HK1063466B - Substituted imidazopyridines - Google Patents

Description

Substituted imidazopyridines

Technical Field

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

Background

With respect to 1H-imidazo [4, 5-c ]]The first reliable report of quinoline ring systems was by Backman et alJ.Org.Chem.15, 1278-one 1284(1950) describes 1- (6-methoxy-8-quinolyl) -2-methyl-1H-imidazo [4, 5-c ] s potentially useful as antimalarial agents]And (4) synthesizing quinoline. Subsequently, various substituted imidazo [4, 5-c ] s have been reported]And (4) synthesizing quinoline. For example, the device described by Jain et al,J. Med.Chem.11pp87-92(1968) which synthesize 1- [2- (4-piperidinyl) ethyl groups which are useful as anticonvulsants and cardiovascular agents]-1H-imidazo [4, 5-c]Quinoline compounds. In addition, Baranov et al are inChem.Abs.85, 94362(1976), several 2-oxoimidazo [4, 5-c ] s are disclosed]Quinoline compounds, and Berenyi et al inJ.Heterocyclic Chem.18, 1537-1540(1981), certain 2-oxoimidazo [4, 5-c ] s have also been disclosed]Quinoline.

It has subsequently been found that certain 1H-imidazo [4, 5-c ] quinolin-4-amines and 1-and 2-substituted derivatives thereof are useful as antiviral agents, bronchodilators and immunomodulators. These are also particularly described in U.S. Pat. nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986, 5268,376; 5,346,905, respectively; and 5,389,640, all of which are incorporated herein by reference.

In US patent US 5,446,153; 5,494,916, respectively; and 5,644,063, substituted 1H-imidazopyridine-4-amine compounds useful as immune response modifiers, but the compounds disclosed in these patents do not have an amine substitution at the 1-position. Certain 1H-imidazo [4, 5-c ] quinolin-4-amines having amide, sulfonamide, and urea functionalities at the 1-position are disclosed in PCT applications WO 00/76505, WO00/76518, WO 00/76519.

Despite the recent new discovery of compounds as immune response modifiers, there is a continuing need for compounds that have the ability to modulate immune responses by inducing cytokine biosynthesis or other mechanisms.

Summary of the invention

We have discovered a new group of compounds that can induce cytokine biosynthesis in animals. Accordingly, the present invention provides imidazopyridine-4-amine compounds having a substituted amine functionality at the 1-position. These compounds are represented by formula (I), more particularly as shown below. Formula (I) is shown below:

wherein X, Y, Z, R₁，R₂，R₃，R₄And R₅As described herein.

The compounds of formula (I) are useful as immune response modifiers because, when administered to an animal, these compounds exhibit the ability to induce cytokine biosynthesis and otherwise modulate the immune response. This makes the compounds useful in the treatment of a range of diseases that respond to these changes in the immune response, such as viral diseases and tumours.

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

In addition, the invention also provides methods for synthesizing the compounds of the invention and intermediates employed in the synthesis of these compounds.

Detailed description of the invention

As previously mentioned, we have discovered certain compounds that can induce cytokine biosynthesis and modulate immune responses in animals. The compound is a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

x represents an alkylene or alkenylene group;

y represents-CO-, -CS-or-SO₂-；

Z represents a bond, -O-, -S-, or-NR₅-；

R₁Represents aryl, heteroaryl, heterocyclyl, C_1-20Alkyl or C_2-20Alkenyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from:

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-a substituted cycloalkyl group;

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1-a heterocyclic group;

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2-an alkyl group;

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1-a heterocyclic group;

- (alkyl)_0-1-N(R₅)₂；

- (alkyl)_0-1-NR₅-CO-O-alkyl;

- (alkyl)_0-1-NR₅-CO-alkyl;

- (alkyl)_0-1-NR₅-CO-aryl;

- (alkyl)_0-1-NR₅-CO-heteroaryl;

-N₃；

-a halogen;

-a haloalkyl group;

-a haloalkoxy group;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO₂；

-CN；

-OH；

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

R₂selected from the following groups:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents each independently selected from:

-OH；

-a halogen;

-N(R₅)₂；

-CO-N(R₅)₂；

-CS-N(R₅)₂；

-SO₂-N(R₅)₂；

-NR₅-CO-C_1-10an alkyl group;

-NR₅-CS-C_1-10an alkyl group;

-NR₅-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

Preparation of the Compounds

The compounds of the present invention may be prepared according to reaction scheme I, wherein R₁，R₂，R₃，R₄，R₅X, Y and Z are as defined above, Bn represents benzyl and R' represents alkyl of 1 to 4 carbon atoms, perfluoroalkyl of 1 to 4 carbon atoms, phenyl or phenyl substituted by halogen or alkyl of 1 to 4 carbon atoms.

In step (1) of reaction scheme I, 3-nitropyridine-2, 4-disulfonate of formula X is reacted with a compound of formula R₁-Z-Y-N(R₅)-X-NH₂The amine shown reacts to give 3-nitro-4-aminopyridine-2-sulfonate of formula XI. Due to the presence of the two sulfonic acid groups which can in principle be displaced, the reaction may give rise to a mixture of products which can be easily separated by conventional techniques such as chromatography. The reaction is preferably carried out by adding the amine to a solution of the compound of formula X in a suitable solvent, such as dichloromethane, in the presence of a tertiary amine, such as triethylamine. Since the sulfonic acid group is a group that easily leaves, the reaction can be carried out at low temperature (0 ℃) to reduce the amount of unwanted 2-amination 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, Lindstom et al, U.S. Pat. No. 5, 5,446,153 et al, and references cited therein.

In step (2) of reaction scheme I, 3-nitro-4-aminopyridine-2-sulfonate, shown in formula XI, is reacted with dibenzylamine to give 2-dibenzylamino-3-nitropyridine-4-amine, shown in formula XII. The reaction is carried out by mixing the compound 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 scheme I, the nitro group in 2-dibenzylamino-3-nitropyridin-4-amine of formula XII is reduced to an amino group. The reduction reaction preferably employs NiB₂It is produced in situ from sodium borohydride and nickel chloride hydrate in methanol. The reaction is preferably carried out at room temperature.

In reaction scheme I, step (4), 2-dibenzylaminopyridine-3, 4-diamine of formula XIII is reacted with a carboxylic acid or equivalent thereof to provide 4-dibenzylamino-1H-imidazo [4, 5 ] of formula XV-c]Pyridine. Suitable equivalents of the carboxylic acid include orthoesters and 1, 1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected so as to give the desired R in the compound of formula XV₂And (4) a substituent. For example, triethyl orthoformate can be prepared wherein R is₂Compounds which are hydrogen, and triethyl orthoacetate may be prepared wherein R₂A compound that is methyl. The reaction can be carried out without solvent or in the presence of an inert solvent such as toluene. Sufficient heat should be applied to remove any by-product alcohol or water produced in the reaction. A catalyst such as pyridine hydrochloride may optionally be added.

