A class of compounds and their medical uses

Abstract

The present invention discloses a class of compounds and their medical uses, belonging to the field of pharmaceutical chemistry and pharmacotherapy, and discloses a class of compounds shown in formula I or their pharmaceutically acceptable salts or esters. The present invention also discloses the use of the compounds or their pharmaceutically acceptable salts or esters in the preparation of STAT3 inhibitors or in the preparation of drugs for preventing and / or treating tumor-related diseases. Pharmacological experiments have shown that the compounds of the present invention achieve the purpose of anti-tumor by inhibiting the proliferation of tumor cells and inducing apoptosis of tumor cells, have anti-tumor effects, and have low toxicity.

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and pharmacotherapy, and in particular to a class of compounds and their medical uses for preparing STAT3 small molecule inhibitors and preparing drugs for treating tumors, and belongs to the field of pharmaceutical technology. Background Art

[0002] Signal transducers and activators of transcription (STATs) are a family of cytoplasmic transcription factor proteins that are responsible for the signal transduction of extracellular cytokines and growth factors and the initiation of downstream gene transcription. Among them, STAT3 (signal transducer and activator of transcription 3) is a transcription factor that participates in the regulation of physiological activities such as cell proliferation, apoptosis, invasion, migration and immune response. Its abnormal activation plays an important role in the occurrence and development of tumors. Abnormal or constitutively activated STAT3 proteins have been observed in many different types of cancers. The activated STAT3 protein enters the cell nucleus and promotes the expression of multiple anti-apoptotic protein genes, thereby supporting the occurrence and development of tumors. At present, this target has become an important anti-tumor target.

[0003] Cytokines or growth factors promote STAT3 signal cascade after binding to surface receptors. Phosphorylation of pTyr705 residue activates cytoplasmic kinase, thereby promoting phosphorylation of STAT3 monomers. Two phosphorylated STAT3 monomers bind at the pTyr705-SH2 domain to form a STAT3 dimerization complex, which then enters the cell nucleus and induces the expression of related tumor genes. Therefore, the pTyr705-SH2 domain plays a key role in the entire pathway.

[0004] However, existing small molecule SH2 domain inhibitors have the problem of insufficient activity or no statistical difference compared with the positive control drug. Therefore, designing and synthesizing new small molecule SH2 domain inhibitors plays an important role in blocking the JAK-STAT3 cell pathway. Summary of the invention

[0005] The SH2 domain of STAT3 plays a key role in activating the recruitment of STAT3 and forming STAT3 homodimers and STAT3 / DNA complexes. Therefore, the purpose of the present invention is to provide an effective STAT3 inhibitor targeting the SH2 domain.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] The compound represented by formula I or a pharmaceutically acceptable salt or ester thereof:

[0008]

[0009] Wherein, R1 is one or more substituents, each independently selected from hydrogen, halogen, C1-C4 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl, trifluoromethyl, trifluoromethoxy, aromatic, heteroaromatic carbocyclic or heterocyclic ring, the heterocyclic ring contains one to two heteroatoms, and the heteroatoms are independently selected from N, O, S; the halogen refers to fluorine, chlorine, bromine or iodine;

[0010] or R1 is selected from

[0011] R2 is a substituent selected from hydrogen, halogen, amino, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 alkylamino, wherein the halogen refers to fluorine, chlorine, bromine or iodine;

[0012] Preferably, R1 is one or more substituents selected from hydrogen, halogen, methoxy, methyl, hydroxy, tert-butyl, isopropoxy, amino, carboxyl, trifluoromethyl, trifluoromethoxy, The halogen refers to chlorine or fluorine; when R1 is multi-substituted fluorine; further preferably: when R1 is 3 substituted fluorine.

[0013] R2 is methylamino, ethylamino, propylamino or dimethylamino.

[0014] Specifically, the compound represented by formula I is selected from:

[0015]

[0016]

[0017] Based on the above preferred structure, the compound of the present invention has the following structural formula:

[0018]

[0019] Chemical name: 3-aminophenyl-4-methylamino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide.

[0020] Pharmacological experiments have shown that compound DB-11 has a strong growth inhibitory effect on lung cancer cells A549. Further mechanism verification shows that compound DB-11 can selectively bind to the SH2 domain of STAT3 protein and inhibit the formation of STAT3 homodimers.

[0021] The pharmaceutically acceptable salts of the compounds described in the present invention are sodium salt and hydrochloride.

[0022] Another object of the present invention is to provide the use of the compound or its pharmaceutically acceptable salt or ester in the preparation of STAT3 inhibitors.

