UA77264C2 - Pyperazinyl, pyperidinyl and morpholinyl derivatives as histone deacetylase inhibitors - Google Patents

Abstract

This invention comprises the novel compounds of formula (I) wherein t, R1, R2, L, Q, X, Y, Z, and (a) have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Description

Description of the invention

The present invention relates to compounds having histone deacetylase (NOAS) inhibitory enzyme activity. 2 In addition, it relates to methods of preparing these compounds, compositions containing these compounds, as well as their uses, both ip myo and ip mimo, for the inhibition of NSAIDS and as drugs, for example, as drugs for inhibiting proliferative conditions, such as cancer and psoriasis.

In all eukaryotic cells, genomic DNA in chromatin binds to histones to form nucleosomes. Each nucleosome consists of a protein octamer formed from two copies of each histone H2A, H2B, NZ and HA. 70 DNA is wrapped around this protein core, and the basic amino acids of these histones interact with the negatively charged phosphate groups of this DNA. The most common post-translational modification of these nuclear histones is reversible acetylation of β-amino groups of conserved, highly basic M-terminal lysine residues. The steady state of histone adetylation is established by achieving a dynamic equilibrium between competing histone acetyltransferase(s) and histone deacetylase(s), referred to herein 795 as "SPNA". Histone non-acetylation and deacetylation have long been associated with transcriptional control. Recent cloning of genes encoding various histone acetyltransferases and histone deacetylases has provided a possible explanation for the relationship between histone acetylation and transcriptional control. This reversible histone acetylation can cause chromatin remodeling, and as such it acts as a control mechanism for gene transcription. In general, histone hyperacetylation facilitates gene expression, whereas histone deacetylation correlates with transcriptional repression. Histone acetyltransferases have been shown to act as transcriptional coactivators, while histone deacetylases have been found to be associated with transcriptional repression pathways.

A dynamic balance between histone acetylation and deacetylation is essential for normal cell growth. Inhibition of histone deacetylase leads to the delay of the cell cycle, cell differentiation, c 29 apoptosis and changes in the transformed phenotype. Therefore, NOAS inhibitors can have a high therapeutic potential in the treatment of diseases or conditions associated with cell proliferation (Magke ei ai., Maishge Kemiemv:

Sapseg 1: 194-202, 20011.

Research on histone deacetylase inhibitors (HAIs) indicates that these enzymes do play an important role in cell proliferation and differentiation. Inhibitor trichostatin A (Thispoviaip A) (T5A) causes a delay in the cell cycle in both C1 and 52 phases, changes the transformed phenotype of various cell lines, induces (Ce) differentiation of leukemic cells of Orend (Egiepa) and others. As reported, TZA (and suberoylanilide hydroxamic acid ZANA) inhibit cell growth, induce terminal differentiation and prevent tumor formation in mice (Rippip et al., Mayige, 401: 188-193, 1999). -

Trichostatin A has also been reported to be useful in the treatment of fibrosis, such as liver fibrosis, and

From cirrhosis of the liver (Seegiz ei ai. Epgoreap Raiepi Arriisaiop ER 0827742, ribiiznea 11 Magepy. 19981. t

Patent application UMUO 01/383222 dated May 31, 2001 discloses, among other things, inhibitors of histone deacetylase of the general formula Su-I 1-Ag-Zh71-C(0)-MH-7, compositions and methods of treatment of diseases and conditions related with cell proliferation. « 20 Patent application MO 01/70675 dated September 27, 2001 discloses histone deacetylase inhibitors of the formulas with Су-х-м-М/ and Су-5(0)5-МН-МЗ-М/ and also introduces compositions and methods of treatment diseases and conditions associated with cell proliferation. The problem to be solved is to introduce histone deacetylase inhibitors with high enzymatic activity that exhibit improved properties such as cellular activity and increased bioavailability, preferably oral bioavailability, and have little or no have -1 side effects.

The new compounds of this invention solve the above problems. These compounds differ from the compounds - preliminary modification in their structure.

The compounds of this invention exhibit excellent histone deacetylase inhibitory enzyme activity. 20 These compounds have improved properties regarding cellular activity and specific properties regarding

Me, inhibition of cell cycle development in both 01 and 052 control points (p21 induction capacity).

Their" Compounds of the present invention exhibit good metabolic stability and high bioavailability, and more specifically, they exhibit oral bioavailability.

This invention relates to compounds of the formula (I)

PACK

60 of their M-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms, where

It is equal to 0, 1, 2, 3 or 4, and when it is equal to 0, then a direct connection is meant; each C) represents nitrogen or ve; ak b5 and each X represents nitrogen or ve;

Because Fr

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B is hydrogen, C is alkyl, Si. alkylcarbonyl, arylC. alkyl, C. alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl; t VZ is hydrogen or S. valkyl;

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three voices valkyloxy; C. alkyl substituted by aryl and C3-4ocycloalkyl; S. valkyloxy;

C. valkyloxyC and valkyloxy; C. alkylcarbonyl; S. valkyloxycarbonyl; S..alkylsulfonyl; cyanosis valkyla; hydroxyS. valkyla; hydroxyS. valkyloxy; hydroxyS. valkylamino; aminos valkyloxy; di(C-alkyl)aminocarbonyl; di(hydroxyC. alkyl)amino; (aryl(C. valkyl)amino; di(C. valkyl)aminoC . valkyloxy; di(C. valkyl)aminoC . valkylamino; di(C. valkyl)aminos 4 valkylaminos valkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxysC. valkyl; arylC » valkenediyl; alkyl; di(C. alkyl)amino 4 alkyl(C. alkyl) amino; di(C. alkyl) amino 4 alkyl(C . alkyl) amino 4 alkyl; /o aminosulfonylamino(C /.alkyl)amino; aminosulfonylamino(C .alkyl)amino 4 alkyl; di(C. alkyl)aminosulfonylamino(C 4 alkyl)amino; di(C. alkyl)aminosulfonylamino(cC 4 alkyl)amino 4 alkyl; cyano; thiophenyl; thiophenyl substituted by di(C. alkyl) amino 4-alkyl(C 4-alkyl)amino 4-alkyl, di(C-alkyl)amino 4-alkyl, C-alkylpiperazinyl 4-alkyl, hydroxyC-alkylpiperazinyl 4-alkyl, hydroxyC 4-alkyloxyC 4-alkylpizinyl 4-peralkyl, di(C.alkyl)aminosulfonylpiperazinyl 4 by valkyl, 75 Si-valkyl oxypiperidinyl, S. valkyloxypiperidinyls 4 valkyl, morpholinyl. valkyl, hydroxyC .valkyl (C 4. valkyl) and aminoC. alkyl, or di(hydroxyC. alkyl)aminoC and alkyl; furanil; furanyl substituted by hydroxyC. by valkyl; benzofuranil; imidazolyl; oxazolyl; oxazolyl substituted with aryl and

Si valkilom; S. valkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinyl C. valkyloxy; morpholinil;

Si alkylmorpholinyl; morpholinyl valkyloxy; morpholinyl valkyl; morpholinyls. valkylamino; Morpholinyls in valkylaminoS. valkyla; piperazinil; S. valkylpiperazinil; C. valkylpiperazinilC in valkyloxy; piperazinilC. valkyla; naphthalenylsulfonylpiperazinyl; naphthalenylsulfonylpiperidinyl, naphthalenylsulfonyl; C. valkylpiperazinils 4 valkyl; S. valkylpiperazinilC in valkylamino;

C) valkylpiperazinyl 4 valkylaminosC. valkyla; Si alkylpiperazinylsulfonyl; aminosulfonylpiperazinyl - valkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC. valkyla; DY(Ci-alkyl)aminosulfonylpiperazinyl compound; di(C-.-alkyl)aminosulfonylpiperazinyl 4.alkyl; hydroxyC. valkylpiperazinil; hydroxyS. alkylpiperazinyl 4 alkyl; S. valkyloxypiperidinyl; and)

C. valkyloxypiperidinylC valkyl; piperidinylaminos. valkylamino; piperidinylaminos. - valkylaminos. valkyla; (Si alkylpiperidinyl)(hydroxy 4 alkyl)amino and valkylamino; (Si alkylpiperidinyl)(hydroxy 4 alkyl)amino 4 alkylamino 4 alkyl; "g zo HydroxysS valkyloxysS /.valkylpiperazinil; hydroxyS. valkyloxysC 1 valkylpiperazinils /.valkylu; (hydroxyC 4 alkyl) (C. alkyl) amino; (hydroxyC. valkyl(C. valkyl)aminos 4 valkyl; ise) hydroxyC valkylaminos 4. valkyl; di(hydroxyC. alkyl)amino 4 alkyl; pyrrolidinyl C-alkyl; su pyrrolidinyl 4 valkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C valkyl or trihalos. valkyla; pyridinyl substituted with C. valkyloxy, aryloxy or aryl; pyrimidinyl; y- tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC. valkyla; quinolinyl; Indole; phenyl; y- phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C. valkyl, C. valkyloxy, hydroxyC. dalalkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC dalalkyloxy, C dalalkylsulfonyl, C. lalalkyloxyC and dalalkyloxy, C. dalalkyloxycarbonyl, aminoC. dalalkyloxy, di(C.alkyl)amino 4. dalalkyloxy, di(C.alkyl)amino, di(C.alkyl)aminocarbonyl, "

YOU(S.i-dalkyl)aminoS. dalkylu, di(S.-dalkyl)aminoS 4.allkylaminoS. alkyl, di(C.-alkyl)amino(C-alkyl)amino, Che) with di(C.4 alkyl)amino(C.4.alkyl)amino 4.alkyl, di(C.alkyl)amino 4. -alkyl( C 4 lalkyl)amino, di(C 4 lalkyl)aminos 4. alkyl(C. lalkyl)aminos 4 dalkyl, aminosulfonylamino(C. dalkyl)amino, ; » aminosulfonylamino(C 4.alkyl)iamino 4 dalalkyl, di(C. dalkyl)aminosulfonylamino(C 4.4alkyl)amino, di(C. 1alkyl)iaminosulfonylamino(cC 4 dalkyl)amino 4 alkyl, cyano, piperidinylC. lalkyloxy, Pyrrolidinyls /u.dalkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinyl. lalkyl, -I di(C.4 alkyl)aminosulfonylpiperazinyl, di(C.lalkyl)aminosulfonylpiperazinyl 4.alkyl, hydroxyC dalalkylpiperazinyl, hydroxyC. dalkylpiperazinils and dalkylu, S. lalkyloxypiperidinyl, sh- C. dalkyloxypiperidinyls 4. dalkylu, hydroxyC. lalalkyloxysC 4 .alkylpiperazinyl, co hydroxyC dalalkyloxysC 4 lalkylpiperazinyl C.alkyl, (hydroxyC. dalalkyl(C dalalkyl)amino, (hydroxysC 4-dalalkyl(C .alkyl)aminos 4.alkyl, di(hydroxyC..alkyl)amino 4 lalkyl, furanyl, furanyl, me) substituted -bnNA:cSn-SnH-AsnH-, pyrrolidinyl, lalalkyl, pyrrolidinyls. lalalkyloxy, morpholinyl, i» morpholinyls 4.dalalkyloxy, morpholinyl. lalalkyl, morpholinyl. dalalkylamino, morpholinyls 4.allkylaminos 4 lalalkyl, piperazinil, S. dalkylpiperazinil,

C) dalalkylpiperazinyl 4 lalyloxy, piperazinylC. dalkylom, S. dalkylpiperazinilo 4 dalkylom, two Si-dalkylpiperazinilS u. dalkylamino, C. .dalkylpiperazinylC /.dalkylaminosC in valkylom, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC. far away

F) piperidinylamino 4 dalkilamino, piperidinylaminoS. lalkylaminosС 4 .lalkylom, ka (Ci dalkylpiperidinyl)(hydroxy 4 lalkyl)aminos and dalkylamino, (C dalkylpiperidinyl)(hydroxys 4 lalkyl)aminos and dalkylaminos u. lalkyl, pyridinyl. dalalkyloxy, because "hydroxyC.alkylamino, hydroxyC.dalalkylamino 4-alkyl, di(C..alkyl)amino 4-alkylamino, aminothiadiazolyl, aminosulfonylpiperazinyl-C.alkyloxy, or thiophenyl.alkylamino; each BE and BZ can be placed on nitrogen to replace hydrogen; the above aryl is phenyl, or phenyl substituted with one or more substituents, each independently selected from halo, C 4 alkyl, C 1 alkyloxy, trifluoromethyl, cyano, or 65 hydroxycarbonyl.

The expression "histone deacetylase inhibitor" or "histone deacetylase inhibitor" is used to identify a compound that is able to interact with histone deacetylase and inhibit its activity, more specifically, its enzymatic activity. Inhibition of the enzymatic activity of histone deacetylase means reducing the ability of histone deacetylase to remove an acetyl group from histone It is better when such inhibition is specific, that is, the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove an acetyl group from histone at a concentration that is lower than the concentration of the given inhibitor that is required to produce some other, unrelated biological effect.

As used in the foregoing definitions and in the following, the term halo is generic to fluoro, chloro, bromo, and iodo; C1-alkyl defines saturated hydrocarbon radicals with straight or branched /0 chains having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C. alkyl includes C.. dalalkyl and its higher homologues having from 5 to 6 carbon atoms, such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like;

S. valkandil defines bivalent saturated hydrocarbon radicals with straight and branched chains having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1, 5-pentanediyl, 1,6-hexanedyl, and their branched isomers, such as 2-methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3-dimethylbutanediyl and the like; trihaloS. alkyl defines C. alkyl containing three identical or different halo substituents, for example, trifluoromethyl; C»ovalkendyl defines bivalent hydrocarbon radicals with straight and branched chains containing one double bond and having from 2 to b carbon atoms, such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl,

3-pentenediyl, 3-methyl-2-butenyl and the like; aminoaryl defines aryl substituted with amino; and as used in the foregoing definitions and hereinafter, the term halo is generic to fluoro, chloro, bromo, and iodo; C..alkyl defines saturated hydrocarbon radicals with straight or branched chains having from 71 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C 1 alkyl includes C 1 alkyl and its higher homologues having from 5 to 6 carbon atoms, such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like;

C. valkandil defines bivalent saturated hydrocarbon radicals with straight and branched chains that i) have from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanedyl, and their branched isomers, such as 2-methylpentanediyl, 3-methylpentanediyl, 2,2-dimethylbutanediyl, 2,3-dimethylbutanediyl and the like; trihaloS. alkyl defines C. alkyl containing three identical or different halo substituents, for example, trifluoromethyl; C»valkendyl defines bivalent hydrocarbon radicals with straight and branched chains containing one double bond and having from x, 2 to b carbon atoms, such as, for example, ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, with

3-pentenediyl, 3-methyl-2-butenediyl and the like; aminoaryl defines aryl substituted with amino; and C3-4docycloalkyl includes cyclic hydrocarbon groups having from 3 to 10 carbon atoms, such as cyclopropyl, t-cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

The term "another 7p-chelating group" refers to a group capable of interacting with a 7p-ion that may be present in the enzyme binding site.

Pharmaceutically acceptable addition salts include pharmaceutically acceptable acidic addition salts and pharmaceutically acceptable basic addition salts. Pharmaceutically acceptable acid addition salts, as mentioned above, include, as is believed, therapeutically active non-toxic acid forms of addition salts capable of forming compounds of formula (I). Compounds of formula (I), which have the main properties, can be transformed into their pharmaceutically acceptable acid addition salts by processing and? of the specified basic form with the corresponding acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example, hydrochloric or hydrobromic acid; sulfuric acid; nitrogen; phosphoric and similar acids; or organic acids such as, for example, acetic, trifluoroacetic, -I propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e., butaneic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,

Sh-p-toluenesulfonic, cyclamine, salicylic, p-aminosalicylic, pamic and similar acids. Compounds of formula (I) having acidic properties can be converted into their pharmaceutically acceptable basic addition salts by treatment of said acid form with suitable organic or inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, benzathine, M-methyl-O- glucamine, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like.

The expression "acidic or basic salt of addition" also includes hydrate and solvate forms of addition, which are capable of forming compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholates and the like.

F) The expression "stereochemically isomeric forms of compounds of formula (I)", as used in this text, defines all possible compounds consisting of the same atoms, which are connected by the same sequence of bonds, but have different three-dimensional structures, which are not equivalent, which may have compounds of formula (I). Unless otherwise specified or indicated, the chemical designation of the compounds corresponds to the mixture of all possible stereochemically isomeric forms that the specified compounds may have. The specified mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of the specified compound. It is intended that all stereochemically isomeric forms of the compounds of formula (I), both in pure form and in admixture with each other, are within the scope of this invention. 65 M-oxide forms of compounds of formula (I) are intended to include those compounds of formula (I) where one or more nitrogen atoms are oxidized to a so-called M-oxide, in particular, those M-oxides where one or more piperidine, piperazine or pyridazinyl nitrogens are M-oxidized.

Some of the compounds of formula (I) may also exist in their tautomeric form. Although such forms are not explicitly stated in the above formulas, they are also intended to be within the scope of this invention.

As used herein, the term "compound of formula (I)" is intended to include all pharmaceutically acceptable addition salts and all stereoisomeric forms.

As used herein, the terms "histone deacetylase" and "NOAA" are intended to refer to any member of the enzyme family that removes acetyl groups from the E-amino groups of 7/0 lysine residues in the M-terminus of histone. Unless otherwise indicated in the context, the term "histone" is intended to refer to any histone protein, including NO, H2A, H2B, NZ, HA, and H5, from any species.

Human SPOA proteins or gene products include, but are not limited to, SPOA-1, SPOA-2, SPOA-3,

SPEA-4, SPEA-5, SPEA-6, SPEA-7, SPEA-8, SPEA-9 and SPEA-10. Histone deacetylase can also be obtained from protozoan or fungal sources.

