MXPA06006473A - Azabicyclic heterocycles as cannabinoid receptor modulators - Google Patents

Abstract

The present application describes compounds according to Formula (I), pharmaceutical compositions comprising at least one compound according to Formula (I) and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula (I) both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula (I) including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3, R6, R7, m and n are described herein.

Description

AZABICICLIC HETEROCICLES AS MODULATORS OF THE CANABINOID RECEIVER Background of the Invention Delta-9-tetrahydrocannabinol or Delta-9 THC, the main active component of Cannabis sativa (marijuana), is a member of a large family of lipophilic compounds (ie, cannabinoids) that mediate physiological and psychotropic effects They include the regulation of appetite, immunosuppression, analgesia, inflammation, emesis, antinociception, sedation, and intraocular pressure. Other members of the cannabinoid family include endogenous ligands (arachidonic acid derivatives), anandamide, 2-arachidonyl glycerol and 2-arachidonyl glycerol ether. Cannabinoids work through the selective binding to, and activation of cannabinoid receptors coupled to protein G. Two types of cannabinoid receptors have been cloned and include CB-1 (LA Matsuda, et al, Nature, 346, 561-564 (1990)), and CB-2 (S. Munro et al., Nature, 365, 61-65 1993)). The CB-1 receptor is highly expressed in the central and peripheral nervous systems (M. Glass, et al., Neuroscience, 77, 299-318 (1997)), whereas the CB-2 receptor is highly expressed in immune tissue. , particularly in the spleen and tonsils. The CB-2 receptor is also expressed in other cells of immune systems, such REF. : 173398 as lymphoid cells (S. Galiegue, et al., Eur J Biochem, 232, 54-61 (1995)). The agonist activation of cannabinoid receptors results in the inhibition of cAMP accumulation, stimulation of MAP kinase activity, and closed calcium channels. There is substantial evidence that cannabinoids regulate appetite behavior. Stimulation of CB-1 activity by anandamide or Delta-9 THC results in increased dietary intake and weight gain in multiple species including humans (Williams and Kirkham, Psychopharm., 143, 315-317 (1999)). The genetic age of CB-1 results in mice that are hypophagic and skinny in relation to their wild type mates (DiMarzo, et al., Nature, 410, 822-825 (2001)). Published studies with CB-1 small molecule antagonists have shown a reduction in dietary intake and body weight in rats (Trillou, et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., R345-R353, (2003)). Chronic administration of the AM-251 antagonist of CB-1 for two weeks results in a substantial reduction in body weight and a reduction in adipose tissue mass (Hildebrandt, et al., Eur. J. Pharm, 462, 125-132 (2003)). There are multiple studies evaluating the anorexic effect of the antagonist Sanofi CB-1, SR-14176 (Rowland et al., Pyschopharm., 159, 111-116 (2001); Colombo et al., Life Sci., 63, 113-117. (1998)). There are at least two CB-1 antagonists in clinical trials for regulation of appetite, SR-141716 from Sanofi and SLV-319 from Solvay. The published Ilb phase data reveal that body weight is reduced dependently on the dose of SR-141716 in human subjects during a 16-week trial period. CB-1 antagonists have also been shown to promote cessation of smoking behavior. Phase II clinical data on cessation of smoking were presented in September 2002 at the information meeting of Sanofi-Synthelabo. These data show that 30.2% of patients treated with the higher dose of SR-141716 show a cigarette abstinence compared to 14.8% for placebo. DETAILED DESCRIPTION OF THE INVENTION The present application document describes compounds according to formula I, pharmaceutical compositions comprising at least one compound according to formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds in accordance with Formula I, both alone and in combination with one or more additional therapeutic agents. The compounds have the general formula I I including all pharmaceutically acceptable prodrugs, salts and stereoisomers, R1, R2, R3, R6, R7 and n are described herein.

DEFINITIONS The following definitions apply to terms as used throughout this specification, unless otherwise limited in specific stays. As used herein, the term "alkyl" means branched or unbranched hydrocarbon chains containing 1 to 20 carbons, preferably 1 to 12 carbons, and more preferably 1 to 8 carbons, in the normal chain, such as, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. In addition, alkyl groups, as defined herein, may optionally be substituted on any of the available carbon atoms with one or more functional groups commonly linked to such chains, such as, but not limited to hydroxy, halo, haloalkyl, mercapto, or thio, cyanoalkylthio cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, -OC (0) NR8R9, -OC (0) R8, -0P03H, -OS03H, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl, and the like. Unless indicated otherwise, the term "alkenyl" as used herein by itself or as part of another group refers to straight or branched chains of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons with one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2- heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl, and the like. In addition, alkenyl groups, as defined herein, may optionally be substituted at any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to halo, haloalkyl, alkyl, alkoxy , alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and / or any of the alkyl substituents set forth herein. Unless otherwise indicated, the term "alkynyl" as used herein by itself or as part of another group, refers to straight or branched chains of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons with one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, A-nonnyl, 4-decynyl, 3- undecinyl, 4-dodecinyl and the like. In addition, alkynyl groups as defined herein, may optionally be substituted at any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to halo, haloalkyl, alkyl, alkoxy, alkenyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and / or any of the alkyl substituents set forth herein. Unless indicated otherwise, the term "cycloalkyl" as used herein alone or as part of a group including cyclic hydrocarbon groups (containing one or more double bonds) saturated or partially unsaturated containing 1 to 3 rings, attached or fused, including monocyclylalkyl, bicyclylalkyl, and tricycloalkyl, containing a total of 3 to 20 carbons which form the rings, preferably 3 to 10 carbons forming the ring and which can be fused to 1 or 2 aromatic rings as described by aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl, cyclohexenyl , In addition, any cycloalkyl can optionally be substituted through any of the available carbon atoms with one or more groups selected from hydrogen, halo, haloalkyl, alkyl, alkoxy, haloalkyloxy, hydroxyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy , arylalkyl, heteroarylalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or any of the alkyl substituents. The term "cycloalkylalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having a cycloalkyl substituent wherein the "cycloalkyl" and / or "alkyl" groups may optionally be replaced as defined above. Unless otherwise indicated, the term "aryl" as used herein alone or as part of another group refers to aromatic monocyclic and bicyclic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2- naphthyl) and may optionally include 1 to 3 additional rings fused to the carbocyclic ring or a heterocyclic ring, for example, or. o - o -co o.

In addition, "aryl" as defined herein, may optionally be substituted with one or more functional groups, such as halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl, or any of the other aforementioned aryl compounds) in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, ammonicarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, or arylsulfoaminocarbonyl and / or any the alkyl substituents set forth herein. Unless otherwise indicated, the term "heteroaryl" as used herein alone or as part of another group, refers to a 506-membered aromatic ring that includes 1, 2, 3, or 4 heteroatoms such as nitrogen, oxygen, or sulfur. Such rings can be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl and include possible N-oxides as described in Katritzky, AR and Rees, CW, eds Comprehensive Heterocyclic Chemistry: The Structure, Reactions Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; and Katritzky, A.R., Ress C.W., Scriven, E.F., eds Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; and references in the present document. In addition "heteroaryl" as defined herein, can optionally be substituted with one or more substituents such as the substituents included above in the definition of "substituted alkyl" and "substituted aryl". Examples of heteroaryl groups include the following: and the like The term "heteroarylalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having a heteroaryl substituent, wherein the heteroaryl and / or alkyl groups may optionally be substituted as defined above.

The term "heterocycle", "heterocycle", "heterocyclyl" or "heterocyclic ring" as used herein, represents a substituted or unsubstituted stable 4 to 7 membered monocyclic ring system which may be saturated or unsaturated, and consists of carbon atoms, with 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring can be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl. , pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and other heterocycles described in Katritzky, AR and Rees, CW, eds Comprehensive Heterocyclic Chemistry: The Structure, Reactions Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; and Katritzky, A.R., Rees C.W., Scriven, E.F., Eds Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; and references in the present document. The term "heterocycloalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having a heterocyclyl substituent, wherein the heterocyclyl and / or alkyl groups may optionally be substituted as defined above. The terms "arylalkyl" "arylkenyl" and "arylalkynyl" as used alone or as part of another group, refer to alkyl, alkenyl and alkynyl groups as described above having an aryl substituent. Representative examples of arylalkyl include, but are not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like. The terms "alkoxy", "aryloxy", "heteroaryloxy", "arylalkyloxy", or "heteroarylalkyloxy" as used herein alone or as part of another group include an alkyl or aryl group as defined above linked through a oxygen atom. The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine, with bromine, chlorine or fluorine being preferred. The term, "cyano," as used herein, refers to a -CN group. The term "methylene", as used herein, refers to a -CH2- group. The term "nitro", as used herein, refers to a group -N02. The compounds of formula I can be present as salts, which are also within the scope of this invention. Preferred are pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable). If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with organic carboxylic acids, such as alkanocarboxylic acids of 1 to 4 carbon atoms, for example, acid acetic, which are substituted or unsubstituted, for example, by halogen as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, italic or terephthalic acids, such as hydroxycarboxylic acids, example ascorbic, glycolic, lactic, malic, tartaric or citric, such as amino acids, (for example, aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as alkyl (C? -C4) or arylsulfonic acids which are unsubstituted or substituted , for example by halogen, for example, methyl- or p-toluenesulfonic acid. The corresponding acid addition salts can also be formed which have, if desired, additionally a basic center present. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example, ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. The corresponding internal salts can also be formed. Salts which are unsuitable for pharmaceutical uses but which can be used, for example, for isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included. Preferred salts of the compounds of formula I which contain a basic group include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, nitrate or acetate. Preferred salts of the compounds of formula I which contain an acidic group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines. The term "modulator" refers to a chemical compound capable of either improving (e.g., "agonist" activity) or partially improving (e.g., "partial agonist" activity) or inhibiting (e.g., "antagonistic" activity or "inverse agonist" activity) a functional property of biological activity or process (e.g., enzyme activity or receptor binding); such improvement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction path, and / or may only be manifest in particular cell types. The term "bioactive metabolite" as used herein refers to any functional group contained in a compound of formula I with an open valency for further substitution wherein such substitution may, in biotransformation, generate a compound of formula I. such functional groups of bioactive metabolites include, but are not limited to, -OH, -NH or functional groups wherein the hydrogen may be replaced with a functional group such as -P03H2 for example, which, in biotransformation, generates a -OH or -NH functional group of a compound of formula I. The term "prodrug esters" as used herein includes esters and carbonates formed by reacting one or more hydroxyls of the compounds of formula I with alkyl, alkoxy, or substituted aryl acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, and the like. Prodrug esters may also include, but are not limited to, groups such as phosphate esters, phosphonate esters, phosphonamidate esters, sulfate esters, sulfonate esters and sulfonamidate esters wherein the ester may be further substituted with groups which confer a pharmaceutical advantage such as, but not limited to, favorable aqueous solubility or in vivo exposure to the bioactive component of formula I. The term "prodrug" as used herein includes functionality of bioactive amine or hydroxyl-containing compounds of formula I to form substituted alkyl, acyl, sulfonyl, phosphoryl, or carbohydrate derivatives. Such derivatives are formed by reacting compounds of formula I with alkylating reagents, acylation, sulfonylation, or phosphorylation that they employ procedures known to those skilled in the art. The alkylation of amines of formula I may result in, but is not limited to, derivatives that include spacer units for other prodrug portions such as alkoxymethyl, acyloxymethyl, phosphoryloxymethyl, or substituted sulfonyloxymethyl groups. The alkylation of amines of formula I can result in the generation of quaternary amine salts that act in vivo to provide the bioactive agent (ie, the compounds of formula I). Preferred prodrugs consist of a compound of formula I wherein a pendant hydroxyl is phosphorylated to generate a phosphate derivative. Such a prodrug may also include a spacer group between the compound of formula I and the phosphate group, such as a methyleneoxy group. Methods for generating such a prodrug of a compound of formula I are known to those skilled in the art, and are listed in the references below. Preferred prodrugs also consist of a compound of formula I wherein a pendant amine, such as a pyridine group, is alkylated with a group, such as methyl or acyloxymethylene, to form a quaternary ammonium ion salt. Methods for generating such a prodrug of a compound of formula I are known to those skilled in the art and are listed in the references below. Any compound that can be converted in vivo to provide the bioactive agent (ie, the compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives are described in: The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pp. 113-191 (Harwood Academic Publishers, 1991). Hydrolyses in Drug and Prodrug Metabolism, B. Testa and J. M. Mayer, (Verlag Helvética Chimica Acta AG, Zurich, Switzerland, Wiley-VCH, Weinheim, Federal Republic of Germany, 2003). Ettmayer, P .; Amidon, G. L .; Clement, B .; Testa B. "Lessons Learned from Marketed and Investigational Prodrugs" J. Med. Chem. 2004, 47 (10), 2393-2404. Davidsen, S. K. et al., "N- (Acyloxyalkyl) pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Antagonist Factor "J. Med. Chem. 1994, 37 (26), 4423-4429.References are incorporated herein by reference.An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat or procure a treatable condition by administration of a composition of the invention. That amount is sufficient to exhibit a detectable or preventive or relieving therapeutic effect. The effect may include, for example, treatment or prevention of the conditions listed in this document. The precise effective amount for a subject will depend on the subject's size and health, the nature and extent of the condition to be treated, recommendations of the treating physician, and the therapeutic or combination of therapeutics selected for administration. All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers on any of the carbon atoms that include any of one of the R substituents. Consequently, the compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can use racemates, enantiomers or diastereomers as materials of departure. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic techniques, chiral HPLC or fractional crystallization. The compounds of formula I of the invention can be prepared as shown in the following reaction schemes and description thereof, in addition to relevant published literature procedures that can be used by anyone skilled in the art. The reagents and exemplary procedures for these reactions appear hereinafter and in the working examples.

ABBREVIATIONS The following abbreviations are used in the Reaction Schemes, Examples and elsewhere in this document: Ac = Acetyl AcOH = Acetic acid Boc = Tert-butoxycarbonyl DCM = dichloromethane DIPEA = N, N-diisopropylethylamine DMF = N, N-dimethylformamide EDAC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride EtOAc = ethyl acetate Et3N = triethylamine Et20 = diethyl ether HOBt = 1-hydroxybenzotriazole hydrate CLAR = high performance liquid chromatography. LAH = lithium aluminum hydride MeOH = methanol EM or mass spec = mass spectrometry NaOH = sodium hydroxide GP = protecting group TA = room temperature TFA = trifluoroacetic acid THF = tetrahydrofuran min = minute (s) h = hour (s) L = liter mL = milliliter μL = microliter g = gram (s) mg = milligram (s) mol = moles mmol = millimol (s) nM = nanomolar The compounds of the present invention can be prepared by procedures illustrated in the accompanying schemes.

METHODS OF PREPARATION. The compounds of the present invention can be prepared by methods such as those illustrated in the following Reaction Schemes 1 through 9. Solvents, temperatures, pressures, and other reaction conditions can be readily selected by one skilled in the art. The starting materials are commercially available or can be easily prepared by one of ordinary skill in the art using known methods. For all the reaction schemes and compounds described below, R1, R2, R3, R6 and R7 are as described for the compound of formula I. The following are definitions of symbols used through Schemes 1 through 9: PG protecting group of suitable nitrogen, exemplified by benzyl, methoxymethyl- [MOM], benzyloxymethyl- [BOM], 2- (trimethylsilyl) ethoxymethyl- [SEM], methoxyethoxymethyl- [MEM], or t-butyl groups; EE leaving group Sn2 or Snl exemplified by halogen (Cl, Br, I) and sulfonates (-OS02-aryl (e.g., 0S02Ph or -OS02PhCH3), or -0S02-alkyl (e.g., OS02CH3 or -OS02CF3)); MM boronate ester or boronic acid, or trialkylstannane; or metal atom such as zinc, magnesium or lithium as part of an organometallic compound used as an intermediate for coupling reactions mediated by the transition metal. REACTION SCHEME 1 XI Compounds of formula II are either commercially available or are available by means known to one skilled in the art. The compounds of formula III can be prepared by reacting compounds of formula II with an appropriate protecting group such as benzyl bromide. The exemplary nitrogen shielding groups and nitrogen protection methods are similar to those for protective amines, such as those described in T. W. Greene and P.M. Wutsd, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1991. Preferred nitrogen protecting groups are benzyl, tert-butyl, methoxymethyl (MOM), methoxyethoxymethyl (MEM), and 2- (tri-ethylsilyl) ethoxymethyl (SEM) groups. The compounds of formula IV can be prepared from compounds of formula III by selective displacement of the leaving group (EE) by the conjugate base of an appropriate alcohol, RO-M, wherein R is alkyl or benzyl, and M is a metalloid such as Li, Na, Mg (halide) and the like in solvents such as dioxane. Similar reactions have been described in the literature (Riedl, Z. et al., Tetrahedron, 2002, 5645-5650). The compounds of formula V can be prepared by the reactions of compounds of formula IV with activated R 2, such as activated by boronic acids, tin, Grignard reagents, zinc, Cu, etc., in the presence of an appropriate catalyst if needed such as Pdd. (PPh3). Compounds of formula V can also be prepared from a compound of formula IV by displacement of the leaving group (EE) by the conjugate base of a compound R2-H, where R2 is as previously defined, using a base in an inert solvent. Exemplary bases include Sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, or alkyl lithium. The compounds of formula VI, wherein EE = C1, can be prepared by reacting the compounds of formula V with a chlorinating agent such as P0C13 in an inert solvent such as toluene at elevated temperature. Compounds of formula VII, wherein MM is a metal or a borate ester, can be prepared by lithiating the compound of formula VI wherein EE is hydrogen or a halogen (chlorine, bromine, iodine), and reacting the lithium aryl resulting with an appropriate borate derivative or with reagents such as trialkyltin halide. The compounds of formula VIII can be prepared by the reactions of compounds of formula VI with activated R1, such as activated by boronic acids, tin, Grignard reagents, zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (Ph3) 4. The compounds of formula VIII can also be prepared from a compound of formula VI by displacement of the leaving group (EE) by the conjugate base of compound R1-H, wherein R1 is as previously defined, using a base in a inert solvent. The compounds of formula VIII can also be prepared by a catalysed coupling in palladium or nickel of a compound of formula VII wherein MM is a borate ester with an appropriately activated R1 such as halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium, and lithium, similar cross-coupling reactions can be performed using activated R1 such as halide or borate esters with an appropriate catalyst such as tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) nickel (II). The compounds of formula IX can be prepared by removing the protecting group (PG) in a compound VIII under acidic conditions (for example, TFA for t-butyl or Boc), basic (for example, NaOH for amide), catalytic hydrogenation (for benzyl), or Lewis acid (eg, A1C13 for benzyl). The compounds of formula X can be prepared by reacting the compounds of formula IX with a chlorinating agent such as P0C13 in an inert solvent such as toluene at elevated temperature. The compounds of formula XI can be prepared by reacting the compounds of formula X with a hydrazine in an inert solvent such as pyridine at elevated temperature. The compounds of formula XII can be prepared by reacting the compounds of formula XI with a carbonylating agent such as carbonyldimidazole, phosgene, triphosgene., or urea in an inert solvent such as tetrahydrofuran. The compounds of formula I can be prepared by reacting the compounds of formula XII with R3-X (X is a leaving group such as F, Cl, Br, I, -OMs, -OTos), or epoxides at elevated temperatures. I can also be prepared by reacting the compounds of formula XII with R3-OH under Mitsunobu conditions. REACTION SCHEME 2 As illustrated in scheme 2, the compounds of formula XIII can be prepared from compounds of formula III by selective displacement of the leaving group (EE) by the conjugate base of an appropriate alcohol, RO-M, wherein R is alkyl or benzyl, and M is a metal such as Li, Na, Mg (halide) and the like, in solvents such as methanol. Such selective shifts, for example when EE = C1, have been reported in the literature. (Riedl, Z. et al., Tetrahedron, 2002, 5645-5650). The compounds of formula XIV can be prepared by the reactions of compounds of formula XIII with R1, such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd ( PPh3) 4. Compounds of formula XIV can also be prepared from a compound of formula XIII by displacement of the leaving group (EE) by the conjugate base of compound R1-H, wherein R1 is as previously defined, using a base in a inert solvent. The compounds of formula XV, wherein EE = C1, can be prepared by reacting the compounds of formula XIV with a chlorinating agent such as P0C13 in an inert solvent such as toluene at elevated temperature. Alternatively, compounds of formula XV, where EE = C1, can also be prepared by the reactions of the compounds of formula III with activated R1, such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of a suitable catalyst if necessary such as Pd (PPh3) - Compounds of formula XVI, where MM is a metal or a borate ester, can be prepared by lithiating the compound of formula XV where EE is hydrogen or a halogen (chlorine, bromine, iodine), and reacting the resulting aryl lithium with an appropriate borate derivative or with reagents such as trialkyl tin halide. The compounds of formula VIII can be prepared with the reactions of compounds of formula XV with active R 2, such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh3) 4. The compounds of formula VIII can also be prepared from a compound of formula XV by displacement of the leaving group (EE) by the conjugate base of the compound R2-H, wherein R2 is as previously defined, using a base in an inert solvent. The compounds of formula VIII can also be prepared by a palladium or nickel catalyzed coupling of a compound of formula XVI wherein MM is a borate ester with an appropriately activated R 2 such as halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium and lithium, similar cross-coupling reactions can be performed using activated R2 such as halide or borate esters with an appropriate catalyst such as tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) nickel (II).

The compounds of formula I can be prepared from the compound of formula VIII as described in Reaction Scheme 1. REACTION SCHEME 3 XIII XVII XVIII XIX As illustrated in Scheme 3, the compounds of formula XVII can be prepared from the compound of formula XIII (from Reaction Scheme 2) by displacement of the group R (R = alkyl) using bases such as sodium hydroxide in a appropriate solvent such as water. The hydroxyl group in XVII can be activated by becoming react with "reagents" such as trifluoromethane sulfonic anhydride in the presence of a suitable base such as triethylamine. This activated portion can then be selectively coupled with activated R 2, such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh 3) 4 to provide the compounds XVIII. The compounds of formula XIX can also be made by the treatment of compounds of formula V with POC13 at elevated temperatures. The compounds of formula XIX can be prepared from compounds XVIII in a 2-step sequence: (a) by removing the protecting group (PG) in compound XVIII under acidic conditions (e.g., TFA for t-butyl or BOC) , basic (e.g., NaOH for amides), catalytic hydrogenation (for benzyl), or Lewis acid (e.g., ICI3 for benzyl), followed by (b) reacting the resulting intermediate with a chlorinating agent such as POCI3 in an inert solvent such as toluene at elevated temperature. In certain cases, direct treatment of XVIII with chlorinating agents such as P0C13 at a higher temperature, may provide compounds of formula XIX in one step from XVIII. The compounds of formula XX can be prepared at reacting compounds of formula XIX with hydrazine in selected solvents such as isobutanol. The compounds of formula XXI can be prepared by reacting compounds of formula XX with a carbonylating agent such as carbonidiimidazole, phosgene, triphosgene or urea in an inert solvent such as tetrahydrofuran. The compounds of formula XXII can be prepared by reacting the compounds of formula XXI with R3-X (X is a leaving group such as F, Cl, Br, I, -OMs, -OTos), or epoxides at elevated temperatures. The XXII can also be prepared by reacting compounds of formula XXI with R3-OH under Mitsunobu conditions. The compounds of formula I can be prepared by the reactions of compounds of formula XXII with activated R1, such as activated by boronic acids, tin, reactants Grignard, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh3) 4. The compounds of formula I can also be prepared from a compound of formula XXII by displacement of the leaving group (EE) by the conjugate base of compound R1-H, wherein R1 is as previously defined, using a base in a inert solvent. The compounds of formula XXII, wherein MM is a metal or a borate ester, can be prepared by lithiation of the compound of formula XXII wherein EE is hydrogen or a halogen (chlorine, bromine, iodine), and reacting the resulting aryl lithium with an appropriate borate derivative or with reagents such as trialkyltin halide. The compounds of formula I can also be prepared by a palladium or nickel catalyzed coupling of a compound of formula XXIII wherein MM is a borate ester with an appropriate activated R1 such as halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium and lithium, similar cross-coupling reactions can be performed using activated R1 such as halide or borate esters with an appropriate catalyst such as tetrakis (triphenylphosphine) palladium (0) and dichlorobis. (triphenylphosphine) nickel (II). The compounds of formula I can also be prepared from XXI in a two-step sequence: (a) XXI cross-coupling with an activated R1,. such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh3) 4 or displacement of EE in XXI with a conjugate base of R1-H, to provide the compounds XII, followed by (b) reacting the compounds of formula XII with R3-X (X is a leaving group such as F, Cl, Br, I, -OMs, -Otos), or epoxides at elevated temperatures .

REACTION SCHEME 4 As illustrated in reaction scheme 4, compounds of formula XXIV can be prepared from compounds XV in a two-step sequence: (a) removing the protecting group (PG) in compound XV under acidic conditions ( example, TFA for t-butyl or Boc), basic (e.g., NaOH for amide), catalytic hydrogenation (for benzyl), or Lewis acid (e.g., A1C13 for benzyl) followed by (b) reacting the intermediate resulting with a chlorinating agent such as P0C13 in a solvent inert such as toluene at elevated temperature. The compounds of formula XXV can be prepared by reacting compounds of formula XXIV with hydrazine in selected solvents such as isobutanol. The compounds of formula XXVI can be prepared by reacting compounds of formula XXV with a carbonylating agent such as carbonyldiimidazole, phosgene, triphosgene or urea in an inert solvent such as tetrahydrofuran. The objective compounds of formula I can be prepared from compounds of formula XXVI following an analogous sequence of reactions as described in Reaction Scheme 3 by means of intermediates XII, XXVII and XXVIII. REACTION SCHEME 5 As illustrated in reaction scheme 5, when R1 and R2 are the same, compounds of formula VIII can be prepared by the reactions of compounds of formula III with activated R1 and R2, such as activated by boronic acids, tin, Grignard reagents , Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh3). The compounds of formula VIII can also be prepared from the compounds of formula III by displacement of the leaving group (EE) by the conjugate base of a compound R1-H and R2-H, wherein R1 and R2 is as previously defined, using a base in an inert solvent. The objective compounds of formula I can then be prepared from compounds of formula VIII following an analogous sequence of reactions as described in reaction scheme 1. REACTION SCHEME 6 As illustrated in Reaction Scheme 6, the compounds of formula X can be prepared by the reaction of the compounds of formula XXIV with activated R 2, such as activated by boronic acids, tin, Grignard reagents, zinc, Cu, etc., in the presence of an appropriate catalyst if necessary such as Pd (PPh3.) 4. The compounds of formula I can then be prepared from compounds of formula I by following an analogous sequence of reactions as described in Reaction Scheme 1 .

REACTION SCHEME 7 As illustrated in reaction scheme 7, analogs having certain arbitrarily defined substrings of R1 and R2 and R3 can be interchanged with other analogs having certain other arbitrarily defined substrings of R1 and R2 and R3 by manipulation of the functional groups placed in these groups R. For example, when Rla, R2a, R3a are groups such as amino, aminoaryl, aminoalkyl or aminoaryloxy, they can be reacted with either carboxylic acids or acid chlorides or sulfonyl chlorides to provide amide or sulfonamide derivatives. Such manipulation can also be conducted by means of a parallel synthesis.

In addition, when Rla, R 2a, R 3a are substituted with an activated group such as halogen or boronic acid, cross coupling reactions catalyzed by additional metal can be performed to provide a further series of analogs as described by formula I. Such manipulation also it can be conducted by means of a parallel synthesis. REACTION SCHEME 8 As illustrated in reaction scheme 8, the compounds of formula I can be prepared by parallel synthesis using solid phase synthesis. For example, compounds of formula XXI can be reacted with a resin attached to the polymer to provide compounds XXIX. The compounds of formula XXX can be prepared by the reactions of the compounds of formula XXIX with activated Ra, such as activated by boronic acids, tin, Grignard reagents, Zinc, Cu, etc., in the presence of an appropriate catalyst if necessary, such as Pd (PPh3) 4. The removal of the resin bound to the polymer then provides compounds of formula XII. The compounds of formula XII can be converted to compounds of formula I as shown in Reaction Scheme 1. Objective compounds of formula I can also be prepared from compounds of formula XXVI following an analogous sequence of reactions as described above . REACTION SCHEME 9 The compounds of formula XXXIII can undergo a reaction with an activated R6, such as R6-M wherein M is a metalloid such as Li, Na, Mg (halide) and the like in solvents such as THF to give compounds of formula XXXIV, which it is recognized with a subset of compounds of formula I wherein n is a single bond and R7 is hydrogen. A compound of formula XXXIV can be reacted with a oxidizer, such as atmospheric oxygen or 2,3-dichloro-5,6-dicyanohydroquinone and the like, to give compounds of formula I wherein n is a double bond and R 7 is absent. A compound of formula XXXIV can be reacted with an alkylating agent, such as alkyl halide, or an acylation group, such as acetic anhydride, benzoyl chloride and the like to give compounds of formula I. A compound of formula XXXIV can be react with a phosphorylation reagent, such as P0C13 or Cl-P (O) (OEt) 2 to give, then hydrolysis, compounds of formula I. Examples of transformation of amines to phosphonamidates can be found in: Wang R. et al. J. Med. Chem. 2003, 46 (22), 4799-4802; Guillaume, H. A. J. Org. Chem. 1989, 54 (24), 5731-5736. A compound of formula XXXIV can be reacted with a sulfonylating agent, such as pyridine-S03 or Cl-S (0) mR8 complex, to give compound of formula I. Transformation examples can be found in Tschamber, T. and Streith , J. Heterocycles 1990, 30 (1), 551-559; Couloigner, E., Cartier, D., Labia, R. Bioorg. Med. Chem. Lett. 1990, 9, 2205-2206; Tschamber, T. et al. Heterocycles 1985, 23 (10), 2589-2601. A parallel synthesis can be employed in the preparation of the compounds, for example, wherein the intermediates possess an activated reaction center: such as, but not limited to, traizolone nitrogen, a heteroaryl chloride reactive for Suzuki coupling chemistry or a carboxylic acid for amide coupling chemistry. EXAMPLES The following examples serve to better illustrate, but not to limit, some of the preferred embodiments of the invention.

