Tripterine thiazole derivative as well as preparation method and application thereof

Abstract

The invention discloses a tripterine thiazole derivative with a structure as shown in a formula III or pharmaceutically acceptable salt thereof. R is selected from # imgabs0 # R1 and R3 which are independently selected from H, C3-C4 alkyl and halogen, and # imgabs1 # R2 and R4 are independently selected from H and C1-C4 alkyl; and n is an integer of 1-5. The tripterine thiazole derivative disclosed by the invention has an obvious inhibition effect on proliferation of various tumor cells, and the inhibition effect is obviously better than that of tripterine. The invention discloses application of the tripterine thiazole derivative or the pharmaceutically acceptable salt thereof in preparation of an Hsp90 protein inhibitor. The invention also discloses application of the tripterine thiazole derivative or the pharmaceutically acceptable salt thereof in preparation of antitumor drugs. # imgabs2 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry and pharmacotherapy, and relates to a thiazole derivative of tripterygium wilfordii and a preparation method thereof and use thereof in preparing anticancer drugs. Technical Background

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

[0003] Heat shock protein (HSP) is a heat stress chaperone protein widely present in mammals and is highly conserved. Usually, Hsp90 is expressed at a low abundance in normal cells, while Hsp90 is highly expressed in tumor cells and often combines with other molecular co-chaperones to form complexes to participate in cell signal transduction, client protein folding and degradation, etc. Therefore, inhibiting the function of Hsp90 protein is one of the effective strategies for treating tumors.

[0004] Natural products have become an important treasure trove for drug development due to their unique molecular structure and diverse biological activities, and have attracted extensive attention from researchers. Celastrol (CEL) is a pentacyclic triterpene compound containing quinone methyl groups derived from the root of Tripterygium wilfordii. Studies have shown that Celastrol has good effects on a variety of diseases such as tumors, inflammation, obesity, and nerve damage. Although Celastrol has obvious anti-tumor activity, its activity needs to be improved.

[0005] Summary of the invention

[0006] The purpose of the present invention is to use tripterygium wilfordii as a lead compound and introduce thiazole compounds to modify its structure, thereby providing a tripterygium wilfordii thiazole derivative. Pharmacological experiments show that the tripterygium wilfordii derivative described in the present invention has excellent anti-tumor activity, and the activity is significantly improved compared with tripterygium wilfordii.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] The structure of the tripterygium wilfordii thiazole derivative or a pharmaceutically acceptable salt thereof is shown in Formula III:

[0009]

[0010] Among them, R is selected from

[0011] R 1 , R 3 Each independently selected from H, C3-C4 alkyl, halogen,

[0012] R 2 , R 4 Each independently selected from H, C1-C4 alkyl;

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

[0014] But not including: R 1 =CH 3 , R 2 =H, n = 4, 5; R 2 =CH 3 , n=3,5.

[0015] Preferably, R 1 =H、CH 3 Br

[0016] R 2 =H、CH 3 ;

[0017] R 3 =H、CH 3 , CH 3 CH 2 、CH(CH 3 ) 2 ;

[0018] R 4 =H、CH 3 ;

[0019] n = 3, 4, 5;

[0020] But not including: R 1 =CH 3 , R 2 =H, n = 4, 5; R 2 =CH 3 , n=3,5.

[0021] More preferably, R 1 =H、CH 3 , Br;

[0022] R 2 =H、CH 3 ;

[0023] R 3 =H、CH 3 , CH3 CH 2 、CH(CH 3 ) 2 ;

[0024] R 4 =H、CH 3 ;

[0025] n = 3, 4, 5;

[0026] But not including: R 1 =CH 3 , R 2 =H, n=4,5.

[0027] More preferably, R 1 =H, R 2 =H、CH 3 , n=3,4,5; R 1 =CH 3 , R 2 =CH 3 , n = 3; R 1 =Br, R 2 =H, n=3; R 3 =H、CH 3 、CH(CH 3 ) 2 , R 4 =H、CH 3 , n = 3, 4, 5; but not including: R 3 =CH(CH 3 ) 2 , R 4 =H, n=5.

[0028] When R is selected from When, the structure of the tripterygium wilfordii thiazole derivative is as shown in Formula I:

[0029]

[0030] Among them, R 1 , R 2 , n as described above.

[0031] When R is selected from When, the structure of the tripterygium wilfordii thiazole derivative is as shown in Formula II:

[0032]

[0033] Among them, R 3 , R 4 , n as described above.

[0034] Specifically, the thiazole derivatives of tripterygium wilfordii or pharmaceutically acceptable salts thereof are selected from the following structures:

[0035]

[0036] Another object of the present invention is to provide a method for preparing the thiazole derivatives of tripterygium wilfordii, and the synthetic route is as follows:

[0037]

[0038]

[0039] Among them, R is selected from R 1 , R 2 , R 3 , R 4 , n as described above.

[0040] The following steps are involved:

[0041] Step (1), using acetone as the reaction solvent and triethylamine as the base catalyst, the formula The thiazole compound shown in the formula The dibromoalkane shown is refluxed to give intermediate IV;

[0042] Step (2), using NaHCO 3 The intermediate IV is reacted with celastrol in reflux reaction with N,N-dimethylformamide (DMF) as a base catalyst and triptolide to obtain celastrol thiazole derivatives.

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

[0044] In step (2), the molar ratio of tripterygium wilfordii to intermediate IV is 1:0.4 to 1:0.6; the molar ratio of tripterygium wilfordii to NaHCO 3 The molar ratio is 1:1.3~1:5.

[0045] Another object of the present invention is to provide a use of the tripterygium wilfordii thiazole derivative or a pharmaceutically acceptable salt thereof in the preparation of an Hsp90 protein inhibitor.

[0046] Compared with tripterygium wilfordii, the tripterygium wilfordii thiazole derivatives of the present invention have significantly enhanced inhibitory effects on tumor cells. Another object of the present invention is to provide the use of the tripterygium wilfordii thiazole derivatives or pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs.

