RU2771027C1 - Hybrid derivatives of (1h-1,2,4) triazole and sulphur-containing heterocycles: derivatives of thiazolidine-2,4-dione, thiomorpholine-3-one, and 1,4-thiazepan-3-one, exhibiting antimicrobial activity - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to pharmaceutical chemistry and includes a compound by the general formula (I) or a stereoisomer, enantiomer, diastereoisomer, racemate, pharmaceutically acceptable salt thereof. In the formula (I), R₁ constitutes hydrogen or methyl; Q constitutes a covalent bond, -NH-, -NR₅-, -(CH₂)_n-NH-, -(CH₂)_n-NR₅- or -(CH₂)_n-, wherein n=0, 1 or 2; R₅ constitutes a -C_1-4-alkyl, benzyl or benzoyl, wherein the benzyl or benzoyl may optionally be substituted with 0 to 2 substituents, independently selected from a partially or fully halogenated -C_1-4-alkyl, halogen; X constitutes -CH- or -N-; A is the fragment specified in the claim, R₃ and R₄ are independently selected from fluorine or chlorine. The group of inventions also relates to a pharmaceutical composition containing a compound by the formula (I) and to an application thereof.

EFFECT: compound by the general formula (I), applied as an antifungal agent for treating and/or preventiing an infectious disease of a microbial etiology in a subject, caused by a fungal infection, in particular, dermatophytosis, superficial mycosis, candidiasis of the skin and/or nails, vaginal candidiasis, candidiasis of internal organs, oral candidiasis, or endocarditis.

14 cl, 5 dwg, 1 tbl

Description

Technical field

The invention relates to chemistry of organic compounds, pharmacology and medicine and relates to new chemical compounds characterized by high antifungal activity, which, in particular, can be used for the prevention and treatment of infectious diseases in a subject.

State of the art

The prior art known commercial systemic antifungal drugs, which are hybrids of triazole with various heterocycles [Liu, N. Et al. Journal of Medicinal Chemistry, 2018, 61(13), 5484-5511], but losing their activity due to the development of resistance to them and the presence of various undesirable manifestations: adverse pharmacokinetic profiles, significant side effects and drug interactions. In this regard, there is a need to optimize and improve the existing unfavorable situation through the introduction of new antifungal agents.

All over the world intensively conducted a constant search for new hybrid derivatives of triazole [Emami E. Et al. Eur. J Med. Chim., 2019, 10, 173-194]. Numerous biologically active hybrid derivatives of triazole are described, linked to it through a piperazinyl fragment connected to various heterocycles: 2-, or 3-, or 4-substituted pyridines, 2- or 4-substituted pyrimidines [CN 1405157 A], as well as substituted thiophene, benzthiazole, benzimidazole, etc. [Jiang Z. et al., Eur. J Med. Chem., 2013, 64, 16-22], triazole [Jiang Yetal., Eur. J Med. Chem., 2011, 46, 3135-3141, Chai X. et al., Arch. Pharm. Res., 2012, 35, 11, 1895-1901, Wang Y et al. Molecules 2014, 19, 11336]. The prior art describes methods for obtaining biologically active hybrid derivatives of thiazolidines and (1H-1,2,4)-triazole, directly linked to each other using a methylene unit (Wu S. et al., ChemMedChem., 2014, 9, 2639-2646 ). Other hybrid derivatives are also known, where various esters (RU 2662153), amides (RU 2703997) or alkyl-phenyl (RU 2690161) substituents are used as a connecting linker between two heterocycles: thiazolidine and triazole.

However, there remains a high need to develop new effective agents against infectious diseases, in particular antifungal agents, for the treatment of a wide range of diseases, in particular those caused by fungal infections.

The objective of the present invention is the development and creation of new effective antimicrobial agents that are promising for use in clinical practice for the treatment and/or prevention of infectious diseases, in particular for the treatment of diseases caused by a fungal infection.

The technical result of the invention is the development and production of new chemical compounds with high antimicrobial activity, a wide spectrum of action and promising for use in the treatment of infectious diseases in a subject, in particular diseases caused by fungal infections, for example, caused by Candida and filamentous pathogens, in particular for the treatment dermatophytosis, superficial mycosis, candidiasis of the skin and nails, candidiasis of internal organs, vaginal candidiasis, candidiasis stomatitis, endocarditis and other diseases of humans and animals, in addition, the compounds according to the present invention are promising for use in the treatment of diseases caused by a fungal infection that manifested itself against the background of decrease in the subject's immunity due to coronavirus infection. Surprisingly, it has been found that the compounds of the invention are characterized by the ability to inhibit strains of pathogens that are not susceptible to commonly used drugs, in particular fluconazole, for example, the compounds of the invention are able to inhibit strains of Candida non-albicans and others.

The compounds of the invention, when used prophylactically, may also reduce the risk of serious Candida infections in people who are immunocompromised as a result of therapy (eg, chemotherapy), organ transplantation, or in people with infectious diseases caused by other pathogens (particularly HIV). In addition, the compounds of the invention are characterized by high antimicrobial activity against resistant strains of fungi.

The activity of the claimed compounds was studied in cultures of microbial cells. Compounds according to the invention in relation to Candida parapsilosis ATCC 22019 are many times superior to the activity of Fluconazole and Nystatin, not inferior or superior to the activity of Ketoconazole (for example, compounds 25, 26, 28, 29). With respect to C. albicans ATCC 24433, the compounds of the invention (in particular compound 3, 4, 6, 7, 13, 17-29, 32-34) showed advantages over ketoconazole. Against the fungus A. niger, the compounds of the invention, in particular compounds 9, 14, 41, were significantly more active than Fluconazole, and were comparable in activity to Nystatin or more active (for example, compound 3-7). In addition, the compounds of the invention, unlike fluconazole, inhibit the growth of filamentous fungi M.canis B-200 and T.rubrum 2002 and are active against fluconazole-resistant pathogens. These types of pathogenic fungi cause various lesions of both internal organs and mucous membranes: surfaces, and external integuments of the skin and its appendages. A high anti-candidiasis activity was revealed in relation to both typical Candida aibinans fungi and Fluconazole-resistant strains of Candida non-aibicans microorganisms.

The specified technical result is achieved by developing and creating a compound of general formula (I):

or its stereoisomer or enantiomer, diastereoisomer, racemate, pharmaceutically acceptable salt, solvate or hydrate, where:

R ₁ is independently selected and is hydrogen or methyl;

Q is selected independently and is a covalent bond, -NH-, -NR ₅ -, -(CH ₂ ) _n -NH-, -(CH ₂ ) _n -NR ₅ - or -(CH ₂ ) _n - where n=0 , 1 or 2;

R ₅ is independently selected and is -C _1-4 -alkyl, -OC _1-4 -alkyl, partially or fully halogenated -C _1-4 -alkyl, benzyl or benzoyl, and benzyl or benzoyl may be optionally substituted with 0-2 substituents independently selected from -C _1-4 -alkyl, -O-C _1-4 -alkyl, partially or fully halogenated -C _1-4 -alkyl, halogen;

X is independently selected and is -CH- or -N-;

A is selected independently and is a fragment selected from:

where Ar is independently selected and represents phenyl, and phenyl may be optionally substituted with 1-2 substituents selected from halogen, -C _1-4 -alkyl, -O-C _1-4 -alkyl, or from substituents that are:

R ₂ is independently selected and is chlorine or fluorine;

Z is independently selected and is -(CH ₂ ) _m - where m is independently selected and is 1 or 2; -CH(OH)CH ₂ -, -CH=CH-CH ₂ - or -CH(CH ₃ )-O-C(=O)-;

where * (asterisk) indicates the place of attachment of the substituent;

R ₃ is independently selected and is fluorine or chlorine;

R ₄ is independently selected and represents fluorine or chlorine;

Me is methyl.

In particular embodiments of the invention, the compound of the invention is selected from the group:

5-(4-chlorobenzylidene)-3-(2-(4-[2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl) piperazin-1-yl)ethyl)thiazolidin-2,4-dione;

(E)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl) propyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione;

3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-ethylbenzylidene)thiazalidine-2,4-dione;

3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione;

3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-methoxybenzylidene)thiazolidine-2,4-dione;

3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-ethoxybenzylidene)thiazolidine-2,4-dione;

5-(4-chloro-2-(4-methylpiperazin-1-yl)benzylidene)-3-(3-(4-(2-[2,4-difluorophenyl)-2-hydroxy-3-(1H-1 ,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione;

(Z)-N-(1-(5-chloro-2-((3-[3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide;

(Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)amine dihydrochloride;

4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-yl;

(Z)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzylidene)thiazolidine-2,4-dione;

5-(2,4-dichlorobenzylidene)-3-(3-(4-(2-(2,4-dichlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) propyl) thiazolidin-2,4-dione;

1-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazine-1-carboxylate;

1-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazine-1-carboxylate;

5-(4-chlorobenzylidene)-3-((Z)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1Н-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione

5-(4-chlorobenzylidene)-3-((E)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione

5-(4-ethylbenzylidene)-3-((E)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione;

3-((E)-4-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl) amino)piperidin-1-yl)but-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione;

racemate 5-(4-chlorobenzylidene)-3-(3-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl)amino)piperidin-1-yl)propyl)thiazolidin-2,4-dione;

racemate 5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl)propyl)amino)ethyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione 2-hydroxypropane-1,2,3-tricarboxylate;

racemate (RS)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

(R) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

(S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)propan-2-yl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione;

racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)butan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione;

racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)(4-fluorophenyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione;

racemate (R,S) (Z)-N-(2-(4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypopyl)piperazin-1-yl )ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide;

(Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-5-methylthiomorpholin-3-one;

(Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-methylthiomorpholin-3-one;

(Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-(4-fluorophenyl)thiomorpholin-3-one;

racemate (R,S) (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1,4-thiazepan-3-one.

The present invention relates to the use of the compounds of the invention as an antimicrobial drug.

The present invention relates to the use of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of an infectious disease of microbial etiology in a subject caused by a fungal infection.

In particular embodiments of the invention, the subject is a human or an animal.

In particular embodiments of the invention, the disease of microbial etymology is caused by a fungus of the genus Candida spp., Aspergillus spp., Microsporum spp., Trichophyton spp. and/or Epidermophyton spp.

In particular embodiments of the invention, the disease of microbial etymology is caused by a fungus of the species Aspergillus fumigatus, Aspergillus niger.

In particular embodiments of the invention, the disease of microbial etymology is caused by a fungus of the species Candida aulis.

In particular embodiments of the invention, the disease of microbial etymology is caused by a fungus of the species Microsporum canis or Trichophyton rubrum.

In particular embodiments of the invention, the infectious disease is a disease of the skin, nails, or internal organs, in particular, such as dermatophytosis, superficial mycosis, skin and/or nail candidiasis, vaginal candidiasis, internal candidiasis, candidal stomatitis, endocarditis, and other human or animal diseases. .

In addition, the invention provides pharmaceutical compositions for the treatment and/or prevention of infectious diseases of microbial etiology, comprising a therapeutically effective amount of at least one compound that is the subject of the invention, and at least one pharmaceutically acceptable excipient.

In some embodiments, the excipient may be a carrier, excipient and/or solvent.

In some embodiments, the infectious disease of microbial etiology is caused by a fungal infection.

In particular embodiments of the invention, the pharmaceutical composition is intended for the treatment and / or prevention of a disease that is a disease of the skin, nails or internal organs, in particular dermatophytosis, superficial mycosis, candidiasis of the skin and / or nails, vaginal candidiasis, candidiasis of the internal organs, candidiasis stomatitis , endocarditis and other human or animal diseases.

The present invention also relates to a method for the treatment and/or prevention of infectious diseases, comprising the administration (as monotherapy or in combination with one or more agents) of a therapeutically effective amount of a compound of the invention to a human or animal in need of treatment and/or prevention of such diseases. The term "administration" of a compound of the present invention includes delivery to a recipient of a compound of the present invention, a prodrug, or other pharmacologically acceptable derivative of such a compound, using any acceptable formulation or route of administration well known to those skilled in the art.

The invention also includes the preparation of compounds of general formula (I).

Brief description of the drawings

Figure 1. ¹³ C NMR spectrum of compound (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)piperazin-1-carbonyl)-5-methylthiomorpholin-3-one (31).

Figure 2. ¹³ C NMR spectrum of compound (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)piperazin-1-carbonyl)-6-methylthiomorpholin-3-one (32).

Figure 3. ¹³ C NMR spectrum of compound (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)piperazin-1-carbonyl)-6-(4-fluorophenyl)thiomorpholin-3-one (33).

Figure 4. ¹³ C NMR spectrum of compound (R,S) (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1,4-thiazepan-3-one (34).

Figure 5. NMR spectra: ¹ H- ¹ H DQF-COSY, ¹ H- ¹ H-ROESY, ¹ H- ¹³ C-HMBC compound (R,S) (Z)-2-(4-chlorobenzylidene)-4- (4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1 ,4-thiazepan-3-one (35).

Detailed disclosure of the invention

Definitions (terms)

For a better understanding of the present invention, below are some of the terms used in the present description of the invention. In addition, unless otherwise indicated, all occurrences of functional groups are chosen independently, two occurrences can be either the same or different.

In the description of the present invention, the terms "comprises" and "comprising" are interpreted to mean "includes, among other things." These terms are not intended to be construed as "consisting only of".

This invention contains only such combinations of substituents and derivatives that form a stable or chemically possible connection. A stable or chemically possible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40°C in the absence of reactive conditions for at least one week. Unless otherwise noted, all occurrences of functional groups are selected independently.

Unless otherwise stated, the structures of the compounds given in the application materials also imply all stereoisomers, that is, the R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, the present invention embraces each diastereomer or enantiomer substantially free of other isomers (>90%; more preferably >95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by separating a racemic mixture according to a standard procedure, for example by preparing diastereomeric salts by treatment with an optically active acid or base, followed by separation of the mixture of diastereomers by crystallization, followed by isolating the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional means, such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

Optically active compounds of this invention can be obtained using optically active starting materials. Such isomers may be in free acid, free base, ester or salt form.

The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "hydrate" refers to a complex where the solvent molecules are water.

The compounds of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative. The term "pharmaceutically acceptable salt" as used herein refers to those salts which, within the limits of medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable ratio of benefit. and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be obtained in situ during the isolation or purification of the compounds of the invention, and can also be obtained separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic acid salts are amino salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valeriate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium, and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic ammonium, quaternary ammonium and amine cations derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The term "microbe", including in the compound words (eg, antimicrobial, antimicrobial), in this document includes, for example, bacteria, fungi, yeasts and protozoa.

The term "alkyl" in this document means both straight and branched. In addition, "alkyl" may be either substituted or unsubstituted.

The term "alkyl" as used herein refers to groups typically having one to three carbon atoms. For example, the term -C _1-4 -alkyl means methyl, ethyl, isopropyl, n-propyl, etc.

The term "partially or fully halogenated alkyl" includes branched and linear saturated hydrocarbon chains in which one or more hydrogen atoms are replaced by a halogen, such as fluorine or chlorine. Examples of haloalkyl groups include, but are not limited to, the following groups: trifluoromethyl, trichloromethyl, pentafluoroethyl, -C(CF ₃ ) ₂ CH ₃ and the like.

Preparation of Compounds of the Invention

Compounds that are the subject of the present invention can be obtained using the synthetic methods described below. The methods listed are not exhaustive and are subject to reasonable modifications. These reactions must be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples given in the application materials are not limiting and are provided only to illustrate the present invention.

The construction of hybrid compounds consisting of 2 different heterocycles - triazole and thiazolidine, linked together using a linker is possible in several ways: by attaching various: amino-substituted heterocycles (including thiazolidine derivatives) to the triazole part of the molecule by opening the oxirane ring containing a triazole fragment (method A); as a result of alkylation of a previously obtained piperazinyl or piperidinyl triazole derivative with a thiazolidine derivative (method B); and as a result of alkylation with the halogen-containing part of the triazole fragment of the thiazolidine K-salt molecule (method B). Method A is the most studied and widespread; in this case, hybrids are most often obtained as a result of the interaction of fragments containing primary or secondary amines with triazole oxirane. The process is carried out in various solvents: alcohols, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (MP).

In the present work, depending on the structural features of the initial intermediates and the yields of intermediate products, all available methods were used. In addition, when obtaining hybrid compounds, depending on the structure and reaction conditions, in addition to the synthesis of target hybrid molecules based on a five-membered thiazolidine ring, it was possible to obtain various six- and seven-membered molecules associated with the triazole part of the molecule through a urea linker and also possessing fungicide activity. .

Overview of Methods for the Preparation of Compounds of the Invention

Compounds that are the subject of the present invention can be obtained using the synthetic methods described below. The methods listed are not exhaustive and are subject to reasonable modifications.

I. Examples for the Preparation of Intermediates

Intermediates for obtaining some compounds of the invention can be obtained by the following methods.

Obtaining potassium salt of thiazolidine-2,4-dione (01)

Scheme 1. Obtaining the potassium salt of thiazolidine-2,4-dione

Thiazolidine-2,4-dione (hereinafter - TZD) (3.51 g, 0.3 mol, 1 eq) was suspended in 50 ml of ethanol, then a solution of potassium hydroxide (1.08 g, 0.3 mol, 1 eq) in ethanol was added ( 15 ml). The resulting suspension was stirred at room temperature for 3 hours. Then the precipitate was filtered off, washed with ethanol (20 ml) and diethyl ether (2*30 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 98% (4.56 g), white powder. For subsequent reactions, it is used without further purification.

Preparation of 3-(2-hydroxy-3-chloropropyl)thiazolidine-2,4-dione (02)

Scheme 2. Preparation of 3-(2-hydroxy-3-chloropropyl)thiazolidine-2,4-dione

To epichlorohydrin (6.0 g, 0.065 mol) was added thiazolidine-2,4-dione (3.4 g, 0.02 mol) and tetra-butylammonium chloride (3.5 mg, 0.3 mmol). The reaction mixture was intensively stirred while heating to 80-90°C in a water bath for 2 hours. Then it was cooled to room temperature, the remains of epichlorohydrin were evaporated in vacuum. The oily residue was dissolved in ethyl acetate (hereinafter - EtOAc) (20 ml), washed with water (10 ml) and evaporated in vacuum. Further, it was purified by flash chromatography using petroleum ether: EtOAc (5:1-1:1) as eluent. Received (5.30 g, 88%) as a colorless oily liquid. C ₆ H ₈ ClNO ₃ S. Exact weight: 208.9913. LC MS (M+1) ⁺ = 209 ⁺ .

¹ H NMR (600 MHz, DMSO-d) δ 5.47 (d, J=5.6 Hz, 1H), 4.14 (s, 2H), 3.92 (dd, J=7.9, 5.0, 4.1, 0.9 Hz, 1H), 3.64 -3.57 (m, 2H), 3.52 (d, J=5.5 Hz, 1H), 3.50 (dd, J=5.5, 2.2 Hz, 1H).

¹³ C NMR (151 MHz, DMSO-d) δ 172.41, 172.08, 66.77, 47.39, 44.79, 39.50 (m, DMSO-d ₆ ), 33.83.

Preparation of 3-(2-hydroxy-3-chloropropyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (03)

Scheme 3. Preparation of 3-(2-hydroxy-3-chloropropyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

To a solution of 3-(2-hydroxy-3-chloropropyl)thiazolidine-2,4-dione (5.0 g, 0.024 mol) in AcOH (50 ml) was added MeNH ₂ (40% aqueous solution, 0.05 ml, 0.006 mol) and (0.025 mol) 4-chlorobenzaldehyde. The reaction mass was heated with stirring under reflux for 12 hours, then cooled to room temperature, the precipitate was filtered off, washed with water (100 ml), and dried in air at room temperature. Received (6.59 g, 83%) as colorless crystals. C ₁₃ H ₁₁ C ₁₂ NO ₃ s. Exact mass: 330.9837. LCMS(M+1) ⁺ = 331 ⁺ .

¹ H NMR (600 MHz, DMSO) δ 7.92 (s, 1H). 7.67-7.63 (m, 2H), 7.62-7.59 (m. 2H), 5.57 (d, J=5.5 Hz, 1H), 4.01 (dp, J=8.4, 5.1 Hz, 1H). 3.77 (dd, J=13.6, 8.4 Hz, 1H), 3.71-3.64 (m, 2H), 3.58 (dd, J=11.3, 5.7 Hz, 1H).

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 167.15, 165.66, 135.15, 131.92, 131.68, 131.25, 129.45, 122.26, 66.74, 47.29, 45.24, 39.50 (m, DMSO-d ₆ ).

Preparation of 3-(4-bromopropyl)thiazolidine-2,4-dione (04)

Scheme 4. Preparation of 3-(4-bromopropyl)thiazolidine-2,4-dione

The potassium salt of TZD (2 g, 12.88 mmol, 1 eq) was suspended in DMF (15 ml), then the calculated amount of dibromopropane (7.8 g, 38.65 mmol, 3 eq) was added. The reaction mass was stirred overnight at a temperature of 50°C, then cooled, diluted with water (50 ml) and extracted three times with diethyl ether (3×15 ml). The organic layer was separated, dried over sodium sulfate, the ether was removed on a rotary evaporator, the residue was dissolved in hexane and applied to a column. The material was purified by silica gel column chromatography, eluting with hexane - methylene chloride - 10% ethyl acetate in methylene chloride. Yield 76.60% (2.35 g). ¹ H NMR (CDCl ₃ ): 3.95 (s, 2H), 3.78 (t, J=6.7 Hz, 2H), 3.38 (t, J=6.7 Hz, 2H), 2.19 (qw, J=6.7 Hz, 2H) .

