UA74593C2 - Substituted imidazopyridines - Google Patents

Abstract

Imidazopyridine compounds that contain substituted amine functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Description

Description of the invention

This invention relates to imidazopyridine compounds having a substituted amino group in position 1 and 2 pharmaceutical compositions containing such compounds. An additional aspect of the present invention relates to the use of these compounds as immunomodulators for the induction of cytokine synthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.

The first reliable report on the 1H-imidazo|4,5-c|quinoline ring system, Vasktap et al.,

U. Oga. Spet. 15, 1278-1284 (1950) describes the synthesis of 1-(6b-methoxy-8-quinolinyl)-2-methyl-1H-imidazo|4,5-c)quinoline 70 for possible use as an antimalarial agent. According to this, the syntheses of various substituted 1H-imidazo|4,5-c|quinolines were described. For example, .aip ei aiYi., 9. May. Spent 11, pp. 87-92 (1968) synthesized 1-(-2-(4-piperidyl)ethyl|-1H-imidazo|4,5-syquinoline as a possible anticonvulsant and cardiovascular agent.

Also, Vagapom eyi ai., Spet. Arv. 85, 94362 (1976) reported several 2-oxoimidazo|4,5-c)quinolines, and

Vegepui eig a), 9. Neiegosussis. Spent 18, 1537-1540 (1981) reported several individual 2-oxoimidazo(4,5-c)quinolines.

Later, some 1H-imidazo|4,5-c|quinoline-4-amines and 1- and 2-substituted derivatives were found to be useful as antiviral) agents, bronchodilators, and immunomodulators. They are described in, inter alia, in US patents

Mo4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; 5,389,640, all of which are incorporated herein by reference.

Compounds of substituted 1H-imidazopyridin-4-amine, which are suitable as modifiers of the immune response, are described in patents OB MoMo.5,446,153; 5,494,916 and 5,644,063. The compounds described in these patents do not have a substituent containing an amino group in the 1st position. Certain 1H-imidazo|4,5-c|quinolin-4-amines containing amide, sulfonamide, and urea groups in the 1-position are described in PCT applications with publication numbers MO 00/76505,

MO 00/76518 and UMO 00/76519. with

Despite the recent development of compounds useful as immune response modifiers, there is still a need for compounds capable of modulating the immune response by inducing cytokine biosynthesis or other mechanisms.

We have discovered a new class of compounds useful for inducing cytokine biosynthesis in animals.

Accordingly, the present invention provides imidazopyridine-4-amine compounds having a substituted amino group at position o 301. Compounds which have been found to be useful inducers of cytokine biosynthesis are defined by Formula (1), Ge»! which is described in more detail below. Formula (I) is presented as follows:

MN, cha u « ny U-v, Z s pe M » 5 I

Х І К, с ий о 50 ци с» (I) where Х, У, 2, Кч, Ко, Кз, Ка and Кб are as defined here. 29 Compounds of Formula (I) are useful as immune response modifiers due to their ability to induce

GF) biosynthesis of cytokines and, thus, modulate the immune response when administered to animals. This makes these compounds useful in the treatment of various conditions, such as viral diseases and tumors, that are sensitive to such changes in the immune response.

The invention also encompasses pharmaceutical compositions containing immune response modifying compounds and 60 methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal and/or treating a neoplastic disease in an animal by administering a compound of Formula (I) to an animal.

In addition, the invention encompasses methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of the aforementioned compounds.

As mentioned earlier, we discovered that certain compounds induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented below by formula (1):

MH,

Koch well

MY

70 i he z i i X (where X means alkylene or alkenylene;

U means -СО-, -С8- or -80»5-; c 7 means connection, -O-, -5- or -MEB-; at

Ku means aryl, heteroaryl, heterocyclyl, C-oo alkyl or C-oo alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of 3: -alkyl; and -alkenyl; Pho -aryl; -heteroaryl; o -heterocyclyl; "r-substituted cycloalkyl;

Zo -O-alkyl; in. -O-(alkyl)o 1-aryl; -O-(alkyl)o 1-heteroaryl; -O-(alkyl)o 4-heterocyclyl; "-bsoon; -CO-O-alkyl; o) c -CO-alkyl; "» -5(O)0.»-alkyl; "-5(0)0.2-(alkyl)o-1-aryl; -Z(O)0.2-(alkyl)o.4-heteroaryl; -8(0)0.o-(alkyl)o.1-heterocyclyl; and -alkyl)o-1-M(Bv)"; their -(alkyl)o.4-MK;-CO-O-alkyl; -(alkyl)o.4-MK;-CO-alkyl; o -(alkyl)o.4-MK;-CO-aryl; co 020 -(alkyl)o.4-MV5-CO-heteroaryl; -Mz; c" - halogen; -haloalkyl; - haloalkoxy; 99 -CO-haloalkyl;

HF) -CoO-halo-alkoxy; -MO», o -cm; -OH; 6o -ZN; and in the case of alkyl, alkenyl and heterocyclyl, oxo;

EC" selected from the group consisting of: - hydrogen; alkyl; - alkenyl; bo -alkyl-O-alkyl;

-alkyl-5-alkyl; -alkyl-O-aryl; -alkyl-5-aryl; -alkyl-O-alkenyl; -alkyl-5-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; - halogen; 70 - ShkKoe)"; -СО-М(Вв)2; -С8-Ш(В2)о; -502-Msh(Kv)2; -MAK5-CO-C.4.10o alkyl; -MKe-C5-C4.40 alkyl; -MKe5-505-C..40o alkyl; -b0-C..1o alkyl; -60-0-C. o alkyl; -Mz; - aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; high school

Mz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and (8) each K" is independently H or C 1-40 alkyl; or a pharmaceutically acceptable salt thereof.

Preparation of compounds

Compounds according to the invention can be prepared according to Reaction Scheme II, in which K, Co, Kz, Ka, Kv, c zo X, M and 7 are as defined above, Bp is benzyl and K' is alkyl, which having one to four carbon atoms, perfluoroalkyl having one to four carbon atoms, phenyl or phenyl substituted with Me halogen or alkyl having one to four carbon atoms. yu

At stage (1) of the reaction scheme | Z-nitropyridine-2,4-disulfonate of the formula X reacts with the amine of the formula

K-2-X-M(K5)-X-MN" to obtain 3-nitro-4-aminopyridine-2-sulfonate of formula XI. Due to the presence of two sulfonate groups, which, in principle, can be replaced, the reaction can produce a mixture of products that can be easily separated using standard techniques, such as column chromatography.

The reaction is preferably carried out by adding an amine to a solution of a compound of formula X in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. Since the sulfonate group is "

With a relatively easy leaving group, the reaction can occur at low temperature (02) in order to reduce the amount of unwanted 2-aminated and 2,4-diaminated by-products from c. и З-Nitropyridine-2,4-disulfonates are known and can be easily obtained using known methods of synthesis, и? see, for example, Ipaviot et al., patent Sh.5. MO.-5,446,153 and sources of information cited there.

At stage (2) of reaction scheme I! C-nitro-4-aminopyridine-2-sulfonate of the formula X is reacted with dibenzylamine to obtain 2-dibenzylamino-C-nitro-4-amine of the formula XII. The reaction is carried out by mixing a compound of formula Xi, dibenzylamine and a tertiary amine such as triethylamine in an inert solvent such as benzene, toluene or xylene and heating the resulting mixture. At stage (3) of the reaction scheme |! nitro group of 2-dibenzylamino-3-nitropyridin-4-amine of the formula (XII c is reduced to an amino group. The reduction is preferably carried out using MiV 5", which is formed by

Lashes of sodium borohydride and nickel chloride hydrate in methanol. The reaction is preferably carried out at ambient temperature. se" At stage (4) of the reaction scheme | 2-Dibenzylaminopyridine-3,4-diamine of the formula X is reacted with a carboxylic acid or its equivalent to obtain 4-dibenzylamino-1H-imidazo|4,5-c|Ipyridine of the formula XU.

Suitable carboxylic acid equivalents include orthoesters and 1,1-dialkoxyalkylalkanoates. The carbonic acid or equivalent is chosen to provide the necessary Co substituent in the compound of formula XM. For example, triethylorthoformate will provide a compound in which K» is hydrogen, and iF) triethylorthoacetate will provide a compound in which K» is methyl. The reaction can take place in the absence of solvent or in an inert solvent such as toluene. The reaction occurs with sufficient heat to remove any alcohol or water produced as a byproduct of the reaction. It is not necessary, because a catalyst such as pyridine hydrochloride can be used.

