SK7142003A3 - Substituted imidazopyridines - Google Patents

Abstract

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

Description

Technical field

The present invention relates to imidazopyridine compounds having a substituted amine functionality at the 1-position, and pharmaceutical compositions containing such compounds. Another aspect of the invention relates to the use of these compounds as immunomodulators, for inducing cytokines in animals and in the treatment of diseases, including viral and tumor diseases.

BACKGROUND OF THE INVENTION

The first reliable study of the 1H-imidazo [4,5-c] quinoline cyclic system by Backman et al., J. Qrg. Chem. 15, 1278-1284 (1950) describes synthesis

1- (6-methoxy-8-quinolinyl) -2-methyl-1H-imidazo [4,5-c] quinoline for its possible use as an anti-malaria agent. Later, syntheses of various substituted 1H-imidazo [4,5-c] quinolines have been reported. For example, Jain et al., J. Med. Chem. 11, p. 87-92 (1968) synthesized 1- [2- (4-piperidyl) ethyl] -1H-imidazo [4,5-c] quinoline as a possible antispasmodic and cardiovascular agent. Also Baranov et al., Chem. Abs. 85, 94362 (1976) published several 2-oxo imidazo [4,5-c] quinolines and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981) reported certain 2-oxoimidazo [4,5-c] quinolines.

Later it was found that certain 1H-imidazo [4,5-c] quinolin-4-amines and their 1-

2-substituted derivatives can be used as antiviral agents, bronchodilators and immunomodulators. These are described, inter alia, in U.S. Pat. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905 and 5,389,640, all of which are incorporated herein by reference.

The substituted 1H-imidazopyridin-4-amine compounds may be useful as immune response modifiers as described in U.S. Pat. 5,446,153; 5,494,916 and 5,644,063. The compounds disclosed in these patents have no amine-containing substituent at the 1-position. Certain 1H-imidazo [4,5-c] quinolin-4-amines having an amide, sulfonamide or urea functionality at the 1-position are described in publications. PCT WO 00/76505; WO

00/76518 and WO 00/76519.

Despite these recent discoveries of compounds that can be used as immune response modifiers, there is still a need for compounds that would have the ability to modulate the immune response by inducing cytokine biosynthesis or other mechanisms.

SUMMARY OF THE INVENTION

We have discovered a new class of compounds that can be used to induce cytokine biosynthesis in animals. Accordingly, the present invention provides compounds of the imidazopyridin-4-amine having a substituted amine functionality at the 1-position. Compounds which have been found to be useful in inducing bio-synthesis of cytokines are defined by Formula (I), which is described below. detail. The formula (I) is as follows:

wherein X, Y, Z, R 1, R ₂ , R 1, R ₄ and R 5 are as defined herein.

The compounds of formula (I) may be useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes these compounds useful in the treatment of various disease states, such as viral diseases and tumors, that respond to such changes in the immune response.

The invention further provides pharmaceutical compositions comprising immune response modifying compounds and methods for inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and / or treating a cancer in an animal by administering a compound of formula (I) to the animal.

In addition, the present invention provides methods of synthesizing the compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As already mentioned, we have found that certain compounds induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formula (I) below.

(I) wherein: X is alkylene or alkenylene;

Y is -CO-, -CS- or -SO ₂ -;

Z is a bond, -O-, -S- or -NR 5 -;

R _t is aryl, heteroaryl, heterocyclyl, C1-20 alkyl or C2.20 alkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of:

alkyl;

-alkenyl;

aryl;

-heteroaryl;

-heterocyclyl;

-substituted cycloalkyl;

-O-alkyl;

-O- (alkyl) _O -aryl;

-0- (alkyl) o-i-heteroaryl;

-0- (alkyl) o-i-heterocyclyl;

COOH;

-CO-O-alkyl;

-CO-alkyl;

-S (O) _0-2 -alkyl;

-S (0) o-2- (alkyl) o-i-aryl;

-S (0) _o-2 - (alkyl) heteroaryl et al;

-S (0) _o-2 - (alkyl) -heterocyclyl et al;

- (alkyl) _0-1 N (R ₅ ) ₂ ;

- (alkyl) o] -NR ₅ -CO-O-alkyl;

- (alkyl) _O -NR ₅ -CO-alkyl;

- (alkyl) OH in-NR-CO-aryl;

- (alkyl) et al -NR ₅ -CO-heteroaryl;

-Ν ₃ ;

-halogen;

-haloalkyl;

-haloalkoxy;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO ₂ ;

-CN;

OH;

SH; and in the case of alkyl, alkenyl and heterocyclyl oxo;

R ₂ is selected from the group consisting of:

-hydrogen;

alkyl;

-alkenyl;

-alkyl-O-alkyl;

alkyl-S-alkyl; .

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

OH;

-halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N _{(R) 2;}

-SO ₂ -N (R ₅ ) ₂ ;

-NR 5 -CO-C 1-10 alkyl;

-NR 5 -C 5 -C 1-10 alkyl;

-NR ₅ -SO ₂ -C 1-10 alkyl;

-CO- C 1-10 alkyl;

-CO-O-C 1-10 alkyl;

-N ₃ ;

aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

CO-heteroaryl;

R ₃ and R ₄ are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

Preparation of compounds

The compounds of the invention can be prepared according to Reaction Scheme I wherein R], R _2, R _3, R _4, R _s, X, Y and Z are as defined above, Bn is benzyl and R 'is alkyl of one to four carbon atoms, C1 -C4 perfluoroalkyl, phenyl or phenyl substituted by halogen or C1 -C4 alkyl.

In step (1) of Reaction Scheme I, a 3-nitropyridine-2,4-disulfonate having the formula X is reacted with an amine of the formula R 1 -ZYN (R 5) -X-NH ₂ to give 3-nitro-4-aminopyridine-2 of the sulfonate of formula XI. Due to the presence of two sulfonate groups which could in principle be removed, the reaction may give a mixture of products that can be readily separated by conventional techniques such as column chromatography. The reaction is preferably carried out by adding an amine to a solution of a compound of formula X in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. Since the sulfonate group is a relatively easily leaving group, the reaction can be carried out at a reduced temperature (0 ° C) to reduce the amount of unwanted 2-amino and 2,4-diamino by-products. 3-Nitropyridine-2,4-disulfonates are known and can be readily prepared by known synthetic methods, see, for example, Lindst, et al., U.S. Pat. No. 5,446,153 and references cited therein.

In step (2) of Reaction Scheme I, the 3-nitro-4-aminopyridine-2-sulfonate of formula XI is reacted with benzylamine to give the 2-dibenzylamino-3-nitropyridin-4-amine of formula XII. The reaction is carried out by mixing the compound of formula XI, dibenzylamine and a tertiary amine such as triethylamine in an inert solvent such as benzene, toluene or xylene and heating the resulting mixture.

In step (3) of Reaction Scheme I, the nitro group of 2-benzylamino-3-nitropyridin-4-amine of formula XII is reduced to the amino group. The reduction is preferably carried out using NiB ₂ which is formed in situ from sodium borohydride and nickel chloride hydrate in methanol. The reaction is preferably carried out at ambient temperature.

In step (4) of Reaction Scheme I, 2-dibenzylaminopyridine-3,4-diamine of formula XIII is reacted with a carboxylic acid or equivalent to give 4-dibenzylamino-1 H -imidazo [4,5- c] pyridine of formula XV . Suitable carboxylic acid equivalents include orthoesters and 1,1-dialkoxyalkylalkanoates. The carboxylic acid or equivalent is selected to provide the desired R ₂ substituent in the compound of Formula XV. For example, triethyl orthoformate provides a compound wherein R ₂ is hydrogen, and triethyl orthoacetate provides a compound wherein R ₂ is methyl. The reaction may be carried out in the absence of a solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to remove the alcohol or water that is formed as a by-product of the reaction. A catalyst such as pyridine hydrochloride can also optionally be used.

