UA80743C2 - Dihydropteridinones, method for the production and use thereof in the form of drugs - Google Patents

Abstract

The invention relates to novel dihydropteridinones of general formula (I), , (I) wherein residues L, R1-R5 have the meaning defined in claims and a specification, isomers thereof, a method for producing and using said dihydropteridinones in the form of drugs.

Description

Description of the invention

This invention relates to new dihydropteridinones of the general formula (I) () duty

F | in nm tm and in t

FO,

Ge)in |y - t in which the residues I, B", 2, 23, 27 and VE? have the meanings indicated in the formula of the invention and in the description, their isomers, the method of obtaining these dihydropteridinones, as well as their use as medicinal products.

Derivatives of pteridinones are known from the prior art as active substances with antiproliferative effects. So, in particular, (in MO application 01/019825) the use of pteridinon derivatives for the treatment of oncological and viral diseases is described. The persistence of many types of tumors necessitates the development and creation of new highly effective anticancer drugs. Based on the above, this invention was based on the task of obtaining new compounds that have anti-inflammatory and anti-proliferative effects. Go)

During the creation of the invention, it was found that the compounds of the general formula (I), in which the residues I and B 7-69 have the following values, unexpectedly show effectiveness as inhibitors of special kinases involved in the regulation of the cell cycle. Thanks to this, the compounds proposed in the invention can be used, for example, for the treatment of diseases that are one way or another associated with the activity of specific kinases involved in the regulation of the cell cycle, and which are characterized by excessive or abnormal cell proliferation. "AND

Accordingly, the present invention relates to compounds of the general formula (I) im () | "c) m M. iv) (ee)

Di in nm M M B in B «

F, - s o yin . » p G 5 i t" (ee) in which («c) 1 2 . . BUT - ' I - .

КЕ" and К- have identical or different values and mean hydrogen or optionally substituted C.--Svalkyl or - and B" and B2 together form a 2-5-membered alkyl bridge, which may contain 1-2 heteroatoms, their 20 BZ is hydrogen or a residue selected from the group consisting of optionally substituted C 1 -C 1 alkyl, C 1 -C 2 alkenyl, C 2 -C 6 alkyl and C 6 -Cidaryl, or a residue selected from the group consisting optionally substituted and/or bridged

C3-C.ocycloalkyl, C3-C4ocycloalkenyl, C-C4polycycloalkyl, C-C/polycycloalkenyl, C-C.ospirocycloalkyl,

C3-C.heterocycloalkyl containing 1-2 heteroatoms and C3-C4heterocycloalkenyl containing 1-2 heteroatoms, b or

GF) B' and Z or B? and KZ together form a saturated or unsaturated Ca-Alalkyl bridge, which can contain 1 heteroatom,

ВЕ" is a residue selected from the group consisting of hydrogen, -СМ, a hydroxy group, -МК 6К;, and a halogen, vo or a residue selected from the group consisting of optionally substituted Co 4-Salkyl, Co- swalkenil,

Co-Svalkynyl, S.-Svalkyloxy group, Co-Svalkenyloxy group, Co-Svalkynyloxy group, S.-Svalkylthio group,

C.4-Salkylsulfox group and C.-Salkylsulfonyl,

It is a linker selected from the group consisting of optionally substituted Co5-Siralalkyl, VeCo-Siralkenyl, Ce-Si4aryl, -Co-C6alkyl-Se-Sdaryl, -Cb-Silaryl-C.1- Subalkyl, optionally connected by a C3-C12 cycloalkyl bridge and heteroaryl containing 1 or 2 nitrogen atoms,

n means 0 or 1, t means 1 or 2,

WO is a residue selected from the group that includes optionally substituted morpholinyl, piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, KZ. diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -ME 82 and azacycloheptyl, 2? and B" have identical or different meanings and mean hydrogen or S.-Sualkil, and

VZ and B? are unsubstituted nitrogen substituents at BK 9, have identical or different values and mean either hydrogen or a residue selected from the group that includes (C . Ce-Siaryl, -Si4-C, alkyl-Se-Sidaryl, pyranyl, pyridinyl, pyrimidinyl, Si-C; alkyloxycarbonyl, Ce-C-4arylcarbonyl-, C.-C.alkylcarbonyl-, Ce-Si4arylmethyloxycarbonyl-,

Ce-Si4arylsulfonyl-, Ci-C; alkylsulfonyl- and Co-Silaryl-C-C; alkylsulfonyl-, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in in the form of their pharmacologically acceptable acid addition salts. Those compounds 19 of formula (I) are best, where

B!-K7, B5 and KE" have the above values, and

Y is a linker selected from the group consisting of optionally substituted Co 5 -Cyralalkyl,

Co-Syralkenyl, Se-Ci4aryl, -Co-C;alkyl-Ce-Sdaryl, -Cb-Silaryl-C.1-Sulalkyl, optionally bridged C3-C42cycloalkyl and heteroaryl containing 1 or 2 nitrogen atoms, n means 1, t means 1 or 2,

VE? represents a residue connected to I. through a nitrogen atom selected from the group that includes optionally substituted morpholinyl, piperidinyl, E8-piperazinyl, pyrrolidinyl, tropenyl, KZ. diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -MEZEZ and azacycloheptyl,

BZ and KO represent unsubstituted nitrogen substituents at K 9, have identical or different values, and o means hydrogen or a residue selected from the group that includes C.-Salkyl, -C.sub.4-C.alkyl-C.sub.3-Siocycloalkyl,

C3-Cocycloalkyl, C4-C4aryl, - C3-C4alkyl-C6-C4aryl, pyranyl, pyridinyl, pyrimidinyl, C4i-C,alkyloxycarbonyl,

Ce-Ci4arylcarbonyl-, C.-C.alkylcarbonyl-, Ce-Ci4arylmethyloxycarbonyl-, Ce-Sildarylsulfonyl-, "U C41-Slalkylsulfonyl- and Co-Silaryl-C4-C; alkylsulfonyl-, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts. The compounds of formula (I) where o

B!-K7, B5 and KE" have the above values, and

It is a linker selected from the group that includes optionally substituted Co 5-Siralalkyl, d)

Co-Syralkenyl, Se-Ci4aryl, -Co-C;alkyl-Ce-Sdaryl, -Cb-Silaryl-C.1-Sulalkyl, optionally bridged C3-C42cycloalkyl and heteroaryl containing 1 or 2 nitrogen atoms, n means 0 or 1, "t means 1 or 2,

VO is related to | through a carbon atom, a residue selected from the group that includes 3 c БЕ8-piperidinyl-, КЗВЗ-piperazinyl-, КЗ-pyrrolidinyl, КЗ- piperazinylcarbonyl -, КЗ-tropenyl, КЗ-morpholinyl and :3» Б8-azabicycloheptyl, and

VZ and B? represent unsubstituted nitrogen substituents at B 9, have identical or different values and mean hydrogen or a residue selected from the group that includes C.4-Salkyl, -C4-C;alkyl-C3-Ciocycloalkyl, o C3-Cocycloalkyl, Ce -Si4aryl, -Sb.-C/alkyl-Cv-Silaryl, pyranyl, pyridinyl, pyrimidinyl,

C.-C.alkyloxycarbonyl, C.-C.arylcarbonyl-, C.-C.alkylcarbonyl-, C.-C.4arylmethyloxycarbonyl-, o C.-C.4arylsulfonyl-, C.-Slalkylsulfonyl- and C.-C.4aryl-C.-Slalkylsulfonyl-, - neob' necessarily in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts. Those compounds of the formula (I) where I, t, p and K 3-K9 have the values indicated above, c» and 2! and B? have the same or different values and represent a residue selected from the group consisting of hydrogen, Me, EI, Pg or VE! and 22 together form a C0-C alkyl bridge, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts. o The most preferred are those compounds of formula (I), where

B", B, t, n and EZ-E8 have the above values, and where BZ is a residue selected from the group consisting of optionally substituted Co/4-Sralkyl,

C.-C,cycloalkyl, C3-Csheterocycloalkyl and C6-Sudaryl, or 60 B and BZ or in? and KZ together form a saturated or unsaturated Ca-Slalkyl bridge, which may contain 1-2 heteroatoms, B is a residue selected from the group that includes hydrogen,

OMe, OH, Me, E., Rg, OEI, MNMe, MH», RE, SI, Vg, O-propargyl, O-butynyl, CM, ZMe, MMe», SOMN», ethynyl, propynyl, butynyl and allyl, and 65 Y is a linker selected from the group that includes optionally substituted phenyl, phenylmethyl, cyclohexyl, and branched C.-alkyl, optionally in the form of their tautomers, their racemates, their enantiomers,

their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts.

Another object of the invention are compounds of formula (I) for their use as medicinal products.

Particular importance according to the invention is given to the compounds of formula (I) for their use as medicinal products with antiproliferative action.

Another object of the invention is the use of the compound of formula (I) for the preparation of a medicinal product intended for the treatment and/or prevention of cancer, infectious, inflammatory and autoimmune diseases.

Another object of the invention is a method of treatment and/or prevention of cancer, infectious, inflammatory and/or autoimmune diseases, which differs in that the patient is administered an effective amount of the compound of the formula (I.

Another object of the invention are pharmaceutical compositions containing as an active substance one or more compounds of the general formula (I) or its (their) physiologically compatible salts, if necessary in combination with usual auxiliary substances and/or carriers.

Another object of the invention is a method of obtaining a compound of the general formula (I) () we M o

A De ni M M 1, k- Way

FU o iy s » R o

Um in which V!-VU, t, n and | have the above-mentioned values, which differ in that the compound of the general formula со (I) « (З у

We are M o o

AJ ru; и и ке со in which К 1-23 have the values indicated above, and A means a leaving group, are subjected to interaction with an "optionally substituted compound of the general formula (III) with c (1) n МН, "" in" (p), (ee) o otv" 7 5 ri : 10 5 : : in which K" has the above values, and KU is the group OH, МН-И-К 9,- O-methyl, -O-ethyl , and then it is, under certain conditions, the product of the general formula (IM) m u | (M) me M (o)

A - in nu M M in? o and v ah name) 60 Ge) in which K!-K7 have the above values, and K 79 represents the group OH, -MH-I-2K5, -O-methyl or -O-ethyl, when necessary after preliminary hydrolysis of the ester group -SOK 10. are subjected to interaction with amine 65 of the general formula (M)

AND

Mn -yu (Uh in which E? has the above values.

Another object of the invention is the compound of formula (II) (1)

J IV,

A Me and their HB) in which K!-EZ have the above values, and A means a leaving group. 19 Alkyl groups individually and as fragments of other residues mean branched and unbranched alkyl groups containing from 1 to 12 carbon atoms, preferably 1-6, especially preferably 1-4 carbon atoms, for example, methyl, ethyl, propyl, butyl , pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl. The residues mentioned above, which include propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and dodecyl, also mean, unless otherwise specified, all their possible isomeric forms. So, for example, the concept of "propyl" includes both isomeric residues n-propyl and isopropyl, the concept of "butyl" includes i-butyl, isobutyl, sec-butyp and tert-butyl, the concept of "pentyl" includes isopentyl, neopentyl, etc.

In the aforementioned alkyl groups, one or more hydrogen atoms can be replaced by other residues under certain conditions. So, for example, these alkyl groups can be replaced by fluorine atoms. Under certain conditions, it is also possible to replace all hydrogen atoms of the alkyl group. with

The term "alkyl bridge" means, unless otherwise specified, branched or unbranched alkyl groups, Ge) containing 1-5 carbon atoms, for example, methylene, ethylene, propylene, isopropylene, n-butylene, isobutyl, sec-butyl, tert- butyl and similar bridges. Especially preferred are methylene, ethylene, propylene and butylene bridges. In the mentioned alkyl bridges, 1-2 C-atoms can under certain conditions be replaced by one or more heteroatoms selected from the group including oxygen, nitrogen and sulfur. at

By alkenyl groups (including those cases when these groups are components of other residues) are meant branched or unbranched alkenyl groups containing from 2 to 10 carbon atoms, preferably from 2 to b, especially preferably 2-3 carbon atoms , provided they have at least one double bond. Examples include ethenyl, propenyl, butenyl, pentenyl, etc. Unless otherwise indicated, from the number ("3 above-mentioned concepts propenyl, butenyl, etc. include all possible isomeric forms. So, for example, the concept

zo "butenyl" includes 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 1-ethyl-1-ethenyl.

In the aforementioned alkenyl groups, unless otherwise indicated, one or more hydrogen atoms may be substituted for other residues under certain conditions. So, for example, these alkenyl groups can be replaced by halogen fluorine atoms. Under certain conditions, it is also possible to replace all hydrogen atoms of the alkenyl group. - 70 By alkynyl groups (including those cases when these groups are components of other residues) are meant branched or unbranched alkynyl groups containing from 2 to 10 carbon atoms, provided that they have at least one triple bond connection, as an example can be called ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc., the best of them are ethynyl and propynyl.

In the aforementioned alkynyl groups, unless otherwise indicated, one or more hydrogen atoms may be substituted for other residues under certain conditions. So, for example, these alkynyl groups can be replaced by fluorine atoms. со Under certain conditions, it is also possible to replace all hydrogen atoms of the alkynyl group. aw! The term "aryl" means an aromatic ring system containing from 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise specified, may bear, for example, one or more

of the following substituents: group OH, MO», CM, -«OSNE», -OSRE»z, -MH»o, halogen, better fluorine or chlorine, C.4-Sralkyl, "" 20 better C.-Svalkyl, more preferably C-C alkyl, especially preferably methyl or ethyl, -O-C4i-C alkyl, preferably -O-methyl or si -O-ethyl, group -soon, -b00-C.-C/alkyl, preferably -O-methyl or -O-ethyl, the "SOMN" group.

