RU2746395C1 - Method for inhibiting tumor cells with new derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide containing a diamine residue in the benzene moiety of the quinoxaline ring as well as its pharmacologically acceptable salts, hydrates, corresponding to the formula:

EFFECT: new derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide capable of inhibiting the division of tumor cells.

9 cl, 2 tbl, 50 ex

Description

Technology area

The invention relates to the pharmaceutical industry, in particular to the medical use of derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide for inhibiting the growth of tumor cells, as well as their structure and methods of production.

State of the art

Quinoxaline 1,4-dioxides have a high potential for practical application in medicine. Compounds of this series have a wide spectrum of pharmacological activity, in particular, they have antibacterial [Vieira Μ. et al. Microbiol Res., 2014, 169, 287-293], anti-tuberculosis [Jaso A. et al. J. Med. Chem., 2005, 48, 2019-2025], antitumor [Das U. et al. Bioorg.Med. Chem., 2009,17, 3909-3915], antifungal [Carta A. et al. Eur. J. Med. Chem., 2002, 37, 355-66], antiparasitic [Marin A. et al. Exp. Parasitol, 2008, 118, 25-31], antioxidant [Burguete A. et al. Chem. Biol. Drug Des., 2011, 77, 255-267] activities. Moreover, derivatives of quinoxaline 1,4-dioxide are able to selectively suppress the growth of tumor cells under conditions of hypoxia [Cheng G. et al. Front. Pharmacol, 2016, 7, 1-21].

In recent studies, it has been established that hypoxic conditions contribute to the formation of an aggressive phenotype of tumor cells, the development of multidrug resistance in them, which is associated with a poor prognosis of patient survival. The cellular response to hypoxia is mainly mediated by the induction of the transcription factor HIF-1α (hypoxia-inducible factor-1α), which regulates the expression of various genes responsible for the adaptation and progression of tumor cells [Bertou J.A. et al. Proc. Natl. Acad. Sci, 2009, 106, 14391-14396; Martin, B. et al. Nat. Rev. Cancer, 2004,4,437-447]. There are several classes of organic compounds active against hypoxic tumor cells, including derivatives of quinoxaline 1,4-dioxide [Wigerup C. et al. Pharmacology & Therapeutics, 2016, 164, 152-169; Wilson, W.R. et al. Nat. Rev. Cancer, 2011,11, 393-410]. For example, cytotoxic derivatives of quinoxaline-2-carbonitrile 1,4-dioxide (for example, a derivative of formula 1) [Scherbakov AM et al. Cancer Invest., 2018, 3, 199-209; Hu Y. et al. Molecules, 2012, 17, 9683-9696], as well as 3-aminoquinoxaline 1,4-dioxide (for example, compounds 2 and 3) [Monge A. et al. J. Med. Chem. 1995, 38, 1786; GB 2297089,1996; Ortega M. et al. Eur. J. Med. Chem., 2000, 35, 21-30; Ismail M.M.F. et al. Eur. J. Med. Chem., 2010, 45, 2733.] are superior in cytotoxicity and hypoxic selectivity, the reference drug tirapazamine.

In addition, described are water-soluble quinoxaline-2-carbonitrile 1,4-dioxides containing residues of cyclic diamines (for example, compound 4), capable of blocking the growth of tumor cells under hypoxic conditions [RU 2640304]. It is also known that quinoxaline-2-carbonitrile 1,4-dioxides have high antiproliferative activity against multidrug-resistant tumor cells [PCT Int. Appl. WO 2015167350, RU 2640304]. It is known that some 2-acyl and 3-trifluoromethyl derivatives are able to suppress the division of tumor cells (for example, derivatives of formulas 5 and 6), however, practical use is hampered by the low solubility of these compounds in aqueous media [Zarranz B. et al. Bioorg. Med. Chem., 2004,12, 3711-3721; Solano B. et al. J. Med. Chem. 2007,50 5485-5492; Das U. et al. Bioorg. Med. Chem., 2009,17, 3909-3915].

The aim of the present invention was to obtain new derivatives of 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with solubility in aqueous media, capable of inducing the death of tumor cells and exhibiting selectivity under hypoxic conditions.

Disclosure of invention

The present invention is intended to obtain more active antitumor derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide, containing fragments of cyclic diamines, increasing the solubility of compounds in aqueous media, with high activity against tumor cells.

The present invention includes derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide corresponding to formula 7, containing in position 2 an acyl or alkoxycarbonyl radical and a cyclic diamine residue linked by one of the nitrogen atoms to the benzene moiety of the quinoxaline ring, their water-soluble salts and solvates or hydrates thereof basis, suitable for use in medicine as therapeutically active substances for the treatment of diseases associated with uncontrolled cell division, especially various solid tumors.

where X is independently C _1-6 alkyl, C _1-6 alkoxy, aryl or heteroaryl moiety, with one heteroatom selected from N, O and S, containing 1, 2, 5 or 6 atoms, optionally substituted with one or several substituents selected from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio or halogen;

Υ - independently means an optionally substituted diamine residue directly linked by one of the nitrogen atoms to the benzene moiety of the quinoxaline ring. Examples of diamines suitable for forming structure 7 include, but are not limited to, cyclic diamines (e.g. piperazine, 1,4-diazepine), amino derivatives of cyclic amines (e.g. 3-aminopyrrolidine, 3-aminopiperidine, 4-aminopiperidine), optionally substituted at nitrogen or carbon with one or more substituents selected from alkyl, hydroxyalkyl;

Ζ - independently means a hydrogen or halogen atom.

The present invention also relates to the use of such compounds as therapeutically active for the treatment of human diseases associated with an increased rate of cell growth (i.e., hyperproliferation), especially oncological diseases of various origins, including, but not limited to, carcinoma, sarcoma, leukemia, etc. ...

The compounds of the present invention can be prepared in a variety of ways. The schemes described below only illustrate the possibility of synthesizing the claimed structures. Starting materials and reagents used in the preparation of compounds of formula 7 are commercial chemicals supplied by companies such as Merck, Acros, Aldrich, or they can be prepared by methods known to the person skilled in the art or described in the literature. ...

Unless otherwise indicated, the reactions described in the description of the application are preferably carried out at atmospheric pressure from about -78 ° C to 180 ° C, more preferably from 0 ° C to 120 ° C in an inert solvent or without it.

One of the methods for the preparation of the 2-acyl-3-trifluoromethylquinoxaline-1,4-dioxides according to formula 7 according to the invention is a method based on the substitution of the leaving groups (LG) at the 6 or 7 positions of 3-trifluoromethylquinoxaline-1,4- dioxide to the residues of diamines (Y) (Scheme A). If necessary, to achieve a more complete conversion of the starting materials and / or a higher yield of the target products during the reaction, additional organic or inorganic bases (B) can be used, and to ensure the selectivity of substitution, the functional groups contained in the diamine residue (Y / Z) can be blocked with protective groups with their subsequent removal.

Starting 3-trifluoromethylquinoxaline 1,4-dioxides 8 can be obtained by various methods, for example, according to the methods described in the literature [Solano B. et al. J. Med. Chem. 2007,50 5485-5492; Zarranz B. et al. Bioorg. Med. Chem., 2004,12, 3711-3721; Perez-Silanes S. et al. Bioorg. Med. Chem. Lett., 2016, 26, 903-906; Benitez D. et al. J. Med. Chem., 2011, 54, 3624-3636; Vicente E. et al. Molecules, 2008,13, 69-77; Torres E. et al. Eur. J. Med. Chem., 2013, 66, 324-334].

Another possible method for preparing the claimed compounds of formula 7 is based on the Beirut reaction of benzofuroxans 9 containing a diamine residue Υ and trifluoromethyl-substituted 1,3-dicarbonyl compounds in the presence of bases C (Scheme B). If necessary, to ensure selectivity of substitution, the functional groups contained in the diamine residue () can also be blocked with protective groups, followed by their removal.

The starting benzofuroxans 9 and trifluoro derivatives of 1,3-dicarbonyl compounds can be obtained by various methods described in the literature [US Pat. RF No. 2640304; Kotovskaya S.K. J. Fluorine Chem. 2004,125,421-428; Wang N.Y. et al. Bioorg. & Med. Chem. Let., 2014, 24, 1581-1588; Stevenson R. et al. Bioorg. Med. Chem., 2018,26,3406-3413; Zhou Y. et al. Tetrahedron, 2014, 70.4668-4674].

In the present invention, the authors have shown that the compounds of formula 7 in submicromolar and micromolar concentrations inhibit the proliferation of all types of investigated tumor cells under conditions of normoxia. In addition, most of the described derivatives of formula 7 have a high antiproliferative activity against tumor cells under hypoxic conditions.

Unless otherwise indicated, the terms used in the description of the application and the claims have the meanings indicated below. It should be noted that, unless otherwise indicated, as used in the description and in the claims, the singular also includes the plural.

"Alkyl" means, unless otherwise indicated, a monovalent saturated hydrocarbon radical with a straight or branched chain or a cyclic radical containing only carbon and hydrogen atoms and containing from 1 to 6 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, and the like.

"Alkoxy" means the radical —OR, where R is the aforementioned alkyl radical. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, isobutoxy, and the like.

"Amino" means the groups —NH ₂ , —NHR ¹ , —NR ¹ R ² , where R ¹ and R ^{2 are} each independently the alkyl radicals defined above. Examples of amino radicals include, but are not limited to, amino, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, and the like.

"Aryl" means, unless otherwise indicated, a monovalent cyclic aromatic hydrocarbon radical containing one or more fused rings, of which at least one ring is aromatic, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkylthio, alkoxy, halogen. Examples of aryl radicals include, but are not limited to, phenyl, biphenyl, naphthyl, indanyl, anthraquinonyl, and the like.

"Halogen" means a radical of fluorine, chlorine, bromine, iodine.

