UA98334C2 - Purine compounds and use thereof as modulators of toll-like receptor 7 - Google Patents

Abstract

The present application includes purine compounds of Formula I or II: or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods that include the administration of such compounds with at least one additional active agent. Said compounds are used as modulators of Toll-like receptor 7.III

Description

carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl;

IN? is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is an integer from 0 to 5; and under the following condition: (a) When X! represents -СНе-, О represents 1,4-phenylene, ВЗ-И3- represents СНЗСН.СНоСНо- or СН3-О-

СНеСНе-О, н-0, т-1, then MVV is not: (1) 4-substituted or 4,4-disubstituted piperidine or piperazine, or (2) -

Ministry of Emergency Situations of the Republic of Kazakhstan; (B) When X' is -CHe-, O is 1,4-phenylene or 1,4-piperidinylene.

BZ-IZ- is CH3-O-CHNaSNeg-O, n-0, m:1, then neither B", nor B? is substituted alkyl, substituted heterocyclyl, or substituted benzyl; and (c) When X' is -СНе-, О is 2,5-pyridylene, ВЗ-ИЗ- is СНЗСНг.СНеСНгО- or СНз-

O-SNeSNe-O, n-0, t:-11, then MVV? is not pyrrolyl, piperazyl or M(CHZ3)".

According to another variant of implementation, Formula I can be represented by Formula Ia:

M» tn in A J that

ЗМ TM ие (В, мий х ки х выз or a pharmaceutically acceptable salt of the specified compound, where:

B' represents -MV- B;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)B, -

С(ОЮНе, -С(О)MAVU, -5(002087 or -5Х0)2М В ВВ;

IZ represents -МН-, -О-, -5-, -Щ8У)С(О)-, -5(0)2-, -5(О) - or a covalent bond;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

In and in? each independently represents H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)83, -(O)83 , -5(0)283, -С(ООВЗ or -С(О)МА VU; or

VI and B? together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

BA" and Bb are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or

B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, protecting group or prodrug fragment;

IN!? is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is an integer from 0 to 4.

According to another variant of implementation, Formula II can be represented by Formula Pa: mne

Am

CC Zone M, in Zh i l-o i:

ZM i rya x-Vu

Pa or a pharmaceutically acceptable salt of the specified compound, where:

B' is -MV"B5;

IN? is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl,

carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)AE, -C(O)OH, -C(O)MA"A8, -5(002087 or -5(0)2MA AB ;

IZ represents -МН-, -О-, -5-, -Щ8У)С(О)-, -5(0)2-, -5(О) - or a covalent bond;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

In and in? each independently represents H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)AZ, -5(0) H83, -5(0)285, -С(О)ОВЗ or -С(О)МА"НВВ; or

B and B5, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

B and B are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl. or substituted heterocyclylalkyl; or

B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl, protecting group or prodrug fragment;

IN!? is halogen, cyano, azido, nitro, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is 0, 1, 2, or 3.

According to another embodiment, the present invention provides a pharmaceutical composition containing at least one compound of Formula I or II or a pharmaceutically acceptable salt, solvate and/or ester of the said compound, and a pharmaceutically acceptable carrier or filler.

According to another embodiment, the present invention proposes a pharmaceutical composition containing at least one compound of Formula | or II or a pharmaceutically acceptable salt, solvate and/or ester of said compound, at least one additional active agent and a pharmaceutically acceptable carrier or excipient.

According to another embodiment of the present invention, a method of treating or preventing a viral infection is proposed, which includes administering to a patient in need of it a therapeutically effective amount of at least one compound of Formula I or II or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound.

According to another embodiment, the present invention proposes a combined pharmaceutical agent containing: a) a first pharmaceutical composition containing a compound of Formula I or II or a pharmaceutically acceptable salt, solvate and/or ether of the specified compound; and p) the second pharmaceutical composition containing at least one additional active agent selected from the group including interferons, ribavirin or its analogs, M5Z protease inhibitors, hepatitis C viruses (HC), alpha-glucosidase 1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors polymerases M55B NSMU, non-nucleoside inhibitors of polymerase MO5B NSU, Inhibitors M55BA NSMU, TI B-7 agonists, cyclophilin inhibitors, ИВЕ5 inhibitors NSU, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus or their mixtures.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description of certain aspects of the present invention, examples of which are illustrated by appropriate structures and formulas. Despite the fact that in the description of this invention there are references to the numbered claims, it should be understood that the present invention is not limited only to the specified claims. On the contrary, it is intended that the present invention includes all alternatives, modifications and equivalents that can be included in the present invention described in the claims.

The contents of each of the documents referenced herein are incorporated herein by reference in their entirety for all purposes.

Definition

Unless otherwise specified, the following terms have the following meanings:

When a trade name is indicated in this description, it is understood that such indication refers independently to both the product with such trade name and the active pharmaceutical ingredient (ingredients) of the specified product.

The term "compound according to the present invention" or "compound corresponding to formula I or II" means in this description a compound corresponding to formula I or II or a pharmaceutically acceptable salt, solvate, ether or physiologically functional derivative of said compound. Compounds according to the invention also include the corresponding tautomeric forms, for example, the tautomeric "enols" specified in this description. Similarly, with respect to isolated intermediates such as, for example, compounds of formula (2), the term "compound of formula (number)" refers to a compound of this formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives of the specified compound. "Alkyl" refers to a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.

For example, an alkyl group can contain from 1 to 20 carbon atoms (ie, C1-C6 alkyl), from 1 to 10 carbon atoms (ie, C1-C6 alkyl), or from 1 to 6 carbon atoms (ie, C1-C6 alkyl). . Examples of suitable alkyl groups include (Me, -CH333), ethyl (Ei, -CNeCHnz), 1-propyl (n-Pt, n-propyl, -CHNaSNeCnNv), 2-propyl (iso-Pg, iso-propyl, -

CH(CHZ)"), 1-butyl (n-Vy, n-butyl, -"СНаСНоСНосСнХ»z), 2-methyl-1-propyl (iso-Vy, iso-butyl, -CH»CH(CHZ)2g ), 2-butyl (5-Vy, tert-butyl, -CH(CH3)CHneCH3), 2-methyl-2-propyl (Vy, tert-butyl, -C(CH3)z), 1-pentyl (n- pentyl, -

SnNa.sSnNa.sSnNosSNoSIN:I), o 2-pentyl (-CH(CH3)СНоСНаСН:I), C-pentyl o (-СН(СНоСН3)2), 2-methyl-2-butyl /(- с(Снз "cSnNosnH"z), 3-methyl-2-butyl.

СсНсн(СН3)СНоСН»3), 1-hexyl. (-"СНаСНо.СнОсСНосСНосСН"), 2-hexyl (-СН(СН3)СН»СНоСНоСНн»), 3-hexyl and (- сн(СснН:еНнзуСнНсНн»еснН")), 2-methyl-2-pentyl ( -С(СН3)»СНегСНесСнН»3з), 3-methyl-2-pentyl (-СН(СН3)СН(СН3)СНеСН»), 4-methyl-2-pentyl o (-СН(СН3)СнНосСнН(СН3) :6), 3-methyl-3-pentyl (-C(CH3uCHneaCH3)g2), 2-methyl-3-pentyl o /(-

СснН(СнННзЗСН(СНЗ)»), 2,3-dimethyl-2-butyl (-С(СН3)»СН(СНВ33)2), С,3-dimethyl-2-butyl (-СН(СН3)С(СнНз )z and octyl (- (CHg)7CH»z), but are not limited to them.

The term "Alkoxy" refers to a group corresponding to the formula -O-alkyl, in which the alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl part of the alkoxy group can contain from 1 to 20 carbon atoms (ie, C1-C8 alkoxy), from 1 to 12 carbon atoms (ie, C1-C0 alkoxy), or from 1 to 6 carbon atoms (ie, C1-C8 alkoxy). Examples of suitable alkyl groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2aCH3 or -OEO), tert-butoxy (-O-C(CH23)3 or -OIII).

The term "haloalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of the haloalkyl group may contain from 1 to 20 carbon atoms (ie, C1-C0 haloalkyl), from 1 to 12 carbon atoms (ie, C1-C0 haloalkyl), or from 1 to 6 carbon atoms (ie, C1-C0 alkyl) . Examples of suitable haloalkyl groups include, but are not limited to, -CE3, -"SNE", -SEN", -CHNoCE:3 and the like. "Alkenyl" refers to a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon 5p" double bond. For example, an alkenyl group may contain from 2 to 20 carbon atoms (ie, alkenyl C2-C8), from 2 to 12 carbon atoms (ie, alkenyl Co-Ci2) or from 2 to 6 carbon atoms (ie, alkenyl C2-C8). Examples of suitable alkenyl groups include ethylene, vinyl (-SNESCH:), allyl (-CHNaCHNiCH»), cyclopentyl (-C5H7) and 5-hexynyl (-

СснснснНносСнНеснН»), but are not limited to them. "Alkynyl" denotes a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon 5p triple bond. For example, an alkynyl group can contain from 2 to 20 carbon atoms (ie, C2-C8 alkynyl), from 1 to 12 carbon atoms (ie, C2-C2 alkynyl), or from 1 to 6 carbon atoms (ie, C2-C8 alkynyl) . Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-SECH), propargylic (-CHgSECH), and the like. "Alkylene" denotes a saturated hydrocarbon radical with a branched or straight chain or cyclic containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkylene group can contain from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 2 carbon atoms. Typical alkylene radicals include methylene (-СНе-), 1,1-ethyl (-СН(СН3)-), 1,2-ethyl (-СНоСнНе-), 1,1-propyl (-СН(СНоСН33)-), 1,2-propyl (-СНаСН(СНЗ)-), 1,3-propyl (-СНСНесСнНег-), 1,4-butyl (-СНаСНоСНнСнН »-) and the like, but are not limited to them. "Alkenylene" means an unsaturated hydrocarbon radical with a branched or straight chain or cyclic containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkene. For example, an alkenylene group can contain from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-SNEeCH-). "Alkynylene" denotes an unsaturated hydrocarbon radical with a branched or straight chain or a cyclic one containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. For example, an alkynylene group can contain from 1 to carbon atoms, from 17 to 10 carbon atoms, or from 1 to b carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-СЕС-), propargyl (-СН2СЕС-), and 4-pentynyl (-СНаСН»СНгСЕСН-). "Aminoalkyl" denotes an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, is replaced by an amino radical. "Amidoalkyl" denotes an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, is replaced by a group -МВ2СОРЕ, in which Ba is hydrogen or alkyl, and B? is alkyl, substituted alkyl, aryl, or substituted aryl as defined herein, for example, -(CHn)2-MNO(O)CnH3, -(CHNg)3-MH-C(O0)-CH:3 and the like . "Aryl" denotes a monovalent aromatic hydrocarbon radical formed by substituting one hydrogen atom for one carbon atom of the original aromatic ring system. For example, an aryl group can contain from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Typical aryl groups include, but are not limited to, radicals formed from benzene (eg, phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylene" refers to an aryl, as defined above, containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent aryl. Typical arylene radicals include, but are not limited to, phenylene. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p carbon atom, is replaced by an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. An arylalkyl group can contain from b to 20 carbon atoms, for example, an alkyl fragment contains from 1 to b carbon atoms, and an aryl fragment contains from 6 to 14 carbon atoms. "Arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, but also a 5p7 carbon atom, is replaced by an aryl radical. The aryl part of arylalkenyl can include, for example, each of the aryl groups specified in this description, and the alkenyl part can include, for example, each of the alkenyl groups specified in this description.

An arylalkenyl group can contain from 6 to 20 carbon atoms, for example, an alkenyl moiety contains from 1 to 6 carbon atoms and an aryl moiety contains from 6 to 14 carbon atoms. "Arylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, but also a 5p carbon atom, is replaced by an aryl radical. The aryl part of arylalkenyl can include, for example, each of the aryl groups specified in this description, and the alkynyl part can include, for example, each of the alkynyl groups specified in this description.

An arylalkynyl group can contain from 6 to 20 carbon atoms, for example, an alkynyl moiety contains from 1 to 6 carbon atoms and an aryl moiety contains from 6 to 14 carbon atoms.

The term "substituted" as used in reference to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, etc., e.g., "substituted alkyl," "substituted alkylene," "substituted aryl," "substituted arylalkyl," "substituted heterocyclyl," and "substituted carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl, respectively, in which one or more hydrogen atoms are independently substituted with a substituent other than hydrogen. Typical substituents include -X, -H, -0, 20, -ОВ, -58, 5--57, -МНА2, -М"Az, МВА, -СХз, -СМ, -ОСМ, -5СМ, -М -0-0, -МО5, -МО, -МО», -М2, -Мз, -МНО(-0О)8, -С(-0)МАА -5-:0)207, -5(-0) 2OH, -5(-0)28, -0О5(-0)20О8, -53-0)2МА, -5(-0)Н8, -

ОР(-ФОХОВ)», -Р(И-ОХОВ)», -Р(И-ОХХО)2, -Р(ХОХОХОН)», -Р(ФСОВХО), -С(-О)Н8, -С(5 )8, -Ф(О)ЮВ, -С(0)0, -С(5)ОВ, - с(Оо)5А, -С(5)58, -С(О)MAV, -С(5) MAA, -C(-MA)MAV, where X is independently a halogen: E, SI, Bg or I; and each is independently H, alkyl, aryl, arylalkyl, heterocycle, or a prodrug protecting group or moiety.

Alkylene, alkenylene and alkynylene groups may also be substituted in a similar manner.

Those skilled in the art should understand that when such fragments as "alkyl", "aryl", "heterocyclyl", etc. substituted by one or more substituents, these fragments may be designated differently as "alkylene", "arylene", "heterocyclene", etc. fragments (ie, indicating that at least one of the hydrogen atoms in the original "alkyl", "aryl", "heterocycle", etc. was replaced by the specified substituent(s)). When such fragments as "alkyl", "aryl", "heterocyclyl", etc. referred to herein as "substituted" or schematically depicted as substituted (or optionally substituted, for example, when the number of substituents is in the range from zero to a positive integer), then the terms "alkyl", "aryl", "heterocyclyl" and others are interchangeable with the terms "alkylene", "arylene", "heterocyclylene", etc.

The term "prodrug" is used in this description to denote a compound that, when introduced into a biological system, forms a medicinal substance, that is, an active ingredient, as a result of a spontaneous chemical reaction(s), chemical reaction(s), enzymatically catalyzed, photolysis and/or metabolic chemical reaction( reactions). Thus, a prodrug is a covalently modified analogue or latent form of a therapeutically active compound.

One of skill in the art should understand that the substituents and other moieties of the corresponding compounds

Formulas I or II should be selected to provide a compound that is sufficiently stable to provide a pharmaceutically acceptable compound that can be incorporated into an acceptably stable pharmaceutical composition. Compounds of Formula I or II having such stability are within the scope of this invention. "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom, such as O, M, or 5. For example, if the carbon atom of the alkyl group attached to the parent molecule is replaced by a heteroatom (eg, O, M, or 5 ), the formed heteroalkyl groups, respectively, represent an alkoxy group (for example, -OSH3, etc.), an amino group (for example, -MNH3, -M(CH3)", etc.) or a thioalkyl group (for example, -5СН3). If the non-terminal carbon atom of the alkyl group, not attached to the parent molecule, is replaced by a heteroatom (for example, O, M, or 5), the heteroalkyl groups formed are, respectively, an alkyl ether (for example, -СНа.СНг-О-СнНз and etc.) alkylamine (for example, -СНаМНСН3, -СН»М(СнНВз)»г, etc.) or thioalkyl ether (for example, -СН2-5-СН3). If the terminal carbon atom is replaced by a heteroatom (e.g., O, M, or 5), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CHNaCH2-OH), an aminoalkyl group (e.g., -CHNaMHn), or an alkylthio group (e.g. , -

СнНеСНо-5Н). A heteroalkyl group can contain, for example, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, from 1 to 6 carbon atoms. "Ci-Cv heteroalkyl group" means a heteroalkyl group containing from 1 to 6 carbon atoms.

The term "heterocycle" or "heterocyclyl" as used herein includes, by way of example, but without limitation, the heterocycles described in Radiets, I. and A.; Riipsirie5 oi Modegp Heterosusiis Spetivigu (M.A. Vepiatip, Mem/

Wogg, 1968), particularly in Chapters 1, 3, 4, 6, 7 and 9; Tpe Spetivigu oi Neiegosusiis Sotroipaz, A bZepyez oi Mopodgarnv" (Chopp UMieu and Bopv, Mem Mogk, 1950 (about rgezepi), in particular, in Volumes 13, 14, 16, 1911 28; and in U. At. Spet. bos. ( 1960) 82:5566 In one particular embodiment of the present invention, the term "heterocycle" includes a "carbocycle" as defined herein in which one or more (e.g., 1, 2, C, or 4) atoms carbons have been substituted by a heteroatom (eg, O, M, or 5). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (ie, heteroaromatic rings). Substituted heterocycles include, for example, heterocyclic rings substituted with either substituents specified in this description, including carbonyl groups. A non-limiting example of a carbonyl-substituted heterocycle is:

Examples of heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl

(piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxylated tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thiananaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl . ) dan-carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanil, phenoxazinyl, isochromanil, chromanil, imidazolidinyl, imidazolinyl .

By way of example, but without limitation, carbon-linked heterocycles linked at the 2, 3, 4, 5, or 6 position of pyridine, at the 3, 4, 5, or 6 position of pyridazine, at the 2, 3, 4, or 5 furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, in position 2, 4, or 5, oxazole, imidazole, or thiazole, in position 3, 4, or isoxazole, pyrazole, or isothiazole, in position 2, or with aziridine, in position 2, with or 4 azetidine, at position 2, 3, 4, 5, 6, 7 or 8 of quinoline or at position 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. However, even more typical carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, b-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, b-pyridazinyl, 2-pyrimidinyl , 4-pyrimidinyl, 5-pyrimidinyl, b-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, b-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

By way of example, but without limitation, heterocycles bonded to nitrogen at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-myroline, 3-pyrroline, imidazole, imidazoline, 2-imidazoline, 3-imidazoline, pyrazole , pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, in position 2 of isoindole or isoindoline, in position 4 of morpholine and in position 9 of carbazole or p-carboline. However, even more typical nitrogen-linked heterocycles include 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term "heterocyclylene" denotes a heterocyclyl, as defined herein, obtained by substituting a hydrogen atom for a carbon atom or a heteroatom in a heterocyclyl, with free valency. Similarly, the term "heteroaryline" refers to an aromatic heterocyclyline.

The term "heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, is replaced by a heterocyclyl radical (ie, a heterocyclyl-alkylene fragment). Typical heterocyclyl alkyl groups include, but are not limited to, heterocyclyl-CHe-, 2-(heterocyclyl)ethan-y-yl, and the like where the "heterocyclyl" moiety includes each of the heterocyclyl groups described above, including groups described in the References

Spitiwig One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkyl portion of a heterocyclyl-alkyl by a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. A heterocyclyl-alkyl group contains from 2 to 20 carbon atoms, for example, the alkyl part of an arylalkyl group contains from 1 to 6 atoms, and the heterocyclyl part contains from 1 to 14 carbon atoms. Examples of heterocyclylalkyls include, by way of example, but without limitation, 5-membered heterocycles containing sulfur, oxygen, and/or nitrogen, such as thiazolylmethyl, 2-thiazolylethane-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., b- membered heterocycles containing sulfur, oxygen and/or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

The term "Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or 5p3 carbon atom, but also a 5p7 carbon atom, is replaced by a heterocyclyl radical (ie, a heterocyclyl-alkenylene fragment). . The heterocyclyl portion of the heterocyclyl-alkenyl group includes each of the heterocyclyl groups described above, including groups described in Spiethwig's Riipsiriev oi Modegp Heterosusiis Spiethvig, and the alkenyl portion of the heterocyclyl-alkenyl group includes any of the alkynyl groups specified herein. One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkenyl portion of a heterocyclyl-alkenyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. A heterocyclyl-alkenyl group contains from 2 to 20 carbon atoms, for example, the alkenyl part of a heterocyclyl-alkenyl group contains from 1 to 6 atoms, and the heterocyclyl part contains from 1 to 14 carbon atoms.

The term "heterocyclylalkynyl" denotes an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, usually the terminal or 5p3 carbon atom, but also with the 5p carbon atom, is replaced by a heterocyclyl radical (ie, a heterocyclyl-alkynylene moiety) . The heterocyclyl part of the heterocyclyl-alkynyl group includes each of the heterocyclyl groups described above, including the groups described in Rigipsirieh oi Modegp Negiegosusiis Spetivzig, and the alkynyl part of the heterocyclyl-alkenyl group includes any of the alkynyl groups specified in this description. One skilled in the art will also appreciate that a heterocyclyl group can be attached to the alkynyl portion of a heterocyclyl-alkenyl via a carbon-carbon bond or a carbon-heteroatom bond, provided the resulting group is chemically stable. A heterocyclyl-alkynyl group contains from 2 to 20 carbon atoms, for example, the alkynyl part of a heterocyclyl-alkynyl group contains from 1 to 6 atoms, and the heterocyclyl part contains from 1 to 14 carbon atoms.

The term "heteroaryl" refers to a monovalent aromatic heterocyclyl containing at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all rings listed in the definition of "heterocyclyl" including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

The term "carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic ring containing from 3 to 7 carbon atoms in a monocycle, from 7 to 12 carbon atoms in a bicycle, and up to about 3 carbon atoms in a polycycle. Monocyclic carbocycles contain from 3 to 6 ring atoms, but more typically from 5 to 6 ring atoms. Bicyclic carbocycles contain 7 to 12 ring atoms, for example forming a bicyclic (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms that form a bicyclic (5,6) or (6,6) system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-i-enyl, i-dcyclohex-2- enyl, 1-cyclohex-3-enyl, phenyl, etc.

The term "carbocyclyl" refers to a carbocyclyl or carbocycle as defined above, containing two monovalent radical centers formed by the removal of two hydrogen atoms from the same or from two different carbon atoms in the parent carbocyclyl. Typical carbocyclyl radicals include, but are not limited to, phenylene.

The term "arylheteroalkyl" refers to a heteroalkyl as defined above in which a hydrogen atom (which may be attached to either a carbon atom or a heteroatom) has been replaced by an aryl group as defined above. Aryl groups can be connected to a carbon atom of a heteroalkyl group or to a heteroatom of a heteroalkyl group, provided that the resulting arylheteroalkyl group provides the formation of a chemically stable fragment. For example, an arylheteroalkyl group can correspond to the general formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-MH-aryl, -alkylene-MH-alkylene-aryl, -alkylene-5-aryl, alkylene-5 -alkylene-aryl, etc. In addition, each of the alkylene moieties in the general formula above may also be substituted with each of the substituents defined above.

The term "heteroarylalkyl" refers to an alkyl group as defined herein in which the hydrogen atom has been replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl include -CHne-pyridinyl, -CHne-pyrrolyl, -CHne-oxazolyl, -CHne-indolyl, -CHneo-isoindolyl, -CHneo-purinyl, -CHn-furanyl, -CHne-thienyl, -CHne-benzofuranyl, -CHne- СНо-benzothiophenyl, -СНо-carbazolyl, -

СНе-imidazolyl, -СНо-thiazolyl, -СНо-isoxazolyl, -СНо-pyrazolyl, -СНе-isothiazolyl, -СНо-quinolyl, -СНе»-isoquinolyl, -

CHne-pyridazyl, -CHno-pyrimidyl, -CHneo-pyrazyl, -CH(CH3)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3)-oxazolyl, -CH(CH3)- indolyl, -CH(CH3 )-isoindolyl, -CH(CH3)-purinyl, -CH(CH3)-furanyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -

CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -

CH(CH3)-pyrazolyl, -CH(CH33)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl, -CH(CH3)- pyrimidyl, -CH( CH3)-pyrazyl, etc.

The term "optionally substituted" in relation to a particular fragment of a compound corresponding to the Formula (eg, an optionally substituted aryl group) means a fragment containing 0, 1, 2 or more substituents. "Ester" means any ester of a compound in which any functional groups -COOH in the molecule are replaced by a functional group -C(O)ОВ, or in which any functional groups -HIN in the molecule are replaced by a functional group -"C(OOUB) in which the ester moiety A is any carbon-containing group that forms a stable ether moiety, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof , but are not limited to Esters can also include esters of - as described above - "tautomeric enols", for example as shown below:

Mn.

G many,

MM in

Ii G -on mm "When, ok snu zhi EN N same yasna eru GK mi o Her shchi o ; av en ery let your i: tyash schi and M Y h ynya

Chi -K : gin

The term "ester(s)" includes, but is not limited to, pharmaceutically acceptable esters of said compound.

The term "chiral" refers to molecules that, when superimposed, do not coincide with their mirror image, and the term "achiral" refers to molecules that, when superimposed, coincide with their mirror image.

The term "stereoisomers" refers to compounds that have an identical chemical structure, but differ in the arrangement of atoms or groups in space.

The term "diastereomer" refers to a stereoisomer with two or more centers of chirality, the molecules of which are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography.

The term "enantiomers" refers to two stereoisomers of a compound, the images of which do not coincide with each other when superimposed.

The stereochemical definitions and rules used in this description generally correspond to 5.

R. Raikeg, Ea., MesStgam-NII Oisiopagu oi Spetis! Teptz (1984) Mestgam-NiYi Vook Sotrapu, Mem MogkK; apa EiiYei!, E. i

Mep, 5., Z(iegeospetivhigu oi Ogdapis Sotroipav (1994) dopp UMieu and bopv5, Ips., Mem MogiKk. Many organic compounds exist in an optically active form, that is, they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefix is used Yu or Yi, or A or 5 to indicate the absolute configuration of the molecule relative to its chiral center(s). The prefix a or 1, or (kyu) or (-) is used to indicate the sign of rotation of plane-polarized light by a given compound, and (-) or 1 means that the compound is levorotatory. A compound with the prefix (yh) or is dextrorotatory. For a given chemical structure, such stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called enantiomeric mixture A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can exist in the case when during a chemical reaction or the process lacks stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two types of enantiomers that has no optical activity.