[0047] The tumors are gastric cancer, lung cancer and breast cancer.

[0048] Another object of the present invention is to provide the use of the tripterygium wilfordii thiazole derivatives or their pharmaceutically acceptable salts having a structure as shown in Formula I in the preparation of anti-tumor drugs; the tumors are lung cancer and breast cancer.

[0049] Another object of the present invention is to provide the use of a thiazole derivative of tripterygium wilfordii or a pharmaceutically acceptable salt thereof having a structure as shown in Formula II in the preparation of an anti-tumor drug; the tumor is gastric cancer, lung cancer and breast cancer.

[0050] Another object of the present invention is to provide a use of a thiazole derivative of tripterygium wilfordii or a pharmaceutically acceptable salt thereof having the following structure in the preparation of an anti-triple-negative breast cancer drug:

[0051]

[0052] Another object of the present invention is to provide a pharmaceutical composition, which comprises the thiazole derivative of tripterygium wilfordii or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutical carrier to prepare any pharmaceutically acceptable dosage form.

[0053] The dosage forms include tablets, capsules, pills, granules, powders, lozenges, aqueous or oily suspensions, injections, patches, and nano preparations.

[0054] Beneficial effects of the present invention:

[0055] Pharmacological experiments have shown that the thiazole derivatives of tripterygium wilfordii of the present invention have a significant inhibitory effect on the proliferation of various tumor cells, which is significantly better than tripterygium wilfordii, and has a better selectivity for breast cancer cells; the thiazole derivatives of tripterygium wilfordii of the present invention can covalently bind to Hsp90 protein, inhibit Hsp90 protein and thus exert anti-tumor activity. Therefore, the compounds of the present invention are expected to become new anti-tumor drug candidates and are worthy of further in-depth study.

[0056] The thiazole derivatives of tripterygium wilfordii of the present invention have novel structures, simple preparation methods, mild reaction conditions, low-toxic reagents, cheap and readily available raw materials, convenient post-processing, high yields, and no harmful substances are produced, which conforms to "green science". BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 These are the results of in vitro thiol binding experiments of compound II-10. Specific implementation plan

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

[0059] Example 1

[0060]

[0061] In a single-necked bottle, add 65 mg (0.5 mmol) of thiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,3-dibromopropane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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] 130 mg (0.3 mmol) of celastrol was dissolved in 3 mL of DMF and 100 mg of NaHCO was added. 3 (0.4mmol) was added, 112mg (0.12mmol) of intermediate A1 was heated to 60°C for reflux reaction, and the reaction was monitored by TLC until the reaction was completed; after the reaction was completed, 50mL of ethyl acetate was added to the reaction solution for dilution, 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 spin-dried and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 270:1 v:v) to obtain compound I-1 (orange-red solid, 60.2mg, yield 32.5%).

[0063] Compound I-1 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.88(s,1H),8.49(s,1H),7.03(dd,J=7.0,1.4Hz,1H),6.52(d,J=1.5Hz,1H),6.34(d,J=7.2Hz,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). 13 C NMR (126 MHz, CDCl 3)δ178.32,178.24,169.84,164.68,161.03,158.20,149.15,146.04,134. 14,129.20,127.39,119.58,118.17,117.15,62.19,60.72,45.06,44.26,4 2.93,40.49,39.43,38.25,36.36,34.82,33.50,32.85,31.61,31.54,30.57,29.80,29.73,28.62,27.81,21.65,18.58,10.31.HRMS(ESI)calculated for C 36 H 45 NO 6 S[M+H] + 620.3040, found 620.3033.

[0064] Example 2

[0065]

[0066] In a single-necked bottle, 52 mg (0.4 mmol) of thiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (1.2 mmol) of 1,4-dibromobutane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 10:1 v:v) to obtain intermediate A2 (82 mg, yield 77.3%).

[0067] 100 mg (0.24 mmol) of tripterygium wilfordii was dissolved in 3 mL of DMF and 77 mg (0.9 mmol) of NaHCO was added. 3 , 82 mg (0.12 mmol) of intermediate A2, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried 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 structural identification data: 1 H NMR (400 MHz, CDCl 3)δ8.98(s,1H),8.53(s,1H),7.03(dd,J=7.0,1.4Hz,1H),6.54(d,J=1.5Hz,1H),6.36(d,J=7.1Hz,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, CDCl 3 )δ178.37,178.22,169.86,164.69,161.14,158.19,148.97,146.06,134.05 ,129.68,127.46,119.58,118.19,117.13,65.25,63.88,45.07,44.29,42.9 3,40.45,39.46,38.26,36.38,34.81,33.54,32.83,31.61,30.84,30.58,29 .84,29.72,28.67,25.54,25.19,21.67,18.56,10.28.HRMS(ESI)calculated for C 37 H 47 NO 6 S[M+H] + 634.3196, found 634.3200.

[0069] Example 3

[0070]

[0071] In a single-necked bottle, 58 mg (0.45 mmol) of thiazole-5-carboxylic acid, 0.25 mL (1.8 mmol) of triethylamine, and 0.25 mL (1.3 mmol) of 1,5-dibromopentane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 9:1 v:v) to obtain intermediate A3 (92 mg, yield 74.1%).

[0072] 100 mg (0.24 mmol) of tripterygium wilfordii was dissolved in 3 mL of DMF and 77 mg of NaHCO was added. 3(0.9mmol), 92mg (0.12mmol) of intermediate A3, heated to 60°C for reflux reaction, until TLC detection showed that the reaction was complete, 50mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound I-3 (orange-red solid, 45mg, yield 30.0%).