[0023] Another object of the present invention is to provide a method for preparing the compound represented by the general formula I, and the synthetic route is as follows:

[0024]

[0025] include:

[0026] (1) (Compound 1) 1-naphthalenesulfonyl chloride is subjected to substitution reaction to obtain (Compound 2) 1-naphthalenesulfonamide;

[0027] (2) (Compound 2) 1-naphthalenesulfonamide is subjected to oxidation reaction to obtain (Compound 3) 5,8-dioxo-dihydronaphthalene;

[0028] (3) (Compound 3) 5,8-dioxo-dihydronaphthalene is subjected to Michael addition reaction to obtain (Compound 4) 4-substituted amino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide;

[0029] (4) (Compound 4) 5,8-dioxo-dihydronaphthalene is subjected to Michael addition reaction to obtain (Formula I) 4-substituted amino-3-m-substituted phenyl-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide

[0030] Furthermore, step (1) specifically refers to: adding compound 1 to a reactor containing a solvent, stirring, adding 0°C ammonia water dropwise in an ice bath, after the addition is complete, tracking the reaction with a thin layer, and after the reaction is completed, distilling under reduced pressure, precipitating a solid, filtering, and vacuum drying to obtain compound 2.

[0031] Preferably, the solvent is acetone.

[0032] Step (2) specifically refers to: adding (compound 2) 1-naphthalenesulfonamide to a reactor containing an organic solvent, controlling the temperature at 65°C-70°C and stirring; dissolving ten times the equivalent of cerium sulfate with 2 mol / L dilute sulfuric acid, controlling the temperature at 65°C-70°C and stirring, slowly adding dropwise to the system, starting the timing from the dropwise addition, stopping the reaction after 25-35 minutes, cooling and filtering, then adding dichloromethane to the filtrate for extraction, taking the dichloromethane layer, and vacuum drying to obtain 5,8-dioxo-dihydronaphthalene. More preferably, the temperature is 65°C and the reaction time is 27 minutes.

[0033] Furthermore, in step (2), the organic solvent is one or more of glacial acetic acid and trifluoroacetic acid.

[0034] Step (3) specifically refers to: adding (compound 3) 5,8-dioxo-dihydronaphthalene into a reactor containing an organic solvent, stirring, adding the corresponding substituted amine at 0°C dropwise in an ice bath, stirring for one hour after the addition is complete, tracking the reaction with thin layer chromatography, and after the reaction is completed, distilling under reduced pressure to precipitate a solid, filtering, and vacuum drying to obtain compound 4.

[0035] Furthermore, the solvent is one or more protic solvents.

[0036] Step (4) specifically refers to: adding compound 4 to a reactor containing an organic solvent, adding the corresponding substituted phenylboronic acid and manganese acetate dihydrate, and stirring at 105° C. for 26 hours. The reaction is detected by thin layer tracking. After the reaction is completed, the reaction solution is cooled to room temperature, 50 mL of water is added, filtered, extracted with ethyl acetate, and the ethyl acetate layer is taken and dried in vacuo to obtain the compound shown in formula I.

[0037] Preferably, the solvent is one or more aprotic solvents. DETAILED DESCRIPTION

[0038] In order to further illustrate the present invention, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the present invention, and should not be understood as limiting the present invention.

[0039] Example 1

[0040] 1) Preparation of 1-naphthalenesulfonamide

[0041]

[0042] 1-Naphthalenesulfonyl chloride (10 g, 21.9 mmol) was added to a 1 L round bottom flask containing 200 ml of acetone, stirred, and 240 mL of 0°C ammonia water was added dropwise in an ice bath. After the addition was complete, the reaction was detected by thin layer tracking. After the reaction was completed, the organic solvent and the ammonia gas decomposed by the ammonia water were distilled off under reduced pressure, and the solid was precipitated, filtered, and vacuum dried to obtain 1-naphthalenesulfonamide (8.7 g, yield 96.7%). The compound was used directly in the next step without further purification.

[0043] 1 H NMR (400MHz, DMSO-d6) δ8.65 (d, J=8.3Hz, 1H, Ar-H), 8.20 (d, J=8.2Hz, 1H, Ar-H), 8.17–8.06 (m, 2H, Ar-H), 7.75–7.69(m,1H,Ar-H),7.69–7.68(m,1H,Ar-H),7.67(d,J=3.9Hz,2H,NH2),7.63(d,J=7.9Hz,1H,Ar-H).

[0044] 2) Preparation of 5,8-dioxo-dihydronaphthalene-1-sulfonamide

[0045]

[0046] Dissolve anhydrous cerium sulfate (160g, 677.45mmol) in 750ml 2mol / L dilute sulfuric acid, and control the temperature to 65°C. Add 1-naphthalenesulfonamide (8.70g, 48.49mmol) to a 500mL round-bottom flask containing 200ml acetonitrile, control the temperature to 65°C, stir at this temperature, and slowly dropwise add to the cerium sulfate aqueous phase system, start timing from the dropwise addition, monitor with thin layer chromatography, and stop the reaction after 27 minutes. After the reaction solution is cooled, filter, extract the filtrate with 1200mL dichloromethane, dry and remove water, and then low-pressure rotary evaporation to obtain a light yellow solid, which is vacuum dried to obtain 5,8-dioxo-dihydronaphthalene (5.85g, yield 58.43%). Use it directly in the next step without purification.

