Preparation of novel STAT3 inhibitor and application of novel STAT3 inhibitor in treatment of STAT3-mediated diseases

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a furo-quinoline diketone compound and medical application thereof. Specifically, the invention relates to a compound as shown in a formula (I), a prodrug, a stereoisomer or pharmaceutically acceptable salt, a hydrate or a crystal form thereof, a pharmaceutical composition thereof, a preparation method thereof and medical application thereof.

Description

Technical Field

[0001] This invention relates to the use of a class of STAT3 inhibitors or their pharmaceutically acceptable salts, hydrates or crystal forms in antitumor and anti-inflammatory applications, and belongs to the field of chemical medicine. Background Technology

[0002] The signal transducer and activator of transcription (STAT) family is a group of transcription factors located in the cytoplasm that play crucial roles in the reception and transmission of extracellular signals and the regulation of gene expression. STAT family members, including STAT1, STAT2, STAT3, STAT4, STAT5α, STAT5β, and STAT6, share high homology and can activate the transcription of specific genes in response to extracellular signals. Among these members, STAT3 is particularly critical, participating in the regulation of key biological processes such as the cell cycle, cell survival, and immune responses. In normal cells, STAT3 activation is tightly regulated, but when cytokines or growth factors bind to their receptors, STAT3 is activated, transmitting signals into the nucleus to regulate the expression of related genes. However, in various human cancers, persistent STAT3 activation is closely associated with tumor development and poor prognosis. It promotes tumor cell growth and survival by controlling cell cycle progression and inhibiting apoptosis. Furthermore, STAT3 is also involved in the development of various autoimmune and inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, atherosclerosis, and inflammatory bowel disease. Given the crucial role of STAT3 in these diseases, developing STAT3 inhibitors to block its signaling and transcriptional activation functions has become an important direction in drug research. These inhibitors hold promise as novel therapies for treating related diseases, improving patient outcomes and quality of life.

[0003] Currently discovered inhibitors directly target the STAT3 protein itself, such as C188-9. These inhibitors have shown some anti-tumor effects in in vitro and in vivo experiments. However, despite their therapeutic efficacy, these compounds still face challenges in clinical application. First, some inhibitors have poor water solubility and cell permeability, limiting their bioavailability. Second, selectivity is also an important consideration, as a lack of selectivity may affect other non-target proteins, leading to side effects. Furthermore, some inhibitors may produce significant toxic side effects at high doses, impacting patient experience and treatment outcomes. Finally, long-term use of certain inhibitors may lead to drug resistance in tumor cells, reducing treatment efficacy. Therefore, developing more effective, safer, and more specific STAT3-targeting compounds remains an important research direction.

[0004] This invention aims to provide a novel class of STAT3 inhibitors, their preparation methods, and their application in the preparation of drugs for treating STAT3-mediated diseases. The STAT3 inhibitors provided by this invention exhibit high inhibitory activity against HCT116 cells and hold promise as novel drugs for treating STAT3-mediated diseases. Summary of the Invention

[0005] In order to discover anti-tumor drugs and therapeutics for inflammatory bowel disease targeting STAT3, the inventors conducted extensive research and creative work, developing a new type of STAT3 inhibitor with a novel scaffold, as well as its preparation method and applications.

[0006] Specifically, the technical solution and content of the present invention involve the following three aspects.

[0007] On one hand, the present invention relates to a class of compounds with structures characterized by said compounds being those of Formula I, their prodrugs, stereoisomers, or pharmaceutically acceptable salts:

[0008]

[0009] Where X is N, O, or S;

[0010] Ring A is a 5- or 6-membered aromatic ring containing 0 to 3 O, S, and N heteroatoms as constituent atoms. Preferably, R1 is a cyano, substituted, or unsubstituted carbonyl amino group;

[0011] R2 is hydrogen or alkyl;

[0012] R3 is hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, aryl, and heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkoxy, aryl, and heteroaryl are unsubstituted or substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, and cyano.

[0013] Preferably, ring A is a benzene ring, X is an O atom, and R2 is a hydrogen atom.