The first group of compounds of interest consists of those compounds of formula (I), for which one or more of the following restrictions apply: a) Ii is 0 or 1;

B) each O is a ve; "i c) each X is nitrogen; 4) 2" is -C(OMN(OH); c) 2 is hydrogen, hydroxy, C..alkyl or aryls. valkyl; счи)-I- is a bivalent radical selected from -МНС(О)- or -МНБЗО»-; 9). db represents a radical chosen from (a-1) or (a-20); (at)

P) each of is equal, independently, to 0 or 1; i) each B? is selected, independently, from hydrogen or phenyl. WITH

The second group of interesting compounds consists of those compounds of the formula (I), in relation to which one or (Te) more of the following restrictions apply: a) equal to 1; with

B) each O is a ve; cha i - c) each X represents nitrogen; a) each U represents nitrogen; "e) each 7 is -O- or -CH";

I am V! represents -С(ОМН(ОН); т с 9) ВЕ" represents hydrogen; "» P) --- represents a bivalent radical selected from -МНО(О)- or -МНЗО»-; "y) -7 is a radical selected from (a-1) or (a-20); , y and - y) each 5 is independently equal to 0 or 1;

K) each EE? is selected, independently, from hydrogen or phenyl. 7 The third group of interesting compounds consists of those compounds of formula (I), where K" represents -С(О)МН(ОН). The fourth group of interesting compounds consists of those compounds of formula (I), where K" represents -С (O)MH(OH), bu Y K2 is hydrogen.

The fifth group of interesting compounds consists of those compounds of the formula (I), in relation to which one or more of the following restrictions apply: a) equal to 0;

B) B is -С(О)МА ZВ", -С(0)-Si valkandiile 7, -MVZS(OMSHCHONV "7, -MAZS(О) С. valkandiile B 7, 99 -МА8С(0О)С- M(OH)B or another 7p-chelating group, where KZ and B" are each independently selected from hydrogen,

HF) hydroxy, hydroxyS. valkyla or aminos. valkyla; with c) VK? represents hydrogen, hydroxy, amino, hydroxyC 4. alkyl, C. alkyl, C. alkyloxy, aryls. valkyl, aminocarbonyl, aminos". alkyl, C-alkylaminosC 4.alkyl or di(C.alkyl)aminos 4.alkyl; in a) -I- is a bivalent radical selected from -МНО(О)- or -МНЗО»-; f) is a radical selected from (а-1), (а-3), (а-4), (а-5), (а-6), (а-7), (а-8) , (а-9), (а-10), (а-11), (а-12), (а-13), (а-143, (а-153), (а-16), (а -17), (а-18), (а-19), (а-20), (а-21), (а-22), (а-23), (а-24), (а-25 ), (а-26), (а-28), (а-29), (а-30), (а-31), (а-32), (а-33), (а-34), (а-35), 65 C (а-36), (а-37), (а-38), (а-39), (а-40), (а-41), (а-42) , (а-44), (а-45), (а-46), (а-47), (а-48) or (а-51); 7) each of is equal, independently, to 0, 1, 2 , Z or 4;

9) R? is hydrogen; halo; hydroxy; amino; nitro; trihalosS / valkil; trihalosS. valkyloxy; S. valkil;

S. valkyloxy; S. valkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; hydroxyS. valkyl; aryloxy; di(C.-alkyl)amino; cyano; thiophenyl; furanil; furanyl substituted by hydroxyC.. valkyl; benzofuranil; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C. alkyl; C. valkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinil; Si alkylmorpholinyl; piperazinil; Si valkylpiperazinil; hydroxyS. valkylpiperazinil;

C. valkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from

Si valkilu or trihalosS. valkyla; pyridinyl; pyridinyl substituted with C. valkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents selected independently from halo, C1-alkyl, C1-4alkyloxy or trifluoromethyl;

M) 2? is hydrogen; halo; hydroxy; amino; nitro; trihalosS 4 valkil; trihaloCi valkyloxy; C- valkyl;

S. valkyloxy; S. valkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; hydroxyS. valkyl; aryloxy; di(Ci-alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C 1 -alkyl, C 1 -alkyloxy or trifluoromethyl.

The sixth group of compounds of interest consists of those compounds of formula (I) for which one or more of the following restrictions apply: a) each VZ and c? is independently selected from hydrogen, hydroxy, hydroxyC4alkyl, aminoC4alkyl, or aminoaryl;

B) pe is a radical selected from (а-1), (а-2), (а-3), (а-4), (а-5), (а-6), (а-7 ), about (a-8), "(a-9), (a-10), (a-11), "(a-12), (a-13), (a-14), (a- 15), (а-16), (а-17), (а-18), (а-19), (а-20), (а-21), (а-22), (а-23) , (а-24), (а-25), (а-26), (а-27), (а-28), (а-29), (а-30), (а-31), ( a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a- 40), (а-41), (а-42), (а-43) or (а-44); c c) each VE or v9 is selected, independently, from hydrogen; halo; hydroxy; amino; nitro; trihalos 4 valkyla; three voices valkyloxy; S. valkilu; S. valkyloxy; Su valkyloxyS. valkyloxy; C. alkylcarbonyl; and)

Si alkylsulfonyl; cyanoS. valkyla; hydroxyS. valkyla; hydroxyS. valkyloxy; hydroxyS. valkylamino; aminos valkyloxy; di(C 1 -alkyl)aminocarbonyl; di(hydroxyC. alkyl)amino; (aryl(C.alkyl)amino; di(C.alkyl)amino 4alkyloxy; di(C.alkyl)amino 4alkylamino; arylsulfonyl; aryloxy; arylC» valkenediyl group; di(C.alkyl)amino; di(Si alkyl)amino 4.alkyl; di(C.alkyl)amino 4alkyl(C.alkyl)amino in alkyl; cyano; thiophenyl; thiophenyl substituted by di(C.alkyl)amino 4alkyl(C.alkyl)amino 4alkyl , di(C. valkyl)aminos 4 by valkyl, Ge

C) alkylpiperazinyl 4 alkyl or di(hydroxyC. alkyl)amino 4 alkyl; furanil; imidazolyl;

Su valkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinyl C. valkyloxy; morpholinil; C. valkylmorpholinyl; -

MmorpholinilS. valkyloxy; morpholinyls. valkyla; Si valkylpiperazinil; S. valkylpiperazinilS. valkyloxy; Cha

C. valkylpiperazinils 4 valkyl; Si alkylpiperazinylsulfonyl; aminosulfonylpiperazinyl. valkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC. valkyla; di(Cu alkyl)aminosulfonylpiperazinyl; di(C. alkyl)aminosulfonylpiperazinyl 4 alkyl; hydroxyS. valkylpiperazinil; " hydroxyC in 4 alkyl piperazinyl; Alkyloxypiperidinyl seeds; C. valkyloxypiperidinyls 4 valkyl; hydroxyS. valkyloxyS .valkylpiperazinyl; hydroxyS. valkyloxyS ..valkylpiperazinyl 4-alkyl; - c (hydroxyC 4.alkyl)(C.alkyl)amino; (hydroxyC. alkylC. alkyl) amino 4 alkyl; pyrrolidinylS. valkyloxy; c pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C4alkyl or "» trihaloC..alkyl; pyridinyl; pyridinyl substituted with C1alkyloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents selected , independently, from halo, amino, C. alkyl, C. alkyloxy, hydroxyC. dalalkyl, trifluoromethyl, trifluoromethyloxy, - hydroxyC dalalkyloxy, C. lalalkyloxyC in dalalkyloxy, aminoC. dalalkyloxy, di(C. lalalkyl)amino 4. dalalkyloxy, - di(C 4 lalkyl)amino, di(Si lalkyl)amino 4.dalkyl, di(C.lalkyl)amino 4.dalkyl(C.lalkyl)amino 4 dalkyl, piperidinyl C.lalkyloxy, pyrrolidinyl.lalkyloxy, aminosulfonylpiperazinyl, co aminosulfonylpiperazinyl 4 .lalkyl, di(C4 dalalkyl)aminosulfonylpiperazinyl, di(C.sub.4 alkyl)daminosulfonylpiperazinyl 4 dalalkyl, hydroxyC. dalalkylpiperazinyl, b hydroxyC dalalkylpiperazinyls 4.alkyl, C. lalalkyloxypiperidinyl, C. dalalkyloxypiperidinyls and dalalkyl,

Chl» hydroxyC dalalkyloxyC 4 lalkylpiperazinyl, hydroxyC. lalkyloxyS.alkylpiperazinyl and dalalkyl, (hydroxyS. 4. dalkyl)(C. dalkyl) amino, (hydroxyS..lalkyl)(C 4 dalkyl) aminos 4 dalkyl, pyrrolidinylC. dalalkyloxy, morpholinylC and alkyloxy, morpholinylC. dalkylu, C. lalkylpiperazinyl, C. dalkylpiperazinyl 4 lalkyloxy,

Silalkylpiperazinyl 4 dalalkyl, hydroxyC. dalalkylamino, di(hydroxyC.4alkyl)amino, di(C.lalkyl)amino and dalalkylamino, aminothiadiazolyl, aminosulfonylpiperazinyl. lalkyloxy, or about thiophsnilo and. alkylamino ime) A group of preferred compounds consists of those compounds of formula (I) wherein each KV and B 7 is independently selected from hydrogen, hydroxy, hydroxyC. valkilu, aminoS. alkyl or aminoaryl; is a radical selected from (a-1), (a-2), (a-3), (a. 4), (a-5), (a-6), (a-7 ), (а-8), (а-9), (а-10), (а-11), (а-12), (а-13), (а-14), (а-15), (а-16), (а-17), (а-18), (а-19), (а-20), (а-21), (а-22), (а-23), (а -24), (а-25), (а-26), (а-27), (а-28), (а-29), (а-30), (а-31), (а-32 ), (а-33), (а-34), (а-35), (а-36), (а-37), (а-38), (а-39), (а-40), (а-41), (а-42), (а-43) or (а-44); because every BC? or 25 is independently selected from hydrogen; halo; hydroxy; amino; nitro; trihalosC /4 valkyla;

three voices valkyloxy; S. valkilu; S. valkyloxy; Su valkyloxyS. valkyloxy; C. alkylcarbonyl;

Si alkylsulfonyl; cyanoS. valkyla; hydroxyS. valkyla; hydroxyS. valkyloxy; hydroxyS. valkylamino; aminos valkyloxy; di(Ci alkyl)aminocarbonyl; di(hydroxyC. alkyl)amino; aryl(C.alkyl)amino; di(S. valkyl)yaminoS. valkyloxy; di(C. valkyl)amino and valkylamino; arylsulfonyl; arylsulfonylamino; aryloxy; arileo Valkendiil; di(C.alkyl)amino; di(Si alkyl)aminos 4. alkyl; di(C. alkyl)amino 4 alkyl(C. alkyl)amino in alkyl; cyano; thiophenyl; thiophenyl substituted by di(C.alkyl)amino 4alkyl(C.alkyl)amino 4alkyl, di(C.alkyl)amino 4alkyl,

C) alkylpiperazinyl 4 alkyl or di(hydroxyC. alkyl)amino 4 alkyl; furanil; imidazolyl; 7/0. C-alkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinyl C. valkyloxy; morpholinil; C. valkylmorpholinyl; morpholinilS. valkyloxy; morpholinilS. valkyla; S. valkylpiperazinil; Su valkylpiperazinylC 4 valkyloxy;

C) alkylpiperazinyl 4 alkyl; S. valkylpiperazinylsulfonyl; aminosulfonylpiperazinyls. valkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC. valkyla; di(Cu alkyl)aminosulfonylpiperazinyl; di(C.alkyl)aminosulfonylpiperazinyl 4alkyl; hydroxyS. valkylpiperazinil; 7/5 Pidroxys .alkylpiperazinils 4 alkyl; S. valkyloxypiperidinyl; C. valkyloxypiperidinyls 4 valkyl; hydroxyC valkyloxyC 4 valkylpiperazinyl; hydroxyS. valkyloxyS 4 valkylpiperazinils 4 valkyl; (hydroxyC 4.alkylCC.alkyl)amino; (hydroxyC. alkyl)x C. alkyl) aminoC. valkyla; pyrrolidinyl valkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C4alkyl or trihaloC..alkyl; pyridinyl; pyridinyl substituted with C. valkyloxy or aryl; pyrimidinyl; quinolinyl; Indole; phenyl; phenine substituted with one, two or three substituents independently selected from halo, amino, C. valkyl, C. valkyloxy, hydroxyC. dalalkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC dalalkyloxy, C. lalkyloxyC in dalalkyloxy, aminosC. dalalkyloxy, di(C.lalkyl)amino 4.dalalkyloxy, di(C 4alkyl)amino, di(C.lalkyl)amino 4.dalkyl, di(C.lalkyl)amino 4. dalkyl(C.lalkyl)amino 4.dalkyl, piperidinyl C. lalalkyloxy, pyrrolidinyl. lalalkyloxy, aminosulfonylpiperazinyl, sch ov aminosulfonylpiperazinyl /.dalalkyl, di(C..-4alkyl)aminosulfonylpiperazinyl, di(C.lalkyl)aminosulfonylpiperazinyl 4.alkyl, hydroxyC. lalalkylpiperazinyl, and) hydroxyC 4 dalalkylpiperazinylC 4.4alkyl, C. dalalkyloxypiperidinyl, Su dalalkyloxypiperidinyl 4.alkyl, hydroxy(C 4 dalalkyloxyC in .lalkylpiperazinyl, hydroxyC. lalalkyloxyC .alkylpiperazinyl and dalalkyl, (hydroxyC 4.alkyl)(C. dalkyl)amino , (hydroxyC. dalalkyl(C 4.lalkyl)amino 4. dalalkyl, pyrrolidinylC. dalalkyloxy, /-«f zo mMorpholinylC. dalalkyloxy, morpholinyl. alkyl, C.. dalalkylpiperazinyl, C. . dalalkylpiperazinyl 4. alkyloxy,

S. lalkylpiperazinyl 4.alkyl, hydroxyS. dalalkylamino, di(hydroxyC. dalalkyl)amino, ise) di(C. lalkyl)amino and dalalkylamino, aminothiadiazolyl, aminosulfonylpiperazinyl. lalkyloxy, or si thiophenyl 4.alkylamino.

Another group of preferred compounds consists of those compounds of formula (I) where y is 0; uh-

В' represents -С(О)МА ZВ", -С(0)-Si valkandilZV", -MVZS(OMZHSHCHONA", -MAZS(О)С. valkandilZV", p -МА8С(0О)С-М(OH )B or other 7p-chelating group, where KZ and B" are each independently selected from hydrogen, hydroxy, hydroxyC-alkyl or amino-alkyl; 22 is hydrogen, hydroxy, amino, hydroxyC-4 alkyl,

C. alkyl, Sualkyloxy, arylC. alkyl, aminocarbonyl, aminoC.alkyl, C. alkylaminoSialkyl or "di(C. alkyl)amino 4 alkyl; -Г- is a bivalent radical selected from -МНС(О)- or -МНБЗО»-; C is a radical selected from (а-1), (а-3), (а-4), (а-5), (а-6), (а-7), (а-8) , (a-9),

I" shk (а-10), (а-11), (а-12), (а-13), (а-14), (а-15), (а-16), (а-17) , (а-18), (а-19), (а-20), (а-21), (а-22), 415 (а-23), (а-24), (а-25), (а-26), (а-28), (а-29), (а-30), (а-31), (а-32), (а-33), (а-34), (а -35), (а-36), - (а-37), (а-38), (а-39), (а-40), (а-41), (а-42), (а- 44), (а-45), (а-46), (а-47), (а-48) or (а-51); each 5 is independently equal to 0, 1, 2, C or 4; - VO represents hydrogen; halo; hydroxy; amino; nitro; trihaloC 4. valkyl; trihaloS. valkyloxy; S. valkil; ko S. valkyloxy; Su alkylcarbonyl; Su valkyloxycarbonyl; Su alkylsulfonyl; hydroxyS. valkyl; aryloxy; diY(Si alkyl)amino; cyano; thiophenyl; furanil; furanyl substituted by hydroxyC. by valkyl; benzofuranil; imidazolyl;

Pho oxazolyl; oxazolyl substituted with aryl and C..alkyl; C. valkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl;

Chl» morpholinil; C. valkylmorpholinyl; piperazinil; S. valkylpiperazinil; hydroxyS. valkylpiperazinil;

Su valkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from

Si valkilu or trihalosS. valkyla; pyridinyl; pyridinyl substituted with C. valkyloxy or aryl; pyrimidinyl; Quinolinil; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C1-4alkyl, C1-4alkyloxy or trifluoromethyl;

IF) and 297 is hydrogen; halo; hydroxy; amino; nitro; trihaloC 4 valkyl; trihaloS. valkyloxy; S. valkil; ime) S. valkyloxy; S. valkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; hydroxyS. valkyl; aryloxy; di(Ci-alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.

Another group of preferred compounds consists of those compounds of formula (I) where Y is 0 or 1; each 0 is a ve; each X is nitrogen; KE represents - C(IOOMN(OH); ВK? represents ac 65 Al hydrogen, hydroxy, C..alkyl or arylC..alkyl; -I- is a bivalent radical selected from -МНО(О)-

or -MNBZO"-; t is a radical selected from (a-1) or (a-20); each of is equal to

MORE. i -80- TO us: independently, 0 or 1; and each v is selected, independently, from hydrogen or phenyl.

