Compounds with arylamide structure and their medical uses

Abstract

The present invention discloses a class of compounds having an arylamide structure and their medical uses. Using in vitro anti-tumor cell assays, the present invention evaluated the efficacy of compounds represented by Formula I or Formula II in treating various cancers. The compounds were found to exhibit good in vitro activity and extremely high selectivity, suggesting that they could serve as precursors for further development of therapeutic agents that selectively inhibit aldehyde-keto reductase 1C3 to treat cancer.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a compound having an aromatic amide structure and its medical use. Background Art

[0002] Aldo-keto reductase 1C (AKR1C) is a subfamily of the aldo-keto reductase (AKR) superfamily. The human AKR1C subfamily consists of four isoforms (AKR1C1-AKR1C4). As phase I metabolic enzymes, they play a key role in steroid reduction, relying on nicotinamide adenine dinucleotide phosphate (NADPH). These enzymes have a wide range of substrates, including endogenous steroids, prostaglandins, and exogenous compounds.

[0003] AKR1C3, also known as peripheral type 5 17β-hydroxysteroid dehydrogenase (17β-HSD), reduces the androgen 4-androstene-3,17-dione (Δ4-AD) to testosterone, an androgen with stronger affinity for the androgen receptor, and reduces the weak estrogen estrone to 17β-estradiol, an estrogen with even stronger affinity for the estrogen receptor. AKR1C3, also known as prostaglandin F synthase, catalyzes the conversion of prostaglandin D2 (PGD2) to 9α,11β-PGF2α. AKR1C3 is involved in normal physiological processes and is a key enzyme in steroid metabolism. Therefore, abnormal AKR1C3 expression can lead to hormone metabolism disorders, potentially causing various diseases. AKR1C3 expression levels are correlated with disease aggressiveness. Therefore, AKR1C3 may serve as a potential biomarker and therapeutic target for various cancer progression, including prostate cancer, castration-resistant prostate cancer, and breast cancer. Furthermore, AKR1C3 has been associated with polycystic ovary syndrome, endometriosis, cervical cancer, leukemia, lung cancer, and chronic obstructive pulmonary disease. Notably, high AKR1C3 expression in various tumor cells is often associated with poor prognosis. Its role in inducing tumor resistance is related to altering drug performance. AKR1C3 catalyzes the metabolism of anthracyclines into inactive products, significantly reducing their cytotoxicity and ability to bind to tumor cell DNA, significantly diminishing their antitumor activity and leading to tumor resistance. Accumulating evidence indicates a crucial role for AKR1C3 in chemotherapeutic drug resistance, and inhibiting its expression or activity can reverse chemotherapeutic resistance in tumor cells. At present, there are few reports on the biological function research and inhibitors of AKR1C3 in China. The development of inhibitors specifically targeting AKR1C3 may provide an effective treatment strategy for tumors. At the same time, AKR1C3 inhibitors can be used as tool molecules for pathological mechanism research. More importantly, the discovery of effective drugs targeting AKR1C3 may provide a new research direction for reversing drug resistance and overcome key difficulties in tumor treatment. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a class of compounds having an arylamide structure or a pharmaceutically acceptable salt thereof, wherein the structural formula of the compound is as shown in Formula I or Formula II.

[0005]

[0006] Wherein, n is 1, 2 or 3; X is N or O; and R is selected from an arbitrarily substituted C1 to C7 alkyl group.

[0007] In the present invention, the pharmaceutically acceptable salt is hydrochloride, maleate or citrate. The pharmaceutically acceptable salt of the compound has the same or better pharmacodynamic activity as the compound.

[0008] The preparation method of the compound shown in Formula I comprises the following steps:

[0009] (1) m-Hydroxybenzoic acid reacts with 3,5-dimethyl-4-chloromethylisoxazole to obtain compound 2;

[0010] (2) Compound 2 reacts with 5-amino-4-nitrofuran-2-ol to obtain compound 3;

[0011] (3) Compound 3 reacts with dibromoalkyl linker chains of different lengths to obtain compound 4;

[0012] (4) Compound 4 is reacted with 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione or 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione or 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione or 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain a compound represented by the general formula I.

