WO2007034278A2

WO2007034278A2 - Fused imidazole derivatives as c3a receptor antagonists

Info

Publication number: WO2007034278A2
Application number: PCT/IB2006/002561
Authority: WO
Inventors: Michelle Marie Claffey; Steven Wayne Goldstein
Original assignee: Pfizer Products Inc.
Priority date: 2005-09-19
Filing date: 2006-09-18
Publication date: 2007-03-29
Also published as: WO2007034278A3

Abstract

Aryl substituted imidazo[4,5-c] pyridine compounds are provided. These compounds are useful in pharmaceutical compositions as C3a antagonists for treating a variety of medical conditions associated with the Complement cascade. Methods for treating such conditions are also provided.

Description

NOVEL C3A REGEPTORANTAGONISTS

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 amyloidogenϊc peptide termed A-beta protein, and which is surrounded by dystrophic neurttes. 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 immunosurveillaπce , 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 at., 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 antirheumatic drugs with a greatly reduced (right?) risk of developing AD (see, for example, McGeer, PL,, 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 phylogenetϊcaily old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault. Complement activation is a praminent feature of the inflammatory response in Alzheimer's disease, 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 proteolytically 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 indude macrophages, neutrophils, eosiniphϋs, 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 (suGh 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 Ernbler et al. in The Human Complement System in Health and Disease, Marcel Dekker, New York. pp. 241-284. 1998). Traditionally, C3aRwas thought to be present only on myeloid cells, such as macrophages, eosinϊpnils 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 trie 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 Huntϊngton's disease, Pick's disease, and Gullian Barre syndrome. (See Campos-Torτes et aL, (August 2000), Irnmunophamiacology, 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/rβperfusion injury. (See Kirεhfink, M., (1997), Immunopharmacology, 38, 51-62; see also LucGhesi 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, Huntiπgton'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, hyperlipϊdemia, hypercholesterolemia, edema, and obesity; and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, lung inflammation and rheumatoid arthritis. -A-

Summary of the Invention Accordingly, there are provided compounds according to the formula

wherein

W is selected from the group consisting of

A₁ is O or S;

A₂ is N or CH, with the proviso that if Ai is O, A_∑ is N; n is between 3 and 5;

Z at each occurrence is independently selected from CR¹, CHR¹ ,C=O, N, NR¹, N=O, S, and O, wherein a bond between two groups Z bonded to each other may be a single bond or a double bond; the ring containing Z is a 5, 6, or 7-membered heterocyclic or heteroaryl ring containing 1-3 heteroatoms independently selected from the group consisting of O, N and S;

R¹ at each occurrence is independently selected from H₁ optionally substituted Cn-C₈ alkyl, optionally substituted C₁-C₅ alkoxy, halo, SO₂N(R₆J₂, N(R₆)SO₂N(Ra)₂, SO₂R_e,

CONHSO₂Re. CONHSO₂(NRe)₂, optionally substituted 3-10-membered heteroCycloalkyl, optionally substituted C₃-C₁₀ cycloaikyl, cyano, optionally substituted 5- 10-membered heteroaryl, COR^S, CO₂R⁶, N(R⁶J₂, NR⁶COR⁶, C0N(R⁹)₂, and CONCO(R⁶)₂;

R^β at each occurrence is independently selected from H, optionally substituted CI-C_B alkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted Ce-C₁Q aryl, optionally substituted C₃-C₁₀ cycloaikyl, and optionally substituted 3-10 membered heterocycloalkyl; R² and R³ are selected independently from H, optionally substituted Ci-C_ealkyl, halo, optionally substituted G,-Csalkenyl, optionally substituted C₃-C₁₀ cycloaikyl, trϊfluoromethyl, CO- optionally substituted C₁-C₆ alkyl, CO_2- optionally substituted Ci-C₆ alkyl, optionally substituted Ci-C₆alkαxy, and optionally substituted C^Cβalkylthio; Y¹, Y², Y³, Y⁴ are independently selected from CH, CF, or N where no more than 2 N are in the ring; or a pharmaceutically acceptable salt thereof.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I). Exemplary 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, hydrobrornide, hydraiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleste, fumarate, gluconate, saccharate, beπzoate, methanesulfonate, ethaπesulfanate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1'-methylene- bis-(2-hydroxy-3-πaphthoate)]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, Le., 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 alkaπαlammoπiurn and other base salts of pharmaceutically acceptable organic amines.

The subject invention also includes jsotopically-Iabelied 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, ¹³C₁ ¹⁴C₁ ¹⁵ N, ¹⁸O₁ ¹⁷0, ³¹ P, ³²P, ³⁵S, ¹⁸ F, and ³⁶ 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-labellβd compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ^M C are incorporated, are useful in drug and/or substrate tissue distribution assays. Treated, 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 noπ-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, Huntϊngton's chorea, Pick's disease, Guillϊan 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 iSGhemia and reperfusion injury, shock and hypertension, hyperlipidernϊa, hypercholesterolemia, edema, obesity; nephritis, graft rejection, and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, iung 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, Huntingtoπ'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 cornpound(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 compouπd(s) of the present 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 "subjecf 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 "alkyny!" 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, alkenyi 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 Ce-Ci_D areπe" or "fused to an arene", as used herein, unless otherwise indicated, indicates, respectively, a group or substituent fused to a Ca-C₁₀ aromatic hydrocarbon and a group or substituent fused to a C_6-C₃₀ aromatic hydrocarbon.

The C₆-C₁₀ aromatic hydrocarbon, or the Ce-C₃₀ aromatic hydrocarbon, may be substituted by one or more substϊtuents 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. 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 (C₆-C_1D) 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. 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-C₁Q) 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 substitueπts, and perferabiy the number of subsfrtuents is between 0 and 3, more preferably between o 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 substitueπts wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferabiy 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, thϊenyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrralyl, triazolyl, tetrazolyl, ϊrnidazolyl, 1 ,3,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyi, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyi, 1 ,3,5-triazinyi, pyrazoio[3,4-b]pyridinyl, cinπolinyl, pterldϊnyl, purinyl; 6,7- dϊhydro-5H-I1]pyrindiπyl, benzo[b]thiophenyi, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazαlyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isoben∑ofuranyl, isoindoiyl, iπdolyl, iπdolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quiπoxalinyi, quinazolinyl, and benzoxazinyl; and the like.

A "cycloalkyl" group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic (C₃-Ci_)cycloalkyl compound, by removal of a hydrogen radical from a ring carbon of the cycloatkyl compound. A cycloalkyi group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substitueπts, and perferabiy 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 fadlity of synthesis. Representative cycloalkyi groups include cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopeπtenyl, cyclohexeπyl, cyclohepteπyl, 1,3- cyclobutadienyl, 1 ,3-cydopentadienyl, 1 ,3-cyclohexadienyl, 1,4-cydohexadieπyl, 1,3- cycloheptadienyl, 1,4-cycIoheptadienyl, 1,3,5-cycloheptatrieπyl, bicyclo[3.2.1]octane, bicyclo [2.2.1] heptane, and the norborn-2-eπe unsaturated form thereof. Thus, the term cycloalkyi 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 heterocycloalkyl 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 substitueπts, 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 heterαcycloatkyl groups include pyrrolidinyi, tetrahydrαfuranyl, dihydrofuranyl, tetrahydropyranyl, pyraπyl, thiopyranyl, azirϊdinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, ϊsothiazoiϊdinyl, 1 ,3-thiazolidin-3-yI, 1 ,2-pyrazo!idiπ-2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholiπyl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyi, moφholinyl, 1,2-tetrahydrodϊazin~2-yl, 1,3-tetrahydrodϊazin-i-yI, tetrahydroazepinyl, piperazinyl, and chromanyl.

In connection with the terms "alkyl", "aryl", "heteroaryl", "cycloalkyr and "heterocycloalkyl", as herein defined, the term "optionally substituted" means that at least one chemically and pharmaceutically acceptable functional group may be bonded thereto. Such a functional group is selected from the group consisting of hydroxy, halo, amino, trifluoromethyl, carboxy, (C₁-C₆)aIkOXy-, (C₁-C₆)acyIoxy-, (C1-C₆)a!kyiamino-, ((C₁-C₆)alky)l₂amino-, (C₁- C₆)acylamϊπo-, cyano, nitro, (C₁C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyI-, cyano(C1-C6)alkyl-, trifluoromethyl(C₁C₆)alkyl-, πitro(C₁C₆)alkyl-_, (C₁-C₃)alkyl(moπofliuoroa[kylene)(CrC₃)alkyl-, (C₁C₆)alkyll(polyfluoroalkylene)(C-₁C₃)alky!-, (C₁-C₆)acyIamino(C₁-C₈)alkyl-, (C₁-C6)aIkOXy(C₁ - C₆)acylamino-, amino(C₁C₆)acyl-, amino(C1-C₆)acyl(C₁-C₈)alkyl-, (C₁-C₆)alkylamino(C₁- C₆)acyl-, ((C₁C-₆)alkyl)₂amino(C₁-C₆)acyl-, (C₉-C₁₀)cycloalkyl(C₁ -C₆)alkyl-, (C₆-C₁₀)aryl(C1- C₆)alkoxy(C₁-C₆)alkyl-, 5-10-membered heteroaryKd-CeJalkoxytC-i-CBjalkyl-, (C₆- Cio)arylsulfinyi -, (Ci-C_e)alkylsu!fony](C₁C-₆)alkyl-, (C₆-C_1α)arylsulfonyl-, (C₁-C₆ alkyl)-(C_B- C₁₀)arylenesulfinyl -, (C₁-C₆ alkyl)-(CB-C,₀)arylenesuifonyh aminotCrCeJalkyi-, (C₁- C_e)alkylamino(C₁C-₆)alkyi-, (C^C_BjalkyKdϊfluoromethylene)-, (C_rC_B)alkoxy(Ci-C_e)acyl-, (G₆- C₁₀)aryl-, 5-10-membered heteroaryl-, (Cg-C_toJaryKCrCeJalkyl-, 5-10-membβrθd heieroaryKCrCisJalkyl-, (Cs-CioJaryKCe-CiQjaryl-, (C_B-C^JaryKCe-C^JaryKCrCsJalkyl- (C₃- C₁₀)cycloalkyl-, 3-10-membered heterocycloalkyl-, 3-10-membered heteracycloalkyI(Ci- C_e)alkyl-, hydroxy(C₂-C₃)alky[-, (d-CeJacyloxytCz-CeJalkyl-, (CrCeJalkoxytCz-CaJalkyl, (C₁- C₅)a!kylthio(C₁-C₆)alkyl-, (C_e-C₁₀)arylthio(C_rC₆)alkyl', (C₁-C₆)alkylsuifinyl(C₁-C_e)aikyl-, (C₆- C^JarylsulfinyKCrCsJalkyi-, (C_B-doJarylsulfonyKCrCeJalkyi-, ((C_TC_BjalkyOaamiπotCrCeJalkyl, (d-CeJalkylJS-IO-membered heteroaryl-, C₁-C₆ alkyl-CONH, wherein the C_rC_s 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-C₅ alkoxy, or a combination thereof, C₈- C_1O aryl-CONH-, wherein the Ce-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-mernbered heteroaryl may be unsubstituted or substituted with one or more C,-C_e alky!, halo, Ci-C_e alkoxy, or a combination thereof, 5-10-membered heteroaryl-CONH-, wherein the 5-10- membered heteroaryl may be uπsubεtituted or substituted with one or more C₁-C₈ alkyl, halo,

C₁-C₈ alkoxy, or a combination thereof, 3-10-membered heterocydoalkyl-CONH- wherein the 3-10-membered heterocycloalkyl 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 C₅-C-I₀ arene, C₃-C₁₀ cycIoaikyl-CQNH- wherein the 3-10-membered heterocycloalkyl 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

In one embodiment of the invention, Y¹, Y², Y³, Y⁴ are each CH. In another embodiment of the invention, R¹ is selected from H, optionally substituted C₁-C₆ alkyl, CO₂-optionally substituted C₁-C₆ alkyl, halo, amino, CHO₁ CO-optionally substituted Ci-C₆ alkyl. and cyano. In another embodiment of the invention, R¹ is a 5-10 membered heteroaryl selected from the group consisting of tetrazolyl, oxadiazolyl optionally substituted withOH, and pyrrolyl optionally substituted with one or two CrC_β alkyl.

In another embodiment of the invention, the group

is selected from the group consisting of the group

(A) wherein Y₅ = CR¹, CHR¹, N or NR¹; Y_β and Y₇ are each independently CH or C; and Y₈ is CR¹ or CHR¹; and the group

(B) wherein Y₉ is CR¹, CHR¹, N or NR₁; Y₁₀ is C or CH; and Y₁₁ is NR¹, N, or S. In structure (A), the dotted bonds indicate that the bond between Y₅ and Y_6,Y₇and Y_8, and Y₆ and Y₇, respectively, may be independently single or double. Similarly, in (B), the dotted bonds indicate that the bond between Y₁₀ and Y₁₁, and Y₉ and Y₁₀, respectively, may be independently single or double.

It will be understood by one skilled in the art that the choice of groups that in the recitation "wherein a bond between two groups Z bonded to each other may be a single bond or a double bond", whether the bonds between adjacent 2 groups are independently single bonds or double bonds may be determined in accordance with the valence, independently, of each of the Z groups. Similarly, the choice of groups Y_Sl Y₆, Y₇, Y₈, Yg, Y_1O and Yn, and whether the bonds between and Y₅ and Y₆, Y₆ and Y₇, Yr and Y_8, Y₈ and Y₉, and Y₁₀ and Y₁₁. are independently single bonds or double bonds, may be determined in accordance with the valence, independently, of each of the groups Y₅, Y_s, Yr₁Ys. Yg, Y₁₀ and Y₁₁. As an example, if

Y₅ is a divalent group such as CHR¹, the bond to Y₈ is a single bond; if it is a trivaleπt group such CR¹, the bond to Y_B is a double bond.

In an exemplary embodiment of group (A), at least one R₁ is H.

In an exemplary embodiment of group (A), group (A) is selected from the group consisting of

In another embodiment of the invention, R² and R³ are selected independently from H, optionally substituted C₁-C₅alkyl, trifiuoromethyl, CO-optioπally substituted C₁-C₆ alkyl, and COa-optionally substituted C₁-C_B alkyl. In another embodiment of the invention, R¹ at each occurrence is independently selected from preferably optionally substituted C₁-C₈ alkyl, preferably optionally substituted C₁-C₆ alkoxy, preferably optionally substituted 3-10-membered heterocycioalkyl, preferably optionally substituted C₃-C₁₀ cycloalkyl, and preferably optionally substituted 5- 10-membered heteroaryl. In another embodiment of the invention, R^β at each occurrence is independently selected from preferably optionally substituted C₁-C₆ alkyl, preferably optionally substituted 5- 10 membered heteroaryl, preferably optionally substituted C₆-C₁₀ aryl, preferably optionally substituted C₃-C₁₀ cycloalkyl, and preferably optionally substituted 3-10 membered heterocycioalkyl. In another embodiment of the invention, R² and R^s are selected independently from preferably optionally substituted CrC₆alKyl. preferably optionally substituted Ci-C₃alkenyl, preferably optionally substituted C₃-C₁₀ cycloalkyl, CO- preferably optionally substituted C₁-C₅ alkyl, CO_2- preferably optionally substituted C₁-C₈ alkyl, preferably optionally substituted C₁- C₆alkoxy, and preferably optionally substituted C_rC₆alkylthio. Exemplary compounds according to the invention include

2-[4-(1-Methyt-5-trifluoromethyl-iH-pyrazol-3_"yl)-phenyl]-imidazo[1,2-a3pyridine hydrochloride salt;

2-[4-(i-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl3-5,6,7,8-tetrahydro- imidazα[1 ,2-a]ρyridϊne p-toluenesulfoπic acid;

2-[4-(i -Ethyl-5-trifluoromethyl-i H-pyrazol-3-yl)-phenyl]-irnidazo[1 ,2-a3pyridiπe p- toluenesulfonic acid salt;

2-[4-(1-Ethyl-5-trifluororπethyI~1H-pyrazol-3-yI)-phenyl]-5,6,7_lS-tetrahydro- imidazo[1 ,2-a]pyridine p-tolueπesulfonic acid salt; 5-(4-lmidazot1,2-a]pyrϊdin-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester;

2-[4-(1 -Methyl-5-trifIuoromethyl~1 H-pyrazαl-3-yl)-phenyl]-imidazo[1 ,2-a]pyridine-6- carboxylic acid ethyl ester;

{2-[4-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-imida2X)[1,2-a]pyridiπ-6-yl}- methanol;

{2-[4-(1-MethyI-5-trif!uoromethyl-1H_'-pyrazol-3-yI)-phenyl]-5,6,7_I8-tetrahydro- imidazo[1,2-a]pyridiπ-6-yl}-methanol;

6-Chloro-2-[4-(1 -methyl-5-trifluoromethy!-1 H-pyrazol-3-yI)-phenyl]-imidazo[l ,2- b]pyrida2ine; 2-[4-(1 -Methyl-5-trifluoromethyl-1 H-pyra∑ol-3-yl)-phenyl]-im[dazo[1 ,2-b]pyridazin-6- ylamine p-toluene sulfonic acid salt;

2-[4-(1 -Methy!-5-trifluoromethyI_"1 H-pyrazol-3-yl)-phenyl]-imidazo[1 ,2-b]ρyridazine p- toluene sulfonic acid salt;

2-[4-(1-Methyl-5-trifluoromethyl-1H-pyra2ol-3-yi)-phenyI]-5,6,7,8-tetrahydro- imidazo[1 ,2-b]pyridaziπe p-toluenesulfoπic acid salt;

2-[4-(1-MetriyI-5-trifluorometriyI-iH-pyrazol-3-yI)-phenyi]-imidazo[1,2-a]pyridine-6- carbaldehyde;

1-{2-f4-(1 -Methyl-5-trifIuoromethyl-1 H-pyra2θl-3-yl)-ρhenyi]"imidazo[1 ,2-a]pyridin-6- yl}-ethaπol; 1 -{2-[4-(1 -Methyl-5-trifluoromethyl-i H-pyrazoI-3-yl)-phenyl]-5,6,7,8-tetrahydro- imidazo[1,2-a]pyridin-θ-yl}-ethanol;

{2-[4-(1-Methyl-5-trifluoromethyl-iH-pyrazol-3-yl)-phenyl]-irπidazo[1_l2-a]pyridin-7-yl}- methanol p-toluene sulfonic acid salt;

1 -{2-[4-(1 -Methyl-5-triπuoromethyl-1 H-pyrazol-3-yl)-pheπyl]-imtdazo[1 ,2-a]pyridin-7- yi}-ethanol;

