UA79793C2 - Azolidinone-vinyl fused-benzene derivatives - Google Patents

Abstract

The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Formula (I), wherein A, X, Y, Z, R1, R2 and n are as described in the description.

Description

Description of the invention

This invention relates to the use of azolidinone derivatives of condensed vinylbenzenes of formula (I) for the treatment and/or prevention of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, rejection transplants or lung injuries. In particular, this invention relates to substituted azolidinone derivatives of fused vinylbenzenes for modulating, especially inhibiting, the activity or function of the family of phosphoinositide-3'ON-kinases, RISK, especially RIZKA.

Cell plasma membranes can be viewed as a large reservoir of second messengers that can be incorporated into a variety of signaling pathways. With regard to the function and regulation of effector enzymes in phospholipid signaling pathways, these enzymes that generate second messengers from membrane phospholipid depots (class I RIZ kinases (e.g., RIZKU)) are dual-specificity enzymes, i.e., they act simultaneously as lipid kinases (phosphorylation of phosphoinositides), as well as protein kinases; it is shown that they are able to phosphorylate other protein substrates as well, including causing auto-phosphorylation as an intramolecular regulatory mechanism. These phospholipid signaling pathway enzymes are activated in response to a variety of extracellular signals, such as growth factors, mitogens, integrin hormones (intercellular communication hormones), cytokines, viruses, and neurotransmitters, as shown, for example, below in

Scheme 1, as well as under the influence of intracellular cross-regulation caused by other signaling compounds (cross-talk, in which the initial signal can activate certain parallel transmission pathways, which in the second stage transmit signals to the enzymes of the RZK as a result of intracellular signaling events), for example, low-molecular STR- enzymes, kinases or phosphatases.

The intracellular signal transmission pathway involving inositol phospholipids (phosphoinositides) begins with the binding of signaling molecules (extracellular ligands, stimuli, receptor dimerization, or transactivation under the influence of heterologous receptors (for example, tyrosine kinase receptor)) with a transmembrane receptor integrated into the plasma membrane, which has O-protein as a bridging element. RZK converts the membrane phospholipid PIP(4,5)2 into PIP(3,4,5)3, which, in turn, can undergo further transformation into another 33'-phosphorylated form of phosphoinositides under the influence of 5'-specific phosphoinositide phosphatases ; in such a way, the enzymatic activity of RIZK directly or indirectly causes the formation of two subtypes of (o) 3-phosphoinositides, which act as secondary messengers during intracellular signal transmission |Thepaz

Viospet Zsi. 22(7) pp. 267-272 (1997) Bu Mappaesergoesk V. ei a); Spent To whom 101(8) r.2365-2380 (2001) ru -

It is written by M.MK. her aI. (2001); Apps. To whom SeiYi Yum. Vioi 17 r.615-675 (2001) ru Kaivo K. ei aI.; apa Seiyi My. (F)

She eats. 59(5) r.761-779 (2002) ru ToKeg A. ei a. In this enzyme reaction, numerous isoforms of RAZK are involved, which are classified according to the corresponding catalytic subunits, according to regulation under the influence of the corresponding regulatory subunits, according to expression patterns and according to specific signaling functions (p110A,

B, b and u) (Ehr. SeiYi. Kev. 25(1) r.239-254 (1999) ru Mappaesergoesk V.; Appy. Kem. SeiYi. Oem. Vioi. 17 r.b15-675 (2001) ru Kaivo K. ei ai/.|. « 20 Evolutionarily stable isoforms ri 10 A and B are expressed by almost all tissues, on the contrary, isoforms 5 and y -v c are expressed more specifically in cells of the hematopoietic system, smooth muscle cells, myocytes and in in endothelial cells |Tgepaz Viospet. Zsi. 22(7) p.267-272 (1997) ru Mapipaezergoesk V. ei a. It is possible that their expression can also be regulated by inducing, depending on the type of cells, tissue and stimuli, as well as from the general picture of the disease.

At present, eight RZK kinases have been identified in mammals, which are divided into three main classes (I, II, and -II I) based on homologous sequence, structure, binding partners, mode of activation, and preferred ip miigo substrate. RAZK class | can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate and re) phosphatidylinositol-4,5-diphosphate (PIP2) with the formation of phosphatidylinositol-3-phosphate (PIP), -I phosphatidylinositol-3,4-diphosphate and phosphatidylinositol-3, respectively ,4,5-triphosphate. RIZK class II phosphorylate RI and phosphatidylinositol-4-phosphate. RIZK5 of class I can phosphorylate only RI Ptepase Viospet. from the U.S. 22(7) is) p. 267-272 (1997) ru Mappaesergoesk V. ei aiY., Ehr. SeiYi Kev. 25(1) p.239-254 (1999) ru Mappaesergoesk V. and p. Spet. To whom 101(8) p.2365-2380 (2001) ru Yevie M.K. (2001)). OS protein-coupled receptors mediate activation of phosphoinositide-3'OH-kinase through STR-ases, such as Wu and Kazv, and thus the signaling pathway involving RIZK reveals a central role in establishing and coordinating 5B cell polarity and dynamic organization of the cytoskeleton, i.e. factors that jointly provide the driving force for cell movement.

F) has) 60 b5 and ' . y pk pdv 3-dofye cm dv l i shchi

As shown above in Scheme 1, phosphoinositide-3-kinase (RIZK) is involved in the phosphorylation of i) phosphatidylinositol (RiaIpv) on the third carbon atom of the inositol cycle. Phosphorylation products of Ria|pz to 3,4,5-triphosphate (RiaIp5v(3,4,5)Ra), RiaIp5(3,4)P» and Ridiaz(ZR) act as second messengers for various signaling pathways, including for those essential for cell proliferation, cell differentiation, cell growth, cell size, survival, cell apoptosis and cell adhesion, cell contractility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes, Me vesicle movement and metabolic pathways (Appy. Kemu. SeiYi. YuOem. VioYi. 17 r.615-675 (2001) ru Kaivgo ei aiYi. apa Moi. Mea. M

Todau 6(9) p. 347-357 (2000) ru bieip K.S). Chemotaxis, i.e., the orderly movement of cells in the direction of the concentration gradient of chemical attractants, also called chemokines, is a constituent element in many important medical diseases, for example, in inflammatory and autoimmune disorders, neurodegeneration, angiogenesis, tumor invasion and the formation of metastases, and also in wound healing (ttipoi. Todau 21(6) p.260-264 (2000) ru Muutap M.R. ei a).;

Zsiepse 287(5455) r.1049-1053 (2000) ru Nigespy ei a; RABEV U. 15(11) r. 2019-2021 (2001) ru Nigzsp ei ai. Maya's aunt And so on. 2(2) p.108-115 (2001) Bu Segaga S. ega/.|.

Modern studies using genetic approaches and pharmacological agents have provided an understanding of the signaling and molecular pathways that mediate chemotaxis in response to chemoattractants through activated receptors attached to O-protein. The action of RiZ-kinase, which is responsible for the production of these

And phosphorylated signaling products were originally characterized as activity associated with by viral oncoproteins and tyrosine kinases of growth factor receptors, which phosphorylates phosphatidylinositol (RI) and its derivatives, phosphorylated on the hydroxyl at the 3' position of the inositol cycle. Vioi 2 p. 358-360 (1992)). However, during later biochemical studies, it was found that RiIZ-kinases -I class | (for example, the RizK isoform of class IV) are dual-specificity kinases, i.e. they act simultaneously as lipid kinases (phosphoinositide phosphorylation) and as protein kinases, which have been shown to be capable of phosphorylating other proteins as substrates, including autophosphorylation as to - And the intramolecular regulatory mechanism.

Therefore, it is believed that the activation of RiZ-kinases is involved in various cellular reactions, including cell growth, differentiation and apoptosis. se" Zsiepse, 267, 2003-2005 (1995)).

RiIZ-kinase may be involved in multiple aspects of leukocyte activation. It has been shown that the activity of the p85-related RIZ-kinase is physically related to the cytoplasmic site of CO28, which is an important additional stimulator of T-cell activation in response to an antigen. 1994); Kiawah,

Ipttipyu 4 r.527-534 (1996)). Activation of T cells under the influence of CO28 lowers the threshold of antigen activation and iF) increases the intensity and duration of the proliferative reaction. These effects are associated with the transcription of numerous cogenes, including interleukin-2 (1I2), which is an important factor in the growth of T cells (Egazeg ei ai., Zsiepse, 251 r.313-316 (1991)). Mutation of СО28, as a result of which it can interact longer with RIZ-kinase, causes a loss of the ability to initiate the production of 1/2, which indicates the decisive role of RIZ-kinase in the activation of T cells. RIZK y was identified as a mediator of О-В- y-dependent regulation of MK activity, while О-В and -y are subunits of heterotrimeric O-proteins (U. Vioi. Spets. 273(5) p. 2505-2508 (1998)) . Cellular processes in which RIZ kinases play an important role include inhibition of apoptosis, reorganization of the actin skeleton, cardiomyocyte growth, stimulation of glycogen synthase by insulin, TMEA-mediated priming and production of 65 peroxides, as well as leukocyte migration and their adhesion to endothelial cells.

Recently (pttipyu 16(3) pp. 441-451 (2002) it was described that RIZKu switches inflammatory signals through the mediation of various receptors connected with (ii) and plays a key role in the functioning of mast cells, stimulation of leukocytes, in immunological processes in which participate, for example, cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones M. Sei. Zsi. 114(RI 16) p.2903-2910 (2001) ru Iaumog M.A. ei aiYi., Ittipyu 16(3) pp. 441-451 (2002) ru Iapagdtse M. ei ai. apa

satiated Oriope Seii. Vioi 14(2) r.203-213 (2002) ru erpepz I. ei ai.).

Specific inhibitors of the activity of individual members of the enzyme family are invaluable tools for the precise determination of the functions of each enzyme. Two compounds, namely I U294002 and wortmannin (formulae of which are given below), are widely used as inhibitors of RiIZ-kinases. These compounds are non-specific RISK inhibitors because 7/0 They do not show selective affinity for any of the four members of the group of RISK kinases of class I. For example, the IC value of 50 for wortmannin against each of the different RISK kinases of class | lie in the range from NM to ТОнNM.

Similarly, the ISvo values for I 294002 relative to each of these RAZ-kinases lie within 15-20 μM (Egytap eyi aIm., Ap. Chem. Viospet., 67 p. 481-507 (1998)). These compounds also show an IS 59 value of 5-10 mM relative to protein kinase SK»o and a certain inhibitory effect on phospholipases. Wortmannin is a product of the metabolism of fungi, which irreversibly inhibits the activity of RISK due to covalent binding to the catalytic domain of this enzyme.

Inhibition of RISK activity by wortmannin eliminates the subsequent response of the cell to the extracellular factor. For example, neutrophils respond to the chemokine yMei ec-Rpe (MI R) by stimulating RZK and synthesizing RiaIp5(3,4,5)P. with.

This synthesis correlates with the activation of the release of respirators, which is involved in the destruction of foreign microorganisms in neutrophils. Treatment of neutrophils with wortmannin prevents the IMR-induced respiratory emission reaction (Tpeiep eyi a. RMAZ 91 p.4960-4964 (1994). Obviously, these experiments with wortmannin, as well as other experimental evidence, show that the activity of RIZK in the cells of the hematopoietic system, in particular , in neutrophils, monocytes and other types of leukocytes, is an element of many non-sensitized immune responses associated with acute and chronic inflammation.

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Studies with the use of wortmannin indicate that the functioning of RiZ-kinases is also necessary in some aspects of signal transmission to leukocytes through C-protein-coupled receptors. Maya F

Asad si. OBA, 91 p. 4960-4964 (1994)). In addition, wortmannin and /M294002 have been shown to block neutrophil activation and peroxide release. However, since these compounds do not show selectivity for specific RAZK isoforms, it remains unclear which RAZK isoform or isoforms are involved in these phenomena.

Azolidinone derivatives of vinylbenzene, which, however, necessarily include a benzimidazole fragment (described in MO 02/051409). These compounds are reported to inhibit telomerase and have targeted benefits in the treatment of cancer. - c Brief description of the invention "c This invention relates to the use of azolidinone derivatives of condensed vinylbenzenes of the formula (I) n

A () 45. - -th

He) Fri and Co Sat 70 ! c" where A, X, M, 7, p, B! and B? described in detail in the description below, as well as pharmaceutically acceptable salts of these compounds, for the manufacture of pharmaceutical compositions for the treatment and/or prevention of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative

Diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, transplant complications, transplant rejection, or lung injuries. The compounds of this invention are 3-kinase inhibitors

F, phosphatoinositides (RIZKzv), especially gamma-3-kinase of phosphatoinositides (RIZKU). So far, it has been established that the compounds according to this invention are modulators of phosphatoinositide 3-kinases (POK), especially phosphatoinositide 3-kinase (RIZKU). If the enzyme - phosphoinositide 3-kinase (PZK) - is inhibited by the compounds according to the present invention, the PZK is not able to show its enzymatic, biological and/or pharmacological effects.

The compounds of the present invention are thus useful for the treatment and prevention of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplant complications, transplant rejection and lung injuries. . bB Below are definitions of the terms that mean the various chemical moieties and groups that make up the compounds of this invention; these terms are intended for unambiguous use in the text of the description and in the claims of the invention, unless another explicitly given definition implies a broader meaning.

The term "C. -C. alkyl" means a monovalent alkyl group containing from 1 to b carbon atoms.

Examples of the meanings of this term include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.

The term "aryl" means an unsaturated aromatic carbocyclic group containing from b atoms to 14 carbon atoms and including one ring (eg, phenyl) or several fused rings (eg, naphthyl). Preferred aryls include phenyl, naphthyl, phenanthryl, and the like. 70 The term "C1-C6-alkylaryl" means C1-C6-alkyl having an aryl substituent, including benzyl, phenethyl, and the like.

The term "heteroaryl" means a monocyclic heteroaromatic group or a bicyclic or tricyclic heteroaromatic group containing fused rings. Specific examples of heteroaromatic FUPs include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,

I(2,Z-dihydroYbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl,

ZH-indolyl, benzimidazolyl, imidazo|1,2-a|pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, naphthyridinyl, pyridoyZ,4-b|pyridyl, pyridoyZ,2-b|pyridyl, pyrido( |4,3-b|pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl and benzoquinolyl.

The term "C1-C6-alkylheteroaryl" means C1-C6-alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl, and the like.

The term "C4-Cv-alkenyl" means alkenyl groups that preferably contain from 2 to 6 carbon atoms and include at least 1 site or 2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-SNACH"), n-2-propenyl (allyl, -SNACH") and the like. and)

The term "Ci-C6-alkenylaryl" means C0-C6-alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like.

The term "C1-C6-alkenylheteroaryl" means C0-C6-alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.

The term "C.i-Cv-alkynyl" means alkynyl groups that preferably contain from 2 to 6 carbon atoms and Me include at least 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups M include ethynyl (-С--CH), propargyl (-СНС--CH) and the like.

The term "C1-C6-alkynylaryl" means C1-C6-alkynyl groups having an aryl substituent, including o-phenylethynyl and the like. -

The term "C 1 -C 1 -alkynyl etheraryl" means C 1 -C 6 -alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.

The term "C3-C6-cycloalkyl" means a saturated carbocyclic ring that contains from 3 to 8 carbon atoms and includes one ring (eg, cyclohexyl) or several fused rings (eg, norbornyl). 70 Preferred cycloalkyls include cyclopentyl, cyclohexyl, norbornyl, and the like. - с The term "heterocycloalkyl" means a C3-C6-cycloalkyl group according to the definition given above, in which C carbon atoms in an amount up to C are replaced by heteroatoms selected from the group consisting of O, 5, MK, and и"? K is hydrogen or methyl Preferred heterocycloalkyls include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.

The term "Ci-Cv-alkylcycloalkyl" means C-Ci-Cv-alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, etc. The term "C.-C.sub.6-alkylheterocycloalkyl" means C.sub.1-C.sub.6-alkyl groups having a heterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl etc. -I The term "carboxy(l)" means the group -"UZ"O)OH.

The term "C4-C6-alkylcarboxy(l)y" means C1-C6-alkyl groups having a carboxyl substituent, including 2-carboxyethyl, etc. c» The term "acyl" means the group -C(O)ZHK, where K is "C 1 -C 8 -alkyl", "aryl", "heteroaryl", "C 1 -C 8 -alkylaryl" or "C 1 -C 8 -alkylheteroaryl" .

The term "C1-C6-alkylacyl" means C1-C6-alkyl groups having an acyl substituent, including 2-acetylethyl and the like.

The term "arylacyl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

F. The term "heteroarylacyl" refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.

The term "C53-Cv-(hetero)cycloalkylacyl" means 3-8-membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.

The term "acyloxy(group)" means the group -OC(OK, where K is H, "C.4-Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl", "C3-Cv- cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylheteroaryl", "Co-C6-alkenylaryl", "Co-C6-alkenylheteroaryl", "Co -C6-alkynylaryl", "Co-C6-alkynylheteroaryl", "Ci-C6-alkylcycloalkyl", "C4-C6-alkylheterocycle salkyl". 65 The term "C.-C6-alkylacyloxy (group)" means C.-C6- alkyl groups having an acyloxy group as a substituent, including 2-(acetyloxy)ethyl and the like.

"Alkoxy(group)" means the group -O-K, where K is "C-C-alkyl", "aryl", "heteroaryl", "C-C-alkylaryl" or 1756 1796 "Ci-Cv -alkylteteroaryl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.

The term "C.-C.-alkylalkyloxy" means C.-C.-alkyl groups which have an alkoxy group as a substituent, including 2-ethoxyethyl, etc.

"Alkoxycarbonyl" means the group -C(O)OC where K is H, "C1-C6-alkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl" or "C1-C6-alkylaryl" -alkylheteroaryl".

The term "C 1 -C 6 -alkylalkyloxycarbonyl" means C 1 -C 6 -alkyl groups having a 7/0 alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.

The term "aminocarbonyl" means the group -C(O)MAKK, where each of K, K' independently of the other is hydrogen or

C1-C6-alkyl, aryl, heteroaryl, "C4-C6-alkylaryl" or "C6-C6-alkylheteroaryl".

The term "C1-C6-alkyl aminocarbonyl" means C1-C6-alkyl groups having an aminocarbonyl substituent, including 2-dimethylaminocarbonyl)ethyl and the like.

The term "acylamino(group)" means the group -МКС(О)Ж, where each of K, K independently of the other is hydrogen, "Ci-Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl ", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C8-alkylaryl" or "C1-C8-alkylheteroaryl", "Co-C8-alkenylaryl", "Co- C6-alkenylheteroaryl", "Co-C6-alkynylaryl", "Co-C6-alkynylheteroaryl", "C4-C6-alkylcycloalkyl", "C4-C6-alkylheterocycloalkyl".

The term "C4-C6-alkylacylamino group)" means C1-C6-alkyl groups having an acylamino group as a substituent,

Including 2-(propionylamino)ethyl, etc.

The term "Ureido(group)" means the group -МКС(О)МА'К", where each of K, K, K" independently of the other is hydrogen, "Ci-Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl", "C3-Cv-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Cv-alkylaryl" or "C.-Cv-alkylheteroaryl", "Co-Cv- alkenylaryl", "Co-Cv-alkenylheteroaryl", "Co-Cv-alkynylaryl", "Co-Cv--alkynylheteroaryl", "C.4-Cv-alkylcycloalkyl", "C.--Cv-alkylheterocycloalkyl", and where high school

K and K", together with the nitrogen atom to which they are attached, can optionally form 3-8-ene heterocycloalkyl. i)

The term "C4-Cv-alkylureido(group)" means C.--Cv-alkyl groups having a ureido group as a substituent, including 2-(M'-methylureido)ethyl, etc.

The term "carbamate" means the group -MKS(O)OK, where each of EC, K, independently of the other, is hydrogen, co zo 7 C4-Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl" , "C3-Cv-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Cv-alkylaryl" or "Ci-Cb-alkylheteroaryl", "Co-Cv-alkenylaryl", "Co-Cv- alkenylheteroaryl", Me) 1756 1 2556 2-56 "Co-Cv-alkynylaryl", "Co-Cv-alkynylheteroaryl", "C4-Cv-alkylcycloalkyl", "C4-Cv-alkylheterocycloalkyl". M

The term "amino (group)" means the group -"MKK", where each of K, K' independently of the other is hydrogen, "C.4-Cv-alkyl", "aryl", "heteroaryl", "C.-C -alkylaryl", "C.-Cv-alkylheteroaryl", "dichloroalkyl" or "heterocycloalkyl" and where K (22) 1796 1796 zv And K, together with the nitrogen atom to which they are attached, can optionally form 3-8-- linoleic heterocycloalkyl.

The term "C 1 -C 1 -alkylamino(group)" means C 1 -C 2 -alkyl groups having an amino group as a substituent, including 2-(1-pyrrolidinyl)ethyl and the like.

The term "ammonium" means a positively charged group -MAKK'K" where each of K,KK" independently of the others is « 400 "C4-Cv-alkyl", "Ci-Cv-alkylaryl", "C4-Cv-alkylheteroaryl", "cycloalkyl" or "heterocycloalkyl" and where K and KK, Z c together with the nitrogen atom to which they are attached, can optionally form a 3- to 8-membered heterocycloalkyl. iv . NO. . . NO. . a The term "C 1 -C 1 -alkylammonium" means "C 1 -C 2 -alkyl groups having ammonium as a substituent, including 2-(1-pyrrolidinyl)ethyl and the like.

The term "halogen" means fluorine, chlorine, bromine or iodine atoms.

The term "sulfonyloxy(group)" means the group -050.-K, where K is selected from the group consisting of H, -I 2 "C 1 -C 6 -alkyl", "C 1 -C 10 -alkyl" substituted with halogens, for example, the group -0505-SEz, "C.-S.sub.-alkenyl", 1756 1756 mog 27526 ik "Co-Cv-alkynyl", "C3-Cv-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C.i-Cv-alkylaryl" or -I "Ci-Cv-alkylheteroaryl", "Co-Cv-alkenylaryl", "Co-Cv-alkenylheteroaryl", "Co-Cv-alkynylaryl", 500 Co-Cv-alkynylheteroaryl ", "Ci-Ci-alkylcycloalkyl", "Ci-Ci-alkylheterocycloalkyl". se) The term "Ci-Ci-alkylsulfonyloxy(group)" means Ci-Ci-alkyl groups that have a sulfonyloxy group as 1796 1756 4 ) substituent, including 2-(methylsulfonyloxy)ethyl, etc.

The term "sulfonyl" means the group "-505-K", where K is selected from the group consisting of H, "aryl", "heteroaryl", "C1-C6-alkyl", "C1-C6-alkyl" , substituted by halogens, for example, the -505-SEz group, "Co-Ce-alkenyl", vv Co-Cv-alkynyl, "C3-Cv-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C. i-Cv-alkylaryl" or "Ci-Cv-alkylheteroaryl", "Co-Cv-alkenylaryl", "Co-Cv-alkenylheteroaryl", "Co-Cv-alkynylaryl",

F) "Co-Cv-alkynylheteroaryl", "C4-Cv-alkylcycloalkyl", "C4-Cv-alkylheterocycloalkyl". ka The term "Ci-Cv-alkylsulfonyl" means "C.-Cv-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl, etc. vo The term "sulfinyl" means the group "-5(0)-K ", where K is selected from the group that includes H, "C 4-Ce-alkyl", "C.i-Cv-alkyl", substituted by halogens, for example, the group -ZO-Cez, "Co-Cv-alkenyl" , "Co-Ci-alkynyl", "C3-Ci-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ci-alkylaryl" or "Ci-Ci-alkylheteroaryl", "Co-Ci -alkenylaryl", "Co-Cv-alkenylheteroaryl", "Co-Cv-alkynylaryl", "Co-Cv-alkynylheteroaryl", "Ci-Cv-alkylcycloalkyl", "C4-Cv-alkylheterocycloalkyl". 65 The term "C.- C 1 -C 6 -alkylsulfinyl" means "C 1 -C 6 -alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.

The term "sulfanyl" refers to groups -5-K, where K is H, "C.sub.-Ce-alkyl", "Ci-Cv-alkyl", substituted with halogens, for example, the group -50-Cez, "Co-Cv-alkenyl ", "Co-Cv-alkynyl", "C3-Cv-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Cv-alkylaryl" or "C.-C.-alkylheteroaryl", "Co -Cv-alkenylaryl", "Co-Cv-alkenylheteroaryl", 500 Co-Cv-alkynylaryl", "Co-Cv-alkynylheteroaryl", "C.i-Cv-alkylcycloalkyl", "C.-Cv-alkylheterocycloalkyl". preferred sulfonyl groups include methylsulfanil, ethyl sulfanil, and the like.

The term "C1-C6-alkylsulfanyl" means "C1-C6-alkyl groups having a sulfanyl substituent, including 2-ethylsulfanyl)ethyl, etc.

The term "sulfonylamino(group)" means the group -МК5О»2-K, where each of K, K' independently of the other is hydrogen, 70. "C1-Cv-alkyl", "Co-Cv-alkenyl", "Co- C 1 -alkynyl", "C 3 -C 6 -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C 1 -C 6 -alkylaryl" or "C 1 -C 6 -alkylheteroaryl", "Co -C 6 -alkenylaryl", "Co-Cv-alkenylheteroaryl", "Co-Cv-alkynylaryl", "Co-Cv-alkynylheteroaryl", "C4-Cv-alkylcycloalkyl", "C4-Cv-alkylheterocycloalkyl".

The term "C 1 -C 6 -alkylsulfonylamino(group)" means "C 1 -C 6 -alkyl groups having a sulfonylamino group as a substituent, including 2-ethylsulfonylamino)ethyl and the like.

The term "aminosulfonyl" means the group -502-MEKK, where each of K, K' independently of the other is hydrogen, "Ci-Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl", "C3 -C 1 -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C 1 -C 2 -alkylaryl" or "C 1 -C 2 -alkylheteroaryl", "C 1 -C 2 -alkenylaryl", "Co -C 2 -alkenylheteroaryl" , "Co-Cv-alkynylaryl", "Co-Cv-alkynylteteroaryl", "C4-Cv-alkylcycloalkyl", "Ci-Cv-alkylheterocycloalkyl".