"Teteroaryl" means, unless otherwise indicated, a monovalent aromatic carbocyclic radical containing one or more rings containing one, two or three heteroatoms in the ring (selected from N, O or S), and optionally substituted with a substituent selected from the group consisting of alkyl , alkoxy, alkylthio, halogen Examples of heteroaryl radicals include, but are not limited to, pyrrolyl, furyl, thiophenyl, pyridinyl, and the like.

"Hydroxyalkyl" means an alkyl radical as defined above substituted with one or more, preferably one, two or three hydroxy groups, with the proviso that at most one hydroxy group is attached to one carbon atom. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and the like.

The term "protecting group" refers to a group suitable for blocking a functional group under reaction conditions as described in the literature [Wuts P.G.M. Greene's Protective Groups in Organic Synthesis. J. Wiley & Sons, N.-J., 2014, 1360]. Examples of such groups for blocking an amino group include, but are not limited to, mpem-butoxycarbonyl (Boc), adamantyloxycarbonyl (Adoc), fluorenylmethyloxycarbonyl (Fmoc).

The term "isomers" means compounds with the same molecular formula, but differing in the nature or sequence of chemical bonds or the spatial arrangement of atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". A carbon atom bonded to four different substituents is called a "chiral center".

"Inert organic solvent" means a solvent that is inert under the reaction conditions described herein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, chloroform dichloromethane, dichloroethane, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, vanished, isopropanol, tert-butanol, dioxane, pyridine, etc. Unless otherwise indicated, the solvents used in the reactions of the present invention are inert solvents.

"Optional" or "optional" means that a subsequent event or circumstance can occur, but does not necessarily occur, and that the description includes when that event or circumstance will occur and when it will not. For example, the term "optionally substituted" when used in connection with the term "aryl", "phenyl" or "heteroaryl" means aryl, phenyl, or heteroaryl, which optionally and independently contains from one to four substituents, preferably one or two substituents selected from a group including alkyl, alkylthio, alkoxy, halogen and the like.

"Solvates" means solvated forms containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds are able to hold a fixed number of solvent molecules in the crystal lattice, forming a solvate. Hydrates are formed when water is used as a solvent, and alcoholates are formed when the solvent is alcohol.

"Tautomers" means compounds whose structures differ in the spatial arrangement of atoms, but are in an equilibrium state. Compounds of formula 7 may contain groups that may be in tautomeric equilibrium. It is understood that if the compounds of Formula 7 may exist in tautomeric forms, then the present invention includes all tautomeric forms, and the names of the compounds do not exclude any tautomeric form.

"Leaving group" means a group whose name is usually associated with its use in synthetic organic chemistry, i. E. means an atom or group that is substituted under the reaction conditions. Examples of the leaving group include, but are not limited to, halogen, alkane or arenesulfonyloxy (such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, tosyloxy, and thienyloxy), alkoxy, alkylthio, hydroxy, and the like.

"Pharmacological action" means the term used in the description of the application, includes the results of exposure to a subject, in which the intended goal of therapy is achieved. For example, a pharmacological action means those results of exposure that lead to a cure or slow down the development, prevention of recurrence of the disease.

"Pharmaceutically acceptable" means a substance or material used in both veterinary and pharmaceutical medicine that is generally non-toxic, biologically or otherwise safe.

"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include acid addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, or organic acids such as acetic acid, benzoic acid, citric acid, fumaric acid, glutamic acid, glycolic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, toluenesulfonic acid and the like. Pharmaceutically acceptable salts are intended to include solvates or crystalline forms (polymorphs) of said acid addition salt. Preferred pharmaceutically acceptable salts are the salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, maleic acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium salts.

"Chiral compound" means a compound with one or more chiral centers. This compound has two enantiomeric forms with opposite chirality and can exist both as individual enantiomers and as a mixture of enantiomers. A mixture containing equal amounts of the individual enantiomers is called a "racemic mixture". Compounds containing more than one chiral center can exist as an individual diastereomer or as a mixture of diastereomers, which is called a "diastereomeric mixture". In the presence of a chiral center, stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration means the spatial arrangement of the substituents at the chiral center. These substituents associated with the chiral center are classified according to the rule of Cahn, Ingold and Prelog [Cahn et al., Angew. Chem., 1966, 78, 413].

"Cyclic amine" means a cyclic, predominantly saturated, compound in which one nitrogen atom participates in the formation of the cyclic system. Examples of cyclic amines include, but are not limited to, pyrrolidine, piperidine, azepine, and the like.

"Cyclic diamine" means a cyclic, predominantly saturated, compound in which two nitrogen atoms participate in the formation of a cyclic system. Examples of cyclic diamines include, but are not limited to, piperazine, 1,4-diazepane, and the like.

Typical compounds of the invention, methods of synthesis and biological activity are given in a number of examples described below.

Examples showing the possibility of obtaining new derivatives of quinoxaline 1,4-dioxide, which are the subject of the present invention, as well as their physicochemical properties and ability to inhibit tumor growth, described below, are given only to illustrate the present invention and not to limit the scope of claims.

Example 1

2-Acetyl-7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride

(7-1a)

To a solution of 140 mg (0.48 mmol) 3-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = Η, Scheme A), obtained by the method [Zarranz B . et al. Bioorg. Med. Chem., 2004, 12, 3711-3721], piperazine (210 mg, 2.41 mmol) is added in tetrahydrofuran (10 ml) and the mixture is stirred at room temperature for 3 hours. After the reaction is complete, the reaction mixture is evaporated, the residue is purified by column chromatography (chloroform- methanol, 6: 1). The free base of derivative 7-1а is dissolved in tetrahydrofuran (3 ml), a saturated solution of HCl in diethyl ether (2 ml) is added. The mixture was evaporated and the residue was dissolved in distilled water (1 ml), the solution was filtered, methanol (4 ml) and diethyl ether (10 ml) were added to precipitate the product. The formed precipitate was filtered off and washed with a mixture of methanol-diethyl ether (1: 5, 10 ml), diethyl ether (2 × 10 ml) and hexane (10 ml). Yield 140 mg (83%) 7-1а in the form of a yellow-orange powder. T. pl. 215-217 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 336 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 12.3 min, 94.6% purity UV spectrum nm (EtOH):. 216, 271, 301, 336, 381. ¹ H NMR (400 MHz, DMSO-d _6, δ, ppm . (J, Hz): 9.73 (br.s, 2H, NH ₂ ⁺ ); 8.30 (d, J = 9.6, 1H, H-5); 7.86 (d, J = 9.6, 1H, H-6); 7.51 (s, 1H, H-8); 3.83 (m br, 4H, CH ₂ ); 3.24 (m br, 4H, CH ₂ ); 2.58 (s, 3H, CH ₃ ) Found: m / z (ESI) 357.1197 [M + H] ⁺ C ₁₅ H ₁₆ F ₃ N ₄ O ₃ ⁺ Calculated: 357.1169.

Example 2

2-Acetyl-7- (piperazin-1-yl) -6-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-1b)

Prepared according to a procedure similar to that described in example 1, from 2-acetyl-6,7-difluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = F, scheme A) and piperazine ... The yield is 63%. T. pl. 165-167 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 330 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 10.2 min, purity 95.1%. NMR spectrum ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm, (J, Hz): 9.79 (s, 2H, NH ₂ ⁺ ) ; 8.24 (d, J = 12.9, 1H, H-5); 7.74 (d, J = 7.8, 1H, H-8); 3.65 (m br, 4H, CH ₂ ); 3.29 (m br, 4H , CH ₂ ); 2.59 (s, 3H, CH ₃ ) Found: m / z (ESI), 375.1091 [M + H] ⁺ C ₁₅ H ₁₅ F ₄ N ₄ O ₃ ⁺ . Calculated: 375.1075.

Example 3

2-Acetyl-6- (piperazin-1-yl) -7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-1s)

Received as a minor component in the synthesis of the derivative 7-1b described in example 2. Yield 26%. T. pl. 158-160 ° C (decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 9.6 min, 95.9% purity UV spectrum nm (EtOH):. 216, 274, 334, 381, 423. ¹ H NMR (400 MHz, DMSO-d _6), δ, m. d., (J, Hz): 9.79 (s, 2H, NH ₂ ⁺ ); 8.24 (d, J = 12.9, 1H, H-5); 7.74 (d, J = 7.8, 1H, H-8); 3.65 (m br, 4H, CH ₂ ); 3.29 (m br, 4H, CH ₂ ); 2.59 (s, 3H, CH ₃ ) Found: m / z (ESI), 375.1167. [M + H] ⁺ C ₁₅ H ₁₅ F ₄ N ₄ O ₃ ⁺ . Calculated: 375.1075.

Example 4

2-Acetyl-7- (piperazin-1-yl) -3-trifluoromethyl-6-chloroquinoxaline 1,4-dioxide

hydrochloride (7-1d)

Prepared according to a procedure similar to that described in example 1, from 2-acetyl-3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = Cl, Ζ = Cl, scheme A) and piperazine ... The yield is 78%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 340 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 14.0 min, 95.2% purity UV spectrum nm (EtOH):. 222, 244, 282, 342, 391. ¹ H NMR (400 MHz, DMSO-d _6), δ, m. d. (J, Hz): 9.82 (br.s, 2H, NH ₂ ⁺ ); 8.52 (s, 1H, H-5); 7.86 (s, 1H, H-8); 3.53-3.51 (m, 4H , CH ₂ ); 3.31-3.30 (m, 4H, CH ₂ ); 2.60 (s, 3H, CH ₃ ) Found: m / z (ESI), 391.0797. [M + H] ⁺ C ₁₅ H ₁₅ ClF ₃ N ₄ O ₃ ⁺ . Calculated: 391.0779.

