UA81292C2 - Hiv replication inhibiting pyrimidines and triazines - Google Patents

Abstract

This invention concerns HIV replication inhibitors of formula (I), The N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

Description

Description of the invention

The present invention relates to pyrimidine and triazine derivatives that have the ability to inhibit the replication of human immunodeficiency virus 2 (HIV). The invention also relates to production methods and pharmaceutical compositions containing these compounds. The invention also relates to the use of the mentioned derivatives for the production of a medicinal product for the prevention or treatment of HIV infection.

The purpose of this invention is to provide a new group of pyridine derivatives that have activity in relation to HIV replication. Some substituted 70 aminopyrimidines are described in (publications MO 99/50250, MUO 00/27825 and MO 01/85700), and in (publications UMO 99/50256 and ER 0834507) aminotriazines are described that have properties of inhibiting HIV replication.

The compounds of the present invention differ from the compounds known from the prior art in terms of structure, pharmacological activity and/or pharmacological efficacy. It was found that the compounds of the present invention act in a beneficial way not only in terms of their ability to inhibit the replication of human immunodeficiency virus 72 (HIV), but also because of their increased ability to inhibit the replication of mutant strains, in particular strains that have become resistant to commercially available drugs ( i.e. so-called drug or multi-drug resistant strains of HIV).

Thus, according to one aspect, the present invention relates to a compound of formula I

E) 4 uche o fo ; 25 M A o Sh-ed o yat n: T (in and c 30 of its M-oxide, a pharmaceutically acceptable additive salt, a quaternary amine or its stereochemically isomeric (o) form, in which 1-a82.8Z-d 4 I her с -а"-а--аг-а"- is a bivalent radical of the formula "- -SNASN-SNASN- (a-1); 35 -MASNA-SNASN-A (a-2); 09 -MASNAMASN-A ( a-3); -MASNASNAM- -(a-4); -MAMASNASN-A (a-5); "c is -61-62-p3. is a bivalent radical of the formula a z" -O-СНо-СНо- (6-1); -О-сн-СН-А (р-2); -8-СНо-СНо- (р-3); со -8-СН-СН- (р-4); -Сно- сСНАСсН- (6-5); - р n is equal to 0, 1, 2, З or 4; and when -а5а2-аЗ-а?- is (а-1); then н can also be equal to 5; т is equal to 0 , 1, 2, Z; d) a is equal to 0, 1 or 2; because p is equal to 1 or 2;

BE" represents hydrogen; aryl; formyl; C/4.alkylcarbonyl; C. alkyl; C. alkyloxycarbonyl; C. alkyl substituted by formyl, C. alkylcarbonyl, C. alkyloxycarbonyl, C. alkylcarbonyloxy; C. alkyloxyC i. alkylcarbonyl, substituted by C. alkyloxycarbonyl; each B? is independently hydroxy, halogen, C 4.alkyl, optionally substituted by cyano or -C-ov, C.sub.3.cycloalkyl, C.sub.alkenyl, optionally substituted by one or more halogen atoms or cyano , ko Co.valkynyl, optionally substituted by one or more halogen or cyano atoms, C 4 valkyloxycarbonyl, carboxyl, cyano, nitro, MAV", polyhalogenmethyl, polyhalogenmethylthio, -5(хО)рВ?, -МН-5(-О )р?, -С(хО)е, 60 -Мне(5о)н, -С(-ОМНИМН», -«МНе(-Ов5, -«С(-МНЕ? or the radical of the formula b5 but te and (о)

A, 8 in which every A; independently represents M, CH or se; and

Ag is MH, О, 5 or МАЕ;

X is -MA 5-, -МН-МН-, -М-М-, -О-, -С(50)-, С. p-, -MA3-0(-0)-, -F(50)-MA73-, -X»-C.4alkanediyl- or -Si4alkanediyl-X o-;

Ho represents -MeE2-, -МН-МН-, -МеМ-, -О-, -Фщ-0)-, -СНОНУ-, -5-, -8(50)р-;

VZ is hydrogen, halogen, C 4.alkyl, MUSCLE, -с(50)-МК ЗВ, -с(50)-К75, -"СНАМ-МН-С(-0)-К 5, -в (-m-0-28)-S. dalkil, B or -Xa-87; or C..alkyl substituted by one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, MKU 9, -C(-0)-MEUV 9, -C(50)-C. valkyl or VC", and in addition to the specified list of substituents, two geminal hydrogen atoms of the specified C alkyl may also be replaced by Co alkandyl, thus forming a spirocycle; selected from hydroxy, cyano, ME?9, -c(50)-MAEUV U, -b(-0)-C alkyl or HeCo valkenyl, substituted with one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, MAEUV'O, -сС(50)-МВУВ"9, -с(-0)-С. valkyl or B"; Co valkynyl substituted by one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, MK zvo, sc dv 7 o(50)-MAUV , -C(-0)-C. valkyl or K";

Xz represents -МК 5., -МН-МН-, -МЕМ-, -О-, -ФШ-0)-, -5-, -3(-Ор-, -Хо-С. lalkandiyl-, -С4 .lalkandiil-X za-, o -S. dalkandiil-Hoh-Smalkandiil, -s(-M-Ok8)-S. dalkandiil-; where

Hoa is -MIN-MH-, -MEM-, -О-, -С(20)-, -5-, -8(5О) p-; and

Khoi represents -МН-МН-, -MEM-, -С(50)-, -5-, -3(2-0 р-; с

B" represents halogen, hydroxy, C 4 alkyl, C 4 alkyl, Co valkenyl, Co valkynyl, C 7 ucycloalkyl, C 7 alkyloxy, cyano, He! nitro, polyhalogen. alkyl, polyhalogenC. alkyloxy, -F(50)-MA ZB, C alkyloxycarbonyl ,

S. valkylcarbonyl, formyl, -MA ZA" or B 7;

VO is hydrogen; aryl; formyl; C 4. alkyl carbonyl; S. valkil; C. valkyloxycarbonyl; C..valkyl, -- z5 Substituted by formyl, C. valkylcarbonyl, C. valkyloxycarbonyl or C. valkylcarbonyloxy; at

C. valkyloxys 4 valkylcarbonyl, substituted with C. valkyloxycarbonyl;

VZ is S. dalkil, -MAE ZV" or polyhalogens. dalkil;

B is a monocyclic, bicyclic or tricyclic saturated, partially saturated or "aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the specified carbocyclic or heterocyclic systems can be optionally substituted by one, two, with three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C.alkyl, hydroxyC.alkyl, aminoC.ialkyl, mono- or "di(C.alkyl)amino 4alkyl, formyl, C. alkylcarbonyl, C. cycloalkyl, C. alkyloxy,

S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. valkyloxy, aminocarbonyl, -CH(-M-O-K8), K 72, -X3-K 72 or K72-C. far away CO represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or - aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the specified carbocyclic or heterocyclic systems can be optionally substituted by one, two, by three, four or five substitutes, each of them independently

Ge) 20 is selected from halogen, hydroxy, mercapto, C-alkyl, hydroxy-alkyl, amino-alkyl, mono- or di(C-alkyl)amino 4-alkyl, formyl, C-alkylcarbonyl, C-cycloalkyl, C-alkyloxy, etc. S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. valkyloxy, -F(-0)-MK1zv i, sn(-M-O-25);

BZ is hydrogen, C 1 alkyl, aryl or arylC. dalkil;

ВО and В'9О are each independently hydrogen; hydroxy; C 4-alkyl; Si valkyloxy; S. valkylcarbonyl; i) C. valkyloxycarbonyl; UIA; -С(50)-МА ЗА"; "СН(-МА ") or K", where each of the above C.i.alkyl co groups can be optionally and independently substituted by one or two substituents, each of which independently selected from hydroxy, C. alkyloxy, hydroxyC-.alkyloxy, carboxyl, C. alkyloxycarbonyl, cyano, imino, 60 -MA'ZV m, polyhalogenmethyl, polyhalogenmethyloxy, polyhalogenmethylthio, -B(хО)рАЯ, -«МН-8(- О)рА, -С(-О в, -МНе(-о)н, -с(ОМНМНН», -МНе(-о)в59, -С(-МНВ, В"; or

IN? and KO can together form a bivalent or trivalent radical of the formula -СНо-СНо-СНо-СНо- (4-7) b5 -СНо-СНо-СНо-СНо-СНо- (4-2)

-СНо-СНо-О-СНо-СНо- (4-3) -СНо-СНо-8-СНо-СНо- (4-3 -СнНо-СНо-МА 12-сНо-СНо- (9-5) 2 - СНо-СНАСН-СНо- (а-6) «снАСНАСНАСНАСН- (а-7)

B" represents cyano; C 44 alkylcarbonyl; C. dalalkyloxycarbonyl; -C(-0)-MV'ZVY'; or C. dalalkyl, optionally substituted with Si daloxy-, cyano, -MK 3877 or -C(-0 )-ME Sv;

K is hydrogen or C 1 -alkyl;

VZ and EK" each independently represents hydrogen, Ni, C 1-alkyl, optionally substituted by cyano or aminocarbonyl, Co. valkenyl, optionally substituted by cyano or aminocarbonyl, C».valkynyl, optionally substituted by cyano or aminocarbonyl ; 75 V": represents C. alkyl, optionally substituted by cyano or -C(-0)-MvZVya;

B" represents KE" or C. alkyl, optionally substituted by cyano or -C(-0)-MA ZV;

B", if present, each independently represents cyano, halogen, hydroxy, -С(-О)-МА "ЗВ, C. alkyl optionally substituted with one or more substituents independently selected from cyano, -С(-0 )-MA 387 or halogen; Co. valkenyl, optionally substituted by one or more substituents independently selected from cyano, -C(хО)-МВ ЗВ" or halogen; Co valkynyl, optionally substituted by one or more substituents independently selected from cyano, -С(-0 )-ME'38'? or halogen; and, when possible, K'/ can also be attached to the -57-62-653- fragment by means of a double bond, whereby B" is then -O, -5, МН, "М-В5, -М-В 7, -М-О-К75, -М-О-К7, "СНО, "СН-С(-0)-МВ ЗВ, -СН-В or -SN-K Z; where "CHO can be optionally substituted by cyano, hydroxy, halogen, nitro; with

O is hydrogen, S is alkyl, halogen, polyhalogenS. valkyl, -C(-0)-ME ZV "7 or -MEUV o; (o) 7 represents C-U or M, where

M represents hydrogen, hydroxy, halogen, C4-alkyl, C3-7cycloalkyl, C-alkyloxy, C-alkyloxycarbonyl, carbonyl, cyano, nitro, -ME'ZE"Y, polyhalogenmethyl, polyhalogenmethyloxy, polyhalogenmethylthio, -B(xO) рА, с зо -МН-8(-0)88, -МН-505-К8, -МН-505-(Si 4-alkanediyl)-СО-М(ВУ)», -С(-0)88, - МНе(OH, 0 -С(ОМНМН», -МНе(-:о3в8, -с(50)-МН-28, -С(-МНВ8, aryl or Ф

Co. valkenyl, optionally substituted by one or more halogen atoms; with

Co.valkynyl, optionally substituted by one or more halogen atoms; -

S. valkyl, substituted by cyano or -С(-О)К8;

C5 aryl is phenyl or phenyl substituted with one, two, three, four or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C 4 alkyl, hydroxyC. valkyla,

C. valkyl-MV"ZV 7, C. valkylcarbonyl, C3cycloalkyl, C. valkyloxy, Si valkyloxycarbonyl, C. .valkylthio, cyano, nitro, polyhalogenC. valkyl, polyhalogenC. valkyloxy, -C(20)-MA"ZV Ya, B" or -Xa-K 7; « 20 It is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the specified carbocyclic or heterocyclic systems can be optionally substituted by one, two, three, four or five substituents, each of which is independently selected from halogen, C-hydroxy, mercapto, C-alkyl, hydroxy-C-alkyl, amino-C-alkyl, mono- or di(C-alkyl)amino 4-alkyl, formyl, C .alkylcarbonyl, C3/cycloalkyl, C.alkyloxy,

S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. valkyloxy,

Go! -6(50)-МА1ЗВ 14, сН(-М-О-88), with The term "C..alkyl", used in this description above or further when designating a group or part of a group, refers to saturated hydrocarbon radicals with direct or a branched chain containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl; the term "C..alkyl" when denoting a group or part of a group refers to saturated hydrocarbon radicals with a straight or branched chain containing from 1 to b carbon atoms, such as groups defined by the term "C 4.alkyl", as well as pentyl , hexyl,

Kz 2-methylbutyl, etc.; the term "co-alkyl" when referring to a group or part of a group refers to saturated hydrocarbon radicals containing from 2 to 6 carbon atoms, such as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, etc. ; the term "C..4alkanediyl" refers to straight or branched chain bivalent saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as methylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanedyl or 1,3-propylidene, 1,4-butandyl or 1,4-butylidene, etc.; term

F, "C37cycloalkyl" is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; where the term "Co. valkenyl" refers to hydrocarbon radicals with a straight or branched chain containing from 2 to b carbon atoms and containing a double bond, such as ethenyl, propenyl, butenyl, pentenyl, bo hexenyl, etc. ; the term "co-valkynyl" refers to straight or branched chain hydrocarbon radicals containing from 2 to b carbon atoms and containing a triple bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

In some examples, the radicals С.4.valkynyl, Sovalkenyl or Со valkynyl can be substituted by one or more substituents. In the case when the presence of 1, 2, 3, 4, 5, 6 and more substituents is possible, their 65 number is limited by the number of carbon atoms and the degree of unsaturation of the hydrocarbon radical. Radicals

Su valkynyl, Co valkenyl or Co valkynyl are preferably substituted and contain up to C substituents.

A monocyclic, bicyclic or tricyclic saturated carbocycle is a cyclic system containing 1, 2 or 3 rings, and this cyclic system contains only carbon atoms and contains only single bonds; A monocyclic, bicyclic or tricyclic partially saturated carbocycle is a ring system that contains 1, 2 or C rings, and said ring system consists only of carbon atoms and includes at least one double bond, provided that the ring system is not aromatic cyclic system; monocyclic, bicyclic or tricyclic aromatic carbocycle is an aromatic cyclic system containing 1, 2 or 3 rings, and the specified cyclic system consists only of carbon atoms; the term "aromatic" is well known to one skilled in the art and 70 refers to cyclically conjugated systems with 4p42 electrons, i.e. 6, 10, 14, etc. l-electrons (rule

Hückel); monocyclic, bicyclic or tricyclic saturated heterocycle is a cyclic system that contains 1, 2 or 3 rings and that contains at least one heteroatom selected from atoms 0, M or 5, and the specified cyclic system contains only single bonds; monocyclic, bicyclic or tricyclic partially saturated heterocycle is a cyclic system that contains 1, 2 or C rings and that contains, 7/5 at least one heteroatom selected from O, M or 5 atoms, and that contains at least one double bond provided that the ring system is not an aromatic ring system; monocyclic, bicyclic or tricyclic aromatic heterocycle is an aromatic cyclic system containing 1, 2 or 3 rings and containing at least one heteroatom selected from O, M or 5 atoms.

Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, isocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo|4,2,0|octanyl, cyclononanil, cyclodecanyl, decahydronaphthalenyl, tetradecahydroanthracenyl, etc. Preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; cyclopentyl, cyclohexyl, cycloheptyl are more preferred.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, su bicyclo|4,2,F|octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4 4a,9,9a,10-octahydroanthracenyl, etc. Cyclopentenyl, cyclohexenyl, cycloheptenyl are preferred. and)

Specific examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthalenyl, anthracenyl. Phenyl is preferred.

Конкретними прикладами моноциклічних, біциклічних або трициклічних насичених огетероциклів є су 3о тетрагідрофураніл, піролідиніл, діоксоланіл, імідазолідиніл, тіазолідиніл, тетрагідротієніл, дигідрооксазоліл, ізотіазолідиніл, ізоксазолідиніл, оксадіазолідиніл, триазолідиніл, тіадіазолідиніл, б» піразолідиніл, піперидиніл, гексагідропіримідиніл, гексагідропіразиніл, діоксаніл, морфолініл, dithianyl, Ha thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl, etc. Preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl, -piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl. Particularly preferred are tetrahydrofuranyl, o pyrrolidinyl, dioxolanyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxynyl, indolinyl, etc. Preferred are pyrrolinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, indolyl. Concrete examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are acetyl, oxyethylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and? benzofuryl , бензотриазоліл, пуриніл, хінолініл, ізохінолініл, цинолініл, хінолізиніл, фталазиніл, щщ хіноксалініл, хіназолініл, нафтиридиніл, птеридиніл, бензопіраніл, піролопіридил, тієнопіридил, фуропіридил, ізотіазолопіридил, тіазолопіридил, ізоксазолопіридил, оксазолопіридил, піразолопіридил, |імідазопіридил, ка піролопіразиніл, тіенопіразиніл, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidine, is, isothiazolopyramidinyl, thiazolopyrimidinyl, isoxazolopyramidinyl, imidazopyrimidinyl, oxazolopyramidinyl піридазиніл, тієнопіридазиніл, фуропіридазиніл, ізотіазолопіридазиніл, тіазолопіридазиніл, ізоксазолопіридазиніл, оксазолопіридазиніл, піразолопіридазиніл, імідазопіридазиніл, оксадіазолопіридил, тіадіазолопіридил, триазолопіридил, оксадіазолопіразиніл, тіадіазолопіразиніл, триазолопіразиніл, оксадіазолопіримідиніл, тіадіазолопіримідиніл, триазолопіримідиніл, оксадіазолопіридазиніл, тіадіазолопіридазиніл, триазолопіридазиніл, імідазооксазоліл, імідазотіазоліл, (Ф, імідазоімідазоліл , isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, cothiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc. Preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles.

