Diamidino-containing compound and application of pharmaceutically available salt in antifungal treatment

Abstract

The invention provides an application of a diamidino-containing compound and a pharmaceutically available salt in antifungal treatment, and belongs to the technical field of medicines. The diamidino-containing compound has a structure shown in a formula I, R1 and R2 are independently selected from hydrogen, substituted or unsubstituted C1-12 alkyl or C3-12 cycloalkyl, or R1, R2 and N form a substituted or unsubstituted 3-6-membered ring, and R3 is independently selected from hydrogen, substituted or unsubstituted alkyl; or R2 and R3 are connected to form a substituted or unsubstituted 5-7-membered ring with amidino, and R1 is independently selected from hydrogen and substituted or unsubstituted alkyl; r is independently selected from hydrogen, halogen, halogenated alkyl or alkoxy; x and Y are independently selected from C or N; q is independently selected from oxygen, amido, alkylamino, alkynyl and alkoxy, or Q group does not exist, that is, two aromatic rings are directly connected. The diamidino-containing compound provided by the invention has good Candida albicans activity and therapeutic index, can be used for clinical treatment of Candida albicans, and solves the problem of fungal drug resistance.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the use of a compound containing a double amidine group and a pharmaceutically acceptable salt thereof in antifungal treatment. Background Art

[0002] In recent years, the incidence of fungal infections has been continuously increasing. The report in 2017 showed that infections caused by molds and yeasts (such as Aspergillus and Candida) result in more than 1.5 million deaths globally every year. A recent study published in The Lancet Infectious Diseases found that the global deaths related to fungal infections are severely underestimated, being about twice the previous estimate, approximately 3.75 million, among which about 2.6 million (68%) deaths are directly caused by fungal infections. Many fungi have developed resistance to commonly used drugs, and the clinically available drugs are very limited.

[0003] Currently, the drugs clinically used for the treatment of fungal diseases mainly fall into three categories: polyenes, triazoles, and echinocandins. The main dosage forms include oral, topical, and intravenous injection drugs. Polyene compounds are macrolide organic molecules. Such drugs have strong antifungal activity and a broad antibacterial spectrum. The representative drugs commonly used clinically are nystatin and amphotericin B (AmB). Triazoles are the most widely used class of antifungal drugs at present, mainly including fluconazole, itraconazole, voriconazole, etc., and are clinically used for the treatment of candidiasis, cryptococcosis, coccidioidomycosis, etc. The echinocandin antifungal drugs launched in the 21st century are natural or semi-synthetic lipopeptides, which are currently active in the domestic and foreign markets. The main products are caspofungin, micafungin, and anidulafungin. With the extensive clinical application, Candida albicans has developed varying degrees of drug resistance to such drugs, and echinocandins are commonly used in combination with triazoles or polyenes for the treatment of invasive candidal infections clinically.

[0004] With the long-term drug abuse and unnecessary drug exposure, the drug resistance of fungi is increasing, restricting the treatment options for patients clinically, which is an increasingly severe challenge faced by clinicians and patients globally. Therefore, it has become an urgent need to discover new antifungal drugs with new action targets and new structures. Summary of the Invention

[0005] In view of this, the present invention provides a compound containing a double amidine group, a pharmaceutically acceptable salt thereof, and their applications, which are candidate new-structured antifungal drugs, and solve the problems of few choices of antifungal drugs and fungal drug resistance caused by drug abuse.

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

[0007] The present invention provides an application of a compound containing a double amidine group and a pharmaceutically acceptable salt thereof in antifungal treatment. The compound has a structural formula shown in Formula I:

[0008]

[0009] Preferably, R 1 and R 2 independently selected from hydrogen, substituted or unsubstituted C 1-12 linear alkyl, C 3-12 branched alkyl or C 3-12 cycloalkyl.

[0010] Preferably, R 1 and R 2 together with the N connecting them form a substituted or unsubstituted 3- to 6-membered ring; R 3 independently selected from hydrogen, substituted or unsubstituted alkyl.

[0011] Preferably, R 2 and R 3 are connected to form a substituted or unsubstituted 5- to 7-membered ring with the amidine group; R 1 independently selected from hydrogen, substituted or unsubstituted alkyl.

[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 the Q group is absent, and the two aromatic rings are directly connected.

[0013] The present invention also provides an application of a compound containing a double amidine group and a pharmaceutically acceptable salt thereof in antifungal treatment. The compound has a structural formula shown in Formula II:

[0014]

[0015] Preferably, R 1 and R 2 independently selected from hydrogen, substituted or unsubstituted C 1-12 linear alkyl, C 3-12 branched alkyl or C 3-12 cycloalkyl.

[0016] Preferably, R 1 and R 2 together with the N connecting them form a substituted or unsubstituted 3- to 6-membered ring.

[0017] Preferably, R 2 and R 3 are connected to form a substituted or unsubstituted 5- to 7-membered ring with the amidine group; R 1 independently selected from hydrogen, substituted or unsubstituted alkyl.

[0018] Preferably, R 3 is independently selected from hydrogen, substituted or unsubstituted alkyl.

