Chloroform-d)δ8.21–8.17(m,1H),8.01(t,J=1.7Hz,1H),6.99–6 .90(m,2H),6.81(dt,J=10.4,2.5Hz,1H),4.62(tt,J=6.9,3.5Hz,1H),3.99(d, J=1.3Hz,3H),3.73(ddd,J=12.4,8.1,3.5Hz,2H),3.48(ddd,J=13.4,7.2,3.7H z,2H),2.10(ddt,J=12.1,7.7,3.7Hz,2H),1.93(dtd,J=13.4,6.8,3.5Hz,2H).

[0064] Dissolve D5 (1 eq) in a 1:1 mixture of tetrahydrofuran and water. Add lithium hydroxide (6 eq) at room temperature and stir overnight. After the reaction is complete, adjust the mixture to a pH <5 with 1N hydrochloric acid solution, extract with dichloromethane, and separate the organic phase. Evaporate the solvent to obtain D6. 1 HNMR(400MHz,Chloroform-d)δ8.36(d,J=2.1Hz,1H),8.00(d,J=2.1Hz,1H),7.00–6.90(m,2H),6.82(dt,J=10.3,2.3Hz,1H),4.65(tt,J=6.7,3.5Hz ,1H),3.77(ddt,J=11.0,6.3,3.0Hz,2H),3.59(ddd,J=13.3,7.0,3.8Hz,2 H), 2.17(ddt,J=12.3,7.9,3.7Hz,2H), 2.00(dtd,J=13.6,6.7,3.4Hz,2H).

[0065] D6 (1 eq), RNH2 (1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq), and 4-dimethylaminopyridine (0.5 eq) were dissolved in dichloromethane and stirred at room temperature for 10 minutes. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The yellow oil S1 was obtained by column chromatography. Analytical data of S11 H NMR(400MHz,Chloroform-d)δ10.03(s,1H),9.27(s,1H),9.06(d,J=5.9Hz,1H),8.30(t,J=2.0Hz,1H),8.19(dd,J=5.9,2.9Hz,1H),7.97(t,J=2.0Hz,1H) ,6.98–6.89(m,2H),6.81(dd,J=10.1,2.4Hz,1H),4.65(s,1H),3.83–3.75(m ,2H),3.58(d,J=13.8Hz,2H),2.15(d,J=9.3Hz,2H),2.01(d,J=12.5Hz,2H).

[0066] Example 2 Synthesis of Compound S2

[0067]

[0068] The synthesis method of S2 is the same as that of S1, except that compound D7 is replaced by compound D8.

[0069] S2 analysis data: 1 H NMR(400MHz,Chloroform-d)δ10.42(s,1H),8.93(t,J=1.9Hz,1H),8.67–8.6 5(m,1H),8.29(d,J=2.1Hz,1H),7.99(d,J=2.1Hz,1H),7.01–6.91(m,2H),6.8 4–6.78(m,1H),4.65(tt,J=6.9,3.5Hz,1H),3.82–3.77(m,2H),3.58(ddd,J= 13.4,7.2,3.8Hz,2H),2.22–2.12(m,2H),2.00(dtd,J=13.7,6.9,3.5Hz,3H).

[0070] Example 3 Synthesis of Compound S3

[0071]

[0072] The synthesis method of S3 is the same as that of S1, except that compound D7 is replaced by compound D9.

[0073] S3 analysis data: 1H NMR(400MHz,Chloroform-d)δ10.26(s,1H),9.69(d,J=1.5Hz,1H),8.35(d,J=2.5Hz,1H),8.29(dd,J=2 .6,1.5Hz,1H),8.26(d,J=2.1Hz,1H),7.97(d,J=2.1Hz,1H),6.98–6.94(m,1H),6.91(dt,J=8.3,1.9Hz, 1H), 6.81 (dt, J=10.3, 2.3Hz, 1H), 4.64 (tt, J=6.9, 3.6Hz, 1H), 3.79 (ddd, J=12.3, 8.2, 3.5Hz, 2H), 3.5 8(ddd,J=13.4,7.2,3.8Hz,2H), 2.17(ddt,J=12.1,7.8,3.7Hz,2H), 1.98(dtd,J=13.7,6.9,3.5Hz,2H).

[0074] Example 4 Synthesis of Compound S4

[0075]

[0076] The synthesis method of S4 is the same as that of S1, except that the raw material D7 is replaced by D10.

[0077] S4 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.83(s,1H),9.16(d,J=1.8Hz,2H),8.99(d,J=1.8Hz,1H),8.28(t,J=2.0Hz,1H),7.96(t,J=2.0Hz,1H),6.99 –6.88(m,2H),6.81(dd,J=10.4,2.5Hz,1H),4.64(s,1H),3.83–3.74(m,2H),3.59(dd,J=13.2,7.0Hz,2H),2.21–2.10(m,2H),1.99(s,2H).

[0078] Example 5 Synthesis of Compound S5

[0079]

[0080] The synthesis method of S5 is the same as that of S1, except that compound D7 is replaced by compound D11.

[0081] S5 analysis data: 1H NMR(400MHz,Chloroform-d)δ10.56(s,1H),8.67(d,J=4.8Hz,2H),8.25(d,J=2.1Hz,1H) ,7.95(d,J=2.1Hz,1H),7.03(t,J=4.9Hz,1H),6.98–6.87(m,2H),6.80(dt,J=10.4,2.3Hz ,1H),4.62(dt,J=6.7,3.4Hz,1H),3.81(ddd,J=12.2,8.0,3.5Hz,2H),3.59(ddd,J=13.3 ,7.3,3.8Hz,3H),2.17(ddd,J=16.1,7.8,3.8Hz,2H),1.97(dtd,J=13.8,7.0,3.5Hz,2H).

[0082] Example 6 Synthesis of Compound S6

[0083]

[0084] The synthesis method of S6 is the same as that of S1, except that compound D7 is replaced by compound D12.

[0085] S6 analysis data: 1 HNMR(400MHz,Chloroform-d)δ10.81(s,1H),8.96(td,J=4.0,3.2,1.5Hz,1H),8.65(dt,J=9.0,1.9Hz,1H),8.29 (d,J=2.0Hz,1H),8.02(d,J=2.0Hz,1H),7.57–7.48(m,1H),6.99(t,J=1.9Hz,1H),6.92(dt,J=8.3,1.9Hz,1H),6. 83(dt,J=10.4,2.3Hz,1H),4.66(tt,J=6.9,3.5Hz,1H),3.81(td,J=8.7,8.2,3.8Hz,3H),3.58(ddd,J=13.3,7.2 ,3.7Hz,2H),2.37(dp,J=5.9,2.9Hz,1H),2.18(ddt,J=12.2,7.7,3.6Hz,2H),2.00(dtd,J=13.6,6.9,3.4Hz,2H).

[0086] Example 7 Synthesis of Compound S7

[0087]

[0088] The synthesis method of S7 is the same as that of S1, except that compound D7 is replaced by compound D13.