Alternatively, the compound of formula XV can be prepared in two steps: (a) reacting a diamine of formula XIII with a diamine of formula R₂C (O) Cl or R₂C (O) Br to give the compound of formula XIV, followed by (b) cyclization. In step (4a), the acid 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 room temperature. In step (4b), the product of step (4a) is heated in an alcoholic solvent in the presence of a base, preferably in ethanol under heating to reflux in the presence of excess triethylamine or with an ammonia methanol solution. Alternatively, step (4b) may be carried out by heating the product of step (4a) in pyridine. If step (4a) is carried out in pyridine, step (4b) may be carried out by heating the reaction mixture directly after analysis shows that step (4a) has been completed.

In reaction scheme I, step (5), 4-dibenzylamino-1H-imidazo [4, 5-c ] pyridine, represented by formula XV, is hydrolyzed to give 4-amino-1H-imidazo [4, 5-c ] pyridine, represented by formula I. Preferably, the resulting product or a pharmaceutically acceptable salt thereof is isolated by heating a solution of the XV compound in formic acid in the presence of palladium hydroxide on carbon using conventional techniques.

Reaction scheme I

Compounds of the invention can be prepared according to reaction scheme IIWherein R is₁，R₂，R₃，R₄，R₅And X is as defined above, Bn is benzyl, BOC is t-butyloxycarbonyl and W is O or S.

Removal of 1H-imidazo [4, 5-c ] of formula XVI in step (1) of reaction scheme II]The amino protecting group on pyridine gives 1H-imidazo [4, 5-c ] of formula II]Pyridine. Preferably, a solution of a compound of formula XVI in a suitable solvent such as dichloromethane is treated with triflic acid (triflic acid) at room temperature. The compound of formula XVI can be prepared using the synthetic methods described in reaction scheme I. In step (1), the 2, 4-disulfonate of formula X is reacted with a compound of formula BOC-NR₅-X-NH₂The reaction, followed by steps 2-4 as described above, affords the compound of formula XVI, which is the lower group of formula XV.

In reaction scheme II, step (2a), 1H-imidazo [4, 5-c ] of formula II]Pyridine and formula R₁-C (O) Cl acid chloride or of the formula R₁-C(O)OC(O)-R₁Acid anhydride reaction to obtain 1H-imidazo [4, 5-c ] shown as formula XVII]Pyridin-1-ylamide, which is a member of the group of formula I. The reaction is preferably carried out by adding the acid halide or anhydride to a solution of the 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 low temperature (0 ℃) or at room temperature. The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

In reaction scheme II, step (2b), 1H-imidazo [4, 5-c ] of formula II]Pyridine and formula R₁An isocyanate of formula R or N ═ C ═ O₁Reaction of an isothiocyanate represented by-N ═ C ═ S to give 1H-imidazo [4, 5-C ] represented by formula XVIII]Pyridin-1-ylurea or thiourea, which is the lower group of formula I. The reaction is preferably carried out by adding the isocyanate or isothioisocyanate to a solution of the compound of formula II in a suitable solvent such as methylene chloride at low temperature (. degree.C.).

In reaction scheme II, step (2c), 1H-imidazo [4, 5-c ] of formula II]Pyridine and formula R₁-S(O)₂Sulfonyl chlorides of formula R or₁-S(O)₂-O-S(O)₂-R₁Sulfonic anhydride reaction shownTo obtain 1H-imidazo [4, 5-c ] of formula XIX]Pyridin-1-yl-sulfonamides, which are the lower group of formula I. The reaction is preferably carried out by adding a sulfonyl chloride or sulfonic anhydride 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 can be carried out at low temperature (0 ℃) or at room temperature. The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

Reaction scheme II

Compounds of the present invention can be prepared according to reaction scheme III, where R₁，R₂，R₃，R₄，R₅And X is as defined above.

In step (1) of reaction scheme III, 1H-imidazo [4, 5-c ] of formula II]Pyridine and formula R₁-N(R₅)S(O)₂Reaction with Cl sulfonyl chloride to give 1H-imidazo [4, 5-c ] of formula XXI]Pyridin-1-yl-sulfonamides, which are the lower group of formula I. The reaction is preferably carried out by adding sulfamoyl chloride to a solution of the compound of formula II in a suitable solvent, such as 1, 2-dichloroethane, in the presence of a base, such as triethylamine. The reaction may be carried out at elevated temperature. The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

Alternatively, sulfonamides of formula XXI may be prepared in two steps, (a) 1H-imidazo [4, 5-c ] of formula II]Reacting pyridine with sulfonyl chloride to form sulfamoyl chloride of formula XX in situ, and (b) reacting the sulfamoyl chloride with a compound of formula R₁-N(R₅) And H, reacting amine. In step (1a), a solution of sulfonyl chloride in methylene chloride is added 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 low temperature (-78 ℃). After the addition is complete, the reaction mixture can optionally be allowed to return to room temperature. In step (1b), 2 equivalents of R will be present₁-N(R₅) A solution of H and 2 equivalents of triethylamine in methylene chloride is added to the reaction mixture of step (1a), preferably at low temperature (-78 deg.C)) The process is carried out as follows. The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

Reaction scheme III

Compounds of the present invention may be prepared according to reaction scheme IV, wherein R₁，R₂，R₃，R₄，R₅And X is as defined above, and BOC represents t-butyloxycarbonyl.

In reaction scheme IV, step (1), 2, 4-dihydroxy-3-nitropyridine of formula XXII is chlorinated using conventional chlorinating agents to provide 2, 4-dichloro-3-nitropyridine of formula XXIII. Preferably, the compound of formula XXII is mixed with phosphorus oxychloride and heated together. Many of the 2, 4-dihydroxy-3-nitropyridines of formula XXII are known and others are readily prepared by known methods, see, for example, Lindstom et al, U.S. Pat. No. 5, 5,446,153 and references cited therein.

In reaction scheme IV, step (2), 2, 4-dichloro-3-nitropyridine of formula XXIII is reacted with a compound of formula BOC-NR₅-X-NH₂The amine reaction gives 2-chloro-3-nitropyridine of the formula XXIV. The reaction is preferably carried out by adding the amine to a solution of the compound of formula XXIII in a suitable solvent such as N, N-dimethylformamide in the presence of a tertiary amine such as triethylamine.

