NO315423B1 - Arylpyridazinones as biosynthesis inhibitors of prostaglandin endoperoxidase H synthase, their preparation and pharmaceutical composition comprising the same - Google Patents

Description

This application is a "continuation-in-part" of U.S. Pat. patent application with serial no. 08/917,023 filed August 22, 1997, which was based on the provisional application 60/056,733 filed August 22, 1997.

Technical area

The present invention comprises new pyridazinone compounds which are useful in the treatment of cyclooxygenase-2-mediated diseases. More specifically, this invention relates to the above compounds, pharmaceutical compositions comprising the same, their use as well as methods of preparing the compounds to inhibit prostaglandin biosynthesis, especially the induced prostaglandin endoperoxide H synthase protein (PGHS-2, cyclooxygenase-2, COX -2).

The background of the invention

The prostaglandins are extremely potent substances that produce many different biological effects, often in the nanomolar to picomolar concentration range. The discovery of two forms of prostaglandin-endoperoxide H synthase, the isoenzymes PGHS-1 and PGHS-2, which catalyze the oxidation of arachidonic acid and lead to prostaglandin biosynthesis, has resulted in renewed research to outline the role of these two enzymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulation and clearly represent different prostaglandin biosynthesis pathways. The PGHS-1 pathway is constitutively expressed in most cell types. It responds by producing prostaglandins that regulate acute events in the vascular homeostasis and also has a role in the maintenance of normal stomach and renal functions. The PGHS-2 pathway involves an induction mechanism that has been linked to inflammation, mitogenesis and ovulation phenomena. Prostaglandin inhibitors provide therapy for pain, fever and inflammation and are useful therapies, for example, in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal anti-inflammatory drugs (NSAID drugs) such as ibuprofen, naproxen and fenamate inhibit both isozymes. Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and cases of renal problems with chronic therapy. Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatory activity without the side effects of PGHS-1 inhibitors.

The problem of side effects in connection with NSAID administration has never before been fully resolved. Enteric-coated tablets and co-administration with miso-prostol, a prostaglandin derivative, have been tried in an attempt to reduce gastric toxicity. It would be advantageous to be able to provide compounds which are selective inhibitors of the induced isozyme PGHS-2.

The present invention describes new compounds which are selective inhibitors of PGHS-2.

Summary of the invention

The present invention describes pyridazinone compounds which are selective inhibitors of cyclooxygenase-2 (COX-2). The compounds according to the present invention have the formula

IN:

where

X is 0;

R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkylcarbonyl-C1-C6-alkyl, halogen-C1-C8-alkyl, halogen-C2-C9-alkenyl, C3- C7-cycloalkyl optionally substituted with C1-C6-alkyl, C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkenyl, C3-C7-cycloalkenyl-C1-C6-alkyl, phenyl, phenyl-C1-C. 6-alkyl, phenyl-Ci-Ce-alkanoyl, phenyl-C2-C7-alkynyl, phenyl-C2-C7-alkenyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, d-C6-alkyl, C -Ce-alkylthio, Ci-Ce-alkylsulfonyl, Ci-Cg-Alkoxy, C2~C7-alkenyl, formyl, CN, NO2, CF3, OH, Ci-C6-alkanoyloxy, Ci-C6-Alkoxy-imino, di-Ci -Ce-alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl, heterocyclyl-Ci-C6-alkyl, heterocyclyloxy-Ci-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, C1-C6-alkyl or NO2), dihydroind enyl, adamantyl or

adamantyloxycarbonyl;

R<2> is

where X<1> is SO or SO2,

r<9> is C1-C6-alkyl, halo-C1-C6-alkyl, amino or -N=CH (NR10R11) where R<1>0 and R1<1> are C1-C6-alkyl;

X 2 is hydrogen, halogen, or C 1 -C 6 alkyl;

R<1> is C 1 -C 8 -alkyloxy, C 1 -C 8 -alkylamino, C 2 -C 6 -alkylenyloxy,

C2-C8-alkynyloxy, C2-C8-alkenyl, C1-C8-alkyl, C2-C8-alkynyloxy, C2-C8-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkenyl, C3-C7-cycloalkoxy optionally substituted with Ci-C6-alkylr C3-C7-cycloalkyl-Ci-C6-alkoxy, C3-C7-cycloalkyl-Ci-C6-alkyl, C3-C7-cycloalkylthio-Ci-C6-alkyl, C3-C7-cycloalkylthio, C3-C7 -cycloalkylamino, C1-C6-Alkoxy-C1-C8-Alkoxy, C1-C6-Alkylthio-C1-C6-Alkoxy, Halo-C1-C6-Alkylthio, C1-C8Alkylthio, C1-C6-Alkoxy-C1-C6- alkylamino, hydroxy-Ci-Ce-alkylamino, cyano-Ci-Ce-alkylamino, di-Ci-C6-alkylamino-Ci-C6-alkoxy, hydroxy-Ci-Cg-alkylamino, Ci-Cs-alkanoyl-Ci-C6- Alkoxy, phenyl-Ci-C6-alkylamino, phenyl, phenylamino, phenyl-Ci-C6-alkyl, phenoxy, phenoxy-Ci-C6-alkyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6-alkoxy, phenylthio, phenyl-Ci-C6-alkylthio or benzoyloxy-Ci-Ce-alkyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy, C2-C7-alkenyl, CNr CF3, NO2, C1-C6-alkylsulfonyl, di-C1-C6-alkylamino, phenyl, carbamoyl or C 1 -C 6 -alkanoyl-amino), heterocyclyl, heterocyclyloxy, heterocyclyl-amino, heterocyclyl-C 1 -C 6 -alkylamino, heterocyclylthio, heterocyclyloxy, heterocyclyl-C 1 -C 6 - alkoxy, (where heterocyclyl is selected from morpholinyl, pyridyl, thienyl, dihydroisobenzofuranyl , furyl, piperidinyl, triazolyl, benzofuranyl, pyrrolidinyl, tetrahydro-furfuryl or imidazolyl, which heterocyclic groups are optionally substituted with one or more groups selected from oxo, hydroxy, halogen or C1-C6-alkoxy), or R<1> is dihydroindenylamino or in-danyloxy;

R<3> is H or C1-C6 alkyl;

or a pharmaceutically acceptable salt or ester thereof.

Detailed description of the invention

All patents, patent applications and literature references referred to in the description are hereby incorporated by reference in their entirety. In case of inconsistency, the present description, including the definitions, will apply.

The present invention describes pyridazinone compounds which are cyclooxygenase inhibitors (COX inhibitors) and selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, in contrast to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important "housekeeping" enzyme in many tissues, including the gastrointestinal (GI) system and the kidney.

In another embodiment, the compounds according to the present invention have the formula II: wherein Z is a group of the formula:

where X<1> is -SO2- or -SO-, and R<9> is C1-C6 alkyl, halo-C1-C8 alkyl or amino;

X<2> is hydrogen, halogen or C1-C6 alkyl;

R is as defined for formula I;

R 1 is hydroxy-C 1 -C 6 -alkyloxy or hydroxy -C 1 -C 8 -alkylamino;

R 3 is hydrogen or C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt or ester thereof.

In yet another embodiment, the compounds according to the present invention have the formula III:

in which

X<1> is SO 2 or SO, and R<9> is C 1 -C 6 alkyl or amino; X<2> is hydrogen or halogen;

R is C1-C9-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkylcarbonyl-Ci-C8-alkyl, C1-C6-alkylsulfonyl phenyl-C1-C8 alkyl, halogen-Ci -C8-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkyl, phenyl, phenyl-C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6~alkyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, C1-C6-alkyl, C1-C8-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkoxy, C2-C7-alkenyl, formyl, CN, NO2, CF3, OH, C1-C6-alkanoyloxy, C1-C6-alkoxyimino, di-C1-C6-alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl, heterocyclyl-C1-C6-alkyl (where said heterocyclyl groups are selected among pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, C1-C6-alkyl or NO2), dihydroindenyl, adamantyl or adamantyloxycarbonyl;

R<1> is hydroxy-C 1 -C 6 alkylamino or hydroxy-C 1 -C 6 -alkyloxy;

R<3> is hydrogen or C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt or ester thereof.

In a preferred embodiment, the compounds according to the present invention have the formula III,

wherein X<1> is -SO2- or -SO-, and R<9> is C1-C6-alkyl or

amino;

X<2> is hydrogen or halogen;

R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkylcarbonyl-C1-C8-alkyl, C1-C6-alkylsulfonylphenyl-C1-C8-alkyl, halogen-Ci- CB-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkyl, phenyl, phenyl-C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6-alkyl (where mentioned phenyl groups are optionally substituted with one or more groups selected from halogen, C1-C6-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkoxy, C2-C7-alkenyl, formyl, CN, NO2, CF3 , OH, C1-C6-alkanoyloxy, C1-C6-alkoxyimino, di-C1-C8-alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl or heterocyclyl-C1-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from

halogen, C 1 -C 6 alkyl or NO 2 );

R<1> is hydroxy-C 1 -C 6 alkoxy;

R<3> is hydrogen or C1-C6 alkyl;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein X<1> is -SO2- or -SO-, and R<9> is C1-C6-alkyl or

amino;

X<2> is hydrogen and halogen;

R is C1-C6-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkylcarbonyl-C1-C8-alkyl, C1-C6-alkylsulfonyl phenyl-C1-C6-alkyl, halogen- C1-C8-alkyl, C3-C-7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkyl, phenyl, phenyl-C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-C1-C6- alkyl{where said phenyl groups are optionally substituted with one or more groups selected from halogen, C1-C6-alkyl, C1-C8-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkoxy, C2-C7-alkenyl, formyl, CN , NO2, CF3, OH, C1-C6-alkanoyloxy, C1-C6-alkoxyimino, di-C1-C6-alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl or heterocyclyl-C1-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, Ci-Cg-alkyl

or N02);

R<1> is hydroxy-C 1 -C 6 -alkylamino or hydroxy-C 1 -C 8 -alkoxy; and

R<3> is C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein X<1> is SO2 or SO, and R<9> is C1-C6 alkyl or amino; X<2> is hydrogen or halogen;

R is Ci-Cb-alkyl, halogen-Ci-Ca-alkyl, phenyl optionally substituted with halogen, heterocyclyl or

heterocyclyl-C 1 -C 6 alkyl;

R<1> is hydroxy-C 1 -C 6 -alkyloxy or hydroxy-C 1 -C 6 -alkylamino;

R 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein X<1> is SO2 or SO, and R<9> is Cx-C6 alkyl or amino; X 1 is hydrogen or halogen;

R is Ci-C8-alkyl, halo-Ci-Ce-alkyl, phenyl optionally substituted with halogen, heterocyclyl or

heterocyclyl-C 1 -C 6 alkyl;

r! is hydroxy-C 1 -C 6 alkoxy; and

r 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein x<1> is SO 2 , and R<9> is C 1 -C 8 alkyl or amino;

X 1 is hydrogen or halogen;

R is halo-Ci-Ce-alkyl, phenyl optionally substituted with

halogen, heterocyclyl or heterocyclyl-C 1 -C 8 alkyl; r! is hydroxy-C 1 -C 6 -alkyloxy; and

R 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein x<1> is SO 2 , and R<9> is C 1 -C 6 alkyl or amino;

X<2> is hydrogen or halogen;

R is C 1 -C 6 alkyl, C 1 -C 8 alkenyl, C 2 -C 9 alkynyl, haloC 1 -C 8 alkyl, phenyl or phenyl C 1 -C 6 alkyl;

R 1 hydroxy-C 1 -C 6 alkoxy; and

R 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein X<1> is SO2, and R<9> is C1-C6 alkyl or amino;

X<2> is hydrogen or fluorine;

R is halo-C1-C8-alkyl, phenyl or C1-C6-alkyl;

r! is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl-butoxy; and

r 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein X1 is SO2, and R<9> is C1-C6 alkyl,

X<2> is hydrogen or fluorine;

R is C 1 -C 6 alkyl, C 1 -C 8 alkenyl, C 2 -C 8 alkynyl, halo-C 1 -C 6 alkyl, phenyl or phenyl C 1 -C 6 alkyl;

R<1> is hydroxy-C 1 -C 6 alkoxy; and

R 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein xl is SO 2 / and R<9> is amino;

X<2> is hydrogen or fluorine;

R is C 1 -C 6 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, halo-C 1 -C 8 -alkyl, phenyl or phenyl-C 1 -C 6 -alkyl;

r! is hydroxy-C 1 -C 6 alkoxy; and

r 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III, wherein x<1> is -SO2- and R<9> is methyl;

X<2> is hydrogen;

R is t-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl,

4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl or

CF3CH2-;

R 1 is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl-butoxy; and

R 3 is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

In another preferred embodiment, the compounds according to the present invention have the formula III,

wherein x<1> is -SO2- and R<9> is amino;

X<2> is hydrogen;

R is t-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl,

4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl or

CF3CH2-;

R 1 is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl-butoxy; and

R<3> is hydrogen;

or a pharmaceutically acceptable salt or ester thereof.

Definitions of expressions

As used throughout this specification and the accompanying claims, the following terms have the meanings specified.

The term "protecting groups" includes "carboxy-protecting group" and "N-protecting groups". "Carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group used to block or protect the carboxylic acid functionality while the reactions involving other functional sites in the compound are carried out. Carboxy protecting groups are described in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be easily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent compound. T. Higuchi and V. Stella provide a thorough review of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society

(1975), which is hereby incorporated herein by reference. Such carboxy-protecting groups are well known to those skilled in the art, having been used extensively for the protection of carboxyl groups in the penicillin-line and cephalogensporin area, as described in U.S. Pat. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups are found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy-protecting groups are C 1 to C 8 alkyl (eg methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example phenylethenyl and the like; aryl and substituted derivatives thereof, for example 5-indanyl and the like; dialkylaminoalkyl (eg, dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxy)-1-ethyl, 1-methyl-1-(propionyloxy)-1 -ethyl, pivalyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl and the like; alkoxycarbonyloxyalkyls such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocyclylcarbonyloxyalkyl such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(lower alkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like ; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or a peptide or to protect an amino group from unwanted reactions during synthetic procedures. Commonly used N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-to-toluenesulfonyl and the like; carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhy-dryloxycarbonyl, t- butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).

The term "alkanoyl" as used herein refers to an alkyl group as defined previously attached to the parent molecule via a carbonyl group (-C(O)-). Examples of alkanoyl include acetyl, propionyl and the like.

The term "C 8 -alkenyl" as used herein refers to a straight chain or branched hydrocarbon radical containing from 2 to 9 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.

The term "C 2 -C 8 alkenyloxy" used herein refers to a C 2 -C 8 alkenyl group, as defined previously, attached to the parent molecular group via an oxygen bond (-0-). Examples of C 2 -C 6 alkenyloxy include isopropenoxy, butenyloxy and the like.

The term "C 1 -C 8 alkoxy" used herein refers to a C 1 -C 6 alkyl group attached to the parent molecule via -O-. Examples of C 1 -C 6 alkoxy include, but are not limited to, ethoxy, isobutyloxy, isopentyloxy, tert-butoxy and the like.

The term "C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkylamino" as used herein refers to a C 1 -C 6 -Alkoxy as defined herein attached to the parent molecular group via a C 1 -C 6 alkylamino as defined herein. Examples of C1-C6-Alkoxy-C1-C6-Alkylamino include, but are not limited to, ethoxymethylamino, isobutyl-oxyethylamino and the like.

Representative examples of C 1 -C 6 -C 1 -C 6 -Alkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoc-simethoxy and the like.

The term "C 1 -C 8 alkyl" and "C 1 -C 6 alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 8 carbon atoms, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

Examples of "Ci-C8-alkylamino" are ethylamino, butylamino and the like.

The term "C 2 -C 6 -alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 2 to 8 carbon atoms by removal of two hydrogen atoms, for example -CH 2 -, -CH 2 CH 2 -, -CH (CH3>-,

-CH2CH2CH2-, -CH2C(C<H>3)2CH2- and the like.

The term "C 1 -C 6 alkylsulfonyl" as used herein refers to a C 1 -C 6 alkyl group as defined previously attached to the parent molecular group via a sulfonyl group (-S{O) 2 -) Examples of C 1 -C 6 alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and such.

The term "C 1 -C 6 alkylthio" used herein refers to a C 1 -C 6 alkyl group attached to the parent compound via -S-.

The term "C 1 -C 6 -alkylthio-C 1 -C 6 -alkoxy" as used herein refers to C 1 -C 6 -alkylthio as defined herein attached to the parent molecular group via a C 1 -C 6 -alkyl group as defined herein.

The term "C 2 -C 8 -alkynyl" as used herein refers to a straight chain or branched hydrocarbon radical containing from 2 to 9 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include

-C=C-H, H-C=C-CH2-, H-C=C-CH(CH3)- and the like.

The term "amino" as used herein refers to -NH 2 .

The term "phenyl-C2-C7-alkenyl" as used herein refers to a C2-C7-alkenyl radical to which is attached a phenyl group, for example phenylethenyl and the like.

The term "phenyl-C2-C7-arylalkynyl" as used herein refers to a C2-C7-alkynyl radical to which is attached a phenyl group, for example phenylethynyl and the like

The term "phenyl-C 1 -C 6 alkoxy" used herein refers to a C 1 -C 6 alkoxy radical to which is attached a phenyl group, for example benzyloxy and the like.

The term "phenyl-C 1 -C 6 alkyl" as used herein refers to a phenyl group as defined previously, attached to a C 1 -C 6 alkyl radical, for example benzyl and the like.

The term "phenyl-C1-C6-alkylamino" as used herein refers to a phenyl-C1-C8-alkyl group as defined previously, attached to the parent molecular group via an amino group. The term "phenyl-C1-C6-alkylthio" used herein refers to a phenyl-C1-C6-alkyl group as defined previously, attached to the parent molecular group via a thiol group.

The term "phenoxy-C1-C8-oxyalkyl" refers to a phenoxy group as defined previously attached to a C1-C6 alkyl radical. Examples of phenoxy-C 1 -C 6 alkyl include phenoxymethyl, 2-phenoxyethyl and the like.

The term "C3-C7-cycloalkyl" as used herein refers to an aliphatic ring system of 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. The cyclo-C3-C7 alkyl groups can be unsubstituted or substituted.

The term "C3-C7-cycloalkenyl" as used herein refers to an aliphatic ring system of 3 to 7 carbon atoms containing at least one double bond in the ring structure.

The term "C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl" as used herein refers to a C 3 -C 7 cycloalkyl group attached to a C 1 -C 8 alkyl radical, including but not limited to cyclohexylmethyl.

The term "C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyloxy" as used herein refers to a C 3 -C 7 -cycloalkyl group attached to a C 1 -C 6 -alkyl group as defined herein, including but not limited to cyclohexylmethyloxy.

The term "C3-C7-cycloalkylamino" used herein refers to a C3-C7-cycloalkyl group attached to the parent molecular group via an amino group as defined herein, including but not limited to cyclohexylamino and the like.

The term "C3-C7-cycloalkenyl-C1-C6-alkyl" as used herein refers to a C3-C7-cycloalkenyl group attached to a C1-C6-alkyl radical, including but not limited to cyclohexenylmethyl.

Examples of "di-C1-C8-alkylamino" refer to, for example, diethylamino, methylpropylamino and the like.

The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.

The term "halo-Ci-CB-alkyl" as used herein refers to a Ci-Cs alkyl radical having at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2,3-difluoropentyl and the like.

The term "halo-C2-C9-alkenyl" as used herein refers to a C2-C8 alkenyl radical having at least one halogen substituent, for example chloromethenyl, fluoroethenyl, trifluoromethenyl or pentafluoroethenyl, 2,3-difluoropentenyl and the like.

The term "hydroxy" used herein refers to -OH.

The term "hydroxy-C 1 -C 8 -hydroxy" as used herein refers to a C 1 -C 6 alkoxy radical as defined previously to which is attached a hydroxy group (-OH). Examples of hydroxy C 1 -C 6 alkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.

The term "hydroxy-C1-C6 alkylamino" as used herein refers to a hydroxy-C1-C6 alkyl group attached to the parent molecular group via an amino. Examples of hydroxy C 1 -C 6 alkylamino include 1-hydroxypropylamino, 4-hydroxybutylamino, 1,3-dihydroxyisopentylamino and the like.

The term "nitro" as used herein refers to -NO 2 .

The compounds according to the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate , heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate , succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. The basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others. Water- or oil-soluble or dispersible products are thereby obtained.

Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric, sulfuric and phosphoric and such organic acids as oxalic, maleic, succinic and citric.

Base addition salts may be prepared in situ during the final isolation and purification of the compounds of formula (I) or separately by reacting a carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations , including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The term "pharmaceutically acceptable ester" as used herein refers to esters that hydrolyze in vivo and includes those that readily degrade in the human body to yield the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkane, alkene, cycloalkane and alkanedic acids, wherein each alkyl or alkenyl group advantageously has no more than 6 carbon atoms. Examples of special esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.

As used throughout this specification, the term metabolically cleavable group denotes a group that is readily cleaved in vivo from the compound bearing it, wherein said compound after cleavage remains, or becomes, pharmacologically active. Metabolically cleavable groups constitute a class of groups which are reactive with the carboxyl group of the compounds according to this invention and are well known to the person skilled in the art. They include, but are not limited to, groups such as, for example, alkanoyl, such as acetyl, propionyl, butyryl and the like; unsubstituted and substituted aroyl, such as benzoyl and substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl; trialkylsilyl, such as trimethyl- and triethylsilyl; monoesters formed with dicarboxylic acids, such as succinyl and the like. Because the metabolically cleavable groups of the compounds of this invention are cleaved in vivo, the compounds bearing such groups act as prodrugs of other prostaglandin biosynthesis inhibitors. The compounds carrying the metabolically cleavable groups have the advantage that they can exhibit improved bioavailability, which is a result of the increased solubility and/or absorption rate compared to the parent compound by virtue of the presence of the metabolically cleavable group.

Asymmetric centers may be present in the compounds according to the present invention. The present invention encompasses the various stereoisomers and mixtures thereof. Individual stereoisomers of the compounds according to the present invention are prepared by synthesis from starting materials containing the chiral centers or by the preparation of mixtures of enantiomeric products followed by separation such as by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds with particular stereochemistry are either commercially available or prepared by the methods detailed below and resolved by techniques well known in the art of organic chemistry.

Preferred embodiments

Compounds useful in the practice of the present invention include, but are not limited to: 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 2-{4-fluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone; 2-{3,4-difluorophenyl)-4-{2-hydroxy-2-methylpropoxy)-5-[4- (aminosulfonyl)phenyl]-3(2H)-pyridazinone; (R)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; (S)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; (R)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone; and

(S)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-{aminosulfonyl)phenyl]-3(2H)-pyridazinone;

or a pharmaceutically acceptable salt or ester thereof.

Preparation of the compounds according to the invention

The compounds according to the invention can be prepared via several different synthetic routes. Representative procedures are set forth in Forms 1-3, below.

A general route to the compounds according to the invention which have Formula III, where the aryl group in the 5-position on the pyridazinone ring is substituted with a sulfonyl group, is described in scheme 1 below. Dichloro-3(2H)-pyridazinone is reacted with benzyl chloride and potassium carbonate in methanol. 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone is then treated with a boric acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst. The methoxy group was hydrolyzed with 48% hydrobromic acid to provide the 5-hydroxypyride-azinone compound. The 5-hydroxypyridazinone product was treated with trifluoromethylsulfonic anhydride followed by substitution on the pyridazinone ring using 4-methylthiobenzeneboronic acid. This gave the methyl thioether compound which was reacted with peracetic acid in acetic acid and methylene chloride to provide the methyl sulfone. The benzyl group is removed using aluminum bromide or another suitable Lewis acid. The R group can be added via substitution using a suitable alkylating agent and a base. Another route to the compounds according to the invention with Formula III is described in scheme 2 below. 4-Bromothioanisole or another suitable thioether is reacted with a trimethoxyborate such as trimethoxyborate or triisopropylborate to convert it to 4-(methylthio)benzeneboronic acid. The boric acid is reacted with 2-benzyl-4,5-dibromo-3(2H)-pyridazinone using tetrakis(triphenylphosphine)palladium(0) in dimethoxyethane. The product is then coupled with a second boronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst to provide the thioether. This gave the methyl thioether compound which was reacted with methachloroperoxybenzoic acid (MCPBA) in methylene chloride to provide the methyl sulfone. The benzyl group is removed using aluminum bromide or another suitable Lewis acid. The R group can be added via substitution using a suitable alkylating agent and a base. A third route to the compounds according to the invention with formula III is described in scheme 3, below. (4-Thiomethyl-phenyl)dimethylthioketene acetal, mono-S-oxide was prepared by reacting 4-thiomethylbenzaldehyde (Y is CH3S) with methyl-(methylsulfinylmethyl)sulfide and sodium hydroxide. Thioketene acetal and methyl 4-fluorophenyl acetate or an appropriate ester (X is fluorine) were treated with a strong base such as sodium hexamethyldisilazide in THF to provide the butyrate ester. The dithioacetal ketene was directly cyclized to the unsubstituted pyridazinone using hydrazine and a salt. The pyridazinone was oxidized with peroxyacetic acid to provide the sulfonylpyridazone. In an alternative route, Scheme 3-A, the thioacetal ketene was treated with perchloric acid to provide an ester aldehyde as a mixture of diastereomers. The oxidation products were treated with hydrazine and then oxidized with peroxyacetic acid to obtain the sulfonyldihydropyridazinone. The dihydropyridazinone can be dehydrogenated to form the pyridazinone by treatment with reagents such as bromine in acetic acid. The R group can be added via substitution using a suitable alkylating agent and a base. The preparation of the 5-hydroxy-2(5H)-furanones can be carried out using the methodologies published in many different sources, including: J. Med. Chem., 1987, 30, 239-249 and WO 96/36623, hereby incorporated in their entirety by reference and shown in Scheme 4.

Method IV:

A general route to the compounds according to the invention with Formula III, where the aryl group in the 5-position on the pyridazinone ring is substituted with a sulfonyl grouping, is described in scheme 5, below. A mucohaloic acid, such as mucobromic or mucochloroic acid, is reacted with a hydrazine with the desired R group to provide the dihalopyridazinone compound, 5A. Treatment of the dihalogen compound with an alcohol in the presence of a base, such as sodium or potassium hydride, will provide an alkoxide, 5B. (If the alkoxy group is to be removed at a later stage, then methanol is the preferred alcohol.) Reaction of the alkoxy halogen with a methylthiophenyl boric acid will provide the alkoxy pyridazinone 5C. The alkoxy group can be converted to a hydrocarbyl group by treatment with a Grignard reagent to provide the thioether 5D. The thioether can be oxidized with an oxidizing agent, such as peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G or the methylsulfone compound 5E. Rearrangement and hydrolysis of the sulfinyl compound, 5G, provides the thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound 5H. Alternatively, the methylsulfonyl compound, 5E, can be converted to the aminosulfonyl compound 5H by treating the methylsulfonyl compound with a diazodicarboxylate, such as DBAD, DIAD, DEAD and the like, and a disilazan anion, such as lithium HMDS and the like, followed by treatment with sodium acetate and hydroxylamine-O-sulfonic acid in water affords the aminosulfonyl compound, 5H.

Alternatively, the alkoxy-pyridazinone 5C can be oxidized, as shown in Scheme 5A. The first step is to use an oxidizing agent, such as peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G' or the methylsulfone compound 5E'. Rearrangement and hydrolysis of the sulfinyl compound provides the thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound 5H<1>. Finally, the methylsulfonyl compound can be converted into the aminosulfonyl compound 5H' by treating the methylsulfonyl compound 5E' with a diazodicarboxylate, such as DBAD, DIAD, DEAD and the like, and a disilazan anion, such as lithium HMDS and the like, followed by treatment with sodium acetate and hydroxylamine-O-sulfonic acid in water affords the aminosulfonyl compound, 5H' .

Preparation of compounds according to the invention with Formula III, where the group in the 4-position on the pyridazinone ring is a substituted alkyl or alkenyl group is described in scheme 6A, below. The thioether 5E, where R<9>^ is alkyl, e.g. methyl as shown is halogenated with a halogenating reagent such as NBS and peroxide to provide the bromo compound 6A. The bromine compound can be reacted with an alcohol and a weak base, such as e.g. sodium or potassium carbonate to provide the 4-alkyl ether, 6B. The bromine compound can be reacted with a thio compound in the presence of a base, such as silver carbonate, to provide the 4-alkyl thioether, 6C. The bromine compound can be reacted with an amine and a weak base such as sodium or potassium carbonate to provide the 4-alkyl amino-alkyl compound 6D.

A general route to the compounds according to the invention with Formula III, where the group in the 4-position on the pyridazinone ring can be easily substituted, is illustrated in scheme 6, above. The synthesis begins with the alkoxide, 5E', where R<9>^ is methyl. The methoxy compound is treated with a base, such as sodium or potassium hydroxide, to provide the 4-hydroxypyradizinone, 6A. The alcohol is treated with p-toluenesulfonyl chloride to provide the tosyloxy compound, 6B. The tosyloxy compound can be easily substituted with a compound R<92>z' which can undergo a Sn2 reaction. Examples of these compounds are compounds such as alcohols, thiols, amines or hydrocarbyl ions. As used throughout this specification and the accompanying claims, the following abbreviations have been used: ACD for acid citrate dextrose, CAP for carrageenan-induced air cushion prostaglandin, CIP for rat carrageenan pleural inflammation model, COX-2 for cyclooxygenase-2, CPE for carrageenan-induced paw edema in rotation, DBAD for di-t-butylazodicarboxylate, DEAD for diethylazodicarboxylate, DIAD for diisopropylazodicarboxylate, DMAP for 4-{dimethylamino)pyridine, DME for 1,2-dimethoxyethane, DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide, DMSO for dimethyl sulfoxide, EDTA for ethylenediaminetetraacetic acid, EIA for enzyme immunoassay, FAB for rapid nuclear bombardment, GI for gastrointestinal, HMDS, lithium or Li-HMDS for lithium 1,1,1,3,3,3-hexamethyldisilazide, HWPX for human whole blood plate -cyclooxygenase-1, MCPBA for meta-chloroperoxybenzoic acid, NSAID drugs for nonsteroidal anti-inflammatory drugs, PEG 400 for polyethylene glycol, PGE2 for prostaglandin E2, PGHS for the prostaglandin doperoxide H-synthase, RHUCXl for recombinant human cyclooxygenase-1, RHUCX2 for recombinant human cyclooxygenase-2, r-hu Coxl for recombinant human Cox-1, TEA for triethylamine, TFA for trifluoroacetic acid and THF for tetrahydrofuran and WISH for human amniotic whole-cell cyclooxygenase- 2. The following examples illustrate the method according to the invention, without limitation.

The compounds according to the present invention include, but are not intended to be limited to, the following examples:

Example 1

4-( Methylthio) benzeneboronic acid

A stirred solution of 4-bromothioanisole (5.0 g, 0.0246 mol) in anhydrous tetrahydrofuran (THF) was cooled to -78 °C under a nitrogen atmosphere. A 2.5 M solution of n-butyllithium (12 mL, 0.030 mol) in hexanes was added dropwise to the cooled solution. When the addition was complete, the reaction mixture was stirred at -78 °C for approx. 45 minutes. Trimethyl borate (8.5 mL, 0.0748) was added by syringe. The reaction mixture was then allowed to warm to room temperature overnight. The room temperature solution was treated successively with 10% aqueous sodium hydroxide solution (50 ml) and water (33.5 ml) and stirred at room temperature for 1 hour. The reaction mixture was lowered to approx. pH = 4-5 using 10% aqueous citric acid, and THF was removed under reduced pressure. The aqueous residue was saturated with sodium chloride and extracted with ethyl acetate. The organic extract was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide a white solid which was washed with hexanes to provide the product as a white solid (yield: 1.5 g; 36%). Temp. 170 °C. 3-H NMR (300 MHz, DMSO-de) δ 2.47 (s, 3H), 7.20 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.96 (br s, 2H).

Example 2

2- Benzyl- 4, 5- dibromo- 3( 2H)- pyridazinone

Benzyl bromide (0.59 mL, 0.005 mol) was added to a stirred solution of 4,5-dibromo-3(2H)-pyridazinone (1.27 g, 0.005 mol) and potassium carbonate (0.76 g, 0.0055 mol) ) in 20 ml anhydrous

dimethylformamide (DMF). The solution was stirred overnight at room temperature and partitioned between aqueous citric acid and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide a beige solid, which was purified by column chromatography (silica gel, 9:1 hexanes/ethyl acetate). The product was obtained as a white solid (yield: 1.32 g, 76.7%). Temp. 95-96 °C. <!>h NMR (300 MHz, CDCl 3 ) 55.31 (s, 2H) , 7.29-7.37 (m, 3H) , 7.41-7.47 (m, 2H), 7.79 ( pp, 1H). MS (DCI-NH3) m/z 345 (M+H)<+.> IR (KBr) 1645 cm"<1>.

Example 3

2- Benzyl- 4- bromo- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

A solution of the boric acid (0.318 g, 0.001889 mol) prepared according to the method of Example 1, the dibromopyridazinone (0.975 g, 0.002834 mol) prepared according to the method of Example 2 and tetrakis(triphenylphosphine)palladium (0) (0.16 g , 0.0142 mol), in dimethoxyethane (30 mL) was prepared. A 2 M aqueous solution of sodium carbonate (2.83 mL, 0.005668 mol) was added to the dimethoxyethane solution and the mixture was heated under reflux. After 16 hours, a chromatographic (TLC) test (9:1 hexanes/ethyl acetate) indicated that both starting materials were still present, and a new aliquot of the palladium catalyst was added. The reaction mixture was stirred under reflux for a further 5 hours, allowed to cool to room temperature and stand over the weekend. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was purified by column chromatography (silica gel, 95:5 hexanes/ethyl acetate). Fractions containing the desired product were pooled and concentrated under reduced pressure. This material was re-chromatographed (95:5 hexanes/ethyl acetate) to provide 0.200 g of a beige solid. The solid was crystallized from ether/hexanes to provide white crystals (yield: 110 mg, 15%) mp. 115-118 °C. <1>H NMR (300 MHz, CDCl 3 ) 52.53 (s, 3H), 5.40 (s, 2H), 7.30-7.42 (m, 7H), 7.49-7.54 (m, 2H), 7.65 (s, 1H). MS (DCl-NH 3 ) m/z 387 (M+H)<+>.

Example 4

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

A solution of the product prepared in Example 3, (0.100 g, 0.000258 mol), 4-fluorobenzeneboronic acid (0.072 g, 0.000516 mol), tetrakis(triphenylphosphine)palladium (0) (0.015 g, 0.000013 mol) and a 2 M aqueous solution of sodium carbonate (0.64 mL, 0.001291 mol) in 30 mL of dimethoxyethane (DME) was stirred under reflux for 16 h. A new aliquot of the palladium catalyst was added with an additional equivalent of the boric acid. The reaction was kept under reflux for 24 hours. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was adsorbed on silica gel. The silica gel/product was placed on top of a column of silica gel and the product was eluted with 93:7 hexanes/ethyl acetate. Fractions containing the product were pooled and concentrated under reduced pressure. The residue was further purified by a second column chromatography (silica gel, 95:5 hexanes/ethyl acetate). Fractions containing the product were concentrated under reduced pressure to provide a viscous oil (yield: 0.028 g, 27%). 1 H NMR (300 MHz, CDCl 3 ) δ 2.46 (s, 3H), 5.39 (s, 2H), 6.95 (t, J = 9 Hz, 2H), 6.99 (d, J = 9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H), 7.16-7.23 (m, 2H), 7.30-7.40 (m, 3H), 7.52- 7.57 (m, 2H), 7.86 (s, 1H). MS (DCl-NH 3 ) m/z 403 (M+H)<+>.

Example 5

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

A solution of meta-chloroperoxybenzoic acid (MPCBA) (0.039 g, 0.00013 mol) in dichloromethane (5 mL) was added dropwise to a stirred solution of the sulfide (0.027 g, 0.000067 mol), prepared according to the method of Example 4, in cooled (0 °C) dichloromethane (10 mL). After 5 minutes, TLC (1:1 hexanes/ethyl acetate) indicated that the starting sulfide had been consumed. The reaction was quenched with aqueous sodium sulfite. The organic layer was washed twice with aqueous sodium hydroxide and once with brine. The dichloromethane solution was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate) to provide the desired sulfone product. Further elution with 100% ethyl acetate removed the sulfoxide from the column. The sulfoxide product was again exposed to the MCPBA oxidant (0.04 g, 1 hour, 0 °C) and worked up as described above. The residue obtained was combined with the sulfone from the first column, and the mixture was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate). Fractions containing product were pooled and concentrated under reduced pressure. The residue was crystallized from ether/hexanes to provide the product as white crystals (yield: 13 mg, 44.6%). Temp. 101-103 °C. <1>H NMR (300 MHz, CDCl 3 ) 53.05 (s, 3H), 5.40 (s, 2H), 6.95 (t, J - 9 Hz, 2H), 7.12-7.20 (m, 2H), 7.28-7.41 (m, 3H), 7.31 (d, J= 9 Hz, 2H), 7.58-7.53 (m, 2H), 7.84 ( s, 1H), 7.87 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 435 (M+H)<+>. MS (FAB, high res.) calcd: m/z 435.1179 (M+H}<+>, found: m/z 435.1184 (M+H)<+>).

Example 6

2- Benzyl- 4-( 4- fluorophenyl)- 5- methoxy- 3( 2H)- pyridazinone

To a mixture of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone, prepared according to the method of S. Cho et al. described in J. Het. Chem., 1996,33, 1579-1582, (2.94 g; 10 mmol), 4-fluorobenzeneboronic acid (1.54 g; 11 mmol) and CsF (3.04 g; 22 mmol) in 25 mL of anhydrous DME were , under N2, added Pd(Ph3P)4 (347 mg 0.3 mmol). After the addition, the mixture was heated under reflux at 100°C for 18 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The acetate layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The solid residue was suspended in ethyl ether-hexanes and filtered to provide a solid product (yield: 3.1 g; ca. 100%; > 95% purity). 1K NMR (300 MHz, CDCl 3 ) δ 3.90 (s, 3H), 5.36 (s, 2H), 7.09 (t, J = 9 Hz, 2H), 7.31 (m, 3H), 7.50 (m, 4H), 7.91 (s, 1H). MS (DCl-NH 3 ) m/z 311 (M+H)<+>, 328 (M+NH 4 )<+>.

Example 7

2- Benzyl- 4-( 4- fluorophenyl)- 5- hydroxy- 3( 2H)- pyridazinone

A mixture of the product prepared according to the method of Example 6 (1.24 g; 4 mmol) in 20 ml of acetic acid was treated with aqueous 48% HBr (25 ml). The mixture was heated under reflux for approx. 5 to approx. 8 hours (TLC analysis). The mixture was concentrated in vacuo. The product was dissolved in ethyl acetate, washed with 10% bicarbonate, brine and concentrated in vacuo. The residue was treated with diethyl ether-hexanes (2:1) and the solid was filtered to provide an almost pure product (yield: 1.16 g; 98%). !h NMR (300 MHz, DMSO-de) δ 5, 24 (2H), 7.21 (m, 2H), 7.30

(m, 5H), 7.55 (m, 2H), 7.85 (s, 1H), 11.31 (broad s, 1H). MS (DCI-NH 3 ) m/z 296 (M+HJ<+>, 314 (M+NH 4 )<+>).

Example 8

2- Benzyl- 4-( 4- fluorophenyl)- 5-( trifluoromethylsulfonyloxy)-3( 2H)- pyridazinone

A solution of the product prepared according to the method of Example 7, (89 mg, 0.3 mmol) in 2.5 ml of anhydrous pyridine was prepared under a N 2 atmosphere and kept at 0 °C. Trifluoromethylsulfonic anhydride (Tf 2 O; 0.06 mL; 0.32 mmol) was added to the solution dropwise. The resulting mixture was stirred at 0°C for 5 minutes and at room temperature for 16 hours. (The pyridine and Tf 2 O should be pure to obtain good results. Occasionally an additional amount of Tf 2 O is required to force the reaction to completion.) The mixture was then poured into a cold solution of citric acid and extracted with ethyl acetate to give an almost pure product (yield: 127 mg, approx. 99%) . 3-H NMR (300 MHz, DMSO-d6) 55.34 (s, 2H), 7.35 (m, 7H), 7.60 (m, 2HJ, 8.48

(p, 1H) . MS (DCI-NH3) m/z 429 (M+H)+, 446 (M+NH4)4".

Example 9

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylthio) phenyl]- 3( 2H)-pyridazinone

A mixture of the product prepared according to the method of Example 8 (154 mg, 0.36 mmol), 4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et3N (0.11 mmol; 0.8 mmol) and Pd (Ph3P)4 (30 mg, 0.025 mmol) in 15 mL toluene was heated under reflux, ca. 100 °C for approx. 45 minutes. The mixture was concentrated in vacuo and the residue was purified by column chromatography (hexanes-ethyl acetate 3:1) to provide the title compound (yield: 98 mg, 68%). 3-H NMR (300 MHz,

CDCl3) 8 2.47 (s, 3H) , 5.38 (s, 2H) , 6.98 (m, 4H) , 7.12 (m, 2H), 7.20 (m, 2H), 7, 35 (m, 3H), 7.54 (m, 2H), 7.86 (s, 1H). MS (DCI-NH3) m/z 403 (M+H)<+>, 420 (M+NH4)<+.>

Example 10

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

To a solution of the product prepared according to the method in Example 9 (140 mg, 0.348 mmol), in 10 ml of CH2Cl2, at 0 °C was added peracetic acid (CH3COOOH; 0.5 ml; 30%). The mixture was stirred at 0 °C for 90 minutes. The dichloromethane was then removed in vacuo. The residue was dissolved in ethyl acetate, washed with 10% NaHCO 3 and brine. The ethyl acetate was removed under reduced pressure. The residue was chromatographed

(silica gel, CH 2 Cl 2 -diethyl ether 19:1) to provide the title compound (yield: 130 mg, 86%). <1>h NMR (300 MHz, CDCl 3 ) δ 3.04 (s, 3H) , 5.40 (s, 2H) , 6.95 (m, 2H) , 7.16 (m, 2H), 7, 33 (m, 5H), 7.55 (m, 2H), 7.86 (rn, 3H). MS (DCI-NH3) m/z 434 (M+H)<+>, 452 (M+NH4)<+.>

Example 11

4-( 4- Fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of the product prepared according to the method in Example 10 (37 mg, 0.085 mmol) and AlBr3 (70 mg, 0.26 mmol) in 10 ml of toluene was heated under reflux, approx. 80 °C for approx. 15 minutes and cooled to 0 °C. The cooled mixture was treated with 1N HCl and extracted with ethyl acetate. The acetate layer was washed with water, brine and concentrated in vacuo. Purification of the residue on a silica gel column (ethyl acetate as eluent) gave the title compound (yield: 22 mg, 76%). 1 H NMR (300 MHz, CDCl 3 ) δ 3.07 (s, 3H), 7.00 (t, J = 9 Hz, 2H), 7.20 (m, 2H), 7.56 (d, J = 9 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J = 9 Hz, 2H), 10.94 (broad s, 1H). MS (DCI-NH3) m/z 345 (M+H)<+>, 362 (M+NH4)<+.>

Example 12

2- Phenyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

12A. 2- Phenyl- 4- chloro- 5- methoxy- 3( 2H)- pyridazinone

The 2-Phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone compound was prepared according to the method described by S. Cho et al. described in J. Het. Chem., 1996, 33, 1579-1582, , starting from N-phenyl-dichloropyridazinone. A mixture of 2-phenyl-4,5-dichloro-3(2H)-pyridazinone (1 g, 4.1 mmol) and finely powdered anhydrous K 2 CO 3 (580 mg, 4.2 mmol) in 50 mL methanol was heated under reflux for 5 hours and concentrated in vacuo.

The residue was partitioned between water and ethyl acetate. The acetate layer was washed with water and brine to provide 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg, 95%). <1>1 NMR (300 MHz, DMSO-d 6 ) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS (DCl-NH 3 ) m/z 237 (M+H}<+>, 254 (M+NH 4 )<+>).

12B. 2- Phenyl- 4-( 4- fluorophenyl)- 5- methoxy- 3( 2H)- pyridazinone

The 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone product was coupled with 4-fluorophenylboronic acid according to the method described in Example 6 to provide 2-phenyl-4-(4-fluorophenyl)-5-methoxy -3(2H)-pyridazinone (yield: 1.1 g; 96%). <!>h NMR (300 MHz, CDCl3) δ 4.00 (s, 3H) , 7.10 (t, J=9 Hz, 2H) , 7.45 (m, 3H), 7.60 (m, 4H), 8.06 (s, 1H). MS (DCl-NH 3 ) m/z 297 (M+H)<+>.

12C. 2- Phenyl- 4-( 4- fluorophenyl)- 5- hydroxy- 3( 2H)- pyridazinone

The 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone product was treated with 48% HBr according to the method described in Example 7 to provide 2-phenyl-4-(4- fluorophenyl)-5-hydroxy-3(2H)-pyridazinone (yield: 957 mg, 92%). MS (DCI-NH3) m/z 283 (M+H)<+>, 300 (M+NH4)<+.>

12D. 2- Phenyl- 4-( 4- fluorophenyl)- 5- trifluoromethanesulfonyloxy-3( 2H)- pyridazinone

The 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone product was sulfonylated according to the method described in Example 8 to provide 2-phenyl-4-(4-fluorophenyl)-5 -trifluoromethanesulfonyloxy-3(2H)-pyridazinone (yield: 1.35 g; 96%) MS (DCI-NH3) m/z 415 (M+H)<+>, 432 (M+NH4)<+.>

12E. 2- Phenyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

2-Phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone was coupled with 4-(methylthio)phenylboronic acid as in Example 9 to provide 2-phenyl-4-(4-fluorophenyl)- 5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 915 mg, 92%) which was immediately oxidized with peracetic acid as in Example 9 to provide the title compound after column chromatography (silica gel, 1:1 hexanes- ethyl acetate) and crystallization from diethyl ether-hexanes (yield: 288 mg, 69%). Temp. 219-220 °C. <!>h NMR (300 MHz, DMSO-dg) 53.25 (s, 3H), 7.15 (t, J = 9 Hz, 2H), 7.30 (m, 2H), 7.46 (m , 1H), 7.56 (rn, 4H), 7.64 (m, 2H), 7.90 (d, J = 9 Hz, 2H), 8.24 (s, 1H). MS {DCI-NH 3 ) m/z 421 (M+H)<+>, 438 (M+NH 4 )<+>.

Example 13

4- Fluorophenylacetic acid, methyl ester

A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL methanol. The solution was stirred under reflux for 4 hours. The volatiles were removed under reduced pressure to provide a colorless oil which was dissolved in ether/ethyl acetate and washed with 2 N aqueous Na 2 CO 3 , brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%). <*>H NMR (300 MHz, CDCl 3 ) δ 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J = 9 Hz, 2H), 7.20-7, 28 (m, 2H). MS (DCl-NH 3 ) m/z 186 (M+NH 4 ) 4 -.

Example 14

[ 4-( Methylthio) phenyl] dimethylthioketene acetal, mono- S- oxide

A mixture of methyl (methylsulfinylmethyl) sulfide (50 g, 0.40 mol) and finely powdered sodium hydroxide (3.12 g, 0.078 mol) was stirred at 70 °C for 4 h. 4-(Methylthio)benzaldehyde (27.4 mL, 0.195 mol) was then added in one portion and the reaction mixture was stirred at 70 °C for an additional 4 h. The mixture was cooled to room temperature and partitioned between 10% aqueous citric acid and dichloromethane. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography (7:3 hexanes/ethyl acetate) to provide a solid. The solid was crystallized from ether/hexanes (yield: 24.7 g; 72%). Temp. 52-53 °C. <*>H NMR (300 MHz, CDCl 3 ) δ 2.33 (s, 3H), 2.53 (s, 3H) , 2.77 (s, 3H) , 7.17 (d, J = 9 Hz, 2H), 7.57 (s, 1H), 7.86 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 259 (M+H)<+> °9 m/z 276 (M+NH 4 )<+>.

Example 15

2-( 4- Fluorophenyl)- 3-[ 4-( methylthio) phenyl]- 4- methylthio- 4- methylsulfinyl- n- butyric acid, methyl ester

A solution of the ester product, prepared according to the method of Example 13, (16.24 g, 0.0966 mol) in 50 mL THF was added dropwise to a stirred solution of 1.0 M sodium hexamethyldisilazide in THF (96.6 mL, 0, 0966 mol), kept at 0 °C, under an atmosphere of dry nitrogen. After 30 minutes, a solution of the ketenethioacetal, prepared according to the method of Example 14 (20.8 g, 0.0805 mol), in 50 ml of THF, was added dropwise to the reaction mixture kept at 0 °C. After 4 hours, the reaction mixture was acidified with 10% aqueous citric acid. The aqueous layer was washed twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide a brown oil which was purified by column chromatography (85:15 to 1:1 dichloromethane/ethyl acetate gradient). Several products with different Rf values and NMR spectra were isolated. These compounds had identical mass spectra. The mixture of compounds was taken to the subsequent reactions (yield: 22.4 g; 65%). MS (DCl-NH 3 ) m/z 444 (M+NH 4 )<+.>

Example 16

2-( 4- Fluorophenyl)- 3-[ 4-( methylthio) phenyl]- 3- formyl- n-propanoic acid, methyl ester

The mixture of compounds prepared according to Example 17 (9.0 g, 0.021 mol) was dissolved in acetonitrile (80 mL) and cooled to 0 °C. Perchloric acid (60%; 1.06 g, 0.006 mol) was added to the stirred solution. The reaction mixture was stirred at 0 °C for 8 h, and the reaction was quenched with 2 N aqueous Na 2 CO 3 . The acetonitrile was removed under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate. The organic solution was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate). Fractions containing the highest Rf diastereomers from the product mixture were concentrated in vacuo, and the residue was crystallized from methanol to provide the title aldehyde ester compound as white crystals (yield: 0.27 g, 4.0%). Temp. = 112-113 °C. <1->H NMR (300 MHz, CDCl 3 ) δ 2.49 (s, 3H), 2.46 (s, 3H), 4.39 (s, 2H), 7.03 (t, J = 9 Hz , 1H), 7.21 (d, J = 9 Hz, 1H), 7.25 (d, J = 9 Hz, 2H), 7.40-7.47 (m, 2H). MS (DCI-NH 3 ) m/z 333 (M+H)<+> °9 m/z 350 (M+NH 4 )<+. >Fractions containing lower Rf compounds from the product mixture were concentrated in vacuo, and the residue was identified as the hydrate of the aldehyde ester (yield: 2.6 g, 35.2%). ^H NMR (300 MHz, CDCl3) δ 2.44 & 2.46 (2 s, 3H) , 3.56 & 3.48 (2 s, 3H), 3.55 & 3.76 (2 dd, J = 6 Hz, J = 6 Hz, 1H), 3.98 & 4.26 (2 d, J = 12 Hz, 1H), 5.41 & 5.47 (2 d, J = 6 Hz, 1H), 6.96 & 7.00 (t, J = 9 Hz, 2H), 7.11-7.26 (m, 6H). MS {DCI-NH 3 ) m/z 333 (M+H) + °9 m/z 350 (M+NH 4 )<+>.

The lowest Rf compound was identified as the hydroxyl lactone formed when a hydroxy group from the hydrate is replaced by the methoxy group from the ester (yield: 1.1 g, 16.4%). <!>h NMR (300 MHz, CDCl 3 ) δ 2.45 (s, 3H), 3.54-3.71 (m, 1H), 3.98-4.21 (m, 1H), 4.61 (broad s, 1H), 5.85-6.01 (m, 1H), 6.98 (t, J = 9 Hz, 2H), 7.12-7.27 (m, 6H). MS {DCI-NH 3 ) m/z 336 (M+NH 4 )<+.>

Example 17

4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-4,5-dihydro-3(2H)-pyridazinone

The aldehyde ester, hydrate and hydroxylactone prepared in Example 16 (0.10 g, 3 mmol) were dissolved in 100 ml of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol), and the resulting solution was stirred under reflux in a Soxhelet apparatus containing molecular sieves. After 18 hours, the reaction mixture was cooled and the volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (4:1 hexanes/ethyl acetate) to obtain the title compound (yield: 50 mg, 53%). 1 H NMR (300 MHz, CDCl 3 ) δ 2.46 (s, 3H), 3.75 (d, J = 12 Hz, 1H), 3.87 (d, J = 12 Hz, 1H), 6.93 -7.08 (m, 6H), 7.16 (d, J = 9 Hz, 2H), 8.71 (s(broad), 1H). MS (DCI-NH3) m/z 315 (M+H)<+> and m/z 332 (M+NH4)<+.>

Example 18

4-( 4- Fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 4, 5- dihydro-3( 2H)- pyridazinone

A solution of peracetic acid, 32% in acetic acid, (0.4 ml, 1.6

mmol) was added to a stirred solution of the sulfide, prepared according to the method in Example 17, (0.050 g, 0.16 mmol) in dichloromethane and kept at 0 °C. The reaction mixture was stirred for 5 hours at 0 °C, then diluted with water. The

organic layers were dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide an oil which solidified by trituration with ether (yield: 47 mg, 85%). <!>h NMR (300 MHz, CDCl3) δ 3.05 (s, 3H), 3.77 (d, J = 12 Hz, 1H), 4.05 (d, J = 12 Hz, 1H), 6 .95-7.08 (m, 4H), 7.28 (d, J = 9 Hz, 2H), 7.90 (d, J = 9 Hz, 2H) , 8.75 (s, wide, 1H) . MS (DCl-NH 3 ) m/z 364 (M+NH 4 )<+.>

Example 19

4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The dihydropyridazinone product prepared according to the method of Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 ml). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95 °C for 20 min. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide a solid which was eluted through a short pad of silica gel with ethyl acetate. The title compound was crystallized from ethyl acetate/hexanes (yield: 35 mg, 75%). Temp. 255-256 °C ^ NMR (300 MHz, CDCl 3 ) 53.07 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.16-7.23 (m, 2H), 7 .35 (d, J = 9 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 345 (M+H)<+> °9 m/z 362 (M+NH4)<+.>

Example 20

2-( 4-Fluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

A solution of the nitrogen-unsubstituted pyridazinone product prepared in Example 19 (160 mg, 0.465 mmol), K 2 CO 3 (193 mg, 1.4 mmol), 4-fluorobenzyl bromide (0.09 mL, 0.7 mmol) and Nal (catalytic) in 10 ml of anhydrous N,N-dimethylformamide (DMF) was stirred at room temperature for 18 h. The reaction was quenched with 2N HCl, and the mixture was extracted with ethyl acetate (2 x 20 mL), washed with brine and water, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (2:2:6 ethyl acetate/dichloromethane/pentanes). Crystallization from ether/pentanes gave white crystals (yield: 110 mg, 52%). Temp. 153-154 °C. <1>H NMR (CDCl3, 300 MHz) 53.06 (s, 3H), 5.36 (s, 2H), 6.96 (t, J = 8.4 Hz, 2H), 7.04 (t , J = 8.7 Hz, 2H) , 7.16 (dd, J = 9.1 Hz, J = 5.4 Hz, 2H) , 7.31 (d, J = 8.5 Hz, 2H), 7.54 (dd, J = 8.8 Hz, 5.5 Hz, 2H), 7.84 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H). MS (DCl-NH 3 ) m/z 453 (M+H)<+.>

Example 21

2-( Phenylpropargyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using phenylpropargyl bromide instead of 4-fluorobenzyl bromide. Temp. 100-103 °C. <!>h NMR (CDCl 3 , 300 MHz) 53.06 (s, 3H), 5.26 (s, 2H), 6.97 (t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.31 (m, 3H), 7.34 (d, J = 9 Hz, 2H), 7.48 (m, 2H), 7.89 (d, J = 9 Hz, 2H), 7.9 (s, 1H). MS (DCl-NH 3 ) m/z 459 (M+H)<+>.

Example 22

2-( 2, 4- Difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2,4-difluorobenzyl bromide instead of 4-fluorobenzyl bromide. Temp. 179-182 °C. 3-H NMR (CDCl 3 , 300 MHz) 53.06 (s, 3H), 5.45 (s, 2H), 6.87 (m, 2H), 6.96 (t, J = 9 Hz, 2H) , 7.17 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.32 (d, J = 9 Hz, 2H), 7.54 (m, 1H), 7.86 (s, 1H ), 7.88 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 471 (M+H)<+>.

Example 23

2-( Methyl- 2- propenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 3-chloro-2-methyl-propene instead of 4-fluorobenzyl bromide. Temp. 140-142 °C. 1 H NMR (CDCl 3 , 300 MHz) 51.86 (s, 3H), 3.08 (s, 3H), 4.83 (s, 2H), 4.94 (t, J = 1 Hz, 1H), 5.05 (t, J = 1 Hz, 1H), 6.98 (t, J 9 Hz, 2H), 7.21 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.37 ( d, J 9 Hz, 2H), 7.89 (s, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 399 (M+H)<+>.

Example 24

2-( 3- Methyl- 2- butenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The desired compound was prepared according to the method described in Example 20 using 4-bromo-2-methyl-2-butene instead of 4-fluorobenzyl bromide. Temp. 169-172 °C. 1 H NMR (CDCl 3 , 300 MHz) 51.78 (s, 3H), 1.85 (s, 3H), 3.06 (s, 3H), 4.86 (d, J = 7.5 Hz, 2H ), 5.47 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, J = 6 Hz, 2H) , 7.33 (d, J = 9 Hz, 2H), 7.84 (s, 1H), 7.88 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 413 (M+H)<+.>

Example 25

2-( 2- Trifluoromethylbenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(trifluoromethyl)benzyl bromide instead of 4-fluorobenzyl bromide. Temp. 87-90 °C. <i>H NMR (CDCl 3 , 300 MHz) δ 3.07 (s, 3H) , 5.66 (s, 2H) , 6.97 (t, J = 9 Hz, 2H), 7.21 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.26 (d, J = 7.7 Hz 1H), 7.37 (d, J = 9 Hz, 2H), 7.42 (t J = 7 .7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.73 (d J = 7.7 Hz, 1H), 7.9 (s, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 503 (M+H)<+>.

Example 26

2-( Cyclopropylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(bromomethyl)-cyclopropane instead of 4-fluorobenzyl bromide. Temp. 118-121 °C. <!>h NMR (CDCl 3 , 300 MHz) δ 0.45-0.52 (m, 2H), 0.54-0.63 (m, 2H), 1.40-1.52 (m, 1H) , 3.07 (s, 3H), 4.07 (d, J=7 Hz, 2H), 6.97 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.35 (d, J = 9 Hz, 2H), 7.83 (s, 1H), 7.88 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 399 (M+H)<+> °9 m/z 416 (M+NH4)<+.>

Example 27

2-( 2- Pyridylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(bromomethyl)pyridine instead of 4-fluorobenzyl bromide. Temp. 182-184 °C. 1 H NMR (CDCl 3 , 300 MHz) δ 3.07 (s, 3H), 5.56 (s, 2H), 6.95 (m, 2H), 7.17 (m, 2H), 7.26 ( m, 1H), 7.35 (m, 2H), 7.46 (m, 1H), 7.71 (m, 1H), 7.90 (m, 3H), 8.63 (m, 1H). MS (DCl-NH 3 ) m/z 436 (M+H)<+>.

Example 28

2-( 4- Pyridylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 4-(bromomethyl)pyridine instead of 4-fluorobenzyl bromide. Temp. 153-156 °C. 1 H NMR (CDCl 3 , 300 MHz) δ 3.07 (s, 3H), 5.40 (s, 2H), 6.97 (m, 2H), 7.17 (m, 2H), 7.34 ( m, 2H), 7.42 (m, 2H), 7.90 (m, 3H), 8.63 (m, 2H). MS (DCl-NH 3 ) m/z 436 (M+H)<+.>

Example 29

2- ( 3- Pyridylmethyl)- 4- ( 4- fluorophenyl)- 5- [ 4- ( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 3-(bromomethyl)pyridine instead of 4-fluorobenzyl bromide. Temp. 160-161 °C. 1 H NMR (CDCl 3 , 300 MHz) 83.07 (s, 3H), 5.43 (s, 2H), 6.97 (m, 2H), 7.15 (m, 2H), 7.34 (m , 4H), 7.35 (m, 2H), 7.87 (m, 2H), 7.97 (s, 1H), 8.60 (m, 1H), 8.81 (m, 1H). MS (DCl-NH 3 ) m/z 436 (M+H)<+>.

Example 30

2-( 6-Fluoroquinolin- 2- ylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methyl-sulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(chloromethyl)-6-fluoroquinoline instead of 4-fluorobenzyl bromide. Temp. 116-119 °C. <!>h NMR (CDCl 3 , 300 MHz) δ 3.07 (s, 3H) , 5.73 (s, 2H) , 6.96 (m, 2H), 7.18 (m, 2H) , 7, 34 (m, 4H) , 7.35 (m, 2H) , 7.46 (m, 2H), 7.58 (m, 3H), 7.90 (m, 3H), 8.12 (m, 2H ). MS (DCl-NH 3 ) m/z 504 (M+H)<+>.

Example 31

2-( Quinolin-2- ylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(chloromethyl)-quinoline instead of 4-fluorobenzyl bromide. Temp. 97-100 °C. 1 H NMR (CDCl 3 , 300 MHz) 53.06 (s, 3H), 5.75 (s, 2H), 6.95 (m, 2H), 7.19 (rn, 2H), 7.35 (m , 2H), 7.55 (m, 2H), 7.73 (m, 1H), 7.82 (m, 1H), 7.90 (m, 3H), 8.15 (m, 2H). MS (DCl-NH 3 ) m/z 386 (M+H)<+>.

Example 32

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazine thione

A mixture of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method in Example 5, (109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) in 15 mL toluene was stirred under reflux for 48 h. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, ethyl acetate) to provide the title compound (yield: 100 mg, 88%). Temp. 88-90 °C. <1>H NMR (300 MHz, CDCl 3 } 8 3.04 (s, 3H) , 6.05 (s, 2H) , 6.96 (m, 2H), 7.08 (m, 2H), 7, 26 (m, 2H), 7.37 {m, 3H), 7.61 (m, 2H), 7.84 (d, J = 9 Hz, 2H), 8.13 (s, 1H). MS (DCl-NH 3 ) m/z 451 (M+H)<+>.

Example 33

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)-pyridazinone

33A. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

A solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 4, (450 mg, 1.12 mmol) in CH 2 Cl 2 (10 mL) was added dropwise to a suspension of hydroxy(tosyloxy)-iodobenzene (439 mg, 1.12 mmol) in CH 2 Cl 2 (15 mL) and the mixture was stirred until a clear solution was obtained (ca. 1 h ). The reaction mixture was then washed with water and dried with MgSO 4 . Removal of the solvent in vacuo gave the corresponding sulfoxide (yield: 485 mg, ca. 100%). 1h NMR (300 MHz, CDCl 3 ) δ 2.72 (s, 3H), 5.40 (s, 2H), 6.90 (rn, 2H), 7.15 (m, 3H), 7.33 (m , 3H) , 7.57 (m, 3H), 7.71 (m, 1H), 7.86 (s, 1H). MS (DCI-NH3) m/z 419 (M+H)<+>, 436 (M+NH4)<+.>

33B. Preparation of 2-benzyl-4-(4-fluorophenyl)-5-(acetoxy-methylsulfonylphenyl)-3(2H)-pyridazinone

The sulfoxide was converted to the sulfonam in accordance with a procedure described by M. De Vleeschauwer and J. V. Gautier in Syn. Lett., 1997,375 with the following modifications: A suspension of the sulfoxide, prepared according to the method in Example 33A, (485 mg, 1.12 mmol) and AcONa (1.4 g) in 15 ml of Ac 2 O was stirred under reflux for 2 hours and concentrated in vacuo. The residue was distilled twice with toluene, dissolved in 25 mL CH 2 Cl 2 , cooled to 0 °C and treated with CH 3 CO 3 H (1 mL). After 1 hour, the mixture was washed successively with saturated NaHCO 3 and brine. The solvent was removed in vacuo. The residue was chromatographed {silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, 2-benzyl-4-{4-fluorophenyl)-5-{acetoxymethylsulfonylphenyl)-3(2H)-pyridazinone (yield: 150 mg, 27%). MS (DCl-NH 3 ) m/z 493 (M+H)<+.>

33C Preparation of 2-benzyl-4-(4-fluorophenyl)-5-[4-(sodium sulfinate)phenyl]-3(2H)-pyridazinone

To a solution of the acetoxymethylsulfone prepared according to the method in Example 33B, (150 mg, 0.305 mmol), in 10 ml of THF and 5 ml of methanol at 0 °C was added 1 N NaOH (0.305 ml, 0.305 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated in vacuo, the remaining water was removed via an EtOH/toluene azeotropic distillation followed by toluene azeotropic distillation. The residue was dried under high vacuum for 48 hours to provide the sodium sulfinate (yield: 140 mg, 96%). MS {DCI-NH 3 ) m/z 443 (M+H) +

33D. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(chlorosulfonyl)phenyl]-3(2H)-pyridazinone

The sodium sulfinate (ca. 0.31 mmol) in CH 2 Cl 2 (10 mL) was treated at 0 °C with SOCl 2 (0.033 mL, 0.4 mmol) for 2 h. The mixture was washed with brine, dried with MgSO 4 and concentrated in vacuo to provide the crude sulfonyl chloride (yield: 145 mg, ca. 100%). MS (DCl-NH 3 ) m/z 455 (M+H)<+>.

