CA2559607A1

CA2559607A1 - Immune response modifier formulations and methods

Info

Publication number: CA2559607A1
Application number: CA002559607A
Authority: CA
Inventors: Terri F. Busch; Leo W. Kueper, Iii
Original assignee: 3M Innovative Properties Company; Terri F. Busch; Leo W. Kueper, Iii; Medicis Pharmaceutical Corporation
Current assignee: Medicis Pharmaceutical Corp
Priority date: 2004-03-15
Filing date: 2005-03-14
Publication date: 2005-09-29
Anticipated expiration: 2025-03-14
Also published as: EP1729768B1; AU2005222995B2; JP4991520B2; WO2005089317A3; EP1729768A2; EP1729768A4; WO2005089317A2; AU2005222995A1; ES2665342T3; US20070167479A1; JP2007529537A; CA2559607C

Abstract

Pharmaceutical formulations including an immune response modifier (IRM) compound having a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring; a preservative system including a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof; an antioxidant; and an optional chelating agent.

Description

IMMUNE RESPONSE MODIFIER FORMULATIONS AND METHODS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present invention claims priority to U.S. Provisional Patent Application Serial No. 60/553148, filed on March 15,2004, which is incorporated herein by to reference.
BACKGROUND
There has been a major effort in recent years to find compounds that modulate the immune system. Examples of such compounds, which have demonstrated cytokine 15 inducing and immunomodulating activity, are disclosed in U.S. Patent Nos.
4,689,338;
4,929,624; 5,266,575; 5,268,376; 5,346,905; 5,352,784; 5,389,640; 5,446,153;
5,482,936; 5,756,747; 6,110,929; 6,194,425; 6,331,539; 6,376,669; 6,451,810;
6,525,064; 6,541,485; 6,545,016; 6,545,017; 6,573,273; 6,656,938; 6,660,735;
6,660,747; 6,664,260; 6,664,264; 6,664,265; 6,667,312; 6,670,372; 6,677,347;
20 6,677,348; 6,677,349; 6,683,088; 6,756,382; 6,797,718; and 6,818,650; and U.S. Patent Publication Nos. 2004/0091491; 2004/0147543; and 2004/0176367. .
Many of these compounds, also known as immune response modifiers (IRMs), are small organic molecules, for example, imidazoquinoline amine derivatives (see, e.g., U.S. 4,689,338), but a number of other compound classes are known as well (see, e.g., 25 U.S. 5,446,153), and more are still being discovered.
Pharmaceutical formulations containing IRM compounds are disclosed in U.S.
Patent Nos. 5,238,944; 5,939,090; and 6,425,776; European Patent 0 394 026;
and U.S.
Patent Publication 2003/0199538. Many such formulations include preservatives such as methylparaben, sorbic acid, propylene glycol, etc.
30 The mechanism for the antiviral and antitumor activity of these IRM
compounds is thought to be due in substantial part to enhancement of the immune response by induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.). Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B
cells to secrete antibodies, which play an important role in these IRM compounds' antiviral and antitumor activities. One of the predominant irninunostimulating responses to these compounds is the induction of interferon (IFN)-a, production, which is believed to be very important in the acute antiviral and antitumor activities seen. Moreover, up regulation of other cytokines, such as, for example, tumor necrosis factor (TNF), Interleukin-1 (IL-1) and IL-6 also have potentially beneficial activities and are believed .
1 o to contribute to the antiviral and antitumor properties of these compounds.
Accordingly, in view of their importance and potential benefit, there is a continuing need for new formulations of these unique compounds.
SUMMARY OF THE INVENTION
Although some of the beneficial effects of IRMs are known, the ability to provide therapeutic benefit via topical application of an IRM compound for treatment of a particular condition at a particular location may be hindered by a variety of factors.
These factors include, e.g., irritation of the skin to which the formulation is applied;
formulation wash away; insolubility and/or degradation of the IRM compound in the 2o formulation; physical instability of the formulation (e.g., separation of components, thickening, precipitation/agglomeration of active ingredient, and the like);
degradation of excipients; poor permeation; and undesired systemic delivery of the topically applied IRM compound.
It has now been found that formulations of IRM compounds containing a 2-aminopyridine moiety fused to a five-membered nitrogen- containing heterocyclic ring in combination with sorbic acid may suffer impaired stability of both the IRM
compound and the sorbic acid. However, it has further been found that addition of a pharmaceutically acceptable antioxidant compound to the formulation can reduce degradation of the IRM compound and sorbic acid, thereby providing improved stability. Sorbic acid and related salts and esters are often used as preservative systems and can be particularly suitable for use in a mufti-dose dispenser formulation (see, for example, U.S. Patent No. 6,245,776 (Skwierczynski et al.)), but stability is an important issue for formulations and can reduce shelf life of a product or even jeopardize regulatory approvability.
In particular, it appears that IRMs containing a 2-aminopyridine moiety fused to a five-membered nitrogen- containing heterocyclic ring interact with preservatives such as sorbic acid, resulting in decreased concentrations (relative to the initial concentrations in the freshly prepared formulation) of both the IRM and preservative, with the resulting formation of unwanted impurities. Although not intending to be 1 o bound to any particular theory or mechanism, it is hypothesized that these IRMs interact with intermediates and products resulting from autoxidation of the sorbic acid preservative.
It has been discovered that stability can be improved through the addition of a compound acting as an antioxidant. The antioxidant maybeneficially have hydrogen 15 atom donating functionality. Moreover, when an antioxidant compound is included with the IRM compound and sorbic acid, stability of the formulation may be further improved by adding a chelating agent.
In one embodiment, the present invention provides a pharmaceutical formulation that includes: an immune response modifier (IRM) compound having a 2-2o aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring;
a preservative system that includes sorbic acid, esters thereof, salts thereof, or combinations thereof; and an antioxidant.
A chelating agent may also beneficially be included in any of the formulations described herein. Furthermore, a fatty acid, a hydrophobic, aprotic component miscible 25 with the fatty acid and including a hydrocarbyl group of 7 or more carbon atoms, or combinations thereof, may also be included in any of the formulations described herein.
For example, in another embodiment, the present invention provides a pharmaceutical formulation that includes: an immune response modifier (IRM) compound having a 2-aminopyridine moiety fused to a five-membered nitrogen-3o containing heterocyclic ring; a preservative system that includes a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof; an antioxidant having hydrogen atom donating functionality; a fatty acid; and a hydrophobic, aprotic component miscible with the fatty acid and having a hydrocarbyl group of 7 or more carbon atoms. A chelating agent may also beneficially be included.
In another embodiment, the present invention provides a pharmaceutical formulation that includes: 0.001% by weight to 5.0% by weight of an immune response modifier (IR1VI) compound having a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring (preferably, an imidazonaphthyridine amine, and to more preferably 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c][1,5]naphthyridin-4-amine); a preservative system; 0.001 % by weight to 0.2% by weight of an antioxidant having hydrogen atom donating functionality; 0 to 0.1 % by weight of a chelating agent;
1 % by weight to 30% by weight of a fatty acid; 1 % by weight to 15% by weight of a medium-chain triglyceride; 0.2% by weight to 2.0% by weight of a viscosity enhancing agent; 0.1 % by weight to 6.0% by weight of an emulsifier; and water; wherein the formulation has a pH of 4.0 to 6.0 and the weight percentages are based on the total weight of the formulation. In this embodiment, the preservative system includes: 0.02%
by weight to 0.2% by weight of a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof; 0 to 10.0% by weight of a preservative enhancing solubilizer; and 0.05% by weight to 0.2%
by weight of a secondary preservative compound.
Certain embodiments of the present invention include a hydrophilic viscosity agent, such as those selected from cellulose ethers and carbomers. If used, the hydrophilic viscosity agent is preferably present in an amount of 0.2% by weight to 2.0% by weight. Other useful additives include, for example, a pH adjuster, an emulsifier, or combinations thereof.
The present invention also provides methods.
In one embodiment, the present invention provides a method of stabilizing a pharmaceutical formulation that includes: an immune response modifier (IRM) 3o compound having a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring; and a preservative system that includes a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof. The method includes adding an antioxidant and optionally a chelating agent to the formulation.
In another embodiment, the present invention provides a method for delivering an immune response modifier (IRM) to a dermal surface. The method includes selecting a formulation of the present invention and applying the selected formulation to the dermal and/or mucosal surface.
In another embodiment, the present invention provides a method of treating a to dermal associated condition (particularly, actinic keratosis). The method includes applying to a dermal surface of a patient in need thereof a pharmaceutical formulation of the present invention.
As used herein, a "sorbic acid preservative" means sorbic acid, esters of sorbic acid, salts of sorbic acid, or combinations thereof.
15 As used herein "remains substantially constant" means that the concentration of sorbic acid preservative in an IRM-containing formulation does not decrease by more than 15% of the initial concentration (i.e., its concentration when initially formulated) when stored for at least 6 months at 40°C and 75% relative humidity.
As used herein, "a" or "an" or "the" are used interchangeably with "at least one,"
2o to mean "one or more" of the listed element.
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of 25 examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present invention provides pharmaceutical formulations that include an immune response modifier containing a 2-aminopyridine fused to a five-membered nitrogen-containing heterocyclic ring, a preservative system that includes a sorbic acid preservative (i.e., sorbic acid, esters of sorbic acid, salts of sorbic acid, or combinations thereof). Surprisingly, such formulations are stabilized through the incorporation of an antioxidant, more preferably an antioxidant having hydrogen atom donating functionality. Additional stability, particularly of the antioxidant, can be obtained through the incorporation of a chelating agent.
to Through the use of an antioxidant and an optional chelating agent, the concentration of the sorbic acid preservative in an IRM-containing formulation remains substantially constant relative to its initial concentration (i.e., its concentration when initially formulated) when stored for at least 6 months at 40°C and 75%
relative humidity.
As used herein "remains substantially constant" means that the concentration of sorbic acid preservative in an IRM-containing formulation does not decrease by more than 15% of the initial concentration (i.e., its concentration when initially formulated) when stored for at least 6 months at 40°C and 75% relative humidity.
Preferably, the concentration of the sorbic acid preservative in an IRM-containing formulation does not 2o decrease by more than 10% of the initial concentration when stored for at least 6 months at 40°C and 75% relative humidity. More preferably, the concentration of the sorbic acid preservative in an IRM-containing formulation does not decrease by more than 5% of the initial concentration when stored for at least 6 months at 40°C and 75%
relative humidity.
In certain embodiments, formulations described herein can be in the form of an oil-in-water emulsion such as a cream or a lotion. Such an emulsion can include an oil phase that includes one or more IRM compounds, a fatty acid in an amount sufficient to solubilize the IRM compound(s), a hydrophobic, aprotic component; and an aqueous phase that includes a preservative system, and a hydrophilic viscosity enhancing agent.
3o Such components, as well as all others of the formulations described herein, are preferably pharmaceutically acceptable.
Inunune Response Modifiers In one aspect, the present invention provides a formulation that includes an immune response modifier containing a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring.
Immune response modifier compounds ("IRMs") include compounds that possess potent immunomodulating activity including but not limited to antiviral and antitumor activity. Certain IRMs modulate the production and secretion of cytokines.
to For example, certain IRM compounds induce the production and secretion of cytokines such as, e.g., Type I interferons, TNF-a, IL-1, IL-6, IL-8, IL-10, IL-12, MIP-1, and/or MCP-1. As another example, certain IRM compounds can inhibit production and secretion of certain TH2 cytokines, such as IL-4 and IL-5. Additionally, some IRM
compounds are said to suppress IL-1 and TNF (LT.S. Patent No. 6,518,265).
IRM compounds suitable for use in the invention include compounds having a 2-aminopyridine fused to a five-membered nitrogen-containing heterocyclic ring. Such compounds include, for example, imidazoquinoline amines including, but not limited to, substituted imidazoquinoline amines such as, for example, amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea 2o substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, and 6-, 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinoline amines;
tetrahydroimidazoquinoline amines including, but not limited to, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines, heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted 3o tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, and thioether substituted tetrahydroimidazoquinoline amines; imidazopyridine amines including, but not limited to, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers, and thioether substituted imidazopyridine amines; 1,2-bridged imidazoquinoline amines; 6,7-fused cycloalkylimidazopyridine amines; imidazonaphthyridine amines;
1 o tetrahydroimidazonaphthyridine amines; oxazoloquinoline amines;
thiazoloquinoline amines; oxazolopyridine amines; tluazolopyridine amines; oxazolonaphthyridine amines; thiazolonaphthyridine amines; imidazoquinoline-1,4-diamines; and 1H
imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines.
These immune response modifier compounds, methods of making them, methods of using them and compositions containing them are disclosed in U.S.
Patent Nos. 4,689,338; 4,929,624; 4,988,815; 5,037,986; 5,175,296; 5,238,944;
5,266,575;
5,268,376; 5,346,905; 5,352,784; 5,367,076; 5,389,640; 5,395,937; 5,446,153;
5,482,936; 5,693,811; 5,741,908; 5,756,747; 5,939,090; 6,039,969; 6,069,149;
6,083,505; 6,110,929; 6,194,425; 6,245,776; 6,331,539; 6,376,669; 6,451,810;
6,525,064; 6,541,485; 6,545,016; 6,545,017; 6,558,951; 6,573,273; 6,656,938;
6,660,735; 6,660,747; 6,664,260; 6,664,264; 6,664,265; 6,667,312; 6,670,372;
6,677,347; 6,677,348; 6,677,349; 6,683,088; 6,743,920; 6,756,382; 6,797,718;
and 6,818,650; European Patent 0 394 026; U.S. Patent Publication Nos.
2002/0016332;
2002/0055517; 2002/0110840; 2003/0133913; 2003/0161797; 2003/0199538;
2004/0014779;2004/0147543; 2004/0175336; 2004/0176367; 2004/0180919;
2004/0181130; 2004/0181211; and 2004/0192585.
As noted above, many of the IRM compounds useful in the present invention have demonstrated immunomodulating activity. In certain embodiments of the present invention the IRM compound can be chosen from 1H-imidazo[4,5-c]quinolin-4-amines defined by one of Formulas I-V below:

N
~~Rz~
'N
~R1)n ~
wherein Rl1 is selected from alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms;
R21 is selected from hydrogen, alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms;
and 2o each Rl is independently selected from alkoxy of one to four carbon atoms, halogen, and alkyl of one to four carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said Rl groups together contain no more than six carbon atoms;

NHz N
/ ~~ Rzz 'N
~Rz)n ~ R~z II
wherein R12 is selected from straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from straight chain or branched chain alkyl containing one to four carbon atoms and cycloalkyl containing three to six carbon atoms; and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon 1 o atoms; and RZZ is selected from hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl containing is one to four carbon atoms, straight chain or branched chain alkoxy containing one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each RZ is independently selected from straight chain or branched chain alkoxy 2o containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R~ groups together contain no more than six carbon atoms;
to NHz N
/ ~~ Rzs 'N
H
~Rsy /
III
wherein R23 is selected from hydrogen, straight chain or branched chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy of one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such l0 moieties, then the moieties together contain no more than six carbon atoms;
and each R3 is independently selected from straight chain or branched chain alkoxy of one to four carbon atoms, halogen, and straight chain or branched chain alkyl of one to four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R3 groups together contain no more than six carbon atoms;
NHz N
/ ~~ Rza 'N
15 R4 / ~~a IV
wherein R14 is -CHRXRywherein Ry is hydrogen or a carbon-carbon bond, with the proviso that when Ry is hydrogen RX is alkoxy of one to four carbon atoms, 2o hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, or 2-, 3-, or 4-pyridyl, and with the further proviso that when Ry is a carbon-carbon bond Ry and Rx together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms;
Rz4 is selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and R4 is selected from hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms;
NHz N
/ \~ Rzs 'N

