A triazol derivative of tripterine and its preparation method and use

Abstract

The application discloses a triazol derivative of tripterine or a pharmaceutically acceptable salt thereof, and a structure of the triazol derivative of tripterine is shown in formula III, R is selected from R1 and R3, R1 and R3 are independently selected from H, C3-C4 alkyl, halogen and R2, R2 is selected from H and C1-C4 alkyl, R4 is selected from H and C1-C4 alkyl, and n is an integer from 1 to 5. The triazol derivative of tripterine has obvious inhibiting effect on the proliferation of various tumor cells, and is obviously superior to tripterine. The application discloses a use of the triazol derivative of tripterine or the pharmaceutically acceptable salt thereof in preparation of an Hsp90 protein inhibitor. The application discloses a use of the triazol derivative of tripterine or the pharmaceutically acceptable salt thereof in preparation of an antitumor drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry and pharmacology, and relates to a celastrol thiazole derivative, a preparation method thereof and use thereof in the preparation of anticancer drugs. BACKGROUND

[0002] Cancer is a major challenge to global public health and is closely related to global health. Millions of people die from cancer every year. Therefore, the prevention and treatment of cancer is still a key problem to be solved, and the development of efficient and safe anticancer drugs is not only of great significance to patients and the medical system, but also one of the responsibilities and missions of pharmaceutical researchers.

[0003] Heat shock protein (HSP) is a heat stress molecular chaperone protein widely present in mammals, which has high conservation. Generally, Hsp90 is expressed at low abundance in normal cells, while Hsp90 is maintained at a high expression state in tumor cells, and is combined with other molecular chaperones to form a complex to participate in cell signal transduction, client protein folding and degradation, etc. Therefore, inhibiting the function of Hsp90 protein is one of the strategies for effective treatment of tumors.

[0004] Natural products have become an important treasure trove for drug development due to their unique molecular structures and diverse biological activities, and have attracted extensive attention from researchers. Celastrol (CEL) is a quinone-methyl-containing pentacyclic triterpenoid compound derived from the roots of Tripterygium. Studies have shown that celastrol has good efficacy on tumors, inflammation, obesity, nerve injury and other diseases. Although celastrol has obvious anti-tumor activity, its activity needs to be improved.

[0005] SUMMARY

[0006] The purpose of the present application is to introduce thiazole compounds to modify the structure of celastrol as a lead, and to provide a celastrol thiazole derivative. Pharmacological experiments show that the anti-tumor activity of the celastrol derivative of the present application is excellent, and the activity is significantly improved compared with celastrol.

[0007] The purpose of the present application is achieved by the following technical solutions:

[0008] The celastrol thiazole derivative or pharmaceutically acceptable salt thereof has the structure shown in formula III:

[0009]

[0010] wherein R is selected from

[0011] R1, R3 are independently selected from H, C3-C4alkyl, halogen,

[0012] R2, R4 are independently selected from H, C1-C4alkyl;

[0013] n = an integer from 1 to 5;

[0014] but not including: R1= CH3, R2= H, n = 4, 5; R2= CH3, n = 3, 5.

[0015] Preferably, R1= H, CH3, Br,

[0016] R2= H, CH3;

[0017] R3= H, CH3, CH3CH2, CH(CH3)2;

[0018] R4= H, CH3;

[0019] n = 3, 4, 5;

[0020] but not including: R1= CH3, R2= H, n = 4, 5; R2= CH3, n = 3, 5.

[0021] More preferably, R1= H, CH3, Br,

[0022] R2= H, CH3;

[0023] R3= H, CH3, CH3CH2, CH(CH3)2;

[0024] R4= H, CH3;

[0025] n = 3, 4, 5;

[0026] but not including: R1= CH3, R2= H, n = 4, 5.

[0027] Further more preferably, R1= H, R2= H, CH3, n = 3, 4, 5; R1= CH3, R2= CH3, n = 3; R1= Br, R2= H, n = 3; R3= H, CH3, CH(CH3)2, R4= H, CH3, n = 3, 4, 5; but not including: R3= CH(CH3)2, R4= H, n = 5.

[0028] when R is selected from the structure of said tripterine thiazole derivatives is shown in formula I:

[0029]

[0030] wherein R1, R2, n are as described above.

[0031] when R is selected from the structure of the emladine thiazole derivative is shown in formula II:

[0032]

[0033] wherein R3, R4, n are as described above.

[0034] In particular, the emladine thiazole derivative or its pharmaceutically acceptable salt is selected from the following structure:

[0035]

[0036] Another object of the present application is to provide a preparation method of the emladine thiazole derivative, and the synthetic route is as follows:

[0037]

[0038]

[0039] wherein R is selected from R1, R2, R3, R4, n are as described above.

[0040] comprising the following steps:

[0041] Step (1), using acetone as the reaction solvent, using triethylamine as the base catalyst, refluxing the thiazole compound shown in formula with the dibromoalkane shown in formula to obtain the intermediate IV;

[0042] Step (2), using NaHCO3 as the base catalyst, using N,N-dimethylformamide (DMF) as the reaction solvent, refluxing the intermediate IV with emladine to obtain the emladine thiazole derivative.

[0043] In step (1), the molar ratio of the thiazole compound to the dibromoalkane is 1:2.5-1:4; the volume ratio of the dibromoalkane to triethylamine is 1:1.

[0044] In step (2), the molar ratio of the emladine to the intermediate IV is 1:0.4-1:0.6; the molar ratio of the emladine to NaHCO3 is 1:1.3-1:5.

[0045] Another object of the present application is to provide the use of the emladine thiazole derivative or its pharmaceutically acceptable salt in the preparation of Hsp90 protein inhibitors.

[0046] Compared with tripterine, the tripterine thiazole derivatives of the present application have significantly enhanced inhibitory effect on tumor cells.

[0047] The tumor is gastric cancer, lung cancer and breast cancer.

[0048] Another object of the present application is to provide the use of the tripterine thiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs; the tumor is lung cancer and breast cancer.

[0049] Another object of the present application is to provide the use of the tripterine thiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs; the tumor is gastric cancer, lung cancer and breast cancer.

[0050] Another object of the present application is to provide the use of the tripterine thiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of anti-triple negative breast cancer drugs:

[0051]

[0052] Another object of the present application is to provide a pharmaceutical composition, which comprises the tripterine thiazole derivatives or pharmaceutically acceptable salts thereof as an effective component, and any pharmaceutically acceptable dosage form prepared with a pharmaceutical carrier.

[0053] The dosage form includes tablets, capsules, dripping pills, granules, powders, lozenges, aqueous or oily suspensions, injections, patches, nano-preparations.

[0054] The present application has the following advantages:

[0055] Pharmacological experimental studies show that the tripterine thiazole derivatives of the present application have obvious inhibitory effect on the proliferation of various tumor cells, are significantly better than tripterine, and have better selectivity for breast cancer cells; the tripterine thiazole derivatives of the present application can covalently bind to Hsp90 protein, inhibit Hsp90 protein and thus exert anti-tumor activity. Therefore, the compounds of the present application are expected to become new anti-tumor candidate drugs, and are worthy of further in-depth study.

[0056] The tripterine thiazole derivatives of the present application have novel structure, simple preparation method, mild reaction conditions, low-toxicity reagents, cheap and readily available raw materials, convenient post-treatment, high yield, no harmful substances generated, and meet the "green science". BRIEF DESCRIPTION OF DRAWINGS

[0057] Figure 1Results of the in vitro thiol binding experiment for compound II-10. Specific embodiments

[0058] To further illustrate the technical solutions of the present application, a series of examples are listed below. These examples are illustrative and should not be construed as limiting the present application.

[0059] Example 1

[0060]

[0061] In a single-neck flask, add thiazole-5-carboxylic acid 65 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,3-dibromopropane 0.2 mL (2 mmol), dissolve in 3 mL acetone, heat to 50 °C and reflux, monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 v:v) to obtain intermediate A1 (112 mg, yield 89.2%).