[0014] Preferably, the compound has the structure shown in Formula II:

[0015]

[0016] Wherein, R4 is a substituted or unsubstituted methylamino group, a substituted or unsubstituted diethylamino group, a substituted or unsubstituted isopropylamino group, a substituted or unsubstituted isopropanolamino group, a substituted or unsubstituted diethanolamino group, a substituted or unsubstituted isobutylamino group, a substituted or unsubstituted cyclopentanamino group, a substituted or unsubstituted cyclohexylamino group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted piperazine group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted pyridinyl group, a substituted or unsubstituted ethanolamino group, a substituted or unsubstituted tetrahydropyrroleyl group, a substituted or unsubstituted tetrahydrofuranyl group, a substituted or unsubstituted furanyl group, or a substituted or unsubstituted thiopheneyl group. Preferably, it has Any of the structures shown:

[0017]

[0018] The present invention also provides the use of the above-mentioned compounds in the treatment of STAT3-mediated inflammatory diseases and tumor-related diseases.

[0019] Preferably, the inflammatory disease is inflammatory bowel disease, etc., and the tumor includes one or more of colorectal cancer, lung cancer, melanoma, breast cancer, prostate cancer, kidney cancer, ovarian cancer, liver cancer, pancreatic cancer, multiple myeloma, and leukemia.

[0020] Secondly, the method for preparing the compound described in this invention includes the following synthetic route:

[0021]

[0022] Reagents and conditions: (a) iodophenyl diacetic acid, chloroform; (b) propargyl alcohol, cuprous oxide, 80°C; (c) PCC, dichloromethane; (d) piperidine, ethanol.

[0023] Thirdly, the technical solution and content of this invention relate to the use of the compound of Formula I for anti-tumor drugs and the treatment of inflammatory diseases. The compound of Formula I can be used as a STAT3 inhibitor, achieving inhibition of STAT3-related signaling pathways, thereby affecting cell proliferation, apoptosis, etc. This enriches the variety of STAT3 inhibitors and provides new compounds for the treatment of STAT3-related tumors and inflammatory bowel diseases. Attached Figure Description

[0024] Figure 1 The preferred compounds of this invention exhibit in vivo antitumor activity. Detailed Implementation

[0025] Example 1. Phenyl(1,3,4-trioxo-1,2,3,4-tetrahydronaphtho[2,3-b]furan-2-yl)iodonium (2)

[0026]

[0027] A solution of 2-hydroxy-1,4-naphthoquinone (3) (5 g, 28.7 mmol) was added to CHCl3 (60 mL), followed by the addition of iodine diacetate (15 g, 46.6 mmol) at room temperature. The reaction mixture was stirred at this temperature for 6 hours, filtered to obtain an orange precipitate, washed three times with CHCl3, and dried to give an orange solid compound 2 (9.8 g, 91.0%).

[0028] Example 2.2-(hydroxymethyl)naphtho[2,3-b]furan-4,9-dione (3)

[0029]

[0030] At room temperature, 5.0 g (13.3 mmol) of compound 2 was added to 60 mL of pyridine and stirred. Then, 5.0 g of cuprous oxide was added, and the reaction mixture was heated to 80 °C and stirred for 2.5 hours. Then, 10 mL of propynyl alcohol was slowly added. After cooling to room temperature and filtering, the mixture was diluted with 400 mL of 10% HCl aqueous solution. The acidic solution was then extracted three times with 50 mL of ethyl acetate. The organic layer was washed with copper sulfate and dried over anhydrous Na₂SO₄, then concentrated under reduced pressure. Finally, column chromatography gave compound 3 (540 mg, 15.6%) as an orange solid.

[0031] Example 3.4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-carboxaldehyde (4)

[0032]

[0033] 60 mL of chloroform was added to 2-hydroxy-1,4-naphthoquinone (3) (5 g, 28.7 mmol), followed by the addition of iodine diacetate (15 g, 46.6 mmol). The reaction mixture was stirred at room temperature for 6 hours, then filtered and washed three times with chloroform, and dried to give compound 4 as an orange solid (9.8 g, 91.0%). 1 H NMR (400MHz, DMSO-d6) δ9.90 (d, J = 0.8 Hz, 1H), 8.15 (dtt, J = 7.5, 4.6, 2.3 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.97–7.89 (m, 2H).

