UA73504C2 - Imidazoquinolines substituted by urea - Google Patents

Abstract

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain urea, thiourea, acylurea, or sulfonylurea 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 me treatment of a variety of conditions including viral diseases and neoplasric diseases.

Description

Description of the invention

This invention relates to imidazoquinoline compounds having a substituent in the 1-position which contains a urea, thiourea, acylurea or sulfonylurea residue 2, to pharmaceutical compositions containing such compounds, and to pharmaceutical compositions comprising imidazoquinoline compounds having a carbamate residue in the 1 - provisions The invention also relates to the use of these compounds as immunomodulators, to induce cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases. 70 The first reliable publication on the 1H-imidazo|4,5-c|Yquinoline cyclic system, VasKtap ei ai.,

U.Ogad.Spet. 15, 1278-1284 (1950), describes the synthesis of 1-(b-methoxy-8-quinolinyl)-2-methyl-1H-imidazo|4,5-c|quinoline for possible use as an antimalarial agent. Then it was about the synthesis of various substituted 1Zhmidazoi|4,5-s|quinolines. For example, aip ei ai., 9U.Mei.Spet. 11, pp. 87-92 (1968), synthesized the compound 1-(2-«(4-piperidyl)ethyl|-1H-imidazo|4,5-c|quinoline as a possible anticonvulsant and cardiovascular 75 agent, also by Vagap et al., Spect. Arv. 85, 94362 (1976), reported several 2-oxoimidazo|4,5-c|quinolines, and Vegepuy et al. reported certain 2-oxoimidazo|4,5-c)quinolines.

Later, some 1H-imidazo|4,5-c|quinolin-4-amines and their 1- and 2-substituted derivatives were found to be useful as antiviral agents, bronchodilators, and immunomodulators. It is recorded in, ipieg aa, patents

United States MoMo4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,258,376; 5,346,905; and 5,389,640, which are incorporated herein by reference.

Interest in the imidazoquinoline cyclic system does not disappear. For example, EP 894 797 describes imidazoquinoline derivatives bearing a substituent containing an amide group in the 1-position. The description of this patent states that the active compounds of this series require a terminal amino substituent that can be introduced into the heterocyclic ring. As another example, MUO 00/09506 describes imidazopyridine and (3) imidazoquinoline derivatives that can have a substituent that contains an amide or urea, in the 1-position. Compounds described in this publication that are useful contain a 1-substituent in which the amide or urea nitrogen is part of the heterocyclic ring. Despite efforts to identify compounds that are useful as immune response modifiers, there the need for compounds that have the ability to modulate the immune response by inducing Z cytokine biosynthesis or by another mechanism.

We have discovered compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, the invention relates to imidazoquinoline and tetraimidazoquinoline compounds of the formula (1):

Mn () m i - her I U-yiv

Without M

With " in - p. 49) ;" " in which Ku, K»| and K have the following values. The invention also relates to pharmaceutical compositions containing compounds of the formula (Ia), the compounds of which have the same general structural formula as the above-mentioned compounds (Y). -i Compounds of formulas (I) and (Ia); are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and thereby modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that respond on changes 1 in the immune response. o 50 The invention also relates to pharmaceutical compositions that contain a therapeutically effective amount of a compound of formula (I) or (Ia), methods of inducing cytokine biosynthesis in an animal, treatment of viral infections in an animal's brain, and/or treatment of neoplastic diseases in animals by introducing a compound of formula (I) or (Ia) to an animal.

In addition, methods of synthesizing compounds of the present invention and intermediates useful in the synthesis

These compounds are also included in the present invention.

As previously stated, we have discovered that certain compounds induce cytokine biosynthesis in animals. Such compounds are represented by the following formulas (I) and (Ia). The invention relates to compounds of formula (1): име) 60 b5

Mn () 2nd M

I | University of Western M

I

Ka 9) in which

Ku is -alkyl-MK5-SU-MK 5-X-K. or -alkenyl-MKa-СХ-МК 5-Х- Ku, where

In is BO or -C;

X is a -CO- or -505- bond;

K. is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: -alkyl; - alkenyl; - aryl; -heteroaryl; -heterocyclyl; - substituted aryl; -substituted heteroaryl; - substituted heterocyclyl; He -O-alkyl; o -O-(alkyl)o 4-aryl; -O-(alkyl)o.4-substituted aryl; -O-(alkyl)o 4-heteroaryl; -O-(alkyl)o 4-substituted heteroaryl; "And -O-(alkyl)o 4-heterocyclyl; o -O-(alkyl)o 4-substituted heterocyclyl; -bsoon; iv) -CoO-O-alkyl; -CO-alkyl; o -5(O)O-alkyl; - -5(0)0-2-(alkyl)o--aryl; -5(O)0.2-(alkyl)o 4-substituted aryl; -Z(O)O.o-(alkyl)o -heteroaryl; "-5(O)0.2-(alkyl)o 4-substituted heteroaryl; -Z(O)0.2-(alkyl)o -heterocyclyl; - c -5(O)0.2-(alkyl)o 4-substituted heterocyclyl; . "alkyl)o-4-MEzKz; is" -(alkyl)o.4-MKa3-CO-O-alkyl; -(alkyl)o.4-MKz-CO-alkyl; -(alkyl)o-4-MKz-CoO-alkyl; - and -(alkyl)o.4-MK3-CO-substituted aryl; syu -(alkyl)o.4-MKa-CO-heteroaryl; -(alkyl)o.4-MK3-CO-substituted heteroaryl; about -Mz; o 50 -talogen; -haloalkyl; iz" - haloalkoxy; -CoO-halo-alkoxy; -MO"; -SM; o -OH; and -VZN; and in the case of alkyl, alkenyl, or heterocyclyl, oxo; ko under the condition that if X is a bond, Ki. may additionally be hydrogen;

E" is selected from the group consisting of: 60 - hydrogen; -alkyl; - alkenyl; - aryl; - substituted aryl; 65 -heteroaryl; -substituted heteroaryl;

-alkyl-O-alkyl; -alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; - halogen; -MZh (Kz)"; -EO-M (Vz)"; -b0-S. 4o alkyl; 70 -60-0-С. 4o alkyl; -Ma; - aryl; - substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; - substituted heterocyclyl; -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); each Kz is independently selected from the group consisting of hydrogen and C.4.4o alkyl;

K5 is selected from the group consisting of hydrogen and C 4-40 alkyl, or K, and K5 together form a 3- to 7-membered heterocyclic or substituted heterocyclic ring; c n is from 0 to 4, and each K present is independently selected from the group consisting of C 4-40 alkyl, C 1-40 alkoxy, halogen, and trifluoromethyl, or a pharmaceutically acceptable salt thereof. and)

The invention also relates to pharmaceutical compositions that contain a therapeutically effective amount of the compound of formula (IV): | Mn (in) z y o kana o to z:

Kk and -

Ka aa) in which ch

Ku is -alkyl-MK5-CO-0O-K. or -alkenyl-МК53-СО-О-К,; o, c K. is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted "" or substituted by one or more substituents selected from the group consisting of: "-alkyl; - alkenyl; - aryl; and -heteroaryl; c -heterocyclyl; - substituted aryl; o -substituted heteroaryl; o 20-substituted heterocyclyl; -O-alkyl; iz» -O-(alkyl)o 1-aryl; -O-(alkyl)o.4-substituted aryl; -O-(alkyl)o 4-heteroaryl; oo -O-(alkyl)o 1-substituted heteroaryl; o -O-(alkyl)o 4-heterocyclyl; -O-(alkyl)o of 4-substituted heterocyclyl; o - soon; -CoO-O-alkyl; 60 -CO-alkyl; -5(O)O-alkyl; -5(0)0-2-(alkyl)o--aryl; -5(O)0.2-(alkyl)o 4-substituted aryl; -Z(O)O.o-(alkyl)o -heteroaryl; b5 -5(O)0.2-(alkyl)o 4-substituted heteroaryl; -5(O)O2-(alkyl)o 4-heterocyclyl;

-5(O)0.2-(alkyl)o 4-substituted heterocyclyl; -(alkyl)o.4-MKzKz; -(alkyl)o.4-MK3-CO-O-alkyl; -(alkyl)o.4-MKa-CO-alkyl; -(alkyl)o.4-MK3-CO-aryl; -(alkyl)o.4-MK3-CO-substituted aryl; -(alkyl)o.4-MKa-CO-heteroaryl; -(alkyl)o.4-MK3-CO-substituted heteroaryl; 70 "Mz; -halogen; -haloalkyl; -haloalkyl; -CoO-haloalkyl; -MO"; -CM; -OH; and -BZN; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;

E" is selected from the group consisting of: - hydrogen; -alkyl; - alkenyl; - aryl; - substituted aryl; c -heteroaryl; -substituted heteroaryl; i) -alkyl-O-alkyl; -alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: "E zo -OH; - halogen; about -MZh (Kz)"; yuyu -EO-M(Vz)"; -b0-S. 4o alkyl; at -60-0-C. 4o alkyl; i- -Mz; - aryl; - substituted aryl; -heteroaryl; « -substituted heteroaryl; in c -heterocyclyl; - substituted heterocyclyl; ;" -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -I -CO-(substituted heteroaryl); each Kz is independently selected from the group consisting of hydrogen and C.4.4o alkyl; and n is from 0 to 4, and each K present is independently selected from the group consisting of C 4-40 alkyl, C 1-40 c alkoxy, halogen, and trifluoromethyl, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective carrier. o Preparation of compounds i» Imidazoquinolines according to the present invention can be obtained according to the Reaction Scheme I dec, K,»ip have the above values.

In step (1) of Reaction Scheme I, 4-chloro-3-nitroquinoline of formula II reacts with an amine of formula K.MH", where Ki dv has the above value, with the production of 3-nitroquinoline-4-amine of formula II. The reaction can be carried out by adding an amine to a solution of a compound of formula I in a suitable solvent, such as chloroform or (F) dichloromethane, and optionally by heating. Many of the quinolines of formula II are known compounds (see, for example, United States Patent 4,689,338 and references therein).

In stage (2) Schemes of the reaction ! Z-nitroquinoline-4-amine of formula I was reduced to obtain bo/Quinoline-3,4-diamine of formula IM. Preferably, the reduction is carried out using a known heterogeneous hydrogenation catalyst, such as platinum on carbon or palladium on carbon. The reaction is conveniently carried out on a Parr apparatus in a suitable solvent such as isopropyl alcohol or toluene.

In step (3) of Reaction Scheme I, quinoline-3,4-diamine of the formula IM reacts with a carboxylic acid or its equivalent to obtain 1H-imidazo|4,5-c|yquinoline of the formula M. Suitable equivalents of the carboxylic acid b5 include halide anhydrides acids, orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or its equivalent is chosen so as to provide the desired K" substituent in the compound of formula M.

For example, using triethyl orthoformate, we get a compound where Co is hydrogen, and using triethyl orthoacetate, we get a compound where Co is methyl. The reaction can take place in the absence of a solvent, or in an inert solvent such as toluene. The reaction takes place with sufficient heating to remove the alcohol or water formed as by-products of the reaction.

In step (4) of the Scheme of the reaction !/ 1H-imidazo|4,5-cYquinoline of the formula M was oxidized to obtain 1nH-imidazo|4,5-c|quinoline-2M-oxide of the formula MI, using a known oxidizing agent that is capable of forming M -oxides. Preferred conditions for the reaction involve the reaction of a solution of the compound of formula M in chloroform with 3-chloroperoxybenzoic acid under ambient conditions. 70 In stage (5) Schemes of the reaction | 1H-imidazo|4,5-c|quinoline-6M-oxide of formula MI was aminated to obtain 1H-imidazo|4,5-c-quinoline-4-amine of formula MII, which is a subspecies of formula I. Step (5) includes (i) reaction of a compound of formula MI with an acylating agent, and then (ii) reaction of the product with an aminating agent. Part (i) of step (5) involves the reaction of the M-oxide of the formula MI with an adilating agent. Acceptable acylating agents include alkyl or arylsulfonyl chlorides (eg, benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl 7/5 Chloride). Arylsulfonyl chlorides are preferred. The most preferred are para-toluenesulfonyl chlorides.

Part (ii) of step (5) involves the reaction of the product of part (ii) with an excess of aminating agent. Suitable aminating agents include ammonia (eg, in the form of ammonium hydroxide) and ammonium salts (eg, ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is most preferred. The reaction mainly takes place by dissolving the M-oxide of the formula M! in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then slowly adding the acylating agent. The product or its pharmaceutically acceptable salt can be isolated using known techniques.

Alternatively, step (5) can proceed by (i) reaction of M-oxide of formula MI with isocyanate and then (ii) hydrolysis of the resulting product. Part (iii) involves the reaction of the M-oxide with an isocyanate in which the isocyanato group is attached to the carbonyl group. Preferred isocyanates include trichloroacetyl isocyanate and aroyl isocyanate, such as benzoyl isocyanate. The reaction of isocyanate with M-oxide generally takes place in an anhydrous environment by adding isocyanate to a solution of M-oxide in an inert solvent such as chloroform or i) dichloromethane. Part (its) includes the hydrolysis of the product from part (ii). Hydrolysis can be carried out by known methods, such as heating in the presence of water. or a lower alcohol, optionally in the presence of a catalyst such as an alkali metal hydroxide or a lower alkoxide. "IS

The scheme of the reaction o we MO, measures MO, m kh MH, oyu

I ry not Y I o Y - in A Shchi i "i M -. ! (z)

Mn, Y « ng v, -- ru uv, Z s -k (0) avu! (c) and t. in V p V v i, i?

M and m U

Compounds according to the present invention in which the K substituent contains urea or thiourea can be obtained -I according to Reaction Scheme II, where K, Co, K and n have the above values, Y is O or 5, and t is an integer from 1 to 20. o In reaction Scheme II, the aminoalkyl-substituted 1H-imidazo|4,5-cquinolin-4-amine of the formula MI reacts with isocyanate or thioisocyanate of the formula X to obtain the compound of the formula X, which is a subspecies of the formula |.

The reaction can be carried out by adding a solution of the (thio)isocyanate in a suitable solvent, such as dichloromethane, to a solution of the compound of formula Mi, optionally at reduced temperature. Many of the 1H-imidazo|4,5-c|quinoline-4-amines of formula MI are known compounds (see, for example, United States Patent 6,069,149 (Mapra)); others can be easily obtained using known methods of synthesis. Many isocyanates and thioisocyanates of formula IX are commercially available; others can be easily obtained using known methods of synthesis. The product or its pharmaceutically acceptable salt can be isolated using known techniques.

HF) Scheme of the reaction I ime) Mn, mn, ist m y ! And Mole to Vichesv -- ! ri vd pe nov wa nat we their x krah nm 65 V,

Compounds according to the present invention, in which CC. substitute contains urea, can be obtained according to

Schemes of reaction Ii, where K, Ko, Ku, Kb and n have the above values, and t is an integer from 1 to 20.

