Preparation of Piperidine-Bisoxadiazole and Piperidine-Aminothiazole Substituted Antitumor Curcumol Derivatives and Their Application in Antitumor

Abstract

The present invention discloses the preparation and application of piperidine-linked oxadiazole and piperidine-fused aminothiazole-substituted anti-tumor curcumol derivatives. Through multiple groups of experiments, the anti-tumor activities of these newly synthesized derivatives are explored.

Description

Technical Field

[0001] The present invention relates to the synthesis of piperidine-linked 1,2,4-oxadiazole and piperidine-aminothiazole-substituted curcumol derivatives and their application in the treatment of malignant tumors, belonging to the field of pharmaceutical technology. Background Art

[0002] Environmental pollution and the change of human lifestyle have led to an adult increase in the incidence of malignant tumors, seriously threatening human health.

[0003] Small molecule chemical drugs are the main means to combat malignant tumors. The commonly used anti-tumor drugs in clinical practice mainly include cytotoxic drugs and targeted drugs. However, cytotoxic drugs usually show strong toxic and side effects, seriously affecting the quality of life of malignant tumor patients. Targeted drugs show increasing drug resistance, becoming a bottleneck in their clinical application. Therefore, there is an urgent need to develop anti-tumor drugs with high efficiency, low toxicity and high therapeutic index to meet this challenge.

[0004] The natural product molecules contained in traditional Chinese medicine are the material basis for their clinical treatment, especially those with relatively high contents. Therefore, searching for drug lead compounds from traditional Chinese medicine has become an effective way for new drug development and an inevitable requirement for the modernization of traditional Chinese medicine. Rhizoma Curcumae is the dried rhizome of Curcuma phaeocaulis Val., Curcuma kwangsiensis S.G. Lee et C.F. Liang, Curcuma wenyujin Y.H. Chen et C.Ling of the Zingiberaceae family, and it is a traditional genuine medicinal material with a long history of use in China. Rhizoma Curcumae was first recorded in "Yaoxing Lun" by Zhen Quan in the Tang Dynasty. "Compendium of Materia Medica" records that "Rhizoma Curcumae is pungent, warm, and non-toxic. Its color is black, and it can break blood in qi." "Explanation of the Classic of Materia Medica" once recorded that "Rhizoma Curcumae phaeocaulis has a pungent taste and a strong nature, specifically attacking blood in qi, mainly breaking accumulation and eliminating firmness, removing accumulations and lumps, amenorrhea and blood stasis, and traumatic pain." "Cui Jinqiu Ben Cao Shu Lu" also pointed out that "Guangmao is Rhizoma Curcumae. It is used for promoting qi and breaking blood, eliminating accumulation and dissipating nodules." Correspondingly, modern medicine has proven that the volatile oil of Rhizoma Curcumae has various therapeutic functions such as anti-tumor, antibacterial, anti-early pregnancy, anti-inflammatory, and liver protection. Especially the anti-tumor effect is definite and obvious, which has attracted wide attention. Curcumol is one of the material bases for the anti-tumor effect of the volatile oil of Rhizoma Curcumae. It can play an anti-tumor role through multiple mechanisms such as blocking the cell cycle and inducing apoptosis, and has inhibitory activity against various types of malignant tumor cells such as colon cancer, bladder cancer, melanoma, liver cancer, osteosarcoma, nasopharyngeal carcinoma, breast cancer, ovarian cancer, cervical cancer, lung cancer, gastric cancer, and cholangiocarcinoma. Moreover, as a topical drug, it was once briefly used in the clinical treatment of cervical cancer in China. However, problems such as poor anti-tumor activity, poor water solubility, and unclear action mechanism have severely restricted the further development of new drugs.

[0005] Piperidine-fused 1,2,4-oxadiazole and piperidine-fused aminothiazole rings, as privileged scaffolds, exhibit diverse protein-binding properties and good pharmacokinetic properties, and have been widely used in drug molecules. In view of this, aiming to improve anti-tumor activity and drug-likeness, we introduced these two types of privileged scaffolds into the side chain of curcumol, combined with necessary group transformations, synthesized two types of novel derivatives, and carried out in vitro anti-tumor activity tests. Summary of the Invention

[0006] The present invention aims to prepare piperidine-fused 1,2,4-oxadiazole and piperidine-fused aminothiazole substituted curcumol derivatives and study their anti-tumor activities.

[0007] The structural general formula of the compounds of the present invention is as follows:

[0008]

[0009] In the general structural formulas Ⅰ and Ⅱ, the R group represents aryl and heteroaryl. Among them:

[0010] The aryl is phenyl and substituted phenyl;

[0011] For the substituted phenyl, the substituents are alkyl, halogen, sulfonyl group, etc.;

[0012] The heteroaryl is pyridyl or substituted pyridyl, thienyl or substituted thienyl, furyl or substituted furyl, pyrazinyl or substituted pyrazinyl, pyrrolyl or substituted pyrrolyl, quinolinyl or substituted quinolinyl, isoquinolinyl or substituted isoquinolinyl, benzothiazolyl or substituted benzothiazolyl, indolyl or substituted indolyl, benzimidazolyl or substituted benzimidazolyl, benzoxazolyl or substituted benzoxazolyl, imidazolyl or substituted imidazolyl, oxazolyl or substituted oxazolyl, thiazolyl or substituted thiazolyl, etc.;

[0013] The alkyl is C1-C6 alkyl or deuterated alkyl.

[0014]

[0015] In the general structural formulas Ⅲ and Ⅳ, the R group represents hydrogen, arylcarbonyl, heteroarylcarbonyl. Among them:

[0016] The arylcarbonyl is benzoyl and substituted benzoyl;

[0017] For the substituted benzoyl, the substituents are alkyl, halogen, acyl, alkenyl, fluoroalkyl, cyano, nitro, etc.;

[0018] The heteroarylcarbonyl is pyridinecarbonyl or substituted pyridinecarbonyl, thiophenecarbonyl or substituted thiophenecarbonyl, furancarbonyl or substituted furancarbonyl, pyrazinecarbonyl or substituted pyrazinecarbonyl, pyrrolecarbonyl or substituted pyrrolecarbonyl, quinolinecarbonyl or substituted quinolinecarbonyl, isoquinolinecarbonyl or substituted isoquinolinecarbonyl, benzothiazolecarbonyl or substituted benzothiazolecarbonyl, indolecarbonyl or substituted indolecarbonyl, benzimidazolecarbonyl or substituted benzimidazolecarbonyl, benzoxazolecarbonyl or substituted benzoxazolecarbonyl, imidazolecarbonyl or substituted imidazolecarbonyl, oxazolecarbonyl or substituted oxazolecarbonyl, thiazolecarbonyl or substituted thiazolecarbonyl, etc.;

[0019] The alkyl is C1-C6 alkyl or deuterated alkyl;

[0020] The fluoroalkyl is C1-C6 fluoroalkyl.

[0021] Further preferably, the derivative is the following compound:

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032] The piperidine-linked 1,2,4-oxadiazole-substituted curcumol derivative of the present invention is obtained by the following preparation method:

[0033]

[0034] The present invention also provides a preparation method of the above derivative, and the method comprises the following steps:

[0035] (1) Under heating and alkaline conditions, hydroxylamine hydrochloride undergoes nucleophilic addition with a cyano-substituted aryl (hetero) ring to generate an oximinoamine intermediate 2, and the yield is 77-99%.

