Dual-targeted polyhydroxy alkaloid compounds, their preparation methods and uses

Abstract

The present invention provides a dual-targeted polyhydroxy alkaloid compound, a preparation method and uses thereof, relating to the field of medicine. The dual-targeted polyhydroxy alkaloid compound provided by the present invention combines 1-deoxynojirimycin with thiazolidinedione to synthesize a novel 1-deoxynojirimycin derivative having effects such as treating diabetes. The synthesis method is simple and the product purity is high. The derivative has excellent α-glucosidase inhibitory activity and can directly bind to PPARγ, thereby improving insulin resistance and enhancing the blood glucose lowering effect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a dual-targeted polyhydroxy alkaloid compound, a preparation method thereof, and uses thereof. Background Art

[0002] Diabetes is a chronic metabolic disease characterized by elevated blood glucose levels. High blood glucose can damage normal tissues and organs, affecting the physiological functions of the human body. People with diabetes will be accompanied by a series of complications, such as: diabetic nephropathy, diabetic encephalopathy, diabetic foot, and effects on the eyes, teeth, nerves, heart, and blood vessels, etc., and severe cases can lead to death.

[0003] 1-Deoxynojirimycin (DNJ) is a polyhydroxy alkaloid, which was first isolated and identified from mulberry leaves. Its structure is (2R,3R,4R,5S)-2-(hydroxymethyl-3,4,5-trihydroxy)pyridine. It can competitively bind to α-glucosidase and is a natural and highly efficient α-glucosidase inhibitor. Studies on the urinary metabolism of DNJ in db / db diabetic mice showed that DNJ not only inhibits the activity of glucosidase in glucose metabolism, but also affects the metabolism of fat and amino acids. In addition to the study of hypoglycemic activity, DNJ also has good activities in anti-tumor, anti-virus, antioxidant, etc. Total alkaloids tablets from mulberry branches, as a natural hypoglycemic drug, are used to treat type II diabetes. The main component of this drug is the total alkaloids extracted from mulberry branches, among which the content of 1-deoxynojirimycin is the highest. Although DNJ has excellent α-glucosidase inhibitory effects in vitro, its in vivo efficacy is not high. Therefore, structural modification and transformation of DNJ to design new DNJ derivatives have broad scientific research value.

[0004] Patent CN 109293564 A discloses a 1-deoxynojirimycin-hydroxycinnamic acid methyl ester hybrid derivative, a preparation method thereof, and applications thereof. The 1-deoxynojirimycin-hydroxycinnamic acid methyl ester hybrid derivative has the structure shown in formula (I). It has been proven by in vitro tests that this type of compound is a potent α-glucosidase inhibitor, and its inhibitory activity against α-glucosidase is significantly higher than that of acarbose, the most commonly used postprandial blood glucose control agent at present.

[0005]

[0006] Patent CN 101696186 A discloses a method for synthesizing 1-deoxynojirimycin derivatives. Using 1-deoxynojirimycin and aryl epoxides as raw materials, with methanol as the solvent, reacting at room temperature for 12 - 24 h, removing the solvent by rotary evaporation under vacuum, and then separating and purifying by column chromatography, using ethyl acetate / methanol as the eluent, 1-deoxynojirimycin derivatives are obtained. The general structural formula is as follows:

[0007]

[0008] Peroxisome proliferator-activated receptors (PPARs) are ligand-activated dependent transcription factors and belong to the nuclear receptor superfamily members, including three subtypes: PPARα, PPARβ, and PPARγ. Among them, PPARγ receptor agonists can stimulate and regulate insulin-regulated genes, improve insulin sensitivity in peripheral tissues and adipose tissues, promote 2-deoxyglucose and glucose consumption, have obvious anti-hyperglycemic effects, and can improve insulin resistance and the control of glucagon, thereby reducing the insulin level in plasma. Currently, the marketed insulin sensitizers are full agonists of PPARγ, and representative drugs include rosiglitazone, pioglitazone, etc. It has been found that the thiazolidinedione fragment in its structure is the active fragment for exerting anti-hyperglycemic effects and has good research value.

[0009] The present invention provides a preparation method and activity research of DNJ and thiazolidinedione conjugated compounds. The synthesized compounds have dual functions of inhibiting α-glucosidase activity and activating PPARγ, can improve insulin resistance, and have the potential for treating type II diabetes.

[0010] SUMMARY OF THE INVENTION

[0011] Aiming at the problems, the present invention provides a dual-targeted polyhydroxy alkaloid compound, its preparation method and use. By conjugating 1-deoxynojirimycin with thiazolidinedione, a novel 1-deoxynojirimycin derivative with functions such as treating diabetes is synthesized. The synthesis method is simple and the product purity is high.

[0012] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0013] On the one hand, the present invention provides a dual-targeted polyhydroxy alkaloid compound with the following general structural formula:

[0014]

[0015] Wherein,

[0016]

[0017] Preferably, it is selected from the following structures:

[0018]

[0019] Further preferably, it is selected from the following structures:

[0020]

[0021] On the other hand, the present invention provides a preparation method of a dual-targeted polyhydroxy alkaloid compound, comprising the following steps:

[0022]

[0023] 1) Using 1-deoxynojirimycin as a raw material to carry out intra-ring amino protection to prepare intermediate C2; carrying out polyhydroxy protection on intermediate C2 to prepare intermediate C3; carrying out amino deprotection on intermediate C3 to prepare intermediate C4;

[0024] 2) Using p-hydroxybenzaldehyde as a raw material, the hydroxyl group first undergoes substitution with carbon chains of different lengths to prepare intermediates L2 and L3, and then these intermediates undergo Knoevenagel condensation reaction with the N-terminal substituted thiazolidinedione fragments B2-a - B2-h to prepare intermediates B3-a - B3-h and B4-a - B4-h;

[0025] 3) Reacting intermediate B3-a - B3-h or B4-a - B4-h with intermediate C4 to prepare intermediate C5-a - C5-h or C6-a - C6-h;

[0026] 4) Carrying out double bond reduction on intermediate C5-a - C5-h or C6-a - C6-h by Pd / C-catalyzed hydrogenation at room temperature to prepare intermediate C7-a - C7-h or C8-a - C8-h;

[0027] 5) Removing the protecting groups of the hydroxyl groups from intermediate C5-a - C5-h or C6-a - C6-h or C7-a - C7-h or C8-a - C8-h to obtain the final product ASP-1 - ASP-32.

[0028] Preferably, the reaction conditions for preparing intermediate C2 are: 1-deoxynojirimycin is dissolved in saturated sodium bicarbonate aqueous solution, Cbz-Cl is added at 0 °C, after stirring for 10 - 20 min, the temperature is raised to room temperature, and the reaction is carried out for 14 - 18 h.

[0029] Preferably, the molar ratio of 1-deoxynojirimycin to Cbz-Cl is 1:1.1 - 1.3; further preferably, the molar ratio of 1-deoxynojirimycin to Cbz-Cl is 1:1.2.

[0030] Preferably, the reaction conditions for preparing intermediate C3 are as follows: Compound C2 is dissolved in a solvent, TBSOTf and 2,6-lutidine are added at 0 °C, and the reaction is carried out at room temperature for 14 - 18 h.

[0031] Preferably, the molar ratio of compound C2 to TBSOTf and 2,6-lutidine is 1:5 - 8:8 - 12; more preferably, the molar ratio of compound C2 to TBSOTf and 2,6-lutidine is 1:6:10.

[0032] Preferably, the reaction conditions for preparing intermediate C4 are as follows: Compound C3 is dissolved in a solvent, and a catalytic amount of Pd / C and Pd(OH) 2 / C are added, and the catalytic hydrogenation reaction is carried out at room temperature.

[0033] Preferably, the molar ratio of Pd / C and Pd(OH) 2 / C is 1:1.

[0034] Preferably, the reaction conditions for preparing intermediate L2 are as follows: Compound L1 is dissolved in a solvent, potassium carbonate and 1,2-dibromoethane are added, and the mixture is heated to 80 - 100 °C and reacted for 7 - 11 h.

[0035] Preferably, the reaction conditions for preparing intermediate L3 are as follows: Compound L1 is dissolved in a solvent, potassium carbonate and 1,3-dibromopropane are added, and the reaction is carried out at room temperature for 7 - 11 h.

[0036] Preferably, the reaction conditions for preparing intermediates B3-a - B3-h are as follows: Intermediate L2 is dissolved in a solvent, a catalytic amount of piperidine acetate is added, and the mixture is refluxed for 2 - 3 h.

[0037] Preferably, the reaction conditions for preparing intermediates B4-a - B4-h are as follows: Intermediate L3 is dissolved in a solvent, a catalytic amount of piperidine acetate is added, and the mixture is refluxed for 2 - 4 h.