In reaction scheme IV, step (3), 2-chloro-3-nitropyridine of formula XXIV is reacted with phenol to give 3-nitro-2-phenoxypyridine of formula XXV. Phenol is reacted with sodium hydride in a suitable solvent such as diglyme to give the phenolate. The resulting phenoxide is then reacted at elevated temperature with a compound of formula XXIV.

In reaction scheme IV, step (4), the 3-nitro-2-phenoxypyridine shown in XXV is reduced to give a 3-amino-2-phenoxypyridine shown in XXVI. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon, or palladium on carbon. The reaction is carried out in a parr reactor in a suitable solvent such as isopropanol or toluene.

In reaction scheme IV, step (5), 3-amino-2-phenoxypyridine of formula XXVI is reacted with a carboxylic acid or its equivalent to give 4-phenoxy-1H-imidazo [4, 5-c ] of formula IV]Quinoline. Suitable equivalents of the carboxylic acid include orthoesters and 1, 1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected so as to give the desired R in the compound of formula IV₂And (4) a substituent. For example, triethyl orthoformate can be prepared wherein R is₂Compounds which are hydrogen, and trimethyl orthovalerate may be prepared wherein R₂A compound that is butyl. The reaction can be carried out without solvent or in the presence of an inert solvent such as toluene. Sufficient heat should be applied to remove any by-product alcohol or water produced in the reaction. A catalyst such as pyridine hydrochloride may optionally be added.

Or the step (5) may be performed by: (i) reacting a compound of formula XXVI with a compound of formula R₂C (O) Cl or R₂C (o) acyl halide reaction of Br followed by (ii) cyclization. In step (i), the acid halide is added to a solution of the compound of formula XXV in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction may be carried out at room temperature. In step (ii), the product of step (i) is heated in pyridine.

In reaction scheme IV, step (6), the BOC group is removed from the compound of formula IV to provide the 4-phenoxy-IH-imidazo [4, 5-c ] quinoline of formula V. Preferably, a solution of the compound of formula IV in a suitable solvent such as dichloromethane is treated with trifluoroacetic acid or hydrochloric acid at low temperature.

In step (7) of scheme IV, the 4-phenoxy-1H-imidazo [4, 5-c ] quinoline of formula V is converted to the 4-phenoxy-1H-imidazo [4, 5-c ] quinolin-1-ylsulfonamide of formula VI by the method of scheme II, step 2 c.

In step (8) of scheme IV, the 4-phenoxy-1H-imidazo [4, 5-c ] quinolin-1-yl sulfonamide of formula VI is aminated to provide the 4-amino-1H-imidazo [4, 5-c ] quinolin-1-yl sulfonamide of formula XIX, which is the next group of formula I. The reaction can be carried out by mixing compound VI with ammonium acetate in a sealed tube and heating (. about.150 ℃ C.). The product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.

Reaction scheme IV

The invention also provides novel intermediate compounds useful in the synthesis of compounds of formula I, which intermediates are described in detail below in formulas (II) - (VI).

A group of intermediate compounds represented by formula (II):

wherein:

x represents an alkylene or alkenylene group;

R₂selected from the following groups:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents each independently selected from:

-OH；

-a halogen;

-N(R₅)₂；

-CO-N(R₅)₂；

-CS-N(R₅)₂；

-SO₂-N(R₅)₂；

-NR₅-CO-C_1-10an alkyl group;

-NR₅-CS-C_1-10an alkyl group;

-NR₅-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

Another group of intermediate compounds represented by formula (III):

wherein:

q represents NO₂Or NH₂；

X represents an alkylene or alkenylene group;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

Another group of intermediate compounds represented by formula (IV) or a pharmaceutically acceptable salt thereof:

wherein:

x represents an alkylene or alkenylene group;

R₂selected from the following groups:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents each independently selected from:

-OH；

-a halogen;

-N(R₅)₂；

-CO-N(R₅)₂；

-CS-N(R₅)₂；

-SO₂-N(R₅)₂；

-NR₅-CO-C_1-10an alkyl group;

-NR₅-CS-C_1-10an alkyl group;

-NR₅-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

Another group of intermediate compounds represented by formula (V):

wherein:

x represents an alkylene or alkenylene group;

R₂selected from the following groups:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents each independently selected from:

-OH；

-a halogen;

-N(R₅)₂；

-CO-N(R₅)₂；

-CS-N(R₅)₂；

-SO₂-N(R₅)₂；

-NR₅-CO-C_1-10an alkyl group;

-NR₅-CS-C_1-10an alkyl group;

-NR₅-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

Another group of intermediate compounds represented by formula (VI):

wherein:

x represents an alkylene or alkenylene group;

R₁represents aryl, heteroaryl, heterocyclyl, C_1-20Alkyl or C_2-20Alkenyl, each of which may be unsubstituted or substituted with one or more substituents each independently selected from:

-an alkyl group;

-an alkenyl group;

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-a substituted cycloalkyl group;

-O-alkyl;

-O- (alkyl)_0-1-an aryl group;

-O- (alkyl)_0-1-a heteroaryl group;

-O- (alkyl)_0-1-a heterocyclic group;

-COOH；

-CO-O-alkyl;

-CO-alkyl;

-S(O)_0-2-an alkyl group;

-S(O)_0-2- (alkyl)_0-1-an aryl group;

-S(O)_0-2- (alkyl)_0-1-a heteroaryl group;

-S(O)_0-2- (alkyl)_0-1-a heterocyclic group;

- (alkyl)_0-1-N(R₅)₂；

- (alkyl)_0-1-NR₅-CO-O-alkyl;

- (alkyl)_0-1-NR₅-CO-alkyl;

- (alkyl)_0-1-NR₅-CO-aryl;

- (alkyl)_0-1-NR₅-CO-heteroaryl;

-N₃；

-a halogen;

-a haloalkyl group;

-a haloalkoxy group;

-CO-haloalkyl;

-CO-haloalkoxy;

-NO₂；

-CN；

-OH；

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

R₂selected from the following groups:

-hydrogen;

-an alkyl group;

-an alkenyl group;

-alkyl-O-alkyl;

-alkyl-S-alkyl;

-alkyl-O-aryl;

-alkyl-S-aryl;

-alkyl-O-alkenyl;

-alkyl-S-alkenyl; and

-alkyl or alkenyl substituted by one or more substituents each independently selected from:

-OH；

-a halogen;

-N(R₅)₂；

-CO-N(R₅)₂；

-CS-N(R₅)₂；

-SO₂-N(R₅)₂；

-NR₅-CO-C_1-10an alkyl group;

-NR₅-CS-C_1-10an alkyl group;

-NR₅-SO₂-C_1-10an alkyl group;

-CO-C_1-10an alkyl group;

-CO-O-C_1-10an alkyl group;

-N₃；

-an aryl group;

-a heteroaryl group;

-a heterocyclic group;

-CO-aryl; and

-CO-heteroaryl;

R₃and R₄Each independently selected from: alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; and

R₅each independently represents H or C_1-10An alkyl group.