[0034] Example 4. Formic acid (E)-4-(2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamido)butyl ester (NW1)

[0035]

[0036] 0.42 mmol of 4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-carboxaldehyde (4) was added to 5 mL of ethanol solution, followed by a catalytic amount of piperidine and 0.62 mmol of a cyano compound. The reaction was carried out overnight at room temperature, and the mixture was then filtered and washed three times with 10 mL of ethanol to give a yellow solid compound NW1 in 48.5% yield. 1 H NMR (400MHz, DMSO-d6) δ8.62(t,J=5.7Hz,1H),8.18(s,1H),8.16–8.07(m,2H),7.97–7.86(m,2H ),7.78(s,1H),3.61(s,3H),3.26(q,J=6.6Hz,2H),2.38(t,J=7.4Hz,2H),1.78(p,J=7.2Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ180.02,173.54,173.42,160.34,153.88,153.06,135.46,135.01,134.91,1 33.16,133.05,131.04,127.13,126.99,116.39,115.65,107.86,51.78,51.75,39.68,31.11,24.53.

[0037] Example 5. (E)-2-cyano-N-(2-acetamidoethyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW2)

[0038]

[0039] The synthetic route and operation steps of compound NW2 are the same as those for the preparation of NW1, and a yellow solid is finally obtained with a yield of 58.6%. 1 HNMR(400MHz,DMSO-d6)δ8.64(t,J=5.6Hz,1H),8.20(s,1H),8.18–8.10(m,2H),7.9 7(t,J=5.8Hz,1H),7.94–7.87(m,2H),7.81(s,1H),3.30–3.17(m,4H),1.81(s,3H). 13C NMR(101MHz,DMSO-d6)δ180.09,173.50,169.98,160.46,153.99,153.01,135.58,135.04 ,134.94,133.21,133.11,131.07,127.15,127.02,116.51,115.65,107.82,38.33,23.13.

[0040] Example 6. (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-N-phenylacrylamide (NW3)

[0041]

[0042] The synthetic route and procedures for compound NW3 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 64.7%. 1 HNMR(400MHz,DMSO-d6)δ10.49(s,1H),8.33(s,1H),8.18–8.11(m,2H),7.96–7.89(m,2H ),7.82(s,1H),7.69(ddd,J=8.6,2.3,1.1Hz,2H),7.43–7.35(m,2H),7.20–7.13(m,1H). 13 CNMR(101MHz,DMSO)δ180.01,173.49,154.14,152.75,151.66,148.70,139.00,136.26,1 35.04,134.95,133.21,133.11,131.05,127.15,127.03,121.04,116.72,115.57,114.98.

[0043] Example 7. (E)-N-(1-benzylpiperidin-4-yl)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW4)

[0044]

[0045] The synthetic route and procedures for compound NW4 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 51.1%. 1HNMR(400MHz, DMSO-d6)δ8.46(d,J=7.6Hz,1H),8.18–8.08(m,3H),7.91(dd,J=6.2,3.0Hz,2H),7.77(s,1H),7.36–7.22(m,5H),3.76–3. 62(m,1H),3.48(s,2H),2.83(dd,J=9.6,5.6Hz,2H),2.03(t,J=11.6Hz,2H),1.77(dd,J=12.8,4.0Hz,2H),1.61(qd,J=11.8,3.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.02,173.42,159.94,153.85,153.03,135.24,135.01,134.92,133.16,133.0 5,131.03,129.24,128.65,127.38,127.13,126.99,115.99,115.68,108.42,62.46,52.46,48.33,31.42.

[0046] Example 8. (E)-2-cyano-N-(4-cyanophenyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW5)

[0047]

[0048] The synthetic route and procedures for compound NW5 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 42.3%. 1 HNMR (400MHz, DMSO-d6) δ10.88(s,1H),8.37(s,1H),8.15(ddt,J=6.4,4.2,2.6Hz,2H),7.97–7.82(m,7H). 13 C NMR(101MHz,DMSO-d6)δ180.01,173.52,160.42,154.24,152.68,142.81,136.58,135.07,134.99, 133.75,133.22,133.11,131.04,127.18,127.04,121.11,119.32,116.82,115.40,108.27,106.85.

[0049] Example 9. (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-N-(propyl)acrylamide (NW6)

[0050]

[0051] The synthetic route and procedures for compound NW6 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 65.2%. 1 HNMR (400MHz, DMSO-d6) δ8.20(s,1H),8.18–8.07(m,2H),8.05(s,1H),7.95(m,1H),7.93–7.85(m,2H),7.78(s,1H). 13 C NMR (101MHz, DMSO-d6) δ180.02,173.43,161.93,153.89,153.02,135.63,135. 02,134.93,133.16,133.05,131.03,127.13,127.00,116.19,115.83,108.30.