Alternatively, the compound of the formula XM can be obtained in two stages (a) by the interaction of the diamine of the formula XII with the halide hydrides of the formula Ko»С(О)СИ or К»С(О)Вг to obtain the compound of the formula XIM and subsequent (B) cyclization. In step (48), the halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine, or dichloromethane. The reaction can be carried out at ambient temperature. 65 In stage (45), the product of stage (42) is heated in an alcohol solvent in the presence of a base. Preferably, the product of stage (4a) is boiled in methanol in the presence of an excess of triethylamine or heated with a methanolic solution of ammonia. Alternatively, step (45) can be carried out by heating the product of step (4a) in pyridine. If step (4a) was carried out in pyridine, step (45) can be carried out by heating the reaction mixture after analysis shows that step (4a) is complete.

At stage (5) of the reaction scheme /!/ 4-dibenzylamino-1H-imidazo(4,5-s|Ipyridine of the formula XM is subjected to hydrogenolysis to obtain 4-amino-1H-imidazo|4,5-s|Ipyridine of the formula I. Mostly a compound of formula XM is heated in formic acid in the presence of palladium hydroxide on charcoal. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. c o c o (22)

IS) « m. - s. and? -I sh» 1 o 50 syu»

F) name) 60 b5

The reaction scheme of the V 0-30 o:5:0 and potsuut o, uro o, ke o o -i - her s 82 5 МН in Mn oi and 4 4 her и /as mA, х хи ! kh i i s (3) o (Vp), Her M(Va), so s N Fo x. In him, - "II today and IS o) i, Kn - MN « | is Х Я M им ' MA, hm Х х « - І 8 - Г z - 45 . | (5, (4) sh» sl Mn, in(VlH, 7 m in zar 9 de - 1 Z uv vy VI

Compounds of the invention can be prepared according to Reaction Scheme II, in which K., Ko, Kz, Ku, Kv and X are as defined above, Vp stands for benzyl, BOC stands for tert-butoxycarbonyl and MU stands for O or 5.

At stage (1) of Reaction Scheme II, amino-protecting groups of 1H-imidazo|(4,5-s|pyridine of the formula HMI are removed, obtaining 1H-imidazo|4,5-s|pyridine of the formula II. Preferably, a solution of the compound of the formula HMI in a suitable agent, such as dichloromethane, is treated with trifluoromethylsulfonic acid at ambient temperature. Compounds of formula XM can be obtained using the synthesis methods described in Reaction Scheme I. In step (1), the 2,4-disulfonate of formula X is reacted with an amine of the formula

VOS-MA5-X-MN". Stages 2-4 are then carried out as described above, obtaining a compound of the formula XMI, which is a subgenus of the formula XU. 70 At stage (2a) of Reaction scheme I, 1H-imidazo(4,5-s|Ipyridine of formula I is subjected to reaction with acid chloride of formula K.--С(ОСИ or with acid anhydride of formula K--С(0О0ОС(О0) -K 1 With the preparation of 1nH-imidazo|4,5-c|Ipyridin-1-ylamide of the formula CHMII, which is a subspecies of the formula I. The reaction is preferably carried out by adding acid chloride or acid anhydride to a solution of the compound of the formula H in a suitable solvent, such as dichloromethane or acetonitrile, in the presence of a base such as triethylamine. The reaction may take place at reduced temperature (022) or at ambient temperature. The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

At stage (25) of Reaction scheme II, 1H-imidazo|(4,5-s|Ipyridine of the formula I is subjected to interaction with the isocyanate of the formula K--M-C-O or with the isothiocyanate of the formula K--M-C-5, obtaining 1H-imidazo|4,5-c|Ipyridin-1-yl urea or thiourea of formula HMIII, which is a subgenus of formula I. The reaction is preferably carried out by adding an isocyanate or isothiocyanate to a solution of a compound of formula II in a suitable solvent, such as dichloromethane, at reduced temperature (022).The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.

At stage (2c) of Reaction Scheme I, 1H-imidazo(4,5-c|Ipyridine of formula I is subjected to interaction with sulfonyl chloride of formula K.-5X0)2СИ or sulfonic anhydride of formula K.-5(0)205(0)2- Ki. with is the preparation of 1H-imidazo|4,5-c|Ipyridin-1-ylsulfonamide of formula XIX, which is a subgenus of formula |. The reaction o is preferably carried out by adding sulfonyl chloride or sulfonic anhydride to a solution of the compound of the formula

It is in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. The reaction can occur at reduced temperature (022) or at ambient temperature. The product or its pharmaceutically acceptable salt can be isolated using conventional methods. Ge) (22)

IS) « and - - p. and? -I sh» 1 o 50 syu»

F) name) 60 b5 ch

Reaction scheme |!

Because uv, v. X e |. t, and X 15. M v, Nn hm and os and Ye

M | M, I (8)

MN, chn, mn, y U-v, uv "fi shk « i, ; t and 7" M 00 p! m-2 - m. "5 t II um B v as, - s Compounds of the invention can be obtained according to Reaction scheme I, where K., Ko, Kz, Ku, K5 and X are "» as defined above. " At stage (1) of the reaction scheme Ш 1H-imidazo|4,5-s|Ipyridine of the formula || is subjected to interaction with sulfamoyl chloride of the formula K.-M(K5)5(0)2СІ, obtaining 1H-imidazo|4,5- c|Ipyridin-1-ylsulfamide of the formula

XXI, which is a subgenus of formula I. Preferably, sulfamoyl chloride is added to a solution of a compound of formula II in a suitable solvent, such as 1,2-dichloroethane, in the presence of a base, such as triethylamine. The reaction can occur at elevated temperatures. The product or its pharmaceutically acceptable salt can be isolated using conventional methods. o Alternatively, the sulfamide of formula XXI can be obtained in two stages (a) by interaction

Ge) 20 1H-imidazo|4,5-c|Ipyridine of formula II with sulfuryl chloride with formation of sulfamoyl chloride of formula XX and subsequent (B) interaction of sulfamoyl chloride with amine of formula K.--М(К5)Н. At stage (Ia), the reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of the compound of formula (ii) in the presence of 1 equivalent of 4-(dimethylamino)pyridine. The reaction is preferably carried out at a low temperature (-782C). Optionally, after the addition is complete, the reaction mixture is allowed to warm to 29 ambient temperature. At stage (IB), a solution containing 2 equivalents of K -M(K5)H and 2

HF) equivalents of triethylamine in dichloromethane are added to the reaction mixture from stage (Ia). The reaction is mainly carried out at a low temperature (-782C). The product or its pharmaceutically acceptable salt can be isolated using conventional methods. 60 b5 point

The reaction scheme of HER 70 and input (and 8) p.

M i t i v; them and Kh

Kk, MN u

Y t, M. -0 s mn, o

Shk

AND HER Uv at 30. "2 M F e h oyu

Kk 6 h | В, И , и-

XXI evo

Her" - with from B, .

The compounds of the invention can be prepared according to Reaction Scheme M, where K, Co, Kz, Ku, Kv and X are -I as defined above and BOC means tert-butoxycarbonyl.

At stage (1) of the IM reaction scheme, 2,4-dihydroxy-3-nitropyridine of the formula XXIII is chlorinated with the use of commonly accepted chlorinating agents, obtaining 2,4-dichloro-3-nitropyridine of the formula XXIII. Preferably, the compound of formula XXII is combined with phosphorus oxychloride and heated. Many 2,4-dihydroxy-3-nitropyridines of the formula

CHNs are known, and others can be easily obtained using known synthesis methods, see for example, ik I pazyut, etc., patent O.5. Mo. 5,446,153 and sources of information cited therein. 4) At stage (2) of the IM reaction scheme, 2,4-dichloro-Z-nitropyridine of the formula XXIII is reacted with an amine of the formula BOS-MK:-X-MNo, obtaining 2-chloro-Z-nitropyridine of the formula XXIM. The reaction is preferably carried out by adding an amine to a solution of the compound of formula XXIN in a suitable solvent, such as dimethylformamide, in the presence of a tertiary amine, such as triethylamine.