Heteroaryl residues, in which up to two C atoms can be replaced by one or two nitrogen atoms, can be named, for example, pyrrole, pyrazole, imidazole, thiazole, pyridine and pyrimidine, while each of the above-mentioned heteroaryl rings can be in its own alternately, under certain conditions, annelated with a benzene ring, preferably with a benzimidazole, and, in addition, these heterocycles, unless otherwise indicated, can bear,

HF) for example, one or more of the following substituents: E, SI, Vg, OH, OMe, methyl, ethyl, CM, СОМН», МН», where optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl

By cycloalkyl residues are meant cycloalkyl residues containing from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably 60 cyclopropyl, cyclopentyl or cyclohexyl, while each of the aforementioned cycloalkyl residues in turn can carry under certain conditions one or more substituents, for example, the group OH, MO», CM, OMe, -OSNE», -OSEz, -MNo or a halogen, preferably fluorine or chlorine, C.i-Sialkyl, preferably C.-Svalkyl , more preferably C.-C alkyl, especially preferably methyl or ethyl, -O-C.-C alkyl, preferably -O-methyl or -O-ethyl, -COOH, -C0О0О-C.-C,alkyl, preferably -СбО- methyl or -COO-ethyl or -СОМН». Especially the best substitutes for cycloalkyl residues are 5-0, group ОН, МН», methyl or P.

By cycloalkenyl residues is meant cycloalkyl residues containing from 3 to 12 carbon atoms and having at least one double bond, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, preferably cyclopropenyl, cyclopentenyl or cyclohexenyl, while each of the above cycloalkenyl residues, in turn, may carry one or more substituents under certain conditions. "ko" means an oxygen atom attached through a double bond.

By heterocycloalkyl residues are meant, unless otherwise indicated, 5-, 6- or 7-membered saturated or unsaturated heterocycles that may contain nitrogen, oxygen or sulfur as heteroatoms, for example, tetrahydrofuran, tetrahydrofuranone, y-butyrolactone, А-pyran . diazepane, oxazine, tetrahydrooxazinyl, isothiazole, and pyrazolidine, preferably morpholine, pyrrolidine, piperidine, or piperazine, while such a heterocycle in turn may carry substituents under certain conditions, for example,

C.-C.alkyl, preferably methyl, ethyl or propyl.

By polycycloalkyl residues are meant optionally substituted bi-, tri-, tetra- or pentacyclic cycloalkyl residues, for example, pinane, 2,2,2-octane, 2,2,1-heptane or adamantane. By polycycloalkenyl residues are meant optionally connected by a bridging bond and/or substituted 8-linked bi-,. tri-, tetra- or pentacyclic cycloalkenyl residues, preferably bicycloalkenyl or tricycloalkenyl residues, provided that they have at least one double bond, for example Norbornene.

By spiroalkyl residues we mean optionally substituted spirocyclic C5-C2alkyl residues.

The term "halogen" means, as a rule, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, especially chlorine. with

By the leaving group A, having the same or different values, is meant a leaving group such as -, O-methyl-, ZCM, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or i) p-toluenesulfonyl , chlorine is better.

The compounds proposed in the invention can be presented in the form of individual optical isomers, mixtures of individual enantiomers, diastereomers or racemates, in the form of tautomers, as well as in the form of free bases or corresponding acid-addition salts formed with pharmacologically acceptable acids, for example, acid- addition salts with hydrohalic acids, such as hydrochloric or hydrobromic acid, C or with organic acids, such as oxalic, fumaric, diglycolic or methanesulfonic acid. what

Substituent KE" can be hydrogen or a residue from the group including optionally substituted and/or branched C.-Svalkyl, preferably methyl or ethyl. o

Substitute KE? may be hydrogen or a residue from the group including optionally substituted and/or (ee) branched C.-Salkyl, preferably methyl or ethyl.

B" and Kk? can jointly form a 2-5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge, which can contain 1-2 heteroatoms, preferably oxygen or nitrogen, especially the best of the named "ethylene and propylene bridges. 50 The substituent EC? can be hydrogen or a residue selected from the group that includes optionally substituted C.-C. isoalkyl, preferably ethyl, propyl, butyl, pentyl or hexyl, especially preferably propyl, butyl, pentyl c" or hexyl, C 1 -C 1 alkenyl, preferably C 5 -C 7 alkenyl, C 5 -C 7 alkenyl, C 5 -C 7 alkynyl, preferably C 5 -C 5 -C 7 alkynyl, and C 1 -C 1 -aryl, preferably phenyl, or may be a residue selected from the group consisting optionally of substituted and/or bridged C3-C4ocycloalkyl, preferably cyclopentyl or cyclohexyl, C-C4ocycloalkenyl, preferably

C5-C.cycloalkenyl, C.,-C.polycycloalkyl, C.-C.polycycloalkenyl, C.-C.spirocycloalkyl, because C3-C.heterocycloalkyl, preferably pyranyl or piperinyl, pyrrolidinyl, pyrazinyl or morpholinyl containing 1-2 o heteroatoms, preferably oxygen or nitrogen, and C3-Sioheterocycloalkenyl containing 1-2 heteroatoms, preferably oxygen -1 or nitrogen. The most preferred substituents for B C are isopropyl, isobutyl, isopentyl, cyclopentyl, phenyl or cyclohexyl. и3 70 V" and KZ or EK? and KZ can jointly form a saturated or unsaturated C3-Slalalkyl bridge, which can contain 1 heteroatom, preferably oxygen or nitrogen.

Substituent 7 can be a residue selected from the group consisting of hydrogen, -CM, a hydroxy group, -MA 92 7 and halogen, preferably chlorine or fluorine, especially preferably chlorine, or can be a residue selected from the group consisting of neobo necessarily substituted C 4-Salkyl, preferably methyl, ethyl or propyl, C-Salkylenyl, preferably ethynyl or propenyl, C-Salkylenyl, preferably ethynyl, propynyl or butynyl, C-Salkyloxy group, preferably methoxy-, ethoxy- or iF) propargyloxy group . The most preferred substituent of K7 is a methoxy group, methyl, ethoxy group, ethyl, propargyloxy group or chlorine. 60 Y can be a linker selected from the group that includes optionally substituted Co 25-C-alkyl, preferably ethyl, propyl, butyl or pentyl, Co-Syralkenyl, Ce-C-daryl, preferably phenyl, -C5- C;alkyl-Ce-Ci4aryl, -Ce-Ci4aryl-C.-C.alkyl, preferably -phenylmethyl, optionally connected by a bridge bond C 3-C.ocycloalkyl, preferably cyclohexyl, and heteroaryl containing 1 -2 nitrogen atoms. n means 0 or 1. 65 t means 1 or 2, preferably 1.

IN? may be a residue selected from the group consisting of optionally substituted morpholinyl,

piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, EZ-dimethoxymethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -MEZVO and azacycloheptyl, preferably piperidinyl, morpholinyl, pyrrolidinyl, sulfoxomorpholinyl, piperazinyl, thiomorpholinyl, or tropenyl.

The residues KZ and KE" can be identical or different and represent hydrogen or C, C alkyl, preferably methyl or ethyl.

Balances WITHOUT and BE? can be unsubstituted nitrogen substituents at B C, have identical or different values and mean either hydrogen or a residue selected from the group that includes C 41-Salkyl, preferably methyl, ethyl or propyl, -C4-C;alkyl-C3 -Siocycloalkyl, better -CHnocyclopropyl, C3-Socycloalkyl, Ce-Ci4aryl, better 70 phenyl, - C.i-Slalkyl-Cv-C-laryl, better benzyl, pyranyl, pyridinyl, pyrimidinyl, pyranyl,

C.-C.alkyloxycarbonyl, Ce-Ci,arylcarbonyl-, C.-C.alkylcarbonyl-, Ce-Ci4arylmethyloxycarbonyl-,

Ce-Ci4arylsulfonyl-, C.-C;,alkylsulfonyl- and Ce-Ci,aryl-C--C,alkylsulfonyl-. Methyl, ethyl or propyl are most preferred as a substitute for K8. The best as a substitute for RE? methyl, ethyl or propyl.

BO can be a substituent selected from the group that includes the group OH, MH 2-5, -O-methyl and -O-ethyl, preferably the group OH, I K5, -O-methyl or -O-ethyl.

All residues indicated when revealing the values of B-2/9 may, under certain conditions, be branched and/or may be substituted.

The compounds proposed in the invention can be synthesized using the method A described below, while the substituents in the general formulas (A1)-(A9) have the values indicated above. The presented method is intended only for a more detailed explanation of the invention, without limiting its scope.

Method A

LA stage

The compound of the formula (At) is transformed into the compound of the formula (АЗ) by interaction with the compound of the formula (Аг) (scheme of part 1A). This reaction can be carried out in accordance with MUO 00/43369 or UUO 00/43372). The compound (At) is a commercially available product and is supplied, in particular, by the company of Sue Spatis! GIS located at the address: 139 o)

Aiipdz Stozvipd Koaid, UUevi Namep, ST, 06516, OA. The compound (Ag) can be obtained by the method known from the literature: (a) ER. EPepregdeg, TSI. Vyka, 9. MUMYiKany, Pieridz App. Spent 1986, pp. 314-333; b) T.

Eikyuata, S.-K. house, M. Spetspo, Teigapedgop Gen. 1995, 36, pp. 6373-6374; c) K.K. OiIvep, U. Ogd. Spent 1970, pp. Z5, pp. 1912-1915; d) B.E. YuOyShyop, V.N. Vutspo, Teiapedgop Iey. 1998, 30, pp. 5313-5316; e) 9.M. Capaisni,

M.M. dotsshie, eat. Sottype 1996, 26, pp. 1379-13841. "

Scheme 1A them about; y te y o m" "o y Kk o. . Her o s

Hr KK m ke t o cm M «

Kk o 2 t-ry s (A) (d) and Kk . (c) and? (AZ)

At the TA stage, 1 equivalent of the compound (At) and 1-1.5 equivalents, preferably 1.1 equivalents, of the corresponding base, preferably potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate, calcium carbonate, (ab) especially potassium carbonate , mixed in a diluent, optionally with water, for example, in acetone, tetrahydrofuran, diethyl ether, cyclohexane, petroleum ether or dioxane, preferably in cyclohexane or - diethyl ether. Further, at a temperature in the range from 0 to 152C, preferably from 5 to 102C, add 1 dropwise

Its 50 equivalent amino acid of the formula (A2) is dissolved in an organic solvent, for example, in acetone, c» tetrahydrofuran, diethyl ether, cyclohexane or dioxane. The reaction mixture is heated with stirring to a temperature in the range from 18 to 302C, preferably to about 222C, and then stirring is continued for the next 10-24 hours, preferably for about 12 hours. After that, the diluent is distilled off, the residue 5 is mixed with water and the mixture is extracted two or three times with an organic solvent, for example, diethyl ether or ethyl acetate. The combined organic extracts are dried, and the solvent is distilled off. The residue (F) (compound (AZ)) can be used in step 2 without prior purification.

Ge Stage 2A

The compound (AZ) obtained at stage TA is reduced by the nitro group and cyclized to form compound (A4) (Scheme 2A) 60 Scheme 2A b5 o, H ke: M. o me M o. ? AJ le V. ra r vk

SI M M VIiIDnNOVlniy si M M v2 "track v

KE

70 about; (Aa) (AZ)

In stage 2A, 1 equivalent of the nitro compound (AZ) is dissolved in an appropriate acid, preferably glacial acetic acid, formic acid, or aqueous hydrochloric acid, preferably glacial acetic acid, and heated to 75 50-709C, preferably to about 602C. Then, until the end of the exothermic reaction, a reducing agent is added, for example, zinc, tin or iron, preferably iron powder, and for 0.2-2 hours, better for 0.5 hours, stir at a temperature in the range from 100 to 1252C, better at a temperature approximately 11720. After cooling to room temperature, the iron salt is filtered off, and the solvent is distilled off. The residue is dissolved in a suitable solvent or a mixture of solvents, for example, in ethyl acetate or in a mixture of dichloromethane/methanol, taken in a ratio of 9:1, and half-saturated Massey's solution, and filtered, for example, through kieselguhr. The organic phase is dried and concentrated. The residue (compound (A4)) can be purified by chromatography or crystallization or used as a crude product in the ZA stage of the synthesis.

Stage ZA

The compound (A4) obtained in stage 2A can be converted into a compound of the formula (AB) by electrophilic substitution according to scheme ЗА with

M. so mo me M o 1 t z | 1 (ze) 3o Z - V ra - V si M M 2 SI M M 2 c

From AK and; it's in! - "c) (A4) (AB) d)

At stage ZA 1, the equivalent of the amide of the formula (A4) is dissolved in a suitable organic solvent, for example, in dimethylformamide or dimethylacetamide, preferably in dimethylacetamide, and cooled to a temperature in the range from approximately -5 to 59, preferably to 092C. Then add 0.9-1.3 equivalents of sodium hydride and 0.9-1.3 equivalents of a methylating agent, for example, methyl iodide. The reaction mixture is stirred at 0-102С, preferably at a temperature of about 52С for 0.1-H, better at 470 for about 1h, after which, if necessary, it can be kept in the specified temperature range for the next 12h. Then the reaction mixture is poured onto a mixture of water and ice and the sediment is isolated. The residue (compound (A5)) can be purified by chromatography, preferably on silica gel, or by crystallization or used as a crude product in step 4A of the synthesis.