[0073] Compound I-3 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.97(s,1H),8.52(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),4.36-4 .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, CDCl 3 )δ178.32,178.23,172.40,169.79,164.67,161.13,148.46,146.01,134.09, 128.55,127.41,119.55,118.17,117.13,61.89,60.78,45.07,44.28,42.94,4 0.50,39.45,38.24,36.37,34.85,33.46,32.83,31.63,31.47,30.85,30.55,3 0.22,29.73,28.62,27.84,21.67,19.69,18.55,10.31.HRMS(ESI)calculated forC 38 H 49 NO 6 S[M+H] + 648.3353, found 648.3349.

[0074] Example 4

[0075]

[0076] In a single-necked bottle, add 72 mg (0.5 mmol) of 2-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,3-dibromopropane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A4 (105 mg, yield 79.5%).

[0077] 100 mg (0.24 mmol) of tripterygium wilfordii was dissolved in 3 mL of DMF and 77 mg of NaHCO was added. 3 (0.9mmol), 105mg (0.12mmol) of intermediate A4, heated to 60°C for reflux reaction, until TLC detection showed that the reaction was complete, 50mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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, 54mg, yield 38.4%).

[0078] Compound I-4 structure identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.21(s,1H),7.02(dd,J=7.1,1.4Hz,1H),6.51(d,J=1.5Hz,1H),6.35(d,J=7.1Hz,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, CDCl 3 )δ178.37,178.26,170.00,164.75,161.22,158.10,148.89,146.04,134.14 ,129.81,127.43,119.57,118.19,117.16,65.47,64.11,45.08,44.29,42.9 5,40.43,39.45,38.27,36.38,34.80,33.55,32.82,31.62,30.82,30.58,29 .83,29.73,28.30,28.09,22.61,21.66,18.52,10.30.HRMS(ESI)calculated for C37 H 47 NO 6 S[M+H] + 634.3196, found 634.3205.

[0079] Example 5

[0080]

[0081] In a single-necked bottle, add 72 mg (0.5 mmol) of 2-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,4-dibromobutane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A4 (115 mg, yield 83.3%).

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

[0083] Compound I-5 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.25(s,1H),7.03(dd,J=7.0,1.4Hz,1H),6.53(d,J=1.5Hz,1H),6.36(d,J=7.2Hz,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). 13 C NMR (126 MHz, CDCl 3)δ178.39,178.23,172.24,169.83,164.69,161.26,148.31,146.08,133.99, 129.01,127.49,119.61,118.20,117.11,64.95,63.90,45.08,44.32,42.95,4 0.47,39.47,38.27,36.41,34.83,33.56,32.84,31.63,30.87,30.60,29.85,2 9.73,28.70,25.60,25.19,21.70,19.75,18.57,10.28.HRMS(ESI)calculated forC 38 H 49 NO 6 S[M+H] + 648.3353, found 648.3341.

[0084] Example 6

[0085]

[0086] In a single-necked bottle, add 72 mg (0.5 mmol) of 2-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,5-dibromopentane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A6 (127 mg, yield 86.9%).

[0087] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 67 mg of NaHCO was added. 3 (0.8mmol), 127mg (0.12mmol) of intermediate A6, heated to 60°C for reflux reaction, until TLC detection showed that the reaction was complete, 50mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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, 43mg, yield 33.5%).

[0088] Compound I-6 structural identification data: 1 H NMR (400 MHz, CDCl 3)δ8.24(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.5Hz,1H),6.36(d,J=7.2Hz,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, CDCl 3 )δ178.39,178.26,172.15,169.92,164.73,161.34,148.22,146.08,134.04,12 9.12,127.48,119.60,118.19,117.12,65.19,64.13,45.09,44.34,42.96,40.4 6,39.48,38.26,36.41,34.84,33.59,32.83,31.64,30.84,30.60,29.85,29.73 ,28.70,28.34,28.12,22.64,21.69,19.74,18.53,10.28.HRMS(ESI)calculated forC 39 H 51 NO 6 S[M+H] + 662.3509, found 662.3503.

[0089] Example 7

[0090]

[0091] In a single-necked bottle, 72 mg (0.5 mmol) of 4-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,3-dibromopropane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A7 (66 mg, yield 50.0%).

[0092] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg of NaHCO was added. 3(0.8mmol), 66mg (0.12mmol) of intermediate A7, heated to 60°C for reflux reaction, until TLC detection showed that the reaction was complete, 50mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9:1 v:v) to obtain compound I-7 (orange-red solid, 45mg, yield 35.7%).

[0093] Compound I-7 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.69(s,1H),7.03(dd,J=7.0,1.4Hz,1H),6.52(d,J=1.5Hz,1H),6.32(d,J=7.2Hz,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, CDCl 3 )δ178.34,178.24,169.79,164.67,161.91,161.05,155.41,146.08,134.01 ,127.43,121.63,119.59,118.15,117.10,61.73,60.78,45.07,44.31,42.9 4,40.52,39.45,38.26,36.39,34.85,33.52,32.86,31.63,30.92,30.59,29 .82,29.76,28.65,27.85,21.67,18.62,17.38,10.30.HRMS(ESI)calculated for C 37 H 47 NO 6 S[M+H] + 634.3196, found 634.3195.

[0094] Example 8

[0095]

[0096] In a single-necked bottle, add 72 mg (0.5 mmol) of 4-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,4-dibromobutane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A8 (62 mg, yield 45.1%).

[0097] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 62 mg (0.12 mmol) of intermediate A8, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.80(s,1H),7.03(dd,J=7.0,1.4Hz,1H),6.53(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,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, CDCl 3 )δ178.38,178.23,169.83,164.68,162.05,160.78,155.44,146.08,134.01, 127.49,122.09,119.60,118.20,117.12,64.85,63.92,45.08,44.33,42.95,4 0.47,39.48,38.27,36.41,34.84,33.57,32.84,31.63,30.86,30.60,29.86,2 9.74,28.70,25.59,25.26,21.70,18.58,17.40,10.29.HRMS(ESI)calculated forC38 H 49 NO 6 S[M+H] + 648.3353, found 648.3345.

