Use of a bis-amidine containing compound and pharmaceutically acceptable salts in antifungal

Abstract

The application provides a kind of double amidino-containing compound and the application of pharmaceutically acceptable salt in antifungal, belong to medical technical field.The double amidino-containing compound of the application has the structure shown in formula I R1 and R2 independently selected from hydrogen, substituted or unsubstituted C 1‑12 Alkyl or C 3‑12 Cycloalkyl, or R1 and R2 and N form substituted or unsubstituted 3-6 membered ring, R3 is independently selected from hydrogen, substituted or unsubstituted alkyl; or R2 and R3 are connected to form substituted or unsubstituted 5-7 membered ring with amidino, R1 is independently selected from hydrogen, substituted or unsubstituted alkyl; R is independently selected from hydrogen, halogen, haloalkyl or alkoxy; X and Y are independently selected from C or N; Q is independently selected from oxygen, amine group, alkylamine group, alkyne group, alkoxy or Q group is not present, i.e. two aromatic rings are directly connected.The double amidino-containing compound of the application has good Candida albicans activity and therapeutic index, and can be used for clinical treatment of Candida albicans, to solve the problem of fungal drug resistance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a compound containing a diamidinium group and the application of a pharmaceutically usable salt in antifungal activity. Background Technology

[0002] In recent years, the incidence of fungal infections has been rising steadily. A 2017 report indicated that fungal and yeast infections (such as Aspergillus and Candida) cause more than 1.5 million deaths globally each year. A recent study published in *The Lancet Infectious Diseases* found that global deaths related to fungal infections are severely underestimated, estimated at approximately 3.75 million, double the previous estimate. Of these, about 2.6 million (68%) deaths are directly caused by fungal infections. Many fungi develop resistance to commonly used drugs, resulting in a very limited range of clinically available treatments.

[0003] Currently, there are three main classes of antifungal drugs used clinically to treat fungal infections: polyenes, triazoles, and echinocandins. These are primarily available in oral, topical, and intravenous formulations. Polyenes are macrolide organic molecules with strong antifungal activity and a broad antibacterial spectrum. Commonly used representative drugs include nystatin and amphotericin B (AmB). Triazoles are the most widely used class of antifungal drugs, including fluconazole, itraconazole, and voriconazole, used clinically to treat candidiasis, cryptococcosis, coccidioidomycosis, and other fungal infections. Echinocandins, which were introduced in the 21st century, are natural or semi-synthetic lipopeptides and are currently active in domestic and international markets. Major products include capapfungin, micafungin, and anidulafungin. With its widespread clinical application, Candida albicans has developed varying degrees of resistance to these drugs. Clinically, echinocandins are often used in combination with triazoles or polyenes to treat invasive Candida infections.

[0004] With prolonged drug abuse and unnecessary drug exposure, fungal resistance to these drugs is increasing, limiting treatment options for patients and posing a growing challenge to clinicians and patients worldwide. Therefore, the discovery of new targets and novel structures for antifungal drugs has become an urgent need. Summary of the Invention

[0005] In view of this, the present invention provides a compound containing a diamidinium group and a pharmaceutically usable salt thereof, which is a candidate antifungal drug with a novel structure, solving the problems of limited antifungal drug selection and fungal resistance caused by drug abuse.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides the use of a compound containing a diamidinium group and a pharmaceutically usable salt in antifungal applications, said compound having the structural formula shown in Formula I:

[0008]

[0009] Preferably, R1 and R2 are independently selected from hydrogen, substituted or unsubstituted C. 1-12 straight-chain alkyl, C 3-12 Branched alkyl or C 3-12 Cycloalkyl.

[0010] Preferably, R1 and R2 together with the N connecting them form a substituted or unsubstituted 3-6 membered ring; R3 is independently selected from hydrogen, substituted or unsubstituted alkyl groups.

[0011] Preferably, R2 and R3 are connected to an amidoyl group to form a substituted or unsubstituted 5-7 membered ring; R1 is independently selected from hydrogen, substituted or unsubstituted alkyl groups.

[0012] Preferably, R is independently selected from hydrogen, halogen, haloalkyl or alkoxy; X and Y are independently selected from C or N; Q is independently selected from oxygen, amino, alkylamino, alkynyl, alkoxy or no Q group is present, and the two aromatic rings are directly connected.

[0013] The present invention also provides the use of a compound containing a diamidinium group and a pharmaceutically usable salt in antifungal activity, said compound having the structural formula shown in Formula II:

[0014]

[0015] Preferably, R1 and R2 are independently selected from hydrogen, substituted or unsubstituted C. 1-12 straight-chain alkyl, C 3-12 Branched alkyl or C 3-12 Cycloalkyl.

[0016] Preferably, R1 and R2, together with N connecting them, form substituted or unsubstituted 3-6 membered rings.

[0017] Preferably, R2 and R3 are connected to an amidoyl group to form a substituted or unsubstituted 5-7 membered ring; R1 is independently selected from hydrogen, substituted or unsubstituted alkyl groups.

[0018] Preferably, R3 is independently selected from hydrogen, substituted or unsubstituted alkyl groups.

[0019] The specific synthetic processes of the compounds shown in Formula I and Formula II can be described as follows, with the reaction formulas as follows:

[0020]

[0021] In the above synthetic route,

[0022] Process a: 4-methyl-3-nitrophenylacetonitrile, the diphenyl ether obtained in the previous step, a small amount of piperidine, under nitrogen protection, was heated to 100°C and stirred to react. After 2 hours, the mixture was cooled to obtain a large amount of yellow solid.

[0023] Process b: The yellow solid in process b is crushed, triethyl phosphite is added, and the mixture is heated under nitrogen protection and refluxed until the TCL shows that the reactants have reacted completely. Heating is then stopped, methanol is added, and a large amount of yellow solid precipitates out and is collected.

[0024] Step c: In a three-necked flask, add the crushed yellow solid obtained in step c, followed by tetrahydrofuran and absolutely anhydrous ethanol. At low temperature, purge with dry hydrogen chloride gas until the solution is saturated. React at room temperature for at least 24 hours, and perform TLC until the TCL shows that all the starting materials have been consumed. Evaporate most of the ethanol, filter the precipitated solid, and dry it.

[0025] Process d: Add ethanol and excess of the corresponding amine to the solid obtained in process c, and react until the starting material is completely consumed. Filter off the insoluble matter, distill the filtrate under reduced pressure to 2-3 mL, add acetone or diethyl ether, and continue until the solid slowly precipitates. Dry and weigh to obtain the final product.

[0026] Preferably, the fungus is Candida albicans.