[0047] 1 H NMR (300MHz, DMSO-d6) δ8.45(d,J=9.2Hz,1H,Ar-H),8.28(d,J=8.9Hz,1H,Ar-H),8.06(t,J=7.8Hz,1H,Ar-H),7.38(s,2H,NH2),7.23–7.10(m,2H,Ar-H).

[0048] 3) Synthesis of 4-methylamino-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide

[0049]

[0050] 5,8-dioxo-dihydronaphthalene (5.00g 21.08mmol) was added to a 500mL round-bottom flask containing 200mL methanol, and 4.43g (44.26mmol) of 2M methylamine ethanol solution was slowly added dropwise, and stirred at room temperature for 1 hour. After the reaction was completed, the black crude product was obtained by vacuum rotary evaporation. It was dissolved in 500mL ethyl acetate for extraction, and anhydrous sodium sulfate was added to dry overnight. Filtered, vacuum rotary evaporation was performed to remove ethyl acetate to obtain a dark red powdery solid crude product, and the obtained crude product was purified by column chromatography, and the eluent was petroleum ether / ethyl acetate (4:1, v:v), and the solvent was vacuum rotary dried to obtain 4-methylamino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (2.76g, yield 52.75%).

[0051] 1 H NMR (400MHz, Pyridine-d5) δ8.90(d,J=5.8Hz,1H,Ar-H),8.18–8.11(m,2H,Ar-H),7.73(t,J=7.6Hz,1H,Ar-H),5.93(s,1H,NH),2.86(d,J=5.0Hz,3H,CH3).

[0052] 4) Synthesis of the target compound 3-phenyl-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-0):

[0053] In a 100mL single-necked flask, add 2.01mmol 4-methylamino-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide, 3.02mmol phenylboronic acid, 4.03mmol manganese acetate dihydrate dissolved in 6mL dimethyl sulfoxide, and stir at 105°C for 26 hours. After the reaction is completed, the reaction solution is cooled to room temperature, 50mL water is added, filtered, the filter residue is washed three times with ethyl acetate, the ethyl acetate layer is separated, and the water layer is extracted three times with ethyl acetate. After the organic layer is combined, the organic layer is washed once with water and saturated sodium chloride respectively, and the organic layer is separated and dried over anhydrous sodium sulfate overnight. Filter and vacuum rotary evaporation to obtain a dark red powdery solid crude product, and the obtained crude product is purified by column chromatography to obtain the target product DB-0 with a yield of 47.98%, a red powdery solid.

[0054] Melting point 235.8-237.9℃. IR(KBr):3322.90,1619.23,1312.76cm -1 ; 1 H NMR(400MHz, CDCl3)δ8.18(d,J=7.1Hz,1H,Ar-H),8.07–7.96(m,1H,Ar-H),7.90(d,J=7.8Hz,1H,A r-H),7.47(d,J=7.2Hz,3H,Ar-H),7.32(d,J=6.4Hz,2H,Ar-H),5.59(s,1H,NH),2.73(s,3H,CH3); 13 C NMR (101MHz, CDCl3) δ179.8,161.2,143.0,136.8,134.5,133.3,131.2,129.8,128.4,128.2,128.0,127.8,124.5,120.8,33.2; HRMS(ESI)calcd for C 17 H 13 N2O3S[M+H] + 325.0642, found 325.0641.

[0055] Example 2

[0056] Synthetic compound 3-(3-methoxyphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-1):

[0057] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-methoxyphenylboronic acid to obtain compound DB-1 with a yield of 46.88% as a red powdery solid.

[0058] Melting point 194.4-195.2℃. IR (KBr): 3320.49, 1619.05, 1322.28, 1256.68cm -1 ; 1 HNMR (300MHz, CDCl3) δ8.17(d,J=7.5Hz,1H,Ar-H),8.01(d,J=7.5Hz,1H,Ar-H),7.89(t,J=7.6Hz,1H,Ar-H),7.37(d,J=7. 9Hz,1H,Ar-H),6.97(d,J=8.1Hz,1H,Ar-H),6.93–6.83(m,2H,Ar-H),5.61(s,1H,NH),3.85(s,3H,CH3),2.79(s,3H,CH3); 13 C NMR (75MHz, CDCl3) δ179.7,161.2,159.4,143.0,136.7,134.6,134.5,129.8,129 .3,128.0,127.7,124.5,123.6,120.6,116.8,114.0,55.3,33.1; HRMS(ESI)calcd for C 18 H 16 N2O4S[M+H] + 355.0749, found 355.0747.