Monocyclic, bicyclic or tricyclic aromatic heterocycles of interest are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl .

піролопіридил, тієнопіридил, фуропіридил, ізотіазолопіридил, тіазолопіридил, ізоксазолопіридил, оксазолопіридил, піразолопіридил, імідазопіридил, піролопіразиніл, тієнопіразиніл, фуропіразиніл, ізотіазолопіразиніл, тіазолопіразиніл, ізоксазолопіразиніл, оксазолопіразиніл, піразолопіразиніл, імідазопіразиніл, піролопіримідил, тієнопіримідиніл, фуропіримідиніл, ізотіазолопіримідиніл, тіазолопіримідиніл, ізоксазолопіримідиніл, оксазолопіримідиніл, pyrazolopyrimidinyl, imidazopyrimidinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxodiazolopyrimidinyl, thiodiazolopyrimidinyl, triazolopyridinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, etc. 70 Aromatic heterocycles of particular interest are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, etc.

The term (50) as used herein above forms a carbonyl moiety when the group is attached to a carbon atom, a sulfoxide moiety when the group is attached to a sulfur atom, and a sulfonyl moiety when the two groups are attached to a sulfur atom.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "polyhalomethyl," as used herein to refer to a group or part of a group, refers to mono- or polyhalogen substituted methyl, in particular, methyl with one or more fluorine atoms, for example, difluoromethyl or trifluoromethyl; the term "polyhalogenSialkyl" or "polyhalogenC. "alkyl", used in this description to denote a group or part of a group, means a mono- or polyhalogen-substituted C.alkyl or Sialkyl, for example, the groups given in the definition of the term thalogenmethyl" 1,1-difluoroethyl, etc. In the case when the alkyl group in the definition of polyhalogenmethyl, polyhalogenC..4alkyl or polyhalogenC. more than one halogen atom is attached to the valkyl, (8) then they can be the same or different.

It is understood that the term "heterocycle" in the definition of B/ or B/2 includes all possible isomeric forms of heterocycles, for example, pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl. Ge

A carbocycle or heterocycle as defined by K' or K"2 may be attached to the remainder of the molecule of formula (I) through any suitable ring carbon atom or heteroatom, except in cases specifically defined. F

Thus, for example, when the heterocycle is imidazolyl, it can be 1-imidazolyl, 2-imidazolyl, sem 4-imidazolyl, etc., or when the carbocycle is naphthalenyl, it can be 1-naphthalenyl, 2-naphthalenyl, and - etc.

If any variable (eg, VC", heteroatom, Xo) occurs more than once in any d) component, each definition is independent.

Lines drawn from the substituents in the ring systems show that the bond can be attached to any suitable ring atom. "

For therapeutic use, salts of compounds of formula (I) are salts in which the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, regardless of whether they are pharmaceutically acceptable or not, are within the scope of this invention. It is understood that the term "pharmaceutically acceptable addition salts" mentioned above includes therapeutically active non-toxic forms of addition salts of acids that can form compounds of formula (I). The latter can usually be obtained by treating the basic form with suitable acids, such as inorganic acids, such as, for example, hydrohalic acids, in particular, hydrochloric acid, hydrobromic acid, etc.; sulfuric acid; - nitric acid; phosphoric acid, etc.; or organic acids, for example, acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, oxalic acid, imo) malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, about 50 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid,

IR) 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid, etc. | conversely, the salt form can be converted to the free base form by treatment with alkali.

Compounds of formula (I) containing acidic protons can be converted into their therapeutically active non-toxic metal or amine salt addition forms by treatment with suitable organic and inorganic

Gee! basics Suitable basic salt forms include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium, and the like, salts with organic co-bases, for example, with primary, secondary and tertiary aliphatic and aromatic amines, such as salts of methylamine, ethylamine, propylamine, isopropylamine, four isomers of butylamine, dimethylamine, 60 diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, M-methyl-O-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine and salts with amino acids such as, for example, arginine, lysine, etc. . | conversely, the salt form can be converted by acid treatment to the free acid form. The term "addition salt" also includes hydrates and addition forms with b5 solvent (solvates) that can form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholates, etc.

The term "quaternary amine" as used above refers to the quaternary ammonium salts that compounds of formula (I) can form upon reaction between the basic nitrogen of the compound of formula (I) and a suitable quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, for example methyl iodide or benzyl iodide. Other reagents with a readily leaving group can be used, such as alkyltrifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine contains a positively charged nitrogen atom. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, trifluoroacetate and acetate. The selected counterion can be introduced using ion-exchange resins. 70 It is understood that M-oxide forms of the presented compounds include compounds of formula (I), where one or more tertiary nitrogen atoms are oxidized to the so-called M-oxide.

It should be noted that some compounds of formula (I) and their M-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more chiral centers and exist as stereochemically isomeric forms.

The term "stereochemically isomeric forms" used above includes all possible stereoisomeric forms that compounds of formula (I) and their M-oxides, addition salts, quaternary amines or physiologically functional derivatives may have. Except in cases specifically mentioned or indicated, the chemical designation of compounds includes a mixture of all possible stereoisomeric forms, and said mixtures contain all diastereomers and enantiomers of the basic molecular structure, as well as each of the individual isomeric forms of formula (I) and their

M-oxides, salts, solvates or quaternary amines, strictly speaking free, that is, which contains less than 1095, preferably less than 595, especially preferably less than 2905 and most preferably 195 other isomers. Thus, when a compound of formula (I) is described, for example, as (E), it means that the compound is, strictly speaking, free of the (7) isomer.

In particular, stereoisomeric centers can have K- or 5-configuration; Substituents on bivalent cyclic (partially) saturated radicals can have a cis- or trans-configuration. Compounds containing double bonds can have Е (epidedep) or 7 (2isotep)-stereochemistry at said double bond. The terms "cis-", i) "trans-", "KK", "8", "EE" and "7" are well known to those skilled in the art. It is clear that stereochemically isomeric forms of the compounds of formula (I) are included within the scope of this invention.

For some compounds of formula (I), their prodrugs, M-oxides, salts, solvates, quaternary amines or

Of the metal complexes, as well as the intermediate products used in their preparation, the absolute stereochemical configuration has not been determined experimentally. In these cases, the stereoisomeric form that was isolated first is denoted as "A" and the second is denoted as "B" without further indication of the actual c stereochemical configuration. However, the specified stereoisomeric forms A" and "B" can be unambiguously characterized, for example, by their optical rotation, when "A" and "B" have enantiomeric differences. --

A skilled person can determine the absolute configuration of such compounds using known methods, such as, for example, radiography. When "A" and "B" are stereoisomeric mixtures, they may be separated and the corresponding first fractions separated are designated as "A7" and "B1" and the second as "TA2" and "B2" without further indication of the actual stereochemical configuration.

Some compounds of formula (I) may also exist in tautomeric form. It is understood that such forms, although not specifically indicated in the formula presented above, are included within the scope of this invention. It is understood that the term "compounds of formula (I) used in this description includes those

M-oxides, salts, quaternary amines and stereochemically isomeric forms. Compounds are of particular interest;" of formula (I), which are stereochemically pure.

In all preceding or subsequent cases, mention is made that each of the substituents may be independently selected from a plurality of definitions, such as, for example, for K 9 and VZ. are meant all chemically

Ge | possible combinations or combinations that provide chemically stable molecules.

A separate subgroup of compounds of formula (I) is represented by compounds in which 7 is M. Another subgroup is represented by compounds of formula (I) in which 7 is C-U. име) A separate subgroup of compounds of the formula (I) is represented by compounds in which -5 1-62-63- is a bivalent radical of the formula se)

ГЯ6) -О-СНо-СНо- (p-1); -О-сн-СН- (p-2); -8-СНо-СНо- (p-3); -8-CH-CH- (p-4). o In this subgroup, compounds in which -651-62-63- is a radical (B-1) or (p-2) are of particular interest. o Another separate subgroup of compounds of formula (I) is represented by compounds in which -5.1-62-53- represents a bivalent radical of formula 60 -Сно-сСнНАСсн- (p-5).

Other subgroups are subgroups in which the specified limiting conditions apply for 7 and for -51-62-63-,

Subgroups of compounds of formula (I) of interest are compounds in which one or more of the restrictions (a)-(M) apply: (a) -a"-a2-aZ-a"- is a bivalent radical of the formula

-SNASN-SNASN- (a-1); (5) n equals 0, 1, 2, Z; 2 (c) t is equal to 0, 1 or 2; (4) KE" represents hydrogen; formyl; C 4 alkylcarbonyl; C. alkyl; C. alkyloxycarbonyl; C. alkylcarbonyl,

C-6 alkyloxycarbonyl; (e) every K? independently represents hydroxy, halogen, C 4 alkyl, optionally substituted cyano or -«-OzhZh b Cz /cycloalkyl, Si. valkenyl, optionally substituted by one or more halogen or cyano atoms, C»valkynyl, optionally substituted by one or more halogen or cyano atoms,

C. valkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono(C. valkyl)amino, di(C. valkyl)amino, polyhalogenmethyl, polyhalogenmethylthio, -5(-0)р8?, -МН-5(-О)р ?, -б(50)б, МНе(ЗО)Н, -С(О)МНИМН», -МНе(-:о85, -С(-МН)Б5 or the radical of the formula , pom di)

AND

AND,

Fe in which every A! independently represents M, CH or CE; and

A represents MH, O, 5 or ME; сч () Hu represents -ME 9-, -МН-МН-, -М-М-, -О-, -С(-0)-, Si dalkanediyl, -СНОН-, -5-, -8( 5O)p-, -"MA"-0(50)-, -F(50)-MA 73-, -X"-C.4alkanediyl- or -Si 4alkanediyl-X o-; o (9) Ho represents is -ME 2-, -O-; (p) KZ is hydrogen, halogen, C 4alkyl, -MK ZV, -С(50)-МА"ЗВ7Я, -С(-0)-875, -Х3-К 7; C. valkyl, substituted by one or several substituents, each of which is independently selected from cyano, B / or c -C(50)-MVUVO; Co valkenyl substituted with one or more substituents each selected from halogen, (o) cyano or -F(50)-MeUvB7o or B"; or Co valkynyl substituted with one or more substituents each independently selected from halogen , cyano, -"C(-0)-MEUV 9 or B"; () Xz represents -ME2-, -МН-МН-, -М-М-, -О- or -5-; - () BE" is halogen, hydroxy, C 4 alkyl, Sovalkenyl, Co valkynyl, C valkyloxy, cyano, nitro, (oo) polyhalogenC and valkyl, polyhalogenC and valkyloxy, -C(-0)-MA" ZV"", C. valkyloxycarbonyl, C. valkylcarbonyl, formyl, -MAE ZE" or B 7; (Y) B? represents hydrogen; formyl; C. valkylcarbonyl; C. valkyl or C. valkyloxycarbonyl; « ю () 29 is S. dalkil, -MAE ZV" or polyhalogen. dalkil; C c (t) VK' is a monocyclic or bicyclic, partially saturated or aromatic carbocycle or a monocyclic or bicyclic, partially saturated or aromatic heterocycle, where each of the specified "c" carbocyclic or heterocyclic systems can be optionally substituted by one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C /.alkyl, hydroxyC. valkyl, 415 aminoC.i valkyl, C. valkylcarbonyl, C. valkyloxy, Si valkyloxycarbonyl, C. valkylthio, cyano, nitro, o polyhalogen 4 valkyl, polyhalogenS. alkyloxy or aminocarbonyl; (n) K is hydrogen, C-C-alkyl or arylC-C-alkyl; - (about) EC? and K"O each independently represents hydrogen; C 4 alkyl; C. alkyloxy; C. alkylcarbonyl or

GI S. valkyloxycarbonyl; sg (p) BZ and B" each independently represents hydrogen or C. alkyl; (4) KE "5 represents C. alkyl, optionally substituted by cyano or -С(-0)-МВ ЗВ; r" () 8" represents cyano, halogen, hydroxy, -С(-О0)-МА "ЗВ", C. valkyl, optionally substituted cyano, -Ф(50)-МВ ЗК"? or halogen; Co valkenyl, optionally substituted by cyano or -C(-0)-MA ZV; C» valkynyl, optionally substituted cyano or -C(-0)-MEA "ZV; and, when possible, BC!" can also be attached to the fragment -51-62-63- by means of a double bond, and in this case B" represents -О, -5, -МН, (Ф; -М-Б'5, -М- К7, -М-0-К75, -М-ОО-К7, СНО, "СН-С(50)-МAZВ"Я, -СН-К/ or -СН-К"З; where -СНо can be optional necessarily substituted by cyano, hydroxy, halogen, nitro; (5) O represents hydrogen, C1-6 alkyl or -MEUV 79; 60 (0 M represents hydrogen, hydroxy, halogen, C 46 alkyl, C. alkyloxy, cyano, nitro . ; (0) aryl is phenyl or phenyl substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C. alkyl, hydroxyC alkyl, C alkylM "ZVU, bo C. alkylcarbonyl, C. valkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogens, valkyl,

polyhalogen 4 valkyloxy, -C(-0)-ME ZV, in 7 or -Xa-8 7; (y) It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle, where each of the specified carbocyclic or heterocyclic systems may be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C / valkyl, hydroxyC valkyl, aminoC.i valkyl, Si valkylcarbonyl, C. valkyloxy, C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, polyhalogenS. valkyla, polyhalogenS. valkyloxy.

A subgroup of compounds of special interest is composed of compounds of formula (I), in which all the above restrictions (a)-(M) apply. 70 Subgroups of compounds of formula (I), which are of additional interest, are compounds in which one or more of the above restrictions (a) and (M) apply, as well as one or more of the following restrictions (a)-(Mu: (аЗ)-а" а?-аЗ3 а"- is a bivalent radical of the formula -СНАСН-СНАСН- (а-1); (B) n is equal to 1 or 2; (c) t is equal to 1 or 2; (a) БЕ" represents hydrogen; C. alkyl; (e) each K? independently represents hydroxy, halogen, C. alkyl, optionally substituted by cyano or -C(-O)B 6. Sovalkenyl, optionally substituted by cyano, C ovalkinyl, optionally substituted with cyano,

C. valkyloxycarbonyl, carboxy, cyano, nitro, amino, mono(C. valkyl)amino, di(C.-valkyl)amino, -B(5O)pA, -MH-8(-O) rve, -v(yhoK8 .

Au-N

KA, sch « Fo in which every A; independently represents M, СН or Св: and no more than two A. represent M; with

Ag is MH, О, 5 or МАЕ; - (0 Xi represents-ME 2-, -МН-МН-, -М-М-, -О-, -С(-0)-, S. dalkanediyl, -"СНОН-", -MA"З-с (-0)-, -C(50)-MA U,

From -X-Silalkanediyl- or -C4 zalkanediyl-X 2-; so (9) Ho represents -ME 7-, -O-; (n) BZ is hydrogen, halogen, C 4 alkyl, -MV ZB, -с(50)-MA ZB, -с(50)-875, -Х3-B; Si alkyl substituted with one or two substituents, each of which is independently selected from cyano, B or -C(-0)-MAUV 9; "

Co valkenyl, substituted with one or more substituents, each of which is selected from halogen, cyano or sshc with -F(50)-ME VO; or C" valkynyl, substituted by one or more substituents, each of which is independently selected from "from halogen, cyano, -С(-:0)-МКУВ 9; " (7) Xz represents -ME "З. or -О- ; 15 ( ВЕ" is a halogen, hydroxy, C 4. alkyl, Sovalkenyl, Co valkynyl, C. valkyloxy, cyano, nitro, co -F(50)-MK zv, C. valkyloxycarbonyl, C. valkyl carbonyl, formyl, -MV ZB; (Kk) C represents hydrogen; C. alkyl; - (2) 9 represents C. dalalkyl; ko (t) K'/ represents any of the specific monocyclic or bicyclic, partially saturated or c 50 aromatic carbocycles or monocyclic or bicyclic, partially saturated or aromatic heterocycles, precisely defined in this description, where each of said carbocyclic or heterocyclic systems

Co) may be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, alkyl, hydroxyC. valkilu, aminoS. alkyl, S. alkylcarbonyl,

C. valkyloxy, C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, polyhalogenS..valkylu, polyhalogenS. alkyloxy or aminocarbonyl; o (n) 28 is hydrogen or S. dalkil; (o) Z and E"O each independently represents hydrogen or S. valkyl; o (r) KZ and KE"? each independently represents hydrogen or S. valkyl; d (4) KE 5 is C. alkyl, optionally substituted by cyano or -C(-0)-MA ZVya; (7) 2" represents cyano, halogen, hydroxy, -С(-О0)-МА "ЗЕ", С. valkyl, optionally substituted by cyano, -С(50)-МВ ZВ: Со valkenyl, optionally substituted cyano or -C(-0)-MV ZB; C" valkynyl, optionally substituted cyano or -C(-0)-MV'ZB"": and, whenever possible, B'/ may also be attached to fragment -B1-62-653 using a double bond, and in this case BC 77 is 50, МН, -М-В 75, -М-В7, 65 -М-О-К15 -М-0О- В7, -СНо, "СН-С(-0)-МВ'ЗВ", -СН-В' or -СН-К"?; where -СНо may be optionally substituted by cyano;

(5) O is hydrogen, C is alkyl or -MEUV 9; (0) M represents hydrogen, hydroxy, halogen, C 6 alkyl, C alkyloxy, cyano, nitro, -ME'ZV"", polyhalomethyloxy, -MH-505-K8, -MH-805-(C.4 dalcanediyl)- SO-MSH(KZ)"; (4) aryl is phenyl or phenyl substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, C-alkyl, hydroxy-C-alkyl, C-alkylcarbonyl, C-alkyloxy,

C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, -C(-0)-MA ZVya; (M) It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle, specifically mentioned in this description, where each of said heterocyclic systems can be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, S. valkilu, hydroxyS. valkilu, aminoS. alkyl, C alkylcarbonyl, C alkyloxy,

S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogenS. valkyla, polyhalogen. valkyloxy.