Protective groups

In the context of this invention, protecting groups include prodrug fragments and chemical protecting groups.

Protecting groups are available, well known and widely used and can be used to prevent side reactions involving the protected group during the synthesis, i.e. routes or methods of preparing the compounds of the present invention. For the most part, the decision about which group to protect, when it should be done, and what the nature of the chemical protecting group "ZG" should be will depend on the chemistry of the reaction to prevent the occurrence of which the protection is carried out (for example, acidic, basic, oxidative, reducing or other conditions) and from the expected direction of synthesis. The HG groups do not have to be and usually are not the same if the compound is replaced by many HGs. In general, HGs should be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups, and so as to prevent side reactions or otherwise promote synthesis efficiency. The order of removal of protective groups to obtain free unprotected groups depends on the planned direction of synthesis and on the conditions of the reaction and can be carried out in any order determined by a specialist in this field of technology.

It is possible to protect various functional groups in the composition of the compounds proposed in the invention. For example, protecting groups for -OH groups (or hydroxyl, carboxylic acid, phosphoric acid, or other functional groups) include "ester or ester-forming groups." Ether or ester-forming groups may act as chemical protecting groups in the synthesis schemes provided herein. However, some hydroxyl and thio protecting groups are not ester or ester forming groups, as should be understood by those skilled in the art, and belong to the amides discussed below.

A very large number of hydroxyl protecting groups and amide-forming groups, as well as the corresponding chemical cleavage reactions, are described in Rgoyesiime Sigotsirz ip Ogdapis Zupipeziv, TPpeodoga MU. Steep apa Reieg S. M. Uutsiv (Chonp ULiIeu a Bopv, Ips., Mem/ Hogk, 1999, IZVM 471-16019-9) ("Sgeep"). Also see the work of Kosiepeki, RpNiir 9.; Rgoyesiipa Sgoire (Seogd Tpiyete Mepad bida, Mem Mogk, 1994), the contents of which are fully incorporated into this description by reference. In particular, Chapter 1, Rgoiesiipd Stoire: Ap Omega/em, p. 1-20, Chapter 2, Nuagohu! Rgoiesiipd Stgoyrz, p. 21-94, Chapter 3, io! Rgoiesiipd Stocirv, p. 95-117, Chapter, 4, Sagrohu! Rgoiesiipd Stocirv, p. 118-154,

Chapter 5, Sagopu! Rgoiesiipd Stotsre, p. 155-184. For carboxylic acid, phosphoric acid, phosphonate, sulfonic acid, and other acid protecting groups, see work

Steep as below. Such groups include, by way of example, but without limitation, esters, amides, hydrazides, and the like.

Groups that form a simple or complex ether

Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphonbisamidates; (2) ester-forming carboxyl groups such as sulfonate, sulfate, and sulfinate.

Metabolites of the compounds proposed in the invention

The present invention also includes the metabolic products of the compounds of the present invention. Such products can be formed, for example, during oxidation, reduction, hydrolysis, amidation, esterification and other similar transformations of the introduced compound, mainly as a result of enzymatic processes.

Accordingly, the invention includes compounds formed by processes involving contacting a compound of the present invention with a mammal for a period of time sufficient to produce a corresponding metabolic product. Such products are usually identified by radiolabelling (e.g., C" or NU) a compound of the invention, administering said compound parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur (usually about 30 seconds to 30 hours), and isolating the appropriate conversion product from urine, blood, or other biological samples. These products are easily isolated, because they are labeled (others are isolated using antibodies capable of binding conserved epitopes in that metabolite). Metabolite structures are determined in a traditional way, such as by MS or NMR analysis. In general, metabolite analysis is carried out in the same way as traditional drug metabolism studies well known to those skilled in the art.

The transformation products, provided that they are not otherwise detectable, are valuable for diagnostic analysis of the therapeutic dosage of the compounds of the invention, even if said products themselves have no anti-infective activity.

Compounds corresponding to Formula | or HER

According to one embodiment, the present invention provides compounds corresponding to the Formula

І or ІІ given in this description.

In each of the implementations presented in this description, the following conditions are imposed when applicable: (a) When X! represents -СНе-, О represents 1,4-phenylene, ВЗ-И3- represents СНЗСН.СНоСНо- or СН3-О-

СНеСН»-О, н-0, т-1, then MVV: does not represent: (1) 4-substituted or 4,4-disubstituted piperidine or piperazine (2) -МНеНз; (B) When X' is -СНо-, ХО is 1,4-phenylene or 1,4-piperidinylene, BZ-I3- is

SNsSnNg.sSNasSNngoO- or CH3-O-CHnoSN»o-O, n-0, ie!, then neither B", nor B? is substituted alkyl, substituted heterocyclyl or substituted benzyl; and (c) When X! is -СНе-, O is 2,5-pyridylene, B3-І3- is СНЗСНаСНоСНГОо- or СНз-

О-СНеСНе-О, н-0, т-1, then MV"В? is not pyrrolyl, piperazyl or M(СНЗ3)".

The compounds proposed in this invention do not include any of the compounds proposed in UUO 07/034817,

MO 07/034917, US Patent Application Publications 2006/0052403, UR 2005/089334 or 5 6 329 381, the content of each of which is incorporated herein by reference in its entirety. Definitions and substitutes for various species and subspecies of these compounds are given and illustrated in this application. One skilled in the art should understand that any combination of the definitions and substituents described above should not result in the formation of an unrealized species or compound.

The term "unrealized species or compound" refers to structures of compounds that contradict relevant scientific principles (such as, for example, a carbon atom connected with more than four covalent bonds), or compounds that are too unstable to be possible isolate them and include them in the composition of pharmaceutically acceptable dosage forms. For example, one skilled in the art should understand that the definition of 12 as a covalent bond is applicable only to Formula I, but not to Formula I.

Similarly, the specialist must understand that when And? represents -MH-, -O- or -5-, in Formula II, 12 characterizes -MH (imine), O (carbonyl) or -5 (thiocarbonyl) group.

According to one embodiment of Formula I or II, X' represents alkylene or substituted alkylene; wherein substituted alkylene comprises alkylene substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, heteroalkyl, substituted heteroalkyl, cyano, azido, nitro, alkyl, substituted alkyl, and combinations thereof.

According to another version of the implementation of Formula I or II, t is equal to 1.

According to another variant of implementation of Formula I or II, I" represents -СНе- or -СНеСНе-.

According to another version of the implementation of Formula I or II, B! represents independently -MV" B"; and B" and B? together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

According to another version of the implementation of Formula I or II, B! represents independently -MV"B?; and B" and B", together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; where the heterocycle is a 4-8-membered monocyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O and 5; or a 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O and 5.

According to another version of the implementation of Formula I or II, B! represents independently -MV" B"; and B" and B? together with the nitrogen to which they are both attached form a substituted or unsubstituted heteroaryl.

According to another embodiment of Formula I or II, B' represents independently -MV"B?; and B" represents H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and B? is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, -С(О)Н, -

S(O)VZ, -FS(O)YUVZ or -S(O)MA VV.

According to another version of the implementation of Formula I or II, B' represents independently -MV"B?; B" represents

H or carbocyclylalkyl and B? is alkyl, substituted alkyl, carbocyclylalkyl or substituted carbocyclylalkyl.

According to another embodiment of Formula I or II, O is aryline or heteroaryline.

According to another embodiment of Formula I or II, 12 represents -O-.

According to one embodiment of Formula I, -12-B82 is -OH.

According to another version of the implementation of Formula I! or II, I? is -O-; and B? is -С(О)Н, - с(ФоюНе, -С(О)MA AB, -(ФООНВ, -(ОМАНВ, -5(0)2ОВ" or -5(0)2MA HB.

According to another version of the implementation of Formula | or II, B? is -C(FOOSN", -C(OOSNeSN", -

C(FOSN(SNZz)»2, -F(O)MNUNz, -"C(O)MNON»CHz, -C(O)MNONI(SNZz)".

According to another version of implementation of Formula I or II, 12 represents -O-; and B? is alkyl, substituted alkyl, cyclylalkyl, substituted cyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

According to another version of the implementation of Formula I or II, B? is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl or methoxybenzyl.

According to another version of the implementation of Formula I or II, IZ is -O-.

According to another embodiment of Formula I or II, BZ is alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl.

According to another embodiment of Formula I or II, -13-A8Z is -O-alkyl or -O-alkylene-O-alkyl.

According to another version of the implementation of Formula | or II, -13-B83 is -ОСНаСНгОСсСН»z or -

OosnNg.sNngsSNnesn".

According to another embodiment of Formula I, B" and B" are not H or alkyl at the same time.

According to another version of the implementation of this invention, Formula I is represented by Formula Ia: solution

M-8,

Ia or a pharmaceutically acceptable salt of the specified compound, where:

B' represents -MV- B;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)A, -

С(ОЮНе, -С(О)MAVU, -5(002087 or -5Х0)2М В ВВ;

IZ represents -МН-, -О-, -5-, -Щ8У)С(О)-, -5(0)2-, -5(О) - or a covalent bond;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

In and in? each independently represents H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)AZ, -5(0) H83, -5(0)285, -С(О)ОВЗ or -С(О)МА"НВВ; or

B and B5, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

B and B are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or

B" and B? together with the nitrogen to which they are both attached form a substituted or unsubstituted heterocycle;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl, protecting group or prodrug fragment;

IN!? is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is an integer from 0 to 4.

According to one embodiment of Formula Ia, B' represents MB"; and B" and BZ, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

According to another version of the implementation of Formula Ia, B' is an MVV"; and B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; where the heterocycle is a 4-8-membered monocyclic fully saturated, partially unsaturated or heteroaryl ring containing at least one heteroatom selected from M , O and 5, or a 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O and 5.

According to another embodiment of Formula Ia, the heterocycle is selected from the group consisting of:

Ku Ky I her dune K sht i "k- gy Ah, eh Sheche k "M; 7 1 er; Z i: i x Xia iy M "E » shchi M z jak r pe pk re k

With shi i in her g 7 in as shu

Y : 7 zi M Z y ke and y and y

НН з тех у т У ; | g E ; Dn - R let's fight I" and : ; In : S u «sh MN, t ; AMNO-M; in and poison

A I y: KU Mi GY x

M shkh I N r i I - r; dbssite - in r - and write and sh-sh and

Be and

According to another version of the implementation of Formula Ia, B' is an MVV"; IN? is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and B? is carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)88, -C(O)OVZ or -C (O) MVV8.

According to another embodiment of Formula Ia, B" represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl or cyclopropylmethyleneyl, B" represents phenyl, pyridinyl, -C(O)CH3, -C( OOSN", -

С(О)СНгСН» or -С(ООСНоСН»).

According to another version of the implementation of Formula Ia, B' is an MVV"; B" is H; and B" is alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl.

According to another version of the implementation of Formula Ia, B! represents independently -MV"B"; B? represents H; a

A: represents alkyl, substituted alkyl, carbocyclylalkyl or substituted carbocyclylalkyl.

According to another version of the implementation of Formula Ia, B' represents independently -MV"B"; B" represents H; and

A: is selected from the group consisting of: as as . - still -th VE Mas

Le AYU as, I" Hon Akt K

Zk with ma? Sh

According to another version of the implementation of Formula a, B? is N.

According to another version of the implementation of Formula Ia, B? is -С(0О)8Е, -С(ООВЯ, -С(О)МВ VU, - (FON, -5(О)МАВ8, -(0)2ОВ" or -5(0)2MA VU.

According to another version of the implementation of Formula Ia, B? is -С(ФОО)ОСН»з, -С(ООСНеСН», -

С(ФОСН(СНЗ3)»2, -Ф(О)МНОН3, -«С(О)МНОН»СН3, -С(О)МНОН(СН33)».

According to another version of the implementation of Formula Ia, B? is alkyl, substituted alkyl, cyclylalkyl, substituted cyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

According to another version of the implementation of Formula Ia, B? is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl or methoxybenzyl.

According to another version of the implementation of Formula a, ИZ is -О-.

According to another embodiment of Formula Ia, -13-BZ is -O-alkyl, -O-(substituted alkyl), -O- carbocyclyl, -O-heterocyclyl, -O-carbocyclylalkyl, -O-heterocyclylalkyl or -O- alkylene-O-alkyl. According to this variant of implementation, it is better that B? was H. It is also preferred that B' be MB"B", and B" and B?, together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

i g Ku where and Kya -

Ж - b, Z s "Ж Z x "M" She g , Sy ; M and N shiya ' y shk M ko : z ;

Ya ka, re g mesy she Z i -mshchi and vok tu ey sch bod

And Her 8 y. ; you ku Z i

T t h to. i : : i ' kN I ! and EE - iy shchi de fiya shi U d-i i, Shena Mne i m y ; 7 ше 4 у и и И; in

Uh Mei

According to another version of the implementation of Formula Ia, -I3-VZ is -OSNaSNgOSsN", -"OSNa.SNeSNeSN 5,

OSN.SNoSE:», -OSNo.SE»SEz, OSNSN(SNZ)2, -OSNoSE with, her pk dich Shchy bno i 1 more : 4 more Med potny - pn K, zh i - Y tt, myh he NK ssh ! g. what about us | Me

According to this variant of implementation, it is better that B? was represented by N. It is also better that B' represented himself

The Ministry of Internal Affairs and Communications, and B: and B? together with the nitrogen to which they are both attached, formed a heterocycle selected from the group consisting of:

Don't do me More M TZ! and and !

S and En; y a u S. she z Zen Mo y i ty t syke y V y ke N

She: she be 5 koadsche y t m vedy tat - So M what shk now is

God forbid

K shd ONE p ray Danya ek M I v NI I

SCHI J re

Kay, I don't

According to another version of the implementation of Formula Ia, B' represents -MV"B?; B? represents H, -С(О)Р, -

С(Ф)ОНе, -С(О)МАВ8, -55002087 or -5(0)2МА"В8; IS is -O-; BZ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl , heterocyclylalkyl; and B and 85 are independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)AZ , -5(0О)AZ, -50)283, -"С(О)ОВЗ or -С(О)МА"ВВ; or B" and A?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

According to another embodiment of Formula Ia, B: and B: are not simultaneously H or alkyl.

According to another version of the implementation of Formula Ia, -13-AVZ is -"OSNa.SNgOSsN", -OSNaSNegSN",", -

OosSnNasSNosSNosSnN», -Oiso-butyl, -Oc-butyl, -Oc-pentyl, -OsNegc-propyl, -OsNegc-butyl, -OsNeaSnhec-propyl, - base. nnsNngon, -OSNoCE», -OSHgSNoCE», -«OSNa.CH.SNoCE: or (tetrahydrofuran-2-yl)methoxy.

According to another version of the implementation of Formula Ia, -13-VZ3 is -ОСНа.СнНгОСснН», -ОСНа.СнНоСНеснН», -

OSN».SNoCE», -OSNa.SnNa.SNosSNgOn, -Oiso-butyl, -OSNoSNegc-propyl or -OSNgc-propyl. According to another version of implementation, -And 3-VZ is as defined immediately above, B? is H, B! is MVV, a

VI and B? together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of: and | M Z h

Kk still k still 'bo oy 2. E 1 still M -k i - x; ek se balu KU | i am

Y. o mu m bo : t. St. ! EE s and me y

At

A ri -y X y oo, Xia Sh zhi Ho

According to another version of the implementation of Formula Ia, -I3-VZ is -OSNa.SNaSNegsSN", -"OSNaSNgOSsN", -

OSNeSNoCE", -"OSNaSNgSNoSNgON or -OSNgc-propyl. According to another embodiment, -13-B8Z is as defined immediately before, B? represents H, B' represents MVV, and B: and B? together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

U i-- / z shcha i Y byte EE 7 or M Beh i i Y i I sa Ne ped t i koe

With respect to M. V

EE KE

; and Ku v as, pt as r tt, sew lice. o slo o ey X sk ele u ny Y I el My

According to the additional variant of implementation, -I3-VZ represents -"OSNa.SNaSNeSN".

According to one version of the implementation of this invention, Formula II is represented by Formula Ia: мне Ве всч

Vk on

WHAT? Oh! y "m M rea i ky

I min

Pa or a pharmaceutically acceptable salt of the specified compound, where:

B' is -MV"B5;

IN? is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)AE, -C(O)OH, -C (O)MA"A8, -5(002087 or -5(0)2MA AB;

ИZ represents -МН-, -О-, -5-, -ШХАУ)С(О)-, -5(0)2-, -«5(О) - or a covalent bond;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylpyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

VI Her B? each independently is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)83, -5(0)83 , -5(0)283, -С(О)OVZ or -

С(О)МА" VV; or

B and B5, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

AND? is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl;

B and B are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or

B" and B? together with the nitrogen to which they are both attached form a substituted or unsubstituted heterocycle;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl, protecting group or prodrug fragment;

IN!? is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is 0, 1, 2, or 3.

According to one version of the implementation of Formula Pa, B' represents MVV"; and B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

According to another version of the implementation of Formula Pa, B' represents MVV"; and B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle, where the heterocycle is a 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O and 5 , or a 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O, and 5.

According to another version of the implementation of Formula Ia, the heterocycle is selected from the group, which includes: Si, that p still | E Ky, ; zd She and this where else ku shk and | g 4 t ' ! and, KO"

EV

; da che eerdyk t v, shi Ky dya ; y In I23 schi X dit Ki shen

According to another version of the implementation of the MPa Formula, A! represents MAYA"; IN? is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and B? is carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)88, -C(O)OVZ or -C (O) MVV8.

According to another version of the implementation of Formula Pa, B? is -С(О)8Э, -С(О)ЯВЭ, -С(О)МВ VU, - (FON, -5(О)МАВ8, -(0)2ОВ" or -5(0)2MA VU.

According to another embodiment of Formula Ia, B" represents H, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl or cyclopropylmethyleneyl, B" represents phenyl, pyridinyl, -C(O)CH3, -C( ФО)ОСН», -С(О)СНеСНз or -ФСКюююсНнсн».

According to another version of the implementation of Formula Pa, B? is alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

According to another version of the implementation of Formula Pa, B? is methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, cyclopropyl, methylcyclopropyl, cyclopropylmethylene, benzyl or methoxybenzyl.

According to another version of the implementation of Formula Ia, IZ represents -O-.

According to another embodiment of Formula Pa, -I 3-BZ is -O-alkyl or -O-alkylene-O-alkyl.

According to another version of the implementation of Formula Pa, -13-83 represents -ОСН»СН»ОСН3 or -

Oosng.sNnegsSnesn".

According to another version of the implementation of Formula Ma, B' represents -MV/B?; IN? is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cyclylalkyl, substituted cyclylalkyl, cyclylalkylalkyl, substituted cyclylalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl; IZ is -O-; BZ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl; and B and BZ, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

According to one version of the implementation of Formula I, 17 is a covalent bond, and B? is hydrogen or halogen. Thus, Formula I is represented by Formula Ir:

MN m» se M Y yaz I) Y U v

Zk kwi sei

With digging and a

PTO ia x y

Ki

Where:

B' represents -MV- B;

B2 is H or halogen;

ИZ represents -МН-, -О-, -5-, -ШХАУ)С(О)-, -5(0)2-, -«5(О) - or a covalent bond;

BZ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;

VI and B? each independently represents H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, -C(O)H, -C(O)AZ, -5(0) H83, -5(0)285, -С(О)ОВЗ or -С(О)МА"НВВ; or

B and B5, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

AND? is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl;

B and B are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl. or substituted heterocyclylalkyl; or

B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

IN? is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl or substituted heterocyclylalkyl, protecting group or prodrug fragment;

IN!? is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl or substituted heteroalkyl; and n is an integer from 0 to 4.

According to one version of the implementation of Formula IU, B' represents MVV"; and B" and B?, together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle, where the heterocycle is a 4-membered monocyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O and 5. According to this version of implementation, the heterocycle can be selected from the group that includes: ! what is it with me in T N ke and in i !.

According to one embodiment of Formula IB, -13-8Z is -O-alkyl or -O-alkylene-O-alkyl.

It is better that -1I3-VZ is -ОСНа.СНгОСсН" or -"ОСНаСНСНеСН».

According to one version of the implementation of Formula Ir, B' represents MVV"; -13-BZ is -O-alkyl or -O-alkylene-O-alkyl; and V'ii V? together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; where the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one heteroatom selected from M, O, and 5.

According to another embodiment of Formula (I) or (II), the compound is selected from the group including:

MN a t o M Ao-o y vach 27 U y M

A and shi a and M No chn. oyu, y x Kk skh rek She ok M. y ОН щ- M o EF) р ty go Щ Ще Чо ре щ з M р, ше ше С Н mmM, y вч в шеча -e don y ! h re tu on g chi k ch ze wdo iy | child: SHO with NO Sho i A I ne M Sy E i ,

Le it Ge M i n

Ka y i Ol pk, AD he b Y ri ron hto 2. M ny zd M "M KO Yake ; in z still sh

E Kt /

E B.

MN;

KK And Not MN"

M te Kk ke ; ts E | sne M myad She M. ron ne des re y | slo, m a r As I GG You ON Y iie o b o g I M Y iy U m 630 5

E E E

Mn" g and I

And | IVF she M, x g Shan. ше B Ж сн чна - я щ у г шх ше М.

NYA Y T U-on you and YOU

With N

/ tya p Her ri 1 sh

to me

M g M. t, I carried what sho n

SHHA» x Her ha. M I what what m) ee pa -- 5

Eye: k. l-ton - ran ke ony t iy rea ee na A I ra yi I I 7 / Vi wai tele s i y a v mia M, on y y

E H and | and i x E Posad E dit m J ol EI ek i / -ON

And the ice skating rink, but where

Yes - ee -M I M M se No

M 7 m: 7 -aN and -o iy sht g Koran ve cy i gbrtcha 5 M M : - Kk - S v she ote i hu M U match E Sho Ga s

MN me M Mn,

U - : he and uv! in M r M We x ! sh- (ol Ya A ra

I'm still shaking my hands and feet,

In! ery on blue .nshcn in si

M.O

M ka M Mn; year on Ku

Ota t y no her t 5-He i ra sashe NIE SCHA ve ne ed M

M Her. dyan b Y What Me sh

And about | with me

MN; ; "In MN; t GU on y shen U dk sh KZ TY Sho ryenya r., Seya z -K 7 t te o M hya Kk h i s won NN X se kolon v shi s che y

In Sya khy rshe yah -- m Mokh 006 o Okorana nak tiy ry ya teh! (: OM Iv

Dream of children M di di

OO SHY; with shk in Ky I

And I; and

MNE yang MN i

A OM kr nya M mmM, and: all the rest and I echo my Ben A o Shk as I am passionate about MKU

E and peki I I ee as rogo" GI: ku s esch ze de esche le

Bak and shi red ah more Two M si OK and they take m M ,

M kit um

She was born in Shk r

MA" mV li on s-m ryti i YO on ke sh tya oi i M tykh M shk y "a lk

I: a ke t s-m U ly mia

MN"

AJ NN mm A 5. | and the tone is the same! db sani yo 000-on i shiy i or M shiy min ra I sh X pen

Zh. So what?

And more. - United Nations General Assembly Shk u den, m i se

Her Z ke

KI --th mn,

E and Y -on MN.

Mu Be em ka o nach shchi 4 -E ikh on

Ko ) mm pe Z o D T -o nn

Ye yatti tmish u - y i As syu i d ts M u sort, she -fK 7

Ki un chna we ma m Where and. chle ah t Y --ONn

Kch I Che U and S my a go M

In 7 u ha o x s i -kn. he

Her" che MN p.

OK -- Yes, Mr

M t Z Y i y G M -ON mah - rana nya Ye p M mo M i 7 i o M ! MIN! ko "Z li i x X hvo i no i z vych Koch

MN» Mne che zhit y she M shin A ai GU sk o V Ben sh M y y y

C 5 in No

M emche still: and what nn MA; s syu M ich Zo M jo h -on shiv: no o

Ex "in nn - in p xx Ko M KM and that 4 th che

There is S r zh she DY shi ch a TE and Mne

MN. A M p 1 on o d Her S 5 On bot" and yo Goy and chny ta td ; M muzhd My s y Z y e y u it E M Z -M what kh t

I'm dead

Mn; MN; re -M «o M

M". I'm waiting for the sun, they're early, and they're like r 7 Hecytus, X and Ye co

Kit nn

M) M mn o MA Sho

Mne tt myt, MNE ih osh kt, r i still M pi u o Her sh

A: and here 7 ay I and | in 3 hard ho

Another 5, - and sh

Ge - shki: Ku

I M ry; pd o Y I. U y r u o n n y a d sadiv M a y a r e y

Oh, she loves it in Kk

And r

GU r F still 0 kh still "and what eh

Kur r -eB-IE tm i i: " x 2 a ,- Mo mem o mam no p she O-a

ЕВ ве Ж A s o ked yk Eh o sy reve o" M "ICH in 07 sh" M u y mk ; y - s y hek Z

From what Zh

MN" ne me M. miv, o 1 o-on kah tk, Z Y. he i pyt in "M ikh s" M M di E

Kv X r is her shchi

To me MN

TK. M m u zh ki U d-y her h o she . h

MN. o - Mne nam 5-0 is m uk Po-na i. Yeonevry Mkt MV. aunt Zmshi ti x. is KE i and r

Go Ga V - - ve

She oh x men More o00- y Y - kny M, -o o. ek taki SHY man o and M ded ee a de 3-9 years; she ke and uyu shchi S (i

ONE M Z ich,

M. I. Z

MN. sho MN she Ok i I K / 7 G 5 sh Zo M I: (FI che - M

I xx; х Ne et re What stings: Ж vi. yo Sushi A r yo letu s on b uz i 7 - shk chu

Mn" I I -M. Sh-

In U-on g pene Z what something -M sit OS on r; an Shah o aa i it h , in her --k m Si y y M ikh sho tm y

E E cha STe g Te pyToh Me s M M Eh most

Mt Z-he sewed shih rel al shcha y! mm and with y

S uri hi - -i a u rovy -M IY a -M I Y i she

Iii" Her tr, sly M o on Her SG U-en td then ki an vo kh dya chu M zh he uche ee h uh what

SHK zho tn | We are the | ra ka she IR pi

M M U zh - / I u» nya No

Mo M, Mne! | ! ON And dogo kol

From the wallpaper, in the classrooms of Mary M

What's up?