The group of compounds, which are given greater preference, consists of those floccule compounds (I), where Y is equal to 1; each O is a ve; each X is nitrogen; each U is nitrogen; each 7 represents -0-

S. g i 70 or -СНо-; VK! is -C(O)MH(OH); K 2 is hydrogen; -I- is a bivalent radical selected from -МНО(О0)- or -МНБЗО 5-; and is a radical selected from (a-1) or (a-20);

MORE. I -80- TO us: each of is equal, independently, to 0 or 1; and each v is selected, independently, from hydrogen or phenyl. /5 The greatest preference is given to compounds numbered Мо4, Мо10, Мо8, Моб, Мо1, Мо12 and Мо14. pe y Tk di syum pk du peo an dn tnyh ro y But oczen sauce I and eye rev es sov sko no ne shko: peso kny y I yak Z Z y YA nt same ik liy I schen - ZYSCHICHI I

With her and her and t h No t wer h - shh. yah v des, z dyan i i o, i , sii Nizh. I: Y Ж і t zno Uruuke zo I l lived and s s d ov i I SHE nn n s s, tk s ss: I: SHE S I how Z-D E I 5 JAV 2 yah E

Also me too. You today "Like I E UZH Her. In MG ТЯ и ше ша и ря Ж ш ше и аз г нан З ШЧМе the phenomenon is reduced EE BI; y rey BE y y Yi ku ih go

Pi in IN I lyh 0 BE || m vennenn kN in: same p. 25. and p. 8) same e snakh Le» SHK U yak ve I z

Z ke still ET k iy vkr I her! and them Mne y g B y aa 5 I Y I-- o. more

Z и и в ди сте Shchy и ido и stiche че as I E. з дай , Й CHE Pr. B NI lany: WHAT i lm her | DE She. listen

KI Kv "ok etnu her E; Man i sh Shchy: y : tttottiath Shev ss se v y Zluki ki ch kah so. and and in p. and: Z Ta Z Pn ssh ni sh |! re; IN: i Hey "Zh i ke "eta YOU se u se 0 I I as IF eV You sna i, oh tv and oti lay She she slshishe and Yar she with Z she: : I with al sho schi: I still With I but there is; ; in. MORE s Z Z M Be more Same s ШІ Ж

Brook ten p v ni VA yari h

E x Koch -y KE Z Y r. s I EN OTCHE I nyu sno sykhyuy des do ido khdevii DAYE che. Ladle with shnneyu Zh. E: ssh r z ez x; SHE and. o i E s - roya PMyazhI SHE se a your zjo i; 5 g 45. 17 zh vo zh 00 fax y 7 Z gie y ah Kk This sh kh i: surrendered, - sbyaya Ah, nya i ali ne neatnivshaya inii a OV y nni i va i pi nyiya to save g Biy 5-

Compounds of formula (I) and their pharmaceutically acceptable salts and M-oxides, and their stereochemically isomeric forms (o) can be prepared in a conventional manner. The general synthesis scheme includes, for example:

T» a) Hydroxamic acids of the formula (I), where K' represents -С(О)МН(ОН), these compounds are referred to as compounds of the formula (1-a), can be obtained by the reaction of an intermediate compound of the formula ( II) with a suitable acid, such as, for example, trifluoroacetic acid. This reaction is carried out in a suitable solvent, such as, for example, methanol. name) 60 b5 rev yo pk vagi dey «zhi g fi nt-a S SVY PU ok me pl i y JAK s he or vezhu id What o zha tya still y, KgY eco shh i y

M: ha y yy yy; Led where EK vno and Shchi. -

I and lo osa skin and M he Va V. NE Rai pan: Vo TAKU chen : She and lower ssh she to SHYH pany Eh :A lek fe in B eedesoyusti ne y yan

And if the Central Committee of Ukraine owns the power of the government, it will be possible: Kur Sha Zhe skh | A sne A zervvnnktya I would soenya

Cold YOU preedreny rromeennk rozhnnnny he shsh es o V SVO, owls he

P) intermediate compounds of the formula (II) can be obtained by reacting an intermediate compound of the formula (PI) with an intermediate compound of the formula (M) in the presence of appropriate reagents, such as

M'-«(«ethylcarbonimidoyl)-M,M-dimethyl-1,3-propanediamine, monohydrochloride (EC) and 1-hydroxy-1H-benzotriazole (NOVT). This reaction can be carried out in a suitable solvent, such as a mixture of OSM and TNE. Yes Se

Mu z Ko iyi pi as 4

What are the U.N.'s trade unions?

She rivne ee sh.. se de and svv I poly I and ex tr neiknkh TK

It's your fault

Shchi i ChreoBOK o Voeya She i V Jhe, Shch -

Zhora" and yo days pay "ih ha 5 more to her! še pu sch

Om o oh sakhu Ve - Zhnya "y z i che ie ne Ka ky y Zk Y ryn zagre shnnk sosn OV MINE sa MINE NI ZHY

Kai E i i b rr i i i i; in-vo OO VI iy shk eV ss: hoЯ 30 . ххих. ЗК жк В, аваН «о c) intermediate compounds of formula (III) can be obtained by reacting an intermediate compound of formula (M) with a suitable base, such as Masson, in the presence of a suitable solvent, such as ethanol. m

I'm in I'm in vics: -e , as i- oh A de SR si pria KE sec t

Bshi y y Her SNI se, Vl pp en inii nt chu r E o IMK le siv vno Zk KHYZHYH a z DE ve " quince 7 y sh s B h tary: I - ;" r I ne kh I "y pika se KL. f

Mpa se el V she (y ee y y zer son eky y y y y y y vyni vya; ble lezi y v ;

FO 50 | not

Compounds of formula (I) can also be conveniently obtained using the method of solid-phase synthesis. In general, solid-phase synthesis involves the reaction of an intermediate compound in combination with a polymer carrier. This polymer-supported intermediate can then be used in a number of synthesis steps. After each stage, repeated filtration of the resin and its washing with the use of various solvents cleans it of impurities and impurities. At each stage, this resin can be separated to carry out reactions with various intermediate compounds at the next stage, which allows the synthesis of a large number of compounds. After the last stage of this (F, procedure), the specified resin is treated with a reagent for separation from the sample. A more detailed explanation of the methods used in solid-phase chemistry is given in such works as, for example, ("Pe Sotripaiogia!

Ipdeh" (V. Vypip, Asadetis Rgezv) and Momariospet' 1999 Saiaiosdpe 5 Reriide Naparook (Momariospet As, bo Zmygepapa)) to which reference is made in this text.

Compounds of formula (I) and some intermediates may have at least one stereogenic center in their structure. This stereogenic center can be present in the K or 5 configuration.

Compounds of formula (I) obtained in the processes described above are, in general, racemic mixtures of enantiomers that can be separated from each other using art-known separation procedures. Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The indicated diastereomeric salt forms are then separated,

for example, by means of selective or fractional crystallization, and the enantiomers are liberated therefrom with alkali.

An alternative method of separation of enantiomeric forms of compounds of formula (I) includes liquid chromatography using a chiral stationary phase. The specified pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of the corresponding starting materials, provided that this reaction is stereospecific. If a specific stereoisomer is desired, the specified compound can be synthesized using stereospecific methods of preparation, which is preferred. In these methods, it is advantageous to use enantiomerically pure starting materials.

The compounds of formula (I), their pharmaceutically acceptable acid addition salts and stereoisomeric forms have 7/0 active pharmacological properties, which consist in the fact that they have an inhibitory effect on histone deacetylase (NOAS).

The present invention provides a method of inhibiting the abnormal growth of cells, including transformed cells, by applying an effective amount of a compound of the present invention. Abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition). This /5 Includes inhibition of tumor growth both directly, by arresting growth, terminal differentiation and/or apoptosis of cancer cells, and indirectly, by inhibiting revascularization of tumors.

The present invention also provides a method of inhibiting the growth of tumors by administering an effective amount of a compound of the present invention to a subject, for example, a mammal (and more specifically, a human) in need of such treatment. In particular, the present invention introduces a method of inhibiting the growth of tumors by using an effective amount of compounds of the present invention. Examples of tumors that may be inhibited include, but are not limited to, lung cancer (e.g., adenocarcinoma and non-small cell lung cancer), pancreatic cancers (e.g., pancreatic carcinoma, such as, e.g., exocrine pancreatic carcinoma), colon cancer, bowel (eg, colorectal carcinomas, such as, for example, colon adenocarcinoma and adenoma of the colon), prostate cancer, including chronic prostate cancer, hematopoietic tumors of lymphoid origin (eg, acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myeloblastic leukemia (AMI)), i) thyroid-follicular cancer, myelodysplastic syndrome (MOB), tumors of mesenchymal origin (for example, fibrosarcomas and rhabdomyosarcomas), melanomas, teratocarcinomas, neuroblastomas, gliomas, benign skin tumors (for example , keratoacanthomas), carcinoma of the mammary gland (for example, old cancer "g

From the breast), kidney cancer, ovarian cancer, bladder cancer and epidermoid cancer.

The compound according to the present invention can be used for other therapeutic purposes, for example: ix, a) sensitizing tumors to radiation therapy by using the compound according to the present invention c before, during or after irradiation of the given tumor for the treatment of cancer; p) treatment of atrophies and osteopathological conditions, such as rheumatoid arthritis, osteoarthritis, juvenile arthritis, gout, polyarthritis, psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus; c) inhibition of the proliferation of smooth muscle cells, including vascular proliferative disorders, atherosclerosis and restenosis; a) treatment of inflammatory conditions and dermal conditions, such as ulcerative colitis, Crohn's disease, allergic rhinitis, graft-versus-host disease, conjunctivitis, asthma, respiratory distress syndrome in adults (AKO5), Behcet's disease, transplant rejection, urticaria, allergic dermatitis, alopecia areata, with scleroderma, exanthema, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosus, Kawasaki disease,

And multiple sclerosis, emphysema, cystic fibrosis and chronic bronchitis; and?" f) treatment of endometriosis, uterine fibroids, dysfunctional uterine bleeding and endometrial hyperplasia; 7) treatment of ocular vascularization, including vasculopathy affecting retinal and choroidal vessels; -And 9) treatment of cardiac dysfunction;

P) inhibition of immunosuppressive conditions, such as treatment of HIV infections;

Sh- i) treatment of renal dysfunction; ko Y) suppression of endocrine disorders;

K) inhibition of gluconeogenesis dysfunction;

Me, I) treatment of neuropathology, for example, Parkinson's disease or neuropathology that leads to a disorder of the cognitive system, for example, Alzheimer's disease, or neuron diseases associated with polyglutamine; t) inhibition of neuromuscular pathologies, for example, amyotrophic lateral sclerosis; n) treatment of spinal muscular atrophy; o) treatment of other pathological conditions amenable to treatment by enhancing gene expression; r) enhancement of gene therapy.

F) Thus, the present invention discloses the compounds of formula (I) for use as drugs, as well as the use of these compounds for the manufacture of drugs for the treatment of one or more of the conditions and diseases listed above. The compounds of formula (I), their pharmaceutically acceptable acid addition salts and stereoisomeric forms may have valuable diagnostic properties in that they may be used for the detection or identification of an ASAO in a biological sample, which involves detecting or measuring the formation of a complex between a labeled compound and SPLA.

In methods of detection or identification, compounds that are labeled with labeling agents, such as radioactive isotopes, enzymes, fluorescent substances, luminous substances, etc., can be used. Examples of radioactive isotopes include 72921, 131, ZN, and "C. Enzymes are usually made detectable by conjugation to an appropriate carrier, which in turn catalyzes the detectable reaction. Examples of such enzymes are beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidase, and malate dehydrogenase, preferably horseradish peroxidase Luminescent substances include, for example, luminol, luminol derivatives, luciferin, aequorin and luciferase.

Biological samples can be defined as body tissues or body fluids. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, saliva, and the like.

Due to their useful pharmacological properties, the considered compounds can be used for the preparation of various pharmaceutical forms intended for use. 70 To prepare the pharmaceutical compositions of this invention, an effective amount of this compound in the form of a basic or acid addition salt, as an active ingredient, is combined in the form of a thin mixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms, depending on the form of the drug required for use. It is desirable to have these pharmaceutical compositions in a unit dosage form, which is suitable, preferably, for oral, rectal, transdermal use or in the form of parenteral injections. For example, in the preparation of oral dosage compositions, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols, and the like, in the case of oral liquid preparations, such as suspensions, syrups, elixirs, and solutions ; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets.

Due to ease of use, tablets and capsules are the most suitable standard dosage forms for oral administration, and in this case, obviously solid pharmaceutical carriers are used. For parenteral compositions, the vehicle usually includes sterile water, at least in its majority, although other ingredients may be included, for example, to improve solubility. For injections, for example, solutions can be prepared in which the carrier includes a saline solution, a glucose solution, or a mixture of a saline solution and a glucose solution. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. In compositions suitable (8) for transdermal administration, the carrier includes, if necessary, a penetration-promoting agent and/or a suitable wetting agent, which may, if necessary, be combined with suitable additives of any nature in minor proportions, additives that do not have a significant harmful effect on the skin. These additives may facilitate application to the skin and/or may be useful in the preparation of the desired compositions. These compositions can be applied in various ways, for example, as transdermal patches, as patches or as an ointment. ise)

Particular preference is given to the preparation of the above-mentioned pharmaceutical compositions in a standard dosage form for ease of use and uniformity of dosage. The standard dosage form in this specification and the claims of the invention refers to physically discrete units as unified dosage forms, each unit containing a predetermined amount of the active ingredient calculated to obtain the desired therapeutic effect, compatible with the required pharmaceutical carrier. Examples of such standard dosage forms include tablets (including rough or coated tablets), capsules, pills, powder packages, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and the like, and segregated multiples thereof. "

Those skilled in the art can easily determine the effective amount from the test results presented in the text. In general, it is believed that the effective amount is from 0.005mg/kg to 1OOmg/kg of body weight, and in particular, . from О.0О05mg/kg to 1Омг/kg of body weight. In some cases, it is advisable to divide the required dose into two, three, four, etc. or more subdoses and use at appropriate time intervals throughout the day. These subdoses can be formulated as standard dosage forms, containing, for example, from 0.5 to 500 mg, and, in particular, from 10 to 500 mg of the active ingredient per standard dosage form. -I As another aspect of the present invention, the combination of an ASAO inhibitor with another anticancer agent is contemplated, particularly for use as a drug, particularly for the treatment of cancer or related diseases. For the treatment of the above conditions, the compounds of this invention can be advantageously used in combination with one or more other medicinal products, more specifically, with other anticancer agents. Examples of anticancer agents are:

Me. - coordination compounds of platinum, for example, cisplatin, carboplatin or oxaliplatin; i" - taxane compounds, for example, paclitaxel or docetaxel; - topoisomerase inhibitors (topoisomerase I), such as camptothecin compounds, for example, irinotecan or topotecan; - topoisomerase inhibitors (topoisomerase I), such as antitumor podophyllotoxin derivatives, for example, etoposide or teniposide; (F) - antitumor periwinkle alkaloids, for example, vinblastine, vincristine or vinorelbine; ka - antitumor nucleoside derivatives, for example, 5-fluorosuracil, gemcitabine or capecitabine; - nitrogen-mustard or nitrosourea alkylating agents, for example, cyclophosphamide, chlorambucil, boron Kcarmustine or lomustine; - antitumor anthracycline derivatives, for example, daunorubicin, doxorubicin, idarubicin or mitoxantrone; - NEC? antibodies, for example, trastuzumab; - estrogen receptor antagonists or selective estrogen receptor modulators, for example, tamoxifen, toremifene, droloxifene, faslodex or raloxifene; 65 - aromatase inhibitors such as exemestane, anastrozole, letrazol and vorozol; - differentiation agents, such as retinoids, vitamin ХО and agents that block the metabolism of retinoic acid (CAMBA), for example, Accutane; - inhibitors of DNA methyltransferase, for example, azacitidine; - kinase inhibitors, for example, flavoperidol, imatinib mesylate or gefitinib; - farnesyltransferase inhibitors; or - other NSAID inhibitors.

The term "platinum coordination compound" is used herein to refer to any platinum coordination compound that inhibits the growth of tumor cells, which supplies platinum in the form of ions.

The term "taxane compounds" indicates a class of compounds having a taxane ring system and relating to or obtained from wood extracts of yew trees (Takhiv).

The expression "topoisomerase inhibitors" is used to denote enzymes capable of changing the topology of DNA in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, namely, type | and HER type.

Topoisomerase I is a monomeric enzyme with an approximate molecular weight of 100,000. This enzyme /5 binds to DNA and introduces a temporary break in the single strand, unwinds the double helix (or allows it to unwind) and then closes this break again before separating from the DNA strand. Topoisomerase II has a similar mechanism of action, which involves inducing DNA strand breaks or the formation of free radicals.

The term "camptothecin compounds" is used to refer to compounds related to or derived from the parent camptothecin compound, which is a water-insoluble alkaloid obtained from the wood of the Chinese tree Satrioi Nesip asitipaya or the wood of the Indian tree Moiparoduez ioeyaa.

The term "podophyllotoxin compounds" is used to refer to compounds related to or derived from the parent podophyllotoxin that is extracted from mandrake.

The term "antitumor periwinkle alkaloids" is used to refer to compounds relating to or derived from periwinkle (Mipsa gozea) extracts. high school

The expression "alkylating agents" covers various groups of chemical substances, the common feature of which is that they have the ability to introduce, under physiological conditions, alkyl groups into biologically vital macromolecules, such as and)

DNA. In the case of most of the most important agents, such as nitrogen mustards and nitrosoureas, the active alkylating moieties are generated immediately after complex cleavage reactions, some of which are enzymatic. The most important pharmacological effects of these alkylating agents are that they disrupt fundamental mechanisms related to cell proliferation, in particular DNA synthesis, and cell division. The ability of alkylating agents to disrupt the function and integrity of DNA in rapidly proliferating tissues (i.e.) provides the basis for their therapeutic use and their many toxic properties. with

The term "antitumor anthracycline derivatives" includes antibiotics derived from the fungus Zieger. Receisis mag. saeviy5, and their derivatives, which are characterized by the presence of a tetracycline ring structure with an unusual sugar, donosamine, attached by a glycosidic bond. Cha

Amplification of the human epidermal growth factor receptor 2 (EGF 2) protein in primary breast carcinomas has been shown to correlate with an adverse clinical prognosis in some patients.

Trastuzumab is a highly purified humanized monoclonal Ids1 kappa antibody derived from recombinant

DNA binding with high affinity and specificity to the extracellular domain of the HEK 2 receptor. "

Many types of breast cancer have estrogen receptors, and the growth of these tumors can be stimulated(s) with estrogen. The terms "estrogen receptor antagonists" and "selective estrogen receptor modulators"

And are used to determine competitive inhibitors of binding of estradiol to the estrogen receptor and? (EC). Selective modulators of estrogen receptors, when they are bound to this EC, induce changes in the three-dimensional configuration of this receptor, which inhibits its binding to the estrogen-sensitive element

HEKE) on DNA. -I In postmenopausal women, the main source of circulating estrogen is the conversion of adrenal and ovarian androgens (androstenedione and testosterone). into estrogens (estrone and

Ш-estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition or co-inactivation is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Meh, The term "antiestrogen agent" is used herein to refer not only to estrogen receptor antagonists and selective estrogen receptor modulators, but also to aromatase inhibitors, as discussed above.

