Novel tri-derivative compounds and their uses

Abstract

The present invention relates to a novel tricyclic derivative compound or a pharma- ceutical acceptable salt thereof and use thereof, which has excellent STAT3 inhibitory activity and has been confirmed to exhibit a superior inhibitory effect to known compounds currently undergoing phase 3 clinical trials, and can be used as a therapeutic agent for STAT3-related diseases.

Description

[Technical Field]

[0001] The present invention relates to novel tricyclic derivative compounds and uses thereof. [Background technology]

[0002] STATs, first discovered as STAT proteins in 1994, are known to play a major role in cytokine and growth factor signaling pathways. The STAT family consists of seven structurally and functionally similar proteins, including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6, which have been shown to regulate cell proliferation, survival, differentiation, angiogenesis, and related gene expression.

[0003] STATs are inactive transcription factors confined to the cytoplasm. The binding of many cytokines, hormones, and growth factors to their receptors activates receptor-associated Janus-activated kinases (JAKs), which can phosphorylate tyrosine residues in the cytoplasmic domain of the receptor, providing docking sites for SRC homology 2 (SH2) domains. Consequently, these STAT proteins are activated by JAKs through phosphorylation of tyrosine residues at their C-termini, inducing homo- or heterodimerization and activation. Finally, these STAT dimers translocate to the nucleus and bind to specific sequences in the promoters of target genes, inducing transcription.

[0004] In particular, the transcriptional regulator STAT3 plays an important role in vertebrate development and mature tissue function, including inflammation and immune regulation. Mutations in human STAT3 have been linked to diseases such as immune deficiency, autoimmunity, and cancer. Surprisingly, however, overactivation or inactivation of STAT3 can induce human disease, indicating that tightly regulated STAT3 function is crucial for health. Abnormal STAT3 function is used to regulate human disease-inducing mechanisms and disease outcomes. In particular, activated STAT3 can downregulate lymphocyte formation, E-cadherin expression by vascular endothelial cells, Treg cell activity, and antiviral immune responses (including type I IFN-mediated signaling, NK cell activity, Th1 cell responses, and CD8+ CTLs). Activated STAT-3 can upregulate lymphopenia, vascular leakage, hyperinflammation and viral persistence, extracellular matrix formation, lasminogen activator inhibitor-1 expression, Th17 cell polarization and activation, pulmonary fibrosis, thrombosis, and M2 macrophage polarization, which promotes hyperinflammation / cytokine storm. Based on the various papers and publications mentioned above, the development of STAT-3 inhibitors will enable the development of effective drugs for the treatment of inflammatory and autoimmune diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel tricyclic derivative compound or a pharmaceutically acceptable salt thereof.

[0006] It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating STAT3-related diseases, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0007] It is still another object of the present invention to provide a health food composition for preventing or ameliorating STAT3-related diseases, which contains the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] It is still another object of the present invention to provide a reagent composition for inhibiting STAT3 activity, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient. [Means for solving the problem]

[0009] To achieve the above object, the present invention provides a tricyclic derivative compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [ka]

[0011] In the above Chemical Formula 1, A1 to A8 may be the same or different and each represent CH or N; L1 and L2 may be the same or different and each represent one of CH2, CO, NH, O, S, SO, SO2, NR2 and CHR2; l and n may be the same or different and each represent 0 or 1; m is 1 or 2; X is one of H, halogen, (C1-C4) alkyl and (C1-C4) alkoxy; and R1 is [ka] wherein E1 to E8 may be the same or different and are CH or N, and R2 may be selected from the group consisting of H, a hydroxy group, an ether group, a halogen atom, a carbonyl group, a nitro group, a naphthyl group, a cyano group, an amino group, an amidino group, a hydrazine, a hydrazone, a carboxyl group, a sulfone group, a phosphate group, a (C1-C12) alkyl, a (C1-C12) alkenyl, a (C1-C12) alkynyl, a (C6-C10) aryl, and a (C7-C10) arylalkyl.