M- Ka and She

Ki i ich a g M Ve M

Z Kh une MN ee in V ambassador M o ItON o i deya "M

Here is the "7th century" of Ko Kkst,

We Mo and ; ze

M she t en pl. 20. then - M is still -M y : S x y Y y -on y g I. child y y. as Otto m la "M o shkyk chi

And Znyy z

Mn"

Mne Am rAshit i a 2-on i | | - he Oto rev Gaya sn M kiomi tosti p

Xia o x y m u ym

M. Ot s o dinya, "

to me

Mne A. Mshko - M M M a"

G.D. Mr. KE and. g. x -

T 5--oN Otut KM d-Mn

A tya a Kk y M Y 7 , S U r. go ie A ts V x 2 dk

Ko - x. Penn

Who "M

M! And MN d-mn with o You and

MN is still -M

B -on tyu, pev k de di i to i i ig - gmya or pharmaceutically acceptable salts, solvates and/or esters of the specified compounds.

According to one embodiment, the present invention provides compounds corresponding to the Formula

Ia:

MN» me -M a -e-e

To the 3rd -- to the link

ShK rec VV

Gene her x ( --B, iz or pharmaceutically acceptable salts, solvates and/or esters of the specified compounds, where: -I3-BZ is -ОСНаСНоСН»С», -ОСНаСНоСН»СН»з, -ОСНасСНоСН»еСН», -Oiso- butyl, -Oc-butyl, -Oc-pentyl, -

OSNegz-propyl, -OSNgz-butyl, -OSNaSNz-propyl, -OSN».SN».SN»osSnNg.ONn, -OSNoCEz, -OSNoSNoCE», /-

OoSnH.SNoSNesE:;: or (tetrahydrofuran-2-yl) methoxy;

B2 is H; n is equal to 0;

IN! is -MV"B"5; and B: and B?, together with the nitrogen to which they are both attached, form a heterocycle selected from the group including: as

M MU Z y, also executioner; and still son from Kyi and Sht and as cha sho. SHE mavva Y E chi t E and Y i shi M a

According to one version of the implementation of Formula Ia, -I3-VZ represents -"ОСНа.СНоСНеСН", -"ОСНа.СНоСНеСН with, -

OoSN.SNSE;», -OSNaSNnNSNnSNeOH, -Oiso-butyl, OSN».SNHc-propyl or -OSHnc-propyl.

According to one variant of implementation of Formula Ia, -I3-VZ represents -"ОСНа.СНаСНегСН", -"ОСНСНгОСН5, -

ОСнеСНеСЕ», -ОСНа.СН»СНоСНоН or -ОСНГц-propyl.

According to one version of the implementation of Formula a, -13-VZ is -"ОСНа.СНоСНеСнН".

According to one embodiment of Formula Ia, B" and B? together with the nitrogen to which they are both attached form a heterocycle selected from the group consisting of: I am where I am

SHY S So

According to yet another embodiment, compounds of Formula I and II are listed below in tabular form (Table 5) as compounds of general Formula I:

Shk in "ta

The formula is NO.

Compounds corresponding to the general Formula II are depicted as four fragments T1, T2, T3 and T4, connected as shown above. Tables A-O show, respectively, the structures of fragments T1, T2, TZ and

T4, indicating the joining places of adjacent fragments. Each fragment of TI, T2, TZ and T4 in Tables A-O is represented by a "code" consisting of letters and numbers. Each structure of the corresponding compound

IP formulas can be marked in tabular form by combining the "code" that displays each structural fragment using the following syntax: T1.12.T3.T4. So, for example, T1A.T2A.TZA.T4A represents the following structure:

MN" of St

A r a alkny MO K apknlene-apyalene-alugen-tn but schalyakny where the terms "alkylene", "aryline", "alkyl", "cycloalkylalkyl", "heteroaryline", "carboxycyclyline", "carbocyclyl", "heterocyclyl" and others . meet the definitions given in this description.

Table 1: Structures of T1

MA 1 Gbalilo//////1111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111112

Table 2: Structures of T2

Designation Structure of GT DNA M

M OT:

I don't want to

N Ti M g i

I t I

TA MA" o aku! ka she aa

E Y and k y

OO

Oats M

Designation The structure of the neck 2 m З и чиа шешЯ M

T--t, !

I do it and I | MN ak : , N ptn M I still I pom u : : Taz. and

Table 3: TK structures

Table 4; Structures of T4 -M(alkyl)5(O)"-alkyl -M(cycloalkylalkyl)C(O)O-alkyl -M(cycloalkylalkyl)C(O)M(alkyl)"

Table 5

List of structures of compounds corresponding to Formula HER

TIALZATZALYAA, TIALZALAALYAV, TALATZATYAE. 0 T1ALZATZALYAV,

TPALIZALZALYAE, PA LIALZALYAE, TIALIA:TZA.TYAO, TALIALZALYAN.

TIALZALTZV TA, TAL?TALZIVLYAV, TIALZALTZV TS, TIALTZATTZV. THEN,

CHAMBER, CHAMBER OF THE, TIALZATIVTYAS, TALZALZVLAN,

CHAMBER, PTIALTALISTYAV, TATA LZSTS, MALA TAYETYAV,

PALZALZSLIB PALI ATZELIAK, PALZATZSTAYU, TALA LZSLTYAN,

TALOALZOLYAA, TIALTALIULYAV, TIALZALIYUTYAS, TALA LZOLTYAYU,

TIAOALTIUTAE, AND LATIV, T1ALIATZVLIAO, I 1ALALIOLUN,

TIALTOVTZALYAA, 0 TIALOVLIZALYAV, TIALOVIZALYAS, 0 TIALOVTZALYAYU,

TIALOVTZALYAS, OO TIALOVLTZA LYA, 0 TIALOVITZALYA 0 TALOVLZALYAN,

TIALIV TZ TYAA, TATO VLTYAV, TIiAlOVllLIVLLAS, 0 TIALLOVTUVLIU,

TIA LLC. ZVLYAV, LA LOIVLZVOYAE, OP ASTOVLZVLYAES, 0TALOVLZVLTYAN,

TIALOV TISTA, LIALOVLTZOLYAV, TpALIVLZELIAS 0 PALOVLZISLYAU,

TIALTOVZSLYE, TIAOSTIVLTZSTYAE, TIALIVTISLTYAO, TATO LZSLYAN,

TIALLOOVLLZOLLYAA, OTIALOVIZOOTYAV, BPALOVLUMTYAS, 0 LTALOVITZOL,

LIZA TIATOV, TT ALTOV.TZOTYAE, T1ASTaVLZOTYAO, PALOVLZOLYAN,

TALISLZALYAA, TIALOSLZALYAV, PALOSTZALYAS, 0 TpALOSTZATIU,

TALOSLIALYAV. TRALOSTZALYAV, 0 PIALOSLTZALTYA,. 0 PALOSLIZALYAN,

TIAOTOS TIV TIAA, TIALOSTZVLYAV, 0 TIAOTOST3V.TYA4S, 0 LALASLIVLYAYU,

TIASTOELIVOTYAV, TIALOSLIVLYAK, AND LOSLZVTYAO, 0 PIALOSTAVLYAYN,

TALOSLZSLIAA, tiAlOSlIietaVv; MA LOSTISTYAE, 0 pIALOSLTISLYAU,

WAIST, TPALISTZSTAV, PALOSLISTYAE, TTALTOSTZSTIAN,

TIALOS TZVLYAA, LIALOSTZOLLYAV, TIALOSTZVLYAE, 0 PALIA,

TIALOSTZOTYAV, TAS LIRTYAV, PALOSTZOLIAO, TTAOLTOSLTZYULYAN,

TIALZOTZALTYAAA, TIALOITZASTAV, TIALOVLZALYAE, TALIU LALYA,

TALIU LTZALYAE, T1ALOOTZZALYAE, PALAT, 0 TPALOVLIALYANI,

TiA tor lavlyAAA, LIAOTOOTZVOTYaAV, TIALOOLZVLYAE 0 PALOVLIUVLYAYU,

TIALOYUTZVOTYAE, TIAOT2YUTZVOTYAE, IA LOROTZV I, 0IALOOYUliIVLYAN,

TPALOVLZSLYAA, PA LOYULZSTYAV, TIALOVLIETYAYE. 0 TIALOVtTZSLYAV,

PALET PALYUZVLZETYAK TYASRZOTZSYE TO, TATO TZSLYAN,

DAD YAA, LALOYULZYULYAV, pALOVLZOTAE. 0 TALORVTZULIAU,

TEALOVLZVLYAE, TRAT, TZ YAK, ALLO LIAS, TALOYUTZO YAN,

TIVL2ALZALYAA, TVA LTZATYAV, LIV ZALA TYAE, 0 TIV TOALIZATYAYU,

TIV OA TZALYAE, TIV L2ALZALYAE, TIV TZATZALYAO, 0 TIVLIALZAL,

TIVLOADZV AHA, TIPOTO2ALTZVLYAV, 0 TIVLOA ZVO TYAS, 0 TIVLOALZVLYAV,

TIVLTZA TZVLYAV, 0 TIVLOZATZVLYAK, TIV T2AT3V.TAO, TIVLOADZVLYAN,

TIVLTZATZSLYAA, 0 TIVL2ALZSTYAV, TIV T2ALTZSYETYAS, 0 TIV TZALZSTYA

TIVLIALZSTYAK, GIVLTZAEZSTYAE, TIVLZA TS taye, TIV TA TZS:TaN,

TIVLTZALZOLYAA, 0 TIVLOALIYUTYAV, TIV lLZAT TS. 0 TIVlzALZYUTYAYU,

TIV T2ATZOTYAV, TIV. ALZUTYAR, TIV LASTI, TIV T2ALTUYUTYAN,

TIVLOVLZALYAA, T1VLTOVLZALYAV, TIVOLOVtTZALYAS, 0 TIVLOIVlLZALYAYU,

TIVlLOVISAALYAVB. LIV LOVLZALYAK, TIV LOVLZALYAE, 0 TIVLOVLZALYAN,

TIV.T2V.TZVllYAA, 0 TIVLOVlZVOYAV, TIV LOV TV LYAS, 0 TIVOTOIVTaVLlar,

TivLlovVtZVlYav. TIV LloVl3vVlYag, 0 TIVL2VL3VLLYAE, 0 TIVLOVTZVLAN,

TIVOOVlZSLYAA, LIV LOVTISLYAV. TIV LLOIV TS LYAE, 0 TIVLOVtTASLUYU,

TIVOVLZ3StYAE. TIVLOVZSTTYAK, TIVTOV 3 TYA, TIVLOVLZELYAN,

TIV.TOV.TZI:TIAA, TIV LlovltZrlav, tIVLOVOlZOllYAS, 0 tivlovVl130l140,

TIV.T2V.TZOO TAB, TI VIV TZ I, TIV 28.30.40, TIV.TOV TON,

TIV OS TZALYAA, TIVLOSTZALYAV. TIV LOSTTZALLIAS, 0 TIVLOSTZALTIU,

TIVLOSTZALYAV, 0 TIVLOSLZALTYAK, 0 TIVLOETZALYAE, 0 TIVLOSLZALYAN,

TIVLOSL3VOTYAA, 0 tIVlostZVOTYAV, tiv loSlZVlasS, 03,

TIV LIS T3VOLYAV, TIV OLTOSTZVOTYAB, TIV OS T3VOTYU, 0 T1V/LOSTZ3V LAN, tTIVLOStTZSlaA, TIVLOSTYE tav, TIV LLOYEtasTYAS, 0 TIVLOSTZSTa4YU,

TIV TS TZ TtaE, TIV TISTI Z ta, TIV TSN,

TIVLISLZULLYAA, VOLOS tar tTYAV, TIVOTOSarTaS, 0 IVloSlLZrlYA tivloslarlav, TIV TaStZOLYAV, TIV tost, Tas, TIVLaSLZrlYAN,

TIVLLIrtTZALYAD, TIVLIYUZALLYAV, TIV LORTTZATYAE, 0OTIVLTaVLZALYAVYU,

TIV THEN. I apologize TIVLIVLZALYAV, TIVLL2ryutTZATYAAE, 0 TIVLOVLZALYAN,

TIV Or. TZVOYAA 0 BODY. T3V. TIAV. 0 TIVOO0OT3VT4S, 0 T18.12О. 138140,

TIVLOOOTZVOTYAE, Riv lorlZVOYav, TIVLORtavVlYAS, 0 TtIVLOVlZVchY,

TIVLLORTASTAA, LEFT TS TYAV, TIVLORTTISYETYAE, 0 TIVLOVLLISTYAYU,

TIV TOYU, TZS TYA, GIV.T20.T3STYAB, TIV 340, TVO. STATE,

TIvlorltzrtyaA, livlorltzrlyav, tiv totzorlyas, 0 tiVlor. three

TIVL2OTZOTYAV, TIVLorltzolav, tivloot3o, cha, yours. total

TISI2ALTZALTYAA, LISLOALZATYAV, TISLZALZALYASYE. OO TISTIALZALYA,

TISLOZALZATYAE, TISLIALTZALYAV, TISTA TIALA, OSTI AND TZA, TUN,

TISLZATZVLYAA, LOALZVLYAV FOREST, TISTA STYAVOTYAE, 0 TS LTZATIV.TYAV,

TISLIA.TZVLYAB,. TISTA LIUVLYAV, TISLO2ATZV LYAE, 0LISLIALZVLAN,

TISLOASTISLTYAA, 0 LISLZALZSLYAV, TISTA LIAS, TISTA LZSLAYAU,

TISOZATUS TYA TISLZALZSLYAV, TISTA LISLYAU, TISTA TIAN,

TISA TA, TISTA STZOLYAV, TISTO ATZOLYAE, 0 tIELaALTZO,TYAYU,

TISLIALTZOTYAV, TISLIALZOLYAV, TISLZALIV TO, TESLTZALTZOLAN,

TIS.TOV.TZALTYAA, 0OTISLOV ZAYAV, TISLOVLZALYAS, 0 TISTOVLZALYAV,

TIS. TOVOTZALYAE, TIELOVTZALYAR, 0 TISLOVLZALYAE, 0 TISLOVLZALYAN,

TISLLOV ZV TYAA, TISTO VOTZVOYAV, IS LoVlZVTYAS. 0 tests. ZV,

TISTovlavlyaYavye, O TiSoltovoAV lav, 0 TiSovVOtZ3VOTYAS, 0 TISLIVLZVLIAN,

TISLOVLTZSTYAA, TS LOVLZETYAV, TISTO tZSLYAE, 0 TISLOVLTZSETYAYU,

ISI ts, TS LZSTYAK, Dough VTSTYab, Dough TSN, testavlarlyaA, 0 tISlavVltaltav, 0 tISLOVIZOLYAS, 0 LISLOVLZULTYAYU,

TISIVlZrlYAE, TISTO TZ TYAE, TIS.TIV t3OLYAE, HISTTovV ZON,

TISLOSLZALYAA, 0 TIETOS ZAYAV, 0 TISLAStTZALYAS, 0 TISLOSLZA,TYAV,

TISLOSTZALYAE, TISTO TZALYAV, 0 TISLOStTZALTYA, 0 TISLOSLZALAN,

TISLOSLZVLYAA, TI LOSlaZV lav, 0 TISOSlZVlLYAS, 0 TISLLOST3V.TAYU,

TIELOSlZvllYAv, TISTOSTZVLYav, 0 TISLOSTIVLYAS, 0 TISLOSTIVLTAN,

TISlLIS, Tata ChlislaetIlaVv, testa taS, 01 father-in-law, tISlISlZetav, TISlasSlZelyav, TISTI, TISTO T3StAN,

TISTISZOLYAA, TTISLOSLZYUOTAV, TITAYeltartaye, 0TISLLOSTZYU.TAV, TISLOSTZYUVLTYAav, TISLOSTIVLLYAAV ptos lae, TISTO LZYU.TN,

TISLOYULIZATYAA, TISTI ZALTYAV, TS ZALAYE, 0OTISLOZLZALAYA,

TISLOVLTZALYAE, T1SLOYUTZALYAAV, TISLOVLZALO, 0 T1SL20LZALAYAN,

TISlLOrlavVltYAA, those 2Oot3VLLYAV, TISLOrOZVtTYAS, 0 tIЕT2Ol3V.TAO, tIslovlavlyav, 0 TISlLorlizvVlYag, TtisSlorlzvlas. 0 tislortZv tan, tislorotastam, tislorlizelyav, tislIrtaYetaYe, 0 tisLIYULIElYAYU, tislIr te tav YELOVTZYetav, tislavtasltayu, PSLIYULISTYAN,

TSTOLZOLYAA, TISTI LAV. Dough is made, so I'm 20-30.T4r, carpentry, carpentry. TISLOYU TZ otv, TISLOR Z rana,

POLA LTZALYAA, LO LZALZATYAV, GPIULZALZALTYAS. TILA LTZATYAO,

TIZALZALYAE THE BODY ALZALYAV TIV LOALZALYAE, 0 TZALTZALAN,

TIOLTOASTZVOTYAA, TILO ALTZVLYAV TIO TAZ TYAS. 0 L?ALIVLYAV,

TIZL2ALZVLYAE, TI0LZALZVTYAK, LO LLOALTZVONO, 0 TILO ALZVLYAN,

TIBVLIALTZSTYAA, THE BODY ALZSTYAV, TIBLOALZSLYAE, TIV TZATISTYAYU,

TISTA TZS TYA, TATI LIV, TTOLOA.TZS TYA, TITA YOU,

TIVLIALZOLYAA, IOLZALZYUSTAV, LIV LIATIOLYE, 0 YOU OALUVTYAYU,

TILA LZOLYAV, T10.T2ATZOLTYAE, TILA LZRYAO, TO TZATZOTYAN,

TIOTOVOT3ALYAA, TIBLOVTSALAYAV, LIOLOVTZALYAE, LIVA,

TIBLOVLZASLYAAB, ZO LOVLAZATYAE, TNOTOVLZALYAE, HIMTOVTZATAN,

TIVLOvVLZVlYAA, TIVLIVOLtaVOTYAV; TIOLOVOt3VOTYAE, 0 TIV 3B TYA,

TiblovlavlyaYav, IYultovlavlYag, tiblovV ZV la, 0 TIZLIVlZVllYAN,

TIVLOVLZSLYAA, TIRDOOVLLITYAV, TirlovtzstaYE, 0 tnihtoVlasltyayu, tIVltIvotaëltav, Tros tar, trava as tia, ready ts len,

TI0LoVIZriYAA, lIrlovlizrlav, To loViZOolaE, 0 TtIrlovlZOlYAV, tpzlIvtzrtav; TivVLloVlZyulYav, TT t3o tav. ttolov then Lch

TOLOSLZALYAA, TIOTOSLZALIAV, TIVLOSLZALYAS, 0 TITISLIALAYAV,

TIYUBLOSTZALYAE, TIBLOSTTZALYAV, TIVLISTZALAYES, TIM TOSLZALYAN,

TIYULOSTZVLYAA, TIRTOYETIVLYAV, LIBBLOSTZVLYAS. 0OtI0.T20 zv, tOoloetavlav, lIvloetivlyAv, oh loEtIvlyas, TIV lasti ten,

TIYULLISTazslaA, TO LLOSLISLAV, TIBLOSLITAYE, 0 LIVLOETZELYAV, prlostzelav, porlostastav, To tar lzstab, oh tost3slyan,

ТирлостзрляА, БЮ лосСлЗзюлав, тіірюлостіюляс, 0 лірлоістtзрлляр, тівллостзрвляв, тілослзртак, Т1Олист30ляв, TI TS тля,

TIPLOVLZASTAA, TILI lZALYAV, TILO TZALYAE, 0 LYULOVLZALYAV, tTIvlovlZALYav, TI LIVlLaALYA, OTIOLOVLZALYAB, 0TIOL20OTZALYAN, tirlorltzvlyaYah, tiblogogzVOYAV, TZ tZVlaS, 0OtN20.t38T40, prloyultzvlyak. tin yav, 0 tIvlortIvlyaz 0 plIrLLOIIULivlYAN,

THIOLOROTAZslYAA. loloriaslaV, tIvVlorlzslyas, liv lorlaslyar, tprlavzstav, TIOoOtart3s tar, Ira taye, TZ to. TZS. TYAN,

You" tortzrlaA tIVBlortZOLYAV tla ptzrlyae, 0 ТЙ»taritzo tya, tyvlovVtzVlYav, trolotzolav, prlzrlzrtyayu, prlIdtarlyai,

TPELZALTZALYAA, TIBELALTZALYAV, OPIBLZALZALYAE PE LZALZALYAU,

TIELOASTZALYAV, OO TIELOALZALYAV, LITE LIZALTZALYAE, 0 T2ALTZALYAN,

TIETOALTZVLYAA, TIELOALZVLYAV 0 OTIBLOALTZVTYAS, 0 TELA LZVLAYAV,

TIBLZALYAVLYAE, IBLOALIUVLYAK. 0 PELZALZNLYAO. 0 TIBLOALAVLIAN,

TIBELZASZSLYAA, 0 TIBLOZALZSTYAV, 0 TIBLOALTIETYAE, 0 TIELOZALISTYAYU,

TE LTZATZSTYAE, TELA LZSTAE, TEZA TYA, TITA ZIES TAN,

TIBLOALZVLYAA, YOU TZAOTZOLYAV, LRELOALTZOLYAE,. YOU LOATOYUTYAV,

TIELOATZOTIAV, TIV. T2ALZVLYAE, PEDA ELLA TZN,

SHELOVLTZALYAA, 0OTIBLOV LIZA TYAV, 0OTIBLOVLTZATYE, OT TOVTZALYAYU,

TtIBDOV ZAYAV, TIBELTOVTZALYAE, 0 OTIBLOVlZALYAE, OTIB TOV tTZATIN,

TIVLOVLZNLYAA, 0OTIBOVotZVOYAV, 0 tyStaVOtavlyYAS, 01 LOVlLZVlLar, tiv lov layav, 01 LlovlzvyAV, OPO TOV TZ TYAE, 0OTIB.T2VLlL3V.TYAN,