Stage 4A (ee) Amination of the compound (A5) obtained in stage ZA to obtain the compound of formula (AZ) (Scheme 4A) can be carried out by methods known from the literature, namely, in accordance with the following options: (4LA (a)

M.R.M. Voapapa, 9U.B.MU. MsOtie, U. Spet. Zos. 1951, pp. 1218-1221; b) R.N.5. Syga, B.S. Goat, u). Spent wasps - and 1946, pp. 343-348, 4.2A (a) Vapk5, U. At. Spent Zos. 1944, 66, pp. 1131; b) Spozp apa Ooiu, 9. Ipdiap Spet. their 50 Zos. 1981, 58, pp. 512-513; c) M.R. Keadau and M. Tapaka, Teigapedgop I! hey 1997, 38, pp. 4807-4810).

Scheme 4A syu"

F) name) 60 b5

MH,

Kk (Av)

M. ro o7 Ton 70 ml M (o) in' MO

SIM Mr. Zhe Ya

From A "she pa ie

Boo (AB)

MN, 4

Kk (dO) s 1 oto o so « - «c)

M .8) ex c 1

HA Min

NOSE

4 This "

Кк Кк - с и (АВ) и? 1 juice (ee)

For example, according to option 4.1A, 1 equivalent of compound (AB) and 1-3 equivalents, preferably 2 equivalents, of compound (AB) without the use of a solvent or in a suitable organic solvent, such as -I sulfolane, dimethylformamide, dimethylacetamide, toluene, M-methylpyrrolidone, dimethylsulfoxide or dioxane, 5o Better in sulfolane, heated to 100-2202C, better to about 1602C, holding at this temperature for 0.1-4 hours, better for 1 hour. After cooling by adding organic solvents or mixtures of solvents, for example, diethyl ether/methanol, ethyl acetate, methylene chloride or diethyl ether, preferably a mixture of diethyl ether/methanol in the ratio 9:11, the product (AZ) is crystallized or purified by chromatography.

According to option 4.2A, 1 equivalent of the compound (A5) and 1-3 equivalents of the compound (Ab) are stirred under reflux for 1-48 hours, preferably for about 5 hours, together with the appropriate acid,

F) for example, with 1-10 equivalents of 10-3895 hydrochloric acid, and/or with a suitable alcohol, for example, ethanol, co-propanol, butanol, preferably with ethanol. The precipitated product (AZ) is filtered, washed with water if necessary, dried and crystallized from a suitable organic solvent. According to option 4.3 A, 1 equivalent of compound (A5) and 1-3 equivalents of compound (A7) are dissolved in a suitable solvent, for example, toluene or dioxane, mixed with a suitable phosphine ligand, for example, 2,2'-bis(diphenylphosphino)- 1,1-binaphthyl, and a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), and a suitable base, for example, cesium carbonate, and refluxed for 1-24 hours, preferably for 17 hours. Then the reaction mixture is purified, 65 For example, on silica gel, and the product (AB) is isolated from the solution, obtained by the appropriate crystallization.

The product (Av) is dissolved in a suitable solvent, such as dioxane, and added together with an acid,

for example, with semi-concentrated hydrochloric acid, for example in a 3:1 solvent/acid ratio. Then for 1-48 hours, for example, for 12 hours, it is heated under reflux and the precipitate that has fallen out is isolated. If necessary, the product (AZU) is purified by crystallization.

Scheme 5A div a ak p y Z sho paize zey sht: a pot y y y: is Y y sha o soye she she es sk t: to food i Y ' y I ren sh zak v 15 i puppy i. danu and toni pe

Option 5LA

According to this variant, for example, 1 equivalent of the compound (A9U) together with 1 equivalent of an activating reagent, such as, for example, O-benzotriazolyl-M,M,M'M'-tetramethyluronium tetrafluoroborate (TBTU), and c 25 is about 1, 5 equivalents of a suitable base, such as diisopropylethylamine (DIPEA), is dissolved in a suitable d) organic solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide, M-methylpyrrolidone or dimethylacetamide, preferably dichloromethane or dimethylformamide. After adding 1 equivalent of amine (A10), the reaction mixture is stirred for 0.1-24 hours, preferably for about 2 hours, at a temperature in the range from 20 to 1002C. As a result, for example, of crystallization or chromatographic purification, a product of the formula (A11) is obtained. "AND

New compounds of the general formula (I) can be synthesized analogously to the examples presented below. These examples are intended only to explain the invention in more detail, without limiting its scope. in

The preparation of some intermediate compounds used for the synthesis of compounds of formula (I) in the examples is also described below. 3o Preparation of acids so

For the synthesis of compounds in examples 94 and 95, intermediate compound 21 (27) is first obtained by the method described below.

M. lo ne - ev le ;" nm Mom 21 (ee) (av) oon -I 50.0 g (0.48 mol) methyl ester of ХО-alanine. NSI and 49.1 g (0.50 mol) of cyclohexanone were previously placed in 100 ml of dichloromethane, after which they were mixed with 41.0 g (0.50 mol) of sodium acetate and 159.0 g (0.75 mol) of sodium triacetoxyborohydride. The mixture was stirred overnight, and then 10 mL of a 1095% sodium bicarbonate solution was added. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1095% sodium bicarbonate solution, dried over NaCl, and concentrated.

Yield: 72.5 g of compound 71a (clear liquid). 72.5 g of compound 21a was previously placed in 00 ml of water and 76 b, bg (0.3 mol) of 2,4-dichloro-5-nitropyrimidine in 50 mol of diethyl ether was added. At a temperature of -59C0, 100 ml of a 1096th solution of potassium bicarbonate was added dropwise. Initially, during the Agreement stirred at -52C, and then for 12 hours. at room temperature. The organic phase was separated and dried over NaCl5O). Upon concentration, product 60 precipitated as crystals.

Yield: 48.0 g of compound 216 (yellow crystals). 48.0 g of compound 2716 was dissolved in ZbOml of glacial acetic acid and heated to 60 2С. Then 47.5 g of iron powder was added in portions, while the temperature was raised to 10520. The reaction mixture during

According to stirred at 802C, then hot filtered through cellulose and concentrated. The residue was separated by mixing in water and ethyl acetic acid, separated by vacuum filtration, and the resulting light gray precipitate was washed with ethyl acetic acid. The filtrate was washed with dilute ammonia and water, the organic phase was dried over NaCl, filtered through activated carbon and concentrated. As a result, a certain amount of light gray solid was obtained.

Yield: 29.5 g of compound 21c (light gray crystals). 32.1 g of compound 71c was previously placed in 3000 ml of dimethylacetamide and mixed with 13 ml (0.2 mol) of methyl iodide. Then, at -59C, 6.4 g (0.1 bmol) of sodium hydride was added in portions in the form of a 6b095-th dispersion in mineral oil. In 2 hours the reaction mixture was poured into 800 ml of a mixture of water and ice. The precipitate that fell out was separated by vacuum filtration and washed with petroleum ether. 70 Yield: 33.0 g of compound 214 (beige crystals). 4.0 g of compound 714 and 2.3 g (AIBmmol) of 4-amino-3-methylbenzoic acid were suspended in 500 ml of ethanol and 120 ml of water, mixed with 2 ml of concentrated hydrochloric acid and for 48 hours. boiled under reflux. The precipitate formed during cooling was separated by vacuum filtration and washed with water, ethanol and diethyl ether.

Yield: 2.9 g of compound 71 (colorless crystals).

For the synthesis of the compounds in examples 188 and 203, the intermediate compound 72 (22) is first obtained by the method described below; oh oh he

A solution of 128.2 g (0.83 mol) ethyl ether of SO-alanine.HCI and 71.5 g (0.85 mol) of cyclopentanone in 1500 ml and. dichloromethane was mixed with 70.1 g (0.85 mol) of sodium acetate and 265.6 g (1.25 mol) of sodium triacetoxyborohydride. "Zh

The reaction mixture was stirred for 12 hours. and then poured into 1.5 liters of 1095 sodium bicarbonate solution.

The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Ma»so and concentrated. -

Yield: 143.4 g of compound 72a (colorless oil). aw! b6b,Og of compound 72a was previously placed in BbbBbOOml of water and mixed with 85.0g (0.44mol) of 2,4-dichloro-5-nitropyrimidine in 50Oml of diethyl ether. At a temperature of -59С0, 100 ml of a 1096th solution of potassium bicarbonate was added dropwise and the reaction mixture was added over 48 hours. stirred at room temperature. The aqueous phase was extracted with diethyl ether, the combined organic phases were dried over Ma»zo, and concentrated. The dark red solid was separated by mixing with petroleum ether and separated by vacuum filtration. -o 70 Yield: 88.0 g of compound 2265 (yellow crystals). 88.0 g of compound 2206 was dissolved in 1000 ml of glacial acetic acid and mixed with portions of 85 g of iron powder at 60 °C, while the temperature rose to 11092 °C. The mixture for an hour. stirred at 602C, then separated while hot by vacuum filtration through cellulose and concentrated. Hard

The brown substance was separated by mixing with 700 ml of water and separated by vacuum filtration.

Yield: 53.3 g of compound 22c (light brown crystals). 53.3 g of compound 72c was dissolved in 300 ml of dimethylacetamide and mixed with 13 ml (0.21 mol) of methyl iodide. Then 5.0 g (0.21 mol) of sodium hydride in the form of a 6b090-th dispersion in mineral oil was added in portions to -I at -59С5.

After 12 hours the reaction mixture was poured into 1000 ml of a mixture of water and ice, and the resulting precipitate was separated by vacuum filtration.

GC) Yield: 40.0 g of compound 224 (colorless crystals). 4.0 g of compound 72a and 2.8 g (1 mmol) of 4-amino-3-methylbenzoic acid were suspended in 25 ml of ethanol and 1 ml of water, mixed with 3 ml of concentrated hydrochloric acid and for 4 hours. boiled with the reverse in the refrigerator. The precipitate formed during cooling was separated by vacuum filtration and washed with water, ethanol and diethyl ether. (F, Yield: 0.9 g of compound 72 (colorless crystals). ka For the synthesis of compounds in examples 19, 21, 22, 23, 45, 55, 58, 116, 128, 131, 133, 134, 136, 138, 177 , 217, 231, 239, Ab, 184, 166, and 187 first obtain the intermediate compound 23 60 b5 in the way described below

C, not M

At 23 o'clock, 54.0 g (0.52 mol) of O0-2-aminobutyric acid was suspended in 540 ml of methanol and slowly mixed with 132 g (1.1 mol) of thionyl chloride while cooling with ice. During 1.5 hours. the mixture was refluxed and then concentrated. The resulting oil was mixed with 54 ml of tert-butyl methyl ether and the 19 crystals formed were separated by vacuum filtration.

Yield: 78.8 g of compound 2Za (colorless crystals). 74.2 g of compound 7Za and 43.5 ml (0.49 mol) of cyclopentanone were dissolved in 300 ml of dichloromethane. After adding 40.0 g (0.49 mol) of sodium acetate and 150.0 g (0.71 mol) of sodium triacetoxyborohydride at 092C, they were stirred for 12 hours. at room temperature and then added 50O0ml of 2095 sodium bicarbonate solution.

The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried over Mo5o, and concentrated.

Yield: 85.8 g of compound 236 (oil, slightly colored in yellow). 40.0 g of compound 7365 and 30.0 g (0.22 mol) of potassium carbonate were suspended in bbOml of acetone and, under ice cooling, were mixed with 45.0 g (0.2 mol) of 2,4-dichloro-5-nitropyrimidine in 200 ml of acetone. After 12 hours added another 5.0 g. 2,4-dichloro-5-nitropyrimidine and stirred during the Accord. Then the reaction mixture was concentrated, (U was dissolved in 800 ml of ethyl acetic acid and 50 ml of water, and the aqueous phase was extracted with ethyl acetic acid. The combined organic phases were washed with water, dried over Ma5O, and concentrated.

Yield: 75.0 g of compound 2Zs (brown oil). 100 g of compound 7С was dissolved in bbOml of glacial acetic acid and mixed with portions of 20 g of iron powder at 70 °C. Then, at first, for an hour. stirred at 702C, and then for 1.5 hours. at 1002C, "and then filtered while hot through kieselguhr. The reaction mixture was concentrated, dissolved in a mixture of methanol and dichloromethane, applied to silica gel and purified by Soxhlet extraction with the help of ethyl acetic acid. The solvent was removed and the residue was separated by stirring with | "c) with methanol. co

Yield: ZO,Og of compound 23a (light brown crystals). 25.0 g of compounds 73a and b. 5 ml (0.1 mol) of methyl iodide was previously placed in 250 ml of dimethylacetamide and mixed with 3.8 g (0.95 mol) of sodium hydride in the form of a 6090 dispersion in mineral oil at -140a907. Next, they were mixed first for 20 minutes. at 09C, and then during ZOkhv. at room temperature and ice was added at the end. The reaction mixture was concentrated and mixed with ZOO ml of water. The resulting precipitate was separated from c by vacuum filtration and washed with petroleum ether.