Analytical HPLC and CLAR / MS methods used in the Characterization of Examples The analytical HPLC was performed in liquid chromatographs Shimadzu LC10AS. Analytical HPLC / MS was performed on Shimadzu LC10AS liquid chromatographs and Waters ZMD mass spectrometers using the following methods: Unless indicated otherwise, method A is used in the characterization of intermediates or final compounds of the examples listed in experiments or in the tables.

Method A. Linear gradient from 0 to 100% solvent B for 4 minutes with 1 minute waiting at 100% B; UV visualization at 220 nm Column: Phenomenex Luna C18 4.6 x 50 mm Flow rate: 4 ml / min; Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol Solvent B: 0.2% phosphoric acid, 90% methanol, 10% water Method B. Linear gradient from 0 to 100% solvent B for 8 minutes, with 3 minutes waiting at 100% B; UV display at 220 nm Column: Phenomenex Luna C18 4.6 x 75 mm or Zorbaz SB C18 4.6 x 75 mm Flow rate: 2.5 ml / min Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol Solvent B : 0.2% phosphoric acid, 90% methanol, 10% water Method C. Linear gradient from 0 to 100% solvent B for 4.0 minutes, with 0.5 minutes waiting at 100% B; UV display at 220 nm Column: Xterra MS-C18 4.6 x 50 mm Flow rate: 4 ml / min Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% acetonitrile Solvent B: 0.1% trifluoroacetic acid, 10% water, 90% acetonitrile Method D. Linear gradient from 0 to 100% solvent B during 4 minutes, with 1 minute of waiting at 100% B; UV display at 220 nm Column: Phenomenex Luna C18 4.6 x 50 mm Flow rate: 4 ml / min Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol Solvent B: 0.1% trifluoroacetic acid, 90% of methanol, 10% water Method E. Linear gradient from 0 to 100% solvent B over 4 minutes, with 1 minute waiting at 100% B; UV visualization at 220 nm Column: Phenomenex Luna C18 4.6 x 50 mm Flow rate: 4 ml / min Solvent A: 10 mM NH4OAc, 90% water, 10% methanol Solvent B: 10 mM NH4OAc, 90% methanol, 10% water Method F. Linear gradient from 1 to 100% solvent B lasts 2.35 minutes, with 0.5 minutes wait at 100% B; UV display at 220 nm Column: Xterra MS-C18, 2.1 x 50 mm Flow rate: 1.0 ml / min Solvent A: 0.1% trifluoroacetic acid, 100% water Solvent B: 0.1% trifluoroacetic acid, 100% acetonitrile Method G. Linear gradient from 10 to 100% solvent B over 2.0 minutes, with 0.56 minutes waiting at 100% B; UV display at 220 nm Column: Xterra MS-C18 4.6 x 50 mm - Flow ratio: 1.0 ml / min Solvent A: 10 mM NHOAc, 95% water, 5% acetonitrile Solvent B: 10 mM NH4OAc, 95% acetonitrile, 5 % Water NMR Used in the characterization of the Examples. XH NMR spectra were obtained with Bruker or JOEL fourier transform spectrometers operating at the following frequencies: ^? NMR: 400 MHz (Bruker), 400 MHz (JOEL), or 500 MHz (JOEL); 13C NMR: 100 MHz (Bruker), 100 MHz (JOEL) or 125 MHz (JOEL). Spectral data are reported as chemical displacement (multiplicity, number of hydrogens, linking constants in Hz) and are reported in ppm (units d) relative to either an internal standard (tetramethylsilane = 0 ppm) for 1 H NMR spectra, or are reference for the residual solvent peak (2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2H0D, 7.24 ppm for CHC13, 39.7 ppm for CD3SOCD3, 49.0 ppm for CD30D, 77.0 ppm for CDC13). All 13C NMR spectra were uncoupled from proton.

EXAMPLE 1 Preparation of 7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one. ÍA. Preparation of 2-Benzyl-4,5-dibromopyridazin-3 (2H) -one.

To a solution of dibromopyridazinone (50.0 g, 197.0 mmol) in DMF (200 ml) at room temperature, K2C03 was added. (32.6 g, 236.4 mmol). Benzyl bromide (37.0 g, 216.7 mmol) was added via syringe. The resulting green suspension was stirred at room temperature for 6 hours until all the pyridazinone was consumed as judged by HPLC. The reaction mixture was then poured into an Erlenmeyer flask containing water (500 ml) with stirring. A beige solid formed. The suspension was stirred for 15 min at room temperature and then filtered. The solid was rinsed thoroughly with water until color was evident in the filtrate. The solid was dried in a vacuum oven at 50 ° C overnight. The title compound, 2-benzyl-4,5-dibromopyridazin-3 (2H) -one, (68.0 g, 196.5 mmol) it was > 95 pure as judged by CLAR and obtained as a solid. MS: M + H = 343. 1 H NMR (CDC13, 500 MHz): d 7.80 (ΔH, s), 7.45 (2H, d, J = 5.0 Hz), 7.29-7.36 (3H,), 5.31 (2H, s ). IB. Preparation of 2-Benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one.

To a suspension of 2-benzyl-4,5-dibromopyridazin-3 (2H) -one (40 g, 116.0 mmol) in toluene (300 mL) was added Pd (PPh 3) 4 (4.0 g, 3.5 mmol) under one atmosphere of argon. 4-Chlorophenylboronic acid (40.0 g, 255.2 mmol) was added subsequently in portions. Under vigorous stirring, Na2CO3 (27.0 g, 255.2 mmol) dissolved in water (50 mL) was added to the suspension. The argon was bubbled through this suspension for 10 minutes, before the flask was placed in a pre-heated oil bath at 120 ° C. The reaction was refluxed for 6 hours. The reaction was then allowed to cool to room temperature and poured into water (500 mL). The aqueous mixture was extracted with EtOAc (3 x 300 L).

The combined organic layers were washed with NaOH (0.5 N, 200 ml) and water (2 x 500 ml). The organic layer was filtered through a pad of silica gel (-50 g) in a sintered glass funnel to remove impurities from Dark color. The solvents were then evaporated under reduced pressure. The resulting thick syrup containing predominantly the title compound 2-benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one which can be used directly in the next reaction, 1C. MS: M + H = 407. '' 'H NMR (CDC13, 500 MHz): d 7.87 (OH, s), 7.54 (2H, d, J = 5.0 Hz), 7.32-7.38 (3H, m), 7.22 -7.28 (4H, m), 7.12 (2H, d, J = 10.0 Hz), 7.03 (2H, d, J = 10 Hz), 5.40 (2H, s). 1 C . Preparation of 4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -on.

The crude 2-benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one from the previous reaction was dissolved in toluene (350 ml). Aluminum chloride was then added (A1C13, 46.3 g, 348. 0 mmol) to the toluene solution, to produce an exotherm. The reaction was then placed in a preheated oil bath at 75 ° C for 3 hours. After this time, the reaction mixture was poured into ice water (1000 ml), and the resulting mixture was extracted with EtOAc (3 x 500 ml). The combined organic layers were washed with water (500 ml), then filtered through a pad of silica gel (-50 g) to remove residual alumina salts. The organic solvents were evaporated under reduced pressure until almost dry. Diethyl ether (Et20, 500 ml) was added with stirring. After stirring for 15 minutes at room temperature, hexane (1000 ml) was subsequently added. The resulting beige solid was collected by filtration and subsequently washed with a hexane-ether mixture (8: 2). The title compound, 4, 5-bis (4-chlorophenyl) pyridazin-3 (2H) -one, (33.0 g, 92%) was obtained as a solid. MS: M + H = 317. aH NMR (CDC13, 500 MHz): d 11.94 (HH, br), 7.89 (HH, s), 7.23-7.32 (4H, m), 7.18 (2H, d, J = 10.0 Hz), 7.07 (2H, d, J = 10 Hz). ID. Preparation of 3-Chloro-4,5-bis (4-chlorophenyl) pyridazine. 4,5-Bis (4-chlorophenyl) pyridazin-3 (2H) -one (16.5 g, 52.2 mmol) was suspended in toluene (50 mL). To the resulting solution was added pyridine (8.3 ml, 104.4 mmol), followed by the addition of P0C13 (14.3 ml, 156.6 mmol). The reaction mixture was placed in an oil bath pre-heated to 110 ° C. After 4 hours, the reaction mixture was cooled to room temperature, then poured into 500 g of ice until the excess of POCI3 was quenched. The dark mixture was extracted with EtOAc (2 x 300 ml). The combined organic layers were washed with water (500 ml), and filtered at through a pad of silica gel (~ 50 g). The filtrate was concentrated under reduced pressure to give the title compound, 3-chloro-4,5-bis (4-chlorophenyl) pyridazine as a pale-colored solid (16.0 g, 92%). MS: M + H = 335. a H NMR (CDC13, 500 MHz): d 9.24 (1H, s), 7.35 (2H, d, J = 10 Hz), 7.26 (2H, d, J = 10.0 Hz), 7.08 -7.16 (4H, m). 1E. Preparation of 1- (4,5-Bis (4-chlorophenyl) pyridazin-3-yl) hydrazine 3-Chloro-4,5-bis (4-chlorophenyl) pyridazine (10.0 g, 30.0 mmol) was dissolved in pyridine (30 ml) and hydrazine monohydrate (4.5 g, 90.0 mmol) was added. The reaction mixture was refluxed for 3 hours and then added to water (100 ml). The pale-colored solid was collected by filtration and rinsed thoroughly with water. The product was dried in a vacuum oven to give the title compound, 1- (4,5-bis (4-chlorophenyl) pyridazin-3-yl) hydrazine (9.5 g, 96%). MS: M + H = 331. X H NMR (DMS0-d 6, 500 MHz): d 8.59 (1H, s), 8.56 (OH, br), 7.40 (2H, d, J = 10 Hz), 7.35 (2H, d, J = 10.0 Hz), 7.14-7.16 (4H, m). ÍF. Preparation of 7, 8-bis (4-chlorophenyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one To a THF solution (20 ml) of carbonyldiimidazole (CDI), (1.7 g, 10.5 mmol) was added 1- (4,5-bis (4-chlorofenyl) pyridazin-3-yl) hydrazine (0.7 g, 2.1 mmol). The resulting brown solution was stirred at room temperature for 15 minutes.

After this time, the reaction solution was poured into water (50 ml). The resulting pale-colored solid was collected by filtration. Water was used to thoroughly rinse the solid to provide 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (0.75 g, 100% ). MS (M + H) = 357; H NMR (DMSO-d6, 500 MHz): d 12.86 (ÍH, s), 8.37 (1H, s), 7.42-7.48 (4H, m), 7.35 (2H, d, J = 10.0 Hz), 7.27 (2H, d, J = 10.0 Hz). EXAMPLE 2 Preparation of 2- (4-Chlorobenzyl) -7,8-bis (4-chlorophenyl) - (1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one.

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (0.4 g, 1.1 mmol), prepared as described in Example 1 in DMF (5 ml), K2C03 (0.46 g, 3.3 mmol) and 4-chlorobenzyl bromide (0.28 g, 1.3 mmol) were added. The reaction mixture was heated at 60 ° C for 20 minutes. After this time, water was added (50 ml) was added to the reaction mixture and the resulting solid was collected by filtration. The final product (0.32 g, 60%) was obtained by purification using preparative reverse phase HPLC. MS (M + H) = 481; kH NMR (CDC13): d 8.18 (1H, s), 7.25-7.40 (10H, m), 7.08 (2H, d, J = 10.0 Hz), 5.18 (2H, s).

EXAMPLE 3 Preparation of 7,8-Bis (4-chlorophenyl) -2- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1,2,4] riazole [4,3-b] pyridazine- 3 (2H) -one To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (100 mg, 0.28 mmol) was prepared as described in Example 1, Ph3P (220 mg, 0.84 mmol) and (5-trifluoromethyl-pyridin-2-yl) methanol (50 mg, 0. 28 mmol) in THF (2.0 ml) was added a solution of diethyl azodicarboxylate (DEAD) 40 wt.% In toluene (0.33 ml, 0.84 mmol) at room temperature under argon. The reaction was stirred at room temperature for 30 minutes. Then water (5.0 ml) was added and the resulting mixture was extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with water (2x5 ml) followed by saturated aqueous NaCl (2 5 ml). The combined organic layers were concentrated under reduced pressure to obtain the crude product. This crude product was purified using reverse phase preparative HPLC to give the title compound 7,8-bis (4-chlorophenyl) -2- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1, 2 , 4] triazol [4, 3-b] pyridazin-3 (2H) -one (69.2 mg, 48%) as a yellow solid. MS (M + H) = 516; XH NMR (CDC13): d 8.83 (HH, s), 8.20 (HH, s), 7.93 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 10.0 Hz), 7.26-7.34 (6H , m), 7.11 (2H, d, J = 10.0 Hz), 5.47 (2H, s). EXAMPLE 4 Preparation of 7, 8-Bis (4-chlorophenyl) -2- ((1- (pyrimidin-2-yl) piperidin-4-yl) methyl) - [1,2,4] riazole [4.3- b] pyridazin-3 (2H) -one The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (50 mg, 0. 14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (1- (pyrimidin-2-yl) iperidin-4-yl) methanol (28 mg, 0.14 mmol) in THF (1.0 ml) and following the procedure described in Example 2. The title compound, 7, 8-bis (4-chlorophenyl) -2- ((1- (pyrimidin-2-yl) piperidin-4-yl) methyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one, (31 mg, 42%) was obtained as a yellow powder. MS M + H = 532; H NMR (CDC13) d 8.28 (2H, d, J = 5.0 Hz), 8.16 (1H, s), 7.28-7.36 (6H, m), 7.11 (2H, d, J = 10.0 Hz), 6.44 (1H, t, J = 5.0 Hz), 4.75 (2H, d, J = 15.0 Hz), 3.96 (2H, d, J = 10.0 Hz), 2.85 (2H, m), 2.20-2.30 (ÍH, m), 1.74 ( 2H, d, J = 10.0 Hz), 1.30-1.40 (2H, m). EXAMPLE 5 Preparation of (R) -7,8-bis (4-chlorophenyl) -2- ((5-oxopyrrolidin-2-yl) methyl) - [1,2,4] riazole [4, 3-b] pyridazin -3 (2H) -one The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (50 mg, 0.14 mmol), prepared as described in Example 1, PhP (110 mg, 0.42 mmol) and (R) -5- (hydroxymethyl) pyrrolidin-2-one (17 mg, 0.14 mmol) in THF (1.0 ml) and following the procedure described in Example 2. The title compound, (R) -7,8-bis (4-chlorophenyl) -2- ((5-oxopyrrolidin-2-yl) ethyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (38.5 mg, 85%) was obtained as a yellow powder. MS M + H = 454; XH NMR (CDC13) d 8.15 (HH, s), 7.24-7.36 (6H,), 7.09 (2H, d, J = 10.0 Hz), 6.59 (HH, s), 4.17-4.20 '(HH, m), 4.03-4.10 (2H, m), 2.25-2.35 (3H,), 1.92-2.02 (ÍH, m). EXAMPLE 6 Preparation of (R) -2- ((1-Benzylpyrrolidin-2-yl) methyl) -7,8-bis (4-chlorophenyl) - [1,2,4] riazole [4,3-b] pyridazine -3 (2H) -one The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P. { 110 mg, 0.42 mmol) and (S) -l-benzyl-2-pyrrolidinemethanol (27 mg, 0.14 mmol) in THF (1.0 ml) and following the procedure described in Example 2. The title compound, (R) - 2 - ((1-benzylpyrrolidin-2-yl.) Methyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) - ona, (8 mg, 11%) was obtained as yellow powder, MS M + H = 530, 1 H NMR (CDC13) d 8. 14 (HH, s), 7.22-7.38 (11H, m), 7.10 (2H, d, J = 10.0 Hz), 4.61-4.63 (HH, m), 3.50-3.56 (2H, q = 13.2 Hz) , 3.01 (HH, d, J = 10.0 Hz), 2.85 (HH, d, J = 10.0 Hz), 2.37-2.42 (1H, t, J = 10.7 Hz), 1.99-2.02 (2H, m), 1.82- 1.95 (ÍH, m), 1.70-1.80 (2H, m). EXAMPLE 7 Preparation of 7,8-Bis (4-chlorophenyl) -2- ((6-morpholinopyridin-3-yl) methyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H -one The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (50 mg, 0.14 mmol), prepared as described in Example 1, P? 13P (110 mg, 0.42 mmol) and (6-morpholinopyridin-3-yl) methanol (29 mg, 0.14 mmol) in THF (1.0 ml) and following the procedure described in Example 2. The title compound, 7, 8-bis (4-chlorophenyl) -2- ((6-morpholinopyridin-3-yl) methyl) - [1,2,4] triazole [4, 3-b] pyridazin -3 (2H) -one, (20.5 mg, 11%) was obtained as a yellow powder. MS M + H = 533; H NMR (CDC13) 8.26 d (ΔI, d, J = 5.0 Hz), 8.15 (ΔI, s), 7.65 (ΔI, d, J = 5.0 Hz), 7.25-7.36 (6H, m), 7.09 (2H, d, J = 10.0 Hz), 6.60 (ÍH, d, J = 10.0 Hz), 5.10 (2H, s), 3.80 (4H, t, J = 5.0 Hz), 3.50 (4H, t, J = 5.0 Hz) .

EXAMPLE 8 Preparation of 7, 8-bis (4-chlorophenyl) -2- (pyridin-N-oxide-4-ylmethyl) - [1,2,4] riazole [, 3-b] pyridazin-3 (2H) - ona The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1,2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), prepared as described in Example 1, Ph3P (32 mg, 0.12 mmol) and 4-pyridyl carbinol-N-oxide (15 mg, 0.12 mmol) in THF (1.0 ml) and following the procedure described in Example 2. The title compound, 7, 8-bis (4-chlorophenyl) -2- (pyridin-N-oxide-4-ylmethyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H ) -one (14 mg, 27%) was obtained as a yellow solid. MS M + H = 464; aH NMR (CDC13) d 8.20 (ÍH, s), 8.15 (2H, d, J = 5.0 Hz), 7.28-7.36 (6H, m), 7.25 (2H, d, J = 5.0 Hz), 7. 10 (2H, d, J = 5.0 Hz), 5.16 (2H, s).

EXAMPLE 9 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (2-morofolinoethyl) [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one To 7, 8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), prepared as described in Example 1, in DMF (1 ml) was added Cs2CO3 (110 mg, 0.33 mmol) and 4- (2-chloroethyl) morpholine hydrochloride. { 31 mg, 0.166 mmol). The reaction mixture was stirred at 70 ° C for 30 minutes under argon. After this time, the reaction mixture was diluted with water (5 ml). The resulting solution was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (2 x 5 ml) and saturated aqueous sodium chloride (2 x 5 ml). The organic layer was concentrated. The resulting crude material was purified by preparative HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (2-morpholinoethyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (35 mg, 67%) as a yellow solid. MS M + H = 470; XH NMR (CDC13) d 8.17 (HH, s), 7.28-7.34 (6H, m), 7.10 (2H, d, J = 10.0 Hz), 4.44 (4H, t, J = 5.0 Hz), 3.96-4.01 ( 4H), 3.50 (4H, t, J = 5.0 Hz).

EXAMPLE 10 Preparation of 7,8-bis (4-chlorophenyl) -2-cyclohexyl- [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one The title compound was prepared using 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), prepared as described in Example 1, Cs2CÜ3 (44 mg, 0.135 mmol), bromochlorohexane (100 mg, 0.61 mmol) in DMF (1 ml) and following the procedure described in Example 9. The title compound, 7, 8 bis (4-chlorophenyl) -2-cyclohexyl- [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one (26 mg, 54%) was obtained as yellow lyophilate. MS M + H = 439; H NMR (CDC13) d 8.17 (HH, s), 7.30-7.38 (6H, m), 7.11 (2H, d, J = 5.0 Hz), 4.38-4.41 (1H, m), 1.75-2.0 (6H, m ), 1.65-1.75 (ÍH, m), 1.35-1.50 (2H, m), 1.1-1.30 (ÍH, m).

EXAMPLE 11 Preparation of 2, 7, 8-tris (4-chlorophenyl) [1,2,4] riazole [4,3-b] pyridazin-3 (2H) -one To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (50 mg, 0.14 mmol) prepared as described in Example 1 and 4-chlorophenylboronic acid (44 mg, 0.28 mmol) in pyridine (1.5 ml) was added copper (II) acetate (51 mg, 0.28 mmol) followed by triethylamine (0.04 ml, 0.28 mmol) and sieves Molecular 3Á (100 mg) under argon. The reaction mixture was stirred at reflux for 6 hours. After this time, the reaction mixture was cooled to room temperature and diluted with water (5 ml). The resulting mixture was extracted with EtOAc (3 mL). The combined organic layers were washed with water (2 x 5 ml) and saturated aqueous NaCl (2 x 5 ml). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to give 2, 7, 8-tris (4-chlorophenyl) - [1, 2,4] triazole [4, 3-b] pyridazin-3 (2H) -one (5 mg, 8%) as yellow lyophilate. CLAR: 4.35 min; M + H = 467; kH NMR (CDC13) d 8.22 (ÍH, s), 8.10 (2H, d, J = 10.0 Hz), 7.43 (2H, d, J = 10.0 Hz), 7.35-7.38 (6H, m), 7.15 (2H, d, J = 10.0 Hz).

EXAMPLE 12 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (3-phenylpropyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one To a solution of tetrahydrofuran (2 mL) of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), prepared as described in Example 1, 3-phenylpropan-1-ol (0.018 ml, 0.13 mmol), and triphenylphosphine (86 mg, 0.32 mmol) was added diethyl azodicarboxylate (0.15 ml, 0.38 mmol). After 1 hour, the solution was concentrated. The crude material was purified by preparative HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (3-phenylpropyl) - [1,2,4] triazole [4, 3-b] pyridazin -3 (2H) -one (17.9 mg, 34%) as a yellow solid. MS M + H = 475; H NMR (CDC13) 8.18 (1H, s), 7.3-7.1 (13H, m), 4.13 (2H), 2.70 (2H), 2.21 (2H).

EXAMPLE 13 Preparation of 2- (4-Fluorophene-il) -7,8-bis (4-chlorophenyl) [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (40 mg, 0.11 mmol) was prepared as described in Example 1, 2- (4-fluorophenyl) ethyl bromide (22 mg), and K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 70 ° C for 6 hours. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. The crude product was purified using reverse phase preparative HPLC to give the title compound, 2- (4-fluorophenethyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4.3- b] pyridazin-3 (2H) -one (21.2 mg, 40%) as a yellow foam. MS M + H = 479; aH NMR (CDC13) d 8.18 (ÍH), 7.35 (4H), 7.26 (4H), 7.12 (2H), 6.95 (2H), 4.29 (2H), 3. 13 (2H).

EXAMPLE 14 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (2-hydroxycyclohexyl) [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one.

A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (40 mg, 0.11 mmol) was prepared as described in Example 1, cyclohexene oxide (12 mg, 0.12 mmol) and K2C03 (35 mg, 0.25 mmol) in DMF (1 ml) was heated at 100 ° C for 3 hours. After this time the solution was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound, 7,8-bis (4-chlorophenyl) -2- (2-hydroxycyclohexyl) - [1,2,4] triazole [4,3-b] pyridazin -3 (2H) - (24.1 mg, 48%) as a yellow solid. EM M + H = 455; aH NMR (CDC13) d 8.17 (ÍH), 7.33 (6H), 7.08 (2H), 4. 26 (ÍH), 3.98 (1H), 2.17 (ÍH), 1.99 (ÍH), 1.82 (3H), 1.50-1.30 (3H).

EXAMPLE 15 Preparation of 2- ((l-Benzylpiperidin-4-yl) methyl) -7,8-bis (4-chloro enyl) - [1,2,4] riazole [4,3-b] pyridazin-3 ( 2H) -one.

To a solution in THF (2 mL) of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), was prepared as described in Example 1, (1-benzyl-4-piperidyl) methanol (27 mg, 0.13 mmol), and triphenylphosphine (86 mg, 0.32 mmol), diethyl azodicarboxylate (0.15 ml, 0.38 mmol). After 1 hour, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 2- ((1-benzylpiperidin-4-yl) methyl) -7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [ 4, 3-b] iridazin-3 (2H) -one (6.1 mg, 10%) as a yellow solid. MS M + H = 544; XH NMR (CDC13) d 8.19 (HH), 7.42 (2H), 7.32-7.20 (9H), 7.11 (2H), 4.19 (ÍH), 4.02 (2H), 3.66 (2H), 2.63 (2H), 2.12 ( 2H), 1.91 (4H).

EXAMPLE 16 Preparation of 2- (7,8-Bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4 (3-b] pyridazin-2 (3H) -yl) -N, 4 -dimethylpentanamide. 16A. Preparation of 2-bromo-N, 4-dimethylpentanamide, To the solution of DL-alpha-bro oisocaproic acid in THF (4 ml) was added N-methylmorphine (0.18 ml, 1.63 mmol), followed by dropwise addition of isobutylchloroformate (0.15 ml, 1.16 mmol). A white solid precipitate formed. After stirring at room temperature for 1.5 hours, the white solid was filtered. Methylamine (1 ml, 2N in THF) was added to the filtrate. The reaction mixture was concentrated after 0.5 hours. The resulting crude material was diluted with ethyl acetate and washed with water. The organic layer was dried over Na 2 SO and concentrated to give the title compound, 2-bromo-N, 4-dimethylpentanamide, (0.18 g, 78%) as an oil. 16B._Preparation_of_2- (7,8-Bis (4-chlorophenyl) -3-oxo- [1,2, 4] triazole [4, 3-b] pyridazin-2 (3H) -yl) -N, 4-dimethylpentanamide A solution of 7,8-bis (4-chlorophenyl) - [1, 2,] triazole [4, 3-b] pyridazin-3 (2H) -one, (40 mg, 0.11 mmol), was prepared as described in Example 1, 2-bromo-N, 4-dimethylpentanamide (25 mg) and K2CO3 (31 mg, 0.22 mmol) in DMF (2 ml), was heated at 85 ° C for 1.5 hours. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. The crude product was purified using reverse phase preparative HPLC to give the title compound, 2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4, 3-b ] pyridazin-2 (3H) -yl) -N, 4-dimethylpentanamide (28 mg, 40%) as a yellow solid. MS M + H = 484; H NMR (CDC13) d 8.23 (HH), 7.36-7.30 (6H), 7.12 (2H), 6.90 (HH), 5.13 (HH), 2.81 (3H), 2.22 (1H), 1.98 (HH), 1.42 ( ÍH), 0.93 (6H).

EXAMPLE 17 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chloro-enyl) - [1,4] riazole [4, 3-b] pyridazin-3 (2H) - ona A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (300 mg, 0.84 mmol) was prepared as described. described in Example 1, 4- (trifluoromethyl) benzyl bromide (200 mg, 0.84 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10 mL), was heated at 90 ° C for 2 hours. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4, 3 b] pyridazin-3 (2H) -one (120 mg, 28%) as a yellow solid. MS M + H = 515; H NMR (CDC13) d 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).

EXAMPLE 18 Preparation of 2- (2- (4-Chlorophenoxy) ethyl) -7,8-bis (4-chlorophenyl) - [1,2,4] riazole [4,3-b] pyridazin-3 (2H) - ona The solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (30 mg, 0.084 mmol) was prepared as described in Example 1, l- (2-bromoethoxy) -4-chlorobenzene (22 mg, 0.094 mmol) and K2C03 (18 mg, 0. 013 mmol) in DMF (1 ml) was heated at 70 ° C for 4 hours.

After this time, the solution was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2- (2- (4-chlorophenoxy) ethyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one, (25.5 mg, 59%) was obtained as a yellow solid. MS M + H = 511; H NMR (CDC13) d 8.19 (ÍH), 7.34 (4H), 7.28 (2H), 7.18 (2H), 7. 28 (2H), 6.80 (2H), 4.44 (2H), 4.36 (2H).

