CN108047145A - There is 2- aryl quinoxaline compounds of affinity and preparation method and application with Tau albumen - Google Patents

Abstract

The present invention provides a kind of 2-arylquinoxaline compound that has affinity with Tau protein, and its structure is as shown in formula (I): The present invention also provides the preparation method of the compound of formula (I). Such compounds can be directly used as fluorescent probes for detecting neurofibrillary tangles in vivo or in tissue samples. When used in nuclear medicine imaging, they need to be labeled with appropriate radioactive isotopes. Such compounds are particularly useful in the diagnosis of patients with neurofibrillary tangles (Tau protein deposits), including Alzheimer's disease.

Description

2-arylquinoxaline compounds having affinity with Tau protein and preparation method thereof Law and Application

technical field

The invention relates to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine, in particular to a 2-arylquinoxaline compound with high affinity with Tau protein and its preparation method and application.

Background technique

The progressive and fatal neurodegenerative disease Alzheimer's disease (Alzheimer's Disease, AD) has become the fourth major disease that seriously threatens the health of the elderly after tumors, heart disease, stroke and diabetes. Its clinical manifestations are mainly the decline of cognition, memory and life ability, accompanied by neuropsychiatric symptoms and behavioral disturbances. Lancet reported in mid-2013 that there were 1.93 million AD patients in China in 1990, 3.71 million in 2000, and 5.96 million in 2010. It is predicted that the number of AD patients in the world will increase from 26.1 million in 2006 to 110 million in 2050. Therefore, research on the prevention and early diagnosis of AD is of great significance.

AD is caused by a combination of factors, such as age, genetics, environment, brain trauma, depression, diabetes, hyperlipidemia, and vascular diseases. Excluding the complexity of AD itself, its early and accurate diagnosis and the lack of detection methods also hinder its effective treatment. At present, the clinical diagnosis of AD can only rely on the autopsy after the patient's death. Autopsy results revealed two main pathological features of AD: 1) deposition of senile plaques (SPs) composed of Aβ polypeptide; 2) neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau protein. Therefore, it has great application value for the quantification of Aβ polypeptide and Tau protein levels in the brain. Modern molecular imaging has the advantages of non-invasive, accurate diagnosis and monitoring of disease development, and has been greatly developed in recent years. In particular, positron emission tomography (PET) imaging is a very powerful tool in drug development and monitoring of disease changes. There are a lot of clinical data on PET imaging agents targeting Aβ deposition. However, the Aβ deposition density in the brain tissue is not well correlated with neurodegeneration and sensory impairment, which may cause false positive imaging results. Relative to Aβ deposition, the density of tau protein in the brain and its diffusion in the cerebral cortex were well correlated. Therefore, Tau protein is an ideal target for AD diagnosis. Other studies have also shown that Tau protein is a core factor in the pathogenesis of AD.

There have been many reports on PET probes targeting Tau protein in the world. Among the THK series compounds, THK-5105 (Okamura, N et al. Journal of Nuclear Medicine. 2013, 54:1420-1427) was able to distinguish AD patients from normal controls in the first clinical trial. However, its high non-specific binding in the brainstem, thalamus and subcortical white matter, and its slow clearance rate further limit its clinical application. The modified THK-5117 and THK-5331 are currently only in clinical research. PBB3 (Maruyama, M et al. Neuron. 2013, 79:1-15) has high affinity for Tau protein and high selectivity relative to Aβ protein, but it is unstable in vivo, which is due to the presence of cis Anti-configuration. T808 (Cashion, D et al. International Patent WO 2011/119565A1, 2011), which almost meets all the requirements of the Tau probe, has severe defluorination in vivo, which hinders its further clinical development, and its analog T807 is currently in the experimental stage .

Contents of the invention

The object of the present invention is to provide a 2-arylquinoxaline compound with high affinity with Tau protein, its preparation method and application.

In order to realize the object of the present invention, the present invention has the 2-arylquinoxaline compound of affinity with Tau protein, and the structure of described compound is as shown in formula (I):

Wherein, X and Y independently represent N or CH; R ₁ is located at the 4-7 position, and R ₂ is located at the 2', 3' or 4' position.

R ₁ and R ₂ independently represent H, ¹⁸ F, ¹⁹ F, ¹²³ I, ¹²⁵ I, ¹²⁷ I, OH, O ¹¹ CH ₃ , O ¹² CH ₃ , NH ₂ , NH ¹¹ CH ₃ , NH ¹² CH ₃ , N(CH ₃ ) ₂ , O(CH ₂ ) _m ¹⁸ F or O(CH ₂ ) _m ¹⁹ F. Wherein, R is OH, ¹⁸ F or ¹⁹ F, and m is an integer between 1-6.

Preferably, the compound of the present invention is any compound in the following formulas 1) to 13):

Wherein, F in formulas 4) to 13) is ¹⁸ F or ¹⁹ F.

The preparation method of compound of the present invention is as follows:

Taking X and Y as CH, R ₁ as N(CH ₃ ) ₂ at the 5th or 6th position, and R ₂ as OH at the 4' position as an example, that is, the compounds described in formula 1) and formula 2), other different substituents or different Substitution positions are prepared in a similar manner:

(1) Take 10mmol Dissolved in 10mL DMSO, stirred at room temperature for 30 minutes, then slowly added 10mmol 10mL of DMSO solution, raised to room temperature, continued to react for 2 hours, added 200mL saturated NaHCO ₃ solution, a yellow precipitate was precipitated, filtered with suction, washed with a large amount of water, and dried to obtain a 5- or 6-substituted mixture;

(2) Under heating conditions, 1.0 g of the above mixture and 2.0 g of oxalic acid dihydrate were dissolved in 200 mL of absolute ethanol to obtain a purple-red solution. After cooling, a solid precipitated and was suction filtered to obtain a purple-red oxalate crystal substituted at the 6-position. After adding petroleum ether dropwise to the filtrate, the solid was precipitated, filtered with suction to obtain dark red oxalate crystals substituted at the 5-position, and 5.0 mL of concentrated ammonia water was added to the above crystals to obtain a yellow solid, filtered with suction, washed and dried to obtain formula 1) and 2) the compound shown.

Take X and Y as CH, R ₁ as 6-position substituted N(CH ₃ ) ₂ , R ₂ as 4'-position O(CH ₂ ) ₂ ¹⁸ F, For example, the compounds described in formula 3), formula 6) or formula 11), other different carbon chain lengths, different optical configurations, different substituents or different substitution positions are prepared by similar methods:

(1) Take 1mmol of the compound shown in formula 1), 1mmol of CsF and 1.2mmo Dissolve in 5mL of anhydrous DMF, stir and react at 90°C for 2 hours, add 50mL of ice water, a large amount of yellow precipitate precipitates, filter with suction, wash and dry to obtain formula (V), formula (VI) or formula (VII) the indicated compound;

(2) Dissolve 1 mmol of the compound represented by formula (VI) in 20 mL of THF, add 10 mL of 1M HCl, heat at 60°C for 1 hour, then remove THF by rotary evaporation, add 5.0 mL of ammonia water, a yellow precipitate precipitates, filter with suction, wash and dry Obtain compound shown in formula (VIII);

(3) Dissolve 1 mmol of the compound shown in formula (VIII) in 10 mL of anhydrous dichloromethane, add 1 mmol of p-toluenesulfonyl chloride and 10 mmol of triethylamine, react at room temperature for 12 hours, then remove the solvent by rotary evaporation, and separate by column chromatography to obtain Compound (yellow solid) shown in formula (IX);

(4) Dissolve 1 mmol of the compound represented by formula (IX) in 10 mL of anhydrous dichloromethane, add 4 mmol of 3,4-dihydropyran and 1.0 g of pyridine p-toluenesulfonate (PPTS), and stir the reaction at 50°C After 12 hours, after the reaction was finished, the solvent was removed by rotary evaporation, and the compound (oily liquid) shown in the column chromatography was separated to obtain the formula (X);

(5) Dissolve 1-5 mg of compound (V) or (VII) or (X) in 1 mL of anhydrous acetonitrile, _and add it to a _{5-30 mCi} ^{18 F-} In the reaction tube, label at 100°C for 5 minutes; for compounds (VII) and (X), add 100 μL of 1M HCl, continue to react at 100°C for 5 minutes, then add saturated NaHCO ₃ solution to neutralize; finally pass through C18 Reversed-phase column (Sep-pak), washed with water to remove salt and remaining ¹⁸ F ^- , and then rinsed with acetonitrile to obtain the final product, after drying with N ₂ , separated by HPLC to obtain the formula (V ), the compound shown in formula (VI) or formula (VII).

Derivatives of the compound represented by formula (I), such as pharmaceutically acceptable salts, esters or amides or prodrugs, all belong to the protection scope of the present invention.

The present invention also provides a diagnostic or detection reagent for neurofibrillary tangle disease caused by Tau protein deposition, the active ingredient of which is the compound represented by formula (I), and/or its derivatives.

These diseases include, but are not limited to, Alzheimer's disease, frontotemporal lobar degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, or Pick's disease, among others.

The present invention further provides the use of the compound represented by formula (I) and/or its derivatives in the preparation of nuclear medicine imaging agents (such as dual-functional imaging agents) or optical imaging agents.

Compared with the prior art, the present invention has the following advantages:

The compound of formula (I) provided by the present invention can be directly used as a fluorescent probe for detecting neurofibrillary tangles in vivo or in tissue samples. When 1 μM ¹⁹ F compound solution is used for staining tissue sections, the staining time is fast and effective (within 30 seconds) effectively stains neurofibrillary tangles in sections without the need for washing), and when used for nuclear medicine imaging, label them with an appropriate radioisotope. Such compounds are particularly useful in the diagnosis of patients with neurofibrillary tangles (Tau protein deposits), including Alzheimer's disease.

Description of drawings

Fig. 1 is a schematic diagram of the synthetic process of the compound of Example 1-21 of the present invention; wherein the reaction reagents and conditions involved are: (a) dimethyl sulfoxide, room temperature, 10 hours; (b) hydrazine hydrate, palladium carbon, methanol, 90°C, reflux for 2 hours; (c) paraformaldehyde, sodium methoxide, sodium borohydride, methanol, 90°C, reflux for 5 hours; (d) (R)-glycidyl-3-nitrobenzenesulfonate, Cesium fluoride, nitrogen nitrogen dimethylformamide, 65℃, 6 hours; (e) tetrabutylammonium fluoride, anhydrous tetrahydrofuran, reflux for 6 hours; (f) (R)-(-)-p-methyl Benzenesulfonic acid-2,2-dimethyl-1,3-dioxolanyl-4-methyl ester, cesium fluoride, nitrogen nitrogen dimethylformamide, 65°C, 6 hours; (g) hydrochloric acid ( 1M), 90°C, reflux for 30 minutes, sodium bicarbonate; (h) tert-butyldimethylsilyl chloride, imidazole, acetonitrile, room temperature, 12 hours; (i) di-tert-butyl dicarbonate, anhydrous tetrahydrofuran, 90 ℃, reflux for 48 hours; (j) tetrabutylammonium fluoride, anhydrous tetrahydrofuran, reflux for 3 hours; (k) p-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature, 6 hours; (l) 3, 4-Dihydro-2H-pyran, pyridinium 4-methylbenzenesulfonate (PPTS), dichloromethane, room temperature, 5 hours; (m)(1) ¹⁸ F-ion, 4,7,13,21, 24-hexaoxa-1,10-diazabicyclo[8,8,8]-hexacane, potassium carbonate, 100°C, 6 minutes, (2) 1M hydrochloric acid, 100°C, 5 minutes; (n )(S)-glycidyl-3-nitrobenzenesulfonate, cesium fluoride, nitrogen dimethylformamide, 65℃, 6 hours; (o)(S)-(-)-p-methyl Benzenesulfonic acid-2,2-dimethyl-1,3-dioxolanyl-4-methyl ester, cesium fluoride, nitrogen nitrogen dimethylformamide, 65°C, 6 hours.

Figure 2 is a schematic diagram of the synthesis process of the compounds of Examples 22-48 of the present invention; the reaction reagents and conditions involved are: (a) nitrogen nitrogen dimethylformamide, potassium carbonate, 150 ° C, reflux for 12h; (b) ( 1) hydrogen, palladium carbon, methanol, room temperature, 6 hours; (2) dimethyl sulfoxide, room temperature, 10 hours; (c) (R)-glycidyl-3-nitrobenzenesulfonate, fluorinated Cesium, nitrogen nitrogen dimethylformamide, 65℃, 6 hours; (d) Tetrabutylammonium fluoride, anhydrous tetrahydrofuran, reflux for 6 hours; (e) (R)-(-)-p-methylbenzenesulfonate Acid-2,2-dimethyl-1,3-dioxolanyl-4-methyl ester, cesium fluoride, nitrogen nitrogen dimethylformamide, 65°C, 6 hours; (f) hydrochloric acid (1M) , 90°C, reflux for 30 minutes, sodium bicarbonate; (g) p-toluenesulfonyl chloride, triethylamine, dichloromethane, room temperature, 6 hours; (h) 3,4-dihydro-2H-pyran, 4- Pyridinium toluenesulfonate (PPTS), dichloromethane, room temperature, 5 hours; (i) (1) ¹⁸ F-ion, 4,7,13,21,24-hexaoxa-1,10-diazepine Heterobicyclo[8,8,8]-hexacane, potassium carbonate, 100°C, 6 minutes, (2) 1M hydrochloric acid, 100°C, 5 minutes; (j) (S)-glycidyl-3-nitrate phenyl sulfonate, cesium fluoride, nitrogen nitrogen dimethylformamide, 65 ℃, 6 hours; (k) (S)-(-)-p-toluenesulfonic acid-2,2-dimethyl- 1,3-dioxolanyl-4-methyl ester, cesium fluoride, nitrogen nitrogen dimethylformamide, 65°C, 6 hours.