A special subgroup of compounds of formula (I) is represented by compounds in which all restrictions (a)-(M)) described above apply.

Of particular interest are any subgroups of compounds of formula (I) in which one or more of the restrictions (a)-(M) or restrictions (a)-(M') described above, as well as one or more restrictions, optionally apply (а")-(М"): (а -а!-а2-аЗ-аз- is a bivalent radical of the formula -СНеСН-СН-СН- (а-1); (6") n is equal to 1; (с ") t is equal to 1; (ah BE" is hydrogen; methyl; c (e") K is halogen, C. .alkyl, optionally substituted by cyano, Co valkenyl, optionally substituted by cyano, Sovalkynyl, nonob necessarily substituted cyano, C 4 alkyloxycarbonyl, carboxyl, cyano, amino, mono(C.. alkyl)amino, di(C. alkyl)amino; (2) Hu represents -MV 2U-, -O-, -ME 3-с(50)-, -С(50)-ME 13-; (n) VZ is hydrogen, halogen, C 4 alkyl, -ME 3814, -С(50)-MA Zvya, -с(50) -K75; C. valkyl, substituted with cyano; Co.valkenyl, substituted with cyano; or C» valkynyl, substituted with cyano; He) (Z Cl is a halogen, hydroxy, C 4 valkyl, Sovalkenyl, Co. valkynyl, C. valkyloxy, cyano, nitro, sch -F(50)-MV 1z3d14 MV ZdYa (Kk) C is hydrogen; S. valkil; - (t") B" represents any of the specific monocyclic or bicyclic, partially saturated or aromatic carbocycles or monocyclic or bicyclic, partially saturated or aromatic heterocycles specified in this application, where each of the specified carbocyclic or heterocyclic systems can optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, alkyl, hydroxyC. valkilu, aminoS. alkyl, S. alkylcarbonyl,

Si valkyloxy, Si. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogenS.. valkylu, polyhalogenS. valkyloxy - with or aminocarbonyl; h» (n") VZ represents hydrogen or S. dalkil; " (07) Z and KO represent hydrogen; (р "З and КЕ" represent hydrogen; со 395 (47) 25 represents C. alkyl, optionally substituted by cyano; (pt) В" represents cyano, -С(-0)-МА "ЗВ, С . valkyl, optionally substituted by cyano, -C(-0)-MA "Zv; - C. valkenyl, optionally substituted by cyano or -F(50)-MA ZV; Co valkynyl, optionally substituted by cyano or o -с(50)-MA ZV 74; and, when possible, K"" can also be attached to the fragment -51-62-63- by means of a CO double bond, in which case KK" is 0, МН, -М-В 75, -М-К7, -М-0О-875, -М-0-К7, "СН",

ESNAS(O)-MV ЗВ, -СН-В 7 or -СН-В У; where "СНо can be optionally substituted by cyano; iz (c") O represents hydrogen or -"MEOV 0; (2) M represents hydrogen, hydroxy, halogen, C 4 alkyl, C. alkyloxy, cyano, -MK'387, -MH-505-K8, - MH-50,-(C. dalcanediyl)-CO-Ш(B9)"; (y") aryl is phenyl or phenyl substituted with one, two or three substituents, each of which (F; independently selected from halogen, hydroxy , C..valkylu, C. valkyloxy, C. valkylthio, cyano, nitro; co (y") It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle, precisely defined in this application, where each of the specified heterocyclic systems can be necessarily substituted by one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto,

C. alkyl, hydroxyC-alkyl, aminoC.alkyl, C. alkylcarbonyl, C. alkyloxy, C. alkyloxycarbonyl,

S. valkilthio, cyano, nitro, polyhalogens. valkyla, polyhalogenS. valkyloxy.

A special subgroup of compounds of formula (I) is represented by compounds in which all restrictions (a")-(M") described above apply. 65 For compounds of formula (I) in which -65 1-62-63- takes the value (p-5), subgroups where one or more of the following limiting conditions apply are of particular interest.

(a-1) -a"ta?23-a3 - is a bivalent radical of the formula -"СН-СН-СН-СН- (а-1); (а-2) t is equal to 0, 1 or 2, especially 1 or 2, more particularly 2; and the BK" substituents are in the ortho-position relative to the Hu fragment; (a-3) Xy is attached to one of the carbon atoms in the meta position, which is common to both rings of the bicyclic system to which xX 4 is connected; (a-4) if acceptable, n equals 0 or n equals 1 and the substituent B 2 is in position 4 (para-position) relative to the ME linker; (а-5) CC? is hydroxy, halogen, C 6 alkyl, optionally substituted cyano or -C(-O)B 5,

S. /cycloalkyl, So. valkenyl, optionally substituted by one or more halogen or cyano atoms,

Co.valkynyl, optionally substituted by one or more halogen or cyano atoms, C 4 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.4 alkyl)amino, polyhalomethyl, polyhalomethylthio, -B(5O)pA , -MH-8(хО) p? -МНе(тО)Н, -"С(О)МНМН", -МНО(:Ов5, -С(-МН)В or the radical of the formula "no di

AI

And a in which every A; independently represents M, CH or svo;

Ag is MH, О, 5 or МАЕ; (а-6) VZ is C. valkyl, optionally substituted by cyano. сч » Among the compounds of formula (I), in which -5.1-62-63- is (p-3) or (p-2) or (p-3) or (p-4), subgroups are interesting, in of which one or, when possible, several of the following conditions are fulfilled: (c-1) t is equal to 1, 2 or 3, especially 2 or З, more especially 2, even more especially t is equal to 2 and the said two EC" substituents are in positions 2 and 6 (ortho position) relative to the X fragment; c zo (c-2) Xy is attached to one of the carbon atoms in the meta position, which is common to both rings of the bicyclic system to which XX 4 is connected ; Me) (c-3) if acceptable, n equals 0; n equals 1 and the indicated substituent K is in the 4s position (para-position) relative to the ME 1-linker; (c-4) VK? represents hydroxy, halogen, C 4 alkyl, optionally substituted cyano or -С(-О)В 5, --

S. /cycloalkyl, So. valkenyl, optionally substituted by one or more halogen or cyano atoms, (ee)

Co.valkynyl, optionally substituted by one or more halogen or cyano atoms, C 4 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C.4.alkyl)amino, polyhalogenmethyl, polyhalogenmethylthio, -B(tO) рА, -МН-8(-0) р, -"МНе(хО)Н, -С(О)МНМН", "-"МНе(хО)в8, "(МН or the radical of the formula " ! shi s Ba ;" A dm (o)

A, and (ee) z in which each A; independently represents M, CH or svo;

Ag is MH, О, 5 or МАЕ; ime) (p-5) VZ is S. valkyl, optionally substituted by cyano.

Ge) 20 In addition, an interesting group of compounds is represented by the compounds of formula (I), in which B C is C /.alkyl, optionally substituted by cyano. o The predominant subgroup is the subgroup of compounds in which K2 is cyano and VE! is hydrogen.

An interesting group of compounds is represented by compounds of the formula (I), in which one or more, preferably all limiting conditions are fulfilled: 55 (6-1) n equals at least 1, in particular, 1; or n is 0;

HF) (p-2) K is cyano; yuyu (p-3) t is equal to 1, 2 or 3; (p-4) VE is C. alkyl, in particular methyl; halogen; (rB-5) Xy represents MH or 0; (p-6) V! represents hydrogen or S. dalkil.

Compounds of interest are compounds of formula (I) or any of the subgroups defined herein in which K is halogen.

Another group of interesting compounds is represented by compounds of formula (I) or any compounds from the subgroups defined in section 5 of this description, in which KE" represents halogen, cyano.

Another group of interesting compounds is represented by the compounds of formula (I) or any of the subgroups defined in this description, in which B is oxo, C 1-alkyl, optionally substituted cyano, -M-0O-C 4 alkyl- aryl, hydrogen, oxo, S. alkyl, optionally substituted cyano, or Ni.

Another group of interesting compounds is represented by the compounds of formula (I) or any of the subgroups defined in this description, in which t is 2 or З and X 4 is -МК 5З., -О-, -Ф-90)- , -СНо-, -СНОНУ-, -5-, -3(-Ор-), especially in which Хи is -ME 2- or -О-

Additional subgroups of compounds according to this invention are compounds of formula (I) or any compounds from the subgroups of compounds of formula (I) defined in this description, in which one or more of C.4.alkyl, limited by C.- .lalalkyl, one or more C...alkyls, limited by C.1»oalkyl; one or more 70 Co valkenyls limited by Co. dalkenil; one or more So. of valkynyl bounded by Co lalkynyl.

Additional subgroups of compounds according to this invention are compounds of formula (I) or any compounds from the subgroups of compounds of formula (I) defined in this description, where one or more radicals representing (or one or more radicals containing) heterocycles or carbocycles are heterocycles or carbocycles as defined herein.

Synthesis

Compounds of formula (I) can be obtained in various ways, some of which are described below in more detail.

Usually, compounds of formula (I) can be obtained by the interaction of an intermediate compound of formula (a-1) with a pyrimidine or triazine derivative (a-2). NH groups. and MU; are chosen in such a way that the connecting fragment X.. t 5. dz is formed Ha M M-« (Kl ha (9 she sch zo same M F

TT (a-3) c o - d)

Reagent (a-2) corresponds to the general formula (y their chi zy - s and Iv y (a-2). represents a heteroatom Examples of suitable leaving groups in (a-2) include halogen, including chlorine and bromine, tosylate, mesylate, triflate and the like.

Ge) 20 The transformation of (a-1) upon interaction with (a-2) into (a-3) in the scheme presented above is especially used when MU4 is a leaving group and X 4 is a heteroatom, for example, a group - M 2-, -MH-MH-, -MeM-, -O-, i» -8-, Kh-C;.4alkanediyl. This transformation is especially suitable in the case when X. represents -O-. When X 4 is 5, it can be conveniently converted to the corresponding sulfoxide or sulfone using well-known oxidation techniques.

The reaction described above is usually carried out in the presence of a suitable solvent. Suitable

HF) solvents are, for example, acetonitrile, alcohols, such as, for example, ethanol, 2-propanol, ethylene glycol, propylene glycol, polar aprotic solvents, such as M,M-dimethylformamide; M,M-dimethylacetamide, o dimethylsulfoxide, 1-methyl-2-pyrrolidinone, (Btit|PEv; ethers such as 1,4-dioxane, propylene glycol monomethyl ether. 60 When Hu is -C(-0)-, the starting compound (a-1), where the -X AN group is a Grignard reagent group (-Mo-halogen) or lithium, is subjected to interaction with the starting substance (a-2), where M/ is an ether group (-COOalkyl) .This ester can also be reduced to an alcohol using e.g.

PAN, and then can be oxidized by a mild oxidant, such as MpO 5, to the corresponding aldehyde, which is then subjected to interaction with the starting substance (а-1), in which -ХН is a Grignard reagent group (-Mao-halogen ) 62 or lithium. Compounds in which -X.- is -C(-0)- can be converted into -CHON-analogs by means of a suitable reduction reaction, for example, using GiAlIIin y.

When Hu. is C 4.alkanediyl, the bridge can be introduced according to the Grignard reaction, for example, by means of the reaction of the starting substance (a-1), where the -X/H group is C. ..alkanediyl-Mo-halogen, with the reagent ( a-2), where MU is a halogen group, or vice versa. When X represents methylene, the methylene group can be oxidized to the group -C(-0)- (Xi represents -C(-0)-), for example, when using selenium dioxide. The -b(50)- group, in turn, can be reduced by a suitable hydride, such as HiAIN, to give the -CHNOH- group.

When Xy is -ME 73-C(50)- or -C(50)-MK"Z-, the Xy bridge can be obtained using a suitable amide bond formation reaction, starting from the intermediate compound HE "Z, and the intermediate compound 70 (a-2), in which MU is a carboxyl group or its active derivative, or vice versa, based on the intermediate compound (a-1), in which -X-H is a carboxyl group or its active derivative, and intermediate compound (a-2), in which MU; represents the group -МНЕ "3. The formation of the amide bond can be carried out according to well-known techniques, for example, by activating the carboxyl group to carbonyl chloride or bromide or using a suitable binding agent.

When Hu. represents -X 25-C.4 dalcanediyl, the intermediate compound (a-1), in which -X-H represents -X 2H, is subjected to interaction with the intermediate compound (a-2), in which MU is -C 4 .alkanediyl-MU", in which MM" represents a suitable leaving group. Or when -X4 is -C 4 -alkanediyl-Xo-, intermediate compound (a-1) in which -X-H is -C 4 alkanediyl-MUo, in which M/o is a suitable group that departs, is subjected to interaction with the intermediate compound (а-2), in which MU is -ХоН.

A Xo bridge that is other than a heteroatom (ie, Xo is -C(-0)-, -CHOH-) can be prepared according to techniques similar to those used to form the X. linker.

When X. represents -ME "-, the interaction (a-1) with the reagent (a-2) is usually carried out under neutral conditions or, preferably, under acidic conditions, usually at elevated temperatures and with stirring. Acidic conditions can be obtained by adding appropriate amounts of a suitable acid or using acidic solvents, for example, hydrochloric acid dissolved in an alkanol such as 1- or 2-propanol. d)

The reaction described above can be carried out in the presence of a suitable solvent. Suitable solvents are, for example, acetonitrile, an alcohol such as, for example, ethanol, 2-propanol, 2-propanol-HCl;

M,M-dimethylformamide; M,M-dimethylacetamide, 1-methyl-2-pyrrolidinone; 1,4-dioxane, or propylene glycol monomethyl ether. Preferably, the solvent is 2-propanol, BN HCI in 2-propanol or acetonitrile, especially preferably acetonitrile. Optionally, sodium hydride may be present. Gee!

When Hu; is -O-, the reaction is usually carried out as follows. The intermediate compound (а-1) is first subjected to interaction with hydrides in an organic solvent with stirring at room temperature. After that, a solvent such as M-methylpyrrolidinone, dimethylacetamide or dimethylformamide is added to the mixture, followed by the addition of reagent (a-2). Usually, the reaction mixture is stirred overnight at elevated temperatures

From the temperatures with obtaining the compound (a-3). co

Compounds of the formula (a-3) containing the substituent B 77, which is an oxo group (5-0) (represented by the structure (a-3-1)), can be used as starting substances for obtaining compounds of the formula (I), which contain a substituent

VT, which is a substitute -М-В 79, where -М-В/З is -МН, -М-В 75, -М-В7, -М-О-815, -М-О-В', as defined above. In this method of synthesis, the intermediate product (а-3-1) is subjected to interaction with the reagent (а-7) 8 75, МН»-О-В 7, in particular Ag-С. valkyl-О-МНо) at elevated temperatures in an alcohol solvent in the presence of a base to obtain a compound of the formula (a-8).

Similarly, compounds of the formula (a-3-1) can be used as starting substances for obtaining compounds of the formula (I) containing the substituent K 17, which is the substituent -X, where -X is -CH 2, co -CH -AF(-O)-MK ZL, -CH-B' or -CH-B'Z5, as defined above. The intermediate product (a-3-1) is then subjected to interaction with the reagent (a-4) according to the Wittig reaction or the Wittig-Horner reaction. Reagent (a-4) is a Wittig reagent, such as triphenylphosphoniylide, or a Wittig-Horner reagent, in particular, a phosphonate, such as, for example, a reagent of the formula di(Si valkyloxy)-P(-O)-X4, where Xa is a substituent B 7/7, which can be c 50 attached to the ring by means of a double bond (double exo-bond). The Witig-Horner reaction is usually carried out in the presence of a base, preferably a strong base, in an aprotic organic solvent at room temperature. The reaction must be carried out for a time sufficient for its completeness, usually during the night, to obtain the compound (a-5). This last compound can be further reacted in an alcohol solvent under reducing conditions to obtain the compound of formula (a-6).

Both conversion reactions are shown in the diagram below.

F) name) 60 b5

En y

Y t wo a Z,

Her and tn m--dz 1 i See TE dv (vah shcha M r!' aa to y y (8-7 Y le / u t Shk (v y / De iv-3-1) T y ХА M A y in the -th

Ha

Fly t a X, and to "o shii sha vz cen

That h HC a vyk I cha renewal ; Czech Kan o kuru --I Om om. an 1 tt t t y zo b (a-5) (2-8) F p

The oxo group in compounds (а-3-1) can also be in other positions in the ring containing substituents) -

B", a transformation of a similar type can lead to isomers of position (а-8), (а-5) and (а-6).