EXAMPLE 19 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (2- (phenylamino) ethyl) [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one.

To a THF solution (2 ml) of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (50 mg, 0.14 mmol ), was prepared as described in Example 1, 2- (phenylamino) ethanol (19 mg, 0.13 mmol), triphenylphosphine (55 mg, 0.21 mmol) was added diethyl azodicarboxylate (0.09 ml, 42% by weight in toluene, 0.21 mmol). After 1 hour, the reaction mixture was concentrated. The crude material was purified by preparative HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (2- (phenylamino) ethyl) - [1,2,4] triazole [4.3- b] pyridazin-3 (2H) -one (14.4 mg, 23%) as a yellow solid. MS M + H = 476; A NMR (CDC13) d 8.20 (1H), 7.41-7.20 (11H), 7.10 (2H), 4.51 (2H), 3.91 (2H).

EXAMPLE 20. Preparation of 2- (7,8-Bis (4-chlorophenyl) -3-oxo- [1,2,4] riazole- [4, 3-b] pyridazin-2 (3H) -yl) -N - (4- (trifluoromethyl) -phenyl) acetamide.

A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (30 mg, 0.084 mmol) was prepared as described in Example 1, 2-chloro- N- (4- (trifluoromethyl) phenyl) acetamide (22 mg, 0.092 mmol), K2C03 (35 mg, 0.25 mmol) in DMF (1 ml) was heated at 80 ° C for 1 hour. After this time, the solution was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4,3-b] pyridazin- 2 (3H) -yl) -N- (4-trifluoromethyl) phenyl) acetamide (38 mg, 81%) as a yellow solid. MS M + H = 558; aH NMR (CDC13) d 8.26 (ÍH), 7.60 (2H), 7.38-7.20 (8H), 7.11 (2H), 5.07 (2H).

EXAMPLE 21 Preparation of 2- (2-Aminoethyl) -7,8-bis (4-chlorofenyl) [1, 2, 4] riazole [4, 3-b] pyridazin-3 (2H) -one. 21A. Preparation of 2- (2- (7,8-Bis (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4, 3-b] pyridazin-2 (3H) -yl) ethyl) isoindolin -l, 3-dione.

A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (290 mg, 0.81 mmol) was prepared as described in Example 1, N- (2-bromoethyl) phthalimide (215 mg, 0.84 mmol) and K2CO (337 mg, 2.44 mmol) in DMF (3 mL), was heated at 80 ° C for 2.5 hours.

After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. He crude material was purified using silica gel column chromatography using an automated system eluting with a 1: 1 mixture of ethyl acetate: hexane to give the title compound, 2- (2- (7,8-bis (4- chlorophenyl) -3-oxo- [1,2,4] triazole [4, 3-b] pyridazin-2 (3H) -yl) ethyl) isoindoline-1,3-dione as a yellow solid (290 mg, 68% ). MS M + H = 530. 21B. Preparation of 2- (2-Aminoethyl) -7,8-bis (4-chlorophenyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one. 2- (2- (7,8-Bis (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4, 3-b] pyridazin-2 (3H) -yl) ethyl) isoindolin-1 , 3-dione (180 mg, 0.34 mmol) was reacted with hirazine hydrate (0.9 mL, 18.5 mmol) in ethanol (10 mL) and stirred overnight. After this time, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2- (2-aminoethyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin -3 (2H) -one (22 mg, 13%) as a yellow foam. MS M + H = 400; H NMR (CDC13) d 8.12 (broad, 2H), 7.38-7.15 (6H), 7.05 (2H), 4.45 (2H), 3.59 (2H).

EXAMPLE 22 Preparation of (R) -7,8-Bis (4-chlorophenyl) -2- (2- (3-slorophenyl) 2-hydroxyethyl) - [1,2,4] riazole [4,3-b] pyridazine -3 (2H) -one.

To a stirred solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (20 mg, 0.06 mmol) was prepared as described in Example 1, in 0.25 ml of DMF, R- (+) - 3-chlorostyrene oxide (0.007 ml, 0.06 mmol) and 15 mg of K2C03 were added. The resulting red solution was heated to 60 ° C for 19 hours and, after cooling to room temperature, the mixture was diluted with 5 ml of ethyl acetate and 5 ml of 1N HCl. The layers were separated, and the organic layer was washed with 5 ml of saturated aqueous NaCl. The organic layer was dried over MgSO, filtered and evaporated to give a yellow oil. The material was purified using reverse phase HPLC to give the title compound, (R) -7,8-bis (4-chlorophenyl) -2- (2- (3-chlorophenyl) -2-hydroxyethyl) - [1, 2,4] triazole [4,3-b] pyridazin-3 (2H) -one, (15 mg, 52% yield) as a yellow solid. Analysis Calculated EMAR for C25H17Cl3N4? 2, 510.04, [M + H] + = 511.0509 observed. \ H NMR (400 MHz, CDCI3) d 8.01 (s, ÍH), 7.16 (s, 1H), 7.15-7.05 (m, 9H), 6.92 (d, 2H, J = 8.6 Hz), 5.05-4.95 (m, 1H) , 4.13-4.08 (, 2H), 1.55 (br s, 1H). EXAMPLE 23 Preparation of 7,8-Bis (4-chlorophenyl) -2- (2-hydroxy-3-phenylpropyl) - [1,2,4) riazole [4, 3-b] pyridazin-3 (2H) -one .

To a stirred solution of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (500 mg, 1.4 mmol), was prepared as described in Example 1, in 7 ml of DMF was added 2,3-epoxypropylbenzene (0.18 ml, 1.4 mmol) and 0.39 g of K2CO3. The resulting red solution was heated to 85 ° C for 27 hours and, after cooling to room temperature, the mixture was diluted with 200 ml of ethyl acetate and 200 ml of 1N HCl. The layers were extracted, and the organic layer was washed with 200 ml of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to a yellow oil. The material was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate / hexanes to give 484 mg of 7,8-bis (4-chlorophenyl) -2- (2-hydroxy-3-) phenylpropyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one racemic as a yellow solid containing 15% starting material 7,8-bis (4-chlorophenyl) - [1, 2,] triazol [4, 3-b] pyridazin-3 (2H) -one. The separation of enantiomers in 200 mg of material was performed using Chiracel OD column 5 cm x 50 cm 20 micron, flow ratio 50 ml / min isocratic 65% heptane / 17.5% ethanol / 17.5% methanol, detection of monochrome at 220 nm. Fraction A was collected 49 minutes after injection to give 47 mg of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one enantiomer A as a yellow solid; Fraction B was collected at 55 minutes after injection to give 45 mg of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one enantiomer B as a yellow solid. Enantiomer A of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one: Analysis Calculated for EMAR for C26H2oCl2N402, 490.0963, [M + H ] 491.1057 observed; XH NMR (400 MHz, CDC13) d 8.18 (s, ÍH), 7.33-7.09 (m, 13H), 5.05-4.95 (m, ÍH), 4.33-4.30 (m, ÍH), 4.20 (dd, 1H, J = 3.1, 14.5 Hz), 4.06 (dd, 1H, J = 7.9, 14.1 Hz) 2.88 (m, 2H). Enantiomer B of 7,8-bis (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one: Calculated Analysis HRMS for C25H2oCl2N402, 490.0963, [M + H] 491.1042 observed; H NMR (400 MHz, CDC13) d 8.18 (s, ÍH), 7.33-7.09 (m, 13H), . 05-4.95 (m, ÍH), 4.33-4.30 (m, ÍH), 4.20 (dd, ÍH, J = 3.1, 14.5 Hz), 4.06 (dd, ÍH, J = 7.9, 14.1 Hz) 2.88 (m, 2H ).

EXAMPLE 24 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (1-phenyl-lH-tetrazol-5-yl) - [1,2,4] riazole [4, 3-b] pyridazin-3 ( 2H) -one.

To a stirred solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (50 mg, 0.14 mmol), was prepared as described in Example 1, in 0.7 ml of DMF was added N-phenyl-5-chlorotetrazole (25 mg, 0.14 mmol) and 19 mg of K2CÜ3. The resulting red solution was heated at 80 ° C for 4 days and, after cooling to room temperature, the mixture was diluted with 50 ml of ethyl acetate and 50 ml of 1N HCl. The layers were extracted, and the organic layer was washed with 50 ml of saturated aqueous NaCl. The organic layer was dried over MgSO, filtered and evaporated to an orange solid. The material was purified by silica gel column chromatography followed by reverse phase HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (1-phenyl-1H-tetrazole-5 -yl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one, (7 mg, 10%) produced as a yellow solid. LCMS Calculated Analysis for C2Ha4C? 2N80, 500.07, [M + H] 501 observed; 1 H NMR (400 MHz, CD 3 CN) d 8.30 (s, 1 H), 7.69-7.55 (m, 5 H), 7. 39 (dt, 2H, J = 2.1, 6.6 Hz), 7.28 (dt, 2H, J = 1.9, 8.6 Hz), 7.23 (dt, 2H, J = 2.2, 8.6 Hz), 7.06 (dt, 2H, J = 2.1, 8.7 Hz). EXAMPLE 25 Preparation of 2- (2-Hydroxybenzyl) -7,8-bis (4-chlorophenyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one. 25A. Preparation of 2- ((7,8-Bis (4-chlorophenyl) -3-oxo- [1, 2,4] riazole [4, 3-b] pyridazin-2 (3H) -yl) methyl) phenyl acetate .

To a solution of 7,8-bis (4-chlorophenyl) -l, 2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, (800 mg, 2.24 mmol), was prepared as described in Example 1, in 30 ml of DMF, 2- (chloromethyl) phenyl acetate (497 mg, 2.69 mmol) was added, followed by K2CO3 (619 mg, 4.48 mmol). The reaction was heated at 60 ° C overnight. After this time, the reaction was allowed to cool to room temperature environment and then diluted with 250 ml EtOAc. The resulting solution was washed with saturated aqueous NaCl (100 ml X 3). The organic layer was dried over MgSO4, filtered, evaporated under reduced pressure to provide the title compound, 2- ((7,8-bis (4-chlorophenyl) -3-oxo- [1, 2, 4] acetate. triazole [4, 3-b] pyridazin-2 (3H) -yl) methyl) phenyl, (1.13 gm) as a yellow solid. 25B. Preparation of 2- (2-Hydroxybenzyl) -7,8-bis (4-chlorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one 2- ((7,8-Bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4, 3-b] pyridazin-2 (3H) -yl) methyl) phenyl acetate was prepared , as described in 25A, (1.13 g), dissolved in 25 ml of CH3OH. A solution of Na0CH3 (121 mg, 2.24 mmol) in a small amount of CH3OH (2 mL) was added to the reaction, and then, the reaction was stirred overnight. After this time, 0.3 ml of acetic acid was added to the reaction. The reaction was stirred for an additional 10 minutes, and then the resulting solution was concentrated under reduced pressure. The crude residue was purified using silica gel column chromatography using an automated system, eluting with a gradient of 0% to 60% EtOAc / hexanes for 30 minutes followed by 60% EtOAc / hexanes for an additional 15 minutes. The title compound, 2- (2-hydroxybenzyl) -7,8-bis (4-chlorophenyl) - [1,4] triazole [4, 3-b] pyridazin-3 (2H) -one (818 mg , 79% yield) was obtained as a yellow solid. MS [M + H] + = 463; k NMR (CDC13, 400 MHz) d 8.54 (s, ÍH), 8.14 (s, 1H), 7.32-7.17 (m, 8H), 7.04-7.00 (, 2H), 6.94 (dd, ÍH), 6.81 (td) , 1H), 5.13 (s, 2H). EXAMPLE 26 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (2-hydroxy-2-methylpropyl) - [1,2,4] riazole [4,3-b] pyridazin-3 (2H) -one .

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (20 mg, 0.056 mmol) was prepared as described in Example 1, isobutylene oxide (4.0 mg, 0.056 mmol) was added in 0.6 ml of DMF, followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated to 85 ° C. After stirring overnight, the reaction was allowed to cool to room temperature. The reaction mixture was filtered (to remove excess K2C03). The solution collected was concentrated under pressure reduced. The crude product was purified by reverse phase HPLC to give the title compound, 7,8-bis (4-chlorophenyl) -2- (2-hydroxy-2-methylpropyl) - [1,2,4] triazole [4 , 3-b] pyridazin-3 (2H) -one, (18.4 mg, 77% yield) as a yellow oil. MS [M + H] +: found 429; A NMR (CDC13, 400 MHz) d 8.28 (s, ÍH), 7.39-7.27 (m, 6H), 7.16-7.12 (m, 2H), 4.16 (s, 2H), 4.00 (s, ÍH), 1.34 ( s, 6H). EXAMPLE 27 Preparation of (R) -7,8-Bis (4-chlorophenyl) -2- (2-hydroxyhexyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one .

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (20 mg, 0.056 mmol) was prepared as described in Example 1, in 0.6 ml of DMF was added (R) - (+) -1,2-epoxyhexane (5.6 mg, 0.056 mmol), followed by K2C03 (15.5 mg, 0.112 mmol). The mixture was heated to 85 ° C. After stirring overnight, the reaction was allowed to cool to room temperature. The reaction mixture was filtered to remove excess K2C03. The collected solution was concentrated under reduced pressure. The crude product was purified using column chromatography of silica gel using an automated system, eluting with a gradient of (0% to 60% EtOAc / hexanes for 30 minutes followed by 60% EtOAc / hexanes to 100% EtOAc for 10 minutes.The title compound, (R) -7 , 8-Bis (4-chlorophenyl) -2- (2-hydroxyhexyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one (8.3 mg, 32% yield) A yellow oil was obtained.MS [M + H] +: found 457; A NMR (CDC13, 400 MHz) 88.12 (s, 1H), 7.28-7.19 (, 6H), 7.06-7.02 (m, 2H), 4.13-4.08 (m, ÍH), 4.00-3.90 (m, 2H), 1.49-1.24 (m, 6H), 0.83 (t, 3H) EXAMPLE 28 Preparation of 3,4-Bis (4-chlorophenyl) -6 - (2-hydroxy-3-isobutoxypropyl) imidazo [1, 5-b] pyridazin-7 (6H) -one.

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (20 mg, 0.056 mmol) was prepared as described in Example 1, in 0.6 ml of DMF was added isobutyl glycidyl ether (7.3 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated to 85 ° C. After stirring overnight, the reaction was allowed to cool to room temperature. The 1 The reaction mixture was filtered to remove excess K2CO3.

The collected solution was concentrated under reduced pressure. The crude product was purified using reverse phase HPLC to give the title compound, 3,4-bis (4-chlorophenyl) -6- (2-hydroxy-3-isobutoxypropyl) imidazo [1,5-b] pyridazine-7 (6H) -one (17.8 mg, 65% yield) as a yellow solid, in 65% yield. MS [M + H] +: found 487; 1 H NMR (CDC13, 400 MHz) d 8.08 (s, ÍH), 7.23-7.15 (m, 6H), 7.00-6.96 (, 2H), 4. 20-4.00 (m, 3H), 3.41 (d, 2H), 3.11 (d, 2H), 1.80-1.65 (m, 1H), 0.76 (d, 6H). EXAMPLE 29 Preparation of 7, 8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxypropyl) - [1,2,4] riazole [4,3-b] pyridazin-3 (2H) -one .

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (300 mg, 0.84 mmol) was prepared as described in Example 1, in 8 ml of DMF was added ethyl glycidyl ether (86 mg, 0.84 mmol), followed by K2CO3 (232 mg, 1.68 mmol). The mixture was heated to 85 ° C. After stirring overnight, the reaction was allowed to cool to room temperature. The mixture of The reaction was diluted with EtOAc (200 ml). The resulting solution was washed with saturated aqueous NaCl (3 x 40 ml). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified using silica gel column chromatography using an automated system, eluting with a gradient of 0% to 60% EtOAc / hexanes for 30 minutes followed by 100% EtOAc for 40 minutes. The title compound, 7, 8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxypropyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) - ona, (0.3 gm, 78% yield) as a yellow solid. MS [M + H] +: found 459; 1 H NMR (CDC 13, 400 MHz) d 8.20 (s, ÍH), 7.34-7.25 (m, 6H), 7.09 (d, 2H), 4.29-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.57-3.49 (, 4H), 1.17 (t, 3H). EXAMPLE 30 Preparation of 7, 8-bis (4-chlorophenyl) -2- (3-ethoxy-2-oxopropyl) - [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one .

The Dess-Martin reagent (56 mg, 0.131 mmol) was added to a solution of 7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxypropyl) - [1, 2, 4] triazole [ 4, 3-b] pyridazin-3 (2H) -one, prepared as described in Example 29, (50 mg, 0.109 mmol) in 1 ml of CH2C12. The reaction was stirred for 2 hours, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (3-ethoxy-2-oxopropyl) - [1, 2, 4] triazole [4 , 3-b] pyridazin-3 (2H) -one, (47 mg, 95% yield) as a yellow solid. MS [M + H] +: found 457; EXAMPLE 31 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxy-2-methylpropyl) - [1,2,4] riazole [4,3-b] pyridazin-3 ( 2H) -one.

MeMgBr (0.03 ml, 0.08 mmol, 3.0 M in Et20) was added to a solution of 7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-oxopropyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one, was prepared as described in Example 30, (23 mg, 0.05 mmol) at -78 ° C. The reaction was stirred for 30 minutes at -78 ° C. After this time, saturated aqueous NH 4 Cl (2 ml) was added to the reaction and the resulting solution was warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAC (3 x 10 ml). The organic layers combined were dried (MgSO4), filtered, and concentrated. The crude product was purified by reverse phase HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxy-2-methylpropyl) - [1,2,4] ] triazole [4, 3-b] pyridazin-3 (2H) -one (4 mg, 16% yield) as a yellow oil. MS [M + H] +: found 473; A NMR (CDC13, 400 MHz) d 8.13 (s, ÍH), 7.29-7.18 (m, 6H), 7.06-7.02 (m, 2H), 4.25 (d, ÍH), 3.98 (d, 1H), 3, 43 (q, 2H), 3.35 (d, 1H), 3.25 (d, 1H), 1.18 (s, 3H), 1.07 (t, 3H). EXAMPLE 32 Preparation of 7, 8-Bis (4-chlorophenyl) -2- (3-hydroxy-3-methylbutan-2-yl) - [1, 2, 4] riazole [4,3-b] pyridazin-3 ( 2H) -one.

To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (300 mg, 0.84 mmol) was prepared as described in Example 1, in 0.6 ml of DMF was added 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol), followed by K2C03 (15.5 mg, 0.112 mmol). The mixture was heated at 85 ° C for 16 hours. After this time, an additional 10 mg of K2C03 and 2,3-epoxy-2-methylbutane were added. (4.8 mg, 0.056 mmol). The reaction was allowed to continue stirring at 85 ° C for an additional 48 hours. The reaction cooled to room temperature and filtered. The collected solution was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound, 7, 8-bis (4-chlorophenyl) -2- (3-hydroxy-3-methylbutan-2-yl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one, (5 mg, 20% yield) as a yellow oil. MS [M + H] +: found 443; U RMH "(CDC13, 400 MHz) d 8.25 (s, 1H), 7.39-7.27 (m, 6H), 7.14 (dd, 2H), 4.55 (q, 1H), 1.52 (d, 3H), 1.34 (s) , 1H), 1.23 (s, ÍH) EXAMPLE 33 Preparation of 4- ((7,8-bis- (4-chlorofenyl) -3-oxo- [1,2,4] riazole [4,3-b] ] pyridazin-2 (3H) -yl) ethyl) benzonitrile A solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one (192 mg, 0.54 mmol) was prepared as described in Example 1, K2C03 (90 mg), and a-bromo-p-toluonitrile (127 mg, 0.645 mmol) in DMF (2 ml) was heated at 75 ° C for 1 hour. After this time, the solution was concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to provide the title compound, 4- ((7,8-bis- (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4, 3 -b] pyridazin-2 (3H) - il) methyl) benzonitrile (80 mg) as a yellow solid. EM M + H = 472; A NMR (CDC13): d 8.17 (s, 1H), 7.63 (d, J-8.4 Hz, 2H), 7. 49 (d, J-8.3 Hz, 2H), 7.33 (, 2H), Y- 25 (m, 2H), 7.24 (m, 2H), 7.09 (m, 2H), 5.25 (2H). The following examples were prepared in accordance with the procedures given by the preparation of examples 1-33; EXAMPLE 244 Preparation of 7- (4-Chlorophenyl) -8- (pyridin-4-yl) [1,2,4] riazole [4, 3-b] pyridazin-3 (2H) -one 244A. Preparation of 2-benzyl-4,5-dichloropyridazin-3 (2H) -one To a solution of dichloropyridazinone (50.0 g, 303.0 mmol) in DMF (200 ml) was added K2CO3 (50.3 g, 364.0 mmol) at room temperature under vigorous stirring. Benzyl bromide (40.0 ml, 336.0 mmol) was added in rapid drops by means of a syringe. The resulting suspension was stirred at 50 ° C for 1 hour until all the pyridazinone was consumed as judged by HPLC. The reaction mixture was then poured into water (400 ml). The resulting suspension was stirred for 15 minutes at room temperature, and then filtered. The collected solid was completely rinsed with water until no color appeared in the filtrate. The solid was dried in a vacuum oven at 50 ° C overnight to give the title compound, 2-benzyl-4,5-dichloropyridazin-3 (2H) -one, (73.1 g, 95%) as a yellow solid. pale. CLAR: 3.17 min; MS, M + H = 255. 244B. Preparation of 2-Benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one.

To a stirred solution of 2-benzyl-4,5-dichloropyridazin-3 (2H) -one (73.1 g, 286.6 mmol) in 1,4-dioxane (700 ml) was added 25% by weight of NaOMe solution in MeOH (72.0 ml, 315 mmol) at room temperature under argon for 15 minutes. The resulting dark reaction mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated and water (500 ml) was added to the resulting residue. Mix aqueous was extracted with methylene chloride (4 x 120 ml). The combined organic layers were washed with water (2 x 300 ml) and then saturated aqueous NaCl (2 x 150 ml). The organic layer was dried over MgSO4, filtered and concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography eluting with 30% EtOAc / hexanes to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one (56.0 g, 78 %) as a pale yellow oil. CLAR: 3.19 min; MS, M + H = 251. aH NMR. { DMSO-d6, 500 MHz): d 8.05 (H, s), 7.26-7.34 (5H, m), 5.24 (2H, s), 4.15 (3H, s). 244C. Preparation of 2-Benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one.

To a stirred solution of 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one (20.0 g, 79.8 mmol) in toluene (500 mL) was added Pd (PPh3) 4 (5.5 g, 4.76 mmol) under an argon atmosphere. 4-Chlorophenylboronic acid (18.7 g, 119.6 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (33.8 g, 318.9 mmol) was pre-dissolved in water (90 ml) was added to the suspension. A stream of argon was bubbled through this suspension for 10 minutes. After this time, the flask was placed in a pre-heated oil bath at 120 ° C. The reaction was refluxed for 3 h. After this time, the reaction will cooled to room temperature. The reaction mixture was then poured into water (200 mL). The layers were separated and the aqueous mixture was extracted with EtOAc (100 L X 3). The combined organic layers were washed with water (2 x 200 mL) followed by saturated aqueous NaCl (2 x 100 mL). The organic layer was then concentrated under reduced pressure to obtain crude product. This crude product was purified by silica gel column chromatography eluting with 8% EtOAc / hexanes to give the title compound, 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one, (21.5 g, 82%) as a white solid. CLAR: 3.79 min; M + H = 327. NMR (CDC13, 500 MHz): d 7.76 (H, s), 7.48 (2H, d, J = 10.0 Hz), 7.40-7.45 (4H, m), 7.28-7.36 (3H, m), 5.35 (2H, s), 4.10 (3H, s). 244D. Preparation of 2-Benzyl-4-chloro-5- (4-chlorophenyl) pyridazin-3 (2H) -one A mixture of 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one (13.8 g, 42.23 mmol) and POC13 (20.0 mL) was stirred at 75 ° C for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was cooled in an ice bath and water (200 mL) was added. The undissolved material was filtered and washed with water (3 x 150 mL). MeOH (100 mL) was added to the solid thus obtained. The resulting mixture was sonicated for 10 minutes, and then filtered. The collected solid was washed with MeOH (2 x 50 mL). The solid was then dried in a vacuum oven at 50 ° C to give the title compound, 2-benzyl-4-chloro-5- (4-chlorophenyl) pyridazin-3 (2H) -one, (9.2 g, 66 %) as a bright brown solid. CLAR: 3.75 min; M + H = 331. 1 H NMR (CDC13, 500 MHz): d 7.73 (HH, s), 7.50 (2H, d, J = 10.0 Hz), 7.47 (2H, d, J = 10.0 Hz), 7.42 (2H , d, J = 10.0 Hz), 7.30-7.38 (3H, m), 5.39 (2H, s). 244E Preparation of 2-Benzyl-5- (4-chlorophenyl) -4- (pyridxn-4-yl) pyridazxn-3 (2H) -one To a stirred solution of 2-benzyl-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (7.0 g, 21.14 mmol) in toluene (140 mL) in a flask from round bottom, Pd (PPh3) 4 (1.5 g, 1.3 mmol) was added under a stream of argon. 4- (4, 4, 5, 5-Tetramethyl-l, 3, 2-dixoborolan-2-yl) pyridine (5.63 g, 27.5 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (9.2 g, 86.8 mmol) pre-dissolved in water (25 mL) was added to the suspension. A stream of argon was bubbled through the reaction mixture for 10 min. The flask was placed then in a bath of pre-heated oil at 120 ° C. The reaction was stirred at reflux for 48 h. After this time, the reaction mixture was cooled to room temperature and then poured into water (100 mL). The layers separated. The aqueous layer was extracted with EtOAc (3 x 75 L). The combined organic layers were washed with water (2 x 100 L) followed by saturated aqueous NaCl (2 x 50 mL). The organic layer was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography eluting with 40% EtOAc / hexanes to give the title compound, 2-benzyl-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin- 3 (2H) -one, (7.0 g, 89%) as a white solid. CLAR: 2.89 min; M + H = 374. A NMR (CDCl3, 500 MHz): d 8.50 (2H, d, J = 5.0 Hz), 7.86 (1H, s), 7.52 (2H, d, J = 10.0 Hz), 7.28-7.36 (3H,), 7.24 (2H, d, J = 10.0 Hz), 7.09 (2H, d, J = 5.0 Hz), 7.00 (2H, J = 10.0 Hz), 5.38 (2H, s). 244F. Preparation of 5- (4-chlorophexyl) -4- (pxrxdxn-4-xl) pxrxdazin-3 (2H) -one To a solution of 2-benzyl-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (7.0 g, 18.73 mmol) in toluene (50 mL) in a flask of. round bottom was added A1C13 (7.5 g, 56.25 mmol) under a stream of argon. The flask was placed in a preheated oil bath at 80 ° C. After 2 hours, the reaction mixture was cooled to room temperature and then poured into ground ice (200 g). The formed precipitate was collected by filtration, washed with water (2 x 50 mL) followed by ether (50 L) and dried in a vacuum oven at 40 ° C to give the title compound, 5- (4-chlorophenyl) ) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (5.1 g, 96%) as a white solid. CLAR: 1.37 min; MS, M + H = 284. 2446. Preparation of 3-Chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) iridazine A mixture of 5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (5.1 g, 18.0 mmol) and POC1 (20 mL) was stirred at 80 ° C for 2 h . The reaction mixture was cooled to room temperature and P0C13 was removed by rotary evaporator to obtain a gum. This gum was cooled in an ice bath and water (50 mL) was added. The pH of this mixture was adjusted to 6 with aqueous NaHCO 3. The resulting mixture was extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (2 x 50 mL) followed by saturated aqueous NaCl (2 x 25 mL). The organic layer was dried over MgSO4 and filtered through a pad of silica gel (~ 20 g). After evaporation of the solvents under reduced pressure, the title compound, 3-chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazine, (5.1 g, 94%) was obtained as a solid white. CLAR: 2.01 min; MS, M + H = 302. A NMR (CDC13, 500 MHz): d 9.08 (H, s), 8.56 (2 H, d, J = 5.0 Hz), 7.21 (2 H, d, J = 10.0 Hz), 7.09 (2H, d, J = 5.0 Hz), 7.01 (2H, J = 10.0 Hz). 244H. Preparation of 1- (5- (4-chlorophenyl) -4- (pyridxn-4-yl) pyridazxn-3-xl) hydrazine 3-Chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazine (5.1 g, 16.9 mmol) was dissolved in pyridine (20 mL) and hydrazine monohydrate (17.0 mL, 350.5 mmol) was added. The reaction mixture was stirred at reflux for 40 min. After this time, the reaction mixture was cooled to room temperature and then concentrated to half the original volume under reduced pressure. The resulting mixture was diluted with water (100 mL). The yellow solid was collected by filtration and rinsed thoroughly with water. The solid was dried in a vacuum oven at 40 ° C to give the compound of the title, 1- (5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine, (4.4 g, 88%) as a yellow powder. CLAR: 1.01 min; MS, M + H = 298. 2441. t Preparation of 7- (4-Chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4,3-b] pyridazin-3 ( 2H) -one To a solution in THF (100 mL) of carbonyldiimidazole (CDI) (7.25 g, 44.71 mmol) was added 1- (5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine. (3.8 g, 12.76 mmol) in portions at room temperature under an argon atmosphere. The reaction mixture was heated to reflux for 30 min. After this time, the reaction mixture was cooled to room temperature, and subsequently concentrated under reduced pressure to obtain a gum to which water (100 mL) was added. The resulting solid was collected by filtration, washed with water (2 x 50 mL) followed by 1: 1 (w / w) hexanes / ether (2 x 50 mL) to give the title compound, 7- (4- chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (3.75 g, 91%) as a yellow solid. CLAR: 1.67 min; EM, M + H = 324; A NMR (DMS0-d6) d 12.90 (HH, s), 8.59 (2H, d, J = 10.0 Hz), 8.41 (HH, s), 7.44 (2H, d, J = 10.0 Hz), 7.32 (2H, d, J = 5.0 Hz), 7.28 (2H, d, J = 5.O Hz). EXAMPLE 245 Preparation of 7- (4-Chlorophenyl) -2- ((6-chloropyridin-3-yl) methyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4.3- b] pyridazin-3 (2H) -one To a solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (150 mg, 0.46 mmol), was prepared as described in Example 244, in DMF (3 mL), K2C03 (80 mg, 0.58 mmol) and 2-chloro-5- (chloromethyl) pyridine (90 mg, 0.556 mmol) was added. The reaction mixture was stirred at 70 ° C for 15 min. After this time, the solution was cooled to room temperature and diluted with water (20 mL). The resulting solid was collected by filtration and the crude product was purified by reverse phase HPLC to give the title compound, 7- (4-chlorophenyl) -2- ((6-chloropyridin-3-yl) methyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (110 mg, 52%), as a yellow solid. CLAR: 2.61 min; MS, M + H = 449; A NMR (CDC13) d 8.62 (2 H, d, J = 5.0 Hz), 8.43 (1 H, d, J = 5.0 Hz), 8.19 (H, s), 7.33 (1 H, d, J = 5.0 Hz), 7.29 -7.31 (3H, m), 7.20 (2H, d, J = 5.0 Hz), 7.08 (2H, d, J = 10.0 Hz), 5.17 (2H, s) EXAMPLE 246 Preparation of 7- (4-Chlorophenyl) -2- ((6- (dimethylamino) pyridin-3-yl) methyl) -8- (pyridin-4-yl) - [1,2,4] rxazolo [4,3-b] pyridazin-3 (2H) -one A mixture of 7- (4-chlorophenyl) -2- ((6- (chloro) pyridin-3-yl) methyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (30 mg, 0.0667 mmol), was prepared as described in Example 245, and N, N-dimethyl amine in water (1.0 mL) was heated to reflux. After 8 h, the solution was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound, 7- (4-chlorophenyl) -2- ((6- (dimethylamino) pyridin-3-yl) methyl) -8- (pyridin-4-yl) ) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (17.5 mg, 57%) as a yellow solid. CLAR: 1.41 min; M + H = 458; A NMR (CDC13) d 8.63 (2H, d, J = 5.0 hz), 8.23 (H, d, J = 5.0 Hz), 8.17 (1H, s), 7.58 (1H, d, J = 10.0 Hz), 7.33 (2H, d, J = 10.0 Hz), 7.23 (2H, d, J = 5.0 Hz), 7.09 (2H, d, J = 10.0 Hz), 6.47 (IH, d, J = 10.0 Hz), 5.08 (2H , s), 3.07 (6H, s).