33E. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The crude chloride prepared according to the method of Example 33D, in 10 ml THF, was added to a solution of 50% NH 4 OH, in 10 ml THF, kept at 0 °C. The mixture was allowed to warm to room temperature within 3.5 hours. The THF was removed in vacuo and the product was extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the residue was treated with diethyl ether-hexanes 2:1 to provide the sulfonamide (yield: 113 mg, 84%). Temp. 188-191 °C. <3->H NMR (300 MHz, DMSO-d6) δ 2.70 (dd, J = 15 Hz, 2H), 5.36 (s, 2H), 7.13 (t, J = 9 Hz, 2H ), 7.22 (m, 2H), 7.40 (ra, 7H), 7.73 (d, J = 9 Hz, 2H), 8.11 (s, 1H). MS (DCl-NH 3 ) m/z 436 (M+H)<+>.

Example 34

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-iodo-1,1,1-trifluoroethane instead of 4-fluorobenzyl bromide. Temp. 177-179 °C. <!>h NMR (CDCl 3 , 300 MHz) δ 3.06 (s, 3H) , 4.88 (q, J = 9

Hz, 2H), 6.98 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.35 (d, J = 9 Hz, 2H ), 7.89 (s, 1H), 7.91 (d, J = 9 Hz, 2H) . MS (DCI-NH3) m/z 427 (M+H)<+><0>(3 m/z 444 (M+NH4) + .

Example 35

2-( 3, 3- Dichloro- 2- propenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 1,1,3-trichloro-propene instead of 4-fluorobenzyl bromide. Temp. 150-152 C. <i>H NMR (CDCl 3 , 300 MHz) δ 3.06 (s, 3H) , 4.98 (d, J = 7 Hz, 2H) , 6.25 (t, J = 7 Hz , 1H), 6.98 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.33 (d, J = 9 Hz, 2H) , 7.85 (s, 1H) , 7.89 (d, J = 9 Hz, 2H) . MS (DCI-NH3) m/z 453 (M+H)<+><0<>3 m/z 470 (M+NH4)<+.>

Example 36

2-( 3- Phenyl- 2- propenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using cinnamyl bromide instead of 4-fluorobenzyl bromide. Temp. 165-167 °C. NMR (CDCl 3 , 300 MHz) 53.06 (s, 3H), 5.01 (d, J = 7 Hz, 2H), 6.48 (dt, J = 15 Hz, 7 Hz, 1H), 6.79 (d, J = 15 Hz, IH), 6.97 (t, J = 9 Hz, 2H) , 7.19 (dd, J = 9 Hz, J = 6 Hz, 2H)., 7, 25-7 .44 (m, 5H), 7.37 (d, J = 9 Hz, 2H), 7.86 (s, 1H), 7.89 (d, J = 9 Hz, 2H) . MS (DCI-NH3) m/z 461 (M+H)<+> °9 m/z 478 (M+NH4)<+.>

Example 37

2-( 4- Carboxyphenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using methyl 4-(bromomethyl)benzoate instead of 4-fluorobenzyl bromide and hydrolysis of the resulting ester. Temp. 239-241 °C. 1 H NMR (CDCl 3 , 300 MHz) 53.06 (s, 3H), 5.46 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.17 (dd, J = 9 Hz, 6 Hz, 2H), 7.33 (d, J = 9 Hz, 2H), 7.63 (d, J = 9 Hz, 2H), 7.87 (s, IH), 7.89 (d , J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 479 (M+H)<+> °9 m/z 496 (M+NH4)<+.>

Example 38

2-( 5- Methylthiazol- 2- ylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(bromomethyl)-5-methylthiazole instead of 4-fluorobenzyl bromide. Temp. 114-116 °C. <1>H NMR (d6~DMSO, 300 MHz) δ 2.64 (s, 3H), 3.23 (s, 2H), 5.37 (s, 2H}, 7.13 (ra, 2H), 7.23 (m, 2H), 7.40 (s, IH), 7.47 (d, J - 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 8.10 ( s, 1H).MS (DCI-NH3) m/z 356 (M+H)<+.>

Example 39

2-( 5- Chlorothiazol-2- ylmethyl)- 4-( 4- fluorophenyl)- 5- [ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method

described in Example 20, using 2-(bromomethyl)-5-chlorothiazole instead of 4-fluorobenzyl bromide. Temp. 185-186 °C. <!>h NMR (d 6 -DMSO, 300 MHz) δ 2.32 (s, 3H), 5.50 (s, 2H), 7.15 (m, 2H), 7.24 (m, 2H), 7.47 (m, 2H), 7.87 (m, 3H), 8.14 (s, 1H). MS (DCI-NH3) m/z 476 (M+H)<+> °9 m/z 493 (M+NH4)<+.>

Example 40

2-( 2, 3, 3, 4, 4, 4- Hexafluoro- n- buten- l- yl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2,2,3,3,4,4,4-heptafluoro-1-iodobutane instead of 4-fluorobenzyl bromide. Under the alkylation conditions, elimination of HF gave the unsaturated product. Temp. 167-169 °C. <1>H NMR (CDCl3, 300 MHz) 83.07 (s, 3H), 7.00 (t, J = 9 Hz, 2H), 7.17 (dd, J - 9 Hz, 6 Hz, 2H) , 7.33 (d, J = 9 Hz, 2H), 7.68 (d, J = 24 Hz, IH), 7.93 (d, J = 9 Hz, 2H), 8.01 (s, IH ). MS (DCI-NH3) m/z 507 (M+H)<+> °9 m/z 524 (M+NH4)<+.>

Example 41

2-( 2, 4- Difluorophenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-chloro-2',4'-difluoroacetophenone instead of 4-fluorobenzyl bromide. Temp. 191-192 °C. <1>H NMR (CDCl3, 300 MHz) δ 3.08 (s, 3H), 5.57 (d, J = 3 Hz, 2H), 6.94-7.07 (m, 2H), 6, 96 (t, J = 9 Hz, 2H), 7.39 (dd, J = 9 Hz, 6 Hz, 2H), 7.91 (s, IH), 7.91 (d, J = 9 Hz, 2H ), 8.03-8.12 (m, IH). MS (DCI-NH3) m/z 499 (M+H)<+> °9 m/z 516 (M+NH4)<+.>

Example 42

2-( 5- Chlorthien- 2-ylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methyl-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method

described in Example 20, using 2-(bromomethyl)-5-chlorothiophene instead of 4-fluorobenzyl bromide. Temp. 139-141 °C. <!>h NMR (d6-DMSO, 300 MHz) δ 3.23 (s, 3H) , 5.43 (s, 2H) , 7.03 (d, J = 4 Hz, 1H), 7.09- 7.29 (m, 5H), 7.47 (d, J = 8 Hz,

2H), 7.87 (d, J = 8 Hz, 3H), 8.13 (s, 1H). MS (DCI-NH3) m/z 474 (M+H)<+> °g m/z 492 (M+NH4)<+.>

Example 4 3

2-( 5- Methylthien- 2-ylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methyl-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-(bromomethyl)-5-methylthiophene instead of 4-fluorobenzyl bromide. Temp. 172-175 °C. <1>H NMR (d6~DMSO, 300 MHz) δ 3.22 (s, 3H), 5.49 (s, 2H), 7.03 (m, 1H), 7.14 (m, 2H), 7.23 (m, 3H), 7.48 (m, 3H), 7.86 (m, 2H), 8.11 (s, 1H). MS (DCI-NH3) m/z 441 (M+H)<+> °Q m/z 458 <M+NH4)<+.>

Example 4 4

2-( 4- Diethylaminophenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-chloro-4'-diethylaminoacetophenone instead of 4-fluorobenzyl bromide. Temp. 105-108 °C. <X>H NMR (CDCl 3 , 300 MHz) 81.23 (t, J = 7 Hz, 3H), 3.07 (s, 3H), 3.44 (q, J = 7 Hz, 2H), 5, 61 (s, 2H) , 6.66 (d, J = 9 Hz, 2H), 6.94 (t, J = 9 Hz, 2H), 7.21 (dd, J = 9 Hz, 6 Hz, 2H ), 7.38 (d, J = 9 Hz, 2H), 7.87-7.94 (m, 4H), 7.90 (s, 1H). MS (DCl-NH 3 ) m/z 534 (M+H)<+>.

Example 4 5

2- ( 2, 3, 4, 5, 6- Pentafluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method

described in Example 20, using 2,3,4,5,6-penta-fluorobenzyl bromide instead of 4-fluorobenzyl bromide. Temp. 115-116 °C. <i>H NMR (CDCl 3 , 300 MHz) 3.06 (s, 3H), 5.50 (s, 2H) , 6.96 (t, J = 9 Hz, 2H) , 7.17 (dd, J = 9 Hz, 6 Hz, 2H), 7.33 (d, J = 9 Hz, 2H), 7.82 (s, 1H), 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 525 (M+H) + °V m/z 542 (M+NH 4 )<+>.

Example 4 6

2-( Phenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H )- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-bromoacetophenone instead of 4-fluorobenzyl bromide. Temp. 228-230 °C. <X>H NMR

(CDC13, 300 MHz) 3.07 (s, 3H), 5.68 (s, 2H), 6.95 {t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, 6 Hz, 2H), 7.38 (d, J = 9 Hz, 2H), 7.53 (t, J = 7 Hz, 2H), 7.65 (t, J = 7 Hz, IH), 7.90 (d, J = 9 Hz, 2H), 7.91 (s, 1H), 8.04 (d, J = 7 Hz, 2H). MS {DCI-NH 3 } m/z 463 (M+H) + °9 m/z 480 (M+NH 4 )<+>.

Example 47

2-( 4- Chlorophenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-bromo-4'-chloroacetophenone instead of 4-fluorobenzyl bromide. Temp. 186-188 °C. <1>H NMR (CDCl3, 300 MHz) 3.07 (s, 3H), 5.63 (s, 2H), 6.95 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H)( 7.38 (d, J = 9 Hz, 2H), 7.51 (d, J = 9 Hz, 2H), 7.65 (t, J = 7 Hz, IH ), 7.90 (d, J = 9 Hz, 2H), 7.91 (s, 1H), 7.98 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 497 ( M+H)<+> °9 m/z 514 (M+NH4)<+>.

Example 48

2-( Propargyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using propargyl bromide instead of 4-fluorobenzyl bromide. Temp. 196-198 °C. <1>H NMR (CDCl3, 300 MHz) 2.42 (t, J = 3 Hz, 1H), 3.06 (s, 3H), 5.04 (d, J = 3 Hz, 2H), 6, 97 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.34 (d, J = 9 Hz, 2H), 7.90 (s, IH ), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 383 (M+H)<+><<=>>q m/z 400 (M+NH 4 )<+>.

Example 4 9

2-( 4- Cyanophenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-bromo-4'-cyano-acetophenone instead of 4-fluorobenzyl bromide. Temp. 188-189 °C. T-H NMR (CDCl 3 , 300 MHz) 3.08 (s, 3H), 5.64 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz , 6 Hz, 2H), 7.38 (d, J = 9 Hz, 2H), 7.84 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H), 7 .93 (s, 1H), 8.14 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 488 (M+H)<+> .

Example 50

2-( g- Methyl- 4- fluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using α-methyl-4-fluorobenzyl bromide instead of 4-fluorobenzyl bromide. Temp. 162-164 °C. <1>R NMR (CDCl 3 , 300 MHz) 3.06 (s, 3H), 6.40 (t, J = 9 Hz, 2H), 6.95 (t, J = 9 Hz, 2H), 7, 05 (t, J = 9 Hz, 2H), 7.15 (dd, J = 9 Hz and 6 Hz, 2H), 7.31 (d, J = 9 Hz, 2H), 7.53 (dd, J = 9 Hz and 6 Hz, 2H), 7.87 (d, J = 9 Hz, 2H), 7.88 (s, IH). MS (DCI-NH 3 ) m/z 467 (M+H)<+> °9 m/z 484 (M+NH 4 )<+> .

Example 51

2- Phenethyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using (2-bromomethyl)benzene instead of 4-fluorobenzyl bromide. Temp. 170-171 C. <i>H NMR (CDCl 3 , 300 MHz) 3.07 (s, 3H), 3.20 (t, J = 9 Hz, 2H), 4.28 (t, J = 9 Hz, 2H), 6.98 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz and 6 Hz, 2H), 7.22-37 (m, 5 H), 7.34 ( d, J = 9 Hz, 2H), 7.83 (s, 1H), 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 449 (M+H)<+> °9 m/z 466 (M+NH 4 )<+> .

Example 52

2- Benzyl- 4-( 3- chloro- 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Examples 6-10 using 3-chloro-4-fluorobenzeneboronic acid instead of the 4-fluorobenzeneboronic acid used in Example 6. M.p. 134-136 °C. <1>H NMR (CDCl 3 , 300 MHz) 3.06 (s, 3H), 5.41 (s, 2H), 6.96-7.02 (m, 2H), 7.29-7.41 ( m, 3H), 7.33 (d, J = 9 Hz, 2H), 7.51-7.56 (m, 2H), 7.85 (s, IH), 7.91 (d, J = 9 Hz, 2H). MS {DCI-NH 3 ) m/z 469 (M+H)<+> °9 m/z 486 (M+NH 4 )<+> .

Example 53

2- Benzyl- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

The title compound was prepared according to the method described in Examples 6-10, except that 4-chlorobenzeneboronic acid was used instead of the 4-fluorobenzeneboronic acid used in Example 6. M.p. 157-159 °C. <X>H NMR (CDCl 3 , 300 MHz) 3.05 (s, 3H), 5.40 (s, 2H), 7.11 (d, J = 9 Hz, 2H), 7.24 (d, J = 9 Hz, 2H), 7.28-7.40 (rn, 2H), 7.31 (d, J = 9 Hz, 2H), 7.51-7.57 (m, 2H), 7.84 (s, 1H), 7.88 (d, J = 9 Hz, 2H). MS

(DCI-NH 3 ) m/z 451 (M+H)<+> °9 m/z 468 (M+NH 4 )<+>.

Example 54

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- chloro- 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by N-debenzylation of the product prepared in Example 52 according to the method described in Example 11, followed by alkylation with 2-iodo-1,1,1-trifluoroethane according to the method described in Example 20. M.p. 165-166 °C. 1-H NMR (CDCl 3 , 300 MHz) 3.07 {s, 3H), 4.89 (q, J = 9 Hz, 2H), 7.00-7.06 (m, 2H), 7.31- 7.35 <m, 1H), 7.37 (d, J = 9 Hz, 2H), 7.90 (s, 1H), 7.94 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 461 (M+H)<+> °9 m/z 478 (M+NH 4 )<+>.

Example 55

2-( 4- Trifluoromethoxyphenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-bromo-4'-trifluoromethoxyacetophenone instead of 4-fluorobenzyl bromide. Temp. 160-161 °C. <1>H NMR (CDCl3, 300 MHz) 3.08 (s, 3H), 5.65 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, 6 Hz, 2H), 7.37 (d, J = 9 Hz, 2H) , 7.91 (d, J = 9 Hz, 2H) , 7.93 (s, IH) , 8.11 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 547 (M+H)<+> °<3 m/z 564 (M+NH4)<+.>

Example 56

2-( 4- Trifluoromethylphenacyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 2-bromo-4<1->trifluoromethylacetophenone instead of 4-fluorobenzyl bromide. Temp. 205-206 °C. <!>h NMR (CDCl 3 , 300 MHz) 3.07 (s, 3H), 5.66 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, 6 Hz, 2H), 7.38 (d, J = 9 Hz, 2H), 7.80 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H ), 7.92 (s, 1H), 8.15 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 531 (M+H)<+> °g. m/z 548 (M+NH4)<+.>

Example 57

2-[ 2-( Benzofb] thien- 3- yl)- 2- oxoethyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 3-chloroacetyl-benzo[b]thiophene instead of 4-fluorobenzyl bromide. Temp. 183-184 °C. 1 H NMR (CDCl 3 , 300 MHz) 3.08 (s, 3H), 5.68 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.21 (dd, J = 9 Hz , 6 Hz, 2H) , 7.39 (d, J = 9 Hz, 2H), 7.42-7.54 (m, 2H), 7.91 (d, J = 9 Hz, 2H), 7, 91 (d, J = 7 Hz, IH), 7.94 (s, IH), 8.53 (s, IH), 8.72 (d, J = 7 Hz, IH). MS (DCl-NH 3 ) m/z 519 (M+H)<+>.

Example 58

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by N-debenzylation of the product, prepared in Example 54 according to the method described in Example 12, followed by alkylation with 2-iodo-1,1,1-trifluoroethane according to the method described in Example 20. M.p. 55-57 °C. <3->H NMR (CDCl3, 300 MHz) 3.07 (s, 3H), 4.88 (q, J = 9 Hz, 2H), 7.13 (d, J = 9 Hz, 2H), 7 .26 (d, J = 9 Hz, 2H), 7.36 (d, J = 9 Hz, 2H) , 7.89 (s, IH), 7.92 (d, J = 9 Hz, 2H) . MS (DCI-NH3) m/z 443 (M+H)<+> °9 m/z 460 (M+NH4)<+.>

Example 59

2-( 3, 3- Dimethyl- 2- oxobutyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 1-bromopinacolone instead of 4-fluorobenzyl bromide. Temp. 168-170 °C. 1 H NMR (CDCl 3 , 300 MHz) 1.31 (s, 9H), 3.06 (s, 3H), 5.21 (s, 2H), 6.95 (t, J = 9 Hz, 2H), 7.17 (dd, J = 9 Hz, 6 Hz, 2H) , 7.35 (d, J = 7 Hz, 2H), 7.86 (s, IH) 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 443 (M+H)<+><oq> m/z 460 (M+NH 4 )<+>.

Example 60

2-( 3- Thienylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 3-(chloromethyl)-thiophene instead of 4-fluorobenzyl bromide. Temp. 169-172 °C. 3-H NMR (300 MHz, DMSO dg) δ 3.22 (s, 3H) , 5.36 (s, 2H) , 7.18 (m, 5H), 7.51 (m, 4H), 7, 88 (m, 2H); 8.08 (p, 1H). MS (DCI-NH3) m/z 441 (M+H)<+> and m/z 458 (M+NH4)<+.>

Example 61

2-( 2- Benzo[ b ] thienylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20 using 2-(chloromethyl)-benzo[b]thiophene instead of 4-fluorobenzyl bromide. Temp. 93-96 °C. <i>H NMR (300 MHz, CDCl 3 ) 6 3.05 (s, 3H) , 5.64 (s, 2H) , 6.97 (m, 2H), 7.18 (m, 2H), 7, 33 (m, 5H), 7.78 (m, 2H), 7.86 (m, 3H). MS (DCI-NH 3 ) m/z 491 (M+H)<+> and m/z 508 (M+NH 4 )<+>.

Example 62

2, 4- Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A mixture of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172 mg, 0.5 mmol), prepared according to the method of Example 10, Cu powder (32 mg), anhydrous K2CO3 (207 mg, 1.5 mmol) and 4-fluoroiodobenzene (0.12 mL, 1 mmol) were prepared in 20 mL of pyridine. The solution was stirred under reflux for 14 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 10% citric acid, water, brine and concentrated in vacuo. Separation by column chromatography (silica gel, CH2Cl2-diethyl ether 15:1) gave 190 mg of crude product. Crystallization from CH2Cl2~diethyl ether-hexanes afforded the title compound (yield: 175 mg, 79.9%). Temp. 168-169 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 3.07 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.20 (rn, 4H), 7.40 (d, J = 9 Hz, 2H), 7.69 (m, 2H), 7.92 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS (DCl-NH 3 ) m/z 439 (M+H)<+>, 456 (M+NH 4 )<+>. Anal. calcd for C 23 H 16 F 2 N 2 O 3 S-0.25 H 2 O: C, 62.36; H, 3.75; N, 6.32. Found: C, 62.23; H, 3.55; N, 6.26.

Example 63

4-( 4- Fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 6- methyl- 3( 2H) - pyridazinone

The 5-hydroxy-5-methyl-2(5H)-furanone prepared via the methods described above (454 mg, 1.25 mmol) was dissolved in n-butanol (10 mL) and treated with hydrazine hydrate (0.3 mL, 6 .2 mmol) and stirred under reflux for 18 hours. On cooling, white crystals (224 mg, 50%) were obtained. Temp. 290 °C (decomposition) T<->HNMR (300 MHz, de-DMSO) 51.99 (s, 3H) , 3.10

(s, 3H), 7.05 (t, J = 9 Hz, 2H), 7.15 (dd, J 6 Hz, J = 9 Hz, 2H), 7.48 (d, J = 9 Hz, 2H ), 7.85 (d, J = 9 Hz, 2H), 13.10 (br s, IH). MS (DCl/NH 3 ) 376 (M+NH 4 )<+>. Anal. calculated

for C 18 H 15 N 2 FSO 3 0.25 H 2 O: C, 59.57; H, 4.30; N, 7.71.

Found: C, 59.28; H, 4.39; N, 8.39

Example 64

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 6- methyl- 3( 2H)- pyridazinone

The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in the presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60 °C for 2 h. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%). ^HNMR (300 MHz, CDCl3) 52.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J = 9 Hz, 2H), 6.90 (rn, 2H), 7 .10 (dd, J = 6 Hz, J = 9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J = 9 Hz, 2H), MS (DCI/NH3) 458 (M +NH4)<+> Anal. calcd for C20HI6N2F4SO3: c, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N, 6.35.

Example 65

2- Benzyl- 4-( 3, 4- dichlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3(2H)- pyridazinone

The title compound was prepared by coupling 3,4-dichloro-phenylboronic acid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) according to to the method described in Example 6. This product was converted to the 5-hydroxy derivative according to the method described in Example 7. The 5-hydroxy compound was converted to the 5-trifluoromethylsuphonyloxy derivative according to the method described in Example 8. Coupling of 4-(methylthio)phenylboronic acid to the triflate according to the method described in Example 9 gave the 5-[4-(methylthio)phenyl]-intermediate which was oxidized according to the method described in Example 10 to provide the final product (yield: 780 mg, 84%). Temp. 161-163 °C. <!>h NMR (300 MHz, DMSO-d6) δ 3.22 (s, 3H), 5.35 (s, 2H), 7.08 (dd, J = 9 Hz, 3 Hz, 1H), 7 .32-7.44 (m, 5H), 7.47 (dd, J = 9 Hz, 3 Hz, 3H), 7.48 (d, J = 3 Hz, IH), 7.90 (d, J = 9 Hz, 2H), 8.13 (s, 1H). MS (DCI-NH3) m/z 485 (M+H)<+.> Anal. calcd for C 24 H 18 Cl 2 N 2 O 3 S: C, 59.38; H, 3.73; N, 5.77. Found: C, 59.28; H, 3.92; N, 5.42.

Example 66

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- n- propylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by coupling 4-(n-propyl)-phenylboronic acid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) according to the method described in Example 6. This product was converted to the 5-hydroxy derivative according to the method described in Example 7. This product was converted to the 5-trifluoromethyl-suphonyloxy derivative according to the method described in Example 8. Coupling of 4-(methylthio)phenylboronic acid to the triflate according to the method described in Example 9 gave the 5-[4-(methylthio)phenyl]-intermediate which was oxidized according to the method described in Example 10 to provide the final product (yield: 220 mg , 70%). Temp. 64-66 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 0.91 (t, J = 7.5 Hz, 3H), 1.6 (h, J = 7.5 Hz, 2H), 2.55 (q, J = 7.5 Hz, 2H), 3.05 (s, 3H), 4.88 (q, J = 9 Hz, 2H), 7.08 (s, 4H), 7.35 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 7.87 (s, 1H). MS (DCl-NH 3 ) m/z 451 (M+H)<+>. Anal. calcd for C 22 H 21 F 3 N 2 O 3 S: c, 58, 65; H, 4.69; N, 6.21. Found: C, 58.71; H, 4.72; N, 6.20.

Example 67

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- chloro- 3- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by first coupling 3-fluoro-4-chlorophenylboronic acid with 2-benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone according to the method described in Example 6. The product was converted to the 5-hydroxy compound in according to the method described in Example 7. This 5-hydroxy compound was converted to the 5-trifluoromethylsuphonyloxy derivative according to the method described in Example 8. Coupling of 4-(methylthio)phenylboronic acid to the triflate according to the method described in Example 9 gave The 5-[4-(methylthio)phenyl] intermediate was oxidized according to the method described in Example 10 to provide the final product (yield: 170 mg, 84%). Temp. 174-175 °C. <*>H NMR (300 MHz, CDCl 3 ) δ 3.09 (s, 3H) , 4.89 (q, J = 9 Hz, 2H) , 6.87 (dm, J 9 Hz, 1H), 7, 09 (dd, J = 9 Hz, 3 Hz, IH), 7.30 (t, J = 9 Hz, IH), 7.39 (d, J = 9 Hz, 2HJ, 7.91 (s, IH) , 7.95 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 461 (M+H)<+>. Anal. calcd for C19H13CIF4N2O3S: C, 49.52; H, 2, 84; N, 6.07. Found: C, 49.66; H, 2.70; N, 5.96.

Example 68

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (680 mg, 1.53 mmol) in trifluoroacetic anhydride (30 mL) was stirred at room temperature for 1 hour. The excess solvent was evaporated in vacuo, and the residue was treated with a deoxygenated IN solution of methanol-NaOH (50 mL, 4:1) at 0 °C. The solution was stirred at room temperature for 2 hours, and the reaction was quenched with dilute HCl solution until

the solution was sour. The white suspension that formed was concentrated in vacuo to evaporate the methanol. THF was added to the resulting suspension until a clear solution was obtained. Chlorine gas was slowly bubbled into the solution which was kept at 0°C. After 10 minutes, nitrogen gas was bubbled into the solution for a few minutes to remove residual chlorine. Ammonium hydroxide solution (30%, 5 to 10 mL), at 0 °C, was slowly added to the solution (to

consume all starting sulfonyl chloride) and stirred at room temperature for 5 minutes. The solution was partitioned between water and ethyl acetate. The organic layer was washed first with water, then brine and dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (40:60 ethyl acetate/hexanes) to provide the title compound (yield: 500 mg, 75%). Temp. 193-195 °C. 3-H NMR (300 MHz, CDCl 3 ) 54.82 (s, 2H), 4.88 (q, J = 9 Hz, 2H), 6.98 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.30 (d, J = 9 Hz, 2H), 7.88 (d, J = 9 Hz, 2H), 7.90 (s, IH) . MS (DCl-NH 3 ) m/z 428 (M+H)<+>. Anal. calcd for C18H13F4N3O3S: C, 50.58; H, 3.06; N, 9.83. Found: C, 51.04; H, 3.26; N, 9.63.

Example 69

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- chlorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

69A. 2- Benzyl- 4- chloro- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 77. The product was coupled with 4-chlorophenylboronic acid according to the method described in Example 6. The product was N-debenzylated according to the method described in Example 11 and N-alkylated with 2-iodo- 1,1,1-trifluoroethane according to the method described in Example 20 to provide the sulfide compound.

69B. 2- Benzyl- 4- chloro- 5-[ 4-( methylsulfinyl) phenyl]- 3( 2H)- pyridazinone

The sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid to provide the corresponding methyl sulfoxide which was converted to the final sulfonamide product according to the method described in Example 68 (yield: 540 mg, 70%). Temp. 154-156 °C.

<1>h NMR (300 MHz, CDCl3) 6 4.86 (s, 2H) , 4.87 (q, J = 9 Hz, 2H), 7.14 (d, J = 9 Hz, 2H), 7 .29 (d, J = 9 Hz, 2H), 7.31 (d, J = 9 Hz, 2H), 7.89 (d, J = 9 Hz, 2H), 8.00 {s, IH). MS (DCl-NH 3 ) m/z 444 (M+H)<+>. Anal. calcd for C18H13CIF3N3O3S: C, 48.71; H, 2.95; N, 9.46. Found: C, 49.05; H, 3.01; N, 9.15.

Example 70

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The methyl sulfide intermediate prepared in Example 83 was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the sulfonamide final product according to the method described in Example 68 (yield: 396 mg, 60%). Temp. 158-160 °C. <X>H NMR (300 MHz, CDCl 3 ) 51.21 (d, J - 6 Hz, 6H), 4.83 (q, J = 7.5 Hz, 2H), 4.86 (s, 2H), 5.46 (p, J = 6 Hz, IH), 7.72 (d, J 9 Hz, 2H), 7.82 (s, IH), 8.03 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 392 (M+H)<+.> Anal. calcd for C15H16F3N3O4S: C, 46.03; H, 4.12; N, 10.73. Found: C, 46.08; H, 4.22; N, 10.52.

Example 71

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The methyl sulfide intermediate of Example 76 was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the final sulfonamide product according to the method described in Example 68 (yield: 180 mg, 37%). Temp. 150-152 °C. <1>H NMR (300 MHz, CDCl 3 ) 84.71 (q, J = 7.5 Hz, 2H) , 4.72 (s, 2H) , 6.88 (dd, J = 9 Hz, 4.5 Hz, 2H), 7.0 (t, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H), 7.98 (s, IH), 8.05 (d, J = 9 Hz, 2H). MS {DCI-NH3) m/z 444 (M+H)<+.> Anal. calcd for C18H13F4N3O4S: C, 48.76; H, 2.95; N, 9.47. Found: C, 48.49; H, 2.8; N, 8, 95.

Example 72

2, 4- Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

72A- 1. 2- Fluorothioanisole

A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirred at room temperature for 1 hour. A thin layer chromatography sample (100% hexanes) indicated that the reaction was not complete, therefore an additional equivalent of base and iodomethane was added and the reaction mixture was stirred overnight at room temperature. The reaction was acidified with 10% aqueous citric acid and extracted with hexanes (2 x 125 mL). The combined organic extracts were washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound as a pale yellow oil (yield: 6.68 g; 60%).

72A- 2. 2- Fluorothioanisole

An alternative method to prepare 2-fluorothioanisole begins with a solution of 1,2-difluorobenzene (0.79 mL, 8 mmol) in anhydrous DMF (50 mL) was treated with sodium thiomethoxide (0.59 g, 8 mmol). The reaction mixture was stirred at room temperature for 6 hours and partitioned between hexanes and water. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound (1.1 g, 100%) somewhat contaminated with 1,2-bis(methylthio)benzene, a lower Rf material, which was removed by chromatography with 100% hexanes (0.9 g, 80%).

NMR (300 MHz r CDCl 3 ) δ 2.46 (s, 3H), 6.98-7.19 (m, 3H) 2.26 (dt, J = 9 Hz, 3 Hz, 1H).

72B. 4- Bromo- 2- fluorothioanisole

A solution of 2-fluorothioanisole (1.42 g, 10 mmol) and iron powder (0.03 g, 0.5 mmol) in dichloromethane (20 mL) was cooled to °C and treated dropwise with bromine (0.5 ml, 10 mmol). When bromination was complete, the reaction mixture was examined by TLC (100% hexanes). A new material with a higher Rf was present, but the reaction was not complete, so an additional equivalent of bromine was added along with a catalytic amount of aluminum chloride. The reaction mixture was stirred overnight at room temperature. Aqueous sodium sulfite was added to the reaction mixture and the organic layer was isolated, dried over MgSO 4 and filtered. The filtrate was filtered through a pad of silica gel to remove color, then concentrated under reduced pressure to provide the product as a clear, colorless oil (yield: 1.3 g; 60%). <!>h NMR (300 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.31 (t, J = 9 Hz, 1H), 7.43 (dd, J = 9 Hz, 3 Hz , IH) 7.54 (dd, J = 9 Hz, 3 Hz, IH).

72C. 3- Fluoro- 4-( methylthio) benzeneboronic acid

A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol) in dry THF (20 mL) was cooled to -78 °C under a nitrogen atmosphere. The reaction mixture was treated with 1.6 M n-butyllithium in hexanes (1.7 mL, 27.1 mmol) and the mixture was warmed to -40°C where it was held for 0.5 h. The reaction mixture was then cooled to -78°C, and three equivalents of triisopropyl borate (1.56 mL, 67.8 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hours. At this point, 10% aqueous KOH (200 mL, 360 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into an ice/concentrated HCl mixture with stirring to provide a white precipitate. This solid was dried in a vacuum oven (65 °C, 29 in Hg) overnight to provide the title compound (yield: 0.22 g; 52.4%). <*>H NMR (300 MHz, DMS0-d6) δ 2.48 (s, 3H), 7.31 (t, J = 9 Hz, 1H), 7.49 (dd, J = 12 Hz, 1, 5 Hz, IH) 7.54 (dd, J = 9 Hz, 1.5 Hz, IH).

72D. 2, 4- Bis-(4- fluorophenyl)- 5-[ 3- fluoro- 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy analogue according to the method described in Example 7 and then to the 5-trifluoromethylsulfonyloxy analogue according to the method described in Example 8. Subsequent coupling to 3-fluoro-4-(methylthio)phenylboronic acid, according to the method described in Example 9, gave 2-benzyl-4-chloro-5-[ 3-Fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled in the 4-position with 4-fluorophenylboronic acid according to the method described in Example 6. This product was N-debenzylated according to the method described in Example 11 and N-arylated with 4-fluoroiodobenzene according to the method described in Example 62. The resulting sulfide was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the final sulfonamide product according to the method described in Example 68 (yield: 500 mg, 75%). Temp. 222-224 °C. NMR (300 MHz, CDCl 3 ) δ 5.06

(s, 2H), 7.01 (t, J = 9 Hz, 2H), 7.06 (d, J = 9 Hz, 2H),

7.10 (df J = 9 Hz, 2H), 7.18 (t, J = 9 Hz, 2H), 7.69 (dd, J = 9 Hz, 3 Hz, 2H), 7.88 (t, J = 9 Hz, IH), 7.95 (s, IH). MS (DCl-NH 3 ) m/z 458 (M+H)<+>. Anal. calcd for C 22 H 14 F 3 N 3 O 3 S: C, 57.76; H, 3.08; N, 9.18. Found: C, 57.5; H, 3.15; N,

8.8.

Example 73

2-{ 2 , 2 , 2- Trifluoroethyl)- 4-( 3- fluoro- 4- chlorophenyl)- 5-[ 4-( amino-sulfonyl ) phenyl 1- 3( 2H)- pyridazinone

The methyl sulfide intermediate prepared in Example 67 was oxidized with one equivalent of meta-chloroperoxybenzoic acid, according to the method described in Example 68, to provide the methyl sulfoxide. The methyl sulfoxide was converted to the sulfonamide product according to the method described in Example 68 (yield: 1.5 g, 63%). Temp. 180-183 °C. ltt NMR (300 MHz, DMSO-dfi) δ 5.09 (q, J = 9 Hz, 2H), 7.01 (dd, J = 9 Hz, 3 Hz, 1H), 7.15 (dd, J = 9 Hz, 3 Hz, IH), 7.39 (dd, J = 9 Hz, 3 Hz, IH), 7.47 (dd, J = 9 Hz, 3 Hz, IH) , 7.55 (t, J = 9 Hz, IH), 7.71 (t, J = 9 Hz, IH), 7.78 (s, 2H), 8.37 (s, IH). MS (DCl-NH 3 ) m/z 480 (M+H)<+>. Anal. calcd for C18H11CIF5N3O3S: C, 45.05; H, 2.31; N, 8.75. Found: C, 46.19; H, 3.02; N, 7.43.

Example 74

2- Benzyl- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy analogue according to the method described in Example 7 and then to

The 5-trifluoromethylsulfonyloxy analogue according to the method described in Example 8. Subsequent coupling to 4-(methylthio)phenylboric acid according to the method described in Example 9 gave 2-benzyl-4-chloro-5-[4-(methylthio)phenyl] -3(2H)-pyridazinone. This 4-chloro intermediate thus prepared was treated with 2-propanol (20 mL, 261 mmol) and potassium t -butoxide (110 mg, 0.98 mmol) under reflux for 45 min to give 2-benzyl-4-( 2-propoxy)-5-[4-(methylthio)pentyl]-3(2H)-pyridazinone This methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 180 mg, 80%). Temp. 109-111 °C. 1 H NMR

(300 MHz, CDCI3) 51.18 (d, J = 6 Hz, 6H) , 3.12 (s, 3H) , 5.36 (s, 2H), 5.49 (h, J = 6 Hz, IH ), 7.35 (rn, 3H), 7.47 (dd, J = 9 Hz, 3 Hz, 2H), 7.74 (d, J = 9 Hz, 2H), 7.79 (s, IH) , 8.03 (d, J = 9 Hz, 2H). MS {DCI-NH 3 ) m/z 399 (M+H)<+. >Anal. calcd for C 21 H 22 N 2 O 4 S: C, 63.29; H, 5.56; N, 7.03. Found: C, 63.17; H, 5.57; N, 6.95.

Example 7 5

2- Benzyl- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3 ( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 74 using 4-fluorophenol instead of 2-propanol (yield: 180 mg, 99%). Temp. 188-190 °C. <i>H NMR (300 MHz, CDCl 3 ) 53.12 (s, 3H) , 5.26 (s, 2H) , 6.86 (dd, J = 9 Hz, 6 Hz, 2H) , 6.99 ( t, J = 9 Hz, 2H), 7.34 (m, 3H), 7.46 (dd, J = 9 Hz, 3 Hz, 2H), 7.72 (d, J = 9 Hz, 2H), 7.92 (s, 1H), 8.02 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 451 (M+H)<+.> Anal. calcd for C 24 H 19 FN 2 O 4 S: C, 63.98; H, 4.25; N, 6.21. Found: C, 63.74; H, 4.2; N, 6,12.

Example 7 6

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 75 using 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2- benzyl-4-chloro-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (yield: 180 mg, 63%). Temp. 161-164 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 3.09 (s, 3H), 4.81 (q, J = 9 Hz, 2H), 6.88 (dd, J = 9 Hz, 4.5 Hz , 2H), 7.0 (t, J = 9 Hz, 2H), 7.78 (d, J = 9 Hz, 2H), 7.79 (s, IH), 8.06 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 443 (M+H)<+>. Anal. calcd for C19H14F4N2O4S: C, 51.58; H, 3.18; N, 6.33. Found: C, 51.8; H, 3.3; N, 6.22.

Example 77

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfinyl) phenyl]- 3( 2H)- pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy analogue according to the method described in Example 7 and then to the 5-trifluoromethylsulfonyloxy analogue according to the method described in Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method described in Example 9, gave 2-benzyl-4-chloro-5-[4- (methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-chlorophenylboronic acid according to the method described in Example 6. This product was N-debenzylated according to the method described in Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane in according to the method described in Example 20. The resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid according to the method described in Example 5 to provide the title compound (yield: 130 mg, 70%). Temp. 154-155 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 2.74 (s, 3H), 4.88 (q, J = 9 Hz, 2H), 7.14 (d, J = 9 Hz, 2H), 7, 26 (d, J = 9 Hz, 2H), 7.31 (d, J = 9 Hz, 2H), 7.61 (d, J = 9 Hz, 2H), 7.82 (s, 1H). MS (DCl-NH 3 ) m/z 427 (M+H)<+>. Anal. calcd for C19H14CIF3N2O2S: C, 53.46; H, 3.3; N, 6.56. Found: C, 53.58; H, 3.34; N, 6.42.

Example 78

2- Benzyl- 4- chloro- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by oxidizing 2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, (prepared as an intermediate in Example 77} according to the method described in Example 10 ( yield: 180 mg, 83%). M.p. 166-167 °C. <1>H NMR (300 MHz, CDCl 3 ) 53.12 (s, 3H) , 5.41 (s, 2H) , 7.37 ( m, 3H), 7.53 (dd, J = 9 Hz, 3 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 7.74 (s, IH), 8.08 (d , J = 9 Hz, 2H).MS (DCI-NH3) m/z 375 (M+H)<+.> Anal. calcd for C18H15CIN2O3S: C, 57.67; H, 4.03; N, 7, 47. Found: C, 57.43; H, 4.06; N, 7.35.

Example 79

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy analogue according to the method described in Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy analogue according to the method described in Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method described in Example 9, gave 2-benzyl-4-bromo-5- [4-(Methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-methyl-phenylboronic acid according to the method described in Example 6. This product was N-debenzylated according to the method described in Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane in according to the method described in Example 20. The resulting sulfide was oxidized to the title compound according to the method described in Example 10 (yield: 210 mg, 98%). Temp. 154-156 °C. 1-H NMR (300 MHz, CDCl 3 ) 82.33

(s, 3H), 3.07 (s, 3H), 4.89 (q, J = 9 Hz, 2H), 7.08 (s, 4H), 7.37 (d, J = 9 Hz, 2H ), 7.88 (s, 1H), 7.89 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 423 (M+H)<+>. Anal. calcd for C20H17F3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56, 59; H, 4.11; N, 6.53.

Example 80

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- chloro- 3- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy analogue according to the method described in Example 7 and then to the 5-(trifluoromethyl)sulfonyloxy analogue according to the method described in Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid, according to the method described in Example 9, gave 2-benzyl-4-chloro-5- [4-(Methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-chloro-3-fluorophenylboronic acid according to the method described in Example 6. This product was N-debenzylated according to the method described in Example 11 and N-alkylated with 2-iodo-l,l,l- trifluoroethane according to the method described in Example 20. The resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the final sulfamide product according to the method described in Example 68 (yield: 500 mg , 75%). Temp. 214-215 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 4.82 (s, 2H), 4.88 (q, J = 9 Hz, 2H), 6.88 (m, 1H), 7.09 (dd, J = 9 Hz, 3 Hz, IH), 7.31 (d, J = 9 Hz, IH), 7.32 (d, J = 9 Hz, 2H), 7.90 (s, IH), 7, 92 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 462 (M+H)<+>. Anal. calcd for C18H12F4CIN3O3S: C, 46.81; H, 2.61; N, 9.09. Found: C, 46.79; H, 2.59; N, 8.86.

Example 81

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3, 4- dichlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product described in Example 65 was N-debenzylated according to the method described in Example 11. The intermediate product was N-alkylated according to the method described in Example 20, using 2-iodo-1,1,1-trifluoroethane instead of 4-fluorobenzyl bromide to provide the title compound (yield: 165 mg, 55%). Temp. 197-198 °C. <3->H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 4.88 (q, J = 9 Hz, 2H), 6.98 (dd, J = 9 Hz, 3 Hz, 1H), 7.37 (d, J = 9 Hz, 4H), 7.91 (s, 1H), 7.95 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 477 (M+H)<+>. Anal. calcd for C19H13F3CI2N2O3S: C, 47.81; H, 2.74; N, 5.86. Found: C, 47.94; H, 2.87; N, 5.83.

Example 82

2- Benzyl- 4-( 2- propylamino)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

2-Benzyl-4,5-dibromo-3(2H)-pyridazinone (2 g, 6 mmol) was reacted with 2-aminopropane (2 mL, 23.5 mmol) and potassium t -butoxide (910 mg, 6, 6 mmol) in toluene (40 ml) under reflux for 18 h to provide the 4-(2-propylamino) derivative after column chromatography (silica gel, 92:8 hexanes/ethyl acetate). The intermediate was coupled at the 5-position with 4-(methylthio)phenylboronic acid according to the method described in Example 6. The methyl sulfide was oxidized, according to the method described in Example 10, to provide the title compound (yield: 120 mg, 48%). Temp. 146-147 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 0.92 (d, J = 6 Hz, 6H), 3.11 (m, 1H), 3.13 (s, 3H), 5.34 (s, 2H), 5.59 (m, IH), 7.33 (m, 3H), 7.42 (s, IH), 7.48 (dd, J = 9 Hz, 3 Hz, 2H), 7.56 (d, J = 9 Hz, 2H), 8.00 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 399 (M+H)<+>. Anal. calcd for C 21 H 23 N 3 O 3 S: C, 63.45; H, 5.83; N, 10.57. Found: C, 63.31; H, 5.87; N, 10.44.

Example 83

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

83A. 2-( 2, 2, 2- Trifluoroethyl)- 4, 5- dibromo- 3( 2H)- pyridazinone

A solution of mucobromic acid (10 g, 38.8 mmol) and trifluoroethylhydrazine (70% in water, 4.88 mL, 38.8 mmol) in 100 mL of methanol was prepared and heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO 4 , filtered, pressed through a pad of silica gel and concentrated in vacuo. The product was obtained as a yellowish solid (yield: 8.8 g, 68%). <1>H NMR (300 MHz, CDCl 3 ) δ 4.78 (q, J = 9 Hz, 2H), 7.87 (s, 1H). MS (DCl-NH 3 ) m/z 337 (M+H)<+>.

83B. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propoxy)- 5- bromo- 3( 2H)-pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone (2 g, 6 mmol), isopropyl alcohol (3 mL) and sodium hydride (60% dispersed in oil, 290 mg, 7.2 mmol) in toluene (40 mL) was heated under reflux for 5 h. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was filtered and concentrated in vacuo. The residue was purified by chromatography (95:5 hexanes/ethyl acetate) to provide the product as a greenish oil (yield: 1.22 g, 65%). <1>H NMR (300 MHz, CDCl 3 ) 51.46 (d, J = 7.5 Hz, 6H), 5.48 (h, J = 6 Hz, 1H), 7.87 (s, 1H). MS {DCI-NH 3 ) m/z 316 (M+H)<+.>

83C. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propoxy)- 5-[ 4-( methylthio)-phenyl]- 3( 2H)- pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone (1.2 g, 3.8 mmol), 4-(methylthio) phenylboronic acid (704 mg, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 5% mmol) and cesium carbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol dimethyl ether were heated to reflux for 5 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (94:6 hexanes/ethyl acetate). The product was obtained as a greenish solid (yield: 1.1 g, 81%). <i>H NMR (300 MHz, CDCl 3 ) 51.19 (d, J = 7.5 Hz, 6H), 2.55 (s, 3H), 4.83 (q, J = 9 Hz, 2H), 5.28 (h, J = 6 Hz, IH), 7.32 (d, J = 9 Hz, 2H), 7.52 (d, J = 9 Hz, 2H), 7.85 (s, IH) . MS (DCI) m/z 359

(M+H)<+>.

83D. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H) -pyridazinone instead of 4-(4-fluorophenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone (yield: 220 mg, 100%). Temp. 152-153 °C. <i>H NMR (300 MHz, CDCl 3 ) 81.2 (d, J = 6 Hz, 6H) , 3.13 (s, 3H) , 4.84 (q, J = 9 Hz, 2H) , 5, 49 (p, J = 6 Hz, IH), 7.78 (d, J = 9 Hz, 2H), 7.82 (s, IH), 8.05 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 391 (M+H)<+>. Anal. calcd for C16H17F3N2O4S: C, 49.22; H, 4.38; N, 7.17. Found: C, 49.34; H, 4.25; N, 7.01.

Example 84

2-( 2, 2, 2- Trifluoroethyl)- 4- cyclohexyloxy- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 83, using cyclohexanol instead of 2-propanol (yield: 250 mg, 52%). Temp. 129-130 °C. <i>H NMR (300 MHz, CDCl 3 ) 81.1-1.6 (m, 8H), 1.84 (rn, 2H), 3.12 (s, 3H), 4.83 (q, J = 9 Hz, 2H), 5.21 {h, J = 4.5 Hz, IH) , 7.77 (s, IH}, 7.80 (d, J = 9 Hz, 2H), 8.06 <d , J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 431 (M+H)<+>. Anal. calcd for C19H21F3N2O4S: C, 53.01; H, 4.91; N, 6.50. Found: C, 52.96; H, 4.84; N, 6.45.

Example 85

2-( 2, 2, 2- Trifluoroethyl)- 4- cyclopentyloxy- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 83, using cyclopentanol instead of 2-propanol (yield: 250 mg, 52%). Temp. 148-150 °C. 1 H NMR (300 MHz, CDCl 3 ) δ 1.35-1.55 (m, 4H), 1.68-1.75

(m, 4H), 3.12 (s, 3H), 4.83 (q, J = 9 Hz, 2H), 5.89 (h, J = 4.5 Hz, IH), 7.75 (d , J = 9 Hz, 2H), 7.83 (s, 1H), 8.04 (d, j * 9 Hz, 2H). MS (DCI-NH3) m/z 417 (M+H)<+.> Anal. calcd for C18H19F3N2O4S: C, 51.91; H, 4.59; N, 6.72. Found: C, 52.04; H, 4.50; N, 6.65.

Example 86

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

86A. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propylamino)- 5- bromo- 3( 2H)-pyridazinone

The title compound was prepared according to the method in Example 83B, using 2-propylamine instead of 2-propanol (yield: 70%). MS (DCl-NH 3 ) m/z 315 (M+H)<+.>

86B. 2-( 2, 2, 2- Trifluoroethyl) - 4-( 2- propylaTaino) - 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method of Example 83C, using 2-(2,2,2-trifluoroethyl)-4-

(2-propylamino)-5-bromo-3(2H)-pyridazinone instead of 2-(2,2,2-trifluoroethyl)-4-isopropoxy-5-bromo-3(2H)-pyridazinone (yield: 80%). MS (DCl-NH 3 ) m/z 358 (M+H)<+>.

86C. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using 2-(2,2,2-trifluoroethyl)-4-(2-propylamino)-5-[4-(methylthio)phenyl]-3(2H) -pyridazinone instead of 4-(4-fluorophenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone (yield: 180 mg, 83%). Temp. 173-174 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 0.95 (d, J = 6 Hz, 6H) , 3.13 (s, 3H), 4.81 (q, J = 9 Hz, 2H), 5 .97 (p, IH) , 7.45

(s, 1H) , 7.59 (d, J = 9 Hz, 2H) , 8.03 (d, J =» 9 Hz, 2H) . MS (DCI-NH3) m/z 340 (M+H)<+.> Anal. calcd for C16H18F3N3O4S: C, 49.35; H, 4.65; N, 10.79. Found: C, 49.29; H, 4.52; N, 10.65.

Example 87

2- Benzyl- 4-( 4- morpholino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

2-Benzyl-4,5-dichloro-3(2H)-pyridazinone, prepared according to the procedure of Example 2, was reacted with morpholine according to the procedure of Example 86 to provide the 4-morpholino derivative. The morpholino intermediate was coupled at the 5-position with 4-(methylthio)phenylboronic acid according to the method described in Example 6. The resulting methyl sulfide was oxidized to the title compound according to the method described in Example 10 (yield: 150 mg, 69%). Temp. 158-160 °C. <!>h NMR (300 MHz, CDCl 3 ) 53.06 (t, J = 4.5 Hz, 3H) , 3.12 (s, 3H) , 3.69 (t, J = 4.5 Hz, 3H ) , 5.33 (s, 2H) , 7.35 (m, 3H), 7.5 (m, 4H), 7.58 (s, IH), 8.05 (d, J = 9 Hz, 2H ).

MS (DCl-NH 3 ) m/z 426 (M+H) + . Anal. calcd for C22H23N3O4S: C, 62.10; H, 5.44; N, 9.87. Found: C, 61.74; H, 5.47; N, 9.59.

Example 88

2-( 2, 3, 3- Trifluoro- 2- propen- l- yl)]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

88A. 1- Methylsulfonyloxy- 2, 3, 3- trifluoro- 2- propene

2,3,3-Trifluoro-2-propen-1-ol was prepared as reported in J. Org. Chem., 1989, 54, 5640-5642. The mesylate was obtained by reacting 2,3,3-trifluoro-2-propen-1-ol with mesyl chloride in diethyl ether. Standard work-up gave the product, which was used without purification.

88B. 2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.

4-(4-Fluorophenyl)-5-[ 4-(methylthio)phenyl]-3(2H)-pyridazinone is prepared starting from the 2-benzyl-pyridazinone from Example 9 and debenzylation of the compound according to the procedure in Example 11.

A mixture of 4-(4-fluorophenyl)-5-[ 4-(methylthio)phenyl]-3(2H)-pyridazinone (250 mg, 0.8 mmol), CS2CO3 (650 mg, 2 mmol) and 3-methylsulfonyloxy -1,1,2-trifluoropropene (mesylate, 250 mg, 1.19 mmol) in ethyl acetate (30 mL) was stirred at 55 °C for 1.5 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO 4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with 15% ethyl acetate/hexanes to provide the methyl sulfide, 2-(2,3,3-trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5- [4-(Methylthio)phenyl]-3(2H)-pyridazinone as a greenish oil (yield: 175 mg, 53%).

88C. 2-( 2, 3, 3- Trifluoro- 2- propen- l- yl)]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The methyl sulfide, prepared above, was oxidized to the title compound according to the method described in Example 10 (yield: 125 mg, 68%). Temp. 154-156 °C. <3->H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 5.1 (ddd, J = 21 Hz, 3 Hz, 1.5 Hz, 2H), 6.98 (t, J = 9 Hz, 2H) , 7.19 (dd, J = 9 Hz, 6 Hz, 2H) , 7.35 (d, J = 9 Hz, 2H), 7.89 (s, IH), 7, 9 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 439 (M+H)<+>. Anal. calcd for C20H14F4N2O3S: C, 54.79; H, 3.21; N, 6.38. Found: C, 54.52; H, 3.15; N, 6.21.

Example 8 9

2, 4- Bis(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 68 using 2,4-bis(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone instead of 2-(2,2, 2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methyl-sulfinyl)phenyl]-3(2H)-pyridazinone (yield: 118 mg, 43%). Temp. 213-216 °C. <1>ti NMR (300 MHz, DMSO-de) δ 7.15 (t, 2H), 7.27 (rn, 2H), 7.4 (m, 6H), 7.7 (dd, 2H), 7.76 (d, J = 9 Hz, 2H), 8.2 (s, 1H). MS (DCI-NH3) m/z 440 (M+H)<+>, 439.44 (M+NH4)<+.> Anal. calcd for C21H15FN2O3S2: C, 60.13; H, 3.44; N, 9.56. Found: C, 59.94; H, 3.37; N, 9.46.

Example 90

2-( 2, 2, 2- Trifluoroethyl)- 4- cyclopropylmethoxy- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

90A. 2-( 2, 2, 2- Trifluoroethyl)- 4- methoxy- 5- bromo- 3( 2H)- pyridazinone

The title compound was prepared according to the method in Example 83B, using methanol instead of isopropanol (yield: 78%). 1-H NMR (300 MHz, CDCl 3 ) 5 4.3 (s, 3H), 4.76 (q, J = 9 Hz, 2H), 7.85 (s, 1H). MS (DCl-NH 3 ) m/z 288 {M+H)<+>.

90B. 2-( 2, 2, 2- Trifluoroethyl)- 4- methoxy- 5-[ 4-( methylthio) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method of Example 83C, using 2-(2,2,2-trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyridazinone instead of 2-(2,2,2- trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone (yield: 80%). 1H NMR (300 MHz, CDCl 3 ) δ 2.54 (s( 3H) , 4.11

(s, 3H), 4.82 (q, J = 9 Hz, 2H), 7.33 (d, J = 9 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 7, 84 (p, IH). MS (DCI-NH 3 ) m/z 331

(M+H)<+>.

90C. 2- ( 2, 2, 2- Trifluoroethyl)- 4- hydroxy- 5-[ 4-( methylthio) phenyl] - 3( 2H)- pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) in acetic acid (40 mL) was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The crystals formed were filtered, washed with water and 5% ethyl acetate in hexanes and dried to constant weight. The product was obtained as a white solid (yield: 1.75 g, 91%). <*>H NMR (300 MHz, CDCl 3 ) 82.54 (s, 3H), 4.82 (q, J = 9 Hz, 2H), 7.47 (d, J = 9 Hz, 2H), 7, 65 (d, J = 9 Hz, 2H), 7.73 (br s, IH), 8.00 (s, IH). MS (DCI) m/z 317 (M+H)<+>.

90D. 2-( 2, 2, 2- Trifluoroethyl)- 4- cyclopropylmethoxy- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (150 mg, 0.47 mmol), cyclopropyl methanol (43 mL , 0.52 mmol) and triphenylphosphine (124 mg, 0.47 mmol) in freshly distilled THF were prepared and added dropwise to diethyl azodicarboxylate (75 mL, 0.52 mmol) at 0 °C. The mixture was allowed to warm to room temperature, stirred for 5 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel (95:5 hexanes/ethyl acetate) to provide the product as a colorless oil (yield: 140 mg, 81%). <*>H NMR (300 MHz, CDCl 3 ) δ 0.22 (m, 2H), 0.48 (m, 2H) , 1.6 (m, 1H) , 2.53 (s, 3H), 4, 26 (d, J = 7.5 Hz, 2H), 4.72 (q, J - 9 Hz, 2H), 7.32 (d, J = 9 Hz, 2H), 7.55 (d, J = 9 Hz, 2H), 7.87 (s, 1H). MS (DCl-NH 3 ) m/z 371 (M+H)<+>.

9QE. 2-( 2, 2, 2- Trifluoroethyl)- 4- cyclopropylmethoxy- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using 2-(2,2,2-trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 4 -(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 130 mg, 85%). Temp. 133-135 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 0.22 (rn, 2H), 0.5 (m, 2H), 1.07 (m, 1H), 3.12 (s, 3H), 4, 4 (d, J = 9 Hz, 2H), 4.83 (q, J = 9 Hz, 2H), 7.79 (s, IH), 7.83 (d, J = 9 Hz, 2H), 8 .07 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 403 (M+H)<+>. Anal. calcd for C17H17F3N2O4S: C, 50.74; H, 4.25; N, 6.96. Found: C, 50.56; H, 4.09; N, 6.88.

Example 91

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- propen- 1-oxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 90, using 2-propen-1-ol instead of cyclopropyl methanol (yield: 120 mg, 77%). Temp. 121-123 °C. <i>H NMR (300 MHz, CDCl 3 ) 83.12 (s, 3H), 4.84 (q, J = 12 Hz, 2H), 5.07 (d, J = 6 Hz, 2H), 5, 21 (dd, J = 13.5 Hz, 1 Hz, IH), 5.27 (dd, J = 15 Hz, 1 Hz, IH), 5.85 (m, IH), 7.25 (d, J = 9 Hz, 2H), 7.83 (s, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 389 (M+H)<+>. Anal. calcd for C16H15F3N2O4S: C, 49.48; H, 3.89; N, 7.21. Found: C, 49.24; H, 3.77; N, 7.16.

Example 92

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluoro- alpha- methylbenzyloxy)-5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 90, using 4-fluoro-alpha-methylbenzyl alcohol instead of cyclopropyl methanol (yield: 155 mg, 76%). Temp. 133-135 °C. <1>H NMR (300 MHz, CDCl 3 ) 51.57 (d, J = 6 Hz, 3H), 3.13 (s, 3H), 4.75 (q, J = 7.5 Hz, 1H), 4.87 (q, J = 7.5 Hz, IH), 6.34 (q, J = 6 Hz, IH), 6.83 (t, J = 9 Hz, 2H), 6.98 (dd, J = 9 Hz, 6 Hz, 2H), 7.59 (d, J = 9 Hz), 7.70 (s, IH), 8.03 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 471 (M+H)<+>. Anal. calcd for C21H18F4N2O4S: C, 53.61; H, 3.85; N, 5.95. Found: C, 53.54; H, 3.73; N, 5, 86.

Example 93

2-[ 4-( Methylthio) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of the product from Example 11, 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (344 mg, 1.0 mmol), 4-bromothioanisole (812 mg, 4.0 mmol) and copper (70 mg, 1.1 mmol) in 20 mL of pyridine were stirred at reflux under a nitrogen atmosphere for 18 h. After cooling to room temperature, the reaction mixture was diluted with a mixture of water and ethyl acetate. The two layers were filtered through Celite<®> and separated. The organic layer was washed with 10% aqueous citric acid, with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 93:7 dichloromethane/ethyl acetate) to afford the title compound as a foam (yield: 380 mg, 81.5%). <!>h NMR (300 MHz, CDCl 3 ) 52.55 (s, 3H}, 3.05 (s, 3H) , 6.98 (t, J = 9 Hz, 2H), 7.22 (dd, J = 9 Hz, 6 Hz, 2H), 7.38 (dd, J = 8 Hz, 2 Hz, 4H), 7.64 (d, J = 9 Hz, 2H), 7.91 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS {DCI-NH 3 ) m/z 467 (M+H)<+>. Anal. calcd for C24H19FN203S2'<0>'5 H2O: C, 60.63; H, 4.21; N, 5.90. Found: C, 60.72; H, 3.96; N, 5.70.

Example 94

2, 5- Bis[ 4-( methylsulfonyl) phenyl]- 4-( 4- fluorophenyl)- 3( 2H)-pyridazinone

The title compound was prepared by oxidizing the product in Example 93, according to the method described in Example 10 (yield: 156 mg, 78%). <X>H NMR (300 MHz, CDCl 3 ) δ 3.10 (s, 3H), 3.12 (s, 3H), 7.02 (m, 2H), 7.24 (m, 2H), 7, 42 (br d, J = 9 Hz, 2H), 7.94 (dd, J = 9 Hz, 2 Hz, 2H), 8.02 (dd, J = 9 Hz, 2 Hz, 2H), 8.10 (rn, 3H). MS (DCl-NH 3 ) m/z 499 (M+H)<+>, 516 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 FN 2 O 5 S 2 -°'5 H 2 O: C, 56.80; H, 3.94; N, 5.53. Found: C, 56.50; H, 3.88; N, 5, 38.

Example 95

2-( 3- Methyl- 2- thienyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 2-bromo-3-methylthiophene instead of 4-bromothioanisole (yield: 190 mg, 43%). Temp. 215-217 °C. <*>H NMR (300 MHz, CDCl 3 ) 52.21 (s, 3H) , 3.08 (s, 3H) , 6.90 (d, J = 9 Hz, 1H), 6.98 (t, J = 9 Hz, 2H), 7.24 (dd, J = 9 Hz, 6 Hz, 3H), 7.41 (d, J = 9 Hz, 2H), 7.94 (d, J = 9 Hz, 2H ), 7.98 (p, IH) . MS (DCl-NH3) m/z 441 (M+H)<+>, 458 (M+NH4)4-. Anal. calcd for C22H17FN2O3S2•<0>'5 H2O: C, 58.80; H, 4.01; N, 6. 24. Found: C, 58.85; H, 3.78; N, 5.99.

Example 96

2-( 2- Trifluoromethyl- 5- nitrophenyl)- 4-{ 4- fluorophenyl)-5-[4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 2-bromo-5-nitrobenzotrifluoride instead of 4-bromothioanisole (yield: 390 mg, 73%). ^ NMR (300 MHz, CDCl3) 8 3.08 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.21 (dd, J = 9 Hz, 6 Hz, 2H), 7 .43 (d, J = 9 Hz, 2H), 7.80 (d, J = 9 Hz, IH), 7.96 (d, J = 9 Hz, 2H), 8.02 (s, IH) , 8.61 (dd, J = 9 Hz, 3 Hz, IH), 8.75 (d, J = 3 Hz, IH). MS (DCI-NH3) m/z 534 (M+H}<+>, 551 (M+NH4)<+>. Anal. calculated for C24H15F4N305S-°'75 H2O: C, 52.70; H, 3, 02; N, 7.69. Found: C, 52.42; H, 3.04; N, 6.82.

