(12) Patent Application Publication (10) Pub. No.: US 2004/0132766A1 Griesgraber (43) Pub

US 2004O132766A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0132766A1 Griesgraber (43) Pub. Date: Jul. 8, 2004

(54) 1H-MIDAZO DIMERS Publication Classification (76) Inventor: George W. Griesgraber, Eagan, MN (US) (51) Int. Cl." ...... A61K 31/4745; CO7D 471/02 Correspondence Address: (52) U.S. Cl...... 514/303; 546/118 3M INNOVATIVE PROPERTIES COMPANY PO BOX 33427 ST. PAUL, MN 55133-3427 (US) (57) ABSTRACT (21) Appl. No.: 10/670,957 (22)22) FileFilled: Sep.ep. ZS,25, 2003 1H-imidazo dimer compounds are useful as immune Related U.S. Application Data response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines (60) Provisional application No. 60/413,848, filed on Sep. and are useful in the treatment of a variety of conditions 26, 2002. including viral diseases and neoplastic diseases. US 2004/O132766 A1 Jul. 8, 2004

1H-MIDAZO DIMERS ing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or CROSS REFERENCE TO RELATED other mechanisms. APPLICATION 0001. This application claims priority to U.S. Provisional SUMMARY OF THE INVENTION Application No. 60/413,848, filed Sep. 26, 2002. 0007. It has now been found that certain 1H-imidazo dimer compounds induce cytokine biosynthesis. In one FIELD OF THE INVENTION aspect, the present invention provides 1H-imidazo dimer 0002 The present invention relates to 1H-imidazo dimers compounds of the Formula (I): and to pharmaceutical compositions containing Such dimerS. In addition this invention relates to the use of these dimers as immunomodulators, for inducing cytokine biosynthesis in (I) animals, and in the treatment of diseases, including viral and NH2 NH2 neoplastic diseases. This invention further provides methods of making the dimerS and intermediates used in their Syn N N N N NN thesis. N / R ls- X- ck l R BACKGROUND OF THE INVENTION

0003) The first reliable report on the 1H-imidazo[4,5-c. R4 N-A. R4 quinoline ring System, Bachman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy 8-quinolinyl)-2-methyl 1H-imidazo4.5-cquinoline for pos 0008 wherein A, R, R and R are as defined herein. Sible use as an antimalarial agent. Subsequently, Syntheses of various Substituted 1H-imidazo[4,5-cquinolines were 0009. The compounds of Formula I are useful as immune reported. For example, Jain et al., J. Med. Chem. 11, pp. response modifiers (IRMs) due to their ability to induce 87-92 (1968), Synthesized the compound 1-2-(4-piperidyl cytokine biosynthesis (e.g., induce the biosynthesis or pro )ethyl)-1H-imidazo4.5-cquinoline as a possible anticon duction of one or more cytokines) and otherwise modulate Vulsant and cardiovascular agent. Also, Baron et al., Chem. the immune response when administered to animals. This AS. 85,94362 (1976), have reported several 2-oxoimidazo 4.5-cquinolines, and Berenyi et al., J. Heterocyclic Chem. makes the compounds useful in the treatment of a variety of 18, 1537-1540 (1981), have reported certain 2-oxoimidazo conditions Such as Viral diseases, and neoplastic diseases, 4.5-cquinolines. that are responsive to Such changes in the immune response. 0004 Certain 1H-imidazo[4,5-cquinolin-4-amines and 0010. In another aspect, the present invention provides 1- and 2-substituted derivatives thereof were later found to pharmaceutical compositions containing the immune be useful as antiviral agents, bronchodilators and immuno response modifier compounds, and methods of inducing modulators. These are described in, inter ail, U.S. Pat. Nos. cytokine biosynthesis in an animal, treating a viral disease in 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; an animal, and treating a neoplastic disease in an animal, by 5,346,905; and 5,389,640, all of which are incorporated administering an effective amount of one or more com herein by reference. pounds of Formula I and/or pharmaceutically acceptable 0005. Many imidazoquinoline amine, imidazopyridine Salts thereof to the animal. amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2- bridged imidazoquinoline amine, thiazoloquinoline amine, 0011. In addition, the invention provides methods of Oxazoloquinoline amine, thiazolopyridine amine, oxazol Synthesizing the compounds of the invention and interme opyridine amine, imidazonaphthyridine and tetrahydroimi diates useful in the Synthesis of these compounds. dazonaphthyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (includ 0012. As used herein, “a,”“an,”“the,”“at least one,” and ing anticancer) activity, and have also been shown to be “one or more' are used interchangeably. useful as vaccine adjuvants to enhance protective immune 0013 The terms “comprising” and variations thereof do System response to vaccines. Such compounds and methods of making them are disclosed in, for example, U.S. Pat. NoS. not have a limiting meaning where these terms appear in the 4,689,338; 4,929,624, 5,266,575; 5,268,376; 5,352,784; description and claims. 5,389,640; 5,482.936; 5,494,916; 6,110,929; 6,194,425; 0014. The above summary of the present invention is not 6,331,539; 6,376,669; 6,451,810; 6,541,485; 6,573,273; intended to describe each disclosed embodiment or every 6,545,016; 6,545,017; and 6,525,064, and PCT Publications implementation of the present invention. The description WO 02/46188, WO 02/46189; WO 02/46190; WO 02/46191; WO O2/46192; and WO 02/46193, the disclosures that follows more particularly exemplifies illustrative of which are specifically incorporated by reference herein. embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In 0006 Despite these recent discoveries of compounds that each instance, the recited list Serves only as a representative are useful as immune response modifiers, there is a continu group and should not be interpreted as an exclusive list. US 2004/O132766 A1 Jul. 8, 2004

DETAILED DESCRIPTION OF THE 0.042 straight or branched chain Co alky INVENTION nylene, 0.015. In one aspect, the present invention provides 0.043 straight or branched chain perfluoro Co 1H-imidazo dimer compounds of the Formula (I): alkylene, 0044 C- alkylene-O-C alkylene; (I) 0045 –C(O)-; NH2 NH2 0046 -S(O) ; N N N N NN 0047 –OC(O)O-; - Y-R,y- a -(K. 2 0048 -N(R)C(O)N(R)-; R R Y 7 o R4 N-A. R4

0016 wherein: 0017 A is a divalent linking group selected from the group consisting of 0018 straight or branched chain Co alkylene; 0019 straight or branched chain Coalkenylene; 0020 straight or branched chain Co alky 0049) 1.5-naphthylene; nylene, and 0050 2,6-pyridinylene; 0051 12-cyclohexylene; 0022 each Z is independently selected from the 0052) 1,3-cyclohexylene; group consisting of 0053 14-cyclohexylene; 0023 straight or branched chain Co alkylene; 0.054 trans-1,4-cyclohexylene; 0024) Straight or branched chain Coalkenylene; and 0025 straight or branched chain Co alky nylene; 0026 any of which may be optionally interrupted by -O-, -N(R)-, or -S(O) ; 0027 each Y is independently selected from the 0055) and group consisting of 0056 trans-5-norbornen-2,3-diyl; 0057 wherein n is 0-4; each R is independently Selected from the group consisting of C alkyl, C, alkoxy, and halogen; and Q is selected from the group consisting of a bond, -CH2-, and -O-, 0.058 R is selected from the group consisting of: 0059 -hydrogen; 0060) -alkyl; 0061 -alkenyl; 0062 -aryl; 0063) -substituted aryl; 0064 -heteroaryl; 0039 W is selected from the group consisting of: 0065 -substituted heteroaryl; 0040 straight or branched chain Co alkylene; 0.066 -alkyl-X-alkyl; 0041 Straight or branched chain Coalkenylene; 0067 -alkyl-X-aryl; US 2004/O132766 A1 Jul. 8, 2004

0068) -alkyl-X- alkenyl; and to 2 heteroatoms and unsubstituted or substituted by one or more Substituents Selected from the group 0069 -alkyl or alkenyl substituted by one or more consisting of: Substituents Selected from the group consisting of: -halogen; 0070) -OH: 01.06) 0071 -halogen; 01.07 -alkyl, -alkenyl, 0.072 -N(R); 0108) 0.073 –C(O)-N(R); 01.09) -X-alkyl; and 0.074 –C(S)-N(R); 0110 -N(R), 0111 each Rs is independently selected from the 0075) -S(O)-N(R); group consisting of 0076 -N(R)-C(O)-Co alkyl; 0112 hydrogen; 0077 -N(R)-C(S)-Co alkyl; 0113) Ce alkyl, 0078 -N(R)-S(O)-Co alkyl; 0114 C-7 cycloalkyl, and 0079 –C(O)-Co alkyl; 0115) benzyl; or 0080 -C(O)-O-C alkyl; 0116 when Y is -N(Rs)C(O)-, -C(O)N(Rs), 0081 -N: -N(R)C(O)N(R)-, -N(R)S(O), 0082) -aryl; -S(O)N(R)-, -N(Rs)C(O)O-, or -OC(O)N(R)- and the nitrogen of the N(Rs) 0083) -substituted aryl; group is bonded to Z, then Rs can join with Z to form 0084 -heteroaryl; a ring having the Structure 0085 -substituted heteroaryl; 0.086 -heterocyclyl; 0087 -substituted heterocyclyl; -O-M R7 0088 –C(O)-aryl; 0089 –C(O)-(substituted aryl); 0117) each R is independently hydrogen or Co 0090 –C(O)-heteroaryl; and alkyl, 0.091 –C(O)-(substituted heteroaryl); 0118 R, is Cls alkylene; and 0092 R and R are each independently selected 0119 X is -O- or -S-; from the group consisting of: 0120 with the proviso that if Wis-C(O)-, -S(O), 0093 -hydrogen; -OC(O)O-, or -N(R)C(O)N(R)- then each Y is a 0094) -halogen; bond; 0095) -alkyl; 0121 or a pharmaceutically acceptable salt thereof. 0096) -alkenyl; 0.122 The present invention also provides compounds that are useful as intermediates in the Synthesis of com 0097 –X-alkyl; and pounds of Formula (I). These intermediate compounds have 0098) -N(R); the structural Formulas (II)-(V), described below. 0099 or when taken together, R and R form a 0123 The present invention provides intermediate com fused aryl or heteroaryl ring that is unsubstituted or pounds of the Formula (II): substituted by one or more substituents selected from the group consisting of: (II) 01.00) -halogen; O 01.01 -alkyl, 01.02) -alkenyl; r 0103) -X-alkyl; and 2ng 0.104) -N(R), (R)R"). 21 (R) 01.05) or when taken together, R and R form a fused 5 to 7 membered Saturated ring, containing 0 US 2004/O132766 A1 Jul. 8, 2004

0124 wherein: 0153. The present invention also provides intermediate 0.125 A is a divalent linking group selected from compounds of Formula (IV): the group consisting of: 0.126 Straight or branched chain Co alkylene; (IV)