[0099] Example 9

[0100]

[0101] In a single-necked bottle, 72 mg (0.5 mmol) of 4-methylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,5-dibromopentane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 20:1 v:v) to obtain intermediate A9 (60 mg, yield 41.1%).

[0102] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 60 mg (0.12 mmol) of intermediate A9, heated to 60 ° C and refluxed to react until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution to dilute, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.79(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J=7.1Hz,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). 13 C NMR (126 MHz, CDCl 3)δ178.38,178.25,169.92,164.73,162.13,160.65,155.34,146.08,134.05,12 7.48,122.38,119.59,118.19,117.13,65.08,64.15,45.09,44.34,42.96,40.4 5,39.48,38.26,36.41,34.84,33.58,32.83,31.63,30.85,30.60,29.86,29.73 ,28.70,28.35,28.13,22.71,21.69,18.53,17.40,10.28.HRMS(ESI)calculated forC 39 H 51 NO 6 S[M+H] + 662.3509, found 662.3502.

[0104] Example 10

[0105]

[0106] In a single-necked bottle, add 79 mg (0.5 mmol) of 2,4-dimethylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,3-dibromopropane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 30:1 v:v) to obtain intermediate A10 (66 mg, yield 47.8%).

[0107] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 66 mg (0.12 mmol) of intermediate A10, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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 structural identification data: 1 H NMR (400 MHz, CDCl 3)δ7.02(dd,J=7.0,1.4Hz,1H),6.51(d,J=1.4Hz,1H),6.34(d,J=7.1Hz,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 (126MHz, CDCl 3 )δ178.33,178.22,169.73,169.26,164.65,161.92,160.40,146.06,133.93, 127.45,123.51,119.57,118.13,117.07,61.45,60.83,45.08,44.33,42.95,4 0.53,39.47,38.25,36.40,34.89,33.47,32.84,31.55,30.88,30.58,30.19,2 9.73,28.66,27.89,21.71,19.38,18.59,17.33,10.29.HRMS(ESI)calculated for C 38 H 49 NO 6 S[M+H] + 648.3353, found 648.3344.

[0109] Embodiment 11

[0110]

[0111] In a single-necked bottle, add 79 mg (0.5 mmol) of 2,4-dimethylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,4-dibromobutane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 30:1 v:v) to obtain intermediate A11 (75 mg, yield 51.4%).

[0112] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3, 75 mg (0.12 mmol) of intermediate A11, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9: 1 v: v) to obtain compound I-11 (orange-red solid, 46 mg, yield 34.1%).

[0113] Compound I-11 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ7.03(dd,J=7.0,1.4Hz,1H),6.53(d,J=1.5Hz,1H),6.36(d,J=7.2Hz,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, CDCl 3 )δ178.39,178.24,169.85,169.15,164.70,162.09,160.13,146.08,133.99,12 7.51,124.50,119.61,118.20,117.12,64.57,63.93,45.09,44.33,42.95,40.4 6,39.47,38.27,36.41,34.83,33.55,32.84,31.48,30.88,30.61,30.25,29.73 ,28.70,25.64,25.24,21.70,19.47,18.58,17.34,10.28.HRMS(ESI)calculated forC 39 H 51 NO 6 S[M+H] + 662.3509, found 662.3497.

[0114] Example 12

[0115]

[0116] In a single-necked bottle, add 79 mg (0.5 mmol) of 2,4-dimethylthiazole-5-carboxylic acid, 0.2 mL (1.5 mmol) of triethylamine, and 0.2 mL (2 mmol) of 1,5-dibromopentane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 30:1 v:v) to obtain intermediate A12 (70 mg, yield 46.1%).

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

[0118] Compound I-12 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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 (126 MHz, CDCl 3)δ178.39,178.26,169.92,169.06,164.73,162.18,160.01,146.08,134.04,127 .49,123.51,119.60,118.19,117.13,64.81,64.17,45.09,44.35,42.96,40.45,3 9.48,38.26,36.41,34.84,33.58,32.83,31.55,30.85,30.60,30.19,29.73,28.7 0,28.37,28.13,22.72,21.69,19.46,18.53,17.34,10.28.HRMS(ESI)calculated for C 40 H 53 NO 6 S[M+H] + 676.3664, found 676.3658.

[0119] Embodiment 13

[0120]

[0121] In a single-necked bottle, 83 mg (0.4 mmol) of 2-bromothiazole-5-carboxylic acid, 0.15 mL (1.6 mmol) of triethylamine, and 0.15 mL (0.12 mmol) of 1,3-dibromopropane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 90:1 v:v) to obtain intermediate A13 (76 mg, yield 58.0%).

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

[0123] Compound I-13 structural identification data: 1 H NMR (400 MHz, CDCl 3)δ8.12(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),4.49-4.30(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). 13 CNMR (126MHz, CDCl 3 )δ178.36,178.18,169.60,164.61,159.79,148.11,146.07,142.28,133. 96,127.50,123.51,119.60,118.19,117.17,62.45,60.68,45.07,44.32,4 2.92,40.54,39.47,38.25,36.39,34.87,33.51,32.82,31.64,30.88,30.57,29.86,29.81,28.66,27.81,21.68,18.58,10.33.HRMS(ESI)calculated for C 36 H 44 BrNO 6 S[M+H] + 698.2145, found 700.2125.

[0124] Embodiment 14

[0125]

[0126] In a single-necked bottle, 83 mg (0.4 mmol) of 2-bromothiazole-5-carboxylic acid, 0.15 mL (1.6 mmol) of triethylamine, and 0.15 mL (0.12 mmol) of 1,4-dibromobutane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 90:1 v:v) to obtain intermediate A14 (85 mg, yield 62.5%).

