A preparation method and application of substituted triaminotriazine compounds

Abstract

The present invention discloses a preparation method and application of a substituted triaminotriazine compound. The substituted triaminotriazine compound is shown in Formula I and Formula II. The present invention also provides a salt, solvate or prodrug of the compound in the preparation of an antifungal pharmaceutical composition, a preparation method and application. The present invention overcomes the problems of strong drug resistance of antifungal drugs in the prior art and poor or ineffective antifungal combined drug effects. The synthesized novel substituted triaminotriazine compound has an obvious synergistic effect on fluconazole-resistant Candida albicans 901 and 904. The present invention opens up a new research path for in-depth research and development of new antifungal drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compounds, in particular to a preparation method of a substituted triaminotriazine compound and its application. Background Art

[0002] In recent years, invasive fungal infections (IFIs) have become increasingly serious, often with Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus infections as the main causes of death in patients with immunodeficiency, organ transplantation and cancer, with a mortality rate of more than 50%. Invasive fungal infections in my country are also on the rise, with a mortality rate of 10%-60%. At present, commonly used antifungal drugs in clinical practice include allylamines (terbinafine), polyene antibiotics (amphotericin B), pyrimidines (5-flucytosine), etc. Nitrogen azole drugs are the first-line drugs for clinical use, mainly fluconazole and voriconazole. However, the annual mortality rate caused by IFIs remains high. The main reason is that in addition to the toxicity, broad spectrum and drug-drug interactions of antifungal drugs themselves, the inherent or acquired cross-resistance of fungi often makes existing drugs lose their therapeutic effects. Among them, the resistance to fluconazole is the most serious.

[0003] In response to the problem of fungal resistance, in addition to developing new drugs, increasing drug dosages, changing the route of administration, or starting from the mechanism of drug resistance, the combination of drugs has become a hot topic of research in recent years, that is, by developing a class of small molecule compounds that can cooperate with fluconazole to fight drug-resistant fungi, which have no or certain antifungal activity, and then combined with fluconazole, they can restore the sensitivity of drug-resistant fungi to drugs, thereby playing an antibacterial or bactericidal role. This type of small molecule is called a synergist or synergist.

[0004] In order to discover new small molecule compounds with synergistic effects, 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-substituted acetamide (Ⅰ) and N-(substituted)phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-(substituted)carboxamide (Ⅱ) were obtained by activity screening and structural modification of self-built small molecule compounds. They have synergistic activity against fluconazole-resistant fungi. So far, there has been no report on the synthesis of such compounds and their synergistic antifungal activity in vitro. Summary of the invention

[0005] The first purpose of the present invention is to overcome the problems of strong drug resistance of antifungal drugs in the prior art and poor or ineffective antifungal combination drug effects, and to provide a substituted triaminotriazine compound.

[0006] The second object of the present invention is to provide the substituted triaminotriazine compound or its pharmaceutically acceptable salt, solvate or prodrug for preparing an antifungal drug combination.

[0007] The third object of the present invention is to provide pharmaceutically acceptable salts of the substituted triaminotriazine compounds.

[0008] The fourth object of the present invention is to provide a method for preparing the substituted triaminotriazine compounds.

[0009] The fifth object of the present invention is to provide the use of the substituted triaminotriazine compounds in pharmaceutically acceptable salts.

[0010] In order to achieve the above first and second purposes, the technical solution adopted by the present invention is:

[0011] A substituted triaminotriazine compound as shown in formula I:

[0012]

[0013] Where n is 0, 1 or 2;

[0014] R represents a benzene ring or a substituted benzene or an aromatic heterocycle, C2-C8 amino, amide, oxime acid;

[0015] Description A in the formula is a C3-C6 cycloalkyl group, and forms a ring structure with the benzene ring;

[0016] Said R 1 With R 2 Connect R 3 is a C1-C3 alkyl group;

[0017] In the present invention, the R can be selected from any of the following structures:

[0018]

[0019] The substituted triaminotriazine compound represented by formula I can be selected from any of the following compounds:

[0020] Compound 1, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-fluorophenyl)acetamide, structural formula:

[0021]

[0022] Compound 2, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-fluorophenyl)acetamide, structural formula:

[0023]

[0024] Compound 3, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-fluorophenyl)acetamide, structural formula:

[0025]

[0026] Compound 4, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-methoxyphenyl)acetamide, structural formula:

[0027]

[0028] Compound 5, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-methoxyphenyl)acetamide, structural formula:

[0029]

[0030] Compound 6, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-methoxyphenyl)acetamide, structural formula:

[0031]

[0032] Compound 7, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-(2-methoxyethoxy)phenyl)acetamide, structural formula:

[0033]

[0034] Compound 8, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-isopropylacetamide, structural formula:

[0035]

[0036] Compound 9, chemical name: (R)-2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-indanacetamide, structural formula:

[0037]

[0038] Compound 10, chemical name: (S)-2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-indanacetamide, structural formula:

[0039]

[0040] Compound 11, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)-N-(5-(2-methyl)-1,3,4-thiadiazol-2-yl)acetamide, structural formula:

[0041]

[0042] Compound 12, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-fluorobenzyl)acetamide, structural formula:

[0043]

[0044] Compound 13, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-fluorobenzyl)acetamide, structural formula:

[0045]

[0046] Compound 14, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-fluorobenzyl)acetamide, structural formula:

[0047]

[0048] Compound 15, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-methylbenzyl)acetamide, structural formula:

[0049]

[0050] Compound 16, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-methylbenzyl)acetamide, structural formula:

[0051]

[0052] Compound 17, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-methylbenzyl)acetamide, structural formula:

[0053]

[0054] Compound 18, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(furan-2-methyl)acetamide, structural formula:

[0055]

[0056] Compound 19, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-((5-phenylfuran-2-yl)methyl)acetamide, structural formula:

[0057]

[0058] Compound 20, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(benzo[d][1,3]dioxol-5-yl)acetamide, structural formula:

[0059]

[0060] Compound 21, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-acetamide, structural formula:

[0061]

[0062] Compound 22, chemical name: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-((2-aminoethyl)disulfanyl)ethyl)-acetamide, structural formula:

[0063]

[0064] Compound 23, chemical name: 6-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylamino)-N-hydroxyhexanamide, structural formula:

[0065]

[0066] In the application, the pharmaceutical composition comprises a substituted triaminotriazine compound as shown in Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof and fluconazole.