TIELOV ZES TYAA, 00 TITOV TZSYETYAV, TIV TovtZYelYAE; 0OT1ELovTZ3SLtYao,

TET TS TYA, TEO V, TELOVLSL TITOVZSLAN,

TIB.T2V.TZOOTYAA, 0 TIBLoVOZ3OO tav, 0 TIELOVLONOLYAS, 0OTRELOVTATaV,

TEL tzOtaye, PELOVTZYULYAV, T1ELOV to tya, TELLOV TZN,

TIBTOSZALYAA, TE LOSLZALYAV, TIELOSTTZALAYE 0 TIELIELZALYAYU,

BODY INFLATION. OTIBLOSLZATYAE, 0 TIELOSLZALYAE, 0OSTELOSTZA.TAN,

TIBLOSTZVLTYAA, 0 TIBLOS ZVO YAV, TIBLOESTTIVLLYAE, 0OtiBLOSLIVLLYAR,

TIETOSLZVLYAV, TIV LOSTZVLYAK, 0 TIBTOSLAVTYAS, 0 TIBLOSTZVLYAN,

TIBLOSISLYAA, IB LeSLATIAV,. OTIBLESTAYETYAS, 0TASYETSLYAYU,

TEL TZOV, TEELOSLZSLYAV PVL Tao, TELTISTZSLYAN,

TIBLTOS TO TYAA, OLIETOST3OLYAV, 0 TIBOSTZTYAE, 0 11TET2S.T3040,

TIBLOETAR, HELOETZOTYAV, TE. toSlZ vl, TE LOSYA,

TITOV TZATYAA, TIELOYUTZATYAV, TE LOVLZALYAE, 0 TZALYAV,

TIBLOOTZALYAB. TB TZALYAE, IB TZALYAE, 0TIVBLOVLZALYAN,

BODY TZVTYAA, OTIBOT2O13VOLYAV,. 0 TiBLOYUIZVOYAS. 01.20.1384,

YOU ARE THAT. THE SO-CALLED TYAK 0 OT1BT2YULLZVLYAK, 0 LIELOVLZV TYA. 0 TELOLTN,

TEL ZSLYAA, ZB laYAV,. 0 TIBTORZEETAE, 0,

TIEL?YUVZS av., PELOYur. TS lav, TEO tasteb, TEL TSS YAN,

PHYSICALLY WITH TYAA. OIELOOT3OLlyaYAV 0 li1ET2O3BTYAS, 0 TIVBLODTUTYAYU, pELOOVLZOLYAV, TILO LTZrTYav, BLOZI Tan,

TIELOZATZALYAA, 0 TIKLZALZALYAV, IEE LZALTZALYAS, 0 LZALEZALYAU,

TIEELZATZATYAE, TIEL?ALZALAYAE, META TZALYAE, TIELZALZALYAN,

TIET2ATIZVOYAA, 00 TIRT2AT3VLYAV,. THE BODY ALZES 0 BODIES THAT,

TIELTALTZVLYAV, TIK LoALIZVOTYAV, 0 TYSTOATZVYAS, TT LOALZV TAN,

BODIES OF TS TYAA. 00 TIETZALZSTYAV TILA DaST, TIRLZALZSLYAU,

TIET2ATYAETYAV, NSTOA STATE, THE BODIES OF ZES LYA TELA SLTYAN,

PET2ASTZOLTYAA, LIVE T2ALTZOLYAV, TELA LZOLYAES. That's why I'm writing

TELA TYA, TIK LOALZVLYAV, THESIS, TV TZALZOLYAN,

TIELOVLZALYAA, 0OTIELOVLZALTYAV, OTIROLTOVOTZALYAE, 012728 TZALYA),

TIELOV ZAYAV, TIBLOVLZALYAYU, TIELOVTZALYAE, 0OTIBLOVLZALYAN,

TIELOVOaVLYAA, DIV TOV lavLYAV, you T2VtZVLLYAE. 0 LOVTtZVlLyaAYU,

TIBTOVOTZVOTYAE, 0OTIROLOVOTZVLYAE, LE TOV'T3VOTYAE, 0OtIiStoV TV YAN,

TIELOVOTZSTYAA, 0 TIELOVLZSLYAV, 0 TIBLOVLASYAS, 0 TIBT2VlLZiSLYAU,

TIKLLOV TZ tav, TIELOV ZLE, TIKTOV. TS, HELI ZSTIAN,

ALSO.T2V.T3O,LYAA, 0OTIBOLOVO3ZOOYAV, 0 TIELOovVlarlas. 0 TIV TIV. T3OtaYu,

PetTIVlartyav, Lov lo tav, TIELlovVo TZ t4s, TB. TIV lZO. JAN,

TIB.TIS.TZATYAA, TI LTOSTZALYAV, 0 TIBLOSTZALYAS, 0TIELOSTZA.TYAYU,

TIETOSLZALYAB,. TE TOSLZALYAV, TIBELOSLZALYAS, 0 TIELOSLZALYAN,

TIEETOSLZVLYAA, 0OTIELASTZVLYAV, TIK loStaIvVLYAE, 0OPELOSLZVLYU,

TIELTOSTZAOLYAB, TB TOSEOTZVOLYAV, TE LOSTZVLYAS, 0 T1ELTOSTUVLAN,

TIETAASTZSTYAA, 0 TIBL?ESTIETYAV, TiBLlOSTZStTYAS, 0 T1ELTASTISLYAYU,

TIELOSTZSTYAE, TEO TS tar, TEO tTaS tya, TE LoS.t3StaN,

TIELSTZETYAA, 0 TIELOSLZOLYAW. TI TISLZVLIAS, 0 Tt3r.t40,

TIBLOSLZULYAE, TIELOS Trav, TELOSltaltyav, growth,

TIELIZROZALYAA, TIV LOROZALTYAV, TIBLOVTZASTYAS, OTIBLOVLTZALYAV,

TIBTOO, TZAOTYAE, IB LOOOZALYAE, TIV T2OLZALYA, 0 TIBDZOLZATYAN,

TELYA VOLYAA, ZE TOVLIIVOLYAV, TISTO LIVLLYAS, 0 ELOovtZVlTYA0, tTIBlortzVlYav, TE LOYUOTZVLLYAV, 0 tiBlortzvVlYas, 0 TIELOVlLZvllYAN,

TIET2rOLZEtaA, tIvlLorotzSleV; ZEO Z3STYAE, 0 EDL2OLISLYAV,

TEO TZSLTYAV, PIKLOVLZSLYAK, TRL20OT3SL40. TRIO TZSLYAN, tTIELORlZrlaA, TIV tOOlaOLYAV, 0 lIELIOLZOlyAS. 0 ELTO2OLZ0LYAYU,

TIELIrtZV tav Ivo TtUYulav, pen, TI t2r. trillion,

THIOLOALZALYAL, THIOLOALZALYAV, OTIOLOALZALYAS, TO TIALZATYAYU,

TIIL2ALTZALYAV, LISLOALZALYAV, TIOLOALTZALTYAO, 0OTIBLYALZATAY,

TO T2ATZVTYAA, TISTA TUVLYAV. TI0TZALTUVTYAE, 0 LTOASTZV.TYAYU,

THIOLZALAVLYAE TIBLO2ALZVLYAK, LIBLOATAZVlYab, 0 LoALUVTUN,

Dough ALTZSTYA, pIBLOASTISTYAV, pelzATZSE TS, pla ATRISTYAYU,

POELZALZSLYAE, TS LOALTZSTYAK TO LTALZSTYAO, POLA LZSETAN,

POLA TZVLIAA, TISTA, T3O I, HOLA, ZISLIASTZOTYA

TLA YAV POLA TYA POLA LZOLYAO, TK TAZ: TAN,

POV LTALYAA, 1T16.128,.t3A,TaV, T10LOV.TZA.TYAE, words TZATYAYU,

TS TZALTYE, TISTA. tTYAK, TIV TZV:TZATYAE, THOSE HALLS,

TESTOVA TA, DOUGH TV TV, tlovlZv.tas, DOUGH,

TISLOVLLIVTYAV, IS LOVLLZVLLYAV, 0 TI0.T28.13VLYA0, 0 TIOLOVTZV.TaN,

MSS taA, TEO TZS.tTaV, BODY, TTL, half, POLO tZSlav, Ov ts tya, Kola ts tan,

TIN TA, tISLIVLZYUTYAV, DOUGH, TIOLOV.T30.LT, the body is tav, then t2vt3rotYAE, PISTtIVl Zla al Zla N,

T16.12SUTZALYAA, T16T2S.T3A:TYAV, TIOLOSTZATYAS, TISSTOSLZASTYA

TISTI S ZAL, TOTIS TA, TO.T2STZALYAS, TIOLOSLIZALIYAYA, talostZvV tA, losiv lav, TISTI TYA, TISHLOSTZV.TYAO,

TOolLOStZV.TYAE, TISTO STZVLYAE, T1OT2S.13810, TISTO STUV.TYAN, pOolLoSlZslyAA, TI OStTISTtTYAV, tloslayeta, 0 POLYSYA,

TISTI taStaYelYav, 16.23, THEN TISTYAM,

TOLIATZYULYAA, tb tos TZOV, tot2SelZrlyas, TIO.T2S130190, ward poestasttav, tota tiIty POLOSTMUTYAY,

TILO ZALAA, Dough LZALYAV 0 TISLOOTZALYAS, T16.120.ZA.140,

TIOLOVLZALYAV, TISTA LIV OSTI LOO CJSC, TOLI ZALAY,

POL2OT3VlLA, tiolo2rtzv.T4B, TOLOOVLZVYAS, T10.120138.T40,

POTU tTYAK, TEST ZVT, TET, tiVSLlTZrLZVLlan,

TI6bLZVTASTZA, THEY. TYAV, pazhtartaet Tit BLSETYAYU, tivtarltzstav, bodies taetayu pola ltIstaye, tyu tota, pPalOvlZvlaA, MmOol20.t30 TB, pOol25135L14s: tOolot3o.t4r, pblordlazrlav, t tzoltzvlav, P1olgrltzrtaye, tot tZolan,

In yet another embodiment, selected compounds of Formulas I and II are tabulated below (Table 10) as compounds of general Formula IM (below):

HANA Come on

Formulas U where X, A, Y and 7 are defined in Tables 6-9 below. Each compound is designated in tabular form by concatenating the "code" representing each structural fragment using the following syntax: H.A.U.7. So, for example, X1.A1.U1.71 represents the following structure:

MN. mm o Su tovrya z-d ikh i o

M!

Table 6: Structures "A"

Code 000 Struyuuracha" (00000000

AK and ! And the whole nah

MO" i Ya i-2 m shi shmrchyn nn

M

: I dn, ny, CHI

To" : a cha

Uch-ezh pi and Iyi shi: pa a La azhajatetsCDL d? p

Grout

AI Shen; she 2-0 kt M

I AM ! Roma of MN

Seams:

B MO: i-2

Table 7: "X" structures

nin the same hTTttTtnnnnnnny mete p nn nnya She- x3 i 5 - pav poko o nn i vk pana AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAT M " : In he r ! "M Shk !

And more!

Table 8: "U" structures

Code o Etructure "U" day Mn ITT ryn popy ra ta ! - rdinntnnnnntnnetnynntya tt vh pinni nn su I, eat more

Table 9: Structures 727" and Code I Structure "Yu. and ! te

Yes, yes

N and Z V i-.5 hi and 1 I . and pi

OZH in mme

Code | Structure "Y": y ke t a tei she chy

Hook

Table 10

List of structures of compounds corresponding to the PP Formula

HIABUBY1, Hi AT 2, HIT HA BUTIM HATI, HA I,

HIATUTY HA EAT, HA UMY HIABUYI?, HIATUMIS Hi ATM Y,

ХИА1 2 FROM THE HOUSE, ХА IN Я7, Хи АХ, ХІІІ OF THEIR HOUSE,

HATU IZ, HA UZ I, HATU I5, HA I6, HA UZI. X1 AX 8,

HA UYA I, HI AB UZH, HA HYA 3, HA UIYA, Hi ASU I5, HA I in,

Hi AT ZHAI?, HiAI AV KHATY! KHAI IY HGAHUBIZ, MAU,

ХІ АХ І5, WHO JV, IS IT UTY? Khai. HIAUMIM HAI,

XII AAU IZ, HA YAM HA? UYH, HA UZ YW, MI IT, HAY,

HA UZI, HA UZI. HA» UZI, HA IYA, HYAMUSIV, KID. 2,

HYAZUZITE, Хи АУЗХХ, ХАЙ, ХА UAIO, ХІІ AZMUYAIZ, ХА У ИЯ,

ХИА2Х4Й5, ХАТУ Ів, ХХІ AZMAІІ?

KHIAZ UT IZ, KHIAZU I, KHIAZZHIYA5,. KHIAZUIV KHIAZZHI MAZI IV,

KHEAZ UZI, Kh1AZU2 Y. KHIAZUOIZ, XII AZI, Kh1AZ UZI, XII AZ UZ I6,

ХІІ AZI, ХІІ АЗИ, ХБАЗМУЗИЙ, ХИАХ УЗИ, Х1AZ УЗИ, ХИАЗУЮЯ,

ЖІ AZ Ж и5, ХІІ AZ UZI, X1 AZI? HYAZUSIV, HYAZ YAMI HYAZUCHI,

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KhZAZ UZ, Kha UZ IY, KhZAZUYA IY, Kh3ZAZZHAIO. X3AZ I, X3 A AND UT,

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HVAMIEV, LET THEM LET THEM, HOUSES in HOUSES Khzayautyav,

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HA UZI, HA UZ IV HA MY1, HATS, Ha IZ, HATA,

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X5AZ UA, X5AZOYAA 9, X5AZ I Y, X5AZ I I, ХА Я ХБАМУМИЭ;

HOUSES Х5AZ AV, ХА У, ХА. ХБАМХИ M ХВ АХ,

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X5AMUZY, XA UZ I2, XA 33, XA UZ IX, XA I5, XA UZY,

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X5 Aa i5, X5. AAU Ib, Х5 AV STREET, ХА У4.І8, ХВАТ ИЙ, ХвАМУЙ,

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KhbAMKH1Y, KhvA 12, MHbARKHUI YAZ, KhbAMKHIIYA, KHAI I5, KhbAZH 16,

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KhbA Y.L., KhbAZ Zhav, KhbAZU1 IY, Khb.AZ UZ, KhbAZ UZ, KheAMHI UA,

Hb.AZ ZHI. 75, Khb AZY, KhbAZ HUY, KhbAZ UT IV, KhbAZ OY, KhbAZUKHYH,

Khb.AZ 23, Khb.AZ IA, Kh6AZ U, HOA OV, KhbAZUZYAT KhvAZLUMYV,

Khv.AZ UZY, KhbAZ, UZY, Khb.AZ 33, HOAZ UZY, Khb.AZ UZY, HA UZYAV,

KhbAZ ultrasound? KhbAZ UZY, KhbAZUI, KhBAZZHYA?, KhBAZIZ, KhbAZ MA, Khhb.AZ Kha, Khb.AZ Ua, Khb.AZULYAT, KhBoAZ UIV, Khbayeya, Kha U IZ,

Hb.АЯ4.1.73, Hb.АЯ UT ЯЯ, HbАХХ1 5, Hb.АХИ b, Hvoya I), HvАЖlВ,

HvAYAO Y, HAY HBAUOIZI HbAUIYA, HA UTYV, HVAYUUV,

HbAYAU2Y. Khb. ADH2UV, He AYA UZI, HU, KhB. AYA UZI, He UZ IYA,

HbAYA.UZY5, HbAYA AZY HA MY, HbAUZIV HbAYA Ua, HbAYA IY,

HOLLAYA TYA Kb A I TA I Ho A, HA i, HA TIA i Hv AHA IW

Pharmaceutical compounds

The compounds of the present invention are administered in compound dosage forms using conventional carriers and excipients selected in accordance with generally accepted practice. Tablets contain excipients, substances that promote gliding, fillers, binders, etc. Aqueous compounds are prepared in sterile form and, when intended for delivery by a route other than oral, are usually prepared isotonic. All compounds may contain fillers, such as those described in Naparook oi Rpaptaseszshiisa! Ekhsiriepiv (1986), the content of which is incorporated into this description by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl ethyl cellulose, stearic acid, and others. The pH of these compounds ranges from 3 to 11, but is usually around 7 to 10.

Although it is possible to administer the active ingredients separately, it may be better to present them as pharmaceutical compounds. The compounds of the present invention, both for veterinary use and for human use, contain at least one active ingredient together with one or more acceptable carriers and possibly other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense that it must be compatible with the other ingredients of the compound and physiologically safe for the recipient.

Compounds according to the invention include compounds suitable for the above routes of administration.

The compounds can be conventionally presented in the form of a dosage form and can be obtained using any of the methods well known in the field of pharmacy. Preparation methods and compounds in the general case can be found in the work of Netipdiopje Rpagtaseciis! bsiepses (Mask Rybiizpipd So., Easiop, Ra.), the content of which is included in this description by reference in its entirety. Such methods include the step of combining the active ingredient with a carrier containing one or more auxiliary ingredients. In general, the compounds are prepared by uniformly and carefully combining the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product.

The compounds proposed in this invention suitable for oral administration can be presented in the form of discrete units, such as capsules, sachets or tablets, each of which contains a predetermined amount of the active ingredient; in the form of powders or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be administered in the form of boluses, electuary or paste.

The tablet is obtained by compression or molding, possibly with one or more auxiliary ingredients. Compressed tablets can be prepared by pressing in a suitable apparatus the active ingredient in a free-flowing form, such as a powder or granules, possibly in admixture with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Formed tablets can be obtained by forming in a suitable apparatus a mixture of a powdered active ingredient moistened with an inert liquid diluent. Tablets can be coated or scored, and the composition of said tablets can be such as to provide a delayed or controlled release of the active ingredient.

For administration to the eye or other external tissues, e.g., the oral cavity or the skin, said compounds are preferably applied in the form of topical ointments or creams containing the active ingredient(s) in an amount of, for example, 0.075-95 m/m (including active ingredient(s) in the range from 0.1 95 to 20 95 in steps of 0.1 95 0.1 90 m/m, such as 0.6 bo m/m, 0.7 9o m/m, etc.) , preferably from 0.2 to 15 95 m/m, and more preferably from 0.5 to 10 95 m/m. When obtaining a compound in the form of an ointment, the active ingredients can be used either in combination with paraffin or with a water-soluble ointment base. Alternatively, the active ingredients can be incorporated into the cream using an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 3095 m/m of a polyhydric alcohol, that is, an alcohol containing two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400) and their mixtures. Compounds for topical application may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples are obtained according to any method known in the art for the production of pharmaceutical compositions, while such compositions may contain one or more agents, including sweeteners, flavorings, dyes and preservatives, to obtain a pleasant-tasting preparation. Tablets containing the active ingredients in admixture with a non-toxic pharmaceutically acceptable excipient suitable for tableting are also suitable. Such excipients can, for example, be inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated using known methods, including microencapsulation, to slow down disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over an even longer period. For example, a delivery retarding agent such as glyceryl distearate can be used alone or in combination with a wax.

Compounds for oral administration may also be prepared as hard gelatin capsules in which the active ingredients are mixed with a solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredients are mixed with an aqueous or oily base such as like coconut oil, liquid paraffin, or olive oil.

Aqueous suspensions proposed in the invention contain active substances in a mixture with fillers suitable for obtaining aqueous emulsions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gum tragacanth, and guar gum, and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), alkylene oxide condensation products, and fatty acids (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide and a long-chain aliphatic alcohol (for example, heptadecaethyleneoxyethanol), a condensation product of ethylene oxide and a partial ester obtained from a fatty acid and hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions can be prepared by suspending the active ingredients in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.

Oral suspensions may contain thickeners such as wax, hard paraffin or cetyl alcohol. Sweeteners, such as those described herein, and flavoring agents may be added to make the preparation palatable. Such compositions can be preserved by adding an antioxidant such as ascorbic acid.

The dispersible powders and granules of the invention, which are suitable for preparing aqueous suspensions by adding water, provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersing or wetting agents are given above. Additional excipients such as sweeteners, flavors and colors may also be present.

The pharmaceutical compositions proposed in the invention can also be in the form of emulsions of the "oil-in-water" type.

The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include natural gums such as guar gum and tragacanth, natural phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with oxidn. ethylene, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. Syrups and elixirs can be made with sweeteners such as glycerin, sorbitol and sucrose. Such compounds may also contain an irritant, preservative, flavoring or coloring agent.

Pharmaceutical compositions proposed in the invention can be in the form of sterile injectable preparations, such as sterile aqueous or oily injectable suspensions. These suspensions can be prepared according to known methods using such suitable dispersing or wetting agents and suspending agents as are specified herein. The sterile injectable preparation may also be a sterile solution for injection or a suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol, or prepared as a lyophilized powder. Acceptable carriers and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be conventionally used as a solvent or suspending medium. Any soft non-volatile oil can be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid can be used in a similar manner in the preparation of injectable forms.

The amount of active ingredient that can be combined with the carrier substance to obtain a form for single administration can vary depending on the host being treated and the particular method of administration.

For example, a controlled-release composition intended for oral administration to a human may contain from about 1 to 1000 mg of active ingredient mixed with a suitable and convenient amount of carrier material, which can vary from about 5 to about 95 95 by weight of the entire composition (w/w ). The pharmaceutical composition can be prepared in such a way as to provide an easily measured amount of the composition for administration.

For example, an aqueous solution intended for intravenous infusion may contain from 3 to 500 μg of active ingredient per milliliter of solution in such a way as to infuse a suitable volume at a rate of approximately 30 ml/h.

Compounds suitable for administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially in an aqueous solvent for the active ingredient. The active ingredient is preferably present in such compounds in a concentration of 0.5-20 95, preferably 0.5-10 95, in particular approximately 1.5 95 m/m.

Compounds suitable for topical oral administration include lozenges containing the active ingredient in a flavored carrier, usually sucrose or guar gum or tragacanth; lozenges containing the active ingredient in an inert carrier such as gelatin or glycerin or sucrose and guar gum; and rinses containing the active ingredient in a suitable liquid carrier.

Compounds for rectal administration can be presented in the form of suppositories with a suitable base containing, for example, cocoa butter or salicylate.

Compounds suitable for intrapulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 µm (including a particle size in the range of 0.1 to 5000 µm in steps such as 0.5 µm, 1 µm , 30 μm, 35 μm, etc.), which are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so that they reach the alveolar sacs. Suitable compounds include aqueous or oily solutions of the active ingredient. Compounds suitable for administration as an aerosol or dry powder may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used to treat or prevent infections as described herein.

Compounds suitable for vaginal administration may be presented in the form of uterine rings, tampons, creams, gels, pastes, foams or sprays containing, along with the active ingredient, such carriers as are known in the art to be suitable.

Compounds suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the compound isotonic with respect to the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners.

The compounds are presented in containers containing a single dose or multiple doses, for example, sealed ampoules and vials, while said compounds can be stored in a sublimated (lyophilized) state, which only requires the addition of a sterile liquid carrier, for example, water for injections, immediately before use. Injectable solutions prepared for immediate administration and suspensions are prepared from sterile powders, granules and tablets, such as described earlier. Preferred dosed compounds are compounds containing a daily dose or unit daily subdose, as previously described herein, or a corresponding fraction of said dose or subdose of the active ingredient.

It should be understood that in addition to the ingredients specifically mentioned above, the compounds proposed in this invention may include other agents conventionally used in the art, given the type of compound in question; for example, compounds suitable for oral administration may include flavoring agents.

According to the invention, veterinary compositions containing at least one active ingredient defined above together with a veterinary carrier are also proposed.

Veterinary carriers are substances suitable for the introduction of the specified composition, and they can be solid, liquid or gaseous substances that are otherwise inert or acceptable in the field of veterinary medicine and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other preferred route.

The compounds proposed in the invention can also be included in a composition that provides a controlled release of the active ingredient, which allows for less frequent dosing or improves the pharmacokinetic or toxic profile of the active ingredient. Accordingly, according to the invention also proposed compositions containing one or more compounds proposed in the invention, where the compound of said compositions provides a sustained or controlled release.

The effective dose of the active ingredient depends at least on the nature of the pathological condition being treated, the toxicity, whether the compound is used prophylactically (even lower doses) or for the treatment of an active disease or pathological condition, the method of delivery and the particular pharmaceutical compound, while the specified the dose should be determined by the doctor using traditional studies with increasing doses.

An effective dose can be expected to range from about 0.0001 to 10 mg/kg body weight per day, typically from about 0.001 to about 1 mg/kg body weight per day, more typically from about 0.01 to about 1 mg/kg body weight per day, more typically from about 0.05 to about 0.5 mg/kg body weight per day.

For example, a possible daily dose for an adult with a body weight of about 70 kg would be in the range of from about 0.05 mg to about 100 mg, or from about 0.1 mg to about 25 mg, or from about 0.4 mg to about 4 mg, and can take the form of single or multiple doses.

According to another embodiment, the present invention proposes pharmaceutical compositions containing a compound corresponding to Formula I, Ia, IB, II, Pa, I or IM, or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound, and pharmaceutically acceptable carrier or filler.

According to another embodiment of the present invention, pharmaceutical compositions containing a compound corresponding to Formula I, Ia, IB, II, Pa, I or IM, or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound in a combination of at least with one additional active agent and a pharmaceutically acceptable carrier or excipient.

According to another embodiment of the present invention, pharmaceutical compositions containing a compound corresponding to Formula I, Ia, IB, II, Pa, I or IM, or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound in a combination of at least with one additional active agent and a pharmaceutically acceptable carrier or excipient. Examples of an additional active agent also include interferons, ribavirin or its analogs, M53 NOM protease inhibitors, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors of M55B NSM polymerase, non-nucleoside M55B NOM polymerase inhibitors, M5BA NOM inhibitors, TI B-7 agonists , cyclophilin inhibitors, ИВЕ5 NSMU inhibitors, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus (HCV) or their mixture.

More specifically, one or more compounds of the present invention can be combined with one or more compounds selected from the group consisting of: (1) interferons selected from the group consisting of pegylated PEM-alpha 25 (PEG-intron), pegylated pPEM-alpha 2a (Redazuz), PEM-alpha 25 (Intron A), PEM-alpha g2a (Roferon-A), interferon alpha (MOV-22, ORS-18,

Alfaferon, Alfanativ, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-pi1 (Velferon), interferon alpha-pi3 (Alferon), interferon-beta (Avonex, 0I-8234), interferon-omega (omega

VYVOZ5, Biomed 510), albinterferon alfa-25 (Albuferon), IEM alfa-2h Kh, VI X-883 (Lokteron), OA-3021, glycosylated interferon alfa-25 (AMI-005), PEG-infergen, Pegylated interferon lambda -1 (Pegylated II -29), bellerophon and their mixtures; (2) ribavirin and its analogues selected from the group including ribavirin (Rebetol, Copegus), taribavirin (Viramidine) and their mixtures;

(3) NSU M5Z3 protease inhibitors selected from the group including boceprevir (5СН-503034, 5СН-7), telaprevir (МХ-950), TMS435350, VI-1335, VI-1230, MK-7009, MVU-376, МХ-500, ВМ5-790052, ВМ5-605339, РНХ-1766, А5Б-101,

UNn-5258, UN5530, UN5B5Z31, ITMM-191 and their mixtures; (4) alpha-glucosidase-1 inhibitors selected from the group consisting of celgozivir (MX-3253), Miglitol, OT-2318, and mixtures thereof; (5) hepatoprotectors selected from the group including IUM-6556, ME 3738, IB-84451, silybilin, MisO) and their mixtures; (6) nucleoside or nucleotide inhibitors of polymerase М55В NSU, selected from the group including НИ1626, 87128 (84048), ИОХ184, IХХ-102, ВСХ-4678, valopicitabine (MM-283), MK-0608 and their mixtures; (7) non-nucleoside inhibitors of polymerase M55B NSMU, selected from the group including RE-868554, MSRI-759, MSN-916, UTK-652, MK-3281, UVU-708, MSN-222, A8BA8837, AMA-598, ( I 60667, (I 59728, A-63890, A-48773, A-48547, vo-2329, MSN-796 (nesbuvir) 45K625433, VIII M-1941, KhTI -2125, (35-9190 and their mixtures; (8 ) M55A NSU inhibitors selected from the group consisting of A2O-2836 (A-831), A-689 and their mixtures; (9) TI 8-7 agonists selected from the group consisting of AMA-975, 5M-360320 and their mixtures; (10) cyclophilin inhibitors selected from the group including OEBIO-025, 5SU-635, MIM811 and their mixtures; (11) ИВЕ5 NSMU inhibitors selected from the group including MS I1-067, (12) enhancers pharmacokinetic characteristics selected from the group consisting of BA5B-100, 5RI-452, RE-4194477, TMO-41629, roxithromycin and mixtures thereof, and (13) other drugs for the treatment of hepatitis C virus selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, MT), VIMM-401 (virostat), RUM-17 (Altirex), KREO2003002, actilon (SRO-10101), KAM-7000, tsivatsir, I-5005, Khti -6865, VIT225, RTH-111, ITH2865, TT-033i, AMA 971, MOM-205, tarvacin,

ENS-18, МОх-410С, EM2-702, AMI 4065, 8ВМ5-650032, ВМ5-791325, Bavituximab, МОХ-1106 (ОМО-4538),

Oglufanid, UH-497 (merimepodib) and their mixtures.