Example 5

2-Acetyl-7- (2-hydroxyethylpiperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-1e)

To a solution of 150 mg (0.52 mmol) of 3-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = H, Scheme A) in N, N-dimethylformamide ( 5 ml), N- (2-hydroxyethyl) piperazine (170 mg, 1.3 mmol) is added and the mixture is stirred at room temperature for 5 h. Ice water (10 ml) is added to the reaction mixture, the precipitate formed is filtered and air-dried. The product was purified by column chromatography (chloroform-methanol, 5: 1). 152 mg (73%) of the free base 7-1e are obtained. The free base of the derivative 7-1е is dissolved in tetrahydrofuran (3 ml), a saturated solution of HCl in diethyl ether (2 ml) is added. The mixture was evaporated, the residue was dissolved in distilled water (2 ml), the solution was filtered, methanol (2 ml) and diethyl ether (10 ml) were added to precipitate the product. The formed precipitate was filtered off and washed with a mixture of methanol-diethyl ether (1: 5, 10 ml), diethyl ether (2 × 10 ml) and hexane (10 ml). 140 mg (67%) of 7-1e are obtained in the form of an orange powder. T. pl. 227-229 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 - »80% (35 min): Rt = 8.3 min, purity 94.9%. UV spectrum, nm (EO * H): 217.270, 299, 336, 380. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, m d (J, Hz): 11.38 (br.s, 1H, NH ⁺ ); 8.31 (d, J = 9.8, 1H, H-5); 7.89 (d, J = 9.8, 1H, H-6) ; 7.53 (s, 1H, H-8); 5.44 (br.s, 1H, OH); 4.28 (br.m, 2H, CH ₂ ); 3.84 (br.m, 2H, CH ₂ ); 3.64-3.59 (m, 4H, CH ₂ ); 3.26-3.25 (m, 4H, CH ₂ ); 2.59 (s, 3H, CH ₃ ) Found: m / z (ESI), 401.1460. [M + H] ⁺ C ₁₇ H ₂₀ F ₃ N ₄ O ₄ ⁺ . Calculated: 401.1431.

Example 6

2-Acetyl-7- (2-hydroxyethylpiperazin-1-yl) -3-trifluoromethyl-6-chloroquinoxaline 1,4-dioxide hydrochloride (7-If)

Prepared according to a procedure similar to that described in example 5, from 2-acetyl-3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = Cl, Ζ = Cl, scheme A) and N -2-hydroxyethylpiperazine. Output 70%. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 250 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% (45 min): Rt = 9.5 min, purity 95.4%. NMR spectrum ¹ Н (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.55 (s, 1Н, Н -8); 7.87 (s, 1H, H-5); 5.42 (br.s, 1H, OH); 3.81 (br.m, 2H, CH ₂ OH); 3.78-3.68 (m, 4H, CH ₂ ) ; 3.32-3.25 (m br, 6H, CH ₂ ); 2.60 (s, 3H, CH ₃ ) Found: m / z (ESI), 435.1019. [M + H] ⁺ C ₁₇ H ₁₉ ClF ₃ N ₄ O ₄ ⁺ . Calculated: 435.1041.

Example 7

2-Acetyl-6- (2-hydroxyethylpiperazin-1-yl) -3-trifluoromethyl-7-chloroquinoxaline 1,4-dioxide hydrochloride (7-1g)

Received as a minor component in the synthesis of the derivative 7-1f described in example 6. Yield 21%. T. pl. 181-182 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 250 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 9.7 min, purity 97.1% NMR ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.55 (s, 1H, H-8); 7.87 (s, 1H, H-5); 5.42 (br.s, 1H, OH); 3.81 (br.m, 2H, CH ₂ OH); 3.78-3.68 (m, 4H, CH ₂ ); 3.32-3.25 (br m, 6H, CH ₂ ); 2.60 (s, 3H, CH ₃ ) Found: m / z (ESI), 435.1031. [M + H] ⁺ C ₁₇ H19ClF ₃ N ₄ O4 ⁺ . Calculated: 435.1041 ...

Example 8

2-Acetyl-7- (homopiperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-1h)

Prepared according to a procedure similar to that described in example 1, from 2-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = Η, scheme A) and homopiperazine. The yield is 41%. T. pl. 254-257 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 10.1 min, purity 96.7%. NMR spectrum ¹ Н (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 9.58 (br.s, 2Н, ΝΗ ₂ ⁺ ; 8.27 (d, J = 9.8, 1H, H-5); 7.74 (dd, J ¹ = 9.8, J ² = 2.7, 1H, H-5); 7.30 (d, J = 2.7, 1H, H-8 ); 3.99 (m br, 2H, CH ₂ ); 3.76 (t, J = 5.9, 2H, CH ₂ ); 3.30 (m br, 2H, CH ₂ ); 3.14 (m br, 2H, CH ₂ ); 2.59 (s, 3H, CH ₃ ); 2.19 (m br, 2H, CH ₂ ) Found: m / z (ESI), 371.1334. [M + H] ⁺ C ₁₆ H ₁₈ F ₃ N ₄ O ₃ ⁺ Calcd. 371.1326.

Example 9

2-Acetyl-7- (methylhomopiperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-1j)

Prepared according to a procedure similar to that described in example 5, from 3-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = H, scheme A) and-methyl homopiperazine ... The yield is 47%. T. pl. 245-246 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 8.6 min, purity 95.6% UV spectrum, nm (EtOH): 218, 267, 337, 381, 484. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. d. (J, Hz): 11.40 (br.s, 1H, NH ⁺ ); 8.27 (dd, J = 9.4, J = 5.1, 1H, H-5); 7.74 (d, J = 9.4, 1H, H -6); 7.27 (s, 1H, H-8); 4.05 (br.m, 2H, CH ₂ ); 3.68 (br.m, 2H, CH ₂ ); 3.40 (br.m, 4H, CH ₂ ) ; 3.30-3.14 (m, 2H, CH ₂ ); 2.79 (s, 3H, NCH ₃ ); 2.59 (s, 3H, COCH ₃ ) Found: m / z (ESI), 385.1535. [M + H] ⁺ C ₁₇ H ₂₀ F ₃ N ₄ O ₃ ⁺ . Calculated: 385.1482.

Example 10

7- (4-Aminopiperidin-1-yl) -2-acetyl-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-1k)

To a solution of 150 mg (0.51 mmol) of 2-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = H, Scheme A) in tetrahydrofuran (4 ml) is added 4-N-Boc-aminopiperidine (258 mg, 1.3 mmol) and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated, the residue was purified by column chromatography (chloroform-ethyl acetate, 30: 1). 168 mg (89%) of Boc derivative 7-1k are obtained. The semi-product is dissolved in tetrahydrofuran (2 ml), a saturated solution of HCl in diethyl ether (2 ml) is added and the mixture is stirred for 2 hours.The reaction mixture is evaporated, and the residue is dissolved in distilled water (2 ml), the solution is filtered, methanol (2 ml) is added and diethyl ether (10 ml) to precipitate the product. The formed precipitate was filtered off and washed with a mixture of methanol-diethyl ether (1:10, 10 ml), diethyl ether (2 × 10 ml) and hexane (10 ml). 151 mg (80%) 7-1k are obtained in the form of an orange powder. T. pl. 240-242 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 490 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 9.0 min, 96.9% purity UV spectrum nm (EtOH):. 218, 268, 338, 382, 489. ¹ H NMR (400 MHz, DMSO-d _6), δ, m. d. (J, Hz): 8.47 (br.s, 3H, NH ₃ ⁺ ); 8.25 (d, J = 9.8, 1H, H-5); 7.85 (dd, J = 9.8, J = 1.9.1H, H-6); 7.42 (s, 1H, H-8); 4.18 (d, J = 12.9, 2H, CH ₂ ); 3.37-3.34 (m, 1H, CH); 3.17 (t, J = 9.8, 2H , CH ₂ ); 2.58 (s, 3H, CH ₃ ); 2.08 (d, J = 10.9, 2H, CH ₂ ); 1.64 (q, J = 10.9, 2H, CH ₂ ) Found: m / z (ESI ), 371.1343. [M + H] ⁺ C ₁₆ H ₁₈ F ₃ N ₄ O ₃ ⁺ . Calculated: 371.1326.

Example 11

7- (4-Aminopiperidin- -yl) -2-acetyl-6-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-11)

Prepared according to a procedure similar to that described in example 10, from 2-acetyl-6,7-difluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₃ , LG = F, Ζ = F, scheme A) and 4 -Bos-aminopiperidine. The yield is 64%. T. pl. 221-223 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 80% (45 min): Rt = 10.3 min, purity 97.6%. UV spectrum, nm (EtOH): 219, 275, 336, 388, 448. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm . (J, Hz): 8.48 (br.s, 3H, NH ₃ ⁺ ); 8.21 (d, J = 12.9, 1H, H-5); 7.67 (d, J = 8.2, 1H, H-8); 3.79 (d, J = 12.9, 2H, CH ₂ ); 3.30 (br m, 1H, CH); 3.10 (t, J = 12.9.2H, CH ₂ ); 2.58 (s, 3H, CH ₃ ); 2.12 (d, J = 10.9, 2H, CH ₂ ); 1.76 (q, J = 10.9.2H, CH ₂ ) Found: m / z (ESI), 389.1261. [M + H] ⁺ C ₁₆ H ₁₇ F ₄ N ₄ O ₃ ⁺ . Calculated: 389.1231.

Example 12

6- (4-Aminopiperidin-1-yl) -2-acetyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-1m)

Received as a minor component in the synthesis of derivative 7-11 described in example 11. Yield 17%. T. pl. 230-231 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 345 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 9.8 min, purity 95.3% UV spectrum, nm (EtOH): 217, 272, 343, 382. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. (J, Hz): 8.48 (br.s, 3H, NH ₃ ⁺ ); 8.21 (d, J = 12.9, 1H, H-5); 7.67 (d, J = 8.2, 1H, H-8); 3.79 (d, J = 12.9, 2H, CH ₂ ); 3.30 (br m, 1H, CH); 3.10 (t, J = 12.9, 2H, CH ₂ ); 2.58 (s, 3H, COCH ₃ ); 2.12 (d, J = 10.9, 2H, CH ₂ ); 1.76 (q, J = 10.9, 2H, CH ₂ ) Found: m / z (ESI), 389.1250. [M + H] ⁺ C ₁₆ H ₁₇ F ₄ N ₄ O ₃ ⁺ . Calculated: 389.1231.