[0052] Example 10. (E)-2-cyano-N-(4-methoxyphenyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW7)

[0053]

[0054] The synthetic route and procedures for compound NW7 are the same as those for NW1, ultimately yielding a red solid with a yield of 53.8%. 1 HNMR(400MHz,DMSO-d6)δ10.37(s,1H),8.30(s,1H),8.16(d,J=7.2Hz,2H),7.96–7 .90(m,2H),7.82(s,1H),7.60(d,J=8.6Hz,2H),6.96(d,J=8.5Hz,2H),3.76(s,3H). 13 C NMR(101MHz,DMSO-d6)δ180.09,173.51,159.30,156.69,154.04,152.96,135.64,135.05,134.96, 133.24,133.13,131.82,130.31,127.17,127.03,122.84,116.27,115.67,114.40,108.80,55.70.

[0055] Example 11. (E)-N-(2-(1H-indol-3-yl)ethyl)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW8)

[0056]

[0057] The synthetic route and procedures for compound NW8 are the same as those for NW1, ultimately yielding a red solid with a yield of 38.3%. 1 HNMR (400MHz, DMSO-d6) δ10.89–10.75 (m, 1H), 8.32 (d, J = 1.4Hz, 1H), 8.14–8. 05(m,2H),7.92–7.83(m,2H),7.58(d,J=7.8Hz,1H),7.41(s,1H),7.34(d,J=8. 1Hz,1H),7.17(d,J=2.3Hz,1H),7.06(ddd,J=8.1,6.9,1.2Hz,1H),6.98(ddd,J =8.0,7.0,1.1Hz,1H),3.95(td,J=8.4,7.8,1.9Hz,2H),3.09(t,J=7.3Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.37,173.62,156.26,152.77,150.37,136.69,134.82,134.70,133.20,132.84 ,131.04,127.64,127.01,126.86,123.41,121.38,118.89,118.68,112.31,111.83,110.84,62.15,26.84.

[0058] Example 12. (E)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-2-(4-hydroxypiperidine-1-carbonyl)acrylonitrile (NW9)

[0059]

[0060] The synthetic route and procedures for compound NW9 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 25.3%. 1 HNMR(400MHz,DMSO-d6)δ8.19–8.07(m,2H),7.98–7.87(m,2H),7.85(s,1H),7.67(s,1H) ,4.85(d,J=3.9Hz,1H),3.95–3.75(m,3H),3.30(s,2H),1.85–1.75(m,2H),1.44(s,2H). 13CNMR(101MHz,DMSO-d6)δ180.12,173.40,161.15,153.58,153.27,135.03,134.91,134.7 8,133.19,133.07,131.05,127.13,127.02,115.67,115.29,108.21,65.45,65.34,34.22.

[0061] Example 13. (E)-2-cyano-N-(2-morpholinoethyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW10)

[0062]

[0063] The synthetic route and procedures for compound NW10 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 29.4%. 1 H NMR (400MHz, DMSO-d6) δ8.50(t,J=5.7Hz,1H),8.20(s,1H),8.14(ddt,J=8.1,6.5,3.9Hz,2H),7 .98–7.87(m,2H),7.81(s,1H),3.58(t,J=4.6Hz,4H),3.41–3.32(m,4H),2.44(d,J=4.7Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ180.07,173.48,160.11,153.97,153.02,135.59,135.04,134.94,13 3.19,133.10,131.06,127.15,127.02,116.69,115.72,107.60,66.64,57.19,53.62,37.51.

[0064] Example 14. (E)-2-cyano-N-(3-phenylpropyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW11)

[0065]

[0066] The synthetic route and operation steps of compound NW11 are the same as those for the preparation of NW1, and a yellow solid is finally obtained with a yield of 58.0%. 1H NMR (400MHz, DMSO-d6) δ8.63(t,J=5.6Hz,1H),8.17(s,1H),8.13(ddt,J=6.8,4.2,2.6Hz,2H),7.96–7.86(m,2H),7.78(s,1H),7. 29(t,J=7.4Hz,2H),7.27–7.21(m,2H),7.18(td,J=6.9,1.6Hz,1H),3.31–3.17(m,2H),2.63(t,J=7.6Hz,2H),1.91–1.77(m,2H). 13 C NMR(101MHz,DMSO-d6)δ180.02,173.42,160.24,153.86,153.08,142.04,135.38,135.01,134.91,13 3.16,133.06,131.04,128.77,127.13,126.99,126.25,116.30,115.68,107.98,40.07,32.96,30.85.