A compound of formula XV can also be prepared in two steps, (a) by reacting a diamine of formula XIII with an acyl halide of formula R ₂ C (O) Cl or R ₂ C (O) Br to form a compound of formula XIV and then (b) by cyclization. In step (4a), the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction may be carried out at ambient temperature. In step (4b), the product of step (4a) is heated in an alcoholic solvent in the presence of a base. The product of step (4a) is preferably heated under reflux in ethanol in the presence of excess triethylamine or heated with methanolic ammonia solution. Step (4b) can also be carried out by heating the product of step (4a) in pyridine. If step (4a) was carried out in pyridine, step (4b) may be carried out by heating the reaction mixture after analysis shows that step (4a) is complete.

In step (5) of Reaction Scheme I, 4-dibenzylamino-1 H -imidazo [4,5- c] pyridine of formula XV is hydrogenolyzed to give 4-amino-1 H -imidazo [4,5- c] pyridine with The compound of formula XV is preferably heated in formic acid in the presence of palladium hydroxide on carbon. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Reaction Scheme I

Compounds of the invention can be prepared according to Reaction Scheme II wherein R 1, R ₂ , R 3, R ₄ , R 5 and X are as defined above, Bn is benzyl, BOC is tert-butoxycarbonyl, and W is O or S.

In step (1) of Reaction Scheme II, the amine protecting groups of 1/7-imidazo [4,5-c] pyridine of formula XVI are removed to give 1, 7-imidazo [4,5-c] pyridine of formula II. A solution of the compound of formula XVI in a suitable solvent such as dichloromethane is preferably treated with trifluoromethanesulfonic acid at ambient temperature. Compounds of formula XVI can be prepared using the synthesis method described in Reaction Scheme I. In step (1), the 2,4-disulfonate of formula X is reacted with an amine of formula BOC-NR 5 -X-NH 2. Steps 2-4 are then performed as described above to give a compound of formula XVI, which is one of formulas corresponding to formula XV.

In step (2a) of Reaction Scheme II, 1 H -imidazo [4,5- c] pyridine of formula II is reacted with an acid chloride of formula R 1 -C (O) Cl or an acid anhydride of formula R 1 -C (O OC (O) -R 1 to give 17-imidazo [4,5-c] pyridin-1-ylamide of formula XVII, which is one of the formulas corresponding to formula I. The reaction is preferably carried out by adding an acid chloride or an acid anhydride to the of a compound of formula II in a suitable solvent such as dichloromethane or acetonitrile in the presence of a base such as triethylamine. The reaction can be carried out at reduced temperature (0 ° C) or at ambient temperature. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

In step (2b) of Reaction Scheme II, the 177-imidazo [4,5-c] pyridine of formula II is reacted with an isocyanate of formula R 1 -N = C = O or an isothiocyanate of formula R 1 -N = C = S to the formation of 1H-imidazo [4,5-c] pyridin-lylurea or thiourea of formula XVIII, which is one of the formulas corresponding to formula I. The reaction is preferably carried out by adding an isocyanate or isothiocyanate to a solution of a compound of formula II in a suitable solvent, such as dichloromethane at reduced temperature (0 ° C). The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

In step (2c) of Reaction Scheme II, 1 H -imidazo [4,5- c] pyridine of formula II is reacted with a sulfonyl chloride of formula R 1 -S (O) ₂ Cl or a sulfonate anhydride of formula R 1 -S (O) ₂ OS (O) ₂ -Ri to give 177-imidazo [4,5-c] pyridin-1-ylsulfonamide of formula XIX which is one of formulas corresponding to formula I. This reaction is preferably carried out by adding sulfonyl chloride or sulfonanhydride to a solution of the compound. of Formula II in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. The reaction may be carried out at reduced temperature (0 ° C) or ambient temperature. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Reaction Scheme II

Compounds of the invention can be prepared according to Reaction Scheme III wherein R 1, R ₂ , R ₃ , R 4, R 5 and X are as defined above.

In step (1) of Reaction Scheme III, 1H-imidazo [4,5-c] pyridine of formula II is reacted with sulfamoyl chloride of formula R 1 -N (R 5) S (O) ₂ Cl to give 1 H -imidazo [4] 5-c] pyridin-lylsulfamide of formula XXI, which is one of the formulas corresponding to formula I. Preferably, sulfamoyl chloride is added to a solution of a compound of formula II in a suitable solvent such as 1,2-dichloroethane in the presence of a base such as is triethylamine. The reaction may be carried out at elevated temperature. The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

The sulfamide of formula XXI can also be prepared in two steps, (a) reacting the 1H-imidazo [4,5-c] pyridine of formula II with sulfuryl chloride to in situ form the sulfamoyl chloride of formula XX, and then ( b) reacting the sulfamoyl chloride with an amine of the formula R 1 -N (R 5) H. In step (1a), the reaction is carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of the compound of formula II in the presence of 1 equivalent of 4- (dimethylamino) pyridine. The reaction is preferably carried out at a reduced temperature (-78 ° C). Optionally, after the addition is complete, the reaction mixture may be allowed to warm to ambient temperature. In step (1b), a solution containing 2 equivalents of R 1 -N (R 5) H and 2 equivalents of triethylamine in dichloromethane is added to the reaction mixture of step (1a). The reaction is preferably carried out at a reduced temperature (-78 ° C). The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Reaction Scheme III

R.

Compounds of the invention can be prepared according to Reaction Scheme IV wherein R 1, R ₂ , R 3, R 4, R 5 and X are as defined above and BOC is tert-butoxycarbonyl.

In step (1) of Reaction Scheme IV, 2,4-dihydroxy-3-nitropyridine of formula XXII is chlorinated with conventional chlorinating agents to give 2,4-dichloro-3-nitropyridine of formula XXIII. The compound of formula XXII is preferably mixed with phosphorus oxychloride and heated. Many 2,4-dihydroxy-3-nitropyridines of formula XXII are known and others can be readily prepared by known synthesis methods, see, for example, Lindst, et al., U.S. Pat. No. 5,446,153 and references cited therein.

In step (2) of Reaction Scheme IV, 2,4-dichloro-3-nitropyridine of the formula

XXIII is reacted with an amine of formula BOC-NR ₅ -X-NH ₂ to give 2-chloro-3-nitropyridine of formula XXIV. The reaction is preferably carried out by adding an amine to a solution of a compound of formula XXIII in a suitable solvent such as Ν, Ν-dimethylformamide in the presence of a tertiary amine such as trimethylamine.

In step (3) of Reaction Scheme IV, 2-chloro-3-nitropyridine of the formula

XXIV is reacted with phenol to give 3-nitro-2-phenoxypyridine of formula XXV. The phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form the phenoxide. The phenoxide is then reacted at elevated temperature with a compound of formula XXIV.

In step (4) of Reaction Scheme IV, the 3-nitro-2-phenoxypyridine is of the formula

XXV is reduced to give 3-amino-2-phenoxypyridine of formula XXVI. re-

The induction is preferably carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction may conveniently be carried out in a Parr apparatus in a suitable solvent such as isopropyl alcohol or toluene.

In step (5) of Reaction Scheme IV, the 3-amino-2-phenoxypyridine is of the formula

XXVI is reacted with a carboxylic acid or equivalent to give 4-phenoxy-1H-imidazo [4,5-c] quinoline of formula IV. Suitable carboxylic acid equivalents include orthoesters and 1,1-diakoxyalkylalkanoates. The carboxylic acid or equivalent is selected to provide the desired R ₂ substituent in the compound of Formula IV. For example, triethyl orthoformate provides a compound wherein R ₂ is hydrogen, and trimethyl orthovalerate provides a compound wherein R ₂ is butyl. The reaction may be carried out in the absence of a solvent or in an inert solvent such as toluene. The reaction is carried out with sufficient heating to remove the alcohol or water that is formed as a by-product of the reaction. A catalyst such as pyridine hydrochloride can also optionally be used.