According to another embodiment, the present invention proposes pharmaceutical compositions containing a combined pharmaceutical agent containing: a) a first pharmaceutical composition containing a compound corresponding to Formula I, Ia, IB, Ii, Pa, I or IM, or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound; b) the second pharmaceutical composition containing at least one additional active agent selected from the group including interferons, ribavirin or its analogues, M5Z3 NOM protease inhibitors, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide polymerase M55B NSU inhibitors, non-nucleoside inhibitors of polymerase М55В8 НОМУ, inhibitors М55А НС, agonists of TI В-7, cyclophilin inhibitors, ИВЕ5 inhibitors НСМУ, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus or their mixtures.

Methods of introduction

One or more compounds of the invention (referred to herein as active ingredients) are administered by any route suitable for the pathological condition to be treated. Suitable routes of administration include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous and intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It should be noted that the preferred route of administration may vary, for example, depending on the specific pathological condition of the recipient. An advantage of the compounds of the present invention is that said compounds are orally bioavailable and can be administered orally.

Combined therapy

According to one embodiment, the compounds proposed in this invention are used in combination with other active therapeutic ingredients or agents. Combinations of corresponding compounds

Formulations I, Ta, IB, PI, Pa, I, or IM, and additional active agents may be selected to treat patients with viral infection, such as viral hepatitis B, viral hepatitis C, or HIV infection.

It is better that other active therapeutic ingredients are interferons, ribavirin or its analogs, protease inhibitors M5Z3 NSM, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors of polymerase M55B NSU, non-nucleoside inhibitors of polymerase M55B NS, Inhibitors M55A NSMU, agonists

TI B8A-7, inhibitors of cyclophilin, inhibitors of ИВЕ5 NSM, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus or their mixture.

Combinations of compounds corresponding to Formula I, Ia, IB, Ii, Pa, X or IM are usually chosen based on the pathological condition to be treated, the cross-reaction of the ingredients and the pharmacological properties of the combination. For example, when treating an infection (eg, hepatitis C virus), the compositions of the invention are combined with active agents (such as those described herein).

Suitable active agents or ingredients that can be combined with compounds of Formula I, Ia,

IB, Ii, Pa, IS or IM may include one or more compounds selected from the group consisting of: (1) interferons selected from the group consisting of pegylated PEM-alpha 25 (PEG-intron), pegylated pPEM-alpha 2a (Redazuz), PEM-alpha 265 (Intron A), PEM-alpha 2a (Roferon-A), interferon alpha (MOV-22, ORS-18,

Alfaferon, Alfanativ, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-pi1 (Velferon), interferon alpha-pi3 (Alferon), interferon-beta (Avonex, 0I-8234), interferon-omega (omega

VYVOZ5, Biomed 510), albinterferon alfa-25 (Albuferon), IEM alfa-2h Kh, VI X-883 (Lokteron), OA-3021, glycosylated interferon alfa-25 (AMI-005), PEG-infergen, Pegylated interferon lambda -1 (Pegylated II -29), bellerophon and their mixtures; (2) ribavirin and its analogues selected from the group including ribavirin (Rebetol, Copegus), taribavirin (Viramidine) and their mixture; (3) NSU M53 protease inhibitors selected from the group consisting of bodeprevir (5СН-503034, 5СН-7), telaprevir (МХ-950), TMS435350, VI-1335, VI-1230, MK-7009, MVU-376, МХ-500, ВМ5-790052, ВМ5-605339, РНХ-1766, А5Б-101,

In Нн-5258, УН5530, УН55З1, ITMM-191 and their mixtures;

(4) alpha-glucosidase-1 inhibitors selected from the group consisting of celgozivir (MX-3253), Miglitol, OT-2318, and mixtures thereof; (5) hepatoprotectors selected from the group consisting of IUM-6556, ME 3738, IB-84451, silybilin, Miu and their mixtures; (6) nucleoside or nucleotide inhibitors of polymerase М55В NSU, selected from the group including НИ1626, 87128 (84048), ИОХ184, IХХ-102, ВСХ-4678, valopicitabine (MM-283), MK-0608 and their mixtures; (7) non-nucleoside inhibitors of polymerase М55В NS, selected from the group including RE-868554, MCIN-759, MOSN-916, UTK-652, MK-3281, UVU-708, MSN-222, AV48837, AMA-598, ( I 60667, (I 59728, A-63890, A-48773, A-48547, vo-2329, MSN-796 (nesbuvir), 5K625433, VII M-1941, KhTI-2125, (145-9190 and their mixtures; ( 8) М55А NSU inhibitors selected from the group including A2O-2836 (A-831), A-689 and their mixtures; (9) TI 8-7 agonists selected from the group including AMA-975, 5М-360320 and their mixtures; (10) cyclophilin inhibitors selected from the group including OEVIO-025, 5SU-635, MIM811 and their mixtures; (11) ИВЕ5 NSMU inhibitors selected from the group including MS I1-067, (12) pharmacokinetic enhancers selected from the group consisting of BA5B-100, 5RI-452, RE-4194477, TMO-41629, roxithromycin and mixtures thereof, and (13) other drugs for the treatment of hepatitis C virus selected from the group consisting of includes thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, MT), VIMM-401 (Virostat), RUM-17 (Altirex), KREO2003002, actilon ( SRO-10101), KAM-7000, tsivatsir, I-5005, KhTI -6865, VIT225, RTH-111, ITH2865, TT-033i, AMA 971, MOM-205, tarvacin,

ENS-18, МОх-410С, EM2-702, AMI 4065, 8ВМ5-650032, ВМ5-791325, Bavituximab, МОХ-1106 (ОМО-4538),

Oglufanid, UH-497 (merimepodib) and their mixtures.

According to another embodiment, the present invention provides pharmaceutical compositions containing a compound of the present invention, or a pharmaceutically acceptable salt, solvate and/or ester thereof, in combination with at least one additional active agent and a pharmaceutically acceptable carrier or excipient.

According to the present invention, an active agent used in combination with a compound of the present invention can be any agent that has a therapeutic effect when used in combination with a compound of the present invention. For example, the active agent used in combination with the compound proposed in the present invention can be interferons, ribavirin or its analogs, M53 HOM protease inhibitors, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide polymerase M55B NSU inhibitors, non-nucleoside inhibitors polymerases M55B NSMU, inhibitors M5BA

NSM, TI B-7 agonists, cyclophilin inhibitors, ИВЕ5 NSU inhibitors, pharmacokinetic enhancers and other drugs for the treatment of hepatitis C virus or their mixture.

According to another embodiment, the present invention provides pharmaceutical compositions containing a compound of the present invention, or a pharmaceutically acceptable salt, solvate and/or ester thereof, in combination with at least one additional active agent selected from the group consisting of: (14) interferons selected from the group consisting of pegylated gpPEM-alpha 265 (PEG-intron), pegylated PEM-alpha 2a (Pegasys), PEM-alpha 25 (Intron A), PEM-alpha 2a (Roferon-A), interferon alpha (MOV-22, ORS-18,

Alfaferon, Alfanativ, Multiferon, subalin), interferon alfakon-1 (Infergen), interferon alpha-pi1 (Velferon), interferon alpha-pi3 (Alferon), interferon-beta (Avonex, 0I-8234), interferon-omega (omega

VYVOZ5, Biomed 510), albinterferon alfa-25 (Albuferon), IEM alfa-2b Х., VI X-883 (Lokteron), OA-3021, glycosylated interferon alfa-25 (AMI-005), PEG-infergen, Pegylated interferon lambda-1 (Pegylated II -29), bellerophon and their mixtures; (15) ribavirin and its analogues selected from the group including ribavirin (Rebetol, Copegus), taribavirin (Viramidine) and their mixtures; (16) NSU M5Z protease inhibitors selected from the group including boceprevir (5СН-503034, 5СН-7), telaprevir (МХ-950), TMS435350, VI-1335, VI-1230, MK-7009, MVU-376, МХ-500, ВМ5-790052, ВМ5-605339, РНХ-1766, А5Б-101,

In H-5258, UN5530, UN55Z1, ITMM-191 and their mixtures; (17) alpha-glucosidase-1 inhibitors selected from the group consisting of celgozivir (MX-3253), Miglitol, OT-2318, and mixtures thereof; (18) hepatoprotectors selected from the group including IUOM-6556, ME 3738, I 8-84451, silybilin, Miu and their mixtures; (19) nucleoside or nucleotide inhibitors of polymerase М55В NSU, selected from the group including Н1626, 87128 (84048), ИОХ184, IХХ-102, ВСХ-4678, valopicitabine (MM-283), MK-0608 and their mixtures; (20) non-nucleoside inhibitors of polymerase М55В NSU, selected from the group including РЕ-868554, МСН-759, МСН-916, 9UTK-652, MK-3281, МВУ-708, МСН-222, А848837, AMA-598, ( I 60667, (I 59728, A-63890, A-48773, A-48547, vos-2329, MSN-796 (nesbuvir), 5K625433, VII M-1941, KhTI-2125, (145-9190 and their mixtures; 21) M55A NSU inhibitors selected from the group including A2O-2836 (A-831), A-689 and their mixtures; (22) TI 8-7 agonists selected from the group including AMA-975, 5M-360320 and their mixtures; (23) cyclophilin inhibitors selected from the group including OEVIO-025, 5SU-635, MIM811 and their mixtures; (24) ИВЕ5 NSMU inhibitors selected from the group including MS I1-067, (25) pharmacokinetic enhancers selected from the group consisting of BA5B-100, 5RI-452, RE-4194477, TMO-41629, roxithromycin and mixtures thereof, and (26) other drugs for the treatment of hepatitis C virus selected from the group consisting of includes thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, MT7), VIMM-401 (Virostat), RUM-17 (Altirex), KREO2003002, acti lon (SRO-10101), KAM-7000, civatsir, SI-5005, Khti -6865, VIT225, RTX-111, ITX2865, TT-033i, AMA 971, MOM-205, tarvacin,

ENS-18, МОх-410С, EM2-702, AMI 4065, 8ВМ5-650032, ВМ5-791325, Bavituximab, МОХ-1106 (ОМО-4538),

Oglufanid, UH-497 (merimepodib) and their mixtures.

According to another embodiment of the present invention, a combined pharmaceutical agent is proposed, containing: a) the first pharmaceutical composition containing the compound proposed in the present invention, or its pharmaceutically acceptable salt, solvate and/or ester; and b) the second pharmaceutical composition containing at least one additional active agent selected from the group including interferons, ribavirin or its analogs, M5Z3 HOM protease inhibitors, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide polymerase M55B NSU inhibitors, non-nucleoside inhibitors of М55В8 НОМУ polymerase, М55А НС inhibitors, TI В-7 agonists, cyclophilin inhibitors, ИВЕ5 НСМУ inhibitors, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus or their mixtures.

It is also possible to combine any compound of the invention with one or more active agents in a dosage form for simultaneous or sequential administration to a patient. Combined therapy can be carried out simultaneously or sequentially. With sequential administration, the combination can be administered as two or more administrations.

Co-administration of a compound of the invention with one or more other active agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active agents in such a manner as to provide therapeutically effective amounts of both the compound of the invention and one or more other active agents in the human body.

Co-administration includes administration of dosage forms of the compounds of the invention before or after administration of a dosage form of one or more other active agents, for example, administration of the compounds of the invention within seconds, minutes or hours before or after administration of one or more more other active agents. For example, one dose of a compound of the invention can be administered first, followed by one dose of one or more other active agents within seconds or minutes. Alternatively, one dose of one or more other active agents can be administered first, followed by one dose of the compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a single dose of a compound of the invention first, followed by a single dose of one or more other active agents several hours later (eg, 1-12 hours). In other cases, it may be desirable to administer a single dose of one or more other active agents, followed by a single dose of a compound of the invention several hours later (eg, 1-12 hours).

Combination therapy may provide "synergy" or a "synergistic effect," meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from the use of the compounds individually. A synergistic effect can be achieved when the active ingredients: (1) are prepared together as a single compound and administered or delivered simultaneously in a combined compound; (2) delivered sequentially or in parallel as separate compounds; or (3) in some other mode. If delivery is carried out in the course of alternating therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, in different tablets or capsules, or when different injections are given using different syringes. Usually, during alternating therapy, an effective dose of each active ingredient is administered sequentially, that is, serially, and in combination therapy, effective doses of two or more active ingredients are administered together.

According to another embodiment, the present invention provides methods of treating a viral infection in a patient, including: administering to the patient a therapeutically effective amount of a compound corresponding to

Formula I, Ia, IB, Ii, Pa, Ii or IM or its pharmaceutically acceptable salt, solvate and/or ester.

According to another embodiment, the present invention provides methods of treating a viral infection in a patient, including: administering to the patient a therapeutically effective amount of a compound corresponding to

Formulas I, Ia, IB, Ii, Pa, SHI or IM or its pharmaceutically acceptable salt, solvate and/or ester and at least one additional active agent.

According to another embodiment of the present invention, methods of treating viral hepatitis C in a patient are proposed, which include: administering to the patient a therapeutically effective amount of a compound corresponding to Formula I, Ia, IB, II, Pa, I or IM or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound.

According to another embodiment of the present invention, methods of treating viral hepatitis C in a patient are proposed, which include: administering to the patient a therapeutically effective amount of a compound corresponding to Formula I, Ia, IB, Ii, Pa, I or IM or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound and at least one additional active agent.

According to another embodiment of the present invention, methods of treating viral hepatitis C in a patient are proposed, which include: administering to the patient a therapeutically effective amount of a compound corresponding to Formula I, Ia, IB, Ii, Pa, I or IM or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound and at least one additional active agent selected from the group including interferons, ribavirin or its analogs, protease inhibitors M53 НОМ, alpha-glucosidase-1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors of polymerase М55В НСМ, non-nucleoside polymerase inhibitors M55B NOM, inhibitors M5BA NOMU, agonists TI 8-7, cyclophilin inhibitors, ИВЕ5 inhibitors NSMU, enhancers of pharmacokinetic characteristics and other drugs for the treatment of hepatitis C virus or their mixtures.

According to another embodiment, the present invention proposes the use of a compound or its pharmaceutically acceptable salt, solvate and/or ester for the preparation of a drug for the treatment of a viral infection, for example, hepatitis B virus/hepatitis C virus infection.

According to another embodiment, the present invention provides a method of treating or preventing a viral infection, which includes co-administering to a patient in need of it a therapeutically effective amount of at least one compound corresponding to Formula I, Ia, IB, II, Pa, II or IM and at least one additional active agent selected from the group consisting of: (1) interferons selected from the group consisting of pegylated gpPEM-alpha 25 (PEG-Intron), pegylated PEM-alpha ha (Pegasys), PEM-alpha 25 ( Intron A), PEM-alpha 2a (Roferon-A), interferon alpha (MOV-22, ORS-18,

Alfaferon, Alfanativ, Multiferon, subalin), Interferon alfakon-1 (Infergen), interferon alfa-pi1

(Velferon), interferon alpha-p3 (Alferon), interferon-beta (Avonex, 0I-8234), interferon-omega (omega

VYVOZ5, Biomed 510), albinterferon alfa-25 (Albuferon), IEM alfa-2b Х., VI X-883 (Lokteron), OA-3021, glycosylated interferon alfa-25 (AMI-005), PEG-infergen, Pegylated interferon lambda-1 (Pegylated II -29), bellerophon and their mixtures; (2) ribavirin and its analogues selected from the group including ribavirin (Rebetol, Copegus), taribavirin (Viramidine) and their mixture; (3) NSU M5Z3 protease inhibitors selected from the group including boceprevir (5СН-503034, 5СН-7), telaprevir (МХ-950), TMS435350, VI-1335, VI-1230, MK-7009, MVU-376, МХ-500, ВМ5-790052, ВМ5-605339, РНХ-1766, А5Б-101,

In Нн-5258, УН5530, УН55З1, ITMM-191 and their mixtures; (4) alpha-glucosidase-1 inhibitors selected from the group consisting of celgozivir (MX-3253), Miglitol, OT-2318, and mixtures thereof; (5) hepatoprotectors selected from the group including IUOM-6556, ME 3738, IB-84451, silybilin, MiO and their mixtures; (6) nucleoside or nucleotide inhibitors of polymerase М55В NSU, selected from the group including НИ1626, 87128 (84048), ИОХ184, IХХ-102, ВСХ-4678, valopicitabine (MM-283), MK-0608 and their mixtures; (7) non-nucleoside inhibitors of polymerase М55В NS, selected from the group including RE-868554, MCIN-759, MOSN-916, 9UTK-652, MK-3281, UVU-708, MSN-222, AV48837, AMA-598, ( I 60667, (I 59728, A-63890, A-48773, A-48547, vos-2329, MSN-796 (nesbuvir), 5K625433, VII M-1941, KhTI-2125, (145-9190 and their mixtures; 8) inhibitors of М55А НСХ, selected from the group including А2О-2836 (А-831), А-689 and their mixtures; (9) agonists of TI 8-7, selected from the group including AMA-975, 5М-360320 and their mixtures; (10) cyclophilin inhibitors selected from the group including OEVIO-025, 5SU-635, MIM811 and their mixtures; (11) ИВЕ5 NSMU inhibitors selected from the group including MS I1-067, (12) pharmacokinetic enhancers selected from the group consisting of BA5B-100, 5RI-452, RE-4194477, TMO-41629, roxithromycin and mixtures thereof, and (13) other drugs for the treatment of hepatitis C virus selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, MT72), VIMM-401 (Virostat), RZHUM-17 (Altirex), KREO2003002, actilon (СРО- 10101), KAM-7000, tsivatsir, (3531-5005, KhTI-6865, VIT225, RTH-111, ITH2865, TT-033i, AMA 971, MOM-205, tarvacin, ENS-18,

Uakh-410C, EM2-702, AMI 4065, ВМ5-650032, ВМ5-791325, Bavituximab, МОХ-1106 (0МО-4538), Oglufanid, УХ-497 (merimepodib) and their mixtures.

According to another embodiment, the present invention proposes a method of modulating toll-like receptor 7, which includes bringing a cell carrying toll-like receptor 7 into contact with an effective amount of a compound corresponding to Formula I, Ia, IB, II, Pa, Ii or IM or its pharmaceutically acceptable salt, solvate mMabo ester. The term "modulation" refers to bringing the toll-like receptor 7 into contact with a compound of Formula I, Ia, IB, Ii, Pa, NP or IM, which, for example, is an agonist or partial agonist of the toll-like receptor 7.

According to another embodiment, the present invention provides a method of inducing the production of interferon (or IPM-a) in a patient in need thereof, which includes administering to said patient a therapeutically effective amount of at least one compound corresponding to Formula I, Ia, IB, Ii , Pa, I or IM, or a pharmaceutically acceptable salt, solvate and/or ester of the specified compound.

Examples

Synthesis of Example A:

Scheme in 2 V ster "Where else and I Km ru uni ni y, I it Ko yusoOME it about LANGUAGE ' | 2 sho

I

! mV, nNaeM

MN;

TV and M. MNK Mo dn A du S Ve Sy schy (9) M y GU u arte AD I X Ve a r schy rem dy o i y t M y t Ve

OO h. More h and she - dak I a

Z Mne pon o st i y on 1. KOoN, Meon yatitchu t More 2. Wow. NOAH - and myth

Chlnt

Compound 2 2-(2-Methoxy-ethoxy)-9H-purine-b-ylamine (1 g, 4.78 mmol) (1), o,o-dibromo-m-xylene (2.52 g, 9.56 mmol) and anhydrous potassium carbonate (1.32 g, 9.56 mmol) were combined in DMF (10 mL) and stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (120 ml), washed with water (2x), brine, dried over Na»5O» and evaporated in vacuo. The crude product was purified by chromatography on silica gel with 0-10 956 methanol in ethyl acetate as eluent. Evaporation of the corresponding fractions gave 9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purine-b-ylamine (2) (1.1 g, 2.80 mmol, 59 95). MO: 392/394 (MNU).

Compound C 9-(3-Bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purine-b-ylamine (2) (1 g, 2.54 mmol) was dissolved in acetonitrile (10 mL). M-bromosuccinimide (1.5 g, 8.4 mmol) was added portionwise over 5 min. The mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate (100 mL), washed with 956 aqueous solution of Mag52Oz and brine, dried over Mag50O", and evaporated in vacuo. Crude 8-Bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purine-b-ylamine (3) (1 g) was used for the next step without purification.

Example A

Crude 8-bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purine-b-ylamine (3) (-1 g) was dissolved in dichloroethane (10 ml) and pyrrolidone was added (1 ml). The reaction mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue (4) was dissolved in methanol (20 ml), and 50 95 aq

KOH (2 ml). The mixture was heated under irrigation until HPLC analysis indicated complete disappearance of the starting material (-3 hours). Then the mixture was cooled to ambient temperature and concentrated aqueous NH (5 ml) was added. Heating with irrigation was continued for 1 hour, after which the reaction mixture was evaporated to a dry substance under vacuum. The solid residue was extracted with methanol to separate it from the salts. The methanol solution was evaporated in vacuo, and the crude product was purified by reversed-phase HPLC (5-45 906 acetonitrile/40 mM aqueous HCl) to give 6b-amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidine) -1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (450 mg 1.13 mmol) as a yellow solid in the form of NOSI salt.

IN-NMR (DMSO) 6: 10.09 (in, 1H), 9.78 (0g, 1H), 7.47-7.33 (t, 4H), 6.54 (ri, 2H), 4, 87 (5, 2H), 4.32 (0, 9-51, 2H), 4.23 (1. 9-45 Hz, 2H), 3.56 (Her, 9-45 Hz, 2H), 3, 25 (5, ZN), 3, 38-3,00 (t, 4H), 2, 05-1,75 (t, 4H), MO: 399 (MNU).

Examples B, C, O, E, P, O, H, I, Y, K, I, M, and M were prepared using procedures similar to those used for the preparation of Example A, except that the pyrrolidine was replaced by the appropriate amine in each of these Examples.

Example B:

German

L che uu-on M o; 6-Amino-2-(2-methoxy-ethoxy)-9-(3-morpholin-4-ylmethyl-benzyl)-9H-purin-8-ol

IN-NMR (DMSO) 5: 10.08 (5, 1H), 9.85 (big, 1H), 7.55-7.35 (t, AN), 6.53 (rg, 2H), 4, 89 (5, 2H), 4.32 (5, 2H), 4.23 (i, 44.5 Hz, 2H), 3.98-3.89 (t, 2H), 3.66-3.52 (t, 4H), 3.25 (5, ЗН), 3.25-3.02 (t, 4H), MS: 415 (МН).

Example C: Pommy m "uton Mossy acid OA in is 6-Amino-2-(2-methoxy-ethoxy)-9-13-(4-methyl-piperazin-1-ylmethyl)-benzyl|-9UN- purin-8-ol

IN-NMR (DMSO) 5: 11.6 (Big, 2H), 10.75 (v, 1H), 7.59-7.33 (t, 4H), 4.89 (5, 2H), 4, 37-4.28 (t, 4H), 3.60-3.27 (t,

TON), 3.26 (in, ZN), 2.80 (z, ZN), MS: 428 (MNU).

Example 0: ah /» Mi M. Mo sho y ! ; st neo- p i

M M heh!

to me

I) 6-Amino-9-(3-(cyclopropylmethyl-amino)-methyl|-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-8-ol

1N-NMR (DMSO) 5: 10.89 (5, 1H), 9.18 (g, 2H), 7.50-7.32 (t, 4H), 5.58 (Bry, 2H), 4, 89 (5, 2H), 4.32 (i, 9-4 Hz, 2H), 4.09 (, 9U-4.5 Hz, 2H), 3.59 (i, 94.5 Hz, 2H), 3.26 (in, ZN), 2.80-2.74 (t, 2H), 1.10-1.03 (t, 1H), 0.57-0.52 (t, 2H), 0, 34-0.30 (t, 2H), MS: 399 (MNU.

Example E: : EM

And you

Noim was born. - gav ZhK and "o u SCHE: 7 c

IS

6-Amino-9-(3-imidazol-1-ylmethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purin-8-ol

1N-NMR (DMSO) 5: 10.85 (5, 1H), 9.28 (5, 1H), 7.76 (5, 1H), 7.68 (in, 1H), 7, 40-7, 26 (t, 4H), 5.42 (5, 2H), 5.40 (Bi, 2H), 4.87 (5, 2H), 4.29 (I, 9-45 Hz, 2H), 3, 59 (Y, 9-45 Hz, 2H), 3.26 (z, ЗН), MS: 396 (МН).

Example E:

NM shih ns to Y,

I b-amino-9-I3-(3,5-dimethyl-piperidin-1-ylmethyl)-benzyl|-2-(2-methoxy-ethoxy)-9H-purin-d-ol (a mixture of cis and trans); MS: 441 (MNU).