Example 97

2-[ 3-( Methylthio) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 3-bromothioanisole instead of 4-bromothioanisole (yield: 355 mg, 76%). Temp. 196 °C. <!>h NMR (300 MHz, CDCl 3 ) 52.55 (s, 3H) , 3.08 (s, 3H) , 6.99 (t, J = 9 Hz, 2H), 7.23 (dd, J = 9 Hz, 6 Hz, 2H), 7.28-7.33 (m, IH), 7.37-7.49 (rn, 2H), 7.40 (d, J = 9 Hz, 2H), 7.58 (m, 1H), 7.92 (d, J = 9 Hz, 2H), 7.99 (m, 1H). MS (DCl-NH 3 ) m/z 467 (M+H)<+>, 484 (M+NH 4 )<+>. Anal. calcd for C24H19FN2O3S2: C, 61.80; H, 4.08; N, 6.01. Found: C, 61.56; H, 3.93; N, 5, 86.

Example 98

2-[ 3-( Methylsulfonyl ) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H )- pyridazinone

The title compound was prepared by oxidizing the product in Example 97, according to the method described in Example 10 (yield: 98 mg, 65.6%). Temp. 141-142 °C. <1>H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H) , 3.35 (s, 3H) , 7.18 (t, J = 9 Hz, 2H), 7.32 ( dd, J = 9 Hz, 6 Hz, 2H), 7.52 (d, J = 9 Hz, 2H), 7.83 (t, J = 9 Hz, IH), 7.95 (d, J = 9 Hz, 2H), 8.05 (m, IH), 8.25 (t, J = 1.5 Hz, IH), 8.33 (s, IH). MS (DCI-NH 3 ) m/z 516 {M+NH 4 )<+>. Anal. calcd for C24H19FN2O5S2•H2O: C, 55.81; H, 4.07; N, 5.43. Found: C, 56.24; H, 4.29; N, 5,10.

Example 99

2-( 4- Fluorophenyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

4-(4-Chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone is prepared starting from the 2-benzylpyridazinone from Example 53 and debenzylating the compound according to the method described in Example 11.

The title compound was prepared according to the method described in Example 93 starting from 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4 -(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 1-fluoro-4-iodobenzene instead of 4-bromothioanisole (yield: 245 mg, 54%). Temp. 195-197 °C. <!>h NMR (300 MHz, CDCl 3 ) 83.08 (s, 3H) , 7.19 (m, 4H) , 7.25 (m, 2H) , 7.41 (d, J = 9 Hz, 2H ), 7.70 (m, 2H), 7.95 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCI-NH 3 ) m/z 455 (M+H)<+>, 472 (M+NH 4 )"1". Anal. calcd for C 23 H 16 CIFN 2 O 3 S: C, 60.78; H, 3.52; N, 6.17. Found: C, 60.81; H, 3.53; N, 5.93.

Example 100

2-( 5- Chloro- 2- thienyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 2-bromo-5-chlorothiophene instead of 4-bromothioanisole (yield: 150 mg, 45%). Temp. 249-251 °C. <1>h NMR (300 MHz, CDCl3) 53.05 (s, 3H), 6.92 (d, J = 9 Hz, 1H), 7.18 (d, J = 9 Hz, 2H), 7, 31 (d, J = 9 Hz, 2H), 7.39 (d, J = 9 Hz, 2H), 7.58 (d, J = 6 Hz, IH), 7.94 (d, J = 9 Hz , 2 Hz, 2H), 8.04 (s, 1H). MS (DCl-NH 3 ) m/z 477 (M+H)<+>, 494 (M+NH 4 )<+>. Anal. calcd for C 21 H 14 Cl 2 N 2 O 3 S 2 -H 2 O: C, 50.9; H, 3.03; N, 5.60. Found: C, 50.5; H, 2.79; N, 5.26.

Example 101

2-( 3- Trifluoromethylphenyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 starting from 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4-(methyl -sulfonyl)phenyl]-3(2H)-pyridazinone and using 3-iodobenzotrifluoride instead of 4-bromothioanisole (yield: 210 mg, 59.5%). Temp. 103-105 °C. <*>H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.18 (d, J = 9 Hz, 2H), 7.28 (d, J = 9 Hz, 2H), 7 .41 (d, J = 9 Hz, 2H), 7.65 (m, 2H), 7.95 (m, 3H), 8.04 (m, 2H). MS (DCI-NH 3 ) m/z 505 (M+H)<+>, 525 (M+NH 4 )<+>. Anal. calcd for C 24 H 16 CIF 3 N 2 O 3 S: C, 57.14; H, 3.17; N, 5.56. Found: C, 56.61; H, 3.28; N, 5.38.

Example 102

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 starting from 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (described in Example 99) instead of 4-(4-fluorophenyl)-5 -[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 1-bromo-3-chloro-4-fluorobenzene instead of 4-bromothioanisole (yield: 330 mg, 58.8%). Temp. 205 °C. 3-H NMR (300 MHz, CDCl 3 ) 83.10 (s, 3H), 7.17 (d, J = 9 Hz, 2H), 7.23-7.31 (m, 1H), 7.28 ( d, J = 9 Hz, 2H), 7.41 (d, J = 9 Hz, 2H) , 7.65 (ddd, J = 9 Hz, 3 Hz, 1.5 Hz, IH) , 7.85 ( dd, J = 9 Hz, 3 Hz, 1H), 7.93 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCl-NH 3 ) m/z 489 (M+H)<+>, 508 (M+NH 4 )<+>. Anal. calcd for C 23 H 15 Cl 2 N 2 O 3 S: C, 56.44; H, 3.17; N, 5.73. Found: C, 56.37; H, 3.19; N, 5.64.

Example 103

2-( 3-Fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 1-fluoro-3-iodobenzene instead of 4-bromothioanisole (yield: 310 mg, 70.8%). Temp. 245-247 °C. 3-H NMR (300 MHz, CDCl 3 ) 83.08 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.14 (m, 1H), 7.24 (dd, J = 9 Hz, 6 Hz, 2H), 7.40 (rn, 2H), 7.52 (rn, 3H), 7.92 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCl-NH 3 ) m/z 439 (M+H)<+>, 456 (M+NH 4 )<+>. Anal. calcd for C 23 H 16 F 2 N 2 O 3 S-°r 25 H 2 O: C, 62.34; H, 3.67; N, 6.38. Found: C, 62.33; H, 3.68; N, 6.22.

Example 104

2-[ 2-( Methylthio) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 2-bromothioanisole instead of 4-bromothioanisole (yield: 280 mg, 60%). Temp. 206-208 °C. <3->H NMR (300 MHz, CDCl3) δ 2.49 (s, 3H) , 3.08 (s, 3H) , 6.95 (t, J=9Hz, 2H), 7.25 (dd, J = 9 Hz, 6 Hz, 2H), 7.29-7.51 (rn, 4H), 7.43 (d, J = 9 Hz, 2H), 7.92 (d, J = 9 Hz, 3H ), 8.01 (s, IH), 7.98 (s, IH). MS (DCl-NH 3 ) m/z 467 (M+H)<+>, 484 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 FN 2 O 3 S 2 ■H 2 O: C, 59.50; H, 4.13; N, 5.79. Found: C, 59.62; H, 4.15; N, 5.52.

Example 105

2-( 5- Nitro- 2- thienyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 2-bromo-5-nitrothiophene instead of 4-bromothioanisole (yield: 330 mg, 70%). Temp. 252-253 °C. <L>H NMR (300 MHz, CDCl3) δ 3.06 (s, 3H) , 7.05 (t, J = 9 Hz, 2H) , 7.25 (dd, J = 9 Hz, 6 Hz, 2H ), 7.40 (d, J = 9 Hz, 2H), 7.71 (d, J = 6 Hz, IH), 7.95 (m, 3H), 8.14 (s, IH). MS {DCI-NH 3 ) m/z 472 (M+H)<+>, 489 (M+NH 4 )<+>. Anal. calcd for C 21 H 14 FN 3 O 5 S 2 -0.5 H 2 O: C, 52.50; H, 3.02; N, 8.75. Found: C, 52.79; H, 3.18; N, 8.74.

Example 106

2-( 3, 4- Difluorophenyl)- 4-( 4- chlorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 starting from 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl) )phenyl]-3(2H)-pyridazinone and using 1-bromo-3,4-difluorobenzene instead of 4-bromothioanisole (yield: 310 mg, 65.7%). Temp. 187-188 °C. <!>h NMR (300 MHz,

CDCI3) 8 3.09 (s, 3H), 7.18 (d, J = 9 Hz, 2H) , 7.29 (m, 3H) , 7.41 (d, J = 9 Hz, 2H), 7 .52 (rn, IH), 7.65 (rn, IH), 7.92 (d, J = 9 Hz, 2H), 8.01 (s, IH). MS (DCl-NH 3 ) m/z 473 (M+H)<+>, 490 (M+NH 4 )<+>. Anal. calcd for C 23 H 15 C 1 F 2 N 2 O 3 S-0.5 H 2 O: C, 57.38; H, 3.33; N, 5.82. Found: C, 57.44; H, 3.38; N, 5.52.

Example 107

2-( 3- Benzothienyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example

93, using 3-bromobenzothiophene instead of 4-bromothioanisole (yield: 185 mg, 41%). Temp. 265-267 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 3.09 (s, 3H), 7.0 (t, J = 9 Hz, 2H) , 7.27 (dd, J = 9 Hz, 6 Hz, 2H ), 7.39-7.47 (m, 2H), 7.44 (d, J = 9 Hz, 2H), 7.75-7.82 (m, IH), 7.87-7.94 ( m, 2H), 7.94 (d, J=9 Hz, 2H), 8.05 (s, 1H). MS (DCI-NH3) m/z 477 (M+H)<+>, 494 (M+NH4)<+.> Anal. calcd for C25H17FN2O3S2: C, 63.03; H, 3.57; N, 5.88. Found: C, 62.89; H, 3.55; N, 5.71.

Example 108

2-( 4- Fluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

108A. 4-(4-Fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared by treating 2-benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 75) with AlBr3 in toluene according to the procedure of Example 11 (yield: 1.8 g, 95%).

108B. 2-( 4- Fluorophenyl)- 4-( 4- fluorophenoxy)- 5- [ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 starting from 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone and using 1-fluoro-4-iodobenzene instead of 4-bromothioanisole (yield: 60 mg, 53%). Temp. 83-85 °C. <1>H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 6.89-7.03 (m, 4H), 7.15 (t, J = 9 Hz, 2H), 7, 65 (dd, J = 9 Hz, 6 Hz, 2H), 7.83 (d, J = 6 Hz, 2H), 8.07 (d, J = 9 Hz, 2H),

8.08 (p, 1H). MS (DCl-NH 3 ) m/z 455 (M+H)<+>, 472 (M+NH 4 )<+>.

Example 109

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methyl-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 1-bromo-3,4-difluorobenzene instead of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (Example 108A) instead of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). Temp. 178-180 °C. <3->H NMR (300 MHz, CDCl3) 83.11 (s, 3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45 -7.52 (m, IH), 7.61 (dt, J = 6 Hz, 3 Hz, IH), 7.82 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (DCI-NH3) m/z 473 (M+H)<+>, 490 (M+NH4)<+.> Anal. calcd for C 23 H 15 F 3 N 2 O 4 S-°'5 H 2 O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.

Example 110

2-( 3- Bromophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 1,3-dibromobenzene instead of 4-bromothioanisole and 4-{4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) instead 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 260 mg, 50.5%). Temp. 208-210 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 3.09 (s, 3H), 6.89-7.04 (m, 4H), 7.34 (t, J = 9 Hz, 1H), 7.53 (br d, J = 9 Hz, IH), 7.64 (br d, J = 9 Hz, IH) , 7.82 (d, J = 9 Hz, 2H), 7.87 (t, J = 1 .5 Hz, 1H), 8.08 (d, J = 9 Hz, 2H), 8.09 (s, 1H). MS (DCl-NH 3 ) m/z 517 (M+H)<+>, 534 (M+NH 4 )<+>. Anal. calcd for C 23 Hi 6 BrFN 2 O 4 S: C, 53.7; H, 3.11; N, 5.45. Found: C, 53.46; H, 2.88; N, 5.18.

Example 111

2-( 3, 5- Difluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 1-bromo-3,4-difluorobenzene instead of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (Example 108A) instead of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 175 mg, 37%). Temp. 209-211 °C. <*>H NMR (300 MHz, CDCl 3 ) 53.10 (s, 3H), 6.85 (tt, J = 9 Hz, 3 Hz, 1H), 6.90-7.04 (m, 4H), 7.38 (dd, J = 9 Hz, 3 Hz, 2H), 7.81 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.10 (s , IH). MS (DCl-NH 3 ) m/z 473 (M+H)<+>, 490 (M+NH 4 )<+>. Anal. calcd for C 23 H 15 F 3 N 2 O 4 S-H 2 O: C, 58.47; H, 3.18; N, 5.94. Found: C, 58.31; H, 3.15; N, 5.82.

Example 112

2-( 3- Chlorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to Example 93 using 1-bromo-3-chlorobenzene instead of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A ) instead of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

(yield: 25 mg, 5.3%). Temp. 211-213 °C. <3->H NMR (300 MHz, DMSO-d6) 53.30 (s, 3H), 7.15 (d, J = 9 Hz, 4H), 7.51-7.64 (m, 3H), 7.71-7.75 (m, 1H), 7.91 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H), 8.41 (s, 1H). MS (DCl-NH 3 ) m/z 471 (M+H)<+>, 488 (M+NH 4 )<+>. Anal. calcd for C23H16CIFN2O4S•°'5 H2O: C, 57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.

Example 113

2-( 4- Nitrobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 4-nitrobenzyl bromide instead of 4-fluorobenzyl bromide (yield: 164 mg, 58.9%). Temp. 183-184 °C. ^-H NMR (300 MHz, CDCl 3 ) δ 3.05 (s, 3H), 5.47 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.16 (dd, J = 9 Hz, 3 Hz, 2H), 7.32 (d, J = 9 Hz, 2H), 7.70 (d, J = 9 Hz, 2H), 7.87 (s, IH), 7.88 (d, J = 9 Hz, 2H), 8.22 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 480 (M+H)<+>, m/z 497 (M+NH 4 )<+>. Anal. calcd for C 24 H 18 FN 3 O 5 S: C, 60.12; H, 3.78; N, 8.76. Found: C, 59.89; H, 3.83; N, 8.61.

Example 114

2-( 4- Acetoxybenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 4-(chloromethyl)-phenylacetate instead of 4-fluorobenzyl bromide (yield: 220 mg, 76.9%). Temp. 172-174 °C. 1 H NMR (300 MHz, CDCl 3 ) 82.30 (s, 3H), 3.05 (s, 3H), 5.38 (s, 2H), 6.95 (t, J = 9 Hz, 2H) , 7.06 (d, J = 9 Hz, 2H), 7.16 (dd, J = 9 Hz, 5 Hz, 2H), 7.31 (d, J = 9 Hz, 2H), 7.60 ( d, J = 9 Hz, 2H), 7.81 (s, 1H), 7.87 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 510 (M+NH 4 )<+. >Anal. calcd for C 26 H 21 FN 2 O 5 S: C, 63.40; H, 4.30; N, 5.69. Found: C, 63.28; H, 4.41; N, 5.39.

Example 115

2-( 4- Hydroxybenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

A solution of 2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.2 g, 4.06 mmol)

(Example 114) in THF (20 mL) was treated with a solution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL) was added to provide a homogeneous solution which was stirred at room temperature overnight. The reaction mixture was then acidified with 10% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO 2 and filtered. The filtrate was concentrated in vacuo to provide a white foam which was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate). The product fractions were combined and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexanes (yield: 195 mg, 70%). Temp. 225-226 °C. <3->H NMR (300 MHz, CDCl 3 ) 53.05 (s, 3H), 4.86 (s, 1H), 5.33 (s, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.95 (t, J = 9 Hz, 2H), 7.15 (dd, J = 9 Hz, 5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H ), 7.46 (d, J = 8.5 Hz, 2H), 7.83 (s, 1H), 7.87 (d, J = 8.5 Hz, 2H). MS (DCI-NH3) m/z 451 (M+H)<+.> Anal. calcd for C 24 H 19 FN 2 O 4 S: C, 63.99; H, 4.25; N, 6.22. Found: C, 63.73; H, 4.16; N, 6.11.

Example 116

2-( 3- Nitrobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 3-nitrobenzyl bromide instead of 4-fluorobenzyl bromide (yield: 195 mg, 70%). Temp. 156-157 °C. <1>h NMR (300 MHz, CDCl 3 ) 53.05 (s,

3H), 5.48 (s, 2H), 6.96 (t, J = 9 Hz, 2H), 7.16 (dd, J = 9 Hz, 5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.54 (t, J = 7 Hz, IH), 7.88 (s, IH), 7.90 (d, J = 8.5 Hz, 2H), 8, 19 (br d, J = 7 Hz, IH), 8.37 (t, J = 1.7 Hz, IH). MS (DCI-NH 3 ) m/z 480 (M+H)<+>, m/z 497 (M+NH 4 )<+>. Anal. calcd for C 24 H 18 FN 3 O 5 S: C, 60.12; H, 3.78; N, 8.76. Found: C, 59.98; H, 3.73; N, 8, 67.

Example 117

2-( 3, 4, 4- Trifluoro- 3- butenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 4-bromo-1,1,2-trifluoro-1-butene instead of 4-fluorobenzyl bromide (yield: 38 mg, 14.5%). Temp. 131-132 °C. <1>H NMR (300 MHz,

CDCl3) 52, 92 (br d, J = 21.7 Hz, 2H) , 3.06 (s, 3H) , 4.47

(t, J = 6.6 Hz, 2H) , 6.98 (t, J = 9 Hz, 2H) , 7.17 (dd, J = 9 Hz, 5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H). MS (DCI-NH3) m/z 453 (M+H)<+>, m/z 470 (M+NH4)<+.> Anal. calcd for C21H16F4N2O3S: C, 55.75; H, 3.56; N, 6.19. Found: C, 55.63; H, 3.62; N, 6.10.

Example 118

2-( 2- Hexynyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 1-chloro-2-hexyne instead of 4-fluorobenzyl bromide (yield: 170 mg, 69%). Temp. 79-80 °C. <!>h NMR (300 MHz, CDCl 3 ) 50.99 (t, J = 7.5 Hz, 3H), 1.56 (h, J = 7.5 Hz, 2H), 2.21 (rn, 2H ), 3.06 (s, 3H), 5.01 (t, J = 3 Hz, 2H), 6.96 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.34 (d, J = 9 Hz, 2H), 7.88 (s, 1H), 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 425 (M+H)<+.> Anal. calcd for C 23 H 21 FN 2 O 3 S: C, 65.07; H, 4.98; N, 6.59. Found: C, 64.87; H, 4.90; N, 6.58.

Example 119

2-( 3, 3- Dichloro- 2- propenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using 1,1,3-trichloro-propene instead of 4-fluorobenzyl bromide (yield: 1.15 g, 68%). Temp. 184-185 °C. <1>H NMR (300 MHz, DMS0-d6) 54.39 (d, J = 7.5 Hz, 2H), 6.43 (t, J = 7.5 Hz, 1H), 7.14 (t , J = 9 Hz, 2H), 7.23 (dd, J = 9 Hz, 6 Hz, 2H), 7.38 (d, J = 9 Hz, 2H), 7.43 (s, 2H), 7 .73 (d, J = 9 Hz, 2H), 8.11 (s, IH). MS (DCl-NH 3 ) m/z 454 (M+H)<+>. Anal. calcd for C19H14CI2F4N3O3S: C, 50.23; H, 3.1; N, 9.24. Found: C, 50.28; H, 3.29; N, 9.19.

Example 120

2- Cyclohexyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20 using cyclohexyl bromide instead of 4-fluorobenzyl bromide (yield: 163 mg, 76%). Temp. 169-171 °C. <X>H NMR (DMSO-de, 300 MHz) 51.23 (m, 1H), 1.41 (m, 2H), 1.71 (m, 3H), 1.87 (m, 4H), 3 .23 (s, 3H), 4.85 (m, IH), 7.11 (m, 2H), 7.22 (m, 2H), 7.46 (d, J = 9 Hz, 2H), 7 .85 (d, J = 9 Hz, 2H), 8.11 (s, IH). MS (DCI-NH 3 ) m/z 427 (M+H)<+> °9 m/z 4 44 (M+NH 4 )<+>. Anal. calcd for C 23 H 23 FN 2 O 3 S-O.5 H 2 O: C, 63.43; H, 5.55; N, 6.43. Found: C, 63.25; H, 5.28; N, 6.28.

Example 121

2- Cyclopentyl- 4-( 4- fluorophenyl) - 5- [ 4-( methylsulfonyl) phenyl] - 3 ( 2H_) - pyridazinone

The title compound was prepared according to the method described in Example 20, using cyclopentyl bromide instead of 4-fluorobenzyl bromide (yield: 165 g, 80%). Temp. 191-193 °C. <*>H NMR (DMSO-d6, 300 MHz) 81.67 (m, 2H), 1.85 (m, 4H), 2.05 (m, 2H), 3.23 (s, 3H), 5 .36 (m, IH), 7.12 (t, J = 9 Hz, 2H), 7.22 (rn, 2H), 7.45 (d, J = 9 Hz, 2H), 7.85 (d , J = 9 Hz, 2H), 8.13 (s, 1H). MS (DCI-NH 3 ) m/z 413 (M+H)<+> °9 m/z 430 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 FN 2 O 3 S-°'5 H 2 O: C, 62.69; H, 5.26; N, 6.57. Found: C, 62.53; H, 4.93; N, 6.50.

Example 122

2- Cyclobutyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 20, using cyclobutyl bromide instead of 4-fluorobenzyl bromide (yield: 270 g, 68%). Temp. 202-203 °C. <1>H NMR (DMS0-d6, 300 MHz) 51.85 (m, 2H), 2.32 (m, 2H), 2.50 (m, 2H), 5.40 (quintet, J = 7 Hz , IH), 7.11 (t, J = 9 Hz, 2H), 7.21 (m, 2H), 7.47 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.16 (s, 1H). MS (DCI-NH 3 ) m/z 399 (M+H)<+> and m/z 416 (M+NH 4 )<+>. Anal. calcd for C 21 H 19 FN 2 O 3 S-0.75 H 2 O: C, 61.22; H, 5.01; N, 6.80. Found: C, 61.19; H, 4.62; N, 6.73.

Example 123

2-( 3- Methyl- 2- butenyl)- 4-( 4- fluorophenyl)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)-phenyl]-3(2H)-pyridazinone prepared according to the method in Example 68 was N-debenzylated according to the method described in Example 11. The intermediate was N-alkylated according to the method described in Example 20, using 1-bromo-3-methyl-2-butene instead of 4-fluorobenzyl bromide, to provide the title compound (yield: 50 mg, 30%). Temp. 134-136 °C. <3>H NMR (300 MHz, CDCl 3 ) 51.79

(s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J = 7.5 Hz, 2H), 5.48 (t, J = 6 Hz , IH), 6.96 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.28 (d, J = 9 Hz, 2H) , 7 .83 (s, 1H), 7.85 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 414 (M+H)<+>. Anal. calculated for C21H20FN3O3S: C, 61; H, 4.87; N, 10,16. Found: C, 60.98; H, 4.66; N, 9.95.

Example 124

2-( 2, 4- Difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 123 using 2,4-difluorobenzyl bromide instead of 1-bromo-3-methyl-2-butene (yield: 65 mg, 24%). Temp. 236-238 °C. 1 H NMR (300 MHz, CDCl 3 ) 84.78

(s, 2H), 5.43 (s, 2H), 6.88 (rn, 2H), 6.97 (t, J = 9 Hz, 2H), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.38 (d, J = 9 Hz, 2H), 7.55 (rn, IH), 7.85 (s, IH), 7.86 (d, J = 9 Hz, 2H) . MS (DCI-NH3) m/z 472 (M+H)<+.> Anal. calcd for C23H16F3N3O3S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.44; H, 3.47; N, 8.72.

Example 125

2-( Pentafluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 123 using 2,3,4,5,6-penta-fluorobenzyl bromide instead of 1-bromo-3-methyl-2-butene (yield: 105 mg, 35%). Temp. 201-203 °C. <1>H NMR (300 MHz, CDCl 3 ) 84.8 (s, 2H) , 5.5 (s, 2H), 6.98 (t, J = 9 Hz, 2H) , 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.28 (d, J = 9 Hz, 2H), 7.32 (s, IH), 7.37 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 526 (M+H)<+>. Anal. calcd for C23H13F6N3O3S: C, 52.57; H, 2.49; N, 7.99. Found: C, 52.66; H, 2.68; N, 7,8.

Example 126

2-( 3- Cyclohexenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 123 using 3-bromocyclohexene instead of 1-bromo-3-methyl-2-butene (yield: 30 mg, 10%). Temp. 206-208 °C. <1>h NMR (300 MHz, CDCl 3 ) 81.75-1.85 (m, 3H), 2.1-2.3 (m, 3H), 4.8 (s, 2H), 5.75 ( m, 2H), 6.1 (m, IH), 6.97 (t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, 6 Hz, 2H), 7.28 (d , J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 7.90 (s, 1H). MS (DCl-NH 3 ) m/z 426 (M+H)<+>. Anal. calcd for C22H20FN3O3S: C, 62.10; H, 4.73; N, 9.87. Found: C, 61.27; H, 4.75; N, 9.56.

Example 127

2-( 3, 4- Difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 123 using 3,4-difluorobenzyl bromide instead of 1-bromo-3-methyl-2-butene and allowing the reaction to proceed in DMSO instead of DMF to prevent the formation of by-products (yield: 210 mg , 62%). Temp. 253-255 °C. T-H NMR (300 MHz, DMS0-d6) S 5.33 (s, 2H), 7.13 (t, J = 9 Hz, 2H), 7.22 (dd, J = 9 Hz, 6 Hz, 2H) , 7.28 (m, IH), 7.39 (d, J = 9 Hz, 2H), 7.42 (s, 2H), 7.47 (rn, 2H), 7.73 (d, J - 9 Hz, 2H), 8.12 (s, 1H). MS (DCI-NH3) m/z 472 (M+H}<+>. Anal. calcd. for C23H16F3N3O3S: C, 58.59; H, 3.42; N, 8.91. Found: C, 58.05 ; H, 3.55; N, 8.49.

Example 128

2-( 2, 3- Dihydro- 1H- inden- 2- yl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172 mg, 0.5 mmol), prepared in Example 11, 2-indanol (67 mg, 0.5 mmol) and Ph3P (262 mg, 1 mmol) in toluene (20 mL) and ethyl acetate (5 mL) were prepared and added dropwise to a solution of DIAD (0.2 mL, 1 mmol) in toluene (10 mL) . The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH 2 Cl 2 -ethyl acetate) to provide 200 mg of product (contaminated with reduced DIAD). A second column chromatography (hexanes-ethyl acetate 1:1) gave the title product (yield: 170 mg, 74%). Temp. 97-100 °C. <1>H NMR (DMSO-d6, 300 MHz) δ 3.22 (s, 3H) , 3.32 (m, 2H), 3.44 (dd, J = 9 Hz and 15 Hz, 2H), 5 .83 (m, IH), 7.25 (rn, 4H), 7.34 (m, 4H) , 7.46 (d, J = 9 Hz, 2H) , 7.85 (d, J = 9 Hz , 2H) , 8.06 (s, 1H). MS (DCI-NH 3 ) m/z 461 (M+H)<+> and m/z 478 {M+NH 4 )<+>.

Example 129

2-( 2, 3- Dihydro- 1H- inden- 1- yl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 128 using 1-indanol instead of 2-indanol (yield: 110 mg, 48%). Temp. 128-130 °C. <1>H NMR (DMS0-d6, 300 MHz) δ 2.40 (m, 1H), 2.60 (m, 1H), 3.00 (m, 1H), 3.22 (s+m, 4H ), 6.60 (dd, J = 9 Hz, 6 Hz, IH), 7.16 (rn, 4H), 7.27 (m, 4H), 7.47 (d, J = 9 Hz, 2H) , 7.85 (d, J = 9 Hz, 2H), 8.02 (s, 1H). MS (DCI-NH3) m/z 461 (M+H)<+> °9 m/z 478 (M+NH4)<+.>

Example 130

2-( 4- Tetrahydro- 2H- pyran- 4- yl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 128 using 4-tetrahydro-pyranol instead of 2-indanol (yield: 140 g, 65%). Temp. 230-231 °C. <i>H NMR (300 MHz, DMSO-de) 51.75 (m, 2H), 1.93 (m, 2H), 3.14 (s, 3H), 3.46 (m, 2H), 3 .93 (m, 2H); 5.02 (m, IH), 7.05 (t, J = 9 Hz, 2H), 7.15 (rn, 2H), 7.40 (d, J = 9 Hz, 2H), 7.80 ( d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (APCI-) m/z 428 (M-H)~ and m/z 463 (M+C1)~. Anal. calculated for C 22 H 2 1FN 2 O 4 S-1.25 H 2 °: C, 58.59; H, 5.25; N, 6.21. Found: C, 58.31; H, 4.75; N, 6.05.

Example 131

2-( 2- Methylcyclopentyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 128 using 2-methylcyclopentanol instead of 2-indanol (yield: 230 g, 86%). Temp. 180-181 °C. <i>H NMR (300 MHz, DMSO-d6) 50.75 (d, J = 7 Hz, 3H), 1.60 (m, 2H), 1.89 (m, 2H), 2.10 (rn , IH), 2.21 (rn, IH), 2.40 (m, IH), 3.23 (s, 3H) , 5.37 (q, J = 7 Hz, IH) , 7.12 (t , J = 9 Hz, 2H), 7.21 (m, 2H), 7.47 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.11 ( pp, IH). MS (APCI+) m/z 427 (M+H)<+> and (APCI-) m/z 461 (M+Clp. Anal. calculated for C23H23FN2O3S: C, 64.77; H, 5.43; N, 6.56 Found: C, 64.71, H, 5.34, N, 6.28.

Example 132

2-( 2- Adamantyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 128 using 2-adamantanol

instead of 2-indanol, (yield: 75 g, 25%). M.p. 195-197 °C. <i>H NMR (300 MHz, DMS0-d6) 51.60 (rn, 2H), 1.77 (m, 2H), 1.94 (rn, 6H), 2.35 (m, 4H), 3 .23 (s, 3H), 4.83 (m, IH), 7.11 (t, J = 9 Hz, 2H), 7.22 (m, 2H), 7.47 (d, J = 9 Hz , 2H), 7.87

(d, J = 9 Hz, 2H), 8.11 (s, 1H). MS (APCI+) m/z 479 (M+H)<+ >and (APCI-) m/z 478 (M-H)~, m/z 513 (M+Cl)-. Anal. calcd for C 27 H 27 FN 2 O 3 S-0.25 H 2 O: C, 67.13; H, 5.73; N, 5.79. Found: C, 67.06; H, 5.76; N, 5.06.

Example 133

2-( 3- Methylcyclopentyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 128 using 3-methylcyclopentanol instead of 2-indanol (yield: 155 g, 73%). Temp. 169-171 °C. <i>H NMR (300 MHz, DMSO-de) 51.05 (dd, 2:1, 3H), I, 24 (m, 1H), 1.63 (m, 1H), 2.00 (m, 3H), 2.22 (m, 2H), 3.23 (s, 3H), 5.43 (m, IH), 7.1 (t, J = 9 Hz, 2H), 7.21 (m, 2H), 7.46 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.12 (two s, 2:1, IH). MS (APCI+) m/z 27 (M+H)<+> and (APCI-) m/z 426 (M-H)-, m/z 461 (M+Cl)-. Anal. calcd for C27H27FN2O3S-0.25H2O: C, 64.09; H, 5.49; N, 6.49. Found: C, 64.27; H, 5.62; N, 6.46.

Example 134

2-( 1- Methylcyclopentyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (206 mg, 0.6 mmol), prepared according to the method of Example 11, 1-methyl-1 -cyclopentanol (60 mg, 0.6 mmol), DMAP (18 mg, 0.12 mmol) and Ph3P (262 mg, 1 mmol) in toluene (30 mL) in ethyl acetate (5 mL) were prepared and added dropwise to a solution of DIAD (0.2 mL, 1 mmol) in 10 mL toluene. The mixture was stirred at room temperature for 6 hours and then concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH 2 Cl 2 -ethyl acetate) to provide 80 mg of product (contaminated with reduced DIAD). A second column chromatography (hexanes-ethyl acetate 1:1) gave the title product, (yield: 50 mg, 19%). Temp. 107-110 °C. 3-H NMR (DMSO-d6, 300 MHz) δ 1.55 (s, 3H) , 1.70 (m, 4H) , 2.08

(m, 2H) , 2.32 (rn, 2H) , 3.22 (s, 3H) , 7.10 (t, J = 9 Hz, 2H), 7.20 (m, 2H), 7.45 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.03 (s, 1H). MS (APCI+) m/z 427 (M+H)<+> and (APCI-) m/z 426 (M-H)-, m/z 461 (M+Cl)-.

Example 135

2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

135A. 5- Bromo- 2- fluorostyrene.

A mixture of methyltriphenylphosphonium bromide (2.14 g, 6 mmol) and potassium t -butoxide (672 mg, 6 mmol) in 50 mL of THF was heated under reflux for 30 min under N 2 and then cooled to room temperature. 5-Bromo-2-fluorobenzaldehyde (1.02 g, 5 mmol) was added and the resulting mixture was heated under reflux for 2 hours (until TLC showed that the starting aldehyde had disappeared). The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The acetate layer was washed with water and brine. The solution was dried over MgSO/j and concentrated in vacuo. The residue was purified by chromatography (silica gel, 15:1 hexanes-diethyl ether) to provide 900 mg (90%) of 5-bromo-2-fluorostyrene.

135B. 2-( 3, 4- Difluorophenyl)- 4-( 4- fluoro- 3- vinylphenyl)- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone.

The bromostyrene compound prepared above in 10 mL of THF was added dropwise to a heated mixture of magnesium filings (120 mg, 5 mmol) and a few drops of 1,2-dibromoethane in THF (20 mL) at such a rate that gentle reflux was maintained . The mixture was heated under reflux for the next 30 minutes and cooled to room temperature. The Grignard reagent solution was cooled to -78 <C>C and added dropwise to a solution of 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (540 mg, 1.5 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature for 12 hours. Then a saturated solution of NH 4 Cl was added and the mixture was extracted with ethyl acetate to provide 320 mg of the crude sulfide.

135C. 2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The sulfide prepared above was dissolved in CH 2 Cl 2 (20 mL) and treated at 0 °C with 30% CH 3 CO 3 H in CH 3 CO 2 H (0.5 mL). After 1.5 h, 10% NaHCO 3 was added and the mixture was extracted with CH 2 Cl 2 • The extract was concentrated in vacuo and the residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 270 mg, 37%). <1>H NMR <DMSO-d6, 300 MHz) 53.22 (s, 3H), 5.37 (d, J = 12 Hz, 1H), 5.65 (d, J = 18 Hz, 1H), 6.77 (dd, J = 12 Hz and 18 Hz, IH), 7.15 (m, 2H), 7.57 (m, 5H), 7.90 (m, 3H), 8.28 (s, IH). MS (APCI+) m/z 483 (M+H)<+> °9 (APCI-) m/z 517 (M+Cl)"~. Anal. calculated for C25H17F3N203S-0.5 H2O: C, 61.09 ; H, 3.69; N, 5.69. Found: C, 61.04; H, 3.71; N, 5.34.

Example 136

2-( 3, 4- Difluorophenyl)- 4-( 6- methyl- 3- heptenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A Grignard compound prepared as described in Example 135 using 2-(2-bromomethyl)-1,3-dioxane (586 mg, 3 mmol) instead of 5-bromo-2-fluorostyrene was added to a solution of 2- (3,4-Difluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone (720 mg, 2 mmol) in THF (30 mL) at -78 °C. The mixture was allowed to stand at room temperature for 14 hours, the reaction was quenched with a saturated solution of NH 4 Cl, and the solution was extracted with ethyl acetate to obtain 900 mg of impure sulfide.

The intermediate sulfide product was dissolved in CH 2 Cl 2 (10 mL) and treated at 0 °C with 33% solution of CH 3 CO 3 H in CH 3 CO 2 H (0.7 mL) for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between saturated NaHCO 3 and ethyl acetate. The acetate layer was dried over MgSO 4 and concentrated in vacuo to provide 950 mg of crude sulfonyl derivative.

The sulfonyl compound prepared above was dissolved in acetone (50 mL) and treated with 2 N HCl (10 mL). The resulting mixture was heated under reflux for 16 h and concentrated in vacuo. The residue was extracted with ethyl acetate to provide 900 mg of 2-(3,4-difluorophenyl)-4-(2-formylethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (crude aldehyde, contaminated with some unreacted starting dioxane derivative).

A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t -butoxide (112 mg, 1 mmol) in toluene (25 mL) was heated under reflux for 30 min and then cooled to room temperature. The crude aldehyde was added and the mixture was heated under reflux for 14 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water, 10% citric acid, brine, dried over MgSO 4 and concentrated in vacuo. Purification by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) afforded the title compound as an oil (yield: 120 mg, 13%). <!>h NMR (300 MHz, DMSO-de) δ 0.74 (d, J = 7 Hz, 6H), 1.44 (m, 1H), 1.70 (t, J = 7 Hz, 2H) , 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m, 2H), 7.51 (m, IH), 7.63 (m, IH), 7.74 (d, J = 9 Hz, 2H), 7.82 (m, IH), 8.02 (s, IH), 8.10 (d, J = 9 Hz, 2H). MS (APCI+) m/z 473 (M+H)<+ >and (APCI-) m/z 471 (M-H)-, m/z 507 (M+Cl)-. Anal. calcd for C25H26F2N2O3S: C, 63.54; H, 5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.

Example 137

2-( 3, 4- Difluorophenyl)- 4-( 3- cyclopropylidenepropyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 136 using cyclopropyltriphenylphosphonium bromide instead of isoamyltriphenylphosphonium bromide (yield: 55 mg, 12%). Temp. 128-129 °C. <X>H NMR (300 MHz, DMS0-d6) 50.81 (m, 2H), 0.97 (m, 2H), 2.34 (m, 2H), 2.65 (m, 2H), 3 .32 (s, 3H), 5.64 (rn, IH), 7.52 (m, IH), 7.63 (rn, IH), 7.73 (d, J = 9 Hz, 2H), 7 .81 (m, IH), 8.02 (s, IH), 8.10 (d, J = 9 Hz, 2H). MS (APCI+) m/z 443 (M+H)<+ >and (APCI-) m/z 441 (M-H)-, m/z 477 (M+Cl)-. Anal. calcd for C23H20F2N2O3S-0.5 H2O: C, 61.18; H, 4.68; N, 6.20. Found: C, 61.48; H, 4.60; N, 6.02.

Example 138

2-( 3, 4- Difluorophenyl)- 4-( 5- methyl- 3- hexenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound, an oil, was prepared according to the method described in Example 136 using iso-butyltriphenylphosphonium bromide instead of isoamyltriphenylphosphonium bromide (yield: 110 mg, 7 4%). <X>H NMR (300 MHz, DMSO-d6) 80.75 (d, J = 7 Hz, 6H), 2.22 (m, 3H), 2.54 (m, 2H), 3.32 (s , 3H), 5.12 (m, 2H), 7.52 (ra, IH), 7.60 (m, IH), 7.72 (d, J = 9 Hz, 2H), 7.80 (m , 1H), 8.02 (s, 1H), 8.10 (d, J = 9 Hz, 2H). MS (APCI+) m/z 459 (M+H)<+> and (APCI-) m/z 457 (M-H)-, m/z 493 (M+Cl)-. Anal. calcd for C 24 H 24 F 2 N 2 O 3 S: C, 62.86; H, 5.27; N, 6.10. Found: C, 62.57; H, 5.32; N, 5.81.

Example 139

2-( 3, 4- Difluorophenyl)- 4-( 5- methylhexyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound, an oil, was prepared according to the method described in Example 135B, using 5-methylhexylmagnesium bromide in 3-fluoro-4-vinylphenylmagnesium bromide, (yield: 28 mg, 10%). <1>h NMR (300 MHz, DMSO-

de) 6 0.77 (d, J - 7 Hz, 6H) , 0.88 (m, IH) , 1.03 (m, 2H) , 1.20 (m, IH), 1.46 (m, 5H), 3.32 (s, 3H), 7.52 (m, IH), 7.62 (m, IH), 7.75 (d, J = 9 Hz, 2H), 7.82 (m, 1H), 8.02 (s, 1H), 8.11 (d, J = 9 Hz, 2H). MS (APCI+) m/z 461 (M+H) + and (APCI-) m/z 459 (M-H)-, m/z 495 (M+Cl)~.

Example 140

2-( 3- Chloro-1- methyl- 2E- propenyl)- 4-( 4- fluorophenyl)- 5- [ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 1,3-dichloro-1-butene instead of 3,4-difluorobenzyl bromide (yield: 55 mg, 30%). Temp. 152-154 °C. <X>H NMR (300 MHz, CDCl 3 ) 54.71 (dt, J = 15 Hz, 7.5 Hz, 2H), 2.28 (d, J » 1.5 Hz, 3H), 4.8 ( s, 2H), 4.99 (d, J = 1 Hz, IH), 5.02 (d, J = 1 Hz, IH), 5.85 (td, J = 4 Hz, 1 Hz, IH), 6.98 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.28 (d, J = 9 Hz, 2H), 7.86 (s , 1H) , 7.87 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 434 (M+H)<+>. Anal. calcd for C20H17CIFN3O3S: C, 55.36; H, 3.94; N, 9.68. Found: C, 54.99; H, 3.83; N, 9.34.

Example 141

2-( 2, 3, 3- Trifluoro- 2- propen- l- yl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 1-methylsulfonyloxy-2,2,3-trifluoro-1-propene (mesylate), prepared in Example 88, instead of 3,4-difluorobenzyl bromide (yield: 10 mg , 4%). Temp. 173-175 °C. <X>H NMR (300 MHz, CDCl 3 ) 64.39 (s, 2H), 5.09 (ddd, J = 26 Hz, J = 3 Hz, J = 1 Hz, 2H), 6.98 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, J = 6 Hz, 2H), 7.29 (d, J = 9 Hz, 2H), 7.78 (s, IH), 7.78 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 440 (M+H)<+>, MS (FAB, high res.) m/z calc. for C19H14F4N3O3S: 440.0692 (M+H)<+>. Found: 440.0695 (M+H)<+>, (0.7 ppm error).

Example 142

2-( 1, 1, 2- Trifluoro- 2- propenyl)- 4-( 4- fluorophenyl)-5-[4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was isolated from the same reaction mixture (Example 141) used to prepare 2-(2,3,3-trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4- (aminosulfonyl)phenyl]-3(2H)-pyridazinone. (The title product is the result of a Sn2' attack.) (yield: 50 mg, 20%). Temp. 230-232 °C. <X>H NMR (300 MHz, CDCl 3 ) 84.7 (s, 2H), 5.28 (dd, J = 15 Hz, 4.5 Hz, 1H), 5.39 (dd, J = 45 Hz, 4.5 Hz, IH), 6.98 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.31 (d, J = 9 Hz, 2H) , 7.9 (d, J = 9 Hz, 2H) , 7.92 (s, 1H) , . MS (DCI-NH3) m/z 440 (M+H)<+.> Anal. calcd for C19H13F4N3O3S: C, 51.93; H, 2.98; N, 9.56. Found: C, 51.88; H, 3.01; N, 9.15.

Example 143

2-( 3, 3- Difluoro- 2- propenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( amino- sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 1,3-dibromo-1,1-difluoropropane instead of 3,4-difluorobenzyl bromide and using 5 equivalents of potassium carbonate (yield: 220 mg, 65%). Temp. 191-194 °C. <i>H NMR (300 MHz, DMSO-de) δ 4 , 77 (d, J = 7.5 Hz, 2H), 4.95 (dtd, J = 24 Hz, 7.5 Hz, 1 Hz, IH ), 7.12 (t, J = 9 Hz, 2H), 7.23 (dd, J = 9 Hz, 6 Hz, 2H) , 7.49 (d, J = 9 Hz, 2H), 7.50 (s, 2H), 7.74 (d, J = 9 Hz, 2H), 8.1 (s, 1H). MS (DCl-NH 3 ) m/z 422 (M+H)<+>. Anal. calcd for C19H14F3N3O3S: C, 54.15; H, 3.34; N, 9.97. Found: C, 53.88; H, 3.42; N, 9.76.

Example 14 4

2-( a- Methyl- 3- fluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 3-fluoro-α-methylbenzyl chloride instead of 3,4-difluorobenzyl bromide (yield: 220 mg, 65%). Temp. 192-194 °C. <*>H NMR (300 MHz, DMSO-d6) 81.76 (d, 6 Hz, 3H), 6.27 (q, J = 7 Hz, 1H), 7.1 (t, J = 9 Hz, 2H), 7.22 (dd, J = 9 Hz, 6 Hz, 2H), 7.49 (d, J = 9 Hz, 2H), 7.51 (s, 2H), 7.72 (d, J = 9 Hz, 2H), 8.18 (s, 1H). MS {DCI-NH 3 ) m/z 468 (M+H)<+>. Anal. calcd for C24H19F2N3O3S: C, 61.66; H, 4.09; N, 8.98. Found: C, 61.36; H, 3.96; N, 8.86.

Example 145

2-( 1- Cyclohexenylmethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 1-bromomethyl-cyclohexene instead of 3,4-difluorobenzyl bromide (yield: 70 mg, 28%). Temp. 192-193 °C. <3->H NMR (300 MHz, DMSO-d6) δ 1.55 (rn, 4H), 1.98 (m, 4H), 4.64 (s, 2H), 5.53 (s, 1H) , 7.12 (t, J = 9 Hz, 2H), 7.22 (dd, J = 9 Hz, 6 Hz, 2H), 7.39 (d, J = 9 Hz, 2H), 7.39 ( s, 2H), 7.72 (d, J = 9 Hz, 2H), 8.07 (s, 1H). MS (DCl-NH 3 ) m/z 440 (M+H)<+>. Anal. calcd for C 23 H 22 FN 3 O 3 S: C, 62.85; H, 5.04; N, 9.56. Found: C, 62.47; H, 5.23; N, 9,14.

Example 146

2-( g- Methyl- 2, 3, 4- trifluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 2,3,4-trifluoro-α-methylbenzyl chloride instead of 3,4-difluorobenzyl bromide (yield: 70 mg, 50%). Temp. 192-194 °C. 3-H NMR (300 MHz, CDCl 3 ) 51.84 (d, J = 6 Hz, 3H), 4.8 (s, 2H), 6.54 (q, J = 7 Hz, 1H), 6.96 (t, J = 9 Hz, 2H), 6.99 (m, IH), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.2 (m, IH), 7.38 ( d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 7.88 (s, 1H). MS (DCI-NH3) m/z 504 (M+H)<+.> Anal. calcd for C24H17F4N3O3S: C, 57.25; H, 3.4; N, 8.34. Found: C, 56.84; H, 3.52; N, 7.91.

Example 14 7

2-( a- Methyl- 3, 5- difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( amino-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 3,5-difluoro-α-methylbenzyl chloride instead of 3,4-difluorobenzyl bromide (yield: 80 mg, 45%). Temp. 139-141 °C. 3-H NMR (300 MHz, CDCl 3 ) 51.83 (d, J = 6 Hz, 3H), 4.79 (s, 2H), 6.32 (q, J 7 Hz, 1H), 6.84 ( m, IH), 6.97 (t, J = 9 Hz, 2H), 7.02 (dd, J = 6 Hz, 1.5 Hz, 2H), 7.18 (dd, J - 9 Hz, 6 Hz, 2H), 7.28 (d, J - 9 Hz, 2H), 7.85 (s, 1H), 7.9 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 486 (M+H)<+.> Anal. calcd for C 24 H 18 F 3 N 3 O 3 S: C, 59.37; H, 3.73; N, 8.65. Found: C, 59.00; H, 3.70; N, 8.35.

Example 148

2-( a- Methyl- 3, 4- difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 3,4-difluoro-α-methylbenzyl chloride instead of 3,4-difluorobenzyl bromide (yield: 200 mg, 58%). Temp. 214-215 °C. 1-H NMR (300 MHz, CDCl 3 ) 81.82 (d, J = 6 Hz, 3H), 4.7 (s, 2H), 6.35 (q, J = 7 Hz, 1H), 6.96 (t, J = 9 Hz, 2H), 7.16 (m, 4H), 7.28 (d, J = 9 Hz, 2H), 7.37 (m, IH), 7.84 (d, J = 9 Hz, 2H), 7.90 (s, 1H) . MS (DCl-NH 3 ) m/z 486 (M+H) 4 *. Anal. calcd for C 24 H 18 F 3 N 3 O 3 S: C, 59.37; H, 3.73; N, 8.65. Found: C, 59.13; H, 3.73; N, 8.54.

Example 149

2-( 3-Fluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 3-fluorobenzyl bromide instead of 3,4-difluorobenzyl bromide (yield: 160 mg, 61%). Temp. 220-222 °C. <X>H NMR (300 MHz, DMS0-d6) 55.37 (s, 2H), 7.12 (t, J = 9 Hz, 2H), 7.22 (m, 5H), 7.39 (m , 5H), 7.73 (d, J = 9 Hz, 2H), 8.11 (s, 1H). MS {DCI-NH 3 ) m/z 454 (M+H)<+>. Anal. calcd for C23H17F2N3O3S: C, 60.92; H, 3.77; N, 9.26. Found: C, 61.06; H, 4.22; N, 8.88.

Example 150

2-( 4-Fluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 4-fluorobenzyl bromide instead of 3,4-difluorobenzyl bromide (yield: 85 mg, 34%). Temp. 237-239 °C. <X>H NMR (300 MHz, DMSO-d6) 85.32 (s, 2H), 7.12 (t, J = 9 Hz, 2H), 7.22 (m, 4H), 7.38 (m , 4H), 7.47 (dd, J = 9 Hz, 6 Hz, 2H), 7.72 (d, J = 9 Hz, 2H), 8.10 (s, 1H). MS (DCl-NH 3 ) m/z 454 (M+H)<+>. Anal. calcd for C23H17F2N3O3S: C, 60.92; H, 3.77; N, 9.26. Found: C, 60.61; H, 3.96; N, 8.74.

Example 151

2-( 2, 4, 6- Trifluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 2,4,6-trifluorobenzyl bromide instead of 3,4-difluorobenzyl bromide (yield: 255 mg, 73%). Temp. 201-203 °C. <3->H NMR (300 MHz, DMSO-

de) 8 5, 38 (s, 2H) , 7.13 (t, J = 9 Hz, 2H) , 7.23 (m, 4H) , 7.38 (d, J = 9 Hz, 2H), 7 .42 (s, 2H), 7.70 (d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (DCl-NH 3 ) m/z 490 (M+H)<+>. Anal. calcd for C23H15F4N3O3S: C, 56.44; H, 3.08; N, 8.58. Found: C, 56.31; H, 3.09; N, 8.40.

Example 152

2-( 2, 4, 5- Trifluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127, using 2,4,5-trifluorobenzyl bromide instead of 3,4-difluorobenzyl bromide (yield: 180 mg, 49%). Temp. 236-238 °C. <3->H NMR (300 MHz, DMSO-d6) 85.35 (s, 2H), 7.13 (t, J = 9 Hz, 2H), 7.23 (dd, J = 9 Hz, 6 Hz , 2H), 7.39 (d, J = 9 Hz, 2H), 7.41 (s, 2H), 7.6 (m, 2H), 7.72 (d, J = 9 Hz, 2H), 8,11 (p, IH) . MS (DCl-NH 3 ) m/z 490 (M+H)<+>. Anal. calcd for C23H15F4N3O3S: C, 56.44; H, 3.08; N, 8.58. Found: C, 56.38; H, 3.28; N, 8.41.

Example 153

2-( 2, 3, 4- Trifluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 127 using 2,3,4-trifluorobenzyl bromide instead of 3,4-difluorobenzyl bromide (yield: 220 mg, 63%). Temp. 218-220 °C. <1>h NMR (300 MHz, DMSO-de)-5 5.40 (s, 2H) , 7.13 (t, J = 9 Hz, 2H) , 7.22 (dd, J = 9 Hz, 6 Hz, 2H), 7.34 (m, 2H), 7.39 (d, J = 9 Hz, 2H), 7.42 (s, 2H), 7.73 (d, J = 9 Hz, 2H) , 8,12 (p, IH). MS (DCl-NH 3 ) m/z 490 (M+H)<+>. Anal. calcd for C23H15F4N3O3S: C, 56.44; H, 3.08; N, 8.58. Found: C, 56.32; H, 3.24; N, 8.31.

Example 154

2-( 4, 4, 4- Trifluoro- 3- methyl- 2E- butenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 123 using l-bromo-3-methyl-4,4,4-trifluoro-2-butene instead of l-bromo-3-methyl-2-butene (yield: 160 mg, 48%). Temp. 155-157 °C. 1 H NMR (300 MHz, CDCl 3 ) 52.00 (s, 3H), 4.8 (s, 2H), 4.96 (d, J = 7.5 Hz, 2H), 6.33 (m, 1H ), 6.99 (t, J = 9 Hz, 2H), 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.29 (d, J = 9 Hz, 2H), 7.95 (s, 1H), 7.97 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 468 (M+H)<+>. Anal. calcd for C21H17F4N3O3S: C, 53.96; H, 3.66; N, 8.98. Found: C, 53.84; H, 3.51; N, 8.77.

Example 155

2-( 4- Biphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-bromobiphenyl instead of 4-iodo-1-fluorobenzene (yield: 0.275 g, 100%). Temp. 249-251 °C. <3->H NMR (300 MHz, DMSO de) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.30 (m, 2H), 7.42 (m, 1H), 7.48-7.58 (m, 4H), 7.75 (m, 4H), 7.84 (m, 2H), 7.91 (m, 2H), 8.27 (s, 1H). MS (DCI-NH3) m/z 497 (M+H)<+>, 514 (M+NH4)<+.> Anal. calcd for C 23 H 21 FN 2 O 3 S: C, 70.15; H, 4.26; N, 5.64. Found: C, 69.81; H, 4.42; N, 5.41.

Example_ 156

2-( 4- Bromophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1,4-dibromobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.337 g, 93%). 1 H NMR (300 MHz, DMSO d6) 83.24 (s, 3H), 7.14 (m, 2H), 7.28 (rn, 2H), 7.64 (m, 2H), 7.75 ( m, 2H), 7.90 (m, 2H), 8.25 (s, 1H). MS (DCl-NH 3 ) m/z 499 (M+H)<+>, 518 (M+NH 4 )<+>. Anal. calcd for C 23 Hi 6 BrFN 2 O 3 S■0.75 H 2 O: C, 53.86; H, 3.43; N, 5.46. Found: C, 53.92; H, 3.16; N, 5.34.

Example_ 157

2-( 4- Nitrophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1-iodo-4-nitrobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.45 g, 100%). Temp. 110-116 °C. 3-H NMR (300 MHz, DMSO d6) δ 3.24 (s, 3H), 7.17 (rn, 2H), 7.32 (m, 2H), 7.53 (m, 2H), 7, 91 (m, 2H), 8.03 (rn, 2H), 8.34 (s, 1H), 8.40 (rn, 2H). MS (DCl-NH 3 ) m/z 466 (M+H)<+>, 483 (M+NH 4 )<+>. Anal. calcd for C 23 H 16 FN 3 O 5 S: C, 59.35; H, 3.46; N, 9.03. Found: C, 59.02; H, 3.62; N, 8.82.

Example 158

2-( 4- Phenoxyphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-bromodiphenyl ether instead of 4-iodo-1-fluorobenzene (yield: 0.667 g, 22%). Temp. 118-125 °C. 11 NMR (300 MHz, DMSO de) δ 3.24 (s, 3H), 7.12 (m, 5H), 7.15-7.33 (m, 4H), 7.46 (m, 2H), 7.52 (m, 2H), 765 (m, 2H), 7.90 (m, 2H), 8.23 (s, 1H). MS (DCl-NH 3 ) m/z 513 (M+H)<+>. Anal. calculated for C25H21FN2O4S•°»75 H2O: C, 66.21; H, 4.31; N, 5.32. Found: C, 65.98; H, 4.25; N, 5.27.

Example 159

2-( 4- t- Butylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1-bromo-4-t-butylbenzene instead of 4-iodo-1-fluorobenzene. No product was observed. The solution was concentrated in vacuo. The resulting solid was dissolved in DMF (5 mL) and Cul (13.3 mg, 0.07 mmol) was added. The solution was refluxed overnight. When the reaction was complete, the mixture was poured into 10% citric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO 4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO 2 ), eluting with 5% diethyl ether/CH 2 Cl 2 to afford the desired product (yield: 0.292 g, 84%). Temp. 132-136 °C. !h NMR (300 MHz, DMSO de) 51.34 (s, 9H), 3.24 (s, 3H), 7.14 (m, 2H), 7.29 (m, 2H), 7.54 ( m, 6H), 7.90 (m, 2H), 8.23 (s, 1H). MS (DCl-NH 3 ) m/z 477 (M+H)<+>, 494 (M+NH 4 )<+>. Anal. calcd for C27H25FN2O3S: C, 68.05; H, 5.29; N, 5.88. Found: C, 67.94; H, 5.31; N, 5.67.

Example 160

2-( 4- Chlorophenyl)- A -( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-bromo-1-chlorobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.254 g, 83.5%). Temp. 214-216 °C. <1>H NMR (300 MHz, DMSO de) 83.24 (s, 3H), 7.16 (m, 2H) , 7.29 (m, 2H) , 7.52 (m, 2H) , 7, 61 (m, 2H), 7.71 (m, 2H), 7.91 (rn, 2H), 8.26 (s, 1H). MS (DCl-NH 3 ) m/z 455 (M+H)<+>, 472 (M+NH 4 )<+>. Anal. calcd for C 23 H 16 CIFN 2 O 3 S: C, 60.73; H, 3.55; N, 6.16. Found: C, 60.45, H, 3.41; N, 6.05.

Example 161

2-( 3- Methylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-bromotoluene instead of 4-iodo-1-fluorobenzene (yield: 0.262 g, 83%). Temp. 213-216 °C. 3-H NMR (300 MHz, DMSO d6) δ 2.39 (s, 3H), 3.24 (s, 3H), 7.14 (rn, 2H), 7.28 (m, 3H), 7, 43 (m, 3H), 7.53 (m, 2H), 7.80 (m, 2H), 8.22 (s, 1H). MS (DCl-NH 3 ) m/z 435 (M+H)<+>, 452 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 FN 2 O 3 S: C, 66.35; H, 4.41; N, 6.45. Found: C, 66.00, H, 4.16; N, 6.23.

Example 162

2-( 3- Vinylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-bromostyrene instead of 4-iodo-1-fluorobenzene (yield: 0.202 g, 62%). Temp. 182-183 °C. ^-H NMR (300 MHz, DMSO d6) δ 3.25 (s, 3H), 5.35 (d, J = 12 Hz, 1H), 5.92 (d, J = 15 Hz, 1H), 6 .82 (m, IH), 7.15 (m, 2H), 7.30 (m, 2H), 7, 50-7, 60 (m, 4H) , 7.74 (m, IH), 7, 91 (m, 2H), 8.24 (s, 1H). MS (DCl-NH 3 ) m/z 447 (M+H)<+>, 4 64 (M+NH 4 )<+>. Anal. calcd for C25H19FN2O3S•0.50 H2O: C, 65.92; H, 4.42; N, 6.14. Found: C, 65.86; H, 4.40; N, 6.07.

Example 163

2-( 2- Formylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 2-bromobenzaldehyde instead of 4-iodo-1-fluorobenzene (yield: 0.196 g, 60%). Temp. 234-236 °C. <!>h NMR (300 MHz, DMSO de) δ 3.24 (s, 3H), 7.15 (m, 2H), 7.27 (m, 2H), 7.54 (m, 2H), 7 .64-7.75 (m, 2H), 7.86-7.95 (m, 3H), 8.01 (m, IH), 8.29 (s, IH) , 10.02 (s, IH ). MS {DCI-NH3) m/z 449 (M+H)<+.> Anal. calcd for C24H17FN2O4S-0.50 H2O: C, 63.01; H, 3.96; N, 6,12. Found: 63.04; H, 3.82; N, 5.88.

Example 164

2-( 2- Nitrophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1-bromo-2-nitrobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.307 g, 90.8%). Temp. 236-239 °C. <!>h NMR (300 MHz, DMSO de) 53.24

(s, 3H), 7.12-7.27 (m, 4H), 7.56 (m, 2H), 7.7-8.01 (m, 5H), 8.18 (m, IH), 8.35 (p, 1H). MS (DCl-NH 3 ) m/z 466 (M+H)<+>, 483 (M+NH 4 )<+>. Anal. calcd for C 23 H 16 FN 3 O 5 S•0.25 H 2 O: C, 58.78; H, 3.53; N, 8.94. Found: C, 58.63; H, 3.54; N, 8.88.

Example 165

2-( 3- Chlorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1-bromo-3-chlorobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.255 g, 77%). Temp. 232-235 °C. 1-H NMR (300 MHz, DMSO de) δ 3.23 (s, 3H), 7.14 (m, 2H), 7.29 (m, 2H), 7.49-7.58 (m, 4H ), 7.66 (m, IH), 7.79 (m, IH), 7.90 (m, 2H), 8.25 (s, IH). MS (DCl-NH 3 ) m/z 455 (M+H)<+>, 472 (M+NH 4 )<+>. Anal. calcd for C 23 HI 6 CIFN 2 O 3 S: C, 60.73; H, 3.55; N, 6.16. Found: C, 60.40; H, 3.43; N, 5.98.

Example 166

2-(3-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 62 using 1,3-dibromobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.216 g, 60%). Temp. 210-212 °C. <1>H NMR (300 MHz, DMSO de) 63.23 (s, 3H), 7.15 (m, 2H), 7.29 (m, 2H), 7.48-7.55 (m, 3H ), 7.69 (m, 2H), 7.90 (rn, 3H), 8.26 (s, 1H). MS (DCI-NH3) m/z 499 (M+H)<+>, 519 {M+NH4)<+.> Anal. calcd for C 23 HieBrFN 2 O 3 S: C, 55.32; H, 3.23; N, 5.61. Found: C, 55.12; H, 3.12; N, 5, 51.

Example 167

2-( 4- Cyanophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-bromobenzonitrile instead of 4-iodo-1-fluorobenzene (yield: 0.349 g, 100%). Temp. 273-278 °C. <*>H NMR (300 MHz, DMSO d6) 83.24 (s, 3H), 7.11-7.21 (rn, 2H), 7.25-7.35 (m, 2H), 7.52 (m, 2H), 7.88-7.96 (rn, 4H), 8.04 (m, 2H), 8.31 (s, 1H). MS (DCl-NH 3 ) m/z 445 (M+H)<+>. Anal. calcd for C 24 H 16 FN 3 O 3 S: C, 64.71; H, 3.62; N, 9.43. Found: C, 64.50; H, 3.53; N, 9.35.

Example 168

2-( 5- Methyl- 2- thienyl))- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 2-bromo-5-methyl-thiophene instead of 4-iodo-1-fluorobenzene (yield: 0.200 g, 62%). Temp. 219-224 °C. <!>h NMR (300 MHz, DMSO d6) 52.45 (s, 3H), 3.23 (s, 3H), 6.80 (m, 1H), 7.17 (m, 2H), 7, 29 (m, 2H), 7.52 (m, 3H), 7.89 (m, 2H), 8.33 (s, 1H). MS (DCI-NH3) m/z 441 (M+H)<+>, 458 {M+NH4)<+.> Anal. calcd for C22H17FN2O3S2: C, 59.99; H, 3.89; N, 6.36. Found: C, 59.90; H, 3.91; N, 6.26.

Example 169

2-( 3- Biphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-bromobiphenyl instead of 4-iodo-1-fluorobenzene (yield: 0.28 g, 78%). Temp. 126-134 °C. !h NMR (300 MHz, DMSO d6 ) δ 3.24 (s, 3H), 7.15 (m, 2H), 7.31 (m, 2H), 7.37-7.45 (m, 1H) , 7.51 (m, 4H), 7.64 (m, 2H), 7.68-7.79 (m, 3H), 7.92 (m, 3H), 8.27 (s, 1H). MS (DCl-NH 3 ) m/z 497 (M+H)<+>, 514 (M+NH 4 )<+>. Anal. calcd for C29H21FN2O3S: C, 70.15; H, 4.26; N, 5.64. Found: C, 69.91; H, 4.33; N, 5.74.