Step (5) can also be carried out by (a) reacting a compound of formula XXVI with an acyl halide of formula R ₂ C (O) Cl or R ₂ C (O) Br and then (b) cyclization. In part (i), an acyl halide is added to a solution of a compound of formula XXV in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction may be carried out at ambient temperature. In part (ii), the product of part (i) is heated in pyridine.

In step (6) of Reaction Scheme IV, the BOC group is removed from the compound of Formula IV to give 4-phenoxy-1H-imidazo [4,5-c] quinoline of Formula V. To a solution of the compound of Formula IV in a suitable solvent, such as dichloromethane is treated with trifluoroacetic acid or hydrochloric acid at reduced temperature.

In step (7) of Reaction Scheme IV, 4-phenoxy-17 H -imidazo [4,5- c] quinoline of formula V is converted to 4-phenoxy-17 H -imidazo [4,5- c] quinolin-lylsulfonamide of formula VI using the method of step (2c) of Reaction Scheme II.

In step (8) of Reaction Scheme IV, the 4-phenoxy-1 H -imidazo [4,5- c] quinolin-1-ylsulfonamide of formula VI is aminated to give 4-amino-1 H -imidazo [4,5- c] quinoline- The reaction can be carried out by mixing the compound of formula VI with ammonium acetate in a sealed tube and heating (~ 150 ° C). The product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.

Reaction Scheme IV

The present invention also discloses novel compounds which are useful as intermediates in the synthesis of compounds of formula I. These intermediates have the structural formulas (II) - (VI), which are described in more detail below.

One class of intermediate compounds has the formula (II):

wherein: X is alkylene or alkenylene;

R 2 is selected from the group consisting of:

-hydrogen;

alkyl;

-alkenyl;

-alkyl-O-alkyl;

alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

OH;

-halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C 1-10 alkyl;

-NR ₅ -CS-C 1-10 alkyl;

-NR ₅ -SO ₂ -C 1-10 alkyl;

-CO-C 1-10 alkyl;

-CO-O-C 1-10 alkyl;

-N ₃ ;

aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

CO-heteroaryl;

R ₃ and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

Another class of intermediates has the formula III:

(III) wherein: Q is NO ₂ or NH ₂ ;

X is alkylene or alkenylene;

R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

Another class of intermediates has the formula (IV):

(IV) wherein: X is alkylene or alkenylene;

R-2 is selected from the group consisting of:

-hydrogen;

F

alkyl;

-alkenyl;

-alkyl-O-alkyl;

alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

OH;

-halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR ₅ -CO-C 1. ₁₀ alkyl;

-NR 5 -C 5 -C 10 alkyl;

-NR 5 -SO ₂ -C 1-10 alkyl;

-CO-C 1-10 alkyl;

-CO-O-C 1-10 alkyl;

-N ₃ ;

aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

CO-heteroaryl;

R ₃ and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

Another class of intermediates has the formula (V):

(IN)

in which: X is alkylene or alkenylene; R 2 is selected from the group consisting of: -hydrogen; alkyl; -alkenyl; -alkyl-O-alkyl; alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: -OH; -halogen; -N (R ₅ ) ₂ ; -CO-N (R ₅ ) ₂ ; -CS-N _{(R) 2;} -SO ₂ -N (R ₅ ) 2; -NR 5 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl;

-NR5-SO2-C1-10 alkyl;

-CO-C 1-10 alkyl;

-CO-O-C 1-10 alkyl;

-N ₃ ;

aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

CO-heteroaryl;

R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

Another class of intermediates has the formula (VI):

(VI)

in which: X is alkylene or alkenylene; R 1 is aryl, heteroaryl, heterocyclyl, C 1-20 alkyl or C ₂ . ₂ alkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of: -alkyl; -alkenyl; aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -O-alkyl; -O- (alkyl) _O -aryl; -0- (alkyl) o-1-heteroaryl; -O- (alkyl) _0-1 -heterocyclyl; COOH; -CO-O-alkyl; -CO-alkyl; -S (O) _0-2 -alkyl; -S (0) o-2- (alkyl) -aryl et al; -S (0) _o-2 - (alkyl) heteroaryl et al; -S (0) o-2- (alkyl) -heterocyclyl et al;

- (alkyl) _0-1 N (R ₅ ) ₂ ;

- (alkyl) _O, -NR ₅ -CO-O-alkyl;

- (alkyl) _O -NR ₅ -CO-alkyl;

- (alkyl) et al -NR ₅ -CO-aryl;

- (alkyl) and -NR 5 -CO-heteroaryl;

-N ₃ ;

-halogen;

-haloalkyl;

-haloalkoxy;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO ₂ ;

-CN;

OH;

SH; and in the case of alkyl, alkenyl and heterocyclyl oxo;

R ₂ is selected from the group consisting of:

-hydrogen;

alkyl;

-alkenyl;

-alkyl-O-alkyl;

alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted with one or more substituents selected from the group consisting of:

OH;

-halogen;

-N (R ₅ ) ₂ ;

-CO-N (R ₅ ) ₂ ;

-CS-N (R ₅ ) ₂ ;

-SO ₂ -N (R ₅ ) ₂ ;

-NR 5 -CO-C 1-6 alkyl;

-NR 5 -C 5 -C 1-10 alkyl;

-NR ₅ -SO ₂ -C 1-10 alkyl;

-CO-C 1-10 alkyl;

-CO-O-C 1-10 alkyl;

-N ₃ ;

aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

CO-heteroaryl;

R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl;

or a pharmaceutically acceptable salt thereof.

The terms "alkyl", "alkenyl" and the prefix "alk-" as used herein include both straight and branched chain groups and cyclic groups, i. j. cycloalkyl and cycloalkenyl. Unless otherwise stated, these groups contain 1 to 20 carbon atoms, alkenyl groups contain 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. The cyclic groups may be monocyclic or polycyclic and preferably have 3 to 10 carbon atoms per cycle. Examples of cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and adamantyl.

The term "haloalkyl" includes groups that are substituted with one or more halogen atoms, including perfluorinated groups. The same applies to groups containing the prefix "halogen -". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

The term "aryl" as used herein includes carbocyclic aromatic rings or cyclic systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term "heteroaryl" includes aromatic rings or cyclic systems containing at least one heteroatom (e.g., O, S, N) in a cycle. Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzfuranyl, benzthiopentyl, benzazolyl, benzazolyl, pyridoxinyl, pyroxyl, benzoxazolyl, pyrimidyl, benzoxazolyl, pyrido, , isoxazolyl, isothiazolyl, purinyl, quinazolinyl and the like.

"Heterocyclyl" includes non-aromatic rings or cyclic systems that contain at least one heteroatom (e.g., O, S, N) in a cycle and include all fully saturated and partially unsaturated derivatives of the above heteroaryl groups. Examples of heterocyclic groups include pyrrolidines 1, tet27 rahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl and imidazolidinyl.

The aryl, heteroaryl and heterocyclic groups may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkoxycarbonyl, haloalkoxycarbonyl, haloalkoxycarbonyl alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonyl amino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylsulphonylamino, alkenylsulphonylamino, arylsulphonylamino, arylalkylsulphonylamino, heteroarylsulphonylamino, heteroarylalkylsulphonylamino, alkylaminocarbonyarbonylamino, alkenylaminocinonylamino, alkenylaminocinonylamino, arylalkylsulphonylamino, arylalkylsulphonylamino, arylalkylcarbonylamino, arylalkylcarbonylamino, If any other groups are designated as "substituted" or "optionally substituted", then these groups may also be substituted by one or more of the substituents listed above.