[0013] The reaction route is as follows:

[0014]

[0015] The preparation method of the compound shown in Formula II comprises the following steps:

[0016] (1) m-Hydroxybenzoic acid reacts with 3,5-dimethyl-4-chloromethylisoxazole to obtain compound 2;

[0017] (2) Compound 2 reacts with 5-amino-4-nitrofuran-2-ol to obtain compound 3;

[0018] (3) Compound 3 reacts with 1,5-dibromopentane to obtain compound 4;

[0019] (4) Compound 4 reacts with R-substituted piperazine to obtain compound 5;

[0020] (5) Compound 5 reacts with 1,2-dibromoethane to obtain compound 6;

[0021] (6) Compound 6 reacts with 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione or 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione or 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione or 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain a compound represented by general formula II.

[0022] The reaction route is as follows:

[0023]

[0024] A second object of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer, such as pancreatic cancer, liver cancer, etc.

[0025] The compounds of the present invention can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, and injections, and can be added with common pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers or diluents.

[0026] The third object of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a selective aldehyde-keto reductase 1C3 inhibitor.

[0027] The clinical dosage of the compound of the present invention is 0.01 mg to 1000 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0028] Beneficial effects: The present invention uses in vitro anti-tumor cell experiments as a carrier to evaluate the efficacy of the compound in treating various cancers. It is found that it has good in vitro activity and extremely high selectivity, and can be used as a precursor substance for further development of a cancer treatment effect by selectively inhibiting aldehyde-keto reductase 1C3. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present invention will be described in detail below with reference to the examples. It should be understood that the following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0030] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0031] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0032] Example 1

[0033] (1) Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid

[0034] 3-Hydroxybenzoic acid (1 g, 6.57 mmol) was dissolved in acetonitrile (20 mL) in an eggplant-shaped flask. Potassium carbonate (1.36 g, 9.86 mmol) and 4-chloromethyl-3,5-dimethylisoxazole (0.96 g, 6.57 mmol) were then added sequentially. The mixture was reacted at 70°C for 12 hours. The filtrate was collected and the solvent removed under reduced pressure to yield 3-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 H NMR (300MHz, DMSO-d6): δ8.01(dd,J=7.7,1.5Hz,1H),7.45(td,J=7.9,1.5Hz,1H),7.05-6.98(m,2H),5.03(s,2H),2.29(s,3H),2.27(s,3H).

[0035] (2) Synthesis of 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide

[0036] 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (1 g, 4.04 mmol) was dissolved in 10 mL of DMF. HATU (2.3 g, 6.07 mmol), 5-amino-4-nitrofuran-2-ol (0.6 g, 4.04 mmol), and DIPEA (0.8 g, 6.07 mmol) were added and allowed to react at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide as a white solid. 1 H NMR (500 MHz, Chloroform) δ7.70 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 6.31 (s, 1H), 5.16 (s, 2H), 4.47 (s, 1H), 2.59 (s, 3H), 2.43 (s, 3H). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm.

[0037] (3) Synthesis of N-(5-(4-bromobutoxy)-3-nitrofuran-2-yl)-3-(3,5-dimethylisoxazol-4-yl)methoxy)benzamide

[0038] 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide (1 g, 2.68 mmol) was dissolved in 10 mL of DMF. Cesium carbonate (0.9 g, 2.68 mmol) and 1,4-dibromobutane (0.6 g, 2.68 mmol) were added sequentially and allowed to react at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield N-(5-(4-bromobutoxy)-3-nitrofuran-2-yl)-3-(3,5-dimethylisoxazol-4-yl)methoxy)benzamide as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.31(s,3H),7.68(s,3H),7.60(s,3H),7.12(s,3H),6.74(s,3H),6.10 (s,3H),5.14(s,6H),4.09(s,6H),3.45(s,4H),2.58(s,9H),2.42(s,9H),1.81(d,J=14.9Hz,12H).