[0027] By adopting the above technical solution, the present invention has the following beneficial effects: the compound containing a diamidinium group of the present invention has the structure shown in Formula I, where R1 and R2 are independently selected from hydrogen, substituted or unsubstituted C. 1-12 Alkyl or C 3-12 The compound contains a cycloalkyl group, or R1 and R2 forming a substituted or unsubstituted 3-6 membered ring with N, where R3 is independently selected from hydrogen, a substituted or unsubstituted alkyl group; or R2 and R3 are linked with an amidine group to form a substituted or unsubstituted 5-7 membered ring, where R1 is independently selected from hydrogen, a substituted or unsubstituted alkyl group; R is independently selected from hydrogen, halogen, haloalkyl, or alkoxy; X and Y are independently selected from C or N; Q is independently selected from oxygen, amino, alkylamino, alkynyl, alkoxy, or the Q group is absent, i.e., the two aromatic rings are directly linked. The diamidinium-containing compound of this invention exhibits excellent Candida albicans activity and a therapeutic index, and can be used clinically for the treatment of Candida albicans, addressing the problem of fungal drug resistance. Detailed Implementation

[0028] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0029] Example 1

[0030] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboximide) (compound KJ-7)

[0031] 1) Preparation of 2,2'-(oxybis(4,1-phenylene))bis(1H-indole-6-nitrile)

[0032] [(4-formylphenyl)oxy]benzaldehyde (10.0 mmol) and 4-methyl-3-nitrobenzenenitrile (20.0 mmol) were mixed with 0.4 mL of piperidine. The mixture was heated to 150 °C and stirred for 6 hours, then cooled to room temperature. The solid was crushed and 10 mL of ethyl acetate was added with stirring to obtain a yellow powder, which was used directly in the next reaction.

[0033] The yellow powder (300 mg) from the previous step was added to triethyl phosphite (5 mL), and refluxed for 12 hours under nitrogen protection. The solvent was removed under vacuum, and methanol (10 mL) was added. A solid precipitated out, with a yield of 37%.

[0034] 2) The solid from the previous step (250 mg) was dissolved in ultra-dry tetrahydrofuran (7 mL) and ethanol (14 mL), cooled to 5°C, and dry hydrogen chloride gas was bubbled into the solution for 2 hours. Then, the solution was sealed and stirred at room temperature for 3 days, and concentrated under reduced pressure below 40°C. Diethyl ether was added to the residue, and a solid precipitated.

[0035] The solid was dissolved in ethanol, and an ethanol solution of methylamine (4 equivalents) was added. The mixture was stirred at 60°C for 2 hours, the solvent was removed, and the target compound was purified using a chromatographic column (Sephadex LH-20) to obtain the target compound KJ-7 in 45% yield.

[0036] The spectral information for KJ-7 is as follows: 1 HNMR(DMSO-d6,400MHz,δppm)12.30(2H,s,2NH),9.69(2H,s,2NH),9.38(2H,S,2NH),8.78(2H,s,2NH),8.02(4H,d,J=8.8,Ph-H),7.84(2H,s,Indole-H ),7.71(2H,d,J=8.4,Indole-H),7.36(2H,d,J=8.4,Indole-H),7.22(4H,d,J=8.8,Ph-H),7.02(2H,s,Indole-H),3.03(6H,d,J=4.8,2CH3); HR-ESI-MS m / z:(M+H) + caled forC32H28N6O 513.2397, found 513.2400.

[0037] Example 2

[0038] Preparation of 1-(2-(4-(4-(6-(1-iminoethyl)-1H-indol-2-yl)phenoxy)phenyl)-1H-indol-6-yl)-N-methylethane-1-imine (KJ-7d)

[0039] In Example 1, another product was obtained when the final product was purified by a chromatographic column (Sephadex LH-20).

[0040] The spectral information for KJ-7d is: HR-ESI-MS m / z:(M+H) + caled for C33H31N6O 527.2559,found527.2559.

[0041] Example 3

[0042] Preparation of 1,1'-(oxybis(4,1-phenylene))bis(1H-indole-2,6-diyl))bis(N-methylethane-1-imine) (KJ-7L)

[0043] In Example 1, the final step involved adding an ethanol solution of methylamine (10 equivalents), stirring at 60°C for 24 hours, and the precipitated solid was KJ-7L.

[0044] The spectral information for KJ-7L is: HR-ESI-MS m / z:(M+H) + caled for C34H33N6O 541.2716,found541.2715.

[0045] Example 4

[0046] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-ethyl-1H-indole-6-carboximide) (compound KJ-a1)

[0047] In Example 1, methylamine was replaced with ethylamine, and KJ-a1 was obtained using a method similar to that of Example 1.

[0048] KJ-a1: 1HNMR(DMSO-d6,400MHz,δppm)12.38(2H,s,2NH),9.65(2H,s,2NH),9.35(2H,S,2 NH),8.88(2H,s,2NH),8.03(4H,d,J=8.4,Ph-H),7.84(2H,s,Indole-H),7.71(2 H,d,J=8.4,Indole-H),7.35(2H,d,J=8.4,Indole-H),7.21(4H,d,J=8.4,Ph-H) ,7.02(2H,s,Indole-H),3.47(4H,m,2CH2),1.26(6H,1,J=7.2,2CH3);HR-ESI-MS m / z:(M+H) + caledfor C34H32N6O 541.2710, found 541.2714.

[0049] Example 5

[0050] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-propyl-1H-indole-6-carboximide) (compound KJ-18)

[0051] In Example 1, methylamine was replaced with propylamine, and KJ-18 was obtained using a method similar to that of Example 1.

[0052] KJ-18: 1 HNMR(DMSO-d6,400MHz,δppm)12.16(2H,s,2NH),9.53(2H,s,2NH),9.23(2H,s,2NH),8. 75(2H,s,2NH),7.92(4H,d,J=8.4,Ph-H),7.72(2H,s,Indole-H),7.63(2H,d,J=8.4,Ind ole-H),7.26(2H,d,J=8.4,Indole-H),7.13(4H,d,J=8.4,Ph-H),6.94(2H,s,Indole-H ),3.30(4H,m,2CH2),1.59(4H,m,2CH2),0.89(6H,t,J=7.2,2CH3); HR-ESI-MSm / z:(M+H) + caled for C36H36N6O 569.3023, found 569.3027.

[0053] Example 6

[0054] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-isobutyl-1H-indole-6-carboximide) (compound KJ-8)

[0055] In Example 1, methylamine was replaced with 2-isobutylamine, and KJ-8 was obtained using a method similar to that of Example 1.

[0056] KJ-8: 1 HNMR(DMSO-d6,400MHz,δppm)12.26(2H,s,2NH),9.39(2H,s,2NH),9.28(2H,s,2NH),8.87(2H ,s,2NH),8.00(4H,d,J=8.4,Ph-H),7.79found,(2H,s,Indole-H),7.72(2H,d,J=8.4,Indole -H),7.34(2H,d,J=8.4,Indole-H),7.22(4H,d,J=8.4,Ph-H),7.03(2H,s,Indole-H),3.89(2 HR-ESI-MS m / z:(M+H) + caled for C38H40N6O 597.3336,found597.3340.

[0057] Example 7

[0058] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-3-isopentyl-1H-indole-6-carboximide) (compound KJ-9)

[0059] In Example 1, methylamine was replaced with 3-isoamylamine, and KJ-9 was obtained using a method similar to that of Example 1.

[0060] KJ-9: 1 HNMR (DMSO-d6, 400MHz, δppm); 12.30 (2H, s, 2NH), 9.32 (2H, d, J = 8.0,

[0061] 2NH),9.28(2H,s,2NH),8.91(2H,s,2NH),8.91(2H,s,2NH),8.02(4H,d,J=8.4,Ph-H),7.81(2H,s,Indole-H),7.72(2H,d,J=8.4,Indole-H),7.34(2 H,m,Indole-H),7.22(4H,d,J=8.4,Ph-H),7.03(2H,d,J=1.2,Indole-H), 3.79 (2H, t, 2СH), 1.66 (8H, m, 4СH2), 0.95 (12H, t, J = 7.2, 4СH3); HR-ESI-MS m / z:(M+H) + caled for C40H44N6O625.3649,found625.3654.