[0089] S7 analysis data: 1 HNMR(400MHz,Chloroform-d)δ10.21(s,1H),8.39–8.32(m,2H),8.23(t,J=2.0Hz,1H) ,7.97(t,J=2.0Hz,1H),7.73(t,J=7.8Hz,1H),7.05(t,J=6.1Hz,1H),6.96(s,1H),6.91 (d,J=8.2Hz,1H),6.80(dd,J=10.1,2.4Hz,1H),4.62(s,1H),3.79(td,J=8.9,8.3,4.5 Hz,2H),3.55(ddd,J=12.9,7.4,3.5Hz,2H),2.16(dd,J=13.8,8.4Hz,2H),1.98(s,2H).

[0090] Example 8 Synthesis of Compound S8

[0091]

[0092] The synthesis method of S8 is the same as that of S1, except that compound D7 is replaced by compound D14.

[0093] S8 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.83(s,1H),8.74(d,J=2.6Hz,1H),8.33(dd,J=4.7,1.5Hz,1H),8.30(ddd,J=8.3 ,2.7,1.5Hz,1H),8.21(d,J=2.1Hz,1H),7.91(d,J=2.2Hz,1H),7.30–7.25(m,1H),6.93(t,J=1.9Hz,1H),6.88(d t,J=8.3,1.9Hz,1H),6.78(dt,J=10.4,2.3Hz,1H),4.59(tt,J=6.9,3.6Hz,1H),3.76(ddd,J=13.3,8.0,3.5Hz, 2H), 3.53(ddd,J=13.3,7.3,3.7Hz,2H), 2.12(ddt,J=12.1,7.8,3.7Hz,2H), 1.94(dtd,J=13.7,7.0,3.5Hz,2H).

[0094] Example 9 Synthesis of Compound S9

[0095]

[0096] The synthesis method of S9 is the same as that of S1, except that compound D7 is replaced by compound D15.

[0097] S9 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),8.58–8.49(m,2H),8.28(d,J=2.2Hz,1H),7 .96(d,J=2.2Hz,1H),7.68–7.62(m,2H),6.98–6.91(m,2H),6.82(dt,J=10.5,2.3Hz,1H ),4.65(td,J=6.8,3.5Hz,1H),3.80(ddd,J=13.3,8.0,3.4Hz,2H),3.58(ddd,J=13.4,7 .2,3.8Hz,2H),2.17(ddd,J=12.1,8.3,3.9Hz,2H),2.00(ddt,J=10.4,6.7,3.5Hz,2H).

[0098] Example 10 Synthesis of Compound S10

[0099]

[0100] The synthesis method of S10 is the same as that of S1, except that compound D7 is replaced by compound D16.

[0101] S10 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.85(s,1H),8.42(d,J=5.6Hz,1H),8.27(d,J=2.1Hz,1H),7.95(d,J=2.1Hz, 1H),7.57(d,J=2.1Hz,1H),7.44(dd,J=5.6,2.1Hz,1H),6.97(d,J=2.0Hz,1H),6.93(dt,J=8.4,1.9Hz,1H), 6.82(dt,J=10.3,2.3Hz,1H),4.64(tt,J=6.9,3.5Hz,1H),3.80(ddd,J=12.3,8.0,3.4Hz,2H),3.58(ddd,J= 13.4,7.2,3.8Hz,2H),2.57(s,3H),2.17(ddt,J=12.0,7.7,3.7Hz,2H),1.99(dtd,J=13.7,7.0,3.5Hz,3H).

[0102] Example 11 Synthesis of Compound S11

[0103]

[0104] The synthesis method of S11 is the same as that of S1, except that compound D7 is replaced by compound D18.

[0105] Analysis data of S11: R145: 1 H NMR(400MHz,Chloroform-d)δ10.31(d,J=2.6Hz,1H),8.53(tt,J=5.9,2.6Hz,1H),8.46(t,J=3.1H z,1H),8.37(t,J=4.4Hz,1H),8.32–8.27(m,1H),8.03–7.97(m,1H),6.98(d,J=2.5Hz,1H),6.96–6 .89(m,1H),6.83(dt,J=10.3,2.5Hz,1H),4.65(dh,J=6.4,3.1Hz,1H),3.84–3.78(m,2H),3.58(dd t,J=13.6,6.7,3.2Hz,2H),2.18(ddt,J=11.2,7.6,3.3Hz,2H),2.00(dtt,J=13.4,6.6,2.9Hz,2H).

[0106] Example 12 Synthesis of Compound S12

[0107]

[0108] The synthesis method of S12 is the same as that of S1, except that compound D7 is replaced by compound D19.

[0109] S12 analysis data: 1HNMR(400MHz,Chloroform-d)δ10.13(d,J=3.9Hz,1H),8.27(dd,J=7.7,2.1Hz,1H),8.10(ddd,J=8.4,5.6,2.4Hz,1H),7.93(d d,J=9.4,2.1Hz,1H),7.54(t,J=2.1Hz,1H),7.35(ddq,J=5.8,4.1,2.3,1.9Hz,1H),6.98(dt,J=4.7,1.9Hz,1H),6.91(tt,J=8. 1,1.9Hz,1H),6.82(ddt,J=10.0,4.9,2.3Hz,1H),4.69–4.61(m,1H),3.92(dp,J=8.1,2.7Hz,1H),3.80(ddt,J=12.3,7.7,3.8H z,3H),3.58(ddq,J=13.4,6.6,3.7Hz,2H),2.36(dqd,J=10.1,5.5,2.7Hz,1H),2.17(tq,J=9.8,3.6Hz,2H),2.04–1.93(m,2H).

[0110] Example 13 Synthesis of Compound S13

[0111]

[0112] The synthesis method of S13 is the same as that of S1, except that compound D7 is replaced by compound D20.

[0113] S13 analysis data: 1 H NMR(400MHz,Chloroform-d)δ10.23(s,1H),8.30(d,J=2.1Hz,1H),7.95(d,J=2.1Hz,1H),7.23(s,3H),7.00–6.90(m,2H),6.83(dt,J=10.3,2.3Hz,1H),4 .66(tt,J=6.8,3.5Hz,1H),3.85–3.75(m,3H),3.59(ddd,J=13.4,7.1,3.8Hz ,2H),2.18(ddt,J=12.1,7.7,3.7Hz,2H),2.00(dtd,J=13.6,6.9,3.5Hz,2H).

[0114] Example 14 Synthesis of Compound S14

[0115]

[0116] The synthesis method of S14 is the same as that of S1, except that compound D7 is replaced by compound D21.