0127 Straight or branched chain Coalkenylene; n N N and Y- R" R" –6. 0128 straight or branched chain Co alky 2 N N nylene; 0.129 any of which may be optionally interrupted (R) 2 N A.-/ by -S(O)- or a protected 0.130) –C(O)–: 0154 wherein: 0131 n is 0 to 4; 0.155) A is a divalent linking group selected from 0132 each R" present is independently selected from the group consisting of: the group consisting of: 0156) Straight or branched chain Co alkylene; 0133 halogen; O157) Straight or branched chain Coalkenylene; 0134) alkyl; and 0135) alkenyl; and 0158 straight or branched chain Co alky nylene, 0136 -O-alkyl; 0159 any of which may be optionally interrupted 0.137 or a pharmaceutically acceptable salt thereof. by -S(O)- or a protected -C(O)-; 0.138. The present invention also provides intermediate 0160 R" is selected from the group consisting of: compounds of the Formula (III): 0161) -hydrogen; 0162 -alkyl, (III) 0163) -alkenyl, NH2 HN N1 N 0164) 21 0165) -Substituted aryl; 0166) -heteroaryl; (R), 21 A. 0167) -Substituted heteroaryl; 0168) -alkyl-O-alkyl; 0139 wherein: 0169 -alkyl-O-aryl; 0140) A is a divalent linking group selected from 0170 -alkyl-O-alkenyl; and the group consisting of: 0171 -alkyl or alkenyl substituted by one or more 0141 Straight or branched chain Co alkylene; Substituents Selected from the group consisting of: 0142) Straight or branched chain Coalkenylene; 0172 –OH: and 0173 -halogen; 0.143 Straight or branched chain Co alky 0174) nylene; -C(O)-N(R); 0175) -C(S)-N(R); 0144) any of which may be optionally interrupted by -S(O)- or a protected 0176) -S(O)N(R); 0145 –C(O)–: 0177) -N(R)-C(O)-Co alkyl; 0146 n is 0 to 4; 0178) -N(R)-C(S)-Co alkyl; 0147 each R" present is independently selected from 0179 -N(R)-S(O)--Co alkyl, the group consisting of: 0180) -C(O)-Co alkyl, 0148 halogen; 0181 -C(O)-O-C alkyl; 0149) alkyl, 0182 -N; 0150 alkenyl; and 0183 -aryl; 0151. -O-alkyl; 0184 -Substituted aryl; 0152 or a pharmaceutically acceptable salt thereof. 0185 -heteroaryl; US 2004/O132766 A1 Jul. 8, 2004

0186 -substituted heteroaryl; 0217 -alkyl-O-aryl; 0187 -heterocyclyl; 0218 -alkyl-O-alkenyl; and 0188 -substituted heterocyclyl; 0219) -alkyl or alkenyl substituted by one or more 0189 –C(O)-aryl; Substituents Selected from the group consisting of: 0.190 –C(O)-(substituted aryl); 0220 –OH: 0191) –C(O)-heteroaryl; and 0221) -halogen; 0192 -C(O)-(substituted heteroaryl); 0222 -C(O)-N(R); 0193 n is 0 to 4; 0223) -C(S)-N(R); 0194 each R" present is independently selected from the group consisting of: 0224) -S(O)N(R); 0195 halogen; 0225 -N(R)-C(O)-Co alkyl; 0196) alkyl; 0226 -N(R)-C(S)-Co alkyl; 0197) alkenyl; and 0227 -N(R)-S(O)-Co alkyl; 0198 -O-alkyl; 0228) -C(O)-Co alkyl; 0199 each R is independently hydrogen or Co 0229 -C(O)-O-C alkyl; alkyl, 0230 -N: 0200 or a pharmaceutically acceptable salt thereof. 0231 -aryl; 0201 The present invention also provides intermediate compounds of the Formula (V): 0232 -substituted aryl; 0233 -heteroaryl; (V) 0234 -substituted heteroaryl; 0235 -heterocyclyl; 0236 -substituted heterocyclyl; 0237) –C(O)-aryl; 0238 -C(O)-(substituted aryl); 0239 –C(O)-heteroaryl; and 0202) wherein: 0240 -C(O)-(substituted heteroaryl); 0203) A is a divalent linking group selected from the group consisting of: 0241 n is 0 to 4; 0242 each R" present is independently selected from 0204) Straight or branched chain Co alkylene; the group consisting of: 0205) Straight or branched chain Coalkenylene; and 0243 halogen; 0206 straight or branched chain Co alky 0244 alkyl; nylene; 0245 alkenyl; and 0207 any of which may be optionally interrupted by -S(O)- or a protected -C(O)-; 0246 -O-alkyl; 0247 each Re is independently hydrogen or Co. 0208 R" is selected from the group consisting of: alkyl, 0209 -hydrogen; 0248 or a pharmaceutically acceptable salt thereof. 0210 -alkyl; 0249. In some embodiments of the present invention A is 0211 -alkenyl; Straight or branched chain Co alkylene. 0212 -aryl; 0250 In other embodiments of the present invention A is -Z-Y-W-Y-Z-. In certain embodiments each Z is straight or 0213) -substituted aryl; branched chain Co alkylene optionally interrupted by 0214 -heteroaryl; -O-. In certain embodiments each Z is selected from the group consisting of Straight or branched chain C alkylene 0215 -substituted heteroaryl; and C alkylene-O-C alkylene. In certain embodiments 0216) -alkyl-O-alkyl; Rs is joined with Z to form a ring having the Structure US 2004/O132766 A1 Jul. 8, 2004

0260 Preparation of the Compounds 0261 Compounds of the invention can be prepared according to Reaction Scheme I wherein R', R", A and n are -O-/ as defined above. 0262 In step (1) of Reaction Scheme I a 4-chloro-3- nitroquinoline of Formula VI is reacted with a diamine of Formula VII to provide a dimer compound of Formula II. 0251 wherein R, is C alkylene. The reaction can be carried out by adding a diamine of 0252) In certain embodiments each Y is independently Formula VII to a solution of a compound of Formula VI in a Suitable Solvent Such as dichloromethane in the presence of Selected from the group consisting of a bond; a base Such as triethylamine. The reaction can be run at -N(R)C(O)-, -C(O)N(R)-; -N(R)C(O)N(R)-; ambient temperature. Many compounds of Formula VI are -S(O)N(R)-; and known or can be prepared using known Synthetic methods, 0253) see for example, U.S. Pat. Nos. 4,689,338; 5,175,296; 5,367, 076; 5,389, 640; and 6,194,425 and the references cited 0254. In certain embodiments W is selected from the therein. Many diamines of Formula VII are commercially group consisting of Straight or branched chain Co alky available; others can be readily prepared using known lene; -N(Rs)C(O)N(R)-; Synthetic methods. 0263. In step (2) of Reaction Scheme I a compound of Formula II is reduced to provide a compound of Formula III. The reduction can be carried out using a conventional heterogeneous hydrogenation catalyst. The reaction can be conveniently carried out on a Parr apparatus in a Suitable Solvent Such as toluene. In those instances where A contains an alkenylene or alkynylene group a catalyst is Selected that is capable of reducing the nitro group without reducing the alkenylene or alkynylene group, examples include tin and Zinc/hydrochloric acid. 0264. In step (3) of Reaction Scheme I a compound of Formula III is (I) reacted with an acyl chloride of Formula RC(O)Cl and then (ii) cyclized to provide a 1H-imidazo dimer compound of Formula IV. In part (i) the acyl chloride is added to a solution of a compound of Formula III in a Suitable Solvent Such as dichloromethane in the presence of a base Such as triethylamine. The reaction can be run at 0255 12-cyclohexylene; 1,3-cyclohexylene; 1,4-cyclo ambient temperature. In part (ii) the product of part (i) is heXylene, and trans-1,4-cyclohexylene. heated in an alcoholic Solvent in the presence of a base. Preferably the product of part (i) is refluxed in ethanol in the 0256 In some embodiments of the present invention Rs presence of excess triethylamine or is heated with methan is hydrogen. olic ammonia. 0257. In some embodiments of the present invention R 0265 Alternatively, step (3) can be carried out by react is hydrogen, alkyl or alkyl-O-alkyl. In certain embodiments ing a compound of Formula III with a carboxylic acid or an R is hydrogen, methyl, ethyl, propyl, butyl, cyclopropylm equivalent thereof. Suitable equivalents to carboxylic acid ethyl, ethoxymethyl or methoxyethyl. include orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is Selected Such that it will 0258. In some embodiments of the present invention R provide the desired R. Substituent in a compound of Formula and R join together to form a fused benzene ring. In other IV. For example, triethyl orthoformate will provide a com embodiments R and R join together to form a fused pound where R is hydrogen and triethyl orthovalerate will pyridine ring. In other embodiments R and R join together provide a compound where R is butyl. The reaction can be to form a fused six membered Saturated ring. In other run in the absence of Solvent or in an inert Solvent Such as embodiments R and R join together to form a fused six toluene. The reaction is run with Sufficient heating to drive membered Saturated ring containing one nitrogen atom. In off any alcohol or water formed as a byproduct of the still other embodiments of the present invention R and R. reaction. Optionally a catalyst Such as pyridine hydrochlo are independently hydrogen or alkyl. ride can be included. 0259. The invention is inclusive of the compounds 0266. In step (4) of Reaction Scheme I a 1H-imidazo described herein in any of their pharmaceutically acceptable dimer compound of Formula IV is oxidized to provide an forms, including isomerS Such as diastereomers and enanti N-oxide of Formula V using a conventional oxidizing agent omers, Salts, Solvates, polymorphs, and the like. In particu that is capable of forming N-oxides. Preferably a solution of lar, if a compound is optically active, the invention Specifi a compound of Formula IV in a suitable solvent such as cally includes each of the compound's enantiomers as well dichloromethane is treated with 3-chloroperoxybenzoic acid as racemic mixtures of the enantiomers. at ambient temperature. US 2004/O132766 A1 Jul. 8, 2004

0267 In step (5) of Reaction Scheme I an N-oxide of 0268 Compounds of the invention can also be prepared Formula V is aminated to provide a 1H-imidazo dimer according to Reaction Scheme II wherein R,R,R,Rs and compound of Formula VIII, which is a subgenus of Formula Z are as defined above and W is Selected from the group I. The reaction is carried out in two parts. In part (i) a consisting of Straight or branched chain Co alkylene; compound of Formula V is reacted with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl Straight or branched chain Co alkenylene, Straight or chorides (e.g., benzenesulfonyl choride, methaneSulfonyl branched chain Co alkynylene; Straight or branched chain choride, and p-toluenesulfonyl chloride). In part (ii) the perfluoro Cao alkylene, C alkylene-O-C alkylene, product of part (i) is reacted with an excess of an aminating agent. Suitable aninating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium Salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). The reaction can be carried out by dissolving a compound of Formula V in a suitable solvent Such as dichloromethane, adding ammonium hydroxide to the Solution, and then adding p-toluenesulfonyl chloride. The product or a pharmaceutically acceptable Salt thereof can be isolated using conventional methods. When A contains a -C(O)- group, the group is protected (e.g., by forming an acetal) throughout the Synthesis and then the protecting group is removed.