Certain substituents are generally preferred. For example, preferred groups Y include -CO- and -SO 2 -; Z is preferably a bond or -NR 5 -; and R 1 is preferably C 1-4 alkyl, aryl or substituted aryl. Preferred R 2 groups include C 1 -C 4 alkyl groups (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl), methoxyethyl, ethoxymethyl, and cyclopropylmethyl. R3 and R4 are preferably methyl. One or more of these preferred substituents in any combination may be present, if present, in the compounds of the invention.

The present invention includes the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphic forms, and the like. In particular, if the compound is optically active, the invention expressly encompasses each of the enantiomers of the compound as well as racemic mixtures of enantiomers. .

Pharmaceutical preparations and biological activity

The pharmaceutical compositions of the invention comprise a therapeutically effective amount of any of the compounds of the invention described above with a pharmaceutically acceptable carrier.

The term "therapeutically effective amount" means that amount of a compound sufficient to produce a therapeutic effect, such as cytokine induction, anti-tumor activity, and / or antiviral activity. Although the exact amount of active compound used in the pharmaceutical composition of the invention will vary according to circumstances known to those skilled in the art, such as the physical and chemical nature of the compound, the nature of the carrier and the intended mode of administration, the compositions of the invention are contemplated sufficient active ingredient to provide the subject with a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 µg / kg to about 5 mg / kg of the compound. Any form of administration such as tablets, lozenges, parenteral preparations, syrups, creams, ointments, aerosol preparations, trandermal patches, transmucosal patches and the like can be used. .

The compounds of the invention may be administered as separate therapeutic agents in a treatment regimen or the compounds of the invention may be administered in combination with one or more other agents, including other immune response modifiers, antiviral agents, antibiotics, and the like.

In experiments performed in accordance with the assays explained below, the compounds of the invention have been shown to induce the production of certain cytokines. These results show that these compounds can be used as immune response modifiers that can modulate the immune response in a number of different ways, making them useful in the treatment of a variety of diseases.

Cytokines that can be induced by administration of the compounds of this invention generally include interferon-α (IFN-α) and / or tumor necrosis factor-α (TNF-α), as well as certain interleukins (IL). Cytokines whose biosynthesis can be induced by the compounds of the invention include IFN-α, TNF-α, IL1, IL-6, IL-10 and IL-12 and many other cytokines. Among other effects, these and other cytokines can inhibit virus production and cancer cell growth, making these compounds useful in the treatment of viral diseases and tumors. The invention therefore provides a method for inducing cytokine biosynthesis in an animal comprising administering to the animal an effective amount of a compound or composition of the invention.

It has been found that certain compounds of the invention preferentially induce IFN-α expression in a hematopoietic cell population, such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cells type 2), without accompanying the formation of significant levels of inflammatory cytokines.

In addition to the ability to induce cytokine production, the compounds of the invention also affect other aspects of the innate immune response. For example, the natural activity of T lymphocytes can be stimulated, an effect that can be induced by cytokines. These compounds may also activate macrophages, which further stimulate nitric oxide secretion and production of other cytokines. Furthermore, the compounds may cause B cell proliferation and differentiation.

The compounds of the invention also have an effect on the acquired immune response. For example, although they are not expected to have any direct effect on T cells or direct induction of T cell cytokines, administration of these compounds induces the formation of T type 1 (Th1) IFN-γ cytokine indirectly and T type 2 (Th2) IL -4, IL-5 and IL-13 are inhibited. This activity means that the compounds are useful in the treatment of diseases in which regulation by increasing Th1 response and / or regulation by decreasing Th2 response is required. In view of the ability of the compounds of the invention to inhibit the Th2 immune response, these compounds are expected to be of benefit in the treatment of atopic diseases such as e.g.

atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosus; as a vaccine adjuvant for cell-mediated immunity; and optionally as a medicament against recurrent fungal diseases and chlamydia.

The immune response modifying compounds of the compounds make them useful in the treatment of a wide variety of disease states. Because of their ability to induce the production of cytokines such as IFN-α and / or TNF-α, these compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulatory activity suggests that the compounds of the invention are useful in the treatment of diseases such as, but not limited to, viral diseases including genital warts; common warts; plantame warts; hepatitis B; hepatitis C; herpes simplex virus type I and type II; contagious moluskum; variola, in particular their heavy form; HIV; CMV; VZV; rhinovirus; adenovirus; coronavirus; influenza and parainfluenza; intraepithelial neoplasia such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasia; fungal diseases, e.g. candida, aspergillus, and cryptococcal meningitis; cancer, e.g. basocellular carcinoma, hair-cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, Nehodgkin's lymphoma, skin T-cell lymphoma and other cancerous diseases; parasitic diseases, e.g. connective tissue pneumocystosis, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g. tuberculosis and avian mycobacteria. Other diseases or conditions that can be treated with the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythemia, leprosy; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; bowenoid papulosis; bearing alopecia; inhibition of keloid formation after surgery and other types of postoperative scars. In addition, these compounds could improve or stimulate wound healing, including chronic wounds. The compounds may be useful in the treatment of opportunistic infections and tumors that occur after suppression of cell-mediated immunity, for example in transplant patients, cancer and HIV.

The amount of compound capable of inducing cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells, and B cells, to produce a certain amount of one or more cytokines, such as IFN -α, TNF-α, IL-1, IL-6, IL-10 and IL-12, which is elevated above the background level of such cytokines. The exact amount will vary depending on factors known in the art, but is expected to be a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 µg / kg to about 5 mg / kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a cancer in an animal, comprising administering to the animal an effective amount of a compound or composition of the invention. An amount effective in treating or inhibiting a viral infection is that amount which will alleviate one or more manifestations of the viral infection, such as viral foci, the extent of the viral infection, the rate of viral formation, and mortality compared to untreated control animals. The exact amount will vary depending on factors known in the art, but is expected to be a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 µg / kg to about 5 mg / kg. The amount of compound effective in the treatment of cancer is that amount which causes a reduction in the size of the tumor or the number of tumor foci. The exact amount will again vary depending on factors known in the art, but is expected to be a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 µg / kg to about 5 mg / kg.

DETAILED DESCRIPTION OF THE INVENTION

The invention is further characterized by the following examples, which are given by way of illustration and not by way of limitation.

EXAMPLE 1 _J N- [4- (4-amino-2-butyl-6,7-dimethyl-l // - imidazo [4,5-c] pyridin-l-yl) butyl] benzamide

Part A

To a suspension of 4-hydroxy-5,6-dimethyl-3-nitro-2 (1H) -pyridone (7.6 g, 41.2 mmol) in dichloromethane (200 mL) was added triethylamine (16.8 mL, 123, 8 mmol). The resulting mixture was cooled in an ice bath. Trifluoromethanesulfonic acid (13.7 mL, 82.5 mmol) was added to the reaction mixture and stirred for 30 minutes. The whole amount of mono- tert -butylcarbonyl-1,4-butyldiamine (7.6 g, 41.2 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was washed with aqueous 1% sodium carbonate solution (2 x 100 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give the crude product. This material was dissolved in dichloromethane and loaded onto a silica gel layer. The silica gel was eluted first with dichloromethane to remove any impurities, and then with 2-5% ethyl acetate in dichloromethane to obtain the desired product. Product containing fractions were combined and then concentrated under reduced pressure to give 12 g of 4 - ({4 - [(tert-butoxycarbonyl) amino] butyl} amino) -5,6-dimethyl-3-nitropyridin-2-yltrifluoromethanesulfonate in in the form of a pale yellow oil.

Part B

The material from Part A was mixed with triethylamine (2.5 g, 24.7 mmol), dibenzylamine (4.8 g, 24.7 mmol) and toluene (150 mL) and then heated under reflux for 4 hours. The reaction mixture was washed with aqueous 1% sodium carbonate solution and then concentrated under reduced pressure to give the crude product. This material was dissolved in dichloromethane and loaded onto silica gel.

