KR20070018824A - Azabicyclic heterocycles as cannabinoid receptor modulators - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising a compound according to formula (I), at least one compound according to formula (I) and optionally one or more additional therapeutic agents, and a treatment using the compound according to formula (I) alone or in combination with one or more additional therapeutic agents. It is about a method. This compound is represented by Formula I (R ¹ , R ² , R ³ , R ⁶ , R ⁷ , m and n are as described herein) and includes all precursors, pharmaceutically acceptable salts and stereoisomers .

<Formula 1>

Cannabinoids, Azabicyclic

Description

Azabicyclic heterocycle, cannabinoid receptor modulator {AZABICYCLIC HETEROCYCLES AS CANNABINOID RECEPTOR MODULATORS}

This application claims the priority rights of U.S. Provisional Application No. 60 / 531,451, filed December 19, 2003 under U.S. Patent Act (Code Title 35) 119 (e), the contents of which are incorporated herein by reference. Included.

Delta-9-tetrahydrocannabinol ("Delta-9 THC"), the main active ingredient in Cannabis sativa (marijuana), is known to control appetite, suppress immunity, analgesia, inflammation, vomiting, and analgesia. is a member of a broad group of lipophilic compounds (ie cannabinoids) that mediate physiological and psychological effects, including nocioception, sedation, and intraocular pressure. Other members of the cannabinoid group include endogenous (arachidonic acid-derived) ligands, anandamides, 2-arachidonyl glycerol, and 2-arachidonyl glycerol ethers. Cannabinoids act through selective binding to G-protein coupled cannabinoid receptors and activation of the receptor. CB 1 (LA Matsuda, et al., Nature, 346,561-564 (1990)), and CB2 (S. Munro, et al., Nature, 365, 61-65 (1993)). Two types of cannabinoid receptors were cloned. CB 1 receptors are highly expressed in the central and peripheral nervous systems (M. Glass, et al., Neuroscience, 77,299-318 (1997)), but CB2 receptors are highly expressed in immune tissues, especially in the spleen and tonsils. CB2 receptors are also highly expressed in other immune system cells, such as lymphoid cells (S. Galiegue, et al., Eur J Biochem, 232,54-61 (1995)). The functional activity of cannabinoid receptors results in inhibition of cAMP accumulation, stimulation of MAP kinase activity, and closure of calcium channels.

There is substantial evidence that cannabinoids control appetite behavior. Stimulating CB-1 activity with anandamide or delta-9 THC results in increased food intake and weight gain in various species, including humans (see Williams and Kirkham, Psychopharm., 143,315-317 (1999)). ). Gene knockout of CB-1 was informed and dried compared to wild-type mice from litter (DiMarzo, et al., Nature, 410,822-825 (2001)). A published study of CB-1 small molecule antagonists demonstrated the reduction of food intake and body weight in rats (Trillou, et. Al., A77J Plzysiol. Regul. Integr. Comp. Physiol., R345-R353, (2003)). . Chronic administration of CB-1 antagonist AM-251 for two weeks results in substantial weight loss and a decrease in adipose tissue mass (Hildebrandt, et. Al., Eur. J. Pharm, 462, 125-132 (2003)). There have been a number of studies examining the anorexic effect of Sanofisa's CB-1 antagonist SR-141716 (Rowland, et. Al., Pyschopharm., 159-11-116, (2001); Colombo, et. Al., Life Sci., 63,113-117 (1998)).

There are at least two CB-1 antagonists as clinical trials for appetite control, such as Sanofi's SR-141716 and Solvay's SLV-319. The published Phase IIb data showed that SR-141716 reduced the weight of human subjects regardless of dose during the 16 week trial period. In addition, CB-1 antagonists have been shown to promote discontinuation of smoking behavior. Phase II clinical data on smoking cessation were presented at an informative meeting in Sanofi-Siltellabo in September 2002. This data shows that 30.2% of patients treated with high doses of SR-141716 control smoking compared to 14.8% for placebo.

The present invention relates to pharmaceutical compositions comprising a compound of formula (I), at least one compound of formula (I), and optionally one or more additional therapeutic agents, and a method of treatment using the compound of formula (I) alone or in combination with one or more additional therapeutic agents. Doing. This compound includes all prodrugs, pharmaceutically acceptable salts and stereoisomers and has the structure of formula (I). R ¹ , R ² , R ³ , R ⁶ , R ⁷ , m and n are as described later.

Definition of Terms

The following definitions apply to the terms used throughout this specification, unless otherwise specified in the specific examples.

As used herein, the term "alkyl" defines a branched or unbranched hydrocarbon chain of 1 to 20 carbon atoms, preferably 1 to 12, more preferably 1 to 8 carbon atoms in a normal chain, eg For example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl Pentyl and the like. Furthermore, alkyl groups are usually attached to possible carbon atoms as defined herein and include, but are not limited to, for example, hydroxyl, halo, haloalkyl, mercapto or thio, cyano, alkylthio, cycloalkyl, heterocyclyl , Aryl, heteroaryl, carboxyl, carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, Optionally substituted with one or more functional groups, such as -OC (O) NR ⁸ R ⁹ , -OC (O) R ⁸ , -OPO ₃ H, -OS0 ₃ H, and the like, trifluoromethyl, 3-hydroxyhexyl, Alkyl groups such as 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like can be formed.

Unless otherwise indicated, the term "alkenyl" as used herein or as part of another group refers to vinyl, 2-propenyl, 3-butenyl, 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 Straight or branched chain having 2 to 20 carbon atoms, preferably 2 to 12 and more preferably 2 to 8 carbon atoms, having at least one double bond in the main chain, such as 4,8,12-tetradecanetrienyl and the like. Refers to. Furthermore, alkenyl groups as defined herein may be halo, haloalkyl, alkyl, alkoxy, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoyl, optionally at any carbon atom. One or more functional groups normally attached to the chain, such as amino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio (not limited to these) and / or any of the alkyl substituents listed above May be optionally substituted with.

Unless otherwise indicated, the term "alkynyl" as used herein or as part of another group refers to 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2 -Hexynyl, 3-hexynyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 3-octinyl, 3-noninyl, 4-decynyl, 3-undecynyl, 4-dodecynyl As such, it refers to a straight or branched chain having 2 to 20, preferably 2 to 12, more preferably 2 to 8 carbon atoms having at least one triple bond in the main chain. Furthermore, alkynyl groups herein are halo, haloalkyl, alkyl, alkoxy, alkenyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoylamino, alkyl at any possible carbon atom. It may optionally be substituted with one or more functional groups normally attached to the chain, such as amido, arylcarbonylamino, nitro, cyano, thiol alkylthio, and / or any of the alkyl substituents listed herein.

Unless otherwise indicated, the term “cycloalkyl”, employed alone or as part of another group, refers to monocyclicalkyl, bicyclicalkyl containing 3 to 20, preferably 3 to 10 carbon atoms constituting the ring. And saturated or partially unsaturated (including one or more double bonds) cyclic hydrocarbon groups containing from one to three rings, including tricyclicalkyl, and suspended or fused. These may be fused with one or two aromatic rings as described for aryl. Examples of these include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

을 포함한다.

It includes.

Furthermore, any cycloalkyl is hydrogen, halo, haloalkyl, alkyl, alkoxy, haloalkyloxy, hydroxyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy, arylalkyl at any possible carbon atom. With one or more groups selected from among heteroarylalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or alkyl substituents May be optionally substituted.

As used herein, alone or as part of another group, the term “cycloalkylalkyl” means an alkyl group as defined above having a cycloalkyl substituent. Wherein said "cycloalkyl" and / or "alkyl" groups may be optionally substituted as described above.

Unless indicated otherwise, the term "aryl" as used herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or 1-naphthyl). And naphthyl including 2-naphthyl). And they may optionally comprise one or three additional rings fused with a carbocyclic ring or a heterocyclic ring, for example the following.

In addition, "aryl" as defined herein refers to 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, hetero Arylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amino, substituted amino, wherein one or two substituents wherein amino is alkyl, aryl or other aryl compounds mentioned in the preceding definitions Including], thiols, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxy Carbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl and / or It may be optionally substituted with any of the alkyl substituents listed above.

Unless otherwise indicated, the term “heteroaryl”, used alone or as part of another group, refers to a 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 hetero atoms, such as nitrogen, oxygen, or sulfur. Refer. Such rings may be fused with aryl, cycloalkyl, heteroaryl or heterocyclyl and are described in Katritzky, A.R. And Rees, C.W. 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 possible N-oxides described in the literature described above. Furthermore, "heteroaryl" as defined herein may be optionally substituted with one or more substituents, such as the substituents previously included in the definitions of "substituted alkyl" and "substituted aryl". Examples of heteroaryl groups include the following.

As used herein, alone or as part of another group, the term “heteroarylalkyl” refers to an alkyl group as described above having a heteroaryl substituent. Wherein said heteroaryl and / or alkyl group may be optionally substituted as described above.

As used herein, the terms "heterocyclo", "heterocycle", "heterocyclyl" or "heterocyclic ring" are substituted or unsubstituted stable consisting of carbon atoms and one to four heteroatoms selected from nitrogen, oxygen or sulfur. 4 to 7-membered monocyclic ring systems are shown. Here, nitrogen and sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms may be tetravalent. Heterocyclic rings may be attached to any heteroatom or carbon atom, resulting in a stable structure. Such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxazinyl, azepineyl, pyrrolyl, pyrrolidinyl, furanyl, Thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isox Sazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and See 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. Compehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; And other heterocycles described in the documents incorporated therein.

“Heterocycloalkyl”, used herein alone or as part of another group, refers to an alkyl group as described above having a heterocyclyl substituent. Wherein said heterocyclyl and / or alkyl group may be optionally substituted as described above.

As used herein, alone or as part of another group, the terms “arylalkyl”, “arylalkenyl” and “arylalkynyl” refer to alkyl, alkenyl and alkynyl as described above having aryl substituents. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl, naphthylmethyl and the like.

The terms "alkoxy", "aryloxy", "heteroaryloxy", "arylalkyloxy", or "heteroarylalkyloxy", used alone or as part of another group herein, are defined above linked through an oxygen atom. Refers to alkyl or aryl.

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.

As used herein, the term “methylene” refers to the group —CH ₂ —.

As used herein, the term "nitro" refers to the group -N0 ₂ .

Compounds of formula I may be provided as salts, which are also within the scope of the present invention. Preferred are pharmaceutically acceptable (ie non-toxic, physiologically acceptable) salts. If the compounds of the formula (I) have, for example, one or more basic centers, they can form acid addition salts. These can be formed, for example, using mineral acids, for example inorganic strong acids such as sulfuric acid, phosphoric acid or hydrohalogenic acid, or using organic carboxylic acids, such as alkanes with 1 to 4 carbon atoms such as acetic acid, where the organic carboxylic acid is Saturated or unsaturated dicarboxylic acids such as chloroacetic acid, which may be substituted or unsubstituted, for example, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid; Hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; Such as amino acids, (eg, aspartic acid or glutamic acid, or lysine or arginine); Or benzoic acid can be used or can be formed using organic sulfonic acids such as (C ₁ -C ₄ ) alkyl or arylsulfonic acids, unsubstituted or substituted with halogen, for example methyl- or p-toluene-sulfonic acid. Having additional base centers can also form corresponding acid addition salts as needed. Compounds of formula (I) with at least one acid group (eg 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 such as sodium, potassium or magnesium salts, or ammonia or organic amines such as morpholine, thiomorpholine, piperidine, pyrroli Dine, mono, di- or tri-lower alkylamines such as ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or mono, di or trihydroxy lower alkylamines, Examples thereof include salts with mono, di or triethanolamine. Furthermore, corresponding internal salts may also be formed. Salts which are not suitable for pharmaceutical use but which can be used for the isolation or purification of the free compounds of formula (I) or pharmaceutically acceptable salts may also be included.

Preferred salts of compounds of formula (I) containing basic groups include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate, nitrate or acetate.

Preferred salts of compounds of formula I containing acidic groups include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

The term "modulator" means to enhance (eg, "partner" activity) or partially enhance (eg, "partial agent" activity) or to inhibit (eg, " Antagonist "activity or" reverse agonist "activity). Such enhancement or inhibition may be incidental to the occurrence of certain events, such as activation of signal transduction pathways, and / or may only be manifested in particular cell types.

The term "bioactive metabolite" as used herein refers to any functional group that has an open valence for further substitutions that are included in the compound of formula (I) and give rise to the compound of formula (I) upon in vivo transformation. Non-limiting examples of such bioactive metabolites include -OH, -NH or functional groups, where the hydrogen is -P0 ₃ H which, upon in vivo transformation, generates, for example, the -OH or -NH functional group of the compound of formula (I). It may be substituted with a functional group such as ₂ .

As used herein, the term “prodrug drug ester” refers to the reaction of acylating agents substituted with one or more hydroxy groups of a compound of formula (I) with alkyl, alkoxy, or aryl using procedures known in the art to provide acetate, pivalate, methylcarbonate, Esters and carbonates formed by producing benzoates and the like. Prodrug esters also include, but are not limited to, groups such as phosphate esters, phosphonate esters, phosphonamidate esters, sulfate esters, sulfonate esters, and sulfonate middate esters, where the esters are limited thereto But may be further substituted with groups that provide a pharmaceutical benefit such as favorable water solubility or exposed in vivo to the bioactive component formula (I).

As used herein, the term “prodrug” refers to those that functionalize the bioactive amine- or hydroxyl-containing compound of Formula I to form alkyl-, acyl-, sulfonyl-, phosphoryl-, or carbohydrate-substituted derivatives. Include. Such derivatives are formed by reacting a compound of formula (I) with an alkylating agent, acylating agent, sulfonylating agent or phosphorylating agent using procedures known in the art. Alkylation of the amines of formula (I) may produce derivatives comprising spacer moieties in other prodrug moieties, such as substituted alkoxymethyl-, acyloxymethyl-, phosphoryloxymethyl-, or sulfonyloxymethyl- groups It is not limited to this. Alkylation of the amines of formula (I) can lead to the production of quaternary amine salts that provide bioactive agents (ie compounds of formula (I)) in vivo.

Preferred prodrugs consist of compounds of formula (I). Here, hydroxyl side groups are phosphorylated to produce phosphate derivatives. Such prodrugs may also include spacer groups, such as methyleneoxy groups, between the compound of formula (I) and the phosphate group. Methods for producing such prodrugs from compounds of formula (I) are known in the art and are listed below in the references.

Preferred prodrugs also consist of compounds of formula (I) in which amine side groups such as pyridine groups are alkylated with groups such as methyl to form quaternary ammonium ion salts. Methods of producing such prodrugs from compounds of formula (I) are known in the art and are listed in the following references.

Any compound that can be converted in vivo to provide a bioactive agent (ie, a compound of formula I) is also a prodrug within the spirit and scope of the present invention.

Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives is disclosed in the following documents:

The Practice of Medicinal Chemistry , Camille G. Wermuth et al., Ch. 31, (Academic Press, 1996);

Design of Prodrug , edited by H. Bundgaard, (Elsevier, 1985);

A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991).

Hydrolysis in Drug and Prodrug Metabolism , B. Testa and JM Mayer, (Verlag Helvetica Chimica Acta AG, Zurich, Switzerland; Wiley-VCH, Weinheim, Federal Republic of Germany, 2003)

Ettmayer, P .; Amidon, GL; Clement, B .; Testa, B. "Lessons Learned from Marketed and Investigational Prodrugs" J. Med . Chem . 2004, 47 (10) , 2393-2404.

Davidsen, SK et al. "N- (Acyloxyalkyl) pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist" J. Med . Chem . 1994, 37 (26), 4423-4429.

Said documents are incorporated herein by reference.

Administration of a therapeutic agent of the invention includes administering a therapeutically effective amount of a drug of the invention. As used herein, the term "therapeutically effective amount" refers to an amount of therapeutic agent that treats a condition that can be treated by administration of a composition of the present invention. The amount is an amount sufficient to produce a detectable therapeutic or prophylactic or alleviative effect. The effect may include, for example, treating or preventing the symptoms listed herein. The exact effective amount for the patient will depend on the size and health of the patient, the nature and extent of the symptoms being treated, the combination of therapeutic agents selected for the treatment or recommendation and administration of the treating agent.

All stereoisomers of the compounds of the invention are considered either in mixtures or in pure or substantially pure form. The compounds of the present invention may have asymmetric centers on any carbon atom, including either of the R substituents. As a result, the compounds of formula (I) may exist in enantiomeric or diastereomeric forms or mixtures thereof. Racemates, enantiomers, or diastereomers can be used as starting materials in the production process. When preparing enantiomeric or diastereomeric products, they can be separated by conventional techniques such as, for example, chromatographic techniques, chiral HPLC or fractional crystallization.

The compounds of formula (I) of the present invention can be prepared as shown in the following schemes and descriptions or as shown in the procedures in the published literature that can be used by those skilled in the art. Exemplary reagents and procedures for these reactions will be shown in the Examples below.

Abbreviation

The following abbreviations are used in the schemes, examples, and other specification parts:

Ac = acetyl

AcOH = acetic acid

Boc = tert-butoxycarbonyl

DCM = dichloromethane

DIPEA = N, N-diisopropylethylamine

DMF = N, N-dimethylformamide

EDAC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrogen chloride

EtOAc = ethyl acetate

Et ₃ N = triethylamine

Et ₂ 0 = diethyl ether

HOBt = 1-hydroxybenzotriazole hydrate

HPLC = high performance liquid chromatography

LAH = lithium aluminum hydride

LC / MS = high performance liquid chromatography and mass spectrometer

NaOH = Sodium Hydroxide

PG = protector

RT = room temperature

TFA = trifluoroacetic acid

THF = tetrahydrofuran

min = minutes

h = hours

L = liter

mL = milliliters

Μl = microliters

g = grams

mg = milligrams

mol = mol

mmol = millimoles

nM = nanomolar

Compounds of the invention can be prepared by the procedures described in the schemes described together.

Manufacturing method

Compounds of the present invention can be prepared by methods such as those described in Schemes 1-9 below. Solvents, temperatures, pressures and other reaction conditions can be readily selected by those skilled in the art. Starting materials are commercially available or can be readily prepared by those skilled in the art using known methods. In all schemes and compounds described below, R ¹ , R ² , R ³ , R ⁶ and R ⁷ are described for compounds of formula (I).

The following are the definitions of the symbols used throughout Schemes 1-9.

PG suitable nitrogen saver. Benzyl, methoxymethyl- [MOM], benzyloxymethyl- [BOM], 2- (trimethylsilyl) ethoxymethyl- [SEM], methoxyethoxymethyl- [MEM], or t-butyl group.

EE Sn2 or Sn1 leaving group. Halogen (Cl, Br, I) and sulfonate (-OS0 ₂ -aryl (eg -OS0 ₂ Ph or -OS0 ₂ PhCH ₃ ), or -OSO ₂ -alkyl (eg -OS0 ₂ CH ₃ or -OS0 ₂ CF ₃ ));

MM boronate ester or boronic acid, or trialkylstanneine; Or metal atoms, such as zinc, magnesium or lithium, used as intermediates for transition metal mediated coupling reactions.

Compounds of formula II are commercially available or available by means known to those skilled in the art. Compounds of formula III can be prepared by reacting compounds of formula II with a suitable protecting group such as benzyl bromide. Exemplary nitrogen protecting groups and methods of protecting nitrogen are described in T. W. Greene and P. G. M. Wuts, 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- (trimethylsilyl) ethoxymethyl (SEM) groups.

The compound of formula IV is prepared by the conjugate base of a suitable alcohol RO-M (R is alkyl or benzyl, M is metalloid such as Li, Na, Mg (halide), etc.) in a solvent such as dioxane. It can be prepared by selectively replacing the leaving group (EE). Similar reactions have been described in Riedl, Z. et. Al. Tetrahedron, 2002, 5645-5650.

Compounds of formula (V) are reacted with activated compounds of formula (IV) by activated R ² such as boric acid, tin, Grignard reagent, zinc, copper and the like, if necessary in the presence of a suitable catalyst such as Pd (PPh ₃ ) _4. It can manufacture by making it. Compounds of formula (V) can also be prepared from compounds of formula (IV) by replacing the leaving group (EE) with the conjugate base of compound R ² -H (R is as defined above) with a base in an inert solvent. . Examples of bases are sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, or alkyl lithium.

Compounds of formula VI (EE = Cl) may be prepared by reacting a compound of formula V with a chloroating agent such as POCl _{3 in an} inert solvent such as toluene at elevated temperature.

Compounds of formula VII (MM is a metal or borate ester) are formulated with a compound of formula VI (EE is lithiated of hydrogen or halogen (chloro, bromo, iodo), and the resulting aryl lithium is suited for use such as trialkyltin halides. It can be prepared by reacting with a borate derivative or reagent.

Compounds of formula (VIII) are those wherein the compound of formula (VI) is activated by activated R ¹ , such as boric acid, tin, Grignard reagent, zinc, copper, and the like, if necessary in the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ . It can be prepared by reacting. Compounds of formula (VIII) may also be prepared from compounds of formula (VI) by replacing the leaving group (EE) with a conjugate base of formula R ¹ -H with a base in an inert solvent.

Compounds of formula (VIII) may also be prepared by coupling a compound of formula (VII) (MM is a borate ester) with a palladium or nickel catalyst with a suitably activated R ¹ such as halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium, and lithium, activated R ¹ such as halide or borate ester is converted to tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) nickel ( Similar crosslinking-coupling reactions can be carried out in combination with a suitable catalyst such as II).

Compounds of formula (IX) may be prepared under acidic (such as TFA for t-butyl or Boc-), basic (such as NaOH for amides), catalytic hydrogen (for benzyl-), or Lewis acids (such as preparations for benzyl) It can manufacture by removing the protecting group (PG) in compound VIII.

Compounds of formula X can be prepared by reacting a compound of formula IX with a chloroating agent such as POCl _{3 in an} inert solvent such as toluene at elevated temperature.

Compounds of formula (XI) may be prepared by reacting compounds of formula (X) with hydrazine in an inert solvent such as pyridine at elevated temperature.

Compounds of formula (XII) may be prepared by reacting a compound of formula (XI) with a carbonylating agent, such as carbonyldiimidazole, phosgene, triphosgene or urea, in an inert solvent such as tetrahydrofuran.

Compounds of formula (I) can be prepared by reacting a compound of formula (XII) with R ³ -X (X is a leaving group such as F, Cl, Br, I, -OMs, -OTos) or epoxide at elevated temperature. Compounds of formula (I) can also be prepared by reacting compounds of formula (XII) with R ³ -OH under Mitsunobu conditions.

As described in Scheme 2, the compound of formula (XIII) may be prepared by reacting the compound of formula (III) with a suitable alcohol RO-M (R is alkyl or benzyl, M is Li, Na, Mg (halide), etc.) in a solvent such as methanol. It can be prepared by the selective substitution of the leaving group (EE) by the conjugate base. For example, where EE = Cl, such selective substitutions are described by Riedl, Z. et. al. Tetrahedron, 2002, 5645-5650.

Compounds of formula (XIV) are prepared by reacting a compound of formula (XIII) with an activated R ¹ , such as activated by boric acid, tin, Grignard reagent, zinc, copper, etc., in the presence of a suitable catalyst, such as Pd (PPh ₃ ) ₄ , if necessary Can be. Compounds of formula (XIV) can also be prepared from compounds of formula (XIII) by replacing the leaving group (EE) with a conjugate base of compound R ¹ -H (R ¹ is as defined above) with a base in an inert solvent. have.

Compounds of formula XV (when EE = Cl) can be prepared by reacting compounds of formula XIV with chloroating agents such as POCl _{3 in an} inert solvent such as toluene at elevated temperatures. Or a compound of formula XV (if EE = Cl), if necessary, activated R ¹ , such as activated by boric acid, tin, Grignard reagent, zinc, copper, etc., in the presence of a suitable catalyst such as Pd (PPh ₃ ) _4; It can be prepared by reacting a compound of formula III.

Compounds of formula (XVI), wherein MM is a metal or borate ester, are lithiated compounds of formula (XV) wherein EE is hydrogen or halogen (chloro, bromo, iodo), and the resulting aryl lithium is combined with a suitable borate derivative or trialkyltin halide. It can be prepared by reacting with the same reagent.

Compounds of formula (VIII) can be reacted if necessary by reacting compounds of formula (XV) with activation R ² such as activated by boric acid, tin, Grignard reagent, zinc, copper, etc. in the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ It can manufacture. Compounds of formula (VIII) may also be prepared from compounds of formula (XV) by replacing the leaving group (EE) with a conjugate base of compound R ² -H (R ² is as defined above) using a base in an inert solvent. Can be.

Compounds of formula (VIII) may also be prepared by coupling a compound of formula (XVI), wherein MM is a borate ester, with a suitable palladium or nickel catalyst with a suitable activation R ² such as halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium, and lithium, activating R ² , such as halide or borate ester, may be converted to tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) nickel ( Similar cross coupling reactions can be carried out in combination with an activation catalyst such as II).

Compounds of formula (I) may be prepared from compounds of formula (VIII) described in Scheme 1.

As described in Scheme 3, compounds of formula XVII can be prepared from compounds of formula XIII by substituting R groups (R = alkyl) with a base such as sodium hydroxide in a suitable solvent such as water (Scheme 2). The hydroxy group of XVII can be activated by reacting with a reagent such as trifluoromethane sulfonic anhydride in the presence of a suitable base such as triethylamine. This activated moiety is then optionally activated with activation R ² , such as activated by boric acid, tin, Grignard reagent, zinc, copper or the like, in the presence of a suitable catalyst, such as Pd (PPh ₃ ) ₄ , to give compound XVIII. Can provide.

Compounds of formula XIX may also be prepared by treating compounds of formula V with POCl ₃ at elevated temperatures.

Compounds of formula (XIX) may be prepared from compounds of formula (XVIII) in two step sequences: (a) acidic (eg TFA for t-butyl or Boc-), basic (eg NaOH for amide), catalytic hydrogenation (benzyl For), or under Lewis acid (eg, AlCl ₃ for benzyl) conditions, removing the protecting group (PG) of compound XVIII, and then (b) POCl ₃ in an inert solvent such as toluene at elevated temperature. Reacting the chloroating agent with the resulting intermediate. In certain instances, direct treatment of XVIII with a chloroating agent such as POCl ₃ at high temperatures will provide the compound of formula XIX in one step from XVIII.

Compounds of formula (XX) can be prepared by reacting compounds of formula (XIX) with hydrazine in selected solvents such as isobutanol.

Compounds of formula (XXI) may be prepared by reacting a compound of formula (XX) with a carbonylating agent, such as carbonyldiimidazole, phosgene, triphosgene or urea, in an inert solvent such as tetrahydrofuran.

The compound of formula (XXII) may be prepared by reacting a compound of formula (XXI) with R ³ -X (X is a leaving group such as F, Cl, Br, I, -OMs, -OTos) or an epoxide at elevated temperature. XXII can also be prepared by reacting a compound of Formula XXI with ROH under Mitsunobu conditions.

Compounds of formula (I) are prepared by reacting compounds of formula (XXII) with activation R ¹ , such as those activated by boric acid, tin, Grignard reagents, zinc, copper, etc., in the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ if necessary Can be. Compounds of formula (I) may be prepared from compounds of formula (XXII) by replacing the leaving group (EE) with a conjugate base of compound R ¹ -H (R ¹ is as defined above) using a base in an inert solvent. have.

Compounds of formula (XXIII), wherein MM is a metal or borate ester, are lithiated compounds of formula (XXII) wherein EE is hydrogen or halogen (chloro, bromo, iodo), and the resulting aryl lithium is combined with a suitable borate derivative or trialkyltin halide It can be prepared by reacting with the same reagent.