The term "C.4-Cv-alkylaminosulfonyl" means C.i.-Cv-alkyl groups having an aminosulfonyl substituent,

Including 2-(cyclohexylaminosulfonyl)ethyl, etc.

The term "substituted or unsubstituted": If the definition of an individual substituent is not otherwise limited, the above groups, for example, "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl", etc., may be optionally substituted with substituents ranging from 1 to 5, selected from the group consisting of "C--Cv-alkyl", "Co-Cv-alkenyl", "Co-Cv-alkynyl", "cycloalkyl", "heterocycloalkyl", "C4-Cv-alkylaryl ", "C.-Cv-alkylheteroaryl", ch two C1-Cv-alkylcycloalkyl", "C.-Cv-alkylheterocycloalkyl", "amino(group)", "ammonium", "acyl", "acyloxy(group)" , "acylamino(group)", "aminocarbonyl", "alkoxycarbonyl", "Ureido(group)", "aryl", "carbamate", "heteroaryl", and) "sulfinyl", "sulfonyl", "alkoxy(group) ", "sulfanyl", "halogen", "carboxy(l)", trihalomethyl, cyano-, hydroxy-, mercapto-, nitro group, etc. Alternatively, such substitution may also include cases where adjacent substituents may be subject to ring closure, particularly when adjacent functional c zo substituents are reacted to form, for example, lactams, lactones, cyclic anhydrides, but also acetals, thioacetals, aminals, which are formed by closing the cycle, for example, with the aim of forming the b" protecting group. M

The term "pharmaceutically acceptable cationic salts or complexes" is intended to include salts such as alkali metal salts (eg, sodium and potassium), alkaline earth metal salts (eg, calcium or magnesium), aluminum salts, ammonium salts, and salts with organic amines, for example, with methylamine, dimethylamine, y-trimethylamine, ethylamine, triethylamine, morpholine, M-Me-O-glucamine,

M,M'-bis(phenylmethyl)-1,2-ethanediamine, ethanolamine, diethanolamine, ethylenediamine, M-methylmorpholine, piperidine, benzathine (M,M'-dibenzylethylenediamine), choline, ethylenediamine, meglumine (M-methylglucamine), benetamine (M-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), procat, as well as amines of the formula -MK,K,A", where K, K, K" sha c is independently hydrogen, alkyl or benzyl. Particularly preferred salts are sodium and potassium salts. ;" The term "pharmaceutically acceptable salts or complexes" means salts or complexes of the following compounds of the present invention that retain the desired biological activity. Examples of such salts include, but are not limited to, salts formed with inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, etc.) and salts formed with organic acids, e.g., acetic, oxalic , tartaric, succinic, malic, fumaric, maleic, ascorbic, se) benzoic, tannic, pamoic, alginic, polyglutamic, naphthalene sulfonic, -I naphthalene disulfonic and polygalacturonic acids. The above-mentioned compounds can also be used in the 5o form of pharmaceutically acceptable quaternary salts known to specialists, which, in particular, include quaternary ammonium salts of the formula -MK,K,K"772", where K, EK", KE" independently of the others are hydrogen , alkyl or benzyl, c» C 1 -C 1 -alkyl, C 1 -C 1 -alkenyl, C 1 -C 2 -alkynyl, C 1 -C 2 -alkylaryl, C 1 -C 2 -alkylheteroaryl, cycloalkyl, heterocycloalkyl and 7 is the counterion, in which including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, madate, fumarate, citrate, tartrate, ascorbate, tinnamoate, mandeloate, and diphenyl acetate ).

The term "pharmaceutical active derivative" means any compound which, when introduced into the body, is capable of providing, directly or indirectly, the action described herein. ime) The term "enantiomeric excess (ee)" refers to products obtained by asymmetric synthesis, that is, synthesis using non-racemic starting materials and/or reagents or synthesis that includes at least one enantioselective stage, and an excess of one enantiomer of the order of at least 5295 ee is obtained.

The general formula (I) according to the present invention also covers tautomers, geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic forms, as well as pharmaceutically acceptable salts of the said compound. Among the pharmaceutically acceptable salts of the formula according to the present invention, 65 salts with pharmaceutically acceptable acids are preferred, for example, the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrophosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,

tartrate, gluconate, methanesulfonate, benzenesulfonate and para-toluenesulfonate.

The compounds of this invention can be obtained as a mixture of E/7 isomers or as practically pure

E-isomers or 7-isomers. Said E/27-isomerism in a preferred embodiment relates to the vinyl bridge between the phenyl and the azolidinone group. In one specific embodiment, the compounds of formula (I) are 2-isomers.

The first aspect of the present invention consists in the use of compounds of formula (I) with () and others, as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of these compounds for the manufacture medicinal product for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, complications of transplantation caused by rejection reactions, transplant rejection or lung injuries.

In a preferred embodiment, these compounds are used for the treatment and/or prevention of autoimmune disorders or inflammatory diseases, such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pneumonia, thrombosis, or infectious disease. or inflammation of the brain, such as meningitis or encephalitis.

According to another preferred embodiment of the present invention, these compounds are used for the treatment and/or prevention of neurodegenerative diseases, including multiple sclerosis,

Alzheimer's, Huntington's chorea, central nervous system trauma, stroke or ischemic conditions. at

According to a particularly preferred embodiment of the present invention, these compounds would be used for the treatment and/or prevention of cardiovascular diseases, for example, atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, elevated blood pressure or vasoconstriction. uh-

According to another embodiment of the present invention, which is particularly preferred, these compounds Ge! are used for the treatment and/or prevention of chronic obstructive pulmonary disease, fibrotic 32 anaphylactic shock, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, aphagia/activation of platelets, atrophy/hypertrophy of skeletal muscle, leukocyte recruitment in cancerous tissue, angiogenesis, tumor metastasis, in particular, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, caused by reactions of rejection complications "transplantation, transplant rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial lung injuries and inflammation of the pulmonary airways in general. Substituents in formula (I) correspond to the following definitions: » A - unsubstituted or substituted 5-8-ene heterocyclic group or unsubstituted or substituted carbocyclic group.

Said carbocyclic group can be fused with unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocycloalkyl. These heterocyclic or carbocyclic groups include aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, including phenyl, phenanthrenyl, cyclopentane, cyclohexyl, norbornyl, pyrrolidine, piperidine, piperazine, -1-methylpiperazine, morpholine, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,

Ge) 20 isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3 ,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,

Fe» 1(2,3-dihydrobenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl,

ZH-indolyl, benzimidazolyl, imidazo|1,2-a|pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinolinyl, naphthyridinyl, pyridoyZ,4-b|pyridyl, pyridoYZ,2-b)|gridyl, 99 pyrido(|4,3-b|pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,

HF) 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl and benzoquinolyl.

Additional examples of heterocyclic or carbocyclic A groups include unsubstituted or substituted de dioxol, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (dihydro)furanyl, unsubstituted or substituted (dihydro)oxazinyl, unsubstituted or substituted 60 oxazinoyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro)naphthalenyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted thiazolyl or unsubstituted unsubstituted or substituted oxadiazolyl. because X is 5, O or MH, whichever option is preferred, 5.

Each of Y" and Y? is independently selected from the group consisting of 5, O and -MH, preferably O. 27 - C or O, preferably O.

He is selected from the group consisting of or including H, CM, carboxyl, acyl, C--Cv-alkyloxy, halogen, hydroxy-, acyloxy group, unsubstituted or substituted C.-Cv-alkylcarboxy group, unsubstituted or substituted C.-Cv -alkylacyloxy group, unsubstituted or substituted C.C.-C.sub.-alkylalkyloxy group, alkoxycarbonyl, unsubstituted or substituted C.-C.sub.-alkylalkyloxycarbonyl, aminocarbonyl, unsubstituted or substituted

C.-Ci-alkylaminocarbonyl, acylamino group, unsubstituted or substituted C.-Ci-alkylacylamino group, ureido group, 70 unsubstituted or substituted C.-Ci-alkylureido group, amino group, unsubstituted or substituted

C.-Ci-alkylamino group, ammonium, sulfonyloxy group, unsubstituted or substituted C.-Ci-alkylsulfonyloxy group, sulfonyl, unsubstituted or substituted C.-Ci-alkylsulfonyl, sulfinyl, unsubstituted or substituted

C.-Ci-alkylsulfinyl, sulfanil, unsubstituted or substituted C.-Ci-alkylsulfonyl, sulfonylamino group, unsubstituted or substituted C.-Ci-alkylsulfonylamino group, and carbamate. According to a specific variant of the implementation of B! yen 2 is selected from the group consisting of or including H, halogen, acyl, amino, unsubstituted or substituted C-C6-alkyl, unsubstituted or substituted C0-C0-alkenyl, unsubstituted or substituted C0-C6-alkynyl, unsubstituted or substituted C.-Ci-alkylcarboxy group, unsubstituted or substituted C.i-Ci-alkylacyl, unsubstituted or substituted C.-Ci-alkylalkyloxycarbonyl, unsubstituted or substituted C.-Ci.-alkylaminocarbonyl, unsubstituted or substituted Ci-Ci-alkylcyclooxy group, unsubstituted or substituted C.--Cv-alkylacylamino group, unsubstituted or substituted C.i-Cv-alkylureido group, unsubstituted or substituted C.i.-C.sub.-alkylcarbamate, unsubstituted or substituted C.-Cv-alkylamino group, unsubstituted or substituted C.-Cv-alkylalkyloxy group , unsubstituted or substituted C 1 -C 6 -alkylsulfanyl, unsubstituted or substituted C 1 -C 6 -alkylsulfinyl, unsubstituted or substituted

C.-Ci-alkylsulfonyl, unsubstituted or substituted C.4-Ce-alkylsulfonylaminoaryl, unsubstituted or substituted CM aryl, unsubstituted or substituted C5-Ci-cycloalkyl or heterocycloalkyl, unsubstituted or substituted o

C 1 -C 6 -alkylaryl, unsubstituted or substituted C 1 -C 6 -alkenylaryl, unsubstituted or substituted

Co-Cv-alkynylaryl, carboxyl, cyano, hydroxyl, C-C-Alkoxy-, nitro-, acylamino-, ureido-, sulfonylamino, sulfanyl, and sulfonyl. n is an integer 0, 1 or 2, according to the preferred option, n is 0 or 1. According to the most preferred option, n-0. Fo

According to a specific embodiment of the present invention, each of B! and B? is N.

According to a further specific embodiment of the present invention, X is 5, each of the joys? е6О, in IV - correspond to the above definitions and n - 0. Ge»)

A further specific aspect of the present invention, which is preferred, concerns the use of thiazolidinedione derivatives of condensed vinylbenzenes of formulas (Ia), (IB), (Is) and (14) for the manufacture of a medicinal product for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases , cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, caused by reactions of rejection complications of "transplantation, transplant rejection or lung injuries: from c (z) 2" A st, i 1 a i 55 --x and Pa -i t-snh se) -

V. ele sn DUH i i i ; KU, M", 2 and H in the formula (Ia) correspond to the above definitions. and), but in the formula (Ia) there is an unsubstituted or substituted C.i.-Cv-alkylene (for example, methylene, ethylene, propylene, etc.) "co or unsubstituted or substituted C.i-C5-alkenylene group (for example, methine (-CH-), -СНАСН-. group, propenylene group, etc.).

Each of Mu and M in formula (Ia) is independently selected from the group consisting of 0, 5, -MA U, where BZ is in H or an unsubstituted or substituted C 1 -C 6 -alkyl group, each of t and o regardless of the other is 0 or 1; o is an integer from 1 to 4 and 4 is an integer from 0 to 4.

F) Even greater preference is given to compounds of formula (Ia), where C is C 4 -C 4 -alkylene, which respectively form compounds of formula (IB) (i.e. p-1, 2, C or 4, according to the preferred option , 1 or 2). at w (in) t " sleep, about Rozhny nn p (M -- Nd. b5

A specific subgroup of the formula (IB) is the compounds having the formula (Ic), and MU, B", M" correspond to the above definitions; in particular, BC can be selected from the group consisting of an unsubstituted or substituted C.-C,-alkyl group or an unsubstituted or substituted C.-C-alkenyl group, carboxyl, cyano-,

Si-C,-Alkoxy-, nitro-, acylamino-, ureido groups. I (Is) k- sh-2f492 7 14 be)

Another specific subgroup of formula (Ia) are compounds where each of M, MU and U" is O, i.e., compounds of formula (Id).

According to the preferred embodiment, in formulas (Ia), (IV) and (Id), n is 0, t is 1, p is 1 or 2.0-0.4-1, and B its 82 correspond to the above definition and)

According to a further specific variant of implementation, in formulas (Ia), (IB) and (Id), t -1, n -0, p-1 or2, 4 -0, o - 1, while B! and 2 correspond to the above definitions, more specifically B! is a halogen or hydrogen atom. co

According to a further specific variant of implementation, in formulas (Ia), (IB) and (Id), p - 1 or 2,4-0,t-0,n-1tav! b and b? meet the above definitions.

The compounds according to the present invention are suitable for modulating, especially inhibiting, the activity of phosphoinositide 3-kinase (PZK), especially y-3-kinase of phosphatoinositides (PZK). Thus, it is intended that the compounds of the present invention would also be particularly useful for the treatment and/or prevention of disorders mediated by

CUT, especially CUT. Said treatment includes modulation - especially inhibition or regulation by type - of negative (feedback) - phosphatoinositide Γ-kinases.

The following compounds are not covered by formula (1):

IS . g "; i: и по сш Й ИЙ что Й б: а, Я с в

Chek vk - V

B' is lower alkyl or aralkyl and B2 is H or halogen. TE compounds are disclosed (in UR 55 045648) as intermediate (Se) compounds without any biological activity, while (as ZA is mentioned in docsgpa! oi Medisipa! Spetivig -1 (1998), 41(18), 3515-3529 ) as inactive in the limb swelling test.

The compounds of this invention, in particular, include compounds that are included in the following group, which (se) 50 consists of: 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidin-2,4 -dione 5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one 5-(2,3-dihydro-1,4-benzodioxin-b-ylmethylene)-1 ,3-thiazolidine-2,4-dione 5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione 5-(7-methoxy-1,3- benzodioxol-5-yl)umethylene|-1,3-thiazolidine-2,4-dione

HF) 5-MK9,10-dioxo-9,10-dihydroanthracen-2-yl)methylene|-1,3-thiazolidine-2,4-dione from (5-K2,2-difluoro-1,3-benzodioxol- 5-yl)umethylene|-1,3-thiazolidine-2,4-dione (527)-5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4- dione in 5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidin-2,4-dione 5-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine- b-yl)methylene-1,3-thiazolidin-2,4-dione 5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidin-4-one 5-quinolin-b6- ylmethylene-thiazolidine-2,4-dione 5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one b 2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one 5-(3-methyl -benzoi|h|isoxazol-5-ylmethylene)-thiazolidine-2,4-dione

5-(4-phenyl-quinazolin-b-ylmethylene)-thiazolidine-2,4-dione 5-(4-dimethylamino-quinazolin-b-ylmethylene)-thiazolidine-2,4-dione 5-K4-aminoquinazolin-b- yl)umethylene-1,3-thiazolidine-2,4-dione 5-K4-piperidin-1-ylquinazolin-b-yl)umethylene)-1,3-thiazolidine-2,4-dione 5-K4-morpholine-4 -ylquinazolin-b6-yl)umethylene|-1,3-thiazolidine-2,4-dione 5-14-(benzylamino)quinazolin-6-yl|methylene)-1,3-thiazolidine-2,4-dione 5- C4-(diethylamino)quinazolin-b6-yl|methylene)-1,3-thiazolidine-2,4-dione 5-(4-(pyrudin-2-ylmethyl)aminoquinazolin-b-yl)umethylene)-1,3- thiazolidine-2,4-dione 70 5-(4-Kpyridin-3-ylmethyl)amino)quinazolin-b-ylumethylene)-1,3-thiazolidine-2,4-dione ethyl-1-16-(2,4- dioxo-1,3-thiazolidin-5-ylidene)methyl/thinazolin-4-ylylpiperidine-3-carboxylate ethyl 1-16-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/thinazolin- 4-Ilupiperidine-4-carboxylate tert-butyl-1-76-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methylquinazolin-4-yl)-I -prolinate 5-(C4-(4- methylpiperazin-1-yl)quinazolin-6-yl|methylene)-1,3-thiazolidin-2,4-dione 5-C4-(4-pyrimidin-2-ylpiperazin-1-i l) quinazolin-b6-yl|methylene)-1,3-thiazolidine-2,4-dione 5-(4-14-(4-fluorophenyl)pyridin-1-yl)quinazolin-b-ylmethylene)-1,3 -thiazolidine-2,4-dione 5-14-(4-benzylpiperidin-1-yl)quinazolin-b-yl)methylene)-1,3-thiazolidine-2,4-dione 5-(4-I4-(2 -phenylethyl)piperidin-1-yl)quinazolin-6-ylmethylene)-1,3-thiazolidine-2,4-dione 5-(C4-(4-methylpiperidin-1-yl)quinazolin-6-yl|methylene)- 1,3-thiazolidine-2,4-dione 5-C4-(4-hydroxypiperidin-1-yl)quinazolin-b6-yl|methylene)-1,3-thiazolidine-2,4-dione 1-(6-( 2,4-dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl|-piperidine-4-carboxylic acid 1-(6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl |-piperidine-33-carboxylic acid 1-(6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl|I-pyrrolidine-2-carboxylic acid 5-(4-methylamino-quinazolin- 6-ylmethylene)-thiazolidine-2,4-dione 5-(4-methoxy-quinazolin-b-ylmethylene)-thiazolidine-2,4-dione 2-imino-5-(4-methylamino-quinazolin-b6-ylmethylene) )-thiazolidin-4-one and) 2-imino-5-(4-piperidin-quinazolin-6-ylmethylene)-thiazolidin-4-one 2-imino-5-(4-dimeth ylamino-quinazolin-b6-ylmethylene)-thiazolidin-4-one 5-(2-methyl-2H-benzotriazol-5-ylmethylene)-thiazolidin-2,4-dione c zo 5-(3-methyl-ZH-benzotriazol- 5-ylmethylene)-thiazolidine-2,4-dione 5-(3Z-ethyl-3H-benzimidazol-5-ylmethylene)-thiazolidine-2,4-dione Me) 5-11-(4-phenylbutyl)-1H-benzimidazole -b-yl|methylene)-1,3-thiazolidine-2,4-dione M 5-((1-prop-2-yn-1-yl-LH-benzimidazol-b-yl)methylene|-1,3 -thiazolidine-2,4-dione 5-(1-2-(4-«(trifluoromethyl)phenyl|ethyl)-1H-benzimidazol-b-yl)methylene|-1,3-thiazolidine-2,4-dione me ) 5-(11-(2-(4-hydroxyphenyl)ethyl|-1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2,4-dione l-methyl-4-16-((2 ,4-dioxo-1,3-thiazolidin-5-ylidene)umethyl|-1H-benzimidazol-1-yl)ucyclohexanecarboxylate 5-(11-(2-(5-methoxy-1H-indol-3-yl)ethyl| -1H-benzimidazol-b-ylmethylene)-1,3-thiazolidine-2,4-dione 5-(41-(1-methyl-1H-pyrazol-4-yl)umethyl|-1H-benzimidazol-b-yl) methylene)-1,3-thiazolidine-2,4-dione 5-(11-(2-(3,4-dimethoxyphenyl)ethyl|-1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2 ,4-dione "5-(11-(2-(4-phenoxyphenyl)ethyl|-1H-b enzymidazole-b-ylmethylene)-1,3-thiazolidine-2,4-dione with 5-(11-(4--trifluoromethyl)benzyl/|-1H-benzimidazole-b-ylmethylene)-1,3-thiazolidine- 2,4-dione. 4-(6-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1H-benzimidazol-1-yl)ucyclohexanecarboxylic acid and? 5-(1-isobutyl-1H-benzimidazol-b-yl)methylene-1,3-thiazolidin-2,4-dione 5-(11-(2-(1,3-benzodioxol-4-yl)ethyl|- 1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2,4-dione 5-(11-(2-(2-phenoxyphenyl)ethyl|-1H-benzimidazol-b-ylumethylene)-1,3 -thiazolidine-2,4-dione -I 5-Ш11-(3,3-diphenylpropyl)-1H-benzimidazol-6b-yl|imethylene)-1,3-thiazolidine-2,4-dione 5-Ш11-(2 -methoxybenzyl)-1H-benzimidazol-b-yl|methylene)-1,3-thiazolidine-2,4-dione and 5-X11-(3-furylmethyl)-1H-benzimidazol-b-yl|methylene)-1, 3-thiazolidine-2,4-dione -I 5-((1-propyl-1H-benzimidazol-b-yl)methylene-1,3-thiazolidine-2,4-dione 5-quinoxalin-b6-ylmethylene-thiazolidine- 2,4-dione se) 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one 4) 2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one 5-benzothiazol-b6-ylmethylene -thiazolidine-2,4-dione 5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione 5-(2-bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2 ,4-dione 5-(3-bromo-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione

F) ethyl ester of 3-I|5-(2,4-dioxo-thiazolidine-5-ylidenemethyl)-benzofuran-3-ylI-acrylic acid ka 3-I5-(2,4-dioxo-thiazolidine-5-ylidenemethyl) )-benzofuran-3-yl|1-acrylic acid 5-3-(3-oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene|/-thiazolidin-2,4-dione in methyl- 1-((3-75-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1-benzofuran-3-yl)iprop-2-enoyl)prolinate methyl-1-((3 -5-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1-benzofuran-3-yl)iprop-2-enoyl)-O-prolinate (5-(13-(3- oxo-3-pyrrolidin-1-ylprop-1-en-1-yl|-1-benzofuran-5-yl)imethylene)-1,3-thiazolidin-2,4-dione 5-(13-13-morpholine- 4-yl-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1,3-thiazolidine-2,4-dione methyl-1-(3-15-( 2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-ylprop-2-enoyl)-I-prolinate 65 M-cyclohexyl-3-15-I((2, 4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-yl)-M-methylacrylamide 3-15-(2,4-dioxo-1,3-thiazolidin-5-ylidene )methylyl-1-benzofuran-3-yl)-M-ethyl-M-(2-hydroxyethyl)acryl.: amide

M-cyclobutyl-3-15-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl-1-benzofuran-3-yl acrylamide 5-(13-13-azetidin-1-yl-3- Oxoprop-1-en-1-yl|-1-benzofuran-5-yl)imethylene)-1,3-thiazolidin-2,4-dione 5-(13-I3-(1,3-dihydro-2H-isoindole) -2-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1,3-thiazolidine-2, 4-dione 5-(13-13-azepan- 1-yl-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1,3-thiazolidine-2,4-dione 3-15-(2,4-dioxo- 1,3-thiazolidin-5-ylidene)methylyl-1-benzofuran-3-yl)-M-piperidin-1-ylacrylamide 3-15-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methylyl -1-benzofuran-3-yl)-N-(pyridin-3-ylmethyl)acrylamide

M-cyclohexyl-3-(5-I((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-ilyacrylamide 70 5-(13-I3-«4- methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)umethylene)-1,3-thiazolidine-2,4-dione

M-cycloheptyl-3-(5-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-ilyacrylamide 5-(13-I3-(2,5- dihydro-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1,3-thiazolidine-2,4-dione

M-cyclopentyl-3-75-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl I-1-benzofuran-3-yl acrylamide ethyl ester 3-I|5-(2,4-dioxo -thiazolidin-5-ylidenemethyl)-benzofuran-3-ylI-propionic acid 3-I5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-propionic acid 5-IZ-(3- oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene|-thiazolidine-2,4-dione tert-butyl ester 6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2, 3-dihydro-benzo|1,oxazine-4-carboxylic acid 5-(3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione 5-(4-benzoyl- 3,4-dihydro-2H-benzo|1,oxazin-6-ylmethylene)-thiazolidine-2,4-dione 5-(4-acetyl-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene )-thiazolidine-2,4-dione tert-butyl ester of 6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzo|1,oxazine-4-carboxylic acid methyl ester

I6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo|1,41-oxazin-4-yl|-acetic acid

M-benzyl-2-I(6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo|1,oxazin-4-yl|-acetamide (8) 5 -(4-butyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione 5-(4-benzyl-3-oxo-3,4 -dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione 5-(2-chloro-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione c zo 5-(3 -amino-benzo|d4|isoxazol-5-ylmethylene)-thiazolidine-2,4-dione 5-(3Z-phenylethynyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione Me 5-benzo|1,2 ,5-Hiadiazol-5-ylmethylene-thiazolidine-2,4-dione M 5-benzo|1,2,5)oxadiazol-5-ylmethylene-thiazolidine-2,4-dione 5-(2-methyl-benzofuran-b-ylmethylene )-thiazolidine-2,4-dione me) 5-(2-carboxymethyl-benzofuran-b-ylmethylene)-thiazolidine-2,4-dione y- 5-(3-bromo-2-fluoro-2,3-dihydro -benzofuran-b-ylmethylene)-thiazolidine-2,4-dione 5-(2-fluoro-benzofuran-b-ylmethylene)-thiazolidine-2,4-dione

A further aspect of the present invention consists in new thiazolidinedione derivatives of condensed vinylbenzenes of the formula (PI-a)

B. o se) - Group A is selected from the group consisting of unsubstituted or substituted dioxol, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (Ce) 20 (dihydro)furanyl, unsubstituted or substituted (dihydrodoxazinyl, unsubstituted or substituted oxazinoyl, c» unsubstituted or substituted pyridinyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro)naphthalenyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or unsubstituted sandazine substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted oxadiazolyl. (F; c: selected from the group consisting of or consisting of H, halogen, acyl, amino, unsubstituted or g substituted C-C 1 -alkyl, unsubstituted or substituted C0-C0-alkenyl, unsubstituted or substituted C0-Ce-alkynyl, unsubstituted or substituted C.-Ce-alkylcarboxy group, unsubstituted or substituted C.i-Cv-alkylacyl, unsubstituted or substituted C.-Ce-alkylalkyloxycarbonyl, unsubstituted or substituted C.-Ce.-alkylaminocarbonyl, unsubstituted or substituted C.--Cv -alkylacyloxy group, unsubstituted or substituted C.4-Cv-alkylacylamino group, unsubstituted or substituted C.i-Cv-alkylureido group, unsubstituted or substituted C.i-C0-alkylcarbamate, unsubstituted or substituted C.-Cv-alkylamino group, unsubstituted or substituted C .-C 1 -alkylalkyloxy group, unsubstituted or substituted C 1 -C 2 -alkylsulfanyl, unsubstituted or substituted C 1 -C 2 -alkylsulfinyl, unsubstituted or substituted C 1 -C 2 -alkylsulfonyl, unsubstituted or substituted C 4 -C 2 -alkylsulfonylaminoaryl , unsubstituted or substituted aryl, unsubstituted or substituted C»-Cv-cycloalkyl or heterocycloalkyl, unsubstituted or substituted

C 1 -C 6 -alkylaryl, unsubstituted or substituted C 1 -C 6 -alkenylaryl, unsubstituted or substituted

C 1 -C 2 -alkynylaryl, carboxyl, cyano, hydroxyl, C 1 -C 6 -alkyl, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.