[0039] (4) Synthesis of 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)-3-nitrofuran-2-yl)benzamide (Example 1)

[0040] 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindoline-1,3-dione (1 g, 3.65 mmol) was added to 10 mL of DMF, and cesium carbonate (2.1 g, 5.48 mmol) and N-(5-(4-bromobutoxy)-3-nitrofuran-2-yl)-3-(3,5-dimethylisoxazol-4-yl)methoxy)benzamide (1.86 g, 3.65 mmol) were added in sequence. The mixture was reacted at room temperature overnight. After quenching with water, the mixture was extracted with ethyl acetate, and the organic phase was collected. The solvent was removed under reduced pressure to obtain a white solid, 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butoxy)-3-nitrofuran-2-yl)benzamide (Example 1). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.51(s,4H),8.47(s,4H),7.92(s,4H),7.80(s,4H),7.68(s,4H),7.60(s,4H),7.33(s,4H),7.12(s,4H),6.74(s,4 H),6.04(s,4H),5.12(d,J=15.5Hz,11H),4.09(d,J=5.0Hz,16H),2.83 (s,2H),2.71–2.56(m,20H),2.42(s,12H),2.32(s,2H),1.88(s,11H).

[0041] Example 2

[0042] Synthesis of 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butoxy)-3-nitrofuran-2-yl)benzamide (Example 2):

[0043] Referring to the synthesis method of Example 1, the 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione in Example 1 was replaced with 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain a white solid, namely 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)butoxy)-3-nitrofuran-2-yl)benzamide (Example 2). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.57(s,4H),8.49(s,4H),7.99(s,4H),7.71(s,4 H),7.63(s,4H),7.37(s,4H),7.12(d,J=25.0Hz,8H),6.77(s,4H),6.05(s,4H ),5.15(d,J=11.8Hz,11H),4.11(s,4H),3.80(s,4H),3.30(s,4H),2.83(s,2H ),2.73–2.57(m,20H),2.43(s,12H),2.33(s,2H),1.80(s,3H),1.48(s,3H).

[0044] Example 3

[0045] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-((6-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)hexyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 3):

[0046] Referring to the synthesis method of Example 1, the 1,4-dibromobutane in Example 1 was replaced with 1,6-dibromohexane to obtain a white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-((6-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)hexyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 3). TLC detection showed one spot, a dark spot under ultraviolet light at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.57(s,2H),8.46(s,2H),7.91(s,2H),7.79(s,2H),7.67(s,2H),7.59(s,2H),7.32(s,2H),7.11(s,2H),6.73(s,2H), 6.01(s,2H),5.12(d,J=9.5Hz,5H),4.09(s,4H),2.82(s,1H),2.71–2.56 (m,10H),2.42(s,6H),2.32(s,1H),1.78(d,J=14.9Hz,5H),1.50(s,6H).

[0047] Example 4

[0048] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)oxy)-3-nitrofuran-2-ylbenzamide (Example 4):

[0049] Referring to the synthesis method of Example 2, the 1,4-dibromobutane in Example 2 was replaced with 1,6-dibromohexane to obtain an off-white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)oxy)-3-nitrofuran-2-ylbenzamide (Example 4). TLC detection showed one spot, a dark spot under ultraviolet light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.51(s,4H),8.48(s,4H),7.96(s,4H),7.68(s,4H),7 .60(s,4H),7.34(s,4H),7.10(d,J=24.9Hz,8H),6.74(s,4H),6.02(s,4H),5.16(d ,J=18.6Hz,11H),4.09(s,4H),3.79(s,4H),3.10(s,4H),2.79(s,2H),2.73–2.44( m,21H),2.73–2.31(m,36H),1.79(s,3H),1.57(s,3H),1.46(s,5H),1.29(s,5H).

[0050] Example 5

[0051] (1) Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid

[0052] 3-Hydroxybenzoic acid (1 g, 6.57 mmol) was dissolved in acetonitrile (20 mL) in an eggplant-shaped flask. Potassium carbonate (1.36 g, 9.86 mmol) and 4-chloromethyl-3,5-dimethylisoxazole (0.96 g, 6.57 mmol) were then added sequentially. The mixture was reacted at 70°C for 12 hours. The filtrate was collected and the solvent removed under reduced pressure to yield 3-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 H NMR (300MHz, DMSO-d6): δ8.01(dd,J=7.7,1.5Hz,1H),7.45(td,J=7.9,1.5Hz,1H),7.05-6.98(m,2H),5.03(s,2H),2.29(s,3H),2.27(s,3H).