[0036] (2) 2 undergoes a condensation reaction with N-Boc-4-piperidinecarboxylic acid, and then cyclizes under the action of DIPEA to obtain an intermediate 3, and the yield is 24-30%.

[0037] (3) 3 is deprotected by Boc under the action of trifluoroacetic acid to obtain an intermediate 4, and the yield is 66-95%.

[0038] (4) 4 undergoes a ring-opening and further elimination reaction with curcumol brominated by NBS to obtain end products S1a-S7a and S1b-S7b, and the yields are 3-21% and 5-22% respectively.

[0039] The piperidine-condensed aminothiazole-substituted curcumol derivative of the present invention is obtained by the following preparation method:

[0040]

[0041] The present invention also provides a preparation method of the above derivative, and the method comprises the following steps:

[0042] (1) 5 undergoes a ring-opening and subsequent elimination reaction with curcumol brominated by NBS to obtain intermediates 6 and 7, and the yields are 30% and 21% respectively.

[0043] (2) 6 and 7 respectively undergo condensation reactions with various substituted aryl(hetero)carboxylic acids 8 to obtain products S8a - S21a and S8b - S21b, with yields of 15 - 71% and 6 - 70% respectively. Detailed implementation mode

[0044] Example 1:

[0045] 1) Synthesis of compound 2:

[0046] Take a 100 mL round-bottom flask, add the raw material heteroaromatic cyano compound 1 (20 mmol, 1 equiv.), hydroxylamine hydrochloride (3.47 g, 50 mmol), sodium bicarbonate (4.2 g, 50 mmol), and 50 mL of ethanol. Heat under reflux for 2 hours. After cooling, filter out the solid, wash the solid with dichloromethane, collect the filtrate, evaporate to dryness, add 100 mL of water, extract with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain product 2 with a yield of 77 - 99%.

[0047] 2) Synthesis of compound 3:

[0048] Dissolve 1-Boc-4-piperidinecarboxylic acid (2.29 g, 10 mmol), HOBt (1.62 g, 12 mmol), EDCI (2.88 g, 15 mmol), and DIPEA (3.48 mL, 20 mmol) in 30 mL of 1,4-dioxane, stir at room temperature for 15 minutes, add the oxime compound 2 (10 mmol, 1 equiv.), stir at room temperature for 18 hours, transfer to an oil bath, heat under reflux for 24 hours, cool and evaporate to dryness, add 50 mL of ethyl acetate, wash successively with water (50 mL × 3), sodium hydroxide solution (1 M, 50 mL × 3), and saturated NaCl solution (50 mL × 1). Dry the organic phase over anhydrous sodium sulfate, filter, evaporate to dryness, and obtain product 3 by column chromatography with a yield of 24 - 30%.

[0049] 3) Synthesis of compound 4:

[0050] Dissolve 3 (2 mmol, 1 equiv) in 20 mL of dichloromethane, add 8 mL of trifluoroacetic acid, stir at room temperature for 1 hour, then quench the reaction with saturated sodium bicarbonate solution. Pour the solution into a separatory funnel, separate the organic phase, extract the aqueous phase with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain product 4 with a yield of 66 - 95%. 4) Synthesis of compound S1a:

[0051] Dissolve curcuminol (47.3 mg, 0.2 mmol) in 2 mL of 1,4-dioxane, add NBS (35.6 mg, 0.2 mmol), react under dark for 24 hours, add tert-butyl 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (0.4 mmol, 2 equiv), react for another 24 hours, evaporate to dryness, add 10 mL of dichloromethane, wash successively with saturated sodium dithionite solution (10 mL×3) and saturated sodium carbonate solution (10 mL×3), dry the organic phase with anhydrous sodium sulfate, filter, evaporate to dryness, and obtain 20 mg of white solid S1a by column chromatography (PE:EA = 1:1) with a yield of 21%. 1 H NMR(400MHz,CDCl3)δ8.08(dd,J=8.7,5.4Hz,2H),7.16(t,J=8.6Hz,2H),2.97-2.79(m,6H),2.50-2.37(m,3H),2.23-1.96(m,9H),1.81-1.66(m,3H),1.61(dd,J=11.5,5.3Hz,1H),1.48-1.42(m,2H),1.04(d,J=6.3Hz,3H),0.94(d,J=7.0Hz,3H),0.90(d,J=6.5Hz,3H);HRMS(ESI)Calcd.forC 28 H 37 FN3O3[(M+H) + 482.2819,found482.2818.

[0052] 5) Synthesis of compound S1b:

[0053] Using the same reagents and procedures as in the synthesis of S1a, 21 mg of white solid S1b was obtained by column chromatography (PE:EA = 1:1) with a yield of 22%. 1 H NMR(400MHz,CDCl3)δ8.08(dd,J=8.7,5.4Hz,2H),7.16(t,J=8.6Hz,2H),2.97-2.79(m,6H),2.50-2.37(m,3H),2.23-1.96(m,9H),1.81-1.66(m,3H),1.61(dd,J=11.5,5.3Hz,1H),1.48-1.42(m,2H),1.04(d,J=6.3Hz,3H),0.94(d,J=7.0Hz,3H),0.90(d,J=6.5Hz,3H);HRMS(ESI)Calcd.for C 28 H 37 FN3O3[(M+H) +482.2819, found 482.2818.

[0054] Example 2:

[0055] 1) Synthesis of compound S2a

[0056] 4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was replaced with an equivalent amount of 4-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester. The remaining reagents and operations were the same as those in the synthesis of S1. 8 mg of white solid S2a was obtained by column chromatography (PE:EA = 1:1), and the yield was 7%. 1 HNMR(400MHz,CDCl3)δ7.95(d,J=8.6Hz,2H),7.61(d,J=8.5Hz,2H),2.99-2.86(m,6H),2.51-2.35(m,3H),2.24-1.96(m,9H),1.84-1.66(m,3H),1.61(dd,J=11.5,5.3Hz,1H),1.49-1.40(m,2H),1.04(d,J=6.3Hz,3H),0.94(d,J=7.0Hz,3H),0.90(d,J=6.5Hz,3H);HRMS(ESI)Calcd.forC 28 H 39 BrN3O3[(M+H) + 542.2018, found 542.2016.

[0057] 2) Synthesis of compound S2b

[0058] The reagents and operations were the same as those in the synthesis of S2a. 5 mg of white solid S1b was obtained by column chromatography (PE:EA = 1:1), and the yield was 5%. 1 H NMR(400MHz,CDCl3)δ7.95(d,J=8.6Hz,2H),7.61(d,J=8.6Hz,2H),5.76(s,1H),3.05(d,J=12.6Hz,1H),3.02-2.90(m,3H),2.77-2.73(m,2H),2.25-1.81(m,11H),1.65-1.64(m,1H),1.61-1.40(m,4H),1.19(dd,J=12.7,7.4Hz,1H),1.01(d,J=6.5Hz,6H),0.89(d,J=6.5Hz,3H);HRMS(ESI)Calcd.for C 28 H 39 BrN3O3[(M+H)+ 542.2018, found 542.2016.