Figure 3 is a schematic diagram of the synthesis process of the compounds of Examples 49-63 of the present invention; the reaction reagents and conditions involved are: (a) (4R,5R)-4,5-bis(tosyloxymethyl)-2, 2-Dimethyl-1,3-dioxolane, cesium fluoride, nitrogen nitrogen dimethylformamide, 65 ° C, 6 hours; (b) tetrabutylammonium fluoride, anhydrous tetrahydrofuran, reflux for 6 hours ; (c) Hydrochloric acid (1M), 90°C, reflux for 30 minutes, sodium bicarbonate; (d) (4S,5S)-4,5-di(tosyloxymethyl)-2,2-dimethyl -1,3-dioxolane, cesium fluoride, nitrogen nitrogen dimethylformamide, 65 ° C, 6 hours; (e) (1) ¹⁸ F-ion, 4,7,13,21,24- Hexaoxa-1,10-diazabicyclo[8,8,8]-hexacane, potassium carbonate, 100°C, 6 minutes, (2) 1M hydrochloric acid, 100°C, 5 minutes.

Figure 4 is a schematic diagram of the synthesis process of the compounds of Examples 64-87 of the present invention; the reaction reagents and conditions involved are: (a) dimethyl sulfoxide, room temperature, 10 hours; (b) 1-bromo-2-fluoroethyl Alkanes, potassium carbonate, nitrogen nitrogen dimethylformamide, 90°C; (c) 10% palladium on carbon, hydrazine hydrate, methanol, 80°C; (d) methyl iodide, acetone, 40°C, water.

Fig. 5 is the fluorescence staining result of S-5, R-5, S-16, R-16, S-23 and R-23 probe in AD patient's brain tissue section in Example 89 of the present invention respectively; GFP channel is based on The staining result of the compound described in the invention, the RFP channel is the staining result of the Aβ plaque-specific probe.

Figure 6 is the autoradiographic results (A, C and E) of S-[ ^18F ]23 in the brain tissue sections of AD patients in Example 90 of the present invention, and the results are confirmed by the staining results of Thioflavin-S (B, D and F). C and D are magnified images.

Detailed ways

The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are all commercially available products.

Embodiment 1: synthetic intermediate 1

The compound 4-nitro-o-phenylenediamine (3.1g, 20.0mmol) was dissolved in a 250mL round bottom flask with 8mL DMSO, and then 2-bromo-4'-hydroxyacetophenone (4.3g, 20.0mmol) was slowly Add it into the reaction bottle and stir at room temperature for 10 hours. After the reaction is complete, a yellow solid precipitates out. The precipitated product is suction filtered and washed with 100 mL of deionized water and 50 mL of methanol. The solid obtained by suction filtration can be obtained after drying 3.1 g of intermediate 1, yield 58.0%, the structure is as follows: MS: m/z calcdfor C ₁₄ H ₁₀ N ₃ O ₃ 268.1; found, M+H+.

Embodiment 2: synthetic intermediate 2

Intermediate 1 (4.3g, 16.1mmol) and palladium carbon (0.8g, 16.1mmol) were dissolved in a 250mL round bottom flask with 150mL of methanol, and hydrazine hydrate (5.1g, 48.0mmol ), and then heated to reflux with a 90°C oil bath for 1 hour. After the reaction was completed, the palladium carbon was removed by suction filtration while it was hot, and the methanol was distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized with methanol to obtain 3.4g of white intermediate 2 , yield 89.0%, the structure is as follows: MS: m/z calcd for C ₁₄ H ₁₂ N ₃ O238.1; found, M+H+.

Embodiment 3: synthetic intermediate 3

Intermediate 2 (1.2g, 5.0mmol) was dissolved in 50mL of methanol, then paraformaldehyde (0.6g, 20.0mmol) and sodium methoxide (2.0mL, 10.0mmol) were added successively, and heated under reflux in an oil bath at 90°C for 2 hours. After the reaction solution was cooled, sodium borohydride (4.3g, 16.1mmol) was slowly added, and continued to reflux at 90°C for 3 hours. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with 1M HCl, and methanol was distilled off under reduced pressure. Add 100mL of deionized water into the round bottom flask, sonicate for half an hour, filter with suction, and dry the obtained compound to obtain 1.2g of intermediate 3 with a yield of 95.5%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.78(s,1H),9.16(s,1H),8.03(d,J=8.2Hz,2H),7.71(d,J=9.1Hz,1H),7.23(d,J=9.1Hz ,1H),6.89(d,J=8.3Hz,2H),6.71(s,1H),6.59(d,J=4.4Hz,1H),2.81(d,J=4.4Hz,3H).MS:m /z calcd for C ₁₅ H ₁₄ N ₃ O 252.1; found 252.2, M+H+.

Embodiment 4: synthetic intermediate (R)-4

Intermediate 3 (0.5g, 2.0mmol) and (R)-glycidyl-3-nitrobenzenesulfonate (0.5g, 2.5mmol) were dissolved in 5mL DMF, cesium fluoride (0.9 g, 6.0mmol), reacted at 65°C for 6 hours. After the reaction is finished, wait for the reaction liquid to cool to room temperature, then add 100 mL of deionized water, a yellow product is precipitated, place it in ultrasonic for 30 minutes, and filter with suction to obtain a yellow crude product. After the crude product was dried, 365.1 mg of a light yellow solid was obtained by column chromatography with a developer whose volume ratio was petroleum ether: ethyl acetate = 2:1. The yield is 59.4%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.05(s, 1H), 8.13–7.98(m, 2H), 7.89(d, J=9.1Hz, 1H), 7.17(dd ,J=9.1,2.4Hz,1H),7.12–7.01(m,2H),4.32(dd,J=11.0,3.1Hz,1H),4.04(dd,J=11.0,5.7Hz,1H),3.40( ddd, J＝7.0, 5.7, 2.9Hz, 1H), 3.02(s, 3H), 2.98–2.85(m, 1H), 2.80(dd, J＝4.9, 2.6Hz, 1H).MS: m/z calcdfor C ₁₈ H ₁₈ N ₃ O ₂ 308.1; found 308.3, M+H+.

Embodiment 5: synthetic intermediate (S)-4

Intermediate (S)-4 was prepared from intermediate 3 according to the method for synthesizing intermediate (R)-4, and 378.4 mg of light yellow solid was obtained. The yield is 61.6%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(s, 1H), 8.14–7.99(m, 2H), 7.88(d, J=9.1Hz, 1H), 7.15(dd ,J=9.1,2.5Hz,1H),7.07(d,J=8.9Hz,2H),7.01(d,J=2.2Hz,1H),4.31(dd,J=11.0,3.1Hz,1H),4.04 (dd,J=11.0,5.7Hz,1H),3.40(ddd,J=7.0,5.8,2.9Hz,1H),3.01(s,3H),2.98–2.91(m,1H),2.80(dd,J =4.9, 2.6Hz, 1H). MS: m/zcalcd for C ₁₈ H ₁₈ N ₃ O ₂ 308.1; found 308.3, M+H+.

Embodiment 6: synthetic intermediate (S)-5

Intermediate (R)-4 (283.4mg, 0.9mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, tetrabutylammonium fluoride (10.0mL, 10.0mmol) was gradually added dropwise, and then heated to reflux in an oil bath at 90°C for reaction 6 Hours, after the reaction was completed, tetrahydrofuran was distilled off under reduced pressure, and 230.6 mg of a yellow solid was obtained by column chromatography with a developer with a volume ratio of petroleum ether: ethyl acetate = 2:1. The yield is 76.2%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.08(s, 1H), 8.08(d, J=8.0Hz, 2H), 7.88(d, J=9.1Hz, 1H), 7.15(dd, J=9.1, 2.6Hz, 1H), 7.07(d, J=8.9Hz, 2H), 7.01(d, J=2.1Hz, 1H), 4.64(dt, J=47.0, 4.6Hz, 2H ), 4.38–4.26(m,1H), 4.21–4.12(m,1H), 3.01(s,3H). HRMS: m/zcalcd for C ₁₈ H ₁₉ FN ₃ O ₂ 328.1461; found 328.1456, M+H+.

Embodiment 7: synthetic intermediate (R)-5

Intermediate (R)-5 was prepared from intermediate (S)-4 according to the method for synthesizing intermediate (S)-5, and 183.4 mg of a yellow solid was obtained. The yield is 68.2%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(s, 1H), 8.08(d, J=8.5Hz, 2H), 7.89(d, J=8.9Hz, 1H), 7.16(d, J=9.3Hz, 1H), 7.10–6.97(m, 3H), 4.63(dt, J=47.1, 5.2Hz, 2H), 4.31(d, J=17.9Hz, 1H), 4.17(d ,J=4.9Hz,2H),3.02(s,3H).HRMS:m/z calcdfor C ₁₈ H ₁₉ FN ₃ O ₂ 328.1461; found 328.1456,M+H+.

Embodiment 8: Synthesis of intermediate (R)-6

Intermediate 3 (756.4mg, 3.0mmol) was mixed with (R)-(-)-p-toluenesulfonic acid-2,2-dimethyl-1,3-dioxolanyl-4-methyl ester ( 1.0g, 3.6mmol) was dissolved in 5mL DMF, cesium fluoride (1.4g, 9.0mmol) was added under stirring, and reacted at 65°C for 6 hours. After the reaction is finished, wait for the reaction liquid to cool to room temperature and then add 100mL of deionized water, a yellow product is precipitated, put it in ultrasonic for 30 minutes, and after suction filtration, dissolve the obtained solid in dichloromethane and dry it with anhydrous Na ₂ SO ₄ , using a developer column chromatography with a volume ratio of petroleum ether: ethyl acetate = 2:1 to obtain 1.0 g of a light yellow solid with a yield of 95.2%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.08( s,1H),8.06(d,J=7.6Hz,2H),7.84(d,J=9.0Hz,1H),7.12(d,J=9.2Hz,1H),7.09–7.02(m,2H), 6.98(s,1H),4.58–4.46(m,1H),4.18(dd,J=15.2,8.6Hz,1H),4.14(dd,J=9.5,5.5Hz,1H),4.02(dd,J= 9.4,5.9Hz,1H),3.94(dd,J＝8.4,5.9Hz,1H),2.99(s,3H),1.48(s,3H),1.42(s,3H).MS:m/z calcd for C ₂₁ H ₂₄ N ₃ O ₃ 366.2; found 366.4, M+H+.

Embodiment 9: synthetic intermediate (S)-6

Intermediate (S)-6 was prepared from intermediate 3 according to the method for synthesizing intermediate (R)-6, and 1.0 g of light yellow solid was obtained with a yield of 94.5%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9 .06(s,1H),8.19–7.95(m,2H),7.82(d,J=9.0Hz,1H),7.15(d,J=9.2Hz,1H),7.04(d,J=8.7Hz, 2H), 6.98(s, 1H), 4.67–4.43(m, 1H), 4.19(dd, J＝8.5, 6.4Hz, 1H), 4.11(d, J＝5.4Hz, 1H), 4.07–3.97(m ,1H),3.93(dd,J＝8.5,5.9Hz,1H),2.98(s,3H),1.48(s,3H),1.42(s,3H).MS:m/z calcd for C ₂₁ H ₂₄ N ₃ O ₃ 366.2; found 366.3, M+H+.

Embodiment 10: Synthesis of Intermediate (R)-7

Intermediate (R)-6 (1.0g, 2.8mmol) was dissolved in 10mL of tetrahydrofuran, and 1M hydrochloric acid was slowly added dropwise under stirring. After the dropwise addition, the mixture was heated to reflux in an oil bath at 90°C for half an hour. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure, the pH of the reaction solution was adjusted to neutral and placed in ultrasound for 30 minutes to precipitate the product, which was filtered by suction and dried to obtain 910.2 mg of a light yellow solid with a yield of 99.9%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.21(s, 1H), 8.13(d, J=8.6Hz, 2H), 7.73(d, J=9.1Hz, 1H), 7.24(dd, J= 9.1,1.7Hz,1H),7.07(d,J=8.6Hz,2H),6.72(s,1H),6.62(d,J=4.8Hz,1H),4.96(d,J=4.9Hz,1H) ,4.67(t,J=5.4Hz,1H),4.07(dd,J=9.8,4.0Hz,1H),3.93(dd,J=9.7,6.2Hz,1H),3.87–3.66(m,1H), 3.46(t, J=5.3Hz, 2H), 2.81(d, J=4.8Hz, 3H). MS: m/z calcd for C ₁₈ H ₂₀ N ₃ O ₃ 326.1; found 326.4, M+H+.

Embodiment 11: Synthesis of Intermediate (S)-7

Intermediate (S)-7 was prepared from intermediate (S)-6 according to the method for synthesizing intermediate (R)-7, and 1.1 g of light yellow solid was obtained with a yield of 99.7%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.21(s,1H),8.13(d,J=8.8Hz,2H),7.73(d,J=9.1Hz,1H),7.24(dd,J=9.1,2.5Hz,1H ), 7.07(d, J=8.9Hz, 2H), 6.72(d, J=2.4Hz, 1H), 6.62(q, J=4.7Hz, 1H), 4.96(d, J=5.2Hz, 1H), 4.66(t, J=5.7Hz, 1H), 4.07(dd, J=9.9, 4.1Hz, 1H), 3.93(dd, J=9.9, 6.2Hz, 1H), 3.81(td, J=12.2, 5.6Hz ,1H),3.45(t,J=5.7Hz,2H),2.81(d,J=4.9Hz,3H).MS:m/z calcd for C ₁₈ H ₂₀ N ₃ O ₃ 326.1; found326.3,M +H+.