More specifically, new thiazolidinone derivatives of condensed vinylbenzenes of the formula (II)

He m (0 -y I, I I: in as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of these compounds, where 7, 7, B", 2 correspond to the above definitions and n is 0 or 1.

In a specific embodiment, B is unsubstituted or substituted C1-C8-alkyl, unsubstituted or substituted C1-C8-alkylaryl, unsubstituted or substituted aryl, unsubstituted or substituted C5-C8-cycloalkyl or -heterocycloalkyl, unsubstituted or substituted C1-C8-cycloalkyl -S-alkylaryl, unsubstituted or substituted

C0-C0-alkenylaryl, unsubstituted or substituted C0-C6-alkenylaryl.

According to another preferred embodiment of the present invention, U.

A further aspect of the present invention consists in new thiazolidinedione derivatives of condensed vinylbenzenes of the formula (PI) and (1). about Афе and созой віра as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of these compounds, /F) zv De B" and Kk? correspond to the above definitions (dashed line means the optional presence of a double bond).

A further embodiment includes compounds of formulas (IM), (M) and (MI): and m sp

B" is selected from the group consisting of hydrogen, halogen, cyano, C1-C8-alkyl, C1-C8-alkyl, acyl, and alkoxycarbonyl, while EC? corresponds to the above definition. According to a specific embodiment, B" : there is an amino group.

A further aspect of the present invention is the use of new compounds of formulas (II), (PI-a), (PI), (M), (M) or - (MI) as medicinal products. o 20 Another additional aspect of the present invention is a pharmaceutical composition containing at least one thiazolidinone derivative of condensed vinylbenzene according to formulas (I), (PI), (IM) (M) or (MI) and a pharmaceutically acceptable carrier, diluent or excipient .

Another additional aspect of the present invention is the use of compounds according to the formulas (II), (PI), (IM), (M) or (MI) for the manufacture of a medicinal product for the prevention and/or treatment of diseases mediated by RIS and Kkinase, especially y-RIS by kinase

GF! Specific diseases are diseases selected from the group consisting of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, rejection reactions, transplant complications, transplant rejection or lung injury. 60 In a preferred embodiment, said compounds are used for the treatment and/or prevention of autoimmune disorders or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pneumonia, thrombosis or infectious disease or inflammation brain, for example, meningitis or encephalitis.

According to another preferred embodiment of the present invention, these compounds are used for the treatment and/or prevention of neurodegenerative diseases, including multiple sclerosis,

Alzheimer's, Huntington's chorea, central nervous system injury, stroke or ischemic conditions.

According to a particularly preferred embodiment of the present invention, these compounds are used for the treatment and/or prevention of cardiovascular diseases, for example, atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, high blood pressure or vasoconstriction.

According to another preferred embodiment of the present invention, these compounds are used for the treatment and/or prevention of chronic obstructive pulmonary disease, fibrotic anaphylactic shock, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, platelet aggregation/activation , atrophy/hypertrophy of skeletal muscle, leukocyte recruitment in cancer tissue, angiogenesis, tumor metastasis, in particular, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis caused by rejection reactions, transplant complications, transplant rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial lung injuries and inflammation of the pulmonary airways in general.

According to the present invention, the compounds of formulas (II), (PI-a), (PP) (IM), (M) or (MI) are suitable for modulating, especially inhibiting, the activity of RISK kinase and more specifically the activity of RISKU.

A further object of the present invention is a method of obtaining thiazolidinone derivatives of condensed vinylbenzenes according to formulas (I), (Ia), (IB), (Is) or (Id), as well as thiazolidinedione derivatives of condensed vinylbenzenes of formulas (II), (PI-a ), (11), (IM), (M) or (MI).

The thiazolidinone derivatives of fused vinylbenzenes exemplified herein can be prepared from readily available starting materials using the following general methods and techniques. It should be borne in mind that in cases where typical or preferred experimental conditions are indicated (i.e., reaction temperatures and durations, molar ratios of reagents, solvents, etc.), other experimental conditions may also be used, unless otherwise specified. Optimal reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be easily determined by one skilled in the art using conventional optimization procedures. with

In the method illustrated in the diagrams below, each of B", 2, 5, M, M, Y, m, 7, t, n, O, p and a 5) is as defined above in this specification.

As a rule, azolidinone derivatives of condensed vinylbenzenes of the general formula (I) can be obtained by several methods of synthesis, using methods of both liquid-phase and solid-phase chemical synthesis

Ivgittop her. AI., 9.0.S., 64, 1723-1726 (1999)) either by conventional methods or using microwave technology. her ze K g. E ke Y A r

I bow and I sew fe

What! : I tya What KI yo Z What is this oh nya i- poshanu vva

What I' 7 J. « that I -- zhk s vi R b "». -y , o tm not h Ж e- pr: syu" As x v ta and Ma

In the first stage, approximately equimolar amounts of the aldehyde reagent RI (Ria) and compound 2 (specifically, thiazolidinedione or rhodanine, RZ) are heated in the presence of a base (weak bases are preferred) and

F) obtain the corresponding olefin of formula (Ia). At the first stage, Ria can be replaced by the starting compounds КА ПТХ and РІС in order to obtain the final compounds, respectively (IB) and (ІС), described above. t bo sk, pe. and t- that ". m-n ShK vk, sno shchi R Ris

Methods particularly preferred by the present invention are illustrated by Schemes 3 and 4 below, in which compounds of formulas (II) and (II) can be prepared, respectively, using the above-mentioned reaction. " d h and dust

IS ; She and "Pybka mastered to p vi t from Siem4 2

Eat and kick an elephant, on the basis - and about

Although this step can be carried out in the absence of a solvent at a temperature high enough to at least partially melt the reaction mixture, it is preferably carried out in the presence of an inert solvent. Temperatures in the range of about 1002C to 2502C are preferred, and temperatures in the range of about 1202C to 20020C are particularly preferred. Examples of solvents suitable for (ze) the above reaction include solvents such as dimethoxymethane, xylene, toluene, o-dichlorobenzene, and the like. Fo

Examples of weak bases suitable for carrying out the above-mentioned reaction are alkaline and alkaline earth salts of weak acids, for example, (C.4-C42)-alkylcarboxylic acids and benzoic acid, carbonates and bicarbonates of alkaline and alkaline earth metals, for example, calcium carbonate, carbonate magnesium, potassium bicarbonate, and Pho secondary amines such as piperidine, morpholine, and tertiary amines such as pyridine, triethylamine, diisopropylethylamine, M-methylmorpholine, M-ethylpiperidine, M-methylpiperidine and the like. Sodium acetate or piperidine are particularly preferred among weak bases for reasons of economy and efficiency.

As a rule, when carrying out a reaction of this type

Regdatop Rgezv, Ohio 1991, Eavz.: Tgtovy V.M., Rietipd I. aldehyde starting material P'a and other starting material (for example, thiazolidinedione) RZ in approximately equimolar amounts are mixed with 0.5-1 equivalent of piperidine in dimethoxymethane or a similar solvent and heated at a temperature from t s 12020 to 2002С, at which the reaction is practically completed in a time of approximately 15 minutes. to Agreement The target c» olefin of formula (Ia) is then isolated by filtration if it precipitates from the reaction mixture on cooling, or, for example, by mixing with water followed by filtration, and a crude product is obtained, which, if necessary, is purified, for example, by crystallization or by standard chromatographic methods.

Alternatively, the compound of formula (Ia) can be prepared typically by mixing equimolar amounts of thiazolidinedione RZ with Ria aldehyde and a molar excess (in the variant,

Ge) which is preferred, with a 2-4-fold excess) of anhydrous sodium acetate and heating the resulting mixture at a temperature high enough for melting; at such a temperature, the reaction is practically completed in the time s- from bhv. to bOkhv.

Ge) 20 In a preferred embodiment, the above reaction is carried out in an acidic medium, for example, in acetic acid, in the presence of sodium acetate or β-alanine. c» Alternatively, the above reactions can be carried out using microwave energy as a heat source. As a rule, aldehyde starting material Ra and thiazolidinedione RZ in approximately equimolar quantities are mixed with 0.5-1 equivalent of piperidine in dimethoxymethane or a similar solvent and heated at a temperature of 22 from 1402С to 2402С, at which the reaction is practically completed in a time from Zhv. up to 10 minutes

GF) Pharmaceutically acceptable cationic salts of the compounds of this invention are easily prepared by reacting their acid forms with a suitable base, usually in the amount of Eq., in a common solvent. Typical bases include sodium hydroxide, sodium methylate, sodium ethylate, sodium hydride, potassium hydroxide, potassium methylate, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benetamine, 60 diethylamine, piperazine, and tromethamine. The resulting salt is isolated by concentrating it to dryness or adding a precipitant (a liquid in which the salt does not dissolve). In some cases, salts can be prepared by mixing a solution of the acid with a solution of a salt containing the appropriate cation (sodium ethylhexanoate, magnesium oleate), using a solvent from which the desired salt precipitates, or by isolating it by concentration and the addition of a precipitant. Because 2,4-azolidinone derivatives of RZ can be purchased on the market from various suppliers.

Aldehydes of the formula Ra are prepared by a variety of known methods, for example, by oxidation and reduction using as starting compound the aliphatic ester of the corresponding carboxylic acid or carboxylic acid using standard methods for the reduction of the carboxylic ester

ACID or carboxylic acid to benzyl alcohol with lithium aluminum hydride, diisopropylaluminum, etc. and subsequent oxidation of the corresponding benzyl alcohol to the corresponding aldehyde by oxidation under mild conditions using, for example, manganese dioxide, chromic acid, Dess-Martin's reagent or Swern's oxidation, or under known conditions for the production of aldehydes from primary alcohols. An alternative method may be the direct reduction of the corresponding complex ester of a carboxylic acid or 70 carboxylic acid to the corresponding aldehyde using RIVAY. at low temperature or any other method known in the art. 7; and Iv shchi tt and shchi 7 I nn

An alternative method of obtaining suitable aldehydes is the selective reduction of the nitrile group to the corresponding aldehyde using known methods, for example, OIVAG. etc. Another method of obtaining sz aldehydes of the formula R'ia is the selective reduction of the corresponding acyl chlorides using, for example, lithium-aluminum tri-tert-butoxyhydride (Spa). 5., Vgomp NS, 9U.O.S 1993, 58, p. 4732-4734| Another Ge) alternative method of obtaining suitable aldehydes is to carry out a Friedel-Crafts type reaction with the corresponding benzene derivative, in which the compound P4, as shown in Scheme 5 above, is reacted with 1,1-dichloromethylmethyl ether in the presence of a Lewis acid, e.g. , titanium tetrachloride or aluminum sodium trichloride, or any suitable Lewis acid suitable for a reaction of this type.

According to the method of the present invention, which is more preferred, described in the literature (Reig Ge)

O.I., Kayispema M.V., Apiopoma A.T., SoPesi. Blind people Spent Sottip, 62, pp. 494-497 (1997)| and illustrated in Scheme 6 below, reagent P2 can be prepared using compound RB as a starting material by reacting it with 1,1-dichloromethylmethyl ether as described above. Ge) z blem b cha g valid o o 7o-z z . t "b : y y y y -1 According to another more preferred method of the present invention illustrated by the following

According to Scheme 7, the RbE reagent can be obtained using the compound P7 as a starting material, by (Ce) carrying out its reaction with OME in the presence of magnesium or n-butyllithium, or by any other method known to specialists. yu SIM se) yu» spruces yu " R.

According to another more preferred method of the present invention, illustrated in Scheme 8 below, the reagent Pb can be prepared using the compound PO as a starting material by reacting it with n-butyllithium or GOA in the presence of the corresponding electrophilic compound BC 7 -X, or in any other way known to specialists. The same method can be applied again to P8 in order to obtain Pb. b5

Stvma 7th entrance

IY and p, c

Similarly, saturated starting compounds of RbE can be obtained without isolation of intermediate products using

PO and the corresponding electrophilic compounds 2-X and B2-X, as shown in Scheme 9.

Scheme 9 15 untranslated, National Academy of Sciences of the 19th century. t, 20 If the above-mentioned general methods of synthesis are not suitable for the preparation of compounds of formula (I) and/or the necessary intermediate compounds for the synthesis of compounds of formula (I), appropriate suitable methods of preparation known to specialists should be used. As a rule, the synthesis scheme of each individual compound of formula (I) depends on the specific substituents that each molecule contains and on the availability of the necessary intermediate products; these factors can also be taken into account by the average specialist. Ha 25 Regarding all methods of introduction and removal of protection groups, |see RpPiyir 9. KosiepeKi, in the monograph "Rgoiesiipd OSgotsirv", Seogd Tpiete Mepad 5ishnodagii, Mem HogK, 1994, apa Tpeodoga MU. Sgeepe, Rebeg S.M. UUtsiv about "Rgogiesiime Sgotsmrz ip Ogdapis Zupipeviv", UMPeu Ipiegesiepse, Zga Edyiop, 1999).

The compounds of this invention can be isolated in combination with solvent molecules by crystallization after evaporation of the solution in a suitable solvent. Pharmaceutically acceptable salts of acids with compounds of this invention containing basic centers can be prepared in a conventional manner. For example, a suitable acid, pure or in a suitable solution, can be added to a solution of a free base, and the resulting salt can be separated by filtration or by vacuum evaporation of the solvent contained in the reaction mixture. rch-

Pharmaceutically acceptable salts of bases can be prepared in a similar manner by combining a solution of a compound of this invention with a suitable base. Both types of salts can be obtained or interconverted using ion exchange resins. -

If the azolidinedione derivatives of condensed vinylbenzenes according to this invention are used as medicinal products, they are introduced into the body, as a rule, in the form of pharmaceutical compositions. Thus, pharmaceutical compositions that contain the compound(s) of the present invention in a pharmaceutically acceptable carrier, diluent, or excipient are also encompassed by the present invention. A variety of such carriers, diluents or excipients suitable for the manufacture of pharmaceutical compositions are known to those skilled in the art. The compounds of the present invention, together with conventional excipients, carriers, diluents or excipients, may be provided in the form of pharmaceutical compositions and dosage units thereof, and such forms may be solid products such as tablets or filled capsules, or liquids. , for example, solutions, suspensions, emulsions, elixirs, or capsules filled with such liquids, and all the mentioned forms are intended for oral use, or the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their dosage units may contain the ingredients in their usual ratios, in the presence or absence of additional active compounds or agents, and such dosage units may contain any suitable effective amount of the active ingredient commensurate with the intended range of daily doses for use .

Pharmaceutical compositions containing azolidinedione derivatives of condensed vinylbenzenes according to the present invention can be prepared by methods well known in pharmaceutical practice and contain at least one active compound. Generally, the compounds of this invention are used in a pharmaceutically effective amount. The actual amount of the compound used is usually determined by the patient's attending physician taking into account the relevant circumstances, including the disease to be treated, the chosen method of administration, the specific compound used, the patient's age, body weight and individual response, the severity of the patient's disease symptoms, etc. .

F. The pharmaceutical compositions of this invention can be administered into the body by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and nasal.

Compositions for oral use can be in the form of bulk liquid solutions or suspensions, or bulk powders. More common, however, is the manufacture of compositions in the form of dosage units in order to facilitate accurate dosage. The term "dosage units" means physically discrete units suitable as unit doses for humans and other mammals, each unit containing a predetermined amount of active material calculated to achieve a desired therapeutic effect, in combination with suitable pharmaceutical excipients. Typical dosage units include pre-filled ampoules or syringes with a metered amount of the composition for liquid compositions or pills, tablets, capsules, etc. for solid compositions. In such compositions, the thiazolidinedione derivative of fused vinylbenzene is usually a minor component (from about 0.195 (wt) to about 5095 (wt) or, in a preferred embodiment, from about 195 (wt) to about 4095 (wt)), while the rest is made up of various media or carriers and technological impurities that contribute to the production of the desired dosage form.

Liquid forms suitable for oral administration may contain suitable aqueous or non-aqueous carriers with buffering compounds, suspending and dispersing agents, dyes, flavorings, and the like. Solid forms may contain, for example, any of the following ingredients or compounds "of a similar nature: binders, for example, microcrystalline cellulose, tragacanth or gelatin; fillers, for example, starch or lactose; disintegrants, for example, alginic acid, Rgitode! or corn starch; lubricating agents such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as mint, methyl salicylate or citrus flavoring.

Solutions for injections are made, as a rule, on the basis of sterile injectable saline or saline with a phosphate buffer, or other media for injections known in the industry. As indicated above, the 7/5 tp iazolidinedione derivative of the condensed vinylbenzene of formula (I) in such compositions is usually a minor component, the content of which is often from 0.0595 (wt.) to 1095 (wt.), the rest being the carrier for injections etc.

The components of the oral and injectable compositions described above are only typical examples. Further information on materials, processing methods, etc. can be found |in Chapter 5

Monographs Ketipdiopz RPagtaseciisai Zsiepsez, 2001 EdyShop, 2000, Magok Rybiizpipu Sotrapu, Eazyup,

Reppzuimapia), which is incorporated herein by reference.

The compounds of this invention may also be used in modified release dosage forms or in modified release therapeutic systems. A description of typical forms with modified release can also be found in the monograph of Ketipdiops Rpagtaseciis!| Zsiepsev high school

This invention is illustrated below by some examples, which should not be construed as limiting the scope of the invention. In the examples below, the following abbreviations are used: min (minutes), h (hours), g (grams), and) mmol (millimoles), t.pl. (melting temperature), eq. (equivalents), ml (milliliters), μl (microliters), ASM (acetonitrile), Bos (butoxycarbonyl), Cr; (carboxybenzyl), SOCIz (deuterated chloroform), SNex (cyclohexane), ra (dibenzylideneacetone), OSM (dichloromethane) OEAJUO (diethylazodicarboxylate), IS czo (disopropylcarbodiimide), OIEA (disopropylethylamine), OMAR (4-dimethylaminopyridine), OME ( dimethoxyethane), OME (dimethylformamide), OM5O (dimethyl sulfoxide), OM5O-d6 (deuterated dimethyl sulfoxide), ES Me (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), EUAs (ethyl acetate), EBO (diethyl ether, M

Ethos (9-fluorenylmethoxy-carbonyl), NOVI (1-hydroxybenzotriazole), KSO" (potassium carbonate), MaoZO, (magnesium sulfate), M8CI (methylsulfonyl chloride), MTBE (tert-butyl methyl ether), Man (sodium hydride), me) z5 MansSoOz (sodium bicarbonate), pVii and (p-butyllithium), ROS (pyridinium chlorochromate), PE, (petroleum ether), OSI cha (tetrabutylammonium chloride), Kk.t. (room temperature), tv (O-benzotriazolyl-M,M,M',M'-tetramethyluronium-tetrafluoroborate), TEA (triethylamine), TEA (trifluoroacetic acid), TNE (tetrahydrofuran), TMOE (trimethyl orthoformate), TMAO (M ,M,M',M'-tetramethylazodicarboxamide),

TossiI (toluenesulfonyl chloride). "

Examples: с с Below is a list of compounds that were synthesized according to the methods described below:

And" in -

F

- 6 vyvlodoxooodipdroantachenomethylenert Ztazelidnoya where: 0000

F in (vovszdnidrogtenyufuranvimetteyu t z tayuldodyodai 11111111

5-C4-(pyridin-2-ylmethyl)amino)quinazolin-b-ylumethylene)-1,3-thiazolidine-2,4-dione 2 sc

Fo with F t

F z t wo B(ivediphenitrols) nsnoimidazole-vilryethylene t zetiaolidineiodyun 00000 i z s

And" yav | vv fmyuovzhnuyualustyuettenteyutduyaya 111 - vv Bimetmleenuturanyylmethylene tezoldinyadon 111

Ф 85 (B(Fbromomethyenotroyunya methyl ttnoidyntia on - z

F s» o yu vo. uchv lyo zlezolidin- pedene methi benzofuran zali methyl (hydrokoyutyukritmya bo 8585 z(BCsdiadocol zlezolidin uchlidenmethyli-benouran-zalu iridine with pmethylivyl

M-cyclohexyl-3-15-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1-benzofuran-3-ilyacrylamide 5-(13-I(3-(4-methylpiperazine- 1-yl)-3-oxoprop-1-en-1-yl|-1 4-24-furan-5-yl)umethylene)-1 /3-thiazolidine-2,4-dione and M-cycloheptyl-3- 15-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1-benzofuran-Z3-yl acrylamide in rchvtcho viditdrolnorol yl) with oxoprot en pi benzofuran ziimethylene p Zlezopidinoya dune (96 B(zadihydroonbenzo and oxazine-bilmethyleneutazolidinoy don yu | yav Bizceitaadjdrozntenyu yuksyazin ilmetientazlidin syade 11111111 (ve (tegbutlyuvy complex "fr. 6-24 duxolivzopidin -pidenmethylu benzoi Yaksvin i herronova slot and cm o

The following intermediate aldehydes are available on the market: 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde, 1,3-benzodioxole-5-carboxaldehyde, 1,4-benzodioxane-b-carboxaldehyde, 9,10-dioxo- 9,10-dihydro-anthracene-2-carbaldehyde, 2,3-dihydro-benzo|p|Ifuran-5-carboxaldehyde,

C-methoxy-4,5-methylenedioxybenzaldehyde. co

Thiazolidinedione and rhodanine are commercially available. Intermediate aldehydes were synthesized according to the method described below. Fo

The characteristics of NRIS, NMR and MS, indicated in the examples below, were obtained under the following conditions: NRI C: column UMaiegs Butteiu C8 50x4, bmm, eluent: Mesm/Noo, 5-»100905 (8 min.), detection at a wavelength of 230 -400 nm; mass spectra: RE-5SIEKH ARI 150 EX (ARSI and EZ5I), and C/M5 spectra: Uuaietv 7MO (E5); "N-NMR: Vgykeg Ge"!

ORH-ZOOMHC. 325 The following conditions were used for purification: preparative chromatograph NRI S UUaiegv Rger I S 4000 Zuviet, - equipped with columns Rger Moma-RakonyaE St18bmkm bOA, 40x3O0mm (up to 100mg) or 40x300mm (up to 1g). During purification in all cases gradient elution of MesSm/Noo with an impurity of 0.0995 TEA was used.

Intermediate compound 1: preparation of 5-formyl-1-benzofuran " her - che 2"

Stage I: ethyl-2-formyl-4-bromophenoxyacetate: - 15 Mixture of 5-bromosalicylaldehyde (50 g, 0.248 mol), ethyl bromoacetate (42 g, 0.248 mol) and KSO»z (6 bv8g, 0.49 mol) in anhydrous OME (200 ml) stirred at room temperature for 12 hours. The reaction mixture (Ce) was filtered, and the filtrate was diluted with water. The resulting mixture was extracted with diethyl ether -1 (4x5200ml), washed with brine and concentrated, obtaining crude ethyl-2-formyl-4-bromophenoxyacetate 20 (6b4g, 9096) as a solid. is) Stage II: 4-bromo-2-formylphenoxyacetic acid: c» Mixture of ethyl 2-formyl-4-bromophenoxyacetate (bog, 0.209 mol), PON (7.5 g, 0.33 mol), TNE (250 ml) and water (100 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was acidified with 1.5 N. NSI to pH-2. The resulting solid precipitate was filtered and dried to give 4-bromo-2-formylphenoxyacetic acid (50g, 94905).

Stage I: 5-bromo-1-benzofuran: (F) To a mixture of 2-formyl-4-bromophenoxyacetic acid (50g, 0.192mol), sodium acetate (100g, 1.21mol) in

Acetic anhydride (10Oml) was added in portions to GI acetic acid (25O0ml) at 1009 for 10 minutes. The reaction mixture was then heated under reflux for 20 hours. The solvent was removed by distillation, and the residue was diluted with Z-n. NSI (500 ml) and heated under reflux for 2 hours. The reaction mixture was then concentrated in vacuo and the product was extracted with petroleum ether (3x200ml). The organic layer was washed with 10956 solution of MansCO3 and evaporated to give 5-bromo-1-benzofuran (15 g, 40905) as a pale yellow liquid.

Stage IM: 5-formyl-1-benzofuran (Ra in scheme 2 for example 9): 65 Mixture of 5-bromo-1-benzofuran (0.5g), mg (0.92g, 0.03Vmol), I" (1 crystal) in anhydrous TNE (2.5 ml) under a nitrogen atmosphere was heated under reflux for ЗОхв. A solution was added to it

5-bromo-1-benzofuran (4.5 g) in 25 ml of anhydrous TNE) as soon as the color I disappeared! and refluxed for an additional 2 hours. The reaction mixture was then cooled to -402C, anhydrous UOME (3.6 bg) was added dropwise and slowly heated to room temperature over 12 hours. The reaction mixture was then cooled to 02С, acidified with 3-n. NSI to рН-2 and stirred for ЗОхв. Then the reaction mixture was diluted with water (500 ml), extracted with ethyl acetate (2x200 ml), washed with brine and dried. The solvent was removed in vacuo and purified by chromatography on a silica gel column (eluent: a mixture of petroleum ether with SNCI) to give 5-formyl-1-benzofuran (2g, 54905) as a liquid. IS-M: M/7 E5I: 1.47 min., 147.34 (Mt).