[0038] Preferably, the reaction conditions for preparing intermediates C5-a - C5-h or C6-a - C6-h are as follows: Compound C4 is dissolved in a solvent, and compounds B3-a - B3-h or B4-a - B4-h, cesium carbonate, and DMF are added in sequence, and the reaction is carried out at 80 °C for 8 hours.

[0039] Preferably, the reagent used for removing the hydroxyl protecting group is 2M hydrochloric acid - ethyl acetate solution.

[0040] On the other hand, the present invention provides the use of the compound described in any one of the above or the compound prepared by the preparation method described in any one of the above in the preparation of a drug for treating diabetes and diseases of glycolipid metabolism disorders.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The present invention combines 1-deoxynojirimycin with thiazolidinedione to synthesize a novel 1-deoxynojirimycin derivative with functions such as treating diabetes. The synthesis method is simple and the product purity is high. The derivative has excellent α-glucosidase inhibitory activity and can directly bind to PPARγ, thereby improving insulin resistance and enhancing the blood glucose lowering effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 Effect of ASP-1-ASP-9 on glucose consumption of L02 cells;

[0044] Figure 2 Effect of ASP-10-ASP-17 on glucose consumption of L02 cells;

[0045] Figure 3 Effect of ASP-18-ASP-25 on glucose consumption of L02 cells;

[0046] Figure 4 Effect of ASP-26-ASP-32 on glucose consumption of L02 cells. DETAILED DESCRIPTION OF THE INVENTION

[0047] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be further clarified below with reference to specific embodiments. However, the following embodiments are only the preferred embodiments of the present invention and not all of them. Based on the embodiments in the embodiments, other embodiments obtained by those skilled in the art without creative efforts all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the same meanings as those commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0048] Preparation of Intermediate C2

[0049] Compound DNJ C1 (5.0 g, 30.64 mmol) was dissolved in 38 mL of saturated sodium bicarbonate aqueous solution. After Cbz-Cl (5.18 mL, 36.77 mmol) was mixed evenly with an equal volume of toluene, it was slowly added to the above solution under ice bath conditions. The reaction was carried out for 15 minutes under ice bath, and then gradually heated to room temperature. After stirring overnight at room temperature and the reaction was completed in 16 h, water was added to dilute the reaction solution, and it was extracted with DCM. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under reduced pressure to obtain a colorless oily product C2, which was freeze-dried with a yield of 81%.

[0050] Preparation of Intermediate C3

[0051] Compound C2 (11 g, 36.7 mmol) was added to 40 mL of chloroform and dissolved by sonication. TBSOTf (61.3 mL, 222 mmol) and 2,6 - lutidine (42.3 mL, 367 mmol) were slowly added at 0 °C. The reaction was maintained at 0 °C for 15 min, then naturally warmed to room temperature and reacted overnight at room temperature. The formation of the product and the completion of the reaction were monitored by TLC. The reaction was complete after 16 h. After the reaction, a large amount of water was added, and the mixture was extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain colorless oily product C3 with a yield of 88.5%.

[0052] Synthesis of Intermediate C4

[0053] Compound C3 (24.5 g, 32.48 mmol) was dissolved in ethyl acetate, and catalytic amounts of Pd / C and Pd(OH) 2 / C (M:M = 1:1) were added. Catalytic hydrogenation was carried out at room temperature, and the reaction progress and product formation were monitored by TLC. The reaction ended after 5 h. After the reaction, it was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain colorless oily product C4 with a yield of 95%.

[0054] Synthesis of Intermediate L2

[0055] Compound L1 (10 g, 81.87 mmol) was added to a round - bottom flask and dissolved in acetonitrile. Then potassium carbonate (22.63 g, 163.74 mmol) and 1,2 - dibromoethane (21.28 mL, 245.7 mmol) were successively added to compound L1. The reaction was heated at 90 °C for 8 h, and the reaction progress was monitored by TLC plate during the reaction. After the reaction was complete, the remaining potassium carbonate solid was removed by suction filtration, washed several times with dichloromethane, the filtrate was collected, concentrated under reduced pressure, and purified by column chromatography to obtain white solid product L2 with a yield of 85%.

[0056] Synthesis of Intermediate L3

[0057] Compound L1 (3 g, 24.57 mmol) was added to a round - bottom flask and dissolved in acetonitrile. Then potassium carbonate (6.79 g, 49.14 mmol) and 1,3 - dibromopropane (7.7 mL, 73.7 mmol) were successively added to compound L1. The reaction was carried out at room temperature for 16 h, and the reaction progress was monitored by TLC plate during the reaction. After the reaction was complete, the remaining potassium carbonate solid was removed by suction filtration, washed several times with dichloromethane, the filtrate was collected, concentrated under reduced pressure, and purified by column chromatography to obtain colorless oily product L3 with a yield of 70%.

[0058] Synthesis of Intermediates B2 - a - B2 - h

[0059] Dissolve compound 1,4-thiazolidinedione (1.5 g, 12.8 mmol) in DMF. Under stirring at room temperature, successively add bromobenzyl or tert-butyl chloroacetate with different group substitutions (1:1.2) and potassium carbonate (3.54 g, 25.6 mmol). React at room temperature for 4 h. During this period, monitor the reaction progress by TLC plate. After the reaction is completed, filter off the remaining potassium carbonate solid, extract with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and purify by column chromatography to obtain white solid products B2-a - B2-h, with a yield of 35% - 94%.

[0060] Synthesis of intermediates B3-a - B3-h

[0061] Dissolve compounds B2-a - B2-h and intermediate L2 in anhydrous ethanol in a ratio of 1:1, then add a catalytic amount of piperidine acetate, and reflux for 2.5 h. During the process, detect the reaction progress by TLC plate. After the reaction is completed, cool to room temperature, and a solid precipitates. Filter, and purify the solid by slurrying with anhydrous ethanol to obtain solid products B3-a - B3-h, with a yield of 57% - 86%.

[0062] Synthesis of intermediates B4-a - B4-h

[0063] Dissolve compounds B2-a - B2-h and intermediate L3 in anhydrous ethanol in an equivalent ratio of 1:1, then add a catalytic amount of piperidine acetate, and reflux for 3 h. During the process, detect the reaction progress by TLC plate. After the reaction is completed, cool to room temperature, and a solid precipitates. Filter, and purify the solid by slurrying with anhydrous ethanol to obtain solid products B4-a - B4-h, with a yield of 40% - 62%.

[0064] Synthesis of intermediates C5-a - C5-h

[0065] Dissolve compound C4 (2 g, 3.22 mmol) in acetone, then successively add compounds B2-a - B2-h (equivalent ratio = 1:1.1) and cesium carbonate, add a small amount of DMF, and react at 80 °C. During the process, monitor the reaction progress by TLC. After the reaction is completed, filter, evaporate the filtrate to dryness, and purify by column chromatography to obtain yellow oily products C5-a - C5-h, with a yield of 40% - 75%.

[0066] Synthesis of intermediates C6-a - C6-h

[0067] Dissolve compound C4 (2 g, 3.22 mmol) in acetone, then successively add compounds B4-a - B4-h (equivalent ratio = 1:1.1) and cesium carbonate. Add a small amount of DMF and react at 80 °C. Monitor the reaction progress by TLC during the process. After the reaction is completed, filter, concentrate the filtrate by rotary evaporation, and perform column chromatography for purification to obtain yellow oily products C6-a - C6-h with a yield of 20% - 68%.

[0068] Synthesis of intermediates C7-a - C7-h

[0069] Dissolve compounds C5-a - C5-h in 1,4-dioxane, add Pd / C under stirring at room temperature, and perform catalytic hydrogenation at room temperature. Monitor the reaction progress by TLC during the process. After the reaction is completed, filter, concentrate the filtrate by rotary evaporation to obtain yellow oily products C7-a - C7-h with a yield of 50% - 65%.

[0070] Synthesis of intermediates C8-a - C8-h

[0071] Dissolve compounds C6-a - C6-h in 1,4-dioxane, add Pd / C under stirring at room temperature, and perform catalytic hydrogenation at room temperature. Monitor the reaction progress by TLC during the process. After the reaction is completed, filter, concentrate the filtrate by rotary evaporation to obtain yellow oily products C8-a - C8-h with a yield of 50% - 65%.

[0072] Example 1: Preparation of compounds ASP-1 - ASP-32

[0073] Dissolve compounds C5-a - C5-h in ethyl acetate, slowly add 2M HCl-ethyl acetate solution at 0 °C, react at 0 °C for 15 minutes, then transfer to room temperature and continue to react for 2 h. Monitor the reaction progress by TLC during the process. After the reaction is completed, filter, concentrate the filtrate by rotary evaporation, perform column chromatography for purification, and further purify by preparative liquid chromatography to obtain the target products ASP-1 - ASP-8.

[0074] Refer to the synthesis method of ASP-1 - ASP-8 in Example 1, only replace C5-a - C5-h with C6-a - C6-h to obtain compounds ASP-9 - ASP-16.