[0062] Dissolve 130 mg (0.3 mmol) of tripterine in 3 mL of DMF, add 100 mg of NaHCO3 (0.4 mmol), add 112 mg (0.12 mmol) of intermediate A1, heat to 60 °C and reflux, monitor the reaction by TLC until the reaction is complete; after the reaction is completed, dilute the reaction solution with 50 mL of ethyl acetate, wash with water 3 times, wash with saturated sodium bicarbonate 3 times, wash with saturated brine 3 times, dry with anhydrous sodium sulfate overnight; dry the organic phase and purify by silica gel column chromatography (eluent: dichloromethane:methanol = 270:1 v:v) to obtain compound I-1 (orange red solid, 60.2 mg, yield 32.5%).

[0063] Structure identification data of compound I-1: 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.49 (s, 1H), 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 4.48-4.35 (m, 2H), 4.17-3.98 (m, 2H), 2.24 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H), 1.21 (s, 3H), 1.12 (s, 3H), 0.56 (s, 3H). 13C NMR (126 MHz, CDC13) δ 178.32, 178.24, 169.84, 164.68, 161.03, 158.20, 149.15, 146.04, 134.14, 129.20, 127.39, 119.58, 118.17, 117.15, 62.19, 60.72, 45.06, 44.26, 42.93, 40.49, 39.43, 38.25, 36.36, 34.82, 33.50, 32.85, 31.61, 31.54, 30.57, 29.80, 29.73, 28.62, 27.81, 21.65, 18.58, 10.31. HRMS (ESI) calculated for C 36 H 45 NO6S[M+H] + 620.3040, found 620.3033.

[0064] Example 2

[0065]

[0066] In a single-neck flask, add thiazole-5-carboxylic acid 52 mg (0.4 mmol), triethylamine 0.2 mL (1.5 mmol), 1,4-dibromobutane 0.2 mL (1.2 mmol), dissolve in 3 mL acetone, heat to 50 °C reflux reaction, TLC monitoring reaction. After the reaction is completed, the organic phase is dried by rotary evaporation, and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 10:1 v:v) to obtain intermediate A2 (82 mg, yield 77.3%).

[0067] Dissolve 100 mg (0.24 mmol) of tripterine in 3 mL of DMF, add 77 mg (0.9 mmol) of NaHCO3, 82 mg (0.12 mmol) of intermediate A2, heat to 60 °C reflux reaction until TLC detection shows that the reaction is complete, add 50 mL of ethyl acetate to dilute the reaction solution, wash with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate overnight; the organic phase is dried by rotary evaporation, and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound I-2 (orange red solid, 37.8 mg, yield 26.1%).

[0068] Compound I-2 structure identification data: 1H NMR (400 MHz, CDC13) δ 8.98 (s, 1H), 8.53 (s, 1H), 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.54 (d, J = 1.5 Hz, 1H), 6.36 (d, J = 7.1 Hz, 1H), 4.37-4.35 (m, 2H), 4.10-3.89 (m, 2H), 2.23 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 178.37, 178.22, 169.86, 164.69, 161.14, 158.19, 148.97, 146.06, 134.05, 129.68, 127.46, 119.58, 118.19, 117.13, 65.25, 63.88, 45.07, 44.29, 42.93, 40.45, 39.46, 38.26, 36.38, 34.81, 33.54, 32.83, 31.61, 30.84, 30.58, 29.84, 29.72, 28.67, 25.54, 25.19, 21.67, 18.56, 10.28. HRMS (ESI) calculated for C 37 H 47 NO6S[M+H] + 634.3196, found 634.3200.

[0069] Example 3

[0070]

[0071] In a single-neck flask, thiazole-5-carboxylic acid 58 mg (0.45 mmol), triethylamine 0.25 mL (1.8 mmol), 1,5-dibromopentane 0.25 mL (1.3 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9: 1 v:v) to obtain intermediate A3 (92 mg, yield 74.1%).

[0072] Compound I-3 was prepared according to the procedure described in Example 1. Compound I-3 (orange red solid, 45 mg, 30.0% yield) was obtained from 100 mg (0.24 mmol) of triptolide, 77 mg of NaHC03(0.9 mmol), and 92 mg (0.12 mmol) of intermediate A3.

[0073] Compound I-3 structural identification data: 1 H NMR (400 MHz, CDC13) δ 8.97 (s, 1H), 8.52 (s, 1H), 7.03 (dd, J = 7.1, 1.4 Hz, 1H), 6.54 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.36-4.33 (m, 2H), 4.05-3.85 (m, 2H), 2.22 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H), 1.11 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 178.32, 178.23, 172.40, 169.79, 164.67, 161.13, 148.46, 146.01, 134.09, 128.55, 127.41, 119.55, 118.17, 117.13, 61.89, 60.78, 45.07, 44.28, 42.94, 40.50, 39.45, 38.24, 36.37, 34.85, 33.46, 32.83, 31.63, 31.47, 30.85, 30.55, 30.22, 29.73, 28.62, 27.84, 21.67, 19.69, 18.55, 10.31. HRMS (ESI) calculated for C 38 H 49 NO6S [M + H] + 648.3353, found 648.3349.

[0074] Example 4

[0075]

[0076] In a single-neck flask, 2-methylthiazole-5-carboxylic acid 72 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,3-dibromopropane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed until TLC showed the reaction was complete. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A4 (105 mg, yield 79.5%).

[0077] 100 mg (0.24 mmol) of tripterine was dissolved in 3 mL of DMF, 77 mg of NaHCO3 (0.9 mmol), 105 mg (0.12 mmol) of intermediate A4 were added, heated to 60 °C and refluxed until TLC showed the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate was dried overnight; the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound I-4 (orange red solid, 54 mg, yield 38.4%).

[0078] Structure identification data of compound I-4: 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.02 (dd, J = 7.1, 1.4 Hz, 1H), 6.51 (d, J = 1.5 Hz, 1H), 6.35 (d, J = 7.1 Hz, 1H), 4.46-4.29 (m, 2H), 4.15-3.98 (m, 2H), 2.72 (s, 3H), 2.23 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 178.37, 178.26, 170.00, 164.75, 161.22, 158.10, 148.89, 146.04, 134.14, 129.81, 127.43, 119.57, 118.19, 117.16, 65.47, 64.11, 45.08, 44.29, 42.95, 40.43, 39.45, 38.27, 36.38, 34.80, 33.55, 32.82, 31.62, 30.82, 30.58, 29.83, 29.73, 28.30, 28.09, 22.61, 21.66, 18.52, 10.30. HRMS (ESI) calculated for C 37 H 47 NO6S[M+H]+ 634.3196, found 634.3205.

[0079] Example 5

[0080]

[0081] In a single-neck flask, 2-methylthiazole-5-carboxylic acid 72 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,4-dibromobutane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A4 (115 mg, yield 83.3%).

[0082] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 67 mg of NaHCO3 (0.8 mmol), 115 mg (0.12 mmol) of intermediate A5 were added, heated to 60 °C and refluxed until TLC detection showed that the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate overnight; The organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 10: 1 v:v) to obtain compound I-5 (orange red solid, 36 mg, yield 28.1%).

[0083] Structure identification data of compound I-5: 1 H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.53 (d, J = 1.5 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.35-4.31 (m, 2H), 4.09-3.88 (m, 2H), 2.77 (s, 3H), 2.22 (s, 3H), 1.46 (s, 3H), 1.28 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13C NMR (126 MHz, CDC13) δ 178.39, 178.23, 172.24, 169.83, 164.69, 161.26, 148.31, 146.08, 133.99, 129.01, 127.49, 119.61, 118.20, 117.11, 64.95, 63.90, 45.08, 44.32, 42.95, 40.47, 39.47, 38.27, 36.41, 34.83, 33.56, 32.84, 31.63, 30.87, 30.60, 29.85, 29.73, 28.70, 25.60, 25.19, 21.70, 19.75, 18.57, 10.28. HRMS (ESI) calculated for C 38 H 49 NO6S[M+H] + 648.3353, found 648.3341.