[0062] Example 8

[0063] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboximide) (compound KJ-a2)

[0064] In Example 1, methylamine was replaced with dimethylamine, and KJ-a2 was obtained using a method similar to that of Example 1.

[0065] KJ-a2: 1 HNMR(DMSO-d6,400MHz,δppm)12.22(2H,s,2NH),9.23(2H,s,2NH),8.86(2H,s,2NH),8.00(4H,d,J=8.8,Ph-H),7.72(2H,d,J=8.0,Indole-H),7.63( HR-ESI-MS m / z:(M+H) + caled forC34H32N6O541.2710, found 541.2714.

[0066] Example 9

[0067] Preparation of N,N'-bis(2-methoxyethyl)-2-(4-(4-(6-(N-(2-methoxyethyl)carbamoyl)-1H-indole-2-yl)phenoxy)phenyl)-1H-indole-6-carboxamide (compound KJ-19)

[0068] In Example 1, methylamine was replaced with methoxyethylamine, and KJ-19 was obtained using a method similar to that in Example 2.

[0069] KJ-19:HR-ESI-MS m / z:(M+H) + caled for C39H43N6O4659.3346,found659.3348.

[0070] Example 10

[0071] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-cyclopropyl-1H-indole-6-carboximide) (compound KJ-3)

[0072] In Example 1, methylamine was replaced with cyclopropaneamine, and KJ-3 was obtained using a method similar to that of Example 1.

[0073] KJ-3: 1 HNMR(DMSO-d6,400MHz,δppm)12.33(2H,s,2NH),9.83(2H,s,2NH),9.55(2H,s,2NH ),8.98(2H,s,2NH),8.02(4H,d,J=8.4,Ph-H),7.82(2H,s,Indole-H),7.70(2H,d,J =8.4,Indole-H),7.34(2H,d,J=8.4,Indole-H),7.21(4H,d,J=8.4,Ph-H),7.02(2 H,s,Indole-H),2.81(2H,m,2CH),0.95(4H,m,2CH2),0.83(4H,m,2CH2); HR-ESI-MS m / z:(M+H) + caled for C36H32N6O 565.2710, found 65.2713.

[0074] Example 11

[0075] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-cyclobutyl-1H-indole-6-carboximide) (compound KJ-5)

[0076] In Example 1, methylamine was replaced with cyclobutaneamine, and KJ-5 was obtained using a method similar to that of Example 1.

[0077] KJ-5: 1 HNMR(DMSO-d6,400MHz,δppm)12.30(2H,s,2NH),9.85(2H,d,J=8.0,

[0078] 2NH),9.35(2H,s,2NH),8.73(2H,s,2NH),8.02(4H,d,J=8.0,Ph-H),7,81found,(2H,s,Indole-H),7.71(2H,d,J=8.4,Indole-H),7.35(2H,dd,J=8.4,1.6, HR-ESI-MS m / z:(M+H) + caled forC38H36N6O593.3023, found 593.3027.

[0079] Example 12

[0080] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-cyclopentyl-1H-indole-6-carboximide) (compound KJ-1)

[0081] In Example 1, methylamine was replaced with cyclopentaneamine, and KJ-1 was obtained using a method similar to that of Example 1.

[0082] KJ-1: 1 HNMR(DMSO-d6,400MHz,δppm)12.27(2H,s,2NH),9.53(2H,d,J=8.0,

[0083] 2NH),9.32(2H,s,2NH),8.84(2H,s,2NH),8.01(4H,d,J=8.0,Ph-H),7.78(2H,s,Indole-H),7.71(2H,d,J=8.4,Indole-H),7.32(2H,dd,J=8.4,1.2,Ind HR-ESI-MS m / z:(M+H) + caled for C40H40N6O621.3340, found 621.3336.

[0084] Example 13

[0085] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(N-cyclohexyl-1H-indole-6-carboximide) (compound KJ-2)

[0086] In Example 1, methylamine was replaced with cyclohexaneamine, and KJ-2 was obtained using a method similar to that of Example 1.

[0087] KJ-2: 1 HNMR(DMSO-d6,400MHz,δppm)12.32(2H,s,2NH),9.41(2H,d,J=8.0,

[0088] 2NH),9.29(2H,s,2NH),8.95(2H,s,2NH),8.02(4H,d,J=8.8,Ph-H),7.79(2H,s,Indole-H),7.71(2H,d,J=8.4,Indole-H),7.32(2H,dd, J=8.4,0.8,Indole-H),7.21(4H,d,J=8.8,Ph-H),7.02(2H,d,J=0.8,Indole-H),3.74(2H,m,2CH),1.13-1.97(20H,m,5CH2); HR-ESI-MS m / z:(M+H) + caled for C42H44N6O 649.3649, found 649.3654.

[0089] Example 14

[0090] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(azacyclobutane-1-ylmethylamine) (compound KJ-22)

[0091] In Example 1, methylamine was replaced with aziridine, and KJ-22 was obtained using a method similar to that of Example 1.

[0092] KJ-22: 1HNMR(DMSO-d6,400MHz,δppm)12.29(2H,s,2NH),9.20(2H,s,2NH),8.64(2H,s,2NH),8.01(4H,d,J=8.8,Ph-H),7.70(4H,m,Indole-H ),7.25(2H,s,Indole-H),7.21(4H,d,J=8.8,Ph-H),7.02(2H,d,J=1.6,Indole-H),4.37(8H,m,4CH2),2.38(4H,m,2CH2); HR-ESI-MS m / z:(M+H) + caled for C36H32N6O 565.2710, found 565.2713.

[0093] Example 15

[0094] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(azacyclopentane-1-ylmethylamine) (compound KJ-4)

[0095] In Example 1, methylamine was replaced with azircyclopentane, and KJ-4 was obtained using a method similar to that of Example 1.

[0096] KJ-4: 1 HNMR(DMSO-d6,400MHz,δppm)12.30(2H,s,2NH),9.20(2H,s,2NH),8.71(2H,s,2NH),8. 01(4H,d,J=8.8,Ph-H),7.70(2H,d,J=8.0,Indole-H),7.66(2H,s,Indole-H),7.23(2H ,d,J=8.0,Indole-H),7.21(4H,d,J=8.8,Ph-H),7.01(2H,s,Indole-H),3.58(4H,t,J= 6.4,2CH2),3.49(4H,t,J=6.4,2CH2),2.07(4H,m,2CH2),1.87(4H,m,2CH2); HR-ESI-MS m / z:(M+H) + caled for C38H36N6O 593.3023, found 593.3027.

[0097] Example 16

[0098] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(azacyclohexane-1-ylmethylamine) (compound KJ-6)

[0099] In Example 1, methylamine was replaced with azircyclohexane, and KJ-6 was obtained using a method similar to that of Example 1.

[0100] KJ-6: 1 HNMR(DMSO-d6,400MHz,δppm)12.32(2H,s,2NH),9.30(2H,s,2NH),9.10(2H,s,2NH),8.0 1(4H,d,J=8.0,Ph-H),7.72(2H,d,J=8.0,Indole-H),7.63(2H,s,Indole-H),7.21(4H,d ,J=8.8,Indole-H),7.15(2H,d,J=8.0,Ph-H),7.02(2H,s,Indole-H),3.75(4H,m,2CH2) ,3.42(4H,m,2CH2),1.76(4H,m,2CH2),1.66(4H,m,2CH2),1.55(4H,m,2CH2); HR-ESI-MS m / z:(M+H) + caled for C40H40N6O 621.3336, found 621.3340.