[0075] Refer to the synthesis method of ASP-1 - ASP-8 in Example 1, only replace C5-a - C5-h with C7-a - C7-h to obtain compounds ASP-17 - ASP-24.

[0076] Refer to the synthesis method of ASP-1 - ASP-8 in Example 1, only replace C5-a - C5-h with C8-a - C8-h to obtain compounds ASP-25 - ASP-32.

[0077] For compound ASP-1-ASP-32 1 1H NMR, 13 C-APT NMR and HRMS data are as follows.

[0078]

[0079] ASP-1: White solid in 16.2% yield. 1 1H NMR(600 MHz, DMSO-d6)δ7.93(s, 1H, CH=CS),

[0080] 7.60(d, J=8.7Hz, 2H, O-Ph-H), 7.38 - 7.28(m, 5H, Ph-H), 7.11(d, J=8.7Hz, 2H, O-Ph-H), 4.84(s, 2H, NCH 2 Ph), 4.78 - 4.69(m, 3H, 3×OH), 4.33 - 4.28(m, 1H, OH), 4.21 - 4.11(m, 2H, COCH 2 ), 3.86 - 3.79(m, 1H, DNJ-H), 3.60 - 3.53(m, 1H, DNJ-H), 3.25 - 3.16(m, 2H, DNJ-H), 3.04 - 2.97(m, 1H, DNJ-H), 2.96 - 2.89(m, 2H, NCH 2 CH 2 O), 2.17(t, J=11.1Hz, 1H, DNJ-H), 2.11 - 2.05(m, 1H, DNJ-H). 13 C-APT NMR(151 MHz, DMSO-d6)δ167.87, 166.13, 161.05, 136.05, 134.01, 132.86, 129.15, 128.26, 128.07, 125.76, 118.13, 115.95, 79.59, 71.10, 69.81, 67.24, 66.23, 59.92, 58.51, 51.17, 45.05. HRMS(ESI): [M+H] + m / z calcd for C 25 H 28 N 2 O 7 S: 501.1690, found, 501.1835.

[0081]

[0082] ASP-2: White solid in 10.5% yield. 1 H NMR(600 MHz, DMSO-d6) δ7.94(s, 1H, CH=CS),

[0083] 7.73(d, J=8.3Hz, 2H, Br-Ph-H), 7.60(d, J=8.8Hz, 2H, O-Ph-H), 7.53(d, J=7.9Hz, 2H, Ph-H), 7.11(d, J=8.8Hz, 2H, O-Ph-H), 4.93(s, 2H, NCH 2 Ph), 4.77 - 4.71(m, 3H, 3×OH), 4.31(dd, J=4.3Hz, 6.1Hz, 1H, OH), 4.21–4.12(m, 2H, COCH 2 ), 3.85–3.80(m, 1H, DNJ-H), 3.59 - 3.53(m, 1H, DNJ-H), 3.23 - 3.17(m, 2H, DNJ-H), 3.03 - 2.97(m, 1H, DNJ-H), 2.95–2.89(m, 2H, NCH 2 CH 2 O), 2.89 - 2.83(m, 1H, DNJ-H), 2.19 - 2.13(m, 1H, DNJ-H), 2.10 - 2.05(m, 1H, DNJ-H). 13 C-APT NMR(151MHz, DMSO-d6) δ167.95, 166.10, 161.09, 140.71, 134.14, 132.88, 128.78, 126.07, 126.04, 125.73, 118.09, 115.97, 79.59, 71.10, 69.81, 67.25, 66.24, 59.93, 58.51, 51.17, 44.58. HRMS(ESI): [M+H] + m / z calcd for C 25 H 27 BrN 2 O 7 S: 579.0795, found, 579.0796.

[0084]

[0085] ASP-3: White solid in 16.2% yield. 1 H NMR(600 MHz, DMSO-d6) δ7.91(s, 1H, CH=CS),

[0086] 7.58 (d, J = 8.7 Hz, 2H, O-Ph-H), 7.18 (d, J = 8.1 Hz, 2H, Ph-H), 7.14 (d, 7.5 Hz, 2H, Ph-H), 7.10 (d, J = 8.7 Hz, 2H, O-Ph-H), 4.89 - 4.77 (m, 3H, 3×OH), 4.76 (s, 2H, NCH 2 Ph), 4.38 - 4.31 (m, 1H, OH), 4.16 - 4.15 (m, 2H, COCH 2 ), 3.81 - 3.78 (m, 1H, DNJ-H), 3.60 - 3.51 (m, 1H, DNJ-H), 3.24 - 3.14 (m, 2H, DNJ-H), 3.04 - 2.96 (m, 1H, DNJ-H), 2.96 - 2.89 (m, 2H, NCH 2 CH 2 O), 2.88 - 2.81 (m, 1H, DNJ-H), 2.25 (s, 3H, CH3), 2.20 - 2.11 (m, 1H, DNJ-H), 2.10 - 2.02 (m, 1H, DNJ-H). 13 C-APT NMR (151 MHz, DMSO) δ 167.82, 166.11, 161.04, 137.55, 133.96, 133.08, 132.85, 129.67, 129.67, 128.15, 125.76, 118.14, 115.94, 79.59, 71.10, 69.81, 67.24, 66.23, 59.92, 58.51, 51.17, 44.84, 21.16. HRMS (ESI): [M + H] + m / z calcd for C 26 H 30 N 2 O 7 S: 515.1847, found, 515.1847.

[0087]

[0088] ASP-4: White solid in 46.2% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.93 (s, 1H, CH=CS),

[0089] 7.60 (d, J = 8.2 Hz, 2H, O-Ph-H), 7.12 (d, J = 9.0 Hz, 2H, O-Ph-H), 6.45 - 6.43 (m, 3H, Ph-H), 4.80 - 4.76 (m, 3H, 3×OH), 4.76 (s, 2H, NCH 2 Ph), 4.35 - 4.33 (m, 1H, OH), 4.21 - 4.13 (m, 2H, COCH 2 ), 3.85 - 3.83 (m, 1H, DNJ-H), 3.72 (s, 6H, 2×OCH 3 ), 3.60 - 3.56 (m, 1H, DNJ-H), 3.25 - 3.17 (m, 2H, DNJ-H), 3.04 - 3.00 (m, 1H, DNJ-H), 2.96 - 2.92 (m, 2H, NCH 2 CH 2 O), 2.90 - 2.85 (m, 1H, DNJ-H), 2.20 - 2.17 (m, 1H, DNJ-H), 2.10 - 2.09 (m, 1H, DNJ-H). 13 C-APT NMR (151 MHz, DMSO-d6) δ 167.87, 166.10, 161.06, 161.03, 138.21, 134.02, 132.87, 125.75, 118.06, 115.92, 106.01, 99.56, 79.58, 71.07, 69.81, 67.21, 66.19, 59.88, 58.49, 55.65, 51.16, 45.01. HRMS (ESI): [M+H] + m / z calcd for C 27 H 32 N 2 O 9 S: 561.1902, found, 561.1902.

[0090]

[0091] ASP-5: White solid in 26.5% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.95 (s, 1H, CH=CS),

[0092] 7.61 (d, J = 9.3 Hz, 2H, Ph-H), 7.11 (d, J = 8.5 Hz, 2H, Ph-H), 4.87 - 4.75 (m, 3H, 3×OH), 4.40 - 4.33 (m, 3H, NCH 2Ph,OH), 4.20–4.12 (m, 2H, COCH2), 3.84–3.79 (m, 1H, DNJ-H), 3.60 - 3.54 (m, 1H, DNJ-H), 3.25 - 3.16 (m, 2H, DNJ-H), 3.04 - 2.99 (m, 1H, DNJ-H), 2.96 - 2.91 (m, 2H, NCH 2 CH 2 O), 2.90–2.84 (m, 1H, DNJ-H), 2.21 - 2.14 (m, 1H, DNJ-H), 2.10 - 2.05 (m, 1H, DNJ-H), 1.41 (s, 9H, 3×CH 3 ). 13 C-APT NMR (151 MHz, DMSO) δ 167.46, 166.17, 165.57, 161.17, 134.53, 132.99, 125.57, 117.51, 115.98, 82.95, 79.56, 71.02, 69.79, 67.21, 66.19, 59.80, 58.44, 51.14, 43.27, 28.01. HRMS (ESI): [M + H] + m / z calcd for C 24 H 32 N 2 O 9 S: 525.1902, found, 525.1890.