Compounds of formula (I) can also be prepared by palladium or nickel catalyzed coupling of a compound of formula (XXIII) in which MM is a borate ester and a suitable activation R ¹ such as a halide or mesylate. When MM is a metal atom such as tin, zinc, magnesium and lithium, activating R ¹ such as a halide or borate ester is converted to tetrakis (triphenylphosphine) palladium (0) and dichlorobis (triphenylphosphine) nickel (II). Similar cross-coupling reactions can be performed with suitable catalysts such as

Compounds of formula (I) can also be prepared from XXI in a two step sequence: (a) if necessary, by boric acid, tin, Grignard reagent, zinc, copper, etc., in the presence of a suitable catalyst such as Pd (PPh ₃ ) _4; Cross-coupling activating R ¹ and XXI as activated, or substituting an EE of XXI with a conjugate base of R ¹ -H to provide a compound of Formula XII, and thereafter (b) at an elevated temperature. Reacting a compound of formula XII with R ³ -X (where X is a leaving group such as F, Cl, Br, I, -OMs, -OTos) or an epoxide.

As described in Scheme 4, compounds of Formula (XXIV) may be prepared from a compound of Formula (XV) in two steps: (a) acidic (eg TFA for t-butyl or Boc-), basic (eg to amide) NaOH), catalytic hydrogenation (benzyl-to), or Lewis acid (eg, auxiliaries for benzyl) to remove the protecting group (PG) of compound XY, and thereafter (b) with toluene at elevated temperature. Reacting the intermediate produced in the same inert solvent with a chloroating agent such as POCl ₃ .

Compounds of formula (XXV) can be prepared by reacting a compound of formula (XXIV) with hydrazine in a selected solvent such as isobutanol.

Compounds of formula (XXVI) can be prepared by reacting a compound of formula (XXV) with a carbonylating agent such as carbonyldiimidazole, phosgene, triphosgene or urea in an inert solvent such as tetrahydrofuran.

Target compounds of formula (I) may be prepared from compounds of formula (XXVI) in an analogous order to the reactions described in Scheme 3 via intermediates XII, XXVII and XXVIII.

As R ¹ and R ² are the same as described in Scheme 5, compounds of formula (VIII), if necessary, may be substituted with compounds of formula (III) in the presence of a suitable catalyst such as Pd (PPh ₃ ) ₄ , boric acid, tin, Grignard reagent, It can be prepared by reacting with activated R ¹ and R ² such as activated by zinc, copper and the like. Compounds of formula (VIII) are also prepared via substitution of the leaving group (EE) with a conjugate base of compounds R ¹ -H and R ² -H (R ¹ and R ² as defined above) using a base in an inert solvent. It can be prepared from a compound of formula III.

The target compound of formula (I) can then be prepared from the compound of formula (VIII) in a similar order to the reaction described in Scheme 1.

As described in Scheme 6, compounds of formula (X), if necessary, may be selected from compounds of formula (XXIV) activated with boric acid, tin, Grignard reagent, zinc, copper, etc. in the presence of a suitable catalyst such as Pd (PPh ₃ ) _4. It can be prepared by reacting with the same activated R ² . The compounds of formula (I) can then be prepared from compounds of formula (I) in an order similar to the reactions described in Scheme I.

As depicted in Scheme 7, analogs having certain optionally defined substituents R ¹ and R ² and R ³ are optionally substituted with other optionally defined substituents R ¹ and R ² and R ³ by manipulation of the functional groups belonging to these R groups. To analogs with For example, if R ^1a , R ^2b , R ^3c are a group such as amino, aminoaryl, aminoalkyl or aminoaryloxyl, they will react with carboxylic acids or with acid chlorides or sulfonyl chlorides to give amino or sulfonamide derivatives. Can be. Such manipulation can be performed by parallel synthesis.

In addition, R ^1a , R ^2b Or when R ^3c is substituted with an activated group such as halogen or boric acid, an additional metal catalyzed cross coupling reaction may be performed to provide a set of additional analogs as described in Formula (I). Such manipulation can be performed through parallel synthesis.

As described in Scheme 8, the compounds of formula I can be prepared by parallel synthesis using solid phase synthesis. For example, the compound of formula XXI can be reacted with a polymer binding resin to provide compound XXIX. Compounds of formula XXX are prepared by reacting compounds of formula XXIX with activation R ¹ , such as those activated by boric acid, tin, Grignard reagent, zinc, copper, etc., in the presence of a suitable catalyst, such as Pd (PPh ₃ ) ₄ , if necessary can do. Removal of the polymer binding resin yields a compound of formula (XII). Compounds of formula (XII) can be converted to compounds of formula (I) as shown in Scheme 1.

The target compound of formula (I) can also be prepared from a compound of formula (XXVI) in an order similar to the scheme described above.

Compounds of formula (XXXIII) can be reacted with activated R ⁶ , such as R ⁶ -M, where M is a metalloid such as Li, Na, Mg (halide), etc. in a solvent such as THF to yield a compound of formula XXXIV, which is n Is a single bond and R ⁷ is hydrogen; The compound of formula XXXIV can be reacted with atmospheric oxygen or an oxidizing agent such as 2,3-dichloro-5,6-dicyanohydroquinone or the like to yield a compound of formula I wherein n is a double bond and R ⁷ is absent. Compounds of formula (XXXIV) may be reacted with alkylating agents, such as alkyl halides, or acylating agents, such as acetic anhydride, benzoyl chloride, and the like, to yield compounds of formula (I). Compounds of formula (XXXIV) can be reacted with phosphorylating agents such as POCl ₃ or Cl-P (O) (OEt) ₂ to form compounds of formula (I) when hydrolyzed. Examples of conversion of amines to phosphonamidates include Wang R. et al. J. Med . Chem . 2003, 46 (22), 4799-4802, Guillaume, HAJ Org. Chem . 1989, 54 (24), 5731-5736. Compounds of formula (XXXIV) can be reacted with sulfonylating agents such as pyridine-S0 ₃ complexes or Cl-S (O) mR ⁸ to produce compounds of formula (I). Examples of such conversions are described in Tschamber, T. and Streith, J. Heterocycles 1990, 30 (1), 551-559, Couloigner, E., Cartier, D., Labia, R. Bioorg . Med . Chem . Lett . 1999, 9, 2205-2206, Tschamber, T. et al. Heterocycles 1985, 23 (10), 2589-2601.

Parallel synthesis is, for example, used in the preparation of compounds having carboxylic acids in the reaction centers for which intermediates are activated, such as nitrogen in triazolone, reactive heteroaryl in Suzuki coupling chemistry or amide coupling chemistry. Can be used.

The following examples are intended to better illustrate some preferred embodiments of the invention and are not limiting.

Example To characterization  Introduced Analysis HPLC  And HPLC / MS Way.

Analytical HPLC was performed on Shimadzu LC10AS liquid chromatography. Analytical HPLC / MS was performed on Shimadzu LC10AS liquid chromatography and Waters ZMD Mass Spectrometer using the following method.

Unless otherwise indicated, Method A was used to characterize the intermediates or final compounds of the examples listed in the experiments or tables.

Method A. Linear gradient of 0 to 100% solvent B over 4 minutes, 1 minute at 100% B:

UV contrast 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 of 0 to 100% solvent B over 8 minutes, 3 minutes standing at 100% B:

UV contrast at 220 nm

Column: Phenomenex Luna C18 4.6 x 75 mm or Zorbax 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 of 10 to 100% solvent B over 4.0 minutes, 0.5 minute standing at 100% B:

UV contrast 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 of 0 to 100% solvent B over 4 minutes, 1 minute standing at 100% B;

UV contrast 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% methanol, 10% water

Method E. Linear gradient of 0 to 100% solvent B over 4 minutes, 1 minute standing at 100% B;

UV contrast at 220 nm

Column: Phenomenex Luna C18 4.6 x 50 mm

Flow rate: 4 ml / min

Solvent A: 10 mM NH ₄ OAc, 90% water, 10% methanol

Solvent B: 10 mM NH ₄ OAc, 90% methanol, 10% water

Method F. Linear gradient of 1 to 100% solvent B over 2.35 minutes, 0.5 minute standing at 100% B;

UV contrast at 220 nm

Column: Extera 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 of 10 to 100% solvent B over 2.0 min, 0.56 min at 100% B;

UV contrast at 220 nm

Column: Extera MS-C 18, 4.6 X 50 mm

Flow rate: 1.0 ml / min

Solvent A: 10 mM NH ₄ OAc, 95% water, 5% acetonitrile

Solvent B: 10 mM NH ₄ 0Ac, 95% acetonitrile, 5% water

Example To characterization  Introduced NMR

¹ H NMR spectra were obtained with a Bruker or JOEL Fourier transform spectrometer operated at the following frequencies: ¹ H NMR: 400 MHz (Brooker), 400 MHz (Joel), or 500 MHz (Joel) ; ¹³ C NMR: 100 MHz (Brooker), 100 MHz (Joel) or 125 MHz (Joel). Record the spectral data in chemical shifts (multiplicity, number of hydrogens, coupling constants in Hz), and ppm (6 units) for any of the internal standards for tetrahsilane (0 tetra) for ¹ H NMR Or residual solvent peak (2.49 ppm for CD ₂ HSOCD ₃ , 3.30 ppm for CD ₂ HOD, 7.24 ppm for CHCl ₃ , 39.7 ppm for CD ₃ SOCD ₃ , 49.0 ppm for CD ₃ 0D, to CDCl ₃ Sea level 77.0 ppm). All ¹³ C NMR spectra were proton decoupled.

Example 1

Preparation of 7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one

1A. Preparation of 2-benzyl-4,5-dibromopyridazine-3 (2H) -one

To a solution of dibromopyridazinone (50.0 g, 197.0 mmol) in DMF (200 mL) at room temperature was added K ₂ CO ₃ (32.6 g, 236.4 mmol). Benzyl bromide (37.0 g, 216.7 mmol) was added via syringe. The resulting green suspension, when judged by HPLC, was stirred for 6 hours at room temperature until all pyridazinone was consumed. The reaction mixture was poured into an Ernmeyer flask containing water (500 mL) with stirring. Beige solid formed. The suspension was stirred at rt for 15 min and filtered. The solid was washed thoroughly with water until no color appeared 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) was determined by HPLC and was> 95 purity and obtained as a solid. MS: M + H = 343. ¹ H NMR (CDCl ₃ , 500 MHz): δ 7.80 (1H, s), 7.45 (2H, d, J = 5.0 Hz), 7.29-7. 36 (3H, m), 5.31 (2H, s).

1B. Preparation of 2-benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one

Argon with Pd (PPh ₃ ) ₄ (4.0 g, 3.5 mmol) in a 2-benzyl-4,5-dibromopyridazine-3 (2H) -one (40 g, 116.0 mmol) suspension in toluene (300 mL). Added under atmosphere. 4-chlorophenylboronic acid (40.0 g, 255.2 mmol) was added in partial succession. Under vigorous stirring, Na ₂ C03 (27.0 g, 255.2 mmol) dissolved in water (50 mL) was added to the suspension. Argon was bubbled through this suspension for 10 minutes and the flask was placed in a preheated oil bath at 120 ° C. The reaction was refluxed for 6 hours. The reaction was then allowed to cool to rt and poured into water (500 mL). The aqueous mixture was extracted with EtOAc (3 x 300 mL). 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 in a sintered glass funnel (˜50 g) to remove dark impurities. The solvent was then evaporated under reduced pressure. The resulting thick syrup mainly contained the title compound 2-benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one, which was used directly in the next reaction 1C. MS: M + H = 407. ¹ H NMR (CDCl ₃ , 500 MHz): δ 7.87 (1H, 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).

1C. Preparation of 4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one

The crude 2-benzyl-4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one obtained in the reaction was dissolved in toluene (350 mL). Aluminum chloride (AlCl ₃ , 46.3 g, 348.0 mmol) was then added to the toluene solution and exothermic. The reaction was then placed in an oil bath and preheated at 75 ° C. for 3 hours. After this time, the reaction mixture was poured into ice water (100 mL) and the resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (500 mL) and then filtered through a pad of silica gel (˜50 g) to remove residual alumina salt. The organic solvent was evaporated under reduced pressure to almost dryness. Diethyl ether (Et ₂ O, 500 mL) was added with stirring. After stirring for 15 minutes at room temperature, hexane (1000 mL) was added successively. The resulting beige solid was collected by filtration and then washed with 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. ¹ H NMR (CDCl ₃ , 500 MHz): δ 11.94 (1H, br), 7.89 (1H, s), 7.23-7.32 (4H, m), 7.18 (2H, d, J = 10.0 Hz), 7.07 (2H, doublet, J = 10 Hz).

1D. 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). The resulting solution was added to pyridine (8.3 mL, 104.4 mmol) and POCl ₃ (14.3 mL, 156.6 mmol). The reaction mixture was placed in an oil bath preheated at 110 ° C. After 4 hours the reaction mixture was cooled to room temperature and poured into 500 g of ice to quench excess POCl ₃ . The dark mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water (500 mL) and filtered through a pad of silica gel (˜50 g). The filtrate was concentrated under reduced pressure to afford the title compound, 3-chloro-4,5-bis (4-chlorophenyl) pyridazine as a pale solid (16.0 g, 92%). MS: M + H = 335. ¹ H NMR (CDCl ₃ , 500 MHz): δ 9.24 (1H, s), 7.35 (2H, doublet, 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 was added (4.5 g, 90.0 mmol). The reaction mixture was refluxed for 3 hours and then added to water (100 mL). The pale solid was collected by filtration and washed 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. 1} H NMR (DMSO-d6, 500 MHz): δ 8.59 (1H, s), 8.56 (1H, br), 7.40 (2H, d, J = 10 Hz), 7.35 (2H , d, J = 10.0 Hz), 7.14-7.16 (4H, m).

1F. Preparation of [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol

Carbonyldiimidazole (CDI), (1.7 g, 10.5 mmol) in THF (20 mL) solution in 1- (4,5-bis (4-chlorophenyl) pyridazin-3-yl) hydrazine (0.7 g, 2.1 mmol) was added. 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 solid was collected by filtration. Rinse the solid thoroughly using water to [8,3-b] pyridazin-3 (2H) -one (0.75 g, 100 with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol %) Was obtained. MS (M + H) = 357; ¹ H NMR (DMSO-d ₆ , 500 MHz): δ 12.86 (1H, s), 8.37 (1H, s), 7.42-7.48 (4H, m), 7.35 (2H, d, J = 10.0 Hz), 7.27 (2H, doublet, J = 10.0 Hz).

Example 2

Preparation of [4,3-b] pyridazin-3 (2H) -one as 2- (4-chlorobenzyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (5 mL). To a solution of -one (0.4 g, 1.1 mmol) was added K ₂ CO ₃ (0.46 g, 3.3 mmol) and 4-chlorobenzyl bromide (0.28 g, 1.3 mmol). The reaction mixture was heated at 60 ° C for 20 minutes. After this time, water (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 reverse phase preparative HPLC. MS (M + H) = 481, ¹ H NMR (CDCl ₃ ): δ 8.18 (1H, s), 7.25-7.40 (10H, m), 7.08 (2H, d, J = 10.0 Hz), 5.18 (2H, s).

Example 3

7,8-bis (4-chlorophenyl) -2-((5- (trifluoromethyl) pyridin-2-yl) methyl)-[1,2,4] triazolo [4,3-b] pyri Preparation of Minced-3 (2H) -one

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (100 mg, prepared as described in Example 1) 0.28 mmol), Ph ₃ P (220 mg, 0.84 mmol) and (5-trifluoromethyl-pyridin-2-yl) methanol (50 mg, 0.28 mmol) in THF (2.0 mL) at room temperature under argon. A 40 wt% diethyl azodicarboxylate (DEAD) solution in toluene (0.33 mL, 0.84 mmol) was added. The reaction was stirred at rt for 30 min. Water (5.0 mL) was then added and the resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with water (2 x 5 mL) and then with aqueous NaCl (2 x 5 mL). The combined organic layers were concentrated under reduced pressure to give crude product. The 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] Triazole gave [4,3-b] pyridazin-3 (2H) -one (69.2 mg, 48%) as a yellow solid. MS (M + H) = 516; ¹ H NMR (CDCl ₃ ): δ 8.83 (1H, s), 8.20 (1H, s), 7.93 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 10 Hz), 7.26 -7.34 (6H, m), 7.11 (2H, d, J = 10.0 Hz), 5.47 (2H, s).

Example 4

7,8-bis (4-chlorophenyl) -2-((1- (pyrimidin-2-yl) piperidin-4-yl) methyl)-[1,2,4] triazolo [4,3 -b] Preparation of Pyridazin-3 (2H) -one

The title compound was prepared as described in Example 1 in THF (1.0 mL) with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H) -one (50 mg, 0.14 mmol), Ph ₃ P (110 mg, 0.42 mmol) and (1- (pyrimidin-2-yl) piperidin-4-yl) methanol (28 mg, 0.14 mmol ) And the method described in Example 2. Title compound, 7,8-bis (4-chlorophenyl) -2-((1- (pyrimidin-2-yl) piperidin-4-yl) methyl)-[1,2,4] triazolo [ 4,3-b] Pyridazin-3 (2H) -one (31 mg, 42%) was obtained as a yellow powder.

MS M + H = 532; ¹ H NMR (CDCl ₃ ) δ 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 (1H, m), 1.74 (2H, doublet, J = 10.0 Hz), 1.30-1. 40 (2H, m).

Example 5

(R) -7,8-bis (4-chlorophenyl) -2-((5-oxopyrrolidin-2-yl) methyl)-[1,2,4] triazolo [4,3-b] Preparation of Pyridazin-3 (2H) -one

The title compound was prepared as described in Example 1 in THF (1.0 mL) with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 With (2H) -one (50 mg, 0.14 mmol), Ph ₃ P (110 mg, 0.42 mmol) and (R) -5- (hydroxymethyl) pyrrolidin-2one (17 mg, 0.14 mmol) And prepared using the method described in Example 2. Title compound (R) -7,8-bis (4-chlorophenyl) -2-((5-oxopyrrolidin-2-yl) methyl)-[1,2,4] triazolo [4,3- b] Pyridazin-3 (2H) -one (38.5 mg, 85%) was obtained as a yellow powder. MS M + H = 454; ¹ H NMR (CDCl ₃ ) δ 8.15 (1H, s), 7.24-7.36 (6H, m), 7.09 (2H, d, J = 10.0 Hz), 6.59 (1H, s), 4.17-4.20 (1H, m ), 4.03-4.10 (2H, m), 2.25-2.35 (3H, m), 1.92-2.02 (1H, m).

Example 6

(R) -2-((1-benzylpyrrolidin-2-yl) methyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] Preparation of Pyridazin-3 (2H) -one

The title compound was prepared as described in Example 1 in THF (1.0 mL) with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 Example using (2H) -one (50 mg, 0.14 mmol), Ph ₃ P (110 mg, 0.42 mmol) and (S) -1-benzyl-2-pyrrolidinemethanol (27 mg, 0.14 mmol) It manufactured using the method of description. Title compound (R) -2-((1-benzylpyrrolidin-2-yl) methyl) -7,8-bis (4chlorophenyl)-[1,2,4] triazolo [4,3-b Pyridazin-3 (2H) -one (8 mg, 11%) was obtained as a yellow powder. MS M + H = 530; ¹ H NMR (CDCl ₃ ) δ 8.14 (1H, s), 7.22-7.38 (11H, m), 7.10 (2H, d, J = 10.0 Hz), 4.61-4.63 (1H, m), 3.50-3.56 (2H , q, J = 13.2 Hz), 3.01 (1H, d, J = 10.0 Hz), 2.85 (1H, 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 (1H, m), 1.70-1.80 (2H, m).

Example 7

7,8-bis (4-chlorophenyl) -2-((6-morpholinopyridin-3-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 Preparation of (2H) -one

The title compound was prepared as described in Example 1 in THF (1.0 mL) with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 Example 2 using (2H) -one (50 mg, 0.14 mmol), Ph ₃ P (110 mg, 0.42 mmol) and (6-morpholinopyridin-3-yl) methanol (29 mg, 0.14 mmol) It manufactured using the method described in. Title compound 7,8-bis (4-chlorophenyl) -2-((6-morpholinopyridin-3-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine -3 (2H) -one (20.5 mg, 11%) was obtained as a yellow powder.

Example 8

7,8-bis (4-chlorophenyl) -2- (pyridin-N-oxide-4-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H ) -On Preparation

The title compound was prepared as described in Example 1 in THF (1.0 mL) with 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H) -one (40 mg, 0.11 mmol), Ph ₃ P (32 mg, 0.12 mmol) and 4-pyridyl carbinol-N-oxide (15 mg, 0.12 mmol) described in Example 2 Prepared using the method. Title compound 7,8-bis (4-chlorophenyl) -2- (pyridine-N-oxide-4-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) -one (14 mg, 27%) was obtained as a yellow solid. MS M + H = 464; ¹ H NMR (CDCl ₃ ) δ 8.20 (1H, 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 [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl) -2- (2-morpholinoethyl)-[1,2,4] triazol

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (1 mL) To -one (40 mg, 0.11 mmol) was added Cs ₂ CO ₃ (110 mg, 0.33 mmol) and 4- (2-chloroethyl) morpholine hydrogen chloride (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 × 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 was purified by preparative HPLC to give the title compound 7,8-bis (4-chlorophenyl) -2- (2-morpholinoethyl)-[1,2,4] triazol [4,3- b] Pyridazin-3 (2H) -one (35 mg, 67%) was obtained as a yellow solid. MS M + H = 470; ¹ H NMR (CDCl 3) δ 8.17 (1H, 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 [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl) -2-cyclohexyl- [1,2,4] triazolo

The title compound was prepared as described in Example 1 in DMF (1 mL) as 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 Prepared using (2H) -one (40 mg, 0.11 mmol), Cs ₂ CO ₃ (44 mg, 0.135 mmol), bromoclohexane (100 mg, 0.61 mmol) and using the method described in Example 9. . Title compound, 7,8-bis (4-chlorophenyl) -2-cyclohexyl- [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (26 mg, 54 %) Was obtained as a yellow lyophilate. MS M + H = 439; ¹ H NMR (CDCl ₃ ) δ 8.17 (1H, 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 (1H, m), 1.35-1.50 (2H, m), 1.1-1.30 (1H, m).

Example 11

Preparation of [4,3-b] pyridazin-3 (2H) -one as 2,7,8-tris (4-chlorophenyl)-[1,2,4] triazolo

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in pyridine (1.5 mL) To a solution of -one (50 mg, 0.14 mmol) and 4-chlorophenicboronic acid (44 mg, 0.28 mmol) is added copper (II) acetate (51 mg, 0.28 mmol) and triethylamine (0.04 mL under argon). , 0.28 mmol) and 3 mm molecular sieve (100 mg) were added. The reaction mixture was stirred 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 x 5 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 MgSO ₄ , filtered and concentrated to give crude product. The crude product was purified by preparative HPLC to give [4,3-b] pyridazin-3 (2H) -one (5,7,8-tris (4-chlorophenyl)-[1,2,4] triazol mg, 8%) was obtained as a yellow lyophylate. HPLC: 4.35 min; M + H = 467; ¹ H NMR (CDCl ₃ ) δ 8.22 (1H, 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 [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl) -2- (3-phenylpropyl)-[1,2,4] triazolo

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (40 mg, 0.1 lmmol) prepared as described in Example 1 ), 3-phenylpropan-1-ol (0.018 ml, 0.13 mmol), and diethyl azodicarboxylate (0.15 ml) in a tetrahydrofuran solution (2 ml) of triphenylphosphine (86 mg, 0.32 mmol) , 0.38 mmol) was added. After 1 hour this 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] triazol [4,3-b] pyridazine -3 (2H) -one (17.9 mg, 34%) was obtained as a yellow solid. MS M + H = 475; ¹ H NMR (CDCl ₃ ) 8.18 (1H, s), 7.3-7.1 (13H, m), 4.13 (2H), 2.70 (2H), 2.21 (2H).

Example 13

Preparation of [4,3-b] pyridazin-3 (2H) -one as 2- (4-fluorophenethyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (1 ml) A solution of -one (40 mg, 0.1 lmmol), 2- (4-fluorophenyl) ethyl bromide (22 mg), and K ₂ CO ₃ (35 mg, 0.25 mmol) 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 ₄ , filtered and concentrated. The crude product was purified by 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%) was obtained as a yellow foam. MS M + H = 479; 1 N NMR (CDCl 3) 6 8.18 (1H), 7.35 (4H), 7.26 (4H), 7.12 (2H), 6.95 (2H), 4.29 (2H), 3.13 (2H).

Example 14

Preparation of [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl) -2- (2-hydroxycyclohexyl)-[1,2,4] triazol

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (1 ml) A solution of -one (40 mg, 0.1 lmmol), cyclohexene oxide (2 mg, 0. 12 mmol) and K ₂ CO ₃ (35 mg, 0.25 mmol) 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 ₄ , 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] triazolo [4,3-b] Pyridazine-3 (2H)-(24.1 mg, 48%) was obtained as a yellow solid. MS M + H = 455; ¹ H NMR (CDCl ₃ ) δ 8.17 (1H), 7.33 (6H), 7.08 (2H), 4.26 (1H), 3.98 (1H), 2.17 (1H), 1. 99 (1 H), 1.82 (3 H), 1.50-1.30 (3 H).

Example 15

2-((1-benzylpiperidin-4-yl) methyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 Preparation of (2H) -one

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one, prepared as described in Example 1, (40 mg, 0.1lmmol), (1-benzyl-4-piperidyl) methanol (27mg 0.13mmol), and diethyl azodicarboxylate (0.15) in THF solution (2ml) of triphenylphosphine (86mg, 0.32mmol) ml, 0.38 mmol) was added. 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] triazol [4,3-b] Pyridazin-3 (2H) -one (6.1 mg, 10%) was obtained as a yellow solid. MS M + H = 544; ¹ H NMR (CDCl ₃ ) δ 8.19 (1H), 7.42 (2H), 7.32-7.20 (9H), 7.11 (2H), 4.19 (1H), 4.02 (2H), 3.66 (2H), 2.63 (2H), 2.12 (2 H), 1.91 (4 H).

Example 16

2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) -N, 4- Preparation of Dimethylpentanamide

16A. Preparation of 2-bromo-N, 4-dimethylpentanamide

To a solution of DL-alpha-bromoisocaproic acid in THF (4 ml) was added N-methylmorphine (0.18 ml, 1.63 mmol) and isobutylchloroformate (0.15 ml, 1.16 mmol) was added dropwise. A white solid precipitate formed. After stirring for 1.5 hours at room temperature, the white solid was filtered off. Methylamine (lml, 2N in THF) was added to the filtrate. After 0.5 h the reaction mixture was concentrated. The resulting crude was diluted with ethyl acetate and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the title compound as an oil, 2-bromo-N, 4-dimethylpentanamide (0.18 g, 78%).

16B. 2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) -N, 4- Preparation of Dimethylpentanamide

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (2 ml). A solution of -one (40 mg, 0.11 mmol), 2-bromo-N, 4-dimethylpentanamide (25 mg) and K ₂ CO ₃ (31 mg, 0.22 mmol) was heated at 85 ° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature and washed with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na ₂ SO ₄ , 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] triazolo [4,3-b] pyri Dajin-2 (3H) -yl) -N, 4-dimethylpentanamide (28 mg, 40%) was obtained as a yellow solid. MS M + H = 484; ¹ H NMR (CDCl ₃ ) δ 8.23 (1H), 7.36-7.30 (6H), 7.12 (2H), 6.90 (1H), 5.13 (1H), 2.81 (3H), 2.22 (1H), 1.98 (1H), 1.42 (1 H), 0.93 (6 H).