Embodiment 12: Synthesis of intermediate (S)-8

Intermediate (R)-7 (0.6g, 2.0mmol) and tert-butyldimethylsilyl chloride (1.8g, 12.0mmol) and imidazole (1.1g, 16.0mmol) were dissolved in 100mL acetonitrile, stirred at room temperature for 12 After completion of the reaction, acetonitrile was removed by distillation under reduced pressure, white powder was precipitated after continuing to add dichloromethane, and the lower floor filtrate was obtained after suction filtration and dichloromethane was removed by distillation under reduced pressure, with a volume ratio of sherwood oil: ethyl acetate=1: 1 was separated by developer column chromatography to obtain 1.0 g of a yellow solid with a yield of 93.7%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(s, 1H), 8.05(d, J=8.6Hz, 2H ),7.88(d,J=9.0Hz,1H),7.15(d,J=9.1Hz,1H),7.09–6.89(m,3H),4.18(dd,J=9.5,3.3Hz,1H),4.14 –4.02(m,1H),3.95(dd,J＝9.4,6.8Hz,1H),3.67–3.65(dd,J＝5.6,2.9Hz,2H),3.01(s,3H),0.91(d,J ＝1.5Hz, 18H), 0.12(d, J＝2.6Hz, 6H), 0.08(s, 6H).MS: m/z calcd for C ₃₀ H ₄₈ N ₃ O ₃ Si ₂ 554.3; found 554.7, M+ H+.

Embodiment 13: Synthesis of Intermediate (R)-8

Intermediate (R)-8 was prepared from intermediate (S)-7 according to the method for synthesizing intermediate (S)-8, and 1.0 g of light yellow solid was obtained with a yield of 87.2%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.07(s,1H),8.05(d,J=8.9Hz,2H),7.89(d,J=9.1Hz,1H),7.15(dd,J=9.1,2.5Hz,1H), 7.05(d, J=8.9Hz, 3H), 4.19(dd, J=9.5, 3.6Hz, 1H), 4.09(dt, J=10.2, 6.6Hz, 1H), 3.95(dd, J=9.5, 6.6Hz ,1H),3.67(dd,J=5.9,3.2Hz,2H),3.02(s,3H),0.91(d,J=2.3Hz,18H),0.12(d,J=3.0Hz,6H),0.08 (d, J＝0.7Hz, 6H). MS: m/z calcd for C ₃₀ H ₄₈ N ₃ O ₃ Si ₂ 554.3; found 554.6, M+H+.

Embodiment 14: Synthesis of intermediate (S)-9

Intermediate (S)-8 (1.0g, 2.0mmol) and di-tert-butyl dicarbonate (4.4g, 20.0mmol) were dissolved in 30mL of tetrahydrofuran, and heated to reflux in an oil bath at 90°C for 48 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and separated by column chromatography with a developing agent with a volume ratio of petroleum ether:ethyl acetate=5:1 to obtain 1.0 g of a light yellow solid with a yield of 80.6%. The structure is as follows: ¹ HNMR (400MHz ,CDCl ₃ )δ9.25(s,1H),8.16(d,J＝8.5Hz,2H),8.10(d,J＝9.1Hz,1H),7.99–7.64(m,2H),7.09(d, J＝8.5Hz, 2H), 4.21(dd, J＝9.4, 3.1Hz, 1H), 4.10(s, 1H), 3.97(dd, J＝8.9, 7.2Hz, 1H), 3.76–3.46(m, 2H ),3.44(s,3H),1.51(s,9H),0.91(d,J＝1.5Hz,18H),0.12(d,J＝3.1Hz,6H),0.08(s,6H).MS:m /z calcd for C ₃₅ H ₅₆ N ₃ O ₅ Si ₂ 654.4; found 654.5, M+H+.

Embodiment 15: Synthesis of Intermediate (R)-9

Intermediate (R)-9 was prepared from intermediate (R)-8 according to the method for synthesizing intermediate (S)-9, and 1.2 g of light yellow solid was obtained with a yield of 89.7%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.25(s,1H),8.17–8.10(m,3H),7.92–7.87(m,2H),7.09(d,J＝8.7Hz,1H),4.21(dd,J＝9.6, 3.4Hz, 1H), 4.15–4.05(m, 1H), 3.97(dd, J＝9.5, 6.7Hz, 1H), 3.67(t, J＝5.6Hz, 2H), 3.44(s, 3H), 1.51( s,9H),0.91(d,J=2.5Hz,18H),0.12(d,J=3.4Hz,6H),0.08(d,J=0.7Hz,6H).MS:m/z calcd for C ₃₅ H ₅₆ N ₃ O ₅ Si ₂ 654.4; found 654.6, M+H+.

Embodiment 16: Synthesis of Intermediate (R)-10

Intermediate (S)-9 (1.0g, 1.5mmol) and tetrabutylammonium fluoride (4.5mL, 4.5mmol) were dissolved in 10mL of tetrahydrofuran, and heated to reflux in an oil bath at 90°C for 3 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and 0.5 g of a yellow solid was obtained by column chromatography with a volume ratio of petroleum ether:ethyl acetate=1:4, and the yield was 73.6%. The structure was as follows: ¹ H NMR (400MHz ,CDCl ₃ )δ9.25(s,1H),8.17(d,J＝7.6Hz,2H),8.09(dd,J＝9.0,3.8Hz,1H),7.91(s,2H),7.10(d, J＝8.1Hz, 2H), 4.21–4.10(m, 3H), 3.89(dd, J＝11.4, 3.5Hz, 1H), 3.80(dd, J＝11.4, 5.0Hz, 1H), 3.44(s, 3H ), 1.51(s,9H).MS: m/z calcd for C ₂₃ H ₂₈ N ₃ O ₅ 426.2; found 426.3, M+H+.

Embodiment 17: Synthesis of Intermediate (S)-10

Intermediate (S)-10 was prepared from intermediate (R)-9 according to the method for synthesizing intermediate (R)-10, and 0.6 g of a yellow solid was obtained with a yield of 91.1%. The structure is as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ9.25(s,1H),8.17(d,J＝8.9Hz,2H),8.11(d,J＝9.0Hz,1H),7.99–7.84(m,2H),7.10(d,J＝ 8.9Hz, 2H), 4.16(d, J=2.8Hz, 3H), 3.89(dd, J=11.4, 3.6Hz, 1H), 3.80(dd, J=11.4, 5.0Hz, 1H), 3.45(s, 3H), 1.51(s, 9H). MS: m/z calcd for C ₂₃ H ₂₈ N ₃ O ₅ 426.2; found 426.4, M+H+.

Embodiment 18: Synthesis of Intermediate (S)-11

Intermediate (R)-10 (0.4g, 1.0mmol) was dissolved in dichloromethane and p-toluenesulfonyl chloride (0.2g, 1.0mmol) was slowly added under stirring, and then 5 mL of triethylamine was continued to be slowly added dropwise, The reaction was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the volume ratio of petroleum ether:ethyl acetate=1:1 was used for column chromatography to obtain 163.7 mg of a yellow oily compound with a yield of 27.8%. The structure is as follows: ¹ H NMR ( 400MHz, CDCl ₃ )δ9.25(s,1H),8.16(d,J=8.7Hz,2H),8.09(d,J=9.0Hz,1H),7.88(d,J=15.8Hz,2H), 7.81(d,J=8.3Hz,2H),7.34(d,J=8.2Hz,2H),7.02(d,J=8.7Hz,2H),4.40–4.18(m,3H),4.10(d,J =4.5Hz, 2H), 3.44(s, 3H), 2.43(s, 3H), 1.51(s, 9H). MS: m/z calcd for C ₃₀ H ₃₄ N ₃ O ₇ S 580.2; found 580.4, M +H+.

Embodiment 19: Synthesis of Intermediate (R)-11

Intermediate (R)-11 was prepared from intermediate (S)-10 according to the method for synthesizing intermediate (S)-11, and 215.3 mg of a yellow oily compound was obtained with a yield of 32.9%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.25(s,1H),8.16(d,J=7.6Hz,2H),8.10(s,1H),7.91(s,2H),7.82(d,J=8.3Hz,2H), 7.34(d, J=8.4Hz, 2H), 7.02(d, J=7.6Hz, 2H), 4.48–4.20(m, 3H), 4.10(d, J=4.4Hz, 2H), 3.45(s, 3H ), 2.43(s,3H), 1.51(s,9H).MS: m/z calcd for C ₃₀ H ₃₄ N ₃ O ₇ S 580.2; found 580.6, M+H+.

Embodiment 20: Synthesis of Intermediate (S)-12

Intermediate (S)-11 (60.4mg, 0.1mmol), dihydropyran (80.5mg, 1.0mmol) and pyridinium 4-methylbenzenesulfonate (52.1mg, 0.2mmol) were dissolved in anhydrous dichloro in methane and stirred at room temperature for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and separated by column chromatography using a developer with a volume ratio of petroleum ether: ethyl acetate = 2:1 to obtain 60.5 mg of a light yellow oily compound with a yield of 90.4%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.25(s,1H),8.16–8.10(m,3H),7.90(d,J＝12.6Hz,2H),7.79(dd,J＝8.2,5.8Hz,2H), 7.30(d,J=7.1Hz,2H),7.08–6.93(m,2H),4.36–4.17(m,3H),4.13–4.06(m,1H),3.92–3.80(m,2H),3.51– 3.49(m,2H)3.45(d,J=1.3Hz,3H),2.41(s,3H),1.82–1.67(m,2H),1.53–1.51(m,4H),1.51(d,J=0.8 Hz,9H).MS:m/z calcd for C ₃₅ H ₄₂ N ₃ O ₈ S 664.3; found 664.6,M+H+.

Example 21: Synthesis of Intermediate (R)-12

According to the method for synthesizing intermediate (2S)-12, intermediate (2R)-12 was prepared from intermediate (R)-11 to obtain 0.1 g of light yellow oily compound with a yield of 72.4%. The structure is as follows: ¹ H NMR (400MHz , CDCl ₃ ) δ9.25(s, 1H), 8.35–8.07(m, 3H), 7.93(d, J=11.6Hz, 2H), 7.80(dd, J=11.5, 8.0Hz, 2H), 7.32( dd,J＝14.0,8.1Hz,2H),7.08–6.86(m,2H),4.38–3.99(m,5H),3.90–3.70(m,2H),3.49(s,1H),3.45(s, 3H), 2.41(s,3H), 1.78–1.70(m,4H), 1.52(s,2H), 1.52(s,9H). MS: m/z calcd for C ₃₅ H ₄₂ N ₃ O ₈ S664. 3; found 664.6, M+H+.

The schematic diagram of the synthesis process of the compounds of the above Examples 1-21 is shown in FIG. 1 .

Example 22: Synthesis of Intermediate 13

Dissolve the intermediate 5-chloro-2-nitroaniline (12.5g, 72.5mmol) and 50mL dimethylamine in 50mL dimethylformamide, slowly add potassium carbonate under stirring, and heat to reflux in an oil bath at 90°C for 12 hours . After the reaction was completed, after the reaction was cooled to room temperature, 200 mL of cooled deionized water was added and placed in ultrasonic for half an hour, the solid was collected by suction filtration, and dried to obtain 8.0 g of a yellow solid with a yield of 60.9%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.02(d, J=9.7Hz, 1H), 6.15(dd, J=9.7, 2.6Hz, 1H), 5.78(d, J=2.6Hz, 1H), 3.05( s,6H).MS:m/z calcd for C ₈ H ₁₂ N ₃ O ₂ 182.1; found 182.2,M+H+.

Example 23: Synthesis of Intermediate 14

Intermediate 13 (3.6g, 20.0mmol) and palladium carbon (1.0g, 20.0mmol) were dissolved in 130mL of methanol, hydrogen gas was continuously passed into the reaction system for 6 hours under stirring at room temperature, palladium carbon was removed by suction filtration, and the After the solvent was distilled off, 5 mL of dimethyl sulfoxide was added, and then 2-bromo-4'-hydroxyacetophenone (4.3 g, 20.0 mmol ), after the dropwise addition, the water bath was removed, and the reaction was stirred at room temperature for 10 hours. After the reaction was completed, it was extracted 10 times with 50 mL of ethyl acetate. The organic phase was dried with anhydrous magnesium sulfate and separated by column chromatography with a developing agent whose volume ratio was methanol:dichloromethane=5:1 to obtain 2.0 g of a yellow solid, which was a mixture of Intermediate 14 and Intermediate 21. Heat the mixture of intermediate 14 and intermediate 21 and dihydrate oxalic acid in a ratio of 1:2 and dissolve it in ethanol with a smaller volume as much as possible to obtain a purple-red solution. After cooling, the purple-red oxalic acid of intermediate 21 is first precipitated Salt crystals, filtered by suction, washed and added a small amount of ammonia water to obtain a yellow solid, filtered by suction, washed and dried to obtain intermediate 21. After adding a large amount of petroleum ether to the mother liquor, the dark red oxalate crystals of intermediate 14 were precipitated, filtered with suction, washed, and then added a small amount of ammonia water to obtain a yellow solid, filtered with suction, washed and dried to obtain intermediate 14. The yield is 30.1%, and the structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.05(s, 1H), 8.12(d, J=8.4Hz, 2H), 7.80(d, J=9.3Hz, 1H ), 7.41(dd, J＝9.2, 1.9Hz, 1H), 6.93(dd, J＝12.6, 5.1Hz, 3H), 3.08(s, 6H).MS: m/z calcd for C ₁₆ H ₁₆ N ₃ O 266.1; found 266.2, M+H+.