[0059] Example 3:

[0060] 1) Synthesis of compound S3a

[0061] Replace tert-butyl 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate with an equivalent amount, and the remaining reagents and operations are the same as those in the synthesis of S1. After column chromatography (PE:EA = 1:1), 8 mg of white solid S3a was obtained, with a yield of 8%. 1 HNMR(400MHz, CDCl3)δ7.96(d, J = 8.2Hz, 2H), 7.28(d, J = 8.8Hz, 2H), 3.04 - 2.79(m, 6H), 2.51 - 2.47(m, 1H), 2.41(s, 1H), 2.41 - 2.38(m, 2H), 2.23 - 1.96(m, 9H), 1.84 - 1.67(m, 3H), 1.62(dd, J = 11.5, 5.3Hz, 1H), 1.48 - 1.40(m, 2H), 1.04(d, J = 6.3Hz, 3H), 0.94(d, J = 7.0Hz, 3H), 0.90(d, J = 6.5Hz, 3H); HRMS(ESI) Calcd. for C 29 H 40 N3O3[(M + H) + 478.3070, found 478.3069.

[0062] 2) Synthesis of compound S3b

[0063] The reagents and operations are the same as those in the synthesis of S3a. After column chromatography (PE:EA = 1:1), 10 mg of white solid S3b was obtained, with a yield of 10%. 1 H NMR(400MHz, CDCl3)δ7.96(d, J = 8.2Hz, 2H), 7.28(d, J = 8.0Hz, 2H), 5.76(s, 1H), 3.05(d, J = 13.2Hz, 1H), 3.01 - 2.90(m, 3H), 2.77 - 2.73(m, 2H), 2.41(s, 3H), 2.25 - 1.83(m, 11H), 1.66 - 1.44(m, 5H), 1.19(dd, J = 12.7, 7.4Hz, 1H), 1.01(d, J = 6.4Hz, 6H), 0.89(d, J = 6.5Hz, 3H); HRMS(ESI) Calcd. for C 29 H 40 N3O3[(M + H) +478.3070, found 478.3069.

[0064] Example 4:

[0065] 1) Synthesis of compound S4a

[0066] tert-Butyl 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was replaced with an equivalent amount of 3-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole. The remaining reagents and operations were the same as those in the synthesis of S1. After column chromatography (PE:EA = 1:1), 18 mg of white solid S4a was obtained with a yield of 17%. 1 HNMR(400MHz,CDCl3)δ8.30(d,J=8.6Hz,2H),8.05(d,J=8.5Hz,2H),3.10(s,3H),3.02 - 2.88(m,6H),2.52 - 2.35(m,3H),2.22 - 1.96(m,9H),1.81 - 1.69(m,3H),1.61(dd,J=11.5,5.3Hz,1H),1.48 - 1.40(m,2H),1.04(d,J=6.3Hz,3H),0.94(d,J=7.0Hz,3H),0.91(d,J=6.5Hz,3H); HRMS(ESI)Calcd.for C 29 H 40 N3O5S[(M + H) + 542.2689, found 542.2691.

[0067] 2) Synthesis of compound S4b

[0068] The reagents and operations were the same as those in the synthesis of S4a. After column chromatography (PE:EA = 1:1), 23 mg of white solid S4b was obtained with a yield of 21%. 1 H NMR(400MHz,CDCl3)δ8.29(d,J=8.6Hz,2H),8.06(d,J=8.5Hz,2H),5.77(s,1H),3.10(s,3H),3.08 - 2.92(m,4H),2.78 - 2.75(m,2H),2.25 - 1.81(m,11H),1.66 - 1.44(m,5H),1.20(dd,J=12.7,7.4Hz,1H),1.02(dd,J=6.5,1.6Hz,6H),0.89(d,J=6.5Hz,3H); HRMS(ESI)Calcd.for C 29 H 40 N3O5S[(M + H) +542.2689, found 542.2690.

[0069] Example 5:

[0070] 1) Synthesis of compound S5a

[0071] 4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was replaced with an equivalent amount of 4-(3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester. The remaining reagents and operations were the same as those in the synthesis of S1. After column chromatography (PE:EA = 1:1), 3 mg of white solid S5a was obtained, with a yield of 3%. 1 HNMR(400MHz,CDCl3)δ8.06(dd,J=3.0,1.1Hz,1H),7.63(dd,J=5.1,1.1Hz,1H),7.42(dd,J=5.0,3.0Hz,1H),5.77(s,1H),3.05(d,J=13.4Hz,1H),3.01 - 2.90(m,3H),2.75(d,J=13.6Hz,1H),2.63(s,1H),2.25 - 1.85(m,11H),1.65 - 1.60(m,2H),1.54 - 1.43(m,3H),1.20(dd,J=12.8,7.4Hz,1H),1.01(dd,J=6.6,0.9Hz,6H),0.89(d,J=6.5Hz,3H); HRMS(ESI)Calcd.for C 26 H 36 N3O3S[(M + H) + 470.2477, found 470.2476.

[0072] 2) Synthesis of compound S5b

[0073] The reagents and operations were the same as those in the synthesis of S5a. After column chromatography (PE:EA = 1:1), 5 mg of white solid S5b was obtained, with a yield of 5%. 11H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 3.7, 1.2 Hz, 1H), 7.49 (dd, J = 5.0, 1.1 Hz, 1H), 7.15 (dd, J = 5.0, 3.7 Hz, 1H), 2.98 - 2.80 (m, 6H), 2.51 - 2.37 (m, 3H), 2.20 - 1.96 (m, 9H), 1.84 - 1.66 (m, 3H), 1.61 (dd, J = 11.5, 5.3 Hz, 1H), 1.48 - 1.41 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 26 H 36 N3O3S[(M + H) + 470.2477, found 470.2478.

[0074] Example 6:

[0075] 1) Synthesis of Compound S6a

[0076] tert-Butyl 4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was replaced with an equivalent amount of tert-butyl 4-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate. The remaining reagents and operations were the same as those in the synthesis of S1. After column chromatography (PE:EA = 1:1), 15 mg of white solid S6a was obtained with a yield of 16%. 1 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 3.7, 1.2 Hz, 1H), 7.49 (dd, J = 5.0, 1.1 Hz, 1H), 7.15 (dd, J = 5.0, 3.7 Hz, 1H), 2.98 - 2.80 (m, 6H), 2.51 - 2.37 (m, 3H), 2.20 - 1.96 (m, 9H), 1.84 - 1.66 (m, 3H), 1.61 (dd, J = 11.5, 5.3 Hz, 1H), 1.48 - 1.41 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 26 H 36 N3O3S[(M + H) + 470.2477, found 470.2478.

[0077] 2) Synthesis of Compound S6b

[0078] The reagent and operation are the same as those for the synthesis of S6a. After column chromatography (PE:EA = 1:1), 21 mg of white solid S6b was obtained with a yield of 22%. 1 H NMR(400MHz,CDCl3)δ7.78(dd,J=3.7,1.1Hz,1H),7.49(dd,J=5.0,1.1Hz,1H),7.15(dd,J=5.0,3.7Hz,1H),5.76(s,1H),3.05(d,J=13.4Hz,1H),3.01-2.89(m,3H),2.80-2.72(m,2H),2.24-1.83(m,11H),1.66-1.42(m,5H),1.19(dd,J=12.7,7.4Hz,1H),1.01(d,J=6.5Hz,6H),0.89(d,J=6.5Hz,3H); HRMS(ESI)Calcd.for C 26 H 36 N3O3S[(M+H) + 470.2477,found470.2476.