The terms "alkyl", "alkenyl" and the prefix "alk" as used herein include straight or branched chain groups as well as cyclic groups, i.e., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups are meant to contain 1-20 carbon atoms, while alkenyl is meant to contain 2-20 carbon atoms. Preferred groups contain up to 10 carbon atoms. The cyclic groups may be monocyclic or polycyclic and preferably contain from 3 to 10 ring carbon atoms. Examples of cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.

The term "haloalkyl" as used herein refers to a group substituted with one or more halogens, including perfluoroalkyl. This definition also applies to groups containing the prefix "halo". Examples of suitable haloalkyl groups include: chloromethyl, trifluoromethyl, and the like.

The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, or indenyl. The term "heteroaryl" is intended to include aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolyl, isoquinolyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, 1, 5-diazanaphthyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and the like.

"Heterocyclyl" means a fully or partially saturated derivative that includes a non-aromatic ring or ring system containing at least one ring heteroatom (e.g., O, S, N) and includes heteroaryl groups as described above. Examples of heterocyclic groups include: pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.

The aryl, heteroaryl, and heterocyclyl groups herein may be unsubstituted or substituted with a substituent selected from the group consisting of: alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxyl, mercapto, cyano, carboxyl, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl (alkylthiocarbonyl), arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl (arylthiocarbonyl), heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarenoyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylalkylaminocarbonylamino, in the case of a heterocyclyl group, also represents oxo. If other groups are described as "substituted" or "optionally substituted," then these groups may be substituted with one or more of the substituents listed above.

Certain substituents are generally preferred. For example, preferred Y's are-CO-and-SO₂-; z preferably represents a bond or-NR₅-; and R₁Preferably represents C_1-4Alkyl, aryl, or substituted aryl. Preferred R₂Including alkyl groups containing 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl), methoxyethyl, ethoxymethyl, and cyclopropylmethyl. R₃And R₄Preferably represents a methyl group. If present, one or more of the above preferred substituents may be present in the compounds of the present invention in any combination.

The compounds of the present invention include pharmaceutically acceptable forms thereof, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention also includes enantiomers of the individual compounds as well as racemic mixtures of the enantiomers.

Pharmaceutical compositions and biological activity

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of the above-described compounds of the present invention and a pharmaceutically acceptable carrier.

The term "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to produce a therapeutic effect, where the therapeutic effect refers to, for example, cytokine-induced effects, anti-tumor activity, and/or anti-viral activity. Although the specific amount of active compound employed in the pharmaceutical compositions of the present invention will depend upon factors well known to those of ordinary skill in the art such as the physicochemical properties of the compound, the nature of the carrier, and the therapeutic regimen being employed, the compositions of the present invention should contain sufficient active ingredient to enable the recipient to obtain a dosage of the compound of from about 100ng/kg to about 50mg/kg, preferably from about 10 μ g/kg to about 5 mg/kg. Any conventional dosage form such as tablets, lozenges, parenteral preparations, syrups, creams, ointments, aerosols, transdermal patches, transmucosal patches, etc. may be employed.

Upon administration, the compounds of the present invention may be used as the sole therapeutic agent in a therapeutic regimen, or may be administered in combination with one or more other active agents, including other immunomodulators, antiviral agents, antibacterial agents and the like.

The following experiments demonstrate that the compounds of the invention are shown to induce the production of certain cytokines. These results indicate that the compounds of the invention can be used as immune response modifiers to modulate immune responses in a number of different ways, making them useful in the treatment of a variety of diseases.

Cytokines which may be induced by administration of the compounds of the present invention 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, IL-1, IL-6, IL-10 and IL-12, as well as various other cytokines. Among these effects, the above cytokines and other cytokines can inhibit virus production and tumor cell growth, making these compounds useful for the treatment of viral diseases and tumors. Accordingly, the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.

It has been found that certain compounds of the present invention can preferentially induce expression of IFN- α in hematopoietic cell populations, e.g., PBMCs (peripheral blood mononuclear cells), containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.

In addition to the ability to induce cytokine production, the compounds of the invention also affect other aspects of the innate immune system, such as stimulating natural killer cell activity, which may also be based on cytokine induction. The compounds of the invention may also activate macrophages, which stimulate the secretion of nitric oxide and the production of further cytokines. Further, the compounds of the present invention may cause proliferation and differentiation of B-lymphocytes.

The compounds of the invention also have an effect on the acquired immune response. For example, while it is not believed that there is a direct effect on T-cells and a direct induction of T-cell cytokines, when administered with the compounds of the present invention, it is possible to directly induce the production of the type 1 helper T cell (Th1) cytokine IFN-. gamma.and to inhibit the production of the type 2 helper T cell (Th2) cytokines IL-4, IL-5 and IL-13. By active is meant that the compounds are useful in the treatment of diseases where promotion of a Th1 response and/or inhibition of a Th2 response is desired. In view of the ability of the compounds of the present invention to inhibit the Th2 immune response, the compounds of the present invention are useful for the treatment of atopic diseases such as atopic dermatitis, asthma, allergy, allergic rhinitis, systemic lupus erythematosus; also useful as vaccine adjuvants for modulating immunity to cells; and may be used to treat recurrent fungal diseases and chlamydial diseases.

The immune response modulating effects of the compounds of the present invention make them useful in the treatment of a number of diseases. Because of their ability to induce the production of the cytokines IFN- α and/or TNF- α, the compounds of the present invention are particularly useful in the treatment of viral diseases and tumors. The immunomodulatory activity of the compounds of the invention indicates that the compounds of the invention can treat diseases such as, but not limited to, the following exemplified diseases: viral diseases include genital warts; common warts; plantar warts; hepatitis B virus; hepatitis C; i and II herpes simplex virus disease; molluscum contagiosum; smallpox, especially variola major; HIV; a CMV; VZV; a rhinovirus; an adenovirus; a coronavirus disease; influenza; and a secondary influenza; intraepithelial neoplasia such as cervical intraepithelial neoplasia; human Papilloma Virus (HPV) and related neoplastic diseases; fungal diseases such as candida infectious diseases, aspergillus infectious diseases and cryptococcal meningitis; neoplastic diseases, such as basal cell carcinoma, hairy cell leukemia, kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myeloid leukemia, multiple myeloma, melanoma, non-hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases such as pneumocystis carinii disease, cryptosporidiosis, histoplasmosis capsulata, toxoplasmosis, trypanosome infections, and leishmaniasis; and bacterial infections such as tuberculosis, and mycobacterium avium infections. Other diseases and conditions that may be treated with the compounds of the present invention include: actinic keratosis; eczema; eosinophilia; essential thrombocythemia; leprosy; multiple sclerosis; olympic syndrome; discoid lupus; bayne's disease; bowenoid papulosis; alopecia areata; inhibiting the formation of keloid and other postoperative scar after operation. In addition, these compounds may promote or stimulate healing of wounds, including chronic wounds. These compounds are also useful in the treatment of opportunistic infections and tumors that arise following suppression of the cell-regulated immune system in, for example, transplant patients, neoplastic patients and HIV patients.