Reaction Scheme I O | N N No N (1) 21 Cl -- HN-A-NH2 1. 2 Her 21 (R)-1C 21 (R)-1C 2

VI VII II o

N 21 (R)-1C 21

III

NH2

N1 N 21 (R) 1(2 US 2004/O132766 A1 Jul. 8, 2004

0269 1,5-naphthylene; 2,6-pyridinylene; 1,2-cyclohexy W and Z are as defined above. In Reaction Scheme III a lene, 1,3-cyclohexylene, 1,4-cyclohexylene; trans-1,4-cy 1H-imidazo compound of Formula IX is reacted with a clohexylene; disulfonyl chloride of Formula XII to provide a 1H-imidazo dimer compound of Formula XIII, which is a subgenus of Formula I. The reaction can be carried out by adding the disulfonyl chloride to a Solution or Suspension of a com pound of Formula IX in a suitable solvent such as dichlo romethane in the presence of a base Such as triethylamine. The reaction can be run at ambient temperature. Many disulfonyl chlorides are commercially available; others can 0270 and trans-5-norbornen-2,3-diyl; wherein n is 0-4; be prepared using known Synthetic methods. The product or each R is independently Selected from the group consisting a pharmaceutically acceptable Salt thereof can be isolated of C alkyl, C. alkoxy, and halogen; and Q is Selected using conventional methods. from the group consisting of a bond, -CH2-, and -O-. 0271 In Reaction Scheme II a 1H-imidazo compound of Reaction Scheme III Formula IX is reacted with a diisocyanate of Formula X to NH2 provide a 1H-imidazo dimer compound of Formula XI, which is a subgenus of Formula I. The reaction can be N1 N N N R Hess carried out by adding the diisocyanate to a Solution or 2 2 CIS(O)-W-S(O)Cl. Suspension of a compound of Formula IX in a Suitable R N XII Solvent Such as dichloromethane. The reaction can be run at Z. ambient temperature. Many 1H-imidazo compounds of For R4 YNH M mula IX are known or can be prepared using known Syn Rs thetic methods, see for example, U.S. Pat. Nos. 6,069,149; IX 6,194,425; 6,331,539; 6,451,810; and 6,545,016, European Patent Application 1104764, and International Publications WO 02/46188 and WO 02/46194. Many diisocyanates are commercially available; others can be prepared using known Synthetic methods. The product or a pharmaceutically NH2 NH2 acceptable Salt thereof can be isolated using conventional methods. N N \ y NN 21 X-R, R-( | 2 R v, O O A. R Reaction Scheme II R4 NN | | N1 R4 NH2 / Ng g1 V R5 a w1 Y || R5 N1S-N O O Y-R 2 O=C=N-W-N=C=O R 21NN 3 V X Z. R4 YNH 0273 Compounds of the invention can also be prepared / according to Reaction Scheme IV wherein R, R., R., Rs. R5 W, and Z are as defined above. In Reaction Scheme IV a DX 1H-imidazo compound of Formula IX is reacted with a diacid chloride of Formula XIV to provide a 1H-imidazo dimer compound of Formula XV, which is a subgenus of Formula I. The reaction can be carried out by adding the acid NH2 NH2 chloride to a Solution or Suspension of a compound of Formula IX in a Suitable solvent Such as dichloromethane in N n N N NN the presence of a base Such as triethylamine. The reaction can be run at ambient temperature. Many diacid chlorides are commercially available; others can be prepared using known Synthetic methods. The product or a pharmaceuti cally acceptable Salt thereof can be isolated using conven tional methods. 0274. Alternatively, the reaction can be carried out by reacting a compound of Formula IX with a diacid of the 0272 Compounds of the invention can also be prepared formula HOC(O)-W-C(O)OH using a standard coupling according to Reaction Scheme III wherein R, R, R, Rs. reagent Such as 1,3-dicyclohexylcarbodiimide. US 2004/O132766 A1 Jul. 8, 2004

0276 Compounds of the invention can also be prepared according to Reaction Scheme VI wherein R, R., R., W. Reaction Scheme IV and Z are as defined above and BOC is tert-butoxycarbonyl. NH2 0277. In step (1) of Reaction Scheme VI the amino group of a 1H-imidazo compound of Formula XVII is protected N N-N with two tert-butoxycarbonyl groups. The reaction can be 21 NNX-R, CIC(O)-W-C(O)Cl. carried out by treating a Solution of a compound of Formula R V XIV XVII with di-tert-butyl dicarbonate in the presence of a base R4 ^NH Such as 4-(dimethylamino)pyridine. Many 1H-imidazo com / pounds of Formula XVII are known or can be prepared using R5 known synthetic methods, see for example, U.S. Pat. Nos. DX 4,698.338; 4.988,815; 5,175,296; 5,268,376; 5,352,784; NH2 NH2 5,389,640; 5,395,937; 5,446,153; 5,741,908; and 6,194,425. N N n 0278 In step (2) of Reaction Scheme VI a protected 1H-imidazo compound of Formula XVIII is reacted with a 2 y-, -(1,2 diisocyanate of Formula X to provide a 1H-imidazo dimer compound of Formula XIX. The reaction can be carried out by adding the diisocyanate to a Solution or Suspension of a compound of Formula XVIII in a suitable solvent such as dichloromethane. The reaction can be run at ambient tem perature. 0279. In step (3) of Reaction Scheme VI the protecting 0275 Compounds of the invention can also be prepared groups are removed by hydrolysis under acidic conditions to according to Reaction Scheme V wherein R, R., R., Rs. provide a 1H-imidazo dimer compound of Formula XX, and Z are as defined above. In Reaction Scheme V a which is a Subgenus of Formula I. The product or a phar 1H-imidazo compound of Formula IX is reacted with car maceutically acceptable Salt thereof can be isolated using bonyldiimidazole to provide a 1H-imidazo dimer compound conventional methods. of Formula XVI, which is a subgenus of Formula I. The reaction can be carried out by adding the carbonyldiimida Zole to a Solution or Suspension of a compound of Formula IX in a Suitable solvent Such as dichloromethane in the presence of a base Such as 4-(dimethylamino)pyridine. The Reaction Scheme VI reaction can be run at ambient temperature. The product or NH2 a pharmaceutically acceptable Salt thereof can be isolated using conventional methods. N NX-R, -O- Reaction Scheme V R 21 N NH2 Z. R4 V OH N N NN XVII R 2NNX-R, - 3 V R4 Zn NH / N(BOC) R5 DX N1S-N NH2 NH2 X-R, N N R 2 N N N N W NN Z. X-R, R-( | R4 V R 21NN N 2 R OH 3 V M 3 Z. Z. XVIII R4 YN N1 R4 / V R5 R5 O XVI US 2004/O132766 A1 Jul. 8, 2004 10

-continued -continued N(BOC) N(BOC) N(BOC) N(BOC) N1S-N N NN N1-S-N N NN R 2NNX-R, R-(N 2 X-R, R-( 3 V A R Z. Z. R 2 N N 4S, R4 V A R4 Z. Z. O H H O R4 V M R4 N N O O Y- NW / ( O O Y-sk XX O O XXI ( % NH2 NH2 NH2 NH2

N1N-N N NN N N N N NN R 2NNX-R, R-(N 2 3 V M R3 2 X-R, R-( Z. Z. R N N 2 R R4 V M R4 Z. Z. O H H O R4 V / R4 N N Y- NW / sk O O O O y-six XX O O

0280 Compounds of the invention can also be prepared according to Reaction Scheme VII wherein R, R., R., W., 0283 Compounds of the invention can also be prepared Z and BOC are as defined above. according to Reaction Scheme VIII wherein R, R, R, Z and BOC are as defined above and W is straight or branched 0281. In step (1) of Reaction Scheme VII a protected chain C2-20 alkylene. 1H-imidazo compound of Formula XVIII is reacted with a 0284. In step (1) Reaction Scheme VIII a protected diacid chloride of Formula XIV to provide a 1H-imidazo 1H-imidazo compound of Formula XVIII is reacted with a dimer compound of Formula XXI. The reaction can be compound of Formula XXIII to provide a 1H-imidazo dimer carried out by adding the diacid chloride to a Solution or compound of Formula XXIV. The reaction can be carried out suspension of a compound of Formula XVIII in a suitable by adding a compound of Formula XXIII to a solution or Solvent Such as dichloromethane in the presence of a base suspension of a compound of Formula XVIII in a suitable Such as triethylamine. The reaction can be run at ambient Solvent Such as dichloromethane in the presence of a base temperature. Such as triethylamine. The reaction can be run at ambient temperature. 0282. In step (2) of Reaction Scheme VII the protecting 0285) In step (2) of Reaction Scheme VIII the protecting groups are removed by hydrolysis under acidic conditions to groups are removed by hydrolysis under acidic conditions to provide a 1H-imidazo dimer compound of Formula XXII, provide a 1H-imidazo dimer compound of Formula XXV, which is a Subgenus of Formula I. The product or a phar which is a Subgenus of Formula I. The product or a phar maceutically acceptable Salt thereof can be isolated using maceutically acceptable Salt thereof can be isolated using conventional methods. conventional methods.

Reaction Scheme VII Reaction Scheme VIII N(BOC) N(BOC)2

N N 1S-N —O - 1S-N R —O - R2 CIC(O)-W-C(O)Cl 2 CIC(O)-W-C(O)Cl. R 21NNV XIV R 21 NNV XXIII Z. Z. R4 V R4 V OH OH XVIII XVIII US 2004/O132766 A1 Jul. 8, 2004 11

-continued -continued N(BOC)2 N(BOC)2 N(BOC) N(BOC)

N1 N-N N NN N N N N NN 2 Y-R, R-( 2 X-R, R-( R y A R R 21 N A 2 R R4 V A R4 O O R4 Sir Z. R4 y- WAsk O O O XXIV XXVI % NH2 NH2 NH2 NH2 N1 N-N N NN N N N N SN 2 Y-R, R-( 2 X-R, R-( R N A. R Z. Z. -N1-x X----, R4 V A R4 O O R4 ^n, o1 Z. R4 O AO W O O XXV

0289 Alternatively, in Reaction Schemes VI-IX when 0286 Compounds of the invention can also be prepared W, does not contain an alkenylene or alkynylene group, the according to Reaction Scheme IX wherein R,R,R, Z and amine can be protected with benzyloxycarbonyl groups BOC are as defined above. instead of tert-butyoxy carbonyl groups. The protected com pound can be prepared by treating a Solution of a compound 0287. In step (1) of Reaction Scheme IX a protected of Formula XVII with dibenzyl dicarbonate or benzyl chlo 1H-imidazo compound of Formula XVIII is reacted with roformate. The protecting groups are later removed by carbonyldiimidazole or phosgene to provide a 1H-imidazo hydrogenolysis. dimer compound of Formula XXVI. The reaction can be carried out by adding carbonyldiimidazole or phosgene to a 0290 AS used herein, the terms “alkyl”, “alkenyl”, “alky nyl' and the prefix “alk-” are inclusive of both straight chain solution or suspension of a compound of Formula XVIII in and branched chain groups and of cyclic groups, i.e. a Suitable Solvent Such as dichloromethane in the presence of cycloalkyl and cycloalkenyl. Unless otherwise Specified, a base Such as 4-(dimethylamino)pyridine. The reaction can these groups contain from 1 to 20 carbon atoms, with be run at ambient temperature. alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In 0288. In step (2) of Reaction Scheme IX the protecting Some embodiments, these groups have a total of up to 10 groups are removed by hydrolysis under acidic conditions to carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, provide a 1H-imidazo dimer compound of Formula XXVII, or up to 4 carbon atoms. Cyclic groups can be monocyclic which is a Subgenus of Formula I. The product or a phar or polycyclic and preferably have from 3 to 10 ring carbon maceutically acceptable Salt thereof can be isolated using atoms. Exemplary cyclic groups include cyclopropyl, cyclo conventional methods. propylmethyl, cyclopentyl, cyclohexyl, adamantyl, and Sub stituted and unsubstituted norbornyl and norbornenyl.