[0079] Example 7:

[0080] 1) Synthesis of compound S7a

[0081] 4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester was replaced with an equivalent amount of 4-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester. The remaining reagents and operations were the same as those for the synthesis of S1. After column chromatography (PE:EA = 1:1), 6 mg of white solid S7a was obtained with a yield of 7%. 1 HNMR(400MHz,CDCl3)δ7.61(dd,J=1.7,0.7Hz,1H),7.13(dd,J=3.5,0.7Hz,1H),6.56(dd,J=3.5,1.8Hz,1H),2.98-2.76(m,6H),2.50-2.35(m,3H),2.22-1.96(m,9H),1.83-1.60(m,4H),1.48-1.41(m,2H),1.04(d,J=6.4Hz,3H),0.94(d,J=7.0Hz,3H),0.90(d,J=6.5Hz,3H); HRMS(ESI)Calcd.for C 26 H 36 N3O4[(M+H) + 454.2706,found454.2707.

[0082] 2) Synthesis of Compound S7b

[0083] Using the same reagents and procedures as in the synthesis of S7a, 6 mg of white solid S7b was obtained by column chromatography (PE:EA = 1:1), with a yield of 7%. 1 H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 1.7, 0.7 Hz, 1H), 7.12 (dd, J = 3.5, 0.7 Hz, 1H), 6.56 (dd, J = 3.5, 1.8 Hz, 1H), 5.76 (s, 1H), 3.04 (d, J = 13.5 Hz, 1H), 3.00 - 2.89 (m, 3H), 2.75 (d, J = 13.6 Hz, 1H), 2.66 (s, 1H), 2.25 - 1.81 (m, 11H), 1.65 - 1.62 (m, 2H), 1.56 - 1.40 (m, 3H), 1.19 (dd, J = 12.7, 7.4 Hz, 1H), 1.01 (dd, J = 6.5 Hz, 6H), 0.89 (d, J = 6.6 Hz, 3H); HRMS (ESI) Calcd. for C 26 H 36 N3O4[(M + H) + 454.2706, found 454.2709.

[0084] Example 8:

[0085] 1) Synthesis of Compounds 6 and 7

[0086] Curcumol (118.2 mg, 0.5 mmol) was dissolved in 5 mL of 1,4 - dioxane. NBS (89.0 mg, 0.5 mmol) was added, and the reaction was carried out under light - free conditions for 24 hours. Then 4,5,6,7 - tetrahydrothiazolo[5,4 - c]pyridin - 2 - amine 5 (77.6 mg, 0.5 mmol) was added, and the reaction was continued for 24 hours. The solvent was evaporated, and the products 6 and 7 were obtained by column chromatography (DCM:MeOH = 15:1).

[0087] 2) Synthesis of Compound S8a

[0088] Compound 6 (39.0 mg, 0.1 mmol) and EDCI (23.0 mg, 0.12 mmol) were dissolved in 2 mL of dichloromethane. HOBt (16.2 mg, 0.12 mmol) and benzoic acid (0.12 mmol, 1.2 equiv.) were added under stirring at room temperature, and the reaction was carried out overnight at room temperature. The reaction solution was subjected to column chromatography (DCM:MeOH = 15:1) to obtain 10 mg of yellow - green solid S8a, with a yield of 20%. 1HNMR(400MHz,CDCl3)δ10.20(s,1H),7.95(d,J=7.2Hz,1H),7.60(t,J=7.4Hz,1H),7.51(d,J=7.5Hz,2H),3.63(s,2H),3.18(s,1H),3.06(s,2H),2.78 - 2.66(m,4H),2.55 - 2.33(m,3H),2.23 - 2.17(m,1H),2.09 - 2.06(m,1H),2.01(t,J=11.7Hz,1H),1.85 - 1.70(m,3H),1.64(dd,J=11.6,5.3Hz,1H),1.48 - 1.43(m,2H),1.02(d,J=6.3Hz,3H),0.92(t,J=7.0Hz,6H); HRMS(ESI) Calcd. for C 28 H 36 N3O3S[(M + H) + 494.2477, found 494.2475.

[0089] 3) Synthesis of Compound S8b

[0090] Replace 6 with an equivalent amount of 7, and the remaining reagents and operations are the same as those for the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 10 mg of yellow - green solid S8b was obtained with a yield of 20%. 1 HNMR(400MHz,CDCl3)δ10.23(s,1H),7.93(d,J=7.2Hz,2H),7.60(t,J=7.4Hz,1H),7.51(t,J=7.6Hz,2H),5.82(s,1H),3.69 - 3.60(m,2H),3.22(d,J=13.6Hz,1H),3.10(s,1H),2.98(d,J=13.5Hz,1H),2.83(dt,J=11.7,5.8Hz,1H),2.74(dt,J=12.1,5.6Hz,1H),2.65 - 2.55(m,2H),2.26 - 2.20(m,1H),2.12 - 2.10(m,1H),2.02 - 1.81(m,4H),1.70 - 1.64(m,2H),1.54 - 1.43(m,3H),1.23 - 1.20(m,1H),1.04(d,J=6.4Hz,3H),0.99(d,J=6.4Hz,3H),0.93(d,J=6.5Hz,3H); HRMS(ESI) Calcd. for C 28 H 36 N3O3S[(M + H) +494.2477, found 494.2476.

[0091] Example 9:

[0092] 1) Synthesis of compound S9a

[0093] Replace benzoic acid with an equivalent amount of p-toluic acid, and use the same reagents and operations as in the synthesis of S8a. 8 mg of yellow-green solid S9a was obtained by column chromatography (DCM:MeOH = 15:1), with a yield of 16%. 1 HNMR(400 MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 3.06 (s, 2H), 2.79 - 2.72 (m, 4H), 2.55 - 2.45 (m, 2H), 2.43 (s, 3H), 2.41 - 2.36 (m, 1H), 2.24 - 2.20 (m, 1H), 2.10 - 2.07 (m, 1H), 2.01 (t, J = 11.6 Hz, 1H), 1.85 - 1.66 (m, 4H), 1.49 - 1.43 (m, 2H), 1.02 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H); HRMS(ESI) Calcd. for C 29 H 38 N3O3S[(M + H) + 508.2634, found 508.2635.

[0094] 2) Synthesis of compound S9b

[0095] Replace benzoic acid with an equivalent amount of p-toluic acid, and use the same reagents and operations as in the synthesis of S8b. 3 mg of yellow-green solid S9b was obtained by column chromatography (DCM:MeOH = 15:1), with a yield of 6%. 1HNMR(600MHz,CDCl3)δ7.84(d,J=7.8Hz,2H),7.32(d,J=8.0Hz,2H),5.83(s,1H),3.66(s,2H),3.26-3.24(m,1H),3.12-3.11(m,1H),3.02-3.00(m,1H),2.88(s,1H),2.78-2.73(m,2H),2.44(s,3H),2.26-2.21(m,2H),1.92-1.83(m,3H),1.68-1.65(m,4H),1.23-1.22(m,1H),1.04(d,J=6.5Hz,3H),1.00(d,J=6.6Hz,3H),0.93(d,J=6.5Hz,3H); HRMS(ESI) Calcd. for C 29 H 38 N3O3S[(M+H) + 508.2634, found 508.2633.