[0019] The specific synthesis processes of the compounds shown in Formula I and Formula II can be described as follows, and the reaction formula is:

[0020]

[0021] In the above synthesis route,

[0022] Process a: 4-Methyl-3-nitrobenzyl cyanide and the diphenyl ether obtained in the previous step are added with a small amount of piperidine. Under nitrogen protection, it is heated to 100 °C and stirred for reaction. After 2 h, the temperature is lowered, and a large amount of yellow solid is obtained.

[0023] Process b: The crushed yellow solid of Process b is added with triethyl phosphite. Under nitrogen protection, it is heated to reflux until TLC shows that the raw materials have completely reacted, then heating is stopped, methanol is added, and a large amount of yellow solid precipitates and is collected.

[0024] Process c: In a three-necked flask, the crushed yellow solid obtained in Process c is added, and then tetrahydrofuran and absolute anhydrous ethanol are added. At low temperature, dry hydrogen chloride gas is introduced until the solution is saturated. React at room temperature for more than 24 h, and spot plate until TLC shows that all raw materials are consumed. Most of the ethanol is distilled off, and the precipitated solid is filtered and dried.

[0025] Process d: The solid obtained in Process c is added with ethanol and an excessive amount of the corresponding amine, and the reaction is carried out until the raw materials are consumed. The insoluble substances are filtered off, the filtrate is distilled under reduced pressure to 2 - 3 mL, and acetone or ether is added 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 solutions, the present invention has the following beneficial effects: The compound containing a bisamidine group of the present invention has the structure shown in Formula I, R 1 and R 2 are independently selected from hydrogen, substituted or unsubstituted C 1-12 alkyl or C 3-12 cycloalkyl, or R 1 and R 2 form a substituted or unsubstituted 3 - 6-membered ring with N, and R 3 is independently selected from hydrogen, substituted or unsubstituted alkyl; or R 2 and R 3 are connected to form a substituted or unsubstituted 5 - 7-membered ring with the amidine group, and R 1independently 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, amino, alkylamino, alkynyl, alkoxy or there is no Q group, that is, the two aromatic rings are directly connected. The bisamidine compound of the present invention has good Candida albicans activity and therapeutic index, and can be used for the clinical treatment of Candida albicans to solve the problem of fungal drug resistance. Detailed implementation mode

[0028] The technical solutions provided by the present invention will be described in detail below in conjunction with the embodiments, but they cannot be understood as limiting the protection scope of the present invention.

[0029] Example 1

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

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

[0032] [(4-Formylphenyl)oxy]benzene-1-carbaldehyde (10.0 mmol) and 4-methyl-3-nitrobenzonitrile (20.0 mmol) were added dropwise 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, 10 mL of ethyl acetate was added and stirred to obtain a yellow powder, which was directly used for the next reaction.

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

[0034] 2) The above solid (250 mg) was dissolved in ultradry 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 it was sealed and stirred at room temperature for 3 days, and concentrated under reduced pressure below 40 °C. Ether was added to the residue, and a solid precipitated out.

[0035] The above 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 KJ-7 was purified using a chromatographic column (Sephadex LH-20) to obtain the target compound KJ-7 with a yield of 45%.

[0036] The spectral information of KJ-7 is as follows: 1HNMR (DMSO-d6, 400 MHz, δ ppm): 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, 2CH 3 ); HR-ESI-MS m / z: (M+H) + calcd for C32H28N6O 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, when finally purified by a chromatographic column (Sephadex LH-20), another product was obtained.

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

[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 the last step of Example 1, an ethanol solution of methylamine (10 equivalents) was added and stirred at 60 °C for 24 hours. The precipitated solid was KJ-7L.

[0044] The spectral information of KJ-7L is: HR-ESI-MS m / z: (M+H) + calcd for C34H33N6O 541.2716, found 541.2715.

[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 using a method similar to that of Example 1, KJ-a1 was obtained.

[0048] KJ-a1: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 12.38 (2H, s, 2NH), 9.65 (2H, s, 2NH), 9.35 (2H, S, 2NH), 8.88 (2H, s, 2NH), 8.03 (4H, d, J = 8.4, Ph-H), 7.84 (2H, s, Indole-H), 7.71 (2H, 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, 2CH 2 ), 1.26 (6H, 1, J = 7.2, 2CH 3 );HR-ESI-MS m / z: (M+H) + caled for 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 using a method similar to that of Example 1, KJ-18 was obtained.

[0052] KJ-18: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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, Indole-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, 2CH 2 ), 1.59 (4H, m, 2CH2 ), 0.89 (6H, t, J = 7.2, 2CH 3 ); HR-ESI-MS m / 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 by a method similar to that of Example 1.

[0056] KJ-8: 1 1H NMR (DMSO-d6, 400 MHz, δ ppm) 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), 7.79 found, (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 (2H, m, 2CH), 1.67 (4Η, m, 2СH 2 ), 1.26 (6Η, d, J = 6.4, 2СH 3 ), 0.96 (6H, t, J = 7.2, 2СH 3 ); HR-ESI-MS m / z: (M+H) + caled for C38H40N6O 597.3336, found 597.3340.