[0093]

[0094] ASP-6: White solid in 18.9% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.94 (s, 1H, CH=CS),

[0095] 7.73 (d, J=8.1 Hz, 2H, Br-Ph-H), 7.60 (d, J=8.9 Hz, 2H, O-Ph-H), 7.53 (d, J=8.1 Hz, 2H, Ph-H), 7.11 (d, J=8.9 Hz, 2H, O-Ph-H), 4.93 (s, 2H, NCH 2 Ph), 4.78 - 4.71 (m, 3H, 3×OH), 4.33 - 4.29 (m, 1H, OH), 4.21–4.11 (m, 2H, COCH 2), 3.85–3.80 (m, 1H, DNJ-H), 3.59 - 3.53 (m, 1H, DNJ-H), 3.24 - 3.17 (m, 2H, DNJ-H), 3.03 - 2.97 (m, 1H, DNJ-H), 2.95–2.89 (m, 2H, NCH 2 CH 2 O), 2.89 - 2.83 (m, 1H, DNJ-H), 2.17 (t, J=10.5 Hz, 1H, DNJ-H), 2.10 - 2.05 (m, 1H, DNJ-H). 13 C-APT NMR (151 MHz, DMSO-d6) δ 167.95, 166.10, 161.09, 140.71, 134.14, 132.89, 128.78, 126.09, 126.07, 126.04, 126.02, 125.73, 118.09, 115.97, 79.59, 71.10, 69.82, 67.25, 66.24, 59.93, 58.51, 51.17, 44.58. HRMS (ESI): [M + H] + m / z calcd for C 26 H 27 F 3 N 2 O 7 S: 569.1564, found, 569.1563.

[0096]

[0097] ASP-7: White solid in 25.7% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (s, 1H, CH=CS),

[0098] 7.59 (d, J=9.0 Hz, 2H, O-Ph-H), 7.37 (d, J=8.3 Hz, 2H, Ph-H), 7.24 (d, J=8.1 Hz, 2H, Ph-H), 7.11 (d, J=9.0 Hz, 2H, O-Ph-H), 4.79 (s, 2H, NCH 2 Ph), 4.78 - 4.71 (m, 3H, 3×OH), 4.31 (dd, J=6.0 Hz, 4.5 Hz, 1H, OH), 4.23–4.10 (m, 2H, COCH 2), 3.86–3.80 (m, 1H, DNJ-H), 3.59 - 3.53 (m, 1H, DNJ-H), 3.24 - 3.16 (m, 2H, DNJ-H), 3.04 - 2.98 (m, 1H, DNJ-H), 2.96–2.90 (m, 2H, NCH 2 CH 2 O), 2.90 - 2.83 (m, 1H, DNJ-H), 2.17 (t, J=10.5 Hz, 1H, DNJ-H), 2.11 - 2.06 (m, 1H, DNJ-H), 1.25 (s, 9H, 3×CH 3 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 167.84, 166.11, 161.04, 150.72, 133.97, 133.11, 132.85, 127.98, 125.92, 125.76, 118.14, 115.94, 79.59, 71.10, 69.81, 67.24, 66.23, 59.92, 58.51, 51.17, 44.74, 34.73, 31.53. HRMS (ESI): [M+H] + m / z calcd for C 29 H 36 N 2 O 7 S: 557.2316, found, 557.2316.

[0099]

[0100] ASP-8: White solid in 20.6% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (s, 1H, CH=CS),

[0101] 7.59 (d, J=9.0 Hz, 2H, O-Ph-H), 7.26 (d, J=8.5 Hz, 2H, Ph-H), 7.11 (d, J=8.5 Hz, 2H, Ph-H), 6.91 (d, J=9.0 Hz, 2H, O-Ph-H), 4.77 - 4.73 (m, 5H, 3×OH, NCH 2 Ph), 4.32 - 4.30 (m, 1H, OH), 4.20 - 4.13 (m, 2H, COCH 2 ), 3.84 - 3.82 (m, 1H, DNJ-H), 3.73 (s, 3H, OCH 3), 3.58 - 3.55 (m, 1H, DNJ - H), 3.23 - 3.18 (m, 2H, DNJ - H), 3.03 - 2.99 (m, 1H, DNJ - H), 2.94 - 2.91 (m, 2H, NCH 2 CH 2 O), 2.88 - 2.84 (m, 1H, DNJ - H), 2.17 (t, J = 10.7 Hz, 1H, DNJ - H), 2.09 - 2.08 (m, 1H, DNJ - H). 13 C - APT NMR (151 MHz, DMSO - d6) δ 167.81, 166.09, 161.03, 159.35, 133.92, 132.84, 129.84, 128.07, 125.75, 118.16, 115.93, 114.48, 79.59, 71.10, 69.81, 67.24, 66.22, 59.92, 58.51, 55.57, 51.17, 44.59. HRMS (ESI): [M + H] + m / z calcd for C 26 H 30 N 2 O 8 S: 531.1796, found, 531.1786.

[0102]

[0103] ASP - 10: White solid in 18.4% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.30 - 7.23 (m, 3H, Ph - H), 6.79 (d, J = 8.7 Hz, 2H, O - Ph - H), 7.13 - 7.08 (m, 2H, Ph - H), 7.05 - 7.00 (m, 1H, Ph - H), 6.83 - 6.78 (m, 2H, Ph - H), 5.05 - 5.00 (m, 1H, S - CH), 4.90 - 4.68 (m, 3H, 3×OH), 4.61 (dd, J = 47.2 Hz, 14.9 Hz, 2H, NCH 2 Ph), 4.40 - 4.17 (m, 1H, OH), 4.10 - 3.97 (m, 2H, COCH 2 ), 3.86–3.79 (m, 1H, DNJ - H), 3.65 - 3.55 (m, 1H, DNJ - H), 3.35 - 3.29 (m, 2H, PhCH 2 CH), 3.28 - 3.12 (m, 3H, DNJ - H, PhCH 2CH), 3.11 - 2.80 (m, 4H, 2×DNJ - H, NCH 2 CH 2 O), 2.33 - 1.96 (m, 2H, DNJ - H). 13 C - APT NMR (151 MHz, DMSO - d6) δ 174.39, 171.57, 160.98, 158.02, 138.07, 130.85, 128.45, 114.70, 106.06, 99.47, 79.58, 71.07, 69.80, 67.22, 67.20, 65.60, 59.78, 58.49, 55.63, 55.41, 51.59, 51.31, 44.82, 36.46. HRMS (ESI): [M + H] + m / z calcd for C 25 H 29 BrN 2 O 7 S: 581.0952, found, 581.0953.

[0104]

[0105] ASP - 12: White solid in 31.9% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.09 (d, J = 8.7Hz, 2H,

[0106] O - Ph - H), 6.79 (d, J = 8.7Hz, 2H, O - Ph - H), 6.43 (s, 1H, Ph - H), 6.32 (d, J = 2.1Hz, 2H, Ph - H), 5.03 (dd, J = 8.4Hz, 4.5Hz, 1H, S - CH), 4.80 - 4.69 (m, 3H, 3×OH), 4.56 (dd, J = 17.6Hz, 15.1Hz, 2H, NCH 2 Ph), 4.30 - 4.22 (m, 1H, OH), 4.06 - 3.96 (m, 2H, COCH 2 ), 3.85 - 3.80 (m, 1H, DNJ - H), 3.71 (s, 6H, 2×OCH 3 ), 3.62 - 3.54 (m, 1H, DNJ - H), 3.35 - 3.32 (m, 1H, PhCH 2 CH), 3.26 - 3.14 (m, 2H, DNJ - H), 3.14 - 3.08 (m, 1H, PhCH 2CH), 3.06 - 2.99 (m, 1H, DNJ - H), 2.96 - 2.90 (m, 2H, NCH 2 CH 2 O), 2.87 - 2.79 (m, 1H, DNJ - H), 2.23 - 2.12 (m, 1H, DNJ - H), 2.12 - 2.03 (m, 1H, DNJ - H). 13 C - APT NMR (151 MHz, DMSO - d6) δ 174.39, 171.57, 160.98, 158.02, 138.07, 130.85, 128.45, 114.70, 106.06, 99.47, 79.58, 71.07, 69.80, 67.22, 67.20, 65.60, 59.78, 58.49, 55.63, 55.41, 51.59, 51.31, 44.82, 36.46. HRMS (ESI): [M + H] + m / z calcd for C 27 H 34 N 2 O 9 S: 563.2058, found, 563.2054.

[0107]

[0108] ASP - 14: White solid in 24.8% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.64 (d, J = 8.8Hz, 2H,

[0109] Ph - H), 7.24 (d, J = 7.6Hz, 2H, Ph - H), 7.11 (d, J = 7.6Hz, 2H, O - Ph - H), 6.81 (d, J = 8.8Hz, 2H, O - Ph - H), 5.03 (dd, J = 7.9Hz, 4.3Hz, 1H, S - CH), 4.85 - 4.64 (m, 5H, 3×OH, NCH 2 Ph), 4.34–4.24 (m, 1H, OH), 4.08–3.95 (m, 2H, COCH 2 ), 3.85–3.78 (m, 1H,DNJ - H), 3.62 - 3.52 (m, 1H, DNJ - H), 3.33 (dd, J = 14.2Hz, 4.1Hz, 1H, PhCH 2 CH), 3.25 - 3.11 (m, 3H, DNJ - H, PhCH 2(CH), 3.07 - 2.97 (m, 1H, DNJ-H), 2.97 - 2.88 (m, 2H, NCH 2 CH 2 O), 2.88–2.78 (m, 1H, DNJ-H), 2.22 - 2.12 (m, 1H, DNJ-H), 2.11 - 2.01 (m, 1H, DNJ-H). 13 C-APT NMR (151 MHz, DMSO-d6) δ 174.22, 171.63, 158.09, 140.49, 131.17, 128.52, 125.82, 125.51, 114.70, 70.58, 71.04, 69.80, 67.18, 65.56, 59.75, 58.49, 51.63, 51.30, 44.26, 40.44, 36.18. HRMS(ESI): [M+H] + m / z calcd for C 29 H 38 F 3 N 2 O 7 S: 559.2473, found, 559.2463.