[0101] Example 17

[0102] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(4-methylazacyclohexane-1-ylmethylamine) (compound KJ-10)

[0103] In Example 1, methylamine was replaced with 4-methylazacyclohexane, and KJ-10 was obtained using a method similar to that of Example 1.

[0104] KJ-10: 1HNMR(DMSO-d6,400MHz,δppm)12.33(2H,s,2NH),9.31(2H,s,2NH),9.12(2H,s,2NH),8.01(4H,d,J=8.8,Ph-H),7. 71(2H,d,J=8.0,Indole-H),7.64(2H,s,Indole-H),7.21(4H,d,J=8.8,Indole-H),7.15(2H,d,J=8.0,Ph-H),7.02 (2H,s,Indole-H),4.21(2H,d,J=12.4,2CH),3.63(2H,d,J=12.4,2CH),3.22(4H,m,2CH2),1.84(4H,m,2CH2),1.7 4(4H,m,2CH2),1.64(2H,d,J=12.4,2CH),1.38(2H,m,2CH),1.24(2H,m,2CH),1.09(6H,d,J=6.8,2CH3); HR-ESI-MS m / z:(M+H) + caled for C42H44N6O 649.3649,found649.3653.

[0105] Example 18

[0106] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(3,5-dimethylazacyclohexane-1-ylmethylamine) (compound KJ-11)

[0107] In Example 1, methylamine was replaced with 3,5-dimethylazacyclohexane, and KJ-11 was obtained using a method similar to that of Example 1.

[0108] KJ-11: 1HNMR(DMSO-d6,400MHz,δppm)12.25(2H,s,2NH),9.31(2H,s,2NH),9.13(2H,s,2NH),8.00(4H,d,J=8.8,Ph-H ),7.72(2H,d,J=8.4,Indole-H),7.63(2H,s,Indole-H),7.22(4H,d,J=8.8,Indole-H),7.15(2H,d,J=8.4,P h-H),7.02(2H,s,Indole-H),4.18(2H,brs,2CH),3.55(2H,brs,2CH),2.80(4H,m,2CH2),1.84(2H,brs,2CH) ,1.71(2H,brs,2CH),1.03(4H,d,J=6.4,2CH2),0.97(6H,d,J=5.6,2CH),0.71(6H,d,J=5.6,2CH); HR-ESI-MS m / z:(M+H) + caled for C44H48N6O 677.3962, found 677.3968.

[0109] Example 19

[0110] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(morpholino-1-ylmethylamine) (compound KJ-14)

[0111] In Example 1, methylamine was replaced with morpholine, and KJ-14 was obtained using a method similar to that of Example 1.

[0112] KJ-14: 1 HNMR(DMSO-d6,400MHz,δppm)12.36(2H,s,2NH),9.51(2H,s,2NH),9.31(2H,s,2 NH),8.02(4H,d,J=8.8,Ph-H),7.72(2H,d,J=8.0,Indole-H),7.67(2H,s,Indole -H),7.21(4H,d,J=8.8,Indole-H),7.18(2H,d,J=8.0,Ph-H),7.02(2H,s,Indol e-H),3.84(8H,brs,4CH2),3.67(4H,brs,2CH2),3.47(4H,brs,2CH2); HR-ESI-MS m / z:(M+H) + caled for C38H36N6O3625.2921, found 625.2925.

[0113] Example 20

[0114] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(piperazin-1-methylamine) (compound KJ-15)

[0115] In Example 1, methylamine was replaced with piperazine, and KJ-15 was obtained using a method similar to that of Example 1.

[0116] KJ-15:HR-ESI-MS m / z:(M+H) + caled for C38H39N8O 623.3247,found623.3246.

[0117] Example 21

[0118] Preparation of ((bis(4,1-phenylene oxide))bis(1H-indole-2,6-diyl))bis(4-(pyrrolidone-1-yl)piperidin-1-ylmethylamine) (compound KJ-13)

[0119] In Example 1, methylamine was replaced with 4-(pyrrolidine-1-yl)piperidine, and KJ-13 was obtained using a method similar to that of Example 1.

[0120] KJ-13: 1 HNMR(DMSO-d6,400MHz,δppm)12.26(2H,s,2NH),9.51(2H,s,2NH),9.29(2H,s,2NH),8.00(4H,d,J =8.4,Ph-H),7.75(2H,d,J=8.4,Indole-H),7.63(2H,s,Indole-H),7.22(4H,d,J=8.8,Indole-H) ,7.16(2H,d,J=8.4,Ph-H),7.04(2H,s,Indole-H),4.34(2h,m,2CH),3.76(2H,m,2CH),3.50(8H,m ,4CH2),3.06(4H,m,4CH),2.88(2H,m,2CH),1.98(8H,brs,4CH2),1.87(8H,brs,4CH2); HR-ESI-MS m / z:(M+H) + caled forC48H54N8O 759.4493,found 759.4499.

[0121] Example 22

[0122] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(6-(4,5-dihydro-1H-imidazol-2-yl)-1H-indole) (compound KJ-20)

[0123] In Example 1, methylamine was replaced with ethylenediamine, and KJ-20 was obtained using a method similar to that of Example 1.

[0124] KJ-20: 1 HNMR(DMSO-d6,400MHz,δppm)12.41(2H,s,2NH),10.45(4H,s,2NH2),8.10(2H,s,Indole-H),8.05(4H,d,J=8.8,Ph-H),7.74(2H,d, J=8.8,Indole-H),7.59(2H,d,J=8.8,Indole-H),7.22(4H,d,J=8.8,Ph-H),7.05(2H,s,Indole-H),3.99(8H,brs,4CH2); HR-ESI-MS m / z:(M+H) + caled for C34H28N6O 537.2397, found 537.2399.

[0125] Example 23

[0126] Preparation of 2,2'-(oxybis(4,1-phenylene))bis(6-(1,4,5,6-tetrahydropyrimidin-2-yl)-1H-indole) (compound KJ-30)

[0127] In Example 1, methylamine was replaced with propylenediamine, and KJ-30 was obtained using a method similar to that of Example 1.

[0128] KJ-30: 1 HNMR(DMSO-d6,400MHz,δppm)12.37(2H,s,2NH),9.87(4H,s,2NH2),8.03(2H,s,Indole-H),7.82(2H,s,Indole-H),7.71(2H,d,J=8.4,Ind HR-ESI-MS m / z:(M+H) + caled for C36H32N6O 565.2710, found 565.2713.

[0129] Example 24

[0130] Preparation of N-isopropyl-3-(3-(4-(6-(N-isopropylcarbamoyl)-1H-indol-2-yl)phenoxy)phenyl)-1H-indol-6-carbamoimide (compound KJ-K2)

[0131] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 3-(4-formylphenoxy)benzaldehyde, and methylamine was replaced with isopropylamine. KJ-K2 was obtained using a method similar to that of Example 1.

[0132] KJY-K2:HR-ESI-MS m / z:(M+H) + caled for C36H37N6O 569.3029,found569.3031.

[0133] Example 25

[0134] Preparation of N-dimethylamino-3-(3-(4-(6-(N-dimethylcarbamoyl)-1H-indol-2-yl)phenoxy)phenyl)-1H-indol-6-carbamoimide (compound KJ-K3)

[0135] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 3-(4-formylphenoxy)benzaldehyde, and methylamine was replaced with dimethylamine. KJ-K3 was obtained by a method similar to that in Example 1.