{2-[4-(1-Methyl-5-trifiuorome{hyl-1H_'-pyrazol-3-yl)-phenyl]-5,6,7,8-tetrahydro- im idazo[1 ,2-a]pyridiπ-7-yl}-methanol; 6-t4-(1-Methyl-5-trifluoromethyt-1H-pyrazol-3-yl)-phenyl]-2_I3-dihydro-iιnidazo[2,1- bjthiazole;

2-[4-(1 -Methyl-5-trifIuoromethyl-i H-ρyrazoI-3-yl)-ρhenyl]-imidazo[1 ,2-a3pyridiπe-6- carbonitrile; 2-[4-(1 -Methyl-5-trrfluoromethy 1-1 H-pyrazol-3-yl)-phenyl]-6-(1 H-tetrazo!-5-yl)- imidazo[1 ,2-a]pyridine;

3-{2-[4-(1 -Methyl-5-trifluoromethyl-i H-pyrazol-3-yl)-phenyl]-imida2:o[1 ,2-a]pyridin-6- yl}-[1 ,2,4]oxadiazol-5-ol;

2-[4-(1 -Methyl-5-trifluoromethyl-1 H-pyra∑θl-3-yl)-phenyl]-imidazo[1 ,2-b]pyridaziπe-6- carbonitrile;

2-[4-(1 -Mβthyl-5-trifluoromethyI-1 H-pyrazol-3-yl)-pheπyl]-6-(1 H-tetrazol-5-yl)- imidazo[i ,2-b]pyridazine;

M-{2-[4-(1-MethyI-5-trif!uoromethyt-1H-pyrazoI-3-yl)'phenyl]-imidazo[1_I2-a]pyridin-6- yl}-acetamide p-toluenesulfonic acid salt; 2-[4-(1 -Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-imidazo[1 ,2-a]pyridin-6- ylamine bis-p-tolueπesulfonic acid salt;

6-(2,5-Dimethyl-pyrrol-1 -y])-2-[4-(1 -methyt-5-trifluoromethyl-i H-pyrazoI'3-yl)-ρhenyl]- imidazo[1 ,2-a]pyridine;

2-[4-(1-Methyl-5-trifluoromethyl-1H-pyra∑oi-3-yl)-pheny!]-5,6J,8-tetrarιydro- imidazo[1 ,2-a]pyrϊdin-6-ylamine bis-p-toluenesulfoπic acid salt;

N-{2-[4-(1-Methy!-5-trifiuoromethyl-1H-pyrazol-3-yi)-phenyl]-5,6,7,8-tetnahydro- imidazo[1 ,2-a]pyrϊdin-6-yl}-acetamide p-toluenesulfoπic acid salt;

C-{2-[4-(1 -Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl3-5,6,7,8-tetrahydro- ϊmida∑o[1,2-a]pyridin-6-yl}-methylamϊne bis-hydrαchloride salt; Cyclopropaπecarboxylic acid {2-[4-(1-methyI-5-trϊfluoromethyl-1 H-pyrazol-3-yI)- phenyl]-5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridiπ-6-ylmethyl}-arnide p-tolueπesulfonic acid salt;

1 H-Pyrrole-2-carboxylic acid {2-[4-(1-methyl-5-trϊfluoromethyl-1 H-pyrazol-3-yl)- ρhenyO-5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridin-6-ylmethyl}-amide bis-p-toiuenesulfonic acid salt; N-{2-[4-(1 -Methyl-5-trifiuoromethyI-i H-pyrazol-3-y[)-phenyl]-6,β,7,8-tetrahydro- ϊmidazoti ,2-a]pyridin-6-y!methyI}-nicotinamide bis-p-toluenesulfonic acid salt;

2-(1 ,1 -Dioxo-tetrahydro-1 l6-thiophen-3-yl)-N-{2-[4-(1-methyl-5-trifluoromethyl-1 H- pyrazol-3-yl)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2_"a]pyridin-6-ylmethyl}-acetarnide p- toluenesulfonic acid salt; 3-Methyl-5-[4-(1 -methyl-5-trifJuoromethyl-1 H-pyrazol-3-yl)-phenyl]-3H~imidazo[i ,2- b][1,2,4]triazole-2-carbaldehyde; {3-Methyl-5-[4-(1 -methyl-5-trifluoromethyI-1 H-pyrazol-3-yl)-phenyl]-3H-imidazo[i ,2- b][1 ,2,4]triazol-2-yI}-methanol p-toluenesuifoπic acid salt;

1 -Methyi-6-[4-(1 -rnethyl-5-trifluoromethyl-1 H-pyrazo!-3-y|)-phenyl]-1 H-imidazo[1 ,2- a]imidazole p-toluenesulfonic acid salt; {1 -MethyI-6-[4-(1 -methyl-5-triflUoromethyl-1 H-pyrazol-3~y|)-phenyl]-1 H-imidazo[1 ,2- a]imidazol-2-yl}-methanoi p-tolueπesulfonic acid salt;

2-[4-(4-Ethyl-thiophen-2-yl)-phenyl]-5,6₇7,8-tetrahydro-imidazo[i,2-a]pyridine hydrochloride;

2- 4-(5-Ethy[-thiophen-2-yl)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine hydrochloride;

2-[4-(5-Methyl-thiophen-2-yl)-phenyl]-5,6,7,8-tetrahydra-imidazo[1,2-a]pyrid[ne hydrochloride;

2-(4-(5-(Trifluoromethyi)-4-methyloxazoI-2-yi)pheπyl)H-imϊda2o[1,2-a]pyridine; aπci 2-(4-(3'(Trifluoromethyl)-4-meihyl-1H-pyrazoi-1-yl)phenyl)-5,6,7,8- tetrahydroimidazo[1 ,2-a]pyridine.

The compounds of Formula (I), there is no formula Il 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, dϊastereσisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Eπantiomers 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 diastereαmeric 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 eπantiomers. Diastereomers and enantiomers may alternatively be separated from mixtures using chiral high pressure liquid chromatographic techniques known to one skilled in the art. Pure stereochemically isomeric forms of the compounds of Formula (I) may also be obtained from the pure stereochemical forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of Formula (I) 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 πot 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. It will be appreciated that Gertaiπ groups represented by letters ("R" groups and the like) in the reaction scheme do not always correspond with similarly defined component groups of the Formula (I) compounds themselves, since certain functionalities of the reactaπts can be modified when the resulting products are formed. Compounds of the invention can be prepared using a variety of methods as outlined below in Schemes 1-3. As shown in Scheme 1, a compound of general Formula I can be prepared by the reaction of a compound with the genera! formula A1 with a compound of general formula B1 in the presence of a base such as NaHCO₃, K₂CO₃, /BuOK, and Cs₂CO₃ in solvents such 1,2-DCE, xylenes, C1-C6 aikyl alcohols, or mixtures thereof, at temperatures ranging from ambient to the boiling point of said mixtures. Compounds of general formula A1 are commercially available or can be prepared by procedures that are well known to^> one skilled in the art of organic chemistry. Compounds of general formula B1 can be prepared by the method outline below in Scheme 3. Following the imidazole ring formation with A1 and B1 starting materials, the resulting compounds of general formula I can be converted, according to methods well known in the art such as oxidation, reduction, catalyst coupling reaction, alkylation, amide formation, to another compound of general formula I.

Scheme 1

A1 B1 I

X - bromo or chloro

A compound of general Formula I can also be prepared by method shown in Scheme 2. Compounds of general formula B2 are commercially available or can be prepared by procedures that are well known to one of skilled in the art of organic chemistry. Compounds of general formula C1 can be prepared by the reaction of 3 compound with the general formula A1 with a compound of general formula B2 in the presence of base such as NaHCO₃, K₂CO₃, fBuOK, and Cs₂CO₃ in solvents such 1,2-DCE, xylenes, C1-C6 alkyl alcohols, or mixtures thereof, at temperatures ranging from ambient to the boiling point of said mixtures. A compound of general formula C1 can be reacted with a pyrazoloboronic acid or pyrazoloboronic ester compound of general formula D1 in the presence of a catalyst suGh as PdCI₂(dppf>CH₂CI₂ in the presence of a ligand such as 1,1 '-bis(diphenylphosphino)ferrocene (dppf) and an inorganic base such as K₃PO₄ in a solvent such as THF or dioxane at temperatures ranging from ambient to the boiling point of said solvents. The resulting compounds of general formula I can be converted, according to methods well known in the art such as oxidation, reduction, catalyst coupling reaction, aikylation, amide formation, etc. to another compound of general formula I. Scheme 2:

mo orchloro ^ma' ^ωfIate' ^iod°

alkyl

A1 B2

C1 I

Scheme 3 outlines the method of preparation of compounds of general formula B1. An acetophenone compound of genera! formula E1 is treated with a base such as fBuOK in a solvent such as THF or MTBE at temperatures ranging from -20 °C to ambient temperature followed by the addition of an ester. The said mixture is continued stirring at temperatures ranging from 0 ⁰C to ambient temperature for reaction times ranging from 2-24 hours. The resulting 1 ,3-diketones of general formula F1 are treated with hydrazine hydrate to form a pyrazole ring. The pyrazole ring of compounds of general formula G1 can be N-alkylated by treatment with an alkylating agent such as (C1-CΘ alkyl) halide, (C1-C6 alkyl) tosyiate, (C1- C6 alkyl) mesylate, and dimethyl sulfate in the presence or absence of a base such as trialkylamine, alkoxides, and K₂CO₃ in a solvent such as THF, toluene, MTBE, and CH₂CI₂ at temperatures ranging from ambient temperature to the boiling point of said mixtures to provide a compound of general formula H1, which may generate along with the other N- aikylated regioϊsomer. A compound of general formula H1 can be converted to compounds of general formula B1 using a variety of methods known to one skilled in the art of organic chemistry. One such method is shown below in Scheme 3 where compounds of general formula H1 are treated with an alkyilithium reagent such as πBuLϊ, .BuLi, and 5BuLi in a solvent such as THF₁ MTBE, toluene, and combinations thereof, at temperatures below 0 "C with subsequent addition of an acylating agent such as 2-chloro-N-methoxy-N- methylacetamide, 2-bromo-N-methoxy-N-methylacetamide, and N-methoxy-N- methylacetamϊde. Compounds of general formula B1 where X is H can be treated with a brominatiπg or chlorinating agent such as N-chlorosuccinamide, N-bromosuccinamide, and bromine in a solvent such as THF, MTBE, ether, and CH₂Ci₂ at temperatures ranging from ambient temperature to the boiling point of said mixtures to provide compounds of general formula B1 where X is chloro or bromo.

Scheme 3

E1 F1 G1

R³X

Another aspect of the present invention is a pharmaceutical composition comprising substantially enriched enantiomeric forms of the compouπd(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-pyroøenic, 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 cornpound(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-phαsphatidyichoiiπe (PC). A composition of this invention may further contain one or more adjuvant substances, such as fillers, thickening agents or the IiKe.

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 solubiliziπg 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 timing.

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, msπnitol 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) algiπic acid; (16) pyrogert-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, oieate, 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, diethgnolamine, 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 composϊtioπ 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 myelins loss (demyelinatioπ). Myelin provides the axoπa! "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 myel in-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 Priπeas 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. ImrπuπσpathoL, 17, 492-505; Molleπes et al._τ (1987), J. Neurol. ScL₁ 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 myleliπ 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) Nylaπd et a!., have shown that GBS serum or purified antibody causes Complement-dependent demyelination in peripheral nerve cultures. (See Nylaind et a!., Acta Neurol, Scand., 58, 35-34) Moreover, [t 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 at., (1987), 37, 1006-1009; Koski et al., (1987), J. Clin- Invest., 80. 1492-1497; Hays et a!.. (1988), J. NeuroimrnuneoL 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 garnmopathy 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 I₁ 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.}

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 πeurites. 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; Eikeienboom, P., Stam, F.C., (1982) Acta Nβuropathαiogϊca, 57, 239-242; see also Itagakϊ, S., Akiyama, H. et al., (1994), Brain Research, 645, 78-84; McGeer, P,L,_T 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; Pouplardbarthetaix, A., Dubas, F.et al., (1986), Neuropathology and Applied Neurobiology, 12, 609-610; Veerhuis, R., Jansseπ, 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 a!., (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 comρound(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 compouπd(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 decade, 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 ceil infiltration into the iung 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 analphylatoxiπ. Other Complement mediated pulmonary disorders include hypersensitivity pneumonites, and anaphylaxis. (See Regal, J., (1997), Immunopharrnacoiogy, 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. Upton et aL, in U.S. Patent No. 6,503,947 discloses attenuation of cerebral ischemia and reperfusϊon 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 μglkg and about 50.0 mg/kg body weight per day, preferably between about 1.0 jwg/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 rng 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 //g 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. Additϊonal detailed information is as follows.

The Druα 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/suiphate, borate, camsylate, citrate, cyclamate, edisylate, esylatθ, formate, fumarate, gluceptate, gluconate, glucurαπate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, maionate, mesylate, methylsulphate, naphthylate, 2-πapsyIate, 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, diethyiamine, diolamine, glycine, lysine, magnesium, meglumine, oiamine, potassium, sodium, tromethamine and zinc salts. Hβmisalts of acids and bases may also be formed, for example, hemisuiphate and 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, ethaπol. 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/soivent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the SGope 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 Commuπ, .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 Halebliaπ (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). Mesomorphiεm 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 -COO-Na+, -COOK *, or -SO₃-Na^*) 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 1 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 I.

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 (T, Higuchϊ and W. Stella) and Bioreversible Carriers in Drug Design. Pβrgamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). Prodrugs iri 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 (C₁-C₈)alkyI;

(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_rC_β)aikanoyloxyrnethyi; 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 formuia I is/are replaced by (C₁-C₁₀)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 -> -CHgOH);

(ii) where the compound of formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iiϊ) 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 carboxylϊc acid derivative thereof (-CONH₂ -> COOH)₁

Compounds of formula 1 containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula 1 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 Otautomerism') can occur.

This can take the form of proton tautomerisrn in compounds of formuta ! 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 saits wherein the couπterion is optically active, for example, d-lactate or I- lysine, or racemϊc, 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 chϊral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or derivative) using, for example, chϊral 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-phenylethylamiπe 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 enaπtiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in eπaπtiomerically-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 alkylamiπβ, 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 βnantiomer.

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 isotαpically-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 ¹⁵0, ¹⁷O and ^1BO, phosphorus, such as ³²P, and sutphur, such as ³³S.

Certain isotopϊcally-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 isotopicaHy substituted, e.g. D₂O, d_β-acetone, d_β- 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 L 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, processabilϊty 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 biopharmaceutϊcal properties, such as solubility and solution stability (across pH), permeability, etc., m ^" 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 wili 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 hydroxypropyirπethylcellulose) 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 disϊntegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl celiulose, croscarmellose sodium, crospovidoπe, polyvinylpyrrolidone, methyl cellulose, mϊcracrystalline 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 Gohesive qualities to a tablet formulation. Suitable binders include microcrystalliπe 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

(moπohydrate, spray-dried moπohydrate, anhydrous and the like), mannitot, xylitol, dextrose, sucrose, sorbitol, microcrystaltine 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 contaln 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 antioxidants, colourants, flavouring agents, preservatives and taste-masKing agents.

.Exemplary tablets contain up to about 80% drug, from about 1 o weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disiπtegrant, 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 Dosaαe Forms: Tablets. Vol. 1 , by H. Liebermaπ and L- Lachman (Marcel Dekker, New York, 1980). Consumable oral films for human or veterinary use are typically pliable water-soluble or water-sweliable 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 function. 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 hydracolloids 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, aπti-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 techπologϊes).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 steriie 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(di-lactic- coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically, (iπtra)dermally, or trεansdermally 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 Fiπnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. powderject™, Bioject^TO, etc.) injection/Topical administration may also be achieved using a patch, such as a transdemal jontophoretic 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 intraπasally 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 iπhaier, 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 propellaπt, 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, chitosaπ or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethaπol, or a suitable alternative agent for dispersing, solubilisiπg, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligoiactic 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 homogenisatioπ, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethyicellulose), 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-ieucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextraπ, 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 Vg to 20mg of the compound of the invention per actuation and the actuation volume may vary from "Iμl to 100//), 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/iπtranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified controlled release using, for example, PGL-A 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 cyclodβxtrin 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 solubiiiser. Most commonly used for these purposes are alpha-, beta- and gamma-cydodextrins, 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, C3a IC₅₀ are provided at the beginning of each example below,

EXAMPLES: {C3a IC₅₀ = 61 nM)

Example 1

2-[4-( 1 -Methy[-5-trif luoromethyl-1 H-pyrazol-3vl)-phenyll-imidazoH .2-aipyridrne hydrochloride salt

A mixture of 2-bromo-1-[4-(1-methyl-5-trifluoromethyi-1 H-pyrazol-3-yI)-phenyl]- ethanoπe (804 mg, 2.32 mmαl), 2-aminopyridine (436 mg, 4.63 rnmol), NaHCO₃ (389 mg,

4.63 mmol), and DCE (23 mL) was heated for 5.25 h at 80 ⁰C. The mixture was poured into

1M aq NaOH (75 mL) and extracted with CH₂CI₂ (3 x 50 mL). The combined extracts were dried (MgSO₄), filtered and concentrated. The resulting solid was purified by chromatography

(loaded with CH₂CI₂; eiuted by gradient of 25-70% EtOAc in hexanes) to provide 690 mg of 2-

[4-(1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yI)-phenyl]-imidazo[1,2-a]pyridine as a white solid.

MS: (M⁺) 343. ¹H NMR (400 MHz, CDCI₃): δ 8.12 (d, 1, J = 6.6), 8.00 (d, 2, J = 8.5), 7.90 (s,

1), 7.84 (d, 2, J = 8.5), 7.63 (d, 1, J = 9.6), 7.15-7.19 (m, 1), 6,93 (s, 1), 6.76-6.79 (m, 1), 4.03 (s, 3). The HCI salt was formed in CH₂Cl₂ by addition of a solution of aq. HCI in Et₂O, concentration, and trituration with EtOAc.