[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-isopentylamine, and KJ-9 was obtained by a method similar to that of Example 1.

[0060] KJ-9: 1HNMR (DMSO-d6, 400 MHz, δ ppm); 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 (2H, m, Indole-H), 7.22 (4H, d, J = 8.4, Ph-H), 7.03 (2Η, d, J = 1.2, Indole-H), 3.79 (2Η, t, 2СH), 1.66 (8Η, m, 4СΗ 2 ), 0.95 (12H, t, J = 7.2, 4СH 3 ); HR-ESI-MS m / z: (M+H) + caled for C40H44N6O6 625.3649, found 625.3654.

[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 using a method similar to that of Example 1, KJ-a2 was obtained.

[0065] KJ-a2: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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 (2H, s, Indole-H), 7.22 (4H, d, J = 8.4, Ph-H), 7.17 (2H, d, J = 8.0, Indole-H), 7.03 (2H, s, Indole-H), 3.28 (6H, d, 2CH 3 ), 3.08 (6H, s, 2CH 3 ); HR-ESI-MS m / z: (M+H) + caled for C34H32N6O5 541.2710, found 541.2714.

[0066] Example 9

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

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

[0069] KJ-19: HR-ESI-MS m / z: (M+H) + caled for C39H43N6O4 659.3346, found 659.3348.

[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 cyclopropanamine, and using a method similar to that of Example 1, KJ-3 was obtained.

[0073] KJ-3: 1 1H NMR (DMSO-d6, 400 MHz, δ ppm) 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 (2H, s, Indole-H), 2.81 (2H, m, 2CH), 0.95 (4H, m, 2CH 2 ), 0.83 (4H, m, 2CH 2 ); 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 cyclobutanamine, and using a method similar to that of Example 1, KJ-5 was obtained.

[0077] KJ-5: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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, Indole-H), 7.21 (4H, d, J = 8.8, Ph-H), 7.03 (2H, d, J = 1.6, Indole-H), 4.33 (2H, m, 2CH), 2.42 (4H, m, 2CH 2 ), 2.22 (4H, m, 2CH 2 ), 1.77 (4H, m, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C38H36N6O5 93.3023, 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 cyclopentylamine, and using a method similar to that of Example 1, KJ-1 was obtained.

[0082] KJ-1: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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, Indole-H), 7.22(4H, d, J=8.4, Ph-H), 7.02(2H, d, J=1.2, Indole-H), 4.16(2H, m, 2CH), 2.06(4H, m, 2CH 2 ), 1.70(8H, m, 4CH 2 ), 1.59(4H, m, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C40H40N6O6 621.3340, found 621.3336.

[0084] Example 13

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

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

[0087] KJ-2: 1 1H NMR (DMSO-d6, 400 MHz, δ ppm) 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, 5CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C42H44N6O 649.3649, found 649.3654.

[0089] Example 14

[0090] Preparation of ((Oxydibenzene-4,1-diyl)bis(1H-indole-2,6-diyl))bis(azetidin-1-ylmethylamine) (Compound KJ-22)

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

[0092] KJ-22: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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, 4CH 2 ), 2.38 (4H, m, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C36H32N6O 565.2710, found 565.2713.

[0093] Example 15

[0094] Preparation of ((Oxydibenzene-4,1-diyl)bis(1H-indole-2,6-diyl))bis(azolidin-1-ylmethylamine) (Compound KJ-4)

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

[0096] KJ-4: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 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, 2CH 2 ), 3.49 (4H, t, J = 6.4, 2CH 2), 2.07 (4H, m, 2CH 2 ), 1.87 (4H, m, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C38H36N6O 593.3023, found 593.3027.

[0097] Example 16

[0098] (Preparation of ((oxybis(4,1-phenylene))bis(1H-indole-2,6-diyl))bis(azepan-1-ylmethanamine) (Compound KJ-6))

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

[0100] KJ-6: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 12.32 (2H, s, 2NH), 9.30 (2H, s, 2NH), 9.10 (2H, s, 2NH), 8.01 (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, 2CH 2 ), 3.42 (4H, m, 2CH 2 ), 1.76 (4H, m, 2CH 2 ), 1.66 (4H, m, 2CH 2 ), 1.55 (4H, m, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C40H40N6O 621.3336, found 621.3340.

[0101] Example 17

[0102] (Preparation of ((oxybis(4,1-phenylene))bis(1H-indole-2,6-diyl))bis(4-methylazepan-1-ylmethanamine) (Compound KJ-10))

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

[0104] KJ-10:1 HNMR (DMSO-d6, 400 MHz, δ ppm): 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, 2CH 2 ), 1.84 (4H, m, 2CH 2 ), 1.74 (4H, m, 2CH 2 ), 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, 2CH 3 ); HR-ESI-MS m / z: (M + H) + calcd for C42H44N6O 649.3649, found 649.3653.