An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cells, such as monocytes, macrophages, dendritic cells and B-cells, to produce one or more cytokines such as IFN- α, TNF- α, IL-1, IL-6, IL-10 and IL-12, the amount of which exhibits an increase over its background level. The exact amount depends on factors well known in the art, but should desirably be in the range of about 100ng/kg to about 50mg/kg, preferably about 10 μ g/kg to about 5 mg/kg. The invention also provides a method of treating viral infections and neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or composition of the invention to the animal. An effective amount of a compound to treat or inhibit a viral infection is an amount of the compound that reduces one or more manifestations of viral infection such as viral damage, viral load, viral productivity, and mortality compared to an untreated control compound. The exact amount depends on factors well known in the art, but should desirably be in the range of about 100ng/kg to about 50mg/kg, preferably about 10 μ g/kg to about 5 mg/kg. An effective amount of a compound for treating a neoplastic disease is an amount of the compound that reduces the size of the tumor or the number of tumor foci. Again, the exact amount will depend upon factors well known in the art, but should desirably be in the range of about 100ng/kg to about 50mg/kg, preferably about 10 μ g/kg to about 5 mg/kg.

The invention further provides the following examples which are intended to be illustrative only and not limiting in any way.

Example 1

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

Step A

Triethylamine (16.8mL, 123.8mmol) was added to a suspension of 4-hydroxy-5, 6-dimethyl-3-nitro-2 (1H) -pyridone (7.6g, 41.2mmol) in dichloromethane (200mL) and the resulting mixture was cooled in an ice bath. Trifluoromethanesulfonic anhydride (13.7mL, 82.5mmol) was added and the resulting reaction mixture was stirred for 30 min. Mono-tert-butoxycarbonyl-1, 4-butyldiamine (7.6g, 41.2mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature. After 1 hour the reaction mixture was washed with 1% aqueous sodium carbonate (2X 100mL), dried over magnesium sulfate and concentrated under reduced pressure to give the crude product. The material was dissolved in dichloromethane and passed through a silica gel layer which was first eluted with dichloromethane to remove some impurities and then eluted with 2-5% ethyl acetate/dichloromethane to recover the desired product. The product-containing fractions were combined and distilled under reduced pressure to give 12g of 4- ({4- [ (tert-butoxycarbonyl) amino ] butyl } amino) -5, 6-dimethyl-3-nitropyridin-2-yl trifluoromethanesulfonate as a pale yellow oil.

Step B

The material from step A was mixed with triethylamine (2.5g, 24.7mmol), dibenzylamine (4.8g, 24.7mmol) and toluene (150mL) and then heated at reflux for 4 hours. The reaction mixture was washed with 1% aqueous sodium carbonate solution and then concentrated under reduced pressure to give a crude product. The material was dissolved in dichloromethane and passed through a layer of silica gel eluting with 2-20% ethyl acetate/dichloromethane. The product containing fractions were combined and distilled under reduced pressure to give 13g of tert-butyl 4- { [2- (dibenzylamino) -5, 6-dimethyl-3-nitropyridin-4-yl ] amino } butylcarbamate.

Step C

Sodium borohydride (1.4g, 36mmol) was slowly added dropwise to a solution of nickel chloride hydrate (2.9g, 12.3mmol) in methanol and the resulting mixture was stirred for 30 minutes. Adding the methanol solution of the product of the step B in one time. Sodium borohydride was added slowly until the resulting foam was colorless. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was mixed with dichloromethane and filtered to remove salts. The filtrate was concentrated under reduced pressure to give 12g of tert-butyl 4- { [ 3-amino-2- (dibenzylamino) -5, 6-dimethylpyridin-4-yl ] amino } butylcarbamate.

Step D

Pentanoyl chloride (3mL, 24.7mmol) was added to the product of step C in acetonitrile (200 mL). The reaction mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with ethanol and triethylamine (5g, 49mmol), and the reaction mixture was heated under reflux overnight, and then concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane and water. The dichloromethane layer was separated and passed through a silica gel column, which was eluted with 9: 90: 1 ethyl acetate: dichloromethane: methanol. The product-containing fractions were combined and concentrated under reduced pressure to give 6.5g of tert-butyl 4- [ 2-butyl-4- (dibenzylamino) -6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] butylcarbamate as an oil.

Step E

Trifluoromethanesulfonic acid (16g, 107mmol) was added to a solution of the product of step D (6.5g, 11.4mmol) in dichloromethane (250mL), the resulting mixture was stirred overnight, ammonium hydroxide (50mL) and water (100mL) were added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined, washed with 1% aqueous sodium bicarbonate, brine and concentrated under reduced pressure. The resulting residue was mixed with methanol (30mL), stirred for 30 minutes and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was mixed with 1% aqueous sodium carbonate solution and stirred. The mixture was extracted with hexane to remove organic impurities and the aqueous layer containing insoluble oil 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 1g of 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine.

Step F

Triethylamine (0.07mL, 0.5mmol) was added to a solution of 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine (150mg, 0.5mmol) in dichloromethane (150mL) and the resulting mixture was cooled in an ice bath. Benzoyl chloride (0.07mL, 0.5mmol) was added and the resulting reaction mixture was removed from the ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The resulting 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 of isopropanol and then ethanesulfonic acid (55mg, 0.5mmol) was added with stirring. The reaction mixture was stirred at room temperature for 1 hour and then heated on a sand bath for a short time until it became homogeneous. The solution was allowed to cool to room temperature and then cooled in an ice bath, and the resulting precipitate was isolated by filtration to give 111mg of N- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] benzamide as solid crystals having a melting point of 127.8-128.8 ℃.

Elemental analysis: theoretical value C₂₃H₃₁N₅O: % C, 70.20; % H, 7.94; % N, 17.80; measured value: % C, 69.82; % H, 7.70; % N, 17.68.