Intermediate compound 2: preparation of 4-methyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazine-6-carbaldehyde a

I am about a

Stage I: 2-(M-methylamino)-phenol: 1 g of benzoxazole was dissolved in 20 ml of TNE. 0.9 g of Mavn was added under a nitrogen atmosphere and mixed. The resulting suspension was cooled to 02C, and 0.8 bml of acetic acid dissolved in 5 ml of TNE was slowly added, maintaining the reaction temperature below 592C. The reaction mixture was stirred at 02C for 30 minutes. and for an additional 2 hours. at room temperature. The reaction mixture was again cooled to 02C, and 50 ml of a saturated solution of MNACI was carefully added. The resulting phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over M950, and filtered. The solvent was removed, and 0.97 g of pure 2-(M-methylamino)-phenol was obtained.

Stage II: 4-methyl-4H-benzo|1,oxazin-3-one He 1g of 2-(M-methylamino)-phenol was dissolved in chloroform, after which 1Oml of saturated solution of Manso with o in water was added. A solution of 1 g of 2-chloroacetyl chloride in acetone was slowly added to this suspension with intensive stirring. The reaction mixture was stirred for 2 hours. at room temperature. The layers were separated. The organic layer was washed with water and dried over Ma»5O). After evaporation of the solvent, the obtained red oil was dissolved in 3 ml of OME and 1 g of K»CO3 was added, the resulting suspension was heated at 702 for an additional 2 hours. co

The cycle closing process was controlled by the TIPH method. 200 ml of EOAc was added, and the organic layer was washed

Zh0.1-n. NSI and 5x brine. The organic residue was dried over MAO5O and filtered. EtOAc was removed under reduced pressure, yielding 1.45 g of pure 4-methyl-4H-benzo|1,Doxazin-3-one. in.

Stage II: 4-methyl-3-oxo-3,4-dihydro-2H-benzo|1,Doxazin-6-carbaldehyde b 1 g of AISI was suspended in 10 ml of OSM, 0.5 ml of nitromethane was added to dissolve AISI»5, and the resulting solution

C5 was cooled to 09C. 4-methyl-4H-benzo|1,oxazin-3-one (0.5 g, 3.0 mmol) was added to the mentioned solution, in dissolved in OSM, and stirred for 15 min. at 09C. To this solution, 0.33 bml of bis-chloromethyl-methyl ether in OSM was additionally added. The reaction mixture was stirred at 09C for 15 minutes. and at room temperature during This crude reaction mixture was then poured onto ice, the layers were separated, and the organic phase was washed with NaCl and brine. It was dried over Mao5O, and filtered, after which the solvent C t0 was evaporated, obtaining 0.43 g of the crude product. The dark oil was purified by flash chromatography (using EtOAc and cyclohexane as eluents to give 0.2 g (3790) of 4-methyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazine-6-carbaldehyde in the form of a colorless solid.

NRI C: 2.07 min. I C-M5: M/2 EI: 1.31 min., 192.28 (M'.-1). 15 Intermediate compound 3: preparation of 4-methyl-3,4-dihydro-2H-benzo!|1,4)oxazine-7-carbaldehyde -I ie -I o 50 I

Stage I: 4-methyl-3,4-dihydro-2H-benzo|1,oxazine c» 0.97 g of 2-(M-methylamino)-phenol was dissolved in 500 ml of acetone, after which 2 g of K 2 CO 3 dissolved in water was added. A solution of 2.6 g of dibromoethane in acetone was slowly added to this suspension. The reaction mixture was stirred for 22 hours. when heated under reflux. Acetone was evaporated, 200 ml of EtOAc was added, and the organic layer was washed with Z3xH0.1-n. NSI and Zh brine. The organic residue was dried over Mo2O and filtered.

F! EtOAc was removed under reduced pressure, obtaining 1 g of pure 4-methyl-3,4-dihydro-2H-benzo |1,4| oxazine

Stage II: 4-methyl-3,4-dihydro-2H-benzo|1,oxazine-7-carbaldehyde and 4-methyl-3,4-dihydro-2H-benzo|1,oxazine were dissolved in 200 μl of UOME in an argon atmosphere. ROSIz was added in an argon atmosphere. The reaction mixture was heated in a closed test tube at 902 C for 75 minutes. 60 mL of Maas in water was added and stirred until a brown oil formed. This oil was extracted by OSM. The organic layer was washed with brine, dried and evaporated to dryness to give 0.18 g (7690) of 4-methyl-3,4-dihydro-2H-benzo|1,oxazine-7-carbaldehyde as a colorless solid.

IIS-mM5: M/7 EZ5I: 1.37 min, 178.35 (M--1).

Intermediate compound 4: preparation of 1,3-dihydroisobenzofuran-5-carbaldehyde b5 o H

Stage I (1.3-dihydro-isobenzofuran-5-yl)-methanol

1.0 g of Z-prop-2-ynyloxy-propyne and 2.08 g of propargyl alcohol in 7 Oml of ethanol were loaded into a round-bottomed flask with an irrigation condenser, after which 9. mg of tris(triphenylphosphine)rhodium chloride 70 "Wilkinson's catalyst (UMiKipzop)) was added at room temperature. The reaction mixture was heated to 702C, while the color of the reaction mixture rapidly turned yellow. After 1 day of stirring at room temperature, TLC analysis confirmed the completion of the transformation of the starting materials. The solvent was evaporated, diluted with OSM and extracted with HO, dried over M95O. The brown mixture was purified by flash chromatography using 8/2 cyclohexane/AcOE as mobile phase to give (1,3-dihydro-isobenzofuran-5-yl)-methanol in the form of 75 colorless pure solid (0.92 g, 60905).

Stage II: 1,3-dihydroisobenzofuran-5-carbaldehyde (1,3-dihydro-isobenzofuran-5-yl)-imethanol and (440 mg, 2.9 mmol) were dissolved in 20 ml of OSM. 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoidoxol-3(1H)-one (Dess-Martin reagent (Oeezv-Mapip)) (1.3 g, 33.2 mmol) was added, and the reaction the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ether, extracted 2x1-n. Mmaon, 2xNoos and dried over M950,. The crude product, which had a sufficient degree of purity, was used without any additional purification. NRI C: 2.0 Ohv. I C-M8: M/7 E5I: 1.50 min., 149.18 (M.-1).

Intermediate compound 5: preparation of quinoline-6-carbaldehyde

Co. with

SH in o

Stage I: quinoline-6-yl-methanol so

5 g of methylquinoline-6-carboxylate was dissolved in anhydrous TNE. In an argon atmosphere, 1 M HyAIN was added, in TNE (2 equiv.) at -202С. The resulting solution was stirred at this temperature for an hour. Isopropanol was added slowly, the crude product was filtered through Celite and washed with OCM. We concentrated and obtained 3.bg cha (8590) of pure alcohol.

NRIS: 1.10 min. I C-M8: M/2 E5I: 0.91 min, 160.43 (M'-1). F

Stage II: quinoline-b-carbaldehyde h-

Dissolve 2 g of quinoline-b-yl-methanol in OSM. 15 g of MPO were added, and the reaction mixture was stirred continuously

bbBh The crude product was filtered through celite and washed extensively with OSM. It was concentrated and 1.85 g (93905) of pure aldehyde was obtained. "

NRI C: 0, entry I C-M5: M/2 EI: 1.07 min., 158.37 (M'1). "IN NMR (O0M50-d) 5 10.19 (z, 1H), 9.06 (Her, U-3Hz, 1H), 8.6-8.66 (t, 2H), 8.15 (in, 2H), 7.68 (da, U-3Hz, 9Hz, 1H). si c The intermediate compounds below were synthesized accordingly using suitable starting materials. "Intermediate compound 6: preparation of 3-methyl-benzo|d|isoxazole-5-carbaldehyde -i usri an se) -i NRI C: 2.06 min. I C-M8: M/7 E8I: 1.26 min, 162 ,31 (M--1). "H NMR (0M5O-dv) 5 10.10 (z, 1H), 8.52 (c, 1H), 8.16 (a, 9-12Hz, 1H), 8 .15 (z, 2H), 7.90 (a, U-9Hz, 1H), 2.63 (c, ЗН). Intermediate compound 7: preparation of methyl ester of 4-chloro-quinazoline-b-carboxylic acid

her

II (F) Stage I: 4-nitroisophthalic acid

GI A mixture of 3-methyl-4-nitrobenzoic acid (150 g, 0.825 mol), pyridine (1.5 L) and water (1.5 L) was heated to boiling. KMpO4 (1 mol) was added to this hot reaction mixture in portions and heated with a reflux condenser for 72 hours. This hot reaction mixture was filtered through celite and washed with hot water. The filtrate was concentrated in vacuo, the residue was diluted with water (75 Oml) and acidified with concentrated

NSII at 02С. The resulting solid was filtered, washed with water and dried under vacuum to give 4-nitroisophthalic acid (98g, 56965).

TLC, chloroform/methanol, 7:3, Ke0.2. 65 Stage II: 4-aminoisophthalic acid

Ra/C (20965) was added to a solution of 4-nitroisophthalic acid (98 g, 0.457 mol) in methanol (bl) and hydrogenated at room temperature for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give 4-aminoisophthalic acid (72 g, 87905) as a solid.

TLC, chloroform/methanol, 7:3, KeO,4.

Stage I: 4-oxo-3.4-dihydroquinazoline-6-carboxylic acid

A mixture of 4-aminoisophthalic acid (17 g, 0.09 mol) and formamide (85 ml) was heated at 18023 for 5 hours.

The reaction mixture was cooled to room temperature and acetone was added. The thus obtained solid precipitate was stirred for 2h, filtered and dried, obtaining 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (11g, 61905). 70 TLC, chloroform/methanol, 8:2, Ke0.25.

Stage IM: 4-oxo-3.4-dihydroquinazoline-b-methylcarboxylate

To a solution of 4-oxo-3,4-dihydroquinazoline-b-carboxylic acid (24g, 0.12bmol) in anhydrous methanol (800ml) was added thionyl chloride (37g) at 52С, and then heated under reflux at 802 for

Bhod The reaction mixture was concentrated in vacuo and crude dissolved in ethyl acetate (25000 ml). The organic layer 75 was washed with 10956 aqueous solution of ManHsSOO»z, water, brine and dried. The solvent was removed in vacuo to give 4-oxo-3,4-dihydroquinazoline-β6-methylcarboxylate (24g, 92905) as a solid.

TLC, chloroform/methanol, 8:2, Ke0.6.

Stage M: methyl-4-chloroquinazoline-b6-carboxylate

A mixture of 4-oxo-3,4-dihydroquinoline-β6-methylcarboxylate (12 g, 0.058 mol) and phosphoryl chloride (18 Oml) was refluxed for 7 hours. Excess phosphoryl chloride was distilled off, and the crude product was dissolved in ethyl acetate (250 mL). The organic layer was washed with 1095% aqueous Manso solution, water, brine and dried. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent 100 ethyl acetate in petroleum ether) to give methyl 4-chloroquinazoline-b-carboxylate (4.5 g, 3490) as a solid. with

TLC, petroleum ether/E(Ac, 1:1, K, 0.65. o

IS-M8: M/7 EZVI: 1.50 min., 223.19 (Ma1). "H NMR (0M5O0-yv) 5 8.66 (a, 9U-1.9Hz, 1H), 8.39 (c, 1H), 8.30 (aa, -0.6Hz, 8.5Hz, 1H) , 7.79 (a, U-8.5 Hz, 1H), 3.90 (c, ZN).

Intermediate compound 8: preparation of the methyl ester of 4-methoxy-quinazoline-b-caobonic acid so zo II y. F

Master of Science (22)

200 mg of methyl-4-chloroquinoline-6-carboxylate was mixed in bml of MeOH in the presence of Teq. OIEEA at 60°C

From within 24 hours. The meonH was evaporated and the resulting crude residue was dissolved in EtOAc and washed with MH As to give a white solid sufficiently pure for the next step.

NRI C: 2, Prov. I C-M5: M/2 EI: 1.19 min., 219.17 (M--1).

The following intermediate compounds were synthesized according to the method of synthesis of intermediate compound 8: Intermediate compound 9: preparation of methyl ester of 4-methylamino-quinazoline-6-carboxylic acid З7З 0 ОО :» ры 75 NRIS: 1.12 min. AND! C-M5: M/2 EI: 1,O6bhv., 218,31 (M'-1). - Intermediate compound 10: preparation of 4-methoxy-quinazoline-6-carbaldehyde poi i tsu o. About 50 syu"

This intermediate compound was obtained by the method of synthesis of intermediate compound 5 using the methyl ester of 4-methoxy-quinazoline-b-carboxylic acid as the starting compound. 29 NRIS: 1.41 min. AND! C-M5: M/2 EI: 1.24 min., 189.31 (M'-1).

GF! Intermediate compound 11: preparation of 4-methylamino-quinazoline-6-carbaldehyde in her and

John 9

This intermediate compound was obtained by the method of synthesis of intermediate compound 5 using the methyl ester of 4-methylamino-quinazoline-6-carboxylic acid as the starting compound. because NRIS: 1, Zhv. And C-M5: M/2 EI: 0.90 min., 188.34 (M '1).

Intermediate 12: preparation of 4-chloro-quinazoline-6-carbaldehyde

Kha m

Stage I: 4-chloroquinazolin-b-ylmethanol

OIVAY-H (4.4 g, 0.031 mol) was added to a solution of methyl-4-chloroquinazoline-b6-carboxylate (3.5 g, 0.015 mol) in anhydrous TNE (Zbml) at -259C and stirred at room temperature for 2 hours. The reaction mixture 70 was cooled to -102C, and the reaction was quenched with an aqueous solution of MansSO" (Oml). The reaction mixture was extracted with ethyl acetate (100 ml), washed with water, brine and dried. The solvent was removed in vacuo to give 4-chloroquinolin-b-yl methanol (2g, 6690).

TLC, chloroform/methanol, 8:2, Ke0.35.

Stage II: 4-chloroquinazoline-b-carboxaldehyde

To a solution of 4-chloroquinazolin-b-yl-methanol (3.5 g, 0.018 mol) in anhydrous СНоСи (100 ml) was added Dess-Martin periodic reagent (8.4 g, 0.019 mol) and stirred at room temperature for 30 minutes.

The reaction mixture was washed with 1095% aqueous solution of MansSoO (75 ml), water, brine and dried. The solvent was removed in vacuo to give 4-chloroquinazoline-b-carboxaldehyde (Zg, 8890) as a pale yellow solid.

TLC, chloroform/methanol, 9:1, K0.6.

Intermediate compound 13: preparation of 4-phenyl-quinazoline-b-carbaldehyde with addition of 4-chloro-quinazoline-6-carbaldehyde (50 mg, 0.2 mmol), Ra(PPH3)4 (1 mg, 0.0 mmol), phenylboronic acid ( bZmgH, so zo 0.52mmol) and sodium carbonate (saturated solution: 5Oml) were called in toluene at 1002C for 12 hours. After evaporation of the solvents, the resulting residue was dissolved in ethyl acetate and washed twice with brine. The Me) organic phases were then concentrated and the starting material was purified on silica gel using a 95:5 OSM/EUN mixture as eluent to give 5mg (82905) of the desired compound in 8595 purity.

NRI S: 2.68 min. I C-M5: M/2 EI: 1.25 min., 235.30 (M'-1). me)

Intermediate compound 14: preparation of 4-dimethylamino-quinazoline-6-carbaldehyde

4-Chloro-quinazoline-6-carbaldehyde (200 mg, 1 mmol) was dissolved in 1 Oml of dioxane. A solution of dimethylamine in water (aq.) was added to this solution. The resulting mixture was stirred for 2 hours. at room temperature. "» The solvents were evaporated, the amine was removed under high vacuum, and pure 4-dimethylamino-quinazoline-b-carbaldehyde was obtained as a yellow solid, which was used in the next step without further purification (19Omg, yield 9195). - NRI C: 0, 91 min. IS-M8: M/7 EV8I: 1.2Zhv., 202.33 (M--1). "H NMR (SOSIz): 5 10.19 (in, 1H), 8.70 (in, 1H ), 8.50 so (a, 9-zHz, 1H), 8.15 (da, U-zGu, Hz, 1H), 7.88 (a, U-9Hz, 1H).

The following intermediates were synthesized in a similar manner, using the appropriate amines as nucleophiles. about 50 is about 28 |4-(4-phenethyl-piperidin-1-yl)-quinazoline-6-carbaldehyde 346.42

(zo 4-(4-(4-fluoro-phenyl)-piperidine-1-ilyquinazoline-6-carbaldehyde

Intermediate compounds 32: Preparation of methyl ester of methyl-benzotriazole-5-carboxylic acid

1 g of methyl ester of benzotriazole-5-carboxylic acid (5.64 mmol) was dissolved in 20 ml of OME at 020. To this solution was added Teq. Mann (6095) at 00. The resulting mixture was stirred during storage. at 02С, 801 mg (Teq.) of methyl iodide was slowly added, and the resulting reaction mixture was stirred for 2 /0 h at room temperature. E(OAc) was added, the organic layer was washed with large amounts of brine and water, dried over NaOH, and filtered to give g of crude methyl ester of methyl-benzotriazole-5-carboxylic acid in the form of three different regioisomers. The separation was carried out on silica gel using a mixture EYUAS/CH 3:7 as eluent.

Intermediate compound 32a: methyl ester of 2-methyl-2H-benzotriazole-5-carboxylic acid

The methyl ester of 2-methyl-2H-benzotriazole-5-carboxylic acid was eluted as the first fraction (25Omg, 2295). NRIS: 2.32 min. "H NMR (0M5O-yv) 5 8.56 (in, 1H), 8.02 (9, U-9Hz, 1H), 7.93 (a, 9-9Hz, 1H), 4.55 (5, ЗН), 3.90 (in, 1Н).

Intermediate compound 32p: 3-methyl-ZH-benzotriazole-5-carboxylic acid methyl ester with 0 zo The 3-methyl-ZH-benzotriazole-5-carboxylic acid methyl ester was eluted as the second fraction o (130mg, 1295). NRIS: 2.03 min. "H NMR (0M5O-yv) 5 8.56 (z, 1H), 8.13 (4, U-6Hz, 1H), 7.93 (a, 9-9Hz, 1H), 4.39. FI ( 8, ZN), 3.92 (in, ZN). Chn

Intermediate compound 32c: methyl ester of 1-methyl-1H-benzotriazole-5-carboxylic acid (22) m. te sg

The methyl ester of 1-methyl-1H-benzotriazole-5-carboxylic acid was eluted as the third fraction - c (135mg, 1295). NRIS: 2.0Zhv. "H NMR (0OM8O-yv) 5 8.62 (5, 1H), 8.11 (a, U-9Hz, 1H), 7.97(d, Hz, 1H), 4.35 "z (5, ZN), 3.90 (in, ZN). " Intermediate compound 33: 2-methyl-2H-benzotriazole-5-carbaldehyde -I se) -i This intermediate compound was synthesized according to the method of synthesis of intermediate compound 5, using methyl so 50 complex ester of 2-methyl-2H-benzotriazole-5-carbon acid (intermediate compound C2a) as a starting compound.

NRI C: 1.88 min. "H NMR (0OM5O-yv) 5 10.12 (in, 1H), 8.65 (z, 1H), 8.06 (y, 9-9Hz, 1), 7.85 (94, U-9Hz, 1H), sat» 4.57 (in, ЗН).

Intermediate compound 34: 3-methyl-ZH-benzotriazole-5-carbaldehyde n

ON

F) d) a

This intermediate compound was synthesized according to the method of synthesis of intermediate compound 5, using the methyl ester of 3-methyl-3H-benzotriazole-5-carboxylic acid (intermediate compound 32b) as the starting compound.

NRI-S: 1.49 min. "H NMR (0M5O-4v6) 5 10.18 (in, 1H), 8.54 (in, 1H), 8.20 (9, 9-9Hz, 1H), 7.88(4, 9-9Hz, 1Н), 4.41 (in, ЗН).

Intermediate compound 35: 1-methyl-1H-benzotriazole-5-carbaldehyde b5 in "A m ia M o

This intermediate compound was synthesized according to the method of synthesis of intermediate compound 5, using methyl ester of 1-methyl-1H-benzotriazole-5-carboxylic acid as the starting compound (intermediate compound 32c). 70 NRI-S: 1.49 min. GO-M8: M/7 EZ8I: 1.07 min., 162.32 (M--1). "H NMR (0M5O-aiv) 5 10.13 (in, 1H), 8.70 (in, 1H), 8.05 (8, 2H), 4.36 (5, ЗН).

Intermediate compound 36: 5-(4-amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione

Stage 1: C-fluoro 4-nitrobenzyl alcohol IVisogd. Honey. Spent 7. 1999, 26471

A suspension of Mavn (204 mg, 5.4 mmol, 2 equiv.) in TNE (10 ml) cooled in an ice bath was added dropwise

3-fluoro-4-nitrobenzoic acid (500 mg, 2.7 mmol, Eq.) in TNE (1 Oml) during ZOkhv. Then it was added drop by drop

VEZ-EBO (7.Zmmol, 2.7 equiv.) during ZOkhv. The resulting solution was stirred at room temperature overnight. Add drops of 1-n. NSI for neutralizing excess Mavn y). The solvent was removed under vacuum, the obtained residue was dissolved in OSM, washed with water and brine. Then the organic layer was dried over Mo5O4, the solvent was removed in vacuo, obtaining 425 mg of 3-fluoro-4-nitrobenzyl alcohol (9295 yield). This compound was used in the next step without further purification.

T"H NMR: 5-(400 MHz, SOSIv): 7.97 (t, 1H), 7.28 (t, 1H), 7.18 (t, 1H), 4.75 (t, 2H). o

Stage II: 3-fluoro-4-nitrobenzylaldehyde Ge")

C-Fluoro-4-nitrobenzyl alcohol (11 mg, 0.8 mmol, eq.) was dissolved in OSM (1 mL) and Mpo 5 (580 mg, 6.7 mmol, 1 eq.) was added, and the resulting suspension was stirred at room temperature overnight. -

MpO" was filtered from the suspension using celite, the solvent was evaporated, obtaining the corresponding /F) aldehyde as a white solid (6695 yield).

T"H NMR: 5-(400MHz, SOS): 9.98 (z, IN, CHO), 8.08 (t, 1H, AgH), 7.78 (t, 2H, AgH). i-

Stage I: 5-(3Z-fluoro-4-nitro-benzylidene)-thiazolidine-2.4-dione U. Med. Spent 37. 2. 1994. 3221

A mixture of 3-fluoro-4-nitrobenzylaldehyde (280 mg, 1.65 mmol, eq.), thiazolidinedione (193 mg, 1.65 mmol, eq.), and β-alanine (95 mg, 1.1 mmol, 0.bbq.) in acetic acid (bml) was stirred overnight at 100 b. « 20 The cooled reaction mixture was added to water and stirred for an hour. The precipitated product -c was filtered off, washed with water and dried to give the final product as a yellow-orange solid (7795 yield). ;" TN NMR: 5-(400MHz, (СО5)2СО): 8.0 (t, 1H, AgH), 7.68 (t, 2H, AgH), 7.53 (5, IN, CH-C).

Stage IM: 5-(3-ethylamino-4-nitro-benzylidene)-thiazolidine-2,4-dione 5-(3-fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione (200 mg, 0.75 mmol, eq.), was dissolved in OME (bml) and TEA-I (208 ml, 1.5 mmol, 2 eq.) and a solution of ethylamine (2 eq.) was added. The reaction mixture was shaken at 602 overnight. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed with 1095% aqueous ammonium chloride solution. The organic layer was dried over Na»5O, and the solvent was evaporated, obtaining the corresponding aniline -I derivative in the form of a red oil, which was used in the next step without additional purification.

Stage M: 5-(3-ethylamino-4-amino-benzylidene)-thiazolidine-2,4-dione

To a stirred solution of 5-(3Z-ethylamino-4-nitro-benzylidene)-thiazolidine-2,4-dione in TNE, slowly

Fe was added to a solution of sodium hydrosulfite (Zeq.) in water, and then an aqueous solution of K»CO3. The reaction mixture was refluxed overnight. The TNE was removed in vacuo and the asphyxia was extracted with ethyl acetate.

The organic layer was dried over Na 2 O 2 , and the solvent was evaporated to give the corresponding aniline derivative, which was used without any further purification.

The following intermediates were synthesized in a similar manner using suitable amines as

IF) nucleophiles, according to the method of stage IM of intermediate compound 36. The co-obtained 3-alkylamino-4-nitrobenzylidene)-thiazolidine-2,4-diones were reduced according to the method of stage M of intermediate compound 36, obtaining 3-alkylamino-4-amino -benzylidene)-thiazolidine-2,4-diones. 60 dv 41 5-4-amino-3-(2-(1H-indol-3-yl)-ethylamino|-benzylidene)-thiazolidine-2,4-dione 409.21 o

Intermediate 55: quinoxaline-b-carbaldehyde g neo

M n

Stage I: quinoxaline-b-carbonyl chloride

Quinoxaline-b-carboxylic acid (20.2g) in B0Oml of TNE was loaded into a 3-neck flask with a capacity of 1 l. Thionyl chloride (42ml, 5eq.) was slowly added to this solution. Stirred with a mechanical stirrer (3), the reaction mixture was heated at reflux, and the course of the reaction was monitored using

NRIS, neutralizing samples of MN.AON. After Agreement name with a reflux condenser, the analysis showed the absence of source material. The solvent was removed under reduced pressure, and ZOSI 5" was removed by washing three times with toluene. The resulting solid was suspended in 100 mL of EtOAc and filtered to give 23.47 g of a beige solid. Gee!

NRI S: 1.114 min. "H NMR (0M50O-dv) 5 9.01-7.40 (t, 5H). m

Stage II: quinoxaline-b-carbaldehyde

Quinoxaline-b-carbonyl chloride in bbOml OME was loaded into a 3-neck flask with a capacity of 1 L under an argon atmosphere. F) with lithium tri-tert-butoxyaluminum hydride (Tekv.) was added to this solution at -789C for 1.5 hours. The reaction mixture M was kept at this temperature for 5 hours. Ice was then added, and the reaction mixture was diluted with Acetone and filtered through celite. The resulting two layers were separated, and the organic phase was washed with a saturated solution

Mmansose-quinoxaline-6-carbaldehyde was obtained after evaporation of the solvent (7395 yield) in the form of a yellowish solid. "

NRIS: 1.49 min. IS-M8: M/7 EI: 0.81 min., 159.37(Me1). "H NMR (SOSIv) 5 10.28 (in, 1H), 8.97 (in, 2), 8.61 s (5, 1H), 8.27 (a, 6Hz, 9Hz, 2H). Intermediate compound 56: benzothiazole-b-carbaldehyde

I» g a -i n (se) This intermediate compound was synthesized according to the method of synthesis of intermediate compound 55 using benzothiazole-b6-carboxylic acid as a starting compound. The total output was 3895. their NRIS: 1.92 min. I C-M8: M/7 EZ8I: 0.97 min., 164.27 (Ma1). "H NMR (0M5O-ydv) 5 10.1 (in, 1H), 9.60 (in, 1H), 8.60 se) 50 (5, 1H), 8.20 (t, 1H), 8, 10 (y, 1H). Intermediate compound 57: 3-methyl-benzofuran-5-carbaldehyde

In a and

F) This intermediate compound was obtained according to the method of synthesis of intermediate compound 1, using co-ethyl-2-acetyl-4-bromophenoxyacetate as starting material. Total output 50965.