[0067] Example 15. (E)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-2-(octahydro-1H-isoindole-2-carbonyl)acrylonitrile (NW12)

[0068]

[0069] The synthetic route and procedures for compound NW12 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 26.8%. 1 H NMR (400MHz, DMSO-d6) δ8.19–8.08(m,2H),8.03(s,1H),7.97–7.87(m,2H),7.72( s,1H),3.72(dd,J=10.1,6.8Hz,1H),3.58(dd,J=10.2,6.2Hz,1H),3.46(dd,J=12 .2,6.9Hz,1H),3.33(dd,J=12.3,5.6Hz,2H),2.26(dp,J=18.0,5.9Hz,2H),1.62– 1.57(m,1H),1.57–1.49(m,2H),1.49–1.44(m,1H),1.37(dt,J=21.7,9.2Hz,3H). 13C NMR (101MHz, DMSO) δ180.09,173.42,160.81,153.71,153.25,135.79,135.03,134.91,133.19,133.0 8,131.04,127.13,127.02,115.75,108.47,52.21,51.37,37.73,35.52,25.68,25.32,22.78,22.53.

[0070] Example 16. (E)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)acrylonitrile (NW13)

[0071]

[0072] The synthetic route and procedures for compound NW13 are the same as those for NW1, and a yellow solid is finally obtained with a yield of 49.5%. 1 H NMR (400MHz, DMSO-d6) δ8.19–8.08(m,2H),7.97–7.88(m,3H),7.69(s,1H),7.21(d,J=2.8Hz,4H),4.73(s,2H),3.84(s,2H),2.95(s,2H). 13 CNMR(101MHz,DMSO-d6)δ180.08,173.40,153.63,153.29,135.36,135.03,134.92,134.65,133 .17,133.06,132.93,131.05,129.03,127.18,127.13,127.03,126.78,115.67,115.59,107.98.

[0073] Example 17. (E)-2-cyano-N-(2-(thiophen-2-yl)ethyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW14)

[0074]

[0075] The synthetic route and procedures for compound NW14 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 43.2%. 1H NMR (400MHz, DMSO-d6) δ8.73(t,J=5.6Hz,1H),8.18(s,1H),8.18–8.07(m,2H),7.96–7.86(m,2H),7.80(s,1H),7.36(dd,J=5 .2,1.2Hz,1H),6.97(dd,J=5.2,3.6Hz,1H),6.93(dd,J=3.6,1.2Hz,1H),3.48(td,J=7.2,5.6Hz,2H),3.07(t,J=7.2Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.00,173.42,160.16,153.92,152.99,141.54,135.65,135.02,134.92,133 .15,133.05,131.04,127.47,127.13,127.00,125.80,124.70,116.63,115.59,107.61,42.01,29.29.

[0076] Example 18. (E)-2-cyano-N-(3-trifluoromethylbenzyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW15)

[0077]

[0078] The synthetic route and procedures for compound NW15 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 51.8%. 1 H NMR (400MHz, DMSO-d6) δ9.24(t,J=6.0Hz,1H),8.24(s,1H),8.13(td,J=7.0,3.6Hz,2H),7.92(h,J=6.4,4 .4Hz,2H),7.80(s,1H),7.71(s,1H),7.65(t,J=7.6Hz,2H),7.61(t,J=7.6Hz,1H),4.53(d,J=6.0Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.00,173.43,160.56,153.97,153.01,140.60,136.00,135.01,134.92,133.16,133 .06,132.20,131.03,129.92,127.13,127.00,124.67,124.63,124.30,124.26,116.81,115.63,107.36,43.50.

[0079] Example 19. (E)-2-cyano-N-(2-hydroxyethyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW16)

[0080]

[0081] The synthetic route and procedures for compound NW16 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 58.8%. 1 H NMR(400MHz,DMSO-d6)δ8.50(t,J=5.6Hz,1H),8.19(s,1H),8.18–8.06(m,2H),7.97–7.85 (m,2H),7.79(s,1H),4.79(t,J=5.6Hz,1H),3.51(q,J=6.0Hz,2H),3.31(q,J=6.0Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.02,173.42,160.34,153.89,153.04,135.46,135.01,134 .92,133.15,133.05,131.04,127.13,127.00,116.43,115.70,107.85,59.69,43.18.