[0067] To achieve the first and second objectives, the present invention also provides a substituted triaminotriazine compound as shown in Formula II:

[0068]

[0069] Wherein: R1 is S or O atom, R2 represents a benzene ring or a substituted benzene ring, the substituents of the substituted benzene ring may be located at various positions of the benzene ring, and may be monosubstituted or polysubstituted, and the substituents are selected from a), b), c) or d):

[0070] a) halogen, wherein the halogen is F, Cl, Br, I,

[0071] b) an electron-withdrawing group, wherein the electron-withdrawing group is cyano, nitro, or trifluoromethyl,

[0072] c) a lower alkyl group having 1 to 4 carbon atoms, an aryl group or a halogen-substituted lower alkyl group,

[0073] d) a lower alkoxy group having 1 to 4 carbon atoms or a halogen-substituted lower alkoxy group.

[0074] Preferably, the lower alkyl group, aryl group or halogen-substituted lower alkyl group of 1-4 carbon atoms is selected from methyl, ethyl, tert-butyl, benzyl or trifluoromethyl; the lower alkoxy group or halogen-substituted lower alkoxy group of 1-4 carbon atoms is selected from methoxy or trifluoromethoxy.

[0075] In the present invention, the R2 is selected from any of the following structures:

[0076]

[0077] The substituted triaminotriazine compound represented by formula II can be selected from any of the following compounds:

[0078] Compound 24, chemical name: N-(2-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0079]

[0080] Compound 25, chemical name: N-(3-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0081]

[0082] Compound 26, chemical name: N-(4-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0083]

[0084] Compound 27, chemical name: N-(2-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0085]

[0086] Compound 28, N-(3-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0087]

[0088] Compound 29, N-(4-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0089]

[0090] Compound 30, chemical name: N-(2-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0091]

[0092] Compound 31, chemical name: N-(3-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0093]

[0094] Compound 32, chemical name: N-(4-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0095]

[0096] Compound 33, chemical name: N-(4-trifluoromethylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0097]

[0098] Compound 34, chemical name: N-(4-trifluoromethoxyphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0099]

[0100] Compound 35, chemical name: N-(4-cyanophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0101]

[0102] Compound 36, chemical name: N-(4-nitrophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0103]

[0104] Compound 37, chemical name: N-phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0105]

[0106] Compound 38, chemical name: N-benzyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, structural formula:

[0107]

[0108] Compound 39, chemical name: N-(2-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0109]

[0110] Compound 40, chemical name: N-(3-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0111]

[0112] Compound 41, chemical name: N-(4-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0113]

[0114] Compound 42, chemical name: N-(2-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0115]

[0116] Compound 43, chemical name: N-(3-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0117]

[0118] Compound 44, chemical name: N-(4-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0119]

[0120] Compound 45, chemical name: N-(2-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0121]

[0122] Compound 46, chemical name: N-(3-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0123]

[0124] Compound 47, chemical name: N-(4-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0125]

[0126] Compound 48, chemical name: N-(4-trifluoromethylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0127]

[0128] Compound 49, chemical name: N-(4-trifluoromethoxyphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0129]

[0130] Compound 50, chemical name: N-(4-cyanophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0131]

[0132] Compound 51, chemical name: N-(4-nitrophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0133]

[0134] Compound 52, chemical name: N-benzyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide, structural formula:

[0135]

[0136] To achieve the third purpose, the technical solution adopted by the present invention is:

[0137] The pharmacologically acceptable salt of the substituted triaminotriazine compound as described above is an inorganic acid salt or an organic acid salt.

[0138] As a preferred example of the present invention, the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.

[0139] To achieve the fourth objective, the present invention adopts the following technical solution:

[0140] The preparation method of the substituted triaminotriazine compound as described above comprises the following steps:

[0141] (1) Preparation of methyl 2-(4-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acetate (B)

[0142] Cyanuric chloride (A) and methyl 2-(4-aminophenyl)acetate are reacted in tetrahydrofuran with stirring in an ice bath for 2 hours to obtain methyl 2-(4-((4,6-dichloro-1,3,5-triazin-2-yl)amino)phenyl)acetate (B);

[0143] (2) Preparation of methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)acetate (C)

[0144] 2-(4-((4,6-dichloro-1,3,5-triazin-2-yl)amino)phenyl)acetic acid methyl ester (B), 4-fluorobenzylamine and 20% NaHCO3 solution were stirred at room temperature for 5 hours to obtain 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid methyl ester (C);

[0145] (3) Preparation of methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)acetate (D)

[0146] Methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (C) and cyclohexylmethylamine are dissolved in 1,4-dioxane, 1,8-diazabicycloundec-7-ene (DBU) is added, and the mixture is refluxed and stirred at 100° C. for 12 hours to obtain methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (D);

[0147] (4) Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (E)

[0148] Methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (D) and LiOH·H2O were reacted in a mixed solvent (THF:MeOH:H2O=3:2:1) with stirring at room temperature for 1 hour to obtain 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (E);

[0149] (5) Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-substituted acetamide (I)

[0150] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (E) and a substituted amine compound are dissolved in DMF, and a condensing agent PyBOP and a base DIEA are added. The mixture is reacted at room temperature for 3 hours to obtain 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-substituted acetamide (Ⅰ);

[0151] (6) Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine (F)

[0152] Methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (D) and hydrazine hydrate were stirred in anhydrous methanol under reflux at 70°C for 12 hours to obtain 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine (F);

[0153] (7) Preparation of N-(substituted)phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-(substituted)carboxamide (II)

[0154] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine (F) and different substituted cyanates or isocyanates are stirred under reflux at 80°C for 3 hours in anhydrous ethanol to obtain N-(substituted)phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-(substituted)carboxamide (II).