Yield: 23.0 g of compound 2Ze (colorless solid). ;" b,Og of the compound 7Ze and 5/1g (3immol) of 4-amino-3-methoxybenzoic acid were suspended in 9Oml of ethanol and

ZB5Oml of water, mixed with 3,bml of concentrated hydrochloric acid and for 48 hours. boiled with reverse Refrigerant. Then the reaction mixture was concentrated, the residue was separated by stirring with the mixture

Go! of methanol and diethyl ether and the resulting precipitate was separated by vacuum filtration.

Yield: 6 g of compound 23 (light beige crystals). o For the synthesis of the compounds in examples 81, 82, 93 and 137, the intermediate -I compound 24 i3 70 is first obtained by the method described below. (24) syume M c) va ny M M lo o p

Ф) име) c) он 60 25.0 g (0.19 mol) of ethyl ether of 1-aminocyclopropane-1-carboxylic acid. HCl and 16.8 g (0.20 mol) of cyclopentanone were dissolved in 3000 ml of dichloromethane and mixed with 16.4 g (0. 20 mol) of sodium acetate and 61.7 g (0.29 mol) of sodium triacetoxyborohydride. It was then stirred overnight, after which the reaction mixture was poured into 400 ml of a 1095% solution of sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over NaCl5O) and concentrated.

Yield: 34.5 g of compound 74a (colorless oil).

42.5 g (0.22 mol) of 2,4-dichloro-5-nitropyrimidine in 35 Oml of diethyl ether was added to a mixture of 34.5 g of compound 24a in 35 Oml of water. Then, at -5930, it was mixed with 30 ml of a 1095-th potassium bicarbonate solution and stirred overnight at room temperature. The aqueous phase was extracted with diethyl ether. The combined organic phases were dried over Na 2 O and concentrated.

Yield: 53.8 g of compound 24565 (brown oil). 20.1 g of compound 246 was dissolved in 200 ml of glacial acetic acid and mixed with 19.1 g of iron powder in portions at 60 °C, while the temperature rose to 1002 °C. Further, during the Agreement stirred at 609, 70 then separated by vacuum filtration through cellulose and concentrated. The residue was separated by stirring in water and ethyl acetic acid, and the resulting yellow precipitate was separated by vacuum filtration. The filtrate was washed with diluted ammonia and water, the organic phase was dried over NaCl, and concentrated. After adding diethyl ether, the further product crystallized.

Yield: 4.0 g of compound 24c (yellow crystals). 7.8g of compound 24c and 2.bml (0.04mol) of methyl iodide were dissolved in 100ml of dimethylacetamide and at -59C were mixed in portions with 1.5g (0.04mol) of sodium hydride in the form of a 6090th dispersion in mineral oil. In 2 hours the reaction mixture was poured onto a mixture of water and ice, and the resulting precipitate was separated by vacuum filtration.

Yield: 7.5 g of compound 74a (crystals slightly colored in brown colors.)

C,Og of compound 244 and 1.9 g (11 mmol) of 4-amino-3-methoxybenzoic acid were suspended in 40 ml of ethanol and 8 ml of water, mixed with 2 ml of concentrated hydrochloric acid and for 20 hours. boiled under reflux. Then another 0.5 g of 4-amino-3-methoxybenzoic acid was added and for 48 hours. continued to boil under reflux. The precipitate formed during cooling was separated by vacuum filtration and washed with water, ethanol and diethyl ether. with

Yield: 2.1 g of compound 24 (colorless crystals), (pl. 222-22396. (5)

For the synthesis of the compounds in examples 162, 43, 53, 161, 202, 211, 215 and 212, the intermediate compound 25 (25) co

20 Mixture of 7 x 4 ml (0.5 mol) ethyl ether of 2-bromoisobutyric acid, 87.1 ml (0.75 mol) w-w

3-methyl-1-butylamine, 82.5 g (O0.bmol) of sodium iodide and 76.0 g (0.bmol) of potassium carbonate in 1000 ml of ethyl acetate were refluxed for 3 days. Then the salts present were filtered off and the filtrate was concentrated.

Yield: 97.0 g of compound 25a (red oil). 49.0 g (0.25 mol) of 2,4-dichloro-5-nitropyrimidine and 38.3 g (0.28 mol) of potassium carbonate were suspended in 500 ml of acetone and mixed at 09 with 93.0 g of compound 75a in 375 ml of acetone. The reaction mixture was then stirred overnight at room temperature, filtered and concentrated. The residue dissolved in acetic acid ethyl ether was washed with water and the organic phase was dried over Ma5O and concentrated. -I Yield: 102.7 g of compound 256 (brown oil). 22.7 g of compound 256 was dissolved in 350 ml of glacial acetic acid and mixed with 17.4 g of iron powder in portions at 60 °C. After adding the specified component within 0.5 hours. boiled with reverse

HC) in a refrigerator, filtered while hot and concentrated. The residue was dissolved in 200 ml of a mixture of dichloromethane and methanol (in a ratio of 9:11) and washed with a solution of sodium chloride. The organic phase was separated by vacuum filtration through kieselguhr, dried over Ma95O, concentrated and purified by column chromatography (eluent: ethyl acetic acid/cyclohexane in a ratio of 1:1).

Yield: 1.9 g of compound 25c (colorless crystals). (F, 1.9 g of compound 75c was dissolved in 32 ml of dimethylacetamide and, under ice cooling, was mixed with 0.3 g (µmol) of sodium hydride in the form of a 6095th dispersion in mineral oil. After 1 hour, 0.5 ml (7 mmol) of methyl iodide was added and mixed at room temperature. The reaction mixture was then concentrated and mixed with water. The precipitate formed was separated by vacuum filtration and washed with petroleum ether.

Yield: 1.6 g of compound 75a (colorless crystals). 14.0 g of compound 754 and 10.0 g (0.00 bmol) of 4-amino-3-methoxybenzoic acid were suspended in 200 ml of dioxane and 8 ml of water, mixed with 1 ml of concentrated hydrochloric acid and boiled for 40 hours. with reverse b5 Refrigerator. The precipitate formed during cooling was separated by vacuum filtration and washed with water, dioxane and diethyl ether.

Yield: 13.9 g of compound 25 (colorless crystals).

For the synthesis of the compounds in examples 88, 194, 229 and 89, the intermediate compound 276 (26) is first obtained by the method described below

Zh - C. 70 nm M M 7o with 26 o on b,Og (0.O0bmol) of I -2-aminobutyric acid was previously placed in 8Oml of 0.5-molar sulfuric acid and at 02 was mixed with 5.5g (0.08mol ) of sodium nitrite in 15 ml of water. The reaction mixture was stirred for 22 hours. at 02C, mixed with ammonium sulfate and filtered. The filtrate was extracted with diethyl ether and the combined organic phases were dried over Moss and concentrated.

Yield: 6b, 00g of compound 2ba (yellow oil). 200 ml of methanol under cooling with ice was successively mixed with 65.0 ml (0.89 mol) of thionyl chloride and 76.0 g of compound 7ba in 50 ml of methanol. The mixture for an hour. stirred at 02C for 2 hours. at room temperature and then methanol and residual thionyl chloride were removed at 02C in vacuo. Ge

Yield: 40.00 g of compound 265 (yellow oil). (5)

30 ml (0.17 mol) of trifluoromethanesulfonic acid anhydride was previously placed in 150 ml of dichloromethane and mixed for an hour while cooling with ice. with a solution of 20.0 g of compounds 26r and 14, O0 ml (0.17 mol) of pyridine in 5 O ml of dichloromethane. The mixture for 2 hours. stirred at room temperature, the salts formed were separated by vacuum filtration and then washed with 100 ml of water. The organic phase was dried (ze) over Mo and concentrated. "

Yield: 42.0 g of compound 26bs (light yellow oil).

To a solution of 15.5 ml (0.17 mol) of aniline and 24.0 ml (0.17 mol) of triethylamine in 400 ml of dichloromethane, while cooling with ice, was added dropwise over the course of an hour. 42.0 g of compound 2bs in 200 ml of dichloromethane. Solution for hours. stirred at room temperature for another 2 hours. at 3592C. The reaction mixture was washed with water, dried over M950, and concentrated. The resulting residue was purified by distillation d) (95-1002C, 1-10 Zmbar).

Yield: 14.0 g of compound 764 (colorless oil). 14.0 g of compound 264 and 16.0 g (O.Tmol) of potassium carbonate were suspended in 100 ml of acetone and mixed with 16.0 g (0.08 mol) of 2,4-dichloro-5-nitropyrimidine at 1023. Then the mixture for 4 hours. were stirred at 409C, the salts formed with t0 were separated by vacuum filtration and the filtrate was concentrated. The residue was dissolved in 10 ml of ethyl acetic acid and washed with water. The organic phase was dried over Mo5O) and concentrated. "from Yield: 31.0 g of compound 2be (brown oil).

1.0 g of compound 2be was dissolved in 200 ml of glacial acetic acid and mixed with portions of 10 g of iron powder at 60 °C, while the temperature rose to 8523. Mixing was continued for another hour. at 602C, then filtered through kieselguhr and concentrated. The residue was separated by mixing with methanol. o Yield: 4.5 g of compound 26 (brown crystals). - To a mixture of 4.5g of compound 26 and 1.00ml (1bmmol) of methyl iodide in 100ml of dimethylacetamide at -20C, 0.6bg (1bmmol) of sodium hydride in the form of a 6095th dispersion in mineral oil was added in portions. After 1 hour the reaction mixture was mixed with 5 ml of water and concentrated. The residue was mixed with 200 ml of water and the precipitate that fell out was separated by vacuum filtration and washed with petroleum ether.

Yield: 4.5 g of compound 269 (colorless crystals).

A suspension of 1.5 g of compound 7269 and 1.4 g (dmmol) of 4-amino-3-methoxybenzoic acid methyl ester in 30 ml of toluene was mixed with O04 g (Obmmol) of 2,2-bis(diphenylphosphino)-1,1-binaphthyl, 0. 23 g (0.3 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 7.0 g (21 mmol) of cesium carbonate and boiled for 17 hours. with (F. reflux. Then the reaction mixture was applied to silica gel and purified by column chromatography (eluent: dichloromethane/methanol in a ratio of 9:1).

Yield: 1.7 g of compound 26P (yellow crystals). 1.7 g of compound 2bp was dissolved in 5 ml of dioxane, mixed with 15 ml of semi-concentrated hydrochloric acid and boiled for 12 hours. with a return cooler. After cooling, the resulting precipitate was separated by vacuum filtration.

Yield: 1.1 g of compound 26 (colorless solid).

For the synthesis of the compounds in examples 26, 20, 32, 56, 101, 112 and 209, the intermediate compound 277 m" М Ф) t more M y-b2o Х 7 710 о on 50.0g (0.3bmol ) of O-alanine methyl ether. HCI was suspended in 500 ml of dichloromethane and 35 ml of acetone and mixed with 30.0 g (0.37 mol) of sodium acetate and 80.0 g (0.38 mol) of sodium triacetoxyborohydride. Then it was stirred for 12 hours, after which it was poured into 400 ml of sodium bicarbonate solution of 1095. The organic phase was dried over Na 2 O and concentrated.

Yield: 51.0 g of compound 27a (yellow oil).

A suspension of 51.0 g of compound 27a in 450 ml of water was mixed with 80.0 g (0.41 mol) of 2,4-dichloro-5-nitropyridine in 400 ml of diethyl ether. At -59C, 100 ml of a 1095 potassium bicarbonate solution was added dropwise. The reaction mixture was stirred for 10 minutes, the organic phase was dried over MgSO), and concentrated.

Yield: 74 g of compound 476 (yellow oil). 18.6 g of compound 2776 was dissolved in 200 ml of glacial acetic acid and mixed with 20.0 g of iron powder in portions at 60 °C. The mixture for 2 hours. stirred at 602C and then vacuum filtration through cellulose. The residue was dissolved in ethyl acetic acid and washed with water and concentrated ammonia. The organic phase was dried over Na»50O) and concentrated. The residue was crystallized from diethyl ether.

Yield: 9 g of compound 277c (colorless crystals). o) 17.0 g of compound 77c and 7 ml (0.1 mol) of methyl iodide were dissolved in 200 ml of dimethylacetamide and mixed with 4.0 g (0.1 mol) of sodium hydride in the form of a 6090th dispersion in mineral oil at -5 C. The reaction mixture was stirred for ZOhv. and then poured a mixture of water and ice onto ZOOml. The resulting precipitate was separated by vacuum filtration and isolated by mixing with petroleum ether.

Yield: 14.8 g of compound 274 (beige crystals). - 0.9 g of compound 27a and 1.5 g (Zummol) of 4-amino-3-methoxybenzoic acid were heated to 21023 with keeping M at this temperature for 30 minutes. After cooling, the residue was separated by mixing with ethyl acetic acid and the resulting precipitate was separated by vacuum filtration. -

Yield: 1.2 g of compound 27 (gray crystals). Gee)

Analogous to the synthesis options described above, the following acids were obtained, among others:

M lo rya

NM not M - I oh oh;" ogoon o7 tone (og) 78 29 o

Mo in Russian. MK e rf S. ne cm s» nm M M o - 7 o7oon oon

F) that m name)

Synthesis of amine structural units of I-29 in The following amines were obtained by the method described below: 1,1-dimethyl-2-dimethylamino-1-ylethylamine and 1,1-dimethyl-2-piperidin-1-ylethylamine b5 bar

And I" In,

These compounds were obtained by the method described in the following sources: (a) 5. Zspcei; etc.