[0127] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3, 85 mg (0.12 mmol) of intermediate A14, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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] Compound I-14 structure identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.17(s,1H),7.03(dd,J=7.1,1.4Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J=7.1Hz,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 (126MHz, CDCl 3 )δ178.39,178.22,169.81,164.69,159.92,147.99,146.09,142.15,134.00 ,127.51,123.51,119.61,118.22,117.14,65.48,63.80,45.08,44.32,42.9 4,40.47,39.46,38.28,36.40,34.82,33.57,32.85,31.63,30.87,30.61,30 .19,29.74,28.70,25.52,25.17,21.69,18.60,10.29.HRMS(ESI)calculated for C 37 H 46 BrNO 6 S[M+H] + 712.2302, found 714.2279.

[0129] Embodiment 15

[0130]

[0131] In a single-necked bottle, 83 mg (0.4 mmol) of 2-bromothiazole-5-carboxylic acid, 0.15 mL (1.6 mmol) of triethylamine, and 0.15 mL (0.12 mmol) of 1,5-dibromopentane were added, and 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 90:1 v:v) to obtain intermediate A15 (78 mg, yield 54.9%).

[0132] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 78 mg (0.12 mmol) of intermediate A15, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 24:1 v:v) to obtain compound I-15 (orange-red solid, 80 mg, yield 55.2%).

[0133] Compound I-15 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ8.16(s,1H),7.03(dd,J=7.1,1.5Hz,1H),6.54(d,J=1.4Hz,1H),6.36(d,J=7.2Hz,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 (126MHz, CDCl 3 )δ178.38,178.24,169.90,164.72,159.99,147.89,146.08,142.07,134.05, 127.49,121.51,119.59,118.20,117.14,65.70,64.08,45.09,44.34,42.96,4 0.46,39.48,38.26,36.40,34.83,33.60,32.83,31.63,30.84,30.60,29.86,2 9.74,28.70,28.27,28.10,22.59,21.68,18.53,10.28.HRMS(ESI)calculated for C38 H 48 BrNO 6 S[M+H] + 726.2458, found 728.2442.

[0134] Example 16

[0135]

[0136] In a single-necked bottle, add 2-(3-pyridine)-4-methylthiazole-5-carboxylic acid 88mg (0.4mmol), triethylamine 0.2mL (1.6mmol), 1,3-dibromopropane 0.2mL (0.12mmol), add 3mL acetone to dissolve, heat to 50℃ reflux reaction, and monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12:1 v:v) to obtain intermediate A16 (67mg, yield 49.6%).

[0137] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 67 mg (0.12 mmol) of intermediate A16, heated to 60 ° C and refluxed until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution to dilute, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-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] Compound I-16 structural identification data: 1 H NMR (400 MHz, CDCl 3 )δ9.10(s,1H),8.71(s,1H),8.23(d,J=7.9Hz,1H),7.42(dd,J=8.0,4.8Hz,1H),6.92(d,J=7.3Hz,1H),6.45(s,1H),6.34(d,J=7.1Hz, 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). 13 C NMR (126 MHz, CDCl 3)δ178.24,178.19,169.55,166.41,164.55,161.87,161.67,151.64,147.89,145.90,1 33.93,133.79,128.99,127.39,123.83,123.50,119.45,118.12,117.04,61.61,60.82 ,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 N 2 O 6 S[M+H] + 711.3462, found 711.3457.

[0139] Embodiment 17

[0140]

[0141] In a single-necked bottle, add 2-(3-pyridine)-4-methylthiazole-5-carboxylic acid 88mg (0.4mmol), triethylamine 0.2mL (1.6mmol), 1,4-dibromobutane 0.2mL (0.12mmol), add 3mL acetone to dissolve, heat to 50℃ reflux reaction, and monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12: 1v:v) to obtain intermediate A17 (86mg, yield 60.6%).

[0142] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 86 mg (0.12 mmol) of intermediate A17, heated to 60 ° C and refluxed to react until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution to dilute, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 24:1 v:v) to obtain compound I-17 (orange-red solid, 63 mg, yield 43.7%).

[0143] Compound I-17 structural identification data: 1 H NMR (400 MHz, 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),6.34(d,J=7. 2Hz,1H),4.37-4.34(m,2H),4.11-3.91(m,2H),2.81(s,3H),2.21(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 (126 MHz, CDCl 3 )δ178.37,178.24,169.82,166.46,164.68,161.90,161.51,151.67,147.96,146.07,13 3.98,129.09,127.49,123.85,123.50,122.48,119.58,118.19,117.14,64.93,63.92,45 .08,44.33,42.93,40.48,39.46,38.27,36.40,34.83,33.55,32.86,31.63,30.88,30.6 1,30.19,29.73,28.70,25.63,25.28,21.70,18.61,17.56,10.27.HRMS(ESI)calculated for C 43 H 52 N 2 O 6 S[M+H] + 725.3618, found 725.3610.

[0144] Embodiment 18

[0145]

[0146] In a single-necked bottle, add 2-(3-pyridine)-4-methylthiazole-5-carboxylic acid 88mg (0.4mmol), triethylamine 0.2mL (1.6mmol), 1,5-dibromopentane 0.2mL (0.12mmol), add 3mL acetone to dissolve, heat to 50℃ reflux reaction, and monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12: 1v:v) to obtain intermediate A18 (105mg, yield 70.9%).

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

[0148] Compound I-18 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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),6.35(d,J=7. 2Hz,1H),4.35-4.32(m,2H),4.05-3.87(m,2H),2.81(s,3H),2.21(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 (126 MHz, CDCl 3 )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 N 2 O 6 S[M+H] + 739.3775, found 739.3771.

[0149] Embodiment 19

[0150]

[0151] In a single-necked bottle, 65 mg (0.4 mmol) of thiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 3:1 v:v) to obtain intermediate A19 (84 mg, yield 67.2%).

[0152] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 84 mg (0.12 mmol) of intermediate A19, heated to 60 ° C and refluxed to react until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution to dilute, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound II-1 (orange-red solid, 50 mg, yield 40.6%).