V
wherein Rls is selected from hydrogen; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms;
hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl; and phenyl;
said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms;
RZS is X
~R
R r s wherein Rs and RT are independently selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
l0 X is selected from alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl 15 of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio of one to four carbon atoms; and RS is selected from hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms;
2o and pharmaceutically acceptable salts of any of the foregoing.
In another embodiment, the IRM compound can be chosen from 6,7 fused cycloalkylimidazopyridine amines defined by Formula VI below:
N
y R2s N
2 m ~16 VI
25 wherein N
I , Rs (CH ) m is l, 2, or 3;
R16 is selected from hydrogen; cyclic alkyl of three, four, or five carbon atoms;
straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms;
straight chain or branched chain alkenyl containing two to ten carbon atoms and 1 o substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, with the proviso that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl group does not have a fully carbon substituted carbon atom bonded 2o directly to the nitrogen atom; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and -CHRXRy wherein Ry is hydrogen or a carbon-carbon bond, with the proviso that when Ry is hydrogen RX is alkoxy of one to four carbon atoms; hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when Ry is a carbon-carbon bond RY and RX together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms, R26 is selected from hydrogen; straight chain or branched chain alkyl containing one to eight carbon atoms; straight chain or branched chain hydroxyalkyl containing one to six carbon atoms; morpholinoalkyl; benzyl; (phenyl)ethyl; and phenyl, the benzyl, (phenyl)ethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and -C(Rs)(RT)(X) 1 o wherein Rs and RT are independently selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
X is selected from alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety 15 contains one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is allcyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms, and 2o R6 is selected from hydrogen, fluoro, chloro, straight chain or branched chain alkyl containing one to four carbon atoms, and straight chain or branched chain fluoro-or chloroalkyl containing one to four carbon atoms and at least one fluorine or chlorine atom;
and pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound can be chosen from imidazopyridine amines defined by Formula VII below:
NHS
N
~~Rz~
~N
Rs~
R~~ ~~~
VII
wherein R17 is selected from hydrogen; -CH2RW wherein RW is selected from straight chain, branched chain, or cyclic alkyl containing one to ten carbon atoms, straight chain or branched chain alkenyl containing two to ten carbon atoms, straight chain or branched chain hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein to the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, and phenylethyl; and -CH=CRZRz wherein each Rz is independently straight chain, branched chain, or cyclic alkyl of one to six carbon atoms;
R27 is selected from hydrogen; straight chain or branched chain alkyl containing one to eight carbon atoms; straight chain or branched chain hydroxyalkyl containing 15 one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl and phenyl being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon 20 atoms;
R67 and R77 are independently selected from hydrogen and alkyl of one to five carbon atoms, with the proviso that R~7 and R77 taken together contain no more than six carbon atoms, and with the further proviso that when R77 is hydrogen then R67 is other than hydrogen and R27 is other than hydrogen or morpholinoalkyl, and with the further 25 proviso that when R~7 is hydrogen then R77 and R27 are other than hydrogen;
and pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound can be chosen from 1,2-bridged imidazoquiizoline amines defined by Formula VIII below:
NHS
N
N yCHz N
(R$ q / CH~Z
VIII
wherein Z is selected from -(CHZ)p wherein p is 1 to 4;
-(CHZ)a C(RDRE)(CHZ)b-, wherein a and b are integers and a+b is 0 to 3, RD is hydrogen or alkyl of one to four carbon atoms, and RE is selected from alkyl of one to 1o four carbon atoms, hydroxy, -ORF wherein RF is alkyl of one to four carbon atoms, and -NR~R'G wherein R~ and R'G are independently hydrogen or alkyl of one to four carbon atoms; and -(CHZ)a (Y)-(CHZ)b- wherein a and b are integers and a+b is 0 to 3, and Y is O, S, or -NRJ- wherein RJ is hydrogen or alkyl of one to four carbon atoms;
qis0orl;and R$ is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound can be chosen from thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, thiazolonaphthyridine amines and oxazolonaphthyridine amines defined by Formula IX below:
NHz R~Rzs Ras IX
wherein:
Rl~ is selected from oxygen, sulfur and selenium;
l0 RZ9 is selected from -hydrogen;
-alkyl;
-alkyl-OH;
-haloalkyl;
-alkenyl;
-alkyl-X-alkyl;
-alkyl-X-alkenyl;
-alkenyl-X-alkyl;
-alkenyl-X-alkenyl;
-alkyl-N(R5~)2;
-alkyl-N3;
-alkyl-O-C(O)-N(R5~)2;
-heterocyclyl;
-alkyl-X-heterocyclyl;
-alkenyl-X-heterocyclyl;
-ar'Yl~
-alkyl-X-aryl;

-alkenyl-X-aryl;
-heteroaryl;
-alkyl-X-heteroaryl; and -alkenyl-X-heteroaryl;
R39 and R49 are each independently:
-hydrogen;
-X-alkyl;
-halo;
-haloalkyl;
l o -N(R59)a;
or when taken together, R39 and R49 form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;
X is selected from-O-, -S-, -NRS~-, -C(O)-, -C(O)O-, -OC(O)-, and a bond; and each R59 is independently H or C1_$alkyl;
and pharmaceutically acceptable salts thereof.
In another embodiment, the IRM compound can be chosen from imidazonaphthyridine amines and imidazotetrahydronaphthyridine amines defined by Formulas X and XI below:
NHZ
N / ~ N~R2~o ~'N
R~~o X
wherein A is =N-CR=CR-CR--; =CR-N=CR-CR=; =CR-CR=N-CR--; or =CR-CR--CR-N=;
Rico is selected from:
- hydrogen;

-Ci-zo alkyl or Cz_zo alkenyl that is unsubstituted or substituted by one or more substituents selected from:
-aryl;
-heteroaryl;
-heterocyclyl;
-O-Ci-zo alkyl;
-O-(C1_zo alkyl)o_1-aryl;
-O-(C1_zo alkyl)o_1-heteroaryl;
-O-(C1-zo alkyl)o_1-heterocyclyl;
-CO-O-C1-zo alkyl;
-S(O)o-z-Ci-zo alkyl;
-S(O)o_z-(C1_zo alkyl)o_1-aryl;
-S(O)o-z-(Ci-zo alkyl)o_1-heteroaryl;
-S(O)o_z-(C1-zo alkyl)o_1-heterocyclyl;
1 s -N(R3 i o)z;
-N3;
oxo;
-halogen;
-NOz;
-OH; and -SH; and -Ci-zo alkyl-NR3lo-Q-X-R4io or -Cz_zo alkenyl-NR3io-Q-X-Raio wherein Q is -CO- or -SOz-; X is a bond, -O- or -NR3io- and R4lo is aryl; heteroaryl;
heterocyclyl; or -C1_zo alkyl or Cz_zo alkenyl that is unsubstituted or substituted by one or more substituents selected from:
-aryl;
-hetero aryl;
-heterocyclyl;
-O-C1_zo alkyl;
3o -O-(C1_zo alkyl)o_1-aryl;

-O-(C1_zo alkyl)o_1-heteroaryl;
-O-(C1-zo alkyl)o_1-heterocyclyl;
-CO-O-Ci_zo alkyl;
-S(O)o_z -Ci-zo alkyl;
-S(O)o_z-(C1_zo a~Yl)o-i-aryl;
-S(O)o_z-(CI_zo alkyl)o_1-heteroaryl;
-S(O)o_z-(C1_zo alkyl)o_1-heterocyclyl;
-N(R3lo)z;
-NR3lo-CO-O-C1-zo alkyl;
l o -N3;
oxo;
-halogen;
-NOz;
-OH; and -SH; or Rmo is / \ ~ \
( i )o-, (CH2)~-s N(Rs~o)2 wherein Y is N- or -CR-;
Raio is selected from:
-hydrogen;
-C1_lo alkyl;
-Cz_lo alkenyl;
-aryl;
-Ci-to alkyl-O-C1_lo alkyl;
-Ci-to alkyl-O-Cz_io alkenyl; and -Cl_io alkyl or Cz_lo alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R3lo)z;
s -CO-N(R3 i o)z;
-CO-C1_io alkyl;
-N3;
-aryl;
-hetero aryl;
1 o -heterocyclyl;
-CO-aryl; and -CO-hetero aryl;
each R3io is independently selected from hydrogen and C1_lo alkyl; and each R is independently selected from hydrogen, C1_lo alkyl, C1_lo alkoxy, Is halogen and trifluoromethyl;
NHz N~ Rzl1 ~'N

XI
wherein B is -NR-C(R)z-C(R)z-C(R)z-; -C(R)z-NR-C(R)z-C(R)z-;
2o -C(R)z-C(R)z-NR-C(R)z- or -C(R)z-C(R)z-C(R)z-NR-;
Ri l l is selected from:
- hydrogen;
-C12o alkyl or Cz_zo alkenyl that is unsubstituted or substituted by one or more substituents selected from:
2s -aryl;
-heteroaryl;

-heterocyclyl;
-O-C 1 _zo alkyl;
-O-(C1_zo alkyl)o_1-aryl;
-O-(C1_zo alkyl)o_1-heteroaryl;
.. 5 -O-(C1_zo alkyl)o_1-heterocyclyl;
-CO-O-Cl_zo alkyl;
-S(O)o_z-C1-zo alkyl;
-S(O)o_z-(C1_zo alkyl)o_1-aryl;
-S(O)o_z-(C1-zo alkyl)o_1-heteroaryl;
-S(O)o_z-(C1-zo alkyl)o_1-heterocyclyl;
-N(R311)2~
-N3;
oxo;
-halogen;
1 s -NOz;
-OH; and -SH; and -C1-zo alkyl-NR311-Q-X-8411 or -Cz_zo alkenyl-NR311-Q-X-8411 wherein Q is -CO- or -SOz-; X is a bond, -O- or -NR311- and 8411 is aryl; heteroaryl;
heterocyclyl; or -2o C1-zo alkyl or CZ_zo alkenyl that is unsubstituted or substituted by one or more substituents selected from:
-aryl;
-heteroaryl;
-heterocyclyl;
25 -O-C1_zo alkyl;
-O-(C1-zo alkyl)o_1-aryl;
-O-(C1-zo alkyl)o_1-heteroaryl;
-O-(C1-zo alkyl)o_1-heterocyclyl;
-CO-O-C1-zo alkyl;
30 -S(O)o_z-C1-zo alkyl;

-S(O)o_z-(C1_zo alkyl)o_1-aryl;
-S(O)o_z-(C1-zo alkyl)o_1-heteroaryl;
-S(O)o_z-(C1-zo alkyl)o_1-heterocyclyl;
-N(R3 i i )z;
-NR311-CO-O-C1_zo alkyl;
-N3;
oxo;
-halogen;
-NOz;
1 o -OH; and -SH; or 8411 is / ~ ~ ~ /
(~)0-1 (CHZ)~_s N(Rg~~)z wherein Y is N- or -CR-;
Rzll is selected from:
-hydrogen;
-C1-to alkyl;
-Cz-to alkenyl;
-aryl;
-C1-to alkyl -O-C1_lo-alkyl;
2o -C1_lo alkyl-O-Cz_lo alkenyl; and -C1-to alkyl or Cz_lo alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R311)z;

-CO-N(R311)z;
-CO-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3n is independently selected from hydrogen and Cl_lo alkyl; and to each R is independently selected from hydrogen, C1_lo alkyl, C1_lo alkoxy, halogen, and trifluoromethyl;
and pharmaceutically acceptable salts thereof.
In another embodiment, the IRM compound can be chosen from 1H
imidazo[4,5-c]quinolin-4-amines and tetrahydro- 1H imidazo[4,5-c]quinolin-4-amines defined by Formulas XII, XIII and XIV below:
NHz N
Rz~z 'N
~R~z)~ ~ R~~z XII
wherein 2o Rllz is -alkyl-NR3lz-CO-Rmz or -alkenyl-NR3lz-CO- R4lz wherein Rmz is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)o_1-aryl;

-(alkyl)o_1-(substituted aryl);
-(alkyl)o_1-heteroaryl;
-(alkyl)o_1-(substituted heteroaryl);
-O-alkyl;
-O-(alkyl)o_1-aryl;
-O-(alkyl)o_1-(substituted aryl);
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-(substituted heteroaryl);
-CO-aryl;
to -CO-(substituted aryl);
-CO-heteroaryl;
-CO-(substituted heteroaryl);
-COOH;
-CO-O-alkyl;
1 s -CO-alkyl;
-S(O)o_2 -alkyl;
-S(O)o_2-(alkyl)o_1-aryl;
-S(O)o_2-(alkyl)o_1-(substituted aryl);
-S(O)o_2-(alkyl)o_1-heteroaryl;
20 -S(O)o_2-(alkyl)o_1-(substituted heteroaryl);
-p(~)(~R312)2, -NR312-CO-O-alkyl;
-N3;
-halogen;
25 -N02;
-CN;
-haloalkyl;
-O-haloalkyl;
-CO-haloalkyl;
30 -OH;

-SH; and in the case that 8412 is alkyl, alkenyl, or heterocyclyl, oxo;
or 8412 is ~ys1-10aI~CyI~-NRg12 U~-~oalkyl)-Rs~a wherein 8512 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
8212 is selected from:
-hydrogen;
-alkyl; ' l o -alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R312)20 -CO-N(R3lz)2;
-CO-C1_lo alkyl;
-CO-O-C1-to alkyl;
-N3;
-aryl;

-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-CO-aryl; and -CO-hetero aryl;
each R3lz is independently selected from hydrogen; C1_lo alkyl-heteroaryl;
C1_io alkyl-(substituted heteroaryl); C1_lo alkyl-aryl; C1_lo alkyl-(substituted aryl) and Cl_io 1 o alkyl;
visOto4;
and each Rlz present is independently selected from C1_lo alkyl, C1_io alkoxy, halogen, and trifluoromethyl;
NHz N
\~ Rzl3 N
~R13O ~ R113 XIII
wherein 8113 is -alkyl-NR313- SOz -X-8413 or -alkenyl-NR3ls- SOz -X-8413 ;
X is a bond or NR513 ;
8413 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;

-substituted cycloalkyl;
-substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyl;
-O-alkyl;
-O-(alkyl)o_1-aryl;
-O-(alkyl)o_1-substituted aryl;
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-substituted heteroaryl;
l o -O-(alkyl)o_1-heterocyclyl;
-O-(alkyl)o_1-substituted heterocyclyl;
-COOH;
-CO-O-alkyl;
-CO-alkyl;
-S(O)0_2 -alkyl;
-S(O)0_Z-(alkyl)o_1-aryl;
-S(O)o_2-(alkyl)o_1-substituted aryl;
-S(O)0_Z-(alkyl)o_1-heteroaryl;
-S(O)o_2-(alkyl)o_1-substituted heteroaryl;
-S(O)o_2-(alkyl)o_1-heterocyclyl;
-S(O)0_Z-(alkyl)o_1-substituted heterocyclyl;
-(alkyl)o_1-NR313Rsis;
-(alkyl)o_1-NR3 i3-CO-O-alkyl;
-(alkyl)o_1-NR3 i3-CO-alkyl;
-(alkyl)o_1-NR313-CO-aryl;
-(alkyl)o_1-NR3i3-CO-substituted aryl;
-(alkyl)o_1-NR3 i3-CO-heteroaryl;
-(alkyl)o_1-NR3i3-CO-substituted heteroaryl;
-N3;
-halogen;

-haloalkyl;
-haloalkoxy;
-CO-haloalkyl;
-CO-haloalkoxy;
-NOz;
-CN;
-OH;
-SH; and in the case that 8413 is alkyl, alkenyl, or heterocyclyl, oxo;
8213 is selected from:
1 o -hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
- alkyl-O-alkyl;
- alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected 2o from:
-OH;
-halogen;
-N(R3 i3)2;
-CO-N(R3i3)a;
-CO-C1_lo alkyl;
-CO-O-Ci_lo alkyl;
-N3;
-aryl;
-substituted aryl;
-heteroaryl;

-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-CO-aryl;
-CO-(substituted aryl);
-CO-heteroaryl; and -CO-(substituted heteroaryl);
each 8313 is independently selected from hydrogen and Cl_io alkyl; or when X
is a bond 8313 and 8413 can join to form a 3 to 7 membered heterocyclic or substituted to heterocyclic ring;
Rsl3 is selected from hydrogen and C1_lo alkyl, or 8413 and Rsl3 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring;
visOto4;
and each R13 present is independently selected from C1-to alkyl, C1_lo alkoxy, halogen, and trifluoromethyl;

N
R2la 'N
~R14 v ~ R114 XIV
wherein 2o Rll4 is -alkyl-NR314-CY-NRsl4-X-8414 or -alkenyl-NR314-CY- NRsl4-X- 8414 wherein Y is =O or =S;
X is a bond, -CO- or -SOZ-;
8414 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from:
-alkyl;

-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyl;
-O-alkyl;
-O-(alkyl)o_l-aryl;
l o -O-(alkyl)o_1-substituted aryl;
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-substituted heteroaryl;
-O-(alkyl)o_1-heterocyclyl;
-O-(alkyl)o_1-substituted heterocyclyl;
-COOH;
-CO-O-alkyl;
-CO-alkyl;
-S(O)o_2 -alkyl;
-S(O)o_2 -(alkyl)o_1-aryl;
-S(O)o_2-(alkyl)o_1-substituted aryl;
-S(O)o_Z-(alkyl)o_1-heteroaryl;
-S(O)o_2-(alkyl)o_1-substituted heteroaryl;
-S(O)o_2 -(alkyl)o_1-heterocyclyl;
-S(O)o_Z-(alkyl)o_1-substituted heterocyclyl;
-(alkyl)o_i-NR31dR3i4;
-(alkyl)o_1-NR314-CO-O-alkyl;
-(alkyl)o_1-NR314-CO-alkyl;
-(alkyl)o_1-NR314-CO-aryl;
-(alkyl)o_1-NR3la-CO-substituted aryl;
-(alkyl)o_1-NR314-CO-heteroaryl;