Reaction Scheme IX 0291 Unless otherwise specified, “alkylene”, “alk enylene', and “alkynylene' are the divalent forms of the N(BOC) “alkyl”, “alkenyl', and “alkynyl groups defined above. N N 0292. The term “haloalkyl is inclusive of groups that are Substituted by one or more halogen atoms, including per X-R, -d- fluorinated groups. This is also true of other groups that R 2 N include the prefix "halo-”. Examples of suitable haloalkyl Z. groups are chloromethyl, trifluoromethyl, and the like. R4 V OH 0293. The term “aryl” as used herein includes carbocyclic XVIII aromatic rings or ring Systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. US 2004/O132766 A1 Jul. 8, 2004

0294 The term “heteroaryl' includes aromatic rings or men, or the compounds of the invention may be adminis ring Systems that contain at least one ring hetero atom (e.g., tered in combination with one another or with other active O, S, N). Suitable heteroaryl groups include furyl, thienyl, agents, including additional immune response modifiers, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triaz antivirals, antibiotics, antibodies, proteins, peptides, oligo olyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, nucleotides, etc. thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, ben ZOxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, ben 0302) The compounds of the invention have been shown Zothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, puri to induce the production of certain cytokines in experiments nyl, quinazolinyl, and So on. performed according to the tests set forth below. These results indicate that the compounds are useful as immune 0295) “Heterocyclyl” includes non-aromatic rings or ring response modifiers that can modulate the immune response Systems that contain at least one ring hetero atom (e.g., O, in a number of different ways, rendering them useful in the S, N) and includes all of the fully saturated and partially treatment of a variety of disorders. unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, 0303 Cytokines whose production may be induced by tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidi the administration of compounds according to the invention nyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imida generally include interferon-C. (IFN-C) and/or tumor necro Zolidinyl. sis factor-O. (TNF-C) as well as certain interleukins (IL). 0296. The aryl, heteroaryl, and heterocyclyl groups can Cytokines whose biosynthesis may be induced by com be unsubstituted or substituted by one or more substituents pounds of the invention include IFN-C, TNF-C., IL-1, IL-6, independently Selected from the group consisting of alkyl, IL-10 and IL-12, and a variety of other cytokines. Among alkenyl, alkoxy, alkylthio, halogen, amino, alkylamino and other effects, these and other cytokines can inhibit virus dialkylamino. production and tumor cell growth, making the compounds useful in the treatment of Viral diseases and neoplastic 0297 The term “protected -C(O)-” means a carbonyl diseases. Accordingly, the invention provides a method of group that has been converted into another functional group inducing cytokine biosynthesis in an animal comprising which will stand up to and not interfere with the reaction administering an effective amount of a compound or com conditions of the Succeeding Steps in the Synthesis and then position of the invention to the animal. The animal to which can be readily removed. For example, the carbonyl group the compound or composition is administered for induction may be converted to an acyclic ketal, a cyclic ketal or a of cytokine biosynthesis may have a disease as described cyclic dithio ketal. The use of protecting groups is well infra, for example a viral disease or a neoplastic disease, and known and methods for Selecting appropriate groups, intro administration of the compound may provide therapeutic ducing them into the molecule, and then later removing them treatment. Alternatively, the compound may be administered have been discussed in for example, Greene, Theodora to the animal prior to the animal acquiring the disease So that (1999), Protective Groups in Organic Synthesis, John Wiley administration of the compound may provide a prophylactic & Sons, Inc. treatment. 0298 Pharmaceutical Compositions and Biological Activity 0304. In addition to the ability to induce the production of cytokines, the compounds of the invention affect other 0299 Pharmaceutical compositions of the invention con aspects of the innate immune response. For example, natural tain a therapeutically effective amount of a compound of the killer cell activity may be stimulated, an effect that may be invention as described above in combination with a phar due to cytokine induction. The compounds may also activate maceutically acceptable carrier. macrophages, which in turn Stimulate Secretion of nitric 0300. The term “a therapeutically effective amount” or oxide and the production of additional cytokines. Further, “effective amount’ means an amount of the compound the compounds may cause proliferation and differentiation Sufficient to induce a therapeutic effect, Such as cytokine of B-lymphocytes. induction, immunomodulation, antitumor activity, and/or 0305 Compounds of the invention also have an effect on antiviral activity. Although the exact amount of active com the acquired immune response. For example, the production pound used in a pharmaceutical composition of the inven tion will vary according to factors known to those of skill in of the T helper type 1 (Th1) cytokine IFN-Y is induced the art, Such as the physical and chemical nature of the indirectly and the production of the T helper type 2 (Th2) compound, the nature of the carrier, and the intended dosing cytokines IL-4, IL-5 and IL-13 are inhibited upon adminis regimen, it is anticipated that the compositions of the tration of the compounds. invention will contain Sufficient active ingredient to provide 0306 Whether for prophylaxis or therapeutic treatment a dose of about 100 ng/kg to about 50 mg/kg, preferably of a disease, and whether for effecting innate or acquired about 10 ug/kg to about 5 mg/kg, of the compound to the immunity, the compound or composition may be adminis Subject. A variety of dosage forms may be used, Such as tered alone or in combination with one or more active tablets, lozenges, capsules, parenteral formulations, Syrups, components as in, for example, a vaccine adjuvant. When creams, ointments, aerosol formulations, transdermal administered with other components, the compound and patches, transmucosal patches and the like. other component or components may be administered Sepa 0301 The compounds of the invention can be adminis rately; together but independently Such as in a Solution; or tered as the Single therapeutic agent in the treatment regi together and associated with one another Such as (a) US 2004/O132766 A1 Jul. 8, 2004 covalently linked or (b) non-covalently associated, e.g., in a disease) by administering a therapeutically effective amount colloidal Suspension. of a compound or Salt of formula (I) to the animal. 0307 Diseases for which IRMs identified herein may be 0316. An amount of a compound effective to induce used as treatments include, but are not limited to: cytokine biosynthesis is an amount Sufficient to cause one or 0308 (a) viral diseases, such as genital warts, com more cell types, Such as monocytes, macrophages, dendritic mon warts, plantar warts, hepatitis B, hepatitis C, cells and B-cells to produce an amount of one or more herpes simplex virus type I and type II, molluscum cytokines such as, for example, IFN-O, TNF-C., IL-1, IL-6, contagiosum, variola, HIV, CMV, VZV, rhinovirus, IL-10 and IL-12 that is increased over the background level adenovirus, coronavirus, influenza, para-influenza, of Such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of 0309 (b) bacterial diseases, such as tuberculosis, about 100 ng/kg to about 50 mg/kg, preferably about 10 and mycobacterium avium, leprosy, tug/kg to about 5 mg/kg. The invention also provides a 0310 (c) other infectious diseases, such as fungal method of treating a viral infection in an animal and a diseases, chlamydia, candida, aspergillus, cryptococ method of treating a neoplastic disease in an animal com cal meningitis, pneumocystis camii, cryptosporidi prising administering an effective amount of a compound or osis, histoplasmosis, toxoplasmosis, trypanoSome composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that infection, leishmaniasis, will cause a reduction in one or more of the manifestations 0311 (d) neoplastic diseases, such as intraepithelial of Viral infection, Such as viral lesions, Viral load, rate of neoplasias, cervical dysplasia, actinic keratosis, Virus production, and mortality as compared to untreated basal cell carcinoma, Squamous cell carcinoma, control animals. The precise amount that is effective for Such hairy cell leukemia, Karposi's Sarcoma, melanoma, treatment will vary according to factors known in the art but renal cell carcinoma, myelogeous leukemia, multiple is expected to be a dose of about 100 ng/kg to about 50 myeloma, non-Hodgkin’s lymphoma, cutaneous mg/kg, preferably about 10 ug/kg to about 5 mg/kg. An T-cell lymphoma, and other cancers, amount of a compound effective to treat a neoplastic con dition is an amount that will cause a reduction in tumor size 0312 (e) Th2 mediated, atopic, and autoimmune or in the number of tumor foci. Again, the precise amount diseases, Such as atopic dermatitis or eczema, eosi will vary according to factors known in the art but is nophilia, asthma, allergy, allergic rhinitis, Systemic expected to be a dose of about 100 ng/kg to about 50 mg/kg, lupus erythematosis, essential thrombocythaemia, preferably about 10 ug/kg to about 5 mg/kg. multiple Sclerosis, Ommen’s Syndrome, discoid lupus, alopecia areata, inhibition of keloid formation 0317. The invention is further described by the following and other types of Scarring, and enhancing would examples, which are provided for illustration only and are healing, including chronic wounds, and not intended to be limiting in any way.