Example 170

2-( 3, 5- Dimethylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 5-bromo-m-xylene instead of 4-iodo-1-fluorobenzene (yield: 0.152 g, 46.5%). Temp. 130-134 °C. <1>H NMR (300 MHz, DMSO de) 52.34 (s, 6H), 3.23 (s, 3H), 7.07-7.12 (rn, 2H), 7.15 (m, 1H ), 7.21-7.32 (m, 4H), 7.52 (m, 2H), 7.90 (rn, 2H), 8.29 (s, 1H). MS (DCl-NH 3 ) m/z 449 (M+H)<+>, 466 (M+NH 4 )<+>. Anal. calcd for C 25 H 21 FN 2 O 3 S: C, 66.95; H, 4.72; N, 6.25. Found: C, 66.81; H, 4.57; N, 6.07.

Example 171

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

4-(4-Fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 11, starting from 2-benzyl-4-(4-fluorophenylmethyl)- 5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.3319 g, 83%).

The title compound was prepared according to the method described in Example 62 using 4-(4-fluorophenyl-methyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)- 5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 1-bromo-3,4-difluorobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.085 g, 54%). Temp. 157-159 °C. <1>H NMR (300 MHz, DMSO de) 53.30 (s, 3H), 3.88 (bs, 2H), 7.04 (m, 4H), 7.49-7.66 (m, 2H ), 7.70 (m, 2H), 7.81 (rn, 1H), 8.12 (s, 1H). MS (DCl-NH 3 ) m/z 471 (M+H)<+>, 488 (M+NH 4 )<+>. Anal. calcd for C 24 H 17 F 3 N 2 O 3 S•0.25 H 2 O: C, 60.69; H, 3.71; N, 5.84. Found: C, 6.39; H, 3.76; N, 5.81.

Example 172

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-(4-fluorophenyl-methyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)- 5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-bromo-2-chloro-1-fluorobenzene instead of 4-iodo-1-fluorobenzene (yield: 0.110 g, 74%). Temp. 153-156 °C. <X>H NMR (300 MHz, DMSO d.6) δ 3.30 (s, 3H), 3.89 (bs, 2H), 7.02-7.07 (m, 4H), 7.59 ( m, 1H), 7.65-7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCI-NH3) m/z 487 (M+H)<+>, 504 (M+NH4)<+.> Anal. calcd for C24H17C1F2N2O3S-0.25H2O: C, 58.65; H, 3.58; N, 5.64. Found: C, 58.41; H, 3.56; N, 5.36.

Example 173

2-( 2- Thienyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 2-bromothiophene instead of 1-bromo-4-fluorobenzene (yield: 98 mg, 40%). Temp. 215-217 °C. <i>H NMR (300 MHz, DMSO-de) δ 3.25 (s, 3H) , 7.18 (m, J = 9 Hz, 3H), 7.29 (m, 2H), 7.42 ( d, 2H), 7.75 (d, 1H), 7.93 (d, J = 9 Hz), 8.4 (s, 1H). MS (DCl-NH 3 ) m/z 427 (M+H)<+>, 444 (M+NH 4 )<+>. Anal. calcd for C21H15FN2O3S2: C, 59.14; H, 3.54; N, 6.57.

Example 174

2-( 4- Trifluoromethylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using l-bromo-4-trifluoromethylbenzene instead of l-bromo-4-fluorobenzene (yield: 185 mg, 64%). Temp. 171-173 °C. <1->H NMR (300 MHz, DMSO-de) 63.25 (s, 3H) , 7.18 (t, 2H) , 7.29 (m, 2H) , 7.52 (d, J = 9 Hz 2H), 7.91 (d, J = 9 Hz, 2H), 7.93 (s, 4H), 8.32 (s, 1H). MS (DCl-NH 3 ) m/z 489 (M+H)<+>, 506 (M+NH 4 )<+>. Anal. calcd for C24H16F4N2O3S: C, 59.02; H, 3.3; N, 5.74. Found: C, 58.75; H, 3.35; N, 5.69.

Example 175

2-[ 4-( 1- Pyrroyl) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 1-(4-iodophenyl)-pyrrole instead of 1-bromo-4-fluorobenzene (yield: 140 mg, 50%). Temp. 229-231 °C. <X>H NMR (300 MHz, DMSO-d6) 53.25 (s, 3H), 6.3 (t, 2H), 7.18 (t, 2H), 7.29 (m, 2H), 7 .46 (t, 2H) 7.53 (d, J = 9 Hz 2H), 7.75 (s, 4H), 7.91 (d, J = 9 Hz, 2H), 8.27 (s, IH ). MS (DCI-NH3) m/z 486 (M+H)<+>, 504 (M+NH4)<+.> Anal. calc'd for C 27 H 20 FN 3 O 3 S' 0.5 H 2 O: C, 66.79; H, 4.15; N, 8.65. Found: C, 65.21; H, 4.29; N, 8, 12.

Example 176

2-( 5- Chloro- 2- thienyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using l-bromo-5-chlorothiophene instead of l-bromo-4-fluorobenzene (yield: 225 mg, 93%). Temp. 190-192 °C. 3-H NMR (300 MHz, DMSO-d6) δ 2.38 (s, 3H), δ 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (rn, 4H), 7.5 (D, 4H) 7.91 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 435 (M+H)<+>, 452 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 F N 2 O 3 S: C, 66.35; H, 4.41; N, 6.45. Found: C, 66.15; H, 4.37; N, 6.3.

Example 177

2-( 4- Methylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using l-bromo-4-methylbenzene instead of l-bromo-4-fluorobenzene (yield: 79 mg, 31%). Temp. 190-192 °C. <1>H NMR (300 MHz, DMSO-d6) δ 2.38 (s, 3H), 63.25 (s, 3H) , 7.15 (t, 2H) , 7.29 (rn, 4H) , 7.5 (D, 4H) 7.91 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 435 (M+H)<+>, 452 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 F N 2 O 3 S: C, 66.35; H, 4.41; N, 6.45. Found: C, 66.15; H, 4.37; N, 6.3.

Example 178

2-( 4- Fluorophenyl)- 4-( 2- ethyl- 1- hexyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) at room temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol), and after 10 min 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (193 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for the next 2 hours. The reaction was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried with MgSO 4 and purified by chromatography (silica gel, 2:1 hexanes-ethyl acetate) to provide the desired product (yield: 140 mg, 60%). Temp. 120-122 °C. <!>h NMR (300 MHz, DMSO-de) δ 0.75 (m, 6H), 1.1

(m, 6H), 1.20 (quintet, J = 7 Hz, 2H), 1.44 (m, IH), 3.27 (s, 3H), 4.30 (d, J = 6 Hz, 2H ), 7.37 (t, J = 9 Hz, 2H), 7.65 (m, 2H), 7.89 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 473 (M+H)<+>; (APCI-) m/z 507 (M+Cl)-. Anal. calcd for C 25 H 29 FN 2 O 4 S■0.5 H 2 O: C, 62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22.

Example 179

2-( 3- Thienyl)- 4-( 4- fluorophenyl }- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H )- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-bromothiophene instead of 1-bromo-4-fluorobenzene (yield: 225 mg, 93%). Temp. 200-202 °C. <X>H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m, 2H), 7.5 (d, J = 9 Hz, 2H), 7.6 (M, IH) 7.66 (dd, IH), 7.91 (d, J = 9 Hz, 2H), 8.13 (dd, IH), 8.25 (s , IH). MS (DCl-NH 3 ) m/z 427 (M+H)<+>, 444 (M+NH 4 )<+. >Anal. calcd for C21H15FN2O3S2: C, 55.07; H, 4.07; N, 6.11. Found: C, 54.63; H, 3.47; N, 6.01.

Example 180

2-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 62 using 3,5-difluorobromobenzene instead of 1-bromo-4-fluorobenzene (yield: 250 mg, 96%). Temp. 166-168 °C. 3-H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 57.15 (t, 2H), 7.27 (rn, 2H), 7.4 (m, 1H), 7 .41 (m, 2H), 7.51 (d, J = 9 Hz, 4H), 7.9 (d, J = 9 Hz, 2H), 8.3 (s, IH). MS {DCI-NH3) m/z 457 (M+HJ<+>, 474 (M+NH4)<+.> Anal. calcd. for C23H15F3N2O3S: C, 60.13; H, 3.31; N, 6, 14. Found: C, 60.49; H, 3.31; N, 6.03.

Example 181

2-( 2, 4- Difluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 2,4-difluorobromobenzene instead of 1-bromo-4-fluorobenzene (yield: 40 mg, 15%). Temp. 245-247 °C. 1 H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 57.15 (t, 2H), 7.3 (t, 2H), 7.54 (m, 2H), 7, 57 (m, 2H), 7.75 (m, 1H), 7.9 (d, J = 9 Hz, 2H), 8.27 (s, 1H). MS {DCI-NH 3 ) m/z 457 (M+H)<+>, 474 (M+NH 4 )<+>. Anal. calcd for C28H15F3N2O3S: C, 60.52; H, 3.31; N, 6.03.

Example 182

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenyl)- 5- f 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3,4-difluorobromobenzene instead of 1-bromo-4-fluorobenzene (yield: 170 mg, 70%). Temp. 109-110 °C. <i>H NMR (300 MHz, DMSO-de) 53.23 (s, 3H), 57.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H), 7 .59 (m,

4H), 7.83 (ra, 1H), 7.9 (d, J = 9 Hz, 2H), 8.27 (s, 1H). MS {DCI-NH3) m/z 457 (M+H)<+>, 474 (M+NH4)<+.> Anal. calcd for C23H15F3N3O3S: C, 60.52; H, 3.31; N, 6.14. Found 60.60; H, 3.48; N, 5.89

Example 183

2-( 3- Furyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-bromofuran instead of 1-bromo-4-fluorobenzene (yield: 175 mg, 73%). Temp. 239-242 °C. <3->H NMR (300 MHz, DMSO-de) 53.25 (s, 3H), 7.09 (d, 1H), 7.15 (t, 2H), 7.29 (m, 2H), 7.5 (d, J = 9 Hz 2H), 7.8 (t, IH) 7.91 (d, J = 9 Hz, 2H), 8.3 (s IH), 8.58

<s, IH) . MS (DCl-NH3) m/z 411 (M+H)<+>, 428 (M4-NH4) + . Anal. calcd for C21H15F N2C>4S-0'5 H2O: C, 61.46; H, 3.68; N, 6.83. Found: C, 59.91; H, 3.54; N, 6.54.

Example 184

2-( 3- Fluoro- 4- methoxyphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-fluoro-4-methoxy-bromobenzene instead of 1-bromo-4-fluorobenzene (yield: 230 mg, 85%). Temp. 97-101 °C. 3-H NMR (300 MHz, DMSO-d6) S 3.25 (s, 3H), 3.9 (s, 3H), 7.16 (d, 1H), 7.29 (m, 3H), 7 .5 (m, 4H), 7.91 (d, J = 9 Hz, 2H), 8.23 (s IH). MS (DCl-NH 3 ) m/z 469 (M+H)<+>, 491 (M+NH 4 )<+>. Anal. calcd for C 24 H 18 F 2 N 2 O 4 S-0.5 H 2 O: C, 61.53; H, 3.87; N, 5.98. Found: C, 61.18; H, 4.01; N, 5.58.

Example 185

2-( 2-Fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 2-fluorobromobenzene instead of 1-bromo-4-fluorobenzene (yield: 195 mg, 75%). Temp. 96-103 °C. ^-H NMR (300 MHz, DMSO-de) 83.23 (s, 3H), 87.15 (t, 2H), 7.3 (m, 3H), 7.55 (m, 5H), 7, 9 (d, J = 9 Hz, 2H), 8.27 (s, 1H). MS (ESI) m/z 437 (M-H)<+>). Anal. calcd for C23H16F2N2O3S: C, 63.01; H, 3.68; N, 6.39. Found, C, 62.91; H, 4.06; N, 5.99.

Example 186

2-[ 4-( Aminosulfonyl) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 4-aminosulfonyl-1-bromobenzene instead of 1-bromo-4-fluorobenzene. Temp. 213-216 °C. 3-H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H) , 7.15 (t, 2H) , 7.29 (m, 2H), 7.53 (s, 2H) 7, 55 (s, 1H), 7.7 (dd, 2H) 7.91 (t, 4H), 7.98 (d, 2H), 8.3 (s, 1H). MS (DCl-NH 3 ) m/z 499 (M+H)<+>, 517 (M+NH 4 )<+>. Anal. calcd for C23H18FN3O5S2•0.5H2O: C, 55.30; H, 3.63; N, 8.41. Found: C, 54.4; H, 3.79; N, 7.78.

Example 187

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3-chloro-4-fluoro-1-bromobenzene instead of 1-bromo-4-fluorobenzene (yield: 320 mg, 78%). Temp. 155-157 °C. <i>H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 57.15 (t, 2H), 7.3 (t, 2H) , 7.25 (m, 2H) , 7.53 (d, J = 9 Hz, 2H), 7.59 (t, IH), 7.73 (m, IH), 7.9 (d, J = 9 Hz, 2H) 7.96 (m , 1H), 8.27 (s, 1H). MS (DCI-NH3) m/z 473 (M+H)<+>, 490 (M+NH4)4". Anal. calcd. for C23H15CIF2N2O3S: C, 58.42; H, 3.2; N, 5, 92. Found 58.23; H, 2.87; N, 5.70

Example 188

2-( 3, 5- Dichlorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using 3,5-dichlorobenzene instead of 1-bromo-4-fluorobenzene (yield: 360 mg, 78%).

Temp. 289-294 °C. 3-H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H) , 87.15 (t, 2H), 7.27 (m, 2H) , 7.51 (d, J = 9 Hz , 4H) , 7.75 (t, 1H), 7.83 (d, 2H), 7.9 (d, J = 9 Hz, 2H), 8.3 (s, 1H). MS (DCl-NH 3 ) m/z 490 (M+H)<+>, 507 (M+NH 4 )<+>. Anal. calcd for C 23 H 15 C 12 FN 2 O 3 S-0.5 H 2 O: C, 56.45; H, 3.09; N, 5.72. Found: C, 55.36; H, 3.00; N, 5.50.

Example 189

2-( 4- Fluoro- 3- methylphenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62 using l-bromo-4-fluoro-3-methylbenzene instead of l-bromo-4-fluorobenzene (yield: 275 mg, 71%). Temp. 168-170 °C. 3-H NMR (300 MHz, DMSO-d6) 52.3 (s, 3H), δ 3.25 (s, 3H) , 7.15 (t, 2H) , 7.3 (m, 3H) , 7 .56 (m, 4H), 7.9 (d, 2H), 8.23 (s, 2H). MS (DCl-NH 3 ) m/z 453 (M+H)<+>, 471 (M+NH 4 )<+>. Anal. calcd for C 24 H 18 F 2 N 2 O 3 S: C, 63.71; H, 4.01; N, 6.01. Found: C, 63.53; H, 4.06; N, 5, 92.

Example 190

2-( 4- Chloro- 3- fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone:

The title compound was prepared according to the method described in Example 62 using 4-bromo-1-chloro-2-fluorobenzene instead of 1-bromo-4-fluorobenzene (yield: 220 mg, 80%). Temp. 102-110 °C. <1>H NMR (300 MHz, DMSO-de) 83.23 (s, 3H), 7.11-7.19 (m, 2H), 7.25-7.32 (m, 2H), 7, 51 (d, J= 5.6 Hz, 2H), 7.58-7.64 (m, IH), 7.75-7.87 (rn, 2H), 7.91 (d, J = 5, 6 Hz, 2H), 8.28 (s, 1H). MS (APCI+) m/z 473 (M+H)<+. >Example 191 2-( 4- Chloro-2- fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H )- pyridazinone: The title compound was prepared according to the method described in Example 62 using l-bromo-4-chloro-2-fluorobenzene instead of l-bromo-4-fluorobenzene (yield: 65 mg 24%). Temp. 250-260 °C. ^-H NMR (300 MHz, DMSO-dg) δ 3.21 (s, 3H), 7.12-7.19 (m, 2H), 7.25-7.32 (rn, 2H), 7, 49-7.58 (m, 3H), 7.68-7.78 (m, 2H), 7.91 (d, J = 8.7 Hz, 2H), 8.29 (s, 1H). MS (APCI+) m/z 473 (M+H)<+.> Anal. calcd for C 23 H 15 CIF 2 N 2 O 3 S: C, 58.41; H, 3.19; N, 5.92. Found: C, 58.69; H, 3.45; N, 5.78.

Example 192

2-( 1- Adamantyloxycarbonyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the procedure of Example 11 (200 mg, 0.58 mmol) in CH 2 Cl 2 (8 ml) was prepared and stirred. 1-Adamantyl fluoroformate (172 mg, 0.87 mmol), dimethylaminopyridine (14 mg, 0.011 mmol) and triethylamine (0.12 mL, 0.87 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH 2 Cl 2 (50 mL) and washed with 10% citric acid (50 mL), brine (50 mL) and dried over MgSO 4 and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiC<2, eluting with 15:1 CH 2 Cl 2 : diethyl ether) to afford the desired product (yield: 55 mg, 18%). 1 H NMR (300 MHz, DMSO-de) 51.66 (bs, 6HJ , 2.25 (bd, 10H), 3.21 (s, 3H), ?7.15 (t, 2H), 7.24 (m, 2H), 7.6 (dd, 2H), 7.88 (d, J = 9 Hz, 2H), 8.15 (s, 1H). MS (ESI) m/z 521 (M-H)< +.> Anal calcd for C 21 H 15 F N 2 O 3 S 2 : C, 64.35; H, 5.20; N, 5.36.

Example 193

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

193A. 2-( 2, 2, 2- Trifluoroethyl)- 4, 5- dichloro- 3( 2H)- pyridazinone

2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and heated under reflux for 5 h. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 67.5%). <1>H NMR (300 MHz, CDCl 3 ) d 4.8 (q, J = 9 Hz, 2H), 7.85 (s, 1H). MS (DCI-NH 3 ) m/z 264 (M+NH 4 )<+.>

193B. 2-( 2, 2, 2- Trifluoroethyl)- 4- chloro- 5- hydroxy- 3( 2H)-pyridazinone

2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone (15.0 m 60.7 mmol) and potassium carbonate (10 g, 72.4 mmol.) were mixed with water (500 ml) and stirred under reflux for 6 hours. TLC (1:1:2 CH2Cl2/hexanes/ethyl acetate) indicated that allt

starting material was consumed.) The reaction mixture was cooled to room temperature. The pH value in the reaction mixture was adjusted to approx. 4 with hydrochloric acid (15%). The product was extracted with ethyl acetate (700 mL). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The hydroxy compound was obtained as a light brown solid (yield: 13.1 g, 94%). <1>H NMR (300 MHz, DMSO-d 6 ) δ 4.92 (q, J = 9 Hz, 2H), 7.9 (s, 1H). MS {DCI-NH 3 ) m/z 229 (M+H)<+>.

193C. 2-( 2, 2, 2- Trifluoroethyl)- 4- chloro- 5-( trifluoromethylsulfonyloxy)- 3( 2H)- pyridazinone

Anhydrous Na 2 CO 3 (9.04 m, 85.32 mmol) was placed in a 500 mL round bottom flask and anhydrous CH 2 Cl 2 (200 mL) was added. The reaction mixture was cooled to 0 °C under N 2 -The halohydroxypyridazinone prepared in Example 193B was dissolved in CH 2 Cl 2 (100 mL) and added slowly to the flask and stirred overnight. The reaction was slowly warmed to room temperature. (TLC (2:1 hexanes/ethyl acetate) indicated the reaction was complete) The reaction was quenched with H 2 O. The organic phase containing the product was separated, washed with brine and dried over MgSO 4 . The resulting filtrate was concentrated under reduced pressure. The crude product was isolated as a deep red-brown residue. Purification using a silica gel column (30:70 ethyl acetate/pentanes) afforded the title compound as a dark reddish residue (14.3 m, 70%). <1>H NMR (300 MHz, CDCl 3 ) 54.85 (q, J = 9 Hz, 2H), 7.9 (s, 1H). MS (DCl-NH 3 ) m/z 378 (M+NH 4 )<+>.

193D. 2-( 2, 2, 2- Trifluoroethyl)- 4- chloro- 5-[ 4-( methylthio) phenyl]-3( 2H)- pyridazinone

A solution of the triflate prepared in Example 193C (1.56 g 4.3 mmol), 4-(methylthio)phenylboronic acid (870 mg, 5.16 mmol), tetrakis(triphenylphosphine)palladium(0) (250 mg, 5% mmol ) and triethylamine (1.44 mL, 10.32 mmol) in toluene was heated under reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, then brine, followed by drying over MgSO 4 and filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 92:8 hexanes/ethyl acetate) to provide the coupled intermediate as a bright green-yellow solid (yield: 500 mg, 35%). Temp. 130-139 °C. ^-H NMR (300 MHz,

CDCl3) 52.55 (s, 3H), 4.87 (q, J = 9 Hz, 2H), 7.37 (d, J = 9 Hz, 2H), 7.48 (d, J = 9 Hz, 2H), 7.82 (s, 1H). MS (DCl-NH 3 ) m/z 335 (M+H)<+>.

193E. 2-( 2, 2, 2- Trifluoroethyl)- 4- chloro- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using the coupled intermediate prepared in Example 193D instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H) -pyridazinone (yield: 440 mg, 81%). Temp. 221-222 °C. ^-H NMR (300 MHz, DMSO-d6) 53.33 (s, 3H), 5.10 (q, J = 9 Hz, 2H), 7.90 (d, J = 9 Hz, 2H), 8 .12 (d, J = 9 Hz, 2H) , 8.20 (s, IH). MS {DCI-NH 3 ) m/z 367 (M+H)<+.>

193F. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

Magnesium shavings (500 mg) were placed in a dry 250 ml round bottom flask. Anhydrous ether (20 mL) was added under N 2 at room temperature, then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 40 °C for 2 hours. All the magnesium was consumed and yielded a light brownish-yellow solution. The 2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a saturated NH 4 Cl solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH 4 Cl and brine. The ethyl acetate solution was dried over MgSC*4 and filtered. The filtrate was concentrated under reduced pressure. The product was isolated as an orange residue. Purification using a silica gel column (20:80 ethyl acetate/pentanes) afforded the title compound as a pale yellow powder (yield: 140 mg, 28%). <1>H NMR (300 MHz, CDCl 3 ) δ 3.13 (s, 3H), 4.85 (m, 2H), 6.93 (m, 4H), 7.49 (d, J = 9 Hz , 2H) 7.72 (s, 1H), 8.08 (d, J = 9 Hz, 2H). MS (DCI-NH 3 ) m/z 441

(M+H)<+.> Anal. calcd for C20HI6F4N2O3S•°'5 H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23.

Example 194

2-( 4- Fluorophenyl)- 4-( 4- fluorophenoxymethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

194A. 2-( 4- Fluorophenyl)- 4, 5~ dibromo- 3( 2H)- pyridazinone

Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenylhydrazine•HCl, and the heterogeneous mixture was heated to reflux at a bath temperature of 115 °C for 15 h. During the course of the reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23 °C a crystalline precipitate was formed. The solution was poured into ice water (1000 ml) and stirred for 20 minutes. The yellow/brown crystals were filtered off, washed with additional cold water and dried in vacuo to provide 5.8 g (86%) of product. (J. Het. Chem.., 1993, 30, 1501; Heterocycles 1985, 23, 2603) <1->H NMR (300 MHz, DMSO-

d6) 57.31-7.41 (rn, 2H), 7.57-7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347 (Br7gBr79 M+H)<+>, m/z 349 (Br7gBr81 M+H)<+>, m/z 364 (Br79Br79 M+NH4)<+> and m/z 366 (Br7gBr81 M+NH4)<+.>

194B. 2-( 4- Fluorophenyl)- 4- methoxy- 5- bromo- 3( 2H)- pyridazinone

A 23 °C homogeneous solution of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (7.18 g, 20.6 mmol) prepared above in tetrahydrofuran (322 mL) was treated with methanol (0.843 ml, 20.8 mmol) and after 5 min with NaH (0.833 g, 20.8 mmol, 60% oil dispersion). The reaction was exothermic for several minutes and then allowed to proceed for 8 hours at 23 °C (Note: several reactions are complete at this point). The reaction was not complete and therefore the temperature was raised to reflux for a further 4 hours. The reaction was apparently not complete. An additional 0.1 equivalent of NaOMe solution was prepared in a separate flask as above with the amounts: 32 ml of tetrahydrofuran, 0.084 ml of methanol and 83 mg of 60% NaH oil dispersion. This NaOMe solution was added by syringe to the reaction mixture cooled to 23 °C, and then the temperature was raised to the reflux temperature for 4 hours. The reaction was still not complete, and therefore an additional 0.1 equivalent of NaOMe solution was prepared and added , and the reaction was brought to reflux, as above. After 4 hours the reaction was complete. The mixture was cooled to 23 °C and diluted to 2000 ml with water. The yellow/white precipitate that formed was filtered off, washed with additional water and concentrated in vacuo to provide 5.39 g (88%) of the product. (J. Het. Chem., 1988, 25, 1757) <1>h NMR (300 MHz, DMSO-de) 54.13 (s, 3H) , 7.30-7.40 (m, 2H) , 7 , 56-7.62 (m, 2H), 8.22 (s, 1H). MS (APCI+) m/z 299 (Br79 M+H)<+> and m/z 301 (Br81 M+H)<+.>

194C. 2-( 4- Fluorophenyl)- 4- methoxy- 5-[ 4-( methylthio) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 6 starting from 2-(4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone instead of 2-benzyl-4-bromo-5-methoxy-3( 2H)-pyridazinone and using 4-(methylthio)benzeneboronic acid instead of 4-fluorobenzeneboronic acid (yield: 70 mg, 61%). <X>H NMR (500 MHz, DMSO-de) δ 2.54 (s, 3H), 4.02 (s, 3H), 7.35 (dd, J = 9.0, 9.0 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H) , 7.61 (d, J = 8.5 Hz, 2H) , 7.65 (dd, J = 9.0, 5.0 Hz, 2H), 8,14 (p, 1H). MS (APCI+) m/z 343 (M+H)<+>.

194D. 2-(4-Fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 228 using methyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 0.83 g, 87%). <i>H NMR (300 MHz, CDCl 3 ) 52.25 (s, 3H), 2.55 (s, 3H), 7.17 (dd, J = 8.8, 8.8 Hz, 2H), 7 .31 (d, J = 8.7 Hz, 2H) , 7.38 (d, J = 8.7 Hz, 2H), 7.61-7.68 (m, 2H), 7.82 (s, IH). MS (APCI+) m/z 327 (M+H)<+>.

194E. 2-( 4- Fluorophenyl)- 4- methyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10 using 2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-benzyl-4- (4-Fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 473 mg, 86%). ^-H NMR (300 MHz,

CDCI3) 8 2.24 (s, 3H), 3.14 (s, 3H) , 7.19 (dd, J=8.8, 8.8 Hz, 2H) , 7.61 (d, J = 8 .4 Hz, 2H) , 7.63-7.69 (rn, 2H) , 7.80 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H). MS (APCI+) m/z 359 (M+H)<+> and m/z 376 (M+NH4)<+.>

194F. 2-( 4- Fluorophenyl)- 4- bromomethyl- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

To a heterogeneous refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL ) was rapidly added N -bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour the reaction was almost 50% complete. Additional benzoyl peroxide (12 mg, 0.05 mmol) was added and the reaction was checked after an additional 1 h. The reaction was still not complete, so more benzoyl peroxide (4 mg, 0.017 mmol) was added. After 30 minutes the reaction was complete. The mixture was cooled to 23 °C and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO 3 , water and brine. The solution was dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes, gradient 1:1 to 4:1) to provide the product (yield: 530 mg, 74%). <1>H NMR (300 MHz,

CDCl3) 83.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.67-7.74 (m, 2H), 7.82 (d, J = 8.7 Hz, 2H), 7.86

(s, 1H), 8.17 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 437

(M+H)<+>.

194G. 2-( 4- Fluorophenyl)- 4-( 4- fluorophenoxymethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

To a homogeneous solution of 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared above, (107 mg, 0.246 mmol) and 4-fluorophenol ( 30.3 mg, 0.270 mmol) dissolved in acetone (4 mL) was added powdered K 2 CO 3 (37.3 mg, 0.270 mmol). The mixture was stirred at 23 °C for 2 h, filtered through a pad of Celite<®> and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 3:2) to provide the product (yield: 83 mg, 72%). Temp. 65-80 °C. <*>H NMR (300 MHz, CDCl 3 ) 83.12 (s, 3H), 4.94 (s, 2H) , 6.78-6.86 (m, 2H) , 6.91-7.00 ( rn, 2H), 7.15-7.24 (m, 2H), 7.65-7.72 (m, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 469 (M+H)<+>. Anal. calcd for C24H18F2N2O4S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.22; H, 3.63; N, 5.64.

Example 195

2-( 4- Fluorophenyl)- 4-( 3- fluorophenoxymethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 194G using 3-fluorophenol instead of 4-fluorophenol (yield: 94 mg, 88%). Temp. 142-144 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 3.12 (s, 3H) , 4.98 (s, 2H) , 6.49-6.56 (m, 1H) , 6.60-6.73 (m, 2H) , 7.15-7.25 (m, 3H) , 7.65-7.75 (m, 4H), 7.93 (s, IH), 8.07 (d, J = 8 .7 Hz, 2H). MS (APCI+) m/z 469 (M+H)<+.> Anal. calcd for C24HI8F2N2O4S: Cf 61.53; H, 3.87; N, 5.97. Found: C, 61.20; H, 3.92; N, 5.86.

Example 196

2-( 4- Fluorophenyl)- 4- phenoxymethyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 294G using phenol instead of 4-fluorophenol (yield: 67 g, 93%). Temp. 42-75 °C. <X>H NMR (300 MHz, DMSO-de) δ 3.28 (s, 3H), 4.92 (s, 2H), 6.83-6.90 (m, 2H), 6.91-6 .99 (rn, 1H) , 7.22-7.30 (m, 2H) , 7.35-7.44 (m, 2H), 7.66-7.73 (rn, 2H), 7.81 -7.88 (m, 2H), 8.02-8.08 (m, 2H), 8.21 (s, 1H). MS (APCI+) m/z 451 (M+H)<+.>

Example 197

2-( 4- Fluorophenyl)- 4-( t-butylthiomethyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

A 0 °C solution of the 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) was treated with Nal (35 mg, 0.233 mmol), and after 5 min the cooling bath was removed and the reaction was warmed to 23 °C. After 30 minutes, the conversion to 2-{4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was complete (thin layer chromatography, ethyl acetate/hexanes 4:1). NaBr and remaining Nal were filtered off through a pad of Celite<®>. Additional acetone (2 mL) was added along with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol) and the solution was cooled to 0 °C before addition of Ag 2 CO 3 (63 mg, 0.227 mmol). After 5 minutes, the cooling bath was removed and the solution was heated to 23 °C for 5 hours. The reaction mixture was filtered through Celite<®> and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 3:2) to provide the product (yield: 57 mg, 60%). Temp. 50-70 °C. <1>h NMR (300 MHz, CDCl 3 ) 51.34 (s, 9H), 3.14 (s, 3H), 3.65 (s, 2H), 7.13-7.21 (m, 2H) , 7.63-7.70 (m, 2H), 7.79 (s, IH) , 7.84

(d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 447 (M+H)<+>. Anal. calcd for C 22 H 23 FN 2 O 3 S 2 : C, 59.17; H, 5.19; N, 6.27. Found: C, 59.48; H, 5.36; N, 5.90.

Example 198

2-( 4- Fluorophenyl)- 4-( 2- methylpropylthiomethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 197 using 2-methyl-1-propanethiol instead of 2-methyl-2-propanethiol (yield: 66 mg, 70%). Temp. 45-60 °C. <X>H NMR (300 MHz, CDCl 3 ) 50.95 (d, J 6.6 Hz, 6H), 1.67-1.82 (m, 1H) , 2.62 (d, J = 6.6 Hz, 2H) , 3.15 (s, 3H), 3.61 <s, 2H), 7.19 (dd, J = 8.2, 8.2 Hz, 2H), 7.62-7.71 (m, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H). MS (APCI+) m/z 447 (M+H)<+>. Anal. calcd for C 22 H 23 FN 2 O 3 S 2 : C, 59.17; H, 5.19; N, 6.27. Found: C, 59.35; H, 5.25; N, 6.05.

Example 199

2-( 4- Fluorophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylthio) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared by the following reaction sequences. Mucobromic acid and 4-fluorophenylhydrazine hydrochloride were reacted to provide 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone according to the procedure of Example 194A. The dibromo intermediate was reacted according to the procedure described in Example 194B, using isopropanol instead of methanol, to selectively react at the 4-position to provide 2-(4-fluorophenyl)-4-(2-propoxy)-5-bromo -3(2H)-pyridazinone.

The 5-bromo compound was coupled to 4-(methylthio)phenylboronic acid according to the method described in Example 6 to provide the title compound (yield: 435 mg, 53.9%). Temp.

135-137 °C. 3-H NMR (300 MHz, CDCl 3 ) 81.21 (d, J = 6 Hz, 6H), 2.55 (s, 3H), 5.26 (sept, J = 6 Hz, 1H), 7.17 (t, J = 9 Hz, 2H), 7.34 (d, J = 9 Hz, 2H), 7.57 (d, J = 9 Hz, 2H) , 7.58-7.66 (m, 2H ), 7.95 (p, IH). MS {DCI-NH 3 ) m/z 371

(M+H)<+>.

Example 200

2-( 4- Fluorophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The methyl sulfide compound prepared in Example 199 was oxidized according to the method described in Example 10 to provide the title compound (yield: 240 mg, 92%). Temp. 160-162 °C. <1>H NMR (300 MHz, DMSO-d6) 51.30 (d, J = 6 Hz, 6H), 3.41 (s, 3H), 5.41 (m, 1H), 7.48 (t , J = 9 Hz, 2H), 7.77 (dd, J - 9 Hz, 6 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.19 (d, J = 9 Hz , 2H), 8.31 (s, 1H). MS (DCI-NH3) m/z 403 (M+H)<+>, 420 (M+NH4)<+.> Anal. calcd for C20H19FN2O4S: C, 59.70; H, 4.73; N, 6.97. Found: C, 59.40; H, 4.86; N, 6, 69.

Example 201

2-( 3- Chlorophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 199 using 3-chlorophenylhydrazine hydro- chloride instead of 4-fluorophenylhydrazine hydrochloride, in the first step. The resulting methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 260 mg, 80%). Temp. 134-136 °C. <3->H NMR (300 MHz, CDCl3) 81.24 (d, J = 6 Hz, 6H), 3.13 (s, 3H), 5.48 (sept, J = 6 Hz, 1H), 7 .37-7.48 (m, 2H), 7.59 (dt, J = 7 Hz, 1.5 Hz, IH), 7.70 (br s, IH), 7.84 (d, J = 9 Hz, 2H), 7.93 (s, 1H), 8.06 (d, J = 9 Hz, 2H). MS

(DCI-NH3) m/z 419 (M+H)<+>, 436 (M+NH4)4-. Anal. calcd for C20H19CIN2O4S: C, 57.42; H, 4.55; N, 6.70. Found: C, 57.08; H, 4.59; N, 6.44.

Example 202

2-( 3- Fluorophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The methyl sulfide intermediate was prepared according to the method described in Example 199 using 3-fluorophenylhydrazine hydrochloride instead of 4-fluorophenylhydrazine hydrochloride in the first step. The resulting methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 290 mg, 72%). Temp. 110-112 °C. 3-H NMR (300 MHz, CDCl 3 ) 51.31 (d, J = 6 Hz, 6H), 3.11 (s, 3H), 5.47 (sept, J = 6 Hz, 1H), 7.09 -7.18 (m, IH), 7.41-7.52 (rn, 3H), 7.83 (d, J = 9 Hz, 2H), 7.93 (s, IH), 8.08 ( d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 403 (M+H)<+>, 447 (M+NH4)<+.> Anal. calcd for C20H19FN2O4S: C, 59.70; H, 4.73; N, 6.97. Found: C, 59.54; H, 4.87; N, 6.70.

Example 203

2-( 3- Bromophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The methyl sulfide intermediate was prepared according to the method described in Example 199 using 3-bromophenylhydrazine hydrochloride instead of 4-fluorophenylhydrazine hydrochloride. The resulting methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 75 mg, 77.6%). Temp. 130-132 °C. <3->H NMR (300 MHz, CDCl3) 51.23 (d, J = 6 Hz, 6H), 3.15 (s, 3H), 5.48 (sept, J = 6 Hz, 1H), 7 .38 (t, J = 9 Hz, IH), 7.55 (br d, J = 7 Hz, IH), 7.65 (br d, J = 7 Hz, IH), 7.79-7.87 (m, IH), 7.83 (d,

J = 9 Hz, 2H), 8.13 (s, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 465 (M+H)<+>, 480 (M+NH4)<+.> Anal. calcd for C20H19BrN2O4S: C, 51.84; H, 4.10; N, 6.05. Found: C, 51.95; H, 4.18; N, 5.74.

Example 204

2-( 2, 5- Difluorophenyl)- 4-( 2- propoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 199 using 2,5 -difluoro-phenylhydrazine hydrochloride instead of 4-fluorophenylhydrazine hydrochloride.

The resulting methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 390 mg, 90%). Temp. 161-164 °C. <1>H NMR (300 MHz, CDCl3) 51.23 (d, J = 6 Hz, 6H), 3.12 (s, 3H), 5.55 (sept, J = 6 Hz, 1H), 7, 12-7.29 (m, 3H), 7.82 (d, J = 9 Hz, 2H), 7.92 (s, 1H), 8.07 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 421 (M+H)<+>, 438 (M+NH4)<+.> Anal. calcd for C20H18 F2N2O4S-0.5 H2O: C, 55.94; H, 4.31; N, 6.53. Found: C, 55.86; H, 4.19; N, 6.38.

Example 205

2-( 3- Chloro- 4- fluorophenyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared by the following reaction sequences. Mucobromic acid and 3-chloro-4-fluorophenylhydrazine hydrochloride were reacted to provide 2-{3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone according to the method described in Example 194A. The intermediate was selectively reacted at the 4-position with isobutanol and a base to provide 2-(4-fluorophenyl)-4-[1-(2-methylprop-oxy)]-5-bromo-3(2H)-pyridazinone according to to the method described in Example 194B. The 5-bromo compound was coupled to 3-fluoro-4-(methylthio)phenylboronic acid prepared in Example 194C according to the method described in Example 6 to prepare the intermediate methyl sulfide. The sulfide compound was oxidized to the above-mentioned methyl sulfone according to the method described in Example 10 (yield: 810 mg, 83.8%). Temp. 142-144 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 0.90 (d, J = 6 Hz, 6H), 1.95 (sept, J = 6 Hz, 1H), 3.30 (s, 3H), 4, 37 (d, J = 6 Hz, 2H), 7.26 (t, J = 9 Hz, IH), 7.52-7.61 (m, 3H), 7.75 (dd, J = 9 Hz, 3 Hz, IH), 7.89 (s, IH), 8.10 (t, J = 9 Hz, IH). MS (DCl-NH 3 ) m/z 469 (M+H)<+>, 486 (M+NH 4 )<+>.

Example 206

JR27 JR 283100

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 3- methyl- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

206A. 2- Methylthioanisole

A solution of 2-bromothioanisole (10.53 g, 52 mmol) in tetrahydrofuran (173 mL) was prepared and cooled to -78 °C. n-BuLi (21.8 mL, 54.5 mmol, 2.5 M solution in hexanes) was slowly added along the inner wall of the reaction vessel. The resulting pale yellow solution was stirred for 30 minutes before methyl iodide (8.10 g, 57.1 mmol) diluted with tetrahydrofuran (6 mL) was slowly added along the inner wall of the reaction vessel. The mixture was stirred for an additional 30 minutes at -78°C. The cooling bath was removed and the mixture was stirred for 1 hour. The solution was cooled to 0 °C, and a saturated aqueous NH 4 Cl solution was added. The resulting solution was extracted several hours with ethyl acetate, and the combined acetate layers were washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:19) to provide the product (yield: 6.74 g, 94%). ^H

NMR (300MHz, CDCl 3 ) 52.34 (s, 3H), 2.46 (s, 3H), 7.02-7.09 (m, 1H), 7.12-7.22 (m, 3H).

206B. 4- Bromo- 2- methylthioanisole.

To a 0 °C solution of 2-methylthioanisole (0.50 g, 3.57 mmol) in methylene chloride (40 mL) was added powdered Fe (20 mg, 0.36 mmol) followed by dropwise addition of bromine (0.58 g, 3.54 mmol). After 30 minutes the starting material had been consumed (thin layer chromatography, hexanes). The excess bromine was quenched by adding a solution of NaHSO 3 and stirring for several minutes. The methylene chloride layer was separated and the aqueous phase was extracted with additional methylene chloride. The combined methylene chloride solution was dried over MgSO 4 , filtered and concentrated in vacuo. The resulting oil was chromatographed (flash silica gel, ethyl acetate/hexanes 1:49) to provide the product (yield: 0.74 g, 96%). <1>11 NMR (300 MHz, CDCl 3 ) 82.30 (s, 3H), 2.45 (s, 3H), 7.00 (d, J = 8.4 Hz, 1H), 7.27-7 .33 (m, 2H).

206C. 3- Methyl- 4-( methylthio) benzeneboronic acid.

3-Methyl-4-(methylthio)benzeneboronic acid was prepared according to the method described in Example 1, using 4-bromo-2-(methylthio)anisole instead of 4-bromothioanisole (yield: 5.3 g, 67%). Temp. 208-210. 3-H NMR 2.28 (s, 3H), 2.46 (s, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J = 8.4 Hz, IH) .

2Q6D. 2-(3,4-Difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 194A, using 3,4-difluorophenylhydrazine•HC1 instead of 4-fluorophenylhydrazine•HC1 (yield: 39 g, 78%). 3-H NMR (300 MHz, DMSO-d 6 ) δ 7.45 (m, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 8.30 (s, 1H). MS (DCl-NH 3 ) m/z 382 (M+NH 4 )<+.>

206E. 2-(3,4-Difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 194B, using 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4,5- dibromo-3(2H)-pyridazinone (yield: 15 mg, 88%). <!>h NMR (300 MHz, DMSO-d6) δ 4.14 (s, 3H), 7.45 (m, 1H), 7.60 (m, 1H), 7.74 (m, 1H), 8.24 (p, 1H). MS (DCI-NH 3 ) m/z 317 (M+H)<+> and m/z 334 (M+NH 4 )<+>.

206F. 2-( 3, 4- Difluorophenyl)- 4- methoxy- 5-[ 3- methyl- 4-( methylthio) phenyl]- 3( 2H)- pyridazinone.

The title compound was prepared according to the method described in Example 6 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone instead of 2-benzyl-4-bromo-5-methoxy- 3(2H)-pyridazinone and using 3-methyl-4-(methylthio)benzeneboronic acid instead of 4-fluorobenzeneboronic acid (yield: 2.0 g, 85%). <!>h NMR (300 MHz, CDCl 3 ) δ 2.39 (s, 3H), 2.53 (s, 3H), 4.11 (s, 3H), 7.22-7.32 (m, 2H ), 7.34 (s, 1H), 7.42-7.50 (m, 2H), 7.55-7.64 (m, 1H), 7.92 (s, 1H). MS (APCI+) m/z 375 (M+H)<+>.

206G. 2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 3- methyl- 4-( methylthio) phenyl]- 3( 2H)- pyridazinone.

2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228, starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4- methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and using 4-fluorophenylmagnesium bromide instead of cyclohexylmagnesium chloride (yield: 330 mg, 56%). <!>h NMR (300 MHz, CDCl 3 ) δ 2.24 (s, 3H), 2.47 (s, 3H), 6.90-7.03 (m, 6H), 7.22-7.31 (m, 2H), 7.49-7.54 (m, 1H), 7.60-7.68 (m, 1H), 8.02 (s, 1H). MS (APCI+) m/z 439 (M+H)<+>.

206H. 2-( 3, 4- Difluorophenyl)- A -( 4- fluorophenyl)- 5-[ 3- methyl- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone.

The title compound was prepared according to the method described in Example 10, using 2-(3,4-difluoro-.phenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl] -3(2H)-pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 251 mg, 82%) M.p. 80-100 °C. 1-H NMR (300 MHz, DMSO-de) 82.59 (s, 3H), 3.25 (s, 3H), 7.13-7.34 (m, 5H), 7.45 (s, 1H ), 7.52-7.69 (m, 2H), 7.81 (d, J = 8.4 Hz, IH), 7.81-7.90 (m, IH), 8.27 (s, IH). MS (APCI+) m/z 471 (M+H)<+> and m/z 488 (M+NH4)<+>. Anal. calcd for C24H17F3N2O3S: C, 61.27; H, 3.64; N, 5.95. Found: C, 61.53; H, 3.92; N, 5.67.

Example 207

2-( 3- Chlorophenyl)- 4-( 4- fluorophenoxymethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

207A. 2-( 3- Chlorophenyl)- 4, 5- dibromo- 3( 2H)- pyridazinone.

The title compound was prepared according to the method described in Example 194A, using 3-chlorophenylhydrazine-HCl instead of 4-fluorophenylhydrazine*HC1 (yield: 24.8 g, 88%). Ifi NMR (300 MHz, DMSO-de) δ 7.53-7.57 (m, 3H), 7.67-7.70 (m, 1H), 8.29 (s, 1H). MS (DCI-NH3) m/z 365 (M+H)<+> °9 m/z 382 (M+NH4<+>)<+.>

2Q7B. 2-(3-Chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 194B, using 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4,5-dibromo- 3(2H)-pyridazinone (yield: 12.4 g, 95%). <!>h NMR (300 MHz, DMS0-d6) δ 4.21 (s, 3H), 7.58-7.62 (m, 3H), 7.73-7.76 (rn, 1H), 8 ,28 (p, IH). MS (DCI-NH 3 ) m/z 317 (M+H)<+> °9 m/z 334 (M+NH 4 + )"1".

2Q7C. 2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 6 starting from 2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone instead of 2-benzyl-4-bromo-5-methoxy-3( 2H)-pyridazinone and using 4-(methylthio)benzeneboronic acid instead of 4-fluorobenzeneboronic acid (yield: 3.3 g, 68%). <1>h NMR (300 MHz, DMSO-de) δ 2.54 (s, 3H), 4.03 (s, 3H), 7.40 (d, J = 9.0 Hz, 2H), 7, 50-7.64 (m, 5H), 7.73-7.77 (rn, 1H), 8.18 (s, 1H). MS (DCI-NH 3 ) m/z 359

(M+H) + .

207D. 2-(3-Chlorophenyl)-4-methyl-5-[3-methyl-4-(methylthio)-phenyl]-3(2H)-pyridazinone.

2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-chlorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4-methoxy-5-[ 4-(methylthio)phenyl]-3(2H)-pyridazinone and using 4-fluorophenylmagnesium bromide instead of cyclohexylmagnesium chloride (yield: 180 mg, 94%). <3->H NMR (300 MHz, CDCl 3 ) δ 2.25 (s, 3H), 2.56 (s, 3H), 7.28-7.45 (rn, 6H), 7.58-7, 63 (m, IH), 7.71-7.74 (m, IH), 7.82 (s, IH). MS (APCI+) m/z 343 <M+H)<+> °g m/z 360 (M+NH4)<+.>

207E. 2-( 3- Chlorophenyl)- 4- methyl- 5-[ 4-( methylsulfonylphenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using 2-(3-chlorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone in 2-benzyl-4 -(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 125 mg, 67%). Temp. 164-168. <1>H NMR (300 MHz, CDCl 3 ) δ 2.23 (s, 3H), 3.13 (s, 3H), 7.37-7.46 (m, 2H), 7.61 {m, 3H ), 7.71-7.74 (m, 1H), 7.81 (s, 1H), 8.13 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 343 (M+H)<+> °9 m/z 360 (M+NH4)<+>.

207F. 2-( 3- Chlorophenyl)- 4- bromomethyl- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(3-Chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 194F, using 2-(3-chlorophenyl) -4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)-phenyl]-3(2H )-pyridazinone (yield: 90 mg, 99%). <1>H NMR (300 MHz, CDCl3) §3.13 (s, 3H), 4.33 (s, 2H), 7.40-7.47 (m, 2H), 7.66 (ddd, J = 2.4, 2.4, 7.2 Hz, IH), 7.76-7.78 (m, IH), 7.81 (d, J = 8.7 Hz, 2H), 7.86 ( s, 1H), 8.17 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 453 (M+H)<+> °9 m/z 470 (M+NH4)<+>.

207G. 2-( 3- Chlorophenyl)- 4-( 4- fluorophenoxymethyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 194G, using 2-(3-chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 30 mg, 31%). Temp. 50-80 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 3.11 (s, 3H), 4.94 (s, 2H), 6.78-6.85 (m, 2H), 6.91-6.99 (m, 2H), 7.39-7.48 (m, 2H), 7.64 (ddd, J = 7.5, 1.9, 1.9 Hz, 1H), 7.71-7.77 (m, 3H), 7.93 (s, 1H), 8.08 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 485 (M+H)<+>.

Example 208

2-( 3- Chlorophenyl)- 4-( benzoyloxymethyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 207 using benzoic acid instead of 4-fluorophenol (yield: 33 mg, 34%). Temp. 50-70 °C. 1-H NMR {300 MHz, CDCl 3 ) δ 3.00 (s, 3H) , 5.36 (s, 2H) , 7.36-7.48 (m, 4H), 7.52-7.59 ( m, IH) , 7.61-7.68 (m, 3H) , 7.75-7.78 (m, IH), 7.83-7.88 (rn, 2H), 7.89 (s, 1H), 8.02 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 495 (M+H)<+.>

Example 209

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 193 using 1-bromo-4-methylpentane instead of 4-fluorobenzyl bromide (yield: 80 mg, 19%). !h NMR (300 MHz, CDCl 3 ) 50.81 (d, J= 7.5 Hz, 6H), 1.3-1.6 (m, 3H), 2.52 (m, 2H), 3.14 (3 H, s) 4.85 (q, J = 9 Hz, 2H), 7.55 (d, J = 9 Hz, 2H) 7.67 (s, IH), 8.1 (d, J = 9 Hz, 2H). MS (DCI-NH3), m/z 403 (M+H)<+.> Anal. calcd for C18H21F3N2O3S-0.25 H2O: C, 53.12; H, 5.32; N, 6.88. Found C, 52.90; H, 5.14; N, 6.43.

Example 210

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

21QA. Preparation of boric acid:

2-Fluorotoluene-5-bromo (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to -78 C under N 2 . n-BuLi (14 mL, 2.5 M solution in THF) was added slowly using a dry syringe. The mixture became cloudy. The reaction mixture was stirred for 40 minutes at -78 °C. Triisopropyl borate (22 mL, 95 mmol) was slowly added with stirring. The reaction mixture was allowed to warm to room temperature. Stirring was continued for another 2 hours. A pale yellow cloudy solution was formed. (TLC (1:2 ethyl acetate/hexanes) indicated that the starting material had disappeared.)

The reaction was suppressed by the addition of 10% aqueous

NaOH {200 mL). After stirring for 45 minutes, 10% citric acid solution (300 ml) was added until, pH ~5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to provide a whitish solid (yield: 4.1 g, 84%).

210B. Suzuki Clutch:

Boric acid (231 mg, 1.5 mmol), prepared in Example 210A, 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone ( 500 mg, 1.36 mmol), tetrakis-(triphenylphosphine)-palladium(O) (47 mg, 0.041 mmol) and CsF (413 mg, 2.72 mmol) were stirred under reflux in DME (20 mL) under N2 in 5 hours. TLC (1:1 hexanes/ethyl acetate) indicated that all starting material was consumed. The volatile substances were removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo. A whitish powder was obtained (yield: 275 mg, 46%). Temp. 88-91 °C; ^H NMR (300 MHz, CDCl3, a mixture of rotamers) δ 2.2, 2.25 (2d, J = 1.5 Hz, 3H) 3.05, 3.09 (2s, 3H) 4.78 -4.92 (m, 2H) 6.61-6.8 (m, IH) 6.82-6.98 (m, IH) 7.35 (d, J = 9 Hz, IH) 7.78 ( d, J = 9 Hz, 1H) 7.86-8.09 (m, 4H). MS (DCl-NH 3 ), m/z 441 (M+H)<+>. Anal. calcd for C20H16F4N2O3S-0.5 H2O: C, 53.45; H, 3.81; N, 6.23. Found C, 53.17; H, 3.65; N, 5.88.

Example 211

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3, 5- dichlorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.409 mmol) (Example 193E) was dissolved in anhydrous DME ( 8 ml) and heated to reflux with 3,5-dimethylbenzeneboronic acid in the presence of CsF {150 mg, 0.98

mmol) and tetrakis{triphenylphosphine)-palladium (17.38 mg, 0.015 mmol) for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, to provide the title compound (yield: 110 mg, 58%). ^-H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H) , 4.88 (q, J = 9 Hz, 2H) , 7.06 (d, J = 1.5 Hz, 9 Hz, 2H) , 7.31 (t, J = 1.5 Hz, IH), 7.36 (d, J = 9 Hz, 2H), 7.94 (s, IH), 7.96 (d, J = 9 Hz , 2H). MS {DCI-NH 3 ) m/z 496 (M+NH 4 )<+>. Anal. calcd for C19H13CI2F3N2O3S: C, 47.81; H, 2.75; N, 5.87. Found: C, 47.77; H, 2.75; N, 5.65

Example 212

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- ethoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 (using 3-ethoxyphenylboronic acid in 3,5-dimethylbenzeneboronic acid (yield: 155 mg, 86%). <1>H NMR (300 MHz, CDCl3) 51.42 (t, J= 7.5 Hz, 3H) , 3.06 (s, 3H), 3.90 (q, J = 7.5 Hz, 2H), 4.88 (q, J = 9 Hz, 2H), 6.65 (d, J = 7.5 Hz, IH) , 6.75 (t, J = 1.5 Hz, IH) , 6.85 (dd, J = 1.5 Hz, 9 Hz, IH) , 7.15 (t, J = 9 Hz, IH), 7.38 (d, J = 9 Hz, 2H), 7.88 (d, J = 9 Hz, 2H), 7.90 (s, IH ) MS (DCI-NH3) m/z 470 (M+NH4)4-. Anal calcd for C21H19CI2F3N2O4S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55, 62; H, 4.30; N, 5.99

Example 213

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- trifluoromethylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 4-(trifluoromethyl)benzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 85 mg, 44%). <1>H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 4.90 (q, J = 9 Hz, 2H), 7.35 (t, J = 9 Hz, 4H), 7 .58 (d, J = 9 Hz, 2H), 7.90 (d, J = 9 Hz, 3H). MS (DCI-NH3) m/z 494 (M+NH4)<+.> Anal. calcd for C20H14F6N2O3S: C, 50.42; H, 2.96; N, 5.88. Found: C, 50.20; H, 3.02; N, 5.70

Example 214

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- nitrophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 3-nitrobenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 40 mg, 22%). 1 H NMR (300 MHz, CDCl 3 ) 53.05 (s, 3H), 4.92 (q, J = 9 Hz, 2H), 7.36 (d, J = 9 Hz, 2H), 7.45- 7.60 (m, 2H), 7.91 (d, J = 9 Hz, 2H), 7.95 (s, IH), 8.05 (m, IH), 8.15-8.21 (m , IH). MS (DCl-NH 3 ) m/z 471 (M+NH 4 )<+>. Anal. calcd for C 19 Hi 4 Cl 2 F 3 N 3 O 5 S-°'5 EtOAc: C, 50.70; H, 3.64; N, 8.44. Found: C, 50.61; H, 3.58; N, 8.53

Example 215

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 2-methylbenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 45 mg, 27%). 3-H NMR (300 MHz, CDCl 3 ) 52.05, 2.12 (2s, 3H), 3.01 (s, 3H), 4.75-5.05 (m, 2H), 6.88 (d , J = 9 Hz, IH) , 7.03-7.25 (m, 3H), 7.31 (d, J = 9 Hz, 2H), 7.85 (d, J = 9 Hz, 2H), 7.95 (pp, IH). MS (DCI-NH3) m/z 440 (M+NH4)<+.> Anal. calcd for C20H17F3N2O3S: C, 55.10; H, 4.27; N, 6.42. Found: C, 55.17; H, 4.18; N, 6.10

Example 216

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- vinylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 4-vinylbenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 56 mg, 32%). Ifi NMR (300 MHz, CDCl 3 ) δ 3.06, 3.08 (2s, 3H),

4.78-4.95 (m, 2H), 5.30 (t, J = 6 Hz, IH), 5.65, 5.75(2d, J = 18 Hz, IH), 6.58-6 .92 (m, 1H), 7.1-7.4 (m, 6H), 7.75-8.08 (m, 3H). MS (DCl-NH 3 ) m/z 452 (M+NH 4 )<+>. Anal. calcd for C21H17F3N2O3S: C, 58.06; H, 3.94; N, 6.45. Found: C, 57, 82; H, 4.01; N, 6.09

Example 217

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 3-( trifluoromethyl) phenyl]- 5- [ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method

described in Example 211 using 3-trifluoromethylbenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 120 mg, 63%). <1>H NMR (300 MHz, CDCl 3 ) 53.03, 3.08 (2s, 3H), 4.75-4.98 (m, 2H), 7.30-7.60 (m, 6H), 7.75-8.10 (rn, 3H). MS {DCI-NH3) m/z 494 (M+NH4)<+.> Anal. calcd for C20H14F6N2O3S: C, 50.42; H, 2.96; N, 5.88. Found: C, 50.38; H, 2.97; N, 5.74

Example 218

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- fluoro- 4- methoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 3-fluoro-4-methoxybenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 32 mg, 18%). <!>h NMR (300 MHz, CDCl 3 ) 63.05, 3.09 <2s, 3H), 3.85, 3.87 (2s, 3H), 4.78-4.90 (m, 2H), 6.60-7.10 (m, 3H), 7.30-8.15 (m, 5H). MS (DCl-NH 3 ) m/z 474 (M+NH 4 )<+. >Anal. calcd for C20H16F4N2O4S•0.5 H2O: C, 51.61; H, 3.68; N, 6.01. Found: C, 51.52; H, 3.65; N, 5.93

Example 219

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- fluoro- 4- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 3-fluoro-4-methylbenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 58 mg, 33%). <1>H NMR (300 MHz, CDCl 3 ) 82.21, 2.25 (2d, J = 1.5 Hz, 3H), 3.50, 3.55 (2s, 3H), 4.75-4, 95 (m, 2H), 6.56-7.15 (m, 3H), 7.30-8.10 (m, 5H). MS (DCl-NH 3 ) m/z 458 (M+NH 4 )<+>. Anal. calcd for C20HI6F4N2O3S•0.5H2O: C, 53.45; H, 3.81; N, 6.23. Found: C, 53.14; H, 3.80; N, 5.97

Example 220

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3, 5- difluoro- 4- methoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 211 using 3,5-difluoro-4-methoxybenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid. <!>h NMR (300 MHz, CDCl 3 ) 82.9, 3.1 (2s, 3H), 3.92, 4.01 (2s, 3H), 4.78-4.95 (m, 2H), 6.25-6.80 (m, 1H), 7.30-7.5 (m, 2H), 7.7-8.15 (m, 4H). MS (DCl-NH 3 ) m/z 492 (M+NH 4 )<+>. Anal. calcd for C20H15F5N2O4S: C, 50.64; H, 3.19; N, 5.90. Found: C, 50.542; H, 3.41; N, 5.67

Example 221

2-( 2, 2, 2- Trifluoroethyl)- 4-( 1, 3- dihydro- l- oxo- 5- isobenzo-furanyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

6-Bromophthalide (300 mg, 1.40 mmol, Teppema et al Reel. Trav. Chim. Pays-Bays ,1923, 42, 47) and hexamethylditinne (326 µl, 1.55 mmol) were dissolved in toluene (5 ml) , degassed with a stream of nitrogen for 5 min, treated with (Ph3P)4Pd (79 mg) and heated under reflux for 1 h. The reaction was cooled and purified directly by chromatography on a Biotage 40S column (pretreated with hexanes-TEA 400:1 then rinsed with hexanes) eluted with 4:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the intermediate, 6-(trimethyltin)phthalide (yield: 362 mg, 87%).

The tin reagent (180 mg, 0.61 mmol), prepared above and 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 193E, (223 mg, 0.61 mmol) was dissolved in dry toluene (10 mL), degassed with a stream of nitrogen for 5 min, treated with (Ph 3 P ) 4 Pd (34 mg) and heated under reflux for 1 day. The reaction was cooled and purified directly by chromatography on a Biotage 40S column eluted with 4:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the title compound together with the 4-(1,3-dihydro-1-oxo-6-isobenzofuranyl) isomer in a 9:1 ratio. Further manipulations to attempt to remove the minor isomer (ie, chromatography, recrystallization from ethyl acetate-hexanes) failed (yield: 176 mg, 62%). Temp. 237-239 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 3.07 (s, 3H), 4.91 (q, J = 8 Hz, 2H), 5.30 (s, 2 H, major isomer), 5.33 (s, 2 H, bi-isomer), 7.20 (dd, J = 1 Hz, 7 Hz, IH), 7.36 (d, J = 8 Hz, 2H), 7.52 (s, IH) , 7.79 (d, J = 7 Hz, 1H), 7.92 (d, J 8 Hz, 2H), 7.96 (s, 1H). MS (DCl-NH 3 ) m/z 482 (M+NH 4 )<+. >Anal. calcd for C21H15F3N2O5S: C, 54.31; H, 3.26; N, 6.03. Found: C, 54.15; H, 3.12; N, 5.76.

Example 222

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- propenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

A suspension of 2-{2,2,2-trifluoroethyl)-4-chloro-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared according to the method in Example 193E, in THF (27 mL) was cooled to -78 °C. A solution of isopropenyl magnesium bromide (2.8 mL, 0.5 M in THF, Aldrich) was added. The reaction was warmed to room temperature and stirred for 30 minutes. The reaction was quenched at 0 °C by addition of saturated ammonium chloride solution and partitioned between ethyl acetate and additional ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a tan solid. The impure material was dissolved in methylene chloride and adsorbed on silica gel (2

g). The solvent was removed under reduced pressure, the adsorbed silica gel was placed over an Extract-Clean

Cartridge<®> (Alltech, packing: 5 g silica gel), and the cartridge was eluted with a hexanes/acetone stepwise gradient consisting of 40 mL of the following mixtures: hexanes, 8:1 hexanes/acetone, 4:1, 2:1 and 1:1. Fractions containing the desired product were pooled, concentrated and further purified using HPLC (Technikrom Kromasil 60-5sil column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 ml/min over 50 minutes. Fractions containing the title product were combined and concentrated under reduced pressure to provide a pale yellow solid (yield: 99.3 mg, 49%). Temp. 192-195 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 17.4 Hz, 2H), 7.76 (s, 1H), 7.55 (d, 2H, J = 17.4 Hz), 5.23 (br s, 1H), 4.84 (rn, 3H), 3.11 (s, 3H), 1.98 (s, 3H). MS (DCI-NH 3 ) m/z 373 (M+H)<+>, m/z 390 (M+NH 4 )<+>. Anal. calcd for C16H15F3N2O3S: C, 51.61; H, 4.06; N, 7.52. Found: C, 51.72; H, 4.24; N, 7.35.

Example 223

2-( 2, 2, 2- Trifluoroethyl)- A -( 2- buten- 2- yl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 222 using 1-methyl-1-propenyl magnesium bromide instead of isopropenyl magnesium bromide to provide a mixture of geometric isomers (-3:1 ratio) as an off-white solid (yield: 44 .8 mg, 21%). Temp. 175-180 °C. <!>h NMR (300 MHz, CDCl 3 } 58.03 (d, J = 18.0 Hz, 1.5H), 8.01 (d, J = 18.0 Hz, 0.5H), 7.29 (s, 0.75H), 7.28 (s, 0.25H), 7.56 (d, J = 17.4 Hz, 1.5H), 7.51 (d, J = 17.4 Hz, 0.5H), 5.55 (m, 0.75H), 5.33 (m, 0.25H), 5.86 (q, J= 17.4 Hz, 2H), 3.12 (s, 2 .25H), 3.11 (s, 0.75H), 2.88 (m, 2H), 2.85 (m, 1H), 1.27 (m, 3H). MS (DCI-NH 3 ) w/ z 387 (M+H)<+>, m/z 404 (M+NH4)<+>, m/z 421 (M+2NH4~H)<+.> Anal calcd for C17H17F3N2O3S: C, 52.85 ; H, 4.43; N, 7.25. Found: C, 53.16; H, 4.68; N, 6.92.