Example 13

7- (Piperazin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide

methanesulfonate (7-2а)

To a solution of 150 mg (0.49 mmol) 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = H, scheme A), obtained by the method [ Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721], piperazine (210 mg, 2.41 mmol) is added in tetrahydrofuran (10 ml) and the reaction mixture is stirred at room temperature. After completion of the reaction (monitoring by TLC), the reaction mixture was evaporated, the residue was purified by column chromatography (chloroform-methanol, 6: 1). The free base of derivative 7-2а was dissolved in chloroform (3 ml), a solution of methanesulfonic acid (58 mg, 0.61 mmol) in chloroform (1 ml) was added and stirred for 3 h. The reaction mixture was evaporated, and the residue was dissolved in distilled water (1 ml), the solution was filtered, methanol (2 ml) and diethyl ether (10 ml) were added to precipitate the product. The formed precipitate was filtered off and washed with a mixture of methanol-diethyl ether (1: 5, 10 ml), diethyl ether (2 × 10 ml) and hexane (10 ml). 138 mg (76%) of 7-2a are obtained in the form of a yellow-orange powder. T. pl. 200-201 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 16.2 min, purity 95.5%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.99 (br.s, 2H, NH ₂ ⁺ ); 8.31 (d, J = 8.0, 1H, H-5); 7.86 (d, J = 8.0, 1H, H-6); 7.52 (s, 1H, H-8); 3.79 (m br, 4H , CH ₂ ); 3.45 (m br, 4H, CH ₂ ); 2.90 (m br, 2H, SOSN ₂ CH ₃ ); 2.41 (s, 3H, CH ₃ SO ₃ ); 1.14 (m br, 3H , СОСН ₂ СН ₃ ). Found: m / z (ESI), 371.1346. [М + Н] ⁺ C ₁₁ H ₄ F ₇ N ₂ O ₃ ⁺ . Calculated: 371.1326. Found,%: С 43.69, Η 4.86, N 12.17; calculated for C ₁₆ H ₁₇ F ₃ N ₄ O ₃ * MsOH * 2H ₂ 0,%: C, 43.78; H, 4.54; N, 12.01.

Example 14

7- (Piperazin-1-yl) -2-propionyl-6-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-2b)

Prepared according to a procedure similar to that shown in example 1, from 2-propionyl-6,7-difluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = F, Scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. Yield 58%. T. pl. 233-235 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 14.5 min, purity 94.9% UV spectrum, nm (EtOH): 216, 274, 335, 388. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. , (J, Hz): 9.77 (br.s, 2H, NH ₂ ⁺ ); 8.24 (d, J = 12.9, 1H, H-5); 7.74 (d, J = 8.2, 1H, H-8); 3.64 (br.m, 4H, CH ₂ ); 3.37-3.35 (m, 4H, CH ₂ ); 2.90 (q, J = 7.3, 2H, COCH ₂ CH ₃ ); 1.14 (t, J = 7.3, 3H , СОСН ₂ СН ₃ ). Found: m / z (ESI), 389.1221. [М + Н] ⁺ C ₁₆ H ₁₇ F ₄ N ₄ O ₃ ⁺ . Calculated: 389.1231. Found,%: С 43.47, Η 4.29, N 12.66; calculated for C ₁₆ H ₁₆ F ₄ N ₄ O ₃ * HCl * H ₂ O,%: C, 43.40; H, 4.33; N, 12.65.

Example 15

7- (Piperazin-1-yl) -2-propionyl-3-trifluoromethyl-6-chloroquinoxaline 1,4-dioxide

methanesulfonate (7-2s)

To a solution of 140 mg (0.39 mmol) 6- (4-Boc-piperazin-1-yl) -5-chlorobenzofuroxan (9, Ζ = Cl, Υ = 4-Boc-piperazin-1-yl, Scheme B)), obtained according to the method [RU 2640304], and 332 mg (1.97 mmol) of 1,1,1-trifluorohexane-2,4-dione (X = CH ₂ CH ₃ , scheme B) in chloroform (10 ml) add triethylamine (7 mg; 0.05 mmol) and the reaction mixture was stirred at room temperature for 4 h. The precipitate formed was filtered off, washed with chloroform (3 × 1 ml), and reprecipitated from a mixture of methylene chloride - petroleum ether. 111 mg (54%) of Boc-derivative 7-2c are obtained.

The semi-product is dissolved in chloroform (5 ml), a solution of methanesulfonic acid (58 mg, 0.61 mmol) in chloroform (1 ml) is added, the mixture is stirred for 1 h, and the reaction mixture is evaporated. The residue was dissolved in distilled water (2 ml), the solution was filtered, methanol (2 ml) and diethyl ether (10 ml) were added to precipitate the product. The formed precipitate was filtered off and washed with a mixture of methanol-diethyl ether (1: 5, 10 ml), diethyl ether (2 × 10 ml) and hexane (10 ml). 51 mg (45%) of 7-2s are obtained in the form of a yellow powder. T. pl. 243-246 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 15.8 min, purity 97.3%. NMR spectrum ¹ Н (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 9.03 (br.s, 2Н, NH ₂ ⁺ ); 8.51 (s, 1H, H-8); 7.85 (s, 1H, H-5); 3.47 (m br, 4H, CH ₂ ); 3.35 (m br, 4H, CH ₂ ); 2.90 ( q, J = 6.8, 2H, COCH ₂ CH ₃ ); 2.43 (s, 3H, CH ₃ SO ₃ ^- ); 1.13 (t, J = 6.8, 3H, COCH ₂ CH ₃ ); Found: m / z ( ESI) 405.0947 [M + H] ⁺ C ₁₆ H ₁₇ ClF ₃ N ₄ O ₃ ⁺ Calculated: 405.0936.

Example 16

7- (3-Methylpiperazin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide

methanesulfonate (7-2d)

Prepared according to a procedure similar to that described in example 10, from 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = Η, scheme A) and 1 -Boc-2-methylpiperazine. The yield is 84%. T. pl. 257-258 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 295 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 13.5 min, purity 98.4%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 9.29-8.98 (m, 2H, ⁺ NH ₂ ); 8.29 (d, J = 9.4, 1H, H-5); 7.88 (d, J = 9.4, 1H, H-6); 7.52 (s, 1H, H-8); 4.28-4.19 (m, 2H , CH ₂ ); 3.46-3.34 (m, 3H, CH, CH ₂ ); 3.20-3.12 (m, 2H, CH ₂ ); 2.89 (q, J = 6.8, 2H, COCH ₂ CH ₃ ); 2.43 (s , 3H, CH ₃ S0 ₃ ^- ); 1.33 (d, J = 5.9, 3H, CH ₃ ); 1.13 (t, J = 6.8, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 385.1476 [M + H] ⁺ C ₁₇ H ₂₀ F ₃ N ₄ O ₃ ⁺ Calculated: 385.1482.

Example 17

2-Propionyl-3-trifluoromethyl-7- (ethylpiperazin-1-yl) quinoxaline 1,4-dioxide

hydrochloride (7-2e)

Prepared according to a procedure similar to that described in example 5, from 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = Η, scheme A) and Ν -ethylpiperazine. Output 81%. T. pl. > 250 ° С (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 12.2 min, purity 96.9%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 11.61 (m br, 2H, ⁺ NH ₂ ); 8.32 (d, J = 9.4, 1H, H-5); 7.88 (d, J = 9.4, 1H, H-6); 7.54 (d, J = 9.4, 1H, H-8); 4.30 (q , J = 12.9, 2H, -NCH ₂ CH ₃ ); 3.61-3.48 (m, 4H, CH ₂ ); 3.18-3.10 (m, 4H, CH ₂ ); 2.90 (q, J = 6.6, 2H, COCH ₂ CH ₃ ); 1.30 (t, J = 7.0, 3H, -NCH ₂ CH ₃ ); 1.14 (t, J = 7.4, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 399.1645. [М + H] ⁺ C ₁₈ H ₂₂ F ₃ N ₄ O ₃ ⁺ . Calculated: 399.1639.

Example 18

7- (2-Hydroxyethylpiperazin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-2f)

Prepared according to a procedure similar to that shown in example 5, from 2-propionyl-7-φτορ-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = Η, scheme A) and Ν - (2-hydroxyethyl) piperazine. The yield is 51%. Mp> 250 ° С (decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 320 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 10.6 min, purity 97.2%. UV spectrum, nm (EtOH): 217, 270, 298, 337, 382. NMR spectrum Ή (400 MHz, DMSO-d ₆ ), δ, ppm . (J, Hz): 11.02 (br.s, 2H, NH ₂ ⁺ ); 8.33 (d, J = 9.8, 1H, H-5); 7.88 (d, J = 9.8, 1H, H-8); 7.55 (s, 1H, H-8); 5.42 (br.s, 1H, OH); 3.82 (br.m, 2H, CH ₂ ); 3.65 (br.m, 2H, CH ₂ OH); 3.54 (br .m, 2H, CH ₂ CH ₂ OH); 3.25 (br.m, 2H, CH ₂ ); 2.90 (q, J = 6.8, 2H, COCH ₂ CH ₃ ); 1.14 (t, J = 6.8, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 415.1556 [M + H] ⁺ C ₁₈ H ₂₂ F ₃ N ₄ O ₄ ⁺ Calculated: 415.1588.