[0012] The present invention also provides a pharmaceutical composition for preventing or treating a STAT3-related disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] The present invention also provides a health food composition for preventing or ameliorating STAT3-related diseases, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0014] The present invention also provides a reagent composition for inhibiting STAT3 transcriptional activity, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient. [Effects of the Invention]

[0015] The present invention relates to a novel tricyclic derivative compound or a pharmaceutically acceptable salt thereof, and uses thereof. The compound has been confirmed to exhibit a more potent inhibitory effect on STAT3 transcription activity than BBI608, which is currently undergoing phase 3 clinical trials. This indicates that the compound has previously unknown superior STAT3 inhibitory activity, and can be used as a therapeutic agent for STAT3-related diseases. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a graph showing the results of an experiment on the STAT3 inhibitory effect of novel tricyclic derivative compounds. DETAILED DESCRIPTION OF THE INVENTION

[0017] Throughout the specification of the present invention, when a part is said to "comprise" a certain component, this does not mean that it may further include other components, unless otherwise specified to the contrary.

[0018] The present invention will now be described in more detail.

[0019] The present invention provides a tricyclic derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0020] [ka]

[0021] In the above Chemical Formula 1, A1 to A8 may be the same or different and each represent CH or N; L1 and L2 may be the same or different and each represent one of CH2, CO, NH, O, S, SO, SO2, NR2 and CHR2; l and n may be the same or different and each represent 0 or 1; m is 1 or 2; X is one of H, halogen, (C1-C4) alkyl and (C1-C4) alkoxy; and R1 is [ka] wherein E1 to E8 may be the same or different and are CH or N, and R2 may be selected from the group consisting of H, a hydroxy group, an ether group, a halogen atom, a carbonyl group, a nitro group, a naphthyl group, a cyano group, an amino group, an amidino group, a hydrazine, a hydrazone, a carboxyl group, a sulfone group, a phosphate group, a (C1-C12) alkyl, a (C1-C12) alkenyl, a (C1-C12) alkynyl, a (C6-C10) aryl, and a (C7-C10) arylalkyl.

[0022] The above-mentioned Chemical Formula 1 may be the following Chemical Formula 1-1. [ka]

[0023] In the above Chemical Formula 1-1, A'1 to A'8 may be the same or different and each represent CH or N; L1 and L2 may be the same or different and each represent one of CH2, CO, NH, O, S, and SO; n is 0 or 1; m is 1 or 2; and X is H or a halogen atom; R1 is [ka] and E1 to E8 may be the same or different and may be CH or N.

[0024] In the above chemical formula 1-1, A'1, A'2, A'4 to A'8 are CH, A'3 is CH or N, L1 and L2 may be the same or different and are any one of CO, NH, O and S, and X may be H or Br.

[0025] The compounds include 3-(isoquinolin-4-yl)-9H-fluoren-9-one, 2-bromo-7-(isoquinolin-4-yl)phenanthrene-9,10-dione, 2-(isoquinolin-4-yl)-9H-xanthen-9-one, 2-(isoquinolin-4-yl)-9H-xanthen-9-one, 2-(isoquinolin-4-yl)-9H-fluoren-9-one, 2-bromo-7-(isoquinolin-4-yl)phenanthrene-9,10-di ... 2-(isoquinolin-4-yl)-9H-thioxanthen-9-one, 2-(pyrido[3,4-b]pyrazin-8-yl)-9H-fluoren-9-one, 2-(quinazolin-4-yl)-9H-fluoren-9-one, 2-(1,6-naphthyridin-8-yl)-9H-fluoren-9-one 2-(1,6-naphthyridin-8-yl)-9H-fluoren-9-one, 2-(1,6-naphthyridin-5-yl)-9H-fluoren-9-one, 2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-fluoren-9-one, 2-(imidazo[1,2-a]pyridin-3-yl)-9H-fluoren-9-one, ]pyridin-3-yl)-9H-fluoren-9-one (2-(imidazo[1,2-a]pyridin-3-yl)-9H-fluoren-9-one), 4-(dibenzo[b,d]thiophen-3-yl)isoquinoline, 4-(dibenzo[b,d]furan-3-yl)isoquinoline, 7-(isoquinolin-4-yl)-5H-pyrido[4,7-(isoquinolin-4-yl)-5H-pyrido[4,3-b]indole, 2-(isoquinolin-4-yl)-9H-fluoren-9-one, 2-(isoquinolin-4-yl)-9H-carbazole, 7-(isoquinolin-4 7-(isoquinolin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole, 2-(isoquinolin-8-yl)-9H-fluoren-9-one, 2-(isoquinolin-5-yl)-9H-fluoren-9-one 2-(imidazo[1,2-a]pyridin-5-yl)-9H-fluoren-9-one, 2-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-9H-fluoren-9-one, 2-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-9H-fluoren-9-one, 2-(isoquinolin-1-yl)-9H-fluoren-9-one, 2-(isoquinolin-1-yl)-9H-fluoren-9-one, and 2-(imidazo[1,2-a]pyridin-8-yl)-9H-fluoren-9-one.