[0110]

[0111] ASP-16: White solid in 29.5% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.08 (d, J=8.4 Hz, 2H,

[0112] O-Ph-H), 7.05 (d, J=8.4 Hz, 2H, Ph-H), 6.85 (d, J=8.7 Hz, 2H, Ph-H), 6.78 (d, J=8.4 Hz, 2H, O-Ph-H), 4.97 (dd, J=8.0 Hz, 4.4 Hz, 1H, S-CH), 4.80 - 4.76 (m, 2H, 2×OH), 4.76 - 4.73 (d, J=4.7 Hz, 1H, OH), 4.55 (d, J=38.9 Hz, 14.7 Hz, 2H, NCH 2 Ph), 4.30–4.27 (m, 1H, OH), 4.06–3.96 (m, 2H, COCH 2 ), 3.85–3.79 (m, 1H, DNJ-H), 3.73 (s, 3H, CH 3 ), 3.60 - 3.54 (m, 1H, DNJ-H), 3.33 - 3.28 (m, 1H, PhCH 2(CH), 3.24 - 3.18 (m, 1H, DNJ - H), 3.18 - 3.08 (m, 2H, PhCH 2 CH), 3.05 - 2.99 (m, 1H, DNJ - H), 2.96 - 2.90 (m, 2H, NCH 2 CH 2 O), 2.86–2.79 (m, 1H, DNJ - H), 2.20 - 2.14 (m, 1H, DNJ - H), 2.10 - 2.05 (m, 1H, DNJ - H). 13 C - APT NMR (151 MHz, DMSO - d6) δ 174.22, 171.63, 158.09, 140.49, 131.17, 128.52, 125.82, 125.51, 114.70, 70.58, 71.04, 69.80, 67.18, 65.56, 59.75, 58.49, 51.63, 51.30, 44.26, 40.44, 36.18. HRMS (ESI): [M + H] + m / z calcd for C 26 H 32 N 2 O 8 S: 533.1952, found, 533.1940.

[0113]

[0114] ASP - 17: Yellow oil in 33.5% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.93 (s, 1H, CH=CS),

[0115] 7.60 (d, J=9.4Hz, 2H, O - Ph - H), 7.37 - 7.30 (m, 5H, Ph - H), 7.10 (d, J=9.4Hz, 2H, O - Ph - H), 4.83 (s, 2H, NCH 2 Ph), 4.75 - 4.70 (m, 3H, 3×OH), 4.20 (dd, J=5.9Hz, 4.2Hz, 1H, OH), 4.06 (t, J=6.32Hz, 2H, COCH 2 ), 3.77–3.74 (m, 1H, DNJ - H), 3.54 - 3.50 (m, 1H, DNJ - H), 3.23 - 3.19 (m, 1H, DNJ - H), 3.03 - 2.99 (m, 1H, DNJ - H), 2.97 - 2.90 (m, 2H, NCH 2 CH 2O), 2.84–2.81 (m, 1H, DNJ-H), 2.54 - 2.52 (m, 1H, DNJ-H), 1.99 - 1.94 (m, 2H, DNJ-H), 1.90 - 1.80 (m, 2H, CH 2 CH 2 CH 2 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 167.88, 166.13, 161.18, 136.05, 134.04, 132.87, 129.15, 128.26, 128.06, 125.69, 118.08, 115.91, 79.64, 71.23, 69.86, 67.31, 66.99, 59.76, 57.51, 48.99, 45.05, 24.86. HRMS (ESI): [M+H] + m / z calcd for C 26 H 30 N 2 O 7 S: 515.1847, found, 515.1835.

[0116]

[0117] ASP-18: White solid in 27.3% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.94 (s, 1H, CH=CS),

[0118] 7.62 (d, J=8.7 Hz, 2H, Ph-H), 7.56 (d, J=8.3 Hz, 2H, O-Ph-H), 7.28 (d, J=8.7 Hz, 2H, Ph-H), 7.14 (d, J=8.7 Hz, 2H, O-Ph-H), 5.76 (s, 1H, OH), 5.63 (s, 2H, 2×OH), 5.45 (s, 1H, OH), 4.81 (s, 2H, NCH 2 Ph), 4.16 (t, J=5.7 Hz, 2H, COCH 2 ), 3.93 (d, J=12 Hz, 1H, DNJ-H), 3.84 (d, J=12.3 Hz, 1H, DNJ-H), 3.71 - 3.64 (m, 1H, DNJ-H), 3.51 - 3.43 (m, 2H, DNJ-H), 3.34 - 3.28 (m, 1H, DNJ-H), 3.28 - 3.20 (m, 2H, NCH 2 CH 2O), 3.05 (t, J=10.1 Hz, 1H, DNJ-H), 2.97 (q, J=10.7 Hz, 1H, DNJ-H), 2.26 - 2.12 (m, 2H, CH 2 CH 2 CH 2 ). HRMS(ESI): [M+H] + m / z calcd for C 26 H 29 BrN 2 O 7 S: 593.0952, found, 593.0938.

[0119]

[0120] ASP-19: White solid in 29.5% yield. 1 1H NMR(600 MHz, DMSO-d6) δ 7.92 (s, 1H, CH=CS),

[0121] 7.59 (d, J=8.5 Hz, 2H, Ph-H), 7.19 (d, J=8.5 Hz, 2H, O-Ph-H), 7.15 (d, J=8.5 Hz, 2H, Ph-H), 7.10 (d, J=9.1 Hz, 2H, O-Ph-H), 4.77 (s, 2H, NCH 2 Ph), 4.74 - 4.70 (m, 3H, 3×OH), 4.20 (s, 1H, OH), 4.06 (t, J=5.9 Hz, 2H, COCH 2 ), 3.77 - 3.74 (m, 1H, DNJ-H), 3.53 - 3.52 (m, 1H, DNJ-H), 3.25 - 3.16 (m, 1H, DNJ-H), 3.05 - 2.98 (m, 1H, DNJ-H), 2.98 - 2.88 (m, 2H, NCH 2 CH 2 O), 2.87 - 2.78 (m, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.27 (s, 3H, CH 3 ), 2.01 - 1.92 (m, 2H, DNJ-H), 1.91 - 1.78 (m, 2H, CH 2 CH 2 CH 2 ). 13C-APT NMR (151 MHz, DMSO-d6) δ 167.81, 166.11, 161.16, 137.55, 133.97, 133.08, 132.86, 129.67, 128.15, 125.70, 118.09, 115.90, 79.64, 71.22, 69.86, 67.31, 66.98, 59.76, 57.51, 48.99, 44.84, 24.86, 21.16. HRMS (ESI): [M+H] + m / z calcd for C 27 H 32 N 2 O 7 S: 529.2003, found, 529.1990.

[0122]

[0123] ASP-21: White solid in 21.1% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.96 (s, 1H, CH=CS),

[0124] 7.62 (d, J = 8.6 Hz, 2H, O-Ph-H), 7.11 (d, J = 9.5 Hz, 2H, O-Ph-H), 4.76 - 4.69 (m, 3H, 3×OH), 4.37 (s, 2H, NCH 2 Ph), 4.20 (dd, J = 6.4 Hz, 4.2 Hz, 1H, OH), 4.06 (t, J = 6.4 Hz, 2H, COCH 2 ), 3.79 - 3.73 (m, 1H, DNJ-H), 3.55 - 3.49 (m, 1H, DNJ-H), 3.24 - 3.18 (m, 1H, DNJ-H), 3.01 (ddd, J = 14.1 Hz, 8.8 Hz, 5.3 Hz, 1H, DNJ-H), 2.99 - 2.89 (m, 2H, NCH 2 CH 2 O), 2.83 (dd, J = 11.0 Hz, 4.6 Hz, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.00 - 1.93 (m, 2H, DNJ-H), 1.91 - 1.79 (m, 2H, CH 2 CH 2 CH 2 ), 1.42 (s, 9H, 3×CH 3 ). 13C-APT NMR (151 MHz, DMSO-d6) δ 167.47, 166.17, 165.58, 161.33, 134.55, 133.00, 125.53, 117.49, 115.95, 82.95, 79.64, 71.23, 69.86, 67.32, 67.02, 59.77, 57.52, 48.98, 43.29, 28.02, 24.86. HRMS (ESI): [M+H] + m / z calcd for C 25 H 32 N 2 O 9 S: 539.2058, found, 539.2044.

