Pyrazinamide compound as well as preparation method and application thereof

Abstract

The invention discloses a pyrazinamide compound, which is a compound with a structure as shown in a general formula (I) or a tautomer, an enantiomer, a diastereomer, a racemate, a metabolite or a metabolic precursor of the compound, or pharmaceutically acceptable salt, ester and prodrug of the compound, or a hydrate of the compound, the invention also discloses a preparation method of the pyrazinamide compound and an application of the pyrazinamide compound in preparation of medicines for preventing and treating GPR52 related diseases. The invention also discloses a preparation method of the pyrazinamide compound and an application of the pyrazinamide compound in preparation of medicines for preventing and treating GPR52 related diseases.

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 of the pyrazinamide compound in preparing drugs for preventing and treating diseases related to GPR52. Background Art

[0002] 1. Structural characteristics of GPR52

[0003] GPR52 is a member of GPCR, which is the largest class of membrane protein receptors in eukaryotes, with more than 800 members. GPCR contains 7 transmembrane proteins in its structure, which are widely distributed in organs and tissues such as the central nervous system, immune system, cardiovascular system, and retina. It is responsible for intracellular and intercellular information exchange, and is widely involved in the regulation of human physiological or pathological states. When GPCR function is disordered, it can lead to the occurrence of a variety of diseases, including cancer, central nervous system (CNS) disorders, metabolic disorders, inflammation, infection, immune diseases, etc. Therefore, GPCR has always been the focus of drug research and development. Currently, more than 30% of the drugs on the market target GPCRs. Among these drugs targeting GPCRs on the market, only 108 unique GPCRs are targeted. There are still 56% of non-sensory GPCRs that have not been successfully targeted, and some of them are called orphan GPCR receptors (oGPCRs). Although the endogenous ligands of oGPCRs are unknown, studies have found that oGPCRs play an indispensable role in important physiological processes in human life activities and are closely related to the occurrence and development 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, and a single exon encodes a 7TM-spanning protein of 361 amino acids. GPR52 contains an extracellular N-terminal domain (amino acid residues 1-39), seven classical TM domains (TM1-TM7), three extracellular loops (ECL), three intracellular loops (ICL), and a C-terminal helix (H8, amino acid residues 327-361). Recently, the high-resolution crystal structure of human GPR52 was published in three states: the ligand-free state, the Gs-coupled auto-activated state, and the synthetic agonist C17-bound state. In order to stabilize GPR52 for crystallography, the ligand-free state crystal structure was determined with seven mutation-modified GPR52 and two ICL3 fusion protein partners, rubredoxin and flavoxin. The conformations of the two GPR52 structures are very similar, indicating that the ICL3 fusion protein does not alter crystal packing or change the conformation of the receptor. 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 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, especially in the striatum. In 2014, Komatsu et al. found that GPR52 has the potential to be a target for drug discovery for the treatment of schizophrenia through detailed histological studies and analysis of GPR52 knockout and transgenic mice. Studies on GPR52 have found that GPR52 can inhibit dopamine D2 receptor signal transduction and activate dopamine D1 / N-methyl-D-aspartate (NMDA) receptors through the accumulation of intracellular cAMP. Therefore, GPR52 agonists are expected to become a new class of anti-schizophrenia drugs. Interestingly, GPR52 exhibits a unique expression pattern. The receptor is expressed in almost all D2-expressing mononuclear cells in the basal ganglia, and is expressed in large quantities in D1-expressing neurons in the medial prefrontal cortex. This raises the possibility that activation of GPR52 could improve positive symptoms of schizophrenia by antagonizing the activity of Gi / o-coupled D2 receptors in striatal mononeurons and improve negative symptoms and cognitive impairment of schizophrenia by enhancing 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 GPR52 knockout mice have lower expression of D2R mRNA and enkephalin in the striatum compared to GPR52 wild-type mice, indicating that GPR52 deficiency enhances D2R signaling in the basal ganglia and reduces the activity of striatal neurons. Using histological methods in genetically manipulated mouse models, studies have shown that transgenic mice overexpressing GPR52 exhibit antipsychotic-like behaviors, while GPR52 knockout mice exhibit behaviors associated with psychosis. In addition, activation of GPR52 by alternative agonists increased cAMP levels in vitro and showed antipsychotic-like activity, inhibiting amphetamine- or methamphetamine-induced motor hyperactivity. At the same time, studies of wild-type excitatory postsynaptic potentials (fEPSPs) after GPR52 agonist treatment at synapses in rat cortical slices showed a dose-dependent potentiation effect. In addition, in a rat social recognition model, GPR52 agonist activation significantly increased episodic memory, indicating that targeting GPR52 can improve cognitive impairment associated with psychiatric disorders. Given the above circumstances, GPR52 has emerged as a new promising target for the treatment of psychiatric disorders such as schizophrenia and substance use disorder.