[0105] Example 18

[0106] (Preparation of bis(3,5-dimethylazepan-1-ylmethyl)amine of (oxybis(4,1-phenylene))bis(1H-indole-2,6-diyl)) (Compound KJ-11)

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

[0108] KJ-11: 1 HNMR (DMSO-d6, 400 MHz, δ ppm): 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, Ph-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, 2CH 2 ), 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 ((Oxidized bis(4,1-phenylene))bis(1H-indole-2,6-diyl))bis(morpholine-1-ylmethanamine) (Compound KJ-14)

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

[0112] KJ-14: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 12.36 (2H, s, 2NH), 9.51 (2H, s, 2NH), 9.31 (2H, s, 2NH), 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, Indole-H), 3.84 (8H, brs, 4CH 2 ), 3.67 (4H, brs, 2CH 2 ), 3.47 (4H, brs, 2CH 2 ); HR-ESI-MS m / z: (M+H) + caled for C38H36N6O3 625.2921, found 625.2925.

[0113] Example 20

[0114] Preparation of ((Oxidized bis(4,1-phenylene))bis(1H-indole-2,6-diyl))bis(piperazine-1-ylmethanamine) (Compound KJ-15)

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

[0116] KJ-15: HR-ESI-MS m / z: (M+H) + Calculated for C38H39N8O 623.3247, found 623.3246.

[0117] Example 21

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

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

[0120] KJ-13: 1 1H NMR (DMSO-d6, 400 MHz, δ ppm) 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, 4CH 2 ), 3.06 (4H, m, 4CH), 2.88 (2H, m, 2CH), 1.98 (8H, brs, 4CH 2 ), 1.87 (8H, brs, 4CH 2 ); HR-ESI-MS m / z: (M+H) + Calculated for C48H54N8O 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 by a method similar to that of Example 1.

[0124] KJ-20: 1HNMR (DMSO-d6, 400 MHz, δ ppm) 12.41 (2H, s, 2NH), 10.45 (4H, s, 2NH 2 ), 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, 4CH 2 ); 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 propanediamine, and using a method similar to that of Example 1, KJ-30 was obtained.

[0128] KJ-30: 1 HNMR (DMSO-d6, 400 MHz, δ ppm) 12.37 (2H, s, 2NH), 9.87 (4H, s, 2NH 2 ), 8.03 (2H, s, Indole-H), 7.82 (2H, s, Indole-H), 7.71 (2H, d, J = 8.4, Indole-H), 7.34 (2H, d, J = 8.4, Indole-H), 7.21 (4H, d, J = 8.8, Ph-H), 7.01 (2H, s, Indole-H), 3.59 (4H, m, 2CH 2 ), 1.99 (4H, m, 2CH 2 ); 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-indole-6-carboximide (Compound KJ-K2)

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

[0132] KJY-K2: HR-ESI-MS m / z: (M+H) + caled for C36H37N6O 569.3029, found 569.3031.

[0133] Example 25

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

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

[0136] KJY-K3: HR-ESI-MS m / z: (M+H) + caled for C34H33N6O 541.2716, found 541.2717.

[0137] Example 26

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

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

[0140] KJY-G1: 1 H NMR (400 MHz, DMSO) δ 12.34 (s, 1H, indole-NH), 12.16 (s, 1H, indole-NH), 9.72 (br, 2H, 2 NH CH 3), 9.40 (br, 2H, C=NH 2 ), 8.81 (br, 2H, C=NH 2 ), 8.10 (d, 2H, J=8.4 Hz, 2Ph-H), 7.72 (m, 5H, 4indole-H, 1Ph-H), 7.28 (m, 6H, 2indole-H, 4Ph-H), 7.22 (s, 1H, indole-H), 6.98 (s, 1H, indole-H), 2.92 (s, 6H, 2CH 3 ). HRMS(ESI) m / z: 547.2000 (Calcd [M+H] for C32H28ClN6O: 547.2008 m / z).

[0141] Example 27

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

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

[0144] KJY-G2: 1 H NMR(400 MHz, DMSO) δ 12.25 (s, 1H, indole-NH), 12.10 (s, 1H, indole-NH), 9.70 (br, 2H, 2 NH CH 3 ), 9.39 (br, 2H, C=NH 2 ), 8.79 (br, 2H, C=NH 2 ), 8.05 (m, 2H, J=8.8 Hz, 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, CHCH 3 ), 1.31 (d, 12H, J=6.4 Hz, 4CH 3 ). HRMS(ESI) m / z: 603.2624 (Calcd [M+H] for C36H36ClN6O: 603.2634 m / z).

[0145] Example 28

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

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

[0148] KJY-G3: 1 H NMR (400 MHz, DMSO) δ 12.24 (s, 1H, indole-NH), 12.06 (s, 1H, indole-NH), 9.23 (s, 2H, C=NH 2 ), 8.86 (br, 2H, C=NH 2 ), 8.04 (d, 2H, J=8.8 Hz, 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=8.8 Hz, 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, 2CH 3 ), 3.08 (d, 6H, J=2.4 Hz, 2CH 3 ). HRMS (ESI) m / z: 575.2312 (Calcd [M+H] for C34H32ClN6O: 575.2321 m / z).