Compounds of formula (I) can also be prepared as shown in the reaction scheme presented below. (ee) in - in (km ( vyv in arch "

He 0 Mu WHAT va" nHx her I zh t ma petini plans y 4 And what s SHI - ri y M lays Her 4

I" (in t (I fer; ol (a) (a-9) 1 t (an11) "(a-10) M (ee) - T name) o 50

From (Van wav eh to (from sa and shop (F) (8 a Te and t oh MA M-ya

Also, the reagent of formula (a-1) is reacted with a pyrimidine or triazine derivative of formula (a-9), where the substituents are as defined herein, and MU is a suitable leaving group, such as

for example, halogen, triflate, tosylate, methylsulfonyl, etc., to obtain the intermediate product (a-10). This reaction can be carried out similarly to the one shown above for the reaction (a-1) with (a-2), especially for different possible values of the -X4- bridge. When necessary, the M/- group, which does not affect the course of this reaction, can be replaced by a precursor of the leaving group, such as the OH functional group, which is converted into a leaving group at a specific stage of the reaction, for example, by converting the OH group into halogen or interaction with a suitable reagent, such as ROCI3, tosyl chloride, mesyl chloride, etc.

End products (I) can be obtained from the starting substance (a-10) by interaction with an amino-substituted aromatic compound (a-11) using an arylation reaction. 70 Suitable solvents for the interaction of (a-1) with (a-9) and (a-10) with (a-11) are ethers, for example, 1,4-dioxane,

THF, alcohols, ethanol, propanol, butanol, ethylene glycol, propylene glycol, propylene glycol monometallic ether, aprotic solvents such as acetonitrile, DMF, DMA, 1-methyl-2-pyrrolidinone, etc. If necessary, a base can be added. Suitable bases for this reaction are, for example, sodium acetate, potassium acetate,

M,M-diethylthanamine, sodium bicarbonate, sodium hydroxide, etc.

Compounds of formula (I), in which -57-62-63- represents -"СНо-СН-СН- (р-5), can also be obtained starting from the indane derivative of formula (а-12), as shown in the following below the diagram. The indane derivative (a-12) is converted to (a-13) using the Wittig or Wittig-Horner reaction as shown above. The transformation of (a-12) into (a-13) is carried out in the same way as described above for the reaction (a-3-1) to obtain (a-5). MU 4 and NH. are selected in such a way that the connecting fragment X. is formed. After that, the product (а-13) is subjected to a coupling reaction with the reagent (а-2). Mostly MU. is a suitable leaving group, and X 4 is a heteroatom. This reaction is carried out using methods similar to those described above for the interaction of (a-1) with (a-2). H. takes similar values as described above to obtain (a-5) and (a-6). In this coupling reaction, two final products are obtained: on the one hand, the compound (a-14), on the other hand, the isomer (a-14), where X4 is connected by means of a double exo-bond. Ha - z o v a not o T le sc 17 (7) (Kii a: a v 8 -- b 4 U, | I, M she and s - "- (8 same volume and U id so

AND! 1 (a-13) aa (a123 shi s Hu ch (Anya 22 "" dz a (Vr - zu ad 82 - Kh. M sh--ya- yu schey sg sha z (a-14) c)

Compounds of formula (I), in which -51-62-653- is -CH--CH-CH- (p-5) can also be obtained starting from 29 from the indane derivative of formula (a-16), as shown in the presented further scheme.

F) ime) 60 b5 o He 1 17 ; YAN da s ny .ya2u «l , i la (59 Ж Her. - (89 Ж Te a, t 1 ШЧI 1 0 Kh Moy t pinni nu p h-v shko a-15 t » d (a45) d (a -16)

In this alternative method of preparation, the intermediate product (a-15) is reacted with a suitable halogenating agent, for example, phosphorus oxychloride, to obtain a compound of the formula (a-16), in which X 5 is a halogen. Usually, the specified reaction is carried out overnight at elevated temperatures.

The intermediate product (а-15) can also be subjected to interaction with a bromine derivative, such as РВг.

Compounds of formula (I), in which 7 represents M (triazines), can also be obtained by condensation reactions with the formation of triazines, as described, for example, in (EP-A-834507). Triazine derivatives of formula (I), in which the radical

O represents ME "KO, can be obtained by the interaction of a triazine derivative of the formula (I), in which O represents a halogen, in particular, when C) represents chlorine or bromine, with the amine H-MeUV 9 according to known methods.

In this and the following preparation methods, the reaction products can be isolated from the reaction medium and, if necessary, can be further purified using methods that are well known in the art, such as, for example, extraction, crystallization, distillation, trituration and chromatography.

Compounds of formula (I) can also be obtained by converting compounds of formula (I) into one another according to known group transformation reactions.

Compounds of formula (I) can be converted into the corresponding M-oxide forms according to known techniques for converting trivalent nitrogen into its M-oxide form. The specified M-oxidation reaction can usually be carried out by the interaction of the starting compound of formula (I) with a suitable organic or inorganic peroxide.

Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may include peracids such as, for example, perbenzoic acid or halogenated perbenzoic acid, such as 3-chloroperbenzoic acid, peralkanoic acids, such as peracetic acid, co-alkyl hydroperoxides, such as tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and mixtures of such solvents. "

For example, a compound of formula (I) in which B C contains cyano can be converted into a compound of formula (I) in which C 70 contains aminocarbonyl by reaction with HCOOH in the presence of a suitable acid, such as hydrochloric acid. c A compound of formula (I) in which B contains cyano can also be converted into a compound of formula (I) in which B C:c" contains tetrazolyl by reaction with sodium azide in the presence of ammonium chloride and N,M-dimethylacetamide.

Compounds of formula (I), in which the KZ contains an aminocarbonyl, can be transformed into compounds of formula (1), in

WHICH VZ contains cyano, in the presence of a suitable dehydrating agent. Dehydration can be carried out according to methods well known to the skilled person, such as the methods described in the publication "Sotrgepepzime Ogdapis Tgapveiogtaiyyope. A diide yu Tpsiiope!| dgoir rgeragayopv" Kisnaga S I agos, dopp Umieu E - Zopv, Ips ., 1999, 1983-1985), which is included in this description as a reference. In the mentioned publication

Various suitable reagents are listed in GI, such as, for example, OSI", NOBOZOMN", SIBO2MSO, MekhSM5O2 ME, RYBO-Si,

Ts, Rob, (RIZROZZSE5)05ZSE with, complex polyphosphate ether, (ESoPOR(OEO), (EOzRI", so 2-chloro-1,3,2-dioxaphospholane, 2,2,2-trichloro-2,2-dihydro -1,3,2-dioxaphospholane, РОСИ»5, РРН3, Р(МСИ»)з, Р(IMEB)»з,

GI SOSI", Masi.AISIz, SISOSOCI, SISOMe, SIZSOSI, (SERzSO)2O, SIZSMASSI", 2,4,6-trichloro-1,3,5-triazine,

Masi.AISIz, NM(ZiMe»)z, M(ZIiMe»)l, GIAIN.; etc. All reagents listed in this publication are incorporated herein by reference.

Compounds of formula (I) in which EZ contains Co valkenyl can be converted into compounds of formula (I) in which 3 contains C 1 -alkyl by reduction in the presence of a suitable reducing agent such as, for example, H 5 in the presence

F) a suitable catalyst, such as, for example, palladium on carbon, and in the presence of a suitable solvent, such as, for example, an alcohol, for example, methanol.

Compounds of formula (I), in which B? is CH(OH)-K 79, can be converted into compounds of formula (1), in which BZ is C(-O)-B 79, by interaction with the Jones reagent in the presence of a suitable solvent, such as, for example, 2 -propanone

Compounds of formula (I), in which KZ is С(-О)-СНо-К 192, where K/ba is cyano or aminocarbonyl, can be converted into compounds of formula (I), in which B is С(СИ )-СН-К 92, interaction with ROSIv.

Compounds of formula (I), in which K is a monocyclic, bicyclic or tricyclic saturated, because partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated,

a partially saturated or aromatic heterocycle substituted by formyl can be converted into compounds of formula (I), in which EZ is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, substituted by the CH(-M-O-KZ) group, by interaction with MNoOKZ in the presence of a suitable base, such as, for example, sodium hydroxide, in a suitable solvent, such as, for example, an alcohol, for example, ethanol, etc. Compounds of formula (I), in which B C is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle substituted by the CH(-M-O-KZ) group, can be converted into compounds of the formula (I), in which B C is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, substituted by a CM group, by interaction with carbodiimide in the presence of a suitable solvent, such as, for example, tetrahydrofuran. /5 Compounds of formula (I), in which B is nitro, can be converted into compounds of formula (), in which B7 is amino, in the presence of a suitable reducing agent, such as, for example, H 5 , in the presence of a suitable catalyst, such such as Raney nickel, and in the presence of a suitable solvent such as an alcohol such as methanol.

Compounds of formula (I) in which B is hydrogen can be converted into compounds of formula (I) in which CO is C1-6 alkyl by reaction with a suitable alkylating agent such as, for example, iodoC, alkyl, in in the presence of a suitable base, such as, for example, sodium hydride, and a suitable solvent, such as, for example, tetrahydrofuran.

Some compounds of formula (I) and some intermediate compounds in this invention may contain an asymmetric carbon atom. Stereochemically pure isomeric forms of the specified compounds and specified intermediate products can be CM 25 obtained using known methods. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic methods such as countercurrent partitioning, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable separating solvents, such as, for example, chiral acids, in a mixture of diastereomeric salts or compounds; then by physical separation of said mixtures of He 30 diastereomeric salts or compounds using, for example, selective crystallization or chromatographic methods, for example, liquid chromatography, etc.; and finally, by converting the indicated separated F diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms can also be obtained by SM from pure stereochemically isomeric forms of the corresponding intermediate products and starting substances, provided that the interaction reactions occur stereospecifically. - 35 An alternative method of separation of enantiomeric forms of compounds of formula (I) and intermediate products includes liquid chromatography, in particular, liquid chromatography using a stationary chiral phase.

Some of the intermediates and starting substances are known compounds and may be commercially available or may be prepared according to known methods, or some of the compounds of formula (I) or the described "intermediates may be obtained according to the methods described in (publications UUCHO 99 /50250 and MO 400 00/27825). - c Intermediate compounds of the formula (a-2) can be obtained by the interaction of the intermediate product of the formula (bB-1) with a leaving group introduction agent of the formula (p-2), where MU is a leaving group, and K is itself "» the remainder of the input agent of the leaving group, such as, for example, ROSI".

M! M - name) children's alley (p-2)

PE) (B-) (a-2)

Suitable leaving groups in the above reaction are, for example, halogen, triflate, tosylate, mesylate, and the like. preferably, MU is halogen, more preferably iodine or bromine. 29 Suitable bases in the above reaction are, for example, sodium acetate, potassium acetate, (FI M,M-diethylethanamine, sodium bicarbonate, sodium hydroxide, etc.

Suitable solvents in the above reaction are, for example, acetonitrile, M,M-dimethylacetamide, diionic liquid, for example |rt|PEv, M,M-dimethylformamide, water, tetrahydrofuran, dimethylsulfoxide, 1-methyl-2-pyrrolidinone, etc. p. for Compounds of formula (I) containing a double carbon-carbon bond can be reduced to the corresponding compounds with a single bond using catalytic hydrogenation methods. In these methods, a noble metal catalyst is used. The most famous such catalyst is Ra. The palladium (Ra) catalyst can be a homogeneous Ra catalyst, such as, for example, RY(OAc) 5", Rasi",

РА(PPРiz)4, РАРАЗСІ», bis(dibenzylideneacetone)palladium, palladium metallocycle thiomethylphenylglutaramide, etc., or a heterogeneous Ra catalyst, such as, for example, palladium on carbon, palladium on metal oxides,

palladium on zeolites.

Preferably, the Pa catalyst is a heterogeneous palladium catalyst, more preferably palladium on carbon (Pa/C). Ra/C is a renewable catalyst, stable and relatively inexpensive. It can be easily isolated (filtered) from the reaction mixture, thus reducing the risk of a small amount of Ra entering the final product. The use of Ra/C also eliminates the need for ligands such as, for example, phosphine ligands, which are expensive, toxic, and contaminate the synthesized products.

Compounds of formula (I), obtained by the methods described above, can be synthesized in the form of a mixture of stereoisomeric forms, in particular, in the form of racemic mixtures of enantiomers, which can be separated by known separation methods. Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by interaction with a suitable chiral acid. The indicated diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and enantiomers are isolated from them using alkali. An alternative method of separation of enantiomeric forms of compounds of formula (I) includes liquid chromatography using a chiral stationary phase. The specified pure stereochemically isomeric forms can also be obtained from the corresponding pure stereochemically isomeric forms of suitable starting substances, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is required, said compound will be synthesized by stereospecific methods of preparation. In such methods, enantiomerically pure starting substances will preferably be used.

It will be clear to the skilled person that in the methods described above, the functional groups of the intermediate compounds can be blocked by protective groups if necessary.

Functional groups that are preferably protected include hydroxy, amino and carboxyl groups. Suitable hydroxy protecting groups include trialkylsilyl groups (eg, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), benzyl, and tetrahydropyranyl. Suitable protecting groups for the amino group include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for the carboxyl group include C. alkyl or benzyl ethers.

Protection and deprotection of functional groups can be carried out before and after the reaction step. and)

The use of protective groups is described in detail in the publications "Rgoyesime Sgoire ip Ogdapis Spetivigu", eadye Bu UM/.E. MsOtipe, Riepyt Rgevzz (1973); and "Rgoyesime Sgoire ip Ogdapis Z!ipipeviv" 279 eayop, TM.

OSgeepe 85 R.O.M. Mu, UMieu Ipiegssiepse (1991)). Ge

Compounds of formula (I) exhibit antiretroviral properties (revertase inhibition properties), in particular with respect to human immunodeficiency virus (HIV), which is the etiological agent of acquired immunodeficiency syndrome (AIDS) in humans. The HIV virus primarily infects human T-4 cells and destroys them or changes their normal function, including coordination of the immune system. As a result, the number of T-4 cells, which, in addition, function in a pathological manner, always decreases in an infected patient. Thus, the protective immune system is unable to fight infections and neoplasms, and an HIV-infected subject usually dies from opportunistic infections, such as pneumonia, or from malignant tumors. Other conditions associated with HIV infection include thrombocytopenia, Kaposi's sarcoma, and central nervous system infection characterized by progressive demyelination leading to dementia and symptoms such as progressive dysarthria, ataxia, and disorientation. HIV infection, in addition, is also associated with peripheral neuropathy, progressive 70 generalized lymphadenopathy (GLP) and AIDS-associated complex (ACS). - c The compounds of the present invention also show activity against HIV strains resistant to (numerous) drugs, in particular, against (numerous) drug-resistant strains of HIV-1, more precisely, the compounds of the present invention show activity with respect to HIV strains, especially HIV-1 strains, that have acquired resistance to one or more known non-nucleoside revertase inhibitors.The non-nucleoside revertase inhibitors known in the art are compounds other than the compounds of the present invention, and in particular, (ee) commercial non-nucleoside revertase inhibitors. Compounds of the present invention also have little or no affinity for binding to human α-1 acid glycoprotein; α-1 acid glycoprotein has no or little effect on the anti-HIV activity of the compounds of the present invention. properties, especially anti-HIV properties and, in particular, anti-HIV-1 activity, compounds of formula (I), their M-oxides, pharmaceutically acceptable ad ative salts, quaternary amines and their stereochemically isomeric forms are used for the treatment of HIV-infected patients and the prevention of such infections. In general, the compounds according to the present invention can be used for the treatment of warm-blooded animals infected with viruses, the vital activity of which is mediated or depends on the enzyme revertase.

Conditions that can be prevented or treated with the compounds of the present invention, particularly conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-associated complex (ACS), progressive generalized lymphadenopathy (PGL), and chronic diseases of the central nervous system. nervous

F, systems caused by retroviruses, such as, for example, HIV-mediated dementia and multiple sclerosis. Thus, the compounds of the present invention, or any subset thereof, may be used as drugs for the above conditions. Said use as a medicament or method of treatment comprises administering to an HIV-infected subject an amount of the compound effective to combat conditions associated with HIV and other pathogenic retroviruses, particularly HIV-1. In particular, the compounds of formula (I) can be used for the production of a medicinal product for the treatment or prevention of HIV infections.

Due to the utility of compounds of formula (I), a method of treating warm-blooded animals, including humans, suffering from viral infections, particularly HIV infections, or a method of preventing viral infections, particularly HIV infections, in warm-blooded animals, including humans, has been developed. The specified method includes administration, preferably oral administration, of an effective amount of the compound of formula (I), their M-oxide form,

of a pharmaceutically acceptable addition salt, quaternary amine, or possible stereoisomeric form to a warm-blooded animal, including humans.

According to another aspect, the present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

According to yet another aspect, there is provided a method of preparing the pharmaceutical composition described above, comprising mixing a compound of formula (I) with a suitable pharmaceutically acceptable carrier or diluent.