EXAMPLE 247 Preparation of 7- (4-Chlorophenyl) -8- (pyridin-4-yl) -2- ((6- (trxfluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4 , 3- b] pyridazxn-3 (2H) -one A solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (1.1 g, 3.4 mmol ), was prepared as described in Example 244, K2C03 (940 mg, 6.8 mmol), and 5-chloromethyl-2-trifluoromethylpyridine (800 mg, 4.1 mmol) in DMF (8.3 mL) was heated at 65 ° C for 40 minutes. min. After this time, the solution was cooled to room temperature. The reaction mixture was partitioned between water and EtOAc. The separated organic layer was washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexanes / EtOAc to give the title compound, 7- (4-chlorophenyl) -8- (pyridin-4-yl) -2- ((6- ( trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, (1.25 g, 76%) as a yellow solid.

CLAR: 2.84 min; MS, M + H = 483; A NMR (CDC13) d 8.80 (d, J = 1. Hz, 1H), 8.65 (Abq, J = 1.6, 4. 4 Hz, 2H), 8.23 (s, ÍH), 7.96. (m, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.34 (m, 2H), 7.23 (, 2H), 7. 10 (m, 2H), 5.31 (2H). EXAMPLE 248 Preparation of 7- (4-chlorophenyl) -8- (pyridxn-4-xl) -2- ((5- (rifluoromethyl) pyridin-2-yl) ethyl) - [1,2,4] rxazolo [4 , 3-b] pyridazin-3 (2H) -one A solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (32.4 mg, 0.1 mmol ), was prepared as described in Example 244, K2C03 (56 mg, 0.4 mmol), and 2-chloromethyl-5-trifluoromethylpyridine hydrochloride (37 mg, 0.4 mmol) in DMF (0.4 L) was heated at 65 ° C for 2 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by HPLC reverse phase to give the title compound, 7- (4-chlorophenyl) -8- (pyridin-4-yl) -2- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1, 2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (27 mg) as a yellow solid. CLAR TA: 2.78 min; M + H = 483; A NMR (CDC13): d 8.82 (s, 1H), 8.62 (m, 2H), 8.24 (s, 1H), 7.91 (, 1H), 7.38-7.10 (, 7H), 5.45 (2H).

EXAMPLE 249 Preparation of 4- ((7- (4-Chlorophenyl) -3-oxo-8- (pyridxn-4-yl) - [1,2,4] riazolo [4, 3-b] pyridazin-2 (3H ) -yl) methyl) benzonitrile A solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (96 mg, 0.3 mmol ), prepared as described in Example 244, K2CO3 (82 mg, 0.59 mmol), and cx-bromo-p-toluonitrile (70 mg, 0.356 mmol) in DMF (1 mL), was heated at 65 ° C for 2.5 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by reverse phase HPLC to give the title compound, 4 - ((7- (4-chlorophenyl) -3-oxo-8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-2 (3H) -yl) methyl) benzonitrile (27 mg) as a yellow solid. CLAR TA: 2.45 min; M + H = 439; A NMR (CDC13): d 8.63 (d, J = 6.04 Hz, 2H), 8.21 (s, ÍH), 7.63 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.33 (m, 2H), 7.21 (m, 2H), 7.08 (m, 2H), 5.25 (2H).

EXAMPLE 250 Preparation of 2- (4- (Isoxazole-5-xl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4, 3 b] pirxdazxn-3 (2H) -one 250A. Preparation of 5- (4-bromomethyl) phenyl) isoxazole To a solution of 5- (4-methylphenyl) isoxazole (4.0 g, . 13 mmol) in carbon tetrachloride (125 mL), N-bromosuccinimide (4.47 g, 25.13 mmol) and benzoyl peroxide were added. (0.12 g, 0.50 mmol). The resulting mixture was refluxed for 1 h. After this time, the reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with hexanes / EtOAc to give the title compound, 5- (4- (bromomethyl) phenyl) isoxazole, 4.2 g as an off-white solid. A NMR (CDC13): d 8.30 (d, J = 2.2 Hz, ÍH), 7.78 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 6.54 (d, J = 1.7 Hz, ÍH), 4.51 (s, 2H). 250b. Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4,3-b] pyridazin-3 (2H) -one A solution of 7- (4-chlorofenyl) -8- (pyridin-4-yl) - [1,2, 4] triazolo [4, 3-b] pyridine zin-3 (2H) -one ( 3.0 g, 9.27 mmol), prepared as described in Example 244, K2C03 (2.56 g, 18.53 mmol) and 5- (4- (bromomethyl) phenyl) isoxazole (2.65 g, 11.12 mmol), in DMF (23 mL) . The resulting mixture was heated to 60 ° C. After 2 h, the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 1:10 hexanes / EtOAc to give the title compound, 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorofenyl) - 8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one, as a solid bright yellow. CLAR TA: 2.64 min; MS, M + H = 481; A NMR (CDC13): d 8.62-8.64 (m, 2H), 8.29 (d, JYL.8 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.51 (d , J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.22 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.51 (d, JYL.6 Hz, 1H ), 5.25 (s, 2H). EXAMPLE 251 Preparation of 2- (4- (Isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4.3- b] pyridazin-3 (2H) -one 251A. Preparation of 3- (4-bromomethyl) phenyl) isoxazole To a solution of 3- (4-methylphenyl) isoxazole (prepared using literature methods) (1.95 g, 12.25 mtnol) in carbon tetrachloride (60 mL), N-bromosuccinimide (2.18 g, 12.25 mmol) was added and Benzoyl peroxide (0.059 g, 0.245 mmol) and the mixture was refluxed for 1 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with hexanes / EtOAc to give the title compound, 3- (4- (bromomethyl) phenyl) isoxazolo, (0.6 g) as a white solid. A NMR (CDC13): d 8.48 (d, J = 1.6 Hz, ÍH), 7.83 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 6.67 (d, J = 1.6 Hz, 1H), 4.53 (s, 2H). 251B. Preparation of 2- (4- (Isoxazol-3-yl) encyl) -7- (4-chlorophenol) -8- (pxridin-4-yl) - [1,2,4] riazolo [4,3-b] pyridazin-3 (2H) -one To a solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1, 2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (0.27 g, 0.834 mmol), prepared as described in Example 244, in DMF (4 mL), potassium carbonate (0.23 g, 1.67 g) was added and 3- (4- (bromomethyl) phenyl) isoxazole (0.248 g, 1.04 mmol). The resulting mixture was heated to 65 ° C. After 2 h, the reaction mixture was then cooled to room temperature and diluted with EtOAc (200 mL). The resulting solution was then washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with hexanes / EtOAc to give the title compound, 2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3 -b] pyridazin-3 (2H) -one, as a bright yellow solid. CLAR TA: 2.60 min; A NMR (CDC13): d 8.64 (d, J = 1. 1 Hz, 1H), 8.63 (d, J = 1.7-Hz, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.20 ( s, ÍH), 7.80 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 6.65 (d, J = 2 .2 Hz, 1H), 5.26 (s, 2H).

EXAMPLES 252 TO 272 The following examples were prepared in accordance with the above methods and procedures: EXAMPLE 273 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7-chloro-8- (4-chlorophenyl) - [1,2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one 273A Preparation of 2-Benzyl-5-chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one To a mixture of 2-benzyl-4,5-dichloropyridazine- 3 (2H) -one (30.6 g, 120 mmol), prepared as described in Example 244A, 4-chlorophenyl boronic acid (20.6 g, 132 mmol) and tetrakis (trif enilf osf ina) palladium (5 g, 4.3 mmol ) in toluene (300 mL) under an argon atmosphere, an aqueous Na 2 CO 3 solution (2M, 66 mL, 132 mmol) was added. The reaction mixture was stirred at 100 ° C under argon for 16 h. The reaction was then allowed to cool to room temperature and subsequently poured into water (200 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The thick syrup obtained was dissolved in MeOH (100 mL) and the resulting solution was kept at 0 ° C until the white solid precipitated. The solid was collected by filtration, washed with hexanes, and then triturated with EtOAc-hexanes to give the title compound, 2-benzyl-5-chloro-4- (4-chlorofenyl) pyridazin-3 (2H) - ona (12 g, 30%) as a white powder. LC / MS (method A, general procedure): RT = 3.81 min, (M + H) + = 331. 273B. Preparation of 5-Chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one To a solution of 2-benzyl-5-chloro-4- (4- chlorophenyl) pyridazin-3 (2H) -one (10.2 gm, 30.8 mmol) in toluene (154 mL) was added aluminum chloride (10.3 g, 77 mmol). The mixture was stirred at 50 A for 1 h. After this time, the solution was cooled to room temperature, and the reaction mixture was poured into water (200 mL). The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 5-chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one as an off-white solid (6.8 g, 92%). LC / MS (method A): RT = 2.91 min, (M + H) + = 241; 273C. Preparation of 3,5-Dichloro-4- (4-chlorophenyl) pyrdazine A suspension. of 5-chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one, (6.8 g, 28.2 mmol) in P0C13 (14 mL) was heated at 100 ° C for lh. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between EtOAc and water.

The aqueous layer was extracted with EtOAc (2 x 100 L). The combined organic layers were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried (Na 2 SO), filtered and concentrated to give the title compound, 3,5-dichloro-4- (4-chlorophenyl) pyridazine as an off-white solid (6.9 g, 96%). LC / MS (method A): RT = 3.20 min, (M + H) + = 259; 273D. Preparation of 1- (5-Chloro-4- (4-chlorophenyl) pyridazin-3-yl) hydrazine To a solution of 3,5-dichloro-4- (4-chlorophenyl) pyridazine (2.56 g, 10 mmol) in dioxane (36 mL) at room temperature was added hydrazine (3.2 mL, 100 mL).

After the addition, the reaction was heated to 70 ° C for 2 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. To the obtained residue was added 2-propanol (80 mL) and the resulting white solid was removed by filtration. The collected liquid was concentrated under reduced pressure to give the title compound 1- (5-chloro-4- (4-chlorophenyl) pyridazin-3-yl) hydrazine as a whitish solid (560 mg, 22%) which contained % of the derivative (1- (3-chloro-4- (4-chlorophenyl) iridazin-5-yl) hydrazine). The mixture was used directly in the next step, 273E. LC / MS (method A): RT = 1.89 min, (M + H) + = 255. 273E. Preparation of 7-Chloro-8- (4-chlorophenyl) [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one To a solution of 1,1 '-carbonyldiimidazole (1.78 g, 11 mmol) in THF (10 mL) at room temperature, a suspension of 1- (5-chloro-4- (4-chlorophenyl) pyridazin-3 was added. il) hydrazine (560 mg, 2.19 mmol) in THF (10 mL). After the addition, the reaction became a clear solution and was stirred at room temperature overnight for 1 h. The reaction mixture was then poured into water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na 2 SO), filtered and concentrated. To the obtained residue was added EtOAc (20 mL), and the resulting yellow precipitate was collected by filtration and washed with hexane to give the title compound, 7-chloro-8- (4-chlorophenyl) - [1, 2.4 ] triazolo [4, 3-b] pyridazin-3 (2H) -one as a yellow solid (300 mg, 61%). LC / MS (method A): RT = 2.86 min, (M + H) + = 281.

EXAMPLE 274 Preparation of 2- (4-Trifluoromethyl) benzyl) -7-chloro-8- (4-chlorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one To a solution of 7-chloro-8- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (86.4 mg, 0.31 mmol), was prepared as described in Example 273, in DMF (1 mL) at room temperature was added 4-trifluoromethylbenzyl bromide (112 mg, 0.47 mmol), followed by K2CO3 (86 mg, 0.62 mmol). The reaction mixture was heated to 50 ° C for Ih. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was poured into water (30 mL), and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by column chromatography (12 g) of silica gel eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound, 2- (4-trifluoromethyl) benzyl) -7- chloro-8- (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a yellow solid (100 mg, 74%). CLAR: 99% to 7.76 min (time of retention) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H20 - 10% MeOH - 0.1% H3P04 and B = 10% H20 - 90 % MeOH - 0.1% H3P04); Flow rate at 2.5 mL / min, UV detection at 220 nm). MS (ES): m / z 439 [M + H] +; NMR (DMS0-d6, 400 MHz): d 5.25 (s, 2H), 7.49 (d, J = 8 Hz, 2H), 7.65 (S, 4H), 7.70 (d, J = 8 Hz, 2H), 8.53 (s, ÍH). EXAMPLE 275 Preparation of 2- (4- (Trxfluoromethyl) benzyl) -8- (4-chlorophenyl) -7-phenoxy- [1,2,4] riazolo [4,3-b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (17 mg, 0.039 mmol), prepared as described in Example 274 in DMF (0.5 mL), phenol (7.2 mg, 0.077 mmol) was added, followed by K2C03 (11 mg, 0.077 mmol). The reaction mixture was stirred at room temperature for 16 h, and then diluted with 1M aqueous NaOH (3 mL). A yellow precipitate formed. The solid was collected by filtration and washed thoroughly with H20. The crude product was purified by Reversed phase HPLC to give the title compound, 2- (4-trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-phenoxy- [1,2,4] triazolo [4, 3-b] pyridazin- 3 (2H) -one (12 mg, 62%) as a yellow solid. CLAR: 99% at 8.31 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H20 - 10% MeOH - 0.1 % H3P04 and B = 10% H20 - 90% MeOH - 0.1% H3P04); Flow rate at 2.5 mL / min, UV detection at 220 nm). MS (ES): m / z 497 [M + H] +; A NMR (CDC13, 400 MHz): d 5.25 (s, 2H), 6.99 (d, J = 8 Hz, 2H), 7.21 (t, J = 8 Hz, 1H), 7.37-7.44 (m, 4H), 7.54 (d, J = 8 Hz, 2H), 7.61 (d, J = 8 Hz, 2H), 7.79-7.82 (m, 2H), 7.90 (s, 1H). EXAMPLE 276 Preparation of 2- (4-Trxfluoromethyl) benzyl) -8- (4-chlorophenyl) -7- (4-fluorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H -one To a mixture of 2- (4- (trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-chloro- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (30 mg, 0.068 mmol), prepared as described in Example 274, 4-fluorophenylboronic acid (47.6 mg, 0.34 mmol), in toluene (1 mL), was added tetrakis (triphenylphosphine) palladium (12 mg, 0.01 mmol) followed by a solution of Na 2 CO 3 in H 2 O (2M, 0.19 mL, 0.38 mmol). The reaction mixture was stirred at 100 ° C for 16 h, and then diluted with water. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel chromatography (12 g) eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound, 2- (4-trifluoromethyl) benzyl) -8- (4 chlorophenyl) -7- (4-fluorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (27 mg, 79%) as a yellow solid. CLAR: 99% at 8.13 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H20 - 10% MeOH - 0.1% H3P04 and B = 10% H2O-90% MeOH-0.1% H3P04); Flow rate at 2.5 mL / min. UV detection at 220 nm). EM (ES): m / z 499 [M + H] +; A NMR (CDC13, 400 MHz): d 5.26 (s, 2H), 7. 03-7.08 (m, 2H), 7.12-7.18 (m, 2H), 7.25-7.28 (m, 2H), 7. 30-7.34 (m, 2H), 7.52 (d, J = 8 Hz, 2H), 7.60 (d, J = 8 Hz, 2H), 8.19 (s, ÍH).

EXAMPLE 277 Preparation of 7-Chloro-8- (4-chlorophenyl) -2- (6- (rifluoromethyl) pyridin-3-yl) methyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one Using the procedure described in Example 274, 7-chloro-8- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one prepared as described in Example 273 was reacted with 5- (bromomethyl) -2- (trifluoromethyl) pyridine to give the title compound, 7-chloro-8- (4-chlorophenyl) -2- (6- (trifluoromethyl) pyridin-3-yl) ) methyl- [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one.

EXAMPLE 278. Preparation of 8- (4-Chlorophenyl) -7- (4- (oxazol-2-yl) phenyl) -2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2 , 4] riazolo [4, 3-b] pyridazin-3 (2H) -one 278A. Preparation of 2- (4-Bromophenyl) oxazole 2- (4-Bromophenyl) oxazole was prepared from 4-bromobenzoyl chloride and aminoacetaldehyde dimethyl acetal following the procedures of the literature. 278B. Preparation of 2- (4- (4, 4,5,5-Tetramethyl-l, 3,2-dioxaborolan-2-yl) phenyl 2- (4-Bromophenyl) oxazole was reacted with bis (pinacolato) diboro following literature procedures to give the title compound, 2- (4- (4,4,5, 5-tetramethyl-l, 3, 2 -dioxaborolan-2-yl) phenyl) oxazole. 278C. Preparation of 8- (4-Chlorophenyl) -7- (4- (oxazol-2-yl) phenyl) -2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one 7-Chloro-8- (4-chlorophenyl) -2- (6- (trifluoromethyl) pyridin-3-yl) methyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) - ona, prepared as described in Example 277 and 2- (4- (4, 4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl) phenyl) oxazole were reacted using analogous procedures to those described in Example 276 to give the title compound, 8- (4-chlorophenyl) -7- (4- (oxazol-2-yl) phenyl) -2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one. HPLC: 99% at 8.42 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient (A = 90% H20 - 10% MeOH - 0.1% H3P04 and B = 10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL / min, UV detection at 220 nm). MS (ES): m / z 549 [M + H] +; A NMR CDCI3, 400 MHz): d 5.32 (s, 2H), 7.23-7.32 (m, 2H), 7.40-7.59 (m, 4H.), 7.62-7.78 (m, 4H), 7.90-8.05 (, 2H), 8.24-8.27 (m, ÍH), 8.81 (s, ÍH).

EXAMPLE 279 Preparation of 7- (4-Fluorophenyl) -8- (pyridin-4-xl) - [1,2,4] riazo zin-3 (2H) -one 279A. Preparation of 2-Benzyl-5-chloro-4- (4-pxrxdin-4-yl) pyridazin-3 (H) -one To a mixture of 2-benzyl-4,5-dichloropyridazin-3 (2H) -one (10.8 g, 42 mmol), prepared as described in Example 244A, 4- (4,, 5, 5, -tetramethyl- 1, 3, 2-dioxoborolan-2-yl) pyridine (7.9 g, 38.5 mmol) in toluene (80 L) under a stream of argon, tetrakis (triphenylphosphine) palladium (4.4 g, 3.8 mmol) was added, followed by a aqueous Na2CO3 solution (2M, 21 mL, 42 mmol). The reaction mixture was heated at 100 ° C under argon for 16 h. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (330 g) eluting with a gradient of EtOAc (30-100%) in hexanes to give the title compound, 2-benzyl-5-chloro-4- (4 -pyridin-4-yl) pyridazin-3 (2H) -one (3.1 g, 27%) as a yellow solid. LC / MS (method A): RT = 1.95 min, (M + H) + = 298. 279B. Preparation of 2-Benzyl-5- (4-fluorophenyl) -4- (pyridin-4-yl) pxridazin-3 (2H) -one The title compound was prepared from 2-benzyl-5-chloro-4- (4-pyridin-4-yl) pyridazin-3 (2H) -one and 4-fluorophenylboronic acid using procedures analogous to those described in Example 276. The crude product was purified by silica gel column chromatography to give the title compound, 2-benzyl-5- (4-fluorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one. LC / MS (method A): RT = 2.52 min, (M + H) + = 358. 279C. Preparation of 5- (4-Fluorophenyl) -4- (pyridin-4-yl) pxridazin-3 (2H) -one To a solution of 2-benzyl-5- (4-fluorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (1.04 g, 2.91 mmol) in toluene (15 mL) was added aluminum (970 mg, 7.28 mmol). The reaction was stirred at 90 ° C for 30 min. After cool to room temperature, the reaction mixture was poured into water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 5- (4-fluorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one as an off-white solid (560 mg, 70 %). LC / MS (method A): RT = 1.25 min, (M + H) + = 268. 279D. Preparation of 3-Chloro-5- (4-fluorophenyl) 4- (pyridin-4-xl) pyridazine - (4-Fluorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one was reacted with P0C13 using procedures analogous to those described in Example 273C to give the title compound, 3-chloro -5- (4-fluorophenyl) - (pyridin-4-yl) pyridazine. LC / MS (method A): RT = 1.43 min, (M + H) + = 286. 279E. Preparation of 1- (5- (4-fluorophenol) 4- (pyridin-4-yl) pyridazin-3-yl) hydrazine To a solution of 3-chloro-5- (4-fluorophenyl) 4- (pyridin-4-yl) pyridazine (586 mg, 2.05 mmol) in pyridine (3 mL) at room temperature was added hydrazine monohydrate (0.6 mL) . After the addition, the reaction was heated to 100 A for 3 h. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The resulting mixture was then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na 2 SO), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 1- (5- (4-fluorophenyl) 4- (pyridin-4-yl) pyridazin-3-yl) hydrazine (450 mg, 78%) as a whitish solid. LC / MS (method A): RT = 1.10 min, (M + H) + = 282. 279F. Preparation of 7- (4-Fluorophenyl) -8- (pyridine-4-xl) [1, 2, 4] triazglo [4, 3-b] pirxdazin-3 (2H) -one To a solution of 1,1 '-carbonyldiimidazole (1.27 g, 7.86 mmol) in THF (20 mL) was added a suspension of l- (5- (-fluorophenyl) - (pyridin-4-yl) pyridazin-3-yl. ) hydrazine (442 mg, 1.57 mmol) in THF (5 mL). After the addition, the reaction mixture was heated to 66 ° C. After 20 min, the reaction mixture was cooled to room temperature and the reaction mixture was then concentrated under reduced pressure. The residue was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na 2 SO), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 7- (4-fluorophenyl) -8- (pyridin-4-yl) - [1, 2, 4] trlazolo [4, 3-b] pyridazin -3 (2H) -one (440 mg, 91%) as a yellow solid. LC / MS (method A): RT = 1.27 min, (M + H) + = 308.

EXAMPLE 280 Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-fluorophenyl) 8- (pyridin-4-yl) - [1,2,4] trlazolo [4, 3-b ] pyridazxn-3 (2H) -one The title compound was prepared by reacting 7- (4-fluorophenyl) -8- (pyridin-4-yl) - [1,2,4] -triazolo [4, 3-b] pyridazin-3 (2H) - ona, prepared as described in Example 279F, 5- (4- (bromomethyl) phenyl) isoxazole, was prepared as described in Example 250A by procedures analogous to those described in Example 2 as a yellow solid (68%) . CLAR: 99% at 5.46 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H20 -10% MeOH - 0.1 % H3P04 and B = 10% H20 - 90% MeOH - 0.1% H3P04); Flow rate at 2.5 mL / min, UV detection at 220 nm). MS (ES): m / z 465 [M + H] +; A NMR (CDC13, 400 MHz): d 5.25 (s, 2H), 6.51 (d, J = 0.96 Hz, ÍH), 7.01-7.09 (m, 2H), 7.11-7.18 (m, 2H), 7.23 (dd) , Jx = 4.40 Hz, J2 = 1.76 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 8.21 (s, 1H), 8.28 (d, J = 1.76 Hz, ÍH), 8.61-8.64 (m, 2H).

EXAMPLE 281 Preparation of 2- (4-Isoxazol-3-yl) benzyl) -7- (4-fluorophenyl) -8- (pyridin-4-yl) - [1,2,4] riazolo [4, 3-b ] pyridazin-3 (2H) -one The title compound was prepared by reacting 7- (4-fluorophenyl) -8-. { pyridin-4-yl) - [1, 2, 4] -triazolo [4, 3-b] pyridazin-3 (2H) -one, prepared as described in Example 279F, 3- (4- (bromomethyl) phenyl isoxazole, was prepared as described in Example 251A by procedures analogous to those described in Example 2 to give 2- (4-isoxazol-3-yl) benzyl) -7-. { 4-fluorophenyl) -8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a yellow solid (59%). CIAR: 99% at 5.33 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H2O-10% MeOH-0.1 % H3P0 and B = 10% H20 - 90% MeOH-0.1% H3P04); Flow rate at 2.5 mL / min. UV detection at 220 nm). MS (ES): m / z 465 [M + H] +; A NMR (CDCl3, 400 MHz): d 5.26 (s, 2H), 6.65 (S, 1H), 7.07 (t, J = 8.36 Hz, 2H), 7.10-7.18 (m, 2H), 7.23 (d, J = 5.30 Hz, 2H), 7 51 (d, J = 8.36 Hz, 2H), 7.80 (d, J = 7.88 Hz, 2H), 8.21 (s, ÍH), 8.45 (s, ÍH), 8.62 (d, J = 5.30 Hz, 2H) _.