[0125]

[0126] ASP-22: White solid in 34.2% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.93 (s, 1H, CH=CS),

[0127] 7.73 (d, J = 7.7 Hz, 2H, Ph-H), 7.60 (d, J = 8.8 Hz, 2H, O-Ph-H), 7.53 (d, J = 8.3 Hz, 2H, Ph-H), 7.11 (d, J = 8.8 Hz, 2H, O-Ph-H), 4.93 (s, 2H, NCH 2 Ph), 4.76 - 4.69 (m, 3H, 3×OH), 4.22 - 4.18 (m, 1H, OH), 4.06 (t, J = 5.9 Hz, 2H, COCH 2 ), 3.78 - 3.73 (m, 1H, DNJ-H), 3.55 - 3.50 (m, 1H, DNJ-H), 3.24 - 3.18 (m, 1H, DNJ-H), 3.05 - 2.98 (m, 1H, DNJ-H), 2.98 - 2.89 (m, 2H, NCH 2 CH 2 O), 2.82 (dd, J = 10.6 Hz, 4.7 Hz, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.01 - 1.93 (m, 2H, DNJ-H), 1.91 - 1.78 (m, 2H, CH 2 CH 2 CH 2 ). 13C-APT NMR (151 MHz, DMSO-d6) δ 167.95, 166.11, 161.22, 140.71, 134.16, 132.90, 128.78, 126.09, 126.07, 126.05, 126.02, 125.66, 118.04, 115.93, 79.64, 71.23, 69.86, 67.32, 59.76, 57.51, 48.99, 44.58, 24.86. HRMS (ESI): [M+H] + m / z calcd for C 27 H 29 F 3 N 2 O 7 S: 583.1721, found, 583.1705.

[0128]

[0129] ASP-23: White solid in 39.7% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.91 (s, 1H, CH=CS),

[0130] 7.59 (d, J = 8.9 Hz, 2H, Ph-H), 7.36 (d, J = 8.4 Hz, 2H, O-Ph-H), 7.22 (d, J = 8.9 Hz, 2H, Ph-H), 7.10 (d, J = 8.4 Hz, 2H, O-Ph-H), 5.29 - 4.67 (m, 5H, NCH 2 Ph, 3×OH), 4.08 (s, 2H, COCH 2 ), 3.82 - 3.72 (m, 1H, OH), 3.71 - 3.54 (m, 1H, DNJ-H), 3.25 - 2.77 (m, 5H, DNJ-H, NCH 2 CH 2 O), 2.76 - 2.52 (m, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.33 - 1.55 (m, 4H, DNJ-H, CH 2 CH 2 CH 2 ), 1.24 (s, 9H, 3×CH 3 ). 13C-APT NMR (151 MHz, DMSO-d6) δ 167.85, 166.11, 161.17, 150.72, 134.00, 133.10, 132.86, 127.97, 125.92, 125.69, 118.08, 115.90, 79.64, 71.23, 69.86, 67.30, 66.99, 59.75, 57.51, 48.99, 44.74, 34.73, 31.53, 24.85. HRMS (ESI): [M+H] + m / z calcd for C 30 H 38 N 2 O 7 S: 571.2473, found, 571.2458.

[0131]

[0132] ASP-24: White solid in 25.6% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.90 (s, 1H, CH=CS),

[0133] 7.58 (d, J = 8.1 Hz, 2H, Ph-H), 7.25 (d, J = 9.1 Hz, 2H, O-Ph-H), 7.10 (d, J = 9.1 Hz, 2H, Ph-H), 6.90 (d, J = 9.1 Hz, 2H, O-Ph-H), 5.87 - 5.15 (m, 3H, 3×OH), 4.74 (s, 2H, NCH 2 Ph), 4.11 (s, 2H, COCH 2 ), 3.85 - 3.77 (m, 1H, OH), 3.71 (s, 3H, CH 3 ), 3.45 - 3.31 (m, 3H, DNJ-H), 3.31 - 2.98 (m, 1H, DNJ-H), 2.98 - 2.89 (m, 2H, NCH 2 CH 2 O), 2.82 (dd, J = 10.6 Hz, 4.7 Hz, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.01 - 1.93 (m, 2H, DNJ-H), 2.25 - 1.91 (m, 2H, CH 2 CH 2 CH 2 ). 13C-APTNMR (151 MHz, DMSO-d6) δ 167.95, 166.11, 161.22, 140.71, 134.16, 132.90, 128.78, 126.09, 126.07, 126.05, 126.02, 125.66, 118.04, 115.93, 79.64, 71.23, 69.86, 67.32, 59.76, 57.51, 48.99, 44.58, 24.86. HRMS (ESI): [M+H] + m / z calcd for C 27 H 32 N 2 O 8 S: 545.1952, found, 545.1940.

[0134]

[0135] ASP-25: White solid in 27.8% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.30 - 7.26 (m, 3H, Ph-H), 7.09 (d, J = 8.1 Hz, 2H, O-Ph-H), 7.07 - 7.03 (m, 2H, Ph-H), 6.79 (d, J = 7.4 Hz, 2H, O-Ph-H), 5.02 (dd, J = 8.0 Hz, 4.3 Hz, 1H, S-CH), 4.74 (dd, J = 7.2 Hz, 4.3 Hz, 2H, 2×OH), 4.71 (d, J = 4.5 Hz, 1H, OH), 4.62 (dd, J = 42.3 Hz, 14.9 Hz, 2H, NCH 2 Ph), 4.21 - 4.17 (m, 1H, OH), 3.91 (t, J = 6.4 Hz, 2H, COCH 2 ), 3.79–3.74 (m, 1H, DNJ-H), 3.57 - 3.52 (m, 1H, DNJ-H), 3.34 - 3.29 (m, 1H, DNJ-H), 3.25 - 3.19 (m, 2H, PhCH 2 CH), 3.17 - 3.12 (m, 1H, DNJ-H), 3.06 - 3.00 (m,, 1H, DNJ-H), 2.98 - 2.90 (m, 2H, NCH 2 CH 2 ), 2.85–2.81 (dd, J = 11.2 Hz, 4.8 Hz, 1H, PhCH 2CH), 2.55 - 2.51 (m, 1H, DNJ - H), 2.00 - 1.92 (m, 2H, DNJ - H), 1.88 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C - APT NMR (151 MHz, DMSO - d6) δ 174.30, 171.57, 158.21, 135.79, 131.10, 128.94, 128.09, 128.04, 127.76, 114.70, 79.66, 71.22, 69.88, 67.29, 66.46, 59.69, 57.50, 51.53, 49.16, 44.74, 36.25, 24.97.

[0136]

[0137] ASP - 27: White solid in 22.6% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.08 (d, J = 8.6 Hz, 4H,

[0138] Ph - H), 6.96 - 6.93 (m, 2H, O - Ph - H), 7.07 - 7.03 (m, 2H, Ph - H), 6.78 (d, J = 8.4 Hz, 2H, O - Ph - H), 5.00 (dd, J = 8.1 Hz, 4.6 Hz, 1H, S - CH), 4.73 (dd, J = 6.5 Hz, 4.2 Hz, 2H, 2×OH), 4.70 (d, J = 4.6 Hz, 1H, OH), 4.56 (dd, J = 41.4 Hz, 15.0 Hz, 2H, NCH 2 Ph), 4.18 (dd, J = 6.1 Hz, 4.2 Hz, 1H, OH), 3.95 - 3.88 (m, 2H, COCH 2 ), 3.78–3.73 (m, 1H, DNJ - H), 3.56 - 3.51 (m, 1H, DNJ - H), 3.33 - 3.28 (m, 1H, DNJ - H), 3.24 - 3.18 (m, 2H, PhCH 2 CH), 3.15 - 3.09 (m, 1H, DNJ - H), 3.05 - 3.00 (m,, 1H, DNJ - H), 2.97 - 2.89 (m, 2H, NCH 2 CH 2 ), 2.86–2.80 (dd, J = 10.7 Hz, 4.6 Hz, 1H, PhCH 2CH), 2.57 - 2.51 (m, 1H, DNJ - H), 2.27 (s, 3H, CH 3 ), 2.01 - 1.92 (m, 2H, DNJ - H), 1.88 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C - APT NMR (151 MHz, DMSO - d6) δ 174.28, 171.52, 158.19, 137.26, 132.85, 131.06, 129.47, 128.11, 127.88, 114.68, 79.65, 71.22, 69.88, 67.24, 66.44, 59.69, 57.52, 51.48, 49.18, 44.54, 36.29, 24.95, 21.18. HRMS (ESI): [M + H] + m / z calcd for C 27 H 32 N 2 O 7 S: 531.2160, found, 531.2148.

