WO2007034277A1

WO2007034277A1 - Aryl substituted imidazo [4,5-c] pyridine compounds as c3a receptor antagonists

Info

Publication number: WO2007034277A1
Application number: PCT/IB2006/002557
Authority: WO
Inventors: Todd William Butler
Original assignee: Pfizer Products Inc.
Priority date: 2005-09-19
Filing date: 2006-09-17
Publication date: 2007-03-29

Abstract

Aryl substituted imidazo[4,5-c] pyridine compounds of formula (I) or pharmaceutically acceptable salt thereof are provided. These compounds are useful in pharmaceutical compositions as C3a antagonists for treating a variety of medical conditions associated with the Complement cascade.

Description

ARYL SUBSTITUTED IMlDAZO r4.5-C1 PYRIDINE COMPOUNDS AS C3A RECEPTOR

ANTAGONISTS

Field of the Invention

The present invention provides novel pharmaceutically active compounds that act as antagonists of the mammalian C3a receptor, and methods of using these compounds to treat chronic inflammatory diseases, including, but not limited to inflammations in the central nervous system, peripheral nervous system, lungs, and bone joints. Additionally, disease states not classically categorized as inflammatory diseases, but which in fact have inflammatory components, can also be effectively treated according to the practice of the invention. Alzheimer's disease represents a particularly important example of this latter type of disease state, and its discussion usefully demonstrates that disease states not classically categorized as inflammatory share mechanistic linkages with disease states classically characterized as inflammations. The present invention relates to treatment of both such types of disease states via inhibition of binding of the C3a protein to its cellular receptors. Background of the Invention

The pathological hallmark of Alzheimer's disease (AD) is the senile amyloid plaque, a proteinaceous extracellular deposit composed primarily of an amyloidogenic peptide termed A-beta protein, and which is surrounded by dystrophic neurites. Senile plaques are the focus of a robust and chronic inflammatory response mounted by microglia, the brain's endogenous macrophage cells. Macrophage cells are phagocytic immune system cells of monocytic origin that circulate in the tissues and participate both in first-line initial immunosurveillance, and acquired immunity processes.

Although inflammatory responses are designed to protect the body at sites of infection or tissue damage, chronic inflammation itself often causes tissue damage. As a further complication in regard of treatment of Alzheimer's disease, since many of the biochemical products of microglial cell activation are known to be very toxic to nerve cells, blocking the inflammatory response is very significant in the treatment of AD. In this regard, see generally, J. Rogers et a!., Inflammation and Alzheimer's disease pathogenesis, Neurobiol. Aging, v. 17, pp. 425-432, 1996. The critical need for anti-inflammatory therapy for AD is underscored by numerous epidemiological studies associating chronic use of nonsteroidal antiinflammatory drugs or disease-modifying anti-rheumatic drugs with a greatly increased risk of developing AD (see, for example, McGeer, P.L., Schulzer, M., and McGeer, E.G. (1996) Arthritis and antiinflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies. Neurology 47: 425-432).

One of the key host defense mechanisms provided by macrophages involves use of Complement, a phylogenetically old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault. Complement activation is a prominent feature of the inflammatory response in Alzheimer's diseas'e, and is apparently triggered by the presence of senile plaques. The triggering of the Complement system involves the sequential activation of numerous proteins by a cascade effect. The Complement cascade is best defined as a series of binding and cleavage events wherein active forms of Complement proteins are produced, which in turn act upon each other, often by proteolysis, to produce further active proteins and protein fragments, and complexes thereof, which then interact with immune system components, or with cellular debris, endogenous or foreign macromolecules, or invading cells which are then targeted for destruction.

During Complement activation, Complement protein C3 is prpteolytically cleaved, resulting in a large fragment (C3b) and the smaller 77 residue peptide, C3a. C3a is known to regulate vasodilation increasing the permeability of small blood vessels, induce contraction of smooth muscles, induce oxidative burst, regulate cytokine release, and stimulate chemotaxis, depending on the involved cells, all inflammation related events. Target cells- include macrophages, neutrophils, eosiniphils, basophils, T-lyphocytes and mast cells, all having important immune and inflammation related functions.

Receptors for C3a are expressed on a variety of macrophages and macrophage cell lines. Functionally, C3a binding to C3a receptors in macrphages causes a mobilization of intracellular calcium ions, and leads to both chemotaxis and respiratory burst, which are both host defense mechanism that generate high levels of cytotoxic superoxide. Again, although such mechanisms are useful in protecting against invading bacterial cells, for example, the triggering of such defense mechanism against normal cells (such as brain neurons that happen to be proximal to the site of plaque formation) is devastating to normal brain function. Similar disadvantageous results operate in regard of other inflammatory conditions.

In summary, substantial evidence indicates that a chronic inflammatory response to senile plaques contributes significantly to the neurotoxicity of Alzheimer's disease. A key step in this inflammatory response is the formation of C3a, which upon binding to microglial C3a receptors, causes recruitment of microglia to the plaque followed by activation of neurotoxin release. Blocking of C3a receptors would thus be expected to inhibit these deleterious microglial responses and slow the progression of Alzheimer's disease.

The C3a receptor (C3aR) belongs to the rhodopsin family of G protein-coupled receptors (see Embler et al. in The Human Complement System in Health and Disease, Marcel Dekker, New York, pp. 241-284, 1998). Traditionally, C3aR was thought to be present only on myeloid cells, such as macrophages, eosiniphils and mast cells. However, the demonstration that C3aR receptor messenger RNA is expressed throughout the body (and in particular in the adrenal gland, pituitary.gland, and the central nervous system) is consistent with participation of C3a in a wide variety of cellular process and mediate numerous disease states. Recently, C3a receptor-immunoreactivity has been detected in areas of inflammation in multiple sclerosis and bacterial meningitis patients. In the latter disorder, abundant C3a receptor expression on activated microglia and reactive astrocytes was noted. Additionally, Complement activation has been implicated in the pathogenesis of neurodegenerative disorders in both the central nervous system and the peripheral nervous system such as Huntington's disease, Pick's disease, and Gullian Barre syndrome. (See Campos-Torres et al.., (August 2000), Immunopharmacology, volume 49, Issues 1-2, page 48; see also, (Vogt, W. (1986) Complement 3, 177-188; Morgan, B. P. (1994) European J. Clin. Investigation, 24, 219-228; and Morgan et al., (1997), Immunopharmacology, 38, 43-50). It is also recognized that Complement activation plays a significant role in allergic lung damage caused by repeated inhalation of antigen, which is consistent with the etiology of asthma. (See Abe et al., Immunopharmacology, Volume 49, Issues 1-2, page 26 (August 2000)). Importantly, it is also recognized that controlling the Complement system can impact the treatment or prevention of disease states such as sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/reperfusion injury. (See Kirshfink, M., (1997), Immunopharmacology, 38, 51-62; see also Lucchesi et al., (1997), Immunopharmacology, 38, 27-42 ).

Taken together, these observations strongly support the use of pharmaceutically active compounds, effective as C3a receptor antagonists, in the prevention and treatment of a wide range of disease states, whether or not the disease state is classically recognized to include an inflammatory component., and whether or not the activation of the Complement system is involved, in whole or part, in the pathology of the disease state. Such disease states include, but are not limited to: neurological diseases such as Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke; and hemorrhagic stroke; cancer generally and leukemia particularly; allergic and respiratory diseases including allergic dermatitis, anaphylaxis, asthma, eczema, rhinitis, and respiratory distress; cardiovascular or metabolic disease states including shock and hypertension, hyperlipidemia, hypercholesterolemia, edema, and obesity; and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, lung inflammation and rheumatoid arthritis. Summary of the Invention Accordingly, there are provided compounds according to the formula

(formula¹1) or a pharmaceutically acceptable salt thereof, wherein

X represents a single bond or a C1-C6 alkylene optionally containing one or more heteroatoms selected from the group consisting of O, S, and N, with the proviso that the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core; - Ri represents one or more substituents selected from the group consisting of hydrogen, halo, hydroxyl, C(O)R₇, C(O)OR₇, N(R₇)₂, NHR₇, C(O)NHR₇, C(O)(R₇J₂, cyano, nitro, optionally substituted (Ci-C₆) alkyl, optionally substituted (C₃-C₁₀) cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, (C₁-C₆) acylamino, SO₂N(R₇)^₁ SO₂NHR₇, O- (C₁-C₆) alkyl, 80₂((C₁-C₆) alkyl), and S(O)(C₁-C₆ alkyl); R₂ is hydrogen, halo, (C₁-C₆) alkyl, cyano, hydroxyl, 0-((C₁-C₆) alkyl), nitro, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl), SO₂NH(C₁-C₆ alkyl), OR SO₂N(C₁-C₆ alkyl)₂;

R₃ is hydrogen, halo, (C₁-C₆) alkyl, cyano, hydroxyl, OR 0-(C₁-C₆ alkyl);

R₄ is hydrogen, optionally substituted (C₁-C₆) alkyl, optionally substituted (C₂-C₁₀) alkenyl, optionally substituted (C₂-C₁₀) alkynyl, CH₂CN, CH₂C(O)(C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, C(0)-optionally substituted 5-10-membered heteroaryl, C(O)-optionally substituted . (C6-C10) aryl, CH(OH)- optionally substituted 5-10-membered heteroaryl, C(O)O-(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl), OH,

NH₂, -CHOH-(C₁-C₆ alkyl), C(N-OCH₃)(C₁-C₆ alkyl), (C1-C6) alkoxy-(C2-C6) alkenylene- C(O)O-(C₁-C₆ alkyl), C(O)NH₂, C(O)NH-(C₁-C₆ alkyl), or C(O)N(C₁-C₆ alkyl)₂; with the proviso that if X is a single bond and R4 contains a heteroatom, the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core; or R₃ and R₄, taken together with the ring carbon attached to R₃, the nitrogen attached to the ring carbon, and X, form an optionally substituted 3-10-membered heterocycloalkyl or an optionally substituted 5-10-membered heteroaryl when X is a single bond, and form an optionally substituted 3-10-membered heterocycloalkyl when X is a C₁-Ce alkylene; with the proviso that if X is a single bond and R4 contains a heteroatom, the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core; and R₇, independently for each occurrence, is selected from the group consisting of H, optionally substituted (C₁-Ci₀) alkyl, optionally substituted (C₂-C₁₀) alkenyl , optionally substituted (C₂-C₁₀) alkynyl, (C₆-C₁₀) aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted (C₃-C₁₀) cycloalkyl, and optionally substituted 3-10-membered heterocycloalkyl; , with the proviso that the compound of formula I is not a compound selected from the group consisting of

The compounds and pharmaceutical compositions of this invention include all isomers of compounds of formula I (such as cis and trans isomers, whether or not involving double bonds). The compounds of the invention include all optical isomers of the compounds of formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of all such isomers. This invention further relates to tautomers and stereoisomers of the compounds of formula (I), and mixtures of any of the aforementioned forms.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I). The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1 '-methylene- bis-(2-hydroxy-3-naphthoate)]salts.

The present invention also relates to the pharmaceutically acceptable base addition salts of compounds of the formula (I). The bases which are used to prepare the pharmaceutically acceptable base addition salts of the aforementioned base compounds of this invention are those which form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eq., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O₁ ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ^3δ Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon 14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. lsotopically labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. The present invention provides for the treatment of a medical condition selected from the group consisting of Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke; and hemorrhagic stroke; cancer generally and leukemia particularly; allergic and respiratory diseases including allergic dermatitis, anaphylaxis, asthma, eczema, rhinitis, and adult respiratory distress syndrome; cardiovascular or metabolic disease states including ischemia and reperfusion injury, shock and hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity; nephritis, graft rejection, and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, lung inflammation and rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. Exemplary conditions that may be treated by the compound of the invention are Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke, and hemorrhagic stroke.

Another aspect of the present invention is a method for preventing excessive Complement activation in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention.

Another aspect of the present invention is a method for treating or preventing Complement-mediated tissue damage in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention.

Another aspect of the present invention is a method for treating diseases characterized by chronic Complement activation comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.

Another aspect of the present invention is a method for antagonizing the C3a receptor in a patient by administering an effective amount of a compound(s) of the pres.ent invention. Definitions

In connection with the practice of the invention, the following definitions will generally apply.

An "effective amount" or "therapeutically effective amount" of a subject compound, with respect to the subject method of treatment, refers to an amount of the therapeutic in a preparation which, when applied as part of a desired dosage regimen provides a benefit according to clinically acceptable standards for the treatment or prophylaxis of a particular disorder. A "patient" or "subject" to be treated by the subject method can mean either a human or non-human subject.

The term "treating", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.

The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Similarly, the terms "alkenyl" and "alkynyl" define hydrocarbon radicals having straight, branched or cyclic moities wherein at least one double bond, or at least one triple bond, respectively, is present. Such definitions also apply when the alkyl, alkenyl or alkynyl group is present within another group, such as alkoxy or alkylamine.

The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is as defined above. The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.

A group or substituent "fused to C₆-Ci₀ arene" or "fused to an arene", as used herein, unless otherwise indicated, indicates, respectively, a group or substituent fused to a C₆-C₁₀ aromatic hydrocarbon and a group or substituent fused to a C_6-C₃₀ aromatic hydrocarbon. The C₆-C₁₀ aromatic hydrocarbon, or the C_6-C₃₀ aromatic hydrocarbon, may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and preferably the number of substituents is between 0 and 3, more preferably between 0 and 2. Representative aromatic hydrocarbon compounds are benzene and naphthalene. An "aryl" group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic or bicylic (C_6-C₁₀) aromatic hydrocarbon compound by removal of a hydrogen radical from a ring carbon of the aryl compound. An aryl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis. Representative aryl groups are phenyl and naphthyl.

An "arylene" group as used herein, unless otherwise indicated, includes an organic diradical derived from a monocyclic or bicylic (C_6-C₁₀) aromatic hydrocarbon compound by removal of two hydrogen radicals from two ring carbons of the aryl compound. An arylene group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis. Representative aryl groups are phenyl and naphthyl.

A "heteroaryl" group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic or bicyclic 3-10-membered aromatic heterocyclic compound by removal of a hydrogen radical from a ring atom of the heteroaryl compound, said ring atom being uncharged in said compound. A heteroaryl group may be substituted by one or more substituents wherein, μnless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis. Representative heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadiazolyl, 1 ,2,4-oxadiazoIyl, 1,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7- dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, and benzoxazinyl; and the like. A "cycloalkyl" group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic (C₃-C₁₀)cycloalkyl compound, by removal of a hydrogen radical from a ring carbon of the cycloalkyl compound. A cycloalkyl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3- cyclobutadienyl, 1 ,3-cyclopentadienyl, 1 ,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1 ,3- cycloheptadienyl, 1,4-cycloheptadienyl, 1 ,3,5-cycloheptatrienyl, bicyclo[3.2.1]octane, bicyclo [2.2.1] heptane, and the norbom-2-ene unsaturated form thereof. Thus, the term cycloalkyl also includes cycloalkenyl groups having one or two double bonds.

A "heterocycloalkyl" group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic 3-10-membered heterocycloalkyl compound by removal of a hydrogen radical from a ring atom of the heterocycloaikyl compound. A heterocycloalkyl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred numbe'r of substituents is determined in part by facility of synthesis. Representative heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yI, tetrahydrothiadiazinyl, morpholinyl, 1 ,2-tetrahydrodiazin-2-yl, 1 ,3-tetrahydrodiazin-1-yf, tetrahydroazepinyl, piperazinyl, and chromanyl. In connection with the terms "alkyl", "aryl", "heteroaryl", "cycloalkyl" and

"heterocycloalkyl", as herein defined, the term "optionally substituted" means that at least one chemically and pharmaceutically acceptable functional group may be ponded thereto. Such a functional group is selected from the group consisting of hydroxy, halo, amino, trifluoromethyl, carboxy, (C₁-C₆)SIkOXy-, (CrC₆)acyloxy-, (CrC^alkylamino-, ((CrC^alkyl^amino-, (C₁- C₆)acylamino-, cyano, nitro, (CrC^alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, cyano(C₁-C₆)alkyl-, trifluoromethyKC_TCeJalkyl-, nitro(C₁-C₆)alkyl-_I (C₁-C₃)alkyl(monofluoroalkylene)(C₁-C₃)alkyl-, (CrCaJalkyKpolyfluoroalkyleneJ^rCaJalkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)BIkOXy(C₁- C₆)acylamino-, amino(Ci-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁- C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-, (Cs-C^cycloalkyKCrC^alkyl-, (C₆-C₁₀)aryl(C_r C₆)alkoxy(C_rC₆)alkyl-, 5-10-membered heteroaryI(C₁-C₆)alkoxy(C₁-C₆)alkyl-, (C₆- C₁₀)arylsulfinyl -, (CrCeJalkylsulfonyKCrC_tOalkyl-, (C₆-C₁₀)arylsulfonyl-, (C₁-C₆ alkyl)-(C₆- C₁₀)arylenesulfinyl -, (C₁-C₆ alkyl)-(C₆-Ci₀)arylenesulfonyl-, amino(C₁-C₆)alkyl-, (C₁-

(CrCeJalkyKdifluoromethylene)-, (C₁-C₆)alkbxy(C₁-C₆)acyl-, (C₆- C₁₀)aryl-, 5-10-membered heteroaryl-, (C₆-C₁₀)aryl(CrC₆)alkyl-, 5-10-membered heteroaryl(C_rC₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-, (C₆-C_1o)aryl(C₆-C₁o)aryl(C₁-C₆)alkyl- (C₃- C₁₀)cycloalkyl-, 3-10-membered heterocycloalkyl-, 3-10-membered heterocycloalkyl(Cr C₆)alkyl-, hydroxy(C₂-C₆)alkyl-, (C_rC₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl, (C₁- C₆)alkylthio(C_rC₆)alkyl-, (C₆-C₁₀)arylthio(CrC₆)alkyl-, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆- C₁₀)arylsulfinyl(Ci-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C_rC₆)alkyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, (CrCeJalkyOδ-IO-membered heteroaryl-, C₁-C₆ alkyl-CONH, wherein the C₁-C₆ alkyl may be substitituted with a 5-10-membered heteroaryl or with a C₆-C₁₀ aryl that may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, C₆- Cio aryl-CONH-, wherein the C₆-C₁₀ aryl may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, wherein the 5-10-membered heteroaryl may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, 5-10-membered heteroaryl-CONH-, wherein the 5-10- membered heteroaryl may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, 3-10-membered heterocycloalkyl-CONH- wherein the 3-10-membered heterocycloaikyl may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, and is optionally fused to a C₆-Cio arene, C₃-C₁₀ cycloalkyl-CONH- wherein the 3-10-membered heterocycloaikyl may be unsubstituted or substituted with one or more C₁-C₆ alkyl, halo, C₁-C₆ alkoxy, or a combination thereof, and is optionally fused to a C₆-C₁₀ arene, and a combination thereof.

Further aspects of the invention are described in accord with the Detailed Description of the Invention which follows directly.

Detailed Description of the Invention One aspect of the present invention are compounds represented by Formula I above wherein X is a (C1-C6) alkylene.

In a further embodiment of the invention, X represents a single bond or -CH₂- In a further embodiment of the invention, X is a single bond and R4 is not hydrogen. In a further embodiment of the invention, X is a single bond, and R₄ is hydrogen. In this embodiment, the compounds exist as tautomers, according to the formulas:

I Ia

Both tautomers are within the scope of the invention.

In a further embodiment of the invention, R₁ represents one or more substituents selected from the group consisting of methyl, methoxy, fluoro, and chloro. In this embodiment, R₁ may be, for example, a methyl, methoxy, fluoro, or chloro that is meta or para to the carbon-carbon bond between the two phenyl rings of formula I, or R-i may be, for example, a methyl group at the para and at either of the meta positions.

In a further embodiment of the invention, R-i represents one or more substituents selected from the group consisting of hydrogen, halo, hydroxyl, 0-(C₁-C₆ alkyl), optionally substituted (C₁-C₆) alkyl, cyano, nitro, N(R₇)₂, and NHR₇;

R₂ is hydrogen, halo, C₁-C₆ alkyl, cyano, hydroxyl, or 0-(C₁-C₆ alkyl); R₃ is hydrogen, halo, or C₁-C₆ alkyl;

R₄ is Ci-C₆ alkyl, ally!, propargyl, CH₂CN, CH₂C(O)(C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl,

C(O)-optionally substituted 5-10-membered heteroaryl, C(O)-optionally substituted (C6-C10) aryl, CH(OH)-optionally substituted 5-10-membered heteroaryl, C(O)O-(C₁-C₆ alkyl), C(O)(C₁- C₆ alkyl), OH, NH₂, -CHOH-(C₁-C₆ alkyl), C(N-OCH₃)(C₁-C₆ alkyl), (C1-C6) alkoxy-(C2-C6) alkenylene-C(O)O-(C₁-C₆ alkyl), C(O)NH₂, C(O)NH-(C₁-C₆ alkyl), or C(O)N(C₁-C₆ alkyl)₂; and R₇, independently for each occurrence, is selected from the group consisting of H, optionally substituted (C₁-C₁₀) alkyl, optionally substituted (C₂-Ci₀) 'alkenyl , optionally substituted (C₂-C₁₀) alkynyl, (C₆-C₁₀) aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted (C₃-C₁₀) cycloalkyl, and optionally substituted 3-10-membered heterocycloalkyl.