Example 224

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

224A. 3- Fluorobenzyl magnesium bromide.

3-Fluorobenzyl bromide (613 µL, 5 mmol), followed by dibromoethane (10 µL), was added dropwise to an oven-dried flask containing small pieces of magnesium ribbon (134 mg, 5.5 mmol) and diethyl ether (12 mL). Gas evolution was observed followed by careful reflux of the ether. The reaction was stirred until gas evolution ceased and most of the magnesium had dissolved. The resulting pale yellow solution of 3-fluorobenzylmagnesium bromide was used directly in the next reaction.

224B. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone.

A suspension of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared according to the method in Example 193E, in THF (10 mL) was cooled to 0 °C. A solution of 3-fluorobenzylmagnesium bromide (4.0 mL, -0.42 M in diethyl ether), prepared above, was added. The reaction mixture was stirred at 0 °C for 3 hours, the reaction was quenched by the addition of saturated ammonium chloride solution and partitioned between ethyl acetate and additional ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a yellow oil. The crude material was dissolved in methylene chloride and adsorbed on silica gel (2 g). The solvent was removed under reduced pressure, the silica gel with the product adsorbed was placed over an Extract-Clean Cartridge<®> (Alltech, package: 10 g silica gel) and the cartridge was eluted with a stepwise hexanes/acetone gradient consisting of 60 ml each of the following mixtures: hexanes, 8:1 hexanes/acetone, 4:1, 2:1 and 1:1. Fractions containing the desired product were pooled, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil silicene column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 ml/min. for 50 minutes. Fractions containing the title product were combined and concentrated under reduced pressure to provide a pale yellow solid (yield: 130.9 mg, 54%). Temp. 58-62 °C. <!>h NMR (300 MHz, CDCl 3 ) 8 8.07 (d, J = 18.0 Hz, 2H) , 7.73 (s, 1H) , 7.47 (d, J = 17.4 Hz, 2H), 7.18 (m, IH), 6.88 (m, IH), 6.76 (br d, J = 15.6 Hz, IH) , 6.68 (br d, J = 18.6 Hz, 1H), 4.86 (g, J = 17.4 Hz, 2H), 3.93 (s, 2H), 3.12 (s, 3H). MS (DCI-NH3) m/z 441 (M+H)<+>, m/z 458 (M+NH4)<+>, m/z 475 (M+2NH4-H)4-. Anal. calcd for C20H16E4N2O3S: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.52; H, 3.81; N, 6.17.

Example 225

2-( 2, 2, 2- Trifluoroethyl)- 4-( 1- cyclohexenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

225A. 1- Cyclohexenyl triflate.

n-Butyllithium (2.5M in hexanes, 2.20 mL, 5.50 mmol) was added to a solution of diisopropylamine (0.77 mL, 5.50 mmol) in THF (20 mL) at -78 °C. The resulting pale yellow solution was heated to 0 °C for 30 min, then cooled to -78 °C. Cyclohexanone (0.52 mL, 5.0 mmol) was added and the nearly colorless solution was warmed to 0 °C for 1 h. N-Phenyltrifluoromethanesulfonimide (1.79 g, 5.5 mmol) was added as a solid. The solution was stirred at room temperature for 12 hours. The reaction mixture was then partitioned between diethyl ether and saturated sodium bicarbonate solution. The ether layer was washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (20:1 hexanes/ethyl acetate) to provide the triflate as a pale yellow oil (yield: 0.73 g, 64%).

225B. 1- Cyclohexenyltrimethyltin.

A solution of 1-cyclohexenyl triflate (412 mg, 1.79 mmol), prepared according to the method of Example 225A and LiCl (380 mg, 8.95 mmol) in THF (9 mL) was deoxygenated by bubbling a stream of N 2 through the solution . Hexamethylditinne (339 µl,

1.61 mmol) and tetrakis(triphenylphosphine)palladium(0) (414 mg, 0.36 mmol) were added and the reaction solution was heated under reflux for 12 h. The reaction solution was cooled to room temperature and partitioned between diethyl ether and sat

sodium bicarbonate solution. The ether layer was washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was dissolved in hexanes (1 mL) and transferred to an Extract-Clean

Cartridge<®> (Alltech, packaging: 10 g silica gel) which had been moistened with 10% triethylamine in hexanes. The cartridge was eluted with hexanes, and fractions containing the triflate were combined and concentrated under reduced pressure to provide 1-cyclohexenyltrimethyltin as a clear oil (yield: 150 mg, 34%).

225C. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 1- cyclohexenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone.

A solution of 1-cyclohexenyltrimethyltin (150 mg, 0.61 mmol), prepared according to the method of Example 225B and 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (172 mg, 0.47 mmol), prepared according to the method of Example 193E, in anhydrous N-methylpyrrolidinone (1 mL) was deoxygenated with nitrogen. Dichlorobis(triphenylphosphine)-palladium(II) (6.6 mg, 0.009 mmol) and [1,1'-bis-(diphenylphosphino)ferrocene] dichloropalladium(II) (7.7 mg, 0.009 mmol) were added and the reaction mixture was heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and partitioned between diethyl ether and water. The ether was washed with two additional portions of water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was dissolved in acetone and adsorbed on silica gel (1 g). The solvent was removed under reduced pressure, the adsorbed silica gel was placed over an Extract-Clean Cartridge<®>

(Alltech, package: 10 g silica gel), and the cartridge was eluted with a stepwise hexanes/acetone gradient consisting of the following mixtures: hexanes (60 mL), 8:1 hexanes/acetone (80 mL), 4:1 hexanes/acetone (150 ml). Fractions containing the desired product were pooled, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil silicene column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 ml/min. within 50 minutes. Fractions containing the title product were pooled and concentrated under reduced pressure to

afford a pale yellow foam (yield: 95.0 mg, 49%). Temp. 75-81 °C. <!>h NMR (300 MHz, CDCl 3 ) 58.02 (d, J = 17.4 Hz, 2H), 7.76 (s, 1H), 7.55 (d, J = 17.4 Hz, 2H ), 5.51 (br s, IH), 4.83 (br q, J = 16.2 Hz, 3H), 3.11 (s, 3H), 2.18 (br, 2H), 1.96 (br, 2H), 1.70-1.50 (m, 4H). MS (DCI-NH3) m/z 413 (M+H)<+>, m/z 430 (M+NH4)<+>, m/z 447 (M+2NH4-H)"1". Anal. calcd for C19H19F3N2O3S: C, 55.33; H, 4.64; N, 6.79. Found: C, 55.53; H, 4.71; N, 6.55.

Example 226

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

226A. 3- Fluoro- 4-( methylthio) benzeneboronic acid.

3-Fluoro-4-(methylthio)benzeneboronic acid was prepared according to the method described by Example 1, using 4-bromo-3-fluorothioanisole instead of 4-bromothioanisole.

226B. 2- Benzyl- 4- methoxy- 5- bromo- 3( 2H)- pyridazinone

2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone is prepared according to the method in Example 83B starting from 2-benzyl-4,5-dibromo-3(2H)-pyridazinone, instead of 2-(2,2 ,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone and using methanol instead of isopropanol.

226C. 2- Benzyl- 4- methoxy- 5-[ 3- fluoro- 4-( methylthio) phenyl]-3( 2H)- pyridazinone

3-Fluoro-4-(methylthio)benzeneboronic acid and 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone were coupled according to the method described in Example 83C to provide 2-benzyl-4-methoxy- 5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a yellow solid (yield: 4.98 g, 91%). T-H NMR (300 MHz, CDC13) ? 7.76 (s, 1H), 7.47 (m, 2H), 7.39-7.21 (m, 7H),

5.34 (s, 2H), 4.13 (s, 3H), 2.51 (s, 3H). MS (DCI-NH 3 ) m/z 357 (M+H)<+>, m/z 374 (M+NH 4 )<+>.

226D. 3- Methylbutyl magnesium bromide

An oven-dried flask containing small pieces of magnesium ribbon (134 mg, 5.5 mmol) was charged with diethyl ether (12 mL). 1-Bromo-3-methylbutane (600 µL, 5 mmol) was added dropwise, followed by dibromoethane (10 µL). The reaction required heating by careful reflux before gas evolution was observed. The reaction mixture was heated under reflux for 3 hours and cooled to room temperature. The light gray solution of 3-methylbutylmagnesium bromide was used in the next reaction.

226E. 2- Benzyl- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

A solution of 2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)-phenyl]-3(2H)-pyridazinone (500 mg, 1.40 mmol), prepared according to the method of Example 226C, in THF (20 mL) was cooled to -78 °C. 3-Methylbutylmagnesium bromide (5 mL, 1.96 mmol), prepared in Example 226D, was added dropwise. When the addition was complete, the reaction mixture was placed in an ice bath. After 2.5 hours, the reaction was quenched by the addition of saturated ammonium chloride solution. The crude reaction mixture was partitioned between ethyl acetate and additional ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide a yellow oil (yield: 550 mg, 99%). <*>H NMR (300 MHz, CDCl 3 ) ? 7.67 (s, 1H), 7.49 (m, 2H), 7.39-7.25 (m, 4H), 7.02 (m, 2H), 5.35 (s, 2H), 2.57 -2.49 (rn, 2H), 2.52 (s, 3H), 1.62-1.36 (m, 3H), 0.83 (d, 6H, J = 12.0 Hz). MS (DCI-NH 3 ) m/z 397 (M+H)<+>, m/z 414 (M+NH 4 )<+>. MS (DCI-NH3) m/z 397 (M+H)<+>, m/z 414 (M+NH4)<+.>

226F. 4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone.

2-Benzyl-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone (550 mg, 1.39 mmol), prepared in Example 226E, was debenzylated according to the method described in Example 11 to provide 4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a pale yellow solid (yield: 375 mg , 88%). <1>H NMR (300 MHz, CDCl 3 ) δ 7.65 (s, 1H), 7.34 (dd, 1H, J = 16.2, 16.2 Hz), 7.11-6.98 (m , 2H), 2.60-2.50 (m, 2H), 2.54 (s, 3H), 1.65-1.37 (m, 3H), 0.83 (d, 6H, J = 12 .0 Hz). MS (DCI-NH3) m/z 307 (M+H)<+>, m/z 324 (M+NH4)<+> MS (DCI-NH3) m/z 307 (M+H)<+>, m/z 324 (M+NH4)<+.>

226G. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( methylthio) phenyl]- 3( 2H)- pyridazinone.

4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone (375 mg, 1.23 mmol), prepared in Example 226F, was alkylated according to the method described in Example 20 to provide 2-(2,2,2-trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a clear oil (yield: 331 mg, 69%). 1 H NMR (300 MHz, CDCl 3 ) 5?7.67 (s, 1H), 7.34 (dd, 1H, J= 16.8, 16.8 Hz), 7.11-6.98 (m , 2H), 4.82 (dd, 2H, J = 17.4, 17.4 Hz), 2.60-2.51 (m, 2H), 2.53 (s, 3H), 1.61- 1.32 (rn, 3H), 0.85 (d, 6H, J = 12.0 Hz). MS (DCI-NH3) m/z 389 (M+H)<+>, m/z 406 (M+NH4)<+.> MS (DCI-NH3) m/z 389 (M+H)<+> , m/z 406 (M+NH4)<+>.

226H. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( methylsulfinyl) phenyl]- 3( 2H)- pyridazinone.

2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone (331 mg, 0.85 mmol) , prepared in Example 226G, was oxidized according to the method described in Example 5 using only one equivalent of MCPBA to provide 2-(2,2,2-trifluoro-

ethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone as a whitish solid (yield: 240 mg, 69%). 3-H NMR (300 MHz, CDCl 3 ) 5?8.02 (dd, 1H, J = 15.0, 15.0 Hz), 7.67 (s, 1H), 7.37 (dd, 1H, J = 17 .4, 3.0 Hz), 7.11 (dd, IH, J = 18.6, 3.0 Hz), 4.84 (dd, 2H, J = 17.4, 17.4 Hz), 2 .91 (s, 3H), 2.53 (m, 2H), 1.60-1.35 (m, 3H), 0.57 (d, 6H, J = 12.0 Hz). MS (DCI-NH 3 ) m/z 405 (M+H)<+>, m/z 422 (M+NH 4 )<+>. MS (DCI-NH 3 ) m/z 405 (M+H)<+>, m/z 422 (M+NH 4 )<+>.

22 61. 2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (240 mg, 0.594 mmol), prepared in Example 226H, was converted to the sulfonamide according to the procedure of Example 68 to provide the title compound as a white solid (yield: 109 mg, 44%). Temp. 153-156 °C. <3->H NMR (300 MHz, CDCl3) δ 8.07 (dd, J = 15.0, 15.0 Hz, 1H), 7.74 (s, 1H), 7.27-7.19 (m, 2H), 5.14 (br s, 2H), 4.83 (q, J = 18.0 Hz, 2H), 2.52 (rn, 2H), 1.55 (m, IH), 1.41 (m, 2H), 0.85 (d, J = 12.6 Hz, 6H). MS (ESI (-)) m/z 420 (M-H)-. Anal. calcd for C17H19F4N3O3S: C, 48.45; H, 4.54; N, 9.97. Found: C, 48, 24; H, 4.56; N, 9.80.

Example 227

2-( 2, 2, 2- Trifluoroethyl)- 4- benzyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared by adding 1.0 M benzyl magnesium chloride in ether (0.53 mL, 0.53 mmol) to a THF solution (20 mL) of 2-(2,2,2-trifluoroethyl)-4-chloro- 5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared according to the method of Example 193E, at 0 °C, then allow the mixture to warm to room temperature for 2 h. After an aqueous workup, the crude material was purified by column chromatography (silica gel, 65:35 hexanes/ethyl acetate) and crystallized from ethyl acetate/hexanes to provide a white crystalline product (yield: 74 mg, 43%). Temp. 112-114 °C. <3->H NMR (300 MHz, CDCl3) 83.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J=12Hz, 2H), 6.99 (dd, J = 7.5 Hz, 3 Hz, 2H), 7.2 (m, 3H), 7.48 (d, J = 9 Hz, 2H), 7.72 (s, IH), 8.06 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 423 (M+H)<+>. Anal. calcd for C20H17E3N2O3S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.

Example 22 8

2-( 4- Fluorophenyl)- 4- cyclohexyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

A solution of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone, prepared in Example 194C, (200 mg, 0.51 mmol), in THF (8 mL) was cooled to -78 °C and treated with cyclohexylmagnesium chloride, 2 M solution in ether (0.31 mL, 0.7 mmol). The reaction mixture was stirred at -78 °C for 2 hours, and then it was warmed to room temperature by removing the cooling bath. While stirring at room temperature for 2 hours, water (50 ml) was added to the reaction mixture and extracted with ethyl acetate (50 ml). The organic layer was dried over MgSO 4 , concentrated in vacuo. The resulting methyl sulfide compound was purified by flash chromatography (SiO 2 , eluting with 9:1 hexanes:ethyl acetate) to afford the desired product (yield: 128 mg, 69%). MS (DCI-NH3) m/z 395 (M+H)<+>, 412 (M+NH4)<+.>

The methyl sulfide compound prepared above (122 mg, 0.3 mmol) in CH 2 Cl 2 (10 mL) at 0 °C was treated with CH 3 CO 3 H (0.3 mL, 1 mmol). The reaction was complete after 2 hours. The reaction mixture was diluted with CH 2 Cl 2 and washed with saturated NaHCO 3 or salt water. The resulting crude residue was purified by flash chromatography (SiO 2 , eluting with 1:1 hexanes:ethyl acetate) to afford the desired product (yield: 110 mg, 93%). Temp. 231-233 °C. <3->H NMR (300 MHz, DMSO-d6) 81,1 (m, 3H), 1.6 (m, 6H), 2.15 (m, 2H), 7.35 (t, 2H), 7.65 (m, 2H), 7.73 (dd, 2H) 7.93 (s, 1H), 8.1 (d, 2H). MS (DCl-NH 3 ) m/z 427 (M+H)<+>, 444 (M+NH 4 )<+>. Anal. calcd for C23 H23FN2O3S•0.75 H2O: C, 64.77; H, 5.44; N, 6.57. Found: C, 62.86; H, 5.53; N, 5.78.

Example 22 9

2-( 4- Fluorophenyl)- 4-( 4- methylphenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 using p-tolyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 90 mg, 39%). Temp. 242-244 °C. 3-H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3H), δ 3.25 (s, 3H) , 7.1 (t, 4H) , 7.35

(t, 2H), 7.5 (d, J = 9 Hz, 2H), 7.7 (dd, 2H) 7.9 (d, J = 9 Hz, 2H), 8.2 (s, IH) . MS (DCI-NH3) m/z 435 (M+H)<+>, 452 (M+NH4)<+.> Anal. calcd for C 24 H 19 FN 2 O 3 S■0.5 H 2 O: C, 66.34; H, 4.41; N, 6.45. Found: C, 64.61; H, 4.57; N, 6, 10.

Example 230

2-(4-Fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 228 using benzyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 179 mg, 81%). Temp. 180-182 °C. <1>H NMR (300 MHz, DMSO-d6) 63.3 (s, 3H), 7.0 (d, 2H), 7.2 (m, 3H), 7.35 (t, 2H), 7 .65 (m, 2H) 7.72 (d, 2H) 8.05 (m, 3H). MS (DCl-NH 3 ) m/z 435 (M+H)<+>, 452 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 FN 2 O 3 S•0.5 H 2 O: C, 66.34; H, 4.41; N, 6.45. Found: C, 66.48; H, 4.17; N, 6.36.

Example 231

2-( 4- Fluorophenyl)- 4-( phenylethynyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 using phenylacetylene magnesium bromide instead of cyclohexyl magnesium chloride (yield: 150 mg, 55.5%). Temp. 203-204 °C. <1>H NMR (300 MHz, DMSO-d6)8 3.3 (s, 3H), 7.4 (m, 8H), 7.7 (m, 2H), 8.16 (m, 4H); 8.35 (p, 1H). MS (DCl-NH3) m/z 435 (M+H)<+>, 452 (M+NH4)4-. Anal. calcd for C 25 H 17 FN 2 O 3 S: C, 67.56; H, 3.86; N, 6.30. Found: C, 67.63; H, 3.86; N, 6.30.

Example 232

2-( 3, 4- Difluorophenyl)- 4- cyclohexyl- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]3(2H)-pyridazinone instead of 2-(4-fluorophenyl) )-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 245 mg, 80%). Temp. 80-83 °C. <1>ti NMR (300 MHz, DMSO-d6) 5l,l (m, 3H) , 1.6 (rn, 6H) , 2.15 (m, 2H), 7.5 (m, 1H), 7 .6 (m, 2H), 7.7 (d, 2H), 7.78 (m, 2H), 7.93 (s, 1H), 8.1 (d, 2H). MS (DCI-NH3) m/z 445 (M+H)<+>, 462 (M+NH4)<+.> Anal. calcd for C23H22F2N2O3S: C, 62.15; H, 4.99; N, 6.30. Found: C, 62.65; H, 5.25; N, 5.97.

Example 233

2-(3,4-Difluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3, 4-difluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using benzyl magnesium bromide instead of cyclohexyl magnesium chloride (yield 206 mg, 66%). Temp. 166-168 °C. <1>H NMR (300 MHz, DMSO-d6) 53.3 (s, 3H) , 3.9 (s, 2H) , 7.0 (d, 2H) , 7.2 (m, 3H), 7 .6 (m, 2H), 7.72 (d, 2H), 7.8 (d, 1H), 8.05 (d, 2H), 8.12 (s, 1H). MS (DCI-NH 3 ) m/z 453 (M+H)<+>, 470 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 F 2 N 2 O 3 S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.53; H, 4.33; N, 5.76.

Example 234

2-(3,4-Difluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3, 4-difluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using cyclohexylmagnesium chloride instead of p-tolylmagnesium bromide (yield: 140 mg, 56%). Temp. 190-192 °C. <!>h NMR (300 MHz, DMSO-

d6) 52.28 (s, 2H), 5 3, 25 (s, 3H) , 7.1 (s, 4H) , 7.5 (m, 4H) , 7.89 (m, 3H), 8, 05 (d, 2H), 8.23 (s, 1H). MS (DCI-NH 3 ) m/z 453 (M+H)<+>, 470 (M+NH 4 )<+>. Anal. calcd for C 24 F 2 H 18 N 2 O 3 S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.69; H, 4.29; N, 5, 96.

Example 235

2-( 3, 4- Difluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using 4-fluoro-3-methylbenzenemagnesium bromide instead of cyclohexylmagnesium chloride (yield: 180 mg, 72.5%). Temp. 166-168 °C. <1>h NMR (300 MHz, DMSO-d6) 52.15 (s, 3H), δ 3.25 (s, 3H), 7.01 (m, 2H), 7.25 (d, 1H), 7.6 (rn, 4H), 7.9 (m, 3H), 8.26 (s, 2H). MS (DCl-NH 3 ) m/z 471 (M+H)<+>, 488 (M+NH 4 )<+>. Anal. calcd for C24F3H17N2O3S: C, 61.27; H, 3.64; N, 5.95. Found: C, 61.47; H, 3.84; N, 5.67.

Example 236

2-( 3, 4- Difluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl] - 4- vinyl-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using vinyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 85 mg, 31.8%). 1 H NMR (300 MHz, DMSO-de) 6 2.15

(s, 3H),53.3 (s, 3H), 5.7 (dd, IH), 6.4 (dd, IH), 6.7 (dd, IH) 7.01 (m, 2H), 7.5 (m, 1H), 7.65 (m, 1H), 7.8 (m, 3H), 8.1 (s, 3H) . MS (DCl-NH3) m/z 389 (M+H)<+>, 406 (M+NH4)4-.

Example 237

2-( 3, 4- Difluorophenyl)- 4-( 2- thienyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using 2-thienylmagnesium bromide instead of cyclohexylmagnesium chloride (yield: 66 mg, 28%). Temp. 189-191 °C <3->H NMR (300 MHz, DMSO-d6)5 3.3 (s, 3H) , 6.95 (m, 2H) , 7.55 (m, 1H) , 7.7 (m, 5H), 7.85 (m, 1H), 8.03 (d, J = 9 Hz, 2H), 8.13 (s, 1H). MS (DCl-NH3) m/z 445 (M+H)<+>, 462 (M+NH4)4-. Anal. calcd for C21H14F2N2O3S2: C, 56.75; H, 3.17; N, 6.30. Found: C, 56, 92, H, 3.92, N, 5.79.

Example 238

2-( 3, 4- Difluorophenyl)- 4-( 1- propynyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using methylacetylenemagnesium bromide instead of cyclohexylmagnesium chloride (yield: 65 mg, 24%). Temp. 149-150 °C. <!>h NMR (300 MHz, DMSO-d6)S2,1 (s, 3H) , 3.3 (s, 3H) , 7.51 (m, 1H) , 7.65 (m, 1H), 7 .8 (m, 1H), 8.1 (m, 4H); 8.3 (p, 1H). MS (DCl-NH3) m/z 463M+H)<+>, 480 (M+NH4)<+>. Anal. calcd for C20H14F2N2O3S-0.25 H2O: C, 59.94; H, 3.52; N, 7.00. Found: C, 59.49; H, 3.63; N, 6.34.

Example 239

2-( 3, 4- Difluorophenyl)- 4- t- butyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using t-butyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 60 mg, 24%). Temp. 158-161 °C. 1-H NMR (300 MHz, DMSO-d6) 81.21, (s, 9H), 3.3 (s, 3H), 7.51 (m, 1H), 7.45 (m, 1H), 7 .75 (m, 4H), 8.02 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 419 (M+H)<+>, 436 {M+NH 4 )<+>. Anal. calcd for C21H20F2N2O3S: C, 60.27; H, 4.82; N, 6.69. Found: C, 60.15; H, 5.10; N, 6.39

Example 240

2-( 2, 2, 2- Trifluoroethyl)- 4- cyclohexyl- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 193E, instead of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, (yield: 120 mg, 53%). Temp. 215-218 °C. 3-H NMR (300 MHz, CDCl3)5l,l (tt, J = 9 Hz, J = 4.5 Hz, 2H), 1.25 (tt, J = 9 Hz, 4.5 Hz, 1H), 1.49 (d, J = 12 Hz, 2H), 1.63 (d, J = 12 Hz, IH), 1.75 (dt, J = 12 Hz, 3 Hz, 2H), 2.21 (qd , J = 9 Hz, 4.5 Hz, 2H), 2.51 (tt, J = 12 Hz, 3 Hz, IH), 3.17 (s, 3H), 4.83 (q, J = 12 Hz , 2H), 7.49 (d, J = 9 Hz, 2H), 7.6 (s, 1H), 8.09 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 415 (M+H)<+>. Anal. calcd for C19H21F3N2O3S: C, 55.06; H, 5.1; N, 6.75. Found: C, 55.08; H, 5.10; N, 6.70.

Example 241

2-( 3- Chlorophenyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3- chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared 1 Example 331 and using 3-fluorobenzyl magnesium chloride instead of cyclohexyl magnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 180 mg, 55%). Temp. 142-143 °C. <*>H NMR (300 MHz, CDCl 3 } 83.14 (s, 3H) , 3.98 (s, 2H) , 6.75 (br d, J = 9 Hz, 1H), 6.82 (br d , J = 9 Hz, IH), 6.88 (br t, J = 9 Hz, IH), 7.15-7.23 (rn, IH), 7.37-7.47 (m, 2H), 7.54 (d, J = 9 Hz, 2H), 7.63 (dt, J = 9 Hz, 2 Hz, IH), 7.75 (t, J = 2 Hz, IH), 7.82 (s , IH), 8.10 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 469 (M+H)<+>, 486 (M+NH4)<+.> Anal. calcd. for C 24 H 18 C 1 F 2 N 2 O 3 S-0.5 H 2 O: C, 60.38; H, 3.88; N, 5.87. Found: C, 60.62; H, 3.89; N, 5.82.

Example 242

2-( 4- Fluorophenyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(4- fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 194C and using 3-fluorobenzyl magnesium chloride instead of cyclohexyl magnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method described in Example 10, to provide the title compound (yield: 450 mg, 66.8%). Temp. 176-178 °C. <*>H NMR (300 MHz, CDCl 3 ) 83.14 (s, 3H) , 3.95 (s, 2H) , 6.75 (br d, J = 9 Hz, 1H), 6.82 (br d , J = 9 Hz, IH), 6.88 (br t, J = 9 Hz, IH), 7.14-7.23 (m, 3H), 7.54 (d, J = 9 Hz, 2H) , 7.67 (dd, J = 9 Hz, 6 Hz, 2H) , 7.81 (s, IH) , 8.10 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 516 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 F 2 N 2 O 5 S-H 2 O: C, 61.28; H, 4.04; N, 5.96. Found: C, 61.24; H, 4.09; N, 5.77.

Example 243

2-( 3, 4- Difluorophenyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2- (3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 206E and using 3-fluorobenzyl magnesium chloride instead of cyclohexyl magnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 390 mg, 68%). Temp. 161-163 °C. <1->H NMR (300 MHz, CDCl 3 ) 83.14 (s, 3H), 3.95 (s, 2H), 6.74 (br d, J = 9 Hz, 1H), 6.82 (br d, J = 9 Hz, IH), 6.89 (br t, J = 9 Hz, IH), 7.15-7.33 (m, 2H), 7.48-7.57 (m, IH) , 7.53 (d, J = 9 Hz, 2H), 7.59-7.67 (m, IH), 7.83 (s, IH), 8.10 (d, J = 9 Hz, 2H) . MS (DCl-NH 3 ) m/z 471 (M+H)<+>, 488 (M+NH 4 )<+>. Anal. calcd for C24H17F3N2O3S•0.5H2O: C, 60.13; H, 3.65; N, 5.85. Found: C, 60.08; H, 3.81; N, 5.54.

Example 244

2-( 3- Chlorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 207B and using 4-fluoro-3-methylphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 620 mg, 57%). Temp. 228-230 °C. <1->H

NMR (300 MHz, CDCl3) 82.20 (s, 3H), 3.06 (s, 3H), 6.83-6.93 (m, 2H), 7.19 (br d, J = 9 Hz, IH), 7.37-7.47 (m, 2H), 7.40 (d, J = 9 Hz, 2H), 7.65 (dt, J = 7 Hz, 3 Hz, IH), 7.68 (t, J = 3 Hz, 1H), 7.91 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS (DCl-NH 3 ) m/z 469 (M+H)<+>, 486 (M+NH 4 )<+>. Anal. calcd for C 24 H 18 CIFN 2 O 3 S: C, 61.54; H, 3.85; N, 5.99. Found: C, 61.39; H, 3.84; N, 5.82.

Example 245

2-( 4- Fluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( methyl- sulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 194C and using 4-fluoro-3-methylphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 590 mg, 74.4%). Temp. 245-247 °C. 3-H NMR (300 MHz, CDCl 3 ) 82.01 (s, 3H), 3.07 (s, 3H), 6.87 (m, 2H), 7.21 (m, 3H), 7.41 ( d, J = 9 Hz, 2H), 7.68 (m, 2H),

7.92 (d, J = 9 Hz, 2H), 7.97 (s, 1H). MS (DCl-NH 3 ) m/z 453 (M+H)<+>, 470 {M+NH 4 )<+>. Anal. calcd for C 24 H 18 F 2 N 2 O 3 S•0.5 H 2 O: C, 62.47; H, 3.90; N, 6.08. Found: C, 62.11; H, 4.11; N, 5.81.

Example 24 6

2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

246A. 2-(3-Chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.

The title compound is prepared according to the method in Example 194A, using 3-chloro-4-fluorophenylhydrazine-HCl instead of 4-fluorophenylhydrazine-HCl (yield: 9.1 g, 9%). <i>H NMR (300 MHz, CDCl 3 ) 7.22 (d, J = 9 Hz, 1H), 7.53-7.58 (m, 1H), 7.73 (dd, J = 9 Hz, 3 Hz, 1H), 7.94 (s, 1H). MS (DCI-NH3) m/z 383 (M+H)<+>, 400 (M+NH4)<+>

246B. 2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone.

The title compound is prepared according to the method in Example 194B, using 2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4,5-dibromo- 3(2H)-pyridazinone (yield: 5.6 g, 84%). <1>H NMR (300 MHz, CDCl 3 ) 4.32 (s, 3H), 7.22-7.30 (m, 1H), 7.45-7.55 (m, 1H), 7.64- 7.74 (m, 1H), 7.94 (d, J = 9 Hz, 1H). MS (DCI-NH3) m/z 335 (M+H)<+>, 352 (M+NH4)<+.>

246C. 2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.

The title compound is prepared according to the method in Example 6 starting from 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone instead of 2-benzyl-5-methoxy-4-bromo-3( 2H)-pyridazinone and using 3-methyl-4-(methylthio)benzeneboronic acid instead of 4-fluorobenzeneboronic acid (yield: 3.2 g, 63%). 1 H NMR (300 MHz, CDCl 3 ) δ 2.53 (s, 3H), 4.13 (s, 3H), 7.25 (t, J = 9 Hz, 1H), 7.35 (d, J = 9 Hz, 2H) , 7.52 (d, J = 9 Hz, 2H), 7.55-7.64 (m, IH), 7.78 (dd, J = 9 Hz, 3 Hz, IH), 7 .93 (p, 2H). MS (DCI-NH3) m/z 377 (M+H)<+>, 394 (M+NH4)<+.>

246D. 2-( 3- Chloro- 4- fluorophenyl)- 4- cyclohexyl- 5-[ 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

The title compound is prepared starting from 2-{3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl)-4-methoxy- 5-[4-(methylthio)phenyl]-3(2H)-pyridazinone by treating the methoxy sulfide compound with cyclohexylmagnesium chloride according to the method described in Example 228 to provide the cyclohexyl sulfide compound.

246E. 2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 150 mg, 53%). Temp. 180-181 °C. <i>H NMR (300 MHz, CDCl 3 ) 61.02-1.36 (rn, 2H), 1.49-1.68 (m, 4H), 1.75 (br d, J = 12 Hz, 2H ), 2.28 (dq, J = 12 Hz, 3 Hz, 2H), 2.57 (tt, J = 12 Hz, 3 Hz, IH), 3.17 (s, 3H), 7.25 (t , J = 9 Hz, IH), 7.53 (d, J = 9 Hz, IH), 7.53-7.61 (m, 2H), 7.69 (s, IH), 7.78 (dd , J = 9 Hz, 3 Hz, 1H), 8.12 (d, J = 9 Hz, 2H) . MS (DCl-NH3) m/z 461 (M+H)<+>, 478 (M+NH4)4-. Anal. calcd for C 23 H 22 CIFN 2 O 3 S: C, 60.01; H, 4.78; N, 6.09. Found: C, 59.85; H, 4.97; N, 5.79.

Example 247

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246D and using 4-fluoro-3 -methylphenylmagnesium bromide instead of cyclohexylmagnesium chloride to provide the methylsulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 118 mg, 53.7%). Temp. 207-208 °C. <1>-H NMR (300 MHz, CDCl 3 ) 52.21 (br s, 3H) , 3.08 (s, 3H) , 6.81-6.93 (m, 2H) , 7.15-7, 30 (m, 2H), 7.41 (d, J = 9 Hz, 2H) , 7.60-7.68 (m, IH), 7.85 (dd, J = 9 Hz, 3 Hz, IH) , 7.93 (d, J = 9 Hz, 2H), 7.99 (s, 1H). MS (DCl-NH 3 ) m/z 487 (M+H)<+>, 504 (M+NH 4 )<+>. Anal. calcd for C 24 H 17 CIF 2 N 2 O 3 S■0.25 H 2 O: C, 58.75; H, 3.52; N, 5.72. Found: C, 58.74; H, 3.60; N, 5.32.

Example 248

2-( 3- Chloro- 4- fluorophenyl)- 4- benzyl- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3- chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246D and using benzyl magnesium chloride instead of cyclohexyl magnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 110 mg, 38.4%). Temp. 164-166 °C. <*>H NMR (300 MHz, CDCl 3 ) δ 3.11 (s, 3H), 3.99 (s, 2H), 7.01-7.06 (m, 2H), 7.17-7.28 (m, 4H), 7.53 (d, J = 9 Hz, 2H>, 7.59-7.66 (m, IH), 7.81 (s, IH), 7.82 (dd, J = 6 Hz, 3 Hz, IH), 8.09 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 473 (M+H)<+>, 490 (M+NH4)<+ >. Anal calcd for C 24 H 18 CIFN 2 O 3 S: C, 61.54; H, 3.85; N, 5.99. Found: C, 61.40; H, 3.82; N, 5.54.

Example 24 9

2-( 3- Chloro- 4- fluorophenyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246D and using 3-fluorobenzyl magnesium chloride instead of cyclohexyl magnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 33 mg, 15%). Temp. 101-103 °C. ^ NMR (300 MHz, CDCl3) 53.15 (s, 3H), 3.95 (s, 2H), 6.73 (br d, J = 9 Hz, IH), 6.81 (br d, J = 9 Hz, IH), 6.88 (br t, J = 9 Hz, IH), 7.15-7.28 (m, 2H), 7.51 (d, J = 9 Hz, 2H), 7, 53 (ddd, J = 9 Hz, 3 Hz, 1.5 Hz, IH), 7.83 (dd, J = 6 Hz, 3 Hz, IH), 7.83 (s, IH), 8.10 ( d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 487 (M+H)<+>, 504 (M+NH 4 )<+>. Anal. calcd for C 24 H 17 CIF 2 N 2 O 3 S: C, 58.75; H, 3.52; N, 5.62. Found: C, 58.50; H, 3.65; N, 5.29.

Example 250

2-( 4- Fluorophenyl)- 4-( 3- fluoro- 4- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 194C and using 3-fluoro-4-methylphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 540 mg, 73%). Temp. 245-248 °C. <1>h NMR (300 MHz, CDCl 3 ) 52.22 (br s, 3H) , 3.05 (s, 3H) , 6.83 (dd, J = 9 Hz, 1.5 Hz, 1H), 6 .96 (dd, J = 9 Hz, 1.5 Hz, IH), 7.06 (t, J = 9 Hz, IH), 7.18 (t, J = 9 Hz, 2H), 7.41 ( d, J = 9 Hz, 2H), 7.65-7.72 (m, 2H), 7.91 (d, J = 9 Hz, 2H), 7.95 (s, 1H). MS {DCI-NH3) m/z 452 (M+H)<+>, 470 (M+NH4)4-. Anal. calcd for C 24 H 18 F 2 N 2 O 3 S: C, 63.86; H, 3.99; N, 6.21. Found: C, 63.49; H, 4.13; N, 5.98.

Example 251

2-( 3- Chloro- 4- fluorophenyl)- 4-( 3, 5- difluoro- 4- methoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-_[3,5-difluoro-4-methoxyphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246D and as 3,5-difluoro-4-methoxyphenylmagnesium bromide was used instead of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 590 mg, 65.7%). Temp. 195-197 °C. ^-H NMR (300 MHz, CDCl 3 ) 53.10 (s, 3H), 4.12 (s, 3H), 6.81 (br d, J = 9 Hz, 2H), 7.27 (t, J = 9 Hz, IH), 7.43 (d, J = 9 Hz, 2H), 7.60-7.67 (m, IH), 7.83 (br d, J = 9 Hz, IH), 7 .98 (d, J « 9 Hz, 2H), 7.98 (s, IH). MS (DCl-NH 3 ) m/z 487 (M+H)<+>, 504 (M+NH 4 )<+>. Anal. calcd for C 24 H 16 CIF 3 N 2 O 3 S•0.5 H 2 O: C, 54.44; H, 3.12; N, 5.30. Found: C, 54.50; H, 3.12; N, 5, 15.

Example 252

2-( 3- Chloro- 4- fluorophenyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 228 starting from 2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246D using 1-(3-methylbutyl)magnesium bromide instead of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 425 mg, 54.4%). Temp. 102-104 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 0.85 (d, J = 9 Hz, 6H) , 1.41-1.62 (m, 1H) , 2.50-2.63 (rn, 2H ) , 3.30 (s, 3H) , 7.22-7.38 (rn, 3H) , 7.57-7.64 (m, IH), 7.72 (br s, IH), 7.80 (br d, J = 6 Hz, IH), 8.15 (t, J = 9 Hz, IH). MS (DCI-NH3) m/z 467 (M+H)<+>, 484 (M+NH4)<+.> Anal. calcd for C 22 H 21 CIF 2 N 2 O 3 S: C, 56.65; H, 4.51; N, 6.01. Found: C, 56.25; H, 4.49; N, 6.06.

Example 253

2-( 4- Fluorophenyl)- 4-( 3- fluorobenzyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The methyl sulfide intermediate from Example 242 was oxidized to the methyl sulfoxide with one equivalent of meta-chloroperoxybenzoic acid according to the procedure of Example 69B to provide the sulfinyl compound.

The sulfoxide was converted to the title sulfonamide according to the method described in Example 68 (yield: 120 mg, 31%). Temp. 199-202 °C. 1(1 NMR (300 MHz, DMSO-d6) 8 3.92 (s, 2H) , 6.85 (br t, J = 9 Hz, 2H), 6.99 (br t, J = 9 Hz, IH ), 7.26 (q, J = 7 Hz, IH), 7.35 (t, J = 9 Hz, 2H), 7.50 (s, 2H), 7.62-7.71 (m, 4H ), 7.95 (d, J = 9 Hz, 2H), 8.11 (s, 1H). MS (DCI-NH3) m/z 454 (M+H)<+>, 471 (M+NH4) <+>. Anal calcd for C23H17F2N3O3S: C, 60.86; H, 3.75; N, 9.27. Found: C, 60.99; H, 3.76; N, 9.02.

Example 254

2-( 3, 4- Difluorophenyl)- 4-( phenylethynyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 232 using phenylethynyl magnesium bromide instead of chloride (yield: 195 mg, 61%). Temp. 211-213 °C. <i>H NMR (300 MHz, DMSO-de) 87.46 (m, 5H), 7.65 (m, 2H), 8.18 (t, 4H); 8.4 (p, 1H). MS (DCI-NH3) m/z 463M+H)<+>, 480 (M+NH4)<+.> Anal. calcd for C25H16F2N2O3S: C, 64.56; H, 3.49; N, 6.06. Found: C, 64.49; H, 3.68; N, 5, 86.

Example 255

2-( 3, 4- Difluorophenyl)- 4-( 3, 4- difluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)_- pyridazinone

3,4-Difluorobenzyl bromide (0.1 mL, 0.8 mmol) in ether (10 mL) was treated with magnesium shavings (19.4 mg, 0.81 mmol), and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled and added to a solution of 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone (0.25 g, 0.7 mmol) in THF (10 mL) at -78 °C. The reaction mixture was stirred at room temperature for 18 hours. Water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO 4 , concentrated in vacuo. The resulting crude residue was purified by flash chromatography (SiO 2 eluting with 9:1 hexanes:ethyl acetate) to provide 120 mg of the desired product and some starting material.

The methylthio compound (120 mg, 0.3 mmol) from above in CH 2 Cl 2 (10 mL) at 0 °C was treated with CH 3 CO 3 H (0.3 mL, 1 mmol). The reaction was complete after 2 hours. The reaction mixture was diluted with CH 2 Cl 2 and washed with saturated NaHCO 3 or salt water. The resulting crude residue was purified by flash chromatography (SiO 2 eluting with 1:1 hexanes:ethyl acetate) to afford the desired product (yield: 44 mg, 13%). Temp. 177-179 °C. <!>h NMR (300 MHz, DMSO-d6)5 3.3 (s, 3H) , 3.9 (s, 2H) , 6.85 (m, 1H) , 7.15 (rn, 1H) , 7.25 (m, 2H), 7.6 (m, 7H), 8.15 (rn, 3H). MS {DCI-NH3) m/z 489 (M+H)<+>, 506 (M+NH4)<+.> Anal. calcd for C24H16F4N2O3S•0.25 H2O: C, 59.01; H, 3.30; N, 5.74. Found: C, 58.16; H, 3.56; N, 4.51.

Example 256

2-( 3, 4- Difluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 233 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3, 4-difluorophenyl)-4-methoxy-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using 1-bromo-3-methylbutane instead of 3,4-difluorobenzyl bromide (yield: 198 mg, 48%). Temp. 55-58 °C. <1>H NMR (300 MHz, DMS0-d6) δ 0.75

(d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (rn, IH), 7.65 (m, IH ), 7.75 (d, J = 9 Hz, 2H), 7.81 (m, IH) 8.05 (s, IH), 8.12 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 433 (M+H)<+>, 450 (M+NH 4 )<+>. Anal. calcd for C 22 H 22 F 2 N 2 O 3 S■0.25 H 2 O: C, 61.10; H, 5.13; N, 6.48. Found: C, 61.09; H, 5.23; N, 6.36.

Example 257

2-( 3- Chloro- 4- fluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 233 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone with 2-(3- chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and using 1-bromo-3-methylbutane instead of 3,4-difluorobenzyl bromide (yield: 256 mg , 88%). Temp. 55-58 °C. <1>H NMR (300 MHz, DMS0-d6) 50.75 (d, 6H), 1.4, (m, 3H) , 2.48 (m, 2H) , 3.3 (s, 3H) , 7.62 (m, 2H), 7.75 (d, 2H), 7.93 (dd, 1H), 8.05 (s, 1H), 8.12 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 449 (M+H)<+>, 466 (M+NH 4 ) + . Anal. calcd for C22H22FN2O3SCI • 0.25 H2O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.

Example 258

2-( 3, 4- Difluorophenyl)- 4-( 3- methylbutyl)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 233 starting from 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chloro-4-fluorophenyl)-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone and using 1-bromo-3-methylbutane instead of 3,4-difluorobenzyl bromide ( yield: 100 mg, 20%) . Temp. 119-121 °C. <3->H NMR (300 MHz, DMSO-d6) 50.75 (d, 6H), 1.4, (m, 3H), 2.48 (rn, 2H), 3.4 (s, 3H) , 7.51 (m, 1H), 7.8 (m, 2H), 7.81 (m, 2H). MS (DCI-NH 3 ) m/z 451 (M+H)<+>, 468 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 F 3 N 2 O 3 S: C, 58.66; H, 4.7; N, 6.22.

Example 259

2-[ 4- Fluoro- 3-( methylthio) phenyl]- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A stirred solution of 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (315 mg, 0.69 mmol) in DMF (10 mL) at room temperature was treated with sodium thiomethoxide (51 mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 3.15 hours. The reaction mixture was poured into water (75 mL) and extracted into ethyl acetate. The organic layer was washed two hours with brine, dried over MgSO 4 and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiO 2 , eluting with (15:1 CH 2 Cl 2 :diethyl ether)) to afford the desired product (yield: 30 mg, 8%). mp 105-107 °C .<!>h NMR (300 MHz, DMSO-dg) δ 2.55 (s, 3H) , 3.23 (s, 3H), 87.15 (m, 2H) , 7.3

(m, 2H), 7.55 (m, 5H), 7.9 (d, 2H), 8.25 (s, 1H). MS (DCI-NH3) m/z 485 (M+H)<+>, 502 (M+NH4)<+.> Anal. calcd for C 24 H 18 F 2 N 2 O 3 S 2 : C, 59.49; H, 3.74; N, 5.78.

Example 260

2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-pyridazinone: 260A. 2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfinyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared starting from 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and by oxidizing the sulfide according to the procedure of Example 69B.

260B. Bis( 4-( 5-( 2- benzyl- 4-( 4- fluorophenyl)- 3( 2H )-pyridazinone) phenyl) disulfide: A heterogeneous solution of 2-benzyl-4-(4-fluorophenyl)-5-[ 4-(Methylsulfinyl)phenyl]-3(2H)-pyridazinone (1.0 g, 2.39 mmol) in trifluoroacetic anhydride (10 mL, 70.8 mmol) was stirred rapidly under reflux for 2 h with a bath temperature of 40- 43 °C. The reaction solution was cooled to 23 °C, concentrated in vacuo and distilled azeotropically with toluene (2 x 5-7 mL). The resulting yellow/orange oil was cooled to 0 °C, and methanol/triethylamine (1:1 , 6 mL) was slowly added along the inner wall of the reaction vessel with rapid stirring. The clear red-orange solution was stirred for 10 min at 0 °C, the cooling bath was removed, and the reaction mixture was stirred for an additional 1.5 h while warming to 23 °C C. The mixture was cooled back to 0 °C and a saturated NH 4 Cl solution (200 mL) was slowly added followed by enough aqueous 1 M HCl to adjust the solution to pH 1-2. The cooling bath was removed and the solution was stirred over night n. The mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and brine and concentrated in vacuo. The resulting yellow/brown oil (0.89 g) was a mixture of predominantly mono-sulfide and the desired dis-sulfide. Subsequent rapid stirring of a portion of the crude reaction mixture (360 mg) in benzene

(100 mL) with 12 (648 mg, 2.55 mmol) at 23 °C for 30 min completed the conversion of the mono-sulfide to the dis-sulfide.

(Chem. Pharm. Bull., 1992, 40, 2842) The mixture was treated with a 0.1 M Na 2 S 2 O 3 solution to consume the excess of 12- This solution was extracted with ethyl acetate, and the ethyl acetate layers were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was dissolved in CH 2 CT 2 /- hexanes and concentrated in vacuo to provide the product (yield: 347 mg, 90% for partial conversion). J-H NMR (300 MHz, CDCl 3 ) δ 5.38 (s, 4H), 6.91 (dd, J = 8.8, 8.8 Hz, 4H), 7.02 (d, J = 8.7 Hz , 4H), 7.11-7.20 (m, 4H), 7.28-7.39 (m, 10H), 7.54 (dd, J = 6.9, 1.5 Hz, 4H), 7.83 (p, 2H).

260C. 2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( trifluoromethylthio)-phenyl]- 3( 2H)- pyridazinone:

A rapidly stirred mixture of bis[4-{5-[2-benzyl-4-(4-fluorophenyl)-3(2H)-pyridazinone]}-phenyl]-disulfide (140 mg, 0.181 mmol), potassium trifluoroacetate ( 55 mg, 0.361 mmol) and sulfolane (1.5 mL) were immersed in a 180 °C preheated oil bath. The oil bath was heated to raise the temperature to 210 °C, and the reaction flask was immediately removed from the oil bath after 10 minutes from the time of the first immersion. During the course of the reaction, the mixture changed from colorless and heterogeneous to deep blood red and homogeneous. After cooling to 23 °C, the mixture was diluted with ethyl acetate and washed with aqueous 1 M HCl, water and brine. The ethyl acetate solution was dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed {flash silica gel, ethyl acetate/hexanes 1:4) to provide the product (yield: 17 mg, 41%). (Tetrahedron Lett., 1996, 37, 9057) <!>h NMR (300 MHz, CDCl 3 ) 55.41 (s, 2H), 6.94 (dd, J = 8.2, 8.2 Hz, 2H) , 7.11-7.20 (rn, 4H), 7.31-7.42 (m, 3H), 7.52-7.61 (rn, 4H), 7.86 (s, 1H). MS (APCI+) m/z 457 (M+H)<+> and m/z 474 (M+NH4)<+. >26QD. 2- Benzyl- 4-( 4-fluorophenyl)- 5-[ 4-( trifluoromethyl-sulfonyl) phenyl]- 3( 2H)- pyridazinone: A solution of 2-benzyl-4-(4-fluorophenyl)-5-[ 4-(Trifluoromethylthio)phenyl]-3(2H)-pyridazinone (100 mg, 0.219 mmol), 3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%) and methylene chloride (5 mL) were brought to reflux at a bath temperature of 55 °C. After 1.75 h, 3.5 h, 5 h and 6 h, the reaction was not complete and additional 3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%) was added each time. When the reaction was complete after 7.75 hours, the mixture was cooled to 23 °C and concentrated in vacuo. The residue was diluted with ethyl acetate and gently shaken with a NaHSO 3 solution, 3 times, for several minutes to consume the excess 3-chloroperoxybenzoic acid. The ethyl acetate solution was then washed with a saturated Na 2 CO 3 solution (3x), water and brine and dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/methylene chloride/hexanes 1:2:7) to provide the product (yield: 93 mg, 87%). (J. Med. Chem., 1990, 33, 2569) mp. 80-115 °C. <!>h NMR (300 MHz, DMSO-d6) 85.36 (s, 2H), 7.11 (dd, J= 9.0, 9.0 Hz, 2H), 7.18-7.26 (m, 2H), 7.29-7.46 (m, 5H), 7.66 (d, J = 8.7 Hz, 2H), 8.10 (d, J = 8.7 Hz, 2H), 8, 18 (p, IH). MS (APCI+) m/z 489 (M+H)<+> and m/z 506 (M+NH4)<+>. Anal. calcd for C24H16F4N2O3S: C, 59.02; H, 3.30; N, 5.74. Found: C, 59.30; H, 3.48; N, 5.59.

Example 261

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared in Example 193E, and neopentyl alcohol (43 mg, 0.49 mmol) was dissolved in DMF (2 mL) and NaH (25 mg, 0.62 mmol, 60% in mineral oil) was added with shaking and the mixture was allowed to stand

the night. The reaction was carefully quenched with saturated NH 2 Cl solution, diluted with ethyl acetate and extracted with 1 N HCl, twice, then water 3 times, and then dried over MgSO/j. After filtering the drying agent and concentrating the filtrate in vacuo, the residue was purified by means of chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the title compound (yield: 137 mg, 76%). Temp. 145-146 °C. 11 NMR (300 MHz, DMSO-d6) δ 0.76 (s, 9H) , 3.28 (s, 3H) , 4.06 (s, 2H) , 5.02

(q, J = 9 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H), 8.13 (s, 1H). MS (DCl-NH 3 ) m/z 419 (M+H)<+>, 436 (M+NH 4 )<+>. Anal. calcd for C18H21F3N2O4S: C, 51.67; H, 5.06; N, 6.69. Found: C, 51.47; H, 5.12; N, 6.48.

Example 262

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- methoxyphenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-methoxyphenol instead of neopentyl alcohol (yield: 130 mg, 54%). Temp. 194-195 °C. <!>h NMR (300 MHz, DMS0-d6) δ 2.24 (s, 3H), 3.26 (s, 3H), 5.00 (q, J = 9 Hz, 2H), 6.88 ( d, J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H ), 8.33 (p, 1H). MS (ESI-) m/z 439 (M-H)-. Anal. calcd for C19H17F3N2O4S: C, 54.79; H, 3.91; N, 6.39. Found: C, 55.04; H, 4.00; N, 6.11.

Example 263

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- fluoro- 5- trifluoromethylphenoxy)-5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 2-fluoro-5-trifluoromethylphenol instead of neopentyl alcohol (yield:

155 mg, 89%). Temp. 133-135 °C. <1>H NMR (300 MHz, DMSO-

de) 53.28 (s, 3H), 5.03 (q, J = 9 Hz, 2H), 7.10-7.53 (m, 2H), 7.72 (dd, J = 1 Hz, 7 Hz 1H), 7.92 (d, J = 8 Hz, 2H), 8.07 (d, J = 8 Hz, 2H), 8.38 (s, 1H). MS (DCl-NH 3 ) m/z 528 (M+NH 4 ). Anal. calcd for C20H13F7N2O4S: C, 47.66; H, 3.09; N, 5.05. Found: C, 47.68; H, 2.95; N, 5.16.

Example 264

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- cyanophenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-cyanophenol instead of neopentyl alcohol (yield: 109 mg, 71%). Temp. 179-181 °C. <1>H NMR (300 MHz, DMSO-d6) 63.26 (s, 3H), 5.02 (q, J = 9 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 7.81 (d, J = 9 Hz, 2H), 7.86 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 8.37 (s, IH) . MS (DCl-NH 3 ) m/z 467 (M+NH 4 )<+>. Anal. calcd for C20H14E3N3O4S: C, 53.45; H, 3.14; N, 9.35. Found: C, 53.19; H, 3.01; N, 9.09.

Example 265

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- pyridyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 3-hydroxypyridine instead of neopentyl alcohol (yield: 120 mg, 69%). Temp. 191-193 °C. <i>H NMR (300 MHz, DMS0-d6) δ 3.26 (s, 3H), 5.01 (q, J = 9 Hz, 2H), 7.36 (dd, J = 3 Hz, 8 Hz , IH), 7.55 (ddd, J = 1 Hz, 3 Hz, 8 Hz, IH), 7.88 (d, J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H ), 8.31 (dd, J = 1 Hz, 5 Hz, IH) , 8.36 (s, IH), 8.38 (d, J = 3 Hz, IH). MS (DCI-NH3) m/z 426 (M+H) +, 443 (M+NH4)<+.> Anal. calcd for C18H14F3N3O4S: C, 50.82; H, 3.32; N, 9.88. Found: C, 50.95; H, 3.57; N, 9, 71.

Example 266

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- n- propylphenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-(n-propyl)-phenol instead of neopentyl alcohol (yield: 147 mg, 77%). Temp. 152-153 °C. <*>H NMR (300 MHz, DMSO-d6) 80.87 (t, J = 7 Hz, 3H), 1.54 (h, J = 7 Hz, 2H), 3.25 (s, 3H), 5.00 (q, J = 9 Hz, 2H), 6.88 (d, J = 9 Hz, 2H), 7.09 (d, J = 9 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 8.02 (d, J = 8 H2, 2H), 8.32 (s, 1H). MS (DCI-NH3) m/z 484 (M+H)<+.> Anal. calcd for C 22 H 21 E 3 N 2 O 4 S: C, 56.33; H, 4.54; N, 6.01. Found: C, 56.23; H, 4.75; N, 5.79.

Example 267

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 4-( methylsulfonyl) phenoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-(methylsulfonyl)phenol instead of neopentyl alcohol (yield: 115 mg, 56%). Temp. 212-213 °C. <!>h NMR (300 MHz, DMSO-d6) 83.21 (s, 3H), 3.27 (s, 3H), 5.03 (q, J = 9 Hz, 2H), 7.31 (d , J = 9 Hz, 2H), 7.83-7.89 (m, 4H), 8.04 (d, J = 8 Hz, 2H), 8.40 (s, 1H). MS (DCI-NH3) m/z 520 (M+NH4)<+.> Anal. calcd for C20H17F3N2OeS2: C, 47.81; H, 3.41; N, 5.58. Found: C, 47.92; H, 3.18; N, 5.52.

Example 268

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- phenylphenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-phenylphenol instead of neopentyl alcohol (yield: 105 mg, 51%). Temp. 163-165 °C. <X>H NMR (300 MHz, DMSO-d6) S 3.26 (s, 3H) , 5.02

(q, J = 9 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 7.33 (br t, J = 7 Hz, IH), 7.44 (t, J = 7 Hz , 2H), 7.57-7.63 (m, 4H), 7.92 (d, J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H), 8.37 (s , IH). MS (DCI-NH3) m/z 518 (M+NH4)<+.> Anal. calculated for C25H19F3N2O4S: C, 60.00; H, 3.83; N, 5.60. Found: C, 60.18; H, 3.66; N, 5.52.

Example 269

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 2-( methylthio) ethoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 2-(methylthio)-ethanol instead of neopentyl alcohol (yield: 105 mg, 61%). Temp. 103-105 °C. <i>H NMR (300 MHz, DMS0-d6) 52.01 (s, 3H), 2.72 (t, J = 7 Hz, 2H), 3.29 (s, 3H), 4.59 (t , J = 7 Hz, 2H), 5.03 (q, J = 9 Hz, 2H), 7.91 (d, J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H) , 8.15 (p, IH). MS (DCI-NH 3 ) m/z 423 (M+H)<+>, 440 (M+NH 4 )<+>. Anal. calcd for C16H17F3N2O4S2: C, 45.49; H, 4.06; N, 6.33. Found: C, 45.83; H, 4.11; N, 6, 42.

Example 270

2-( 2, 2, 2- Trifluoroethyl)- 4-( phenylmethoxy)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using benzyl alcohol instead of neopentyl alcohol (yield: 137 mg, 76%). Temp. 121-123 °C. <!>h NMR (300 MHz, DMSO-d6) δ 3.28 (s, 3H) , 5.06 (q, J = 9 Hz, 2H), 5.48 (s, 2H), 7.20- 7.25 (rn, 2H), 7.27-7.81 (m, 3H), 7.76 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 8,12 (pp, IH). MS (DCl-NH 3 ) m/z 456 (M+H)<+>. Anal. calcd for C20H17F3N2O4S: C, 54.79; H, 3.91; N, 6.39. Found: C, 55.10; H, 3.91; N, 6.13.

Example 271

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- furylmethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 2-(hydroxymethyl)furan instead of neopentyl alcohol (yield: 101 mg, 58%). Temp. 113-115 °C. 3-H NMR (300 MHz, DMSO-de) 83.28 (s, 3H), 5.07 (q, J = 9 Hz, 2H), 5.52 (s, 2H), 6.41 (dd, J = 2 Hz, 3 Hz, IH), 6.45 (d, J = 4 Hz, IH), 7.62 (d, J = 2 Hz, IH), 7.69 (d, J = 8 Hz, 2H), 7.97 (d, J = 8 Hz, 2H), 8.13 (s, 1H). MS (DCl-NH 3 ) m/z 446 (M+NH 4 )<+>. Anal. calcd for C18H15F3N2O5S: C, 50.66; H, 3.80; N, 6.21. Found: C, 51.02; H, 3.71; N, 6.23.

Example 272

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 2-( 3, 4- dimethoxyphenyl) ethoxy)]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 2-(3,4-dimethoxyphenyl)ethanol instead of neopentyl alcohol (yield: 118 mg, 56%). Temp. 133-134 °C. ^-H NMR (300 MHz, DMSO-

de) 8 2.82 (t, J = 7 Hz, 2H) , 3.28 (s, 3H) , 3.63 (s, 3H) , 3.70 (s, 3H), 4.68 (t, J = 7 Hz, 2H), 5.01 (q, J = 9 Hz, 2H), 6.61 (dd, J = 2 Hz, 8 Hz, IH), 6.74 (d, J = 2 Hz, IH), 6.77 (d, J = 8 Hz, IH), 7.74 (d, J = 8 Hz, 2H), 7.93 (d, J = 8 Hz, 2H), 8.11 (s , IH). MS (DCl-NH 3 ) m/z 530 (M+NH 4 )<+. >Anal. calcd for C23H23F3N2O6S: C, 53.90; H, 4.52; N, 5.47. Found: C, 53.87; H, 4.48; N, 5.45.

Example 273

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 2-( 4- morpholino) ethoxy)]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-(2-hydroxyethyl)morpholine instead of neopentyl alcohol (yield: 111 mg, 59%). Temp. 147-148 °C. <!>h NMR (300 MHz, DMSO-d6) δ 2.23 (m, 4H) , 2.46 {t, J = 5 Hz, 2H> , 3.28 (s, 3H) , 3.40 ( rn, 4H) , 4.60 (t, J = 5 Hz, 2H), 5.02 (q, J = 8 Hz, 2H), 7.96 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 8.17 (s, 1H). MS (DCI-NH3) m/z 462 (M+H)<+.> Anal. calcd for C19H22E3N3O5S: C, 49.45; H, 4.81; N, 9,11. Found: C, 49.59; H, 4.80; N, 8.88.

Example 274

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 2-( 1- piperidinyl) ethoxy)]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 1-(2-hydroxyethyl)piperidine instead of neopentyl alcohol (yield: 103 mg, 55%). Temp. 117-118 °C. 1 H NMR (300 MHz, DMSO-d6) δ 1.30 (br s, 6H), 2.20 (br s, 4H), 2.41 (t, J = 4 Hz, 2H), 3.28 ( s, 3H), 4.60 (t, J = 5 Hz, 2H), 5.02 (q, J = 9 Hz, 2H), 7.97 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 8.15 (s, 1H). MS (DCl-NH 3 ) m/z 460 (M+H)<+>. Anal. calcd for C20H24F3N3O4S: Cf 52.28; H, 5.26; N, 9.15. Found: C, 52.22; H, 5.08; N, 8.94.

Example 275

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 4-( carboxamido) phenoxy)]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-hydroxybenzamide instead of neopentyl alcohol (yield: 50 mg, 26%). Temp. > 250 °C. <3->H NMR (300 MHz, DMSO-d6) δ 3.26 {s, 3H) , 5.02 (q, J = 8 Hz, 2H), 7.08 {d, J = 9 Hz, 2H ), 7.30 (s, IH), 7.82 (d, J = 9 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 7.92 (s, IH), 8, 03 (d, J = 8 Hz, 2H), 8.47 (s, IH). MS (DCT-NH 3 ) m/z 468 (M+H)<+>, 485 (M+NH 4 )"1". Anal. calcd for C20HI6F3N3O5S: C, 51.39/ H, 3.45; N, 8.99. Found: C, 51.31; H, 3.28; N, 8.77.

Example 276

2-( 2, 2, 2- Trifluoroethyl)- 4-{ 1- indanyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 1-indanol instead of neopentyl alcohol (yield: 84 mg, 44%). Temp. 113-114 °C. <*>H NMR (300 MHz, DMSO-dg) 52.07-2.14 (rn, 1H), 2.22-2.35 (m, 1H), 2.73 (dd, J = 5 Hz, 7 Hz, 2H) , 3.24 (s, 3H), 5.00-5.22 (m, 2H), 6.48 (dd, J = 2 Hz, 6 Hz, IH), 7.12-7 .24 (m, 2H), 7.21-7.28 (rn, 2H), 7.44 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 8 ,09 (p, IH). MS (DCI-NH3) m/z 482 (M+NH4)<+.> Anal. calcd for C22H19F3N2O4S: C, 57.19; H, 4.48; N, 5.80. Found: C, 57.36; H, 4.30; N, 5.78.