Example 19

7- (4-Aminopiperidin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-2g)

Prepared according to a procedure similar to that described in example 10, from 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = H, scheme A) and 4 -N-Boc-aminopiperidine. The yield is 63%. T. pl. 243-245 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 340 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 11.2 min, purity 98.8% UV spectrum, nm (EtOH): 219, 269, 339, 383.486 ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.47 (br.s, 3H, NH ₃ ⁺ ; 8.25 (d, J = 8.9, 1H, H-5); 7.84 (d, 7 = 8.9, 1H, H-6); 7.41 ( s, 1H, H-8); 4.18 (d, J = 13.3, 2H, CH ₂ ); 3.38 (br m, 1H, CH); 3.17 (t, J = 13.3, 2H, CH ₂ ); 2.89 ( q, J = 7.0, 2H, COCH ₂ CH ₃ ); 2.09 (d, J = 10.9, 2H, CH ₂ ); 1.64 (q, J = 10.9, 2H, CH ₂ ); 1.13 (t, J = 7.0 , 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 385.1464 [M + H] ⁺ C ₁₇ H ₂₀ F ₃ N ₄ O ₃ ⁺ . Calculated: 385.1482.

Example 20

7- (4-Aminopiperazin-1-yl) -2-propionyl-6-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-2h)

Prepared according to a procedure similar to that shown in example 10, from 2-propionyl-6,7-difluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = F, Scheme A) and 4-N-Boc-aminopiperidine. Yield 49%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 14.1 min, purity 95.3%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.19 (d, J = 12.9, 1H, H -5); 8.06 (br.s, 3H, NH ₃ ⁺ ); 7.66 (d, J = 7.8, 1H, H-8); 3.77 (d, J = 12.3, 2H, CH ₂ ); 3.32 (br. m, 1H, CH); 3.10 (t, J = 12.3, 2H, CH ₂ ); 2.89 (q, J = 6.6, 2H, COCH ₂ CH ₃ ); 2.08 (d, J = 10.7, 2H, CH ₂ ) ; 1.72 (q, J = 10.7, 2H, CH ₂ ); 1.13 (t, J = 6.6, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 403.1310. [M + H] ⁺ C ₁₇ H ₁₉ F ₄ N ₄ O ₃ ⁺ . Calculated: 403.1388.

Example 21

7- (4-Aminopiperazin-1-yl) -2-propionyl-3-trifluoromethyl-6-chloroquinoxaline 1,4-dioxide hydrochloride (7-2j)

Prepared according to a procedure similar to that described in example 10, from 2-propionyl-3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = Cl, Ζ = Cl, scheme A) and 4-N-Boc-aminopiperidine. Yield 60%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 295 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 12.9 min, 95.2% purity UV spectrum nm (EtOH):. 228, 285.345, 393. ¹ H NMR (400 MHz, DMSO-d ₆₎ 6 ppm (J , Hz): 8.41 (br.s, 3H, NH ₃ ⁺ ); 8.46 (s, 1H, H-8); 7.79 (s, 1H, H-5); 3.61 (d, J = 12.1, 2H, CH ₂ ); 3.26 (br.m, 1H, CH); 2.97 (t, J = 11.3, 2H, CH ₂ ); 2.87 (q, J = 7.0.2H, COCH ₂ CH ₃ ); 2.11 (d, J = 11.3,2H, CH ₂ ); 1.79 (q, J = 11.3, 2H, CH ₂ ); 1.12 (t, J = 7.0, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 419.1053. [ M + H] ⁺ C ₁₇ H ₁₉ ClF ₃ N ₄ O ₃ ⁺ Calculated: 419.1092.

Example 22

6- (4-Aminopiperazin-1-yl) -2-propionyl-3-trifluoromethyl-7-chloroquinoxaline 1,4-dioxide hydrochloride (7-2k)

Received as a minor component in the synthesis of the derivative 7-2j described in example 21. Yield 22%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 330 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80 % (45 min): Rt = 13.7 min, purity 95.0% UV spectrum, nm (EtOH): 228, 285, 345, 393. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. d. (J, Hz): 8.41 (br.s, 3H, NH ₃ ⁺ ); 8.46 (s, 1H, H-8); 7.79 (s, 1H, H-5); 3.61 (d, J = 12.1 , 2H, CH ₂ ); 3.26 (br m, 1H, CH); 2.97 (t, J = 11.3, 2H, CH ₂ ); 2.87 (q, J = 7.0.2H, COCH ₂ CH ₃ ); 2.11 ( d, J = 11.3, 2H, CH ₂ ); 1.79 (q, J = 11.3, 2H, CH ₂ ); 1.12 (t, J = 7.0, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI) , 419.1067 [M + H] ⁺ C ₁₇ H ₁₉ ClF ₃ N ₄ O ₃ ⁺ . Calculated: 419.1092.

Example 23

7- (Homopiperazin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-21)

Prepared according to a procedure similar to that described in example 1, from 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = H, scheme A) and homopiperazine ... The yield is 35%. T. pl. 215-216 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 11.7 min, purity 90.8%. NMR spectrum ¹ Н (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 9.52 (br.s, 2Н, ⁺ NH ₂ ); 8.28 (d, J = 8.7, 1H, H-5); 7.73 (d, J = 8.7, 1H, H-6); 7.30 (s, 1H, H-8); 3.98 (m br, 2H , CH ₂ ); 3.76 (br.m., 2H, CH ₂ ); 3.30 (br.m., 2H, CH ₂ ); 2.90 (q, J = 6.3, 3H, SOSN ₂ CH ₃ ); 2.19 (br.m , 2H, CH ₂ ); 1.13 (t, J = 6.3, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI), 385.1471. [M + H] ⁺ C ₁₇ H ₂₀ F ₃ N ₄ O ₃ ⁺ . Calculated: 385.1482.

Example 24

7- (4-Methylhomopiperazin-1-yl) -2-propionyl-3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-2 t)

Prepared according to a procedure similar to that described in example 5, from 2-propionyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = CH ₂ CH ₃ , LG = F, Ζ = Η, scheme A) and Ν -methyl homopiperazine. The yield is 31%. T. pl. 240-242 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 320 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 10.9 min, purity 95.1% UV spectrum, nm (EtOH): 218, 268, 305, 338, 382. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. d (J, Hz): 11.46 (br.s, 1H, NH ⁺ ); 8.27 (d, J = 9.4, 1H, H-5); 7.75 (d, J = 9.4, 1H, H-6); 7.26 (s, 1H, H-8); 4.13-3.93 (m, 2H, CH ₂ ); 3.67-3.56 (m, 4H, CH ₂ ); 3.27-3.15 (m, 2H, CH ₂ ); 2.89 (q , J = 7.0, 2H, COCH ₂ CH ₃ ); 2.78 (s, 3H, NCH ₃ ); 2.24-2.21 (m, 2H, CH ₂ ); 1.13 (t, J = 7.0, 3H, COCH ₂ CH ₃ ) Found: m / z (ESI) 399.1704 [M + H] ⁺ C ₁₈ H ₂₂ F ₃ N ₄ O ₃ ⁺ . Calculated: 399.1639.

Example 25

7- (Piperazin-1-yl) -3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-dioxide

hydrochloride (7-3а)

Prepared according to a procedure similar to that described in example 1, from 7-fluoro-3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-dioxide (8, X = OCH ₂ CH ₃ , LG = F, Ζ = Η, scheme A) obtained according to the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperase. The yield is 46%. T. pl. 185-187 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 60% ( 45 min): Rt = 12.9 min, purity 95.6% UV spectrum, nm (EtOH): 272, 302, 337, 382. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. (J, Hz): 9.64 (br.s, 2H, NH ₂ ⁺ ); 8.27 (d, J = 9.0, 1H, H-5); 7.84 (d, J = 9.0, 1H, H-6); 7.48 (s, 1H, H-8); 4.45 (q, J = 7.0, 2H, OCH ₂ CH ₃ ); 3.82 (m, 4H, CH ₂ ); 3.27 (m, 4H, CH ₂ ); 1.32 (t, J = 7.0, 3H, OCH ₂ CH ₃ ) Found: m / z (ESI), 387.1250 [M + H] ⁺ C ₁₆ H ₁₈ F ₃ N ₄ O ₄ ⁺ . Calculated: 387.1275.

Example 26

7- (Piperazin-1-yl) -6-fluoro-3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-dioxide hydrochloride (7-3b)

Prepared according to a procedure similar to that described in example 1, from 6,7-difluoro-3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-dioxide (8, X = OCH ₂ CH ₃ , LG = F, Ζ = F, Scheme A) and piperazine. The yield is 42%. T. pl. 211-213 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 335 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN;

gradient B 20 → 80% (45 min): Rt = 11.9 min, purity 95.5%. UV spectrum, nm (EtOH): 215, 275, 337, 388. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. (J, Hz): 9.69 (s, 2H, NH ₂ ⁺ ); 8.24 (d, J = 12.9, 1H, H-5); 7.73 (d, J = 8.2, 1H, H-8); 4.47 (q, J = 7.0, 2H, OCH ₂ CH ₃ ); 3.62 (m br, 2H, CH ₂ ); 3.29 (m br, 4H, CH ₂ ); 1.32 (t, J = 7.0, 3H, OCH ₂ CH ₃ ). Found: m / z (ESI), 405.1233. [M + H] ⁺ C _l6 H ₁₇ F ₄ N ₄ O ₄ ⁺ . Calculated: 405.1180.

Example 27

6- (Piperazin-1-yl) -7-fluoro-3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-

dioxide hydrochloride (7-3s)

Received as a minor component of the product in the synthesis of the derivative 7-3 s described in example 26. Yield 34%. T. pl. 226-228 ° C (with decomp.). HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 340 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 11.3 min, 96.5% purity UV spectrum nm (EtOH):. 213, 272, 342, 382. ¹ H NMR (400 MHz, DMSO-d _6), δ, ppm (J, Hz): 9.69 (s, 2H, NH ₂ ⁺ ); 8.24 (d, J = 12.9.1H, H-5); 7.73 (d, J = 8.2, 1H, H-8); 4.47 (q , J = 7.0, 2H, OCH ₂ CH ₃ ); 3.62 (br m, 2H, CH ₂ ); 3.29 (br m, 4H, CH ₂ ); 1.32 (t, J = 7.0, 3H, OCH ₂ CH ₃ ) Found: m / z (ESI) 405.1221 [M + H] ⁺ C ₁₆ H ₁₇ F ₄ N ₄ O ₄ ⁺ Calculated: 405.1180.