The silica gel was eluted with 2-20% ethyl acetate in dichloromethane. Product containing fractions were combined and then concentrated under reduced pressure to give ~ 13 g of tert-butyl 4 - {[2- (dibenzylamino) -5,6-dimethyl-3-nitropyridin-2-yl] aminobutylcarbamate.

Part C

To a solution of nickel chloride hydrate (2.9 g, 12.3 mmol) in methanol was slowly added sodium borohydride (1.4 g, 36 mmol) and the resulting mixture was stirred for 30 minutes. A whole amount of a solution of the material from Part B in methanol was added at once. Sodium borohydride was added slowly until the foam turned discolored. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was mixed with dichloromethane and the mixture was filtered to remove the salt. The filtrate was concentrated under reduced pressure to give ~ 12 g of tert-butyl 4 - {[3-amino-2- (dibenzylamino) -5,6-dimethylpyridin-4-yl] amino} butylcarbamate.

Part D

To a solution of the material from Part C in acetonitrile (200 mL) was added valeryl chloride (3 mL, 24.7 mmol). The reaction mixture was stirred at ambient temperature. The residue was treated with ethanol and triethylamine (5 g, 49 mmol). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue obtained was shaken with dichloromethane and water. The dichloromethane layer was separated and then loaded onto a silica gel column. The column was eluted with 9: 90: 1 ethyl acetate: dichloromethane: methanol. The fractions containing the product were combined and then concentrated under reduced pressure to give 6.5 g of tert-butyl 4- [2-butyl-4- (dibenzylamino). 12,7-Dimethyl-12Z-imidazo [4,5-c] pyridin-1-yl] butylcarbamate as an oil.

Often

To a solution of the material from Part D (6.5 g, 11.4 mmol) in dichloromethane (250 mL) was added trifluoromethanesulfonic acid (16 g, 107 mmol). The resulting mixture was stirred overnight. Ammonium hydroxide (50 mL) and water (100 mL) were added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous fraction was extracted with dichloromethane (100 mL). The organic fractions were combined, washed with aqueous 1% sodium carbonate solution, washed with brine, and concentrated under reduced pressure. The residue was mixed with methanol (30 mL), stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was mixed with aqueous 1% sodium carbonate solution and mixed. The mixture was extracted with hexane to remove organic impurities. The aqueous layer contained an insoluble oily component which was extracted with dichloromethane. The organic layer was mixed with magnesium sulfate, stirred for 5 minutes and filtered. The filtrate was concentrated under reduced pressure to give a solid which was recrystallized from toluene to give 1 g of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5] c] pyridin-4-amine.

Part C

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-177-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL) triethylamine (0.07 mL, 0.5 mmol) was added. The reaction mixture was cooled in an ice bath. Benzoyl chloride (0.07 mL, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to give an oily brown material. This material was dissolved in a minimum amount of isopropanol and then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring. The reaction mixture was stirred for about 1 hour at ambient temperature and then heated rapidly in a sand bath until it became homogeneous. The solution was allowed to cool to ambient temperature and then cooled in an ice bath. The resulting precipitate was collected by filtration to give 111 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide in the form of a crystalline solid, b. t.

127.8-128.8 ° C.

Analysis: Calculated for C 23 H 31 N 5 O: 70.20% C; H, 7.94; 17.80% N; Found: 69.82% C; H, 7.70; N, 17.68.

Example 2

AL [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide ¹ NH.

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-e] pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane ( 160 mL) was added triethylamine (0.07 mL, 0.5 mmol). The reaction mixture was cooled in an ice bath. Methanesulfonic anhydride (90 mg, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was stirred for 35 minutes. The reaction mixture was washed three times with water, concentrated under reduced pressure and triturated with a minimum volume of methyl acetate. The resulting crystalline solid was collected by filtration and then dried in an Abderhalden dryer to give 94 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5- c] pyridin-1-yl) butyl] methanesulfonamide, b. t. 130-130.5 ° C.

Analysis: Calculated for C 17 H 29 N 5 O 2 S: 55.56% C; H, 7.95; 19.06% N; Found: C, 55.37; H, 7.89; N, 18.03.

Example 3

N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] 4-fluorobenzenesulfonamide hydrate

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 triethylamine (0.07 ml, 0.5 mmol) was added. The reaction mixture was cooled in an ice bath. Fluorobenzenesulfonyl chloride (113 mg, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was stirred at ambient temperature for 48 hours. The reaction mixture was washed with water (2 x 150 mL) and then concentrated under reduced pressure. The residue obtained was recrystallized from methyl acetate and then dried in an Abderhalden dryer to give 50 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5] hydrate). -c] pyridin-1-yl) butyl] 4-fluorobenzenesulfonamide as a white crystalline solid; b. t. 133.1-133.7 ° C.

Analysis: Calculated for C 22 H 30 FN ₅ O ₂ S · H ₂ O: 56.75% C; H, 6.93; 15.04% N; Found: C, 56.99; H, 6.58; N, 15.24.

Example 4 N- [4- (4-amino-2-butyl-6,7-dimethyl-l / 7-imidazo [4,5-c] pyridin-l-yl) butyl] -N ^{& apos} phenylurea

To a cooled solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-11H-imidazo [4,5-c] pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL) Phenylisocyanate (0.056 mL, 0.5 mmol) was added. The ice bath was removed. After 5 minutes a white precipitate formed. The reaction mixture was allowed to stir for 30 minutes and then concentrated under reduced pressure to give an off-white crystalline solid. This material was collected by filtration using a small amount of diethyl ether to transfer the material to the filter and then dried in an Abderhalden dryer to give 185 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl- 1 H -imidazo [4,5- c] pyridin-1-yl) butyl] -N'-phenylurea, b. t. 195.8-196.8 ° C.

Analysis: Calculated for C 23 H 32 N 6 O: 67.62% C; H, 7.89; N, 20.57;

Found: C, 66.84; H, 7.71; N, 20.54.

Example 5

^N - [4- (4-amino-2-butyl-6,7-dimethyl-l // - imidazo [4,5-c] pyridin-l-yl) butyl] -N'-phenyl thiourea hydrate

Using the method of Example 4, 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (100 mg, 0.35) was reacted mmol) with phenisisothiocyanate (0.041 mL, 0.35 mmol) to give 97 mg of N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine-1) hydrate. -yl) butyl] -N'-phenylthiourea as a white crystalline solid, b. t. 160.0-160.8 ° C.

Analysis: Calculated for C 23 H 32 N 6 S: 62.41% C; H, 7.74; 18.99% N;

Found: C, 62.39; H, 7.47; N, 18.52.

Example 6? 7 '- [4- (4-amino-2-butyl-6,7-dimethyl-imidazo [4,5-c] pyridin-l-yl) butyl] _-V>? / - dimethylsulfamide

To a solution of 1- (4-aminobutyl) -2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-4-amine (67 mg, 0.23 mmol) in dichloromethane (45 mL) was added triethylamine (0.031 mL, 0.23 mmol). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol) was added. The reaction mixture was removed from the ice bath. The reaction mixture was allowed to stir for 11113 hours at ambient temperature. Analysis by HPLC showed that the reaction was not complete. Dichloromethane was removed under reduced pressure. 1,2-Dichloroethane (50 mL) was added and the reaction mixture was heated to 60 ° C. After 3 hours, additional dimethylsulfamoyl chloride (2.5 μΐ) was added and heating continued. After 22 hours, the reaction temperature was raised to reflux, and the reaction mixture was heated under reflux for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The obtained residue was recrystallized from methyl acetate to give 10 mg of 7 '- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) (butyl) -Y, N'-dimethylsulfamide as an off-white crystalline solid, mp 129.5-131 ° C. M / Z 397.1 (M + H) < ^{+ &gt};.