Example 277

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 4-( acetamido) phenoxy)]- 5- [ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 4-acetamidophenol instead of neopentyl alcohol (yield: 45 mg, 23%). Temp. 215-216 °C. <!>h NMR (300 MHz, DMSO-d6) 52.02 (s, 3H), 3.26 (s, 3H), 5.02 (q, J= 8 Hz, 2H), 6.61-6 .65 (m, IH), 7.17-7.20 (m, 2H), 7.34 (br s, IH), 7.88 (d, J = 9 Hz, 2H), 8.03 (d , J = 8 Hz, 2H), 8.36 (s, 1H), 9.97 (s, 1H). MS (DCl-NH 3 ) m/z 499 (M+NH 4 )<+>. Anal. calcd for C21H18F3N3O5S: C, 52.39; H, 3.77; N, 8.73. Found: C, 52.57; H, 4.02; N, 8.37.

Example 278

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- methylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 2-methylpropanol instead of neopentyl alcohol (yield: 111 mg, 50%). Temp. 108-110 °C. <X>H NMR (300 MHz, DMSO-de) 50, 77 (d, J = 6.4 Hz, 6H), 1.52 (sept, J = 6.4 Hz, 1H), 3.28 (s , 3H), 4.17 (d, J = 6 Hz, 2H), 5.02 (q, J = 9 Hz, 2H), 7.88 (d, J = 9 Hz, 2H), 8.04 ( d, J = 9 Hz, 2H), 8.14 (s, 1H). MS (DCl-NH3) m/z 405 (M+H)<+>, 422 (M+NH4)4-. Anal. calcd for C17H19F3N2O4S: C, 50.49; H, 4.74; N, 6.93. Found: C, 50.69; H, 4.89; N, 6.75.

Example 279

2-( 2, 2, 2- Trifluoroethyl)- 4-( 1- methylcyclopropylmethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 1-methylcyclopropanemethanol instead of neopentyl alcohol (yield: 360 mg, 75.5%). Temp. 98-99 °C. <*>H NMR (300 MHz, CDCl 3 ) 80.35 (dt, J = 40 Hz, 5 Hz, 4H), 0.91 (s, 3H), 3.11 (s, 3H), 4.32 ( s, 2H), 4.82 (q, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.84 (s, IH), 8.06 ( d, J = 9 Hz, 2H). MS {DCI-NH3) m/z 417 (M+H)<+>, m/z 434 (M+NH4)<+.> Anal. calcd for C18H19F3N2O4S: C, 51.92; H, 4.60; N, 6.73. Found: C, 51.87; H, 4.72; N, 6, 69.

Example 280

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3, 3- dimethylbutoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 261 using 3,3-dimethyl-1-butanol instead of neopentyl alcohol (yield: 270 mg, 67.4%). Temp. 83-85 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 0.88 (s, 9H), 1.56 (t, J = 8 Hz, 2H), 4.60 (t, J = 8 Hz, 2H), 4, 83 (q, J = 8.5 Hz, 2H), 7.73 (d, J - 8.5 Hz, 2H), 7.81 (s, IH), 8.05 (d, J = 8.5 Hz, 2H). MS (DCI-NH 3 ) m/z 433 (M+H)<+>, m/z 450 (M+NH 4 )<+>. Anal. calcd for C19H23F3N2O4S: C, 52.77; H, 5.36; N, 6.48. Found: C, 52.95; H, 5.29; N, 6, 35.

Example 281

2-( 3, 4- Difluorophenyl)- 4-( 4- chlorophenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of 2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (187 mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg, 0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25 mL) heated under reflux at 50 °C for 3 h and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 2-benzyl-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 200 mg , 82%).

The above derivative was dissolved in toluene (25 mL) and treated with AlBr 3 (400 mg, 1.5 mmol) for 20 min at 80 °C. The mixture was cooled to room temperature and poured into ice-10% citric acid-ethyl acetate. The organic layer was separated, dried over MgSO 4 and concentrated in vacuo to provide the crude desbenzyl derivative. This compound was immediately dissolved in pyridine (50 mL) and treated with 3,4-difluorobromobenzene (0.17 mL, 1.5 mmol), Cu (20 mg) and K 2 CO 3 (100 mg, 1.5 mmol) under reflux for 16 hours. After the mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with water, 10% citric acid and brine. Purification by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) afforded the title compound (yield: 73 mg, 30%). Temp. 192-194 °C. <3->H NMR (300 MHz, DMS0-d6) 53.22 (s, 3H), 7.13 (rn, 2H), 7.35 (m, 2H), 7.50 (m, 1H), 7.60 (m, IH), 7.75 (m, IH), 7.87 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.41 ( pp, IH). MS (APCI+) m/z 488 (M+H) + and (APCI-) m/z 523 (M+Cl)-.

Example 282

2-(3,4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 281 using p-bromophenol instead of p-chlorophenol (yield: 54 mg, 20%). Temp. 196-199 °C. <i>H NMR (300 MHz, DMS0-d6) δ 3.25 (s, 3H), 7.09 (d, J = 9 Hz, 2H), 7.47 (d, J = 9 Hz, 2H) , 7.52 (m, IH), 7.62 (m, IH), 7.78 (rn, IH), 7.89 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.41 (s, 1H). MS (APCI+) m/z 533 (M+H)<+> and (APCI-) m/z 569 (M+Cl)-.

Example 283

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclopentylthio)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

To a solution of NaH (26 mg, 1.1 mmol) in acetonitrile (3.0 mL), under nitrogen, was added cyclopentyl mercaptan (120 µL, 1.1 mmol) dropwise with a syringe. The resulting solution was flushed with nitrogen for a period of 20 minutes; after which 2-(trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone, prepared in Example 193E, (200 mg, 0.52 mmol) was added in one portion. The solution was stirred for an additional 20 minutes, at which point all of the 4-bromopyridazinone was consumed. The solution was analyzed by TLC (1:1, ethyl acetate-Hex). Water (5 mL) was carefully added and the reaction mixture was partitioned between ethyl acetate (125 mL) and saturated brine (50 mL). The organic layer was washed with saturated brine (50 mL), dried over MgSC*4 and concentrated in vacuo. Silica gel chromatography (20% ethyl acetate-80% hexanes) gave a pale yellow solid (yield: 202 mg, 83.1%). Temp. 149-151 °C. <1>h NMR (300 MHz, CDCl 3 ) δ 1.40-1.34 (m, 2H) , 1.62-1.54 (m, 4H) , 1.93-1.88 (m, 2H) , 3.13 (s, 3H), 4.40-4.35 (m, IH), 4.85 (q, J = 8.2 Hz, 2H) , 7.58 (d, J - 8.5 Hz, 2H) , 7.66 (s,

1H), 8.06 (d, J = 8.4 Hz, 2H). MS (DCI-NH3) m/z 432 (M+H)<+>, (M+NH4)<+.> Anal. calcd for C18H19F3N2O3S2: C, 49.99; H, 4.43; N, 6.48. Found: C, 50.15; H, 4.39; N, 6.45.

Example 284

2-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using 1H-1,2,4-triazole-3-thiol instead of cyclopentyl mercaptan (yield: 164 mg, 93%). Temp. 197-200 °C. 1 H NMR (300 MHz, CDCl 3 ) 53.14

(s, 3H), 4.84 (q, J = 8.1 Hz, 2H), 7.41 (s, IH), 7.68 (d, J = 6.8 Hz, 2H), 7.83 (s, 1H), 8.00 (d, J = 7.1 Hz, 2H), 8.05 (s, 1H). MS (DCl-NH 3 ) m/z 431 (M+H)<+>, (M+NH 4 )<+>. Anal. calcd for C15H12F3N2O3S2: C, 41.76; H, 2.80; N, 16.23. Found: C, 41.68; H, 2.85; N, 15.99.

Example 285

2-(2,2,2-Trifluoroethyl)-4-phenylmethylthio-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using benzyl mercaptan instead of cyclopentyl mercaptan (yield: 141 mg, 76%). Temp. 108-111 °C. <!>h NMR (300 MHz, CDCl 3 ) 63.01 (s, 3H), 4.38 (s, 2H), 4.87 (q, J = Hz, 2H), 7.10-7.06 ( m, 2H), 7.22-7.20 (m, 5H), 7.59 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H). MS {DCI-NH3) m/z 454 (M+H)<+>, (M+NH4)<+.> Anal. calcd for C20H17F3N2O3S2, 0.75 EtOAc: C, 53.06; H, 4.45; N, 5.38. Found: C, 53.55; H, 4.16; N, 5.84.

Example 28 6

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluorophenylthio)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 283 using 4-fluorophenyl-methyl-mercaptan instead of cyclopentyl-mercaptan (yield: 184 mg, 73.5%). Temp. 182-185 °C. ^-H NMR (300 MHz,

CDCl3) 5 3.08 (s, 3H), 4.82 (q, J = 8.5 Hz, 2H), 6.87-6.81 (m, 2H), 7.19-7.11 (m , 2H), 7.48 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H). MS (DCI-NH3) m/z 458 (M+H)<+>, (M+NH4)<+.> Anal. calcd for C19H14F4N2O3S2: C, 49.78; H, 3.08; N, 6.11. Found: C, 49.89 ; H, 3.18; N, 5, 86

Example 287

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclohexylthio)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 283 using cyclohexyl mercaptan instead of cyclopentyl mercaptan (yield: 189 mg, 78%). Temp. 165-167 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 1.28-1.17 (m, 5H), 1.64-1.56 (m, 3H), 1.82-1.79 (m, 2H) , 3.13 (s, 3H), 4.08-4.05 (m, IH), 4.86 (q, J = 8.5 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H). MS (DCl-NH 3 ) m/z 446 (M+H)<+>, (M+NH 4 )<+>. Anal. calcd for C19H21F3N2O3S2: C, 51.11; H, 4.74; N, 6.27. Found: C, 51.39 ; H, 4.72; N, 5.91.

Example 288

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- chloro- 4- fluorophenylthio)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 283 using 3-chloro-4-fluorothiophenol instead of cyclopentyl mercaptan {yield: 190 mg, 65%). Temp. 142-145 °C. <!>h NMR {300 MHz, CDCl 3 ) 63.18 (s, 3H), 4.85 (q, J = 8.4 Hz, 2H), 6.96 (ov. t, J = 8.5 Hz , IH) , 7.14-7.10 {m, IH) , 7.18 (dd, J = 2.1, 6.5 Hz, IH,), 7.53 (d, J = 8.4 Hz , 2H), 7.77 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H). MS (Cl) m/z 493 (M+1)<+>, (M+NH4)<+.> Anal. calcd for CigHi3ClF4N2O3S2"0.25 C6H6-H2O: C, 47.36 ; H, 2.92; N, 5.41. Found: C, 4 7.88 ; H, 2.95; N, 5.24.

Example 289

2-(2,2,2-Trifluoroethyl)-4-(2,2,2-trifluoroethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using 2,2,2-trifluoroethyl mercaptan instead of cyclopentyl mercaptan (yield: 175 mg, 66%). Temp. 155-158 °C. ^-H NMR (300 MHz, CDCl 3 ) δ 3.14 (s, 3H) , 3.98 (q, J = 9.8 Hz, 2H) , 4.86 (q, J = 8.1 Hz, 2H ), 7.58 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H). MS (DCl-NH 3 ) m/z 446 (M+H)<+>, (M+NH 4 )<+. >Anal. calculated for C15H12F6N2O3S2: C, 40.36 ; H, 2.71; N, 6.28. Found: C, 40.50; H, 2.72; N, 6.01.

Example 290

2-(2,2,2-Trifluoroethyl)-4-(tert-butylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283, using tert-butyl mercaptan instead of cyclopentyl mercaptan (yield: 212 mg, 85%). Temp. 186-189 °C. <1>H NMR (300 MHz, CDCl 3 ) 51.25 (s, 9H), 3.13 (s, 3H), 4.87 (q, J = 8.1 Hz, 2H), 7.62 (d , J = 8.5 Hz, 2H), 7.67 (s, 1H), 8.05 (d, J = 8.1 Hz, 2H). MS (ESI) m/z 420 (M+H)<+>, (M+Na)<+.> Anal. calculated for C17H19F3N2O3S2: C, 48.56 ; H, 4.55; N, 6.66. Found: C, 50.15; H, 4.39; N, 6.45.

Example 291

2-(2,2,2-Trifluoroethyl)-4-(4-acetamidophenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using 4-acetamido-thiophenol instead of cyclopentyl mercaptan (yield: 100 mg, 37%). Temp. 191-193 °C. <1>H NMR (300 MHz, CDCl 3 ) 52.16 (s, 3H), 3.08 (s, 3H), 4.83 (q, J = 8.2 Hz, 2H), 7.00 (d , J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.58 (s, IH ), 7.78 (d, J = 8.1 Hz, 2H). MS (CI) m/z 497 (M+H)<+>, (M+NH 4 )<+>. Anal. calcd for C21Hi8F3N3O4S2'0.25H2O, 0.25 C6H6: C, 52.83; H, 4.06; N, 7.70. Found: C, 52.97; H, 3.85; N, 7.65.

Example 292

2-(2,2,2-Trifluoroethyl)-4-(2-propylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using isopropyl mercaptan instead of cyclopentyl mercaptan (yield: 180 mg, 81%). Temp. 165-167 °C. <3->H NMR (300 MHz, CDCl3) 51.17 (d, J = 6.8 Hz, 6H), 3.13 (s, 3H), 4.33 (p, J = 6.8 Hz, IH) , 4.86 (q, J = 8.5 Hz, 2H) , 6.59 (d, J = 8.5 Hz, 2H) , 7.68 (s, IH), 8.07 (d, J = 8.1 Hz, 2H). MS (DCl-NH 3 ) m/z 406 (M+H)<+>, (M+NH 4 )<+>. Anal. calculated for C16H17F3N2O3S2, 0.75H2O: C, 45.76 ; H, 4.4; N, 6.67. Found: C, 45.91; H, 3.98; N, 6.46.

Example 293

2-(2,2,2-Trifluoroethyl)-4-(2-methylpropyl-1-ylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 283 using 2-methyl-1-propyl mercaptan instead of cyclopentyl mercaptan (yield: 100 mg, 83%). Temp. 135-138 °C. <X>H NMR (300 MHz,

CDCI3) 5 0.87 (d, J= 6.4 Hz, 6H) , 1. 67-1.60 (m, 1H) , 3.00 (d, J = 6.7 Hz, 2H), 3, 14 (s, 3H), 4.84 (q, J = 8.5 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.67 (s, IH), 8, 08 (d, J 8.5 Hz, 2H). MS (DCI-NH3) m/z 420 (M+H)<+>, (M+NH4)<+.> Anal. calculated for C17H19F3N2O3S2: C, 48.56 ; H, 4.55; N, 6.66. Found: C, 47.86; H, 4.57; N, 6.51.

Example 294

2-( 2, 2, 2- Trifluoroethyl)- 4- amino- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, prepared according to Example 193E, (500 mg, 1.36 mmol) was dissolved in DMF (10 mL) and treated with NaN3 (100 mg, 1.5 mmol). After 2 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with water, 4 times, and dried over MgSO 4 . After filtering the desiccant and concentrating the filtrate in vacuo, the residue was purified by chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the azido intermediate, 2-(2,2,2-trifluoroethyl)-4-azido-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 481 mg, 95%).

The above 4-Azido compound (39 mg, 0.105 mmol) was dissolved in THF (3 mL) and MeOH (2 mL) and treated with an excess of NaBH 4 . After 15 minutes the reaction was quenched with saturated NH 4 Cl solution and the product was extracted into ethyl acetate. The organic layer was washed with water, 3 times, and dried over MgSO4. Filtration of the drying agent and evaporation of the solvent gave the title compound (yield: 26 mg, 71%). Temp. > 260 °C. 3-H NMR (300 MHz, DMSO-d6) 53.26 (s, 3H), 4.93 (q, J = 9 Hz, 2H), 6.71 (s, 2H), 7.72 (s, 1H), 7.76 (d, J = 8 Hz, 2H), 8.02 (d, J = 8 Hz, 2H). MS (ESI-) m/z 346 (M-H)-. Anal. calcd for C13H12F3N3O3S: C, 44.96; H, 3.48; N, 12.10. Found: C, 44.59; H, 3.52; N, 11.93.

Example 295

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methoxypropylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared according to the method in Example 193E and 3-methoxypropylamine (145 mg, 1.64 mmol) in pyridine (4 mL) were heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and mixed with silica gel (2 g), and the solvent was removed under reduced pressure. The adsorbed silica gel was placed over an Extract-Clean Cartridge<®> (Alltech, package: 10 g silica gel), and the cartridge was eluted with a stepwise hexanes/acetone gradient consisting of 60 mL each of the following mixtures: hexanes, 8:1 hexanes/ acetone, 4:1, 2:1 and 1:1. Fractions containing the desired product were pooled, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil silicene column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 ml/min over 50 minutes. Fractions containing product were pooled and concentrated under reduced pressure to provide the product as whitish crystals (yield: 215 mg, 95%). Temp. 110-113 °C. <X>H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 18.0 Hz, 2H), 7.55 (d, 2H, J = 18.0 Hz), 7.48 (s, IH), 6.57 (br t, IH, J = 9.0 Hz), 4.81 (q, J = 17.4 Hz, 2H), 3.33 (t, J = 12.0 Hz, 2H ), 3.28 (s, 3H), 3.12 (s, 3H), 2.76 (dt, J = 12.0, 12.0 Hz, 2H), 1.65 (tt, J = 12.0, 12.0, Hz, 2H). MS {DCI-NH3) m/z 420 (M+H)<+>, m/z 437 [M+NH4]<+.> Anal. calcd for C17H20F3N3O4S: C, 48.68; H, 4.81; N, 10.02. Found: C, 48.74; H, 4.69; N, 9.84.

Example 296

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclopentylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using cyclopentylamine instead of 3-methoxypropylamine to provide brown crystals (yield: 195 mg, 86%). Temp. 134-139 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 18.0 Hz, 2H), 7.56 (d, J = 18.0 Hz, 2H), 7.45 (s, IH), 6.12 (br d, J = 16.8 Hz, IH), 4.79 (q, J = 17.4 Hz, 2H), 3.33 (br m, IH), 3.12 ( s, 3H), 1.64-1.23 (br m, 8H). MS (DCI-NH3) m/z 416 (M+H}<+>, m/z 433 (M+NH4)<+>. Anal. calcd. for C18H20F3N3O3S: C, 52.04; H, 4.85; N, 10.11 Found: C, 52.40, H, 4.93, N, 10.03.

Example 297

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclobutylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using cyclobutylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 206 mg, 94%). Temp. 169-172 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 17.4 Hz, 2H), 7.54 (d, J = 17.4 Hz, 2H), 7.45 (s, IH), 6.28 (br d, J = 16.2 Hz, IH), 4.81 (q, J= 17.4 Hz, 2H), 3.42 (m, IH), 3.13 (s , 3H), 1.79 (m, 4H), 1.64 (m, 1H), 1.39 (m, 1H). MS (DCI-NH 3 ) m/z 402 (M+H)<+>, m/z 419 (M+NH 4 )<+>. Anal. calcd for C17H18F3N3O3S-0.25 CH3COCH3: C, 51.25; H, 4.72; N, 10.10; found: C, 51.38; H, 4.68; N, 10.25.

Example 298

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3, 4- dimethoxyphenethylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using 3,4-dimethoxyphenethylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 206 mg, 94%). Temp. 163-165 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 18.0 Hz, 2H), 7.52 (d, J = 18.0 Hz, 2H), 7.45 (s, 1H ), 6.75 (d, J = 16.2 Hz, IH), 6.50 (m, 2H), 6.16 (br d, J = 11.4 Hz, IH), 4.79 (q, J = 17.4 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.11 (s, 3H), 2.91 (dt, J = 12.6, 12 .6 Hz, 2H) , 2.60 (t, J = 13.8 Hz, 2H). MS (DCI-NH3) m/z 529 (M+NH4)<+.> Anal. calcd for C23H24F3N3O5S: C, 54.01; H, 4.73; N, 8.21. Found: C, 54.30; H, 4.69; N, 8.16.

Example 299

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclohexylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using cyclohexylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 103 mg, 42%). 3-H NMR (300 MHz, CDCl 3 ) δ 8.04 (d, J = 18.0 Hz, 2H), 7.58 (d, J = 18.0 Hz, 2H), 7.44 (s, 1H ), 6.06 (br d, J = 18.6 Hz, IH), 4.81 (q, J = 18.0 Hz, 2H), 3.11 (s, 3H), 2.70 (m, 1H), 1.66-1.48 (m, 4H), 1.42 (m, 1H), 1.07 (m, 3H), 0.76 (m, 2H). MS (DCI-NH 3 ) m/z 430 (M+H)<+>, m/z 447 (M+NH 4 )<+>. Anal. calcd for C19H22F3N3O3S: C, 53.14; H, 5.16; N, 9.78. Found: C, 52.86; H, 5.06; N, 9.52.

Example 300

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 2-( 1- piperidinyl) ethylamino]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using cyclopentylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 210 mg, 84%). <*>H NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 18.0 Hz, 2H), 7.56 (d, J = 18.0 Hz, 2H), 7.49 (s, IH), 6.91 (br, IH), 4.82 (q, J = 18.0 Hz, 2H), 3.13 (s, 3H), 2.64 (br, 2H), 2.32 ( br, 4H), 1.58 (br, 6H), 1.42 (br, 2H). MS (DCI-NH3) m/z 459 (M+H)<+.> Anal. calcd for C19H22F3N3O3S: C, 52.39; H, 5.50; N, 12,22. Found: C, 52.64; H, 5.59; N, 12.00.

Example 301

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- tetrahydrofurfurylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using tetrahydrofurfurylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 150 mg, 64%). Temp. 128-129 °C. <!>h NMR (300 MHz, CDCl 3 ) 58.03 (d, J = 18.0 Hz, 2H), 7.56 (d, J = 18.0 Hz, 2H), 7.47 (s, 1H ), 6.48 (br t, J = 9.0 Hz, IH), 4.81 (q, J = 18.0 Hz, 2H), 3.84 (rn, 2H), 3.72 (m, 1H), 3.12 (s, 3H), 2.83 (rn, 1H), 2.64 (rn, 1H), 1.84 (m, 3H), 1.34 (m, 1H). MS (DCI-NH 3 ) m/z 432 (M+H)<+>, m/z 449 (M+NH 4 )<+>. Anal. calcd for C18H20F3N3O3S: C, 50.11; H, 4.67; N, 9.74. Found: C, 50.25; H, 4.68; N, 9.68.

Example 302

2-( 2, 2, 2- Trifluoroethyl)- 4-( cyclopropylamino)- 5-[ 4-( methylsulfonyl) phenyl)- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using cyclopropylmethylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 130 mg, 59%). Temp. 145-146 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 8.01 (d, J = 18.0 Hz, 2H), 7.53 (d, J = 18.0 Hz, 2H), 7.48 (s, IH), 6.20 (br, IH), 4.82 (q, J = 18.0 Hz, 2H), 3.12 (s, 3H), 2.45 (br d, J = 13.2 Hz , 2H), 0.88 (m, 1H), 0.51 (m, 2H), 0.10 (m, 2H). MS (DCl-NH 3 ) m/z 402 (M+H)<+>, m/z 419 {M+NH 4 )<+>. Anal. calcd for C17H18F3N3O3S: C, 50.87; H, 4.52; N, 10.47. Found: C, 51.00; H, 4.52; N, 10.44.

Example 303

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 3- dihydro- 1H- inden- 1-ylamino)-5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using 1-indanylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 82 mg, 32%). Temp. 155-158 °C. <X>W NMR (300 MHz, CDCl 3 ) δ 8.04 (d, J = 18.0 Hz, 2H), 7.68 (d, J = 18.0 Hz, 2H), 7.49 (s, IH), 7.27-7.14 (m, 4H), 6.30 (brd, J= 18.0 Hz, IH), 4.81 (q, J = 18.0 Hz, 2H), 4, 57 (m, IH), 3.09 (s, 3H), 2.89 (m, IH), 2.60 (m, IH), 1.85 (m, IH), 1.68 (m, IH ). MS (ESI (-) m/z 462 (M-H)-. Anal. calcd. for C22H20F3N3O3S: C, 57.01; H, 4.35; N, 9.07. Found: C, 57.30; H, 4 .45; N, 8.86.

Example 304

2-( 2, 2, 2- Trifluoroethyl)- 4-( 1- piperidinyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using piperidine instead of 3-methoxypropylamine to provide an off-white solid (yield: 180 mg, 79%). Temp. 160-161 °C. <X>H NMR (300 MHz, CDCl 3 ) δ 8.04 (d, J = 18.0 Hz, 2H) , 7.58 (s, 1H) , 7.46 (d, J = 18.0 Hz, 2H), 4.80 (q, J = 18.0 Hz, 2H), 3.13 (s, 3H), 2.96 (m, 4H), 1.65-1.52 (m, 6H). MS (DCI-NH3) m/z 416 (M+H)<+.> Anal. calcd for C18H20F3N3°3s*H2O: C, 52.04; H, 4.85; N, 10,11. Found: C, 52.21; H, 5.02; N, 9.75.

Example 305

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- hydroxypropylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using 3-hydroxypropylamine instead of 3-methoxypropylamine to provide a white solid (yield: 109.6 mg, 50%). Temp. 152-154 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 8.02 (d, J = 18.0 Hz, 2H), 7.56 (d, J = 18.0 Hz, 2H), 7.48 (s, IH), 6.48 (br, IH), 4.79 (q, J = 17.4 Hz, 2H), 3.63 (t, J = 12.0 Hz, 2H), 3.12 (s, 3H), 2.81 (dt, J = 12.0, 12.0 Hz, 2H), 1.65 (tt, J = 12.0, 12.0 Hz, 2H). MS {DCI-NH3) m/z 406 (M+HJ<+>, m/z 423 (M+NH4)<+.> Anal. calculated for C16H18F3N3O4S: C, 47.41; H, 4.48; N , 10.37.Found: C, 47.53; H, 4.33; N, 10.27.

Example 306

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 3-( 1H- imidazol- 1- yl) propylamino]-5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using (3-aminopropyl)imidazole instead of 3-methoxypropylamine. The reaction mixture was concentrated to dryness and the residue was purified using RP-HPLC (Rainin Dynamax C-18 column, 60 Å pore size, 21.4 mm i.d.). The column was eluted with a linear gradient consisting of 20% acetonitrile (containing 0.1% TFA)/80% water (containing 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) at 15 mL/min over 70 minutes. The peak corresponding to the title product was collected and lyophilized to provide a beige hygroscopic foam (yield: 70.2 mg, 28%). <1>H NMR (300 MHz, DMSO) 88.95 (br s, 1H), 7.97 (d, J = 16.8 Hz, 2H), 7.66 (d, J = 16.2 Hz, 2H), 7.61 (s, IH), 7.58 (d, J = 15.0 Hz, 2H), 6.99 (br t, IH, J = 13.2 Hz), 4.97 (dt , J = 18.0, 18.0 Hz, 2H) , 3.97 (t, J = 13.2 Hz, 2H), 3.28 (s, 3H), 2.69 (m, 2H), 1.81 (tt, J = 13.2, 13.2 Hz, 2H). MS (DCl-NH 3 ) m/z 456 (M+H)<+>. Anal. calcd for C19H20F3N5O3S•1.4CF3COOH: C, 42.57; H, 3.51; N, 11.39. Found: C, 42.78; H, 3.58; N, 11.24.

Example 307

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2R- hydroxylpropylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using (R)-(-)-2-propanolamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 109.6 mg, 50%). M.p. = 140-142 °C. <1->H NMR (300 MHz, CDCl 3 ) 8 8.04 (d, J = 18.0 Hz, 2H) , 7.56 (d, J = 18.0 Hz, 2H), 7.49 (s , IH), 6.42 (br, IH), 4.79 (m, 2H), 3.80 (m, IH), 3.12 (s, 3H), 2.68 (m, 2H), 1 .02 (d, J = 12.0 Hz, 3H). MS (DCI-NH 3 ) m/z 406 (M+H)<+>, m/z 423 (M+NH 4 )<+>. Anal. calcd for C16H18F3N3O4S: C, 47.41; H, 4.48; N, 10.37. Found: C, 47.56; H, 4.41; N, 10.25.

Example 308

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- cyanoethylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 295 using 1-cyanoethylamine instead of 3-methoxypropylamine to provide an off-white solid (yield: 27 mg, 12%). Temp. 172-174 °C. <3->H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 18.0 Hz, 2H), 7.63 (d, J = 18.0 Hz, 2H), 7.51 (s , IH), 6.08 (br t, IH), 4.87 (q, J = 18.0 Hz, 2H), 3.17 (dt, J = 13.2, 13.2 Hz, 2H), 3.13 (s, 3H), 2.39 (t, J = 13.2 Hz, 2H). MS (DCl-NH 3 ) m/z 418 (M+NH 4 )<+. >Anal. calcd for C16H15F3N4O3S: C, 48.00; H, 3.78; N, 13.99. Found: C, 48.28; H, 3.77; N, 13.80.

Example 309

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- cyanoanilino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A suspension of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (300 mg, 0.820 mmol), prepared according to method of Example 193E, 4-aminobenzonitrile (290 mg, 2.46 mmol) and silver oxide (760 mg, 3.28 mmol) in pyridine (1.5 mL) were stirred at 80 °C for 24 h. The reaction was cooled to room temperature and adsorbed onto silica gel (2 g), and the solvent was removed under reduced pressure. The adsorbed silica gel was placed over an Extract-Clean Cartridge<®> (Alltech, package: 10 g silica gel), and the cartridge was eluted with a stepwise hexanes/acetone gradient consisting of 60 mL each of the following mixtures: hexanes, 8:1 hexanes /acetone, 4:1, 2:1 and 1:1. Fractions containing the desired product were pooled, concentrated and further purified using HPLC (Technikrom Kromasil 60-5sil column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 ml/min for 50 minutes. Fractions containing the product were pooled and concentrated under reduced pressure to provide the product as a beige solid (yield: 149.9 mg, 41%). M.p.>230 °C. <1->H NMR (300 MHz, DMSO) δ 9.49 (s, 1H), 8.00 (s, 1H), 7.69 (d, J = 17.4 Hz, 2H), 7.43 (d, J = 16.8 Hz, 2H), 7.32 (d, J = 18.0 Hz, 2H), 6.78 (d, J = 18.0 Hz, 2H), 5.06 (q , J = 18.0 Hz, 2H) , 3.13 (s, 3H) , 2.68 (m, 2H), 1.02 (d, J = 12.0 Hz, 3H). MS (DCl-NH 3 ) m/z 466 (M+NH 4 )<+>. Anal. calcd for C20H15F3N4O3S: C, 53.57; H, 3.37; N, 12.49. Found: C, 53.47; H, 3.49; N, 12.35.

Example 310

2-( 2, 2, 2- Trifluoroethyl)- 4-[ 3- methoxy- 5-( trifluoromethyl)-anilino]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in

Example 309 using 3-methoxy-5-(trifluoromethyl)-aniline instead of 4-aminobenzonitrile to provide a brown solid (yield: 226.5 mg, 80%). Temp. 206-208 °C. 1-H NMR (300 MHz, CDCl 3 ) δ 7.90 (s, 1H) , 7.77 (s, 1H) , 7.71

(d, J = 18.0 Hz, 2H), 7.28 (d, J = 17.4 Hz, 2H), 6.61 (br s, IH), 6.46 (br s, IH), 6 .31 (br s, 1H), 4.90 (q, J = 17.4 Hz, 2H), 3.72 (s, 3H), 2.94 (s, 3H). MS (DCl-NH 3 ) m/z 539 (M+NH 4 )<+>. Anal. calcd for C21H17F6N3O4S: C, 48.37; H, 3.29; N, 8.06. Found: C, 48.60; H, 3.33; N, 7.94.

Example 311

2-( 2, 2, 2- Trifluoroethyl)- 4- anilino- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using aniline in place of 4-aminobenzonitrile to provide a beige solid

(yield: 90 mg, 53%). Temp. 154-156 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 7.89 (br s, 1H) , 7.72 (s, 1H) , 7.62 (d, J=18.0 Hz, 2H), 7.19 (d, J = 18.0 Hz, 2H), 7.96-7.82 (m, 3H), 6.61 (d, J = 14.4 Hz, 2H), 4.90 (q, J = 18.0 Hz, 2H), 2.94 (s, 3H). MS {DCI-NH 3 ) m/z 424 (M+H)<+>, m/z 441 (M+NH 4 )<+>. Anal. calcd for C19H16F3N3O3S: C, 53.90; H, 3.81; N, 9.92. Found: C, 53.87; H, 3.73; N, 9.89.

Example 312

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 5- dimethoxyphenylamino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using 2,5-dimethoxyaniline instead of 4-aminobenzonitrile to provide a beige solid (yield: 140 mg, 53%). Temp. 95-96 °C. <!>h NMR (300 MHz, CDCl 3 ) δ 7.78 (br s, 1H) , 7.72 (s, 1H) , 7.63 (d, J = 18.0 Hz, 2H), 7.18 (d, J = 18.0 Hz, 2H), 6.54 (d, J = 18.0 Hz, IH), 6.38 (dd, J = 6.0, 18.0 Hz, IH), 4.89 (q, J = 18.0 Hz, 2H), 3.73 (s, 3H), 3.47 (s, 3H), 2.96 (s, 3H). MS (DCI-NH3) m/z 484 (M+H)<+>, m/z 501 (M+NH4)<+.> Anal. calcd for C21H20F3N3O5S: C, 52.17; H, 4.17; N, 8.69. Found: C, 52.47; H, 4.17; N, 8.43.

Example 313

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- fluoroanilino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using 3-fluoroaniline instead of 4-aminobenzonitrile to provide a beige solid (yield: 151.3 mg, 42%). Temp. 156-158 °C. <1>H NMR (300 MHz, DMSO) 89.18 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 17.4 Hz, 2H), 7.36 (d , J = 17.4 Hz, 2H), 6.88 (dd, J = 15.0, 15.0 Hz, IH), 6.56 (m, IH), 6.49 (m, 2H), 5.04 (q, J = 18.0 Hz, 2H), 3.08 (s, 3H). MS (DCI-NH3) m/z 442 (M+H)<+>, m/z 459

(M+NH4)<+>, m/z 476 (M+2NH4-H)<+.> Anal. calcd for C19H15F4N3O3S-0.5 CH3COCH3: C, 52.33; H, 3.85; N, 8.93. Found: C, 52.51; H, 3.58; N, 8.81.

Example 314

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 4- difluoroanilino)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using 2,4-difluoroaniline instead of 4-aminobenzonitrile to provide a beige solid (yield: 63.1 mg, 17%). Temp. 170-175 °C. 3-H NMR (300 MHz, DMSO) δ 9.00 (s, 1H), 7.80 (s, 1H), 7.57 (d, J = 17.4 Hz, 2H), 7.26 (d , J = 17.4 Hz, 2H), 7.05 (m, IH), 6.75 (m, 2H), 5.05 (q, J = 18.0 Hz, 2H), 3.09 (s , 3H). MS (DCI-NH3) m/z 460 (M+H)<+>, m/z 477 (M+NH4)<+.> Anal. calcd for C19H14F5N3O3S: C, 49.68; H, 3.07; N, 9.15; found: C, 50.00; H, 2.95; N, 9,10.

Example 315

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 3, 5- trifluoroanilino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using 2,3,5-trifluoroaniline instead of 4-aminobenzonitrile to provide a light purple solid (yield: 85.3 mg, 22%). Temp. 190-194 °C. <i>H NMR (300 MHz, DMSO) 89.27 (s, 1H), 7.90 (S, 1H), 7.70 (d, J = 17.4 Hz, 2H), 7.39 (d , J = 17.4 Hz, 2H), 7.03 (rn, IH), 6.76 (m, IH), 5.06 (q, J = 18.0 Hz, 2H), 3.14 (s , 3H). MS (DCl-NH 3 ) m/z 495 (M+NH 4 )<+>. Anal. calcd for C19H13F6N3O3S: C, 47.80; H, 2.74; N, 8.80. Found: C, 47.51; H, 2.55; N, 8.63.

Example 316

2-( 2, 2, 2- Trifluoroethyl)- 4-( 4- fluoroanilino)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The product was prepared according to the method described in Example 309 using 4-fluoroaniline instead of 4-aminobenzonitrile to provide a beige solid (yield: 15.8 mg, 4%). Temp. 158-160 °C. <3->H NMR (300 MHz, CDCl3) δ 7.80 (br s, 1H) , 7.69 (s, 1H) , 7.65 (d, J = 18.0 Hz, 2H) , 7, 18 (d, J = 18.0 Hz, 2H) , 6.63 (d, J = 3.6 Hz, 2H) , 6.61 (s, 2H), 4.89 (q, J = 17.4 Hz, 2H) , 2.96 (s, 3H) . MS (DCI-NH3) m/z 459 (M+NH4)<+.> Anal. calcd for C 19 Hi 5 F 4 N 3 O 3 S-1.25 H 2 O: C, 49.19; H, 3.80; N, 9.05. Found: C, 59.57; H, 3.53; N, 8.70.

Example 317

2- Benzyl- 4-( 3- thienyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

2- Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid (66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (13.9 mg, 0.012 mmol) in DME (25 mL) were stirred under reflux for 6 hours. TLC (1CH2Cl2:1 hexanes:1.5 ethyl acetate) indicated that all starting materials were consumed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (0.5:2.5:0.5 CH 2 Cl 2 /hexanes/ethyl acetate). A yellow powder was obtained (yield: 50 mg, 31%). <!>h NMR (300 MHz,

CDCI3) 6 3.09 (s, 3H) , 5.41 (s, 2H) , 6.72 (dd, J= 1.5 Hz, 9 Hz, IH), 7.13 (dd, J = 3 Hz , 3 Hz, IH), 7.3-7.45 (m, 5H), 7.5-7.6 (m, 3H), 7.78 (s, IH), 7.92 (d, 9 Hz , 2H). MS (DCI-NH3) m/z 423 (M+H)<+.> Anal. calculated for C22 H18N2O3S2. 0.5 H 2 O: C, 6.23; H, 4.43; N, 6.49. Found C, 61.29; H, 4.40; N, 6.16.

Example 318

2- Benzyl- 4-( 2- benzofuranyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 317 using 2-benzofuranboronic acid-3-thiophenboronic acid (yield: 46 mg, 25%). 1 H NMR (300 MHz, CDCl 3 ) 53.13 (s, 3H), 5.5 (s, 2 H, ) , 6.85-6.92 (rn, 1H), 7.15-7.25 ( m, 3H), 7.3-7.42 (m, 3H), 7.45-7.7 (m, 5H), 7.79 (s, IH) 8.0 (d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (DCI-NH3), m/z 457 (M+H)<+.> Anal. calcd for C26H20N2O4S•H2O: C, 65.80; H, 4.67; N, 5.90. Found C, 65.44; H, 4.42; N, 6, 14 .

Example 319

2- Benzyl- 4-( 1, 3- dihydro- l- oxo- 5- isobenzofuranyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 221 using 2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 78, instead of 2-(2 ,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (yield: 112 mg, 44%). Temp. > 250 °C. <3->H NMR (300 MHz, DMSO-d6) δ 3.20 (s, 3H), 5.34 (s, 2H), 5.36 (s, 2H), 7.30-7.44 ( m, 6H), 7.48 (d, J = 8 Hz, 2H), 7.57 (s, IH), 7.73 (d, J = 8 Hz, IH), 7.85 (d, J = 8 Hz, 2H), 8.17 (s, 1H). MS (DCl-NH 3 ) m/z 473 (M+H)<+>, 490 (M+NH 4 )<+>. Anal. calcd for C26H20N2O5S: C, 65.46; H, 4.33; N, 5.87. Found: C, 65.56; H, 4.48; N, 5.75.

Example 320

2- Benzyl- 4-( 5- chloro- 2- thienyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 317 using 4-chloro-2-thiophenboronic acid instead of 3-thiophenboronic acid (yield: 21 mg, 17%). <1>H NMR (300 MHz, CDCl 3 ) 53.15 (s, 3H), 5.45 (s, 2H), 6.51 (d, J = 4.5 Hz, 1H), 6.7 (d , J = 4.5 Hz, IH), 7.3-7.4 (m, 3H), 7.5 = 7.6 (m, 4H), 7.6 (s, IH), 8.05 ( d, J = 9 Hz, 2H). MS (DCl-NH 3 ), m/z 457 (M+H)<+>. Anal. calcd for C18H15CIN2O3S: C, 57.68; H, 4.03; N, 7.47. Found C, 57.61; H, 3.84; N, 7.14.

Example 321

2- Benzyl- 4-( 3- nitrophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H) - pyridazinone

The title compound was prepared according to the method described in Example 317 using 3-nitrobenzeneboronic acid instead of 3-thiopheneboronic acid (yield: 20 mg, 11%). <!>h NMR (300 MHz, CDCl 3 ) 53.0 (s, 3H) , 5.93 (s, 2H) , 7.6-7.8 (m, 9H), 7.8 (t, J = 4.5 Hz, 3H), 8.04 (s, IH), 8.15 (m, IH). MS (DCl-NH 3 ), m/z 462 (M+H)<+>. Anal. calculated for C24 H19N3O5S. 0.75 H 2 O: C, 60.68; H, 4.35; N, 8.84. Found C, 60.99; H, 3.97; N, 8.35.

Example 322

2- Benzyl- 4-( 4- vinylphenyl)- 5-( 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

The title compound was prepared according to the method described in Example 317 using 4-vinylbenzeneboronic acid instead of 3-thiopheneboronic acid (yield: 40 mg, 23%). <i>H NMR (300 MHz, CDCl 3 ) δ 3.05 (s, 3H), 5.28 (d, J = 12 Hz, 1H), 5.41 (s, 2H), 5.74 {d, J = 18 Hz, IH) 6.65 (dd , J = 12 Hz, 18 Hz, IH), 7.1-7.6 (m, 11H) 7.83 (d, J = 3 Hz, 2H), 7.85 (p, 1H). MS (DCl-NH3), m/z 443 (M+H)<+>. Anal. calcd for C26 H22N2O3S: C, 70.57; H, 5.01; N, 6.33. Found C, 70.34; H, 4.67; N, 5.97.

Example 323

2- Benzyl- 4-( 4- trifluoromethylphenyl)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 317 using 4-(trifluoromethyl)benzeneboronic acid instead of 3-thiopheneboronic acid (yield: 101 mg, 52%). 11 NMR (300 MHz, CDCl 3 ) δ 3.05 (s, 3H), 5.42 (s, 2H), 7.3-7.5 (m, 8H), 7.55-7.6 m, 3H ), 7.85 (s, 2H), 7.9 (s, 1H). MS (DCl-NH 3 ) m/z 485 (M+H)<+>. Anal. calcd for C25Hi9F3N2O3S-0.25H2O: C, 61.40; H, 4.01; N, 5.72. Found C, 61.26; H, 4.01; N, 5.35.

Example 324

2- Benzyl- 4-( 2- methoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 317 using 2-methoxybenzeneboronic acid instead of 3-thiopheneboronic acid (yield: 75 mg, 42%). 3-H NMR (300 MHz, CDCl 3 ) 53.01 (s, 3H), 3.5 (s, 3H), 5.40 (dd, J = 12 Hz, 18 Hz, 2H), 6.76 (d , J = 9 Hz, IH), 6.85-6.95 (m, IH), 7.09 (dd, J = 1.5 Hz, 9 Hz, IH), 7.26-7.41 (m , 6H), 7.55 (dd, J = 1.5 Hz, 9 Hz, 2H), 7.82 (d, J = 9 Hz, 3H). MS (DCI-NH3) m/z 447 (M+H)<+.> Anal. calcd for C 25 H 22 N 2 O 4 S- °r 5 H 2 O: C, 65.91; H, 5.08; N, 6.14. Found C, 65.86; H, 5.08; N, 5.58.

Example 325

2- Benzyl- 4-( 3, 4- dimethylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.4 mmol) prepared in Example 78 was dissolved in anhydrous DME (10 mL) and heated to refluxed with 3,4-dimethylbenzeneboronic acid in the presence of CsF (146 mg, 0.96 mmol) and tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) for 6 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, which gave the desired compound (yield: 100 mg, 56%). <1->H NMR (300 MHz, CDCl3) δ 2.15, 2.20 (2s, 3H) , 2.25, 2.30 (2s, 3H) , 3.05, 3.08 (2s, 3H ), 5, 35, 5, 40 (2s, 2H) , 6.60-7.1 (m, 3H) , 7.30-7.40 (m, 4H), 7.42-7.60 (m , 2H), 7.70-8.02 (m, 4H).

MS (DCI-NH3) m/z 445 (M+H)<+.> Anal. calcd for C 26 H 24 N 2 O 3 S-H 2 O: C, 67.51; H, 5.66; N, 6.05. Found: C, 67.45; H, 5.56; N, 5.85.

Example 326

2- Benzyl- 4-( 3- fluoro- 4- methoxyphenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 325 using 3-fluoro-4-methoxybenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%). J-H NMR (300 MHz, CDCl 3 ) δ 3.05 (s, 3H), 3.85 (s, 3H), 5.3, 5.4 (2s, 2H), 6.75-7.03 (m, 3H), 7.3-7.40 (m, 5H), 7.4-7.55 (dd, J = 1.5 Hz; 7.5 Hz, 2H), 7.8-7.95 (m , 3H). MS (DCl-NH 3 ) m/z 465 (M+H)<+>. Anal. calcd for C25H21N2O4S■°'25 H2O: C, 64.02; H, 4.62; N, 5.97. Found: C, 63.93; H, 4.54; N, 5.43

Example 327

2- Benzyl- 4-[ 3-( 2- methoxypyridyl)]- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 325 using 2-methoxy-3-pyridylboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%). <3->H NMR (300 MHz, CDCl3) 83.05 (s, 3H), 3.58 (s, 3H), 5.4 (dd, J = 15 Hz, 18 Hz; 2H), 6.88 (m, IH), 7.28-7.40 (m, 5H), 7.5-7.6 (dd, J = 1.5 Hz; 7.5 Hz, 3H), 7.82 (s, IH), 7.85 (d, J = 18 Hz, 2H), 8.15 (br s, IH). MS (DCl-NH 3 ) m/z 448 (M+H)<+>. Anal. calcd for C 24 H 21 N 3 O 4 S: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.17; H, 5.11; N, 9.04

Example 328

2- Benzyl- 4-( 3- ethoxyphenyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 325 using 3-ethoxybenzeneboronic acid instead of 3,4-dimethylbenzeneboronic acid (yield: 115 mg, 67%). <1>H NMR (300 MHz, CDCl 3 ) 81.31 (t, J = 7.5 Hz, 3H), 3.05 (s, 3H), 3.89 (q, J = 7.5 Hz, 2H ), 5.14 (s, 2H), 6.65 (d, J = 9 Hz, IH), 6.72 (t, J = 1.5 Hz, IH), 6.8 (dd, J = 1 .5 Hz, 9 Hz, IH), 7.15 (t, J = 9 Hz, IH), 7.3-7.4 (m, 5H), 7.5-7.6 (m, 2H), 7.85 (d, J = 9 Hz, 3H). MS (DCl-NH 3 ) m/z 461 (M+H)<+>. Anal. calcd for C26H24N2O4S-0.5H2O: C, 66.50; H, 5.36; N, 5.96. Found: C, 66.39; H, 5.02; N, 5.77

Example 329

2- Benzyl- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl) phenyl]-( 2H)-pyridazinone

329A. 2- Benzyl- 4, 5- dibromo- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 194A, using benzyl hydrazine hydrochloride instead of 4-fluorophenylhydrazine hydrochloride (yield: 7.86 g, 60%). <1>H NMR (300 MHz, DMSO d6 ) 5.27 (s, 2H), 7.26-7.41 (m, 5H), 8.19 (s, 1H). MS {DCI-NH 3 ) m/z 345 (M+H)<+>, 362 (M+H)<+>.

329B. 2- Benzyl- 5- bromo- 4- methoxy- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 194B, using 2-benzyl-4,5-dibromo-3(2H)-pyridazinone in 2-(4-fluorophenyl)-4,5-dibromo-3(2H) -pyridazinone (yield: 2.877 g; 85%). <3>-H NMR (300 MHz, DMSO-de) δ 4.14 (s, 3H), 5.23 (s, 2H), 7.26-7.38 (m, 5H), 8.11 ( pp, IH). MS (DCI-NH 3 ) m/z 295 (M+H)<+>, 312 (M+NH 4 )<+>.

329C. 2- Benzyl- 4- methoxy- 5-[ 4-( methylthio) phenyl]- 3( 2H)-pyridazinone

The title compound was prepared according to the method described in Example 6, using 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone in 2-benzyl-4-methoxy-5-bromo-3(2H) -pyridazinone (yield: 3.705 g). <!>h NMR (300 MHz, DMS0-d6) δ 2.52 (s, 3H), 3.99 (s, 3H), 5.28 (s, 2H), 7.26-7.41 (m , 7H), 7.55 (m, 2H), 8.02 (s, 1H). MS (DCI-NH3) m/z 339 (M+H)<+>, 356 (M+NH4)<+.>

329D. 2- Benzyl- 4-( 4- fluorobenzyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 233 using 4-fluorobenzylmagnesium chloride instead of cyclohexylmagnesium chloride and 2-benzyl-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was used instead of 2- (4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.

329E. 2- Benzyl- 4- methoxy- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)-pyridazinone

The sulfide compound (Example 329D) was oxidized to the methyl sulfonyl sulfide compound according to the method described in Example 10. M.p. 186-189 °C. <1>H NMR (300 MHz, DMSO

de) 5 3.27 (s, 3H), 3.83 (s, 2H) , 5.31 (s, 2H) , 6.94-7.05 (m, 4H), 7.27-7.40 (m, 5H), 7.67 (m, 2H), 7.94 (s, 1H), 8.03 (m, 2H). MS (DCl-NH 3 ) m/z 449 (M+H)<+>, 466 (M+NH 3 )<+>. Anal. calcd for C 25 H 21 FN 2 O 3 S: C, 66.95; H, 4.72; N, 6.25. Found: C, 66.68; H, 4.75; N, 6.14.

Example 330

2-( tert.-Butyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

330A. 2-( tert.-Butyl)- 4, 5- dichloro- 3( 2H)- pyridazinone

A solution of mucoclolic acid (33.8 g, 200 mmol) and tert-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) was stirred under reflux overnight. Methanol was removed in vacuo and the residue was partitioned between ether and water. The organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 100% hexanes). Product-containing fractions were pooled and the title compound was crystallized from ether/hexanes

(yield: 10.0 g, 22.6%). Temp. 63-64 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 1.65 (s, 9H), 7.73 (s, 1H). MS (DCI-NH 3 ) m/z 221 (M+H)<+>, 238 (M+NH 4 )<+>.

330B. 2-( tert.-Butyl)- 4-( 3- methylbutoxy)- 5- chloro- 3( 2H)-pyridazinone

A stirred room temperature solution of 3-methyl-l-butanol (0.5 mL, 4.52 mmol) in tetrahydrofuran (10 mL) was treated with a 60% oil suspension of sodium hydride (0.24 g, 5.88 mmol) . After 5 minutes hydrogen gas evolution had ceased, then the dichloro intermediate from Example 330A (1.0 g, 4.52 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, 100% hexanes). The title compound was obtained as a pale yellow oil (yield: 0.7 g, 56.7%). <X>H NMR (300 MHz, CDCl3) δ 0.95 (d, J = 6 Hz, 6H), 1.63 (s, 9H), 1.64 (q, J = 6 Hz, 2H), 1 .85 (nonet, J = 6 Hz, IH), 4.49 (t, J = 6 Hz, 2H), 7.64 (s, IH). MS (DCI-NH3) m/z 273 (M+H)<+>, 290 (M+NH4)<+.>

330C. 2-( tert.-Butyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylthio)-phenyl]- 3( 2H)- pyridazinone

A solution of the intermediate from Example 330B (700 mg, 2.57 mmol), 4-(methylthio)benzeneboronic acid (560 mg, 3.34 mmol), cesium carbonate (2.17 g, 6.67 mmol) and tetrakis(triphenylphosphine) palladium(0) (210 mg, 0.18 mmol) in dimethoxyethane (40 mL) was heated under reflux for 5 h. The heat source was then removed and the reaction mixture was stirred at room temperature for 64 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to provide a brown oil. This oil was purified by column chromatography twice (silica gel, 97:3 hexanes/ethyl acetate, then 96:4 hexanes/ethyl acetate) to provide a semi-solid product (yield: 270 mg, 29.2%). 1-H NMR (300 MHz, CDCl 3 ) δ 0.81 (d, J = 6 Hz, 6H), 1.49 (q, J = 6 Hz, 2H), 1.63 (nonet, J = 6 Hz, 1H), 1.69 (s, 9H), 2.52 (s, 3H), 7.32 (d, J = 9 Hz, 2H), 7.50 (d, J = 9 Hz, 2H), 7 .73 (p, IH). MS (DCI) m/z 361 (M+H) + .

330D. 2-( tert.-Butyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 10, using 2-(tert-butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone in 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 188 mg, 63.9%). Temp. 138-139°C. <1>H NMR (300 MHz, CDCl 3 ) δ 0.81 (d, J = 6 Hz, 2H), 1.48 (q, J = 6 Hz, 2H), 1.48-1.68 (m, IH), 1.69 (s, 9H), 3.10 (s, 3H), 4.38 (t, J = 6 Hz, 2H), 7.71 (s, IH), 7.74 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 393 (M+H)<+>. Anal. calcd for C20H28N2O4S: C, 61.20; H, 7.19; N, 7.14. Found: C, 61.13; H, 7.23; N, 6.89.

Example 331

2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method

described in Example 10, using 2-{3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (Example 207C) instead of 2-benzyl-4-{4 -fluorophenyl)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone (yield: 3.31 g, 96%). Temp. 112-114 °C. 1 H NMR (300 MHz, DMSO d6 ) δ 3.31 (m, 3H), 4.10 (m, 3H), 7.52-7.65 (m, 3H), 7.75 (rn, 1H ), 7.90 (rn, 2H), 8.07

(m, 2H), 8.21 (s, 1H). MS {DCI-NH 3 ) m/z 391 (M+H)<+>, 408 (M+NH 4 )<+>. Anal. calculated for: C18H15CIN2O4S■<0.>25 H2O: C, 54.68; H, 3.95; N, 7.08. Found: C, 54.59; H, 3.65; N, 6, 98.

Example 332

2-( 3- Chlorophenyl)- 4- hydroxy- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

A suspension of 2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (6.26 g, 16 mmol) in 5% NaOH (54 ml) dioxane (39.4 ml) was heated under reflux and stirred for 1.5 hours, as the reaction progresses, the solution turns orange and homogeneous. The mixture was cooled and poured into IN HCl, with constant stirring. The resulting white solid was filtered and rinsed with H2O and allowed to dry overnight. The almost dry product was taken up in CH 2 Cl 2 and azeotropically distilled with toluene to remove any residual H 2 O to afford the desired product as a white solid (yield: 6.79 g, >100%). <X>H NMR (300 MHz, DMSO de) 52.27 (s, 3H), 7.51-7.62 (m, 2H), 7.68 (rn, 1H), 7.79 (m, 1H ), 8.03 (m, 4H), 8.24 (s, 1H). MS (DCl-NH 3 ) m/z 377 (M+H)<+>, 396 (M+NH 4 )<+>.

Example 333

2-( 3- Chlorophenyl)- 4- tosyloxy- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

To a 0 °C solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 mmol ) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution was slowly warmed to room temperature with stirring under nitrogen. After 2.5 hours, the mixture was poured into H2O with constant stirring. The resulting whitish solid was filtered, rinsed with H 2 O and dried to provide the desired product (yield: 6.26 g, 79%). Temp. 198-200 °C. <i>H NMR (300 MHz, DMSO d6 ) δ 2.35 (s, 3H) , 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m, 3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI<+> 531 (M+H)<+>, 548 (M+H 2 O)<+>, APCI-493 (M+35)-. Anal. calcd for C 24 H 19 CIN 2 O 6 S 2 : c, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.

Example 334

2-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

A solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, in POCl3 was heated to reflux for 3 hours with stirring under nitrogen. The mixture was cooled to room temperature and poured into ice with constant swirling. The resulting white solid was extracted with ethyl acetate. The combined organic extracts were washed with H 2 O, dried over MgSO 4 and concentrated to a solid. The crude product was purified using flash chromatography (SiO 2 , eluting with 1:1 ethyl acetate/hexanes) to provide the desired product (yield: 0.151 g, 29%). Temp. 203-204 °C. <*>H NMR (300 MHz, DMSO

de) 83.29-3.36 (3H, obstructed by H2O), 7.60 (m, 3H), 7.76 (m, IH), 7.92 (rn, 2H), 8.14 (m, 2H), 8.25 (s, 1H). MS (DCl-NH 3 ) m/z 395 (M+H)<+>, 412 (M+NH 4 )<+>. Anal. calcd for C17H12CI2N2O3S: C, 51.66; H, 3.06; N, 7.09. Found: C, 51.67; H, 3.03; N, 6.93.

Example 335

2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in To THF (3.3 mL) was added isobutanol (0.03 mL, 0.33 mmol) and NaH (0.0132 g, 0.33 mmol). The resulting solution was stirred under nitrogen for 1 hour. The reaction mixture was poured into H2O and extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO 2 / 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.1088 g 76%). Temp. 166-169 °C. ^ NMR (300 MHz, DMSO d6) 50.78 (d, J = 6 Hz, 6H), 1.84 (ra, 1H), 3.29 (s, 3H), 4.20 (d, J = 6 Hz, 2H), 7.51-7.63 (m, 3H), 7.76 (m, IH), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s , IH). MS (DCI-NH3) m/z 433 (M+H)<+>, 450 (M+NH4)<+.> Anal. calcd for C 21 H 21 CIN 2 O 4 S: C, 57.07; H, 5.01; N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.

Example 336

2-( 3- Chlorophenyl)- 4-( t- butoxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using t-butanol instead of isobutanol (yield: 0.093 g, 66%). Temp. 232-235 °C. <X>H NMR (300 MHz, DMSO de) 51.18 (s, 9H), 3.30 (s, 3H), 7.52-7.64 (m, 3H), 7.74 (m, 1H ), 7.92 (m, 2H), 8.08 (m, 2H), 8.20 (s, 1H). MS (DCI-NH3) m/z 433 (M+H)<+>, 450 (M+NH4)<+.> Anal. calcd for C 21 H 21 CIN 2 O 4 S: C, 58.26; H, 4.89; N, 6.47. Found: C, 58.21; H, 4.88; N, 6.28.

Example 337

2-( 3- Chlorophenyl)- 4-( cyclohexyloxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using cyclohexanol instead of isobutanol (yield: 0.139 g, 92%). semi-solid; 1 H NMR (300MHz, CDCl 3 ) 61.09-1.50 (m, 6H), 1.57 (m, 2H), 1.88 (m, 2H), 3.13 (s, 3H), 5, 19 (m, IH), 7.38-7.48 (m, 2H), 7.59 (m, IH), 7.70 (m, IH), 7.83 (m, 2H), 7.92 (s, 1H) , 8.07 (m, 2H) . MS APCI<+> 459 (M+H)<+>, 476 (M+H 2 O)"1", APCI-458 (M)", 493 (M+35)". Anal. calcd for C 23 H 23 CIN 2 O 4 S•0.25 H 2 O: C, 59.60; H, 5.11; N, 6.04. Found: C, 59.48; H, 4.86; N, 5.88.

Example 338

2-( 3- Chlorophenyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using neopentyl alcohol instead of isobutanol (yield: 0.109 g, 74%). Temp. 151-153 °C. <1>H NMR (300 MHz, DMSO de) 50.78 (s, 9H), 3.29 (s, 3H), 4.10 (s, 2H), 7.52-7.64 (m, 3H ), 7.76 (m, 1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.20 (s, 1H). MS (DCI-NH3) m/z 447 (M+H)<+>, 4 64 (M+NH4)<+.> Anal. calcd for C 22 H 23 CIN 2 O 4 S: C, 59.12; H, 5.19; N, 6.27. Found C, 59.40; H, 5.31; N, 5, 99.

Example 339

2-( 3- Chlorophenyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-methyl-1-butanol instead of isobutanol (yield: 0.229 g, 80.5%). Temp. 134-135 °C. <1>H NMR (300 MHz, DMSO de) 50.79 (d, J = 6 Hz, 6H), 1.42-1.64 (m, 3H), 3.30 (s, 3H), 4, 43 (t, J = 6 Hz, 2H), 7.52-7.65 (m, 3H), 7.76 (m, IH), 7.90 (m, 2H), 8.07 (m, 2H ), 8.21 (p, 1H). MS (DCI-NH3) m/z 447 (M+H)<+>, 464 (M+NH4)<+.> Anal. calcd for C 22 H 23 CIN 2 O 4 S: c, 59.12; H, 5.19; N, 6.27. Found: C, 58.91; H, 5.12; N, 6, 01.

Example 340

2-( 3- Chlorophenyl)- 4-( 3- octyn- l-yloxy)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-octyn-1-ol instead of isobutanol (yield: 0.128 g, 77%). Oil. <1>h NMR (300 MHz, CDCl 3 ) δ 0.88 (m, 3H), 1.25-1.44 (m, 4H), 2.05 (m, 2H), 2.52 (rn, 2H ), 4.68 (t, J = 6 Hz, 2H), 7.43 (m, 2H),

7.59 (m, IH), 7.70 (m, IH), 7.86 (m, 2H), 7.92 (s, IH). MS (DCI-NH3) m/z 485 (M+H)<+.> Anal. calcd for C 25 H 25 CIN 2 O 4 S: C, 61.94; H, 5.20; N, 5.78. Found: C, 61.82; H, 4.99; N, 5, 57.

Example 341

2-( 3- Chlorophenyl)- 4-[ 2-( dimethylamino) ethoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using N,N-(dimethyl)-ethanolamine instead of isobutanol (yield: 0.111 g, 75%). Temp. 110-113 °C. <i>H NMR (300 MHz, DMSO de) 52.29 (bs, 6H), 2.68 (bs, 2H), 4.68 (t, J = 5 Hz, 2H), 7.38-7, 48 (m, 2H), 7.57 (m, 1H), 7.68 (m, 1H), 7.89 (m, 2H), 8.07 (m, 2H). MS (DCI-NH3} m/z 448 (M+H)<+>. Anal. calculated for C21H22CIN3O4S•0.50 H2O: C, 55.19; H, 5.07; N, 9.19. Found: C, 55.24, H, 4.97, N, 9.07.

Example 342

2-( 3- Chlorophenyl)- 4-[ 2- methyl- 1-( 1- methylethyl) propoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2,4-dimethyl-3-pentanol instead of isobutanol (yield: 0.075 g, 48%). Semi-solid; 3-H NMR (300 MHz, DMSO d6) 50.79 (m, 12H), 1.78-1.92 (m, J 6 Hz, 2H), 3.29 (s, 3H), 5.40 ( t, J = 6 Hz, IH), 7.57 (m, 3H), 7.72 (m, IH), 7.91 (m, 2H), 8.07 (m, 2H), 8.17 ( m, IH). MS (DCI-NH3) m/z 475 (M+H)<+>, 492 (M+NH4)<+.> Anal. calcd for C 24 H 27 CIN 2 O 4 S (0.75 H 2 O): C, 59.00; H, 5.88; N, 5.78. Found: C, 58.83; H, 5.74; N, 5.52.

Example 343

2-( 3- Chlorophenyl)- 4-( phenoxy)- 5-[ 4-( methylsulfonyl) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method

described in Example 335, using phenol instead of isobutanol (yield: 0.053 g, 35%). Temp. 205-207 °C. <3->H NMR (300 MHz, DMSO d6) δ 3.28 (s, 3H) , 7.08 (m, 3H) , 7.31 (m 2H), 7.50-7.64 (m, 3H), 7.73 (m, 1H), 7.90 (m, 2H), 8.05 (m, 2H), 8.40 (s, 1H). MS (DCI-NH3) m/z 453 (M+H)<+>, 470 (M+NH4)<+.> Anal. calcd for C 23 H 17 CIN 2 O 4 S: C, 60.99; H, 3.78; N, 6.19. Found: C, 60.79; H, 3.65; N, 5.87.

Example 34 4

2-( 3- Chlorophenyl)- 4-[ 3-( dimethylamino) phenyl]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-(dimethylamino)phenol instead of isobutanol (yield: 0.057 g, 60%). Temp. 191-193; <3->H NMR (300 MHz, DMSO de) δ 2.85 (s, 6H), 3.27 (s, 3H), 6.36 (m, 3H), 7.05 (m, 1H), 7.51-7.63 (m, 3H), 7.72 (m, 1H), 7.90 (m, 2H), 8.05 (m, 2H), 8.39 (s, 1H). MS APCI<+> 495 (M+H)<+>, APCI-, 495 (M)_, 590 (M+35)-. Anal. calcd for C 25 H 22 CIN 3 O 4 S: C, 60.54; H, 4.47; N, 8.47. Found: C, 60.04; H, 4.49; N, 8.26.