Preparation of tert-butyl 4-(3-(2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate (05)

Scheme 5. Preparation of tert-butyl 4-(3-(2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate

3-(4-Bromopropyl)thiazolidine-2,4-dione (5.0 g, 1 eq), Boc-piperazine (4.3 g, 1.1 eq), and potassium carbonate (8.7 g, 3 eq) in 50 ml of acetonitrile are mixed overnight at 70°C. The mixture is cooled, the salt precipitate is filtered off, the solvent is evaporated. The residue is chromatographed on silica gel (eluent - ethyl acetate in hexane 2:1). The fractions obtained after chromatography are evaporated to give the product as an oil. Yield 6.94 g (96%).

¹ H NMR (CDCl ₃ ): 3.94 (s, 2H), 3.72 (t, J=6.8Hz, 2H), 3.56 (m, 4H), 2.59 (m, 6H), 1.95 (m, 2H), 1.45 9H).

Preparation of tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate (06)

Scheme 6. Preparation of tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate

3-Substituted thiazolidine-2,4-dione (6.94 g, 1 equiv) and 4-chlorobenzaldehyde (2.84 g, 1 equiv) are stirred at 80°C in ethanol with the addition of piperidine (172 mg, 0.1 equiv). After cooling to room temperature, the clear solution is evaporated, the liquid residue is purified on silica gel (eluent - ethyl acetate in hexane 1:1). The fractions obtained are evaporated to give the product as an oil. Yield 3.57 g (38%).

¹ H NMR (CDCl ₃ ): 7.83 (s, 1H), 7.44 (m, 4H), 3.86 (t, J=6.6 Hz, 2H), 3.55 (m, 4H), 2.61 (m, 6H), 2.03 (m, 2H), 1.44 (s, 9H).

Obtaining 5-(4-chlorobenzylidene)-3-(3-(piperazin-1-yl)prolyl)thiazolidine-2,4-dione hydrochloride (07)

Scheme 7. Preparation of 5-(4-chlorobenzylidene)-3-(3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione hydrochloride

A solution of Boc-piperazinyl amide (4.30 g) in a saturated solution of hydrogen chloride in ethyl acetate (30 ml) was stirred overnight at room temperature, while a precipitate gradually formed. The mixture is stirred overnight, then the precipitate is filtered off and washed with ethyl acetate. Yield 2.62 g (64.71%).

¹ H NMR (DMSO-d ₆ ): 11.97 (bs, 1H), 9.88 (bs, 2H), 7.91 (s, 1H), 7.64 (d, 2H, J=8.56 Hz), 7.60 (d, 2H, J =8.56 Hz), 3.72 (m, 2H), 3.57 (m, 4H), 3.17 (m, 6H), 2.06 (m, 2H).

Preparation of 5-(4-chlorobenzylidene) thiazolidine-2,4-dione (08)

Scheme 8. Obtaining 5-(4-chlorobenzylidene) thiazolidine-2,4-dione

Thiazolidine-2,4-dione (3.22 g, 27.46 mmol, 1 eq) was suspended in 50 ml of acetic acid. 4-chlorobenzaldehyde (3.86 g, 27.46 mmol, 1 eq) was added to the obtained reaction mixture, then a 40% aqueous solution of methylamine (1.42 ml, 0.51 g in terms of methylamine, 16.48 mmol, 0.6 eq). The reaction mass was stirred overnight at 100°C, then cooled to room temperature. The precipitate formed was filtered off, washed twice with water (2 x 30 ml), dried in air, and washed once with diethyl ether (40 ml). Yield 96% (6.32 g), white powder. C ₁₀ H ₆ ClNO ₂ S. m/z 239.68. LCMS (M+1) 239 ⁺ . ¹ H NMR (DMSO-d ₆ ): δ 12.7 (1H, s, H), 7.8 (1H, CH=C, m), 7.6-7.7 (4H, m, Ph).

Preparation of K-salt of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione (09)

Scheme 9. Obtaining K-salt of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione

5-(4-Chlorobenzylidene)thiazolidine-2,4-dione (5.0 g, 20.86 mmol, 1 eq) was suspended in 80 ml of ethanol, then a solution of potassium hydroxide (1.17 g, 20.86 mmol, 1 eq) in ethanol was added ( 20 ml). The resulting suspension was stirred at room temperature for 3 hours. Then the precipitate was filtered off, washed with ethanol (50 ml) and diethyl ether (2*60 ml) and transferred to a round bottom flask. The substance was dried on a rotary evaporator to constant weight. Yield 90% (5.23 g), white powder.

Preparation of 5-(2,4-dichlorobenzylidene) thiazolidine-2,4-dione (010)

Scheme 10. Preparation of 5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione

The connection was obtained analogously to the example of connection 08. Aromatic aldehyde - 2,4-dichlorobenzaldehyde. Yield 81% (5.70 g), yellowish powder.

C ₁₀ H ₅ Cl ₂ NO ₂ S. m/z 274, 13. LCMS [M+1] ⁺ = 275 ⁺ .

¹ H NMR (DMSO-d ₆ ): δ 12.65 (s, 1H), 7.9-7.8 (m, 2H), 7.7-7.5 (m, 3H).

Obtaining K-salt of 5-(2,4-dichlorobenzylidene) thiazolidine-2,4-dione (011)

Scheme 11. Obtaining the K-salt of 5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione

The compound was obtained analogously to the example of compound 09. Yield 92% (1.05 g), white powder.

Preparation of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione (012)

Scheme 12. Obtaining 5-(4-methoxybenzylidene) thiazolidine-2,4-dione

The compound was prepared analogously to compound example 08. Aromatic aldehyde-4-methoxy-benzaldehyde. Yield 89% (4.80 g), yellowish powder. C ₁₁ H ₉ NO ₃ S, m/z 235.26. LCMS [M+1] ⁺ = 236 ⁺ .

¹ H NMR (DMSO-d ₆ ): δ 12.4 (s, 1H, NH), 7.75 (m, 1H, CH=C), 7.55, 7.09 (m, 4H, Ph), 3.82(s, 3H).

Obtaining K-salt of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione (013)

Scheme 13. Obtaining K-salt of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione

Prepared analogously to compound 09. Yield 81% (1.42 g), white powder.

Preparation of 5-(4-ethylbenzylidene)-thiazolidine-2,4-dione (014)

Scheme 14. Obtaining 5-(4-ethylbenzylidene)-thiazolidine-2,4-dione

The method for preparing the present compound is similar to that of the previous Knoevenagel reaction in isopropyl alcohol with a piperidine catalyst. Aromatic aldehyde-4-ethyl-benzaldehyde. Yield 68%. C ₁₂ H ₁₁ NO ₂ S. m/z 233.29. LCMS [M+H] ⁺ = 234 ⁺ . ¹ H NMR(500 MHz, CDCl ₃ ): δ=12.56 (bs, 1H), 7.75 (s, 1H), 7.49 (d, 2H, J=8.07 Hz), 7.36 (d, 2H, J=8.07 Hz) , 2.64 (q, 2H, J ₁ =7.58 Hz, J ₂ =15.16 Hz), 1.18 (t, 3H, J ₁ =7.58 Hz, J ₂ =15.16 Hz).

Obtaining potassium salt of 5-(4-ethylbenzylidene)-2,4-dioxothiazolidine (015)

Scheme 15. Preparation of potassium salt of 5-(4-ethylbenzylidene)-2,4-dioxothiazolidine The compound was obtained analogously to the example of compound 09. Yield 1.04 g (87%). C ₁₂ H ₁₀ KNO ₂ S.

Preparation of 5-(4-isopropylbenzylidene)thiazolidine-2,4-dione (016)

Scheme 16. Preparation of 5-(4-isopropylbenzylidene)thiazolidine-2,4-dione

The compound was obtained analogously to compound 08. Aromatic aldehyde-4-isopropyl-benzaldehyde. Yield 75% (1.59 g). C ₁₃ H ₁₃ NO ₂ S. m/z 248.32. LC MS (M+1) ⁺ = 249 ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ): δ=12.57 (bs, 1H), 7.75 (s, 1H), 7.51 (d, 2H, J=8.32 Hz), 7.39 (d, 2H, J=8.32 Hz) , 2.92 (m, 1H), 1.20 (m, 6H).

Obtaining potassium salt of 5-(4-isopropylbenzylidene)-2,4-dioxothiazolidine (017)

Scheme 17. Preparation of potassium salt of 5-(4-isopropylbenzylidene)-2,4-dioxothiazolidine

Obtained analogously to the example of compound 09. Yield 967 mg (53%). C ₁₃ H ₁₂ KNO ₂ S.

Preparation of 5-(4-tert-butylbenzylidene)thiazolidine-2,4-dione (018)

Scheme 18. Obtaining 5-(4-tert-butylbenzylidene)thiazolidine-2,4-dione

Prepared analogously to the compound of example 08. Aromatic aldehyde-4-tert-butyl-benzaldehyde. Yield 70% (1.57 g). C ₁₄ H ₁₅ NO ₂ S. LC MS [M+H] ⁺ = 262 ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ): δ=12.57 (bs, 1H), 7.75 (s, 1H), 7.55 (d, 2H, J=8.80 Hz), 7.52 (d, 2H, J=8.80 Hz) , 1.29(s, 9H).

Obtaining potassium salt of 5-(4-tert-butylbenzylidene)-2,4-dioxothiazolidine (019)

Scheme 19. Preparation of potassium salt of 5-(4-tert-butylbenzylidene)-2,4-dioxothiazolidine

The compound was obtained analogously to the compound of example 09. Yield 1.5 g (83%). C ₁₄ H ₁₄ KNO ₂ S.

Obtaining tert-butyl 2-bromoethyl piperazine-1-carboxylate (020)

Scheme 20. Obtaining tert-butyl 2-bromoethyl piperazine-1-carboxylate

To a solution of Boc-piperazine (3.5 g, 1 equiv, 18.8 mmol) in anhydrous tetrahydrofuran (50 ml) dibromoethane (3.8 g, 1.2 equiv) and 3.9 g (28.2 mmol 1.5 equiv) of potassium carbonate are added successively. The reaction mass is stirred overnight at room temperature, the solvent is removed on the rotor, the residue is suspended in ethanol, filtered off, washed 2 times with ethanol and 1 time with diethyl ether. Used without further purification.

Preparation of tert-butyl 4-((5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl)piperazine-1-carboxylate (021)

Scheme 21. Preparation of tert-butyl 4-((5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl)piperazine-1-carboxylate

To a solution of the potassium salt of 5-(4-chlorobenzylidene)-thiazolidine-2,4-dione (4.5 g, 1.2 eq, 13 mmol) was slowly added dropwise 2-bromoethyl piperazine carboxylate (2 g, 1 eq, 10.7 mmol) in acetonitrile (30 ml) and the calculated amount of potassium carbonate (4.45 g, 3 eq, 32 mmol) and stirred for 10 minutes. The reaction mixture was refluxed overnight. Afterwards, the inorganic precipitate was filtered off and acetonitrile was removed on a rotary evaporator. The resulting residue was purified by chromatography on silica gel in the system methylene - 2% methanol in methylene. Yield 24% (1.15 g). C ₂₁ H ₂₆ ClN ₃ O ₄ S. m/z 451.9750. LC MS (M+1) ⁺ = 451 ⁺ .

Preparation of 5-(4-chlorobenzylidene)-3-(2-(piperazin-1-yl)ethyl)thiazolidin-2,4-dione dihydrochloride (022)

Scheme 22. Preparation of 5-(4-chlorobenzylidene)-3-(2-(piperazin-1-yl)ethyl)thiazolidin-2,4-dione dihydrochloride

To a solution of the Boc derivative of 5-(4-chlorobenzylidene)-3-(2-(piperazin-1-yl)ethyl)thiazolidin-2,4-dione (1.15 g, 1 eq, 2.5 mmol) in a minimum amount of ethyl acetate was added 8 ml of 5.64 M hydrochloric ethyl acetate and stirred the reaction mass overnight at room temperature. The ethyl acetate was then removed on a rotary evaporator. The substance was obtained as a double hydrochloride. Yield 94% (1 g). C ₁₆ H ₁₈ ClN ₃ O ₂ S. m/z 351.86. LC MS (M+1) ⁺ = 352 ⁺ .

¹ H NMR (DMSO-d ₆ ): 9.64 (s, 2H), 7.67 (d, 2H, J=8.68 Hz), 7.66 (s, 1H), 7.53 (d, 2H, 8.68 Hz), 3.89 (m, 2H), 3.69 (m, 4H), 3.35 (m, 4H), 3.25 (bs, 1H), 3.14 (m, 2H).

Preparation of 3-(3-bromopropyl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (023)

Scheme 23. Obtaining 3-(3-bromopropyl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione

Triphenylphosphine (1.01 g, 3.86 mmol, 1.5 eq.) , alkylator - 1-bromopropan-2-ol (536 mg, 3.86 mmol, 1.5 eq) and dropwise catalyst - diethyl azocarboxylate (DEAD) (672 mg, 3.86 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature, then tetrahydrofuran was evaporated on a rotor, the resulting mixture was triturated in ethanol (3 ml), filtered, washed with ethanol (2 ml), and dried in air to constant weight. Yield 41.38% (377 mg).

Preparation of 3-(3-bromopropyl)-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione (024)

Scheme 24. Preparation of 3-(3-bromopropyl)-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione

Triphenylphosphine (861 mg, 3.28 mmol, 1.5 eq), alkylator - 1-bromopropan-2-ol (456 mg, 3.28 mmol, 1.5 eq) and dropwise catalyst - diethyl azocarboxylate (DEAD) (572 mg, 3.28 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature, then tetrahydrofuran was evaporated on a rotor, the resulting mixture was triturated in ethanol (5 ml), filtered, washed with ethanol (4 ml), and dried in air to constant weight. Yield 43.83% (379 mg).

Preparation of 3-(3-bromopropyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (025)

Scheme 25 Preparation of 3-(3-bromopropyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione

Triphenylphosphine (1.00 g, 3.83 mmol, 1.5 eq.) , alkylator - 1-bromopropan-2-ol (532 mg, 3.83 mmol, 1.5 eq) and dropwise catalyst - diethyl azocarboxylate (DEAD) (666 mg, 3.83 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature, then tetrahydrofuran was evaporated on a rotor, the resulting mixture was triturated in ethanol (5 ml), filtered, washed with ethanol (4 ml), and dried in air to constant weight. Yield 60.54% (550 mg).

Preparation of 3-(3-bromopropyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (026)

Scheme 26. Obtaining 3-(3-bromopropyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione

Triphenylphosphine (0.95 g, 3.61 mmol, 1.5 eq.) , alkylator - 1-bromopropan-2-ol (502 mg, 3.61 mmol, 1.5 eq) and dropwise DEAD (629 mg, 3.61 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature, then tetrahydrofuran was evaporated on a rotor, the resulting mixture was triturated in ethanol (5 ml), filtered, washed with ethanol (4 ml), and dried in air to constant weight. Yield 68.45% (610 mg).

Preparation of (R)-tert-butyl 4-(4-bromobut-2-en-1-yl)piperazine-1-carboxylate (027)

Scheme 27. Preparation of (R)-tert-butyl 4-(4-bromobut-2-en-1-yl)piperazine-1-carboxylate

Trans-1,4-dibromobut-2-ene (R) (2.30 g, 10.74 mmol, 4 eq) was dissolved in acetonitrile (20 ml), then potassium carbonate (928 mg, 6.71 mmol, 2.5 eq) was added. The reaction mass is stirred for 5 minutes at room temperature, then cooled to 0°C with an ice bath and a solution of Boc-piperazine (500 mg, 2.68 mmol, 1 eq) in acetonitrile (10 ml) is added dropwise. The reaction mass is gradually heated to room temperature and stirred at it for 16 hours. Then inorganic salts are filtered off, the precipitate is washed twice with methylene chloride (2*20 ml). The filtrate is evaporated on a rotary evaporator, the resulting crystalline substance is washed 4 times with diethyl ether (4*15 ml). The precipitate is dried and used further without further purification. Yield quantitative (857 mg). C ₁₃ H ₂₃ BrN ₂ O ₂ . LC MS [M+H] ⁺ 320 ⁺ . ¹ H MNR (CDCl ₃ ): 6.55 (m, 1H), 6.11 (m, 1H), 4.53 (m, 2H), 4.07 (m, 2H), 3.83 (m, 4H), 3.64 (m, 4H), 1.44 (s, 9H).

Preparation of (R) tert-butyl 4-(4-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)but-2-en-1-yl)piperazin-1-carboxylate (028)

Scheme 28 Preparation of (R) tert-butyl 4-(4-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)but-2-en-1-yl)piperazin-1-carboxylate

(R)-tert-butyl 4-(4-bromobut-2-en-1-yl)piperazin-1 -carboxylate (840 mg, 2.63 mmol, 1 eq). The reaction mass was kept for 16 hours at 50°C, then cooled and poured into water (15 ml). The precipitate formed was filtered off, washed with water (3 x 10 ml), dried in air and washed with diethyl ether (10 ml). Yield 38% (480 mg). C ₂₃ H ₂₈ ClN ₃ O ₄ S. LC MS [M+H] ⁺ 479 ⁺ .

¹ H NMR (DMSO-d ₆ ): 7.88 (s, 1H), 7.58 (m, 4H), 6.08 (m, 1H), 5.93 (m, 1H), 4.34 (m, 2H), 4.01 (m, 2H ), 3.65 (m, 2Н), 3.33 (m, 6Н), 1.40 (m, 9Н).

Preparation of (R) 5-(4-chlorobenzylidene)-3-(4-(piperazin-1-yl)but-2-en-1-yl)thiazolidin-2,4-dione hydrochloride (029)

Scheme 29. Preparation of (R) 5-(4-chlorobenzylidene)-3-(4-(piperazin-1-yl)but-2-en-1-yl)thiazolidin-2,4-dione hydrochloride

Solution (R) tert-Butyl 4-(4-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)but-2-en-1-yl)piperazin-1-carboxylate (480 mg) in a saturated solution of hydrogen chloride in ethyl acetate (10 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The precipitate formed is filtered off and washed with ethyl acetate. Yield quantitative (416 mg). C ₁₇ H ₂₁ ClN ₃ O ₂ S. LC MS [M+H] ⁺ = 378 ⁺ .

¹ H NMR (DMSO-d ₆ ): 10.02 (bs, 1H), 7.90 (s, 1H), 7.59 (m, 5H), 6.17 (m, 1H), 5.95 (m, 1H), 4.36 (m, 2H ), 4.12 (m, 2Н), 3.57 (m, 8Н).

Preparation of (R) 3-(4-bromobut-2-en-1-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (030)

Scheme 30. Preparation of (R) 3-(4-bromobut-2-en-1-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

(R)-1,4-dibromobut-2-ene (2.54 g, 11.88 mmol, 3 equiv). The reaction mass was kept for 16 hours at 50 degrees, then cooled and the precipitate of inorganic salts was filtered off, which was then washed with dichloromethane (2*15 ml). The resulting filtrate was evaporated on a rotary evaporator, then the residue was washed with diethyl ether (4*10 ml) and dried. Yield 85% (1.25 g). C ₁₄ H ₁₁ BrClNO ₂ S. LC MS [M+H] ⁺ = 373 ⁺ .

Preparation of (R) 3-(4-bromobut-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (031)

Scheme 31 Preparation of (R) 3-(4-bromobut-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione

To a suspension of the potassium salt of 4-ethylbenzylidenethiazolidinedione (1.0 g, 3.9 mmol, 1 eq) in DMF (10 ml) was added (R) 1,4-dibromobut-2-ene (2.54 g, 11.88 mmol, 3 eq). The reaction mass was kept for 16 hours at 50 degrees, then it was cooled and the precipitate of inorganic salts was filtered off, which was then washed with dichloromethane (2*15 ml). The resulting filtrate was evaporated on a rotary evaporator, then the residue was washed with diethyl ether (4*10 ml) and dried. Yield 85% (1.25 g). C ₁₆ H ₁₆ BrNO ₂ S. LC MS [M+H] ⁺ = 367 ⁺ .

Preparation of 6-(4-chlorobenzylidene)-3-(4-bromopropyl)thiazolidine-2,4-dione (032)

Scheme 32. Obtaining 5-(4-chlorobenzylidene)-3-(4-bromopropyl)thiazolidine-2,4-dione

To a solution of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione in anhydrous tetrahydrofuran (800 mg, 1 eq., 3 mmol), triphenylphosphine (1.3 g, 1.5 eq., 5 mmol), , 1.5 eq, 5 mmol) and diethyl azocarboxylate catalyst (DEAD) (872 mg, 1.5 eq, 5 mmol). The reaction mass is stirred overnight at room temperature, the solvent is removed on the rotor, the residue is suspended in ethanol, filtered off, washed 1 time with ethanol and 1 time with diethyl ether. Yield 43% (515 mg). C ₁₃ H ₁₁ BrClNO ₂ S. m/z 361.66. LCMS [M+H] ⁺ 362 ⁺ . ¹ H NMR (CDCl ₃ ): 7.84 (s, 1H), 7.46-7.42 (m, 4H), 3.91 (m, 2H), 3.40 (m, 2H), 2.25 (m, 2H).