[0084] Example 6

[0085]

[0086] In a single-neck flask, 2-methylthiazole-5-carboxylic acid 72 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,5-dibromopentane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A6 (127 mg, yield 86.9%).

[0087] 90 mg (0.2 mmol) of tripterine was dissolved in 3 mL of DMF, 67 mg of NaHCO3 (0.8 mmol), 127 mg (0.12 mmol) of intermediate A6 were added, heated to 60 °C and refluxed until TLC detection showed that the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate overnight; The organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 9: 1 v:v) to obtain compound I-6 (orange red solid, 43 mg, yield 33.5%).

[0088] Compound I-6 structural identification data: 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.03 (dd, J = 7.1, 1.4 Hz, 1H), 6.54 (d, J = 1.5 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.32-4.29 (m, 2H), 4.04-3.85 (m, 2H), 2.76 (s, 3H), 2.22 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H), 1.19 (s, 3H), 1.11 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 178.39, 178.26, 172.15, 169.92, 164.73, 161.34, 148.22, 146.08, 134.04, 129.12, 127.48, 119.60, 118.19, 117.12, 65.19, 64.13, 45.09, 44.34, 42.96, 40.46, 39.48, 38.26, 36.41, 34.84, 33.59, 32.83, 31.64, 30.84, 30.60, 29.85, 29.73, 28.70, 28.34, 28.12, 22.64, 21.69, 19.74, 18.53, 10.28. HRMS (ESI) calculated for C 39 H 51 NO6S[M+H] + 662.3509, found 662.3503.

[0089] Example 7

[0090]

[0091] In a single-neck flask, 4-methylthiazole-5-carboxylic acid 72 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,3-dibromopropane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A7 (66 mg, yield 50.0%).

[0092] Compound I-7 was prepared according to the procedure described in Example 1. Compound I-7 (orange red solid, 45 mg, 35.7% yield) was obtained from 90 mg (0.2 mmol) of triptolide, 65 mg of NaHC03(0.8 mmol), and 66 mg (0.12 mmol) of intermediate A7.

[0093] Structural identification data of compound I-7: 1 H NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 4.45-4.31 (m, 2H), 4.16-3.98 (m, 2H), 2.77 (s, 3H), 2.24 (s, 3H), 1.45 (s, 3H), 1.27 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.56 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 178.34, 178.24, 169.79, 164.67, 161.91, 161.05, 155.41, 146.08, 134.01, 127.43, 121.63, 119.59, 118.15, 117.10, 61.73, 60.78, 45.07, 44.31, 42.94, 40.52, 39.45, 38.26, 36.39, 34.85, 33.52, 32.86, 31.63, 30.92, 30.59, 29.82, 29.76, 28.65, 27.85, 21.67, 18.62, 17.38, 10.30. HRMS (ESI) calculated for C 37 H 47 NO6S [M+H] + 634.3196, found 634.3195.

[0094] Example 8

[0095]

[0096] In a single-neck flask, 72 mg (0.5 mmol) of 4-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, 0.2 mL (2 mmol) of 1,4-dibromobutane were dissolved in 3 mL of acetone, heated to 50°C and refluxed until the reaction was completed by TLC monitoring. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A8 (62 mg, yield 45.1%).

[0097] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHCO3, 62 mg (0.12 mmol) of intermediate A8 were added, heated to 60°C and refluxed until the reaction was completed by TLC monitoring. The reaction solution was diluted with 50 mL of ethyl acetate, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, and dried with anhydrous sodium sulfate overnight; the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9: 1 v:v) to obtain compound I-8 (orange red solid, 58 mg, yield 44.9%).

[0098] Compound I-8 structure identification data: 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.53 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.34-4.31 (m, 2H), 4.10-3.89 (m, 2H), 2.79 (s, 3H), 2.22 (s, 3H), 1.46 (s, 3H), 1.28 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 178.38, 178.23, 169.83, 164.68, 162.05, 160.78, 155.44, 146.08, 134.01, 127.49, 122.09, 119.60, 118.20, 117.12, 64.85, 63.92, 45.08, 44.33, 42.95, 40.47, 39.48, 38.27, 36.41, 34.84, 33.57, 32.84, 31.63, 30.86, 30.60, 29.86, 29.74, 28.70, 25.59, 25.26, 21.70, 18.58, 17.40, 10.29. HRMS (ESI) calculated for C 38 H 49 NO6S[M+H]+ 648.3353, found 648.3345.

[0099] Example 9

[0100]

[0101] In a single-neck flask, 4-methylthiazole-5-carboxylic acid 72 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,5-dibromopentane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed until TLC showed the reaction was complete. After the reaction was complete, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20: 1 v:v) to obtain intermediate A9 (60 mg, yield 41.1%).

[0102] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHCO3, 60 mg (0.12 mmol) of intermediate A9 were added, and heated to 60 °C and refluxed until TLC showed the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, and anhydrous sodium sulfate was dried overnight; the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9: 1 v:v) to obtain compound I-9 (orange red solid, 54 mg, yield 40.9%).

[0103] Compound I-9 structure identification data: 1 H NMR (400 MHz, CDC13) δ 8.79 (s, 1H), 7.03 (dd, J = 7.1, 1.4 Hz, 1H), 6.54 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 7.1 Hz, 1H), 4.33-3.29 (m, 2H), 4.05-3.85 (m, 2H), 2.79 (s, 3H), 2.22 (s, 3H), 1.46 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H), 1.11 (s, 3H), 0.57 (s, 3H). 13C NMR (126 MHz, CDC13) δ 178.38, 178.25, 169.92, 164.73, 162.13, 160.65, 155.34, 146.08, 134.05, 127.48, 122.38, 119.59, 118.19, 117.13, 65.08, 64.15, 45.09, 44.34, 42.96, 40.45, 39.48, 38.26, 36.41, 34.84, 33.58, 32.83, 31.63, 30.85, 30.60, 29.86, 29.73, 28.70, 28.35, 28.13, 22.71, 21.69, 18.53, 17.40, 10.28. HRMS (ESI) calculated for C 39 H 51 NO6S[M+H] + 662.3509, found 662.3502.

[0104] Example 10

[0105]

[0106] In a single-neck flask, 2,4-dimethylthiazole-5-carboxylic acid 79 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,3-dibromopropane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 30: 1 v:v) to obtain intermediate A10 (66 mg, yield 47.8%).

[0107] 90 mg (0.2 mmol) of tripterine was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHCO3, 66 mg (0.12 mmol) of intermediate A10 were added, heated to 60 °C and refluxed until TLC detection showed that the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate overnight; The organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 9: 1 v:v) to obtain compound I-10 (orange red solid, 69 mg, yield 53.5%).

[0108] Compound I-10 structure identification data: 1H NMR (400 MHz, CDC13) δ 7.02 (dd, J = 7.0, 1.4 Hz, 1H), 6.51 (d, J = 1.4 Hz, 1H), 6.34 (d, J = 7.1 Hz, 1H), 4.42 - 4.25 (m, 2H), 4.14 - 3.97 (m, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 2.23 (s, 3H), 1.46 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 CNMR (126 MHz, CDC13) δ 178.33, 178.22, 169.73, 169.26, 164.65, 161.92, 160.40, 146.06, 133.93, 127.45, 123.51, 119.57, 118.13, 117.07, 61.45, 60.83, 45.08, 44.33, 42.95, 40.53, 39.47, 38.25, 36.40, 34.89, 33.47, 32.84, 31.55, 30.88, 30.58, 30.19, 29.73, 28.66, 27.89, 21.71, 19.38, 18.59, 17.33, 10.29. HRMS (ESI) calculated for C 38 H 49 NO6S[M+H] + 648.3353, found 648.3344.