Example 28

7- (Piperazin-1-yl) -3-trifluoromethyl-6-chloro-2-ethoxycarbonylquinoxaline 1,4-

dioxide methanesulfonate (7-3d)

Prepared by a method similar to that described in example 15, from 6- (4-Boc-piperazin-1-yl) -5-chlorobenzofuroxan (9, Ζ = Cl, Υ = 4-Boc-piperazin-1-yl, scheme B) , obtained by the method [RU 2640304], and ethyl 4,4,4-trifluoroacetoacetate (X = OCH ₂ CH ₃ , Scheme B). The yield is 83%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 280 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80 % (45 min): Rt = 13.9 min, 96.6% purity UV spectrum nm (EtOH):. 235, 267, 282, 345, 393. ¹ H NMR (400 MHz, DMSO-d ₆₎ 6 ppm: 8.97 (br.s, 2H, NH ₂ ⁺ ); 8.50 (s, 1H, H-8); 7.86 (s, 1H, H-5); 4.47 (q, .7 = 7.0, 2H , OCH ₂ CH ₃ ); 4.31 (m br, 4H, CH ₂ ); 3.46 (m br, 4H, CH ₂ ); 1.32 (q, J = 7.0, 3H, OCH ₂ CH ₃ ). Found: m / z (ESI) 421.0883 [M + H] ⁺ C ₁₆ H ₁₇ ClF ₃ N ₄ O4 ⁺ Calculated: 421.0885.

Example 29

7- (4-Aminopiperidin-1-yl) -3-trifluoromethyl-6-chloro-2-ethoxycarbonylquinoxaline

1,4-dioxide hydrochloride (7-Ze)

Prepared according to a procedure similar to that described in example 10, from 3-trifluoromethyl-6,7-dichloro-2-ethoxycarbonylquinoxaline 1,4-dioxide (8, X = OCH ₂ CH ₃ , LG = Cl, Ζ = Cl, Scheme A) and 4-N-Boc-aminopiperidine. The yield is 52%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 254 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 60% ( 30 min): Rt = 14.4 min, purity 90.9% NMR ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.45 (s, 1H, H-8); 8.24 (br.s, 3H, NH ₃ ⁺ ); 7.78 (s, 1H, H-5); 4.45 (q, .7 = 6.8, 2H, OCH ₂ CH ₃ ); 3.61 (d, J = 10.6, 2H , CH ₂ ); 3.26 (br m, 1H, CH); 2.96 (d, J = 10.6.2H, CH ₂ ); 2.10 (d, J = 9.0, 2H, CH ₂ ); 1.76 (q, J = 9.0, 2H, CH ₂ ); 1.30 (t, J = 6.8, 3H, OCH ₂ CH ₃ ) Found: m / z (ESI), 435.1038. [M + H] ⁺ C ₁₆ H ₁₇ ClF ₃ N ₄ O ₄ ⁺ Calcd. 435.1041.

Example 30

2-Benzoyl-7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride

(7-4a)

Prepared according to a procedure similar to that shown in example 1, from 2-benzoyl-7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = C ₆ H ₅ , LG = F, Ζ = Η, scheme A) obtained according to the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004,12, 3711-3721] and piperazine. The yield is 76%. T. pl. 258-159 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 340 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 90% (45 min): Rt = 16.0 min, 95.4% purity UV spectrum nm (EtOH):. 206, 275, 340, 383. ¹ H NMR (400 MHz, DMSO-d ₆₎ 6 ppm ( J, Hz): 9.65 (br.s, 2H, NH ₂ ⁺ ); 8.38 (d, J = 9.8, 1H, H-5); 8.09 (d, J = 7.8, 2H, C ₆ H ₅ ); 7.89 (d, J = 9.8, 1H, H-6); 7.75 (t, J = 7.8, 1H, C ₆ H ₅ ); 7.58 (t, J = 7.8, 2H, C ₆ H ₅ ); 7.49 (s, 1H, H-8); 3.82 (m br, 4H, CH ₂ ); 3.25 (m br, 4H, CH ₂ ) Found: m / z (ESI), 419.1327. [M + H] ⁺ C ₂₀ H ₁₈ F ₃ N ₄ O ₃ ⁺ . Calculated: 419.1326.

Example 31

2-Benzoyl-7- (piperazin-1-yl) -6-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-4b)

Prepared according to a procedure similar to that described in example 1, from 2-benzoyl-6,7-difluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = C ₆ H ₅ , LG = F, Ζ = F, Scheme A) and piperazine. The yield is 53%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 270 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 -> 80% (45 min): Rt = 14.7 min, purity 95.1% UV spectrum, nm (EtOH): 271, 338, 391. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm, (J, Hz): 9.71 (br.s, 2H, NH ₂ ⁺ ); 8.32 (d, J = 12.5, 1H, H-5); 8.10 (d, J = 8.2, 2H, C ₆ H ₅ ); 7.76 (t, J = 7A, 1H, C ₆ H ₅ ); 7.71 (d, J = 8.2, 1H, H-8); 7.59 (t, J = 7.4, 2H, C ₆ H ₅ ); 3.62 (br .m, 4H, CH ₂ ); 3.29 (m br, 4H, CH ₂ ) Found: m / z (ESI), 437.1253. [M + H] ⁺ C ₂₀ H ₁₇ F ₄ N ₄ O ₃ ⁺ . Calculated: 437.1231.

Example 32

2-Benzoyl-7- (piperazin-1-yl) -3-trifluoromethyl-6-chloroquinoxaline 1,4-dioxide

hydrochloride (7-4 s)

Prepared by a method similar to that described in example 1, from 2-benzoyl-3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = C ₆ H ₅ , LG = Cl, Ζ = Cl, scheme A) and piperazine. The yield is 84%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 345 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 17.5 min, purity 94.6% UV spectrum, nm (EtOH): 258, 284, 345, 394. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. (J, Hz): 9.88 (br.s, 2H, NH ₂ ⁺ ), 8.57 (s, 1H, H-8); 8.10 (d, J = 7.8, 2H, C ₆ H ₅ ); 7.82 (s, 1H, H-5); 7.74 (m, 1H, C ₆ H ₅ ); 7.59 (t, J = 7.8, 2H, C ₆ H ₅ ); 3.51 (br m, 4H, CH ₂ ); 3.29 (br m, 4H, CH ₂ ) Found: m / z (ESI), 453.0918 [M + H] ⁺ C ₂₀ H ₁₇ ClF ₃ N ₄ O ₃ ⁺ . Calculated: 453.0936.

Example 33

2- (4-Methylbenzoyl) -7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-4d)

Prepared according to a procedure similar to that shown in example 1, from 2- (4-methylbenzoyl) -7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = 4-CH ₃ C ₆ H ₄ , LG = F, Ζ = H, scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. The yield is 83%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 15.2 min, purity 97.0%. UV spectrum, nm (EtOH): 206, 275, 342, 386. Found: m / z (ESI), 433.1493. [М + Н] ⁺ C ₂₁ H ₂₀ F ₃ N ₄ O ₃ ⁺ . Calculated: 433.1482.

Example 34

7- (Piperazin-1-yl) -3-trifluoromethyl-2- (4-chlorobenzoyl) quinoxaline 1,4-dioxide

hydrochloride (7-4e)

Prepared according to a procedure similar to that shown in example 1, from 7-fluoro-3-trifluoromethyl-2- (4-chlorobenzoyl) quinoxaline 1,4-dioxide (8, X = 4-ClC ₆ H ₄ , LG = F, Ζ = Η, scheme A), obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. The yield is 77%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 15.4 min, purity 95.1%. UV spectrum, nm (EtOH): 210, 270, 344, 385. Found: m / z (ESI), 453.0921. [М + Н] ⁺ C ₂₀ H ₁₇ ClF ₃ N ₄ O ₃ ⁺ . Calculated: 453.0936.

Example 35

2- (4-Methylthiobenzoyl) -7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-4f)

Prepared according to a procedure similar to that described in example 1, from 2- (4-methylthiobenzoyl) -7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = 4-CH ₃ SC ₆ H ₄ , LG = F, Ζ = H, scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004,12, 3711-3721] and piperazine. The yield is 63%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 60% ( 30 min): Rt = 17.0 min, purity 94.8%. UV spectrum, nm (EtOH): 210, 279, 346, 390. Found: m / z (ESI), 465.1210. [М + Н] ⁺ C ₂₁ H ₂₀ F ₃ N ₄ O ₃ S ⁺ . Calculated: 465.1203.

Example 36

2- (3,4-Dimethylbenzoyl) -7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide

hydrochloride (7-4g)

Prepared according to a procedure similar to that described in example 1, from 2- (3,4-dimethylbenzoyl) -7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = 3,4- (CH ₃ ) ₂ C ₆ H ₃ , LG = F, Ζ = H, scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. Yield 72%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 16.4 min, purity 94.7% UV spectrum, nm (EtOH): 211, 267, 341, 385. Found: m / z (ESI), 447.1628. [М + Н] ⁺ C ₂₂ H ₂₂ F ₃ N ₄ O ₃ ⁺ . Calculated: 447.1639.

Example 37

7- (Piperazin-1-yl) -3-trifluoromethyl-2- (3,4-dichlorobenzoyl) quinoxaline 1,4-dioxide

hydrochloride (7-4h)

Prepared according to a procedure similar to that shown in example 1, from 7-fluoro-3-trifluoromethyl-2- (3,4-dichlorobenzoyl) quinoxaline 1,4-dioxide (8, X = 3,5-C1 ₂ C ₆ H ₃ , LG = F, Ζ = Η, scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004,12, 3711-3721] and piperazine. Yield 69%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 17.8 min, purity 95.5%. UV spectrum, nm (EtOH): 211, 272, 340, 389. Found: m / z (ESI), 487.0554. [М + Н] ⁺ C ₂₀ Η ₁₆ Cl ₂ F ₃ Ν ₄ O ₃ ⁺ . Calculated: 487.0546.