In Reaction Scheme I, aminoalkyl-substituted 1H-imidazo|4,5-s|quinolin-4-amine of the formula MI reacts

with a carbamoyl chloride of formula XI to give a compound of formula XI, which is a subspecies of formula I. The reaction can be carried out by adding a solution of carbamoyl chloride in a suitable solvent, such as pyridine, to a solution of a compound of formula MI at ambient temperature. Some carbamoyl chlorides of the formula

CIs are commercially available; others can be easily obtained using known methods of synthesis. The product or its pharmaceutically acceptable salt can be isolated using known techniques. 70 PI reaction scheme

Mn, k o mn,

The same

I A "y . vykta--ya ! r. v y 75. ya (ryu t ya na t

M mi 7 hi hi poro i

IN,

Compounds according to the present invention, in which the K./ substituent contains a carbamate, can be obtained according to

Schemes of the IM reaction, where K, Ko, Ka, p and t have the above values.

In Reaction Scheme IM, the aminoalkyl-substituted 1H-imidazo|4,5-siquinolin-4-amine of formula MIII reacts with chloroformate of formula XIII to obtain a compound of formula XIM, which is a subspecies of formula Ia. The reaction can be carried out by adding a solution of chloroformate in a suitable solvent, such as dichloromethane or c pyridine, to a solution of the compound of formula MI, optionally at reduced temperature. Many chloroformates of formula XII are commercially available; others can be easily obtained using known methods of synthesis.

The product or its pharmaceutically acceptable salt can be isolated using known techniques.

Scheme of MI reaction

Mn. With | and mine her m o

Y vd J drlogste--k I Vi vd, yu

Wa (not yap not so

Book

M! and Khim p ugo M o i

I

Compounds according to the present invention, where the Ki substituent contains an acylurea, can be obtained according to " du Scheme of the reaction U, where K, K", K., p and t have the above values. with

In Reaction Scheme M, the aminoalkyl-substituted 1H-imidazo|4,5-c|quinolin-4-amine of the formula MI reacts with the acyl isocyanate of the formula XM to obtain the compound of the formula XMI, which is a subspecies of the formula I. The reaction can be carried out by adding of a solution of an acyl isocyanate in a suitable solvent such as dichloromethane to a solution of a compound of formula MI at reduced temperature. Some acyl isocyanates of formula XM are commercially available; others can be easily obtained using known methods of synthesis. The product or its -1 15 pharmaceutically acceptable salt can be isolated using known methods.

Reaction scheme M (95) 1 Her" M o Her:

With o Yi is "y y vyb nnsvo -- Ua, s ih im y; iz

Mn, NM

In HUH HM! eye

Chun in; (F) Compounds according to the present invention, where the Ki substituent contains a sulfonylurea, can be obtained according to the MI reaction scheme, where K, K", K., p and t have the above values.

In the Scheme of the reaction MI substituted by aminoalkyl 1H-imidazo|4,5-cIquinolin-4-amine of the formula MIII reacts with sulfonyl isocyanate of the formula HMIII to obtain a compound of the formula XM, which is a subspecies of the formula I. The reaction can be carried out by adding a solution of the sulfonyl isocyanate in a suitable solvent, such as dichloromethane, to a solution of a compound of formula MI, optionally at reduced temperature. Some sulfonyl isocyanates of the formula CHMII! are commercially available; others can be easily obtained using known methods of synthesis. The product or its pharmaceutically acceptable salt can be isolated using known techniques.

MI reaction scheme

Mn, mn, my oh)

Di "ai i v u nnogo ir rba v (sna -5 niyu we hu NM go

HM scha and v

Tetrahydroimidazoquinolines according to the present invention can be obtained according to the MIA reaction scheme, where Co,

R», Ku, K», X, U Her t have the above values.

In stage (1) of the Scheme of reaction MI! aminoalkyl-substituted 1H-imidazo|4,5-c|quinolin-4-amine of formula XX was reduced to obtain aminoalkyl-substituted 6,7,8,9-tetrahydro-1H-imidazo|4,5-c)quinoline-4-amine of formula XX. Preferably, the reduction was carried out by suspending or dissolving the compound of formula XIX in trifluoroacetic acid, adding a catalytic amount of platinum oxide (PI), then the mixture was subjected to hydrogenation in the presence of hydrogen. The reaction is conveniently carried out on a Parr apparatus. The product or its salt can be isolated using known techniques.

Step (2) Schemes of reaction MII can be carried out using the methods described in Schemes of reactions II, PI, M, M and MI to obtain a compound of formula XXI, which is a subspecies of formula I.

MI reaction scheme

Mn, Mn,

M» M Hez M ml M, Ge

I s» KD tru WHAT vd i o ! (Sn) t (dna t (a t

Mn, Mn, neo xih xx XXI M.

ВХ - I, oh

Tetrahydroimidazoquinolines according to the present invention can be obtained according to the MI reaction scheme, where

E, B", KU, Ka, K", X, U, p and t have the above values. Shit,

In stage (1) of the Scheme of reaction MI! 6,7,8,9-tetrahydro-1H-imidazo|4,5-quinolinyl. tert-butylcarbamate of formula p

XXI! hydrolyzed to obtain aminoalkyl-substituted 6,7,8,9-tetrahydro-1H-imidazo|4,5-c)quinoline-4-amine 32 of formula XXI. The reaction can be carried out by dissolving the compound of formula XXI! in a mixture of trifluoroacetic acid and acetonitrile, stirring at ambient temperature. Alternatively, the compound of formula XXI can be combined with dilute hydrochloric acid and heated on a steam bath.

Tetrahydro-1H-imidazo|4,5-siquinolinyl tert-butylcarbamates of formula XXI! can be obtained using the method of synthesis described in United States Patent 5,352,784 (Mikoiaidev). The product or its salt can be isolated using known techniques. From c Step (2) Schemes of the reaction of MI can be carried out using the methods described in the Schemes of reactions of Ii, PP, M, "» M iMI with obtaining a compound of the formula XX/IM, which is a subspecies of the formula |. " Scheme of the reaction of MI 15 and Te m и и- в чн, н " - Fdnatya raki he s ve not la not o (no "sl xx pro xx still XhiM iv 9 vyh («v) kt "vi chz" Some compounds of the formula | can be easily obtained from other compounds of the formula I. For example, compounds in which the K 4 substituent contains a chloroalkyl group can react with an amine to give K; a substituent substituted by a secondary or tertiary amino group; compounds in which the K 4 substituent contains a nitro group can

Restore to obtain a compound in which Ku. the substituent contains a primary amine.

As used herein, the terms "alkyl," "alkenyl," "alkynyl," and the prefix "-alk7" include both straight-chain and branched-chain cyclic groups, i.e., cycloalkyl and cycloalkenyl. Unless otherwise indicated, these groups range from 1 to 20 carbon atoms, with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms. Groups generally having more than 10 carbon atoms are preferred. Cyclic groups 60 can be monocyclic or polycyclic, and preferably have from 3 to 10 carbon atoms in the ring .

Examples of cyclic groups are cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.

The term "haloalkyl" includes groups substituted with one or more halogen atoms, including groups in which all of the hydrogen atoms present are substituted with halogen atoms. This applies to groups containing the prefix "haloalk-".

Examples of haloalkyl groups are chloromethyl, trifluoromethyl, etc. 65 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 that contain at least one ring heteroatom (eg, O, 5, M).

Acceptable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, tetrazolyl, imidazo, pyrazolo, oxazolo, thiazolo, and the like. "Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring heteroatom (eg, O, 5, M). Examples of heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, and imidazolidinyl.

Unless otherwise indicated, the terms "substituted aryl", "substituted heteroaryl" and "substituted heterocyclyl" mean that the rings or ring systems contemplated are substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloalkylcarbonyl, halomethoxy (e.g., trifluoromethoxy), nitro, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, alkylxycarbonyl, alkanoyloxy, alkanoylthio and, in the case of heterocyclyl, oxo.

In the structural formulas representing the compounds of the present invention, some bonds are indicated by dashed lines. These lines mean that the connections represented by these lines may or may not be present. Accordingly, the compounds of the present invention may be either imidazoquinoline derivatives or tetrahydroimidazoquinoline derivatives.

The invention also includes the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.

Pharmaceutical compositions and biological activity

Pharmaceutical compositions according to the present invention contain a therapeutically effective amount of a compound according to the present invention in combination with a pharmaceutically acceptable carrier.

The term "therapeutically effective amount" means an amount of a compound sufficient to produce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition according to the present invention will vary due to factors known to those skilled in the art, such as the physical and chemical nature of the compound, as well as the nature of the carrier i) and the acceptable dosage interval, it is contemplated that compositions of the present invention will contain a sufficiently active ingredient to yield a dose of from about 100ng/kg to about 5mg/kg, preferably from about 1mg/kg to about 5mg/kg of the compound. Any known dosage form may be used, such as tablets, pills, parenteral compositions, syrups, creams, ointments, aerosol compositions, transdermal patches, transmucosal patches, and the like. at

The compounds of the present invention may be administered as independent therapeutic agents in treatment, or the compounds of the present invention may be administered in combination with each other or with other active agents, including additional immune response modifiers, antiviral agents, antibiotics, etc. . and)

Compounds according to the present invention have shown the ability to induce the production of certain cytokines during the experiments carried out in accordance with the following tests. These results indicate that the compounds are useful as immune response modifiers that can modify the immune response in a variety of ways and are useful in the treatment of various disorders.

Cytokines, the production of which can be induced by the appointment of a compound according to the present invention, generally "

These include interferon (IM) and or tumor necrosis factor-A (TME-A), as well as certain interleukins (I). Cytokines, the biosynthesis of which can be induced by compounds according to the present invention, include IEM-A, TMP-A, 1Y-1, 6, 10 and 12, and other cytokines. Among other actions, cytokines inhibit virus production and tumor cell growth, which ;" makes the compounds useful in the treatment of tumors and viral diseases.

In addition to the ability to induce cytokine production, the compounds of the present invention affect other aspects of the natural immune response. For example, natural killer cell activity can be stimulated, and this effect can be induced by cytokine induction. The compounds can also activate macrophages, which, in turn, simulate the secretion of nitric oxide and the production of additional cytokines. In addition, the compounds can induce proliferation and differentiation of B-lymphocytes. c The compounds of the present invention also have an effect on the acquired immune response. For example, although there is no direct effect on T cells or direct induction of T cell cytokines, the production of T helper type 1 o (ТР) cytokine IEM-H is indirectly induced and the production of T helper type 2 (ТН2) cytokines II -4, 1-5 and и" I/--13 is inhibited after compound administration. This means that the compounds are useful in the treatment of diseases in which an increase in the intensity of the TA1 reaction and/or a decrease in the intensity of the TA2 reaction is desired. Due to the ability of the compounds of formula Ia to inhibit the Tp2 immune response, it is assumed that the compounds are effective in the treatment of conditions caused by excessive stimulation of the Tp2 reaction, such as atopic diseases, for example, atopic dermatitis, asthma, allergies, allergic rhinitis; systemic lupus erythematosus; as a vaccine adjuvant for

F) cell-mediated immunity; and possibly for the treatment of recurrent fungal diseases and chlamydia. ka The action of the compounds, which results in modification of the immune response, makes the compounds useful in the treatment of a wide range of conditions. Because of their ability to induce the production of cytokines such as IREM-A and/or TMP-A, the compounds are particularly useful in the treatment of viral diseases and tumors. The immunomodulatory action suggests that the compounds of the present invention are useful in the treatment of diseases such as, but not limited to, viral diseases including apical warts; ordinary warts; plantar wart; hepatitis B; hepatitis C; herpes simplex virus I and II types; molluscum contagiosum; OX; CMV; BBB (chicken pox virus); intraepithelial neoplasia, such as cervical intraepithelial neoplasia; Human papillomavirus 65 (HPV) and caused neoplasias; fungal diseases, for example Sapaida, Azregoiv and cryptococcal meningitis; non-plastic diseases, for example, basal cell carcinoma, leukemic reticuloendotheliosis,

Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma and other malignant tumors; parasitic diseases, such as Rpeshitosuvziev sagpi, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, such as tuberculosis and Musorasiegisht amisht. Additional diseases or conditions that may be treated using the compounds of the present invention include eczema; eosinophilia; essential thrombocythemia; leprosy; multiple sclerosis; Omen syndrome; discoid lupus; Bowen's disease; bowenoid papulosis; and to accelerate or stimulate wound healing, including chronic wounds. Accordingly, the invention relates to a method of inducing cytokine biosynthesis in an animal, which comprises administering to an animal an effective amount of a compound or composition according to the invention.

Accordingly, the invention relates to a method of inducing cytokine biosynthesis in animals, which comprises administering an effective amount of a compound of formula Ia to an animal. An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or two types of cells, such as monocytes, macrophages, dendritic cells, and B cells, to produce a certain amount of one or more cytokines, such as, for example, IRM-A, TMRE-A, 1-1, 6, 10 and 12, the number of which is increased compared to the usual level of these cytokines. The exact amount will vary depending on factors known to those skilled in the art, but a dose of from about 100ng/kg to about B50mg/kg, preferably from about 10ng/kg to about

Bmg/kg. The invention also relates to a method of treating a viral infection in animals, which comprises administering an effective amount of a compound of formula Ia to an animal. An amount effective to treat or inhibit a viral infection is an amount that causes a reduction in one or more of the markers of viral infection, such as viral foci, viral load, viral production rate, and animal mortality compared to untreated control animals. The exact amount will vary due to factors known to those skilled in the art, but a dose of from about 1OOng/kg to about B5Omg/kg, preferably from about 10mcg/kg to about Bmg/kg, is contemplated. An amount of a compound effective in the treatment of neoplastic conditions is an amount that will cause a reduction in the size of a tumor or in a given number of tumor cells. Again, the exact amount will vary due to factors known to those skilled in the art, but a dose ranging from about 10Omg/kg to about i)

Bomg/kg, preferably about 10 mg/kg to about 5 mg/kg.

The invention is further described by examples, which serve as illustrations and do not limit the invention in any way.