The term "differentiation agents" includes compounds that can, in various ways, inhibit the proliferation of two cells and induce differentiation. Vitamin O and retinoids are known to play a major role in regulating the growth and differentiation of a wide variety of normal and malignant cell types. Blocking agents

F) metabolism of retinoic acid (KAMBA" 5), increase the levels of endogenous retinoic acids by inhibiting cytochrome P450-mediated catabolism of retinoic acids.

Changes in DNA methylation are among the most common abnormalities in human neoplasia. Hypermethylation in the promoters of selected genes is usually associated with inactivation of the involved genes. The term "DPK methyltransferase inhibitors" is used to refer to compounds that act through pharmacological inhibition of DPK methyltransferase and reactivation of tumor suppressor gene expression.

The term "kinase inhibitors" includes active inhibitors of kinases involved in cell cycle initiation and programmed cell necrosis (apoptosis). 65 The term "farnesyltransferase inhibitors" is used to refer to compounds that have been developed to prevent farnesylation of Cas and other intracellular proteins. They have been shown to influence the proliferation and survival of malignant tumors.

The expression "other SSRI inhibitors" includes, but is not limited to, the following compounds: - fatty acids with short chains, for example, butyrate, 4-phenylbutyrate or valproic acid; - hydroxamic acids, for example, suberoylanilide hydroxamic acid (ZANA), biaryl hydroxamate

A-161906, bicyclic aryl-M-hydroxycarboxamides, pyroxamide, CO-1521, PHO-101, sulfonamide hydroxamic acid, I AO-824, trichostatin A (T5A), oxamflatin, scripted, t-carboxycinnamic acid, bishydroxamic acid or an analogue of trapoxin- hydroxamic acid; - cyclic tetrapeptides, for example, trapoxin, apidicin or depsipeptide; 70 - benzamides, for example, M5-275 or SI-994, or - depudecin.

For the treatment of cancer, the compounds of the present invention may be administered to a patient as defined above in combination with radiation. Irradiation refers to the application of ionizing radiation, and in particular, gamma radiation, especially that emitted by linear accelerators or radioisotopes, which are commonly used today. Irradiation of the tumor with radioisotopes can be external or internal.

The present invention also relates to a combination according to the present invention of an anticancer agent and an inhibitor

SPSS according to the present invention.

The present invention also relates to a combination according to the present invention for use in pharmacotherapy, e.g. to inhibit the growth of tumor cells.

The present invention relates to a method of inhibiting the growth of tumor cells in a human subject, which includes administering to the subject an effective amount of a combination according to the present invention.

The present invention also provides a method of inhibiting abnormal growth of cells, including transformed cells, by administering an effective amount of a combination according to the present invention. high school

The other drug and the NSAID inhibitor may be administered simultaneously (eg, in separate or single formulations) or sequentially in any order. In the latter case, said two compounds will i) be used for such a period and in such an amount and in such a manner as to ensure that a beneficial or synergistic effect is achieved. It is understood that the preferred route, order of administration, appropriate dosage amounts and schedules for each component of a given combination will depend on the particular other medicinal product and NSAID inhibitor being used, the route of administration, the type of tumor being treated, and the specific host undergoing treatment. X,

The optimal method and order of application, dosage amounts and scheme can be easily determined by those skilled in the art using conventional methods and taking into account the information provided herein.

The coordination compound of platinum is used, preferably, in a dose of 1-500mg per square meter (mg/m2) - body surface area, for example, 50-400mg/m2, in particular, cisplatin in a dose of about 75mg/m2 and carboplatin in a dose of about Zb0Omg/m? for a course of treatment.

The taxane compound is preferably used at a dose of 50-400 mg per square meter (mg/m?) of body surface area, for example, 75-250 mg/m2, in particular, paclitaxel at a dose of about 175-250 mg/Mm2 and docetaxel at a dose of about 75- 150mg/m? for a course of treatment. from p. 70 Campotequin compound is used, preferably, in a dose of 0.1-400 mg per square meter (mg/m 2) of area. body surface, for example, 1-300 mg/m2, in particular, irinotecan at a dose of approximately 100-150 mg/m2 and topotecan at a dose of approximately 1-2 mg/m? per course of treatment.

The antitumor nodophyllotocasin derivative is used, preferably, in a dose of 30-30O0mg per square meter (mg/m7) of the surface of the dead body, for example, 50-250mg/m?, in particular, etonoside in a dose of about 35-100mg/m? and - teninoside in a dose of approximately 50-250mg/m? for a course of treatment. -I Antitumor periwinkle alkaloid is used, preferably, in a dose of 2-3O0mg per square meter (mg/m) of body surface area, in particular, vinblastine in a dose of approximately 3-12mg/m2, vincristine in a dose of approximately 1-2mg/m2 di and vinorelbine in a dose of approximately 10-ZOmg/m2 per course of treatment.

Ge") 20 Antitumor nucleoside derivative is used, mainly, in a dose of 200-2500 mg per square meter

HT" (mg/m) of body surface area, for example, 700-1500mg/m?, in particular, 5-BO at a dose of 200-500mg/m?, gemcitabine at a dose of approximately 800-1200mg/m? and capecitabine in a dose of approximately 1000-2500mg/m? for a course of treatment.

Alkylating agents, such as nitrogen-mustard or nitrosoureas, are used, preferably, in a dose of two 100-500mg per square meter (mg/m?) of body surface area, for example, 120-200mg/m2, in particular, cyclophosphamide in a dose of about 100- 500mg/m2, chlorambucil at a dose of approximately 0.1-0.2mg/kg, carmustine at a dose of approximately 150-200mg/m2 and lomustine at a dose of approximately 100-150mg/m2 per course of treatment. Namely) Antitumor anthracycline derivatives are used, preferably, in a dose of 10-75mg per square meter (mg/m2) of body surface area, for example, 15-bOmg/m2, in particular, doxorubicin in a dose of approximately 40-75mg/m?, 60 daunorubicin in at a dose of approximately 25-45mg/m2 and idarubicin at a dose of approximately 10-15mg/m2 per course of treatment.

Trastuzumab is mainly used in a dose of 1-5 mg per square meter (mg/m 2 ) of body surface area, in particular, 2-4 mg/m? for a course of treatment.

An anti-estrogenic agent is used, preferably, in a dose of approximately 1-100 mg per day, depending on the specific agent and the condition being treated. Tamoxifen is mainly used orally in a daily dose of 5-5 mg, preferably 10-20 mg twice a day, the therapy is continued for a sufficient time to achieve and maintain the therapeutic effect. Toremifene is used, preferably, orally in a dose of about bOmg once a day, therapy is continued for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is mainly used orally in a dose of approximately 1 mg once a day. Droloxifen is mainly used orally in a dose of approximately 20-100 mg once a day. Raloxifene is used, preferably, orally in a dose of about bOmg once a day. Exemestane is mainly used orally in a dose of approximately 25 mg once a day.

The specified doses can be prescribed, for example, once, twice or more times per course of treatment, which can be repeated, for example, every 7, 14, 21 or 28 days. 70 Taking into account their beneficial pharmacological properties, the components of the combinations according to the present invention, i.e., another drug and an NOAS inhibitor, can be used to formulate various pharmaceutical forms intended for use. The specified components can be used separately in individual pharmaceutical compositions or in a unitary pharmaceutical composition containing both of the specified components.

Therefore, the present invention also relates to a pharmaceutical composition comprising another medicinal product and an inhibitor of an SSRI in combination with one or more pharmaceutical carriers.

The present invention also relates to a combination according to the present invention in the form of a pharmaceutical composition comprising an anti-cancer agent and an inhibitor of an ASAP according to the present invention in combination with one or more pharmaceutical carriers.

The present invention also relates to the use of the combination according to the present invention in the production of a pharmaceutical composition for inhibiting the growth of tumor cells.

The present invention also relates to a product containing as a first active ingredient an NOAA inhibitor according to the present invention and as a second active ingredient an anticancer agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer. with

Experimental part

The following examples are introduced for illustration. and)

In this text, "OSM" means dichloromethane, "OME" means dimethylformamide, "EUAc" means ethyl acetate, "IRGON" means isopropyl, "MeOonH" means methanol, " "EUN" refers to ethanol, "TEA" refers to triethylamine, "TEA" refers to trifluoroacetic acid, "TNE" refers to tetrahydrofuran, "VZA" refers to bovine serum albumin, "OMBO" refers to dimethylsulfoxide, and "Nerevz" refers to x, 4-(-2-hydroxyethyl)-1-piperazine-ethanesulfonic acid. with

Under (93509) is meant the optical rotation measured at the wavelength of the O-line of sodium at a temperature of 209C. In addition to the actual value, the concentration and solvent of the solution used to measure the optical rotation are given.

A. Preparation of intermediate compounds a) Preparation o son ki TI sho pi ih s Ya. t schi ia osa ay: p - As sec secr ok che i schik "" in ZE Z z i a z - y -1 de ziv nt ste on I sassy you

A solution of |1,1"-biphenyl|-4-sulfonyl chloride (0.01 bmol) in OSM (5 Oml) was added dropwise at 029C to a solution of 4-(phenylmethyl)-2-morpholinemethanamine (0.0145 mol) and TEA (0. 02Zmol) in OSM (5Oml).This mixture

He" 20 was brought to room temperature, then stirred overnight, poured into ice water and extracted with OCM. The organic layer was separated, dried (Mo9505), filtered, and the solvent was evaporated. The residue (bg) was crystallized from diethyl ether. The precipitate was filtered and dried, yielding 3.1 g (6295) of intermediate compound 1, TGpl. 12820.

B) Obtaining 25 EE he

Ф, sen and you, ki a and oi i zah svi 60 - sh SHE penetrates 65 A mixture of intermediate compound 1 (0.0071mol) and Ra/C (0.5g) in MeonH (5Oml) and acetic acid (5ml) hydrogenated at room temperature for 5 days under Zbar pressure, then filtered through celite. The celite was washed with rcmM/meon. The filtrate was evaporated. The residue (Zg) was dissolved in diethyl ether. The precipitate was filtered, washed with diethyl ether and dried, yielding 2.6 g (10090) of intermediate compound 2, Tpl. 1519260, p) Obtaining Sh o dy: gesture Ш svo vy SYNA nu y z " kt i. h aveni i CY Not i dnya dv EE KK ZHY u kt ki pol y I She av pk V SCHI Y pec. sm: r .

Sodium hydride 6095 (0.014 mol) was added in portions at 02С to a mixture of intermediate compound 2 (0.0069 mol) in

TNE (ZoOml) under a stream of nitrogen. This mixture was stirred at 02C for 1 hour. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.009 mol) in TNE (2 Oml) was added dropwise. This mixture was stirred at room temperature for 4 hours, poured into ice water and extracted

EUAs. The organic layer was washed with water, dried (M950), filtered, and the solvent was evaporated. The residue (3g) was purified by column chromatography on silica gel (15-40 μm) (eluent: OSM/MeOH 99/5). Pure EM fractions were collected and the solvent was evaporated. The residue (0.6 g) was purified by column chromatography on silica gel (chiralpak) (eluent: SNUSM 100). The two fractions were collected, and the solvent was evaporated, yielding 0.255 g (890) of intermediate C(A), (Codo-9--32.6 (c-0.00485 OME) and 0.25 g (895) of intermediate 4( B), Io1029-33.8 (c-0.005, OMRB).

Example A2 a) Obtaining that (Se) r. Ve Z se. i -

Zo oi sao 3 c.

In ож лк нн in:

TE Ivan» I - with eV. ;" 35 days from

Sh- Tetrahydroaluminate(1-), lithium (0.04 mol) was added in portions at 52C to TNE (40 ml) under a stream of nitrogen. A solution of 1-benzyl-4-triphenylmethylpiperazine-2-carboxylic acid ethyl ether (0.01 mol) was added dropwise

In TNE (40 Oml). This mixture was stirred for 2 hours, poured into an EtOAc/water mixture and filtered through

Me celit. The organic layer was separated, dried (Mao), filtered, and the solvent was evaporated to give

Ta» 4.05 and intermediate compound 5. This product is used directly in the next reaction stage. 5) Receipt

F) name) 60 b5

- sya sho KE gad: this is Y od:

Z an: ШЕ NK: - выш - Vkasynae shcha dit che 70 si si soi i: s brochi man

A solution of diazendicarboxylic acid, bis(1-methylethyl)ether (0.0097 mol) in TNE (1 Oml) was added dropwise at 59 to a solution of intermediate compound 5 (0.00 b4 mol), 1H-isoindole-1,3(2H)-dione (0.0097 mol) in TNE (5 Oml) under a stream of nitrogen. This mixture was stirred at room temperature for 6 hours, poured into ice water and extracted with E(Ac. The organic layer was separated, dried (MaozO,), filtered, and the solvent was evaporated. The residue (11g) was purified by column chromatography on silica gel (15-4μm ) (eluent:

OSM/EUAs 99/1). Pure fractions were collected and the solvent was evaporated to yield 2.8 g (7595) of intermediate 6,

Tpl. 100960, c) Obtaining PI with a:

VN about

Bank. I she I Z shchi My ayu

KV to VE ty her: and BC

SI and I Ko Z also and what director LSH Y not -Zy і- and -

EK MYKOM Kook i

Hydrazine monohydrobromide (000.005 mol) was added to a solution of intermediate compound 6 (0.0025 mol) in EYN (25 ml). "

This mixture was stirred and heated under reflux for 4 hours, then cooled to 70°C at room temperature. The solvent was evaporated. The residue was dissolved in the mass extracted with ЕЯАС/ОСМ. The organic layer was separated, dried (Ma95O4), filtered, and the solvent was evaporated, yielding 3.55 g of intermediate compound 7. This product was used directly in the next reaction stage. a) Preparation

J. Even - and Sh. Ko. snie ku - I pkya aktah y -Yi i zn psom si z Ian Ya shi Yi sa ch i» S YA L

FA g, ke about her and about TYA same sh I I her 7 and " (o) 50 Not "Ki and Eetesnn u de lysh e peki sonne Zh cha

AND; sht, set a Tsi pi eh o t visn so I

M. and dad o

A mixture of intermediate compound 7 (0.0025 mol), 2-naphthalenesulfonyl chloride (0.0027 mol) and TEA (0.004 mol) in OCM (20 mL) was stirred at room temperature overnight, poured into ice water and extracted

OSM The organic layer was separated, dried (M950), filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel (15-40 μm) (eluent: OSM/EUAs 98/2). Pure fractions were collected and the solvent was evaporated. The residue was filtered and dried, yielding 0.693 g (4195) of intermediate compound 8, mp 21996. 65 f) Obtaining

BA

EC

Nese ee BY zva ta m to Na ikh t kt jo Ba t y : 95 I two I with I and in ml v y

A mixture of intermediate compound 8 (0.0009mol) in HCl 12M (0.bml) and 2-propanone (18ml) was stirred at room temperature for 4 hours. The solvent was evaporated. The residue was dissolved in water. The aqueous layer was washed with diethyl ether, basified with potassium carbonate and extracted with E(Ac. The organic layer was separated, dried (MazO)), filtered, and the solvent was evaporated. The residue (0.5 g) was crystallized from diethyl ether. The precipitate was filtered and dried. The residue (0.38g) was dissolved in a mixture of water/E(UAc. The organic layer 20 was evaporated. The residue was dissolved in diethyl ether. The precipitate was filtered and dried, yielding 0.044g (48905) of intermediate compound 9, mp. 21096,

U) Receipt of another payment of a dollar, TV trde with 25 V, i.e. From the end

SE, oh х я t есть г и Е. k-th ge

Ber ti cha p i » y

2-(Methylsulfonyl)-5-pyrimidinecarboxylic acid ethyl ester (0.0029 mol) was added at room temperature to a solution of intermediate 9 (0.002 mol) and potassium carbonate (0.007 mol) in acetonitrile (5 0 mL). "

The mixture was stirred at room temperature for 3 hours, then stirred at 8022 for 3 nights, cooled to room temperature, poured into ice water, and extracted with E(OAc). The organic layer was separated, dried (MazO54), filtered, and the solvent was evaporated. The residue (2d) was purified by column chromatography on silica gel (15-40μm) (eluent: OSM/MeOH 99/1). Pure fractions were collected and the solvent was evaporated, yielding 0.76 bg (4895) of intermediate 10.

Example AZ a) Obtaining - | uk - vady shchi zo zve ZO brzhe spa an piy zho ZV I she ne "shcha i se tsi vn, y y zr A i v b 50 No No otr z Ko, s"

Y ko ho; and o A solution of 2-naphthalenesulfonyl chloride (0.01 bmol) in OSM (5 Oml) was added dropwise at 02С to a solution of 4-(phenyl methyl)-2-morpholinemethanamine (0.015 mol) and TEA (0.024 mol) in OSM (5 Oml) under a stream nitrogen This mixture was stirred at room temperature overnight, poured into ice water, and extracted with OCM.