Example 17

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H), prepared as described in Example 1, in DMF (10 ml) A solution of -one (300 mg, 0.84 mmol), 4- (trifluoromethyl) benzyl bromide (200 mg, 0.884 mmol) and K ₂ C03 (290 mg, 2.1 mmol) 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] triazol [4,3 -b] Pyridazin-3 (2H) -one (120 mg, 28%) was obtained as a yellow solid. MS M + H = 515; ¹ H NMR (CDCl ₃ ) δ 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).

Example 18

2- (2- (4-chlorophenoxy) ethyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (1 ml) ) -One (30 mg, 0.084 mmol), 1- (2-bromoethoxy) -4-chlorobenzene (22 mg, 0.094 mmol) and K ₂ CO ₃ (18 mg, 0.013 mmol) 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%) as a yellow solid. MS M + H = 511; ¹ H NMR (CDCl ₃ ) δ 8.19 (1H), 7.34 (4H), 7. 28 (2H), 7.18 (2H), 7.28 (2H), 6.80 (2H), 4.44 (2H), 4.36 (2H).

Example 19

7,8-bis (4-chlorophenyl) -2- (2- (phenylamino) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) -one Produce

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3b] pyridazin-3 (2H) -one (50 mg, 0.14 mmol) prepared as described in Example 1 To a solution of 2- (phenylamino) ethanol (19 mg, 0.13 mmol), triphenylphosphine (55 mg, 0.21 mmol), diethyl azodicarboxylate (0.09 ml, 42 wt% in toluene, 0.21 mmol) was added. It was. 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] triazol [4,3-b Pyridazin-3 (2H) -one (14.4 mg, 23%) was obtained as a yellow solid. MS M + H = 476; ¹ H NMR (CDCl ₃ ) δ 8.20 (1H), 7.41-7.20 (11H), 7.10 (2H), 4.51 (2H), 3.91 (2H).

Example 20

2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) -N- (4 Preparation of-(trifluoromethyl) phenyl) acetamide

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (1 ml) A solution of) -one (30 mg, 0.084 mmol), 2-chloro-N- (4- (trifluoromethyl) phenyl) acetamide (22 mg, 0.092 mmol), K ₂ CO ₃ (35 mg, 0.25 mmol) Heated at 캜 for 1 h. 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] triazol [4,3-b] pyridazine-2 (3H) -yl) -N- (4- (trifluoromethyl) phenyl) acetamide (38 mg, 81%) was obtained as a yellow solid. MS M + H = 558; ¹ H NMR (CDCl ₃ ) δ 8.26 (1H), 7.60 (2H), 7.38-7.20 (8H), 7.11 (2H), 5.07 (2H).

Example 21

Preparation of [4,3-b] pyridazin-3 (2H) -one as 2- (2-aminoethyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

21A. 2- (2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) ethyl) Preparation of Isoindolin-1,3-Dione

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (3 ml) A solution of -one (290 mg, 0.81 mmol), N- (2-bromoethyl) phthalimide (215 mg, 0.84 mmol) and K ₂ CO ₃ (337 mg, 2.44 mmol) was heated at 80 ° C for 2.5 h. 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 using silica gel column chromatography using an automated system eluting with a 1: 1 mixture of ethyl acetate: hexanes to give the title compound 2- (2- (7,8-bis (4-chlorophenyl) -3- Oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) ethyl) isoindolin-1,3-dione as a yellow solid (290 mg, 68%) It was. MS M + H = 530.

21B. Preparation of [4,3-b] pyridazin-3 (2H) -one as 2- (2-aminoethyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

2- (2- (7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) ethyl) Isoindolin-1,3-dione (180 mg, 0.34 mmol) was reacted with hydrazine 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 was purified by preparative HPLC to give the title compound, 2- (2-aminoethyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyri. Dajin-3 (2H) -one (22 mg, 13%) was obtained as a yellow foam. MS M + H = 400; ¹ H NMR (CDCl 3) δ 8.12 (wide, 2H), 7.38-7.15 (6H), 7.05 (2H), 4.45 (2H), 3.59 (2H).

Example 22

(R) -7,8-bis (4-chlorophenyl) -2- (2- (3-chlorophenyl) -2-hydroxyethyl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one prepared as described in Example 1 in 0.25 mL of DMF. To (20 mg, 0.06 mmol) of the stirred solution was added R-(+)-3-chlorostyrene oxide (0.007 mL, 0.06 mmol) and 15 mg of K2CO3. The resulting red solution was heated at 60 ° C. for 19 h and when cooled 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. Organic layer MgS0 ₄ Dried over, filtered and evaporated to afford a yellow oil. The material was purified by reverse phase HPLC to give the title compound (R) -7,8-bis (4-chlorophenyl) -2- (2- (3-chlorophenyl) -2-hydroxyethyl)-[1,2,4 ] Triazol [4,3-b] pyridazin-3 (2H) -one (15 mg, 52% yield) was obtained as a yellow solid. HRMS analysis. C ₂₅ H _l7 Cl ₃ N ₄ calculated for the _{0 2, 510.04, [M +} H] + = 511.0509 observed. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 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 (m, 2H), 1.55 (br s, 1H).

Example 23

7,8-bis (4-chlorophenyl) -2- (2-hydroxy-3-phenylpropyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one prepared as described in Example 1 in 7 mL of DMF. To a stirred solution of (500 mg, 1.4 mmol) was added 2,3-epoxypropylbenzene (0.18 mL, 1.4 mmol) and 0.39 g of K ₂ CO ₃ . The resulting red solution was heated to 85 ° C. for 27 hours and when cooled 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. Organic layer MgS0 ₄ Dried over, filtered and evaporated to afford a yellow oil. Purify the material by silica gel column chromatography using a gradient of 0-100% ethyl acetate / hexanes to obtain 15% starting material 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4, 3-b] 484 mg racemic 7,8-bis (4-chlorophenyl) -2- (2-hydroxy-3-phenylpropyl)-[1, containing pyridazin-3 (2H) -one 2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one as a yellow solid. Separation of the enantiomers was carried out on a Chiracel OD 5 cm x 50 cm 20 micron column on 200 mg of material, flow rate 50 mL / min isocratic 65% heptane / 17.5% ethanol / 17.5% methanol, monochrome at 220 nm Detection was performed using. Fraction A was collected in 49 minutes post infusion to yield 47 mg of 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H)- Warm enantiomer A was obtained as a yellow solid; Fraction B was injected into a 55 mg post-injection with 45 mg of 7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H) -one enantiomer Obtained as a yellow solid of B. Enantiomer A of 7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one: HRMS analysis. Calculated for C ₂₆ H ₂ 0C ₁₂ N ₄ 0 ₂ , 490.0963, [M + H] 491.1057 observed; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.33-7.09 (m, 13H), 5.05-4.95 (m, 1H), 4.33-4.30 (m, 1H), 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] triazolo [4,3-b] pyridazin-3 (2H) -one: HRMS analysis. Calculated for C ₂₆ H ₂₀ Cl ₂ N ₄ 0 ₂ , 490.0963, observed [M + H] 491.1042; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.33-7.09 (m, 13H), 5.05-4.95 (m, 1H), 4.33-4. 30 (m, 1H), 4.20 (dd, 1H, J = 3.1, 14.5 Hz), 4.06 (dd, 1H, J = 7.9, 14. 1 Hz) 2.88 (m, 2H).

Example 24

7,8-bis (4-chlorophenyl) -2- (1-phenyl-1H-tetrazol-5-yl)-[1,2,4] triazolo [4,3-b] pyridazine-3 ( Preparation of 2H) -one

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-, prepared as described in Example 1 in 0.7 mL of DMF. To a stirred solution of on, (50 mg, 0.14 mmol) was added N-phenyl-5-chlorotetrazole (25 mg, 0.14 mmol) and 19 mg of K ₂ CO ₃ . The resulting red solution was heated at 80 ° C. for 4 days and cooled to room temperature to dilute the mixture 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 ₄ , filtered and evaporated to give an orange solid. The material was purified via silica gel column chromatography followed by reverse phase HPLC to give the title compound 7,8-bis (4-chlorophenyl) -2- (1-phenyl-1H-tetrazol-5-yl)-[1 , 2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (7 mg, 10% yield) as a yellow solid. LCMS analysis. Calculated for C ₂₄ H ₄ Cl ₂ N ₈ O, 500.07, [M + H] 501; ¹ H NMR (400 MHz, CD ₃ CN) δ 8.30 (s, 1H), 7.69-7.55 (m, 5H), 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 [4,3-b] pyridazin-3 (2H) -one as 2- (2-hydroxybenzyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

25A. 2-((7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) methyl) phenyl acetate Manufacture

7,8-bis (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H)-prepared as described in Example 1 in 30 mL of DMF. To a solution of warm (800 mg, 2.24 mmol) was added 2- (chloromethyl) phenyl acetate (497 mg, 2.69 mmol) and K ₂ CO ₃ (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 and then diluted with 250 mL of EtOAc. The resulting solution was washed with saturated aqueous NaCl (100 mL × 3). The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure to afford the title compound 2-((7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazole [4,3- b] pyridazin-2 (3H) -yl) methyl) phenyl acetate (1.13 gm) was obtained as a yellow solid.

25B. Preparation of [4,3-b] pyridazin-3 (2H) -one as 2- (2-hydroxybenzyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazol

2-((7,8-bis (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazine-2 (3H)-, prepared as described in 25A. Yl) methyl) phenyl acetate (1.13 g) was dissolved in 25 mL of CH ₃ 0H. A small amount of NaOCH ₃ (121 mg, 2.24 mmol) solution in CH ₃ 0H (2 mL) was added to the reaction and 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 the resulting solution was then concentrated under reduced pressure. The crude residue was purified for 30 minutes using silica gel column chromatography using an automated system eluting with a gradient of 0% -60% EtOAc / hexanes, then further 60 minutes with 60% EtOAc / hexanes. Title compound 2- (2-hydroxybenzyl) -7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one ( 818 mg, 79% yield) was obtained as a yellow solid. MS [M + H] ⁺ = 463; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.54 (s, 1H), 8.14 (s, 1H), 7.32-7.17 (m, 8H), 7.04-7.00 (m, 2H), 6.94 (dd, 1H), 6.81 (td, 1 H), 5.13 (s, 2 H).

Example 26

7,8-bis (4-chlorophenyl) -2- (2-hydroxy-2-methylpropyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one prepared as described in Example 1 in 0.6 mL of DMF. To a solution of (20 mg, 0.056 mmol) isobutylene oxide (4.0 mg, 0.056 mmol) was added and K ₂ CO ₃ (15.5 mg, 0.112 mmol) was added. The mixture was heated to 85 ° C. Stir overnight and cool the reaction to room temperature. The reaction mixture was filtered (to remove excess K ₂ CO ₃ ). The collected solution was concentrated under reduced pressure. 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] triazol [4,3- b] Pyridazin-3 (2H) -one (18.4 mg, 77% yield) was obtained as a yellow oil. MS [M + H] ⁺ : 429 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.28 (s, 1H), 7.39-7. 27 (m, 6H), 7.16-7.12 (m, 2H), 4.16 (s, 2H), 4.00 (s, 1H), 1.34 (s, 6H).

Example 27

(R) -7,8-bis (4-chlorophenyl) -2- (2-hydroxyhexyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-prepared as described in Example 1 in 0.6 mL of DMF. To a solution of warm (20 mg, 0.056 mmol), (R)-(+)-1,2-epoxyhexane (5.6 mg, 0.056 mmol) was added, followed by K ₂ CO ₃ (15.5 mg, 0.112 mmol). Added. This mixture was heated at 85 ° C. After stirring overnight, the reaction was cooled to room temperature. The reaction mixture was filtered to remove excess K ₂ CO ₃ . The collected solution was concentrated under reduced pressure. The crude product was purified using silica gel column chromatography using an automated system eluting with a gradient of 0% -60% EtOAc / hexanes for 30 minutes with 60% EtOAc / hexanes to 100% EtOAc for 10 minutes. Title compound (R) -7,8-bis (4-chlorophenyl) -2- (2-hydroxyhexyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H ) -One (8.3 mg, 32% yield) was obtained as a yellow oil. MS [M + H] ⁺ : 457 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.12 (s, 1H), 7.28-7.19 (m, 6H), 7.06-7.02 (m, 2H), 4.13-4.08 (m, 1H), 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

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-prepared as described in Example 1 in 0.6 mL of DMF. To a solution of warm (20 mg, 0.056 mmol) was added glycidyl isobutyl ether (7.3 mg, 0.056 mmol) and K ₂ CO ₃ (15.5 mg, 0.112 mmol). The mixture was heated at 85 ° C. After stirring overnight, the reaction was cooled to room temperature. The reaction mixture was filtered to remove excess K ₂ CO ₃ . 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) was obtained as a yellow solid. MS [M + H] ⁺ : 487 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.08 (s, 1H), 7.23-7.15 (m, 6H), 7.00-6.96 (m, 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

7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxypropyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-, prepared as described in Example 1 in 8 mL of DMFT. To a solution of warm (300 mg, 0. 84 mmol) was added ethyl glycidyl ether (86 mg, 0.84 mmol) and K ₂ CO 3 (232 mg, 1.68 mmol). This mixture was heated at 85 ° C. After stirring overnight, the reaction was allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (200 mL). The resulting solution was washed with saturated aqueous NaCl (3 × 40 mL). The organic layer was dried over MgSO ₄ , 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 and 100% EtOAc for 40 minutes. Title compound 7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxypropyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 ( 2H) -one (0.3 gm, 78% yield) was obtained as a yellow solid. MS [M + H] ⁺ : 459 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.20 (s, 1H), 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 (m, 4H), 1.17 (t, 3H).

Example 30

7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-oxopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

Dess-Martin reagent (56 mg, 0.131 mmol) was prepared in 1 mL of CH ₂ Cl ₂ according to the method described in Example 29 in 7,8-bis (4-chlorophenyl) -2- (3- To a solution of [4,3-b] pyridazin-3 (2H) -one as oxy-2-hydroxypropyl)-[1,2,4] triazole was added. 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] triazol [4,3- b] Pyridazin-3 (2H) -one (47 mg, 95% yield) was obtained as a yellow solid. MS [M + H] ⁺ : 457 found.

Example 31

7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-hydroxy-2-methylpropyl)-[1,2,4] triazolo [4,3-b] pyridazine- Preparation of 3 (2H) -one

7,8-bis (4-chlorophenyl) -2- (3-ethoxy-2-oxopropyl)-[1 prepared as MeMgBr (0.03 mL, 0.08 mmol, 3.0 M in Et 2 O) as described in Example 30. , 2,4] triazole was added to a solution of [4,3-b] pyridazin-3 (2H) -one (23 mg, 0.05 mmol) at -78 ° C. The reaction was stirred for 30 min 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 × 10 mL). The combined organic layers were dried (Mg0 ₄ ), 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) was obtained as a yellow oil. MS [M + H] ⁺ : 473 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.13 (s, 1H), 7.29-7.18 (m, 6H), 7.06-7.02 (m, 2H), 4.25 (d, 1H), 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

7,8-bis (4-chlorophenyl) -2- (3-hydroxy-3-methylbutan-2-yl)-[1,2,4] triazolo [4,3-b] pyridazine-3 Preparation of (2H) -one

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)-prepared as described in Example 1 in 0.6 mL of DMF. To a solution of warm (300 mg, 0.84 mmol) 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol) was added and K ₂ CO ₃ (15.5 mg, 0.112 mmol) was added. This mixture was heated at 85 ° C. for 16 h. After this time, additional 10 mg K ₂ CO ₃ and 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol) were added. The reaction was continued to stir at 85 ° C. for a further 48 hours. The reaction was 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) was obtained as a yellow oil. MS [M + H] ⁺ : 443 found; ¹ H NMR (CDCl ₃ , 400 MHz) δ 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, 1 H), 1.23 (s, 1 H).

Example 33

4-((7,8-bis- (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyridazin-2 (3H) -yl) methyl) benzo Preparation of Nitrile

7,8-bis (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 1 in DMF (2 mL). A solution of -one (192 mg, 0.54 mmol), K ₂ CO ₃ (90 mg) and α-bromo-p-toluonitrile (127 mg, 0.645 mmol) 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 give the title compound 4-((7,8-bis- (4-chlorophenyl) -3-oxo- [1,2,4] triazolo [4,3-b] pyri Dajin-2 (3H) -yl) methyl) benzonitrile (80 mg) was obtained as a yellow solid. MS M + H = 472; ¹ H NMR (CDCl ₃ ): δ 8.17 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.33 (m, 2H), 7.25 (m , 2H), 7.24 (m, 2H), 7.09 (m, 2H), 5.25 (2H).

Examples 34-243

The following examples were prepared according to the methods presented in the preparation of Examples 1-33.

Example 244

Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo

244A. Preparation of 2-benzyl-4,5-dichloropyridazin-3 (2H) -one

To a solution of dichloropyridazone (50.0 g, 303.0 mmol) in DMF (200 mL) was added K ₂ CO ₃ (50.3 g, 364.0 mmol) with vigorous stirring at room temperature. Benzyl bromide (40.0 mL, 336.0 mmol) was added dropwise via syringe. The resulting suspension was judged by HPCL and stirred at 50 ° C. for 1 hour until all pyridazinone was consumed. The reaction mixture was then poured into water (400 mL). The resulting suspension was stirred for 15 minutes at room temperature. The collected solid was washed thoroughly with water until no color appeared in the filtrate. The solid was dried in a vacuum oven at 50 ° C. overnight to afford the title compound 2-benzyl-4, 5-dichloropyridazine-3 (2H) -one (73.1 g, 95%) as a pale yellow solid. HPLC: 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-dichloropyridazine-3 (2H) -one (73.1 g, 286.6 mmol) in 1,4-dioxane (700 mL) under argon over 15 minutes at room temperature A 25 wt.% Solution of NaOMe (72.0 mL, 315 mmol) in MeOH was added. The resulting dark reaction mixture was stirred at rt for 1.5 h. The solvent was evaporated and water (500 mL) was added to the resulting residue. The aqueous mixture was extracted with methylene chloride (4 x 120 mL). The combined organic layers were washed with water (2 x 300 mL) and then with saturated aqueous NaCl (2 x 150 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc / hexanes to afford the title compound 2-benzyl-5-chloro-4-methoxypyridazine-3 (2H) -one (56.0 g, 78%). Obtained as a pale yellow oil. HPLC: 3.19 min; MS, M + H = 251. ¹ H NMR (DMSO-d ₆ , 500 MHz): δ 8.05 (1H, s), 7.26-7.34 (5H, m), 5.24 (2H, s), 4.15 (3H, s).

244C. Preparation of 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazine-3 (2H) -one

To a stirred solution of 2-benzyl-5-chloro-4-methoxypyridazine-3 (2H) -one (20.0 g, 79.8 mmol) in toluene (500 mL) Pd (PPh ₃ ) ₄ (5.5 g, 4.76 mmol) was added under argon atmosphere. 4-chlorophenylboronic acid (18.7 g, 119.6 mmol) was added sequentially. Under vigorous stirring, Na ₂ CO ₃ (33.8 g, 318.9 mmol) predissolved in water (90 mL) was added to the suspension. The argon stream was bubbled through this suspension for 10 minutes. After this time, the flask was placed in a preheated oil bath at 120 ° C. The reaction was refluxed for 3 hours. After this time, the reaction was 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 mL X 3). The combined organic layers were washed with water (2 x 200 mL) and washed with saturated aqueous NaCl (2 x 100 mL). The organic layer was concentrated under reduced pressure to give the crude product. The 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%) was obtained as a white solid. HPLC: 3.79 min; M + H = 327. ¹ H NMR (CDCl ₃ , 500 MHz): δ 7.76 (1H, 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-methoxypyridazine-3 (2H) -one (13.8 g, 42.23 mmol) and POCl ₃ (20.0 mL) was stirred at 75 ° C. for 4 hours. It was. 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. Undissolved material was filtered off and washed with water (3 × 150 mL). MeOH (100 mL) was added to the so obtained solid. 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 at 50 ° C. in a vacuum oven to afford the title compound 2-benzyl-4-chloro-5- (4-chlorophenyl) pyridazin-3 (2H) -one (9.2 g, 66%) as a light brown solid. Obtained. HPLC: 3.75 min; M + H = 331. ¹ H NMR (CDCl ₃ , 500 MHz): δ 7.73 (1H, 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- (pyridin-4-yl) pyridazin-3 (2H) -one

Stirring 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 round bottom flask To the resulting solution was added Pd (PPh ₃ ) ₄ (1.5 g, 1.3 mmol) under an argon stream. 4- (4,4,5,5-tetramethyl-1,3,2-dixoborolan-2-yl) pyridine (5.63 g, 27.5 mmol) was added sequentially. Under vigorous stirring, Na ₂ CO ₃ (9.2 g, 86.8 mmol) predissolved in water (25 mL) was added to the suspension. A stream of argon was bubbled through the reaction mixture for 10 minutes. The flask was then placed in an oil bath preheated at 120 ° C. The reaction was stirred at reflux for 48 hours. After this time, the reaction mixture was cooled to room temperature and poured into water (100 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3 x 75 mL). The 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) pyridazine-3 (2H) -One (7.0 g, 89%) was obtained as a white solid. HPLC: 2.89 min; M + H = 374. ¹ H NMR (CDCl ₃ , 500 MHz): δ 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, m ), 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-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one

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 round bottom flask. To AlCl ₃ (7.5 g, 56.25 mmol) was added 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 placed in crushed ice (200 g). The precipitate formed was collected by filtration, collected with water (2 × 50 mL), and with ether (50 mL) and dried in a vacuum oven at 40 ° C. to give the title compound 5- (4-chlorophenyl) -4- (pyridine -4-yl) pyridazin-3 (2H) -one (5.1 g, 96%) was obtained as a white solid. HPLC: 1.37 min; MS, M + H = 284.

244G. Preparation of 3-chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazine

A mixture of 5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (5.1 g, 18.0 mmol) and POCl ₃ (20 mL) was heated at 80 ° C. for 2 hours. Stirred. The reaction mixture was cooled to room temperature and POCl ₃ was removed with a rotary evaporator to give a gum. The 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 × 75 mL). The combined organic layers were washed with water (2 x 50 mL) and washed with saturated aqueous NaCl (2 x 25 mL). The organic layer was dried over MgSO ₄ and filtered through a pad of silica gel (˜20 g). Evaporation of the solvent under reduced pressure gave the title compound 3-chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazine (5.1 g, 94%) as a white solid. HPLC: 2.01 min; MS, M + H = 302. 1 H NMR (CDCl ₃ , 500 MHz): δ 9.08 (1H, s), 8.56 (2H, d, J = 5.0 Hz), 7.21 (2H, 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- (pyridin-4-yl) pyridazin-3-yl) hydrazine

3-chloro-5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazine (5.1 g, 16.9 mmol) is 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 minutes. After this time, the reaction mixture was cooled to room temperature and then concentrated to concentrated to half of original volume under reduced pressure. The resulting mixture was diluted with water (100 mL). The yellow solid was collected by filtration and washed thoroughly with water. The solid was dried in a vacuum oven at 40 ° C. to give the title compound 1- (5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine (4.4 g, 88%) yellow Obtained as a powder. HPLC: 1.01 min; MS, M + H = 298.

244I. Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo

1- (5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3-yl in a THF (100 mL) solution of carbonyldiimidazole (CDI) (7.25 g, 44.71 mmol) ) Hydrazine (3.8 g, 12.76 mmol) was added in portions under argon atmosphere at room temperature. The reaction mixture was heated to reflux for 30 minutes. After this time, the reaction mixture was cooled to room temperature and subsequently concentrated under reduced pressure to give a gum to which water (100 mL) was added. The resulting solid was collected by filtration, washed with water (2 x 50 mL) and with 1: 1 (v / v) hexanes / ether (2 x 50 mL) to give the title compound 7- (4-chlorophenyl). -8- (pyridin-4-yl)-[1,2,4] triazol gave [4,3-b] pyridazin-3 (2H) -one (3.75 g, 91%) as a yellow solid. HPLC: 1.67 min; MS, M + H = 324; ¹ H NMR (DMSO-d ₆ ) δ 12.90 (1H, s), 8.59 (2H, d, J = 10.0 Hz), 8.41 (1H, s), 7.44 (2H, d, J = 10.0 Hz), 7.32 ( 2H, d, J = 5.0 Hz), 7.28 (2H, d, J = 5.0 Hz).

Example 245

7- (4-chlorophenyl) -2-((6-chloropyridin-3-yl) methyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine prepared as described in Example 244 in DMF (3 mL) To a solution of -3 (2H) -one (150 mg, 0.46 mmol) was added K ₂ CO ₃ (80 mg, 0.58 mmol) and 2-chloro-5- (chloromethyl) pyridine (90 mg, 0.556 mmol). . The reaction mixture was stirred at 70 ° C. for 15 minutes. 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- (pyridine-4- Yl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (110 mg, 52%) as a yellow solid. HPLC: 2.61 min; MS, M + H = 449; ¹ H NMR (CDCl ₃ ) δ 8.62 (2H, d, J = 5.0 Hz), 8.43 (1H, d, J = 5.0 Hz), 8.19 (1H, s), 7.33 (1H, 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

7- (4-chlorophenyl) -2-((6- (dimethylamino) pyridin-3-yl) methyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4, 3-b] Preparation of pyridazin-3 (2H) -one

7- (4-chlorophenyl) -2-((6- (chloro) pyridin-3-yl) methyl) -8- (pyridin-4-yl)-prepared as described in Example 245 in water (1.0 mL). A mixture of [4,3-b] pyridazin-3 (2H) -one (30 mg, 0.0667 mmol) and N, N-dimethyl amine was heated to reflux with [1,2,4] triazole. After 8 hours, 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] triazole gave [4,3-b] pyridazin-3 (2H) -one (17.5 mg, 57%) as a yellow solid. HPLC: 1.41 min; M + H = 458; ¹ H NMR (CDCl 3) δ 8.63 (2H, d, J = 5.0 hz), 8.23 (1H, 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 (1H, d, J = 10 Hz), 5.08 (2H, s), 3.07 (6H, s).

Example 247

7- (4-chlorophenyl) -8- (pyridin-4-yl) -2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo Preparation of [4,3-b] pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridine prepared as described in Example 244 in DMF (8.3 mL) Solution of Dajin-3 (2H) -one (1.1 g, 3.4 mmol), K ₂ CO ₃ (940 mg, 6.8 mmol), and 5-chloromethyl-2-trifluoromethylpyridine (800 mg, 4.1 mmol) Heated at 65 ° C. for 40 min. After this time, the solution was cooled to room temperature. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated and 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 silica gel column chromatography eluting with hexanes / EtOAc to give the title compound 7- (4-chlorophenyl) -8- (pyridin-4-yl) -2-((6- (trifluoromethyl) pyridine 3-yl) methyl)-[1,2,4] triazol gave [4,3-b] pyridazin-3 (2H) -one (1.25 g, 76%) as a yellow solid. HPLC: 2.84 min; MS, M + H = 483; ¹ H NMR (CDCl ₃ ) δ 8.80 (d, J = 1.4 Hz, 1H), 8.65 (Abq, J = 1.6, 4.4 Hz, 2H), 8.23 (s, 1H), 7.96 (m, 1H), 7.68 ( d, J = 8.3 Hz, 1H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 5.31 (2H).