Another aspect of the present invention are compounds represented by Formula I above wherein,

X is a single bond or -CH₂-

R₁ is hydrogen, halo, or C₁-C₆ alkyl;

R₂ is hydrogen or halo;

R₃ is hydrogen, halo, or C₁-C₆ alkyl; and

R₄ is CH₂CN, CH₂C(O)(C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, C(O)-optionally substituted 5-10-membered heteroaryl, C(O)-optionally substituted (C6-C10) aryl, or CH(OH)-optionally substituted 5-10-membered heteroaryl.

Another aspect of the present invention are compounds represented by Formula I above wherein R₁, R₂, and R₃, independently for each occurrence, are selected from the group consisting of a hydrogen, a halogen, a (C₁-C₆) alkyl, and a (C₁-C₆) alkoxyl.

Another aspect of the present invention are compounds represented by Formula I above wherein X is -CH₂- and R₄ is selected from the group consisting of a cyano, (C₁-C₆) alkyl, (C₂-C₁₀) alkenyl, and (C₂-C₁₀) alkynyl.

Another aspect of the present invention are compounds represented by the formula I' shown below,

R₁, R₂, and R₃, independently for each occurrence, represent one or more substitutents selected from hydrogen, halogen, and (C₁-C₆) alkyl; and R₈ is (C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, (C₁-C₆ alkoxy), amino, -NH-(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)₂.

Exemplary compounds according to the invention include 2-(3',4'-dimethyl-biphenyl-4- yl)-3H-imidazo[4,5-c]pyridine; 2-(3\4'-dimethyl-biphenyl-4-yl)-5-methyl-5H-imidazo[4,5- φyridine; [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid methyl ester; ^-(S'^'-dimethyl-biphenyl^-ylJ-imidazo^.δ-clpyridin-S-ylJ-acetonitrile; 5-allyl-2-(3',4'-dimethyl- biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 1-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-propan-2-one; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-prop-2-ynyl-5H-imidazo[4,5- φyridine; 4-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-3-ethoxy-but-2-enoic acid ethyl ester; 5-benzyl-2-(3¹,4¹-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-pyridin-3-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4^l-dimethyl- biphenyl-4-yl)-5-pyridin-4-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dirhethyl-biphenyl-4-yl)- 5-pyridin-2-ylmethyl-5l^-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-[1-(toluene- 4-sulfonyl)-1 H-imidazol-2-ylmethyl]-5H-imidazo[4,5-c]pyridine; 2-(3¹,4'-dimethyl-biphenyl-4-yl)- 5-[1-(toluene-4-sulfonyl)-1 H-imidazol-4-ylmethyl]-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-thiazol-2-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-[2-(1 H-imidazol-4-yl)-ethyl]-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-(3-methyl-3H-imidazol-4-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(1 -methyl-1 H-imidazol-4-ylmethyl)-5H-imidazo[4,5c]pyridine; 2-[2- (3',4'-dimethyl-biphenyl^:4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-1 H-imidazol-4-yl)- ethanone; 2-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)- ethanone; 1-(2-Amino-4-methyl-thiazol-5-yl)-2-I2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yI]-ethanone; 2-(3',4¹-dimethyl-biphenyl-4-yl)-5-[2-(2H-pyrazol-3-yl)-ethyl]-5H- imidazo[4,5-c]pyridine; 2-[2-(4'-methoxy-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone hydrochloride; 2-{2-[4-(1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)- phenyl]-imidazo[4,5-c]pyridin-5-yl}-1 -(2H-pyrazol-3-yl)-ethanone maleate; 2-[2-(4'-fluoro- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone hydrochloride; 2-[2-(3'- methyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone; 2-[2-(3'-Chloro- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone hydrochloride; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2- (3'-chloro-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2- (3¹-methyl-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethanol; 2-f2-(3',4'-dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethylamine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(1 H- tetrazol-5-ylmethyl)-5H-imidazo[4,5-c]pyridine1-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-propan-2-ol; 1-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- propan-2-one O-methyl-oxime; 2-[2-(3^I,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- N,N-dimethyl-acetamide; 2-[2-(3¹,4¹-dimethyl-biphenyl-4-yl)-imidazo[4₁5-c]pyridin-5-yl]- acetamide; 2-[2-(3',4¹-dimethyl-biphenyl-4-yl)-imidazo[4,5τC]pyridin-5-yl]-N-methyl-acetamide; S-p-CS'^'-dimethyl-biphenyl^-yO-imidazoμ.δ-clpyridin-δ-ylmethyll-i ^-dihydro-pyrazol-S-one; 2-(3^I ₎4'-dirnethyl-biphenyl-4-yl)-5-(1 H-imidazol-2-ylmethyl)-5H-irnidazot4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(1 H-imidazol-4-ylmethyl)-5H-imidazo[4,5-c]pyrid'ine; 5-[2-(3',4'- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-2,4-dihydro-[1 ,2,4]triazol-3-one; 2- (3^I,4'-dimethyl-biphenyl-4-yl)-5-(1 H-[1 ₎2,4]triazol-3-ylmethyl)-5H-imidazo[4,5c]pyridirie; 5-[2- (S'^'-dimethyl-biphenyl^-ylJ-imidazoμ.δ-^pyridin-S-ylmethylJ-SH-π .S^Joxadiazol^-one; 5- [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-[1 ,3,4]oxadiazol-2-ylamine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(2-methyl-1 H-imidazol-4-yImethyl)-5H-imidazo[4,5c]pyridine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(1 H-pyrazol-4-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-[2- (3\4^imethyl-biphenyi-4-yl)-imidazo[4,5-φyridin-5-yl]-1 -{2-methy!-1 -[2-(2-methyl-1 H- imidazol-4-yl)-2-oxo-ethyl]-1 H-imidazol-4-yl}-ethanone: 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-1 H-imidazol-4-yl)-ethanol; 2-[2-(3',4'-dimethyl-biphenyl- 4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanol; 2-[2-(3,',4^I-Dimethyl-biphenyl-4- yI)-imidazo[4,5-c]pyridin-5-yI]-1-pyrazin-2-yl-ethanol; 2-(4-bromo-phenyl)-3H-imidazo[4,5- c]pyridine; 2-[4-(1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-3H-imidazo[4,5-c]pyridine hydrochloride; 2-(4'-methoxy-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; 2-(4'-fluoro-biphenyl-4- yl)-3H-imidazo[4,5-c]pyridine; 2-(3'-methyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; and 2-(3'- chloro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine.

Additional compounds of the invention include: 2-(3-Fluoro-3',4'-dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; 2-(2,5-Difluoro- 3',4'-dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; 2-(3¹,4'-Dimethyl-biphenyl-4-yl)-6- trifluoromethyl-3H-imidazo[4,5-c]pyridine; 2-(3',4^l-Dimethyl-biphenyl-4-yl)-6-methoxy-3H- imidazo[4,5-c]pyridine; 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2- methyl-2H-pyrazol-3-yl)-ethanone; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-[1 ,3,4]oxadiazol-2- ylmethyl-5H-imidazo[4,5-c]pyridine; {δ-p-CS'^'-Dimethyl-biphenyl^-yO-imidazo^.S-clpyridin- 5-ylmethyl]-[1 ,3,4]oxadiazol-2-yl}-dimethyl-amine; 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-oxazol-5-yl-ethanone; 2-t2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-[1 ,3,4]oxadiazol-2-yl-ethanone; 2-[2-(3',4'-Dimethyl-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-yl]-1-oxazol-2-yl-ethanone; 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imida2o[4,5-c]pyridin-5-yl]-1-(4-methyl-oxazol-2-yl)-ethanone; 2-[2-(3',4'-Dimethyl-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-yl]-1-(5-methyl-oxazol-2-yl)-ethanone; 2-(3-Fluoro-3',4'-dimethyl- biphenyl-4-yl)-5-(4-methyl-thiazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl- biphenyl-4-yl)-6-methoxy-5-prop-2-ynyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl- 4-yl)-5-[3-(1 H-imidazol-4-yl)-propyl]-5H-imidazo[4,5-c]pyridine; 2-[2-(4'-Methoxy-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-1 H-imidazol-4-yl)-ethanone; 2-(3',4'-Dimethyl- biphenyl-4-yl)-5-(2-hydroxy-ethyl)-5H-imidazo[4,5-c]pyridine-6-carbonitrile; 2-[2-(3',4¹-

Dimethyl-biphenyl-4-yl)-6-methoxy-imidazo[4,5-c]pyridin-5-yl]-ethanol; 2-(3',4'-Dimethyl- biphenyl-4-yl)-5-(2-methoxy-ethyl)-5H-imidazo[4,5-c]pyridine; {2-[2-(3',4'-Dimethyl-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-climethyl-amine; N-{2-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-ethyl}-N-methyl-acetamide; N-{2-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-ethyl}-acetamide; 1-{2-[2-(3\4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-ethyl}-pyrrolidin-2-one; 1-{2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one; i-^-β-β'^'-Dimethyl-biphenyM-yl)- imidazo[4,5-c]pyridin-5-yl]-ethyl}-imidazolidin-2-one; 1-{2-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-ethyl}-3-methyl-imidazolidin-2-one; 1-{2-[2-(3',4'-Dimethyl-biphenyl- 4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-3-methyl-1 ,3-dihydro-imidazol-2-one; 2-^3',4'-Dimethyl- biphenyl-4-yl)-5-(2-methyl-2H-tetrazol-5-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-{2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(1 ,2-dimethyl-1 H-imidazol-4-yl)- ethanone; 2-(3¹,4'-Dimethyl-biphenyl-4-yl)-5-(2-methyl-2H-pyrazol-3-ylmethy!)-5H-imidazo[4,5- c]pyridine; 1-{5-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyI]-pyrazol-1- yl}-ethanone; 1 -(1 -Acetyl-2-methyl-1 H-imidazol-4-yl)-2-[2-(3',4'-dimethyI-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-ethanone; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyrimidin-2-ylmethyl- 5H-imidazo[4,5-c]pyridine; 6-[2-(3\4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5- ylmethyl]-pyridin-2-ol; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyridazin-3-ylmethyl-5H-imidazo[4,5- c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyrimidin-5-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyrazin-2-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-

Dimethyl-biphenyl-4-yl)-5-pyrimidin-4-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-[2-(3',4'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1 -pyridin-4-yl-ethanone; 2-[2-(3',4'-Dimethyi- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyridin-3-yl-ethanone; 2-[2-(3',4'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyridin-2-yl-ethanone; 2-[2-(3',4'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyrimidin-4-yl-ethanone; 2-[2-(3',4'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyridazin-3-yl-ethanone; 2-[2-(3',4'-Dimethyl- biphenyI-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyrimidin-2-yl-ethanone; 5-Benzo[d]isoxazol-3- ylmethyl-2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine 5-Benzooxazol-2-ylmethyl- 2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 5-(1 H-Benzoimidazol-2-ylmethyI)-2- (S'^'-dimethyl-biphenyl^-ylJ-SH-imidazoμ.δ-cJpyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(1- methyl-1 H-benzoimidazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4- yl)-5-(1 H-indol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4^l-Dimethyl-biphenyl-4-yl)-5-(1- methyl-1 H-indol-2-ylmethy!)-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(1 H- indol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(1-methyl-1H- indol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine.

The compounds of Formula (I), (II), and some of the intermediates in the present invention may contain one or more asymmetric carbons. Pure stereochemical^ isomeric forms of said compounds and said intermediates can be obtained by the application of art- known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.

Pure stereochemically isomeric forms of the compounds of Formula (I) or (II) may also be obtained from the pure stereochemical forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereos,pecifically. The pure and mixed stereochemically isomeric forms of the compounds of, Formula (I) or (II) are intended to be embraced within the scope of the present invention.

The compounds of the invention may operate by more than one mechanism of action, including those unrelated to the Complement cascade, and the utility of the, present compounds in the practice of the invention, including for use in treating other disease states not mentioned herein , is not limited by any particular theory of operation or mechanism of action as described herein, or by those theories or mechanisms generally recognized by those skilled in the art. One aspect of the present invention is a method of synthesizing the C3a antagonists described herein. The following reaction schemes are intended to illustrate the preparation of the antagonists of the present invention.

Scheme 1

1a

Scheme 1 above illustrates a general method suitable for the preparation of compounds of formula 1a having R₁, R₂, R₃ and R₄ substituents. The synthesis of the biphenyl carboxylic acid 3 with Ri and R₂ substituents may be accomplished by the catalytic metal coupling of a substituted aryl metal species 1 with a substituted benzoic acid 2, where Y is chloride, bromide, iodide or triflate. For instance, when M is trialkylstannyl, the coupling of 1 with 2 may be performed with various phosphorylated palladium catalysts according to general procedures described by J. K. StHIe (Angew.Chem. Int.Ed. Engl., 25, (1986), 508).The preferred method of coupling, the Suzuki type coupling (Miyaura, Suzuki, Chem. Rev. 1995, 95, 2457), where M is B(OH)₂ and the X group of compound 2 is bromide, may be accomplished in the presence of a phosphorylated palladium species, where (Ph₃P)₄Pd is preferred, or a mixture of palladium species, such as palladium acetate or tris(dibenzylidineacetone)dipalladium and a triarylphosphine such as triphenylphosphine, tri(o- tolyl)phosphine or a trialkylphosphine such as tri t-butylphosphine, a base such as an alkali metal carbonate, an alkali metal phosphate, an alkali metal hydroxide or alkali metal fluoride, where sodium carbonate is preferred, in a protic or non-protic solvent such as benzene, toluene, ethanol, tetrahydrofuran, dimethylformamide, water or preferably 1 ,2- dimethoxyethane, at a temperature of from about 4O⁰C to 160⁰C, where 8O⁰C to 120⁰C is preferred. Conversion of 3 into 4 can be achieved by treatment of 3 with an R₃ substituted 3 ,4-diaminopyridine in the presence of an acidic dehydrating agent such as phosphorus oxychloride or preferably polyphosphoric acid at temperatures ranging from 140⁰C to 260⁰C, where 200°C is preferred. Alkylation of 4 to give 1a can be accomplished by deprotonation of 4 with a metal hydride base such as potassium hydride or sodium hydridό, where sodium hydride is preferred, in a polar aprotic solvent such as dimethylformamide, tetrahydrofύran or preferably dimethylsulfoxide, followed by treatment with an alkylating agent 5 having an R₄ substituent at a temperature of 15-50⁰C, where ambient temperature is preferred. The R₄ group in compound 1a may be then further modified into other R₄ groups by methods that will be immediately obvious to those skilled in the art.

Scheme 2

1a Scheme 2 above shows a variation of the synthetic sequences that may be used to synthesize compound 1a having R₁, R₂, R₃ and R₄ substituents. For instance, when group R₁ is incompatible with strong acidic compound, 1a may be prepared by first condensing R₂ substituted 2 with R₃ substituted 2,3-diaminopyridine as previously described to afford compound 6. Suzuki or Stille coupling of R₁ substituted compound 1 as previously described affords compound 4, which may be alkylated with R₄ substituted compound 5 as described earlier to afford compound 1a. When group R₁ is incompatible with strong acid and hydride bases, compound 1a may be prepared by first condensing R₂ substituted 2 with R₃ substituted 2,3-diaminopyridine as previously described to afford compound 6. Alkylation of compound 6 with R₄ substituted compound 5 as described earlier gives compound 7 that may be coupled with R₁ substituted compound 1 via Stille or Suzuki coupling as described previously to yield compound 1a.

Another aspect of the present invention is a pharmaceutical composition comprising substantially enriched enantiomeric forms of the compound(s) of the present invention, or pharmaceutically acceptable addition salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments these compositions may be formulated in unit dosage forms.

The compositions of the present invention are preferably non-pyrogenic, e.g., do not trigger elevation of a patient's body temperature by more than a clinically acceptable amount.

Another aspect of the present invention is a pharmaceutical composition comprising a compound(s) of the present invention, or pharmaceutically acceptable addition salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments these compositions may be formulated in unit dosage forms.

Plasticizers and stabilizing agents known in the art may be incorporated in the pharmaceutical compositions of the present invention. In certain embodiments, additives such as plasticizers and stabilizing agents are selected for their biocompatibility. In certain embodiments, the additives are lung surfactants, such as 1 ,2-dipalmitoylphosphatidylcholine

(DPPC) and L-α-phosphatidylcholine (PC).

A composition of this invention may further contain one or more adjuvant substances, such as fillers, thickening agents or the like. In certain embodiments, a subject composition includes an excipient. A particular excipient may be selected based on its melting point, solubility in a selected solvent (e.g., a solvent that dissolves the therapeutic agent), and the resulting characteristics of the microparticles.

Excipients may comprise a few percent, about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or higher percentage of the subject compositions.

Buffers, acids and bases may be incorporated in the subject compositions to adjust their pH. Agents to increase the diffusion distance of therapeutic may also be included.

The pharmaceutical compositions as described herein can be administered in various pharmaceutical formulations, depending on the disorder to be treated and the age, condition and body weight of the patient, as is well known in the art. For example, where the compounds are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, they may be formulated as eye-drops or eye ointments. These formulations can be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent. Although the dosage will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration and the form of the drug, in general, a daily dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses.

The precise time of administration and/or amount of therapeutic agent that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, etc. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or tim ing .

The phrase "pharmaceutically acceptable" is employed herein to refer to those therapeutic agents, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations/ The term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the therapeutic agents. These salts can be prepared in situ during the final isolation and purification of the therapeutic agent, or by separately reacting a purified therapeutic agent in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, besylate, glucoheptonate',' lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19)

In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic or organic base addition salts of the compounds of the present invention.. These salts can likewise be prepared in situ during the final isolation and purification of the therapeutic agent, or by separately reacting the purified therapeutic agent in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra). When the therapeutic agent of the present invention is administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Another aspect of the present invention is a method for preventing excessive Complement activation in a patient comprising administering to said patient; a therapeutically effective amount of the compounds of the present invention.

Another aspect of the present invention is a method for treating or preventing Complement-mediated tissue damage in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention. Another aspect of the present invention is a method for treating diseases characterized by chronic Complement activation comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. In certain embodiments, these diseases are selected from neurodegenerative diseases and pulmonary diseases. The neurodegenerative diseases may be ones which affect' the central nervous system (CNS) or the peripheral nervous system (PNS).

For example, the present compounds can be used in a method for treating Complement mediated nerve myeline loss (demyelination). Myelin provides the axonal "insulation" essential for efficient neural signal conduction in both the CNS and PNS. The cell which produces myelin in the CNS is the oligodendrocyte whereas the myelin-producing cell in the PNS is the Schwann cell. Diseases characterized by demyelination occur both in the CNS and the PNS. Accordingly, one aspect of the present invention is a method of treating Complement mediated demyelination of nerves in the CNS or in the PNS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.

In the CNS, the most common demyelination disease is .multiple sclerosis (MS).

While it is now widely accepted that MS is an autoimmune disease of the nervous system driven by infiltrating T cells specific for CNS antigens (See Prineas et al., (1987), Lab. Invest, 38, 409-421), there is evidence to suggest that Complement and other inflammation- mediating substances might be involved in myelin damage in MS. (See Yam et al., (1980), Clin. Immunol. Immunopathol., 17, 492-505; Mollenes et al., (1987), J. Neurol. Sci., 78, 17-28; Compston et al., (1989), Neuropathol. Appl. Neurobiol., 15, 307-316) Accordingly, one aspect of the present invention is a method of treating MS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.

In the PNS, several neuropathies, including, Gulliain-Barre syndrome (GBS) and Miller-Fisher syndrome (MFS) are characterized by the presence of inflammation and extensive demyelination. The majority of GBS patients have serum IgM antibodies against Schwann cells and/or PNS mylelin which can , in vitro, efficiently activate the Complement cascade. (See Koski et al., (1986), Ann. Neurol., 19, 573-577; Koski et al, (1990), Ann. Neurol., 27, S44-S47) Nyland et al., have shown that GBS serum or purified antibody causes Complement-dependent demyelination in peripheral nerve cultures. (See Nylaind et al., Acta Neurol. Scand., 58, 35-34) Moreover, it has been shown that C activation products (C3a, C5a, terminal C complex) are found in the CSF, plasma, and peripheral nerves of GBS patients. (See Hartung et al., (1987), 37, 1006-1009; Koski et al., (1987), J. Clin. Invest., 80. 1492-1497; Hays et al., (1988), J. Neuroimmuneol. 18, 231-244). Accordingly, one aspect of the present invention is a method of treating GBS or MFS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.