Example 7

N- [4- (4-amino-2,6,7-trimethyl-l / f-imidazo [4,5-c] pyridin-l-yl) butyl] methanesulfonamide

Part A

A mixture of 5,6-dimethyl-3-nitropyridine-2,4-diol (60.0 g, 326 mmol) and phosphorus oxychloride (600 mL) was heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with ethyl acetate (300 mL) and filtered. The filtrate was washed with an aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with magnesium sulfate and then concentrated under reduced pressure to give a brown solid. This material was purified by chromatography (silica gel eluted with ethyl acetate / hexane 60/40) to give 55 g of 2,4-dichloro-5,6-dimethyl-3-nitropyridine.

Part B

To a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol), anhydrous N, N-dimethylformamide (500 mL) and triethylamine (50 mL, 339 mmol) was slowly added tert-butyl 4-Aminobutylcarbamate (60 g, 339 mmol). The reaction mixture was allowed to stir overnight and then concentrated under reduced pressure to give an oily liquid. The oily liquid was dissolved in ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to give a dark oily liquid. This material was purified by column chromatography (silica gel eluted with ethyl acetate / hexane 40/60) to give 64.5 g of tert-butyl-4- (2-chloro-5,6-dimethyl-3-nitropyridin-1-yl) butylcarbamate as a light orange oil which solidified on standing.

Part C

To a cooled (0 ° C) suspension of sodium hydride (8.28 g 60% solution in mineral oil, 207 mmol) in diglyme (50 mL) was slowly added dropwise a solution of phenol (18.50 g, 196 mmol) in diglyme ( 50 ml). Gas evolution ceased after 1 hour. To the reaction mixture was slowly added dropwise a solution of tert-butyl 4- (2-chloro-5,6-dimethyl-3-nitropyridin-1-yl) butyicarbamate (68.95 g, 185 mmol) in diglyme (200 mL). . After the addition was complete, the reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure to give a black oil. This oil was dissolved in ethyl acetate and then extracted with 1 N sodium hydroxide solution to remove excess phenol. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel eluted with ethyl acetate / hexane 30/70) to give 40.67 g of tert-butyl-4 - [(2,3-dimethyl-5-nitro-6-phenoxypyridin-1-yl) amino] butylcarbamate as an orange oil.

Part D

Tert -Butyl 4 - [(2,3-dimethyl-5-nitro-6-phenoxypyridin-1-yl) amino] butylbutylcarbamate (9.17 g, 21.3 mmol), toluene (50 mL), isopropanol (5 mL) were combined. ml) and 5% platinum on carbon (7.0 g) and the mixture was kept in a Parr apparatus under 50 psi (3.5 kg / cm ² ) of hydrogen overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting brown oil was dried under high vacuum to give 7.47 g of tert-butyl 4 - [(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butylcarbamate.

Often

A mixture of Part D material, triethyl orthoacetate (3.59 mL, 19.58 mmol), anhydrous toluene (75 mL) and pyridine hydrochloride (0.75 g) was heated under reflux for 1 hour and then concentrated under reduced pressure to give a brown an oily liquid. This oil was dissolved in ethyl acetate and then washed with water (2x), washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to give 6.74 g of tert-butyl-4- (2,6, 7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butylcarbamate as a brown oil.

Part F

To a cooled (0 ° C) mixture of trifluoroacetic acid (60 mL) and dichloromethane (100 mL) was slowly added a solution of tert-butyl-4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [ 4,5-c] pyridin-1-yl) butylcarbamate (6.70 g, 15.8 mmol) in dichloromethane (50 mL). The reaction mixture was allowed to warm to ambient temperature and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. This oil was dissolved in dichloromethane and the solution basified (to pH 14) with aqueous 5% sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to give 4.50 g of 4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridine). 1-yl) butylamine as a brown oil.

Part G

A mixture of Part F material, triethylamine (2.0 mL, 14.6 mmol) and anhydrous acetonitrile (450 mL) was heated until a homogeneous solution was obtained. Methanesulfonic anhydride (2.54 g, 14.6 mmol) was added slowly to the reaction mixture. The reaction was considered complete after 10 minutes. The reaction mixture was concentrated under reduced pressure to give a brown oil. This oil was dissolved in dichloromethane and washed with aqueous 5% sodium hydroxide solution. The aqueous layer was separated and then extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to give a brown oil. This material was purified by column chromatography (silica gel eluting with dichloromethane / methanol 95/5) to give 4.49 g / 7- (4- (2,6,7-trimethyl-4-phenoxy-1/7-imidazo [4]). 5-c] pyridin-1-yl) butyl] methanesulfonamide as a light brown solid.

Part H

N- [4- (2,6,7-trimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide (4.20 g, 10.4 mmol) and ammonium acetate (42 g) were mixed and then heated in a sealed tube at 150 ° C for 36 hours. The reaction mixture was allowed to cool and then dissolved in chloroform. The solution was extracted with aqueous 10% sodium hydroxide solution. The aqueous layer was separated and then extracted several times with chloroform. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to give a yellow oil. This oil was dissolved in methanol and treated with 1M hydrochloric acid in ethyl ether (10.4 mL). The resulting white precipitate was collected by filtration and dried. The solid was dissolved in water and the pH of the solution was adjusted to 10 with solid sodium carbonate. The white precipitate obtained was collected by filtration, washed with diethyl ether and then dried in a vacuum oven at 80 ° C to give 2.00 g of N- [4]. - (4-amino-2,6,7-trimethyl-177-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide, b. t. Mp 228-230 ° C.

Analysis: Calculated for C 14 H 23 N 5 O 2 S: 51.67% C; 7.12% H; N, 21.52; Found: C, 51.48; H, 6.95; N, 21.51.

Example 8

N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-17 / -imidazo [4,5-c] pyridin-l-yl] butyljmetánsulfónamid

Part A

To the cooled (0 ° C) / tert-butyl 4 - [(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl) amino] butylcarbamate mixture (8.60 g, 21.5 mmol) and Anhydrous dichloromethane (200 mL) was added triethylamine (3.3 mL, 23.7 mmol). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After 1 hour, the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give tert-butyl 4 - ({3 - [(ethoxyacetyl) amino] -5,6-dimethyl-2-phenoxypyridin-4-yl} amino) butylcarbamate as a brown oil. This oil was mixed with pyridine (130 mL) and heated under reflux overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. This oil was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to give 8.21 g of tert-butyl-4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1 H -imidazo [4], 5-c] pyridin-l-yl] butylcarbamate.

Part B

Using the method of Part F of Example 7, the material of Part A was hydrolyzed to give 5.76 g of 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5- c] pyridin-1-yl] butan-1-amine as a brown oil.

Part C

Using the method of Part G of Example 7, 4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-1 H -imidazo [4,5- c] pyridin-1-yl] butan-1-amine (5.52 g, 15.0 µmol) was reacted with methanesulfonic anhydride (2.74 g, 15.7 mmol) to give 6.26 g of N- {4- [2- (ethoxymethyl) -6,7] -dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl] butyl} methanesulfonamide as a brown oil.

Part D

Using the general method of Part H of Example 7, 2 V ^N - {4- [2- (ethoxymethyl) -6,7-dimethyl-4-phenoxy-l // - imidazo [4,5-c] pyridin--yljbutyljmetánsulfónamid ( 5.86 g (13.1 mmol) was aminated to give 1.58 g of N- {4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5] -c] pyridin-1-yl] butyl} methanesulfonamide as a white solid, mp 165-167 ° C.