Example 2

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

Triethylamine (0.07mL, 0.5mmol) was added to a solution of 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine (150mg, 0.5mmol) in dichloromethane (160mL) and the resulting mixture was cooled in an ice bath. Methanesulfonic anhydride (90mg, 0.5mmol) was added and the resulting reaction mixture was removed from the ice bath. The reaction mixture was stirred for 35 minutes, washed 3 times with water, concentrated under reduced pressure, and triturated with a small volume of methyl acetate. The resulting solid crystals were isolated and then dried in an Abderhalden dryer to give 94mg of N- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] methanesulfonamide, m.p. 130-130.5 ℃.

Elemental analysis: theoretical value C₁₇H₂₉N₅O₂S: % C, 55.56; % H, 7.95; % N, 19.06; measured value: % 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

Triethylamine (0.07mL, 0.5mmol) was added to a solution of 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine (150mg, 0.5mmol) in dichloromethane (150mL) and the resulting mixture was cooled in an ice bath. 4-fluorobenzenesulfonyl chloride (11.3mg, 0.5mmol) was added and the resulting reaction mixture was removed from the ice bath. The reaction mixture was stirred at room temperature for 48 hours, washed with water (2X 150mL), and then concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate and then dried in an Abderhalden dryer to give 50mg of N- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] -4-fluorobenzenesulfonamide hydrate as white crystals having a melting point of 133.1-133.7 ℃.

Elemental analysis: theoretical value C₂₂H₃₀FN₅O₂S·H₂O: % C, 56.75; % H, 6.93; % N, 15.04; found% C, 56.99; % H, 6.58; % N, 15.24.

Example 4

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

Phenyl isocyanate (0.056mL, 0.5mmol) was added to a cooled solution of 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine (150mg, 0.5mmol) in dichloromethane (150mL) and the ice bath removed. After 5 minutes a white precipitate formed and the reaction mixture was stirred for 30 minutes and then concentrated under reduced pressure to give an off-white solid as crystals. The desired material was isolated by filtration with a small amount of diethyl ether to transfer to a funnel and then dried in an Abderhalden dryer to give 185mg of N- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] -N' -phenylurea, m.p. 195.8-196.8 ℃.

Elemental analysis: theoretical value C₂₃H₃₂N₆O: % C, 67.62; % H, 7.89; % N, 20.57; measured value: % C, 66.84; % H, 7.71; % N, 20.54.

Example 5

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

1- (4-Aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-4-amine (100mg, 0.35mmol) was reacted with phenyl isothiocyanate (0.041mL, 0.35mmol) using the procedure of example 4 to give 97mg of N- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] -N' -phenylthiourea hydrate as white crystals, melting point 160.0-160.8 ℃.

Elemental analysis: theoretical value C₂₃H₃₂N₆S·H₂O：％C，62.41；％H，7.74; % N, 18.99; measured value: % C, 62.39; % H, 7.47; % N, 18.52.

Example 6

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

Triethylamine (0.031mL, 0.23mmol) is added to 1- (4-aminobutyl) -2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c)]Pyridin-4-amine (67mg, 0.23mmol) in dichloromethane (45mL) and the resulting mixture cooled in an ice bath. Dimethylsulfamoyl chloride (0.025mL, 0.23mmol) was added and the resulting reaction mixture was removed from the ice bath. The reaction mixture was stirred at room temperature for 113 hours and analysis by HPLC indicated that the reaction was not complete. The dichloromethane was removed under reduced pressure. 1, 2-dichloroethane (50mL) was added and the reaction mixture was heated to 60 ℃. After 3 hours more dimethylsulfamoyl chloride (2.5. mu.l) was added and heating was continued. After 22 hours the reaction temperature was raised to reflux and the reaction mixture was kept at reflux for 100 hours. The reaction mixture was extracted 2 times with water, the aqueous phases were combined and concentrated under reduced pressure. The residue obtained was recrystallized from methyl acetate to give 10mg of N' - [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ]]Pyridin-1-yl) butyl]-N, N-dimethylsulfonamide as off-white crystals with melting point 129.5-131 ℃. M/Z397.1 (M + H)⁺。

Example 7

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

Step A

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

Step B

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

Step C

A solution of phenol (18.50g, 196mmol) in diglyme (50mL) was slowly added dropwise to a cooled (0 ℃ C.) suspension of sodium hydride (8.28g, 60% in mineral oil, 207mmol) in diglyme (50 mL). After 1 hour the evolution of gas had ceased and a solution of tert-butyl 4- (2-chloro-5, 6-dimethyl-3-nitropyridin-4-yl) butylcarbamate (68.95g, 185mmol) in diglyme (200mL) was slowly added dropwise to the reaction mixture. After the completion of the addition, the reaction mixture was heated under reflux for 4 hours, and the reaction mixture was concentrated under reduced pressure to give a black oil. The resulting oil was dissolved in ethyl acetate and extracted with 1N sodium hydroxide 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 30/70 ethyl acetate/hexane) to give 40.67g of tert-butyl 4- [ (2, 3-dimethyl-5-nitro-6-phenoxypyridin-4-yl) amino ] butylcarbamate as an orange oil.

Step D

Mixed 4- [ (2, 3-dimethyl-5-nitro-6-phenoxypyridin-4-yl) amino]Tert-butyl butylcarbamate (9.17g, 21.3mmol), toluene (50mL), isopropanol (5mL) and 5% platinum on charcoal (7.0g) in a Parr reactor under a hydrogen atmosphere (50psi, 3.5 Kg/cm)²) Left 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 7.47g of 4- [ (3-amino-5, 6-dimethyl-2-phenoxypyridin-4-yl) amino group]Tert-butyl carbamate.

Step E

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

Step F

A solution of tert-butyl 4- (2, 6, 7-trimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl) butylcarbamate (6.70g, 15.8mmol) in dichloromethane (50mL) was slowly added dropwise to a cooled (0 ℃ C.) mixture of trifluoroacetic acid (60mL) and dichloromethane (100mL) and the reaction mixture was allowed to warm to room temperature and left overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. The resulting oil was dissolved in dichloromethane and made basic (pH14) with 5% aqueous sodium hydroxide. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give 4.50g of 4- (2, 6, 7-trimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl) butylamine as a brown oil.

Step G

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

Step H

N- [4- (2, 6, 7-trimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] methanesulfonamide (4.20g, 10.4mmol) and ammonium acetate (42g) were mixed and heated at 150 ℃ for 36 hours in a sealed tube, and the reaction mixture was cooled and then dissolved in chloroform. The resulting solution was extracted with 10% aqueous sodium hydroxide. The aqueous layer was separated and then extracted with chloroform several times. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in methanol and mixed with 1M hydrochloric acid in diethyl ether (10.4 mL). The resulting white solid was isolated by filtration and then dried. The solid was dissolved in water and adjusted to pH10 with solid sodium carbonate. The resulting white solid was isolated by filtration, washed with diethyl ether and then dried under vacuum at 80 ℃ to give 2.00g of N- [4- (4-amino-2, 6, 7-trimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] methanesulfonamide, m.p. 228 and 230 ℃.