Example 24: Synthesis of Intermediate (R)-15

Intermediate (R)-15 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-4 to obtain 536.1 mg of light yellow solid. The yield is 83.4%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.12(d, J=8.8Hz, 2H), 7.90(d, J=9.3Hz, 1H), 7.33(dd, J=9.3, 2.8Hz, 1H), 7.15(s, 1H), 7.08(dd, J=6.9, 4.9Hz, 2H), 4.32(dd, J=11.0, 3.1Hz, 1H), 4.04 (dd,J=11.0,5.7Hz,1H),3.44–3.36(m,1H),3.15(s,6H),2.97–2.91(m,1H),2.80(dd,J=4.9,2.6Hz,1H ).MS: m/z calcd for C ₁₉ H ₂₀ N ₃ O ₂ 322.1; found 322.2, M+H+.

Example 25: Synthesis of intermediate (S)-15

Intermediate (S)-15 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-4, and 581.2 mg of light yellow solid was obtained. The yield is 90.7%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.12(d, J=8.8Hz, 2H), 7.89(d, J=9.3Hz, 1H), 7.33(dd,J=9.3,2.8Hz,1H),7.13(s,1H),7.10–7.03(m,2H),4.32(dd,J=11.0,3.1Hz,1H),4.04(dd,J= 11.0,5.7Hz,1H),3.44–3.36(m,1H),3.15(s,6H),2.95–2.88(m,1H),2.80(dd,J＝4.9,2.6Hz,1H).MS:m /z calcd for C ₁₉ H ₂₀ N ₃ O ₂ 322.1; found 322.3, M+H+.

Example 26: Synthesis of Intermediate (S)-16

Intermediate (S)-16 was prepared from intermediate (R)-15 according to the method for synthesizing intermediate (S)-5, and 196.5 mg of a yellow solid was obtained. The yield is 84.6%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.14(d, J=8.8Hz, 2H), 7.92(d, J=9.3Hz, 1H), 7.35(dd, J=9.3, 2.8Hz, 1H), 7.20(s, 1H), 7.08(d, J=8.9Hz, 2H), 4.63(dt, J=47.0, 4.7Hz, 2H), 4.33-4.28 (m,1H),4.18–4.16(dd,J＝4.6,2.6Hz,2H),3.17(s,6H).HRMS:m/z calcd for C ₁₉ H ₂₁ FN ₃ O ₂ 342.1612; found 342.1615,M +H+.

Example 27: Synthesis of Intermediate (R)-16

Intermediate (R)-16 was prepared from intermediate (S)-15 according to the method for synthesizing intermediate (S)-5 to obtain 158.3 mg of a yellow solid. The yield is 86.7%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.18(d, J=8.2Hz, 2H), 7.94(d, J=9.4Hz, 1H), 7.37(dd, J=9.4, 2.4Hz, 1H), 7.10(d, J=8.9Hz, 2H), 4.63(dt, J=47.1, 5.0Hz, 2H), 4.34-4.29(m, 1H), 4.18 -4.17(m,2H),3.19(s,6H).HRMS:m/z calcdfor C ₁₉ H ₂₁ FN ₃ O ₂ 342.1612; found 342.1609,M+H+.

Example 28: Synthesis of Intermediate (R)-17

Intermediate (R)-17 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-6, and 756.0 mg of light yellow solid was obtained with a yield of 99.6%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8 .93(s,1H),8.13(d,J=3.2Hz,2H),7.92(s,1H),7.35(s,1H),7.18(s,1H),7.08(s,2H),4.69– 4.40(m,1H),4.20(dd,J=8.5,6.4Hz,1H),4.14(dd,J=9.5,5.5Hz,1H),4.05(d,J=5.8Hz,1H),3.94(dd ,J=8.5,5.9Hz,1H),3.17(s,6H),1.48(s,3H),1.32(s,3H).MS: m/z calcd for C ₂ 2H ₂₆ N ₃ O ₃ 380.2; found 380.4,M+H+.

Example 29: Synthesis of Intermediate (S)-17

Intermediate (S)-17 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-6, and 630.2 mg of light yellow solid was obtained with a yield of 83.4%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8 .93(s,1H),8.13(d,J=8.7Hz,2H),7.92(d,J=9.3Hz,1H),7.35(dd,J=9.4,2.4Hz,1H),7.09(d, J＝8.8Hz, 2H), 4.51(dd, J＝11.8, 5.9Hz, 1H), 4.20(dd, J＝8.5, 6.5Hz, 1H), 4.14(dd, J＝9.6, 5.5Hz, 1H), 4.04(dd,J=9.5,5.8Hz,1H),3.93(dd,J=8.5,5.9Hz,1H),3.18(s,6H),1.48(s,3H),1.42(s,3H).MS : m/z calcd for C ₂₂ H ₂₆ N _3O3 380.2; found 380.4, M+H+.

Example 30: Synthesis of Intermediate (R)-18

Intermediate (R)-18 was prepared from intermediate (R)-17 according to the method for synthesizing intermediate (R)-7, and 676.3 mg of light yellow solid was obtained with a yield of 98.4%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s,1H),8.22(d,J=8.5Hz,2H),7.82(d,J=9.3Hz,1H),7.43(dd,J=9.3,2.0Hz,1H ), 7.09(d, J=8.5Hz, 2H), 6.96(d, J=1.9Hz, 1H), 4.98(d, J=5.0Hz, 1H), 4.69(t, J=5.6Hz, 1H), 4.08(dd, J=9.8, 4.0Hz, 1H), 3.94(dd, J=9.8, 6.2Hz, 1H), 3.82(dd, J=10.1, 5.2Hz, 1H), 3.46(t, J=5.6Hz ,2H), 3.09(s,6H).MS: m/z calcd for C ₁₉ H ₂₂ N ₃ O ₃ 340.2; found 340.4, M+H+.

Example 31: Synthesis of Intermediate (S)-18

Intermediate (S)-18 was prepared from intermediate (S)-17 according to the method for synthesizing intermediate (R)-7, and 500.4 mg of light yellow solid was obtained with a yield of 88.5%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.28(s,1H),8.19(dd,J=19.8,8.5Hz,2H),7.84(dd,J=14.4,9.3Hz,1H),7.47(dd,J=26.6, 9.2Hz, 1H), 7.09(t, J=7.7Hz, 2H), 6.97(s, 1H), 4.98(s, 1H), 4.68(s, 2H), 4.09–4.05(m, 1H), 4.02– 3.88(m,1H),3.81(s,1H),3.46(s,2H),3.09(s,6H).MS: m/z calcd for C ₁₉ H ₂₂ N ₃ O ₃ 340.2; found 340.5, M+ H+.

Example 32: Synthesis of Intermediate (S)-19

Intermediate (S)-19 was prepared from intermediate (R)-18 according to the method for synthesizing intermediate (S)-11, and 260.5 mg of a yellow oily compound was obtained with a yield of 38.2%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8.91(s, 1H), 8.07(d, J=8.9Hz, 2H), 7.90(d, J=9.3Hz, 1H), 7.79(d, J=8.3Hz, 1H), 7.32( dd,J=13.3,5.5Hz,3H),7.10(d,J=2.6Hz,1H),7.07–7.02(m,1H),6.94(dd,J=8.8,3.9Hz,1H),4.33–4.18 (m,3H),4.12(d,J=7.2Hz,1H),4.05(d,J=4.5Hz,1H),3.15(s,6H),2.40(s,3H).MS:m/z calcdfor C ₂₆ H ₂₈ N ₃ O ₅ S 494.2; found 494.5, M+H+.

Example 33: Synthesis of Intermediate (R)-19

Intermediate (R)-19 was prepared from intermediate (S)-18 according to the method for synthesizing intermediate (S)-11, and 170.7 mg of a yellow oily compound was obtained with a yield of 33.8%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8.92(s,1H),8.21–7.99(m,2H),7.90(d,J=9.3Hz,1H),7.80(d,J=8.3Hz,2H),7.33(dd,J =13.3,5.4Hz,3H),7.11(dd,J=13.4,2.5Hz,1H),6.98–6.89(m,2H),4.26(ddd,J=16.0,11.3,5.5Hz,3H),4.13– 3.97(m,2H),3.16(s,6H),2.41(s,3H). MS: m/z calcd for C ₂₆ H ₂₈ N ₃ O ₅ S 494.2; found 494.7, M+H+.

Example 34: Synthesis of Intermediate (S)-20

According to the method for synthesizing intermediate (2S)-12, intermediate (2S)-20 was prepared from intermediate (S)-19 to obtain 120.8 mg of light yellow oily compound with a yield of 77.5%. The structure is as follows: ¹ H NMR (400MHz ,CDCl ₃ )δ8.94(s,1H),8.11(d,J=8.7Hz,2H),7.91(d,J=9.3Hz,1H),7.79(dd,J=8.2,5.6Hz,2H) ,7.35(dd,J=9.3,2.7Hz,1H),7.32–7.27(m,1H),7.22(s,1H),7.08(dd,J=11.7,5.2Hz,1H),6.96(dd,J ＝8.8,5.8Hz,1H),4.36–4.05(m,6H),3.57–3.47(m,2H),3.17(s,6H),2.40(s,3H),1.82–1.67(m,2H), 1.56–1.50(m,4H).MS: m/z calcd for C ₃₁ H ₃ 6N ₃ O ₆ S 578.2; found 578.6, M+H+.

Example 35: Synthesis of Intermediate (R)-20

According to the method for synthesizing intermediate (2S)-12, intermediate (2R)-20 was prepared from intermediate (R)-19 to obtain 62.1 mg of light yellow oily compound with a yield of 74.4%. The structure is as follows: ¹ H NMR (400MHz ,CDCl ₃ )δ8.93(s,1H),8.21(s,2H),8.00(dd,J=25.9,9.2Hz,2H),7.79(dd,J=8.2,5.8Hz,2H),7.40( d,J=7.6Hz,1H),7.31(d,J=7.0Hz,2H),7.06–6.88(m,2H),4.40–4.14(m,4H),4.12–4.06(m,2H),3.50 (s,2H),3.23(s,6H),2.42(s,3H),1.53(s,4H),1.26(s,2H).MS:m/z calcd for C ₃₁ H ₃₆ N ₃ O ₆ S578 .2; found 578.6, M+H+.

Example 36: Synthesis of Intermediate 21

According to the method for the synthesis of intermediate 14, intermediate 21 was prepared from intermediate ₁₃ with a yield of 6.3% ^. 8.4Hz, 2H), 7.81(d, J＝9.3Hz, 1H), 7.48(dd, J＝9.2, 1.9Hz, 1H), 6.95-6.86(m, 3H), 3.06(s, 6H).MS: m/z calcd for C ₁₆ H ₁₆ N ₃ O 266.1; found 266.2, M+H+.

Example 37: Synthesis of Intermediate (R)-22

Intermediate (R)-22 was prepared from intermediate 21 according to the method for synthesizing intermediate (R)-4 to obtain 536.1 mg of light yellow solid. The yield is 83.4%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.09(s, 1H), 8.21–8.01(m, 2H), 7.94(d, J=9.3Hz, 1H), 7.39(dd ,J=9.4,2.8Hz,1H),7.09(d,J=2.8Hz,1H),7.06(d,J=1.9Hz,2H),4.31(dd,J=11.0,3.1Hz,1H),4.04 (dd,J=11.0,5.7Hz,1H),3.40(ddd,J=7.0,5.8,3.0Hz,1H),3.15(s,6H),3.00–2.89(m,1H),2.80(dd,J =4.9, 2.6Hz, 1H). MS: m/zcalcd for C ₁₉ H ₂₀ N ₃ O ₂ 322.1; found 322.3, M+H+.

Example 38: Synthesis of Intermediate (S)-22

Intermediate (S)-22 was prepared from intermediate 21 according to the method for synthesizing intermediate (R)-4 to obtain 532.5 mg of light yellow solid. The yield is 84.9%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(s, 1H), 8.08(d, J=8.9Hz, 2H), 7.96(d, J=9.4Hz, 1H), 7.41(dd, J=9.4, 2.7Hz, 1H), 7.13(d, J=2.5Hz, 1H), 7.07(d, J=8.8Hz, 2H), 4.32(dd, J=11.0, 3.1Hz, 1H ),4.04(dd,J=11.0,5.7Hz,1H),3.40(dt,J=8.6,3.0Hz,1H),3.17(s,6H),2.94(t,J=4.5Hz,1H),2.80 (dd, J＝4.9, 2.6Hz, 1H). MS: m/zcalcd for C ₁₉ H ₂₀ N ₃ O ₂ 322.1; found 322.3, M+H+.

Example 39: Synthesis of Intermediate (S)-23

Intermediate (S)-23 was prepared from intermediate (R)-22 according to the method for synthesizing intermediate (S)-5 to obtain 187.2 mg of a yellow solid. The yield is 85.3%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.08(s, 1H), 8.08(d, J=8.8Hz, 2H), 7.95(d, J=9.3Hz, 1H), 7.41(dd, J=9.4, 2.7Hz, 1H), 7.12(s, 1H), 7.07(d, J=8.8Hz, 2H), 4.75–4.64(m, 1H), 4.62–4.50(m, 1H) ,4.41–4.23(m,1H),4.16(d,J＝4.8Hz,2H),3.16(s,6H).HRMS:m/z calcd for C ₁₉ H ₂₁ FN ₃ O ₂ 342.1618;found,M+ H+.