Example 1 "g from Tret-Butyl. M-(2-(4-Amino-1H-imidazo|4,5-c|quinolin-1-yl)ethylcarbamate

Mn, oh magicians, you

IN;

M so - er and - o

Part A

Triethylamine (66.8 g, 0.3 mol) was added to a solution of tert-butyl M-(2-aminoethyl)carbamate (55.0 g, 0.34 mol) in anhydrous dichloromethane (50 mol). 4-Chloro-3-nitroquinoline (68.2 g, 0.3 mol) was slowly added and the reaction with c proceeded exothermicly. The reaction mixture was allowed to stir at ambient temperature overnight. The resulting precipitate was isolated by filtration to obtain a product in the form of yellow solid. The filtrate was washed with water, dried over magnesium sulfate and then concentrated in vacuo. The resulting residue was suspended in hexane and filtered to obtain an additional product as a yellow solid. The two outputs were combined to obtain 101 g of tert-butyl -I I-(2-(3-nitroquinolin-4-yl)u'aminoethyl|carbamate in the form of a yellow solid, melting point 157-158. o Part B "sl Platinum on coal (g, 1090) and sodium sulfate (2g) were added to the suspension of tert-butyl

IM-(2-(3-nitroquinolin-4-yl)uaminoethylcarbamate (100g, 00.00mol) in toluene (5000ml). The mixture was placed in a hydrogen atmosphere at 5oOpsi (3.4x107 pascal) on a Parr apparatus at ambient temperature at

People's night The reaction mixture was filtered. The filtrate was concentrated to obtain 7g of tert-butyl

I-(2-(3Z-aminoquinolin-4-yl)luaminoethylcarbamate) in the form of a dark golden oil.

Part C

Triethyl orthoformate (11.3 g, 73.AmMmmol) was added to a solution of tert-butyl

I-(2-(3Z-aminoquinolin-4-ylluaminoethylcarbamate) (21g, 69.4mmol) in anhydrous toluene solution (250ml).

F, The reaction mixture was heated at reflux for 5 hours and then allowed to cool slowly to ambient temperature. The obtained precipitate was isolated by filtration and dried to obtain 17.b6g of tert-butyl /M-(2-(1H-imidazo|4,5-c|quinolin-1-yl)ethyl|carbamate in the form of a light yellow-brown solid substance , melting point 154-15520.

Part

C-Chloroperoxybenzoic acid (17.4g, 60.bmol) was added in small portions to a solution of tert-butyl

IM-(2-(1H-imidazo|4,5-c)quinolin-1-yl)ethylcarbamate (17.2g, 55.1mmol) in chloroform (250ml). The reaction mixture was maintained at ambient temperature overnight and then quenched with 595% sodium carbonate solution 65%. The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated in vacuo to obtain 15.0 g of 1-(2-(tert-butylcarbamyl)ethyl|-1H-imidazo|(4,5-s|quinoline-OM-oxide in the form of a not quite white solid substances, melting point 213-21596.

Part E

Trichloroacetyl isocyanate (9.5g, 50.2mmol) was slowly added to a stirred solution of 1-(2-(tert-butylcarbamyl)ethyl)|-1H-imidazo|4,5-c|quinoline-5M-oxide (15.0g, 45.7mmol) in chloroform (200 ml).

After 2 hours, the reaction mixture was quenched with concentrated ammonium hydroxide (10 Oml). Water (10 Oml) was added and the layers were separated. The aqueous layer was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate, and then concentrated in vacuo to give a white solid. This material was suspended in warm methyl acetate and then filtered to give 15 g of tert-butyl 70... M-(2-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)ethyl|carbamate in the form white solid, melting point 21520. "H NMR (500 MHz, OM5O-yv) 5 8.13 (t, J-8.OHc, 1H), 8.03 (s, 1H), 7.61 (d, J-8.OHc, 1H ), 7.44 (t, J-8.OGC, 1), 7.23 (t, J-8.0Hz, 1), 7.06 (t, J-b.OGC, 71H), 6.56 (wide c, 2H), 4.63 ( t

J-7.OGts, 2H), 3.43 (sq, J-b.OGts, 2H), 1.32 (s, 9H); M5 (EI) m/e 327.1696 (327.1695 calculated for С47Н24М5О»).

Example 2

Tret-Butyl. M-(2-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl Icarbamate

Mn,

M and V; ve mch--20 ze 7

Part A see

Using the general methodology of Example 1, Part A, tert-butyl. M-(4-aminobutyl)carbamate (254 g, (5) 1.35 mol) reacted with 4-chloro-Z-nitroquinoline hydrochloride (331 g, 1.35 mmol) to give 486 g of tert-butyl M-(4-((Z- Nitroquinolin-4-yl)amino|IbFutiliucarbamate in the form of a yellow solid. Analysis:

Calculated for Si8NodMaOd: 90, 59.99; 90Н, 6.71; 95M, 15.55; Found: 95, 59.68; 95Н, 6.59; 90M, 15.74.

Part B "I

Using the general methodology of Example 1, Part B, tert-butyl o

M-(4-((3-nitroquinolin-4-yl)amino|1-butyl)carbamate (162.bg, 0.451 mol) was oxyhydrogenated to obtain 149 g of tert-butyl M-(4-(3-aminoquinolin-4-yl)liamino (butyl) carbamate in the form of a dark golden rubbery substance. And c)

Part C of p

Using the general methodology of Example 1, Part C, tert-butyl

M-(4-(3-Aminoquinolin-4-yl)iamino|butyl)carbamate (149g, 0.451mol) was reacted with triethylorthoformate to give the crude product. This material was recrystallized from isopropyl alcohol to obtain 84 g of tert-butyl M-I4-(1H-imidazo|4,5-c|quinolin-1-yl)butyl Icarbamate as a crystalline solid.

Part "

Using the general procedure of Example 1, Part p, tert-butyl 40. M-I4-(1H-imidazo|4,5-c)quinolin-1-yl)/butyl|carbamate (84.0g, 0.247mol) was oxidized to give 87.9 g - c 1-(4-tert-butylcarbamyl)butyl-1H-imidazo|4,5-c|quinoline-5M-oxide in the form of a green/yellow foam. and Part E. Concentrated ammonium hydroxide (250 mM) was added to a strongly stirred solution of 1-(4-(tert-butylcarbamyl)butyl I-1H-imidazo|4,5-c|quinoline-5M-oxide (87.9g, 0.247mol ) in dichloromethane (75 Oml).

Tosyl chloride (47.0 g, 0.247 mol) was added in small portions over 30 minutes. The reaction mixture was left to stir at ambient temperature overnight, then it was filtered to remove the yellow-brown precipitate. The filtrate layers were separated. The aqueous layer was extracted with dichloromethane (4x55Oml). The dichloromethane fractions were combined, dried over sodium sulfate, and then concentrated in vacuo to give a pale yellow-brown solid. This material was recrystallized from 50% isopropyl alcohol to obtain 75.7 g of tert-butyl M-I(2-(4-amino-1H-imidazo|4,5-quinolin-1-yl)/butyl|carbamate as a pale yellow solid substance, melting point 171-1732 C. "H NMR (500 MHz, SOSIv) 5 8.19 (s, 1Н),

T» 8.03 (d, J-8.OGC, 71H), 7.62 (d, J-8.OGC, 71H), 7.44 (t, J-8.0ГЦц, 1Н), 7.26 (d, J-8.0ГЦц, 1Н ), 6.83 (t,

J-6.OGC, 1H), 6.60 (wide c, 2H), 4.59 (t, J-7.0Hz, 2H), 2.95 (q, J-b.OGC, 2H), 1.83 (quintet,

J-7.OGts, 2H), 1.42 (quintet, J-7.OGts, 2H), 1.33 (s, 9H). M5 (EI) m/e 355.2001 (355.2008 calculated for Sl9No5BM5O»z). 29 Example C

HF) Phenyl. M-I4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|carbamate

GI mn, 60 me cho (c) b5 , y. and and and

A solution of 1-(4-aminobutyl)-1H-imidazo|4,5-c|quinolin-4-amine (9.3 mg, Zbmmol) in 10ml of dichloromethane was cooled to -59C, and a solution of phenyl chloroformate (/mg, 45mmol) was added in 1.5 mL dichloromethane, bubbling argon to facilitate mixing. The mixture was then left to warm to room temperature with stirring for 10 minutes. Aminomethylpolystyrene (approximately 8Omg, Imek/g, 100-200mesh, Vaspet) was added to quench excess chloroformate, and the mixture was boiled and stirred for several hours. The mixture was chromatographed through a thin layer of silica gel with 10:1 dichloromethane-methanol as eluent to isolate the product as a solid. "H NMR (500MHz, OM5O-ydv) 5 8.28 (s, 1H), 8.06 (d, J-7.6Hz, 1H), 7.76 (t, J-5.6Hz, 71H), 7.63 (d. J-8.2Hz , 1H), 7.45 (t, J-7Hz, 1H), 7.34 (t, J-8.2Hz, 2H), 7.27 (t,

J-7.5Hz, 1), 7.18 (t, J-7.Z3Hz, 71H), 7.00 (d, J-8.bHz, 2H), 6.65 (wide c, 2H), 4.64 (t, 3-7Hz, 2H), 70 3.10 (quartet, J-bHz, 2H), 1.92 (quintet, J- 7 Hz, 2H), 1.52 (quintet, J- 7Hz, 2H). M (ARSI) m/e 376.15 (M'-N).

Example 4 9nH-9-Fluorenylmethyl M-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butylcarbamate

To a solution of 1-(4-aminobutyl)-1H-imidazo|4,5-c|quinolin-4-amine (9.3 mg, Zbmmol) in 10ml of dichloromethane at ambient temperature was added 9-fluorenylmethyl chloroformate (8mg, 30mmol) in the form solid matter. The mixture was stirred at room temperature for about 1 h, causing it to become slightly cloudy. Aminomethylpolystyrene (approximately 39Omg, 0.b4mek/g, 100-200mesh, Vaspet) was added to quench excess chloroformate, and after a few minutes the mixture was filtered through a thin layer of silica gel, eluted with a 10:1 dichloromethane-methanol mixture to isolate the product as a solid substances "NN NMR (o) (50OoMHz, 0MO-yv) 5 8.27 (s, 1H), 8.08 (d, J-8.1Hz, 1H), 7.87 (d, J-7/.6Hz, 2H), 7.65 (m , ZN), 7.50 (t,

J-7.6bHz, 1H), 7.40 (t, J-7.3HzC, 2H), 7.3 (m, 4H), 7.15 (wide c, 2H), 4.62 (t, J-7Hz, 2H), 4.27 (d ,

J-7Hz, 2H), 4.17 (t, J-7/Hutz, 1H), 3.03 (q, J-7/Hz, 2H), 1.84 (quintet, J-/Hz, 2H), 1.45 (quintet, J - /Hz, «E zo 2H). M5 (ARSI) m/e 478.28 (M.N).

Example 5 o

M-I4-(4-Amino-1H-imidazo|4,5-c|quinolin-1-yl)butyl|-4-morpholinecarboxamide oyu hyso

Java; and - no, about « in - p

4-Morpholinecarbonyl chloride (0.15 mL, 1.3 mmol) was added to a stirred solution of 1-(4-aminobutyl)-1H-imidazo|4,5-cquinoline-4-amine (0.3 g, 1.2 mmol) and pyridine (7Oml). The reaction mixture was kept at room temperature overnight. The solvent was removed by massio and the residue was purified by flash column chromatography (silica gel, a mixture of 9:11 dichloromethane/methanol). The fractions containing the product were combined, washed with a saturated aqueous solution of sodium bicarbonate, dried (Mo950), filtered, and (95) concentrated to obtain 0.86 g of M 7-I4-(4-amino-1H-imidazo|4 ,5-s|quinolin-1-yl)ubutyl|-4A-morpholinecarboxamide sl in the form of a yellow-brown powder, melting point 177.0-179.5 "С. "YAN NMR (Z00MHz, OM5O-dv) 5 8.22 (s, 1H), 8.04 (d, J-7.1Hz, 1H), 7.64 (d, J-7.5Hz, 1H), 7.47 (t, J-7.1Hz . (t J-4.bHz, 4H), 3.18 (t,

Their" J-4.6Hz, 4H), 3.05 (m, 2H), 1.84 (m, 2H), 1.44 (m, 2H); M5 (EI) m/e 368.1966 (368.1961 calculated for Sl9NoaMeO»z).

Example 6

M1-I(4-(4-Amino-1H-imidazo|4,5-c|quinolin-1-yl)butyl|-M-methyl-M-phenylurea

Mn, (F) in; ime) not at 60 - what

According to the general procedure of Example 5, 1-(4-aminobutyl)-1H-imidazo|4,5-c|quinolin-4-amine and 65 M-methyl-M-phenylcarbamoyl chloride were combined to give

M1-I4-(4-amino-1H-imidazo|4,5-c|quinolin-1-ylbutyl|-M-methyl-M-phenylurea in the form of a yellow-brown powder, melting point 87.0-88.02C. "H NMR (ЗО0МГЦц, ОМ5О-dv) 5 8.19 (s, 1Н), 8.04 (d, J-8.y1Hz, 1Н), 7.63 (dd, J-8.1, 1.2Хц, 1Н), 7.45 (dt, J-8.1, 1.2Hz, 1H), 7.31-7.24 (m, ЗН), 7.18-7.09 (m, ЗН), 6.62 (s, 2H), 5.95 (wide s, 1H), 4.59 (t, J-b6.9Hz, 2H ), 3.07 (s, ZN), 3.03 (m, 2H), 1.82 (quintet, J-7.2Hz, 2H), 1.42 (quintet, J-7.2Hz, 2H); M5 (EI) m/e 388.2023 (388.2012 estimated for SooNod Me).

Example 7 (1kK,25,5K)-2-Isopropyl-5--methylcyclohexyl M-(3-(4-amino-1H-imidazo|4,5-c|quinolin-1-yl)butyl|carbamate as

M

M in o k-

3-Methyl chloroformate (0.675 mL, 3.15 mmol) was added dropwise to a stirred solution of 1-(4-aminobutyl)-1H-imidazo|4,5-quinoline-4-amine (0.80 g, 3.14 mmol) and pyridine (2000 ml). The reaction mixture was kept at room temperature overnight. The solvent was removed by massio and the residue was purified by flash column chromatography (silica gel, a mixture of 95:5 dichloromethane methanol). The fractions containing the product were combined, washed with sat. aqueous sodium bicarbonate solution, dried (Ma5O), filtered and concentrated to obtain 0.32 g of (1K,25,5K)-2-isopropyl-5-methylcyclohexyl

IM-IZ-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butylcarbamate in the form of a yellow-brown powder, melting point 84.0-86.02С. 13C IMR (75MHz, OM5O-IV) 5 156.5, 152.5, 145.3, 143.1, 131.9, 128.5, 127.0, 126.5, 121.5, 120.8, 115.2, 73.0, 47.2, 46.5, 23.7 23.4, 22.3, 20.8, 16.6; M5 (EI) (o) m/e 437.2797 (437.2791 calculated for Со5НаЗзМ»5О»).