IS-M8: M/7 EZVI: 1.5 Bhv., 161.34 (M-1). "H NMR (0M5O0-ydv) 5 10.1 (in, 1H), 8.21 (y, 91.5 Hz 1H), 7.92 (a, 6o 0 9-1.3Hz, 1H), 7, 88-7.84 (aa, 9-1.6Hz, 1), 7.73-7.71 (a, 9-8.5Hz, 1H), 2.25 (v, ЗН).

Intermediate 58: 3-bromo-benzofuran-5-carbaldehyde

Z Y A yu b5 ve n

Stage I: 2.3-dibromo-2.3-dihydro-benzofuran-5-carbaldehyde

Intermediate compound 1 (2g, 13./mmol) was dissolved in 10 ml of SNHCl and cooled to -102C. To it was added a solution of HgO in SNCI3 (1.55 eq., c-4.162 mol/l). The reaction mixture darkened and was allowed to stand for titration

At room temperature for 1 hour. NRI/S confirmed the completion of bromine addition. The solvent and residual bromine were evaporated under reduced pressure to give a reddish oil (4.1 g, yield 9095), which was used in the next step without further purification.

NRI C: 3.43Xmin.

Stage II: 3-bromo-1-benzofuran-5-carbaldehyde 70 KOH solution was added to a solution of 2,3-dibromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (4.1 g) in anhydrous ethanol (15 ml) (2.2 equiv.) in anhydrous ethanol (14 mL) and heated under reflux at 702 for 1 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3x5Oml). The organic layer was washed with water, brine and dried. The solvent was removed in vacuo, and the resulting residue was purified by flash chromatography (eluent petroleum ether/E(OAc 99.5:0.5), obtaining the title compound as a pale yellow solid (2.91 g (8095 purity) , output 7895).

DRAWING: 3, ZBhv. "H NMR (0M5O-yv, ZOOMHz) 5 10.12 (in, 1H), 8.47 (in, 1H), 8.14 (a, 9-1.5Hz, 1H), 7.97 (da, 3-86, 1.5Hz, 1H), 7.87 (a, U-8.6Hz, 1H).

Intermediate compound 59: 3-phenylethynyl-benzofuran-5-carbaldehyde.

And oh

What about

In a dry flask, 3-bromo-1-benzofuran-5-carbaldehyde (1 g, 44 mmol) was dissolved in anhydrous TNE (5 Oml). To this solution was added bis(triphenylphosphine)palladium (II) chloride (1 mg, 0.2 mmol), TEA (2.81 ml, bq.), Si! (40 mg, 0.2 mmol) and phenylacetylene (897 mg, 8.8 mmol). The reaction mixture was heated at 5590°C for 2 days. The crude product was filtered through celite and purified on silica gel using cyclohexane-ethyl acetate (7-3) as eluent to give 680 mg (yield: 56905). b"

NRIS: 4.71 min. "H NMR (0M5O-yv) 5 10.14 (in, 1H), 8.64 (z, 1H), 8.38 (z, 1H), 7.97 (ad, 9-1.5 Hz, 8, 3Hz, 1nH), 7.90 (a, 2-8.6Hz, 1H), 7.65 (t, 2H), 7.46 (t, ЗН).

Intermediate compound 60: ethyl ester of 3-(5-formyl-benzofuran-3-yl)-acrylic acid F i - i « -

IN

"z In a sealed tube, 3-bromo-1-benzofuran-5-carbaldehyde (500 mg, 2.22 mmol) was dissolved in 7 ml of ASM. PP" (1.16 g, 4.44 mmol), Ra(III) acetate ( 500mg, 2.2mmol), EBM (073ml, 5.55mmol) and finally acrylic acid ethyl ester (2.41ml, 22mmol). The tube was sealed and the reaction mixture was heated at -1 75 at 1202 for 7h. The crude product was filtered through celite to remove inorganic contaminants. The solvents were evaporated and the resulting crude product was purified by chromatography on (Ce) silica gel using a mixture of cyclohexane-AcOEII (gradient from 95:5 to 50:50) to give a pale yellow solid (40mg, yield: 42905 ).

DRAWING: 3Z, bohv. "H NMR (0M5O-yv) 5 10.15 (in, 1H), 8.70 (z, 2H), 7.97 (a, 9-9 Hz 1H), 7.88 (z, 1H), 7 ... intermediate compound 61: b-methyl ester of //4-tert-butyl ester of 2,3-dihydro-benzo|1,oxazine-4,6-dicarboxylic acid (F) -X o o a bo o

Stage I: methyl ester of 3-amino-4-hydroxy-benzoic acid

Palladium on charcoal in water (2g in 1Oml of water) was added to a 200Oml three-necked flask containing 3-nitro-4-hydroxybenzoic acid methyl ester (43g, 218mmol) in Meon (8bOml; 20 volumes).

Ammonium formate (68.76 bg, beq.) was added in one portion while stirring. After 2-3 minutes. because a suspension was formed, and the temperature rose from 20 C to 309 C. An ice bath was used to cool the reaction mixture to 202C, and the reaction mixture was stirred at 202 for 40 minutes. until the completion of the reaction (disappearance of the yellow color). The reaction mixture was filtered through a pad of silica gel, washed with Meon, and the filtrate was concentrated in vacuo to give a green oil, which was dissolved in ethyl acetate (4000 mL). The organic phase was washed twice with water, dried over Ma 5 O), filtered and concentrated to give a cream solid t-31.35 g (8690).

IIS-mM5: M/7 EZ5I: 0.81 min, 168.37 (M'-1).

Stage II: 3,4-dihydro-2H-benzo|1,oxazine-b6-carboxylic acid methyl ester hydrochloride

In a three-necked flask with a capacity of 200 Oml, which contained the methyl ester of 3-amino-4-hydroxy-benzoic acid 70 (31.35 g, 187 mmol) in anhydrous OME (63 Oml; 20 volumes) at room temperature under a nitrogen atmosphere, one portion of CoCOz was added (103 g, 4 eq.), and then one portion of 1,2-dibromoethane (b5 ml, 4 eq.).

The reaction mixture was stirred at 702C for 12 hours. Allow the mixture to cool to room temperature, add 1-n. NCI until reaching pH-8, and extracted using diethyl ether (C x 200 ml).

The organic phase was washed with water (2 x 200 mL), dried over Mo5O, and concentrated to give 75 a brown-red oil with a solid, which was redissolved in diethyl ether (450 mL) and

TNE (5 Oml) and filtered to remove the white solid. To the filtrate was added 1-n. NCI, after which diethyl ether (13 Oml) was added, the suspension was stirred at room temperature for 5 min. and filtered to give 27.6 bg of crude product. The aqueous phases were re-extracted with ethyl acetate, yielding an additional 6.23 g of product. The combined fractions (32g) were recrystallized from BEN (420ml; 13 volumes), filtered, dried and a white powder was obtained (19.47g (16.37g free base)), yield 40965.

NRIS: 1.954 min. I C-M8: M/2 E5I: 1.27 min., 194.45 (M--1).

Stage MG 4-tert-butyl ester of b-methyl ester of 2,3-dihydro-benzo|1,oxazine-4,6-dicarboxylic acid

In a three-necked flask with a capacity of Bb00ml, which contained hydrochloride of the methyl ester of C 25 C,4-dihydro-2H-benzo|1,oxazine-b6-carboxylic acid, suspended in TNE (145 ml; 10 volumes), was added (5) in one with a portion of OIEA (27 ml, 2, equiv.) at room temperature in a nitrogen atmosphere and partial dissolution was observed. Butoxycarbonyl anhydride (16.4 g, 1.2 equiv.) was added in one portion, and the reaction mixture was stirred at 6523 for 5 days. During this time, 0.2 equiv was added in several small portions.

Vos»O and OIEA. TNE was removed in vacuo, and the resulting residue was dissolved in OSM (15 Oml). The organic phase of CO 30 was washed with a saturated solution of MancSO" and then with brine. It was dried over Ma95O and filtered, after which the volatile fractions were removed under vacuum; the obtained residue was recrystallized from EUN (8Oml), obtaining cream crystals (14.8g, 7690). -

NRI-S: 4.038 min. "H NMR (SOSI") 5 8.49 (z, 1H), 7.68 (da, 9-3Hz, Hz, 1H), 6.89 (4, 9-9Hz, 1H), 4.30 (d , b

UZHz, 9Hz, 2H), 3.89 (t, 5H), 1.62 (in, 9H). 35 Intermediate compound 62: 6b-formyl-2,3-dihydro-benzo (1,4)oxazine-4-carboxylic acid tert-butyl ester

This intermediate compound was obtained by oxidation-reduction according to the procedure described for intermediate -1 compound 5.

NRIS: 3.727 min. IS-M8: M/7 E5I: 1.81 min., 264.34 (Ma1). "H NMR (0M5O-y5) 5 9.83 (in, 1H), 8.35 (in, 1H), ee, 7.53 (a, 9-6Hz, 1), 7.05 (a, U- 9HzC, 1H), 4.31 (i, U-3HcC, 2H), 3.83 (i, U-6Hc, 2H), 1.50 (z, 9H). -i Intermediate compound 63: tert-butyl complex ester of b-formyl-benzo|1,Zoxazin-4-carboxylic acid со ; с -Ко о

H o Stage I: b-methyl ester of 4-tert-butyl ester of 2,3-dibromo-2,3-dihydro-benzo|1,oxazine-4,6-dicarboxylic acid

To a solution of β-methyl ester of 4-tertiary-butyl ester of (2,3-dihydro-benzo|1,Shoxazin-4,6-dicarboxylic acid) (500 mg, 1.7 mmol) in anhydrous carbon tetrachloride (200 ml) M-bromosuccinimide (6.7 mg, 3.75 mmol) and a catalytic amount of benzoyl peroxide were added.

The resulting mixture was stirred and heated using a lamp (100 W) with a reflux condenser for 45 minutes. The resulting mixture was left to cool, and the succinimide was filtered off. The filtrate was evaporated to give an oil (767 mg, 9995) of sufficient purity for use in the next step. 65 NRIS: 3.978xMin.

Stage II: b-methyl ester of 4-tert-butyl ester of benzo|1,oxazine-4,b-dicarboxylic acid b-methyl ester of 4-tert-butyl ester 2,3-dibromo-2,3-dihydro -benzo|1,oxazine-4,6-dicarboxylic acid (767 mg, 1.7 mmol) from the previous stage was stirred in acetone (14 ml) at room temperature for 2 hours. with Ma! (1.27 g, 8.5 mmol). The solvent was removed, and EJ Ac, water and 1 M sodium thiosulfate were added. The phases were separated and the organic layer was washed with brine. The solvent was concentrated, and the resulting crude product was purified on silica gel using CH/EuAc 7:3 to give a colorless oil (456 mg, 9290).

NRIS: 4.386 min. 70 Stage I: tert-butyl ester of b-hydroxymethyl-benzo (1,4) oxazine-4-carboxylic acid

Stage IM: tert-butyl ester of b-formyl-benzo|1,oxazine-4-carboxylic acid

Stage III and Stage IM were performed as described for the synthesis of intermediate 5.

NRIS: 3.388Xmin.

Intermediate compound 64: methyl ester of (b-formyl-3-oxo-2,3-dihydro-benzo|1,oxazin-4-yl)-acetic /5 ACIDS o o 20

Stage I: methyl-3-amino-4-hydroxybenzoate

To a solution of 3-amino-4-hydroxybenzoic acid (100g, 0.bbmol) in methanol (1.5l), thionyl chloride (233g, 1.9bmol) was added dropwise at 5-102С with stirring and heated under reflux at b59С for 25 1 day Excess methanol and thionyl chloride were distilled off, and the crude product was dissolved in ethyl acetate (H0) (500 mL). The organic layer was washed with 595% aqueous solution of ManNnsSOOz, water, brine and dried. The solvent was removed in vacuo to give methyl 3-amino-4-hydroxybenzoate (105g, 9590).

Stage II: methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-b6-carboxylate

To a mixture of methyl-33-amino-4-hydroxybenzoate (105 g, 0.62 mol) and benzyltriethylammonium chloride (142 g, i. 30 0.2 mol) in anhydrous CHO" (1.5 L) was added ManHsSoO" (211 g, 2.5 mol) while stirring. The reaction mixture was cooled to -59C, chloroacetyl chloride (85g, 0.75mol) in anhydrous CHCl3 (350ml) was added over 1.5h. at the same temperature. The reaction mixture was then titrated to 55923 for 1 h. The solvent was removed in vacuo, water (Zl) was added, and the solid was filtered off. The resulting solid was dried and (c) recrystallized from ethanol to give methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6b-carboxylate (108G, 35 8395). -

Stage II: b-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one

A solution of methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-b6-carboxylate (ZOg, 0.145 mol) in anhydrous СНоСи" (500 ml) was cooled to -782С, RIVAY -H (51 g, 0 ,3bmol) for 45 minutes. and then stirred at the same temperature for 14 hours. The reaction mixture was quenched with 1.5-N. NSI, and the obtained solid from c was filtered. The solid was dried in vacuo to give 6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (18G, bean). :z» Stage IM: TVRM8-6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one

Imidazole (13.7g, 0.2mol) was added to a solution of 6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (18g, 0.1mol) in anhydrous OME (2500ml) and stirred at 09С during ЗОхв. TVOM5IiSi (23g, 0.15mol) was added to the resulting reaction mixture in portions and stirred at room temperature for 4 hours.

The reaction mixture was diluted with water, and the resulting solid was filtered. The solid was dried under vacuum to give TVOM5-6-(hydroxymethyl)-2H-1,4-benzoxazin-3(4H)-one (24.5g, 8390). - Stage M: methyl-Ib-(hydroxymethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl|acetate

To a suspension of Mann (0.3 g, 0.01 mmol) in anhydrous OME (15 ml) was added with stirring, 2M5-6-(hydroxymethyl)2H-1,4-benzoxazin-3(4H)-one (2g, 0, 00b68mol) at 02C and stirred at room temperature for 2 hours. The reaction mixture was cooled to 02C, methyl chloroacetate (1 g, 0.0088 mol) was added and stirred at room temperature for 12 hours. The reaction mixture was additionally cooled to 02С, 50ml of 1.5-n was added. solution of NSI and stirred at room temperature for 12 hours. The reaction mixture was diluted with water (200 ml), extracted with ethyl acetate (3x15O0 ml). The combined organic layers were washed with 1095% aqueous solution of MnSO 3 , brine and dried. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on a silica gel column (eluent CHCl2/methanol, 99.5:0.5) to give methyl-β-(hydroxymethyl)-3-oxo-2, 3-dihydro-4H-1,4-benzoxazine-4-ilyacetate (1.2 g, 7090).

Stage MI: methyl-Ib-(formyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl| acetate in A mixture of ROSS (4.2 g, 0.019 mol) and celite (4 g) in anhydrous СНоСиИ» (100 ml) was cooled to 02С and a solution of methyl-|β-(hydroxymethyl)-3-oxo-2,3-dihydro- of 4H-1,4-benzoxazin-4-yl acetate (1.2 g, 0.0048 mol) in СНоСИ» (30 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h, passed through celite, washed with CHCl (50 mL) and concentrated to give the crude product, which was purified on silica gel to give 1.05 g (87905). 65 IS-M8: M/7 EVI: 1.15 min., 250.41 (Ma-1). "YAN NMR (0M5O-yv) 5 9.88 (c, 1H), 7.65-7.60 (t, 2H), 7.24 (a,

U-8.1Hz, 1H), 4.85 (a, 9U-9.9Hz, 4H), 3.71 (v, ЗН).

Intermediate 65: 4-butyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazine-6b-carbaldehyde

This intermediate was synthesized according to the method of synthesis of intermediate 2. Total yield 33965.

IS-M8: M/7 ESI: 1.60 V, 234.35 (Mt). "H NMR (0M5O-aiv) 5 7.66 (a, U-0.7Hz, 1), 7.58 (aa, 9U-1.7Hz, 8y1Hz, 1), 7.18 (a, 0-8 ... t, ZN), 0.91 (6 9U-7.3Hz, ZN).

Intermediate compound 66: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo|1,Zoxazin-b6-carbaldehyde -

This intermediate was synthesized according to the procedure for the synthesis of intermediate 2. Total yield 29965.

TN NMR (0M5O-yv) 5 9.78 (in, 1H), 7.58 (aY, 9U-1.5Hz, 7.9Hz, 1), 7.47 (9, 9-1.9Hz, 7, 40-7.18 (t, 6H), 5.22 (8, 2H), 4.95 (v, 2H), 3.3 (y, 9-7.2Hz, 1H). Intermediate compound 67: 2- chlor-5-11,3|dioxolan-2-yl-benzofuran sch -y vo ?

SI and Sh,; co

Stage I: 5-I1.3)dioxolan-2-yl-benzofuran Fo

A mixture of benzofuran-5-carbaldehyde (15 µg, 1.0 µmmol), ethylene glycol (23 µl, eq.), trimethyl orthoformate (123 µl, 1.1 eq.) and tetrabutylammonium tribromide (49 mg, 00.eq.) was stirred at room temperature overnight . After that, TLC could still detect some starting materials. at

However, the reaction mixture was poured into saturated Manso solution, and the resulting product was extracted with ethyl acetate.

The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by flash chromatography using a mixture of cyclohexane/ethyl acetate 20:0.75 as the solvent. The title compound was obtained with a yield of 3690 (7OmgH).

I C-mM5: M/7 EZ5I: 1.51 min, 191.30 (M'-1). "

Stage II: 2-chloro-5-I1,3)dioxolan-2-yl-benzofuran 5-11,3|dioxolan-2-yl-benzofuran (5Omg, 0.2bmmol) was dissolved in TNE (2ml), and the resulting solution t s was cooled to -782C. Butyllithium (18 µM, 1.1 eq.) was added dropwise. This mixture was mixed with ZOkhv. at "» 2590. Then the reaction mixture was cooled to -782С, and MOZ (ZOmg, " 1.1 equiv.), dissolved in ml of TNE, was added dropwise to the reaction mixture. After 1 hour ЗОхв. At -782С, only a small amount of starting materials was detected. The temperature was slowly raised to room temperature overnight. Water and ethyl acetate were added to the mixture, and the aqueous layer was extracted 3 times. The combined organic phases were dried over Mazo, and filtered and evaporated to give 2-chloro-5-11,3|)dioxolan-2-yl-benzofuran (48.1 mg, 8195) of sufficient purity (Ce) for use in the next stage

IIS-mM5: M/2 E5I: 1.77 min., 225.23 (M--1). 7 Intermediate compound 68: Z-amino-benzo(e|isoxazole-5-carbaldehyde for 50 s» UA and H 22 Kaiser oxime resin (Momariospet 01-64-0188) (250 mg) was washed with OSM and TNE (Z times for 5 min ), added

Gee! 2 ml of TNE, after which 300 µl of potassium tert-butoxide (1 M in TNE, 1.2 equiv.) was added at room temperature.

The resin, which turned orange, was shaken on an Ocevi 210 device for 15 minutes. 2-Fluoro-5-formyl-benzonitrile (75 mg, 2 equiv.) in 1 ml of TNE was added, and the reaction mixture was heated at 5593 for 12 h.

The resin was washed with OSM, Meon, water (each time 2 x 2 min.) and MeonN (4 x 5 min.). The resin was dried at 402C in 60 argon jets for 30 minutes, after which it was subjected to cleavage.

The dried resin was treated with a mixture of TEA/5M NOI 4:1 (2.5 ml) for 2 hours at 55 2С. The obtained solution was collected in test tubes with a capacity of 20 ml, and the resin was washed twice with 4 Aml OSM. The collected fractions were evaporated on the device

Sepemas NTA to dryness, yielding 37mg (9295) of pure 3-amino-benzo|a|isoxazole-5-carbaldehyde.

NRIS: 1.47 min. I C-M8: M/2 E5I: 0.82 min, 163.26 (M'-1). bo Intermediate compound 69: methyl ester of 4-piperidin-1-yl-quinazoline-b-carboxylic acid and that This intermediate compound was obtained by the method of synthesis of intermediate compound 8 using the methyl ester of 4-chloro-quinazoline-6-carboxylic acid ( intermediate compound 7) as a starting compound.

NRIS: 1.81 min. And C-M8: M/2 EI: 1.78 min, 272.32(M 1).

Intermediate compound 70: 4-piperidin-1-yl-quinazoline-b-carbaldehyde n

This intermediate was obtained by the method of synthesis of intermediate 5 using 4-piperidine-quinazoline-6-carboxylic acid methyl ester (intermediate 71) as the starting compound.

NRIS: 1.36 min. And C-M5: M/2 EI: 1.4 Ohv, 242.32(M 1).

Intermediate compound 71: ethyl ester of 3-(5-formyl-benzofuran-3-yl)-propionic acid with di o i and so o (o) 100 mg of ethyl ester of 3-(5-formyl-benzofuran-3-yl) of y-acrylic acid (intermediate compound 62) was dissolved in EtOAc in the presence of palladium on carbon and argon. An elastic chamber with hydrogen was attached to the reaction vessel and hydrogenated for 12 hours. The palladium was filtered off and the solvents were evaporated to give (o) the pure title compound (8Omg, 8095).

NRIS: 3.53 min. I C-M8: M/2 E5I: 1.68 min, 247.25 (M'.-1). hey

Intermediate compound 72: 2-methyl-5-(/1,3|dioxolan-2-yl-benzofuran ' - | « - c i- "» 5-(11,3|dioxolan-2-yl-benzofuran) (5Omg, 0.2bmmol) was dissolved in TNE (2ml), and the resulting solution was cooled to -782С. Butyllithium (18µl, 1.1 eq.) was added dropwise. This mixture was stirred by RT at 2590. Then the reaction mixture was cooled to -782С, and to to the reaction mixture was added dropwise iodomethane (18.1 µL, 1.Eq.) dissolved in 1 mL of TNE. The temperature was slowly raised to room temperature 7 overnight. Although some starting materials were detected, water was added to the resulting mixture (Ce) and ethyl acetate, and the aqueous layer was extracted 3 times.The combined organic phases were dried over Na 5 O, filtered and evaporated to give 2-methyl-5-(1,3|dioxolan-2-yl-benzofuran) (41.2 mg, 7095) sufficient and pure for use in the next stage. so 020 IS-M8: M/7 EVI: 1.71 min, 205.34 (M). (c Intermediate compound 73: methyl ester 5-11,3)dioxolane-2- yl-benzofuran-2-carboxylic acid » at; and 5-11.3|dioxolan-2-yl-benzofuran (5mg, 0.2bmmol) was dissolved in TNE (2ml), and the resulting solution was cooled to -782C. Butyl lithium (180 μl, 1.1 eq.) was added dropwise. This mixture was stirred ZOkhv. at 259C. Then the reaction mixture was cooled to -7892C, and 60 methyl cyanoformate (2 µl, 1.1 equiv.), dissolved in 1 ml of TNE, was added dropwise to the reaction mixture. Through berries. REFERENCE detected only a small amount of starting materials and two major compounds formed (expected product/dimer 73:27). The temperature was slowly raised to room temperature overnight. Water and ethyl acetate were added to the resulting mixture, and the aqueous layer was extracted three times. The combined organic phases were dried over NaCl, filtered and evaporated to give 5-(1/1,3)dioxolan-2-yl-benzofuran-2-carboxylic acid methyl ester (31.9mg, 4495) mixed with dimer (expected product/dimer 46:54). The resulting mixture was used directly in the next stage.

IIS-mM5: M/7 EI: 1.54 min, 249.26 (M'1) and 1.88 min, 407.20 (M--1, dimer).

Intermediate 74: 3-bromo-2-fluoro-benzofuran-5-carbaldehyde

E" g 70 Benzofuran-5-carbaldehyde (100mg, 0.6v8mmol) in ether (1ml) was added to a cooled solution (-78C) of MV (158mg, 1.Eq.) and poly(hydrogen fluoride)-pyridinium 7095 (0.850ml ) in ether (4 mL) in a polypropylene tube.The reaction mixture was allowed to stand at room temperature overnight.

The reaction mixture was poured into ice water and extracted with ether. The ether phase was washed with aqueous bicarbonate solution, dried over sodium sulfate, filtered and evaporated, obtaining 75. 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (141.bmg). It was purified by NRI C with an inverted phase (eluent gradient

H2O/CH3SM 0.195 TPA) to give the title compound (62 mg, 3795), which was used by VNKoristoOVuvmn in the next step.

IS-M5: M/2 EVBI: 1.56 bkhv. NRIS-3.11 min. (99.3495). "NN NMR: (0M50-46) 5 9.94 (z, 1), 8.09 (a, 1H, 39-1.8Hz), 7.99 (aa, YAN, 39-84, 1.8Hz) . 0M50O-yv) 5 -114.80, -114.88.