Preparation of tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate (033)

Scheme 33. Preparation of tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate

Alkylator - 5-(4-chlorobenzylidene)-3-(4-bromopropyl)thiazolidine-2,4-dione (3.84 g, 10.65 mmol, 1 eq), N-Boc-piperazine (1.98 g, 10.65 mmol, 1 eq) , potassium carbonate (4.41 g, 31.94 mmol, 3 eq) and potassium iodide (1.77 g, 10.65 mmol, 1 eq) are suspended in dimethylformamide (40 ml) and kept overnight at 80°C. The reaction mass is cooled, diluted with water (100 ml) and the resulting precipitate is filtered off, then washed with water and dried in air. Yield 87% (4.32 g). C ₂₂ H ₂₈ ClN ₃ O ₄ S. m/z 466.00. LC MS [M+H] ⁺ 467 ⁺ .

¹ H NMR (CDCl ₃ ): 7.83 (s, 1H), 7.44 (m, 4H), 3.86 (t, J=6.6Hz, 2H), 3.55 (m, 4H), 2.61 (m, 6H), 2.03 (m, 2H), 1.44 (s, 9H).

Preparation of 5-(4-chlorobenzylidene)-3-(3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione dihydrochloride (034)

Scheme 34. Preparation of 5-(4-chlorobenzylidene)-3-(3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione dihydrochloride

A solution of tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazine-1-carboxylate (6.21 g) in saturated hydrogen chloride in ethyl acetate (40 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The precipitate formed is filtered off and washed with ethyl acetate. Yield 5.55 g (95%). C ₁₇ H ₂₀ CIN ₃ O ₂ S. m/z 365.88. LC MS [M+H] ⁺ = 366 ⁺ . ¹ H NMR (DMSO-d ₆ ): 11.97 (bs, 1H), 9.88 (bs, 2H), 7.91 (s, 1H), 7.64 (d, 2H, J=8.56 Hz), 7.60 (d, 2H, J =8.56 Hz), 3.72 (m, 2H), 3.33 (m, 8H), 3.17 (m, 2H), 2.06 (m, 2H).

Preparation of tert-butyl (2-(4-(3-(5-(4-chlorobenzylidene))-2,4-dioxothiazolidin-3-yl)propyl)piperazin-1-yl)ethyl)carbamate (035)

Scheme 35. Preparation of tert-butyl (2-(4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)propyl)piperazin-1-yl)ethyl)carbamate

5-(4-Chlorobenzylidene)-3-(3-(piperazin-1-yl)propyl)thiazolidin-2,4-dione dihydrochloride (5.55 g, 12.65 mmol, 1 eq) was suspended in acetonitrile (30 ml), then added calculated amounts of potassium carbonate (7 g, 50.59 mmol, 4 equiv), tert-butyl (2-bromoethyl)carbamate (2.83 g, 12.65 mmol, 1 equiv) and potassium iodide (2.10 g, 12.65 mmol, 1 equiv). The reaction mass is stirred for 16 hours at 80°C, then cooled, inorganic salts are filtered off and used further without further purification. C ₂₄ H ₃₃ ClN ₄ O ₄ S. LC MS [M+H] ⁺ 510 ⁺ .

¹ H NMR (CDCl ₃ ): 7.83 (s, 1H), 7.45 (m, 4H), 5.27 (bs, 1H), 3.84 (m, 2H), 3.31 (m, 2H), 2.62 (m, 12H), 1.90 (m, 2H), 1.44 (s, 9H).

Preparation of 3-(3-(4-(2-aminoethyl)piperazin-1-yl)propyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione hydrochloride (036)

Scheme 36. Preparation of 3-(3-(4-(2-aminoethyl)piperazin-1-yl)propyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione hydrochloride

A solution of tert-butyl (2-(4-(3-(5-(4-chlorobenzylidene))-2,4-dioxothiazolidin-3-yl)propyl)piperazin-1-yl)ethyl)carbamate (600 mg) in saturated solution hydrogen chloride in ethyl acetate (10 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The precipitate formed is filtered off and washed with ethyl acetate. Yield 420 mg (80%). C ₁₉ H ₂₆ ClN ₄ O ₂ S. LC MS [M+H] ⁺ 409 ⁺ .

¹ H NMR (DMSO-d ₆ ): 8.25 (bs, 1H), 7.90 (s, 1H), 7.60 (m, 4H), 3.73 (m, 2H), 3.50 (m, 5H), 3.17 (m, 8H ), 2.94 (m, 1H), 2.06 (m, 3H), 1.92 (m, 1H).

Preparation of 1Н-1,2,4-triazole derivatives

Preparation of 2-(2,4-difluorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (037)

Scheme 37. Preparation of 2-(2,4-difluorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

A mixture of oxirane 1-((2-(2,4-difluorophenyl)-2-oxiranyl)methyl)-1H-1,2,4-triazole, methanesulfonate (17.2 g, 1 eq), Boc-piperazine (9, 6 g, 1 eq.) and triethylamine (10.4 ml, 1.5 eq.) is boiled in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with aqueous citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The foamed oil product crystallized upon standing. Yield 13.02 g (59%). C ₂₀ H ₂₇ F ₂ N ₅ O ₃ . m/z 423. LCMS [M+1] = 424 ⁺ .

¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.13 (s, 1H), 7.79 (s, 1H), 7.56 (m, 1H), 6.83 (m, 2H), 4.54 (dd, J ₁ =25.2 Hz , J2 ₌ 14.2 Hz, 2H), 3.33 (m, 5H), 3.10 (m, 1H), 2.77 (m, 1H), 2.36 (m, 4H), 1.43 (s, 9H). Individuality was confirmed chromatographically.

Preparation of 2-(2,4-difluorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride (038)

Scheme 38. Preparation of 2-(2,4-difluorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride

2-(2,4-difluorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol solution (10.0 g ) in a saturated solution of hydrogen chloride in ethyl acetate (60 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The next day the precipitate formed is filtered off and washed with ethyl acetate. Yield 8.44 g (98.0%). C ₁₅ H ₁₉ F ₂ N ₅ O × HCl m/z 323. LCMS [M+1] = 324 ⁺ .

¹ H NMR: (500 MHz, DMSO d ₆ ) δ = 9.63 (bs, 2H), 8.56 (s, 1H), 7.88 (s, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 4.79 (d, J=14 Hz, 1H), 4.70 (d, J=14 Hz, 1H), 4.56 (bs, 1H), 4.02 (dd, J ₁ =14.2 Hz, J ₂ = 7.1 Hz, 2H), 3.71-3.19 (m, 8H).

Individuality was confirmed chromatographically.

Preparation of 1-((2-(2,4-dichlorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (039)

Scheme 39. Preparation of 1-((2-(2,4-dichlorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole

To a mixture of 2,4-dichloro-alpha (1H-1,2,4-triazolyl) acetophenone (2.0 g, 7.81 mmol, 1 eq), trimethylsulfoxonium iodide (1.72 g, 7.81 mmol, 1 eq) and hexadecyltrimethylammonium bromide ( 71 mg, 0.20 mmol, 0.025 eq) 1.28 ml of 20% sodium hydroxide solution (312 mg, 7.81 mmol, 1 eq) is added to 20 ml of toluene. The mixture is stirred at 60°C for 2 hours. The emulsion is filtered, the toluene phase is separated and evaporated. The resulting substance is used further without purification. Yield 51.2% (1.51 g), brown oil. C ₁₁ H ₁₂ Cl ₂ N ₃ O m/z 273.14. LCMS [M+1] = 274 ⁺ .

¹ H NMR (CDCl ₃ ): 8.10 (s, 1H), 7.88 (s, 1H), 7.38 (d, J=14.9Hz, 1H), 7.16 (dd, J ₁ =8.2 Hz, J ₂ =1.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 4.86 (d, J=14.9 Hz, 1H) 4.48 (d, J=14.9 Hz, 1H), 2.96 (d, J=4.3 Hz, 1H), 2.88 (d, J=4.3 Hz, 1H).

Preparation of 2-(2,4-dichlorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4 triazol-1-yl)propan-2-ol (040)

Scheme 40. Preparation of 2-(2,4-dichlorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

Oxirane mixture 1-((2-(2,4-dichlorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole (2.1 g, 7.77 mmol, 1 eq), Boc-piperazine (1.45 g , 7.77 mol, 1 eq.) and triethylamine (944 mg, 9.33 mmol, 1.2 eq.) is boiled in ethanol overnight. Ethanol is evaporated, the residue is dissolved in methylene chloride and washed with aqueous citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The residue is dissolved in methylene chloride and the substance is purified by chromatography on silica gel (elution system methylene chloride - 3% methanol in methylene chloride. Yield 13% (465 mg), brown oil. C ₂₀ H ₂₇ Cl ₂ N ₅ O ₃ m / z 456.37 LCMS [M+1] ⁺ = ⁴⁵⁷⁺ Individuality was confirmed chromatographically.

Preparation of 2-(2,4-dichlorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride (041)

Scheme 41. Preparation of 2-(2,4-dichlorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride.

A solution of 2-(2,4-dichlorophenyl)-4-(tert-butoxycarbonylpiperazin-1-yl)-3-(1H-1,2,4 triazolyl-1-yl)propan-2-ol (456 mg) in saturated a solution of hydrogen chloride in ethyl acetate (5 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The next day the precipitate formed is filtered off and washed with ethyl acetate. Yield 2-(2,4-dichlorophenyl)-4-(piperazin-1-yl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride 381 mg (97.0 %). C ₁₅ H ₁₉ Cl ₂ N ₅ O. m/z 356.25. LCMS [M+1] = 357 ⁺ . Individuality was confirmed chromatographically.

Preparation of 1-azido-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (042)

Scheme 42. Preparation of 1-azido-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

Oxirane methanesulfonate (2 g, 6.30 mmol, 1 eq), ammonium chloride (341 mg, 6.37 mmol, 1.01 eq) and sodium azide (1.23 g, 18.91 mmol, 3 eq) were suspended in methanol and refluxed for 16 hours. Then the methanol was evaporated, the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with saturated sodium chloride solution (15 ml), dried over sodium sulfate and the ethyl acetate was removed on a rotary evaporator. The resulting product was used further without purification. The output is quantitative. C ₁₁ H ₁₀ F ₂ N ₆ O. LC MS [M+H] ⁺ = 281 ⁺ .

¹ H NMR (CDCl ₃ ): 8.13 (s, 1H), 7.90 (s, 1H), 7.52 (m, 1H), 6.80 (m, 2H), 4.76 (m, 3H), 3.68 (d, 1H, J =12.72 Hz), 3.54 (d, 1H, J=12.72 Hz).

Preparation of 1-amino-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (043)

Scheme 43. Preparation of 1-amino-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

To a solution of azide (1.11 g) in ethanol (120 ml) was added 111 mg of palladium on charcoal and intensively stirred for 16 hours at room temperature in a hydrogen atmosphere at a pressure of 1 atm. Then the palladium on charcoal was filtered through celite, the ethanol was evaporated, and the resulting substance was used further without further purification. Yield quantitative (1 g). C ₁₁ H ₁₂ F ₂ N ₄ O. m/z 254.24. LC MS [M+H] ⁺ = 255 ⁺ .

¹ H NMR (CDCl ₃ ): 8.07 (s, 1H), 7.81 (s, 1H), 7.55 (m, 1H), 6.81 (m, 2H), 4.58 (m, 2H), 3.19 (m, 1H), 3.00 (m, 1H), 2.44 (bs, 3H).

Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)piperidine-1-carboxylate (044 )

Scheme 44. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)piperidin-1- carboxylate

To a solution of 1-amino-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1 g, 3.93 mmol, 1 eq) in methanol (50 ml) add Boc-piperidone (784 mg, 3.93 mmol, 1 eq), acetic acid (23 mc) and sodium cyanoborohydride (297 mg, 4.72 mmol, 1.2 eq). The reaction mass is stirred for 16 hours at room temperature, then the methanol is evaporated, the residue is distributed between ethyl acetate and water, ethyl acetate is separated. The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the substance is used further without further purification. Yield quantitative (1.72 g). C ₂₁ H ₂₉ F ₂ N ₅ O ₃ . LC MS [M+H] ⁺ = 438 ⁺ .

¹ H NMR (CDCl ₃ ): 8.46 (s, 1H), 7.84 (s, 1H), 7.56 (m, 1H), 7.21 (bs, 1H), 6.82 (m, 2H), 4.76 (m, 1H), 4.62 (m, 1Н), 4.24 (m, 2Н), 3.82 (m, 1Н), 3.59 (m, 2Н), 2.67 (m, 2Н), 2.18 (m, 2Н), 1.72 (m, 1Н), 1.64 (m, 1Н), 1.49 (s, 9Н), 1.34 (m, 1Н).

Preparation of 2-(2,4-difluorophenyl)-1-(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol dihydrochloride (045)

Scheme 45. Obtaining 2-(2,4-difluorophenyl)-1-(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1 -yl)propan-2-ol dihydrochloride

Boc-amide solution 2-(2,4-difluorophenyl)-1-(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (310 mg) in a saturated solution of hydrogen chloride in ethyl acetate (6 ml) is stirred overnight at room temperature, while a precipitate gradually forms. The precipitate formed is filtered off and washed with ethyl acetate. Yield quantitative (290 mg). C ₁₄ H ₂₃ F ₂ N ₅ O x 2 HCl. LC MS [M+H] ⁺ 338.3 ⁺ . ¹ H NMR (DMSO-d ₆ ): 9.56 (bs, 1H), 9.18 (m, 2H), 8.58 (m, 1H), 7.84 (s, 1H), 7.47 (m, 2H), 7.27 (m, 1H ), 7.05 (m, 1Н), 4.85 (m, 1Н), 4.71 (m, 1Н), 3.64 (m, 4Н), 3.36 (m, 2Н), 2.87 (m, 2Н), 2.70 (m, 1Н ), 2.43 (m, 2Н), 2.19 (m, 2Н), 1.89 (m, 1Н).

Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)piperidine-1- carboxylate (046)

Scheme 46. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)piperidine -1-carboxylate

To a solution of Boc-amide (570 mg, 1.30 mmol, 1 eq) in methanol (20 ml) was added an aqueous solution of formalin (88 μl of a 40% solution, 39 mg in terms of pure formalin, 1.30 mmol, 1 eq), acetic acid (8 µl) and sodium cyanoborohydride (98 mg, 1.56 mmol, 1.2 eq). The reaction mass is stirred for 16 hours at room temperature, then the methanol is evaporated, the residue is distributed between ethyl acetate and water, ethyl acetate is separated. The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the substance is isolated by chromatography on silica gel (elution system ethyl acetate - methanol: ethyl acetate 1:4). Yield 98% (577 mg). C ₂₂ H ₃₁ F ₂ N ₅ O ₃ . m/z 451.51. LC MS [M+H] ⁺ = 452 ⁺ .

¹ H NMR (CDCl ₃ ): 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (m, 1H), 6.84 (m, 2H), 4.62 (m, 2H), 4.15 (m, 2H), 3.85 (m, 1Н), 3.04 (m, 1Н), 2.67 (m, 4Н), 2.09 (m, 4Н), 1.85 (m, 1Н), 1.69 (m, 2Н), 1.47 (s, 9Н).

Preparation of 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol dihydrochloride (047 )

Scheme 47. Preparation of 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol dihydrochloride

A solution of Boc-amide (550 mg) in a saturated solution of hydrogen chloride in ethyl acetate (10 ml) was stirred overnight at room temperature, while a precipitate gradually formed. The precipitate formed is filtered off and washed with ethyl acetate. Yield 77% (400 mg). C ₁₇ H ₂₃ F ₂ N ₅ O × 2HCl. m/z 351.39. LC MS [M+H] ⁺ = 352.3 ⁺ . ¹ H NMR (DMSO-d ₆ ): 9.48 (bs, 1H), 9.25 (bs, 1H), 9.10 (bs, 1H), 8.61 (s, 1H), 7.86 (s, 1H), 7.49 (m, 1H ), 7.31 (m, 1Н), 7.07 (m, 1Н), 4.83 (m, 1Н), 4.73 (m, 1Н), 3.38 (m, 4Н), 3.14 (m, 2Н), 2.88 (m, 2Н) , 2.71 (m, 1Н), 2.42 (m, 1Н), 2.18 (m, 2Н), 1.90 (s, 3Н).

Preparation of racemate 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4- triazol-1-yl)propan-2-ol (048)

Scheme 48. Preparation of racemate 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2 ,4-triazol-1-yl)propan-2-ol

To a solution of the base 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol ( 250 mg, 0.7 mmol) in ethanol (10 ml) was added racemate epichlorohydrin (200 mg, 2 mmol). The reaction mass was stirred at room temperature for 24 hours. Then evaporated in vacuum, the residue was chromatographed by flash chromatography using the system petroleum ether - ethyl acetate (10:1 - 0:1) as eluent. Received 240 mg, (76%) as a colorless oil. C ₂₀ H ₂₈ ClF ₂ N ₅ O ₂ . Exact weight: 443.2165. LC MS (M+1) ⁺ = 443.9 ⁺ .

Note: the base 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol was obtained from the salt form by re-extraction. 2-(2,4-Difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol hydrochloride (350 mg ) was dissolved in water (10 ml), butanol (2 ml) was added and Na ₂ CO ₃ (200 mg, 1.9 mmol) was carefully added, stirred at room temperature for 10 minutes, then the organic phase was separated, and the aqueous part was re-extracted with butanol (2 ml). The organic extracts were combined and evaporated in vacuo with water (1 ml). The residue was dissolved in ethyl acetate (5 ml), filtered and evaporated to give the base 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4- triazol-1-yl)propan-2-ol (250 mg, 84%) as a colorless oil.

Preparation of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)ethyl)piperazine- 1-carboxylate (049)

Scheme 49. Preparation of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)ethyl )piperazine-1-carboxylate

Triethylamine ( 6.0 g, 60 mmol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (3.5 g, 16 mmol). The reaction mass was stirred at reflux for 10 hours, then cooled to room temperature and evaporated in vacuum. The residue was mixed with water (100 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) was added and stirred, then the organic part was separated, and the aqueous was re-extracted with ethyl acetate (2×50 ml). The extracts were combined, washed with water (25 ml), brine (10 ml). Dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography using methylene chloride:methanol (50:1-20:1) as eluent. Received (5.02 g, 72%) as a colorless oil. C ₂₂ H ₃₂ F ₂ N ₆ O ₃ . Exact weight: 466.2504. LC MS (M+1) ⁺ =467.1 ⁺ .

Preparation of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl )piperazine-1-carboxylate (050)

Scheme 50. Preparation of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl) amino)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)ethyl)piperazine -1-carboxylate (2.8 g, 6 mmol) in methanol (100 ml) was added formaldehyde (37% aqueous solution 0.7 ml, 8 mmol), acetic acid (100 μl) and sodium cyanoborohydride (0.5 g, 8 mmol) in portions. The reaction mass was stirred for 12 hours, then evaporated in vacuo. The residue was mixed with water (100 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) and stirred, then the organic part was separated, and the aqueous was re-extracted with ethyl acetate (50 ml). The extracts were combined, washed with water (25 ml), brine (10 ml). Dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by column chromatography using methylene chloride:methanol (50:1-25:1) as eluent. Received (2.6 g, 90%) as a colorless oil. C ₂₃ H ₃₄ F ₂ N ₆ O ₃ . Exact mass: 480.2660. LC MS (M+1) ⁺ = 480.9 ⁺ .

Preparation of 2-(2,4-fluorophenyl)-1-(methyl(2-(piperazin-4-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan-2 -ola (051)

Scheme 51. Preparation of 2-(2,4-fluorophenyl)-1-(methyl(2-(piperazin-4-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl) propan-2-ol

To a solution of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino) ethyl)piperazine-1-carboxylate (2.6 g, 5.4 mmol) in methylene chloride (80 ml) trifluoroacetic acid (10 ml, 0.12 mol) was added. The reaction mixture was stirred for 1 hour, then evaporated in vacuo. The residue was mixed with water (50 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) and stirred, then the organic part was separated, and the aqueous was re-extracted with butanol (20 ml). The extracts were combined, washed with brine (10 ml) and evaporated in vacuo. The residue was dissolved in EtOAc (50 ml), filtered and evaporated in vacuo. Received 1.96 g of 2-(2,4-fluorophenyl)-1-(methyl(2-(piperazin-4-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl)propane -2-ol (96%) as a colorless oil. C ₁₈ H ₂₆ F ₂ N ₆ O. Exact weight: 380.2136. LC MS (M+1) ⁺ = 381.2 ⁺ .