[0109] Example 11

[0110]

[0111] In a single-neck flask, 2,4-dimethylthiazole-5-carboxylic acid 79 mg (0.5 mmol), triethylamine 0.2 mL (1.5 mmol), 1,4-dibromobutane 0.2 mL (2 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate = 30: 1 v:v) to obtain intermediate A11 (75 mg, yield 51.4%).

[0112] To a solution of 90 mg (0.2 mmol) triptolide in 3 mL DMF, 65 mg (0.8 mmol) NaHC03, 75 mg (0.12 mmol) intermediate Al l were added, and the reaction was heated to 60 °C until TLC detection showed that the reaction was complete. The reaction was diluted with 50 mL ethyl acetate, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, and dried over anhydrous sodium sulfate overnight. The organic phase was rotary evaporated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9: 1 v:v) to give compound I-11 (orange red solid, 46 mg, yield 34.1%).

[0113] Structure identification data of compound I-11: 1 H NMR (400 MHz, CDC13) δ 7.03 (dd, J = 7.0, 1.4 Hz, 1H), 6.53 (d, J = 1.5 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.31-4.28 (m, 2H), 4.09-3.88 (m, 2H), 2.71 (s, 3H), 2.69 (s, 3H), 2.23 (s, 3H), 1.47 (s, 3H), 1.30 (s, 4H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 178.39, 178.24, 169.85, 169.15, 164.70, 162.09, 160.13, 146.08, 133.99, 127.51, 124.50, 119.61, 118.20, 117.12, 64.57, 63.93, 45.09, 44.33, 42.95, 40.46, 39.47, 38.27, 36.41, 34.83, 33.55, 32.84, 31.48, 30.88, 30.61, 30.25, 29.73, 28.70, 25.64, 25.24, 21.70, 19.47, 18.58, 17.34, 10.28. HRMS (ESI) calculated for C 39 H 51 NO6S[M+H] + 662.3509, found 662.3497.

[0114] Example 12

[0115]

[0116] In a single-necked flask, 79 mg (0.5 mmol) of 2,4-dimethylthiazol-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 30:1 v:v) to give intermediate A12 (70 mg, yield 46.1%).

[0117] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 70 mg (0.12 mmol) of intermediate A12 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 9:1 v:v) to give compound I-12 (orange-red solid, 43 mg, yield 31.8%).

[0118] Structural identification data of compound I-12: 1 H NMR(400MHz, CDCl3)δ7.03(dd,J=7.0,1.4Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,1H),4.29-4.26(m,2H),4.04 -3.85(m,2H),2.70(s,3H),2.69(s,3H),2.22(s,3H),1.47(s,3H),1.30(s,3H),1.19(s,3H),1.12(s,3H),0.57(s,3H). 13 C NMR (126MHz, CDCl3) δ178.39,178.26,169.92,169.06,164.73,162.18,160.01,146.0 8,134.04,127.49,123.51,119.60,118.19,117.13,64.81,64.17,45.09,44.35,42.96 ,40.45,39.48,38.26,36.41,34.84,33.58,32.83,31.55,30.85,30.60,30.19,29.73, 28.70,28.37,28.13,22.72,21.69,19.46,18.53,17.34,10.28.HRMS(ESI)calculated for C 40 H53 NO6S[M+H] + 676.3664, found 676.3658.

[0119] Example 13

[0120]

[0121] In a single-neck flask, 2-bromothiazole-5-carboxylic acid 83 mg (0.4 mmol), triethylamine 0.15 mL (1.6 mmol), 1,3-dibromopropane 0.15 mL (0.12 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed until TLC showed the reaction was complete. The organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 90: 1 v:v) to give intermediate A13 (76 mg, yield 58.0%).

[0122] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHC03, 76 mg (0.12 mmol) of intermediate A13 were added, heated to 60 °C and refluxed until TLC showed the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, dried with anhydrous sodium sulfate overnight; the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 24: 1 v:v) to give compound I-13 (orange red solid, 90 mg, yield 64.7%).

[0123] Structure identification data of compound I-13: 1 H NMR (400 MHz, CDC13) δ 8.12 (s, 1H), 7.03 (dd, J = 7.1, 1.4 Hz, 1H), 6.52 (d, J = 1.4 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 4.49-4.30 (m, 2H), 4.14-3.98 (m, 2H), 2.24 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.56 (s, 3H). 13CNMR (126 MHz, CDC13) δ 178.36, 178.18, 169.60, 164.61, 159.79, 148.11, 146.07, 142.28, 133.96, 127.50, 123.51, 119.60, 118.19, 117.17, 62.45, 60.68, 45.07, 44.32, 42.92, 40.54, 39.47, 38.25, 36.39, 34.87, 33.51, 32.82, 31.64, 30.88, 30.57, 29.86, 29.81, 28.66, 27.81, 21.68, 18.58, 10.33. HRMS (ESI) calculated for C 36 H 44 BrNO6S[M+H] + 698.2145, found 700.2125.

[0124] Example 14

[0125]

[0126] In a single-neck flask, 2-bromothiazole-5-carboxylic acid 83 mg (0.4 mmol), triethylamine 0.15 mL (1.6 mmol), 1,4-dibromobutane 0.15 mL (0.12 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed until TLC showed the reaction was complete. The organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 90: 1 v:v) to obtain intermediate A14 (85 mg, yield 62.5%).

[0127] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHCO3, 85 mg (0.12 mmol) of intermediate A14 were added, heated to 60 °C and refluxed until TLC showed the reaction was complete, 50 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, anhydrous sodium sulfate was dried overnight; the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 24: 1 v:v) to obtain compound I-14 (orange red solid, 90 mg, yield 63.4%).

[0128] Structure identification data of compound I-14: 1H NMR (400 MHz, CDC13) δ 8.17 (s, 1H), 7.03 (dd, J = 7.1, 1.4 Hz, 1H), 6.54 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 7.1 Hz, 1H), 4.36-4.33 (m, 2H), 4.09-3.89 (m, 2H), 2.23 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 CNMR (126 MHz, CDC13) δ 178.39, 178.22, 169.81, 164.69, 159.92, 147.99, 146.09, 142.15, 134.00, 127.51, 123.51, 119.61, 118.22, 117.14, 65.48, 63.80, 45.08, 44.32, 42.94, 40.47, 39.46, 38.28, 36.40, 34.82, 33.57, 32.85, 31.63, 30.87, 30.61, 30.19, 29.74, 28.70, 25.52, 25.17, 21.69, 18.60, 10.29. HRMS (ESI) calculated for C 37 H 46 BrNO6S[M+H] + 712.2302, found 714.2279.

[0129] Example 15

[0130]

[0131] In a single-neck flask, 2-bromothiazole-5-carboxylic acid 83 mg (0.4 mmol), triethylamine 0.15 mL (1.6 mmol), 1,5-dibromopentane 0.15 mL (0.12 mmol) were added and dissolved in 3 mL of acetone, heated to 50 °C and refluxed, TLC monitored the reaction. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 90: 1 v:v) to obtain intermediate A15 (78 mg, yield 54.9%).

[0132] Compound I-15 was prepared according to the procedure described in Example 1. Compound I-15 (orange red solid, 80 mg, 55.2% yield) was obtained from 90 mg (0.2 mmol) triptolide, 65 mg (0.8 mmol) NaHC03, 78 mg (0.12 mmol) intermediate A15, 3 mL DMF, 50 mL ethyl acetate, water, saturated sodium bicarbonate, saturated brine, and anhydrous sodium sulfate.