[0026] The above-mentioned Chemical Formula 1 may be the following Chemical Formula 1-2.

[0027] [ka]

[0028] In the above Chemical Formula 1-2, A"1 to A"7 may be the same or different and each represent CH or N; L1 and L2 may be the same or different and each represent one of CH2, CO, NH, O, S, and SO; n is 0 or 1; m is 1 or 2; and X is H or a halogen atom; R1 is [ka] and E1 to E8 may be the same or different and may be CH or N.

[0029] In the above Chemical Formula 1-2, A''1 to A''7 are CH, n is 0, m is 1, L1 is CH2 or NH, and X may be H.

[0030] The compound may be 6-(isoquinolin-4-yl)-1,2,3,4-tetrahydrocyclopenta[b]indole.

[0031] The present invention also provides a pharmaceutical composition for preventing or treating a STAT3-related disease, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0032] The STAT3-related disease may be any one of cancer, osteoporosis, atopy, viral inflammatory disease, diabetic retinopathy, diabetes, hemophilic arthropathy, atherosclerosis, keloid, wound granulation, vascular adhesion, autoimmune disease, restenosis, intestinal adhesion, cat scratch disease, ulcer, liver cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, renal glomerular disease, neurodegenerative disease, and inflammatory disease.

[0033] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, flavoring agents, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0034] Specifically, the carrier, excipient, and diluent may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be prepared by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Oral liquid preparations include suspensions, liquid preparations, emulsions, syrups, etc., which may contain various excipients such as wetting agents, sweeteners, flavorings, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, etc. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, glycerogelatin, etc.

[0035] According to one embodiment of the present invention, the pharmaceutical composition may be administered to a subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes.

[0036] The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and severity of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art, and may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg per day. The dosage may be administered once a day or in divided doses, and the scope of the present invention is not limited by this.

[0037] The present invention also provides a health food composition for preventing or ameliorating STAT3-related diseases, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] The health functional foods may contain various nutrients, vitamins, minerals (electrolytes), flavorings such as synthetic flavorings and natural flavorings, coloring agents and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc.

[0039] In addition, fruit pulp may be included to produce natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. The health functional food composition may also be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, energy drink, alcohol, and vitamin complex.

[0040] In addition, the health functional food may further contain food additives, and whether or not a food additive qualifies as a "food additive" is determined in accordance with the specifications and standards for that item, such as the general provisions and general test methods of the Food Additives Code approved by the Food and Drug Administration, unless otherwise specified.

[0041] Examples of items listed in the "Food Additives Code" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon color, licorice extract, crystalline cellulose, sorghum color, and guar gum; and mixed preparations such as monosodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0042] In this case, the content of the active ingredient added to the food during the process of producing the health functional food may be appropriately adjusted as needed, and preferably, it may be added so that it is contained in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0043] The present invention also provides a reagent composition for inhibiting STAT3 activity, which comprises the compound or a pharmaceutically acceptable salt thereof as an active ingredient. [Embodiment]

[0044] The present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

[0045] [Synthesis example] Synthesis of tricyclic derivative compounds

[0046] The synthesis of all compounds of the present invention was carried out by Suzuki-Miyaura reaction. The synthesis method is as follows.