Preparation of racemate 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1 ,2,4-triazol-1-yl)propan-2-ol (052)

Scheme 52. Preparation of racemate 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(methyl)amino)-2-(2,4-difluorophenyl)-3-( 1Н-1,2,4-triazol-1-yl)propan-2-ol

To a solution of 2-(2,4-fluorophenyl)-1-(methyl(2-(piperazin-4-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl)propan- 2-ol (1.0 g, 2.6 mmol) in ethanol (20 ml) epichlorohydrin racemate (0.3 g, 3 mmol) was added. The reaction mass was stirred at a temperature of 50°C for 12 hours, then cooled to room temperature and evaporated in vacuum. The residue was purified by column chromatography using methylene chloride:methanol (50:1 - 25:1) as eluent. 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl) (methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.37 g, 30%) as a colorless oil. C ₂₁ H ₃₁ ClF ₂ N ₆ O ₂ Exact mass: 472.2165. LC MS (M+1) ⁺ = 473 ⁺ .

Preparation of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(4-fluorobenzyl)amino )ethyl)piperazine-1-carboxylate (053)

Scheme 53 fluorobenzyl)amino)ethyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)ethyl)piperazine -1-carboxylate (2.8 g, 6 mmol) in methanol (100 ml) was added 4-fluorobenzaldehyde (0.8 ml, 8 mmol), acetic acid (100 μl), and sodium cyanoborohydride (0.5 g, 8 mmol) in portions. The reaction mass was stirred for 12 hours, then evaporated in vacuo. The residue was mixed with water (100 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) and stirred, then the organic part was separated, and the aqueous was re-extracted with ethyl acetate (50 ml). The extracts were combined, washed with water (25 ml), brine (10 ml). Dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by column chromatography using methylene chloride:methanol (50:1-25:1) as eluent. Received tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(4-fluorobenzyl)amino )ethyl)piperazine-1-carboxylate (2.25 g, 50%) as a colorless oil. C ₂₉ H ₃₇ F ₂ N ₆ O ₃ m/z: 555.6393. LC MS (M+1) ⁺ = 556.1 ⁺ .

Preparation of 2-(2,4-difluorophenyl)-1-((4-fluorobenzyl)(2-(piperazin-1-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl )propan-2-ol (054)

Scheme 54. Preparation of 2-(2,4-difluorophenyl)-1-((4-fluorobenzyl)(2-(piperazin-1-yl)ethyl)amino)-3-(1H-1,2,4-triazol- 1-yl)propan-2-ol

To a solution of tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(4-fluorobenzyl) amino)ethyl)piperazine-1-carboxylate (2.85 g, 5.0 mmol) in methylene chloride (80 ml) trifluoroacetic acid (10 ml, 0.12 mol) was added. The reaction mixture was stirred for 1 hour, then evaporated in vacuo. The residue was mixed with water (50 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) and stirred, then the organic part was separated, and the aqueous was re-extracted with butanol (20 ml). The extracts were combined, washed with brine (10 ml) and evaporated in vacuo. The residue was taken up in ethyl acetate (50 ml), filtered and evaporated in vacuo. Received 2-(2,4-difluorophenyl)-1-((4-fluorobenzyl)(2-(piperazin-1-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1-yl )propan-2-ol (1.96 g, 96%) as a colorless oil. C ₂₄ H ₂₉ F ₃ N ₆ O. m/z: 474.5322. LC MS (M+1) ⁺ = 475.2 ⁺ .

Preparation of racemate 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(4-fluorobenzyl)amino)-2-(2,4-difluorophenyl)-3-(1H -1,2,4-triazol-1-yl)propan-2-ol (055)

Scheme 55. Preparation of racemate 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(4-fluorobenzyl)amino)-2-(2,4-difluorophenyl)-3 -(1H-1,2,4-triazol-1-yl)propan-2-ol

To a solution of 2-(2,4-difluorophenyl)-1-((4-fluorobenzyl)(2-(piperazin-1-yl)ethyl)amino)-3-(1H-1,2,4-triazol-1- yl)propan-2-ol (0.47 g, 1.0 mmol) in EtOH (20 mL) epichlorohydrin racemate (0.3 g, 3 mmol) was added. The reaction mass was stirred at a temperature of 50°C for 12 hours, then cooled to room temperature and evaporated in vacuum. The residue was purified by column chromatography using methylene chloride:methanol (50:1-25:1) as eluent. Received 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(4-fluorobenzyl)amino)-2-(2,4-difluorophenyl)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol (0.37 g, 30%) as a colorless oil. C ₂₇ H ₃₄ ClF ₃ N ₆ O ₂ . Exact weight: 551.0467. LC MS (M+1) ⁺ = 552.1 ⁺ .

Preparation of tert-butyl 4-(2-(N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-( trifluoromethyl)benzamido)ethyl)piperazine-1-carboxylate (056)

Scheme 56 4-(trifluoromethyl)benzamido)ethyl)piperazine-1-carboxylate

K tert-butyl 4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)ethyl)piperazine- 1-carboxylate (0.9 g, 1.931 mmol) was added 10 ml of dry pyridine (10 ml) and dropwise at a temperature of 3-5°C (0.30 g, 2.0 mmol) (4-trifluoromethyl)benzoyl chloride. After adding the entire portion, the mixture was stirred for 1 hour at room temperature, while a precipitate fell out. The reaction mass was evaporated in vacuo, the residue was dissolved in a mixture of water-ethyl acetate (5+10 ml), the organic layer was separated and evaporated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 1:1 + 1% triethylamine). -(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamido)ethyl)piperazine-1-carboxylate (1.3 g target fraction) C ₃₀ H ₃₅ F ₅ N ₆ O ₄ m/z: 638.6400 LC MS (M+1) ⁺ = 639 ⁺ .

Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-(2-(piperazin-1-yl) ethyl)-4-(trifluoromethyl)benzamide (057)

Scheme 57 -yl)ethyl)-4-(trifluoromethyl)benzamide

To a solution of tert-butyl 4-(2-(N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4- (trifluoromethyl)benzamido)ethyl)piperazine-1-carboxylate (1.28 g, 2.0 mmol) in CH ₂ Cl ₂ (60 ml) was added trifluoroacetic acid (10 ml, 0.12 mol). The reaction mixture was stirred for 1 hour, then evaporated in vacuo. The residue was mixed with water (50 ml), ethyl acetate (50 ml), Na ₂ CO ₃ (2.0 g, 20 mmol) and stirred, then the organic part was separated, and the aqueous was re-extracted with butanol (20 ml). The extracts were combined, washed with saturated sodium chloride solution (10 ml), and evaporated in vacuo. The residue was taken up in ethyl acetate (50 ml), filtered and evaporated in vacuo. Received N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-(2-(piperazin-1-yl) ethyl)-4-(trifluoromethyl)benzamide (1.96 g, 96%) as a colorless oil. C ₂₅ H ₂₇ F ₅ N ₆ O ₂ . m/z: 538.5230. LC MS (M+1) ⁺ = 539.0 ⁺ .

Preparation of racemate [R,S) N-(2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-ide)ethyl)-N-(2-(2,4-difgorphenyl)-2-hydroxy- 3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide (058)

Scheme 58. Preparation of racemate (R,S) N-(2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-ide)ethyl)-N-(2-(2,4-difluorophenyl)-2 -hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide

To a solution of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-N-(2-(piperazin-1-yl )ethyl)-4-(trifluoromethyl)benzamide (1.1 g, 2.0 mmol) in EtOH (20 mL) epichlorohydrin racemate (0.3 g, 3 mmol) was added. The reaction mass was stirred at a temperature of 50°C for 12 hours, then cooled to room temperature and evaporated in vacuum. The residue was purified by column chromatography using methylene chloride:methanol (50:1-25:1) as eluent. (R,S) N-(2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-ide)ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3 -(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide (0.47 g, 38%) as a colorless oil. C ₂₈ H ₃₂ ClF ₅ N ₆ O ₃ . m/z: 631.0450. LC MS(M+1) ⁺ = 632.1 ⁺ .

Obtaining hybrid alkyl-piperazinyl derivatives of thiazolidine-2,4-dione and triazole according to the invention

Preparation of 5-(4-chlorobenzylidene)-3-(2-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-[1H-1,2,4-triazol-1-yl)propyl )piperazin-1-yl)ethyl)thiazolidin-2,4-dione (1)

Method A

Scheme 59. Preparation of 5-(4-chlorobenzylidene)-3-(2-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) ethyl) thiazolidin-2,4-dione

To a suspension of 5-(4-chlorobenzylidene)-3-(2-(piperazin-1-yl)ethyl)thiazolidin-2,4-dione dihydrochloride (100 mg, 1 eq, 0.24 mmol) in ethanol (3 ml) was added ( 75 mg, 1 eq, 0.24 mmol) of methane sulfone of this triazole epoxide, then triethylamine (60 mg, 2.5 eq, 0.59 mmol) was added. The resulting reaction mass was boiled overnight, then ethanol was removed on a rotary evaporator. The residue was dissolved in methylene chloride (2 ml), washed with an aqueous citric acid solution until acidic, the organic layer was separated, dried over sodium sulfate. The resulting material was purified by silica gel chromatography (elution system methylene chloride - 5% methanol in methylene chloride). Yield 21.63% (30 mg). C ₂₇ H ₂₇ ClF ₂ N ₆ O ₃ S. m/z 590.07, LC MS (M+H) ⁺ = 591 ⁺ . ¹ H NMR (DMSO-d ₆ ): 8.28 (s, 1H), 7.75 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.62 (s, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.42 (m, 1H), 7.14 (m, 1H), 6.97 (m, 1H), 5.68 (bs, 1H), 4.58 (s, 2H), 3.81 (m, 2H), 3.49 (m , 2H), 3.21 (m,4H), 2.9 (d, J=13.4 Hz, 1H), 2.71 (d, J=13.4 Hz, 1H), 2.61-2.25 (m, 4H).

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (2)

Method A

Scheme 60. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

Method A

A mixture of oxirane methanesulfonate (2.55 g, 1 eq), substituted piperazine (3.08 g, 1 eq) and triethylamine (3.2 ml, 3 eq) is refluxed in ethanol overnight. Ethanol is evaporated, the residue is dissolved in ethyl acetate and washed with aqueous citric acid until acidic, then with water. The organic phase is dried over Na ₂ SO ₄ and evaporated. The oil product is purified on silica gel (5% methanol in dichloromethane). The fractions obtained as a result of chromatography with the target compound are evaporated, the residue is triturated with ether to obtain a light yellow powder, yield 1.23 g (27%). C ₂₈ H ₂₉ ClF ₂ N ₆ O ₃ S. m/z 603.10. LC MS (M+1) ⁺ = 603.7 ⁺ .

¹ H NMR (CDCl ₃ ): 8.09 (s, 1H), 7.79-7.75 (m, 2H), 7.53-7.40 (m, 5H), 6.80-6.74 (m, 2H), 5.18 (bs, 1H), 4.51 -4.44 (m, 2H), 3.80-3.77 (m, 2H), 2.99-2.96 (m, 1H), 2.63-2.60 (m, 1H), 2.34-2.32 (m, 8H).

Method B

Scheme 61. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(4-chlorobenzylidene)thiazalidin-2,4-dione method B

Piperazine hydrochloride (430 mg, 1 eq, 1.2 mmol) and 3-(3-bromopropyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione alkylator (517 mg, 1.2 eq, 1.4 mmol) is dissolved in DMF (5 ml), then potassium carbonate (496 mg, 3 eq, 3.6 mmol) and potassium iodide (198 mg, 1 eq, 1.2 mmol) are added. The reaction mass is kept overnight at 70°C, then dimethylformamide is evaporated on the rotor and the resulting residue is diluted with water (3 ml). The aqueous phase is extracted with ethyl acetate (2 times 3 ml), dried over sodium sulfate and the ethyl acetate is evaporated on a rotor. The material is purified by flash chromatography on silica gel (eluent methylene chloride - 5% methanol in methylene chloride). 205 mg of the expected product are obtained (yield 28%).

¹ H NMR (CDCl): 8.09 (s, 1H), 7.79-7.75 (m, 2H), 7.53-7.40 (m 5H), 6.80-6.74 (m, 2H), 5.18 (bs, 1H), 4.51-4.44 (m, 2Н), 3.80-3.77 (m, 2Н), 2.99-2.96 (m, 1Н), 2.63-2.60 (m, 2Н), 2.34 (m, 9Н), 1.81 (m, 2Н).

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (3)

Method B.

Scheme 62. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione

To a solution of piperazine hydrochloride (0.170 g, 0.47 mmol, 1 equiv) in DMF (2 ml) was added 3-(3-bromopropyl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (184 mg, 0.52 mmol, 1.1 eq), potassium carbonate (196 mg, 1.42 mmol, 3 eq) and potassium iodide (78 mg, 0.47 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (6 ml) and extracted three times with ethyl acetate (2 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (methylene chloride - 6% methanol in methylene chloride system). Yield 15.61% (44 mg). C ₃₀ H ₃₄ F ₂ N ₆ O ₃ S.

¹ H NMR (CDCl ₃ ): 8.11 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.50 (m, 1H), 7.42 (d, 2H, J=7.84 Hz), 7.31 ( d, 2H, J=7.84 Hz), 6.81-6.75 (m, 2H), 5.24 (bs, 1H), 4.48 (m, 2H), 3.79 (m, 2H), 3.01-2.88 (m, 2H), 2.70 (q, 2H, J=7.71 Hz), 2.62 (m, 2H), 2.33 (m, 8H), 1.81 (m, 2H), 1.27 (t, 3H, J=7.71 Hz).

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione (4.

Method B

Scheme 63. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione

To a solution of piperazine hydrochloride (0.150 g, 0.42 mmol, 1 equiv) in DMF (2 ml) was added 3-(3-bromopropyl)-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione (181 mg, 0.46 mmol, 1.1 eq), potassium carbonate (173 mg, 1.25 mmol, 3 eq) and potassium iodide (69 mg, 0.42 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (6 ml) and extracted three times with ethyl acetate (2 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (methylene chloride - 6% methanol in methylene chloride system). Yield 17.68% (47 mg). C ₂₈ H ₂₈ Cl ₂ F ₂ N ₆ O ₃ S. m/z 638.54.

¹ H NMR (CDCl ₃ ): 8.12 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H). 7.52 (m, 1H), 7.44 (d, 1H, J=8.36 Hz), 7.37 (d, 1H, J=8.36 Hz), 7.26 (m, 1H), 6.82-6.77 (m, 2H), 5.20 (bs , 1H), 4.51 (m, 2H), 3.48-3.27 (m, 2H), 3.05 (m, 1H), 3.82 (m, 2H), 2.66 (m, 3H), 2.31 (m, 6H), 1.78 ( m, 2H). C ₂₈ H ₂₈ Cl ₂ F ₂ N ₆ O ₃ S.

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )-5-(4-methoxy6enzylidene)thiazolidine-2,4-dione (5)

Method B

Scheme 64. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione

To a solution of piperazine hydrochloride (0.200 g, 0.56 mmol, 1 equiv) in DMF (2 ml) was added 3-(3-bromopropyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (198 mg, 0.56 mmol, 1 eq), potassium carbonate (231 mg, 1.67 mmol, 3 eq) and potassium iodide (92 mg, 0.56 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (6 ml) and extracted three times with ethyl acetate (2 ml each). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (methylene chloride - 6% methanol in methylene chloride system). Yield 29.45% (98 Mr). C ₂₉ H ₃₂ F ₂ N ₆ O ₄ S. m/z 648.61.

¹ H NMR (CDCl ₃ ): 8.10 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.50 (m, 1H), 7.45 (d, 2H, J=8.81 Hz), 7.00 ( d, 2H, J=8.81 Hz), 6.80-6.74 (m, 2H), 5.20 (bs, 1H), 4.4S (m, 2H), 3.87 (s, 3H), 3.78 (m, 2H), 2.98 ( m, 1H), 2.63 (m, 2H), 2.36 (m, 8H), 2.02 (m, 1H), 1.82 (m, 2H).

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6)

Method B

Scheme 65. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione

To a solution of piperazine hydrochloride (0.200 g, 0.56 mmol, 1 equiv) in DMF (2 ml) was added 3-(3-bromopropyl)-5-(4-ethoxybenzylidene)thiazalidine-2,4-dione (206 mg, 0.56 mmol, 1 eq), potassium carbonate (231 mg, 1.67 mmol, 3 eq) and potassium iodide (92 mg, 0.56 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (6 ml) and extracted three times with ethyl acetate (2 ml each). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (methylene chloride - 6% methanol in methylene chloride system). Yield 17.62% (60 mg). C ₃₀ H ₃₄ F ₂ N ₆ O ₄ S. m/z 613.70.

¹ H NMR (CDCl ₃ ): 8.11 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.50 (m, 1H), 7.43 (d, 2H, J=8.73 Hz), 6.98 ( d, 2H, J=8.73 Hz), 6.80-6.74 (m, 2H), 5.23 (bs, 1H), 4.48 (m, 2H), 4.09 (q, 2H, J=6.88 Hz), 3.78 (m, 2H ), 3.00 (m, 1H), 2.62 (m, 2H), 2.33 (m, 8H), 2.02 (m, 1H), 1.80 (m, 2H), 1.44 (t, 3H, J=6.88 Hz).

An example of a general scheme for the preparation of hybrid 5-arylidene derivatives of thiazolidine-2,4-dione and triazole according to the invention by the Knoevenagel reaction (compounds 7-12)

Scheme 66. General scheme for the preparation of hybrid derivatives (in particular, for the preparation of compounds 7-12)

Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )thiazolidine-2,4-dione (059)

Scheme 67. Preparation of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl) propyl) thiazolidine-2,4-dione

To a solution of piperazine hydrochloride (1.6 g, 4.45 mmol, 1 equiv) in DMF (10 ml) was added 3-(3-bromopropyl)thiazalidine-2,4-dione (1.16 g, 4.89 mmol, 1.1 equiv), potassium carbonate (1.84 g, 1 3.34 mmol, 3 eq) and potassium iodide (738 mg, 4.45 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (25 ml) and extracted three times with diethyl ether (5 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Diethyl ether was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (eluent system methylene chloride - 7% methanol in methylene chloride). Yield 29.48% (630 mg). C ₂₁ H ₂₆ F ₂ N ₆ O ₃ S. m/z 480.54.

¹ H NMR (CDCl ₃ ): 8.11 (s, 1H), 7.78 (s, 1H), 7.55-7.50 (m, 1H), 6.81-6.77 (m, 2H), 5.17 (bs, 1H), 4.51 (dd , 2H, J ₁ =14.49 Hz, J ₂ =23.20 Hz), 3.90 (m, 2H), 3.85 (m, 2H), 3.06 (m, 1H), 2.66 (m, 1H), 2.38 (m, 8H) , 1.77 (m, 4H).

Preparation of 5-(4-chloro-2-(4-methylpiperazin-1-yl)benzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione (7)

Stage 1. Obtaining the starting reagent - 4-chloro-2-(4-methylpiperazin-1-yl)benzaldehyde (060) for compound 7

Scheme 68. Obtaining 4-chloro-2-(4-methylpiperazin-1-yl)benzaldehyde

To a solution of 4-chloro-2-fluorobenzaldehyde (0.5 g, 3.15 mmol, 1 eq) in acetonitrile (8 ml) was added N-methylpiperazine (316 mg, 3.15 mmol, 1 eq) and potassium carbonate (1.31 g, 9.46 mmol, 3 eq). The reaction mass was kept overnight at 80°C, the inorganic salts were filtered off, the residue was washed twice with methylene chloride (2 ml each). The solvents were evaporated on a rotary evaporator, the residue was taken up in methylene chloride and purified by silica gel chromatography (2% methanol in methylene chloride - 6% methanol in methylene chloride system). Yield 47.42% (357 mg).

¹ H NMR (CDCl ₃ ): 10.20 (s, 1H), 7.73 (m, 1H), 7.07 (m, 2H), 3.14 (m, 4H), 2.65 (m, 4H), 2.39 (s, 3H).

Stage 2. Preparation of 5-(4-chloro-2-(4-methylpiperazin-1-yl)benzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione (7)

Scheme 69 (1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione

To a solution of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl) propyl)thiazolidin-2,4-dione (213 mg, 0.44 mmol, 1 eq) in ethanol (2 ml) 4-chloro-2-(4-methylpiperazin-1-yl)benzaldehyde (116 mg, 0.49 mmol, 1.1 equiv) and piperidine (8 mg, 0.0E mmol, 0.2 equiv). The reaction mass was kept overnight at a temperature of 80°C, then cooled and ethanol was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and the material was purified by flash chromatography on silica gel (elution system ethyl acetate:methylene 1:1 - ethyl acetate - ethyl acetate:methanol 2:3). Yield 34.74% (108 mg). C ₃₃ H ₃₉ ClF ₂ N ₈ O ₃ S. m/z 702.24.

¹ H NMR (CDCl ₃ ): 8.11 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 7.09 (m, 1H), 7.05 (m, 1H), 6.78 (m, 2H), 5.22 (bs, 1H), 4.47 (dd, 2H, J ₁ =14.57 Hz, J ₂ =24.48 Hz), 3.77 (m, 2H), 2.99 (m , 5H), 2.62 (m, 5H), 2.38–2.30 (m, 12H), 1.78 (m, 3H).