The compounds of this invention, or any subgroup thereof, may be manufactured in various pharmaceutical forms intended for administration. Suitable compositions include all compositions that are usually used for systemic administration of medicinal products. To obtain pharmaceutical compositions according to the present invention, an effective amount of a specific compound, not necessarily in the form of an additive salt, as an active ingredient, is combined into a homogeneous mixture with a pharmaceutically acceptable carrier, which can take different forms depending on the form of the drug desired for administration. Pharmaceutical compositions preferably represent a 7/5 unit dosage form suitable, in particular, for administration orally, rectally, subcutaneously or by parenteral injection. For example, when preparing the composition in the form of a dosage form for oral administration, any conventional pharmaceutical medium can be used, such as, for example, water, glycols, oils, alcohols, and the like. - in the case of liquid preparations for oral administration, such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents, etc. - in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules are the most preferred oral unit dosage forms, which of course use solid pharmaceutical carriers. In compositions for parenteral administration, the vehicle will usually contain at least a significant portion of sterile water, although other ingredients may be included, for example, to aid dissolution. There can be prepared solutions for injections, in which the carrier contains a saline solution, a glucose solution, or a mixture of a saline solution and a glucose solution. Suspensions for injections can also be prepared, while i) suitable liquid carriers, suspending agents, etc. can be used. Preparations in solid form can also be obtained, intended for conversion, immediately before use, into liquid forms. In compositions suitable for subcutaneous administration, the carrier optionally contains a penetration enhancing agent and/or a suitable wetting agent, optionally in combination with suitable additives of any nature in small amounts, said additives not have a significant harmful effect on the skin. Said Me) additives may facilitate transdermal administration and/or may be useful in obtaining the desired compositions. The mentioned compositions can be introduced in different ways, for example, in the form of a transdermal patch, in the form of patches, in the form of an ointment. Compounds of the present invention may also be administered --

BY inhalation or insufflation using methods and formulations used in the art to administer in a similar manner. Thus, in general, the compounds according to this invention can be introduced into the lungs in the form of a solution, suspension or dry powder. Any system designed to deliver solutions, suspensions, or dry powders by oral or nasal inhalation or insufflation is suitable for administration of these compounds. "

To improve the solubility of the compounds of formula (I), suitable ingredients can be included in the composition, for example, cyclodextrins. Suitable cyclodextrins are o-, p-, u cyclodextrins or ethers and their mixed ethers, where one or more hydroxyl groups of the anhydroglucose units of the cyclodextrin are и? substituted C. alkyl, in particular, methyl, ethyl or isopropyl, for example, randomly methylated Bp-CO; hydroxyalkyl, in particular hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyS. alkyl, in particular carboxymethyl or carboxyethyl; C. alkylcarbonyl, in particular acetyl. As complexing agents and/or solubilizing agents, it is especially worth mentioning D-CO, randomly methylated p-CO, 2,6-dimethyl-p-CO, - 2-hydroxyethyl-D-CO, 2-hydroxyethyl-D-CO, 2-hydroxypropyl-D-CO and (2-carboxymethoxy)propyl-D-CO, in particular, 2-hydroxypropyl-B-CO (2-HP-D-CO). The term "mixed ether" refers to cyclodextrin derivatives in which at least two of the 20 hydroxyl groups of the cyclodextrin are esterified with different groups, such as, for example, hydroxypropyl and hydroxyethyl.

IR) The average molar substitution (M.5.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average degree of substitution (0.5.) means the average number of substituted hydroxyls on the anhydroglucose link. Magnitudes M.5. and 05. can be determined by various analytical methods such as nuclear magnetic resonance (NMR), mass spectroscopy (MS) and infrared spectroscopy (IR). Depending on the method used, several different values can be obtained for one specific cyclodextrin derivative. When using mass spectroscopy M.5. mostly ranges from 0.125 to 10, and O5. - from 0.125 to 3. ko Other suitable compositions for oral or rectal administration include particles consisting of a solid dispersion containing compounds of formula (I) and one or more suitable, pharmaceutically acceptable, 60 water-soluble polymers.

The term "solid dispersion", as used below, refers to a system in a solid state (as opposed to a liquid or gaseous state) containing at least two components, in this case a compound of formula (I) and a water-soluble polymer, where one component is dispersed more or less uniformly in the other component or components (in the case when additional pharmaceutically acceptable agents are included, which contribute to the preparation of the drug, which are known in the field of technology, such as plasticizers, preservatives, etc.). If said dispersion of components is such that the system is chemically and physically uniform and homogeneous throughout the volume or consists of a single phase as defined in thermodynamics, such a solid dispersion is called a "solid solution". Solid solutions are preferred physical systems because their components are usually readily bioavailable to the organisms into which they are administered. This advantage can probably be explained by the ease with which said solid solutions are able to form liquid solutions when in contact with a liquid environment such as gastrointestinal juices. Ease of dissolution is due, at least in part, to the fact that the energy required to dissolve components from a solid solution is less than the energy required to dissolve components from a crystalline or microcrystalline solid phase.

The term "solid dispersion" also refers to dispersions that are generally less homogeneous throughout the volume than solid solutions. Such dispersions are not chemically and physically homogeneous throughout the volume or contain more than one phase. For example, the term "solid dispersion" also refers to a system containing domains or small regions in which an amorphous, microcrystalline or crystalline compound of formula (I) or an amorphous, microcrystalline or crystalline water-soluble polymer, or both compounds, are dispersed more or less uniformly in another a phase containing a water-soluble polymer or a compound of formula (I), or a solid solution containing a compound of formula (I) and a water-soluble polymer. The mentioned domains are areas in the solid dispersion that clearly differ in some physical feature, are small in size and are uniformly and arbitrarily distributed throughout the volume of the solid dispersion.

There are various methods of preparing solid dispersions, including melt extrusion, spray drying, and solution evaporation.

The method of evaporation of the solution includes the following stages: a) dissolving the compound of formula (I) and the water-soluble polymer in the appropriate solvent, optionally, at elevated temperatures;

B) heating the solution obtained according to point a), optionally, in a vacuum, until the solvent evaporates.

The solution can also be poured onto a large surface to form a thin film, and the solvent can be evaporated from it.

During spray drying, the two components are also dissolved in the appropriate solvent and the resulting i) solution is then sprayed through the nozzle of a spray dryer followed by evaporation of the solvent from the resulting droplets at elevated temperatures.

The preferred method of obtaining solid dispersions is the melt extrusion method, which includes the following three stages: a) mixing the compound of formula (I) and the corresponding water-soluble polymer; Me

B) optional addition of additives to the mixture obtained in this way; c c) heating and stirring the mixture obtained in this way until a homogeneous melt is obtained; a) extrusion of the melt obtained in this way through one or more nozzles; -- f) cooling of the melt until it solidifies. co

The terms "melt" and "melting" have a broad interpretation. The mentioned terms mean not only the transition from a solid state to a liquid state, but can also refer to a transition to a glassy state or an elastic state, in which one component of the mixture can be distributed more or less homogeneously in another component. In specific cases, one component will melt and the other component(s) will dissolve in the melt, thus forming a solution that, upon cooling, may form a solid solution that has better solubility.

After obtaining the solid dispersions as described above, the resulting products may optionally be crushed and sifted.

The solid dispersion product can be ground or ground into particles having a size of less than 10 microns, preferably less than 40 microns, and most preferably less than 125 microns. o From the particles obtained as described above, pharmaceutical dosage forms, such as tablets and capsules, can then be prepared using known methods. - It is obvious that a specialist in this field of technology is able to optimize the parameters of the methods described above for obtaining a solid dispersion, such as the most suitable solvent, operating temperature, type of device used, speed of spray drying, speed of the melt passing through the extruder.

Ge Water-soluble polymers in particles are polymers that have a structural viscosity when dissolved at 202С in an aqueous solution at 295 (w/v) in the range from 1 to 5000 mPa.s, more preferably in the range from 1 to 7OO0 mPa.s , and, most preferably - from 1 to 100 mPa.s. For example, suitable water-soluble polymers

Include alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, carboxyalkyl cellulose, alkali metal salts carboxyalkyl cellulose, carboxyalkyl alkyl cellulose, esters of carboxyalkyl cellulose, (F, starches, pectins, chitin derivatives, di-, oligo- and polysaccharides, such as trehalose, alginic acid or its alkali metal salts and ammonium salts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guar gum and xanthan gum, polyacrylic acids and their salts, polymethacrylic acids and their salts, copolymers of methacrylate, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene oxides, and copolymers of ethylene oxide and propylene oxide.The preferred water-soluble polymers are hydroxypropylmethylcellulose.

As described in (MO 97/188391), as a water-soluble polymer in the preparation of the above-mentioned particles, one or more cyclodextrins can also be used. Said cyclodextrins include known in the field b5 techniques pharmaceutically acceptable, unsubstituted and substituted cyclodextrins, more specifically, co-, D- or y-cyclodextrins or their pharmaceutically acceptable derivatives.

Substituted cyclodextrins that can be used to prepare the particles described above include the polyesters described in (US Patent 3,459,731). In addition, substituted cyclodextrins are ethers in which the hydrogen of one or more hydroxyl groups of cyclodextrin is replaced by C/4 alkyl, hypohydroxy C alkyl, carboxyC alkyl, or C alkyl, or their mixed ethers. In particular, such substituted cyclodextrins are ethers in which the hydrogen of one or more hydroxyl groups of the cyclodextrin is replaced by C-alkyl, hydroxyC-alkyl, or carboxyC-alkyl, or more precisely by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, or carboxyethyl. 70 Simple ethers of p-cyclodextrins are especially used, for example, dimethyl-dD-cyclodextrin, which is described in (Ogodvoi (She Eshiige, Moi. 9, Mo. 8, pp. 577-578 ru. M. Modgadi (1984)3), and polyethers, examples of which are hydroxypropyl D-cyclodextrin and hydroxyethyl D-cyclodextrin. Such a simple alkyl ether can be a methyl ether with a degree of substitution from about 0.125 to 3, for example, from about 0.3 to 2. Such a hydroxypropyl ring o dextrin can be , for example, obtained by the interaction between pD-cyclodextrin 75 and propylene oxide and can have an M5 value of from about 0.125 to 10, for example from about 0.3 to 3.

Another type of substituted cyclodextrins includes sulfobutylcyclodextrins.

The ratio of the compound of formula (I) to the water-soluble polymer can vary widely.

For example, the ratio can be from 1/100 to 100/1. Of interest is the range of the ratio of compounds of formula (I) to cyclodextrin from approximately 1/10 to 10/1. Of greater interest is the ratio interval from about 1/5 to 5/1.

It may also be appropriate to obtain the compounds of formula (I) in the form of nanoparticles containing a surface modifier absorbed on their surface in an amount sufficient to maintain an effective average particle size of less than 100O0nm. It is believed that useful surface modifiers include such modifiers that physically attach to the surface of the compound of formula (I), but are not chemically bound by the aforementioned ECS compound. at

Suitable surface modifiers may preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Ge

Another interesting way of preparing the compounds of formula (I) involves a pharmaceutical composition where the compounds of formula (I) are incorporated into hydrophilic polymers and the application of such a mixture as a film coating on a plurality of F small beads, resulting in a composition that can be easily manufactured and which suits Gee! to obtain pharmaceutical dosage forms for oral administration.

Said balls include a central, rounded or spherical core, a film coating of a hydrophilic polymer and a compound of formula (I), and, optionally, an insulating layer. (se)

Materials suitable for use as cores in the beads may be varied, provided that said materials are pharmaceutically acceptable and of suitable size and hardness. Examples of such materials are polymers, inorganic substances, organic substances and saccharides and their derivatives. "

It is especially expedient to manufacture the above-mentioned pharmaceutical compositions in the form of a unit 70 dosage form in order to facilitate administration and ensure uniformity of the dose. The term "unit dosage form" used in this application refers to physically discrete units that are used as unit doses, while each unit contains a defined amount of the active ingredient calculated to "" obtain the desired therapeutic effect in combination with the necessary pharmaceutical carrier Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, 475 powder sachets, wafers, suppositories, injectable solutions or suspensions, etc., as well as combinations thereof. (ee) Professionals in the treatment of HIV infection are able to determine an effective daily amount based on the test results presented here.

BOmg/kg of body weight, more preferably - from 0.1mg/kg to 1Omg/kg of body weight. The required dose can be administered in the form of two, three, four or more divided doses at appropriate intervals during the day. Specified c 50 split doses can be made in the form of single dosage forms containing, for example, from 1 to 10 mg, in particular, from 5 to 200 mg, of the active ingredient per unit dosage form. c) As is well known to those skilled in the art, the exact dosage and frequency of administration will depend on the particular compound of formula (I) being used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient. as well as from other medicines that the patient may take. In addition, it is clear that said effective daily amount may be reduced or increased depending on the response of the subject being treated and/or depending on the judgment of i) the physician who prescribes the compounds according to this invention. Therefore, the aforementioned effective daily dosage ranges are indicative only and should not in any way limit the scope or use of the present invention. 60 These compounds of formula (I) can be used alone or in combination with other therapeutic agents, such as antiviral drugs, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They can also be used alone or in combination with other prophylactic agents to prevent viral infections. These compounds can be used in vaccines and methods of protecting individuals against viral infections over a long period of time. The compounds can be used in 65 such vaccines either alone or together with other compounds according to the present invention, or together with other antiviral agents in a manner consistent with the traditional use of revertase inhibitors in vaccines. Thus, these compounds can be combined with pharmaceutically acceptable adjuvants traditionally used in vaccines and administered in prophylactically effective amounts to protect subjects against HIV infection for a long period of time.

A combination of an antiretroviral compound and a compound of the present invention can also be used as a medicinal product. Thus, the present invention also relates to a product containing (a) a compound of formula (I) and (B) another antiretroviral compound in the form of a combined preparation for simultaneous, separate or sequential use for the prevention or treatment of retroviral infections, in particular, for the treatment of infections retroviruses with multiple drug resistance. Thus, for the control, 7/0 prevention or treatment of HIV infections or infections and diseases associated with HIV infections, such as acquired immunodeficiency syndrome (AIDS) or AIDS-associated complex (ACS), the compounds of the present invention can be administered together in combination, for example, with binding inhibitors, such as, for example, dextran sulfate, suramin, polyanions, soluble CO4, RKO-542, BM5-806; fusion inhibitors, such as, for example, 120, 71249, KRK 103611, UK-RENZ12, 1C 9564, 5-peijh, O-peptide AOZ-1; inhibitors of /5 Coreceptor binding, such as, for example, AMO 3100, AMO-3465, AMO7049, AMOZ451 (Visusiatev), TAK 779, T-22,

AI X40-4S; HO-S (5С2НЗ51125), zHO-О, RKO-140, КРК1О03611; CT inhibitors, such as, for example, foscarnet (ozsagey) and prodrugs; KTI nucleosides, such as, for example, AT, ZTS, SOC, O0I, 04T, abacavir, ETS, OARO (amdoxovir), F00TS (VSN-10652), fosivudine, ORS 817; KTI nucleotides, such as, for example, PMEA, PMRA (tenofovir); MMACTIs, such as, for example, nevirapine, delavirdine, efavirenz, 8 and 9-CI TIVO (Ttivirapine), poviride, TMO-125, dapivirine, MKO-442, OS 781, OS 782, capravirine, OM96521, SUU420867X, ORSZ961, ORS9B6Z ,

ОРСО82, ОРСОВ8ФЗ, TMO-125, calanolide A, 59-3366, T5AO, 4"-deaminated TAE, MM150, ММО026048,

RMY-142721; ribonuclease inhibitors, such as, for example, ЗР1093М, РО126338; TAT inhibitors, such as, for example, KO-5-3335, K12, KZ7; integrase inhibitors, such as, for example, HER 708906, 1 731988, 5-1360; protease inhibitors, such as, for example, amprenavir and ZUUZO8 prodrugs (fosamprenavir), ritonavir, SC nelfinavir, saquinavir, indinavir, lopinavir, palinavir, VM5 186316, atazanavir ORS 681, ORS 684, tipranavir, AS1776, mozenavir, OMR-323, 553333 , KMT-413, KMI-272, I 754394, I 756425, I 6-71350, RO161374, i)

РО173606, РО177298, РО178390, РО178392, РМО 140135, ТМО-114, oleic acid, 0-140690; glycosylation inhibitors, such as, for example, castanospermine, deoxynojirimycin; SORb4222 entry inhibitors.

When the compounds of the present invention are administered together with other antiviral agents targeting different stages of the virus life cycle, the therapeutic effect of these compounds can be enhanced. The combination therapies described above have a synergistic effect in inhibiting HIV replication, as each component of the Me combination affects a separate site of HIV replication. The use of such combinations can reduce the dosage of a given standard antiretroviral agent that would be required for the desired therapeutic or prophylactic effect, compared to the use of this agent in monotherapy. Such combinations can reduce or eliminate the side effects of traditional antiretroviral therapy with the use of a single agent, without affecting the co-antiviral activity of these agents. Such combinations reduce the potential for resistance to therapeutic agents used alone because they minimize any associated toxicity. Such combinations may also increase the effectiveness of a conventional agent without increasing its associated toxicity. "

Compounds according to this invention can also be administered in combination with immunomodulatory agents, for example, levamisole, bropyrimine, human anti-alpha-interferon antibody, . alpha-interferon, interleukin 2, methionine enkephalin, diethyldithiocarbamate, necrosis factor and? tumors, naltrexone, etc.; antibiotics, for example, pentamidine isethiorate, etc.; cholinergic agents, for example, tacrine, rivastigmine, donepezil, galantamine, etc.; MMOA channel blockers, such as memantine, to prevent or treat infections and diseases or symptoms

Go! diseases associated with HIV infections, such as AIDS and ACS, for example, dementia. The compound of formula (I) can also be combined with another compound of formula (1). - Despite the fact that the present invention is directed to the use of these compounds for the prevention or treatment of HIV infections, these compounds can also be used as inhibitors for other viruses,

Obligatory stages of the life cycle of which depend on similar revertases. se) Examples

Ge The following examples are intended to illustrate the present invention.

Hereinafter, DMF stands for M,M-dimethylformamide, DPTE stands for diisopropyl ether, THF stands for tetrahydrofuran, DMSO stands for dimethylsulfoxide, EtOAc stands for ethyl acetate, "Rug" stands for pyridine.