[0149] Example 29

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

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

[0152] KJY-D1: 11H NMR (400 MHz, DMSO) δ 12.30 (s, 1H, indole-NH), 12.11 (s, 1H, indole-NH), 9.69, 9.68 (2s, 2H, 2 NH CH 3 ), 9.38 (s, 2H, 2C=NH), 8.81, 8.78 (2s, 2H, 2C=NH), 8.08 (d, 2H, J = 8.8 Hz, 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 = 8.8 Hz, 2Ph-H), 7.07 (s, 1H, indole-H), 6.70 (s, 1H, indole-H), 3.04 (m, 6H, 2CH 3 ). HRMS (ESI) m / z: 581.2251 (Calcd [M+H] for C 33 H 28 ON 6 F 3 : 581.2271 m / z).

[0153] Example 30

[0154] Preparation of 2-(2-(Trifluoromethyl)-4-(4-(6-(N-Isopropylcarbamoylamino)-1H-indol-2-yl)phenoxy)phenyl)-N-isopropyl-1H-indole-6-carboximide (Compound KJ-D2)

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

[0156] KJY-D2: 1 1H NMR (400 MHz, DMSO) δ 12.32 (s, 1H, indole-NH), 12.06 (s, 1H, indole-NH), 9.46, 9.44 (2s, 2H, 2 NH CH 3), 9.31 (s, 2H, 2C=NH), 8.90, 8.88 (2s, 2H, 2C=NH), 8.08 (d, 2H, J=8.4 Hz, 2Ph-H), 7.73 (m, 5H, 4 indole-H, Ph-H), 7.56 (s, 1H, Ph-H), 7.48 (m, 1H, Ph-H), 7.32 (m, 4H, 2 indole-H, 2Ph-H), 7.08 (s, 1H, indole-H), 6.71 (s, 1H, indole-H), 4.10 (m, 2H, 2CHCH 3 ), 1.31 (m, 12H, 4CH 3 ). HRMS (ESI) m / z: 637.2927 (Calcd [M+H] for C 37 H 36 ON 6 F 3 : 637.2897 m / z).

[0157] Example 31

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

[0159] In Example 1, replace [(4-formylphenyl)oxy]benzene-1-carbaldehyde with 2-trifluoromethyl-[(4-formylphenyl)oxy]benzene-1-carbaldehyde, and methylamine with dimethylamine, and use a method similar to that of Example 1 to obtain KJ-D3.

[0160] KJY-D3: 11H NMR (400 MHz, DMSO) δ 12.35 (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 = 8.8 Hz, 2Ph-H), 7.75 (m, 3H, 2indole-H, Ph-H), 7.65 (m, 2H, 2indole-H), 7.56 (s, 1H, Ph-H), 7.49 (m, 1H, Ph-H), 7.39 (d, 2H, J = 8.8 Hz, 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: 609.2584 m / z).

[0161] Example 32

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

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

[0164] KJY-F1: 1 1H NMR (400 MHz, DMSO) δ 12.29 (s, 1H, indole-NH), 12.14 (s, 1H, indole-NH), 9.66 (m, 2H, 2 NH CH 3 ), 9.39, 9.35 (2s, 2H, C=NH 2 ), 8.80, 8.75 (2s, 2H, C=NH 2), 7.80 (d, 2H, J = 8.8 Hz, 2Ph-H), 7.72 (s, 1H, indole-H), 7.62 (m, 4H, 4 indole-H), 7.60 (d, 1H, J = 2.0 Hz, Ph-H), 7.39 (m, 2H, 2 indole-H), 7.35 (m, 2H, 2 indole-H), 7.25 (m, 1H, Ph-H), 7.15 (s, 1H, Ph-1), 7.05 (d, 2H, J = 8.8 Hz, 2Ph-H), 6.98 (s, 1H, indole-H), 3.91 (s, 3H, OCH 3 ), 3.04 (m, 6H, 2CH 3 ). HRMS(ESI) m / z: 543.2506 (Calcd [M+H] for C33H31O2N6: 543.2503 m / z).

[0165] Example 33

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

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

[0168] KJY-F2: 1 H NMR (400 MHz, DMSO) δ 12.35 (s, 1H, indole-NH), 12.17 (s, 1H, indole-NH), 9.44 (m, 2H, 2NHCH 3 ), 9.32, 9.28 (2s, 2H, 2C=NH), 8.87, 8.84 (2s, 2H, 2C=NH), 7.81 (d, 2H, J = 8.8 Hz, 2Ph-H), 7.72 (m, 5H, 5 indole-H), 7.60 (d, 1H, Ph-H), 7.34 (m, 2H, 2 indole-H), 7.24 (d, 1H, Ph-H), 7.14 (d, 1H, Ph-1), 7.04 (d, 2H, J = 8.8 Hz, 2Ph-H), 6.97 (d, 1H, J = 1.6 Hz, indole-H), 4.07 (m, 2H, 2CHCH 3 ), 3.91 (s, 3H, OCH 3 ), 1.31 (m, 12H, 4CH3 ).HRMS(ESI) m / z: 599.3134 (Calcd [M+H] for C37H39O2N6: 599.3129 m / z).