[0133] Structure identification data of compound I-15: 1 H NMR (400 MHz, CDC13) δ 8.16 (s, 1H), 7.03 (dd, J = 7.1, 1.5 Hz, 1H), 6.54 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 7.2 Hz, 1H), 4.34-4.31 (m, 2H), 4.04-3.86 (m, 2H), 2.23 (s, 3H), 1.47 (s, 3H), 1.28 (s, 3H), 1.19 (s, 3H), 1.12 (s, 3H), 0.57 (s, 3H). 13 CNMR (126 MHz, CDC13) δ 178.38, 178.24, 169.90, 164.72, 159.99, 147.89, 146.08, 142.07, 134.05, 127.49, 121.51, 119.59, 118.20, 117.14, 65.70, 64.08, 45.09, 44.34, 42.96, 40.46, 39.48, 38.26, 36.40, 34.83, 33.60, 32.83, 31.63, 30.84, 30.60, 29.86, 29.74, 28.70, 28.27, 28.10, 22.59, 21.68, 18.53, 10.28. HRMS (ESI) calculated for C 38 H 48 BrNO6S[M+H] + 726.2458, found 728.2442.

[0134] Example 16

[0135]

[0136] In a single-neck flask, 88 mg (0.4 mmol) of 2-(3-pyridyl)-4-methylthiazole-5-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, 0.2 mL (0.12 mmol) of 1,3-dibromopropane were added and dissolved in 3 mL of acetone, and the reaction was heated to 50°C and refluxed. The reaction was monitored by TLC. After the reaction was completed, the organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 12:1 v:v) to obtain intermediate A16 (67 mg, yield 49.6%).

[0137] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, 65 mg (0.8 mmol) of NaHCO3, 67 mg (0.12 mmol) of intermediate A16 were added, and the reaction was heated to 60°C and refluxed until the reaction was completed as detected by TLC. The reaction solution was diluted with 50 mL of ethyl acetate, washed with water 3 times, saturated sodium bicarbonate 3 times, saturated brine 3 times, and dried with anhydrous sodium sulfate overnight. The organic phase was dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 24:1 v:v) to obtain compound I-16 (orange red solid, 50 mg, yield 35.2%).

[0138] Structure identification data of compound I-16: 1 H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.71 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.45 (s, 1H), 6.34 (d, J = 7.1 Hz, 1H), 4.55-4.27 (m, 2H), 4.15-4.03 (m, 2H), 2.78 (s, 3H), 2.06 (s, 3H), 1.43 (s, 3H), 1.30 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H), 0.62 (s, 3H). 13C NMR (126MHz, CDCl3) δ178.24,178.19,169.55,166.41,164.55,161.87,161.67,151.64,147 .89,145.90,133.93,133.79,128.99,127.39,123.83,123.50,119.45,118.12,117.04,61. 61,60.82,45.08,44.35,42.91,40.55,39.47,38.24,36.41,34.89,33.41,32.81,31.55,30 .89,30.57,30.19,29.73,28.66,27.92,21.68,18.65,17.53,10.12.HRMS(ESI)calculated for C 42 H 50 N₂O₆S[M+H] + 711.3462, found 711.3457.

[0139] Example 17

[0140]

[0141] In a single-necked flask, 88 mg (0.4 mmol) of 2-(3-pyridine)-4-methylthiazol-5-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,4-dibromobutane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1 v:v) to give intermediate A17 (86 mg, yield 60.6%).

[0142] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 86 mg (0.12 mmol) of intermediate A17 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried overnight with anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 24:1 v:v) to give compound I-17 (orange-red solid, 63 mg, yield 43.7%).

[0143] Structural identification data of compound I-17: 1H NMR (400MHz, CDCl3) δ9.19(s,1H),8.72(s,1H),8.29(d,J=8.1Hz,1H),7.43(dd,J=8.0,4.9Hz,1H),7.01(d,J=1.4Hz,1H),6.52(d,J=1.5Hz,1H),6.3 4(d,J=7.2Hz,1H),4.37-4.34(m,2H),4.11-3.91(m,2H),2.81(s,3H),2.2 1(s,3H),1.44(s,3H),1.30(s,3H),1.21(s,3H),1.12(s,3H),0.58(s,3H). 13 C NMR (126MHz, CDCl3) δ178.37,178.24,169.82,166.46,164.68,161.90,161.51,151.67,147. 96,146.07,133.98,129.09,127.49,123.85,123.50,122.48,119.58,118.19,117.14,64.93, 63.92,45.08,44.33,42.93,40.48,39.46,38.27,36.40,34.83,33.55,32.86,31.63,30.88, 30.61,30.19,29.73,28.70,25.63,25.28,21.70,18.61,17.56,10.27.HRMS(ESI)calculated for C 43 H 52 N₂O₆S[M+H] + 725.3618, found 725.3610.

[0144] Example 18

[0145]

[0146] In a single-necked flask, 88 mg (0.4 mmol) of 2-(3-pyridine)-4-methylthiazol-5-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1 v:v) to give intermediate A18 (105 mg, yield 70.9%).

[0147] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 105 mg (0.12 mmol) of intermediate A18 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 24:1 v:v) to give compound I-18 (orange-red solid, 65 mg, yield 44.2%).

[0148] Structural identification data of compound I-18: 1 H NMR (400MHz, CDCl3) δ9.19(s,1H),8.72(s,1H),8.28(d,J=8.0Hz,1H),7.43(dd,J=8.0,4.8Hz,1H),7.01(d,J=1.5Hz,1H),6.54(d,J=1.4Hz,1H),6.3 5(d,J=7.2Hz,1H),4.35-4.32(m,2H),4.05-3.87(m,2H),2.81(s,3H),2.2 1(s,3H),1.46(s,3H),1.30(s,3H),1.19(s,3H),1.10(s,3H),0.57(s,3H). 13 C NMR (126MHz, CDCl3) δ178.39,178.24,169.88,166.41,164.70,161.98,161.38,151.65,147.96 ,146.09,134.02,133.96,129.12,127.49,123.84,122.62,119.62,118.19,117.16,65.14,64. 17,45.09,44.34,42.95,40.45,39.47,38.26,36.39,34.83,33.59,32.82,31.62,30.84,30.59 ,30.19,29.73,28.70,28.39,28.14,22.72,21.68,18.53,17.55,10.27.HRMS(ESI)calculated for C 44 H 54 N₂O₆S[M+H] + 739.3775, found 739.3771.

[0149] Example 19

[0150]

[0151] In a single-necked flask, 65 mg (0.4 mmol) of thiazolyl-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,3-dibromopropane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give intermediate A19 (84 mg, yield 67.2%).

[0152] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 84 mg (0.12 mmol) of intermediate A19 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-1 (orange-red solid, 50 mg, yield 40.6%).

[0153] Structural identification data of compound II-1: 1 H NMR (400MHz, CDCl3) δ8.83(d,J=2.1Hz,1H),8.21(d,J=1.9Hz,1H),7.03(dd,J=7.1,1.4Hz,1H),6.52(s,1H),6.35(d,J=7.2H z,1H),4.53-4.38(m,2H),4.19-3.98(m,2H),2.23(s,3H),1.45(s,3H),1.26(s,3H),1.20(s,3H),1.11(s,3H),0.55(s,3H). 13 C NMR (126MHz, CDCl3) δ178.36,178.25,169.93,164.72,161.12,153.57,147.70 ,146.09,134.07,127.53,127.44,119.61,118.17,117.09,62.02,60.87,45.10 ,44.32,42.99,40.51,39.48,38.25,36.40,34.88,33.50,32.88,31.63,30.88, 30.58,30.19,29.74,28.66,27.93,21.70,18.59,10.30.HRMS(ESI)calculated forC36 H 45 NO6S[M+H] + 620.3040, found 620.3028.

[0154] Example 20

[0155]

[0156] In a single-necked flask, 65 mg (0.4 mmol) of thiazolyl-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,4-dibromobutane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1 v:v) to give intermediate A20 (85 mg, yield 64.4%).

[0157] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 85 mg (0.12 mmol) of intermediate A20 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1 v:v) to give compound II-2 (orange-red solid, 40 mg, yield 31.7%).