F) name) 60 b5

Scheme I nn s y y

SI Zh im 70 MOV pi nn nn 12 t 9 t sy 20 s - o i

I p 25 1 o)

Example 1. Preparation of intermediate product 1p6

M-Chlorosuccinimide (0.025 mol) is added in small portions to a mixture of 5-hydroxy-1-indanone Ta (0.022 mol) in acetonitrile (bOml). The mixture is refluxed with stirring overnight. Add 30% H2O and the resulting mixture is extracted with СНоСи". The organic layer is separated, dried over MOZO, filtered and evaporated. The residue (bg) is purified by column chromatography on silica gel (eluent: cyclohexane/E(OAc 60/40; 15-40μm). Collect two fractions and evaporate them, obtaining: 2.2g of 1 and 1.3g of the starting substance. E1c is crystallized from of diisopropyl ether.The precipitate was filtered off and dried to give 0.9 g of intermediate - de (2296) (mp: 21290).

Example 2 so

Sodium hydride (6095 in oil) (0.0054 mol) was added to a mixture of 165 (0.0049 mol) in 1,4-dioxane (110 mL). The mixture is stirred for 10 minutes. Add 1-methylpyrrolidinone (1 Oml). The mixture is stirred for 10 minutes.

Intermediate product I-1 (0.0049 mol) is added. The mixture is stirred overnight at 1402C. The mixture is extracted

SNOSI". The organic layer is washed with 1095 K»CO3 solution, dried (Ma5O)), filtered, and the solvent is not evaporated. They receive 1, bg of the balance. The residue is crystallized from SNUSM. The precipitate is filtered and dried. c 0.46 g of compound 1 (2995) is obtained. Melting point: 22602С. (MN k): (388). ;" (ee) - name) at 50

Co.)

F) name) 60 b5

-

Scheme 2

SHI

"M dm where? t

M ich SM Ya nin i5 th as im. MBO

Shk 24 t what a piece!

With and

Shi about

STILL 1 nie M M » zr y

F also M p

Example 3 - from A mixture of 5-aminoindan-1-one (0.000 mol) and intermediate product 1 (0.000 mol) in a Zn solution of HCI (2 ml) was refluxed with stirring for 2 hours. The precipitate is filtered and washed

H2O and isopropyl ether and dried. As a result, 0.06 bg (5290) of the product is obtained. The obtained fraction is recrystallized from a CH3CM/diisopropyl ether mixture. The precipitate was filtered off and dried to give 0.035 g of intermediate 25 (3090). (Melting point: 22602). « 20 Example 4 Preparation of compound 2.1 from c A mixture of intermediate product 25 (0.0012 mol) in ROSIZ (Iml) is refluxed with stirring overnight. The solvent is evaporated to dryness. The residue is transferred to 1095 K 2CO3 solution. Mixture: with" extract СНоСи". The organic layer is separated, dried (M95O04), filtered and evaporated. The residue (0.73 g) is purified by column chromatography on cromasil (eluent: СНоСИ/СНЗОНН 99/1; B5μm). Two fractions are collected, the solvent is evaporated, obtaining O0.08g of E1 (1795) and 0.14g of 2 (3390). E1 is crystallized from a mixture of oo CHnzsM/diisopropyl ether. The precipitate is filtered and dried. 0.038 g of compound 2.1 is obtained. (Melting temperature: 22702; (MNew):370). - Examples 5-8: synthesis of other indene-substituted 2,6-diaminopyrimidines (name) about 50

Co.)

F) name) 60 b5

-- NM g Nd M Renei t

Мск МеонитнЕ о и,

Oh -- oh her Yi! 1 in nen sen

N ; Mch - en pan dk I tu "o yo S - Ko and schi o MO. Mn, for e kt ze (also to her dpa what have i

YIVOK, not me.

ТЕ вснё пад Фото ванна т SI чн. y Gl syu uk iy sch

And I and shoyu o / tyh v de naya y i t ia

WE WE are "m now Py r vk - Nd t En, shi

KAY S t y shk v s y ' - I 1

N.M. MN NM. im VN F and KO more M more M "-

Ze 18 so

Example 5. Obtaining an intermediate product Zr

Fuming nitric acid (0.3 b2 mol) is added at -409C to 5-chloro-1-indane (intermediate compound Za, 26.7 mmol). The mixture is stirred for two hours at -40 "С. The mixture was poured into ice and extracted with dichloromethane. The organic layer is separated, washed with a saturated salt solution, dried over Mo5zoO, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent: h cyclohexane/E(OAc 65/35 15-40μm). Pure fractions are collected, and the solvent is evaporated, obtaining 4.15 g of the intermediate product 3b (7395). (Melting point: 12925).

Example 6. Obtaining the intermediate product Zs

In the Para hydrogenation apparatus, 0.5 g of Raney nickel is added to a solution of the intermediate product Zr (8.600 mmol) in a mixture of THF and Meon (6/1). The vessel is blown with nitrogen and a hydrogen atmosphere is introduced into it (Zbar). The mixture was stirred for 1 hour at room temperature, filtered through Celite and evaporated to dryness, yielding 1.50 g of intermediate Cs (96 95). (Melting point: 21420). Example 7. Obtaining an intermediate product According to (E/2-89/11)

Gee! 20 Potassium tert-butoxide (56.4 mmol) is added in portions at 02С to a solution of cyanomethylphosphonate (56.4 mmol) in

THF. The mixture is stirred for 15 minutes at 1520. Then, a solution of intermediate Ze (14.1 mmol) in THF is added dropwise to the mixture at 02. The reaction mixture was stirred at room temperature overnight, poured into water, acidified with hydrochloric acid and extracted with dichloromethane. The organic layer is separated, washed with 1095% potassium carbonate solution, saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent:

HF) dichloromethane; 35-7O0μm). Pure fractions were collected, and the solvent was evaporated, yielding 1.88 g of the intermediate according to (65 90). (Melting point: 19625).

Example 8. Preparation of compound 1.9 and Ze (7 100965)

Intermediate compounds За and И-1 are carefully ground and fused using a heat gun. The residue is transferred to a mixture of dichloromethane and methanol (90/10) and 1095 potassium carbonate solution. The organic layer is separated, washed with saturated salt solution, dried over magnesium sulfate, filtered and evaporated.

The residue is purified by column chromatography on silica gel (eluent: dichloromethane/AcOEi 85/15; 15-40 μm).

The fractions were collected and evaporated to give 0.126 g of the Ze isomer (13905) and 0.104 g of compound 1.9 (1195). Each fraction is recrystallized from acetonitrile, obtaining the Ze isomer (melting point: 248-2492С) and compound 1.9 65 (melting point: 225020).

Examples 9-11. Synthesis of 2-amino-4-benzofuran-intercalated pyrimidines in the laboratory / KieM, ve sN vann Z a naya a | ; and A 2 and A with GG ik Zo ! m ak Be vk. y -0 zh sh | Her a rivN caress is JAK

You are crazy. dioxen siv shk vidosna; let's go more Z rubber, 15 O.M MN o i OK pétanque o o ! . I'm messing up your nose

Ide ven tv he poksSTI B s divleoMma pah 19 15 tva nzh po some te m Nino vogosNU; VI Van a z shchi Zh vk Kiz no, kahN 32 o yur yo r iy vizM,schuvsNi VS, at 313 " in y eh nivenema, Va, plak 3.19 n da v pichona; vanadya-n 3.20 vooyutya von. riya. ze, KaeSNZ z4 sch 25 Kk viazen; nenlesna 5 o'clock, Nagsna vah Kt

Example 9. Preparation of compound 3.61

Sodium hydride (6095 in oil) (0.0134 mol) was added to a mixture of Ta (0.0122 mol) in 1,4-dioxane (2 0 mL). The CM 30 mixture is stirred for 10 minutes. Add 1-methylpyrrolidinone (20 ml) and stir the resulting mixture for about minutes. Reagent I-1 (0.0122 mol) is added to the mixture and the mixture is stirred at 1409227 overnight. HO is added to the mixture, after which the mixture is extracted with a mixture of CH»CI./CHZOnH. The organic layer is washed with KSO solution at 1095 s, dried over MAZO, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent: СНоСИО/СНЗОН 99/1; 15-40μm). The two fractions are collected and evaporated. 0.271 g of E1 (695) and 0.74 E2 (second product) are obtained, respectively. 0.1 g of E1 is recrystallized from a mixture of diisopropyl ether/CHZSM. co

The sediment is filtered and dried. The total yield according to the synthesis method is 0.034 g of compound 3.61 (melting point: 2532, (MH k): 359).

Example 10. Preparation of compound 3.62 «

Sodium hydride (6095 in oil) (0.027 mol) was added to a solution of 165 (0.027 mol) in 1,4-dioxane (4 0 mL). The mixture is stirred at room temperature for 15 minutes. 1-methylpyrrolidinone (30 ml) is added to the mixture and the resulting mixture is stirred for 10 minutes, after which reagent I (0.027 mol) is added. The mixture with" is stirred at 1402С during the night, poured into HO and extracted with СНоСи". The organic layer is separated, dried over NaSO, then filtered and the solvent is evaporated. The residue (9g) is purified by column chromatography on silica gel (eluent: cyclohexane/E(OAc 70/30; 20-45μm). Fractions are collected and the solvent is evaporated. O,bg (995) of product is obtained. This fraction containing compound 3.62 is recrystallized with SO SNZON The precipitate is filtered off and dried, obtaining: 0.044 g of compound 3.62 (melting point: 22609С; -th (MH): 345).

Compounds of formulas 3.63 and 3.65 are obtained according to the methods of examples 9 and 10. o Example 11. Preparation of compound 3.1 (Ce) 50 Sodium hydride (6095 in oil) (0.0008 mol) is added at 590 to a mixture of diethylcyanomethylphosphonate

Kz (0.0008 mol) in THF (1 mL) in a stream of Mo. The mixture is stirred. Add compound 3.61 (0.0005 mol). The mixture is stirred at room temperature overnight, poured into NOO and extracted with СНоСі. The organic layer was separated, dried (Mo95O)), filtered and evaporated. The residue (0.23 g) is purified by column chromatography on silica gel (eluent: СНоСиИ» 100; 15-40μm). Fractions containing compound 3.1 are collected and evaporated (yield: O0.1g). The obtained product is recrystallized from a mixture of diisopropyl ether/CHZSM. Precipitate

HF) was filtered and dried, obtaining 0.058 g of compound 3.1 (2695). (Melting temperature. 2262; (MN Kk): 382). d Example 12. Preparation of compound 3.2

Potassium tert-butoxide (0.001 Zmol) is added at 52C to a solution of diethyl cyanomethylphosphonate (0.001 Zmol) in THF (5 ml) in a stream of M". The mixture is stirred at room temperature for 1 hour. A mixture of compound 3.62 (0.0008 mol) and THF (5 ml) was added. The mixture is stirred at room temperature for 1 hour. NoO is added to the resulting mixture and the mixture is extracted with СНоСі. The organic layer was separated, dried (M9505), filtered and evaporated (yielding 0.3 g (93905)). The fraction containing compound 3.2 is recrystallized from the mixture

СНЗОнН/СН»оСИи». The precipitate was filtered off and dried to give 0.045 g of compound 3.2 (14965). (Melting point: 65 2279; (MN): 368).

Compounds of formulas 3.3-3.6 and 3.19-3.20 are obtained in accordance with the scheme of examples 11 or 12.

Synthesis of compounds 4.8-4.11 и и и и З о и о о, Ф МН, dioxene | и весно сту 00 Шка MM и я чананье ki ttefin и и

Heh as: kon, eYUN, o cher

N on vochs On! - cha 45 av-yali

Example 13: Preparation of intermediate product 4p-1

LE o s on o 46

Compound 4a (12.2 mmol) was mixed with 4-pyridinecarboxaldehyde (13.4 mmol) in ethanol. Potassium hydroxide (97.bmol) was added and the reaction mixture was stirred for two hours at 502C. The precipitate is filtered.

The mother liquor is evaporated to dryness. The precipitate and the residue after evaporation are transferred to water and acidified with hydrochloric acid. The precipitate was filtered off and dried to give 2.59 g (8495) of intermediate 46B-1. (He) (Melting point: 22602). high school

Example 14: Preparation of compounds 4.8-4.11

Compounds 4.8, 4.9, 4.10 and 4.11 are synthesized according to the method described in example 2, but using intermediate 46 as a starting material. co

Ah o

In her

I S Z Fri then in s OD YAM. AN. 5 and? | F de pn didi 0000ittnya -- "I - 5." - - I- with ZhMo At- Physical data - | 4.8 phenyl ko t M nin zuyunnizh ui chuU t- 4.9 s T. pl. 22602 with so and with with !

Kz 2-Ж-- у 5552-2222 2 Ж ж A 4 4 :« - Д---Х- 5 - - - - ---ЕЙЗЙЙЙ222222 2 2 2 З - 2 - - -«---- А 410 me T. pl. 726090

It's only nn o | 41 p. T. pl. 22606 конн Mt vo Compounds presented in the following tables can be obtained according to the methods of the examples described above or their obvious equivalents. b5

Table 1 of their R" sk dela 4 in!

From Zn Is 7 | n/|n|nn nn 14 |Mn snensM | N | nu nu NINI " r mn rom | nn a|ninniui o 16 |mn |CM 7 | n| no|svistvrn urnu e i te brya vis|snono 5 tia 6 | nni nnno tz o noisnm |nin en « 2 re ysveko |ninis|fni|in| z 5 frogi revseo ni nisvi|ssj|n ono 7. rr feno | seu sen r yu o 50

Pe) (F)

Po) because b5

Table 2 9,173 children

K | M ris 10 ik sh x Mhz MN

Z vo: ke 20 o kv k ko, will start; ; and sch

She " "28 yur rn nisunininui i s ;"

Ge) 9) so 50

TC) (F) 9) because 65

Table 3

Shchl vit and 7170 -th and ku | M M. k- y ka TO

M

IV; my "zga V U o dl sho 7 ron sn NN NO NO 00-00 32 n non no Fon usnsm y 33 N SNI SI NO NoO00-sneM Shchi sc for dno no non -СЩ(СНи)-СМ o

ОО Ин sni IN ОН ОНО 0 сН(СНнUSМоСссссссс

Pe Kr NIMY Mir -- Street 36 Yu | СНу (с н нн |-СН(СН»)-СМ Ф 37 0 nn |nН НМ e 38 0 НН СН Н nn -СМ ШЙ - 35 190 In SNI (С НН -сМ со 310 хи IN snu Н non 0000 ssneM p « - s with (ee) shk ko o 50

What)

F! co 60 65

3 mn |n no in nn |Stsm "evil yichnn sta N iv ss 313 MN |N n no NO no SSS 0 for hnn st Z no Z ssshsnuem Z tyu |Ddl5 We |n rya is 316 Mn IN N nn nn -sM 323 0 |N N N IN |N SNO (23out iz on essay i: sch 325 0 no Snu S sin no 0 SneFRuet SS o 326 0 nNoB NN no nn SpeO)Ruye 000000 1 o IN SNI NN No |N SNAS)rut 00000 sch zo mV o no Snu s Yad-ya-- spbtu 333 o 3729 MNN non nn SNi(Ruye 000001 sch 3.30 |MN yin Snu IN nn sovy 773 - for 1331 MNN Sn. (S wn ya-- STRU s so

4

FOR MN |n St | nn kololi o) s 3350 |n Sta N no sn, spe SHI "jav v - ee ev 3376 v n nn no sn; SN(SNIiSM

Phobia o zno s no sn 0 sneSNnUM0SsSSs -z re o no Sn s rya svo dbYAM s yu 340 o sto sno (S 00sscheSVBUSM SCHI yuyu EI her sni |N no Sn. SsNASM sh zaz Mn nN OO NO nos som 343 MN NN n i no Sn, Tenenu-sm zv za Mnono st NO ns sp; eetuyeyut o 345 MN | sna et sn 00IsNeSMO S Y volya fest se kn sht SNO new non b5

IZa8 byn NO yn ho SNeSM 349 0 IN NO No V |nN SN(SNUYEEM SSS 3500 no (Snz |nN Vi (|n SN(SNIASM yu 13510 IN St S VR NSS s dn 352 0 No Snu. (SI VOIN 00 snSvUSM 5 V |MnNOnNoO Sn No (Wt 6 svSM s 354 IMCHN NN yn N Vi |N t igo YN 355 shi no |V - snsvSM 3.56. |MN N SNI Vi IN SSHSNIZASM 3.57 MN N SNa (SI VIN 0 SVSEEMO00000SSs 358 МНН СН, оС СИ VO SNSNVUSM 0000 ИЙ 7 3590 NN Н sn |no(n ho no shk 5; tov sire no no no 0 sum y Zh y se (ee) « - s z so 45 ko o 50 more)

o ko bo b5 for

Table 4 in:

N

(and «00, and 'ie and in SM

I"l but the same

РН .СНВ-Н 49. Н «Н «-Н 43-00 sn-s sch z da |SN, o 450000 t PI s zo te Н F 47 -SNU. 0000000 -sti-sn y "Ernst y 4.9 |-CH-(2-pyridinyl) -CHzn 909 -ASNA(Z-pyridinyl "SNU 5 s li -SiA-(2-pyridinyl)|I-SNI H Ш :" - - - - z 6l- (ee) ko so 50 do) o ko bo 65

Table 5 51 y "o y y y vh y y

SHY j yad da a

BENESIS OF AMOUNTS C Za SZ i 7 5110 IN ISI -СсН-СМ no-СМ Н 8; 5210 In |SY.-snNAsm -MO» N c zo 5.3 10 IN si -sNnoASM pd N o

On ; zv 54 o In IsSb-snASM -SO-MN)O Nn so 5.5 10 IN ISP -SsN-SM E N « yu 560 IN si -sn.-SM s N z - 57 o In S-SNASM Ve N