IgM monoclonal gammopathy and peripheral neuropathy constitute other instances of PNS diseases which are associated with (aberrant) Complement activation. (See Monaco et al., (1990, Peripheral neuropathy is a condition common in later stage (Type I, or Type II) diabetic patients. Accordingly, one aspect of the present invention is a method of treating IgM monoclonal gammopathy and peripheral neuropathy comprising administration of a therapeutically effective amount of a compound(s) of the present invention.

Another aspect of the present invention is a method of treating neuromuscular diseases wherein Complement is implicated, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. An example of such neuromuscular disease is myasthenia gravis. (See Asghar SS. Pasch MC, Frontiers in

Bioscience. 5:E63-81 , 2000 Sep 1.) v- • Another aspect of the present invention is a method for treating Alzheimer's disease comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention., The pathological hallmark of Alzheimer's disease (AD) is the senile plaque, a proteinaceous extracellular deposit composed primarily of an amyloidogenic peptide termed R-protein, and which is surrounded by dystrophic neurites. Senile plaques are the focus of a robust and chronic inflammatory response mounted by microglia, the brain's endogenous macrophage. Eikenbloom et al. disclose Complement activation in amyloid plaques in Alzheimer's dementia. ^See Eikelenboom, P., Hack, CE. et al., 1989. Virchows Archiv B - Cell Pathology Including Molecular Pathology 56, 259- 26; Eikelenboom, P., Stam, F.C., (1982) Acta Neu'ropathologica, 57, 239-242; see also Itagaki, S., Akiyama, H. et al., (1994), Brain Research, 645, 78-84; McGeer, P.L., Walker, D.G. et al., (1995), Abstracts of Papers of the American Chemical Society 210, 247, MEDI; McGeer, P. L., Akiyama, H. et al., (1989), Neuroscience Letters 107, 341-346; Pouplardbarthelaix, A., Dubas, F.et al., (1986), Neuropathology and Applied Neurobiology, 12, 609-610; Veerhuis, R., Janssen, I. et al., (1998a), Molecular Immunology 35, 312; Webster, S., Lue, L.F. et al., (1997b), Neurobiology of Aging 18, 415-421; Zhan, S.S., Veerhuis, R. et al., (1994), Neurodegeneration 3, 111- 117; see also references cited in Gasque et al., (2000), lmmunopharmacology 49, 171- 186). Implication of Complement activation in Huntington's disease has been disclosed. (See Morgan, B. P., Gasque, P. et al., (1997), lmmunopharmacology 38, 43-50, Morgan, B. P., Gasque, P., (1996), Immunology Today 17, 461-466, Morgan, B.P., Gasque, P., (1997), Clinical and Experimental Immunology 107, 1-7)

Another aspect of the present invention is a method for treating Huntington's disease (HD) comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by the onset in mid-life of chorea, dementia, personality disturbance and inexorable progression to death. Singhrao et al. have reported significant presence of Complement factors C1q, C4, C3, iC3b-neoepitope and C9- neoepitope in HD striatum, neurons, myelin and astrocytes. (See Singhrao et al., (1999), Exper. Neurolo., 159, 362-376) Another aspect of the present invention is a method for treating Pick's disease (PD) comprising administering to a patient a therapeutically effective amount'of a compound(s) of the present invention. PD is a neurodegenerative disorder, the histological hallmarks of which is the Pick body, a dense, amorphous body which is strongly stained for tau protein and ubiquitin. Neuronal loss and astrocyte proliferation occur in the areas of disease which appear to be restricted to the frontal and temporal lobes. Yasuhura et al. has shown that Complement in implicated in Pick's disease. (See Yasuhura et al., (1994), Brain Res., 652, 346-349).

Another aspect of the present invention is a method for treating asthma comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. Asthma is a disease. that affects approximately 10% of the population. The overall annual prevalence of cases has increased by 42% in the past cjecade, and despite the availability of more potent and selective therapy, the annual incidence of asthma mortality has risen by 40% over this same time period. Asthma is an allergenic reaction toward an inhaled antigen, characterized by a strong bronchoconstriction and edema formation with subsequent cell infiltration into the lung parenchyma and alveoli, mainly lymphocytes and eosinophils. Although IgE mediated histamine release is generally regarded as the major pathophysiological pathway for asthma, other non-lgE mediated mechanisms also contribute to the disease. A major candidate in that respect is the C3a analphylatoxin. Other Complement mediated pulmonary disorders include hypersensitivity pneumonites, and anaphylaxis. (See Regal, J., (1997), Immunopharmacology, 38, 17-25)

Another aspect of the present invention is a method for treating or preventing a selected from sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/reperfusion injury, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention. Lipton et al., in U.S. Patent No. 6,503,947 discloses attenuation of cerebral ischemia and reperfusion injury by administrating a Complement inhibitor.

Pharmaceutical Compositions and Their Use The pharmaceutical compositions of the present invention comprise any one or more of the above-described compounds, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier in accordance with the properties and expected performance of such a carrier, as is well-known in the art.

The dosage and dose rate of the compounds identified in the present invention effective for treating or preventing a disease or condition exhibiting, caused by or relating to amyloid formation, or a disease or condition caused by, exhibiting or relating to the activities of microglia or cells of macrophage lineage, will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.

For example, where the dosage form is oral, e.g., a tablet or capsule, suitable dosage levels may be between about 0.1 ,μg/kg and about 50.0 mg/kg body weight per day, preferably between about 1.0 μg/kg and about 5.0 mg/kg body weight per day, more preferably between about 10.0 //g/kg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 //g/kg and about 0.5 mg/kg of body weight per day of the active ingredient.

Using representative body weights of 10 kg and 100 kg in order to illustrate the range of daily aerosolized topical dosages that might be used as described above, suitable dosage levels of a compound identified in the present invention will be between about 1.0-10.0 μg and 500.0-5000.0 mg per day, preferably between about 5.0-50.0 μg and 5.0-50.0 mg per day, more preferably between about 100.0-1000.0 μg and 10.0-100.0 mg per day, and most preferably between about 200.0-2000.0 μg and about 5.0-50.0 mg per day of the active ingredient. These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. The number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half- life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient that are required for therapeutic efficacy.

Numerous other factors must also be considered in deciding upon the number of doses per day and the amount of active ingredient per dose that will be administered. Not the least important of such other factors is the individual response of the patient being treated. Thus, for example, where the active ingredient is administered topically via aerosol inhalation into the lungs, from one to four doses consisting of acuations of a dispensing device, i.e., "puffs" of an inhaler, will be administered each day, each dose containing from about 50.0 μg to about 10.0 mg of active ingredient.

Additional detailed information is as follows.

The Drug Substance Pharmaceutically acceptable salts of the compounds of formula I. include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, : hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamide, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and

If ' hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Pharmaceutically acceptable salts of compounds of formula I, for example, may be prepared by one or more of three methods:

(i) by reacting the compound of formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) by converting one salt of the compound of formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COCTNa⁺, -COO^"K⁺, or -SO₃TMa⁺) or non-ionic (such as -N^'N⁺(CH₃)₃) polar .head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970).

Hereinafter all references to compounds of formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof. The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula 1.

As indicated, so-called 'prodrugs' of the compounds of formula I are also within the scope of the invention. Thus certain derivatives of compounds of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may, be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS

Symposium Series (TJ Higuchi and W. Stella) and Bioreversible Carriers in Drug Design. Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs In accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in

Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:

(i) where the compound of formula I contains a carboxylic acid functionality (- COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C_rC₈)alkyl;

(ii) where the compound of formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula I is replaced by (C_rC₆)alkanoyloxymethyl; and

(iii) where the compound of formula I contains a primary or secondary amino functionality (-NH₂ or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is/are replaced by (CrC^alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. Moreover, certain compounds of formula I may themselves act as prodrugs of- other compounds of formula I. Also included within the scope of the invention are metabolites of compounds of formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include:

(i) where the compound of formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH); (ii) where the compound of formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (Hi) where, the. compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²);

(iv) where the compound of formula I contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂); (v) where the compound of formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula I contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH).

Compounds of formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula I contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur.

This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or I- lysine, or racemic, for example, dl-tartrate or dl-arginine.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. v ' ,

While both of the crystal forms present in a racemic mixture have identical physical properties, they may ,have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O₁ ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.Similarly, substitution with ¹²³I can be useful for Single Photon Emission Computed Tomography (SPECT) studies.

Isotopically-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆- DMSO.

Also within the scope of the invention are intermediate compounds of formula Il as hereinbefore defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula I. The invention includes all polymorphs of the aforementioned species and crystal habits thereof.

When preparing compounds of formula I in accordance with "the invention, it is open to a person skilled in the art to routinely select the form of compound of formula Il which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The Drug Product

The compounds of formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they lbut will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Oral Administration

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and and buccal/mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft, or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include . sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to, about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable, oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one functio₍n.

The compound of formula I may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula I may be in the form of multiparticulate beads. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified controlled release.. Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Additional Aspects of Drug Administration The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include .intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration . include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

An example of a needle free injection is a powderjet to provide an example of suitable technologies).formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as powdered a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for use. with needle-free injection administration comprise a compound of the invention in powdered form in conjunction with a suitable vehicle such as sterile, pyogen-free water.

Formulations for parenteral administration may be formulated to be immediate and/or modified controlled release.. Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or tragettedtargeted and programmed release. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(dl-lactic- coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically, (intra)dermaHy, or transdermal^ to the skin or mucosa. Typical formulations for this purpose tio include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). ..

Other means of topical administration include delivery by electropσration, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e:g. Powderject™, Bioject™, etc.) injection.Topical administration may also be achieved using a patch, such as a transdernal iontophoretic patch. Formulations for topical administration may be formulated to be immediate and/or modified controlled release.. Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or tragettedtargeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised ^• container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump,, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of φe invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1//I to 100//I. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified controlled release using, for example, PGLA.. Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or tragettedtargeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing the compound of formula I. The overall daily dose will typically be in the range 50 μg to 2000 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention may also be combined with "soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used foe these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 2000 mg depending, of course, on the mode of administration. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. In regard of the present specification, all patents and publications cited herein are incorporated by reference, as if fully set forth.

Example 1: Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine,

(1) A mixture of 3',4'-Dimethyl-biphenyl-4-carboxylic acid (0.50 g, 2.21 mmol, Preparation

1), 3,4-diaminopyridine (0.24 g, 2.22 mmol) and polyphosphoric acid (2g) were heated at 200⁰C for 2 h then poured into water and stirred vigorously. Trie slurry was made basic with sat. NaHCO₃ and the gray solid was filtered and dried (0.52g, 79%). Recrystallization from ethanol/1 N HCI gave 0.27 g of 2-(3¹,4'-dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine hydrochloride as a light yellow solid which had: mp >260°C; NMR (DMSOd₆) δ 9.38 (s, 1H), 8.53 (d, J= 7.1 Hz, 1 H), 8.09 (d, J = 6.2Hz, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.55 (s, 1H), 7.48 (dd, J= 7.5, 2.3 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1H), 2.27 (s, 3H), 2.24 (s, 3H); Anal. Calculated for C₂₀H₁₇N₃. HCI. 0.75 H₂O: C, 68.76; H, 5.41; N, 12.03. Found: C, 68.83; H, 5.43; N, 12.0δ! Example 2: Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-methyl-5H-imidazo[4,5- cjpyridine, (2)

2-(3\4'-Dimethyl-biphenyl-4-yl)-3H-imidazoj4,5-c]pyridine hydrochloride (Example 1, 0.50 g, 1.49 mmol) was added to a slurry of 60% sodium hydride (0.13 g, 3.25 mmol) in DMSO (10 mL). This mixture was stirred until the solids dissolved (-15 min) and methyl iodide (0.10 mL, 1.61 mmol) was added and the reaction was stirred 60 h at rt.. A white solid precipitated from solution - water (80 mL) was added and the solids were filtered and air dried (0.52g). Recrystallization from EtOAc/MeOH (6:1) with two hot filtrations gave 0.25 g (55%) of 2-(3',4'-dimethyl-biphenyl-4-yl)-5-methyl-5H-imidazo[4,5-c]pyridine as a dull yellow solid which had: mp 243-244⁰C; NMR (DMSO-d₆) δ 8.82 (d, J= 1.7 Hz, 1H), 8.37 (d, J= 8.3 Hz, 2H), 7.96 (dd, J = 6.6, 1.7 Hz₁ 1 H), 7.70 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 6.6 Hz, 1 H), 7.50 (d, J = 1.6 Hz, 1 H)₁ 7.42 (dd, J = 7.9, 1.5 Hz, 1H), 7.19 (d, J = 7.9 Hz₁ 1 H), 4.16 (s, 3H), 2.26 (s,3H), 2.22 (S₁ 3H); ¹³C NMR (DMSO-d₆) δ 171.29, 155.99, 146.04, 141.37, 137.82, 137.43, 136.39, 134.56, 132.75, 132.23, 130.74, 128.77, 128.28, 126.97, 124.51 , 112.56, 46.28, 20.20, 19.74; Anal. Calculated for C₂₁H₁₉N₃. 0.25 H₂O: C, 79.34; H, 6.18; N, 13.22. Found: C, 79.30; H, 5.97; N, 13.34. Example 3

The title compounds below were all made by essentially the same procedure as exemplified in Example 2.

A. Synthesis of [2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid methyl ester, (3) The compound of Example 1 was alkylated with methyl bromoacetate for a yield of

76%. The maleate salt prepared in ethyl acetate had: mp 194-195⁰C; NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.55 (dd, J = 7.1 , 1.3 Hz, 1 H), 8.33 (d, J = 8.7 Hz, 2H), 8.17 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (s, 1 H), 7.49 (dd, J = 7.9, 1.7 Hz, 1 H), 7.23 (d, J = 7.9 Hz₁ 1 H), 6.01 (s, 2H), 5.62 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d'₆) δ 168.36, 167.74, 144.17, 138.28,, 137.67, 137.36, 136.88, 133.82 (broad), 130.88, 129.14, 128.49, 127.75, 124.82, 60.04, 53.65, 20.19, 19.79; Anal. Calculated for C₂₃H₂₁N₃O₂-C₄H₄O₄ . 0.25 H₂O: C, 66.52; H, 5.17; N, 8.62. Found: C, 66.81 ; H, 5.04; N, 8.40

B. Synthesis of [2-(3\4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- acetonitrile, (4)

The compound of Example 1 was alkylated with bromoacetonitrile for a yield 87%. The maleate salt prepared in ethyl acetate/ethanol (4:1) had: mp 190-190.5⁰C; NMR (DMSO- d₆) δ 9.48 (s, 1H), 8.63 (dd, J = 7.1 , 1.5 Hz, 1H), 8.34 (d, J= 8.7 Hz, 2H), 8.15 (d, J = 7.1 Hz, 1 H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (s, 1 H), 7.48 (dd, J = 7.9, 1.9 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 6.04 (s, 2H), 5.88 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.71 , 144.00, 137.65, 137.30, 136.95, 136.49 (broad), 135.35 (broad), 130.87, 129.18, 128.48, 127.69, 124.79, 115.96, 47.16, 20.19, 19.79; Anal. Calculated for C₂₂H₁₈N₄-C₄H₄O₄- O^S H₂O: C, 68.04; H, 4.94; N, 12.21. Found: C, 68.25; H, 4.82; N, 12.12.

C. Synthesis of 5-Allyl-2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine,

(5)

The compound of Example 1 was alkylated with allyl bromide. The maleate salt had: mp 140-141⁰C; NMR (DMSO-d₆) δ 9.42 (s, 1 H), 8.52 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 6.6 Hz, 1 H)₁ 7.90 (d, J = 8.3 Hz, 2H), 6.23-6.13 (sym. mult., 1 H), 5.99 <s, 2H), 5.38-5.23 (m, 4H), 2.28 (s, 3H), 2.24 (s, 3H).

D. Synthesis of 1-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- propan-2-one, (6)

The compound of Example 1 was reacted with chloroacetone for a 45% yield. The maleate salt had: mp 172-173⁰C; NMR (DMSO-d₆) δ 9.24 (s, 1 H), 8.40 (d, J = 6.6 Hz, 1 H),

8.35 (d, J = 8.3 Hz, 2H), 8.17 <d, J = 7.1 Hz, 1 H)₁ 7.93 (d, J = 8.3 Hz, 2H), 7.59 (s, 1 H), 7.51

(d, J = 7.9 Hz, 1 H), 7.26 (d, J = 7.9 Hz₁ 1H)₁ 6.03 (s, 2H), 5.72 (s, 2H), 2.32 (s, 3H), 2.31 (s,

3H), 2.27 (s, 3H); ¹³C NMR (DMSO-d₆) δ 200.89, 167.83, 143.99, 137.75, 137.31 , 137.16,

136.93, 136.39 (broad), 130.87, 129.09, .128.48, 128.02. 127.71 ; 124.80, 111.70, 68.03, 27.65, 20.21 , 19.80; Anal. Calculated for C₂₃H_2IN₃O-C₄H₄O₄: C₁ 68.78; H, 5.34; N₁ 8.91.

Found: C₁ 68.71 ; H, 5.59; N, 8.92.

E. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-prop-2-ynyl-5H-imidazo[4,5- c]pyridine, (7)

The compound of Example 1 was alkylated with propargyl chloride for a 42% yield. The maleate salt had: mp 148-149.5⁰C; NMR (DMSO~d₆) δ 9.35 (s, 1H), 8.54-(d, J = 6.2 Hz,

1H), 8.33 (d, J = 8.7 Hz₁ 2H)₁ 8.11 (d, J = 6.6 Hz, 1H), 7.96-7.87 (m, 3H), 7.56 (s, I H)₁ 7.49

(dd, J = 7.5, 2.1 Hz, 1 H), 7.23 (d, J = 7.9 Hz₁ 1H), 6.18 (d, J = 6.2 Hz, 2H), 6.04 (s, 2H), 2.28 (s, 3H)₁ 2.24 (s, 3H); Anal. Calculated for C₂₃H₁₉N₃-C₄H₄O₄-H₂O: C, 68.78; H, 5.34; N, 8.91. Found: C, 68.79; H, 5.27; N, 8.92.

F. Synthesis of 4-[2-(3',4'-Dimethyl-biphenyl-4-y|)-imidazo[4,5-c]pyridin-5-yl]-3- ethoxy-but-2-enoic acid ethyl ester, (8) The compound of Example 1 was alkylated with ethyl-4-bromo-3-ethoxy-but-2-enoate for a 71 % yield. A sample purified by flash chromatography (2-5% methanol/methylene chloride) followed by< ethyl acetate trituration gave a white solid which had: mp 180-180.5⁰C; NMR (CDCI₃) δ 8.94 (s, 1 H), 8.56 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 5.8 Hz, 1 H), 8.00-7.98 (m, 1H), 7.74 (d, J= 8.3 Hz, 2H), 7.43 (s, 1 H), 7.39 (d, J= 7.5 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1 H), 5.64 (s, 2H), 5.27 (d, J = 3.8 Hz, 1 H), 4.22 (q, J= 7.2 Hz, 2H), 3.85 (q, J = 6.9 Hz, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 1.31 (t, J = 7.3 Hz, 6H); Anal. Calculated for C₂₈H₂₉N₃O₃. 0.50 H₂O:C, 72.39; H, 6.51 ; N, 9.04. Found: C, 72.66; H, 6.39; N, 9.07.

G Synthesis of 5-Benzyl-2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5- φyridine, (9) The compound of Example 1 was alkylated with benzyl bromide for a yield of .85%.