[0047] [ka]

[0048] The bromide compound (1 eq) and the boronate pinacol ester compound (1 eq) were dissolved in 4:1 DME / H2O and stirred. Then, K2CO3 (3 eq) and Pd(Ph3P)4 (0.2 eq) were added, heated to 80°C, and stirred. After stirring for 3 hours, the reaction was confirmed by TLC, and when the reaction was complete, the temperature was lowered to room temperature. The mixture was extracted with brine and ethyl acetate, and then washed twice more with brine. The extracted ethyl acetate was dried over Na2SO4 and filtered. The filtered solution was dried under reduced pressure and purified through a column to obtain the target compound.

[0049] By the above synthesis, the present inventors synthesized the following compounds.

[0050] <Compound 1>

[0051] 3-(isoquinolin-4-yl)-9H-fluoren-9-one [ka]

[0052] NMR(H):9.45(s,1H),8.59(s,1H),8.29(d,1H),8.07(s,1H),8.07~7.85(m,3H),7.80(d,2H),7.65(dd,2H),7.57(d,1H),7.40(t,1H);MS:308.48

[0053] <Compound 2>

[0054] 2-bromo-7-(isoquinolin-4-yl)phenanthrene-9,10-dione [ka]

[0055] H NMR:9.45(s,1H),8.56(s,1H),8.53(d,1H),8.38(d,1H),8.28(d,1H),8. 15(d,2H),8.02~7.95(m,2H),7.87(s,2H),7.82~7.78(m,1H);MS:413.95

[0056] <Compound 3>

[0057] 2-(isoquinolin-4-yl)-9H-xanthen-9-one [ka]

[0058] H NMR:9.42(s,1H),8.55(s,1H),8.28~8.23(m,3H),8.08(d,1H),7.98~7.75(m,6H),7.55(t,1H);MS:324.50

[0059] <Compound 4>

[0060] 2-(isoquinolin-4-yl)-9H-thioxanthen-9-one [ka]

[0061] H NMR:9.43(s,1H),8.6~8.55(m,2H)8.51(d,1H),8.28(d,1H),8.10(d,1H),8.02(d,1H),7.93(d,1H),7.88~7.75(m,4H),7.65(t,1H);MS:340.35

[0062] <Compound 5>

[0063] 2-(pyrido[3,4-b]pyrazin-8-yl)-9H-fluoren-9-one [ka]

[0064] H NMR:9.57(s,1H),9.25(s,1H),9.18(s,1H),9.02(s,1H),8.01(s,3H),7.93(d,1H),7.69~7.65(m,2H),7.45(t,1H);MS:310.23

[0065] <Compound 6>

[0066] 2-(quinazolin-4-yl)-9H-fluoren-9-one [ka]

[0067] H NMR:9.38(s,1H),8.20~8.08(m,5H),7.98~7.92(m,2H),7.75(t,1H),7.72~7.68(m,2H),7.49(t,1H);MS:309.15

[0068] <Compound 7>

[0069] 2-(1,6-naphthyridin-8-yl)-9H-fluoren-9-one [ka]

[0070] H NMR:9.47(s,1H),9.20(d,1H),8.89(s,1H),8.70(d,1H),8.02~7.92(m,3 H),7.89(d,1H),7.80(dd,1H),7.70~7.62(m,2H),7.45(t,1H);MS:309.24

[0071] <Compound 8>

[0072] 2-(1,6-naphthyridin-5-yl)-9H-fluoren-9-one [ka]

[0073] H NMR:9.47(s,1H),9.14(d,1H),8.70(s,1H),8.33(d,1H),8.03(d,1H),7.93 (d,1H),7.84(d,2H),7.76(s,1H),7.70~7.62(m,2H)7.45(t,1H);MS:309.29

[0074] <Compound 9>

[0075] 2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-fluoren-9-one [ka]

[0076] NMR(H):8.78(d,1H),8.54(S,1H),8.03(d,1H),7.95(d,1H),7.95~7.89(m,3H),7.68~7.63(m,2H),7.40(q,2H),7.03(t,1H); MS+: 297.40

[0077] <Compound 10>

[0078] 2-(imidazo[1,2-a]pyridin-3-yl)-9H-fluoren-9-one [ka]