Preparation of (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2 ,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide (8)

Stage 1. Preparation of the starting reagent - N-(1-(5-chloro-2-fluoro-myl-phenyl)-piperidin-4-yl)-acetamide (061) to obtain compound 8

Scheme 70. Preparation of N-(1-(5-chloro-2-formylphenyl)piperidin-4-yl)acetamide

To a solution of 4-chloro-2-fluorobenzaldehyde (0.66 g, 4.16 mmol, 1 eq) in acetonitrile (9 ml) was added N-(piperidin-4-yl)acetamide hydrochloride (743 mg, 4.16 mmol, 1 eq) and potassium carbonate (2.88 g, 20.81 mmol, 5 equiv). The reaction mass was kept overnight at 80°C, the inorganic salts were filtered off, the residue was washed twice with methylene chloride (3 ml each). The solvents were evaporated on a rotary evaporator, the residue was taken up in methylene chloride and purified by silica gel chromatography (2% methanol in methylene chloride - 6% methanol in methylene chloride system). Yield 85.40% (998 mg).

¹ H NMR (CDCl ₃ ): 10.16 (s, 1H), 7.71 (m, 1H), 7.06 (m, 2H), 5.58 (bs, 1H), 3.96 (m, 1H), 3.26 (m, 2H), 2.98 (m, 2H), 2.08 (m, 2H), 1.99 (s, 3H), 1.66 (m, 2H).

Stage 2. Preparation Example of (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1, 2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide (8)

Scheme 71. Preparation of (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroisi-3-(1H- 1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide

To a solution of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl) propyl)thiazolidine-24-dione (431 mg, 0.90 mmol, 1 eq) in ethanol (3 ml) was added N-(1-(5-chloro-2-formylphenyl)piperidin-4-yl)acetamide (252 mg, 0.90 mmol, 1 eq) and piperidine (15 mg, 0.18 mmol, 0.2 eq). The reaction mass was kept overnight at a temperature of 80°C, then cooled and ethanol was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and the material was purified by flash chromatography on silica gel (elution system: ethyl acetate methylene 1:1 - ethyl acetate - ethyl acetate: methanol 2:3). Yield 37.20% (248 mg). C ₃₅ H ₄₁ ClF ₂ N ₈ O ₄ S. m/z 743.28.

¹ H NMR (CDCl ₃ ): 8.10 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.51 (m, 1H), 7.37 (m, 1H), 7.09 (m, 1H), 7.05 (s, 1H), 6.80 (m, 2H), 5.46 (bs. 1H), 5.18 (bs, 1H). 4.51 (m, 2Н), 3.95 (m, 1Н), 3.79 (m, 2Н), 3.11 (m, 2Н), 2.99 (m, 1Н), 2.83 (m, 3Н), 2.64 (m, 2Н), 2.35 (m, 8Н), 2.05 (m, 3Н), 1.99 (m, 3Н), 1.83 (m, 2Н), 1.64 (m, 1Н).

Preparation of (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2 ,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin4-yl)amine dihydrochloride (9)

Scheme 72. Preparation of (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)amine dihydrochloride

(Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide (220 mg, 0.30 mmol, 1 eq) dissolved in 4 ml of 1N hydrochloric acid and kept at 100°C for 16 hours. The hydrochloric acid was then evaporated off and the resulting residue was triturated in ether. Yield 15.27% (35 mg). C ₃₃ H ₃₉ ClF ₂ N ₈ O ₃ S × 2 HCl. m/z 701.24. ¹ H (DMSO-d ₆ ): 8.53 (s, 1H), 8.27 (m, 4H), 7.86 (s, 1H), 7.44 (m, 2H), 7.24 (m, 3H), 7.11 (m, 1H) , 7.02 (m, 1H), 4.70 (m, 2H), 3.70 (m, 2H), 3.61 (m, 1H), 3.44 (m, 3H), 3.26 (m, 1H), 3.17 (m, 8H), 2.84 (m, 2H), 2.02 (m, 4H), 1.88 (m, 1H), 1.70 (m, 3H), 1.35 (m 1H).

Preparation of tert-butyl 4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole- 1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-carboxylate (10)

Stage 1. Obtaining the starting reagent - tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate (062) to obtain compound 10

Scheme 73. Obtaining tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate

To a solution of N-Boc-piperazine (3.5 g, 18.79 mmol, 1 equiv) was added dibromopropane (4.55 g, 22.55 mmol, 1.2 equiv) and potassium carbonate (3.90 g, 28.19 mmol, 1.5 equiv) in acetone (40 ml). The reaction mass is stirred overnight at room temperature. Inorganic salts were filtered off, acetone was evaporated on a rotary evaporator. The material was used further without purification.

Stage 2. Preparation of starting reagent tert-butyl 4-(3-(2-ethoxy-4-formylphenoxy)propyl)piperazine-1-carboxylate (063) to obtain compound 10

Scheme 74. Preparation of tert-butyl 4-(3-(2-ethoxy-4-formylphenoxy)propyl)piperazine-1-carboxylate

To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.5 g, 3.01 mmol, 1 eq) was added tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate (1.11 g, 3.61 mmol, 1.2 eq) and potassium carbonate (1.25 g, 9.03 mmol, 3 equiv) in acetone (30 ml). The reaction mass is stirred overnight at room temperature. Inorganic salts were filtered off, acetone was evaporated on a rotary evaporator. The material was purified by silica gel chromatography (elution system ethyl acetate-methanol:ethyl acetate 1:4). Yield 54.11% (639 mg).

¹ H NMR (CDCl ₃ ): 9.81 (s, 1H), 7.38 (m, 2H), 6.97 (m, 1H), 4.21 (m, 2H), 4.09 (m, 2H), 3.64 (m, 2H), 3.33 (m, 1Н), 2.88 (m, 4Н), 2.45 (m, 1Н), 1.88 (m, 4Н), 1.40 (m, 12Н).

Stage 3. Preparation of tert-butyl 4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole- 1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-carboxylate (10)

Scheme 75 -triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-carboxylate

To a solution of 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl) propyl)thiazolidine-2,4-dione (309 mg, 0.64 mmol, 1 eq) in ethanol (3 ml) was added tert-butyl 4-(3-(2-ethoxy-4-formylphenoxy)propyl)piperazine-1-carboxylate (252 mg, 0.64 mmol, 1 eq) and piperidine (11 mg, 0.13 mmol, 0.2 eq). The reaction mass was kept overnight at a temperature of 80°C, then cooled and ethanol was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and the material was purified by flash chromatography on silica gel (elution system: ethyl acetate-ethyl acetate:methanol 2:3). The resulting substance was triturated in ether and filtered. Yield 22.37% (123 mg). C ₄₂ H ₅₆ F ₂ N ₈ O ₇ S. m/z 855.02. ¹ H NMR (CDCl ₃ ): 8.10 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.50 (m, 1H), 7.07 (m, 1H), 6.99 (m, 1H), 6.96 (m, 1H), 6.77 (m, 2H), 4.48 (m, 2H), 4.12 (m, 4H), 3.78 (m, 2H), 3.51 (m, 4H), 2.99 (m, 1H), 2.65 (m, 3H), 2.53 (m, 4H), 2.37 (m, 9H), 2.11 (m, 4H), 1.82 (m, 2H), 1.46 (m, 12H).

Preparation of 4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl )propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-yl (11)

Scheme 76 yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-yl

tert-Butyl 4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl) propyl) piperazin-1-yl) propyl) -2,4-dioxothiazolidin-5-ylidene) methyl) -2-ethoxyphenoxy) propyl) piperazine-1-carboxylate (100 mg, 0.12 mmol, 1 eq) was dissolved in ethyl acetate (2 ml), then a hydrochloric acid solution in anhydrous ethyl acetate (saturated solution) was added. The resulting mixture was stirred overnight at room temperature, then the solvent was evaporated on a rotary evaporator. The resulting precipitate was washed with ethyl acetate (500 ml), then twice with diethyl ether (500 ml each) and dried to constant weight. Yield 38.88% (36 mg). C ₃₇ H ₄₈ CF ₂ N ₈ O ₅ S × HCl. m/z 754.91. ¹ H NMR (DMSO-d ₆ ): 8.41 (s, 1H), 7.88 (s, 1H), 7.81 (s, 1H), 7.41 (m, 1H), 7.23-7.16 (m,4H), 6.98 (m , 1Н), 4.64 (m, 2Н), 4.17 -4.03 (m, 7Н), 3.29 (m, 12Н), 3.06 (m, 10Н), 2.24 (m, 2H), 1.99 (m, 2Н), 1.37 ( m, 2Н), 1.18 (m, 3Н).

Preparation of (Z)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1 -yl)propyl)-5-(3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzylidene)thiazolidine-2,4-dione (12)

Stage 1. Obtaining the starting reagent - 4-(3-bromopropoxy)-3-ethoxybenzaldehyde (063) to obtain compound 12

Scheme 77. Obtaining 4-(3-bromopropoxy)-3-ethoxybenzaldehyde

To a solution of 3-ethoxy-4-hydroxybenzaldehyde (720 mg, 4.33 mmol, 1 eq) in acetone (3 ml) was added dibromopropane (2.18 g, 10.83 mmol, 2.5 eq) and potassium carbonate (1.80 g, 13.00 mmol, 3 eq) . The reaction mass was kept overnight at room temperature, inorganic salts were filtered off, the residue was washed twice with methylene chloride (2 ml each). The solvents were evaporated on a rotary evaporator, the residue was taken up in methylene chloride and purified by silica gel chromatography (eluting system hexane-ethyl acetate:hexane 1:3). Yield 20.01% (249 mg). ¹ H NMR (CDCl ₃ ): 9.84 (s, 1H), 7.40 (m, 2H), 7.01 (m, 1H), 4.24 (m, 2H), 4.14 (m, 2H), 3.63 (m, 2H), 2.40 (m, 2H), 1.46 (m, 3H).

Stage 2. Obtaining the starting reagent - 3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzaldehyde (064) to obtain compound 12

Scheme 78. Preparation of 3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzaldehyde

N-methylpiperazine (80 mg, 0.80 mmol, 1 eq) and potassium carbonate (331 mg, 2.40 mmol, 3 equiv). The reaction mass was kept overnight at 80°C, the inorganic salts were filtered off, the residue was washed twice with methylene chloride (2 ml each). The solvents were evaporated on a rotary evaporator, the residue was dissolved in methylene chloride and purified by chromatography on silica gel (elution system 2% methanol in methylene chloride - 8% methanol in methylene chloride). Yield 79.27% (194 mg).

¹ H NMR (CDCl ₃ ): 9.83 (s. 1H), 7.39 (m, 2H), 6.97 (m, 1H), 4.15 (m, 4H), 2.60 (m, 10H), 2.36 (s, 3H), 2.06 (m, 2Н), 1.45 (m, 3Н).

Stage 3. Preparation of (Z)-3-(3-(4-(2-(2,4-difluorophenyl)-2-tdroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1 -yl)propyl)-5-(3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzylidene)thiazolidine-2,4-dione (12)

Scheme 79 Preparation of (Z)-3-(3-(4-(2-(2,4difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin- 1-yl)propyl)-5-(3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzylidei)thiazolidine-2,4-dione

To a solution of 3-(3-(4(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl )thiazolidine-2,4-dione (280 mg, 0.58 mmol, 1 eq) in ethanol (2 ml) was added 3-ethoxy-4(3-(4-methylpiperazin-1-yl)propoxy)benzaldehyde (179 mg, 0.58 mmol, 1 eq) and piperidine (10 mg, 0.12 mmol, 0.2 eq). The reaction mass was kept overnight at a temperature of 80°C, then cooled and ethanol was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and the material was purified by flash chromatography on silica gel (elution system: ethyl acetate:methylene 1:1 - ethyl acetate - ethyl acetate:methanol 2:3). After purification, the substance was triturated in ether and filtered. Yield 3.35% (15 mg). C ₃₈ H ₅₀ F ₂ N ₈ O ₅ S. m/z 768.93.

¹ H NMR (CDCl ₃ ): 8.07 (m, 1H), 7.74 (m, 1H), 7.72 (s, 1H), 7.44 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.91 (m, 1H), 6.76 (m, 2H), 4.56 (s, 1H), 4.47 (s, 1H), 4.08 (m, 3H), 3.75 (m, 1H), 3.30 (m, 2H), 3.24 (m, 1Н), 3.01 (m, 4Н), 2.77 (m, 4Н), 2.64 (m, 3Н), 2.40 (m, 12Н), 2.08 (m, 2Н), 1.93(m, 1Н), 1.84( 171, 2H), 1.49-1.43 (m, 4H).

Preparation of 5-(2,4-dichlorobenzylidene)-3-(3-(4-(2-(2,4-dichlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl) propyl) piperazin-1-yl) propyl) thiazolidin-2,4-dione (13)

Method B

Scheme 80 triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione

To a solution of piperazine hydrochloride (0.185 g, 0.47 mmol, 1 equiv) in DMF (2 ml) was added 3-(3-bromopropyl)-5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione (186 mg, 0.47 mmol, 1 eq), potassium carbonate (195 mg, 1.41 mmol, 3 eq) and potassium iodide (78 mg, 0.47 mmol, 1 eq). The reaction mass was stirred overnight at 80°C, then cooled, diluted with water (6 ml) and extracted three times with ethyl acetate (2 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was dissolved in methylene chloride and purified by silica gel chromatography (eluent system methylene chloride-6% methanol in methylene chloride). Yield 21.5 3% (68 mg). C ₂₈ H ₂₈ Cl ₄ N ₆ O ₃ S. m/z 671.45.

¹ H NMR (CDCl ₃ ): 8.13 (s, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.70 (d, 1H, J=6.92 Hz), 7.52 (m, 1H), 7.43 ( d, 1H, J=6.92 Hz), 7.35 (m, 2H), 7.17 (m, 1H), 5.40 (bs, 1H), 4.68 (m, 2H), 4.16 (m, 1H), 3.79 (m, 3H ), 3.45 (m, 1H), 3.34 (m, 1H), 2.63 (m, 1H), 2.45–2.27 (m, 9H).

Preparation of 1-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)piperazine-1-carboxylate (14)

Stage 1. Preparation of starting compound 1-chloroethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-carboxylate (065) to get compound 14

Scheme 81. Preparation of 1-chloroethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazine-1-carboxylate

1-Chloroethyl chloroformate (2.09 g, 1.05 equiv) is added dropwise while cooling in an ice bath to a mixture of 2-(2,4-difluorophenyl)-1-(piperazin-1-yl)-3-(1H-1,2,4 -triazol-1-yl)propan-2-ol hydrochloride (5 g, 1 eq), triethylamine (2.81 g, 2 eq) in 100 ml anhydrous (<0.01%) dichloromethane. The next day the reaction mass is diluted with water, the organic phase is washed with a weak solution of citric acid and dried over Na ₂ SO ₄ . The solution is evaporated, the residue is chromatographed on silica gel (eluent - ethyl acetate). The fractions obtained after chromatography are evaporated to give an oily substance. Yield 1.71 g (29%). C ₁₈ H ₂₂ ClF ₂ N ₅ O ₃ , LC-MS m/z = 430. ¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.09 (s, 1H), 7.86 (m, 1H), 7.47 (s , 1Н), 6.74 (m, 3Н), 6.43 (s, 1Н), 4.50 (m, 2Н), 4.09–2.04 (m, 8Н), 1.93 (m, 2Н), 1.68 (m, 3Н).

Stage 2. Preparation of 1-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2 ,4-triazol-1-yl)propyl)piperazine-1-carboxylate (14)

Scheme 82 2,4-triazol-1-yl) propyl) piperazine-1-carboxylate

1-Chloroethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazine-1-carboxylate (0.2 g, 1 eq. ) and potassium salt of 5-(4-chlorobenzylidene)-2,4-dioxothiazolidine (0.13 g, 1 equiv) in 2 ml of DMF are stirred overnight at room temperature. The mixture is poured into water and extracted with ether. The solution is evaporated, the residue is chromatographed on silica gel (ethyl acetate). The fractions are evaporated to give an oily substance. Yield 37 mg (13%). C ₂₈ H ₂₇ ClF ₂ N ₆ O ₅ S, m/z 633.066. LC-MS m/z = ^634.32.1H NMR: (500 MHz, CDCl ₃ ) δ = 8.15 (s, 1H), 7.80 (s, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.81 (m, 2H), 6.69 (m, 1H), 4.53 (m, 2H), 3.60-3.04 (m, 4H), 2.89-2.25 (m, 4H ), 2.06 (m, 3H), 1.76 (m, 2H), 1.25 (m, 3H).

Preparation of 1-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)piperazine-1-carboxylate (15)

Method B

Scheme 83. Preparation of 1-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1, 2,4-triazol-1-yl) propyl) piperazine-1-carboxylate

1-Chloroethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl) piperazin-1-carboxylate (1.11 g, 1 eq. ) and potassium salt of 5-(4-ethylbenzylidene)-2,4-dioxothiazolidine (0.7 g, 1 eq) in 10 ml of DMF are stirred overnight at room temperature. The mixture is poured into water and extracted with ether. The solution is evaporated, the residue is chromatographed on silica gel (eluent - ethyl acetate). The fractions are evaporated to give an oily substance. Yield 337 mg (20%). C ₃₀ H ₃₂ F ₂ N ₆ O ₅ S. LC-MS m/z (M+1) ⁺ = 627 ⁺ .

¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.12 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.55 (m, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 6.83 (m, 2H), 6.73 (q, J=6.4 Hz, 1 H), 4.53 (m, 2H), 3.52-3.24 (m, 4H) , 3.08 (m, 1H), 2.70 (q, J=7.3 Hz, 2H), 2.46-2.21 (m, 4H), 1.76 (d, J=6.4 Hz, 3H), 1.64 (m, 2H), 1.27 (t, J=7.3Hz, 3H).

Preparation of 5-(4-chlorobenzylidene)-3-((2)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione (16)

Method B

Scheme 84. Preparation of 5-(4-chlorobenzylidene)-3-((Z)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazin-1-yl)but-2-en-1-yl)thiazolidin-2,4-dione

Piperazine hydrochloride (260 mg, 0.72 mmol, 1 eq) was dissolved in DMF (4 ml), potassium carbonate (300 mg, 2.17 mmol, 3 eq) was added, alkylator - 3-((R)-4-chlorobut-2-ene -1-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione) (cis form) (237 mg, 0.72 mmol, 1 eq) and potassium iodide (120 mg, 0.72 mmol, 1 eq). The reaction mass was stirred for 16 hours at 80°C, then cooled, diluted with water (6 ml) and was extracted three times with a mixture of diethyl ether - ethyl acetate 1:1 (3*2 ml). The organic phase was separated, dried over sodium sulfate and applied to silica gel. The material was purified by chromatography on silica gel (hexane:ethyl acetate 1:5 - ethyl acetate - methanol:ethyl acetate 1:4). The organic fractions containing the product were evaporated, the residue was triturated in diethyl ether. Yield 9% (40 mg). C ₂₉ H ₂₉ ClF ₂ N ₆ O ₃ S. [M + H] ⁺ 616.11. ¹ H NMR (CDCl ₃ ): 8.05 (m, 1H), 7.86 (s, 1H), 7.82 (m, 1H), 7.46 (m, 5H), 6.82 (m, 2H), 6.12-6.00 (m, 1H ), 5.86 (m, 1Н), 4.61 (m, 2Н), 4.38 (m, 2Н), 3.79 (m, 1Н), 3.44 (m, 1Н), 3.30-2.72 (m, 11Н).

Preparation of (R) 5-(4-chlorobenzylidene)-3-(4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione (17)

Method B

Scheme 85. Preparation of (R) 5-(4-chlorobenzylidene)-3-(4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)but-2-en-1-yl)thiazolidin-2,4-dione

Piperazine hydrochloride (386 mg, 1.07 mmol, 1 eq) was suspended in acetonitrile (3 ml), then potassium carbonate (445 mg, 3.22 mmol, 3 eq) was added and the reaction mixture was stirred for 10 minutes at room temperature. Then (R) 3-(4-bromobut-2-en-1-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (trans form) (400 mg, 1.07 mmol, 1 eq) was added. The reaction mass was stirred for 16 hours at 80°C, then cooled and the precipitate of inorganic salts was filtered off, which was then washed with dichloromethane (2*5 ml). The resulting filtrate was evaporated on a rotary evaporator, then the residue was purified by chromatography on silica gel (ethyl acetate:hexane 3:1 - ethyl acetate - ethyl acetate:methanol 3:2 system). Yield 29% (190 mg). C ₂₉ H ₂₉ ClF ₂ N ₆ O ₃ S. LC MS [M+H] ⁺ 616 ⁺ .

¹ H NMR (CDCl ₃ ): 8.12 (s, 1H), 7.82 (s, 1H), 7.77 (s, 1H), 7.51 (m, 1H), 7.44 (m, 4H), 6.79 (m, 2H), 5.72 (m, 1Н), 5.65 (m, 1Н), 4.51 (m, 3Н), 4.30 (m, 2Н), 3.07 (m, 1Н), 2.99 (m, 2Н), 2.67 (m, 1Н), 2.42 (m, 8H).