-(alkyl)0_1-NR314-CO-substituted heteroaryl;
-N3;
-halogen;
-haloalkyl;
-haloalkoxy;
-CO-haloalkoxy;
-NOz -CN;
-OH;
to -SH; and, in the case that 8414 is alkyl, alkenyl or heterocyclyl, oxo;
with the proviso that when X is a bond 8414 can additionally be hydrogen;
Rzl4 is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
- alkyl-O-alkyl;
-alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R314)2;
-CO-N(R314)z;
-CO-C 1 _ 1 o alkyl;
-CO-O-C1_lo alkyl;
-N3;

-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-CO-aryl;
-CO-(substituted aryl);
-CO-heteroaryl; and to -CO-(substituted heteroaryl);
each R3i4 is independently selected from hydrogen and C1_lo alkyl;
Rsi4 is selected from hydrogen and C1-to alkyl, or 8414 and Rsi4 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring;
visOto4;
and each R14 present is independently selected from C1-to alkyl, Ci-io alkoxy, halogen, and trifluoromethyl;
and pharmaceutically acceptable salts thereof.
In another embodiment, the IRM compound can be chosen from 1H
imidazo[4,5-c]quinolin-4-amines and tetrahydro- 1H imidazo[4,5-c]quinolin-4-amines 2o defined by Formulas XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, and XXVI below:

N
N

'N
~R15)v X-~-R115 wherein: X is -CHRs i s-, -CHRs i s-alkyl-, or -CHRs 1 s-alkenyl-;
RI is is selected from:

-R41 s-CR31 s-Z R61 s-alkyl;
-R41 s-CR31 s-z-R61 s-alkenyl;
-R4ls-CR3ls-z-R6ls-aryl;
-R41 s-CR31 s-Z-Rs 1 s-heteroaryl;
-Ra ls-CR3ls-z-R6ls-heterocyclyl;
-R4ls-CR3ls-z-H
-Rals-NR7ls -CR3ls-Rsls-alkyl;
-R41 s-NR71 s -CR31 s-R61 s-alkenyl;
-R41 s-NR71 s-CR31 s-R61 s-~yl;
l o -R41 s-NR71 s-CR31 s-R61 s-hetero aryl;
-Rals-NR7ls-CR3ls-R6ls heterocyclyl; and -8415-NR715 -CR315-R81 S;
z 1S NR515-~ -~-a Or -S-;
Rzls is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(Rsls)z;
-CO-N(Rs i s)z;
-CO-C1_lo alkyl;

-CO-O-Cl_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R3ls is =O or =S;
R4ls is alkyl or alkenyl, which may be interrupted by one or more to -O- groups;
each Rs 1 s is independently H or C 1 _ 1 o alkyl;
Rsls is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7ls is H, C1_IO alkyl, or arylalkyl; or R4ls and R7ls can join together to form a ring;
R81 s is H or C 1 _ 1 o alkyl; or R71 s and R$1 s can join together to form a ring;
Y is -O- or -S(O)o_Z-;
v is 0 to 4; and each Rls present is independently selected from C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;

N
~R216 'N
~R~s)v X-O-R~~s XVI
wherein: X is -CHRsIG-, -CHRsIG-alkyl-, or -CHRsIG-alkenyl-;
R11G is selected from:
-8416-CR316-z-RG 1 G-a11Cy1;

-8416-CR316-z-Rs 16-allcenyl;
-8416-CR316-z-8616-'aryl;
-8416-CR316 Z-8616-heteroaryl;
-8416-CR316 Z-8616 heterocyclyl;
-8416-CR316-Z-H, -8416-NR716 -CR3ls-Rsl6-alkyl;
-8416-NR716 -CR316-8616-alkenyl;
-8416-NR716-CR316-8616-aryl;
-8416 NR716-CR316-8616-heteroaryl;
l o -8416-NR716-CR316-8616-heterocyclyl; and -8416-NR716 -CR316-8816;
Z 1S NRS 16-, -~-, Or -S-;
8216 is selected from:
-hydrogen;
15 -alkyl;
-allcenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
20 -alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
25 -OH;
-halogen;
-N(R516)z;
-CO-N(R516)z;
-CO-C1_lo alkyl;
30 -CO-O-C1_lo alkyl;

-N3;
-az'Yh -heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
8316 is =O or =S;
R.al6 is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
to each 8516 is independently H or C1_lo alkyl;
8616 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
8716 is H, C1_lo alkyl, arylalkyl; or 8416 and 8716 can join together to form a ring;
8816 is H or C1_lo alkyl; or 8716 and 8816 can join together to form a ring;
Y is -O- or -S(O)o_2-;
v is 0 to 4; and each R16 present is independently selected from C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
NHZ
N
\~Rz~~
'N
~R~~)~ ~ . X-O-R~~~
XVII
wherein: X is -CHR317-, -CHR317-alkyl-, or -CHR317-alkenyl-;
8117 is selected from:
-alkenyl;
-aryl; and -8417-~'Yl~
Rzl7 is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
l o -alkyl-Y- alkenyl;
-allcyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R317)z;
-CO-N(R317)2, -CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-hetero aryl;
8417 is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each 8317 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_z-;
3o v is 0 to 4; and each R17 present is independently selected from C1-to allcyl, C1_lo allcoxy, hydroxy, halogen, and trifluoromethyl;
NHS
N
~Rz~s 'N
~R~a)~ X-O-R~~a XVIII
wherein: X is -CHR318-, -CHR31$-alkyl-, or -CHR31$-alkenyl-;
8118 is selected from:
-aryl;
-alkenyl; and =Ra ls-a~'Yl~
RzlB is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-aryl;
- alkyl-Y- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R31 a)z;
-CO-N(R318)2;

-CO-Ci_lo alkyl;
-CO-O-C1_io alkyl;
-N3;
-aryl;
s -heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
8418 is alkyl or alkenyl, which may be interrupted by one or more to -O- groups;
each 8318 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
v is 0 to 4; and each Rl$ present is independently selected C1_lo alkyl, C1_lo alkoxy, 15 hydroxy, halogen, and trifluoromethyl;
NHz N
~Ra,s 'N
~R19w / X-O-R~~s XIX
2o wherein: X is -CHR319-, -CHR31 ~-alkyl-, or -CHR319-alkenyl-;
8119 is selected from:
-heteroaryl;
-heterocyclyl;
-R4 19- heteroaryl; and 25 -R41~-heterocyclyl;
Rzl9 is selected from:
-hydrogen;

-allcyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected 1 o from:
-OH;
-halogen;
-N(R319)2;
-CO-N(R319)2, -CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R41~ is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each 8319 is independently H or C1_lo alkyl;
each Y is independently -O- or -S(O)o_2-;
v is 0 to 4; and each R19 present is independently selected from C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;

NHa N
~Rzzo 'N
~R2o)v X-O-R~Zo XX
wherein: X is -CHR3zo-, -CHR3zo-alkyl-, or -CHR3zo-alkenyl-;
Rizo is selected from:
-heteroaryl;
-heterocyclyl;
-R4zo- heteroaryl; and -Ra.zo-heterocyclyl;
1 o Rzzo is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-allcyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R3zo)z;
-CO-N(R320)2;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;

-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
R42o is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R32o is independently H or C1_lo alkyl;
to each Y is independently -O- or -S(O)o_z-;
v is 0 to 4; and each Rzo present is independently selected from C1_lo alkyl, C1_lo allcoxy, hydroxy, halogen, and trifluoromethyl;
NHZ
N
~Ra2~
'N
~R21~~ ~ X-O-R~~a XXI
wherein: X is -CHRsz l-, -CHRs21-alkyl-, or -CHRs21-alkenyl-;
Rlzl is selected from:
-8421 321-SOz-8621-alkyl;
-8421 NR321-SOz-8621-alkenyl;
-8421 NR3z1-SOz-R6z1-aryl;
-8421 NR321-SOz-R6z1-heteroaryl;
-R4z1 NR321-SO2-8621-heterocyclyl;
-8421 NRs21-SOz-8721;
-R421-~321-SO2-~521'R621-alkyl;
-8421-NR321-SOz-NRs21-8621-alkenyl;

-Raz 1-NR3z 1-SOz-NRsz 1-Rsz 1-ar y1;
-R4z1-NR3z1-SOz-NRszl-R6z1-heteroaryl;
-8421-NR321-s~2-NRs21'R621-heteroCyClyl; and 'R421-NR321-s~2-NH2;
Rzzl is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
l o -heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and ~ - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(Rszl)z;
-CO-N(Rszl)z;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-hetero aryl;
Y is -O- or -S(O)o_z-;
3o R3z1 is H, C1_lo alkyl, or arylalkyl;

each R4zi is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R3zi and R42i can join together to form a nng;
each Rszl is independently H, C1_lo alkyl, or C2_lo alkenyl;
R6z1 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
8721 is CI_lo alkyl; or R3zi and 8721 can join together to form a ring;
v is 0 to 4; and each R21 present is independently selected from C1_lo alkyl, C1_lo alkoxy, 1 o hydroxy, halogen, and trifluoromethyl;
NHz N
~Rzzz 'N
~Rzz)~ X-O-Razz XXII
wherein: X is -CHRszz-, -CHRSzz-alkyl-, or -CHRszz-alkenyl-;
Ritz is selected from:
-8422-322-SO2 Rszz-alkyl;
-8422 NR322-SO2-8622-alkenyl, -Razz 322-SO2 R6zz-aryl;
-8422 322-SO2-R62z-heteroaryl;
-8422-322-SO2-8622 heterocyclyl;
-8422-322-SO2-R722i -R422-~322'S~2-~522-R622-alkyl;
-R.4z2-NR3zz-sOz-NRsz2-R6zz-alkenyl;
-R422-~322-SO2-NR522-R622-a~l, -8422-NR32z-SOz-NRszz-Rbzz-heteroaryl;
-R4zz-NR3zz-s02-NR522-R6zz-heterocyclyl; and -8422-~322'S02'NH2;
Rzzz is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
1 o -alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(RSZZ)z;
-CO-N(Rszz)z;
-CO-C1_io alkyl;
-CO-O-C 1 _ i o alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_z-;
R3zz is H, C1_lo alkyl, or arylalkyl;
each R4z2 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R32z and R4zz can join together to form a ring;

each RSZZ is independently H, CI_lo alkyl, or Cz_lo alkenyl;
Rszz is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7zz is Cl_lo alkyl; or Razz and R7zz can join together to form a ring;
v is 0 to 4; and each Rzz present is independently selected from Ci_io alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
NHZ
N
Rays 'N
~Ras~~
Z-R~zs XXIII
wherein: X is -CHR3z3-, -CHR3zs-alkyl-, or -CHR3zs-alkenyl-;
Z is -S-, -SO-, or-SOz-;
Rizs is selected from:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
-R4z3-aryl;
-R4zs- heteroaryl; and 'R423 heterocyclyl;
Rzzs is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;

-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
- allcyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R323)2;
-CO-N(R323)2;
-CO-C1_lo alkyl;
-CO-O-Cl_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
2o each 8323 is independently H or C1_lo alkyl;
each 8423 is independently alkyl or alkenyl;
each Y is independently -O- or -S(O)o_z-;
v is 0 to 4; and each R23 present is independently selected from C1_io alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;

N
R22a ~N
~R2a)~ I
X-z-8124 XXIV
wherein: X is -CHR324-, -CHR324-alkyl-, or -CHR324-alkenyl-;
Z is -S-, -SO-, or -S02-;
Ri24 is selected from:
-alkyl;
-aryl;
-heteroaryl;
l o -heterocyclyl;
-alkenyl;
-8424-~l0 -8424- heteroaryl; and -R4z4-heterocyclyl;
8224 is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
- alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
so -halogen;
-N(R324)2, -C~-N(R324)2, -CO-C1_lo alkyl;
-CO-O-C1_io alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
to -CO-aryl; and -CO-heteroaryl;
each 8324 is independently H or C1_lo alkyl;
each 8424 is independently alkyl or alkenyl;
each Y is independently-O- or-S(O)o_2-;
v is 0 to 4; and each R24 present is independently selected from C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
NHz N
/ ~ Rzzs 'N
~Rzs)~ ~ X-O-R~zS
XXV
wherein: X is -CHRs2s-, -CHRszs-alkyl-, or -CHRszs-alkenyl-;
Ri2s is selected from:
-8425 825-CR325 525-Z-8625-alkyl;
-R42s-NRa2s-CR325 NRs2s Z-R62s-alkenyl;
-R42s-NRszs-CR32s-NRs2s Z R62s-aryl;
-R4zs-~25-CR325 NRs2s-z-R62s-heteroaryl;

-Razs-NR825-CR325 NRs2s Z R62s-heterocyclyl;
-R42s-NR825-CR325-NRs2sR725, '8425-NR825-CR325-NR92s-z-8625-alkyl, -Ra2s-NRszs-CR3zs-NR9zs-z-R62s-alkenyl;
-8425 NR825-CR325-NR92s-Z-8625-a~l;
-R42s-NRszs-CR3zs-NR925 Z Rszs-heteroaryl; and -R42s-NRazs-CR3zs-NR9zs Z R62s-heterocyclyl;
RZZS is selected from:
-hydrogen;
l o -alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(RSZS)z;
-CO-N(Rs2s)2;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R3zs is =O or =S;
each R42s is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each Rszs is independently H or C1_io alkyl;
R6zs is a bond, alkyl, or alkenyl, wluch may be interrupted by one or more -O- groups;
R7zs is H or C1_lo alkyl which may be interrupted by a hetero atom, or R7zs can join with Rszs to form a ring;
Rg25 1S H, C1_lo alkyl, or arylalkyl; or R4zs and R82s can join together to form a ring;
R92s is C1_lo alkyl which can join together with Rszs to form a ring;
each Y is independently -O- or -S(O)o_z-;
Z is a bond, -CO-, or -SOz-;
v is 0 to 4; and each R2s present is independently selected C1_lo alkyl, C1_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
NHz N
N / ~ Rzzs 'N
tRzs)v X-O-R~zs XXVI
wherein: X is -CHRsz6-, -CHRs26-alkyl-, or -CHRsz6-alkenyl-;
Riz6 is selected from:
-8426 ~82G-~R326-X526-Z-RC26-alkyl;
-R4z6-X826-CR326-NRsz6-Z-R6z6-alkenyl;
-8426-NR8z6-CR3z6-NR526-Z-8626-aryli -8426 ~826'CR3z6-~52G Z-8626-heteroaryl;

-Ra26-X826-CR326--NRsz6-z 8626-heterocyclyl;
-8426-826-CR326-NR526R726~
-8426-X826-CR326-'~92G Z 8626-alkyl;
-R4z6-NR826-CR326-~92G Z-Rs26-alkenyl;
-8426-NR826-CR326--X926 Z-8626-~ylo -8426-NR826-CR326 X926-Z-8626-heteroaryl; and -8426-NRsz6-CR326-NR926-Z-Rb26-heterocyclyl;
R2z6 is selected from:
-hydrogen;
l o -alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y- alkenyl;
-alkyl-Y-aryl; and alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R526)2 ~
-CO-N(Rsz6)2;
-CO-C1_lo alkyl;
-CO-O-C1-to alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
each R32s is =O or =S;
each R4zs is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups;
each R52s is independently H or C1_lo alkyl;
Rszs is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R72s 1S H or C1_lo alkyl which may be interrupted by a hetero atom, or R7zs can join with Rsas to form a ring;
to R$ZS is H, C1_io alkyl, or arylalkyl; or R4zs and R82s can join together to form a ring;
8926 1S Cl_lo alkyl which can join together with R82s to form a ring;
each Y is independently -O- or -S(O)o_2-;
Z is a bond, -CO-, or -SOZ-;
v is 0 to 4; and each RZS present is independently selected from C1_lo alkyl, CI_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
and pharmaceutically acceptable salts of any of the foregoing.
In another embodiment, the IRM compound can be chosen from 1H
2o imidazo[4,5-c]pyridin-4-amines defined by Formula XXVII below:

N
N

'N

Ra27 X ~N~Y~Zw XXVII
wherein X is alkylene or alkenylene;
Y is -CO- or -CS;
Z is a bond, -O-, or -S-;