Example 38

2- (3,4,5-Trimeoxybenzoyl) -7- (piperazin-1-yl) -3-trifluoromethylquinoxaline 1,4-dioxide hydrochloride (7-4j)

Prepared according to a procedure similar to that shown in example 1, from 2- (3,4,5-trimethoxybenzoyl) -7-fluoro-3-trifluoromethylquinoxaline 1,4-dioxide (8, X = 3,4,5-C ₆ H ₂ (OCH ₃ ) ₃ , LG = F, Ζ = H, scheme A), obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004,12, 3711-3721] and piperazine. The yield is 48%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 19.7 min, purity 96.2% UV spectrum, nm (EtOH): 214, 275, 340, 386. Found: m / z (ESI), 509.1633. [М + Н] ⁺ C ₂₃ H ₂₄ F ₃ N ₄ O ₆ ⁺ Calculated: 509.1642.

Example 39

7- (Piperazin-1-yl) -3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide

hydrochloride (7-5а)

Prepared according to a procedure similar to that shown in example 1, from 7-fluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-С ₄ Н ₃ О, LG = F, Ζ = Η, scheme A), obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. The yield is 71%. T. pl. 220-222 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 340 nm, eluent: A - H ₃ PO ₄ (0.01 Μ) ρΗ = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 11.0 min, purity 95.3%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 9.60 (br.s, 2H, NH ₂ ⁺ ); 8.37 (d, J = 8.9.1H, H-5); 8.20 (br.m, 1H, C ₄ H ₃ O); 7.89 (d, J = 8.9, 1H, H-6); 7.85 (br m, 1H, C ₄ H ₃ O); 7.50 (s, 1H, H-8); 6.82 (m br, 1H, C ₄ H ₃ O); 3.81 (m br, 4H, CH ₂ ); 3.24 (m, 4H, CH ₂ ) Found: m / z (ESI), 409.1078 [M + H] ⁺ C ₁₈ H ₁₆ F ₃ N ₄ O ₄ ⁺ Calculated: 409.1118.

Example 40

7- (Piperazin-1-yl) -6-fluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide

hydrochloride (7-5b)

Prepared according to a procedure similar to that shown in example 1, from 6,7-difluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = F , Ζ = F, scheme A) and piperazine. The yield is 47%. T. pl. 230-232 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 12.0 min, purity 95.8%. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ , δ, ppm (J, Hz): 9.58 (br.s, 2H, NH ₂ ⁺ ) ; 8.33 (d, J = 12.9, 1H, H-5); 8.23 (m br, 1H, C ₄ H ₃ O); 7.86 (m br, 1H, C ₄ H ₃ O); 7.73 (d, J = 8.2, 1H, H-8); 6.83-6.82 (m, 1H, C ₄ H ₃ O); 3.61 (m br, 4H, CH ₂ ); 3.29 (m br, 4H, CH ₂ ). Found: m / z (ESI), 427.1030. [M + H] ⁺ C ₁₈ H ₁₅ F ₄ N ₄ O ₄ ⁺ . Calculated: 427.1024.

Example 41

7- (Piperazin-1-yl) -3-trifluoromethyl-2- (2-furoyl) -6-chloroquinoxaline 1,4-dioxide

hydrochloride (7-5 s)

Prepared according to a procedure similar to that described in example 1, from 3-trifluoromethyl-6,7-dichloro-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = Cl , Ζ = Cl, scheme A) and piperazine. The yield is 82%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 10 → 90% ( 45 min): Rt = 13.0 min, 96.4% purity UV spectrum nm (EtOH):. 291, 374, 499. ¹ H NMR (400 MHz, DMSO-d _6), δ, ppm (J , Hz): 8.53 (s, 1H, H-5); 8.14 (br.m, 1H, C ₄ H ₃ O); 7.83 (s, 1H, H-8); 7.76 (br.m, 1H, C ₄ H ₃ O); 6.80-6.79 (m, 1H, C ₄ H ₃ O); 3.45 (m br, 4H, CH ₂ ); 3.31 (m br, 4H, CH ₂ ) Found: m / z (ESI) 443.0734 [M + H] ⁺ C ₁₈ H ₁₅ ClF ₃ N ₄ O ₄ ⁺ Calculated: 443.0728.

Example 42

7- (4-Aminopiperidin-1-yl) -3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide

hydrochloride (7-5d)

Prepared according to a procedure similar to that described in example 10, from 7-fluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = F, Ζ = Η, scheme A) and 4-N-Boc-aminopiperidine. The yield is 68%. T. pl. 255-257 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 295 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 60% ( 30 min): Rt = 11.2 min, purity 94.9%. UV spectrum, nm (EtOH): 219, 236, 342, 383.490. NMR spectrum ¹ H (400 MHz, DMSO-d ₆ ), δ, ppm. (J, Hz): 8.43 (br.s, 3H, NH ₃ ⁺ ); 8.30 (d, J = 8.9, 1H, H-5); 8.20 (br.m, 1H, C ₄ H ₃ O); 7.88 (d, J = 8.9, 1H, H-6); 7.85 (m br, 1H, C ₄ H ₃ O); 7.42 (s, 1H, H-8); 6.81 (m br, 1H, C ₄ H ₃ O); 4.19 (d, J = 7.8, 2H, CH ₂ ); 3.41 (br m, 1H, CH); 3.16 (t, J = 9.8, 2H, CH ₂ ); 2.08 (d, J = 7.8, 2H, CH ₂ ); 1.63 (d, J = 7.8, 2H, CH ₂ ) Found: m / z (ESI), 423.1280. [M + H] ⁺ C ₁₉ H ₁₈ F ₃ N ₄ O ₄ ⁺ Calculated: 423.1275.

Example 43

7- (3- (R) -Aminopyrrolidin-1-yl) -6-fluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline

1,4-dioxide hydrochloride (7-5e)

Prepared according to a procedure similar to that shown in example 10, from 6,7-difluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = F , Ζ = F, scheme A) and 3- (S) -N-Boc-aminopyrrolidine. The yield is 46%. T. pl. 241-243 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - HCOONH ₄ (0.2%) pH = 6.5, B - MeCN; gradient B 20 → 60% (45 min ): Rt = 15.2 min, purity 95.1% UV spectrum, nm (EtOH): 223, 276, 297, 338, 379, 475. ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm. d. (J, Hz): 8.54 (br.s, 3H, NH ₃ ⁺ ); 8.23 (d, J = 11.5, 1H, H-5); 8.20 (m br, 1H, C ₄ H ₃ O) ; 7.84 (t, J = 3.8, 1H, C ₄ H ₃ O); 7.17 (d, J = 8.2.1H, H-8); 6.82 (dd, J ¹ = 3.8, J ² = 1.7.1H, C ₄ H ₃ O); 3.98 (d, J = 5.9, 2H, CH ₂ ); 3.89-3.87 (m, 1H, CH ₂ ); 3.80-3.78 (m, 1H, CH); 3.74-3.67 (m, 1H , CH ₂ ); 2.40-2.29 (m, 1H, CH ₂ ); 2.22-2.18 (m, 1H, CH ₂ ) Found: m / z (ESI), 427.1016. [M + H] ⁺ C ₁₈ H ₁₅ F ₄ N ₄ O ₄ ⁺ . Calculated: 427.1024.

Example 44

7- (3- (S) -Aminopyrrolidin-1-yl) -6-fluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline

1,4-dioxide hydrochloride (7-5f)

Prepared according to a procedure similar to that shown in example 10, from 6,7-difluoro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = F , Ζ = F, scheme A) and 3- (S) -N-Boc-aminopyrrolidine. The yield is 43%. T. pl. 252-254 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - HCOONH ₄ (0.2%) pH = 6.5, B - MeCN; gradient B 20 → 60% (45 min ): Rt = 15.1 min, purity 95.4% UV spectrum, nm (EtOH): 220, 277, 297, 338, 379.474 ¹ H NMR spectrum (400 MHz, DMSO-d ₆ ), δ, ppm (J, Hz): 8.54 (br.s, 3H, NH ₃ ⁺ ); 8.23 (d, J = 11.5, 1H, H-5); 8.20 (br.m, 1H, C ₄ H ₃ O); 7.84 (t, J = 3.8,1H, C ₄ H ₃ O); 7.17 (d, J = 8.2, 1H, H-8); 6.82 (dd, J ¹ = 3.8, J ² = 1.7, 1H, C ₄ H ₃ O); 3.98 (d, J = 5.9, 2H, CH ₂ ); 3.89-3.87 (m, 1H, CH ₂ ); 3.80-3.78 (m, 1H, CH); 3.74-3.67 (m, 1H, CH ₂ ); 2.40-2.29 (m, 1H, CH ₂ ); 2.22-2.18 (m, 1H, CH ₂ ) Found: m / z (ESI), 427.1004. [M + H] ⁺ C ₁₈ H ₁₅ F ₄ N ₄ O ₄ ⁺ . Calculated: 427.1024.

Example 45

7- (3-Aminopyrrolidin-1-yl) -3-trifluoromethyl-2- (2-furoyl) -6-chloroquinoxaline 1,4-dioxide hydrochloride (7-5g)

Prepared according to a procedure similar to that shown in example 10, from 6,7-dichloro-3-trifluoromethyl-2- (2-furoyl) quinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ O, LG = CI , Ζ = Cl, scheme A) and 3- (R) -N-Boc-aminopyrrolidine. The yield is 77%. T. pl. 195-196 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - HCOONH ₄ (0.2%) pH = 6.5, B - MeCN; gradient B 20 → 60% (45 min ): Rt = 18.5 min, 95.2% purity UV spectrum nm (EtOH):. 225, 300, 353, 389, 483. ¹ H NMR (400 MHz, DMSO-d _6), δ, ppm (J, Hz): 8.62 (br.s, 3H, NH ₃ ⁺ ); 8.42 (s, 1H, Н-5); 8.22 (br.m, 1H, C ₄ H ₃ O); 7.85-7.84 (m , 1H, C ₄ H ₃ O); 7.31 (s, 1H, H-8); 6.82-6.81 (m, 1H, C ₄ H ₃ O); 4.09-4.03 (m, 1H, CH); 3.93-3.91 (m, 2H, CH ₂ ); 3.89-3.61 (m, 2H, CH ₂ ); 2.35-2.18 (m, 2H, CH ₂ ) Found: m / z (ESI), 443.0703. [M + H] ⁺ C ₁₈ H ₁₅ ClF ₃ N ₄ O ₄ ⁺ Calculated: 443.0728.