[0053] (2) Synthesis of 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide

[0054] 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoic acid (1 g, 4.04 mmol) was dissolved in 10 mL of DMF. HATU (2.3 g, 6.07 mmol), 5-amino-4-nitrofuran-2-ol (0.6 g, 4.04 mmol), and DIPEA (0.8 g, 6.07 mmol) were added and allowed to react at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide as a white solid. 1 H NMR (500 MHz, Chloroform) δ7.70 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 6.31 (s, 1H), 5.16 (s, 2H), 4.47 (s, 1H), 2.59 (s, 3H), 2.43 (s, 3H). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm.

[0055] (3) Synthesis of N-(5-bromopentyloxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide

[0056] 3-(3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-hydroxy-3-nitrofuran-2-yl)benzamide (1 g, 2.68 mmol) was dissolved in 10 mL of DMF. Cesium carbonate (0.9 g, 2.68 mmol) and 1,5-dibromopentane (0.6 g, 2.68 mmol) were added sequentially and allowed to react at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield N-(5-bromopentyloxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 H NMR(500MHz,Chloroform)δ9.56(s,5H),7.71(s,5H),7.63(s,5H),7.15(s,5H),6.77(s,5H),6.00(s,5H), 5.16(s,10H),4.11(s,5H),3.52(s,5H),2.59(s,15H),2.43(s,15H),1.81(d,J=10.0Hz,13H),1.33(s,4H).

[0057] (4) Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-nitro-5-((5-(piperazin-1-yl)pentyl)oxy)furan-2-yl)benzamide

[0058] N-(5-bromopentyloxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide (1 g, 1.91 mmol) was added to 10 mL of DMF. Piperazine (0.16 g, 1.91 mmol) and cesium carbonate (0.9 g, 2.87 mmol) were added sequentially and allowed to react at room temperature overnight. After quenching with water, the mixture was extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-nitro-5-((5-(piperazin-1-yl)pentyl)oxy)furan-2-yl)benzamide as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1 HNMR(500MHz,Chloroform)δ9.56(s,1H),7.71(s,1H),7.63(s,1H),7.15(s,1H),6.77(s,1H),6.01(s,1H),5.16(s,2H),4. 11(s,1H),2.69(d,J=12.0Hz,5H),2.59(s,3H),2.43(s,3H),2.34(s,3H),1.80(s,2H),1.34(d,J=10.0Hz,4H),1.10(s,1H).

[0059] (5) Synthesis of N-(5-(5-(4-(2-bromoethyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide

[0060] 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-nitro-5-((5-(piperazin-1-yl)pentyl)oxy)furan-2-yl)benzamide (1 g, 1.91 mmol) was added to 10 mL of DMF. 1,2-dibromoethane (0.4 g, 1.9 mmol) and cesium carbonate (0.6 g, 1.9 mmol) were added sequentially and allowed to react at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was collected and the solvent removed under reduced pressure to yield N-(5-(5-(4-(2-bromoethyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide as a white solid. TLC revealed a single spot, a dark spot at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.53(s,3H),7.71(s,3H),7.63(s,3H),7.15(s,3H),6.77(s,3H),6.02(s,3H),5.16(s,6H),4.11( s,3H),3.58(s,3H),2.89(s,3H),2.70(s,4H),2.59(s,9H),2.43(s,9H),2.29(s,24H),1.80(s,5H),1.34(d,J=10.0Hz,12H).

[0061] (6) Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 5)

[0062] N-(5-(5-(4-(2-bromoethyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)-3-((3,5-dimethylisoxazol-4-yl)methoxy)benzamide (1 g, 1.58 mmol) was added to 10 mL of DMF, and 2-(2,6-dioxopiperidin-3-yl)-3-hydroxyisoindoline-1,3-dione (0.4 g, 1.58 mmol) and cesium carbonate (0.5 g, 1.58 mmol) were added in sequence. The mixture was reacted at room temperature overnight. After quenching with water, the mixture was extracted with ethyl acetate, and the organic phase was collected. The solvent was removed under reduced pressure to obtain 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 5) as a white solid. TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.55(s,29H),8.49(s,29H),7.96(s,15H),7.71(s,29H),7.63(s, 30H),7.53(s,29H),7.21(d,J=55.0Hz,60H),6.77(s,29H),6.02(s,29H),5.16(d,J=0.5Hz,73 H),4.11(s,44H),4.07(s,45H),2.82(s,14H),2.70(s,62H),2.68–2.51(m,205H),2.54(d,J= 9.0Hz, 3H), 2.43 (s, 87H), 2.31 (d, J = 17.8Hz, 254H), 1.80 (s, 52H), 1.34 (d, J = 10.0Hz, 117H).