[0153] Structural identification data of compound II-1: 1 H NMR (400 MHz, CDCl 3 )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=7.2Hz,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 (126 MHz, CDCl 3)δ178.36,178.25,169.93,164.72,161.12,153.57,147.70,146.09,134. 07,127.53,127.44,119.61,118.17,117.09,62.02,60.87,45.10,44.32,4 2.99,40.51,39.48,38.25,36.40,34.88,33.50,32.88,31.63,30.88,30.58,30.19,29.74,28.66,27.93,21.70,18.59,10.30.HRMS(ESI)calculated forC 36 H 45 NO 6 S[M+H] + 620.3040, found 620.3028.

[0154] Embodiment 20

[0155]

[0156] In a single-necked bottle, 65 mg (0.4 mmol) of thiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 5:1 v:v) to obtain intermediate A20 (85 mg, yield 64.4%).

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

[0158] Compound II-2 structural identification data: 1 H NMR (400 MHz, CDCl 3)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). 13 C NMR (126 MHz, CDCl 3 )δ178.40,178.27,169.91,164.72,161.28,153.51,148.03,146.08,134.04 ,127.53,127.49,119.60,118.19,117.11,65.04,63.98,45.09,44.33,42.9 6,40.46,39.49,38.27,36.41,34.85,33.55,32.84,31.63,30.87,30.60,29 .85,29.73,28.70,25.66,25.22,21.70,18.55,10.29.HRMS(ESI)calculated for C 37 H 47 NO 6 S[M+H] + 634.3196, found 634.3188.

[0159] Embodiment 21

[0160]

[0161] In a single-necked bottle, 65 mg (0.4 mmol) of thiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A21 (104 mg, yield 75.4%).

[0162] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3, 104 mg (0.12 mmol) of intermediate A21, heated to 60 ° C for reflux reaction until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution for dilution, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1 v:v) to obtain compound II-3 (orange-red solid, 52 mg, yield 40.3%).

[0163] Compound II-3 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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 (126 MHz, CDCl 3 )δ178.39,178.27,169.97,164.75,161.34,153.45,148.14,146.07,134.08, 127.47,127.29,119.60,118.19,117.12,65.23,64.15,45.09,44.34,42.97,4 0.45,39.49,38.26,36.41,34.84,33.58,32.83,31.64,30.85,30.60,29.84,2 9.72,28.70,28.38,28.14,22.60,21.68,18.53,10.28.HRMS(ESI)calculated for C 38 H 49 NO 6 S[M+H] + 648.3353, found 648.3346.

[0164] Embodiment 22

[0165]

[0166] In a single-necked bottle, add 72 mg (0.4 mmol) of 2-methylthiazole-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,3-dibromopropane, add 3 mL of acetone to dissolve, heat to 50 ° C and reflux to react, and 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 = 7: 1 v: v) to obtain intermediate A22 (90 mg, yield 68.2%).

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

[0168] Compound II-4 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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,2 H),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 (126 MHz, CDCl 3)δ178.36,178.24,169.90,166.90,164.70,161.20,146.40,146.07,133.99 ,127.60,127.46,119.61,118.16,117.05,61.91,60.95,45.10,44.32,42.9 8,40.51,39.48,38.27,36.40,34.87,33.52,32.86,31.63,30.87,30.59,29 .82,29.74,28.68,27.99,21.71,19.36,18.59,10.29.HRMS(ESI)calculated for C 37 H 47 NO 6 S[M+H] + 634.3196, found 634.3189.

[0169] Embodiment 23

[0170]

[0171] In a single-necked bottle, add 72 mg (0.4 mmol) of 2-methylthiazole-4-carboxylic acid, 0.2 mL (1.6 mmol) of triethylamine, and 0.2 mL (0.12 mmol) of 1,4-dibromobutane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A23 (90 mg, yield 65.7%).

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

[0173] Compound II-5 structural identification data: 1 H NMR (400 MHz, CDCl 3)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 (126 MHz, CDCl 3 )δ178.39,178.27,169.90,166.86,164.71,161.32,146.67,146.07,134.02, 127.51,127.48,119.60,118.19,117.10,64.86,64.00,45.09,44.32,42.95,4 0.46,39.48,38.26,36.41,34.84,33.55,32.84,31.63,30.87,30.60,29.84,2 9.71,28.70,25.70,25.19,21.70,19.39,18.55,10.28.HRMS(ESI)calculated forC 38 H 49 NO 6 S[M+H] + 648.3342, found 648.3353.

[0174] Embodiment 24

[0175]

[0176] In a single-necked bottle, 72 mg (0.4 mmol) of 2-methylthiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A24 (96 mg, yield 69.5%).

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

[0178] Compound II-6 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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,2H),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). 13 CNMR (126MHz, CDCl 3 )δ178.38,178.27,169.96,166.80,164.75,161.39,146.79,146.07,134.07,12 7.46,127.33,119.60,118.19,117.12,65.05,64.15,45.09,44.34,42.97,40.4 5,39.48,38.26,36.41,34.84,33.58,32.84,31.64,30.85,30.59,30.19,29.71 ,28.70,28.40,28.14,22.56,21.68,19.40,18.52,10.28.HRMS(ESI)calculated forC 39 H 51 NO 6 S[M+H] + 662.3509, found 662.3501.

[0179] Embodiment 25

[0180]

[0181] In a single-necked bottle, 72 mg (0.4 mmol) of 5-methylthiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A25 (70 mg, yield 53.3%).

[0182] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 After stirring, 70 mg (0.12 mmol) of intermediate A25 was added, and the mixture was heated to 60°C and refluxed to react until TLC detection showed that the reaction was complete. 50 mL of ethyl acetate was added to the reaction solution to dilute it, and the mixture was 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 spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound II-7 (orange-red solid, 42 mg, yield 33.3%).