Example 248

7- (4-chlorophenyl) -8- (pyridin-4-yl) -2-((5- (trifluoromethyl) pyridin-2-yl) methyl)-[1,2,4] triazolo [ 4,3-b] Preparation of pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridine prepared as described in Example 244 in DMF (0.4 mL). Solution of Dazine-3 (2H) -one (32.4 mg, 0.1 mmol), K ₂ CO ₃ (56 mg, 0.4 mmol) and 2-chloromethyl-5-trifluoromethylpyridine hydrogen chloride (37 mg, 0.4 mmol) Heated at 65 ° C. for 2 h. The crude product was obtained using a method similar to the method described in Example 247. The crude product was purified by reverse phase HPLC to give the title compound 7- (4-chlorophenyl) -8- (pyridin-4-yl) -2-((5- (trifluoromethyl) pyridin-2-yl) methyl)- [1,2,4] Triazole gave [4,3-b] pyridazine-3 (2H) -one (27 mg) as a yellow solid. HPLC RT: 2.78 min; M + H = 483; ¹ H NMR (CDCl ₃ ): δ 8.82 (s, 1H), 8.62 (m, 2H), 8.24 (s, 1H), 7.91 (m, 1H), 7.38-7.10 (m, 7H), 5.45 (2H) .

Example 249

4-((7- (4-chlorophenyl) -3-oxo-8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine-2 (3H) Preparation of -yl) methyl) benzonitrile

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3b] pyridazine- prepared as described in Example 244 in DMF (1 mL) A solution of 3 (2H) -one (96 mg, 0.3 mmol), K ₂ CO ₃ (82 mg, 0.59 mmol) and α-bromo-p-toluonitrile (70 mg, 0.356 mmol) was 2.5 at 65 ° C. Heated for hours. Using a method analogous to that 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] triazol [4,3 -b] pyridazin-2 (3H) -yl) methyl) benzonitrile (27 mg) was obtained as a yellow solid. HPLC RT: 2.45 min; M + H = 439; ¹ H NMR (CDCl ₃ ): δ 8.63 (d, J = 6.04 Hz, 2H), 8.21 (s, 1H), 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

2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

250A. Preparation of 5- (4- (bromomethyl) phenyl) isoxazole

To a solution of 5- (4-methylphenyl) isoxazole (4.0 g, 25.13 mmol) in carbon tetrachloride (125 mL), N-bromosuccinimide (4.47 g, 25.13 mmol) and benzoyl peroxide (0.12 g, 0.50 mmol) Was added. The resulting mixture was refluxed for 1 hour. After this time, the reaction mixture was 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 4.2 g of the title compound 5- (4- (bromomethyl) phenyl) isoxazole as off-white solid. ¹ H NMR (CDCl ₃ ): δ 8.30 (d, J = 2. 2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 6.54 (d , J = 1.7 Hz, lH), 4.51 (s, 2H).

250b. 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridine prepared as described in Example 244 in DMF (23 mL). Dajin-3 (2H) -one (3.0 g, 9.27 mmol), K ₂ C0 ₃ (2.56 g, 18. 53 mmol) and 5- (4- (bromomethyl) phenyl) isoxazole (2.65 g, 11.12 mmol ) Solution was added. The resulting mixture was heated to 60 ° C. After 2 hours, the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was separated and the aqueous layer 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 hexanes / EtOAc 1: 10 to give the title compound 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridine- 4-yl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one as a light yellow solid. HPLC RT: 2.64 min; MS, M + H = 481; ¹ H NMR (CDCl ₃ ): δ 8. 62-8.64 (m, 2H), 8. 29 (d, J = 1. 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, J = 1.6 Hz, 1H), 5.25 (s, 2H).

Example 251

2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

251A. Preparation of 3- (4- (bromomethyl) phenyl) isoxazole

To a solution of 3- (4-methylphenyl) isoxazole (prepared by the method mentioned) (1.95 g, 12.25 mmol) in carbon tetrachloride (60 mL), N-bromosuccinimide (2.18 g, 12.25 mmol) and benzoyl peroxide (0.059 g, 0.245 mmol) was added and the mixture was refluxed for 1 hour. 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 afford the title compound 3- (4- (bromomethyl) phenyl) isoxazole (0.6 g) as a white solid. ¹ H NMR (CDCl ₃ ): δ 8.48 (d, J = 1.6 Hz, 1H), 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. 2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyriri prepared as described in Example 244 in DMF (4 mL) To a solution of dazin-3 (2H) -one (0.27 g, 0.834 mmol) potassium carbonate (0.23 g, 1.67 mmol) and 3- (4- (bromomethyl) phenyl) isoxazole (0.248 g, 1.04 mmol) Was added. The resulting mixture was heated to 65 ° C. After 2 h, the reaction mixture was cooled to rt and diluted with EtOAc (200 mL). The resulting solution was then washed with water and with saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography eluting with hexanes / EtOAc to give the title compound 2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridine-4- Il)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one as a light yellow solid. HPLC RT: 2.60 min; ¹ H NMR (CDCl ₃ ): δ 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, 1H ), 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 252-272

The following examples were prepared according to the methods and procedures described above:

Example 273

2- (4- (trifluoromethyl) benzyl) -7-chloro-8- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

273A. Preparation of 2-benzyl-5-chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one

2-benzyl-4, 5-dichloropyridazin-3 (2H) -one (30.6 g, 120 mmol), 4-chlorophenyl boronic acid (20.6 g, prepared as described in Example 244A in toluene (300 mL) 132 mmol) and tetrakis (triphenylphosphine) palladium (Sg, 4.3 mmol) under an argon atmosphere were added an aqueous Na ₂ CO ₃ solution (2M, 66 mL, 132 mmol). The reaction mixture was stirred at 100 ° C for 16 h under argon. The reaction was then allowed to cool to room temperature and continuously poured into water (200 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting thick syrup was dissolved in MeOH (100 mL) and the resulting solution was kept at 0 ° C. until a white solid precipitated at 0 ° C. The solid was collected by filtration, washed with hexane and then EtOAc-hexane trituration to give the title compound 2-benzyl-5-chloro-4- (4-chlorophenyl) pyridazine-3 (2H)- Warm (12 g, 30%) was obtained 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). Added. The mixture was stirred at 50 ° C. for 1 hour. 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 (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was triturated with EtOAc-hexanes 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) pyridazine

A suspension of 5-chloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one (6.8 g, 28.2 mmol) in POCl ₃ (14 mL) was heated at 100 ° C. for 1 hour. After this time, the reaction mixture was cooled to room temperature. Then the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ and saturated aqueous NaCl. The organic layer was dried (Na ₂ SO ₄ ), 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

Hydrazine (3.2 mL, 100 mL) was added to a solution of 3,5-dichloro-4- (4-chlorophenyl) pyridazine (2.56 g, 10 mmol) in dioxane (36 mL) at room temperature. After addition, the reaction was heated to 70 ° C. for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. 2-propanol (80 mL) was added to the obtained residue and the resulting white solid was filtered off. The collected liquid was concentrated under reduced pressure to give the title compound 1- (5-chloro-4- (4-chlorophenyl) pyridazin-3-yl) hydrazine, 15% byproduct (1- (3-chloro-4). -(4-chlorophenyl) pyridazin-5-yl) hydrazine). This mixture was used directly for the next step, 273E. LC / MS (Method A): RT = 1.89 min, (M + H) ⁺ = 255.

273E. Preparation of [4,3-b] pyridazin-3 (2H) -one with 7-chloro-8- (4-chlorophenyl)-[1,2,4] triazol

To a solution of 1,1'-carbonyldiimidazole (1.78 g, 11 mmol) in THF (10 mL) at room temperature in 1- (5-chloro-4- (4-chlorophenyl) pyridazine in THF (10 mL) -3-yl) a suspension of hydrazine (560 mg, 2.19 mmol) was added. After addition, the reaction became a clear solution and stirred at room temperature for 1 hour. Then the reaction mixture was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. EtOAc (20 mL) was added to the obtained residue, 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] triazole. [4,3-b] pyridazin-3 (2H) -one was obtained as a yellow solid (300 mg, 61%). LC / MS (Method A): RT = 2.86 min, (M + H) ⁺ = 281.

Example 274

2- (4-trifluoromethyl) benzyl) -7-chloro-8- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H)- Manufacture of

[4,3-b] pyridazine-3 (7-chloro-8- (4-chlorophenyl)-[1,2,4] triazol prepared as described in Example 273 in DMF (1 mL) at room temperature. To a solution of 2H) -one (86.4 mg, 0.31 mmol) was added 4-trifluoromethylbenzyl bromide (112 mg, 0.47 mmol) and K ₂ CO ₃ (86 mg, 0.62 mmol). The reaction mixture was heated to 50 ° C. for 1 hour. 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 (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by silica gel (12 g) column chromatography eluting with an EtOAc (0-60%) gradient in hexanes to give the title compound 2- (4-trifluoromethyl) benzyl) -7-chloro-8- (4-chlorophenyl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one as a yellow solid (100 mg, 74%). HPLC: 99% (ret. Time) at 7.76 min (Conditions: Zorbax SBC18 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ 0-10% MeOH-0.1) % H ₃ PO ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ P0 ₄ ); flow rate at 2.5 mL / min. UV detection at 220 nm). MS (ES): m / z 439 [M + H] ^{+; 1} H NMR (DMSO-d ₆ , 400 MHz): δ 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, 1 H).

Example 275

2- (4- (trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-phenoxy- [1,2,4] triazolo [4,3-b] pyridazine-3 (2H ) -On Preparation

2- (4- (trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-chloro- [1,2,4] triazolo prepared as described in Example 274 in DMF (0.5 mL) To a solution of [4,3-b] pyridazin-3 (2H) -one (17 mg, 0.039 mmol) was added phenol (7.2 mg, 0.077 mmol) and K ₂ CO ₃ (11 mg, 0.077 mmol) was added. Added. The reaction mixture was stirred at rt 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 H ₂ O. The crude product was purified by reverse phase HPLC to give the title compound 2- (4-trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-phenoxy- [1,2,4] triazol [4,3 -b] Pyridazin-3 (2H) -one (12 mg, 62%) was obtained as a yellow solid. HPLC: 99% at 8.31 min (ret. Time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ 0-10% MeOH- 0.1% H ₃ PO ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; UV detection at 220 nm). MS (ES): m / z 497 [M + H] ⁺ ; ¹ H NMR (CDCl ₃ , 400 MHz): δ 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, 2 H), 7.90 (s, 1 H).

Example 276

2- (4-trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7- (4-fluorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine Preparation of -3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -8- (4-chlorophenyl) -7-chloro- [1,2,4] triazolo prepared as described in Example 274 in toluene (1 mL) Tetrakis (triphenylphosphine) palladium in a mixture of [4,3-b] pyridazin-3 (2H) -one (30 mg, 0.068 mmol), 4-fluorophenylboronic acid (47.6 mg, 0.34 mmol) (12 mg, 0.01 mmol) was added and Na ₂ CO ₃ (2M, 0.19 mL, 0.38 mmol) in H ₂ O was added. The reaction mixture was stirred at 100 ° C for 16 h and diluted with water. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by silica gel (12 g) chromatography eluting with an EtOAc gradient in hexanes (0-60%) to give the title compound 2- (4-trifluoromethyl) benzyl) -8- (4-chlorophenyl ) -7- (4-fluorophenyl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (27 mg, 79%) as a yellow solid. . HPLC: 99% (ret. Time) at 8.13 min (Conditions: Zorbax SB C18 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ 0-10% MeOH- 0.1% H ₃ PO ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; UV detection at 220 mn). MS (ES): m / z 499 [M + H] ^{+; 1} H NMR (CDCl ₃ , 400 MHz): δ 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, 1H).

Example 277

7-chloro-8- (4-chlorophenyl) -2- (6- (trifluoromethyl) pyridin-3-yl) methyl- [1,2,4] triazolo [4,3-b] pyridazine Preparation of -3 (2H) -one

7-chloro-8- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3, prepared as described in Example 273, using the method described in Example 274 (2H) -one is reacted with 5- (bromomethyl) -2- (trifluoromethyl) pyridine to give the title compound 7-chloro-8- (4-chlorophenyl) -2- (6- (trifluoro) Methyl) pyridin-3-yl) methyl- [1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one.

Example 278

8- (4-chlorophenyl) -7- (4- (oxazol-2-yl) phenyl) -2-((6- (trifluoromethyl) pyridin-3-yl) methyl) -1,2, 4] Preparation of [4,3-b] pyridazin-3 (2H) -one with triazolo

278A. Preparation of 2- (4-bromophenyl) oxazole

2- (4-bromophenyl) oxazole was prepared from 4-bromobenzoyl chloride and aminoacetaldehyde dimethyl acetal according to the method described in the literature.

278B. Preparation of 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) oxazole

2- (4-bromophenyl) oxazole is reacted with bis (pinacolato) diboron according to the method of literature to give the title compound 2- (4- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl) phenyl) oxazole was obtained.

278C. 8- (4-chlorophenyl) -7- (4- (oxazol-2-yl) phenyl) -2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2 , 4] triazolo [4,3-b] pyridazine-3 (2H) -one

7-Chloro-8- (4-chlorophenyl) -2- (6- (trifluoromethyl) pyridin-3-yl) methyl- [1,2,4] triazolo prepared as described in Example 277 [ 4,3-b] pyridazin-3 (2H) -one and 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) The oxazole was reacted using a method similar to that 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 was obtained. HPLC: 99% (conditions: Zorbax SB C18 (4.6 x 75 mm) at 8.42 min (ret. Time); eluting with 0% to 100% B, 8 min gradient. (A = 90% H ₂ 0-10% MeOH- 0.1% H ₃ PO ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; UV detection at 220 nm). MS (ES): m / z 549 [M + H] ^{+; 1} H NMR (CDCl ₃ , 400 MHz): δ 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 ( m, 2H), 8.24-8.27 (m, 1 H), 8.81 (s, 1 H).

Example 279

Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo

279A. Preparation of 2-benzyl-5-chloro-4- (4-pyridin-4-yl) pyridazin-3 (2H) -one

2-benzyl-4, 5-dichloropyridazine-3 (2H) -one (10.8 g, 42 mmol), 4- (4,4) prepared as described in Example 244A in toluene (80 mL) under an argon stream. Tetrakis (triphenylphosphine) palladium (4.4 g, 3.8) in a mixture of 5,5, -tetramethyl-1,3,2-dioxoborolan-2-yl) pyridine (7.9 g, 38.5 mmol) mmol) was added and aqueous Na ₂ CO ₃ solution (2M, 21 mL, 42 mmol) was added. The reaction mixture was heated to 100 ° C. under argon for 16 hours. After cooling to rt, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting residue was purified using silica gel (330 g) column chromatography eluting with an EtOAc gradient in hexanes (30-100%) to give the title compound 2-benzyl-5-chloro-4- (4-pyridine-4 -Yl) pyridazin-3 (2H) -one (3.1 g, 27%) was obtained 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) pyridazin-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, similar to the method described in Example 276. It was prepared using. 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) pyridazin-3 (2H) -one

Aluminum chloride in 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) (970 mg, 7.28 mmol) was added. The reaction was stirred at 90 ° C for 30 minutes. After cooling to room temperature, the reaction mixture was poured into water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO ₃ , saturated aqueous NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was triturated with EtOAc-hexanes 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-yl) pyridazine

5- (4-fluorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one is reacted with POCl ₃ using a method analogous to that described in Example 273C to give the title compound 3- Chloro-5- (4-fluorophenyl) 4- (pyridin-4-yl) pyridazine was obtained. LC / MS (Method A): RT = 1.43 min, (M + H) ⁺ = 286.

279E. Preparation of 1- (5- (4-fluorophenyl) 4- (pyridin-4-yl) pyridazin-3-yl) hydrazine

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 to hydrazine monohydrate (0.6 mL) It was. After addition, the reaction was heated at 100 ° C. for 3 hours. 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 ₄ ), filtered and concentrated. The resulting residue was triturated with EtOAc-hexanes to give the title compound 1- (5- (4-fluorophenyl) 4- (pyridin-4-yl) pyridazin-3-yl) hydrazine (450 mg, 78% ) Was obtained as an off-white solid. LC / MS (Method A): RT = 1.10 min, (M + H) ⁺ = 282.

279F. Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo

To a solution of 1,1′-carbonyldiimidazole (1.27 g, 7.86 mmol) in THF (20 mL) 1- (5- (4-fluorophenyl) 4- (pyridine-4- in THF (5 mL) I) pyridazin-3-yl) hydrazine (442 mg, 1.57 mmol) suspension was added. After addition, the reaction mixture was heated to 66 ° C. After 20 minutes, the reaction mixture was cooled to room temperature and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was triturated with EtOAc-hexanes to give the title compound 7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazol [4,3-b Pyridazin-3 (2H) -one (440 mg, 91%) was obtained as a yellow solid. LC / MS (Method A): RT = 1.27 min, (M + H) ⁺ = 308.

Example 280

2- (4- (isoxazol-5-yl) benzyl) -7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3- b] Preparation of pyridazine-3 (2H) -one

7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] -triazolo [4,3-b] pyridazine-3 (prepared as described in Example 279F) 2H) -one, 5- (4- (bromomethyl) phenyl) isoxazole, prepared as described in Example 250A by a similar method as described in Example 2, to prepare the title compound as a yellow solid (68 %). HPLC: 99% at 5.46 min (ret. Time) (Conditions: Zorbax SB C13 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ 0-10% MeOH- 0.1% H ₃ P0 ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; UV detection at 220 mn). MS (ES): m / z 465 [M + H] ^{+; 1} H NMR (CDCl ₃ , 400 MHz): δ 5.25 (s, 2H), 6.51 (d, J = 0.96 Hz, 1H), 7.01-7.09 (m, 2H), 7.11-7.18 (m, 2H), 7.23 (dd, J _l = 4.40 Hz, J ₂ = 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, 1H), 8.61-8.64 (m, 2H).

Example 281

2- (4-isoxazol-3-yl) benzyl) -7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7- (4-fluorophenyl) -8- (pyridin-4-yl)-[1,2,4] -triazolo [4,3-b] pyridazine-3 (prepared as described in Example 279F) 2H) -one, reacting 3- (4- (bromomethyl) phenyl) isoxazole prepared as described in Example 251A, to give the title compound by a method similar to that 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] pyridazine- 3 (2H) -one was obtained as a yellow solid (59%). HPLC: 99% at 5.33 min (ret. Time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ O-10% MeOH- 0.1% H ₃ PO ₄ and B = 10% H ₂ O-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; UV detection at 220 nm). MS (ES): m / z 465 [M + H] ^{+; 1} H NMR (CDCl ₃ , 400 MHz): δ 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, 1H), 8.45 (s, 1H), 8.62 ( d, J = 5.30 Hz, 2H).

Example 282

Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-methoxyphenyI) -8- (pyridin-4-yl)-[1,4] triazolo

282A. Preparation of 5-chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one

Of toluene (65 mL) of 2-benzyl-5-chloro-4- (4-pyridin-4-yl) pyridazin-3 (2H) -one (3.9 g, 13.1 mmol) prepared as described in Example 297A. To the suspension was added aluminum chloride (4.37 g, 32.7 mmol). The mixture was stirred at 90 ° C. for 1 hour. After this time, the reaction mixture was cooled to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO ₃ (pH adjusted to 7). The precipitate formed was collected by filtration and washed with EtOAc to give 1.8 g of the title compound. The aqueous layer was extracted with EtOAc (2 ×) and the combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue obtained was triturated with EtOAc-hexane to give an additional 0.7 g. 5-chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one was obtained as an off-white solid with 2.5 g (92%) of the title compound. LC / MS (Method A): RT = 0.48 min, (M + H) ⁺ = 208.

282B. Preparation of 3,5-dichloro-4- (pyridin-4-yl) pyridazine

A suspension of compound 5-chloro-4- (pyridin-4-yl) pyridazin-3 (2H) -one (2.5 g, 12 mmol) in POCl ₃ (20 mL) was heated at 120 ° C. for 3 hours. 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 ice cold saturated aqueous NaHCO ₃ . The precipitate formed 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-pyridin-4-yl) pyridazine

By reacting 3,5-dichloro-4- (pyridin-4-yl) pyridazine with 4-methoxyphenylboronic acid by a method similar to that described in Example 279D to prepare the title compound, 3-chloro-5- ( 4-methoxyphenyl) -4-pyridin-4-yl) pyridazine was obtained. LC / MS (Method A): RT = 1.58 min, (M + H) ⁺ = 298.

282D. Preparation of 1- (5- (4-methoxyphenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine

3-Chloro-5- (4-methoxyphenyl) -4-pyridin-4-yl) pyridazine and hydrazine monohydrate were reacted by a method similar to that described in Example 244H to prepare the title compound. -(4-methoxyphenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine was obtained. LC / MS (Method A): RT = 1.18 min, (M + H) ⁺ = 294.

282E. Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-methoxyphenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo

1- (5- (4-methoxyphenyl) -4- (pyridin-4-yl) pyridazin-3-yl) hydrazine and carbonyldiimidazole (CDI) were prepared by a method similar to that described in Example 279F. By reaction to form the title compound, 7- (4-methoxyphenyl) -8- (pyridin-4-yl)-[1,2,4] triazol [4,3-b] pyridazine-3 (2H) -On was obtained. LC / MS (Method A): RT = 1.37 min, (M + H) ⁺ = 320.

Example 283

2- (4-isoxazol-5-yl) benzyl) -7- (4-methoxyphenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b Preparation of Pyridazin-3 (2H) -one

7- (4-methoxyphenyl) -8- (pyridin-4-yl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H, prepared as described in Example 282 ) -One, 5- (4- (bromomethyl) phenyl) isoxazole, prepared as described in Example 250A, was reacted by a similar method as described in Example 2 to give the title compound as a yellow solid. HPLC: 99% at 5.53 min (ret. Time) (Conditions: Zorbax SB C18 (4.6 x 75 mm); eluted with 0% to 100% B, 8 min gradient. (A = 90% H ₂ O-10% MeOH- 0.1% H ₃ PO ₄ and B = 10% H ₂ 0-90% MeOH-0.1% H ₃ PO ₄ ); 2.5 mL / min flow rate; 220 nm UV detection). MS (ES): m / z 477 [M + H] ^{+; 1} H NMR (CDCl ₃ , 400 MHz): δ 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 ( m, 2H), 8.60-8.70 (m, 2H).

Examples 284-353

The following examples were prepared according to the methods and procedures described above.

Example 354

Preparation of [4,3-b] pyridazin-3-one with 8-chloro-7- (4-chloro-phenyl) -2H- [1,2,4] triazol

354A. Preparation of 2-benzyl-4-chloro-5-methoxypyridazin-3 (2H) -one

Sodium methoxide in methanol in 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 0 ° C. MeOH (175 mL). The solution of the side (25% by weight in MeOH, 25 mL) was added dropwise. The mixture was slowly warmed up to room temperature and stirred for 18 hours. The reaction mixture was diluted with methylene chloride (200 mL) and filtered. Concentrate the filtrate and determine by HPLC to give the title compound 2-benzyl-4-chloro-5methoxypyridazin-3 (2H) -one (22.2 g) with purity> 95% and further in reaction example 354B Used without further purification.

354B. Preparation of 2-benzyl-4-chloro-5-hydroxypyridazin-3 (2H) -one

To a suspension of 2-benzyl-4-chloro-5-methoxypyridazine-3 (2H) -one (22.2 g, 87.47 mmol) in water (150.0 mL) is added potassium hydroxide (5.89 g) and the mixture is heated. To reflux. After 3 hours, the mixture was cooled to room temperature, 6N aqueous hydrochloric acid was added and the pH of the solution was adjusted to 3.0. The precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound 2-benzyl-4-chloro-5-hydroxypyridazin-3 (2H) -one (20.45 g) as a white solid. HPLC: 2.40 min

354 C. Preparation of 2-benzyl-4-chloro-5- (4-chlorophenyl) -2H-pyridazin-3-one

Triethylamine (4.02 g) in 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 ° C. , 39.75 mmol), and trifluoromethane sulfonic anhydride (10 g, 35. 45 mmol) were added. The mixture was stirred for 30 minutes and poured into an ice cold solution (200 mL) of 0.5 N aqueous hydrochloric acid solution. This mixture was 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 ₄ ), filtered and concentrated under reduced pressure to afford the corresponding triflate as a pink oil (12.91 g). 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 (chlorodi-tert-butylphosphine) palladium (0.89 g, 1.65 mmol) and potassium carbonate (13.67 g) were added and the reaction mixture was at room temperature. Stir for 1.5 hours. The reaction mixture was then diluted with water (200 mL). The resulting solution was extracted with CH ₂ Cl ₂ (2 × 200 mL). The combined organic layers were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue is then purified by column chromatography using hexane / EtOAc (2: 1) to give the title compound 2-benzyl-4-chloro-5- (4-chloro-phenyl) -2H-pyridazine-3 3.9 g of -one was obtained as a white solid. HPLC: 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). And aluminum chloride (A1C1 ₃ , 3.22 g, 24.1 mmol) was added and the reaction mixture was heated at 50 ° C. After 20 minutes, the reaction mixture was cooled to room temperature and poured into ice water (200 mL). The resulting solution was extracted with EtOAc (3 × 200 mL). 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 as a white solid (2.33 g). HPLC: 2.74 min

354E. Preparation of 3,4-dichloro-5- (4-chlorophenyl) -pyridazine

4-Chloro-5- (4-chlororphenyl-2H-pyridazin-3-one (2.33 g, 9.65 mmol) was suspended in POCl ₃ (11 mL) The reaction mixture was placed in an oil bath and 1 h at 110 ° C. After cooling to room temperature, the mixture was poured onto 200 g ice to quench excess POCl ₃ and the resulting solution was extracted with EtOAc The combined organic layers were washed with water The organic layer was dried (MgSO ₄ ) , 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) is suspended in isobutanol (150 mL) at 0 ° C. and hydrazine monohydrate (11.1 g) is added dropwise over 10 minutes. It was. The reaction mixture was slowly warmed up to room temperature and stirred for 24 hours. This mixture was cooled in ice / water bath for 15 minutes 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. . HPLC: 1.65 min

354G. Preparation of [4,3-b] pyridazin-3-one with 8-chloro-7- (4-chlorophenyl) -2H-1,2,4] triazol

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 several times over 15 minutes at room temperature. The mixture was stirred at rt for 4 h. After this time, the solution was poured into ice / water (500 mL) and the resulting light yellow solid was collected by filtration. The solid was rinsed with aqueous 0.5 N HCl and water. Then, drying in vacuo, the title compound was 2.81 g of 8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazol [4,3-b] pyridazin-3-one. Was obtained as a light yellow solid. HPLC: 2.78 min; MS, M + H = 281.

Example 355

2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 ( Preparation of 2H) -one

8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) prepared as described in Example 354 in DMF (5 mL). 5- (4- (bromomethyl) phenyl) isoxazole prepared as described in Example 250A after addition of K ₂ CO ₃ (180 mg, 1.3 mmol) to a solution of -one (300 mg, 1.07 mmol). (305 mg, 1.28 mmol) was added. The reaction mixture was stirred at 70 ° C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (25 mL) to form a precipitate. The solid was collected by filtration. The solid was washed with water (2x 25 mL) and washed with hexanes (20 mL). The solid was dried in a vacuum oven at 40 ° C. Title compound 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine- 3 (2H) -one (450 mg, 96%) was obtained as a yellow solid. HPLC: 3.50 min; M + H = 438.