Example C: nom shk Kk -- ih ve: hu-on - o

And in

There is also b-amino-9-I3-(2,6-dimethyl-morpholin-4-ylmethyl)-benzyl|-2-(2-methoxy-ethoxy)-9H-purin-8-ol

NMR (DMSO) 5: 11.31 (p, 1), 10.90 (5, 1H), 7.60-7.36 (t, 4H), 5.10 (rg, 2H), 4, 91 (5, 2H), 4.33 (i, 9-45 Hz, 2H), 4.26 (t, 2H), 3.98-3.89 (t, 2H), 3.59 (i, 94 .5 Hz, 2H), 3.26 (v, ЗН), 3.18 (y, 9-11.7 Hz, 2H), 2.65-2.50 (t, 2H), 1.07 (9 , 9-6.3 Hz, 6H), MS: 443 (MNU).

Example N: 19) writes m ee x

M shoi nn o : m- ko ut m x ! NOM To me

M

Sun b-amino-9-I3-(2,3-dihydro-indol-1-ylmethyl)-benzyl|-2-(2-methoxy-ethoxy)-9H-purin-8-ol

IN-NMR (DMSO) 5: 9.94 (in, 1H), 7.32-7.15 (t, 4H), 7.01 (a, 2-6.9 Hz, 1H), 6.93 ( i, 9-72 Hz, 1H), 6.59-6.49 (t, 2H), 6.46 (v, 2H), 4.84 (v, 2H), 4.23 (I, 9-45 Hz, 2H), 4.21 (5, 2H), 3.55 (Her, 9-45 Hz, 2H), 3.25 (in, ZN), 3.19 (i, 9-8.4 Hz, 2H), 2.85 (i, 9-8.4 Hz, 2H), MS: 447 (MNU.

Example I:

NM

And Yin z she ov a SCHO p that

WITH

I b-amino-9-I3-(1,3-dihydro-isoindol-2-ylmethyl)-benzyl|-2-(2-methoxy-ethoxy)-9H-purin-8-ol

IN-NMR (DMSO) 5: 11.31 (B, 1H), 10.42 (5, 1H), 7.63-7.34 (t, 8H), 6.77 (BIG, 2H), 4, 91 (5, 2H), 4, 60-4.52 (t, 6H),

4.26 (Her, U-4.5 Hz, 2H), 3.56 (Her, U-4.5 Hz, 2H), 3.24 (5, ZN), MO: 447 (MN).

Example 3: nem

And shi M, ; at. M Yang purely M le u ni b-amino-2-(2-methoxy-ethoxy)-9-(3-piperidin-1-ylmethyl-benzyl)-9H-purin-8-ol

IN-NMR (DMSO) 6: 10.67 (5, 1H), 10.08 (Bg, 1H), 7.51-7.34 (t, AN), 4.90 (in, 2H), 4, 51 (ri, 2H), 4, 30-4,20 (t, 4H), 3,57 (I, 94,5 Hz, 2H), 3,25 (5, ЗН), 3, 30-3,20 (t, 2H), 2.87-2.74 (t, 2H), 1.80-1.25 (t, 6H), MS: 413 (MNU).

Example K.

NM

Mo. tu u en -H and Z r u per om osi o -

Кк b-amino-9-I3-(4-fluoro-piperidin-1-ylmethyl)-benzyl|-2-(2-methoxy-ethoxy)-9H-purin-8-ol

IN-NMR (DMSO) 5: 10.90 (in, 1H), 10.85 (g, 1H), 7.58-7.34 (t, 4H), 4.91 (in, 2H), 4, 30-4.20 (t, 4H), 3.59 (9-45

Hz, 2H), 3.26 (5, ZN), 3.30-2.90 (t, 5H), 2.25-1.95 (t, 4H), MS: 431 (MNU).

Example D: and them

My Day »

E-T no-« 7 u

E. M. Z

Mn;

Y. b-amino-9-I3-(3,3-difluoro-piperidin-1-ylmethyl)-benzyl|/|-2-(2-methoxy-ethoxy)-UN-purin-8-ol

IN-NMR (DMSO) 5: 11.05 (g, 1H), 11.00 (5, 1H), 7.53-7.38 (t, 4H), 4.92 (5, 2H), 4, 38-4.29 (t, 4H), 3.59 (9-45

Hz, 2H), 3.55-3.45 (t, 2H), 3.26 (5, ЗН), 3.05-2.90 (t, 2H), 2.20-1.85 (t, 4H), MS: 449 (MN).

Example M: ah

We m. -M sh

Me | Zh - neo-X p i 2 o

Mn;

M

9-(3-((pyridin-2-ylamino)methyl)benzyl)-6b-amino-2-(2-methoxyethoxy)-9H-purin-8-ol

IN-NMR (DMSO) 5: 10.47 (in, 1H), 8.53 (ri, 2H), 8.09 (y, 9-6.3 Hz, 1H), 7.90 (y, 9- 7.5 Hz, 1H), 7.37 (i, 9-8 Hz, 1H) 7.28 (9, 97.5 Hz, 1H) 7.12-7.03 (t, ЗН), 6.91 (II, 9-:7.5 Hz, 1H), 5.42 (5, 2H), 4.84 (5, 2H), 4.25 (I, 9-45 Hz, 2H), 3.59 ( i, y-4.5 Hz, 2H), 3.27 (5, ZN), MS: 422 (MNU.

Example M:

IN,

Nam I Moi i i shim che " ih U K. Ya 9-(3-(azetidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-ol

IN NMR (DMSO) 6: 2, 17-2, A41 (t, 2H), 3.25 (5, ЗН), 3.59 (у, ЗН, уУ-4.5 Hz), 3, 82-4 ... ... SNZSM in NGO.

Synthesis of Example 0:

Scheme 2

MN.

I am M

MN as OH; g (ve Dav

M M M child in ve M

Z H Yaou-V ptn u x M u iy ek yah , p

In rME MA

Z M y 5 -f0 t uU-i

Mn; oh well OHM

M. Shih

TV and Uya

Kaya Uyut, I'm 7, he's me, or with 7 M

And as 1. KOH, mMeoN x. and Y m. of water. KO about A,

M rod il o

Compound 5

Crude 8-bromo-9-(3-bromomethyl-benzyl)-2-(2-methoxy-ethoxy)-9H-purine-b-ylamine (-70 mg) was dissolved in

DMF (2 ml). 2-Hydroxypyridine (100 mg) and anhydrous potassium carbonate (100 mg) were added, and the reaction mixture was stirred overnight. After dilution with ethyl acetate (100 ml), the solution was washed with water and brine, dried over Ma»5O» and evaporated in vacuo. The crude product (5) was converted into 1 -((3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)umethyl)phenyl)methyl)pyridin-2(1H )-one (Example O, 41 mg) using procedures similar to those used to convert Compound 4 to Example A.

1N-NMR (DMSO) 5: 10.54 (5, 1H), 7.72 (d, 9-7 Hz, 1H), 7.40 (Her, 9-7 Hz, 1H), 7.29 (927 ,2 Hz, 1H), 7, 22-711 (t,

ZN), 6.38 (9, 9-9 Hu, 1H), 6.20 (Her, 96.6 Hu, 1H), 5.06 (5, 2H), 4.84 (in, 2H), 4 .91 (I, 90-45 Hz, 2H), 3.60 (Her, 9-45 Hz, 2H), 3.27 (in, ZN), MS: 423 (MNU).

Synthesis of Example P:

Scheme With co. iy I -

MN" o Mn u ma y M. S y: meh M, pashi a nie in ya pan y t o M z koso", " M y zhi

A H i r y"

Example P b-amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (31 mg 0.078 mmol) was dissolved in DMF (2 ml). Anhydrous potassium carbonate (50 mg) was added followed by p-methoxybenzyl chloride (13.7 μL, 0.101 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and saline, dried over Mag25O4 and evaporated in a vacuum. Purification by preparative HPLC (5-60 95 acetonitrile/40 mM aqueous HCl) gave b-amino-7-(4-methoxy-benzyl)-2-(2-methoxy-ethoxy)-9-(3-pyrrolidine-1 -ylmethyl-benzyl)-7,9-dihydro-purin-8-one (Example P) (6 mg) in the form of NOSI salt.

IN-NMR (SOCI3) 6: 12.54 (rg, 1H), 7.85-6.88 (t, TON), 5.24 (5, 2H), 5.14 (5, 2H), 4, 66 (5, 2H), 4.20 (ri, 2H), 3.81 (in,

ЗН), 3.72 (Bi, 2Н), 3.58 (B, 2Н), 3.36 (в, ЗН), 2.85 (g, 2Н), 2.25-2.00 (t, 4Н ), MS: 519 (MN).

Synthesis Example 0:

Scheme 4 pe mi no

He and m. he a And I. -and

Me gay sh r OSOSI Uk z y y "My writing r

S TREA, OSM. and

B-amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (60 mg , 0.15 mmol) was dissolved in dichloroethane (2 ml). M,M-diisopropylethylamine (0.1 ml) was added and the mixture was cooled to 0 °C.

Ethyl chloroformate (0.04 mL, 0.42 mmol) was added. After stirring for 30 minutes, the reaction was quenched with water and concentrated in vacuo. Purification by preparative reversed-phase HPLC (5-45 95 acetonitrile/40 mM aqueous HCl) afforded 9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6- amino-2-(2-methoxyethoxy)-9H-purin-8-yl-ethyl carbonate (Example C) (24 mg) as a white glassy solid, NOSI salt.

IN-NMR (DMSO) 65: 9.99 (ri, 1H), 7.45-7.32 (t, 4H), 7.08 (ri, 2H), 4.89 (v, 2H), 4, 37 (d, 9U-6.9 Hz, 2H), 4.29 (i 44.5 Hz, 2H), 4.20 (Bg, 2H), 3.58 (Her, 94.5 Hz, 2H), 3.26 (5, ZN), 3.15-2.85 (t, 4H), 1.92-1.78 (t, 4H), 1.31 (i, 9-6.9 Hz,

ZN), MS: 471 (MN).

Examples PN, 5, T, M, and M were prepared using procedures similar to those used to prepare

Example O, except that ethyl chloroformate was substituted for isopropyl chloroformate and the corresponding starting material was used for each of these Examples.

Example B:

Oslo pl vash o c

And iya rya an i - M -

Kk 9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6b-amino-2-(2-methoxyethoxy)-9H-purin-8-yl-isopropyl carbonate prepared from Example A.

IN-NMR (DMSO) 5: 10.65 (g, 1H), 7.55-7.37 (t, 4H), 7.10 (rg, 2H), 5.11 (zero, U-6.3 Hz, 1H), 4.89 (5, 2H), 4.33-4.25 (t, 4H), 3.58 (i, 9-4.5 Hz, 2H), 3.36-3.26 (t, 2H), 3.26 (5, ЗН), 3.08-2.95 (t, 2H), 2.05-1.80 (t, 4H), 1.33 (a, y-6 ,3 Hz, 6H), MS: 485 (MNU.

Example 5: Ше НИШ Ше ; vn and

NM - fa

Al M.I

9-(3-((4-fluoropiperidin-1-yl)methyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-yl- isopropyl carbonate prepared from Example K.

IN-NMR (DMSO) 5: 10.95 (brg, 1H), 7.59-7.38 (t, 4H), 7.10 (rg, 2H), 5.10 (vzeri, U-6.3 Hz, 1H), 4.89 (5, 2H), 4.33-4.23 (t, 4H), 3.58 (I, U-4.5 Hz, 2H), 3.36-2.87 (t, 5H), 3.26 (5, ZN), 2.25-1.95 (t, 4H), 1.33 (a, 9-6.3 Hz, 6H), MO: 517 (MNU) .

Example T: about -0 GI and yours; what's up

9-(3-(piperidin-1-ylmethyl)benzyl)-6b-amino-2-(2-methoxyethoxy)-9H-purin-8-yl-isopropyl carbonate, prepared from Example .).

IN NMR (COzO0) 6: 1.43 (a, 6H, 9-6 Hu), 1.72-1.97 (t, 6H), 2.95 (i, 4H, y-9.3 Hz), 3.38 (in, ZN), 3.75 (i, 2H, 9-45, 9 Gu), 4.28 (5, 2H), 4.62 (I 2H, 20-45, 9 Hz), 5 ,11 (v, 2H), 5, 21-5.31 (t, 1H), 7.48 (9, 2H, 20-42 Gu), 7.56 (a, 1H, 0-3.6

Hz), 7.66 (5.1H), LC-MS: t/2 for C25NzaMeO5 7--H observed 499.2 after 2.31 minutes 3.5-minute cycles, gradient 5-95 95 CH2ZSM in NgO.

Example M:

O.O. Yours

NOM In g ih o workshop c

And these 9-(3-((4-methylpiperazin-1-yl)methyl)benzyl)-6b-amino-2-(2-methoxyethoxy)-9H-purin-8-yl-isopropyl carbonate prepared from example Example C .

IN NMR (COzO0O) 5: 1.43 (а, EN, 9-6 Hz), 3.0 (c, 4Н), 3.39 (5, ЗН), 3.64 (5, 2Н), 3, 77 (i, 2H, uU-4.5 Hz), 4.49 (in, 2H), 4.63 (I 2H, 9-45 Hz), 5.11 (in, 2H), 5, 23-5 .91 (t, 1H), 7.46-7.62 (t, ZN), 7.72 (85, 1H). LC-MS: t/2 for С25Нз5М7О5 7 --

H observed 514, after 2.09 minutes 3, 5-minute cycles, gradient 5-95 95 SNZSM in NgO.

Example In: o -o t

NIM " sho shi

Mch Y shko!

IN

9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6b-amino-2-butoxy-9H-purin-8-yl-isopropyl carbonate, prepared (from

For example, MU.

IN NMR (DMSO) 5: 0.89 (y, ZN, 9U-7.2 Gu), 3.17 (y, 6H), 1.29-42 (t, 2H), 1.62 (a, 2H , 9U-7.5), 1.79-2.02 (t, 4H), 2.91-3.08 (t, 2H), 3.21-3.36 (t, 2H), 4.17 (2H, U-6.6), 4.29 (y, 2H, 9-6), 4.89 (v, 2H), 5.06-5.15 (t, 1H), 7.38-7 .57 (t, 4H), 10.95 (in, 13). LC-MSO: t/2 for C25NzaMeO4 7 - H observed 483.2 after 2.64 minutes 3, 5-minute cycles, gradient 5-95 95 СНзСМ in Ngo.

Synthesis of the MU Example:

Scheme 5

MN» Mt u yati7on sh- t -- M y sh-

In the last She M EVvyOOK raft in M

H 170es, 40tip n i 6

Microwave radiation is mm, as in these examples. -ON nku ZM

Be «y u m x t

Compound 6 2-chloroadenine (1.53 g, 9.03 mmol) was separated and poured into three microwavable vials (10-20 mL), each containing 1-butanol (10 mL) and 1-ViOK (5 mL , 1 M in THF). Each vial was heated to 170 "C for minutes. The three reaction mixtures were combined, the solvent was removed using a rotary evaporator, and the product was purified on columns for the distillation of light fractions, using 10 95 methanol in ethyl acetate as an eluent.

Evaporation of the solution gave 1.33 g (7095) of 2-butoxy-9H-purine-b6-amine (b) as an off-white solid. "H NMR (DMSO) 5: 0.919 (i, 3H), 1.39 (t, 2H), 1.62 (t, 2H), 4.09 (i, 2H), 6.00 (5, 2H) .

Example MU was prepared from Compound b using procedures similar to those used to prepare Example A.

IN NMR (DMSO) 5: 0.89 (i, ZN, 9U-7.2 Hz), 1.29-1.42 (t, 2H), 1.60 (d, 2H, 9-72), 1 , 77-2.04 (t, 4H), 2.97-3.10 (t, 2H), 3.26-3.37 (t, 2H), 4.12 (0 2H, 0-7), 4.30 (a, 2H, 9-6), 4.89 (c, 2H), 7, 30-7.50 (t, 4H), 10.26 (5, 1), SMS: t/2 for С2г1Но8МеО» 7 4 N observed 397.2 after 2.50 minutes of a 3.5 minute cycle, gradient 5-95 95 СНзСМ in ngo.

Synthesis of Example X:

Scheme 0 and MN sk I mim My

O.K Ya. ON mes Y 07 on yaru tsi otu YAM and TYAREA, YUSM! t kt kh yy yy y y bot KO tsi 5 HM it

M. I

Example X

Example O (40 mg, 0.100 mmol) was dissolved in dichloroethane (2 mL) and cooled to 0 °C. Diisopropylethylamine (0.1 mL) was added sequentially, followed by methanesulfonyl chloride (0.012 mL, 0.154 mmol). After stirring for 1 hour at At 0 "C, the reaction mixture was quenched with water (1 ml) and evaporated until a dry substance was formed.

Purification by reversed-phase HPLC (5-60 95 acetonitrile/40 mM aqueous HCl) gave Example X (23 mg).

IN-NMR (DMSO) 5: 9.96 (5, 1H), 7, 34-7.18 (t, 4H), 6.45 (Bg, 2H), 4.85 (5, 2H), 4, 37 (in, 2H), 4.24 (I, 2-45 Hz, 2H), 3.57 (I, 9U-4.5 Hz, 2H), 3.26 (in, ЗН), 2.94 ( в, ЗН), 2.91 (а, У-6.9 Hz, 2Н), 0.88-0.78 (t, 1Н), 0.35-0.29 (t, 2Н), 0.04 - 0.00 (t, 2H), MS: 477 (MNU).

Synthesis of Example C:

Scheme 7

Kn, IA" o m: no CHYN me -mo0 kn

Y -on seMmso I S zh-a rod for mm pt yaOotyu and M M r; REA, OM in «y S d Y in M. y

M Zoichn school M dit Banya

Example U

Example A (30 mg, 0.075 mmol) was dissolved in dichloroethane (2 mL). Diisopropylethylamine (0.1 mL) was added followed by ethyl isocyanate (0.05 mL). After stirring at room temperature overnight, the reaction mixture was evaporated to dryness in vacuo. Purification by reverse-phase HPLC (5-60% acetonitrile/40 mM aqueous CARRIER) afforded Example C (23 mg) as a white solid as the CARRIER salt.

1N-NMR (DMSO) 5: 10.96 (rg, 1H), 8.87 (Hii, t:5.7Hz, 1H), 7.57-7.36 (t, 4H), 4.95 (5 , 2H), 4, 32-4,25 (t, 4H), 3,58 (5 9-45 Hz, 2H), 3,25 (5, ЗН), 3, 36-3,25 (t, 4H ), 3.05-2.92 (t, 2H), 2.02-1.80 (t, 4H), 1.13 (I, 9-7.2 Hz, ZN), MO: 470 (MNU) .

Synthesis of Example 7:

Sem 8! MA

Mne 7. 2 mk nu pe dz CHI M Me y: - ! Y z tan E un Ost A she y E ey noya tm ES shk ruk g , 0-0 pony 0 000- to BVA, OSM S o «y 7 I y

Kon a! in M what em

Example 7

Example O (40 mg, 0.10 mmol) was dissolved in dichloroethane (2 mL). N,M-diisopropylethylamine (0.1 mL) was added and the mixture was cooled to 0". Ethyl chloroformate (0.021 mL, 0.22 mmol) was added. After stirring for 30 minutes, the reaction was quenched with water and concentrated in vacuo. Purification by preparative reversed-phase HPLC (5-60 95 acetonitrile/40 mM aqueous HCl) gave Example 2 (17 mg) as a white solid.

IN-NMR (DMSO) 65: 7.32-7.11 (t, 4H), 7.06 (g, 2H), 4.85 (5, 2H), 4.45 (v, 2H), 4, 36 (a, 9-7.5 Hz, 2H), 4.28 (i, 3-45

Hz, 2H), 4.02 (g, 2H), 3.58 (I, 9-45 Hz, 2H), 3.26 (v, ЗН), 3.06-2.97 (t, 2H), 1.30 (Her, 9U-6.9 Hz, ZN), 1.22-1.02 (t, ZN), 0.93-0.81 (t, 1H), 0.38-0.29 ( t, 2H), 0.12-0.05 (t, 2H), MS: 543 (MNU).

Synthesis of Example AA and Example AB:

Scheme 9

MN; Mn» mno v ps, sok M vya eV I hni oo ton ie eshnku cut and revolutions nem vo TT still Ya k oto tm id shk

M tet 2 | welcome and pray VEA Han What! ut i: oh I what AA M-I . we

I un Be i ha Kk A od i "M yo

H ne Doekde be M

Examples AA and AB

Example O (40 mg, 0.10 mmol) was dissolved in dichloroethane (2 mL). M,M-diisopropylethylamine (0.1 mL) was added followed by ethyl isocyanate (0.05 mL). After stirring at room temperature for 30 minutes, the reaction mixture was evaporated to dryness in vacuo. Purification by reversed-phase HPLC (5-60 95 acetonitrile/40 mM aqueous NH) gave Example AA (4 mg) and Example AB (6.5 mg) as white solids.

Example AA: "H-NMR (DMSO) 65: 9.93 (in, 1H), 7.30-7.09 (t, 4H), 6.44 (B, 2H), 6.30 (t, 1H ), 4.82 (5, 2H), 4.46 (5, 2H), 4.24 (20-45 Hz, 2H), 3.57 (Y, 94.5 Hz, 2H), 3.26 ( 5, ЗН), 3.10-2.94 (t, 4Н), 0.96 (I, 9-6.9 Hz, ЗН), 0.93-0.81 (t, 1Н), 0.34 -0.25 (t, 2H), 0.08-0.01 (t, 2H), MO: 470 (MN).

Example AB: "H-NMR (DMSO) 5: 8.88 (t, 1H), 7.30-7.05 (t, AN), 6.29 (t, 1H), 4.90 (5, 2H ), 4.46 (5, 2H), 4.29 (i 94.5 Hz, 2H), 3.59 (I, 94.5 Hz, 2H), 3.30 (t, 2H), 3.26 (in, ZN), 3.08-2.94 (t, 4Н), 1.13 (9-6.9 Hz, ZN), 0.95 (i, U-6.9

Hz, ZN), 0.90-0.80 (t, 1H), 0.34-0.25 (t, 2H), 0.08-0.01 (t, 2H), MS: 541 (MNU) .

Synthesis of AS

Scheme 10

Mne dych M Mne o I; took care of yuso" pn: in i

BUT Me 7 and 1 more; al: MN

MN r! I don't want to sleep ОД 5 осн как Ов доты нееке жены з ем ок Даше До о ет Ган ЕН мав, Том - КОН ) snasM o MON show a H ro 8 7 ey M y

SM

Mn; t and Gn miy av vodya. Noah's | re o Od eh. Me at 4. water. sho Os pd zu m shi shk z zd r

Z. b, YuyuSO", OME | Another SIV. dk - ra Z I b Ye peM 1 I i sho h r hy

What min cm more

Not t t i ko ny Oche cyM

Article

MaVn(OAs)ya i a hu de Kk i

МеОН, АСОН po - it -- ZHK

Compound 7 2-(2-Methoxyethoxy)-9H-purine-b-amine (1) (1.28 g, 6.12 mmol), 5-bromo-m-tolunitrile (1.37 g, 7.0 mmol) and potassium carbonate (0.97 g, 7.0 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (200 ml), washed with water and brine, dried over Ma?5O4 and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 3-((6β-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (7) (1.0 g) as a white solid.

Compound 9 3-(6b-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (7) (1.0 g) was suspended in acetonitrile. M-bromosuccinimide (1.0 g) was added in small portions over 10 minutes. After stirring for 1 hour, the mixture was diluted with ethyl acetate, washed with 10 95 aqueous solution of Magn52Oz, saturated aqueous solution of MansCo»z and brine, dried over Ma»25O54 and evaporated to a dry substance under vacuum. Crude 3-((b-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (8) was dissolved in methanol (50 mL), and 50 95 aqueous KOH solution was added (1 ml). The mixture was heated under irrigation for 3 hours and then concentrated in vacuo. The product was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried over Ma»5Ox and evaporated in vacuo. Purification by flash chromatography on silica gel (eluent: 0-1090 MeN in ethyl acetate) afforded 3-(6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)umethyl)benzonitrile ( 9) (0.45 g) in the form of a pinkish solid.

Compound 10 3-(6b-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-O-yl)umethyl)benzonitrile (9) (50 mg) was dissolved in acetonitrile (2 mL). A 6N aqueous solution of NOSI (2 mL) was added, and the mixture was stirred at room temperature overnight. After evaporation to dryness, the residue was dissolved in DMF (1 mL). Potassium carbonate (100 mg/g) and ethyl iodide (0.02 mL) were added, and the mixture was stirred at room temperature for 5 hours.

After dilution with water (20 ml), the product was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over Ma»5Ox and evaporated in vacuo. Purification by flash chromatography on silica gel (eluent: 0-1095 MeonN in ethyl acetate) gave 3-((6b-amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurine-9 -ilumethyl)benzonitrile (10) (35 mg) in the form of a colorless glassy substance.

AC example 3-(6-amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurin-9-yl)umethyl)benzonitrile (35 mg) was dissolved in dichloroethane (2 ml) and was cooled to 0 "C. A 1 M solution of OIVAG (diisobutylaluminum hydride) in toluene (0.5 ml) was added. After stirring for 1 hour, the reaction was quenched with water and a saturated solution of potassium sodium tartaric acid was added. After intensive stirring for 30 minutes, the mixture extracted with dichloromethane.The combined organic layers were washed with water and brine, dried over

Mag50O5 and evaporated in a vacuum. The crude product (11) was dissolved in methanol (1 mL) and acetic acid (0.5 mL).

Pyrrolidine (0.1 mL) was added followed by sodium triacetoxyborohydride (100 mg). The mixture was stirred for 1 hour at room temperature and then evaporated to a dry substance. The residue was dissolved in aqueous HCl/acetonitrile and purified by preparative reversed-phase HPLC (5-60 95 acetonitrile/40 mM aqueous HCl), which gave Example AC (9 mg) in the form of the HCl salt as a colorless glassy substance.