Maleate salt had: mp 177-178⁰C; NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.69 (dd, J = 6.6, 1.2 Hz, 1 H), 8.32 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 6.6 Hz, 1 H), 7.89 (d, J = 8.7' Hz, 2H), 7.56 (s, 1 H), 7.51-7.47 (m, 3H), 7.42 -7.34 (m, 3H), 7.22 (d, J = 7.9 Hz, 1 H), 6.01 <s, 2H), 5.83 (s, 2H), 2.28 (S, 3H), 2.23 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.81, 161.68, 148.21 , 144.10, 141.03, 137.66, 137.34, 136.88, 136.24, 136.19, 135.57, 130.86, 129.80, 129.66,. 129.04, 128.95, 128.50, 127.75, 124.79, 112.44, 63.08, 20.21 , 19.80; Anal. Calculated for C₂₇H₂₃N₃-C₄H₄O₄. 0.50 H₂O: C, 72.36; H, 5.48; N, 8.17. Found: C, 72.21 ; H₁ 5.57; N, 8.09. ,,

H. Synthesis of 2-(3',4'-Dirnethyl-biphenyl-4-yl)-5-pyridin-3-ylmethyl-5H- imidazo[4,5-c]pyridine, (10) The compound of Example 1 was alkylated with (3-bromomethyl) pyridine hydrobromide with 2.2 equivalent sodium hydride as a base for a yield of 46%. Dimaleate salt had: mp 184-185⁰C; NMR (DMSO-d₆) δ 9.73 (s, 1 H), 8.79-8.76 (m, 2H), 8.57 (dd, J = 4.6, 1.3 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 7.1 Hz, 1 H), 7.94-7.90 <m, 3H)₁ 7.56 (s, 1 H), 7.49 (dd, J = 7.9, 1.7 Hz, 1 H), 7.43 (dd, J = 7.9, 5.4 Hz, 1 H), 7.23 (d_> J = 7.9 Hz, 1 H), 6.07 (s, 4H), 5.90 (S₁ 2H)₁ 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.70, 160.71 , 150.88, 150.18, 144.40, 137.69, 137.44, 137.34, 136.85, 136.78, 136.08 (broad), 134.85, 131.86, 130.88, 129.07, 128.49, 127.84, 126.99, 124.83, 124.72, 112.49, 60.80, 20.21 , 19.80; Anal. Calculated for C₂₆H₂₂N₄^C₄H₄O₄: C, 65.59; H, 4.86; N, 9.00. Found: C, 65.34; H, 5.18; N 9.61. I. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyridin-4-ylmethyl-5H- imidazo[4,5-c]pyridine, (11) The compound of Example 1 was alkylated with (4-bromomethyl) pyridine hydrobromide (J.Org.Chem., 1958, 23, 575) with 3.4 equivalent sodium hydride as the base for a yield of 52%. Maleate salt had: mp 204.5-205⁰C; NMR (DMSO-d₆) δ 9.63 (s, 1H) 8.67 (d, J = 6.6 Hz, 1 H), 8.58 (d, J = 5.8 Hz, 2H), 8.33 (d, J = 7.8 Hz, 2H), 8.16 (d, J «= 7.1 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J = 7.9 Hz, 1 H), 7.34 (d, J = 5.8 Hz, 2H), 7,23 (d, J = 7.9 Hz, 1 H), 6.02 (s, 2H), 5.90 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSOd₆) δ 167.78, 161.83, 150.94, 148.39, 144.92, 144.17, 141.13, 137.67, 137.25, 136.87, 135.96, 130.87, 129.08, 128.51 , 127.78, 127.65, 124.80, 122.93, 112.49, 61.69, 20.21 , 19.80; Anal. Calculated for C₂₆H₂₂N₄-C₄H₄O₄-O-SH₂O: C, 69.89; H, 5.28; N, 10.87. Found: C, 70.05; H, 5.21; N 10,82.

J. Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-pyridin-2-ylmethyl-5H- imidazo[4,5-c]pyridine, (12)

The compound of Example 1 was alkylated with -(2-bromomethyl) pyridine hydrobromide (prepared from 2-pyridylcarbinol following the procedure of: J.Org.Chem., 1958, 23, 575) with 3.4 equivalent sodium hydride as the base for a yield of 41%. Maleate salt had: mp 177-178⁰C; NMR (DMSO-d₆) δ 9.58 (s, 1H), 8.66 <dd, J = 6.6, 1.2 Hz, 1HO, 8.47-8.45 (m, 1H), 8.32 (d, J = 8.7 Hz, 2H), 8.14 (d, J = 6.6 Hz, 1 H), 7.92-7.85 (m, 3H), 7.57-7.54 (m, 2H), 7.49 (dd, J = 7.9, 1.7 Hz, 1H), 7.38-7.34 (sym. mult., 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5.99 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.77, 154.66, 150.26, 144.17, 138.27, 137.95, 137.67, 137.37, 136.87, 136.11, 130.87, 129.07, 128.51, 127.77, 127.554, 124.82, 124.46, 123.19, 112.49, 63.77, 20.21 , 19.80; Anal. Calculated for C₂₆H₂₂N₄-C₄H₄O₄-0.5H₂O: C, 69.89; H, 5.28; N, 10.87. Found: C, 70.11 ; H, 5.35; N 10.79.

K. Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-i;i-(toluene-4-sυlfonyl)-1H- imidazol-2-ylmethyl]-5H-imidazo[4,5-c]pyridine, (13) The compound of Example 1 was alkylated with methanesulfonic acid 1-(toluene-4- sulfonyl)-1 H-imidazol-2-ylmethyl ester (J. Med. Chem., 1996, 39, 2907) for a yield of 74%. Maleate salt had: mp 167-168.5⁰C; NMR (DMSO-d₆) δ 9.55 (s, 1 H), 8.67 (dd, J = 6.6, 1.2 Hz, 1H), 8.34 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 7.1 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 1.7 Hz, 1 H), 7.58-7.49 (m, 4H), 7.25 (d, J = 7.9 Hz, 1H), 6.99 (d, J= 1.7 Hz, 1H), 6.29 (s, 2H), 6.04 (s, 2H), 2.42 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H); ¹³C NMR (DMSO-de) δ 167.77, 147.69, 144.32, 143.72, 138.67, 137.71 , 137.43, 136.90, 135.82, 134.55, 131.40, 130.93, 130.08, 129.17, 128.52, 127.81 , 127.39, 124.85, 122.13, 57.46, 21.85, 20.15, 19.77; Anal. Calculated for C₃₁H₂₇N₅O₂S-C₄H₄O₄-O-SH₂O: C, 63.86; H, 4.90; N₁ 10.64. Found: C, 63.45; H, 4.97; N 10.49. L. Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-[1-(toluene-4-sulfonyl)-1 H- imidazol-4-ylmethyl]-5H-irnidazo[4,5-c]pyridine, (14) The compound of Example 1 was alkylated with methanesulfonic acid 1-(toluene-4- sulfonyl)-1 H-imidazol-4-ylmethyl ester (J. Med. Chem., 1996, 39, 2907) for a yield of 53%. 1.5 Maleate salt had: mp 190-195⁰C; NMR (DMSOd₆) δ 9.57 (s, 1H), 8.67 (dd, J = 6.6, 1.0 Hz, 1H), 8.43 (d, J = 0.8 Hz, I H), 8.32 (d, J = 8.7 Hz, 2H), 8.15 (d, J = 6.6 Hz, 1 H), 7.99-7.92 (m, 5H), 7.58 (s, 1H), 7.51-7.49 (m, 3H), 7.25 (d, J= 7.9 hz, 1H), 6.11 (s, 3H), 5.78 (s, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.66, 147.59, 144.47, 138.75, 137.72, 137.48, 136.81 , 134.52, 134.13, 131.47, 130.93, 129.10, 128.57, 128.20, 127.87, 126.90, 124.89, 117.86, 56.85, 21.85, 20.24, 19.80; Anal. Calculated for C₃₁H₂₇N₅O₂S-LSC₄H₄O₄-I ^SH₂O: C, 60.85; H, 4.90; N, 9.59. Found: C, 60.45; H, 4.86; N 9.49.

M. Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-(5-rnethyl-[1 ,3,4]oxadiazol-2- ylmethyl)-5H-imidazo[4,5-c]pyridine, (15)

The compound of Example 1 was alkylated with 2-chloromethyl-5-methyl- [1,3,4]oxadiazole (Helv.Chim. Acta, 1972, 55, 1979) for a yield of 64%. Maleate salt had: mp 196-198⁰C; NMR (DMSO-d₆) δ 9.62 (s, 1 H), 8.71 (d, J = 6.6 Hz, 1H), 8.45 (d, J = 8.3 Hz; 2H), 8.19 (d, J = 7.1 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 2H), 7.57 {s, 1H), 7.49 (d, J = 7.5 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 6.28 (s, 2H), 6.02 (s, 2H), 2.48 (s, 3H), 2.28 (s,'3H), 2.23 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.77, 165.77, 162.12, 144.25, 138.94, 137.92, 137.66, 137.34, Ϊ36.90, 135.95, 130.86, 129.35, 128.53, 127.72, 124.83, 53.57, 20.19, 19.79, 11.16. N. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-thiazol-2-ylmethyl-5H- imidazo[4,5-c]pyridine, (16)

The compound of Example 1 was alkylated with methanesulfonic acid thiazol-2- ylmethyl ester (Preparation 3) for a yield of 64%. The maleate salt prepared in ethyl acetate had: mp 187-189⁰C; NMR (DMSO-d₆) δ 9.62 (s, 1H), 8.71 (d, J= 7.1 Hz, 1H), 8.32 (d, J = 8.3 Hz, 2H), 8.15 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.82 (AB quartet,Δ_v=9.1 , J = 3.3 Hz, 2H), 7.56 (s, 1 H), 7.48 (dd, J = 7.9, 1.7 Hz, 1 H), 7.23 (d, J= 8.3 Hz, 1 H), 6.25 (s, 2H), 6.02 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.90, 163.07, 162.05, 148.73, 144.14, 143.78, 143.70, 140.80, 137.65, 1137.49, 137.34, 136.87, 136.20, 136.15, 136.02, 130.89, 130.83, 129.11 , 129.51 , 128.43, 127.72, 127.66, 124.82, 124.77, 123.30, 123.26, 123.22, 112.30, 59.63, 20.20, 20.15, 19.80, 19.74; Anal. Calculated for C₂₄H₂₀N₄S-C₄H₄O₄-I ^SH₂O: C, 62.85; H, 5.00; N, 10.47. Found: C, 62.57; H, 4.76; N, 10.29. O. Synthesis of 2-(3^l,4'-Dimethyl-biphenyl-4-yl)-5-[2-(1 H-imidazol-4-yl)-ethyl]-5H- imidazo[4,5-c]pyridine, (17)

The compound of Example 1 was alkylated with methanesulfonic acid 2-(1-(toluene- 4-sulfonyl)-1H-imidazol-4-yl]-ethyl ester (Preparation 5) and heating to 155° C for a yield of 56%. The dihydrochloride salt as a yellow solid had: mp >260°C; NMR (DMSO-d₆) δ 14.46 (s, 1 H), 9.58 (s, 1 H), 9.04 (d, J = 1.2 Hz, 1 H), 8.62 (dd, J = 7.1 , 1.3 Hz, 1 H), 8.43 (d, J= 8.3 Hz, 2H), 8.13 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.49 (dd, J= 7.5, 1.9 Hz₁ 1 H), 7.39 (s, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 5.01 (t, J = 7.1 Hz, 2H)₁ 3.42 <t." J = 7.1 Hz, 2H), 2.8 (s, 3H), 2.24 (s, 3H); FlA- MS -394 (PH⁺).^'

P. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-.(3-methyl-3H-imidazol-4- ylmethyl)-5H-imidazo[4,5-c]pyridine, (18)

The compound of Example 1 was _, alkylated with 5-chloromethyl-1-methyl-1 H- imidazole hydrochloride (Preparation 8) for a yield of 18%. The dihydrochloride salt had: mp

248-25O⁰C; NMR (DMSOd₆) δ 9.66 (s, 1 H), 9.17 (s, 1 H), 8.77 (dd, J = 6.6, 1.2 Hz, 1H), 8.42

(d, J = 8.3 Hz, 2H), 8.20 (d, J = 7.1 Hz, 1 H), 7.94-7.91 (m, 3H), 7.57 (s, 1 H), 7.50 (dd, J = 7.5, 1.9 Hz, 1H), 7.24 (d, J= 7.9 Hz, 1H), 6.13 (s, 2H), 3.83 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H).

Q. Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-(1-methyl-1H-imidazol-4- ylmethyl)-5H-imidazo[4,5c]pyridine, (19)

The compound of Example 1 was alkylated with 4^:chloromethyl-1-methyl-1 H- imidazole hydrochloride (Preparation 9) for a yield of 18%. Dihydrochloride had: mp 235- 237⁰C (EtOH); NMR (DMSO-d₆) δ 9.70 (s, 1 H), 8.99 (br s, 1 H), 8.79 (d, J = 6.2 Hz, 1 H), 8.41

(d, J = 8.3 Hz₁ 2H), 8.19 (d, J = 6.2 Hz, 1H), 7.92-7.89 (m, 3H), 7.57 (s, 1 H), 7.49 (d, J = 7.9

Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 5.96 (br s, 2H), 3.80 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).

R. Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1- (2-methyl-1 H-imidazol-4-yl)-ethanone, (20) The compound of Example 1 was alkylated with 2-bromo-1-(2-methyl-1 H-imidazol-4- yl)-ethanone, hydrobromide (Preparation 10) for a yield of 66%. Dihydrochloride had: mp >260°C; NMR (DMSO-d₆) δ 9.49 (s, 1 H), 8.62 (dd, J= 6.6, 1.0 Hz, 1H), „8.51 (br s, 1H), 8.40 (d, J = 8.3 Hz, 2H), 8.24 (d, J = 6.6 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 2H), 7.57 <s, 1H), 7.49 (d, J= 7.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.27 (s, 2H), 2.53 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H); Anal. Calculated for C₂₆H₂₃N₅02HCI«2HCI.H₂0: C, 60.94; H, 5.31 ; N, 13.67. Found: C, 60.92; H, 5.43; N, 13.55.

S. Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1- (2H-pyrazol-3-yl)-ethanone, (21)

The compound of Example 1 was alkylated with 2-bromo-1-(2H-pyrazol-3-yl)- ethanone (Preparation 11A) for a yield of 47%. The hydrochloride salt prepared in EtOH had: mp>260°C; NMR (DMSO-d₆) δ 9.48 (s, 1 H), 8.62 (dd, J = 6.6, 1.2 Hz, 1 H), 8.41 (d, J = 8.3 Hz,

2H), 8.21 (d, J = 6.6 Hz, 1 H), 8.00 (d, J = 2.5 Hz, 1 H), 7.90 (d, J= 8.3 Hz, 2H), 7.56 (s, 1 H),

7.48 (dd, J= 7.9, 1.7 Hz, 1 H), 7.22 (d, J = 7.9, 1.0 Hz, 1H), 6.86 (d, J= 2.5 Hz, 1 H), 6.34 (s,

2H), 2.27 (s, 3H), 2.23 (s, 3H). ¹³C NMR (DMSO-d₆) 8 187.29, 160.31 , 148.16, 144.43, 139.21, 137.67, 137.42, 136.79, 132.07, 130.86, 129.28, 127.77, 26.79, 124.83, 111.56,

106.58, 65.83, 20.17, 19.78; Anal. Calculated for C₂₅H₂₁ N₅O»2HCI: C, 62.51 ; H, 4.83; N,

14.58. Found: C, 62.93; H, 5.08; N, 14.59. T. Synthesis of 1-(2-Amino-4-methyl-thiazol-5-yl)-2-[2-(3\4'-dimethyl-biphenyl-4- y))-imidazo[4,5-c]pyridin-5-yl]-ethanone, (22)

The compound of Example 1 was alkylated with 1-(2-amino-4-methyl-thiazol-5-yl)-2- bromo-ethanone (Preparation 11B) for a yield of 58%. The hydrochloride salt prepared in EtOH had: mp>260°C; NMR (DMSOd₆) δ 9.45 (s, 1 H), 8.58 (dd, J = 7.1 , 1.3 Hz, 1 H), 8.50 (br s, 1 H), 8.46 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 6.6 Hz, 1 H), 7.92 (d, J = 8.3 Hz, 2H), 7.59 (s, 1 H), 7.51 (d, J = 7.8 Hz, IH), 7.24 (d, J= 7.9 Hz, 1 H), 6.15 (m, 3H), 2.53 (s, 3H), 2.29 (s, 3H)₁ 2.25 (s, 3H). ¹³C NMR (DMSO-dβ) δ 182.65, 172.04, 144.43, 139.15, 137.67, 136.82, 134.40,130.89, 129.32, 128.57, 127.76, 126.82, 117.74, 66.57, 20.17, 19.78, 18.71. U. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-[2-(2H-pyrazol-3-yl)-ethyl]-5H- imidazo[4,5-c]pyridine, (23)

The compound of Example 1 was alkylated with toluene-4-sulfonic acid 2-[2-(toluene- 4-sulfonyl)-2H-pyrazol-3-yl]-ethyl ester (Preparation 14) for a yield of 17%. The dihydrochloride salt prepared in ethanol had: mp 240-243⁰C; NMR (DMSO-d₆) δ 9.47 (s, 1 H), 8.61 (dd, J = 6.6, 1.3 Hz, 1 H), 8.39 (d, J = 8.3 Hz, 2H), 8.10 (d, J= 7.1 Hz, 1 H), 7.90 <(d; J = 8.7 Hz, 2H), 7.60 (d, J = 2.5 Hz, 1 H), 7.57 (s, 1 H), 7.49 (dd, J = 7.5, 1.9 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1H), 6.12 (d, J= 2.1 Hz, 1H), 4.93 (t, J = 7.1 Hz, 2H), 3.31 (t, J = 6.8 Hz, 2H), 2.76 (s, 3H), 2.24 (S, 3H).

V. Synthesis of 2-[2-(4'-Methoxy-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone hydrochloride, (24)

2-(4'-methoxy-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 23 37) was alkylated with 2-bromo-1-(2H-pyrazol-3-yl)-ethanone (Preparation 11A) for a yield of 22%. The hydrochloride salt prepared in EtOH had: mp>260°C; NMR (DMSO-d₆) δ 9.48 (s, 1H), 8.63 (dd, J = 6.6, 1.2 Hz, 1 H), 8.38 (d, J = 8.3 Hz, 2H), 8.24 (d, J = 6.6 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 2.5 Hz, 1 H), 6.33 (s, 2H), 3.79 (s, 3H); ¹³C NMR (DMSO-d₆) δ 187.31, 160.34, 148.15, 144.05, 139.20, 137.34, 132.10, 131.60, 129.33, 128.79, 127.47, 126.41 , 115.23, 111.61 , 106.59, 65.83, 55.96; Anal. Calculated for C₂₄H₁₉N₅O«2HCI.1.5 H₂O: C, 56.59; H, 4.75; N, 13.75. Found: C, 56.93; H, 4.51 ; N, 14.05. X. Synthesis of 2-[2-(4'-Fluoro-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone hydrochloride, (25)

2-(4'-fluoro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 24A) was alkylated with 2-bromo-1-(2H-pyrazol-3-yl)-ethanone (Preparation 11A) for a yield of 48%. The hydrochloride salt had: mp >260°C; NMR (DMSO-d₆) δ 9.51 (s, 1 H), 8.64 (dd, J = 6.6, 1.2 Hz, 1H), 8.44 (d, J = 8.3 Hz, 2H), 8.24 (d, J = 6.6 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 2H), 7.86-7.82 (m, 2H), 7.33 (t, J = 8.9 Hz, 2H), 6.88 (d, J = 1.5 Hz, 1 H), 6.35 (s, 2H); ¹³C NMR (DMSO-d₆) δ 187.32, 164.30, 161.86, 160.15, 148.14, 147.33, 143.27, 139.24, 137.49, 135.91 , 135.88, 132.03, 129.76, 129.68, 129.39, 128.10, 127.20, 116.75, 116.53, 111.64, 106.57, 65.83.

Y. Synthesis of 2-[2-(3'-Methyl-biphenyl-4-yl)-imidazo[4,5-φyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone, (26) 2-(3'-methyl-biphenylr4-yl)-3H-imida2o[4,5-c]pyridine (Example 24B) was alkylated with 2-bromo-1-(2H-pyrazol-3-yl)-ethanone (Preparation 11A) for a yield of 10%: mp 250- 260⁰C (decomp); NMR (DMSO-d₆) δ 8.79 (s, 1 H), 8.35 (d, J = 8.3 Z₁ 2H), 7.96-7.94 (m, 2H)₁ 7.69-7.65 (m, 3H), 7.49 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.79 (s, 1H), 6.03 (s, 2H), 2.30 (s, 3H). Z. Synthesis of 2-[2-(3'-Chloro-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone hydrochloride, (27)

2-(3'-chloro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 24C) was alkylated with 2-bromo-1-(2H-pyrazol-3-yl)-ethanone (Preparation 11A) for a yield of 47%. The hydrochloride salt had: mp ~195-200°C; NMR (DMSOd₆) δ 9.54 (s, 1 H), 8.67 (dd, J= 7.1, 1.1 Hz, 1 H), 8.49 (d, J = 8.7 Hz, 2H), 8.26 (d, J = 6.6 Hz, 1H), 8.03-8.00 (m, 3H), 7.88 (t, J = 1.9

Hz, 1 H), 7.80-7.76 (m, 1 H), 7.56-7.47 (m, 2H), 6.90 (d, J = 2.5 Hz, 1 H), 6.37 (s, 2H).