Example 357

2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yl)-[1,2,4] triazolo [4,3- b] Preparation of pyridazine-3 (2H) -one

2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1, in toluene (2 mL) prepared as described in Example 355 in a round bottom flask. To a stirred solution of [4,3-b] pyridazin-3 (2H) -one (100 mg, 0.23 mmol) with 2,4] triazol was added Pd (PPh ₃ ) ₄ (16 mg, 0.014 mmol) under an argon stream. Added. 3- (4,4,5,5-tetramethyl-1,3,2-dixoborolan-2-yl) pyridine (61 mg, 0.3 mmol) was subsequently added. Under vigorous stirring, Na ₂ CO ₃ (97 mg, 0.91 mmol) predissolved in water (0.25 mL) was added to the suspension. Argon was bubbled through this suspension for 10 minutes before placing the flask in an oil bath preheated at 120 ° C. The reaction was stirred at 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 × 10 mL). The combined organic layers were washed with water (2 x 10 mL) and washed with saturated aqueous NaCl (2 x 5 mL). The organic layer was concentrated under reduced pressure. The resulting product 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] pyridazine-3 (2H) -one (8.5 mg, 8%) was obtained as a pale yellow solid.

HPLC: 2.98 min; M + H = 481, ¹ H NMR (CDCl ₃ ), ppm: 8.61 (1H, d, J = 6.05 Hz), 8.55 (1H, d, J = 5.0 Hz), 8.28 (1H, d, J = 2.0 Hz )), 8.19 (1H, 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 (1H, s), 5.25 (2H, s).

Example 357

2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8-phenyl- [1,2,4] triazolo [4,3-b] pyridazine-3 ( Preparation of 2H) -one

2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1, in toluene (2 mL) prepared as described in Example 355 in a round bottom flask. 2,4] Pd (PPh ₃ ) ₄ (16 mg, 0.014 mmol) was added to a stirred solution of [4,3-b] pyridazin-3 (2H) -one (100 mg, 0.23 mmol) with triazole. Add under bubbling. Phenylboronic acid (36 mg, 0.3 mmol) was subsequently added. Under vigorous stirring, Na ₂ CO ₃ (97 mg, 0.91 mmol) predissolved in water (0.25 mL) was added to the suspension. Argon was bubbled through this suspension for 10 minutes before placing the flask in a preheated oil bath at 120 ° C. 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 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and then with saturated aqueous NaCl (2 × 5 mL). The organic layer was dried (MgSO ₄ ), filtered and concentrated to give crude product. The 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] triazol [ 4,3-b] Pyridazin-3 (2H) -one (15.5 mg, 14%) was obtained as a pale yellow solid. HPLC: 3.68 min; MS, M + H = 480; ¹ H NMR (CDCl 3), ppm: 8.31 (1H, d, J = 2.0 Hz), 8.22 (1H, 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 (2H, d, J = 10 Hz), 6.54 (1H, d, J = 5.0 Hz), 5.29 (2H, s).

Example 358

Preparation of [4,3-b] pyridazin-3-one with 8-chloro-7- (4-chlorophenyl) -2- (pyrazin-2-ylmethyl) -2H- [1,2,4] triazolo

8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazolo [4,3-b] pyridazine- prepared as described in Example 354 in DMF (10 mL) at room temperature. To a solution of 3-one (0.62 g, 2. 21 mmol) was added K ₂ CO ₃ (0.61 g, 4.4 mmol) and 2- (chloromethyl) pyrazine (0.83 g). The reaction mixture was heated at 50 ° C. for 2 hours. 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 column chromatography on silica gel eluting with hexanes: EtOAc 1: 2 to give 0.61 g of the title compound 8-chloro-7- (4-chlorophenyl) -2- (pyrazin-2-ylmethyl)- 2H- [1,2,4] triazol gave [4,3-b] pyridazin-3-one as a yellow solid. HPLC RT: 2.86 min; MS, M + H = 373; ¹ H NMR (CDCl ₃ ): δ 8.64 (d, 1H), 8.54 (m, 2H), 8.11 (s, 1H), 7.54-7.49 (m, 4H), 5.48 (s, 2H).

Example 359

2- (4- (trifluoromethyl) benzyl-8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazolo [4,3-b] pyridazin-3-one Manufacture

[4,3-b] pyridazine- with 8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] triazol, prepared as described in Example 354 in DMF (5 mL) at room temperature. To a solution of 3-one (0.54 g, 1.91 mmol) was added K ₂ CO ₃ (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 with 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 0.74 g of the title compound 2- (4- (trifluoromethyl) benzyl-8-chloro-7- (4-chloro- Phenyl) -2H- [1,2,4] triazol gave [4,3-b] pyridazin-3-one as a yellow solid HPLC RT: 3.84 min; MS, M + H = 439. ¹ H NMR (CDCl ₃ ): δ 8.08 (s, 1H), 7.44-7.61 (m, 8H), 5.30 (s, 2H).

Example 360

2- (4- (trifluoromethyl) benzyl-7- (4-chloro-phenyl) -8-phenoxy-2H- [1,2,4] triazolo [4,3-b] pyridazine-3 Manufacture of

2- (4- (trifluoromethyl) benzyl-8-chloro-7- (4-chlorophenyl) -2H- [1,2,4] prepared as described in Example 359 in 0.3 mL of DMF at room temperature. To triazol [4,3-b] pyridazin-3-one (16.5 mg, 0.376 mmol) was added potassium carbonate (19.4 mg, 0.14 mmol) and phenol (13.2 mg, 0.14 mmol). Stir for 4 h After this time, the reaction mixture was diluted with 5 mL of 1 N aqueous sodium hydroxide The precipitate was collected by filtration and washed with 1 N aqueous NaOH and water The solid was dried to give the title compound 2- (4 -(Trifluoromethyl) benzyl-7- (4-chlorophenyl) -8-phenoxy-2H- [1,2,4] triazolo [4,3-b] pyridazin-3-one (15.8 mg ) Was obtained as a light yellow solid HPLC RT: 4.02 min; MS, M + H = 497, ¹ H NMR (CDCl ₃ ): δ 8.21 (s, 1H), 7.52-6.97 (m, 13H), 5.12 ( s, 2H).

Example 361

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Other manufacture of -on

361A. Preparation of 2-benzyl-4,5-dichloropyridazin-3 (2H) -one

To a stirring suspension of 4, 5-dichloro-3-hydroxypyridazine (33 g, 200 mmol) in DMF (260 mL) at room temperature under argon, K ₂ CO ₃ (55 g, 400 mmol) is added, Benzyl bromide (41 g, 505.8 mmol) was added. After 16 h the reaction mixture was poured into a flask containing water (500 mL) with stirring. After 15 min stirring, the precipitated product was collected by filtration and washed thoroughly with water. The solid was dried in an oven at 50 ° C. in vacuum for 16 hours to give the title compound 2-benzyl-4,5-dichloropyridazin-3 (2H) -one (49.2 g, 96%) as an off-white solid. MS [M + H] ⁺ 255; HPLC retention time = 3.02 min.

361B. Preparation of 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one

To a stirring 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 (22.4 mL, 25% solution in MeOH, 97.9 mmol) was added by syringe over 10 minutes. After 2 hours, TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. Saturated NaCl (200 mL) solution was added and the resulting solution was extracted with CH ₂ Cl ₂ (2 × 100 mL). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel column chromatography eluting with CH ₂ Cl ₂ to give the title compound 2-benzyl-5-chloro-4methoxypyridazine-3 (2H). -One (20.3 g, 90%) was obtained as a colorless oil. TLC (CH ₂ Cl ₂ , Rf = 0.4); MS [M + H] ⁺ 251; HPLC retention time = 2.74 min.

361C. Preparation of 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazine-3 (2H) -one

At room temperature under argon, 2-benzyl-5-chloro-4-methoxypyridazine-3 (2H) -one (20 g, 80 mmol) and 4-chlorophenyl in toluene / EtOH (2: 1, 600 mL) To a solution of boric acid (15.6 g, 100 mmol) was added (Ph ₃ P) ₄ Pd (1.85 g, 1.8 mmol) and 2 M Na ₂ CO ₃ aqueous solution (160 mL, 320 mmol). The resulting suspension was heated with stirring at 90 ° C. for 16 h. HPLC / MS showed that about 4% of 2-benzyl-5-chloro-4methoxypyridazin-3 (2H) -one still remained. After cooling the reaction mixture to room temperature, the solution was extracted with CH ₂ Cl ₂ (2 × 150 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc to give the pure title compound 2-benzyl-5- (4-chlorophenyl) -4-methoxypyridazin-3 (2H) -one (21.7 g, 83%) was obtained as a white solid. MS [M + H] ⁺ 327; HPLC 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-methoxypyridazine-3 (2H) -one (16.3 g, 50 mmol) in POCl ₃ (100 mL) was dried at 80 ° C. in a sealed flask. Heated at for 16 h. The reaction mixture was cooled to room temperature and additional POCl ₃ (50 mL) was added. The reaction mixture was then heated at 120 ° C. for 1 d and then cooled to room temperature. Most of the solvent was removed under vacuum. Ice (300 g) was added carefully to the residue with stirring and the resulting mixture was extracted with CH ₂ Cl ₂ (250 mL × 2). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc / CH ₂ Cl ₂ . The desired product (9.6 g) was obtained as a brown solid with 95% purity. It was washed with methanol (20 mL × 2) and dried to give pure title compound 3,4-dichloro-5 (4-chlorophenyl) pyridazine (5.3 g, 41%) as off-white solid. MS [M + H] ⁺ = 259; HPLC retention time = 3.40 min; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (s, 1H), 7.47-7.55 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.4, 150.6, 139.4, 136.7, 135.1, 130.6, 130.3, 129.3.

361E. Preparation of 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) hydrazine

Anhydrous hydrazine (4.80 g, 150 mmol) was added to a stirred suspension of 3,4-dichloro-5- (4-chlorophenyl) pyridazine (2.58 g, 10 mmol) in 2-BuOH (150 mL) at room temperature. The reaction mixture was heated at 60 ° C. under argon. After 5 hours HPLC / MS analysis showed the reaction was complete. The reaction mixture was cooled to 0 ° C and the product was collected by filtration. The solid was then washed with cold 2-propanol (10 mL x 2). After drying the solid under vacuum at room temperature for 16 hours, the title compound 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) hydrazine was removed from 1- (3-chloro-5- ( 4-chlorophenyl) pyridazin-4-yl) hydrazine (2.16 g total) was obtained in a 1.6: 1 ratio. 1- (4-chloro-5- (4-chlorophenyl) pyridazin-3-yl) hydrazine MS [M + H] ⁺ 255; HPLC retention time = 1.63 min. 1- (3-chloro-5- (4-chlorophenyl) pyridazin-4-yl) hydrazine MS [M + H] &lt; + &gt;255; HPLC retention time = 1.09 min.

361F. Preparation of [4,3-b] pyridazin-3 (2H) -one with 8-chloro-7- (4-chlorophenyl)-[1,2,4] triazol

Triphosgene (17.5 g, 59.0 mmol) in THF (150 mL) was cooled to 0 ° C. under argon and prepared as described in Example 361E 1- (4-chloro-5- (4-chlorophenyl) pyridazine-3 A mixture of -yl) hydrazine and 1- (3-chloro-5- (4-chlorophenyl) pyridazin-4-yl) hydrazine (3.0 g total) was added over 3 minutes. The reaction mixture was then warmed to room temperature and stirred for 16 hours. The solvent was removed in vacuo to reduce the reaction mixture to half of the original volume and the resulting suspension was cooled in an ice bath. Ice water (300 mL) was added and then stirred for 30 minutes. The product was collected by filtration and washed with 0.5 N aqueous HCl (20 mL x 2) and with H ₂ 0 (20 mL x 2). After drying under vacuum at room temperature for 16 hours, the title compound 8-chloro-7- (4-chlorophenyl)-[1,2,4] triazol [4,3-b] pyridazin-3 (2H) -one (2.1 g) was obtained as a yellow solid. MS [M + H] ⁺ 281; HPLC retention time = 2.71 min.

361G. 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

At room temperature under argon, [4,3-b] pyridazin-3 (2H) -one (8-chloro-7- (4-chlorophenyl)-[1,2,4] triazol in DMF (15 mL) ( To a stirred suspension of 1.12 g, 4.0 mmol) and 4- (trifluoromethyl) benzyl bromide (1.24 g, 5.2 mmol) was added K ₂ CO ₃ (0.83 g, 5.2 mmol). The resulting mixture was heated at 55 ° C. for 2 hours. After 2 hours HPLC / MS analysis indicated the reaction was complete. The reaction mixture was cooled to rt and EtOAc (100 mL) was added. The resulting mixture was washed with saturated NaCl (50 mL × 2). The organic layer was dried (Na ₂ SO ₄ ), filtered with co-evaporation of toluene (10 mL × 2) and concentrated to give a dark yellow solid. The crude product was washed with MeOH (10 mL × 2) and dried under vacuum at room temperature for 3 hours to give the title compound 2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chloro Phenyl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (1.3 g, 74%) as a yellow solid. MS [M + H] ⁺ 439; HPLC retention time = 3.92 min; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (s, 1H), 7.45-7.61 (m, 8H), 5.32 (s, 2H).

Example 362

8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine- Preparation of 3 (2H) -one

362A. Preparation of 2-benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one

At room temperature under argon, 2-benzyl-5-chloro-4-methoxypyridazin-3 (2H) -one (20 g, 80 mmol) and 4- prepared as described in Example 361B in toluene (300 mL). To a solution of methylphenylboronic acid (13 g, 96 mmol) was added (Ph ₃ P) ₄ Pd (1.85 g, 1.8 mmol) and 2 M Na ₂ CO ₃ aqueous solution (160 mL, 320 mmol). The resulting suspension was heated with stirring at 100 ° C. for 5 hours. HPLC / MS indicated complete reaction. After cooling the reaction mixture to room temperature, it was extracted with CH ₂ Cl ₂ (200 mL × 2), dried (Na ₂ SO ₄ ), filtered under reduced pressure and concentrated. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc to give the title compound 2-benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one (21.9 g, 89% ) Was obtained in white foam. MS [M + H] ⁺ 307; HPLC retention time = 3.78 min.

362B. Preparation of 3,4-dichloro-5-p-tolylpyridazine

A stirred solution of 2-benzyl-4-methoxy-5-p-tolylpyridazin-3 (2H) -one (15.3 g, 50 mmol) in POCl ₃ (100 mL) was stirred at 120 ° C. for 24 hours in a sealed flask. Heated. The reaction mixture was cooled to room temperature and additional POCl ₃ (50 mL) was added. The reaction mixture was again heated at 120 ° C. for 1 d and cooled to room temperature. Most solvents were removed in vacuo. Ice (200 g) was added carefully to the residue with stirring and the resulting mixture was extracted with CH ₂ Cl ₂ (250 mL × 2). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc / CH ₂ Cl ₂ . Unwanted impure product (10 g) was obtained as a brown solid. Washing with methanol (15 mL × 2) and then drying the solid gave the pure title compound 3,4-dichloro-5-p-tolylpyridazine (5.1 g, 43%) as off-white solid. MS [M + H] ⁺ 239; HPLC retention time = 3.34 min.

362C. Preparation of 1- (4-chloro-5-p-tolylpyridazin-3-yl) hydrazine

Anhydrous hydrazine (9.1 g, 284 mmol) was added 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. The reaction mixture was heated at 60 ° C. under argon. HPLC / MS analysis indicated the reaction was complete after 15 hours. The reaction mixture was cooled to 0 ° C. and the product collected by filtration and further washed with cold 2-propanol (20 mL × 2). After drying for 16 hours in vacuo at room temperature, the title compound 1- (4-chloro-5-p-tolylpyridazin-3-yl) hydrazine is unwanted 1- (3-chloro-5-p-tolylpyridazine-4 -Yl) hydrazine (3.6 g total) and 2.6: 1 ratio. MS [M + H] ⁺ 235; HPLC retention time = 1.84 min. 1- (3-chloro-5-p-tolylpyridazin-4-yl) hydrazine MS [M + H] ⁺ 235; HPLC retention time = 1.35 min.

362D. Preparation of [4,3-b] pyridazin-3 (2H) -one with 8-chloro-7-p-tolyl- [1,2,4] triazol

A stirred solution of triphosgene (19.0 g, 64.0 mmol) in THF (200 mL) was cooled to 0 ° C. under argon and prepared as described in Example 362C 1- (4-chloro-5-p-tolylpyridazine- 3-day) A mixture of hydrazine and 1- (3-chloro-5-p-tolylpyridazin-4-yl) hydrazine (3.0 g total) was added over 3 minutes. The reaction mixture was gradually warmed up to room temperature and then stirred for 16 hours. The solvent was removed in vacuo to reduce the reaction mixture to half of the original volume and the resulting suspension was cooled in an ice bath. Ice water (300 mL) was added and then stirred for 1 hour. The product was collected by filtration and washed with 0.1 M aqueous HCl (50 mL × 2) and washed with H ₂ O (50 mL × 2). After drying at 50 ° C. under vacuum 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; HPLC retention time = 2.75 min; ¹ H NMR (400 MHz, THF-d ₈ ) δ 11.69 (s, 1H), 8.10 (s, 1H), 7.49-7.51 (m, 2H), 7.34-7.35 (m, 2H).

362E. 8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine- Preparation of 3 (2H) -one

At room temperature under argon, [4,3-b] pyridazin-3 (2H) -one (2.2 g, in 8-chloro-7-p-tolyl- [1,2,4] triazol in DMF (15 mL) 8.4 mmol) and K ₂ CO ₃ (1.74 g, 12.6 mmol) were added to a stirred suspension of 5- (chloromethyl) -2- (trifluoromethyl) pyridine (2.1 g, 11 mmol). The resulting mixture was heated at 55 ° C. for 2 hours. HPLC / MS shock analysis indicated the reaction was complete. The reaction mixture was concentrated with coevaporation of toluene (10 mL x 2) to give a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc / CH ₂ Cl ₂ . The desired product (2.1 g) was obtained as a brown solid. Washed with MeOH (10 mL × 2) and dried to give the pure title compound 8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2 , 4] Triazole gave [4,3-b] pyridazin-3 (2H) -one (1.76 g, 56%) as a light yellow solid. MS [M + H] ⁺ 420; HPLC retention time = 3.53 min, ^l H NMR (400 MHz, CDCl ₃ ) 58.89 (s, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.30-7.50 (m , 4H), 5.36 (s, 2H), 2.45 (s, 3H).

Example 363

2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazol-1-yl)-[1,2,4] triazolo [4, 3-b] Preparation of pyridazin-3 (2H) -one

363A. 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 ( Preparation of 2H) -one

[4,3-b] pyridazine with 8-chloro-7- (4-chlorophenyl)-[1,2,4] triazol prepared as described in Example 354G in DMF (5 mL) at room temperature under argon. K ₂ CO ₃ (119 mg, 0.86) in a stirred suspension of 5- (4- (bromomethyl) phenyl) isoxazole (122 mg, 0.51 mmol) prepared as described in Example 250A and -3 (2H) -one. mmol) was added. The resulting mixture was heated at 50 ° C. for 3 hours. HPLC / MS analysis indicated complete reaction. The reaction mixture was concentrated in vacuo with co-evaporation (10 mL × 2) with toluene to give a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with hexanes / EtOAc to give the pure title compound 2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl )-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (149 mg, 79%) as a yellow solid. MS [M + H] ⁺ 438; HPLC retention time = 3.55 min.

363B. 2- (4- (isoxazol-5-yl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazol-1-yl)-[1,2,4] triazolo [4, 3-b] Preparation of pyridazin-3 (2H) -one

2- (4- (isoxazol-5-yl) benzyl) -8-chloro-7- (4-chlorophenyl)-[1,2,4 in dry 1-methyl-2-pyrrolidinone (3 mL) ] A solution of [4,3-b] pyridazin-3 (2H) -one (149 mg, 0.34 mmol) and imidazole (69.5 mg, 1.02 mmol) with triazole was heated at 100 ° C. for 18 hours. HPLC / MS analysis showed 90% reaction completion. The reaction mixture was concentrated in vacuo with co-evaporation of toluene (5 mL × 2) to afford a dark yellow solid. The crude product was purified by silica gel column chromatography (ISCO) eluting with CH ₂ Cl ₂ / EtOAc to afford the pure title compound (87 mg, 55%) as a yellow solid. MS [M + H] ⁺ 470; HPLC retention time = 2.59 min; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, 1H, J = 0. 5 Hz), 8.18 (s, 1H), 7.80-7.85 (m, 2H), 7.78 (s, 1H), 7.49 (d , 2H, J = 7.0Hz), 7.43 (d, 2H, J = 7.0Hz), 7.13-7.15 (m, 3H), 6.94 (m, 1H), 6.53 (d, 1H, J = 0.5 Hz), 5.27 (s, 2H).

Example 364

2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (1H-imidazol-1-yl)-[1,2,4] triazolo [4, 3-b] Preparation of pyridazin-3 (2H) -one

364A. Preparation of [4,3-b] pyridazin-3 (2H) -one as 7- (4-chlorophenyl) -8- (1H-imidazol-1-yl)-[1,2,4] triazolo

8-chloro-7- (4-chlorophenyl)-[1,2,4] triazol prepared as described in Example 361F in dry 1-methyl-2-pyrrolidinone (1 mL) [4,3- b] A solution of pyridazin-3 (2H) -one (56 mg, 0.20 mmol) and imidazole (100 mg, 1.5 mmol) was heated at 100 ° C. for 5 hours. HPLC / MS analysis indicated the reaction was complete. The reaction mixture was reduced to half the original volume with a stream of argon while still heating to 100 ° C. After cooling to room temperature, the pH was lowered to 1 by adding 0.7 M aqueous TFA solution (3 mL). A precipitate formed. Subsequent extracts of the precipitate obtained by repeated dissolution in supernatant and NMP and dilution with water were purified by reverse phase preparative HPLC (C-18, MeOH / H ₂ 0 gradient, 0.1% TFA). This was carried out through a polymer laboratories PL-PIP piperidine resin (100 mg, 3.21 mmol / g) in a 1: 1 MeOH / CH ₂ Cl ₂ solution to increase the purity of the desired compound to the TFA salt. Provided. Then evaporated in vacuo to give the title compound 7- (4-chlorophenyl) -8- (lH-imidazol-1-yl)-[1,2,4] triazol [4,3-b] pyridazine- 3 (2H) -one (15 mg, 24%) was obtained as a yellow solid. MS [M + H] ⁺ 313; HPLC retention time = 1.37 min (C-18, MeOH / H ₂ 0 with 0.1% TFA) gradient).

364B. 2- (4- (isoxazol-3-yl) benzyl) -7- (4-chlorophenyl) -8- (lH-imidazol-1-yl)-[1,2,4] triazolo [4, 3-b] Preparation of pyridazin-3 (2H) -one

7- (4-chlorophenyl) -8- (lH-imidazol-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 a stirred mixture of K ₂ C0 ₃ (40 mg, 1.0 mmol) under D, DMF (0.5 mL) ) Was heated to 55 ° C. for 30 minutes. HPLC / MS analysis indicated 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), resulting in some precipitation and acidified with TFA to pH 1. Subsequent extracts of the supernatants and precipitates obtained by repeated stirring in MeOH and dilution with water were purified by reverse phase preparative HPLC (C-18, MeOH / H ₂ 0 gradient, 0.1% TFA). This was carried out through a polymer laboratories PL-PIP piperidine resin (100 mg, 3.21 mmol / g) in a 1: 1 MeOH / CH ₂ Cl ₂ solution to increase the purity of the desired compound to the TFA salt. Provided. Then evaporation gave pure title compound (5.6 mg, 25%) as a yellow solid. ^{MS [M + H] + 470} , [MH] - 468; HPLC retention time = 2.96 min (C-18, MeOH / H ₂ 0 (10 mM NH ₄ OAc) gradient); ¹ H NMR (500 MHz, CD ₃ 0D) δ 8.70 (d, 1H, J = 1.6 Hz), 8.43 (s, 1H), 7.85 (d, 2H, J = 8.2 Hz), 7.85 (s, 1H), 7.53 (d, 2H, J = 8.2 Hz), 7.46 (d, 2H, J = 8.8 Hz), 7.29 (d, 2H, J = 8.8 Hz), 7.15 (t, 1H, J = 1.6 Hz), 7.07 (s, 1 H), 6.90 (d, 1 H, J = 1.6 Hz), 5.30 (s, 2H).

Example 365

2- (4- (trifluoromethyl) benzyl) -8-amino-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) prepared as described in Example 361 Step G in dry 1-methyl-2pyrrolidinone (2 mL). -A solution of [4,3-b] pyridazin-3 (2H) -one (43.8 mg, 0.10 mmol) and KOCN (81 mg, 1.0 mmol) with [1,2,4] triazol for 2 hours under argon Heated at 120 ° C. HPLC / MS analysis indicated the reaction was complete. The reaction mixture was concentrated while co-evaporating with toluene (5 mL x 2) under vacuum to give a yellow solid. The crude product was purified by reverse phase preparative HPLC (C-18, MeOH / H ₂ O gradient, 0.1% TFA) to give the title compound 2- (4- (trifluoromethyl) benzyl) -8-amino-7- (4 Chlorophenyl)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (34 mg, 81%) as a yellow solid. MS [M + H] ⁺ 420; HPLC retention time = 3.70 min.

Example 366

2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -3-oxo-2,3-dihydro- [1,2,4] triazolo [4,3-b] Preparation of Pyridazine-8-carbonitrile

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl)-prepared as described in Example 361G in dry 1-methyl-2-pyrrolidinone (1 mL). [4,3-b] pyridazin-3 (2H) -one (43.8 mg, 0.10 mmol) and KCN (33 mg, 0.5 mmol) with [1,2,4] triazol at 120 ° C. for 2 hours under argon. Heated to. HPLC / MS indicated reaction completion. The reaction mixture was concentrated under argon with co-evaporation of toluene (5 mL x 2) to give a yellow solid. The crude product was purified by reverse phase preparative HPLC (C-18, MeOH / H ₂ 0 gradient, 0.1% TFA) to give the title compound (31 mg, 72%) 2- (4- (trifluoromethyl) benzyl) -7 [4,3-b] pyridazine-8-carbonitrile was obtained as a yellow solid with-(4-chlorophenyl) -3-oxo-2,3-dihydro- [1,2,4] triazol. MS [M + H] ⁺ 430; HPLC retention time = 3.76 min.

Example 367

8- (6-fluoropyridin-3-yl) -7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo Preparation of [4,3-b] pyridazin-3 (2H) -one

To the microwave reaction vessel with a stir bar, Pd (Ph ₃ P) ₄ catalyst (30 mg, 25 μmol) was added and dioxane anhydride (0.5 mL) was added. To this 8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo prepared as described in Example 362 [4,3-b] pyridazin-3 (2H) -one (20 mg, 47umol), 2-fluoropyridin-5-boronic acid (28.2 mg, 200llmol), dioxane anhydride (0.5 mL) and 2M K ₃ P0 ₄ aqueous solution (0.25 mL) was added. The reaction vessel was flushed with nitrogen, capped in a microwave reactor and heated at 120 ° C. for 10 minutes. The reaction mixture was purified by Whatman 0.45 μm syringe filter and the crude product was eluted with preparative HPLC (Xterra MS-C18, 30 × 50 mm; 30% to 100% B, 8 min gradient, (A = water + 0.1) % TFA and B = acetonitrile + 0.1% TFA); 30 mL / min flow rate; 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 Got it. This compound was taken up in 2 mL methanol in a filtration column attached with stopcock and polystyrene based carbonate resin PL-C03 MP-resin (100 mg, 2.4 mmol / g loaded) was added. The contents were shaken for 2 hours, 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) pyridine -3-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one in freebase form (7.6 mg, 32% yield), yellow crystalline Obtained as a solid. MS (M + H) = 481; _{^{l H NMR CDCl 3: δ 8.8}} (1H, s), 8.21 (1H, s), 8.23 (1H, s), 7.95 (1H, d, J = 8.2 Hz), 7.79 (lH, m), 7.66-7.68 (1H, m), 7.03-7.18 (4H, m), 6.94 (1H, m), 5.3 (2H, s). Analytical HPLC Purity: 99% at 2.27 min (ret. Time), (Xterra MS-C18, 4.6 × 50 mm); Eluting with 30% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate of 2.5 mL / min. UV detection at 220 nm.