[0183] Compound II-7 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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 (126 MHz, CDCl 3 )δ178.37,178.23,169.90,164.71,162.29,149.21,146.07,144.90,141.79 ,134.00,127.45,119.60,118.15,117.05,61.77,61.07,45.09,44.32,42.9 8,40.50,39.48,38.26,36.40,34.87,33.51,32.86,31.63,30.88,30.58,29 .81,29.73,28.68,27.98,21.71,18.59,13.11,10.29.HRMS(ESI)calculated for C37 H 47 NO 6 S[M+H] + 634.3196, found 634.3189.

[0184] Embodiment 26

[0185]

[0186] In a single-necked bottle, 72 mg (0.4 mmol) of 5-methylthiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A26 (80 mg, yield 57.9%).

[0187] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 80mg (0.12mmol) of intermediate A26, heated to 60°C for reflux reaction, until TLC detection showed that the reaction was complete, 50mL of ethyl acetate was added to the reaction solution for dilution, 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 spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3: 1 v: v) to obtain compound II-8 (orange-red solid, 56mg, yield 43.4%).

[0188] Compound II-8 structural identification data: 1 H NMR (400 MHz, CDCl 3 )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 (126 MHz, CDCl 3)δ178.38,178.26,169.88,164.70,162.41,149.16,146.07,144.81,142.01, 134.01,127.48,119.61,118.18,117.07,64.63,64.00,45.09,44.33,42.96,4 0.46,39.49,38.26,36.42,34.86,33.55,32.85,31.64,30.88,30.60,29.83,2 9.73,28.70,25.68,25.25,21.71,18.55,13.12,10.29.HRMS(ESI)calculated forC 38 H 49 NO 6 S[M+H] + 648.3353, found 648.3342.

[0189] Embodiment 27

[0190]

[0191] In a single-necked bottle, 72 mg (0.4 mmol) of 2-methylthiazole-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 3 mL of acetone was added to dissolve, and the mixture was heated to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A27 (70 mg, yield 47.9%).

[0192] 90 mg (0.2 mmol) of celastrol was dissolved in 3 mL of DMF and 65 mg (0.8 mmol) of NaHCO 3 , 70 mg (0.12 mmol) of intermediate A27, heated to 60 ° C and refluxed to react until TLC detection showed that the reaction was completed, 50 mL of ethyl acetate was added to the reaction solution to dilute, washed with water 3 times, washed with saturated sodium bicarbonate 3 times, washed with saturated brine 3 times, and dried over anhydrous sodium sulfate overnight; the organic phase was spin-dried and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 v:v) to obtain compound II-9 (orange-red solid, 34 mg, yield 25.8%).

[0193] Compound II-9 structural identification data: 1 H NMR (400 MHz, CDCl 3)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 (126 MHz, CDCl 3 )δ178.39,178.28,169.95,164.73,162.49,149.13,146.07,144.62,142.11,13 4.05,127.47,119.61,118.18,117.10,64.88,64.19,45.09,44.34,42.97,40.4 4,39.49,38.25,36.42,34.85,33.58,32.83,31.64,30.86,30.59,30.25,29.72 ,28.71,28.43,28.16,22.65,21.69,18.52,13.11,10.28.HRMS(ESI)calculated forC 39 H 51 NO 6 S[M+H] + 662.3509, found 662.3499.

[0194] Embodiment 28

[0195]

[0196] In a single-necked bottle, add 2-isopropylthiazole-4-carboxylic acid 77mg (0.45mmol), triethylamine 0.2mL (1.8mmol), 1,3-dibromopropane 0.2mL (1.35mmol), add 3mL acetone to dissolve, heat to 50℃ reflux reaction, and monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 6:1 v:v) to obtain intermediate A28 (73mg, yield 50.0%).

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

[0198] Compound II-10 structural identification data: 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). 13 C 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 NO 6 S[M+H] + 662.3509, found 662.3499.

[0199] Embodiment 29

[0200]

[0201] In a single-necked bottle, add 2-isopropylthiazole-4-carboxylic acid 77mg (0.45mmol), triethylamine 0.2mL (1.8mmol), 1,4-dibromobutane 0.2mL (1.35mmol), add 3mL acetone to dissolve, heat to 50℃ reflux reaction, and monitor the reaction by TLC. After the reaction is completed, the organic phase is dried and purified by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 6:1 v:v) to obtain intermediate A29 (72mg, yield 47.1%).

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

[0203] Compound II-11 structural identification data: 1 H 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). 13C 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 NO 6 S[M+H] + 676.3664, found 676.3655.

[0204] Embodiment 30

[0205]

[0206] In a single-necked bottle, add 77 mg (0.45 mmol) of 2-isopropylthiazole-4-carboxylic acid, 0.2 mL (1.8 mmol) of triethylamine, and 0.2 mL (1.35 mmol) of 1,5-dibromopentane, add 3 mL of acetone to dissolve, heat to 50°C for reflux reaction, and 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 = 6:1 v:v) to obtain intermediate A30 (82 mg, yield 51.3%).

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

[0208] Compound II-12 structural identification data: 1H 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 NO 6 S[M+H] + 690.3822, found 690.3813.

[0209] Embodiment 31

[0210] (I) In vitro antitumor activity studies

[0211] The MTT colorimetric method was used to test the in vitro antitumor activity of celastrol thiazole derivatives (Compounds I-1 to I-18, Compounds II-1 to II-12), and celastrol (CEL) and CDDO-Me (Bardoxolonemethyl) were selected as positive control drugs.

[0212] Instruments: Clean bench (SW-CJ-1FD, AIRTECH, Sujing Antai), constant temperature CO 2Incubator (Heracell instruction manual 14VIOS160i, Thermo, USA), biological microscope (IX71, Olympus, Japan), multifunctional 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, human lung cancer cell line A549 (all provided by Jiangsu KeyGen Biotech Co., Ltd.).