Analysis: Calculated for C 16 H 27 N 5 O 3 S: 52.01% C; H, 7.37; 18.95% N;

Found: C, 51.83; H, 7.39; 18.88% N.>

Example 9

N- [4- (4-amino-2-butyl-6,7-dimethyl-l // - imidazo [4,5-c] pyridin-l-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide

Part A

4- (2-Butyl-6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butan-1-amine (122 mg, 0.33 mmol) dissolved in dichloromethane and triethylamine (0.093 mL, 0.67 mmol) under a nitrogen atmosphere. The solution was cooled in a water bath and 4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzoyl chloride (106 mg, 0.33 mmol) was dissolved / stirred in dichloromethane and added dropwise. The ice bath was removed and the reaction stirred for an additional 16 hours. The reaction was quenched with aqueous 10% sodium carbonate solution. The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water and then brine, dried over (Na ₂ SO ₄ ), decanted and evaporated to give a yellow oil. Purification by flash column chromatography (silica gel, dichloromethane / methanol 92: 8 with a gradient to dichloromethane / methanol 95: 5) afforded 101 mg of N- [4- (2-butyl) -6,7-dimethyl-4-phenoxy- 17 H -imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide as a pale yellow solid. The purity of the product was determined to be > 97% by HPLC.

MS (CI): 648 (M + H);

Part B

N - [4- (2-Butyl) -6,7-dimethyl-4-phenoxy-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 was added to the pressure tube with a mixer. - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide (101 mg, 0.16 mmol) and ammonium acetate (1.1 g). The tube was sealed and heated at 150 ° C for 16 hours. The reaction mixture was cooled to room temperature and dissolved in water. The resulting cloudy cloudy mixture was basified with aqueous 10% sodium hydroxide solution and extracted with chloroform (3 x 25 mL). The combined organic fractions were washed with water and then brine, dried (Na ₂ SO ₄ ), decanted and evaporated to give a yellow oil. Purification by flash column chromatography (silica gel, dichloromethane / methanol 95: 5 with a gradient to dichloromethane / methanol 9: 1 and finally dichloromethane / methanol / triethylamine 94: 5: 1) gave 14 mg of N- [4- (4- amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl) methyl] benzamide as a yellow oil.

1 H-NMR (500 MHz, DMSO-d 6) δ = 8.41 (t, J = 5.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.43 ( d, J = 8.3 Hz, 2H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 5.84 (broad singlet, 2H), 5, 52 (s, 1H), 4.22 (t, J = 7.7Hz, 2H), 3.49 (t, J = 5.8Hz, 2H), 3.29 (dd, J = 6.4) Hz, 12.4 Hz, 2H), 2.76 (t, J = 0.5 Hz, 2H), 2.58 (t, J = 5.7 Hz, 2H), 2.32 (s, 3H) 2.27 (s, 3H), 2.22 (s, 6H), 1.73-1.65 (m, 4H), 1.611.55 (m, 2H), 1.35 (sextet, J = 7) 4 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H);

¹³ C-NMR (125 MHz, DMSO-d ₆ ) δ = 165.9, 153.0, 148.1, 145.4, 142.0, 138.6, 133.5, 128.23, 127.4 , 127.3, 127.1, 126.4, 126.1, 124.5, 103.0, 82.0, 66.3, 58.0, 45.2, 43.6, 38.4, 29 , 3, 28.8, 26.1, 26.0, 21.7, 21.0, 13.6, 12.2.

HRMS (CI) m / e 571.3763 (M + H), 571.3761 calcd. for C34H47N6O2,

M + H).

INDUCTION OF CYTOKINS IN HUMAN CELLS

A set of human blood cells in vitro is used to assess cytokine induction. Activity is based on measurement of interferon (a) and tumor necrosis factor (a) (IFN and TNF, respectively) secreted into the culture medium, as described by Testerman et al. in "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September 1995).

Preparation of blood cells for culture

Whole blood is obtained by venipuncture from healthy donors into the EDTA vacutainer reservoir. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque®-1077. The PBMCs were washed twice with Hank's balanced salt solution and then suspended in complete RPMI to a density of 3-4 x 10 ⁶ cells / ml. The PBMC suspension is plated on 48 well sterile flat bottom tissue culture plates (Costar, Cambridge, MA, or Becton Dickinson Labware, Lincoln Park, NJ) containing equal volumes of complete RPMI test compound medium. .

Preparation of compounds

Compounds are dissolved in dimethylsulfoxide (DMSO). For addition to culture wells, DMSO concentrations should not exceed a final concentration of 1%. Compounds are generally tested at concentrations ranging from 0.12 to 30 μΜ.

incubation

A solution of the test compound at a concentration of 60 μΜ is added to the first well containing complete RPMI, and a series of 3-fold dilutions are prepared into the next wells. PBMC suspension is then added to the wells in an equal volume to give test compound concentrations in the desired range (0.12 to 30 μΜ). The final concentration of PBMC suspension is 1.5 - 2 x 10 ⁶ cells / ml. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18-24 hours at 37 ° C in a 5% carbon dioxide atmosphere.

separation

After incubation, the plates are centrifuged for 5-10 minutes at 4 ° C and 1000 rpm (~ 200 x g). The cell-free culture supernatant is collected with a sterile polypropylene pipette and transferred to sterile polypropylene tubes. Samples are stored at -30 to -70 ° C until analysis. Samples are analyzed for interferon (a) for tumor necrosis factor (a) by ELISA.

Tumor necrosis factor (a) analysis of interferon (a) by ELISA

The concentration of interferon (a) was determined by ELISA using the Human Multispecific Kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg / ml. .

Tumor necrosis factor (a) (TNF) concentration is determined using an ELISA kit supplied by Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg / ml.

The table below shows the lowest concentration for which interferon induction was observed and the lowest concentration for which tumor necrosis factor induction was observed for each compound. The asterisk indicates that no induction was observed at any of the concentrations tested.

Induction of cytokines in human cells Example number Lowest effective concentration (μΜ) interferon Tumor necrosis factor 1 0.12 1.11 2 0.0046 0.01 3 0.01 0.37 4 0.12 0.37 5 0.01 0.12 6 0.01 0.01 7 0.37 * 8 0.04 10

The present invention is described with reference to several practical embodiments thereof. The foregoing detailed description and examples are provided for clarity and understanding only and are not to be construed as undue limitations thereof. It will be clear to those skilled in the art that many changes can be made to the described practical embodiments without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited by the precise details of the compositions and structures described herein, but rather by the wording of the claims that follow.

Claims (34)