[0096] Example 10:

[0097] 1) Synthesis of compound S10a

[0098] Replace benzoic acid with an equivalent amount of p-acetylbenzoic acid, and use the same other reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 8 mg of yellow-green solid S10a was obtained, with a yield of 15%. 1 H NMR(400MHz,CDCl3)δ10.80(s,1H),8.07-8.02(m,4H),3.60(s,2H),3.07-3.00(m,2H),2.77-2.70(m,1H),2.66(s,3H),2.61-2.46(m,5H),2.41-2.32(m,1H),2.22-2.16(m,1H),2.07-2.04(m,1H),2.00(t,J=11.8Hz,1H),1.84-1.73(m,2H),1.63(dd,J=11.7,5.2Hz,1H),1.49-1.42(m,2H),1.02(d,J=6.3Hz,3H),0.90(t,J=5.9Hz,6H); HRMS(ESI) Calcd. for C 30 H 38 N3O4S[(M+H) + 536.2583, found 536.2584.

[0099] 2) Synthesis of compound S10b

[0100] Replace benzoic acid with an equivalent amount of 4-acetylbenzoic acid, and use the same reagents and procedures as in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 8 mg of yellow-green solid S10b was obtained with a yield of 15%. 1 HNMR(400MHz,CDCl3)δ10.49(s,1H),8.08 - 8.02(m,4H),5.82(s,1H),3.69 - 3.61(m,2H),3.10(s,1H),3.22(d,J=13.4Hz,1H),2.98(d,J=13.6Hz,1H),2.83(dt,J=12.3,6.1Hz,1H),2.74(dt,J=11.9,6.2Hz,1H),2.65(s,1H),2.62 - 2.61(m,2H),2.23(dd,J=12.7,10.9Hz,1H),2.11(t,J=8.7Hz,1H),1.94 - 1.78(m,2H),1.71 - 1.64(m,3H),1.52 - 1.45(m,3H),1.22 - 1.19(m,1H),1.04(d,J=6.5Hz,3H),0.97(d,J=6.4Hz,3H),0.92(d,J=6.5Hz,3H); HRMS(ESI) Calcd.for C 30 H 38 N3O4S[(M + H) + 536.2583,found 536.2582.

[0101] Example 11:

[0102] 1) Synthesis of compound S11a

[0103] Replace benzoic acid with an equivalent amount of 4-fluorobenzoic acid, and use the same reagents and procedures as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 10 mg of yellow-green solid S11a was obtained with a yield of 20%. 1HNMR (400 MHz, CDCl3) δ 10.75 (s, 1H), 7.98 (dd, J = 8.8, 5.2 Hz, 2H), 7.17 (t, J = 8.5 Hz, 2H), 3.89 (s, 1H), 3.59 (s, 2H), 3.08 - 3.01 (m, 2H), 2.77 - 2.73 (m, 1H), 2.68 - 2.58 (m, 3H), 2.48 (s, 2H), 2.41 - 2.35 (m, 1H), 2.22 - 2.16 (m, 1H), 2.06 - 2.05 (m, 1H), 2.00 (t, J = 11.7 Hz, 1H), 1.83 - 1.73 (m, 3H), 1.63 (dd, J = 11.7, 5.2 Hz, 1H), 1.49 - 1.42 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 7.1 Hz, 6H); HRMS (ESI) Calcd. for C 28 H 35 FN3O3S[(M + H) + 512.2383, found 512.2381.

[0104] 2) Synthesis of compound S11b

[0105] Replace benzoic acid with an equivalent amount of 4 - fluorobenzoic acid, and the remaining reagents and operations are the same as those in the synthesis of S8b. 4 mg of yellow - green solid S11b was obtained by column chromatography (DCM:MeOH = 15:1), and the yield was 8%. 1 HNMR (400 MHz, CDCl3) δ 8.05 (dd, J = 8.1, 5.3 Hz, 2H), 7.19 (t, J = 8.4 Hz, 2H), 5.83 (s, 1H), 3.65 (s, 2H), 3.24 (d, J = 13.4 Hz, 1H), 3.00 (d, J = 13.5 Hz, 1H), 2.85 - 2.78 (m, 2H), 2.66 - 2.62 (m, 2H), 2.26 - 2.20 (m, 1H), 2.13 - 2.11 (m, 1H), 1.98 - 1.81 (m, 4H), 1.71 - 1.64 (m, 2H), 1.52 - 1.49 (m, 3H), 1.23 - 1.20 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.1 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); HRMS (ESI) Calcd. for C 28 H 35 FN3O3S[(M + H) + 512.2383, found 512.2382.

[0106] Example 12:

[0107] 1) Synthesis of Compound S12a

[0108] Replace benzoic acid with an equivalent amount of 4-chlorobenzoic acid, and use the same other reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 9 mg of yellow-green solid S12a was obtained, with a yield of 17%. 1 HNMR(400MHz,CDCl3)δ10.54(s,1H),7.88(d,J=8.6Hz,2H),7.46(d,J=8.6Hz,2H),3.79(s,1H),3.61(s,2H),3.09 - 3.02(m,2H),2.77 - 2.75(m,1H),2.68 - 2.64(m,1H),2.59(s,2H),2.49(s,2H),2.39 - 2.35(m,1H),2.22 - 2.17(m,1H),2.09 - 2.04(m,1H),2.00(t,J=11.9Hz,1H),1.84 - 1.73(m,3H),1.63(dd,J=11.7,5.3Hz,1H),1.47 - 1.42(m,2H),1.01(d,J=6.3Hz,3H),0.91(d,J=6.9Hz,3H),0.89(d,J=7.1Hz,3H); HRMS(ESI) Calcd.for C 28 H 35 ClN3O3S[(M + H) + 528.2088,found528.2086.

[0109] 2) Synthesis of Compound S12b

[0110] Replace benzoic acid with an equivalent amount of 4-chlorobenzoic acid, and use the same other reagents and operations as in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 4 mg of yellow-green solid S12b was obtained, with a yield of 8%. 1HNMR(400MHz, CDCl3) δ 10.37(s, 1H), 7.88(d, J = 8.6Hz, 2H), 7.47(d, J = 8.6Hz, 2H), 5.82(s, 1H), 3.68 - 3.59(m, 2H), 3.22(d, J = 12.8Hz, 1H), 2.98(d, J = 13.6Hz, 1H), 2.83(dt, J = 11.6, 5.6Hz, 1H), 2.73(dt, J = 12.1, 5.6Hz, 1H), 2.65 - 2.54(m, 2H), 2.23(dd, J = 12.7, 10.8Hz, 1H), 2.12(t, J = 9.0Hz, 1H), 1.98 - 1.81(m, 3H), 1.70 - 1.67(m, 1H), 1.52 - 1.42(m, 4H), 1.22 - 1.19(m, 1H), 1.04(d, J = 6.4Hz, 3H), 0.98(d, J = 6.4Hz, 3H), 0.92(d, J = 6.5Hz, 3H); HRMS(ESI) Calcd. for C 28 H 35 ClN3O3S[(M + H) + 528.2088, found 528.2086.