[0155] To achieve the fifth purpose, the present invention adopts the following technical solution:

[0156] Use of any of the above substituted triaminotriazine compounds, or any of the above pharmacologically acceptable salts in the preparation of antifungal drugs.

[0157] As a preferred example of the present invention, the fungi are Candida albicans 901 and 904 resistant to fluconazole.

[0158] The advantages of the present invention are:

[0159] The invention synthesizes a novel substituted triaminotriazine compound, which has an obvious synergistic effect on fluconazole-resistant Candida albicans 901 and 904. DETAILED DESCRIPTION

[0160] The specific embodiments provided by the present invention are described in detail below. The reagents and raw materials used in the present invention are all commercially available or can be prepared according to literature methods. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The reagents used in the examples are all commercially available analytically pure.

[0161] The synthetic route of the compound of the present invention is as follows:

[0162]

[0163]

[0164] The structural formula and NMR data of each preferred compound are shown in Table 1.

[0165] Table 1 Chemical structures and NMR data of preferred compounds

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176] The compound described in the present invention is a new type of synergistic small molecule compound with a new structural type, which has good in vitro synergistic activity with fluconazole against drug-resistant fungi, opens up a new way for in-depth research and development of synergistic antifungal drugs of new structural types, and can be further used to prepare therapeutic antifungal drugs, especially to alleviate the problem of azole drug resistance produced by fungi.

[0177] The present invention is described in detail below in conjunction with the examples. However, the following examples should not be considered as limiting the scope of the present invention.

[0178] Example 1: Preparation of methyl 2-(4-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acetate (B)

[0179] Dissolve cyanuric chloride (4.61 g, 25 mmol, 1 equiv) in 20 mL of tetrahydrofuran and stir to 0°C in an ice bath. Slowly add 20 mL of tetrahydrofuran solution containing methyl 2-(4-aminophenyl)acetate (4.13 g, 25 mmol, 1 equiv) and continue stirring to react until room temperature is restored for 2 hours. Monitor by TLC spot plate. After the reaction is complete, pour in an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, decompress and spin dry the solvent, add methanol and water (volume ratio 2:1) for recrystallization, and obtain 6.63 g of white solid intermediate with a yield of 85%.

[0180] Example 2: Preparation of methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (C)

[0181] Dissolve methyl 2-(4-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acetate (6.24 g, 20 mmol, 1 equiv) in 20 mL of tetrahydrofuran, add 4-fluorobenzylamine (2.50 g, 20 mmol, 1 equiv) and 20 mL of 20% NaHCO3 solution, and stir at room temperature for 5 hours. Monitor by TLC spot plate. After the reaction is complete, pour in an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, spin dry the solvent under reduced pressure, add methanol and water (volume ratio 2:1) for recrystallization, and obtain 5.61 g of a white solid intermediate with a yield of 70%.

[0182] Example 3: Preparation of methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (D)

[0183] Dissolve methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)acetate (4.01 g, 10 mmol, 1 equiv) in 20 mL 1,4-dioxane, add cyclohexylmethylamine (1.25 g, 11 mmol, 1.1 equiv) and 1,8-diazabicycloundec-7-ene (DBU, 2.76 mL, 20 mmol, 2.0 equiv), and reflux at 100°C for 12 hours. Monitor by TLC spot plate. After the reaction is complete, pour in an appropriate amount of water, extract with ethyl acetate, combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, spin dry the solvent under reduced pressure, purify by column chromatography, and elute with ethyl acetate and petroleum ether system to obtain 2.87 g of white foamy intermediate with a yield of 60%. 1H NMR (300MHz, DMSO-d6) δ9.05–8.73(m,1H), 7.68(d,J=8.5Hz,2H), 7.46–7.02(m,7H), 6.84(t,J=32.8Hz,1H), 4.44(d, J=5.7Hz,2H), 3.60(s,3H), 3.57(s,2H), 3.10–3.02(m,2H), 1.73–1.40(m,6H), 1.23–0.99(m,3H), 0.99–0.68(m,2H). 13 C NMR (75MHz, DMSO-d6) δ172.35, 166.43, 166.30, 166.18, 164.58, 163.08, 159.88, 139.98, 137.61, 137.33, 129.50, 129.42, 129.31, 12 7.25, 120.09, 119.97, 119.82, 115.38, 115.10, 99.99, 52.02, 46.98, 46.66, 43.27, 43.15, 42.98, 38.08, 37.92, 31.07, 26.65, 25.93. ESI-MS(m / z): 479.1[M+1].

[0184] Example 4: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (E)

[0185] Dissolve methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)acetate (1.5 g, 3.1 mmol, 1 equiv) in 10 mL of a mixed solvent (THF:MeOH:H2O=3:2:1) and stir at room temperature for 1 hour. The solvent was dried under reduced pressure, 20 mL of water was added, and 1 M dilute hydrochloric acid was used to adjust the pH to 2.0-3.0, and a white precipitate gradually precipitated. After stirring at room temperature for 30 minutes, the precipitate was filtered, washed with cold water 2-3 times, and the solvent was dried under vacuum to obtain 1.04 g of a white solid with a yield of 72%. 1H NMR(300MHz,DMSO-d6)δ12.20(s,1H),9.03–8.63(m,1H),7.75–7.53(m,2H),7.46–7.01(m,7H),6.83(t,J=30.7Hz,1 H), 4.43(d,J=5.0Hz,2H), 3.45(s,2H), 3.10–3.02(m,2H), 1.74–1.36(m,6H), 1.23–0.97(m,3H), 0.95–0.61(m,2H). 13 C NMR (75MHz, DMSO-d6) δ173.48, 166.39, 166.33, 166.28, 166.21, 166.17, 164.57, 163.09, 159.86, 139.74, 137.35, 129.52, 128.02, 120.11, 119.75, 115.39, 115.11, 46.99, 46.66, 43.23, 43.12, 43.04, 42.96, 37.95, 31.08, 26.65, 25.94. ESI-MS (m / z): 465.1[M+1].