(C3a IC₅₀ = 102 πM)

Example 2

2-[4-(1-MethvI-5-trifluoromethvI-1H-pyrazol-3-vπ-pheπyll-5,β,7,8-tetrahydro-imidazo[i,2- alpyridine p-toluenesulfonic acid

A mixture of 2-[4-(1-metriyl-5-trif!uoromethyI-1H-pyrazo[-3-yI)-phenyl]-imidazo[1,2- a]pyridine (350 mg, 1.02 mmol) and 10% Pd/C (700 mg) in EtOH (100 mL) was placed under a H₂ atmosphere (47 psi) in a Parr shaker at rt. After 5 h the Parr bottle was purged with N₂. The reaction mixture was filtered through a plug of celite, rinsing with CH₂CI₂/MβOH (2:1). The filtrate was concentrated and chromatogrøphed (loaded With CH₂CI₂ and eluted with a gradient of 2.5-10% MeOH in CH₂CI₂) to provide 299 mg of 2-[4-(1 -methyl-5-trifluoromethyl- iH-.pyrazo!-3-yi)-phenyI]_"5,6,7,8-tetrahydro-imidazo[1,2-a3pyridine as a white solid. MS: (M*) 347. 47863-5-02 The tosylate salt was formed using the general procedure to provide the tosylate salt as a white solid. MS: (M⁺) 347. ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, 2, J = 8.5), 7-85 (S, 1), 7.78 (d, 2, J = 8.5), 7.75 (d, 2, J = 8.1), 7.28 (s, 1), 7,26 (d, 2. J = 7.9), 4.26 (t, 2. J = 5.8). 4.12 (S, 3), 3.14 (t, 2, J = 6.2), 2.40 (S, 3), 2.09-2-21 (m, 4). (C3a IC₅₀ = 73 nM)

Example 3 2-[4-C\ -Ethvl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenvl]-imidazo[1 ,2-alpyridine p- toluenesulfonic acid salt

A mixture of 2-bromo-1-[4-(1-ethyl-5-irifluoromethyl-1H-pyrazol-3-yl)-pheny!]- θthanone (1,35 g, 3.74 mmol), 2-aminopyridine (457 mg, 4.86 mmol), NaHCO₃ (628 mg, 7.48 mmol), and DCE (63 mL) was heated for 18 h at 80 ⁰C. The mixture was poured into sat.

NaHCO₃ (200 mL) and extracted with CH₂Cl₂ (3 x 100 mL). The combined extracts were dried (MgSO₄), filtered, concentrated and purified by chromatography (loaded with CH₂CI₂; eluted by gradient of 0-40% EtOAc in hexanes) to provide 980 mg of 2-[4-(1-ethyI-5- trifluαromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid. MS: (M⁺)

357. ¹H NMR (400 MHz. CDCI₃): δ 8,14 (d, 1 , J = 8.9), 8.02 (d, 2, J = 8.5), 7.91 (s, 1), 7.86 (d,

2, J - 8.3), 7.64 (d, 1, J = 9.1), 7.15-7.21 (m, 1). 6.92 (S, 1). 6.77-6.81 (rn. 1). 4.33 (q, 2, J =

7.3), 1.55 (t, 3, J = 7.3). The tosylate solid was formed using the general prσcedure.

(C3a IC₅₀ = 88 nM) Example 4

2-[4-(1 -Ethyl-5-trifluoromethyl-1 H-pyrazo[-3-vl)-phenvIT-5,6,7,8-tetrahvdro-imidazo[1 ,2- alpyridiπe p-toluenesulfonϊc acid salt

A mixture of 2-[4-(1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[1,2- a]pyridiπe (680 mg, 1.90 mmol) and 10% Pd/C (1.00 g) in EtOH (100 mL) was placed under a H₂ atmosphere (50 psi) in a Parr shaker at rt. After 5 h the Parr bottle was purged with N₂. The reaction mixture was filtered through a plug of celite, rinsing with CH₂CI₂/MeOH (2:1). The filtrate was concentrated and chromatographed (loaded with CH₂Clz; eluted with a gradient of 0-50% EtOAc in hexanes) to provide 542 mg of 2-[4-(1-ethyl-5-trifluorometriyl-1 H- pyrazo[-3-yi)-phenyl]-5,6,7,8-tetrahydro-imida2O[1,2-a]pyridine as a white solid. The tosylate salt was formed using the general procedure. MS: (M⁺) 362. ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d, 2. J - 8.3), 7-78 (s, 4), 7.24 (d, 1, J = 1.9), 7.18 (d, 2, J = 8.1), 6.86 (S, 1), 4.32 (q, 2, J = 7.3), 4.08 (t, 2, J = 5.9), 3.37 (t, 2, J = 6.4), 2.35 (s, 3). 1.94-2.08 (m, 4), 1.54 (t 3, J = 7.3).

(C3a IC₅₀ - 356 nM) Example 5

5-(4-lmidazoπ ^-alPyridin-Σ-yl-phenyll-Σ-methyl^H-PVrazols-S-carboxylic acid methyl ester

A flask was charged with 2-(4-bromo-phenyl)-imidazo[1_l2-a]pyridine (78.7 mg, 0.288 mmol), 2-methyl-S-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yI)-2H-pyrazoIe-3-carboxyIic acid methyl ester (115 mg, 0.432 mmol}, PdCI₂(dppf)-CH₂CI₂ (23.5 mg, 0.0288 mmol), 1,1'- bis(diphenylphosphino)ferroceπe (16 mg, 0.029 mmol), and K₃PO₄ (183 mg, 0.0864 mmol) and placed under a nitrogen atmosphere. To the flask was added dry THF (2.0 mL). The reaction mixture was heated at 70 ⁰C for 16 h and then cooled, filtered through a plug of celite rinsing with CH₂CI₂, and concentrated. The crude material was purified by flash chromatography (loaded with CH₂Cl₂ and eluted with a gradient of 1-2% MeOH in CH_ZCI₂) to provide 80.0 mg of 5-(4-imidazo[1,2-a3pyridin-2-yl-phenyl)-2-methyl-2H-pyrazoIe-3-carboxylic acid methyl ester as a pale-yellow solid. MS: (M*) 333. ¹H NMR (400 MHz, CDCl₃): δ 8.08

(d, 1, J = 7.9), 7.97 (d, 2, J = ^β.3), 7.85 (s, 1), 7.S3 (d, 2, J = 8.5), 7.61 (d, 1, J » 9-8), 7.13 (s, 1), 7.12-7.16 (rπ, 1), 6.72-6.76 (m. 1), 4.21 (S, 3), 3.88 (s, 3).

(C3a IC₅₀ = 214 nM)

Example 6 2-r4-(1-Methyl-5-trffIuororπ6thyl-1H-Dyrazol-3-vπ-phenvn-Smidazori.2-a1pyridiπe-6- carboxylic acid ethyl ester A mixture of 2-bromo-1-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]- ethaπone (1.064 g, 3.065 mmol), 6-amino-nicotinic acid ethyi ester hydrochloride (683 mg, 3.37 mmol), NaHCO₃ (309 mg, 3.68 mmol), and DCE (61 mL) was heated at reflux for 1 d. Tne reaction mixture was cooled and poured into sat aq NaHCO₃ (100 mL) and extracted with CH₂Cl₂ (2 x 100 mL). The combined extracts were dried (MgSO₄), filtered, and concentrated. The crude solid was purified by chromatography (loaded with CH₂Cl₂; eluted with gradient of 15-50% EtOAc in hexanes) to provide 606 mg of 2-[4-(1-methyi-5-trffluoromethyl-1H-pyrazol- 3-yl)-pheπyl]-irnidazo[1,2-a]pyπ^"dine-6-carboxylic acid ethyi ester as an orange solid. ¹H NMR (400 MHz): δ 8.91 (W₁ 1. J ■= 1.2), 8.02 (d, 2, J = 8.3), 7.97 (s, 1), 7.86 (d. 2, J " 8.3), 7.75 (dd, I₁ J = 9.5, 1.7), 7.63 (d, 1, J = 9.5), 6-95 (s, 1), 4.42 (q, 2, J = 7.2), 4.05 (s, 3), 1.43 (t, 3, J = 7.2).

(C3a IC₅₀ = 41 nM)

Example 7 ■f2-r4-f1-lVlethv>-5-trifluorom8thyl-1H-pyrazo(-3-vπ-phenvnHmidazori.2-aipyridϊn-6-yl>- methanol A mixture of (6-amiπo-pyridin-3-yl)-methanol (102.5 mg, 0.819 mmol) and 2-bromo-i-

[4-(1-methyl-5-trifluoromethyl-1H-pyrazo]-3-yl)-pheny]]-ethanoπe (258 mg, 0.744 mmol) in DCE (15 mL) was heated at 80 ⁶C for 16 h. NaHCO₃ (62 mg, 0.74 mmol) was added to the reaction mixture, which was continued heating for 1 d. The resulting orange solution was cooled and white solid feil out of solution. The mixture was filtered to provide 120,7 mg of {2- [4-{1 -methyl-5-trifluoromethyI-1 H-pyrazol-3-yl)-phenyl]-irnidazo[1 ,2-a]pyridin-6-yl}-rπethanol as a white solid. MS: (M*) 373. ¹H NMR (400 MHz₁ CD₃OD); δ 8.41 (s, 1), 8.23 (s, 1), 7.98 (d, 2, J = 8.5), 7.90 (d, 2, J = 8.5), 7.54 (d, 1, J - 9.3), 7.33 (dd, 1 , J = 9.3, 1.7), 7.19 (s, 1), 4.64 (s, 2), 4,05 (s, 3).

(C3a IC₅₀ = 84 nM) racemic, (C3a IC₅₀ = 63 nM), (C3a IC₅₀ = 75 nM) enantiomers

Example 8

{2-Γ4-(1 -IVI athyl-5-trif luoromethyl-1 H-pyrazol-3-yl) phenvl]-5,6,7,8-tetrahvdro- imidazori.2-alpyridin-6-yl}-methanol

A slurry of {2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3~yi)-phenyl]-imϊda2θ[1 ,2- a]pyridin-6-yl)-methanol (790 rπg, 2.12 mrnol) and 10% Pd on carbon (1 :6 g) in EtOAc (20 ml_) and EtOH (80 mL) was placed in a Parr shaker under an H₂ atmosphere (48 psi) for 18 h.

The Parr bottle was purged with N₂ and then filtered through a plug of celite and rinsing with CH₂Cl₂ and followed by a mixture of 25% MeOH in CH₂CI₂. The filtrate was concentrated and the resulting solid was purified by chromatography (preabsorbed to silica gel, eluted with a gradient of 2.5-10% MeOH in CH₂CI₂) to provide 572.8 mg of {2-[4-(1-methyl-5- trifluoromethyI-iH-pyrazoI-3-yI)-phenyl]-5,6,7,8-tetrahydro-imida2θt1,2-a]pyridin-6-yl}- methanol as a pale-yellow solid. MS: (M⁺) 377. ¹H NMR (400 MHz, CD₃OD): δ 7.79 (d, 2, J ~ 8.5), 7.74 (d, 2, J = 8.5), 7.36 (s, 1), 7.11 (s, 1), 4.21 (dd, 1, J = 12.3, 5.1), 4.03 (s, 3), 3.73-

3.78 (m, 1), 3.68 (dd, 1, J = 11.1, 5.7), 3.60 (dd, 1, J = 11.0, 7.0), 2.96-3.03 (m, 1), 2.77-2.87

(m, 1), 2.17-2.27 (m. 1), 2.06-2.14 (m, 1), 1.64-1.75 (m, 1). The enantiomers were separated by HPLC (Chiralpak AS column, 80/20 heptane/EtQH). The tosylate salts were formed using the general procedure. (C3a IC₅₀ = 1963 nM)

Example 9 6-Chloro-2-r4-(1 -methyl-5-trifluoroinethyl-1 H-PVrazol-3-vl)pheπvπ-imidazor 1 ,2- b]pyridazine

A slurry of 2"Chloro-1-[4-(1-methyI-5-trifluorornethyl-i H-pyrazol-3-yl)-phenyl]- ethanone (1.51 g, 4.99 mmol) and 6-chloro-pyridazin-3-ylamϊne (0.78 g, 6.0 mmoi) in xylenes

(30 mL) was heated at reflux for 24 h. NaHCO₃ (0.63 g, 7.5 mmol) was added. After 2 fi a mixture of EtOAc, H₂O, and sat aq NaHCO₃ was added and then extracted with EtOAc (2 x).

The combined extracts were washed with H₂O and brine, dried (MgSO4 ), filtered and concentrated. The crude material was chromatographed (loaded using CH₂CI₂, eluted using a gradient of 0-40% EtOAc in hexanes) to provide 1.10 g of 6-chloro-2-[4-(1-methyl-5- trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-imidazo[1,2-b]pyndazine as a yellow solid. MS: (M⁺) 378, 380. ¹H NMR (400 MHz, DMSO-D₈): δ 8.95 (S, 1), 8.21 (d, 1, J = 9.5), 8.10 (d, 2, J = 8.3), 7.95 (d. 2, J = 8.5), 7.49 (s, 1), 7.37 (d, 1, J = 9.5). (C3a IC₅₀ = 18 πM)

Example 10 2-f4-(1 -Methy!-5-trif[uoromethvI-1 H-pyrazύI^-yl)-ρhenvn-imidazof1 ,2-frlpyridazin-6- ylamine p-toluene sulfonic acid salt

A flask was charged With 6-chloro-2-[4-(1-methy!-5-trifluoromethyl-1H-pyrazol-3-yl)- phenylj-imidazo[1,2-b]pyridaziπe (130 mg, 0.344 mmol), 2-(dW-butylphosphino)biphenyl (10.2 mg, 0.0342 mmol), sodium t-butoxide (66 mg, 0.6S mrnol), and Pd₂(dba)3 (16 mg, 0.018 mmol) and then purged with N₂- Toluene (5 mL) and 2,4-dimethoxybenzylamiπe (144 uL,

0,96 mmol) were added to the flask that was subsequently heated at 100 "C for 1 h. The reaction mixture was cooled, diluted with CH₂CI₂ and MeOH, filtered through a plug of celite, and concentrated. The resulting gummy solid was dissolved in CH₂CI₂ (20 mL) at rt and TFA

(2 mL) was added. After 1 h the reaction mixture was concentrated and H₂O and 1 M aq NaOH (pH = 10) were added. The mixture was extracted with CH₂CI₂ (3 x). The combined extracts were dried (MgSO₄), filtered and concentrated. The crude material was chromatographed (loaded with CH₂CI₂, eluted with a gradient of 0-2.5% MeOH in CH₂CI₂) to provide 92 mg of 2-[4-(1-methyl-5-trifIuoromethyl-1H-pyrazoi-3-yl)-pheny!3-imidazo[1,2- b]pyrldazϊπ-6-ylamine as a yellow solid. MS: (M^"1") 359. ¹H NMR (400 MHz, DMSO-D₁₃): δ 8.31 (s, 1), 7,95 (d, 2, J = 8.5), 7.85 (d, 2, J = 8.5), 7.69 (d. 1, J = 9.6), 7.43 (s, 1), 6.60 (d, 1, J =

9.6), 6.35 (s, 2), 3.99 (s, 3). The tosylate salt was formed using the general procedure.

(C3a IC₅₀ = 61 nM)

Example 11

2-F4-(1-Methvi-5-trifluoromethyl-1H-Pyrazol-3-vH-phenvπ-imida--ori,2-biPyridaziπe p- toluene sulfonic acid salt

A slurry of 6-chloro-2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]- imida∑o[1 ,2-l3]pyridazine (100 mg, 0.2S5 mmol) and 10% Pd on carbon (200 mg) in 1:1

EtOAc/EtOH (200 mL) was placed in a Parr shaker under a H₂ atmosphere (5 psi) at rt for 1 h. The Parr bottle was purged with N₂ and the reaction mixture was filtered through a plug of celite, which was rinsed with 1:1 CH₂Cf₂ZMeOH- The filtrate was concentrated and the tosylate salt was formed using the general procedure to provide 67.8 mg of 2-[4-(1-methyl-5- trifIuoromethyl-1 H-pyrazol-3-yl)-phenyl]-irπidazo[1 ,2-b]pyridazϊne toluene sulfonic acid salt as a white solid. MS: (M*) 344. ¹H NMR (400 MHz, DMSO-D₆): 69.08 (s, 1), 8.69 (dd, 1, J -

4.6, 1.4). 8.26-8.30 (m, 1), 8.16 (d, 2, J = 8.5), 3.04 (d, 2, J = 8.3) 7.56 (s, 1), 7.51 (d, 2, J = 8.1), 7.45 (dd, 1 , J = 9.2, 4.5), 7-15 (d, 2, J = 7.9), 4.08 (s, 3), 2.33 (s, 3).

(C3a IC₅₀ = 942 πM) Example 12

2-[4-(1 -Methyl-5-trif luoromethyl-1 H-pyrazol-3-vl)-phenvl]5,6,7,8-tetrahvdro-irnidazo[1.2- bipyridazine p-tolueπesulfonic acid salt

A slurry of 6-chlαro-2-[4-(1-methyI-5-trjfluoromethyl~1H-pyrazol-3-yl)-pheπyl]- imidazo[1 ,2-b]pyrϊdazine (100 mg, 0.265 mrnol) and 10% Pd on carbon (200 mg) In 1:1

EtOAc/EtOH (200 mL) was placed in a Parr shaker under a H₂ atmosphere (50 psi) at rt for 3 h. The Parr bottle was purged with N₂, additional 10% Pd on carbon (200 mg) was added, and the Parr bottle was placed back under H₂ atmosphere (50 psi). After 20 h the reaction mixture was purged with N₂ and filtered through a plug of celite, which was rinsed with 1:1 CH₂Cl₂ /MeOH. The filtrate was concentrated and then redissolved in CH₂CI₂/MeOH and filtered to remove insoluble material. After concentrating again, the tosylate salt was formed using the general procedure to provide 74,5 mg of 2-[4-(1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl)-phenyl]-S,6,7,8~tetrahydro-irnidazo[1,2-b]pyridazϊne toluene sulfonic acid salt as a white solid. MS: (M⁺) 348. ¹H NMR (400 MHz. DMSO-D₆): δ 8.20 (s, 1), 8.04 (d, 2, J = 8.5), 7.92 (d, 2, J = 8.5), 7.57 (s, 1 ), 7.51 (d, 2, J - S-1), 7.15 (d, 2, J = 7.9), 4,07 (s, 3), 3.32-3.37

(m, 2), 3.17 (t, 2. J = 6.6), 2.32 (s, 3). 1.95-2.02 (m, 2).

Example 13 2-[4-(1 -Methyl-5-trifluoromethyl-1 H-Pyrazol-3-vl-phenyl]-imidazoH .2-alpyridine-6- carbaldehyde To a slurry of {2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[1,2- a]pyridϊn-6-yl}-methaπol (105.2 mg, 0.2825 mmol) in CH₂CI₂ (10.0 mL) at rt was added Dess- Martiπ perϊodinaπe (150 mg, 0.353 mmol). After 30 min, the reaction mixture was poured into 1 M NaOH (50 mL) and extracted with CH₂Cl₂ (3 x 50 mL). The combined extracts were dried (Na₂SO₄), filtered and concentrated to provide 93.8 mg of 2-[4-(1-methyI-5-trifluoromethyt-1H- ρyrazoi-3-yl)-ρhenyl]-imidazoIi,2-a]pyridϊπe-6-carbaldehyde. MS: (M^*) 371. ¹H NMR (400 MHz, CDCI₃): δ 9.95 (s, 1), 8.67 (t, 1. J = 1.2)₇ 8.00-8.04 (m, 3), 7.87 (dt, 2, J = 8.5, 1.9), 7.71 (d, 1, J = 9,3), 7.67 (dd, 1, J = 9.4, 1.6), 6.95 (s, 1), 4.05 (S, 3).