Riz7 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-substituted cycloalkyl;
to -substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyl;
O-alkyl;
-O-(alkyl)o_1-aryl;
-O-(alkyl)o_1-(substituted aryl);
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-(substituted heteroaryl);
-O-(alkyl)o_1-heterocyclyl;
-O-(alkyl)o_1-(substituted heterocyclyl);
-COOH;
-CO-O-alkyl;
-CO-alkyl;
-S(O)o_z -alkyl;
-S(O)o_z -(alkyl)o_1-aryl;
-S(O)o_z-(alkyl)o_I-(substituted aryl);
-S(O)o_z-(alkyl)o_1-heteroaryl;
-S(O)o_z-(alkyl)o_1-(substituted heteroaryl);
-S(O)o_z-(alkyl)o_1-heterocyclyl;
-S(O)o_z-(alkyl)o_1-(substituted heterocyclyl);
-(alkyl)o_1-N(R6z~)z;

-(alkyl)o_1-NR6z7-CO-O-alkyl;
-(alkyl)o_1-NR6z7-CO-alkyl;
-(alkyl)o_1-NR~z~-CO-aryl;
-(alkyl)o_1-NR6z7-CO-(substituted aryl);
-(alkyl)o_1-NR6z7-CO-heteroaryl;
-(alkyl)o_i-NR~z7-CO-(substituted heteroaryl);
-N3;
-halogen;
-haloalkyl;
l o -haloalkoxy;
-CO-haloalkyl;
-CO-haloalkoxy;
-NOz -CN;
~ s -OH;
-SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo;
Rzz7 is selected from:
-hydrogen;
-alkyl;
20 -alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
25 -alkyl-O-alkyl;
-alkyl-S-alkyl;
-alkyl-O-aryl;
-alkyl-S-aryl:
-alkyl-O- alkenyl;
30 -alkyl-S- alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R627)2;
-CO-N(R627)2;
-CS-N(R627)2;
-SO2-N(R627)2, -NR627-CO-Cl_10 alkyl;
to -NR627-CS-C1_lo alkyl;
-NR627-S02-Cl_lo alkyl;
-CO-C1_lo alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
' -substituted heterocyclyl;
-CO-aryl;
-CO-(substituted aryl);
-CO-heteroaryl; and -CO-(substituted heteroaryl);
8327 and 8427 are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio;
8527 is H or C1_lo alkyl, or 8527 can join with X to form a ring that contains one or two heteroatoms; or when 8127 is alkyl, 8527 and 8127 can join to form a ring;
3o each 8627 is independently H or C1_loalkyl;

and pharmaceutically acceptable salts thereof.
In another embodiment, the IRM compound can be chosen from 1H
imidazo[4,5-c]pyridin-4-amines defined by Formula XXVIII below:

N
R22s 'N

R42s ~ ~N
R52s Y\Z'R~2s XXVIII
wherein X is alkylene or alkenylene;
Y is -SOZ-;
Z is a bond or NR6zs-;
l0 R12$ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of wluch may be unsubstituted or substituted by one or more substituents independently selected from:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-substituted cycloalkyl;
-substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyl;
O-alkyl;
-O-(alkyl)o_1-aryl;
-O-(alkyl)o_1-(substituted aryl);
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-(substituted heteroaryl);

-O-(alkyl)o_l-heterocyclyl;
-O-(alkyl)o_1-(substituted heterocyclyl);
-COOH;
-CO-O-alkyl;
-CO-alkyl;
-S(O)o_z -alkyl;
-S(O)0_z-(alkyl)o_1-aryl;
-S(O)o_z-(alkyl)o_l-(substituted aryl);
-S(O)o_z-(alkyl)o_1-heteroaryl;
to -S(O)o_z-(alkyl)o_1-(substituted heteroaryl);
-S(O)o_z-(alkyl)o_1-heterocyclyl;
-S(O)o_z-(alkyl)o_1-(substituted heterocyclyl);
-(alkyl)o_1-N(R6zs)z;
-(alkyl)o_1-NR~zg-CO-O-alkyl;
-(alkyl)o_ I-NR$z8-CO-alkyl;
-(alkyl)o_1-NR6z$-CO-aryl;
-(alkyl)o_l-NR6zs-CO-(substituted aryl);
-(alkyl)o_1-NR6z$-CO-heteroaryl;
-(alkyl)o_i-NRszs-CO-(substituted heteroaryl);
-N3;
-halogen;
-haloalkyl;
-haloalkoxy;
-CO-haloalkyl;
-CO-haloalkoxy;
-NOz -CN;
-OH;
-SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo;
3o Rzz$ is selected from:

-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-alkyl-O-alkyl;
-alkyl-S-alkyl;
1 o -alkyl-O-aryl;
-alkyl-S-aryl:
-alkyl-O- alkenyl;
-alkyl-S- alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;
-N(R628)2, -CO-N(R6zs)2;
-CS-N(R6zs)z;
-S~2-N(R628)2, -NR62s-CO-C1_lo alkyl;
-NR62a-CS-Ci-to alkyl;
-NR6zs-S02-Cl_lo alkyl;
-CO-Ci_io alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-substituted aryl;
3o -heteroaryl;

-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-CO-aryl;
-CO-(substituted aryl);
-CO-heteroaryl; and -CO-(substituted heteroaryl);
8328 and 8428 are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio;
1o 8528 is H or C1_lo alkyl, or R52$ can join with X to form a ring; or when R12$ is alkyl, R52$ and R12$ can join to form a ring;
each 8628 is independently H or C1_loalkyl;
and pharmaceutically acceptable salts thereof.
In another embodiment, the IRM compound can be chosen from 1H
imidazo[4,5-c]pyridin-4-amines defined by Formula XXIX below:

N
\~ R229 'N

8429 X ~N ~Y~Z w XXIX
wherein X is alkylene or alkenylene;
2o Y is -CO- or -CS;
z 15 NR629' '~629-CO-, -~629'S02-, OT NR729o R12~ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from:
-alkyl;
-alkenyl;

-aryl;
-heteroaryl;
-heterocyclyl;
-substituted cycloalkyl;
-substituted aryl;
-substituted heteroaryl;
-substituted heterocyclyl;
-O-alkyl;
-O-(alkyl)o_1-aryl;
to -O-(alkyl)o_1-(substituted aryl);
-O-(alkyl)o_1-heteroaryl;
-O-(alkyl)o_1-(substituted heteroaryl);
-O-(alkyl)o_1-heterocyclyl;
-O-(alkyl)o_1-(substituted heterocyclyl);
-COOH;
-CO-O-alkyl;
-CO-alkyl;
-S(O)o_z -alkyl;
-S(O)o_z-(alkyl)o_1-aryl;
-S(O)o_z-(alkyl)o_1-(substituted aryl);
-S(O)o_z -(alkyl)o_1-heteroaryl;
-S(O)o_z-(alkyl)o_1-(substituted heteroaryl);
-S(O)o_z-(alkyl)o_1-heterocyclyl;
-S(O)0_z-(alkyl)o_1-(substituted heterocyclyl);
-(alkyl)o_ 1-N(R6z~)z;
-(alkyl)o_l-NR6z~-CO-O-alkyl;
-(alkyl)o_I-NR6z~-CO-alkyl;
-(alkyl)o_1-NRsz9-CO-aryl;
-(alkyl)o_1-NR~z~-CO-(substituted aryl);
3o -(alkyl)o_1-NR6z~-CO-heteroaryl;

-(alkyl)o_1-NR6z~-CO-(substituted heteroaryl);
-P(O)(O-alkyl)z;
-Ns -halogen;
-haloalkyl;
-haloalkoxy;
-CO-haloalkyl;
-CO-haloalkoxy;
-NOz -CN;
-OH;
-SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo;
Rzz9 is selected from:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-alkyl-O-alkyl;
-alkyl-S-alkyl;
-alkyl-O-aryl;
-alkyl-S-aryl:
-alkyl-O- alkenyl;
-alkyl-S- allcenyl; and -alkyl or alkenyl substituted by one or more substituents selected from:
-OH;
-halogen;

-N(Rsz9)z;
-CO-N(Rsz9)z;
-CS-N(R6z9)z;
-SOZ-N(R629)z;
-NR6z9-CO-Ci-io alkyl;
-NR6z9-CS-C1_lo alkyl;
-NR6z9-SOz-C1_io alkyl;
-CO-C1_io alkyl;
-CO-O-C1_io alkyl;
i o -N3;
-ar'Yl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-CO-aryl;
-CO-(substituted aryl);
-CO-heteroaryl; and -CO-(substituted heteroaryl);
R3z9 and R4z~ are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio;
8529 1S H or C1_lo alkyl, or Rsz~ can join with X to form a ring that contains one or two heteroatoms;
each R6z~ is independently H or C1_ioalkyl;
R7z9 is H or C1_to alkyl which may be interrupted by a heteroatom; or when Rlz9 is alkyl, R7z~ and Rlz~ can join to form a ring;
and pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound can be chosen from 1-position ether or thioether substituted 1H imidazo[4,5-c]pyridin-4-amines defined by Formula XXX
below:
NHS
N ~ N
\~ R230 N
8330 ~ _ W-R~3o wherein:
1 o X is -CH(R53o)-, -CH(R53o)-alkylene-, -CH(R53o)-alkenylene-, or CH(R53o)-alkylene-Y-alkylene-;
Y is -O-, or -S(O)o_z-;
-W-Ri3o is selected from -O-Rl3o_i_s and -S(O)o_2-8130-6~
Ri3o-i-s is selected from -RG3o-C(R73o) Z Rs3o-alkyl;
-8630-C(R730) Z-Rs3o-alkenyl;
-RG30-~(R730)-z-8830-~yl, -8630-C(R730)-z-8830 heteroaryl;
-8630-C(R730)-z-8830 heterocyclyl;
-RG3o-C(R73o)-z-H;
-8630 N(R93o)-C(R73o)-Ra3o-alkyl;
-RG3o-N(R93o)-C(R73o)-Ra3o-alkenyl;
-RG3o-N(R93o)-C(R73o)-Rs3o-aryl;
-8630 N(R93o)-C(R73o)-Rs3o-heteroaryl;
a5 -8630 N(R93o)-C(R73o)-Rs3o-heterocyclyl;
-8630 N(R93o)-C(R73o)-Rio3o;
'R630 N(R93o)-S02-Rs3o-alkyl;

-RG30 N(R93o)-SOz Rs3o-alkenyl;
-8630 N(R930)-S~2-R830-~ylo -Rs3o-N(R93o)-SOz-R83o-heteroaryl;
-8630-N(R93o)-SOz-Rs3o-heterocyclyl;
-8630 N(R930)-S~2 R1030, -Rs3o-N(R93o)-SOz-N(Rs3o)-Rs3o-alkyl;
-Rs3o-N(R93o)-SOz-N(Rs3o)-Rs3o-alkenyl;
-Rs3o-N(R93o)-SOz-N(Rs3o)-Rs3o-aryl;
-R63o-N(R93o)-SOz-N(Rs3o)-Ra3o-heteroaryl;
1 o -Rs3o-N(R93o)-SOz-N(Rs3o)-Rs3o-heterocyclyl;
'R630-N(R930)-s~2-NH2;
-Rs3o-N(R93o)-~(R73o)-N(Rs3oyQ-R83o-alkyl;
-8630 N(R93o~C(R73o)-N(Rs3o)-Q-Rs3o-alkenyl;
-Rs3o-N(R93o)-C(R73o)-N(Rs3o~Q-Ra3o-aryl -Rs3o-N(R93o)- C(R73o)-N(Rs3o)-Q-Rs3o-heteroaryl;
-Rs3o-N(R93o)- C(R73o)-N(Rs3o)-Q-Rs3o-heterocyclyl;
-Rs3o-N(R93o)-C(R73o~N(Rs3o)z;
n -Rs3o-N(R93o)-C(R73o)--8630 N(R93o)-C(R73o)-N(RI i3o)-Q-R83o-alkyl;
-Rs3o-N(R930)-C(R730~ N(Ri i3o)-Q-Rs3o-alkenyl;
-8630 N(R93o)-C(R73o)-N(Rn3o)-Q-Ra3o-~'Yl;
-Rs3o-N(R93o)- ~(R73o)-N(Ri iso~Q-R83o-heteroaryl;
-Rs3o-N(R93o)- C(R73o)-N(Ri i3o)-Q-Rs3o-heterocyclyl;
-Rs3o-N(R93o)- C(R73o)-N(Ri i3o)H;
-alkenyl;
-aryl;
-Rs3o-aryl;
-heteroaryl;
-heterocyclyl;

-RG30- heteroaryl; and 'R630 heterocyclyl;
Z is-N(Rsso)-, -O-, or -S-;
Q is a bond, -CO-, or -S02-;
A represents the atoms necessary to provide a 5- or 6-membered heterocyclic or heteroaromatic ring that contains up to three heteroatoms;
Rico-6 is selected from:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
-R63o-aryl;
-8630- heteroaryl; and -R63o-heterocyclyl;
each Rsso is independently hydrogen, C1-to alkyl, or CZ_lo alkenyl;
R6so is alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups;
R7s0 is =O or =S;
R83o is a bond, alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups;
8930 1S hydrogen, C1_lo alkyl, or arylalkyl; or R~3o can join together with any carbon atom of R63o to form a ring of the formula ~N
OH2~3-8 Rio3o is hydrogen or C1_lo alkyl; or R~3o and Rloso can join together to form a ring selected from N C(R73o) N S(O)2 and ;
Rn3o is C1_io alkyl; or R93o and Rl3o can join together to form a ring having the structure - N- C(R~so) N-(CHz)z_o Ria3o is CZ_7 alkylene which is straight chain or branched, wherein the branching does not prevent formation of the ring; and Ra3o, R33o and R43o are independently selected from hydrogen and non-interfering substitutents;
and pharmaceutically acceptable salts thereof.
to Illustrative non-interfering R23o substituents include:
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkylene-Y-alkyl;
-alkylene-Y- alkenyl;
-alkylene-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from 2o the group consisting of:
-OH;
-halogen;
-N(R530)2, -C(O)-C1_lo alkyl;
-C(O)-O-CI_lo alkyl;
-N3;

-aryl;
-heteroaryl;
-heterocyclyl;
-C(O)-aryl; and -C(O)-heteroaryl.
Illustrative non-interfering R3so and Rq3o substitutents include:
C1_lo alkyl, Cz_lo alkenyl, Cz_lo alkynyl, CI-to alkoxy, C1_to alkylthio, amino, alkylamino, dialkylamino, halogen, and nitro.
In another embodiment, the IRM compound can be chosen from 1H imidazo to dimers of the formula (XXXI):
NHz NHz N ~ N N wN
I ~~ Rz31 Rz3~~

8431 ~ A ~ R431 XXXI
wherein:
A is a divalent linking group selected from the group consisting of straight or branched chain C4_zo alkylene;
straight or branched chain C4_zo alkenylene;
straight or branched chain C4_zo alkynylene; and _Z_Y_W_Y_Z_~
2o each Z is independently selected from the group consisting of:
straight or branched chain Cz_zo alkylene;
straight or branched chain C4_zo alkenylene; and straight or branched chain C4_zo alkynylene;
any of which may be optionally interrupted by -O-, -N(Rssi)-, or -S(O)z-;
each Y is independently selected from the group consisting of:
a bond;

-N(Rs3i)C(O)-;
-C(O)N(Rs3 i)-;
-N(Rssi)C(O)N(Rssi)-;
- N(Rs3 i)S(O)z-;
s -S(O)zN(Rs3i)-;
-OC(O)O-;
-OC(O)-;
-C(O)O-;
-N(Rs3i)C(O)O-; and to -OC(O)N(Rs31)-;
W is selected from the group consisting of straight or branched chain Cz_zo alkylene;
straight or branched chain Cz_zo alkenylene;
straight or branched chain C4_zo alkynylene;
15 straight or branched chain perfluoro Cz_zo alkylene;
C1~ alkylene-O-C1~ alkylene;
_C(0)_;
-S(O)z-;
-OC(O)O ;
20 -N(Rs3 i )C(O)N(Rs3 i )-;
/ ~~Ry 1,5-naphthylene;
25 2, 6-pyridinylene;

1,2-cyclohexylene;
1,3-cyclohexylene;
1,4-cyclohexylene;
traps-1,4-cyclohexylene;
;
and traps-5-norbornen-2,3-diyl;
wherein n is 0 - 4; each R is independently selected from the group consisting of C1_4 alkyl, C1~ alkoxy, and halogen; and Q is selected from the 1 o group consisting of a bond, -CH2-, and -O-;
8231 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-alkyl-X-alkyl;
-alkyl-X-aryl;
-alkyl-X- alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH;
-halogen;
-N~R631 ~2;
-C O~-N~R631~2a -C(S)-N(R631)a;
-S O)2-N(R~31)2, -N(Rs31)-C(C)-C1-to amyl;
-N(R631)-C(S)-C1-to alkyl;
-N(R631)- S(~)z-Cl-to alkyl;
-C(O)-C1_lo alkyl;
-C(O)-O-C1_lo alkyl;
-N3;
-aryl;
1 o -substituted aryl;
-heteroaryl;
-substituted heteroaryl;
-heterocyclyl;
-substituted heterocyclyl;
-C(O)-aryl;
-C(O)-(substituted aryl);
-C(O)-heteroaryl; and -C(O)-(substituted heteroaryl);
8331 and 8431 are each independently selected from the group consisting of:
-hydrogen;
-halogen;
-alkyl;
-alkenyl;
-X-alkyl; and -N(Rg31 )2;
or when taken together, 8331 and 8431 form a fused aryl or heteroaryl ring that is unsubstituted or substituted by one or more substituents selected from the group consisting of:
-halogen;
3o -alkyl;

-alkenyl;
-X-alkyl; and -N(Rg31)2, or when taken together, 8331 and 8431 form a fused 5 to 7 membered saturated ring, containing 0 to 2 heteroatoms and unsubstituted or substituted by one or more substituents selected from the group consisting of:
-halogen;
-alkyl;
l o -alkenyl;
-X-alkyl; and -N(R631)z~
each Rs31 is independently selected from the group consisting of hydrogen;
C1_6 alkyl;
C3_~ cycloalkyl; and benzyl; or when Y is N(Rs31)C(O)-, -C(O)N(Rs31)-, -N(Rs31)C(O)N(Rs31)-, -N(Rs31)S(O)z-, -S(Oz)N(Rs31)-, N(Rs31)C(O)O-, or -OC(O)N(Rs31)- and the nitrogen of the N(Rs31) group is bonded to Z, then Rs31 can join with Z to form a ring having the structure N-each 8631 is independently hydrogen or C1_lo alkyl;
8731 is C3_$ alkylene; and X is -O- or -S-;
with the proviso that if W is -C(O)-, -S(O)z-, -OC(O)O-, or -N(Rs31)C(O)N(Rs31)- then each Y is a bond;
and pharmaceutically acceptable salts thereof.