[0169] Example 34

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

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

[0172] KJY-F3: 1 H NMR (400 MHz, DMSO) δ 12.42 (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 = 8.8 Hz, 2Ph-H), 7.75 (s, 1H, indole-H), 7.66 (m, 5H, 4indole-H, Ph-H), 7.24 (d, 1H, Ph-H), 7.17 (m, 3H, 2indole-H, Ph-1), 7.03 (d, 2H, J = 8.8 Hz, 2Ph-H), 6.96 (d, 1H, J = 0.6 Hz, indole-H), 3.91 (s, 3H, OCH3), 3.25, 3.23 (2s, 6H, 2CH 3 ), 3.07, 3.04 (2s, 6H, 2CH3). HRMS HRMS(ESI) m / z: 571.2820 (Calcd [M+H] for C35H35O2N6: 571.2816 m / z).

[0173] Example 35

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

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

[0176] KJY-E1: 1 H NMR (400 MHz, DMSO / 1d CH 3 CH 2 OH) δ 12.40, 12.39 (2s, 2H, 2 indole-NH), 8.57 (d, 1H, J = 2.8 Hz, Py-H), 8.20 (m, 1H, J = 8.8 Hz, Py-H), 8.06 (d, 2H, J = 8.8 Hz, 2 Ph-H), 7.80 (s, 1H, Py-H), 7.70 (m, 4H, 4 indole-H), 7.37 (m, 2H, 2 indole-H), 7.27 (m, 3H, 2 Ph-H, indole-H), 7.05 (s, 1H, indole-H), 3.04 (m, 6H, 2CH 3 ). HRMS (ESI) m / z: 514.2353 (Calcd [M+H] for C31H28ON7: 514.2350 m / z).

[0177] Example 36

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

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

[0180] KJY-E3: 1 H NMR (400 MHz, DMSO) δ 12.33, 12.28 (2s, 2H, 2 indole-NH), 9.26, 9.25 (2s, 2H, 2 C=NH), 8.90 (s, 2H, 2 C=NH), 8.56 (d, 1H, J = 2.8 Hz, Py-H), 8.16 (d, 1H, J = 8.4 Hz, Py-H), 8.04 (d, 2H, J = 7.2 Hz, 2 Ph-H), 7.70 (m, 5H, 4 indole-H, Py-H), 7.27 (m, 3H, 2 Ph-H, 1 indole-H), 7.20 (m, 2H, 2 indole-H), 7.06 (s, 1H, indole-H), 3.26 (s, 6H, 2CH 3 ), 3.08, 3.06 (2s, 6H, 2CH 3). HRMS(ESI) m / z: 542.2640 (Calcd [M+H] for C33H32ON7: 542.2663 m / z).

[0181] Example 37

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

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

[0184] KJY-E4: HRMS(ESI) m / z: 628.3511 (Calcd [M+H] for C37H42N9O: 628.3512 m / 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-indole-6-carboximide (Compound KJ-M1)

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

[0188] KJY-M1: 1 H NMR(400 MHz, DMSO) δ 12.42 (s, 1H, indole-NH), 12.16 (s, 1H, indole-NH), 9.72 (brs, 2H, 2 NH CH 3 ), 9.42 (brs, 2H, 2C=NH), 8.83 (brs, 2H, C=NH 2), 8.66 (s, 1H, Py-H), 8.20 (d, 1H, J = 2.4 Hz, Py-H), 7.87 (s, 2H, 2 indole-H), 7.78 (m, 4H, 2 indole-H, 2 Ph-H), 7.66 (s, 1H, Ph-H), 7.56 (d, 1H, J = 0.4 Hz, Py-H), 7.42 (d, 1H, J = 0.4 Hz, indole-H), 7.3 (d, 1H, J = 0.4 Hz, indole-H), 7.29 (s, 1H, indole-H), 6.70 (s, 1H, indole-H), 3.04 (d, 6H, J = 0.4 Hz, 2CH 3 ). HRMS (ESI) m / z: 582.2217 (Calcd [M+H] for C32H27N7OF3: 582.2224 m / 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-indole-6-carboximide (Compound KJ-M2)

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

[0192] KJY-M2: 1 H NMR (400 MHz, DMSO) δ 12.33 (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 = 2.8 Hz, Py-H), 8.22 (d, 1H, J = 8.4 Hz, Py-H), 7.78 (m, 6H, 4 indole-H, 2 Ph-H), 7.68 (d, 1H, J = 2.8 Hz, Ph-H), 7.54 (dd, 1H, J = 2.4 Hz, J = 8.4 Hz, Py-H), 7.33 (m, 3H, 3 indole-H), 6.70 (s, 1H, indole-H), 4.04 (m, 2H, CH), 1.30, 1.29 (2s, 12H, 4CH 3). HRMS(ESI) m / z: 638.2887 (Calcd [M+H] for C36H35ON7F3: 638.2850 m / 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-indole-6-carboximide (Compound KJ-M3)

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

[0196] KJY-M3: 1 H NMR (400 MHz, DMSO) δ 12.31 (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=2.8 Hz, Py-H), 8.22 (d, 1H, J=8.4 Hz, Py-H), 7.77 (m, 4H, 2indole-H, 2Ph-H), 7.66 (m, 3H, 2indole-H, Ph-H), 7.56 (dd, 1H, J=2.4 Hz, 2.8 Hz, Py-H), 7.31 (d, 1H, J=1.6 Hz, indole-H), 7.19 (m, 2H, 2indole-H), 6.71 (s, 1H, indole-H), 3.26 (s, 6H, 2CH 3 ), 3.08, 3.07 (2s, 6H, 2CH 3 ). HRMS(ESI) m / z: 610.2571 (Calcd [M+H] for C34H31ON7F3: 610.2537 m / z).