[0079] NMR(H):8.62(d,1H),8.54(S,1H),8.40(d,1H),8.08(1H,S),7.95(d,1H ),7.90(d,1H),7.70~7.65(m,4H),7.43(t,1H),7.03(t,1H);MS+:297.54

[0080]

[0081] <Compound 11>

[0082] 4-(dibenzo[b,d]thiophen-3-yl)isoquinoline [ka]

[0083] NMR(H):9.40(s,1H),8.57(d,2H),8.49(d,1H),8.30(d,2H),8.10(d,1H),7 .92(d,1H),7.83(t,1H),7.75(t,1H),7.70(d,1H),7.58(d,2H);MS+:312.89

[0084] <Compound 12>

[0085] 4-(dibenzo[b,d]furan-3-yl)isoquinoline [ka]

[0086] MS+: 296.37

[0087] <Compound 13>

[0088] 7-(isoquinolin-4-yl)-5H-pyrido[4,3-b]indole [ka]

[0089] NMR(H):9.39(d,2H),8.55(s,1H),8.43(d,1H),8.41(d,1H),8.25(d,1H) ,8.00(d,1H),7.82~7.74(m,3H),7.65(br,1H),7.40(d,1H);MS+:296.28

[0090] <Compound 14>

[0091] 2-(isoquinolin-4-yl)-9H-fluoren-9-one [ka]

[0092] H NMR:9.30(s,1H),8.52(s,1H),8.07(d,1H),7.90(d,1H),7.84(s,1H),7.74~7.56(m,7H),7.38(t,1H);MS:308.04

[0093] <Compound 15>

[0094] 2-(isoquinolin-4-yl)-9H-carbazole [ka]

[0095] H NMR:9.30(s,1H),8.60(s,1H),8.27(s,1H),8.21(d,1H),8.14(d,1H),8.12~8.01(m,2H), 7.69~7.64(m,2H),7.58(s,1H),7.51(t,2H),7.40(d,1H),7.30~7.26(m,1H);MS+:295.40

[0096] <Compound 16>

[0097] 7-(isoquinolin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole [ka]

[0098] NMR(DMSO d6):10.82(s,1H),9.29(s,1H),8.45(s,1H),8.20(d,1H),7.95(d,1H),7.76(m,1H),7.7 1(m,1H),7.50(d,1H),7.39(d,1H),7.09(dd,1H),2.75(m,2H),2.69(m,2H),1.86(m,4H);

[0099] MS+: 299.25

[0100] <Compound 17>

[0101] 2-(isoquinolin-8-yl)-9H-fluoren-9-one [ka]

[0102] NMR(CDCl3):9.33(s,1H),8.58(d,1H),7.90(d,1H),7.83(d,1H),7.79(m,2H),7.73(d, 1H),7.70(dd,1H),7.65(dd,1H),7.63(m,1H),7.60(dd,1H),7.56(m,1H),7.36(m,1H);

[0103] MS+:308.22

[0104] <Compound 18>

[0105] 2-(isoquinolin-5-yl)-9H-fluoren-9-one [ka]

[0106] NMR(CDCl3):9.36(s,1H),8.52(d,1H),8.07(dd,1H),7.80(d,1H),7.73(m,5H),7.62(d,2H),7.56(m,1H),7.36(m,1H);

[0107] MS+:308.26

[0108] <Compound 19>

[0109] 2-(imidazo[1,2-a]pyridin-5-yl)-9H-fluoren-9-one [ka]

[0110] NMR(CDCl3):7.94(d.1H),7.79(dd,1H),7.69(m,6H),7.57(m,1H),7.39(m,1H),7.31(m,1H),6.84(d,1H);

[0111] MS+: 297.24

[0112] <Compound 20>

[0113] 2-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-9H-fluoren-9-one [ka]

[0114] NMR(DMSO d6):9.29(d,1H),8.06(s,2H),7.96(m,2H),7.85(d,1H),7.71(m,2H),7.49(m,2H),7.13(dd,1H);

[0115] MS+: 298.23

[0116] <Compound 21>

[0117] 6-(isoquinolin-4-yl)-1,2,3,4-tetrahydrocyclopenta[b]indole [ka]