[0117] S14 analysis data: 1 H NMR(400MHz,Chloroform-d)δ10.00–9.93(m,1H),8.48(td,J=8.1,1.7Hz,1H),8.23(d,J=2. 2Hz,1H),7.97(d,J=2.2Hz,1H),7.19–7.01(m,3H),6.96(t,J=1.8Hz,1H),6.90(dt,J=8.2,2 .0Hz,1H),6.80(dt,J=10.4,2.3Hz,1H),3.78(ddd,J=12.3,8.1,3.5Hz,2H),3.54(ddd,J=13 .4,7.3,3.7Hz,2H),2.15(ddt,J=12.0,7.8,3.7Hz,2H),1.97(dtd,J=13.7,7.0,3.5Hz,2H).

[0118] Example 15 Synthesis of Compound S15

[0119]

[0120] The synthesis method of S15 is the same as that of S1, except that compound D7 is replaced by compound D22.

[0121] S15 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.64(s,1H),8.22(t,J=2.1Hz,1H),7.94(d,J=2.1Hz,1H),7. 70(d,J=7.9Hz,2H),7.42–7.31(m,2H),7.13(t,J=7.4Hz,1H),6.96(s,1H),6.91(d,J=8.3Hz ,1H),6.80(dd,J=10.3,2.3Hz,1H),4.61(tt,J=6.6,3.4Hz,1H),3.79(ddd,J=13.1,8.8,3.3 Hz,2H),3.60–3.50(m,2H),2.16(dq,J=13.5,4.3Hz,2H),1.97(dq,J=15.8,6.3,5.2Hz,2H).

[0122] Example 16 Synthesis of Compound S16

[0123]

[0124] E1 (1 eq), E2 (1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq), and 4-dimethylaminopyridine (0.5 eq) were dissolved in dichloromethane and stirred at room temperature for 10 minutes. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. E3 was separated by column chromatography. Analytical data of E3 1 HNMR(400MHz,Chloroform-d)δ9.88(s,1H),8.61(d,J=2.2Hz,1H),8.54(t,J=2.9Hz,3H),7.68–7.60(m,2H).

[0125] E3 (1.5 eq-2 eq) and E4 (1 eq) were dissolved in ethanol, triethylamine (2 eq) was added at room temperature, and the temperature was gradually raised to 78°C for overnight reaction. After the reaction was completed and the mixture was cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. E5 was separated by column chromatography. Analytical data of E5: 1 HNMR(400MHz,Chloroform-d)δ9.96(s,1H),8.50(d,J=5.9Hz,2H),8.24(d,J=2.1Hz,1H),7.92(d,J=2.1Hz,1H),7.71–7. 65(m,2H),4.03–3.86(m,3H),3.31(ddd,J=13.2,9.6,3.2Hz,2H),2.08–1.98(m,2H),1.69(dtd,J=13.0,9.2,3.8Hz,2H).

[0126] E5 (1 eq), E6 (1 eq), and triphenylphosphine (2 eq) were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes. Diethyl azodicarboxylate (2 eq) was then added. After stirring at room temperature for 8 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain compound S16. Analytical data for S16: 1H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.52(s,2H),8.24(d,J=1.9Hz,1H),7.91 (d,J=1.9Hz,1H),7.67(d,J=5.7Hz,2H),7.22(q,J=7.9Hz,1H),6.75–6.59(m,3H),4. 58(tt,J=6.9,3.5Hz,1H),3.81(ddd,J=12.5,8.0,3.5Hz,2H),3.55(ddd,J=12.9,7.4 ,3.6Hz,2H),2.12(ddt,J=12.3,7.8,3.7Hz,2H),1.96(dtd,J=13.8,7.0,3.4Hz,2H).

[0127] Example 17 Synthesis of Compound S17

[0128]

[0129] The synthesis method of S17 is the same as that of S16, except that compound E6 is replaced by compound E7.

[0130] S17 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.54(d,J=5.7Hz,2H),8.26(d,J=2.2Hz,1H) ,7.94(d,J=2.2Hz,1H),7.66(d,J=5.6Hz,2H),6.95(t,J=1.8Hz,1H),6.83(d,J=1.8Hz,2 H),4.58(tt,J=6.9,3.5Hz,1H),3.78(ddd,J=12.3,8.1,3.4Hz,2H),3.56(ddd,J=13.3, 7.3,3.7Hz,2H),2.14(ddt,J=12.2,7.7,3.7Hz,2H),1.96(dtd,J=13.8,6.9,3.5Hz,2H).

[0131] Example 18 Synthesis of Compound S18

[0132]

[0133] The synthesis method of S18 is the same as that of S16, except that compound E6 is replaced by compound E8.

[0134] S18 analysis data: 1H NMR(400MHz,Chloroform-d)δ9.96(s,1H),8.54(d,J=5.6Hz,2H),8.26(d,J=2.1Hz,1H ),7.94(d,J=2.2Hz,1H),7.66(d,J=5.4Hz,2H),6.44(dtd,J=17.3,8.9,7.8,3.4Hz,3H) ,4.56(tt,J=7.0,3.5Hz,1H),3.79(ddd,J=12.4,8.1,3.5Hz,2H),3.56(ddd,J=13.4,7 .3,3.7Hz,2H),2.14(ddt,J=12.2,7.8,3.7Hz,2H),1.97(dtd,J=14.0,7.2,3.5Hz,2H).

[0135] Example 19 Synthesis of Compound S19

[0136]

[0137] The synthesis method of S19 is the same as that of S16, except that compound E6 is replaced by compound E9.

[0138] S19 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.54(d,J=5.9Hz,2H),8.26(d,J=2.1Hz,1H) ,7.94(d,J=2.2Hz,1H),7.70–7.61(m,2H),6.76–6.66(m,2H),6.56(dt,J=10.5,2.3Hz,1 H),4.57(tt,J=6.9,3.5Hz,1H),3.79(ddd,J=13.3,8.1,3.5Hz,2H),3.56(ddd,J=13.4, 7.3,3.7Hz,2H),2.14(ddt,J=12.0,7.7,3.7Hz,2H),1.96(dtd,J=13.7,7.0,3.5Hz,2H).

[0139] Example 20 Synthesis of Compound S20

[0140]

[0141] The synthesis method of S20 is the same as that of S16, except that compound E6 is replaced by compound E10.

[0142] S20 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.92(s,1H),8.55(s,2H),8.26(d,J=2.1Hz,1H),7.94(d,J=2.1H z,1H),7.66(d,J=5.3Hz,2H),7.07(q,J=9.4Hz,1H),6.76(ddd,J=11.9,6.6,2.9Hz,1H),6.64(dq ,J=8.5,2.7Hz,1H),4.51(tt,J=7.0,3.6Hz,1H),3.80(ddd,J=12.4,8.0,3.5Hz,2H),3.54(ddd, J=13.4,7.4,3.7Hz,2H),2.12(ddt,J=12.4,8.0,3.8Hz,2H),1.95(dtd,J=13.8,7.2,3.5Hz,2H).

[0143] Example 21 Synthesis of Compound S21

[0144]

[0145] The synthesis method of S21 is the same as that of S16, except that compound E6 is replaced by compound E11.