[0059] Example 3

[0060] Synthetic compound 3-(3-methylphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-2):

[0061] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-methylphenylboronic acid to obtain compound DB-2 with a yield of 45.68%, a red powdery solid, and a melting point of 203.1-205.5°C. IR (KBr): 3323.45, 1619.41, 1318.05cm -1 ; 1H NMR (400MHz, CDCl3) δ8.17(d,J=7.5Hz,1H,Ar-H),8.00(d,J=7.6Hz,1H,Ar-H),7.89(t,J=7.6Hz,1H,Ar-H),7.36(t,J=7.5 Hz,1H,Ar-H),7.24(d,J=7.7Hz,1H,Ar-H),7.13(s,1H),7.10(s,1H),5.56(s,1H,NH),2.75(s,3H,CH3),2.42(s,3H,CH3); 13 C NMR (101MHz, CDCl3) δ179.8,161.2,143.0,137.9,136.7,134.6,133.1,131.7, 129.8,129.3,128.2,128.1,127.8,124.4,121.1,33.2,21.5; HRMS(ESI)calcd forC 18 H 15 N2O3S[M+H] + 339.0797, found 339.0798.

[0062] Example 4

[0063] Synthetic compound 3-(3-chlorophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-3):

[0064] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-chlorophenylboronic acid to obtain compound DB-3 with a yield of 47.53%, a red powdery solid, and a melting point of 230.6-231.5°C. IR (KBr): 3320.81, 1618.93, 1316.13, 771.28cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.18 (d, J=7.5Hz, 1H, Ar-H), 8.02 (d, J=7.6Hz, 1H, Ar-H), 7.91 (t, J=7.6Hz, 1H, Ar- H),7.41(d,J=4.5Hz,2H,Ar-H),7.34(s,1H,Ar-H),7.22(s,1H,Ar-H),5.64(s,1H,NH),2.74(s,3H,CH3); 13C NMR (101MHz, CDCl3) δ179.6,161.1,143.1,137.0,135.2,134.8,134.1,131.3, 129.9,129.5,129.4,128.6,127.8,127.6,124.7,118.9,33.4; HRMS(ESI)calcd for C 17 H 12 ClN2O3S[M+H] + 359.0251, found 359.0252.

[0065] Example 5

[0066] Synthetic compound 3-(3-bromophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-4):

[0067] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-bromophenylboronic acid to obtain compound DB-4 with a yield of 48.56%, a red powdery solid, and a melting point of 222.7-223.7°C. IR (KBr): 3319.84, 1619.72, 1315.44, 633.69cm -1 ; 1 H NMR (400MHz, DMSO-d6) δ8.39(d,J=7.3Hz,1H,Ar-H),8.07(d,J=8.7Hz,1H,Ar-H),8.02(t,J=7.5Hz,2H,Ar-H),7. 57(d,J=4.7Hz,2H,Ar-H),7.49(s,1H,NH),7.38(t,J=7.8Hz,1H,Ar-H),7.30(d,J=6.3Hz,1H),2.47(s,3H,CH3); 13 CNMR(101MHz,DMSO-d6)δ179.5,162.2,144.2,137.7,136.4,135.8,134.6,131.2 ,130.8,130.0,129.7,128.4,127.8,125.4,121.2,117.2,33.4; HRMS(ESI)calcd forC 17 H 11 BrN2NaO3S[M+Na] + 424.9565, found 424.9566.

[0068] Example 6

[0069] Synthetic compound 3-(3-fluorophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-5):

[0070] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-fluorophenylboronic acid to obtain compound DB-5 with a yield of 53.73%, a red powdery solid, and a melting point of 217.2-219.5°C. IR (KBr): 3324.19, 1622.21, 1316.93, 1174.98 cm -1 ; 1 H NMR (300MHz, CDCl3) δ8.18(d,J=7.5Hz,1H,Ar-H),8.02(d,J=7.5Hz,1H,Ar-H),7.91(t,J=7.6Hz,1H,Ar-H),7.50–7.39(m,1 H,Ar-H),7.14(dd,J=11.9,8.9Hz,2H,Ar-H),7.07(dd,J=9.2,2.0Hz,1H,Ar-H),5.69(s,1H,NH),2.73(d,J=5.7Hz,3H,CH3); 13 C NMR (75MHz, CDCl3) δ179.6,164.0,161.1,143.1,136.9,134.8,129.9,129.8,129. 6,127.9,127.6,127.1,124.7,118.6,118.3,115.6,115.3,33.2; HRMS(ESI)calcd for C 17 H 12 FN2O3S[M+H] + 343.0546, found 343.0547.

[0071] Example 7

[0072] Synthetic compound 3-(3-tert-butylphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-6):

[0073] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-tert-butylphenylboronic acid to obtain compound DB-6 with a yield of 46.34%, a red powdery solid, and a melting point of 244.2-246.4°C. IR (KBr): 3324.65, 1618.60, 1409.05, 1316.13 cm -1 ; 1H NMR(300MHz,DMSO-d6)δ8.37(d,J=8.4Hz,Ar-H),8.09–7.97(m,2H,Ar-H),7.47–7.36(m,2H,Ar-H),7.34(d,J=7.3Hz, 1H, Ar-H), 7.29 (d, J=1.9Hz, 1H, NH), 7.12 (dt, J=7.1, 1.6Hz, 1H, Ar-H), 2.34 (d, J=5.4Hz, 3H, CH3), 1.30 (s, 9H, 3CH3); 13 C NMR(75MHz,DMSO-d6)δ180.0,162.4,149.8,143.7,136.4,135.7,134.7,129.7,129.5, 128.9,128.4,127.9,127.4,125.3,124.6,118.4,34.8,32.8,31.6; HRMS(ESI)calcdfor C 21 H 21 N2O3S[M+H] + 381.1266, found 381.1267.