[0158] Structural identification data of compound II-2: 1 H NMR (400MHz, CDCl3) δ8.87(d,J=2.1Hz,1H),8.29(d,J=2.1Hz,1H),7.03(dd,J=7.1,1.4Hz,1H),6.53(d,J=1.4Hz,1H),6.36(d,J= 7.1Hz,1H),4.45-4.40(m,2H),4.08-3.88(m,2H),2.22(s,3H),1.45(s,3H),1.27(s,3H),1.19(s,3H),1.11(s,3H),0.56(s,3H). 13C NMR (126MHz, CDCl3) δ178.40,178.27,169.91,164.72,161.28,153.51,148.03,1 46.08,134.04,127.53,127.49,119.60,118.19,117.11,65.04,63.98,45.09,44 .33,42.96,40.46,39.49,38.27,36.41,34.85,33.55,32.84,31.63,30.87,30.6 0,29.85,29.73,28.70,25.66,25.22,21.70,18.55,10.29.HRMS(ESI)calculated for C 37 H 47 NO6S[M+H] + 634.3196, found 634.3188.

[0159] Example 21

[0160]

[0161] In a single-necked flask, 65 mg (0.4 mmol) of thiazolyl-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A21 (104 mg, yield 75.4%).

[0162] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 104 mg (0.12 mmol) of intermediate A21 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1 v:v) to give compound II-3 (orange-red solid, 52 mg, yield 40.3%).

[0163] Structural identification data of compound II-3: 1H NMR (400MHz, CDCl3) δ8.87(d,J=2.1Hz,1H),8.26(d,J=2.1Hz,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J= 7.2Hz,1H),4.41-4.37(m,2H),4.03-3.84(m,2H),2.22(s,3H),1.46(s,3H),1.27(s,3H),1.17(s,3H),1.10(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.39,178.27,169.97,164.75,161.34,153.45,148.14,14 6.07,134.08,127.47,127.29,119.60,118.19,117.12,65.23,64.15,45.09,44.34 ,42.97,40.45,39.49,38.26,36.41,34.84,33.58,32.83,31.64,30.85,30.60,29. 84,29.72,28.70,28.38,28.14,22.60,21.68,18.53,10.28.HRMS(ESI)calculated for C 38 H 49 NO6S[M+H] + 648.3353, found 648.3346.

[0164] Example 22

[0165]

[0166] In a single-necked flask, 72 mg (0.4 mmol) of 2-methylthiazolyl-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,3-dibromopropane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 7:1 v:v) to give intermediate A22 (90 mg, yield 68.2%).

[0167] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 was added. After stirring, 90 mg (0.12 mmol) of intermediate A22 was added, and the mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried overnight with anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-4 (orange-red solid, 40 mg, yield 32.7%).

[0168] Structural identification data of compound II-4: 1 H NMR (400MHz, CDCl3) δ7.99(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.52(d,J=1.4Hz,1H),6.35(d,J=7.1Hz,1H),4.48-4.38(m,2H),4.17- 3.97(m,2H),4.00(dt,J=11.5,5.9Hz,1H),2.75(s,3H),2.18(s,4H),1.45(s,3H),1.27(s,3H),1.19(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.36,178.24,169.90,166.90,164.70,161.20,146.40,1 46.07,133.99,127.60,127.46,119.61,118.16,117.05,61.91,60.95,45.10,44 .32,42.98,40.51,39.48,38.27,36.40,34.87,33.52,32.86,31.63,30.87,30.5 9,29.82,29.74,28.68,27.99,21.71,19.36,18.59,10.29.HRMS(ESI)calculated for C 37 H 47 NO6S[M+H] + 634.3196, found 634.3189.

[0169] Example 23

[0170]

[0171] In a single-necked flask, 72 mg (0.4 mmol) of 2-methylthiazo-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,4-dibromobutane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A23 (90 mg, yield 65.7%).

[0172] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 90 mg (0.12 mmol) of intermediate A23 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-5 (orange-red solid, 42 mg, yield 32.5%).

[0173] Structural identification data of compound II-5: 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.53(d,J=1.4Hz,1H),6.36(d,J=7.1Hz,1H),4.41-4.38 (m,2H),4.08-3.87(m,2H),2.78(s,3H),2.22(s,3H),1.45(s,3H),1.27(s,3H),1.19(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.39,178.27,169.90,166.86,164.71,161.32,146.67,14 6.07,134.02,127.51,127.48,119.60,118.19,117.10,64.86,64.00,45.09,44.32 ,42.95,40.46,39.48,38.26,36.41,34.84,33.55,32.84,31.63,30.87,30.60,29. 84,29.71,28.70,25.70,25.19,21.70,19.39,18.55,10.28.HRMS(ESI)calculated forC 38 H 49 NO6S[M+H]+ 648.3342, found 648.3353.

[0174] Example 24

[0175]

[0176] In a single-necked flask, 72 mg (0.4 mmol) of 2-methylthiazolyl-4-carboxylic acid, 0.25 mL (1.6 mmol) of triethylamine, and 0.25 mL (0.12 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A24 (96 mg, yield 69.5%).

[0177] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 96 mg (0.12 mmol) of intermediate A24 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1 v:v) to give compound II-6 (orange-red solid, 41 mg, yield 31.1%).

[0178] Structural identification data of compound II-6: 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(s,1H),6.36(d,J=7.1Hz,1H),4.38-4.34(m,2 H),4.03-3.83(m,2H),2.78(s,3H),2.22(s,3H),1.46(s,3H),1.27(s,3H),1.17(s,3H),1.10(s,3H),0.56(s,3H). 13CNMR (126MHz, CDCl3) δ178.38,178.27,169.96,166.80,164.75,161.39,146.79,146 .07,134.07,127.46,127.33,119.60,118.19,117.12,65.05,64.15,45.09,44.34,42 .97,40.45,39.48,38.26,36.41,34.84,33.58,32.84,31.64,30.85,30.59,30.19,2 9.71,28.70,28.40,28.14,22.56,21.68,19.40,18.52,10.28.HRMS(ESI)calculated forC 39 H 51 NO6S[M+H] + 662.3509, found 662.3501.

[0179] Example 25

[0180]

[0181] In a single-necked flask, 72 mg (0.4 mmol) of 5-methylthiazolyl-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,3-dibromopropane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A25 (70 mg, yield 53.3%).

[0182] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 was added. After stirring, 70 mg (0.12 mmol) of intermediate A25 was added, and the mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried overnight with anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-7 (orange-red solid, 42 mg, yield 33.3%).

[0183] Structural identification data of compound II-7: 1H NMR (400MHz, CDCl3) δ8.55(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.52(d,J=1.4Hz,1H),6.35(d,J=7.2Hz,1H),4.49-4.38 (m,2H),4.20-3.98(m,2H),2.78(s,3H),2.22(s,3H),1.45(s,3H),1.27(s,3H),1.20(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.37,178.23,169.90,164.71,162.29,149.21,146.07,1 44.90,141.79,134.00,127.45,119.60,118.15,117.05,61.77,61.07,45.09,44 .32,42.98,40.50,39.48,38.26,36.40,34.87,33.51,32.86,31.63,30.88,30.5 8,29.81,29.73,28.68,27.98,21.71,18.59,13.11,10.29.HRMS(ESI)calculated for C 37 H 47 NO6S[M+H] + 634.3196, found 634.3189.

[0184] Example 26

[0185]

[0186] In a single-necked flask, 72 mg (0.4 mmol) of 5-methylthiazo-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,4-dibromobutane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A26 (80 mg, yield 57.9%).

[0187] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 80 mg (0.12 mmol) of intermediate A26 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-8 (orange-red solid, 56 mg, yield 43.4%).