Example 345

2-( 3- Chlorophenyl)- 4-( 4- methoxyphenoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 4-methoxyphenol instead of isobutanol (yield: 0.080 g, 69%). Temp. 182-184 °C. <i>H NMR (300 MHz, DMSO d6) δ 3.27 (s, 3H) , 3.70 (s, 3H) , 6.84 (m, 2H), 7.00 (ra, 2H), 7 .56 (m, 3H), 7.72 (m, 1H), 7.90 (m, 2H), 8.04 (m, 2H), 8.38 (s, 1H). MS (DCI-NH 3 ) m/z 483 (M+H)<+>, 500 (M+NH 4 )<+>. Anal. calcd for C 24 H 19 CIN 2 O 5 S: C, 59.64; H, 3.97; N, 5.80. Found: C, 59.86; H, 3.94; N, 5, 62.

Example 34 6

2-( 3, 4- Difluorophenyl)- 4-( 2- arethylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-( 3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 150 mg, 61%). Temp. 116-117 DC. T-H NMR (300 MHz, DMSO-de) δ 0.78 (d, 6H), 1.84, (m, 1H), 3.3 (s, 3H), 4.2 (d, 2H), 7, 54 (m, IH), 7.6 (m, IH), 7.82 (m, IH), 7.91 (d, 2H), 8.07 (d, 2H), 8.21 (s, IH ). MS (DCI-NH3) m/z 435 (M+HJ<+>, 452 (M+NH4)<+>. Anal. calcd. for C21F2H20N2O4S: C, 58.06; H, 4.64; N, 6, 45.

Example 347

2-( 3, 4- Difluorophenyl)- 4-( 3- methyl- 1- butoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 346 using 3-methyl-1-butanol instead of isobutanol {yield: 63 mg, 23%). Temp. 121-123 °C. <!>h NMR (300 MHz, DMSO-d 6 ) 50.78 (d, 6H), 1.48, (m, 3H), 3.3 (s, 3H), 4.43 (t, 2H), 7.54 (m, IH), 7.6 {m, IH), 7.82 (m, IH), 7.91 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.2 (s, 1H). MS {DCI-NH3) m/z 449 (M+H)<+>, 466 (M+NH4)<+.> Anal. calcd for C 22 H 22 F 2 N 2 O 4 S: C, 58.92; H, 4.94; N, 6.25. Found, C, 59.22; H, 4.97; N, 6.07.

Example 348

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 346 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3 (2H)-pyridazinone instead of 2 -(3-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-fluorophenol instead of isobutanol M.p. 168-170 °C. <i>H NMR (300 MHz, DMSO-de) δ 3.39 (s, 3H) , 7.15 (d, 4H) , 7.51 (m, 1H), 7.6 (m, 1H) 7 .75 (m, 3H), 7.97 (t, 1H); 8.4 (p, 1H). MS (DCI-NH3) m/z 491 (M+H)<+>, 508 (M+NH4)<+.> Anal. calcd for C23H14F4N2O4S: C, 56.33; H, 2.88; N, 5.71. Found, C, 56.07; H, 2.94; N, 5.33.

Example 34 9

2-( 3, 4- Difluorophenyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 34 6 using neopentyl alcohol instead of isobutanol (yield: 1.18 g, 94%). Temp. 126-128 °C. 1 H NMR (300 MHz, DMSO-d6) 80.78 (s, 9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 1H), 7.6 ( m, IH), 7.82 (m, IH), 7.91 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.21 (s, IH) . MS (DCI-NH3) m/z 449 (M+H)<+>, 466 (M+NH4)<+.> Anal. calcd for C 22 H 22 F 2 N 2 O 4 S: C, 58.92; H, 4.94; N, 6.25. Found: C, 59.03; H, 5.03; N, 6.18.

Example 350

2-( 3, 4- Difluorophenyl)- 4-[ 2-( isopropoxy) ethoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 346 using 2-(isopropoxy)-ethanol instead of isobutanol (yield: 432 mg, 72%). Temp. 105-107 °C. <!>h NMR (300 MHz, DMSO-de) 80.95 (d, 6H), 3.3 (s, 3H), 3.43 (rn, 1H), 3.54 (m, 2H), 4 .63 (m, 2H), 7.54 (m, IH), 7.6 (m, IH), 7.8 (m, IH), 8.01 (m, 4H), 8.2 (s, IH). MS (DCl-NH 3 ) m/z 465 (M+H)<+>, 482 (M+NH 4 )<+>. Anal. calcd for C 22 H 22 F 2 N 2 O 5 S: C, 56.89; H, 4.77; N, 6.03. Found, C, 57.03; H, 4.65; N, 5.83.

Example 351

2-( 3, 4- Difluorophenyl)- 4-( 3- methylpentyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 346 using 3-methylpentyl-1-ol instead of isobutanol (yield: 400 mg, 80%). Temp. 100-102 °C. <i>H NMR (300 MHz, DMSO-d6) 8 0.75 (m, 6H) , 1.05 (m, 1H), 1.28 (m, 3H) 1.6 (m, 1H), 3 .3 (s, 3H), 4.45 (m, 2H), 7.5 (m, IH), 7.6 (m, IH), 7.8 (m, IH), 7.9 (d, J = 9 Hz, 2H) 8.05 (d, J = 9 Hz, 2H), 8.2 (s, 1H). MS (DCI-NH3) m/z 463 (M+H)<+>, 480 (M+NH4)<+.> Anal. calcd for C23H24F2N2O4S: C, 59.73; H, 5.23; N, 6.06. Found, C, 59.78; H, 5.31; N, 6, 00.

Example 352

2-( 3, 4- Difluorophenyl)- 4-( 4- methyl- 3- penten- l- yloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 5- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 34 6 using 4-methyl-3-penten-1-ol instead of isobutanol (yield: 405 mg, 67.8%). Temp. 88-90 °C. <3->H NMR (300 MHz, DMSO-d6) 51.5 (d, 6H), 2.27 (m, 2H) 3.3 (s, 3H), 4.43 (t, 2H), 4 .95 (m, IH), 7.5 (m, IH), 7.6 (m, IH), 7.8 (m, IH), 7.9 (d, 2H), 8.06 (d, 2H), 8.2 (s, 1H). MS (DCl-NH 3 ) m/z 461 (M+H)<+>, 478 (M+NH 4 )<+>. Anal. calcd for C23H22F2N2O4S: C, 59.99; H, 4.82; N, 6.08. Found, C, 59.88; H, 4.76; N, 5.84.

Example 353

2-( 3, 4- Difluorophenyl)- 4-[ 3-( methoxy) butoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 34 6, using 3-methoxybutyl-1-ol instead of isobutanol (yield: 350 mg, 68%). Temp. 99-101 °C. <!>h NMR (300 MHz, DMSO-d6) 8 0.97 (d, 3H) , 1.7 (m, 2H), 3.05 (s, 3H), 3.2 (m, 1H) 3 .3 (s, 3H), 4.45 (m, 2H), 7.54 (m, IH), 7.6 (m, IH), 7.8 (m, IH), 7.9 (d, J = 9 Hz, 2H) 8.01 (d, J = 9 Hz, 2H), 8.2 (s, 1H). MS (DCl-NH 3 ) m/z 465 (M+H)<+>, 482 (M+NH 4 )<+>. Anal. calcd for C 22 H 22 F 2 N 2 O 5 S: C, 56.89; H, 4.77; N, 6.03. Found, C, 56.60; H, 4.83; N, 5, 96.

Example 354

2- ( 3- Chlorophenyl) - 4- ( N- rrtethylbenzylamino) - 5- [ 4- ( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone: To a rapidly stirred 0°C mixture of N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7 mL) was

slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). The reaction mixture was stirred for 10 minutes at 0 °C and 1 hour at 23 °C. The solution was cooled to -78 °C, and a tetrahydrofuran solution (10-15 ml) of 2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (200 mg, 0.56 mmol) was slowly added along the inner wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23 °C as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated and the ethyl acetate layer was washed with additional water and brine and dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:9) to provide 2-(3-chlorophenyl)- A -(N-methyl benzylamino)-5-[4-(methylthio)phenyl]-3(2H) -pyridazinone (yield: 145 mg, 58%).

The title compound was prepared according to the method described in Example 10, using 2-(3-chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2 -benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 143 mg, 95%). Temp. 60-85 °C. <1>H NMR (300 MHz, CDCl 3 ) 6 2.46 (s, 3H), 3.09 (s, 3H), 4.63 (s, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.24-7.29 (m, 2H), 7.32-7.48 (m, 5H), 7.60 (ddd, J = 7.2, 1.8, 1.8 Hz, IH), 7.67 (s, IH), 7.70 (dd, J = 1.8, 1.8 Hz, IH), 7.91 (d, J = 8.7 Hz, 2H). MS (APCI+) m/z 480 (M+H)<+>.

Example 355

2-( 4- Fluorophenyl)- 4-( 1- piperidinyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

To a somewhat heterogeneous solution of piperidine {99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to -78 °C was slowly added dropwise a n-BuLi solution (0.235 mL, 0.59 mmol, 2, 5 M in hexanes). After stirring at -78 °C for 10 min, the cooling bath was removed and the mixture was stirred for an additional 1 h at 23 °C. 2-(4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3 x 6-7 ml aliquots) with a heat gun and cooled to 0 °C before transferring with a syringe to the lithium amide solution (cooled to -78 °C). The addition was carried out slowly along the inner wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23 °C as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated and the ethyl acetate layer was washed with additional water and brine and dried over MgSO 4 , filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3 (2H)-pyridazinone.

The title compound was prepared according to the method described in Example 10, using 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone instead of 2-benzyl-4 -(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 165 mg, 98%). Temp. 80-100 °C. 3-H NMR (300 MHz, CDCl 3 ) δ 1.59 (br s, 6H) , 2.59 (br s, 4H) , 3.14 (s, 3H), 7.17 (dd, J = 8, 7, 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.55-7.62 (m, 2H), 7.68 (s, IH), 8, 06 (d, J= 8.7 Hz, 2H). MS (APCI+) m/z 428 (M+H)<+>. Pulverized out in CH2CI2/C6H14. Anal. calcd for C22H22F<N>3O3S■0.25C6H14: C, 62.85; H, 5.72; N, 9.35. Found: C, 62.46; H, 5.77; N, 9, 13.

Example 356

2-( 4- Fluorophenyl)- 4-( 1- pyrrolidinyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 355 using pyrrolidine for piperidine (yield: 107 mg, 82%). Temp. 192-195 °C. <*>H NMR

(300 MHz, CDCl3) 81.71-1.80 (m, 4H), 3.13 (s, 3H), 3.40-3.49 (m, 4H), 7.16 (dd, J = 8 .7, 8.7 Hz, 2H), 7.47-7.60 (m, 5H), 7.99 (d, J - 8.7 Hz, 2H). MS (APCI+) m/z 414 (M+H)<+>. Anal. calcd for C21H20FN3O3S: C, 61.00; H, 4.87; N, 10,16. Found: C, 60.95; H, 4.94; N, 10.07.

Example 357

2-( 3- Chlorophenyl)- 4-( 4- methylphenylthio)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.0802 g, 0.15 mmol ) in EtOH (1.5 mL) was added thiocresol (0.019 g, 0.15 mmol) and K 2 CO 3 (0.0203 g, 0.15 mmol). The suspension was heated to 50°C with stirring for 2.5 hours. The mixture was poured into H2O with constant stirring. The resulting precipitate was filtered, rinsed with H 2 O and dried to provide the desired product (yield: 0.060 g, 83%). Temp. 178-178 °C. 1-H NMR (300 MHz, DMSO d6) 82.19 (s, 3H) , 3.23 (s, 3H) , 6.95 (m, 2H) , 7.08 (m, 2H), 7.52 -7.66 (m, 3H), 7.72 (m, 1H), 7.88 (m, 2H), 8.08 (s, 1H). MS (DCI-NH 3 ) m/z 483 (M+H)<+>, 500 (M+NH 4 )<+. >Anal. calculated for: C24H19CIN2O3S2■0.75 H2O: C, 58.05; H, 4.16; N, 5.64. Found: C, 57.99; H, 3.69; N, 5.76.

Example 358

2-( 3- Chlorophenyl)- 4-( 2- pyridylthio)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 357, using 2-mercapto-pyridine instead of thiocresol (yield: 0.061 g, 39%). Temp. 110-114 °C. <1->H NMR (300 MHz, DMSO dg) δ 3.28 (s, 3H), 7.16 (m, 1H), 7.37 (m, 1H), 7.51-7.71 (m , 5H), 7.81 (m, 2H), 8.03 (m, 2H), 8.27 (s, 1H), 8.34 (m, 1H). MS (DCl-NH 3 ) m/z 470 (M+H)<+>. Anal. calcd for C22HI6CIN3O3S2•0.50 H2O: C, 55.16; H, 3.57; N, 8.77. Found: C, 54.88; H, 3.19; N, 8.59.

Example 359

2-( 3- Chlorophenyl)- 4-( phenylmethylthio)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in To THF (3.3 mL) was added benzyl mercaptan (0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The mixture was poured into H 2 O and extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO 2 , 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.136 g 85%). Temp. 142-145 °C. 1 H NMR (300 MHz, DMSO de) 83.31 (s, 3H), 4.36 (s, 2H), 7.17 (m, 2H), 7.21-7.33 (rn, 3H) , 7.51 (m, 2H), 7.57-7.64 (m, 3H), 7.74 (m, 1H), 8.01 (m, 2H). MS (DCI-NH3) m/z 483 (M+H)<+>, 500 {M+NH4)<+.> Anal. calcd for C 24 H 19 CIN 2 O 3 S 2 : C, 59.68; H, 3.96; N, 5.80. Found: C, 59.40; H, 4.11; N, 5.71.

Example 360

2-( 3- Chlorophenyl)- 4-( 2- furylmethylthio)- 5-[ 4-( methylsulfonyl)-phenylj- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 359, using furfuryl mercaptan instead of benzyl mercaptan (yield: 0.162 g, 100%). Temp. 140-149 °C. <X>H NMR (300 MHz, DMSO d6) 53.31 (s, 3H), 4.46 (s, 2H), 6.20 (m, 1H), 6.37 (m, 1H), 7, 50-7.67 (m, 6H), 7.77 (m, 1H), 8.03 (m, 2H), 8.08 (s, 1H). MS (DCl-NH 3 ) m/z 473 (M+H)<+>, 490 (M+NH 4 )<+>. Anal. calcd for C 22 H 17 CIN 2 O 4 S 2 : C, 55.87; H, 3.62; N, 5.92. Found: C, 55.84; H, 3.61; N, 5.82.

Example 361

2-( 3- Chlorophenyl)- 4-] 2-( methylpropyl) thio]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 359, using 2-methyl-1-propanethiol instead of benzyl mercaptan (yield: 0.134 g, 91%). Oil. <!>h NMR (300 MHz, DMSO de) δ 0.61 (d, J = 6 Hz, 6H) , 1.54-1.69 (m, 1H) , 2.91 (d, J = 6 Hz , 2H) , 3.33 (s, 3H), 7.52-7.64 (m, 3H), 7.74 (rn, IH), 7.79 (m, 2H) , 8.04 (m, 3H). MS (DCI-NH3) m/z 449 (M+H)<+>, 466 (M+NH4)4". Anal. calcd. for C21H21CIN2O3S2 (0.50 H2O): C, 55.07; H, 4, 84; N, 6.11. Found: C, 54.70; H, 4.64; N, 5.85.

Example 362

2-( 3- Chlorophenyl)- 4-( cyclopentyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

To a -78 °C solution of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentylmagnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution was stirred under nitrogen less than 1 hour with warming to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO 2 , 2:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.1328 g, 94%). Temp. 155-157 °C. <i>H NMR (300 MHz, DMSO de) 51.50 (m, 2H) , 1.66 (rn, 2H) , 1.79 (m, 2H), 2.09 (m, 2H), 2, 90 (m, J = 8 Hz, IH), 3.26-3.37 (3H, obstructed by H2O), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7 .97 (s, 1H), 8.10 (m, 2H). MS (DCl-NH 3 ) m/z 429 (M+H)<+>, 44 6 {M+NH 4 )<+>. Anal. calcd for C 22 H 21 CIN 2 O 3 S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.

Example 363

2-( 3- Chlorophenyl)- 4-( 3- methylpropyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound, an oil, was prepared according to the method described in Example 362, using isobutyl magnesium chloride instead of cyclohexyl magnesium chloride, (yield: 0.132 g, 96%). <X>H NMR (300 MHz,

CDCl3) 5 0.77 (d, J = 6 Hz, 6H) , 2.08 (m, 1H) , 2.54 (d, J = 7 Hz, 2H), 7.36-7.46 (m, 2H), 7.56 (m, 2H), 7.62 (m, 1H), 7.73 (m, 2H), 8.11 (m, 2H). MS (DCl-NH 3 ) m/z 417 (M+H)<+> , 434 (M+NH 4 )<+>. Anal. calcd for C21H21CIN2O3S•0.50 H2O: C, 59.21; H, 5.20; N, 6.57. Found: C, 59.27; H, 5.40; N, 6, 12.

Example 364

2-( 3- Chlorophenyl)- 4-( cyclohexylmethyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound, an oil, was prepared according to the method described in Example 362, using cyclohexylmethylmagnesium bromide instead of cyclopentylmagnesium chloride (yield: 0.0579 g, 38%). <1>H NMR (300 MHz, DMSO d6) 6 0.66 (ra, 2H) , 1.03 (m, 3H) , 1.50 (m, 6H) , 1.61 (m, 1H), 2 .46 (m, IH), 3.27-3.42 (3H, obstructed by H2O), 7.50-7.66 (m, 3H), 7.75 (m, 3H), 7.99 (s , 1H), 8.10 (m, 2H). MS (DCl-NH 3 ) m/z 457 (M+H)<+>, 474 (M+NH 4 )<+>. Anal. calcd for C 24 H 25 CIN 2 O 3 S: C, 63.08; H, 5.51; N, 6.13. Found: C, 63.08; H, 5.47; N, 6.04.

Example 365

2-( 3- Chlorophenyl)- 4-( 2- cyclohexylethyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362, using cyclohexyl ethyl magnesium bromide instead of cyclopentyl magnesium chloride (yield: 0.165 g, 94%). <1>H NMR (300 MHz, DMSO d6) δ 0.76 (m, 3H), 0.99-1.21 (m, 5H), 1.31-1.62 (m, 8H), 2, 42-2.56 (IH, obstructed by DMSO), 3.25-3.34 (2H, obstructed by H2O), 7.48-7.65 (m, 3H), 7.48-7.65 (m , 3H), 7.76 (m, 3H), 8.01 (s, 1H), 8.10 (m, 2H). MS (DCI-NH3) m/z 471 (M+H)<+>, 488 (M+NH4)4". Anal. calcd. for C25H27CIN2O3S: C, 63.75; H, 5.78; N, 5, 95. Found: C, 63.48; H, 5.70; N, 5.67.

Example 366

2-( 3- Chlorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362, using 3-methylbutyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 0.0221 g, 16%). Temp. 60-65 °C. <!>h NMR (300 MHz, DMSO d6) 8 0.75 (d, J = 7 Hz, 6H), 1.32-1.52 (m, 3H), 3.31 (s, 3H), 7 .50-7.65 (rn, 3H), 7.77 (m, 3H), 8.03 (s, 1H), 8.11 (m, 2H). MS (DCl-NH 3 ) m/z 431 (M+H)<+>, 448 (M+NH 4 )<+. >Anal. calcd for C 22 H 23 CIN 2 O 3 S•0.25 H 2 O: C, 60.68; H, 5.43; H, 6.43. Found C, 60.29; H, 5.60; N, 6.17.

Example 367

2-(3-Chlorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 362, using benzyl magnesium chloride instead of cyclohexyl magnesium chloride. Temp. 174-177 °C (yield: 25.9 g, 57%). <*>H NMR (300 MHz, DMSO de) δ 3.30 (s, 3H), 3.91 (bs, 2H) , 7.02 (m, 2H) , 7.12-7.25 (m, 3H), 7.51-7.64 (m, 3H), 7.72 (m, 3H), 8.07 (m, 2H), 8.12 (s, 1H). MS (DCl-NH 3 ) m/z 451 (M+H)<+>, 468 (M+NH 4 )<+. >Anal. calcd for C 24 H 19 CIN 2 O 3 S: C, 63.92; H, 4.25; N, 6.21. Found: C, 63.69; H, 4.28; N, 6.02.

Example 368

2-( 3- Chlorophenyl)- 4- cyclohexyl- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362 using cyclohexyl magnesium chloride instead of cyclopentyl magnesium chloride (yield: 0.099 g, 68%). Temp. 85-90 °C. <!>h NMR (300 MHz, CDCl 3 ) 61.01-1.30 (m, 3H), 1.48-1.69 (m, 3H), 1.75 (rn, 2H), 2.28 ( m, 2H), 2.57 (m, 1H), 3.16 (s, 3H), 7, 35-7, 46 (m, 2H), 7.50-7.62 (m, 3H), 7 .68 (m, 2H), 8.11 (m, 2H). MS (DCl-NH 3 ) m/z 443 (M+H)<+>, 460 (M+NH 4 )<+>. Anal. calcd for C 23 H 23 CIN 2 O 3 S (1.25 H 2 O): C, 59.34; H, 5.52; N, 6.01. Found: C, 59.02; H, 5.24; N, 5.65.

Example 369

2-( 3- Chlorophenyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 using 4-fluorobenzyl magnesium chloride instead of cyclopentyl magnesium chloride (yield: 0.1895 g, 41%). Temp. 183-185 °C. <l>H NMR (300 MHz, DMSO de) 6 3.25-3.36 (3H, obstructed by H2O) , 3.89 (bs, 2H) , 6.97-7.09 (m, 4H), 7.50-7.64 (m, 3H), 7.71 (ra, 3H), 8.06 (ra, 2H), 8.11 (s, 1H). MS (DCI-NH3) m/z 469 (M+H)<+>, 486 (M+NH4)<+.> Anal. calcd for C 24 H 18 CIFN 2 O 3 S: C, 61.47; H, 3.87; N, 5.97. Found: C, 61.23; H, 3.84; N, 5.77.

Example 370

2-( 3- Chlorophenyl)- 4-( 4- methylphenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362 using p-tolyl magnesium bromide instead of cyclopentyl magnesium chloride (yield: 65 mg, 40.9%). Temp. 222-224 °C. <1->H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H) , 3.25 (s, 3H) , 7.12 (t, 4H) , 7.6 (rn, 5H) , 7.79 (t, 1H) 7.9 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (DCI-NH 3 ) m/z 451 (M+H)<+>, 468 (M+NH 4 )<+>. Anal. calcd for C 24 HigClN 2 O 3 S-0.25 H 2 O: C, 63.92; H, 4.25; N, 6.21. Found: C, 62.99; H, 4.28; N, 5.85.

Example 371

2-( 3, 4- Difluorophenyl)- 4-( 3- fluoro- 4- methylphenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 362, starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 3-fluoro-4-methylphenylmagnesium bromide instead of cyclohexylmagnesium chloride to provide the methyl sulfide compound.

The methyl sulfide was oxidized according to the method described in Example 10 to provide the title compound (yield: 265 mg, 85.4%). Temp. 204-206 °C. <1>H NMR (300 MHz, CDCl3) δ 2.25 (br s, 3H) , 3.08 (s, 3H) , 6.83 (dd, J = 9 Hz, 1.5 Hz, 1H) , 6.96 (dd, J = 9 Hz, 1.5 Hz, IH), 7.08 (t, J = 9 Hz, IH), 7.23-7.33 (m, IH), 7.41 ( d, J = 9 Hz, 2H), 7.49-7.56 (m, IH), 7.61-7.69 (m, IH) , 7.93 (d, J = 9 Hz, 2H) , 7.99 (pp, IH). MS (DCl-NH 3 ) m/z 471 (M+H)<+>, 488 (M+NH 4 )<+>. Anal. calcd for C24H17F3N2O3S: C, 61.28; H, 3.62; N, 5.96. Found: C, 61.07; H, 3.95; N, 5.56.

Example 372

2-( 3- Chlorophenyl)- 4-( phenethyl)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 starting from 2-(3-chlorophenyl}-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl) -4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and using phenethylmagnesium chloride instead of cyclohexylmagnesium chloride and then oxidized according to the method of Example 10 (yield: 0.100 g, 39%). M.p. 142 -145° C. <3->H NMR (300 MHz, DMSO d6) δ 2.80 (rn, 4H) , 3.30

(s, 3H), 7.01 (m, 2H), 7.21 (m, 3H), 7.51-7.60 (m, 4H),

7.63 (m, 1H), 7.78 (m, 1H), 8.03 (m, 3H). MS (DCI-NH3) m/z 465 (M+H)<+>, 482 (M+NH4)<+.> Anal. calcd for C 25 H 21 CIN 2 O 3 S: C, 64.58; H, 4.55; N, 6.02. Found: C, 64.24; H, 4.50; N, 5, 90.

Example 373

2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

373A. 2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone.

The title compound is prepared according to the method in Example 194B, starting from 2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone (Example 207A) instead of 2-(4-fluorophenyl)-4,5-dibromo-3 (2H)-pyridazinone and using 2-methyl-1-propanol instead of methanol.

373B. 2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( methylthio) phenyl]- 3( 2H)- pyridazinone

The title compound is prepared according to the method in Example 6, starting from 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone instead of 2-benzyl-4-bromo-5-methoxy-3 (2H)-pyridazinone and using 3-fluoro-4-(methylthio)benzeneboronic acid (Example 72C) instead of 4-fluorobenzeneboronic acid.

373C. 2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The methyl sulfide compound was oxidized according to the method described in Example 10 to provide the title compound (yield: 0.73 g, 100%). Temp. 180-183 °C. <1>h NMR (300 MHz, DMSO d6) δ 0.82 (d, J = 6 Hz, 2H) , 3.30-3.39 (3H, obstructed by H2O) 4.25 (d, J = 6 Hz, 2H), 7.57 (m, 3H), 7.75 (m, IH), 7.85 (m, IH), 8.00 (rn, IH), 8.23 (s, IH). MS (DCI-NH 3 ) m/z 451 (M+H)<+>, 468 (M+NH 4 )<+>. Anal. calcd for C21H20CIFN2O4S: C, 55.94; H, 4.47; N, 6.21. Found: C, 55.73; H, 4.58; N, 6.01.

Example 37 4

2-( 3- Chlorophenyl)- 4-( benzyloxy)- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

To a stirred solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 332)

(0.100 g, 0.28 mmol) in DMF (2.8 mL) was added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution was stirred with heating to 60 °C overnight. The solvent was removed in vacuo, and the resulting residue was partitioned between ethyl acetate and 10% citric acid. After extraction with ethyl acetate, the combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The crude product was purified using flash chromatography (SiO 2 , 1:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.096 g, 76%). Temp. 110-113 °C. <1>H NMR (300 MHz, DMSO d6) δ 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59-7.71 (m, 3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS {DCI-NH3) m/z 467 (M+H)<+>,

484 (M+NH4)<+>. Anal. calcd for C 24 H 19 CIN 2 O 4 S: C, 61.73; H, 4.10; N, 6.00. Found: C, 62.00; H, 4.18; N, 5.93.

Example 375

2-( 4- Fluorophenyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone (Example 194B) is converted to 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl] -3(2H)-pyridazinone according to the method described in Example 194C followed by the oxidation method in Example 10. The methoxy compound is converted to 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone, by treatment with NaOH according to the procedure of Example 332. The hydroxy compound is treated with p-toluenesulfonyl chloride according to the procedure of Example 333, to provide 2-(4-fluorophenyl)-5-[4-( methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone.

The title compound was prepared according to the method described in Example 335, starting from 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone instead of 2-(3-chlorophenyl) )-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone using 3-methyl-1-butanol instead of isobutanol (yield: 0.3932 g, 94%). Temp. 117-120 °C. <!>h NMR (300 MHz, DMSO d6) δ 0.79 (d, J = 6 Hz, 6H), 1.41-1.59 (m, 3H), 3.30 (s, 3H), 4 .42 (d, J = 5 Hz, 2H), 7.36 (m, 2H), 7.65 (m, 2H), 7.90 (rn, 2H), 8.06 (m, 2H), 8 ,18 (p, IH). MS (DCl-NH 3 ) m/z 431 (M+H)<+>, 448 (M+NH 4 )<+>. Anal. calcd for C 22 H 23 FN 2 O 4 S: C, 61.38; H, 5.39; N, 6.51. Found: C, 61.42; H, 5.30; N, 6.40.

Example 376

2-( 4- Fluorophenyl)- 4-( 2- methylpropoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) instead of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). Temp. 121-128 °C. <1>H NMR (300 MHz, DMSO d6) δ 0.78 (d, J ~ 7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d , J = 6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s , IH). MS (DCl-NH 3 ) m/z 417 (M+H)<+>, 434 (M+NH 4 )<+. >Anal. calcd for C21H21FN2O4S•0.50 H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34.

Example 377

2-( 4-Fluorophenyl)- 4-( 4- fluorobenzyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 62, starting from 4-(4-fluorophenyl-methyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and reaction with 1-iodo-4- fluorobenzene (yield: 0.0881 g, 78%). Temp. 175-177 °C. <l>H NMR (300 MHz, DMSO d6) 53.27-3.36 (3H, obstructed by H2O), 3.88 (bs, 2H), 6.98-7.09 (m, 4H), 7 .34 (m, 2H), 7.65 (m, 2H), 7.71 (m, 2H), 8.06 (m, 3H). MS (DCI-NH3) m/z 453 (M+H)<+>, 470 (M+NH4)<+.> Anal. calcd for C 24 H 18 F 2 N 2 O 3 S: C, 63.71; H, 4.01; N, 6.19. Found: C, 63.61; H, 4.26; N, 6.03.

Example 378

2-( 4- Fluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 228 using 3-methylbutyl magnesium bromide instead of cyclohexyl magnesium chloride (yield: 0.325 g, 69%). Temp. 151-154 °C. <1>H NMR (300 MHz, DMSO dg) δ 0.75 (d, J = 7 Hz, 6H) , 1.32-1.51 (m, 3H) , 3.31 (s, 3H), 7 .37 (rn, 2H), 7.66 (m, 2H), 7.77 (m, 2H), 8.00 (s, 1H), 8.10 (m, 2H). MS (DCl-NH 3 ) m/z 415 (M+H)<+>, 432 (M+NH 4 )<+>. Anal. calcd for C 22 H 23 FN 2 O 3 S•0.50 H 2 O: C, 62.39; H, 5.71; N, 6.61. Found: C, 62.04; H, 5.78; N, 6, 46.

Example 379

2-( Tetrahydro- 2H- pyrano- 2-yl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

To the solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone prepared according to Example 11 (172 mg, 0.5 mmol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in dioxane (10 mL) was added 2,3-dihydropyran (2 mL). The mixture was stirred at room temperature for 6 hours. The mixture was then poured into a solution of saturated NaHCO 3 and extracted with ethyl acetate. The ethyl acetate was concentrated in vacuo and the residue chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 25 mg, 11%). 3 H NMR (DMSO-dg, 300 MHz) δ 1.54 (m, 2H), 1.74 (m, 2H), 2.00 (m, 1H), 2.17 (m, 1H), 3 .23 (s, 3H), 3.62 (m, IH), 4.00 (m, IH), 5.98 (m, IH), 7.13 (7, J= 9 Hz, 2H), 7 .23 (m, 2H), 7.47 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 8.12 (s, IH). MS {DCI-NH 3 ) m/z 429 (M+H)<+.>

Example 380

2-( 3-( 4- Fluorophenyl) phenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 4, starting from 2-(3-bromophenyl)-4-{4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

(Example 166) instead of 2-benzyl-4-bromo-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone and using cesium fluoride instead of sodium carbonate (yield: 0.62g, 62%). Temp. 222-225 °C. <1>H NMR (300 MHz, DMSO d6) δ 3.24 (s, 3H), 7.16 (rn, 2H), 7.36 (rn, 3H), 7.53 (m, 2H), 7 .64 (m, 2H), 7.73-7.81 (rn, 3H), 7.93 (m, 3H), 8.27 (s, 1H). MS (DCl-NH 3 ) m/z 515 (M+H)<+>, 532 (M+NH 4 )<+>. Anal. calcd for C29H20F2N2O3S■0.25 H2O: C, 67.10; H, 3.98; N, 5.35. Found: C, 66.93; H, 3.99; N, 5.17.

Example 381

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 3- fluoro-4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method described in Example 261 using 2-(2,2,2-trifluoroethyl)-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone instead of 2-(2, 2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.

The methyl sulphide was oxidized with one equivalent of meta-chloroperoxybenzoic acid to give the methyl sulphoxide. The sulfoxide was converted to the title compound according to the method described in Example 68 (yield: 196 mg, 28%). Temp. 144-145 °C. <X>H NMR (300 MHz, CDCl 3 ) δ 0.86 (s, 9H), 4.23 (s, 2H), 4.82 (q, J = 8 Hz, 2H), 5.10 (s, 2H), 7.46 (s, IH), 7.48 (br s, IH), 7.79 (s, IH), 8.03 (t, J = 8 Hz, IH). MS (DCI-NH3) m/z 438 (M+H)<+.> Anal. calcd for C17H19F3N3O4S: C, 46, 68; H, 4.38; N, 9.61. Found: C, 46.76; H, 4.30; N, 9.52.

Example 382

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 68 using 2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H)- pyridazinone instead of 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (yield: 260 mg, 26%). Temp. 163-164 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 0.86 (d, J = 6.6 Hz, 6H), 1.91 (sept, J = 6.6 Hz, 1H), 4.34 (d, J = 6.6 Hz, 2H), 5.11 (br s, 2H), 7.43-7.52 (m, 2H), 7.80 (s, IH), 8.02 (t, J = 8 Hz, IH). MS (DCI-NH 3 ) m/z 424 (M+H)<+>, m/z 441 (M+NH 4 )<+>. Anal. calcd for C16H17F4N3O4S: C, 45.39; H, 4.05; N, 9.92. Found: C, 59, 89; H, 3.83; N, 8.61.

Example 383

2- Benzyl- 4-( 4- fluorobenzyl)- 5-[ 4-( aminosulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3, 4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.5723 g 34%). Temp. 120-123 °C. <X>H NMR (300 MHz, DMSO dg) 53.83 (bs, 2H), 5.30 (bs, 2H), 6.95-7.06 (m, 4H), 7.28-7.40 (m, 5H), 7.48 (m, 2H), 7.60 (m, 2H), 7.91 (m, 2H), 7.95 (s, 1H). MS (DCl-NH 3 ) m/z 450 (M+H)<+>, 467 (M+NH 4 )<+>. Anal. calcd for C 24 H 20 FN 3 O 3 S: C, 64.13; H, 4.48; N, 9.35. Found: C, 63.76; H, 4.71; N, 9.02.

Example 384

2- Benzyl- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)-pyridazinone

To a solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (130 mg, 0.3 mmol) and di-t-butyl azodicarboxylate (DBAD ) (69 mg, 0.3 mmol) in THF (30 mL) at -78 °C was added dropwise a 1 N solution of lithium 1,1,1,3,3,3-hexamethyldisilazide (0.9 mL, 0.9 mmol) in THF. After the addition, the reaction was stirred for an additional 45 minutes at -78°C (or until TLC indicated that the starting material had disappeared). The reaction was quenched with a saturated solution of NH 4 Cl and extracted with ethyl acetate. The acetate extract was dried over MgSO 4 and concentrated in vacuo to give 220 mg of crude adduct.

The above adduct was dissolved in THF (30 mL) and treated at room temperature with 1 N NaOH (3 mL) for 5 h. Sodium acetate (NaOAc 3 H 2 O, 1.38 g, 10 mmol) was added followed by the addition of hydroxylamine-O-sulfonic acid (1.13 g, 10 mmol) and H 2 O (30 mL). The resulting mixture was stirred at room temperature for 18 hours and then extracted with ethyl acetate. The extract was washed with water, brine, dried over MgSO 4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 70 mg, 54%). Temp. 185-189 °C. <!>h NMR (DMSO-d6, 300 MHz) 85.33 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.40 (m, 7H), 7 .83 (d, J = 9 Hz, 2H), 8.10 (s, IH). MS (DCl-NH 3 ) m/z 436 (M+H)<+>. Anal. calculated for C 23 H 18 FN 3 O 3 S • 0.75 H 2 O: C, 61.65; H, 4.26; N, 9.04. Found: C, 61.67; H, 4.61; N, 8.66.

Example 385

2-( 4- Fluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The product from Example 108 was converted to the title sulfonamide according to the method described in Example 384 (yield: 65 mg, 28.8%). Temp. 227-229 °C. <*>H NMR (300 MHz, DMSO-dfc) 87.08-7.17 (m, 4H), 7.36 (t, J = 3 Hz, 2H),

7.47 (br s, 2H), 7.61-7.69 (m, 2H), 7.83 (d, J = 9 Hz, 2H), 7.93 (d, J = 9 Hz, 2H) , 8.40 (p, IH). MS (DCI-NH3) m/z 469 (M+H)<+>, 486 (M+NH4)<+.> Anal. calcd for C 24 H 15 F 2 N 3 O 4 S: C, 58.02; H, 3.30; N, 9.24. Found: C, 57.84; H, 3.34; N, 9.01.

Example 386

2-( 3, 4- Difluorophenyl)- 4-( 3- fluoro- 4- methylphenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The product from Example 371 was converted to the title sulfonamide according to the method described in Example 384 (yield: 45 mg, 28%). Temp. 198-200 °C. <3->H NMR (300 MHz, DMSO-d6) 6 6.87 (dd, J = 9 Hz, 3 Hz, 1H), 7.13 (dt, J = 9 Hz, 3 Hz, 1H), 7 .19 (t, J = 7 Hz, IH), 7.46 (d, J = 9 Hz, 2H), 7.47 (br s, 2H), 7.52-7.69 (m, 2H), 7.79 (d, J = 9 Hz, 2H), 7.82-7.89 (m, IH), 8.25 (s, IH). MS (DCI-NH3) m/z 472 (M+H)<+>, 489 (M+NH4)<+->

Example 387

2-( 4- Fluorophenyl)- 4-( 3- fluoro- 4- methylphenyl)- 5-[ 4-( amino-sulfonyl ) phenyl]- 3( 2H)- pyridazinone

The product from Example 250 was converted to the title sulfonamide according to the method described in Example 384 (yield: 185 mg, 46%). Temp. 187-188 "C. ^ NMR (300 MHz, DMSO-d6) δ 2.22 (br s, 3H) , 6.87 (dd, J = 9 Hz, 3 Hz, 1H) , 7.16 (q, J = 9 Hz, 2H), 7.38 (t, J = 9 Hz, 2H) , 7.46 (br s, 2H), 7.47 {d, J = 9 Hz, 2H), 7.67- 7.73 (rn, 2H), 7.77 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (DCI-NH3) m/z 454 (M+H)<+> , 471 (M+NH4)4-. Anal calcd for C23H17F2N3O3S•0.25 H2O: C, 60.36; H, 3.87; N, 9.19. Found: C, 60.30; H, 4 .26; N, 8.83.

Example 388

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 4-( amino-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The product from Example 109 was converted to the title sulfonamide according to the method described in Example 384 (yield: 110 mg, 45.7%). Temp. 224-226 °C. <1>H NMR (300 MHz, CDCl 3 ) 84.86 (br s, 2H), 6.89-7.03 (rn, 4H), 7.19-7.30 (m, 1H), 7.45 -7.52 (m, IH), 7.56-7.66 (m, IH), 7.79 (d, J= 9 Hz, 2H), 8.04 (d, J = 9 Hz, IH) , 8.08 (p, 1H). MS (DCl-NH 3 ) m/z 474 (M+H)<+>, 491 (M+NH 4 )<+>. Anal. calcd for C 22 H 14 F 3 N 3 O 4 S-0.25 H 2 O: C, 55.32; H, 2.93; N, 8.80. Found: C, 55.26; H, 3.11; N, 8.58.

Example 38 9

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The product from Example 247 was converted to the title sulfonamide according to the method described in Example 384 (yield: 230 mg, 38%). Temp. 243-245 °C. <1>H NMR (300 MHz, DMSO-d6) 82.17 (br s, 3H), 6.94-7.09 (m, 2H), 7.25 (dd, J= 9 Hz, 3 Hz, IH), 7.41-7.48 (m, 4H), 7.60 (t, J = 9 Hz, IH), 7.68-7.75 (m, IH), 7.77 (d, J = 9 Hz, 2H), 7.95 (dd, J = 6 Hz, 3 Hz, IH), 8.25 (s, IH). MS (DCI-NH3) m/z 469 (M+H)<+>, 486 (M+NH4)<+.> Anal. calcd for C 23 H 16 CIF 2 N 3 O 3 S: C, 56.67; H, 3.29; N, 8.63. Found: C, 56.81; H, 3.35; N, 8.95.

Example 390

2-( 4- Fluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( amino-sulfonyl ) phenyl]- 3( 2H)- pyridazinone

The methylsulfone product in Example 24 5 was converted to the title sulfonamide according to the method described in Example 384 (yield: 78 mg, 28.3%). Temp. 202-204 °C. 3-H NMR (300 MHz, CDCl 3 ) 82.22 (s, 3H), 4.86 (s, 2H), 6.83-6.91 (m, 2H), 7.14-7.25 (m , 3H), 7.36 (d, J = 9 Hz, 2H), 7.65-7.72 (m, 2H), 7.91 (d, J = 9 Hz, 2H), 8.0 (s , IH). MS (DCI-NH3) m/z 454 (M+H)<+>, 471 (M+NH4)<+.> Anal. calcd for C 23 H 17 F 2 N 3 O 3 S-0.25 H 2 O: C, 60.36; H, 3.77; N, 9.19. Found: C, 60.24; H, 3.93; N, 9.25.

Example 391

2-( 3- Chlorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2h)- pyridazinone

The methylsulfone product of Example 244 was converted to the title sulfonamide according to the method described in Example 384 (yield: 125 mg, 39%). Temp. 187-188 °C. <1>H NMR (300 MHz, CDCl3) 82.21 (s, 3H), 4.71 (s, 2H), 6.85-6.92 (m, 2H), 7.21 (d, J = 9 Hz, IH), 7.32-7.47 (m, 2H), 7.37 (d, J = 9 Hz, 2H), 7.64 (dt, J = 7 Hz, 3 Hz, IH), 7.77 (br s, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 470 (M+H)<+>, 487 (M+NH 4 )<+>. Anal. calcd for C 23 Hi 7 ClFN 3 O 3 S-0.25 H 2 O: C, 58.32; H, 3.65; N, 8.88. Found: C, 58.27; H, 3.91; N, 8.62.

Example 392

2-( 3- Chlorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 366) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0756 g, 16%). Temp. 167-170 °C. <1>H NMR (300 MHz, DMSO de) δ 0.78 (d, J = 6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51-7.65 (m, 4H) , 7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H). MS (DCl-NH 3 ) m/z 432 (M+H)<+>, 449 (M+NH 4 )<+>. Anal. calcd for C 21 H 22 CIN 3 O 3 S (0.25 H 2 O): C, 57.79; H, 5.19; N, 9.62. Found: C, 57.78; H, 5.02; N, 9.40.

Example 393

2-( 3- Chlorophenyl)- 4-( phenethyl)- 5-[ 4-( aminosulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]~3(2H)-pyridazinone (Example 372) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.075 g, 17%). semi-solid; <!>h NMR (300 MHz, DMSO de)8 2.80 (m, 4H) , 3.29-3.42 (3H, obstructed by H2O) , 6.96 (m, 2H), 7.14- 7.28 (rn, 3H), 7.46-7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCl-NH 3 ) m/z 466 (M+H)<+>, 483 (M+NH 4 )<+>. Anal. calcd for C 24 H 20 CIN 2 O 3 S•0.25 H 2 O: C, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.

Example 394

2-( 3- Chlorophenyl)- 4-( 3- methylbutoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 339) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.575 g, 18%). Temp. 137-139 °C. <1>H NMR (300 MHz, DMSO de) δ 0.81 (d, J = 7 Hz, 6H) , 1.49 (m, 2H) , 1.57 (m, 1H), 4.42 (t , J = 7 Hz, 2H), 7.44-7.65 (m, 5H), 7.76 (m, IH), 7.84 (m, 2H), 7.94 (m, 2H), 8 ,20 (p, IH). MS (DCl-NH 3 ) m/z 448 (M+H)<+>, 465 (M+NH 4 )<+>. Anal. calcd for C 21 H 22 CIN 3 O 4 S: C, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N, 9.31.

Example 395

2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 335) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0458 g, 25%). Temp. 80-85 °C. <1>h NMR (300 MHz, DMSO de) δ 0.80 (d, J = 6 Hz, 6H) , 1.74-1.92 (m, 3H) , 4.20 (d, J = 6 Hz , 2H), 7.49-7.64 (m, 5H), 7.76 (rn, 1H), 7.85 (m, 2H), 7.95 (m, 2H), 8.21 (m, IH). MS (DCI-NH3) m/z 434 (M+H)<+>, 451 (M+NH4)<+.> Anal. calcd for C 20 H 20 C 1 N 3 O 4 S: C, 55.36; H, 4.65; N, 9.68. Found: C, 55.12; H, 4.58; N, 9, 42.

Example 396

2-( 4- Fluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 378) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.090 g 21%). Temp. 180-183 °C. 3-H NMR (300 MHz, DMSO d 6 ) 60.78

(d, J = 6 Hz, 6H), 1.49 (m, 5H), 7.36 (m, 2H), 7.53 (m, 2H), 7.62-7.73 (m, 4H) , 7.98 (m, 3H). MS (DCl-NH 3 ) m/z 416 (M+H)<+>, 433 (M+NH 4 )<+>. Anal. calcd for C 21 H 22 FN 3 O 3 S: C, 60.71; H, 5.34; N, 10,11. Found: C, 60.37, H, 5.36, N, 9, 84.

Example 397

2-( 4- Fluorophenyl)- 4-( 2- methylpropoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 376) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.024 g, 6%). Temp. 132-136 °C. ^-H NMR (300 MHz, DMSO d6) 6 0.79 (d, J = 6 Hz, 6H) , 1.83 (m, 1H) , 4.19 (d, J = 6 Hz, 2H), 7 .36 (m, 2H), 7.50 (m, 2H), 7.66 (m, 2H), 7.84 (m, 2H), 7.95 (m, 2H), 8.18 (s, IH). MS {DCI-NH3) m/z 418 (M+H)<+>, 435 (M+NH4)4-. Anal. calcd for C20H20FN3O4S: C, 57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.

Example 398

2-( 4- Fluorophenyl)- 4-( 3- methylbutoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 375) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.051 g, 18%). Yellow oil. <!>h NMR (300 MHz, DMSO d6) 6 0.80 (d, J = 5 Hz, 6H) , 1.47 (rn, 3H) , 4.42 (t, J = 6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, IH), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s , IH), 8.60 (bs, IH). MS (DCl-NH 3 ) m/z 432 (M+H)<+>, 449 (M+NH 4 )<+>. Anal. calcd for C 21 H 22 FN 3 O 4 S: C, 58.46; H, 5.14; N, 9.74. Found: C, 58.16; H, 5.21; N, 9.57.

Example 399

2-( t-Butyl)- 4-( 3- methyl- 1- butoxy)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 330C was oxidized with one equivalent of meta-chloroperoxybenzoic acid to the corresponding methyl sulfoxide. The sulfoxide was converted to the title sulfonamide by the method of Example 68 (yield: 1.25 g, 54%). Temp. 153-155°C. <*>H NMR (300 MHz, CDCl 3 ) δ 0.82 (d, J = 6 Hz, 2H), 1.48 (q, J = 6 Hz, 2H), 1.49-1.69 (m, IH), I, 70 (s, 9H), 4.37 (t, J = 6 Hz, 2H), 4.32 (s, 2H), 7.70 (d, J = 9 Hz, 2H), 7 .72 (s, 1H), 8.01 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 394 (M+H)<+.> Anal. calcd for C19H27N3O4S: C, 57.99; H, 6.91; N, 10.67. Found: C, 58.11; H, 6.71; N, 10.58.

Example 400

2-( 3, 4- Difluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 4-( 4- fluorophenyl)- 3( 2H)- pyridazinone

The title compound was prepared according to Example 384 using 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 182) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (yield: 950 mg, 54%). Temp. 177-181 °C. <1>H NMR (300 MHz, DMSO-dg) 87.15 (t, 2H), 7.29 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H), 7 .59 (m, 2H), 7.76 (d, J = 9 Hz, 2H), 7.85 (m, IH), 8.27 (s, IH). MS (DCl-NH 3 ) m/z 458 (M+H)<+>, 475 (M+NH 4 )<+>. Anal. calcd for C 22 H 14 F 3 N 3 O 3 S: C, 57.77; H, 3.08; N, 9.19. Found, C, 57.22; H, 3.28; N, 8, 99.

Example 401

2-( 3- Chloro- 4- fluorophenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384, using 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H) -pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 380 mg, 47%). Temp. 208-210 °C. <1>H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.43 (s, 1H) , 7.45 (bs, 2H) 7 .51 (d, J = 9 Hz, 4H), 7.6 (t, IH), 7.7 (m, IH), 7.75 (d, J = 9 Hz, 2H), 7.94 (dd , IH), 8.25 (s, IH). MS (DCl-NH 3 ) m/z 474 (M+H)<+>, 491 (M+NH 4 )<+>. Anal. calcd for C 22 H 14 F 2 C 12 N 3 O 3 S-0.5 H 2 O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H, 3.42; N, 8.65.

Example 402

2-( 3, 4- Difluorophenyl)- 4-( 4- fluoro- 3- methylphenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the procedure method in Example 384, using 2-(3,4-difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3 (2H)-pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 mg, 27%). Temp. 243-245 °C. ^ NMR (300 MHz, DMSO-de) 52.2 (s, 3H), 7.01 (m, 2H), 7.25 (rn, 1H), 7.45 (s, 1H), 7.47 ( bs, 2H), 7.6 (m, 2H), 7.77 (d, J = 9 Hz, 2H), 7.85 (m, 1H), 8.26 (s, 2H). MS (DCI-NH3) m/z 472 (M+H)<+>, 489 (M+NH4)<+.> Anal. calcd for C24H17F3N2C-3S-0.5 H2O: C, 58.59; H, 3.42; N, 8.91. Found: C, 57; H, 4.23; N, 8.89.

Example 403

2-( 3, 4- Difluorophenyl)- 4-( 2- methylpropoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). Temp. 169-171 °C. <!>h NMR (300 MHz, DMSO-dg) 60.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 436 (M+H)<+>, 453 (M+NH 4 )<+>. Anal. calcd for C20H19F2N3O4S-0.25H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35

Example 4 04

2-( 3, 4- Difluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( aminosulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 58 mg, 52%). Temp. 171-173 °C. <1>H NMR (300 MHz, DMSO-de) 50.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, IH), 7.65 (m, IH), 7.75 (d, J= 9 Hz, 2H), 7.81 (m, IH) 8.05 (s, IH), 8 .12 (d, J = 9 Hz, 2H). MS {DCI-NH3) m/z 434 (M+H)<+>, 451 (M+NH4)<+.> Anal. calcd for C 21 H 21 F 2 N 3 O 3 S•0.25 H 2 O: C, 58.19; H, 4.88; N, 9.69. Found: C, 57.69; H, 5.01; N, 9.18.

Example 405

2-( 3- Chloro- 4- fluorophenyl)- 4-( 3- methylbutyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)- pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102 mg, 61.8%). Temp. 154-156 °C. ^H NMR (300 MHz, DMSO-

d6) 5 0.75 (d, 6H) , 1.4, (m, 3H) , 2.48 (m, 2H) , 7.54 (s, 2H), 7.6 (m, 1H), 7 .69 (m, 2H), 7.93 (dd, 1H), 8.05 (m, 2H). MS (DCl-NH 3 ) m/z 450 (M+H)<+>, 468 (M+NH 4 )<+>. Anal. calcd for C 22 H 22 FN 2 O 3 SC 1 • 0.25 H 2 O: C, 58.86; H, 4.94; N, 6.24. Found: C, 59.23; H, 5.12; N, 6.00.

Example 406

2-( 3, 4- Difluorophenyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)- pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 310 mg, 38%). Temp. 173-175 °C. T-H NMR (300 MHz, DMS0-d6) δ 0.8 (s, 9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 3H), 7.6 (m, 1H), 7.85 (m, 3H), 7.95 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 450 (M+H)<+>, 467 (M+NH 4 )<+>. Anal. calcd for C21H21F2N3O4S: C, 56.12; H, 4.71; N, 9.35. Found, C, 55.83; H, 4.73; N, 9.08.

Example 407

2-( 3, 4- Difluorophenyl)- 4-( 4- fluorophenoxy)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 400 using 2-(3,4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 125 mg, 31%). Temp. 224-226 °C. 3-H NMR (300 MHz, DMSO-

de) 57.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 2H) 7.75 (m, 4H), 7.9 (t, 1H); 8.4 (p, 1H). MS (DCI-NH3) m/z 492 (M+H)<+>, 509 (M+NH4)<+.> Anal. calcd for C 22 H 13 F 4 N 3 O 4 S: C, 53.77; H, 2.67; N, 8.55. Found,; C, 53.33; H, 2.84; N, 8.22

Example 4 08

2-( 3, 3- Difluoro- 2- propenyl)]- 4-( 4- fluorophenyl)- 5-[ 3- fluoro- 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The intermediate, 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone prepared according to the method of Example 72 was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the sulfonamide according to the method described in Example 68. The sulfonamide material was N-debenzylated according to the method described in Example 11 and N-alkylated according to the method described in Example 127 using 1,3- dibromo-1,1-difluoropropane instead of 3,4-difluorobenzyl bromide and using 4 equivalents of potassium carbonate to provide the title compound (yield: 120 mg, 27%). Temp. 180-183 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 4.71 (dt, J = 15 Hz, 7.5 Hz, 2H), 4.75 (d, J = 7.5 Hz, 2H), 5.06 (s, 2H) , 7.02 (m, 2H) , 7.19 (dd, J = 9 Hz, 6 Hz, 2H), 7.81 (s, IH), 7.87 (t, J = 7 .5 Hz, 2H). MS (DCl-NH 3 ) m/z 440 (M+H)<+>. Anal. calcd for C19H13F4N3O3S: C, 51.93; H, 2.98; N, 9.56. Found: C, 51.71; H, 3.15; N, 9.28.

Example 409

2-( 3, 4- Difluorophenyl)- 4-[ 2-( 2- propoxy) ethoxy]- 5-[ 4-( amino-sulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3( 2H)-pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 110 mg, 34%). Temp. 54-56 °C. <1>H NMR (300 MHz, DMSO-d6) 51.0 (d, 6H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7 .5 (m, 3H), 7.6 (m, IH), 7.8 (m, IH), 7.95 (m, 4H), 8.2 (s, IH). MS (DCl-NH 3 ) m/z 466 (M+H)<+>, 483 (M+NH 4 )<+>. Anal. calcd for C21H21F2N3O5S: C, 54.19; H, 4.55; N, 9.03. Found, C, 54.29; H, 4.67; N, 8.95.

Example 410

2-( 3, 4- Difluorophenyl)- 4-( 4- methyl- 3- pentenyloxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)-phenyl]-3( 2H)-pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. Temp. 70-73 °C. <X>H NMR (300 MHz, DMSO-d6)S1.5 (d, 6H), 2.27 (m, 2H) 4.43 (t, 2H), 4.5 (m, 1H), 7, 5 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 7.92 (d, J = 2H, 2H), 8.2 (s, 1H). MS (DCl-NH 3 ) m/z 462 (M+H)<+>, 479 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 F 2 N 3 O 4 S: c, 57.26; H, 4.59; N, 9,11. Found, : C, 56.96; H, 4.70; N, 9.01.

Example 411

2-( 3- Chlorophenyl)- 4-( 3- fluorophenoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-fluorophenol instead of isobutanol (yield: 0.034 g, 22%). Temp. 178-180 °C. <!>h NMR (300 MHz, DMSO de) δ 3.27 (s, 3H), 6.88-7.00 (m, 2H), 7.10 (m, 1H), 7.36 (m, 1H), 7.59 (rn, 3H), 7.74 (m, 1H), 7.90 (m, 2H), 8.06 (m, 2H), 8.43 (s, 1H). MS (DCl-NH 3 ) m/z 488 (M+H)<+>. Anal. calcd for C 23 H 16 CIFN 2 O 4 S•0.25 H 2 O: C, 58.10; H, 3.49; N, 5.89. Found C, 58.04; H, 3.59; N, 5, 80.

Example 412

2-( 3- Chlorophenyl)- 4-( 2- methylpropoxy)- 5-[ 3- fluoro- 4-( amino-sulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 384 using 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)- pyridazinone instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.019 g, 10%). Temp. 157-159 °C. <1>H NMR (300 MHz, DMSO d6) 80.81 (d, J = 6 Hz, 6H), 1.86 (m, 1H), 4.24 (d, J = 6 Hz, 2H), 7 .75 (m, 3H), 7.66 (m, IH), 7.73 (m, 2H), 7.83 (m, 2H), 7.91 (m, IH), 8.23 (s, IH). Anal. calcd for C21H19CIFN3O4S: C, 53.16; H, 4.24; N, 9.30. Found: C, 53.02; H, 4.43; N, 9,10.

Example 413

2-( 3- Chlorophenyl)- 4-( 4- methylpentyloxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 4-methyl-1-pentanol instead of isobutanol (yield: 0.137 g, 90%). Temp. 139-140 °C. <3->H NMR (300 MHz, DMSO de) δ 0.74 (d, J = 6 Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 ( m, 2H), 3.29 (s, 3H), 4.40 (t, J = 5 Hz, 2H), 7.51-7.60 (m, 3H), 7.75 (m, IH), 7.90 (m, 2H), 8.07 (rn, 2H), 8.20 (s, 1H). MS (DCl-NH 3 ) m/z 461 (M+H)<+>, 478 (M+NH 4 )<+>. Anal. calcd for C 23 H 25 CIN 2 O 4 S: C, 59.95; H, 5.97; N, 6.08. Found: C, 59, 62; H, 5.63; N, 5.86.

Example 414

2-( 4- Fluorophenyl)- 4-( 4- methylpentyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, starting from 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3-chlorophenyl) )-4-tosyloxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone and using 4-methyl-1-pentanol instead of isobutanol (yield: 0.128 g, 85%). Temp. 123-125 °C. <X>H NMR (300 MHz, DMSO d6) 50.74 (d, J = 6 Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 (rn, 2H) , 3.28 (s, 3H), 4.39 (t, J = 6 Hz, 2H), 7.37 (m, 2H), 7.66 (rn, 2H), 7.91 (m, 2H), 8.07 (m, 2H), 8.18 (s, 1H). MS (DCl-NH 3 ) m/z 445 (M+H)<+>. Anal. calcd for C 23 H 25 FN 2 O 4 S: C, 62.14; H, 5.67; N, 6.30. Found: C, 62.28; H, 5.59; N, 6.25.

Example 415

2-( 4- Fluorophenyl)- 4- hydroxy- 5-[ 4-( methylsulfonyl) phenyl] - 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 332, using 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in 2-(3- chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone (yield: 2.022 g, 97%). ^-H NMR (300 MHz, DMSO de) δ 3.28 (s, 3H) , 7.38 (m, 2H) , 7.70 (m, 2H), 8.03 (m, 4H), 8, 22 (p, IH). MS (APCI-+Q1MS) 361 (M+H)<+>, (-Q1MS) 359 (M-H)-.

Example 416

2-( 4- Fluorophenyl)- 4- cyclopropylmethoxy- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using cyclopropylmethanol instead of isobutanol (yield: 0.117 g, 83%). Temp. 166-167 °C. <!>h NMR (300 MHz, DMSO de) 80.22 (m, 2H) , 0.46 (m, 2H) , 1.10 (rn, 1H) , 3.31 (s, 3H) , 4, 30 (d, J = 7 Hz, 2H), 7.36 (m, 2H), 7.66 (m, 2H), 7.96 (m, 2H), 8.07 (m, 2H), 8, 20 (p, IH). MS (DCl-NH 3 ) m/z 415 (M+H)<+>, 432 (M+NH 4 )<+>. Anal. calcd for C 23 H 25 CIN 2 O 4 S: C, 60.86; H, 4.62; N, 6.76. Found: C, 60.76; H, 4.72; N, 6, 61.

Example 417

2-( 4- Fluorophenyl)- 4-( 2- cyclopropyl- 1- ethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 2-cyclopropane ethanol instead of isobutanol (yield: 0.1472 g, 100%). Temp. 111-117 °C. <*>H NMR (300 MHz, DMSO dg) 5-0.01 (m, 2H) , 0.31 (m, 2H) , 0.60 (m, 1H) , 1.49 (q, J = 6 Hz, 2H), 3.29 (s, 3H), 4.48 (t, J = 6 Hz, 2H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 ( m, 2H), 8.06 (m, 2H), 8.17 (s, 1H). MS (DCI-NH3) m/z 429 (M+H)<+>, 446 (M+NH4)<+.> Anal. calcd for C 22 H 21 FN 2 O 4 S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.59; H, 5.02; N, 6.45.

Example 418

2-( 3- Chlorophenyl)- 4- cyclopropanemethoxy- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using cyclopropane methanol instead of isobutanol (yield: 0.0917 g, 64%). Temp. 158-161 °C. <1>H NMR (300 MHz, DMSO dg) 50.22 (m, 2H) , 0.46 (m, 2H) , 1.13 (m, 1H) , 3.31 (s, 3H) , 4, 31 (d, J = 7 Hz, 2H), 7.57 (m, 3H), 7.75 (m, IH), 7.96 (m, 2H), 8.08 (m, 2H), 8, 23 (p, IH). MS {DCI-NH3) m/z 431 (M+H)<+>, 448 (M+NH4)<+.> Anal. calcd for C21H19CIN2O4S■0.25 H2O: C, 57.92; H, 4.51; N, 6.43. Found: C, 57.86; H, 4.35; N, 6.27.

Example 419

2-( 3- Chlorophenyl)- 4-( 2- cyclopropane- 1- ethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-cyclopropane ethanol instead of isobutanol (yield: 0.114 g, 78%). Temp. 124-128 °C. <1>H NMR (300 MHz, DMSO dg) δ 0.00 (m, 2H), 0.32 (m, 2H), 0.61 (m, 1H), 1.49 (q, J = 6 Hz , 2H) , 3.30 (s, 3H), 4.50 (t, J = 6 Hz, 2H), 7.58 (rn, 3H), 7.76 (m, IH), 7.91 (m , 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 445 (M+H)<+>, 462 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 CIN 2 O 4 S: C, 59.39; H, 4.76; N, 6.30. Found: C, 58.92; H, 4.94; N, 6.15.

Example 420

2-( 4- Fluorophenyl)- 4-( 4- methylpentyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-methylpentane-1-magnesium bromide instead of cyclopropylmagnesium chloride (yield: 0.165 g, 99%). Temp. 112-115 °C. <3->H NMR (300 MHz, DMSO d6) δ 0.75 (d, J = 7 Hz, 6H), 1.07 (q, J = 7 Hz, 2H), 1.32-1.53 ( rn, 3H), 2.45 (t, 2H), 3.31 (s, 3H), 7.37 (m, 2H), 7.66 (m, 2H), 7.76 (m, 2H), 8.00 (s, IH), 8.10 (m, 2H). MS {DCI-NH 3 ) m/z 429 (M+H)<+>. 446 (M+NH4)<+>. Anal. calcd for C 23 H 25 FN 2 O 3 S: C, 64.47; H, 5.88; N, 6.54. Found: C, 64.44; H, 5.90; N, 6, 49.