[0063] Example 6

[0064] Synthesis of 4-(2-(2-(3,5-dimethylisoxazole-4-methoxy)phenyl)-2-oxoethyl)-4-nitrofuran-2-oxy)pentyl)piperazine-1-ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Example 6):

[0065] Referring to the synthesis method of Example 5, the 2-(2,6-dioxopiperidin-3-yl)-3-hydroxyisoindoline-1,3-dione in Example 5 was replaced with 3-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain an off-white solid, namely 4-(2-(2-(3,5-dimethylisoxazole-4-methoxy)phenyl)-2-oxoethyl)-4-nitrofuran-2-oxy)pentyl)piperazine-1-ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Example 6). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ8.52(s,13H),7.66(d,J=15.0Hz,27H),7.59(s,8H),7.40(s,13H),7.25(s, 14H),7.04(d,J=55.0Hz,27H),6.23(s,13H),5.46(s,13H),5.14(d,J=16.0Hz,36H),4.38(s,26H),4.1 1(s,20H),3.45(s,15H),2.84(s,6H),2.70(s,19H),2.66(s,17H),2.60(d,J=12.6Hz,52H),2.50(s,16 H), 2.43 (s, 39H), 2.31 (d, J = 22.1Hz, 116H), 2.27–1.93 (m, 3H), 1.80 (s, 27H), 1.34 (d, J = 10.0Hz, 48H).

[0066] Example 7

[0067] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)-2-propylpiperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 7)

[0068] Referring to the synthesis method of Example 5, the piperazine in Example 5 was replaced with 2-propylpiperazine to obtain an off-white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)-2-propylpiperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 7). TLC detection showed one spot, a dark spot under ultraviolet light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.55(s,4H),8.48(s,4H),7.95(s,2H),7.70(s,4H),7.62(s, 4H),7.52(s,4H),7.20(d,J=54.9Hz,8H),6.76(s,4H),6.01(s,4H),5.15(d,J=1.0Hz,10H ),4.08(d,J=20.0Hz,12H),2.84–2.57(m,50H),2.43(s,16H),2.32(s,4H),2.22(d,J=1. 0Hz, 5H), 1.80 (s, 3H), 1.51 (s, 5H), 1.35 (d, J = 26.3Hz, 15H), 1.30 (s, 6H), 0.89 (s, 12H).

[0069] Example 8

[0070] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethyl)-2-propylpiperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 8):

[0071] Referring to the synthesis of Example 7, the 2-(2,6-dioxopiperidin-3-yl)-3-hydroxyisoindoline-1,3-dione in Example 7 was replaced with 3-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain an off-white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-ylamino)ethyl)-2-propylpiperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 8). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.56(s,3H),8.50(s,3H),7.71(s,3H),7.63(s,3H),7.59(s,2H),7.20(d ,J=50.0Hz,6H),6.98(s,3H),6.77(s,3H),6.02(s,3H),5.14(d,J=15.0Hz,8H),4.92(s,3H),4.11(s, 3H),3.45(s,3H),2.83(s,2H),2.78–2.71(m,8H),2.71–2.57(m,27H),2.43(s,12H),2.35–2.10(m,8 H),2.20–2.10(m,1H),1.80(s,2H),1.52(s,4H),1.38(s,4H),1.32(d,J=12.1Hz,10H),0.89(s,9H).