AA. Synthesis of 2-(3',4^l-Dimethyl-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H- imidazo[4,5-c]pyridine hydrochloride, (28)

2-(3',4'-dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 1) was alkylated with 5-chloromethyl-I H-pyrazole (JACS, 1949, 71 , 3994) for a yield of 55%. The hydrochloride salt had: mp ~185-200°C; NMR (DMSO-d₆) δ 9.64 (s, 1H), 8.70 (dd, J= 6.6, 1.2 Hz, 1H), 8.42 (d, J = 8.3 Hz, 2H), 8.13 (d, J = 6.6 Hz, 1 H), 7.89 d_t J = 8.7 Hz, 2H), 7.72 (d, J = 2.5 Hz, 1 H), 7.56 (s, 1 H), 7.48 (dd, J= 7.9, 1.7 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 6.44 (d, J= 2.5 Hz, 1H), 5.89 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H). BB. Synthesis of 2-(3'-Chloro-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H- imidazo[4,5-c]pyridine hydrochloride, (29)

2-(3'-chloro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 24C) was alkylated with 5-chloromethyl-1 H-pyrazole (JACS, 1949, 71, 3994). The hydrochloride salt had: mp -172-175⁰C (dec); NMR (DMSO-d₆) δ 9.66 (s, 1H), 8.70 (d, J = 7.5 Hz, 1H), 8.43 <d, J = 8.7 Hz, 2H), 8.13 (d, J= 6.6 hz, 1 H), 7.93 (d, J = 8.7 Hz, 2H), 7.81 (t, J = 1.7 Hz₁ 1 H), 7.76-7.71 (m, 2H), 7.50-7.41 (m , 2H), 6.45 (d, J = 2.1 Hz, 1 H)₁ 5.90 (s, 2H); ¹³C NMR (DMSO-d₆) δ 159.91, 145.59, 142.61 , 141.51 , 137.68, 136.09, 134.58, 131.58, 131.50, 129.32, 128.84, 128.34, 127.79, 127.29, 126.27, 112.18, 105.13, 57.19.

CC. Synthesis of 2-(3'-Methyl-biphenyl-4-yl)-5-(2H-pyrazol-3-ylrnethyl)-5H- imidazo[4,5-c]pyridine hydrochloride, (30)

2-(3'-methyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (Example 24B) was alkylated with 5-chloromethyl-I H-pyrazole (JACS, 1949, 71 , 3994). The hydrochloride salt had: mp ~164-167°C; NMR (DMSOd₆) δ 9.65 (s, 1 H), 8.70 (dd, J = 6.6, 1.2 Hz, 1H), 8.42 (d, J = 8.7 Hz, 2H), 8.12 (d, J= 6.6 Hz, 1 H)₁ 7.88 (d, J= 8.7 Hz, 2H), 7.72 (d, J= 2.5 Hz, 1 H), 7.56 (s, 1 H), 7.52 (d, J= 8.3 Hz, 1 H), 7.33 (t, J = 7.7 Hz, 1 H), 7.18 (d, J= 7.5 Hz, 1 H), 6.45 (d, J = 2.5 Hz, 1H), 5,89 (s, 2H), 2.34 (s, 3H); ¹³C NMR (DMSOd₆) δ 160.13, 147.09, 145.58, 144.41 , 139.32, 138.97, 137.64, 135.87, 131.51 , 129.65, 129.27, 128.16, 128.O7, 127.10 ,124.65, 112.13, 105.13, 57.15, 21.76.

Example 4: ' Synthesis of 2-[2-(3',4'-Dinnethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-ethanol, (31)

A slurry of [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid methyl ester (2.92 g, 7.86 mmol, Example 3A) in THF (150 mL) was added dropwise over 10 min. to a stirring slurry of lithium aluminum hydride (0.30 g, 7.91 mmol) in THF (50 mL)at rt. Two additional 100 mg portions of LAH were added at 1h and 2h. The reaction was carefully quenched with sodium sulfate decahydrate, then dried with anhydrous sodium sulfate. The mixture was filtered through Celite and the filter pad rinsed with 4:1 methylene chloride/ methanol (150 mL). The filtrate was concentrated onto silica gel and purified by flash chromatography, flushing first with methylene chloride and 5% methanol/ methylene chloride than eluting with 10% methanol/ methylene chloride to give 1.35 g (50%) of 2-[2-(3',4'- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethanol as a yellow-orange solid which had: mp >260°C; NMR (DMSO-d₆) δ 8.81 (d, J = 1.3 Hz, 1 H), 8.37 (d, J = 8.7 Hz, 2H), 7.98 (dd, J = 6.6, 1.5 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 6.6 Hz, 1 H), 7.50 (s, 1 H), 7.42 (dd, J = 7.9, 2.1 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 4.43 (t, J = 5.0 Hz, 2H), 3.80-3.78 (m, 2H), 3.29 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H); ¹³C NMR (DMSO-d₆) δ 171.06, 156.23, 145.76, 141.43, 137.85, 137.44, 136.40, 134.48, 132.55, 132.03, 130.75, 128.78, 128.28, 127.00, 124.52, 112.35, 61.52, 20.22, 20.19, 19.74; Anal. Calculated for C₂₂H₂₁N₃O. 0.50 H₂O: C, 74.97; H, 6.29; N, 11.92. Found: C, 74.56; H, 6.21 ; N, 12.11.

Example 5: Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-ethylamine, (32)

The title compound was made by essentially the same procedure as exemplified in Example 4 from [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetonitrile (Example 3B). The dimaleate salt had: mp 165-166⁰C; NMR (MeOH-d₄) δ 9.26 <s, 1 H), 8.53 (d, J = 6.6 Hz, 1 H), 8.30 (d, J= 8.7 Hz, 2H), 8.09 (d, J = 7.1 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.49 (s, 1 H), 7.43 (dd, J = 7.9, 2.1 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 6.21 (s, 4H), 4.94 (t, J = 6.0 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H); Anal. Calculated for C₂₂H₂₂N₄«2C₄H₄O₄.0.75 H₂O C, 61.27; H, 5.40; N, 9.53. Found: C, 61.13; H₁ 5.45; N, 9.56. Example 6: Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-(1 H-tetrazol-5- ylmethyl)-5H-imidazo[4,5-c]pyridine, (33)

[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c3pyridin-5-yl]-acetonitrile (0.100 g, 0.295 mmol, Example 3B) and azidotrimethyl tin (0.125 g, 0.607 mmol) were refluxed in THF (10 mL) for 18 h. The reaction was cooled and a light tan solid was filtered off. This was slurried in methylene chloride (15 mL) and saturated with HCI gas. After stirring for 90 min, light tan- yellow solid was filtered off to give 77 mg (63%) of 2-(3\4^l-dimethyl-biphenyl-4-yl)-5-(1H-

''^{' '} ' tetrazol-5-ylmethyl)-5H-imidazo[4,5-c]pyridine dihydrochloride salt which had: mp 220-230 C

(foams and melts); NMR (DMSO-d₆) δ 9.69 (s, 1 H), 8.77 (dd, J = 6.6, 1.3 Hz, 1H), 8.39 (d, J = 8.7 Hz, 2H), 8.24 (d, J = 6.6 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 2H), 7.58 (s, 1H), 7.50 (dd, J = 7.9, 1.9 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 6.34 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); Anal. Calculated for C₂₂H₁₉N₇.2HCI: C, 58.16; H, 4.66; N, 21.58. Found: C, 57.92; H, 4.89; N, 21.38.

Example 7: Synthesis of 1-[2-(3\4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-propan-2-ol, (34) Sodium borohydride (0.043 g, 1.14 mmol) was added to a solution of 1-[2-(3¹A¹- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-propan-2-one (0.200 g, 0.563 mmol, Example 3D) in ethanol (10 mL), and the mixture was stirred at room temperature for 16 h. A white solid had precipitated from solution. Water (20 mL) was added and the mixture was heated nearly to reflux and stirred for 15 min. The solids were filtered off, rinsed with water and dried to give 0.171 g (85%) of 1-[2-(3\4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5- yl]-propan-2-ol as a light yellow solid. The maleate salt had: mp 212-213⁰C; NMR (DMSO-d₆) δ 9.35 (S₁ 1H), 8.52 (d, J = 7.9 Hz, 1 H), 8.32 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.48 (dd, J = 7.9, 1.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 5.99 (s, 2H), 5.18 (d, J = 4.1 Hz₁ 1 H)₁ 4.66 (dd, J = 12.9, 2.9 Hz, 1 H), 4.34 (dd, J= 13.3, 8.5 Hz, 1 H), 4.05 (br s, 1 H), 2.28 (s, 3H)₁ 2.24 (s, 3H), 1.15 (d, J = 6.2 Hz₁ 3H); ¹³C NMR (DMSO-d₆) δ 167.80, 144.17, 137.77, 137.68, 137.38, 136.86, 136.29 (broad), 130.87, 129.02, 128.48, 127.78, 127.45, 124.82, 111.46, 66.76, 66.60, 21.12, 20.21 , 19.80; Anal. Calculated for C₂₃H₂₃N₃OC₄H₄O₄: C, 68.48; H, 5.75; N, 8.87. Found: C, 68.46; H, 5.92; N, 8.87.

Example 8: Synthesis of 1-[2-(3\4'-Dimethyl-biphenyl-4-yl)-irnidazo[4,5-c]pyridin- 5-yl]-propan-2-one O-methyl-oxime, (35)

1-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-propan-2-one (0.100 g, 0.281 mmol, Example 3D) and methoxylamine hydrochloride (0.50 g, 0.599 mmol) in pyridine (4 mL) was heated to 75⁰C and stirred for 3 h. The reaction was concentrated and the residue filtered and washed with water. The resulting solid was dissolved in hot ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. This solid was triturated with ether to give a 0.067 g (62%) of a white solid which proton NMR showed to be a 4:1 mixture of trans and cis isomers of 1-[2-(3',4'-dimethyl-biphenyl-4-yl)-irnidazo[4,5- c]pyridin-5-yl]-propan-2-one O-methyl-oxime. The maleate salt prepared by precipitation from an ethyl acetate solution was a 5:1 mixture of trans and cis isomers which had: mp 152- 154⁰C; NMR (DMSO-d₆) δ trans oxime: Si .40 (s, 1H), 8.49 (d, J = 6.6 Hz, 1H), 8.37 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H)₁ 7.49 (dd, J = 7.9, 1.7 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 6.00 (s, 2H), 5.39 (s, 2H), 3.65 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 1.85 (s, 3H). cis oxime: δ 9.43 (s, 1 H), 8.55 (d, J = 6.6 Hz, 1 H), 8.33 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.56 (s, 1 H), 7.49 (dd, J = 7.θ[ 1.7 Hz₁ 1H)₁ 7.23 (d, J= 8.3 Hz, 1 H), 6.00 (s, 2H), 5.54 (s, 2H), 3.84 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H)₁ 1.62 (s, 3H). Example 9: Synthesis of 2-[2-(3'₁4¹-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-

5-yl]-N,N-dimethyl-acetamide, (36)

Trimethylaluminum (2M in toluene, 0.34 ml_, 0.68 mmol) was added to a slurry of dimethyl amine hydrochloride (0.056 g, 0.69 mmol) in benzene {2 mL). This mixture was stirred until the solids dissolved, then a slurry of [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-acetic acid methyl ester (0.100 g, 0.269 mmol, Example 3A) in benzene (8 mL) was added and the resulting mixture was refluxed for 3h. The reaction was cooled, made acidic with ~5 mL 1N HCI then brought back to ~ pH 8 with saturated sodium bicarbonate solution. The suspended solid was filtered then loaded on silica gel and purified by flash chromatography using 20% methanol/ methylene chloride as eluent to give 0.092 g (89%) of 2-[2-(3'₁4^I-dimethyl-biphenyl-4-yl)-imidazo[4₁5-c]pyridin-5-yl]-N,N-dimethyl-acetamide as a white solid. The maleate salt prepared in hot ethanol had: mp 221-222⁰C; NMR (DMSO-d₆) δ 9.31 (s, 1 H), 8.46 (d, J = 7.9 Hz₁ 1Η), 8.35 (d, J = 8.3 Hz, 2H)₁ 8.16 (d, ,J = 7.1 Hz, 1H)₁ 7.93 (d, J =8.3 Hz, 2H), 7.59 (s, 1H)₁ 7.52 (dd, J = 7.5, 1.9 Hz₁ 1H), 7.26 <d, J = 7.9 Hz, 1H), 6.02 (s, 2H)₁ 5.70 (s, 2H), 3.09 (s, 3H)₁ 2.92 (s, 3H)₁ 2.31 (s, 3H)₁ 2.27 (s, 3H); ¹³C NMR (DMSO- d₆) δ 165.94, 144.18, 138.64, 137.68, 137.37, 136.87, 136.17, 130.89, 129.10, 128.51 , 127.76, 127.51, 124.82, 61.06, 36.42, 36.09, 20.21 , 19.79: Anal. Calculated for C₂₄H₂₄N₄O-C₄H₄O₄: C₁ 67.19; H₁ 5.64; N₁ 11.19. Found: C₁ 67.05; H, 5.72; N, 11.16. Example 10 The title compounds below were made by essentially the same procedure as exemplified in Example 9.

A. Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- acetamide, (37)

The half maleate salt had: mp 223-225°C; NMR (DMSO-d₆) δ 9.37 (s, 1H)₁ 8.51 (d, J = 7.1 Hz₁ 1 H)₁ 8.33 (d, J = 8.7 Hz₁ 2H)₁ 8.12 (d, J = 6.6 Hz₁ 1 H)₁ 7.95 (s, 1H)₁ 7.91 (d, J= 8.7 Hz₁ 1H), 7.61 (s, 1 H)₁ 7.57 (s, 1 H), 7.49 (d, J = 7.9 Hz, 1 H)₁ 7.23 (d, J= 7.9 Hz, 1 H), 5.99 (s, 1 H), 5.35 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H). B. Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imjda2o[4,5-c]pyridin-5-yl]-N- methyl-acetamide, (38)

The maleate salt had: mp 120-10O⁰C (amorphous); NMR (DMSO-d₆) δ 9.41 (s, 1H), 8.54 (dd, J = 7.1, 1.0 Hz₁ 1H), 8.48 (q, J = 4.8 Hz, 1H), 8.36 (d, J = 8.7 Hz, 2H), 8.14 (d, J = 6.6 Hz, 1 H), 7.91 (d, J= 8.3 Hz₁ 2H), 7.57 (s, 1 H), 7.49 (dd, J= 7.9, 1.7 Hz, 1 H), 7.23 (d, J= 7.9 Hz, 1 H), 5.39 <s, 2H), 2.66 (d, J= 4.6 Hz, 3H), 2.28 (s, 3H), 2.24 (s, 3H).

Example 11 : ^• Synthesis of 5-[2-(3\4¹-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-ylmethyl]-1 ,2-dihydro-pyrazol-3-one, (39)

4-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-3-ethoxy-but-2-enoic acid ethyl ester (0.100 g, 0.220 mmol, Example 3F) and hydrazine hydrate (1 mL) in ethanol (2 mL) were refluxed for 2.5 h. The reaction was concentrated and thβ iresidue washed with water and dried. Treatment of this solid with maleic acid in ethanol to give 62 mg (55%) of 5- [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-1 ,2-dihydro-pyrazol-3-one maleate salt as a tan solid which had: mp - foams at -24O⁰C; NMR (DMSO-d₆) δ 9.53 (s, 1 H), 8.61 (d, J = 6.2 Hz, 1 H), 8.34 (d, J = 8.3 Hz, 2H), 8.13 (d, J = 7.1 Hz₁ 1H)₁ 7.93 (d, J = 8.3 Hz₁ 2H), 7.59 (s, 1H)₁ 7.51 (dd, J = 7.9, 1.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H)₁ 6.04 (s, 2H), 5.70 (s, 2H)₁ 5.59 (s, 1H), 2.31 (s, 3H), 2.27 (s, 3H); ¹³C NMR (DMSCkJ₆) S 167.82, 144.22, 137.67, 137.39, 137.02, 136.83, 136.03, 130.88, 129.05, 128.49, 127.78, 127.36, 124.81, 112.12, 20.19, 19.80; Anal. Calculated for C₂₄H₂₁N₅O-C₄H₄O₄-O-S H₂O: C₁ 64.61 ; H, 5.03; N₁ 13.45. Found: C₁ 64.60; H₁ 4.99; N₁ 13.54.

Example 12: Synthesis of 2-(3^l,4'-Dirnethyl-biphenyl-4-yl)-5-(1 H-imidazol-2- ylmethyl)-5H-imidazo[4,5-c]pyridine, (40)

A saturated solution of HCI in ether (10 mL) was added to solution of 2-(3',4'- dimethyl-biphenyl-4-yl)-5-[1-(toluene-4-sulfonyl)-1 H-imidazol-2-ylmethyl]-5H-imidazo[4,5- c]pyridine (0.100 g, 0.187 mmol, Example 3K) in methylene chloride (10 mL). After stirring at room temperature for 16 h, the mixture was resaturated with HCI gas and stirred for an additional 2h. The yellow precipitate was filtered off and pulped with 2mL ethanol, cooled and collected to give 40 mg (47%) of the tri-HCI salt of 2-(3\4^l-dimethyl-biphenyl-4-yl)-5-(1 H- imidazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine as a yellow solid which had: mp 235-236⁰C; NMR (DMSO-d₆) δ 9.87 (s, 1H), 8.95 (dd, J = 6.6, 1.2 Hz, 1 H), 8.44 (d, J = 8.3 Hz, 2H), 8.27 (d, J = 7.1 Hz₁ 1 H)₁ 7.94 (d, J = 8.7 Hz₁ 2H)₁ 7.72 (s, 2H), 7.60 (s, 1 H), 7.52 (dd, J = 7.9, 1.7 Hz₁ 1H), 7.26 (d, J = 7.9 Hz₁ 1 H)₁ 6.31 (s, 2H)₁ 2.30 (s, 3H), 2.26 (s, 3H); ¹³C NMR (DMSO-d₆) δ 114.60, 140.46, 138.28, 137.68, 137.47, 136.77, 130.90, 130.85, 129.35, 128.59, 128.51 , 127.81, 126.63, 124.89, 124.83, 120.90, 120.81, 112.49, 52.73, 20.16. 19.76; Anal. Calculated for C₂₄H₂₁ N₅»3HCI»0.75 H₂O: C, 57.38; H₁ 5.12; N, 13.94. Found: C, 57.43; H₁ 5.31; N₁ 13.82. Example 13: Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(1 H-innidazol-4- ylmethyl)-5H-imidazo[4,5-c]pyridine, (41 )

The title compound was prepared following the procedure exemplified in Example 12 from 2-(3^l,4'-dimethyl-biphenyl-4-yl)-5-[1-(toluene-4-sulfonyl)-1H-imidazol-4-ylmethyl]-5H- imidazo[4,5-c]pyridine, Example 3L) for a yield of 67% of a yellow solid which had: mp >260°C; NMR (DMSO-d₆) δ 9.75 (s, 1H), 8.90 (s, 1 H), 8.83 (d, J = 7.9 Hz, 1 H), 8.43 (d, J = 8.3 Hz, 2H), 8.21 (d, J = 6.6 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7.85 (s, 1 H), 7.59 (s, 1H), 7.52 (dd, J = 7.9, 1.7 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1 H), 6.02 (s, 2H), 2.30 (s, 3H), 2.26 <s, 3H); ¹³C NMR (DMSOd₆) δ 144.49, 137.67, 137.43, 136.78, 136.15, 130.85, 129.29, 128.58, 128.50, 128.18, 127.79, 126.71, 124.88, 120.47, 120.41, 53.24, 20.22, 20.16, 19.82, 19.76; Anal. Calculated for C₂₄H₂₁ N₅»2HCI«0.5 H₂O: C, 62.48; H, 5.24; N, 15.18. Found: C, 62.44; H, 5.22; N, 15.12.

Example 14: Synthesis of 5-[2-(3\4'-Dimethyl-biphenyl-4-yl)-imidazo];4,5-c]pyridin- 5-ylmethyl]-2,4-dihydro-[1 ,2,4]triazol-3-one, (42) 2-(3',4'-Dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine (0.25 g, 0.744 mmol,

Example 1) was added to a slurry of 60% sodium hydride (0.0663 g, 1.65 mmol) in DMSO (10 mL). This mixture was stirred until the solids dissolved (-20 min). N'-(2-chloro-1-imino-ethyl)- hydrazinecarboxylic acid methyl ester ( J.Med Chem. 1996, 39, 2907) (0.134 g, 0.809 mmol) was added, and the reaction was stirred 16 h at room temperature. The reaction was diluted with water (100 mL), and the light yellow-tan solid was filtered off. This was pulped with ethyl acetate (25 mL) to give 0.183 g (57%) of N'-^-β-β'^'-dimethyl-biphenyM-ylHmidazoμ.δ- cJpyridin-S-yrj-i-imino-ethyty-hydrazinecarboxylic acid methyl ester as a light tan solid which had: NMR (DMSO-d₆) δ 9.17 (br s, 1 H), 8.85 (d, J = 1.2 Hz, 1 H), 8.40 (d, J = 8.7 Hz, 2H), 7.99 (dd, J = 6.6, 1.2 hz, 1 H), 7.74 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 6.6 Hz, 1 H), 7.54 (s, 1 H), 7.46 (dd, J = 7.5, 1.7 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 6.37 (s, 2H), 5.02 (s, 2H), 3.56 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H).