The organic layer was separated, dried (Ma 5 O)), filtered, and the solvent was evaporated to yield bg (10095) of intermediate 11. This product was used directly in the next reaction step. 5) Obtaining b5

-k

Ek Ya z tsi Zoche pok yy Y v Ve, kako zsch tya

SYA yana en i y le la

And t ee foam and appeared ru lEt in Te

A solution of 1-chloroethyl ether of chlorocarbonic acid (0.01 bmol) in 1,2-dichloroethane (2 mL) was added at room temperature to a mixture of intermediate compound 11 (0.014 mol) in 1,2-dichloroethane (48 mL). This mixture was stirred at room temperature for 45 minutes, then at 802C for 3 hours. MeOH (100 ml) was added. This mixture was stirred at 802C for 4 days, poured into water and extracted with E(OAc). The organic layer was separated, dried (M9504), filtered, and the solvent was evaporated. The residue (3.5 g) was purified by column chromatography on silica gel (15-40 μm ) (eluent: UOSM/Meon/MnH.OnH 92/8/0.5).. Pure fractions were collected and the solvent was evaporated. The residue (0.38g, 995) was crystallized from diethyl ether. The precipitate was filtered and dried, yielding 0 , 21 g of intermediate compound 12, melting point 14090,

Example A4 20 a) Obtaining Sho 25 i m Ekh ki ; vl x . AND? and still with fri F Still -- ZV (o)

Mini ran under me

A solution of (1,1-biphenyl)|-4-carbonyl chloride (0.01 bmol) in OSM (5 Oml) was added dropwise at 02С to a solution of 4-(phenylmethyl)-2-morpholinemethanamine (0.0145 mol) and TEA (0. 02Z3mol) in OSM (5Oml). This mixture was stirred at room temperature for 12 hours, poured into ice-cold iodine and extracted with OCM. - 35 The organic layer was washed with potassium carbonate 1095, separated, dried (M95O)), filtered, and the solvent was evaporated. The residue (6.2 g) was crystallized from a CH3CM/diethyl ether mixture. The precipitate was filtered and dried. The mother layer was evaporated. The residue (3.3 gH) was purified by column chromatography on silica gel (15-40 μm) (eluent: OSM/MeoOHn/MH.OH 198/2/0.1). Pure fractions were collected and the solvent was evaporated, yielding 1.5 g (2790). The fraction (0.39 g) was crystallized from a CH3CM/diethyl ether mixture. The precipitate was filtered off and dried to yield 0.12 g of intermediate compound 13, m.p. 13390. шщ с 5) Obtaining on хз" и и "7 4 з шля; an я и ;

B Ya. ha : - About name) pe Pd oto ko kt hg vlktuvvuknt t II

1-Chloroethyl ether of chlorocarbonic acid (0.006 bmol) was added at room temperature to a mixture of intermediate compound 13 (0.00 bmol) in 1,2-dichloroethane (Zbml). This mixture was stirred at room temperature for 45 minutes, then at 809C for 3 hours. MeOH (bOml) was added. This mixture was stirred at 802C for 8 days, then cooled to room temperature. The solvent was evaporated.

GF) Added EUDAs. The precipitate was filtered, washed with diethyl ether and dried, yielding 1.8 g (100905) of intermediate compound 14, Tpl. 28496. o Example A5 a) Obtaining 60 b5 ote at ZD aku HOW sec Le ney dk How

Me g I ; which 7 in k with her s k;

Kk nii Esekt ei ssha ZE - ke, TANDII in schi au. pi any gray hair, yah 70 DSA TK ECO DAN KYA DAN YA

A solution of 2-naphthalene carbonyl chloride (0.017 mol) in OSM (bOml) was added dropwise at 029C to a mixture of 4-(phenyl.methyl)-2-morpholinemethanamine (0.015 mol) and TEA (0.02 bmol) in OSM (bOml). During the night, the temperature of this mixture was brought to room temperature and this mixture was poured into ice water. The organic layer was separated, washed with potassium carbonate 1095, dried (M950), filtered, and the solvent was evaporated. 75 The residue was crystallized from a mixture of diethyl ether/OIRE. The precipitate was filtered off and dried, yielding 4.6 bg (8590) of intermediate 15, Tpl. 10490, 5) Receipt

I I ee KK in more:

I: a mixture of intermediate compound 15 (0.0109 mol) and Ra/cS (1 g) in Meon (8 Oml) and acetic acid (ml) was subjected to hydrogenation at room temperature for 4 days under Zbar pressure and then filtered through Celite. Celite was washed with Meon/OSM. The filtrate was evaporated. The residue (7.2 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: OSM/Meon/MH.OH 97/3/0.1). Pure fractions were collected, and the solvent was evaporated, with "0 with a yield of 0.8 g of intermediate compound 16.

Example Ab sch a) Obtaining h- zv YM that y- - ke se y z : y t a z y se: : Her. SHE; shk more « 20 Zones with SA - with ! more;" shshchrOMmnasnonuka

A solution of 2-naphthalenesulfonyl chloride (0.01 mol) in OSM (bml) was added at 590 to a mixture of 3-(aminomethyl)-1-piperidinecarboxylic acid, 1,1-dimethyl ether (0.01 mol) and TEA (0.014 mol) in OSM

Sh- (15 ml). This mixture was stirred at 202C for 18 hours. Potassium carbonate 1095 was added. The organic layer -I was separated, dried (MazO)), filtered, and the solvent was evaporated to dryness, yielding 4.6 g (210095) of intermediate compound 17. o B) Preparation

FO I and

BASKET: pt ras k t DE Not to her

Z he sodi z Y t ba Ya o sshd. ep non oi med mi le o Seh o o | A mixture of intermediate compound 17 (0.0089 mol) in 5M NSILHrgon (4 Oml) was stirred at 502C for 15 minutes, basified with MNAOH. This solvent was evaporated to dryness. The residue was dissolved in OSM and filtered. The filtrate was dried (M950), filtered, and the solvent was evaporated to dryness, yielding 2.9 g (210095) of intermediate 18.

Example A7 a) Obtaining b5 schi And what I se I and I 9 Mel you, not on KB son: Urine 70 and pegt -gi shehe

M-(phenylmethyl)-benzenemethanamine (thymol) was dissolved in diethyl ether and converted into the hydrochloric acid salt (1:11) using 6M HCI/2-propanol. The precipitate was filtered off and dried to give 234g and then added to 4-oxo-1-piperidinecarboxylic acid, ethyl ether and (CHO) (ZOg) in acetic acid (1600ml). This mixture was stirred for 110 minutes at 60-652C, then cooled to room temperature and poured onto a mixture of ice/water/mN.AOH. The resulting white oily precipitate was extracted with diethyl ether. The separated organic layer was washed with water, dried (Ma5zo)), filtered, and the solvent was evaporated at room temperature, yielding 436 g of intermediate compound 19. 5) Preparation of ten zr and ZE pe i, ne. oh well

A zh ie she Ga shoi that 000 v i) pe shSchya Y x za y Sche: cheh tu 7 rivers

DYN NN vu oat

Tit Take 7 shk. that;

VI

Krona s 3o ID Zk SHY MINA - nen VO p y PI A ki py Pone i

YAN was. What. UAH: y tni eri You dity E sht Kuwait ashtnt vsttMi

Intermediate compound 19 (max. 0.55 mol of the crude residue) was stirred in EN (150 Oml). A portion of sodium hydroborate was added in portions, which led to an exothermic increase in temperature to 302С. Therefore, this reaction mixture was cooled in an ice-water bath, and sodium hydroborate was added (in general, 1.000 g/mole), and the reaction temperature remained at -162C. This reaction mixture was stirred for 1 hour at 4162. By evaporation, this mixture was concentrated to half the original volume. The concentrate was cooled. Water was added. This mixture was subjected to additional concentration (significant foaming!) until complete evaporation of ethanol. The aqueous concentrate was cooled, then extracted with diethyl ether. The organic layer was separated, washed with water, dried (Mo950), filtered, and that's it. the solvent was evaporated. The oily residue was dissolved in sulfur dioxide and treated with a mixture of HCl/2-propanol. As a result, a sticky precipitate was formed. The solvent was evaporated. The residue was suspended in warm acetonitrile, then cooled, and the precipitate was removed by filtration. The filtrate was evaporated. The residue was dissolved in water. basified with MNAOH, then extracted with diethyl ether. The separated organic layer was dried (Mazo)),

He») 20 was filtered and the solvent was evaporated. The residue (267g) was separated by high performance liquid chromatography (eluent: toluene/ethanol 98.5/1.5). Pure fractions were collected and the solvent was evaporated. One of the fractions was crystallized from acetonitrile, filtered and dried, with a yield of 107 g of (trans) intermediate compound 20. c) Preparation of 60 b5 as a gray solid. not WHOSE

Kg in t i: this ; et bek yo x ; and

live:

FEM:

A mixture of intermediate compound 20 (0.0 mol) and Ra/C (1.57) in EUN (20 Oml) was hydrogenated at 5092C overnight under Zbar pressure, then filtered through celite. The filtrate was evaporated to dryness, yielding 2.1 g (210095) of intermediate compound 21). a) Obtaining I . I SE . es v sn YAZ ss VE a au z Vk i pot dru sht di SHI (8) more. ПОЖХ ТХ seneeya ХI

AVK OKA MK sho

A solution of 2-naphthalene sulfonyl chloride (0.0054 mol) in OSM (2 ml) was added at 59C to a mixture of intermediate compound 21 (0.0049 mol) and TEA (0.00b69 mol) in OSM (1 Oml) under a stream of nitrogen. This mixture was stirred for 18 hours at room temperature. Potassium carbonate 1095 was added. The smoke mixture was extracted with OCM. t

The organic layer was separated and dried (M9504). was filtered, and the solvent was evaporated to dryness, yielding 2 g (10095) of intermediate compound 22 (trans). f) Receipt

Te sh i: m vi i i "i i 2

I. I "Kss:z" fl

S UMNYN, che - serane - gri naavnya But three whole nte t pschrth ns nal, "and im zhna SPO Nuka i koste kernu and odnyd ne nsasy aven eti sk al al: in

A mixture of intermediate compound 22 (0.0043mol) in HCl b6M (20ml) was stirred and heated under reflux (2) for 24 hours. The solvent was evaporated to dryness. The remainder was served by Mahon, deceased.

They" were added by ETOAs. This mixture was stirred at room temperature overnight. The precipitate was filtered, washed with diethyl ether and dried to yield 1.37 g (9795) of intermediate 23 (trans).

B. Preparation of final compounds

Example B1 a) Obtaining

F) name) 60 b5 b c. same

A mixture of intermediate compound 4 (0.0004 mol) and Masson (00008 mol) in EUN (1 Oml) was stirred at 802C for 48 hours, then cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried, yielding 0.188 g (9095) of intermediate compound 24 (B) Ma.

B) Obtaining

I ru LE GT and I tya yo I sli and I zt st ten and si VK, IN and di and I In her and in and also and k.ih 3 and she dele still In Shsya rya Sh site i au -

Vin Ge)

Shk ich- ivan stkk povi y. her re ect in

PVA nNa san a te

UM EE

A solution of M'-(ethylcarbonimidoyl)-M,M-dimethyl-1,3-propanediamine, monohydrochloride (0.0005 mol) in OSM (5 ml), then a solution of 1-hydroxy-1H-benzotriazole (0.000 b5 mol) in TNE (bml) was added at room temperature to a mixture of intermediate compound 24 (0.000 mol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (0O0.0005 mol) in OSM (1 mol). This mixture was stirred at room temperature overnight, poured into water and extracted - with OSM. The organic layer was separated, dried (M950), filtered, and the solvent was evaporated. The residue "from (0.29 g) was purified by column chromatography on silica gel (MOμm) (eluent: OSM/Meon 99/1). The pure " fractions were collected, and the solvent was evaporated, yielding 0.142 g (6695) of intermediate compound 25 (B ). c) Obtaining b ro s How: t y Ai y x Shk DE

Gee)! KE. NEK ev ate

KAIN sr zhene, M o ko A mixture of intermediate compound 25 (B) (0.0002 mol) in TRA (1 ml) and Meon (15 ml) was stirred at room temperature for 4 days. The precipitate was filtered and dried. The residue (0.08 g) was dissolved in MeEOH/CH ZSM. The precipitate was filtered, washed with Meoson, then with diethyl ether and dried, yielding 0.046 g of compound 1 (B), to U-32.85 (c-0.0047, OME), Tpl. 164260.

Example B2

Obtaining b5 dey o sg pr E Z ry vysh : age v zny : ; kyu and intermediate education

A mixture of intermediate compound 10 (0.0088 mol) and Ra/C 1095 (1.3 g) in acetic acid (2 ml) and EUN (200 ml) was stirred at room temperature for 9 days under Zbar pressure, then filtered through celite.

The filtrate was evaporated to dryness. The mixture was filtered through celite. The filtrate was evaporated to dryness. 792 The residue was dissolved in OSM. The organic layer was washed with potassium carbonate 1095, dried (Mo50O)/), filtered, and the solvent was evaporated. The residue (2.7 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: toluene//"RHOH/MH.OH 90/10/0.2). Pure fractions were collected, and the solvent was evaporated, yielding 0, 29g (895) of intermediate compound 26.

Intermediate compound 26 was processed similarly to that described in example (B1), with the receipt of 0.065 g (51965) of compound 2, Tpl. 2439. and | kur i aro yaoO V sZ her - BUT o eh ZVO es

BNYAOya pke "epOonUka 7. F

An example of VZ Ga

Intermediate compound 10 was processed similarly to that described in example (B1), with the receipt of 0.26 bg (100965) of compound C, Tpl. 13596. - shi ME -zya yi-

AGE THEY You are from: ши «

I I'M NOT WITH SHEU Na ska Veni chen 000 DN s che 2 her boti LE g» o

I'm ZE

B y - i konina xx am Z y I y - o 50 Example B4

Obtaining riches

Shy: DYA

Ko: z ozh K., I'm in the 60s of spring Yerka

Vovki pa o ZD 65 nem mki PKMU VE kurts Y

Sodium hydride 6095 (0.0059 mol) was added at 02С to a mixture of intermediate compound 2 (0.0039 mol) in TNE (15 ml)

under a stream of nitrogen. This mixture was stirred at 09C for 1 hour. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.0051 mol) in TNE (1 Oml) was added dropwise. This mixture was stirred at 02C for 2 hours, then brought to room temperature for 2 hours, poured into ice water and extracted with E(Ac. The organic layer was separated, dried (Mo5O4), filtered, and the solvent was evaporated. The residue (2g) was purified by column chromatography on silica gel (15-40μm) (eluent: OSM/MeOH/MH, OH 97/3/0.1). Pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered and dried to give 0.075 g of intermediate compound 27, melting point 17096.

Intermediate compound 27 was processed similarly to that described in example (B1) to obtain 0.236 g (64965) 70 of compound 4, Tpl. 16390. : BUT, ; ai sia vk also and how

Also: g she and Bery ZYM a: in i

Ben pk and ka in ke ; tea with wine E with t

I and gun nak: and and with ve and : Bk and y

From the grave

MM

Example B5

Obtaining with 5 AK! oh both t, Dena

I. I. ris uch nya day: dr yk mn s, 5 more x Sg, Zhurayu est verch pukh ZI nyny pkt, and: SK «so

She s and dosya shi: sttvvenal tn psa VE - z y

Sodium hydride 6095 (0.004 mol) was added portionwise at 02C to a mixture of intermediate 2 (0.003 bmol) and b-chloro-3-pyridinecarboxylic acid, ethyl ether (0.0047 mol) in OME (20 mL) under a stream of nitrogen. This mixture was stirred at 902 for 12 hours, then cooled to room temperature and poured into ice water. E(SUAc) was added. This mixture was extracted with E(SUAc. The organic layer was washed with water, dried (Mo5O), filtered, and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography on silica gel (15-40 μm) ( eluent: OSM/EUAs 85/15 then OSM/MeOHn/MH.OH 97/3/0.1). Pure fractions were collected, and "" the solvent was evaporated. The residue (0.42 g) was crystallized from diethyl ether. The precipitate was filtered and " dried, yielding 0.36 g (22905) of intermediate 28, mp 18690.

Intermediate compound 28 was processed similarly to that described in example (B1) to obtain 0.155 g (62965) of compound 5, Tpl. 21020. and SEC -I PO: ok still

With Sei yah ke yi I Her: B ko KE and I Her She. nk a ey sh 7 Shchy ss « b) 20 "dyn Z vi y (I schu z g Example Bb

Obtaining 60 b5

0

In Ya in Ya p nai "yet zh o r u a sotu, M lysyny lei sao Shah prizhshzheiUchu

Sodium hydride (0.0032 mol) was added at 02C to a mixture of intermediate compound 12 (0.001 bmol) in TNE (1 Oml) under a 75° stream of nitrogen. This mixture was stirred at room temperature 45 for 1 hour. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.0019 mol) in TNE (1 Oml) was added dropwise at 02С. This mixture was stirred at room temperature for 2 hours. Ice and EIUAs were added. The mixture was extracted with EOAc. The organic layer was separated, dried (MAOA53O)), filtered, and the solvent was evaporated. The residue (0.75 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: rosm/meon 99/1). Pure fractions were collected and the solvent was evaporated to yield 0.22 g (7395) of intermediate 29.

Intermediate compound 29 was processed similarly to that described in example (B1) to obtain 0.055 g (50965) of compound 6, Tpl. 17996,

As 5 Y; high school

Be shiivki ka shk n Go)

KZ I "Ж | What else is there? I'm in like tt te

МY pa vah UM YAKA" (Se) from the s zhpoluk and in the p deya ryklad B7 m

Receipt of kv more min her I her «

UK 8 kt ze meso hi Hey yo sinya t, sia TE ba to her and I still shsh s and i sh p Be dlshii and B: Uh a Uth -i mi schen y SCHE ;

Sodium hydride 6095 (0.0052 mol) was added at 02C to a mixture of intermediate compound 12 (0.002 bmol) in OME (20 mL) under a stream of nitrogen. This mixture was stirred at 02C for 1 hour. A solution (e) of 50 b-chloro-3-pyridinecarboxylic acid, ethyl ether (0.0034 mol) in OME (1 Oml) was added dropwise at 02С. This mixture was brought to

T» at room temperature, then stirred at 9092 for 12 hours, poured into ice water and extracted with OSM. The organic layer was washed with water, dried (Mo9504), filtered, and the solvent was evaporated. The residue (1.4g) was purified by column chromatography on silica gel (15-40μm) (eluent: cyclohexane/g(OAc 60/40). Pure fractions were collected and the solvent was evaporated, yielding 0.5g (4295) of intermediate compound 30.

HF) The intermediate compound ZO was processed similarly to that described in example (B1|І with the receipt of 0.23 g (66905)

HF compound 7, Tpl. 15796. 60 b5

WITH; o and se NN

ZNU and

Example B8

Receiving a dream

SAME WITH ZH. B. ee

PE what

E Masses of St

A mixture of intermediate compound 14 (0.00 mol), 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.004 mol) and potassium carbonate (0.006 mol) in acetonitrile (30 mL) was stirred at room temperature for 12 hours, poured into water and extracted with E(SO4). The organic layer was separated, washed with water, dried (M95O), filtered, and the solvent was evaporated. The residue (1.4 g) was crystallized from a mixture of SNUSM/diethyl ether. The precipitate was filtered and dried, yielding 1, 1g (79905) of intermediate 30 of compound 31, M.P. 18492 C. Intermediate compound 31 was treated similarly to that described in example |B1Y| with (Ce) to obtain 0.156g (4795) of compound 8, M.P. 290260.