AggpeiitiyeI-Rogespipud 21, 1971, pp. 739-763; c) M.M. Veiikom et al., Teiapedgop 26, 1970, pp. 1199-1216; c) 70 E.V. VshSheg and MeMiPap, doigp. Ateg. Spent boss. 72, 1950, p. 2978).

The following amines were also obtained according to the method modified in the cited sources: 1,1-dimethyl-2-morpholine-1-ylethylamine

cat

About 8.7 ml of morpholine and 9.3 ml of 2-nitropropane were previously placed together in a reaction vessel under ice cooling, and then 7.5 ml of formaldehyde (37905) and 4 ml of 0.5-molar Mahon solution (102C) were slowly added dropwise. After that, it was stirred for an hour. at 252C and during hours at 5020. The solution was treated with water and ether and the aqueous phase was extracted three times with ether. The organic phase was dried over NaCl, and mixed with NCI in dioxane (4 mol/l). The resulting precipitate was separated by vacuum filtration.

Yield: 21.7 g of white powder. 5 g of this powder was dissolved in 8 ml of methanol and, with the addition of 2 g of Raney nickel, was treated with hydrogen for 40 min. at 352C and a pressure of 5Olbs/sq.in. As a result, 3.6 g of 1,1-dimethyl-2-morpholin-1-ylethylamine was obtained.

Analogously to this technique, the following amines were obtained: 1,1-dim ethyl-2-methylpiperazine-1-ylethylamine so n-K Ya-

M sh-- x / і- 1,1-dimethyl-2-pyrrolidin-1-ylethylamine o d) sh-K y "

Synthesis of 1,3-dimorpholine-2-aminopropane - with Mn,

M M

(ee) about in; (o; 5 g of 1,3-dimorpholine-2-nitropropane from the company AiYidgis was dissolved in 8 ml of methanol and, with the addition of 2 g of nickel-Raney, was treated for 5.5 hours with hydrogen at 30 °C and a pressure of 5 O pounds/square inch. As a result, 4, 2 years

ChT" 70 of 1,3-dimorpholine-2-aminopropane. and 4-aminobenzylmorpholine m

NM

- OA

GF! My name)

The production of this amine is described in the following publication: (5. Miyzygy et al., dUoigp. Mei. Spet. 43, 2000, pp. 2049-20631I. bo 4-amino-1-tetrahydro-4H-pyran-4-ylpiperidine 6E 20g (10 b0 mmol) of 4-tert-butyloxycarbonylaminopiperidine was dissolved in 250 ml of CHCl and for 12 hours was stirred at RT with 10 g (10 mmol) of tetrahydro-4H-pyran-4-one and 42 g (200 mmol) of Mavn(OdAs)z. Then it was mixed with water and potassium carbonate, the organic phase was separated, dried, and the solvent was removed under vacuum. The residue was dissolved in 200 mL of SNeoSi" and stirred for 12 hours at RT with 100 mL of trifluoroacetic acid. The solvent was removed under vacuum, the residue was dissolved using SNS and re-evaporated, after

What was dissolved in acetone, and the hydrochloride was precipitated using a CARRIER in ether. Yield: 14.3g (5690). cis- and trans-4-morpholinocyclohexylamine; n- Sq

KI / 2 kh

Dibenzyl-4-morpholinocyclohexylamine 3.9 g (ZOmmol) of 4-dibenzylcyclohexanone was dissolved in 100 ml of SNeSi" and for 12 hours. was mixed at RT with 3.9 g (A4A5 mmol) of morpholine and 9.5 g (45 mmol) of Mavn(OAs)z. Then it was mixed with water and potassium carbonate, the organic phase was separated, dried and the solvent was removed under vacuum. The residue was purified on a silica gel column (approximately 20 ml of silica gel; approximately 500 ml of acetic acid ether and methanol in the ratio of 79 90:104-195 concentrated ammonia). The corresponding fractions were concentrated under vacuum. Yield: 6b, bg (6095) of the cis-isomer and 2d (1895) of the trans-isomer.

According to another variant, trans-dibenzyl-4-morpholinocyclohexylamine can be obtained as follows:

33 g (112 mmol) of 4-dibenzylcyclohexanone was dissolved in 30 ml of MeonN, mixed with 17.4 g (250 mmol) of hydroxylamine hydrochloride and stirred for 4 hours. at 602C. The solvent was evaporated in a vacuum, then 500 ml of water and 50 g of potassium carbonate were mixed and extracted twice with dichloromethane in 300 ml portions.

The organic phase was dried, concentrated in a vacuum, the residue was crystallized from petroleum ether, dissolved in 1.5 l of EN and heated to 702C. Next, 166 mg of sodium was added in portions and refluxed until the sodium was completely dissolved. Then the solvent was removed in a vacuum, the residue was mixed with 100 ml of water and the compound 29 was extracted twice with simple ether in portions of 40 Oml. The organic phase was washed with water, dried, Ge) concentrated in a vacuum and with the help of a suitable column (approximately 1.5 l of silica gel; approximately 2 l of acetic acid ether and methanol in the ratio of 80:24295 concentrated ammonia) the trans isomer was isolated. Yield: 12.6g (41.2965). 6b,vg (233 mmol) of trans-1-amino-4-dibenzylaminocyclohexane was dissolved in 10 ml of DMF and for 8 hours. was stirred at 1002 with 5 ml (42 mmol) of 2,2'-dichloroethyl ether and 5 g of potassium carbonate. After cooling, "I was mixed with 30 ml of water, the precipitated crystals were separated by vacuum filtration and purified on a low column (about 20 ml of silica gel, about 100 ml of acetic acid ether). The residue was crystallized from methanol and concentrated HCl to give the dihydrochloride. Output: 7, Zg (724905). (ав) trans-4-morpholinocyclohexylamine 7.2 g (16.4 mmol) of trans-dibenzyl-4-morpholinocyclohexylamine was dissolved in 1.000 ml Meon and hydrogenated in CO in the presence of 1.4 g Ra/C (1095 g) at a temperature from 30 to 502C. The solvent was then removed in vacuo and the residue was crystallized from ethanol and concentrated NOS. Yield: 3.9 g (93905) ypl 31296. The cis-isomer can be obtained in a similar way. "20 cis- and trans-4-piperidinocyclohexylamine s-v ind); nn » ;» trans-dibenzyl-4-piperidinocyclohexylamine 2.0 g (6.mmol) of trans-1-amino-4-dibenzylaminocyclohexane (see example 2) was dissolved in 500 ml of DMF and (ee) for 48 hours. was mixed at RT with 1.6 g (ummol) of 1,5-dibromopentane and 2 g of potassium carbonate. Then the mixture was cooled, mixed with water, extracted twice with dichloromethane in portions of 1000 ml each, dried, and the solvent was removed under vacuum. The residue was purified on a suitable column (approximately 100 ml of silica gel; - approximately 500 ml of acetic acid ether and methanol in the ratio of 80:20-195 concentrated ammonia). 20 The corresponding fractions were concentrated in vacuo and crystallized from petroleum ether. Output: 1.2g (49905). trans-4-piperidinocyclohexylamine c» 1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidinocyclohexylamine was dissolved in 35 ml of MeonN and hydrogenated in the presence of ZBOmg Ra/С (1095th) at 2020. Then the solvent was removed in vacuo and the residue was crystallized from ethanol and concentrated NOS. Output: 1.1g (7890). 99 The cis-isomer can be obtained in a similar way.

GF! cis- and trans-4-(4-phenylpiperazin-1-yl)ucyclohexylamine in OO 41 g (25.3 mmol) of 4-dibenzylcyclohexanone was dissolved in 5 bBOml of dichloromethane and for 12 hours. 60 was mixed at RT with 7.4 g (25.33 mmol) of M-phenylpiperazine and 7.4 g (35 mmol) of Mavn(OAc)". Then it was mixed with water and potassium carbonate, the organic phase was separated, dried and the solvent was removed under vacuum. The residue was purified on a silica gel column (acetic acid ether and methanol in a ratio of 80:20-0.590 concentrated ammonia). Yield: 1.7 g (15.895) of the cis isomer and 0.27 g (2.596) of the trans isomer. trans-4-(4-phenylpiperazin-1-yl)ucyclohexylamine and 27 mg (0.61 mmol) of trans-dibenzyl-I4-(4-phenylpiperazin-1-yl)ucyclohexylamine were dissolved in 5 ml of Meon and at a temperature in the range from 20 to 302С hydrogenated in the presence of 40 mg Ra/s (1090th). The solvent was then removed in vacuo and the residue was crystallized from ethanol and concentrated NOS. Output: 11Omg (69965). The cis-isomer can be obtained in a similar way. cis- and trans-4-(4-cyclopropylmethylpiperazin-1-yl)cyclohexylamine

Nm CO, 9.8 g (33.4 mmol) of 4-dibenzylcyclohexanone was dissolved in 1000 ml of dichloromethane and for 12 hours. 7o was mixed at RT with 5.6 g (40 mmol) of M-cyclopropylmethylpiperazine and 8.5 g (40 mmol) of Mavn(OAc)z. Then it was mixed with water and potassium carbonate, the organic phase was separated, dried and the solvent was removed under vacuum. The residue was purified on a silica gel column (approximately 5 Oml of silica gel; approximately 3 ml of acetic acid ether and methanol in the ratio of 95:5 to 0.2596 concentrated ammonia). The corresponding fractions were concentrated in a vacuum, the cis compound, which eluted at a higher rate, was crystallized from acetic acid ether. 75 The trans compound was crystallized from ethanol and concentrated HCl. Yield: 8.5 g (6195) of the cis-isomer and 2.2 (1395) of the trans-isomer. cme-4-(4-cyclopropylmethylpiperazin-1-yl)ucyclohexylamine 8.5 g (2O0mmol) cis-dibenzyl-I4-(4-dcyclopropylmethylpiperazin-1-yl)ucyclohexyl|Iamine was dissolved in 17Oml of meon and at a temperature in the range from ZO to 502С was hydrogenated in the presence of 1.7 g of Ra/С (10905th). The solvent was then removed in vacuo and the residue was crystallized from ethanol and concentrated NOS. Output: 4.4g (9196). The trans isomer can be obtained in a similar way.

Synthesis of the compounds given in the examples

Example 152

0.15 g of compound 210, 0.14 g of TBTU, 0.1 mL of DIPEA were dissolved in dichloromethane and stirred for 2 h. at Ga 25960. Then 9 µl of 1-(3-aminopropyl)-4-methylpiperazine was added and stirring was continued for another 2 hours. at 259C. After that, the solution was diluted with dichloromethane and extracted with water. By adding petroleum ether, ether and ethyl acetate to the organic phase, the product was precipitated. Yield: 0.16 g of solid beige color.

Example 164 so

0.10 g of compound 210, 0.1 g of TBTU, 0.8 ml of DIPEA were dissolved in 4 ml of dichloromethane and stirred for 2 h. " at 2520. Then 44 μl of dimethylaminopropylamine was added and stirring was continued for another 2 hours. at 2520. After that, the solution was diluted with dichloromethane and extracted with water. By adding petroleum ether, ether and acetone to the organic phase, the product was precipitated. Yield: 0.08 g of yellow solid substance.

From Example 242 p

0.15 g of compound 210, 0.14 g of TBTU, 0.1 mL of DIPEA were dissolved in 5 mL of dichloromethane and stirred for 2 h. at 2520. Then 75 μl of 1-(2-aminoethyl)piperidine was added and stirring was continued for another 2 hours. at 259C. After that, the solution was diluted with dichloromethane and extracted with water. The product was precipitated by adding petroleum ether, ether and ethyl acetate to the organic phase. Yield: 0.14 g of solid Z 70 yellow substance. with Example 188

0.1 g of compound 22, 0.09 g of TBTU, 0.05 ml of DIPEA were dissolved in 15 ml of dichloromethane and stirred for 2 h. at 2520. Then 300 g of 1-methyl-4-aminopiperidine was added and stirring was continued for the duration of Acc. at 2520. The solution was extracted with 20 ml of water, after which it was concentrated in a vacuum. With the help of simple ether, the product was crystallized. Yield: 0.047 g of white crystals.

Example 203 (a) 0.1 g of compound 22, 0.09 g of TBTU, 0.5 ml of DIPEA were dissolved in 15 ml of dichloromethane and stirred for 30 minutes. - at 2520. Then 50 mg of 4-amino-1-benzylpiperidine was added and stirring was continued for the duration of Accord. at 252C. The solution was extracted with 20 ml of water, after which it was concentrated in a vacuum. Then it was chromatographed on - silica gel and the isolated product was crystallized with ether. Yield: 0.015 g of white "Fo" crystals.