(C3a IC₅₀ - 78 nM), (C3a IC₅₀ = 32 nM), other enantiomer not recovered in sufficient quantity Example 14

1-{2-[4-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenvl-imidazori.2-alPyridin-6-yl}- ethaπol

To a solution of 2-[4-(1-methyl-5-trifluoromethyI-1 H-pyrazol-3-yl)-phenyQ-imidazo[1 ,2- a]pyridine-6-carbaldehyde (93.8 mg, 0.253 rnmoi) in THF (7.0 mL) at 0 °C was added MeMgBr (361 uL of a 1.4 M solution in 3:1 toluene/THF, 0.51 mmol), After 30 min. the reaction mixture was poured into sat. NaHCO₃ (50 mL) and extracted with CH₂CI₂ (3 x 50 mL). The combined extracts were dried (MgSO₄), filtered and concentrated. The crude solid was chramatographed (preabsorbed to silica, eluted with 2.5% MeOH in CH₂CI₂) to provide 33.3 mg of 1-{2-[4-(1-methyl-5-trifluoromethyI-1H-pyrazol-3-yl)-pheπyl]-ipnidazo[1,2-a]pyridiπ- 6~y!}-ethanol as a pale-yellow solid. MS: (M^1-) 387. ¹H NMR (400 MHz, CD₃OD); δ 8.45 (s, 1), 8.26 (s, 1), 8-01 (d. 2, J = 8.5), 7.93 (d, 2, J = 8.B)₁ 7.57 (d, 1, J = 9.3), 7.41 (dd. 1, J = 9-3, 1.9), 7.22 (s, 1), 4.09 (s, 3), 1.55 (d, 3 J = 6.6). The enantiomers were separated by HPLC (Chiraipak AS column, 85/15 heptane/EtOH).

(C3a lCso = 70 nM) (racemate), (C3a IC₅₀ Ξ 54 nM), (C3a IC₅₀ = 61 nM), (C3a IC₅₀ = 74 nM), (C3a IC₅0 = 48 nM) (diastereomers)

Example 15 1 -f2-r4-(1 -Methyl-5-trif luoromethyl-1 H-PVrazol-3-yl)-phenvn-5.6.7,8-tetrahydro- imidazori.2-alpyridin-6-yl)ethaπo]

To a slurry of {2-[4-(1-methyl-5-trifIuoromethyi-1H-pyrazol-3-yl)-phenyl]-5,67,8- tetrahydro-imidazo[1,2-a]pyrϊdin-6-yl}-methaπo] (200.2 rπg, 0.532 mmol) in CH₂CI₂ (15 ml_) at rt was added Dess-Martin periodinane (282 mg, 0.665 mrnol). After 30 min, the reaction mixture was poured into 1M NaOH (50 mL) and extracted with CH₂CI₂ (3 x 50 ml_). The combined extracts were dried (Na₂SO₄), filtered and concentrated. The resulting solid was slurried in THF (15 mL) at 0 ⁰C. MeMgBr (1.14 mL of a 1.4 M solution in 3:1 toluene/THF, 1.6 mmol) was added to the reaction mixture. After 30 min, additional MeMgBr (0,38 mL of a 1.4 M solution in 3:1 toluene/THF, 0.53 mmol) was added. The reaction mixture was stirred for an additional 30 min and then poured into sat. NaHCO₃ (50 mL) and extracted with CH₂CI₂ (3 x 50 mL). The combined extracts were dried (Na₂SO₄), filtered and concentrated. The crude solid was chromatographed (preabsorbed to silica, eluted with a gradient of 2,5-5% MeOH in CH₂CI₂) to provide 189.5 mg of 1-{2-t4-(1-methyl-5-tπfluoromethyl-1H-pyrazol-3-yl)-pheπyl]- 5,6,7,8-tetrahydro-ϊmϊdazo[1,2-a]pyridiπ-6~yl}-ethaηol as a white solid. MS: (M+) 391. ¹H NMR (400 MHz, CD₃OD): S 7.83 (d, 2, J = 8.5), 7.77 (d, 2, J = 8.5), 7.40 (s, 2), 7.39 (s, 1), 7.16 (s, 1), 4.13-4.33 (m, 1), 4.07 (s, 3), 3.75-3.91 (m, 2), 2.99-3.10 (m, 1), 2.76-2.89 (m, 1), 1.98-2.35 (m. 2), 1.64-1.82 (m, 1), 1.34 (d, 2, J = 6.2), 1.30 (d, 1, J = 6.4). The diastereomers were separated by HPLC (Chiraipak AS column, heptane/EtOH).

(C3a IC₅₀ = 35 nM) Example 16

{2-[4-(1 -Methyl-5-trifluoromethvl-1 H-pyrazol-3-vI)-pheπvπ-imidazo[ 1.2-alpyridin-7-yl}- methanol p-toluene sulfonic acid salt

A mixture of (2-arπino-pyridiπ-4-yl)-methanol (553,3 mg, 4.422 mmol), 2-bromo-1-[4-

(1-methyl-5-trifluoromethyl-1H-ρyrazol-3-yl)-ρhenyl]-ethaπone (1.28 g, 3.68 mmol) and NaHCO₃ (371 mg, 4.42 mmol) in DCE (46 mL) was heated at reflux for 5 h. MeOH (50 mL) was added to the reaction mixture, which was then filtered. The resulting material was absorbed to silica gel and purified by chromatography (gradient elutioπ starting with EtOAc/hexanes to MeOH/EtOAc to MeOH/CH₂Cl₂) to provide 1.363 g of a pale orange solid. A portion of the solid (31.8 mg) was slurried in EtOAc and P-TsOH-H₂O (32.5 mg, 0.171 mmol) was added. After stirring overnight, the mixture was filtered to provide a white solid, which was then dissolved in hot 3:1 /PrOH/MeOH filtered to provide 7.1 mg of {2-[4-(1-methyI- 5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-imidazo[i ^-alpyridin^-yiy-methanot p-toluene sulfonic acid salt as a white solid. MS: (MT) 373. ¹H NMR (400 MHz, DMSO-D₆): δ 8,84 (d, 2, J = 6.4), 8.14 (d, 2, J = 8.5), 8.05 (d, 2, J = 8.5), 7.80 (s, 1), 7.62 (s, 1), 7-51 (d, 2, J = 8.1), 7.43 (bd, 1, J = 6.6), 7.14 (d, 2, J = 8.1), -4.78 (s, 2), 4.09 (S, 3), 2.32 (S, 3).

(C3a IC₅₀ = 94 nM), (C3a IC₅₀ = 103 nM), (C3a IC₅₀ = 98 nM) (enantϊomers) Example 17

1-f2-r4-⁽1-Wlethyl.5-trifluoroinethvMH-oyrazoU3-yl)-phenv1l-imidazori.2-alpyridin-7-ylV ethanol

The starting material for this procedure was a portion (600 mg) of the impure orange solid that was isolated from the chromatography in the preparation of {2-[4-(1-methyl-5- trifluoromethyl-IH-pyrazol-S-yO-phenylJ-imidazofi^-aJpyrϊclin^-ylJ-methanol. This material was slurried in CH₂CI₂ (40 mL) at rt and Dess-Martin periodtnane (854 mg, 2.01 mmol) was added. After 55 min, additional Dess-Martin periodinane (300 rng, 0.707 mmol) was added. The reaction mixture was stirred at rtfor another 40 min and then poured into 1 M NaOH (150 mL) and extracted with CH₂CI₂ (3 x 75 mL). The combined extracts were dried (Na₂SO₄), filtered and cone The resulting solid was dissolved in THF (40 mL) at 0 ⁰C and MeMgBr (4.0 mL of a 1.4 M solution in 3:1 toluene/THF, 5.638 mmol) was added. After 45 min the reaction mixture was poured into sat. NaHCO₃ (150 mL) and extracted with CH₂Cl₂ (3 x 75 mL). The combined extracts were dried (Na₂SO₄), filtered, concentrated and purified by chromatography (loaded with CH₂CI₂, eiuted with gradient of 25-75% EtOAc in hexanes) to provide an undesired bromiπated product (255 mg, 0.548 mmol), which was hydrogenated in EtOH (15 mL) with 10% Pd on carbon (255 mg) under an H≤ atmosphere (1 atm). After 2.25 h, the reaction mixture was purged with N₂, filtered through a plug of celite that was rinsed with EtOH/CH₂Cl₂, concentrated, and purified by chromatography (preabsorbed to silica, eiuted with 0-5% MeOH in CH₂CI₂) to provide 122.7 mg of 1-{2-[4-(1-methyl-5-trifluoromethyl- 1H-ρyrazoi-3-yl)-ρhenyl]-imidazo[i,2-a]pyridin-7~yl}-ethanoi as a white solid. MS: (M⁺) 387. ¹H NMR (400 MHz, CD₃OD): δ 8.36 (d, 1, J = 7.0), 8.18 (s, 1), 7.96 (d, 2, J = 8.5), 7.89 (d, 2, J = 8.5), 7.53 (S, 1), 7.17 (s, 1), 6.95 (dd, 1, J - 7.0, 1.7), 4.05 (s, 3), 1.49 (d, 3, J = 6.4). The enantϊomers were separated by HPLC (Chiralcel OD column, heptøne/EtOH).

(C3a ICso ~ 114 nM), (C3a IC₅₀ - 176 nM), (C3a lc_SD = 98 nM) (enantiomers) Examole 1.8

■fa^-fi-MethvI-S-trifluoromethvt-IH-pyrazoI-S-vπ-ohenvπ-S.e.T.a-tetrahvdro- imidazori.2-aiPyridin-7-v»-methanol

A slurry of {2-[4-(1 -methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-irnidazo[1 ,2- a]pyrϊdiπ-7-yl}-methano! {705 mg, 1.89 mmol) and 10% Pd on carbon (0.7 g) in EtOH (30 mL) was placed in a Parr shaker under an H₂ atmosphere (40 psi) for 18 h. The Parr bottle was purged with N₂ and then filtered through a plug of celite that was rinsed with CH₂Cl₂/MeOH, concentrated and purified by chromatography (2.5-10% MeOH in CH₂Cl₂) to provide 169.4 mg of {2-[4-(1-methyl-5-triflϋoromethyl-1 H-pyrazol-3-yl)-pheπyl]-5,6,7,8-tetrahydro»imidazo[1 ,2- a]pyridϊn-7-yl}-methanol as a white solid,

MS: (M^*) 377. ¹H NMR (400 MHz, CD₃OD): δ 7.67-7.77 (m, 4), 7.23-7.29 (m, 1), 7,07

(bs, 1), 4.04-4.13 (m, 1), 3-99 (s, 3), 3.83-3.94 (m, 1), 3.50-3.61 (m, 2), 2.94-3.02 (m, 1), 2,42-

2.52 (m, 1), 2.00-2.16 (m, 2), 1.62-1.75 (m, 1). The enantiomers were separated by HPLC

(Chiralcel OD column, heptane/EtOH). The tosylate salts were formed using the general procedure.

(C3a lC_SD = 171 nM)

Example 19 6-r4-f1-IVlethyl-5-trifluoromethyl-1H-pyfrazol-3-ylVpheπvn-2,3-dihvdro-imidazor2,1- bithiazole A mixture of 2-bromo-1-[4-(1-methyI-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]- ethanone (34.7 mg, 0.100 mmol), 2-amino-2-thiazoline hydrochloride (13.9 mg, 0.100 mmol), NaHCO₃ (16-8 mg, 0,200 mmol), and DCE (2 mL) was heated at 65 ⁰C for 1 d. The reaction mixture was concentrated and chromatographed (loaded with CH₂CI₂; eluted with gradient of 0-100% EtOAc in hexanes) to provide 17.0 mg of 6-[4-(1-methyl-5-trϊfluoromethyl-1H-pyrazol- 3-yl)-prienyI]-2,3-dihydro-imidazo[2,1-b]thϊa≥oie as a solid. MS: (M") 351. ¹H NMR (400 MHz, CDCI₃): δ 7.75 (S₁ 4), 7.27 (S, 1), 6,89 (s, 1), 4.18 (t, 2, J = 7.3), 4,02 (s, 3), 3,82 (t, 2, J = 7.3).

Example 20 2-F4-C1 -Methyl-5-trif luoromethvM H-pyragol-3-vπ-phenvπ-imicjazoH ,2-aTpyridine-6- carbonitrile A mixture of 2-bromo-1-[4-(1-methyl"5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]- ethanoπe (173,5 mg, 0.5000 mmol), 6-amino-πicotinonitrile (59.5 mg, 0.500 mmol), NaHCO₃ (42 mg, 0,50 mmol), and DCE (10 mL) was heated at reflux for 48 h. The mixture was cooled to rt and stirred for 2 d. The resulting solid was isolated by filtration and rinsed with EtOAc and Et₂O and dried under vacuum to provide 46 mg of 2-[4-(1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl)-phenyl]-imidazo[1,2-a]pyridiπe-6-carbonitriie as a solid. The filtrate was concentrated and chromatographed (1 :1 EtOAc/hexanes) to provide an additional 20 mg of 2- ^-(i-methyl-S-trifluoromethyl-iH-pyrazol-S-ylJ-phenyO-imidazoti^-alpyridtne-e-carbonitriie as a solid, MS: (M^*) 368, ¹H NMR (400 MHz₁ DMSO-D₆): δ 9.41 (ε, 1), 8.61 (s, 1), 8.12 (d, 2, J = 8.5), 8.01 (d, 2, J = 8.5), 7.79 (d, 1, J = 9.3), 7.57 <dd, 1, J = 9.4, 1.7), 7.54 (s, 1), 4.07 (s, 3),

(C3a IC₅₀ ^a 74 πM) Example 21

2-F4-f 1 -Methyl-5-trif luoromethyl-1 H-pyrazol-3-vn-phen vH-6-f 1 H-tetrazol'-S-vπ- imictezoH .2-alpyridiπe

A mixture of 2-[4-(1-methyl-5-trifluoromethyl-iH-pyrazoi-3-yl)-phenyl]-imidazo[1 ,2- a]pyridine-6-carbonitrite (37 mg, 0.10 mmol), azidotrimethylsilaπe (13 uL, 0.20 mmol), and dibutyltin oxide (4 mg, 0.015 mmol) in toluene (5 mL) was heated at 90 ^DC for 14 h. Additional azidσtrimethylsilane (120 uL, 0.905 mmol) and dibutyltin oxide (4 rng, 0.015 mmol) were added. The reaction mixture was heated at 90 ⁰C for another 24 h and then concentrated- Trie resulting solid was triturated with hot EtOAc to provide a solid, which was purified by prep TLC (eluted with 20% MeOH in CH₂CI₂) to provide 5.0 mg of 2-[4-(1-methyl-5-trifluoromethyl- 1 H-pyrazol-3-vl)-prienyl]-6-(1 H-tetra∑ol-5-yl)-imidazo[1 ,2-a]pyridine as a solid. MS: (M^*) 411. ¹H NMR (400 MHz, CD₃OD): δ 9.04 <s, 1), 8.38 (S₁ 1), 8.01 (d, 2, J = 8.5), 7.98 (dd, 1, J = 9.3, 1.7), 7.92 (d, 2, J = 8.5), 7.67 (d, 1, J = 9.5), 4.06 (s, 3). (C3a lCso = 27 nM)

Example 22 3-f 2-f4-(1 -Methyl-5-trifluoromethyl-1 H-pyrazoI-3-ylVphenvπ-imidazori ,2-a1pyridin-6-yll- π ,2,4ioxadiazol-5-ol

A mixture of 2-[4-(1-methyl-54rifluoromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[i,2- a]pyridine-6-carbonitrile (60 mg, 0.16 mmol), hydroxylamiπe hydrochloride (45.4 mg, 0.653 mmol), Et₃N (91 uL, 0.65 mmol) in DMF (5 mL) was heated at 80 °C for 3 h. The reaction mixture was cooled, stirred for 14 h, poured into H₂O, and extracted with EtOAc (4 x). The combined extracts were dried (MgSO.*), filtered and concentrated. The resulting tan solid was combined with Et₃N (0.110 mL, 0.788 mmol) and 2-ethylhexylchloroformate (0.155 mL, 0.738 mmol) in DMF (5 mL) and heated at 100 °C for 4 h. The reaction mixture was cooled to rt, stirred for 14 h, poured into H₂O and 1 M HCI (pH = 2,5), and extracted with EtOAc (4 x). The combined extracts were dried (MgSO₄), filtered, concentrated, and purified by prep TLC (10:1 CH₂CI₂/MeOH) and flash chromatography (10-15 % MeOH in CH₂Ci₂) to provide 7 mg of 3-{2- [4-(1 -methyl-5-trif luoromethyl-1 H-pyrazol-3-y!)-phenyl]-imidazo[1 ,2-a]pyridin-6-yl}~ [1,2,4]0Xadϊazol-5-0l as a solid. MS: (M⁺) 427. ¹H NMR (400 MHz, CD₃OD): 58.82 (s, 1), 8.24 (S, 1), 7.95 (d, 2, J = 8.3), 7.85 (d, 2, J = 8.3),. 7,64 (s, 2), 7.05 (S, 1), 4.03 (S, 3). Example 23

2>F4-(1 -Methyl-5-trifluoromethγI-i H-pyrazol-3-vπ-pheπvπ-imidazoπ .2-bipyridazine-^β- carbonitrile

A mixture of N'(6-cyano-pyridaziπ-3-yl)_"2,2-dimethyl-ρropioπamide (167 mg, 0.818 mmol) and 6 IVl HCI (2,0 mL) in EtOH (10 mL) was heated at 75 ⁰C for 5.5 h. The reaction mixture was cooled and concentrated. The resulting yellow solid was concentrated from

_/PrOH and then combined with 2-bromo-i-[4-(1-methyl-5-trϊfluDrornethyi-1H-pyrazαl-3-yl)- phenyll-ethanone (284 mg, 0.81 S mmol) and NaHCO₃ (282 mg, 3.36 mmol) in DCE (16 mL) and heated at 80 ⁰C for 1.5 d. The reaction mixture was cooled, poured into sat. NaHCO₃ (50 mL), extracted with CH₂CI₂ (7 X 50 mL), dried (MgSO₄), filtered and concentrated. The resulting yellow solid was dissolved in a minimal volume of hot EtOH and cooled to rt. The precipitate was isolated by filtration to provide 147 mg of 2-[4-(1-methyl-5-trifluoromethyl-1H- pyrazαl-3-yi)-phenyl]-imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid. MS: (M⁺) 369.

¹H NMR (400 MHz, DMSO-D₆): δ 9.24 (s, 1), 8.42-8.49 (m, 1), 8,18-8.25 (m, 2), 8.00-8.08 (m, 2), 7.78-7.83 (m, 1 ), 7.58 (s, 1 ), 4.08 (s, 3).