[0136] KJY-K3:HR-ESI-MS m / z:(M+H) + caled for C34H33N6O 541.2716,found541.2717.

[0137] Example 26

[0138] Preparation of 2-(2-chloro-4-(4-(6-(N-methylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-methyl-1H-indol-6-carbamoylimide (compound KJ-G1)

[0139] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-chloro-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and KJ-G1 was obtained using a method similar to that of Example 1.

[0140] KJY-G1: 1H NMR(400MHz,DMSO)δ12.34(s,1H,indole-NH),12.16(s,1H,indole-NH),9.72(br,2H,2 NH CH3),9.40(br,2H,C=NH2),8.81(br,2H,C=NH2),8.10(d,2H,J=8.4Hz,2Ph-H),7.72(m,5H,4indole-H,1Ph-H),7.28(m,6H,2i ndole-H,4Ph-H),7.22(s,1H,indole-H),6.98(s,1H,indole-H),2.92(s,6H,2CH3).HRMS(ESI)m / z:547.2000(Calcd[M+H]for C32H28ClN6O:547.2008m / z).

[0141] Example 27

[0142] Preparation of 2-(2-chloro-4-(4-(6-(N-isopropylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-isopropyl-1H-indol-6-carbamoylimide (compound KJ-G2)

[0143] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-chloro-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with isopropylamine. KJ-G2 was obtained using a method similar to that of Example 1.

[0144] KJY-G2: 1 H NMR(400MHz,DMSO)δ12.25(s,1H,indole-NH),12.10(s,1H,indole-NH),9.70(br,2H,2 NH CH3),9.39(br,2H,C=NH2),8.79(br,2H,C=NH2),8.05(m,2H,J=8.8Hz,2Ph-H),7.75(m,5H,4indole-H,1Ph-H),7.33(m,6H,2indole-H,4Ph-H ),7.22(s,1H,indole-H),6.98(s,1H,indole-H),4.07(m,2H,CHCH3),1.31(d,12H,J=6.4Hz,4CH3).HRMS(ESI)m / z:603.2624(Calcd[M+H]for C36H36ClN6O:603.2634m / z).

[0145] Example 28

[0146] Preparation of 2-(2-chloro-4-(4-(6-(N-dimethylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-dimethyl-1H-indol-6-carboximide (compound KJ-G3)

[0147] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-chloro-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with dimethylamine. KJ-G3 was obtained using a method similar to that of Example 1.

[0148] KJY-G3: 1 H NMR (400MHz, DMSO) δ12.24(s,1H,indole-NH),12.06(s,1H,indole-NH),9.23(s,2H,C=NH2),8.86(br,2H,C=NH2),8.04(d,2H,J=8.8Hz ,2Ph-H),7.80(m,2H,2indole-H),7.73(m,1H,Ph-H),7.62(m,2H,2indole-H),7.31(m,1H,Ph-H),7.24(d,2H,J=8.8Hz,2Ph-H),7.19(m 3H,2indole-H,1Ph-H),7.06(s,1H,indole-H),6.97(s,1H,indole-H),3.28(s,6H,2CH3),3.08(d,6H,J=2.4Hz,2CH3).HRMS(ESI)m / z:575.2312(Calcd[M+H]for C34H32ClN6O:575.2321m / z).

[0149] Example 29

[0150] Preparation of 2-(2-trifluoromethyl-4-(4-(6-(N-methylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-methyl-1H-indol-6-carbamoimide (compound KJ-D1)

[0151] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-trifluoromethyl-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and KJ-D1 was obtained using a method similar to that of Example 1.

[0152] KJY-D1: 1H NMR(400MHz,DMSO)δ12.30(s,1H,indole-NH),12.11(s,1H,indole-NH),9.69,9.68(2s,2H,2 NH CH3),9.38(s,2H,2C=NH),8.81,8.78(2s,2H,2C=NH),8.08(d,2H,J=8.8Hz,2Ph -H),7.73(m,5H,4indole-H,Ph-H),7.56(s,1H,Ph-H),7.48(m,1H,Ph-H),7.40 (m,2H,2indole-H),7.34(d,2H,J=8.8Hz,2Ph-H),7.07(s,1H,indole-H),6.70(s,1H,indole-H),3.04(m,6H,2CH3).HRMS(ESI)m / z:581.2251(Calcd[M+H]for C 33 H 28 ON6F3:581.2271m / z).

[0153] Example 30

[0154] Preparation of 2-(2-trifluoromethyl-4-(4-(6-(N-isopropylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-isopropyl-1H-indol-6-carbamoylimide (compound KJ-D2)

[0155] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-trifluoromethyl-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with isopropylamine. KJ-D2 was obtained using a method similar to that of Example 1.

[0156] KJY-D2: 1 H NMR(400MHz,DMSO)δ12.32(s,1H,indole-NH),12.06(s,1H,indole-NH),9.46,9.44(2s,2H,2 NHCH3),9.31(s,2H,2C=NH),8.90,8.88(2s,2H,2C=NH),8.08(d,2H,J=8.4Hz,2Ph -H),7.73(m,5H,4indole-H,Ph-H),7.56(s,1H,Ph-H),7.48(m,1H,Ph-H),7.32 (m,4H,2indole-H,2Ph-H),7.08(s,1H,indole-H),6.71(s,1H,indole-H),4.10(m,2H,2CHCH3),1.31(m,12H,4CH3).HRMS(ESI)m / z:637.2927(Calcd[M+H]for C 37 H 36 ON6F3:637.2897m / z).

[0157] Example 31

[0158] Preparation of 2-(2-trifluoromethyl-4-(4-(6-(N-dimethylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-dimethyl-1H-indol-6-carboximide (compound KJ-D3)

[0159] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-trifluoromethyl-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with dimethylamine. KJ-D3 was obtained using a method similar to that of Example 1.

[0160] KJY-D3: 1 H NMR (400MHz, DMSO) δ12.35(s,1H,indole-NH),12.09(s,1H,indole-NH),9.28,9.20(2s,2H,2C=NH),8.88,8. 85(2s,2H,2C=NH),8.08(d,2H,J=8.8Hz,2Ph-H),7.75(m,3H,2indole-H,Ph-H),7.65(m,2H,2indole-H),7.5 6(s,1H,Ph-H),7.49(m,1H,Ph-H),7.39(d,2H,J=8.8Hz,2Ph-H),7.20(m,2H,2indole-H),7.06(s,1H,indole -H),6.70(s,1H,indole-H),3.26(s,6H,2CH3),3.08(s,6H,2CH3).HRMS(ESI)m / z:609.2560(Calcd[M+H]for C35H32F3N6O:609.2584m / z).

[0161] Example 32

[0162] Preparation of 2-(2-methoxy-4-(4-(6-(N-methylcarbamoylamino)-1H-indole-2-yl)phenoxy)phenyl)-N-methyl-1H-indole-6-carbamoylimide (compound KJ-F1)

[0163] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-methoxy-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and KJ-F1 was obtained using a method similar to that of Example 1.