[0186] Example 5: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-fluorophenyl)acetamide (Compound 1 in the table)

[0187] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (0.46 g, 1.0 mmol, 1 equiv) and 2-fluoroaniline (0.12 g, 1.1 mmol, 1.1 equiv) were dissolved in DMF, and condensation agent PyBOP (0.57 g, 1.1 mmol, 1.1 equiv) and DIEA (0.44 ml, 3.0 mmol, 3 equiv) were added, and the mixture was stirred at room temperature for 3 hours. TLC spot plate monitoring was performed, and after the reaction was complete, an appropriate amount of water was poured in, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Recrystallization from methanol and water (volume ratio 1:1 to 1:2) gave a white solid 1 (0.32 g, yield: 58%, ESI-MS (m / z): 558.1 [M+1]).

[0188] Example 6: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-fluorophenyl)acetamide (Compound 2 in the Table)

[0189] The preparation process of compound 2 was similar to that of compound 1, and a white solid 2 (0.36 g, yield: 64%, ESI-MS (m / z): 558.1 [M+1]) was finally obtained.

[0190] Example 7: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-fluorophenyl)acetamide (Compound 3 in the Table)

[0191] The preparation process of compound 3 was similar to that of compound 1, and a white solid 3 (0.31 g, yield: 55%, ESI-MS (m / z): 558.1 [M+1]) was finally obtained.

[0192] Example 8: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-methoxyphenyl)acetamide (Compound 4 in the Table)

[0193] The preparation process of compound 4 was similar to that of compound 1, and a white solid 4 (0.35 g, yield: 63%, ESI-MS (m / z): 570.1 [M+1]) was finally obtained.

[0194] Example 9: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-methoxyphenyl)acetamide (Compound 5 in the table)

[0195] The preparation process of compound 5 was similar to that of compound 1, and a white solid 5 (0.41 g, yield: 72%, ESI-MS (m / z): 570.1 [M+1]) was finally obtained.

[0196] Example 10: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-methoxyphenyl)acetamide (Compound 6 in the Table)

[0197] The preparation process of compound 6 was similar to that of compound 1, and a white solid 6 (0.43 g, yield: 75%, ESI-MS (m / z): 570.1 [M+1]) was finally obtained.

[0198] Example 11: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-(2-methoxyethoxy)phenyl)acetamide (Compound 7 in the Table)

[0199] The preparation process of compound 7 was similar to that of compound 1, and a white solid 7 (0.41 g, yield: 66%, ESI-MS (m / z): 614.1 [M+1]) was finally obtained.

[0200] Example 12: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-isopropylacetamide (Compound 8 in the Table)

[0201] The preparation process of compound 8 was similar to that of compound 1, and a white solid 8 (0.24 g, yield: 48%, ESI-MS (m / z): 505.1 [M+1]) was finally obtained.

[0202] Example 13: Preparation of (R)-2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-indanacetamide (Compound 9 in the Table)

[0203] The preparation process of compound 9 is similar to that of compound 1, and a white solid 9 (0.26 g, yield: 45%, ESI-MS (m / z): 580.1 [M+1]) is finally obtained. The chiral center involved in the product is brought in by the reaction raw materials. Since the reaction process does not involve chiral changes, the chiral purity does not need to be tested again.

[0204] Example 14: Preparation of (S)-2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-indanacetamide (Compound 10 in the Table)

[0205] The preparation process of compound 10 is similar to that of compound 1, and a white solid 10 (0.31 g, yield: 53%, ESI-MS (m / z): 580.1 [M+1]) is finally obtained. The chiral center involved in the product is brought in by the reaction raw materials. Since the reaction process does not involve chiral changes, the chiral purity does not need to be tested again.

[0206] Example 15: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(5-(2-methyl)-1,3,4-thiadiazol-2-yl)acetamide (Compound 11 in the Table)

[0207] The preparation process of compound 11 was similar to that of compound 1, and finally a white solid 11 (0.40 g, yield: 70%, ESI-MS (m / z): 572.1 [M+1]) was obtained.

[0208] Example 16: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-fluorobenzyl)acetamide (Compound 12 in the Table)

[0209] The preparation process of compound 12 was similar to that of compound 1, and finally a white solid 12 (0.40 g, yield: 70%, ESI-MS (m / z): 572.1 [M+1]) was obtained.

[0210] Example 17: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-fluorobenzyl)acetamide (Compound 13 in the Table)

[0211] The preparation process of compound 13 was similar to that of compound 1, and white solid 13 (0.35 g, yield: 62%, ESI-MS (m / z): 572.1 [M+1]) was finally obtained.

[0212] Example 18: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-fluorobenzyl)acetamide (Compound 14 in the Table)

[0213] The preparation process of compound 14 was similar to that of compound 1, and white solid 14 (0.39 g, yield: 68%, ESI-MS (m / z): 572.1 [M+1]) was finally obtained.

[0214] Example 19: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-methylbenzyl)acetamide (Compound 15 in the Table)

[0215] The preparation process of compound 15 was similar to that of compound 1, and white solid 15 (0.29 g, yield: 51%, ESI-MS (m / z): 568.1 [M+1]) was finally obtained.

[0216] Example 20: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(3-methylbenzyl)acetamide (Compound 16 in the Table)

[0217] The preparation process of compound 16 was similar to that of compound 1, and white solid 16 (0.23 g, yield: 40%, ESI-MS (m / z): 568.1 [M+1]) was finally obtained.

[0218] Example 21: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(4-methylbenzyl)acetamide (Compound 17 in the Table)

[0219] The preparation process of compound 17 was similar to that of compound 1, and white solid 17 (0.27 g, yield: 47%, ESI-MS (m / z): 568.1 [M+1]) was finally obtained.