Example 94 0.17 g of compound 21, 0.19 g of TBTU, 0.11 ml of DIPEA were dissolved in 500 ml of dichloromethane and stirred for

REFERENCE at 2520. Then bZmg of 1-methyl-4-aminopiperidine was added and stirring was continued for another 17 hours. at 2520. Next, 5 ml of water and 1 g of potassium carbonate were added to the solution, and the organic phase was separated into

F) a special column for phase separation, after which it was concentrated in a vacuum. The product was then purified by column chromatography on silica gel and the purified product was crystallized with ether. Yield: 0.1 g of white crystals. in Example 95, 0.17 g of compound 21, 0.19 g of TBTU, 0.11 ml of DIPEA were dissolved in 500 ml of dichloromethane and stirred for

REFERENCE at 25907. Then 77 mg of exo-3-B-aminotropane was added and stirring was continued for another 17 hours. at 2520. Next, 5 Oml of water and 1 g of potassium carbonate were added to the solution, and the organic phase was separated using a special phase separation column, after which it was concentrated in a vacuum. The product was then purified by silica gel chromatography and the purified product was crystallized with ether. Yield: 0.03g of white crystals.

Example 46

0.15 g of compound 23, 0.12 g of TBTU, 0.12 ml of DIPEA were dissolved in 5 ml of dichloromethane and stirred for 30 minutes. at 259C. Then 500 mg of 1-methyl-4-aminopiperidine was added and stirring was continued for another 2 hours. at 2520. Next, the solution was extracted with water and then concentrated. The residue was dissolved in warm ethyl acetate and crystallized with ether and petroleum ether. Yield: 0.025 g of white crystals (dl 2032 (in the form of a base).

Example 80

0.2 g of compound 728, 0.2 g of TBTU, 0.1 ml of DIPEA were dissolved in 100 ml of dichloromethane and stirred for 30 minutes. 70 at 259C. Then 100 mg of 1-methyl-4-aminopiperidine was added and stirring was continued for another 17 hours. at 2520. Next, the solution was extracted with a dilute solution of potassium carbonate and concentrated. The residue was crystallized with ether. Yield: 0.12 g of white crystals.

Example 190

0.2 g of compound 28, 0.2 g of TBTU, 0.3 ml of DIPEA were dissolved in 5 ml of dichloromethane and stirred for an hour. at 25960. Then 0.1 mg of 4-amino-1-benzylpiperidine was added and stirring was continued for another hour. at 25922. Next, the solution was diluted with 1 ml of methylene chloride and extracted with 20 ml of water. The product was then purified on silica gel and crystallized from ethyl acetate and ether. Yield: 0.23 g of compound 28. 0.23 g of benzylamine 28 was dissolved in 1 ml of methanol, mixed with 50 mg of Ra/C and hydrogenated during at a pressure of Zbar and a temperature of 2520. As a result of the addition of petroleum ether and ethyl acetate, white crystals were obtained, which were then chromatographed on silica gel and crystallized using ethyl acetate and ether. Yield: 0.075 g of white crystals.

Example 196

0.1 g of compound 210, 0.09 g of TBTU, 0.3 ml of DIPEA were dissolved in 4 ml of dichloromethane and stirred for 20 minutes. at 2592C. Then b/mg amine was added and stirring was continued for another 2 hours. at 25 20. Next, the solution was diluted with dichloromethane and extracted with water. Then the residue was chromatographed on silica gel. (U was dissolved in acetone, mixed with NCI in ether and the resulting precipitate was isolated. Yield: O0.09g of a light yellow solid.

Example 166

0.1 g of compound 210, 0.11 g of TBTU, 0.14 ml of DIPEA were dissolved in 2 ml of dimethylformamide and stirred for about

According to at 502C. Then 55 mg of 4-morpholinomethylphenylamine was added. Due to cooling, the temperature of the reaction during 17 hours. was lowered to room temperature. After that, dimethylformamide was removed in vacuo, the residue was dissolved in dichloromethane and extracted with water. Finally, the product was chromatographed on silica gel and crystallized from ethyl acetate and ether. Yield: 0.06 bg of yellowish crystals. (av)

Example 81

0.2 g of compound 724, 0.2 g of TBTU, 0.1 ml of DIPEA were dissolved in 100 ml of dichloromethane and stirred for 30 minutes. 09 at 2520. Then 0.1 g of 1-methyl-4-aminopiperidine was added and stirring was continued for another 17 hours. at 252C. Next, the solution was extracted with an aqueous solution of potassium carbonate, after which it was concentrated. The product was crystallized with simple ether. Yield: 0.16 g of white crystals. 20 Example 162 with 0.1 g of compound 25, 0.07 g of TBTU, 0.15 ml of DIPEA was dissolved in 5 ml of dichloromethane and stirred for 20 minutes. at 2520. Then 0.04 g of 1-methyl-4-aminopiperidine was added and stirring was continued for another 2 hours. :z" at 2520. Next, the solution was diluted with 15 ml of dichloromethane and extracted with 20 ml of water. The residue was dissolved in Meon and acetone, mixed with ml of HC in ether and concentrated. With the help of simple ether, ethyl acetate and a small amount of MeOH, a crystalline product was obtained. Yield: 0.1 g of white crystals.

Go) Example 88

0.1g of compound 26, 0.12g of TBTU, 0.12ml of DIPEA were dissolved in 10ml of dichloromethane and stirred for 30 minutes. at 2520. Then 0.04 g of 1-methyl-4-aminopiperidine was added and stirring was continued for another 2 hours. -I at 2520. Next, the solution was diluted with 100 ml of dichloromethane and extracted with 100 ml of water. With the help of ethyl acetate, ether and petroleum ether, a crystalline product was obtained. Yield: 0.bg of white crystals. Example 89

Fe 0.1 g of compound 26, 0.08 g of TBTU, 0.08 ml of DIPEA were dissolved in 10 ml of dichloromethane and stirred for 30 minutes. at 2590. Then 37 μl of M,M-dimethylneopentendiamine was added and stirring was continued for another 2 hours. at 2520. Next, the solution was diluted with 100 ml of dichloromethane and extracted with 100 ml of water. Finally, the product

Chromatographed on silica gel and crystallized using ethyl acetate, ether and petroleum ether. Yield: 0.005 g of white crystals.

Example 26 (name) O.15g of compound 27, 0.16bg of TBTU, 1ml of DIPEA were dissolved in 5ml of dichloromethane and stirred for 30 minutes. at 2520. Then 0.1 g of 4-morpholinocyclohexylamine was added and stirring was continued for another 60 17 hours. at 259C. The residue was mixed with 1 Oml of 1095 potassium carbonate solution, the precipitate was isolated and washed with water. It was then dissolved in dichloromethane and re-concentrated. The product was crystallized using ethyl acetate. Yield: 0.1 g of white crystals.

Example 9 150 mg of compound 729 and 9 mg of amine were dissolved in 5 ml of dichloromethane and for 12 hours. mixed at CT with 160 mg (0.50 mmol) of TBTU and 1 ml of DIPEA. Then the solvent was removed in vacuo and the residue was mixed with 10 ml of 10965 potassium carbonate solution. The precipitate was separated by vacuum filtration, washed with water, dissolved in dichloromethane, dried, and the solvent was removed under vacuum. The residue was crystallized from acetic acid ether. Output: 82,Omg, (dl 2532 (in the form of a base).

Example 16 1500 mg of compound 28 and 7 mg of trans-4-piperidinocyclohexylamine were dissolved in 5 ml of dichloromethane and stirred for 12 hours. mixed at RT with 16bOmg (0.50mmol) of TBTU and ml of DIPEA. Then the solvent was removed in vacuo and the residue was mixed with 1 Oml of 1095 potassium carbonate solution. The precipitate was separated by vacuum filtration, washed with water, dissolved in dichloromethane, dried, and the solvent was removed under vacuum. The residue was crystallized 70 from acetic acid ether. Yield: 87.0 mg, ypl 2372C (as base).

Example 37 100 mg of compound 29 and 42 mg of 3-amino-1-ethylpyrrolidene were dissolved in 10 ml of dichloromethane and for 12 hours. was mixed at CT with 9Omg of TBTU and 0.5ml of DIPEA. Then the solvent was removed in vacuo and the residue was mixed with 1 Oml of 1095 potassium carbonate solution. The precipitate was separated by vacuum filtration, washed with water, dissolved in 75% dichloromethane, dried, and the solvent was removed under vacuum. The residue was crystallized from acetic acid ether and petroleum ether. Output: 24, Ohm.

Example 120 100 mg of compound 211 and 7 mg of 4-amino-1-tetrahydro-4H-pyran-4-ylpyridine were dissolved in 1 ml of dichloromethane and for an hour. was mixed at CT with 9Omg of TBTU and 0.bBml of DIPEA. Then the solvent was removed under vacuum and the 2nd residue was mixed with T7Oml of 1095% potassium carbonate solution. The precipitate was separated by vacuum filtration, washed with water, dissolved in dichloromethane, dried, and the solvent was removed under vacuum. The residue was crystallized from acetic acid ether and petroleum ether. Output: 89 mg.

Example 212 150 mg of compound 25 and 1500 mg of trans-4--4-cyclopropylmethylpiperazin-1-yl)cyclohexylamine (in the form of 1 g; hydrochloride) were dissolved in 5 ml of dichloromethane and for 2 hours. mixed at CT with 1b0mg of TBTU and 2ml

DIPEA. Then the solvent was removed in vacuo and the residue was mixed with 1 Oml of 1095 potassium carbonate solution. The precipitate was separated by vacuum filtration, washed with water, dissolved in dichloromethane, dried, and the solvent was removed under vacuum. The residue was purified on a suitable column (20 ml of silica gel; ZOO ml of acetic acid ether and methanol in a ratio of 90:10-290 concentrated ammonia). The corresponding fractions were concentrated in vacuo and crystallized from acetic acid ether. Yield: 140 mg, (Pl 1872C (in the form of a base).

Example 232 vol

390 mg of compound 711 and 240 mg of trans-4-(4-tert-butyloxycarbonylpiperazin-1-yl)ucyclohexylamine were dissolved in 1-2.5 ml of M-methylpyrrolidone and for 2 hours. was mixed at CT with 482 mg of TBTU and ml of triethylamine. Then it was mixed with 100 ml of water and 200 mg of potassium carbonate, the precipitate was separated by vacuum filtration, washed with water at 5°C and purified on a silica gel column. The corresponding fractions were concentrated in a vacuum, dissolved in 2 ml (se) of dichloromethane, mixed with 2 ml of trifluoroacetic acid and stirred for 2 hours. at CT. Then it was re-mixed with 100 ml of water and 200 mg of potassium carbonate, the precipitate was separated by vacuum filtration and washed with water. After that, the sediment was purified on a silica gel column. The corresponding fractions were concentrated in vacuo and the residue was crystallized from ethanol and concentrated hydrochloric acid. Output: 95mg; (dl 29126.

Example 213 - c bOmg of the compound from example 232 was dissolved in 1Oml of acetic acid ether and during ZOkhv. mixed with 1 mL of acetic anhydride and 1 mL of triethylamine. Then the solvent was removed under vacuum, the residue was mixed with water and ammonia, the precipitated crystals were separated by vacuum filtration and washed with water and a small amount of cold acetone. Output: 4Omg, (dl 24826.

Example 218 (ee) 1.2 g of compound 29 and 0.5 g of 1,4-dioxaspiro(4,5|dec-8-ylamine) were dissolved in 20 ml of dichloromethane and stirred at RT for 12 hours with 1.28 g of TBTU and 4 ml of triethylamine. Then it was mixed with 50 ml of water and 0.5 g of potassium carbonate, the organic phase was separated, dried and concentrated in a vacuum. After that, the methanol was removed under vacuum, the precipitate was separated by vacuum filtration, washed with water and dried.

Fe" and 0.5 g of Mavn(OAs)z. Then water and potassium carbonate were mixed, the organic phase was separated, dried and the solvent was removed under vacuum. The residue was purified on a silica gel column. The corresponding fractions were concentrated in a vacuum and the hydrochloride was precipitated with the help of NSI in ether. Yield: 8 mg of trans-isomer, amorphous powder.

GF! Example 187 200 mg of compound 23, dissolved in 5 ml of dichloromethane, was mixed with 0.1 ml of diisopropylethylamine (DIPEA) and 180 mg of TBTU and stirred for 30 minutes. Then 191 mg of 4-(4-methylpiperazin-1-yl)phenylamine was added and stirred overnight. The reaction mixture was mixed with water and the aqueous phase was extracted with 60% dichloromethane. The combined organic phases were dried over Na»5O,; and concentrated. The residue was purified by column chromatography (eluent: dichloromethane/methanol in the ratio 100:7). Yield: 128 mg (crystals, slightly colored in yellow).

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ГЧ и B E TT E ! speech, SHY nka interrogation and NU ns - in ' ! : 1 E and I | : (o) fFetrdtt Bedevlya Yak- Ten A and she SHE she in pod v o s ! as Tag mon y o f s h o: You and SHE iz 20 | | | |! ! - And 1 KE i

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Iryk BAKA NIVI EE V ee shi she shi ee i Chapter b y Ya ka, " ! Her ; 7 ! Ж в -ій d : . Ж so vyy - that I х 70 | | -- . |. ІІ і | | І that and -, |. i zhd A i

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Her I | FROM AND | ІІ 4. І « el nyny en ie i shRUd i i ; | | in : SU Zh 0. sh shen ! ! | ! | and | Sa / What would you do?

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WE ARE YOU VIM KN M MA A MN A NN

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MO she sl: there is that en shiv VIM I and ischi pi 60 b5

In Va B Vch i vane in this VC, LJ Zvhny spe t ; и ши Ше в ше де ча в и Х ! g ke: ШЙ Shk "7 g ob od y | ny she she no vir en | y | Id zh

I | 4

E NYA: eh! | ! | nnsy | ! " - (I'm in the Inkcheu language

LY SCHI MISHIOV ry NI VYN MN ke and Ba shin ze

Also and | ; ! her and. oh, I ha 1 -I x Y Kk | Men in : !