At stage (3) of the IM reaction scheme, 2-chloro-3-nitropyridine of formula XXIM is subjected to interaction with phenol,

F) obtaining 3-nitro-2-phenoxypyridine of formula XXMU. Phenol is reacted with sodium hydride in a suitable solvent, such as diglyme, to form phenoxide. Then, the phenoxide is reacted at elevated temperature with the compound of formula XXIM. In stage (4) of the IM reaction scheme, 3-nitro-2-phenoxypyridine of the formula XXM is reduced to obtain

Z-amino-2-phenoxypyridine formula XXMI. The reduction is preferably carried out using a conventional heterogeneous hydrogenation catalyst, such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Ragga apparatus in a suitable solvent such as isopropyl alcohol or toluene. 65 At stage (5) of the IM reaction scheme, 3-amino-2-phenoxypyridine of the formula XXMI is subjected to interaction with a carboxylic acid or its equivalent to produce 4-phenoxy-1H-imidazo|4,5-c|quinoline of the formula M. Suitable equivalents of a carboxylic acid include orthoesters and 1,1-dialkoxyalkylalkanoates. The carboxylic acid or equivalent is selected to provide the required Co substituent in the compound of formula M.

For example, triethyl orthoformate will provide a compound in which K 2 is hydrogen, and trimethyl orthovalerate will provide a compound in which Co is butyl. The reaction can occur in the absence of solvent or in an inert solvent such as toluene. The reaction occurs with sufficient heat to remove any alcohol or water produced as reaction byproducts.

Optionally, a catalyst such as pyridine hydrochloride can be used.

Alternatively, stage (5) can be carried out by (i) the interaction of a compound of the formula XXM| with an acylhalide 7/0 of the Formula K»C(O)CI or CoC(O)Bg and then (iii) cyclization. In part (i), the acyl halide is added to a solution of the compound of formula XXMU in an inert solvent, such as acetonitrile, pyridine, or dichloromethane. The reaction can be carried out at ambient temperature. In part (ii), the product of part (ii) is heated in pyridine.

At stage (6) of the IM reaction scheme, the BOC group is removed from the compound of the formula IM to obtain 4-phenoxy-1H-imidazo|4,5-sylquinoline of the formula M. Preferably, a solution of the compound of the formula IM in a suitable solvent, such as dichloromethane, treated with trifluoroacetic acid or hydrochloric acid at a reduced temperature.

At stage (7) of the IM reaction scheme, 4-phenoxy-1H-imidazo|4,5-cIquinoline of the formula M is converted into 4-phenoxy-1H-imidazo|4,5-cIquinolin-1-ylsulfonamide of the formula MI, using the method of stage (2c ) of her reaction scheme.

At stage (8) of the IM reaction scheme 4-phenoxy-1H-imidazo|4,5-s|quinolin-1-ylulfonamide of formula MI is aminated to obtain 4-amino-1H-imidazo|4,5-s|quinoline-1- ylsulfonamide of formula XIX, which is a subgenus of formula I.

The reaction can be carried out by combining the compound of formula MI with ammonium acetate in a sealed tube and heating (-1502С). The product or its pharmaceutically acceptable salt can be isolated using generally accepted methods (6) and (22)

IS) « and - - p. and? -I sh» 1 o 50 syu»

F) name) 60 b5

Reaction scheme of MI "and in: a

VK "o mch M. -

M ro o 0 and i. o -2 and a in; "Hey, I'm in and in. and

ХХ xx ХХ ve vos (3) o Phi : with С 0; 8)

ZM (5) Mn, i and zdv pi "schi ke; Ft; ! e 4 MN. in 7 or yu ku X x iy u 4 i XX 4 M xhu 4 X i- "shi sodi" a z

MN, -1 ZM (7 Z M railway - t

M M - 5. s! m t ' I M so 20 | in y R. x x so 4 In "Mo o Kk, ". who spoke Mo vruyuo I, K,

F) z The invention also covers new compounds: useful as intermediate compounds in the synthesis of compounds of formula I. Such intermediate compounds have structural formulas (II) - (MI): described in more detail below. One class of intermediate compounds has the formula (II) b5

; Soa " in gav

I 1 Mn and (1) where: X means alkylene or alkenylene;

EC" is selected from the group consisting of: c - hydrogen; o -alkyl; - alkenyl; -alkyl-O-alkyl; -alkyl-5-alkyl; and -alkyl-O-aryl; Pho -alkyl-5-aryl; -alkyl-O-alkenyl; Shcheo, -alkyl-from-alkenyl; and "C -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -Hon; m. -halogen; -MZh(Kv)2; -CO-MSH(Kv)2; "-С8-МЩ(Вв)о; 0-80)» n- s -MK5-CO-C..4o alkyl; "» -МКе-С5-С4.40 alkyl; "-МЕ5-805-С. 40 alkyl; -b0-C..1o alkyl; -60-0-C. 40 alkyl; -Mz; i5" - aryl; -heteroaryl; o -heterocyclyl; CO 020 -CO-aryl; and -CO-heteroaryl;

Fe" Kz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and every Ke; means independently H or C..40 alkyl; or a pharmaceutically acceptable salt thereof. 59 another class of intermediate compounds has the formula I: (Ф) ko bo b5 o " "m -- o z" V chn y, I riv se (Ш) o where: ОО means MO» or МН»;

X means alkylene or alkenylene;

Kz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, and alkylamino, dialkylamino, and alkylthio; and Gee! every Ke; means independently H or C..40 alkyl; or a pharmaceutically acceptable salt thereof.

Another class of intermediate compounds has the formula (IM): o "I

I Phi I - s:z" in She U

Kk, - - M i» t; And in X so 20 Ya I

Fe u o FU: ko de: X means alkylene or alkenylene; 60 EC" selected from the group consisting of: - hydrogen; -alkyl; - alkenyl; -alkyl-O-alkyl; bo -alkyl-b-alkyl;

-alkyl-O-aryl; -alkyl-5-aryl; -alkyl-O-alkenyl; -alkyl-from-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; - halogen; -ScheKv)2,- )СО-М(Вв)"; -С8-МЩ(Вв)о; -502-Msh(Kv)2; -MKe5-CO-C..4o alkyl; -MAK5-C5-C.4.10o alkyl; -MKe5-505-C..40o alkyl; -b0-C..1o alkyl; -60-0-C. o alkyl; -Mz; - aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl;

Kz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, lower alkylamino, dialkylamino, and alkylthio; and every Ke; independently means H or C..40 alkyl; or a pharmaceutically acceptable salt thereof. i) another class of intermediate compounds has the formula (M):

Gee)

Fo yuyu o " m. her M - g" X 4 sh u iz - v, 1 o 50 i (M) where: X means alkylene or alkenylene;

EC" selected from the group consisting of: - hydrogen;

IF) -alkyl; ime) -alkenyl; -alkyl-O-alkyl; 60 -alkyl-5-alkyl; -alkyl-O-aryl; -alkyl-5-aryl; -alkyl-O-alkenyl; -alkyl-5-alkenyl; and 6E -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH;

- halogen; -ShckKoe)"; -СО-М(Вв)2; -С8-МЩ(Вв)о; -502-Msh(Kv)2; -MKe5-CO-C..4o alkyl; -MKe-C5-C4.40 alkyl; -MKe5-505-C..40o alkyl; 70 -b0-C..1o alkyl; -60-0-C. o alkyl; -Mz; - aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl;

Kz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and every Ke; means independently H or C..40 alkyl; or a pharmaceutically acceptable salt thereof.

Another class of intermediate compounds has the formula (MI) с (8) со т 5 Ф и 5-п, it includes s and -

Kk, | « 70 va M, m/o not with KE 287 and Ov,

В (У) ш» s in which: X means alkylene or alkenylene;

Ku means aryl, heteroaryl, heterocyclyl, C-oo alkyl or Co-oo alkenyl, each of which may be i, unsubstituted or substituted by one or more substituents independently selected from the group consisting of si-8: -alkyl; - alkenyl; 5B - aryl; -heteroaryl;

F) -heterocyclyl; ka -substituted cycloalkyl; -O-alkyl; in -O-(alkyl)o 1-aryl; -O-(alkyl)o 14-heteroaryl; -O-(alkyl)o 4-heterocyclyl; -bsoon; -CoO-O-alkyl; 65 -CO-alkyl; -5(O)O»-alkyl;

-5(0)0.2-(alkyl)o-1-aryl; -Z(O)0.2-(alkyl)o.4-heteroaryl; -Z(O)O'-(alkyl)o.4-heterocyclyl; "alkyl)o-1-M(Kv)2; -(alkyl)o.4-MK;-CO-O-alkyl; -(alkyl)o.4-MK;-CO-alkyl; -(alkyl)o.4-MK;-CO-aryl; -(alkyl)o.4-MK;-CO-heteroaryl; 70 "M; -halogen; -haloalkyl; -haloalkyl; -CO-haloalkyl; -CoO-haloalkyl; -MO"; -CM; -OH; -ZH; and in the case of alkyl, alkenyl and heterocyclyl, oxo;