[0164] KJY-F1: 1 H NMR(400MHz,DMSO)δ12.29(s,1H,indole-NH),12.14(s,1H,indole-NH),9.66(m,2H,2 NH CH3),9.39,9.35(2s,2H,C=NH2),8.80,8.75(2s,2H,C=NH2),7.80(d,2H,J=8.8Hz,2Ph-H),7.72( s,1H,indole-H),7.62(m,4H,4indole-H),7.60(d,1H,J=2.0Hz,Ph-H),7.39(m,2H,2indole-H),7 .35(m,2H,2indole-H),7.25(m,1H,Ph-H),7.15(s,1H,Ph-1),7.05(d,2H,J=8.8Hz,2Ph-H),6.98( s,1H,indole-H),3.91(s,3H,OCH3),3.04(m,6H,2CH3).HRMS(ESI)m / z:543.2506(Calcd[M+H]for C33H31O2N6:543.2503m / z).

[0165] Example 33

[0166] Preparation of 2-(2-methoxy-4-(4-(6-(N-isopropylcarbamoylamino)-1H-indole-2-yl)phenoxy)phenyl)-N-isopropyl-1H-indole-6-carbamoylimide (compound KJ-F2)

[0167] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-methoxy-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with isopropylamine. KJ-F2 was obtained using a method similar to that of Example 1.

[0168] KJY-F2:1 H NMR(400MHz,DMSO)δ12.35(s,1H,indole-NH),12.17(s,1H,indole-NH),9.44(m,2H,2NHCH3),9.32,9.28(2s,2H ,2C=NH),8.87,8.84(2s,2H,2C=NH),7.81(d,2H,J=8.8Hz,2Ph-H),7.72(m,5H,5indole-H),7.60(d,1H,Ph-H),7. 34(m,2H,2indole-H),7.24(d,1H,Ph-H),7.14(d,1H,Ph-1),7.04(d,2H,J=8.8Hz,2Ph-H),6.97(d,1H,J=1.6Hz,i ndole-H),4.07(m,2H,2CHCH3),3.91(s,3H,OCH3),1.31(m,12H,4CH3).HRMS(ESI)m / z:599.3134(Calcd[M+H]for C37H39O2N6:599.3129m / z).

[0169] Example 34

[0170] Preparation of 2-(2-methoxy-4-(4-(6-(N-dimethylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-dimethyl-1H-indol-6-carboximide (compound KJ-F3)

[0171] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 2-methoxy-[(4-formylphenyl)oxy]benzene-1-carboxaldehyde, and methylamine was replaced with dimethylamine. KJ-F3 was obtained using a method similar to that of Example 1.

[0172] KJY-F3: 1H NMR(400MHz,DMSO)δ12.42(s,1H,indole-NH),12.20(s,1H,indole-NH),9.26,9.23(2s,2H,2C=NH), 8.90,8.87(2s,2H,2C=NH),7.91(d,2H,J=8.8Hz,2Ph-H),7.75(s,1H,indole-H),7.66(m,5H,4indol e-H,Ph-H),7.24(d,1H,Ph-H),7.17(m,3H,2indole-H,Ph-1),7.03(d,2H,J=8.8Hz,2Ph-H),6.96(d, 1H,J=0.6Hz,indole-H),3.91(s,3H,OCH3),3.25,3.23(2s,6H,2CH3),3.07,3.04(2s,6H,2CH3).HRMS HRMS(ESI)m / z:571.2820(Calcd[M+H]for C35H35O2N6:571.2816m / z).

[0173] Example 35

[0174] Preparation of N-methyl-2-(5-(4-(6-(N-methylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-2-yl)-1H-indol-6-carbamoimide (compound KJ-E1)

[0175] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formylphenoxy)pyridinecarboxaldehyde, and KJ-E1 was obtained using a method similar to that of Example 1.

[0176] KJY-E1: 1 H NMR(400MHz,DMSO / 1d CH3CH2OH)δ12.40,12.39(2s,2H,2indole-NH),8.57(d,1H,J=2.8Hz,Py-H),8.2 0(m,1H,J=8.8Hz,Py-H),8.06(d,2H,J=8.8Hz,2Ph-H),7.80(s,1H,Py-H),7.70( m,4H,4indole-H),7.37(m,2H,2indole-H),7.27(m,3H,2Ph-H,indole-H),7.05(s,1H,indole-H),3.04(m,6H,2CH3).HRMS(ESI)m / z:514.2353(Calcd[M+H]for C31H28ON7:514.2350m / z).

[0177] Example 36

[0178] Preparation of N-dimethyl-2-(5-(4-(6-(N-dimethylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-2-yl)-1H-indol-6-carboximide (compound KJ-E3)

[0179] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formylphenoxy)pyridinecarboxaldehyde, and methylamine was replaced with dimethylamine. KJ-E3 was obtained by a method similar to that of Example 1.

[0180] KJY-E3: 1 HNMR(400MHz,DMSO)δ12.33,12.28(2s,2H,2indole-NH),9.26,9.25(2s,2H,2C=NH),8.90(s,2H,2 C=NH),8.56(d,1H,J=2.8Hz,Py-H),8.16(d,1H,J=8.4Hz,Py-H),8.04(d,2H,J=7.2Hz,2Ph-H),7.7 0(m,5H,4indole-H,Py-H),7.27(m,3H,2Ph-H,1indole-H),7.20(m,2H,2indole-H),7.06(s,1H,i ndole-H),3.26(s,6H,2CH3),3.08,3.06(2s,6H,2CH3).HRMS(ESI)m / z:542.2640(Calcd[M+H]for C33H32ON7:542.2663m / z).

[0181] Example 37

[0182] Preparation of N-dimethylaminoethyl-2-(5-(4-(6-(N-dimethylaminoethylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-2-yl)-1H-indol-6-carbamoylimide (compound KJ-E4)

[0183] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formylphenoxy)pyridinecarboxaldehyde, and methylamine was replaced with dimethylaminoethylamine. KJ-E4 was obtained using a method similar to that of Example 1.

[0184] KJY-E4:HRMS(ESI)m / z:628.3511(Calcd[M+H]for C37H42N9O:628.3512m / z).

[0185] Example 38

[0186] Preparation of N-methyl-2-(5-(4-(6-(N-methylcarbamoyl)-1H-indol-2-yl)-3-(trifluoromethyl)phenoxy)pyridin-2-yl)-1H-indol-6-carboximide (compound KJ-M1)

[0187] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formyl-3-(trifluoromethyl)phenoxy)pyridinecarboxaldehyde, and KJ-M1 was obtained using a method similar to that of Example 1.

[0188] KJY-M1: 1 H NMR(400MHz,DMSO)δ12.42(s,1H,indole-NH),12.16(s,1H,indole-NH),9.72(brs,2H,2 NH CH3),9.42(brs,2H,2C=NH),8.83(brs,2H,C=NH2),8.66(s,1H,Py-H),8.20(d,1H,J=2.4Hz,Py-H ),7.87(s,2H,2indole-H),7.78(m,4H,2indole-H,2Ph-H),7.66(s,1H,Ph-H),7.56(d,1H,J=0.4 Hz,Py-H),7.42(d,1H,J=0.4Hz,indole-H),7.3(d,1H,J=0.4Hz,indole-H),7.29(s,1H,indole- H),6.70(s,1H,indole-H),3.04(d,6H,J=0.4Hz,2CH3).HRMS(ESI)m / z:582.2217(Calcd[M+H]for C32H27N7OF3:582.2224m / z).

[0189] Example 39

[0190] Preparation of N-isopropyl-2-(5-(4-(6-(N-isopropylcarbamoyl)-1H-indol-2-yl)-3-(trifluoromethyl)phenoxy)pyridin-2-yl)-1H-indol-6-carboximide (compound KJ-M2)

[0191] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formyl-3-(trifluoromethyl)phenoxy)pyridinecarboxaldehyde, and methylamine was replaced with isopropylamine. KJ-M2 was obtained using a method similar to that of Example 1.