Y 58 o no IS1-snH-SM cm ОН со 5.9 0 In |СИ-СНо.СМ СМ СІ sh 5010 NO |СИ-СНАсМ Е E

Fo 5 1Oo IN si -sn.SM -S-so-M N

What) 51210 sms - spO-SM cm N zv 513! МНИСМИСИ-СНО-АСМ СМ НН at 5140

Table about 2 actions C. Goes to the village! shi go t de same dga o

Y m khiv 4 sh "| в" 61 1О IN o ISNnaSNYI-SNeASM OO -SNASM A sch 29 o2 ОН stіs; -СНО-СМ -МО» НН about sch

Fo sch (ee) « - s z so yuyu o 50 to (F) yuyu bo 65

6.3 |O In (cSniIsSnNz-СНо-СМ in IN b o.4 0 Iv! СН С Из -СН-СМ -СО-МН» n 6.5 o IN ISNZISNII-SNASM CE Н 665 Mch IsnSnNZ-СНо-СМ СИ Н 7 BOB SN. SV, -SN.-S M V: H 6.5 To NO stisnu-SNO-SM SM on 716910 NO snusNnI-SNeSM SM si vloo NO IstSni|-SNO-SM E k ts 7 LO NO SNI SNUI-SNO- SM -snN.-CO-MNIN o v12 MnIiSMISN SNI-SNO-SM SM Nn m with |61310 SMS SNIASNoA-SM SM N F 6140 |n (snusn-SNoASOMN, SM n 7 with |64151MNIN (enZISnNI-SNASOMNO SM N so "40 - s;" so 45 ko so 50

What)

F) co

Table 7 di ditv -k 70 f vita (i do Fo V hi M ch nia She o i3 s " o more ect To ho 71 MNS non No t her "oorziknNk r ; "nNeSsnN-sMIN IN " le ev ko o 7.3 | MNI-SN-SM non SINO ON

From 739 1SNn»АСМ no |ns nn (F; yu t317o sn.АСМ NO |Н snusni|ni

Table 8 is the name of children and children from the village of VI

Well! M "y

Shi shchi Zh

WHAT? y o io; with "in hul" vk ku with tkn in PI

S seshosoi SI SOVY SOVY SLEEP hv nene 7 I I SM NO o ko

Table 9 2 children 7170 o and Kh shchi n

In M

Ki z y to 20 M m r zh ni sh

WITH

Ge 25 , (o) he rev tv

Y 91 o In sn no rstek sch (o)

Y 93 10 sno rSnem and for nou un revisnuskh sh--- « y 9.5 o snz|N NO -СН(СНЙ)А-СМ With snsi no renenom and o Shcho sh 980 |nN СН» СМ still 990 In SNSI TN

What) (F; ko -A1-

eternal ev otknn rya rensnosh o and INN 9 I8IMNINO |na noOgem 91940 slo noOsnSMo oo | NS sno s t» vo |n en o y oz0mnin ISnuNOINO (Sni(Orukh - 35 p SNo-(2Rug so 933 MNN snunO IN SNo-(3)Rut « o z s

I» yan ino |SNaSnosm

SN (SNIO-SM

Ф 7 сн (sleep

Bru svi snkyasnush

F y no snIsn(snUsM 5 Byamyar (nov ovsyassyu o en ov svt yu b5 mov tvov

So Baotn Zenuetun Ispenoe (o Table 10 4 and Her and b o, and Me ih in VI Ky s

Me V | cm 7 SV Ge) : (ee) : - - yu That oh! ССН about pyridine) SN TA about 50 iz -Sn-(Z-pyridinyl) H

F) ko -A3-

Table ZI in ; ; de v y, "u g Gl o M i tt s lo Kk KE" sch » hro "o o 11 1O NO ISTS-SNIASMI-SNI-SM N zo 2 ON TST-SNO-OSMI-MO, N her

ZO IN ss o n sh ia : (ee) 11.4 10 NO SII-SNOASMI-SO-MA, |! « s zo 115 10 IN SPTS-SNASMIE NN n-;» i ko so 020 do) (F) ko uter er 116 o NOSI -SNO.ASMISI N y MO NO C1-SNO-SMIVg N

MON 1 - SNO-SMISM ON and Po BUT SPAS SMISM SI

PLOO TYA TST-SNOI-ASMIE E and PO A SPAS SMI- SN. СО-МНО пло СМ СС-сСНн.-СМИСМ N я plzizhnism su-snesm|cm H z s zo F s iy « shi s z so 45 ko s what)

F) co

Table 12 days! y o di: vo» / ma AK riz kr chto a - Me hro uv ryn»

IZLOO A ISNU StI-SNOASMI-SNO-STYA n

I TO TTN SNU ІНІИ-СНоАСИМИ-МО» gi sch y I3.3 10 dno (SnSniI-SNneSMI du N F srya - g) 134 OO NO TSNAISNI-SNOASMI-SO-KN» H 513510 yin |sn|Sn|СNoСМЕ N Z - 13.6 10 NO 1SNUISNUII-SNO-SMI SI n i? 13.7 0; H SN. SN, -SbnNASM Vg NN so 13.5 0 NO Snu sSNII-SNOASMISTM On yuyu 13.9 a TTN SNI SNI-SNASMISM SI a zadozn |snusnu(-snesSME E

LO AN ENUusSNnI-SNASMI-SN.ASO-MNIN o 1312I1MNISMISNU SNUI-SNOASMISM N with 151310 SMS SNI -SNOo-SMISM N drikpvly drugs

The active ingredient, in this case the compound of formula (I), can be dissolved in an organic solvent such as ethanol, methanol or methylene chloride, preferably in a mixture of ethanol and methylene chloride. Polymers such as copolymer of polyvinylpyrrolidone and vinyl acetate (PMP-MA) or hydroxypropylmethylcellulose (HPMC), usually with a viscosity of 5 mPa.s, can be dissolved in organic solvents such as ethanol, methanol, methylene chloride.

Ethanol can be a suitable solvent for the polymer. Polymer and compound solutions can be mixed and then dried by spray drying. The compound/polymer ratio can be chosen in the range from 1/1 to 1/6. Intermediate intervals can have values from 1/1.5 to 1/3. A suitable ratio might be 1/6.

The spray-dried powder, a solid dispersion, can then be filled into capsules for administration. The value of drug loading in one capsule can be in the range from 50 to 10 Ω depending on the size of the capsule used.

Film-coated tablets 70 Production of the tablet core

A mixture of 100g of the active ingredient, in this case the compound of formula (I), 570g of lactose and 200g of starch can be thoroughly mixed and then moistened with a solution of 5g of sodium dodecyl sulfate and 10g of polyvinylpyrrolidone in approximately 200ml of water. The wet powder mixture can be sieved, dried and sieved again. Then you can add 100g of microcrystalline cellulose and 15g of hydrogenated vegetable oil. Mass /5 Can be thoroughly mixed and pressed into tablets to produce 10,000 tablets, each containing 10mg of active ingredient.

Coating

A solution of 10 g of methylcellulose in 75 ml of denatured ethanol can be added to a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. After that, /bml of dichloromethane and 2.5 ml of 1,2,3-propanetriol can be added. 10 g of polyethylene glycol can be melted and dissolved in 75 ml of dichloromethane. The obtained solution can be added to the first solution, and then you can add 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated dye suspension and homogenize the whole mixture. The tablet cores can be coated with the resulting mixture in a coating machine.

Anti-virus studies of the school

The compounds of the present invention were tested for antiviral activity in a cellular assay. The analysis showed that these compounds exhibit significant anti-HIV activity against the laboratory HIV strain "wild type" i) (HIV-1 GAI strain). Research at the cellular level was carried out according to the following methodology.

Experimental method of cell analysis

MTA cells, HIV-infected or pseudo-infected, are incubated for five days in the presence of different concentrations of the inhibitor. At the end of the incubation period, all HIV-infected cells were killed by replicating virus in control cultures in the absence of any inhibitor. Cell viability is determined by measuring the concentration of MTT, a yellow water-soluble tetrazolium dye that turns into a purple water-insoluble formazan only in the mitochondria of living cells. In the process of solubilization of the formazan crystals obtained with isopropanol, the spectral absorption of the solution is observed at 54 Ohm. --

The values correlate directly with the number of living cells remaining in the culture after five hundred days of incubation. The inhibitory activity of the compound is monitored on virus-infected cells and expressed as

ESyo and ESed. These values represent the amount of compound required to protect 5095 and 9095 cells, respectively, from the cytopathogenic effect of the virus. The toxicity of the compound is determined on pseudo-infected cells and expressed as CC 50), which represents the concentration of the compound required to inhibit cell growth by 509605.

The selectivity index (SI) (the ratio of SS 5o/ESvo) is an indicator of the selectivity of the inhibitor's anti-HIV activity. schu c When the results are expressed in the form of, for example, pECvo or pSso values, the result is expressed in the form of . of the negative logarithm of the obtained value of ECo or SSvo, respectively. and?" Antivirus spectrum:

Due to the increase in the emergence of drug-resistant HIV strains, the compounds of the present invention will be tested for their activity against clinically isolated HIV strains that include some mutations. Such mutations

Go! are associated with resistance to revertase inhibitors and result in viruses exhibiting varying degrees of cross-resistance to currently commercially available drugs such as A/LT and delavirdine.

GI Table 13

The antiviral activity of the compounds according to the present invention is evaluated in the presence of wild-type HIV and HIV ik mutants that have mutations in the revertase gene. The activity of the compounds is evaluated using a cell experiment

He and residual activity are expressed in the form of pEC 5o values. In column A, the values of rESC are presented in relation to strain A (strain A contains mutation 1001 in HIV revertase), in column B there are values of rESeo in relation to strain B (strain B contains mutations 1001 and 103M in HIV revertase), in column C there are values in RESvo In relation to strain C (strain C contains mutation 10Z3M in HIV revertase), column O presents the values of pES»o in relation to strain O (strain O contains mutation 181 in HIV revertase), in column E the values are presented

F) pRESvo in relation to strain E (strain E contains mutation 188! in HIV revertase), in column E the values of pRESvo are presented in relation to strain E (strain E contains mutation 227C in HIV revertase), and in column C the values of pRESvo are presented relations of strain C (strain C contains mutation 106A and 2271 in HIV revertase). In the IV column, the values of РЕС are presented in relation to the HIV-HA strain! "wild type. MO means that this value was not determined.

Claims (11)