IN-NMR (DMSO) 6: 10.66 (Bi, 1), 7.54-7.29 (t, 4H), 6.74 (Bg, 2H), 4.92 (v, 2H), 4, 31-4.25 (t, 4H), 3.97 (t, 2H, ipaeg (She maieg reak), 3.58 (Yii, U-4.5 Hz, 2H), 3.26 (5, ЗН) , 3.35-3.25 (t, 2H), 3.07-2.95 (t, 2H), 2.05-1.80 (t, 4H), 1.12 (1, 9U-6, 9 Hz, ZN), MO: 427 (MN).

Synthesis of the AYU Example:

Scheme | 1 shk MN

I still chi: and

Kn; Ve Sg plan yaz, may bod that mit Pn

ЧО стю Ko y sbchyo Kse,OoME s TMM I2bes cm p HER 6 cm zu euy

And her

Mne yaku plydi AS Mne / ih i la ra ; KE zh i o a -- -x M y y sly M Shchi pit Ka s sh pd Sh voru zo,

Se lo | in - neck

Compound 12

To a suspension of 2-chloroadenine (1.7 g, 10.18 mmol) in DMF (10 ml) was added K»CO3 (1.4 g, 10.18 mmol), 2-bromomethylbenzonitrile (2 g, 10.18 mmol) . The reaction proceeded at 80 "C. After the completion of the reaction, the reaction mixture was diluted with water, and then the sediment was collected. The solid was washed with water, then with an aldehyde ether. The product (12) was dried under high vacuum. MS: 285 (MH).

Compound 13

Ma (60 95, 840 mg, 21 mmol) was added to a vessel with p-»VION (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 5 min. Compound 12 (2.4 g, 8.4 mmol) was then added.

The mixtures were allowed to react at 120 "C for about half an hour. The reaction mixture was then cooled, washed with saturated MNACI solution and extracted with DCM. The organic layers were dried over Mag25O4 and filtered. The filtrate was concentrated and the residue (13) was purified on a silica gel column using as solvent DXM/MeOnH in.

IN NMR (a6-DMSO) 5: 0.90 (i, ZN), 1.33-1.41 (t, 2H), 1.58-1.67 (t, 2H), 4.19 (i, 2H), 5.32 (5, 2H), 7.22 (5, 2H), 7.52-7.84 (t, 4H), 8.06 (5, 1H); 323 (MNU).

Example AI was prepared from Compound 13 using procedures similar to those used to prepare Example AC except that Compound 10 was replaced by Compound 13.

IN NMR (COzO0) 5: 0.99 (i, ZN), 1.46-1.54 (t, 2H), 1.76-1.1.83 (t, 2H), 2.01-2, 11 (t, 2H), 2, 15-2.17 (t, 2H), 3, 16-3.18 (t, 2H), 3, 45-3.47 (t, 2H), 3.61 ( 5, ZN), 4.36 (5, 2H), 4.54 (i, 2H), 5.14 (v, 2H), 7.48-7.60 (t, 4H); MS: 411 (MNU).

Examples AE, AB, AC, and AN were prepared using procedures similar to those used to prepare Example AOS, except that during the 7-M-alkylation step, the corresponding iodide was used to obtain the corresponding compounds.

Example AE n yy g

And ok M,

X Lo

I will ask M - " si t m eto

ME M cho ki chto chii

IN NMR (COzO0) 6: 0.99 (i, ZN), 1.47-1.54 (t, 2H), 1.77-1.86 (t, 2H), 2.02-2.07 ( t, 2H), 2.10-2.16 (t, 2H), 3.15-3.19 (t, 2H), 3.44-3.47 (t, 2H), 4.37 (in, 2H), 4.56 (I, 2H), 4.70 (in, 2H), 5.08-5.26 (t, 4H), 5.98-6.07 (t, 1H), 7.44 -7.63 (t, 4H); MS: 437 (MNU).

An example of AR

AND

МН» rn mmM, v -o y, tyu a zm M y ol yayu 7

AE and M 5. Zh ve -y

IN NMR (COzO0) 5: 0.41-0.42 (t, 2H), 0.53-0.56 (t, 2H), 0.99 (i, ZN), 1.53-1.57 ( t, 1H), 1.47-1.55 (t, 2H), 1.78-1.84 (t, 2H), 2.01-2.04 (t, 2H), 2.14-2, 17 (t, 2H), 3.15-3.19 (t, 2H), 3.44-3.47 (t, 2H), 3.97 (0, 2H), 4.38 (v, 2H) , 4.55 (I, 2H), 5.16 (5, 2H), 7.50-7.61 (t, 4H); MO:451 (MNU).

Example AC / plural d-

Х Ш,

I was running

Her o ra che J u o M ! and and Gya still m Su

IN (СОзО0) 6: 0.90-1.01 (t, 6Н), 1.46-1.54 (t, 2Н), 1.69-1.84 (t, 4Н), 2.00-2 ,04 (t, 2H), 2, 15-2,17 (t, 2H), 3, 16-3,19 (t, 2H), 3, 44-3,47 (t, 2H), 4,04 (t, 2H), 4.37 (5, 2H), 4.56 (I, 2H), 5.16 (5, 2H), 7.46-7.61 (t, 2H); MS: 439 (MNU).

An example of AN dog M

M She Ya oo td sht sh t a M yah, and y

And what else

IN NMR (COzO0) 5: 0.99 (i, ZN), 1.46-1.54 (t, 2H), 1.59 (0, 6H), 1.77-1.82 (t, 2H) , 2.00-2.04 (t, 2H), 2.15-2.18 (t, 2H), 3.16-3.20 (t, 2H), 3.45-3.49 (t, 2H), 4.38 (5, 2H), 4.55 (i, 3H), 5.11 (5, 2H), 7.48-7.60 (t, 4H); MS: 439 (MNU.

Synthesis of AI Example

Scheme 12

A cykpobutanol Mai i mm shesshuo shu 00 MM MB, ASM

SHE: and there is a 5th

ХА splits the beginning with the whole flesh of Х

Shk and it -k ah I 12 th and m Her and ve ve

МН МН» 207 5 ovo meomemeonsya AZ you AoMono

I am in the Pn for the death of M. tdoM

Y - 416 more l)pivAi, OSM iy 1 riv ne -eshkooO -M, he snasti e holi, : Z s I N He

Mn vya t 2) pyrolides H o Ak i i i se MafASVNIO MON 9 MO 17 ше: ж ж | di treortuu

M z I SCHI -o ich

Compound 14 was prepared using procedures similar to those used to prepare Compound 13 except that cyclobutanol was used instead of p-VION.

IN NMR (SOSIzv) 6: 1.61-1.95 (t, 2H), 2.14-2.44 (t, 4H), 5.13-5.18 (t, 1H), 5.30 ( 5, 2H), 5.94 (in, 2H), 7.44-7.64 (t, 5H); MO: 321 (MNU).

Example AI was prepared using procedures shown in Scheme 12 and similar to those used to prepare Example AC. Data from the spectral analysis of the intermediates and Example AS are shown below.

Compound 15

IN NMR (SOS zv) 5: 1.62-1.88 (t, 2H), 2.11-2.45 (t, 4H), 5.14-5.16 (t, 1H), 5.30 (5, 2H), 6.23 (5, 2H), 7.44-7.65 (t, 4H); MO: 399 (MNU).

Splukaya 16b

IN NMR (SOS with) 5: 1.52-1.77 (t, 2H), 1.96-2.17 (t, 2H), 2.29-2.38 (t, 2H), 4.02 (5, ЗН), 5.01-5.08 (t, ЗН), 5.91 (5, 2Н), 7.32-7.56 (t, 4Н); MS: 351 (MNU).

Compound 17

IN NMR (SOSIv) 5: 1.68-1.88 (t, 2H), 3.20-3.37 (t, AN), 5.00-5.02 (t, 2H), 5.19- 5.20 (t, 1H), 7.45-7.68 (t,

Academy of Sciences); MS: 337 (MNU).

An example of AI

IN NMR (COzO0B) 6: 1.73-2.28 (t, 8H), 2.44-2.48 (t, 2H), 3.15-3.20 (t, 2H), 4.44- 4.48 (t, 2H), 4.37 (5, 2H), 5.10 (5, 2H), 5.25-5.34 (t, 1H), 7.49-7.59 (t, 4H); MS: 395 (MNU).

Synthesis of Example A)

Scheme 13

M But Ve -7 tu with them

To me and | And M

A n Tabutandiod, Man t re Eh oyu

What is it and I! and Ka. ;

OV AND BUT. okt kyaM 0 yusOz OME dreams 1107 protyayum 7 0 m Y i

I have that

MN"

to me

Her. m MVBASM мя, ранх и І ; AMC

M t po, x - 1 y Ka Be yuololodyu t tot ots a ys Nega n M M o rech y ta Still i

MN

MasMmemeon her and ev ASM. NS pk NO tuya nya koef koh; wai she TU VIVAI, SM Her:

YO UNO) visolidin Zh ze g ko masudeyan, Meon I shi - M. lym y it, g SHI | What are we? ; K-t he still - he 22 t di t

Example A/U was prepared using procedures shown in Scheme 13 and similar to those used to prepare Example AS. Data from the spectral analysis of the intermediates and Example A/ are shown below.

Compound 18

IN NMR (DMSO) 5: 1.47-1.56 (t, 2H), 1.64-1.74 (t, 2H), 3.33-3.43 (t, 2H), 4.16 ( i, 2H), 7.05 (5, 2H), 7.87 (5, 1H), 12.55 (5, 1H); MS: 224 (MNU.

Compound 19

IN NMR (SOSIZz) 6: 1.65-1.74 (t, 2H), 1.81-1.87 (t, 2H), 3.69 (Hii, 2H), 5.27 (5, 2H) , 6.52 (5, 2H), 7.39-7.68 (t, 5H);

MS: 339 (MNU).

Compound 20

IN NMR (SOSIv) 6: 1.70-1.76 (t, 2H), 1.82-1.87 (t, 2H), 3.69 (I, 2H), 4.32 ( 2H), 5 .28 (5, 2H), 6.57 (5, 2H), 7.39-7.63 (t, 4H); MS: 419 (MN).

Compound 21

IN NMR (SOSIzv) 5: 1.70-1.74 (t, 2H), 1.81-1.87 (t, 2H), 3.69 (i, 2H), 4.07 (5, ЗН) , 4.29 (ii, 2H), 5.08 (5, 2H), 5.81 (5, 2H), 7.37-7.61 (t, 4H); MS: 369 (MNU).

Compound 22

IN NMR (COzO0) 5: 1.69-1.70 (t, 2H), 1.87-1.91 (t, 2H), 3.63 (i, 2H), 4.56 (i, 2H) , 5.11 (5, 2H), 7.56-7.82 (AN);

MS: 355 (MNU).

An example of AU

IN NMR (COzO0) 6: 1.66-1.72 (t, 2H), 1.87-1.93 (t, 2H), 2.01-2.04 (t, 2H), 2.15- 2.18 (t, 2H), 3.15-3.19 (t, 2H), 3.45-3.49 (t, 2H), 3.62 (i, 2H), 4.38 (, 2H ), 4.58 (i, 2H), 5.12 (v, 2H), 7.47-7.61 (t, 4H); MS: 413 (MNU).

Synthesis of Example AK and Example AI.

Scheme 14

We; ku -SM Mne

C 2 Y B; her DI and

Moi, Sime and MV, ASM "and H YO Ii G syu "bita ZMO yus" OME dO ik in 23 shchi

Be: z oh em 7 ov v vy mayme/meon a: nn shi ma m S

Mk

Мне МН ne de M. ri me I Ж in Ж ш-о и и о.0-9 kotru tyat mmM

IY 28 ry o z K roy 1U NS, ASM Ole ek NI ny 21 rivA, SM 2YUIVAYU, VOM

Z)rupoga te Z)rupoiane

Man, ma(de»an | Men, ma(oleden many more things pe -M tuye and that of the Father; he is here to pour us; ( Z -y Zabza

Ak OTO A

Example AK and Example AG were prepared using procedures shown in Scheme 14 and similar to those used to prepare Example AC. Bromide (23), used in the first stage, was obtained by treating the corresponding benzenemethyl Compound M-bromosuccinimicide in acetonitrile at room temperature or at 40 "C. The data of the spectral analysis of the intermediate products, as well as Example AK and Example A. are listed below.

Compound 23

IN YAME (SOSIv) 6: 3.43 (in, ZN), 3.75 (i, 2H), 4.47 (in, 2H), 5.28 (5, 2H), 5.85 (5, 2H ), 7, 47-7.65 (t, 4H); MO: 359 (MNU).

Compound 24

IN NMR (COzO0B) 65: 3.40 (5, ЗН), 3.73 (5, 2Н), 4.47 (5, 2Н), 5.38 (5, 2Н), 7.58-7.62 (t, 2H), 7.84 (5, 1H); MS: 437 (MNU).

Compound 25

IN NMR (SOSIv) 5: 3.41 (5, ЗН), 3.74 (і, 2Н), 4.09 (в, ЗН), 4.44 (і, 2Н), 5.06 (5, 2Н ), 5.48 (5, 2H), 7.42-7.61 (t, ZN);

MS: 389 (MNU).

Compound 26

IN NMR (SOS) 6: 3.41 (5, ZN), 3.72-3.76 (t, 2H), 3.89 (5, ZN), 4.09 (5, ZN), 3.42 -3.47 (t, 2H), 5.00 (v, 2H), 5.48 (5, 2H), 7.45-7.62 (t, ЗН); MS: 385 (MNU).

An example of AK

IN NMR (COzO0B) 6: 2.02-2.06 (t, 2H), 2.20-2.23 (t, 2H), 3.10-3.16 (t, 2H), 3.40 ( 5, ZN), 3.54-3.58 (t, 2H), 3.76 (6 2H), 4.63 (I, 2H), 5.10 (5, 2H), 7.52-7, 59 (t, 2H), 7.74 (5, 1H); MS: 433 (MNU).

An example of AI.

IN NMR (COzO0B) 6: 2.01-2.03 (t, 2H), 2.15-2.19 (t, 2H), 3.18-3.23 (t, 2H), 3.41 ( 5, ZN), 4, 44-3.49 (t, 2H), 3.77

(I, 2H), 3.93 (5, ЗН), 4.36 (in, 2H), 4.66 (I, 2H), 5.03 (5, 2H), 7.11 (0, 1H) , 7, 52-7.58 (t, 2H); MS: 429 (MNU.

Synthesis of Example AM

Scheme 15

MN ze ;

Mn vu Mn

Va; in mim, MV8, ASM. and K. mezh: shchi oyu Kan What! A. and zttnth nya rn

And MD yusoomME then t M

And in Bo OM 27 TI and r shcha

And a

MN" dm Mmayme/meon in"

MO YOU remember r u an Ben g : vy m i o t u. S I And what Y from al or and from weights! tre pk her M b | y I z a Y i za v i schi g y t I. also a ok 1une AS 2IYUIVA, OSM MN.

Zrutoaiye Y sh

MeOH, ma(rAscVN mm nn od ku with M

AND

. n J vro

Am NN;

Because Mr. Ked

Example AM was prepared using procedures shown in Scheme 15 and similar to those used to prepare Example AC. Spectral analysis data of intermediates and Example AM are listed below.

Compound 27

IN NMR (COzOO) 5: 3.39 (5, ЗН), 3.73 (, 2Н), 4.45 (Б, 2Н), 5.44 (5, 2Н), 7.36 (Б 1Н), 7.78-7.87 (t, 2H), 8.01 (c, 1H);

MO: 343 (MNU).

Compound 28

IN NMR (COzO0) 5: 3.39 (in, ЗН), 3.72 (in, 2Н), 4.44 (in, 2Н), 5.44 (in, 2Н), 7.37 (6 1) , 7, 67-7.79 (t, 2H); MS: 421 (MNU).

Compound 29

IN NMR (SOSIzv) 6: 3.40 (5, ZN), 3.73 (I, 2H), 3.92 (5, ZN), 4.11 (5, ZN), 4.46 (i, 2H ), 5.12 (5, 2H), 6.94 (y, 1H), 7.14 (5, 1H), 7.60 (aa, 1); MS: 385 (MN).

An example of AM

IN NMR (COzO0B) 6: 1.97-1.99 (t, 2H), 2.13-2.16 (t, 2H), 3.12-3.17 (t, 2H), 3.37 ( 5, ЗН), 3, 38-3.44 (t, 2Н), 3.72 (Y, 2Н), 3.89 (5, ЗН), 4.27 (5, 2Н), 4.56 (и , 2H), 5.08 (c, 2H), 7.09 (y, 1), 7.33 (5, 1H), 7.45 (ad, 1H); MS: 429 (MNU.

Synthesis of Example AM

Example AM was prepared using procedures shown in Scheme 16 and similar to those used to prepare Example AC. Spectral analysis data of intermediates and Example AM are listed below.

Scheme of 16 units of VM Mn; chne VI A same in vyt mo 5 AS seni M ! She doesn't care; Ma, SM

M y Eh pila ie mon av sn Koch "I loop жжжнююююннккниХКх b. gtdy to which yubovomE that Y and sp a s | A and 30 TT no

MN" PURIVES SM chn; what stump re ЧЦ ММ 0 5у1МеОН, MaАСВН, we still --- VE ni NOde Щ ОВ: , yad. oh vane I'm a lirogidik Y codes a mm in OM oh I shk ! Ro, I 31 more 32 Ta «r i-e 1) maomemeon. more

National Academy of Sciences

Skoryk, zv I i » z SYA ey TE

Compound 30

IN NMR (COzO0B) 6: 3.40 (5, ZN), 3.73 (I, 2H), 4.47 (I 2H), 5.36 (5, 2H), 7.35 (Her, 1H) , 7.72-7.86 (t, 2H), 8.03 (5, 1H);

MS: 343 (MNU).

Compound 31

IN NMR (SOS) 6: 3.44 (5, ЗН), 3.77 (Y, 2Н), 4.53 (5, 2Н), 5.30 (в, 2Н), 6.11 (рв, 2Н ), 7.21-7.27 (t, 2H), 7.64-7.68 (t, 2H); MS: 421 (MNU).

Compound 32

IN NMR (COzO0B) 6: 2.00-2.12 (t, 2H), 2.13-2.17 (t, 2H), 3.19-3.22 (t, 2H), 3.40 ( 5, ZN), 3, 42-3.54 (t, 2H), 3.74 ( 2H), 4.45 (5, 2H), 4.54 (Her, 2H), 5.39 (in, 2H ), 7.29 (M 1), 7.52-7.56 (t, 2H); MS: 479 (MNU).

An example of AM

IN NMR (COzO0B) 5: 2.01-2.06 (t, 2H), 2.18-2.20 (t, 2H), 3.18-3.24 (t, 2H), 3.40 ( 5, ZN), 3, 51-3,55 (t, 2H), 3, 76-3,79 (t, 2H), 4,46 (5, 2H), 4, 66-4,69 (t, 2H), 5.10 (in, 2H), 7.27 (, 1H), 7.61-7.63 (t, 1H), 7.68-7.72 (t, 1H); MO: 417 (MNU).

Example AO was prepared using procedures similar to those used to prepare Example

AM (Scheme 15), that in the first stage, 1-bromo-(3-cyanophenyl)ethane was used for the alkylation of Compound 1.

The product obtained in the first step was then subjected to the other steps described in Scheme 15 to give

Example of AO. 1-Bromo-(3-cyanophenyl)ethane was synthesized using a two-step procedure, by initial reduction of 3-acetylbenzonitrile to 1-(3-cyanophenyl)u-ethanol followed by conversion to 1-bromo-(3-cyanophenyl)ethane. Examples AR, AOS, AB, and A5 were prepared using procedures similar to those used to prepare Example AM (Scheme 16) by using the appropriate bromide in the first alkylation step. For Compound AR, during reductive amination, instead of Ma(OAc)zVN, they were used

Ma(SMIzvVN. Structural data and data of spectral analysis of these compounds are listed below.

Example AO her I xx them.

Mt

S and u

IN NMR (COzO0) 5: 2.00-2.20 (t, 7Н), 3.12-3.20 (t, 2Н), 3.38 (5, ЗН), 3.44-3.50 ( t, 2H), 3.74 (i, 2H), 4.39 (v, 2H), 4.56-4.64 (t, 2H), 5.78 (4, 1H), 7.48-7 .69 (t, 4H); MS: 413 (MNU.

An example of AR

MN.

She z i ro U-ON re o. In Still mash

Esh U Ya cheek : shki

IN NMR (SOzOB) 5: 1.72 (9, ZN), 1.92-2.18 (t, 4H), 2.92-3.04 (t, 2H), 3.19-3.29 ( t, 2H), 3.39 (z, ЗН), 3.75-3.84 (t, ЗН), 4.40 (а, 1Н), 4.64-4.67 (t, 2Н), 5 , 10-5.13 (t, 2H), 7.47-7.64 (t, 4H); MS: 413 (MNU).

Example of AO

MN.

RO b-on dbchouyae Hey and td ve l si

Mon; yes M -

SEU

IN NMR (COzO0B) 5: 2.00-2.05 (t, 2H), 2.08-2.19 (t, 2H), 3.16-3.21 (t, 2H), 3.38 ( 5, ZN), 3, 47-3.52 (t, 2H), 3, 74-3.77 (t, 2H), 4.49 (v, 2H), 4.65 (I, 2H), 5 .20 (in, 2H), 7.90-7.92 (t, ZN); MO: 467 (MNU).

Example AB

MM

SHY o akeh lived M o. ku not 77

Ak y I S VZ che i

AND.

CE"

IN NMR (COzO0B) 6: 3.20-3.35 (t, 4H), 3.39 (5, ZN), 3.75-3.78 (t, 4H), 3.86-3.87 ( t, 2H), 4.00-4.04 (t, 2H), 4.46 (5, 2H), 4.65-4.68 (t, 2H), 5.20 (5, 2H), 7 , 90-7.97 (t, ZN); MS: 483 (MNU).

Example A5 sl a M mes s Y po -on r 8) zd t y et a M ru ЧО де и щ | and with Z-

SE;

IN NMR (COzO0) 6: 1.54-1.58 (t, 1H), 1.80-1.90 (t, 5H), 2.99 (i, 2H), 3.39 (v, ЗН) , 3.42 (5, 2H), 3.76 (t, 2H), 4.39 (5, 2H), 4.66 (i, 2H), 5.20 (2H), 7, 87-7, 93 (t, ZN); MO: 481 (MNU).

Examples AT, AS, AM, and AM/ were prepared using procedures similar to those used to prepare Example MU, except that M-methylpyrrolidone was used as the solvent, and different alcohols were used instead of butanol. For Example AT, the first stage was carried out at 200 "С.

An example of JSC

No I M ikh Mak r-on mo shi Kesh KI vo TO TMM

Er M vk : | Where am I?

IN NMR (DMSO) 5: 1.84-1.97 (t, AN), 2.98-3.00 (t, 2H), 3.27-3.29 (t, 2H), 4.30 ( yes, 2H), 4.80-4.90 (t, AN), 7.33-7.54 (t, 4H), 10.70 (c, 1H); MS: 423 (MNU.

Example ASH plural, ha Don et tfu Z o tra, di b -

IN NMR (DMSO) 5: 0.05-0.07 (t, 2H), 0.38-0.40 (t, 2H), 0.73-0.76 (t, 1H), 1.51- 1.58 (t, 2H), 1.82-1.98 (t,

AN), 2.97-3.02 (t, 2H), 3.26-3.30 (t, 2H), 4.22-4.30 (t, 4H), 10.65 (5, 1H) ; MS: 409 (MNU).

An example of the AM zone of M o se Ya

M on ghetto pe sy "t Kt sho;

Bonya Khny

Ah yes

IN NMR (COzO0B) 5: 1.92-2.20 (t, 11), 3.15-3.21 (t, 2H), 3.43-3.52 (t, 2H), 4.38 ( 5, 2H), 4.50 (y, 2H), 5.12 (5, 2H), 7.49-7.60 (t, 4H); MS: 409 (MNU).

Example of AM/ university of the city: in the Cheka

The tone of one hundred meters; shi and sh

AAU

IN NMR (DMSO) 65: 0.27-0.31 (t, 2H), 0.49-0.61 (t, 2H), 1.64-1.84 (t, 1H), 1.84- 1.98 (t, 4H), 2, 98-3.01 (t, 2H), 3, 27-3.29 (t, 2H), 4, 29-4.31 (t, 4H), 5, 01 (in, 2H), 7.34-7.55 (t, 4H), 10.65 (5, 1H); MO: 395 (MNU).

Example of AH

MN

And also M

Choose and 0-0 O ko Z de

S zho

Ah

Example AH was prepared using procedures similar to those used for preparation

Example AC, except that Compound 1 was replaced by Compound 6.1

IN NMR (DMSO) 5: 0.89 (y-7.5 Hz, ZN), 1.13 (5 9-7.2 Hz, ZN), 1.35 (vehi, 9U-7.2 Hz, 2H ), 1.63 (diypi, U-7.5 Hz, 2H), 1.80-2.02 (t, 4H), 2.91-3.04 (t, 2H), 3.20-3.931 ( t, 2H), 4.00 (a, 9U-7.2 Hz, 2H), 4.21-4.30 (t, 4H), 4.94 (5, 2H), 7.00 (rg, 2H ), 7.30-7.58 (t, 4H), 11.23 (5, 1H); MS: 425 (MNU).

Examples AH, A7 and BA were prepared using procedures similar to those used for preparation

Example A, except that pyrrolidine was replaced by the corresponding amine. For example, in Example A7, pyrrolidine was replaced by cyclohexyl ethane amine.