Example 46

6- (3-Aminopyrrolidin-1-yl) -3-trifluoromethyl-2- (2-furoyl) -7-chloroquinoxaline 1,4-dioxide hydrochloride (7-5h)

Received as a minor component in the synthesis of the derivative 7-5g described in example 45. Yield 15%. T. pl. 205-207 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - HCOONH ₄ (0.2%) pH = 6.5, B - MeCN; gradient B 20 → 60% (45 min ): Rt = 18.9 min, purity 95.6%. ¹ H NMR spectrum (400 MHz, MDCO4rt-d ₆ ), δ, ppm (J, Hz): 8.62 (br.s, 3H, NH ₃ ⁺ ) ; 8.42 (s, 1H, H-5); 8.22 (m br, 1H, C ₄ H ₃ O); 7.85-7.84 (m, 1H, C ₄ H ₃ O); 7.31 (s, 1H, H- 8); 6.82-6.81 (m, 1H, C ₄ H ₃ O); 4.09-4.03 (m, 1H, CH); 3.93-3.91 (m, 2H, CH ₂ ); 3.89-3.61 (m, 2H, CH ₂ ); 2.35-2.18 (m, 2H, CH ₂ ) Found: m / z (ESI), 443.0715 [M + H] ⁺ C ₁₈ H ₁₅ ClF ₃ N ₄ O ₄ ⁺ . Calculated: 443.0728.

Example 47

7- (Piperazin-1-yl) -2 - ((thien-2-yl) carbonyl) -3-trifluoromethyl-6

-chlorocarbonylquinoxaline 1,4-dioxide hydrochloride (7-6а)

Prepared according to a procedure similar to that described in example 1, from 2 - ((thien-2-yl) carbonyl) -3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = 2-C ₄ H ₃ S , LG = Cl, Ζ = Cl, scheme A), obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. The yield is 34%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 13.5 min, purity 94.9%. UV spectrum, nm (EtOH): 220, 245, 380, 495. Found: m / z (ESI), 459.0512. [М + Н] ⁺ C ₁₈ H ₁₅ ClF ₃ N ₄ O ₃ S ⁺ . Calculated: 459.0500.

Example 48

2-Isonicotinoyl-7- (piperazin-1-yl) -3-trifluoromethyl-6-chlorocarbonylquinoxaline

1,4-dioxide hydrochloride (7-7а)

Prepared according to a procedure similar to that shown in example 1, from 2- (isonicotinoyl) -3-trifluoromethyl-6,7-dichloroquinoxaline 1,4-dioxide (8, X = 3-C ₅ H ₄ N, LG = Cl, Ζ = Cl, scheme A) obtained by the method [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721] and piperazine. The yield is 27%. T. pl. > 250 ° C. HPLC (column Kromasil-100-5-μm C-18 4.6 × 250 mm, LW = 300 nm, eluent: A - H ₃ PO ₄ (0.01 M) pH = 2.6, B - MeCN; gradient B 20 → 80% ( 45 min): Rt = 17.9 min, purity 95.1%. UV spectrum, nm (EtOH): 213, 340, 376, 492. Found: m / z (ESI), 454.0873. [М + Н] ⁺ C ₁₉ H ₁₆ ClF ₃ N ₅ O ₃ ⁺ . Calculated: 454.0888.

Examples confirming the presence of biological activity

Example 49

Inhibition of tumor cell growth under normoxia and hypoxia by 2-acyl-3-trifluoromethylquinoxaline by 1,4-dioxides

Evaluation of the antitumor activity of the claimed compounds 7 was carried out on the human mammary adenocarcinoma cell line MCF-7 under normoxia and hypoxia, with incubation in an atmosphere containing 1% oxygen. Data on antiproliferative activity (IC ₅₀ - concentration inhibiting cell growth by 50% compared to control) under conditions of normoxia and hypoxia; the index of hypoxic cytotoxicity (HCR = IC _{50 (normoxia)} / IC _{50 (hypoxia)} ) of the inventive derivatives of formula 7, including the IC ₅₀ and HCR values for the reference drugs - doxorubicin, cisplatin, the experimental hypoxia-selective agent tirapazamine and the previously described quinoxaline -2-carbonitrile 1,4-dioxide 4 [RU 2640304] are shown in table 1. Determination of IC ₅₀ was carried out using the MTT test according to the standard method described in the literature [Scherbakov AM et al. Cancer Invest., 2018, 3, 199-209].

The results of the study of cytotoxic properties show that the compounds described in the invention are capable of affecting tumor cells in low micromolar and submicromolar concentrations. The data obtained prove that the activity of the derivatives obtained, in most cases, exceeds the activity of the reference drugs cisplatin and doxorubicin both under hypoxia and normoxia conditions, and also have a higher hypoxic cytotoxicity index (HCR). In addition, most derivatives of 3-trifluoromethylquinoxaline 1,4-dioxide 7 more effectively inhibit the proliferation of MCF-7 breast adenocarcinoma cells in both normoxia and hypoxic conditions than the reference drug tirapazamine and the previously described water-soluble quinoxaline-2- carbonitrile 1,4-dioxide 4.

It should be noted that, in contrast to the previously described 3-trifluoromethylquinoxaline 1,4-dioxides (for example, compound 5 [Zarranz B. et al. Bioorg. & Med. Chem., 2004, 12, 3711-3721]), derivatives Formulas 7, which are the subject of the present invention, have high solubility in pharmacologically acceptable aqueous media, which greatly simplifies their practical application in medicine.

Example 50

The ability of 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides to inhibit the growth of various types of tumor cells

A comparative study of the cytotoxicity of compounds of general formula 7 and their previously described quinoxalin-2-carbonitrile 1,4-dioxides (derivative 4, RU 2640304) was carried out in in vitro tests on cell cultures of adenocarcinoma of the pancreas Capan-1, chronic myeloid leukemia Nar-1, colon adenocarcinoma HCT-116, non-small cell lung carcinoma NCI-H460, human promyelocytic leukemia HL-60 and human lymphocytic leukemia K562. Data on antiproliferative activity (IC ₅₀ - concentration inhibiting cell growth by 50%) are presented in table 2. Determination of IC ₅₀ was carried out using the MTT test according to the standard method described in the literature [MossmanT. J. Immunol. Methods, 1983, 65, 55].

It can be seen from the results obtained that the claimed 3-trifluoromethylquinoxaline 1,4-dioxides of formula 7 inhibit the growth of tumor cells at low micromolar and submicromolar concentrations. Moreover, the cytotoxicity of the obtained compounds of formula 7 (7-2a, 7-2c and 7-3a) is 2-10 times higher than for their water-soluble analogue of formula 4, the antiproliferative properties of which were described earlier [RU 2640304].

Claims (14)

1. Derivative of 3-trifluoromethylquinoxaline 1,4-dioxide containing a diamine residue in the benzene moiety of the quinoxaline ring, as well as its pharmacologically acceptable salts, hydrates corresponding to the formula:

where Y independently denotes a diamine residue directly bonded by one of the nitrogen atoms to the benzene moiety of the quinoxaline ring, selected from the group of 6-7 membered cyclic diamines such as piperazine, 1,4-diazepane, 5-6 membered cyclic amines such as piperidine or pyrrolidine substituted with an amino group, optionally substituted at nitrogen or carbon atoms with one or more substituents selected from C _1-4 alkyl, hydroxyC _1-4 alkyl; X independently means C _1-4 alkyl, C _1-4 alkoxy, phenyl or heteroaryl containing 5 or 6 atoms, with one heteroatom selected from N, O and S, optionally substituted with 1-3 substituents selected from C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio or halogen; Ζ independently means a hydrogen or halogen atom, provided that the 3-trifluoromethylquinoxaline 1,4-dioxide derivative is not 6- (piperazin-1-yl) -7-fluoro-3-trifluoromethyl-2-ethoxycarbonylquinoxaline 1,4-dioxide. 2. The derivative of claim 1, wherein X is independently 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl optionally substituted with 1-3 substituents selected from alkyl , alkoxy or halogen. 3. A derivative according to claim 1, characterized in that the optionally substituted diamine is independently selected from the group: piperazine, 1,4-diazepane, 4-aminopiperidine. 4. A derivative according to claim 1, characterized in that the optionally substituted diamine is an individual enantiomer of 3-aminopiperidine or 3-aminopyrrolidine, or a mixture with different enantiomeric contents. 5. A derivative according to claim 1, characterized in that the optionally substituted diamine is attached by a nitrogen atom to the carbon atom at the 6 or 7 position of the 3-trifluoromethylquinoxaline 1,4-dioxide. 6. Derivative according to claim 1, characterized in that Ζ independently means hydrogen, fluorine, chlorine. 7. A method for inhibiting the division of tumor cells, comprising contacting the cells with an effective amount of a derivative of quinoxaline 1,4-dioxide according to claim 1, or according to claim 2, or according to claim 3, or according to claim 4, or according to claim 5, or according to claim 6. 8. The method of inhibiting the division of tumor cells according to claim 7, in which the malignant neoplasm is selected from a tumor of the breast, lung, gastrointestinal canal, pancreas, leukemia. 9. The method according to claim 8, characterized in that said tumor cells are characterized by drug resistance against other anticancer drugs.