[0082] Example 20. (E)-2-cyano-N-(4-hydroxyphenylethyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW17)

[0083]

[0084] The synthetic route and operation steps of compound NW17 are the same as those for the preparation of NW1, and an orange solid is finally obtained with a yield of 45.6%. 1 H NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 8.61 (t, J = 5.6Hz, 1H), 8.14 (s, 1H), 8.14–8.05 (m, 2H), 7.95–7.8 4(m,2H),7.77(s,1H),7.07–6.99(m,2H),6.74–6.64(m,2H),3.43–3.36(m,2H),2.72(t,J=6.4Hz,2H). 13C NMR(101MHz,DMSO-d6)δ179.95,173.35,159.98,156.20,153.81,153.05,135.42,134.99,134.90,13 3.10,133.00,131.02,129.98,129.56,127.12,126.98,116.39,115.63,107.81,42.29,34.42,19.02.

[0085] Example 21. (E)-2-cyano-N-(2-pyridin-2-yl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW18)

[0086]

[0087] The synthetic route and procedures for compound NW18 are the same as those for NW1, and a yellow solid is finally obtained with a yield of 35.5%. 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.45–8.37(m,2H),8.20–8.08(m,2H),8.05( d,J=8.4Hz,1H),7.98–7.84(m,3H),7.81(s,1H),7.22(ddd,J=7.4,4.9,1.0Hz,1H). 13 CNMR(101MHz,DMSO)δ180.04,173.49,159.74,154.06,152.89,138.47,135.88,135.05,134.96,1 33.21,133.10,131.07,129.29,127.16,127.03,125.11,121.16,121.05,116.32,115.61,108.80.

[0088] Example 22. (E)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)-2-(octahydrocyclopentenyrrole-2-carbonyl)acrylonitrile (NW19)

[0089]

[0090] The synthetic route and procedures for compound NW19 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 27.7%. 1H NMR (400MHz, DMSO) δ8.19–8.08(m,2H),8.03(s,1H),7.97–7.87(m,2H),7.72(s, 1H), 3.72 (dd, J=10.1, 6.8Hz, 1H), 3.58 (dd, J=10.2, 6.2Hz, 1H), 3.46 (dd, J=12. 2,6.9Hz,1H),3.33(dd,J=12.3,5.6Hz,2H),2.26(dp,J=18.0,5.9Hz,2H),1.62– 1.57(m,1H),1.57–1.49(m,2H),1.49–1.44(m,1H),1.37(dt,J=21.7,9.2Hz,3H). 13 C NMR (101MHz, DMSO) δ180.10,173.42,161.25,159.96,153.23,135.65,134.97,134.92,133.09 ,132.51,131.04,127.02,126.96,115.70,108.57,51.92,43.17,41.63,32.21,31.64,25.50.

[0091] Example 23. (E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW20)

[0092]

[0093] The synthetic route and procedures for compound NW20 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 38.1%. 1 H NMR (400MHz, DMSO-d6) δ8.56(t,J=5.6Hz,1H),8.17(s,1H),8.17–8.06(m,2H),7.96–7.85(m,2H),7. 78(s,1H),4.55(t,J=5.1Hz,1H),3.48(q,J=5.9Hz,2H),3.30(q,J=6.6Hz,2H),1.68(p,J=6.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ180.00,173.40,160.11,153.85,153.07,135.36,135.01,134.91 ,133.13,133.03,131.03,127.12,126.99,116.40,115.68,107.87,59.10,38.04,32.31.

[0094] Example 24. (R,E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW21)

[0095]

[0096] The synthetic route and procedures for compound NW21 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 40.9%. 1 H NMR (400MHz, DMSO-d6) δ8.38(t,J=5.6Hz,1H),8.19(s,1H),8.17–8.05(m,2H),7.96–7.85(m,2H),7.77(s,1H),4.91(d, J=5.0Hz,1H),4.65(t,J=5.6Hz,1H),3.66(dt,J=6.8,5.0Hz,1H),3.44–3.36(m,3H),3.19(ddd,J=13.2,7.2,5.6Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ179.96,173.36,160.34,153.83,153.06,135.39,135.00,134.91 ,133.10,133.00,131.02,127.12,126.98,116.35,115.73,107.87,70.19,64.43,44.10.