[0146] S21 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),8.54(d,J=5.5Hz,2H),8.26(d,J=2.1Hz,1H),7. 94(d,J=2.1Hz,1H),7.66(d,J=5.7Hz,2H),7.27(t,J=8.7Hz,1H),6.71(ddd,J=24.0,9.8,2 .8Hz,2H),4.56(tt,J=7.0,3.5Hz,1H),3.80(ddd,J=12.4,8.0,3.4Hz,2H),3.55(ddd,J=13 .4,7.3,3.7Hz,2H),2.13(ddt,J=12.3,7.8,3.7Hz,2H),1.96(dtd,J=13.8,7.0,3.5Hz,2H).

[0147] Example 22 Synthesis of Compound S22

[0148]

[0149] The synthesis method of S22 is the same as that of S16, except that compound E6 is replaced by compound E12.

[0150] S22 analysis data: 1H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.53(d,J=5.9Hz,2H),8.26(d,J=2.1Hz,1H),7.93(d,J= 2.1Hz,1H),7.69–7.62(m,2H),7.40(t,J=8.0Hz,1H),7.21(d,J=7.7Hz,1H),7.17(t,J=2.1Hz,1H),7 .11(dd,J=8.2,2.5Hz,1H),4.67(tt,J=6.9,3.5Hz,1H),3.82(ddd,J=12.3,8.1,3.5Hz,2H),3.58(d dd,J=13.4,7.2,3.7Hz,2H),2.16(ddt,J=12.1,7.7,3.7Hz,2H),1.98(dtd,J=13.6,6.9,3.5Hz,2H).

[0151] Example 23 Synthesis of Compound S23

[0152]

[0153] The synthesis method of S23 is the same as that of S16, except that compound E6 is replaced by compound E13.

[0154] S23 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.54(d,J=5.9Hz,2H),8.27(d,J=2.1 Hz,1H),7.95(d,J=2.1Hz,1H),7.69–7.62(m,2H),6.59–6.50(m,2H),4.49(tt,J =7.0,3.6Hz,1H),3.79(ddd,J=12.2,8.1,3.4Hz,2H),3.54(ddd,J=13.4,7.4,3. 7Hz,2H),2.13(ddt,J=12.0,7.7,3.7Hz,2H),1.95(dtd,J=13.8,7.0,3.5Hz,2H).

[0155] Example 24 Synthesis of Compound S24

[0156]

[0157] The synthesis method of S24 is the same as that of S16, except that compound E6 is replaced by compound E14.

[0158] S24 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.91(s,1H),8.57–8.47(m,2H),8.25(t,J=1.6Hz,1H), 7.92(t,J=1.5Hz,1H),7.70–7.62(m,2H),7.19(t,J=8.1Hz,1H),6.57–6.49(m,3H),4.6 0(tt,J=6.9,3.6Hz,1H),3.87–3.80(m,2H),3.79(d,J=0.9Hz,3H),3.55(ddd,J=13.1,7 .3,3.7Hz,2H),2.13(ddt,J=12.0,7.7,3.7Hz,2H),1.97(ddt,J=13.7,7.1,3.5Hz,2H).

[0159] Example 25 Synthesis of Compound S25

[0160]

[0161] The synthesis method of S25 is the same as that of S16, except that compound E6 is replaced by compound E15.

[0162] S25 analysis data: 1 HNMR(400MHz,Chloroform-d)δ9.94(s,1H),8.57–8.48(m,2H),8.24(t,J=1.9Hz,1H ),7.91(t,J=1.9Hz,1H),7.69–7.62(m,2H),7.33–7.24(m,2H),6.99–6.89(m,3H),4. 62(dp,J=6.8,3.4Hz,1H),3.83(ddd,J=12.8,8.3,3.7Hz,2H),3.55(ddd,J=13.1,7.4 ,3.7Hz,2H),2.13(ddt,J=12.1,7.6,3.7Hz,2H),1.96(dtd,J=13.7,7.1,3.5Hz,2H).

[0163] Example 26 Synthesis of Compound S26

[0164]

[0165] The synthesis method of S26 is the same as that of S16, except that compound E6 is replaced by compound E16.

[0166] S26 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.90(s,1H),8.54(s,2H),8.25(d,J=2.1Hz,1H),7.92(d ,J=2.1Hz,1H),7.66(d,J=5.8Hz,2H),7.17(t,J=8.0Hz,1H),6.81–6.72(m,3H),4.60(tt ,J=6.9,3.6Hz,1H),3.82(ddd,J=13.3,8.1,3.5Hz,2H),3.56(ddd,J=13.4,7.3,3.7Hz,2 H), 2.33 (s, 3H), 2.13 (ddt, J = 16.5, 7.7, 4.5Hz, 2H), 1.96 (dtd, J = 13.6, 7.0, 3.5Hz, 2H).

[0167] Example 27 Synthesis of Compound S27

[0168]

[0169] The synthesis method of S27 is the same as that of S16, except that compound E6 is replaced by compound E17.

[0170] S27 analysis data: 1 HNMR(400MHz,Chloroform-d)δ9.93(s,1H),8.54(s,2H),8.24(d,J=2.1Hz,1H), 7.91(d,J=2.1Hz,1H),7.66(d,J=5.0Hz,2H),7.19(t,J=8.2Hz,1H),6.58–6.48(m ,3H),4.59(tt,J=6.9,3.6Hz,1H),3.87–3.80(m,2H),3.55(ddd,J=13.4,7.4,3. 7Hz,2H),2.12(ddt,J=11.8,7.5,3.6Hz,2H),1.96(dtd,J=13.8,7.1,3.6Hz,2H).

[0171] Example 28 Synthesis of Compound S28

[0172]

[0173] F1 (1 eq), F2 (1 eq), and cesium carbonate (3 eq) were dissolved in N,N-dimethylformamide and stirred under reflux for 12 hours. After the reaction was completed, the solvent was evaporated and the mixture was dissolved in dichloromethane. Trifluoroacetic acid was added and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain F3. Analytical data of F3: 1 H NMR(400MHz,Chloroform-d)δ9.17(s,1H),7.72(t,J=1.8Hz,1H),7.67(d,J=1.8Hz,1H),7.57(d, J=1.5Hz,1H),3.51–3.34(m,3H),3.06(s,2H),2.23(d,J=13.9Hz,2H),1.92(p,J=8.6,7.8Hz,2H).

[0174] F3 (1.5 eq-2 eq) and E3 (1 eq) were dissolved in ethanol, triethylamine (2 eq) was added at room temperature, and the temperature was gradually raised to 78°C for overnight reaction. After the reaction was completed and cooled to room temperature, saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Compound S28 was isolated by column chromatography. Analytical data of S28: 1 HNMR(400MHz,Chloroform-d)δ9.93(s,1H),8.59–8.49(m,2H),8.26(d,J=2.2Hz,1 H),7.95(d,J=2.2Hz,1H),7.72(d,J=1.8Hz,1H),7.69–7.63(m,2H),7.62(s,1H),7. 57(s,1H),4.02(dd,J=13.6,4.3Hz,2H),3.46(dd,J=6.9,3.1Hz,1H),3.29(ddd,J= 13.4,10.3,2.9Hz,2H),2.13(dt,J=13.7,3.9Hz,2H),1.84(dd,J=10.0,3.6Hz,2H).