This material was mixed with potassium carbonate (0.12 g, 0.87 mmol) in DMF (3.5 mL), and heated between 140° and 160⁰C for 1h. After concentration, the residue was triturated with water and ethyl acetate to give 0.052 g (31%) of 5-[2-(3',4'-dimethyl-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one as a tan solid. Treatment with maleic acid in ethanol/ethyl acetate followed by concentration and ethyl acetate trituration gave the -90-95% pure maleate salt as a white solid which had: mp > 26O⁰C; NMR (DMSO- d₆) δ 11.80 (br s, 1 H), 11.62 (s, 1 H), 9.50 (s, 1 H), 8.59 (d, J = 6.6 Hz, 1 H), 8.37 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 6.6 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7.59 (s, 1 H), 7.52 (d, J = 7.5 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 1 H), 6.04 (s, 2H), 5.78 (s, 2H), 2.31 (s, 3H), 2.27 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.78, 156.58, 144.25, 142.98, 137.67, 137.38, 136.87, 135.88, 130.92, 129.16, 128.55, 128.47, 127.77, 127.49, 124.86, 112.51 , 55.22, 20.22, 19.82. Example 15: Synthesis of 2-(3\4'-Dimethyl-biphenyl-4-yl)-5-(1 H-[1 ,2,4]triazol-3- ylmethyl)-5H-imidazo[4,5c]pyridine, (43)

The title compound below was made by essentially the same procedure as exemplified in Example 14 using formic acid N'-(2-chloro-1-imino-ethyl)-hydrazide (Preparation 2),as the alkylating agent. The maleate salt had: mp 227-23O⁰C; NMR (DMSO- d₆) δ 14.24 (br s, 1 H), 9.58 (s, 1 H), 8.68 (d, J = 5.8 Hz, 1 H), 8.59 (br s, 1 H)₁ 8.32 (d, J = 8.3

Hz₁ 2H), 8.15 (d, J =7.1 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.49 (dd, J = 7.5, 2.1

Hz, 1 H), 7.24 (d, J= 7.9 Hz, 1 H), 6.02 (s, 2H), 5.99 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C

NMR (DMSOd₆) δ 167.78, 144.27, 137.67, 137.40, 136.84, 136.38, 135.82, 130.85, 129.11 , 128.54, 128.46, 127.77, 127.34, 124.80, 112.09, 56.95, 20.21, 19.82; ; Anal. Calculated for

C₂₃H₂₀N₆-C₄H₄O₄-H₂O: C, 63.03; H, 5.09; N, 16.33. Found: C, 62.71 ; H, 4.94; N, 16.44.

Example 16: Synthesis of 5-[2-(3',4'-Dimethyl-biphenyl-4tyl)-imidazo[4,5-c]pyridin- 5-ylmethyl]-3H-[1 ,3,4]oxadiazol-2-one, (44)

2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid hydrazide (0.20 g, 0.538 mmol, Preparation 4), triphosgene (0.44 g, 1.48 mmol) and triethylamine^>(0.31 ml_, 2.22 mmol) were refluxed in THF (25 mL) for 3h. After cooling, the yellow solid was collected and triturated with ethanol to give 0.161 g (64%) of 5-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-ylmethyl]-3H-[1 ,3,4]oxadiazol-2-one, the dihydrochloride salt of which had: mp >260°C; NMR (DMSO-d₆) δ 12.66 (s, 1 H)₁ 9.60 (s, 1 H), 8.71 (dd, J = 6.6, 1.5 Hz, 1 H), 8.41 (d, J = 8.7 Hz, 2H), 8.23 (d, J = 6.6 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 2H), 7.58 (s, 1 H)₁

7.50 (dd, J = 7.9, 1.9 Hz, 1 H)₁ 7.24 (d, J = 8.3 Hz₁ 1 H)₁ 5.96 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H);

¹³C NMR (DMSO-d₆) δ 195.84, 160.73, 155.08, 152.04, 144.59, 13§.56, 137.68, 137.46,

136.77, 130.90, 129.37, 128.58, 128.51 , 127.80, 126.64, 124.88, 112.23, 54.36, 20.21 , 20.16,

19.81 , 19.76; Anal. Calculated for C₂₃H₁₉N₅O«2HCI.0.25H_zO: C, 58.17; H, 4.56; N, 14.75. Found: C, 58.23; H, 4.76; N, 14.87.

Example 17: Synthesis of 5-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-ylmethyl]-[1 ,3,4]oxadiazol-2-ylamine, (45)

2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid hydrazide

(0.100 g, 0.269 mmol, Preparation 4) and sodium carbonate (0.029 g, 0.274 mmol) in water (1 mL)/ dioxane (5 mL) were heated to ~40-50°C for 1h. The resulting yellow solution was cooled to room temperature. Bromocyanogen (5M in CH₃CN₁ 0.054 mL, 0.27 mmol) was added and the mixture was stirred for 16h. The reaction was concentrated and triturated with water, ethyl acetate and methylene chloride to give 0.085 g (80%) of 5-[2-(3',4'-dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-[1 ,3,4]oxadiazol-2-ylamine as a brown solid. The maleate salt prepared in ethanol, concentrated and triturated with ethyl acetate had: mp

235-245⁰C; NMR (DMSO-d₆) δ 9.50 (s, 1H), 8.61 (d, J = 6.6 Hz₁ 1H)₁ 8.34 (d, J = 8.3 Hz₁ 2H)₁

8.15 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.57 (s, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.24- 7.23 (m, 3H), 6.02 (s, 2H), 6.01 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.78, 165.30, 154.62, 144.14, 138.94, 137.67, 137.34, 136.91 , 135.78, 130.85, 129.15, 128.53, 127.74, 124.83, 112.49, 53.72, 20.22, 19.82; Anal. Calculated for C₂₃H₂₀NeO.C4H₄O₄-2.5H₂O: C, 58.16; H, 5.24; N, 15.07. Found: C, 58.35; H, 4.84; N, 15.16. Example 18

The title compounds below were made by essentially the alkylation procedures shown in Example 2_t, followed by the tosylate hydrolysis procedure as described in Example 12.

A. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(2-methyl-1 H-imidazol-4- ylmethyl)-5H-imidazo[4,5c]pyridine, (46)

The compound of Example 1 was alkylated with methanesulfonic acid 2-methyl-1- (toluene-4-sulfonyl)-1 H-imidazol-4-ylmethyl ester (Preparation 6) for a yield of 71%. The dihydrochloride obtained as a yellow solid had: mp >260°C; NMR <OMSO-d₆) ,δ 9.73 (s, 1 H), 8.81 (dd, J= 6.6, 1.0 Hz, 1 H), 8.42 (d, J = 8.3 Hz, 2H), 8.20 (d, J = 6.6 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 2H), 7.76 (s, 1 H), 7.57 (s, 1 H), 7.49 (dd, J = 7.9, 1.9 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1 H), 5.99 (s, 2H), 2.50 (s, 3H), 2.28 <s, 3H), 2.24 (s, 3H); Anal. Calculated for C₂₅H₂₃N₆^HCI-O-SH₂O: C, 63.16; H, 5.51; N, 14.73. Found: C, 63.37; H, 5.33; N, 14.67.

B. Synthesis of 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(1 H-pyrazol-4-ylmethyl)-5H- imidazo[4,5-c]pyridine, (47) The compound of Example 1 was alkylated with methanesulfonic acid 1-(toluene-4- sulfonyl)-1 H-pyrazol-4-ylmethyl ester (Preparation 7). The dihydrochloride, obtained as a light yellow solid, had: mp 226-232⁰C; NMR (DMSO-d₆) δ 9.67 (s, 1 H), 8.74 (dd, J = 6.6, 1.2 Hz, 1H), 8.39 (d, J = 8.3 Hz, 2H), 8.12 (d, J = 6.6 Hz, 1 H)₁ 7.91-7.88 <m, 4H), 7.56 <s, 1H), 7.49 (dd, J = 7.9, 2.1 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 5.76 <s, 2H), 2.28 (s, 3H), 2.24 (s, 3H). Example 19. Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-

5-yl]-1 -{2-methyl-1 -[2-(2-methyl-1 H-imidazol-4-yl)-2-oxo-ethyl]-1 H-imidazol-4-yl}-ethanone, (48)

2-(3^I,4'-Dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine hydrochloride (4.14 g, 12.33 mmol, Example 1) was added to a slurry of 60% sodium hydride (1.75 g, 43.80 mmol) in DMSO (100 mL). This mixture was stirred until the solids dissolved (-60 min), and 2- bromo-1-(2-methyl-1 H-imidazol-4-yl)-ethanone, hydrobromide (Preparation 10) (3.50 g, 12.33 mmol) was added and the reaction was stirred for 1 h at room temperature. Additional portions of sodium hydride (0.4Og, 10.0 mmol) and 2-bromo-1-(2-methyl-1 H-imidazol-4-yl)- ethanone, hydrobromide (1.25 g, 4.40 mmol) were added, and after stirring 1hr more, the mixture was poured into water (3 L). The pink precipitate was collected on a Celite pad and the material was then removed by rinsing with MeOH. Concentration of the rinse gave a yellow-orange solid that was partially purified by flash chromatography (10-20% MeOH/EtOAc as eluent) to give 2.18 g of a -4:1 mixture of 2-[2-(3^I,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-1-{2-methyl-1-[2-(2-methyl-1 H-imidazol-4-yl)-2-oxo-ethyl]-1H-imida2ol-4-yl}- ethanone, and 2-[2-(3\4'-dimethyl-biphenyl-4-yl)-irnidazo[4,5-c]pyridin-5-yl]-1 -(2-methyl-1 H- imidazol-4-yl)-ethanone (Example 2R) as an orange foam. A portion (0.5 gj of this mixture was treated with triethylamine (0.4 mL, 2.87 mmol) and p-toluenesulfonyl chloride (0.25 g, 1.31 mmol) in CH₂CI₂ (25 mL) and stirred overnight.. The reaction was washed with water, dried (MgSO₄) and concentrated onto silica gel. Flash chromatography using a 5%-20% MeOH/EtOAc gradient elution gave" first 0.19 g of 2-[2-(3\4'- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1 -[2-methyl-1 -(toluene-4-sulfonyl)-1 H- imidazol-4-yl]-ethanone, and then 0.31 g of N-tosylated 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1 -{2-methyl-1 -[2-(2-methyl-1 H-imidazol-4-yl)-2,-oxo-ethyl]-1 H- imidazol-4-yl}-ethanone.

Saturation of a solution of 0.2 g of N-tosylated 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1 -{2-methyl-1 -[2-(2-methyl-1 H-imidazol-4-yl)-2-oxo-ethyl]-1 H- imidazol-4-yl}-ethanone in ethanol (5 mL) with HCI gas, followed by 2h stirring gave 0.137 g of the hydrochloride salt of 2-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-{2- methyl-1-[2-(2-methyl-1H-imidazol-4-yl)-2-oxo-ethyl]-1 H-imidazol-4-yl}-ethanone as a tan- yellow which had: mp = 243-248°C (decomposes); H-NMR (DMSO-d₆) δ 9.50 (s, 1 H), 8.69 (s, 1 H), 8.62 (dd, J = 6.6, 1.2 Hz, 1 H), 8.44 (d, J = 8.3 Hz, 2H), 8.25 (s, 1 H), 8.22 (d, J = 6.6 Hz, 1 H), 7.90 (d, J = 8.7 Hz, 2H), 7.57 (s, 1 H), 7.49 (dd, J = 7.5, 1.9 Hz, 1 H), 7.22 (d, J = 8.3 Hz₁. 1H), 6.28 (s, 2H), 5.79 (s, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). Anal. Calculated for C₃₂H₂₉N₇O₂»4HCU2.5H₂O: C, 52.33; H, 5.21 ; N₁. 13.35. Found: C, 52.20; H, 5.35; N, 13.09.

Example 20: Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-1 -(2-methyl-1 H-imidazol-4-yl)-ethanol, (49)

Sodium borohydride (0.015 g, 0.397 mmol) was added to 2-[2-(3',4'-dimethyl- biphenyl^-yO-imidazo^.δ-cJpyridin-δ-ylJ-i-p-methyl-i-Ooluene^-sulfonyO-I H-imidazol^-yl]- ethanone (Example 3R) (0.200 g, 0.347 mmol) in ethanol (15 mL) and stirred 18 h at room temperature. Water (5 mL) was added and the mixture was concentrated, then redissolved in ethanol (10 mL) and filtered to remove a white solid. Saturation of the filtrate solution with HCI gas produced a yellow precipitate which was filtered and recrystallized from water/ethanol to give 0.039 g (23%) of -[2-(3^I,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl- 1 H-imidazol-4-yl)-ethanol hydrochloride as a light yellow solid which had: mp >260°C; NMR (DMSO-d₆) δ 9.51 (br s, 1 H), 8.61 (d, J = 7.1 Hz, 1H), 8.40 (br d, J = 7.5 Hz, 2H), 8.18 (br d, J = 6.2 Hz, 1 H), 7.91 (d, J = 8.7 Hz, 2H), 7.56 (s, 1 H), 7.49 (d, J = 7.9 Hz, 1H), 7.25 (s, 1H), 7.23 (d, J = 8.3 Hz, 1 H), 6.64 (d, J = 5.4 Hz, 1H), .19-5.23 (m, 1 H), 5.09-5.12 (br d, J = 12.9 Hz, 1 H), 4.82 (dd, J= 12.9, 8.7 Hz, 1 H), 2.53 (s, 3H), 2.28 (s, 3H), 2.23 (s, 3H). Example 21 : Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-y!]-1 -(2H-pyrazol-3-yl)-ethanol, (50)

Sodium borohydride (0.015 g, 0.40 mmol) was added to 2-[2-(3',4'-dimethyl-biphenyl- 4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone (Example 3S) (0.12 g, 0.29 mmol) in ethanol (15 mL) and then stirred 2hr at room temperature. Water was added to precipitate a yellow solid which was collected and dried to give 0.087 g (73%) of 2-[2-(3',4'- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanol. The maleate salt (EtOAc/EtOH) of this material had: mp ~ 230-245⁰C; NMR (DMSO-d₆) δ 9.42 (s, 1 H), 8.61 (d, J = 6.6 Hz, 1H), 8.34 (d, J = 8.3 Hz, 2H)₁ 8.15 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 8.3 Hz₁ 2H), 7.69 (S₁ 1 H), 7.59 (s, 1 H), 7.51 (d, J = 7.5 Hz, 1H)₁ 7.26 (d, J = 7.9 Hz₁ 1H), 6.27 (s, 1 H)₁ 6.03 (s, 2H), 5.91 (br s, 1H), 5.11 (br s, 1 H), 5.02 (d, J = 12.9 Hz, 1 H)₁ 4.85-4.79 (m, 1 H), 2.30 (S₁ 3H)₁ 2.26 (S₁ 3H); ¹³C NMR (DMSO-d₆) δ 167.79, 160.49, 144.28, 138.22, 137.69, 137.41 , 136.82, 135.98, 130.89, 129.05, 128.50, 127.80, 127.14, 124.83, 111.37, 103.33, 67.45, 65.16, 20.19, 19.80; Anal. Calculated for C₂₅H₂₃N₅O* C₄H₄O₄-CSH₂O C, 65.16; H, 5.28; N, 13.10. Found: C, 64.79; H₁ 5.27; N₁ 12.84.

Example 22: Synthesis of 2-[2-(3'₁4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-1-pyrazin-2-yl-ethanol, (51 )

2-(3',4'-Dimethyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine hydrochloride (0.150 g, 0.447 mmol, the title compound from Example 1 ) was added to a slurry of 60% sodium hydride (0.055 g, 1.375 mmol) in DMSO (10 mL). This mixture was stirred until the solids dissolved (-15 min), and 2-bromo-1-pyrazin-2-yl-ethanone hydrobromide (Preparation 13) (0.151 g, 0.536 mmol) was added to give a burgundy red solution. The reaction was stirred 18 h at room temperature, concentrated and loaded onto silica gel. Flash chromatography with 5- 10% methanol/ethyl acetate gave 0.199 g of crude 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-pyrazin-2-yl-ethanone as an orange solid. This was dissolved in 10 mL 20:1 ethyl acetate/ methanol, leaving behind an insoluble pinkish tan impurity. The solution was concentrated, redissolved in ethanol and treated with sodium borohydride (0.050 g, 1.32 mmol) and stirred for 2 h. The mixture was diluted with water and the tan colored precipitate was collected to yield 0.058 g (31%) of 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-pyrazin-2-yl-ethanol, the maleate salt of which had: mp ~230°C (dec); NMR (DMSO-d₆) δ 9.43 (s, 1 H), 8.77 (d, J = 1.2 Hz, 1 H), 8.68-8.64 (m, 2H), 8.57 (d, J = 7.5 Hz, 1 H), 8.34 (d, J = 8.7 Hz₁ 2H), 8.13 (d, J = 6.6 Hz, 1 H)₁ 7.92 (d, J = 8.7Hz₁ 2H)₁ 7.58 (s, 1 H)₁ 7.50 (dd, J = 7.9, 1.6 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 6.39 (d, J = 5.8 Hz₁ 1H)₁ 6.01 (S, 2H), 5.28-5.22 (m , 1 H), 5.13 (dd, J = 13.3, 3.3 Hz₁ 1 H)₁ 4.87 (dd, J = 13.3, 8.7 Hz₁ 1H)₁ 2.30 (s, 3H)₁ 2.25 (s, 3H); ¹³C NMR (DMSO-d₆) δ 167.79, 160.67, 155.73, 145.07, 144.41 , 144.31 , 144.05, 138.24, 137.69, 137.42, 136.81 , 135.84, 130.89, 129.07, 128.50, 127.81 , 127.16, 124.83, 114.46, 71.56, 64.57, 20.19, 19.79; Anal. Calculated for C₂₆H₂₃N₅O-C₄H₄O₄: C, 67.03; H, 5.06; N, 13.03. Found: C; 66.66; H, 5.08; N, 12.85.

Example 23: Synthesis of 2-(4'-Methoxy-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine, (65) 2-(4-Bromo-phenyl)-3H-imidazo[4,5-c]pyridine (Preparation 12A) (0.25 g, 0.912 mmol), 4-methoxyphenylborρnic acid (0.20 g, 1.32 mmol), tetrakis(triphenylphosphine)palladium (0) and potassium carbonate (0.126 g, 2.32 mmol) in ethanol/water (13 mL/1.5 mL) were refluxed for 2.5h. The mixture was diluted with ethanol (20 mL) and water (20 mL), filtered (Celite) and concentrated. The residue was triturated with saturated aq. NaHCO₃ (20 mL), water and ether (50 mL) to give 0.26 g (95%) of 2-(4'- methoxy-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine as a light pink-tan tiηted solid which had: mp > 260⁰C; NMR (DMSO-d₆) δ 8.90 (s, 1 H), 8.26 (d, J = 5.4 Hz, ,1 H), 8.22 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 9.1 Hz, 2H), 7.55 (d, J = 5.4 Hz, 1 H), 7.02 (J = 8.7 Hz, 2H), 3.77 (S, 3H). Example 24: The compounds below were made by a procedure analogousΛo that exemplified in Example 23.

A. 2-(4'-Fluoro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine, (66)

The compound of Preparation 12A was reacted with 4-fluorophenylboronic acid for a yield of 80% as a tan solid which had: mp > 26O⁰C; NMR (DMSO-d₆) δ 8.85 (d, J = 0.8 Hz, 1 H), 8.27 (d, J = 8.3 Hz, 2H), 8.18 (d, J = 5.4 Hz, 1 H), 7.82-7.77 (m, 4H), 7.50 (dd, J = 5.4, 0.8 Hz, 1 H), 7.29 (t, J = 8.7 Hz, 2H).

B. 2-(3'-Methyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine, (67)

The compound of Preparation 12A was reacted with 3-tolylboronic acid to yield the title compound having: mp 209-211°C; NMR (DMSO-d₆) δ 13.36^" (br s, 1 H), 8.91 <s, 1H), 8.28-8.24 (m, 3H), 7.83 (d, J = 7.5 Hz, 2H), 7.55 (s, 2H), 7.51 (d, J = 7.9 z, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1 H), 7.16<d,J = 7.5 Hz, 1 H), 2.34 (s, 3H).

C. 2-(3'-Chloro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine, (68)

The compound of Preparation 12A was reacted with 3-chlorophenylboronic acid to yield a compound having: mp 250-252⁰C; NMR (DMSO-d₆) δ 8.87 (s, 1 H), 8.29 (d, J = 8.0 Hz, 2H), 8.21 (d, J = 5.0 Hz, 1 H), 7.85 (d, J = 7.9 Hz₁, 2H), 7.79 <s, 1 H), 7.69 (d, J = 7.5 Hz,

1 H), 7.58-7.40 (m 4H).

Preparation 1 : Synthesis of 3',4'-Dimethyl-biphenyl-4-carboxylic acid, (52)

3,4 - Dimethylphenylboronic acid (6.4 g, 42.7 mmol), 4-bromobenzoic acid (10.5g,

52.7 mmol) sodium carbonate (13.6 g, 128.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.2 g, 1.0 mmol) in dimethoxyethane (90 mL)/ water (30 mL) were refluxed for 5 h then concentrated. The residue was carefully treated with 1 N HCI and extracted into ethyl acetate.