In another embodiment, the IRM compound can be chosen from 6-, 7-, 8-, or 9-position aryl or heteroaryl substituted 1H imidazo[4,5-c]quinolin-4-amines of the following Formula (XXXII):

N ~ N
N~z3z ~R3z~n XXXII
wherein:
R32 is selected from the group consisting of alkyl, alkoxy, hydroxy, and 1 o trifluoromethyl;
nis0orl;
8132 and 8232 are independently selected from the group consisting of hydrogen and non-interfering substitutents;
8332 is selected from the group consisting of:
-Z-Ar, 'z'Ar''~'R432~
'Z'Ar~'X'Y'R432, -Z-Ar'-R532, and -Z-Ar'-X-R53z;
2o Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;

Ar' is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, 1 o heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O-groups;
Y is selected from the group consisting of:
_S(O)o_z_~
-S(O)z-N(R83z)-, -C(~532)-, -C(Rs3z)-O-, -O-C(R632)' -O-C(O)-O-, -N(Rs3z)-Q--C(R632)-N(R832)-, -O-C(Rs3z)-N(Ra3z)--C(R63z)-N(OR93z)-, N-Q-~''~o3z - ~C~R632~ W
\\\ 873 ~2 - ~R73zyQ-R73 Jz -V-N

\ Rtos~z ~ and N -C(Rssz) - N

R ~ R

~osz aos2 Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;
R43~ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl to groups can be unsubstituted or substituted by one or more substituents independently .
selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
Rssa is selected from the group consisting of -N- C(R632) -N- S(C)z -V-N~(CHz)a A
R~sz R~sz ~ (CH~)b-~
> > >
~(CHZ)a 1 N C(Rsoz)-N A
l and 81032 (CH2)b each R6sa is independently selected from the group consisting of =O and =S;
2o each 8732 is independently C2_~ alkylene;
each 8832 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R~32 is selected from the group consisting of hydrogen and alkyl;

each Rlo3z is independently C3_8 alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(O)o_2-, -CH2-, and -N(R432)-, Q is selected from the group consisting of a bond, -C(R632)-, -C(R632)-C(R632y -S(~)2-~ -C(R63z)-N(Rs3z)-W-~ -s(~)2-N(R832)' -C(R632)-O-~
and -C(R632)-N(~R932)-a V is selected from the group consisting of -C(R632)-, -O-C(R632)-, -N(Rs3z)-C(R632)-~ arid -S(O)2-i W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and 1 o a and b are independently integers from 1 to 6 with the proviso that a + b is ~ 7;
and pharmaceutically acceptable salts thereof.
Illustrative non-interfering 8132 substituents include:
-8432, -X-8432, 15 -X-Y-R43z, -X-Y-X-Y-8432, and -X-8532;
wherein:
each X is independently selected from the group consisting of alkylene, 2o alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups;
each Y is independently selected from the group consisting of:
2s -S(O)o_2-, -S(O)2-N(R83z)-, -C(R632)' -C(Rs3z)-O-~
-O-C(RS32)-, 30 -O-C(O)-O-, -N(Ra32)-Q-, -C(R632)-N(R832)', -~-C(R63z)-N(Rs3z)-, -C(R632)-N(~R932)-, N-Q -Rlo3z , -N-C(R63z) --N-W
~

R~3 z , -N-8732 ~-Q-//

R~3 z , -V-N

~ R1o32 ~
and N -C(R632) - N

81032 ~ 8103 , 1o Rd32 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, allcylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl 15 groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and 2o heterocyclyl, oxo;
Rs32 is selected from the group consisting of:

-N-C(Rss2) -N-S(O)S -V_N~(CHZ)a C , A
R~s2 R~sz ~ (CHZ)b~
a a a ~(CH~)a N C(Rssz)-N A
l and 81032 ~(CH2)b -~
a each 8632 is independently selected from the group consisting of =O and =S;
each 8732 is independently C2_7 alkylene;
each 8832 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
each 8932 is independently selected from the group consisting of hydrogen and alkyl;
each R1o32 is independently C3_8 alkylene;
1 o A is selected from the group consisting of -O-, -C(O)-, -S(O)o_2-, -CH2-, and -N(R432)-, each Q is independently selected from the group consisting of a bond, -C(RG32)-a -C(~32)-C~R632)-a -S(~)2-a -~(R632)-N(R832)-W-a -S(0)2-N(R832)-a -C(R632)-O-a and -C(R632)-N(OR932)-;
each V is independently selected from the group consisting Of -C(R632)-a -O-C(R632)-a -N(R832)-C(R632)-a and -S(O)2-i each W is independently selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
2o Illustrative non-interfering R23z substitutents include:
-8432, -X-Rø32a -X-Y-R432a and -X-R53z;
wherein:

X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O-groups;
Y is selected from the group consisting o~
_S(O)o_2_~
-S(~)2-N(R832)-~
-~(R632)-, -C(R632)-O-, -O-C(R632)-, -O-C(O)-O-, -N(R832)-Q-, -C(Rs3z)-N(Ra32)-, -O-C(Rg32)-N(R832)-, -C(R63z)-N(OR~32)-, N-Q -l s - ~C~Rs32~ -W-873 ~2 \ R73z -V-N
~ Rio32 ~ and N -C(R63z) -N
81032 ~ 81032 s 8l 8432 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, to dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
Rs32 is selected from the group consisting of:
-N- C'(R632) -N- S(C)2 -V-N~ (CH2)a A
8732 8732 ~ ( C H 2 )b > > >
~(CH2)a C(Rs32)-n1 A
J
and R~o32 ~(CH2)b --~ .
each 8632 is independently selected from the group consisting of =O and =S;
each 8732 is independently C2_7 alkylene;
each 8832 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
R~32 is selected from the group consisting of hydrogen and alkyl;
2o each Rlo3z is independently C3_$ alkylene;
A is selected from the group consisting of -O-, -C(O)-, -S(O)o_2-, -CH2-, and -N(R432)-~
Q is selected from the group consisting of a bond, -C(R632)-, -C(R632)-C(R632)' -S(~)2-~ -~(R632)-N(Rs32)-W-~ -S(~)2-N(Rs32)-~ -C(R632)-On and -C(R632)-N(OR932)-~
V is selected from the group consisting of -C(R632)-, -O-C(R63z)-, -N(Ra3z)-C(R632)-~ and -S(O)2-W is selected from the group consisting of a bond, -C(O)-, and -S(O)Z-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
Herein, "non-interfering" means that the ability of the compound or salt to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substituent.
As used herein, the terms "alkyl", "alkenyl", "alkynyl" and the prefix "alk-"
are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e.
1 o cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms.
Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
Unless otherwise specified, "alkylene", "alkenylene", and "alkynylene°' are the divalent forms of the "alkyl", "alkenyl", and "alkynyl" groups defined above.
For 2o example, an arylalkenyl group comprises an alkylene moiety to which an aryl group is attached.
The term "haloalkyl" is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix "halo-". Examples of suitable haloalkyl groups are 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, and indenyl.
The term "hetero atom" refers to the atoms O, S, or N.

The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring hetero atom. Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1 oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom and includes all of the fully saturated and partially 1 o unsaturated derivatives of the above mentioned heteroaryl groups.
Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent 15. forms of the "aryl," "heteroaryl,°' and "heterocyclyl" groups defined above. Likewise, "arylenyl," "heteroarylenyl," and "heterocyclylenyl" are the divalent forms of the "aryl,"
"heteroaryl," and "heterocyclyl" groups defined above. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
Unless otherwise specified, the aryl, heteroaryl, and heterocyclyl groups of 2o Formulas IX - XXX can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, 25 alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio, aroylamino, 3o alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, to heteroarylalkylaminocarbonylamino and, in the case of heterocyclyl, oxo. If any other groups are identified as being "substituted" or "optionally substituted", then those groups can also be substituted by one or more of the above enumerated substituents.
The IRM compounds and salts thereof described herein include any of their pharmaceutically acceptable forms, such as isomers (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes the use of each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
In some embodiments, the topical formulations of the present invention are 2o prepared using the free base form of the IRM compound.
In certain embodiments, the IRM is an imidazonaphthyridine amine. In other embodiments, the IRM is 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c] [1,5]naphthyridin-4-amine.
The amount of an IRM compound that will be therapeutically effective in a specific situation will depend on such things as the activity of the particular compound, the dosing regimen, the application site, the particular formulation and the condition being treated. As such, it is generally not practical to identify specific administration amounts herein; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to these compounds, and routine testing. The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, inhibition of TH2 immune response, antiviral or antitumor activity, reduction or elimination of postsurgical scarring, reduction or resolution of actinic keratosis or pre-actinic keratosis lesions, reduction in the recurrence of actinic keratosis, or protection against uv-induced epidermal neoplasia, or as an adjuvant for therapeutic and prophylactic vaccines, including DNA, whole cell, protein subunit, attenuated virus, and all other vaccines, where the formulation may be applied before, during and/or after vaccine delivery.
In general, the amount of the IRM compound present in a topical formulation of 1 o the invention will be an amount effective to treat a targeted condition, to prevent recurrence of the condition, or to promote immunity against the condition. In certain embodiments, the amount or concentration of the IRM compound is at least 0.0001% by weight, such as, for example, at least 0.001%, at least 0.003%, at least 0.005%, at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.25%, at least 0.27%, at i5 least 0.30%, and at least 1.0%, by weight based on the total weight of the formulation.
In other embodiments, the amount of the IRM compound is at most 10% by weight, such as, for example, at most 5.0%, at most 3.0%, at most 1.0%, at most 0.5%, at most 0.4%, at most 0.35%, at most 0.33%, and at most 0.3%, by weight based on the total weight of the formulation.
Preservative System The formulation includes a preservative system. The preservative system includes one or more compounds that inhibit microbial growth (e.g., fungal and bacterial growth) within the formulation (for example, during manufacturing and use).
The preservative system includes at least one preservative compound chosen from sorbic acid, esters or salts thereof, such as, for example, isopropyl sorbate, calcium sorbate, potassium sorbate, sodium sorbate, and triethanolammonium sorbate.
Combinations of these may be used in formulations of the present invention.
Such preservatives adversely affect the stability of the formulations as described herein.

According to the present invention, the sorbic acid preservative (i.e., sorbic acid, esters or salts thereof, or combinations thereof) is preferably present in a formulation in an amount of at least 0.005% by weight, more preferably at least 0.01% by weight, even more preferably at least 0.02% by weight, even more preferably at least 0.05%
by weight, and even more preferably at least 0.08% by weight, based on the total weight of the formulation. The sorbic acid preservative is preferably present in a formulation in an amount of no greater than 1 % by weight, more preferably no greater than 0.5% by weight, even more preferably no greater than 0.2% by weight, even more preferably no greater than 0.12% by weight, and even more preferably, no greater than 0.10%
by to weight, based on the total weight of the formulation.
In certain embodiments, in addition to the sorbic acid preservative, the preservative system will generally include at least one additional (i.e., secondary) preservative compound, such as, for example, methylparaben, ethylparaben, propylparaben, butylparaben, and phenoxyethanol. Various combinations of these 15 compounds can be included in the preservative system. In some embodiments of the invention, the secondary preservative compound is methylparaben.
In some embodiments of the invention, the secondary preservative compound is present in an amount of at least 0.01% by weight, such as for example, at least 0.02%, at least 0.03%, at least 0.04%, and at least 0.05%, by weight based on the total weight of 2o the formulation. In other embodiments of the invention the secondary preservative compound is present in an amount of at most 0.5 %, such as for example, at most 0.4%, at most 0.3%, and at most 0.2%, by weight based on the total weight of the formulation.
The preservative system may also include a preservative enhancing solubilizer which enhances the solubility of the preservative in the aqueous phase, examples of 25 which include diethylene glycol monoethyl ether, propylene glycol, and polyethylene glycol)(4) monolaurate. Combinations of such enhancing solubilizers can be used in formulations of the present invention.
In some embodiments of the present invention, propylene glycol is present in an amount of at least 1.0% by weight, such as for example, at least 2.0%, at least 3.0%, at 30 least 4.0%, and at least 5.0%, by weight based on the total weight of the formulation. In other embodiments of the present invention, propylene glycol is present in at most 10.0% by weight, such as for example, at most 8.0%, at most 6.0%, and at most 5.0%, by weight based on the total weight of the formulation.
Antioxidants Surprisingly, it has been discovered that the stability issue of the IRM/sorbic acid preservative combination can be addressed through the addition of one or more antioxidants. Antioxidants suitable for use herein are those that inhibit the autoxidation of the sorbic acid preservative. In particular, antioxidants having hydrogen atom 1 o donating functionality have demonstrated much greater improvement than others.
Although not intending to be limiting, it is believed that antioxidants react with autoxidation intermediates (typically, radicals) of the sorbic acid preservative to form products that do not react with the IRM.
Suitable antioxidants are those that are pharmaceutically acceptable and 15 described in the International Cosmetic Ingredient Dictionary and Handbook, Ninth Edition, Volume 4, 2002, and in the USP NF 2004: The United States Pharmacopeia, 27th Revision and The National Formulary, 22"d Edition.
Examples of suitable antioxidants include ascorbic acid (D and/or L
enantiomers), ascorbyl palmitate (D and/or L enantiomers), butylated hydroxyanisole 20 (BHA), butylated hydroxytoluene (BHT), cysteine (D and/or L enantiomers), propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, including all of its stereoisomers, and tocopherol polyethylene glycol 1000 succinate, including all of its stereoisomers.
Preferred antioxidants are those containing hydrogen atom donating functional 25 groups. Examples of such antioxidants include ascorbic acid, ascorbyl palmitate, BHT, BHA, cysteine, propyl gallate, sodium formaldehyde sulfoxylate, tocopherol including all of its stereoisomers, and tocopherol polyethylene glycol 1000 succinate, including all of its stereoisomers.
More preferred antioxidants are those containing aromatic hydroxy groups 30 capable of hydrogen atom donation. Examples of such antioxidants include BHA, 8s BHT, propyl gallate, tocopherol, including all of its stereoisomers, and tocopherol polyethylene glycol 1000 succinate, including all of its stereoisomers.
Most preferred antioxidants are BHA and BHT, which can be used in combination.
According to the present invention, the antioxidant is preferably present in a formulation in an amount of at least 0.001% by weight, more preferably at least 0.005%
by weight, even more preferably at least 0.008% by weight, and even more preferably at least 0.01 % by weight, based on the total weight of the formulation. The antioxidant is preferably present in a formulation in an amount of no greater than 0.3% by weight, 1 o more preferably no greater than 0.2% by weight, and even more preferably no greater than 0.012% by weight, and even more preferably no greater than 0.1 % by weight, based on the total weight of the formulation.
According to the present invention, the sorbic acid preservative (i.e., sorbic acid/esterlsalt) to antioxidant weight ratio is preferably at least 1:20, more preferably at 15 least 1:l, and even more preferably at least 5:1. The sorbic acid to antioxidant weight ratio is preferably no greater than 1000:1, more preferably no greater than 20:1, and even more preferably no greater than 10:1.
Chelating Agents 2o In certain embodiments of the present invention, the formulation can also include at least one chelating agent. The chelating agent functions to stabilize the antioxidants) present in the formulation.
Chelating agents are compounds that complex with metal ions. Suitable chelating agents are those that are pharmaceutically acceptable and described in the 25 International Cosmetic Ingredient Dictionary and Handbook, Ninth Edition, Volume 4, 2002.
Suitable chelating agents include ethylenediaminetetraacetic acid (EDTA) and citric acid, hydrates thereof, salts thereof, and hydrates of the salts thereof. Examples of such chelating agents include ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid disodium salt dehydrate, and citric acid monohydrate.
Various combinations of chelating agents can be used if desired.
According to the present invention, if included, the chelating agent is preferably present in a formulation in an amount of at least 0.001% by weight, more preferably at least 0.005% by weight, even more preferably at least 0.01% by weight, and even more preferably at least 0.05% by weight, based on the total weight of the formulation. The chelating agent is preferably present in a formulation in an amount of no greater than 0.2% by weight, and more preferably no greater than 0.1 % by weight, based on the total weight of the formulation.
to According to the present invention, if included, the antioxidant to chelating agent weight ratio is preferably at least 1:200, more preferably at least 1:10, and even more preferably at least 1:5. The antioxidant to chelating agent weight ratio is preferably no greater than 300:1, more preferably no greater than 10:1, and even more preferably no greater than 2:1.
Fatty Acids The topical formulations of the invention can additionally include a fatty acid.
As used herein, the term "fatty acid" means a carboxylic acid, either saturated or unsaturated having 6 to 28 carbon atoms, such as, for example, from 10 to 22 carbon 2o atoms. Non-limiting examples of such fatty acids include isostearic acid, oleic acid, and linear- or branched-chain carboxylic acids of 6 to 18 carbon atoms.
The fatty acid may be present in the formulation in an amount sufficient to solubilize the IRM compound. In certain embodiments, the amount of the fatty acid is at least 0.05% by weight, at least 1.0% by weight, at least 3.0% by weight, at least 5.0%
by weight, at least 6.0% by weight, at least 7.0% by weight, at least 10% by weight, at least 15% by weight, or at least 25% by weight, based on the total weight of the formulation. In certain embodiments, the amount of the fatty acid is at most 40% by weight, at most 30% by weight, at most 15% by weight, at most 10% by weight, or at most 8.0% by weight based on the total weight of the formulation. The fatty acid 3o component of the formulation can comprise one or more fatty acids.