[0175] Example 29 Synthesis of Compound S29

[0176]

[0177] The synthesis method of F5 is the same as that of D3, except that compound D2 is replaced by compound F4.

[0178] F5 analysis data: 1H NMR(400MHz,Chloroform-d)δ7.02(d,J=5.9Hz,2H),6.88(dd,J=10.0,2.4Hz,1H),5.20–5.02(m,1H),4.76(d d,J=15.4,6.9Hz,1H),3.62(d,J=8.1Hz,1H),3.46(dt,J=21.4,12.5Hz,2H),3.29(s,1H),2.41–2.17(m,2H).

[0179] The synthesis method of S29 is the same as that of S28, except that compound F3 is replaced by compound F5.

[0180] S29 analysis data: 1 HNMR(400MHz,Chloroform-d)δ9.94(s,1H),8.59–8.49(m,2H),8.30(d,J=2.0Hz,1H),8 .01(t,J=2.1Hz,1H),7.67–7.60(m,2H),7.03(s,1H),6.96(d,J=8.3Hz,1H),6.88(dd,J= 10.4,2.4Hz,1H),4.97(ddd,J=46.4,7.7,4.9Hz,1H),4.79–4.67(m,1H),3.97–3.80(m,3 H), 3.62–3.52 (m, 1H) 2.25 (dtdJ = 15.8, 8.88.04.4Hz1H) 2.08 (dqJ = 12.97.9, 5.8Hz, 1H).

[0181] Example 30 Synthesis of Compound S30

[0182]

[0183] The synthesis method of F7 is the same as that of D3, except that compound D2 is replaced by compound F6.

[0184] F7 analysis data: 1 H NMR(400MHz,Chloroform-d)δ7.02(dt,J=8.1,1.9Hz,1H),6.99(s,1H),6.87(dd,J=9.8,7.4Hz,1H),6.20–6.05(m, 1H),4.73(p,J=3.9Hz,1H),3.66–3.57(m,1H),3.41–3.29(m,2H),2.48–2.32(m,1H),2.14(dd,J=15.6,3.8Hz,1H).

[0185] The synthesis method of S30 is the same as that of S28, except that compound F3 is replaced by compound F5.

[0186] S30 analysis data: 1 HNMR(400MHz,Chloroform-d)δ9.94(s,1H),8.58–8.48(m,2H),8.30(d,J=2.1Hz,1H),8.02(d, J=2.1Hz,1H),7.67–7.60(m,2H),7.02(s,1H),6.96(d,J=8.2Hz,1H),6.87(dd,J=10.2,2.4Hz,1 H),4.95–4.74(m,1H),4.57(ddt,J=13.5,9.8,5.4Hz,1H),4.26–4.12(m,1H),3.84(dt,J=11.9, 5.1Hz,1H),3.61–3.43(m,2H),2.33(tq,J=7.9,4.4Hz,1H),1.96(ddt,J=14.0,9.9,4.9Hz,1H).

[0187] Example 31 Synthesis of Compound S31

[0188]

[0189] The synthesis method of F9 is the same as that of D3, except that compound D2 is replaced by compound F8.

[0190] F9 analysis data: 1 HNMR(400MHz,Chloroform-d)δ11.10(s,1H),6.97–6.89(m,2H),6.76(dt,J=10.2,2.4Hz,1H),3.88(d ,J=5.8Hz,2H),3.57(d,J=12.4Hz,2H),3.02(q,J=11.8Hz,2H),2.20–2.02(m,3H),1.82–1.65(m,2H).

[0191] The synthesis method of S31 is the same as that of S28, except that compound F3 is replaced by compound F9.

[0192] S31 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.93(s,1H),8.60–8.48(m,2H),8.26(t,J=2.1Hz,1H), 7.92(t,J=2.1Hz,1H),7.70–7.63(m,2H),6.97–6.88(m,2H),6.78(dt,J=10.4,2.2Hz, 1H), 4.15 (dd, J=13.4, 3.4Hz, 2H), 3.89 (dd, J=6.4, 1.7Hz, 2H), 3.12 (td, J=12.8, 2.6H z,2H),2.22–2.05(m,1H),1.96(dd,J=13.7,3.8Hz,2H),1.60(qd,J=12.5,4.1Hz,2H).

[0193] Example 32 Synthesis of Compound S32

[0194]

[0195] F0 (1 eq), F10 (1 eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 eq), and potassium acetate (4 eq) were dissolved in dioxane and stirred under reflux for 12 hours. After the reaction, the solvent was evaporated and the mixture was dissolved in dichloromethane. Trifluoroacetic acid was added and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and isolated by column chromatography to obtain F11.

[0196] F11 analysis data: 1 H NMR(400MHz,Chloroform-d)δ10.90–10.72(m,1H),9.18(s,2H),7.41(s,1H),7.30(dt,J=8.2,1.9Hz,1H),7.2 6–7.22(m,1H),6.13(tt,J=3.4,1.6Hz,1H),3.96–3.87(m,2H),3.54–3.45(m,2H),2.81(tq,J=6.1,2.2Hz,2H).

[0197] F11 (2 eq) and palladium carbon (0.2 m) were dissolved in ethanol and stirred at 50 ° C for 5 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a colorless oil. The colorless oil, E3 (1 eq) and triethylamine (2 eq) were mixed in ethanol, gradually heated to 78 ° C and reacted overnight. After the reaction was completed and cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and S32 was separated by column chromatography.

[0198] S32 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.93(s,1H),8.55(d,J=5.4Hz,2H),8.29(d,J=2.1Hz,1H),7.96(d,J=2.1Hz,1H),7.71–7.64(m,2H),7.33(s,1H ),7.18(ddt,J=8.7,6.8,2.3Hz,2H),4.28–4.19(m,2H),3.17(ddd,J=13.2,11.7,3.1Hz,2H),2.89(tt,J=11.7,4.2Hz,1H),2.02–1.90(m,4H).

[0199] Example 33 Synthesis of Compound S33

[0200]

[0201] F0 (1 eq), F12 (1 eq), cesium carbonate (2 eq), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.1 eq), and palladium acetate (0.05 eq) were added to dioxane and refluxed at 100°C overnight. After evaporation of the solvent, the mixture was dissolved in dichloromethane and trifluoroacetic acid was added. After stirring at room temperature for 6 hours, the mixture was added with water and ethyl acetate, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and isolated by column chromatography to obtain F13.

[0202] F13 analysis data: 1 H NMR (400MHz, Chloroform-d) δ6.89 (t, J = 1.9 Hz, 1H), 6.78 (dt, J = 8.2, 1.9 Hz, 1H), 6.71 (dt, J = 11.7, 2.3 Hz, 1H), 3.63–3.55 (m, 4H), 3.21 (t, J = 5.2 Hz, 4H).