0313 (f) as a vaccine adjuvant for use in conjunc EXAMPLE 1. tion with any material that raises either humoral and/or cell mediated immune response, Such live Viral and bacterial immunogens and inactivated viral, N,N'-bis(4-(4-amino-2-butyl-1H-imidazo 4.5-c tumor-derived, protozoal, organism-derived, fungal, quinolin-1-yl)butylurea and bacterial immunogens, toxoids, toxins, polysac charides, proteins, glycoproteins, peptides, cellular 0318) vaccines, DNA vaccines, recombinant proteins, gly coproteins, and peptides, and the like, for use in connection with, e.g., BCG, cholera, plague, NH2 NH2 typhoid, hepatitis A, B, and C, influenza A and B, parainfluenza, polio, rabies, measles, mumps, N N rubella, yellow fever, tetanus, diphtheria, hemophi N-y Sr. luS influenza b, tuberculosis, meningococcal and 21NN N1S pneumococcal vaccines, adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory Syncytial virus, rotavirus, papilloma virus, and yellow fever. 0314 IRMs may also be particularly helpful in individu als having compromised immune function. For example, IRM compounds may be used for treating the opportunistic infections and tumors that occur after Suppression of cell ...O mediated immunity in, for example, transplant patients, cancer patients and HIV patients. 0319) A suspension of 1-(4-aminobutyl)-2-butyl-1H-imi 0315 Thus, one or more of the above diseases or types of dazo[4,5-cquinolin-4-amine (267 mg, 0.859 mmol) in 10 diseases, for example, a viral disease or a neoplastic disease mL of CHCl was treated with carbonyldiimidazole (71 mg, may be treated in an animal in need there of (having the 0.438 mmol) and stirred under N overnight. The reaction US 2004/O132766 A1 Jul. 8, 2004 mixture was then treated with 2 mg of 4-(dimethylamino)py 0325 A suspension of 1-(4-aminobutyl)-2-butyl-1H-imi ridine and stirred an additional 3 days (d). The reaction dazo[4,5-cquinolin-4-amine (3.11g, 10.0 mmol) in 100 mL mixture was then concentrated under reduced preSSure and the resulting white solid was triturated with HO and fil of CHCl was treated with 1,3-phenylene diisocyanate (800 tered. The resulting Solid was purified by column chroma mg, 5.0 mmol) and stirred under N overnight. The reaction tography (SiO, 10-20% MeOH/CHCl) to give a white mixture was then concentrated under reduced preSSure to solid. Crystallization from propyl acetate/MeOH gave the desired product (168 mg). M. p. 218.1-219.7 C.; give a white solid. The white solid was then dissolved in 150 0320 "H NMR (300 MHz, DMSO-d) & 7.98 (d, J-7.8 mL of hot 15% MeOH/CHCls. After slow evaporation of the Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.39 (t, J=7.1 Hz, 2H), 7.23 Solvent, a white precipitate had formed. The Solid was (t, J=7.0 Hz, 2H), 6.48 (s, 4H), 5.81 (t, J=5.6 Hz, 2H), 4.47 isolated by filtration, washed with 10% MeOH/CHCl (3x10 (t, J=7.3 Hz, 4H), 3.02 (q, J=6.2 Hz, 4H), 2.89 (t, J=7.7 Hz, mL) and dried under vacuum to give the desired product 4H), 1.82-1.72 (m, 8H), 1.58-1.37 (m, 8H), 0.93 (t, J=7.3 HZ, 6H); (400 mg) as a white powder. M. p. 160.3-165.6° C.; H NMR (300 MHz, DMSO-d) & 8.34 (s, 2H), 8.01 (d, J-7.9 0321) MS. 649 (M+H)"; Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.43 (s, 1H), 7.38 (t, J=7.6 0322 Anal calcd for C.H.N.O.0.87H2O: % C, 66.88; % H, 7.54; % N, 21.08. Found: % C, 66.92; % H, 7.57; % Hz, 2H), 7.22 (t, J=7.0 Hz, 2H), 7.05-6.94 (m, 3H), 6.45 (s, N, 20.92. 4H), 6.07 (t, J=5.4 Hz, 2H), 4.53 (t, J=7.4 Hz, 4H), 3.15 (m, 0323 Karl Fisher titration 2.36% H.O. 4H), 2.92 (t, J=7.7 Hz, 4H), 1.88-1.74 (m, 8H), 1.66 (m, 4H), 1.43 (m, 4H), 0.92 (t, J=7.3 Hz, 6H); EXAMPLE 2 0326 °C NMR (75 MHz, DMSO-d) & 155.6, 153.4, N.N"-1,3-phenylenebis N'-[4-(4-amino-2-butyl-1H imidazo[4,5-clquinolin-1-yl)butyllurea} 152.1, 145.1, 1412, 132.6, 129.0, 126.8, 126.7, 126.6, 121.5, 120.3, 115.2, 111.0, 107.3, 45.0, 38.9, 30.1, 27.6, 0324) 27.2, 26.5, 22.3, 14.1; Anal calcd for CHNO2.72HO:% C, 63.52;%H, 7.20;% N, 2020. Found: % C, 63.29; % H, 7.19; % N, 20.16. 0327 Karl Fisher titration 5.88% H.O.

EXAMPLE 3

N-4-(4-amino-2-butyl-1H-imidazo[4,5-cquinolin 1-yl)butyl-N'-(4-4-(4-(4-amino-2-butyl-1H imidazo4.5-cquinolin-1-yl)butyl aminocarbonyl)aminophenoxyphenyl)urea 0328)

NH2 NH2 tryN / N 21 NN N1S US 2004/O132766 A1 Jul. 8, 2004

0329. A suspension of 1-(4-aminobutyl)-2-butyl-1H-imi pyridine. The resulting crystals were isolated by filtration dazo[4,5-cquinolin-4-amine (3.11g, 10.0 mmol) in 100 mL and dried under vacuum at 55 C. for 3 d to give the desired of CH2Cl was treated with 4,4'-oxybis(phenyl isocyanate) product (1.45 g). M. p. 184.5-188.8° C.; (1.26g, 5.0 mmol) and stirred under N for 2d. The reaction 0335 H NMR (300 MHz, DMSO-d) & 8.00 (d, J-8.0 mixture was then filtered and the resulting Solid was washed Hz, 2H), 7.61 (d, J=8.1 Hz, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.24 with EtO to give 3.97g of a white solid. The white solid (t, J=7.2 Hz, 2H), 6.45 (s, 4H), 5.70 (t, J=5.2 Hz, 2H), 5.62 was then treated with 100 mL of hot pyridine and filtered to (d, J=7.8 Hz, 2H), 4.50 (m, 4H), 3.25 (m, 2H), 3.03 (m, 4H), remove the insoluble material. The filtrate was then concen 2.91 (t, J=7.7 Hz, 4H), 1.87-1.70 (m, 12H), 1.53-1.39 (m, trated under reduced pressure and the residue was dissolved 8H), 1.05 (m, 4H), 0.96 (t, J=7.3 Hz, 6H); in 50 mL of hot pyridine. After several days, a crystalline 0336 °C NMR (125 MHz, DMSO-d) & 157.4, 152.9, product formed. The crystals were isolated by filtration and 151.6, 144.6, 132.1, 126.3, 126.2, 126.1, 121.0, 119.8, dried under vacuum at 55 C. for 3 d to give the desired 114.7, 47.5, 44.5, 38.5, 31.9, 29.6, 27.2, 27.1, 26.1, 21.9, product (2.5 g). M. p. 152.1-156.1 C.; 13.7; Anal calcd for CHNO.1.43H2O: % C, 64.86; % H, 7.78; % N, 20.63. Found: C, 9%64.79; % H, 7.92; % N, 0330 "H NMR (300 MHz, DMSO-d) & 8.36 (s, 2H), 20.44. 8.02 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.34 (d, J=9.0 Hz, 4H), 7.22 (t, J=7.9 Hz, 2H), 6.84 0337 Karl Fisher titration 3.17% H.O. (d, J=8.9 Hz, 4H), 6.45 (s, 4H), 6.10 (t, J=6.0 Hz, 2H), 4.53 EXAMPLE 5 (t, J=7.3 Hz, 4H), 3.15 (q, J=6.0 Hz, 4H), 2.92 (t, J=7.7 Hz, 4H), 1.90-1.74 (m, 8H), 1.60 (m, 4H), 1.44 (m, 4H), 0.93 (t, N,N'-bis(2-2-4-amino-2-(2-methoxyethyl)-1H J-7.3 Hz, 6H); imidazo[4,5-clquinolin-1-yl)ethoxyethyl)benzene 1,3-disulfonamide 0331 °C NMR (75 MHz, DMSO-d) & 155.3, 152.9, 151.6, 151.2, 144.6, 135.9, 132.1, 126.3, 126.2, 126.1, 0338) 121.1, 119.8, 119.2, 118.5, 114.7, 44.5, 38.9, 29.6, 27.2, NH2 26.8, 26.1, 21.9, 13.7; Anal calcd for CH.N.O.0.24H2O: % C, 68.29;% H, 6.70;% N, 19.11. N1 n Found: % C, 68.11; % H, 6.70; % N, 19.17. 2 0332 Karl Fisher titration 0.49% H.O. O EXAMPLE 4 O N,N'-trans-1,4-cyclohexylenebis{N-4-(4-amino-2- l, N1 V sus,NN ? butyl-1H-imidazo[4,5-cquinolin-1-yl)butylurea} 0333) NH2try / NH2 2NN N-1S

in-H ---H O O

0334) A suspension of 1-(4-aminobutyl)-2-butyl-1H-imi 0339 A solution of 1-2-(2-aminoethoxy)ethyl)-2-(2- dazo[4,5-cquinolin-4-amine (3.11g, 10.0 mmol) in 100 mL methoxyethyl)-1H-imidazo 4.5-cquinolin-4-amine (500 of CHCl was treated with trans-1,4-cyclohexylene diiso mg, 1.52 mmol) in 15 mL of CH2Cl was treated with cyanate (831 mg, 5.0 mmol) and stirred under N for 3 d. triethylamine (417 ul, 3.04 mmol) and 1,3-benzenedisulfo The reaction mixture was then filtered and the resulting Solid nyl chloride (209 mg, 0.75 mmol) and stirred under N was washed with EtO to give a white solid. The white solid overnight. The reaction mixture was then treated with Satu was then triturated with hot MeOH and filtered to give a rated NaHCO Solution, 50 mL of CH2Cl and 5 mL of white Solid. The Solid was then dissolved in 150 mL of hot MeOH. The layers were separated and the organic portion 15% MeOH/CHC1. After slow evaporation of the solvent, was washed with HO and brine. The organic portion was a white precipitate had formed. The solid was isolated by then dried over Na2SO and concentrated. Column chroma filtration and then dissolved in a minimum amount of hot tography (SiO, 8% MeOH/CHCl saturated with NHOH)