Example 368

8- (5-fluoro-6-methoxypyridin-3-yl) -7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2 , 4] Preparation of [4,3-b] pyridazin-3 (2H) -one with triazol.

To a microwave reaction vessel comprising a stir bar, Pd (Ph ₃ P) ₄ catalyst (30 mg, 25 pmol) was added and dioxane anhydrous (0.5 mL) was added. To this 8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo prepared as described in Example 362 [4,3-b] pyridazine-3 (2H) -one (20 mg, 47 μmol), 3-fluoro-2-methoxypyridin-5-boronic acid (34.2 mg, 200 μmol), dioxane anhydride (0.5 mL) and 2M K ₃ P0 ₄ aqueous solution (0.25 mL) were added. The reaction vessel was flushed with nitrogen and plugged in a micro reactor and heated at 120 ° C. for 10 minutes. The reaction mixture was filtered through a 0.45 μm syringe filter and the crude product was eluted with preparative HPLC (Xterra MS-C18, 30 × 50 mm; 30% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 30 mL / min flow rate; UV detection at 220 nm) using 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 to TFA Obtained as a salt. The compound was taken up in 2 mL methanol in a stopcocked filtration column and PL-C03 MP-resin (100 mg, 2.4 mmol / g loaded), a polystyrene based carbonate resin, was added. The contents were shaken for 2 hours, 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 (9.6 mg, 38% yield ) Was obtained as a yellow crystalline solid. MS (M + H) = 511; ¹ H NMR (CD ₃ 0D): δ 8.67 (1H, s), 8.25 (1H, s), 7.97 (1H, d, J = 8.2 Hz), 7.82 (lH, s), 7.7 (1H, m), 7.38-7.40 (1H, m), 7.09-7.14 (4H, m), 5.3 (2H, s), 3.8 (3H, s). Analytical HPLC concentration: 99% at 2.44 min (ret. Time), (Xterra MS-C18, 4.6 X 50 mm); Eluting with 30% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 2.5 mL / min flow rate. UV detection at 220 nm.

Example 369

8- (2-methoxypyrimidin-5-yl) -7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] tria Preparation of zolo [4,3-b] pyridazin-3 (2H) -one

To a microwave reaction vessel comprising a stir bar, Pd (Ph ₃ P) ₄ catalyst (30 mg, 25 μmol) was added and dioxane anhydride (0.5 mL) was added. To this 8-chloro-7-p-tolyl-2-((6- (trifluoromethyl) pyridin-3-yl) methyl)-[1,2,4] triazolo prepared as described in Example 362 [4,3-b] pyridazin-3 (2H) -one (20 mg, 47 J. mol), 2-methoxypyrimidine-5-boronic acid (28.2 mg, 200. mol), dioxane anhydride (0.5 mL) and 2M K ₃ P0 ₄ aqueous solution (0.25 mL) were added. The reaction vessel was flushed with nitrogen, plugged and heated at 120 ° C. for 10 minutes in a micro reactor. The reaction mixture was filtered through Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra MS-C18, 30 × 50 mm) (eluting with 30% to 100% B, gradient 8 min, ( A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 30 mL / min flow rate UV detection at 220 nm) 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 Was obtained as a TFA salt. The compound was taken up in 2 mL methanol in a stopcocked filtration column and PL-C03 MP-resin (100 mg, 2.4 mmol / g loaded), a polystyrene based carbonate resin, was added. The contents were shaken for 2 hours and the 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 (7.6 mg, 31% yield) yellow crystals Obtained as a sexual solid. MS (M + H) = 494. ¹ H NMR (CD ₃ 0D): δ 8.79 (1H, s), 8.39 (1H, s), 8.07 (1H, 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 (ret. Time), (Xterra MS-C18, 4.6 X 50 mm); Eluting with 30% to 100% B, 4.5 min gradient, (A = water +0.1% TFA and B = acetonitrile + 0.1% TFA); 2.5 mL / min flow rate. UV detection at 220 nm.

Example 370

2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yloxy)-[1,2,4] triazolo [4,3-b] Preparation of Pyridazin-3 (2H) -one

8-chloro-7- (4-chlorophenyl)-[1,2,4] triazolo [4,3- in 1 dram vial prepared as described in Example 361F in 1-methylpyrrolidone (1 mL) b] 3-hydroxypyridine (9.5 mg, 100 mol) and anhydrous potassium carbonate (21 mg, 150 μmol) were added to pyridazin-3 (2H) -one (20 mg, 47 μmol). The reaction vessel was capped and heated at 80 degrees for 16 hours in a turbo coil heater while shaking. The reaction mixture was filtered through Whatman 0.45 um syringe filter and the crude product was preparative HPLC (Xterra MS-C18, 30 × 50 mm); Eluting with 10% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 30 mL / min flow rate. Filtered using UV detection at 220 nm) to give the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (pyridin-3-yloxy)-[1, 2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one as a TFA salt. This compound was taken up in methanol in 2 mL in a stopcocked filtration column and polystyrene based carbonate resin PL-C03 MP-resin (100 mg, 2.4 mmol / g loaded) was added. The contents were shaken for 2 hours and the methanol solution was filtered and evaporated under reduced pressure to give 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (pyridine- in the form of the title compound freebase. 3-yloxy)-[1,2,4] triazole gave [4,3-b] pyridazin-3 (2H) -one (5.7 mg, 16% yield) as a yellow crystalline solid. MS (M + H) = 498; ¹ H NMR (CD ₃ 0D) :: δ 8.34 (1H, s), 8.30 (1H, s), 8.29 (1H, s), 7.51-7.53 (3H, m), 7.37 (2H, m), 7.31- 7.32 (2H, m), 7.23-7.24 (2H, m), 7.22 (1H, s), 5.07 (2H, s). Analytical HPLC Purity: 99% (Xterra MS-C18, 4.6 X 50 mm) at 2.07 min (ret. Time); Eluting with 10% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 2.5 mL / min flow rate. UV detection at 220 mn.

Example 371

2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (3-hydroxypyrrolidin-1-yl)-[1,2,4] triazolo [4 , 3-b] Preparation of pyridazin-3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl)-prepared as described in Example 361 in 1-methylpyrrolidone (1 mL) in 1 dram vial. To a solution of [4,3-b] pyridazin-3 (2H) -one (20 mg, 46 μmol) with [1,2,4] triazole was added 3-pyrrolidinol (8.7 mg, 100 μmol). . The reaction vessel was capped and heated at 80 ° C. for 16 hours in a turbo coil heater while shaking. The reaction mixture was filtered through Whatman 0.45 μm syringe filter and the crude product was preparative HPLC (Xterra MS-C18, 30 × 50 mm); Eluting with 10% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); mL / min flow rate. Filtered using 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] triazole gave [4,3-b] pyridazine-3 (2H) -one TFA salt (18.5 mg, 52% yield) as a yellow crystalline solid. MS (M + H) = 498; ¹ H NMR (CD ₃ 0D) :: 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, lH), 3.52 (2H, m), 1.88 (2H, m). Analytical HPLC Purity: 99% at 2.06 min (ret. Time), (Xterra MS-C18 (4.6 X 50 mm); elution 10% to 100% B, 4.5 min gradient, (A = water + 0.1% TFA and B = aceto Nitrile + 0.1% TFA); 2.5 mL / min flow rate.UV detection at 220 nm.

Example 372

2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (lH-imidazol-1-yl)-[1,2,4] triazolo [4,3- b] Preparation of pyridazine-3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl)-prepared as described in Example 361 in 1 dram vial of 1-methylpyrrolidone (1 mL). To a solution of [4,3-b] pyridazine-3 (2H) -one (20 mg, 46 μmol) with [1,2,4] triazole was added imidazole (6.8 mg, 100 μmol). The reaction vessel was capped and heated with shaking at 80 ° C. for 16 hours in a turbo coil heater. The reaction mixture was filtered through Whatman syringe filter and the crude product was purified by preparative HPLC (XterraMS-C18, 30 × 50 mm; elution 10% to 100% B, 8 min gradient, (A = water + 0.1% TFA and B). = Acetonitrile + 0.1% TFA); 30 mL / min flow rate (detected at 220 nm UV) to filter the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl ) -8- (lH-imidazol-1-yl)-[1,2,4] triazol [4,3-b] pyridazin-3 (2H) -one as a TFA salt. This compound was taken up in 2 mL methanol in a stopcocked filtration column and PL-C03 MP-resin (100 mg, 2.4 mmol / g loaded), a polystyrene based carbonate resin, was added. The contents were shaken for 2 hours, the methanol solution was filtered and evaporated under reduced pressure to give the title compound 2- (4- (trifluoromethyl) benzyl) -7- (4-chlorophenyl) -8- (1H- in freebase form. Imidazol-1-yl)-[1,2,4] triazolo [4,3b] pyridazin-3 (2H) -one (18.5 mg, 52% yield) was obtained as a yellow crystalline solid. MS (M + H) = 471; ¹ H NMR (CD ₃ 0D): δ 8.42 (1H, s), 7.83 (1H, 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 (1H, s), 7.07 (1H, s), 5.33 (2H, s). Analytical HPLC Purity: 9% at 2.06 min (ret. Time), (Xterra MS-C18, 4.6 X 50 mm); 10% to 100% B eluting, 4.5 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); Flow rate 2.5 mL / min. UV detection at 220 nm.

Example 373

2- (4- (trifluoromethyl) benzyl) -8- (benzyloxy) -7- (4-chlorophenyl)-[1,2,4] triazolo [4,3-b] pyridazine-3 Preparation of (2H) -one

2- (4- (trifluoromethyl) benzyl) -8-chloro-7- (4-chlorophenyl) prepared as described in Example 361 in 1-methylpyrrolidone (1 mL) in 1 dram vial Benzyl alcohol (10.8 mg, 100 μmol) and THF (100 uL) in a solution of [4,3-b] pyridazin-3 (2H) -one (20 mg, 46 μmol) with [[1,2,4] triazol A 1M solution of potassium t-butoxide in) was added. The reaction vessel was capped and stirred at room temperature for 16 hours. The reaction mixture was quenched with 100 uL of methanol and filtered through Whatman 0.45 μm syringe filter and the crude product was preparative HPLC (Xterra MS-C18, 30 × 50 mm); 10% to 100% B eluting, 8 min gradient, (A = water + 0.1% TFA and B = acetonitrile + 0.1% TFA); 30 mL / min flow rate. Purification using UV detection at 220 nm) gave the title compound 2- (4- (trifluoromethyl) benzyl) -8- (benzyloxy) -7- (4-chlorophenyl)-[1,2,4] Triazole gave [4,3-b] pyridazin-3 (2H) -one (4.9 mg, 16% yield) as a yellow crystalline solid. MS (M + H) = 511 ;. ¹ H NMR MeOD: δ 8.25 (1H, 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 (ret. Time), (Xterra MS-C18, 4.6 X 50 mm); Eluting 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.

Examples 374-468

The following examples were prepared according to the methods and procedures described above:

Example 469

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4,3 -b] preparation of pyridazine-3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl)-[1,2, prepared as described in Example 17 in THF (4 mL) at -20 ° C. 4] To a solution of [4,3-b] pyridazin-3 (2H) -one (250 mg, 0.485 mmol) with triazol was added methyl magnesium bromide (0.81 mL, 2.43 mmol, 3.0 M in Et ₂ 0). . The reaction was stirred at -20 ° C for 30 minutes. LC-MS indicated completion of the reaction. 20 mL of MeOH was added to the reaction mixture to quench the reaction. The reaction was warmed to room temperature and the solvent evaporated. The residue was diluted with EtOAc (100 mL) and washed with H ₂ 0 (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 silica gel column chromatography using an automated system eluting with a gradient (0% to 80% EtOAc for 40 minutes and standing at 80% for 10 minutes) 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] pyridazine-3 (2H) -One (254 mg) was obtained in a beigesek solid, 98% yield. HPLC retention time: 4.23 min; MS [M + H] ⁺ : 531 found. ¹ H NMR (CDCl ₃ , 400 MHz) δ 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, 1H), 1.24 (d, 3H).

Example 470

(R) -2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo [4,3-b] pyridazine-3 (2H) -one and (S) -2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl Preparation of [4,3-b] pyridazin-3 (2H) -one with -5,6-dihydro- [1,2,4] triazol

(R, S) -2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro prepared as described in Example 466 -[1,2,4] triazol [4,3-b] pyridazine-3 (2H) -one 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% in MeOH DEA: EtOH (1: 1); 15% isocratic B; Flow rate: 1 mL / min .; Injection volume: 10 μl; UV wavelength: 254 nm. Isomer A: HPLC: 6.81 min .; MS [M + H] ⁺ : found 531. Isomer B: HPLC: 11.45 min .; MS [M + H] ⁺ : 531 found.

Example 471

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl- [1,2,4] triazolo [4,3-b] pyridazine-3 Preparation of (2H) -one

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5 prepared as described in Example 469 in CH ₂ Cl ₂ (0.5 mL) at room temperature. To a solution of [4,3-b] pyridazin-3 (2H) -one (28 mg, 0.053 mmol) with, 6-dihydro- [1,2,4] triazol was added DDQ (15 mg, 0.064 mmol). Added. The reaction was stirred at rt for 1 h. LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an automated system eluting with a gradient (0% to 80% EtOAc for 20 minutes) to give the title compound 2- (4- (trifluoromethyl) benzyl) -7, 8-bis (4-chlorophenyl) -6-methyl- [1,2,4] triazolo 84% to [4,3-b] pyridazin-3 (2H) -one (23 mg, 84% yield) Obtained as a yellow solid in yield. HPLC retention time: 4.18 min; MS [M + H] ⁺ : 529 found. ¹ H NMR (CDCl ₃ , 400 MHz) δ 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

2- (4- (trifluoromethyl) benzyl) -5-acetyl-7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo Preparation of [4,3-b] pyridazin-3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5 prepared as described in Example 469 in CH ₂ Cl ₂ (0.2 mL) at room temperature. To a solution of [4,3-b] pyridazin-3 (2H) -one (8 mg, 0.015 mmol) with 6-dihydro- [1,2,4] triazol (5.8 mg, 0.045 mmol), and acetyl chloride (2.4 mg, 0.030 mmol) was added. The reaction was stirred at rt for 2 h. LC-MS indicated 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] triazole gave [4,3-b] pyridazin-3 (2H) -one (6 mg, 70%) as a white solid. HPLC retention time: 4.23 min; MS [M + H] ⁺ : 573 found. ¹ H NMR (CDCl ₃ , 400 MHz) 8 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, 1 H), 5.14-5. 11 (m, 2 H), 2.28 (s, 3 H), 1.28 (s, 3 H).

Example 473

2- (4- (trifluoromethyl) benzyl) -5-benzyl-7,8-bis (4-chlorophenyl) -6-methyl-5,6-dihydro- [1,2,4] triazolo Preparation of [4,3-b] pyridazin-3 (2H) -one

2- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6-methyl-5,6 prepared as described in Example 469 in DMF (0.5 mL) at room temperature. K ₂ CO ₃ (11.6 mg, 0.084 mmol) in a solution of [4,3-b] pyridazin-3 (2H) -one (15 mg, 0.028 mmol) with dihydro- [1,2,4] triazolo Was added and benzyl bromide (9.6 mg, 0.056 mmol) was added. The reaction heated at80 C for overnight. The reaction was filtered. The collected solution was concentrated under educed pressure. Crude product was purified using Reversed Phase HPLC to give 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] pyridazine-3 (2H) -one, (2 mg, 11%) as a white solid. HPLC retention time: 4.44 min; MS [M + H] ⁺ : 621 found. ¹ H NMR (CDCl ₃ , 400 MHz) δ 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, 1 H), 1.30 (d, 3 H).

Example 474

Preparation of [4,3-b] pyridazin-3 (2H) -one with 7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazol

[4,3-b] pyridazine-3 (7,8-bis (4-chlorophenyl)-[1,2,4] triazol prepared as described in Example 1 in DMF (3 mL) at room temperature. To a solution of 2H) -one (100 mg, 0.28 mmol) was added K ₂ CO ₃ (116 mg, 0.84 mmol) and iomethane (79 mg, 0.56 mmol). The reaction was heated at 60 ° C overnight. The reaction was diluted with EtOAc (20 mL) and 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] triazol [4,3-b] pyri Minced-3 (2H) -one (104 mg, 100%) was obtained as a yellow oil. HPLC retention time: 3.67 min; MS [M + H] ⁺ : found 371.

Example 475

6-benzyl-7,8-bis (4-chlorophenyl) -2-methyl-5, 6-dihydro- [1,2,4] triazolo [4,3-b] pyridazine-3 (2H) Manufacture of

7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4,3-b] prepared as described in Example 474 in THF (1 mL) at -20 ° C. To pyridazin-3 (2H) -one (50 mg, 0.135 mmol) benzyl magnesium bromide (0.34 mL, 0.675 mmol, 2.0 M in THF) was added. The reaction was stirred at -20 ° C for 30 minutes. After this time MeOH (5 mL) was added to quench. The reaction was allowed to cool to rt and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an automated system eluting with a gradient (20 minutes with 0% to 80% EtOAc and standing at 80% for 20 minutes) to give the title compound 6-benzyl-7,8-bis ( 4-chlorophenyl) -2-methyl-5,6-dihydro- [1,2,4] triazol to [4,3-b] pyridazin-3 (2H) -one (29 mg, 46%) Obtained as a beige solid. HPLC retention time: 4.10 min; MS [M + H] ⁺ : 463 found. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.30-6.90 (m, 13H), 4.22 (t, 1H), 3.36 (s, 3H), 2.90-2.75 (m, 2H).

Examples 476-487

The following examples were prepared according to the methods and procedures described above:

Compounds of set A below (R ¹ is varied, R ² is 4-chlorophenyl, R ³ is 2- (trifluoromethyl) pyridin-5-ylmethyl, R ⁶ is hydrogen, R ⁷ is absent, n is double Binding) can be prepared by one skilled in the art by the methods described above. Compound Set A is intended to further illustrate without limiting the scope of the invention.

Set A:

As confirmed above, set A consists of a compound which differs only from the identity of R ¹ with R ² fixed with 4-chlorophenyl. If you change both R ¹ and R ² , a two-dimensional library of example compounds will be created. Set B is a two-dimensional library consisting of all the variants of R ¹ shown in set A and all permutations of the set of R ² variants listed below. In set B, R ³ is 2- (trifluoromethyl) pyridin-5-ylmethyl, R ⁶ is hydrogen, R ⁷ is absent, n is double bond. Compounds of set B can be prepared by one skilled in the art by the methods described above. The compounds of set B are intended to further illustrate without limiting the scope of the invention.

Variation of R ² of Set B:

In addition, as identified above, set B consists of R ³ immobilized with 2- (trifluoromethyl) pyridin-5-ylmethyl with all the sides of R ¹ shown in set A and with the R ² variant set listed above. It is a two-dimensional library. If R ¹ and R ² and R ³ are changed, a three-dimensional library of example compounds is obtained. Set C is a three-dimensional library consisting of all the variations of R ¹ shown in set A, all the R ² variants listed above for set B, and a set of R ³ listed below. In set C R ⁶ is hydrogen, R ⁷ is absent, n is a double bond. Compounds of set C can be prepared by one skilled in the art by the methods described below. Compounds of set C are intended to further illustrate without limiting the scope of the invention.

R ³ variation of set C:

As an additional explanation of the meaning of set C, those listed below are three representative structures of set C that describe how they fall within the scope of set C above. These representative structures are intended to be described without limitation.

When R ¹ is selected from the first listed member of set A, R ² is selected to be the first listed R ² variant of set B, and R ³ is selected to be the first listed R ³ variant of set C, resulting in the following structure: .

When R ¹ is selected from the last listed member of set A, R ² is selected to be the last listed R ² variant of set B, and R ³ is selected to be the last listed R ³ variant of set C, resulting in the following structure: .

When R ¹ is selected randomly from set A, R ² is selected to be a randomly selected R ² variant of set B, and R ³ is selected to be a randomly selected R ³ variant of set C, resulting in the following structure: .

Additional non-limiting examples which can be prepared by those skilled in the art by the methods described above are as follows.

Biological assessment

Cannabinoid receptor binding assay

Radioligand binding studies were performed on membranes prepared from Chinese hamster ovary (CHO) cells overexpressing recombinant human CB-1 (CHO-CB-1 cells). Total assay volume for binding studies was 100 μl. 5 μg of membrane was added to binding volume (25 mM HEPES, 150 mM NaCl, 2.5 mM CaCl ₂ , 1 mM MgCl ₂ , 0.25% BSA) to a final volume of 95 μl. This diluted membrane was precultured using compound or DMSO excipient. The binding reaction was initiated by the addition of 2 nM final ³ H-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 a GF / B 96 well plate (prewetted with 0.3% polyethyleneimine) using a Packard Cell Harvester. The filter was washed with 0.25 × PBS, 30 μl MicroScint was added per well, and the bound radiolabels were quantified by scintillation counting on a Packard TopCount Scintillation Counter. The CB-2 radioligand binding assay was performed identically except using membranes from CHO-CB-2 cells.

For compounds considered to be CB-1 antagonists, the compounds should have a CB-1 receptor binding affinity K _i of less than 13000 nM. As determined by the assay described above, the CB-1 receptor binding affinity K _i values of Examples 1-63 ranged between 0.01 nM and 10000 nM.

Cannabinoid Receptor Function Activity Assay

Functional CB-1 inverse agonist activity of test compounds was determined in CHO-CB-1 cells using the cAMP accumulation assay. CHO-CB-1 cells were grown in 96 well plates. On the day of the functional assay, growth media was aspirated and assay buffer 100 (PBS plus 25 mM HEPES / 0.1 mM 3-isobutyl-1-methylxanthine / 0.1% BSA combined) was added. This compound was added to the assay buffer diluted 1: 100 with 100% DMSO and preincubated for 10 minutes prior to the addition of 5 uM forskolin. The mixture was run at room temperature for 15 minutes and terminated by addition of 0.1N HCl. Total intracellular cAMP concentration was quantified using the Amersham cAMP SPA kit.

Usage and Combination

Usage

Compounds of the present invention are cannabinoid receptor modulators and include compounds that are, for example, selective agonists, partial agonists, inverse agonists, antagonists or partial antagonists of cannabinoid receptors.

Thus, the compounds of the present invention may be useful for the treatment or prevention of diseases and disorders associated with G-protein coupled cannabinoid receptor activity. Preferably, the compounds of the present invention have an activity as an antagonist or an agonist of the CB-1 receptor and can be used for the treatment of diseases or disorders associated with the activity of the CB-1 receptor.

Thus, metabolic and eating disorders, as well as symptoms associated with metabolic disorders (e.g., obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, skin disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia) For the treatment of various symptoms and disorders, including but not limited to steatosis, cholelithiasis and sleep disorders, hyperlipidemia symptoms, neuroses, and compulsive eating disorders) or psychotic disorders such as substance abuse, depression, anxiety, manic and schizophrenia. The compounds of the present invention can be administered to mammals, preferably humans. In addition, these compounds can improve cognitive function (eg, treatment of dementia, short-term memory loss and concentration deficit disorders including Alzheimer's disease); Neurodegenerative disorders (eg, Parkinson's disease, stroke and brain trauma) and hypotension (eg, bleeding and endotoxin-induced hypotension). These compounds may also be used for the treatment of catabolism associated with pulmonary dysfunction and respiratory dependence; Treatment of heart disease dysfunction (eg, associated with heart valve disease, myocardial infarction, heart disease hypertrophy or congestive heart failure); And improving overall lung function; Transplant rejection; Rheumatoid arthritis; Multiple sclerosis; Inflammatory bowel disease; Lupus; Transplant vs. host disease; T-cell mediated hypersensitivity disease; psoriasis; asthma; Hashimoto's thyroiditis; Guillain-Barré syndrome; cancer; Contact dermatitis; Allergic rhinitis; And ischemia or reperfusion injury.

Compounds useful for the treatment of appetite or motivational disorders control the desire to consume sugars, carbohydrates, alcohols or drugs and more generally the consumption of ingredients of pleasure. In the present specification and claims, appetite disorders are understood in the following senses: disorders associated with substances and in particular causing abuse and / or dependence on substances, disorders of eating behavior, particularly causing overweight regardless of origin Easy ones, such as: nervous hunger, cravings for sugars. Thus, the present invention further provides CB-1 receptor antagonists or adverse reactions for the treatment of any disease that leads to hunger and obesity, such as obesity associated with type II diabetes (non-insulin-dependent diabetes), more generally overweight patients It relates to the use of the offer. Obesity as described herein is defined by a weight index (kg / m ² ) of at least 26 years. Genetic or environmental, overeating and hunger, polycystic ovary disease, craniopharyngeoma, Prader-Willi syndrome, Frorich syndrome, type II diabetes, growth hormone deficiency, Turner syndrome and reduced metabolic activity or energy consumption And may be due to any cause, including other pathological conditions characterized by a reduction. The term “treating” or “treatment” includes the prevention, partial alleviation, or treatment of a disease or disorder. Furthermore, the treatment of obesity progresses to the medical star of obesity such as arteriosclerosis, type II diabetes, polycystic ovary disease, cardiovascular disease, osteoarthritis, skin disorders, high blood pressure, insulin resistance, hypercholesterolemia, hypertriglyceridemia, gallstones and sleep disorders It is expected to prevent.

The compounds of the present invention may also be useful for treating substance abuse disorders including substance dependence or abuse without physiological dependence. Abuse substances include alcohols, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, penciclidine (or penciclidine-type compounds), stable-hypnotics or benzodiazepines, and others (or Unknown substances) and combinations of the above.

The term "substance abuse disorder" also includes drug or alcohol withdrawal syndrome and substance-induced anxiety or mood disorders that occur during discontinuation.

Compounds of the invention may be useful in the treatment of memory and cognitive disorders. Memory disorder symptoms are manifested as impairment in the ability to store new information and / or degradation in the ability to store previously learned information. Memory disorders are the primary signs of dementia and may be related to age-related cognitive declines such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease, and head trauma. have. Dementia is a disease that includes memory loss and additional intellectual impairment separated from memory. Cannabinoid receptor modulators may also be useful for treating cognitive impairment associated with lack of attention, such as attention deficit disorder.

In addition, the compounds of the present invention may be useful for treating diseases associated with dysfunction of the brain dopamine system, such as Parkinson's disease and substance abuse disorders. Parkinson's disease is a neurodegenerative progression disorder characterized by motor slowness and tremor.