[0008] GPR52 agonists

[0009] The discovery of anti-neuropsychiatric drugs targeting GPR52 has attracted more and more attention from researchers. Researchers have made some progress in the study of nervous system drugs targeting GPR52, especially the development of small molecule agonists. Currently, one small molecule agonist has entered clinical phase I research and three small molecule agonists have entered systemic preclinical research, and clinical trials are expected to be carried out soon.

[0010] The abnormal inactivation of GPR52 is closely related to the occurrence and development of many diseases such as schizophrenia, mental disorders and cognitive impairment symptoms. The current GPR52 agonist small molecules have poor water solubility, poor pharmacokinetic properties, and poor ability to pass through the blood-brain barrier. In addition, the activity and efficacy of the current GPR52 agonists are low. The pEC50 of most compounds is in the nanomolar or even micromolar range, which does not reach the ideal activity level, which also limits their drug development prospects to a certain extent. As a drug that needs to pass through the blood-brain barrier, the pharmacokinetic properties and physicochemical properties of GPR52 agonists in the body (LogP is between 2 and 5; the molecular mass is usually less than 450Da; most of them are neutral or weakly alkaline molecules, and pKa is between 7.5 and 10.5) are also higher than those of general 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] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows: a pyrazinamide compound, which is a compound having a structure as shown in the 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] Among them, L is selected from One of;

[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, 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 by one or more substituents selected from the following: halogen, cyano, nitro, hydroxyl, 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, aromatic ring refers to substitution by 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 by one or more substituents selected from the following: halogen, cyano, nitro, hydroxyl, 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 of the structure represented by the general formula (I) is selected from:

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028] The above 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, 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. to react overnight; 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 D5 was separated by column chromatography;

[0036] (3) D5 (1 eq) was dissolved in a 1:1 mixed solvent of tetrahydrofuran and water, lithium hydroxide (6 eq) 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 1N hydrochloric acid solution, 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, the solvent was evaporated and I was obtained by column chromatography.

[0038] The present invention also provides a second method for preparing the above-mentioned pyrazinamide compounds, and the reaction route 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, 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. to react overnight; 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 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 compounds, characterized in that the reaction route of the pyrazinamide compounds is as follows:

[0046]

[0047] Wherein, G is hydroxyl 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) F1 was used to synthesize F2 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-dicyclohexylphosphine-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 reaction overnight; 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 the use of the above 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 pyrazinamide compound.

[0056] Beneficial effects of the present invention: 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, shows 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 in conjunction with 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 obtained by drying according to standard methods; unless otherwise stated, all reactions were carried out under nitrogen protection and tracked by TLC, and post-treatment was performed by washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate; the 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 plate was 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. 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. 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] D3 (1.5eq-2eq) and D4 (1eq) were dissolved in ethanol, triethylamine (2eq) 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, 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. 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 mixed solvent of tetrahydrofuran and water, add lithium hydroxide (6 eq) at room temperature, and stir overnight at room temperature; after the reaction is completed, adjust the mixture to pH < 5 with 1N hydrochloric acid solution, add dichloromethane for extraction 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 separated 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, the solvent was evaporated, and E3 was obtained 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 (1.5eq-2eq) and E4 (1eq) were dissolved in ethanol, triethylamine (2eq) 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, 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 obtained by column chromatography. The analytical data of E5 are as follows: 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. 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 compound S16. The analytical data of S16 are as follows: 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), cesium carbonate (3 eq), dissolved in N, N-dimethylformamide, stirred under reflux for 12 hours. After the reaction was completed, 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 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 (1.5eq-2eq) and E3 (1eq) were dissolved in ethanol, triethylamine (2eq) 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, 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 compound S28 was obtained 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] dichloropalladium (0.1 eq) and potassium acetate (4 eq) were dissolved in dioxane and stirred for 12 hours under reflux. After the reaction was completed, 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 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] Dissolve F11 (2 eq) and palladium carbon (0.2 m) in ethanol and stir at 50 ° C for 5 hours. After the reaction is completed, filter the mixture with diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain a colorless oil. Mix the colorless oil, E3 (1 eq) and triethylamine (2 eq) in ethanol, gradually heat 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. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent, and separate S32 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), palladium acetate (0.05 eq) were added to dioxane and refluxed overnight at 100°C. 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 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 transfectant