[0192] KJY-M2: 1H NMR(400MHz,DMSO)δ12.33(s,1H,indole-NH),12.06(s,1H,indole-NH),9.46(m,2H,NH),9.30(br,2H,2C= NH),8.87(br,2H,2C=NH),8.64(s,1H,J=2.8Hz,Py-H),8.22(d,1H,J=8.4Hz,Py-H),7.78(m,6H,4indole-H ,2Ph-H),7.68(d,1H,J=2.8Hz,Ph-H),7.54(dd,1H,J=2.4Hz,J=8.4Hz,Py-H),7.33(m,3H,3indole-H),6.7 0(s,1H,indole-H),4.04(m,2H,CH),1.30,1.29(2s,12H,4CH3).HRMS(ESI)m / z:638.2887(Calcd[M+H]for C36H35ON7F3:638.2850m / z).

[0193] Example 40

[0194] Preparation of N-dimethyl-2-(5-(4-(6-(N-dimethylcarbamoyl)-1H-indol-2-yl)-3-(trifluoromethyl)phenoxy)pyridin-2-yl)-1H-indol-6-carboximide (compound KJ-M3)

[0195] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 5-(4-formyl-3-(trifluoromethyl)phenoxy)pyridinecarboxaldehyde, and methylamine was replaced with dimethylamine. KJ-M3 was obtained by a method similar to that in Example 1.

[0196] KJY-M3: 1H NMR(400MHz,DMSO)δ12.31(s,1H,indole-NH),12.10(s,1H,indole-NH),9.27,9.24(2s,2H,2C=NH),8.89(br,2H ,2C=NH),8.65(s,1H,J=2.8Hz,Py-H),8.22(d,1H,J=8.4Hz,Py-H),7.77(m,4H,2indole-H,2Ph-H),7.66(m,3H,2 indole-H,Ph-H),7.56(dd,1H,J=2.4Hz,2.8Hz,Py-H),7.31(d,1H,J=1.6Hz,indole-H),7.19(m,2H,2indole-H) ,6.71(s,1H,indole-H),3.26(s,6H,2CH3),3.08,3.07(2s,6H,2CH3).HRMS(ESI)m / z:610.2571(Calcd[M+H]for C34H31ON7F3:610.2537m / z).

[0197] Example 41

[0198] Preparation of N-methyl-2-(6-(4-(6-(N-methylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-3-yl)-1H-indol-6-carboximide (compound KJ-L1)

[0199] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 6-(4-formylphenoxy)nicotinaldehyde, and KJ-L1 was obtained using a method similar to that of Example 1.

[0200] KJY-L1: 1 H NMR(400MHz,DMSO)δ12.56(s,1H,indole-NH),12.39(s,1H,indole-NH),9.76(brs,2H,2 NHCH3),9.42(brs,2H,2C=NH),8.83(m,3H,2C=NH,Py-H),8.47(dd,1H,J=2.4,8.8Hz,Py-H),8.04 (d,2H,J=8.8Hz,2Ph-H),7.88(m,2H,2indole-H),7.72(m,2H,2indole-H),7.39(m,2H,2indole -H),7.34(d,2H,J=8.8Hz,2Ph-H),7.26(d,1H,J=8.8Hz,Py-H),7.10(d,1H,J=1.6Hz,indole-H) ,7.06(d,1H,J=1.2Hz,indole-H),3.04(m,6H,2CH3).HRMS(ESI)m / z:514.2338(Calcd[M+H]for C31H28N7O:514.2350m / z).

[0201] Example 42

[0202] Preparation of N-isopropyl-2-(6-(4-(6-(N-isopropylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-3-yl)-1H-indol-6-carbamoylimide (compound KJ-L2)

[0203] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 6-(4-formylphenoxy)nicotinaldehyde, and methylamine was replaced with isopropylamine. KJ-L2 was obtained using a method similar to that of Example 1.

[0204] KJY-L2: 1 H NMR(400MHz,DMSO)δ12.49(s,1H,indole-NH),12.33(s,1H,indole-NH),9.47(m,2H, 2NHCH),9.33(br,2H,C=NH2),8.95(br,2H,C=NH2),8.81(d,1H,J=2.0Hz,Py-H),8.43(dd,1H, J=2.4Hz,J=8.4Hz,Py-H),8.04(d,2H,J=8.8Hz,2Ph-H),7.82(s,2H,2indole-H),7.74(m,2 H,2indole-H),7.30(m,5H,2indole-H,2Ph-H,Py-H),7.11(s,1H,indole-H),7.07(s,1H,i ndole-H),4.09(m,2H,2CH),1.31(m,12H,4CH3).HRMS(ESI)m / z:570.2969(Calcd[M+H]for C35H36N7O:570.2976m / z).

[0205] Example 43

[0206] Preparation of N-dimethyl-2-(6-(4-(6-(N-dimethylcarbamoyl)-1H-indol-2-yl)phenoxy)pyridin-3-yl)-1H-indol-6-carboximide (compound KJ-L3)

[0207] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 6-(4-formylphenoxy)nicotinaldehyde, and methylamine was replaced with dimethylamine. KJ-L3 was obtained by a method similar to that in Example 1.

[0208] KJY-L3: 1H NMR (400MHz, DMSO) δ12.45(brs,1H,indole-NH),12.30(brs,1H,indole-NH),9.25(br,2H,2C=NH),8.90(br,2H,2C=N H2),8.80(s,1H,Py-H),8.44(d,1H,J=8.8Hz,Py-H),8.02(d,2H,J=8.4Hz,2Ph-H),7.74(m,2H,2indole-H),7.65(s,2 H,2indole-H),7.34(d,2H,J=8.8Hz,2Ph-H),7.26(d,1H,J=8.8Hz,Py-H),7.18(m,2H,2indole-H),7.10(s,1H,indol e-H),7.06(s,1H,indole-H),3.26(2s,6H,2CH3),3.08,3.07(2s,6H,2CH3).HRMS(ESI)m / z:542.2663(Calcd[M+H]for C33H32N7O:542.2654m / z).

[0209] Example 44

[0210] Preparation of 2,2'((methylazadiacyl)bis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboximide) (compound KJ-N1)

[0211] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(methylazido)dibenzaldehyde, and KJ-N1 was obtained using a method similar to that of Example 1.

[0212] KJY-N1:HRMS(ESI)m / z:526.2720(Calcd[M+H]for C33H32N7:526.2719m / z).

[0213] Example 45

[0214] Preparation of 2,2'((isopropylazadiacyl)bis(4,1-phenylene))bis(N-isopropyl-1H-indole-6-carboximide) (compound KJ-N2)

[0215] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(methylazido)dibenzaldehyde, and methylamine was replaced with isopropylamine. KJ-N2 was obtained using a method similar to that of Example 1.

[0216] KJL-N2:HRMS(ESI)m / z:582.3344(Calcd[M+H]for C37H40N7:582.3345m / z).

[0217] Example 46

[0218] Preparation of 2,2'((dimethylazadiacyl)bis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboximide) (compound KJ-N3)

[0219] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(methylazido)dibenzaldehyde, and methylamine was replaced with dimethylamine. KJ-N3 was obtained using a method similar to that of Example 1.