Intermediate compound 75: 2-fluoro-5-|11,3)dioxolan-2-yl-benzofuran (8) 5-11,3|dioxolan-2-yl-benzofuran (5 mg, 0.2 mmol ) was dissolved in TNE (2 ml), and the resulting solution was cooled to -782C. Butyllithium (18 µM, 1.1 eq.) was added dropwise. This mixture was stirred ZOkhv. at p. 259C. Then the reaction mixture was cooled to -782C, and was added dropwise to the reaction mixture

M-fluorodibenzenesulfonamide (91 mg, 1.Eq.), dissolved in iml TNE. The resulting mixture was stirred overnight at a temperature between -782C and room temperature. Water and ethyl acetate were added to the resulting mixture, and the aqueous layer was extracted 3 times. The combined organic phases were dried over M950O5, filtered and evaporated to give 2-fluoro-5-11,3|dioxolan-2-yl-benzofuran (75 mg) mixed with by-products. However, it had a sufficient degree of purity to be used at the next stage. uh-

Synthesized compounds indicated in the following examples:

Example 1: Preparation of 5-P,Z-benzoduxol-5-ylmethylene)-1,3-thiazolidin-2,4-dione and "green"

20 g of thiazolidine, 15.6 g of piperonal, and 7.7 g of beta-alanine were loaded into a round-bottom flask with a capacity of 100 ml

In 8Oml of acetic acid. The reaction mixture was stirred for at 10022 and then -I was slowly cooled to room temperature, while the desired condensation product crystallized. The obtained crystals were filtered, washed with acetic acid (rt) and water, after which they were recrystallized from OME (25 ml), thus obtaining 28 g (8495) of pure 5-(1,3-benzodioxol-5-ylmethylene)-1, 3-thiazolidine-2,4-dione. The corresponding potassium -I salt was obtained as follows: 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione was suspended in TNE, after

What was added 1-n. solution of KOH in water (1.0 equiv.). A clear solution was obtained, from which, after lyophilization, the pure potassium salt of 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione was obtained. syu NRI S: 3.48 min. I C-M5: M/7 E5I: 1.31 min, 248.12 (M-1). NMR (initial compound): "H NMR (OOM5O-ydv) 5 12.5 (bg. 8, 1H), 7.71 (v, 1H), 7.06-7.16 (t, ЗН), 6, 12 (in, 2H).

In cases where the final compounds did not crystallize from the reaction solution, small amounts of water were added, causing precipitation of the desired condensation product. o The crude product was either precipitated in a sufficiently pure form from the reaction mixture, or recrystallized from a suitable solvent, for example, UOME, methanol, EtAs, or purified by flash chromatography using mixtures of Et(OAc/cyclohexane as an eluent.

Alternatively, the final compounds can be synthesized in parallel using the following methodology:

A parallel Ocezi 210tm synthesizer was loaded with the appropriate aldehyde, to which a mixture of piperidine (17.9 mg in each tube) and 2,4-thiazolidinedione (49.2 mg in each tube) in OME (2 ml in each tube) was added.

The reaction mixture was stirred for 1 h at 1202C and then cooled to room temperature with stirring. 2 ml of N.O. was added. Those compounds that precipitated were filtered through the lower collector. Because the remains of clear solutions were concentrated, after which water was added. The solids thus obtained were filtered off and washed with a small amount of OME to give pure condensation products.

Example 2: Preparation of 5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one

1 g of commercially available rhodanine, 1.3 g of piperonal and 0.5 ml of TEA in 70 1 Oml of OME were loaded into a 24 ml test tube. The reaction mixture was stirred for two hours at 120 2С and then cooled to room temperature, while the final product was precipitated. The solid was filtered and washed with OME to give 1.6 g (8095) of an orange powder.

IS-M5: M/7 EI: 1.46 min, 266.00 (M--1), 264.08 (M-1). NMR (initial compound): "H NMR (OOM5O-yv) 5 13.75 (Bg. /5 8, 1H), 7.58 (8, 1H), 7.08-7.18 (t, ЗН), 6.14 (5.2H).

Example C: Preparation of 5-(2,3-dihydro-1,4-benzodioxin-b-ylmethylene)-1,3-thiazolidine-2,4-dione

According to the general procedure described in Example 1, using 2,3-dihydro-1,4-benzodioxin-β6-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. with

NRI S: 2.58 min. IS-M8: M/7 E5I: 1.32 min, 262.16 (M-1). "H NMR: (0M5O-ydv) 5 12.52 (rg. 8, 1H), 7.68 (v, 1H), o 7.09 (aa, 2H, 9-1.9, 7.1), 7.00 (a, 1H, U-9.0Gu), 4.36-4.22 (t, 4H).

Example 4: Preparation of 5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione

Ge) i n F cha

According to the general method described in Example 1, with the use of b 2,3-dihydro-1-benzofuran-5-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, the compound indicated in the title was obtained.

NRIS: 3.27 min. IS-M8: M/7 E5I: 1.37 min, 246.18 (M-1). "H NMR: (0M5O-y5) 5 9.80 (Bg. 8, 1H), 7.37 (v, 1H)), 7.25 (9, 1H, y-8.3), 7.21 ( c, 1H), 6.80 (a, 1H, U-8.3Hz), 4.54 (I, 2H, U-8.85Hz), 3.19 (I, 2H, U-8.85Hz). "

Example 5: Preparation of 5-((7-methoxy-1,3-benzodioxol-5-yl)umethylene|-1,3-thiazolidine-2,4-dione)

According to the general method described in Example 1, using is) (7-methoxy-1,3-benzodioxol-5-yl)carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, -I indicated in title compound.

NRIS: 3.57 min. I C-M8: M/7 E8I: 1.3 Ohv, 278.07 (M-1). "H NMR: (0M5O-yv) 5 12.63 (rg. 8, 1H), 7.78 (v, 1H)), o 7.65 (v, 1H), 7.57 (y, 1H, 2 -8.5Hz), 7.45 (aa, 2H, 2-0.8, 7.6). s» Example 6: Preparation of 5-((9,10-dioxo-9,10-dihydroanthracen-2-yl )umethylene|-1,3-thiazolidine-2,4-dione . and cho: (F) de and yu

According to the general method described in Example 1, using bo (9,10-dioxo-9,10-dihydroanthracen-2-yl)carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, the title indicated compound

NRI C: 4.12 min. And C-M5: M/2 EI: 1.50 min, 334.09 (M-1).

Example 7: Preparation of (5-((2,2-difluoro-1,3-benzodioxol-5-yl)umethylene|-1,3-thiazolidine-2,4-dione b5 ich)

E about dO

According to the general procedure described in Example 1, using (2,2-difluoro-1,3-benzodioxol-5-yl)carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, 0 indicated in the title was obtained compound

NRIS: 3.8 Bhv. IS-M5 (10 min.): M/7 EV8I: Z, 15 min, 284.11 (M-1). "H NMR: (0М5О0-ав) 5 12.63 (bg. in, 1Н), 7.78 (5, 1Н,), 7.65 (в, 1Н), 7.57 (а, 1Н, У- 8.5Hz), 7.45 (ad, 2H, 2-08, 7.6Hz).

Example 8: Preparation of 5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidin-2,4-dione -4 ko n

According to the general procedure described in Example 1, using 1,3-dihydro-2-benzofuran-5-carbaldehyde (intermediate compound 4) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained .

NRI S: 2.89 min. I S-M8: M/7 EZ8I: 1.20 min, 246.20 (M-1). "H NMR: (OM5O-dv) 5 12.60 (Bg. 8, 1H), 7.80 (v, 1H), 7.56-7.42 (t, 2H), 5.03 (5, 4H Example 9: Preparation of 5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidin-2,4-dione

Yi Ge) "F

According to the general procedure described in Example 1, using 1-benzofuran-5-carbaldehyde (intermediate compound 1) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained.

NRIS: C3, B54 min. IS-M8: M/7 E5I: 1.47 min, 244.20 (M-1). "H NMR: (0M5O-yv) 5 12.58 (rg. in, 1H), 810 (a, MH, me) 2.2 Hz), 7.92 (in, 2H), 7.74 (a, 1H, U-8.6Hz), 7.57 (a, 1H, U-8.6Hz), 7.07 (8, 1H).

Example 10: Preparation of 5-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-b-yl)methylene-1,3-thiazolidine-2,4-dione - with z

According to the general procedure described in Example 1, using (4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-b-yl)carbaldehyde (intermediate compound 2) and -i 1,3 -thiazolidine-2,4-dione as starting compounds, the title compound was obtained.

Gee! NRI S: 2.79 min. IS-M8: M/7 EZ8I: 1.19 min, 289.22 (M-1). "H NMR: (0OM5O-yv) 5 12.58 (rg. 8, 1H), 7.81 (c, 1H), 7.A1 (8, 1H), 7.13-7.26 (9, 2H ), 4.74 (5, 2H), 2.99 (in, ЗН). ш- Example 11: Preparation of 5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidine- 4-onu (se) and z chn (Z - o bl Ei s» Ki " g

The title compound was obtained by the general method described in Example 1, using 1,3-benzodioxole-5-carbaldehyde and 2-imino-1,3-thiazolidin-4-one as starting compounds. name) NRI C: 2.29 min. And S-M8: M/2 EI: 1.21 min, 247.25 (M-1).

Example 12: Preparation of 5-quinolin-6-ylmethylene-thiazolidine-2,4-dione bo o od b5 o)

According to the general procedure described in Example 1, using quinoline-b-carbaldehyde (intermediate compound 5) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained.

NRIS: 1,445 Bhv. IS-M8: M/7 E5I: 1.17 min, 257.21 (Mt). "H NMR: (0M5O0-4y5) 5 8.88 (a, U-6Hz, 1H), 8.40 (a,

U9Hz, 1H), 8.07-7.90 (t, ZN), 7.55 (a, U-6Hz, 9Gu, 1H), 7.45 (v, 1H).

Example 13: 5-quinolin-b-ylmethylene-2-thioxo-thiazolidin-4-one

F a about the 70s

Following the general procedure described in Example 1, using quinoline-b-carbaldehyde (intermediate compound 5) and rhodanine as starting compounds, the title compound was obtained.

NRIS: 2.05 min. AND! S-M8: M/2 EI: 1.25 min, 273.14 (M-1). 1H NMR: (0M5O-ag) 5 14.00 (rg. c, 1), 8.97 (a, 75 2, ZHC, 1H), 8.23 (a, U-9Hz, 1H), 8.10 (a, U-9Gu, 1H), 7.95 (a, U-9Hz, 1H), 7.79 (c, 1H), 7.61 (a, U-zHz, 9Gu, 1H).

Example 14: 2-imino-5-quinolin-b-ylmethylene-thiazolidin-4-one

According to the general procedure described in Example 1, using quinoline-b-carbaldehyde (intermediate compound 5) and 2-imino-1,3-thiazolidin-4-one as starting compounds, the title compound was obtained.

NRI-S: 1.16 min. I C-M8: M/7 EV8I: 1.10 min, 256.18 (M--1). "H NMR: (0M8O-yv) 5 12.58 (Bg. 8, 1H), 8.84 (v, 1H), CSE 8.37 (0, 9-6HzC, 1H), 8.02-7 ...

Example 15: 5-(3-methyl-benzo|d|isoxazol-5-ylmethylene)-thiazolidine-2,4-dione t ai o

Ge) cha

According to the general method described in Example 1, using

of 3-methyl-benzoyl|a|zoxazole-5-carbaldehyde (intermediate compound 6) and 1,3-thiazolidine-2,4-dione as starting Me)

335 compounds, the title compound was obtained. Cha

NRIS: 2.90 min. IS-M8: M/7 E5I: 1.3 Ohv, 259.17 (M-1). "H NMR: (0M5O-ydv) 5 12.58 (rg. 5, 1H), 8.08 (b, 1H), 7.95 (b, 1H), 7.85 (b, 2H), 2, 59 (in, ZN).

Example 16: 5-(4-phenyl-quinazolin-b6-ylmethylene)-thiazolidine-2,4-dione

HA and

І» І 5 С - According to the general method described in Example 1, using 4-phenyl-quinazoline-b-carbaldehyde so (intermediate compound 13) and 1,3-thiazolidine-2,4-dione as starting compounds, obtain the specified compound in the title.

DRAWING: Z,45 Bhv. I C-M8: M/7 E8I: 1.25 min, 334.15 (Ma-1). "H NMR: (0M5O-yv) 5 12.74 (rg. 8, 1H), 943 (v, 1H), and 8.24 (t, 2H), 8.00-7.86 (t, 2H) , 7.72-7.66 (t, 5H). (se) 20 Example 17: 5-(4-dimethylamino-quinazolin-b-ylmethylene)-thiazolidine-2,4-dione

Fe

AND

0 -E n y (F) , !

According to the general procedure described in Example 1, using co 4-dimethylamino-quinazoline-b-carbaldehyde (intermediate compound 14) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. 60 NRIS: 1.47 min. IS-M5: M/7 E5I: 1.26 bkhv, 301.26 (Ma1). "H NMR: (0M5O-4d5) 5 8.81 (z, 1H), 8.54 (v, 1H), 8.16-7.95 (t, ЗН), 7.13-7.26 (y , 2H), 3.63 (in, 6H).

The following examples were synthesized as described in Example 1 and Example 17 using intermediates 15-31 and 1,3-thiazolidine-2,4-dione as starting compounds. -d41-

5-(4-aminoquinazolin-b-yl)umethylene-1,3-thiazolidine-2,4-dione 273.29 ra 8 B(A-piperidine-ylquinazolin-b-yl)umethylene-1,3-thiazolidine-2 ... -yl|methylene)-1,3-hiazolidine-2,4-dione 363.10 5-(4-(diethylamino)quinazolin-6-yl|imethylene)-1,3-hiazolidine-2,4-dione 329, 30 5-C4-(pyridin-2-ylmethyl)aminoYquinazolin-b-ylumethylene)-1,3-thiazolidine-2,4-dione 364.40 5-C4-(pyridin-3-ylmethyl)amino)quinazolin-b- ilumethylene)-1,3-thiazolidine-2,4-dione 364.40 ethyl-1-6-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/dinazolin-4-ylpiperidine-3- carboxylate 13.20 70 ethyl 1-6-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/dinazolin-4-ylpiperidine-4-carboxylate 413.30 tert-butyl-1-46- (2,4-dioxo-1,3-thiazolidin-5-ylidene)methylquinazolin-4-yl)-I -prolinate 421.20 5-(4-(4-methylpiperazin-1-yl)quinazolin-b-ylimethylene) -1,3-thiazolidine-2,4-dione 356.13 5-4C4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazolin-b-ylmethylene)-1,3-thiazolidine-2,4-thione 42 0.20 5-(C4-I4-(4-fluorophenyl)piperidin-1-ylquinazolin-b-ylumethylene)-1,3-thiazolidine-2,4-dione 435.30 5-(4-(4-benzylpiperidine- 1-yl)quinazolin-b-yl| methylene)-1,3-thiazolidine-2,4-dione AZ31,30 5-C4-I4-(2-phenylethyl)piperidin-1-ylIquinazolin-b-ylumethylene)-1,3-thiazolidine-2,4-dione 44540 5-(4-(4-methylpiperidin-1-yl)quinazolin-b-yl|methylene)-1,3-thiazolidine-2,4-dione 355.20 5-4C4-(4-hydroxypiperidin-1-yl) )quinazolin-b-yl|methylene)-1,3-thiazolidine-2,4-dione 357.40

Example 35: 1-I(6-(2,4-duxo-thiazolidin-5-ylidenemethyl)-quinazolin-4-yl|-piperidine-4-carboxylic acid m s os o

B5Omg of ethyl 1-76-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/quinazoline-4-yl-piperidine-4-carboxylate (example 26) was dissolved in 2 ml of TNE solution in water (1/1 ). A few drops of 5-n were added. Mahon and the reaction mixture were stirred for 12 hours at room temperature. After completion of the reactions, the solvents were evaporated, and the title compound was precipitated in diethyl ether as a yellow solid (4Omg, (22) 8290). Cha

NRI C: 1.4 Khv. And C-M5: M/2 EI: 1.15 min, 385.20 (M-1).

Example 36: 1-(6-(2,4-dioxo-thiazolidin-5-ylstenmethyl)-quinazolin-4-yl|-piperidine-3-carboxylic acid (22) by the method described in Example 35, the title compound was obtained.

Example 37: 1-I6-(2,4-dioxo-thiazolidin-5-ylsenemethyl)-quinazolin-4-yl|-pyrrolidine-2-carboxylic acid t

Fe I and :. y y y y 10 mg / tert-butyl-1-(6-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-quinazolin-4-yl-|-prolinate (example (27)) was mixed in 2595 solution (TEA/OSM) for 12 h at room temperature.The solvents were evaporated in vacuo and the expected compound was precipitated with diethyl ether to give /- pure 59 1-(6-(2,4-dioxo-thiazolidine-5-ylidenemethyl) -quinazolin-4-yl|-pyrrolidine-2-carboxylic acid (7 mg, 81965).

GF) NRI C: 1.4 Zhv. I C-M5: M/2 E5I: 1.10 min, 371.30 (M-1). Example 38: 5-(4-methylamino-quinazolin-b6-ylmethylene)-thiazolidine-2,4-dione

NC. IS

According to the general procedure described in Example 1, using 4-methylamino-quinazoline-6-carbaldehyde bo (intermediate compound 11) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. -d42-

NRI C: 1.4 Khv. IS-M8: M/7 EVI: 1.0Zhv, 287.19 (Ma-1). "H NMR: (0OM5O-ydv) 5 11.97 (Bg. 8, 1H), 8.53 (Bg. c, 2H), 8.37 (c, 1H), 7.92 (a, U-8HzC , 1H), 7.76 (in, 2H), 3.03 (in, ЗН)

Example 39: 5-(4-methoxy-quinazolin-b6-ylmethylene)-thiazolidin-2,4-dione, m.p. 70 o. at

According to the general procedure described in Example 1, using 4-methoxy-quinazoline-b6-carbaldehyde (intermediate compound 10) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained.

NRI S: 2.57 min. IS-M8: M/7 EV8I: 1.12 min, 288.20 (Ma1). "H NMR: (0M8O-aiv) 5 12.74 (rg. 8, 1H), 8.86 (v, 1H), 8.32 (8, 1H), 8.11 (t, 1H), 8, 03-7.98 (t, 2H), 4.18 (v, ZN).

Example 40: 2-imino-5-(4-methylamino-quinazolin-b6-ylmethylene)-thiazolidin-4-one n oo, "a

According to the general procedure described in Example 1, using 4-methylamino-quinazoline-6-carbaldehyde (intermediate compound 11) and 2-imino-1,3-thiazolidin-4-one as starting compounds, the title compound was obtained.

NRIS: 2.43 Khv. I C-M8: M/2 E5I: 1.07 min, 286.14 (M'-1). Ha

Example 41: 2-imino-5-(4-piperidine-quinazolin-b6-ylmethylene)-thiazolidin-4-one o

I shchi v-y ge U. (o) m them-

According to the general procedure described in Example 1, using 4-piperidine-quinazoline-6-carbaldehyde o (intermediate compound 72) and 2-imino-1,3-thiazolidin-4-one as starting compounds, the title compound was obtained.

NRI S: 1.78 min. I C-M8: M/7 E8I: 1.40 min, 340.26 (Ma-1). "H NMR: (0M5O-yv) 5 8.76 (in, 1H), 8.18 (in, 1H), 8.16 - (a, 9-6 Hz, 1H), 7.88 (a, U- OHz, 1H), 7.80 (8, 1H), 4.09 (in, 4H), 1.80 (in, 6H).

Example 42: 2-imino-5-(4-dimethylamino-quinazolin-b6-ylmethylene)-thiazolidin-4-one "section 2" - 415 According to the general method described in Example 1, using 4-piperidine- of quinazoline-6-carbaldehyde-1 (intermediate compound 14) and 2-imino-1,3-thiazolidin-4-one as starting compounds gave the title compound.

NRIS: 1.32 min. I C-M (10 min.): M/7 EB5I: 1.54 min, 300.23 (Ma-1). "H NMR: (0M5O-yv) 5 8.82 (8, 1H), 8.53 (z, o 1H), 8.16 (a, U-OHc, 1), 7.87 (i, U- 9Hz, 2H), 3.65 (in, 6H). -I Example 43: 5-(2-methyl-2H-benzotriazol-5-ylmethylene')-thiazolin-2 4-dione i 6-5 syu n- more and

According to the general method described in Example 1, using

HF) of 2-methyl-2H-benzotriazole-5-carbaldehyde (intermediate compound 33) and thiazolidinedione as starting compounds,

GF obtained the title compound.

NRIS: 2.68 min. "H NMR: (0M50-yv) 5 12.58 (rg. 8, 1H), 7.98 (b, 1H), 7.92 (a, uU-9Hz, 1H), 7.62 (a, U -6 Hz, bo 1), 7.43 (5, 1H), 4.48 (in, ЗН).

Example 44: 5-(3-methyl-ZN-benzotriazol-5-ylmethylene)-thiazolin-2,4-dione

SS 5 and 65 and | AND

SH.

According to the general method described in Example 1, using

of 3-methyl-3H-benzotriazole-5-carbaldehyde (intermediate compound 34) and thiazolidinedione as starting compounds gave the title compound.

NRIS: 2.3 Bhv. IS-M8: M/7 EV8I: 1.22 min, 259.23 (M-1). "H NMR: (0M5O-yv5) 5 12.58 (rg. in, 1H), 8.17 (49,

U9Hz, 1H), 8.07 (in, 1H), 7.62 (a, 9-6Hz, 1H), 7.47 (in, 1H), 4.33 (in, ЗН).

Example 45: 5-(3-ethyl-ZN-benzimidazol-5-ylmethylene)-thiazolidin-2.4-dione

Ul 5-(4-amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione (5mg, 0.19mmol) (intermediate 36) was dissolved in formic acid (bml) and the resulting solution was stirred at 1002C overnight . The formic acid was then removed in vacuo. The resulting crude residue was purified on a silica gel column to give the title compound (35mg, 6395).

NRI C: 1.71 min. I C-M5: M/2 E5I: 0.82 min, 274.21 (M--1).

The following examples were synthesized as described in Example 45 using intermediates 37-54 and 1,3-thiazolidine-2,4-dione as starting compounds. starting material (M) sch o -yl)ucyclohexanecarboxylate

F from F m

F

N-benzimidazol-1-yl cyclohexanecarboxylic acid in "1778. Bi-addyreniprolyl-benzimidazole-vpnethylene Z tazoidinoiodyun 0002027 8 s z" p

Example 64: 5-quinoxaline-b-ylmethylene-thiazolidine-2,4-dione - i and She s zh shchy. n -I (se) 50 According to the general procedure described in Example 1, using quinoxaline-β6-carbaldehyde (intermediate compound 55) and thiazolidinedione as starting compounds, the title compound was obtained.

NRI S: 2.48 min. 1 0-M8: M/7 EZ8I: 1.01 min, 256.20 (M-). "H NMR: (0OM8O-dv) 5 12.58 (Bg. c, 1H), 8.93 (a, 9U-9Hz, 2H), 8.18 (c, 1H), 8.10 (a, 2 -9Hz, 1H), 8.03 (a, U-9HzC, 1H), 7.51 (c, 1H).

Example 65: 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-one 5 (Ф) С их: co nt ry Hn bo

According to the general procedure described in Example 1, using quinoxaline-β6-carbaldehyde (intermediate compound 55) and rhodanine as starting compounds, the title compound was obtained.

DRAWING: From 1 Okhv. GS-M5: M/2 EI: 1.17 min, 272.13 (M-1). -H NMR: (0M5O-yv) 6 12.00 (Brg. 8, 1H), 9.02 (c, 2H), 8.91 (c, 1H), 8.21 (a, 2-9Htsu, 1H ), 8.04 (a, 2-9Hz, 1H), 7.90 (c, 1H). bo Example 66: 2-imino-5-quinoxalin-b-ylmethylene-thiazolidin-4-one -dA-

not N

According to the general procedure described in Example 1, using quinoxaline-b6-carbaldehyde (intermediate compound 55) and 2-imino-1,3-thiazolidin-4-one as starting compounds, the title compound was obtained. 70 NRIS: 1.97 min. IS-M8: M/2 EI: 1.02 min, 255.19 (M-1). "H NMR: (0M5O-yv) 5 9.57-9.30 (r. 4, U-81HCts, 2H), 9.00 (v, 2H), 8.26-8.07 (t, ЗН) , 7.84 (in, 1H).

Example 67: 5-benzothiazol-b-ylmethylene-thiazolidine-2,4-dione g - 5 - n

Following the general procedure described in Example I, using quinoxaline-b-carbaldehyde (intermediate 56) and thiazolidinedione as starting compounds, the title compound was obtained.

NRI S: 2.85 min. IS-M8: M/7 EZ8I: 1.0 bkhv, 261.11 (M-1). "H NMR: (0OM5O-yv) 5 12.58 (rg. 8, 1H), 9.39 (v, 1H), 8.27 (v, 1H), 8.11 (9, 9-9Hz, 1 ), 7.70 (a, 9-O9Hz, 1H), 7.42 (c, 1H).

Example 68: 5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione; There is s t o sht n

According to the general procedure described in Example 1, using 3-methyl-benzofuran-5-carbaldehyde o (intermediate compound 57) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. Ge")

NRIS: 1.47 min. IS-M8: M/7 EI: 1.15 min, 257.21 (M-1). "H NMR: (0М5О-4в5) 5 12.50 (rg. z, 1Н), 8.87 (9, m

U-6HzC, 1H), 8.38 (a, U-OHc, 1H), 8.07 (5 9U-12Hz, 2H), 7.92 (a, 9-9Hz, 1), 7.53 (a , U-6Hz, 12HzC, 1H), 7.45 (in, 1H).

Example 69: 5-(2-bromo-3-methyl-benzofuran-5-ylmethylene)-thiazolidin-2,4-dione (22)

5-(3-methyl-benzofuran-5-ylmethylene)-thiazolidine-2,4-dione (100 mg, 0.39 mmol) was loaded into a 3-neck flask with a capacity of 25 ml (example 68) and HgO (200 μl, Teq.) in 2 ml of AsOH at 02С. The resulting mixture was left for the title to room temperature. After 2 hours at room temperature, more Teq was added. After 3 h, the reaction mixture was filtered to give a yellow product, which was the title compound (87 mg, 6695). - and IS-M5: M/7 EVI: 1.69 min, 339.8 (Mt). "H NMR: (0M5O0-yv) 5 12.50 (Bg. 8, 1H), 7.93 (v, 1H), 7.82 (8, 1H), 7.12 (a, 20-6Hz, 1 ), 7.54 (а, У-6Hz, 1Н), 2.20 (в, ЗН). se)

Example 70: 5-(3-bromo-benzofuran-5-ylmethylene)-thiazolidin-2,4-dione

Following the general procedure described in Example 1, using 3-bromo-benzofuran-5-carbaldehyde (intermediate compound 58) and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. (F, NRI C: 3.92 min. I C-M8: M/7 EV8I: 1.57 min, 325.17 (Ma1). "H NMR: (0M8O-yv) 5 12.60 (rg. 8, 1H ), 8.42 (v, 1H), ko 8.00 (v, 1H), 7.85 (9, U-23HC, 1H), 7.76 (v, 1H), 7.63 (y, 9 -23Hz, 1H).