[0074] Example 8

[0075] Synthetic compound 3-(3-isopropoxyphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-7):

[0076] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-isopropoxyphenylboronic acid to obtain compound DB-7 with a yield of 47.20%, a red powdery solid, and a melting point of 205.6-206.4°C. IR (KBr): 3353.32, 1625.70, 1316.94, 1248.39cm -1 ; 1 H NMR (300MHz, CDCl3) δ8.18(d,J=7.5Hz,1H,Ar-H),8.01(d,J=8.5Hz,1H,Ar-H),7.89(t,J=7.6Hz,1H,Ar-H),7.37(t,J=7.9Hz,1H,Ar-H),6.95( dd,J=8.4,1.6Hz,1H,Ar-H),6.89–6.83(m,2H,Ar-H),5.61(s,1H,NH),4.59(p,J=6.1Hz,1H,CH),2.81(s,3H,CH3),1.38(d,J=6.0Hz,6H,2CH3); 13C NMR (75MHz, CDCl3) δ179.6,161.2,157.7,143.0,136.7,134.6,134.4,129.8,129 .4,128.0,127.8,124.4,123.3,118.6,116.0,70.1,33.1,22.1; HRMS(ESI)calcd for C 20 H 19 N2O4S[M+H] + 383.1060, found 383.1060.

[0077] Example 9

[0078] Synthetic compound 3-(3-trifluoromethylphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-8):

[0079] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-trifluoromethylphenylboronic acid to obtain compound DB-8 with a yield of 49.87%, a red powdery solid, and a melting point of 228.6-229.2°C. IR (KBr): 3322.53, 1621.41, 1317.07, 1197.57 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.19(d,J=7.5Hz,1H,Ar-H),8.04(d,J=7.6Hz,1H,Ar-H),7.92(t,J=7.6Hz,1H,Ar-H),7.70( d,J=7.8Hz,1H,Ar-H),7.62(d,J=8.9Hz,2H,Ar-H),7.55(d,J=7.1Hz,1H,Ar-H),5.74(s,1H,NH),2.65(s,3H,CH3); 13 C NMR(101MHz, CDCl3)δ179.8,161.1,143.2,137.1,134.9,134.3,130.0,128.6,128.1,127.8,127.5,125.2,124.8,33.5; HRMS(ESI)calcd for C 18 H 12 F3N2O3S[M+H] + 393.0513, found 393.0515.

[0080] Example 10

[0081] Synthetic compound 3-(3-trifluoromethoxyphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-9):

[0082] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-trifluoromethoxyphenylboronic acid to obtain compound DB-10 with a yield of 40.25%, a red powdery solid, and a melting point of 219.1-220.9°C. IR (KBr): 3323.28, 1620.64, 1319.08, 1285.73, 1204.66cm -1 ; 1 HNMR (400MHz, CDCl3) δ8.19 (d, J=7.6Hz, 1H, Ar-H), 8.02 (d, J=7.6Hz, 1H, Ar-H), 7.91 (t, J=7.6Hz, 1H, Ar- H),7.51(t,J=7.9Hz,1H,Ar-H),7.30(s,2H,Ar-H),7.22(s,1H,Ar-H),5.76(s,1H,NH),2.68(s,3H,CH3); 13 C NMR (101MHz, CDCl3) δ179.6,161.1,148.9,143.1,137.0,135.4,134.8,130.0,129.9, 129.4,127.8,127.6,124.8,123.9,121.8,120.8,119.2,118.4,33.2; HRMS(ESI)calcd forC 18 H 12 F3N2O4S[M+H] + 409.0462, found 409.0464.

[0083] Embodiment 11

[0084] Synthetic compound 3-(3-carboxyphenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-10):

[0085] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-carboxyphenylboronic acid to obtain compound DB-10 with a yield of 38.37%, a red powdery solid, and a melting point of >250°C. IR (KBr): 3431.70, 3322.01, 1688.82, 1620.09, 1318.92 cm -1 ; 1H NMR(300MHz,DMSO-d6)δ13.10(s,1H,COOH),8.38(d,J=7.0Hz,1H,Ar-H),8.10–7.99(m,2H,Ar-H),7.94(t,J= 3.7Hz,1H,Ar-H),7.86(s,1H,Ar-H),7.56(d,J=7.9Hz,1H,NH),7.53(s,2H,Ar-H),2.41(d,J=5.3Hz,3H,CH3); 13 C NMR(75MHz,DMSO-d6)δ179.7,167.9,162.3,144.2,136.4,135.7,135.5,132.9, 130.6,129.7,128.8,128.5,128.2,127.9,125.3,117.8,33.5; HRMS(ESI)calcd for C 18 H 13 N2O5S[M+H] + 369.0542, found 369.0540.