EC" selected from the group consisting of: - hydrogen; -alkyl; - alkenyl; -alkyl-O-alkyl; C -alkyl-5-alkyl; -alkyl-O-aryl; i) -alkyl-5-aryl; -alkyl-O-alkenyl; -alkyl-from-alkenyl; and c zo -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; (o) -halogen; yu -ShkKoe)"; -СО-М(Вв)"; With -C5-MSH(K5)2; in. -502-Msh(Kv)2; -MKe5-CO-C..4o alkyl; -MKe-C5-C4.40 alkyl; -MKe5-505-C..40o alkyl; « -b0-C..1o alkyl; with -60-0-C. o alkyl; -Mz; ;" - aryl; -heteroaryl; -heterocyclyl; -I -CO-aryl; and -CO-heteroaryl; pi Kz apa KK; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each Ke represents independently H or C. 40 alkyl; or a pharmaceutically acceptable salt thereof. 4) In this context, the terms "alkyl", "alkenyl" and the prefix "alk-" include both straight and branched chain groups and cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise indicated, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups generally have up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 carbon atoms in the ring. Examples of cyclic groups are (F, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.) The term "haloalkyl" includes groups substituted by one or more halogen atoms, including perfluorinated groups. It also includes groups containing the prefix "halo -". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, etc.

The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.

Examples of aryl groups are phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or ring systems containing at least one heteroatom in the ring (eg, o, 5, M).

Suitable heteroaryl groups are furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, 65 triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, quinoxalinyl, benzoimidazolyl, naphthyridinazolyl. ,

isoxazolyl, isothiazolyl, purinyl, quinozolinyl, and so on. "Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one heteroatom in the ring (eg, O, 5, M) and includes all fully saturated and partially unsaturated derivatives of the above-mentioned Heteroaryl groups. Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl.

Aryl, heteroaryl and heterocyclyl groups may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkyl, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl . . арилкарбоніламіно, арилалкілкарбоніламіно, гетероарилкарбоніламіно, гетероарилалкілкарбоніламіно, алкілсульфоніламіно, алкенілсульфоніламіно, арилсульфоніламіно, арилалкілсульфоніламіно, гетероарилсульфоніламіно, гетероарилалкілсульфоніламіно, алкіламінокарбоніламіно, алкеніламінокарбоніламіно, ариламінокарбоніламіно, арилалкіламійокарбоніламіно, гетероариламінокарбоніламіно, гетероарилалкілкарбоніламіно і, у випадку гетероциклілу, оксо. If any other groups are specified to be "substituted" or "optionally substituted", then these groups may also be substituted with one or more of the substituents mentioned above.

Some substitutes are particularly preferred. For example, the preferred M groups are - СО - and -50 5-; 5 7 mainly means a connection or - MK -; and Ki is preferably alkyl, aryl or substituted aryl. Preferred groups include alkyl groups having from 1 to 4 carbon atoms (ie, methyl, ethyl, propyl, isopropyl, m-butyl, sec-butyl, isobutyl, and tert-butyl), methoxyethyl, ethoxymethyl, and cyclopropylmethyl. Kz and Ku i) are mostly methyl. One or more of these preferred substituents, if present, may be present in the compounds of the invention in any combination.

The invention includes the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, etc. In particular, if the compound is optically active, the invention particularly includes each of the enantiomers of the compound, as well as racemic mixtures of Me enantiomers. yu

Pharmaceutical compositions and biological activity

Pharmaceutical compositions according to the invention contain a therapeutically effective amount of the compound of the invention, as "

As described above, in combination with a pharmaceutically acceptable carrier. uh-

The term "therapeutically effective amount" means an amount of a compound sufficient to cause a therapeutic effect, such as induction of cytokines, antitumor activity and/or antiviral activity.

Although the exact amount of active compound used in a pharmaceutical composition according to the invention will vary depending on factors known to those skilled in the art, such as

The physical and chemical nature of the compound, the nature of the carrier, the prescribed dosage regime, it is assumed that the compositions according to the invention will contain a sufficient amount of the active ingredient to provide a dose. from about 100ng/kg to about 5mg/kg, preferably from about 1mg/kg to about 5mg/kg of the compound for subject Any conventional dosage form can be used, such as tablets, lozenges, parenteral compositions, syrups, creams, ointments, aerosol compositions, transdermal patches, transmucosal patches, etc. -I Compounds of the invention may be administered as a single therapeutic agent in a treatment regimen, or compounds of the invention may be administered in combination with another or other active agents, including additional immune response modifiers, antiviral agents, antibiotics, etc. c The compounds of the invention have been shown to induce the production of certain cytokines in experiments conducted according to the set of tests presented below. These results indicate that the compounds are useful as immune response modifiers that modulate the immune response in many different ways, making them 4) useful in the treatment of a variety of disorders.

Cytokines, the production of which can be induced by the administration of compounds according to the invention, generally include interferon-o, (EM-o) and/or tumor necrosis factor-o (TME-o), as well as some interleukins

AND). Cytokines whose biosynthesis can be induced by compounds of the invention include IEM-o, TME-o, 1-1, 1-6, 1-10 and 1-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making these compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in animals, which involves administering to the animal an effective amount of a compound or composition according to the invention. 60 It was found that some compounds of the invention preferentially induce the expression of IPM-du in the population of hematopoietic cells, such as PBMCs (peripheral blood mononuclear cells) containing pOS2 cells (progenitors of dendritic cells type 2) without concomitant production of significant levels of inflammatory cytokines.

In addition to the ability to induce cytokine production, the compounds of the invention elicit other aspects of the innate immune response. For example, the activity of natural killer cells can be stimulated, an effect that can occur due to the induction of cytokines. The compounds can also activate macrophages, which in turn stimulate the secretion of nitric oxide and the production of additional cytokines. In addition, the compounds can induce proliferation and differentiation of B-lymphocytes.

The compounds of the invention may also have an effect on the acquired immune response. For example, although no direct effect on T cells or direct induction of cytokines is suggested to exist

T-cells, cytokine production in IEM by T-helpers type 1 (TN1) is induced indirectly, and production of cytokines 1-4, I/-5 and I/-13 by helpers type 2 (Tn2) is inhibited by the introduction of compounds according to the invention. This activity means that the compounds are useful in the treatment of diseases in which an increase in the TA1 response and a decrease in the Tp2 response are desired. Given the ability of the compounds of the invention to inhibit the TN2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, for example, 7/0 atopic dermatitis, asthma, allergies, allergic rhinitis; systemic lupus erythematosus; as a vaccine adjuvant for cell-mediated immunity; and possible as a means for the treatment of recurrent fungal diseases and chlamydia.

The modifying effect of the compounds on the immune response makes them useful in the treatment of a wide range of conditions.

Due to their ability to induce the production of cytokines, such as IEM-o; and TME-o, the compounds are particularly useful 75 in the treatment of viral diseases and cancer. This immunomodulatory activity suggests that the compounds of the invention are useful in the treatment of diseases that include, but are not limited to, viral diseases, including genital warts, common warts, plantar warts, hepatitis B, hepatitis

C, herpes simplex virus type 1 and type 2, molluscum contagiosum, smallpox, especially smallpox of the head, HIV, CMV,

MA, rhinovirus, adenovirus, coronavirus; influenza and parainfluenza virus, intraepithelial neoplasms such as cervical intraepithelial neoplasia, human papillomavirus (HPV) and associated neoplasias, fungal diseases such as candidiasis, aspergillosis and cryptococcal meningitis, neoplastic diseases such as basal cell carcinoma, villous cell leukemia, sarcoma Kaposi, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous

T-cell lymphoma and other cancers, parasitic diseases such as pneumocystis carnii, Ha Cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis, bacterial infections such as tuberculosis and mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention are actinic keratosis, eczema, eosinophilia, essential thrombocythemia, leprosy, multiple sclerosis, Ommen's syndrome, discoid lupus, Bowen's disease, Bowenoid papulosis, alopecia areata, inhibition of keloid formation after surgery and other types of scars after surgery. In addition, these compounds may improve or stimulate the healing of wounds, including chronic wounds. The compounds may be useful in the treatment of opportunistic infections and tumors resulting from suppression of cell-mediated immunity in, for example, bone graft recipients, cancer patients, and HIV patients.