(C3a IC₅₀ = 188 nM)

Example 24 2-r4-(1 -Methyl-5-trif lυoromethyl-1 H-pyrazoi-3-yl)-phenyll-6-( 1 H-tetrazol-5-vD- ϊmidazoli ,2-bipyridazine A mixture of 2-[4-(1-methyl-5-trtfluoromethyl-1H-pyrazol-3-yl)-phenyl]-6-(1H-tetrazol-

5-yl)-imidazo[1 ,2-bJpyrida∑ine (3S.8 mg, 0.100 mmol), azidotrimethylsilane (13 uL, 0.20 mmol), and dibutyltiπ oxide (4 mg, 0,015 mmol) in toluene (5 mL) was heated at 90 *C for 14 h. Additional azidotrimethylsilane (120 uL, 0.905 mmol) and dibutyltin oxide (4 mg, 0.015 mrnol) were added. The reaction mixture was heated at 90 ⁰C for another 24 h, cooled, and filtered. The isolated solid was triturated with hot EtOAc to provide 18,4 mg of 2-[4-(1 -methyi- 5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-6-(1 H-tetrazo!-5-yI)-imϊdazo[1 ,2-b]pyrida∑ine as a yellow solid. MS: (M^*) 412. ¹H NMR (400 MHz, DMSO-D₈): δ 9.06 (s_r 1), 8.42 (d, 1, J = 9.3), 8.24 (d, 2, J = 8.5 ), 8.03 (d, 2, J = 8,3), 7.99 (d. 1 , J = 9.3), 7.57 (a, 1 ), 4.08 (s, 3).

(C3a IC₅₀ = 29 nM) Example 25

N^^-fi-Methyl-S-trifluoromethyl-IH'Pyrazol-a-yl^phenvπ-imidazofi.Z-aipyridin-e-yll- acetamide p-toluenesulfonic acid salt

A solution Of 2-[4-(1-methyl-5-trifluoromethyI-1H-pyra2Ol-3-yl)-phenyl]-imidaHo[1,2- a]pyridin-6-ylamiπe p-tolueπesulfonic acid salt (36 mg, 0.051 mmol), Et₃N (56 uL, 0.40 mmol), and acetyl chloride (8 uL, 0.1 mmol) in CH₂CI₂ (6 mL) was stirred at rt for 20 h, then poured into 1 M NaOH (20 mL), and extracted with EtOAc (3 x). The organic extracts were combined, dried (MgSO₄), filtered, concentrated, and purified by prep TLC (10:1 CH_£CI₂/MeOH) to provide 16 mg of N-{2-[4-(i-methyl-5-trifIuoromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[1,2- a]pyridin-6-yl}-acetamide as an off-white solid. The tosylate salt was formed using the general procedure. MS: (M⁺) 400. ¹H NMR (400 MHz₁ CD₃OD): δ 9.62 (s, 1), 8,63 (s, 1), 8.07 (d, 2, J = 8.5), 7.94 (d, 2, J = 8.5), 7.89 (d, 1, J = 9.5), 7.S7 (s, 1), 7.83 (dd, 1, J = 9.6, 1.8), 7.74 (d, 2, J = 8.3), 7.24 (d. 2, J = 8.4), 4.19 (s, 3), 2.39 (s, 3), Z.25 (s, 3). (C3a IC₅₀ = 161 nM)

Example 26 2-[4-( 1 -Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-imidazo[1.,2-alpyridin-6- ylamine bis-p-toluenesulfonic acid salt To a solution of 6-(2,5-dimethyl-pyrrol-l-yi)-2-[4-(1-methyl-5-trifluoromethyl-iH- pyrazol-3-yl)-phenyl]-imidazo[1,2-a]pyrϊdine (4.696 g, 10.78 mrnσl) in EtOH (200 mL) was added hydrazine hydrate (10 mL) and cone. HCI (20 mL). The mixture was heated at reflux for 2 d, cooled, poured into 1 M NaOH (400 mL) and H2O (200 mL), and extracted with

CH₂CI₂ (6 x 250 mL). The combined extracts were dried

filtered, and concentrated to and dissolved in hot hexanes with minimal EtOAc. To the hot solution was added p-

TsOH-H₂O (8.20 g, 43.1 mmol). The mixture was cooled and filtered and placed the isolated solid under high vacuum to provide 2-[4-(1-methyI-5-trifluoromethyM H-pyrazol-3-yl)-phenyrj- imidazo[1 ,2-a]pyridin-6-ylamine as a light tan solid as the bistosylate salt. MS: (M⁺) 358. ¹H NMR (400 IVIHz, DMSO-D₆): δ 8.73 (S. 1), 8.12 (d, 2, J = 8.5), 7.96-8.00 (m, 3), 7-75 (d, 1, J - 9.5), 7.61 (s, 1), 7.49-7.53 (m, 5), 7.15 (d, 4, J = 7.9), 4.09 (S, 3), 2.32 (S, 6).

(C3a IC₅₀ = 199 nM)

Example 27 6-(2.5-Dimethyl-pyrrol-1 -vl)-2-[4-(1 -methyl-5-trif luorornethyl-1 H-pyrazol-3-yl)-phenvπ- imidazo{1.2-alpyridine A mixture of 5-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamiπe (4.00 g, 21.4 mmol), 2- bromo-1-[4-(1-methyi-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl3-ethaπone (6.74 g, 21.4 mmol), and NaHCO₃ (1.79 g, 21.36 mmol) in DCE (150 mL) was heated at 80 ^oC for 15 h, cooled, poured into 1 M NaOH (500 mL), and extracted with CH₂CI₂ (3 x 200 mL). The combined extracts were dried (MgSO₄), filtered, concentrated, and chromatographed (loaded with CH₂CI₂, eluted with a gradient of 5-30% EtOAc in hexanes). The resulting orange solid was triturated with hexanes and minimal EtOAc to provide 4,57 g of 6-(2,5-dimethyl-pyrroI-1- yl)-2-t4-(1-methyl-5-trifluoromethy!-iH-pyrazol-3-yI)-phenyl]-imida∑o[1,2-a]pyridine as a white solid. MS: (M⁺) 436. ¹H NMR (400 MHz, CDCI₃): d 8.10-8.12 (m, 1), 8.03 (d, 2, J = 8.3), 7.97 (s, 1), 7.87 (d, 2, J = 8.5), 7.70 (d, 1, J = 9.5), 7.05 (dd, 1, J = 9.4, 2.0), 6.95 (S, 1), 5.94 (S, 2), 4.05 (s, 3), 2.09 (s, 6).

(C3a IC₅₀ = 187 nM) Example 28

2-^4-f1-Methyl-5-trifluoromethvI-1H-pyra2Ql-3-vO-pheπyl]-5,6.7.8-tetrahvdro-imidazof1,2- alpyrϊdin-βfylamrπe bis-p-toluenesulfonic acid salt

A solution of 2-[4-(1-methyl-5-trϊfiuoromethyl-1H-pyrazol-3-yl}-pheπyl]-irnidazo[1,2- a]ρyridin-6-ylamlne bis-p-toluenesulfαnic acid salt (5.38 g, 7.66 mmol) in EtOH (200 mL) under an N₂ atmosphere was charged with 10% palladium on carbon (5.4 g) and placed on a

Parr shaker under a H≥ atmosphere (45 pεi) for 21 h. The Parr bottle was purged with N₂ and the mixture was filtered through a plug of celite and concentrated. The resulting solid was dissolved in hot EtOH and hexanes was added slowly until cloudiness persisted. Cooled and filtered to provide 1.988 g of 2-[4-(1-rnethyl-5-trifluoromethyl-1 H-pyrazol-3-yI)-phenyl]-5,6,7,8- tetrahydro-imidazo[1,2-a]pyridin-6-ylarnine bis-jø-toluenesulfonic acid salt as a light gray solid.

MS: (M⁴) 362. ¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, 2, J = 8.5), 7,88 (s, 1), 7.73 (d, 2, J =

8.5), 7.70 (d, 4, J = 8.1), 7.26 (s, 1), 7.23 (d. 4, J = 8.1), 4.64 (dd, 1, J = 13.4, 4.9), 4.32 (dd,

1, J = 13.4, 7.1), 4.10 (S₁ 3), 4.08-4.15 (m, 1), 3.30-3.33 (m, 1), 2.46-2.54 (m, 1), 2.36 (s, 6), 2.27-2.35 (m, 1).

nM)

Example 29 N-fΣ-r^ft-Methvt-S-trifluoronriathyl-IH'-Dyrazol-a-vπ'-ohenvπ-δ.β.T.B-tetrahvdro- imidazori.2-aipyrϊdin-6-yl>-aeetamid6 p-toluenesulfonic acid salt A solution of 2-[4-(1-methyI-5-trifluoromethy[-1H-pyra?;ol-3-yl)-phenyl]-5,6,7,8- tetrahydro-imidazo[1,2-a]pyridϊn-6-ylamine p-toluenesulfonic acid salt (36 mg, 0.051 rnmol), EtjN (56 uL, 0.40 mmol), and acetyl chloride (δ uU 0.1 mmol) in CH₂Cl₂ (6 mL) was stirred at rt for 20 h, then poured into 1 M NaOH (20 mL), and extracted with EtOAc (3 x). The organic extracts were combined, dried (MgSO₄), filtered, concentrated, and purified by prep TLC (10:1 CH₂CI₂/Me0H) to provide 16.7 mg of N-{2-[4-(1-methyl-5-trifluoromethyl-1H-pyra∑ol-3-yl)- phenyl]-5,6,7,8-tetrahydro-imidazo[i,2-a]pyridin-6-y⁾}-acetarnϊde as an off-white solid. The tosylate salt was formed using the general procedure. MS: (M*) 404. ¹H NMR (400 MHz, CD₃OD): d 8.01 (d, 2, J = 8.5), 7.85 (s, 1), 7.76 (d, 2, J = 8.5), 7.72 (d, 2, J = 8.3), 7.23-7.27 (m, 3), 4.44-4.56 (m, 2), 4.09 (s, 3), 4.07-4.13 (m, 1). 3.22-3.30 (m, 2), 2.39 (s, 3), 2.15-2.32 (m, 2), 2.02 (s, 3).

(C3a ICso = 352 nM)

Example 30 C-f2-f4-(1-MethvI-S-trifluoromgthyl-1H-ρyrazol-3-yl)^phenvn-5.6.7,S-tetrahvdro- imidazori.2-a1pyridϊπ-6-yl}-methylamine bis-hvdrochloride salt To a slurry of {2-[4-(1-methyl-54rifluoromethy)-1H-pyrazol-3-yl)-phenyη-5,6_r7,8- tetrøhydrα-imidazo[1,2-a]pyridϊn-6-yl}-methanol (376 mg, 1.00 mmol) in CH₂CI₂ (75 mL) at rt was added Dess-Martin periodϊnaπe (636 mg, 1.50 mmol). The mixture was stirred for 40 miπ, then poured into 1 M NaOH (100 mL), and extracted with CH₂CI₂ (3 x). The combined extracts were dried (MgSO₄), filtered, and concentrated. The resulting yellow solid was dissolved in EtOH (50 mL). To the solution was added a mixture of hydroxylamiπe hydrochloride {82 rng, 1.2 mmol) and sodium acetate (111 mg, 1.35 mmol) in H₂O (10 mL). The mixture was stirred at rt for 3 h, H₂O was added, and the mixture was filtered, rinsing with H₂O and Et₂O. The isolated solid (300 mg) was dissolved in 250 mL EtOH with 12 M HCl (0.10 mL) in a Parr bottle. The bottle was placed under a N₂ atmosphere, charged with 10% Pd/C (350 mg), and then place under an H₂ atmosphere (50 psi) at rt on a Parr shaker for 2 h. The bottle was purged with N₂ and additional 12 M HCI (0.10 mL) and 10% Pd/C (1.0 g) were added. The bottle was placed back under an H≥ atmosphere (50 psi) for 20 h and then purged with N₂- The mixture was diluted with CH₂CI₂ (200 mL), filtered through a plug of celite, and concentrated to provide 310 mg of C-{2-[4-(1-rπethyl-5-trifiuoromethyl-1H-ρyrazol- 3-yl)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridiπ-6-yl}-methylamine as the bis-HCI salt as a pale yellow solid. The HCI salt was free based by partitioning between 1 M NaOH and CH₂CI₂. The CH₂CI₂ layer was concentrated and the tosylate salt was formed using the general procedure. MS: (M^*) 376. ¹H NMR (400 MHz, CD₃OD): δ 8.00 (d, 2, J = 8.5), T.82 (s, 1), 7.70-7.76 (m, 6), 7.22-7.25 (m, 5), 4,46 (dd, 1 , J - 13.1, 5,0), 4.09 (s, 3), 3.96-1.03 (m, 1), 3,09-3.32 (m, 4), 2.55-2.65 (m, 1), 2.37 (s, β), 2.30-2.37 (m, 1), 1.84-1.95 (m, 1).

General Procedure for Amide Formation: A mixture of C-{2-[4-(1-rnethyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-5,6,7,8- tetrahydro-ϊmidazo[1,2-a]pyrjdin-6-yl^methyfamine bis-hydrochloride salt (41 mg, 0.091 rnmol), carboxylic acid (0.2 mmol), /-PrEt₂N (0.087 mL, 0.50 mmol), and EDCIΗCI (48 mg, 0.25 mmol) in 1,2-DCE (4 mL) and DMF (1 mL) was heated at 80 "C for 1 d, cooled, then poured into sat. NaHCO₃ and extracted with CH₂Cl₂ (3 x). The combined extracts were dried (MgSO₄), concentrated, and purified by prep-TLC (10:1 CH₂Cl₂), The tosylate salt was formed using the general procedure. (C3a ICso = 61 nM)

Example 31 Cyclopropanecarboxyiic acid -f2-r4-(1 ■methyl-5-triflJoromethyl-i H-ρyrazol-3-yl)-phonvπ- 5,6,7,8-tetrahvdro-imϊdazori .2-alpyridin-β-ylrπethvfl-amide p-toluenesulfoπic acid salt

MS: (M^*) 444. ¹H NIVlR (400 MHz, CD₃OD): δ 8.44 (bt, 1, J = 6.1), 8.01 (d, 2, J = 8.5),

7.83 (S₁ 1), 7.76 (d, 2, J = 8,5), 7.73 (d, 2, J = 8.3). 7.24-7.27 (m, 3), 4.34 (dd, 1, J = 13.2,

5.1), 4.09 (S, 3), 3.91 (dd, 1, J = 12.8, 9.7), 3.37-3.41 (m, 2), 3.22-3.30 (m, 1), 3.06-3.15 (m,

1), 2-39 (s, 3), 2.37-2.46 (m, 1), 2.19-2.26 (m, 1), 1.79-1.90 (m, 1), 1.61-1.67 (m, 1), 0.79-0-93 (m, 4).

(C3a IC₅₀ = 61 nM) Example 32

1 H-Pyrrolβ-2-carboxylic acid {2-r4-H -methyl-5--rifluoromethyl-1 H-pyrazol»3-yll-phenvπ- 5,6 J,S-t6trahvdro-imidazori .2-aiPyridin-6-ylmethyl}-aπiide bis-p-toluenesulfonic acid salt MS: (M^r) 469. ¹H NMR (400 MHz, CD₃OD): QB.30 (bt, 1, J = 6.5), 8.00 (d, 2, J = 8,5),

7.81 (s, 1), 7.72-7-77 (m, 6), 7.24-7.28 (m, 5), 6.95-6.97 (m, 1), 6.83-6.85 (m, 1), 6.20-6.22 (m, 1), 4.35-4.41 (m, 1), 4.09 (s, 2), 3.94-4,00 (m, 1), 3.50-3.55 (m, 1), 3.05-3.31 (m, 4), 2.40 (s, 6), 2.23-2.32 (m, 1), 1.82-1.95 (m, 1).

(C3a IC_5O a 120 πM) Example 33

N-f2-f4-f1-Methyl-5-tr»fluoromethv]-1H-pyrazol-3-v»-phenvπ-5,6,7.S-tetrahvdro- imidazor1.2-aiPVridin-6-ylmethyl>-nicotiπarnide bis-p-tolueπesulfonic acid salt

MS: (M⁺) 481. ¹H NMR (400 MHz, CD₃OD): d 9.33 (s, 1 ), 9.24 (bt. 1, J = 5.5), 8.98- 9.02 (m, 2), 8.14-8.19 (m, 1), 8.01 (d, 2, J = 8.3), 7.81 (s, 1), 7.75 (d, 2, J = 8.5), 7.72 (d, 4, J = 8.3), 7.23-7.26 (m, 5), 4.44-4.49 (m, 1), 4.09 (s, 3), 3.99-4.06 (rn. 1), 3.63-3.68 (m, 2), 3.25- 3.32 (m, 1), 3.08-3.17 (m, 1), 2.55-2.66 (m, 1), 2.38 (s, 6), 2-26-2.34 (rn, 1), 1.88-1.89 (m, 1). (C3a IC₅₀ = 268 nM)

Example 34

2-( 1 ,1 »Dioxo-tetrahvdro-1 l6-thfopheπ»3-vQ-N-f2»r4-( 1 -methyl[-5-trif tuoromethyl-1 H- pyrazoI-S-vπ-phenylT-S_^ ^βJ.β-tetrahvdro-imiidazofi.a-aTPyridiπ-e-ylmethvD-acetamide p- toluenesulfonic acid salt

MS: (M^*) 536. ¹H NMR (400 MHz, CD₃OD): S 8.36 (bt, 1, J = 6.1), 8.01 (d, 2, J = 8.5), 7.84 (s, 1), 7.76 (d, 2_T J ^«= 8.5), 7.73 (d, 2, J = 8.1), 7.24-7.28 (m, 3), 7.35 (dd. 1, J = 13.2, 5.1), 4.09 (s, 3), 3.88-3.95 (m, 1), 3.36-3.42 (m, 2), 3.21-3.31 (m, 3), 3.06-3.16 (m, 2), 2,81-2.90 (m, 2), 2.39 (s, 3), 2.37-2.53 (m, 4), 2.18-2.26 (rn, 1), 1.78-2.00 (m, 2). (C3a IC₃₀ - 29 nM)

Example 35 3-Methyl-5-r4-(1-methyl-5-trifluoroinethvi-1H-Pyra2ol-3-yl>-phenvn-3H-imidazori_t2- biπ,2,41triazole-2-carbaldahvde To a slurry of {3-methyl-5-[4-(1-methyl-5-trifluoromethyl-1H-pyra20l-3-y!)-phenyll-3H- imida2o[1,2-b][1,2,4]triazoI-2-yI>metrianoi (700 mg, 1.86 mmol) in CH₂CI₂ (100 mt_) at rt was added Dess-Martin periodiπane (1-1S g, 2.80 mmol). After 1 h, a mixture of 1 Wl NaOH (65 mL) and brine was added and the mixture was extracted with CH₂Cl₂ (3 x). The combined extracts were dried (Na₂SO₄), filtered and concentrated to provide 400 mg of 3-methyl-5-[4-(1- methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyt]-3H"ϊmidazo[1 ,2-b]E1 ,2,4]triazole-2- carbaldehyde as a yellow solid. MS: (M^*) 375. ¹H NMR (400 MHz, CDCI₃ZCD₃OD): δ 9.33 (s, 1), 7.33(d, 2, J = 8.5), 7.28 (d. 2, J = 8.7), 6.84 (s, 1), 6.42 (s. 1), 3.56 (S, 3), 3.52 (S, 3). (C3a IC₅₀ = 166 nM)