As modulators of cannabinoid receptors, the compounds of the present invention are further useful for the treatment and prevention of circulatory diseases and disorders. Non-limiting examples of circulatory diseases for which cannabinoid receptor modulators are useful include chronic lung obstruction, pneumonia, asthma, and bronchitis. In addition, cannabinoid receptor modulators block the activation of pulmonary epithelial cells by such drugs as allergic drugs, inflammatory cytokines or smoking and thereby limit the release of mucin, cytokines, and chemokines, or selectively limit pulmonary epithelial cell activity. Suppress

Moreover, compounds employed in the present invention can stimulate the inhibitory pathways of cells, in particular leukocytes, lung epithelial cells, or both, and thus may be useful for the treatment of these diseases. “Leukocyte activation” described herein is defined as any or all of cell proliferation, cytokine production, adhesion protein expression, and production of inflammatory modulators. "Epithelial cell activation" is defined as the production of either or both mucin, cytokine, chemokine, and adhesion protein expression.

Non-limiting examples of the use of a compound of the present invention for treating a disorder associated with leukocyte activation include rejection of transplantation (such as tissue transplantation, acute transplantation, xenograft transplantation or heterograft or allograft (as used in burn treatment)). ; Protection from ischemia or reperfusion injury such as ischemia or reperfusion injury, myocardial infarction, cerebral stroke or other disease that occurs during tissue transplantation; Induction of transplant resistance; Arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); Multiple sclerosis; Respiratory and lung diseases, including but not limited to chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, and acute respiratory pain syndrome (ARDS); Inflammatory bowel disease such as ulcerative colitis and Crohn's disease; Lupus (systemic lupus erythematosus); Transplant vs. host disease; T-cell mediated hypersensitivity diseases such as contact hypersensitivity, delayed type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; Contact dermatitis (including contact dermatitis due to ivy); Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune hyperthyroidism such as Graves' disease; Addison's disease (autoimmune disease of the adrenal gland); Autoimmune polymorphic disease (also known as autoimmune polymorphism syndrome); Autoimmune alopecia; Pernicious anemia; Vitiligo; Autoimmune hypoglycemia; Guillain-Barré syndrome; Other autoimmune diseases; Glomerulonephritis; Serum diseases; hives; Allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; Scleroderma; Mycelial sarcoma; Acute inflammatory and respiratory responses (such as acute respiratory pain syndrome and ischemia / reperfusion injury); Dermatitis; Alopecia areata; Chronic ray dermatitis; Eczema; Plantar pustules; Necrotic purulent dermatosis; Trident syndrome; Atopic dermatitis; Systemic sclerosis; And treating a wide range of disorders, such as ecchymosis. As used herein, the term “associated with leukocyte activation” or “mediated leukocyte activation” includes each of the diseases or disorders mentioned above. In a particular aspect, the compounds of the present invention are useful for treating the above mentioned exemplary disorders regardless of the etiology. The combined activity of the compounds herein on monocytes, macrophages, T-cells, etc. may be useful for the treatment of the disorders mentioned above.

Cannabinoid receptors are important for the regulation of Fc gamma receptor responses in monocytes and macrophages. Compounds of the invention inhibit Fc gamma dependent production of TNF alpha in human monocytes / macrophages.

The ability to inhibit Fc gamma receptor dependent monocytes and macrophage responses results in additional anti-inflammatory activity against the present compounds.

For example, the activity is particularly useful for treating inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, the present compounds are useful for treating other cases of glomerulonephritis induced by deposition of immune complexes in the kidneys that initiate the Fc gamma receptor response resulting in glomerulonephritis and damage to the kidneys.

Cannabinoid receptors are expressed in lung epithelial cells. These cells are responsible for the secretion of mucin and inflammatory cytokines / chemokines in the lungs and are closely linked to the production and progression of respiratory diseases. Cannabinoid receptor modulators regulate both spontaneous and stimulatory production of both mucins and cytokines. Thus, such compounds are useful for treating respiratory and lung diseases, including COPD, ARDS, and bronchitis.

Furthermore, cannabinoid receptors can be expressed in intestinal epithelial cells and thus can be clinically useful for regulating cytokine and mucin production and for treating inflammatory diseases associated with the intestines. Cannabinoid receptors can also be expressed on subtypes of lymphocytes, white blood cells. Thus, cannabinoid receptor modulators will inhibit B and T-cell activation, proliferation and differentiation. Thus, such compounds may be useful for treating autoimmune diseases involving antibodies or cell mediated responses such as multiple sclerosis and lupus.

In addition, cannabinoid receptors regulate Fc epsilon receptors and chemokine induced degranulation of mast cells and basophils. They play an important role in asthma, allergic rhinitis, and other allergic diseases. Fc epsilon receptors are stimulated by IgE-antigen complexes. Compounds of the invention inhibit the Fc epsilon induced degranulation reaction, including basophilic cell lines, RBL.

The ability to inhibit Fc epsilon receptor dependent mast cells and basophilic cellular responses results in further anti-inflammatory and antiallergic activity of the present compounds. In particular, the present compounds are useful for treating asthma, allergic rhinitis, and other cases of allergic diseases.

Combination

The present invention includes within its scope a pharmaceutical composition comprising as active ingredient at least one therapeutically effective amount of a compound of formula (I), alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compounds of the present invention can be used alone or in combination with other suitable therapeutic agents useful for treating the aforementioned disorders. Such other suitable therapeutic agents include, for example, anti-obesity agents; Antidiabetic agents, appetite suppressants; cholesterol / lipid lowering agents, HDL-increasing agents, cognitive enhancers, neurodegenerative agents, respiratory disease agents, intestinal disorders agents, anti-inflammatory agents; Anti-anxiety agents; Antidepressants; Antihypertensives; Cardiac glycosides; And anti-tumor agents.

Such other therapeutic agent (s) may be administered prior to, concurrently with or following administration of the cannabinoid receptor modulator according to the invention.

Examples of anti-obesity agents suitable for use in combination with the compounds of the present invention include melanocortin receptor (MC4R) agonists, melanin enriched hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanine receptor modulators, orexins Antagonists, CCK agonists, GLP-1 agonists, and other pre-proglucagon-derived peptides; NPY1 or NPY5 antagonists, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11- β-HSD-1 inhibitors, adenofectin receptor modulators; Beta 3 adrenergic agents such as AJ9677 (Takeda / Dainippon), L750355 (Merck), or CP331648 (Pfizer) or U. S. Patent Nos. 5,541, 204, 5,770, 615,5, 491,134, 5,776, 983 and other known beta 3 agonists described in 5,488, 064, WO97 / 21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98 / 284425 (KaroBio Thyroid receptor beta modulators such as thyroid receptor ligands; Lipase inhibitors such as olistat 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, chlorpentermine, cloporex, chlortermin, picilrex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or marginol; Appetite suppressants such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophicfactor) / Axokin® (Regeneron), BDNF (brain-induced neuronal factor), leptin and leptin receptor modulators, or cannabinoid-1 receptor antagonists such as SR- 141716 (Sanofi) or SLV-319 (Solvay).

Examples of antidiabetic agents suitable for use in combination with the compounds of the present invention are insulin secretagogues or insulin sensitizers, which are biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPARγ agonists such as thiazolidine Diones, PPARα agonists (such as fibric acid derivatives), PPARδ antagonists or agents, PPARα / γ dual agonists, 11-β-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase Inhibitors, and / or meglitinides, as well as insulin, and / or glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and / or PTP-1B inhibitors (protein tyrosine phosphatase-1B inhibitors ) May be included.

The antidiabetic agent may be an oral antihypertensive agent, preferably biguanides such as metformin or phenformin or salts thereof, preferably metformin HCl. Wherein when the antidiabetic agent is biguanide, the compound of the invention has a weight ratio of compound of the invention to biguanide in a range from about 0.001: 1 to about 10: 1, preferably from about 0.01: 1 to about 5: 1 Can be adopted.

In addition, antidiabetic agents are preferably sulfonyl ureas such as glyburide (also known as glibenclamide), glymepiride (as disclosed in US Patent No. 4,379, 785), glyphide, glyclazide or chlorpropamide Or other known sulfonyl urea or other hyperglycemic agents that act on ATP-dependent channels of beta-cells, with glyburide and glipizide being preferred, which may be administered in the same or separate oral dosage forms. The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in US Patent No. 4,904, 769) or miglitol (disclosed in US Patent No. 4,639, 436), which is administered orally or separately. Can be administered in the form.

Compounds of the present invention may be prepared using PPARγ agonists such as thiazolidinedione oral anti-obesity agents or other insulin sensitizers, which have insulin selectivity effects in patients with NIDDM, such as rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi Corporation MCC-555 (disclosed in US Patent No. 5,594, 016), GL-262570, Englitazone (CP-68722, Pfizer) or Darglitazone (CP-86325, Pfizer, Isaglitazone from Glaxo-Welcome ( MIT / J & J), JTT-501 (JPNT / P & U), L-895645 (Merck), R-119702 (Sankyo / WL), NN-2344 (Dr. Reddy / NN), or YM-440 ( Yamanouchi), and preferably in combination with rosiglitazone and pioglitazone.

Compounds of the present invention are described in PPAR α / γ dual agents such as MK-767 / KRP-297 (Merck / Kyorin; K. Yajima, et. Al., Am. J: Physiol. Endocrinol. Metab., 284: E966- E971 (2003)), AZ-242 (tesaglitazar; Astra-Zeneca; described in B. Ljung, et. Al., J Lipid Res., 43,1855- 1863 (2002)); Muraglitaza; Or in combination with compounds described in US Pat. No. 6,414, 002.

The compounds of the present invention can be used in combination with antihyperlipidemic agents or agents for treating atherosclerosis. Examples of hyperlipidemia may be HMG CoA reductase inhibitors, including, but not limited to mevastatin and U. S. Patent No. Related compounds described in 3,983, 140, lovastatin (mebinolin) and U. S. Patent No. Related compounds described in 4,231,938, pravastatin and U. S. Patent No. Related compounds described in 4,346, 227, simvastatin and U. S. Patent Nos. 4,448, 784 and related compounds described in 4,450, 171. Non-limiting examples of other HMG CoA reductase inhibitors that may be employed herein include U. S. Patent No. Fluvastatin described in 5,354, 772, U. S. Patent Nos. Cerivastatin described in 5,006,530 and 5,177,080, U. S. Patent Nos. Atorvastatin described in 4,681, 893,5, 273,995, 5,385, 929 and 5,686, 104, U. S. Patent No. Pitavastatin (Nissan / Sankyo, Nisvastatin (NK-104) or Itavastatin) described in U. S. Patent No. 5,011, 930; Rosuvastatin (bissastatin (ZD-4522) from Shionogi-Astra / Zeneca, disclosed in 5,260, 440), and U. S. Patent No. Related statin compounds disclosed in 5,753, 675, U. S. Patent No. 4,613, 610 pyrazole derivatives of mevalololactone derivatives, indene analogs of mevalonolactone derivatives disclosed in PCT application WO 86/03488, U. S. Patent No. 6- [2- (substituted-pyrrole-1-yl) -alkyl] pyran-2-one and derivatives thereof disclosed in 4,647,576, SC-45355 (3-substituted pentanedioic acid derivatives) of Searle Dichloroacetate, imidazole analogue of mevalonolactone described in PCT application WO86 / 07054, French Patent No. 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives described in 2,596, 393, European Patent Application No. 2,3-2 substituted pyrrole, furan and thiophene derivatives disclosed in 0221025, U. S. Patent No. Naphthyl analogs of mevalonolactone disclosed in 4,686, 237, U. S. Patent No. Octahydronaphthalene disclosed in 4,499, 289, keto analogs of mebinolin (lovastatin) disclosed in European Patent Application No. 0, 142,146 A2, and U. S. Patent Nos. Quinoline and pyridine derivatives disclosed in 5,506, 219 and 5,691, 322. In addition, phosphonic acid compounds useful for inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.

Non-limiting examples of squalene synthetase inhibitors suitable for use herein include those described in U. S. Patent No. 1-A-1. Α-phosphono-sulfonate, isoprenoid (phosphinyl-methyl) phosphonate, disclosed in 5,712, 396, including Miller, et al., J Med. Chem., 31, 1869-1871 (1998), as well as, for example, U. S. Patent No. 4,871, 721 and 4,924, 024 and other known squalene synthes disclosed in Biller, SA, Neuenschwander, K., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2,1-40 (1996) And other inhibitors.

In addition, other squalene synthetase inhibitors suitable for use herein are described in [P. Ortiz de Montellano, et al., J. Med. Chem., 20,243-249 (1977), terpenoid pyrophosphate, farnesyl diphosphate analog A and Corey and Volante, J Am. Chem. Soc., 98,1291-1293 (1976), a prisqualene pyrophosphate (PSQ-PP) analog, described in McClard, R. W. et al., J: Am. Chem. Soc., 109, 5544 (1987) and phosphinylphosphonates and Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16,17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein are fibric acid derivatives such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, cipropibrate, clinfibrate and the like, probucol, and U. S. Patent No. Probucol and gemfibrozil are preferred, including, but not limited to, related compounds disclosed in 3,674,836, and bile acid sequestrants such as cholestyramine, cholestipol and DEAE-sefadex (secholex, polysecsid) and cholestagel (Sankyo / Geltex), as well as Ripostabil (Rhone-Poulenc), Eisai E-5050 (N-substituted ethanolamine derivatives), Imanicil (HOE-402), tetrahydrolipstatin (THL), isigmastanil Phosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), melinamid (Sumitomo), Sandoz 58-035, CL-277,082 and CL by American Cyanamid 283,546 (bisubstituted urea derivatives), nicotinic acid (niacin), acipimox, aciran, neomycin, p-aminosalicylic acid, aspirin, poly (diallylmethylamine), US Pat. Derivatives described in 4,759, 923, U. S. Patent No. Quaternary amine poly (diallyldimethylammonium chloride) and ionene and other known serum cholesterol lowering agents disclosed in 4,027, 009.

Other hyperlipidemic agents are described, for example, in Drugs of the Future, 24,9-15 (1999), (Avasimibe); "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 secretionof ApoB100-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 acitivities in experimental animals", Krause et al., Editor (s): Ruffolo, Robert R., Jr .: Hollinger, Mannfred A., Inflaimmation: Mediators Pathways, 173- 98 (1995), Publisher: CRC, Boca Raton, Fla: "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al. Curr, Med. Chem., 1 (3) 204-25 (1994); "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water soluble ACAT inhibitor with lipid-regulating activity.Inhibitiors of acyl-CoA: cholesterol acyltransferase (ACAT). series of substituted N-phenyl-N '-[(1-phenylcyclopentyl) methyl] ureas with enhanced hypocholesterolemic acitivity "; Stout et al., Chemtracts: Org. Chem., 8 (6) 359-62 (1995)] or ACAT inhibitors (also have anti-atherosclerosis activity) or TS-962 (Taisho Pharmaceutical Co. Ltd) As well as F-1394, CS505, F-12511, HL-004, K-10085 and YIC-C8-434.

Hyperlipidemia may be a synergistic modulator of LDL receptor activity, such as MD-700 (Tasho Pharmaceutical Co., Ltd.) and LY295427 (Eli Lilly). Hyperlipidemia agents include cholesterol absorption inhibitors, preferably Schering-Plough's SCH48461 (ezetimibe) as well as Atherosclerosis 115,45-63 (1995) and J. Med. Chem. 41,973 (1998).

Other lipid agonists or lipomodulators are cholesteryl transfer protein inhibitors (CETP) such as CP-529,414 of Fuser, as well as those disclosed in WO / 0038722 and EP818448 (Bayer) and EP 992496, and SC-744 and SC of Pharmacia. -795, as well as CETi-1 and JTT-705.

Hyperlipidemic agents are ileal Na ⁺ / bile acid co-carrier inhibitors such as those described in Drugs of the Future, 24,425-430 (1999). ATP citrate lyase inhibitors that can be used in combination with the present invention are described, for example, in US Pat. And those disclosed in 5,447, 954.

In addition, other lipid agents may be phytoestrogens such as those described in WO 00/30665, such as isolated soy protein, soy protein concentrate or soybean powder, as well as isoflavones such as genistein, design, glycitine or equol, or phyto Sterols, phytostanol or tocotrienols as described in WO2000 / 015201; Beta-lactam cholesterol absorption inhibitors disclosed in EP 675714; HDL synergists such as LXR agonists, PPAR a-agonists and / or FXR agonists; LDL catabolic promoters described in EP 1022272; Sodium-proton exchange inhibitors described in DE 19622222; U. S. Patent No. LDL-receptor inducers or steroidal glycosides described in 5,698, 527 and GB 2304106; Antioxidants such as beta-carotene, ascorbic acid, α-tocopherol or retinol as described in WO 94/15592, as well as vitamin C and antihomocysteine agents such as folic acid, folate (folate), vitamin B6, vitamin B12 and vitamin E; Isoniazids disclosed in WO 97/35576; Cholesterol absorption inhibitors disclosed in WO 97/48701, and HMG-CoA synthase inhibitors, or lanosterol demethylase inhibitors disclosed in WO 97/48701; PPAR δ agonists for treating dyslipidemia; Or sterol regulatory element binding protein-I (SREBP-1) such as sphingolipids, such as ceramides, or neutral sphingomyelenase (N-SMase) or fragments thereof, as disclosed in WO 2000/050574. Preferred hypolipidemic agents include pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin and rosuvastatin, as well as niacin and / or cholestagel.

The compounds of the present invention can be employed in combination with antihypertensive agents. Suitable examples of antihypertensive agents suitable for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and / or T-type; for example diltiazem, verapamil, nifedipine, amlodipine and mibefra Dill), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethagezide, polythiazide, Benzthiazide, ethacrytriic trifenaphene, chlorthalidone, furosemide, musolimine, bomethanide, triamterene, amylolide, spironolactone), renin inhibitors, ACE inhibitors (e.g. , Captopril, zofenopril, posinopril, enalapril, serranopril, silazopril, delapril, pentopril, quinapril, ramipril, risinopril), AT-1 receptor antagonists (eg, Rosa Ertan, Sartan), ET receptor antagonists (e.g., citaxentane, atrsentan and compounds described in U. S Patent Nos. 5, 612, 359 and 6,043, 265), dual ET / AII antagonists (e.g., Compounds described in WO00 / 01389), neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g. omapatrilat and chemopatatart), and nitrates Include.

Cannabinoid receptor modulators may be useful for treating diseases associated with obesity, such as sleep disorders. Thus, the compounds disclosed herein can be used in combination with medicaments for the treatment of sleep disorders. Examples of suitable therapies for treating sleep disorders that can be used in combination with the compounds of the invention include melatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABA receptor modulators; NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators.

Cannabinoid receptor modulators can reduce or alleviate substance abuse or addiction disorders. Thus, the combination of cannabinoid receptor modulators with drugs used to treat addiction disorders can reduce the conditions of administration or enhance the efficacy of current treatments for addiction disorders. Examples of drugs used to treat substance abuse or addiction disorders are: selective serotonin reuptake inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion.

Cannabinoid receptor modulators can reduce anxiety or depression; Thus, the compounds disclosed herein can be used in combination with anti-anxiety agents or antidepressants. Examples of suitable anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazepines (e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazate, halazepam and pra Zepam), 5HT1A receptor agonists (eg, buspyrone, flashinic acid, gepyron and incident pyron), and corticotropin releasing factor (CRF) antagonists.

Examples of suitable classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclic compounds), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine , Paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxides, phenelzin, tranilcipromin, selegiline), reversible inhibitors of monoamine oxidase (RIMAs) (moclobemid ), Serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor antagonists, alpha-adrenergic receptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and biloxazine) It includes.

In addition, the combination of conventional psychiatric drugs with CB-1 receptor antagonists can enhance the reduction of symptoms in the treatment of psychosis or manic illness. Furthermore, such a combination may enable rapid symptom reduction and reduce the need for chronic treatment of psychosis. In addition, this combination can reduce the effective psychopathic conditions, resulting in a lower likelihood of improving motor dysfunction typical of the treatment of chronic psychosis.

Examples of suitable antipsychotics that can be used in combination with the compounds of the present invention include phenothiazines (chlorpromazine, mesodazine, thiolidazine, acetophenazine, flufenazine, perphenazine and trifluoroperazine), Thioxanthin (chlorproxetene, thioticsen), heterocyclic dibenzezepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipalebutylpiperidine (pimozide) and psychopathy grades Indoleones (molindolenes). Other psychiatric drugs with potent therapeutic value in combination with the compounds of the present invention include roxapin, sulfides and risperidone.

In addition, the combination of a compound of the present invention with conventional psychiatric drugs can provide an improved therapeutic effect for the treatment of schizophrenia disorders as described above for manic disorders. Schizophrenia disorders used here include paranoid schizophrenia, disorganized schizophrenia, tension schizophrenia, undifferentiated and sequelae, schizophrenia, schizophrenia disorders, schizophrenic emotional disorders, delusional disorders, simple psychotic disorders and psychiatric disorders It cannot be specified by this alone. Suitable psychiatric agents that may be combined with the compounds of the present invention include the aforementioned psychiatric agents, as well as dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A / dopamine receptor antagonists or partial agents (e.g., olanzepine, Aripiprazole, risperidone, ziprasidone).

Compounds disclosed herein include, for example, acetylcholinesterase inhibitors (e.g. tacrine), muscarinic receptor-1 agonists (e.g. mimelaline), nicotine agonists, glutamic acid receptors (AMPA and NMDA) modulators, and It can be used to enhance the effectiveness of cognitive enhancers, such as nootropic agents (eg, piracetam, levetiracetam). Suitable examples of agents suitable for the treatment of Alzheimer's disease and cognitive disorders used in combination with the compounds of the invention include donepezil, tacrine, levastine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channels Blockers, Maxi-K blockers, and KCNQs blockers.

The compounds disclosed herein can be used to enhance the effectiveness of agents used in the treatment of Parkinson's disease. Examples of Parkinson's disease therapeutic agents include levadopa, antiglutamic acid medications (Amantadine, Riluzole), alpha-2 adrenergic antagonists such as idazoic acid, opiate antagonists such as naltrexone, other dopamine agonists or carriers with or without COMT inhibitors. Modulators such as rofinirol, or pramipexole or neurological factors such as glial induced neuronal factor (GDNF).

The compounds disclosed herein can be used in combination with suitable anti-inflammatory agents. Examples of suitable anti-inflammatory agents that can be used in combination with the compounds of the invention include prednisone, dexamethasone, cyclooxygenase inhibitors (ie, COX-1 and / or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, pyroxi Camm, naproxen®, Celebrex®, Viox®), CTLA4-Ig agonists / antagonists, CD40 ligand antagonists, IMPDH inhibitors such as mycophenolate (CellCept®), integrin antagonists, alpha-4-beta-7 Integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists [e.g. infliximab, OR1384, such as TNF-alpha inhibitors, e.g. Tennyb, anti-TNF antibodies or soluble TNF receptors such as etanercept (Enbrel®), rapamycin (syrolimus or rapmoon) and leflunomide (araba)), prostaglandin synthesis inhibitors, budesonide, clofazimin, CNI-1493, CD4 antagonists (eg For example plicimab), p38 mitogen activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors and therapeutic agents used in the treatment of irritable bowel syndrome (eg, Gelnome® and Maxi-). K® openers such as those described in US Patent No., 184, 231 B1.

Examples of such other therapeutic agents that can be used in combination with cannabinoid receptor modulators include cyclosporin (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 OKT3; Blockers of the action of CD40 and gp39; Antibodies specific for CD40 and / or gp39 (CD154), fusion proteins (CD40Ig and CD8gp39) constructed from CD40 and gp39; Nuclear translocation inhibitors of NF-kappa B function such as deoxyspergualin (DSG); Gold compounds; Antiproliferatives selected from methotrexate, FK506 (tacrolimus, prograf) and mycophenolate mofetil; Cytotoxic drugs selected from azatyprine and cyclophosphamide; Anticytokines selected from anti IL-4 or IL-4 receptor fusion proteins; PDE 4 inhibitors, including Ariflo and Serial Nos. 09/097, 338, filed June 15, 1998, 09 / 094,797, filed June 15, 1998; 09 / 173,413, filed Oct. 15, 1998, and 09 / 262,525, filed March 4, 1999, include PTK inhibitors incorporated herein by reference in their entirety. See also, Hollenbaugh, D., et al., "The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Receptor: Expression, incorporated herein by this reference. of a Soluble Form of Gp39 with B Cell Co-Stimulatory Activity ", EMBO J (England), 11 (12), pp 4313-4321 (December 1992); and Moreland LW et al., "Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (P75) -Fc Fusion Protein," New England J. of Medicine, 337 (3), pp. 141-147 (1997)]. See also.

When used in combination with a compound of the present invention, such other therapeutic agents may be used in the amounts indicated in the US Physicians' Desk Reference (PDR) or otherwise as determined by one of skill in the art.

Compounds of formula (I) of the present invention may be prepared in various dosage forms known as patients for such diseases by dividing the daily dosage divided by one, two or four into an effective amount of 1 gram or less, preferably up to 200 mg, more preferably Species, for example, can be administered to humans orally or non-integralally such as subcutaneously or intravenously, as well as nasal application, rectal or sublingual.

The compound of formula (I), for example orally, such as in the form of tablets, capsules, granules or powders; Sublingually; By mouth; Non-invasive, such as subcutaneously, intravenously, intramuscularly, or intrasternal injection or infusion techniques (eg, as sterile injectable aqueous solutions or non-aqueous solutions or suspensions); Nasal, including administration to a nasal membrane, such as an inhalation spray; Topically, such as in the form of a cream or ointment; Or rectally, such as suppositories; Administration may be by any suitable means of the use described herein, by any suitable means, including in dosage unit formulations containing non-toxic, pharmaceutically acceptable excipients or diluents, and the like. For example, the compounds may be administered in the form of immediate release or extended release. Immediate release or sustained release can be achieved by the use of a suitable pharmaceutical composition comprising the compound of the present application, particularly in the case of the slow release using a device such as a subcutaneous implant or an osmotic pump. In addition, the present compounds can be administered using liposomes.

Exemplary compositions for oral administration include suspensions that may include microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as suspending agent, methylcellulose as thickening agent, and sweeteners or flavoring agents known in the art; And immediate release tablets which may include microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other additives, binders, extenders, disintegrants, diluents and lubricants known in the art. It may include. In addition, the compounds of formula (I) may be delivered through the oral cavity by sublingual and / or oral administration. Molded tablets, compressed tablets, or lyophilized tablets are representative forms that may be used. Exemplary compositions include those formulated with the compound (s) of the present application in combination with rapidly soluble diluents such as mannitol, lactose, sucrose and / or cyclodextrin. In addition, high molecular weight additives such as cellulose (avicel) or polyethylene glycol (PEG) may be included in the formulation. Such formulations may also contain additives to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymers (eg, Gantrez) Reagents that control release such as Gantrez) and polyacrylic copolymers (eg, Carbopol 934). Lubricants, lubricants, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.

Exemplary compositions for nasal aerosol or inhalation administration are, for example, in saline, which may contain benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, and / or other solubilizers or dispersants as known in the art. Solution may be included.

Exemplary non-intestinal administration compositions are, for example, suitable non-toxic, non-intestinal, acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersion or Injectable solutions or suspensions which may include wetting and suspending agents, fatty acids including synthetic mono- or di-glycerides and oleic acid, or cremaphor.

Exemplary rectal dosage compositions include suppositories, which may contain, for example, suitable anti-itch additives such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at normal temperatures or liquefied and / or dissolved in the rectum to drug Emits.

Exemplary topical compositions include topical carriers such as Plastibase (mineral oil gelled with polyethylene).

For a particular patient, the specific compound's activity, metabolic stability and length of action, species, age, weight, general health, patient's sex and meal, mode and time of administration, rate of excretion, It will be appreciated that various factors may vary depending upon the combination of drug and severity of the particular symptom.