EXAMPLE 282 Preparation of 7- (4-Methoxyphenyl) -8- (pyridxna-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one 282A. Preparation of 5-Chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one To a suspension of 2-benzyl-5-chloro-4- (4-pyridin-4-yl) pyridazin-3 (2H) -one (3.9 g, 13.1 mmol) prepared as described in 279A, in toluene (65 mL aluminum chloride (4.37 g, 32.7 mmol) was added.The mixture was stirred at 90 A for Ih After this time, the reaction mixture was cooled to room temperature.The reaction mixture was partitioned between EtOAc and Saturated aqueous NaHC03 (adjusting the pH to 7) The precipitate formed was collected by filtration and washed with EtOAc to give 1.8 g of the composed of the title. The aqueous layer was extracted with EtOAc (2x) and the combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried (NaS0), filtered and concentrated. The residue obtained was triturated with EtOAc-hexane to give an additional 0.7 g. Together with 2.5 g (92%) of the title compound, 5-chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one was obtained as a whitish solid. LC / MS (method A) RT = 0.48 min, (M + H) + = 208. 282B. Preparation of 3,5-Dichloro-4- (pyridin-4-xl) pyridazine A suspension of the compound 5-chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one (2.5 g, 12 mmol) in POC13 (20 mL) was heated at 120 Aj for 3 h. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue obtained was treated with cooling in ice-cold saturated aqueous NaHCO3. The formed precipitate was collected by filtration and washed with water to give the title compound, 3,5-dichloro-4- (pyridin-4-yl) pyridazine as an off-white solid (1.8 g, 67%). LC / MS (method A): RT = 0.70 min, (M + H) + = 226. 282C. Preparation of 3-Chloro-5- (4-methoxyphenyl) -4-pxridin-4-yl) pyridazine The title compound was prepared by reacting 3,5-dichloro-4- (pyridin-4-yl) pyridazine with 4-methoxyphenyl boronic acid by procedures analogous to those described in Example 279D to give 3-chloro-5- ( 4-methoxyphenyl) -4-pyridin-4-yl) pyridazine. LC / MS (method A): RT = 1.58 min, (M + H) + = 298. 282D. Preparation of 1- (5- (4-Methoxy-nyl) -4- (pyridin-4-xl) pxrxdazxn-3-xl) hydrazine The title compound was prepared by reacting 3-chloro-5- (4-methoxyphenyl) -4-pyridin-4-yl) pyridazine with hydrazine monohydrate by procedures analogous to those described in Example 244H to give 1- (5 - (4-methoxyphenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine. LC / MS (method A): TR = 1.18 min, (M + H) + = 294. 282E. Preparation of 7- (4-Methoxy-nyl) -8- (pyridine-4-yl) [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one The title compound was prepared by making l- (5- (4-methoxyphenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine with carbonyldiimidazole (CDI) by procedures analogous to those described in Example 279F to give 7- (4-methoxyphenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one. LC / MS (method A): RT = 1.37 min, (M + H) + = 320.

EXAMPLE 283 Preparation of 2- (4-Isoxazol-5-yl) benzyl) -7- (4-mexophenyl) -8- (pyridin-4-yl [1,2,4] riazolo [4, 3-b] pxrxdazin-3 (2H) -one The title compound was prepared by reacting 7- (4-methoxyphenyl) -8- (pyridine-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one, prepared as described in Example 282, 5- (4- (bromomethyl) phenyl) isoxazole, was prepared as described in Example 250A by procedures analogous to those described in Example 2 to give as a yellow solid. CLAR: 99% at 5.53 min (retention time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); Eluting with 0% up to 100% B, 8 min gradient. (A = 90% H2O-10% MeOH-0.1% H3P04 and B = 10% H2O-90% MeOH-0.1% H3P04); i Flow rate at 2.5 mL / min. UV detection at 220 nm). MS (ES): m / z 477 [M + H] +; A NMR (CDC13, 400 MHz): d 3.81 (s, 3H), 5.25 (s, 2H), 6.51 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.10 = 7.30 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 8.22-8.30 (, 2H), 8.60-8.70 ( m, 2H).

EXAMPLES 284 TO 353 The following examples were prepared in accordance with the above methods and procedures: EXAMPLE 354 Preparation of 8-Chloro-7- (4-chloro-phenyl) -2H- [1,2,4] rxazolo [4, 3-b] pyridazin-3-one 354A: Preparation of 2-Benzyl-4-chloro-5-methoxypyridazxn-3 (2H) -one To a solution of 2-benzyl-4,5-dichloro-2H-pyridazin-3-one (22.31 g, 87.47 mmol), prepared as described in Example 244A, in dry MeOH (175 mL) at 0 ° C, a solution of sodium methoxide in methanol (25% by weight in MeOH, 25 L) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. The filtrate was concentrated to provide the title compound, 2-benzyl-4-chloro-5-methoxypyridazin-3 (2H) -one (22.2 g) which was > 95% pure was judged by HPLC and used in the next reaction, example 354B, without further purification. 354B: Preparation of 2-Benzyl-4-chloro-5-hydroxxpxridazin-3 (2H) -one At a Yensikon ode of 2-benzyl-4-chloro-5-methoxypyridazin-3 (2H) -one (22.2g, 87.47 mmol) in water (150.0 mL), potassium hydroxide (5.89g) was added and the mixture was added. heated until reflux. After 3h, the mixture is then cooled to room temperature and 6N aqueous hydrochloric acid was added and the pH of the solution was adjusted to 3.0. The precipitate was filtered, washed with water and dried under reduced pressure to give the title compound, 2-benzyl-4-chloro-5-hydroxypyridazin-3 (2H) -one (20.45g) as a white solid. CLAR: 2.40 min. 354C: Preparation of 2-Benzyl-4-Chloro-5- (4-chlorophenyl) -2H-pyridazin-3-one To a solution of 2-benzyl-4-chloro-5-hydroxypyridazin-3 (2H) -one (7.84 g, 33.1 mmol) in methylene chloride (110.0 mL) at -10 Aj, triethylamine (4.02 g, 39.75) was added. mmol) followed by trifluoromethanesulfonic anhydride (10g, 35.45 mmol). The mixture was stirred for 30 min, and then poured into an ice-cooled solution of 0.5N aqueous hydrochloric acid (200 mL). The mixture was then extracted with methylene chloride (3 x 200 mL). The combined organic layers were washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO), filtered and concentrated under reduced pressure to give the corresponding triflate (12.91 g) as a rose oil. This material was dissolved in a 1: 1 mixture of THF (55 mL) and MeOH (55 mL) and the solution was degassed with argon. 4- Chlorophenylboronic acid (2.37 g, 15.18 mmol), dichloro-bis (chloroditert-butylphosphine) palladium (0.89g, 1.65 mmol) and potassium carbonate (13.67 g) were added and the reaction mixture was stirred at room temperature. for 1.5 h. The reaction mixture was then diluted with water (200 mL). The resulting solution was extracted with CH2C12 (2 x 200 mL). The combined organic layers were washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel using hexanes / EtOAc (2: 1) to give the title compound, 2-benzyl-4-chloro-5- (4-chloro-phenyl) -2H-pyridazin -3-one 3.9 g as a white solid. CLAR: 3.72 min. 354D. Preparation of 4-Chloro-5- (4-chlorophenyl) -2H-pyridazin-3-one 2-Benzyl-4-Chloro-5- (4-chloro-phenyl) -2H-pyridazin-3-one (3.19 g, 9.65 mmol) was dissolved in toluene (50 mL). Then aluminum chloride (A1C13, 3.22 g, 24.1 mmol) was added and the reaction mixture was heated to 50 ° C. After 20 min, the reaction mixture was cooled to room temperature and then poured into ice water (200 mL). The resulting solution it was extracted with EtOAc (3 x 200 L). The combined organic layers were washed with water (500 mL). The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc to give the title compound, 4-chloro-5- (4-chlorophenyl) -2H-pyridazin-3-one (2.33 g) as a white solid. CLAR: 2.74 min. 354E. Preparation of 3,4-Dichloro-5- (4-chlorofonyl) -pyridazine 4-Chloro-5- (4-chlorophenyl-2H-pyridazine-3-one (2.33 g, 9.65 mmol) was suspended in P0C13 (llmL) .The reaction mixture was placed in a preheated oil bath at 110 Aj for 1 hour. After cooling to room temperature, the mixture was poured onto 200 g of ice to quench the excess of POCI3 and the resulting solution was extracted with EtOAc The combined organic layers were washed with water The organic layer was dried (MgSO4) , filtered and concentrated under reduced pressure to give the title compound, 3,4-dichloro-5- (4-chlorophenyl) -pyridazine (2.6 g) as a light yellow solid, HPLC: 3.26 min. 354F. Preparation of 1- [4-Chloro-5- (4-chlorophenyl) pyridazin-3-yl] -hydrazine 3,4-Dichloro-5- (4-chlorophenyl) -pyridazine (6.0 g, 23.1 mmol) was suspended in isobutanol (150 mL) at 0 ° C and hydrazine monohydrate (11.1 g) was added dropwise over 10 min. . The reaction mixture was slowly warmed to room temperature and stirred for 24 h. The mixture was cooled in a water / ice bath for 15 min., And filtered. The white solid thus obtained was washed with cold isopropanol and dried to give the title compound, 1- [4-chloro-5- (4-chloro-phenyl) -pyridazin-3-yl] -hydrazine, (5.0 g) as a white solid. CLAR: 1.65 min. 354G. Preparation of 8-Chloro-7- (4-chlorophenyl) -2H- [1,2,4] riazolo [4, 3-b] pxridazin-3-one To a solution of triphosgene (30.4 g, 102.4 mmol) in THF (300 mL), 1- [4-chloro-5- (4-chloro-phenyl) -pyridazin-3-yl] -hydrazine (6.52 g, 25.61 mmol ) was added in portions for 15 min., at room temperature. The mixture was stirred room temperature for 4 h. After this time, the solution was poured into ice / water (500 L), and the resulting light yellow solid was collected by filtration. The solid was rinsed with 0.5N aqueous HCl and water. This was then dried under vacuum to give the title compound, 2.81 g of 8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazolo [4,3-b] pyridazin-3-one. as a light yellow solid. CLAR: 2.78 min .; MS, M + H = 281. EXAMPLE 355 Preparation of 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1, 2, 4] triazole [4, 3-b] pyridazin-3 (2H) -one To a solution of 8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (300 mg, 1.07 mmol), prepared as debed in Example 354, in DMF (5 mL) was added K2C03 (180 mg, 1.3 mmol) followed by 5- (4- (bromomethyl) phenyl) isoxazole (305 mg, 1.28 mmol), was prepared as debed in example 250A. The reaction mixture was stirred at 70 ° C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and a form precipitated. The solid was collected by filtration. The solid is washed with water (2 x 25 mL) followed by hexanes (20 mL). The solid was dried in a vacuum oven at 40 ° C. The title compound 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7 - (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 ( 2 H) -one (450 mg, 96%) was obtained as a yellow solid. CLAR: 3.50 min; M + H = 438. EXAMPLE 356 Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one To a stirred solution of 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2 H) -one (100 mg, 0.23 mmol), prepared as debed in Example 355, in toluene (2 mL) in a round bottom flask was added Pd (PPh 3) 4 (16 mg, 0.014 mmol) under a Argon current. 3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dixoborolan-2-yl) pyridine (61 mg, 0.3 mmol) was added sequentially. Under vigorous stirring, Na2CO3 (97 mg, 0.91 mmol) predisposed in water (0.25 mL) was added to the suspension. The argon was bubbled through this suspension for 10 min. Before the flask was placed in a preheated oil bath at 120 Aj. The reaction was stirred to reflux for 6 days. The reaction was then allowed to cool to room temperature and poured into water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) followed by saturated aqueous NaCl (2x5 mL). The organic layer was concentrated under reduced pressure. The product obtained was purified by reverse phase HPLC to give the title compound, 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (8.5 mg, 8%) as a pale yellow solid. CLAR: 2.98 min; M + H = 481; A NMR (CDC13), ppm: 8.61 (H, d, J = 6.05 Hz), 8.55 (HH, d, J = 5.0 Hz), 8.28 (HH, d, J = 2.0 Hz)), 8.19 (HH, s), 7. 76 (2H, d, J = 10.0 Hz), 7.69 (1H, d, J = 5.0 Hz), 7.51 (2H, d, J = 10.0 Hz), 7.31-7.33 (3H, m), 7.09 (2H, d , J = 5.0 Hz), 6.51 (ÍH, s), 5.25 (2H, s). EXAMPLE 357 Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8-phenyl- [1,2,4] riazolo [4, 3-b] pyridazin-3 ( 2H) -one To a stirred solution of 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2 H) -one (100 mg, 0.23 mmol), prepared as described in Example 355 in toluene (2 mL) in a round bottom flask, Pd (PPh3) 4 (16 mg, 0.014 mmol) was added under bubbling of argon. Phenyl boronic acid (36 mg, 0.3 mmol) was added subsequently. Under vigorous stirring, Na2CO3 (97 mg, 0.91 mmol) predisposed in water (0.25 mL) was added to the suspension. The argon was bubbled through this suspension for 10 min., Before the flask was placed in a preheated oil bath at 120 Aj. The reaction was stirred at reflux for 6 days. The reaction was then allowed to cool to room temperature. After this time, the reaction mixture was poured into water (10 mL). The resulting solution was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) followed by saturated aqueous NaCl (2 x 5 L). The organic layer was dried (MgSO 4), filtered and concentrated to obtain the crude product. This crude product was purified by reverse phase HPLC to give the title compound, 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8-phenyl- [1, 2.4 ] triazolo [4,3-b] pyridazin-3 (2H) -one, (15.5 mg, 14%) as a pale yellow solid. CLAR: 3.68 min; MS, M + H = 480; A NMR (CDC13), ppm: 8.31 (ΔI, d, J = 2.0 Hz), 8.22 (ΔI, s), 7.77 (2H, d, J = 10.0 Hz), 7.51 (2H, d, J = 10.0 Hz) , 7.26-7.42 (7H, m), 7.09 (HH, d, J = 10.0 Hz), 6.54 (HH, d, J = 5.0 Hz), 5.29 (2H, s).

EXAMPLE 358 Preparation of 8-Chloro-7- (4-chlorophenyl) -2- (pyrazin-2-ylmethyl) -2H- [1,2,4] triazolo [4, 3-b] pyridazin-3-one To a solution of 8-chloro-7- (4-chlorophenyl) -2H- [1, 2,4] triazolo [4,3-b] pyridazin-3-one (0.62 g, 2.21 mmol), was prepared as described in Example 354, in DMF (10 mL) at room temperature was added K2CÜ3 (0.61 g, 4.4 mmol) and 2- (chloromethyl) pyrazine (0.83 g). The reaction mixture was heated at 50 ° C for 2 h. After this time, the mixture was diluted with EtOAc (150 mL). The resulting solution was washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes: EtOAc 1: 2 to provide 0.61 g of the title compound, 8-chloro-7- (4-chlorophenyl) -2- (pyrazin-2-ylmethyl) -2H- [1,2,4] triazolo [4, 3-b] pyridazin-3-one as a yellow solid. CLAR TA: 2.86 min; MS, M + H = 373; To NMR (CDC13): d 8.64 (d, ÍH), 8.54 (m, 2H), 8.11 (s, ÍH), 7.54-7.49 (m, 4H), 5.48 (s, 2H).

EXAMPLE 359 Preparation of 2- (4- (Trifluoromethyl) benzyl-8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazolo [4,3-b] pyridazin-3-one To a solution of 8-chloro-7- (4-chlorophenyl) -2H- [1, 2, 4] triazolo [4, 3-b] pyridazin-3-one (0.54 g, 1.91 mmol), prepared as described in Example 354, in DMF (5 mL) at room temperature was added K2C03 (0.40 g, 2.87 mmol) and 2- (trifluoromethyl) benzyl bromide (0.595 g, 2.49 mmol). The reaction mixture was heated at 55 ° C for 4 h. After this time, the mixture was diluted with EtOAc (150 mL). The resulting solution was washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexanes: EtOAc (2: 1) to give 0.74 g of the title compound, 2- (4- (trifluoromethyl) benzyl-8-chloro-7- (4-chloro-phenyl ) -2H- [1, 2, 4] triazolo [4, 3-b] pyridazin-3-one as a yellow solid, HPLC: 3.84 min, MS, M + H = 439. A NMR (CDC13): d 8.08 (s, ÍH), 7.44-7.61 (, 8H), 5.30 (s, 2H).

EXAMPLE 360 Preparation of 2- (4- (Trifluoromethyl) benzyl-7- (4-chloro-phenyl) -8-phenoxy-2H- [1,2,4] riazolo [4, 3-b] pyridazin-3-one To a solution of 2- (4- (trifluoromethyl) benzyl-8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazolo [4, 3-b] pyridazin-3-one (16.5 mg, 0.376 mmol) pareparada as described in example 359, in 0.3 mL of DMF at room temperature, potassium carbonate (19.4 mg, 0.14 mmol) followed by phenol (13.2 mg, 0.14 mmol) was added. After this time, the reaction mixture was diluted with 5 mL of 1N aqueous sodium hydroxide.The precipitate was collected by filtration and washed with 1N aqueous NaOH, and water.The solid was dried to give the compound, 2- (4 - (Trifluoromethyl) benzyl-7- (4-chlorophenyl) -8-phenoxy-2H- [1, 2,4] triazolo [4, 3-b] pyridazin-3-one (15.8 mg) as a light yellow solid CLAR TA: 4.02 min; MS, M + H = 497; A NMR (CDC13): d 8.21 (s, ÍH), 7.52-6.97 (m, 13H), 5.12 (s, 2H).

EXAMPLE 361 Alternative preparation of 2- (4- (Trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazxn-3 (2H) one 361A. Preparation of 2-Benzyl-4,5-dichloropyridazin-3 (2H) -one To a stirred suspension of 4,5-dichloro-3-hydroxypyridazine (33 g, 200 mmol) in DMF (260 mL) at room temperature under argon was added K2CÜ3 (55 g, 400 mmol), followed by benzyl bromide (41 g, 505.8 mmol). After 16 h the reaction mixture was poured into a flask containing water (500 mL) with stirring. After 15 min. of agitation, the precipitated product was collected by filtration and washed thoroughly with water. The solid was dried in a vacuum oven at 50 ° C for 16 h until obtaining the title compound, 2-benzyl-4,5-dichloropyridazin-3 (2H) -one, (49.2 g, 96%) as a solid whitish. MS [M + H] + 255; CLAR retention time = 3.02 min. 361B. Preparation of 2-benzyl-5-chloro-4-methoxypyridazine-3 To a stirred solution of 2-benzyl-4, 5-dichloropyridazin-3 (2H) -one (22.9 g, 89.8 mmol) in 1,4-dioxane (300 mL) at room temperature under argon NaOMe was added (22.4 L, 25% of the solution in MeOH, 97.9 mmol) for 10 min., By means of a syringe. After 2 h, CCD indicates that the reaction was complete. The reaction mixture was concentrated under reduced pressure. Saturated NaCl solution (200 mL) was added and the resulting solution was extracted with CH2C12 (2 x 100 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography eluting with CH2C12 to give the title compound, 2-benzyl-5-chloro-4-methoxypyridazin-3 ( 2 H) -one (20.3 g, 90%) as a colorless oil. CCD (CH2C12, Rf = 0.4); MS [M + H] + 251; CLAR retention time = 2.74 min. 361C. Preparation of 2-Benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one (20 g, 80 mmol) and 4-chlorophenylboronic acid (15.6 g, 100 mmol) in toluene / EtOH (2: 1, 600 mL) at room temperature under argon was added (Ph3P) 4Pd (1.85 g, 1.8 mmol) and a 2M aqueous Na2C03 solution (160 L, 320 mmol). The resulting suspension was heated at 90 ° C for 16 h with stirring. HPLC / MS indicated that about 4% of 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one remained immobile. After cooling the reaction mixture to room temperature, the solution was extracted with CH2C12 (2 x 150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluted with hexanes / EtOAc to obtain the pure title compound, 2-Benzyl-5- (4-chlorophenyl) -4-methoxypyridazine-3 (2H) -one, (21.7 g, 83%) as a white solid. MS [M + H] + 327; CLAR retention time = 3.85 min. 361D: Preparation of 3,4-dichloro-5- (4-chlorophenyl) pyridazine A stirred solution of 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one (16.3 g, 50 mmol) in POC13 (100 mL) was heated in the sealed flask at 80 ° C for 16 h. The reaction mixture was cooled to room temperature and additional P0C13 (50 mL) was added. The reaction mixture was then heated at 120 ° C for 1 d and then cooled to room temperature. The majority of the solvent was removed under vacuum. The ice (300 g) was carefully added to the residue while stirring, and the resulting mixture was extracted with CH2C12 (250 mL x 2). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc / CH2Cl2. The desired product (9.6 g) was obtained as a brown solid with a purity of 95%. This was washed with methanol (20 mL x 2) and dried to obtain the pure title compound, 3,4-dichloro-5- (4-chlorophenyl) iridazine (5.3 g, 41%) as an opaque white solid. MS [M + H] + = 259; CLAR retention time = 3.40 min .; A NMR (400 MHz, CDC13) d 9.00 (s, 1H), 7.47-7.55 (m, 4H); 13C NMR (100 MHz, CDC13) d 156.4, 150.6, 139.4, 136.7, 135. 1, 130.6, 130.3, 129.3. 361E. Preparation of 1- (4-chloro-5- (4-chloro nyl) pyridazin-3-yl) hydrazine H2 To a stirred suspension of 3,4-dichloro-5- (4-chlorophenyl) pyridazine (2.58 g, 10 mmol) in 2-BuOH (150 L) at At room temperature, hydrazine anhydride (4.80 g, 150 mmol) was added. The reaction mixture was heated to 60 ° C under argon. HPLC / MS analysis indicated that the reaction was complete after 5 h. The reaction mixture was cooled to 0 ° C, and the product was collected by filtration. The solid was washed with 2-propanol (10 mL x 2) cooled with ice. After the solid was dried under vacuum at room temperature for 16 h, the title compound, 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) hydrazine is obtained in a radius of 1.6: 1 with 1 - (3-chloro-5- (4-chlorophenyl) pyridazin-4-yl) undesired hydrazine (2.16 g) 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) hydrazine. MS [M + H] + 255; CLAR retention time = 1.63 min. l- (3-chloro-5- (4-chlorophenyl) pyridazin-4-yl) hydrazine MS [M + H] + 255; CLAR retention time = 1.09 min. 361F. Preparation of 8-Chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one A stirred solution of triphosgene (17.5 g, 59.0 mmol) in THF (150 mL) was collected at 0 ° C under argon and a mixture of 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) Hydrazine and 1- (3-chloro-5- (4-chlorophenyl) pyridazin-4-yl) hydrazine, was prepared in Example 361E, (3.0 g thick) was added during 3 min. The reaction mixture was then allowed to warm to room temperature gradually and then stirred for 16 h. The solvent was removed under vacuum to reduce the reaction mixture to half its original volume and the resulting suspension was cooled in an ice bath. Water with ice (300 L) was added, followed by stirring for 30 min. The product was collected by filtration and washed with aqueous HCl 0.5 N (20 mL x 2), then H20 (20 mL x 2). After drying under vacuum at room temperature for 16 h, the title compound, 8-chloro-7- (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (2.1 g) was obtained as a yellow solid. MS [M + H] + 281; CLAR retention time = 2.71 min. 361G. Preparation of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenol) - [1,2,4] trxazolo [4, 3-b] pyridazin-3 (2H) -one To a stirred suspension of 8-chloro-7- (4-chlorophenyl) - [1, 2,4 '] triazolo [4,3-b] pyridazin-3 (2H) -one (1.12 g, 4.0 mmol) and bromide of 4- (trifluoromethyl) benzyl (1.24 g, -5.2 mmol) in DMF (15 L) at room temperature under argon was added K2CO3 (0.83 g, 5.2 mmol). The resulting mixture was heated at 55 ° C for 2 h. After 2 h, the CLAR / MS analysis indicates that the reaction was terminated. The mixture of reaction was cooled to room temperature and added EtOAc (100 L). The resulting mixture was washed with saturated NaCl (50 L x 2). The organic layer was dried (Na 2 SO 4), filtered and concentrated under vacuum with co-evaporation of toluene (10 mL x 2) to obtain a dark yellow solid.

This crude product was washed with MeOH (10 mL x 2), then dried under vacuum at room temperature for 3 h to obtain the title compound, 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- ( 4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (1.3 g, 74%) as a yellow solid. MS [M + H] + 439; CLAR retention time = 3. 92 min .; Ai NMR (400 MHz, CDC13) d 9.00 (s, 1H), 7.45-7.61 (m, 8H), 5.32 (s, 2H).

EXAMPLE 362 Preparation of 8-Chloro-7-p-tolyl-2- ((6- (rifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] riazolo [4,3- b] pyridazin-3 (2H) -one 362A Preparation of 2-Benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one To a solution of 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one (20 g, 80 mmol), prepared as described in Example 361B, and 4-methylphenylboronic acid (13 g, 96 mmol) in toluene (300 mL) at room temperature under argon (Ph3P) 4Pd (1.85 g, 1.8 mmol) and a 2M aqueous Na 2 CO 3 solution (160 mL, 320 mmol). The resulting suspension was heated at 100 ° C for 5 h with stirring. CLAR / MS indicated the complete reaction. After cooling the reaction mixture to room temperature, this was extracted with CH2C12 (200 L x 2), then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluted with hexanes / EtOAc to give the title compound, 2-benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one, (21.9 g, 89%) as a white foam. MS [M + H] + 307; CLAR retention time = 3.78 min. 362B. Preparation of 3,4-Dichloro-5-p-tolylpxridazine A stirred solution of 2-benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one (15.3 g, 50 mmol) in POC13 (100 mL) was heated in the sealed flask at 120 A for 24 h. The reaction mixture was cooled to room temperature and additional POCI3 (50 mL) was added. The reaction mixture was heated again to 120 A for 1 d and then cooled to room temperature. The majority of the solvent was removed under vacuum. Ice (200 g) was carefully added to the residue while stirring, and the resulting mixture was extracted with CH2C12 (250 mL x 2). The combined organic phases dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluted with hexanes / EtOAc / CH2Cl2. The impure desired product (10 g) was obtained as a brown solid. It was washed with methanol (15 mL x 2), then the solid was dried, to give the pure title compound, 3-dichloro-5-p-tolylpyridazine, (5.1 g, 43%) as an opaque white solid. MS [M + H] + 239; CLAR retention time = 3.34 min. 362C. Preparation of 1- (4-Chloro-5-p-tolylpyridazin-3-yl) hydrazine To a stirred suspension of 3,4-dichloro-5-p-tolylpyridazine (4.5 g, 18.9 mmol) in 2-BuOH (200 mL) at room temperature was added hydrazine anhydride (9.1 g, 284 mmol). The reaction mixture was heated to 60 ° C under argon. The HPLC / MS analysis indicates that the reaction is complete after 15 h. The reaction mixture was cooled to 0 ° C, and the product was collected by filtration and washed further with ice-cold 2-propanol (20 mL x 2). After drying under vacuum at room temperature for 16 h, the title compound, 1- (4-chloro-5-p-tolylpyridazin-3-yl) hydrazine, was obtained in a 2.6: 1 ratio with the I- ( Undesired 3-chloro-5-p-tolylpyridazin-4-yl) hydrazine (3.6 g large). 1- (4-chloro-5-p-tolylpyridazin-3-yl) hydrazine MS [M + H] + 235; CLAR retention time = 1.84 min. l- (3-chloro-5-p-tolylpyridazin-4-yl) hydrazine MS [M + H] + 235; CLAR. Retention time = 1.35 min. 362D. Preparation of 8-Chloro-7-p-tolyl- [1, 2, 4] riazolo [4, 3-b] lpyridazin-3 (2H) -one A stirred solution of triphosgene (19.0 g, 64.0 mmol) in THF (200 mL) was cooled to 0 ° C under argon and the mixture of 1- (4-chloro-5-p-tolylpyridazin-3-yl) hydrazine and 1 - (3-chloro-5-p-tolylpyridazin-4-yl) hydrazine (3.0 g large), prepared as described in example 362C, was added for 3 min. The reaction mixture was allowed to warm to room temperature gradually and then stirred for 16 h. The solvent was removed under vacuum to reduce the reaction mixture to half, that is, its original volume, and the resulting suspension was cooled in an ice bath. Water with ice (300 mL) was added, followed by stirring for 1 h. The product was collected by filtration and washed with 0.1M aqueous HCl (50 mL x 2), then H20 (50 mL x 2). Then it was dried under vacuum at 50 ° C for 2 d, the title compound, 8-chloro-7-p-tolyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (2.2 g) was obtained as a yellow solid. MS [M + H] + 261; CLAR retention time = 2.75 min .; At NMR (400 MHz, THF-d8) d 11.69 (s, ÍH), 8.10 (s, ÍH), 7.49-7.51 (m, 2H), 7.34-7.35 (m, 2H). 362E. Preparation of 8-Chloro-7-p-tolyl-2- ((6- (rifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] rxazolo [4,3-b] pxridazin-3 (2H -one To a stirred suspension of 8 ~ chloro-7-p-tolyl- [1, 2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (2.2 g, 8.4 mmol) and 5- (chloromethyl) ) -2- (trifluoromethyl) pyridine (2.1 g, 11 mmol) in DMF (15 mL) at room temperature under argon was added K2C03 (1.74 g, 12.6 mmol). The resulting mixture was heated at 55 ° C for 2 h. The CLAR / MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL x 2) - to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluted with hexanes / EtOAc / CH2Cl2. The desired product (2.1 g) was obtained as a brown solid. It was washed with MeOH (10 mL x 2) and dried to give the pure title compound, 8-chloro-7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1 , 2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (1.76 g, 56%) as a light yellow solid. MS [M + H] + 420; CLAR retention time = 3.53 min .; A NMR (400 MHz, CDC13) d 8.89 (s, 1H), 8. 13 (s, ÍH), 8.00 (d, 1H), 7.70 (d, ÍH), 7.30-7.50 (m, 4H), 5.36 (s, 2H), 2.45 (s, 3H). EXAMPLE 363 Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (lH-imidazol-yl) - [1, 2, 4] riazolo [4.3- b] pyridazin-3 (2H) -one 363A. Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one To a stirred suspension of 8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one prepared as described in example 354G, and 5- (4- (bromomethyl) phenyl) isoxazole (122 mg, 0.51 mmol), prepared as described in Example 250A in DMF (5 mL) at room temperature under argon was added K2CO3 (119 mg, 0.86 mmol). The resulting mixture was heated at 50 ° C for 3 h. The CLAR / MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (10 mL x 2) to obtain a yellow solid. dark. The crude product was purified by silica gel column chromatography (ISCO) eluted with hexanes / EtOAc to obtain the pure title compound, 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7 - (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, (149 mg, 79%) as a yellow solid.