[0203] The synthesis method of S33 is the same as that of S28, except that compound F3 is replaced by compound F13.

[0204] S33 analysis data: 1 H NMR (400MHz, Chloroform-d) δ9.98 (s, 1H), 8.56 (d, J = 5.7Hz, 2H), 8.32 (d, J = 2.2Hz, 1H), 8.02 (d, J = 2.1Hz, 1H), 7.71–7. 62(m,2H),6.93(t,J=1.8Hz,1H),6.77(tt,J=11.7,2.2Hz,2H),3.76(dd,J=6.6,3.8Hz,4H),3.47(dd,J=6.2,4.0Hz,4H).

[0205] Example 34 Synthesis of Compound S34

[0206]

[0207] The synthesis method of F15 is the same as that of F13, except that compound F12 is replaced by compound F14.

[0208] F15 analysis data: 1 H NMR(400MHz,Chloroform-d)δ6.60(dt,J=8.5,1.9Hz,1H),6.57(d,J=1.9Hz,1H),6.41(dt,J=11.1,2.3Hz,1H),3 .45–3.35(m,1H),2.99–2.89(m,2H),2.80(ddt,J=17.5,13.5,7.1Hz,3H),2.06–1.98(m,2H),1.81–1.75(m,2H).

[0209] The synthesis method of S34 is the same as that of S28, except that compound F3 is replaced by compound F15.

[0210] S34 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.94(s,1H),8.56–8.50(m,2H),8.26(d,J=2.1Hz,1H),7. 95(d,J=2.1Hz,1H),7.68–7.63(m,2H),6.61(dt,J=7.5,2.0Hz,2H),6.44(dt,J=11.1,2.3 Hz,1H),4.14(d,J=7.9Hz,1H),4.10–3.99(m,2H),3.56(ddp,J=10.3,7.2,3.8Hz,1H),3.2 4(ddd,J=13.7,11.2,2.7Hz,2H),2.22–2.13(m,2H),1.68(dtd,J=14.1,10.8,3.9Hz,2H).

[0211] Example 35 Synthesis of Compound S35

[0212]

[0213] The synthesis method of F17 is the same as that of D3, except that compound D2 is replaced by compound F16.

[0214] F17 analysis data: 1 H NMR(400MHz,Chloroform-d)δ7.01(dt,J=8.1,1.9Hz,1H),6.92(d,J=2.3Hz,1H),6 .78(dt,J=9.8,2.3Hz,1H),5.12(d,J=3.9Hz,1H),3.63(s,4H),2.45–2.28(m,2H).

[0215] The synthesis method of S35 is the same as that of S28, except that compound F3 is replaced by compound F17.

[0216] S35 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.82(s,1H),8.57–8.48(m,2H),8.25(d,J=2.1Hz,1H) ,7.89(d,J=2.1Hz,1H),7.70–7.61(m,2H),6.95–6.90(m,2H),6.77(dt,J=10.2,2.3Hz ,1H),5.04(q,J=3.2,2.2Hz,1H),4.17(dd,J=13.1,4.3Hz,1H),3.93(td,J=11.1,6.7H z,1H),3.65(ddd,J=11.1,8.3,2.2Hz,1H),3.50(d,J=13.0Hz,1H),2.39–2.19(m,2H).

[0217] Example 36 Synthesis of Compound S36

[0218]

[0219] The synthesis method of F19 is the same as that of F13, except that compound F12 is replaced by compound F18.

[0220] F19 analysis data: 1 H NMR(400MHz,Chloroform-d)δ6.69(dt,J=8.6,1.8Hz,1H),6.59(d,J=1.8Hz,1H),6.42(dt,J=10.7,2.3Hz, 1H),4.30(tt,J=5.4,2.5Hz,1H),3.61–3.36(m,4H),2.37(dtd,J=14.5,8.8,5.8Hz,1H),2.23–2.12(m,1H).

[0221] The synthesis method of S36 is the same as that of S28, except that compound F3 is replaced by compound F19.

[0222] S36 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.63(s,1H),8.59–8.49(m,2H),8.27(d,J=2.1Hz,1H),7.92(d,J=2.1Hz ,1H),7.65–7.60(m,2H),6.67–6.58(m,2H),6.45(dt,J=10.9,2.3Hz,1H),4.28(d,J=6.8Hz,1H),4.16(h ,J=5.2Hz,1H),3.93(dd,J=12.1,5.6Hz,1H),3.84(dt,J=11.8,7.5Hz,1H),3.61(ddd,J=12.3,7.9,5.1 Hz,1H),3.49(dd,J=11.9,3.8Hz,1H),2.33(dtd,J=13.0,7.8,5.2Hz,1H),2.07(dq,J=12.1,5.4Hz,1H).

[0223] Example 37 Synthesis of Compound S37

[0224]

[0225] The synthesis method of F20 is the same as that of D3, except that compound D2 is replaced by compound F8.

[0226] F21 analysis data: 1 H NMR(400MHz,Chloroform-d)δ11.15(s,1H),7.00(d,J=8.2Hz,1H),6.91(s,1H),6.77 (dt,J=9.8,2.4Hz,1H),5.12(t,J=3.1Hz,1H),3.70–3.48(m,4H),2.45–2.25(m,2H).

[0227] The synthesis method of S37 is the same as that of S28, except that compound F3 is replaced by compound F21.

[0228] S31 analysis data: 1HNMR(400MHz,Chloroform-d)δ9.69(s,1H),8.55(s,2H),8.28(d,J=2.1Hz,1H),7.9 2(d,J=2.1Hz,1H),7.66(d,J=6.0Hz,2H),6.96–6.89(m,2H),6.76(dt,J=10.3,2.3H z,1H),5.04(t,J=4.3Hz,1H),4.19(dd,J=13.1,4.4Hz,1H),3.94(td,J=11.1,6.8Hz ,1H),3.67(ddd,J=11.2,8.3,2.3Hz,1H),3.48(d,J=13.1Hz,1H),2.39–2.21(m,2H).

[0229] Example 38 Synthesis of Compound S38

[0230]

[0231] The synthesis method of F23 is the same as that of F13, except that compound F12 is replaced by compound F22.

[0232] F23 analysis data: 1 H NMR(400MHz,Chloroform-d)δ6.69(d,J=8.4Hz,1H),6.59(s,1H),6.42(dt,J=10.8,2.3Hz,1H),4. 30(dt,J=6.1,3.3Hz,1H),3.63–3.33(m,4H),2.44–2.28(m,1H),2.18(dq,J=13.2,4.2,3.7Hz,1H).

[0233] The synthesis method of S38 is the same as that of S28, except that compound F3 is replaced by compound F23.