Preparation of (R)5-(4-ethylbenzylidene)-3-(4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazole of idine-2,4-dione (18)

Method B

Scheme 86 Preparation of (R) 5-(4-ethylbenzylidene)-3-(4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)but-2-en-1-yl)thiazolidin-2,4-dione

Piperazine hydrochloride (226 mg, 0.63 mmol, 1 eq) was suspended in acetonitrile (4 ml), potassium carbonate (260 mg, 1.88 mmol, 3 eq) was added, alkylator - (trans isomer) (230 mg, 0.63 mmol, 1 eq) and potassium iodide (104 mg, 0.63 mmol, 1 eq). The reaction mass was stirred for 16 hours at 80°C, then cooled, the precipitate of inorganic salts was filtered off and washed with methylene chloride (6 ml). The filtrate was evaporated, dissolved in methylene chloride (2 ml) and applied to silica gel. The material was purified by silica gel chromatography (elution system hexane:ethyl acetate 1:5-ethyl acetate-methanol:ethyl acetate 1:4). Yield 31% (120 mg). C ₃₁ H ₃₄ F ₂ N ₆ O ₃ S. LC MS [M+H] ⁺ 609 ⁺ .

¹ H NMR (CDCl ₃ ): 8.10-7.99 (m, 1H), 7.87 (m, 1H), 7.81 (m, 1H), 7.50 (m, 1H), 7.43 (d, 2H, J=8.04 Hz), 7.31 (d, 2H, J=8.04 Hz), 6.80 (m, 2H), 6.06-5.74 (m, 2H), 4.90-4.72 (m, 1H), 4.62 (m, 2H), 4.40 (m, 2H) , 4.13-3.76 (m, 1H), 3.59 (m, 2H), 3.48-2.83 (m, 8H), 2.70 (q, 2H, J ₁ =7.33 Hz, J ₂ =7.83 Hz), 2.34 (m, 1H ), 1.27 (t, 3H, J ₁ =7.33 Hz, J ₂ =7.83 Hz).

Preparation of (R) 3-((4-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl) (methyl )amino)piperidin-1-yl)but-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidin-2,4-dione (19)

Method B

Scheme 87. Preparation of 3-((R)-4-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )(methyl)amino)piperidin-1-yl)but-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione

Piperazine hydrochloride (670 mg, 1.73 mmol, 1 eq) was dissolved in acetonitrile (10 ml), potassium carbonate (716 mg, 5.18 mmol, 3 eq) was added, alkylator - (trans isomer) (633 mg, 1.73 mmol, 1 eq) and potassium iodide (287 mg, 1.73 mmol, 1 eq). The reaction mass was stirred for 16 hours at 80°C, then cooled and the precipitate of inorganic salts was filtered off. The organic phase was evaporated, dissolved in a mixture of ethyl acetate and methanol and applied to silica gel. The material was purified by silica gel chromatography (elution system ethyl acetate-methanol:ethyl acetate 2:5). Yield 45% (495 mg). C ₃₃ H ₃₈ F ₂ N ₆ O ₃ S. [M+H] ⁺ 637.77.

¹ H NMR (CDCl ₃ ): 8.15-7.57 (m, 2H), 7.32-7.27 (m, 7H), 6.78 (m, 1H), 6.20 (m, 1H), 5.90 (m, 1H), 4.76-4.43 (m, 4H), 4.22 (m, 1H), 4.07 (m, 3H), 3.90 (m, 1H), 3.59 (m, 2H), 2.62 (m, 3H), 2.13 (m, 2H), 2.00 ( s, 3Н), 1.21 (m, 7Н).

Preparation of racemate 5-(4-chlorobenzylidene)-3-(3-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) )propyl)amino)piperidin-1-yl)propyl)thiazolidin-2,4-dione (20)

Method B

Scheme 88. Preparation of the racemate 5-(4-chlorobenzylidene)-3-(3-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole- 1-yl)propyl)amino)piperidin-1-yl)propyl)thiazolidin-2,4-dione

Double hydrochloride (280 mg, 0.68 mmol, 1 eq) was dissolved in DMF (3 ml), potassium carbonate (283 mg, 2.05 mmol, 3 eq), alkylator (246 mg, 0.68 mmol, 1 eq) and potassium iodide (113 mg, 0.68 mmol, 1 equiv). The reaction mass was stirred for 16 hours at 80°C, then cooled, diluted with water (6 ml) and was extracted three times with diethyl ether (3*2 ml). The organic phase was separated, dried over sodium sulfate and applied to silica gel. The material was purified by silica gel chromatography (elution system hexane:ethyl acetate 1:5-ethyl acetate-methanol:ethyl acetate 1:4). Yield 27% (112 mg). C ₂₉ H ₃₁ ClF ₂ N ₆ O ₃ S. [M + H] ⁺ 618.12.

¹ H NMR (CDCl ₃ ): 8.13 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.55 (m, 1H), 7.43(m, 4H), 6.80 (m, 2H), 4.70 (bs, 1Н), 4.50 (m, 1Н), 3.85 (m, 3Н), 3.50 (m, 2Н), 3.08 (m, 3Н), 2.56 (m, 2Н), 2.06 (m, 8Н), 1.60 (m, 1H).

Preparation of racemate 5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole- 1-yl) propyl) amino) ethyl) piperazin-1-yl) propyl) thiazolidin-2,4-dione 2-hydroxypropan-1,2,3-tricarboxylate (21)

Method A

Scheme 89. Preparation of the racemate 5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl)propyl)amino)ethyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione 2-hydroxypropan-1,2,3-tricarboxylate

Amine hydrochloride (365 mg, 0.82 mmol, 1 eq) and oxirane methanesulfonate (260 mg, 0.82 mmol, 1 eq) are suspended in ethanol (5 ml), then the calculated amount of triethylamine (249 mg, 2.46 mmol, 3 eq) is added. The reaction mass is kept for 16 hours at 80 degrees. It is then cooled, the ethanol is evaporated off and the residue is partitioned between methylene chloride (5 ml) and aqueous citric acid solution (8 ml). The aqueous layer is separated, the water is evaporated on a rotary evaporator. The substance is purified by silica gel chromatography, methanol system. The product was isolated as citrate, yield 27% (187 mg). C ₃₆ H ₄₂ ClF ₂ N ₇ O ₁₀ S. [M+H] ⁺ 647.16.

¹ H NMR (DMSO-d ₆ ): 10.39 (bs, 3H), 8.46 (bs, 1H), 7.94(s, 1H), 7.77 (s, 1H), 7.64 (m, 5H), 7.40 (m, 1H ), 7.25 (m, 1Н), 7.03 (m, 1Н), 4.76 (m, 2Н), 4.08 (m, 1Н), 3.72 (m, 3Н), 3.04 (m, 18Н), 2.68 (m, 4H) .

Preparation of racemate (R,S)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl) thiazolidin-2,4-dione (22) and its enantiomers (R) and (S) forms

Preparation of starting reagents for obtaining compounds 22-24 as racemate (R,S) (22) and enantiomers R (23) and S (24) forms

Example for the preparation of racemate (R,S) 2-hydroxy-3-chloropropyl-5-(4-chlorobenzylidene) thiazolidine-2,4-dione (065)

Scheme 90. Preparation of racemate (R,S) tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate

Epichlorohydrin racemate (2.5 g, 27 mmol) was added to a solution of tert-butylpiperazine-1-carboxylate (5.0 g, 26 mmol) in isopropanol (50 mL). The reaction mixture was stirred overnight at room temperature, then evaporated in vacuo to give (7.2 g, 98%) as a colorless oil. C ₁₂ H ₂₃ CIN ₂ O ₃ . m/z: 278.78. LC-MS 279 (M+1) ⁺ . ¹ N NMR (500 MHz, DMSO-d ₆ ): δ ppm 1.42 (s, 9 H) 2.27-2.42 (m, 6 H) 3.22-3.32 (m, 4 H), 3.52-3.56 (m, 1H), 3.79-3/89)m, 1H), 5.04 (d, J=4.9 Hz. 1H).

(S) Tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate (066)

Scheme 91 Preparation of (S) tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate

Received similarly to the racemate from tert-butylpiperazine-1-carboxylate and (S)-epichlorohydrin ((S)-2-(chloromethyl)oxirane) according to the method described above. Received (5.1 g, 98%) as a colorless oil. Used in subsequent synthesis without further purification. C ₁₂ H ₂₃ CIN ₂ O ₃ . m/z 278.776. LC-MS: 278.9 (M+1) ⁺ .

(R) tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate (067)

Scheme 92. Preparation of (R) tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate

Received from tert-butylpiperazine-1-carboxylate and (R)-epichlorohydrin ((R)-2-(chloromethyl)oxirane) according to the method described above. Received (4.9 g, 97%) as a colorless oil. Used in subsequent synthesis without further purification. C ₁₂ H ₂₃ CIN ₂ O ₃ . m/z: 278.776. LC-MS: 278.9 (M+1) ⁺ .

Racemate (R,S) tert-butyl (Z)-4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate (068)

Scheme 93. Preparation of racemate (R,S) tert-butyl (Z)-4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazin-1- carboxylate

(Z)-5-(4-chlorobenzylidene)thiazolidine potassium salt was added to a solution of tert-butyl 4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate (4.0 g, 14 mmol) in dry DMF (50 ml) -2,4-diones. The reaction mixture was vigorously stirred at 90°C for 12 hours, then cooled to room temperature and evaporated in vacuo. The solid residue was mixed with water (50 ml) and EtOAc (100 ml). The organic extract was separated, washed with water (20 ml), the solvent was partially evaporated (1/2 volume) and cooled to +5°C. The precipitate formed was filtered, washed with i-PrOH (5 ml) and dried at room temperature. Received (5.12 g, 74%) as a colorless amorphous powder. C ₂₂ H ₂₈ CIN ₃ O ₅ S. Exact weight: 481.1438. LC-MS m/z: 481.8 (M+1) ⁺ .

¹ N NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.32-1.43 (m, 9H) 2.20-2.44 (m, 6H) 2.24-2.42 (m, 1H) 3.30 (br s, 4 H+water) 3.63- 3.76 (m, 2H) 3.89-4.04 (m, 1H) 5.06 (br d, J=4.77 Hz, 1H), 7.56-7.69 (m, 4H), 7.92 (s, 1H).

(R) tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate (069)

Scheme 94 Preparation of (R) tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate

Received from the K-salt of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione and tert-butyl (R)-4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate according to the method described above. Received (5.26 g, 78%) as a colorless amorphous powder. C ₂₂ H ₂₈ CIN ₃ O ₅ S. Exact weight: 481.1438. LC-MS m/z: 481.8 (M+1) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.32-1.43 (m, 9H) 2.20-2.44 (m, 6H) 2.24-2.42 (m, 1H) 3.30 (br s, 4 H+water) 3.63- 3.76 (m, 2H) 3.89-4.04 (m, 1H) 5.06 (br d, J=4.77 Hz, 1H), 7.56-7.69 (m, 4H), 7.92 (s, 1H).

(S) tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate (070)

Scheme 95 Preparation of (S) tert-butyl 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate

Received from the K-salt of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione and tert-butyl (S)-4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate according to the method described above. Received (5.2 g, 77%) as a colorless amorphous powder. C ₂₂ H ₂₈ CIN ₃ O ₅ S. Exact weight: 481.1438. LC-MS m/z: 481.8 (M+1) ⁺ .

¹ N NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.32-1.43 (m, 9H) 2.20-2.44 (m, 6H) 2.24-2.42 (m, 1H) 3.30 (br s, 4 H+water) 3.63- 3.76 (m, 2H) 3.89-4.04 (m, 1H) 5.06 (br d, J=4.77 Hz, 1H), 7.56-7.69 (m, 4H), 7.92 (s, 1H).

Racemate (R,S) (2)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione (071)

Scheme 96. Preparation of racemate (R,S) (7)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione

To a solution of tert-butyl (R,S) 4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine-1-carboxylate (4.5 g, 9.3 mmol ) in CH ₂ Cl ₂ (50 ml) was added TFA (10 ml, 0.1 mol). The reaction mixture was stirred at room temperature for 5 hours, then evaporated in vacuo. Water (50 ml), EtOAc (100 ml) was added to the dry residue, and Na ₂ CO ₃ (2.1 g, 20 mmol) was added carefully with stirring. Upon completion of the neutralization process, the organic layer was separated, the aqueous was re-extracted with EtOAc (50 ml). The extracts were combined and washed with saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuum. Received (3.5 g, 98%) as a colorless oil. C ₁₇ H ₂₀ CIN ₃ O ₃ S. Exact weight: 381.0914. LC MS m/z: (M+1) + = 381.8.

¹ N NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.07-2.42 (m, 4H), 2.52-2.80 (m,2H) 3.41 (br dd, J=1.79, 1.05 Hz, 6H+water), 3.56- 3.75 (m, 3H), 3.85-4.08 (m, 1H), 7.48-7.70 (m, 4H), 7.90 (s, 1H).

(R) (2)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl) thiazolidine-2,4-dione (072)

Scheme 97. Obtaining the enantiomer of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione

Received from tert-butyl (R)-4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate according to the method described above. Received (3.5 g, 98%) as a colorless oil. C ₁₇ H ₂₀ CIN ₃ O ₃ S. LC MS m/z: (M+1) + = 381.8 ⁺ .

(S) (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione (073)

Scheme 98. Preparation of the (S)(Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione enantiomer

Received from tert-butyl (S)-4-(3-chloro-2-hydroxypropyl)piperazine-1-carboxylate according to the method described above. Received (3.5 g, 98%) as a colorless oil. C ₁₇ H ₂₀ CIN ₃ O ₃ S. Exact Mass: 381.0914. LC MS m/z: (M+1) + = 381.8.

Racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione (22)

Method A

Scheme 99. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl) thiazolidin-2,4-dione

To a solution of the racemate (R,S) (Z)-5-(4-chlorobenzalidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione (3.0 g, 7.8 mmol) in a mixture of toluene/N-methylpyrrolidone -20:1 (100 ml) was added 1-((2-(2,4-difluorophenyl)oxiran-2-yl)methyl)-1H-1,2,4-triazole ( 1.9 g, 8 mmol) and triethylamine (5 ml, 38 mmol). The reaction mass was stirred at a temperature of 90°C for 12 hours, then cooled to room temperature and evaporated in vacuum. The residue was purified by flash chromatography using ethyl acetate:methanol:triethylamine (25:1:0.1) as eluent. Received (3.2 g, 67%) as a colorless oil. C ₂₈ H ₂₉ CIF ₂ N ₆ O ₄ S. Exact weight: 618.1628. LC MS m/z (M+1) ⁺ = 619.1 ⁺ , HPLC-MS, Phenomenex C18 column, 150*3.3 µm column temperature 30°C (mobile phase: acetonitrile), m/z 619.1810, retention time : 10.4-10.5 min.

¹ H NMR: (500 MHz, CDCl ₃ ) δ = 8.11 (s, 1H), 7.85 (m, 1H), 7.80 (s, 1H), 7.58-7.42 (m, 5H), 6.82 (m, 2H), 5.07 (bs, 1H), 4.54 (dd, J ₁ =17.1 Hz, J ₂ =14.4Hz, 2H), 4.12 (m, 1H), 3.87 (m, 1H), 3.76 (m, 1H), 3.50 (m , 1H), 3.07 (d, J=13.4Hz, 1H), 2.72 (d, J=13.4Hz, 1H), 2.69-2.32 (m, 10H).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 11.12 (s, 4H), 8.91 (s, 1H), 8.74 (d, J=1.7 Hz, 3H), 8.13 (s, 1H), 7.98 (s , 3H), 7.90 (s, 4H), 7.67-7.63 (m, 7H), 7.62-7.57 (m, 8H), 7.42 (td, J=9.0, 6.6 Hz, 3H), 7.39-7.34 (m, 1H ), 7.24 (ddd, J=11.8, 9.0, 2.6 Hz, 3H), 7.14 (ddd, J=11.9, 9.2, 2.6 Hz, 1H), 7.01 (t, J=8.5 Hz, 3H), 6.94 (td, J=8.5, 2.6 Hz, 1H), 4.84 (d, J=14.4 Hz, 3H), 4.72 (dd, J=14.5, 3.5 Hz, 3H), 4.65 (d, J=6.7 Hz, 2H), 4.32 ( d, J=8.6 Hz, 4H), 3.79-3.73 (m, 2H), 3.73-3.61 (m, 5H), 3.58 (ddd, J=13.7, 5.7, 2.0 Hz, 4H), 3.49 (s, 0H) , 3.30 (dd, J=13.4, 10.2 Hz, 4H), 3.13 (d, J=11.8 Hz, 3H), 2.49 (p, J=1.9 Hz, DMSO).

¹³ c nmr (151 mhz, dmso-d ₆ ) δ: δ 167.37, 165.73, 163.24, 163.15, 161.60, 161.51, 159.85, 159.78, 158.22, 149.26, 144.83, 135.21, 131.94, 131.71, 131.23, 130.06, 123.29, 123. , 122.45 111.52 111.39 104.65 104.48 104.31 72.90 62.58 62.57 62.03 55.52 48.59 48.53 45.27 29.04

Preparation of (R)(Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione (23)

Scheme 100 2,4-triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione

Prepared from (R)(Z)-5-(4-chlorobenzalidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione by the method described above. The R-enantiomer (3.6 g, 74%) was obtained as a colorless amorphous powder. C ₂₈ H ₂₉ CIF ₂ N ₆ O ₄ S. exact weight: 618.1628. LCMS m/z (M+1) 619 ⁺ .

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.16 (s, 1H), 8.77 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.70-7.63 (m, 2H), 7.63-7.56 (m, 2H), 7.47-7.38 (m, 1H), 7.24 (ddd, J=11.8, 9.0, 2.6 Hz, 1H), 7.01 (t, J=8.5 Hz, 1H), 4.85 (d, J=14.4 Hz, 1H), 4.72 (dd, J=14.4, 3.6 Hz, 1H), 4.32 (d, J=8.7 Hz, 1H), 3.75 (hept, J=6.1 Hz, 1H), 3.68 (dd, J=13.7, 7.3 Hz, 1H), 3.62-3.55 (m, 1H), 3.51 (s, 10H), 3.35-3.25 (m, 1H), 2.49 (p, J=1.8 Hz, DMSO).

(S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione (24)

Scheme 101. Preparation of the enantiomer (S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1, 2,4-triazol-1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl) thiazolidin-2,4-dione

Prepared from (S)(Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(piperazin-1-yl)propyl)thiazolidine-2,4-dione by the method described above. The S-isomer (3.5 g, 73%) was obtained as a colorless amorphous powder. C ₂₈ H ₂₉ CIF ₂ N ₆ O ₄ S. Exact weight: 618.1628. LC MS m/z (M+1) 619 ⁺ .

¹ H NMR(600MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.89 (s, 1H), 7.70 (s, 1H), 7.65-7.58 (m, 3H), 7.37 (dtd, J=16.4, 9.3, 7.3 Hz, 2H), 7.16-7.08 (m, 2H), 6.93 (td, J=8.5, 2.9 Hz, 2H), 5.76 (s, 1H), 5.13-5.05 (m, 2H), 4.57 (d , J=3.4 Hz, 2H), 3.76-3.67 (m, 1H), 3.66-3.56 (m, 2H), 2.49 (p, J=1.9 Hz, DMSO-d5), 2.44-2.20 (m, 5H).

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)propan-2-yl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione (25)

Preparation of starting reagents for the preparation of compounds 27 and 28 as racemates (R,S)

Obtaining (R,S) (3-chloro-2-hydroxypropyl)piperidin-4-one (074)

Scheme 102. Preparation of racemate (R,S) (3-chloro-2-hydroxypropyl)piperidin-4-one

Condensation of piperidin-4-one with racemic epichlorohydrin in alcohol at room temperature proceeded analogously to Example 065 with Boc-piperazine to give the corresponding piperidone derivative. The resulting product was used without further purification.

¹ HMR (500 MHz, DMSO-d ₆ ): δ ppm 2.27-2.38 (m, 4 H), 2.42-2.51 (m 4H), 2.72-2.79 (m, 4H), 3.74-3.76 (m, 2H), 3.89-3.89 (m, 1H), 5.18 (d, J=4.9 Hz. 1H).

Preparation of racemate (R,S) (Z)-(3-(5-(4-chlorobenzylidene)-(2-hydroxy-3-(4-oxo-piperidin-1-yl)propyl)-3-thiazolidine-2,4- dion (075)

Scheme 103. Preparation of racemate (R,S) (Z)-4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperidin-4-one

A solution of 4 (1-(3-chloro-2-hydroxypropyl)piperidine -4-one) 3.98 g (20.80 mmol) in 5 ml DMF. Was stirred for 18 hours at a temperature of 75°C. After the reaction, the reaction mass was poured into 200 ml of distilled water. The precipitate that formed was filtered off, dried, and washed with 50 ml of diethyl ether. Received 7.12, the Yield was 90.08%. C ₁₈ H ₁₉ CIN ₂ O ₄ S. m/z 394.8801. LC MS (M+1) ⁺ = 395 ⁺ .