MS [M + H] + 438; CLAR retention time = 3.55 min. 363B. Preparation of 2- (4- (Isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (lH-imidazo-1-yl) - [1,2,4] riazolo [4, 3- b] pyridazin-3 (2H) -one A solution of 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2 H) -one (149 mg, 0.34 mmol) and imidazole (69.5 mg, 1.02 mmol) in dry l-methyl-2-pyrrolidinone (3 mL) was heated at 100 for 18 h. The CLAR / MS analysis indicated that 90% of the reaction was complete. The reaction mixture was concentrated under vacuum with toluene coevaporation (5 mL x 2) to obtain a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) was eluted with CH2Cl2 / EtOAc to obtain the pure title compound (87 mg, 55%) as a yellow solid. MS [M + H] + 470; CLAR retention time = 2.59 min .; At NMR (400 MHz, CDC13) d 8.29 (d, ÍH, J = 0.5Hz), 8.18 (s, ÍH), 7.80-7.85 (m, 2H), 7.78 (s, ÍH), 7.49 (d, 2H, J = 7.0Hz), 7.43 (d, 2H, J = 7.0 Hz), 7.13-7.15 (m, 3H), 6. 94 (m, ÍH), 6.53 (d, ÍH, J = 0.5 Hz), 5.27 (s, 2H). EXAMPLE 364 Preparation of 2- (4- (Isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazo-1-yl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one 364A. Preparation of 7- (4-chlorophenyl) -8- (lH-imidazo-1-xl) [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one A stirred solution of 8-chloro-7- (4-chlorophenyl) - [1,2,] triazolo [4, 3-b] pyridazin-3 (2H) -one (56 mg, 0.20 mmol), was prepared as described in Example 361F, and imidazole (100 mg, 1.5 mmol) in dry l-methyl-2-pyrrolidinone (1 mL) was heated at 100 AJ for 5 h. The CLAR / MS analysis indicated that the reaction was complete. The reaction mixture was reduced to half its original volume with a current of argon while kept heated to 100 A. After cooling to At room temperature, a 0.7 M aqueous TFA solution (3 mL) was added at a pH lower than 1. A precipitate formed. The supernatant and subsequent extracts of the precipitate were obtained by re-dissolving in NMP and dilution with water, purified by preparative reverse phase HPLC (C-18, MeOH / H20 gradient, 0.1% TFA). This provided the desired product as the TFA salt, which was passed on a free base that is, in a 1: 1 MeOH / CH2Cl2 solution, through a piperidine resin Polymer Laboratories PL-PIP (100 mg, 3.21 mmol / l. g). Evaporation under vacuum then gives the title compound, 7- (4-chlorophenyl) -8- (1H-imidazo-1-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 ( 2 H) -one (15 mg, 24%) as a yellow solid. MS [M + H] + 313; CLAR retention time = 1.37 min. (gradient C-18, MeOH / H20 (containing 0.1% TFA)). 364B. Preparation of 2- (4- (Isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (lH-imidazol-1-yl) - [1,2,4] triazolo [4.3- b] pyridazin-3 (2H) -one A stirred mixture of 7- (4-chlorophenyl) -8- (1H-imidazo-1-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (15 mg , 0.048 mmol), 3- (4- (bromomethyl) phenyl) isoxazole (14 mg, 0.59 mmol), and K2C03 (40 mg, 1.0 mmol) in DMF (0.5 L) under argon was heated at 55 ° C for 30 min. The CLAR / MS analysis indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was diluted with MeOH (3 mL) and filtered through cotton. The filtrate was diluted with water (3 mL), which caused some precipitation, and acid was made up to pH 1 with TFA. The supernatant, and the subsequent extracts of the precipitate obtained by being re-agitated in MeOH and diluted with water, were purified by preparative reverse phase HPLC (C-18, MeOH / H20 gradient, 0.1% TFA). This provided the desired product as the TFA salt, which was passed on a free base that is, in a 1: 1 MeOH / CH2Cl2 solution, through a Polymer Laboratories PL-PIP resin (100 mg, 3.21 mmol / g) . Evaporation then afforded the pure title compound (5.6 mg, 25%) as a yellow solid. MS [M + H] + 470, [M-H] + 468; HPLC retention time = 2.96 min., (C-18, gradient MeOH / H20 (10 mM NH4OAc)); A NMR (500 MHz, CD3OD) d 8.70 (d, 1H, J = 1.6Hz), 8.43 (s, 1H), 7.85 (d, 2H, J = 8.2Hz), 7.85 (s, ÍH), 7.53 (d , 2H, J = 8.2Hz), 7.46 (d, 2H, J = 8.8Hz), 7.29 (d, 2H, J = 8.8Hz), 7.15 (t, ÍH, J = 1.6Hz), 7.07 (s, 1H ), 6.90 (d, ÍH, J = 1.6Hz), 5.30 (s, 2H).

EXAMPLE 365 Preparation of 2- (4- (Trifluoromethyl) benzyl) -8-amino-7- (4-chlorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one A solution of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one ( 43.8 mg, 0.10 tnmol), was prepared as described in Example 361 stage G, and KOCN (81 mg, 1.0 mmol) in dry l-methyl-2-pyrrolidinone (2 mL) was heated at 120 A for 2 h under argon . The CLAR / MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL x 2) to obtain a yellow solid. The crude product was purified by reverse phase preparative HPLC (C-18, MeOH / H20 gradient, 0.1% TFA) to give the title compound 2- (4- (trifluoromethyl) benzyl) -8-amino-7- ( 4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (34 mg, 81%) as a yellow solid. MS [M + H] + 420; CLAR retention time = 3.70 min.

EXAMPLE 366 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7- (4-chlorophenyl) 3-oxo-2,3-dihydro- [1,2,4] riazolo [4, 3-b] pyridazine-8 - carbonitrile A suspension of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1, 2,] triazolo [4, 3-b] pyridazin-3 (2H) -one, ( 43.8 mg, 0.10 mmol), was prepared as described in Example 361G, and KCN (33 mg, 0.5 mmol) in dry 1-methyl-2-pyrrolidinone (1 mL) was heated at 120 A for 2 h under argon. The CLAR / MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum with co-evaporation of toluene (5 mL x 2) to obtain a yellow solid. The crude product was purified by reverse phase preparative HPLC (C-18, Me0H / H20 gradient, 0.1% TFA) to obtain the title compound (31 mg, 72%), 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -3-oxo-2,3-dihydro- [1,2,4] triazolo [4, 3-b] pyridazine-8-carbonitrile as a yellow solid. MS [M + H] + 430; CLAR retention time = 3.76 min.

EXAMPLE 367 Preparation of 8- (6-Fluoropyridin-3-yl) -7-p-tolyl-2- ((6- (rifluoromethyl) pyridin-3-yl) ethyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3 (2H) -one To a microwave reaction vessel containing a stir bar, catalysed Pd (Ph3P) 4 (30 mg, 25 μmol) was added, followed by anhydrous dioxane (0.5 mL). To this was added 8-chloro-7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2 H) -one (20 mg, 47 μmol), prepared as described in example 362, 2-fluoropyridine-5-boronic acid (28.2 mg, 200 jamol), anhydrous dioxane (0.5 mL) and a 2M aqueous K3PO4 solution (0.25 mL). The reaction vessel was flushed with nitrogen, capped and heated at 120 A for 10 minutes in a microwave reactor. The reaction mixture was filtered through a Whatman 0.45 μm filter syringe and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); eluted with 30% up to 100% B, 8 min. gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); flow rate at 30 mL / min. UV detection at 220 nm) to give the title compound, 8- (6-fluoropyridin-3-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1, 2]. , 4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a TFA salt.

This compound was taken in 2 mL of methanol in a filtration column placed with a stopcock and a polystyrene-based carbonate resin, PL-C03 MP-resin, was added, (100 mg, loading 2.4 mmol / g). The contents were stirred for 2 h and the methanol solution was filtered and evaporated under reduced pressure to give the title compound, 8- (6-fluoropyridin-3-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one in a free base form (7.6 mg, 32% yield), as a yellow crystalline solid. MS (M + H) = 481; A NMR CDC13: d 8.8 (H, s), 8.21 (H, s), 8.23 (H, s), 7.95 (1 H, d, J = 8.2 Hz), 7.79 (H, m), 7.66-7.68 (H) , m), 7.03-7.18 (4H, m), 6.94 (1H, m), 5.3 (2H, s). purity analysis HPLC: 99% at 2.27 min. (retention time), (Xterra EM-C18, 4.6 X 50 mm); eluted with 30% up to 100% B, 4.5 min. gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); flow rate at 2.5 mL / min. UV detection. at 220 nm.

EXAMPLE 368 Preparation of 8- (5-Fluoro-6-methoxypyridin-3-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4 ] riazolo [4,3- b] pyridazin-3 (2H) -one To a microwave reaction vessel containing a stir bar, catalysed Pd (PhsP) (30 mg, 25 μmol) was added, followed by dioxane anhydride (0.5 mL). To this was added 8-chloro-7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2, 4] triazolo [4,3-b] pyridazin-3 (2 H) -one (20 mg, 47 μmol), prepared as described in example 362, 3-fluoro-2-methoxypyridine-5-boronic acid (34.2 mg, 200 μmol), anhydrous dioxane (0.5 mL) and a solution of 2M KP04 (0.25 mL). The reaction vessel was flushed with nitrogen, capped and heated at 120 A for 10 minutes in a microwave reactor. The reaction mixture was filtered through a 0.45 μm filter syringe and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); eluted with 30% up to 100% B, 8 min. gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); flow rate at 30 mL / min.

UV detection at 220 nm) to give the title compound, 8- (5-fluoro-6-methoxypyridin-3-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a TFA salt. This compound was taken in 2 mL of methanol in a filtration column placed with a stopcock and polystyrene-based carbonate resin, PL-C03 MP-resin, (100 mg, loading 2.4 mmol / g) was added. The contents were stirred for 2 h and the methanol solution was filtered and evaporated under reduced pressure to give the title compound, 8- (5-fluoro-6-methoxypyridin-3-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one in a free base form (9.6 mg, 38 % yield), as a yellow crystalline solid. MS (M + H) = 511; A NMR (CD3OD):: d 8.67 (H, s), 8.25 (H, s), 7.97 (H, D, J = 8.2 Hz), 7.82 (1 H, s), 7.7 (H, m), 7.38- 7.40 (ÍH, m), 7.09-7.14 (4H, m), 5.3 (2H, s), 3.8 (3H, s). Purity analysis HPLC: 99% at 2.44 min., (Retention time), (Xterra EM-C18, 4.6 X 50 mm); eluted with 30% up to 100% B, 4.5 min. gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); flow rate at 2.5 mL / min. UV detection at 220 nm.

EXAMPLE 369 Preparation of 8- (2-Methoxypyrimidin-5-yl) -7-p-tolyl-2- ((6- (rifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4 , 3-b] pyridazin-3 (2H) -one To a microwave reaction vessel containing a stir bar, catalyst was added Pd (Ph3P) 4 (30 mg, 25 μmol), followed by anhydrous dioxane (0.5 ml). To this was added 8-chloro-7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin- 3 (2H) -one (20 mg, 47 μmol), prepared as described in Example 362, 2-methoxypyrimidin-5-boronic acid (28.2 mg, 200 μmol), anhydrous dioxane (0.5 L) and aqueous K3P04 solution 2M (0.25 ml). The reaction vessel was flushed with nitrogen, closed and heated at 120 ° C for 10 minutes in a microwave reactor. The reaction mixture was filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); eluted with 30% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 30 mL / min. UV detection at 220 nm) for give the title compound 8- (2-methoxypyrimidin-5-yl) -7-p-tolyl-2- ((6- (trifluoromethyl) pyridin-3-yl) methyl) - [1, 2, 4] triazolo [ 4, 3-b] pyridazin-3 (2H) -one as a TFA salt. This compound was taken in 2 mL of methanol in a filtration column placed with a stopper and a polystyrene-based carbonate resin, PL-C03 MP resin, (100 mg, loading 2.4 mmol / g) was added. The contents were stirred for 2 h and methanol solution was filtered and evaporated under reduced pressure to give the title compound 8- (2-methoxypyrimidin-5-yl) -7-p-tolyl-2- ((6- (trifluoromethyl)) pyridin-3-yl) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one in a free base form (7.6 mg, 31% yield), as a solid crystalline yellow MS (M + H) = 494; A NMR (CD30D): d 8.79 (HH, s), 8.39 (1H, s), 8.07 (HH, d, J = 8.2 Hz), 7.84 (1H, s), 7.64-7.69 (2H, m), 7.24 (4H, m), 5.4 (2H, s), 3.81 (3H, s). Analytical HPLC purity: 99% at 2.13 min (retention time), (Xterra EM-C18, 4.6 X 50 mm); it was eluted with 30% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 2.5 mL / min. UV detection at 220 nm.

EXAMPLE 370 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yloxy) - [1,2,4] riazolo [4, 3-b] pyridazin- 3 (2H) -one 8-Chloro-7- (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (20 mg, 47 μmol), was prepared as described in Example 361F in 1-methylpyrrolidone (1 mL) in a 1 dram vial was added 3-hydroxypyridine (9.5 mg, 100 μmol), and anhydrous potassium carbonate (21 mg, 150 μmol). The reaction vessel was closed and heated at 80 ° C for 16 h in a turbo coil heater with stirring. The reaction mixture was filtered through a Whatman 0.45 μ syringe filter and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); it was eluted with 10% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TEA); Flow rate at 30 mL / min.

UV detection at 220 nm) to give the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chloropheyl) -8- (pyridin-3-yloxy) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a salt of TFA This compound was taken in 2 mL of methanol in a filtration column placed with a plug and a carbonate resin.

Based on polystyrene, PL-C03 MP resin was added (100 mg, loading 2.4 mmol / g). The contents were stirred for 2 h and the methanol solution was filtered and evaporated under reduced pressure to give the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-) iloxy) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one in a free base form (5.7 mg, 16% yield), as a crystalline yellow solid. MS (M + H) = 498; A NMR (CD30D): d 8.34 (HH, s), 8.30 (1H, s), 8.29 (HH, s), 7.51-7.53 (3H, m), 7.37 (2H, m), 7.31-7.32 (2H, m), 7.23-7.24 (2H,), 7.22 (1H, s), 5.07 (2H, s). Analytical HPLC purity: 99% at 2.07 min (retention time) (Xterra EM-C18, 4.6 X 50 mm); It was eluted with 10% to 100% B, gradient of 4.5 min, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 2.5 mL / min. UV detection at 220 nm. EXAMPLE 371 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7- (4-chlorofenyl) -8- (3-hydroxypyrrolidin-1-yl) -1, 2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) - ona (20 mg, 46 μmol), was prepared as described in Example 361, in 1-methylpyrrolidone (1 mL) in a 1 dram vial was added 3-pyrrolidinol (8.7 mg, 100 μmol). The reaction vessel was closed and heated at 80 ° C for 16 h in a turbo coil heater with stirring. The reaction mixture was filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); It was eluted with 10% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 30 mL / min. UV detection at 220 nm) to give the title compound, 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (3-hydroxypyrrolidin-1-yl) - [1, 2.4 ] triazolo [4, 3-b] pyridazin-3 (2H) -one, TFA salt, (18.5 mg, 52% yield), as a crystalline yellow solid. MS (M + H) = 498; A NMR (CD3OD): 7.79 (1H, s), 7.7-7.78 (2H, m), 7.58-7.60 (2H, m), 7.44-7.45 (2H, m), 7.35-7.37 (2H, m), 5.36 (2H, s), 3.73 (m, 2H), 3.55 (m, 1H), 3.52 (2H, m), 1.88 (2H, m). Analytical HPLC purity: 99% at 2.06 min (retention time), (Xterra EM-C18 (4.6 X 50 mm); Eluted with -10% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 2.5 mL / min, UV detection at 220 nm.

EXAMPLE 372 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (IH-imidazo-1-yl) -1,2,4] riazolo [4, 3-b] pyridazin -3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (20 mg, 46 μmol), prepared as described in Example 361, in 1-methylpyrrolidone (1 mL) in a 1 dram vial, was added imidazole (6.8 mg, 100 μmol). The reaction vessel was closed and heated at 80 ° C for 16 h in a turbo coil heater with stirring. The reaction mixture was filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra EM-C28, 30 X 50 mm); it was eluted with 10% up to 100% B, gradient of 8 min, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 30 mL / min. UV detection at 220 nm) to give the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazole-1 il) - [1, 2, 4] triazolo [4, 3-b) pyridazin-3 (2H) -one as a TFA salt. This compound was taken in 2 mL of methanol in a filtration column attached with a stopcock and polystyrene-based carbonate resin, PL-C03 MP resin (100 mg, loading 2.4 mmol / g) was added. The contents were shaken for 2 hours and the methanol solution was filtered and evaporated under reduced pressure to give the proposed 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazol-1) -yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3- (2H) -one in a free base form (18.5 mg, 52% yield), as a yellow crystalline solid. MS (M + H) = 471; 1 H NMR (CD3OD): δ 8.42 (ΔI, s), 7.83 (ΔI, s), 7.65-7.66 (2H, m), 7.57 (2H, m), 7.45-7.47 (2H, m), 7.28-7.29 (2H, m), 7.14 (ÍH, s), 7.07 (lH, s), . 33 (2H, s). Analytical HPLC Purity: 99% at 2.06 min (retention time), (Xterra EM-C18, 4.6 X 50 mm); It was eluted with 10% to 100% B, gradient of 4.5 min, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 2.5 mL / min. UV detection at 220 mm.

Example 373 Preparation of 2- (4- (Trifluoromethyl) benzyl) -8- (benzyloxy) -7- (4-chlorophenyl) - [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (20 mg, 46 μmol), prepared as described in Example 361, in 1-methylpyrrolidone (1 mL) in a 1 dram vial was added benzyl alcohol (10.8 mg, 100 μmol), and t-solution. 1M potassium butoxide in THF (100 μL). The reaction vessel was capped and stirred at room temperature for 16 h. The reaction mixture was quenched with 100 uL of methanol, filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra EM-C18, 30 X 50 mm); It was eluted with 10% up to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 30 mL / min.

UV detection at 220 nm) to give the title compound 2- (4- (Trifluoromethyl) benzyl) -8- (benzyloxy) -7- (4-chlorophenyl) - [1,2,4] triazolo [4.3- b] pyridazin-3 (2H) -one. (4.9 mg, 16% yield), as a yellow crystalline solid. MS (M + H) = 511; A NMR MeOD: d 8.25 (H, s), 7.60-7.7 (4H, m), 7.47-7.55 (4H, m), 7.13-7.31 (5H, m), 5.81 (2H, s), 5.39 (2H, s). Analytical HPLC purity: 99% at 2.31 min (retention time), (Xterra EM-C18, 4.6 X 50 mm); It was eluted with 10% to 100% B, gradient of 4.5 min, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate at 2.5 mL / min. UV detection at 220 nm. EXAMPLES 374 TO 468 The following examples were prepared in accordance with previously produced methods: twenty EXAMPLE 469 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7,8-bxs (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] riazolo [4,3- b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, (250 mg, 0.485 mmol), prepared as described in Example 17, in THF (4 mL) at -20 ° C was added methyl magnesium bromide (0.81 mL, 2.43 mmol, 3.0 M in Et20). The reaction was stirred at -20 ° C for 30 min. The LC-MS showed that the reaction was complete. 20 mL of MeOH was added to the reaction mixture to quench the reaction. The reaction was allowed to warm to room temperature and the solvent was evaporated. The residue was diluted with EtOAc (100 mL), washed with H20 (10 mL) and saturated aqueous NaCl (5 mL X 2). The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a system automated, eluted with a gradient of (0% to 80% EtOAc for 40 min and a 80% wait for 10 min.) to give the title compound, 2- (4- (Trifluoromethyl) benzyl) -7, 8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (254 mg), as a solid beige in 98% yield. CLAR retention time: 4.23 min; MS [M + H] +: found 531. At NMR (CDC13, 400MHz) d 7.52 (d, 2H), 7.38 (d, 2H), 7.17-7.11 (m, 4H), 7.05 (dd, 2H), 6.94 (dd, 2H), 4.94 (s, 2H), 4.16 (q, IH), 1.24 (d, 3H).

EXAMPLE 470 Preparation of (R) -2- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4 , 3-b] pyridazin-3 (2H) -one and (S) -2- (4- (Trifluoromethyl) benzyl) -7, 8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] riazolo [4,3- b] pyridazin-3 (2H) -one (R, S) -2- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4, 3- b) pyridazin-3 (2H) -one, prepared as described in 466, was separated into individual stereoisomers using the following chiral HPLC conditions: Chiral HPLC separation conditions: Chiral OJ 4.6 X 250 mm; solvent A: heptane and solvent B: 0.1% DEA in MeOH: EtOH fl: 1); 15% isocratic B; flow rate: 1 mL / min .; injection volume: 10 μL; UV wavelength: 254 nm. Isomer A: HPLC: 6.61 min; MS [M + H] +: found 531. Isomer B: HPLC: 11.45 min; MS [M + H] +: found 531.

EXAMPLE 471 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl- [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H -one To a solution of 2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,4] triazolo [4, 3-b] ] pyridazin-3 (2H) -one (28 mg, 0.053 mmol), prepared as described in Example 466 in CH2C12 (0.5 mL) 'at RT was added DDQ (15 mg, 0.064 mmol). The reaction was stirred at RT per lh.

LC-MS showed the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by using silica gel column chromatography using an automated system that was eluted with a gradient of (0% to 80% EtOAc for 20 min.) To give the title compound, 2- (4- ( trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (23 mg, 84% yield ) as a yellow solid in 84% yield. CLAR retention time: 4.18 min; MS [M + H] +: found 529. A NMR (CDC13, 400 MHz) d 7.61 (d, 2H), 7.52 (d, 2H), 7.35 (dd, 2H), 7.27 (dd, 2H), 7.16 ( dd, 2H), 7.02 (dd, 2H), 5.28 (s, 2H), 2.29 (s, 3H).

EXAMPLE 472 Preparation of 2- (4- (Trifluoromethyl) benzyl) -5-acetyl-7, 8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] riazolo [4 , 3-b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (8 mg, 0.015 mmol), prepared as described in Example 466 in CH2C12 (0.2 mL) at room temperature, He added diisopropyl ethyl amine (5.8 mg, 0.045 mmol), followed by acetyl chloride (2.4 mg, 0.030 mmol). The reaction was stirred at room temperature for 2 h. The LC-MS showed that the reaction was complete. The solvent was evaporated and the residue was purified using reverse phase HPLC to give the title compound, 2- (4- (Trifluoromethyl) benzyl) -5-acetyl-7,8-bis (4-chlorophenyl) -6-methyl 5,6-dihydro- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (6 mg, 70%) as a white solid. CLAR retention time: 4.23 min; MS [M + H] +: found 573. A NMR (CDC13, 400 MHz) d 7.65 (d, 2H), 7.51 (d, 2H), 7.30-7.22 (m, 4H), 7.17 (dd, 2H), 7.06 (dd, 2H), 5.70 (q, ÍH), 5.14-5.11 (m, 2H), 2.28 (s, 3H), 1.28 (s, 3H).

EXAMPLE 473 Preparation of 2- (4- (Trifluoromethyl) benzyl) -5-benzyl-7, 8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4 , 3-b] pyridazin-3 (2H) -one To a solution of 2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4, 3-b] ] pyridazin-3 (2H) -one (15 mg, 0.028 mmol) prepared as described in Example 466 in DMF (0.5 mL) at room temperature was added K2C03 (11.6 mg, 0.084 mmol), followed by benzyl bromide ( 9.6 mg, 0.056 mmol). The reaction was heated to 80 ° C overnight. The reaction was filtered. The collected solution was concentrated under reduced pressure. The crude product was purified using reverse phase HPLC to give the title compound, 2- (4- (Trifluoromethyl) benzyl) -5-benzyl-7,8-bis (4-chlorophenyl) -6-methyl-5,6 -dihydro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one, (2 mg, 11%) as a white solid. CLAR retention time: 4.44 min; MS [M + H] +: found 621. A NMR (CDC13, 400 MHz) d 7.60 (d, 2H), 7.45 (d, 2H), 7.33-7.29 (m, 5H), 7.23-7.13 (m, 4H ), 7.05-7.00 (m, 2H), 6.87-6.81 (m, 2H), 5.04 (s, 2H), 4.26-4.15 (m, 2H), 3.98-3.93 (q, 1H), 1.30 (d, 3H) ).

EXAMPLE 474 Preparation of 7,8-Bis (4-chlorophenyl) -2-methyl- [1,2,4] riazolo [4, 3-b] pyridazin-3 (2H) -one To a solution of 7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (100 mg, 0.28 mmol), prepared as described in Example 1, in DMF (3 mL) at room temperature was added K2C03 (116 mg, 0.84 mmol), followed by iodomethane (79 mg, 0.56 mmol). The reaction was heated to 60 ° C overnight. The reaction was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (20 mL X 3). The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure to give the title compound, 7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4 , 3-b] pyridazin-3 (2H) -one, (104 mg, 100%) as a yellow oil. CLAR retention time: 3.67 min; MS [M + H] A found 371.

EXAMPLE 475 Preparation of 6-Benzyl-7,8-bis (4-chlorophenyl) -2-methyl-5,6-dihydro- [1, 2,41-triazolo [4,3-b] pyridazin- To a solution of 7,8-bis (4-chlorophenyl) -2-methyl- [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (50 mg, 0.135 mmol), prepared as described in Example 471, in THF (1 mL) at -20 ° C was added benzyl magnesium bromide (0.34 mL, 0-675 mmol, 2.0 M in THF). The reaction was stirred at ~ -20 ° C for 30 min. After this time MeOH (5 mL) was added to quench the reaction. The reaction was allowed to warm to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using an automated system eluting with a gradient of (0% to 80% EtOAc for 20 min and a 80% wait for 20 min.) To give the title compound, 6-benzyl-7,8-bis (4-chlorophenyl) -2-methyl-5,6-dihydro- [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one (29 mg, 46%) as a beige solid. CLAR retention time: 4.10 min; MS [M + H] A found 463. A NMR (CDC13, 400 MHz) d 730-6.90 (m, 13H), 4.22 (t, ÍH), 3.36 (s, 3H), 2.90-2.75 (m, 2H) .

EXAMPLES 467 TO 487 The following Examples were prepared in accordance with the methods and procedures described above: The compounds of Series A below, in which R1 varies, R2 is 4-chlorophenyl, R3 is 2- (trifluoromethyl) pyridin-5-ylmethyl, R6 is hydrogen, R7 is absent, and n is a double bond, can be prepared by a person skilled in the art by the methods described above. The compounds of step A mean that they further illustrate the scope of the invention without limiting it in any way.

Stage A: As noted above, the A series consists of compounds that differ from each other only in the identity of R 1 with R 2 fixed as 4-chlorophenyl. Series A can be considered as a one-dimensional library of example compounds. If both R1 and R2 were to be varied, it would result in a two-dimensional library of example compounds. The B series is the two-dimensional library consisting of all the permutations of the variants of R1 represented in the series A and a set of R2 variants listed below. In the B series, R3 is 2 (trifluoromethyl) pyridin-5-ylmethyl, R6 is hydrogen, R7 is absent, and n is a double bond. The compounds of the B series can be prepared by one skilled in the art by the methods described above. The compounds of the B series means that they further illustrate the scope of the invention without limiting it in any way. Variants R2 of Stage B: Furthermore, as noted above, the B series is the two-dimensional library consisting of all the permutations of all the variants of R1 represented in the A series and a set of R2 variants previously listed with fixed R3 as 2- (trifluoromethyl) pyridine- 5-ylmethyl. If R1 and R2 and R3 were to be varied, a three-dimensional library of example compounds would result. The C series is the three-dimensional library consisting of all the permutations of all the variants of R1 represented in the series A, all the variants R2 previously listed for the series B, and a set of variants R listed below. In the C series, R6 is hydrogen, R7 is absent, and n is a double bond. The compounds of the C series can be prepared by one skilled in the art by the methods described above. The compounds of the C series mean that they further illustrate the scope of the invention without limiting it in any way.