Elemental analysis: theoretical value C₁₄H₂₃N₅O₂S: % C, 51.67; % H, 7.12; % N, 21.52; measured value: % C, 51.48; % H, 6.95; % N, 21.51.

Example 8

N- {4- [ 4-amino-2- (ethoxymethyl) -6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] butyl } methanesulfonamide

Step A

Triethylamine (3.3mL, 23.7mL) was added to a cooled (0 ℃ C.) mixture of tert-butyl 4- [ (3-amino-5, 6-dimethyl-2-phenoxypyridin-4-yl) amino ] butylcarbamate (8.60g, 21.5mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76g, 22.5mmol) was added. After 1 hour the reaction mixture was warmed to room 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. The oil was mixed with pyridine (130mL) and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure to give a brown oil. The resulting oil was dissolved in dichloromethane and then washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in diethyl ether and concentrated in vacuo to give 8.21g of tert-butyl 4- [2- (ethoxymethyl) -6, 7-dimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl ] butylcarbamate.

Step B

Hydrolysis of the product of step A, using the procedure of step F of example 7, gave 5.76g of 4- [2- (ethoxymethyl) -6, 7-dimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl ] butan-1-amine as a brown oil.

Step C

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

Step D

N- {4- [2- (ethoxymethyl) -6, 7-dimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl ] butyl } methanesulfonamide (5.86g, 13.1mmol) was aminated using the procedure of example 7, step H, to give 1.58g of N- {4- [ 4-amino-2- (ethoxymethyl) -6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] butyl } methanesulfonamide as a white solid, m.p. 165 and 167 ℃.

Elemental analysis: theoretical value C₁₆H₂₇N₅O₃S: % C, 52.01; % H, 7.37; % N, 18.95; measured value: % C, 51.83; % H, 7.39; % N, 18.88.

Example 9

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

Step A

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

MS(CI)：648(M+H)

Step B

N- [4- (2-butyl-6, 7-dimethyl-4-phenoxy-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] -4- [ [2- (dimethylamino) ethoxy ] (phenyl) methyl ] benzamide (101mg, 0.16mmol) and ammonium acetate (1.1g) were placed in a pressurized tube with a stir bar, the tube was sealed and heated at 150 ℃ for 16 hours. The reaction mixture was cooled to room temperature and diluted with water. The resulting aqueous viscous mixture was made alkaline with 10% aqueous sodium hydroxide and extracted with chloroform (3X 25 mL). The combined organic phases were washed with water, then brine, dried (sodium sulfate), decanted and evaporated to give a yellow oil. Purification by flash chromatography (silica gel eluted with a gradient of 95: 5 dichloromethane/methanol to 9: 1 dichloromethane/methanol and finally 94: 5: 1 dichloromethane/methanol/triethylamine) afforded 14mg 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.

¹H-NMR(500MHz，DMSO-d₆) δ 8.41(t, J ═ 5.5Hz, 1H), 7.76 (d, J ═ 8.3Hz, 2H); 7.43(d, J ═ 8.3, 2H), 7.37-7.31(m, 4H), 7.26-7.22(m, 1H), 5.84(bs, 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, 12.4Hz, 2H), 2.76(t, J ═ 7.7Hz, 2H), 2.58(t, J ═ 5.7Hz, 2H), 2.32(s, 3H), 2.27(s, 3H), 2.22(s, 6H), 1.73-1.65(m, 4H), 1.61-1.55(m, 2H), 1.35 (sextup, 7, 4H), t, 4H (t, 3H), 0.86(t, 3H);¹³C-NMR(125MHz，DMSO-d₆)δ165.9，153.0，148.1，145.4，142.0，138.6，133.5，128.23，127.4，127.3，127.1，126.4，126.1，124.5，103.0，82.0，66.3，58.0，45.2，43.6，38.4，29.3，28.8，26.1，26.0，21.7，21.0，13.6，12.2.

HRMS(CI)m/e 571.3763(M+H)，(571.3761，C₃₄H₄₇N₆O₂calculations, M + H) cytokine Induction in human cellsBy using

Cytokine induction was assessed using an in vitro human blood cell system. As described by Testerman et al in "Cytokine indication by the immunoloderms Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-.

Blood cell preparation for culture

Whole blood obtained from healthy donors was collected by venipuncture in the vacutainer tube of ETDA and Peripheral Blood Mononuclear Cells (PBMCs) were separated from the whole blood by density gradient centrifugation using Histopaque  -1077. PBMC were washed twice with Hank's balanced salt solution and then 3-4X 10⁶cells/mL were suspended in RPMI complete medium. The PBMC suspension was added to a 48-well flat-bottomed sterile tissue culture plate (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) in which an equal volume of RPMI complete medium containing the test compound was placed.

Compound preparation

Compounds were dissolved in dimethyl sulfoxide (DMSO). The concentration of DMSO must not exceed 1% of the final concentration when loading into culture wells. Typically test compounds are tested at concentrations of 0.12-30. mu.M.

Culturing

A solution of the test compound at a concentration of 60. mu.M was added to well 1 containing RPMI complete medium, and serial dilutions 3-fold were prepared in each well. An equal volume of PBMC suspension was then added to each well so that the concentration of test compound was in the desired range (0.12-30 μ M). The final PBMC suspension concentration was 1.5-2X 10⁶cells/mL. Covering the culture plate with a sterile plastic cap, mixing gently, and culturing at 37 deg.C in 5% carbon dioxide atmosphere for 18-24 hr

Separation of

After incubation, the plates were centrifuged at 1000rpm (. about.200 Xg) for 5-10 minutes at 4 ℃ and the cell-free culture supernatant was removed with a sterile polypropylene pipette and transferred to a polypropylene tube. The samples were maintained at-30 ℃ to-70 ℃ before analysis. Samples were analyzed for interferon (α) and tumor necrosis factor (α) by ELISA.

Samples were analyzed for interferon (. alpha.) and tumor necrosis factor (. alpha.) by ELISA

Interferon (α) concentration was determined by ELISA using Human Multi-specifices kit (PBL biological Laboratories, New Brunswick, NJ). The measurement results are expressed in pg/mL.

The TNF-. alpha.concentration was determined using an ELISA kit (Genzyme, Cambridge, MA; R & D Systems, Minneapolis, MN; or Pharmingen, San Diego, Calif.). The measurement results are expressed in pg/mL.