An amount of a compound effective for inducing cytokine biosynthesis is an amount sufficient to cause one or more types of cells, such as monocytes, macrophages, dendritic cells, and B cells, to produce an amount of one or more cytokines such as such as IEM-o, TME-o, 1-1, 1-6, 1-10 and I/-12, which exceeds the background level. The exact amount will vary depending on factors known in the art, but is expected to be a dose of from about 100ng/kg to about 5mg/kg, preferably from about 1mg/kg to about 5mg/kg. The invention also covers a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal, which involves administering to the animal an effective amount of a compound or composition of the invention. An amount effective to treat or inhibit viral infection is an amount that will cause a reduction in one or more manifestations of viral infection such as "" viral damage, viral load, viral production rate and mortality compared to untreated control animals. The exact number will vary depending on known factors

In the art, however, it is expected that the dose is from about 100ng/kg to about 5mg/kg, preferably from about 1mg/kg to about 5mg/kg. An amount of a compound effective in the treatment of a neoplastic condition is an amount that will cause a reduction in the size of the tumor or the number of tumor loci. On the other hand, the exact amount will vary depending on factors known in the art, but it is expected that the dose of 1 will be from about 10 µg/kg to about 5 µg/kg, preferably from about 1 µg/kg to about 50 µg/kg. kg

The invention is also described by the following examples, which are intended for illustration only and are not intended to limit the invention in any way.

Example 1

IM-I(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|benzamide

F) name) 60 b5

Mn, and ana a yam

With Fr

And M

Part A

Triethylamine (16 bg, 123.8 mmol) was added to a suspension of 4-hydroxy-5,6-dimethyl-3-nitro-2(1H)-pyridone (7.6 bg, 41.2 mmol) in dichloromethane (200 Oml).

The resulting mixture was cooled in an ice bath. Trifluoromethanesulfonic anhydride (13.7 ml, 82.0 mmol) was added and the reaction mixture was stirred for 30 minutes. Mono-tert-butoxycarbonyl-1,4-butyldiamine (7.bg, 41.2 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was washed with an aqueous 195 solution of sodium carbonate (2 x 100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure with CO to obtain the crude product. This substance was dissolved in dichloromethane and loaded onto a layer of silica gel.

Silica gel was eluted first with dichloromethane to remove some impurities and then with 2-59060 ethyl acetate in Ge) dichloromethane to obtain the target product. Fractions containing the product were combined and then concentrated under reduced pressure Kk! obtaining 12 g of 4-(4-I(tert-butoxycarbonyl)amino|butyl)amino)-5,6-dimethyl-3-nitropyridin-2-yl trifluoromethanesulfonate in the form of a light yellow oil. and -

Part B

The material from Part A was combined with triethylamine (2.5g, 24.7mmol), dibenzylamine (4.8g, 24.7mmol) and toluene (150ml) and then heated at reflux for 4 hours. The reaction mixture was washed with an aqueous 190% sodium carbonate solution and then concentrated under reduced pressure to obtain the crude product. This product was dissolved in dichloromethane and loaded onto silica gel. Silica gel was eluted with 2-2095 ethyl acetate in -in dichloromethane. Fractions containing the product were combined and then concentrated under reduced pressure to give 13 g of tert-butyl 4-(2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-ylamino)butylcarbamate. :z» Part C

Sodium borohydride (1.4g, Zbmmol) was slowly added to a solution of nickel chloride hydrate (2.9g, 12.3mMmol) in 15% methanol and the resulting mixture was stirred for 30 minutes. A solution of the substance from -1 Part B in methanol was added in one portion. Sodium borohydride was slowly added until the resulting foam became colorless.

The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was combined with dichloromethane and the mixture was filtered to remove salts. The filtrate was concentrated under reduced pressure to obtain 12 g of tert-butyl 4-(3-amino-2-(dibenzylamino)-5,6-dimethylpyridin-4-ylamino)butylcarbamate.

Part (Ce) Valeril chloride (3 mL, 24.7 mmol) was added to a solution of the substance from Part C in acetonitrile (200 mL). "c" The reaction mixture was stirred at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was combined with ethanol and triethylamine (5 g, 49 mmol). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane and water. The dichloromethane layer was separated and then loaded into a silica gel column. The column was eluted with a mixture of 9:90:1 ethyl acetate:dichloromethane:methanol. Fractions containing the product (F) were combined and then concentrated under reduced pressure to obtain 6b.5g of tert-butyl

He 4-(2-butyl-4-(dibenzylamino)-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl|sutilicabamate in the form of oil.

Part E in trifluoromethanesulfonic acid (1 g, 107 mmol) was added to a solution of the substance from Part OO (6.5 g, 11.4 mmol) in dichloromethane (2500 ml). The resulting mixture was stirred overnight. Ammonium hydroxide (5Oml) and water (10Oml) were added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous fraction was extracted with dichloromethane (10 mL). The organic fractions were combined, washed with 195% aqueous sodium carbonate solution, washed with saturated salt solution and concentrated under reduced pressure. The residue in 5 was combined with methanol (3 mL), stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was combined with 196% aqueous sodium carbonate solution and stirred.

The mixture was extracted with hexane to remove organic impurities. The aqueous layer contained an insoluble oil, which was extracted with dichloromethane. The organic layer was combined with magnesium sulfate, stirred for 5 minutes and filtered. The filtrate was concentrated under reduced pressure to obtain a solid substance, which was recrystallized by Kk! toluene Kk! obtaining 1 g of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4-amine.

Part E

Triethylamine (0.07 ml, O.Bmmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4-amine (150 mg, O. bBmmol) in dichloromethane 7/0 5Oml). The reaction mixture was cooled in an ice bath. Benzoyl chloride (0.07 mL, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The obtained residue was purified by flash chromatography, eluting with 1095 methanol in dichloromethane to give a brown oily substance. This substance was dissolved in a minimal amount of isopropanol, and then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring. The reaction mixture /5 was stirred at ambient temperature for 1 hour and then briefly heated in a sand bath until it became homogeneous. The solution was allowed to cool to ambient temperature and then cooled in an ice bath. The resulting precipitate was filtered to obtain 111 mg

IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|(4,5-c|Ipyridin-1-yl)butyl|Ibenzamide) in the form of a crystalline solid, m.p. 127.8-128.820.

Analysis: Calculated for C»zNiziMBO: 90, 70.20; 95Н, 7.94; 90M, 17.80;

Received: 90, 69.82; 90Н, 7.70; 90M, 17.68.

Example 2

IM-(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)ubutyl|Imethanesulfonamide c scha, (o) y x so

M o

IS) « m.

NM. Ka; o3 « shi c Triethylamine (0.07 ml, 0.Bmmol) was added to the solution of "with 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4- amine (150 mg, 0.bMmol) in dichloromethane (160 ml). The reaction mixture was cooled in an ice bath. Methanesulfonic anhydride (9Omg, O0.Bmmol) was added and the reaction mixture was removed from an ice bath. The reaction mixture was stirred for 35 minutes. The reaction mixture was washed three times with water, concentrated under reduced pressure and triturated with a minimum volume of methyl acetate. The obtained solid crystalline substance was separated by filtration and then dried in a drying apparatus. obtaining 94mMg

IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide, m.p. 130-130.59С o Analysis : Calculated for С417НооМ5О»5: 90, 55.56; 9о0Н, 7.95; 90М, 19.06; со 20 Obtained: 90, 55.37; 9оН, 7.89; 90М, 18.03.

Example C c» IM-I(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-4-rfluorobenzenesulfonamide hydrate

F) name) 60 b5

Mn, chh M an a

Etc

WE. -0 o-

Triethylamine (0.07ml, O.Bmmol) was added to a solution of SI 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4-amine (15Omg, O .bBmmol) in dichloromethane o (150 ml). The reaction mixture was cooled in an ice bath. 4-fluorobenzenesulfonyl chloride (113 mg,

O.Bmmol) and the reaction mixture was removed from an ice bath. The reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was washed with water (2 x 15 Oml) and then concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate and dried in an Araegpaidep drying apparatus to obtain 5 mg of Fu hydrate

IM-(4-(4-am)no-2-butyl-6,7-dimethyl-1H-imidazoi|4,5-c|Ipyridin-1-yl)butyl|-4-fluorobenzenesulfonamide In the form of a white solid crystalline substance color, etc. 133.1-133.796. IF)

Analysis: Calculated for So2NzoeMe5O»oseNyo: 90, 56.75; UoN, 6.93; 90M, 15.04; "

received 90, 56.99; 90Н, 6.58; 90M, 15.24.