Variants R3 of stage C: ^ As an additional illustration of the meaning of the C series, three representative structures of the C series are listed below with explanations of how they fall within the scope of the previous set C. These representative structures mean that they are illustrative without limiting it in any way. When R1 is chosen from the first member listed in the series A, R2 is selected as the first variant R2 listed in the series B, and R3 is chosen as the first variant listed R3 of the series C, the following structure results: When R1 is chosen from the last listed member of the series A, R2 is chosen as the last variant listed R2 of the series B, and R3 is chosen as the last variant R3 listed in the series C, the following structure results: When R1 is chosen from a randomly selected member of the A series, R2 is chosen as a variant randomly selected R of the series B, and R is chosen to be a randomly selected variant R3 of the C series, the following structure results: The additional non-limiting exemplary compounds that can be prepared by one skilled in the art by the methods described above are the following: Bioassay of the Canabinoid Receptor Binding Assay Radioligand binding studies were conducted on membranes prepared from Chinese Hamster Ovary (CHO) cells overexpressing human recombinant CB-1 (cells CHO-CB-1). The total assay volume for linkage studies was 100 μl. 5 μl of membranes were brought to a final volume of 95 μl with Binding Buffer solution (25 mM HEPES, 150 mM NaCl, 2.5 mM CaCl 2, 1 mM MgCl 2, 0.25% BSA). The diluted membranes were pre-incubated with a DMSO compound or vehicle. The binding reaction was initiated by the addition of 2 nM final 3H-CP-55,940 (120 Ci / mmol) and proceeded for 2.5 hours at room temperature. The binding reaction was terminated by transferring the reaction to GF / B 96-well plates (pre-soaked with 0.3% polyethylenimine) using a Packard Cell Harvester. The filter was washed with 0.25x PBS, 30 μL MicroScint per cavity was added, and the linked radiolabel was quantified by scintillation counting in a Packard TopCount Scintillator ion Counter. The radioligand binding assay was conducted identically except that the membranes of the CHO-CB-2 cells were used. For a compound to be considered a CB-1 antagonist, the compound must possess a binding affinity of the CB-1 Ki receptor of less than 13,000 nM. As determined by the assay described above, the Ki values of CB-1 receptor binding of Work examples 1-63 fall within the range of 0.01 nM to 10000 nM.

Functional Assay of the Canabinoid Receptor The functional CB-1 reverse agonist activity of the test compounds was determined in CHO-CB-1 cells using a cAMP accumulation assay. CHO-CB-1 cells grew in 96-well plates near confluence. On the day of the functional assay, the growth medium was aspirated and 100 of Assay Buffer Solution (PBS plus 25mM HEPES / 0.1MM 3-isobutyl-1-methylxanthine / 0.1% BSA) were added. The compounds were added to the buffer solution of the diluted 1: 100 Assay of 100% DMSO and allowed to preincubate for 10 minutes before the addition of 5 uM of forskolin. The mixture was allowed to proceed for 15 minutes at room temperature and was terminated by the addition of 0.1 N HCl. The total intracellular cAMP concentration was quantified using the SPA cAMP kit from Amersham.

UTILITIES AND COMBINATIONS Utilities The compounds of the present invention are cannabinoid receptor modulators, and include compounds which are, for example, selective agonists, partial agonists, inverse agonists, antagonists or partial antagonists of the cannabinoid receptor. Accordingly, the compounds of the present invention may be useful for the treatment or prevention of diseases and disorders associated with the G protein-coupled cannabinoid receptor activity. Preferably, the compounds of the present invention possess activity as antagonists or inverse agonists of the CB-1 receptor, and can be used in the treatment of diseases or disorders associated with CB-1 receptor activity. Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for treatment of a variety of conditions and disorders, including, but not limited to, metabolic and feeding disorders in addition to conditions associated with metabolic disorders, ( for example, obesity, diabetes, arteriosclerosis, hypertension, polycystic ovarian disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, hyperlipidemic conditions, bulimia nervosa and compulsive eating disorders) or psychiatric disorders, such as abuse of substance, depression, anxiety, mania and schizophrenia. These compounds can also be used for the improvement of cognitive function (for example, the treatment of dementia, which includes Alzheimer's disease, short-term memory loss and attention deficit disorders); neurodegenerative disorders (e.g., Parkinson's disease, cerebral stroke and craniocerebral trauma) and hypotension (e.g., hemorrhagic hypotension and induced endotoxin). These compounds can also be used for the treatment of catabolism in connection with pulmonary dysfunction and ventilator dependence; treatment of cardiac dysfunction (eg, associated with valvular disease, myocardial infarction, cardiac hypertrophy or failure of congestive heart); and improvement of general lung function; transplant rejection; rheumatoid arthritis; multiple sclerosis; inflammatory bowel disease; lupus, graft versus host disease; T-cell hypersensitivity disease; psoriasis; asthma; Hashimoto's thyroiditis; Guillain Barre syndrome; Cancer; contact dermatitis; allergic rhinitis; and ischemic or reperfusion injury. The compounds used in the treatment of appetite or motive disorders regulate the desire to consume sugars, carbohydrates, alcohol or drugs and more generally regulate the consumption of ingredients with a hedonic value. In the present description and in the claims, appetite disorders are understood as meaning: disorders associated with a substance and especially abuse of a substance and / or dependence on a substance, eating behavior disorders, especially those prone to cause excess of weight, without taking into account its origin, for example: bulimia nervosa, sugar cravings. The present invention therefore further relates to the use of a CB-1 receptor antagonist or inverse agonist for the treatment of bulimia and obesity, which includes obesity associated with type II diabetes (diabetes not dependent on insulin), or more generally any disease that results in the patient becoming overweight. Obesity, as described here, was defined by an index of 'body mass (Kg / m2) of at least 26. This may be due to any cause, - either genetic or environmental that includes overfeeding and bulimia, disease of polycystic ovary, craniofaringeoma, Prader-Willi syndrome, Frohlich syndrome, Type II diabetes, growth hormone deficiency, Turner syndrome and other pathological conditions characterized by reduced metabolic activity or reduced energy expenditure. As used with reference to the uses described herein, the term "treatment" encompasses prevention, partial relief, or cure of the disease or disorder. In addition, the treatment of obesity is expected to prevent progression of medical covariates of obesity, such as arteriosclerosis, Type II diabetes, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders. The compounds in the present invention also they may be useful in the treatment of substance abuse disorders, which includes dependence on substance or abuse without physiological dependence. Substances of abuse include alcohol, amphetamines (or substances similar to amphetamines), caffeine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or compounds similar to phencyclidine), sedative hypnotics or benzodiazepines, and other substances (or not known) and combinations of the above. The terms "substance abuse disorders" also include drug or alcohol withdrawal syndromes and substance induced anxiety or mood disorder with onset during withdrawal. The compounds of the present invention may be useful in the treatment of cognitive disorders and memory impairments. The condition of memory damage is manifested by damage of the ability to learn new information and / or the inability to remember information previously learned. Memory damage is a primary symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creut zfeld-Jakob disease, HIV, disease cardiovascular, and head trauma in addition - cognitive impairment related to age. Dementias are diseases that include memory loss and additional intellectual damage separated from memory. Cannabinoid receptor modulators may also be useful in the treatment of cognitive impairments related to attention deficits, such as attention deficit disorder. The compounds of the present invention can also be used in the treatment of diseases associated with dysfunction of brain dopaminergic systems, such as Parkinson's Disease, and substance abuse disorders. Parkinson's disease is a neurodegenerative movement disorder characterized by bradykinesia and tremor. Like the cannabinoid receptor modulators, the compounds of the present invention are also useful for the treatment and prevention of respiratory diseases and disorders. Respiratory diseases for which cannabinoid receptor modulators are useful include, but are not limited to, chronic obstructive pulmonary disorder, emphysema, asthma, and bronchitis. In addition, the receiver modulators Cannabinoids block the activation of lung epithelial cells by portions such as allergic agents, inflammatory cytokines or smoke, thereby limiting the release of mucin, cytokines, and chemokines, or selective inhibition of lung epithelial cell activation. Moreover, the compounds employed in the present invention can stimulate inhibition pathways in cells, particularly in leukocytes, lung epithelial cells, or both, and thus are useful in the treatment of diseases. "Leukocyte activation" was defined herein as any or all of cell proliferation, cytosine production, adhesion protein expression, and production of inflammatory mediators. "Epithelial cell activation" was defined here as the production of any or all of mucins, cytokines, chemokines, and expression of addition protein. The use of the compounds of the present invention for the treatment of disorders associated with leukocyte activation is exemplified by, but is not limited to, treatment of a range of disorders such as: transplant rejection (such as organ transplantation, acute transplantation). , xenotransplant or heteroinj ert or homograft (as used in the treatment of burn)); protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplant tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis, pulmonary and respiratory diseases that include but are not limited to chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); Inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, lupus, (systemic lupus erythematosus); graft versus host disease; T-cell-mediated hypersensitive diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis, contact dermatitis (which includes that due to poison ivy); Hashimoto's thyroiditis, Sjogren's syndrome, Autoimmune Hyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; Urticaria, allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute respiratory and inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplanteris Pustulosis; Hypoderma gangrenosum; Sezary syndrome; atopic dermatitis; systemic sclerosis; and orfea. The term "disease associated with leukocyte activation" or "leukocyte activation-mediated" as used herein includes each of the diseases or disorders referenced above. In a particular embodiment, the compounds of the present invention are useful for the treatment of the exemplary disorders mentioned above without regard to their etiology. The combined activity of the compounds presented to monocytes, macrophages, T cells, etc., may be useful in the treatment of any of the aforementioned disorders. Cannabinoid receptors are important in the regulation of gamma Fe receptor responses of monocytes and macrophages. The compounds of the present invention inhibit the gamma Fe-dependent production of alpha TNF in human monocytes / macrophages. The ability to inhibit monocyte and macrophage-dependent responses of the gamma Fe receptor results in additional anti-inflammatory activity for the compounds present. This activity is especially valuable, for example, in the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, the present compounds are useful for the treatment of autoimmune glomerulonephritis and other examples of glomerulonephritis induced by deposition of immune complexes in the kidney that cause gamma Fe receptor responses leading to kidney damage. Cannabinoid receptors are expressed in lung epithelial cells. These cells are responsible for the secretion of mucins and inflammatory cytokines / chemokines in the lung and thus are intrinsically involved in the generation and progression of respiratory diseases. Cannabinoid receptor modulators regulate both spontaneous and stimulated production of both mucins and cytokines. Thus, the compounds are useful in the treatment of respiratory and pulmonary diseases including, COPD, ARDS, and bronchitis. In addition, cannabinoid receptors can be expressed in intestinal epithelial cells and hence regulate the production of mucin and cytosine and can be of clinical use in the treatment of inflammatory diseases related to the intestine. Cannabinoid receptors are also expressed in lymphocytes, a subset of leukocytes. Thus the cannabinoid receptor modulators will inhibit the activation, proliferation and differentiation of the T and B cells. Thus, the compounds will be useful in the treatment of autoimmune diseases involving any antibody or cell-mediated response such as multiple sclerosis and lupus. In addition, cannabinoid receptors regulate the induced degranulation of chemokine and epsilon Fe receptor of connective tissue cells and basophils. These play important roles in asthma, allergic rhinitis, and other allergic diseases. The epsilon Fe receptors are stimulated by IgE antigen complexes. The compounds of the present invention inhibit the epsilon Fe induced degranulation responses, which include the basophil cell line, RBL. The ability to inhibit the basophil and cell-dependent connective tissue responses of the epsilon Fe receptor results in additional anti-inflammatory and anti-allergic activity for the compounds present. In particular, the present compounds are useful for the treatment of asthma, allergic rhinitis, and other examples of allergic disease.

Combinations The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compounds of the present invention can be used alone, in combination with other appropriate therapeutic agents useful in the treatment of the aforementioned disorders that include anti-obesity agents; antidiabetic agents, appetite suppressants; cholesterol-lowering agents / lipids, HDL-raising agents, cognition-enhancing agents, agents used for neurodegeneration treatment, agents used for treatment of respiratory conditions, agents used to treat bowel disorders, anti-inflammatory agents; anti-anxiety agents; antidepressants; anti-hypertensive agents; cardiac glycosides; and anti tumor agents. Other therapeutic agents can be administered before, simultaneously with, or followed by the administration of the cannabinoid receptor modulators according to the invention. Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include melanocortin receptor agonists (MC4R), melanin concentration hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor antagonists (GHSR ), galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, and other peptides derived from Pre-proglucagon; antagonists NPY1 or NPY5, modulators NPY2 and NPY4, agonists of factor of release of corticotropin, modulators of histamine 3 receptor (H3), aP2 inhibitors, PPAR range modulators, delta PPAR modulators, acetyl-CoA carboxylase inhibitors (ACC), 11-p-HSD-1 inhibitors, adinopectin receptor modulators, agonists beta 3 -adrenergic agonists known as described in US Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as a thyroid receptor ligand as described in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98 / 284425 (KaroBio), a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (eg, BVT-933 (Biovitrum)), monoamine reuptake inhibitors or release agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline , chlorphentermine, cloforex, clortermine, pi cilorex, sibutramine, dexa fetamine, phentermine, phenylpropanolamine or mazindol, anorexic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor) / Axokine® (Regeneron), BDNF (brain-derived neurotrophic factor), modulators of leptin and leptin receptor, or cannabinoid-1 receptor antagonists, such as SR-141716 (sanofi) or SLV-319 (Solvay). Examples of anti-diabetic agents suitable for use in combination with the compounds of the present invention include: insulin secretagogues or insulin synthesizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR agonists. such as thiazolidinediones, PPARa agonists (such as fibric acid derivatives), PPARβ agonists or agonists, PPAR aa double agonists, 11-β-HSD-1 inhibitors, dipeptidyl peptidase inhibitors IV (DP4), SGLT2 inhibitors, inhibitors of glycogen phosphorylase, and / or meglitinides, in addition to insulin, and / or glucagon-like peptide-1 (GLP-1), GLP-1 agonist, and / or an inhibitor of PTP-1B (tyrosine protein inhibitor) of phosphate asa-lB). The antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl. Where the antidiabetic agent is a biguanide, the compounds of the present invention will be employed in a ratio weight for biguanide within the range of about 0.001: 1 to about 10/1, preferably from about 0.01: 1 to about 5: 1. The antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (described in U.S. Patent No. 4,379,785), glipizide, gliclazide or chlorpropa ida, other known sulfonylureas or other antihyperglycemic agents that act in the ATP-dependent channel of the beta cells, with glyburide and glipizide are preferred, which can be administered in the same oral dosage forms or in separate. The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (described in US Patent No. 4,904,769) or miglitol (described in US Patent No. 4,639,436), which may be administered therein or in a separate oral dosage form. The compounds of the present invention can be used in combination with a PPAR agonist and such as an oral antidiabetic agent thiazolidinedione or other insulin synthesizers (which have an insulin sensitive effect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone (Takeda), MCC-555 from Mitsubishi (described in U.S. Patent No. 5,594,016), GL-262570 of Glaxo-Welcome, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT / J &J), JTT-501 (JPNT / P & U), L-895645 (Merck), R-119702 (Sankyo / WL), NN-2344 (Dr.

Reddy / NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone. The compounds of the present invention can be used with a double PPAR a /? Agonist. such as MK-767 / KRP-297 (Merck / Kyorin; as described in, K. Yajima, et al., Am. J. Physiol. Endocrinol. MEtab., 284: E966-E971 (2003)), AZ-242 (t esaglitazar; Astra-Zeneca, as described in B. Ljung, et al., J. Lipid Res., 43, 1855-1863 (2002)); muraglitazar; or the compounds described in U.S. Patent No. 6,414,002. The compounds of the present invention can be used in combination with antihyperlipidemia agents, or agents used to treat arteriosclerosis. An example of a hypolipidemic agent may be a reductase inhibitor of HMG CoA which includes, but is not limited to, mevastatin and related compounds as described in US Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as described in U.S. Patent No. 4,231,938, pravastatin and related compounds such as described in U.S. Patent No. 4,346,227, simvastatin and related compounds as described in U.S. Patent Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors that may be employed herein include, but are not limited to, fluvastatin, described in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in the Patents US Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin (Nissan / Sankyo nisvastatin (NK-104) or itavastatin), described in U.S. Patent No. 5,011,930, Shionogi-Astra / Zeneca rosuvastatin (Visastatin (ZD-4522 )) described in U.S. Patent No. 5,260,440, and related statin compounds described in U.S. Patent No. 5,753,675, pyrazole analogues of mevalonolactone derivatives as described in U.S. Patent No. 4,613,610. indene analogues of mevalonolactone derivatives as described in the PCT application WO 86/03488, 6- [2- (substituted pyrrol-1-yl) -alkyl] pyran-2-ones and derivatives thereof as described in U.S. Patent No. 4,647,576, SC-45355 from Searle (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as described in PCT application WO 86/07054, 3-carboxylic acid derivatives -2-hydroxy-propan-phosphonic acid as described in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as described in European Patent Application No. 0221025, analogs of mevalonolactone naphthyl as US Pat. No. 4,686,237, octahydronaphthalenes such as described in US Patent No. 4,499,289, mevinolin keto analogs (lovaest atina) as described in European Patent Application No. 0,142,146 A2, and derivatives thereof, were described. quinoline and pyridine described in U.S. Patent Nos. 5,506,219 and 5,691,322. In addition, the phosphinic acid compounds useful in inhibition of HMG CoA reductase suitable for use herein are described in GB 2205837. Suitable scapenase synthetase inhibitors for use herein include, but are not limited to, α-phosphono sulfonates described in U.S. Patent No. 5,712,396, those described by Billar, et al., J. Med. Chem. , 31, 1869-1871 (1998) including isoprenoid phosphonates (phosphinyl-methyl) in addition to other known squalene synthetase inhibitors, for example, as described in U.S. Patent Nos. 4,871,721 and 4,924,024 and in Billar, SA, Neuenschwander, K., Ponpipom, MM, and Poulter, CD, Curren t Pharma ceu ti cal Desi gn, 2, 1-40 (1996). In addition, other inhibitors of squalene synthetase suitable for use herein include the terpenoid pyrophosphates described by P. Ortiz de Montellano, et al., J. Med. Ch em. , 20, 243-249 (1977), analog A of farnesyl diphosphate and presqualene pyrophosphate analogues (PSQ-PP) as broken down by Corey and Volante, J. Am. Chem. Soc. , 98, 1291-1293 (1976), phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem. Soc, 109, 5544 (1987) and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dep. Med. Chem. U of UTA, Summary, Table of Contents, pp. 16, 17, 40-43, 48-51, Compendium. Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and compounds related as disclosed in U.S. Patent No. 3,674,836, with probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and colestagel (Sankyo / Gelte), as well as lipostabil (Rhone -Poulec), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanilfos-forylcholine (SPC, Roche), aminocyclodextine (Tanabe Seiyoku), Ajinomoto AJ-814 (derived from azulen), melinamide (Sumitomo), Sandoz (58-035, American Cyanamid CL-277.082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid, Aspirin, poly (diallylmethylamine) derivatives such as those described in U.S. Patent No. 4,759,923, quaternary amine poly (diallyldimethylammonium chloride) and ionenes such as are described in US Patent No. 4,027,009, and other cholesterol lowering agents in known whey. The other hypolipidemic agent can be an ACAT inhibitor (which also has anti-atherosclerosis activity) as described in, Drugs of the Fu ture, 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters ", Nicolosi et al, Atherosclerosis (Shannon, Irel), 137 (1), 77-85 (1998); "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev., 16 (1), 16-30 (1998); "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C., et al., Bioorg. Med. Chem. Lett, 6 (1), 47-50 (1996); "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animáis", Karuse and collaborators, Editor (s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC, Boca Ratón, Fia .; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al., Curr. Med Chem., 1 (3), 204-25 (1994); "Inhibitors of acyl-Co: cholest erol O-acyl transferase (ACAT) as hypocholesterolemic agents.

The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl- CoA: Cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N '- [(l-phenylcyclopentyl) -methyl] ureas with enhanced hypocholescent erolemic activity ", Stout et al., Ch em tra cts: Org. Chem., 8 (6) , 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), in addition to F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434. Hypolipidemic may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd.) and LY295427 (Eli Lilly). The hypolipidemic agent may be a cholesterol absorption inhibitor preferably SCH48461 (ezetimibe) from Schering-Plow in addition to those described in Atheros cl erosi 115, 45-63 (1995) and J. Med. Ch em 41, 973 (1998) The other lipid agent or lipid modulating agent can be a protein inhibitor of cholesteryl transfer (CETP) such as CP-529,414 from Pfizer in addition to those described in WO / 0038722 and EP 818448 (Bayer) and EP 992496, and SC-744 and SC-795 from Pharmacia, in addition to CETi-1 and JTT-705. The hypolipidemic agent can be a Na + / bile ileal acid cotransporter inhibitor as described in Drugs of the Future, 24, 425-430 (1999). The ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those described in U.S. Patent No. 5,447,954. The other lipid agents also include a phytoestrogen compound as described in WO 00/30665 which includes isolated soybean protein, concentrated soy protein and soybean meal in addition to an isoflavone such as genistein, daidzein, glycitein or equol , or phytosterols, phytostanol, or tocotrienol as described in WO 200/015201; a beta-lactam cholesterol absorption inhibitor as described in EP 675714; an HDL top regulator such as an LXR agonist, a PPAR- agonist and / or an FXR agonist; an LDL catabolism promoter as described in EP 1022272; a sodium proton exchange inhibitor as described in DE 19622222; an LDL receptor inducer or a spheroidal glycoside such as described in U.S. Patent No. 5,698,527 and GB 2304106; an antioxidant such as beta-carotene, ascorbic acid, α-tocopherol or retinol as described in WO 94/15592 in addition to Vitamin C and antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as described in WO 97/35576; a cholesterol absorption inhibitor, a HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor as described in WO 97/48701; a PPAR 5 agonist for treatment of dyslipidemia; or sterol regulating element linking the I (SREBP-1) protein as described in WO 2000/050574 are, for example, a sphingolipid, such as ceramide, or neutral esfingomielenasa (N-SMase) or fragment thereof. Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin and rosuvastatin, in addition to niacin and / or cholestagel. The compounds of the present invention can be used in combination with anti-hypertensive agents. Examples of suitable antihypertensive agents for use in combination with the compounds of the present invention include beta-adrenergic blockers, calcium channel blockers (type L and / or type T, for example diltiazem, verapamil, nifedipine, amoldipine and ibefradil), diuretics (for example, chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricinafen, chlorthalidone, furosemide, musolimine, bumetanide, triamthrenone, amiloride, spironolactone), renin inhibitors, ACE inhibitors (eg, captopril, zofenopril, fosinopril) , enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), angiotensin aT-1 receptor (e.g., losartan, irbesartan, valsartan), ET antagonists receptor (e.g., sitaxsentan, atrsentan and compounds disclosed in uS Patent Nos. 5,612,359 and 6,043,265), dual ET antagonist / AII (eg compounds described in WO 00/01389), neutral endopeptidase inhibitors (NEP) inhibitors, vasopeptidase (double NEP-ACE inhibitors) (by example, omapatrilat and gemopatrilat), and nitrates. Cannabinoid receptor modulators may be useful in the treatment of other diseases associated with obesity, including sleep disorders. Therefore, the compounds described in the present invention can be used in combination with therapeutics for the treatment of sleep disorders. Examples of appropriate therapies for treatment of sleep disorders for use "in combination with the compounds of the present invention include melatonin analogues, melatonin receptor antagonists, ML 1 B agonists, GABA receptor modulators; NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and modulators of orexin receptor. the receptor modulators cannabinoid may reduce or ameliorate substance abuse or addictive disorders. therefore, the combination of receptor modulators cannabinoid with agents used . to treat addictive disorders may they reduce the dose requirement or improve the efficacy of therapeutic current addictive disorder examples used to treat substance abuse or addictive disorders agents are inhibitors selective serotonin reuptake (SSRI), methadone, buprenorphine , nicotine and bupropion, receptor modulators Canabinoids can reduce anxiety or depression; therefore, the compounds described in this application can be used in combination with anti-anxiety or antidepressant agents. Examples of anti-anxiety agents suitable for use in combination with the compounds of the present invention include benzodiazepines (e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, clorazepate, halazepam and prazepam), agonists of 5HT1A receptor (e.g., buspirone, flesinoxan, gepirone and ipsapirone) , and corticotropin releasing factor (CRF) antagonists. Examples of appropriate classes of antidepressants for use in combination with the compounds of the present invention include norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRI) (Fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOI) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible monoamine oxidase inhibitors (RIMA) (moclobemide) , reuptake inhibitors of serotonin and norepinephrine (SNRI) (venlafaxine), corticotropin releasing factor receptor (CRF) antagonists, alpha-adrenoreceptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine). The combination of a conventional antipsychotic drug with a CB-1 receptor antagonist can also improve the reduction of the symptom in the treatment of psychosis or mania. In addition, such a combination can make possible the reduction of the rapid symptom, reducing the need for chronic treatment with antipsychotic agents. Such a combination may also reduce the requirement for effective antipsychotic dose, resulting in reduced likelihood of development of the common motor dysfunction of chronic antipsychotic treatment. Examples of suitable antipsychotic agents for use in combination with the compounds of the present invention include the phenothiazine classes (chlorpromazine, mesoridazine, thioridazine, acet ofenazine, fulfenazine, perphenazine and trifluoperazine), thioxanthin (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), diphenylbutylpiperidine (pimozide) and indole (molindolone) of antipsychotic agents.

Other antipsychotic agents with potential therapeutic value in combination with the compounds of the present invention include loxapine, sulpiride and Risperidone The combination of the compounds in the present invention with conventional antipsychotic drugs can also provide an improved therapeutic effect for the treatment of schizophrenic disorders, as described above for manic disorders. As used herein, schizophrenic disorders include paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, disillusion disorder, brief psychotic disorder and psychotic disorder not otherwise specified. Examples of antipsychotic drugs suitable for combination with the compounds of the present invention include the antipsychotics mentioned above, in addition to dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A / dopamine receptor antagonists or partial agonists (e.g. , olanzepine, aripiprazole, risperidone, ziprasidone). The compounds described in the present invention can be used to improve the effects of cognition enhancing agents, such as acetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1 agonists (eg, milamelin), nicotinic agonists, glutamic acid receptor modulators (AMPA and NMDA), and nootropic agents (eg, piracetam, levetiracetam). Examples of appropriate therapies for the treatment of Alzheimer's disease and cognitive disorders for use in combination with the compounds of the present invention include donepezil, tacrine, stigraine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi blockers. -K, and KCNQ blockers. The compounds described in the present invention can be used to improve the effects of agents used in the treatment of Parkinson's disease. Examples of agents used to treat Parkinson's disease include: levadopa with or without a COMT inhibitor, antiglutamatergic drugs (amantadite, rluluzol), alpha-2 adrenergic antagonists such as idazoxan, opioid antagonists, such as naltrexone, other dopamine agonists or carrier modulators, such as ropinirole, or pramipexole or neurotrophic factors such as glial-derived neurotrophic factor (GDNF) ). The compounds described in the present invention can be used in combination with appropriate anti-inflammatory agents. Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, cyclooxygenase inhibitors (ie,, COX-1 and / or COX-2 inhibitors such as NSAID, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists / antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, integrin alpha-4 beta-7 antagonists, cell adhesion inhibitors, gamma interferon antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (eg, infliximab , OR1384, which includes TNF-alpha inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel®), rapamycin (sirolimus or Rapamune) and leflunomide (Arava)), inhibitors of prostaglandin synthesis, budesonide, clofazimine, CNI-1493, CD4 antagonists (for example, priliximab), activated p38 mitogen protein kinase inhibitors, protein tyrosine kinase inhibitors (PTK), and therapies for the treatment of irritable bowel syndrome (for example, open s of Zelnorm ® and Maxi-K® such as those described in US Patent No. 6,184,231 Bl). Examples of such other therapeutic agents that can be used in combination with cannabinoid receptor modulators include the following: cyclosporins (eg, cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2 , anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody 0KT3, agents that block the interaction between CD40 and gp39, such as antibodies specific for CD40 and / or gp39 (that is, CD154), fusion proteins constructed of CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as inhibitors of nuclear translocation, of function 'NF-kappa B, such as deoxyspergualin (DSG), gold compounds, antiproliferative agents such as meotrexate , FK506 (tacrolimus, Prograf), mycophenolate mofetil, cototoxic drugs such as azathiprine and cyclophospha, anticit ocins such as antiIL-4 or IL-4 receptor fusion proteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitors described in following request U.S. Pat. Nos. 5,200,338, filed on June 15, 1998, are incorporated by reference herein in their entirety: Ser. No. 09 / 097,338; Ser. No. 09 / 094,797, filed June 15, 1998; Ser. No. 09 / 173,413, filed on October 15, 1998; and Ser. No. 09 / 262,525, filed March 4, 1999. See also the following documents and references cited there and incorporated herein by reference: Hollengaugh, D., et al., "Cleavable CD40Ig Fusion PRoteins and the Binding to Sgp39" , J. Immunol. Methods (NetheRlands), 188 (1), pp. 1-7 (Dec. 15, 1995); Hollengaugh, D. et al., "The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Recipient: Expression of a Soluble Form of GP39 with B Cell Co-Stimulatory Activity", EMBO J ( England), 11 (12), pp. 4313-4321 (December 1992); and Moreland, L. W. et al., "Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Receptor Factor (P75) -Fe Fusion Protein," New England J. of Medicine, 337 (3), pp. 141-147 (1997). The other therapeutic agents above, when used in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by an ordinary expert in the technique.