[0111] Example 13:

[0112] 1) Synthesis of Compound S13a

[0113] Replace benzoic acid with an equivalent amount of p - bromobenzoic acid, and use the same other reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 15 mg of yellow - green solid S13a was obtained, with a yield of 26%. 1 HNMR(400MHz, CDCl3) δ 10.96(s, 1H), 7.82(d, J = 8.5Hz, 2H), 7.61(d, J = 8.4Hz, 2H), 3.60(s, 2H), 3.08 - 3.01(m, 2H), 2.77 - 2.72(m, 1H), 2.65 - 2.61(m, 1H), 2.55 - 2.49(m, 3H), 2.41 - 2.32(m, 1H), 2.22 - 2.16(m, 1H), 2.08 - 2.04(m, 1H), 2.00(t, J = 11.8Hz, 1H), 1.83 - 1.73(m, 2H), 1.63(dd, J = 11.7, 5.2Hz, 1H), 1.49 - 1.42(m, 2H), 1.01(d, J = 6.3Hz, 3H), 0.91(d, J = 6.4Hz, 3H), 0.88(d, J = 7.0Hz, 3H); HRMS(ESI) Calcd. for C28 H 35 BrN3O3S[(M+H) + 572.1583, found 572.1581.

[0114] 2) Synthesis of Compound S13b

[0115] Replace benzoic acid with an equivalent amount of 4-bromobenzoic acid, and use the same reagents and operations as in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 18 mg of yellow-green solid S13b was obtained with a yield of 31%. 1 HNMR(400MHz, CDCl3) δ11.04(s, 1H), 7.82(d, J = 8.4Hz, 2H), 7.62(d, J = 8.4Hz, 2H), 5.82(s, 1H), 3.67 - 3.60(m, 2H), 3.21(d, J = 13.4Hz, 1H), 2.97(d, J = 13.5Hz, 1H), 2.81(dt, J = 12.0, 5.7Hz, 1H), 2.71(dt, J = 11.9, 5.8Hz, 1H), 2.57 - 2.46(m, 2H), 2.25 - 2.19(m, 2H), 2.11(t, J = 9.0Hz, 1H), 2.02 - 1.78(m, 4H), 1.72 - 1.65(m, 2H), 1.50 - 1.43(m, 3H), 1.22 - 1.19(m, 1H), 1.04(d, J = 6.4Hz, 3H), 0.96(d, J = 6.2Hz, 3H), 0.92(d, J = 6.5Hz, 3H); HRMS(ESI) Calcd. for C 28 H 35 BrN3O3S[(M+H) + 572.1583, found 572.1579.

[0116] Example 14:

[0117] 1) Synthesis of Compound S14a

[0118] Replace benzoic acid with an equivalent amount of 4-vinylbenzoic acid, and use the same reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 13 mg of yellow-green solid S14a was obtained with a yield of 25%. 11H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 6.76 (dd, J = 17.6, 10.9 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 10.9 Hz, 1H), 3.61 (s, 2H), 3.07 - 3.01 (m, 2H), 2.76 - 2.72 (m, 1H), 2.68 - 2.63 (m, 1H), 2.59 - 2.54 (m, 2H), 2.48 (s, 2H), 2.43 - 2.32 (m, 2H), 2.22 - 2.16 (m, 1H), 2.07 - 2.04 (m, 1H), 2.00 (t, J = 11.7 Hz, 1H), 1.84 - 1.72 (m, 2H), 1.63 (dd, J = 11.6, 5.3 Hz, 1H), 1.50 - 1.42 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.9 Hz, 6H); HRMS (ESI) Calcd. for C 30 H 38 N3O3S [(M + H) + 520.2634, found 520.2633.

[0119] 2) Synthesis of Compound S14b

[0120] Replace benzoic acid with an equivalent amount of p - vinylbenzoic acid, and the other reagents and operations are the same as those in the synthesis of S8b. 10 mg of yellow - green solid S14b was obtained by column chromatography (DCM:MeOH = 15:1), and the yield was 19%. 11H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 6.76 (dd, J = 17.6, 10.9 Hz, 1H), 5.89 (d, J = 17.6 Hz, 1H), 5.83 (s, 1H), 5.40 (d, J = 11.0 Hz, 1H), 3.66 (s, 2H), 3.24 (d, J = 13.8 Hz, 1H), 3.01 - 2.62 (m, 5H), 2.23 (dd, J = 14.8, 9.1 Hz, 1H), 2.14 (s, 1H), 2.02 - 1.82 (m, 3H), 1.69 - 1.62 (m, 3H), 1.54 - 1.45 (m, 3H), 1.23 - 1.20 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 30 H 38 N3O3S [(M + H) + 520.2634, found 520.2633.

[0121] Example 15:

[0122] 1) Synthesis of compound S15a

[0123] Replace benzoic acid with an equivalent amount of 4 - carboxybenzaldehyde, and use the same other reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 11 mg of yellow - green solid S15a was obtained, with a yield of 21%. 1 1H NMR (400 MHz, CDCl3) δ 11.18 (s, 1H), 10.10 (s, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 3.59 (s, 2H), 3.06 - 2.99 (m, 2H), 2.72 - 2.68 (m, 1H), 2.62 - 2.48 (m, 5H), 2.37 - 2.31 (m, 2H), 2.22 - 2.16 (m, 1H), 2.04 - 1.97 (m, 2H), 1.82 - 1.73 (m, 2H), 1.63 (dd, J = 11.7, 5.2 Hz, 1H), 1.49 - 1.40 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H); HRMS (ESI) Calcd. for C 29 H 36 N3O4S [(M + H)+ 522.2427, found 522.2429.

[0124] 2) Synthesis of Compound S15b

[0125] Benzoic acid was replaced with an equivalent amount of 4-carboxybenzaldehyde, and the remaining reagents and operations were the same as those in the synthesis of S8b. 21 mg of yellow-green solid S15b was obtained by column chromatography (DCM:MeOH = 15:1), with a yield of 40%. 1 HNMR(400MHz,CDCl3)δ10.61(s,1H),10.11(s,1H),8.13(d,J=8.2Hz,2H),8.02(d,J=8.2Hz,2H),5.82(s,1H),3.68 - 3.61(m,2H),3.29(s,1H),3.23(d,J=13.6Hz,1H),2.99(d,J=13.7Hz,1H),2.86 - 2.82(m,1H),2.78 - 2.72(m,1H),2.66 - 2.62(m,2H),2.26 - 2.20(m,1H),2.10(t,J=8.7Hz,1H),2.11 - 1.81(m,4H),1.70 - 1.68(m,1H),1.52 - 1.45(m,4H),1.22 - 1.19(m,1H),1.04(d,J=6.4Hz,3H),0.98(d,J=6.3Hz,3H),0.93(d,J=6.5Hz,3H); HRMS(ESI) Calcd.for C 29 H 36 N3O4S[(M + H) + 522.2427, found 522.242.

[0126] Example 16:

[0127] 1) Synthesis of Compound S16a

[0128] Benzoic acid was replaced with an equivalent amount of 4-trifluoromethylbenzoic acid, and the remaining reagents and operations were the same as those in the synthesis of S8a. 32 mg of yellow-green solid S16a was obtained by column chromatography (DCM:MeOH = 15:1), with a yield of 57%. 11H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.70 (t, J = 8.3 Hz, 2H), 4.45 (s, 1H), 3.59 (s, 2H), 3.06 - 2.99 (m, 2H), 2.73 - 2.68 (m, 1H), 2.58 - 2.54 (m, 1H), 2.49 - 2.30 (m, 5H), 2.21 - 2.14 (m, 1H), 2.02 - 1.96 (m, 2H), 1.82 - 1.75 (m, 3H), 1.63 (dd, J = 11.7, 5.2 Hz, 1H), 1.47 - 1.39 (m, 2H), 1.00 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 7.0 Hz, 6H); HRMS (ESI) Calcd. for C 29 H 35 F3N3O3S[(M + H) + 562.2351, found 562.2352.