With svy and M o sa IN

B Ve g. piku Z Tzhy E sho find her their shi - s "more:

And" in

Example B9

Obtaining - х Э и. 5 (F) Sodium hydride (0.0044 mol) was added at 02С to a mixture of intermediate compound 16 (0.0022 mol) in TNE (15 ml) under a stream of nitrogen. This mixture was stirred at 09C for 1 hour. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.0029 mol) in TNE (Bbml) was added dropwise. This mixture was stirred at room temperature for 4 hours, poured into ice water and extracted with E(OAc.

The organic layer was separated, dried (Ma95O), filtered, and the solvent was evaporated. The residue (1 g) was purified by column chromatography on silica gel (15-40 μm) (eluent: OSM/MeOnH/MH.AOH 97/3/0.1).

Pure fractions were collected, and the solvent was evaporated, yielding 0.58 g (9095) of intermediate compound 32. Intermediate compound 32 was processed similarly to that described in example (B1) to obtain 0.091 g (50905) of compound 9, Tpl. 24626. b5

КН как Я за звы осн одер ой о ех, з 2, щЯ E so S. E sashe ZD Bide s I vy povi 10

Example B10

Receipt 5, lot Zh ko

MORE. With nu Koch schem tyag p Zh p. EE. : I'm with her she eh 3 toast Kiz ke and how what kind of ska s slyv an nor rt still TV o

Sodium hydride bObo in oil (0.0042 mol) was added portionwise at 59C to a mixture of intermediate compound 18 (0.0032 mol) in TNE (1 Oml) under a stream of nitrogen. This mixture was stirred for 30 minutes. A solution of 2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.0039 mol) in TNE (2 ml) was added. This mixture was stirred at room temperature for 18 hours. Potassium carbonate 1095 was added. This mixture was extracted with OSM. The organic layer was separated, dried (M950), filtered, and the solvent was evaporated to dryness. The residue (1.6g) was purified by column chromatography on silica gel (15-4O0μm) (eluent: CM from OSM 100 to OSM/MeOH 98/2). Pure fractions were collected and the solvent was evaporated to yield 0.9 g (60905) M of intermediate 33.

The intermediate compound 33 was processed similarly to that described in example (B1|І with obtaining 0.19 g (50965) - compound 10, Mpl. 21096.

Shk PN PD po oeakzhek -i Brak th vk ENK sit pan vinu usu in -I Y: KN V to chu pok her Melon Sya SYA ke aku Yagi and their still tu Ku SYA

Example В11 юю Ор holding

FO As i" I po as.

PEK SCHE t SYA sk pt Gya No, . t, y

I do not dream of "I; et. 65 Sodium hydride (0.0102 mol) was added in portions at 52C to a mixture of intermediate compound 23 (0.004 mol) in TNE (1 Oml) under a stream of nitrogen. This mixture was stirred for 1 hour. The solution was added

2-(methylsulfonyl)-5-pyrimidinecarboxylic acid, ethyl ether (0.0053mol) in TNE (Bbml). This mixture was stirred at room temperature for 24 hours. Potassium carbonate 1095 was added. This mixture was extracted with OCM. The organic layer was separated, dried (M950), filtered, and the solvent was evaporated to dryness. The residue (1.1g) was purified by column chromatography on silica gel (15-4μm) (eluent: osM/mMeon/mn on 95/5/0.1). Pure fractions were collected and the solvent was evaporated to yield 0.17 g (995) of intermediate 34, mp 189960.

Intermediate compound 34 was processed similarly to that described in example (B1) to obtain 0.194 g (68965) of compound 11 (trans), Tpl. 17696. bushes and pines V ze azh: 0 oriya sho: t, Ia Tsdeke one SK

I -5 8: melons ukamia sch

MORE IT s rudnvk rati kah ge)

Table E-1 lists the compounds obtained according to one of the above Examples. The following abbreviations are used in these tables: SONEzO" means trifluoroacetate salt, and So.Mo. means Mo compound, Ex. |Vpe)| refers to the same method as described in Vp with examples. Some compounds are characterized by their melting point (pore). "And "so s cha m. shi s ;" -I -I ime) b 50 s»

F) name) 60 b5

Pn Ya s ee: VN shchi Leh Y sitah y rpa shk ve No TA i te No | IS

It is more difficult for us to know about the Holy Spirit 70 We hear. I! VNCHIU I. -- «r o NN fete

Yan BYY NNYA I. v Ya nn p KY ok KA VKA NO ssh gi i a a s op p p ik Ya s i anch MZHK, Te t lai pe Y t pi . KO DEYA ZUYAYAN: zhshk: no and 15 ii about what lk I STILL Aeneas sleeps. g!

A Ve et movni I STILL pi pi i YN E

N Sha Ia YaEe BE svi V ZB NOT Z YAN ih

And shi and 2 p and shchi S B. still E

I What and ours is still more" and Kolya K

I OO sfe: VO es E| ona miy r 20 BEitka TNK LEM soshenen spon onov I | erev sni V T pvosvssony ov rid zbu nov shock codec

YIT --e roya u na 3 shlya Vede As "shcha t re r anek K Ege pet SY!

I NIV pe s: ZV u y. Horses and pH: x MELONS Hundred Shcha: and stem. He still knew you. "VK

I and HOW IN VE I B I bure o Y how

KE ki or Ot y. shk a . Koch, BE about E; Be a i shcha CHU u ud vo z o v V I V all MeONANIa whose I VE VIN EN ota and kiinyai Es hi how

AK KN and yy KD ov ny: A E ovi svlzhi and nevnedKlS plzhagvit Ky: V « pen tkaty rya pn uv Myty di nt luvtiayi yakh Z Me Y om ny V syak ISHN ON ND Y saun kt wl I 30 Z snih i Beha action Mate Ha tik I Zh pnh tob a to I o A

B ssveat s: which person r setnntnennn sne she znostovmionets zbnnts ssoshsovenschi 0 drawings svoe Ge) tesni nia ini nn wn kn niy aka pini o reioti t EN vyy polk ps yivn yuhnnet si plov ttiy I E o shk. in B. ME; Sha"

E V Ne MO RUSH TI ue pe KM. bakes CHE

N NEO Ko de semester I October I KE o still Y in. i I i AJ SHOULD, "UK i o a I VEN KOH -E and NA vann her dyn KI nn u nen zak Ity tel, NEO sh ro sovok m MET IDS vno l da ote ERA, he sv Ko A wn nau ZM VE YOU ARE NOT A NETWORK IN KK This is EV nn candle B si NE

NOT THE BACKGROUND OF THE NEC, there is a shortage of things. "NV I V Z - de "I ZE I zve z NYANYU works NN CHE ch sche pr v von an, their SR. Zenyk sshnnnni! Syeknnan KZ

And Vi Uiktny yah tki Z Yelzht - Ve ;. Z E u nty in dnyni ory nn ity i Y nik yun i ANNA LO ok t NIH pil Kk payu in Mk Y - I oo ote vk ven BEK NVK i ros g r pn pn Y ih

Ge: I NE ХК as Zv U a and V. ko SHE ie ke zishko, u enter sen shcha sh I 12 Eidnvintnia sne ak, Beze Y ni I SN: SI iy g

Who; EYE Clearly defined vision - EN tiy so rn: COFFEE. F y y Z: BI Zk one tiodsya MY MV Noya. Not V

ZE R OB s Ne Ж B Me a Ne r NN l v.

Ta" "u "pn DE lvret g VY ZNU: oon KE KO zan: nosu EE g " for KI nev sons of Mena in V sovno i NE ee V y Neo Y. ii IN pa it v i o ra V aa I o niv Ms

SCHI Z ko AN Ek i y Za KO PI i V ek o Eco o o u i on vo A OK un Ka ha | given DEN ma skin onco kn rnyh Harry, KE OD still el el v a o V p E I N.

I ze DI ber; ped hote shi she a Yin J schu. Names and names of van Z sin "Ak. NO 713:. y to Y , sh- ss VAK; in YOU school, E

EE ZE OBO EN ssh KB B yav and Shrot teleyat DU BT Tan; She does not have a cheek, she does not have a cheek. te ii hi SCHE Sho YN A V 60 t Tk Java fe KKU i ee EE a SY rama o KE Ak A nd a

LEK for VN a vh A i NN OD i vi: it I vlniv LV nn nyat I grew up pat KK. choyaltN t. et. ET MK et t not

S. Pharmacological example

In the IP myo test for inhibition of histone deacetylase (see example C.1), the inhibition of NOAS enzyme activity, which is achieved with the help of compounds of formula (1), is measured. 6E Cellular activity of compounds of formula (I) was determined on A2780 tumor cells using a colorimetric test for toxicity or cell survival | Moztapp Tit, uWashgpai! oh Ittypoiodis! Mayoad3z 65: -To-

55-63, 1983 (see example C.2)).

Kinetic solubility in aqueous media measures the ability of a compound to remain in aqueous solution when diluted (see example C.3).

Mother OM5BO solutions are diluted with a simple aqueous buffer solvent in three successive stages. Turbidity is measured for each dilution using a nephelometer.

Drug metabolism means that a lipid-soluble xenobiotic or endobiotic compound is enzymatically transformed into a polar, water-soluble, and excretable metabolite(s). The main organ where metabolic transformations of drugs are carried out is the liver. Metabolic products are often less active than the parent drug or are inactive. However, some metabolites may have increased activity or toxic effects. Therefore, drug metabolism can include both "detoxification" and "toxication" processes. One of the main enzyme systems that determines the ability of a given organism to interact with drugs and chemicals is represented by cytochrome RibBO monooxygenases, which are NADP (MAORN)-dependent enzymes. The metabolic stability of compounds can be determined by ip mygo using 7/5 human subcellular tissue (see example C.4). In this text, the metabolic stability of compounds is expressed as 90% of the drug that underwent metabolic transformation after 15 minutes of incubation of these compounds with microsomes. Quantitative data on the motives of the invention were obtained using I C-M5 (liquid chromatographic and mass spectroscopic) analysis

The antitumor suppressor p53 transcriptionally activates a number of genes, including the UUAE1/CIP1 gene, as a 2nd response to DNA damage. The 21 kOa product of the UUAR1 gene is found in a complex that includes cyclins, cyclin-dependent kinases (CYKs), and proliferating cell nuclear antigen (PCNA) in normal but not transformed cells, and appears to be a universal inhibitor of CYP activity. One of the consequences of the binding of p21MuUARI to SOC and inhibition of the latter is the prevention of SOC-dependent phosphorylation and subsequent inactivation of the Kb protein, which is essential for the development of the cell cycle. Therefore, the induction of p21UUARI as a response to cell contact with the NOAS inhibitor is an effective and specific indicator of the inhibition of cell cycle development in both C1 and 52 control points. and)

The ability of these compounds to induce p21MuAE1 was determined using a solid-phase immunoenzymatic p21UMAeI assay (MUARI EII5BA oi Opsodepe). The indicated p21uUuAg1 analysis is a "sandwich" enzyme immunoassay using both a mouse monoclonal antibody and a rabbit polyclonal antibody. A rabbit polyclonal antibody specific for the human UUAN1 protein was immobilized on the surface of the plastic cells introduced in the kit. Any p21uUuAg1 present in the sample to be analyzed will bind to the immobilized antibody. Biotinylated detector monoclonal antibody c also recognizes human p21uMAe1 protein and binds to any p21uMUAg1 retained by said immobilized antibody. This detector antibody, in turn, is bound by peroxidase-conjugated y-z5 streptavidin. This horseradish peroxidase catalyzes the transformation of the chromogenic substrate tetra-methylbenzidine from a colorless solution into a blue solution (or yellow after the addition of an inhibitor), the intensity of which is proportional to the amount of p21uuAE1 protein bound to this surface. The specified colored reaction product is analyzed quantitatively using a spectrophotometer. Quantitative data is obtained by constructing a reference curve using known concentrations of p21UuAE1 (subject to lyophilization). (see example C.5). Example S.I: Ip test for the inhibition of histone deacetylase: Nega nuclear extracts (supplier: Viotoi) were incubated at bOmkg/ml with 2 x 109M radioactive "" isotope-labeled peptide substrate. A synthetic peptide was used as a substrate for determining the activity of NOAS. that is, amino acids 14-21 of histone No. This substrate was subjected to biotinylation in the MNe-terminal part by a b-aminohexanoic acid spacer and protected in the COOH-terminal part by an amide group, and -and specifically INI-acetylated on lysine 16. This substrate, - biotin-( b-aminohexane) Siu-Aia-(IZNI-acetyl-ii uz-Aia-Niv-Ago-I uz-MaI-MH") was added in a buffer containing 25 mM

Nersz, 1M sucrose, 0.1 mg/ml B5A (bovine serum albumin) and 0.0195 Tgyop X-100 at pH 7.4. After 30 minutes, the diacetylation reaction was stopped by adding HCl and acetic acid (final concentration

Ge" 20 was, respectively, 0.035 mm and 3.8 mm). After termination of this reaction, free TH-acetate was extracted with ethyl acetate. After mixing and centrifugation, radioactivity in an aliquot amount and upper

T" of the (organic) phase was measured using a p-meter.

For each experiment, control experiments were carried out in parallel (control samples were used, containing Ne!a nuclear extract and OM5O without the compound), a blind incubation (with OM5O, but without Nei a nuclear extract or compound) and examination of the test samples (containing the compound, dissolved in OM5O, and Ne a

GF) nuclear extract). In the first example, the compounds were tested at a concentration of 10 M. When these compounds d) showed activity at 10 M, a concentration-response curve was constructed, where the compounds were tested at concentrations in the range of 10 72-1072 M. In each test, the value for the blind experiment was subtracted from both the control value and the value for the tested samples. The control sample represented 10,095 substrate deacetylations. For each tested sample, the radioactivity was expressed as a percentage of the average value for the control samples. Corresponding IC values (drug concentration required to reduce the number of metabolites by 5095 relative to control samples) were calculated using probit analysis for ranked data. In this text, the effects of the tested compounds are expressed as riС»o (the negative logarithm of the ISvo value). All 65 tested compounds were found to have rC0 values of 7 (see Table E-2).

Example C.2: Determination of antiproliferative activity on A2780 cells

All tested compounds were dissolved in HOM5O, and additional dilutions were made in the culture medium. In cell proliferation tests, the final concentrations of OMBO did not exceed 0.195 (vol/vol).

Control samples contained A2780 and OM5O cells and no compound, and blank samples contained

ORM5O, but did not contain cells. MTT was dissolved at 5 mg/ml in PB5 (physiological solution with phosphate buffer).

A glycine buffer containing 0.1 M glycine and 0.1 M Mass was prepared, the pH of which was set at 10.5 using Mahon (1 M) (all reagents were from Merck). Human ovarian cancer cells A2780 (kindly provided by Dr. T.K. Hamilton (Roh Spaze Sapseg Sepige, Reppzuimapia, OBA)) were cultured in KRMI 1649 medium supplemented with 2 mM I-glutamine, 5 µg/ml gentamicin, and 1095 fetal bovine serum . Cells, as it should be, 7/0 were maintained as monolayer cultures at 372C in a humidified atmosphere with 595 CO content.

Once a week, the cells were pasteurized using a trypsin/EHUOTA solution at a cleavage ratio of 1:40. All media and additional drugs were obtained from I Me Tesppoiodiev. Cells were free of mycoplasma contamination as determined using the Sep-Rgore Musoriazta Tizzze Siyige kit (supplier: VioMegieh).

Cells were plated in MOMStm 9b cell culture plates (supplier: I Me Tesppoiodiev) and allowed to adhere to the plastic overnight. The seeding density was 1500 cells per cell in a total medium volume of 200 μl. After cell adhesion, the medium was changed, and drugs and/or solvents were added to the final volume of 200 μl. After incubation for four days, the medium was replaced with 200 μl of fresh medium, and cell density and viability were assessed using the MTT 2-based assay. 25 μl of MT solution was added to each cell, and these cells were subjected to additional incubation for 2 hours at 37 2C. Then this medium was carefully suctioned, and blue

The MTT-formazan product was solubilized by adding 25 μl of glycine buffer followed by the addition of 100 μl of HOM5O. These tablets were shaken for 10 minutes on a tablet shaker, and the optical density at a wavelength of 540 nm was measured using a 96-cell spectrophotometer Max (Etakh) (supplier: SM company Zoraspet). Within this experiment, the results for each experimental condition are averages with

From identical cells. For the purpose of primary screening, compounds were tested at one fixed concentration of 10-6 M. For active compounds, these experiments were repeated in order to obtain complete concentration-response curves. For each experiment, control experiments (in which drugs were absent) and blank incubations (in which cells or drugs were absent) were performed in parallel. Values for the blind experiment were subtracted from all control values and values for the tested samples. For each tested sample, the average value for cell growth (in optical density units) was expressed as a percentage of the average value for cell growth of the control samples. Corresponding IC 50 values (drug concentration required to decrease cell growth by 5095 relative to control samples) were calculated using probit analysis for the ranked data. IHippeu, O.)., Rgobii Apaiuzev, 274 Ei. Sparieg 10, Sgadei Kevropzez, Satgidde Opimegvyu Rgezv, Satrbgidde 19621. In this text, the effects of the tested compounds are expressed as riС 5o (negative logarithm - the value of ISO). Most of the compounds tested showed cellular activity at the test concentration of 10 M, and 12 compounds had an rC value of 5 (see Table E-2).

Example C.3: Kinetic solubility in aqueous media "

At the first stage of dilution, 1 μl of the concentrated stock solution of this active compound, C 70 solubilized in OM5O (5 mM), was added to 100 μl of phosphate-citrate buffer pH 7.4 and mixed. At the second stage of dilution, an aliquot amount (200 µl) of the solution of the first stage of dilution was additionally poured into 1000 µl of phosphate-citrate buffer pH 7.4 and mixed. Finally, at the third stage of dilution, the sample (20 µl) of the second stage of dilution was further diluted in 100 µl of phosphate of citrate buffer pH 7.4 and mixed. All dilutions were carried out in 9b-cell plates. Immediately after the last stage of 35 dilutions, the turbidity of the specified three successive stages of dilution was determined using a nephelometer. In order to exclude random errors, three dilutions were made for each compound. -I Based on turbidity measurements, these compounds were ranked into three categories. Compounds with high solubility received category C, and for these compounds the first dilution gives a clear solution. Compounds with medium solubility received category 2. For these compounds, the first dilution gives a cloudy solution , and the second

Ge") 50 dilution gives a clear solution. Compounds with low solubility were given category 1, and for these compounds both the first and second dilutions give a cloudy solution. The solubility of 11 compounds was measured. Of the specified

T» of the compounds were found to be Category C, two compounds were found to be Category 2, and three compounds were found to be Category 1 (see Table E-2).