[0086] Example 12

[0087] Synthetic compound 3-(3-aminophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide hydrochloride (DB-11):

[0088] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of m-aminophenylboronic acid to obtain compound DB-11 with a yield of 31.43%, a red powdery solid, and a melting point of 224.3-225.9°C. IR (KBr): 3463.49, 3355.79, 1624.56, 1325.57 cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ8.39(d,J=7.1Hz,1H,Ar-H),8.11–7.98(m,2H,Ar-H),7.61(s,1H,NH),7.52(t,J=7 .8Hz,1H,Ar-H),7.40–7.28(m,2H,Ar-H),7.24(s,1H,Ar-H),5.57(s,2H,NH2),2.42(d,J=5.1Hz,3H,CH3); 13C NMR(101MHz,DMSO-d6)δ179.6,162.4,144.2,136.90,128.4,127.8,126.3,125.4,122.4,117.1,33.3; HRMS(ESI)calcd for C 17 H 14 N3O3S[M+H] + 340.0750, found 340.0750.

[0089] Example 13

[0090] Synthetic compound 3-(3-morpholinophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-12):

[0091] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of 3-morpholinephenylboronic acid to obtain compound DB-12 with a yield of 31.47%, a lavender powdery solid, and a melting point of 227.7-229.1°C. IR (KBr): 3349.98, 1625.27, 1309.05, 1103.25, 1121.86cm -1 ; 1 HNMR(300MHz,DMSO-d6)δ8.37(d,J=5.7Hz,1H,Ar-H),8.03(t,J=7.3Hz,2H,Ar-H),7.38(s,1H,NH),7.30–7.18(m,1H, Ar-H),7.02–6.82(m,2H,Ar-H),6.74(d,J=7.4Hz,1H,Ar-H),3.74(s,4H,2CH2),3.15(s,4H,2CH2),2.48(s,3H,CH3); 13 C NMR (75MHz, DMSO-d6) δ179.8,163.1,150.6,143.6,136.4,135.7,129.7,128.4,127.9,125.3,123.3,118.9,114.7,66.6,48.9,32.8; HRMS(ESI)calcd forC 21 H 20 N3O4S[M+H] + 410.1167, found 410.1169.

[0092] Embodiment 14

[0093] Synthetic compound 3-(3-methylsulfonylaminophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (DB-13):

[0094] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of 3-methylsulfonylaminophenylboronic acid to obtain compound DB-13 with a yield of 35.82%, a red powdery solid, and a melting point of 231.3-232.8°C. IR (KBr): 3350.43, 3367.66, 1625.89, 1347.40, 1310.29cm -1 ; 1 HNMR(300MHz,CD3CN)δ8.12(ddd,J=11.2,7.6,0.8Hz,2H,Ar-H),7.97(t,J=7.6Hz,1H,Ar-H),7.64(s,1H,NH),7.45(t,J=7.8Hz,1H,Ar-H),7.29(ddd,J= 8.1,2.3,1.1Hz,1H,Ar-H),7.20(t,J=1.9Hz,1H,Ar-H),7.13(dt,J=7.6,1.3 Hz,1H,Ar-H),6.13(s,1H,NH),3.00(s,3H,CH3),2.65(d,J=5.6Hz,3H,CH3); 13 C NMR(75MHz,CD3CN)δ180.0,162.0,143.8,137.5,136.3,135.8,135.1,129.3, 129.0,128.4,128.0,127.9,124.4,123.6,120.0,38.7,32.4; HRMS(ESI)calcd forC 18 H 16 N3O5S2[M+H] + 418.0528, found 418.0526.

[0095] Embodiment 15

[0096] Synthetic compound 3-(4-aminophenyl)-4-(methylamino)-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide hydrochloride (DB-1a):

[0097] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of 4-aminophenylboronic acid to obtain compound DB-1a with a yield of 35.82%. 1H NMR (300MHz, DMSO-d6) δ10.06(s,2H),8.38(d,J=6.6Hz,1H),8.03(d,J=9.5Hz,2H),7.52(d,J=6.0Hz,1H),7.35(s,4H),2.43(d,J=4.8Hz,3H). 13 CNMR(75MHz,DMSO-d6)δ162.27,143.96,136.40,135.78,133.31,129.73,128.40,127.83,125.40,121.75,33.34.

[0098] Example 16

[0099] Synthetic compound 4-(methylamino)-3-(3,4,5-trifluorophenyl)-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (DB-1b):

[0100] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of 3,4,5-trifluorophenylboronic acid to obtain compound DB-1b with a yield of 21.67% as a red powdery solid. 1 H NMR (300MHz, DMSO-d6) δ8.41(d,J=7.2Hz,1H),8.08(d,J=6.9Hz,2H),7.71(d,J=45.8Hz,1H),7.27(td,J=8.6,7.5,4.5Hz,2H),2.62(s,3H).