Example 40: Synthesis of Intermediate (R)-23

Intermediate (S)-23 was prepared from intermediate (S)-22 according to the method for synthesizing intermediate (S)-5, and 168.2 mg of a yellow solid was obtained. The yield is 82.5%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.09(s, 1H), 8.08(dd, J=9.0, 2.4Hz, 2H), 7.94(d, J=9.3Hz, 1H ),7.39(dd,J＝9.4,2.6Hz,1H),7.07(dt,J＝9.1,2.6Hz,3H),4.76–4.63(m,1H),4.62–4.51(m,1H),4.38– 4.25(m,1H),4.16(dd,J＝4.0,1.7Hz,2H),3.15(s,6H).HRMS:m/z calcd for C ₁₉ H ₂₁ FN ₃ O ₂ 342.1618;found,M+H+ .

Example 41: Synthesis of Intermediate (R)-24

According to the method for synthesizing intermediate (R)-6, intermediate (R)-24 was prepared from intermediate 21 to obtain 673.1 mg of light yellow solid with a yield of 93.5%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9 .09(s,1H),8.12–8.04(m,2H),7.94(d,J＝9.3Hz,1H),7.39(d,J＝9.3Hz,1H),7.10–7.05(m,3H), 4.52(p, J=5.8Hz, 1H), 4.20(dd, J=8.5, 6.4Hz, 1H), 4.14(dd, J=9.5, 5.5Hz, 1H), 4.03(dd, J=9.5, 5.8Hz ,1H),3.94(dd,J=8.5,5.9Hz,1H),3.16(d,J=3.0Hz,6H),1.49(s,3H),1.42(s,3H).MS:m/zcalcd for C ₂₂ H ₂₆ N ₃ O ₃ 380.2; found 380.4, M+H+.

Example 42: Synthesis of Intermediate (S)-24

According to the method for synthesizing intermediate (R)-6, intermediate (S)-24 was prepared from intermediate 21 to obtain 660.1 mg of light yellow solid with a yield of 91.4%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9 .09(s,1H),8.07(d,J=8.9Hz,2H),7.95(d,J=9.3Hz,1H),7.48–7.30(m,1H),7.11(s,1H),7.07( t, J＝5.9Hz, 2H), 4.59–4.40(m, 1H), 4.20(dd, J＝8.5, 6.4Hz, 1H), 4.14(dd, J＝9.5, 5.5Hz, 1H), 4.03(dd ,J=9.5,5.8Hz,1H),3.94(dd,J=8.5,5.9Hz,1H),3.16(s,6H),1.49(s,3H),1.42(s,3H).MS:m/ zcalcd for C ₂₂ H ₂₆ N ₃ O ₃ 380.2; found 380.4, M+H+.

Example 43: Synthesis of Intermediate (R)-25

Intermediate (R)-25 was prepared from intermediate (R)-24 according to the method for synthesizing intermediate (R)-7, and 594.2 mg of light yellow solid was obtained with a yield of 95.6%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s,1H),8.17(d,J=8.9Hz,1H),7.85(d,J=9.3Hz,1H),7.50(dd,J=9.4,2.8Hz,1H ),7.08(d,J=8.9Hz,2H),6.97(d,J=2.8Hz,1H),4.98(d,J=4.8Hz,1H),4.68(s,1H),4.07(dd,J =9.9,4.1Hz,1H),3.93(dd,J=9.9,6.2Hz,1H),3.81(d,J=5.0Hz,1H),3.45(t,J=4.8Hz,2H),3.09(s ,6H).MS: m/z calcd for C ₁₉ H ₂₂ N ₃ O ₃ 340.2; found 340.3, M+H+.

Example 44: Synthesis of Intermediate (S)-25

Intermediate (S)-25 was prepared from intermediate (S)-24 according to the method for synthesizing intermediate (R)-7, and 578.4 mg of light yellow solid was obtained with a yield of 94.1%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s,1H),8.17(d,J=8.9Hz,2H),7.85(d,J=9.3Hz,1H),7.50(dd,J=9.4,2.8Hz,1H ),7.08(d,J=8.9Hz,2H),6.97(d,J=2.8Hz,1H),4.97(s,1H),4.68(s,1H),4.07(dd,J=9.9,4.1Hz ,1H),3.93(dd,J=9.9,6.2Hz,1H),3.82(dd,J=10.0,5.5Hz,1H),3.45(d,J=5.7Hz,2H),3.09(s,6H) .MS: m/z calcd for C ₁₉ H ₂₂ N ₃ O ₃ 340.2; found 340.4, M+H+.

Example 45: Synthesis of Intermediate (S)-26

Intermediate (S)-26 was prepared from intermediate (R)-25 according to the method for synthesizing intermediate (S)-11, and 265.2 mg of a yellow oily compound was obtained with a yield of 37.9%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.08(s, 1H), 8.06(d, J=8.8Hz, 2H), 7.95(d, J=9.3Hz, 1H), 7.80(d, J=8.3Hz, 2H), 7.41( d,J=9.4Hz,1H),7.32(d,J=8.0Hz,2H),7.11(s,1H),6.96(d,J=8.6Hz,2H),4.39–4.12(m,3H), 4.07(d, J＝4.5Hz, 2H), 3.16(s, 6H), 2.42(s, 3H). MS: m/z calcd for C ₂₆ H ₂₈ N ₃ O ₅ S 494.2; found 494.4, M+H+ .

Example 46: Synthesis of Intermediate (R)-26

Intermediate (R)-26 was prepared from intermediate (S)-25 according to the method for synthesizing intermediate (S)-11, and 193.6 mg of a yellow oily compound was obtained with a yield of 35.9%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.08(s, 1H), 8.06(d, J=8.8Hz, 2H), 7.95(d, J=9.4Hz, 1H), 7.81(d, J=8.3Hz, 2H), 7.41( dd,J=9.4,2.7Hz,1H),7.33(d,J=8.3Hz,2H),7.12(s,1H),6.98(t,J=7.0Hz,2H),4.24(ddd,J=19.4 ,11.6,7.7Hz,3H),4.07(d,J＝4.5Hz,2H),3.17(s,6H),2.42(s,3H).MS:m/z calcd for C ₂₆ H ₂₈ N ₃ O ₅ S 494.2; found 494.4, M+H+.

Example 47: Synthesis of Intermediate (S)-27

According to the method for synthesizing intermediate (2S)-12, intermediate (2S)-27 was prepared from intermediate (S)-26 to obtain 127.4 mg of light yellow oily compound with a yield of 87.5%. The structure is as follows: ¹ H NMR (400MHz ,CDCl ₃ )δ9.06(s,1H),8.05(d,J=8.3Hz,2H),7.97(d,J=9.3Hz,1H),7.79(dd,J=8.2,5.7Hz,2H) ,7.43(dd,J=9.4,2.6Hz,1H),7.29(d,J=7.3Hz,2H),7.15(s,1H),6.95(dd,J=8.8,5.7Hz,2H),4.42– 4.13(m,4H),4.12–3.99(m,2H),3.52–3.46(dd,J＝14.1,9.0Hz,2H),3.18(s,6H),2.40(s,3H),1.82–1.59( m,2H),1.53(s,4H).MS:m/z calcd for C ₃₁ H ₃₆ N ₃ O ₆ S 578.2; found 578.5,M+H+.

The schematic diagram of the synthesis process of the above compounds of Examples 22-48 is shown in FIG. 2 .

Example 48: Synthesis of Intermediate (R)-27

According to the method for synthesizing intermediate (2S)-12, intermediate (2R)-27 was prepared from intermediate (R)-26 to obtain 100.7 mg of light yellow oily compound with a yield of 90.4%. The structure is as follows: ¹ H NMR (400MHz ,CDCl ₃ )δ9.05(s,1H),8.04(d,J＝8.3Hz,2H),7.98(d,J＝9.1Hz,1H),7.84–7.74(m,2H),7.45(d, J＝7.6Hz, 1H), 7.29(d, J＝7.9Hz, 2H), 7.18(s, 1H), 6.95(dd, J＝8.8, 5.6Hz, 2H), 4.36–4.14(m, 4H), 4.13–4.01(m,2H),3.49(s,2H),3.19(s,6H),2.41(s,3H),1.92–1.64(m,2H),1.53(s,4H).MS:m/ z calcdfor C ₃₁ H ₃₆ N ₃ O ₆ S 578.2; found 578.4, M+H+.

Example 49: Synthesis of intermediate (R,R)-28

Intermediate (R,R)-28 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-6, and 248.8 mg of a light yellow solid was obtained with a yield of 43.9%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8.94(s,1H),8.13(d,J=8.8Hz,2H),7.91(d,J=9.3Hz,1H),7.81(d,J=8.3Hz,2H),7.34(d, J＝8.0Hz, 3H), 7.20(s, 1H), 7.02(d, J＝8.8Hz, 2H), 4.38–4.15(m, 5H), 4.13–4.02(m, 1H), 3.17(s, 6H) ),2.43(s,3H),1.43(s,3H),1.40(s,3H).MS:m/z calcd for C ₃₀ H ₃₄ N ₃ O ₆ S 564.2; found 564.4,M+H+.

Example 50: Synthesis of Intermediate (S,S)-28

Intermediate (S,S)-28 was prepared from intermediate 14 according to the method for synthesizing intermediate (R)-6, and 280.6 mg of a light yellow solid was obtained with a yield of 49.6%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ8.94(s,1H),8.13(d,J=8.8Hz,2H),7.91(d,J=9.3Hz,1H),7.81(d,J=8.3Hz,2H),7.42–7.28( m,3H),7.17(d,J=19.6Hz,1H),7.02(d,J=8.8Hz,2H),4.23(ddd,J=13.9,12.0,4.3Hz,5H),4.14–4.01(m ,1H),3.17(s,6H),2.43(s,3H),1.43(s,3H),1.40(s,3H).MS: m/z calcd for C ₃₀ H ₃₄ N ₃ O ₆ S 564.2; Found 564.4, M+H+.

Example 51: Synthesis of Intermediate (R,S)-29

Intermediate (R,S)-29 was prepared from intermediate (R,R)-28 according to the method for synthesizing intermediate (S)-5, and 54.3 mg of a yellow solid was obtained. The yield is 94.0%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.12(d, J=8.8Hz, 2H), 7.90(d, J=9.3Hz, 1H), 7.33(dd,J=9.3,2.8Hz,1H),7.11(d,J=2.7Hz,1H),7.09–6.98(m,2H),4.74(dd,J=10.2,3.3Hz,0.5H), 4.68–4.60(m,1H),4.54(dd,J=10.2,4.5Hz,0.5H),4.42–4.31(m,1H),4.26(dq,J=8.0,4.3Hz,2H),4.20–4.11 (m,1H),3.15(s,6H),1.49(d,J=2.3Hz,6H).MS:m/z calcd for C ₂₃ H ₂₇ FN ₃ O ₃ 412.2; found 412.4,M+H+.

Example 52: Synthesis of Intermediate (S,R)-29

Intermediate (S,R)-29 was prepared from intermediate (S,S)-28 according to the method for synthesizing intermediate (S)-5, and 103.7 mg of a yellow solid was obtained. The yield is 83.2%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ8.93 (s, 1H), 8.15–8.09 (m, 2H), 7.89 (d, J=9.3Hz, 1H), 7.32 (dd ,J=9.3,2.8Hz,1H),7.10(d,J=2.8Hz,1H),7.09–6.98(m,2H),4.73(dd,J=10.2,3.3Hz,0.5H),4.69–4.58 (m,1H),4.53(dd,J=10.2,4.5Hz,0.5H),4.34(dt,J=8.1,5.1Hz,1H),4.30–4.20(m,2H),4.16(dd,J= 9.7,5.2Hz,1H),3.14(s,6H),1.49(d,J＝2.2Hz,6H).MS:m/z calcd for C ₂₃ H ₂₇ FN ₃ O ₃ 412.2; found 412.4,M+H+ .

Example 53: Synthesis of Intermediate (R,S)-30

Intermediate (R,S)-30 was prepared from intermediate (R,S)-29 according to the method for synthesizing intermediate (R)-7, and 37.5 mg of a light yellow solid was obtained with a yield of 83.3%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 8.22(d, J=8.9Hz, 2H), 7.82(d, J=9.3Hz, 1H), 7.44(dd, J=9.3, 2.8Hz, 1H), 7.10(d, J=8.9Hz, 2H), 6.96(d, J=2.8Hz, 1H), 5.15(dd, J=11.8, 5.9Hz, 2H), 4.59(dd, J= 9.3,3.9Hz,0.5H),4.53–4.43(m,1H),4.35(dd,J＝9.3,6.6Hz,0.5H),4.14(dd,J＝9.7,4.5Hz,1H),3.97(dd ,J＝9.6,6.5Hz,1H),3.91–3.75(m,2H),3.09(s,6H).HRMS:m/z calcd for C ₂₀ H ₂₃ FN ₃ O ₃ 372.1645;found,M+H+.

Example 54: Synthesis of Intermediate (S,R)-30

Intermediate (S,R)-30 was prepared from intermediate (S,R)-29 according to the method for synthesizing intermediate (R)-7, and 86.4 mg of light yellow solid was obtained with a yield of 96.7%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.10(s, 1H), 8.22(d, J=8.9Hz, 2H), 7.82(d, J=9.3Hz, 1H), 7.43(dd, J=9.3, 2.8Hz, 1H), 7.10(d, J=8.9Hz, 2H), 6.96(d, J=2.8Hz, 1H), 5.15(dd, J=11.8, 5.9Hz, 2H), 4.59(dd, J= 9.3,3.9Hz,0.5H),4.53–4.43(m,1H),4.35(dd,J＝9.3,6.6Hz,0.5H),4.14(dd,J＝9.7,4.5Hz,1H),3.98(dd ,J＝9.6,6.5Hz,1H),3.87–3.82(m,2H),3.09(s,6H).HRMS:m/z calcd for C ₂₀ H ₂₃ FN ₃ O ₃ 372.1645;found,M+H+.