From Example 4 -

IM-I(I4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M-phenylurea

MN, "

M shi . t nt -

And M

-I sh» 1

NM

(1) uko o im and GU

F) where Phenyl isocyanate (0.05 bml, O.Bmmol) was added to a cooled solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4-amine ( 150 mg, O.bBmmol) in dichloromethane 60 (150 ml). The ice bath was being cleaned. A white precipitate formed after 5 minutes. The reaction mixture was left to stir for 30 minutes and then it was concentrated under reduced pressure to obtain a whitish crystalline substance. This substance was separated by filtration, using a small amount of diethyl ether to transfer the substance to the filter and then dried in an AbBaegaidep drying apparatus to obtain 185 mg of /M-I4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4 ,5-s|Ipyridin-1-yl)butyl|-M-phenylurea, because m.p. 195.8-196.826.

Analysis: Calculated for SozNz»MEO: dos, 67.62; 9о5Н, 7.89; 90M, 20.57;

Received: 90, 66.84; 9оН, 7.71; 90M, 20.54.

Example 5

IM-I(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M-phenylthiourea hydrate

ZM

" aa fa ni M

And yes

GU with (8)

Using the method of Example 4, 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-4-amine (10mg, 0.35mmol) was reacted with phenylisothiocyanate ( 0.041 ml, 0.ZB5 mmol) to obtain 97 mg of hydrate

IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M-phenylthiourea in the form of

From a white crystalline solid, m.p. 160.0-160.820.

Analysis: Calculated for SozNizoMeZenO: 90, 62.41; 9о0Н, 7.74; 90M, 18.99; Me.

Received: 90, 62.39; 9оН, 7.47; 90M, 18.52. i am

Example 6 "

IM-(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M,M-dimethylsulfamide h i -

Y r yana a 2 s M ;" - And oh no. -0 s o s M-.. y syu"

Triethylamine (0.031 ml, 0.233 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine-4-amine (7 mg, 0.233 mmol) in dichloromethane (45 ml). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 ml, 0.233 mmol) was added. The reaction mixture was removed from the ice bath and allowed to stir at ambient temperature (°F) for 113 hours. NRIS analysis showed that the reaction was not complete. The dichloromethane was removed under reduced pressure. 1,2-dichloroethane (50 mL) was added and the reaction the mixture was heated to 602C. After 3 hours, more dimethylsulfamoyl chloride (2.5 μl) was added and heating was continued. After 22 hours, the reaction temperature was raised to boiling and the reaction mixture was boiled for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The obtained residue was recrystallized from methyl acetate to obtain 10 mg

M'-(4-(4-amino-2-butyl-6,7-dimethyl-1H'-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M,M-dimethylsulfamide in the form of a crystalline solid whitish substance, mp 129.5-13TS. M/27 - 397.1 (MAN). 65 Example 7

IM-(4-(4-Amino-2,6,7-trimethyl-1M-imidazo|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide

Mn,

M iOgU- av h i MN oho

Part A

A mixture of 5,6-dimethyl-3-nitropyridine-2,4-diol (60.0 g, 32 mmol) and phosphorus oxychloride (bOOml) was heated at boiling for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was combined with ethyl acetate (300 ml) and then filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to give a brown solid /-CM. This substance was purified by chromatography (silica gel eluting with 60/40 g ethyl acetate/hexane) to give 55 g of 2,4-dichloro-5,6-dimethyl-3-nitropyridine.

Part B tert-Butyl 4-aminobutylcarbamate (bog, 339mmol) was slowly added to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50g, 22bmmol), anhydrous N,M-dimethylformamide (500ml) and triethylamine (5HOml, 339mmol). The reaction mixture was left to stir overnight and then concentrated with He! it under reduced pressure to obtain oil. The oil was dissolved in ethyl acetate and then washed with water.

The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to give a dark oil. This substance was purified by column chromatography (silica gel eluted with 40/60 g ethyl acetate/hexane), obtaining 64.5 g of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butyl carbamate in the form of 3 bright orange oil that solidified on standing. -

Part C

A solution of phenol (18.50g, 19bmmol) in diglyme (5Oml) was slowly added dropwise to a cooled (02) suspension of sodium hydride (8.28g bObo in mineral oil, 207mmol) in diglyme (5Oml). After 1 hour, gas formation stopped. A solution of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butyl carbamate C (68.95 g, 185 mmol) in diglyme (200 ml) was slowly added dropwise to the reaction mixture. After the addition was completed, the reaction mixture was heated to boiling for 4 hours. The reaction mixture was concentrated under reduced pressure to give a dark oil. The oil was dissolved in ethyl acetate and then extracted with 1M sodium hydroxide solution to remove excess phenol. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel eluted with a mixture of 0/70 ethyl acetate/hexane) to obtain 40.67 g of tert-butyl

4-(2,3-dimethyl-5-nitro-b-phenoxypyridin-4-yl)amino|butylcarbamate is an orange oil. Part O tert-Butyl 4-((2,3-dimethyl-5-nitro-b-phenoxypyridin-4-yl)amino)butylcarbamate (9.17g, 21.33mmol), toluene (50ml), isopropanol (5ml) and 5905 platinum on carbon (7.Og) were mixed and the mixture maintained under hydrogen pressure (50 (Ce) 50 times, 33.Bkg/cm?) in a Wright apparatus overnight. The catalyst was removed by filtration and the filtrate was concentrated at reduced The resulting dark oil was dried under high vacuum to obtain 7.47 g of tert-butyl 4-(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino|butyl carbamate.

Part E

A mixture of the product from Part 0, triethyl orthoacetate (3.5 mL, 19.5 v8 mmol), anhydrous toluene (75 mL), and pyridine hydrochloride (0.75 g) was heated at reflux for 1 h and then concentrated under reduced

GF) pressure to obtain a brown oil. The oil was dissolved in ethyl acetate and then washed with water (xg), saturated salt solution, dried over magnesium sulfate and then concentrated under reduced pressure, obtaining 6.74 g of tert-butyl 4-(2,6,7-trimethyl-4-phenoxy-1H- imidazo|4,5-c|Ipyridin-1-yl)butylcarbamate in the form of a brown oil. because Part E

A solution of tert-butyl 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl)butylcarbamate (6.7Og, 15.8mmol) in dichloromethane (5Oml) was slowly added to a cooled (022) mixture of trifluoroacetic acid (bOml) and dichloromethane (100ml). The reaction mixture was allowed to warm to ambient temperature and then left overnight. The reaction mixture was concentrated under reduced pressure to obtain a brown oil 65. The oil was dissolved in dichloromethane and the solution was made alkaline (pH 14) using 595% aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure, obtaining 4.50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl )butylamine in the form of brown oil.

Part O

A mixture of the product from Part E, triethylamine (2.Oml, 14.bmmol) and anhydrous acetonitrile (45Oml) was heated to obtain a homogeneous solution. Methanesulfonic anhydride (2.54 g, 14 mmol) was slowly added to the reaction mixture. The reaction was considered complete after 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain a brown oil. The oil was dissolved in dichloromethane and washed with 595% aqueous 7/0 sodium hydroxide solution. The aqueous layer was separated and then extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to give a brown solid. This product was purified by column chromatography (silica gel eluted with a mixture of 95/5 dichloromethane/methanol), obtaining 4.49 g

IM-I4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|Imethanesulfonamide in the form of a solid 7/5 light brown substance.

Part N

IM-I4-(2,6,7-Trimethyl-4-phenoxy-1H-imidazoi|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide (4.20g, 10.4mmol) and ammonium acetate (42g) ) were combined and then heated in a sealed tube at 1502C for 36 hours. The reaction mixture was allowed to cool and was then dissolved in chloroform. The solution was extracted with 1095% aqueous sodium hydroxide solution. The aqueous layer was separated and then extracted several times in chloroform. The organic layers were combined, dried over magnesium sulfate, and then concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol and combined with a 1M solution of hydrochloric acid in diethyl ether (10.4 ml). The resulting white precipitate was separated by filtration and dried. The solid was dissolved in water and the pH of the solution was adjusted to 10 with solid sodium carbonate. The obtained white precipitate was separated by filtration, washed with diethyl ether and then dried in a vacuum at a temperature of about 802C, obtaining 2.00 g of

IM-(4-(4-amino-2,6,7-trimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide, m.p. 228-23026.