The compounds of the formula (I) of the invention can be administered orally or parenterally, as well as subcutaneously or intravenously, in addition to by nasal application, rectally or sublingually to various mammalian species known to be subject to such conditions, for example, humans. , in an effective amount of up to 1 gram, preferably up to 200 mg, more preferably up to 100 mg in a regimen of one, two or four divided doses during the day. The compounds of the formula (I) can be administered by any of the uses described herein by any appropriate means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally parenterally, as well as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, as well as by inhalation of dew; externally, such as in the form of a cream or ointment; or rectally as in the form of suppositories; in dosage unit formulations containing pharmaceutically available vehicles or diluents acceptable, non-toxic. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of pharmaceutically appropriate compositions comprising the compounds present, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally. Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for volume imparting, alginic acid or sodium alignate as a suspending agent, methylcellulose as a viscosity improver, and sweetening or flavoring agents such as those known in the art. The technique; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, entenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of the formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those formulations of the present compounds with fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. High molecular weight excipients such as celluloses (avicel) or propylene glycols (PEG) may also be included in such formulations. Such formulations may also include an excipient to aid mucosal adhesion such as hydroxypropylcellulose.

(HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic acid copolymer (e.g., Gantrez), and release controlling agents such as polyacrylic copolymer (e.g., Carbopol 934). Lubricating agents, glidants, flavorings, colorants and stabilizers can also be added for ease of manufacture and use. Exemplary nasal spray compositions or administration by inhalation include saline solutions which may contain, for example, benzyl alcohol and other suitable preservatives, absorption promoters to improve biocapacity, and / or other solubilization or dispersing agents such as those known in the art. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution , or other suitable dispersing or humidifying and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including fatty acids, or Cremafor. Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at normal temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. Exemplary compositions for external administration include an external carrier such as Plastibase ('mineral oil gelled with polyethylene). It will be understood that the specific dose level and frequency of dosing for any particular subject may be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the period of action of that compound, the species , age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of the drug, and severity of the particular condition. It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of the general principles of the invention, and the invention is not necessarily limited thereto. Certain modifications and variations in any given material, process step or chemical formula will be readily apparent to those skilled in the art without departing from the true spirit and scope of the present invention, and all modifications and variations should be considered. within the scope of the claims that follow. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (73)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. Compound of formula I which includes all pharmaceutically acceptable prodrugs, salts and stereoisomers, characterized in that: n is a single bond or a double bond; R1 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NRBRk C02Rc -C0NR 8aRD93 -0R £ NRAOR-NR8CON8R9, -NR8C02R9, -OCONR8R9, -NRA (0) mRs, NR8S (0) mNR8R9, -NR8S (0) mOR9 and -OS (O) mNR8R9; R2 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, eroariloxi het, NR8R9, C02R8, -CONR8R9, -OR8, NR8COR9 , NR8CON8R9, -NR8C02R9, OCONR8R9, -NR 8 S (0) MR9, -NR 8 S (0) mNR8R9, -NR 8 S (0) mOR9 and -OS (0) mNR8R9; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, ein the R6 group has a molecular weight of less than 200 atomic mass units; R7 is absent n is a double bond; R7 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR 8, C02R8, -CONR8R9 and S (0) m-R8 n is a link simple; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can optionally form a 4, 5, 6 or 7 membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; m is an integer of 1 or 2.

2. A compound according to claim 1, ein: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy , heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and NR8R9; R3 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, ein the group R6 has a molecular weight of less than 200 atomic mass units; R7 is absent; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can optionally form a 5-, 6- or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and n is a double bond.

3. Compound according to claim 2, characterized in that: R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; ein the group R5 has a molecular weight of less than 200 atomic mass units.

4. Compound according to claim 3, characterized in that: R2 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR and NR8R9.

5. Compound according to claim 4, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and NR8R9.

6. Compound according to claim 5, characterized in that: R3 is selected from the group consisting of alkyl, cycloalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl.

The compound according to claim 1, characterized in that: R1 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of alkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl and heterocyclyl wherein the group R can have a molecular weight of less than 200 atomic mass units; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 when taken together can optionally form a 5-, 6- or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and n is a double bond.

Compound according to claim 7, characterized in that: R6 is selected from the group consisting of H, methyl, ethyl and isopropyl.

9. Compound according to claim 8, characterized in that: R2 is selected from the group consisting of aryl and heteroaryl wherein the aryl or heteroaryl group is optionally substituted with the group consisting of H, alkyl, haloalkyl, halogen, heterocyclyl , aryl, heteroaryl, -OR8, -C02R8, CONR8R9, -S02R8 and -S02NR8R9.

10. Compound according to claim 9, characterized in that: R1 is selected from the group consisting of heterocyclyl, aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9 wherein the heterocyclyl, aryl, heteroaryl, aryloxy or heteroaryloxy group is optionally substituted with the group consisting of H, cyano, haloalkyl , alkyl, halogen, heterocyclyl, aryl, heteroaryl, -OR8, -C02R8, CONR8R9, S02R8 and S02NR8R9.

11. Compound according to claim 10, characterized in that: R3 is selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl, wherein the arylalkyl, heteroarylalkyl or heterocycloalkyl group is optionally substituted with the group consisting of hydrogen, cyano, haloalkyl, alkyl, cycloalkyl, halogen, hydroxyl, amino, -OR8, -NR8NR9, -S02R8, -S02NR8R9, heteroaryl, heterocyclyl and aryl.

12. Compound according to claim 1, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of alkyl, cycloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the Re group has a molecular weight of less than 200 atomic mass units; R7 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, -CONR8R9, -C02R8, -COR8 and -S02R8; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 when taken together can optionally form a 5-6-7 membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and n is a simple link.

13. Compound according to claim 12, characterized in that: R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the group R6 has a molecular weight of less than 200 atomic mass units.

14. Compound according to claim 13, characterized in that: R7 is selected from the group consisting of H, alkyl, -COR8, -C02R8, -CONR8R9 and -S02R8.

15. Compound in accordance with the claim 14, characterized in that: R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9.

16. Compound in accordance with the claim 15, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9.

17. Compound according to claim 16, characterized in that: R3 is selected from the group consisting of alkyl, cycloalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl.

18. Compound according to claim 1, characterized in that: R1 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of alkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, arylalkyl and heteroarylalkyl, wherein the group R6 has a molecular weight of less than 200 atomic mass units; R7 is selected from the group consisting of H, -COR8, -C02R8, -CONR8R9, and -S02R8; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 when taken together can optionally form a 5-, 6- or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and n is a simple link.

19. Compound in accordance with the claim because it is selected from: 25 25 25 25 25

20. Compound according to claim 1, characterized in that it is selected from: 25 25

21. Compound according to claim 1, characterized in that it is selected from: 25

22. Pharmaceutical composition, characterized in that it comprises: at least one compound according to formula I which includes all prodrugs, salts and stereoisomers pharmaceutically acceptable wherein: n is a single bond or a double bond; R1 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NR8R9, C02R8, -CONR8R9, -OR8, NR8C0R9, NR8CON8R9, -NR8C02R9, -OCONR8R9, -NR8S (0) mR9, NR8S (0) mNR8R9, -NR8S (0) mOR9 and -OS (O) mNR8R9; R2 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NR8R9, C02R8, -CONR8R9, -OR8, NR8COR9, NR8CON8R9, -NR8C02R9, OCONR8R9, -NR8S (0) mR9, -NR8S (O) mNR8R9, -NR8S (0) mOR9 and -OS (0) mNR8R9; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the group R6 has a molecular weight of less than 200 atomic mass units; R7 is absent when n is a double bond; R7 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR8, -C02R8, -C0NR8R9 and S (0) mR8 when n is a single bond; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can optionally form a 4, 5, 6 or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and m is an integer of 1 or 2, and at least one pharmaceutically acceptable diluent or carrier.

23. Pharmaceutical composition according to claim 22, characterized in that it additionally comprises: at least one different therapeutic agent.

24. Method for treating a disease or disorder mediated by the cannabinoid receptor, characterized in that comprising: administering to the patient in need of treatment a therapeutically effective amount of the compound according to formula I: which includes all pharmaceutically acceptable prodrugs, salts and stereoisomers wherein: n is a single bond or a double bond; R1 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NR8R9, C02R8, -CONR8R9, -OR8, NR8COR9, NR8CON8R9, -NR8C02R9, -OCONR8R9, -NR8S (0) mR9, -NR8S (O) mNR8R9, -NR8S (0) mOR9 and -OS (0) mNR8R9; R2 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NR8R9, C02RB, -C0NR > 8BnR93, -0RB, NRBCORk NRBCON 8BpR9k -NRaC02R3 -OCONR8R9, - NR8S (0) mR9, -NR8S (0) mNR8R9, -NR8S (0) mOR9 and -OS (0) mNR8R9; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the R6 group has a molecular weight of less than 200 atomic mass units; R7 is absent when n is a double bond; R7 is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR8, -C02R8, -CONR8R9 and S (0) mR8 when n is a single bond; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can optionally form a 4, 5, 6 or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and m is an integer of 1 or 2.

25. Pharmaceutical combination characterized by comprises a pharmaceutical composition according to claim 22 and a therapeutic agent selected from anti-obesity agents; appetite suppressants; antidiabetic agents; anti-hyperlipidemia agents; hypolipidemic agents; hypocholesterolemic agents; lipid modulating agents; cholesterol reducing agents; lipid reducing agents; agents that raise HDL; anti-hypertension agents; agents used to treat sleep disorders; agents used to treat substance abuse and addictive disorders; anti-anxiety agents; anti-depressants; anti-psychotic agents; agents that increase cognition; agents used to treat cognitive disorders; agents used to treat Alzheimer's disease; agents used to treat Parkinson's disease; anti-inflammatory agents; agents used to treat neurodegeneration; agents used to treat atherosclerosis; agents used to treat respiratory conditions; agents used to treat bowel disorders; cardiac glycosides; and anti-tumor agents.

26. A pharmaceutical combination according to claim 25, characterized in that the other therapeutic agent can be administered before, simultaneously with, or after administration of the pharmaceutical composition according to claim 22.

27. Pharmaceutical combination according to claim 25, characterized in that the anti-obesity agent is selected from melanocortin receptor agonists (MC4R); antagonists of the hormone receptor that concentrates melanin (MCHR); antagonists of the growth hormone secretagogue receptor (GHSR); Galanin receptor modulators; orexin antagonists; CCK agonists; GLP-1 agonists and other peptides derived from pPre-proglucagon; NPY1 or NPY5 antagonists; modulators NPY2 and NPY4; agonists of the corticotropin release factor; modulators of histamine-3 receptor (H3); aP2 inhibitors; PPAR gamma modulators; PPAR delta modulators; acetyl carboxylase inhibitors CoA (ACC); inhibitors ll- (3-HSD-l, adiponectin receptor modulators; beta 3 adrenergic agonists, including AJ9677 that, L750355 and CP331648 or other known beta 3 agonists; beta modulator thyroid receptor; lipase inhibitors, orlistat and including ATL-962; agonists serotonin receptor, including BVT-933; inhibitors or releasing agents monoamine reuptake including fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine , Phentermine, phenylpropanolamine and mazindol; Anorectic agents, including topiramate; ciliary neurotrophic factor, including Axokina; neurotrophic factor derived from the brain; modulators of leptin and leptin receptor and other cannabinoid-1 receptor antagonists, including SR-141716 and SLV-319.

28. Pharmaceutical combination according to claim 25, characterized in that the antidiabetic agent is selected from insulin secretagogues; insulin sensitizers; anti-hyperglycemic agents; biguanides; sulfonyl ureas; glucosidase inhibitors; inhibitors of aldose reductase; PPAR agonist? which include thiazolidinediones; PPAR a agonists, which include fibric acid derivatives; antagonists or PPAR β agonists; PPAR dual agonists a / ?; 11-ß-HSD-1 inhibitors; inhibitors of dipeptidyl peptidase IV; SGLT2 inhibitors; glycogen phosphorylase inhibitors; meglit inidas; insulin; Glucagon type 1 peptide; glucagon type 1 peptide agonists; and inhibitors of the protein tyrosine phosphate asa-lB.

29. Pharmaceutical combination according to claim 28, characterized in that the anti-diabetic agent is an oral anti-hyperglycemic agent. selected from biguanides, metformin, performin, metformin HCl and other salts thereof.

30. The pharmaceutical combination according to claim 29, characterized in that the other therapeutic agent is biguanide and the compound according to claim 1 will be administered in a weight ratio to the biguanide within the range from about 0.001: 1 to about 10: 1 >

31. Pharmaceutical combination in accordance with claim 28 wherein the sulfonyl ureas are selected from glyburide, glibenclamide, glimepiride, glipizide, gliclazide, chlorpropamide, other known sulfonylureas or other anti-hyperglycemic agents acting on the ATP-dependent channel of the beta cells.

32. Pharmaceutical combination according to claim 31, characterized in that the combination of the compound of claim 1 and the sulfonyl urea are administered in the same or in separate oral dosage forms.

33. Pharmaceutical combination according to claim 28, characterized in that the glucosidase inhibitor is selected from acarbose and miglitol.

34. A pharmaceutical combination according to claim 33, characterized in that the combination of the compound of claim 1 and the glucosidase inhibitor is administered in the same or in separate oral dosage forms.

35. Pharmaceutical combination according to the rei indication 28, characterized in that the PPAR agonist? is an oral anti-diabetic agent of thiazolidinedione.

36. Pharmaceutical combination in accordance with claim 28, wherein the insulin sensitizer is selected from rosiglitazone, pioglitazone, MCC-555, GL-262570, englitazone, darglitazone, isaglitazone; JTT-501, L-895645, R119702, NN-2344 and YM-440.

37. Pharmaceutical combination according to claim 28, characterized in that the dual PPAR agonists a /? they are selected from MK-767 / KRP-297, tesaglitazar and muraglitazar.

38. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the HMG CoA reductase selected from mevastatin; compounds related to mevastatin; lovastatin; Mevinolin; compounds related to lovastatin and Mevinolin; pravastatin and compounds related to pravastatin; simvastatin and compounds related to simvastatin; fluvastatin; cerivastatin; atorvastatin; pitavastatin; nisvastatin; itavastatin; rosuvastatin; visastatin; compounds related to rosuvastatin and visastatin; pyrazole analogues derived from mevalonolactone; indene analogues; mevalonolactone derivatives; 6 [-2-substituted-pyrrol-1-yl) alkyl) pyran-2-ones- and derivatives thereof, - SC-45355; substituted pentandioic acid derivatives 3; dichloroacetate; imidazole analogues of mevalonolactone; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives; 2,3-substituted pyrrolo, furan and thiophene derivatives; mevalonolactone naphthyl analogs; octahydronaphthalenes; keto analogs of lovastatin and mevinolin; quinoline and pyridine derivatives; and phosphinic acid compounds.

39. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the squalene synthetase selected from α-phosphono-sulfonates; isoprenoid phosphonates (phosphinyl-methyl); analogue of farnesil of disphosphate and pyrophosphate analogues prescualen; phosphinyl phosphonates; and cyclopropanes.

40. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is a fibric acid derivative selected from fenofibrate; gemfibrozil; clofibrate; bezafibrate; ciprofibrate; elinofibrate; probucol; and compounds related to probucol.

41. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is a bile acid sequestrant selected from cholestyrene ina; colestipol; DEAE-Sephadex; Secholex; Policexido; cholestagel; lipostabil; E-5050; N-substituted ethanolamine derivatives; imanixil; tetrahydrolipstatin; isygmas tañilfos-forilcolina; aminocyclodextrin; AJ-814; azulena derivatives; melinamide; 58-035; CL-277,082; CL-283,546; urea di-substituted derivatives; nicotinic acid; niacin; acipimox; acifran; neomycin; p-aminosalicylic acid; aspirin; poly (diallylmethylamine) derivatives; poly (diallylmethylammonium) chloride of quaternary amine; ionones; and other known serum cholesterol lowering agents.

42. Pharmaceutical combination of compliance with claim 25, characterized in that the hypolipidemic agent is an acyl CoA: 0-acyl cholesterol transferase inhibitor selected from N-phenyl-N '- [(1-phenylcyclopentyl) methyl] urea; TS-962; F-1394; CS-505; F-12511; HL-004; K-10085; and YIC-C8-43.

43. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an up-regulator of LDL receptor activity that includes MD-700.

4 4. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of cholesterol absorption that includes ezetimibe.

45. Pharmaceutical combination according to claim 25, characterized in that the lipid modulating agent is an inhibitor of the transferase cholesterol protein selected from CP-529,414; SC-744; SC-795; CETi-1; and JTT-705.

46. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the co-transport of Na + ileal / biliary acid.

47. Pharmaceutical combination according to claim 25, characterized in that the Hypolipidemic agent is an inhibitor of citrate lyase ATP.

48. Pharmaceutical combination according to claim 25, characterized in that the lipid modulating agents are selected from the selected phytoestrogen compound of isolated soybean protein, soy protein concentrate, soybean meal, isoflavone, genistein, daidzein, glycitein or ecol, or phytosterols, phytostanol and tocotrienol; an inhibitor of beta-lactam cholesterol absorption; an HDL regulatory envelope selected from an LXR agonist, a PPAR agonist and an FXR agonist; a promoter of LDL catabolism; an inhibitor of sodium-proton exchange; an inducer of the LDL receptor; steroidal glucoside; an antioxidant selected from beta-carotene, ascorbic acid, α-tocopherol, retinol, vitamin C antihomocysteine agent, folic acid, folate, vitamin B6, vitamin B12 and vitamin E; isoniazid; an inhibitor of cholesterol absorption; an HMG-CoA synthase inhibitor; a lanosterol demethylase inhibitor; a PPAR d agonist to treat dyslipidemia; a regulatory element of the sterol bound to the protein I selected from sphingolipid, ceramide, neutral sphingomyelinase or fragments thereof.

49. Pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is selected from pravastatin; lovastatin; simvastatin; atorvastatin; fluvastatin; pitavastatin; rosuvastatin; niacin and cholestagel.

50. Pharmaceutical combination according to claim 25, characterized in that the anti-hypertensive agents are selected from beta-adrenergic blockers; blockers of L-type channels selected from diltiazem, verapamil, nifedipine, amlodipine and mibefradil; T-type calcium blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mibefradil; diuretics selected from chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrinafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride and spironolactone, renin inhibitors; selected AGE inhibitors of captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril and lisinopril; antagonists of AT-1 receptor selected from losartan, irbesartan and valsartan; ET receptor antagonists selected from sitaxsentan and atrsentan; ET / AII dual antagonists; inhibitors of the neutral endopeptidase; vasopeptidase inhibitors and dual NEP-ACE inhibitors selected from omapatrilat and gemopatrilat and nitrates.

51. Pharmaceutical combination according to claim 25, characterized in that the agent used to treat sleep disorders is selected from melatonin analogues; Melatonin receptor antagonists; ML 1 B agonists; modulators of the GABA receptor; NMDA receptor modulators; modulators of the histamine-3 receptor (H3); Dopamine agonists and orexin receptor modulators.

52. Pharmaceutical combination according to claim 25, characterized in that the agent used to treat the abuse of addictive substances and disorders is selected from selective serotonin reuptake inhibitors; methadone; buprenorphine; nicotine and bupropion.

53. Pharmaceutical combination according to claim 25, characterized in that the anti-anxiety agent is selected from benzodiazepines selected from diazepam, lorazepam, oxazepam, alprazolam, chlordiazapoxide, clonazepam, clorazepate, halazepam and prazepam; 5HT1A receptor agonists selected from buspirone, flesinoxan, gepirone and ipsapirone; and antagonists of the factor that releases corticotropin.

54. Pharmaceutical combination according to claim 25, characterized in that the antidepressant agent is selected from norepinephrine reuptake inhibitors selected from tertiary and secondary tricyclic amines; selective serotonin reuptake inhibitors selected from fluoxetine, fluvoxamine, paroxetine and sertraline; monoamine oxidase inhibitors selected from isocarboxiazide, phenelzine, t-ranilcypromine and selegiline; reversible inhibitors of monoamine oxidase including moclobemide; serotonin and norepinephrine reuptake inhibitors including venlafaxine; antagonists of the factor receptor that releases corticotropin; alpha-adrenoreceptor antagonists, - and atypical antidepressants selected from bupropion, lithium, nefazodone, trazodone and viloxazine.

55. Pharmaceutical combination according to claim 25, characterized in that the ant i-psychotic agent is selected from phenothiazine selected from chloropromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine; thioxanthin selected from chlorprothixene and thiothixene; heterocyclic dibenzazepine selected from clozapine, olanzepine and aripiprazole; butyrophenone, including haloperidol; diphenylbutylpiperidine, including pimazide; indole and molindolone classes of anti-psychotic agents; loxapine; sulpiride; risperidone; Dopamine receptor antagonists; muscarinic receptor agonists; 5HT2A receptor antagonists, 5HT2 S / dopamine receptor antagonists and selected partial agonists of olanzepine, aripiprazole, risperidone and ziprasidone.

56. Pharmaceutical combination according to claim 25, characterized in that the cognition enhancing agent is selected from acetylcholinesterase inhibitors, including tacrine; muscarinic receptor 1 agonists, including milamelin; nicotinic agonists; modulators of the glutamic acid receptor; and selected nootropic agents of piracetam and levetiracetam.

57. Pharmaceutical combination of compliance with claim 25, characterized in that the agent used to treat Alzheimer's disease and the agent used to treat cognitive disorders are selected from donepezil; tacrine; revast igraina; 5HT6; inhibitors of gamma secretase; inhibitors of beta secretase; SK channel blockers; Maxi-K blockers; and KCNQ blockers.

58. Pharmaceutical combination according to claim 25, characterized in that the agent used to treat Parkinson's disease is selected from levadopa with or without a COMT inhibitor; antiglutamatergic drugs selected from amantadine and riluzole; alpha-2 adrenergic antagonists including idazoxan; opiate antagonists including naltrexone; other dopamine agonists and carrier modulators including ropinirole; and pramipexole or neurotrophic factors that include the neurotrophic factor derived from the gial.

59. Pharmaceutical combination according to claim 25, characterized in that the anti-inflammatory agent is selected from prednisone; dexamethasone; cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors selected from NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen, Celebrex and Vioxx; agonists and CTLA4-Ig antagonists; antagonists of the CD40 ligand; 1MPDH inhibitors including mycophenolate; integrin antagonists; alpha-4 beta-7 integrin antagonists; inhibitors of cell adhesion; interferon gamma antagonists; ICAM-1; tumor necrosis factor antagonists selected from infliximab, OR1384, TNF-alpha inhibitors including tenidap, anti-TNF antibodies or soluble TNF receptors including etanercept; rapacihina selected from sirolimus and Rapamune; eflunomide; inhibitors of prostaglandin synthesis; budesonide; clofazimine; CNI-1493; CD4 antagonists that include priliximab; protein kinase inhibitors activated by the p38 mitogen; inhibitors of the protein tyrosine kinase; IKK inhibitors; and agents for the treatment of irritable bowel syndrome selected from Zelnorm and Maxi-K openers.

60. Pharmaceutical combination according to claim 25, characterized in that the other therapeutic agent is selected from cyclosporins; cyclosporin A; anti-IL-2 receptor; anti-CD45RB; anti-CD2; anti-CD3 (OKT-3); anti-CD4; anti-CD80; anti-CD86; monoclonal antibody OKT3; agents that block the interaction between CD40 and gp39; - antibodies specific for CD40 and / or gp39; CD154; fusion proteins .constructed from CD40 and gp39; CD40Ig; CD8gp39; inhibitors of the nuclear translocation of the NF-kappa B function; deoxyspergualin; gold compounds; antiproliferative agents selected from methotrexate, FK506, tacrolimus, prograf and mycophenolate mofetil; cytotoxic drugs selected from azathiprine and cyclophosphamide; anti icit ocins selected from fusion proteins of the anti-IL-4 or IL-4 receptor; PDE 4 inhibitors including Ariflo and PTK inhibitors.

61. Method according to claim 24, characterized in that the disease or disorders are associated with CB-1 receptor activity.

62. Method according to claim 61, characterized in that the diseases or disorders are bulimia, obesity or any disease that result in the patient belonging to overweight.

63. Method according to claim 61, characterized in that the diseases or disorders are metabolic disorders, eating disorders and appetite disorders, which include the treatment of conditions associated with those disorders, such as obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disease, hypertension, insulin resistance, hypercholesterolemia, hyperglyceridemia, cholelithiasis and sleep disorders , hyperlipidemic conditions, bulimia nervosa and compulsive eating disorders.

64. Method according to claim 61, characterized in that the diseases or disorders are obesity due to genetic or environmental causes, including bulimia and excess food, polycystic disease of the ovaries, craniopharynxoma, Prader-Willi syndrome, Frohlich syndrome, type II diabetes, deficiency of the hormone of the growth, Turner syndrome and other disease states characterized by reduced metabolic activity or reduced energy expenditure.

65. Method according to claim 61, characterized in that the diseases or disorders are psychiatric disorders selected from substance abuse, addictive disorders, depression, anxiety, ania and schizophrenia.

66. Method for the relief of cognitive function and memory impairment, which include the treatment of selected diseases of dementia, Alzheimer's disease, short-term memory loss and disorders in attention deficit, neurodegenerative disorders, Parkinson's, cerebral apoplexy and craniocerebral trauma, hypotension, endotoxin-induced hypotension and hemorrhagic, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, head trauma, and age-related cognitive decline, characterized because it comprises administering to a mammal species in need of treatment, a therapeutically effective amount of a compound as defined in claim 24.

67. Method for the treatment of diseases associated with dysfunction of brain dopaminergic systems including Parkinson's and substance abuse disorders, ca characterized in that it comprises administering to a mammalian species in need of treatment, a therapeutically effective amount of a compound as defined in claim 24.

68. Method for the treatment of diseases selected from catabolism in connection with pulmonary dysfunction and ventilator dependence, cardiac dysfunction, valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure; transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft-versus-host disease, T cell-mediated hypersensitivity disease, psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis and ischemic or reperfusion injury, characterized in that it comprises administering to a mammal species in need of treatment, a therapeutically effective amount of a compound as defined in claim 24.

69. Method for the treatment of substance abuse or disorders of dependence in which substances of abuse or dependence include alcohol, amphetamines, amphetamine-type substances, caffeine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine, compounds of type phencyclidine, sedative hypnotics, benzodiazepines, other known or unknown substances, or combinations of substances of abuse, characterized in that it comprises administering to a species of mammals in need of treatment, a therapeutically effective amount of a compound as defined in claim 24.

70. Method according to claim 69, characterized in that substance abuse or dependence can occur without physiological dependence.

71. Method of treatment of withdrawal syndromes of alcohol or drugs and anxiety induced by substances or mood disorders with start during withdrawal, characterized in that it comprises administering to a species of mammals in need of treatment, a therapeutically effective amount of a compound such as is defined in claim 24.

72. Method for the treatment of disorders associated with the activation of leukocytes, including rejection due to organ transplants, acute transplantation, xenotransplantation, heterograft or homograft; protection from ischemic or reperfusion injury such as ischemic or reperfusion incurred during organ transplantation, myocardial infarction, stroke or other causes; transplant tolerance induction; rheumatoid arthritis, psoriatic arthritis or osteoarthritis; multiple sclerosis, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); Inflammatory bowel disease, ulcerative colitis and Crohn's disease, systemic lupus erythematosus; graft versus host disease; T-cell-mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, gluten-sensitive enteropathy, and Celiac disease; psoriasis, contact dermatitis; Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, such as Graves' disease; Addison's disease, polyglandular autoimmune disease or syndrome; autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; hives, asthma, hay fever, allergic rhinitis and skin allergies; scleracierma; mycosis fungoides; answers acute respiratory and inflammatory, including acute respiratory distress syndrome and ischemia / reperfusion injury; dermatomyositis is; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplanteris Pustulosis; Pyoderma gangrenum; Sezary syndrome; atopic dermatitis; systemic sclerosis; and morphea, characterized in that it comprises administering to a mammalian species a therapeutically effective amount of a compound as defined in claim 24.

73. Method for the treatment of inflammatory diseases, including arthritis, inflammatory bowel disease and autoimmune glomerulonephritis, characterized in that comprises administering to a mammalian species in need of treatment, a therapeutically effective amount of a compound as defined in claim 24.