Example 8 2-Naphthyl M-I4-(4-amino-1H-imidazo|4,5-s|quinolin-1-yl)butyl|carbamate

She

» ив) со -- и- ны «

According to the general procedure of Example 7, 1-(4-aminobutyl)-1H-imidazo|4,5-c)quinolin-4-amine and 2-naphthyl ester of chloroformic acid were combined to obtain 2-naphthyl "» M -(4-(4-amino-1H-imidazo|4,5-s|quinolin-1-yl)butyl|carbamate in the form of a white powder, melting point "154.0-155.06s. "H NMR (300 MHz, OM5O-iv ) 5 8.23 (s, 1H), 8.08 (d, J-7.4Hz, 1H), 7.94-7.86 (m, 4H), 7.64 (dd, J-8.3, 1.0Hz, 1H), 7.56-7.43 (m, 4H), 7.30 (m, 1H), 7.20 (dd, J-8.8, 2.3Hz, 1H), 6.61 (broad c, 2H),

DVB (t, J-6.9Hz, 2H), 3.14 (kv, J-b.4Hz, 2H), 1.94 (m, 2H), 1.56 (m, 2H); MUZ (EI) m/e 426.1927 (426.1930 7 counts for So5NozM'O»z). oz Example 9 sl 1-Naphthyl M-I4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|carbamate tk, o 50 m / iz» B, in o - o

Ф) име) 60 According to the general procedure of Example 7, 1-(4-aminobutyl)-1H-imidazo|4,5-c)quinolin-4-amine and 2-naphthyl ester of chloroformic acid were combined to obtain 1-naphthyl

IM-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butylcarbamate in the form of a yellow-brown powder, melting point 89.0-92.02С. "H NMR (Z00MHZc, OM5O-aiv) 5 8.25 (s, 1H), 8.10 (d, J-7.4Hz, 1H), 8.05 (t, J-5.8Hz, in 1H), 7.96 (d, J-7.6 Hz, 1H), 7.79 (d, J-8.2Hz, 1H), 7.66-7.45 (m, 6H), 7.30 (m, 1H), 7.19 (d, J-7.5Hz, 1H), 6.72 (wide s. 2H), 4.67 (t, J-b. 9Hz, 2H), 3.17 (kv, J-b. ZHCc, 2H), 1.96 (m, 2H), 1.59 (m, 2H); M5 (EI)

m/e 426.1929 (426.1930 calculated for Со5НозМ5О»5).

Example 10

M-(4-(4-Amino-2-(4-methoxybenzyl)-1H-imidazo|4,5-s|quinolin-1-yl|IbFutil)urea nn, ba 7 их о - чн,

Part A

Tert-butyl /N-(4-(2-(4-methoxybenzyl)-1H-imidazo|4,5-c|quinolin-1-yl|Is-Sutil)iocarbamate was reacted according to the general method of Example 1, parts OO and EE, giving tert-butyl

M-aminocarbonyl-M-14-(4-amino-2-(4-methoxybenzyl)-1H-imidazoi|4,5-s|quinolin-1-yl|IS-utilylcarbamate in the form of a solid. "H NMR (30 MHz, М5О -4c) 5 7.93 (d, J-8.1HC, 1H), 7.86 (wide c, 1H), 7.61 (dd,

J-8.3, 1.1Hz, 71), 7.41 (m, 1), 7.24-7.17 (m, 4H), 6.87 (d, J-8.7Hz, 2H), 6.55 (wide s, 2H), 4.45 (wide s , 2H), 4.32 (c, 2H), 3.71 (c, ЗН), 3.49 (m, 2H), 1.49 (m, 4H), 1.31 (c, 9H).

Part B

The tert-butyl carbamoyl group was removed by Kk! tert-butyl

M-aminocarbonyl-M-14-(I4-amino-2-(4-methoxybenzyl)-1H-imidazoi|4,5-cIquinolin-1-yl|Isoethyl)carbamate by heating the compound in a solution of HCl and ethanol. The reaction mixture was neutralized (MH OH) to obtain He)

M-(4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo|4,5-s|quinolin-1-yl|Sutil) truncated in the form of a not quite white solid, melting point 1962C (decomposition .). "H NMR (ZO0MHz, OM5O-dv) 5 7.96 (d, J-7.9Gu, 1H), 7.61 (d, J-8.ZHC, 1H), 7.43 (t, J-7.6Hz, 1H) . .

Example 11

M-4-I4-Amino-2-(2-methoxybenzyl)-1H-imidazo|4,5-siquinolin-1-ylbutyl)-4-morpholinecarboxamide so - i - iv 5. n « dya o - s nt:» SU 15 According to Kk! by the general method of Example 5, - 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo|4,5-cquinolin-4-amine and 4-morpholinecarbonyl chloride were combined

Ck! by obtaining M-4-(4-amino-2-(2-methoxybenzyl)-1H-imidazo|4,5-siquinolin-1-ylbutyl)-4-morpholinecarboxamide. tn NMR c (ZOOMHz, SOSIz) 5 7.85-7.81 (m, 2H), 7.50 (m, 1H), 7.30 (m, 2H), 7.17 (d, J-8.bHz, 2H), 6.86 (d, J -8.6Hz, 2H), 5.62 (wide s, 2H), 4.36 (m, 2H), 4.31 (s, 2H), 3.78 (s, ЗН), 3.64 (t, J-4.9Hz, 4H), 3.25 ( t, av) and

J-4.9Hz, 4H), 3.18 (m, 2H), 1.70 (m, 2H), 1.54 (m, 2H); M5 (EI) m/e 488.2533 (488.2536 calculated for C27NaoMeOz). "d" Example 12

Tert-butyl. M-(4-(4-amino-2-phenyl-1H-imidazo|4,5-c)quinoline-11)butyl Icarbamate

Mn, Mly M! Vo

F) Yam ko ne o 60 M and r

Part A 65 A solution of benzoyl chloride (5.3g, 37.7mmol) in dichloromethane (100ml) was slowly added to the tert-butyl solution

M-(4-((3-Aminoquinolin-4-yl)amino)butylcarbamate (12.5g, 37.7mmol) in dichloromethane (250ml) at ambient temperature. The reaction mixture was maintained at ambient temperature overnight. The resulting precipitate was isolated by filtration and dried to obtain 11.0 g of tert-butyl

M-(4-13-(benzoylamino)quinoline-4-ylaminodbutyl)carbamate hydrochloride as a white solid.

Part B

Triethylamine (7.26g, 71.7mmol) was added to a solution of the material from Part A in ethanol (2000ml) and heated at reflux for 2 days. The reaction mixture was concentrated to obtain an orange syrup. HPLC with mass spectroscopy showed that the syrup contained the desired product and starting material. The syrup was placed in dichloromethane (10 Oml) and then cooled in an ice bath. Triethylamine (bml) and benzoyl chloride 7/0 were added. A. Uml). The reaction mixture was maintained at ambient temperature for 2 days, and HPLC analysis indicated that that the reaction is not yet complete. The reaction mixture was concentrated in vacuo.

The residue was placed in isopropyl alcohol (15 Oml). Triethylamine (bml) was added, and the reaction mixture was heated to boiling overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel; eluted with a 1095 solution of methanol in dichloromethane). The fractions containing the product were combined and concentrated in vacuo. The residue was recrystallized from acetonitrile to obtain 6.7 g of tert-butyl

IM-I(I4-(2-phenyl-1H-imidazo|4,5-cyquinolin-1-yl)butylcarbamate in the form of a solid substance, melting point 158-15926.

Part C

C-Chloroperoxybenzoic acid (1.0 eq., 6590) was slowly added in small portions to a solution of tert-butyl /N-I4-(2-phenyl-1H-imidazo|4,5-c)quinolin-1-ylbutyl)carbamate (6.56 g, 15.75 mmol) in dichloromethane (120 ml). After three hours, the reaction mixture was quenched with an aqueous solution of sodium bicarbonate (200 ml). The layers were separated. The aqueous layer was extracted with dichloromethane (2 x 5 Oml). The organic fractions were combined, dried over magnesium sulfate, and then concentrated in vacuo to give a pale orange syrup. The syrup was rubbed with diethyl ether Kk! by obtaining b.vg Ga 1-I4-(tert-butylcarbamyl)butyl|-2-phenyl-1H-imidazo|4,5-s|quinoline-5M-oxide in the form of a pale yellow-brown solid, melting point 178-18196 . and)

Part

A solution of 1-(4-(tert-butylcarbamyl)butyl|-2-phenyl-1H-imidazo|4,5-c|quinoline-5M-oxide (6.8g, 15.75mmol) in dichloromethane (1000ml) was cooled in an ice bath. Concentrated ammonium hydroxide (0 mL) was added. Tosyl chloride (3.0 g, 15.75 mmol) was added in small portions over 30 minutes. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was quenched with water (35 mL). The layers were separated. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, dried over magnesium sulfate, and then concentrated in vacuo to give a yellow-brown solid. This material was purified by flash chromatography (silica gel was eluted with a 1095 solution of methanol in dichloromethane) to give 4.8 g of product. A small portion recrystallized from toluene to give /tert-butyl -

IM-(4-(4-amino-2-phenyl-1H-imidazo|4,5-c|quinolin-1-yl)butylcarbamate in the form of a solid substance, melting point 182-18320. Analysis: Calculated for Со5НооМь5О»о: 90, 69.58; 90Н, 6.77; 95М, 16.22; Found: 95С, 69.86; 9оН, 6.95; 9о0М, 15.80.

Example 13

M-(4-(4-Amino-2-phenyl-1H-imidazoi|4,5-s|quinolin-1-yl)butyl|-M'-propylthiourea - with Mn,

M g» i ЖОо- u t - o t 1 Part A o 50 Tert-butyl M-(4-(4-amino-2-phenyl-1H-imidazo|4,5-c|quinolin-1-yl)/ butyl carbamate (4.3g, 10.00mmol) was dissolved in methanol (15ml) and 1M hydrochloric acid (100ml), then heated at reflux for 2 hours.

I" was concentrated in a vacuum to a volume of approximately 5 Oml. By adding concentrated ammonium hydroxide with a pH level of up to 12, no precipitate was obtained. The pH level was adjusted to 7 with 1M hydrochloric acid. The mixture was extracted with dichloromethane and then with ethyl acetate. The aqueous layer was concentrated to a dry residue. The residue was dissolved in water (5Oml) and then continuously extracted with boiling chloroform for 36 hours. The chloroform extract was concentrated in vacuo to give a light yellow-brown solid. This material was recrystallized from acetonitrile to give 2.5 g of 1-(4-aminobutyl)-2-phenyl-1H-imidazo|4,5-c|quinoline-4-amine as an off-white solid, melting point 175- 177 S. Analysis: Calculated for С 20NoMv: оС, 72.48; 90Н, 6.39; 90M, 21.13; 60 Found: 95, 72.72; 90Н, 6.32; 95M, 20.71.

Part B

A solution of propyl isothiocyanate (0.78 g, 7.72 mmol) in chloroform (ml) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo|4,5-c|quinoline-4-amine ( 0.256g, 7.72mmol) in a mixture of chloroform (25ml) and pyridine (bml). The reaction mixture was maintained at an ambient temperature of 65 during the weekend. The reaction mixture was quenched with ethanol and then concentrated in vacuo to give a pale orange syrup. This material was purified by flash chromatography (silica gel, eluted with 1095 solution of methanol in dichloromethane). Pure fractions were combined and concentrated in a vacuum to obtain 0.22 g

IM-(4-(4-amino-2-phenyl-1H-imidazoi|4,5-cIquinolin-1-yl)butyl|-M'-propylthiourea in the form of a white solid, melting point 113-1162C. Mass spectroscopy of M- -1-433.2.

Example 14

M-(4-(4-Amino-2-phenyl-1H-imidazo|4,5-c|quinolin-1-yl)butyl|-M-(3-pyridyl)thiourea

Mn, so sah 70 x

WITH

M. d

WITH

A solution of pyridine-3-isothiocyanate (0.136 mg, 1.0 mmol) in chloroform (bml) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo|4,5-s|quinoline- 4-amine (0.331g, 1.0mmol) in a mixture of chloroform (25ml) and pyridine (bml). The reaction mixture was kept at ambient temperature for two days. The reaction mixture was quenched with ethanol and then concentrated in vacuo to give an off-white solid. This material was purified by flash chromatography (silica gel, eluted with 1095 solution of methanol in dichloromethane). Pure fractions were combined and concentrated in a vacuum to obtain 0.2 g of M-I4-(4-amino-2-phenyl-1H-imidazo|4,5-phenolin-1-yl)butyl/)|-M'-(Z -pyridyl)thiourea in the form of a white solid, melting point 118-120 °C. Mass spectroscopy M--1-468.3. Analysis:

Calculated for SovbNovIM,Z: 90, 66.79; 90Н, 5.39; 95M, 20.97; Found: 95, 64.29; 95Н, : 5.46; 90M, 20.06. everything

Example 15 (o)

IM-(4-(4-Amino-2-phenyl-1H-imidazoi|4,5-s|quinolin-1-yl)butyl|-M-(4-fluorophenyl)urea 11

A solution of 4-fluorophenyl isocyanate (0.137 g, 1.00 mmol) in chloroform (bml) was added at ambient temperature to a solution of /1-(4-aminobutyl)-2-phenyl-1H-imidazo|4,5-quinoline-4-amine (0.331g, W 1.O0mmol) in a mixture of chloroform (25ml) and pyridine (bml). The reaction mixture was maintained at ambient temperature for two days. The reaction mixture was quenched with ethanol. The resulting pale yellow precipitate (defined as bis-adduct) was isolated by filtration. The filtrate was concentrated in vacuo to give an off-white solid. This material was purified by flash chromatography (silica gel, eluted with a 1090% solution of methanol in dichloromethane). Pure fractions were combined and concentrated in a vacuum to obtain 0.22 g

M-I4-(4-amino-2-phenyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl/)|-M'-(4-fluorophenyl) truncated in the form of a white solid. substances, melting point 145-15020. Mass spectroscopy M--1-469.2. Analysis: C 27NoBEMeO: 90, 69.21; UN, 5.37; 90M, 17.94; Found: 90, 66.70; 90Н, 5.33; 95M, 17.03.