[0197] Example 41

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

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

[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 NH CH 3 ),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,2CH 3 ).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-indole-6-carboximide (Compound KJ-L2)

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

[0204] KJY-L2: 1 H NMR(400MHz,DMSO)δ12.49(s,1H,indole-NH),12.33(s,1H,indole-NH),9.47(m,2H, 2NH CH),9.33(br,2H,C=NH 2 ),8.95(br,2H,C=NH 2), 8.81 (d, 1H, J = 2.0 Hz, Py-H), 8.43 (dd, 1H, J = 2.4 Hz, J = 8.4 Hz, Py-H), 8.04 (d, 2H, J = 8.8 Hz, 2Ph-H), 7.82 (s, 2H, 2indole-H), 7.74 (m, 2H, 2indole-H), 7.30 (m, 5H, 2indole-H, 2Ph-H, Py-H), 7.11 (s, 1H, indole-H), 7.07 (s, 1H, indole-H), 4.09 (m, 2H, 2CH), 1.31 (m, 12H, 4CH 3 ). HRMS(ESI) m / z: 570.2969 (Calcd [M+H] for C35H36N7O: 570.2976 m / z).

[0205] Example 43

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

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

[0208] KJY-L3: 1 H NMR (400 MHz, DMSO) δ 12.45 (brs, 1H, indole-NH), 12.30 (brs, 1H, indole-NH), 9.25 (br, 2H, 2C=NH), 8.90 (br, 2H, 2C=NH 2 ), 8.80 (s, 1H, Py-H), 8.44 (d, 1H, J = 8.8 Hz, Py-H), 8.02 (d, 2H, J = 8.4 Hz, 2Ph-H), 7.74 (m, 2H, 2indole-H), 7.65 (s, 2H, 2indole-H), 7.34 (d, 2H, J = 8.8 Hz, 2Ph-H), 7.26 (d, 1H, J = 8.8 Hz, Py-H), 7.18 (m, 2H, 2indole-H), 7.10 (s, 1H, indole-H), 7.06 (s, 1H, indole-H), 3.26 (2s, 6H, 2CH 3 ), 3.08, 3.07 (2s, 6H, 2CH 3).HRMS(ESI)m / z:542.2663(Calcd[M+H]for C33H32N7O:542.2654m / z).

[0209] Example 44

[0210] Preparation of 2,2’((methylazanedicarbonyl)bis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboxamide)(Compound KJ-N1)

[0211] In Example 1, [(4-formylphenyl)oxy]benzene-1-carbaldehyde was replaced with 4,4’-(methylazanedicarbonyl)dibenzaldehyde, and by a method similar to that of Example 1, KJ-N1 was obtained.

[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’((isopropylazanedicarbonyl)bis(4,1-phenylene))bis(N-isopropyl-1H-indole-6-carboxamide)(Compound KJ-N2)

[0215] In Example 1, [(4-formylphenyl)oxy]benzene-1-carbaldehyde was replaced with 4,4’-(methylazanedicarbonyl)dibenzaldehyde, and methylamine was replaced with isopropylamine, and by a method similar to that of Example 1, KJ-N2 was obtained.

[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’((dimethylazanedicarbonyl)bis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboxamide)(Compound KJ-N3)

[0219] In Example 1, [(4-formylphenyl)oxy]benzene-1-carbaldehyde was replaced with 4,4’-(methylazanedicarbonyl)dibenzaldehyde, and methylamine was replaced with dimethylamine, and by a method similar to that of Example 1, KJ-N3 was obtained.

[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-carbaldehyde was replaced with 4,4'-biphenylcarbaldehyde, and KJ-C1 was obtained by a method similar to that of Example 1.

[0224] KJL-C1: HRMS(ESI) m / z: 497.2454 (Calcd [M+H] for C32H29N6: 497.2454 m / 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-carbaldehyde was replaced with 4,4'-biphenylcarbaldehyde, and methylamine was replaced with dimethylamine. KJ-C3 was obtained by a method similar to that of Example 1.