US 2004/O132766 A1 Jul. 8, 2004

0351 A solution of 1-2-(2-aminoethoxy) ethyl-2-(2- tography (SiO, O-5% MeOH/CHCl) to give N,N-bis(3- methoxyethyl)-1H-imidazo[4,5-cquinolin-4-amine (500 nitroquinolin-4-yl)decane-1,10-diamine (1.90 g) as a yellow mg, 1.52 mmol) in 25 mL of CH2Cl was treated with foam. 1,8-diisocyanatooctane (148 uL, 0.76 mmol) and stirred under N overnight. The reaction mixture was then concen 0359 Part B trated under reduced preSSure to give a tan foam. Column 0360 The material from Part A (1.90 g) was dissolved in chromatography (SiO, 5-10% MeOH/CHCl) yielded 570 100 mL of MeOH and treated with 5% Pt/C. The reaction mg of a mauve colored foam. This was dissolved in 10 mL mixture was shaken under an atmosphere of H. (50 psi; of hot MeOH and treated with 1 g of decolorizing charcoal. 3.4x10 Pa) overnight. The reaction mixture was then purged The hot solution was filtered through a pad of Celite(R) filter with N and filtered through a pad of Celite(R) filter agent. The filtrate was concentrated to give N,N'-bis(3-amino agent and the filtrate was concentrated to give the desired quinolin-4-yl)clecane-1,10-diamine (0.81 g) as a yellow product (245 mg) as a white powder. M. p. 172.5-177.0° C.; Syrup. 0352 H NMR (300 MHz, DMSO-d) & 8.04 (d, J-8.0 Hz, 2H), 7.61 (d, J-7.5 Hz, 2H), 7.41 (t, J=7.2 Hz, 2H), 7.23 0361 Part C (t, J=7.1 Hz, 2H), 6.48 (s, 4H), 5.82 (t, J=5.5 Hz, 2H), 5.70 0362. The material from Part B (810 mg, 1.78 mmol) was (t, J=5.6 Hz, 2H), 4.73 (t, J=5.0 Hz, 4H), 3.85-3.80 (m, 8H), dissolved in 20 mL of dry CH2Cl and treated with triethy 3.29 (s, 6H), 3.21 (t, J=6.8 Hz, 4H), 3.05 (q, J=5.6 Hz, 4H), lamine (544 uL, 3.91 mmol) and ethoxyacetyl chloride (429 2.92 (q, J=5.9 Hz, 4H), 1.31 (m, 4H), 1.21 (brs, 8H); AiL, 3.91 mmol) and the reaction mixture was stirred under N for 2 h. The reaction mixture was then concentrated 0353 °C NMR (75 MHz, DMSO-d) & 1570, 150.7, under reduced pressure and the resulting Syrup was dis 150.6, 143.8, 1314, 125.4,125.3, 120.2, 119.1, 113.4, 69.5, Solved in 20 mL of ethanol and treated with 1.5 mL of 69.2, 67.9, 57.2, 44.2, 29.1, 27.9, 26.3, 25.4. triethylamine. The reaction mixture was refluxed overnight and then concentrated under reduced pressure. The resulting 0354 Anal calcd for CHNO.0.74H2O: % C, material was partitioned between 100 mL of CH2Cl and 60.86; % H, 7.37; % N, 19.36. Found: % C, 60.87; % H, HO. The layers were separated and the organic portion was 7.36; % N, 19.19. washed with HO (2x) and brine, dried over NaSO and concentrated. Column chromatography (SiO2, 5% MeOH/ 0355 Karl Fisher titration 1.53% H.O. CHCl) gave 2-(ethoxymethyl)-1-10-2-(ethoxymethyl)- 1H-imidazo[4,5-cquinolin-1-yldecyl-1H-imidazo[4,5-c EXAMPLE 8 quinoline (490 mg) as a light yellow Solid. 1-10-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c 0363 Part D quinolin-1-yl)glecyl-2-ethoxymethyl-1H-imidazo4, 5-cquinoline-4-amine 0364) The material from Part C (490 mg, 0.828 mmol) was dissolved in 10 mL of CHCl and treated with 3-chlo roperoxybenzoic acid (77% max., 407 mg, 1.82 mmol). 0356) After Stirring overnight, an additional 40 mg of 3-chlorop eroxybenzoic acid was added. Stirring was continued for 4 h, then the reaction mixture was diluted with 50 mL of CHCl and washed with 1% NaCO, solution (2x), H.O. and brine. The organic portion was dried over NaSO and concentrated to give 2-(ethoxymethyl)-1-10-2-(ethoxym ethyl)-5-oxido-1H-imidazo[4,5-cquinolin-1-yldecyl)-1H imidazo4.5-cquinoline 5-oxide (463 mg) as an off-white powder. 0365) Part E 0366) The material from Part D (463 mg, 0.741 mmol) was dissolved in 20 mL of CH2Cl and treated with 2 mL of concentrated NH-OH solution. The solution was stirred rapidly and tosyl chloride (310 mg) was added in two portions. After Stirring for 30 min, the reaction mixture was diluted with 20 mL of CH2Cl and washed with Ho, 1% 0357 Part A NaCO, solution (3x), H2O, and brine. The organic portion 0358) A solution of 4-chloro-3-nitroquinoline (2.50 g, was dried over Na2SO and concentrated to give a tan 12.2 mmol) in 75 mL of dry CHCl was treated with powder. Column chromatography (SiO, 2.5-3.5% MeOH/ triethylamine (3.40 mL, 24.4 mmol) and 1,10-diaminode CHCl) yielded 362 mg of the desired product as a cream cane (1.05 g, 6.1 mmol) and the reaction mixture was stirred colored foam. M. p. 237-238 C.; under N overnight. The reaction mixture was then concen 0367 H NMR (300 MHz, CDC1) & 7.95 (dd, J=1.0, 8.2 trated under reduced pressure and the resulting yellow Solid Hz, 2H), 7.82 (dd, J=1.1, 8.5 Hz, 2H), 7.52 (ddd, J=1.3, 7.0, was triturated with hot H2O (100 mL). Filtration gave a 8.5 Hz, 2H), 7.32 (ddd, J=1.3, 7.1, 8.5 Hz, 2H), 5.38 (s, 4H), yellow solid which was then subjected to column chroma 4.80 (s, 4H), 4.55 (t, J=7.9 Hz, 4H), 3.60 (q, J=7.0 Hz, 4H), US 2004/O132766 A1 Jul. 8, 2004 18

1.98 (m, 4H), 1.49 (m, 4H), 1.33 (m, 8H), 1.24 (t, J=7.0 Hz, EXAMPLES 9-16 0370. Using the general method of Example 5,4-amino 0368 °C NMR (75 MHz, 10% CDOD/CDC1) & 1515, 149.0, 144.7, 1344, 127.8, 126.7, 126.2, 122.6, 120.0, 1-2-(4-piperidyl)ethyl)-1H-imidazo4.5-cquinoline 115.1, 66.4, 65.0, 46.5, 30.3, 29.4, 29.3, 26.8, 15.1. (Example 113 in EP 1 104764) can be reacted with a 0369 Anal. calcd for C.H.N.O.0.40HO: % C, 68.63; disulfonyl choloride from the table below to provide a dimer % H, 7.49; % N, 17.79. Found: % C, 68.49; % H, 7.54; % of the invention. All of the disulfonyl chlorides in the table N, 17.82. are commercially available.

NH2 NH2

21NNy (rN-1S

N. O. O. N.

Example Disulfonyl Chloride W 9 4,4'-Biphenyldisulfonyl chloride ( ) ( )

1O 2.4-Mesitylenedisulfonyl dichloride CH CH

11 4,4'-Methylene-bis(benzenesulfonylchloride) OUC

12 4,4'-Bis(chlorosulfonyl)diphenylether

13 1,4-Butanedisulfonylchloride -(CH2)-

14 1,3-Benzenedisulfonyl chloride

15 1.2-Benzenedisulfonyl chloride

16 1,4-Bis(chlorosulfonyl)octafluorobutane -(CF)- US 2004/O132766 A1 Jul. 8, 2004

EXAMPLES 17-35 0371 Using the general method of Example 2,1-(2- amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5- cquinolin-4-amine can be reacted with a diisocyanate from the table below to provide a dimer of the invention. All of the diisocyanates in the table are commercially available.

Example Diisocyanate 17 Tolylene 2,6-diisocyanate

18 1,4-Phenylene diisocyanate

19 Hexamethylene diisocyanate 3,3'-Bianisole-4,4'-isocyanic acid ester

CH-O O-CH 21 Dicyclohexylmethane-4,4'-diisocyanate

22 3,3'-Bitolyene-4,4'-diisocyanate

CH CH 23 4,4'-Diisocyanato-3,3'- CH CH dimethyldiphenylmethane

24 m-Xylene diisocyanate US 2004/O132766 A1 Jul. 8, 2004

-continued

Example Diisocyanate

25 4,4'-Diphenylmethane diisocyanate

26 1,2-Diisocyanatododecane

27 4,4'-Methylenebis(2-chlorophenyl isocyanate)

28 1,5-Naphthalenediisocyanate

29 3,3'-Dichlorodiphenyl 4,4'-diisocyanate

Cl Cl

1,4-Diisocyanatobutane -(CH2) -

31 1,3-Bis(isocyanatomethyl)cyclohexane

32 3,3',5,5'-Tetraethyldiphenylmethane-4,4'- CH CH diisocyanate

CH CH

33 1,8-Diisocyanatooctane -(CH2)- US 2004/O132766 A1 Jul. 8, 2004 21

-continued

Example Diisocyanate W, 34 2.4.6-Trimethyl-1,3-phenylene diisocyanate CH CH

CH 35 2,4'-Methylenebis(phenyl isocyanate)

EXAMPLES 36-56 No. 6,451,810) can be reacted with a diacid dichloride from 0372) Using the general method of Example 6,1-(4-ami- the table below to provide a dimer of the invention. All of nobutyl)-6,7,8,9-tetrahydro-2-(methoxyethyl)-1H-imidazo the diacid dichlorides in the table are commercially avail 4.5-cquinolin-4-amine (Example 172 Part A in U.S. Pat. able.

NH2 NH2 Sl-N / Y, NNa 2NNy / \ N1S . HN W1 .

O O Example Diacid Dichioride W 37 Phthaloyl dichloride

38 Isoplithaloyl dichloride US 2004/O132766 A1 Jul. 8, 2004

-continued NH2 / \ NH2 yN / O O \ (rN 21 N N N

is-N- O O

Example Diacid Dichioride W

39 Terephthaloyl dichloride

40 Fumaryl chloride -C=C- 41 Succinyl chloride -(CH2)2- 42 Glutaryl chloride -(CH2)- 43 Adipoyl chloride -(CH2)- 44 Pimeloyl chloride -(CH2)5- 45 Suberoyl chloride -(CH2)6- 46 Azelaoyl chloride -(CH) 7 47 Sebacoyl chloride -(CH2)6-

48 2,6-Pyridinedicarbonyl dichloride N n 2

49 Dodecanedioyl dichloride -(CH2)- 50 Tetrafluorosuccinyl chloride -(CF)- 51 Tetrachloroterephthaloyl chloride C C

C C

52 Hexafluoroglutaryl chloride -(CF)- 53 Octafluoroadipoyl chloride -(CF)-

54 4,4'-Benzoyl chloride

55 2,2'-Oxydiacetyl chloride 56 Trans-5-norbornene-2,3-dicarbonyl chloride US 2004/O132766 A1 Jul. 8, 2004 23

EXAMPLES 57-64 EXAMPLES 65-86 0373) Using the general method of Example 5,4-(4- 0374. Using the general method of Example 2,2-(4- amino-2-butyl-1H-imidazo 4.5-c1,5naphthyridin-1- amino-2-butyl-1H-imidazo4.5-cI1,5naphthyridin-1-yl)e- yl)butaneamine (Example 46 in U.S. Pat. No. 6,194,425) can thaneamine (Example 91 in U.S. Pat. No. 6,194,425) can be be reacted with a disulfonyl chloride from the table below to reacted with a diisocyanate from the table below to provide provide a dimer of the invention. All of the disulfonyl a dimer of the invention. All of the diisocyanates in the table chlorides in the table are commercially available. are commercially available.

NH2 NH2 tryN / / \ N . l- 21 NNh r rNN HN\ O O.\/ NH / Nw1 \,

Example Disulfonyl Chloride W 57 4,4'-Biphenyldisulfonyl chloride

58 2.4-Mesitylenedisulfonyl dichloride CH CH

59 4,4'-Methylene-bis(benzenesulfonylchloride)

60 4,4'-Bis(chlorosulfonyl)diphenylether O

O 61 1,4-Butanedisulfonylchloride -(CH2)- 62 1,3-Benzenedisulfonyl chloride

63 1.2-Benzenedisulfonyl chloride

64 1,4-Bis(chlorosulfonyl)octafluorobutane -(CF)-

US 2004/O132766 A1 Jul. 8, 2004

-continued

N N N y 21 NN 2NN N-1S N 2 Nin HN H N - N W O " O Example Diisocyanate W 74 4,4'-Diphenylmethane diisocyanate OUC

75 1,2-Diisocyanatododecane (CH)- 76 4,4'-Methylenebis(2-chlorophenyl isocyanate)

CI XY C

77 1,5-Naphthalenediisocyanate

78 3,3'-Dichlorodiphenyl 4,4'-diisocyanate

Cl Cl 79 Trans-1,4-cyclohexane diisocyanate III I I ( X

8O 1,4-Diisocyanatobutane -(CH2) - 81 1,3-Bis(isocyanatomethyl)cyclohexane

82 3,3',5,5'-Tetraethyldiphenylmethane-4,4'- CH CH diisocyanate

CH CH

83 1,8-Diisocyanatooctane -(CH2) - US 2004/O132766 A1 Jul. 8, 2004 26

-continued NH2 NH2 N-N N N 7N 21 NN 2 N N1S 2N Nin HN H

y- W NH O O Example Diisocyanate W, 84 Oxybis(4-phenylisocyanate) O O

O 85 2.4.6-Trimethyl-1,3-phenylene diisocyanate CH CH

CH 86 2,4'-Methylenebis(phenyl isocyanate)

EXAMPLES 87-106 ine (Example 111 in U.S. Pat. No. 6,194,425) can be reacted with a diacid dichloride from the table below to provide a 0375] Using the general method of Example 6,4-(4- dimer of the invention. All of the diacid dichlorides in the amino-1H-imidazo[4,5cI1,5naphthyridin-1-yl)butaneam- table are commercially available.