[0101] Embodiment 17

[0102] Synthetic compound 4-(methylamino)-3-(3,4-dimethoxyphenyl)-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (DB-1c):

[0103] Referring to the synthesis method of compound DB-0 in Example 1, only phenylboronic acid was replaced with an equal mole of 3,4-dimethoxyphenylboronic acid to obtain compound DB-1c with a yield of 28.48% as a red powdery solid. 1 H NMR(300MHz,DMSO-d6)δ8.36(dd,J=7.2,1.3Hz,1H),8.07–7.99(m,2H),7.34(d,J=6.1Hz,1H) ,6.99(d,J=8.2Hz,1H),6.85(dd,J=17.7,1.9Hz,2H),3.80(s,3H),3.74(s,3H),3.35(s,3H). 13C NMR(75MHz,DMSO-d6)δ179.83,162.27,148.64,148.18,143.79,136.29,135.69,129.65 ,128.37,127.94,127.09,125.21,124.54,119.24,115.76,111.18,55.93,55.88,32.89.

[0104] Embodiment 18

[0105] Synthesis of 4-propylamino-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (Compound 5)

[0106]

[0107] 5,8-dioxo-dihydronaphthalene (5.00g 21.08mmol) was added to a 500mL round-bottom flask containing 200mL methanol, and 4.43g (44.26mmol) of 2M n-propylamine methanol solution was slowly added dropwise, and stirred at room temperature for 1 hour. After the reaction was completed, the black crude product was obtained by vacuum rotary evaporation. It was dissolved in 500mL ethyl acetate for extraction, and anhydrous sodium sulfate was added to dry overnight. Filtered, vacuum rotary evaporation was performed to remove ethyl acetate to obtain a dark red powdery solid crude product, and the obtained crude product was purified by column chromatography, and the eluent was petroleum ether / ethyl acetate (4:1, v:v), and the solvent was vacuum rotary dried to obtain 4-propylamino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (3.12g, yield 53.57%).

[0108] Synthetic compound 3-(3-aminophenyl)4-(propylamino)-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (DB-2a):

[0109] Referring to the synthesis method of compound DB-0 in Example 1, only compound 4 was replaced by an equal mole of the above compound 5, and phenylboronic acid was replaced by an equal mole of 3-aminophenylboronic acid to obtain compound DB-2a with a yield of 29.76% as a red powdery solid. 1 H NMR(300MHz, DMSO-d6)δ10.26(s,2H),8.39(dd,J=7.0,1.4Hz,1H),8.11–7.96(m,2H),7.52(t ,J=7.7Hz,1H),7.41–7.19(m,4H),2.74(s,2H),1.33(h,J=7.3Hz,2H),0.55(t,J=7.3Hz,3H). 13C NMR(75MHz,DMSO-d6)δ179.45,162.45,143.28,136.82,136.39,135.73,129 .72,129.49,128.56,127.80,125.43,122.18,117.81,46.32,22.87,11.33.

[0110] Embodiment 19

[0111] Synthesis of 4-ethylamino-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (Compound 6)

[0112]

[0113] 5,8-dioxo-dihydronaphthalene (5.00g 21.08mmol) was added to a 500mL round-bottom flask containing 200mL methanol, and 4.43g (44.26mmol) of 2M ethylamine methanol solution was slowly added dropwise, and stirred at room temperature for 1 hour. After the reaction was completed, the black crude product was obtained by vacuum rotary evaporation. It was dissolved in 500mL ethyl acetate for extraction, and anhydrous sodium sulfate was added to dry overnight. Filtered, vacuum rotary evaporation was performed to remove ethyl acetate to obtain a dark red powdery solid crude product, and the obtained crude product was purified by column chromatography, and the eluent was petroleum ether / ethyl acetate (4:1, v:v), and the solvent was vacuum rotary dried to obtain 4-ethylamino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (2.37g, yield 46.38%)

[0114] Synthetic compound 3-(3-aminophenyl)4-(ethylamino)-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (DB-2b):

[0115] Referring to the synthesis method of compound DB-0 in Example 1, compound 4 was replaced by an equal mole of the above compound 6, and phenylboronic acid was replaced by an equal mole of 3-aminophenylboronic acid to obtain compound DB-2b with a yield of 37.42% as a red powdery solid. 1 HNMR(300MHz,DMSO-d6)δ10.16(s,2H),8.39(dd,J=7.1,1.4Hz,1H),8.19–7.88(m,2H), 7.52(t,J=7.8Hz,1H),7.44–7.09(m,4H),2.86(q,J=6.8Hz,2H),0.92(t,J=7.1Hz,3H). 13CNMR(75MHz,DMSO-d6)δ179.45,162.39,143.27,136.84,136.37,135.72,133 .30,130.31,129.71,129.50,128.55,127.78,125.40,122.15,117.79,15.40.