Example 36 l3-n/lethyl-5-f4-f1-methyl-5-trifluoromethv>-iH-ρyrazol-3-.yl)-phenylT-3H-imidazofl2» biri.2.4Ttriazol-Z-yl}-methaπol p-toluenesulfαπic acid satt To a solution of 5-benzyloxymethyl-4-methyl-4H-[1 ,2,43triazol-3-y{amine (1.76 g, 8.06 mmol) in /-propanol (60 mL) and 1,2-DCE (30 mL) was added 2-bromα-i-[4-(1-methyl-5- trffluαromethvi-1 H-pyrazol-3-yl)-phenyl]-ethanone (3.36 g, 9.68 mmol). The mixture was refluxed for 14 h, diluted with Et₂O/hexanes_r cooled to 0 "C, and filtered to provide a pale yellow solid (1.5 g). A portion of the solid (0.75 g) and glacial AcOH (30 mL) was heated in a seated tube to 170 ⁰C for 1,5 d and then concentrated. The residue was diluted with 1 M NaOH and extracted with EtOAc (3 x). The combined extracts were dried (MgSO₄), filtered and concentrated to a brown gum (530 rπg). A portion (53 mg. 0.11 mmol) was combined with ammonium formate (36 mg, 0.57 mmol) and 10% Pd/C (100 mg) in MeOH (5 mL) and was stirred at rt for 7 d. The mixture was filtered through a plug of celite, concentrated, diluted with 1 M NaOH and extracted with EtOAc (3 x). The combined extracts were dried (MgSO₄.), filtered, concentrated, and chromatographed (EtOAc) to provide 13 mg of {3- methyl-5-[4-(1-methyl-5-trif!uoromethyl-1H-pyrazol-3-y()-pheπyl]-3H"imidazo[1,2- b][1 ,2,4]triazol-2-yl]-methanol as an off-white solid. The tosyiate salt was formed Using the general procedure. MS: (M") 377. ¹H NMR (400 MHz, CD₃OD): δ 7.99 (s, 1), 7.89 (d, 2, J = 8.3), 7.69-7.75 (m, 4), 7.17 (d, 2, J s 8.1), 7.04 (s, 1), 4.86 (s, 2), 4.07 (s, 3), 4.04 (S₁ 3), 2.34 (S, 3).

(C3a IC₅₀ = 162 nM)

Example 37 1-Methyl-6-ϊ4»(1-methyl-5-trif[uoromethyl-1 H-pyrazθl-3-vπ-phenvπ-1 H-imidazopf ,2- alimidazole ρ-tolueπesulfonic acid salt

To a solution of 1-methyi-1H-imϊdazol-2-ylamine (100 mg, 0.749 mmol) in 1,2-DCE (14 mL) at rt was added f-BuOK (84 mg, 0.749 mmol)- After 15 min, 2-bromo-i-[4-(1-methyl- 5-trifluoromethyl-1 H-pyrazol-3-yl)-pheπylJ-ethanone (260 mg, 0.749 mmol) was added and the mixture was heated at 80 "C for 2 h. The mixture was cooled and filtered, rinsing with 1,2- DCE- The isolated white fluffy solid (141.5 mg) was stirred in 48% aq. HBr (3.0 mL) for 8 h. The mixture was poured into 1 M NaOH (50 mL) and extracted with CH₂Cl₂ (2 x 50 mL). The combined extracts were dried (Na₂SO₄), filtered, and concentrated to provide 59.7 mg of 1- methyI-6-[4-(1 -methyl-5-trifluoromethyM H-pyrazol-3-yl)-ρhenyI]-1 H-irnidazo[1 ,2-a]ϊmϊdazole as a white solid. The tosyiate salt was formed using the general procedure. MS: (M⁺) 346. ¹H NMR (400 MHz, DMSO-D_e): δ 8.22 (s, 1), 8.07 (d, 2, J = 8.5), 7.90 (d, 2, J = S.5), 7.76 (s, 1), 7.57-7.59 (m, 2), 7,51 (d, 2, J = 8.1), 7.15 (d, 2, J = 7.9), 4.08 (s, 3), 3.85 (s, 3), 2.32 (S, 3). (C3a IC₅₀ = 194 nM) Example 38

{1 -Methyl-6-f4»(1 -rnethyl-5-trif luoromethyl-1 H-pyrazol-3-vO»phenvπ-1 H-imidazoM .2- aiimidazol-2-yll-rπethanol p-toluenesulfonic acid sajt

To a solution of 1-methyl-6-[4-(1-rnethyI-5-trif[uorometh^-iH-pyrazol-3-yl)-phenyl]- iH-imidazo[1,2-a]imidazoie (50.0 mg, 0.145 mrnoi) in THF (2.0 mL) at -78 ⁶C was added π- BuLi (0.071 rnL of a 2.25 M solution in hexanes, 0.160 mmol). After 1 h, DMF (0.056 rnL, 0.72 mmol) was added. The mixture was stirred for 80 min at -78 °C and H₂O (2 mL) was added. The mixture was warmed to rt, poured into H₂O (25 mL) and extracted with CH₂Cl₂ (3 x 30 mL). The combined extracts were dried (Na₂SO₄), filtered, concentrated, and filtered through a plug of silica to provide a yellow oil (50 mg). The oil was dissolved in THF at 0 °C and LAH (11 mg, 0.29 mmol) was added. After 40 min, the sluny was warmed to rt and stirred for another 90 min. 1 M NaOH (0.15 mL) was added followed fay EtOAc. The mixture was dried (Na₂SO₄), filtered, concentrated, and chromatographed (preadsorbed to silica; eluted with a gradient of 0-10% MeOH in CH₂CI₂) to provide a mixture of regioisomers (23.6 mg), which were separated by HPLC (Chiralpak AD column; 75/25 heptaπe//PrOH) and identified structurally by NMR NOe experiments. {1-I\Λethyl-6-[4-(1-methyl-5-trifluoromethyl- iH-pyra2ol-3-yl)-phenyi]-1H-imicJa2:o[1,2-a]imida2ol-2-yl}-mefhano⁾ (7.4 mg) was isolated as a solid. The tosylate salt was formed using the general procedure. MS: (M^*) 376. ¹H NMR (400 MH2, DMSO-D₆): δ S.13 (s, 1), 8.01 (d, 2, J = 7.4), 7.83 (d, 2, J - 8.2), 7.67 (s, 1), 7.51 (s, 1), 7.45 (d, 2, J = 7.8), 7.09 (d, 2, J = 8.2), 4.56 (s, 2), 4.02 (s, 3), 3.78 (s, 3), 2.27 (s, 3). (C3a IC₅₀ = 370 nM)

Example 39

2-r4-f4-EthvI-thiθPhen-2-yl)-pftenvπ-5.6.7.B-tetrahvdro-imidazoπ.2-aTpyridine hydrochloride To a solution of 2-(4-bromo-phenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (0.72 mmol), 4-ethy!-thiopheπe-2-boronic acid dimethyl ester (1.46 mmol), toluene (20 mL), ethaπol (10 mL), water (10 mL) was added sodium carbonate (3.58 mmol). The reaction mixture was degassed with a stream of nitrogen bubbles, and then paltadium(dppf) (60 mg, 10 mol%) was added and heated to reflux for 16 h. The reaction was cooled to rt, concentrated and purified sequentially on silica gel utilizing a methanol/ chloroform gradient as elueπt and then on reverse phase silica gel utilizing a methanol/water gradient as eluent. The resultant oil was dissolved in a minimum amount of ethanol, treated with a few drops of concentrated aqueous HCl and then concentrated to dryness, mp 190-191⁰C. Anal. CaIc. for C^gH2o^N2^s(^HCI)(⁰-⁵ H₂O): C, 64.48; H, 6.27; N, 7.92. Found: C₁ 64.58; H, 6.02; N, 7.46. (C3a IC₅₀ = 217 nM) Example 40

2_wf4-(5.EthyI-thioohen-2-yl>-phenyl1-S.6.7,B-tetrahvdro-imidazuf1,2-a1pyridine hydrochloride

Prepared according to a method analogous to 2-[4-(4-ethyl-thiopheπ-2-yl)-phenyl]- 5,6,7 ,8-tetrahydro-imidazo[1,2-a]pyridine hydrochloride, mp 244-25O⁰C. Anal. CaIc, for C₁₉H₂oN2S{HCI)(0-33H₂0): C₁ 65.04; H, 6.22; N, 7.98. Found: C, 65.16; H, 5.80; N, 7.53.

(C3a iC_S0 = 159 nM)

Example 41

2-|'4-(5-MethVl-thiophen-2-vπ-ph6πvπ-5,6.7,S-tetrahvdro-ϊmidazori,2-alpyridine hydrochloride

Prepared according to a method analogous to 2~[4-(4-ethyl-thiophen-2-yl)-ρheny!]- 5,6,7,8-tetrahydro-imϊdazo[1,2-a]pyridϊne hydrochloride, mp 200-205"C. Anal. CaIc. for C₁₈H₁₈N₂S: C, 73.43; H, 6.16; N, 9.51. Found: C, 73.31; H, 7.27; N, 9.31.

(C3a IC_εo = 183 πM) Example 42

sulfonic acid salt

A mixture of 2-bromo-1-(4-(5-(trifluoromethyl)-4-rπetrιyloxazol-2-yl)pheπyl)ethanone

(225 mg, 0.647 mmol) and 2-amϊnopyridϊne (122 rng, 1.29 mmol) in EtOH (13 mL) was heated at 75 °C for 15 h. The mixture was cooled and filtered to isolate the title compound as a white precipitate (123 mg). MS: (M^*) 344. The tosylate salt was prepared using the general procedure,

(C3a IC₅₀ = 232 nM)

Example 43 2-f4-(3-fTrifluorometriyl)-4'm6thyl-1H-pyrazol-1-yl)phsnyl)^5.G.7,8- tβtrah vdroimidazoH ,2-alPyridine

A mixture of ethyl 1-(4-(2-bromoacetyl)phenyl)-3-(trifiuoromethyl)-1H-pyrazole-4- carboxylate (1.69 g, 4.17 mmol), 2-aminopyridine (785 mg, 8.34 mmol) and NaHCO₃ (700 mg, 8.34 mmol) in dichloroethaπe (50 mL) was heated at 80 "C for 4.5 h, cooled, poured into sat. NaHCO₃ (100 mL), and extracted with CH₂Cl₂ (3 X 50 mL). The combined extracts were dried (MgSO₄), filtered, concentrated, and chromatographed (loaded with CH₂Cl₂; eluted with 2.5% MeOH in CH₂CI₂). The isolated solid (MS: (M+) 401) (1.34 g, 3.35 mmol) was hydrogenated in EtOH (70 mL) with cone. HCI (1.0 mL) and 10% Pd/C (1.3 g) under an H₂ atmosphere (44 psi) on a Parr shaker for 23 h. After purging with nitrogen, the mixture was filtered through a plug of celite and concentrated. The resulting material was partitioned between sat. NaHCO₃ and CH₂CI₂. The aqueous layer was extracted with CH₂Cl₂ (3x). The combined extracts were dried (MgSO₄), filtered, and concentrated. A portion of the white solid (200 mg, 0.494 mmol) was dissolved in CH₂CI₂ (5.0 mL) and cooled to 0 ⁰C. DIBALH (1.0 mL of a 1.5 M soln in toluene, 1,48 mmol) was added. After 10 min, the ice bath was removed and the mixture was stirred at rt for 2 h. MeOH (4.5 mL) was added followed by MgSO₄ (3 g) and CH₂CI₂ (40 mL). The slurry was stirred overnight, filtered, concentrated and chromatographed (loaded with CH₂CI₂; eluted with a gradient of 5-15% MeOH in CH₂CI₂) to provide 125 mg of white solid. The primary alcohol (54 mg, 0.15 mmol) was slurried in THF (3.0 mL) at -78 ⁰C and rt-BuLi (74.8 ^uL of a 2.10 M soln in hexanes, 0.157 mmol) was added. After 45 min, carbon disulfide (78.5 μL of a 2 M soln in THF₁ 0.16 mmol) was added. After 30 min, Me! (78.5 uL of a 2 M soln in THF, 0.16 mmol) was added. The mixture was stirred for an additional hour at -78 °C and then the coid bath was removed. After stirring at rt for 5,5 h, sat. NaHCO₃ (4 mL) was added. The mixture was poured into H₂O (30 mL) and extracted with CH₂CI₂ (3 x 30 mL). The combined extracts were dried (MgSO₄), filtered, concentrated and chromatographed (2.5% IWeOH in CH₂Ci₂) to provide 37.7 mg of yellow oil. The oil was heated in toluene (4.0 mL) with AIBN (2,7 mg, 0.017 mmol) to reflux and nBu₃SnH (0.06 mL, 0.23 mmol) was added. After 1.75 h the mixture was cooled, concentrated, and chromatographed (loaded with CH₂CI₂; eiuted with 2.5% MeOH in CH₂CI₂) several times to provide 9 mg of the title compound as a solid. MS: (M+) 347.

PREPARATIONS: General procedure fortosylate salt formation: To a solution of free base (1 mmol) in EtOAc (15 mL) at rt was added p-TsOH^»H₂O (1 mmol for monobasic compounds and 2 mmol for dibasic compounds). The mixture was stirred for 1 - 24 h, filtered and rinsed with EtOAc to provide the tosylate salt as a solid.

Preparation 1 3-f4-Bromo-phenvO-5-trifluoromethyl-1H-pyrazoHe To a solution of p-bromoacetophenone (30.0 g, 151 mmol) in THF (500 mL) at rt was added f-BuOK (84.6 g, 754 mmol) in 3 portions over 5 min. Used a water bath to maintain temp. Added CF₃CO₂Et (89.7 mL, 754 mmol) to the mixture over 5 min. 18-Crown-6 (7.97 g, 30,1 mmol) was added. The mixture was stirred at rt for 4,5 h and then poured into H₂O (1 L). The aqueous layer was acidified to pH 3-4 with 6M aq HCl and then extracted with EtOAc (3 x 500 mL). The extracts were combined, dried (Na₂SO₄), filtered and concentrated. The resulting yellow oil was concentrated from toluene and then dissolved in toluene (500 mL), Hydrazine hydrate (50 mL) was added over 5 min and the resulting solution was heated at 95 ⁰C for 14 h. The mixture was cooled and concentrated. The yellow/orange solid was purified by stirring in hot hexanes (300 mL). The mixture was cooled and filtered to provide 27.5 g of 3-(4-bromo-phenyl)-5-trrfluoromethyl-1H-pyrazole as a white solid. The mother liquors were concentrated and again stirred with minimal hot hexanes, cooled and filtered to provide an additional 9.36 g of 3-(4-bromo-phenyl)-5-trifluorornethyl-1H-pyrazoIe as an off-white solid. MS: (M⁺) 291, 293. ¹H NMR (400 MHz₁ CDCI₃): δ 11.68 (be, 1), 7.59 (d, 2, J = 8.5), 7.43 (d, 2, J = 8.5), 6.75 (s, 1).

Preparation 2 3-(4-Bronno-phenvl)1-m ethyl-S-trifluoromethyl-iH-pyrazo[e To a solution of 3-(4-bromo-phenyl)-5-trifluoromethyl-1 H-pyrazole (27.5 g, 94.4 mmol) in toluene (700 mL) was added Me₂SO₄ (35.7 mL, 378 mmol). The mixture was heated at 100 ⁰C for 12.5 h, cooled, poured into 1M aq NaOH (1 L), and extracted with EtOAc (3 x 500 mL). The combined extracts were concentrated and purified through a short plug of silica (4"d x 3"h) eluting with 5-10% EtOAc in hexaπes to provide 27.56 g of 3-(4-bromo-phenyl)-1- methyl-5-trifluoromethyl-1H-pyrazoIe as a white solid. MS: (M+) 305, 307. ¹H NMR (400 MHz, CDCI₃): δ 7.64 (d, 2, J = 8.7), 7.53 (d_τ 2, J = 8.5), 6.87 (s_, 1), 4.02 (s, 3).

Preparation 3 2-Chloro-1 -1-4[-(1 -methyl-5-trifluorornethyl-1 H-pyrazol-3-vl)-phenyl]-ethanone

To a solution of 3-(4-bromo-phenyl)-1-methyl-5-trifluoromethyl-1 H-pyrazole (1.50 g, 4.92 mmol) in MTBE (75 mL) at -78 ⁰C was added t-BuLi (6.65 mL of a 1.7 M soln in peπtane, 11.3 mmol) over 2 miπ. After 5 min a solution of 2-chloro-N-methoxy-N- methyiacetamide (1.56 g, 11.3 mmol) in MTBE (15 mL) was added quickly via cannula. After

5 min 1 M aq HCI (20 mL) was added, and the reaction mixture was warmed to rt over 1 h.

EtOAc was added followed by 1 M aq NaOH to basify to pH 10. The mixture was extracted with EtOAc (2x). The combined extracts were washed with H₂O and brine, dried (MgSO₄), filtered and concentrated. The crude solid was purified by chromatography (loaded with hexanes; eluted with a gradient of 5-20% EtOAc in hexaπes) to provide 950 mg of 2-chloro-1-

[4-(1-methyl-5-trϊfluoromethyl-1H-pyrazol-3-yl)-phenyl]-ethaπoπe as a white solid. MS: (M⁺)

303, 305. ¹H NMR (400 MHz, CDCI₃): δ 8,01 (d, 2, J = 8.7), 7.90 (d, 2, J = 87), 6.98 (s, 1), 4.73 (s, 2), 4.06 (s, 3).

Preparation 4 2-Bromo-1 -[4-( 1 -methyl-5-trif luoromethyl-1 H-Pyrazol-3-vl)-phenvπ-ethanone

To a solution of 3-(4-bromo-phenyI)-1-methyl-5-trifluoromethyl-1H-pyrazoie (1.00 g,

3.28 mmol) in toluene (40 mL) at -78 ^oC was added n-BuLi (1.59 mL of a 2.16. M solution in hexanes, 3.44 mmol) over 2 min. THF (2.1 mL) was added to the mixture. After 15 min, a solution of N-methoxy-N-methylacetamide (669 uL, 6.56 mmol) in toluene (5.0 mL) was added via teflon cannula (no rinses). After 15 min, the mixture was poured into 1M aq HCi

(50 mL) at 0 ^oC. The water bath was removed and the mixture was warmed to rt over 1.5 h.