An example of AU

MN"; with M

Not am in SHY iy -oNn rani and vice "M kiti ON

That's it

Ah ksh

IN NMR (DMSO) 5: 1.13 (5, 6H), 2.68-2.74 (t, 2H), 3.25 (5, ZN), 3.57 (I, 9-45 Hz, 2H), 4.05-4.15 (t, 2H), 4.29 (i, 9-45 Hz, 2H), 4.89 (5, 2H), 7.10 (g, 2H), 7, 49-7.32 (t, 4H), 8.84 (Bg, 2H), 10.71 (5, 1H); MS: 417 (MNU).

Example A ii

She M

M - xx : I T ON

This is it

S er z, ry

AT ai sia de

IN NMR (DMSO) 5: 0.94-0.81 (t, 2H), 1.08-1.26 (t, 2H), 1.55-1.77 (t, 6H), 2.66- 2.74 (t, 2H), 3.25 (z, ЗН), 3.57 (6 9-45 Hz, 2H), 4.05-4.15 (t, 2H), 4.26 (i, U-4.5 Hz, 2H), 4.88 (v, 2H), 6.84 (Bri, 2H), 7.32-7.48 (t, 4H), 8.87 (ri, 2H), 10.53 (5, 1H); MS: 441 (MN).

Example VA

to me

M t M - o Pou in dit they and VV on u ee Pesnya M she her no

VA -th

IN NMR (DMSO) 5: 1.12-1.57 (t, TON), 2.68-2.76 (t, 2H), 3.25 (8, ZN), 3.59 (B 9U-4 .5 Hz, 2H), 4.06-4.14 (t, 2H), 4.32 (I, 9-45 Hz, 2H), 4.89 (v, 2H), 7.30 (horn, 2H ), 7.32-7.51 (t, 4H), 8.88 (bg, 2H), 10.96 (5, 1H); MS: 457 (MNU.

Examples of BB and BC were prepared using procedures similar to those used for preparation

Example MU, except that for different compounds, the corresponding amines were used.

Example of BB

Heh mm

Her Her 5-on pl no ek s ke: i forgotten

GG

-d M va

IN NMR (DMSO) 5: 0.88 (B 9U-7.2 Hz, ZN), 1.936 (zechy, 9U-7.2 Hz, 2H), 1.64 (diypy, U-6.6 Hz, 2H ), 2.96-3.19 (t, 4H), 3.72-3.92 (t, 4H), 4.22-4.34 (t, AN), 4.92 (5, 2H), 7.30 (p, 2H), 7.36-7.58 (t, 4H), 11.6 (5, 1H), 11.35 (ri, 1H); MS: 314 (MNU.

An example of VS i- mmM,

AH tons of neck hair you Z

And I eat it all

IN NMR (DMSO) 5: 0.88 (y, 9-7.2 Hz, ZN), 1.35 (zehy, Y-7.2 Hz, 2H), 1.62 (diypy, 9-6.6 Hz, 2H), 4.18 (U-6.6 Hz, 2H), 4.87 (5, 2H), 5.42 (5, 2H), 7.20 (ri, 2H), 7, 25- 7.40 (t, 4H), 7.68 (c, 1H), 7.76 (c, H), 8.29 (c, 1H), 10.90 (c, 1H);

MO: 394 (MNU).

Synthesis of the VO Example:

Scheme 17

To me about | MN ch gam З-(Bobmmetipi-benzaldei m A, - V o ka kit b-k di" rad Sv"o"; AS sht pishe M Ne n y ky "TKA ih i. 3 . Mne yaaftornperidine in s-m zn hydrochloride, і g -on deOH, VTAV;

What else ER

Tag az NOI M i vo

Compound 33

A sample of TFU acid salt and 2-butoxy-8-methoxy-UN-purine-b-amine (7.58 g) was dissolved in CH3CM (400 ml) and treated with C52CO3 (21.1 g) at 23 "C for 5 min. 3-(Bromomethyl)-benzaldehyde (4.27 g) was then added. Once the reaction was judged to be complete based on LC-MS and HPLC data, the mixture was filtered through a bed of Mag5O" on glassy frit. The filtrate was concentrated to give a tan solid. To dissolve the solid substance, a minimum amount of heated ice-cold АСОН (30 ml) was used while stirring in an oil bath at 80 "С. NgO (54 mL) was added slowly with gentle stirring. The turbidity remained, so the reaction was allowed to cool to 23 °C in an oil bath. Yellow-hot oil began to precipitate from the residual solution. ASON (5 ml) was added, but the oil was not reabsorbed into the residual solution. The residual solution was poured off, and white crystals began to grow almost immediately .These crystals at 95 95 were shown to be pure Compound 33 (-1.5 g), which was collected by filtration. 90 95 (the output was not determined).

IN NMR (SOSIv) 5: 0.97 (i, ЗН), 1.46-1.55 (t, 2Н), 1.73-1.81 (t, 2Н), 4.11 (5, ЗН) , 4.31 (y, 2H), 5.18 (y, 4H), 7.47-7.60 (t, 2H), 7.79-7.86 (t, 2H), 9.99 (in , 1H); MO: 356 (MN).

Example VO

To a solution of aldehyde 33 (90 mg) in DMF (1.5 ml) was added 4-fluoropiperidine hydrochloride (106 mg). Ice-cold ASON (90 μl) and Mavn(Ods)z (270 mg) were added, and the reaction mixture was stirred at 23 °C for 1.5 h. As soon as the reaction was judged complete based on LC-MS and HPLC data, 12 M was added aqueous NSI (300 μl).

The next day, aqueous 1.0 M HCl (1.0 mL) was added to facilitate the conversion. As soon as the reaction reached completion, the entire reaction mixture was directly purified on a C-18 column for reversed-phase HPLC (eluent: 0.5 95 m/v aqueous HCl-CH3SM; 5/90 to 100:0), obtaining amine BO (85.5 mg, yield 81 95) in the form of a yellow resin after lyophilization. 1H NMR (DMSO) b: 0.89 (i, ZN), 1.32-1.38 (t, 2H), 1.57-1.63 (t, 2H), 1.90-2, 12 (t, 5H), 3.07-3.21 (t,

AN), 4.12 (I, 2H), 4.28-4.32 (t, 2H), 4.89 (5, 2H), 7.36-7.44 (t, 4H), 10.04 (rev, 1H), 10.28 (in, 1H); MO: 429 (MNU).

Examples of VE and VE were prepared using procedures similar to those used for the preparation

Example BO, except that for various Examples, the appropriate amine was used, and that the step of reductive amination to obtain Example BE was carried out at 80 "C.

Example VE t re no sn: no» Shchy eat tone ra a on en shih s s o SHHYH a NK - she y

M is this she

IN NMR (DMSO) 65: 0.88 (i, ZN), 1.33-1.40 (t, 2H), 1.59-1.68 (t, 2H), 2.26-2.38 ( t, 2H), 3, 87-3.99 (t, 4H), 4.28 (i, 2H), 4.91 (5, 2H), 7, 30-7.42 (t, 4H), 11 .01 (p5, 1H), 11.13 (5, 1H); MS: 383 (MNU).

Example of VE

Mne se NS mm. he ve dk t ee y M: pe MN y sh 1 kb what are you a

IN NMR (DMSO) 5: 0.89 (i, ZN), 1.35-1.42 (t, 2H), 1.58-1.62 (t, 2H), 4.13 (i, 2H) , 4.29 (y, 2H), 4.86 (5, 2H), 6.49-7.97 (t, 7H), 10.02 (5, 1H); MS: 420 (MNU).

Synthesis of Example YOU:

Scheme 1

MN» M r m

And E se: And there is; is Mig SIM m M, | "ViON, Mai | seamstress KU her ik 2 and pi o and child, And how. y se et schi t M ia T su M y I shi zen noi V zi y chit as in the example A ME minya

I. 4 -on nnnnetttttt te sttnnnininnnyaji va a Esh I: і : M: more and ! in the 1st

Compound 34

Sodium hydride (170 mg) was added to an excess of isobutanol (10 mL) until it was completely dissolved. Nitrile 12 (1.26 g) was added, and the mixture was stirred at 83 °C overnight. The mixture was poured into ice-water with 2 mL of ice-cold

NOAc and stirred for 5 minutes. The extract obtained with EtOAc (3x100 ml) was dried over

Mag25O4 and concentrated. Chromatography on silica gel using IZSO sotorShavzpy on a solid-loaded 402 column and eluent OSM/20 95 MeonN in OSM, conducted at a gradient of 4-40 95 over 10 column volumes, gave isobutyl ether 34 (333 mg). (The product was a mixture with the corresponding ether obtained in the reduction of the nitrile, which was carried over and removed later in the reaction sequence). MS: 323 (MNU).

Example VO was prepared from Compound 34 using procedures similar to those used to prepare Example AI.

IN NMR (300 MHz, 45 DMSO) δ: 0.91-0.93 (a 9y-6.6 Hz, 6H); 1, 81-2,04 (t, BN); 3.00 (t, 2H); 3.28 (t, 2H); C, 98-4.01 (and 90-66 Hz, 2H); 4, 28-4.31 (8 9-6.3 Hz, 2H); 4.91 (5, 2H); 7, 34-7,45 (t, ZN); 7, 51-7.53 (and 9U-7.2 Hz, 1H) 10.75,

(re, 1H); 10.92 (5, 1H), MS: 397 (MNU.

A sample of VN was prepared using procedures similar to those used for preparation

Example VO, except that 3,3,3-trifluoropropan-1-ol was used in the first step, and that the mixture was allowed to react in a sealed tube at 94 "C for 2.5 hours.

MN.

M ha p h visitoichtsia and M vn - pi M kt still Sy

IN NMR (300 MGu, ah DMSO) 6: 1.82-1.98 (ra, 8H); 2.68-2.76 (t, 2H); 3.02 (rt, 2H); 3.29 (rt, 2H); 4.29-4.37 (aah,

Academy of Sciences); 4.90 (5, 2H), 7.36-7.50 (t, 4H); 10.40 (p5, 1H); 10.53 (5, 1H); MS: 437 (MNU).

Synthesis of Example VI:

Scheme 19 in homopiperanine | MN axis M; 7. AsON Manv(des; Meon and k 5th tank, A petry, I p from now on VI tone

OM eko potmvodyu BUT LZ

What, - 33 - and there's more! With o Baki

OM in th KE day

Homopiperidine (akahexamethyleneimine) (270 μl) was added to a solution of aldehyde 33 (230 mg) in MeOH (-10 ml).

Ice-cold ASON (100 μl) and MaHnv(OAc)»z (307 mg) were added, and the reaction mixture was stirred at 23 °C for 12 h. As soon as the reaction was determined by LC-MS and HPLC analysis to be complete, the crude Schiff base purified by preparative HPLC All product fractions were combined, neutralized with an excess

KSO", concentrated, removing acetonitrile, and extracted with EtOAc (3x30 ml). The combined organic extracts were dried over Ma»25O4 and concentrated to a solid under vacuum. The formed solid was dissolved in a minimum of CH3SM and conc. NCI (900 μl), stirred at 23 C for 30 minutes, then the entire reaction mixture was directly purified using preparative reversed-phase HPLC on a C-18 column (eluent: 0.5 95 m/o aqueous NCI-CHzCM; 1-40 95 CHzCM in water for 20 minutes), obtaining the amine of Example VI (18 mg) in the form of a lyophilized salt of NSI. "H NMR (300 MHz, ah DMSO) 5: 0.89 (Her, ZN), 1.32-1.40 (t, 2H), 1.54-1.64 (t, 6H), 1.75 -1.77 (t, 4H), 2.98-3.03 (t, 2H), 3.21-3.26 (t, 2H), 4.18 (I, 2H), 4.27 (a , 2H), 7.35-7.54 (t, 4H), 10.22 (p5, 1H), 10.71 (5, 1H); MS: 425 (MNU.

Example V was prepared using procedures similar to those used for the preparation of Example B, except that tetrahydrofuran-3-ol was used in the first step and the reaction mixture was reacted at 94 °C for 2 h.

MN; -- m M

SA Ya on em: I see the evil in cid Ya

IN NMR (300 MHz, a5 DMSO) 6: 1.81-1.98 (ra, vn); 2.09-2.21 (t, 2H); 3.01 (so, 2H); 3.31 (rt, 2H); 3.66-3.88 (t,

Academy of Sciences); 4.29-4.31 (and 2-6.0 Hz, 2H); 4.89, (in, 2H); 5.27 (rt, 1H); 7.35-7.50 (t, 4H); 10.45 (rv, 1H); 10.59 (5, 1H); MS: 410 (MNU).

Example VC was prepared using procedures similar to those used to prepare Example va, except that (tetrahydrofuran-2-ylmethanol) was used in the first step, and that the reaction mixture was reacted in a sealed test tube at 94 °C for 2 h.

WE

A. M

It's raining - he's alone - with І ОМ.

Uonya I sa i vk | r U -n school

IN NMR (300 MHz, 4 DMSO) 6: 1.58-2.01 (t, 8H), 2.87-3.17 (t, 2H), 3.37-3.35 (t, 2H), 3, 60-3.77 (t, 2H), 4, 04-4.14 (t, ЗН), 4.30 (9, 2H), 4.90 (5, 2H), 7, 24-7, 50 (t, 4H), 10.20 (p5, 1H), 10.39 (v, 1H); MS: 425 (MNU).

Example of VI. was prepared using procedures similar to those used for the preparation of Example va, except that 2,2,3,3,3-pentafluoropropanol was used in the first step, and that the reaction mixture was reacted in a sealed tube at 95 °C for 9 hours

her

M us

I'm U-on

Ba. o Y A ry I-th company Y

E pe ok cheh vyr, r nin

IN NMR (300 MGu, ah DMSO) 5: 1.80-1.99 (t, 4H), 3.01-3.18 (t, 2H), 3.27-3.32 (t, 2H), 4.30 (y, 2H), 4.91-4.99 (t, 4H), 7.33-7.52 (t, 4H), 10.48 (p5, 1P), 10.69 (5, 1H); MS: 472 (MNU.

A sample of VM was prepared using procedures similar to those used for the preparation

Example BO, except that cyclopentanol was used on the first ethane. de peu M Same as "M

SH Den ne ey ey M vm tre ak i

IN-NMR (300 MHz, DMSO) 65: 1.54-1.67 (t, 6H), 1.82-1.98 (t, 6H), 3.01 (t, 2H), 3.29 ( t, 2H), 4, 29-4.91 (y, 2H), 4.89 (5, 2H), 5.32 (t, 1H), 7, 35-7.56 (t, 4H), 10 .49 (re, 1H), 10.63 (5, 1H); MS: 409 (MNU).

A sample of VM was prepared using procedures similar to those used for the preparation

Example A, except that Compound 2 reacted directly with 1-methylpiperazine (ie, bromination at the 8th position of the purine ring was not performed). y" still) m yo all i

DI gray Tu r I I Sun, I I ve WEEK

M Yam

IN-NMR (DMSO) 5: 8.04 (in, 1H), 7.33-7.17 (t, 6H), 5.24 (5, 2H), 4.31 (i, 9-4.5Hz , 2H), 3.60 (Her, 9U-4.5 Hz, 2H), 3.46 (5, 2H), 3.27 (5, ЗН), 2.75-2.30 (t, 8H) , 2.40 (5, ZN), MO: 412 (MNU)

Similarly, Example B0 was prepared using procedures similar to those used to prepare Example A, except that Compound 2 was reacted directly with pyrrolidine (and bromination at the 8-position of the purine ring was not performed).

I don't have

NO: 5 houses

SUT TOotm and yo eko in penya ve TU all she

IN-NMR (DMSO) 65: 0.33-0.34 (t, 2H), 0.51-0.55 (t, 2H), 1.20-1.23 (t, 1H), 1.81 -1.96 (t, 4H), 2.96-3.01 (t, 2H), 3.25-3.28 (t, 2H), 4.15-4.29 (t, 4H), 5 .37 (in, 2H), 7.40-7.59 (t, 4H), 8.54 (5, 1H); MS: 379 (MNU).

Examples BP, BO, BE, B5, and BT were prepared using procedures similar to those used to prepare Example A except that the pyrrolidine was replaced by the appropriate amine for each of these

Examples.

MN"

Men that Y -on aka for the 7th and Shchi

Be higher and ID; and -E

What are you planting:

IN-NMR (DMSO) 6: 11.23 (BIG, 1H), 10.69 (5, 1H), 7.54-7.36 (t, 4H), 7.10 (bg, 2H), 4, 87 (5, 2H), 4.32 (5, 2H), 4.27 (i 94.5 Hz, 2H), 3.56 (I, 9-4.5 Hz, 2H), 3, 40-3 .30 (t, 2H), 3.23 (5, ZN), 3.12-3.01 (t, 2H), 2.50-2.22 (t, 4H), MO: 449 (MH")

Me skla M

My battle and Y 2-on yat tm d n SHIK. child, JAK ze and TM

1N-NMR (DMSO) 6: 10.63 (in, 1H), 9.94 (rg, 2H), 7.49-7.34 (t, 4H), 6.94 (rg, 2H), 4, 89 (5, 2H), 4.27 (Her, 9-45 Hz, 2H), 4.19 (in, 2H), 3.99 (a, 9U-18.9 Hz, 2H), 3.57 ( M 9-45 Hz, 2H), 3.25 (5, ЗН), MS: 427 (MNU)

MN he o u ugon rai seeou M ikh vv ZY will sit what More

IN-NMR (DMSO) 6: 10.80 (5, 1H), 9.79 (Brg, 2H), 7.56-7.43 (t, AN), 7.05 (bg, 2H), 4, 92 (5, 2H), 4, 68-4.58 (t, 2H), 4.28 (i, 9-4.5 Hz, 2H), 3, 83-3.45 (t, 8H), 3 ... me M a V ri -on pn ny v nn a A o ti r ya u ! de H. noya Aa M

1N-NMR (DMSO) 5: 11.41 (rg, 1H), 10.75 (v, 1H), 9.58 (g, 1H), 9.42 (ri, 1H), 7, 60-7, 34 (t, 4H), 7.10 (bg, 2H), 4.89 (5, 2H), 4.35 (5, 2H), 4.30 (I, 9-4.5 Hz, 2H), 3.58 (I, 9U-4.5 Hz, 2H), 3.68-3.10 (t, 8H), 3.26 (5, ЗН), 2.18-2.10 (t, 2H) ,

MS: 428 (МН) люй M мя иО4 5-on rod i s What -d -- tk , rai ee ry in K eMN

1N-NMR (DMSO) 5: 11.95 (rg, 1H), 10.88 (5, 1H), 9.69 (rg, 2H), 7.60-7.35 (t, 4H), 7, 20 (brg, 2H), 4.90 (5, 2H), 4.38 (5, 2H), 4.32 (I, U-4.5 Hz, 2H), 3.59 (I, 9-45 Hz, 2H), 3.55-3.10 (t, 8H), 3.26 (v, ZN), MO: 414 (MH)

Samples of VYS and VM were prepared using procedures similar to those used for preparation

Example AC except that bis(cyclopropylmethyl)amine or cyclopropylmethanamine was used instead of pyrrolidine.

Her: on /

WHAT else priv: kt, mon si ВХ: І

Ye zho z Ke s t be ih vi Щ Her M shya

Sha what

IN-NMR (DMSO) 5: 10.46 (Big, 1H), 7.60-7.33 (t, 4H), 6.80 (g, 2H), 4.93 (5, 2H), 4, 39 (y, 9U-4.5 Hz, 2H), 4.29 (i, y4.8 Hz, 2H), 3.98 (a, 9-66 Hz, 2H), 3.58 (Her, 9- 45 Hz, 2H), 3.26 (in, ЗН), 3.05-2.84 (t, 4Н), 1.12 (and 9-69 Hz, ЗН), 1.20- 1.05 (t , 2H), 0.62-0.53 (t, 4H), 0.38-0.28 (t, 4H), MO:481 (MNU) tn - m im, and io -OH KU a o clothes, more: More Her U

And I'm a village of R and SH y

IN-NMR (DMSO) 5: 9.14 (rg, 2H), 7.50-7.28 (t, 4H), 6.71 (0, 2H), 4.92 (5, 2H), 4, 27 (b 9-4.5 Hz, 2H) 4.05-3.93 (t, 4H), 3.58 (I, 9-45 Hz, 2H), 3.26 (c, ЗН), 2, 82-2.72 (t, 2H), 1.13 (1.9-69 Hz, ЗН), 1.15-1.00 (t, 1H), 0.58-0.51 (t, 2H) , 0.35-0.29 (t, 2H), MC: 427 (MN)

A sample of VMU was prepared using procedures similar to those used for preparation

Example AC except that for the alkylation of Compound 1, instead of 3-(bromomethyl)benzonitrile, 4-(bromomethyl)benzonitrile was used, and subsequently, the corresponding analogue of Compound 8 was hydrolyzed to 4-((b-amino-8-hydroxy-2-( 2-methoxyethoxy)-9H-purin-9-yl)umethyl)benzonitrile, without reacting with ethyl iodide, and the corresponding 4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purine- 9-yl)umethyl)benzaldehyde reacted with pyrrolidine.

Hmm

H i son o m how

MA ut a she sh-- va S

IN-NMR (300 MHz, DMSO) 5: 1.82-1.99 (t, 4H), 3.01-3.03 (t, 2H), 3.24-3.28 (t, 5H), 3.59 (i, 2H), 4.28-4.91 (t,

AN), 4.90 (in, 2H), 7.34-7.55 (t, 4H), 10.59 (re, 2H); MS: 399 (MN).

Analysis protocol for the TI 7 reporter gene

A. Analysis of NEK293

1. Cell culture:

NEK293 cells stably transfected with the human TIA7 gene and the inducible luciferase reporter plasmid rMmigiutm MEeE-KV were obtained from the company "Ipmimodep" (San Diego, California). Environment

OMEM/E12, fetal bovine albumin (EB5), Penicillin-Streptomycin (Rep-biger), Blasticidin, and Zeocin were obtained from Ipmimodep (Carlsbad, CA). The NEK293/TI A7/luciferase cell line was constructed by stably transfecting NEK293/11 cells with the rMig(u) plasmid. Cells were grown on OMEM/E12 medium with 1095 heat-inactivated EB5 supplemented with 1X Rep-5iger, 10 μg/mol

Blasticidin and 5 μg/ml of Zeocin. 2. Analysis procedure:

To determine the EC50 and Eth values of TI H7 agonists in the reporter gene assay, 20 μl of 2X test concentration in serial dilutions of the compound in the cell culture medium was added to each well of a white, transparent-bottomed 384-well tablet for cell cultures from the Sogpipd company (Sogpipd, New York). A cell culture medium containing 12,000 cells was dispensed into each well of this plate

NEK293/TI A7/Luciferase. Then the tablet was placed in an incubator (37 "С and 5 95 СО") and incubated for 2 days.

After incubation, 40 μl of pre-mixed lytic buffer/luciferase substrate solution was distributed into each well. Lytic buffer (5X) and luciferase substrate were obtained from Rgooteda (Madison,

Wisconsin), and they were mixed in a ratio of 2:3 (0/0) immediately before use. After 10 minutes of incubation at room temperature, the luminescence signal was measured using a plate reader (Regkeep EItag, Wellesley, MA) with an integration time of 0.1 second per sample.

Data analysis was carried out with the help of "Rgizt" software from the company "sgarpRaai!" (San Diego,

California) using the binding algorithm in one area. The maximum signal from each test

Compounds (Eth) were normalized to the maximum signal from each test control, Resiquimod, on each plate. The concentration of the compound, which corresponded to 50 95 of the maximum signal, was determined as EC20.

The compounds of the present invention had EC 30 HSM (µM) values in the range of about 0.01 to about 1000, or about 0.1 to about 500, or about 0.1 to about 300, or about 0.1 to about 200, or from about 0.1 to about 100, or from about 0.1 to about 50, or less than about 500, or less than about 400, or less than about 300, or less than about 200, or less than about 100, or less than about 50, or less than about 20, or less than about 10.

B. Analysis of IPC

The analysis was performed in order to determine the stimulation of cytokines after 24 hours, obtained from mononuclear cells of peripheral blood (MPC) of a person when using the compounds proposed in this invention. The analysis was performed in two parallels using 8-point semi-logarithmic dilution curves. The compounds proposed in this invention were diluted starting with 10 μM DMSO solution. The conditioned environment of the cells was analyzed directly for the presence of IEMe., and its dilution 1:10 for IEMo. The analysis was carried out in the same way as described in Viogd. May Spent Gay. 16, 4559, (2006). In particular, IPCs stored frozen were thawed and distributed in 96-well plates of 750,000 cells per well with a cell medium content of 190 μl per well. Then the IPC was incubated for 1 hour at 37 "С at 5 95 СО". Then the compounds proposed in this invention were added to 100 μl of the cell medium using an 8-point semi-logarithmic titration. The plates were incubated at 37 "С and 595 СО" for 24 hours and then spun in a centrifuge at 1200 rpm for 10 min, after which the supernatant liquid was collected and stored in the same way at - 80 °C. Cytokine secretion was analyzed with the help of multi-channel sets "I itipekh" and "Orgiaye", using the analytical device " I stipeh". The concentration at which the compound stimulated the maximum production of IEM, which was determined using the method of analysis described above, was taken as the value of ECx IEM for the compound.

The compounds of the present invention had ECx IEM values (nM) ranging from about 0.1 to about 10,000, or from about 0.1 to about 1,000, or from about 0.1 to about 300, or from about 0 .1 to about 100, or from about 0.1 to about 10, or from about 0.1 to about 5, from about 0.1 to about 1, or less than about 5000, or less than about 3000, or less than about 1000, or less than about 500, or less than about 400, or less than about 300, or less than about 200, or less than about 100, or less than about 50, or less than about 20, or less than about 10 , or less than about 5, or less than about 1. Examples A, C, 0, E, y,

М, А, МУ, М, АЙ, Ау, АО, АБ, А, АМ, АМУ, А7, ВЕ, ВО, ВН, and ВМ have ЕСtх IEM (NM) values less than about 5.