[0118] NMR(CDCl3):9.25(s,1H),8.54(s,1H),8.05(m,3H),7.65(m,2H),7.57(d,1H),7.47(d,1H),7.23(dd,1H),2.92(m,4H),2.60(m,2H);

[0119] MS+: 285.27

[0120] <Compound 22>

[0121] 2-(isoquinolin-1-yl)-9H-fluoren-9-one [ka]

[0122] NMR(CDCl3):8.63(d,1H),8.11(d,1H),8.02(s,1H),7.91(t,2H),7.71(m,4H),7.58(m,3H),7.35(t,1H);

[0123] MS+:308.26

[0124] <Compound 23>

[0125] 2-(imidazo[1,2-a]pyridin-8-yl)-9H-fluoren-9-one [ka]

[0126] 8.63(d,1H),8.00(d,1H),7.98~7.92(m,3H),7.86(S,1H),7.72~7.65(m,3H),7.43(t,1H),7.35(t,1H),7.01(t,1H)

[0127] MS+: 297.54

[0128] [Example]

[0129] Confirmation of STAT3 transcriptional activity suppression efficacy

[0130] HEK293 cells, an immortalized human kidney cell line, were transformed with a STAT3 promoter and luciferase reporter stably expressed. HEK293 cells stably expressing the STAT3 promoter were cultured in MEM (10% FBS) medium in a cell incubator at 5% CO2 and 37°C, and the inhibitory effect of STAT3 transcriptional activity was confirmed as follows.

[0131] First, 2 × 10 HEK293 cells stably expressing the STAT3 promoter were placed in a 96-well plate (white, clear bottom culture plate). 4 After seeding at a density of 100 cells / well, the cells were cultured at 37°C in a 5% CO2 incubator for 24 hours. Then, the compound synthesized in the above Synthesis Example (1 μM) or BBI-608 (Napabucasin; control group, 3 μM) was treated with IL-6 (10 ng / mL) and incubated at 37°C in a 5% CO2 incubator for 24 hours. The culture medium was then removed from the 96-well plate, and the cells were lysed using Passive Lysis Buffer (Promega, Cat. Number E1941). Luciferase activity was measured using a Luciferase Assay System (Promega, Cat. Number E1501) with a microplate reader to measure luminescence. Wells without IL-6 (10 ng / mL) treatment without test substance treatment served as a negative control, while wells without IL-6 (10 ng / mL) treatment served as a positive control. The luminescence values ​​from each well were compared to evaluate the degree of the inhibitory effect of the compound of the present invention on STAT3 transcription activity.

[0132] [Table 1]

[0133] As a result, as shown in Figure 1 and Table 1, it was confirmed that Compounds 7, 8, 9, 13, 14, 21 and 23 showed excellent STAT3 activity inhibitory effects even at lower concentrations than BBI-608, which is currently undergoing phase 3 clinical trials in the control group.

[0134] Although the present invention has been described in this specification with reference to limited embodiments, various embodiments are possible within the scope of the present invention. Furthermore, although not described, equivalent means can also be considered to be directly incorporated into the present invention. Therefore, the true scope of protection of the present invention should be determined by the following claims.