[0097] Example 25. (S,E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)acrylamide (NW22)

[0098]

[0099] The synthetic route and procedures for compound NW22 are the same as those for NW1, ultimately yielding a yellow solid with a yield of 43.6%. 1H NMR (400MHz, DMSO-d6) δ8.38(t,J=5.7Hz,1H),8.19(s,1H),8.17–8.05(m,2H),7.96–7.85(m,2H),7.77(s,1H),4.91(d, J=5.0Hz,1H),4.66(t,J=5.6Hz,1H),3.66(dt,J=7.0,5.0Hz,1H),3.46–3.36(m,3H),3.19(ddd,J=13.2,7.2,5.6Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ179.96,173.36,160.34,153.82,153.05,135.39,135.00,134.91 ,133.10,132.99,131.02,127.12,126.98,116.35,115.73,107.87,70.19,64.43,44.10.

[0100] Example 26.2 - ((4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)methylene)malonium (NW23)

[0101]

[0102] The synthetic route and procedures for compound NW23 were the same as those for NW1, ultimately yielding a brown solid with a yield of 59.1%. 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.14 (ddt, J = 8.0, 6.7, 3.9Hz, 2H), 7.98–7.86 (m, 2H), 7.81 (s, 1H). 13 C NMR(101MHz,DMSO-d6)δ179.69,173.57,154.96,151.72,145.01,135.13, 133.18,133.14,130.78,127.22,127.10,119.55,114.11,112.90,82.86.

[0103] Example 27. In vitro antitumor proliferation experiment of the compound

[0104] The purpose of this experiment was to detect the inhibitory activity of the invented compound on the proliferation of tumor cells in vitro using CCK-8 assay. Main reagents: RPMI-1640, DMED high-glucose medium, fetal bovine serum, trypsin, etc., were purchased from Gibco BRL. For in vitro experiments, the test compound was prepared as a 10mM stock solution with DMSO and stored at -20°C protected from light. Before use, it was diluted to the required concentration with complete culture medium. Experimental method: When cells showed good growth during culture, they were digested, centrifuged, and collected. The previous culture medium was discarded, and the cells were resuspended in fresh culture medium. Cell counts were then performed. The cell plating concentration was determined based on the different cell growth rates, generally 3000-5000 cells / well. After determining the plating concentration, the cell suspension was diluted to the required concentration with fresh culture medium and then added to 96-well plates at 100 μL per well. 200 μL of PBS was added to the side wells to prevent evaporation of the culture medium. On the second day, drug treatment was performed. First, the compound was diluted into a series of gradients using culture medium. Then, the drug solutions were added to 96-well plates, with three parallel replicates for each gradient. A blank control group and ONC201 cells were included in each plate as a positive control group. After 72 hours of drug treatment, cell growth in the 96-well plates was observed visually. Then, CCK-8 solution was added to each well, and the plates were incubated for 1-2 hours. Finally, absorbance was measured at 450 nm. The inhibition rate at each drug concentration was calculated as: Cell inhibition rate = (OD450 of blank control group - OD450 of experimental group) / OD450 of blank control group × 100%. IC50 analysis was then performed using Graphpad Prism software. 50 The calculations are shown in Table 1.

[0105] Table 1. Inhibitory activity of representative compounds of the present invention against HCT116 colon cancer cells.

[0106]

[0107] As shown in Table 1, most of the NW series compounds provided by this invention have good inhibitory effects on HCT116. Among them, NW16 has the strongest inhibitory activity against HCT116, with an IC50 of 0.28 μM. Moreover, its inhibitory activity against HCT116 is better than that of the positive compound NAP, showing very good development prospects.