[0261] Using the full-length plasmid of GPR52, the GPR52 fragment was obtained by PCR amplification, the lentiviral vector was double-digested, the fragment was connected to the vector, and transformed into the competent E. coli, the correct transformant was picked, and the bacterial solution with correct sequencing was expanded and cultured to obtain the pCDH-GPR52 plasmid. The plasmid was transfected into HEK293T, the lentivirus was collected, and HEK293 was infected. The HEK293-GPR52 stable strain was obtained by 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, with 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 with a 3-fold concentration gradient at the highest concentration of 3 μM, and a total of 7 concentrations were set; 5 μL of HEK293-GPR52 cells were plated in a 384-well plate, and 5 μL of different concentrations of compound (compound S1-S42 prepared in Example 1-42) solution was added to the corresponding wells, and equal volumes of buffer were added to the wells marked as positive control and negative control, and incubated at 37°C for 4 hours; 5 μL of d2-labeled cAMP receptor and Eu-labeled anti-cAMP donor diluted with 1x HTRF Lysis Buffer were added to the 384-well plate successively, and incubated at room temperature for 1 hour; HTRF fluorescence intensity detection was performed using an enzyme reader, and the Eu donor emission light was collected at a wavelength of 620nm, and the d2 receptor emission light was collected at a wavelength of 665nm; HTRF ratio (665nm / 620nm) was used for data analysis. The experimental 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%. The value is the relative ratio of the compound's agonistic effect on the target protein to that of PW787 at a specific concentration. a-: indicates no detection.

[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 which the agonist activity of the compound in Example 09 on GPR52 is 4 times that of the existing GPR52 agonist PW787, the agonist activity of the compounds in 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 in Examples 01, 10, 12, 13, 20, 23 and 39 on GPR52 is also better than the existing GPR52 agonist PW787.

[0271] The agonistic effect of Example 35 on GPR52 is greater than that of the existing GPR52 agonist PW787. In terms of pharmacokinetic properties, compared with known GPR52 agonists, the compounds of the present invention have suitable physicochemical properties, and thus can be well absorbed in the body, exhibit very high bioavailability, can pass through the blood-brain barrier, and are suitable for use as GPR52 agonists.

[0272] The specification 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 labor, all of which are within the protection scope of the present invention.

Claims

1. A pyrazinamide compound, characterized in that: It is a compound having a structure as shown in 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; Among them, L is selected from One of; Wherein X is selected from one of O, NH, and S; n represents 1, 2; Z is selected from one of nitrogen atom and CH; R 1 Selected from 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 by one or more substituents selected from the following: halogen, cyano, nitro, hydroxyl, amino; 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, aromatic ring refers to substitution by 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 by one or more substituents selected from the following: halogen, cyano, nitro, hydroxyl, amino; 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.

2. A pyrazinamide compound according to claim 1, characterized in that: The compound represented by the general formula (I) is selected from:

3. A method for preparing a pyrazinamide compound according to claim 1 or 2, characterized in that: 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, DMAP is 4-dimethylaminopyridine; The preparation method comprises the following steps: (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; (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. to react overnight; 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 D5 was separated by column chromatography; (3) D5 (1 eq) was dissolved in a 1:1 mixed solvent of tetrahydrofuran and water, lithium hydroxide (6 eq) 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 1N hydrochloric acid solution, dichloromethane was added for extraction, and the organic phase was separated; the solvent was evaporated to obtain D6; (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, the solvent was evaporated and I was obtained by column chromatography.

4. A method for preparing a pyrazinamide compound according to claim 1 or 2, characterized in that: The reaction scheme of the pyrazinamide compound is as follows: The preparation method comprises the following steps: 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, DMAP is 4-dimethylaminopyridine; (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; (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. to react overnight; 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 E5 was separated by column chromatography; (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.

5. The method for preparing a pyrazinamide compound according to claim 1 or 2, characterized in that: The reaction scheme of the pyrazinamide compound is as follows: Wherein, G is hydroxyl or bromine; TFA is trifluoroacetic acid, DCM is dichloromethane, Et3N is triethylamine, and EtOH is ethanol; The preparation method comprises the following steps: (1) F1 was used to synthesize F2 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-dicyclohexylphosphine-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; (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 reaction overnight; 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.

6. Use of a pyrazinamide compound as claimed in claim 1 or 2 as a highly selective GPR52 agonist.

7. Use of a pyrazinamide compound according to claim 1 or 2 in the preparation of a medicament for preventing or treating a disease related to GPR52.

8. The use according to claim 7, characterized in that: The diseases associated with GPR52 include neurodegenerative diseases, and the neurodegenerative diseases include schizophrenia, cognitive impairment, depression, Parkinson's disease, Alzheimer's disease, and muscular dystrophy.

9. A pharmaceutical composition, characterized in that Contains the pyrazinamide compound as described in claim 1 or 2.

Images