Analysis: Calculated for С4/НозМ5О: 90, 51.67; FoN, 7.12; 90M, 21.52;

Received: 90, 51.48; 9оН, 6.95; 90M, 21.51. Geo)

Example 8

M-(4-(4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl|Ib-butyliumethanesulfonamide F

IS)

We, "t s i -

Hog" - M " - s ;" - more-: 0:5:0 s (se) 50 Part A so Triethylamine (3.3ml, 23.7mmMole) was added to a cooled (02) mixture of tert-butyl 4-(3-amino-5,6-dimethyl- of 2-phenoxypyridin-4-yl)uamino|butylcarbamate (8.60g, 21.5mmol) and anhydrous dichloromethane (200ml). Ethoxyacetyl chloride (2.76 mg, 22.5 mmol) was added. After 1 hour, the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure Kk! by obtaining tert-butyl

HF) 4-(13-Ketoxyacetyl)amino|-5,6-dimethyl-2-phenoxypyridine-4-ilyamino)butylcarbamate in the form of a brown oil. The oil was combined with pyridine (13Oml) and boiled overnight. The reaction mixture was concentrated under reduced pressure to obtain a brown oil. The oil was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure, obtaining 8.21 g of tert-butyl 4-(2-ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo|4,5-s|Ipyridine-1 -il|Ibrsutil carbamate.

Part B

Using the procedure of Part E of Example 7, the material from Part A was hydrolyzed to give 5.76 bg b5 c. y y y 4-(2--ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl|IbSutan-1-amine in the form of a brown oil.

Part C

Using the method of Part o Example 7, 4-(2-ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-ylIbutan-1-amine (5.52g, 15.Ommol) were subjected to the interaction of Kk! with methanesulfonic anhydride (2.74g, 15.7mmol), obtaining 6.26g

M-(4-(2-ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo4,5-c|Ipyridin-1-yl|Is-Sutilymethanesulfonamide as a brown solid.

Part 70 Using the methodology of Part H of Example 7,

M-(4-(2-"-ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo4,5-c|Ipyridin-1-yl|Is-sutiliumethanesulfonamide (5.86 Hg, 13.0 mmol) was aminated to give 1.58 Mr

M-(4-(4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo4,5-c|Ipyridin-1-yl|cSutilymethanesulfonamide) in the form of a white solid, m.p. 165- 16726.

Analysis: Calculated for С456Но7М5Оз3: 90, 52.01; FoN, 7.37; 90M, 18.95;

Obtained: dos, 51.83; 90Н, 7.39; 90М, 18.88.

Example 9

IM-(4-(4-Amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl-4-((2-(dimethylamino)ethoxy|( phenyl)m ethyl|benzamid shchi, .zu shch

M

. co

Fo 4 o a Io)

Y - i - « - s chash i» M sh--. I - I

Part A. In nitrogen atmosphere, 4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl)butan-1-amine (122 mgH, c 0. 33 mmol) was dissolved in dichloromethane and triethylamine (0.093 ml, 0.7 mmol). The solution was cooled in an ice-water bath and 4-(2-(dimethylamino)ethoxy|(phenyl)methyl|benzoyl chloride (1 mg, 0.33 mmol) was dissolved/suspended in dichloromethane and added dropwise. The ice bath was removed and the reaction was stirred for another 16 hours.The reaction was stopped by adding 1095 of an aqueous solution of sodium carbonate.

The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water, followed by washing with a saturated salt solution, dried (Ma»5O), decanted and evaporated, obtaining a yellow oil. Purification by flash column chromatography (silica gel, gradient elution from 92:8 dichloromethane/methanol to 955 dichloromethane/methanol) yielded 101 mg of iF) IM-I(I4-(2-butyl-6,7-dimethyl-4-phenoxy-1H- imidazo|4,5-c|Ipyridin-1-yl)butylI-4-(2-(dimethylamino)ethoxy)(phenyl)methcoylbenzamide as a pale yellow solid. The purity of the product was determined by

NRIS, was 9796. in Me(SI): 648 (M.N).

Part B

I-I(I4-(2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo|4,5-c|Ipyridin-1-yl)butylI-4-(2-(dimethylamino)ethoxy)( phenyl)methylbenzamide (101mg, 0.1bmmol) and ammonium acetate (1.1g) were placed in a pressure tube along which a stirrer was placed. The tube was sealed and heated at 1502 for 16 hours. The reaction mixture was cooled at 65°C to room temperature and diluted with water. the opaque aqueous mixture was basified with 1095 aqueous sodium hydroxide solution and extracted with chloroform (3 x 25 ml). The combined organic fractions were washed with saturated salt solution, dried (Ma 2504), decanted and evaporated to give a yellow oil. Flash purification - column chromatography (silica gel, gradient elution from 95:5 dichloromethane/methanol to 9:1 dichloromethane/methanol and at the end 94:51 / dichloromethane/methanol/triethylamine) obtained 14 mg

M-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl/I-4-((2-(dimethylamino)ethoxy )(phenyl)methyl

Ibenzamide in the form of yellow oil.

TN-NMR (5O00MHz, OM8O-yv) 5 8.41 (t, 9 - 5.5Hz, 1H), 7.76.(d, y - 8.3Hz, 2H); 7.43 (d, y - 8.3, 2H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 71H), 5.84 (shs, 2H), 5.52 (s, 1H), 4.22 (t, 9 - 7.7 HC, 2H), 3.49 (t, U - 70 5.8HC, 2H), 3.29 (dd, U - 6.4,12.4АХц, 2H), 2.76 (t, U - 7.7Хц, 2H), 2.58 (t, U - 5.7Hz, 2H), 2.32 (s, ЗН), 2.27 (s, ЗН), 2.22 (s, 6Н), 1/73-1.65 (m, 4Н), 1.61-1.55 (m, 2Н), 1.35 (sextet , y - 7.4 Hz, 2H), 0.86 (t, y - 7.4 Hz, ZN); 1Z-YAMR (125MHz, OM8O-IV) 5 165.9, 153.0, 148.1, 145,4, 142.0, 138.6, 133.5, 128.23, 127.4, 127.3, 127.1, 126.4, 126.1, 126.5, 54.5. , 43.6, 38.4, 29.3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2.

VRMSO (SI) t/e 571.3763 (MAN), (571.3761 calculated for Cz/НА7Ме6О», M'-Н).

Cytokine induction in human cells

To determine the induction of cytokines, a system of human blood cells, i.p. miigo, was used. Activity is based on the measurement of interferon and tumor necrosis factor (0) (EM and TME, respectively) secreted into the culture medium as described in Tewiegptap ei. AI in "SuKipe ipaisiop Bu She

Ittypotoatsiagz itidcytoyd apa C-27609", doigpai! oi I enkosuie Vioiodu, 58, 365-372 (Zerietrbeg, 1995).

Obtaining a culture of blood cells

All blood was collected by venipuncture into tubes of the EOTA vacuum container from healthy people - blood donors. Peripheral blood mononuclear cells (PBMC) were separated from whole blood by density gradient centrifugation using Nizioradoe?-1077 (Zidta Spetisaiiv, 5. I otsiz, Moscow). PBMCs were suspended to 3-4 x 105 cells/ml in ERMI complete. The PBMC suspension was added to 48-well plates with a flat bottom and with sterile tissue culture (Soziag, Satbrgidde, MA or Vesiop OisKipzop I arzhage, Hypsoip Ragk, MU) containing an equal volume of complete KRMI media containing the test compound .

Preparation of the compound

The compounds were dissolved in dimethyl sulfoxide (DMSO). The concentration of DMSO should not exceed the final concentration of 195 to be added to the culture well. Compounds were usually studied starting with a concentration in the range from 0.12 to 3 µM. Gee!

Incubation

The solution of the compound being tested was added to the first well, which contained complete KRMI, in the amount of bOmK, and a series of 3-fold dilutions was made in o wells. The PCMK suspension was added to the wells in equivalent amounts, "and bringing the concentration of the test compound to the desired level (0.12-30 µM). The final concentration of PBMC suspension is 1.5-2 x 109 cells/ml. The tablets were covered with sterile plastic lids, carefully mixed, and then incubated for 18 to 24 hours at 372C in 595 atmospheres of carbon dioxide.

Separation

After incubation, the plates were centrifuged for 5-10 minutes at 71000 rpm. (5200 x 9) at 426. « 20 The supernatant free from culture cells was isolated with a sterile polypropylene pipette and transferred to sterile polypropylene tubes. Samples were stored at -30 to -702C until analysis. Samples were analyzed for interferon-o and tumor necrosis factor (o) using EP I5A. ;" Analysis of interferon (o) and tumor necrosis factor (o) with the help of EIIZA

The concentration of interferon (o) was determined with the help of EGISA using the Nitap Miiki-Zresiez kit

From RVI Vioteaisai I Aroghaigiev, Mem Vgypem/isK, M). The results were expressed in pg/ml. -I The concentration of tumor necrosis factor (o) (TME) was determined using EGISA kits, which received 1" from Sepgute, Satrbigdde, MA; KO Buzvietv, Mippearoii5, MM; or RIaptipdep, Zap Oivedo, SA. The results were expressed in pg/ml. 1 The table below provides the lowest concentrations at which interferon is induced and the lowest so 50 concentrations at which tumor necrosis factor is induced for each compound. A "" indicates that no induction was detected at the concentrations tested. 65 This invention is described with reference to some of its embodiments. The above detailed description and examples are provided for the purpose of understanding only and should not be construed as limiting it. It will be clear to a person skilled in the art that many changes can be made to the described implementation options without changing the essence and scope of the invention.