1. Compound of formula (I): wherein: X is alkylene or alkenylene; Y is -CO-, -CS- or -SO ₂ -; Z is a bond, -O-, -S- or -NR 5 -; R 1 is aryl, heteroaryl, heterocyclyl, C 1-20 alkyl or C 2-20 alkenyl, and each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: alkyl; -alkenyl; aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -O-alkyl; -O- (alkyl) _O -aryl; -0- (alkyl) o-i-heteroaryl; -0- (alkyl) OH in-heterocyclyl; COOH; -CO-O-alkyl; -CO-alkyl; -S (0) o-2-alkyl; -S (0) o-2- (alkyl) o-i-aryl; -S (0) o-2- (alkyl) o-i-heteroaryl; -S (0) _o-2 - (alkyl) -heterocyclyl et al; - (alkyl) _0-1 N (R ₅ ) 2; - (alkyl) _O, -NR ₅ -CO-O-alkyl; - (alkyl) and -NR 5 -CO-alkyl; - (alkyl) and -NR 5 -CO-aryl; - (alkyl) and -NR 5 -CO-heteroaryl; -N ₃ ; -halogen; -haloalkyl; -haloalkoxy; -CO-haloalkyl; -CO-haloalkoxy; -Ν0 ₂ ; -CN; OH; SH; and in the case of alkyl, alkenyl and heterocyclyl oxo; R ₂ is selected from the group consisting of: -hydrogen; alkyl; -alkenyl; -alkyl-O-alkyl; alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: OH; -halogen; -N (R ₅ ) ₂ ; -CO-N (R ₅ ) ₂ ; -CS-N (R ₅ ) ₂ ; -SO ₂ -N (R ₅ ) ₂ ; -NR 5 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl; -NR 5 -SO 2 -C 1-10 alkyl; -CO-C 1-10 alkyl; -CO-O-C 1-10 alkyl; -N ₃ ; aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and CO-heteroaryl; R ₃ and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl; or a pharmaceutically acceptable salt thereof. I The compound or salt of claim 1, wherein Y is -CO-. Third The compound or salt of claim 1 wherein Y is -CO- and Z is a bond. The compound or salt of claim 3, wherein R 1 is alkyl, aryl or substituted aryl. The compound or salt of claim 1, wherein Y is -CS-. The compound or salt of claim 1, wherein Y is -CS- and Z is -NR 5 -. The compound or salt of claim 6, wherein R 5 is H and R 1 is aryl or substituted aryl. The compound or salt of claim 1, wherein Y is -SO 2 -. The compound or salt of claim 1, wherein Y is -SO 2 - and Z is a bond. The compound or salt of claim 9, wherein R 1 is alkyl, aryl or substituted aryl. The compound or salt of claim 10, wherein R; is alkyl. The compound or salt of claim 1, wherein Y is -SO 2 - and Z is -NR ₅ -. The compound or salt of claim 12, wherein R 5 is alkyl and R 1 is alkyl. The compound or salt of claim 1, wherein R ₂ is H, alkyl or alkyl-O-alkyl. The compound or salt of claim 1, wherein X is - (CH ₂ ) ₂ -4- ·, The compound or salt of claim 1, wherein R 3 and R 4 are independently H or alkyl. 17. A compound selected from the group consisting of: N - [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] benzamide; ^N - [4- (4-amino-2-butyl-6,7-dimethyl-l / f-imidazo [4,5-c] pyridin-l-yl) butyl] methanesulfonamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] 4-fluorobenzenesulfonamide monohydrate; ^N - [4- (4-amino-2-butyl-6,7-dimethyl-l // - imidazo [4,5-c] pyridin-l-yl) butyl] -N'-phenyl thiourea monohydrate; N '- [4- (4-amino-2-butyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] -N, N-dimethylsulfamide; N- [4- (4-amino-2-butyl-6,7-dimethyl-LR / '- imidazo [4,5-c] pyridin-yljbutylj-N'-phenyl urea; N- [4- (4-amino-2,6,7-trimethyl-1H-imidazo [4,5-c] pyridin-1-yl) butyl] methanesulfonamide; X- [4- (4-amino-2-butyl-6,7-dimethyl-LRF-imidazo [4,5-c] pyridin-yl) butyl] -4 - [[2- (dimethylamino) ethoxy] (phenyl ) methyl] benzamide; and N- (4- [4-amino-2- (ethoxymethyl) -6,7-dimethyl-IZ / -imidazo ^[4,5-C] pyridine-yl] butyl} methanesulfonamide; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 in combination with a therapeutically acceptable carrier. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 in combination with a therapeutically acceptable carrier. A method of inducing cytokine biosynthesis in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 1. A method of treating a viral disease in an animal comprising administering to the animal a therapeutically effective amount of a compound of claim 1. A method of treating a cancer in an animal comprising administering to the animal a therapeutically effective amount of a compound of claim 1. A method for inducing cytokine biosynthesis in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 9. A method of treating a viral disease in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 9. A method of treating a cancer in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 9. A method of inducing cytokine biosynthesis in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 17. A method of treating a viral disease in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 17. A method of treating a cancer in an animal, comprising administering to the animal a therapeutically effective amount of a compound of claim 17. 30. Compound of formula (II): NH ₂ R. (II) in which: X is alkylene or alkenylene; R ₂ is selected from the group consisting of: -hydrogen; 1 H -alkyl; -alkenyl; -alkyl-O-alkyl; alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: -OH; -halogen; -N (R ₅ ) ₂ ; -CO-N (R ₅ ) ₂ ; -CS-N (R ₅ ) ₂ ; -SO ₂ -N (R ₅ ) ₂ ; -NR 1 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl; -NR ₅ -SO ₂ -C 1-10 alkyl; -CO-C 1-10 alkyl; -CO- O- C 1-10 alkyl; N 3; aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and CO-heteroaryl; R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R5 is independently H or C1-10 alkyl; or a pharmaceutically acceptable salt thereof. 31. Compound of formula (III): BOC (III) wherein: Q is NO ₂ or NH ₂ ; X is alkylene or alkenylene; R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and R 5 is H or C 1-10 alkyl; or a pharmaceutically acceptable salt thereof. 32. Compound of formula (IV): wherein: X is alkylene or alkenylene; R ₂ is selected from the group consisting of: -hydrogen; alkyl: -alkenyl; -alkyl 1-O-alkyl; alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: OH; -halogen; -N (R ₅ ) ₂ ; -CO-N (R ₅ ) ₂ ; -CS-N (R ₅ ) ₂ ; -SO ₂ -N (R ₅ ) ₂ ; -NR 5 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl; -NR 5 -SO ₂ -C 1-10 alkyl; -CO-C 1-10 alkyl; -CO-O-C 1-10 alkyl; -N ₃ ; aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and CO-heteroaryl; R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl; or a pharmaceutically acceptable salt thereof. 33. Compound of formula (V): (V) wherein: X is alkylene or alkenylene; R2 is selected from the group consisting of: -hydrogen; alkyl; -alkyl-O-alkyl; -alkenyl; alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: OH; -halogen; -N (R ₅ ) ₂ ; -co-N (R ₅ ) ₂ ; -CS-N (R ₅ ) ₂ ; -SO ₂ -N (R ₅ ) ₂ ; -NR 5 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl; -NR ₅ -SO ₂ -C 1-10 alkyl; -CO-C 1-10 alkyl; -CO-O-C 1-10 alkyl; -N ₃ ; aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and CO-heteroaryl; R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl; or a pharmaceutically acceptable salt thereof. 34. Compound of formula (VI): wherein: X is alkylene or alkenylene; R 1 is aryl, heteroaryl, heterocyclyl, C 1-20 alkyl or C 2-20 alkenyl, and each of which may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of: alkyl; -alkenyl; aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -O-alkyl; -O- (alkyl) _O -aryl; -0- (alkyl) o-i-heteroaryl; -0- (alkyl) o-i-heterocyclyl; COOH; -CO-O-alkyl; -CO-alkyl; -S (O) _0-2 -alkyl; -S ₍₀₎ 0 .2- (alkyl) -aryl et al; -S (0) o-2- (alkyl) o-i-heteroaryl; -S (0) o-2- (alkyl) o-i-heterocyclyl; - (alkyl) _O , - N (R ₅ ) _2; - (alkyl) _O -NR ₅ -CO-O-alkyl; - (alkyl) _O, -NR ₅ -CO-alkyl; (Alkyl) and -NR 5 -CO-aryl; - (alkyl) and -NR 5 -CO-heteroaryl; -N ₃ ; -halogen; -haloalkyl; -haloalkoxy; I -CO-haloalkyl; -CO-haloalkoxy; -NO ₂ ; -CN; OH; SH; and in the case of alkyl, alkenyl and heterocyclyl oxo; R ₂ is selected from the group consisting of: -hydrogen; alkyl; -alkenyl; -alkyl-O-alkyl; alkyl-S-alkyl; -alkyl-O-aryl; l -alkyl-S-aryl; -alkyl-O-alkenyl; -alkyl-S-alkenyl; and -alkyl or alkenyl substituted with one or more substituents selected from the group consisting of: OH; -halogen; -N (R ₅ ) ₂ ; -CO-N _{(R) 2;} -CS-N (R ₅ ) ₂ ; -SO ₂ N _{(R) 2;} -NR 5 -CO-C 1-10 alkyl; -NR 5 -C 5 -C 1-10 alkyl; -NR ₅ -SO ₂ -C 1-10 alkyl; -CO-C 1-10 alkyl; -CO-O-C 1-10 alkyl; -N ₃ ; aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and CO-heteroaryl; R 3 and R ₄ are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and each R 5 is independently H or C 1-10 alkyl; or a pharmaceutically acceptable salt thereof.