Examples 16-52 «

The compounds given in the table below were obtained according to the method of synthesis of the above Scheme 70 reaction II. c) c A solution of 1-(4-aminobutyl)-1H-imidazo|4,5-c)quinolin-4-amine (Zbmmol) in 17Oml of dichloromethane in a flask for "" carrying out the test with a twist was cooled to -52C. Isocyanate (45mmol ) was added as a 0.3M solution in dichloromethane. Argon was bubbled through the mixture during the addition and for an additional 15 seconds, the mixture was allowed to stand at -59C overnight. About 9Omg of aminomethylpolystyrene resin (0.b2mek/g, 100-200mesh) was added to this mixture, and the mixture was heated to boiling and shaken at and about bObob/min. within 3 hours. The mixtures were filtered through poly-preparation. columns (Vio-Kaid 5731-1550) for resin removal. Three different cleaning methods were used. In method A, the filtrate was loaded onto a silica gel column. The column was eluted with a mixture of 10:11 dichloromethane:methanol, the fractions containing the product were combined and dried by mass. In the C method, the filtrates were dried and purified using av| 20 semi-preparative VRRH on the Gilson system (Kaipip Misgozogo S 18 column, 21.4,250mm, 8 particle size

T» micron, BOA pore, 1 Oml/min, eluent gradient with 2-9595 B solution for 25 min., maintained at 9595 V for 1 h, where A-0.1965 trifluoroacetic acid/water solution and B-0.1906 trifluoroacetic acid/acetonitrile solution , inclusion of fractions with a peak at 254 nm). Semi-preparation fractions. VRPC was analyzed by IC-ARSI/M5 and suitable fractions were lyophilized to obtain the compound in the form of trifluoroacetic acid salts. In Method B, 59 compounds were purified according to Method C and then trifluoroacetic acid salts were dissolved in approximately 3-5 ml

HF) of a mixture of 21 dichloromethane-methanol and shaken with approximately 8mg (300µmol) of diisopropylaminomethyl-polystyrene resin (Agdopashi RBZ-YOOEA, 3.8bmmol/g) for 1-2 hours. to release the free amine, and then filtered and dried with ip mass. The compounds were generally amorphous solids. 60 b5

AI

16 Gi A 375.1... KOM5O-0v) 5 8.38 (s, 11), 8.22 (s, 1H), 8.05 (d, J-7.9 r Gu, 1), 7.61 (d, 7.9 Hz, 1H), 7.43 (t, J-7.6 Hz, 1H), (a; 7.36 (d, J-7?.Z Hz, 2H), 7.24 (t, Jhe?.3 Gu, 1H), 7.20 (t,

Je7.9 Gu, 2H), 6.87 (t, Je7.3 Gu, 1H), 6.60 (wide

I c, 2H), 6.14 (t, Je5.8 Hz, 1H), 4.63 (ti, J-? Gu, 2H), then 3.15 (q, Jeb Gu, 2H), 1.88 (quintet, Je7 Hz, 2H) .

Hz, 1H), 8.12 (d, Je9.3 HC, 2H), 7.74 (d, J-e8.3 Gu, 2 1NU, 7.59 (m, ZN), 7.43 (t, Jeb HC, 1H), 65.58 ( t, J-5.A ie Hz, 1H), 4.88 (t, Je7 Gu, 2H), 3.15 (q, Jeb Hz, 2H), o 1.89 (quintet, Je 7.5 Gu, 2H), 1.52 (quintet, Je7 Hz, ON)

An example of Mo. Structure Cleaning |ARSI-M5 m/e 500 MHz NYM Ha (o) 18 -, С 447

Hey what's up «

IN

(av) i yu iz t, 34122 (OM 50-95) 58.40 (s, 1H), 8.15 (d, J-7.8 Hz, 1H), so 2 at 7.75 (d, J-B8.1 Hz, 1) . .5 Gu, 2H), 3.61 (sextet, - ov, Je-7.5 Gu, 1H), 3.01 (q, Jeb Gu, ?H), 1.84 (quintet,

J-7.5 Hz, 2H), 1.42 (quintet, J: 7 Hz, 2H), 0.97 (d, «

Je6.5 Gu, 6H) - p. 20 her, Z5524 |(OM5O-ov) 5842 (s, 1H), 8.17 (d, ДЖ-8.3 Gu, 1), "» ru 7.76 (d, Dzhe8.3 Hz, 1H), 7.64 (t, Dzhe8. 5 Gu, 1H), 7.48 - sn, (s, 1H), 5.66 (t, Jeb Hz, 1H), 5.54 (s, 1H), A.66 (t,

Zhe, Jet Hz, 2H), 2.98 (ka, Jeb Hz, 2H), 1.84 (quintet, n sia, and about JeV Gu, 2H), 1.41 (quintet, Je8 Hz, 2H), 1.17 (s, (95) 9H) 1 o

T" (F) ko bo 65

An example of Mo. Structure Cleansing! ARSI-M5 50 MHz nym m/e 21 nn, 447.21. ТСОМ5О-дв) 6 8.43 (С, ЗН), 8.3 (wide с, 1 Н), 8.26

С І У (c, 1H), 8.17 (d, J-7.8 Gu, 1H), 7.75 (d, Dzhe8.3 Hz, 1H), 7.61 (t, Dzhe8.1 Gu, 1H), 7.44 (t, Dzhe7 .8 Gu, 1), -O- 7.23 (d, J-b.8 Gu, 2H), 6.78 (d, J-6.8 Gu, 2H), "M i-y 8.12 (t, Jeb.1 Hz . 1.66 (quintet, Je:B Hz, 2H), 1.49 (quintet, Je7 Hz, 2H), 1.41 (quintet, Je? Hz, 2H), 0.92 (t, Je? Hz, ZN) 22 kn, 447.00 (rM50- a5) 5 8.39 (c, 1H), 8.28 (wide c, 1H), 8.15

Er sn (d, Jet.8 Hz, 1 H), 7.75 (d, Je7.8 Hz, 1H), 7.81 (t, t Jet7.8 Gu, 1H), 7.45 (i, Je7.6 Gu, 18) , 5.81 (t,

Jeb Hz, 1H), 5.75 (t, Jev Hz, 1H), 4.65 (t, Je7.5 4 Hz, 2H), 3.02 (kv, Je-b.5 Hz, 2H), 2.92 (kv, J-6.0

HC, 2H), 1.84 (quintet, J-?.5 Hz, 2H), 1.43 (quintet,

J-7 Hz, 28), 1.30 (quintet, J-7 Hz, 2H), 1.22 (wide s, Dzhe:V Gu, 8H), 0.84 (t, Dzhe7.5 Hz, ЗН) s (o)

An example of Mo. Cleansing structure| ARSI-M5 500 MHz NN Pits m/e « 23 , 511.11 (rm50-a) 5 9.6-8.6 (B, 2H), 9.35 (s, 1H), 8.55 (s, 1H), o

SHI: va 8.24 (d, J-8.0 Hz, 1H), 8.08 (s, 2H), 7.82 (d, Je8.0 is Gu, 1H), 7.89 (t, Je 8.0 Hz, 1H), 7.55 (t, Je 8.0 HZ, it) and 1H), 7.54 (s, 1H), 6.70 (1, Je-8.0, 1H), 4.72. (t, co

E and D7.5 Hz, 2H), 3.15 (kv, Jeb.0 Hz, 2H), 1.90 Kk

Zo (quintet, Dzhe7.0 Gu, 2H), 1.54 (quintet, Dzhe7.5 Hz, 2t 24 ik, 459.35 (OM50-av) 5 8.32 (broad c, 1H), 8.28 (broad c, 1 sn, 1H), 8.13 (d, J:8.8 Hz, 1H), 7.70 (d, J-7.6 Hz, 1H), « y 7.55 (t, J-b.8 Hz, 1H), 7.38 (t, 1NU, 7.34 (wide -o s s, 1H), 7.17 (t, Dzhe8 Hz, 1H), 7.06 (d, Dzhe8 Hz, 2H), . m sn, 6.1 (broad s, 2H), 4.66 (z, Dzhe7.5 Hz, 2H), 3.10 "» (broad c, 2H), 3.04 (quintet, Jhe:7 Gu, 1H), 1.88 (broad m, 2H), 1.48 (broad m, 2H), 1.02 (d,

What? Hz, 12H) -I (95) 1 at 50

Thursday" (F) ko bo b5

AI AI

23 t, s 383.52 (OM50-yv) 6 8.52 (s, 1H), 8.22 (d, Dzhe8 Gu, 1H), 7.83 i and U (d. J-8 Gu, 1H), 7.72 (1, Dzhe8 Gu, 1H), 7.58 (t, sho t Je8 Gu, 1), 5.80 (7, Je5 Gu, 1H), 5.75 (t, Je5.5 and Gu, 1H), 4.68 (t, Jet? 0 Hz, 2H ), 3.02 (sq, Jeb.5 Hz, o 2H), 2.92 (sq, Jeb Hz, 2H), 1.84 (quintet, Je? HZ, 2H), 1.44 (quintet, Je7 Gu, 2H), 1.29 ( t, Je? HC, 2H), 1.2 (m, EN), 0.84 (t, Je? Hz, ZN) 28 m, s 341.21 (OM50-yd) 5 8.52 (s, 1H), 8.23 (d. J- 8 Hn, 1H), 7.83 i Y U (d, Dzhe8 HC, 1H), 7.72 (t, Dzhe7.5 Gu, 1H), 7.57 (t, that sn, Dzhe7 Gu, 1K), 5.80 (t, Dzhe: b.5 Hz, 1H), 5.77 (t, Je:b and Hz, 1H), 4.68 her, Je7.5 Hz, 2H), 3.02 (sq, Jeb.5 Hz, o 2H), 2.89 (sq, Jeb .5 Hz, 2H), 1.84 (quintet, J: 7.5

Gu, 2H), 1.43 (quintet, Dzh8 HC, 2H), 1.31 (sextet,

Je7 Gu, 2H), 0.78 (t, Je 7.5 Hz, ZN)

An example of Mo. Cleansing structure| ARSI-MB5 500 MHz NYM m/e s o 27 m, bai1718 (BM5O-45) 69.6-8.6 (w, 2H), 8.55 (s, 1), 8.33

MORE (wide c, 18), 8.24 (d, Dzhe7.5 Hz, 1H), 7.83 (d, sn Dzhet.5 Hz, 1NU, 7.72 (1, Dzhe7.5 Gu, 18), 7.56 (t, -- - Jet.5 Hz, 1H), 7.25 (d, Je 8.0 Gu, ?H), 7.06 (d, t o Je8 Hz, 28), 6.17 (t, Je5.5 Gu, 1H), 4.71 (t, av )

Dje7.0 Hz, 28), 3.12 (q, Dje 5.5 Gu, 2H), 2.79 u (quintet, Dje 7.0 Hz, 1H), 1.89 (quintet, Dje 7.0 Hz, 2H), 1.51 (quintet, Dje7.0 Hz , 2H), 1.16 (d, J-7.0 me) ha. 6H) i- 28 tn, 400.18 (OM 50-a5) 5 8.88 (s, 1H), 8.32 (s, 1H), 8.22 (wide shk U h s, 1H), 8.11 (d, Dzhe8 Hz, 1H ), 7.91 (t, Dzhe1.7 Gu, /j 1H), 7.68 (d, J-e8 Hz, 1H), 7.55 (d, Dzhe9.5 Gu, 1H), « 7.51 (t, Dzhe8.1 Hz, 1H), 7.41 (t, Dzhe8.3 Ru, 1H), 7.34

b (t, J-7.1 Gu, 1H), 6.41 (t, Jet Gu, 1H), 4.66 (y, - s Je6.5 Hz, 2H), 3.13 (q, Jeb Gu, 2), 1.89 (quintet, "with Dzhe?.5 Hz, 2H), 1.50 (quintet, J: 7 Hz, 2H) p -I (95) 1 o 50 "g" (F) ko bo 65 a tn, 443.10 TsOM50-95) 5 8.97 (c, 1H), 8.46 (c, 1H), 8.19 (d, J-7.8 a U Hz. 1), 7.77 (d, Dzhe8.3 Gu, 1H), 7.63 (t, Dzhe8.1 Gu, a 18 ), 7.48 (i, Jhe7.3 Hz, 1H), 7.44 (s, 2H), 7.05 (t, «9 J-1.7 Hz, 1H), 6.49 (t, Jhe5.6 Hz, 1H), 4.69 (i .

From 369.24. TsOM5O-si) 6 8.80 (wide, 28), 8.52 (s, 1H), 8.23 (d, well J 7.5 Hz, 1H), 7.84 (d, J-8.0 Gu, 1H), 7.73 (t, tt J- 8.0 Gu, 1H), 7.58 (t, Je7.5 Hz, 1H), 5.80 (t, as JeB.5 Hz, 1H), 5.75 (t, Je5.5 Gu, 1H), 4.68 (t, Je at 7.0 Hz, 2H), 3.02 (kv, Jeb5.5 Gu, 2H), 2.92 (kv, Je5.5

Hz, 2H), 1.84 (quintet, Je?,0 Hz, 2H), 1.44 (quintet,

Je-?.0 Hz, 2), 1.30 (quintet, Je 7.0 Hz, 2H), 1.23: i(quintet, Je?.0 Hz, 2H), 1.18 (sextet, Je-7.0 Hz, 2H), 0.83 ( t, J-et.0 Gu, ZN)

An example of Mo. Structure Cleansing | ARSI-M5 m/e 500 MHz Yamy s z o

From ty, 477.08 (OM50-05) 5 9.6-8.6 (wide, 2H), 8.60 (d, J-2.0 tru HC, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 8.25 (d, JeV8 Hz, ai 1H), 7.82 (d, J-8.0 Hz, 1H), 7.69 (t, J-8.0 Hz, 1 V

H), 7.64 (d, J-8.0 Hu, 1 H), 7.55 (t, J-8.0 Hu, 1H), o

b 7.28 (dd, Dzhe8.0, 2.0 Hz, 1H), 7.23 (t, Dzhe5.5 Gu, 1H), 4.72 (t, Dzhe 7.0 Hz, 2H), 3.16 (ke, Dzhe 5.5 Hz, o 2H), 1.82 (quintet, Jhe 7 Hz, 2H), 1.54 (quintet, J: so 7.0 Gu, 2H o Ha, 2n) i- 32 t, 411.23 Ts(OM5O-dv) 5 9.6-8.6 (broad, 2H), 8.53 (s, 1H), 8.24 « schu E (d, Dzhe8.5 Hz, 1H), 7.84 (d, Dzhe8.5 Hz, 1H), 7.74 (t, gam, J-8.5 Gu, 1H), 7.59 (t . » -y- 7 2.98 (q, Db-b.0 gu, 2H), 1.83 (quintet, J 7.0 Hz, 2), 1.59 (s, 2H), 1.40 (quintet, Dhe7.0 Hz, 2H), 1.19 415 (c, 6H), 0.84 (c, 9) -I (95) 1 o 50 "g" (F. ko 60 65

The structure of 7 mv 500 MHz NYM 33rd, Go 46721nd no!