[0234] S38 analysis data: 1H NMR(400MHz,Chloroform-d)δ9.69(s,1H),8.53(d,J=5.5Hz,2H),8.26(d,J=2.1Hz,1H),7.90(d,J=2.1 Hz,1H),7.69–7.56(m,2H),6.67–6.58(m,2H),6.44(dt,J=10.9,2.3Hz,1H),4.51–4.45(m,1H),4.14(t q,J=7.3,4.3,3.5Hz,1H),3.92(dd,J=12.1,5.6Hz,1H),3.83(dt,J=11.8,7.5Hz,1H),3.60(ddt,J=12. 2,7.8,4.1Hz,1H),3.48(dd,J=12.1,3.9Hz,1H),2.32(dtd,J=13.0,7.8,5.3Hz,1H),2.12–2.01(m,1H).

[0235] Example 39 Synthesis of Compound S39

[0236]

[0237] The synthesis method of F25 is the same as that of F13, except that compound F12 is replaced by compound F24.

[0238] F25 analysis data: 1 HNMR(400MHz,Chloroform-d)δ6.68(dt,J=8.6,1.9Hz,1H),6.52(t,J=1.9Hz,1H),6.32(dt,J=10.6,2.3Hz,1H), 4.55(d,J=6.4Hz,1H), 4.32(dd,J=8.9,7.1Hz,2H), 4.18(dddd,J=11.6,6.7,4.6,2.1Hz,1H), 3.78–3.71(m,2H).

[0239] The synthesis method of S39 is the same as that of S28, except that compound F3 is replaced by compound F25.

[0240] S39 analysis data: 1H NMR(400MHz,Chloroform-d)δ9.80(s,1H),8.54(d,J=5.3Hz,2H),8.32(t,J=1.9Hz,1H),7.93(t,J=1.9Hz,1H),7.65–7.58(m,2H),6.69(d,J=8.5Hz ,1H),6.55(s,1H),6.36(dd,J=10.6,2.1Hz,1H),4.72–4.61(m,2H),4.50( d, J=6.2Hz, 1H), 4.34 (q, J=6.3, 5.6Hz, 1H), 4.10 (dd, J=10.3, 4.6Hz, 2H).

[0241] Example 40 Synthesis of Compound S40

[0242]

[0243] The synthesis method of F27 is the same as that of F13, except that compound F12 is replaced by compound F24.

[0244] F27 analysis data: 1 HNMR(400MHz,Chloroform-d)δ6.68(dt,J=8.6,1.9Hz,1H),6.52(t,J=1.9Hz,1H),6.32(dt,J=10.6,2.3Hz,1H), 4.55(d,J=6.4Hz,1H), 4.32(dd,J=8.9,7.1Hz,2H), 4.18(dddd,J=11.6,6.7,4.6,2.1Hz,1H), 3.78–3.71(m,2H).

[0245] The synthesis method of S40 is the same as that of S28, except that compound F3 is replaced by compound F27.

[0246] S40 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.79(s,1H),8.54(d,J=5.3Hz,2H),8.32(d,J=2.1Hz,1H),7.93(t,J=2.1Hz,1H),7.61(d,J=5.4Hz,2H),6.70 (d,J=8.5Hz,1H),6.55(s,1H),6.41–6.31(m,1H),4.66(t,J=8.8Hz,2H),4.49(d,J=6.2Hz,1H),4.34(s,1H),4.10(dd,J=10.8,4.5Hz,2H).

[0247] Example 41 Synthesis of Compound S41

[0248]

[0249] The synthesis method of F29 is the same as that of D3, except that compound D2 is replaced by compound F28.

[0250] F29 analysis data: 1 HNMR(400MHz,Chloroform-d)δ6.90(dt,J=8.4,1.9Hz,1H),6.85(t,J=1.9Hz,1H),6.67(dt,J=10.3,2.4 Hz,1H),4.31(p,J=7.0Hz,1H),3.26–3.16(m,1H),2.91(tdt,J=9.2,6.9,2.4Hz,2H),1.93–1.82(m,2H).

[0251] The synthesis method of S41 is the same as that of S28, except that compound F3 is replaced by compound F29.

[0252] S41 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.70(d,J=6.8Hz,1H),8.57(s,2H),8.29 (d,J=2.3Hz,1H),7.80(d,J=2.3Hz,1H),7.63(d,J=5.0Hz,2H),6.96–6.85(m,2H),6. 72(dt,J=10.1,2.3Hz,1H),4.53(p,J=6.9Hz,1H),4.39(ddt,J=16.0,8.8,7.2Hz,1H) ,3.13(dddd,J=12.0,9.0,6.1,2.6Hz,2H),2.23(dddd,J=12.1,9.3,5.0,2.2Hz,2H).

[0253] Example 42 Synthesis of Compound S42

[0254]

[0255] The synthesis method of F31 is the same as that of D3, except that compound D2 is replaced by compound F30.

[0256] Analysis data of F31: R252: 1H NMR(400MHz,Chloroform-d)δ7.00(t,J=1.9Hz,1H),6.96(dt,J=8.2,1.8Hz,1H),6.86(d t,J=10.0,2.4Hz,1H),4.26(d,J=13.0Hz,2H),4.13(d,J=4.9Hz,4H),3.43–3.33(m,1H).

[0257] The synthesis method of S42 is the same as that of S28, except that compound F3 is replaced by compound F31.

[0258] S42 analysis data: 1 H NMR(400MHz,Chloroform-d)δ9.83(s,1H),8.54(d,J=5.6Hz,2H),8.32(d,J=2 .2Hz,1H),7.90(d,J=2.2Hz,1H),7.68–7.61(m,2H),6.94(dt,J=7.0,1.9Hz,2H ),6.78(dt,J=10.2,2.3Hz,1H),4.44(dd,J=10.1,8.3Hz,2H),4.21(d,J=6.5H z,2H),4.16(dd,J=10.1,5.3Hz,2H),3.18(dddd,J=11.8,8.2,4.7,1.3Hz,1H).

[0259] Example 43 HTRF High-Throughput GPR52 Agonist Molecular Level Evaluation

[0260] ① Construction of HEK293-GPR52 stable transgenic line

[0261] Using a full-length GPR52 plasmid, a GPR52 fragment was amplified by PCR. The lentiviral vector was double-digested, the fragment was ligated with the vector, and transformed into competent E. coli. Correct transformants were selected, and the bacterial suspension containing the correct sequence was expanded and extracted to obtain the pCDH-GPR52 plasmid. The plasmid was transfected into HEK293T cells, and the lentivirus was collected and infected with HEK293 cells. Stable HEK293-GPR52 transfectants were obtained through resistance screening.