[0116] Embodiment 19

[0117] Synthesis of 4-ethylamino-5H-naphtho[1,8-cd]isothiazol-5-one-1,1-dioxide (Compound 7)

[0118]

[0119] 5,8-dioxo-dihydronaphthalene (5.00g 21.08mmol) was added to a 500mL round-bottom flask containing 200mL methanol, and 4.43g (44.26mmol) of 2M dimethylamine methanol solution was slowly added dropwise, and stirred at room temperature for 1 hour. After the reaction was completed, the black crude product was obtained by vacuum rotary evaporation. It was dissolved in 500mL ethyl acetate for extraction, and anhydrous sodium sulfate was added to dry overnight. Filtered, vacuum rotary evaporation was used to remove ethyl acetate to obtain a dark red powdery solid crude product, and the obtained crude product was purified by column chromatography, and the eluent was petroleum ether / ethyl acetate (4:1, v:v), and the solvent was vacuum rotary dried to obtain 4-ethylamino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (2.89g, yield 53.98%)

[0120] Synthetic compound 3-(3-aminophenyl)4-(dimethylamino)-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide (DB-2c):

[0121] Referring to the synthesis method of compound DB-0 in Example 1, compound 4 was replaced with an equal mole of the above compound 7, and phenylboronic acid was replaced with an equal mole of 3-aminophenylboronic acid to obtain compound DB-2c with a yield of 41.92% as a red powdery solid.

[0122] Evaluation of the anti-tumor cell proliferation activity of compounds DB-0-13, DB-1a-1c, DB-2a-2c and positive control drug LY-17

[0123] 1.1 MTT assay to test the inhibitory activity of compound 7d on tumor cells

[0124] All cell lines were purchased from the Cell Bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Shanghai, China). Non-small cell lung cancer cells (A549) were cultured in DMEM medium. All cell culture media contained 50 μg / mL penicillin, 50 μg / mL streptomycin, and 10% fetal bovine serum. Cells were grown in tissue culture flasks at 37°C in a humidified environment containing 5% CO2 to 80% confluence, then trypsinized and split with 1×Trypsin-Versene.

[0125] Test compound: Compounds CH3-1 to CH3-10; Positive control: Compound LY-17 (WO2014028909A1):

[0126]

[0127] MTT experiment: A549 cells were counted after passage, and cell suspension was prepared at a density of 6000 cells / well. After mixing, 100 μL of cell suspension was aspirated from each well and inoculated into a 96-well plate. The cells were adhered overnight. The next day, the cells were dosed. 10 mMOL compound stock solution was prepared with biological grade 99.9% DMSO, and the compound was diluted with the corresponding culture medium. The final concentrations were 0, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, and 32 μM, with a total of 10 concentration gradients. The cell culture medium in the 96-well plate was aspirated, and the culture medium containing different concentrations of the compound was added to the 96-well plate at 100 μL per well, and incubated for 24 hours. Then 10 μL MTT was added to each well and incubated for 4 hours in the dark. After the test, the 96-well plate was taken out, the supernatant was carefully removed, and 150 μL DMSO was added to each well for reconstitution. The absorbance of each well was measured by a fluorescent microplate reader with a detection wavelength of 570 nm and a reference wavelength of 630 nm.

[0128] Tumor cell growth inhibition rate: Proliferation inhibition rate (%) = (1-A 实验组 / A 对照组 )×100%.

[0129] Table 1 shows the inhibitory activity results of the compounds on A549 cells, among which compounds DB-0, DB-1, DB-2, DB-3, DB-4, DB-7, DB-11, DB-12, DB-13, DB-1a-1c, and DB-2a-2c have significant inhibitory activity, which is significantly better than the positive drug LY-17.

[0130] Table 1. Inhibitory activity of compounds on A549 cells

[0131]

[0132]

Claims

1. A compound is a compound represented by formula I, or a pharmaceutically acceptable salt thereof: in, R1 is one or more substituents, each independently selected from hydrogen, halogen, C1-C4 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl, trifluoromethyl, trifluoromethoxy, There are one to two heteroatoms in the heterocyclic ring, and the heteroatoms are independently selected from N, O, and S; the halogen refers to fluorine, chlorine, bromine or iodine; or R1 is selected from R2 is a substituent selected from hydrogen, halogen, amino, C1-C3 alkyl, C1-C3 alkylamino, C1-C3 alkoxy, and the halogen refers to fluorine, chlorine, bromine or iodine.

2. The compound according to claim 1, characterized in that The R1 is one or more substituents, each independently selected from hydrogen, halogen, methoxy, methyl, hydroxyl, isopropoxy, amino, The halogen refers to chlorine or fluorine; when R1 is a multi-substituted fluorine.

3. The compound according to claim 2, characterized in that R1 is 3 substituted fluorine.

4. The compound according to claim 1, characterized in that The R2 is methylamino, ethylamino, propylamino or dimethylamino.

5. The compound according to claim 1, characterized in that The compound shown in formula I is selected from:

6. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or ester thereof in the preparation of a STAT3 inhibitor.

7. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for preventing and / or treating tumor-related diseases.

8. The use according to claim 7, characterized in that: The tumor-related disease is lung cancer.

9. A pharmaceutical composition, characterized in that: Contains a therapeutically effective amount of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

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