Claims

1. A tricyclic derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 The compound or a pharmaceutically acceptable salt thereof, wherein the formula 1 is the following formula 1-1: 【Chemistry 2】 In the above Chemical Formula 1-1, A' 1 to A' 8 may be the same or different and each represent CH or N; L 1 and L 2 may be the same or different and each represent one of CH 2 , CO, NH, O, S and SO; n is 0 or 1, m is 1 or 2, X is H or a halogen; R 1 is 【Transformation 3】 wherein E 1 to E 8 may be the same or different and each represents CH or N; The compounds include 3-(isoquinolin-4-yl)-9H-fluoren-9-one, 2-bromo-7-(isoquinolin-4-yl)phenanthrene-9,10-dione, 2-(isoquinolin-4-yl)-9H-xanthen-9-one, and 2-(isoquinolin-4-yl)-9H-xanthen-9-one. 2-(isoquinolin-4-yl)-9H-thioxanthen-9-one), 2-(pyrido[3,4-b]pyrazin-8-yl)-9H-fluoren-9-one, 2-(quinazolin-4-yl)-9H-fluoren-9-one, 2-(1,6-naphthyridin-8-yl)-9H-fluoren-9-one, 2-(1,6-naphthyridin-8-yl)-9H-fluoren-9-one, 2-(1,6-naphthyridin-5-yl)-9H-fluoren-9-one, 2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-fluoren-9-one, 2-(imidazo[1,2-a ]pyridin-3-yl)-9H-fluoren-9-one (2-(imidazo[1,2-a]pyridin-3-yl)-9H-fluoren-9-one), 4-(dibenzo[b,d]thiophen-3-yl)isoquinoline (4-(dibenzo[b,d]thiophen-3-yl)isoquinoline), 4-(dibenzo[b,d]furan-3-yl)isoquinoline (4-(dibenzo[b,d]furan-3-yl)isoquinoline), 7-(isoquinolin-4-yl)-5H-pyrido[4,7-(isoquinolin-4-yl)-5H-pyrido[4,3-b]indole, 2-(isoquinolin-4-yl)-9H-fluoren-9-one, 2-(isoquinolin-4-yl)-9H-carbazole, 7-(isoquinolin-4-yl)- 2,3,4,9-tetrahydro-1H-carbazole (7-(isoquinolin-4-yl)-2,3,4,9-tetrahydro-1H-carbazole), 2-(isoquinolin-8-yl)-9H-fluoren-9-one (2-(isoquinolin-8-yl)-9H-fluoren-9-one), 2-(isoquinolin-5-yl)-9H-fluoren-9-one (2-(isoquinolin-5-yl)-9H- fluoren-9-one), 2-(imidazo[1,2-a]pyridin-5-yl)-9H-fluoren-9-one), 2-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-9H-fluoren-9-one a compound selected from the group consisting of 2-(isoquinolin-1-yl)-9H-fluoren-9-one, 2-(isoquinolin-1-yl)-9H-fluoren-9-one, and 2-(imidazo[1,2-a]pyridin-8-yl)-9H-fluoren-9-one, or a pharmaceutically acceptable salt thereof.

2. A tricyclic derivative compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 The compound of Formula 1 is represented by the following Formula 1-2, or a pharmaceutically acceptable salt thereof: 【Transformation 5】 In the above Chemical Formula 1-2, A'' １ ~A'' ７ are the same or different and are CH or N, L １ and L ２ may be the same or different, CH ２ , CO, NH, O, S, and SO; n is 0 or 1, m is 1 or 2, X is H or a halogen; R １ teeth, 【Transformation 6】 is one of the following: E １ ~E ８ are the same or different and are CH or N, A compound or a pharmaceutically acceptable salt thereof, wherein, in Chemical Formula 1-2, A'' 1 to A'' 7 are CH, n is 0, m is 1, L 1 is CH 2 or NH, and X is H.

3. 3. The compound according to claim 2, wherein the compound is 6-(isoquinolin-4-yl)-1,2,3,4-tetrahydrocyclopenta[b]indole, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition for preventing or treating a STAT3-associated disease, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

5. 5. The pharmaceutical composition for preventing or treating a STAT3-associated disease according to claim 4, wherein the STAT3-associated disease is any one of cancer, osteoporosis, atopy, viral inflammatory disease, diabetic retinopathy, diabetes, hemophilic arthropathy, atherosclerosis, keloid, wound granulation, vascular adhesion, autoimmune disease, restenosis, intestinal adhesion, cat scratch disease, ulcer, cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, glomerular disease, neurodegenerative disease, and inflammatory disease.

6. A health functional food composition for preventing or ameliorating a STAT3-related disease, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. The health functional food composition for preventing or improving a STAT3-related disease according to claim 6, wherein the STAT3-related disease is any one of cancer, osteoporosis, atopy, viral inflammatory disease, diabetic retinopathy, diabetes, hemophilic arthropathy, atherosclerosis, keloid, injury granulation, vascular adhesion, autoimmune disease, restenosis, intestinal adhesion, cat scratch disease, ulcer, cirrhosis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplant rejection, renal glomerular disease, neurodegenerative disease and inflammatory disease.

8. A reagent composition for inhibiting STAT3 activity, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

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