[0139]

[0140] ASP - 28: White solid in 34.4% yield. 1 H NMR (600 MHz, DMSO - d6) δ 7.63 (d, J = 8.1Hz, 2H,

[0141] Ph - H), 7.20 (d, J = 8.1Hz, 2H, Ph - H), 7.10 (d, J = 8.6Hz, 2H, O - Ph - H), 6.80 (d, J = 8.6Hz, 2H, O - Ph - H), 5.03 (dd, J = 8.1Hz, 4.6Hz, 1H, S - CH), 4.79 - 4.63 (m, 5H, 3×OH, NCH 2 Ph), 4.21–4.14 (m, 1H, OH), 3.93–3.88 (m, 2H, COCH 2 ), 3.78–3.73 (m, 1H, DNJ - H), 3.58 - 3.51 (m, 1H, DNJ - H), 3.31 (dd, J = 14.2Hz, 4.1Hz, 1H, DNJ - H), 3.25 - 3.14 (m, 2H, PhCH 2 CH), 3.07 - 3.00 (m, 1H, DNJ - H), 2.97 - 2.88 (m, 2H, NCH 2 CH2 ), 2.86–2.80 (m, 1H, DNJ-H), 2.58 - 2.51 (m, 1H, DNJ-H), 2.04 - 1.89 (m, 2H, DNJ-H), 1.89 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 174.38, 174.30, 171.57, 160.98, 138.07, 135.80, 131.11, 130.86, 128.94, 128.05, 127.77, 114.72, 106.06, 99.48, 55.64, 55.41, 51.60, 51.53, 44.82, 44.75, 36.47, 36.25. HRMS (ESI): [M + H] + m / z calcd for C 28 H 36 N 2 O 9 S: 577.2215, found, 577.2214.

[0142]

[0143] ASP-29: White solid in 18.1% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.18 (d, J = 8.3 Hz, 2H,

[0144] O-Ph-H), 6.86 (d, J = 9.0 Hz, 2H, O-Ph-H), 5.08 (dd, J = 10.4 Hz, 4.8 Hz, 1H, S-CH), 4.77 - 4.68 (m, 3H, 3×OH), 4.19 (d, J = 1.6 Hz, 2H, NCH 2 Ph), 3.93 (t, J = 6.5 Hz, 2H, COCH 2 ), 3.75 (d, J = 11.4 Hz, 1H, OH), 3.53 (d, J = 11.4 Hz, 1H, DNJ-H), 3.55 - 3.44 (dd, J = 14.1 Hz, 4.5 Hz, 1H, DNJ-H), 3.25 - 3.18 (m, 1H, DNJ-H), 3.02 (t, J = 8.9 Hz, 1H, DNJ-H), 2.98 - 2.86 (m, 4H, NCH 2 CH 2, 2×DNJ-H), 2.82 (dd, J=11.0 Hz, 4.7 Hz, 1H, DNJ-H), 2.55 - 2.51 (m, 1H, DNJ-H), 2.01 - 1.91 (m, 2H, CH 2 CH 2 CH 2 ), 1.87 - 1.75 (m, 2H, CH 2 CH 2 O), 1.40 (s, 9H, 3×CH 3 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 173.77, 170.98, 166.01, 158.24, 130.69, 128.75, 114.89, 82.79, 79.64, 71.21, 69.86, 67.23, 66.47, 59.65, 57.49, 51.76, 48.12, 43.07, 37.25, 28.01, 24.92. HRMS (ESI): [M+H] + m / z calcd for C 25 H 34 N 2 O 9 S: 541.2215, found, 541.2203.

[0145]

[0146] ASP-30: White solid in 30.7% yield. 1 1H NMR (600 MHz, DMSO-d6) δ 7.63 (d, J=8.1 Hz, 2H,

[0147] Ph-H), 7.20 (d, J=8.1 Hz, 2H, Ph-H), 7.10 (d, J=8.6 Hz, 2H, O-Ph-H), 6.80 (d, J=8.6 Hz, 2H, O-Ph-H), 5.03 (dd, J=8.1 Hz, 4.6 Hz, 1H, S-CH), 4.79 - 4.63 (m, 5H, 3×OH, NCH 2 Ph), 4.21–4.14 (m, 1H, OH), 3.93–3.88 (m, 2H, COCH 2 ), 3.78–3.73 (m, 1H, DNJ-H), 3.58 - 3.51 (m, 1H, DNJ-H), 3.31 (dd, J=14.2 Hz, 4.1 Hz, 1H, DNJ-H), 3.25 - 3.14 (m, 2H, PhCH 2(CH), 3.07 - 3.00 (m, 1H, DNJ - H), 2.97 - 2.88 (m, 2H, NCH 2 CH 2 ), 2.86–2.80 (m, 1H, DNJ - H), 2.58 - 2.51 (m, 1H, DNJ - H), 2.04 - 1.89 (m, 2H, DNJ - H), 1.89 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C - APT NMR (151MHz, DMSO - d6) δ174.18, 171.62, 158.24, 140.47, 131.23, 128.47, 127.97, 125.82, 125.51, 123.71, 114.69, 79.63, 71.18, 69.85, 67.16, 66.43, 59.59, 57.49, 51.60, 49.13, 44.24, 36.12, 24.87. HRMS(ESI): [M + H] + m / z calcd for C 27 H 31 F 3 N 2 O 7 S: 585.1877, found, 585.1872.

[0148]

[0149] ASP - 31: White solid in 28.7% yield. 1 H NMR (600MHz, DMSO - d6) δ7.63 (d, J=8.1Hz, 2H,

[0150] Ph - H), 7.20 (d, J=8.1Hz, 2H, Ph - H), 7.10 (d, J=8.6Hz, 2H, O - Ph - H), 6.80 (d, J=8.6Hz, 2H, O - Ph - H), 5.03 (dd, J=8.1Hz, 4.6Hz, 1H, S - CH), 4.79 - 4.63 (m, 5H, 3×OH, NCH 2 Ph), 4.21–4.14 (m, 1H, OH), 3.93–3.88 (m, 2H, COCH 2), 3.78–3.73 (m, 1H, DNJ-H), 3.58 - 3.51 (m, 1H, DNJ-H), 3.31 (dd, J=14.2 Hz, 4.1 Hz, 1H, DNJ-H), 3.25 - 3.14 (m, 2H, PhCH 2 CH), 3.07 - 3.00 (m, 1H, DNJ-H), 2.97 - 2.88 (m, 2H, NCH 2 CH 2 ), 2.86–2.80 (m, 1H, DNJ-H), 2.58 - 2.51 (m, 1H, DNJ-H), 2.04 - 1.89 (m, 2H, DNJ-H), 1.89 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 174.18, 171.62, 158.24, 140.47, 131.23, 128.47, 127.97, 125.82, 125.51, 123.71, 114.69, 79.63, 71.18, 69.85, 67.16, 66.43, 59.59, 57.49, 51.60, 49.13, 44.24, 36.12, 24.87. HRMS (ESI): [M+H] + m / z calcd for C 30 H 40 N 2 O 7 S: 573.2629, found, 573.2618.

[0151]

[0152] ASP-32: White solid in 27.4% yield. 1 H NMR (600 MHz, DMSO-d6) δ 7.63 (d, J=8.1 Hz, 2H,

[0153] Ph-H), 7.20 (d, J=8.1 Hz, 2H, Ph-H), 7.10 (d, J=8.6 Hz, 2H, O-Ph-H), 6.80 (d, J=8.6 Hz, 2H, O-Ph-H), 5.03 (dd, J=8.1 Hz, 4.6 Hz, 1H, S-CH), 4.79 - 4.63 (m, 5H, 3×OH, NCH 2 Ph), 4.21–4.14 (m, 1H, OH), 3.93–3.88 (m, 2H, COCH2 ), 3.78–3.73 (m, 1H, DNJ-H), 3.58 - 3.51 (m, 1H, DNJ-H), 3.31 (dd, J=14.2 Hz, 4.1 Hz, 1H, DNJ-H), 3.25 - 3.14 (m, 2H, PhCH 2 CH), 3.07 - 3.00 (m, 1H, DNJ-H), 2.97 - 2.88 (m, 2H, NCH 2 CH 2 ), 2.86–2.80 (m, 1H, DNJ-H), 2.58 - 2.51 (m, 1H, DNJ-H), 2.04 - 1.89 (m, 2H, DNJ-H), 1.89 - 1.76 (m, 2H, CH 2 CH 2 CH 2 ). 13 C-APT NMR (151 MHz, DMSO-d6) δ 174.18, 171.62, 158.24, 140.47, 131.23, 128.47, 127.97, 125.82, 125.51, 123.71, 114.69, 79.63, 71.18, 69.85, 67.16, 66.43, 59.59, 57.49, 51.60, 49.13, 44.24, 36.12, 24.87. HRMS (ESI): [M + H] + m / z calcd for C 27 H 34 N 2 O 8 S: 547.2109, found, 547.2097.