Hydrophobic Component The topical formulations of the invention can additionally include at least one hydrophobic, aprotic component miscible with the fatty acid and comprising a hydrocarbyl group of 7 or more carbon atoms. By "hydrophobic" is meant that the component is essentially insoluble in water, i.e. immiscible with water and unable to form a micelle in water, and does not contain polyoxyethylene or acid salt groups.
Preferably the hydrophobic, aprotic component has a hydrophilic lipophilic balance (HLB) of less than 2. The HLB of a component may be determined as described, for to example, in Attwood, D., Florence, A. T. Surfactant Systems: Their Chemistry, Pharmacy, and Biology; New York: Chapman & Hall, 471-473, 1983. By "aprotic"
is meant that the component cannot donate a proton to the IRM and does not contain groups such as carboxyl, hydroxy, primary and secondary amino, primary and secondary amido, or quaternary ammonium groups. Preferably this component has a 15 pKa of at least 14.2 and does not substantially solubilize or form a complex such as an acid-base pair or complex or a hydrogen bond complex with the IRM compound. By "not substantially" is meant that the ratio of the IRM compound's solubility in the hydrophilic, aprotic component to that in isostearic acid is less than 1:40.
Formulations intended for dermal or topical use typically have amounts of an oil 2o phase and a hydrophobic, aprotic component sufficient to provide desirable qualities such as spreadability and feel.
Examples of useful hydrophobic, aprotic components include but are not limited to fatty acid esters, for example, isopropyl mysristate, isopropyl palmitate, diisopropyl dimer dilinoleate; medium-chain (e.g., 8 to 14 carbon atoms) triglycerides, for example, 25 caprylic/capric triglyceride; cetyl esters; hydrocarbons of 8 or more carbon atoms, for example, light mineral oil, white petrolatum; and waxes, for example, beeswax.
In some embodiments, the hydrophobic, aprotic component is chosen from one or more of isopropyl mysristate, isopropyl palmitate, caprylic/capric triglyceride, and diisopropyl dimer dilinoleate. Various combinations of such hydrophobic, aprotic components can 30 be used if desired.

In certain embodiments, the amount of the hydrophobic, aprotic component is at least 1.0% by weight, at least 3.0% by weight, at least 3.5% by weight, at least 4.0% by weight, at least 4.5% by weight, at least 5.0% by weight, or at least 10% by weight, based on the total weight of the formulation. In certain embodiments, the amount of the hydrophobic, aprotic component is at most 30% by weight, at most 15% by weight, at most 10% by weight, or at most 5.0% by weight based on the total weight of the formulation.
The weight ratio of the hydrophobic, aprotic component to the fatty acid can be 0.025:1 to 600:1, for example, 0.5:1 to 50:1, and 2:1 to 30:1. The combined amount to (weight percent of the total topical formulation weight) of the hydrophobic, aprotic component and the fatty acid can be 2% to 50% by weight, for example 2% to 30%, 5%
to 30%, 5% to 20%, and 10% to 20%.
Viscosity Enhancing Agent The formulations of the present invention can also comprise a viscosity enhancing agent. When water is the continuous phase, the viscosity enhancing agent will be a hydrophilic viscosity enhancing agent. Examples of suitable hydrophilic viscosity enhancing agents include cellulose ethers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and 2o carboxymethylcellulose; polysaccharide gums such as xanthan gum; and homopolymers and copolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythriol such as those polymers designated as carbomers in the United States Pharmacopoeia.
Suitable carbomers include, for example, those available as CARBOPOL 934P, CARBOPOL 971P, CARBOPOL 940, CARBOPOL 974P, CARBOPOL 980, and PEMLTLEN TR-1 (USP/NF Monograph; Carbomer 1342), all available from Noveon, Cleveland, Ohio. In one embodiment of the present invention, the viscosity enhancing agent is chosen from CARBOPOL 974P and 980.
In certain embodiments, the amount of the viscosity enhancing agent, when used, is at least 0.1% by weight, at least 0.2% by weight, at least 0.5% by weight, at least 0.6% by weight, at least 0.7% by weight, at least 0.9% by weight, or at least 1.0%

by weight, based on the total weight of the formulation. In certain embodiments, the amount of the viscosity enhancing agent, when used, is at most 10% by weight, at most 5.0% by weight, at most 3.0% by weight, at most 2.0% by weight, or at most 1.5% by weight, based on the total weight of the formulation.
Emulsifier The formulations of the invention can additionally comprise an emulsifier.
Suitable emulsifiers include non-ionic surfactants such as, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4 oleate, polyoxyethylene(4) lauryl ether, etc. In 1 o certain embodiments, the emulsifier is chosen from poloxamers (e.g., PLURONIC F68, also known as POLOXA1VIER 188, a polyethylene glycol)-block-polypropylene glycol)-block-polyethylene glycol), available from BASF, Ludwigshafen, Germany) and sorbitan trioleate (e.g., SPAN 85 available from Uniqema, New Castle, DE).
If included, the emulsifier is generally present in an amount of 0.1 % to 10%
by 15 weight of total formulation weight, for example, from 0.5% to 5.0% by weight, and from 0.75% to 3.5% by weight. In certain embodiments, the amount of the emulsifier, if used, is present in an amount of at least 0.1% by weight, at least 0.5% by weight, at least 0.75% by weight, at least 1.0% by weight, at least 2.5% by weight, at least 3.5%
by weight, or at least 5.0% by weight, based on the total weight of the formulation. In 2o certain embodiments, the amount of the emulsifier, if used, is present in an amount of at most 10% by weight, at most 5.0% by weight, or at most 3.5% by weight, based on the total weight of the formulation.
pH Adjuster 25 The formulations of the present invention may additionally include at least one pH adjuster. Suitable pH adjusters include organic bases and inorganic bases such as, for example, KOH and NaOH (e.g., aqueous formulations). The pH of the topical formulations of the present invention generally ranges from 3.5 to 7Ø In one embodiment, the pH of the topical formulations of the present invention can range from 30 4.0 to 6.0, preferably 5Ø

Illustrative Formulations Preferred formulations of the present invention are as follows. The water used is typically purified water.
In one embodiment of the present invention, a pharmaceutical formulation includes:
0.001% by weight to 5.0% by weight of an imidazonaphthyridine amine (preferably, 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c][1,5]naphthyridin-4-l0 amine);
0.02% by weight to 0.2% by weight of a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
0 to 10.0% by weight of propylene glycol;
15 0.05% by weight to 0.2% by weight of methylparaben;
0.001% by weight to 0.2% by weight of butylated hydroxyanisole, butylated hydroxytoluene, or combinations thereof;
0 to 0.1 % by weight of ethylenediaminetetraacetic acid, a hydrate thereof, a salt thereof, a hydrate of a the salt thereof, or combinations thereof;
20 1 % by weight to 30% by weight of isostearic acid;
1% by weight to 15% by weight of a medium-chain triglyceride;
0.2% by weight to 2.0% by weight of a carbomer;
0.1 % by weight to 6.0% by weight of a poloxamer; and water;
25 wherein the formulation has a pH of 4.0 to 6.0 and the weight percentages are based on the total weight of the formulation.
In one embodiment, a pharmaceutical formulation includes:
0.3% by weight of 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-30 c][1,5]naphthyridin-4-amine;

0.15% by weight sorbic acid;
5.0% by weight propylene glycol;
0.2% by weight methylparaben;
0.1% by weight butylated hydroxyanisole;
0.05% by weight ethylenediaminetetraacetic acid disodium salt dihydrate;
7.0% by weight isostearic acid;
4.0% by weight of caprylic/capric triglyceride;
1.0% by weight of a carbomer;

3.5% by weight of a poloxamer;
l0 0.8% by weight of an aqueous solution of 20% by weight NaOH in water; and 77.9% by weight water;
wherein the weight percentages are based on the total weight of the formulation.
In one embodiment, a pharmaceutical formulation includes:
0.30% by weight of 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c] [ 1,5]naphthyridin-4-amine;
0.10% by weight sorbic acid;
5.00% by weight propylene glycol;
0.20% by weight methylparaben;
0.01 % by weight butylated hydroxyanisole;
0.05% by weight ethylenediaminetetraacetic acid disodium salt dihydrate;
7.00% by weight isostearic acid;

4.00% by weight of caprylic/capric triglyceride;
1.00% by weight of a carbomer;
3.50% by weight of a poloxamer;
0.80% by weight of an aqueous solution of 20% by weight NaOH in water; and 78.04% by weight water;
wherein the weight percentages are based on the total weight of the formulation.
3o In one embodiment, a pharmaceutical formulation includes:

0.3% by weight of 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c] [1,5]naphthyridin-4-amine;
0.1 % by weight sorbic acid;

5.0% by weight propylene glycol;
0.2% by weight methylparaben;
0.01 % by weight butylated hydroxyanisole;
0.05% by weight ethylenediaminetetraacetic acid disodium salt dihydrate;
7.0% by weight isostearic acid;
4.0% by weight of caprylic/capric triglyceride;
1o 1.0% by weight of a carbomer;
3.5% by weight of a poloxamer;
0.8% by weight of an aqueous solution of 20% by weight NaOH in water; and 78.0% by weight water;
wherein the weight percentages are based on the total weight of the formulation.
In one embodiment, a pharmaceutical formulation includes:
0.03% by weight of 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c] [ 1,5]naphthyridin-4-amine;
0.15% by weight sorbic acid;
5.0% by weight propylene glycol;
0.2% by weight methylparaben;
0.1 % by weight butylated hydroxyanisole;
0.05% by weight ethylenediaminetetraacetic acid disodium salt dihydrate;
5.0% by weight isostearic acid;
4.0% by weight of caprylic/capric triglyceride;
1.0% by weight of a carbomer;
3.5% by weight of a poloxamer;
0.8% by weight of an aqueous solution of 20% by weight NaOH in water; and 80.17% by weight water;
3o wherein the weight percentages are based on the total weight of the formulation.

In one embodiment, a pharmaceutical formulation includes:
0.1% by weight of 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c] [ 1,5]naphthyridin-4-amine;
0.15% by weight sorbic acid;
5.0% by weight propylene glycol;
0.2% by weight methylparaben;
0.1 % by weight butylated hydroxyanisole;
0.05% by weight ethylenediaminetetraacetic acid disodium salt dihydrate;
l0 5.0% by weight isostearic acid;
4.0% by weight of caprylic/capric triglyceride;
1.0% by weight of a carbomer;
3.5% by weight of a poloxamer;
0.8% by weight of an aqueous solution of 20% by weight NaOH in water; and 80.1 % by weight water;
wherein the weight percentages are based on the total weight of the formulation.
Methods of Application Formulations according to the present invention can be applied to any suitable location, for example topically to dermal and/or mucosal surfaces, or internally to a particular tissue location. In the case of dermal application, for example, depending on the IRM compound concentration, formulation composition, and dermal surface, the therapeutic effect of the IRM compound may extend only to the superficial layers of the dermal surface or to tissues below the dermal surface. Thus, another aspect of the present invention is directed to a method for the treatment of a dermal and/or mucosal associated condition comprising applying to skin one of the foregoing formulations. As used herein, a "dermal and/or mucosal associated condition" means an inflammatory, infectious, neoplastic or other condition that involves a dermal and/or mucosal surface or that is in sufficient proximity to a dermal and/or mucosal surface to be affected by a therapeutic agent topically applied to the surface. Examples of a dermal and/or mucosal associated condition include warts, atopic dermatitis, postsurgical scars, lesions caused by a herpes virus, and epidermal neoplasias, such as for example actinic keratosis, pre-actinic keratosis lesions, malignant melanomas, basal cell carcinoma, and squamous cell carcinoma.
In one embodiment, the formulations can be applied to the surface of skin for treatment of actinic keratosis (AK). Actinic keratoses are premalignant lesions considered biologically to be either carcinoma in-situ or squamous intraepidermal neoplasia. AK is the most frequent epidermal tumor and is induced by ultraviolet (UV) radiation, typically from sunlight. Because of its precancerous nature, AK may be 1o considered the most important manifestation of sun-induced skin damage.
In some embodiments, the above described formulations are particularly advantageous for dermal and/or mucosal application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absorption of the IRM.
The precise amount of formulation effective for treating a dermal and/or mucosal associated condition will vary according to factors known in the art including but not limited to the particular IRM compound, the particular formulation, the intended dosing regimen, the particular condition being treated, the state of the subject's immune system (e.g., suppressed, compromised, stimulated), and the species to which the formulation is being administered. In some embodiments the amount of formulation is 2o an amount sufficient to deliver a dose of about 0.02 mg to about 15 mg of IRM
compound. In other embodiments the amount of formulation is an amount sufficient to deliver a dose of about 0.2 mg to about 2.5 mg of IRM compound. In other embodiments the amount of formulation is an amount sufficient to deliver a dose of about 0.5 mg to about 1.7 mg of IRM compound. In one particular embodiment a dose of 0.75 mg of IRM compound is delivered. In another particular embodiment a dose of 1.5 mg of IRM compound is delivered.
The dosing regimen will vary at least in part on many factors known in the art including but not limited to the particular IRM compound, the particular formulation, the amount of formulation being administered, the particular condition being treated, the state of the subject's immune system (e.g., suppressed, compromised, stimulated), and the species to which the formulation is being administered. In some embodiments the formulation is administered at least once a week, at least twice a week, or at least three times a week. In other embodiments the formulation is administered at most seven times a week, at most six times a week, at most five times a week, or at most four times a week. In some embodiments the formulation is administered for at least two weeks, for at least four weeks, for at least six weeks, or for at least eight weeks. In other embodiments the formulation is administered for at most sixteen weeks, for at most twelve weeks, or for at most eight weeks. In some embodiments, about 200 to about 600 mg of formulation is administered twice a week for eight weeks. In one to particular embodiment, about 250 mg of the formulation described in Example below is administered twice a week for eight weeks. In another particular embodiment, about 500 mg of the formulation described in Example 22 below is administered twice a week for eight weeks.
EXAMPLES
The following Examples are provided to further describe various IRM
formulations and methods according to the invention. The examples, however, are not intended to lunit the formulations and methods within the spirit and scope of the invention.
TEST METHODS
Test Method 1- IRM 1 Compound Content and Sorbic Acid Content A gradient reversed phase high performance liquid chromatography (HPLC) method was used to determine the amount of 2-methyl-1-(2-methylpropyl)-lII
imidazo[4,5-c][1,5]naphthyridin-4-amine (IRM Compound 1) and sorbic acid in cream formulations.
HPLC parameters: Analytical column: ZORBAX RX-C8, 5.0 micron particle, 150 x 4.6 mm (available from Agilent Technologies, Wilmington, Delaware, USA);
Column temperature: 30°C; Detector: UV at 254 nm; Flow Rate:,1.0 mL/min; Injection volume: 25 ~,L; Mobile phase A: 62% aqueous (0.2% sodium 1-octanesulfonate, 0.2%
triethylamine, 0.2% of 85% phosphoric acid), 21% acetonitrile, 17% methanol;
Mobile Phase B: 20% aqueous (0.2% sodium 1-octanesulfonate, 0.2% triethylamine, 0.2%
of 85% phosphoric acid), 42% acetonitrile, 38% methanol; Data acquisition time:

minutes; HPLC run time: approximately 30 minutes.
Gradient program: 0 minutes: 100% mobile phase A, 0% mobile phase B; 2.5 minutes: 100% mobile phase A, 0% mobile phase B; 10 minutes: 49% mobile phase A, 51 % mobile phase B; 14 minutes: 49% mobile phase A, 51 % mobile phase B; 20 minutes: 0% mobile phase A, 100% mobile phase B; 23 minutes: 0% mobile phase A, l0 100% mobile phase B; 25 minutes: 100% mobile phase A, 0% mobile phase B; 30 minutes: 100% mobile phase A, 0% mobile phase B.
IRM Compound 1 sample solution: A portion of the cream formulation (1000 mg for creams containing 0.01, 0.03, 0.05 and 0.1% IRM and 250 mg for creams containing 0.3, 0.6, and 1.0% IRM) was accurately weighed into a volumetric flask (50 15 mL for the 1000 mg samples and 100 mL for the 250 mg samples).
Approximately 40 mL of diluent (prepared by combing 200 parts of acetonitrile, 790 parts water, and 10 parts phosphoric acid, all parts by volume) was added to the 50 mL flask or 80 mL to the 100 mL flask. The flask was sonicated with occasional shaking for 20 minutes or until the cream was completely dispersed. The solution was allowed to cool to ambient 2o temperature and then diluted to volume with diluent. A portion of the solution was filtered using a syringe equipped with a 0.2 micron PTFE filter to provide the sample solution.
Sorbic acid sample solution: A 250 mg portion of cream was accurately weighed into a 100 mL volumetric flask. Approximately 80 mL of diluent (prepared by combing 25 200 parts of acetonitrile, 790 parts water, and 10 parts phosphoric acid, all parts by volume) was added to the flask. The flask was sonicated with occasional shaking for 20 minutes or until the cream was completely dispersed. The solution was allowed to cool to ambient temperature and then diluted to volume with diluent. A portion of the solution was filtered using a syringe equipped with a 0.2 micron PTFE filter to provide 3o the sample solution.
loo Test Method 2 - BHA Content A gradient reversed phase high performance liquid chromatography (HPLC) method was used to determine the amount of BHA in cream formulations containing IRM Compound 1.
HPLC parameters: Analytical column: ZORBAX Bonus RP, 3.5 micron particle, 150 x 3.0 mm; Column temperature: 40°C; Detector: UV at 290 nm; Flow Rate: 0.5 mLlmin; Injection volume: 20 ~L; Mobile phase A: 0.1% formic acid in water;
Mobile Phase B: 0.05% formic acid in acetonitrile; Data acquisition time: 12 minutes;
HPLC
l0 run time: approximately 20 minutes.
Gradient program: 0 minutes: 60% mobile phase A, 40% mobile phase B; 10 minutes: 5% mobile phase A, 95% mobile phase B; 12 minutes: 5% mobile phase A, 95% mobile phase B; 13 minutes: 60% mobile phase A, 40% mobile phase B; 20 minutes: 60% mobile phase A, 40% mobile phase B.
15 Sample solution: A portion (approximately 1000 mg) of the cream formulation was accurately weighed into a 100 mL volumetric flask. Approximately 80 mL of diluent (prepared by combining 600 parts of acetonitrile, 400 parts of water, and 1 part formic acid, all parts by volume) was added and the flask was sonicated with occasional shaking for 10 minutes or until the cream was well dispersed. The solution was allowed 20 to cool to ambient temperature and then diluted to volume with diluent. A
portion of the solution was filtered using a syringe equipped with a 0.2 micron PTFE
filter to provide the sample solution.
Test Method 3 - IRM Compound 1 Content 25 A gradient reversed phase high performance liquid chromatography (HPLC) method was used to determine the amount of 2-methyl-1-(2-methylpropyl)-1H
imidazo[4,5-c][1,5]naphthyridin-4-amine (IRM Compound 1) in cream formulations using BHA and BHT as the antioxidants.
HPLC parameters: Analytical column: ZORBAX Bonus RP, 3.5 micron particle, 30 150 x 4.6 mm (available from Agilent Technologies, Wilmington, Delaware, USA);

Column temperature: 3s°C; Detector: LTV at 240 nm; Flow Rate: 1.0 mL/min; Injection volume: 30 ~L; Mobile phase A: 0.05% trifluoroacetic acid in water; Mobile Phase B:
0.05% trifluoroacetic acid in acetonitrile; Data acquisition time: 25 minutes;
HPLC run time: 35 minutes.
Gradient program: 0 minutes: 80% mobile phase A, 20% mobile phase B; 5 minutes: 80% mobile phase A, 20% mobile phase B; 15 minutes: 75% mobile phase A, 25% mobile phase B; 25 minutes: 35% mobile phase A, 65% mobile phase B; 28 minutes: 10% mobile phase A, 90% mobile phase B; 29 minutes: 80% mobile phase A, 20% mobile phase B; 35 minutes: 80% mobile phase A, 20% mobile phase B.
l0 Sample solution: A portion of the cream formulation (2500 mg for creams containing 0.03% IRM; 1500 mg for creams containing 0.1% IRM; and 500 mg for creams containing 0.3% IRM) was accurately weighed into a volumetric flask (50 mL
for creams containing 0.03% IRM; 100 mL for creams containing 0.1 or 0.3%
IRM).
Approximately 40 mL of diluent (prepared by combing 200 parts of acetonitrile, 1 s parts water, and 10 parts phosphoric acid, all parts by volume) was added to the 50 rnL
flask or 80 mL to the 100 mL flask. The flask was shaken or vortexed to dislodge any cream from the neck of the flask and then sonicated with occasional shaking for 10 minutes or until the cream was completely dispersed. The solution was allowed to cool to ambient temperature and then diluted to volume with diluent. A portion of the 2o solution was filtered using a syringe equipped with a 0.2 micron PTFE
filter to provide the sample solution.
Test Method 4 - Sorbic Acid and BHA Content A gradient reversed phase high performance liquid chromatography (HPLC) 2s method was used to determine the amount of sorbic acid and BHA in cream formulations containing IRM Compound 1.
HPLC parameters: Analytical column: ZORBAX Bonus RP, 3.5 micron particle, 150 x 4.6 mm; Column temperature: 35°C; Detector: UV at 285 nm; Flow Rate: 1.0 mL/min; Injection volume: 25 ~L; Mobile phase A: 0.05% trifluoroacetic acid in water;

Mobile Phase B: 0.05% trifluoroacetic acid in acetonitrile; Data acquisition time: 12 minutes; HPLC run time: 18 minutes.
Gradient program: 0 minutes: 60% mobile phase A, 40% mobile phase B; 10 minutes: 5% mobile phase A, 95% mobile phase B; 12 minutes: 5% mobile phase A, 95% mobile phase B; 13 minutes: 60% mobile phase A, 40% mobile phase B; 18 minutes: 60% mobile phase A, 40% mobile phase B.
Sample solution: A portion (approximately 1000 mg) of the cream formulation was accurately weighed into a 100 mL volumetric flask. Approximately 80 mL of diluent (prepared by combining 600 parts of acetonitrile, 400 parts of water, and 1 part l0 trifluoroacetic acid, all parts by volume) was added and the flask was sonicated with occasional shaking for 10 minutes or until the cream was well dispersed. The solution was allowed to cool to ambient temperature and then diluted to volume with diluent. A
portion of the solution was filtered using a syringe equipped with a 0.45 micron PTFE
filter to provide the sample solution.
Preparation of Cream Formulations The cream formulations in the Examples below were prepared using the following general method.
Oil phase preparation: The IRM compound and the BHA or BHT were dissolved 2o in the isostearic acid and medium chain triglycerides, with heat if necessary. Generally the CARBOPOL 980 was then dispersed in the oil phase.
Water phase preparation: Edetate disodium dehydrate, methylparaben, sorbic acid, propylene glycol, and POLOXAMER 188 were added to the water and mixed until dissolved, with heat if necessary. If the CARBOPOL was not dispersed in the oil phase, it was dispersed in the water phase.
Phase combination: The oil phase was added to the water phase at ambient conditions. The emulsion was then homogenized. Sodium hydroxide was added either before or after phase combination. The cream was mixed until smooth and uniform.
The pH of the cream was measured and a pH adjustment was made with additional 3o sodium hydroxide solution, if necessary, to meet the in-process target of pH S.

Examples 1-6 Table 1 summarizes topical formulations made in accordance with the present invention in a percentage weight-by-weight basis. The formulations were packaged in aluminum tubes with an epoxy phenolic lacquer liner.
Table 1 Ingredient Ex Ex Ex Ex Ex Ex6 IRM 1 0.01 0.03 0.10 0.30 0.60 1.00 Isostearic 5.00 5.00 5.00 7.00 10.0010.00 acid *Medium-chain 4.00 4.00 4.00 4.00 4.00 4.00 Triglycerides CARBOPOL 980 1.00 1.00 1.00 1.00 1.00 1.00 POLOXAMER 188 3.50 3.50 3.50 3.50 3.50 3.50 Propylene gylcol5.00 5.00 5.00 5.00 5.00 5.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Sorbic acid 0.15 0.15 0.15 0.15 0.15 0.15 BHA 0.10 0.10 0.10 0.10 0.10 0.10 Edetate disodium0.05 0.05 0.05 0.05 0.05 0.05 dihydrate Sodium hydroxide0.80 0.80 0.80 0.80 0.80 0.80 Solution 20%
w/w Purified water80.1980.17 80.1077.9074.6074.20 *Caprylic/capric triglyceride available under the trade names CRODAMOL
GTCC-PN
(Croda, Inc) and MIGLYOL

(Sasol).

to The creams of Examples 1-6 were stored at 40°C at 75% relative humidity. At selected time points samples were analyzed for IRM l, sorbic acid (SA), and BHA
content. The results are shown in Table 2 below. The initial values (0 month) are the average of 6 independent determinations (2 samples from each of 3 tubes); the values for the later time points are the average of 2 independent determinations (2 samples from 1 tube). Values are not normalized for weight loss that may have occurred during storage. Test Method 1 was used to deterniine the IRM 1 content and sorbic acid content. Test Method 2 was used to determine the BHA content.
Table 2 Ingredient Content and (%
w/w) Time point (% Initial) (40C/75%RH) Ex 1 Ex Ex 3 Ex Ex Ex 6 IRM 1- 0 0.010040.03020.1001 0.306 0.609 1.008 month (100.0)(100.0)(100.0)(100.0)(100.0)(100.0) IRM 1-1 month0.010090.03020.1004 0.306 0.612 1.017 (100.5)(100.0)(100.3)(100.0)(100.5)(100.9) IRM 1- 2 0.009900.03010.0999 0.308 0.602 0.993 month (98.6) (99.7)(99.8) (100.7)(98.9)(98.5) IRM 1- 3 0.010120.02970.0985 0.301 0.615 1.026 month (100.8)(98.3)(98.4) (98.4)(101.0)(101.8) IRM 1- 6 0.010080.03010.1000'0.307 0.616 1.025 month (100.4)(99.7)(99.9 (100.3)(101.1)(101.7) SA - 0 month0.152 0.155 0.152 0.149 0.150 0.150 (100.0)(100.0)(100.0)(100.0)(100.0)(100.0) SA -1 month 0.152 0.153 0.152 0.148 0.150 0.150 (100.0)(98.7)(100.0)(99.3)(100.0)(100.0) SA - 2 month0.155 0.152 0.151 0.149 0.149 0.148 (102.0)(98.1)(99.3) (100.0)(99.3)(98.7) SA - 3 month0.152 0.151 0.149 0.147 0.147 0.148 (100.0)(97.4)(98.0) (98.7)(98.0)(98.7) SA - 6 month0.150 0.153 0.153 0.148 0.150 0.150 (98.7) (98.7)(100.7)(99.3)(100.0)(100.0) BHA - 0 month0.1029 0.10570.1086 0.10300.10250.1030 (100.0)(100.0)(100.0)(100.0)(100.0)(100.0) Table 2 Ingredient Content and (%
w/w) Time point (% Initial) (40C/75%RH) Ex 1 Ex Ex Ex 4 Ex Ex BHA -1 month0.1049 0.10170.1 0.1005 0.1 0.1014 O O
19 l (101.9)(96.2)(93.8)(97.6) (99.4)(98.4) BHA - 2 month0.0995 0.10260.10290.1002 0.10010.0975 (96.7) (97.1)(94.8)(97.3) (97.7)(94.7) BHA - 3 month0.0978 0.10110.09840.0978 0.09840.0973 (95.0) (95.6)(90.6)(95.0) (96.0)(94.5) BHA - 6 month0.1029 0.10040.10070.1001 0.10080.1018 (100.0)(95.0)(92.7)(97.2) (98.3)(98.8) Examples 7 ~ 8 Table 3 summarizes topical formulations made in accordance with the present invention in a percentage weight-by-weight basis and a formulation prepared without an antioxidant (C1). The formulations were packaged in glass containers.

Table 3 Ingredient Ex Ex Ex IRM 1 0.30 0.30 0.30 Isostearic 7.00 7.00 7.00 acid *Medium-chain 8.00 8.00 8.00 Triglycerides CARBOPOL 980 1.00 1.00 1.00 POLOXAMER 188 2.50 2.50 2.50 Propylene gylcol5.00 5.00 5.00 Methylparaben 0.20 0.20 0.20 Sorbic acid 0.15 0.15 0.15 BHA 0.10 - -BHT - 0.10 -Edetate disodium0.05 0.05 0.05 dihydrate Sodium hydroxide0.80 0.80 0.80 Solution 20%
w/w Purified water74.90 74.9075.00 *Caprylic/capric triglyceride available under the trade names CRODAMOL GTCC-PN (Croda, Inc) and MIGLYOL 812N (Sasol).
The creams of Examples 7, 8, and C 1 were stored at 40°C at 75%
relative humidity and at 55°C at ambient humidity. At selected time points samples were analyzed using Test Method 1 described above for IRM 1 and sorbic acid content. The results are shown in Table 4 below where each value is for 1 sample from 1 container of cream. Values were not normalized for weight loss that may have occurred during storage.
to Table 4 Content (%
w/w) Ingredient - Time point (%
Initial) (Conditions) Ex7 Ex8 ExCl IRM 1- 0 month 0.303 0.303 0.304 (40C) (100.0)(100.0)(100.0) IRM 1 -1 month 0.302 0.306 0.302 (40C) (99.7)(101.0)(99.3) IRM 1- 2 month 0.305 0.308 0.307 (40C) (100.7)(101.7)(101.0) IRM 1- 3 month 0.308 0.315 0.303 (40C) ( 1 ( 104.0)(99.7) O
1.7) IRM 1- 6 month 0.305 0.313 0.296 (40C) (100.7)(103.3)(97.4) SA - 0 month (40C)0.147 0.147 0.147 (100.0)(100.0)(100.0) SA - 1 month (40C)0.146 0.147 0.140 (99.3)(100.0)(95.2) SA - 2 month (40C)0.145 0.147 0.133 (98.6)(100.0)(90.5) SA - 3 month (40C)0.147 0.150 0.126 (100.0)(102.0)(85.7) SA - 6 month (40C)0.146 0.148 0.119 (99.3)(100.7)(81.0) IRM 1- 0 weeks 0.303 0.303 0.304 (55C) (100.0)(100.0)(100.0) IRM 1-2 weeks 0.302 0.304 0.301 (55C) (99.7)(100.3)(99.0) Table 4 Content (%
w/w) Ingredient - Time point (% Initial) (Conditions) Ex 7 Ex Ex IRM 1- 4 weeks 0.303 0.308 0.301 (55C) (100.0)(101.7)(99.0) IRM 1- 6 weeks 0.307 0.311 0.301 (55C) (101.3)(102.6)(99.0) IRM 1 - 8 weeks 0.311 0.314 0.298 (55C) ( 102.6)( 103.6)(98.0) SA- 0 weeks (55C)0.147 0.147 0.147 (100.0)(100.0)(100.0) SA-2 weeks (55C) 0.146 0.147 0.138 (99.3) (100.0)(93.9) SA-4 weeks (55C) 0.146 0.148 0.133 (99.3) (100.7)(90.5) SA-6 weeks (55C) 0.148 0.148 0.125 (100.7)(100.7)(85.0) SA-8 weeks (55C) 0.148 0.149 0.118 (100.7)(101.4)(80.3) Examples 9-18 Table 5 summarizes topical formulations made in accordance with the present invention in a percentage weight-by-weight basis. The formulations were packaged in aluminum tubes with an epoxy phenolic lacquer liner. The formulations of Examples 9-18 were stored at 40°C at 75% relative humidity. At selected time points samples were analyzed for IRM 1, sorbic acid (SA), and BHA content. The results are shown in Table 6 below where the initial values of IRM and SA are the average of 6 independent l0 determinations (2 samples from each of 3 tubes), the initial BHA values are the average of 3 independent determinations (1 sample from each of 3 tubes), and the values for later time points are the values for one sample from 1 tube. Values are not normalized for weight loss that may have occurred during storage. Test Method 1 was used to determine the IRM 1 content and sorbic acid content. Test Method 2 was used to determine the BHA content.