The extract was washed with brine, dried (MgSO₄) and concentrated to a light orange solid (11.4 g). Recrystallization from ethanol gave 7.4 g (77% - 2 crops) of -95% pure 3',4'- dimethyl-biphenyl-4-carboxylic acid as a white solid which had: mp 211-213⁰C; NMR (CDCI₃) δ 12.94 (s, 1 H), 7.97 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 1.2 Hz, 1H), 7.43 (dd, J = 7.9, 2.1 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 2.28 (s, 3H), 2.24 (s, 3H). Preparation 2: Synthesis of Formic acid N'-(2-chloro-1-imino-ethyl)-hydrazide, (53)

Sodium methoxide (0.032 g, 0.592 mmol) was added to an icecold solution of chloroacetonitrile (1.26 ml_, 19.9 mmol) in methanol (15 ml_). After stirring for 45 min, acetic acid (0.034 mL, 0.594 mmol) was added to neutralize the methoxide, and formylhydrazine (1.18 g, 19.6 mmol) was added. The mixture was stirred at room temperature for an additional hour and concentrated to a yellow solid. Trituration with ethanol (20 mL) gave 1.15 g (43%) of formic acid N'-(2-'chloro-1-imino-ethyl)-hydrazide as a white solid which NMR (DMSOd₆) showed to be a mixture of hydrated and non-hydrated formamides which was used without further purification.

Preparation 3: Synthesis of Methanesulfonic acid thiazol-2-ylmethyl ester, (54) Sodium borohydride (0.17 g, 4.49 mmol) was added to a solution * of 2- thiazolecarboxaldehyde (0.39 mL, 4.44 mmol) in ethanol (25 mL). After stirring for 1.5 h at room temperature, the reaction was quenched with water and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated to give 0.27 g, (53%) of thiazol-2-yl-methanol as a tan oil which had: NMR (CDCI₃) δ 7.72 (d, J = 3.3 Hz, 1 H), 7.31 (d, J = 3.3 Hz, 1 H), 4.95 9s, 2H); 2.83 (br s, 1 H). This was mixed with triethyl amine (0.33 mL, 2.37 mmol) in methylene chloride (4 mL) and cooled in ice. Methanesulfonylchloride (0.18 mL, 2.33 mmol) in methylene chloride (2mL) was added dropwise over 1 min. After 30 min stirring at O⁰C, the reaction was washed with water and brine, dried over magnesium sulfate and concentrated to yield 0.41 g (91 %) of methanesulfonic acid thiazol-2-ylmethyl ester as an orange oil which had: NMR (CDCI₃) δ 7.83 (d, J = 3.3 Hz, 1 H), 7.45 (d, J = 3.3 Hz, 1 H), 5.50 (s, 2H), 3.06 (s, 3H).

Preparation 4: Synthesis of 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin- 5-yl]-acetic acid hydrazide, (55)

[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid methyl ester (0.40 g, 1.08 mmol, Example 3A) and hydrazine hydrate (0.55 mL, 11.3 mmol) in ethanol (15 mL) were refluxed for 16h. The white precipitate that formed was collected and rinsed with 3mL ethanol to yield 0.290 g (73%) of 85-90% pure 2-[2-(3\4^I-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-acetic acid hydrazide which had NMR (DMSOd₆) δ 8,78 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 8.7 Hz, 2H), 7.92 (dd, J = 6.6, 1.5 Hz, 1 H), 7.73 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 6.6 Hz, 1 H), 7.52 (s, 1 H), 7.44 (dd, J = 7.9, 1.7 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 5.09 (s, 2H), 4.38 (br s, 2H), 2.29 (s, 3H), 2.24 (s, 3H). Preparation s: Synthesis of Methanesulfonic acid 2-[1-(toluene-4-sulfonyl)-1 H- imidazol-4-yl]-ethyl ester, (56)

4-lmidazoleacetic acid hydrochloride (5.93 g, 36.47 mmol) in methanol (125 mL) was saturated with HCI gas and stirred at room temperature for 5.5 h, then concentrated to give a quantitative yield of 4-imidazoleacetic acid methyl ester hydrochloride as a white solid which had NMR (MeOH- d₄) δ 8.87 (d, J = 1.2 Hz, 1H), 7.46 (s, 1 H), 3.89 (s, 2H) 3.72 <s, 3H). This was added portion-wise to a slurry of lithium aluminum hydride (2.8 g, 74.0 mmol) in THF (150 mL). The mixture, was refluxed for 3h, cooled in ice and carefully quenched with excess sodium sulfate decahydrate. This slurry was dried with anhydrous sodium sulfate and filtered through Celite with ethyl acetate rinse. Concentration gave 2.6 g of a colorless oil that NMR (CDCI₃) showed to be a 1.5:1 mixture of starting ester and 2-(1 H-imidazol-4-yl)-ethanol. This crude mixture was slurried in methylene chloride (30 mL) and triethylamine (3.3 mL, 23.6 mmoL) and p-toluenesulfonylchloride (4.45 g, 23.3 mmol) was added. THF (30 mL) was added to help dissolve the starting material. A vigorous reaction ensued. After stirring 20 min, the reaction was concentrated, the residue was partitioned between ethyl acetate and water. The organics were washed with sat. NaHCO₃ solution and brine, dried (MgSO₄) and concentrated to an oily^' white solid. Ether (50 mL) was added and the mixture was stirred vigorously for 30 min. to break up the solid. This material was filtered off and rinsed with ether to give 2.96g (30% from 4-imidazoleacetic acid hydrochloride) of pure 2-[1 -(toluene-4- sulfonyl)-1 H-imidazol-4-yl]-ethanol as a white solid which had: NMR (CDCI₃) δ 7.93 (d, J = 1.2Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.33 (d, J= 8.3 Hz, 2H), 7.05 (d, J = 1.2 Hz, 1 H), 3.83 (t, J = 5.8 Hz, 2H), 2.74-2.71 (m, 2H), 2.42 (s, 3H).

Methanesulfonyl chloride (0.29 mL, 3.75 mmol) in methylene chloride (5 mL) was added dropwise over 1-2 min to an ice cold slurry of 2-[1-(toluene-4-sulfonyl)-1 H-imidazol-4- yl]-ethanol (1.00 g, 3.75 mmol) and triethylamine (0.53 mL, 3.80 mmol) in methylene chloride (20 mL). The solids dissolved to give a light yellow solution which was stirred 1.25h at O⁰C then washed with water, dried (MgSO₄) and concentrated to give 1.1 g (85%) of methanesulfonic acid 2-[1-(toluene-4-sulfonyl)-1 H-imidazol-4-yl]-ethyl ester as a straw colored oil which upon evacuation slowly solidified to a waxy, light yellow solid which had: NMR (CDCI₃) δ 7.92 (s, 1 H), 7.79 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 1.2 Hz, 1 H), 4,42 (t, J = 6.6 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H), 2.86 (s, 3H), 2.42 (s, 3H).

Preparation 6: Synthesis of Methanesulfonic acid 2-methyl-1-(toluene-4-sulfonyl)- 1 H-imidazol-4-ylmethyl ester, (57)

2-Methyl-3H-imidazole-4-carbaldehyde (2.00 g, 18.16 mmol), triethylamine (3.0 mL, 21.5 mmol) and p-toluenesulfonylchloride (3.5 g, 18.36 mmol) were combined in methylene chloride (50 mL) and stirred at room temperature for 16 h. The reaction was concentrated and the residue partitioned between ethyl acetate and water, the organics were then washed with brine, dried (MgSO₄) and concentrated to give 4.1 g (85%) of 2-methyl-1-(toluene-4-sulfonyl)- 1 H-imidazole-4-carbaldehyde as a yellow-solid which had: NMR (CDCI₃) δ 9.79 (s, 1 H), 8.04 (s, 1 H), 7.79 (d, J = 8.7 Hz, 2H), 7.38 (ti, J = 8.7 Hz, 2H), 2.53 (s, 3H), 2.44 (s, 3H). This material was dissolved in ethanol (50 mL) and sodium borohydride (0.30 g, 7.93 mmol) was added, After stirring 2 h at room temperature, water was added and the mixture was concentrated. The residue was partitioned between ethyl acetate and water, the organics were then washed with brine, dried (MgSO₄) and concentrated to give 1.67g (83%) of [2- methyl-1-(toluene-4-sulfonyl)-1 H-imidazol-4-yl]-methanol as a white" solid . which had: NMR (CDCI₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.34 - 7.30 (m, 3H), 4.48 (s, 2H), 2.48 (s, 3H), 2.42 (s, 3H).

[2-Methyl-1-(toluene-4-sulfonyl)-1 H-imidazol-4-yl]-methanol (0.50 g, 1.88 mmol) and triethylamine (0.31 mL, 2.22 mmol) in methylene chloride (22 mL) were cooled in an ice bath and methanesulfonylchloride (0.155 mL, 2.00 mmol) in methylene chloride (3 mL) was added dropwise over 1 min. The ice bath was removed and the reaction was stirred at room temperature for 1h and then concentrated. The residue was partitioned between ethyl acetate and water, the organics then washed with brine, dried (MgSO₄) and concentrated to give 0.61 g (94%) of methanesulfonic acid 2-methyl-1-(toluene-4-sulfonyl)-1 H-im'idazol-4-ylmethyl ester as a white solid which had: NMR (CDCI₃) δ 7.77 (d, J = 8.3 Hz, 2H), 7.51 (s, 1 H), 7.36 (d, J = 8.3 Hz, 2H), 5.07 (s, 2H), 3.00 (s, 3H), 2.50 (s, 3H), 2.44 (s, 3H). Preparation 7: Synthesis of Methanesulfonic acid 1-(toluene-4-sulfonyl)-1 H-pyrazol-

4-ylmethyl ester, (58)

1 H-Pyrazole-4-carboxylic acid ethyl ester (0.50 g, 3.57 mmol), triethylamine {0.55 mL, 3.95 mmol) and p-toluenesulfonylchloride (0,71 g, 3.72 mmol) were combined in methylene chloride (20 mL) and stirred for 1h at room temperature. The mixture was concentrated and the residue partitioned between ethyl acetate and water, the organics were washed with brine, dried (MgSO₄) and concentrated to give 1.05 g of 1-(toluene-4-sulfonyl)-1 H-pyrazole-4- carboxylic acid ethyl ester as an oily white solid: Lithium borohydride (0.10 g, 4.59 mmol) was added to a slurry of this material (0.80 g, 2.72 mmol) and the mixture was stirred at room temperature for 16h. An additional portion of lithium borohydride (0.10 g) was added at 16 h, and another 0.15 g was added at 40 h .with methanol (15 mL) to help dissolve the unreacted starting material. After 64h total reaction time, the mixture was quenched with water and concentrated, the residue was partitioned between ethyl acetate and water, the organics were washed with brine, dried (MgSO₄) and concentrated to give 0.46 g of a 1 :1 mixture of starting ester and [1-(toluene-4-sulfonyi)-1H-pyrazol-4-yl]-methanol as a colorless oil. Flash chromatography using a 20-50% ethyl acetate/hexanes gradient afforded 0.149 g (21%) of pure alcohol as a white solid which had: NMR (CDCI₃) δ 8.07 (s, 1 H), 7.90 (d, J= 8.3 Hz, 2H), 7.73 (s, 1 H), 7.33 (d, J = 8.3 Hz, 2H), 4.61 (s, 2H), 2.43 (s, 3H). This material was combined with triethyl amine (0.10 ml_, 0.72 mmol) in methylene chloride (8 mL), cooled in ice and methanesulfonylchloride (0.046 mL, 0.594 mmol) in methylene chloride (2 mL) was added. After stirring 16h at room temperature, the reaction was concentrated, the residue was partitioned between ethyl acetate and water, the organ ics were washed with brine, dried (MgSO₄) and concentrated to give a 0.13 g of a - 1 :1 :0.5 mixture of [methanesulfonic acid 1- (toluene-4-sulfonyl)-1 H-pyrazol-4-ylmethyl ester, 4-chloromethyl-1-(toluene-4-sulfonyl)-1 H- pyrazole and starting alcohol. This mixture was used immediately without purification.

Preparation 8: Synthesis of 5-Chloromethyl-1-methyl-1 H-imidazole hydrochloride, (59) S-Methyl-SH-imidazole^-carboxylic acid ethyl ester (Chem. Pharm. Bull, 1994, 42,

1463) (0.62 g, 4.02 mmol) in THF (5mL) was added dropwise over 1 min. to a slurry of lithium aluminum hydride (0.25 g, 6.60 mmol) in THF (20 mL). After stirring 16h at room temperature, the reaction was carefully quenched with excess sodium sulfate decahydrate, dried with anhydrous sodium sulfate and filtered through Celite. Concentration gave 0.33 g (73%) of (3- methyl-3H-imidazol-4-yl)-methanol as a white solid which had: NMR (CDCI₃) δ 7.38 (s, 1 H), 6.87 (s, 1 H), 4.60 (s, 2H)₁ 3.69 (s, 3H). A solution of this alcohol (0.150 g, 1.34 mmol) in thionyl chloride (5 mL) was refluxed for 3 h and concentrated. The residue was dissolved in a minimum of ethanol and ether was added to precipitate a white solid. This was collected to yield 0.185 g (83%) of 5-chloromethyl-1-methyl-1H-imidazole hydrochloride which had: NMR (DMSOd₆) δ 9.15 (s, 1 H), 7.75 (d, J = 1.2 Hz, 1 H), 4.99 (s, 2H), 3.84 (s, 3H).

Preparation 9: Synthesis of the compound below was made by essentially the same procedure as exemplified in Preparation 8:

4-Chloromethyl-1-rnethyl-1 H-imidazole hydrochloride, (60)

The above compound was prepared from 1-methyl-1 H-imidazole-4-carboxylic acid ethyl ester (Chem. Pharm. Bull, 1994, 42, 1463). The compound was obtained as a sticky orange solid and used without purification.

Preparation 10: Synthesis of 2-Bromo-1-(2-methyl-1 H-imidazol-4-yl)-ethanone, hydrobromide, (61 )

Bromine (2.1 mL, 40.98 mmol) was added dropwise over 5 min to a ~90-95°C solution of 1-(2-methyl-1 H-imidazol-4-yl)-ethanone (Tetrahedron. Lett, 1985, 26, 3423) (5.00 g,

40.28 mmol) in 48% aq. HBr (100 mL). After 30 min stirring, an additional 0.2 mL (3.90 mmol) of bromine was added and stirring continued for another 30 min. The reaction was concentrated, triturated with acetone, filtered and dried under N₂ to give 9.74 g (85%) of 2- bromo-1-(2-methyl-1 H-imidazol-4-yl)-ethanone, hydrobromide salt as a light tan solid: H-NMR (DMSO-d₆) δ 8.57 (s, 1 H), 4.69 (s, 2H), 2,54 (s, 3H).

Preparation 11 : The compounds below were all made by essentially the same procedure as exemplified in Preparation 10. A. 2-Bromo-1-(2H-pyrazol-3-yl)-ethanone, (62)

The title compound was prepared from 1-(2H-pyrazol-3-yl)-ethanone for a yield of 26%. H-NMR (DMSOd₆) δ 7.87 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1 H), 4.71 (s, 2H).

B. 1-(2-Amino-4-methyl-thiazol-5-yl)-2-bromo-ethanone, (63) The title compound was prepared from 1-(2-amino-4-methyl-thiazol-5-yl)--ethanone for a yield of 70%. H-NMR (MeOH-d₄) δ 4.87 (br s, 3H), 4.42 (s, 2H), 2.59 (s, 3H).

Preparation ^2: The compounds below were made by essentially the same procedure as exemplified in Example 1.

A. 2-(4-Bromo-phenyl)-3H-imidazo[4,5-c]pyridine, (64) The compound of Example 1 was reacted with 4-bromobenzoic acid for a yield of

80%. The free base had: mp > 260⁰C; NMR (DMSOd₆) δ 8.83 (s, 1H), 8.17-8.06 (m, 3H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 5.4 Hz, 1 H); ¹³C NMR (DMSOd₆) δ 155.39, 145.18, 140.82, 139.61 , 132.52, 131.06, 129.52, 124.03, 110.23.

Preparation 13: Synthesis of 2-Bromo-1-pyrazin-2-yl-ethanone hydrobromide, (69) Bromine (0.23 mL, 4.49 mmol) was added over 3 min. to a ~80°C solution of 2- acetylpyrazine (0.50 g, 4.09 mmol) in 48% HBr (10 mL). The resulting mixture was heated between 80-90°C for 1h, concentrated then reconcentrated again from acetone. Trituration of the resulting red-brown solid with ether/acetone (20 mL/5 mL) gave 0.94 g (82%) of 2-bromo- 1-pyrazin-2-yl-ethanone as a hydrobromide salt which had: NMR (DMSOd₆) 9.12 (d, 1.2 Hz, 1 H), 8.89 (d, J = 2.5 Hz, 1 H), 8.78 (dd, J = 2.5, 1.7 Hz, 1 H), 8.07 br s, 1H + residual water), 4.96 (s, 2H).

Preparation 14 Synthesis of Toluene-4-sulfonic acid 2-[2-(toluene-4-sulfonyl)-2H- pyrazol-3-yl]-ethyl ester, (70)

(2H-Pyrazol-3-yl)-acetic acid ethyl ester (JACS, 75, 1953, 4048) <0.94 g, 6.10 mmol) in 50 mL THF was added dropwise over 20 min to a slurry of LAH in 50 mL THF. The resulting mixture was stirred at ambient temperature overnight then refluxed for 7 h. Following quenching with sodium sulfate decahydrate and drying over anh. sodium sulfate, the reaction was filtered (Celite) and concentrated to give 0.49 g (72%) of 2-(2H-pyrazol-3-yl)-ethanol as a colorless oil: NMR (CDCI₃) δ 7.49 (d, J = 2.1 Hz, 1 H), 6.13 (d, J = 2.1 Hz, 1H), 3.90 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.8 Hz, 2H). p-Toluenesulfonyl chloride (0.67 g, 3.51 mmol) was added to an ice cold solution of 2- (1 H-pyrrol-2-yl)-ethanol (0.39 g, 3.48 mmol) and triethylamine (0.98 mL, 7.03 mmol) in methylene chloride (20 mL). After stirring for 2h, the reaction was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried (MgSO₄) and concentrated to a yellow oil. Chromatography on silica gel with 50% ethyl acetate/hexanes gave 0.284 g (19%) of the ditosylate, toluene-4-sulfonic acid 2-[2-(tolυene-4-sulfonyl)-2H- pyrazol-3-yl]-ethyl ester, as a colorless oil: NMR (CDCI₃) δ 7.93 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.28 (d, J= 8.3 Hz, 4H), 6.20 (d, J = 2.5 Hz, 1 H), 4.20 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H), 2.42 (s, 3H), 2.39 (s, 3H).

Example 25

C3a Receptor Binding Assay The present assay utilizes ¹²⁵I labeled human C3a peptide (50 pM, New England

Nuclear) with detection of binding to a human B-cell line (L1.2) that has been stably transfected with a human C3a receptor construct. The C3aR transfected cell line was generated in the laboratory of Dr. Craig Gerard (Harvard Univ.).

In the assay, approximately 375,000 cells are plated per well in a 96-well plate format (200 μL total volume). In a 96-well plate format, 200 cells and C3a ligand are incubated in assay buffer (2OmM HEPES, 125 mM NaCI, 5 mM KCI, 0.5 mM glucose, 0.2% BSA, 1 mM

CaCI2, 1 mM MgCI2, pH=7.4) for 45 minutes while shaking on a titer plate shaker at room temperature. Non-specific binding is defined as binding measured following quenching with a

250-fold excess of unlabelled human C3a peptide. The reaction is pelleted by centrifugation (3500 rpm) and terminated by filtration over glass fiber A filters (1% PEI soaked) with ice-cold wash buffer (50 mM HEPES, 1mM CaCI2, 5 mM MgCI2, 0.5 M NaCI, 0.03% CHAPS). Activity is counted on a Wallac beta scintillation counter. The inhibitor compounds are tested for IC50 potency.

C3a Binding Protocol - Detailed Steps Assay Buffer: 1 L

20 mM Hepes pH 7.4 4.8Og

125 mM NaCI 7.4Og

5 mM KCI 1.02g

0.5 mM Glucose 90.10mg 0.2% BSA (SigmaA7906) 2.0Og

1 mM CaCI₂ 111 mg

1 mM MgCI₂ (hexahydrate) 203.32mg

Wash Buffer: 4L

50 mM Hepes pH 7.4 47.6g 1 mM CaCI₂ 440mg

5 mM MgCI₂ (hexahydrate) 4.08g

0.5 M NaCI 116.8g

0.03 % Chaps (SigmaC3023) 1.2Og

Filtermats: Soak Printed Filtermat A Glass Fiber Filters (Wallac; 1205-401) in 1 % (20g/L) polyethylenimine (PEI, Sigma; P3143) for 60 min. Air dry overnight. Store until used.

Hot Cocktail: 0.2 nM stock ¹²⁵l-C3a (NEN; NEX-356) in L.

C3a cold peptide:

50 μg C3a (Advanced Research Technologies; A118) in 5.4 mL assay buffer.