[0220] Example 22: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(furan-2-methyl)acetamide (Compound 18 in the Table)

[0221] The preparation process of compound 18 was similar to that of compound 1, and white solid 18 (0.39 g, yield: 71%, ESI-MS (m / z): 558.1 [M+1]) was finally obtained.

[0222] Example 23: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-((5-phenylfuran-2-yl)methyl)acetamide (Compound 19 in the Table)

[0223] The preparation process of compound 19 was similar to that of compound 1, and white solid 19 (0.39 g, yield: 64%, ESI-MS (m / z): 620.1 [M+1]) was finally obtained.

[0224] Example 24: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(benzo[d][1,3]dioxol-5-yl)acetamide (Compound 19 in the Table)

[0225] The preparation process of compound 20 was similar to that of compound 1, and a white solid 20 (0.26 g, yield: 43%, ESI-MS (m / z): 612.1 [M+1]) was finally obtained.

[0226] Example 25: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-acetamide (Compound 21 in the Table)

[0227] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (0.46 g, 1.0 mmol, 1 equiv) and tert-butyl 2-(2-(2-aminoethoxy)ethoxy)ethylcarbamate (0.26 mL, 1.1 mmol, 1.1 equiv) were dissolved in DMF, and condensation agent PyBOP (0.57 g, 1.1 mmol, 1.1 equiv) and DIEA (0.44 mL, 3.0 mmol, 3 equiv) were added, and the mixture was stirred at room temperature for 3 hours. TLC spot plate monitoring, after the reaction was complete, appropriate amount of water was poured in, ethyl acetate was extracted, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Subsequently, 10 mL of a mixed solvent of 1.0 M ethyl acetate and hydrochloric acid was added, and the mixture was stirred at room temperature until a white solid precipitated. The precipitate was filtered and dissolved in ethyl acetate. Saturated NaHCO3 solution was added to adjust the pH to 8.0-9.0. The layers were separated and the organic layer was collected and dried under reduced pressure to obtain a free white solid 21 (0.27 g, yield: 38%, ESI-MS (m / z): 595.1 [M+1]).

[0228] Example 26: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-((2-aminoethyl)disulfanyl)ethyl)-acetamide (Compound 22 in the Table)

[0229] The preparation process of compound 22 was similar to that of compound 21, and a white solid 22 (0.19 g, yield: 32%, ESI-MS (m / z): 599.1 [M+1]) was finally obtained.

[0230] Example 27: Preparation of 6-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylamino)-N-hydroxyhexanamide (Compound 23 in the Table)

[0231] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid (0.46 g, 1.0 mmol, 1 equiv) and methyl 6-aminohexanoate (0.16 mL, 1.1 mmol, 1.1 equiv) were dissolved in DMF, and condensation agent PyBOP (0.57 g, 1.1 mmol, 1.1 equiv) and DIEA (0.44 mL, 3.0 mmol, 3 equiv) were added, and the mixture was stirred at room temperature for 3 hours. TLC spot plate monitoring, after the reaction was complete, appropriate amount of water was poured in, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The residual solid was dissolved in methanol, and 10 ml of freshly prepared hydroxylamine methanol solution was added, and stirred at room temperature for 1 hour. Subsequently, glacial acetic acid was added dropwise to adjust the pH to about 7.0, and the precipitate was filtered, washed with cold water 2-3 times, and dried in vacuo to obtain a white solid 23 (0.21 g, yield: 36%, ESI-MS (m / z): 593.1 [M+1]).

[0232] Example 28: Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine (F)

[0233] Methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate (1.5 g, 3.1 mmol, 1 equiv) was dissolved in anhydrous methanol, hydrazine hydrate (0.75 ml, 15.5 mmol, 5 equiv) was added, and the mixture was refluxed and stirred at 70°C for 18 hours. After returning to room temperature, water was added until solids precipitated, filtered, washed with cold water 2-3 times, and dried under vacuum to obtain 0.74 g of a white solid, with a yield of 50%. 1H NMR (300MHz, DMSO-d6) δ9.15 (s, 1H), 8.95–8.63 (m, 1H), 7.74–7.52 (m, 2H), 7.42–7.07 (m, 7H), 6.84 (t, J = 34.0Hz, 1H), 4.4 4(d,J=5.4Hz,2H), 4.23(s,2H), 3.25(s,2H), 3.15–2.95(m,2H), 1.73–1.46(m,6H), 1.19–1.03(m,3H), 0.99–0.68(m,2H). 13 C NMR (75MHz, DMSO-d6) δ170.37, 166.42, 166.29, 166.19, 164.56, 163.06, 159.93, 159.86, 139.52, 137.39, 137.34, 129 .41, 129.27, 129.12, 120.12, 119.69, 115.39, 115.11, 56.52, 46.93, 46.61, 43.26, 37.95, 31.08, 26.65, 25.93, 19.01. ESI-MS(m / z): 479.1[M+1].

[0234] Example 29: Preparation of N-(2-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 24 in the Table)

[0235] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acethydrazide (0.47 g, 1.0 mmol, 1 equiv) and 2-chlorophenyl isothiocyanate (0.18 g, 1.1 mmol, 1.1 equiv) were dissolved in anhydrous ethanol and refluxed at 80°C for 3 hours. After returning to room temperature, water was added until solids precipitated, filtered, washed with cold water 2-3 times, and dried under vacuum to obtain a white solid 24 (0.43 g, yield: 66%, ESI-MS (m / z): 648.1 [M+1]).

[0236] Example 30: N-(3-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 25 in the table)

[0237] The preparation process of compound 25 was similar to that of compound 24, and a white solid 25 (0.35 g, yield: 54%, ESI-MS (m / z): 648.1 [M+1]) was finally obtained.

[0238] Example 31: N-(4-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 26 in the table)

[0239] The preparation process of compound 26 was similar to that of compound 24, and a white solid 26 (0.29 g, yield: 46%, ESI-MS (m / z): 648.1 [M+1]) was finally obtained.