NH2 NH2 N y & 21 2 N N S

Example Diacid Dichloride W 87 Phthaloyl dichloride US 2004/O132766 A1 Jul. 8, 2004 27

-continued

NH2 N N Ny 2NN

Example Diacid Dichloride

88 Isophthaloyl dichloride

89 Terephthaloyl dichloride

90 Fumaryl chloride 91 Succinyl chloride 92 Glutaryl chloride 93 Adipoyl chloride 94 Pimeloyl chloride 95 Suberoyl chloride 96 Azelaoyl chloride 97 Sebacoyl chloride

98 2,6-Pyridinedicarbonyl dichloride

99 Dodecanedioyl dichloride 1OO Tetrafluorosuccinyl chloride

101 Tetrachloroterephthaloyl chloride

102 Hexafluoroglutaryl chloride 103 Octafluoroadipoyl chloride US 2004/O132766 A1 Jul. 8, 2004 28

-continued NH2 N1 2N \y {y l

HN rW1 N H O O Example Diacid Dichloride W, 104 4,4'-Benzoyl chloride

105 2,2'-Oxydiacetyl chloride 106 Trans-5-norbornene-2,3-dicarbonyl chloride

EXAMPLES 107-114 ridin-4-amine (Example 10 in U.S. Pat. No. 6,545,016) can be reacted with a disulfonyl chloride from the table below to 0376. Using the general method of Example 5,1-(4-ami- provide a dimer of the invention. All of the disulfonyl nobutyl)-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-cpy- chlorides in the table are commercially available.

HN\ O O.y NH O/Nw1\ O

Example Disulfonyl Chloride W

107 4,4'-Biphenyldisulfonyl chloride US 2004/O132766 A1 Jul. 8, 2004 29

-continued

HN / V AH S 1 S OM Nw VO

Example Disulfonyl Chloride W,

108 2.4-Mesitylenedisulfonyl dichloride CH CH

CH 109 4,4'-Methylene-bis(benzenesulfonylchloride) OUC

110 4,4'-Bis(chlorosulfonyl)diphenylether

111 1,4-Butanedisulfonylchloride -(C H2) 4.

112 1,3-Benzenedisulfonyl chloride

113 1.2-Benzenedisulfonyl chloride

114 1,4-Bis(chlorosulfonyl)octafluorobutane -(CF)-

EXAMPLES 115-136 amine (Example 18 in U.S. Pat. No. 6,545,016) can be reacted with a diisocyanate from the table below to provide 0377 Using the general method of Example 2,1-(3-ami- a dimer of the invention. All of the diisocyanates in the table nopropyl)-2,6,7-trimethyl-1H-imidazol4.5-cpyridin-4- are commercially available. US 2004/O132766 A1 Jul. 8, 2004 30

NH2 NH2 Ny &N C 2 N N N

O O Example Diisocyanate W, 115 Tolylene 2,6-diisocyanate -Cl

CH 116 1,3-Phenylene diisocyanate o

117 1,4-Phenylene diisocyanate

118 Hexamethylene diisocyanate -(CH2)6- 119 3,3'-Bianisole-4,4'-isocyanic acid ester

CH-O O-CH 120 Dicyclohexylmethane-4,4'-diisocyanate

121 3,3'-Bitolyene-4,4'-diisocyanate

CH CH 122 4,4'-Diisocyanato-3,3'- CH CH dimethyldiphenylmethane 123 m-Xylene diisocyanate se US 2004/O132766 A1 Jul. 8, 2004 31

-continued

NH2 NH2

N1N-NN /NN21N 2 X- –{ N

H H H N N N n Y W r Example Diisocyanate W, 124 4,4'-Diphenylmethane diisocyanate

125 1,2-Diisocyanatododecane -(C H2) 12 126 4,4'-Methylenebis(2-chlorophenyl isocyanate)

C C 127 1,5-Naphthalenediisocyanate

128 3,3'-Dichlorodiphenyl 4,4'-diisocyanate

Cl Cl 129 Trans-1,4-cyclohexane diisocyanate III

130 1,4-Diisocyanatobutane -(C H2) 4 131 1,3-Bis(isocyanatomethyl)cyclohexane ror

132 3,3',5,5'-Tetraethyldiphenylmethane-4,4'- CH CH diisocyanate

133 1,8-Diisocyanatooctane US 2004/O132766 A1 Jul. 8, 2004 32

-continued NH2 NH2

N1 N-NN WNN4NN 2 }- -( N

H H H s Nin W 1 O O Example Diisocyanate W, 134 Oxybis(4-phenylisocyanate) O O

O 135 2.4.6-Trimethyl-1,3-phenylene diisocyanate CH CH

CH 136 2,4'-Methylenebis(phenyl isocyanate) O

EXAMPLES 137-156 ridin-4-amine (Example 26 in U.S. Pat. No. 6,545,016) can be reacted with a diacid dichloride from the table below to 0378 Using the general method of Example 6,1-(4-ami- provide a dimer of the invention. All of the diacid dichlo nobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-cpy- rides in the table are commercially available.

O) / /\- \{O

"N-N- O O Example Diacid Dichloride W 137 Phthaloyl dichloride US 2004/O132766 A1 Jul. 8, 2004

-continued /\ N1S-N O O NN4N

I)N / \ {N

"N-N- O O Example Diacid Dichloride W, 138 Isophthaloyl dichloride

139 Terephthaloyl dichloride

140 Fumaryl chloride 141 Succinyl chloride 142 Glutaryl chloride 143 Adipoyl chloride 144 Pimeloyl chloride 145 Suberoyl chloride 146 Azelaoyl chloride 147 Sebacoyl chlonde 148 2,6-Pyridinedicarbonyl dichloride

149 Dodecanedioyl dichloride 150 Tetrafluorosuccinyl chloride 151 Tetrachloroterephthaloyl chloride

152 Hexafluoroglutaryl chloride 153 Octafluoroadipoyl chloride 154 4,4'-Benzoyl chloride

155 2,2'-Oxydiacetyl chloride 156 Trans-5-norbornene-2,3-dicarbonyl chloride US 2004/O132766 A1 Jul. 8, 2004 34

Cytokine Induction in Human Cells human TNF-C. capture and detection antibody pair from BioSource International, Camarillo, Calif. Results are 0379 An in vitro human blood cell system is used to expressed in pg/mL. assess cytokine induction. Activity is based on the measure ment of interferon and tumor necrosis factor (C) (IFN and 0391 Compounds of the invention were tested for their TNF, respectively) secreted into culture media as described ability to induce cytokine biosynthesis using the method by Testerman et. al. In “Cytokine Induction by the Immu described above. The results are Summarized in the table nomodulators Imiquimod and S-27609”, Journal of Leuko below where a "+" indicates that at concentrations of s 10 cyte Biology, 58, 365-372 (September, 1995). tiM the compound induced the indicated cytokine, a "- indicates that at concentrations of S10 uM the compound 0380 Blood Cell Preparation for Culture did not induce the indicated cytokine, and a “*” indicates 0381) Whole blood from healthy human donors is col that the compound was not adequately soluble in DMSO to lected by Venipuncture into EDTA vacutainer tubes. Periph permit testing. eral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using His topaque(R)-1077. Blood is diluted 1:1 with Dulbecco's Phos phate Buffered Saline (DPBS) or Hank's Balanced Salts Cytokine Induction in Human Cells Solution (HBSS). The PBMC layer is collected and washed Compound of Example Interferon (c.) Tumor Necrosis Factor (C) twice with DPBS or HBSS and resuspended at 4x10 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park, N.J.) containing an equal volume of RPMI complete media containing test compound. 0382 Compound Preparation 0383. The compounds are solubilized in dimethylsulfox ide (DMSO). The DMSO concentration should not exceed a 0392 The complete disclosures of the patents, patent final concentration of 1% for addition to the culture wells. documents, and publications cited herein are incorporated The compounds are generally tested at concentrations rang by reference in their entirety as if each were individually ing from 30-0.014 uM. incorporated. The present invention has been described with reference to Several embodiment thereof. The foregoing 0384) Incubation illustrative embodiments and examples have been provided 0385) The solution of test compound is added at 60 uM for clarity of understanding only, and no unnecessary limi to the first well containing RPMI complete and serial 3 fold tations are to be understood therefrom. It will be apparent to dilutions are made in the wells. The PBMC suspension is those skilled in the art that many changes can be made to the then added to the Wells in an equal Volume, bringing the test described embodiments without departing from the Spirit compound concentrations to the desired range (30-0.014 and Scope of the invention. Thus, the Scope of the invention uM). The final concentration of PBMC suspension is 2x10 is intended to be limited only by the claims that follow. cells/mL. The plates are covered with Sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37 C. What is claimed is: in a 5% carbon dioxide atmosphere. 1. A compound of the formula (I): 0386 Separation 0387 Following incubation the plates are centrifuged for 10 minutes at 1000 rpm (~200xg) at 4 C. The cell-free NH2 NH2 culture Supernatant is removed with a sterile polypropylene pipet and transferred to Sterile polypropylene tubes. Samples N-N N n are maintained at -30 to -70° C. until analysis. The samples N N are analyzed for interferon (C) by ELISA and for tumor 21NNX- R2 R-(N 21 necrosis factor (C) by ELISA or IGEN Assay. R R 0388 Interferon (O) and Tumor Necrosis Factor (O) Analysis by ELISA R4 N A. u/ R4 0389 Interferon (C) concentration is determined by ELISA using a Human Multi-Species kit from PBL Bio wherein: medical Laboratories, New Brunswick, N.J. Results are A is a divalent linking group Selected from the group expressed in pg/mL. consisting of: 0390 Tumor necrosis factor (C) (TNF-C) concentration Straight or branched chain Co alkylene; is determined using ELISA kits available from BioSource International, Camarillo, Calif. Alternately, the TNF-C. con Straight or branched chain Coalkenylene, centration can be determined by Origence M-Series Immu noassay and read on an IGEN M-8 analyzer from IGEN Straight or branched chain Co alkynylene; and International, Gaithersburg, Md. The immunoassay uses a US 2004/O132766 A1 Jul. 8, 2004 35

each Z is independently Selected from the group consist ing of Straight or branched chain Co alkylene; Straight or branched chain Coalkenylene; and Straight or branched chain Co alkynylene; any of which may be optionally interrupted by -O-, -N(R)-, or -S(O)-; and each Y is independently Selected from the group con trans-5-norbornen-2,3-diyl; Sisting of: wherein n is 0-4; each R is independently selected from the group consisting of C- alkyl, C- alkoxy, and halogen; and Q is Selected from the group consisting of a bond, -CH2-, and -O-, R is selected from the group consisting of: -hydrogen; -alkyl, -alkenyl; -aryl; -Substituted aryl; -heteroaryl; -N(Rs)C(O)O-, and -Substituted heteroaryl; -OC(O)N(R)-; -alkyl-X-alkyl; W is selected from the group consisting of: -alkyl-X-aryl; Straight or branched chain Co alkylene; -alkyl-X- alkenyl; and Straight or branched chain Coalkenylene; -alkyl or alkenyl substituted by one or more substitu Straight or branched chain Co alkynylene, ents Selected from the group consisting of Straight or branched chain perfluoro Co alkylene; -OH, -halogen; C. alkylene-O-C alkylene, N(R), -C(O)N(R); C(S)-N(R); -S(O)-N(R); -N(R)-C(O)-Co alkyl; -N(R)-C(S)-Co alkyl; -N(R)-S(O)--Co alkyl, -C(O)-Co alkyl, -C(O)-O-Co alkyl; -N; -aryl; -Substituted aryl; 1,5-naphthylene; -heteroaryl; 2,6-pyridinylene, -Substituted heteroaryl; 1,2-cyclohexylene; -heterocyclyl, 1,3-cyclohexylene; -Substituted heterocyclyl, 1,4-cyclohexylene; -C(O)-aryl; trans-1,4-cyclohexylene; -C(O)-(substituted aryl); US 2004/O132766 A1 Jul. 8, 2004 36