[0220] KJL-N3:HRMS(ESI)m / z:554.3033(Calcd[M+H]for C35H36N7:554.3032m / z).

[0221] Example 47

[0222] Preparation of 2,2'-([1,1'-biphenyl]-4,4'-diyl)bis(N-methyl-1H-indole-6-carboximide) (compound KJ-C1)

[0223] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-biphenylcarboxaldehyde, and KJ-C1 was obtained using a method similar to that of Example 1.

[0224] KJL-C1:HRMS(ESI)m / z:497.2454(Calcd[M+H]for C32H29N6:497.2454m / z).

[0225] Example 48

[0226] Preparation of 2,2'-([1,1'-biphenyl]-4,4'-diyl)bis(N-dimethyl-1H-indole-6-carboximide) (compound KJ-C3)

[0227] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-biphenylcarboxaldehyde, and methylamine was replaced with dimethylamine. KJ-C3 was obtained using a method similar to that of Example 1.

[0228] KJL-C3:HRMS(ESI)m / z:525.2767(Calcd[M+H]for C34H33N6:525.2767m / z).

[0229] Example 49

[0230] Preparation of 2,2'-(acetylene-1,2-diacylbis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboximide) (compound KJ-Q1)

[0231] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(acetylene-1,2-diyl)dibenzaldehyde, and KJ-Q1 was obtained using a method similar to that of Example 1.

[0232] KJL-Q1:HRMS(ESI)m / z:521.2451(Calcd[M+H]for C34H29N6:521.2454m / z).

[0233] Example 50

[0234] Preparation of 2,2'-(acetylene-1,2-diacylbis(4,1-phenylene))bis(N-isopropyl-1H-indole-6-carboximide) (compound KJ-Q2)

[0235] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(acetylene-1,2-diyl)dibenzaldehyde, and methylamine was replaced with isopropylamine. KJ-Q2 was obtained using a method similar to that of Example 1.

[0236] KJL-Q2:HRMS(ESI)m / z:577.3080(Calcd[M+H]for C38H37N6:577.3080m / z).

[0237] Example 51

[0238] Preparation of 2,2'-(acetylene-1,2-diacylbis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboximide) (compound KJ-Q3)

[0239] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(acetylene-1,2-diyl)dibenzaldehyde, and methylamine was replaced with dimethylamine. KJ-Q3 was obtained using a method similar to that of Example 1.

[0240] KJL-Q3:HRMS(ESI)m / z:549.2766(Calcd[M+H]for C36H33N6:549.2767m / z).

[0241] Example 52

[0242] Preparation of 2,2'((ethane-1,2-diacylbis(oxy))bis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboximide) (compound KJ-B1)

[0243] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(ethane-1,2-diacylbis(oxy))dibenzaldehyde, and KJ-B1 was obtained using a method similar to that of Example 1.

[0244] KJL-B1:HRMS(ESI)m / z:557.2664(Calcd[M+H]for C34H33N6O2:557.2665m / z).

[0245] Example 53

[0246] Preparation of 2,2'((ethane-1,2-diacylbis(oxy))bis(4,1-phenylene))bis(N-isopropyl-1H-indole-6-carboximide) (compound KJ-B2)

[0247] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(ethane-1,2-diacylbis(oxy))dibenzaldehyde, and methylamine was replaced with isopropylamine. KJ-B2 was obtained using a method similar to that of Example 1.

[0248] KJL-B2:HRMS(ESI)m / z:613.3291(Calcd[M+H]for C38H41N6O2:613.3291m / z).

[0249] Example 54

[0250] Preparation of 2,2'((ethane-1,2-diacylbis(oxy))bis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboximide) (compound KJ-B3)

[0251] In Example 1, [(4-formylphenyl)oxy]benzene-1-carboxaldehyde was replaced with 4,4'-(ethane-1,2-diacylbis(oxy))dibenzaldehyde, and methylamine was replaced with dimethylamine. KJ-B3 was obtained using a method similar to that of Example 1.

[0252] KJL-B3:HRMS(ESI)m / z:585.2979(Calcd[M+H]for C36H37N6O2:585.2978m / z).

[0253] Example 55. Antifungal and cytotoxic experiments

[0254] (1) Antifungal test

[0255] The minimum inhibitory concentration (MIC) of the compound against Candida albicans (ATCC 10231) was determined according to the M27-A method recommended by the National Committee for Standardization of Clinical Trials (NCCS). Frozen Candida albicans was inoculated onto YPD solid medium, subcultured once, and cultured at 35°C for 24 h. Candida albicans was also inoculated onto Sabouraud agar medium, subcultured once, and cultured at 35°C for 24 h and 48 h, respectively. The strain was adjusted to 1-5 × 10⁻⁵ PbS with physiological saline. 6 The concentration was 1000 cfu / mL, then diluted 1000 times with RPMI 1640. The compound was serially diluted with RPMI from 25.6 μg / mL to 0.0125 μg / mL. 100 μL of bacterial culture and compound solution were added to each well of a 96-well plate, with two replicates. The plates were placed at 35°C and observed at 24h, 48h, and 72h. The concentration at which no bacterial growth was visible to the naked eye was determined as the MIC.

[0256] (2) Cytotoxicity test

[0257] Human embryonic kidney cells HEK 293T were used at a dose of 1×10⁻⁶. 5 Cells were seeded at a concentration of 1 cell / mL and a volume of 200 μL per well into 96-well plates. After incubation at 37°C for 24 h, cell monolayer confluence was confirmed. Different concentrations of DMSO solution were used as the test compound, with a DMSO negative control. 2 μL of diluted compound or DMSO was added to each well, for a total of three backups. After incubation at 37°C with 5% CO2 for 48 h, the supernatant was replaced with fresh medium containing 110 μL of MTS reagent (medium medium containing 10 μL of MTS reagent per well). Incubation was further carried out for 2 h to allow MTS production. Absorbance was read using a microplate reader at a wavelength of 490 nm. The inhibition percentage was calculated using the following formula: Inhibition percentage = [100 - (At / As) × 100%], where At and As refer to the absorbance of the test substance and the DMSO control, respectively. 50 The value, defined as the concentration of the test compound at which 50% cytotoxicity occurs, is... 50 Selection index SI = CC 50 / MIC. A series of compounds exhibiting anti-Candida albicans activity (MIC, cytotoxic CC). 50 The selection index SI is shown in Table 1.

[0258] Table 1 shows the anti-Candida albicans activity, cytotoxicity, and selectivity of a series of compounds.

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] As shown in Table 1, the minimum inhibitory concentrations (MICs) of the series of compounds of this invention against Candida albicans range from 0.025 to 12.5 μg / mL, indicating good antibacterial activity against Candida albicans. Some compounds are superior to the currently used clinical drugs amphotericin B and fluconazole. Cytotoxicity experiments show that some compounds have good cytotoxicity (CC). 50 Compared to the minimum inhibitory concentration (MIC) therapeutic index (SI) value being greater than 100, KJ-30's SI is even greater than 1000. Further research is warranted to develop antifungal drugs with novel structural types.

[0270] As can be seen from the above embodiments, the present invention provides the application of a diamidinium-containing compound and a pharmaceutically usable salt in antifungal activity. The series of diamidinium-containing compounds of the present invention exhibit good antifungal activity against Candida albicans and can be used clinically to treat Candida albicans infections.

[0271] 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. The following compounds containing a diamidinium group and their pharmaceutically usable salts are used in the preparation of drugs against Candida albicans: 。

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