The following table lists the minimum concentrations of interferon and tumor necrosis factor that can be induced by each compound. A "", indicates that no induction was observed at any of the test compound concentrations.

Cytokine induction in human cells
			Example No. 2	Minimum effective concentration (μ M)
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 invention has been described with reference to certain embodiments. The foregoing detailed description and examples have been provided for clarity of understanding only, and no unnecessary limitations are to be understood therefrom. It will be apparent to those skilled in the art that various modifications can be made in the disclosed embodiments without departing from the spirit and scope of the invention. Accordingly, the scope of the present invention should not be limited to the exact compositions and structures described herein, but rather by the language of the following claims.

Claims (31)

1. A compound represented by the following formula (I):

wherein:

x represents C_1-10An alkylene group;

y represents-CO-, -CS-or-SO₂-；

Z represents a bond, -NH-, or-N (C)_1-10Alkyl) -;

R₁represents phenyl, naphthylBiphenyl, pyridyl, thienyl, quinolyl, or C_1-10Alkyl, wherein phenyl is unsubstituted or substituted with: one or more halogens, one or more-C_1-10Alkyl, one or more-O-C_1-10Alkyl, -CN, trifluoromethyl, trifluoromethoxy, -S-C_1-10Alkyl, -SO₂-C_1-10Alkyl, -N (C)_1-10Alkyl radical)₂or-CO-C_1-10An alkyl group; pyridyl is unsubstituted or substituted by halogen; and C_1-10Alkyl being unsubstituted or substituted by phenyl, thienyl, oxo, -O-C_1-10Alkyl-phenyl, or-CO-O-C_1-10Alkyl substitution;

R₂selected from the following groups:

-hydrogen;

-C_1-10an alkyl group; and

-C_1-10alkyl-O-C_1-10An alkyl group;

R₃and R₄Each independently selected from C_1-10Alkyl, or R₃Is C_1-10Alkyl and R₄Is hydrogen;

R₅represents H.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-CO-.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-CO-and Z represents a bond.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R₁Is represented by C_1-10Alkyl, phenyl or substituted phenyl, wherein the substituted phenyl is substituted by one or more halogens, one or more-C_1-10Alkyl, one or more-O-C_1-10Alkyl, -CN, trifluoromethyl, trifluoromethoxy, -S-C_1-10Alkyl, -SO₂-C_1-10Alkyl, -N (C)_1-10Alkyl radical)₂or-CO-C_1-10Alkyl substitution.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-CS-.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-CS-and Z represents-NR₅-。

7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R₅Represents H and R₁Represents phenyl or substituted phenyl, wherein the substituted phenyl is substituted by one or more halogens, one or more-C_1-10Alkyl, one or more-O-C_1-10Alkyl, -CN, trifluoromethyl, trifluoromethoxy, -S-C_1-10Alkyl, -SO₂-C_1-10Alkyl, -N (C)_1-10Alkyl radical)₂or-CO-C_1-10Alkyl substitution.

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-SO₂-。

9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-SO₂-and Z represent a bond.

10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R₁Is represented by C_1-10Alkyl, phenyl or substituted phenyl, wherein the substituted phenyl is substituted by one or more halogens, one or more-C_1-10Alkyl, one or more-O-C_1-10Alkyl, -CN, trifluoromethyl, trifluoromethoxy, -S-C_1-10Alkyl, -SO₂-C_1-10Alkyl, -N (C)_1-10Alkyl radical)₂or-CO-C_1-10Alkyl substitution.

11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R₁Is represented by C_1-10An alkyl group.

12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents-SO₂-and Z represent-NR₅-。

13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R₅Is represented by C_1-10Alkyl and R₁Is represented by C_1-10An alkyl group.

14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₂Is represented by C_1-4Alkyl or C_1-4alkyl-O-C_1-4An alkyl group.

15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X represents- (CH)₂)_2-4-。

16. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₃And R₄Each independently represents C_1-10Alkyl, or R₃Is C_1-10Alkyl and R₄Is hydrogen.

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-1H-imidazo [4, 5-c ] pyridin-1-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-1H-imidazo [4, 5-c ] pyridin-1-yl) -butyl ] -N' -phenylthiourea monohydrate;

n' - [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) -butyl ] -N, N-dimethylsulfonamide;

n- [4- (4-amino-2-butyl-6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) -butyl ] -N' -phenylurea;

n- [4- (4-amino-2, 6, 7-trimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl) butyl ] methanesulfonamide;

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; and

n- {4- [ 4-amino-2- (ethoxymethyl) -6, 7-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl ] butyl } methanesulfonamide.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 9 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 and a pharmaceutically acceptable carrier.

21. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inducing cytokine biosynthesis in an animal.

22. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a viral disease in an animal.

23. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neoplastic disease in an animal.

24. The use of a compound of claim 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inducing cytokine biosynthesis in an animal.

25. The use of a compound of claim 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a viral disease in an animal.

26. The use of a compound of claim 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neoplastic disease in an animal.

27. The use of a compound of claim 17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inducing cytokine biosynthesis in an animal.

28. The use of a compound of claim 17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a viral disease in an animal.

29. The use of a compound of claim 17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a neoplastic disease in an animal.

30. A compound of formula (II):

wherein:

x represents C_1-10An alkylene group;

R₂selected from the following groups:

-hydrogen;

-C_1-10an alkyl group; and

-C_1-10alkyl-O-C_1-10An alkyl group;

R₃and R₄Each independently selected from C_1-10Alkyl, or R₃Is C_1-10Alkyl and R₄Is hydrogen; and

R₅represents H.

31. A compound of formula (VI):

wherein:

x represents C_1-10An alkylene group;

R₁represents phenyl, naphthyl, biphenyl, pyridyl, thienyl, quinolyl, or C_1-10Alkyl, wherein phenyl is unsubstituted or substituted with: one or more halogens, one or more-C_1-10Alkyl, one or more-O-C_1-10Alkyl, -CN, trifluoromethyl, trifluoromethoxy, -S-C_1-10Alkyl, -SO₂-C_1-10Alkyl, -N (C)_1-10Alkyl radical)₂or-CO-C_1-10An alkyl group; pyridyl is unsubstituted or substituted by halogen; and C_1-10Alkyl being unsubstituted or substituted by phenyl, thienyl, oxo, -O-C_1-10Alkyl-phenyl, or-CO-O-C_1-10Alkyl substitution;

R₂selected from the following groups:

-hydrogen;

-C_1-10an alkyl group; and

-C_1-10alkyl-O-C_1-10An alkyl group;

R₃and R₄Each independently selected from C_1-10Alkyl, or R₃Is C_1-10Alkyl and R₄Is hydrogen;

R₅represents H.