[0240] Example 32: N-(2-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 27 in the Table)

[0241] The preparation process of compound 27 was similar to that of compound 24, and a white solid 27 (0.24 g, yield: 38%, ESI-MS (m / z): 632.1 [M+1]) was finally obtained.

[0242] Example 33: N-(3-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 28 in the table)

[0243] The preparation process of compound 28 was similar to that of compound 24, and a white solid 28 (0.28 g, yield: 44%, ESI-MS (m / z): 632.1 [M+1]) was finally obtained.

[0244] Example 34: N-(4-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 29 in the table)

[0245] The preparation process of compound 29 was similar to that of compound 24, and a white solid 29 (0.27 g, yield: 42%, ESI-MS (m / z): 632.1 [M+1]) was finally obtained.

[0246] Example 35: N-(2-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 30 in the Table)

[0247] The preparation process of compound 30 was similar to that of compound 24, and a white solid 30 (0.35 g, yield: 56%, ESI-MS (m / z): 628.1 [M+1]) was finally obtained.

[0248] Example 36: N-(3-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 31 in the table)

[0249] The preparation process of compound 31 was similar to that of compound 24, and a white solid 31 (0.39 g, yield: 62%, ESI-MS (m / z): 628.1 [M+1]) was finally obtained.

[0250] Example 37: N-(4-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 32 in the Table)

[0251] The preparation process of compound 32 was similar to that of compound 24, and a white solid 32 (0.44 g, yield: 70%, ESI-MS (m / z): 628.1 [M+1]) was finally obtained.

[0252] Example 38: N-(4-trifluoromethylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 33 in the Table)

[0253] The preparation process of compound 33 was similar to that of compound 24, and a white solid 33 (0.33 g, yield: 49%, ESI-MS (m / z): 682.1 [M+1]) was finally obtained.

[0254] Example 39: N-(4-trifluoromethoxyphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboamide (Compound 34 in the Table)

[0255] The preparation process of compound 34 was similar to that of compound 24, and finally a white solid 39 (0.31 g, yield: 45%, ESI-MS (m / z): 698.1 [M+1]) was obtained.

[0256] Example 40: N-(4-cyanophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 35 in the Table)

[0257] The preparation process of compound 35 was similar to that of compound 24, and a white solid 35 (0.22 g, yield: 35%, ESI-MS (m / z): 639.1 [M+1]) was finally obtained.

[0258] Example 41: N-(4-nitrophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 36 in the Table)

[0259] The preparation process of compound 36 was similar to that of compound 24, and a white solid 36 (0.27 g, yield: 41%, ESI-MS (m / z): 659.1 [M+1]) was finally obtained.

[0260] Example 42: N-phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 37 in the Table)

[0261] The preparation process of compound 37 was similar to that of compound 24, and a white solid 37 (0.44 g, yield: 67%, ESI-MS (m / z): 614.1 [M+1]) was finally obtained.

[0262] Example 43: N-benzyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide (Compound 38 in the Table)

[0263] The preparation process of compound 38 was similar to that of compound 24, and a white solid 38 (0.35 g, yield: 55%, ESI-MS (m / z): 628.1 [M+1]) was finally obtained.

[0264] Example 44: N-(2-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 39 in the Table)

[0265] 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazide (0.47 g, 1.0 mmol, 1 equiv) and 2-chlorophenylcyanate (0.17 g, 1.1 mmol, 1.1 equiv) were dissolved in anhydrous tetrahydrofuran and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and ethanol and water (volume ratio 1:1 to 1:2) were added for recrystallization. The precipitate was filtered, washed with cold water 2-3 times, and dried under vacuum to obtain a white solid 39 (0.39 g, yield: 62%, ESI-MS (m / z): 632.1 [M+1]).

[0266] Example 45: N-(3-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 40 in the Table)

[0267] The preparation process of compound 40 was similar to that of compound 39, and finally a white solid 40 (0.25 g, yield: 39%, ESI-MS (m / z): 632.1 [M+1]) was obtained.

[0268] Example 46: N-(4-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 41 in the table)

[0269] The preparation process of compound 41 was similar to that of compound 39, and finally a white solid 41 (0.28 g, yield: 44%, ESI-MS (m / z): 632.1 [M+1]) was obtained.

[0270] Example 47: N-(2-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 42 in the Table)

[0271] The preparation process of compound 42 was similar to that of compound 39, and finally a white solid 42 (0.33 g, yield: 53%, ESI-MS (m / z): 616.1 [M+1]) was obtained.

[0272] Example 48: N-(3-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 43 in the Table)

[0273] The preparation process of compound 43 was similar to that of compound 39, and finally a white solid 43 (0.36 g, yield: 58%, ESI-MS (m / z): 616.1 [M+1]) was obtained.

[0274] Example 49: N-(4-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 44 in the Table)

[0275] The preparation process of compound 44 was similar to that of compound 39, and finally a white solid 44 (0.37 g, yield: 60%, ESI-MS (m / z): 616.1 [M+1]) was obtained.

[0276] Example 50: N-(2-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 45 in the table)

[0277] The preparation process of compound 45 was similar to that of compound 39, and a white solid 45 (0.29 g, yield: 48%, ESI-MS (m / z): 612.1 [M+1]) was finally obtained.

[0278] Example 51: N-(3-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 46 in the table)

[0279] The preparation process of compound 46 was similar to that of compound 39, and a white solid 46 (0.21 g, yield: 34%, ESI-MS (m / z): 612.1 [M+1]) was finally obtained.

[0280] Example 52: N-(4-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 47 in the Table)

[0281] The preparation process of compound 47 was similar to that of compound 39, and a white solid 47 (0.25 g, yield: 40%, ESI-MS (m / z): 612.1 [M+1]) was finally obtained.

[0282] Example 53: N-(4-trifluoromethylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 48 in the Table)

[0283] The preparation process of compound 48 was similar to that of compound 39, and finally a white solid 48 (0.29 g, yield: 43%, ESI-MS (m / z): 666.1 [M+1]) was obtained.