[0262] ② Screening of GPR52 agonist activity

[0263] The experimental method was carried out according to the instructions of the HTRF-cAMP kit, using the GPR52 agonist PW0787 as the reference compound, and negative and positive controls were set up. The details are as follows:

[0264] PW0787 and the test compound were diluted in a 3-fold gradient, with a maximum concentration of 3 μM, for a total of seven concentrations. 5 μL of HEK293-GPR52 cells were plated into a 384-well plate, and 5 μL of compound solutions (compounds S1-S42 prepared in Examples 1-42) of varying concentrations were added to the corresponding wells. Equal volumes of buffer were added to the wells designated as positive and negative controls, and the cells were incubated at 37°C for 4 hours. 5 μL of a D2-labeled cAMP receptor and Eu-labeled anti-cAMP donor diluted in 1x HTRF Lysis Buffer were then added to the 384-well plate and incubated at room temperature for 1 hour. HTRF fluorescence intensity was measured using a microplate reader, with the Eu donor emission signal collected at 620 nm and the D2 receptor emission signal collected at 665 nm. Data were analyzed using the HTRF ratio (665 nm / 620 nm). The results are shown in Table 1.

[0265] Table 1. Molecular agonist effects of compounds on GPR52 activity

[0266]

[0267]

[0268]

[0269] *Note: PW787 is a GPR52 agonist reported in the paper, with an EC50 (nM) of 135 nM and an Emax (%) of 136%. Values ​​are the relative ratios of the compound's agonistic effect on the target protein compared to PW787 at a specific concentration. a- indicates not tested.

[0270] As can be seen from Table 1, the compounds obtained in the present invention have stronger agonist activity and agonist effect on GPR52. Among them, the agonist activity of the compound of Example 09 on GPR52 is 4 times that of the existing GPR52 agonist PW787, the agonist activity of the compounds of Examples 13, 18, 19 and 24 on GPR52 is 2 times that of the existing GPR52 agonist PW787, and the agonist activity of the compounds of Examples 01, 10, 12, 13, 20, 23 and 39 on GPR52 is also better than the existing GPR52 agonist PW787.

[0271] Among the compounds, Example 35 exhibits a greater agonistic effect on GPR52 than the existing GPR52 agonist PW787. In terms of pharmacokinetic properties, compared to known GPR52 agonists, the compound of the present invention possesses favorable physicochemical properties, leading to good in vivo absorption and very high bioavailability. It can also cross the blood-brain barrier, making it suitable for use as a GPR52 agonist.

[0272] The description and drawings of the present invention are considered to be illustrative rather than restrictive. On the basis of the present invention, those skilled in the art can make some substitutions and modifications to some of the technical features according to the disclosed technical content without creative work, and all of them are within the scope of protection of the present invention.

Claims

1. A pyrazinamide compound, characterized in that: The compound is selected from:

2. The method for preparing a pyrazinamide compound according to claim 1, wherein: The reaction scheme of the pyrazinamide compound is as follows: PPh3 is triphenylphosphine, DEAD is diethyl azodicarboxylate, TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, EtOH is ethanol, LiOH is lithium hydroxide, THF is tetrahydrofuran, H2O is water, EDCI is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and DMAP is 4-dimethylaminopyridine; The preparation method comprises the following steps: (1) 1 eq D1, 1 eq D2, and 2 eq triphenylphosphine were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes; then 2 eq diethyl azodicarboxylate was added; after stirring at room temperature for 8 hours, the solvent was evaporated and the mixture was dissolved in dichloromethane, and trifluoroacetic acid was added. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain D3; (2) 1.5eq-2eqD3 and 1eqD4 were dissolved in ethanol, 2eq triethylamine was added at room temperature, and the temperature was gradually raised to 78°C for reaction overnight; after the reaction was completed and cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and D5 was separated by column chromatography; (3) 1 eq of D5 was dissolved in a 1:1 mixed solvent of tetrahydrofuran and water, 6 eq of lithium hydroxide was added at room temperature, and the mixture was stirred at room temperature overnight; after the reaction was completed, the pH of the mixture was adjusted to <5 with a 1N hydrochloric acid solution, dichloromethane was added for extraction, and the organic phase was separated; the solvent was evaporated to obtain D6; (4) 1 eq D6, 1 eq W-NH2, 2 eq 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.5 eq 4-dimethylaminopyridine were dissolved in dichloromethane and stirred at room temperature for 10 minutes; after stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and I was separated by column chromatography; the group definitions of the reaction starting materials and intermediates correspond to those of the product.

3. The method for preparing a pyrazinamide compound according to claim 1, wherein: The reaction scheme of the pyrazinamide compound is as follows: The preparation method comprises the following steps: PPh3 is triphenylphosphine, DEAD is diethyl azodicarboxylate, DCM is dichloromethane, Et3N is triethylamine, EtOH is ethanol, THF is tetrahydrofuran, EDCI is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and DMAP is 4-dimethylaminopyridine; (1) 1 eq of E1, 1 eq of E2, 2 eq of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.5 eq of 4-dimethylaminopyridine were dissolved in dichloromethane and stirred at room temperature for 10 minutes; after stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and E3 was separated by column chromatography; (2) 1.5eq-2eq of E3 and 1eq of E4 were dissolved in ethanol, 2eq of triethylamine was added at room temperature, and the temperature was gradually raised to 78°C for reaction overnight; after the reaction was completed and cooled to room temperature, a saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and E5 was separated by column chromatography; (3) 1 eq E5, 1 eq E6, and 2 eq triphenylphosphine were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes; then 2 eq diethyl azodicarboxylate was added, and after stirring at room temperature for 8 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain II; the group definitions of the reaction raw materials and intermediates correspond to those of the product.

4. The method for preparing a pyrazinamide compound according to claim 1, wherein: The reaction scheme of the pyrazinamide compound is as follows: Wherein, G is hydroxy or bromine; TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, EtOH is ethanol, and the E3 is The preparation method comprises the following steps: (1) F3 was synthesized from F1 according to the following method: 1 eq F1, 1 eq F2, and 2 eq triphenylphosphine were mixed in tetrahydrofuran and stirred at room temperature for 10 minutes; then 2 eq diethyl azodicarboxylate was added; after stirring at room temperature for 8 hours; after evaporating the solvent, the mixture was dissolved in dichloromethane, and trifluoroacetic acid was added. After stirring at room temperature for 6 hours, water and ethyl acetate were added to the mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain F3; (4) 1.5eq-2eqF3 and 1eqE3 were dissolved in ethanol, 2eq triethylamine was added at room temperature, and the temperature was gradually raised to 78°C for overnight reaction; after the reaction was completed and cooled to room temperature, saturated ammonium chloride solution was added to the mixture, and dichloromethane was added for extraction and the organic phase was separated; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and III was separated by column chromatography; the group definitions of the reaction raw materials and intermediates correspond to those of the products.

5. Use of a pyrazinamide compound according to claim 1 in the preparation of a medicament for preventing or treating diseases related to GPR52.

6. The use according to claim 5, characterized in that The GPR52-related disease is a neurodegenerative disease, and the neurodegenerative disease is schizophrenia, cognitive impairment, depression, Parkinson's disease, Alzheimer's disease, and muscular dystrophy.

7. A pharmaceutical composition, characterized in that The invention comprises the pyrazinamide compound as claimed in claim 1.

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