Example C.4: Metabolic stability 25 Subcellular tissue preparations were made according to Soitai et al. (Hepobiosis 5: 453-462, 1975) by

HF) of centrifugal separation after mechanical tissue homogenization. The liver tissue was washed in ice-cold 0.1M Tris(Tgiv)-HCl buffer (pH 7.4) to wash away excess blood. The fabric was then blotted dry, weighed, and roughly cut using a . surgical scissors. Pieces of tissue were homogenized in 3 volumes of ice-cold 0.1 M phosphate buffer (pH 7.4) using a homogenizer or Rotseg-5 brand (Vgatsyp, 60 Nau), equipped with a Teflon pestle, or Zogmai! Otpi-Mich within 7 x1Os. In both cases, the vessel was kept on/on ice during the homogenization process.

Tissue homogenates were subjected to centrifugation at 9000 x 9 for 20 minutes at 42C using a Zogmaii centrifuge or a WesKtap ultracentrifuge. The resulting supernatant would be stored at -809С and designated as'"59.

Fraction 59 can be additionally centrifuged at 10,000O0x9 for 60 minutes (422) using a WesKtap ultracentrifuge. The resulting supernatant was carefully aspirated, divided into aliquots and designated as "cytosol". This tablet was re-suspended in 0.1 M phosphate buffer (pH 74) in a final volume of ml per 0.5 g of the original tissue weight and designated as "microsomes!".

All subcellular fractions were aliquoted, snap-frozen in liquid nitrogen, and stored at -802C until use.

For the tested samples, the incubation mixture contained РВ5 (0.1M), compound (5µM), microsomes (mg/ml) and

MAORN-generating system (0.8 mm of glucose-6-phosphate, 0.8 mm of magnesium chloride and 0.8 units of glucose-b-phosphate dehydrogenase). Controls contained the same material, but the microsomes were replaced with 70 heat-inactivated (10 minutes at 9523) microsomes. The recovery of the compounds in the control samples was 10096 in all cases.

These mixtures were pre-incubated for 5 minutes at 37 C. This reaction was started at the zero time point (1-0) by adding 0.8 mm MAOR, and the samples were incubated for 15 minutes ((-15).

The reaction was terminated by adding 2 volumes of OM5O. Then these samples were subjected to centrifugation for 75 10 minutes at 900x4, and the supernatants were stored at room temperature for no more than 24 hours before analysis. All incubations were performed twice. The analysis of the supernatants was carried out using the I C-M5 analysis.

Samples were eluted on a Hieita M5 C18 column (50X4, bmm, 5μm, Uu/aiegv, 05). A high-performance liquid chromatography system of the AlPapse 2790 type was used (supplier: UUay (eg, 05). Elution was carried out with buffer A (25 mM ammonium acetate (pH 5.2) in NaO/acetonitrile (95/5)), solvent B was acetonitrile, and solvent C methanol at a flow rate of 2.4 mL/min.A gradient was used to increase the concentration of the organic phase from 095 to 5090 V and 5095 C over 5 min and to 10095 V over 1 min in a linear fashion, and the concentration of the organic phase was held at steady state for another 1.5 minutes.

The total injection volume of the samples was 25 μl. An Otsaigo triple-quadrupole mass spectrometer (supplier: Misgotavz5, Mapspeviei, OK) with an ESI source was used as a detector. The source and desolvation CM temperatures were set at 120 and 3509C, respectively, and nitrogen was used as the atomizing and drying gas. Data collection was carried out by the method of positive scanning (reaction of a single charged ion). The cone voltage was set at 108 and the dwell time was 1s

Metabolic stability was expressed as 9% of the metabolism of this compound after 15 minutes of incubation in the presence of active microsomes. What are the honors that Zeus brought to us, and this Kezvnyu pushes us, and yours would be patabst, O VagalenenV, nie UK E o ANH va Bei o

Cheve Zhe 1 KYA

Compounds that had a metabolic percentage of less than 2095 were defined as having high metabolic persistence. Compounds that had a metabolism in the range of 20-70905 were defined as having an intermediate metabolic resistance, and compounds that showed a percentage of metabolism above 70 were defined as having a low metabolic resistance. When metabolic resistance screening was performed, three reference compounds were always included. Verapamil was included as a compound with low metabolic stability (96 metabolism - 73965). Cisapride was included as a compound with moderate metabolic resistance (90 metabolism - 4595), and propanol was included as a compound with intermediate - high metabolic resistance (2595 metabolism). The indicated reference compounds - c were used to confirm the reliability of the analysis of metabolic stability. Ten compounds were tested. Six compounds showed a metabolism of less than 20965, and four compounds had a metabolism of 20 to 70905. Example C.5: Ability to induce p21

The following protocol was used to determine the level of p21 protein expression in ovarian cancer cells

People A2780. A2780 cells (20,000 cells/18μl) were seeded in 96-microwell plates in medium -I KRMI 1640, to which 2mM I was added! -glutamine, 5 omkg/ml gentamicin and 1095 fetal bovine serum. 24 hours before the lysis of these cells, compounds were added at final concentrations of 10 79, 105, 1077 and 109M. All tested compounds were dissolved in OM5O, and further dilutions were made in the culture medium. 24 hours after the addition of this compound, the supernatants were separated from these cells. Cells were washed with 20 µl of ice-cold PB5. Cells were suctioned, and 30 ml of lysis buffer (50 mM Ttiv.HCII (pH 7.6), 150 mM Masi, 195 Mopidei p40 and 1095 glycerol) was added. Plates were incubated overnight at -70260.

HT" The appropriate number of microtitre plate cells was removed from the foil bag and placed in an empty cell holder. A working solution(s) of washing buffer was made (20x washing tablet concentrate: 1T00ml of a 20-fold concentrated solution of RVZ and a surface-active compound. Contains 290 chloroacetamide). The lyophilized p21uUMAB standard was reconstituted with distilled water and further diluted with the sample diluent (introduced in the kit). i) Samples were prepared by diluting them 1:4 in sample diluent. Samples (10µl) and p21MuAg1 co standards (10µl) were pipetted into the appropriate cells and incubated at room temperature for 2 hours. The cells were washed 3 times with their washing buffer, and then 700 μl of the reagent of the detector antibody (a solution of 60 biotinylated monoclonal antibody p21uuAE1) was pipetted into each cell. These cells were incubated at room temperature. temperature for 71 hours and then washed three times with their washing buffer. 400x conjugate (peroxidase streptavidin conjugate: 400-fold concentrated solution) was diluted, and 100 μl of their solution was added to these cells. These cells were incubated at room temperature for 30 minutes and then washed three times with 1 x washing buffer and once with distilled water. 65 substrate solution (chromogenic substrate) (10 Ωcl) was added to the cells, and these cells were incubated for 30 minutes in the dark at room temperature. The inhibitory solution was added to each cell in the same order as the previously added substrate solution. The optical density in each cell was measured using a spectrophotometric tablet reader at wavelengths of 450/595 nm.

For each experiment, control experiments (in which drugs were absent) and blank incubations (in which cells or drugs were absent) were performed in parallel. The values for the blank experiment were subtracted from all control values and values for the tested samples. For each tested sample, the values for the induction of p21 M/AE1 (in optical density units) were expressed as a percentage of the value for p21MuAN1 present in the control samples. A percentage of induction above 13095 was defined as significant induction. Eleven compounds were tested in this assay. All of them showed significant induction. iv 1 tvv11111vyav0110 in tm1vaya1z 2 t111tyayu0113 i 8113 sch 1 ta0011vt0011 o vm 11

O. An example of composing a composition: Tablets with a coating "I

Preparation of the pill core

A mixture of 100 g of the compound of formula (I), 570 g of lactose and 200 g of starch is thoroughly mixed and then moistened with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in approximately 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then add 100g of microcrystalline cellulose and 15g of hydrogenated vegetable oil. All substances are thoroughly mixed and pressed into tablets to obtain 10,000 -

335 tablets, each of which contains 10 mg of the compound of formula (1). uh-

Coating

A solution of 5 g of ethyl cellulose in 150 ml of dichloromethane is added to a solution of 10 g of methylcellulose in 75 ml of denatured ethanol. Then add 7/5 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The last solution is added to the previous one, and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colored suspension are added, and then all Pd is homogenized. The tablet cores are coated with the mixture obtained in this way in a coating apparatus.

Claims (1)