Example 55: Synthesis of Intermediate (R,R)-31

According to the method for synthesizing intermediate (R)-6, intermediate (R,R)-31 was prepared from intermediate 21 to obtain 140.4 mg of light yellow solid with a yield of 24.8%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.08(s,1H),8.07(d,J=8.8Hz,2H),7.96(d,J=9.4Hz,1H),7.81(d,J=8.3Hz,2H),7.42(dd, J=9.4,2.7Hz,1H),7.34(d,J=8.1Hz,2H),7.13(d,J=2.5Hz,1H),7.00(d,J=8.8Hz,2H),4.42–4.15( m,5H),4.09(dd,J＝9.3,4.5Hz,1H),3.17(s,6H),2.44(s,3H),1.43(s,3H),1.40(s,3H).MS:m /z calcd for C ₃₀ H ₃₄ N ₃ O ₆ S 564.2; found 564.4, M+H+.

Example 56: Synthesis of Intermediate (S,S)-31

Intermediate (S,S)-31 was prepared from intermediate 21 according to the method for synthesizing intermediate (R)-6, and 150.3 mg of a light yellow solid was obtained with a yield of 53.2%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.09(s,1H),8.07(d,J=8.8Hz,2H),7.95(d,J=9.3Hz,1H),7.81(d,J=8.3Hz,2H),7.40(d, J＝9.3Hz, 1H), 7.33(d, J＝8.1Hz, 2H), 7.10(s, 1H), 7.00(d, J＝8.8Hz, 2H), 4.34–4.13(m, 5H), 4.08( dd,J＝9.3,4.5Hz,1H),3.16(s,6H),2.43(s,3H),1.43(s,3H),1.40(s,3H).MS:m/z calcd for C ₃₀ H ₃₄ N ₃ O ₆ S 564.2; found 564.4, M+H+.

Example 57: Synthesis of Intermediate (R,S)-32

Intermediate (R,S)-32 was prepared from intermediate (R,R)-31 according to the method for synthesizing intermediate (S)-5, and 61.2 mg of a yellow solid was obtained. The yield is 92.5%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.07(s, 1H), 8.08(d, J=8.9Hz, 2H), 7.96(d, J=9.4Hz, 1H), 7.42(dd, J=9.4, 2.8Hz, 1H), 7.13(d, J=2.7Hz, 1H), 7.07(d, J=6.7Hz, 2H), 4.74(dd, J=10.2, 3.3Hz, 0.5 H), 4.70–4.57(m,1H), 4.54(dd,J=10.1,4.5Hz,0.5H),4.31–4.01(m,4H),3.17(s,6H),1.49(d,J=2.3 Hz,6H).MS:m/z calcdfor C ₂₃ H ₂₇ FN ₃ O ₃ 412.2; found 412.4,M+H+.

Example 58: Synthesis of Intermediate (S,R)-32

Intermediate (S,R)-32 was prepared from intermediate (S,S)-31 according to the method for synthesizing intermediate (S)-5, and 97.4 mg of a yellow solid was obtained. The yield is 80.4%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.10(s, 1H), 8.11–8.07(m, 2H), 7.94(d, J=9.3Hz, 1H), 7.39(dd ,J=9.4,2.7Hz,1H),7.13–6.93(m,3H),4.73(dd,J=10.2,3.3Hz,0.5H),4.69–4.59(m,1H),4.53(dd,J= 10.2,4.5Hz,0.5H),4.37–4.32(m,1H),4.30–4.23(m,2H),4.18–4.14(m,1H),3.15(s,6H).MS:m/z calcd for C ₂₃ H ₂₇ FN ₃ O ₃ 412.2; found 412.4, M+H+.

Example 59: Synthesis of Intermediate (R,S)-33

According to the method for synthesizing intermediate (R)-7, intermediate (R,S)-33 was prepared from intermediate (R,S)-32, and 84.2 mg of light yellow solid was obtained with a yield of 73.2%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.28(s, 1H), 8.17(d, J=8.8Hz, 2H), 7.86(d, J=9.3Hz, 1H), 7.50(dd, J=9.4, 2.7Hz, 1H), 7.08(d, J=8.8Hz, 2H), 6.97(d, J=2.6Hz, 1H), 5.15(dd, J=12.7, 5.9Hz, 2H), 4.58(dd, J= 9.1,3.8Hz,0.5H),4.47(dd,J＝9.3,4.3Hz,1H),4.44–4.27(m,0.5H),4.13(dd,J＝9.6,4.4Hz,1H),3.97(d ,J＝6.5Hz,1H),3.87–3.81(m,2H),3.09(s,6H).HRMS:m/z calcd for C ₂₀ H ₂₃ FN ₃ O ₃ 372.1645;found,M+H+.

Example 60: Synthesis of Intermediate (S,R)-33

Intermediate (S,R)-33 was prepared from intermediate (S,R)-32 according to the method for synthesizing intermediate (R)-7, and 86.4 mg of light yellow solid was obtained with a yield of 89.6%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.27(s, 1H), 8.17(d, J=8.9Hz, 2H), 7.86(d, J=9.3Hz, 1H), 7.50(dd, J=9.4, 2.8Hz, 1H), 7.08(d, J=8.9Hz, 2H), 6.97(d, J=2.8Hz, 1H), 5.13(dd, J=12.3, 5.5Hz, 2H), 4.59(dd, J= 9.3,3.9Hz,0.5H),4.56–4.44(m,1H),4.35(dd,J＝9.3,6.6Hz,0.5H),4.13(dd,J＝9.7,4.5Hz,1H),3.97(dd ,J＝9.5,6.6Hz,1H),3.87–3.81(m,2H),3.09(s,6H).HRMS:m/z calcd for C ₂₀ H ₂₃ FN ₃ O ₃ 372.1645;found,M+H+.

Example 61: Synthesis of Intermediate (S,S)-34

Intermediate (S,S)-34 was prepared from intermediate 3 according to the method for synthesizing intermediate (R)-6, and 345.8 mg of light yellow solid was obtained with a yield of 62.7%. The structure is as follows: ¹ H NMR (400MHz, CDCl ₃ )δ9.07(s,1H),8.07(s,2H),7.96–7.73(m,3H),7.41–7.24(m,2H),7.15(s,1H),7.00(s,3H),4.27 –4.09(m,7H),3.00(s,3H),2.43(s,3H),1.41(d,J＝12.0Hz,6H).MS: m/z calcd for C ₂₉ H ₃₂ N ₃ O ₆ S 550.2; found 550.4, M+H+.

Example 62: Synthesis of Intermediate (S,R)-35

Intermediate (S, R)-35 was prepared from intermediate (S, S)-34 according to the method for synthesizing intermediate (S)-5, and 201.5 mg of a yellow solid was obtained. The yield is 84.1%, and the structure is as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ9.08(s, 1H), 8.19–7.98(m, 2H), 7.86(d, J=9.0Hz, 1H), 7.13(d ,J＝9.0Hz,1H),7.11–7.03(m,2H),6.99(s,1H),5.06–4.45(m,2H),4.44–3.90(m,4H),3.00(s,3H), 1.49(s,6H).MS: m/z calcd for C ₂₂ H ₂₅ FN ₃ O ₃ 398.2; found 398.4, M+H+.

Example 63: Synthesis of Intermediate (R,S)-36

Intermediate (R,S)-36 was prepared from intermediate (S,R)-35 according to the method for synthesizing intermediate (R)-7, and 70.5 mg of a light yellow solid was obtained with a yield of 39.1%. The structure is as follows: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.21(s, 1H), 8.14(d, J=8.8Hz, 2H), 7.73(d, J=9.1Hz, 1H), 7.24(dd, J=9.1, 2.5Hz, 1H), 7.07(d, J=8.9Hz, 2H), 6.72(d, J=2.4Hz, 1H), 6.62(q, J=4.9Hz, 1H), 5.13(dd, J=13.2, 5.8Hz, 2H), 4.58(dd, J＝9.3, 3.9Hz, 0.5H), 4.52–4.42(m, 1H), 4.35(dd, J＝9.3, 6.6Hz, 0.5H), 4.13(dd, J =9.7,4.5Hz,1H),3.96(dd,J=9.5,6.5Hz,1H),3.93–3.71(m,2H),2.81(d,J=4.9Hz,3H).HRMS:m/z calcd for C ₁₉ H ₂₁ FN ₃ O ₃ 358.1489; found, M+H+.

The schematic diagram of the synthesis process of the above compounds of Examples 49-63 is shown in FIG. 3 .

Example 64: Synthesis of 3-(4-nitrophenyl)quinoxalin-6-ol(37)

2-Bromo-4'-nitroacetophenone (2.44g, 10.0mmol) was dissolved in 5mL of DMSO, and 5mL of 3,4-diaminophenol (1.24g, 10.0mmol) in DMSO was slowly added thereto under stirring at room temperature . After reacting at room temperature for 2 h, a large amount of precipitate precipitated out, which was filtered by suction and washed with ethanol to give 37 (1.04 g, 39.0%) as a yellow solid. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.69(s,1H),9.44(s,1H),8.58(d,J=9.0Hz,2H),8.42(d,J=9.0Hz,2H) ,8.01(d,J=9.1Hz,1H),7.47(dd,J=9.1,2.7Hz,1H),7.36(d,J=2.6Hz,1H).

Example 65: Synthesis of 3-(3-nitrophenyl)quinoxalin-6-ol(38)

According to the method for preparing compound 37, yellow solid 38 (2.84 g, 61.5%) was prepared from the reaction of 2-bromo-3'-nitroacetophenone and 3,4-diaminophenol. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.67(s,1H),9.46(s,1H),9.08–9.06(m,1H),8.78–8.74(m,1H),8.40(ddd,J =8.2,2.3,0.9Hz,1H),8.00(d,J=9.1Hz,1H),7.92–7.86(m,1H),7.45(dd,J=9.1,2.7Hz,1H),7.37(d, J=2.6Hz,1H).

Example 66: Synthesis of 3-(2-nitrophenyl)quinoxalin-6-ol(39)

According to the method for preparing compound 37, a yellow solid 39 (2.74 g, 50.1%) was prepared from the reaction of 2-bromo-2'-nitroacetophenone and 3,4-diaminophenol.

Example 67: Synthesis of 2-(4-nitrophenyl)quinoxalin-5-ol(40)

According to the method for preparing compound 37, a yellow solid 40 (5.93 g, 44.4%) was prepared from the reaction of 2-bromo-4'-nitroacetophenone and 2,3-diaminophenol. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.56(s,1H),9.59(s,1H),8.62(d,J=8.9Hz,2H),8.44(d,J=8.9Hz,2H) ,7.78–7.72(m,1H),7.65–7.59(m,1H),7.22(dd,J＝7.7,1.0Hz,1H).

Example 68: Synthesis of 2-(3-nitrophenyl)quinoxalin-5-ol(41)

According to the method for preparing compound 37, white solid 41 (4.57 g, 64.3%) was prepared from the reaction of 2-bromo-3'-nitroacetophenone and 2,3-diaminophenol. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.55(s, 1H), 9.71(s, 1H), 9.36–9.34(m, 1H), 8.95(d, J=7.9Hz, 1H), 8.39( dd,J＝8.1,1.7Hz,1H),7.93–7.87(m,1H),7.75–7.69(m,1H),7.59(dd,J＝8.4,1.0Hz,1H),7.24(dd,J＝ 7.7,1.0Hz,1H).

Example 69: Synthesis of 2-(2-nitrophenyl)quinoxalin-5-ol(42)

According to the method for preparing compound 37, a yellow solid 42 (3.16 g, 53.5%) was prepared from the reaction of 2-bromo-2'-nitroacetophenone and 2,3-diaminophenol. ¹ H NMR (400MHz,DMSO-d ₆ )δ10.54(s,1H),9.13(s,1H),8.16(d,J=8.1Hz,1H),7.97(d,J=7.6Hz,1H) ,7.94–7.88(m,1H),7.84–7.77(m,1H),7.73–7.67(m,1H),7.45(d,J＝8.4Hz,1H),7.20(d,J＝7.7Hz,1H ).

Example 70: Synthesis of 7-(2-fluoroethoxy)-2-(4-nitrophenyl)quinoxaline (43)

Compound 37 (388.5mg, 1.5mmol), 1-bromo-2-fluoroethane (184.6mg, 1.5mmol) and K2CO3 were dissolved in 5mL of anhydrous DMF, stirred and refluxed at 90°C for 2h. The reaction was basically completed as monitored by TLC. After cooling to room temperature, 50 mL of deionized water was added, and a precipitate was precipitated. The precipitate was filtered with suction, washed with water, and recrystallized from methanol to obtain a yellow solid 43 (412.7 mg, 90.8%). ¹ H NMR (400MHz, CDCl ₃ ) δ9.25(s, 1H), 8.43(d, J=8.9Hz, 2H), 8.38(d, J=8.9Hz, 2H), 8.09(d, J=9.2Hz ,1H),7.54(dd,J=9.2,2.7Hz,1H),7.47(d,J=2.7Hz,1H),4.96–4.81(m,2H),4.49–4.39(m,2H).