The formula of the invention 1. The compound of formula (I) du (), t hm |i : 170 ri to v to o | what else will I say about this, its M-oxide, a pharmaceutically acceptable additive salt, a quaternary amine or a stereochemically isomeric form in which -a!-a2-aZ-a? - is a bivalent radical of the formula -снеСН-СНеСН- (a-1); -МАСН-СН-АСН- (a-2); -MASN-MASN-A (a-3); -MESN-CH-M-A -(a-4); - MEM-SNASN-A (a-5); c o -61-62-p3 - is a bivalent radical of the formula -0-СНо-СНо- (6-1); -0-CH-CH-A (p-2); c -8-СНо-СНо- (6-3); Pho -8-CH-CH- (6-4); -Сно-СН-СН- (p-5); сч «- п is equal to 0, 1, 2, З or 4; and when -a!a?2-aZ-a? - is (a-1), then n can also be equal to 5; t is equal to 0, 1, 2, Z; so a is equal to 0, 1 or 2; p is equal to 1 or 2; B is hydrogen; aryl; formyl; C /4.alkylcarbonyl; S. valkil; C. valkyloxycarbonyl; C..alkyl, « 20 substituted by formyl, C. valkylcarbonyl, C. valkyloxycarbonyl, C. valkylcarbonyloxy; in C. valkyloxys 4 valkylcarbonyl substituted by C. valkyloxycarbonyl; . each KE? independently represents hydroxy, halogen, C 4 alkyl, optionally substituted by cyano or -k-omK, and C 3 cycloalkyl, Co valkenyl, optionally substituted by one or more halogen or cyano atoms, Co.valkynyl, optionally substituted by one or more halogen or cyano atoms, C 4 valkyloxycarbonyl, carboxyl, cyano, nitro, ME'ZV"", polyhalogenmethyl, polyhalogenmethylthio, -5(-0)р8?, -МН-5( -О)585, -С(хОР, (ее) -МНе(сон, -с(оМнМННн), -"МНе(-Ов5, -С(-МНВ? or the radical of the formula a and (c), from to so tA Kz in which each A is independently M, CH, or SV, and Ag is MH, O, 5, or MAE, and Xy is -МА 5-, -МН-МН-, -М-М-, -О- , -С(50)-, С. . 5-, -3(2-0 p-; BZ is hydrogen, halogen, C 4alkyl, MAE", -С(50)-МА ЗВ, -с(50)-К75, "СН-М-МН-С (-O0)-K 5, di -C(xM-0O-88)-C. dalalkyl, B or -X3-BK 7; or C. alkyl substituted by one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, MKU", -сС(-0)-МВУВ"О, -сС(-0)-Si valkyl or B", and on 60 addition to the specified list of substituents ivy, two geminal hydrogen atoms of the specified C alkyl can also be replaced by Sovalcandil, thus forming a spirocycle; C. valkyloxyC - valkyl, optionally substituted by one or more substituents, each of which is independently selected from hydroxy, cyano, MK zvo, -c(50)-me vo, -b(50)-C. alkyl or ee Co valkenyl substituted with one or more substituents, each of which is independently selected from halogen, hydroxy, cyano, ME UVO, -C(-0)-MAZV "o, -C(-0)-Sialkyl or B" ; C, valkynyl substituted with one or more substituents each independently selected from halogen, hydroxy, cyano, MAV "9, -с(50)-МВУВ 9, -с(50)-C. valkyl or B 7; Xz is -МК 5., -МН-МН-, -МЕМ-, -О -, -FSH-0)-, -5-, -3(2Or-, -Xo-C4 lalkandiyl-, -C.4.lalkandiyl-X ha-, -WITH. dalkandiil-Kho-Si zalkandiil, -s(-M-Ok8)-S. dalcanediyl-, where Hoa is -MH-MH-, -MeM-, -O-, -C(50)-, -5-, -3(2-0 p-; and Hoy is -MH-MH- , -MEM-, -C(50)-, -5-, -3(2-0 p-; B" represents halogen, hydroxy, C 4 alkyl, Co valkenyl, Co valkynyl, C 7 ucycloalkyl, C valkyloxy, cyano, nitro, C. alkyl polyhalogen, C. alkyloxy polyhalogen, -F(50)-MA ZV, C. alkyloxycarbonyl, /at. E-alkylcarbonyl, formyl, -MV ZV": or 27; VE? represents hydrogen; aryl; formyl; C /4.alkylcarbonyl; C. alkyl; C. alkyloxycarbonyl; C.. alkyl substituted by formyl, C. alkylcarbonyl, C. valkyloxycarbonyl or C. valkylcarbonyloxy; C. valkyloxys 4 valkylcarbonyl, substituted with C. valkyloxycarbonyl; 25 represents C. dalalkyl, -MA ZV" or polyhalogen. dalalkyl; B represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of the specified carbocyclic or heterocyclic systems may be optionally substituted with one, two, three, four, or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C-alkyl, hydroxyC-alkyl, aminoC-alkyl, mono- or di (C.alkyl)amino 4.alkyl, formyl, C.alkylcarbonyl, C.cycloalkyl, C.alkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. alkyloxy, aminocarbonyl, -CH(-M-O-K8), K72, -Xa-k'" or K72-C. alkyl; Ba is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic saturated, partially saturated or C 29 aromatic heterocycle, wherein each of said carbocyclic or heterocyclic systems may be (3 optionally substituted with one, two, three, four or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C.alkyl, hydroxyC.sub.alkyl, aminoC.sub.alkyl, mono- or di(C.sub.alkyl)amino 4alkyl, formyl, C.sub.alkylcarbonyl, C.sub.3 /cycloalkyl, C.sub.alkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. valkyloxy, c is -6(50)-МА1ЗВ 14, сН(-М-О-88); Me) E8 is hydrogen, C. alkyl, aryl or arylC. dalkil; c BO and B'"9O each independently represents hydrogen; hydroxy; C 4-alkyl; C 4-alkyloxy; C. alkylcarbonyl; C. valkyloxycarbonyl; ME'ZA"; -С(50)-MA "ZV; -СН(-МА") or K", where each of the above-mentioned C. alkyl groups may be optionally and independently substituted by one or two substituents, each of which is independently selected from hydroxy, C. alkyloxy, hydroxyC- valkyloxy, carboxyl, S. valkyloxycarbonyl, cyano, imino, -MA ZA", polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -5(tO)pA?, -MH-5(-O)p?, -C(-O)25, -МНе(сон, -СК(оМнМн», -"МНе(-Ов5, -С(С-МН В, В; or « 20 В? and KO) can together form a bivalent or trivalent radical of the formula with с -СНо-СНо- СНо-СНо- (8-1); :з» -СНо-СНо-СНо-СНо-СНо- (4-2); -СНо-СНо-О-СНо-СНо- (4-3); -СНо- СНо-8-СНо-СНо- (0-4); (ог) "СНо-СНо-МА 12-сНо-СНо- (4-5); - -Сно-СНАСН-СНо- (9-6); - snАСНАСН-СН-СН- (9-7); име) со 020 V" represents cyano; C 44 alkylcarbonyl; C. dalalkyloxycarbonyl; -C(-0)-MV'ZVYA; or C. dalalkyl, with neoobov' necessarily substituted Si daloxy-, cyano, -MK 3877 or -C(-0)-ME Zv; V" is hydrogen or C. dalkyl; VZ and EK" each independently is hydrogen, Nei, C 1-valk il, optionally substituted with cyano or aminocarbonyl, So. valkenyl, optionally substituted by cyano or aminocarbonyl, C».valkynyl, optionally substituted by cyano or aminocarbonyl; iF) B "5 represents C. alkyl, optionally substituted by cyano or -C(-0)-MA ZV; ko B" represents KE" or C. alkyl, optionally substituted by cyano or -C(-0 )-MA ZB; B", if present, each independently represents cyano, halogen, hydroxy, -C(-0)-MA 738", C. alkyl, 60 optionally substituted with one or more substituents independently selected from cyano , -C(-0)-MA Zv or halogen; Co. valkenyl, optionally substituted by one or more substituents independently selected from cyano, -c(50)-Me Zv or halogen; Co-valkenyl, optionally substituted by one or more substituents independently selected from cyano, -C(-0)-MK'ZB'?, or halogen; and, when possible, BK" may also be attached to the -651-6b5-63- fragment by means of a double connection, as a result of which K"" then represents -O, -5, МН, "М-В5, -М-В7, -М-О-К75, -М-О-К7, "СНО, " CH-C(-0)-MV ZB, -CH-B or -CH-K Z, where "CHO can be optionally substituted by cyano, hydroxy, halogen, nitro; O is hydrogen, S is alkyl, halogen, polyhalogenS. valkyl, -С(:О)-МА 3877 or -МКУВ9; 7 is C-U or M, where M is hydrogen, hydroxy, halogen, C4-alkyl, C3-7cycloalkyl, C-alkyloxy, C-alkyloxycarbonyl, carbonyl, cyano, nitro, -MV'ZV"Y, polyhalomethyl . . Co. valkenyl, optionally substituted by one or more halogen atoms; Co.valkynyl, optionally substituted by one or more halogen atoms; S. valkyl, substituted by cyano or -С(-О)К8; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C ..alkyl, hydroxyC. valkyla, C. valkyl-MV"ZV 7, C. valkylcarbonyl, C3cycloalkyl, C. valkyloxy, Si valkyloxycarbonyl, C. .valkylthio, cyano, nitro, polyhalogenC. valkyl, polyhalogenC. valkyloxy, -C(20)-MA"ZV Ya, V'abo -Ha-K 7; It is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, where each of said carbocyclic or heterocyclic systems may be optionally substituted with one, two, three, four or five substituents, each of which is independently selected from halogen , hydroxy, mercapto, C.alkyl, hydroxyC.alkyl, aminoC.ialkyl, mono- or di(Cialkyl)amino 4alkyl, formyl, C.alkylcarbonyl, C3.7cycloalkyl, C.alkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogen. valkyla, polyhalogenS. valkyloxy, -6(50)-МА1ЗВ 14, сН(-М-О-88), 2. The compound according to claim 1, where 7 represents M. p 3. Compound according to claim 1, where 7 is C-U. at 4. The compound according to any of claims 1-3, where -51-62-53- is a bivalent radical of the formula -О-СНо-СНо- (р-1); -0-SNeSNA (6-2); c -8-СНо-СНо- (6-3); Pho -8-CH-CH- (p-4). with 5. The compound according to any of claims 1-4, where one or more of the following restrictions (a) - (hm) apply: "-- (a) -а"-аг-аЗ-а?- is a bivalent radical formula c -SNASN-SNASN- (a-1); (c) is equal to 0, 1, 2, З; "(c) is equal to 0, 1 or 2; (a) KE" is hydrogen; formyl; C 1-alkylcarbonyl; Si valkil; C. valkyloxycarbonyl; - C. valkylcarbonyl, C. valkyloxycarbonyl; "from (e) each K? independently represents hydroxy, halogen, C 4 alkyl, optionally substituted by cyano or i -"-OzhZ b C3 /cycloalkyl, C. valkenyl, optionally substituted by one or more halogen atoms or 15 cyano, "Sg-valkinil, | optionally substituted by one or more atoms | halogen or | cyano, so C. alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono(C. alkyl)amino, di(C. alkyl)amino, polyhalogenmethyl, polyhalogenmethylthio, -8(5О)рВ?, -МН-5(-О )р?, -6(50)К5, -МНе(ЗхО)Н, -С(ОМНМН», - -МНе(хОв 9, -С(ЕМНВЗ or the radical of the formula ko Ar (c), (Ce) 50 ex m more) 7 A where each A; independently represents M, CH or se; and Ag represents MH, O, 5 or ME; 59 () Hu represents -ME 9-, -МН-МН-, -М-М -, -O-, -C(-0)-, Si dalkanediyl, -"CHON-, -5-, -8(5O)p-, -"MA"-0(50)-, (F. -v(50)-Me 13., -X"-S. zalcandiyl- or -C4 lalcandiyl-X"-; GI (9) Xo is -ME 2-, -O-; (p) KZ represents hydrogen, halogen, C 4 alkyl, -MK ZB, -С(50)-МА"ЗВ7Я, -С(-0)-875, -Х3-К 7; C. alkyl, 60o substituted by one or several substituents, each of which is independently selected from cyano, B / or -c(50)-mv Zv 79; Co valkenyl substituted with one or more substituents, each of which is selected from halogen, cyano or -C(-0)-MAUV 9, or B "; or Co valkynyl substituted by one or more substituents, each of which is independently selected from halogen, cyano, -C(-0)-MAUV "U or B 7; in (Y) Xz is -MeE2-, -MH- МН-, -Ме.М-, -О- or -5-; () ВЕ" is a halogen, hydroxy, C 4. valkyl, Sovalkenyl, Co valkynyl, C. valkyloxy, cyano, nitro, -BO0- polyhalogenC. valkyl, polyhalogenC. valkyloxy, -C(-0)-MV"ZV"Y, C. valkyloxycarbonyl, C. valkylcarbonyl, formyl, -ME ZE" or B 7; (Y) B? represents hydrogen; formyl; C. valkylcarbonyl; C. alkyl or C. alkyloxycarbonyl; () 2? is C. dalalkyl, -MA ZV" or polyhalogen. dalkil; (t) VK" is a monocyclic or bicyclic, partially saturated or aromatic carbocycle or a monocyclic or bicyclic, partially saturated or aromatic heterocycle, where each of the indicated carbocyclic or heterocyclic systems may be optionally substituted with one, two or three substituents, each of which independently selected from halogen, hydroxy, mercapto, C4alkyl, hydroxyC4alkyl, aminoC4alkyl, C4alkylcarbonyl, C4alkyloxy, C4alkyloxycarbonyl, C4alkylthio, cyano, nitro, C4alkyl polyhalogen, C4alkyloxy polyhalogen, or aminocarbonyl ; (n) EZ is hydrogen, C 1-6 alkyl or aryl-C 1 alkyl; (o) EC 1 and CO are each independently hydrogen; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl or C. valkyloxycarbonyl; (p) KE Z and KE" each independently represents hydrogen or S. valkyl; (4) KE"? represents C. valkyl, optionally substituted by cyano or -C(-0)-ME Zv; () KK" represents cyano, halogen, hydroxy, -С(-О)-MA "Zv", S. valkyl, optionally substituted cyano, -F(50)-МВ ЗК"? or halogen; Co valkenyl, optionally substituted by cyano or -C(-0)-MA ZV; C» valkynyl, optionally substituted with cyano or -C(-0)-ME "ЗВ 4; and, when possible, "7" may also be attached to the -61-62-53- fragment by means of a double bond , and in this case B // represents -О, -5, -МН, -М-В75, -М-В7, -М-ОО-К75, -М-О-К7, СН», «СН-С (-0)-МК ЗВ", -СН-ВК/ or -СН-К"; where -СНо can be optionally substituted by cyano, hydroxy, halogen, nitro; сч (5) О is hydrogen, С. alkyl or -"MEUV 0; (0 M represents hydrogen, hydroxy, halogen, C 46 alkyl, C. alkyloxy, cyano, nitro, -ME'ZVYA, o polyhalogenmethyloxy, -MH-505-K8, -MH-505-( C1 4alkanediyl)-CO-MSH(E 8)"; or U is C. alkyl substituted by cyano or -"C(-O)K8; (0) aryl is phenyl or phenyl substituted with one, two or three substituents , each of which is independently selected from halogen, hydroxy, mercapto, C. valkyl, hydroxyC.-valkyl, C. valkylmv ZV, Fo C. valkylcarbonyl, C. valkyloxy, C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, polyhalogen. valkyl, polyhalogen 1 valkyloxy, -"C(-0)-ME "ZB, B" or -Xa-K 7; сч (у) It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle, where - each of the specified carbocyclic or heterocyclic systems may optionally be substituted by one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto , C ..alkyl, co hydroxyC alkyl, aminoC.i alkyl, C alkylcarbonyl, C alkyloxy, C alkyloxycarbonyl, C valalkylthio, cyano, nitro, polyhalogenC. valkyla, polyhalogenS. valkyloxy. 6. Compound according to claim 5, where all restrictions (a)-(x) apply. "du 7. The compound according to any of claims 1-4, where one or more of the restrictions (a)-(x) are applied: with (a) -a!-a2-aZ-ai- is a bivalent radical of the formula "with -SNASN-SNASN- (a-1); (B) n equals 1 or 2; (c) t equals 1 or 2; co (a) ВЕ" represents hydrogen; S. valkil; - (e) every K? independently represents hydroxy, halogen, C. valkyl, optionally substituted cyano or -C(-O)B He 6. Sovalkenyl, optionally substituted cyano, C ovalquinyl, optionally substituted cyano, C. valkyloxycarbonyl, carboxy, cyano, nitro, amino, mono(C. valkyl)amino, di(C.4 valkyl)amino, -B(5О)рА, which -МН-8(-О) rve, -в( ihoK8, -"МНе(с-он, -СК(-оОИМнНМНн", -"МНе(-Ов5, -С(-МНВ? or the radical of the formula г" Ar (c), Sho tsi A Ai ! HF) in which each A; independently represents M, CH or CE; and no more than two A. represent M; with Ag represents MH, O, 5 or MAE; (2) Xy represents -ME 2-, -МН-МН-, -М-М-, -О-, -С(-0)-, Si dalkanediyl, -СНОН-, -МЕ 3-с(50)-, -С(-0)-МЕ3., in 0 7Хо- Si dalcanediyl- or -C4 lalkandiyl-X o-; (9) Xo is -ME 2-, -O-; (p) KZ is hydrogen, halogen, C 4.alkyl, -MV'ZV7Ya, -c( 50)-MA "ЗВ, -с(50)-875, -Х3-7; C. alkyl substituted by one or two substituents, each of which is independently selected from cyano, B or -C(-0)-MEUV 9; C. valkenyl substituted by one or more substituents, each of which is selected from halogen, cyano or bo -c(50)-mv Sv 79; or Sovalquinyl substituted with one or more substituents, each of which is independently selected from halogen, cyano, -C(-0)-MVV 9; (Y) Xz represents -MV "- or -O-; ( БЕ" represents halogen, hydroxy, C 4. valkyl, Sovalkenyl, Co valkynyl, C. valkyloxy, cyano, nitro, -Fb(50)-MK zr i, C. alkyloxycarbonyl, C. alkylcarbonyl, formyl, -MVZVYA; (Y) 2? represents hydrogen; C. alkyl; () 85 represents C. dalalkyl; (t) K'/ represents any of the specific monocyclic or bicyclic, partially saturated or /o aromatic carbocycles or monocyclic or bicyclic, partially saturated or aromatic heterocycles, precisely defined in this application, where each of said carbocyclic or heterocyclic systems may be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C-alkyl, hydroxyC-alkyl, amino-C-alkyl, C-alkylcarbonyl, C. valkyloxy, C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, polyhalogenS..valkylu, polyhalogenS. alkyloxy or aminocarbonyl; (n) VZ is hydrogen or S. dalkil; (about) VE? and KO each independently represents hydrogen or S. alkyl; (p) 2 C and KE"? each independently represents hydrogen or C. alkyl; (4) KZ represents C. alkyl, optionally substituted by cyano or -C(-0)-MA Zv; (7) 2" represents cyano, halogen, hydroxy, -С(-О0)-МА "ЗЕ", C. valkyl, optionally substituted cyano, -Ф(50)-М ЗВ; Co valkenyl, optionally substituted by cyano or -C(-0)-MA ZV; WITH". valkynyl, optionally substituted with cyano or -C(-0)-MA"ZVYA; and, when possible, K"" may also be attached to the -501.62.63. fragment by means of a double bond, and in this case B 7 is 0, МН, -М-В 75, -М-В7, сч дв 8М-О-К15 -М-0-87, СНО, "СН-С(-0)-МВ'ЗВ7Я, -СН -B' or -CH-B'5, where -CH0 may be optionally substituted by cyano; i) (5) O represents hydrogen, C1-alkyl or -MEUV 9; (0) M represents hydrogen, hydroxy, halogen, C 6 alkyl, Sialkyloxy, cyano, nitro, -ME'ZV"", polyhalogenmethyloxy, -MH-505-K5, -MH-80"-(C4 lalkandiyl)-CO-M(K 3)"; c ( 4) aryl is phenyl or phenyl substituted with one, two, or three substituents, each of which is independently selected from halogen, hydroxy, C-alkyl, hydroxyC-alkyl, C-alkylcarbonyl, C-alkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, -C(-0)-MA Zv; c (y) It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle, specifically specified in this application, where each of the specified heterocyclic systems may be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, so mercapto, S. valkyla, hydroxyS. valkilu, aminoS. alkyl, C alkylcarbonyl, C alkyloxy, S. valkyloxycarbonyl, S. valkylthio, cyano, nitro, polyhalogenS. valkyla, polyhalogen. valkyloxy. 8. Compound according to claim 7, where all restrictions (a)-(x) apply. " 9. A compound according to any one of claims 1-4, where one or more of the following restrictions (a")-(m") are applied: З с то (а -а!-а2-аЗ-аз- is a bivalent radical of the formula z» -СНАСН-СНАСН- (а-1); (67) n is equal to 1; (c") t is equal to 1; со (ах БЕ" represents hydrogen; methyl; - (е") В? represents a halogen , C valkyl, optionally substituted cyano, Co valkenyl, optionally substituted ky cyano, C»valkynyl, optionally substituted cyano, C 4 valkyloxycarbonyl, carboxyl, cyano, amino, mono(C..valkyl)amino, di(C. alkyl)amino; 0720000 (fu, represents -MA5-, -O-, -MA/3-C(50)-, -C(50)-MA3.; KZ (n) VZ represents hydrogen, halogen, C 4 valkyl, -ME 9874, -С(50)-MA Zvya, -С(-0)-8 "5; C.valkyl, substituted cyano; Co.valkenyl, substituted cyano; or C» valkynyl , substituted cyano; (Z Cl represents halogen, hydroxy, C 4 alkyl, Sovalkenyl, Co valkynyl, C. valkyloxy, cyano, nitro, -F-0)-MA zr, -MA Zvya; He! (Kk) Z represents is hydrogen; S. alkyl; (t") K is any of the specific monocyclic or bicyclic, partially saturated or co-aromatic carbocycles or monocyclic or bicyclic, partially saturated or aromatic heterocycles specified in this application, where each of the specified carbocyclic or heterocyclic systems may be optionally substituted with one, two or three substituents, each of which independently selected from halogen, hydroxy, mercapto, alkyl, hydroxyC. valkilu, aminoS. alkyl, S. alkylcarbonyl, C. valkyloxy, C. valkyloxycarbonyl, C. valkylthio, cyano, nitro, polyhalogenS..valkylu, polyhalogenS. alkyloxy or aminocarbonyl; (p") VZ represents hydrogen or S. dalkil; because (o") 2? and E"O represent hydrogen; (p) 8 C and B"U represent hydrogen; (47) KZ represents C. alkyl, optionally substituted by cyano; (pt) B" represents cyano, -С(-0)-МА "ЗВ, С . valkyl, optionally substituted by cyano, -С(-0)-MA "Zv; C. valkenyl, optionally substituted cyano or -F(50)-MA ZV; Co valkynyl, optionally substituted with cyano or -C(50)-MV ZV Y: and, when possible, B!" can also be attached to the fragment -61-62-53- by means of a double bond, and in in this case, КК" represents 0, МН, -М-В 75, -М-К7, -М-ОО-875, -М-О-К7, "СН", -СН-С(50)-МА ЗВ" , "CH-K or -CH-K U, where "CH" can be optionally substituted by cyano; 70 (c") O represents hydrogen or -"MEOV 0; (2) M represents hydrogen, hydroxy, halogen, C/alkyl, C alkyloxy, cyano, -ME'ZVYA, -MH-50-K8, -MH-80,-(Si.dalkanediyl)-CO-Щ(U "; (y") aryl is phenyl or phenyl substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, C-alkyl, C-alkyloxy, C-alkylthio, cyano, nitro; (in ") It is a monocyclic or bicyclic, partially saturated or aromatic heterocycle as defined herein, where each of the specified heterocyclic systems may be optionally substituted with one, two or three substituents, each of which is independently selected from halogen, hydroxy, mercapto, C. alkyl, hydroxyC-alkyl, aminoC.alkyl, C. alkylcarbonyl, C. alkyloxy, C. alkyloxycarbonyl, S. valkilthio, cyano, nitro, polyhalogens. valkyla, polyhalogenS. valkyloxy. 10. The compound according to claim 9, where all restrictions (a")-(m") apply. 11. A pharmaceutical composition containing (a) an effective amount of a compound of formula (I) according to claims 1-10 and (B) a pharmaceutically acceptable carrier. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated EM microcircuits", 2008, M 21, 25.12.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. c to F c "- d) - with . and? (ee) - ime) se) Ko) ime) 60 b5