Example 71: ethyl ester of 3-(5-(2.4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-acrylic acid b5

70 According to the general method described in Example 1, using the ethyl ester of 3-(5-formyl-benzofuran-3-yl)-acrylic acid (intermediate compound 60) and 1,3-thiazolidine-2,4 -dione as starting compounds, the title compound was obtained.

NRIS: 4.00 min. IS-M8: M/7 E5I: 1.6 Ohv, 342.20 (M-1). "H NMR: (0M5O-yv) 5 12.50 (rg. 5, 1H), 8.63 (in, 1H), 8.42 (5, 1H), 8.08 (in, 1H), 7, 83 (t, 2H), 7.62 (v, 1H), 4.22 (a, 9-6Hz, 9Hz, 2H), 1.28 (I, U-9Hz, ZN).

Example 72: 3-(5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-acrylic acid

What is pet o nn o sch

Ethyl ester of 3-(5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-acrylic acid (205mg, 0.bmol) (example 71) was dissolved in a mixture of TNE in water (4 :2). To this solution was added with stirring 81 mg (4 eq.) of Ion.NO. The reaction mixture was stirred for 15 hours. The solvents were evaporated, and the resulting residue was precipitated with ether. The solid was washed with 1 N HCl and dried, receiving 17Omg (9096) of pure 3-I(5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-ylI-acrylic acid. (ze)

NRIS: 3.25 min. I C-M8: M/7 E8I: 1.01 min, 314.11 (M-1). "H NMR: (0M5O-yv) 5 8.22 (in, 1H), 8.03 (in, 1H), 7.58 Fo (aa, U-oHu, ZZ3Hz, 2H), 7.43 (in, 1H), 7.25 (a, 9U-18Hz, 1H), 7.07 (c, 1H).

Example 73: 5-I3-(3-oxo-3-piperidin-1-yl-propenyl)-benzofuran-5-ylmethylene-thiazolidin-2,4-dione -

Go y az y dosh Tr

180 mg (0.57 mmol) of 3-I|5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-acrylic acid (example: 3» 72) was suspended in TNE (25 ml). OIBA (2 eq.) and piperidine (1 eq.) were added to this suspension. RUVOR (1.5 eq.) was added while stirring. Through ЗОхв. the reaction mixture became transparent, after another hour a precipitate was formed. The reaction mixture was stirred overnight. The precipitate was filtered and washed with TNE and -1 395 1-n. CARRIERS, obtaining the title compound of high purity.

NRIS: 3.9 of the square. IO-M5: M/7 E5I: 1.58 min, 383.22 (Ma1). "H NMR: (0M5O-4d5) 5 8.46 (z, 1H), 8.19 (c, 1H), se) 7.71-7.51 (t, 4H), 7.23 (a, 9 -15Gu, 1n), 3.73 (a, 9-48Hz, 2H), 1.51 (a, 9-36Hz, ЗН). -1 The following amides were synthesized according to the synthesis method of example 73. 27 material and complex ether complex ether 345-(ol-dioco-Z-pezolidin-lidenemethyl y-benzofuvan z'li-M ethyl-k idocoethylucrylamd 65 84 azepane 5-(3-IZ-azepan-1-yl- Z-oxoprop-1-en-1-yl|-1-benzofuran-5-ylumethylene)-1,3-hiazolidine-2,4-dione -4b-

(ve pyridikzchpmetitam- |945-(oldiokoo Z pezolidin -lidenemethyly -benzofuran z4li M (pyridine castings ze chuloethiamn |Mlcloettit zo 4-duxol z violidine in lidenetit benufuran grains in prolno 000000 (in vch vdiidvolntyrol il) z okoopropt en pi benzofuvan v- iimethylene t Ztazoidin ol dune

Mass o and (MA) sch o

Fo zo F cha

Example 92: ethyl ester of 3-I5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-propionic acid

GU and - hell

Y - c H "z a " According to the general method described in Example 1, using the ethyl ester of 3-(5-formyl-benzofuran-3-yl)y-propionic acid (intermediate compound 71) and 1,3-thiazolidine -2,4-dione as starting compounds, the title compound was obtained. i NRIS: 3.94 min. IS-M8: M/7 EZ8I: 2.87 min, 346.15 (Ma-1). "H NMR: (0M5O-yv) 5 12.58 (rg. 8, 1H), 7.92 (49, (Ce) U-6Hz, zn), 7.72 (a, 9-9Hz, 1), 7.53 (a, 9-9Hz, 1H), 4.03 (a, 9U-9Gu, 15Hz, 2H), 2.94 (5 9-9Hz, 2H), 2.73 -1 (6 9U-6Hz , 2H), 1.14 (i, 2-6 Hz).

Example 93: 3-(5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl|-propionic acid 50%

The title compound was obtained using the standard saponification technique described for example 60 72 using the compound of example 92 as starting material.

NRI C: 3.09 min. I S-M (1Okhv.): M/7 EZ8I: 1.19 min, 316.14 (M-1). "H NMR: (0M5O-yv) 5 12.58 (Bg. 8, 1H), 12.22 (B. c, 1H), 7.93 (a, 9-12Hz, ЗН), 7.70 (a , 9-9Hz, 1), 7.54 (a, U-9Hz, 1H), 2.91 (i, U-9HzC, 2H), 2.65 (i, 6Hz, 2H).

Example 94: 5-I3-(3-oxo-3-piperidin-1-yl-propyl)-benzofuran-5-ylmethylene|-thiazolidine-2,4-dione b5

"p a

The title compound was obtained using the synthesis method described for example 73, then using the compound of example 93 as starting material.

NRIS: 3.783 min. IS-M8: M/7 EI: 1.46 bkhv, 385.14 (Ma1). "H NMR: (0М5О0-ав) 5 12.66 (rg. 85, 1Н), 8.06 (z,

ZH), 8.01 (8, 1H), 7.79 (in, 1H), 3.50-1.60 (t, 14H).

Example 95: tert-butyl ester 75 of 6-(2,4-dioxo-thiazolidine-5-ylidenemethyl)-2,3-dihydro-benzo|1,Zoxazin-4-carboxylic acid o

It's the 20th

According to the general procedure described in Example 1, using tert-butyl ester of b-formyl-2,3-dihydro-benzo|1,4oxazine-4-carboxylic acid (intermediate 62) and 1,3-thiazolidine-2, 4-dione with 25 As starting compounds, the title compound was obtained. at

NRI S: 2.52 min. And S-M8: M/2 EI: min, 261.21 (M-Vos-1).

Example 96: 5-(3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione a o what so 30

To them

Up to 10mg of tert-butyl ester of b-formyl-2,3-dihydro-benzo|1,Doxazin-4-carboxylic acid

To (intermediate compound 62) a mixture of TEA/YUSM 2595 was added for 2 hours. Solvents were evaporated to dryness, and - the crude residue was used to carry out the Knevenagel (Kpoemepadei) reaction as described in

Example 1, without further purification, affording the title compound as a yellow solid. "

NRI S: 2.56 bkhv. IS-M8: M/7 EZ8I: 1.14 min, 261.24 (M-1). "H NMR: (0OM5O-yv) 5 12.58 (rg. 8, 1H), 7.57 (v, 1H), C 6.78 (v, ЗН), 4.17 (6 9U-Z3Hz, 2H ), 3.28 (i, U9-6Hz, 2H). c Example 97: 5-(4-benzoyl-3,4-dihydro-2H-benzo|1,oxazin-b6-ylmethylene)-thiazolidine-2,4 -dion;" at

5-(3,4-dihydro-2H-benzo|1,oxazin-b6-ylmethylene)-thiazolidine-2,4-dione (example 96) (Zb5mg, O0.1 mmol) in 4 ml of anhydrous TNE was treated with benzoyl chloride (15 bml, 1 eq.) in the presence of OIEA (2 eq.) for

The excess of benzoyl chloride was hydrolyzed, EAs was added, and the organic phase was washed with MnSO 4 and brine.

The resulting crude product was purified on silica gel using a mixture of E(OAc) with cyclohexane (3:7) as a vv eluent to give 14 mg (3596) of the title compound.

NRI S: 4.57 min. I C-M8: M/2 E5I: 2.11 min, 364.91 (M-1). (F) The following example was synthesized using the same methodology as described for example 97.

GI Example 98: 5-(4-acetyl-3,4-dihydro-2H-benzo|1.oxazin-b-ylmethylene)-thiazolidine-2,4-dione

A, b5,

Output-4Zmg (9595).

NRI C: 2.65 min. IS-M8: M/7 EVI: 1.12 min, 305.24 (Ma-1). "H NMR: (0OM5O-ydv) 5 12.58 (Bg. 8, 1H), 8.30 (Bg. in, 1NU, 7.71 (in, 1H), 7.35 (a, U-9Hz, 1H), 7.05 (a, 9-9Hz, 1H), 4.33 (Ii, 9-6Hz, 2H), 4.00 (i, 9-6Hz, 2H).

Example 99: tert-butyl alcohol. 6-2,4-dioxo-thiazolidine-5-ylidenemethyl)-benzo|1,oxazine-4-carboxylic acid ester o

I am with

And A"

According to the general procedure described in Example 1, using tert-butyl ester 75. 8-formyl-benzo|1,4|oxazine-4-carboxylic acid (intermediate 63) and 1,3-thiazolidine-2,4- dione as starting compounds, the title compound was obtained.

NRIS: 4.2 Khv. IS-M8: M/7 EZ8I: 1.82 min, 359.16 (M-1). "H NMR: (0M8O-yv) 5 12.50 (Bg. 8, 1H), 7.63 (49,

UZHz, 2H), 7.31 (a, 9-3Hz, 1H), 6.95 (a, 9-6HzC, 1H), 6.30 (c, 2H).

Example 100: methyl ester |6-(2.4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo|1,4|-oxazin-4-yl|-acetic acid o a - y n zhi v s o o y

According to the general procedure described in Example 71, using methyl ester o (6-formyl-3-oxo-2,3-dihydro-benzo|1,oxazin-4-yl)-acetic acid (intermediate compound 64) and F of 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained. M

NRIS: 2.8 Zkhv. IS-M8: M/7 E5I: 1.20 min, 347.25 (M-1). "H NMR: (0M5O-yv) 5 12.58 (rg. 5, 1H), 7.76 (b, 1H), 7.36 (b, 1H), 7.20 (t, 2H), 4, 82 (а, 90-15 Hz, 4H), 3.71 (в, ЗН). (22)

Example 101: M

M-benzyl-2-I(6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-digylro-benzo|1,Zoxazin-4-yl|-acetamide y i Z nya , о - з - Methyl ester of 6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo|1,41-oxazin-4-yl|-acetate Acids (195mg,

0.5 mmol) (example 100) was saponified using 2 equiv. GION, as described for example 74, and I6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydro-benzo|1,oxazin-4-yl|-acetic acid The acid (50 mg, 0.15 mmol) thus obtained with 50 was dissolved in TNE. NOVI (32 mg, 1.5 equiv.), EOS (43 mg, 1. equiv.) and benzylamine (25 mg, 1. equiv.) were added with stirring. The reaction mixture was stirred for 15 h at room temperature. EtOAc was added, and the organic phase was washed with 1-N. NSI, MansSO»z, brine three times each.

The crude residue obtained after evaporation of the solvents was purified on silica gel using

OSM/EUAc as eluent to give the title compound as a colorless powder (35mg, 5490).

NRIS: Z, Obhv. I C-M8: M/2 E5I: 1.27 min, 424.21 (M.-1). o Example 102: 5-(4-butyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione ko X n 60 Hn dO bo According to the general by the method described in Example 1, using

of 4-butyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazine-b6-carbaldehyde (intermediate compound 65) and 1,3-thiazolidine-2,4-dione as starting compounds, the title indicated compound

NRIS: 3.6b7min. IS-M8: M/7 E5I: 1.49 min, 331.23 (M-I). "H NMR: (0M50-av) 5 12.58 (rg. 8, 1H), 7.85 (c, 1H), tT4Z (c, 1), 7.24 (a, 9-6HC, 71), 7.15 (a, 9-9HC, 71H), 4.73 (c, 2H), 3.91 (5 9U-3HC, 2H), 1.57, (t, 2H), 1.36 (t, 2H), 0.91 (i, U-9Hz, ZN).

Example 103: 5-(4-benzyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione

S. and X Sa An she I and ! i am a

According to the general procedure described in Example 1, using 4-benzyl-3-oxo-3,4-dihydro-2H-benzo|1,oxazine-6-carbaldehyde (intermediate 66) and 1,3-thiazolidine-2, of 4-dione as starting compounds, the title compound was obtained. 20 NRIS: 3.b7min. IS-M8: M/7 EZVI: 1.46 bkhv, 365.17 (M-1). "H NMR: (0OM5O-yv) 5 12.58 (rg. 8, 1H), 7.68 (v, 1H), 7.38-7.22 (t, 8H), 5.24 (v, 2H ), 4.97 (in, 2H).

Example 104: 5-(2-chloro-benzofuran-5-ylmethylene)-thiazolidin-2,4-dione o : c 25 -00 o

According to the general procedure described in Example 1, using 2-chloro-5-11,3|dioxolan-2-yl-benzofuran (intermediate compound 67) and 1,3-thiazolidine-2,4-dione as starting compounds, obtained the title compound. at 30 NRIS: 3.84 min. IS-M8: M/7 EI: 1.62 min, 278.12 (M-1). "H NMR: (0M5O-4v5) 5 7.90-7.75 (M, 2H), 7.68 (4, FI

UO9HzC, 1H), 7.52 (a, U-9Hz, 1H), 7.09 (c, 1H). M

Example 105: 5-(3Z-amino-benzo|d|isoxazol-5-ylmethylene)-thiazolidin-2,4-dione about F 35 Fu in them

Nick: "

According to the general method described in Example 1, using C 50 of 3-amino-benzo|d|isoxazole-5-carbaldehyde (intermediate compound 68) and 1,3-thiazolidine-2,4-dione as the starting compound, the indicated compound in the title. with NRIS: 2.4 Bhv. IS-M8: M/7 E5I: 0.97 min, 260.17 (M-1). "H NMR: (0M5O-yv) 5 12.60 (rg. 5, 1H), 8.01 (v, 1H), 7.85 (8, 1H), 7.60 (9, 9-9HzC, 1H ), 6.67 (in, 1H).

Example 106: 5-(Z-phenylethynyl-benzofuran-5-ylmethylene)-thiazolidin-2,4-dione - i - se) - Ex s ho y i p boro syu nn o

According to the general method described in Example 1, using

of 3-phenylethynyl-bbenzofuran-5-carbaldehyde (intermediate compound 59) and 1,3-thiazolidine-2,4-dione as starting compounds (iF) gave the title compound. to NRIS: 4.82 min. IS-M8: M/7 E5I: 2.02 min, 344.18 (M-1). "H NMR: (0M5O-ydv) 5 12.58 (rg. 5, 1H), 8.49 (b, 1H), 7.92 (b, 1H), 7.72 (a, 9-9HzC, 1H ), 7.62 (t, 3H), 7.45 (t, 4H). 60 Example 107: 5-benzo|1,2,5Hyadiazol-5-ylmethylene-thiazolidine-2,4-dione b5 -BO0-

shi

Knish: and brknya, o.

According to the general procedure described in Example 1, using 2,1,3-benzothiadiazole-5-carbaldehyde and 1,3-thiazolidine-2,4-dione as starting compounds, the title compound was obtained.

NRIS: 3.0Zhv. And S-M8: M/7 EI: 1.14 min, 262.11 (M-1). "H NMR: (0M5O-yv) 5 12.58 (Bg. 8, 1H), 8.11 (t, 2H), 755. 7.950 (a, 9-9HzC, 1H), 7.47 (v, 1H ).

Example 108: 5-benzo|1,2,5|oxadiazol-5-ylmethylene-thiazolidine-2,4-dione and n-- : ol o c 29 According to the general method described in Example 1, using 2,1, of 3-benzooxadiazole-5-carbaldehyde and Ge) 1,3-thiazolidine-2,4-dione as starting compounds gave the title compound.

NRI C: 3.02 min. IS-M8: M/7 EV8I: 1.17 min, 246.17 (M-1). "H NMR: (0M8O-yv) 5 12.58 (bg. 8, 1H), 8.07 (t, 2H), 7.82 (a, 92-9Hz, 1), 7.40 (v, 1H Example 109: 5-(2-methyl-benzofuran-b-ylmethylene)-thiazolidine-2,4-dione o (22) and - - ene o He) and -

According to the general procedure described in Example 1, using 2-methyl-5-(1,3)dioxolan-2-yl-benzofuran (intermediate compound 72) and 1,3-thiazolidine-2,4-dione as starting compounds, after purification of NRI C with the inverted phase (eluent gradient H2O/СНЗСМ 0.195 ТРА), the compound specified in « 70 Title was obtained. with c NRI C: 3.b5min, 90.7595. And S-M8: M/7 EVI: 1.65 min, 258.21 (M-1). "H NMR: (0M5O-yv) 5 12.45 (vi, 1H), 7.88 (v, 1), 7.77 (a, 1H, 9U-1.5 Hz), 7.64 (a, 1nH, y-8.6Hz), 7.47 (aa, 1H, 9-8.6, 1.5Hz), 6.69 (v, 1H), 2.37 (v, ЗН). "» Example 110 : 5-(2-carboxymethyl-benzofuran-b-ylmethylene)-thiazolidine-2,4-dione' in Y in -I so o -i .

According to the general procedure described in Example 71, using the methyl ester of 5-11,3)|dioxolan-2-yl-benzofuran-2-carboxylic acid (intermediate compound 73) and 1,3-thiazolidine-2,4- of dione as c» of the starting compounds, after purification by reversed-phase HRI C (eluent gradient HOH/CHHCM 0.195 TEA), the title compound was obtained.

NRIS: 3.32min, 92.0695. IS-M8: M/7 EVI: 1.51 min, 302.19 (M-1). "H NMR: (0M5O-yv) 5 12.52 (vi, 1H), 7.97 (a, 1ZH, 9-ch, 5Hz), 7.82 (t, ЗH), 7.69 (aa, 1H , 9-86, 1.5 Hz), 3.90 (in, ЗН). o Example 111: 5-(3-bromo-2-fluoro-2,3-dihydro-benzofuran-b-ylmethylene)-thiazolidine-2 ,4-dione o

Pe) -i

IS

60 - no

According to the general method described in Example 1, using

of 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (intermediate compound 74) and 1,3-thiazolidine-2,4-dione as starting compounds, after purification by reversed-phase NRI C (eluent gradient HgO/CHNaCM 0.195 TEA ) obtained the title compound.

NRI C: 3.6 bbhv, 92.3795. And S-M8: M/7 EVI: 1.56 min, 343.09 (M-1). "H NMR: (0M5O-yv) 5 12.82 (vi, 1H), 8.00 (a, 1H, 9-1.8Hz), 7.88 (aa, MH, 9-85, 1.8Hz) . "ZE NMR: (0M5O-aiv) 5-114.66.

Example 112: 5-(2-Fluoro-benzofuran-b-ylmethylene)-thiazolidine-2,4-dione

I-Y: t tn ; ee d; i y 70 M SCHI i Gi N z di s: YN pl

IN

According to the general procedure described in Example 1, using 2-fluoro-5-11,3|dioxolan-2-yl-benzofuran (intermediate compound 75) and 1,3-thiazolidine-2,4-dione as starting compounds, after purification of NRI C with reverse phase 75 (eluent gradient NgO/CHZSM 0.195 TEA) gave the title compound.

NRI C: 3.67 min, 9947965. I C-M8: M/7 E8I: 1.51 min, 262.14 (M-1). "H NMR: (0M8O-yv) 5 12.04 (zi, 1H), 7.89 (a, 1H, 9-1.5Hz), 7.83 (a, 1H, U-1.5Hz), 7 .73 (a, 1H, 9U-8.6Hz), 7.55 (yes, 1H, 9-86, 1.5Hz), 6.47 (a, 1H, UOne-64Hz).

NMR: (0M5O-yv) 6-111.28,. -112.18.

Example 113: Preparation of pharmaceutical compositions

The following examples of dosage forms illustrate typical pharmaceutical compositions of the present invention, without limiting its scope.

Pharmaceutical form 1 - Tablets

The compound of formula (I) in the form of a dry powder is mixed with a dry gelatin binder in a mass ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricating agent. The resulting mixture is formed on a tablet press into tablets weighing 240-270 mg (80-9 mg of active azolidinone compound per tablet).

Pharmaceutical form 2 - capsules

The compound of formula (I) in the form of a dry powder is mixed with starch as a diluent in a ratio of about 1:11 by weight. The resulting mixture is packaged in capsules with a capacity of 25 mg (125 mg of active azolidinone compound per capsule). (2)

Medicinal form Z - Liquid to them

The compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed in dry form, passed through a sieve of 10 mesh according to the US standard (hole size 2.0 mm), and then mixed with a previously prepared 9:5 solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 5Omg) in water. them

Sodium benzoate (1Omg), flavoring and coloring are diluted with water and added while stirring. Then add a sufficient amount of water to obtain a final volume of 5 ml.

Pharmaceutical form 4 - Tablets

The compound of formula (I) in the form of a dry powder is mixed with a dry gelatin binder in a mass ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricating agent. The resulting /7u s mixture is formed on a tablet press into tablets weighing 450-900 mg (150-300 mg of active azolidinone compound per tablet). :z» Pharmaceutical Form 5 - Injection solution

The compound of formula (I) is dissolved in sterile saline for injection with a buffer compound at a concentration of approximately 5 mg/ml. -1 Example 114: Biological tests

The compounds of the present invention can be subjected to the following tests: a) High-throughput lipid kinase test RISK (binding test): -1 This test combines affinity test technology with scintillation detection (5RA, 20 Ategepat) and the ability of neomycin (a polycationic antibiotic) to bind to bind phospholipids with high affinity and specificity. The affinity test with scintillation detection (ZPA) uses the properties of isotopes with low radiation energy (for example, ЗН, "29, ЗЗР). Coating of granules for ZPA with neomycin allows detection of phosphorylated lipid substrates after incubation with recombinant RZK and radioactive adenosine triphosphate (ATP). in the same well by capturing radioactive phospholipids on 5RA granules due to their specific binding to neomycin.

In the wells of a 384-well MTP plate, which contained 5 μl of the test compound of the formula (I) (solubilized (F, in 695 OM5O; final concentration of the test compound 100 μM, 3 μM, 1 μM, 3 μM, μM, 0, μM, O, TμM, ko 0 ,0ZμM, 0.01μM, 0.001μM), the following components were added: 1) 5μl (58ng) of recombinant human C5T-RIZKUu (in a mixture of Nerez 40mMM, pH 7.4, OT 1mM and ethylene glycol 595); 2) 1 µl of fat micelles and 3) 1 µl of 60 kinase buffer (RZRU-ATP, 45 µM/bonKi, MoSi» ZOmMM, OTT TMM, p-glycerophosphate imM, MazMO, 100 µM, sodium cholate 0.395, in Nerez 40MM, pH 7.4) . After incubation at room temperature for 18 hours. with gentle mixing, the reaction was stopped by adding bOml of a mixture containing 100 μg of neomycin-coated RMT beads for 5RA in PB5 containing ATP (10 μM) and EOTA (5 μM). The sample was additionally incubated at room temperature for two minutes. with gentle agitation to ensure the binding of 65 phospholipids to neomycin on the fanules for 5RA. After centrifugation of neomycin-coated RMT thrushes for

ZRA within 5 minutes. at 15009, radioactive RiaIp8(3)P was quantified by scintillation counting in a counter for U/aMas MisgtoVeyatm tablets,

The values indicated in relation to RIZK mean ISvo (μM), that is, the amount necessary to achieve 5090 inhibition of the mentioned target. These values testify to the significant effectiveness of azolidinone derivatives of condensed vinylbenzenes with respect to CUT.

Tested compounds of formula (I) exhibit a characteristic inhibition (IC) relative to the CUT of less than 2 μM, and preferred compounds exhibit a characteristic inhibition (IC) of less than 2 μM or less.

Examples of inhibitory activity for compounds 41, 61, 66, 73, 103, 107, and 110 are given in Table 1. 5) Cell-based solid-phase enzyme-linked immunosorbent assay (ELISA) for monitoring RZK inhibition:

Measurement of AK/RKV phosphorylation in macrophages after stimulation of Sba: Kam 264:

Kam 264-7 macrophages (cultivated in OMEM-E12 medium, which contained 1095 fetal bovine serum and antibiotics) were seeded in the amount of 20,000 cells per well in a 9b-well MTP plate 24 hours before stimulation with cells. Before stimulation, the cells were deprived of serum for 2 hours and inhibitors were added for 20 minutes, after which they were stimulated with 5 ONM complement ba (Sba, which is a known chemokine that stimulates the used cells) for 5 minutes. After stimulation, the cells were fixed in 495 formaldehyde for 2 hours. and washed three times

RV5, which contained 195 Triton-x-100 (RVZ/Gryton). Endogenous peroxidase was blocked by 20-minute incubation in 0.695 H.O. and 0.196 sodium azide in РВ5Z/GTryton and washed 3 times with РВ5З/Triton. Then the cells were blocked by boOkhv. incubation with 1095 fetal cow serum in RVZ/Gryton. After that, phosphorylated o

AK/RCV was detected by overnight incubation at 42C with the first antibody (anti-phosphoserine 473 AKI

INS, Sei! Bidpaiipo), diluted 800 times in RVBZ/Gryton, which contained 596 bovine serum albumin - (BA). After washing three times in a mixture of РВ5З/ТГритон, the cells were incubated for 20 h. with peroxidase-conjugated goat anti-rabbit F antibody (1/400 dilution in RVZ/Gryton containing 595 B5A), washed with

3 times in the РВ5Z/Gryton mixture, and 2 times in РВ5B, and additionally incubated in 100 μl of substrate reagent solution (KO) in within 20 minutes The reaction was stopped by the addition of 5 µl of 1 M NzoO, and the absorbance was measured at a wavelength of 4500 nm.