[0072] Example 9

[0073] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)-2-(2-methylbutyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 9):

[0074] Referring to the synthesis of Example 5, the piperazine in Example 5 was replaced with 2-(2-methylbutyl)piperazine to obtain an off-white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethyl)-2-(2-methylbutyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 9). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1H NMR(500MHz,Chloroform)δ9.45(s,2H),8.49(s,2H),7.96(s,1H),7.71(s,2H),7.63(s,2H),7.53(s, 2H),7.20(d,J=55.0Hz,4H),6.77(s,2H),6.07(s,2H),5.16(d,J=3.8Hz,5H),4.09(d,J=20.0Hz,6H), 2.84–2.78(m,5H),2.78–2.57(m,21H),2.41(d,J=16.1Hz,11H),2.31(d,J=16.9Hz,4H),1.89(s,2H), 1.80(s,2H),1.60(s,2H),1.55(d,J=2.5Hz,7H),1.33(s,2H),1.16(s,2H),0.93(s,6H),0.86(s,6H).

[0075] Example 10

[0076] Synthesis of 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-(2-methylbutyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 10):

[0077] Referring to the synthesis of Example 9, the 2-(2,6-dioxopiperidin-3-yl)-3-hydroxyisoindoline-1,3-dione in Example 9 was replaced with 3-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to obtain a white solid, namely 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)ethyl)-2-(2-methylbutyl)piperazin-1-yl)pentyl)oxy)-3-nitrofuran-2-yl)benzamide (Example 10). TLC detection showed one spot, a dark spot under UV light at 254 nm, and no fluorescence at 365 nm. 1HNMR(500MHz,Chloroform)δ9.64(s,7H),8.50(s,7H),7.71(s,7H),7.63(s,7H),7.59(s,4H),7.25(s,6H),7.15( s,8H),6.98(s,7H),6.77(s,7H),6.05(s,7H),5.14(d,J=15.0Hz,19H),4.92(s,7H),4.11(s,7H),3.45(s,7H),2. 95(s,5H),2.84(s,3H),2.75(d,J=15.0Hz,13H),2.71–2.57(m,63H),2.47(s,6H),2.43(s,30H),2.34(d,J=15.5H z,17H),2.11(s,8H),1.80(s,14H),1.63–1.48(m,32H),1.33(s,9H),1.04(s,11H),0.93(s,11H),0.86(s,26H).

[0078] The structural formulas of the compounds synthesized in Examples 1-11 are shown in the following table:

[0079]

[0080]

[0081]

[0082] The following are the pharmacodynamic tests and results of the compounds of the present invention:

[0083] In vitro cytotoxicity assay:

[0084] Drugs and reagents: Test compounds, DMEM medium (01-050-1A), FBS fetal bovine serum (04-001-1A) were purchased from Biological Industries, and MTT thiazolyl blue reagent (KGT525500) was purchased from Keygene Biotechnology.

[0085] Instrument: THERMO Varioskan Flash full wavelength multifunctional microplate reader.

[0086] Experimental method: About 10,000 cells (PANC-1, SMMC-7721 or HepG2) were evenly mixed in 0.1 mL of DMEM medium containing 10% FBS and plated on the bottom plate of a 96-well plate. Incubate overnight at 37°C in an environment containing 5% CO2. Compounds diluted in 0.1 mL of DMEM medium at concentrations of 2.5 μM, 5 μM, 10 μM, 20 μM, 50 μM and 100 μM were treated on the cells for 24 hours. MTT reagent was then added to the well plate, and the plate was incubated at 37°C for 3 hours. The color reaction was measured at 492 nm using a spectrophotometer (Thermo, multiskan FC). The corresponding cell survival rate (SR%) of the test compound was calculated, and the IC 50 The values ​​are shown in the following table:

[0087]

[0088] As can be seen from the above table, the compounds of the present invention exhibit strong killing effects on various cancer cells and can be further developed as candidate molecules for anti-tumor drugs.

Claims

1. A compound as shown in Formula I or Formula II or a pharmaceutically acceptable salt thereof, ； in, n is 1, 2 or 3; X is N or O; and R is a C1-C7 alkyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from one of the following compounds: 。 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salt is hydrochloride, maleate or citrate.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating cancer.

5. The use according to claim 4, characterized in that The drug further includes a pharmaceutically acceptable carrier.

6. A pharmaceutical composition, characterized in that The compound according to claim 1 or a pharmaceutically acceptable salt thereof is used as an effective active ingredient.

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