[0284] Example 54: N-(4-trifluoromethoxyphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 49 in the Table)

[0285] The preparation process of compound 49 was similar to that of compound 39, and a white solid 49 (0.35 g, yield: 52%, ESI-MS (m / z): 682.1 [M+1]) was finally obtained.

[0286] Example 55: N-(4-cyanophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 50 in the table)

[0287] The preparation process of compound 50 was similar to that of compound 39, and a white solid 50 (0.40 g, yield: 65%, ESI-MS (m / z): 623.1 [M+1]) was finally obtained.

[0288] Example 56: N-(4-nitrophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 51 in the Table)

[0289] The preparation process of compound 51 was similar to that of compound 39, and finally a white solid 51 (0.39 g, yield: 61%, ESI-MS (m / z): 643.1 [M+1]) was obtained.

[0290] Example 57: N-benzyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carboxamide (Compound 52 in the Table)

[0291] The preparation process of compound 52 was similar to that of compound 39, and a white solid 52 (0.43 g, yield: 70%, ESI-MS (m / z): 612.1 [M+1]) was finally obtained.

[0292] Embodiment 58: Effect embodiment

[0293] 1. Experimental Materials

[0294] 1. Strains:

[0295] Clinically isolated drug-resistant Candida albicans 901 and 904 were donated by the Strain Conservation Center of Changhai Hospital.

[0296] Culture conditions: All experimental strains were activated by streaking on Sandcastle Dextrose Agar (SDA) medium. After culturing at 30°C for 2 weeks, single clones were picked out and streaked again for activation. The single clones obtained for the second time were placed on SDA slants, cultured using the above method, and stored at 4°C for future use.

[0297] 2. Culture medium:

[0298] Sandburg Dextrose Agar Solid Medium (SDA): 10 g of peptone, 40 g of glucose, and 18 g of agar were dissolved in 900 mL of triple-distilled water, and the pH was adjusted to 7.0. The volume was made up to 1000 mL with triple-distilled water, and the mixture was sterilized by high pressure (121°C, 15 min) and stored at 4°C for later use.

[0299] RPMI 1640 liquid culture medium: RPMI1640 (Gibco BRL) 10 g, NaHCO3 2.0 g, morpholinepropanesulfonic acid (MOPS) (Sigma) 34.5 g (0.165 M), add 900 mL of triple-distilled water to dissolve, adjust the pH to 7.0 (25°C) with 1N NaOH, make up to 1000 mL with triple-distilled water, filter and sterilize with a 0.22 μm microporous filter membrane, and store at 4°C for later use.

[0300] YEPD culture medium: 10 g yeast extract, 20 g peptone, 20 g glucose, add 900 ml triple distilled water to dissolve, make up to 1000 mL with triple distilled water, sterilize by high pressure (121°C, 15 min), and store at 4°C for later use.

[0301] 3. Reagents:

[0302] Fluconazole (FCZ) injection was provided by Dalian Pfizer Pharmaceutical Co., Ltd. Dimethyl sulfoxide (DMSO) was purchased from Anhui Zesheng Anaiji Chemical Reagent Company.

[0303] 4. Instruments and equipment:

[0304] Multiskan MK3 enzyme label detector (Labsystems, Finland); water-proof electric constant temperature incubator (Shanghai Yuejin Medical Instrument Factory); MJX intelligent mold incubator (Ningbo Jiangnan Instrument Factory); THZ-82A desktop constant temperature oscillator (Shanghai Yuejin Medical Instrument Factory); SW-CT-IF ultra-clean workbench (Suzhou Antai Air Technology Co., Ltd.); micropipette (Finnpette, Finland); 96-well cell culture plate (Nunclon, Denmark).

[0305] 2. Experimental Methods

[0306] 1. Preparation of fungal suspension:

[0307] Before the experiment, a small amount of Candida albicans was picked from the SDA medium stored at 4°C with an inoculation loop and inoculated into 1mL YEPD culture medium. The culture was cultured at 30°C and 200rpm with shaking for 16 hours to make the fungus in the late exponential growth phase. The bacterial solution was added to 1mL YEPD culture medium and activated again using the above method. After 16 hours, the cells were counted with a hemocytometer and the concentration of the bacterial solution was adjusted to 1×103-5×103 CFU / mL with RPMI 1640 culture medium.

[0308] 2. Preparation of drug sensitivity plate:

[0309] Take a sterile 96-well plate, add 100 μL of RPMI 1640 liquid culture medium to well 1 of each row as a blank control; add 100 μL of freshly prepared bacterial solution to wells 3 to 12; add 160 μL of bacterial solution and 40 μL of test compound solution to well 2; well 12 does not contain drugs, and only adds 100 μL of bacterial solution as a positive growth control. Wells 2 to 11 are diluted in multiples so that the final drug concentrations in each well are 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 μg / mL, respectively, and the DMSO content in each well is less than 1%. Prepare a quality control bacterial drug sensitivity plate at the same time as the drug sensitivity plate is prepared each time, and each drug sensitivity plate is cultured in a constant temperature box at 30°C.

[0310] 3. Determination of minimum inhibitory concentration (MIC value):

[0311] Refer to the standard (M27 - A3 protocol) proposed by the National Committee for Clinical Laboratory Standards (CLSI) of the United States in 2009: In an incubator at 30°C, after culturing Candida for 24 hours, use an enzyme - labeled analyzer to measure the OD value of each well at 620 nm. The OD value of the positive control well is controlled at about 0.2. Compared with the positive control well, the drug concentration in the lowest - concentration well with an OD value decrease of more than 80% is the MIC 80 (The drug concentration when 80% of fungal growth is inhibited). When the MIC 80 value of the drug exceeds the measured concentration range, perform statistics according to the following method: When the MIC 80 value is higher than the highest concentration of 64 μg / mL, it is recorded as ">64.0 μg / mL"; when the MIC 80 value is the lowest concentration or below the lowest concentration, there is no distinction, and it is all recorded as "≤0.125 μg / mL". The above experiments are all operated in parallel 2 to 3 times.