The indicated values characterize the degree of inhibition of AKT phosphorylation relative to the baseline level. These values testify to the distinct influence of azolidinone derivatives of condensed vinylbenzenes on the activation of AKT phosphorylation in macrophages.

Compounds according to examples 1, 19, 66 and 107, applied at a concentration of 10 μM, completely (by approximately 100905) c) inhibit Sba-mediated phosphorylation of AKT. Compounds according to examples 17, 19 or 73, applied at a concentration of 1 µM, inhibit Sba-mediated phosphorylation of AKT at 9596. p

Claims (36)

Formula of the invention -I part 1. Application of the compound of formula (I) 1; (I sh v e () so | y em z MH : m t ime) as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and 60 racemic forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of this compound, where A is a 5-8-membered heterocyclic or carbocyclic group, and said carbocyclic group can be condensed with aryl, heteroaryl, cycloalkyl or heterocycloalkyl; X-5, 0 or MH; 65 each of U!" and U? independently of each other is 5, О or -МН; 7-5абоо; VE is H, CM, carboxyl, acyl, C.--Cv-alkyloxy group, halogen, hydroxyl, acyloxy-, C.-Ce-alkylcarboxy-, C.-C,-alkylacyloxy-, C.-C.sub.-alkylalkyloxy group, alkoxycarbonyl, C.-C.sub.-alkylalkyloxycarbonyl, aminocarbonyl, C.-Cv-alkylaminocarbonyl, acylamino-, C.i-Cv-alkylacylamino-, ureido-, C.-Cv-alkylureido-, amino-, C-Cv-alkylamino group, ammonium, sulfonyloxy-, C.-Cv-alkylsulfonyloxy group , sulfonyl, C.-Cv-alkylsulfonyl, sulfinyl, C4-Cv-alkylsulfinyl, sulfanil, C.--Cv-alkylsulfanyl, sulfonylamino-, C.-Cv-alkylsulfonylamino group or carbamate; 2 is selected from the group consisting of or consisting of H, halogen, acyl, amino, C and 4-Ce-alkyl, C.-C -alkenyl, C.-Cv-alkynyl, C.-Cv-alkylcarboxyl, C.-Cv-alkylacyl, C.-Cv-alkylalkyloxycarbonyl, 70. C.-Cv-alkylaminocarbonyl, C.-Cv-alkylacyloxy group, C.4-Cv-alkylacylamine, C.-Cv-alkylureido-, C.4-Cv-alkylamino-, C.4-Cv-alkylalkyloxy group, C-Cv-alkylsulfanyl, C-Cv-alkylsulfinyl, C4-Cv-alkylsulfonyl, C.-C.sub.-alkylsulfonylaminoaryl, aryl, C.sub.3-C.sub.a-cycloalkyl or heterocycloalkyl, C.-Cv-alkylaryl, Co-Cv-alkenylaryl, Co-Ce-alkynylaryl, carboxy-, cyano group, hydroxyl, C.-Cv-alkyloxy-, nitro-, acylamino-, ureido group, C-Cv-alkylcarbamate, sulfonylamino group, sulfanil and sulfonyl; n - 0, 1 or 2; with the exception of the following compounds: в" | o M o v? n Hn s rya o' 8--u sch " in Z mno o o so (TE) (A) b where B" is a lower alkyl or aralkyl and B? is H or halogen, rch- for the manufacture of a medicinal product for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or o 3z5 viral infections, kidney diseases, platelet aggregation, cancer, transplant rejection or lung injuries. 2. Use of a compound according to claim 1, wherein said disease is selected from the group consisting of multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pneumonia, thrombosis, or an infectious disease or inflammation of the brain, for example, meningitis or encephalitis. 3. Use of the compound according to claim 1, and said disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, central nervous system injury, stroke, and ischemic conditions. 4. Use of the compound according to claim 1, and the said disease is selected from the group consisting of atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, increased blood pressure, and vasoconstriction. 5. Use of the compound according to claim 1, and said disease is selected from the group consisting of chronic obstructive pulmonary disease, fibrotic anaphylactic shock, psoriasis, allergic diseases, asthma, -I stroke or ischemic conditions, ischemia-reperfusion, aggregation/activation of platelets, atrophy/hypertrophy of skeletal muscle, recruitment of leukocytes in cancer tissue, pancreatitis, multiple organ failure, including angiogenesis, tumor metastasis, in particular, melanomas, Kaposi's sarcomas, acute and chronic bacterial and viral infections, sepsis, transplant rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial lung injuries, and generalized inflammation of the pulmonary airways. this 6. Use according to any of the previous items, wherein each of U" and U? is oxygen. 7. Application according to any of the previous clauses, and n is 1 or 2 and each of КЕ" and В? is Н. 8. The use of compounds according to any of the previous clauses, and X is 5, each of M and y? is 0, B! and B? 22 correspond to the above definitions and n is 0. GF) 9. Application according to any of the previous items, and the mentioned thiazolidinone derivative of condensed vinylbenzene has the formula (Ia) ime) 60 b5 -B4- 2; (Ia in (Iv) E sh sh-5 8-5 - fAMN H2 o where U", B", 2, 7 and n correspond to the above definitions; each of M and Mu independently of the other is O, Z or -MEZ, where VZ is H or C.4-Cv-alkyl; CO is a C-C5-alkylene or C-C5-alkenylene group; each of o and t independently of the other is 0 or 1; d is an integer from 0 to 4. 10. Application according to claim 9, and the said thiazolidinone derivative of condensed vinylbenzene has the formula (IB) in ", B", 82, M, 7, M, t, n, o, 4 correspond to the above definitions and p is an integer from 1 to 4. 11. Application according to any one of claim 9 or claim 10, and the mentioned thiazolidinone derivative of condensed - vinylbenzene has the formula (Is) Ge»! ,; (Is) M "U. i- 1 o 5-4 sh -y MN « - s o . i"? where MU and also VE! and U! meet the above definitions. 12. Application according to any of claim 9 or claim 10, and the thiazolidinone derivative of condensed vinylbenzene has the formula (Id): -1 in? ) or 1, r is an integer from 1 to 4, and d is an integer from 0 to 4. 13. Use of compounds according to any of claim 9, claim 10 or claim 12, where 7-0, т-0, п-1, р-1 or 2, 4 - 60 1, each of VE! and KE? meets the above definitions. 14. The use of compounds according to any of claim 9, claim 10 or claim 12, det -1, p-0, p-1 or 2,4-0, each in and 22 corresponds to the above definitions. 15. Application according to any of claim 9, claim 10 and claims 12-14, det -0, p-1, p -1 or 2, d - 0, each of B and c2 65 corresponds to the definition of claim 1. 16. Use according to any one of claim 9, claim 10 and claims 12-14, wherein B is halogen or hydrogen. 17. Use according to any one of claims 1-16 for modulating, in particular, for inhibiting, the activity of RIZ-kinase. 18. Application according to claim 17, and the mentioned RiIZ-kinase is HIV-kinase. 19. Thiazolidinone derivative of condensed vinylbenzene of formula (1I-a) in? ; (P-c) d- in o where A is selected from the group consisting of dioxol, dioxin, dihydrofuran, (dihydro)furanyl, (dihydro)doxazinyl, pyridinyl, isoxazolyl, oxazolyl(idihydro)naphthalenyl, pyrimidinyl, triazolyl, imidazolyl, pyrazinyl, thiazolidinyl, thiadiazolyl, oxadiazolyl; 2 is selected from the group consisting of or consisting of H, halogen, acyl, amino, C and 4-Ce-alkyl, C.-C -alkenyl, C.-Cv-alkynyl, C.-Cv-alkylcarboxyl, C.-Cv-alkylacyl, C.-Cv-alkylalkyloxycarbonyl, C.-Cv-alkylaminocarbonyl, C.-Cv-alkylacyloxy-, C.-Cv-alkylacylamino-, C.-Cv-alkylureido group, C.-Cv-alkylcarbamate, C.-Ce-alkylamino-, C.-Cv-alkylalkyloxy group, C.4-Cv-alkylsulfanyl, C.-Cv-alkylsulfinyl, C.-Cv-alkylsulfonyl, C.-Cv-alkylsulfonylaminoaryl, aryl, C.sub.3-Cva-cycloalkyl or "c heterocycloalkyl, C.--Cv-alkylaryl, C.-Cv-alkenylaryl, Co-Cv -alkynylaryl, carboxyl, cyano group, hydroxyl, o C.4-Св-Alkoxy-, nitro-, acylamino-, ureido-, sulfonylamino group, sulfanil and sulfonyl. 20. Thiazolidinone derivative of condensed vinylbenzene of the formula (II) 2 (1) 4" and: ve mi so 5 - (22) shsh- pd M MH ych- F 1 Kk o i - as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of this compound, where: 7,7, B, 82 correspond to the above definitions, n is 0 or 1. " 21. Thiazolidinone derivative of condensed vinylbenzene according to claim 20, where U is t0. with 22. Thiazolidinone derivative of condensed vinylbenzene according to any one of claim 20 or claim 21, where in! selected from the group consisting of C 4 -C 4 -alkyl, C 1 -C 6 -alkylaryl, aryl, C 3 -C 10 -cycloalkyl or heterocycloalkyl, C.4-Cv-alkylaryl, Co-Cv-alkenylaryl and Co-Ce-alkynylaryl. 15 23. The thiazolidinone derivative of condensed vinylbenzene according to the formula (PP) PO) - o i H (Se) M - 5 a o (se) E syu» y | E E - o HF) as well as geometric isomers, optically active forms, for example, enantiomers, diastereomers and racemic ky forms, as well as pharmaceutically acceptable salts and pharmaceutically active derivatives of this compound, where EK! and E2 correspond to the above definition. in 24. Thiazolidinone derivative of condensed vinylbenzene according to any of the formulas (IM), (M) and (MI) b5 -58v- o N o N o N u u u a v? 5 / about her o to her o m no" | M | ee ny - 2 yad 1 r n M v M n M (M U) M) where K' is selected from the group consisting of hydrogen, halogen, cyano group, C 4-Cv-alkyl, Ci-Cv- alkoxy group, acyl, alkoxycarbonyl, while KE? corresponds to the above definition. 25. Thiazolidinone derivative of condensed vinylbenzene according to any of claims 19-24, selected from the group consisting of: 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidin-2,4-dione; 5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one; 5-(2,3-dihydro-1,4-benzodioxin-b-ylmethylene)-1,3-thiazolidine-2,4-dione; 5-(2,3-dihydro-1-benzofuran-5-ylmethylene)-1,3-thiazolidine-2,4-dione; 5-(7-methoxy-1,3-benzodioxol-5-yl)umethylene|-1,3-thiazolidine-2,4-dione; 5-MK9,10-dioxo-9,10-dihydroanthracen-2-yl)methylene|-1,3-thiazolidine-2,4-dione; se (5-K2,2-difluoro-1,3-benzodioxol-5-yl)umethylene|-1,3-thiazolidine-2,4-dione; o (527)-5-(1,3-dihydro-2-benzofuran-5-ylmethylene)-1,3-thiazolidin-2,4-dione; 5-(1-benzofuran-5-ylmethylene)-1,3-thiazolidin-2,4-dione; 5-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6b-yl)methylene-1,3-thiazolidine-2,4-dione; 5-(1,3-benzodioxol-5-ylmethylene)-2-imino-1,3-thiazolidin-4-one; so 5-quinolin-b6-ylmethylenethiazolidine-2,4-dione; b 5-quinolin-6-ylmethylene-2-thioxothiazolidin-4-one; 2-imino-5-quinolin-6-ylmethylenethiazolidin-4-one; in. 5-(3-methylbenzo|d4|isoxazol-5-ylmethylene)thiazolidine-2,4-dione; b 5-(4-phenylquinazolin-6-ylmethylene) thiazolidine-2,4-dione; 3 5-(4-dimethylaminoquinazolin-b-ylmethylene)thiazolidine-2,4-dione; in. 5-K4-aminoquinazolin-b-yl)methylene|)-1,3-thiazolidine-2,4-dione; 5-K4-piperidin-1-ylquinazolin-b-yl)umethylene]-1,3-thiazolidine-2,4-dione; 5-K4-morpholin-4-ylquinazolin-b6-yl)umethylene-1,3-thiazolidine-2,4-dione; "5-C4-(benzylamino)quinazolin-6-yl|methylene)-1,3-thiazolidine-2,4-dione; 5-C4-(diethylamino)quinazolin-6-yl|methylene)-1,3-thiazolidine-2,4-dione; With c 5-(4-pyridin-2-ylmethyl)amino)quinazolin-b-ylumethylene)-1,3-thiazolidin-2,4-dione; "» 5-(4-(pyridin-3-ylmethyl)amino)quinazolin-6-ylumethylene)-1,3-thiazolidine-2,4-dione; "ethyl-1-16-((2,4-dioxo- 1,3-thiazolidin-5-ylidene)methyl/quinazolin-4-ylpiperidine-3-carboxylate; ethyl 1-16-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/quinazolin- 4-Ilupiperidine-4-carboxylate; tert-butyl-1-76-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methylquinazolin-4-yl)-I -prolinate; and 5-(C4- (4-methylpiperazin-1-yl)quinazolin-b6-yl|methylene)-1,3-thiazolidin-2,4-dione; co 5-(C4-(4-pyrimidin-2-ylpiperazin-1-yl)quinazoline -β6-yl|methylene)-1,3-thiazolidine-2,4-dione; 5-(4-14-(4-fluorophenyl)piperidin-1-yl)quinazolin-β6-ylmethylene)-1,3-thiazolidine -2,4-dione; and 5-14-(4-benzylpiperidin-1-yl)quinazolin-b-yl)methylene)-1,3-thiazolidin-2,4-dione; so 50 5-(4-I(I4-(2-phenylethyl)piperidin-1-yl)quinazolin-b6-ylumethylene)-1,3-thiazolidine-2,4-dione; 5-(C4-(4-methylpiperidin-1-yl)quinazolin-b-yl|methylene)-1,3-thiazolidine-2,4-dione; 5-C4-(4-hydroxypiperidin-1-yl)quinazolin-b-yl|methylene)-1,3-thiazolidine-2,4-dione; 1-(6-(2,4-dioxothiazolidin-5-ylidenemethyl)quinazolin-4-yl|Ipiperidine-4-carboxylic acid; 1-(6-(2,4-dioxothiazolidin-5-ylidenemethyl)quinazolin-4-yl |Ipiperidine-3-carboxylic acid; 22 1-(6-(2,4-dioxothiazolidin-5-ylidenemethyl)quinazolin-4-yl|Ipyrrolidine-2-carboxylic acid; HF! 5-(4-methylaminoquinazolin-b-ylmethylene) )thiazolidine-2,4-dione, 5-(4-methoxyquinazolin-b-ylmethylene)thiazolidin-2,4-dione, o 2-imino-5-(4-methylaminoquinazolin-b-ylmethylene)thiazolidin-4-one; 2-imino-5-(4-piperidinquinazolin-b-ylmethylene)thiazolidin-4-one; 60 2-imino-5-(4-dimethylaminoquinazolin-b6-ylmethylene)thiazolidin-4-one; 5-(2-methyl- 2H-benzotriazol-5-ylmethylene)thiazolidine-2,4-dione; 5-(3-methyl-3H-benzotriazol-5-ylmethylene)thiazolidine-2,4-dione; 5-(3-ethyl-3H-benzimidazole- 5-ylmethylene)thiazolidine-2,4-dione; 5-X11-(4-phenylbutyl)-1H-benzimidazol-b-yl|methylene)-1,3-thiazolidine-2,4-dione; b5 5-(( 1-prop-2-yn-1-yl-YAN-benzimidazol-b-yl)methylene|-1,3-thiazolidine-2,4-dione; 5-(1-2-14-"trifluoromethyl)phenyl|ethyl )-1H-benzimidazole-b-yl)methylene|-1,3-thiaz olidine-2,4-dione; 5-(11-(2-(4-hydroxyphenyl)ethyl|-1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2,4-dione; methyl 4-16-((2,4-dioxo-1,3-thiazolidin-5-ylidene)umethyl|-1H-benzimidazol-1-yl)ucyclohexanecarboxylate; 5-(11-(2-(5-methoxy-1H-indol-3-yl)ethyl|-1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2,4-dione; 5-(41-(1-methyl-1H-pyrazol-4-yl)umethyl|-1H-benzimidazol-b-yl)imethylene)-1,3-thiazolidine-2,4-dione; 5-(11-(2-(3,4-dimethoxyphenyl)ethyl|-1H-benzimidazol-b-yl)methylene)-1,3-thiazolidine-2,4-dione; 5-(11-(2-(4-phenoxyphenyl)ethyl|-1H-benzimidazol-b-ylumethylene)-1,3-thiazolidine-2,4-dione; 5-(11-(4-trifluoromethyl)benzyl/ |-1H-benzimidazol-b-ylimethylene)-1,3-thiazolidine-2,4-dione; 4-(6-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1H- benzimidazol-1-yl)ucyclohexanecarboxylic acid; 70 5-(1-isobutyl-1H-benzimidazol-b-yl)methylene-1,3-thiazolidin-2,4-dione; 5-(11-(2-(1, 3-benzodioxol-4-yl)ethyl|-1H-benzimidazol-b-yl)imethylene)-1,3-thiazolidine-2,4-dione; 5-(11-(2-(2-phenoxyphenyl)ethyl|- 1H-benzimidazol-b-ylmethylene)-1,3-thiazolidine-2,4-dione; 2,4-dione; 5-X11-(3-furylmethyl)-1H-benzimidazol-b-yl|methylene)-1,3-thiazolidine-2,4-dione; 5-((1-propyl-1H-benzimidazol-b-yl)methylene-1,3-thiazolidine-2,4-dione; 5-quinoxalin-b6-ylmethylenethiazolidine-2,4-dione; 5-quinoxalin-6- ylmethylene-2-thioxothiazolidin-4-one; 2-imino-5-quinoxalin-6-ylmethylenethiazolidin-4-one; 5-benzothiazol-b6-ylmethylenethiazolidin-2,4-dione; 5-(3-methylbenzofuran-5-ylmethylene )thiazolidine-2,4-dione; 5-(2-bromo-3-methylbenzofuran-5-ylmethylene)thiazolidine-2,4-dione; 5-(3-bromobenzofuran-5-ylmethylene)thiazolidine-2,4-dione 3-I|5-(2,4-dioxothiazolidin-5-ylidenemethyl)benzofuran-3-ilyacrylic acid ethyl ester; 3-I5-(2,4-dioxothiazolidin-5-ylidenemethyl)benzofuran-3-yl| Acrylic acid, 5-3-(3-oxo-3-piperidin-1-ylpropenyl)benzofuran-5-ylmethylene)hiazolidine-2,4-dione; i) methyl-1-(3-15-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|/|-1-benzofuran-3-yl)iprop-2-enoyl)prolinate; methyl-1-(3-15-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-ylprop-2-enoyl)-O-prolinate; 5- (13-13-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl|-1-benzofuran-5-ylumethylene)-1,3-thiazolidine-2,4-dione; c zo 5-( 13-13-morpholin-4-yl-3-oxoprop-1-en-1-yl|-1-benzofuran-5-ylumethylene)-1,3-thiazolidine-2,4-dione; methyl-1-(3 -15-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-ylprop-2-enoyl)-I-prolinate; Me M-cyclohexyl-3-15 -I((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl|-1-benzofuran-3-yl)-M-methylacrylamide; M 3-15-(2,4-dioxo-1, 3-thiazolidin-5-ylidene)methyl-1-benzofuran-3-yl)-M-ethyl-M-(2-hydroxyethyl)acrylamide; M-cyclobutyl-3-15-(2,4-dioxo-1,3 -thiazolidin-5-ylidene)methyl-1-benzofuran-3-ylyl acrylamide; me) 5-(13-13-azetidin-1-yl-3-oxoprop-1-en-1-yl|-1-benzofuran-5 -yl)imethylene)-1,3-thiazolidine-2,4-dione; i- 5-(13-I3-(1,3-dihydro-2H-isoindol-2-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1 ,3-thiazolidine-2, 4-dione; 5-(13-13-azepan-1-yl-3-oxoprop-1-en-1-yl|-1-benzofuran-5-ylumethylene)-1,3-thiazolidine-2,4-dione; 3-15-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl-1-benzofuran-3-yl)-M-piperidin-1-yl acrylamide; 3-15-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl-1-benzofuran-3-yl)-N-(pyridin-3-ylmethyl)acrylamide; with M-cyclohexyl-3-(5-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-yl)acrylamide; . 5-(13-I3-4-methylpiperazin-1-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)umethylene)-1,3-thiazolidin-2,4 -dione; and?" M-cycloheptyl-3-(5-((2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl/|-1-benzofuran-3-yl)acrylamide; 5-(13-I3-(2 ,5-dihydro-1H-pyrrol-1-yl)-3-oxoprop-1-en-1-yl|-1-benzofuran-5-yl)methylene)-1,3-thiazolidine-2,4-dione; M-cyclopentyl-3-75-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methylyl-1-benzofuran-3-yl acrylamide; -I ethyl ester of 3-I|5-(2,4-dioxothiazolidin-5-ylidenemethyl)benzofuran-3-yl|Ipropionic acid; 3-15-(2,4-dioxothiazolidin-5-ylidenemethyl)benzofuran-3-yl|propionic acid; 5-III-(3-oxo-3-piperidin-1-ylpropyl)/benzofuran-5-ylmethylene|thiazolidine-2,4-dione compound; -I tert-butyl ester of 6-(2,4-dioxothiazolidin-5-ylidenemethyl)-2,3-dihydrobenzo|1,oxazine-4-carboxylic acid; se) 5-(3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)thiazolidine-2,4-dione; 4) 5-(4-benzoyl-3,4-dihydro-2H-benzo|1,Doxazin-6-ylmethylene)thiazolidine-2,4-dione; 5-(4-acetyl-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)thiazolidine-2,4-dione; tert-butyl ester of 6-(2,4-dioxothiazolidin-5-ylidenemethyl)benzo|1,oxazine-4-carboxylic acid 5B ACID; methyl ester (F) 16-(2,4-dioxothiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydrobenzo|1,4|-oxazin-4-yl|acetic acid; ka M-benzyl-2-I(6-(2,4-dioxothiazolidin-5-ylidenemethyl)-3-oxo-2,3-dihydrobenzo|1,oxazin-4-yl|acetamide; 5-(4-butyl- 3-oxo-3,4-dihydro-2H-benzo|1,oxazin-b-ylmethylene)thiazolidine-2,4-dione; in 5-(4-benzyl-3-oxo-3,4-dihydro-2H- benzo|1,oxazin-b-ylmethylene)-thiazolidine-2,4-dione; 5-(2-chlorobenzofuran-5-ylmethylene)thiazolidine-2,4-dione; 5-(3-aminobenzo|4|isoxazole-5 -ylmethylene)thiazolidine-2,4-dione, 5-(3-phenylethynylbenzofuran-5-ylmethylene)thiazolidine-2,4-dione, 5-benzo|1,2,5Hyadiazol-5-ylmethylenethiazolidine-2,4-dione; 65 5-benzo|1,2,5)oxadiazol-5-ylmethylenethiazolidine-2,4-dione; 5-(2-methylbenzofuran-b-ylmethylene)thiazolidine-2,4-dione; 5-(2-carboxymethylbenzofuran-b-ylmethylene)thiazolidine-2,4-dione; 5-(3-bromo-2-fluoro-2,3-dihydrobenzofuran-b-ylmethylene)thiazolidine-2,4-dione; 5-(2-fluoro-benzofuran-b-ylmethylene)thiazolidine-2,4-dione. 26. Thiazolidinone derivative of condensed vinylbenzene according to any one of claims 19-25 for use as a medicinal product. 27. A pharmaceutical composition containing at least one thiazolidinone derivative of condensed vinylbenzene according to any one of claims 19-25 and a pharmaceutically acceptable carrier, diluent or excipient. 28. Use of a thiazolidinone derivative of condensed vinylbenzene according to any of claims 19-25 for 7/0 Production of a medicinal product for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney disease, platelet aggregation, cancer, transplant rejection, or lung injury. 29. The use of a thiazolidinone derivative of condensed vinylbenzene according to claim 28, wherein said disease is selected from the group consisting of multiple sclerosis, psoriasis, rheumatoid arthritis, systemic /5 lupus erythematosus, inflammatory bowel disease, pneumonia, thrombosis and infectious disease or inflammation of the brain, for example, meningitis or encephalitis. 30. Use of a thiazolidinone derivative of fused vinylbenzene according to claim 28, wherein said disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, central nervous system injury, stroke, and ischemic conditions. 31. The use of a thiazolidinone derivative of condensed vinylbenzene according to claim 28, and said disease is selected from the group consisting of atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, increased blood pressure, and vasoconstriction. 32. The use of a thiazolidinone derivative of condensed vinylbenzene according to claim 28, and said disease is selected from the group consisting of chronic obstructive pulmonary disease, fibrosis with anaphylactic shock, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, aggregation/activation of platelets, atrophy/hypertrophy of skeletal muscle, recruitment of leukocytes in cancer i) tissue, angiogenesis, metastasis of tumors, in particular, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplant rejection, pancreatitis, multiple organ failure, glomerulosclerosis , glomerulonephritis, progressive renal fibrosis, endothelial and epithelial lung injuries, and generalized inflammation of the pulmonary airways. 33. Use according to any one of claims 28-32 for modulating, especially inhibiting, the activity of RIZ-kinase. Me) 34. Application according to claim 33, where said RiZ-kinase is HIV-kinase. M 35. The method of obtaining thiazolidinone derivatives of condensed vinylbenzenes of the formula (I) according to claim 20, which Ge"! includes the following stages: in | - "t, no in the 5th A t (2 p a schi in -NSNHNSHNSNHNYNTSYUTNCHN (2 ip 5-4 « and weak ii p, NN no s in" N o basis in! in . sh (o de B", B2, U, 7 and n correspond to the above definitions. 36. The method of obtaining thiazolidinone derivatives of condensed vinylbenzenes of the formula (II) according to claim 23, which includes the following stages: I corner - 5 -." -x- t o sabka n y 5 N o o s o n o p o p u o where B", V? and U! correspond to the above definitions. Name) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated 60 microcircuits" , 2007, M 11, 25/07/2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5