The mixture was poured into 1M aq NaOH (50 mL) and extracted with EtOAc (2 x 100 mL). The combined extracts were dried (MgSO₄), filtered and concentrated. The crude 1-[4-(1- methyi-5-trifIuoromethyi-1H-pyrazol-3-yl)-phenyl]-ethanone was dissolved in Et₂O (33 mL) at rt, and bromine (169 uL, 3.28 mmol) was added. After 20 miπ, the resulting white slurry was cooled to 0⁰C and sat NaHCO₃ (50 mL) was added. Separated the layers. The aqueous layer was extracted with Et₂O (50 mL). The combined ether extracts were dried (MgSO₄), filtered and concentrated. The crude material was purified by flash chromatography (loaded with CH₂CI₂ and eluted with a gradient from 100% hexanes to 10:90 EtOAc/hexaπes) to provide 663 mg of 2-bromo-1-[4-(1-methyl-5-trifluororπethyl-1H-pyrazoI-3-yl)-phenyl]- ethanone as a white solid. MS: (M^*) 347, 349. ¹H NMR (400 MHz, CDCI₃): δ 7.97 (d, 2, J = 8.5), 7.83 (d, 2, J = 8.5), 6.91 (s, 1), 4.40 (s, 2), 4.00 (s, 3).

Preparation 5

3-(4-Bromo-phenylM -ethvi-5-trif luorornethvM H-pyrazole To a solution of 3-(4-bromo-phenyl)-5-trifluoromethyi-1 H-pyrazoie (4.00 g, 13.7 mmo!) in toluene (172 mL) was added Et₂SO₄ (7.2 mL, 55 mmol). The mixture was heated at 100 "C for 3 d, cooled, poured into 1M NaOH (300 mL), and extracted with EtOAc (3 x 125 mL). The combined extracts were dried (MgSO₄), filtered, concentrated and purified by chromatography (loaded with CH₂CI₂, eluted with a gradient of 5-10% EtOAc in hexanes) to provide 3.13 g of 3-(4-bromo-pheπyl)-1-ethyl-5-trif!uoromethyl-1H-pyrazole as a yellow solid. ¹H NMR (400 MHz₁ CDCl₃): δ 7.65 (d, 2, J = 8.5), 7.53 (d, 2, J - 8.7), 6.84 (S, 1), 4.30 (q, 2, J = 7.3)_; 1.52 (t, 3, J =- 7.3).

Preparation 6

1 -\4-( 1 «Ethyl-5-trif luoromethvI-1 H-pyrazol-3-vQ-phenvπ-ethaπoπe To a solution of 3-(4-bromo-pheπyl)-1-ethyl-5-trifluoromethyl-1H-pyra∑oIe (3.13 g,

10.8 mmol) in MTBE (135 mL) at -78 ⁰C and under N₂ was added fBuLi (12.6 mL of a 1.7 M solution in peπtane, 22 mmol) over 4 min. The reaction mixture was stirred for 7 miπ and then a solution of N-methoxy-N-methylacetamide (2.2 mL, 22 mmol) in MTBE (25 mL) at -78 ⁰C was added via cannula followed by a MTBE rinse (5 mL). After 15 min, 1 M HCl (300 mL) at 0 ⁰C was added. The reaction mixture was warmed to rt over 1.5 h and poured into 1 M NaOH (375 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined extracts were dried (MgSO₄), filtered, concentrated and purified by chromatography (loaded with CH₂CI₂, eluted with gradient of 0 - 15% EtOAc in hexanes) to provide 1.82 g of 1-[4-(1-ethyi-5-trifiuoromethyl-1H-pyrazol-3-yl)-phenyl]- ethaπone as a white solid. MS: (M^*) 283. ¹H NMR (400 MHz, CDCI₃): δ 8.01 (d, 2, J = 8.5), 7.88 (d. 2, J = 8.5), 6.94 (S, 1 ), 4.34 (q, 2, J = 7.3 ), 2.62 (S, 3), 1.55 (t, 3, J = 7.3).

Preparation 7

2-Bromo-1 -r4-(1 -ethyl-5-trif Iuoromethvf-1 H-Pyrazol-3-vO-Phθnvπ-βthanone

To a solution of 1-[4-(1-ethyI-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-ethanone (1.7 g, 6.0 mmol) in Et₂O (100 mL) at reflux was added bromine (0.31 mL, 6.0 mmol). After 35 min, the reaction mixture was cooled, poured into sat. NaHCO₃ (100 mL), and extracted with

Et₂O (3 x 75 mL). The combined extracts were dried (MgSO₄), filtered, concentrated and purified by chromatography (loaded with CH₂Cb, eluted with 0-20% EtOAc in hexanes) to provide 1.35 g of 2-bromo-1-[4-(1-ethyl-5-trffluoromethyl-iH-pyra^ol-3-yl)-phenyl]_"ethanone as a white solid. MS: (M⁺) 361, 363. ¹H NMR (400 MHz, CDCI₃): δ 8.04 (d, 2, J - 8.5), 7.91 (d, 2, J - 8.7), 6.96 (s, 1), 4.47 (s, 2), 4.34 (q, 2, J = 7.3), 1.54 (t, 3, J s 7.3). Preparation S

2-(4-Bromo«phenv0-imidazoP1,2-alPyridine

A slurry of 2-aminopyridϊne (7.52 g, 80.0 mmol) and 2,4¹~dibromαace-αphenoπe (22.24 g, 80.0 mmol) in EtOH (80 mL) was heated at reflux for 8 h. NaHCO₃ (3.36 g, 40.0 mmol) was added to the resulting solution. Gas evolution was observed. After an additional 14 h of refluxiπg, more NaHCO₃ (3.36 g, 40.0 mmol) was added. The reaction mixture was refluxed for another 2 h, cooled to 0 ⁰C for one hour, filtered and rinsed with EtOH and Et₂O to provide 2-(4-bromo-phenyl)-imidazo[1,2-a]pyridϊne (17.3 g) as an off-white solid. MS: (M^*) 273, 275. ¹H NMR (400 MHz, CDCI₃): δ 8.09 (dt, 1, J = 6.8, 1.1), 7.79-7.83 (m, 3), 7.60 (d, I₁ J = 9.1), 7.52-7.56 (m, 2), 7.14-7.19 (m, 1), 6.75-6.79 (m. 1). Preparation 9

2-Methyl-5-trif luoromethanesulfoπyloxy-2H-pyrazoIe-3'-carboxyiiG acid methyl ester

To a solution of dimethyiacetylene dicarboxylate (117.6 g, 0.828 mol) in benzene (600 mL) and glacial AcOH (600 mL) at 0 ⁰C was added methylhydrazine (40.0 mL, 0.753 mol). The resulting mixture was stirred at rt for 1 h, then refluxed for 4 h, cooled to rt overnight, To a solution of dϊmethylacetyleπe dicarboxylate (117.6 g, 0.828 mol) in benzene (600 mL) and glacial AcOH (600 mL) at 0 ⁰C was added methylhydrazine (40.0 mL, 0.753 moi). concentrated, and partitioned between EtOAc and sat. NaHCO₃. The EtOAc layer was washed with NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated. The resulting black oil was triturated with benzene/Et₂O to provide 36.6 g of white solid. The solid (36.5 g) was suspended in CH₂CI₂ (719 mL) and cooled to -5 *C. To the suspension was added Et₃N (47.4 g, 0.468 mol) followed by frifluoromethanesulfoπic anhydride (132.1 g, 0.468 mo!). The reaction mixture was warmed to rt, stirred for 1 h, and poured into H≥O (600 mL). The CH₂CI₂ layer was separated and the aqueous layer was extracted with CH₂CI₂ (2 x). The combined extracts were washed with H₂O, dried (MgSO₄), filtered, concentrated, and chromatographed (20-30% EtOAc in hexanes) to provide 71.1 g of 2-methyl-5-trtfluoromethanesu!fonyloxy-2H~ pyrazole-3-carboxylic acid methyl ester as a yellow oi!» . ¹H NMR (400 MHz, CDCl₃): δ 6.63 (s, 1), 4.12 (s, 3), 3.88 (s, 3).

Preparation iθ

2-Methyl-5-(4,4,5,5-tetramethyl-ri.3,21dioxaborolaπ'-2-vI)-2H-pyrazole-3-carboxyIic acicl methyl ester

A flask under a N₂ atmosphere was charged with 2-methyI-5- triflUoromethanesuIfonyloxy-2H-pyrazole-3-carboxyIic acid methyl ester (30.95 g, 107 mmol), bis(piπacolato)diboron (30.0 g, 118 rnmol), 1,1^l-bis(diphenylphosp(iino)ferrocene (cfppf) (2.97 g, 5.35 mmo!), PdCl₂(dppf)-CH₂CI₂ (4.37 g, 5.35 mmol), and KOAc (31.5 g, 321 mmol). Anhydrous dioxane (642 mL) was added to the flask and the resulting mixture was heated at reflux for 24 h_r cooled to rt, and concentrated to 1/3 the volume. Benzene (500 mL) was added and the mixture was stirred at rt, washed with brine (2 x 500 mL), dried (MgSO₄), filtered and concentrated. The crude material was recrystallized from hexanes and repeated with the mother liquors to provide 13.55 g of 2-methyl-5-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-2H~pyrazole-3-carboxylic acid methyl ester as an off-white solid. MS: (M^*) 267- ¹H NMR (400 MHz₁ GDCI₃): 57.27 (s, 1), 4.26 (ε, 3), 3.88 (s, 3), 1.37 (s, 12). Preparation 11

6-Amino-nicotinic acid ethyl ester bishvdrochloride salt

HCl (g) was bubbled through EtOH (500 mL) at 0 'C for 10 mϊn. 6-Amϊnonicotinic add (10.36 g, 75.00 mmol) was added to the HCI sat EtOH to form a white slurry that was heated at 75 ⁰C for 18 h. Cooled and concentrated to provide 15.18 g of 6-amino-nicotinic acid ethyl ester bishydrochloride as a white solid. ¹H NMR (400 MHz, CD₃OD): S S.46 (d, 1, J

= 2.1), 8.33 (dd, 1, J = 9.3, 2.1), 7.06 (d, 1, J = 9.3), 4.38 (q, 2, J = 7.2), 1.37 (t, 3, J = 7.2).

Preparation 12

(6-Amiπo-pyridiπ>-3-vh-methaπol

To a slurry of 6-amino-nicotinic acid ethyl ester bis HCl salt (17.21 g, 72.06 mmol) in THF (350 mL) at 0 °C was added LAH (11.0 g, 2S9 mmol). Gas evolution was observed. The cold bath was removed and the reaction was allowed to warm to rt over 3 h. An additional portion of LAH (4.0 g, 105 mmol) was added. After 1.5 h the reaction mixture was cooled to 0

°C and 1 M aq NaOH (50 mL) was added slowly until gas evolution ceased. The mixture was warmed to rt and EtOAc and Na₂SO₄ were added. After stirring for 30 miπ, the mixture was filtered and concentrated. The crude solid was preabsorbed to silica gel and chromatographed using 10-15% MeOH in CH₂CI₂ to provide 5.19 g of (6-amino-pyridiπ-3-yl)- methanol as a pale-yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 7.84 (d, 2, J = 2.3), 7.48 (dd,

1, J - 8.5, 2.3), 6.58 (d, 1, J = 8.3), 4.43 (s, 2).

Preparation 13 2-Amiπo-isonicotinic acid ethyl ester bishvdrochloride salt

HCl (g) was bubbled through EtOH (500 mL) at 0 ⁰C for 10 miπ. 2-Arnino-isoπicotinic acid (2.179 g, 15.77 mmol) was added to the HCI sat EtOH and the mixture was heated at 75 ⁰C for 17 h. The reaction mixture was cooled, concentrated, redissolved in hot /PrOH/EtOH, filtered to remove insolubles, and concentrated. The resulting solid was partitioned between sat NaHCO₃ ("100 πiL) and EtOAc (75 mL). The layers were separated and the aq layer was extracted with EtOAc (2 X 75 mL). The combined extracts were dried (Na₂SO₄), filtered and concentrated. The resulting solid was chromatographed (loaded with CH₂CI₂, eluted with a gradient of 30-50% EtOAc in hexanes) to provide 747 mg of 2-amino-isonicotinic acid ethyl ester bishydrochloride salt as a pale-yellow solid, ¹H NMR (400 MHz, CDCI₃): δ 8.18 (d, 1, J = 5.2), 7.18 (dd, 1, J = 5.3, 1,3), 7.07 (bs, 1), 4.57 (bs, 2), 4.37 (q. 2, J = 7.1), 1.39 (t, 3, J = 7.0). Preparation 14

(2-Amino-pyridin-4-vl)-methanol

To a slurry of 2-Amino-isoπicotinic acid ethyl ester bishydrochloride salt (747 mg, 4.50 mmol) in THF (50 mL) at 0 ^oC was added LAH (684 rng, 18 mmol). Gas evolution was observed. The cold bath was removed and the reaction was allowed to warm to rt over 3.5 h. The reaction mixture was cooled to 0 ^oC, and 1 U NaOH (3 mL) and H₂O (3 rnL) were added slowly until gas evolution ceased. The mixture was warmed to rt over 1 h and EtOAc (50 mL) and MgSO₄ were added. The mixture was filtered and concentrated to provide 553,3 mg of (2-amiπo-pyridin-4-yl)-methaπol as a white solid. ¹H NMR (400 MHz₁ CD₃OD): δ 7.80 (d, 1, J = 5.0), 6,58 (bs, 1), 6.55-6.57 (m, 1), 4.50 (S, 2). Preparation 15

N-(6-Cvano-pyridazin-3-vl)-2.2-dirπethv[-propionamide

A flask was charged with N-(6-chloro-pyridazin-3-yl)-2,2-dimethyl-propionamide (Turck. Alain; PIe, Nelly; Ndzi, Bruno; Queguiner, Guy; Haider, Norbert Schuller, Herbert; Heinisch, Gottfried. Tetrahedron. 1993, 49, 599-606.) (500 mg, 2.34 mmol), Pd(PPh₃)₄ (811 mg, 0.701 mmol), and Zn(CN)₂ (192 mg, 1.64 mmol) and placed under a nitrogen atmosphere. DMF (25 mL) was added to the flask and the reaction mixture was heated at 100 ^oC for 2.5 h. The reaction mixture was cooled and poured into H₂O (100 mL) and EtOAc (100 mL), An emulsion formed and the mixture was filtered through a short plug of celite and then the layers were separated. The organic layer was washed with H₂O (100 mL), dried (MgSO₄), filtered, concentrated, and purified by chromatography (loaded with CH₂CI₂, eiuted with a gradient of 10-30% EtOAc in hexanes) to provide 329 mg of N-(6-cyano-pyridazin-3-yl)- 2,2-dimethyl-propionamϊde as a pale yellow solid. MS: (M⁺) 205. ¹H NMR (400 MHz, CDCl₃): δ 8.71 (bs, 1), 8.65 (d, 1, J = 9.3), 7.80 (d, 1, J = 9.3), 1.36 (s, 9).

Preparation 16 5-(2,5-Dimethyl-pyrrol-1-vl) pyridin-2-ylamine

A mixture of pyridϊne-2,5-diarπine (10.0 g, 54.9 mmol), acetonylacetone (7.1 mL, 60 mmol), and Et₃N (15 mL, 110 mmol) in toluene (110 mL) was heated at reflux for 3.5 h, cooled, poured into 1 M NaOH (500 mL), and extracted with CH₂Cl₂ (3 x 300 mL). The combined extracts were dried (Na₂SO₄), filtered, concentrated, and chromatographed (loaded with CH₂CI₂; eiuted with a gradient of 10-50% EtOAc in hexanes) to provide 6.65 g of 5-(2,5- dimethyl-pyrrol-1-y|)-pyridiπ-2-ylamine as an orange solid. ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, 1, J = 2.5), 7.29 (dd, 1, J = 8.6, 2.6), 6.57 (d, 1, J = 8.7), 5.89 (s, 2).2.02 (s, 6). Preparation 17 5-Benzyloxymethyl-4-methyl-4H-ri.2.41triazol-3-vlamire

To a solution of 1,2-dimethyi-2-thiopseudourea-HI (46.42 g, 0.20 mol) in H₂O (SO mL) at rt with N₂ flow to a Clorox trap was added a solution of hydrazine monohydrate (15.76 mL, 0.325 mol) in H₂O (11 mL). After 14 h at rt, the mixture was concentrated under high vacuum, dissolved in hot EtOH (80 mL), cooled, added Et₂O (100 mL), stirred for 2 h, filtered, rinsed with Et₂O to provide 38.4 g of an off-white solid. (Kirsten, G. W.; Smith, G. B. L. J. Am. Chem. Soc. 1936, 58, 800-801.) A portion (25 g) was slurried in EtOH (250 mL), combined with a solution of KOH (7.14 g, 0.127 mol) in EtOH (75 mL), and stirred at rt for 2 h. The resulting slurry was filtered, and benzyloxyacetic acid (23.1 g, 0.139 mol) was added to the filtrate. The mixture was concentrated under high vacuum overnight and then heated between 160- 180 °C for 4 h under a stream of N₂. The resulting material was crystallized from a mixture of MeOH, EtOAc, and Et₂O to provide 7,78 g of 5-benzyloxymethyI-4-methyl-4H-[1,2,4]tria2θl-3- ylamine as an off-white solid. MS: (M+) 219. ¹H NMR (400 MHz, CDCI₃): S 7.27-7.35 (m, 5), 4.62 (s, 2), 4.59 (s, 2),

2.81 (s, 3).