55 ug in 0.61 mis AB. Aliquot into 15 uL and store at -20 C.

Daily, stock is 1 uM - dilute 15 μL + 135 μl_ AB.

L12 C3a CeIJs:

Spin down cells in 50 ml tubes by 3500 rpm for 5 min at RT in the Sorvall RT6000D. Decant supernatant arid resuspend at 5 x 10⁶ cells/mL in assay buffer. Assume 1 flask for 4 plates.

Drug Dilutions

Run in triplicate at Vz log concentrations in the standard HTS format.

Prepare dilutions in 100% DMSO on the BIOMEK robot (LFL 60μL all plates).

Begin at 3.2 μM final (40 X would then be 128 μM, prepare 1.0 ml). Procedure:

Add 75 μL assay buffer to 96 well plate (polypropylene; Costar. VWR #29445-112).

Add 5 μL compound via BIOMEK 5 uL transfer program

Add 10 μL cold C3a (1 uM) to wells D7, D8, and D9. Final 50 nM in assay.

Add 50 μL (0.2nM) hot cocktail. Final -0.05 nM = 50 pM (with 33,000 cpm). Then prepare cells as described above.

Add 75 μL C3a cells (3.75e5 cells per well = 5x10⁶ cells/mL).

Incubate with shaking for 45 min, room temperature at speed 4 on the titer plate shaker.

Collect cells by centrifugation, 3500 rpm for 5 min at RT on the Sorvall. Decant the supernatant (hot) for disposal.

Harvest plate onto filtermat with Skatron Micro 96 Harvester with cold wash buffer.

Dry filtermat in microwave (4 min).

Transfer filtermat to bag (Wallac; 1205-411).

Add 10 mL Wallac beta scintillation cocktail. Seal bag. Let filters set 10 minutes to equilibrate.

Count on 1205 Betaplate liquid scintillation counter with disk for electronic storage, protocol 23.

Precipitation has been observed with ¹²⁵I C3a. To_^ counteract or minimize this it is recommended that fresh batches of radioactivity be thawed, thoroughly mixed and then aliquoted by 5 x 200 μL. Table 1

All of the references, patents, and publications cited herein are hereby incorporated by reference in their entirety.

Those skilled in the art will recognize, or be able to ascertain' using no more than routine experimentation, numerous equivalents to the compounds and methods of use thereof described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

Claims

What is claimed is:

1. A compound according to the formula

{formula I) or a pharmaceutically acceptable salt thereof, wherein

X represents a single bond or a C1-C6 alkylene optionally containing one or more heteroatoms selected from the group consisting of O, S, and N, with the proviso that the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core;

R₁ represents, one or more substituents selected from the group consisting of hydrogen, halo, hydroxyl, C(O)R₇, C(O)OR₇, N(R₇)₂₎ NHR₇, C(O)NHR₇, C(O)(R₇)₂, cyano, nitro, optionally substituted (C₁-C₆) alkyl, optionally substituted (C₃-C₁₀) cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, (C₁-C₆) acylamino, SO₂N(R₇J₂, SO₂NHR₇, O-

(C₁-C₆) alkyl, SO₂((C_rC₆) alkyl), and S(O)(C₁-C₆ alkyl); R₂ is hydrogen, halo, (C₁-C₆) alkyl, cyano, hydroxyl, 0-((C₁-C₆) alkyl), nitro, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, C(O)NH(C₁-C₆ alkyl), C(O)N(C₁-C₆ alkyl)₂, NHC(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl), SO₂NH(C₁-C₆ alkyl), OR

SO₂N(C₁-C₆ alkyl)₂;

R₄ is hydrogen, optionally substituted (C₁-C₆) alkyl, optionally substituted (C₂-C₁O) alkenyl, optionally substituted (C₂-C₁₀) alkynyl, CH₂CN, CH₂C(O)(C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, C(O)-optionally substituted 5-10-membered heteroaryl, C(O)-optionally substituted (C6-C10) aryl, CH(OH)- optionally substituted 5-10-membered heteroaryl, C(O)O-(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl), OH₁

NH₂, -CHOH-(C₁-C₆ alkyl), C(N-OCH₃)(C₁-C₆ alkyl), (C1-C6) alkoxy-(C2-C6) alkenylene-

C(O)O-(C₁-C₆ alkyl), C(O)NH₂, C(O)NH-(C₁-C₆ alkyl), or C(O)N(C₁-C₆ alkyl)₂; with the proviso that if X is a single bond and R4 contains a heteroatom, the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core; or R₃ and R₄, taken together with the ring carbon attached to R₃, the nitrogen attached to the ring carbon, and X, form an optionally substituted 3-10-membered heterocycloalkyl or an optionally substituted 5-10-membered heteroaryl when X is a single bond, and form an optionally substituted 3-10-membered heterocycloalkyl when X is a C1-C6^" alkylene; with the proviso that if X is a single bond and R4 contains a heteroatom, the heteroatom is not linked to the pyridyl nitrogen of the imidazo[4,5-c] pyridine core; and R₇, independently for each occurrence, is selected from the group consisting of H, optionally substituted (C₁-C₁₀) alkyl, optionally substituted (C₂-Ci₀) alkenyl , optionally substituted (C₂-C₁₀) alkynyl, (C₆-C₁₀) aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted (C₃-C₁₀) cycloalkyl, and optionally substituted 3-10-membered heterocycloalkyl; with the proviso that the compound of formula I is not a compound selected from the group consisting of

2. The compound of claim 1 wherein X is a (C1-C6) alkylene.

3. The compound of claim 1 wherein X represents a single bond or -CH₂-.

4. The compound of claim 1 wherein X is a single bond and R4 is not hydrogen.

5. The compound of claim 1 wherein X is a single bond, and R₄ is hydrogen.

6. The compound of claim 1 wherein R₁ represents one or more substituents selected from the group consisting of methyl, methoxy, fluoro, and chloro.'

7. The compound of claim 6 wherein Ri is a methyl, methoxy, fluoro, or chloro that is meta or para to the carbon-carbon bond between the two phenyl rings of formula I.

8. The compound of claim 6 wherein Ri is a methyl group at the para and at either of the meta positions.

9. The compound of claim 1 wherein Ri represents one or more substituents selected from the group consisting of hydrogen, halo, hydroxyl, 0-(C₁-C₆ alkyl), optionally substituted (CrC₆) alkyl, cyano, nitro, N(R₇)₂, and NHR₇; R₂ is hydrogen, halo, C₁-C₆ alkyl, cyano, hydroxyl, or 0-(C₁-C₆ alkyl);

R₃ is hydrogen, halo, or C₁-C₆ alkyl;

R₄ is C₁-C₆ alkyl, allyl, propargyl, CH₂CN, CH₂O(O)(C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, C(0)-optionally substituted 5-10-membered heteroaryl, C(0)-optionally substituted (C6-C10) aryl, CH(OH)-optionally substituted 5-10-membered heteroaryl, C(O)O-(C₁-C₆ alkyl), C(O)(C₁-C₆ alkyl), OH, NH₂, - CHOH-(C₁-C₆ alkyl), C(N-OCH₃)(C₁-C₆ alkyl), (C1-C6) alkoxy-(C2-C6) alkenylene-C(O)O-(C_r C₆ alkyl), C(O)NH₂, C(O)NH-(C₁-C₆ alkyl), or C(O)N(C₁-C₆ alkyl)₂; and '

R₇, independently for each occurrence, is selected from the group consisting of H, optionally substituted (C₁-C₁₀) alkyl, optionally substituted (C₂-C₁₀) alkenyl , optionally substituted (C₂-C₁₀) alkynyl, (C₆-C₁₀) aryl, optionally substituted (C₅-Ci₀) heteroaryl, optionally substituted (C₃-C₁₀) cycloalkyl, and optionally substituted 3-10-membered heterocycloalkyl.

10. The compound of claim 1 wherein X is a single bond or -CH₂- ,

R₁ is hydrogen, halo, or C₁-C₆ alkyl; R₂ is hydrogen or halo;

R₃ is hydrogen, halo, or C₁-C₆ alkyl; and

11. The compound of claim 1 wherein R₁, R₂, and R₃, independently for each occurrence, are selected from the group consisting of a hydrogen, a halogen, a (C₁-C₆) alkyl, and a (C₁-C₆) alkoxyl.

12. The compound of claim 1 wherein X is -CH₂- and R₄ is selected from the group consisting of a cyano, (C₁-C₆) alkyl, (C₂-C₁₀) alkenyl, and (C₂-C₁₀) alkynyl.

13 The compound of claim 1 wherein compound is a compound of the formula I' shown below,

wherein

R₁, R₂, and ' R₃, independently for each occurrence, represent one or more substitutents selected from hydrogen, halogen, and (C₁-C₆) alkyl; and R₈ is (C₁-C₆ alkyl), optionally substituted 5-10-membered heteroaryl, optionally substituted (C6-C10) aryl, (C₁-C₆ alkoxy), amino, -NH-(C₁-C₆ alkyl), and -N(C₁-C₆ alkyl)₂.

14. A compound selected from the group consisting of 2-(3\4'-dimethyl-biphenyl- 4-yl)-3H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-methyl-5H-imidazo[4,5- c]pyridine; [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-acetic acid methyl ester; ^-(S'^'-dimethyl-biphenyl^-yO-imidazo^.S-clpyridin-S-yll-acetonitrile; δ-allyl^-φ'^'-dimethyl- biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 1-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-propan-2-one; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-prop-2-ynyl-5H-imidazo[4,5- c]pyridine; 4-[2-(3¹,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-^:c]pyridin-5-yl]-3-ethoxy-but-2-enoic acid ethyl ester; 5-benzyl-2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-pyridin-3-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yI)-5-pyridin-4-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-{3\4'-dimethyl-biphenyl-4-yl)- 5-pyridin-2-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-{3',4'-dimethyl-biphenyl-4-yl)-5-[1-(toluene- 4-sulfonyl)-1 H-imidazol-2-ylmethyl]-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl-biphenyl-4-yl)- 5-[1-(toluene-4-sulfonyl)-1H-imidazol-4-ylmethyl]-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-thiazol-2-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-[2-(1H-imidazol-4-yl)-ethyl]-5H-imidazo[4,5-c]pyridine; 2-(3',4'-dimethyl- biphenyl-4-yl)-5-(3-methyl-3H-imidazol-4-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(1 -methyl-1 H-imidazol-4-ylmethyl)-5H-imidazo[4,5c]pyridine; 2-[2- (3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-1 H-imidazol-4-yl)- ethanone; 2-[2-(3',4^l-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)- ethanone; 1-(2-Amino-4-methyl-thiazol-5-yl)-2-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-ethanone; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-[2-(2H-pyrazol-3-yl)-ethyl]-5H- imidazo[4,5-c]pyridine; 2-[2-(4'-methoxy-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H- pyrazol-3-yl)-ethanone hydrochloride; 2-{2-[4-(1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)- phenyl]-imidazo[4,5-c]pyridin-5-yl}-1 -(2H-pyrazol-3-yl)-ethanone maleate; 2-[2-(4'-fluoro- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone hydrochloride; 2-[2-{3'- methyl-biphenyl-4-yl)-imidazo[4,5~c]pyridin-5-yl]-1-{2H-pyrazol~3-yl)-ethanone; 2-t2-(3'-Chlόro- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanone hydrochloride; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2- (3'-chloro-biphenyl-4-yl)-5-(2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2- (3'-methyl-biphenyl-4-yl)-5-{2H-pyrazol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine hydrochloride; 2-[2-(3',4^I-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethanol; '2-[2-{3\4'-dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethylamine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(1H- tetrazol-5-ylmethyl)-5H-imidazo[4,5-c]pyridine1-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5- c]pyridin-5-yl]-propan-2-ol; i-p-CS'^'-dimethyl-biphenyl^-yO-imidazoμ.S-cJpyridin-δ-yl]- propan-2-one O-methyl-oxime; 2-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- N,N-dimethyl-acetamide; 2-[2-(3^>,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]- acetamide; 2-[2-(3¹,4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-N-methyl-acetamide; 5-[2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-1 ,2-dihydro-pyrazol-3-one; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(1 H-imidazol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- dimethyl-biphenyl-4-yl)-5-(1H-imidazol-4-ylmethyl)-5H-imidazo[4,5-c]pyridine; 5-t2-(3',4'- dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one; 2- (S'^'-dimethyl-biphenyl^-yO-S^I H-Ii ^^ltriazol-S-ylmethyO-SH-imidazoμ.δclpyridine; 5-[2- (S'^'-dimethyl-biphenyM-ylJ-imidazoμ.δ-cJpyridin-S-ylmethyll-SH-ti .S^loxadiazol^-one; 5- [2-(3',4'-dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-ylmethyl]-[1,3,4]oxadiazol-2-ylamine; 2-(3\4'-diιτiethyl-biphenyl-4-yl)-5-<2-rnethyl-1H-imidazol-4-ylιτiethyl)-5H-irnidazo[4,5c]pyridine; 2-(3',4'-dimethyl-biphenyl-4-yl)-5-(1 H-pyrazol-4-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-[2- (S'^'-dimethyl-biphenyl^-yO-imidazoμ.S-cJpyridin-δ-ylJ-i^-methyl-i-.p^-rnethyl-I H- imidazol-4-yl)-2-oxo-ethyl]-1H-imidazol-4-yl}-ethanone: 2-[2-(3',4'-dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-1 H-imidazol-4-yl)-ethanol; 2-[2-(3',4'-dimethyl-biphenyl- 4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2H-pyrazol-3-yl)-ethanol; 2-[2-(3',4'-Dimethyl-biphenyl-4- yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyrazin-2-yl-ethanol; 2-(4-bromo-phenyl)-3H-imidazo[4,5- c]pyridine; 2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-3H-imidazo[4,5-c]pyridine hydrochloride; 2-(4'-methoxy-bipheπyl-4-yl)-3H-imidazo[4,5-c3pyridine; 2-(4'-fluoro-biphenyl-4- yl)-3H-imidazo[4,5-c]pyridine; 2-{3¹-methyl-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; and 2-(3'- chloro-biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine.

15. A compound selected from the group consisting of 2-(3-Fluoro-3\4'-dimethyl- biphenyl-4-yl)-3H-imidazo[4,5-c]pyridine; 2-(2,5-Difluoro-3',4'-dimethyl-biphenyl-4-yl)-3H- imidazo[4,5-c]pyridine; 2-(3^l,4'-Dimethyl-biphenyl-4-yl)-6-trifluoromethyl-3H-imidazo[4,5- cjpyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-6-methoxy-3H-imidazo[4,5-c]pyridine; 2-[2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(2-methyl-2H-pyrazol-3-yl)-ethanone; 2- (3',4'-Dimethyl-biphenyl-4-yl)-5-[1 ,3,4]oxadia2ol-2-ylmethyl-5H-imidazo[4,5-c]pyridine; {5-[2- (S'^'-Dimethyl-biphenyl^-yO-imidazoμ.S-clpyridin-δ-ylmethyll-ti .S^loxadiazol^-ylϊ-dimethyl- amine; 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-oxazol-5-yl-ethanone; 2-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4₎5-c]pyridin-5-yl]-1-t1,3,4]oxadiazol-2-yl-ethanone; 2-t2-(3',4^l-Dimethyl-biphenyI-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-oxazol-2-yi-ethanone; 2-[2- (3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-(4-methyl-oxazol-2-yl)-ethanone; 2- [2-(3',4'-Dimethyl-biphenyl-4-yl)-imida2o[4,5-c]pyridin-5-yl3-1-(5-methyI-oxazol-2-yl)-ethanone; 2-(3-Fluoro-3',4'-dimethyl-biphenyl-4-yl)-5-(4-methyl-thiaEol-2-ylmethyl)-5H-imidazo[4,5- c]pyridine; 2-(3\4'-Dimethyl-biphenyl-4-yl)-6-methoxy-5-prop-2-ynyl-5H-imidazo[4,5- φyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-[3-(1 H-imidazol-4-yl)-propyl]-5H-imidazo[4,5- c]pyridine; 2-[2-(4'-Methoxy-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-<2-methyl-1 H-imidazol- 4-yl)-ethanone; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(2-hydroxy-ethyl)-5₎H-innidazo[4,5-c]pyridine- 6-carbonitrile; 2-t2-(3',4'-Dimethyl-biphenyl-4-yl)-6-methoxy-imidazo[4,5-c]pyridin-5-yl]- ethanol; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(2-methoxy-ethyl)-5H-imidazo[4_>5-c]pyridine; {2-[2- (3¹,4'-Dimethyl-biphenyl-4-yl)-imidazot4,5-c]pyridin-5-yl]-ethyl}-dimethyl-amine; N-{2-[2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-N-methyl-acetamide; H-{2-[2-{3\4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-acetamide; ^^-^-(S'^'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-pyrrolidin-2-one; 1-{2-[2-(3',4'-Dimethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-1 ,3-dihydro-imidazol-2-one; 1-{2-[2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-imidazolidin-2-one; 1 -{2-[2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-y)]-ethy)}-3-methyl-imidazolidin-2-one; 1-{2-[2- (3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethyl}-3-methyl-1 ,3-dihydro-imidazol- 2-one; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(2-methyl-2H-tetrazol-5-ylmethyl)-5H-imidazo[4,5- cjpyridine; 2-[2-(3',4'-Dinnethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1 -(1 ,2-dimethyl-1 H- imidazo!-4-yl)-ethanone; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-(2-methyl-2H-pyrazol-3-ylmethyl)- 5H-imidazo[4,5-c]pyridine; 1-{5-[2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5- ylmethyl]-pyrazol-1-yl}-ethanone; 1-(1-Acetyl-2-methyI-1 H-imidazol-4-yl)-2-[2-(3',4'-dinnethyl- biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-ethanone; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5- pyrimidin-2-ylmethyl-5H-imidazo(4,5-c]pyridine; 6-[2-(3',4'-Dimethyl-biphenyl-4-yl)- imidazo[4,5-c]pyridin-5-ylmethyl]-pyridin-2-ol; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyridazin-3- ylmethyl-5H-imidazo[4,5-c]pyridine; 2-(3^I,4'-Dimethyl-biphenyl-4-yl)-5-pyrimidin-5-ylmethyl-5H- imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyrazin-2-ylmethyl-5H-imidazo[4,5- cjpyridine; 2-(3',4'-Dimethyl-biphenyl-4-yl)-5-pyrimidin-4-ylmethyl-5H-imidazo[4,5-c]pyridine; 2-[2-(3^l,4'-Dimethyl-biphenyl-4-yl)-imidazot4,5-c]pyridin-5-yl3-1-pyridin-4-yl-ethanone; 2-[2- (3',4'-Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyridin-3-yl-ethanone; 2-[2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazot4,5-c]pyridin-5-yl]-1-pyridin-2-yl-ethanone; 2-[2-(3',4'-

Dimethyl-biphenyl-4-yl)-imidazo{4,5-c]pyridin-5-yl]-1-pyrimidin-4-yl-ethanone; 2-{2-(3',4'- Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyridazin-3-yl-ethanone; 2-[2-(3',4'-

Dimethyl-biphenyl-4-yl)-imidazo[4,5-c]pyridin-5-yl]-1-pyrimidin-2-yI-ethanόne; 5-

Benzo[d]isoxazol-3-ylrnethyl-2-(3',4'-dimeihyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine 5- Benzooxazol-2-ylmethyl-2-(3\4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 5-(1H- Benzoimidazol-2-ylmethyl)-2-(3',4'-dimethyl-biphenyl-4-yl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- Dimethyl-biphenyl-4-yl)-5-(1-methyl-1 H-benzoimidazol-2-ylrriethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4^l-Dimethyl-biphenyl-4-yl)-5-(1H-indol-2-ylmethyl)-5H-imidazot4,5-c]pyridine; 2-(3',4'- Dimethyl-biphenyl-4-yI)-5-(1-methyl-1 H-indol-2-ylmethyl)-5H-imidazo[4,5-c]pyridine; 2-(3',4'- Dimethyl-biphenyl-4-yl)-5-(1H-indol-3-ylmethyi)-5H-imidazo[4,5-c]pyridine; 2-(3',4'-Dimethyl- biphenyl-4-yl)-5-(1 -methyl-1 H-indol-3-ylmethyl)-5H-imidazo[4,5-c]pyridine.

16. A pharmaceutical composition comprising the compounds of claim 1 pharmaceutically acceptable addition salts thereof, or substantially enriched enantiomeric forms thereof, and a pharmaceutically acceptable carrier.

17. A method for treating the excessive Complement activation in a patient comprising administering to said patient, a therapeutically effective amount of a compound of claim 1.

18. A method for treating a condition selected from the group consisting of Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic diseases, respiratory diseases, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity; nephritis, graft rejection, and inflammatory conditions, comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

19. A method for treating a condition selected from the group consisting of Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke, and hemorrhagic stroke, comprising administering to a patient a therapeutically effective amount of a compound of claim 1.

20. A method for antagonizing the C3_a receptor in a patient by administering an effective amount of a composition of claim 16.