Although the present invention has been disclosed in terms of the specific aspects disclosed, it will be understood that the present invention is not necessarily limited thereto because it is provided as a description of the general principles of the invention. Any modifications and stars in a given description, process step or formula will be readily and apparent without departing from the spirit and scope of the present invention, all of which should be considered within the scope of the following claims.

Claims (73)

Compounds of formula (I) including all prodrugs, pharmaceutically acceptable salts and stereoisomers. <Formula I>

Where n is a single bond or a double bond; R ¹ is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ² is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ³ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein R ⁶ Groups have a molecular weight of less than 200 atomic mass units; R ⁷ is absent when n is a double bond; R ⁷ is H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR ⁸ , -CO ₂ R ⁸ , when n is a single bond; -CONR ⁸ R ⁹ and -S (O) mR ⁸ ; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ together optionally form a 4, 5, 6, or 7 membered heterocyclyl ring, or form a 5 or 6 membered heteroaryl ring; m is an integer of 1 or 2. The method of claim 1, R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR ⁸ and -NR ⁸ R ⁹ Selected from the group consisting of; R ² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR ⁸ and -NR ⁸ R ⁹ Selected from the group consisting of; R ³ is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein R ⁶ Groups have a molecular weight of less than 200 atomic mass units; R ⁷ is absent; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ together optionally form a 5, 6 or 7 membered heterocyclyl ring or a 5 or 6 membered heteroaryl ring; n is a double bond. The compound of claim 2, wherein R ⁶ is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein R ⁶ The group has a molecular weight of less than 200 atomic mass units. The compound of claim 3, wherein R ² is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ A compound selected from the group consisting of. The method of claim 4, wherein, R ¹ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, - OR ⁸ and -NR ⁸ R ⁹ A compound selected from the group consisting of. The compound of claim 5, wherein R ³ is selected from the group consisting of alkyl, cycloalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl. The method of claim 1, R ¹ is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ ; R ² is selected from the group consisting of heteroaryl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ ; R ³ is selected from the group consisting of alkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl and heterocyclyl, wherein the R ⁶ group has a molecular weight of less than 200 atomic mass units; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ may together optionally form a 5, 6, or 7 membered heterocyclyl ring or a 5 or 6 membered heteroaryl ring; n is a double bond. 8. A compound according to claim 7, wherein R ⁶ is selected from the group consisting of H, methyl, ethyl and isopropyl. The compound of claim 8, wherein R ² is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl group is optionally H, alkyl, haloalkyl, halogen, heterocyclyl, aryl, heteroaryl, -OR ⁸ ,- A compound substituted with a group consisting of CO ₂ R ⁸ , CONR ⁸ R ⁹ , -SO ₂ R ⁸ , and -SO ₂ NR ⁸ R ⁹ . The compound of claim 9, wherein R ¹ is selected from the group consisting of heterocyclyl, aryl, heteroaryl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ , wherein heterocyclyl, aryl, heteroaryl , Aryloxy or heteroaryloxy group is optionally H, cyano, haloalkyl, alkyl, halogen, heterocyclyl, aryl, heteroaryl, -OR ⁸ , -CO ₂ R ⁸ , CONR ⁸ R ⁹ , -S0 ₂ R ⁸ And -SO ₂ NR ⁸ R ⁹ . The compound of claim 10, wherein R ³ is selected from the group consisting of alkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl, wherein the arylalkyl, heteroarylalkyl or heterocycloalkyl group is optionally hydrogen, cyano, haloalkyl, Substituted by a group consisting of alkyl, cycloalkyl, halogen, hydroxyl, amino, -OR ⁸ , -NR ⁸ NR ⁹ , -S0 ₂ R ⁸ , -SO ₂ NR ⁸ R ⁹ , heteroaryl, heterocyclyl, and aryl Compound. The method of claim 1, R ¹ is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR ⁸ and -NR ⁸ R ⁹ Selected from the group consisting of; R ² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR ⁸ and -NR ⁸ R ⁹ Selected from the group consisting of; R ³ is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the R ⁶ group is less than 200 atomic mass units Has a molecular weight; R ⁷ is H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, -CONR ⁸ R ⁹ , -CO ₂ R ⁸ , -COR ⁸ and -SO ₂ R ⁸ It is selected from the group which consists of; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ may together optionally form a 5, 6 or 7 membered heterocyclyl ring or a 5 or 6 membered heteroaryl ring; n is a single bond. The compound of claim 12, wherein R ⁶ is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the R ⁶ group has a molecular weight of less than 200 atomic mass units. The compound of claim 13, wherein R ⁷ is selected from the group consisting of H, alkyl, -COR ⁸ , -CO ₂ R ⁸ , -CONR ⁸ R ^9, and -SO ₂ R ⁸ . The compound of claim 14, wherein R ² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, —OR ⁸ and -NR ⁸ R ⁹ A compound selected from the group consisting of. The compound of claim 15, wherein R ¹ is alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ A compound selected from the group consisting of. The compound of claim 16, wherein R ³ is selected from the group consisting of alkyl, cycloalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl. The method of claim 1, R ¹ is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ ; R ² is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, —OR ⁸ and —NR ⁸ R ⁹ ; R ³ is selected from the group consisting of alkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, arylalkyl and heteroarylalkyl, wherein the R ⁶ group has a molecular weight of less than 200 atomic mass units; R ⁷ is selected from the group consisting of H, -COR ⁸ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ and -S0 ₂ R ⁸ ; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ may together optionally form a 5, 6 or 7 membered heterocyclyl ring or a 5 or 6 membered heteroaryl ring; n is a single bond. The compound of claim 1, wherein the compound is selected from the following formula:

The compound of claim 1, wherein the compound is selected from the following formula:

The compound of claim 1, wherein the compound is selected from the following formula:

A pharmaceutical composition comprising at least one compound according to formula (I) and at least one pharmaceutically acceptable diluent or carrier, including all prodrugs, pharmaceutically acceptable salts and stereoisomers. <Formula 1>

Where n is a single bond or a double bond; R ¹ is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ² is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ³ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclo alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the R ⁶ group is less than 200 atomic mass units Has a molecular weight; R ⁷ is absent when n is a double bond; R ⁷ is H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR ⁸ , -CO ₂ R ⁸ , when n is a single bond; -CONR ⁸ R ⁹ and -S (O) mR ⁸ ; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ together optionally form a 4, 5, 6, or 7 membered heterocyclyl ring, or form a 5 or 6 membered heteroaryl ring; m is an integer of 1 or 2. The pharmaceutical composition of claim 22, further comprising one or more other therapeutic agents. Of a cannabinoid receptor mediated disease or disorder comprising administering a therapeutically effective amount of a compound of formula (I), including all prodrugs, pharmaceutically acceptable salts and stereoisomers, to a patient in need of treatment of the cannabinoid receptor mediated disease or disorder Method of treatment. <Formula I>

Where n is a single bond or a double bond; R ¹ is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ² is halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryl Oxy, -NR ⁸ R ⁹ , -CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ⁸ , -NR ⁸ COR ⁹ , -NR ⁸ CONR ⁸ R ⁹ , -NR ⁸ CO ₂ R ⁹ , -OCONR ⁸ R ⁹ , -NR ⁸ S (O) mR ⁹ , -NR ⁸ S (O) mNR ⁸ R ⁹ , -NR ⁸ S (O) mOR ⁹ and -OS (O) mNR ⁸ R ⁹ ; R ³ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; R ⁶ is selected from the group consisting of H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein the R ⁶ group is less than 200 atomic mass units Has a molecular weight; R ⁷ is absent when n is a double bond; R ⁷ is H, alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -COR ⁸ , -CO ₂ R ⁸ when n is a single bond; -CONR ⁸ R ⁹ and -S (O) mR ⁸ ; R ⁸ and R ⁹ are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl and heteroarylalkyl; R ⁸ and R ⁹ together optionally form a 4, 5, 6, or 7 membered heterocyclyl ring, or form a 5 or 6 membered heteroaryl ring; m is an integer of 1 or 2. The pharmaceutical composition of claim 22, and an anti-obesity agent; Appetite suppressants; Antidiabetic agents; Antihyperlipidemic agents; Hypolipidemic agents; Blood cholesterol lowering agents; Lipid modulators; Cholesterol lowering agents; Lipid lowering agents; HDL-increasing agents, antihypertensives; Sleep disorder treatments; Substance abuse and addiction disorder treatments; Anti-anxiety agents; Antidepressants; Psychosis; Cognitive enhancers; Cognitive disorder therapy; Alzheimer's disease therapies; Parkinson's disease therapies; Anti-inflammatory agents; Neurodegeneration drugs; Atherosclerosis agents; Respiratory disease therapies; Intestinal disorders; Cardiac glycosides; And a therapeutic agent selected from antitumor agents. The pharmaceutical combination of claim 25, wherein another therapeutic agent can be administered prior to, concurrent with, or following administration of the pharmaceutical composition of claim 22. The method of claim 25, wherein the anti-obesity agent is a melanocortin receptor (MC4R) agonist; Melanin enriched hormone receptor (MCHR) antagonist; Growth hormone secretagogue receptor (GHSR) antagonists; Galanin receptor modulators; Orexin antagonists; CCK agonists; GLP-1 agonists and other pPre-proglucagon-derived peptides; NPY1 or NPY5 antagonists; NPY2 and NPY4 modulators; Corticotropin release factor agonists; Histamine receptor-3 (H3) modulators; aP2 inhibitors; PPAR gamma modulators; PPAR delta modulators; Acetyl-CoA carboxylase (ACC) inhibitors; 11-β-HSD-1 inhibitor; Adiponectin receptor modulators; Beta 3 adrenergic agonists, including AJ9677, L750355 and CP331648, or other known beta 3 agonists; Thyroid receptor beta modulators; Lipase inhibitors, including olistat and ATL-962; Serotonin receptor agonists including BVT-933; Fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorpentermine, cloporex, chlortermin, picylorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine and marginol Monoamine reuptake inhibitors or release agents, including; Appetite suppressants, including topiramate; Ciliary nerve growth factors, including axokines; Brain-induced neurotrophic factor; Pharmaceutical combinations selected from leptin and leptin receptor modulators and other cannabinoid-1 receptor antagonists including SR-141716 and SLV-319. The method of claim 25, wherein the anti-obesity agent is an insulin secretagogue; Insulin sensitizers; Antihyperglycemic agents; Biguanide; Sulfonyl urea; Glucosidase inhibitors; Aldose reductase inhibitors; PPARγ agonists, including thiazolidinediones; PPAR α agonists, including fibric acid derivatives; PPAR δ antagonists or agents; PPAR α / γ dual agent; 11-β-HSD-1 inhibitors; Dipeptidyl peptidase IV inhibitors; SGLT2 inhibitors; Glycogen phosphorylase inhibitors; Meglitinide; insulin; Glucagon-like peptide-1; Glucagon-like peptide 1 agonists; And a protein combination tyrosine phosphatase-1B inhibitor. The pharmaceutical combination according to claim 28, wherein said anti-obesity agent is an oral antihypertensive agent selected from biguanides, metformin, phenformin, metformin HCl and other salts thereof. The method of claim 29, wherein the other therapeutic agent is biguanide and the compound of claim 1 is administered in a weight ratio of the compound of claim 1 to the biguanide in a range from about 0.001: 1 to about 10: 1. Pharmaceutical combination. 29. The ATP-dependent channel of claim 28, wherein the sulfonyl urea is present in an ATP-dependent channel of glyburide, glybenclamide, glymepiride, glipizide, glyclazide, chlorpropamide, other known sulfonylureas or beta-cells. Pharmaceutical combinations selected from other hyperglycemic agents that act. The pharmaceutical combination of claim 31, wherein the combination of the compound of claim 1 and the sulfonyl urea are administered in the same or separate oral unit form. The pharmaceutical combination of claim 28, wherein the glucosidase inhibitor is selected from acarbose and miglitol. The pharmaceutical combination of claim 33, wherein the combination of the compound of claim 1 and the glucosidase inhibitor are administered in the same or separate oral unit form. The pharmaceutical combination of claim 28, wherein the PPARγ agonist is a thiazolidinedione oral antiobesity agent. The method of claim 28, wherein the insulin sensitizer is rojiglitazone, pioglitazone, MCC-555, GL-262570, englitazone, darglitazone, isaglitazone; Pharmaceutical combinations selected from JTT-501, L-895645, R-119702, NN-2344, and YM-440. The pharmaceutical combination of claim 28, wherein the PPAR α / γ dual agent is selected from MK-767 / KRP-297, Tesaglitaza and Muraglitaza. 26. The method of claim 25, wherein the hyperlipidemic agent is mevastatin; Mevastatin related compounds; Lovastatin; Mebinoline; Lovastatin and mevinolin related compounds; Pravastatin and pravastatin related compounds; Simvastatin and simvastatin related compounds; Fluvastatin; Cerivastatin; Atorvastatin; Pitavastatin; Nyvastatin; Itavastatin; Rosuvastatin; Bisastatin; Rosuvastatin and bisastatin related compounds; Pyrazole analogs of mevalonolactone derivatives; Indene analogs of mevalonolactone derivatives; 6- [2- (substituted-pyrrole-1-yl) -alkyl) pyran-2-one and derivatives thereof; SC-45355; 3-substituted pentanedioic acid derivatives; Dichloroacetate; Imidazole analogs of mevalonolactone; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives; 2,3-disubstituted pyrrole, furan and thiophene derivatives; Naphthyl analogs of mevalonolactone; Octahydronaphthalene; Keto analogs of lovastatin and mebinolin; Quinoline and pyridine derivatives; And an HMG CoA reductase inhibitor selected from phosphonic acid compounds. 27. The method of claim 25, wherein the hyperlipidemic agent is selected from α-phosphono-sulfonate; Isoprenoid (phosphinyl-methyl) phosphonate; Terpenoid pyrophosphate; Farnesyl diphosphate derivative A and prisqualene pyrophosphate analogs; Phosphinylphosphonates; And a squalene synthetase inhibitor selected from cyclopropane. The method of claim 25, wherein the hyperlipidemic agent is fenofibrate; Gemfibrozil; Clofibrate; Bezafibrate; Cipropibrate; Clinofibrate; Probucol; And a fibric acid derivative selected from compounds associated with probucol. The method of claim 25, wherein the hyperlipidemic agent is cholestyramine; Cholestipol; DEAE-Sepadex; Secholex; Polysections; Cholestagel; Lipostavill; E-5050; N-substituted ethanolamine derivatives; Imanic room; Tetrahydrolipstatin; Isigmastanylphosphorylcholine; Aminocyclodextrin; AJ-814; Azulene derivatives; Melinamid; 58-035; CL-277,082; CL-283,546; Disubstituted urea derivatives; Nicotinic acid; Niacin; Acipimox; Acifran; Neomycin; p-aminosalicylic acid; aspirin; Poly (diallylmethylamine) derivatives; Pharmaceutical combination, which is a bile acid sequestrant selected from quaternary amine poly (diallyldimethylammonium chloride; ionene; and other known serum cholesterol lowering agents. 27. The method of claim 25, wherein the hyperlipidemic agent is substituted N-phenyl-N '-[(1-phenylcyclopentyl)] methylurea; TS-962; F-1394; CS-505; F-12511; HL-004; K-10085; And an acyl CoA: cholesterol O-acyl transferase inhibitor selected from YIC-C8-434. The pharmaceutical combination according to claim 25, wherein the hyperlipidemic agent is a synergistic regulator of LDL receptor activity, including MD-700. The pharmaceutical combination according to claim 25, wherein the hyperlipidemic agent is a cholesterol absorption inhibitor including ezetimibe. The method of claim 25, wherein the lipid modulator is CP-529,414; SC-744; SC-795; A pharmaceutical combination that is a cholesteryl transfer protein inhibitor selected from CETi-1; and JTT-705. The pharmaceutical combination of claim 25, wherein the hyperlipidemic agent is an ileal Na ⁺ / bile acid co-carrier inhibitor. The pharmaceutical combination according to claim 25, wherein the hyperlipidemic agent is an ATP citrate lyase inhibitor. The phytoestrogen compound according to claim 25, wherein said lipid modulator is isolated from soy protein, soy protein concentrate, soybean powder, isoflavone, genistein, dizain, glycidine or equol, or phytosterol, phytostanol And tocotrienols; Beta-lactam cholesterol absorption inhibitors; HDL synergists selected from LXR agonists, PPAR a-agonists and FXR agonists; LDL catabolic promoter; Sodium-proton exchange inhibitors; LDL-receptor inducer; Steroidal glycosides; Antioxidants selected from beta-carotene, ascorbic acid, α-tocopherol, retinol, vitamin C anti-homocysteine, folate, folate (folate), vitamin B6, vitamin B12 and vitamin E; Isoniazid; Cholesterol absorption inhibitors; HMG-CoA synthase inhibitors; Lanosterol demethylase inhibitors; PPAR δ agonists for treating dyslipidemia; A pharmaceutical combination selected from sterol regulatory element binding protein-I selected from sphingolipids, ceramides, neutral sphingomyelinase or fragments thereof. 26. The method of claim 25, wherein the hyperlipidemic agent is pravastatin; Lovastatin; Simvastatin; Atorvastatin; Fluvastatin; Pitavastatin; Rosuvastatin; Pharmaceutical combinations selected from niacin and cholesterol. The method of claim 25, wherein the hypertension is beta adrenergic blocker; L-type channel blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mibepradil; T-type calcium channel blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mibepradil; Chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumetiazide, bendroflumethiazide, methylchlorothiazide, trichloromethazide, polythiazide, benzthiazide, ethacrylic acid tricreate Diuretics selected from nafen, chlortalidone, furosemide, musolimin, bumetanide, triamtrenen, amylolide and spironolactone; Renin inhibitors; ACE inhibitors selected from captopril, zofenopril, posinopril, enalapril, serranopril, silazopril, delapril, pentopril, quinapril, ramipril and risinopril; AT-1 receptor antagonists selected from losartan, irbesartan and valsartan; ET receptor antagonists selected from citaxentane and atrcentane; Dual ET / AII antagonists; Neutral endopeptidase inhibitors; Vasopeptidase inhibitors and dual NEP-ACE inhibitors selected from omapatrilat and gemotritriat; And nitrates. The method of claim 25, wherein the therapeutic agent for sleep disorders comprises a melatonin analog; Melatonin receptor antagonists; ML 1 B agonist; GABA receptor modulators; NMDA receptor modulators; Histamine-3 (H3) receptor modulators; A pharmaceutical combination selected from dopamine agonists and orexin receptor modulators. The method of claim 25, wherein the agent for treating substance abuse and addiction disorders comprises: a selective serotonin reuptake inhibitor; Methadone; Buprenorphine; nicotine; And a pharmaceutical combination selected from bupropion. The pharmaceutical composition of claim 25, wherein the anti-anxiety agent is selected from diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazate, halazepam and prazepam; 5HT1A receptor agonists selected from buspyrone, plesinoxane, gepyron and incident pyron; And a corticotropin release factor antagonist. The method of claim 25, wherein the antidepressant is selected from a norepinephrine reuptake inhibitor selected from tertiary and secondary amine tricyclics; Selective serotonin reuptake inhibitors selected from fluoxetine, fluvoxamine, paroxetine and sertraline; Monoamine oxidase inhibitors selected from isocarboxazides, phenelzin, tranylcipromine and selegiline; Reversible inhibitors of monoamine oxidases including moclobemides; Serotonin and norepinephrine reuptake inhibitors including venlafaxine; Corticotropin release factor receptor antagonists; Alpha-adrenergic receptor antagonists; And atypical antidepressants selected from bupropion, lithium, nefazodone, trazodone and biloxazine. 27. The method of claim 25, wherein the psychiatric agent is phenothiazine selected from chlorpromazine, mesozinazine, thiolidazine, acetophenazine, flufenazine, perphenazine and trifluoroperazine; Thioxanthine selected from chlorproxetene and thiotixene; Heterocyclic dibenzezepines selected from clozapine, olanzepine and aripiprazole; Butyrophenone, including haloperidol; Dipeylbutylpiperidine, including phimozid; Indolone and molindolone classes of psychosis; Loxapine; Sulfides; Risperidone; Dopamine receptor antagonists; Muscarinic receptor agonists; 5HT2A receptor antagonist, 5HT2A / dopamine receptor antagonist and a pharmaceutical combination selected from partial agents selected from olanzepine, aripiprazole, risperidone and ziprasidone. The method of claim 25, wherein the cognitive enhancer is an acetylcholinesterase inhibitor including tacrine; Muscarinic receptor-1 agonists, including mylamin; Nicotine agonists; Glutamic acid receptor modulators; And a nootropic agent selected from piracetam and levetiracetam. The method of claim 25, wherein the Alzheimer's disease agent and the cognitive impairment agent are donepezil; Tacrine; Levastine; 5HT6; Gamma secretase inhibitors; Beta secretase inhibitors; SK channel blockers; Maxi-K blockers; And a KCNQ blocker. The method of claim 25, wherein the Parkinson's disease therapeutic agent comprises levadopa with or without a COMT inhibitor; Antiglutamic acid medicines selected from amantadine and rilusol; Alpha-2 adrenergic antagonists, including idazoic acid; Opiate antagonists including naltrexone; Ropinirol and other dopamine agonists and carrier modulators; And neuropathy factors, including pramipexole or glial induced neuropathy factors. The method of claim 25, wherein the anti-inflammatory agent is prednisone; Dexamethasone; Cyclooxygenase inhibitors, including COX-1 and COX-2 inhibitors selected from NSAID's, aspirin, indomethacin, ibuprofen, pyroxicam, naproxen, celebrex, and oxox; CTLA4-Ig agonists and antagonists; CD40 ligand antagonist; IMPDH inhibitors, including mycophenolate; Integrin antagonists; Alpha-4 beta-7 integrin antagonist; Cell adhesion inhibitors; Interferon gamma antagonists; ICAM-1; Tumor necrosis factor antagonists selected from infliximab, OR1384, TNF-alpha inhibitors including Tennyb, anti-TNE antibodies including etanercept or soluble TNF receptors; Rapamycin selected from sirolimus and rapamycin; Eflunomide; Prostaglandin synthesis inhibitors; Budesonide; Clofazimin; CNI-1493; CD4 antagonists including priximab; p38 mitogen-active protein kinase inhibitors; Protein tyrosine kinase inhibitors; IKK inhibitors; And a therapeutic agent for irritable bowel syndrome selected from gelnome and maxi-K openers. The method of claim 25, wherein the other therapeutic agent is cyclosporin; Cyclosporin A; Anti-IL-2 receptor; Anti-CD45RB; Anti-CD2; Anti-CD3 (OKT-3); Anti-CD4; Anti-CD80; Anti-CD86; Monoclonal antibody OKT3; Blockers of the action of CD40 and gp39; Antibodies specific for CD40 and / or gp39; CD154; Fusion proteins composed from CD40 and gp39; CD40Ig; CD8gp39; Nuclear translocation inhibitors of NF-kappa B function; Deoxyspergualin; Gold compounds; Antiproliferatives selected from methotrexate, FK506, tacrolimus, prograph and mycophenolate mofetil; Cytotoxic drugs selected from azatyprine and cyclophosphamide; Anticytokines selected from anti IL-4 or IL-4 receptor fusion proteins; Pharmaceutical combinations selected from PDE 4 inhibitors and PTK inhibitors including ariflo. The method of claim 24, wherein the disease or disorder is associated with the activity of the CB-1 receptor. 62. The method of claim 61, wherein the disease or disorder is any disease that results in a patient becoming hungry, obese or overweight. 62. The method of claim 61, wherein the disease or disorder is metabolic disorder, eating disorder and appetite disorder, Obesity, diabetes, arteriosclerosis, high blood pressure, polycystic ovarian disease, cardiovascular disease, osteoarthritis, skin disorders, high blood pressure, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, hyperlipidemia symptoms, neurotic hunger and obsessive compulsive Treatment of symptoms associated with a disorder such as eating disorder. 62. The method of claim 61, wherein the disease or disorder is obesity due to a genetic or environmental cause, Overeating and hunger, polycystic ovary disease, craniopharyngeoma, Prader-Willi syndrome, Frorich syndrome, type II diabetes, growth hormone deficiency, Turner syndrome and other pathological conditions characterized by reduced metabolic activity or reduced energy consumption Treatment method comprising a. 62. The method of claim 61, wherein the disease or disorder is a mental disorder selected from substance abuse, addiction disorder, depression, anxiety, manic and schizophrenia. Dementia, Alzheimer's disease, short-term memory loss and concentration deficit disorders comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need of treatment; Neurodegenerative disorders, Parkinson's disease, stroke and brain trauma; Hypotension, bleeding and endotoxin-induced hypotension; Parkinson's disease; Huntington's disease; Pick disease; Creutzfeldt-Jakob disease; Head trauma; And treating a disease selected from age-related cognitive decline. A method of treating diseases associated with the brain dopamine system, including Parkinson's disease and substance abuse disorders, comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need thereof. Catabolic activity associated with pulmonary dysfunction and respiratory dependence, comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need thereof; Heart disease dysfunction, heart valve disease, myocardial infarction, enlarged heart disease or congestive heart failure; Transplant rejection; Rheumatoid arthritis; Multiple sclerosis; Inflammatory bowel disease; Lupus; Transplant vs. host disease; T-cell mediated hypersensitivity disease; psoriasis; asthma; Hashimoto's thyroiditis; Guillain-Barré syndrome; cancer; Contact dermatitis; Allergic rhinitis; A method of treating a disease selected from ischemia or reperfusion injury. Alcohol, amphetamines, amphetamine-like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, penicills, comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need of treatment A method of treating a substance abuse or dependency disorder for a combination of a dine, a penciclidinic compound, a stabilizer-hypnotic, a benzodiazepine, other known or unknown substance, or a substance of abuse. 70. The method of claim 69, wherein substance abuse or dependence can occur without physiological dependence. A method of treating a drug or alcohol withdrawal syndrome and substance-induced anxiety or mood disorder that occurs during discontinuation, comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need thereof. Comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need of treatment,  Rejection due to tissue transplantation, acute transplant, xenograft, heterograft and allograft; Protection against ischemia or reperfusion injury, such as ischemia or reperfusion injury during tissue transplantation, myocardial infarction, cerebral stroke or other causes; Induction of transplant resistance; Rheumatoid arthritis, psoriatic arthritis and osteoarthritis; Multiple sclerosis; Chronic obstructive pulmonary disease (COPD), pneumonia, bronchitis, and acute respiratory pain syndrome (ARDS); Inflammatory bowel disease, ulcerative colitis and Crohn's disease; Systemic lupus erythematosus; Transplant vs. host disease; T-cell mediated hypersensitivity diseases including contact hypersensitivity, delayed 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; Autoimmune polymorphic diseases or syndromes; Autoimmune alopecia; Pernicious anemia; Vitiligo; Autoimmune hypoglycemia; Guillain-Barré syndrome; Other autoimmune diseases; Glomerulonephritis; Serum diseases; hives; Asthma, hay fever, allergic rhinitis and skin allergies; Scleroderma; Mycelial sarcoma; Acute inflammatory and respiratory reactions such as acute respiratory pain syndrome and ischemia / reperfusion injury; Dermatitis; Alopecia areata; Chronic ray dermatitis; eczema; Behcet's disease; Plantar pustules; Necrotic purulent dermatosis; Trident syndrome; Atopic dermatitis; Systemic sclerosis; And a method for treating leukocyte activation-related disorders, including ecchymoses. A method of treating inflammatory diseases, including arthritis, inflammatory bowel disease and autoimmune glomerulonephritis, comprising administering a therapeutically effective amount of a compound as defined in claim 24 to a mammalian species in need thereof.