[0129] 2) Synthesis of Compound S16b

[0130] Replace benzoic acid with an equivalent amount of p-trifluoromethylbenzoic acid, and the remaining reagents and operations are the same as those in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 11 mg of yellow-green solid S16b was obtained with a yield of 20%. 1 1H NMR (400 MHz, CDCl3) δ 10.90 (s, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 5.83 (s, 1H), 3.66 (s, 2H), 3.23 (d, J = 12.9 Hz, 1H), 2.99 (d, J = 13.4 Hz, 1H), 2.82 - 2.74 (m, 2H), 2.62 - 2.56 (m, 2H), 2.26 - 2.20 (m, 1H), 2.12 (t, J = 8.1 Hz, 1H), 2.02 - 1.78 (m, 4H), 1.71 - 1.64 (m, 2H), 1.52 - 1.42 (m, 3H), 1.22 - 1.19 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 29 H 35 F3N3O3S[(M + H) + 562.2351, found 562.2350.

[0131] Example 17:

[0132] 1) Synthesis of Compound S17a

[0133] Replace benzoic acid with an equivalent amount of 4-nitrobenzoic acid. The remaining reagents and operations are the same as those in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 23 mg of yellow-green solid S17a was obtained with a yield of 43%. 1 H NMR(400MHz,CDCl3)δ11.14(s,1H),8.33(d,J=8.6Hz,2H),8.16(t,J=8.6Hz,2H),3.94(s,1H),3.62(s,2H),3.07(s,2H),2.77 - 2.65(m,4H),2.56 - 2.46(m,2H),2.40 - 2.34(m,1H),2.23 - 2.17(m,1H),2.04 - 1.98(m,2H),1.84 - 1.75(m,2H),1.64(dd,J=11.6,5.3Hz,1H),1.47 - 1.42(m,2H),1.02(d,J=6.2Hz,3H),0.92(d,J=6.3Hz,3H),0.87(d,J=6.9Hz,6H);HRMS(ESI)Calcd.for C 28 H 35 N4O5S[(M + H) + 539.2328,found 539.2330.

[0134] 2) Synthesis of Compound S17b

[0135] Replace benzoic acid with an equivalent amount of 4-nitrobenzoic acid. The remaining reagents and operations are the same as those in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 11 mg of yellow-green solid S17b was obtained with a yield of 21%. 11H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 5.83 (s, 1H), 3.68 - 3.60 (m, 2H), 3.21 (d, J = 13.5 Hz, 1H), 2.98 (d, J = 13.6 Hz, 1H), 2.81 (dt, J = 12.0, 5.4 Hz, 1H), 2.73 (dt, J = 12.2, 5.1 Hz, 1H), 2.63 - 2.50 (m, 2H), 2.22 (dd, J = 12.7, 10.8 Hz, 1H), 2.08 (t, J = 9.1 Hz, 1H), 1.94 - 1.78 (m, 4H), 1.75 - 1.67 (m, 1H), 1.50 - 1.41 (m, 2H), 1.20 (dd, J = 12.8, 7.4 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.5 Hz, 6H); HRMS (ESI) Calcd. for C 28 H 35 N4O5S [(M + H) + 539.2328, found 539.2330.

[0136] Example 18:

[0137] 1) Synthesis of Compound S18a

[0138] Replace benzoic acid with an equivalent amount of 4 - cyanobenzoic acid, and use the same remaining reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 31 mg of yellow - green solid S18a was obtained with a yield of 60%. 1 1H NMR (400 MHz, CD3OH) δ 11.14 (s, 1H), 8.14 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 3.63 (s, 2H), 3.14 - 3.07 (m, 2H), 2.88 - 2.81 (m, 2H), 2.77 - 2.75 (m, 2H), 2.53 - 2.37 (m, 3H), 2.27 - 2.21 (m, 1H), 2.07 - 2.03 (m, 2H), 1.97 (t, J = 11.5 Hz, 1H), 1.89 - 1.74 (m, 2H), 1.69 (dd, J = 11.5, 5.3 Hz, 1H), 1.51 - 1.42 (m, 2H), 1.01 (d, J = 6.2 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.4 Hz, 6H); HRMS (ESI) Calcd. for C 29 H 35N4O3S[(M+H) + 519.2430, found 519.2428.

[0139] 2) Synthesis of compound S18b

[0140] Replace benzoic acid with an equivalent amount of 4-cyanobenzoic acid, and the remaining reagents and operations are the same as those for the synthesis of S8b. 15 mg of yellow-green solid S18b was obtained by column chromatography (DCM:MeOH = 15:1), and the yield was 29%. 1 H NMR(400MHz,CD3OH)δ8.14(d,J=8.5Hz,2H),7.92(d,J=8.5Hz,2H),6.20(s,1H),4.68 - 4.43(m,2H),4.05(d,J=13.8Hz,1H),3.89(d,J=14.0Hz,1H),3.16(s,2H),2.30(dd,J=12.8,11.1Hz,1H),2.20(t,J=9.1Hz,1H),2.10 - 1.89(m,4H),1.77(d,J=10.8,7.6Hz,1H),1.63 - 1.48(m,4H),1.39(dd,J=13.1,7.5Hz,1H),1.06(d,J=6.5Hz,3H),1.03(d,J=6.3Hz,3H),0.97(d,J=6.4Hz,3H); HRMS(ESI) Calcd.for C 29 H 35 N4O3S[(M+H) + 519.2430, found 519.2431.

[0141] Example 19:

[0142] 1) Synthesis of compound S19a

[0143] Replace benzoic acid with an equivalent amount of 2-bromobenzoic acid, and the remaining reagents and operations are the same as those for the synthesis of S8a. 9 mg of yellow-green solid S19a was obtained by column chromatography (DCM:MeOH = 15:1), and the yield was 16%. 1HNMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 7.69 (dd, J = 7.4, 1.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 2H), 3.61 (s, 2H), 3.03 (s, 2H), 2.98 (s, 1H), 2.76 - 2.65 (m, 2H), 2.53 - 2.33 (m, 5H), 2.22 - 2.16 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 (t, J = 11.5 Hz, 1H), 1.85 - 1.68 (m, 3H), 1.63 (dd, J = 11.5, 5.3 Hz, 1H), 1.48 - 1.40 (m, 2H), 1.03 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); HRMS (ESI) Calcd. for C 28 H 35 BrN3O3S[(M + H) + 572.1583, found 572.1585.