Thank you for everything! K. shi

And I her what S I bar I ii o. because 65

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ГР рач жиши ШИ

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AND; E I E Ko ' Z a: shYayak: She i Her i, g Y i o 1 y... iy shi Her | | her 60 65

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And and and

Compounds of the general formula (I) have, as it was established, wide possibilities for use in (Ф, therapeutic purposes. In this case, it should be especially noted the possibility of their use in those cases when an important role is played by the inhibition of specific kinases involved in the regulation of cellular cycle, primarily an inhibitory effect on the proliferation of cultured human tumor cells, as well as on the proliferation of other cells, such as, for example, endothelial cells.

According to the results of the РАСсС35-analysis (cell sorting by the method of excited fluorescence) it was possible to establish that the inhibition of cell proliferation caused by the compounds proposed in the invention is mediated by the delay of cells mainly in the (2/M-period of the cell cycle. Cells depending on their specifically used in the analysis type are delayed in this phase of the cell cycle for a certain period of time, 65 after which programmed cell death sets in. The delay of cells in the s 2/M period of the cell cycle is initiated, for example, by inhibiting specific kinases involved in the regulation of the cell cycle.

Studies conducted in model organisms such as Zspygosspagotusez rotre or Heporiz, or studies conducted in human cells, indicate that the transition from b o period to mitosis is regulated by SOKT/cyclin B kinase (Migwe, 1990). . This kinase, which is also called "mitotic stimulating factor" (MPE) phosphorylates and thereby regulates a large number of different proteins, such as nuclear plates, kinesin-like motor proteins, condensins and matrix proteins of the Golgi complex. , which play an important role in the destruction of the envelope of the cell nucleus, in the separation of centrosomes, in the formation of the mitotic division spindle, in the condensation of chromosomes and in the destruction of the Golgi complex (Mida.

E., 2001). In one of the mouse cell lines with a temperature-sensitive mutant of the SOK1 kinase, after an increase in the 7/0 temperature, a rapid destruction of the SOK1 kinase is observed, followed by a delay of cells in the 5/M period of the cell cycle (Tip et al., 1990). Treatment of human tumor cells with inhibitors directed against

SOCl/cyclin B action, such as, for example, butyrolactone, also leads to the delay of cells in the 2/M-period and their induced apoptosis (Mivznio et al.. 1996). Another kinase that plays a role in So-period and mitosis is

Roio-like kinase 1 ("Roio-iKe Kipase 1", RIKI!), which is responsible for the maturation of centrosomes, for the activation of the 7/5 phosphatase Caс25C, as well as for the activation of the anaphase-stimulating complex ("aparpavze rgotoipu sotrieh") (Siomeg et al. ., 1998, Oiap et al., 2001). Injection of antibodies to RIC! leads to a delay in the o5o-period of non-transformed cells, in contrast to which the delay of tumor cells occurs in mitosis (I ape and Mida, 1996). In addition, according to literary sources, protein kinase ashgog B performs an essential function during mitosis. This ashgog B kinase phosphorylates histone НZ on 5ZekK!11 and thereby initiates the condensation of chromosomes (Nvy U.U. et al., 2000). However, a specific delay, i.e. arrest of the cell cycle in the bo/M-period can also be initiated, for example, as a result of inhibition of special phosphatases, such as, for example, Ca25C (Kizzei! and Mygze, 1986). Yeast with a defective sds25 gene is delayed in the o o period, while overexpression of sas25 leads to premature entry into mitosis (Kizzei!Yi and Migwe, 1987). At the same time, cell arrest, i.e., cell cycle arrest in the C2/M period, can also be initiated as a result of inhibition of certain motor proteins, i.e., so-called kinesins, such as Ed5 (Maueg et al., 1999), or by stabilizing or destabilizing microtubules with agents (for example, colchicine, taxol, and) etoposide, vinblastine, vincristine) (Zspiyi TaNogmiyi, 1980).

The compounds of the general formula (I), their isomers and their physiologically compatible salts proposed in the invention, taking into account their biological properties, are suitable for the treatment of diseases characterized by excess fat or abnormal cell proliferation.

Such diseases include, for example, viral infections (for example, HIV and Kaposi's sarcoma), - inflammatory processes and autoimmune diseases (for example, colitis, arthritis, Alzheimer's disease, glomerulonephritis M and processes occurring during wound healing), bacterial, fungal and /or parasitic infections, various types of leukemia, lymphoma, solid tumors, skin diseases (for example, psoriasis), bone diseases, as well as cardiovascular diseases (for example, restenosis and hypertrophy). In addition, the compounds proposed in the invention are effective in protecting proliferating cells (for example, hair cells, enterocytes, hemocytes and progenitor cells) from damage to their DNA under the influence of radiation, under the influence of UV radiation and/or during pitostatic therapy (Oamiz et al. , 2001).

The new compounds proposed in the invention can be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, including in combination with other active substances used for the same indications, for example, with cytostatics. . The effect of the compounds proposed in the invention was determined, for example, on Her a53Z cells in an experiment on cytotoxicity and? using cultured human tumor cells and/or by GAS analysis. The compounds proposed in the invention, when tested by both of these methods, showed effectiveness from good to very good, i.e., for example, the EC 59 value obtained in the cytotoxicity test using Hez3 cells was

Go! less than 5 μmol/L, usually even less than 1 μmol/L.

Determination of cytotoxicity on cultured human tumor cells o To determine cytotoxicity on cultured human tumor cells, tumor cells of the cervix -I uterine cancer line Hez3 (obtained from the American Type Culture Collection (ATSS)) were cultured in E12-medium 5o Hema (Pe Thesppoiodiyev company) and 1096th fetal calf serum (I Me Thesppoiodiev company) and collected in the phase of logarithmic growth. Then the cells of Ne a53 were introduced into 96b-well tablets (Sozviag company) with a density of 4) 1000 cells per well and incubated overnight in an incubator (at 372C in an atmosphere with a 596% CO content), ar

To this end, wells on each plate were filled only with culture medium (well C was used as a control with culture medium and well C was used for incubation with the reduced AiYiIatagVice blue dye). Active substances were added to the cells in different concentrations (dissolved in DMSO, final concentration 195) (experiments with active substances in iF) were performed in three repetitions for each of the studied concentrations). After incubation for 72 hours. in which 20 μl of AIatagVice dye (AssyMea Ipiegpaiopai company!) was added to each well and the cells were incubated for another 7 hours. For control, 20 μl of the reduced AiatagVice dye (AiatagVice reagent, autoclaved during ZOhv) was added to C wells. After incubation for 7 hours. the color change of the reagent was determined

AItagMore in separate wells in a fluorescent spectrophotometer of RegKkipEIteg company (wavelength of excitation radiation 533Onm, wavelength of emitted radiation 59Onm, 15 slits, integration time 0.1s). The amount of the reagent that reacted (changed color) AIatagMore is a measure of the metabolic activity of cells. The relative activity of the cells was calculated as a percentage of the control (65 NeGazz cells without inhibitor) and the concentration of the active substance at which the activity of the cells is inhibited by 5095 (IC0) was determined from the obtained values. At the same time, the corresponding values were calculated on the basis of the average value based on the results of three separate experiments with correction for the value obtained in the experiment without the inhibitor (control with culture medium).

EASZ-analysis

Propidium iodide (PI) binds stoichiometrically to double-stranded DNA and, due to this property, is suitable for determining the number of cells, expressed as a percentage, that are in the (si-, 5-, and bo/M periods of the cell cycle, based on the DNA content in Cells in the b and o periods contain diploid DNA (2M), and cells in the o and mitosis periods contain 4AM DNA.

For staining with propidium iodide, for example, 0.4 million Her a53 cells were sown in a 70-cm culture flask with a volume of 75 cm" and after 24 hours, 195th DMSO was added to the cells as a control, respectively, the investigated substance in different concentrations (in the 196th Then, the cells were incubated for 24 hours in the presence of the test substance, respectively, DMSO, after which the cells were washed twice with phosphate-buffered saline (PBS) and separated using trypsin/EDTC. Then, the cells were centrifuged (1000 rpm,

Bbhv., 42C) and the sediment containing the cells in the test tube after centrifugation were washed twice with SFR, and then cells 75 were resuspended in 0.1 ml of SFR. After that, the cells were fixed with 80956 ethanol for 16 hours. at 42C or within 2 hours. at -202C. Fixed cells (105 cells) were centrifuged (1000 rpm, 5 min., 42C), washed with SFR and then centrifuged again. After centrifugation, the sediment containing the cells in the test tube was resuspended in 2 ml of Triton X-100 in 0.2596th SFR and incubated for 5 minutes. on ice, after which 5 ml of SFR was added and centrifuged again. The sediment containing the cells in the test tube after centrifugation was resuspended in 350 μl of PI dye solution (0.1 mg/ml RNase A, 10 μg/ml propidium iodide in one-time SFR). Then the cells during 20 Ohv. were incubated in the dark in the presence of a dye buffer solution, after which they were transferred to containers for

EASZ-analysis of samples. The DNA content in the cells was determined in a RASZ-analyzer of the company Vesiop Oiskipvopo using an argon laser (power 500 mW, radiation wavelength 488 nm) and the OMA program

Seiyi Siezy (VO firms). Logarithmic PI fluorescence was determined using a bandpass filter (BP 585/42).. SM

For the quantitative assessment of cell populations in separate periods of the cell cycle, the Modgy IT program developed by Vesiop OiskKipzop was used.

The compounds of the general formula (I) can be used individually or in combination with other active substances proposed in the invention, and under certain conditions - in combination with other pharmacologically active active substances. Examples of acceptable dosage forms include tablets, capsules, suppositories, solutions, especially solutions for injections (subcutaneous, intravenous, intramuscular) and infusions, mixtures, emulsions or dispersible powders. The proportion of pharmaceutically active compound(s) in such dosage forms should be in each case from 0.1 to UOmas.9o, preferably from 0.5 to 5Omas.9o, from the total in of the mass of the drug, i.e. the content of the pharmaceutically active compound(s) in dosage forms should be sufficient for the introduction of the medicinal substance into the body in dosages whose intervals are indicated below. Such doses

If necessary, it can be divided into several doses per day. co

Suitable tablets can be made, for example, by mixing the active substance or substances with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as such as starch or gelatin, lubricants such as magnesium stearate or talc, or depot agents such as carboxymethyl cellulose, cellulose acetophthalate or Cs polyvinyl acetate. Tablets can also consist of several layers. Dragees can accordingly be made by coating the cores obtained similarly to tablets from materials commonly used for these purposes, for example, collidon or shellac, gum arabic, talc, titanium dioxide or sugar. Dragee cores can also be multi-layered to provide a depot effect or to avoid incompatibility. In the same way, the shell of the dragee can also consist of several layers to ensure the depot effect, while it is possible to use auxiliary substances, which are mentioned above for tablets.

In addition to the composition of mixtures based on the active substances proposed in the invention, accordingly, their combinations

They may also include sweetening substances such as saccharin, cyclamate, glycerin or sugar, as well as their flavor enhancer, for example, a flavoring such as vanillin or orange extract. In addition, mixtures may contain suspending aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives (protective substances), such as p-hydroxybenzoates.

Solutions for injection or infusion are prepared according to known technology, for example, with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal

F! salts of ethylenediaminetetraacetic acid, and if necessary with the use of emulsifiers and/or dispersants, while, for example, when using water as a diluent, if necessary, organic solvents can be used as hydrotropic solubilizers or auxiliary solvents, and then filled into bottles or ampoules for injections , respectively, in bottles for infusion. for Capsules containing one or more active substances, respectively a combination of active substances, can be made, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and packaging the resulting mixture into gelatin capsules.

Suitable suppositories can be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycol, respectively, their derivatives. As an example of excipients used in the preparation of dosage forms, we can name water, pharmaceutically acceptable (harmless) organic solvents, such as paraffins (for example, mineral oil fractions), vegetable oil (for example, peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carriers such as natural rock flours (e.g. kaolin, alumina, talc, chalk), synthetic rock flours (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane , milk and grape sugar), emulsifiers (eg lignin, spent sulfite alkali, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Preparations obtained on the basis of the corresponding active substances are introduced into the body by conventional methods, preferably orally or transdermally, preferably orally. In the case of oral administration, the corresponding 70 tablets may, as is obvious, in addition to the above carriers also contain impurities such as, for example, sodium citrate, calcium carbonate and dicalcium phosphate, together with various fillers such as starch, preferably potato starch, gelatin, etc. p. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used in the production of tablets. In the case of aqueous suspensions, the active substances, in addition to the auxiliary substances described above, can also be mixed with various flavor enhancers /5 or dyes. For parenteral administration, you can use solutions of active substances with liquid carriers suitable for this purpose.

With intravenous administration, the dose injected into the body is from 1 to 100 Ωg per hour, preferably from 5 to 50 Ωg per hour.