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

[0229] Example 49

[0230] Preparation of 2,2'-(ethyne-1,2-diylbis(4,1-phenylene))bis(N-methyl-1H-indole-6-carboximide) (Compound KJ-Q1)

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

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

[0233] Example 50

[0234] Preparation of 2,2'-(ethyne-1,2-diylbis(4,1-phenylene))bis(N-isopropyl-1H-indole-6-carboximide) (Compound KJ-Q2)

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

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

[0237] Example 51

[0238] Preparation of 2,2'-(ethyne-1,2-dicarbonylbis(4,1-phenylene))bis(N-dimethyl-1H-indole-6-carboximide) (Compound KJ-Q3)

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

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

[0241] Example 52

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

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

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

[0245] Example 53

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

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

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

[0249] Example 54

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

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

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

[0253] Example 55. Antifungal Experiment and Cytotoxicity Experiment

[0254] (1) Antifungal Experiment

[0255] According to the M27-A method recommended by the National Committee for Clinical Laboratory Standards of the United States, the minimum inhibitory concentration (MIC) of the compound against Candida albicans (ATCC 10231) was detected. The cryopreserved Candida albicans was inoculated on YPD solid medium. After subculturing once, it was cultured at 35 °C for 24 h. Then, Candida albicans was inoculated on Sabouraud agar medium. After subculturing once, it was cultured at 35 °C for 24 h and 48 h respectively. The strain was adjusted to 1 - 5×10 6 cfu / mL with normal saline and then diluted 1000 times with RPMI1640. The compound was serially diluted from 25.6 μg / mL to 0.0125 μg / mL with RPMI. 100 μL of the bacterial solution and the compound solution were taken and added to a 96-well plate. At the same time, two replicate wells were made. The plate was placed at 35 °C and observed at 24 h, 48 h, and 72 h respectively. The concentration at which no visible bacterial growth was observed with the naked eye was judged as the MIC.

[0256] (2) Cytotoxicity Experiment

[0257] Human embryonic kidney cells HEK 293T were seeded at 1×105 Cells were seeded onto 96-well plates at a concentration of 2 cells / mL and a volume of 200 μL per well. After incubation at 37 °C for 24 h, confluence of the cell monolayer was confirmed. Test compounds were dissolved in DMSO at different concentrations, with DMSO as the negative control. 2 μL of the diluted compound or DMSO was added to each well, with three replicates. Incubation was carried out at 37 °C in 5% CO 50 for 48 h. After incubation, the supernatant was replaced with fresh medium containing MTS reagent (110 μL), 50 (10 μL of MTS reagent per well). Incubation was continued for 2 h to allow MTS production. Absorbance was read using a microplate reader at a test wavelength of 490 nm. The percentage of inhibition was calculated using the following formula: Percentage of inhibition = [100 - (At / As)] × 100%. At and As refer to the absorbance of the test substance and the DMSO control, respectively. The CC 50 value, defined as the concentration of the test compound at 50% cytotoxicity (CC 50 ). The selectivity index SI = CC

[0258] Table 1 Antifungal activity, cytotoxicity and selectivity index of a series of compounds against

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] As can be seen from Table 1, the minimum inhibitory concentration (MIC) of the series of compounds of the present invention against Candida albicans ranges from 0.025 to 12.5 μg / mL, indicating good antibacterial activity against Candida albicans. Some compounds are superior to the clinically used drugs amphotericin B and fluconazole. The cytotoxicity experiment shows that the cytotoxicity CC 50 The therapeutic index SI value compared with the minimum inhibitory concentration is greater than 100, and the SI of KJ-30 is even greater than 1000. It is worthy of further research in the future to develop antifungal drugs of new structural types.

[0270] As can be seen from the above examples, the present invention provides the use of a compound containing a bisamidine group and a pharmaceutically acceptable salt thereof in antifungal treatment. The series of compounds containing bisamidine groups of the present invention have good antibacterial activity against Candida albicans and can be used clinically to treat Candida albicans infections.

[0271] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. Use of a bisamidino-containing compound and a pharmaceutically acceptable salt thereof in antifungal treatment, characterized in that: The compound has a structural formula as shown in Formula I:

2. The use according to claim 1, characterized in that: 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.

3. The use according to claim 1, characterized in that: R1 and R2 form a substituted or unsubstituted 3-6 membered ring with the N connecting them, and R3 is independently selected from hydrogen, substituted or unsubstituted alkyl; R2 and R3 are connected with the amidine group to form a substituted or unsubstituted 5-7 membered ring, and R1 is independently selected from hydrogen, substituted or unsubstituted alkyl.

4. The use according to claim 1, characterized in that: 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, alkylamine, alkynyl, alkoxy or there is no Q group and the two aromatic rings are directly connected.

5. Use of a bisamidino-containing compound and a pharmaceutically acceptable salt thereof in antifungal treatment, characterized in that: The compound has a structural formula as shown in Formula II:

6. The use according to claim 5, characterized in that: 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.

7. The use according to claim 5, characterized in that: R1 and R2 form a substituted or unsubstituted 3-6 membered ring with the nitrogen connecting them; R2 and R3 are connected with the amidine group to form a substituted or unsubstituted 5-7 membered ring.

8. The use according to claim 5, characterized in that: R3 is independently selected from hydrogen, substituted or unsubstituted alkyl.

9. The use according to any one of claims 1 to 8, characterized in that: The fungus is Candida albicans.

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