[0108] Example 28. In vivo activity evaluation of preferred compound NW16

[0109] The purpose of this embodiment is to detect the in vivo antitumor activity of the invented compound. 3 × 10 6 HCT116 xenograft tumor model was established by injecting suspension cells into the back of BALB / c nude mice and simultaneously suspending the cells in PBS. The tumors were then cultured until the average tumor size reached 100 mm. 3Mice were randomly divided into 5 groups (n=5), including a drug-loaded control group (0.5% sodium carboxymethyl cellulose, 0.5% CMC-Na), NAP (20 mg / kg), NAP (40 mg / kg), NW16 (20 mg / kg), and NW16 (40 mg / kg) groups, starting with oral administration. Tumor volume and mouse weight were measured every 2 days. At the end of the experiment, the mice were euthanized with carbon dioxide. The results showed that oral administration of NW16 (20 and 40 mg / kg) every 2 days, with NAP (20 and 40 mg / kg) as a positive control and CMC-Na as a negative control, for 2 weeks, significantly reduced tumor growth. Tumor growth curve data showed that at doses of 20 and 40 mg / kg, NW16 exhibited tumor growth inhibition rates of 53.31% and 85.23%, respectively. Figure 1 A). Conversely, the positive control NAP showed moderate therapeutic effects, with TGIs of 49.50% and 75.23% at a dose of 40 mg / kg, respectively. Figure 1 A). After weighing the tumor, it was found that even low doses of NW16 had a stronger anti-tumor effect than NAP. Figure 1 B, D). Furthermore, mice treated with NW16 showed no significant change in body weight, and no obvious damage was observed to the spleen or kidneys. Figure 1 C), which indicates that the preferred compound NW16 has extremely high development potential.

[0110] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. This invention provides a novel class of cyanopropylene compounds, characterized in that... The compound is as shown in Formula I. 、 Its prodrug 、 Stereoisomers or pharmaceutically acceptable salts: Where X is N, O, or S; Ring A is a 5- or 6-membered aromatic ring containing 0 to 3 O, S, and N heteroatoms as constituent atoms.

2. The compound of claim 1 、 Its prodrug 、 Stereoisomers or pharmaceutically acceptable salts, where R1 is a cyano, substituted, or unsubstituted carbonyl amino group; R2 is hydrogen or alkyl; R3 can be hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, aryl, or heteroaryl; among which... The C1-C6 alkyl, C1-C6 alkoxy, aryl, and heteroaryl groups are either unsubstituted or substituted by one or more substituents selected from the following: halogen, hydroxyl, amino, and cyano.

3. The compound according to any one of claims 1-2 、 Its prodrug 、 A stereoisomer or a pharmaceutically acceptable salt, preferably in which ring A is a benzene ring and X is an O atom.

4. The compound according to any one of claims 1-3 、 Its prodrug 、 Stereoisomers or pharmaceutically acceptable salts, wherein... R2 is a hydrogen atom.

5. The compound according to any one of claims 1-4 、 Its prodrug 、 A stereoisomer or a pharmaceutically acceptable salt, wherein the compound has the structure shown in Formula II:

6. The compound of claim 5, its prodrug, stereoisomer, or pharmaceutically acceptable salt, wherein, R4 can be a substituted or unsubstituted methylamino group, a substituted or unsubstituted diethylamino group, a substituted or unsubstituted isopropylamino group, a substituted or unsubstituted isopropanolamino group, a substituted or unsubstituted diethanolamino group, a substituted or unsubstituted isobutylamino group, a substituted or unsubstituted cyclopentanamino group, a substituted or unsubstituted cyclohexylamino group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted piperazine group, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted pyridinyl group, a substituted or unsubstituted ethanolamino group, a substituted or unsubstituted tetrahydropyrroleyl group, a substituted or unsubstituted tetrahydrofuranyl group, a substituted or unsubstituted furanyl group, or a substituted or unsubstituted thiophenyl group.

7. The compound, its prodrug, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-6, having Any of the structures shown:

8. Claims Use of any of the compounds, prodrugs, stereoisomers or pharmaceutically acceptable salts in the treatment of STAT3-mediated inflammatory diseases and tumor-related diseases.

9. Claims The compound, its prodrug, stereoisomer, or pharmaceutically acceptable salt thereof is used to treat one or more of STAT3-regulated malignancies, such as colorectal cancer, lung cancer, melanoma, breast cancer, prostate cancer, kidney cancer, ovarian cancer, liver cancer, pancreatic cancer, multiple myeloma, and leukemia.

10. Claims The compound, its prodrug, stereoisomer, or pharmaceutically acceptable salt of any of these substances is used to treat STAT3-regulated inflammatory diseases, such as inflammatory bowel disease (IBD).

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