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Examples 19-24 Table 7 summarizes topical fornmlations made in accordance with the present invention in a percentage weight-by-weight basis. The formulations were packaged in aluminum tubes with an epoxy phenolic lacquer liner. The formulations of Examples 19-24 were stored at 40°C at 75% relative humidity. At selected time points samples were analyzed for IRM 1, sorbic acid (SA), and BHA content. The results are shown in Table 8 below where the initial values of IRM SA, and BHA are the average of 3 independent determinations, and the values for later time points are from 1 tube. Values are not normalized for weight loss that may have occurred during storage. Test Method 3 was used to determine IRM 1 content.
to Test Method 4 was used to determine SA and BHA content.
Table 7 Ingredient Ex Ex Ex Ex Ex Ex IRM 1 0.03 0.30 0.30 0.30 0.30 0.30 Isostearic 5.00 7.00 7.00 7.00 7.00 7.00 acid *Medium-chain 4.00 4.00 4.00 4.00 4.00 4.00 Triglycerides CARBOPOL 980 1.00 1.00 1.00 1.00 1.00 1.00 POLOXAMER 188 3.50 3.50 3.50 3.50 3.50 3.50 Propylene gylcol5.00 5.00 5.00 5.00 5.00 5.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 Sorbic acid 0.10 0.10 0.10 0.10 0.10 0.10 BHA 0.01 - 0.01 0.01 0.01 0.01 Edetate disodium0.05 0.05 - 0.05 0.03 0.01 dihydrate Sodium hydroxide0.80 0.80 0.80 0.80 0.80 0.80 Solution 20%
w/w Purified water 80.31 78.05 78.09 78.04 78.06 78.08 *Caprylic/capric triglyceride available under the trade names CRODAMOL
GTCC-PN
(Croda, Inc) and MIGLYOL

(Sasol).

Table 8 Ingredient - TimeContent Point (%
w/w) (%
Initial) Ex Ex Ex Ex 22 Ex Ex 24 IRM 1- 0 month 0.02980.303 0.303 0.301 0.302 0.303 (100.0)(100.0)(100.0)(100.0)(100.0)(100.0) IRM 1- 2 month 0.02990.300 0.306 0.303 0.306 0.305 (100.3)(99.0)(101.0)(100.7)(101.3)(100.7) IRM 1- 4 month 0.02990.300 0.304 0.304 0.304 0.305 (100.3)(99.0)(100.3)(101.0)(100.7)(100.7) IRM 1- 6 month 0.02990.296 0.302 0.305 0.306 0.306 (100.3)(97.7)(99.7)(101.3)(101.3)(101.0) SA - 0 month 0.09960.09660.09950.0997 0.10050.1007 (100.0)(100.0)(100.0)(100.0)(100.0)(100.0) SA - 2 month 0.09830.09090.09800.0994 0.10000.0996 (98.7)(94.1)(98.5)(99.7) (99.5)(98.9) SA - 4 month 0.10030.08250.09760.0996 0.09930.0988 (100.7)(85.4)(98.1)(99.9) (98.8)(98.1) SA - 6 month 0.09960.07560.09690.0997 0.09970.0999 (100.0)(78.3)(97.4)(100.0)(99.2)(99.2) BHA- 0 month 0.0095*ND 0.00970.0098 0.01000.0099 (100) (100) (100) (100) (100) BHA - 2 month 0.0092ND 0.00850.0098 0.01000.0099 (97) (88) (100) (100) (100) BHA - 4 month 0.0096ND 0.00830.0101 0.01010.0094 (101) (86) (103) (101) (95) BHA - 6 month 0.0094ND 0.00760.0101 0.01020.0100 (99) (78) (103) (102) (101) *ND = not determined Table 9 summarizes topical formulations made in accordance with the present invention in a percentage weight-by-weight basis. The formulations were packaged in aluminum tubes with an epoxy phenolic lacquer liner.
Table 9 Ingredient Ex Ex Ex Ex Ex IRM 1 0.01 0.05 0.10 0.10 0.10 Isostearic 5.00 5.00 5.00 5.00 5.00 acid *Medium-chain 4.00 4.00 4.00 4.00 4.00 Tri lycerides CARBOPOL 980 1.00 1.00 1.00 1.00 1.00 POLOXAMER 188 3.50 3.50 3.50 3.50 3.50 Propylene gylcol5.00 5.00 5.00 5.00 5.00 Methylparaben 0.20 0.20 0.20 0.20 0.20 Sorbic acid 0.10 0.10 0.10 0.10 0.10 BHA 0.01 0.01 0.01 0.01 0.01 Edetate disodium0.05 0.05 0.05 0.05 0.05 dihydrate Sodium hydroxide0.80 0.80 0.80 0.40 1.20 Solution 20%
w/w Purified water80.33 80.2980.2480.64 79.84 *Caprylic/capric triglyceride available under the trade names CRODAMOL GTCC-PN (Croda, Inc) and MIGLYOL 812N (Sasol).
The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated, l0 except that if there is any apparent conflict or inconsistency the present disclosure is controlling. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.

Claims

1. A pharmaceutical formulation comprising:
an immune response modifier (IRM) compound comprising a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring;
a preservative system comprising a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof; and an antioxidant.

2. A pharmaceutical formulation comprising:
an immune response modifier (IRM) compound comprising a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring;
a preservative system comprising a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
an antioxidant comprising hydrogen atom donating functionality;
a fatty acid; and a hydrophobic, aprotic component miscible with the fatty acid and comprising a hydrocarbyl group of 7 or more carbon atoms.

3. The formulation of claim 1 further comprising a fatty acid.

4. The formulation of claim 1 or claim 3 further comprising a hydrophobic, aprotic component miscible with a fatty acid and comprising a hydrocarbyl group of 7 or more carbon atoms.

5. The formulation of claim 2 or claim 4 wherein the hydrophobic, aprotic component has a hydrophilic lipophilic balance (HLB) of less than 2.

6. The formulation of any one of claims 2, 4, and 5 wherein the hydrophobic, aprotic component has a pKa of at least 14.2.

7. The formulation of any one of claims 2 and 4 through 6 wherein the hydrophobic, aprotic component is selected from the group consisting of fatty acid esters, medium-chain triglycerides, cetyl esters, hydrocarbons of 8 or more carbon atoms, waxes, and combinations thereof.

8. The formulation of claim 7 wherein the hydrophobic, aprotic component is selected from the group consisting of isopropyl mysristate, isopropyl palmitate, caprylic/capric triglyceride, diisopropyl dimer dilinoleate, and combinations thereof.

9. The formulation of any one of claims 2 and 4 through 8 wherein the hydrophobic, aprotic component is present in an amount of 1% by weight to 30% by weight, based on the total weight of the formulation.

10. The formulation of any one of claims 1, 3, 4, and claims 5 through 9 except as dependent on claim 2 wherein the antioxidant comprises hydrogen atom donating functionality.

11. The formulation of any one of claims 1 through 10 wherein the antioxidant is selected from the group consisting of compounds containing aromatic hydroxy groups capable of hydrogen atom donation.

12. The formulation of any one of claims 1, 3, 4, and claims 5 through 9 except as dependent on claim 2 wherein the antioxidant is selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, propyl gallate, sodium formaldehyde sulfoxylate, sodium thiosulfate, sulfur dioxide, tocopherol, and combinations thereof.

13. The formulation of claim 12 wherein the antioxidant is selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, propyl gallate, sodium formaldehyde sulfoxylate, tocopherol, and combinations thereof.

14. The formulation of claim 13 wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tocopherol, and combinations thereof.

15. The formulation of claim 14 wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, and combinations thereof

16. The formulation of any one of claims 1 through 15 wherein the antioxidant is present in an amount of 0.001 % by weight to 0.3% by weight, based on the total weight of the formulation.

17. The formulation of any one of claims 2, 3 and 4 through 16 wherein the fatty acid has 6 to 28 carbon atoms.

18. The formulation of claim 17 wherein the fatty acid is selected from the group consisting of isostearic acid, oleic acid, linear- or branched-chain carboxylic acids of 6 to 18 carbon atoms, and combinations thereof.

19. The formulation of any one of claims 2, 3, and claims 4 through 18 except as they depend directly or indirectly on claim 1, wherein the fatty acid is present in an amount of 0.05% by weight to 40% by weight, based on the total weight of the formulation.

20. The formulation of any one of claims 2, 19, and claims 4 through 18 except as they depend directly or indirectly on claim 1, wherein the ratio of the hydrophobic, aprotic component to the fatty acid is within a range of 0.025:1 to 600:1.

21. The formulation of any one of claims 1 through 20 wherein the preservative system comprises sorbic acid, isopropyl sorbate, calcium sorbate, potassium sorbate, sodium sorbate, triethanolamine sorbate, or combinations thereof.

22. The formulation of any one of claims 1 through 21 wherein the sorbic acid preservative is present in an amount of 0.005% by weight to 1% by weight, based on the total weight of the formulation.

23. The formulation of claim 22 wherein the sorbic acid preservative is present in an amount of 0.02% by weight to 0.2% by weight, based on the total weight of the formulation.

24. The formulation of claim 23 wherein the sorbic acid preservative is present in an amount of 0.05% by weight to 0.15% by weight, based on the total weight of the formulation.

25. The formulation of any one of claims 1 through 24 wherein the weight ratio of the sorbic acid preservative to the antioxidant is within a range of 1:20 to 1000:1.

26. The formulation of any one of claims 1 through 25 wherein the preservative system further includes a preservative enhancing solubilizer.

27. The formulation of claim 26 wherein the preservative enhancing solubilizer is selected from the group consisting of diethylene glycol monoethyl ether, propylene glycol, poly(ethylene glycol)(4) monolaurate, and combinations thereof.

28. The formulation of any one of claims 1 through 27 further comprising a chelating agent.

29. The formulation of claim 28 wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, hydrates thereof, salts thereof, hydrates of the salts thereof, and combinations thereof.

30. The formulation of claim 29 wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid disodium salt, ethylenediaminetetraacetic acid disodium salt dihydrate, citric acid monohydrate, and combinations thereof.

31. The formulation of any one of claims 28 through 30 wherein the chelating agent is present in an amount of 0.001 % by weight to 0.2% by weight, based on the total weight of the formulation.

32. The formulation of any one of claims 28 through 31 wherein the weight ratio of the antioxidant to the chelating agent is within a range of 1:200 to 300:1.

33. The formulation of any one of claims 1 through 32 wherein the preservative system further includes methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol, or combinations thereof.

34. The formulation of any one of claims 1 through 33 further comprising a hydrophilic viscosity enhancing agent.

35. The formulation of claim 34 wherein the hydrophilic viscosity enhancing agent is selected from cellulose ethers and carbomers.

36. The formulation of claim 34 or claim 35 wherein the hydrophilic viscosity enhancing agent is present in an amount of 0.2% by weight to 2.0% by weight, based on the total weight of the formulation.

37. The formulation of any one of claims 1 through 36 further comprising a pH
adjuster, an emulsifier, or combinations thereof.

38. A pharmaceutical formulation comprising:

0.001% by weight to 5.0% by weight of an immune response modifier (IRM) compound comprising a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring;
a preservative system comprising:
0.02% by weight to 0.2% by weight of a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
0 to 10.0% by weight of a preservative enhancing solubilizer; and 0.05% by weight to 0.2% by weight of a secondary preservative compound;
0.001% by weight to 0.2% by weight of an antioxidant comprising hydrogen atom donating functionality;
0 to 0.1% by weight of a chelating agent;
1% by weight to 30% by weight of a fatty acid;
1% by weight to 15% by weight of a medium-chain triglyceride;
0.2% by weight to 2.0% by weight of a viscosity enhancing agent;
0.1% by weight to 6.0% by weight of an emulsifier; and water;
wherein the formulation has a pH of 4.0 to 6.0 and the weight percentages are based on the total weight of the formulation.

39. The formulation of any one of claims 1 through 38 wherein the IRM is selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, imidazoquinoline-1,4-diamines, 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, tetrahydronaphthyridine amines, and combinations thereof.

40. The formulation of claim 39 wherein the IRM is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amide ether substituted imidazoquinoline amines, sulfonamide ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinoline amines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines, heterocyclic ether substituted tetrahydroimidazoquinoline amines, amide ether substituted tetrahydroimidazoquinoline amines, sulfonamide ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazoquinoline amines, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine,amines, heterocyclic ether substituted imidazopyridine amines, amide ether substituted imidazopyridine amines, sulfonamide ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers, thioether substituted imidazopyridine amines, and combinations thereof.

41. The formulation of claim 39 wherein the IRM is an imidazonaphthyridine amine.

42. The formulation of any one of claims 1 through 41 wherein the IRM is present in an amount of 0.03% by weight to 0.3% by weight, based on the total weight of the formulation.

43. A pharmaceutical formulation comprising:
0.001% by weight to 5.0% by weight of an imidazonaphthyridine amine;
0.02% by weight to 0.2% by weight of a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
0 to 10.0% by weight of propylene glycol;
0.05% by weight to 0.2% by weight of methylparaben;

0.001% by weight to 0.2% by weight of butylated hydroxyanisole, butylated hydroxytoluene, or combinations thereof;
0 to 0.1% by weight of ethylenediaminetetraacetic acid, a hydrate thereof, a salt thereof, a hydrate of a the salt thereof, or combinations thereof;
1% by weight to 30% by weight of isostearic acid;
1% by weight to 15% by weight of a medium-chain triglyceride;
0.2% by weight to 2.0% by weight of a carbomer;
0.1% by weight to 6.0% by weight of a poloxamer; and water;
wherein the formulation has a pH of 4.0 to 6.0 and the weight percentages are based on the total weight of the formulation.

44. The formulation of claim 43 wherein the imidazonaphthyridine amine is 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.

45. A method for delivering an immune response modifier (IRM) to a dermal and/or mucosal surface, the method comprising:
selecting a formulation of any one of claims 1 through 44; and applying the selected formulation to the dermal and/or mucosal surface.

46. A method of treating a dermal associated condition, the method comprising applying to a dermal surface of a patient in need thereof the pharmaceutical formulation of any one of claims 1 through 45.

47. The method of claim 46 wherein the dermal associated condition is actinic keratosis.

48. A method of stabilizing a pharmaceutical formulation comprising:
an immune response modifier (IRM) compound comprising a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring; and a preservative system comprising a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
the method comprising:
adding an antioxidant to the formulation.

49. A method of stabilizing a pharmaceutical formulation comprising:
an immune response modifier (IRM) compound comprising a 2-aminopyridine moiety fused to a five-membered nitrogen-containing heterocyclic ring;
a preservative system comprising a sorbic acid preservative selected from the group consisting of sorbic acid, esters thereof, salts thereof, and combinations thereof;
a fatty acid; and a hydrophobic, aprotic component miscible with the fatty acid and comprising a hydrocarbyl group of 7 or more carbon atoms.
the method comprising:
adding an antioxidant comprising hydrogen atom donating functionality to the formulation.