[0154] Example 2 Pharmacology Part

[0155] 1. α-Glucosidase Activity Test

[0156] Using PNPG as the substrate and acarbose as the positive control, the experiment was divided into a blank group, a control group, a sample group, and a sample blank group, with 5 replicate wells set in each group. The reaction system was referred to the literature method. An appropriate amount of PB phosphate buffer (pH 6.8), 20 μL of 0.5 U / mL α-glucosidase solution, and 20 μL of sample solutions with different concentrations were added to a transparent 96-well microplate, mixed well by low-speed oscillation, incubated in an oven at 37 °C for 10 min, 20 μl of 10 mmol / L PNPG solution was added, mixed well by low-speed oscillation, placed at 37 °C for 20 min, and then 0.2 mol / L Na 2 CO 380 μl of the solution was used to terminate the reaction, and the absorbance was measured at a wavelength of 405 nm. The inhibition rate of the target compound on α-glucosidase activity was calculated according to the following formula. The operation was performed in parallel 3 times and the average value was taken.

[0157]

[0158] Ac: blank control; Ab: blank; As: sample; Asb: sample blank

[0159]

[0160] 2. Activity test part of insulin resistance cell model

[0161] In vitro culture of L02 cells: Cell resuscitation and culture: (1) Take out the cryopreserved cells from the liquid nitrogen tank and place them in a preheated constant temperature water bath at 37 °C, and shake to quickly thaw them. (2) Transfer the cryopreservation solution to a centrifuge tube, add a certain volume of complete medium to obtain a cell suspension. (3) Centrifuge the cell suspension at 1000 rpm for 3 min, pour off the supernatant, add 1 mL of complete medium and gently pipette to make the cells evenly distributed, transfer them to a culture flask, add medium to 5 - 8 mL, mix the cells evenly, and culture them in a 5% CO 2 2, 37 °C constant temperature incubator. Cell passage: (1) Observe that when the cell density in the culture flask reaches 80% - 90%, passage is required. (2) Pour off the original medium, add 2 mL of PBS to wash the cells 2 times, and aspirate the PBS. (3) Add 1 mL of trypsin to digest for 1 - 3 min, observe under the microscope, and when the cells shrink and become round, add 2 mL of complete medium to terminate the digestion. (4) Collect the cell suspension into a centrifuge tube, centrifuge at 1000 rpm for 3 min, pour off the supernatant, add 1 mL of complete medium and gently pipette to make the cells evenly distributed, transfer them to a culture flask according to a ratio of 1:2 - 1:3, add medium to 5 - 8 mL per flask, mix the cells evenly, and culture them in a 5% CO 2 2, 37 °C constant temperature incubator.

[0162] For the human normal hepatocyte (L02) cell line, take L02 cells with good growth status and in the exponential growth phase, inoculate them in a 96-well plate at a certain concentration, use RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin / 1% streptomycin, and culture them in an incubator at 37 °C and 5% carbon dioxide. When the cells are fused to 80%, different compounds, namely ASP-1 - ASP-32 (20 μmol / L) and positive drugs (Arc, DNJ, Rosi, 20 μmol / L), are given for treatment, and a blank control group (Control) is set, with 8 replicates in each group. After the treatment is completed, aspirate the liquid in the wells, treat the cells with medium containing insulin, then take the supernatant and detect the absorbance on an enzyme-linked immunosorbent assay (ELISA) reader to evaluate the glucose consumption of the cells.

[0163] The glucose consumption results of the target compound ASP-1-ASP-32 are as follows Figures 1-4 shown. At a concentration of 20 μM, most compounds could promote the glucose consumption in the supernatant medium of L02 cells, and some even had better activities than the positive drugs rosiglitazone and acarbose. Among them, the compound ASP-2-ASP-4 was the most active compound among all the compounds, significantly promoting glucose consumption, nearly 5 times that of the control group, and there was a highly significant difference compared with the control group.

[0164] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A dual-targeted polyhydroxy alkaloid compound, characterized in that it has the following general structural formula: wherein, 2. The compound according to claim 1, characterized in that it is selected from the following structures:

3. A preparation method of a dual-targeted polyhydroxy alkaloid compound, characterized in that it comprises the following steps: 1) Using 1-deoxynojirimycin C1 as a raw material for intraring amino protection to prepare intermediate C2; performing polyhydroxy protection on intermediate C2 to prepare intermediate C3; performing amino deprotection on intermediate C3 to prepare intermediate C4; 2) Using p-hydroxybenzaldehyde L1 as a raw material, first subjecting the hydroxyl group to substitution with 1,2-dibromoethane or 1,3-dibromopropane to prepare intermediates L2 and L3, and then subjecting this intermediate to Knoevenagel condensation reaction with the thiazolidinedione fragment B2-a to B2-h substituted at the N-terminus to prepare intermediates B3-a to B3-h and B4-a to B4-h; 3) Reacting intermediates B3-a to B3-h or B4-a to B4-h with intermediate C4 to prepare intermediates C5-a to C5-h or C6-a to C6-h; 4) Reducing the double bond of intermediates C5-a to C5-h or C6-a to C6-h by Pd / C-catalyzed hydrogenation at room temperature to prepare intermediates C7-a to C7-h or C8-a to C8-h; 5) Removing the protecting groups of the hydroxyl groups from intermediates C5-a to C5-h or C6-a to C6-h or C7-a to C7-h or C8-a to C8-h to obtain the final products ASP-1 to ASP-32.

4. The preparation method according to claim 3, characterized in that the reaction conditions for preparing intermediate C2 are: dissolving 1-deoxynojirimycin C1 in saturated sodium bicarbonate aqueous solution, adding Cbz-Cl at 0 °C, stirring for 10 - 20 min, then raising the temperature to room temperature and reacting for 14 - 18 h.

5. The preparation method according to claim 4, characterized in that the molar ratio of 1-deoxynojirimycin C1 to Cbz-Cl is 1:1.1 - 1.

3.

6. The preparation method according to claim 5, characterized in that the molar ratio of 1-deoxynojirimycin C1 to Cbz-Cl is 1:1.

2.

7. The preparation method according to claim 3, characterized in that the reaction conditions for preparing intermediate C3 are: dissolving compound C2 in a solvent, adding TBSOTf and 2,6-lutidine at 0 °C, and reacting at room temperature for 14 - 18 h.

8. The preparation method according to claim 7, characterized in that the molar ratio of compound C2 to TBSOTf and 2,6-lutidine is 1:5 - 8:8 - 12.

9. The preparation method according to claim 8, characterized in that the molar ratio of compound C2 to TBSOTf and 2,6-lutidine is 1:6:

10.

10. The preparation method according to claim 3, characterized in that The reaction conditions for preparing Intermediate C4 are as follows: Dissolve Compound C3 in a solvent, add a catalytic amount of Pd / C and Pd(OH) 2 / C, and conduct a catalytic hydrogenation reaction at room temperature.

11. The preparation method according to claim 10, characterized in that The Pd / C and Pd(OH) 2 / C have a molar ratio of 1:

1.

12. The preparation method according to claim 3, characterized in that The reaction conditions for preparing intermediate L2 are as follows: Dissolve compound L1 in a solvent, add potassium carbonate and 1,2-dibromoethane, heat to 80 - 100 °C, and react for 7 - 11 h.

13. According to the preparation method described in claim 3, it is characterized in that the reaction conditions for preparing intermediate L3 are as follows: Dissolve compound L1 in a solvent, add potassium carbonate and 1,3-dibromopropane, and react at room temperature for 7 - 11 h.

14. According to the preparation method described in claim 3, it is characterized in that the reaction conditions for preparing intermediates B3-a to B3-h are as follows: Dissolve intermediate L2 in a solvent, add a catalytic amount of piperidine acetate, and reflux for 2 - 3 h.

15. According to the preparation method described in claim 3, it is characterized in that the reaction conditions for preparing intermediates B4-a to B4-h are as follows: Dissolve intermediate L3 in a solvent, add a catalytic amount of piperidine acetate, and reflux for 2 - 4 h.

16. According to the preparation method described in claim 3, it is characterized in that the reaction conditions for preparing intermediates C5-a to C5-h or C6-a to C6-h are as follows: Dissolve compound C4 in a solvent, successively add compounds B3-a to B3-h or B4-a to B4-h, cesium carbonate, and DMF, and react at 80 °C for 8 hours.

17. According to the preparation method described in claim 3, it is characterized in that the reagent used for removing the protecting group of the hydroxyl group is 2M hydrochloric acid - ethyl acetate solution.

18. Use of the compound according to any one of claims 1 - 2 or the compound prepared by the preparation method according to any one of claims 3 - 17 in the preparation of a drug for treating α-glucosidase-mediated glycolipid metabolism disorder diseases.

Images