;" The formula of the invention -I 1. The compound of the formula (I) is what it is. still veni I o Se PN She sh ZU svevny VN su snuyuyu her Kar r: I am with you I SHYN; t Shk- З и Со и Же я я пе 5B its M-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms, where (Ф; І is equal to 0, 1, 2, З or 4, and when і is equal to 0, then mean a direct connection; each O represents nitrogen or i c. represents nitrogen or vezhov and v--i KE. and i - Benieya and d-e dk each 7 represents -MH-, -O- or -CH»o-; /5 V' represents A сС(О MV Zv7, -МНе(Ов" 0/-С(0)-Si valkandilev", /--MAZS(OMON 7, -НЕ8С(О)С. valkandiyl ВK 7, -"МАЗС(0О)С-М(ОНИВ 7 or another 7p-chelating group, where BZ and KE" are each independently selected from hydrogen, hydroxy, C. alkyl, hydroxyalkyl, aminoC. alkyl, or aminoaryl; VE'/ is hydrogen, C. 1-alkyl , C1 alkylcarbonyl, arylC1 alkyl, C1 alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl; EZ is hydrogen or C1 alkyl; 2 is hydrogen, hydroxy, amino, hydroxyC4 alkyl, C4 alkyl, C4 alkyl xy, aryls. alkyl, aminocarbonyl, hydroxycarbonyl, aminoS. alkyl, aminocarbonylS. alkyl, hydroxycarbonylC. valkyl, hydroxyaminocarbonyl, C. valkyloxycarbonyl, C. valkylaminos 4 valkyl or di(C. valkyl)laminosC. valkyl; --- is a bivalent radical selected from -ME. US(0)-, -MK9805- or -MVUSNo-, where BO represents the SM is hydrogen, C.alkyl, C.zocycloalkyl, hydroxyC-alkyl, C.alkyloxy/-alkyl or di(C-alkyl)amino/alkyl; d) I is a radical that is selected from p y h My V actions Ek SEETy sha . - gi ki IBK night zha NA E ge to nya I. I y. o i PV sha V ve o B still M i ek still not BM ke z t ha ' hr pro sg 2 ra uk shcha - Eesvenn so, tat her ze keV yah sohne IY iy U tri. tues s sia i sne zi I and s sat, : dk Se i. ek same Te CODEK i- Hey still and t TE | shchaisya Y Z « ns E EK and tact UK I eYa shen shdeti ES Tena, tre ressneti yav « mchn scho msa a ; they also: WRITE a ge SE ran - She Yaya Dey ESE y Hey eat Ol ur -i nya va Z Turnout zt y Ge za In her i i N ZH. 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I da ME - zu No: z I: av vi prosp nau still sips he Х Х YOU жа BV tya God, I am the same for her KYIAN ZAM - vo ysche A MOV ve Zh that El With them ZA dk 2 tu SCHE sta Ko 5 th She chor I OV t ia DJ; I Tu vka u KO ekon dl Pennee A BEK u pe dm V vk sho By I Skit, y KiyaU, r nya B FO zay as odu NEK chn nn VE a o szeya se ZHEO 0Oeh NK kuye sv pe okv s 5 where TE pa I'm a gentleman I - SEee, shi t i: I S vyav shuzayuh M How there are women Wholesale in Those 7 Hey; vovi shchi resai Z xx pi: um I Gaya dec Greek nenny let shsh gay sce AY z ks Kk pet en zhov pin sne: pd yazhe SYA y Me NK s - Bo OZ vk det I zle she sce y AEN per di po za yan light vya i 7 yav klem sus DK: tuz BEK zna Yatne, sy dov Sl SIGNS de Tu el v v yan Kom ih zn ja he ee ee ee De pn not as this sem Me pacte Ay td A, y eU R lya mi Mt pra re VE st E vysh | (5) ; Yasen skate ee i Sh g arose in Ann tin y yakity | ny nan VEK zo LU in mya ya sn z shcha ya OH shsh kva o Vid Ya ; and I Ba da" and her- and K s I Aeneas trembled and even V shchei y , i. Well: DY se pak lines from svy o niya Manta Mzher sote u se zart sk Z Vu Apple Oh Bas - appeared s i I Se Ж in the song about zoche sh y in y sa I moe hi wn SNYA pe Mavn loka h - ns entaskh i : her yan ON as M okisno KEE dyna ef Chek, I BIK. Mon MNK SHKty et Gvint et that x V di ya che et punk yno, mon nya to 4 Shk z oVaazhi ee pet I de sei Be se: in hr dec shn ban: sere se Ye ze ie ee ee ey SH sk Na s se ply Ese psa » z is her 7 se vksinmtya y-kh-g zi y-ya h z reno z t y vn. KE sny E ke I B svia her chu Kei and -I in jarediya rad i I and MBT I and Shk Murylkh I'm scared 1. I WISH YOU WERE TYAT KT DYA SVIA M Kk: I SH- sty vh v OV Mke NO Mneya SITAK yo zdovnoy nya Kon v vo" res ev, dress of NAAN spsnvayaru ische: life of dream nya not: ke Keynia Ten VN Sbke ekvsk Te" po JE x sleV y Zhyvy; ny se i God's sister | soche KI peneezr te Tu Ka YAK l- dere Mekiya ro and still I s yo Ken Z live MIE b 50 tm o BE. Hemik; Hey I Pernazhtya 7 Kynyati 7 Kern We Tnes iz-ya Y i ke y ; y a y si sze vkh kh yz" I know them they nevya shin VY res KE of 5 iketakh tov events Y o Z pri "y pe vne ve nah ven E Bonya. repo datvnogg t - z Gaya r, 25 EV Sh y t; I) v v det Vule Bru i ) for pk, lo se ne B srdynovy m GF) sei s ih Penya kih Y i ya Shrek 5 . UAH R chaky me ko) no V konyak k petee oi vra KV schivya I Z ia te M KE, Be A tia i ruku Vrs sov -ose slk i dikh i Shock dnk t shen Shi erneAnvno - nk eh she ЩХХ ІЧ field Х sn pre tya iz KE bo izh son Kei y y se same ne p y ee o: DYA sk peni 4 TE SCHO r Ks dyk nyu And still what se s, IV ЖЖ Я чно ве Ве ват Же - е I, DKVvkw sa бы КТЯЕТЕ postha Shuyeroe vosckse rok an i. t EE their ia Is a. 6BE - х - b nition rn i iz i che z zekrrk r Ann v BE I z M. svv V where ZENYE od st vah OEM Dacha village. ge oz ti d ke shcha Me uchi: p. Ho van ge Mk: NI lo higher VYSH j shy pyv en Zenyk kn ruta ek pen Ne Ya yah ; M la NK I smoke hshyudya | zak Ya a y K- tvoy yiv ka schy Kn: Ya en Ж KE Be Y -U y Z: vla zh sh that shk ze ke punk gyurr Beka rYai tia YAK eta ZyKN. indy Be ED no t oh for I NY ra i slo M i OO ny that Beh zeorakeE 15. ( ЖЩ вени с ЯЙ дзи se жк "Женрей Енянта, и: хи пачай секту Шений" as SHE ЧНХХ a B: ож" IN SI Sovki NI ni SHE ss Y M shi 5 Chsch chih, s cm Nekozy removed s NE I OO I z y i ka xen Zhe sha Kai B Kostya Ke a LEN sr theo B 0 POBODNOYU t Bach sve sce Aeneas Lev sce MK in Gv I they re B EH pechene s Yab sce jaye VEU YOU Y nu y ve TU sov DN R y go z: Shiya penya skeesnAh she Seh te ne plyne ble ХХ same stump essay KV - bye Met ik! no and Because soulaya Shonty E is Is Chi I«o) s he I I m g y on this J y How KU still I gy with - them What is in I where NYA y What I dec i x svy naya jye NE oy Y maki vay « De udo ve I Shk nih VE Sv kyavty Zhe sv roya : iya s IT. and: M S nave uno, and I. A EHENNY pebtnanya U s; y 5 sti I I "» Shi Kek he I svshen en I still re KE J Tok i se pE-YInNK ek MU pe -I cho Ky ko where each z is equal, independently, to 0, 1, 2, 3,4 or 5; F 20 each BK? or 25 is independently selected from hydrogen; halo; hydroxy; amino; nitro; trihalo /4 alkyl; trihaloC,. alkyloxy; C alkyl; Sialkyl, substituted with aryl and C 20 cycloalkyl; C. alkyloxy; t» C . valkyloxyC and valkyloxy; C. valkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; cyanos. valkyl; hydroxyC 4.valkyl; hydroxyC- valkyloxy; hydroxyC- valkylamino; aminosC. valkyloxy; di(C- valkyl)aminocarbonyl; di(hydroxy 4 alkyl)amino; (arylC. alkyl)amino; di(C4 alkyl)amino 4 alkyloxy; 22 di(C4 alkyl)aminoC 41 alkylamino; di(C4 alkyl)amino 4 alkylamino 4 alkyl; arylsulfonyl; F! arylsulfonylamino; aryloxy; aryloxyC . alkyl; aryleo. valkenediyl; (aryl(C. alkyl)amino; yuyu (aryl(C.. alkyl)amino 4 alkyl; di(C. alkyl)amino(C 4 alkyl)amino 4 alkyl; di(C- alkyl) )aminos 4 valkyl (S. valkyl)amino; d and (C- alkyl)aminosC 4 alkyl (C. alkyl)aminos 4 alkyl; aminosulfonylamino(C 4 alkyl)iamino; aminosulfonylamino(C. alkyl)aminos 4 alkyl; 60 di(C-alkyl)aminosulfonylamino(C 4 alkyl)amino; di(C.- valkylluaminosulfonylamino(C 4 alkyl)amino 4 alkyl; iano; thiophenyl; thiophenyl, substituted by di(C alkyl)amino 4 alkyl(C . alkyl)amino 4 alkyl, 1-6 1-6 1-6 1- 6 di(C-.alkyl)amino 4 alkyl, C. alkylpiperazinyl 4 alkyl, hydroxyC. alkylpiperazinyl 4 alkyl, hydroxyC 4 alkyloxyS in alkylpiperazinyl 4 alkyl, di(C. alkyl)aminosulfonylpiperazinyl 4 alkyl, Su valkyloxypiperidinyl, C. alkyloxypiperidinyl , morpholinyl, alkyl, because hydroxyC 4 alkyl(C. alkyl)aminoC alkyl, or di(hydroxyC 4 alkyl)uaminoC alkyl; furanyl; furanyl, substituted by hydroxyC-valkyl; benzofuranil; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C 1 alkyl; S. valkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinyl C. valkyloxy; morpholinil; Si alkylmorpholinyl; morpholinyl valkyloxy; morpholinyl valkyl; morpholinyls. valkylamino; MmorpholinylC valkylaminoC. valkyla; piperazinil; S. valkylpiperazinil; C. valkylpiperazinyl in valkyloxy; piperazinilC. valkyla; naphthalenylsulfonylpiperazinyl; naphthalenylsulfonylpiperidinyl, naphthalenylsulfonyl; C. valkylpiperazinils 4 valkyl; S. valkylpiperazinilC in valkylamino; C) valkylpiperazinyl 4 valkylaminosC. valkyla; Si alkylpiperazinylsulfonyl; aminosulfonylpiperazinyl - valkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC. valkyla; 7/0 VKKS. alkyl)aminosulfonylpiperazinyl; di(C-alkyl)aminosulfonylpiperazinyl 4 alkyl; hydroxyC 4 valkylpiperazinyl; hydroxyS. alkylpiperazinyl 4 alkyl; S. valkyloxypiperidinyl; C) alkyloxypiperidinylC and alkyl; piperidinylaminos. valkylamino; piperidinylaminos. Valkylaminos. valkyla; (Si alkylpiperidinyl)y(hydroxy 4 alkyl)amino 4 alkylamino; (C. valkylpiperidinyl)(hydroxy 4 valkyl)amino 4 valkylaminos and valkyl; 7/5 PidroxyS /. valkyloxy valkylpiperazinil; hydroxyS. valkyloxyS and valkylpiperazinils /.valkylu; (hydroxyC 4 alkyl) (C. alkyl) amino; (hydroxy. valkyl)/S. valkyl)aminosS. valkyla; hydroxyS 4 valkylaminos valkyl; di(hydroxy and alkyl)amino 4 alkyl; pyrrolidinylS. valkyla; pyrrolidinyl 4 alkyloxy; prasolil; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C-alkyl or trihalosC. valkyla; pyridinyl; pyridinyl substituted with C. valkyloxy, aryloxy or aryl; Pyrimidinil; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC. valkyla; quinolinyl; Indole; phenyl; phenyl substituted with one, two, or three substituents independently selected from halo, amino, nitro, C alkyl, C alkyloxy, hydroxyC. lalkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC 4. lalkyloxy, C. lalkylsulfonyl, C. lalkyloxys u. lalkyloxy, S. dalkyloxycarbonyl, aminosS. dalalkyloxy, di(C4 alkyl)amino 4. alkyloxy, di(C-alkyl)amino, di(C.alkyl)aminocarbonyl, sch ov DI(C-alkyl)amino /.dalkylu, di(C4 alkyl)amino 4. dalalkylamino 4 alkyl, di(C-.alkyl)amino(C 4 alkyl)amino, di(C4.alkyl amino(C..alkyl)aminos 4 alkyl, di(C-.alkyl)amino 4 alkyl(C.alkyl)amino , i) di(Ci dalalkyl)amino 4 dalalkyl(C. 1alkyl)amino 4.dalalkyl, aminosulfonylamino(C..alkyl)amino, aminosulfonylamino(C. cC 4 dalalkyl)amino, di(C-.dalkyl)aminosulfonylamino(cC 4.lalkyl)aminos 4 dalkylu, cyano, piperidinylC. lalkyloxy, «g Zo Pyrrolidinils /u.dalkyloxy, aminosulfonylpiperazinyl aminosulfonylpiperazinyl. lalkyl, di(Si dalalkyl)uaminosulfonylpiperazinyl, di(C- dalalkyl)iaminosulfonylpiperazinyl 4 dalalkyl, ise) hydroxyS 4. lalkylpiperazinil, hydroxyS. dalkylpiperazinyl C. lalkylu, C. lalkyloxypiperidinyl, c C) dalkyloxypiperidinyl 4. dalkylu, hydroxy. dalalkyloxyS and dalalkylpiperazinyl, hydroxyS 4. lalalkyloxyS dalalkylpiperazinyl 4 dalalkyl, (hydroxyS. lalkyl(C. dalalkyl)amino, - Zv (hydroxyS 4. dalkylu(C. dalalkyl) aminos 4. alkylyl, hydroxys. dalylaminosS and dalalkyl, eat( hydroxy 4 dalalkyl)aminoC in allyl, furanyl, furanyl substituted -"SNASN-SNASN-, pyrrolidinylOS. allyl, pyrrolidinyl 4 dalalkyloxy, morpholinyl, morpholinyl. allyloxy, morpholinyls. allyl, morpholinyl 4.allkylamino, morpholinyl. allylaminos and dalalkyl, piperazinyl , /C..4alkylpiperazinyl, C) dalalkylpiperazinyl 4 lalalkyloxy, piperazinyl C. dalalkyl, C. dalalkylpiperazinyl 4 dalalkyl, « C. dalalkylpiperazinyl C in dalalkylamino, C.. dalalkylpiperazinyl .« alkylamino C.. alkyl, pyrimidinylpiperazinyl, She) with pyrimidinylpiperazinyl lalalkyl, piperidinylaminos. dalkylamino, piperidinylaminos. lalkilaminosS and dalkilom, . (Si dalalkylpiperidinyl)u(hydroxy 4 dalalkyl)amino 4.lalkylamino, and (Si dalalkylpiperidinyl(hydroxy 4.lalkyl)aminosC 4 lalkylaminosC u dalkylom, pyridinyl. dalalkyloxy, hydroxysC 4 dalkylamino, di(hydroxyS. dalkyl)amino, di(C .- alkyl)amino 4.alkylamino, aminothiadiazolyl, aminosulfonylpiperazinyls 4 dalalkyloxy or thiophenylC.dalkylamino; -And each BE and K9 can be placed on nitrogen to replace hydrogen; the above aryl is phenyl, or phenyl substituted with one or more substituents , each of which is chosen independently from the halo, 7 C. alkyl, C-.alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl. ko 2. The compound according to claim 1, which differs in that each eEZ and B? is independently selected from hydrogen, hydroxy, b50 hydroxyC..alkyl, aminoC..alkyl or aminoaryl; is a radical selected from (а-1), (а-2), (а-3), (а-4), (а-5), (а-6), (а-7), Genes (a-8), "(a-9), (a-10), (a-11), "(a-12), (a-13), (a-14), (a-15) , (а-16), (а-17), (а-18), (а-19), (а-20), (а-21), (а-22), (а-23), ( a-24), (a-25), (a-26), (a-27), (a-28). (а-29), (а-30), (а-31), (а-32), (а-33), (а-34), (F. (а-35), (а-36), (а-37), (а-38), (а-39), (а-40), (а-41), (а-42) , (a-43) or (a-44), where each B? or c is independently selected from hydrogen, halo, hydroxy, amino, trihaloC 4 alkyl; trihaloC, valkyloxy; C. valkyl; C. valkyloxy; C. valkyloxyC and valkyloxy; C. valkylcarbonyl; bo C-alkylsulfonyl; cyanosC. valkyl; hydroxyC. valkyl; hydroxyC. valkyloxy; hydroxyC. valkylamino; amino). valkyloxy; di(C..alkyl)aminocarbonyl; di(hydroxyC 4 alkyl)amino; aryl(C.alkyl)amino; di(C4 alkyl)amino 4 alkyloxy; di(C-.alkyl)amino 4 alkylamino; arylsulfonyl; aryloxy; arylC» valkenediyl; di(C4 alkyl)amino; di(C-.alkyl)amino 4 alkyl; di(C-.alkyl)aminos 4 alkyl(C.alkyl)amino C.alkyl; cyano; thiophenyl; 65 thiophenyl substituted by di(C. valkyl)aminoS 4 valkyl(C. valkyl)aminoC. by valkyl, di(S. valkyl)aminoS. with a roller, C. alkylpiperazinyl 4 alkyl or di(hydroxyC. alkyl) amino 4 alkyl; furanil; imidazolyl; Su valkyltriazolyl; tetrazolyl; pyrrolidinyl; piperidinyl C. valkyloxy; morpholinil; C. valkylmorpholinyl; morpholinilS. valkyloxy; morpholinilS. valkyla; S. valkylpiperazinil; Su valkylpiperazinylC 4 valkyloxy; C) alkylpiperazinyl 4 alkyl; S. valkylpiperazinylsulfonyl; aminosulfonylpiperazinyls. valkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC. valkyla; di(C 1 alkyl)aminosulfonylpiperazinyl; di(C-alkyl)aminosulfonylpiperazinyl 4 alkyl; hydroxyC 4 valkylpiperazinyl; hydroxyS. alkylpiperazinyl 4 alkyl; S. valkyloxypiperidinyl; C) alkyloxypiperidinyl 4 alkyl; hydroxyC. valkyloxys in valkylpiperazinyl; hydroxyS 4 alkyloxyS valkylpiperazinyls 4 alkyl; (hydroxyC.-alkyl(C.alkyl)amino; 70 (hydroxyC /.alkylC.-alkyl)aminoC.alkyloxy; pyrrolidinylC.alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C.6alkyl or trihalosC. alkyl; pyridinyl; pyridinyl substituted with C. alkyloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, C.4.alkyl, C.. valkyloxy, hydroxyC dalalkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC-lalalkyloxy, Su dalalkyloxysC and dalalkyloxy, /5 aminosC. dalalkyloxy di(C4 lalkyl)amino 4. alkyloxy, di(C4 lalkyl)amino, di(C-.4alkyl)amino and dalalkyl , di(C-.dalkyl)amino 4-alkyl(C.lalkyl)amino 4.alkyl, piperidinylO.dalkyloxy, pyrrolidinyl.lalkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC.alkyl, di(C.i dalkyl)aminosulfonylpiperazinyl, di(C-.dalkyl )aminosulfonylpiperazinyl 4 lalkyl, hydroxy.lalkylpiperazinyl, hydroxyC 4. lalkylpiperazinils and dalkylu, S. lalkyloxypiperidinil, S. dalkyloxypiperidinils and dalkyl, 2o HydroxysS i.lalkyloxyS .dalkylpiperazinyl, hydroxy. dalalkyloxyS .alkylpiperazinyl /.dalalkyl, (hydroxyC 4.lalkyl in dalalkyl)amino, (hydroxyC. lalkyl)(C. lalkyl)aminos in dalalkyl, pyrrolidinyl. lalalkyloxy, morpholinylC and alkyloxy, morpholinylC. dalkylu, C. lalkylpiperazinyl, C. dalkylpiperazinyl 4 lalkyloxy, C. dalkylpiperazinils 4 lalkyl, hydroxyS. dalkylamipo, di(hydroxy.lalkyl)amino, di(C.4.alkyl)aminosC 4.alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylO dalalkyloxy or sch ov thiophenyls dalkylamino. C. The compound according to claim 1, where и is equal to 0, which differs in that (8) B' represents -С(О)МК ZVU, -С(0)-С.4 valkandiylАВ", -МАЗС(ОМОНВ ", - MAZS(O)C. valkandiile B 7, -MVZS(O)C-M(OH)B or another 7p-chelating group, where BO and B" are each independently selected from hydrogen, hydroxy, hydroxyC-. valkyl or aminos..alkyl; B? represents hydrogen, hydroxy, amino, hydroxy/alkyl, "And C. alkyl, Sialkyloxy, arylC.alkyl, aminocarbonyl, aminoC.alkyl, SualkylaminoSuialkyl or "so di(C--alkyl)amino 4.alkyl; -I - is a bivalent radical selected from -МНО(О)- or -МНБЗО»-; is a radical selected from (а-1), (а-3), (а-4), (а-5), (а-6), (а-7), (а-8), с Vk GA - dk - (а-9), (а-10), (а-11), (а-12), (а-13), (а-143, (а-153), (а-16 ), (а-17), (а-18), (а-19), (а-20), (а-21), (а-22), (а-23), (а-24), (а-25), (а-26), (а-28), (а-29), (а-30), (а-31), (а-32), (а-33), (а -34), (а-35), (а-36), (а-37), (а-38), (а-39), (а-40), (а-41), (а-42 ), (а-44), (а-45), (а-46), (а-47), (а-48) or (а-51); " each of is equal, independently, to 0, 1, 2 - with C. valkyloxy; C 1 alkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; hydroxyC; valkyl; aryloxy; "» di(C--alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted by hydroxyC-alkyl; benzofuranyl; imidazolyl; " oxazolyl; oxazolyl substituted with aryl and C..alkyl; C. valkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinil; Su alkylmorpholinyl; piperazinil; Su valkylpiperazinil; hydroxyS. valkylpiperazinil; C. valkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from - C 1 alkyl or trihaloC. valkyla; pyridinyl; pyridinyl substituted with C. valkyloxy, aryloxy or aryl; - pyrimidinyl; quinolinyl; indole; phenyl or phenyl substituted with one or two substituents independently selected from halo, S. valkilu, Si. alkyloxy or trifluoromethyl; where and 297 is hydrogen; halo; hydroxy; amino; nitro; trihaloC 4 valkyl; trihaloS. valkyloxy; S. valkil; He" 20 C. valkyloxy; C 1 alkylcarbonyl; C. valkyloxycarbonyl; C. valkylsulfonyl; hydroxyC-alkyl; aryloxy; Their di(C-valkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C 1 -alkyl, C 1 -alkyloxy or trifluoromethyl. 4. The compound according to claims 1 and 2, where i is equal to 0 or 1, which differs in that each C) represents v and each X represents nitrogen; B / is a set and co M u dO Yak bo -СЩСХСОМН(ОН); 22 is hydrogen, hydroxy, C 4 alkyl or arylC. valkyl; -I- is a bivalent radical selected from -МНО(О)- or -МНЗО»-; is a radical selected from (a-1) or (a-20); b5 and each of is equal, independently, to 0 or 1; and each B? is selected, independently, from hydrogen or phenyl. 5. The compound according to claims 1, 2 and 4, where Her is equal to 1, which differs in that each O is a wild and each X is a nitrogen; each U is nitrogen; each 7 si and nii Ah 70 represents -O- or -СН»-; B is -C(O)MH(OH); IN? is hydrogen; -I - is a bivalent radical selected from -МНС(О)- or -МНЗО"; z izzhny is a radical selected from (а-1) or (а-20); each of is equal, independently, to 0 sya g. as, in li y t dah sha or 1; and each 5 is independently selected from hydrogen or phenyl. 6. The compound according to claims 1, 2, 4 and 5, which differs in that it is selected from the compounds numbered Mo4, Mo10, Mo8, Mob, Mo1, Mo12 and Mo14. as shi se Psgu shen BOB i desni ОЖВЕЭХ o se ZNO en i "I y (Se) Zo ev vyh dey shii eh yin Eh ya v. - E esh Me Geya sit ss : - is ch wah y t T she ko ze kroni y ini -i ze ey STILL TIRE. ONE Be VVE, pe i UYU V di shi sya Sv ho y S se pi 5 sia i i. vi. koh b 50 De I” (V); So.Mo.1 re She These days TC and where do you take Mr (F. more G ii what y Yake not to graze nai ko oi Or 0oenya y, y І Хе "B sajeyu 0 pebeaya y 4, І Kosa V nya same. kny not і sh So.Mo.14 b5 -BO0- Vr Kay y: s td I shch EMLYU. pesharnykh seYshchye mo - in so En Be oz KE och what and M ia de Ya So.Mo.10 still thin ke Nkosiya V TK ki Kann I im KO sk mya Kt goth znyrh "byh von gorkvya bya o b o" CHA Sho y shi what s Y o yiv o y . . - - t - what train | Yi shi o she ya (Se) E ste. Well done to her! m (A); So.Mo.12 and - - and? nn 7. Pharmaceutical composition containing pharmaceutically suitable carriers and as an active ingredient - a therapeutically effective amount of the compound according to claims 1-6. GI 8. The method of obtaining the pharmaceutical composition according to claim 7, where pharmaceutically acceptable carriers and the compound according to claims 1-6 are thoroughly mixed. Me 9. A compound according to any one of claims 1-6 for use as a medicine. 10. Use of the compound according to any of claims 1-6 for the production of medicines for the treatment of proliferative diseases. 11. The method of obtaining the compound according to claim 1, which is characterized by the fact that the intermediate compound of the formula (II) is subjected to a 5B reaction with a suitable acid, such as, for example, trifluoroacetic acid, to obtain the hydroxamic acid of the formula (I-a), where KE! is -С(О)МН(ОН) име) 60 b5 ах 5. ak I khz shk I dek le and maples Live viv MNYH TSI Shev PEK EE Yuty zha i yah z au i zer - de ALSO. ACTS I Yake ie her yh tr N Ids non nt cones pa ve I. Ye and shk re Ve y y Malu y mate Щ Mesy "y her, in B YAEK Ah I zake shi ro у vok TONY boty E You esrnyat SONS . What do you think about Kn s and I? 12. The method of detection or identification of SPOA in a biological sample, which includes detection or determination of the formation of a complex between the labeled compound according to claim 1 and SPOA. with 13. The combination of an anticancer agent and an ASAO inhibitor according to any one of claims 1-6. d) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 11, 15.11.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - (Se) with u and - - and? -i -i ime) (o) s» ime) 60 b5