Thus, the scope of the invention should not be limited to the specific details of the compositions and structures described herein, but rather may be construed as a form of exposition of the claims set forth below.

Claims (30)

The formula of the invention 1. The compound of formula (I) 70 mn, «(0 mM 5-ya; a: and Kk Kk, x Y--Y- Y, ke where X means alkylene or alkenylene; Y means -CO-, -C5- or -505-; 7 represents a bond, -O-, -5- or -MKv-; Ku represents aryl, heteroaryl, heterocyclyl, C.sub.or-alkyl or C.sub.o-or-alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of ch 3: alkyl; (o) alkenyl; aryl; heteroaryl; heterocyclyl; o ; and substituted cycloalkyl; (22) -O-alkyl; -O-(alkyl)o 1 -aryl; y -O-(alkyl)o 1-heteroaryl; "I -O-(alkyl)o 4-heterocyclyl; soon; y- -bo-O-alkyl; -CO-alkyl; -5(O)0 .»-alkyl; « -5(0)0.5- i - ; du (O)o-2-(alkyl)o-1-aryl; -o -3(O)0.2-(alkyl)o.4-heteroaryl ; c -Z(O)O'-(alkyl)o.4-heterocyclyl; c (alkyl)o-1-M(Kv)2; (alkyl)o 4-MK;-CO-O-alkyl; ( alkyl)o 4-MK;-CO-alkyl; y - (alkyl)o 4-MK;-CO-aryl; (alkyl)o 14-Co-CO-heteroaryl; ve -Mz; sl halogen; haloalkyl; (se ) haloalkoxy; si" -CO-haloalkyl; -CoO-haloalkoxy; -MO"; ra -OH; HF) -ZN; and in the case of alkyl, alkenyl and heterocyclyl, oxo; 7 EC" selected from the group consisting of: hydrogen; in alkyl; alkenyl; alkyl-O-alkyl; alkyl-5-alkyl; alkyl-O-aryl; alkyl-5-aryl; b5 and alkyl-O-alkenyl; alkyl-5-alkenyl and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; halogen; -MZh(Kv)2; -СО-М(Вв)2; -С8-МЩ(Вв)о; -502-Msh(Kv)2; 70 - Mke5-CO-C.4.10-alkyl; -MKe-C5-C4.40-alkyl; -MKe-505-C4.10-alkyl; -b0-S. 1o-alkyl; -6b0-0-S. 1o-alkyl; "M; aryl; heteroaryl; heterocyclyl; -CO-aryl and -CO-heteroaryl; Kz and K; independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each Ke means independently H or C. 4o-alkyl, or their pharmaceutically acceptable salt 2. The compound or salt according to claim 1, in which M means -СО-. 3. A compound or salt according to claim 1, in which У means -CO- and 7 is a bond. (8) 4. The compound or salt according to claim 3, in which Ku. means alkyl, aryl or substituted aryl. 5. The compound or salt according to claim 1, in which M means -C5-. 6. The compound or salt according to claim 1, in which ХМ means -С5-, and 7 means -МКро-. with zo 7. Compound or salt according to point b, in which K5 means H and Ku; means aryl or substituted aryl. 8. The compound or salt according to claim 1, in which M means -505-. Me 9. The compound or salt according to claim 1, in which XM means -505- and 7 is a bond. yu 10. The compound or salt according to claim 9, in which Ku means alkyl, aryl or substituted aryl. 11. The compound or salt according to claim 10, in which Ku; means alkyl. " 12. The compound or salt according to claim 1, in which ХУ means -505-, and 7 means -МКе-. uh- 13. The compound or salt according to claim 12, in which K5 means alkyl and K/ means alkyl. 14. The compound or salt according to claim 1, in which Co is H, alkyl or alkyl-O-alkyl. 15. The compound or salt according to claim 1, in which X means -(СН2)» l-. 16. The compound or salt according to claim 1, in which Kz and K; mean independently H or alkyl. " 17. The compound according to point 1, selected from the group consisting of: c IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridine -1-yl)butyl|benzamide, IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide; » IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)ubutyl|fluorobenzenesulfonamide monohydrate; IM-(4-(4- amino-2-butyl-6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M'-phenylthiourea monohydrate; M'-I(4-(4-amino-2 -butyl-6,7-dimethyl-1H-imidazoi|4,5-c|Ipyridin-1-yl)butyl|-M,M-dimethylsulfamide; -I IM-(4-(4-amino-2-butyl- 6,7-dimethyl-1H-imidazo|4,5-c|Ipyridin-1-yl)butyl|-M'-phenylurea; IM-(4-(4-amino-2,6,7-trimethyl-1H- imidazoi|4,5-c|Ipyridin-1-yl)butyl|methanesulfonamide; and IM-(4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo(|4,5-c| Ipyridin-1-yl)butyl I-4-((2-(dimethylamino)ethoxy|(phenyl)methyl|benzamide and M-(4-(4-amino-2-(ethoxymethyl)-6,7-dimethyl- 1H-imidazo|4,5-c|Ipyridin-1-yl|cSutilymethanesulfonamide; ic or its pharmaceutical preparation exceptional salt 4) 18. A pharmaceutical composition containing a therapeutically effective amount of the compound according to claim 1 in combination with a pharmaceutically acceptable carrier. 19. Pharmaceutical composition according to item 18, which contains a therapeutically effective amount of the compound according to claim 9 in combination with a pharmaceutically acceptable carrier. 20. Pharmaceutical composition according to item 18, which contains a therapeutically effective amount of the compound according to claim 17 F) in combination with a pharmaceutically acceptable carrier. ka 21. The method of inducing the biosynthesis of a cytokine in an animal, which consists in introducing a therapeutically effective amount of the compound according to point 1. 22. The method of inducing cytokine biosynthesis in an animal according to item 21, which consists in administering to the animal a therapeutically effective amount of the compound according to item 9. 23. The method of inducing cytokine biosynthesis in an animal according to item 21, which consists in administering to the animal a therapeutically effective amount of the compound according to item 17. 24. The method of treating a viral disease in an animal, which consists in administering to the animal a therapeutically effective amount of the compound according to point 1. 25. The method of treating a viral disease in an animal according to item 24, which consists in administering to the animal a therapeutically effective amount of the compound according to item 9. 26. The method of treating a viral disease in an animal according to item 24, which consists in administering to the animal a therapeutically effective amount of the compound according to item 17. 27. The method of treating a neoplastic disease in an animal, which consists in administering to the animal a therapeutically effective amount of the compound according to point 1. 28. The method of treating a neoplastic disease in an animal according to item 27, which consists in administering to the animal a therapeutically effective amount of the compound according to item 9. 29. The method of treating a neoplastic disease in an animal according to item 27, which consists in administering to the animal a therapeutically effective amount of the compound according to item 17. 30. Compound of formula (II): many "I m ik | r У- 5 MI KZ I Kk Kk, х р i-y in which: X means alkylene or alkenylene; EC" is selected from the group consisting of: hydrogen; NI with alkyl; In alkenyl; o alkyl-O-alkyl; alkyl-5-alkyl; alkyl-O-aryl; alkyl-5-aryl co; , and alkyl-O-alkenyl; (22) alkyl-5-alkenyl and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; "halogen; In them -MZh(Kv)2; -CO-MSH(Kv)2; -С5-ШЧКв)"; -802-MSH(Ve)2; «-МКе5-СО-С. 40o-alkyl; 5 1-10 and U shsh c -MKe-C5-C4.40-alkyl; -MKe-505-C4.10-alkyl; :z» -SO-S. 10-alkyl; -00-0-C.4 1o-alkyl; -M; C - I aryl, heteroaryl; ve heterocyclyl; c -CO-aryl and -CO-heteroaryl; (se) Kz and K independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, Z A "co alkylamino, dialkylamino and alkylthio; and every Ke; means independently H or C. .4o-alkyl; or a pharmaceutically acceptable salt thereof. name) 60 b5