I . 34 tya IF 431.28 - 35 vn, s 389.20

Fh (o

Gee)

An example of Mo. Structure of Cleaning I(ARSI-M5 m/e 500 MHz NN YAM s z o nn, s 403.22

And but - what and o o I c) 37 t, C 405.19

And in Go) in - and n- U-6 o "

ZV Jan, p. 417.24 and - p. m

G. sn, ,» - Z o sn, -I (95) 1

Ha SHK "g" ko 60 65

The structure of the 5th MHz NYM. 39 nya, p 381,26

We -, kn, Go 403,23 -a i u ch tu u o td, s 42018 si okk z a; nya dv Structure of 500 MHz nNMR syn, He 453.09 tsya; "o" o o | Io) 43 cha S azzla so ru i o re-sv, M. o « 44 vn, IF; 419.18 not - s! m. » V vo -I (95) 1

Ha SHK "g" ko 60 65

An example of Mo. Structure of 500 MHz NMR 45 v, s 451.17 iz: U - 70 2 46 h, s 443.14 s

Her Majesty

M

- at 47 nk, p 421 LA

From pav o

An example of Mo. Cleansing structure| ARSI-MB5 500 MHz NN ЯМе сч 2 Шч о

Kn, p 389,18 and i;

From 5

And in o. o 49 vn, p 421.14 iv)

Sai u ne, so 5

From still g - o 50 p s 475.20 " o soi - s s 5 2" o -I Example Mo. Structure Cleansing |! ARSI-M5 BO MHz N YAMA s m/s 51 them, s 417.20 1 2 A

Ge Sho o ikh o sn, o 52 kn, p 355,21

IC Y Eh

Ф) вн, име) at 60

Examples 53-66

The examples in the table below were prepared according to the synthesis method of the above reaction Scheme 11 using the following general method. 1-(2-Aminoethyl)-2-butyl-1H-imidazo|4,5-c)quinolin-4-amine 65 (5Omg), dichloromethane (2ml) and isocyanate were placed in a bottle with a volume of 2 drachms (7.4ml) . The bottle was placed on a shaker for approximately 2-16 hours at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei! Rak C18 column, ZbOmmx2Omm, particle size 5 microns, 2Oml/min., eluent gradient from 5-9595 V for 10 min., maintained at 95905 V for 2 min., where A- 0.195 solution of trifluoroacetic acid/water and B-0.195 solution of trifluoroacetic acid/acetonitrile, inclusion of fractions with a peak at 254 nm). Semi-preparation fractions. VRRH were analyzed using I|C-ARSI/M5, suitable fractions were combined and lyophilized to obtain the trifluoroacetic acid salt of the desired urea. 53 Mn, SN, 461.2 o'clock. sv cho t, t; 54 Mya, son, 2951 from the city

M

! ! - that n 55 MA, sn, 417 mm, oh shchi p

M

Tv n t o

Mn, sn; 3692 d-d

KV about

M. n

IS) 57 I, sleep, things o sh ek v- m-

Nau n sn, 58 mn, sn, 369.2

M

Her hell " - ev

I en, - with Mn, sn, 383.3

Year: ak " s o i, y -i sn, (95) 1

Ge Sho s» name) 60 b5

MN, n, 4032 rad

M b uv n - 81 chya, sn, 4172

M fi di to sho - sn,

Min, SN, 8172

According to M

With nn not 65 chH, sn, 472 og

Savy -e a nos se (8) 0 lines 1

Ha st 3282 Y yam sh gai

M (av) -- n i; I eat so 65 МН, сн, 431.2 че

M

; r. t ne r: Se « i, sn, 431.2 - m s dh rodi . -at

And" Fr

H St, -| Examples 67-69 o The examples in the table below were prepared by the following method. 1--2-Aminoethyl)-2-ethoxymethyl-1H-imidazo|4,5-c|quinoline-4-amine hydrochloride (5mg), dichloromethane (2ml) and 1 diisopropylethylamine (1.2eq.) were placed in a vial with 2 drachms (7.4 ml). The bottle was placed on a 50° shaker for approximately 1 hour at ambient temperature. A suitable (thio)isocyanate was added and the vial was shaken at ambient temperature for approximately 4 hours. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei Rak C18 column, 35mm x 20mm, 5-micron particle size, 20ml/min., eluent gradient from 5-959o V for 10 min., maintained at 9595 V for 2 min., where

AthO.195 with a solution of trifluoroacetic acid/water and B-0.195 with a solution of trifluoroacetic acid/acetonitrile, including fractions with a peak at 254 nm). Semi-preparation fractions. VRPC were analyzed using I C-ARSI/M5, suitable fractions were combined and lyophilized to obtain the trifluoroacetic acid salt of the desired (thio)urea. name) 60 b5

67 МН, сн. zp

MD that I and p

M.

KU ov, chy, sn, 2054 h y vn x ( ; what n -O

Xia sn 4274

ZM 0-7

I am 0- with

OO

Examples 70-99

The examples in the following table are obtained according to the method of synthesis of the above reaction Scheme II by reacting /1-(4-aminobutyl)-2-butyl-1H-imidazo|4,5-c|quinoline-4-amine with a suitable /isocyanate using the general methodology of Examples 53-66 given above. 70 nn, S I ZOBA p

M, u and o) ay

Nr, «t 7 Mn, Y sn, 3973

WHAT, what, what - n

NU St, Sat 5 Tue, Sun, 2515 - ; re 7 u o de " n sn, shsh 73 Mn, sn, 4312 s "skin / ch i i M

And" o (o) -

OO

-I (95) 1 g SHY s» ime) 60 b5

7 Nya, SN 2373

M what (about) i

N

WITH

75 Htya sn, dB? or

What t u o

M. t, - sn, 76 Gttya n, a2E 56 i th i-k still o - n - r. nn ne 77 chn, sn, 445.2

M

/ fi nt in (in) - -K I sn, | se 2 o'clock 78 Xia sn; 4455

M

M

FI di « more o - (av) - o)

IS

8 GT sya so ma g d y I i - (o - n i

Mn, SNz 456.2 «

M t r U - s b shi h - "» y y h

In Mn, sn,

V.; p

M

(95) still he 5 uh n sn. (av)

GT" ko bo b5

82 Chapter 7 2563 continued about her

Another dream, 83 MN, t, 4593! we

YAM o i-sn, tya, se, 1593 5 c

M

In -

WITH

88 Mn, SN, 2613

M

; I t v o

What is it?

N m X neo (o) o « tya i, 4652

Y DK y t yu o -O Ge) si

Zo 87 Chn, Gaia 1673 Ch- Oz Shchi Sn,

AND

I (c) and "

N

Be ho sn, 4713 t s ih i

M

. » mch p sh- u nik nya n -I

HT sleep; 4753 (95) M

And eh still - t o (oh,

Ge Sho vi n

T" ha;

O-sn, why b5

C p 4762

M, he and dh

M. 2O nn -

MN N, at62

Sai v o i- n -

V r ko, 5 tn, sn, 4785

M ve o iann r; si 53 MN, sm, 4992 rad

M ve (g) g s ko ge) 54 nn; I I 2552 J

Mzoottsi y (av) v o - IF) n E - Kh y n t Ge) tya sia, 459.2, 5011

ZB M - i t still o - n a « sim st 499.2, 5011 -

M ve. "» o cho nn Ko si -I 97 MN, sn, Ob, BT ky (95) shcha M (c) - (av) ve "r" 98 Mn, sn, 508, 5111

M

/ t o v - ho) -0

Vg in 59 MM, sya, 508, 511

M

M i 0 t o - n

Ka 65

Examples 100-119

The examples in the table below are obtained according to the method of synthesis of the above reaction Scheme II by reacting 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-4-amine with a suitable isocyanate, using the general methodology of Examples 53-66 outlined above. 100 KN, sn, 491.3

M o. also (2) on 70th chn, eny 385.2

M fe Di sv she o ud, 102 MN, reg 395.2 " o a

I

(v

Ken, 103 I Mn, day, 413.2 se ra o

Y M ge) t o - in sn. "I - 104 Mn, sn, 433.2 !

M o i i i U | at

M

- n -O o i - 105 Mn, Dn. 439.2

M o

M

A - « t o - s i o, ; t nya, sn, 4472 and Z- still o yuyu (95) sn, 4! 107 kN, sn, avia

M, y - («c) и ve (c) и" -

M. -

IS

108 MN, |. 582

M o

M Z o oz still o dk -

M still bo x b5

Mn, 6 4582

M. and also -

KO yav cho MA, y, 4512

M u 5-7 70 u o ch sn, t kin, sn 261.2

M ge) t o - ten sun, 12 yav, sia, avt

M u 7 a o po i si sch o) 13 kn, sn, 2571 we o

FO - "And from still - Fr

Ka yu 114 MN, sn 478

So about

M she - them

Shch- Zo n so 415 MN; SN 27841

M h o h sh o Z s - n - h Y vai I

I" Ou chi6 MN, dz 502

M

WITH

- | and also about (95) yah - th 1 in s («in)

ХТ» ime) because b5

117 MA, SN, 501.2 o

E is from 501.0, 503.1 zi, so where o i si n H r si 119 Mn; b 51, 513 in ! I t o o

M. n

Ve

Examples 120-122

The examples in the table below are obtained according to the method of synthesis of the above reaction scheme

AI using the following method. 1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-4-amine (5OmgHg), diisopropylethylamine (34µl), dichloromethane (2ml) and carbamyl chloride (1.1eq .) was placed in a bottle with a volume of 2 drachms (7.4 ml). The bottle was placed on a shaker for approximately 2 hours at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei! Rak C18 column, 35 mmx2Omm, particle size 5 microns, 20 ml/min., eluent gradient from 5-9595 V in 10 min., maintained at 9590

In the course of 2 minutes, where A-0.196 with a solution of trifluoroacetic acid/water and B-0.195 with a solution of trifluoroacetic acid/acetonitrile, the inclusion of fractions with a peak at 254 nm). Semi-preparation fractions. VRRC were analyzed using I C-ARSI/M5 and suitable fractions were combined and lyophilized to obtain the trifluoroacetic acid salt of the desired urea. yu so 120 Cha s 4413 o

A t-vk ve o yah n still « 121 Mn, 8 427.2

M,

So - s u o ;" thanks

Co. 122 MN, SN, 411.3

M o - a rya (95) nch o k- v o o o Examples 123-124

Their" Examples in the table below are obtained according to the method of synthesis of the above reaction Scheme II by the reaction /1-(4-aminobutyl)-2-(4-methoxyphenylmethyl)-1H-imidazo|4,5-c|quinoline-4- amine with a suitable isocyanate using the general technique of Examples 53-66 above.

F) name) 60 b5

123 o-sn, 461.3 nn, h va,

Ts m 6

I on, 124 o-sn, 495.3 to h Ba, we ay (si k- t Examples 125-131

The examples in the table below are obtained according to the method of synthesis of the above reaction Scheme II using the following method. 1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-4-amine (5OmgHg), dichloromethane (2mL) and thioisocyanate (1.1eq.) were placed in a vial in 2 drachms (7.4 ml). The bottle was placed on the sonicator for approximately 30-60 minutes at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei! Rak C18 column, Zbmmx20Omm, particle size 5 microns, 20 ml/min., eluent gradient from 5-9595 V ip 10 min., maintained at 95956 V for 2 min., mPpege A-0.190 solution of trifluoroacetic acid/water and B-0.195 solution of trifluoroacetic acid/acetonitrile, including fractions with a peak at 254nm). Semi-preparation fractions. The HRVs were analyzed by IS-ARSI/M5 and suitable fractions were pooled and lyophilized to give the trifluoroacetic acid salt of the desired thiourea. (o) y Structure of the free base Weight 125 Я сн, 450 mm о ! To "I study about -

ОО ой и сн. 5422 0 o shk che n no more 127 M sn, 5 « otsi y - s ko

WITH

M. khz" i

What) 128 N sn, 248 s de aa ! not this

With sl - sh («c) s»

F) name) 60 b5

129 kN, azi

MM, ; don't sleep

I sun, 136 MN, sun, 4292 m at 10 fi Bai sun. ns-I-vbn, a rya i 131 n, 4982 " M schel lo sn, t v,

Examples 132-137

The examples in the table below were prepared using the synthesis method shown above

MI reaction schemes.

Part A

The starting materials of tetrahydroquinolinamine were obtained as follows. A catalytic amount of platinum oxide C (IM) was added to a solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo|4,5-c|quinolin-4-amine (2.2g, 7.Obmmol) in trifluoroacetic acid (200ml). The reaction mixture was hydrogenated at B5Ops (3.445109Pa) on a Parr apparatus for 6 days. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo.

The residue was combined with 1M hydrochloric acid (1O0Oml) and heated on a steam bath for 2 hours. The mixture was cooled, made basic by adding ammonium hydroxide, then extracted with dichloromethane. Extract Z was concentrated in a vacuum to obtain 1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro o -1H-imidazo|4,5-c)quinoline-4-amine in the form of a solid substance, melting point 63-6790.

A catalytic amount of platinum oxide (M) was added to a solution of Scheo, 1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo|4,5-cquinolin-4-amine (7.7g, 24.5mmol) in trifluoroacetic acid ( 250 ml). The reaction mixture was hydrogenated at 5 BOps (3.44x109 Pa) on a Parr apparatus. The progress of the reaction was monitored by LC/MS. Additional catalyst was added on 7, 11, and 17 days from the start of the reaction. After 25 days - the reaction was completed. The reaction mixture was filtered through a layer of Seille filter device? to remove the catalyst and the filtrate was concentrated in a vacuum. The residue was combined with 1M hydrochloric acid (1O0Oml) and stirred overnight. The mixture was made basic (pH-11) by adding ammonium hydroxide and then extracted with dichloromethane (333x3000ml). The extracts were combined and concentrated in a vacuum to obtain 3.5 g of 1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo|4,5-c)quinoline-4- amine in the form of a solid substance. c Part B "z Tetrahydroimidazoquinoline amines from Part A were reacted with a suitable isocyanate or sulfonyl isocyanate using the general procedure of Examples 53-66 above to give the trifluoroacetic acid salt of the desired urea or sulfonyl urea. -I (95) 1 o 50 "z"

F) name) 60 b5

132 chn, sn, y 28320 - - n -O 133 Mn, rn; 449.2 mm, that is

She their KN, rya Zva2 in HU DY

M

With (c)

M. not 135 MN, sleep; 4312

M o

Not about (OB; ch. 6)

The structure of the free base 136 МН, у. N, 4372

M o o n - yu 137 yin sn, 4984

M so i t va i - (o; ko nu to du Examples 138-140 p

The examples in the table below are obtained according to the method of synthesis of the above Scheme of reaction with MI using the following technique. /1H-Imidazo|4,5-c|quinolin-4-amine (5Omg), dichloromethane (2ml) and :z» sulfonyl isocyanate (1.Eq.) were placed in a bottle with a volume of 2 drachms (7.4ml). The bottle was placed on a shaker at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei! Rak C18 column, ZoOmmx2Omm, particle size 5 microns, 20 ml/min., eluent gradient from 5-9595 V for 1 min., maintained at 95905 V for 2 min., where A -0.195 trifluoroacetic acid/water solution and B-0.190 (95) trifluoroacetic acid/acetonitrile solution, inclusion of fractions with a peak at 254nm). Semi-preparation fractions. sl VRRH were analyzed with the help of IC-ARSI/M25, suitable fractions were combined and lyophilized to obtain the trifluoroacetic acid salt of the desired sulfonylurea. (c) "with"

F) name) 60 b5

138 MN, sn, 295.2 c

N

NS

MIN, SN, 4850

Sh b av ch-r. - tn, H 501.0. 5030 m /7

She and ro fe

Example 141

M1-4-I(4-Amino-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-1-yl|butyl)-M 3-benzourea trifluoroacetate mn, in

M

Же х ж-/ и щ t о о я- о, о "

This compound was obtained according to the method of synthesis of the above reaction Scheme M. 1--4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-4-amine (5Omg), dichloromethane (2 ml) and o-benzoyl isocyanate (1.1 eq.) were placed in a bottle with a volume of 2 drachms (7.4 ml). The bottle was placed on a shaker for 2 hours at ambient temperature. The reaction mixture was analyzed using

LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative VRRH (Sarsei! Rak C18 column, ZoOmmx2Omm, micron particle size, 20ml/min., eluent gradient from 5-9595 V for 10 min., maintained at 9595 V for 2 min., where A- 0.195 solution of trifluoroacetic acid/water and B-0.195 solution of trifluoroacetic acid/acetonitrile, inclusion of fractions with a peak at 254 nm).