[0188] Structural identification data of compound II-8: 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.52(d,J=1.4Hz,1H),6.36(d,J=7.1Hz,1H),4.41-4.37 (m,2H),4.08-3.88(m,2H),2.81(s,3H),2.22(s,3H),1.45(s,3H),1.27(s,3H),1.18(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.38,178.26,169.88,164.70,162.41,149.16,146.07,14 4.81,142.01,134.01,127.48,119.61,118.18,117.07,64.63,64.00,45.09,44.33 ,42.96,40.46,39.49,38.26,36.42,34.86,33.55,32.85,31.64,30.88,30.60,29. 83,29.73,28.70,25.68,25.25,21.71,18.55,13.12,10.29.HRMS(ESI)calculated forC 38 H 49 NO6S[M+H] + 648.3353, found 648.3342.

[0189] Example 27

[0190]

[0191] In a single-necked flask, 72 mg (0.4 mmol) of 2-methylthiazolyl-4-carboxylic acid, 0.25 mL (1.6 mmol) of triethylamine, and 0.25 mL (0.12 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A27 (70 mg, yield 47.9%).

[0192] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 70 mg (0.12 mmol) of intermediate A27 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried overnight with anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-9 (orange-red solid, 34 mg, yield 25.8%).

[0193] Structural identification data of compound II-9: 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.5Hz,1H),6.36(d,J=7.1Hz,1H),4.38-4.35 (m,2H),4.03-3.83(m,2H),2.81(s,3H),2.22(s,3H),1.46(s,3H),1.30(s,3H),1.17(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ178.39,178.28,169.95,164.73,162.49,149.13,146.07,144. 62,142.11,134.05,127.47,119.61,118.18,117.10,64.88,64.19,45.09,44.34,42 .97,40.44,39.49,38.25,36.42,34.85,33.58,32.83,31.64,30.86,30.59,30.25,2 9.72,28.71,28.43,28.16,22.65,21.69,18.52,13.11,10.28.HRMS(ESI)calculated forC 39 H 51NO6S[M+H] + 662.3509, found 662.3499.

[0194] Example 28

[0195]

[0196] In a single-necked flask, 77 mg (0.45 mmol) of 2-isopropylthiazo-4-carboxylic acid, 0.2 mL (1.8 mmol) of triethylamine, and 0.2 mL (1.35 mmol) of 1,3-dibromopropane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1 v:v) to give intermediate A28 (73 mg, yield 50.0%).

[0197] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 73 mg (0.12 mmol) of intermediate A28 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-10 (orange-red solid, 53 mg, yield 40.2%).

[0198] Structural identification data of compound II-10: 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.02(dd,J=7.1,1.4Hz,1H),6.53(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,1H),4.48-4.37(m,2H),4.16 -3.98(m,2H),3.41(p,J=6.9Hz,1H),2.22(s,3H),1.46(s,3H),1.42(s ,3H),1.41(s,3H),1.27(s,3H),1.19(s,3H),1.11(s,3H),0.57(s,3H). 13C NMR (126MHz, CDCl3) δ179.08,178.37,178.25,169.89,164.69,161.36,146.12,146. 09,133.99,127.48,126.71,119.63,118.17,117.07,61.87,61.02,45.10,44.32,42 .98,40.51,39.48,38.27,36.40,34.87,33.55,33.53,32.85,31.63,30.87,30.59,2 9.82,29.75,28.69,28.00,23.24,23.23,21.70,18.59,10.29.HRMS(ESI)calculated for C 39 H 51 NO6S[M+H] + 662.3509, found 662.3499.

[0199] Example 29

[0200]

[0201] In a single-necked flask, 77 mg (0.45 mmol) of 2-isopropylthiazo-4-carboxylic acid, 0.2 mL (1.8 mmol) of triethylamine, and 0.2 mL (1.35 mmol) of 1,4-dibromobutane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A29 (72 mg, yield 47.1%).

[0202] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 72 mg (0.12 mmol) of intermediate A29 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of ethyl acetate, washed three times with water, three times with saturated sodium bicarbonate, and three times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-11 (orange-red solid, 47 mg, yield 34.8%).

[0203] Structural identification data of compound II-11: 1H NMR(400MHz,Chloroform-d)δ8.08(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.53(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,1H),4.40-4.37(m,2H),4.08 -3.88(m,2H),3.43(p,J=6.9Hz,1H),2.22(s,3H),1.45(s,3H),1.44(s ,3H),1.42(s,3H),1.27(s,3H),1.19(s,3H),1.11(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ179.06,178.39,178.27,169.89,164.71,161.48,146.38,146.0 7,134.01,127.48,126.61,119.60,118.19,117.10,64.77,64.01,45.09,44.32,42.9 5,40.46,39.48,38.27,36.41,34.84,33.58,33.56,32.84,31.63,30.87,30.60,29.8 4,29.71,28.70,25.70,25.21,23.28(2C),21.69,18.55,10.28.HRMS(ESI)calculated for C 40 H 53 NO6S[M+H] + 676.3664, found 676.3655.

[0204] Example 30

[0205]

[0206] In a single-necked flask, 77 mg (0.45 mmol) of 2-isopropylthiazo-4-carboxylic acid, 0.2 mL (1.8 mmol) of triethylamine, and 0.2 mL (1.35 mmol) of 1,5-dibromopentane were added and dissolved in 3 mL of acetone. The mixture was heated to 50 °C and refluxed, and the reaction was monitored by TLC. After the reaction was complete, the organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1 v:v) to give intermediate A30 (82 mg, yield 51.3%).

[0207] 90 mg (0.2 mmol) of triptolide was dissolved in 3 mL of DMF, and 65 mg (0.8 mmol) of NaHCO3 and 82 mg (0.12 mmol) of intermediate A30 were added. The mixture was heated to 60 °C and refluxed until TLC showed that the reaction was complete. 50 mL of ethyl acetate was added to dilute the reaction solution, and the mixture was washed 3 times with water, 3 times with saturated sodium bicarbonate, and 3 times with saturated brine. The solution was dried over anhydrous sodium sulfate overnight. The organic phase was evaporated to dryness and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v:v) to give compound II-12 (orange-red solid, 75 mg, yield 54.7%).

[0208] Structural identification data of compound II-12: 1 H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,1H),4.37-4.34(m,2H),4.03 -3.84(m,2H),3.43(p,J=6.9Hz,1H),2.22(s,3H),1.46(s,3H),1.44(s ,3H),1.42(s,3H),1.27(s,3H),1.17(s,3H),1.10(s,3H),0.56(s,3H). 13 C NMR (126MHz, CDCl3) δ179.00,178.38,178.27,169.95,164.74,161.54,146.48,146.07 ,134.07,127.46,126.43,119.60,118.19,117.11,64.97,64.17,45.09,44.34,42.97,4 0.45,39.48,38.26,36.41,34.84,33.58,33.54,32.84,31.64,30.85,30.59,29.84,29. 71,28.70,28.40,28.14,23.28(2C),22.59,21.68,18.52,10.28.HRMS(ESI)calculated for C 41 H 55 NO6S[M+H] + 690.3822, found 690.3813.

[0209] Example 31

[0210] (I) In vitro antitumor activity study

[0211] The in vitro antitumor activity of triptolide thiazole derivatives (compounds I-1 to I-18, and compounds II-1 to II-12) was tested using the MTT colorimetric method, with triptolide (CEL) and CDDO-Me (Bardoxolonemethyl) selected as positive control drugs.

[0212] Instruments: Clean bench (SW-CJ-1FD, AIRTECH, Sujing Antai), constant temperature CO2 incubator (Heracell 14VIOS160i, Thermo, USA), biological microscope (IX71, Olympus, Japan), multi-functional microplate reader (POLARstar, Omega, USA).

[0213] Reagents: DMEM, 1640 medium (KeyGEN), fetal bovine serum (BI), trypsin (Sigma), DMSO (Sigma).

[0214] Cell lines: human gastric cancer cell line BGC-823, human breast cancer cell line MCF-7, human triple-negative breast cancer cell line MDA-MB-231, and human lung cancer cell line A549 (all provided by Jiangsu Kaiji Biotechnology Co., Ltd.).