Example 71: Synthesis of 7-(2-fluoroethoxy)-2-(3-nitrophenyl)quinoxaline (44)

According to the method for preparing compound 43, yellow solid 44 (796.6 mg, 89.5%) was obtained from compound 38. ¹ HNMR (400MHz, CDCl ₃ ) δ9.26(s, 1H), 9.11(s, 1H), 8.53(d, J=7.8Hz, 1H), 8.39(dd, J=8.1, 2.1Hz, 1H), 8.13(d,J=9.2Hz,1H),7.80–7.75(m,1H),7.56(dd,J=9.2,2.7Hz,1H),7.51(d,J=2.7Hz,1H),4.97–4.82 (m,2H),4.50–4.40(m,2H).

Example 72: Synthesis of 7-(2-fluoroethoxy)-2-(2-nitrophenyl)quinoxaline (45)

According to the method for preparing compound 43, yellow solid 45 (497.3 mg, 87.7%) was obtained from compound 39. ¹ HNMR (400MHz, CDCl ₃ ) δ8.85(s, 1H), 8.10(dd, J＝8.1, 1.0Hz, 1H), 8.08(d, J＝9.2Hz, 1H), 7.81–7.73(m, 2H ),7.70–7.65(m,1H),7.53(dd,J＝9.2,2.8Hz,1H),7.37(d,J＝2.8Hz,1H),4.93–4.78(m,2H),4.43–4.34( m,2H).

Example 73: Synthesis of 5-(2-fluoroethoxy)-2-(4-nitrophenyl)quinoxaline (46)

According to the method for preparing compound 43, yellow solid 46 (346.1 mg, 91.3%) was obtained from compound 40. ¹ HNMR (400MHz, CDCl ₃ ) δ9.41 (s, 1H), 8.46–8.38 (m, 4H), 7.84 (dd, J＝8.5, 1.2Hz, 1H), 7.80–7.75 (m, 1H), 7.22 (d, J=7.7Hz, 1H), 5.06–4.91(m, 2H), 4.62–4.52(m, 2H).

Example 74: Synthesis of 5-(2-fluoroethoxy)-2-(3-nitrophenyl)quinoxaline (47)

According to the method for preparing compound 43, yellow solid 47 (691.2 mg, 89.3%) was obtained from compound 41. ¹ HNMR (400MHz, CDCl ₃ ) δ9.41(s, 1H), 9.09–9.07(m, 1H), 8.61(d, J＝7.8Hz, 1H), 8.38(dd, J＝8.2, 1.3Hz, 1H ),7.84(d,J=8.5Hz,1H),7.78(d,J=8.3Hz,1H),7.74(d,J=8.6Hz,1H),7.26–7.23(m,1H),5.06–4.92 (m,2H),4.64–4.54(m,2H).

Example 75: Synthesis of 5-(2-fluoroethoxy)-2-(2-nitrophenyl)quinoxaline (48)

Following the method for preparing compound 43, yellow solid 48 (1.20 g, 95.4%) was obtained from compound 42. ¹ H NMR (400MHz, CDCl ₃ ) δ8.99(s, 1H), 8.12(dd, J=8.1, 1.0Hz, 1H), 7.82–7.65(m, 5H), 7.23–7.18(m, 1H), 5.05–4.90(m,2H),4.61–4.52(m,2H).

Example 76: Synthesis of 4-(7-(2-fluoroethoxy)quinoxalin-2-yl)aniline (49)

Compound 43 (268.0mg, 0.9mmol) was dissolved in 50mL of anhydrous methanol, Pd/C catalyst (9.1mg, 0.09mmol) and hydrazine hydrate (430.5mg, 8.6mmol) were added, stirred and refluxed at 80°C for 0.5h. The reaction was basically completed as monitored by TLC, the catalyst was removed by suction filtration, the solvent was removed under reduced pressure, and methanol was recrystallized to obtain 49 (236.7 mg, 97.2%) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ9.12(s, 1H), 8.03(d, J=8.6Hz, 2H), 7.98–7.94(m, 1H), 7.41–7.35(m, 2H), 6.83( d,J＝8.6Hz,2H),4.93–4.78(m,2H),4.45–4.34(m,2H),3.97(s,2H).

Example 77: Synthesis of 3-(7-(2-fluoroethoxy)quinoxalin-2-yl)aniline (50)

According to the method for preparing compound 49, yellow solid 50 (376.2 mg, 96.9%) was obtained from compound 44. ¹ HNMR (400MHz, CDCl ₃ ) δ9.15(s, 1H), 8.01(d, J=9.0Hz, 1H), 7.53–7.48(m, 2H), 7.45(dd, J=9.0, 2.8Hz, 1H ),7.42(d,J＝2.6Hz,1H),7.37–7.32(m,1H),6.87–6.82(m,1H),4.94–4.79(m,2H),4.46–4.35(m,2H), 3.87(s,2H).

Example 78: Synthesis of 2-(7-(2-fluoroethoxy)quinoxalin-2-yl)aniline (51)

According to the method for preparing compound 49, yellow solid 51 (257.9 mg, 92.9%) was obtained from compound 45. ¹ HNMR (400MHz, CDCl ₃ ) δ9.17(s, 1H), 7.99(d, J=9.1Hz, 1H), 7.80(dd, J=8.0, 1.4Hz, 1H), 7.42(dd, J=9.1 ,2.8Hz,1H),7.32(d,J＝2.7Hz,1H),7.29–7.24(m,1H),6.90–6.80(m,2H),4.94–4.79(m,2H),4.46–4.35( m,2H).

Example 79: Synthesis of 4-(5-(2-fluoroethoxy)quinoxalin-2-yl)aniline (52)

According to the method for preparing compound 49, yellow solid 52 (249.7 mg, 92.8%) was obtained from compound 46. ¹ HNMR (400MHz, CDCl ₃ ) δ9.27(s, 1H), 8.06(d, J＝8.7Hz, 2H), 7.72(dd, J＝8.5, 1.1Hz, 1H), 7.67–7.61(m, 1H ),7.07(d,J=7.8Hz,1H),6.83(d,J=8.7Hz,2H),5.04–4.89(m,2H),4.58–4.48(m,2H),4.00(s,2H) .

Example 80: Synthesis of 3-(5-(2-fluoroethoxy)quinoxalin-2-yl)aniline (53)

According to the method for preparing compound 49, yellow solid 53 (417.6 mg, 92.7%) was obtained from compound 47. ¹ HNMR (400MHz, CDCl ₃ ) δ9.31(s, 1H), 7.76(d, J=8.4Hz, 1H), 7.68–7.59(m, 2H), 7.56(d, J=7.8Hz, 1H), 7.36–7.31(m,1H),7.20(d,J=7.8Hz,1H),6.83(dd,J=7.9,2.2Hz,1H),5.04–4.89(m,2H),4.63–4.52(m, 2H),3.90(s,2H).

Example 81: Synthesis of 2-(5-(2-fluoroethoxy)quinoxalin-2-yl)aniline (54)

According to the method of preparing compound 49, yellow solid 54 (119.5 mg, 89.7%) was obtained from compound 48. ¹ HNMR (400MHz, CDCl ₃ )δ9.33(s,1H),7.83(dd,J＝8.0,1.4Hz,1H),7.69–7.64(m,2H),7.28–7.24(m,1H),7.14 –7.09(m,1H),6.89–6.81(m,2H),6.19(s,2H),5.04–4.90(m,2H),4.60–4.50(m,2H).

Example 82: 4-(7-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (55) and 4-(7-(2-fluoroethoxy)quinoxalin-2-yl)-N,N-dimethylaniline Synthesis of (61)

Compound 49 (129.7 mg, 0.5 mmol) was dissolved in 20 mL of acetone, K ₂ CO ₃ (127.2, 0.9 mmol) and iodomethane (97.5 mg, 0.7 mmol) were added, and the reaction was stirred overnight at 40°C. TLC monitors that the reaction is almost complete, the solvent is removed under reduced pressure, and the residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate=3/1) to obtain yellow solids 55 (31.2mg, 22.8%) and 61 (45.7mg, 31.9%) ). 55: ¹ H NMR (400MHz, CDCl ₃ ) δ9.14(s, 1H), 8.10(d, J＝8.7Hz, 2H), 7.96(d, J＝9.1Hz, 1H), 7.48(s, 1H) ,7.37(dd,J=9.1,2.8Hz,1H),6.76(d,J=8.8Hz,2H),4.94–4.78(m,2H),4.46–4.35(m,2H),2.94(s,3H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ159.56, 152.00, 151.05, 143.74, 140.74, 137.11, 130.15, 128.76, 125.26, 121.54, 112.50, 107.42, 82.47, 81.62 (d, J＝171.14 , J＝20.6Hz), 30.37.61: ¹ H NMR (400MHz, CDCl ₃ ) δ9.16(s, 1H), 8.17(d, J＝8.8Hz, 2H), 7.96(d, J＝9.1Hz, 1H), 7.55(s, 1H), 7.37(dd, J＝9.1, 2.7Hz, 1H), 6.88(d, J＝8.5Hz, 2H), 4.93–4.78(m, 2H), 4.47–4.36(m ⁽ _{_} 171.2Hz), 67.44(d, J=20.6Hz), 40.23.

Example 83: 3-(7-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (56) and 3-(7-(2-fluoroethoxy)quinoxalin-2-yl)-N,N-dimethylaniline Synthesis of (62)

Following the procedure for preparing compounds 55 and 61, yellow solids 56 (45.6 mg, 36.6%) and 62 (31.2 mg, 23.9%) were obtained from compound 5. 56: ¹ H NMR (400MHz, CDCl ₃ ) δ9.16(s, 1H), 8.01(d, J=9.9Hz, 1H), 7.50–7.42(m, 4H), 7.41–7.35(m, 1H), 6.85–6.80(m,1H),4.94–4.79(m,2H),4.46–4.36(m,2H),2.97(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ159.64,152.57,149.96,143.71 ,141.40,137.92,137.84,130.26,129.91,122.69,116.56,114.34,111.09,107.68,81.59(d,J=171.3Hz),67.49(d,J=20.6Hz),30.80.62: ¹ H NMR(400MHz ,CDCl ₃ )δ9.18(s,1H),8.01(d,J＝9.9Hz,1H),7.71–7.40(m,5H),7.00(s,1H),4.94–4.79(m,2H), 4.47–4.37 (m, 2H ₎ , 3.10 (s ^, 6H). 107.74, 81.59 (d, J=171.3Hz), 67.48 (d, J=20.6Hz), 40.66.

Example 84: Synthesis of 2-(7-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (57)

According to the method for preparing compound 55, yellow solid 57 (42.7 mg, 53.2%) was obtained from compound 51. ¹ H NMR (400MHz, CDCl ₃ ) δ9.20(s, 1H), 7.99(d, J=9.1Hz, 1H), 7.87(dd, J=7.9, 1.2Hz, 1H), 7.45–7.39(m, 2H), 7.32(d, J=2.7Hz, 1H), 6.96(d, J=8.0Hz, 1H), 6.92–6.86(m, 1H), 4.95–4.80(m, 2H), 4.47–4.38(m ,2H),3.02(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ159.76,153.84,149.53,142.66,141.57,136.28,131.78,130.25,129.49,121.87,117.76,115.99,1107.51( d,J=171.4Hz),67.56(d,J=20.6Hz),30.07.

Example 85: 4-(5-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (58) and 4-(5-(2-fluoroethoxy)quinoxalin-2-yl)-N,N-dimethylaniline Synthesis of (63)

Following the procedure for preparing compounds 55 and 61, yellow solids 58 (193.7 mg, 35.2%) and 63 (211.4 mg, 36.7%) were obtained from compound 52. 58: ¹ H NMR (400MHz, CDCl ₃ ) δ9.28(s, 1H), 8.11(d, J=8.8Hz, 2H), 7.73(d, J=8.1Hz, 1H), 7.66–7.60(m, 1H), 7.06(d, J＝7.2Hz, 1H), 6.78(d, J＝8.7Hz, 2H), 5.03–4.88(m, 2H), 4.58–4.48(m, 2H), 2.94(s, 3H ). ¹³ C NMR (101MHz, CDCl ₃ ) δ154.15, 152.14, 151.14, 143.54, 141.69, 133.03, 129.74, 128.84, 125.08, 121.88, 112.49, 108.55, 81.75 (d, J＝171.1Hz2 (d, J = 171.1Hz2), 68. =21.4Hz), 30.36.63: ¹ H NMR (400MHz, CDCl ₃ ) δ9.31(s, 1H), 8.19(d, J=8.8Hz, 2H), 7.80(d, J=8.1Hz, 1H) ,7.68–7.62(m,1H),7.07(d,J＝7.9Hz,1H),7.01–6.90(s,2H),5.03–4.89(m,2H),4.58–4.49(m,2H),3.10 (s,6H) ^.13 C NMR(101MHz,CDCl ₃ )δ154.17,152.11,151.82,143.62,141.72,133.01,129.70,128.59,123.96,121.89,112.22,108.51,81.766(d,J＝171.23Hz) (d, J=21.4Hz), 40.18.