Semi-preparation fractions. The RPCs were analyzed by IC-ARSI/M5 and suitable fractions were pooled and lyophilized to give the trifluoroacetic acid salt of the desired compound. M5 (ARSI) m/e 461.2 (MAN).

Example 142 - with M-(4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo|4,5-s|quinolin-1-yl|sutil)carbamate and trifluoroacetate;» in m ome

GO em - and more

OO 8) - (9! o a 7 o s»

This compound was obtained according to the synthesis method of the IM reaction scheme given above. 1--4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-4-amine (5mg), diisopropylethylamine (1.2eq), dichloromethane (2ml) and benzyl chloroformate ( 1.1 eq.) was placed in a bottle with a volume of 2 drachms (7.4 ml). o The bottle was placed on a shaker for 2 hours at ambient temperature. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The solvent was removed and the residue was purified by semi-preparative HPLC (Sarsei! Rak C18 column, ZbOmmx2Omm, particle size 5 microns, 2Oml/min., eluent gradient from 5-9595 V for 10 min., maintained at 95905 V for 2 min., where A -0.195 solution of trifluoroacetic acid/water and B-0.195 solution of trifluoroacetic acid/acetonitrile, inclusion of fractions with a peak at 254nm). Semi-preparation fractions. The PPRCs were analyzed by IC-APSMM5 and suitable fractions were combined and lyophilized to give the trifluoroacetic acid salt of the desired compound. M5 (ARSI) m/e 448.2 (MN).

CYTOKINE INDUCTION IN HUMAN CELLS

65 To determine the cytokine induction by the compounds according to the present invention, the human blood cell system i.p. miigo was used. Activity was based on the measurement of interferon and tumor necrosis factor (A) (IEM and

TIME, respectively), which were isolated in the culture medium as described in Teviegtap ey. a!., p.

Preparation of blood cells for culture

All blood was collected by venipuncture in the flasks of the EOTA vacuum container from healthy people - blood donors. Peripheral blood mononuclear cells (PBMCs) were separated from whole blood by density gradient centrifugation using Nizioradtset-1077 (Zidta Spetisai5, ZI. Gotsiz, Moscow). PCMKs were suspended at 3-4x10 cells/ml in ERMI 1640 medium containing 1095 fetal bovine serum solution, 2 mm

I-glutamine and 195 penicillin/streptomycin solution (CRMI complete). PKMKn suspension was added to 48-well cuvettes with 70 flat bottoms and sterile tissue culture (Soviag, Satrbgidde, MA or Vesiop RiskKipgop I arzhmage, I ipsoip

Cancer, M), which contained the same 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 wells.

Incubation

The solution of the tested compound was added at bΩm to the first well, which contained complete KRMI, and a series of solutions (trifold or decafold) was made. The PKMK suspension was added to the wells in the same volume, bringing the concentration of the test compound to the desired level. The final concentration of the suspension is 1.5-2X10 cells/ml. The cuvettes were covered with sterile plastic lids, gently mixed, and then incubated for 18 to 24 hours at 372C in 595 atmospheres of hydrogen dioxide.

Department

After incubation, the cuvettes were centrifuged for 5-10 minutes at 1000 rpm. (7200 xg) at 420. The cell culture supernatant was isolated with a sterile polypropylene pipette and transferred to sterile polypropylene flasks.

Samples were kept at -30 to -702C until analysis. Samples were analyzed for interferon (A) using either c 29 VA or bioassay and for tumor necrosis factor (A) using EI IZA. Gee)

Analysis of interferon (A) and tumor necrosis factor (A) using EGISA

The concentration of interferon (A) was determined with the help of EGISA using the Nytap Miiki-Zresiez kit from RVI. Vioteaisai! And arogaigiez, Mem Vhypemuisk, MU.

The concentration of tumor necrosis factor (A) (TME) was determined with the help of EI IZA kits, which are available in sepgut, C

Satrgidade, MA; KO Zuzietv, Mippearoiis, MM; or Rpagtipdep, Zap Oiedo, APPROX. aw!

The table below provides the lowest concentrations at which interferon is induced and the lowest concentrations at which tumor necrosis factor is induced for each compound. The sign """ indicates that no induction was detected at the concentrations that were tested (0.12, 0.37, 1.11, 3.33, 10 and ZOμm). The sign "xx" indicates that no induction was detected at concentrations that were tested (0.0001, 0.001, 0.01, 01, 1 and 10μm).

F

I" uy o yu v dv for 1.11 10 o and I pe p ti NE in Po to sch 2 o t z oyu so z ts " yu z e iz" in fe - pis tyny skh

Sum them up in 5 tko: 142 0.0001 0.1

9 The present invention has been described with reference to some of its embodiments.

The foregoing detailed description and examples are provided for clarity of understanding only and are not intended to be overly restrictive.

It is obvious to those skilled in the art that many changes can be made to the described embodiments without departing from the spirit and scope of the invention.

Therefore, the scope of the invention should not be limited to the smallest details of the compositions and structures in it

70 are described, or rather, by the following claims.

Claims (1)