[0312] 4. Evaluation of the effect of combined drug use:

[0313] The fractional inhibitory concentration index (FICI) is the main parameter for evaluating the interaction mode of two drugs in combined drug use. The fractional inhibitory concentration (FIC) is the ratio of the minimum inhibitory concentration (MIC) required for each drug to inhibit bacteria in combination to the MIC when used alone. The FICI is equal to the sum of the FICs of the two drugs. When the MIC value is higher than the highest detection limit, twice the highest - limit concentration is used to calculate the FICI. Many literature reports show that when FICI ≤ 0.5, the interaction of the two drugs is determined to be a synergistic effect, and the smaller the FIC index, the stronger the synergistic effect; when 0.5 < FICI ≤ 1, the interaction of the two drugs is determined to be an additive effect; when 1 < FICI ≤ 4, it is an irrelevant effect; when FICI > 4, the two drugs produce an antagonistic effect.

[0314] III. Experimental results

[0315] Table 2. FICI and MIC of some compounds in combination with fluconazole against drug - resistant Candida albicans 901 and 904 80 Measurement results

[0316]

[0317]

[0318]

[0319] The checkerboard dilution method was used to test the synergistic effect of the above compounds against fluconazole-resistant Candida albicans 901 and 904 in an in vitro drug sensitivity experiment. It was found that most of the compounds had obvious synergistic effects against fluconazole-resistant Candida albicans 901 and 904, and could be used as synergists of antifungal drugs against resistant fungi.

[0320] The substituted triaminotriazine compounds of the present invention are active compounds of a new structural type that cooperate with fluconazole to fight drug-resistant fungi. The present invention opens up a new research path for in-depth research and development of new antifungal drugs.

[0321] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof as shown in formula I: ， in, n is 0, 1 or 2; R is selected from the following structures: , or .

2. The substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Select any of the following compounds: 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-acetamide, 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)-N-(2-((2-aminoethyl)disulfanyl)ethyl)-acetamide, 6-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetamido)-N-hydroxyhexanamide.

3. A substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof as shown in formula II: ， in: R1 is an S atom, R2 represents a benzene ring or a substituted benzene ring, the substituents of the substituted benzene ring are located at various positions of the benzene ring, and are monosubstituted or polysubstituted, and the substituents are selected from a), b), c) and d): a) halogen, b) a cyano or nitro group, c) an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted by halogen, d) an alkoxy group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms substituted by halogen.

4. The substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The halogen is F or Cl; The alkyl group of 1 to 4 carbon atoms is methyl, ethyl or tert-butyl; the alkyl group of 1 to 4 carbon atoms substituted by halogen is an alkyl group of 1 to 4 carbon atoms substituted by fluorine; The alkoxy group of 1 to 4 carbon atoms or the alkoxy group of 1 to 4 carbon atoms substituted by halogen is selected from methoxy and trifluoromethoxy.

5. The substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The R2 is selected from any of the following structures: 。 6. A substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof, characterized in that: Select any of the following compounds: N-(2-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(3-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-chlorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(2-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(3-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-fluorophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(2-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(3-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-methylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-trifluoromethylphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-trifluoromethoxyphenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-cyanophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-(4-nitrophenyl)-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-phenyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-thiocarboxamide, N-Benzyl-2-(2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorobenzyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetyl)hydrazine-1-carbothioamide.

7. Use of the substituted triaminotriazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the preparation of an antifungal pharmaceutical composition.

8. The use according to claim 7, characterized in that: The fungi are Candida albicans 901 and 904 that are resistant to fluconazole.

9. The method for preparing a substituted triaminotriazine compound according to claim 1 or 2, characterized in that: The following steps are involved: (1) Preparation of methyl 2-(4-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acetate Cyanuric chloride and methyl 2-(4-aminophenyl)acetate were reacted in tetrahydrofuran with stirring in an ice bath for 2 hours to obtain methyl 2-(4-((4,6-dichloro-1,3,5-triazine-2-yl)amino)phenyl)acetate; (2) preparing methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate; 2-(4-((4,6-dichloro-1,3,5-triazin-2-yl)amino)phenyl)acetic acid methyl ester, 4-fluorobenzylamine and 20% NaHCO3 solution were stirred at room temperature for 5 hours to obtain 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid methyl ester; (3) preparing methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate; Methyl 2-(4-((4-chloro-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate and cyclohexylmethylamine are dissolved in 1,4-dioxane, 1,8-diazabicycloundec-7-ene is added, and the mixture is refluxed and stirred at 100° C. for 12 hours to obtain methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate; (4) Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid; Methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate and LiOH·H2O were reacted in a mixed solvent under stirring at room temperature for 1 hour to obtain 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetic acid; (5) preparing the substituted triaminotriazine compound according to any one of claims 1 to 3; 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)acetic acid and an amine compound are dissolved in DMF, and a condensing agent PyBOP and a base DIEA are added. The mixture is reacted at room temperature for 3 hours to obtain the substituted triaminotriazine compound according to any one of claims 1 to 3.

10. The preparation method according to claim 9, characterized in that In step (4), the mixed solvent is THF:MeOH:H2O = 3:2:

1.

11. The method for preparing a substituted triaminotriazine compound according to any one of claims 3 to 6, characterized in that: The following steps are involved: (1) Preparation of 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine Methyl 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetate and hydrazine hydrate were dissolved in anhydrous methanol and stirred under reflux at 70° C. for 12 hours to obtain 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine; (2) preparing a substituted triaminotriazine compound according to any one of claims 4 to 7; 2-(4-((4-((cyclohexylmethyl)amino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)phenyl)acetylhydrazine and isothiocyanate are mixed in anhydrous ethanol and refluxed at 80° C. for 3 hours to obtain the substituted triaminotriazine compound according to any one of claims 4 to 7.

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