However, in some cases, namely, depending on the patient's body weight, the route of administration, the individual reaction of the body to the drug, the type of pharmaceutical composition and its nature, and from the moment of administration of the drug, the period of time during which the drug is administered, the dose, that is introduced into the body may differ from the quantities indicated above. Thus, in particular, it may sometimes be sufficient to use an active substance or active substances in a dosage lower than the above-mentioned lower limit, while in other cases it may be necessary to use an active substance or active substances in a higher dosage than the above-mentioned upper limit. If it is necessary to introduce an active substance or active substances in a larger dose, it may be appropriate to divide it into several smaller doses based on i) several doses per day.

Below, the invention is illustrated by examples, which present the compositions of some dosage forms and which do not limit its scope. со со Examples of pharmaceutical compositions

A) Tablets - -

Component Contents per tablet active substance 100mg (a.v.) lactose 140mg so corn starch 240mg polyvinylpyrrolidone 1Bmg magnesium stearate Bmg 5OOmMg « | | | | in sh o sh

The finely divided active substance is mixed with lactose and a part of the entire prescribed amount of corn starch. The resulting mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, granulated in a wet state and dried. The obtained granulate together with another amount of corn starch and magnesium stearate is sieved and mixed together. From the resulting mixture, tablets of the required shape and size are pressed. so what B) Tablets av) Component Contents per tablet active substance 8Omg lactose BBmg

Sg" 50 corn starch 190mg "so microcrystalline cellulose ZBmg polyvinylpyrrolidone 1Bmg sodium carboxymethyl starch 23mg magnesium stearate 2mg 400mg

F) t The finely divided active substance is mixed with a part of the entire amount of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone, the resulting mixture is sieved and, together with another amount of corn starch and water, processed into a granulate, which is dried and sieved. Next, 60 sodium carboxymethyl starch and magnesium stearate are added, mixed and tablets of the required size are pressed from the resulting mixture.

B) Solution in ampoules active substance 5BOmg bo sodium chloride /BOmg water for injections ml

The active substance at its own pH or, if necessary, at a pH of 5.5 to 6.5 is dissolved in water and mixed with sodium chloride as an isotonic agent. The obtained solution is filtered in non-pyrogenic conditions and the filtrate is packaged in ampoules under aseptic conditions, which are then sterilized and sealed.

Such ampoules can contain 5 mg, 25 mg or 5 mg of the active substance.

Claims (12)

The formula of the invention 1. Compounds of the general formula (I) ;() | : pe V NI ICH I ve. | ve with and (8) her s, s shchi | 6) -e Kk Pi in which VE! and B? have identical or different meanings and mean hydrogen or optionally substituted C .-Salkyl, 16 zo or "B" and B2 together form a 2-5-membered alkyl bridge that may contain 1-2 heteroatoms, BZ is hydrogen or a residue selected from the group consisting of optionally substituted c. C.-C.oalkyl, C.sub.1-C.sub.2alkenyl, C.sub.1-C.sub.2alkynyl and C.sub.6-Cidaryl, or a residue selected from the group consisting of optionally substituted and/or bridged 35C.sub.3-C.sub.41ocycloalkyl . CC? and KZ together form a saturated or unsaturated C-Silkyl bridge, which may contain 1 heteroatom, 7 40 5 and c B is a residue selected from the group consisting of hydrogen, -CM, hydroxy group, -MV 987 and halogen, or "from residues o selected from the group that includes optionally substituted Co 4-Svalkyl, Co-Svalkenyl, and 16 276 Co-Svalkynyl, C.-Svalkyloxy group, Co-Svalkenyloxy group, Co-Svalkynyloxy group, C.-Svalkylthio group, C.-Salkylsulfoxogroup and C.-Salkylsulfonyl, 45 1756 16 co Y is a linker selected from the group that includes optionally substituted Co 5-Siralalkyl, Co-Siralkenyl, Ce-Cidaryl, -Co-C;alkyl- Св-Cidaryl, -Св-Cidaryl-C.i-C,alkyl, optionally connected (ав) by a bridge bond Ca-C.ocycloalkyl and heterocyclyl containing 1 or 2 nitrogen atoms, 32 n means 0 or 1, -and 50 t means 1 or 2, pi B? is a residue selected from the group consisting of optionally substituted morpholinyl, se» piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl, tropenyl, KZ. diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -ME 82 and azacycloheptyl, and KE" have identical or different values and mean hydrogen or C.-C. alkyl, and 29 BZ and KO represent unsubstituted nitrogen substituents at K 9, have identical or different values and Ge) means either hydrogen or a residue selected from the group consisting of C 4 -C 4 alkyl, -C 1 -C 3 alkyl -C 3 -C 3 -cycloalkyl, C 3 -C 3 -cycloalkyl, Ce -Siaryl, -C 4 -C 4 alkyl -Ce-Sidaryl, pyranyl, pyridinyl, pyrimidinyl, C-C;alkyloxycarbonyl, C-C-4arylcarbonyl-, C.-C.alkylcarbonyl-, Ce-Ci4arylmethyloxycarbonyl-, Ce-Ci4arylsulfonyl-, C-C;,alkylsulfonyl- and Co-Silaryl-C-C;alkylsulfonyl-, because optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts. 2. Compounds according to claim 1, in which В!-К7, В5 and КЕ" have the above values, and Y is a linker selected from the group that includes optionally substituted С-С.ralkyl, 210 bo So- Cioalkenyl, St-Sidaryl, -Co-Slalkyl-Sv-Sidaryl, -Sv-Sidaryl-Si-S.lalkyl, optionally connected -B4- bridge bond C3-C12cycloalkyl and heterocyclyl containing 1 or 2 nitrogen atoms, n means 1, t means 1 or 2, B is a residue connected to I through a nitrogen atom, which is selected from the group consisting of necessarily substituted morpholinyl, piperidinyl, EZ-piperazinyl, pyrrolidinyl, tropenyl, EZ-diketomethylpiperazinyl, sulfoxomorpholinyl, sulfonylmorpholinyl, thiomorpholinyl, -ME ZE? and azacycloheptyl, VZ and B? represent unsubstituted nitrogen substituents at BK 9, have identical or different values and mean hydrogen or a residue selected from the group that includes C .-Salkyl, -C 4 -C;alkyl-C 3 -Siocycloalkyl, 70. cC.3-Cocycloalkyl, Ce-Ci4aryl, -Cc.-C/alkyl-Cv-Silaryl, pyranyl, pyridinyl, pyrimidinyl, C.-C.alkyloxycarbonyl, C.-C.arylcarbonyl-, C.-C.alkylcarbonyl-, C.-C.4arylmethyloxycarbonyl-, C.-C.4arylsulfonyl-, C-C;,alkylsulfonyl- and C.-Silaryl-C-C;alkylsulfonyl- , optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and also optionally in the form of their pharmacologically acceptable acid addition salts. 3. Compounds according to claim 1, in which B"-87, 5 and B" have the above values, and Y is a linker selected from the group that includes optionally substituted Co 5-Cyralalkyl, Co-Cyralkenyl, Ce -Sidaryl, -Co-C;alkyl-Cv-Sidaryl, -Cv-Sidaryl-C.i-C,alkyl, optionally connected by a bridge bond C3-C12cycloalkyl and heterocyclyl containing 1 or 2 nitrogen atoms , n means 0 or 1, t means 1 or 2, B? is a residue connected to I through a carbon atom selected from the group consisting of БЕ8-piperidinyl-, КЗЕ9-piperazinyl-, КЗ-pyrrolidinyl, КЗ-piperazinylcarbonyl-, БЗ-tropenyl, КЗ-morpholinyl and сч VZ azacycloheptyl, and BZ and KO represent unsubstituted nitrogen substituents at K 9, have identical or different values and and 9) mean hydrogen or a residue selected from the group that includes C.-Salkyl, -C.sub.4-C.alkyl-C.sub.3-Siocycloalkyl . C.-C.alkyloxycarbonyl, C.-C.arylcarbonyl-, C.-C.alkylcarbonyl-, C.-C.4arylmethyloxycarbonyl-, C.-C.4arylsulfonyl-, C.-C;alkylsulfonyl- and C.-C.4aryl-C.-C; alkylsulfonyl-, optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and M also optionally in the form of their pharmacologically acceptable acid addition salts. rch- 4. Compounds according to any of claims 1-3, in which И, т, п and КЗ-КЗ9 have the above values, and ВЕ! and B? have the same or different meanings and mean a residue selected from the group consisting of hydrogen, (ee) Me, EC, Pg, or B" and B" together form a Co-Slalkyl bridge, optionally in the form of their tautomers, their racemates , their enantiomers, their diastereomers and their mixtures, as well as optionally in the form of their pharmacologically acceptable acid addition salts. 5. Compounds according to any of claims 1-4, in which З with В", В, т, п and ЕЗ-Е8 have the above values, and :з" ВZ is a residue selected from the group that includes optionally substituted Co 4-Szoalkyl, C.-C.cycloalkyl, C.sub.3-C.sub.heterocycloalkyl and C.sub.6-C.sub.4aryl, or B and BZ or vk? and KZ together form a saturated or unsaturated Ca-Slalkyl bridge, which can Go! contain 1-2 heteroatoms, БЕ" is a residue selected from the group that includes hydrogen, ОМе, ОН, Ме, ЕІІ, Рг, ОЕІ, МНМе, МН», о E, SI, Вг, О-propargyl, О -butynyl, CM, Me, MMe", СОМН", ethynyl, propynyl, butynyl and allyl, and -I Y is a linker selected from the group which includes optionally substituted phenyl, phenylmethyl, cyclohexyl and branched C.- Svalkyl, e is optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and c" is also optionally in the form of their pharmacologically acceptable acid addition salts. 6. The compound of formula (I) according to any one of claims 1-5 for use as a medicine. 7. The compound of formula (I) according to any one of claims 1-5 for use as a medicinal product having an antiproliferative effect. 8. Compounds of the general formula (I) according to claim 1, in which the substituents for each specific compound have values, Ф, are listed in one row of the table: име) в! vd Config. IN! or B2 VZ va Id-vot 60 b5 1 N xz Az Kk g le He o neon. сн З с 2 н Although SN" in хз N ke SNU z nn g Kk r GO) Although" he ate J o o I SNU sch sho xz Az y Kz SN" not Ko o 0 ee o she LO, her " 5 n khz Az y Ha SN» Ten. - 0 о о о и -- фй ее со I SNU it ho SN В nya Sn h. "And oh M - p nyu ostsn. SK, ;" M: pi so y (av) 7 n och Kk ha SN» he - and with p. iz 70 and s» What M: i -- i (F. ko 60 65 vn xx v mk x g esNa z I. x : z ХК x Z 70 I y Khocha Az y g i x nNaelossn. snu 5 Z y 57 o o 1 n Khozhsn v x Sn» ny Z o With so and : и- SA ii s tn Khoch Y Ha cy he o Y 7 sn " 8-2 Z - - schi I" y Z 9: so znos" y ha hi He Z Sr : z iz 70 : s" (S Z I y s ko bo that hucha ON g ike nNaelossn sleep Z 65 ghh -BT- nast to ona m4n xx V Ш sn M , Shvy z Y z ne 5. Kor NI ki sno not sno where the symbols X., Ho, Xz, X1 and X5 given in this table mean the position in which the corresponding residue B", B2, VU, B" and I-E? is attached to another part of the molecule of the general formula (1). 9. A pharmaceutical composition containing as an active substance one or more compounds of the general formula (I) according to any of claims 1-4 or its (their) physiologically acceptable salts, if necessary, together with usual auxiliary substances and/or carriers. 10. The method of obtaining the compound of the general formula (I); to her WE M Her l . koh v Ten p Z that z o un cm (8) I, in which 27-85, t, p and Y have the values specified in claims 1-5, which differs in that the compound of the general "formula (II)"; (I) - MO in A is with ATOM Y in2 Z « in which B !-KZ have the values indicated in claims 1-4, and A means a leaving group selected from O-methyl, -5СМ, chlorine, bromine , iodine, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl, are subjected to reaction with an optionally substituted compound of the general formula (1) xz» Mn. (7) KU. co. . (c) He) group -I 1" 50 in which VE has the values specified in claims 1-5, and 279 represents the group OH, MH-I-B, -O-methyl or -O-ethyl, and then, under certain conditions, the product of the general formula (IM) c» | ; (M) and IR (al M vy and I o nm MI MI E2 in ko . R 60 TV) and ro in which B 7-K7 have the values indicated in claims 1-5, and BO represents the OH group, - МН-И-В 5, -O-methyl or 65 -O-ethyl, if necessary, after preliminary hydrolysis of the ester group -SOK 10. are subjected to interaction with an amine of the general formula (M) MNe-I- (M), in which VE? has the meaning specified in claims 1-5. 11. Compound of formula (II) | ; (1) - M s tn ATOM M v2 yus z in which B !-EZ have the values specified in claims 1-5, and A means a leaving group selected from O-methyl, -VBSM, chlorine, bromine, iodine, methanesulfonyl, trifluoromethanesulfonyl or p-toluenesulfonyl. 12. A compound that is an intermediate for obtaining a compound of the general formula I according to any of claims 1-5, in which Y is cyclohexyl, n means 1, t means 1, and B? is 4-cyclopropylmethylpiperazinyl, and the specified intermediate compound is cis- or trans-4-(4-cyclopropylmethylpiperazin-1-yl)-cyclohexylamine. . And nm pa. MI nm MI b b y. I I o Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 17, 25.10.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. o « cha «c) d) - c;" (ee) («c) -I iz 50 syu» F) ime) 60 b5