[0215] Preparation of drug-containing culture medium: Weigh appropriate amounts of the test compounds (compounds I-1 to I-18, compounds II-1 to II-12), CEL and CDDO-Me, dissolve them in DMSO to prepare a stock solution with a concentration of 10 mmol / L, and then dilute with culture medium to prepare a series of drug-containing culture media with concentrations of 0.25, 0.5, 1, 2 and 4 μmol / L.

[0216] Method: 50 mL of fetal bovine serum was added to 450 mL of DMEM medium to prepare a complete culture medium containing 10% fetal bovine serum. This medium was then stored at 4°C until use. All culture media mentioned below refer to this complete culture medium.

[0217] Revive the frozen cell lines and incubate them in a 37°C, 5% CO2 incubator, changing the medium every 2-3 days. Once the cells are in the exponential growth phase and in good condition, plate them. Add 1 mL of 0.25% trypsin digestion solution and digest for 1-2 minutes. Observe the cell state under a microscope. When the adherent cells become rounded and shrink, add 2 mL of complete culture medium to stop the digestion. Collect the liquid, centrifuge, discard the supernatant, and collect the cells. Add 1-2 mL of complete culture medium containing 10% fetal bovine serum to prepare a cell suspension, and count the cells at a density of 3.5 × 10⁶ cells per well. 3 ~4.5×10 3The required amount of cell suspension was calculated based on the number of cells and the total number of wells. This cell suspension was seeded into 96-well plates at 100 μL / well, sealed with PBS, and incubated in a constant temperature incubator at 37°C and 5% CO2 for 24 h.

[0218] Replace the medium with drug-containing medium and set up a blank control (DMSO) diluted to a concentration of 4 μmol / L. Each drug concentration was used in triplicate. After culturing for 48 h, 20 μL of LTT reagent (5 mg / mL) was added to each well, and incubation continued for another 4 h. The medium was then removed from the plate, and 100 μL of DMSO was added to each well. The absorbance of each well was measured at 570 nm using a multi-mode microplate reader, and the cell inhibition rate was calculated using the following formula.

[0219] Cell inhibition rate % = [(OD value of blank control group - OD value of drug treatment group) / OD value of blank control group] × 100%

[0220] The average of the three initial screening results is the final inhibition rate. The IC50 of the test drug is then calculated. 50 The IC50 value (using GraphPad software) is the final IC50 value of the compound obtained from three repeated experiments. 50 value.

[0221] Table 1. Inhibition rate of the test compound (concentration 0.5 μmol / L) on MDA-MB-231 cells

[0222]

[0223] Table 2. Inhibitory effects of the tested compounds on MDA-MB-231, BGC-823, MCF-7, and A549 cell lines.

[0224]

[0225]

[0226] Based on Tables 1 and 2, it can be seen that, compared with triptolide, the triptolide thiazole derivatives of this invention significantly enhanced the inhibitory effect on most MDA-MB-231 cell lines. Among them, compound II-10 showed the best activity, with its activity in MCF-7 and MD-MBA-231 cells being approximately 4-fold and 3.5-fold higher than that of triptolide, respectively.

[0227] (II) In vitro thiol binding study of compound II-10

[0228] Instruments: Nuclear magnetic resonance spectrometer (Bruker AV-300), ultrasonic cleaner (KH2200E).

[0229] Reagents: DMSO-d6 (Annegi Chemicals), dithiothreitol (Annegi Chemicals).

[0230] Studies have shown that the A / B ring of CEL contains a quinone methyl structure, belonging to a Michael receptor, which can bind to various proteins to form covalent bonds, and is closely related to the antitumor activity of CEL. Taking compound II-10 as an example, the inventors investigated whether the triptolide thiazole derivative of the present invention has the ability to covalently bind to Hsp90 protein to exert antitumor activity through the following methods.

[0231] Methods: CEL (0.02 mmol / L) and dithiothreitol (DTT, 0.01 mmol / L), compound II-10 (0.02 mmol / L) and dithiothreitol (DTT, 0.01 mmol / L) were dissolved separately in DMSO-d6, and each was sonicated for 20 min. 1 Spectroscopy was analyzed after H-NMR detection. Results are shown below. Figure 1 The results show that after CEL binds to DTT, the quinone methyl hydrogen δ 6-H (Red) gradually decreases, δ 1-H Peak shift changes to δ 1-H '(Yellow); CEL quinone methyl δ 6-H The remaining peak area is 0.21, δ 1-H After the reaction and before the reaction (δ) 1-H ' / δ 1-H The peak area ratio was 0.83; while the δ of the quinone methyl group of II-10 was... 6-H The peak disappears, δ 1-H The peak shifts all changed to δ 1-H This indicates that, under the same conditions, CEL cannot completely bind to DTT, while compound II-10 can completely bind to DTT. This demonstrates that compound II-10 exhibits enhanced covalent binding reactivity, confirming that the introduction of thiazole into CEL enhances its covalent binding ability between the quinone methyl group and the thiol group. This suggests that such compounds can covalently bind to Hsp90 protein, inhibiting Hsp90 protein and thus exerting antitumor activity.

Claims

1. Tripterygium thiazole derivatives of the structure shown in Formula III, or pharmaceutically acceptable salts thereof: ； wherein R is selected from , ; R1is selected from H, CH3, halogen, ; R3is selected from H, CH3, CH3CH2, CH(CH3)2, halogen, ; R2 and R4 are independently selected from H and C1-C4 alkyl groups, respectively; n = an integer from 1 to 5.

2. The triazol derivative of tripterine according to claim 1, characterized in that: R1= H, CH3, Br, ; R2=H, CH3; R3=H, CH3, CH3 CH2, CH(CH3)2; R4 = H, CH3; n=3、4、5； But not including: R1= CH3, R2= H, n = 4, 5; R1= , R2= CH3, n = 3, 5.

3. The emodin thiazole derivative according to claim 1, characterized in that: R1 = H, CH3, Br; R2=H, CH3; R3=H, CH3, CH3 CH2, CH(CH3)2; R4 = H, CH3; n=3、4、5； However, it does not include: R1=CH3, R2=H, n=4, 5.

4. Tripterygium thiazole derivatives with structures as shown in Formula III, or pharmaceutically acceptable salts thereof: ； wherein R is selected from , ; R1=H, R2=H, CH3, n=3, 4, 5; R1= CH3, R2=CH3, n=3; R1= Br, R2=H, n=3; R3=H, CH3, CH(CH3)2, R4=H, CH3, n=3, 4, 5; but does not include: R3=CH(CH3)2, R4=H, n=5.

5. Tripterygium thiazole derivatives or pharmaceutically acceptable salts thereof selected from the following structures: ； wherein R is selected from , ; 。 6. A method for preparing the emodin thiazole derivative according to claim 1, characterized by: The synthesis route is as follows: ； wherein R is selected from , ; R1, R2, R3, R4, n are as in claim 1 ; Includes the following steps: Step (1), the thiazole compound shown in formula is reacted with the dibromoalkane shown in formula under reflux to obtain intermediate IV; Step (2): Using NaHCO3 as an alkaline catalyst and N,N-dimethylformamide as a reaction solvent, intermediate IV is refluxed with triptolide to obtain triptolide thiazole derivatives.

7. Use of the triptolide thiazole derivative or a pharmaceutically acceptable salt thereof as described in any one of claims 1-5 in the preparation of an Hsp90 protein inhibitor.

8. Use of the triptolide thiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 in the preparation of an antitumor drug, wherein the tumor is gastric cancer, lung cancer, or breast cancer.

9. A pharmaceutical composition, characterized by: The pharmaceutical composition comprises any pharmaceutically acceptable dosage form of triptolide thiazole derivatives or pharmaceutically acceptable salts thereof as the active ingredient, formulated with a pharmaceutical carrier.

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