¹ HMR (500 MHz, DMSO-d ₆ ): δ ppm 2.27-2.38 (m,4H), 2.42-2.51 (m 4H), 2.72-2.79 (m, 4H), 3.74-3.76 (m, 2H), 3.89 -3.89 (m, 1H), 5.18 (d, J=4.9 Hz. 1H), 7.52-7.71 (m. 4H), 7.82 (s., 1H).

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)propan-2-yl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione (25)

Scheme 104. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1Н -1,2,4-triazol-1-yl)propan-2-yl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione

To a suspension in 25 ml of dichloromethane of 1.00 g of the starting 2,4-dione (2.5 mmol) was added 0.82 g (1.05 mol equiv) of triazole amine and 0.805 g of sodium cyanoborohydride (1.5 mol equiv). Stirred at room temperature for 12 hours. After the reaction, the reaction mixture was treated with 25 ml of concentrated soda solution, the organic layer was separated, which was washed with 25 ml of water, and dried using magnesium sulfate. The excess dichloromethane was evaporated on a rotary evaporator and isolated by column chromatography. The yield was 22% as a colorless amorphous powder. C ₂₉ H ₃₁ CIF ₂ N ₆ O ₄ S. m/z 633.12. LC MS m/z (M+1) ⁺ = 634 ⁺ .

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione (26)

Scheme 105. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1Н -1,2,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione

Received from racemate (R,S) 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol by the formalin reductive amination method described above in the preparation example of compound (050). Received 0.27 g (32%) in the form of a colorless amorphous powder. C ₃₀ H ₃₃ CIF ₂ N ₆ O ₄ S. m/z 647.147. LC MS m/z (M+1) ⁺ = 648 ⁺ .

¹ H NMR(600 MHz, DMSO-d ₆ ) δ: 8.08 (s, 1H), 7.86 (s, 1H), 7.68-7.63 (m, 2H), 7.61-7.56(m, 2H), 7.44-7.38 ( m, 2H), 7.26 (m, 1H), 7.09 (m, 1H), 4.97-4.82 (m, 2H), 4.71 (t, J=13.3 Hz, 2H), 4.60 (td, J=10.5, 9.4, 6.8 Hz, 1H), 4.48 (td, J=12.5, 5.9, Hz, 1H), 4.12 (s, 2H), 4.05 (d, J=13.2 Hz, 1H), 3.73 (d, J=14.0 Hz , 1H) 3.68-3.61 (m, 1H), 3.55 (dd, J=14.1, 7.3 Hz, 2H), 3.46-3.37 (m, 1H), 3.24-3.17 (m, 2H), 2.38 (d, J= 4.3Hz, 3H), 2.04(s, 1H).

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione by counter synthesis (26)

Method B

Scheme 106. Synthesis of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1Н -1,2,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione

Received from racemate (R,S) 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol from the K-salt of a thiazolidine-2,4-dione derivative according to the method described for product series 22-24. Received 0.27 g (32%) in the form of a colorless amorphous powder. C ₃₀ H ₃₃ CIF ₂ N ₆ O ₄ S. m/z 647.147. LC MS m/z (M+1) ⁺ = 648 ⁺ .

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl) bugan-2-yl) (methyl) amino) piperidin-1-yl) -2-hydroxypropyl) thiazolidin-2,4-dione (27)

Preparation of starting reagents for compound 27

Stage 1. Preparation of 1-azido-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol (076)

Scheme 107. Preparation of 1-azido-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol

(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-2,34-triazol-1-yl)methyl)oxirane (287 mg, 1.11 mmol, 1 eq), chloride ammonium (341 mg, 6.37 mmol, 1.01 eq) and sodium azide (1.23 g, 18.91 mmol, 3 eq) were suspended in methanol and refluxed for 16 hours. Then the methanol was evaporated, the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, washed with saturated sodium chloride solution (15 ml), dried over sodium sulfate and the ethyl acetate was removed on a rotary evaporator. The resulting product was used further without purification. The output is quantitative. C ₁₂ H ₁₂ F ₂ N ₆ O. [M + H] ⁺ 295.24.

¹ H NMR (CDCl ₃ ): 7.88 (s, 1H), 7.80 (s, 1H), 7.20-7.70 (m, 1H), 6.5-7.0 (m, 2H), 4.76 (m, 2H), 4.70 (br , 1H), 3.80 (1H, J=7.2 Hz), 1.14 (d, 3H, J=7.2 Hz).

Stage 2. Preparation of 3-amino-2-(2,4-difluorophenyl)-1-(1H-12,4-triazol-1-yl)butan-2-ol (077)

Scheme 108. Obtaining 3-amino-2-(2,4-difluorophenyl)-1-(1H-1,24-triazol-1-yl)butan-2-ol

To a solution of azide (1.11 g) in ethanol (120 ml) was added 111 mg of palladium on charcoal and intensively stirred for 16 hours at room temperature in a hydrogen atmosphere at a pressure of 1 atm. Then the palladium on charcoal was filtered through celite, the ethanol was evaporated, and the resulting substance was used further without further purification. Yield quantitative (1 g). C ₁₂ H ₁₂₄ F ₂ N ₄ O. [M + H] ⁺ 269.24.

¹ H NMR (CDCl ₃ ): 8.00 (s, 1H), 7.81 (s, 1H), 7.55 (m, 1H), 6.60-6.89 (m, 2H), 4.58 (m, 2H), 3.19 (m, 1H ), 3.60 (m, 1Н), 0.91 (bs, 3Н).

Stage 3. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)6util)amino)piperidine-1-car6oxylate (078 )

Scheme 109. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)butyl)amino)piperidine-1- carboxylate

To a solution of 3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1.1 g, 3.93 mmol, 1 eq) in methanol (50 ml) add Boc-piperidone (784 mg, 3.93 mmol, 1 eq), acetic acid (23 μl) and sodium cyanoborohydride (297 mg, 4.72 mmol, 1.2 eq). The reaction mass is stirred for 16 hours at room temperature, then the methanol is evaporated, the residue is distributed between ethyl acetate and water, ethyl acetate is separated. The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the substance is used further without further purification. Yield quantitative (1.72 g). C ₂₂ H ₃₃ F ₂ N ₅ O ₃ . [M+N] ⁺ 452.49.

¹ H NMR (CDCl ₃ ): 846 (s, 1H), 7.84 (s, 1H), 7.56 (m, 1H), 7.21 (bs, 1H), 6.82 (m, 2H), 4.76 (m, 1H), 4.62 (m, 1H). 4.24 (m, 2Н), 3.82 (m, 1Н), 3.59 (m, 2Н), 2.67 (m, 2Н), 2.18 (m, 2Н), 1.72 (m, 1Н), 1.64 (m, 1Н), 1.49 (s, 9Н), 1.34 (m, 1Н), 0.92 (d, J=6.0 Hz, 3Н).

Stage 4. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)6util)(methyl)amino)piperidin-1- carboxylate (079)

Scheme 110. Preparation of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)butyl)(methyl)amino)piperidine -1-carboxylate

To a solution of tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)butyl)amino)piperidine-1-carboxylate ( 590 mg, 1.30 mmol, 1 eq) in methanol (20 ml) was added an aqueous solution of formalin (88 μl of a 40% solution, 39 mg in terms of pure formalin, 1.30 mmol, 1 eq), acetic acid (8 μl) and sodium cyanoborohydride (98 mg, 1.56 mmol, 1.2 eq). The reaction mass is stirred for 16 hours at room temperature, then the methanol is evaporated, the residue is distributed between ethyl acetate and water, ethyl acetate is separated. The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the substance is isolated by chromatography on silica gel (elution system ethyl acetate - methanol: ethyl acetate 1:4). Yield 93% (585 mg). C ₂₃ H ₃₅ F ₂ N ₅ O ₃ . [M+H] ⁺ 465.52.

¹ H NMR (CDCl ₃ ): 8.23 (s, 1H), 7.81 (s, 1H), 7.60 (m, 1H), 6.84 (m, 2H), 4.62 (m, 2H), 4.15 (m, 2H), 3.85 (m, 1Н), 3.04 (m, 1Н), 2.67 (m, 4Н), 2.35 (m, 3Н), 2.09 (m, 4H), 1.85 (m, 1Н), 1.69 (m, 2H), 1.47 (s, 9H), 0.92 (dd, 3H).

Stage 5 Preparation of 2-(2,4-difluorophenyl)-1-(methyl(piperidin4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol trifluoroacetate (080)

Scheme 111. Preparation of 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol trifluoroacetate

K tert-butyl 4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)butyl)(methyl)amino)piperidine-1- carboxylate (550 mg 1 equiv) is added 0.53 g (3.5 equiv) TFA, the reaction mass is stirred at room temperature for 18 hours. After passing the reaction, the reaction mixture is evaporated on a rotary evaporator, the resulting VAT residue is washed with 10 ml of cold dry ether. The resulting precipitate is dried in a vacuum, purged with argon. Yield 77% (400 mg). C ₁₈ H ₂₅ F ₂ N ₅ O. [M+H]+ 365.32.

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.93 (s, 1H), 7.72 (s. 1H), 7.38 (td, J=9.0, 6.5 Hz, 1H), 6.69 (dd, J=18.8, 11.2, 8.3, 2.6 Hz, 2H), 4.82-4.70 (m, 2H), 3.96 (dt, J=12.3, 6.1 Hz, 1H), 3.39 (s, 2H), 3.09 (q, J=7.3 Hz, 1H), 2.86 (q, J=1 2.6 Hz, 2H), 2.27 (s, 3H), 1.97-1.89 (m, 2H), 1.86 (d, J=9.4 Hz, 2H), 1.84-1.73 (m, 1H), 1.27 (t, J=7.3 Hz, 2H), 1.14 (d, J=6.1 Hz, 3H).

Stage 6 Preparation of the racemate (R,S)-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1, 2,4-triazol-1-yl)butan-2-ol (081)

Scheme 112. Preparation of racemate 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H-1,2 ,4-triazol-1-yl)butan-2-ol

Reaction of 2-(2,4-difluorophenyl)-1-(methyl(piperidin-4-yl)amino)-3-(1H-1,2,4-triazol-1-yl)butan-2-ol base with racemate epichlorohydrin was carried out analogously to example (051). Received 200 mg, (70%) as a colorless oil. C ₂₁ H ₃₀ CIF ₂ N ₅ O ₂ . m/z: 457.945. LC MS (M+1) ⁺ = 458.1 ⁺ .

Preparation of racemate (R,S) (2)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1, 2,4-triazol-1-yl)butan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione (27)

Scheme 113. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1Н -1,2,4-triazol-1-yl)butan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione

Received from racemate (R,S) 1-((1-(2-hydroxy-3-chloropropyl)piperidin-4-yl)(methyl)amino)-2-(2,4-difluorophenyl)-3-(1H- 1,2,4-triazol-1-yl)butan-2-ol according to the method described for compound (30). Received 0.22 g (30.5%) in the form of a colorless amorphous powder. C ₃₁ H ₃₅ CIF ₂ N ₆ O ₄ S. m/z 661.174. LC MS m/z (M+1) ⁺ = 662 ⁺ .

¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 8.04 (s, 1H), 7.82 (s, 1H), 7.68-7.63 (m, 2H), 7.61-7.56 (m, 2H), 7.44-7.38 ( m, 2H), 7.26 (m, 1H), 7.09 (m, 1H), 4.97-4.82 (m, 2H), 4.71 (t, J=13.3 Hz, 2H), 4.60 (td, J=10.5, 9.4, 6.8 Hz, 1H), 4.48 (td, J=12.5, 5.9, Hz, 1H), 4.12 (s, 2H), 4.05 (d, J=13.2 Hz, 1H), 3.73 (d, J=14.0 Hz , 1H) 3.68-3.61 (m, 1H), 3.55 (dd, J=14.1, 7.3 Hz, 2H), 3.46-3.37 (m, 1H), 3.24-3.17 (m, 2H), 2.38 (d, J= 4.3 Hz, 3H), 2.04 (s, 1 H), 0.92 (dd, J=1.2 Hz, J=7 Hz, 3H, CH Me).

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H -1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione (28)

Method B.

Scheme 114. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3 -(1H-1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione

To a solution of an alkylator - racemate (R,S) -5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1Н -1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidin-2-dione (0.44 g, 1.0 mmol) in dry DMF (20 ml) was added potassium salt of (Z)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (0.28 g, 1 mmol) and a few crystals of potassium iodide. The reaction mixture was vigorously stirred at 80°C for 18 hours, then cooled to room temperature and evaporated in vacuo. The solid residue was mixed with water (50 ml) and EtOAc (100 ml). The organic extract was separated, washed with water (2×20 ml) and the solvent was evaporated. The precipitate formed was filtered, washed with ether (5 ml) and purified by column chromatography using CH ₂ Cl ₂ :MeOH (50:1-25:1) as eluent. Received (0.21 g, 30%) as an amorphous powder. C ₃₁ H ₃₆ CIF ₂ N ₇ O ₄ S. m/z: 676.1808. LC MS (M+1) ⁺ = 677.1 ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 8.16 (s, 1H), 7.97 (s, 1H), 7.68-7.63 (m, 2H), 7.61-7.56 (m, 2H), 7.42-7.38 ( m, 1H), 7.26 (m, 1H), 7.09 (t, J=8.5 Hz, 1H), 5.45 (b, 1H), 4.82-4.75 (m, 2H), 4.62 (m, 1H), 3.75 -3.73 (m, 2H), 3.68 (m, 1H), 3.51-3.49 (m, 4H), 3.35-3.28 (m, 2H), 2.43-2.38 (m, 6H), 2.09 (s, 3H).

Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H -1,2,4-triazol-1-yl)propyl)(4-fluorophenyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione (29)

Method B

Scheme 115. Preparation of racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3 -(1H-1,2,4-triazol-1-yl)propyl)(4-fluorophenyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione

Prepared from racemate (R,S) 1-((2-(4-(2-hydroxy-3-chloropropyl)piperazin-1-yl)ethyl)(4-fluorophenyl)amino)-2-(2,4-difluorophenyl )-3-(1H-1,2,4-triazol-1-yl)propan-2-ol according to the method described above. Received 0.32 g (34%) in the form of a colorless amorphous powder. C ₃₇ H ₃₉ CIF ₃ N ₇ O ₄ S. Exact weight: 770.2692. LC MS m/z (M+1) ⁺ = 771.0 ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 8.16 (s, 1H), 7.97 (s, 1H), 7.68-7.63 (m, 4H), 7.61-7.56 (m, 4H), 7.40-7.36 ( m, 1H), 7.24 (m, 1H), 7.02 (t, J=8.5 Hz, 1H), 5.60 (s, 2H), 5.50 (b, 1H), 4.82-4.75 (m, 2H), 4.58 (m , 1H), 3.72-3.70 (m, 2H), 3.66 (m, 1H), 3.54-3.42 (m, 6H), 3.35-3.28 (m, 1H), 2.54-2.48 (m, 6H), 2.12-2.10 (m, 2H).

Preparation of racemate (R,S) (Z)-N-(2-(4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypopyl)piperazin-1- yl)ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide (30 )

Method B

Scheme 116. Synthesis of racemate (R,S) (Z)-N-(2-(4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypropyl)piperazine -1-yl)ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl) benzamide.

Prepared from racemate (R,S) N-(2-(4-(3-chloro-2-hydroxypropyl)piperazin-1-yl)ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy -3-(1H-1,2,4-triazol-1-ide)propyl)-4-(trifluoromethyl)benzamide according to the method described above. Received 0.27 g (32%) in the form of a colorless amorphous powder. C ₃₈ H ₃₇ ClF ₅ N ₇ O ₅ S. m/z: 834.2600. LC MS (M+1) ⁺ = 834.9 ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ: 8.24 (s, 1H), 7.94 (s, 1H), 7.68-7.63 (m, 4H), 7.61-7.56 (m, 4H), 7.40-7.36 ( m, 1H), 7.24 (m, 1H), 7.02 (t, J=8.5 Hz, 1H), 5.50 (b, 1H), 4.82-4.75 (m, 2H), 4.58 (m, 1H), 3.72- 3.70 (m, 2H), 3.66 (m, 1H), 3.54 (m, 6H), 3.35-3.28 (m, 2H), 3.22-3.19 (m, 4H), 2.49-2.44 (m, 2H).

An example of obtaining hybrid derivatives based on thiomorpholine and triazole according to the invention.

(Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-5-methylthiomorpholin-3-one (31)

Stage 1. Preparation of 3-(1-bromopropan-2-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (081)

Scheme 117. Obtaining 3-(1-bromopropan-2-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

Triphenylphosphine (821 mg, 3.13 mmol, 1.5 eq.) , alkylator - 1-bromopropan-2-ol (435 mg, 3.13 mmol, 1.5 eq) and dropwise diethyl azocarboxylate (DEAD) catalyst (545 mg, 3.13 mmol, 1.5 eq). The resulting solution was stirred overnight at room temperature, then tetrahydrofuran was evaporated on a rotor, the resulting mixture was triturated in ethanol (3 ml), filtered, washed with ethanol (2 ml), and dried in air to constant weight. Yield 58.48% (440 mg). C ₁₃ H ₁₁ BrClNO ₃ S. m/z 376.66. LC MS [M+1] ⁺ = 377 ⁺ .

(Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-5-methylthiomorpholin-3-one (31)

Scheme 118. Preparation of (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl) propyl) piperazin-1-carbonyl) -5-methylthiomorpholin-3-one

To a solution of the triazole derivative piperazine hydrochloride (0.37 g, 1.03 mmol, 1 equiv) in dimethylformamide (3 ml) was added 3-(1-bromopropan-2-yl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione ( 445 mg, 1.23 mmol, 1.2 eq), potassium carbonate (426 mg, 3.08 mmol, 3 eq) and potassium iodide (171 mg, 1.03 mmol, 1 eq). The reaction mass was stirred overnight at 60°C, then cooled, diluted with water (8 ml) and extracted three times with ethyl acetate (3 ml each). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (methylene chloride-4% methanol in methylene chloride system). Yield 40.80% (253 mg). C ₂₈ H ₂₉ ClF ₂ N ₆ O ₃ S. m/z 603.10. LC MS (M+1) ⁺ = 604 ⁺ .

¹ H NMR (CDCl ₃ ): 8.12 (s, 1H), 7.81 (s, 1H), 7.78 (bs, 1H), 7.56 (d, J=7.97 Hz, 2H), 7.39 (d, J=7.97 Hz, 2H), 7.28 (m, 1H) 6.84 (m, 2H), 4.98 (bs, 1H), 4.60-4.53 (m, 2H), 3.64-3.11 (m, 7H), 2.80-2.72 (m, 2H), 2.55-2.22 (m, 4H), 1.40 (m, 3H).

Preparation of (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl)piperazin-1-carbonyl)-6-methylthiomorpholin-3-one (32)

Obtaining initial reagents

Stage 1. 5-(4-chlorobenzylidene)-3-(2-hydroxypropyl)thiazolidine-2,4-dione (082)

Scheme 119. Obtaining 5-(4-chlorobenzylidene)-3-(2-hydroxypropyl)thiazolidine-2,4-dione

To a suspension of the potassium salt of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione (1 g, 3.6 mmol, 1 equiv) in DMF (20 ml) eq). The reaction mass was stirred overnight at 50°C. The mixture was then cooled, diluted with water (40 ml). The precipitate formed was filtered off, washed with water, and dried in air to constant weight. Yield 68.47% (734 mg). C ₁₃ H ₁₂ ClNO ₃ S. m/z 297.76. LC MS (M+1) ⁺ = 298 ⁺ .

Stage 2. Preparation of (5-(4-chlorobenzylidene)-3-(2-chloropropyl)thiazolidine-2,4-dione (083)

Scheme 120. Obtaining (5-(4-chlorobenzylidene)-3-(2-chloropropyl)thiazolidine-2,4-dione

Thionyl chloride (880 mg, 7.40 mmol , 3 equiv). The reaction mass was stirred overnight at room temperature. Then the solvent was evaporated on a rotary evaporator, the resulting residue was washed with diethyl ether (5 ml) and filtered. Yield 56.32% (439 mg). The resulting chlorine derivative was used for further transformations without purification.

Preparation of (Z)-2-(4-chlorobenzylidene)4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-methylthiomorpholin-3-one (32)

Scheme 121. Preparation of (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl) propyl) piperazin-1-carbonyl) -6-methylthiomorpholin-3-one

To a solution of the triazole derivative piperazine hydrochloride (0.5 g, 1.39 mmol, 1 equiv) in dimethylformamide (4 ml) was added 5-(4-chlorobenzylidene)-3-(2-chloropropyl)thiazolidine-2,4-dione (439 mg, 1.39 mmol, 1 eq), potassium carbonate (768 mg, 5.56 mmol, 4 eq) and potassium iodide (231 mg, 1.39 mmol, 1 eq). The reaction mass was stirred overnight at 60°C, then cooled, diluted with water (10 ml) and extracted three times with ethyl acetate (3 ml). The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate. Ethyl acetate was distilled off on a rotary evaporator. The residue was taken up in methylene chloride and purified by silica gel chromatography (eluent system methylene chloride - 4% methanol in methylene chloride). Yield 75.65% (634 mg). C ₂₈ H ₂₉ CIF ₂ N ₆ O ₃ S. m/z 603.10. LCMS (M+1) ⁺ = 604 ⁺ .