The formula of the invention 1. Compound of formula (1): MN. that) M n | - Ez KK; Ki sch Ky o in which Ku is -alkyl-МК5-СУ-МК 5-Х-К. or -alkenyl-MKa-СХ-МК 5-Х-Ку; where U is BO or -5; With X is a bond, -CO- or -505-; Av K. is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl; alkenyl co; aryl; - heteroaryl; heterocyclyl; substituted aryl; " substituted heteroaryl; 70 substituted heterocyclyl; 8 s O-alkyl; : c» O-(alkyl)o 1-aryl; O-(alkyl)o 4-substituted aryl; O-(alkyl)o 4-heteroaryl; O-(alkyl)o 4-substituted heteroaryl; and O-(alkyl)o 4-heterocyclyl; oz O-(alkyl)o of 4-substituted heterocyclyl; soon and CO-O-alkyl; av | 20 CO-alkyl; C(O)0 o-alkyl; 8(O)o.o-(alkyl)ol-aryl; C(O)0 o-(alkyl)o 4-substituted aryl; C(O)0 o-(alkyl)o 4-heteroaryl; C(O)0 o-(alkyl)o 4-substituted heteroaryl; HF) Z(O)O.o-(alkyl)o 4-heterocyclyl; kyu З(О)0»-(alkyl)о of 4-substituted heterocyclyl; (alkyl)o.4-MAKzz; (alkyl)o 4-MK3-CO-O-alkyl; 60 (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o.4-MKz3-CO-substituted heteroaryl; 65 Ma: halogen; haloalkyl; haloalkoxy; CO-haloalkyl; MO"; SM; ON; ZN; and, in the case of alkyl, alkenyl or heterocyclyl, oxo; 70 provided that X is a bond, K; may additionally be hydrogen; E" is selected from the group consisting of: hydrogen; alkyl; alkenyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; alkyl-O-alkyl; alkyl-O-alkenyl; and alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: OH; halogen; M(K3)"; c in SO-MAz SO-S. zralkilu; i) СО-О-С 4 4ralkilu; Ma; aryl; "E from a substituted aryl; heteroaryl; o substituted heteroaryl; yu heterocyclyl; substituted heterocyclyl; me) CO-aryl; и- CO-(substituted aryl); CO-heteroaryl and CO-(substituted heteroaryl); each Kz is independently selected from the group consisting of hydrogen and C.4.4o alkyl; "KB is selected from the group consisting of hydrogen and C4alkyl, or K and K5 together form a 3-7-membered heterocyclic or substituted heterocyclic ring; n is from 0 to 4, and each K present is independently selected from the group consisting of C 4-4 alkyl, C 4-4 alkyl, C 4-4 alkyl, ; halogen and trifluoromethyl, or its pharmaceutically acceptable salt. 2. The compound according to item 1, in which X is a bond and Y is 50. -And 3. The compound according to item 2, in which np is 0. 4. The compound according to item 2, in which Kz is hydrogen. o 5. The compound according to point 2, in which K. is -"""СНа)".А-МК53-СО-МА 5-Ка. c 6. The compound according to item 2, in which Co is selected from the group consisting of hydrogen, alkyl, alkyl-O-alkyl; 5or C(alkyl)o-aryl, (alkyl)o.1-(substituted aryl); (alkyl)o.-heteroaryl and (alkyl)o.-(substituted heteroaryl). o 7. The compound according to item 2, in which K » is selected from the group consisting of hydrogen; C 4 alkyl and i" Si dalalkyl-O-C. far away 8. Compound according to item 2, in which Ku. is alkyl, phenyl or pyridyl, which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: alkyl; alkenyl; (F, aryl; ka heteroaryl; heterocyclyl; 60 substituted aryl; substituted heteroaryl; substituted heterocyclyl; O-alkyl; O-(alkyl)o.-aryl; 65 O-(alkyl)o 4-substituted aryl; O-(alkyl )o 4-heteroaryl; O-(alkyl)o 4-substituted heteroaryl; O-(alkyl)o 4-heterocyclyl; O-(alkyl)o of 4-substituted heterocyclyl; soon CO-O-alkyl; CO-alkyl; C(O)0 o-alkyl; C(O)o-2-(alkyl)o--aryl; 70 C(O)0 o-(alkyl)o 4-substituted aryl; C(O)0 o-(alkyl)o 4-heteroaryl; C(O)0 o-(alkyl)o 4-substituted heteroaryl; C(O)O.o-(alkyl)o 4-heterocyclyl; C(O)o0.o-(alkyl)o.4-substituted heterocyclyl; (alkyl)o.4-MAKzz; (alkyl)o.4-MKz-CO-O-alkyl; (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o.4-MKz3-CO-substituted heteroaryl; Ma; halogen; haloalkyl; haloalkoxy; CO-haloalkyl; (8) MO"; SM; He; « from ZN; and, in the case of alkyl, oxo. 9. The compound according to item 2, in which K 4 is phenyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of methyl, methoxy, halogen, nitrile, nitro, trifluoromethyl and trifluoromethoxy. 10. The compound according to item 2, in which K 4 and K 5 together form a 3-7-substituted or unsubstituted me) heterocyclic ring. uh- 11. The compound according to item 2, in which K and K5 together form a substituted or unsubstituted pyrrolidine or morpholine ring. 12. The compound according to item 1, in which X is a bond and M is -5. 13. The compound according to item 12, in which np is 0. 14. The compound according to item 12, in which Kz is hydrogen. from p. 15. The compound according to item 12, in which K. is -"СНа)".А-МЕ5-СО-МК 5-Ку. . 16. The compound of claim 12, wherein Co is selected from the group consisting of hydrogen; alkyl; alkyl-O-alkyl; and?" (alkyl)ozaryl, (alkyl)o.4-(substituted aryl); (alkyl)o.-heteroaryl and (alkyl)o.4-(substituted heteroaryl). 17. The compound according to item 12, in which K o" is selected from the group consisting of hydrogen, C /4 alkyl and 45. Si-dalkil-O-S. far away -And 18. Compound according to item 12, in which K.; is alkyl, phenyl or pyridyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: and alkyl; with alkenyl; aryl; o 29 heteroaryl; i" heterocyclyl; substituted aryl; substituted heteroaryl; substituted heterocyclyl; O-alkyl; F) O-(alkyl)o 1-aryl; ka O-(alkyl)o 4-substituted aryl; O-(alkyl)o 4-heteroaryl; in O-(alkyl)o 4-substituted heteroaryl; O-(alkyl)o 4-heterocyclyl; O-(alkyl)o of 4-substituted heterocyclyl; soon CO-O-alkyl; 65 CO-alkyl; C(O)0 o-alkyl; C(O)o-2-(alkyl)o--aryl; C(O)0 o-(alkyl)o 4-substituted aryl; C(O)0 o-(alkyl)o 4-heteroaryl; C(O)0 o-(alkyl)o 4-substituted heteroaryl; C(O)O.o-(alkyl)o 4-heterocyclyl; C(O)O»-(alkyl)o of 4-substituted heterocyclyl; (alkyl)o.4-MAKzz; (alkyl)o.4-MKz-CO-O-alkyl; 70 (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o 4-MK3-CO-substituted heteroaryl; Ma; halogen; haloalkyl; haloalkoxy; CO-haloalkyl; MO"; SM; ON; ZN; and, in the case of alkyl, oxo. 19. The compound according to item 12, in which K.; is phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, methoxy, halogen, nitrile, nitro, trifluoromethyl and trifluoromethoxy. and) 20. The compound according to item 12, in which K 4 and K 5 together form a 3-7-membered substituted or unsubstituted heterocyclic ring. 21. The compound according to item 12, in which Ku; and K5 together form a substituted or unsubstituted pyrrolidine or z zo Mmorpholine ring. 22. The compound of claim 1, wherein X is a bond and K/4 is hydrogen. at 23. The compound according to item 1, in which M is -O and X is -CO.-. yu 24. The compound according to item 23, in which n is 0. 25. The compound according to item 23, in which Kz is hydrogen. and) 26. The compound according to item 23, in which K.4 is -""СНа)".А-МК5-СО-МАК5-СО-Ку. uh- 27. The compound of item 23, wherein Co is selected from the group consisting of hydrogen; alkyl; alkyl-O-alkyl; (alkyl)ozaryl, (alkyl)o.4-(substituted aryl); (alkyl)o.-heteroaryl and (alkyl)o.4-(substituted heteroaryl). 28. The compound according to item 23, in which K is selected from the group consisting of hydrogen, Co ..dalkyl and Si dalkyl-O-C. far away " 29. Compound according to item 23, in which Ku. is alkyl, phenyl or pyridyl, which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: alkyl; from alkenyl; aryl; heteroaryl; -I heterocyclyl; substituted aryl; o substituted heteroaryl; c substituted heterocyclyl; O-alkyl; o 20 O-(alkyl)o.-aryl; і» O-(alkyl)o of 4-substituted aryl; O-(alkyl)o 4-heteroaryl; O-(alkyl)o 4-substituted heteroaryl; O-(alkyl)o 4-heterocyclyl; O-(alkyl)o of 4-substituted heterocyclyl; iF) soon; ka CO-O-alkyl; CO-alkyl; in З(О)0 o-alkyl; C(O)o-2-(alkyl)o--aryl; C(O)0 o-(alkyl)o 4-substituted aryl; C(O)0 o-(alkyl)o 4-heteroaryl; C(O)0 o-(alkyl)o 4-substituted heteroaryl; 65 C(O)O.o-(alkyl)o 4-heterocyclyl; C(O)O»-(alkyl)o of 4-substituted heterocyclyl; (alkyl)o.4-MAKzz; (alkyl)o.4-MKz-CO-O-alkyl; (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o.4-MKz3-CO-substituted heteroaryl; Ma; 70 halogen; haloalkyl; haloalkoxy; CO-haloalkyl; MO"; see ON; ZN; and, in the case of alkyl, oxo. 30. The compound according to item 23, in which CC; is phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, methoxy, halogen, nitrile, nitro, trifluoromethyl and 2o trifluoromethoxy. 31. The compound according to item 23, in which K; and Co together form a 3-7-membered substituted or unsubstituted heterocyclic ring. 32. The compound according to item 23, in which Ki K5 together form a substituted or unsubstituted pyrrolidine or morpholine ring. high school 33. The compound according to item 1, in which M is 50 and X is -5O»-. 34. The compound according to item 33, in which n is 0. i) 35. The compound according to item 33, in which Kz is hydrogen. 36. The compound according to item 33, in which K4 is -""СНо)".А-МК3-СО-МАК5-505-Ку. 37. The compound of item 33, wherein Co is selected from the group consisting of hydrogen; alkyl; alkyl-O-alkyl; "g from C(alkyl)o-aryl, (alkyl)o.1-(substituted aryl); (alkyl)o.«-heteroaryl and (alkyl)o.1-(substituted heteroaryl). 38. The compound according to item 33, in which K 2 is selected from the group consisting of hydrogen, C /44 alkyl and o C dalalkyl-O-C. far away yu 39. The compound according to item 33, in which K.; is alkyl or phenyl, which may be unsubstituted or substituted by one or more substituents selected from the group consisting of: o alkyl; і- alkenyl; aryl; heteroaryl; heterocyclyl; " substituted aryl; in c substituted heteroaryl; substituted heterocyclyl; from O-alkyl; O-(alkyl)o 1-aryl; O-(alkyl)o 4-substituted aryl; -I O-(alkyl)o 4-heteroaryl; O-(alkyl)o 4-substituted heteroaryl; o O-(alkyl) o 4-heterocyclyl; c O-(alkyl)o of 4-substituted heterocyclyl; soon o CO-O-alkyl; і» CO-alkyl; C(O)0 o-alkyl; C(O)o-2-(alkyl)o--aryl; C(O)0 o-(alkyl)o 4-substituted aryl; C(O)0 o-(alkyl)o 4-heteroaryl; Ф) З(О)о0.о-(alkyl)о 4-substituted heteroaryl; ka Z(O)O.o-(alkyl)o 4-heterocyclyl; C(O)O»-(alkyl)o of 4-substituted heterocyclyl; in (alkyl)o.4-MAKzz; (alkyl)o.4-MKz-CO-O-alkyl; (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; 65 (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o.4-MKz3-CO-substituted heteroaryl; Ma; halogen; haloalkyl; haloalkoxy; CO-haloalkyl; MO"; SM; He; 70 ZN; and, in the case of alkyl, oxo. 40. Compound according to item 33, in which K; is phenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, methoxy, halogen, nitrile, nitro, trifluoromethyl and trifluoromethoxy. 41. The compound according to item 33, in which K 4 and K 5 together form a 3-7-substituted or unsubstituted /5 Heterocyclic ring. 42. The compound according to item 33, in which Ki K5 together form a substituted or unsubstituted pyrrolidine or morpholine ring. 43. The compound according to item 1, in which the bonds marked with a dotted line are absent. 44. The compound according to item 2, in which the bonds marked with a dotted line are absent. 45. The compound according to item 12, in which the bonds indicated by a dotted line are absent. 46. The compound according to item 23, in which the bonds indicated by a dotted line are absent. 47. The compound according to item 33, in which the bonds indicated by a dotted line are absent. 48. Compounds selected from the group consisting of: N-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'-benzylurea; sc IM-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-N'-Ebutylurea; IM-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'(2-ethylphenyl)urea; i) IM-(4-(4-amino-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'-cyclohexylurea; M'-(4-(4-amino-1H-imidazoi|4,5-c)quinolin-1-yl)butyl)|-M-methyl-M-phenylurea; IM-(2-(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)ethyl|-M'-phenylurea; "g zo IM-(2-(4-amino-2-butyl-1H-imidazo|4,5-c|quinolin-1-yl)ethyl|-M'"(4-phenoxyphenyl)urea; IM-(2 -(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)ethyl|-M'-benzylurea; o IM-(2-(4-amino-2-butyl-1H) -imidazo|4,5-c)quinolin-1-yl)ethyl|-N'-propylurea; -1-ylphiethyl M'-propylurea; M-12-(4-amino-2-(ethoxymethyl)-1H-imidazoi|4,5-c|quinolin-1-ilyethyl)-M'-phenylurea; me) M-12 -(4-amino-2-(ethoxymethyl)-1H-imidazoi|4,5-c|quinolin-1-yl)|yl)-N'-cyclohexylurea; y- M-12-(4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5-c|quinolin-1-yl)|yl)-M'- cyclohexylureas; M-42-(4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5-c|quinolin-1-yl)|yl)-M'-phenylurea; IM-(4-(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-N'-propylurea; IM-(4-(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'-K15)-1-phenylethyl|urea; « IM-(4-(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'-K1K)-1-phenylethyl|urea; with c IM-(4-(4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'(2-methoxyphenyl)urea; . M-(4-acetylphenyl)-M-I4-(4-amino-2-butyl-1H-imidazo|4,5-c|quinolin-1-yl)butyl|urea; and?" IM-(4-(4-amino-2-butyl-1H-imidazo|4,5-c|quinolin-1-yl)butylI-M'-I4--(dimethylamino)phenyl|urea; IM-(4- (4-amino-2-butyl-1H-imidazo|4,5-c)quinolin-1-yl)butyl|-M'(4-methoxybenzyl)urea; M-(4-(4-amino-2-( 2-methoxyethyl)-1H-imidazoi|4,5-c|quinolin-1-yl|Ibsutyl)-M'-propylurea;-I M-(4-(4-amino-2-(2-methoxyethyl)-1H -imidazoi|4,5-cIquinolin-1-yl|bbutyl)-M'-phenylurea; M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-c|quinoline -1-yl|Ibsutil)-M'-cyclohexylurea; o M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-c|quinolin-1-yl|butyl/ )|-ME(3-methylphenyl)urea; c M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-c|quinolin-1-yl|bsutil) -M'-(3-fluorophenyl)urea; M7-4-I(d-amino-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-1-yl|butyl-4-morpholinecarboxamide o M-(4-(4-amino-2-(4-methoxybenzyl)-1H-imidazoi|4,5-c|quinolin-1-yl|butyl)-M'-propylurea; Chl» M-(4 -(4-amino-2-(4-methoxyethyl)-1H-imidazo|4,5-c)quinolin-1-yl|brutil)-M'-phenylurea and M-(4-(4-amino-2- (4-methoxybenzyl)-1H-imidazo|4,5-c|quinol yn-1-yl|butyl)-M'-(3-pyridyl)urea. 49. Compounds selected from the group consisting of: IM-(4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo|4,5-c|quinoline-1- yl)butyl|-M'-benzylurea; o M'-14-(4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo|4,5-c|quinoline -1-yl|IrsSutil)-M,M-dimethylurea; m co --A-(4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5 -siquinolin-1-yl|sutil)-4-morpholinecarboxamide: and M-(4-(4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo|4,5 -siquinolin-1-yl|b-butyl)-M'-phenylurea. in 50. Compounds selected from the group consisting of: M-12-(4-amino-2-(ethoxymethyl)-1H-imidazoi|4,5 -c|quinolin-1-yl)ethyl)-M'-cyclohexylthiourea; IM-(4-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo|4,5-c |quinolin-1-yl)butyl|-M'-cyclohexylthiourea; M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-c|quinolin-1-yl|bbutyl )-M'-(3-pyridyl)thiourea; M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-1-yl|brutil)-M '-(4--Dimethylamino)-1-naphthyl)thiourea, M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi) 4,5-siquinolin-1-yl|ibsutil)-N'-propylthiourea; M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-c|quinolin-1-yl|Ibsutyl)-M'-phenylthiourea; M-(4-(4- amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5-c|quinolin-1-yl|bbutyl)-M'-phenylthiourea; M-allyl-M' -74-(4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo|4,5-c|quinolin-1-yl|Ibrutylthioureas; M-(4-( 4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5-siquinolin-1-yl|bsutil)-N'-(tert-butyl)thiourea; M-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-1-yl|brsutil)-M'-(1-naphthyl)thiourea; M-( 4-(4-amino-2-(2-methoxyethyl)-1H-imidazoi|4,5-s|quinolin-1-yl|brutil)-M'-(tert-butyl)thiourea and M-allyl-M' -74-(4-amino-2-(2-methoxyethyl)-1H-imidazo|4,5-c|quinolin-1-yl|Ibrutylthioureas. 70 51. Compounds selected from the group consisting of: 4-amino -2-butyl-1-I4-H((phenylsulfonyl)amino|carbonylamino)butyl)-6,7,8,9-tetrahydro-1H-imidazoi|4,5-si)quinoline; 4-amino-2- butyl-1-4-(phenylsulfonyl)amino|carbonyl/amino)butyl|-1H-imidazo|4,5-c)quinoline; 4-amino-2-butyl-1 -14-((4-fluorophenyl)sulfonylamino)carbonyl)amino|butyl)-1H-imidazoi|4,5-s|quinoline; 4-amino-2-butyl-1-14-4(4-chlorophenyl)sulfonylamino)carbonyl)amino|butyl)-1H-imidazoi|4,5-s|quinoline; 4-amino-2-butyl-1-14-4(4-ethylphenyl)sulfonylamino)carbonyl)amino|butyl)-1H-imidazoi|4,5-s|quinoline; 4-amino-2-(2-methoxyethyl)-1-4-(4(4-methylphenyl)sulfonylamino)carbonyl)amino|butyl)-1H-imidazoi|4,5-xynoline; 4-amino-2-(2-methoxyethyl)-1-I4-4((phenylsulfonyl)amino|carbonyl)amino)butyl/)-1H-imidazoi|4,5-s|quinoline; 4-amino-2-(ethoxymethyl)-1-(2-H(phenylsulfonyl)amino|carbonylamino)ethyl/|-1H-imidazo|4,5-c)quinoline; 4-amino-2-butyl-1-2-(4(4-methylphenyl)sulfonyl|iamino)carbonyl)amino|ethyl)-1H-imidazo|4,5-c)quinoline.: and 4-amino-2- butyl-1-12-I4(4-chlorophenyl)sulfonylamino)carbonyl)amino|ethyl)-1H-imidazoi|4,5-s|quinoline. 52. A pharmaceutical composition containing a therapeutically effective amount of a compound of the formula Ia: МН 0O-K. or -alkenyl-МК53-СО-О-К,; K. is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted with one or more substituents selected from the group consisting of: "20 alkyl; s-v alkenyl; with aryl; :z» heteroaryl; heterocyclyl; 415 substituted aryl; -1 substituted heteroaryl; substituted heterocyclyl; i95) O-alkyl; c O-(alkyl)o.-aryl; O-(alkyl)o 4-substituted aryl; («in O-(alkyl)o 4-heteroaryl; T» O-(alkyl)o 4-substituted heteroaryl; O-(alkyl)o 4-heterocyclyl; O-(alkyl)o 4-substituted heterocyclyl; soon; CO -O-alkyl; (F; CO-alkyl; HI З(О)0 o-alkyl; З(О)о0-2-(alkyl)о--aryl; О З(О)0 o-(alkyl)о 4-substituted aryl; C(O)o0.o-(alkyl)o -heteroaryl; C(O)0 o-(alkyl)o 4-substituted heteroaryl; C(O)0.o-(alkyl)o 4- heterocyclyl, 3(O)O'-(alkyl)o 4-substituted heterocyclyl, 65 (alkyl)o 4-MEzEz, (alkyl)o,4-MKz-CO-O-alkyl; (alkyl)o.4-MKz-CO-alkyl; (alkyl)o.4-MKz-CO-aryl; (alkyl)o.4-MKz-CO-substituted aryl; (alkyl)o.4-MKz-CO-heteroaryl; (alkyl)o.4-MKz3-CO-substituted heteroaryl; Ma; halogen; haloalkyl; 70 haloalkoxy; CO-haloalkyl; MO"; SM; ON; ZN; and, in the case of alkyl, alkenyl or heterocyclyl, oxo; E" is selected from the group consisting of: hydrogen; alkyl; alkenyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; alkyl-O-alkyl; ch alkyl-O-alkenyl; and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: i) OH; halogen; M(K3)"; chE zo SO-M(Vz)"; СО-С.4 zralkilu; about СО-0-С. zralkilu; Yu Ma; aryl; substituted aryl co; і - heteroaryl; substituted heteroaryl; heterocyclyl; substituted heterocyclyl; « CO-aryl; with CO-(substituted aryl); CO-heteroaryl and ;" CO-(substituted heteroaryl); each Kz is independently selected from the group consisting of hydrogen and C 1-4 alkyl; n is from 0 to 4 and each K present is independently selected from the group consisting of C-4alkyl, C-4alkyl, -I halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier. o 53. A pharmaceutical composition comprising a therapeutically effective amount of a compound specified in any one of clauses 1, 2, 12, 23 or 33 in combination with a pharmaceutically acceptable carrier. 54. A method of inducing cytokine biosynthesis in an animal, in which the animal is prescribed a therapeutically active amount of the compound specified in any of items 1, 2, 12, 23 or 33. 55. A method of treating a viral disease in an animal, in which the animal is prescribed to the animal an effective amount of a compound specified in any of paragraphs 1, 2, 12, 23 or 33. 56. A method of treating a neoplastic disease in an animal, in which the animal is prescribed an effective amount of the compound specified in any of items 1, 2, 12, 23 or 33. F) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits", 2005, M 8, 15.08.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5