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

[0216] Method: Add 50 mL of fetal bovine serum to 450 mL of DMEM medium to prepare a complete medium containing 10% fetal bovine serum, and store it in a refrigerator at 4°C until use. The culture medium mentioned below is this complete medium.

[0217] Resuscitate frozen cell lines and place them in a constant temperature of 37°C and 5% CO 2 Culture in an incubator, change the medium every 2 to 3 days, and plate when it is in the exponential growth phase and in good condition. Add 1 mL of 0.25% trypsin digestion solution, digest for 1 to 2 minutes, observe the cell state under a microscope, and add 2 mL of complete culture medium to terminate digestion when the adherent cells become round and shrink. Collect the liquid, discard the supernatant after centrifugation, and collect the cells. Add 1 to 2 mL of complete culture medium containing 10% fetal bovine serum to make a cell suspension, count the cells, and count 3.5×10 per well. 3 ~4.5×10 3 The amount of cell suspension required was calculated based on the number of cells per well and the total number of wells. The cell suspension was inoculated on a 96-well plate at 100 μL / well, sealed with PBS, and placed in a constant temperature chamber at 37°C and 5% CO. 2 Culture in an incubator for 24 h.

[0218] Replace with drug-containing culture medium, and set up a blank control (DMSO) diluted with culture medium to a concentration of 4 μmol / L, set up 3 replicates for each drug concentration, and after 48 hours of culture, add 20 μL MTT reagent (5 mg / mL) to each well and continue incubation for 4 hours. Remove the culture medium in the plate, add 100 μL DMSO to each well, use a multifunctional microplate reader to detect the absorbance of each well at a wavelength of 570 nm, and calculate the cell inhibition rate according to the following formula.

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

[0220] The average of the three initial screening results is the final inhibition rate, and the IC of the tested drug is calculated 50 The final IC value of the compound was obtained by 3 repeated experiments (graphpad software). 50 value.

[0221] Table 1. Inhibitory effect of the test compounds (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 tripterygium wilfordii, the inhibitory effects of the tripterygium wilfordii thiazole derivatives of the present invention on the MDA-MB-231 cell line are mostly significantly enhanced. Among them, compound II-10 has the best activity, and its activity in MCF-7 and MD-MBA-231 cells is increased by about 4 times and 3.5 times respectively compared with tripterygium wilfordii.

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

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

[0229] Reagent: DMSO-d 6 (Annaiji Chemical), dithiothreitol (Annaiji Chemical).

[0230] Studies have shown that the A / B ring of CEL has a quinone methyl structure, which is a Michael receptor that can bind to a variety of proteins to form covalent bonds, and is closely related to the anti-tumor activity of CEL. Taking compound II-10 as an example, the inventors investigated whether the thiazole derivatives of tripterygium wilfordii of the present invention have the ability to covalently bind to Hsp90 protein to exert anti-tumor activity by the following method.

[0231] Methods: CEL (0.02mmoL) and dithiothreitol (DTT, 0.01mmoL), compound II-10 (0.02mmoL) and dithiothreitol (DTT, 0.01mmoL) were dissolved in DMSO-d 6 In the experiment, each was ultrasonicated for 20 min. 1 H-NMR detection and analysis of the spectrum. Results are shown in Figure 1 , showing that after CEL combined with DTT, the quinone methyl hydrogen δ 6-H (red) gradually decreases, δ 1-H , peak shift changes to δ 1-H '(yellow); δ of CEL quinone methyl 6-H Peak area residual 0.21, δ 1-H After the reaction and before the reaction (δ 1-H ' / δ 1-H ) peak area ratio is 0.83; while the δ 6-H The peak disappears, δ 1-H The peak shifts all change to δ 1-H '. It shows that under the same conditions, CEL cannot be completely combined with DTT, while compound II-10 can be completely combined with DTT. This indicates that the covalent binding reaction activity of compound II-10 is improved, and it is confirmed that the introduction of thiazole into CEL can enhance the covalent binding ability of its quinone methyl and thiol groups, suggesting that such compounds can covalently bind to Hsp90 protein, inhibit Hsp90 protein, and thus exert anti-tumor activity.

Claims

1. A thiazole derivative of tripterygium wilfordii having a structure as shown in Formula III or a pharmaceutically acceptable salt thereof: in, R is selected from R1 and R3 are independently selected from H, C3-C4 alkyl, halogen, R2 and R4 are independently selected from H and C1-C4 alkyl; n=an integer from 1 to 5.

2. The thiazole derivative of tripterygium wilfordii 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; R2=CH3, n=3,5.

3. The thiazole derivative of tripterygium wilfordii 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.

4. A thiazole derivative of tripterygium wilfordii having a structure as shown in Formula III or a pharmaceutically acceptable salt thereof: in, 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 not including: R3=CH(CH3)2, R4=H, n=5.

5. A thiazole derivative of tripterygium wilfordii selected from the following structures or a pharmaceutically acceptable salt thereof:

6. A method for preparing the tripterygium wilfordii thiazole derivatives according to claim 1, characterized in that: The synthetic route is as follows: Among them, R is selected from R1, R2, R3, R4, n as described in claim 1; The following steps are involved: Step (1), using acetone as the reaction solvent and triethylamine as the base catalyst, the formula The thiazole compound shown in the formula The dibromoalkane shown is refluxed to give intermediate IV; Step (2), using NaHCO3 as a base catalyst and N,N-dimethylformamide as a reaction solvent, the intermediate IV is subjected to a reflux reaction with celastrol to obtain a thiazole derivative of celastrol.

7. Use of the tripterygium wilfordii thiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an Hsp90 protein inhibitor.

8. Use of the tripterygium wilfordii thiazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of anti-tumor drugs.

9. The use according to claim 8, characterized in that: The tumors are gastric cancer, lung cancer and breast cancer.

10. A pharmaceutical composition, characterized in that: The pharmaceutical composition is any pharmaceutically acceptable dosage form prepared by using the thiazole derivative of tripterygium wilfordii or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutical carrier.

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