-C(O)-heteroaryl; and with the proviso that if W is -C(O)-, -S(O), -OC(O)O-, or -N(Rs)C(O)N(R)- then each Y is -C(O)-(substituted heteroaryl); a bond; RandR are each independently Selected from the group consisting of: or a pharmaceutically acceptable Salt thereof. 2. A compound or Salt of claim 1 wherein A is Straight or -hydrogen; branched chain Co alkylene. -halogen; 3. A compound or salt of claim 1 wherein A is -Z-Y-W- Y-Z-. -alkyl, 4. A compound or Salt of claim 3 wherein Z is Straight or -alkenyl, branched chain C- alkylene optionally interrupted by -O-. -X-alkyl; and 5. A compound or salt of claim 4 wherein Z is selected from the group consisting of Straight or branched chain C -N(R), alkylene and C alkylene-O-C alkylene. or when taken together, R and R form a fused aryl or 6. A compound or salt of claim 3 wherein Rs is joined with heteroaryl ring that is unsubstituted or substituted by Z to form a ring having the Structure one or more Substituents Selected from the group consisting of: -halogen; -O- -alkyl, R7 -alkenyl, wherein R, is C alkylene; -X-alkyl; and 7. A compound or salt of claim 3 wherein each Y is independently Selected from the group consisting of: -N(R), or when taken together, R and R form a fused 5 to 7 membered Saturated ring, containing 0 to 2 heteroa toms and unsubstituted or Substituted by one or more Substituents Selected from the group consisting of: -halogen; -alkyl, -alkenyl, 8. A compound or Salt of claim 7 wherein Rs is hydrogen. -X-alkyl; and 9. A compound or salt of claim 3 wherein W is selected from the group consisting of Straight or branched chain Co -N(R), alkylene; each Rs is independently Selected from the group consist ing of hydrogen; C-6 alkyl, C-7 cycloalkyl, and benzyl; or when Y is -N(Rs)C(O)-, -C(O)N(Rs),

-OC(O)N(R)- and the nitrogen of the N(Rs) group is bonded to Z, then Rs can join with Z to form a ring having the Structure

-O-M R7 1,2-cyclohexylene; each R is independently hydrogen or Co alkyl, 1,3-cyclohexylene; R7 is Cls alkylene; and 1,4-cyclohexylene; and X is -O- or -S.-, trans-1,4-cyclohexylene. US 2004/O132766 A1 Jul. 8, 2004 37

10. A compound or salt of claim 1 wherein R is selected 23. The method of claim 22 wherein the compound or salt from the group consisting of hydrogen, alkyl, and alkyl-O- is administered topically. alkyl. 24. A method of treating a viral disease in an animal 11. A compound or salt of claim 10 wherein R is selected comprising administering a therapeutically effective amount from the group consisting of hydrogen, methyl, ethyl, pro pyl, butyl, cyclopropylmethyl, ethoxymethyl and methoxy of a compound or Salt of claim 1 the animal. ethyl. 25. The method of claim 24 wherein the compound or salt 12. A compound or Salt of claim 1 wherein R and R. is administered topically. taken together form a fused benzene ring. 26. A method of treating a viral disease in an animal 13. A compound or Salt of claim 1 wherein R and R. comprising administering a therapeutically effective amount taken together form a fused pyridine ring. of a compound or Salt of claim 1 17 to the animal. 14. A compound or Salt of claim 1 wherein R and R. 27. The method of claim 26 wherein the compound or salt taken together form a six membered Saturated ring. is administered topically. 15. A compound or salt of claim 1 wherein R and R. 28. A method of treating a neoplastic disease in an animal taken together form a six membered Saturated ring contain comprising administering a therapeutically effective amount ing a nitrogen atom. of a compound or Salt of claim 1 to the animal. 16. A compound or Salt of claim 1 wherein R and R are independently Selected from the group consisting of hydro 29. The method of claim 28 wherein the compound or salt gen and alkyl. is administered topically. 30. A method of treating a neoplastic disease in an animal 17. A compound Selected from the group consisting of comprising administering a therapeutically effective amount N,N'-bis(4-(4-amino-2-butyl-1H-imidazo[4,5-cquinolin of a compound or Salt of claim 17 to the animal. 1-yl)butylurea; 31. The method of claim 30 wherein the compound or salt N.N"-1,3-phenylenebis N'-[4-(4-amino-2-butyl-1H-imi is administered topically. dazo[4,5-clquinolin-1-yl)butyllurea}; 32. A compound of Formula (II): N-4-(4-amino-2-butyl-1H-imidazo[4,5-cquinolin-1-yl )butyl-N'-(4-4-(4-(4-amino-2-butyl-1H-imidazo (II) 4.5-clquinolin-1-yl)butylaminocarbonyl)amino O phenoxyphenyl)urea; | N N.N"-trans-1,4-cyclohexylenebisN'-4-(4-amino-2-bu N1 N No o? tyl-1H-imidazo[4,5-cquinolin-1-yl)butylurea}; N,N'-bis(2-2-4-amino-2-(2-methoxyethyl)-1H-imidazo 21 HN 4.5-clquinolin-1-yl)ethoxyethyl)benzene-1,3-disul fonamide, N,N-bis(2-2-4-amino-2-(2-methoxyethyl)-1H-imidazo 4.5-clquinolin-1-yl)ethoxyethyl)terephthalamide; wherein: N.N"-1,8-octanediylbis N'-(2-2-4-amino-2-(methoxy A is a divalent linking group Selected from the group ethyl)-1H-imidazo4.5-cquinolin-1-yl) consisting of: ethoxyethyl)urea); and Straight or branched chain Co alkylene; 1-10-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c quinolin-1-yl)clecyl-2-ethoxymethyl-1H-imidazo[4,5- Straight or branched chain Coalkenylene; and cquinoline-4-amine; Straight or branched chain Co alkynylene, or a pharmaceutically acceptable Salt thereof. 18. A pharmaceutical composition comprising a therapeu any of which may be optionally interrupted by tically effective amount of a compound or Salt of claim 1 and -S(O)- or a protected -C(O)-; a pharmaceutically acceptable carrier. n is 0 to 4; 19. A pharmaceutical composition comprising a therapeu tically effective amount of a compound or salt of claim 17 each R" present is independently Selected from the group and a pharmaceutically acceptable carrier. consisting of: 20. A method of inducing cytokine biosynthesis in an halogen; animal comprising administering an effective amount of a compound or Salt of claim 1 to the animal. alkyl, 21. The method of claim 20 wherein the compound or salt is administered topically. alkenyl; and 22. A method of inducing cytokine biosynthesis in an -O-alkyl; animal comprising administering an effective amount of a compound or Salt of claim 17 to the animal. or a pharmaceutically acceptable Salt thereof. US 2004/O132766 A1 Jul. 8, 2004 38

33. A compound of Formula (III): -Substituted aryl; -heteroaryl; (III) -Substituted heteroaryl; N -alkyl-O-alkyl; 21 -alkyl-O-aryl; (R)- 2 -alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one or more substitu wherein: ents Selected from the group consisting of A is a divalent linking group Selected from the group -OH, consisting of: -halogen; Straight or branched chain Co alkylene; Straight or branched chain Coalkenylene; and -C(O)N(R); Straight or branched chain Co alkynylene, -C(S)-N(R); any of which may be optionally interrupted by -S(O)-N(R); -S(O)- or a protected -C(O)-; -N(R)-C(O)-Co alkyl; n is 0 to 4, each R" present is independently Selected from the group -N(R)-C(S)-Co alkyl; consisting of: -N(R)-S(O)-Co alkyl, halogen; -C(O)-Co alkyl, alkyl, C(O)-O-C alkvl alkenyl; and (O) -U-U,1-10 aalky -O-alkyl; -N; or a pharmaceutically acceptable Salt thereof. -aryl; 34. A compound of Formula (IV): -Substituted aryl; -heteroaryl; (IV)

-Substituted heteroaryl; N1 n N N -heterocyclyl, 21NNX-R R-(N -Substituted heterocyclyl, (R) 2 N A1-/ -C(O)-aryl; -C(O)-(substituted aryl); wherein: -C(O)-heteroaryl; and A is a divalent linking group Selected from the group consisting of: -C(O)-(substituted heteroaryl); Straight or branched chain Co alkylene; n is 0 to 4; Straight or branched chain Coalkenylene; and each R" present is independently Selected from the group Straight or branched chain Co alkynylene, consisting of: any of which may be optionally interrupted by halogen; -S(O)- or a protected -C(O)-; alkyl, R" is Selected from the group consisting of -hydrogen; alkenyl; and -alkyl, -O-alkyl; -alkenyl, each R is independently hydrogen or Co alkyl, -aryl; or a pharmaceutically acceptable Salt thereof. US 2004/O132766 A1 Jul. 8, 2004 39

35. A compound of Formula (V): -C(O)N(R); (V) -C(S)N(R); -S(O)-N(R); -N(R)-C(O)-Co alkyl; -N(R)-C(S)-Co alkyl; -N(R)-S(O)-Co alkyl, -C(O)-Co alkyl, wherein: -C(O)-O-Co alkyl; A is a divalent linking group Selected from the group -N; consisting of: -aryl; Straight or branched chain Co alkylene; y -Substituted aryl; Straight or branched chain Coalkenylene; and -heteroaryl; Straight or branched chain Co alkynylene; -Substituted heteroaryl; any of which may be optionally interrupted by -S(O)- or a protected -C(O)-; -heterocyclyl, R" is Selected from the group consisting of -Substituted heterocyclyl, -hydrogen; -C(O)-aryl; -alkyl, -C(O)-(substituted aryl); -alkenyl, -C(O)-heteroaryl; and -aryl; -C(O)-(substituted heteroaryl); -substituted aryl; n is 0 to 4, -heteroaryl; each R" present is independently Selected from the group consisting of: -Substituted heteroaryl; halogen; -alkyl-O-alkyl; alkyl, -alkyl-O-aryl; alkenyl; and -alkyl-O-alkenyl; and -O-alkyl; -alkyl or alkenyl Substituted by one or more substitu ents Selected from the group consisting of: each R is independently hydrogen or Co alkyl, or a pharmaceutically acceptable Salt thereof. -OH, -halogen; k . . . .