Example 86: 3-(5-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (59) and 3-(5-(2-fluoroethoxy)quinoxalin-2-yl)-N,N-dimethylaniline Synthesis of (64)

Following the procedure for preparing compounds 55 and 61, yellow solids 59 (104.7 mg, 32.0%) and 64 (159.6 mg, 46.6%) were obtained from compound 53. 59: ¹ H NMR (400MHz, CDCl ₃ ) δ9.32(s, 1H), 7.76(dd, J=8.5, 1.0Hz, 1H), 7.67–7.61(m, 1H), 7.61–7.58(m, 1H ),7.56(d,J=7.7Hz,1H),7.41–7.35(m,1H),7.20(dd,J=7.8,0.8Hz,1H),6.84(dd,J=8.0,1.9Hz,1H) ,5.04–4.89(m,2H),4.63–4.53(m,2H),2.97(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ154.40,150.93,150.02,143.74,142.56,137.59,134.88,129.83 , 129.16, 122.15, 116.45, 114.23, 111.79, 111.30, 82.04(d, J=170.8Hz), 69.27(d, J=21.0Hz), 30.70.64: ¹ H NMR (400MHz, CDCl ₃ ) δ9.34( s,1H),7.77(d,J=7.7Hz,1H),7.72–7.50(m,3H),7.48–7.40(m,1H),7.21(d,J=7.5Hz,1H),7.00(s ,1H),5.04–4.87(m,2H),4.64–4.52(m,2H),3.10(s,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ154.44,151.20,151.10,143.83,142.59,137.50, 134.97, 129.72, 129.15, 122.27, 115.98, 114.54, 112.12, 111.53, 82.07(d, J=170.8Hz), 69.41(d, J=21.1Hz), 40.68.

Example 87: Synthesis of 2-(5-(2-fluoroethoxy)quinoxalin-2-yl)-N-methylaniline (60)

According to the method for preparing compound 55, yellow solid 60 (148.4 mg, 45.8%) was obtained from compound 54. ¹ HNMR (400MHz, CDCl ₃ ) δ8.54(d, J＝7.7Hz, 1H), 8.02(d, J＝8.4Hz, 1H), 7.78–7.72(m, 1H), 7.63–7.57(m, 1H ),7.50(d,J＝8.2Hz,1H),7.45–7.39(m,1H),7.27–7.19(m,2H),5.10–4.93(m,2H),4.65–4.54(m,2H), 4.04(s,3H) ^.13C NMR(101MHz,CDCl ₃ )δ154.16,153.94,150.04,143.50,141.18,132.04,131.95,129.98,129.42,121.08,117.02,115.59,111.20,18J.7 171.3Hz), 68.40(d, J=21.3Hz), 29.83.

The schematic diagram of the synthesis process of the above compounds of Examples 64-87 is shown in FIG. 4 .

Example 88: Preparation of ¹⁸ F-labeled ligand

1. Experimental steps:

1) Compounds (S)-[ ¹⁸ F]5, (R)-[ ¹⁸ F]5, (S)-[ ¹⁸ F]16, (R)-[ ¹⁸ F]16, (S)-[ ¹⁸ F] ]23, (R)-[ ^18F ]23, (R,S)-[ ^18F ]30, (S,R)-[ ^18F ]30, (R,S)-[ ^18F ]33 and Preparation of (S,R)-[ ¹⁸ F]33

[ ¹⁸ F] _F ^- ions are enriched on _the QMA column, and [ ¹⁸ F]F ^- Eluted from the QMA column. Take about 20mCi of fluoride ion solution and add it to a 10mL glass reaction tube, heat it in a metal bath at 120°C, blow it dry with N ₂ continuously, then add 1.0mL anhydrous acetonitrile in three times and blow it dry azeotropically to ensure that the reaction system is anhydrous . 3.0 mg of labeled precursors [respectively compounds S-12, R-12, S-20, R-20, S-27, R-27, (R, S)-29, (S, R)-29, (R,S)-32 and (S,R)-32] were dissolved in 600 μL of anhydrous acetonitrile, and the solution was transferred to a glass reaction tube containing [ ¹⁸ F] ^F- . Under the condition of 100° C., the reaction was heated for 6 minutes. After cooling, 400 μL of hydrochloric acid solution (1M) was added, and the reaction was continued for 5 minutes at 100° C. to remove the Boc protecting group. After cooling, saturated NaHCO ₃ solution was added to make the reaction system weakly alkaline, and 10 mL of deionized water was added to dilute the reaction mixture. The mixture was purified by a pretreated Sep-PakPlus PS-2 solid-phase extraction column, and the column was rinsed with 20 mL of deionized water to remove unreacted [ ¹⁸ F]F- and inorganic salts. Rinse the column with anhydrous acetonitrile (washing 3 times, 1 mL each time), elute the labeled compound and label precursor adsorbed on the column, concentrate and separate and purify by HPLC. Separation conditions: Venusil MP C18 reverse column (5 μm, 10mm×250mm), collect the effluent of the target product, remove the solvent by rotary evaporation, dissolve the obtained product in 10% ethanol and prepare the required concentration with purified water.

2. Experimental results:

(S)-[ ¹⁸ F]5, (R)-[ ¹⁸ F]5, (S)-[ ¹⁸ F]16, (R)-[ ¹⁸ F]16, (S)-[ ¹⁸ F]23, (R)-[ ^18F ]23, (R,S)-[ ^18F ]30, (S,R)-[ ^18F ]30, (R,S)-[ ^18F ]33 and (S, The labeling rate of R)-[ ¹⁸ F]33 was 20-30%. After separation and purification by HPLC, the radiochemical purity was greater than 95%, and the retention time was consistent with that of the stable fluorinated ligand (Table 1).

Table 1 Retention time and purity of ¹⁸ F-labeled ligands and their stable ligands

Experiment 89: Fluorescence dyeing experiment

1. Experimental steps:

Fluorescent staining of AD patient brain sections

(1) Prepare the aqueous solution (containing 20% ethanol) of the compound respectively, with a concentration of 1 μM;

(2) Two slices of 8 μm thick AD human brain slices (paraffin) were dewaxed in xylene for 15 min, then 100% ethanol for 2×5 min, 95% ethanol for 2×5 min, and 80% ethanol for 5 min. Wash with ethanol and 70% ethanol for 5min, wash with running water for 10min, and put in 10mM PBS (pH 7.4);

(3) Immerse the brain slices in the solution of the compound to be tested for 15 minutes;

(4) After the sections were washed with 40% ethanol and rapidly differentiated, they were observed with a fluorescence microscope.

2. Experimental results:

The experimental results are shown in Figure 5, the probe of the present invention can clearly label the neurofibrillary tangle NFTs on the AD human brain slices, and does not bind to the Aβ plaque or bind weakly, indicating that the probe provided by the present invention is compatible with Tau protein selectively binds.

Table 2 Staining evaluation and quantitative activity data of fluorinated compounds with tau and Aβ on AD human brain slices

Experimental Example 90: Autoradiography Experiment

After a certain concentration of labeled products were combined with the plaques in the brain slices of AD patients, they were exposed through a phosphor screen, and then the images were analyzed with a phosphor storage screen system.

1. Experimental steps:

(1) Preprocessing AD human brain slices;

(2) Cover AD human brain slices with 100 μL of ¹⁸ F-labeled compound solution of 20 μCi, and incubate at room temperature for 40 minutes;

(3) Rinse with 20% ethanol solution for 1 minute;

(4) After drying, wrap it with plastic wrap and place it under a phosphor screen for exposure for 40 minutes, and analyze the image with a phosphor storage screen system.

2. Experimental results:

The experimental results are shown in Figure 6, which fully demonstrates that the compound of the present invention can be used as a tau protein imaging agent in AD brain after being labeled with a radionuclide, and has potential application prospects in clinical diagnosis.

Experimental Example 91: Biodistribution experiment in normal mice

The pharmacokinetic properties in mice, especially initial brain uptake and brain clearance, were studied by in vivo distribution experiments.

1. Experimental steps:

5-10 μCi of the labeled compound (100 μL of normal saline solution, containing 10% ethanol) was injected into normal mice (ICR, male, 20-22 g, 5 weeks old) through the tail vein (n=5). Minutes, 10 minutes, 30 minutes and 60 minutes, they were executed by decapitation, relevant organs were dissected, and wet weight and radioactive counts were measured. Data are expressed as percent radioactive dose per gram of organ (%ID/g).

2. Experimental results:

The experimental results are shown in Table 3. The probes (S)-[ ¹⁸ F]5, (R)-[ ¹⁸ F]5, (S)-[ ¹⁸ F]16, (R)-[ ^18F ]16, (S)-[ ^18F ]23, (R)-[ ^18F ]23, (R,S)-[ ^18F ]30, (S,R)-[ ^18F ]30, ( Both R,S)-[1 ⁸ F]33 and (S,R)-[ ¹⁸ F]33 can pass through the blood-brain barrier smoothly, and the brain uptake peaks at 2 minutes and is cleared quickly in the brain of normal mice .

Table 3: Biodistribution results of ¹⁸ F-labeled compounds in normal mice

a expressed as %ID/g, n=4-5

Although the present invention has been described in detail with general descriptions and specific embodiments above, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (8)

1. the 2-arylquinoxaline compound that has affinity with Tau protein, it is characterized in that, the structure of described compound is as shown in formula (I): Wherein, R ₁ is located at the 4-7 position, and R ₂ is located at the 2', 3' or 4'position; R ₁ and R ₂ independently represent H, ¹⁸ F, ¹⁹ F, ¹²³ I, ¹²⁵ I, ¹²⁷ I, OH, O ¹¹ CH ₃ , O ¹² CH ₃ , NH ₂ , NH ¹¹ CH ₃ , NH ¹² CH ₃ , N(CH ₃ ) ₂ , O(CH ₂ ) _m ¹⁸ F or O(CH ₂ ) _m ¹⁹ F; wherein, R is OH, ¹⁸ F or ¹⁹ F, and m is an integer between 1-6. 2. The compound according to claim 1, characterized in that, the compound is any compound in formulas 1) to 13): Wherein, F in formulas 4) to 13) is ¹⁸ F or ¹⁹ F. 3. the preparation method of the described compound of claim 2 is characterized in that, formula 1) and formula 2) described compound is prepared according to the following steps: (1) Take 10mmol Dissolved in 10mL DMSO, stirred at room temperature for 30 minutes, then slowly added 10mmol 10mL of DMSO solution, raised to room temperature, continued to react for 2 hours, added 200mL saturated NaHCO ₃ solution, a yellow precipitate was precipitated, filtered by suction, washed with water, and dried to obtain a 5- or 6-substituted mixture; (2) Under heating conditions, 1.0 g of the above mixture and 2.0 g of oxalic acid dihydrate were dissolved in 200 mL of absolute ethanol to obtain a purple-red solution. After cooling, a solid precipitated and was suction filtered to obtain a purple-red oxalate crystal substituted at the 6-position. After adding petroleum ether dropwise to the filtrate, the solid was precipitated, filtered with suction to obtain dark red oxalate crystals substituted at the 5-position, and 5.0 mL of concentrated ammonia water was added to the above crystals to obtain a yellow solid, filtered with suction, washed and dried to obtain formula 1) and 2) the compound shown. 4. the preparation method of the described compound of claim 2 is characterized in that, formula 3), formula 6) or formula 11) described compound is prepared according to the following steps: (1) Take 1mmol of the compound shown in formula 1), 1mmol of CsF and 1.2mmol of Dissolve in 5mL of anhydrous DMF, stir and react at 90°C for 2 hours, add 50mL of ice water, a yellow precipitate precipitates, filter with suction, wash and dry to obtain formula (V), formula (VI) or formula (VII) respectively Show compounds; (2) Dissolve 1 mmol of the compound represented by formula (VI) in 20 mL of THF, add 10 mL of 1M HCl, heat at 60°C for 1 hour, then remove THF by rotary evaporation, add 5.0 mL of ammonia water, a yellow precipitate precipitates, filter with suction, wash and dry Obtain compound shown in formula (VIII); (3) Dissolve 1 mmol of the compound shown in formula (VIII) in 10 mL of anhydrous dichloromethane, add 1 mmol of p-toluenesulfonyl chloride and 10 mmol of triethylamine, react at room temperature for 12 hours, then remove the solvent by rotary evaporation, and separate by column chromatography to obtain Compound shown in formula (IX); (4) 1 mmol of the compound represented by formula (IX) was dissolved in 10 mL of anhydrous dichloromethane, 4 mmol of 3,4-dihydropyran and 1.0 g of pyridine p-toluenesulfonate were added, and the reaction was stirred at 50°C for 12 hours, After the reaction is finished, the solvent is removed by rotary evaporation, and column chromatography is separated to obtain the compound shown in formula (X); (5) Dissolve 1-5 mg of compound (V) or (VII) or (X) in 1 mL of anhydrous acetonitrile, _and add it to a _{5-30 mCi} ^{18 F-} In the reaction tube, label at 100°C for 5 minutes; for compounds (VII) and (X), add 100 μL of 1M HCl, continue to react at 100°C for 5 minutes, then add saturated NaHCO ₃ solution to neutralize; finally pass through C18 Reversed-phase column, washed with water to remove salt and remaining ¹⁸ F ^- , and then rinsed with acetonitrile to obtain the final product, after drying with N ₂ , separated by HPLC to obtain formula (V) and formula (VI) with a purity greater than 98%. ) or a compound represented by formula (VII); Wherein, the preparation of the compound shown in formula 1) described in step (1) is the same as that described in claim 3. 5. The derivatives of the compounds according to claim 1 or 2, including pharmaceutically acceptable salts, esters or amides. 6. A diagnostic or detection reagent for neurofibrillary tangle disease caused by Tau protein deposition, characterized in that the active ingredient is the compound as claimed in claim 1 or 2, and/or the derivative as claimed in claim 5. 7. The diagnosis or detection reagent according to claim 6, wherein the disease comprises Alzheimer's disease, frontotemporal lobe degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal ganglia Degenerative degeneration or Pick's disease. 8. Use of the compound according to claim 1 or 2, or the derivative according to claim 5 in the preparation of nuclear medicine imaging agent or optical imaging agent.