¹ H NMR (CDCl ₃ ): 8.08 (s, 1H), 7.78 (s, 1H), 7.59 (s, 1H), 7.51 (m, 1H), 7.48 (d, J=8.49 Hz, 2H), 7.32 ( d, J=8.49 Hz, 2H), 6.77 (m, 2H), 4.94 (bs, 1H), 4.52 (m, 2H), 3.85 (m, 1H), 3.57-3.07 (m, 8H), 2.67 (m , 1H), 2.43 (m, 3H), 1.33 (m, 3H).

Preparation of (Z)-2-(4-chlorobenzylidene)4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-(4-phorphenyl)thiomorpholin-3-one (33)

An example of obtaining initial reagents

Step 1. 3-(2-(4-fluorophenyl-2-hydroxyethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (083)

Scheme 122. Obtaining 3-(2-(4-fluorophenyl)-2-hydroxyethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

In a 100 ml conical flask equipped with a calcium chloride tube, 5.55 g of 5-(4-chlorobenzylidene)thiazolidine-2,4-dione potassium salt (0.019 mol) are suspended in 25 ml of dry DMF. 4.32 g of 2-bromo-1-(4-fluorophenyl)ethanol (1.05 eq) are added. The reaction mass is stirred at 75°C for 18 hours, heat is removed and cooled to 25°C. The reaction mass is poured into 150 ml of distilled water, waiting for the formation of a stable precipitate. The precipitate is filtered off, squeezed out on the filter, washed with 2 portions of 10 ml of diethyl ether, the remaining precipitate is dried in air for 24 hours. 5.8 g of 3-(2-(4-fluorophenyl)-2-hydroxyethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione is obtained. The dried precipitate is heated in 20 ml of methanol to the boiling point and incubated for 1 hour, cooled to room temperature, the precipitate is filtered off. The yield was 74.6%. C ₁₈ H ₁₃ FclNO ₃ S. LCMS [M+H] ⁺ =379.

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.68 (br d, J=4.62 Hz, 1H) 3.95 (dd, J=13.97, 3.64 Hz, 1H) 4.09 (dd, J=14.00, 8.83 Hz, 1H) 5.00-5.16 (m, 1H) 7.30-7.43 (m, 4H) 7.42-7.52 (m, 4H) 7.87 (s, 1H).

Stage 2. Preparation of 3-(2-(4-fluorophenyl-2-chloroethyl)-5-(4-chlorobenzylidene) thiazolidine-2,4-dione (084)

Scheme 123. Preparation of 3-(2-(4-fluorophenyl-2-chloroethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione

In a 50 ml conical flask, 1.43 g (0.0037 mol) of 3-(2-(4-fluorophenyl)-2-hydroxyethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4 is suspended in 25 ml of methylene chloride -dione, 1.6 g (4 eq) of thionyl chloride are added to the suspension with stirring, and stirred for 18 hours at a temperature of 45°C.

After completion of the reaction, the reaction mixture is evaporated on a rotary evaporator, the resulting VAT residue is washed with 10 ml of cold hexane.

1.37 g of 3-(2-(4-fluorophenyl)-2-chloroethyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione is obtained. The yield was 98.0%. The structure was confirmed by a combination of NMR and mass spectrometry data. C ₁₈ H ₁₂ FCl ₂ NO ₂ S. M+1=381 ⁺ .

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm: 4.14 (dd, J=13.83, 6.43 Hz, 1H) 4.35 (dd, J=13.85, 8.93 Hz, 1H) 5.37 (dd, J=8.74, 6.54 Hz , 1H) 7.09 (t, J=8.56 Hz, 2H) 7.40-7.54 (m, 5H) 7.79-7.90 (m, 1H).

Preparation of (Z)-2-(4-chlorobenzylidene)4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-(4-fgorfeni l)thiomorpholin-3-one (33)

Scheme 124 -yl)propyl)piperazin-1-carbonyl)-6-(4-fluorophenyl)thiomorpholin-3-one

In a 50 ml conical flask, 0.6 g (0.0013 mol) of 3-(2-(4-fluorophenyl)-2-chloroethyl)-5-(4-chlorobenzylidene) thiazolidine-2,4-dione is dissolved in 25 ml of DMF, 0.26 g (1 eq) of piperazinyl triazole and 0.274 g of calcined potassium carbonate are added to the solution with stirring, stirred for 18 hours at a temperature of 60°C.

After the reaction, the reaction mixture is filtered from inorganic salts and evaporated on a rotary evaporator, the resulting VAT residue is purified by column chromatography (elution system hexane-ethyl acetate 2:1). 0.15 g is obtained. The yield was 25.69%. The structure was confirmed by a combination of NMR and mass spectrometry data. C ₃₃ H ₃₀ CIF ₃ N ₆ O ₃ S. M+1=684 ⁺ .

¹ H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.74 (s, 1H), 7.68-7.61 (m, 1H), 7.48 (d, J=8.3 Hz, 4H), 7.42-7.27 (m, 6H), 6.99 (dq. J=11.8. 8.3. 7.8 Hz, 3H), 6.77 (tdd, J=11.0, 8.0, 2.8 Hz, 2H), 4.64-4.44 (m, 4H), 3.97 (p , J=8.7, 7.6 Hz, 2H), 3.77-3.15 (m, 5H), 3.08 (q, J=7.1 Hz, 2H), 2.71 (s, 1H), 2.40 (b. 4H).

An example of obtaining hybrid derivatives based on 1,4-thiazepan-3-one and triazole

Example for the preparation of racemate (R,S) (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4 -triazol-1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1,4-thiazepan-3-one (34)

Scheme 125. Preparation of racemate (R,S) (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2 ,4-triazol-1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1,4-thiazepan-3-one

3-(2-Hydroxy-3-chloropropyl)-5-(4-chlorobenzylidene) thiazolidine-2,4 -dione (0.33 g 0.01 mol, 1 eq.), potash (0.14 g, 1 eq.) and the mixture was vigorously stirred for 18 hours at room temperature, then evaporated in vacuum. The solid residue was mixed with water (50 ml) and EtOAc (100 ml). The organic extract was separated, washed with water (2×20 ml) and the solvent was evaporated. The precipitate formed was filtered, washed with ether (5 ml) and purified by column chromatography using CH ₂ Cl ₂ :MeOH (50:1-25:1) as eluent. Received (0.235 g, 38%) as a white amorphous powder. C ₂₈ H ₂₉ ClF ₂ N ₆ O ₄ S. Exact mass: LC MS (M+1) ⁺ = 619.1 ⁺ , HPLC-MS, Phenomenex C18 column, 150 * 3.3 µm, column temperature 30°C ( mobile phase: acetonitrile), m/z 619.1810, retention time: 11.4-11.6 min.

¹ H NMR (600 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.35-7.32 (m, 2H), 6.78 (d, J=8.1 Hz, 1H), 6.75 (dd, J=11.4, 2.2 Hz, 1H), 5.25 (b, 1H), 4.65-4.58 (m, 1H), 4.52 (d, J =14.3 Hz, 1H), 4.50-4.44 (m, 1 H), 3.80 (d, J=2.2 Hz, 1H), 3.55 (dd, J=6.5, 3.3 Hz, 1H), 3.52-3.46 (m, 1 H), 3.39 (dtd, J=14.5, 5.9, 2.9 Hz, 1H), 3.21 (q, J=10.7, 7.9 Hz, 3H), 3.05-2.97 (m, 1H), 2.92 (dd, J=13.4, 1.8 Hz, 1H), 2.66 (d, J=13.5 Hz, 1H), 2.37 -2.22 (m, 4H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ: 163.28 (CO triaz, 162.37 (CF arom, triaz), 158.36 (CF arom, triaz), 156.80 (CO triaz-triaz linker), 150.78 (CH triaz.), 144.31 (CH triaz.), 135.23 (CH triaz. lyden), 131.13 (CH arom, triaz.), 128.99 (CH arom. triaz), 128.98 (CH arom triaz), 128.42 (CH arom triaz), 125.26 (CH arom triaz), 120.02 (C, triaz), 111.36 (CH arom, triaz), 104.07 (CH arom, triaz), 78.94 (CH-OH triaz), 72.19 (C-OH linker), 62.06 (CH ₂ linker), 55.60 (CH ₂ triaz. linker) 53.55 (CH ₂ pip.), 43.81 (N-CH2 triaz.), 43.34 (CH ₂ pip.), 27.65 (S-CH ₂ triaz.)

To confirm the structure of the 7-membered thiazepane derivative, two-dimensional NMR spectra were measured and studied: ¹ H- ¹ H DQF-COSY, ¹ H- ¹ H-ROESY, ¹ H- ¹³ C-HMBC, showing interactions of atoms through 2-3-bonds.

The use of chemical compounds according to the invention

The use of compounds for medical reasons

The compounds described in this invention can be used for the treatment and/or prevention of infectious diseases.

Method for Therapeutic Use of the Compounds

The subject of the invention also includes administering to a subject in need of appropriate treatment a therapeutically effective amount of a compound of general formula (I).

By a therapeutically effective amount is meant that amount of a compound administered or delivered to a patient that is most likely to result in the desired response to treatment (prophylaxis) in the patient. The exact amount required may vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combination treatment with other drugs, and the like.

The compound of the invention, or a pharmaceutical composition containing the compound, may be administered to a patient in any amount and by any route of administration effective for the treatment or prevention of a disease.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier at the desired dosage, the compositions constituting the essence of the invention can be administered to humans or other animals orally, parenterally, topically, and the like.

When a compound of the invention is used as part of a combination therapy regimen, the dose of each of the components of the combination therapy is administered during the desired treatment period. The compounds constituting the combination therapy can be administered to the patient both at the same time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Pharmaceutical compositions

The invention also relates to pharmaceutical compositions which contain a compound of general formula (I) (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, diluents and/or excipients, such as may be co-administered to a patient with a compound of the present invention that do not interfere with the pharmacological activity of the compound and are non-toxic when administered at doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutical compositions of this invention contain the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, binders, lubricants materials, etc., suitable for a particular dosage form. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safflower, sesame, olive, corn and soybean oils; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer substances such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffer solutions. Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, film formers, sweeteners, flavors and flavors, preservatives and antioxidants may also be included in the composition.

The subject of this invention are also dosage forms - a class of pharmaceutical compositions, the composition of which is optimized for a certain route of administration in the body in a therapeutically effective dose, for example, for administration to the body orally, topically, intraocularly, pulmonary, for example, in the form of an inhalation spray, or intravascular method, intranasally, subcutaneously, intramuscularly, as well as by infusion method, in recommended dosages.

In addition, it is possible to administer the dosage form in the form of suppositories.

The dosage forms of the present invention may contain formulations prepared by liposome techniques, microencapsulation techniques, nanoformulation techniques, or other methods known in the pharmaceutical art.

When preparing a composition, for example in the form of a tablet, the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or similar compounds.

Tablets can be coated with sucrose, a cellulose derivative, or other materials suitable for coating. Tablets can be prepared in a variety of ways, such as direct compression, dry or wet granulation, or hot melting.

A pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active principle with a solvent and filling the resulting mixture into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, which contain pharmacologically compatible agents, such as propylene glycol or butylene glycol.

Characterization of the biological activity of compounds

Comparative study of the spectrum of antifungal activity of the compounds according to the invention in an in vitro experiment by the method of two-fold microdilutions in broth.

The experiment was carried out using standard strains and clinical isolates. Sensitivity to reference strains and standard preparations used in the study is normalized according to GOST R ISO 16256-2015 and serves as a criterion for the accuracy of the experiment.

The standard preparations fluconazole (Fluconazole, Sigma-Aldrich), the antifungal antibiotic Nystatin, and a control strain of Candidaparapsilosis (ATCC 22019) were used to control ongoing studies and comparative activity of the compounds of the invention.

The analysis was carried out by the method of serial microdilutions in accordance with GOST R ISO 16256-2015 “Clinical laboratory studies and in vitro diagnostic test systems. Reference method for broth dilution antifungals usceptibility test in go filamentous fungi; approved standard, 2 ^nd ed. CLSI document M38-A, Antifungal Susceptibility Testing of Yeasts: M27-A2. 2008. Clinical and Laboratory Standards Institute, Wayne, PA.).

All studied samples of compounds were dissolved in dimethyl sulfoxide (DMSO), the concentration of stock solutions was 10,000 µg/mL. To obtain working solutions, stock solutions were diluted in a nutrient medium to a concentration of 64 μg/mL. The range of values of the studied concentrations was from 32.0 to 0.015 μg/ml.

The inoculum of yeast cultures contained 10 ³ CFU/ml, filamentous fungi - 10 ⁴ CFU/ml.

A series of two-fold dilutions of the test samples was prepared in 96-well plates for immunological studies in a volume of 100 μl of RPMI-1640 medium with L-glutamine (Chumakov Federal State Unitary Enterprise PIPVE, Russia) containing 0.2% glucose.

After sowing yeast cultures, the plates were incubated for 24-48 hours at 35°C, filamentous - 48-96 hours.

The minimum inhibitory concentration (MIC) was taken to be the lowest concentration of sample solutions at which no less than 80% inhibition of fungal growth was observed. All experiments were repeated three times. The results are presented in table 1 below.

Comparative evaluation of the activity of the claimed compounds of the invention under in vitro conditions against fungal strains of dermatophytes and reference drugs (fluconazole and nystatin) showed that the compounds of the invention are not inferior to widely used commercial drugs.

The advantage compared to the commercial drug fluconazole is manifested in relation to naturally fluconazole-resistant strains of C. non-albicans fungi, the clinical significance of which has recently increased in almost all countries of the world to 40-60% and has become a problem for the treatment of fungal infections. In addition, experts note an increased increase in the resistance of the entire group of azole drugs to previously susceptible strains of fungi of the genus C albicans. Compounds according to the invention have a wide spectrum of antifungal activity, which confirms their promise for use in clinical practice for the treatment of infectious diseases caused by fungal infections, in particular in dermatology.

The activity of most of the claimed compounds according to the invention against Candida parapsilosis is not inferior or superior to the activity of Fluconazole and approaches Ketoconazole. In addition, the compounds of the invention, unlike fluconazole, inhibit the growth of filamentous fungi M.canis B-200 and T.rubrum 2002. Of particular interest are hybrid derivatives with a 2-hydroxypropyl linker linked to an aminopiperidine moiety between from Fluconazole, affect both yeast and filamentous fungi.

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that various modifications are possible without departing from the essence of the present invention.

Claims (63)

1. Compound of general formula (I):

or its stereoisomer or enantiomer, diastereoisomer, racemate, pharmaceutically acceptable salt, where: R ₁ is independently selected and is hydrogen or methyl; Q is independently selected and is a covalent bond, -NH-, -NR ₅ -, -(CH ₂ ) _n -NH-, -(CH ₂ ) _n -NR ₅ - or -(CH ₂ ) _n - where n= 0, 1 or 2; R ₅ is independently selected and is -C _1-4 -alkyl, benzyl or benzoyl, benzyl or benzoyl may be optionally substituted with 0-2 substituents independently selected from partially or fully halogenated -C _1-4 -alkyl, halogen; X is independently selected and is -CH- or -N-; A is selected independently and is a fragment selected from:

,

,

,

,

,

or

, where Ar is independently selected and represents phenyl, and phenyl may be optionally substituted with 1-2 substituents selected from halogen, -C _1-4 -alkyl, -O-C _1-4 -alkyl or from substituents that are:

R ₂ is independently selected and is chlorine or fluorine; Z is independently selected and is -(CH ₂ ) _m - where m is independently selected and is 1 or 2; -CH(OH)CH ₂ - or -CH=CH-CH ₂ ; and the asterisk (*) indicates the place of attachment of the substituent; R ₃ is independently selected and is fluorine or chlorine; R ₄ is independently selected and represents fluorine or chlorine; Me is methyl. 2. The compound according to claim 1, selected from the group: 5-(4-chlorobenzylidene)-3-(2-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl) piperazin-1-yl)ethyl)thiazolidin-2,4-dione; (E)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl) propyl)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione; 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-ethylbenzylidene)thiazalidine-2,4-dione; 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(2,4-dichlorobenzylidene)thiazolidine-2,4-dione; 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-methoxybenzylidene)thiazolidine-2,4-dione; 3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl) -5-(4-ethoxybenzylidene)thiazolidine-2,4-dione; 5-(4-chloro-2-(4-methylpiperazin-1-yl)benzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1Н-1 ,2,4-triazol-1-yl)propyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione; (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)acetamide; (Z)-N-(1-(5-chloro-2-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2, 4-triazol-1-yl)propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)piperidin-4-yl)amine dihydrochloride; 4-(3-(4-((3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl)piperazin-1-yl)propyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)propyl)piperazin-1-yl; (Z)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)piperazin-1- yl)propyl)-5-(3-ethoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzylidene)thiazolidine-2,4-dione; 5-(2,4-dichlorobenzylidene)-3-(3-(4-(2-(2,4-dichlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) propyl) thiazolidin-2,4-dione; 1-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazine-1-carboxylate; 1-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)ethyl 4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4- triazol-1-yl)propyl)piperazine-1-carboxylate; 5-(4-chlorobenzylidene)-3-((Z)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1Н-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione; 5-(4-chlorobenzylidene)-3-((E)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione; 5-(4-ethylbenzylidene)-3-((E)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1- yl) propyl) piperazin-1-yl) but-2-en-1-yl) thiazolidin-2,4-dione; 3-((E)-4-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)(methyl) amino)piperidin-1-yl)but-2-en-1-yl)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione; racemate 5-(4-chlorobenzylidene)-3-(3-(4-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl) propyl)amino)piperidin-1-yl)propyl)thiazolidin-2,4-dione; racemate 5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl)propyl)amino)ethyl)piperazin-1-yl)propyl)thiazolidin-2,4-dione 2-hydroxypropane-1,2,3-tricarboxylate; racemate (RS)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole-1 -yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; (R) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; (S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl)propyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; racemate (R,S) (Z)-5-(4-xporbenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)propan-2-yl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)propan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione; racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-((3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2 ,4-triazol-1-yl)butan-2-yl)(methyl)amino)piperidin-1-yl)-2-hydroxypropyl)thiazolidin-2,4-dione; racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1Н- 1,2,4-triazol-1-yl)propyl)(methyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; racemate (R,S) (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H- 1,2,4-triazol-1-yl)propyl)(4-fluorophenyl)amino)ethyl)piperazin-1-yl)-2-hydroxypropyl)thiazolidine-2,4-dione; racemate (R,S) (Z)-N-(2-(4-(3-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-2-hydroxypopyl)piperazin-1-yl )ethyl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-4-(trifluoromethyl)benzamide; (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-5-methylthiomorpholin-3-one; (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-methylthiomorpholin-3-one; (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl )piperazin-1-carbonyl)-6-(4-fluorophenyl)thiomorpholin-3-one; racemate (R,S) (Z)-2-(4-chlorobenzylidene)-4-(4-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazole -1-yl-)propyl)piperazin-1-carbonyl)-6-hydroxy-1,4-thiazepan-3-one. 3. Use of a compound according to claim 1 as an antifungal agent. 4. The use of a compound according to claim 1 for the preparation of a pharmaceutical composition for the treatment and/or prevention of an infectious disease of microbial etiology in a subject caused by a fungal infection. 5. The use of a compound according to claim 4, characterized in that the disease of microbial etiology is caused by a fungus of the genus Candida spp., Aspergillus spp., Microsporum spp., Trichophyton spp. and / or Epidermophyton spp. 6. Application according to n. 4, characterized in that the disease of microbial etiology is caused by a fungus of the species Candida auris. 7. Use according to claim 4, characterized in that the disease of microbial etiology is caused by a fungus of the species Aspergillus fumigatus. Aspergillus niger. 8. Use according to claim 4, characterized in that the disease of microbial etiology is caused by a fungus of the species Microsporum canis or Trichophyton rubrum. 9. Use according to claim 5, characterized in that the disease is a disease of the skin, nails and/or internal organs. 10. Use according to claim 8, wherein the disease is dermatophytosis, superficial mycosis, skin and/or nail candidiasis, vaginal candidiasis, internal candidiasis, candidal stomatitis or endocarditis. 11. Pharmaceutical composition for the treatment and/or prevention of an infectious disease of microbial etiology in a subject caused by a fungal infection, containing an effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable excipient. 12. Pharmaceutical composition according to claim 10, characterized in that the pharmaceutically acceptable excipient is a carrier, excipient and/or solvent. 13. Pharmaceutical composition according to claim 10, characterized in that the disease is a disease of the skin, nails and/or internal organs. 14. Pharmaceutical composition according to claim 13, characterized in that the disease is dermatophytosis, superficial mycosis, skin and/or nail candidiasis, vaginal candidiasis, internal candidiasis, candidal stomatitis or endocarditis.

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