Preparation 18

2-Bromo-1-(4-(-5(trifluoromethvl-)4-methyloxazol-2-vl)phenvnethanone A mixture of ethyl 2-(benzylamino)proρanoate (2.1 g, 10 mmol), 4-acetylbenzoic acid (1.64 g, 10 mmol), and EDCl (2.1 g, 11 mmol) in CH₂CI₂ (50 mL) was stirred at rt overnight. The mixture was heated at reflux for 2 h and then additional EDCI (2.1 g, 11 mmol) and 1- hydroxybenzotriazole monohydrate (1.53 g, 10 mmol) and continued refluxiπg for 1.5 h- The mixture was poured into 1M NaOH and extracted with CH₂CI₂ (3x). The combined extracts were dried (MgSO₄), filtered, concentrated and chromatσgraphed (loaded in hexaπes; eluted with gradient 15-40% EtOAc in hexanes) to provide 2.0 g of colorless oil. A portion of this oil (522 mg, 1.48 mmol) was dissolved in MeOH (15 mL) and 1M NaOH (10 mL) and stirred at rt for 4.75 h. The solution was poured into 1M HCI (100 mL) and extracted with EtOAc (2x). The combined extracts were dried (Na₂SO₄), filtered, and concentrated. According to the procedure of M. Kawase, et al. (Chem. Pharm. Bull. 46 (5), 1998, 749), the resulting oil was dissolved in toluene (5 mL) at rt and a solution of trifluoroacetic anhydride (0.84 mL) and pyridine (0.72 mL) in toluene (10 mL) was added. The mixture was heated at 100 ^oC overnight, cooled, diluted with EtOAc (100 mL), washed with 1M NaOH. The organic layer was washed with 1M HCl (150 mL), dried (MgSO₄), filtered, concentrated, and chromatographed (loaded with CH₂CI₂; eluted With 10% EtOAc in hexanes). The resulting white solid (174 mg) was dissolved in Et₂O (10 mL) and refluxed. To this refluxing solution was added bromine (0.037 mL). After 30 min the mixture was cooled and concentrated to provide the title compound as a pale orange solid that was used without further purification. Preparation 19

A slurry of ethyI-3_'{trifluoromethyl)pyra2:ole-4-carboxy!ate (5,20 g, 25 mmol), 4- fluoroacetophenoπe (2.0 mL, 16.7 mmol), and cesium carbonate (8.1 g, 25 mmol) in DMSO (60 mL) was heated at 120 °C for 15 h, cooled, poured into water (500 mL) and 1M NaOM

(100 mL), and extracted with CH₂CI₂. The combined extracts were dried (MgSO₄), filtered, and concentrated. The resulting solid was dissolved in CHCi₃ (150 mL) at rt and bromine

(0.94 mL) was added. The solution was stirred at rt for 3 h, poured into sat. NaHCO₃ (600 mL), and extracted with CH₂CI₂ (2 x 500 mL). The combined extracts were dried (Na₂SO₄.), filtered, concentrated, and chromatographed (loaded with CH₂CI₂; elυted with 5-15% EtOAc in hexanes) to provide 1.69 g of title compound as a white solid.

Preparation 20

4-Ethyl-thiopheπe-2-boroπic acid dimethyl ester

To a solution of 3-ethylthiophene (1.0 g, 8.9 mmol) and THF (20 mL) at -78⁰C was added TMEDA (1.35 mL, 8.9 mmol) followed by nBuLi (1.6 M, 5.6 mL, 8.9 mmol) in a dropwise fashion. After stirring for 30 at -78⁰C, trimethyiborate (1 ,0 mL, 8.9 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was evaporated to give the title compound that was used without further purification.

Preparation 21 4-Methvi-thiophene-2-boronϊc acid dimethyl ester

Prepared according to a method analogous to 4-ethyl-thiophene-2-boronic acid dimethyl ester.

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 traπsfected cell line was generated in the laboratory of Dr. Craig Gerard (Harvard Univ.)-

In the assay, approximately 375,000 cells Sire plated per well in a 96-vvel! plate format

(200 μL total volume). In a 96-well plate format, 200 cells and C3a ligand are incubated in assay buffer (2OmM HEPES₁ 125 mM NaCI₁ 5 mM KCI, 0.5 mM glucose, 0.2% BSA, 1 rnM

CaCt2, 1 mM MgCl2, 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 excεss of unlabelled human C3a peptide. The reaction is pelleted by centrifugatioπ

(3500 rpm) and terminated by filtration over glass fiber A filters (1 % PEi soaked) with ice-cold wash buffer (50 mM HEPES, 1mM CaC12, 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: 1L

20 mM Hepes pH 7.4 4.8Og

125 mM NaCl 7.4Og S rnM KCi 1.02g

0,5 mM Glucose 90.1 Omg

0.2% BSA (SigmaA7906) 2.0Og

1 ITiM CaCl₂ 111mg

1 mM MgCI₂ (hexahydrate) 203.32mg Wash Buffer: 4L

50 mM Hepes pH 7.4 47.6g

1 mM CaCI₂ 440mg

5 mM MgCIg (hexahydrate) 4.08g

0.5 M NaCI 116,8g 0.03 % Chaps (SlgmaC3023) 1.2Og

Filtermats:

Soak Printed Filtermat A Glass Fiber Filters (Wallac; 1205-401) in 1 % (20g/L) polyethyleπimine (PEI, Sigma; P3143) for 60 min. Air dry overnight. Store until used- Hot Cocktail: 0.2 πM stock ¹²⁵l-C3a (NEN; NEX-356) in L.

C3a cold peptide:

50 μg C3a (Advanced Research Technologies; A11S) 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 Cells:

Spin down cells in 50 m! tubes by 3500 rprn for 5 min at RT in the Sorvali RT6Q00D. Decant supernatant and resuspend at 5 x 10⁶ celis/rnL in assay buffer. Assume 1 flask for 4 plates. Drug Dilutions

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

Prepare dilutions in 100% DMSO on the BIOMEK robot (LFL 60μL ail 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 πM 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 = 5x10^β 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 Skatrαπ 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. NOTES

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

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 of formula i

wherein

W is selected from the group consisting of

A₁ is O or S;

A₂ is N or CH, with the proviso that if Ai is O, A₂ is N; n is between 3 and 5; Z at each occurrence is independently selected from CR¹, CHR¹,C=0, N, NR¹, N=O,

S, and O, wherein a bond between two groups Z bonded to each other may be a single bond or a double bond; the ring containing Z is a 5, 6, or 7-membered heterocyclic or heteroaryi ring containing 1-3 heteroatoms independently selected from the group consisting of O, N and S; R¹ at each occurrence is independently selected from H, optionally substituted C₁-C₈ alkyl, optionally substituted C₁-C₆ alkoxy, halo, SO₂N(Re)₂, N(Rs)SO₂N(Rg)₂, SO₂R₈, CONHSO₂Rs, CONHSO₂(NRe)₂, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted C₃-C™ cycloalkyl, cyano, optionally substituted 5- 10-rπembered heteroaryi, COR^Θ, CO₂R^β, N(R^S)₂, NR⁶COR⁶, CON(R⁶)₂, and CONCO(R^e)₂; R^fl at each occurrence is independently selected from H, optionally substituted C₁-C₅ alkyl, optionally substituted 5-10 membered heteroaryi, optionally substituted C₆-Ci₀ aryl, optionally substituted C₃-C₁₀ cycloalkyl, and optionally substituted 3-10 membered heterocydoaikyl;

R² and R³ are selected independently from H₁ optionally substituted C_rC_ealkyI, halo, optionally substituted C_rC₆alkenyl, optionally substituted C₃-C₁₀ cycloalkyl, trifluoromethyl, CO- optionally substituted C₁-C₆ alkyl, CO₂. optionally substituted C₁-C_B alkyl, optionally substituted d-Cealkoxy, and optionally substituted C_rC₅alkylthio; Y¹, Y^z, Y³, Y⁴ are independently selected from CH₁ CF, or N where no more than 2 N are in the ring; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein Y\ Y², Y³, Y⁴ are each CH.

3. A compound according to claim 1, wherein R¹ is selected from H, optionally substituted C₁-C₆ alkyl, C0₂-optionalIy substituted C₁-C8 alkyl, halo, amino, CHO, CO- optionally substituted C₁-C₆ alkyl, and cyano.

4. A compound according to claim 1 , wherein R¹ is a 5-10 membered heteroaryl selected from the group consisting of tetrazolyl, oxadiazolyl optionally substituted with OH₁ and pyrrolyl optionally substituted with one or two C₁-C₈ alkyl.

5. A compound according to claim 1 , wherein

is selected from the group consisting of the group

(A) wherein Y₆ = CR₁, CHR₁, N or NR₁; Y₆ and Y₇ are each independently CH or C; and Y₈ is CR₁ or CHR₁; and the group

(B) wherein Y₉ is CR₁, CHR₁, N or NR₁; Y₁₀ is C or CH; and Y₁₁ is NR₁, N₁ or S.

6. A compound according to claim 6, wherein at least one R, is H-

7. The compound according to claim 5, wherein group (A) is selected from the group consisting of

8. A compound according to claim 1 , wherein R² and R³ are selected independently from H, optionally substituted C1C₆alkyl, trifluoromethyl, CO-optionally substituted C₁-C₆ alkyl, and C0_2-optjonally substituted C₁-C₆ alkyl.

9. A compound according to claim 1, wherein R¹ at each occurrence is independently selected from preferably optionally substituted C₁-Ca alkyl, preferably optionally substituted C₁-C6 alkoxy, preferably optionally substituted 3-10-membered heterocycloalkyl, preferably optionally substituted C₃-C₁₀ cycloalkyi, and preferably optionally substituted 5- 10- membered heteroaryl.

10. A compound according to ciaϊm 1, wherein R⁶ at each occurrence is independently selected from preferably optionally substituted C₁-C₆ alky!, preferably optionally substituted 5-10 membered heteroaryl, preferably optionally substituted C₅-C₁₀ aryl, preferably optionally substituted C₃-C₁₀ cycloalky!, and preferably optionally substituted 3-10 membered heterocycloalkyl.

11. A compound according to claim 1, wherein R² and R³ are selected independently from preferably optionally substituted C1-C₆alkyl, preferably optionally substituted C1C₆alkenyl₇ preferably optionally substituted C₃-C₁₀ cycloalkyi, CO- preferably optionally substituted C₁-C₆ alkyl, CO_2- preferably optionally substituted C₁-C₆ alkyl, preferably optionally substituted C₁C6alkoxy, and preferably optionally substituted C1-C6alkylthio.

12. A com pound selected from the group consisting of 2-[4-(1 -Methyl-5-trifluoromethy]-1 H-pyrazol-3-yl)-pheπyl]-imidazo[1 ,2-a]pyridine hydrochloride salt;

2-[4-(1-Methyl-S-trifluorom ethyl-1H-pyra2ol-3-yl)-phenyl]-5,6,7,8-tetrahydro- imidazo[1,2-a]pyridine p-toluenesulfoπic acid;

2-[4-(1-Ethyl-5-trifluoromethyl-1 H-pyrazoI-3-yl)-phenyI]-imidazo[1 ,2-a]pyridine p- toluenesulfonic acid salt;

2-[4-(1-Ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-5,6,7,8-tetrahydro- imidazo[1,2-a]pyrϊdiπe p-toiuenesulfonic acid salt;

5-(4-Imidazo[1 ,2-a]pyrϊdin-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester; 2-[4-(1-Metriyl-5-trifluoromethyl-1 H-pyrazol-3-yI)-phenyl]-imidazo[1 ,2-a]pyrϊdine-6- carboxylic acid ethyl ester;

{2-[4_(1 -MethyI-5-trifluoromethyI-1 H-ρyrazol-3-yl)-phenyl]-imidazo[1 ,2-a]pyridin-6-yl}- methaπol;

{2-[4-(1-Methyl-5-trifluororπethyI-1H-pyrazoI-3-yl)-phenyl]-5,6,7_,8-tetrahydro- imidazo[1 ,2-a]pyridiπ-6-yl}-methanol;

6-Chloro-2-[4-(1 -methyl-5-trifluoromethyl-1 H-pyrazol-3-yl )-phenyl]-imidazof1 ,2- b]pyridazine; 2-[4-(1 -Methy)-5-trif!-Joromethyl-1 H-pyrazol-3-y))-pheπyfHmidazo[1 ,2-b]pyridazin-6- ylamiπβ p-toluene sulfonic acid salt;

2-[4-(1 -Methyl-5-trifluorome{hy!-1 H-pyrazol-3-y))-ρhenyl]-imidazo[1 ,2-fc>lpyridazine p- toluene sulfonic acid salt; 2-I4-(1 -Methyl-5-tlϊfluoromethyM H-pyrazol-3-yl)-phenyl]-5,6,7,8-tetrahydro- imidazoti ,2-b]pyridazine p-tolueπesulfonic acid salt;

2-[4-(1 -Methyl-5~trifluoromethyM H-pyrazαl-3-yl)-phenyl]-inπidazo[1 ,2-a]pyridine-6- carbaldehyde;

1 -{2-[4-(1 -Methyl-5-trifluoromethyI-1 H-pyra2θ!-3-yl)-pheπyl]-imidazot1 ,2-a]pyridin-6- yl}-ethaπol;

1 -{2-[4-(1 -Methyl-5-trifϊuorømethyl-1 H-pyrazol-3-yl)-phenyl]-5,6,7,8-tetrahydro- imidazo[1_τ2-a]pyridiπ-6-yl}-ethanol;

{2-[4-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yI)-phenyI]-imidazo[1 ,2-a]pyridin-7-yl}- methanol p-toluene sulfonic acid salt; 1-{2-[4-(1-Methy!-5-trifluoroinethyl-l H-pyra2ol-3-yl)-phenyl3-irnida2θ[1 ,2-a]pyridin-7- yl}-ethanol;

{2-[4-(i-MethyI-5-trifluoromethyl-1H-pyrazol-3-yl)-phenylI-5,6,7,8-tetrahydro- ϊmidazo[1,2-a]pyridin-7-yl}-methanαl;

6-[4-(1-Methy!-5-trifluoromethyMH-pyrazol-3-yl)-phenyl]-2,3-dihydro-imida2o[2,1- b]thiazole;

2-[4-(1 -MethyI-5-tn^"fluoromethy!-i H-pyrazol-3-yl)-phenyl]-imidazo[1 ,2-a]pyridine'6- carbonitrile;

2-[4-(1-I\Λethyl-5-trifIuoronnethyl-iH-pyrazol-3-yl)-phenyl]-6-{1H-te-razo)-5-yI)- irnidazo[1 ,2-a]pyridine; 3-{2-[4-(1 -Methyl-5-trifluoromethyl-1 H-pyrazo1-3-yl)-phenyl]-imidazo[1 ,2-a]pyridin-6- yl}-t1 ,2,4]oxadiazol-5-ol;

2-[4-(1 -Methyi-5-trifluoromethyH H-pyrazol-3-yl)-phenyl]"imidazo[1 ,2-b]pyridazine-6- carbonitrile;

2-[4-(1 -MethyI-5-trifluoromethyI-1 H-pyra∑ol-3-yl)-phenyl]-6-(1 H-tetrazoi-5-yI)- imidazo[1,2-b]pyridazine;

N-{2-[4-(1 -MβthyI-5-trifluorσmethyl-1 H-pyrazol-3-yl)-phenyl]-imidazoi;i

yl}-acetamidθ p-tolueπesulfonϊc acid salt;

2-[4-(1 -Methyl-5-trifIuoromethyl-1 H-pyraHoI-3-yl)-phenyl]-imidazo[1 ,2-a]pyridin-6- ylamine bis-p-toluenesulfonic acid salt; 6-(2,5-Dimetfiyl-pyrrol-1-yl)-2-[4-(1-methyI-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyri- imidazo[1 ,2-a]pyridine; a-μ-ζi-iWethyl-S-trifluoramethyl-IH-pyrazol-S-ylJ-pheπylJ-δ.βJ.S-tetrahydrø- imidazo[1,2-a]pyridin-6-y!amiπe bis-p_"toluenesulfoπic acid salt;

N^-μ-CI-Methyl-δ-trϊfluoromethyl-IH-pyrazol-S-yO-pheπyU-S.ej.S-tetralnydro- imidazo[1 ,2-a]pyridiπ-6-yl}-acetamide p-toluenesulfanic acid salt; 0-[2-[4-(I -Methyl-5-trifluoromethyl-i H-pyrazol-3-yl)-phenyl]-5,6,7,84etrahydrø- imidazo[1 ,2-a]pyridiπ-6-yl}~nπethylamine bis-hydrochloride salt;

Cyclopropaπecarboxylic acid {2-(4-(1-methyl-5-trifluoromethyl-1 H-pyrazαl-3-yl)- pheπyl]-5,6,7,8-tetrarιydro-iιnidazo[1 ,2-a]pyridin-6-ylmethy!}-amide p-toluenesulfonic acid salt;

1 H-PyπOle-2-carboxy|ic acid {2-[4-(1-rnethyl-5-trifluoromethyl-i H-pyraεol-3-yl)- pheπyl3-5,6,7,β-tβtrahydro-imfdazo[1 ,2-a3pyridin-6-y!methyl}-amide bis-p-to!υenesulfonic acid salt;

N-{2-[4-(1-Methyl-5-trifluoromethyl_"1H-pyra₂ol-3-yl)-ρheπyl]-5,6,7,8-tetrahydro- imidazo[1 ,2-a]pyridiπ-6-ylmetfiyl)-nicotinamide bis-p-tolueπesulfonic acid salt;

2-(1 ,1 -Dioxo-tetrahydro-116-thiophen-3-yl)-N-{2-[;4-(1 -methyi-5-trifluoromethyl-1 H- pyrazol-3-y!)-phenyl]-5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridin-6-y!methyl}-acetamide p- toluenesulfonic acid salt; a-Methyl-S-^^i-methyl-S-trifluoromethyl-iH-pyrazol-S-yO_'phenylJ-SH-imidazoti^- b][1,2,4]triazQ[e-2-carbaϊdehyde;

{3-Methy!-5-[4-(1 -methyI-5-trifluorometliyl-1 H-pyra20l-3-yl)-pheπyl]-3H-imϊdazo[1 ,2- b][1 ,2,4]triazol-2-yl}-methaπol p-toluenesulfonic acid salt;

1 -Methyl-6-[4-(1 -methyl-5-trifiuoromethyl-1 H-pyrazol-3-yl)-phenyl]-1 H-imϊdazo[1 ,2- ajimidazole p-totuenesulfoπic acid salt;

{1-MetiiyI-6-[4-(1-methyl-5-trffiuoromethyl-1 H-pyrazol-3-yl)-phenyl]-1 H-imidazo[1 ,2- a]imidazol-2-yl}-methaπol p-toluenesulfonic acid salt; 2-[4-(4-EthyI-thϊopheπ-2-yi)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine hydrochloride;

2-[4-(5-Ethyl-thiophen-2-yl)-phenyl]-S,6,7,8-tetrahydro-imidazo[1_i2-a]pyfidine hydrochloride;

2-[4-(5-Methyl-thiophen-2-yl)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyriciine hydrochloride;

2-(4-(5-(TrifIuoromethyl)-4-methyloxazol-2-yl)phenyI)H-imidazo[1,2-a]pyridiπe; and

2-(4-(3"(TrJfluoromethyl)-4-methyI-1H-pyrazoI-1-yl)pheπyi)-5,6,7,S- tetrahydroimidazo[1 ,2-a]pyridine.

13. A composition comprising a compound of claim 1 and optionally a pharmaceutically acceptable carrϊer.

14. A composition as defined in claim 13 in unit dosage form.

15. 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 ,

16. A method for treating Complement-mediated tissue damage in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

17. A method for treating diseases characterized by chronic Complement activation, comprising administering to a 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, Guϊllian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic diseases, respiratory diseases, cardiovascular or metabolic disease states, shock, hypertension, hyperlϊpidemia, 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, Guiltian 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 C3₃ receptor in a patient by administering an effective amount of a composition of claim 13.