[0144] 2) Synthesis of Compound S19b

[0145] Replace benzoic acid with an equivalent amount of 2 - bromobenzoic acid, and the other reagents and operations are the same as those in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 13 mg of yellow - green solid S19b was obtained with a yield of 23%. 1 HNMR (400 MHz, CDCl3) δ 10.74 (s, 1H), 7.69 (dd, J = 7.5, 1.7 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.37 (td, J = 7.6, 1.7 Hz, 1H), 5.81 (s, 1H), 3.67 - 3.59 (m, 2H), 3.20 (d, J = 13.1 Hz, 1H), 2.97 (d, J = 13.3 Hz, 1H), 2.75 - 2.69 (m, 2H), 2.46 - 2.30 (m, 2H), 2.24 (dd, J = 12.5, 10.9 Hz, 1H), 2.13 - 2.10 (m, 1H), 1.95 - 1.81 (m, 3H), 1.69 - 1.61 (m, 1H), 1.56 - 1.45 (m, 3H), 1.23 - 1.20 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 28 H 35 BrN3O3S[(M + H)+ 572.1583, found 572.1581.

[0146] Example 20:

[0147] 1) Synthesis of compound S20a

[0148] Replace benzoic acid with an equivalent amount of isonicotinic acid, and use the same other reagents and operations as in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 35 mg of yellow-green solid S20a was obtained, with a yield of 71%. 1 HNMR(400MHz,CDCl3)δ12.26(s,1H),8.76(d,J=5.7Hz,2H),7.69(d,J=5.8Hz,2H),3.63(d,J=14.4Hz,1H),3.53(d,J=14.4Hz,1H),3.04 - 2.97(m,2H),2.66 - 2.62(m,1H),2.53 - 2.27(m,5H),2.20 - 2.14(m,1H),2.06 - 2.03(m,1H),1.99(t,J=12.0Hz,1H),1.86 - 1.73(m,3H),1.62(dd,J=11.6,5.2Hz,1H),1.48 - 1.39(m,2H),1.04(d,J=6.3Hz,3H),0.91(d,J=6.4Hz,3H),0.87(d,J=7.0Hz,6H); HRMS(ESI) Calcd.for C 27 H 35 N4O3S[(M + H) + 495.2430, found 495.2432.

[0149] 2) Synthesis of compound S20b

[0150] Replace benzoic acid with an equivalent amount of isonicotinic acid, and use the same other reagents and operations as in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 7 mg of yellow-green solid S20b was obtained, with a yield of 14%. 11H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 8.81 (d, J = 5.9 Hz, 2H), 7.76 (d, J = 6.0 Hz, 2H), 5.85 (s, 1H), 3.65 (s, 2H), 3.22 (d, J = 13.7 Hz, 1H), 2.98 (d, J = 13.7 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.58 - 2.41 (m, 2H), 2.23 (dd, J = 12.6, 10.9 Hz, 1H), 2.10 - 2.07 (m, 1H), 1.97 - 1.79 (m, 3H), 1.73 - 1.66 (m, 2H), 1.54 - 1.41 (m, 3H), 1.22 - 1.19 (m, 1H), 1.05 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 27 H 35 N4O3S [(M + H) + 495.2430, found 495.2431.

[0151] Example 21:

[0152] 1) Synthesis of compound S21a

[0153] Benzoic acid was replaced with an equivalent amount of 2 - furan carboxylic acid, and the remaining reagents and operations were the same as those in the synthesis of S8a. After column chromatography (DCM:MeOH = 15:1), 15 mg of yellow - green solid S21a was obtained with a yield of 31%. 1 1H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 3.0 Hz, 1H), 6.59 (d, J = 3.5, 1.7 Hz, 1H), 3.62 (s, 2H), 3.10 - 3.03 (m, 2H), 2.82 - 2.76 (m, 4H), 2.55 - 2.34 (m, 3H), 2.24 - 2.17 (m, 1H), 2.11 - 2.06 (m, 1H), 2.00 (t, J = 11.6 Hz, 1H), 1.85 - 1.69 (m, 3H), 1.63 (dd, J = 11.6, 5.4 Hz, 1H), 1.49 - 1.43 (m, 2H), 1.02 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 26 H 34 N3O4S [(M + H) +484.2270, found 484.2269.

[0154] 2) Synthesis of Compound S21b

[0155] Replace benzoic acid with an equivalent amount of 2-furoic acid. For the rest of the reagents and operations, they are the same as those in the synthesis of S8b. After column chromatography (DCM:MeOH = 15:1), 15 mg of yellow-green solid S21b was obtained, and the yield was 31%. 1 HNMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.34 (d, J = 3.5 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 5.82 (s, 1H), 3.68 - 3.59 (m, 2H), 3.23 (d, J = 13.4 Hz, 1H), 2.99 (d, J = 13.5 Hz, 1H), 2.91 - 2.87 (m, 1H), 2.80 - 2.76 (m, 3H), 2.23 (t, J = 11.8 Hz, 2H), 2.14 (t, J = 8.5 Hz, 1H), 2.01 - 1.80 (m, 4H), 1.69 - 1.62 (m, 2H), 1.57 - 1.44 (m, 3H), 1.23 - 1.20 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H); HRMS (ESI) Calcd. for C 26 H 34 N3O4S [(M + H) + 484.2270, found 484.2272.

[0156] The in vitro anti-tumor activities of the curcumol derivatives synthesized in the present invention are as follows:

[0157] Use the CCK-8 method to carry out the corresponding cell proliferation inhibition activity analysis. The specific operations are as follows:

[0158] 1. Sample preparation: Dissolve it in DMSO (Merck) to prepare a stock solution of 10 mM for storage, and then dilute the sample to a solution of 20 μM with the culture medium.

[0159] 2. Tumor cell lines

[0160] Human glioma cell line U87, human non-small cell lung cancer cell line A549, human skin melanoma cell line A375, human bladder transitional cell carcinoma cell line T24.

[0161] 3. Culture medium

[0162] High-glucose DMEM + 10% FBS + 1% double antibody.

[0163] 4. Other materials

[0164] Full-wavelength multifunctional microplate reader: Model Varioskan Flash, manufactured by Thermo scientific, Corning 96-well plates, etc.

[0165] 5. Experimental methods

[0166] Collect cells in the logarithmic growth phase and inoculate them into 96-well plates at a density of 1×10 4 cells / well. After the cells adhere to the wall, add drugs. The final concentrations of the drugs added to the 96-well plates are 20 μM respectively, and 3 replicate wells are set. Set a positive control drug curcumol group and a blank control group. After culturing for 48 h, aspirate the medium containing the drugs, and add the medium containing 10% CCK-8 solution. Incubate in the dark for 1 - 4 h, and measure the absorbance at 450 nm using a microplate reader. Calculate the growth inhibition rate at different concentrations. Growth inhibition rate (%) = (Average value of the Control group - Average value of the drug-administered group) / Average value of the Control group * 100%. The experimental data are expressed as mean ± SD.

[0167] The results of in vitro non-solid tumor cell inhibitory activity are shown in Table 1:

[0168] Table 1 In vitro tumor cell inhibitory activity

[0169]

[0170]

[0171]

[0172] Note: 1. The drug concentration in the experimental group is 20 μM; 2. ND indicates that the activity was not measured.

Claims

1. The general formula compound is as follows: The general formula compound II has the following structure: The general formula compound III has the following structure: The general formula compound IV has the following structure:

2. The preparation method of the compound according to claim 1, characterized in that, The specific reaction formula is as follows:

3. The method for preparing the compound according to claim 1, characterized in that, The specific reaction formula is as follows:

4. Use of the compound according to claim 1 in the preparation of an anti-tumor drug.

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