Example 421

2-( 3- Chlorophenyl)- 4-( 4- methylpentyl)- 5-[ 4-( methylsulfonyl)- phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 362, using 4-methylpentane-1-magnesium bromide instead of cyclopropylmagnesium chloride (yield: 165 mg, 98%). oil. J-H NMR (300 MHz, DMSO

de) 5 0.76 (d, J = 6 Hz, 6H) , 1.07 (m, 2H) , 1.33-1.55 (m, 3H), 2.45 (m, 2H), 3, 32 (s, 3H), 7.51-7.65 (m, 4H), 7.76 (m, 2H), 8.03 (s, 1H), 8.11 (m, 2H). MS (DCI-NH3) m/z 445 (M+H)<+>, 462 (M+NH4)<+.> Anal. calcd for C 23 H 25 CIN 2 O 3 S: C, 62.06; H, 5.66; N, 6.30. Found: C, 61.86; H, 5.64; N, 6, 18.

Example 422

2-( 4- Fluorophenyl)- 4-( 3- methyl- 2- butenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 3-methyl-2-buten-1-ol instead of isobutanol (yield: 0.1284 g, 88 %). Temp. 128-132 °C. ^-H NMR (300 MHz, DMSO dg) 61.58 (s, 3H), 1.67 (s, 3H), 3.30 (s, 3H), 4.95 (d, J = 7 Hz, 2H ), 5.31 (m, 1H), 7.38 (m, 2H), 7.65 (m, 2H), 7.89 (m, 2H), 8.06 (m, 2H), 8.18 (p, IH). MS (DCI-NH3) m/z 429 (M+H)<+>, 446 (M+NH4)<+.> Anal. calcd for C 22 H 21 FN 2 O 4 S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.41; H, 4.95; N, 6.47.

Example 423

2-( 3- Chlorophenyl)- 4-( 3- methyl- 2- butenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-methyl-2-buten-1-ol instead of isobutanol (yield: 0.119 g, 81%). Temp. 113-115 °C. 3-H NMR (300 MHz, DMSO d6) δ 1.58 (s, 3H), 1.67 (s, 3H), 3.31 (s, 3H), 4.96 (m, 2H), 5, 32 (rn, IH), 7.58 (m, 3H), 7.75 (rn, IH), 7.89 (m, 2H), 8.07 (m, 2H), 8.21 (s, IH ). MS (APCI+Q1MS) 445 (M+H)<+>, (APCI-Q1MS) 479 (M+35)-. Anal. calcd for C 22 H 21 CIN 2 O 4 S: C, 59.39; H, 4.76; N, 6.30. Found: C, 59.14; H, 4.66; N, 6.16.

Example 424

2-( 4- Fluorophenyl)- 4-( 4- methyl- 3- pentenyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-methyl-2-penten-1-ol instead of isobutanol (yield: 0.1165 g, 77 %). Temp. 111-114 °C. <3->H NMR (300 MHz, DMSO de) 51.46 (s, 3H), 1.56 (s, 3H), 2.26 (m, 2H), 3.30 (s, 1H), 4 .43 (t, J = 7 Hz, 2H), 4.96 (m, IH), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8 .06 (m, 2H), 8.18 (s, 1H). MS (DCI-NH3) m/z 443 (M+H)<+>, 460 (M+NH4)<+.> Anal. calcd for C 23 H 23 FN 2 O 4 S: C, 62.43; H, 5.24; N, 6.33. Found: C, 62.32; H, 5.30; N, 6.25.

Example 425

2-( 4- Fluorophenyl)- 4-( 3- methyl- 3- butenoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3- chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 3-methyl-3-buten-1-ol instead of isobutanol (yield: 0.1327 g, 91 %). Temp. 109-111 °C. <3->H NMR (300 MHz, DMSO dg) δ 1.61 (s, 3H), 2.32 (t, J = 7 Hz, 2H), 3.30 (s, 3H), 4.56 ( t, J = 7 Hz, 2H), 4.63 (bs, IH), 4.68 (bs, IH), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 ( m, 2H), 8.05 (m, 2H), 8.19 (s, 1H). MS (DCl-NH 3 ) m/z 429 (M+H)<+>, 446 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 FN 2 O 4 S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.50; H, 5.00; N, 6.45.

Example 426

2-( 3- Chlorophenyl)- 4-( 4- methyl- 3- pentenyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 4-methyl-3-penten-1-ol instead of isobutanol (yield: 0.1149 g, 76%). Temp. 110-111 °C. <3->H NMR (300 MHz, DMSO dg) 51.47 (s, 3H), 1.55 (s, 3H), 2.27 (m, 2H), 3.30 (s, 3H), 4 .44 (t, J = 6 Hz, 2H), 4.96 (m, IH), 7.52-7.64 (m, 3H), 7.75 (m, IH), 7.91 (M, 2H), 8.06 (m, 2H), 8.21 (s, 1H). MS (DCI-NH3) m/z 459 (M+H)<+>, 476 (M+NH4)<+.> Anal. calcd for C 23 H 23 CIN 2 O 4 S: C, 60.19; H, 5.05; N, 6.10. Found: C, 60.06; H, 4.90; N, 5.96.

Example 427

2-( 3- Chlorophenyl)- 4-( 3- methyl- 3- butenoxy)- 5-[ 4-( methylsulfonyl ) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 335, using 3-methyl-3-buten-1-ol instead of isobutanol (yield: 0.1159 g, 79%). Temp. 110-112 °C. <X>H NMR (300 MHz, DMSO d6) 81.62 (s, 3H), 2.32 (t, J = 7 Hz, 2H), 3.30 (s, 3H), 4.57 (t, J = 6 Hz, 2H), 4.63 (bs, IH), 4.68 (bs, IH), 7.51-7.64 (m, 3H), 7.76 (m, IH), 7, 90 (m, 2H), 8.05 (rn, 2H), 8.21 (s, 1H). MS (DCl-NH 3 ) m/z 445 (M+H)<+>, 462 (M+NH 4 )<+>. Anal. calcd for C 22 H 21 CIN 2 O 4 S: C, 59.39; H, 4.76; N, 6.30. Found: C, 59.27; H, 4.68; N, 6.18.

Example 428

2-( 4- Fluorophenyl)- 4-( 1, 5- hexadienyl- 3- oxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178, using 1,5-hexadien-3-ol instead of 2-ethyl-1-hexanol (yield: 150 mg, 85%). Temp. 104-105 °C. <1>H NMR (300 MHz, DMSO-d6) δ 2.42 (m, 2H) , 3.30 (s, 3H) , 5.00 (m, 2H) , 5.17 (m, 2H) , 5.64 (m, 2H) , 7.36 (t, J = 9 Hz, 2H), 7.64 (m, 2H) , 7.92 (d, J = 9 Hz, 2H), 8.06 ( d, J = 9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 441 (M+H)<+>; (APCI-) m/z 475 (M+Cl)-. Anal. calcd for C 23 H 21 FN 2 O 4 S: C, 62.71; H, 4.80; N, 6.35. Found: C, 62.96; H, 4.93; N, 5.85.

Example 429

2-( 4- Fluorophenyl)- 4-( 5- methyl- 2- hexyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 using 5-methyl-2-hexanol instead of 2-ethyl-1-hexanol (yield: 150 mg, 82%). Temp. 102-103 °C. 3-H NMR (300 MHz, DMSO-dg) S 0.73 (d, J = 7 Hz, 6H), 1.04 (m, 2H), 1.14 (d, J = 7 Hz, 3H), 1.40 (m, 3H), 3.29 (s, 3H), 5.12 (m, IH), 7.36 (t, J = 9 Hz, 2H), 7.66 (m, 2H), 7.92 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 459 (M+H)<+>; (APCI-) m/z 493 (M+Cl)-. Anal. calcd for C 24 H 27 FN 2 O 4 S: C, 62.86; H, 5.93; N, 6.10. Found: C, 62.83; H, 5.99; N, 6.07.

Example 430

2-( 4- Fluorophenyl)- 4-( 2- ethyl- 1- butoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 using 2-ethyl-1-butanol instead of 2-ethyl-1-hexanol (yield: 140 mg, 80%). Temp. 107-108 °C. <1>H NMR (300 MHz, DMSO-d6) 60.73 (t, J = 7 Hz, 6H), 1.20 (quintet, J = 7 Hz, 4H), 1.40 (m, 1H), 3.29 (s, 3H), 4.29 (d, J = 7 Hz, 2H), 7.37 (t, J = 9 Hz, 2H), 7.66 (m, 2H), 7.90 ( d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 445 (M+H)<+>; (APCI-) m/z 479 (M+Cl)". Anal. calcd for C23H25FN2O4S: C, 62.14; H, 5.66; N, 6.30. Found: C, 62.05; H, 5 .86; N, 6.30.

Example 432

2-( 4- Fluorophenyl)- 4-( 2- thioisopropyl- 1- ethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 using 2-(isopropyl-thio)ethanol instead of 2-ethyl-1-hexanol (yield: 138 mg, 74%). Temp. 137-139 °C. 3-H NMR (300 MHz, DMS0-d6) δ 1.13 (d, J = 7 Hz, 6H), 2.77 (t, J = 7 Hz, 2H), 2.88 (quintet, J = 7 Hz, IH), 3.29 (s, 3H), 4.58 (t, J = 7 Hz, 2H), 7.37 (t, J = 9 Hz, 2H), 7.66 (m, 2H) , 7.92 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 463 (M+H)<+>. Anal. calculated for C22H23FN2O4S2: C' 57'12'' H' 5.01; N, 6.05. Found: C, 56.82; H, 4.91; N, 5.99.

Example 433

2-( 4- Fluorophenyl)- 4-( 3- methylthio-l- hexyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 using 3-(methylthio)-1-hexanol instead of 2-ethyl-1-hexanol (yield: 155 mg, 79%). Temp. 90-92 °C. 3-H NMR (300 MHz, DMS0-d6) δ 0.78 (t, J = 7 Hz, 3H), 1.30 (m, 4H), 1.76 (m, 2H), 2.82 (s , 3H), 2.38 (m, IH), 3.29 (s, 3H), 4.55 (m, 2H), 7.37 (t, J = 9 Hz, 2H), 7.66 (m , 2H), 7.92 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 491 (M+H)<+>; (APCI-) m/z 525 (M+Cl)-. Anal. calcd for C 24 H 27 FN 2 O 4 S 2 : C, 58.75; H, 5.54; N, 5.70. Found: C, 58.66; H, 5.54; N, 5, 66.

Example 434

2-( 4- Fluorophenyl)- 4-( 2- methyl- 4- pentenyl- l- oxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178, using 2-methyl-4-penten-1-ol instead of 2-ethyl-1-hexanol (yield: 135 mg, 76%). Temp. 106-107 °C. <1>H NMR (300 MHz, DMSO-dg) S0.76 (d, J = 7 Hz, 3H), 1.78 (m, 2H), 2.00 (m, 1H), 3.29 (s , 3H), 4.25 (m, 2H) , 4.90 (m, 2H) , 5.67 (m, IH) , 7.37 (t, J = 9 Hz, 2H), 7.66 (rn , 2H), 7.92 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H), 8.18 (s, 1H). MS (APCI+) m/z 443 (M+H)<+>; (APCI-) m/z 477 (M+Cl)-. Anal. calcd for C 23 H 23 FN 2 O 4 S: C, 62.42/ H, 5.23; N, 6.33. Found: C, 62.13; H, 5.12; N, 6.22.

Example 435

2-( 3, 4- Difluorophenyl)- 4-( 3- trifluoromethyl- 1- butoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

To a solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyidazinone (189mg, 0.5 mmol), Ph3P (262 mg, 1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF (25 mL) was added dropwise to a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL), and the the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo and the residue chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, (yield: 180 mg 71%). Temp. 126-128 °C. <1>H NMR (300 MHz, DMSO-dg) 50.96 (d, J = 7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m , IH), 3.29 (s, 3H), 4.46 (m, 2H), 7.52 (m, IH), 7.62 (m, IH), 7.81 (m, IH), 7 .90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, IH). MS (APCI+) m/z 503 (M+H)<+>; (APCI-) m/z 537 (M+Cl)" . Anal. calcd for C22H19F5N2O4S: C, 52.59; H, 3.81; N, 5.57. Found: C, 52.70; H, 3 .73/N, 5.63.

Example 436

2-( 3, 4- Difluorophenyl)- 4- ethoxy- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl) )-4-tosyloxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone and using ethanol instead of 2-ethyl-1-hexanol (yield: 25 mg, 12%). Temp. 121-123 °C. <!>h NMR (300 MHz, DMSO-dg) 51.23 (t, J = 7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J = 7 Hz, 2H), 7.52 (m, IH), 7.62 (m, IH), 7.81 (rn, IH), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 407 (M+H)<+>; (APCI-) m/z 441 (M+Cl)-. Anal. calcd for C 19 H 16 E 2 N 2 O 4 S-0.25 H 2 O: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.

Example 437

2-( 3, 4- Difluorophenyl)- 4-( 4- methyl- 1- pentyloxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-tosyloxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone and using 4-methyl-1-pentanol instead of 2-ethyl-1-hexanol (yield: 120 mg, 52%). Temp. 98-99 °C. <1>H NMR (300 MHz, DMS0-d6) δ 0.73

(d, J= 7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, IH), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J = 7 Hz, 2H), 7.52 (m, IH), 7.62 (m, IH), 7.81 (m, IH), 7.90 (d, J = 9 Hz, 2H ), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)<+>; (APCI-) m/z 497 (M+C1)~. Anal. calcd for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.

Example 4382-(3,4-Difluorophenyl)-4-(4-methyl-2-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-methyl-2-pentanol in 2-ethyl-1-hexanol (yield: 115 mg, 50 %). Temp. 132-133 °C. <!>h NMR (300 MHz, DMSO-dg) 80.80 (d, J = 7 Hz, 3H), 0.87 (d, J = 7 Hz, 3H), 1.10 (d, J = 7 Hz, 3H), 1.26 (m, IH), 1.50 (m, IH), 1.63 (m, IH), 3.30 (s, 3H), 5.31 (m, IH), 7.52 (m, IH), 7.62 (m, IH), 7.81 (m, IH), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 463 (M+H)<+>; (APCI-) m/z 497 (M+Cl)-Anal. calcd for C23H24F2N2O4S: C, 59.72; H, 5.23; N, 6.05. Found: C, 59.44; H, 5.26; N, 5.99.

Example 439 2-(3,4-Difluorophenyl)-4-(2-cyclopentyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-tosyloxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone and using 2-cyclopentyl-1-ethanol instead of 2-ethyl-1-hexanol (yield: 115 mg, 60%). Temp. 100-101 °C. <1>H NMR (300 MHz, DMSO-

d6) 81.00 (m, 2H) , 1.38 (m, 2H) , 1.57 (m, 7H) , 3.30 (s, 3H), 4.42 (t, J = 7 Hz, 2H ), 7.52 (rn, IH), 7.62 (m, IH), 7.81 (rn, IH), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 475 (M+H)<+>; (APCI-) m/z 509 (M+Cl)-. Anal. calcd for C24H24F2N2O4S•0.25 H2O: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5, 76.

Example 440

2-( 3, 4- Difluorophenyl)- 4-( 2- cyclopenten- 2- enyl- 1- ethoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4-fluorophenyl) )-4-tosyloxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone and using 2-cyclopent-2-enyl-1-ethanol instead of 2-ethyl-1-hexanol (yield: 95 mgr 48%). Temp. 126-127 °C. <1>H NMR (300 MHz,

DMSO-dg) 51.30 (m, 1H), 1.57 (sext, J = 7 Hz, 1H), 1.69 (sext, J = 7 Hz, 1H), 1.87 (m, 2H), 2.57 (m, IH), 3.30 (s, 3H), 4.45 (rn, 2H), 5.60 (rn, IH), 5.68 (m, IH), 7.52 (m , IH), 7.62 (m, IH), 7.81 (m, IH), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (p, 1H). MS (APCI+) m/z 473 (M+H)<+>; (APCI-) m/z 507 (M+Cl)-. Anal. calcd for C24H22F2N2O4S: C, 61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.

Example 441

2-( 2- Hydroxy- 2- phenylethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl.) phenyl]- 3( 2H)- pyridazinone

A mixture of the product of Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (700 mg, 1.5 mmol) and sodium borohydride (69 mg, 1.8 mmol) in ethanol (200 mL), was stirred at 40 °C for 2 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to provide a pale yellow solid which was crystallized from ethyl acetate/hexanes to provide the title compound as white crystals (yield: 540 mg, 78%). Temp. 205-207 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 3.07 (s, 3H), 3.75 (br s,

IH), 4.63-4.47 (m, 2H) , 5.33 (dd, J = 9 Hz, 3 Hz, IH) , 7.00 (t, J = 9 Hz, 2H), 7.20 {dd, J = 9 Hz, 3 Hz, 2H), 7.30-7.45 {m, 5H), 7.52 (d, J = 9 Hz, 2H), 7.91 (s, IH), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 465 (M+H)<+.> Anal. calcd for C 25 H 21 FN 2 O 4 S: C, 64.64; H, 4.55; N, 6.03. Found: C, 64.34; H, 4.66; N, 5.93.

Example 4 42

2-( 2- Methoxy- 2- phenylethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of the product of Example 4412-(2-hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-{methylsulfonyl)phenyl]-3(2H)-pyridazinone (210 mg, 0.45 mmol), iodomethane (56 µl, 0.90 mmol) and an 80% oil dispersion of sodium hydride (18 mg, 0.59 mmol) in anhydrous DMF (16 mL) was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo to provide a yellow oil which was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were pooled and concentrated in vacuo and the residue was triturated with hexanes to provide the title compound (yield: 75 mg, 34.7%). Temp. 135-137 °C. <1>h NMR (300 MHz, CDCl 3 ) S 3.07 (s, 3H), 3.26 (s, 3H), 4.33-4.52 (m, 2H), 4.91 (dd, J = 9 Hz, 3 Hz, IH), 6.99 (t, J = 9 Hz, 2H), 7.20 (dd, J = 9 Hz, 3 Hz, 2H), 7.31-7.50 (m , 7H), 7.87 (s, 1H), 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 479 (M+H)<+.> Anal. calculated for C26H23FN2O4S: C' 65.25; H, 4.84; N, 5.85. Found: C, 64.98; H, 4.83; N, 5.81.

Example 443

2-( 2- Methoxyiminc— 2- phenylethyl)- 4-( 4- fluorophenyl)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of the product of Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol) and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) were stirred under reflux for 48 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine and then dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo to provide a brown oil which was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were pooled and concentrated in vacuo. The residue was crystallized from methanol/water to provide the title compound as a mixture of E- and Z-oximes (yield: 82 mg, 35%). Smp.' 95-99 °C. 11 NMR (300 MHz, CDCl 3 ) δ 3.03 (s, 3H), 4.07 (s, 3H), 5.57 (s, 2H), 6.94 (t, J = 9 Hz, 2H), 7.07 (dd, J = 9 Hz, 3 Hz, 2H), 7.24 (d, J = 9 Hz, 2H), 7.31-7.37 (m, 3H), 7.60-7, 67 (m, 2H), 7.74 (s, 1H), 7.83 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 492 (M+H)<+>. Anal. calcd for C 26 H 22 FN 3 O 4 S: C, 63.53; H, 4.51; N, 8.54. Found: C, 63.40; H, 4.51; N, 8, 31.

Example 444

2-( 3, 4- Difluorophenyl)- 4-( 4- methylpentyl)- 5-[ 3- fluoro- 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 255, using 1-bromo-4-methylpentane instead of 3,4-difluorobenzyl bromide (yield: 145 mg, 58%). Temp. 111-113 °C. <1>H NMR (300 MHz, DMSO-dg) δ 0.75 (d, 6H), 1.09 (m, 2H), 1.4 (m, 3H), 2.48 (m, 2H), 3.4

(s, 3H), 7.61 (m, 2H), 7.75 (d, 2H), 7.81 (m, IH), 8.02 (s, IH), 8.1 (d, 2H) . MS (DCl-NH 3 ) m/z 447 (M+H)<+>, 464 (M+NH 4 )<+>. Anal. calcd for C 23 H 24 F 2 N 2 O 3 S: C, 61.87; H, 5.42; N, 6.27. Found: C, 61.76; H, 5.55; N, 6.11.

Example 44 5

2-( 3, 4- Difluorophenyl)- 4-( 3- methyl- 1- butoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared as described in Example 384, using 2-(3,4-difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)- pyridazinone (Example 347) instead of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 248 mg, 42%). Temp. 149-151 °C. <1>H NMR (300 MHz, DMS0-d6) δ 0.8 (d, J = 6 Hz, 6H), 1.48 (m, 2H), 1.54 (m, 1H), 4.4 ( t, 2H), 7.51 (m, 3H), 7.6 (m, IH), 7.85 (m, 3H), 7.95 (d, J = 9 Hz, 2H), 8.21 ( pp, IH). MS (DCl-NH3) m/z 450 (M+H)<+>, 467 {M+NH4)4-. Anal. calcd for C21H21F2N3O4S: C, 56.12; H, 4.71; N, 9.35. Found, C, 56.12; H, 4.67; N, 9.15.

Example 446

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2, 2- dimethylpropoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 2,2-dimethylpropanol to provide 2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method described in Example 90D. The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The sulfoxide was converted to the title compound according to the method described in Example 68 using 2-(2,2,2-trifluoroethyl)-4-(2,2-dimethyl-propoxy)-5-[4-(methylsulfinyl)phenyl ] -3(2H)-pyridazinone in 2-

(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-{methylsulfinyl)-phenyl]-3(2H)-pyridazinone (yield: 125 mg, 53%). Temp. 123-124 °C. <1>h NMR (300 MHz, CDCl 3 ) δ 0.82 (s, 9H), 4.18 (s, 2H), 4.82 (q, J = 9 Hz, 2H), 4.84 (s, 2H), 7.70 (d, J = 9 Hz, 2H), 7.81 (s, 1H), 8.04 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 420 (M+H)<+>. Anal. calcd for C17H20F3N3O4S: C, 48.68; H, 4.80; N, 10.01. Found: C, 48.76; H, 4.77; N, 9.94.

Example 447

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 83, using 3-methyl-1-butanol instead of isopropanol (yield: 65 mg, 85%). Temp. 111-113 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 0.84 (d, J = 6 Hz, 6H), 1.51 (m, 2H), 1.63 (rn, 1H), 3.11 (s, 3H) , 4.54 (t, J = 6 Hz, 2H), 4.83 (q, J = 9 Hz, 2H), 7.73 (d, J = 9 Hz, 2H), 7.82 (s , 1H), 8.05 (d, J = 9 Hz, 2H); MS (DCI-NH3) m/z 419 (M+H)<+.> Anal. calcd for C18H21F3N2O4S: C, 51.66; H, 5.05; N, 6.69. Found: C, 51.91; H, 5.06; N, 6.56.

Example 448

2-( 2, 2, 2- Trifluoroethyl)- 4-( 3- methylbutoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 3-methyl-1-butanol to to provide 2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone according to the method described in Example 90D. The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The sulfoxide was converted to the title compound according to the method described in Example 68 using 2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-

(methylsulfinyl)phenyl]-3(2H)-pyridazinone in 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (yield: 65 mg, 50%). Temp. 123-124 °C. <!>h NMR (300 MHz, CDCl3) δ 0.84 (d, J = 6 Hz, 6H), 1.52 (q, J = 6 Hz, 2H), 1.60 (h, J = 7, 5 Hz, IH) , 4.52 (t, J = 6 Hz, 2H), 4.83 (q, J = 9 Hz, 2H), 4.90 (s, 2H), 7.69 (d, J = 9 Hz, 2H), 7.82 (s, 1H), 8.04 (d, J = 9 Hz, 2H). MS (DCl-NH 3 ) m/z 420 (M+H)<+>. Anal. calcd for C17H20F3N3O4S: C, 48.68; H, 4.80; N, 10.01. Found: C, 48.86; H, 4.83; N, 9.92.

Example 44 9

2-( 2, 2, 2- Trifluoroethyl)- 4-( 2- methylpropoxy)- 5-[ 4-( amino-sulfonyl ) phenyl]- 3 ( 2H)- pyridazinone

The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 2-methyl-1-propanol to to provide 2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylthio)-phenyl]-3(2H)-pyridazinone according to the method described in Example 90D. The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The sulfoxide was converted to the title compound according to the method described in Example 68 using 2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfinyl)phenyl]-3(2H )-pyridazinone in 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (yield: 120 mg, 40%) . Temp. 170-172 °C. <i>H NMR (300 MHz, CDCl 3 ) δ 0.83 (d, J = 6 Hz, 6H), 1.9 (m, 1H), 4.3 (m, 2H), 4.82 (s, 2H), 4.88 (m, 2H), 7.70 (d, J = 9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J = 9 Hz, 2H); MS (DCI-NH3) m/z 406 (M+H)<+.> Anal. calcd for C16H18F3N3O4S: C, 47.4; H, 4.47; N, 10.36. Found: C, 47.48; H, 4.36; N, 10.25.

Example 450

2-( 2, 3, 3- Trifluoropropenyl)- 4-( 4- fluorophenyl)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The product of Example 4, 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, was N-debenzylated by the method of Example 11 to provide 4-( 4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. The intermediate was mixed with one equivalent of 1-methylsulfonyloxy-2,3,3-trifluoro-2-propene, (Example 88A) in ethyl acetate, followed by one equivalent of cesium carbonate. The reaction mixture was heated to 50 °C for 5 hours. Aqueous work-up followed by chromatography gave 2-(2,3,3-trifluoro-propenyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (650 mg, 63 %). The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which was converted to the title compound according to the method described in Example 68 using 2-(2,3,3-trifluoropropenyl)-4-(4-fluorophenyl)-5 -[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone in 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3 ( 2H)-pyridazinone (yield: 65 mg, 35%). Temp. 190-193°C. NMR (300 MHz, CDCl3) δ 5.07 (s, 2H), 5.10 (dt, J = 21 Hz, J = 3 Hz, 2H), 7.05 (m, 4H), 7.19 (dd , J = 9 Hz, J = 6 Hz, 2H), 7.84 (s, IH), 7.87 (t, J = 7.5 Hz, IH). MS (ESI-NH3) m/z 456 (M-H)<+.> Anal. calcd for C19H12F5N3O3S: C, 49, 89; H, 2.64; N, 9.18. Found: C, 49.89; H, 2.73; N, 9.03.

Example 451

2-( 4- Fluorophenyl)- 4-( 3- hydroxy- 3- methyl- 1- butoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 using 3-methyl-1,3-butanediol instead of 2-ethyl-1-hexanol (yield: 110 mg, 61%), mp. 133-134 °C. 1 H NMR (300 MHz, DMSO-de) 61.04 (s, 6H), 1.72 (t, J = 7 Hz, 2H), 3.29 (s, 3H), 4.32 (s, 1H) , 4.53 (t, J = 7 Hz, 2H), 7.37 (t, J = 9 Hz, 2H) , 7.66 {m, 2H), 7.90 (d, J = 9 Hz, 2H ), 8.07 (d, J = 9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 447 (M+H)<+>; (APCI-) m/z 481 (M+Cl)-. Anal. calcd for C22H23FN2O5S•°'25 H2O: C, 58.59; H, 5.25; N, 6.21. Found: C, 58, 42; H, 5.00; N, 6,"02.

Example 452

2-( 3, 4- D1fluorophenyl)- 4-( 2- hydroxy- 2- methyl- 1- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the method described in Example 178 starting from 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(4- fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 2-methyl-1,2-propanediol instead of 2-ethyl-1-hexanol (yield: 55 mg , 31%). <1>U NMR (300 MHz, DMSO-dg) 50.97 (s, 6H), 3.30 (s, 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7 .52 (m, IH), 7.62 (m, IH), 7.81 (m, IH), 7.98 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz , 2H), 8.21 (s, 1H). MS (APCI+) m/z 451 (M+H)<+>; (APCI-) m/z 485 (M+Cl)-. Anal. calcd for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C, 56.00; H, 4.48; N, 5, 87.

Example 453

2-( 3, 4- Difluorophenyl)- 4- methoxy- 5-[ 4-( methylsulfonyl) phenyl]-3( 2H)- pyridazinone

The title compound was isolated from the reaction mixture in Example 233 as an oxidation product of unreacted starting material (yield: 22 mg, 8%). Temp. 113-115 °C. <i>H NMR (300 MHz, DMSO-d6) 5 3.3 (s, 3H) , 4.1 (s, 3H) , 7.53 (m, 1H) , 7.63 (m, 1H), 7.8 (m, 1H), 8.15 (d, 2H), 8.2 (s, 2H). MS (DCl-NH 3 ) m/z 393 (M+H)<+>, 410 (M+NH 4 )<+>. Anal. calcd for C18H14F2N2O4S: C, 55.10; H, 3.60; N, 7.14.

Example 454

2-( 2, 3, 4, 5, 6- Pentafluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-[( dimethylamino) methylene] aminosulfonylphenyl]- 3( 2H)-pyridazinone

The title compound was isolated from the reaction mixture of Example 125 as a product resulting from a reaction with the solvent, N,N-dimethylformamide (yield: 53 mg, 16%). Temp. 194-196 °C. <1>H NMR (300 MHz, CDCl 3 ) δ 3.05 (s, 3H), 3.17 (s, 3H), 5.49 (s, 2H), 6.97 (t, J = 9 Hz, 2H),

7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 7.81 (s, IH), 7.82 (d, J = 9 Hz , 2H), 8.14 (s, 1H). MS (DCl-NH 3 ) m/Z 581 (M+H)<+>. Anal. calcd for C26HI8F6N4O3S: C, 53.79; H, 3.12; N, 9.65. Found: C, 53.50; H, 3.24; N, 9.56.

Example 4 55

2-( 2, 4- Difluorobenzyl)- 4-( 4- fluorophenyl)- 5-[ 4-[( dimethylamino) methylene] aminosulfonylphenyl]- 3( 2H)- pyridazinone

The title compound was isolated from the reaction mixture of Example 124 as a product resulting from a reaction with the solvent, N,N-dimethylformamide (yield: 55 mg, 18%). Temp. 193-195 "C. <1->H NMR (300 MHz, CDCl3) δ 3.03 (s, 3H), 3.16 (s, 3H), 5.43 (s, 2H), 6.88 ( m, 2H), 6.95 (t, J= 9 Hz, 2H), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 7.52 (m, 1H), 7.81 (d, J = 9 Hz, 2H), 7.84 (s, 1H), 8.13 (s, 1H).MS (DCI-NH3) m/z 527 (M+H)<+.> Anal. calcd for C26H21F3N4O3S: C, 59.30; H, 4.02; N, 10.64. Found: C, 59.08; H, 3.97; N, 10.48.

Example 4 57

2-( 3, 4- Difluorophenyl)- 4-( 3- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared as described in Example 62, starting from 4-(3-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4 -(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 3,4-difluorobromobenzene instead of 1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). Temp. 182-185 °C. <1>h NMR (300 MHz, DMSO-dg) δ 3.23 (s, 3H), 6.98 (d, J = 9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, IH) , 7.52 (d, J = 9 Hz, 2 H) , 7.6 (m, 2H), 7.85 (m, 1 H), 7.9 (d, J - 9 Hz , 2H), 8.3 (s, 1H). MS (DCI-NH3) m/z 457 (M+H)<+>, 474 (M+NH4)<+.>

Example 458

2-( 4- Fluorophenyl)- 4-( 3- fluorophenyl)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound was prepared as described in Example 62, using 4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 4-(4-fluorophenyl)-5-[4 -(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 135 mg, 34%). Temp. 199-201 °C <X>H NMR (300 MHz, DMSO-d6) δ 3.24 (s, 3H), 6.98 (d, J = 9 Hz, 1H), 7.18 (m, 2H) , 7.32 (m, IH), 7.39 (t, IH), 7.54 (d, J = 9 Hz, 2 H), 7.71 (m, 2H), 7.91{d, J = 9 Hz, 2 H), 8.27 (s, 1 H). MS (DCl-NH 3 ) m/z 439 (M+H)<+>, 456 (M+NH 4 )<+>.

Example 459

2-( 3, 4- Difluorophenyl)- 4-( 2- hydroxy- 2- methylpropoxy)- 5-[ 4-( aminosulfonyl)- phenyl]- 3( 2H)- pyridazinone

2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 452)

is converted to the title sulfonamide according to the method described in Example 384.

Example 460

2-( 3, 4- Difluorophenyl)- 4-( 2- oxo- l- propoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), Ph3P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) in THF (25 mL) at room temperature were treated dropwise with a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 205 mg, 48%). Temp. 169-170 °C. 3-H NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7 .62 (q, J = 10 Hz, IH), 7.75 (m, IH), 7.94 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.21 (p, 1H). MS (APCI+) m/z 435 (M+H)<+>, (APCI-) m/z 469 (M+Cl)-. Anal. calcd for C20HI6F2N2O5S■0.75H2O: C, 53.62; H, 3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08.

Example 4 61

2-( 3, 4- Difluorophenyl)- 4-[ 2-( methoxyimino) propoxy]- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of 2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 460 (150 mg, 0 .3 mmol) in H2O (10 mL) and dioxane (20 mL) was treated with methoxylamine hydrochloride (84 mg, 1 mmol) and sodium acetate trihydrate (138 mg, 1 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate and purified by column chromatography! (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 20 mg, 15%). Temp. 143-145 °C. <1>H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, IH), 7.65 (q, J = 10 Hz, IH), 7.82 (m, IH), 7.92 (d, J = 9 Hz, 2H), 8.07 ( d, J = 9 Hz, 2H), 8.24 (s, 1H). MS (APCI+) m/z 464 (M+H)<+>; (APCI-) m/z 498 (M+Cl)'. Anal. calcd for C21H19F2N3O5S: C, 54.42; H, 4.13; N, 9.06. Found: C, 54.33; H, 3.93; N, 8.92.

Example 4 62

( S ) - 2-( 3, 4- Difluorophenyl)- 4-( 3- hydroxy- 2- methylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

462A ( R)- 3- t- Butoxy- 2- methyl- l- propanol

A solution of (S)-(+)-methyl 3-hydroxy-2-methylpropionate (1.18 g, 10 mmol) in t-butyl acetate (30 mL) was treated with 70% HCIO4 (0.1 mL), and the reaction mixture was allowed to stand at room temperature in a sealed flask for 24 hours. The mixture was poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The ether was removed in vacuo and the residue was dissolved in THF (50 mL). To the resulting solution was added sodium borohydride (925 mg, 25 mmol) and at 55 °C methanol dropwise (10 mL). The reaction was allowed to proceed at 55 °C for 1 hour, then the mixture was cooled to room temperature, acidified with 10% citric acid to pH 5 and extracted with ethyl acetate. The acetate extract was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 2:1 hexanes-ethyl acetate) to provide (R)-3-t-butoxy-2-methyl-1-propanol (yield: 1 g, 68%). 1-H NMR (300 MHz, CDCl 3 ) δ 0.85 (d, J = 7 Hz, 3H), 1.20 (s, 9H), 2.03 (m, 1H), 3.30 (t, J = 12 Hz, IH), 3.53 (dd, J = 12 Hz, 4.5 Hz, IH), 3.70 (m, 2H). MS (DCl-NH 3 ) m/z 164 (M+NH 4 )<+.>

462B ( S)- 2-( 3, 4- Difluorophenyl)- 4-( 3- t- butoxy- 2- methyl- propoxy)- 5-[ 4-( methylsulphonyl) phenyl]- 3( 2H)- pyridazinone

To a solution 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-{methyl-sulfonyl)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), PI13P

(524 mg, 2 mmol) and the above alcohol, (R)-3-t-butoxy-2-methyl-l-propanol (146 mg, 1 mmol), in THF (25 mL) at room temperature was added dropwise a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture was then stirred at room temperature for 6 hours and concentrated in vacuo. The residue was passed through a pad of silica gel (hexanes-ethyl acetate as eluent) to provide 550 mg of crudely purified (S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methylpropoxy)-5 -[4-(methylsulphonyl)phenyl]-3(2H)-pyridazinone, still contaminated with reduced DIAD. MS (APCI+) m/z 507 (M+H)<+>; (APCI-) m/z 541 (M+Cl)-.

462C ( S)- 2-( 3, 4- Difluorophenyl)- 4-( 3- hydroxy- 2-methylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

A mixture of the above product (100 mg, -0.2 mmol) in TFA (5 mL) was stirred at room temperature for 24 h and then concentrated in vacuo. The residue was neutralized with saturated NaHCO 3 and extracted with ethyl acetate. Purification by column chromatography (silica gel, 1:2 hexanes-ethyl acetate) gave the title compound (yield: 51 mg, 56%). 3-H NMR (300 MHz, DMSO-de) δ 0.75 (d, J = 7 Hz, 3H), 1.81 (sept, J = 7 Hz, IH), 3.21 (d, J = 6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 12 Hz, 6 Hz, IH), 4.40 (dd, J = 12 Hz, 6 Hz, IH), 4, 48 {br s,

IH), 7.52 (m, IH), 7.61 (m, IH), 7.80 (m, IH), 7.91 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI+) m/z 451 (M+H)<+>; (APCI-) m/z 485 (M+Cl)-. Anal. calcd for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C,

55.65; H, 4.65; N, 5.92.

Example 4 63

( R )- 2-( 3, 4- Difluorophenyl)- 4-( 3- hydroxy- 2- methylpropoxy)- 5-[ 4-( methylsulfonyl) phenyl] pyridazinone

The desired material was prepared according to the procedure in Example 462 starting from (R)-(-)-methyl 3-hydroxy-2-methylpropionate instead of (S)-(-)-methyl 3-hydroxy-2-methyl-propionate ( yield: 65 mg, 61%). <!>h NMR (300 MHz, DMSO-d6) δ 0.75 (d, J = 7 Hz, 3H), 1.81 (sept, J = 7 Hz, 1H), 3.21 (t, J = 6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 6 Hz and 12 Hz, IH), 4.40 (dd, J = 6 Hz and 12 Hz, IH), 4 .49 (t, J = 6 Hz, IH), 7.52 (m, IH), 7.61 (rn, IH), 7.80 (m, IH), 7.91 (d, J = 9 Hz , 2H), 8.07 (d, J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI+) m/z 451 (M+H)<+>; (APCI-) m/z 485 (M+Cl)-. Anal. calcd for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C, 55.62; H, 4.52; N, 6.06.

Example 4 64

( S )- 2-( 3, 4- Difluorophenyl)- 4-( 3- hydroxy- 2- methylpropoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

To a solution of (S)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 462 (450 mg, -0.9 mmol) and DBAD (207 mg, 0.9 mmol) in THF (25 mL) at -78 °C was added dropwise 1 M lithium bis(trimethylsilyl)amide solution in THF (3 mL, 3 mmol). The resulting mixture was stirred at -78°C for 2 hours. The mixture was warmed to room temperature and 1N NaOH (5 mL, 5 mmol) was added. After 12 h at room temperature, sodium acetate trihydrate (2.76 g, 20 mmol) and H 2 O (10 mL) followed by hydroxylamine-O-sulfonic acid (2 g, 15 mmol) were added and the mixture was stirred at room temperature for 5 h. The product was extracted with ethyl acetate and purified by chromatography (silica gel, 1:2 hexanes-ethyl acetate) to provide the desired intermediate

(yield: 160 mg, 35%). MS (APCI+) m/z 508 (M+H)<+>; (APCI-) m/z 542 (M+Cl)-.

TFA (5 mL) was added to the above intermediate, and the resulting solution was stirred at room temperature for 24 h. The TFA was removed in vacuo, and the residue was neutralized with saturated NaHCO 3 and extracted with ethyl acetate. The organic extract was dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed (silica gel, 1:2 hexanes-ethyl acetate) to provide the title compound (yield: 50 mg, 33%). ^H NMR (300 MHz, DMSO-d6) 80.76 (d, J = 7 Hz, 3H), 1.81 (sextet, J = 7 Hz, 1H), 3.22 (t, J = 6 Hz, 2H), 4.28 (dd, J = 12 Hz, 6 Hz, IH), 4.40 (dd, J = 12 Hz, 6 Hz, IH), 4.50 (t, J = 6 Hz, IH) , 7.51 (m, 3H), 7.61 (m, IH), 7.80 (m, IH), 7.84 (d, J = 9 Hz, 2H), 7.95 (d, J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI+) m/z 452 (M+H)<+>; (APCI-) m/z 486

(M+Cl)

Example 4 65

( R )- 2-( 3, 4- Difluorophenyl)- 4-( 3- hydroxy- 2- methylpropoxy)- 5-[ 4-( aminosulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound was prepared according to the procedure in Example 464 starting from (R)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3 (2H)-pyridazinone instead of (S)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone ( yield: 30 mg, 20%). <1->H NMR (300 MHz, DMSO-d6) δ 0.76 (d, J = 7 Hz, 3H), 1.81 (sextet (J = 7 Hz, 1H), 3.22 (t, J = 6 Hz, 2H), 4.28 (dd, J = 6 Hz and 12 Hz, IH), 4.40 (dd, J 6 Hz and 12 Hz, IH), 4.50 (t, J = 6 Hz , IH), 7.51 (m, 3H), 7.61 (m, IH), 7.80 (rn, IH), 7.84 (d, J= 9 Hz, 2H), 7.95 (d , J = 9 Hz, 2H), 8.20 (s, 1H). MS (APCI+) m/z 452 (M+H)<+>; (APCI-) m/z 486 (M+Cl)-. Anal calcd for C20H19F2N3O5S: C, 53.21; H, 4.24; N, 9.30 Found: C, 53.45; H, 5.53; N, 9.50.

Example 4 66

2-( 4- Fluorophenyl)- 4-( 4- hydroxy- 3- methylbutoxy)- 5-[ 4-( methylsulphonyl) phenyl]- 3( 2H)- pyridazinone.

The title compound was prepared according to the method described in Example 178, using 2-methyl-1,4-butanediol instead of 2-ethyl-1-hexanol and separating the regioisomeric products by preparative TLC using silica gel with ethyl acetate:hexanes (4 /1). 3-H NMR (300 MHz, CDCl 3 ) δ 0.87 (d, J = 8.1 Hz, 3H), 1.48-1.87 (rn, 4H), 3.13 (s, 3H), 3 .41 (dd, J = 6.3, 13.5 Hz, IH), 3.46 (dd, J = 6.3, 13.5 Hz, IH), 4.48-4.63 (m, 2H ), 7.15-7.24 (m, 2H), 7.58-7.66 (m, 2H), 7.79 (d, J=10.5 Hz, 2H) , 7.91 (s, IH) ,

8.07 (d, J « 10.5 Hz, 2H). MS (APCI+) m/z 447 (M+H)<+>.

Example 4 67

2-( 3, 4- difluorophenyl)- 4-( 3- oxobutoxy)- 5-[ 4-( methylsulfonyl) phenyl]- 3( 2H)- pyridazinone

The title compound is prepared according to the method in Example 4 60 using 4-hydroxy-2-butanone instead of acetol. (yield: 95.0 mg, 21%). Temp. 134-135 °C. <*>H NMR (300 MHz, CDCl 3 } 5?2.06 (s, 3H), 2.81 (t, J = 9 Hz, 2H), 3.13 (s, 3H), 4.75 (t , J = 9 Hz, 2H), 7.30 (m, IH), 7.45 (m, IH), 7.58 (m, IH), 7.73 (d, J = 9 Hz, 2H) , 7.89 (s, 1H), 8.05 (d, J = 9 Hz, 2H).MS (DCI-NH3) m/z 449 (M+H)<+>, 466 (M+NH4)<+ .> Anal calcd for C21H18F2N2O5S: C, 56.25; H, 4.02; N, 6.25 Found: C, 55.97; H, 4.17; N, 6.11.

Example 4 68

2-( 4- Fluorophenyl)- 4-( 3- oxobutoxy)- 5-[ 4-( methylsulfonyl)-phenyl]- 3( 2H)- pyridazinone

The title compound is prepared according to the method in Example 460 starting from 2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone instead of 2-(3,4-difluorophenyl}-4 -hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and using 4-hydroxy-2-butanone instead of acetol (yield: 85.0 mg, 20%). M.p. 133- 136° C. <1>H NMR (300 MHz, CDCl3) δ 2.04 (s, 3H), 2.80 (t, J = 9 Hz, 2H), 3.13 (s, 3H), 4 .76 (t, J = 9 Hz, 2H) , 7.20 (t, J = 9 Hz, 2H) , 7.55 (m, 2H) , 7.75 (d, J = 9 Hz, 2H) , 7.91 (s, 1H), 8.05 (d, J = 9 Hz, 2H). MS (DCI-NH3) m/z 431 (M+H)<+>, 448 (M+NH4)"1 ". Anal. calcd. for C21H19FN2O5S: C, 58.60; H, 4.42; N, 6.52. Found: C, 58.87; H, 4.55; N, 6.51.

Determination of prostaglandin inhibitorinq

Preparation and administration of the compounds

For oral administration, the test compounds were suspended on the same day of use in 100% polyethylene glycol (PEG 400) with a motorized homogenizer equipped with a Teflon-coated pestle (TRI-R Instrument, Jamaica, NY).

To compare the average responses from the treatment groups, analysis of variance was used. Percent inhibition values were determined by comparing the individual mean treatment values with the mean for the control group. Linear regression was used to determine IC50-/ED50 values in appropriate studies.

EIA determination of prostaglandins

The EIA reagents for prostaglandin determination were purchased from Perseptive Diagnostics, (Cambridge, MA). The prostaglandin E2~ levels (PGE2) in the lavage fluids were determined after the samples had been dried under nitrogen and reconstituted with sample buffer. The PGE2~ levels in the enzyme samples or cell culture media were measured in relation to standards prepared in the same environment. The immunoassays were performed as recommended by the manufacturer. The EIA test was performed in 96-well microtiter plates

(Nunc Roskilde, Denmark), and the optical density was measured using a microplate reader (Vmax, Molecular Devices Corp., Menlo Park, CA).

Recombinant human PGHS-1 and PGHS-2 enzyme studies

Inhibition of prostaglandin biosynthesis in vitro was evaluated using enzyme assays of recombinant human Cox-1 (r-hu Cox1) and Cox-2 (r-hu Cox2). Representative compounds dissolved in DMSO {3.3% v/v) were pre-incubated with microsomes from recombinant human PGHS-1 or PGHS-2 expressed in the baculovirus/Sf9 cell system (Gierse, J. K., Hauser, S. D. , Creely, D. P., Koboldt, C, Rangwala, S., H., Isakson, P. C. and Seibert, K. Expression and selective inhibition of the constitutive and inducible forms of cyclooxygenase, Biochem J. 1995, 305: 479.), together with the cofactors phenol (2 mM) and hematin (1 µM) for 60 min before addition of 10 µM arachidonic acid. The reaction was allowed to proceed for 2.5 minutes at room temperature before being quenched with HCl and neutralized with NaOH. PGE2 production in the presence and absence of the drug was determined by EIA analysis. EIA was performed in 96-well microtiter plates (Nunc Roskilde, Denmark), and optical density was measured using a microplate reader (Vmax, Molecular Devices Corp., Menlo Park, CA). The EIA reagents for the prostaglandin determination were purchased from Perseptive Diagnostics (Cambridge, MA). The PGE2~ levels were measured in relation to standards produced in the same environment. The immunoassays were performed as recommended by the manufacturer.

The data illustrating the inhibition of prostaglandin biosynthesis in vitro by compounds of this invention are shown in Table 1. The compounds are indicated by the numbers of the examples. Column 2 shows percent Cox-1 inhibition at the particular micromolar dose level, and column 3 shows percent Cox-2 inhibition at the indicated nanomolar dose level. The Cox-2 inhibition values in parentheses indicate the IC 50 values.

See attached table

IL-lfl-induced PGE2 production in WISH cells

Human amniotic WISH cells were grown to 80% confluence in 48-well plates. After removal of the growth medium and two washes with Gey's balanced salt solution, 5 ng of IL-lfi/ml (UBI, Lake Placid, NY) was added to the cells with or without test compound in DMSO (0.01% v/v) in Neuman- Tytell's serum-free medium (GIBCO, Grand Island, NY). After 18 hours of incubation to account for the maximum induction of PGHS-2, the conditioned medium was removed and examined for PGE2 content by EIA assay as described above.

Monocyte U937 cells (ATCC, Rockville, MD) were cultured similarly to the WISH cells. After the incubation, the conditioned medium was removed and examined for Cox-1 content by EIA assay as described above.

The data illustrating the inhibition of prostaglandin biosynthesis in vitro by compounds of this invention are shown in Table 2. The U937 values indicate percent Cox-1 inhibition at the indicated micromolar dose level while the values in parentheses indicate the IC 50 values. The WISH cell values indicate percent inhibition at the indicated micromolar dose levels while the values in parentheses indicate the IC50 values.

Cyclooxygenase-I study with human whole blood platelets

(HWCX)

Blood from normal healthy volunteers is drawn into tubes containing ACD ("acid citrate dextrose") as an anti-coagulant. This blood is centrifuged at 175 x g to prepare platelet-rich plasma. The platelet-rich plasma is then centrifuged at 100 x g to pellet the white blood cells, leaving the platelets in the supernatant. The supernatant is placed on a pad of 0.7 ml of 10% bovine serum albumin in Tyrode's solution (Gibco; Grand Island, NY) and then centrifuged at 1000 x g. The resulting supernatant from this centrifugation is then removed, and 11 ml of Tyrode's solution is added to the remaining platelet pellets. The platelets are then aliquoted at 120 µl in a 96 well plate. The test compounds are added and allowed to pre-incubate for 10 minutes. At the end of this pre-incubation period, the calcium ionophore A23187 is added up to a final concentration of 8.8 pM and incubation is continued for ten minutes. The reaction is stopped by the addition of cold 6 mM EDTA, the incubation mixture is centrifuged at 220 x g, and the supernatants are then analyzed for thromboxane using a commercial kit from Cayman Chemical (Ann Arbor, MI).

See attached table

Carrageenan-induced paw edema (CPE) in rats

Hindpaw edema was induced in male rats as described by Winter et al., Proe. Soc. Exp. Biol. Med., 1962, 111, 544. Briefly, male Sprague-Dawley rats weighing between 170 and 190 g were given test compounds orally 1 hour before sub-plantar injection of 0.1 ml of 1% sodium carrageenan {lambda carrageenan, Sigma Chemical Co., St Louis, MO) in the right hind paw. The right hindpaw volume (ml) was measured immediately after the injection of carrageenan to measure the baseline volume using a Buxco plethysmograph (Buxco Electronics, Inc., Troy, NY), three hours after the injection of carrageenan, the right paws were measured at new, and the paw edema was calculated for each rat by subtracting the zero-time reading from the three-hour reading. Data are presented as mean percent inhibition +/- SEM. Statistical significance of the results was analyzed using Dunnett's multiple comparison test where p< 0.05 was considered to be statistically significant.

Model for pleural inflammation with carrageenan (CIP) in rats

Pleural inflammation was induced in male adrenalectomized Sprague-Dawley rats according to the method described by Vinegar et al., Fed. Pro. 1976, 35, 2447-2456. The animals were dosed orally with test compounds, 30 minutes before the intrapleural injection of 2% lambda-carrageenan (Sigma Chemical Co., St. Louis MO). Four hours later, the animals were euthanized, and the pleural cavities were flushed with ice-cold saline. The lavage fluid was then added to two volumes of ice-cold methanol (final methanol concentration 66%) to dissolve the cells and precipitate protein. The eicosanoids were determined by EIA as described above.

The data illustrating the inhibition of prostaglandin biosynthesis in vivo by the compounds of this invention are shown in Table 3. The values given are percentage inhibition at 10 milligrams per kilograms of body weight.

Model for carrageenan-induced prostaglandin biosynthesis with air sacs (CAP)

Air sacs are formed in the back of male Sprague Dawley rats by injecting 20 mL of sterile air on day 0. Three days later, the sac was reinflated with an additional 10 mL of sterile air. On day 7, 1 ml of saline containing 0.2% lambda-carrageenan (Sigma Chemical Co.) is injected into the bag to induce the inflammatory reaction characterized by the release of prostaglandins. The test compounds are dosed at 0.1 to 10 mg/kg 30 minutes before the carrageenan. Four hours after the carrageenan injection, the bag is flushed and the levels of prostaglandins are determined by an enzyme immunoassay using commercially available kits. Percent inhibitions are calculated by comparing the response of the vehicle-treated animals to the compound-treated animals. The Cox-2 inhibition values in parentheses indicate the EDsn values.

The data illustrating the inhibition of prostaglandin biosynthesis in vivo by the compounds of this invention are shown in Table 3. The values given are the percentage inhibition at 10 milligrams per kilogram of body weight for CIP and CPE tests and at 3 milligrams per kilograms of body weight for CAP testing.

See attached table

Pharmaceutical compositions

The present invention also provides pharmaceutical compositions comprising compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions according to the present invention comprise a therapeutically effective amount of a compound according to the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation aid of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; measured; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; sunflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's Solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and perfuming agents, preservatives and antioxidants, may also be present in the composition, according to a person skilled in the art person's procedures and assessment. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intra-cisternally, intravaginally, intraperitoneally, topically (such as by means of powders, ointments or drops), buccally or as an oral or nasal spray.

The compounds according to the present invention can potentially be useful in the treatment of several diseases or disease states such as inflammatory diseases, dysmenorrhoea, asthma, premature labour, adhesions and especially pelvic adhesions, osteoporosis and ankylosing spondylitis. Current Drugs Ltd, ID Patent Fast Alert, AG16, May 9, 1997.

The compounds according to the present invention can also potentially be useful in the treatment of cancer and especially colon cancer. Pro. Nati. Acad. Sei., 94, pp. 3336-3340, 1997.

The compounds of the present invention may be useful for providing a pharmaceutical composition for inhibiting prostaglandin biosynthesis, which composition comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, an ester or a prodrug thereof and a pharmaceutically acceptable carrier.

The compounds of the present invention may be useful for providing a pharmaceutical composition for inhibition of prostaglandin biosynthesis, comprising a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt, ester or prodrug thereof and a pharmaceutically acceptable carrier.

The compounds of the present invention may be useful for providing a pharmaceutical composition for inhibition of prostaglandin biosynthesis, comprising a therapeutically effective amount of a compound of formula III or a pharmaceutically acceptable salt, ester or prodrug thereof and a pharmaceutically acceptable carrier.

In addition, the compounds of the present invention may be useful in providing a method of inhibition

of prostaglandin biosynthesis, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester or prodrug thereof.

The compounds of the present invention may be useful in providing a method of inhibiting prostaglandin biosynthesis, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula II or a pharmaceutically acceptable salt, ester or prodrug hence.

The compounds of the present invention may be useful in providing a method of inhibiting prostaglandin biosynthesis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula III or a pharmaceutically acceptable salt, ester or prodrug hence.

In addition, the compounds of the present invention may be useful in providing a method for treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound having formula I.

In addition, the compounds of the present invention may be useful in providing a method for treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound having formula II.

In addition, the compounds of the present invention may be useful in providing a method for treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound having formula III.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents that are usually used in the art, such as for example water or other solvents, solubilizing agents and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, peanut, corn, germ, olive, castor, sesame oil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and perfumes.

Injectable preparations, such as, for example, sterile injectable aqueous or oily suspensions can be formulated according to what is known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, isotonic sodium chloride solution and the like. In addition, sterile, solid oils are usually used as a solvent or suspension medium. For this purpose, any solid oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the production of injectable preparations.

The injectable formulations can be sterilized by any method known in the art, such as, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The absorption rate of the drug then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are prepared by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio between drug and polymer and the nature of the polymer used, the rate of drug release can be regulated. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with the body's tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum or the vaginal cavity and releases the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is usually mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerating agents such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbing agents such such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium tearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

Solid compositions of a similar type can also be used

as fillers in soft and hard filled gelatin capsules using such excipients as, for example, lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as, for example, lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one or more excipients as indicated above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release-regulating coatings and other coatings that are well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compounds can be mixed with at least one inert diluent such as, for example, sucrose, lactose or starch. Such dosage forms can also include, which is normal practice, further substances than inert diluents, e.g. tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also include buffering agents. They may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient(s) only or preferably in a certain part of the intestinal system, possibly in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound according to this invention include

ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or plasters. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer that may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also intended to be included within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound according to this invention, excipients such as, for example, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to the compounds according to this invention, excipients such as for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The sprays may also contain common propellants such as chlorofluorohydrocarbons.

Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption-promoting agents can also be used to increase the flow of the compound through the skin. The rate can be regulated by either providing a rate-regulating membrane or by dispersing the compound in a polymer matrix or gel.

According to the methods of treatment, a patient, such as a human or an animal, is treated by administering to the patient a therapeutically effective amount of a compound according to the invention, in such amounts and for as long as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound according to the invention is meant a sufficient amount of the compound to provide the desired relief, in a reasonable benefit/risk ratio applicable to any medical treatment. However, it will be understood that the total daily consumption of the compounds and compositions according to the present invention must be determined by the attending physician and be within the scope of sound medical judgment. The specific therapeutically effective dose level for each individual patient will depend on many different factors including the disorder being treated and its severity; the activity of the individual composition used; the actual composition used; the patient's age, body weight, general state of health, gender and diet; the time of administration, the route of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or simultaneously with the specific compound; and similar factors well known in the medical art.

The total daily dose of the compounds of this invention administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.001 to about 1000 mg/kg body weight per day or more, preferably from approx. 0.1 to approx.

100 mg/kg body weight for oral administration or 0.01 to approx. 10 mg/kg for parenteral administration per day. Single-dose mixtures may contain such quantities or submultiples thereof as will constitute the daily dose.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the patient and the particular form of administration.

The reagents necessary for the synthesis of the compounds of the invention are readily available from several different commercial sources such as Aldrich Chemical Co.

{Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc.

(Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) {New Brunswick, NJ 08901); Pfaltz and Bauer (Vannbury, CT. 06708). Compounds that are not commercially available can be prepared by using known methods from the chemical literature.

Claims (30)

1. Compound of Formula I: where X is O; R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8- alkylcarbonyl-Ci-Ce-alkyl, halogen-Cl-Ce-alkyl, halogen-C2-C9-alkenyl, C3-C7-cycloalkyl optionally substituted with Ci-Cg-alkyl, C3-C7-cycloalkyl-Ci-C6-alkyl, C3-C7-cycloalkenyl, C3-C7-cycloalkenyl-C1-C6-alkyl, phenyl, phenyl-C1-C6-alkyl, phenyl-C1-C6-alkanoyl, phenyl-C2-C7-alkynyl, phenyl-C2- C7-alkenyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, C1-C8-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkoxy, C2-C7-alkenyl, formyl , CN, NO2, CF3, OH, C1-C6-alkanoyloxy, C1-C6-alkoxy-imino, di-C1-C6-alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl, heterocyclyl-C1-C6- alkyl, heterocyclyloxy-Ci-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, Ci-C6-alkyl or NO 2 ), dihydroindenyl, adamantyl or adamantyloxycarbonyl; R<2> is where X<1> is SO or SO2, R^ is C1-C6-alkyl, halo-C1-C6-alkyl, amino or -N=CH (NR10Rn) where R<10> and Ru are C1-C6-alkyl; X 1 is hydrogen, halogen, or C 1 -C 6 alkyl; R<1> is C1-C8-alkoxy, C1-C8-alkylamino, C2-C6-alkylenyloxy, C2-C8-alkynyloxy, C2-C8-alkenyl, C1-C8-alkyl, C2-CB-alkynyloxy, C2-C8-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkenyl, C3-C7-cycloalkoxy optionally substituted with C1-C6-alkyl, C3-C7-cycloalkyl-C1-C6-alkoxy, C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkylthio-Ci-C6-alkyl, C3-C7-cycloalkylthio, C3- C7-Cicloalkylamino, C1-C6-Alkoxy-C1-C6-Alkoxy, C1-C6-Alkylthio-C1-C6-Alkoxy, Halo-C1-C6-Alkylthio, C1-C8Alkylthio, C1-C6-Alkoxy-Ci-C6- alkylamino, hydroxy-Ci-C6-alkylamino, cyano-Ci-C6-alkylamino, di-Ci-C6-alkylamino-Ci-C6-alkoxy, hydroxy-Ci-C6-alkoxy, Ci-Ce-alkanoyl-Ci-Ce- alkoxy, phenyl-Ci-C6-alkylamino, phenyl, phenylamino, phenyl-Ci-C6-alkyl, phenoxy, phenoxy-Ci-C6-alkyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6-alkyloxy, phenylthio, phenyl-Cl-Ce-alkylthio or benzoyloxy-Ci-C6-alkyl {where said phenyl groups are optionally substituted with one or more groups selected from halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C7-alkenyl, CN , CF3, NO2, C1-C6-alkylsulfonyl, di-C1-C6-alkylamino, phenyl, carbamoyl or C i-C6-alkanoyl-amino), heterocyclyl, heterocyclyloxy, heterocyclyl-amino, heterocyclyl-C1-C8-alkylamino, heterocyclylthio, heterocyclyloxy, heterocyclyl-C1-C6-alkoxy, (where heterocyclyl is selected from morpholinyl, pyridyl, thienyl, dihydroisobenzofuranyl , furyl, piperidinyl, triazolyl, benzofuranyl, pyrrolidinyl, tetrahydro-furfuryl or imidazolyl, which heterocyclic groups are optionally substituted with one or more groups selected from oxo, hydroxy, halogen or C1-C6-alkoxy), or R<1> is dihydroindenylamino or in-danyloxy; R<3> is H or C1-C6 alkyl; or a pharmaceutically acceptable salt or ester thereof. 2. Compound according to claim 1 with the formula II: where Z is a group of the formula: where X<1> is SO2 or SO, and r<9> is C1-C6-alkyl, halo-C1-C6- alkyl or amino; X<2> is hydrogen, halogen or C 1 -C 6 alkyl; R is as defined in claim 1; R<1> is hydroxy-C1-C6-alkoxy or hydroxy-C1-C6-alkyl amino; R<3> is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt or ester thereof. 3. Compound according to claim 1 with the formula III: in which X<1> is SO 2 or SO, and R<9> is C 1 -C 6 alkyl or amino; X<2> is hydrogen or halogen; R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkyl- carbonyl-Ci-C8-alkyl, Ci-C6-alkylsulfonylphenyl-Ci-Ce-alkyl, halogen-Ci-Cø-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C6-alkyl, phenyl, f en <y>l~C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6-alkyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, Ci-Cg-alkyl, Ci -C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkoxy, C2-C7-alkenyl, formyl, CN, NO2, CF3, OH, C1-C6-alkanoyloxy, C1-C6-alkoxyimino, di-Cl-Ce -alkylamino, OCF3, aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl, heterocyclyl-Ci-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkyl or NO 2 ), dihydroindenyl, adamantyl or adamantyloxycarbonyl; R<1> is hydroxy-C1-C6-alkylamino or hydroxy-C1-C6-alcoc sew; R<3> is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt or ester thereof. 4. Compound according to claim 1, wherein X<1> is SO2 or SO, and R<9> is C1-C6 alkyl or amino; X<2> is hydrogen or halogen; R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkyl- carbonyl-Ci-CB-alkyl, Ci-Cg-alkylsulfonylphenyl-Ci-Cg-alkyl, halo-Ci-Cs-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-Cg-alkyl, phenyl, phenyl -C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-Ci-C6-alkyl (where said phenyl groups are optionally substituted with one or more groups selected from halogen, Ci-C6-alkyl, Ci-C6-alkylthio, C 1 -C 3 -alkylsulfonyl, C 1 -C 5 -alkyl, C 2 -C 7 -alkenyl, formyl, CN, NO 2 , CF 3 , OH, C 1 -C 6 -alkanoyloxy, C 1 -C 6 -alkoxyimino, di-C 1 -C 6 -alkylamino, OCF 3 , aminosulfonyl, phenyl, phenoxy or pyrrolyl), heterocyclyl or heterocyclyl-Ci-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl or NO2); R<1> is hydroxy-C1-C6-<a>lkoxy; R<3> is hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt or ester thereof. 5. Compound according to claim 1, wherein X<1> is SO2 or -SO-, and R<9> is C1-C6 alkyl or amino; X<2> is hydrogen or halogen; R is C1-C8-alkyl, C2-C9-alkenyl, C2-C9-alkynyl, C1-C8-alkyl- carbonyl-Ci-C8-alkyl, Ci-C6-alkylsulfonylphenyl-Ci-C6-alkyl, halo-Ci-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-Cg-alkyl, phenyl, phenyl- C2-C7-alkenyl, phenyl-C2-C7-alkynyl, phenyl-Ci-Ce-alkyl{where said phenyl groups are optionally substituted with one or more groups chosen from halogen, Ci-Ce-alkyl, Ci-C6-alkylthio, Ci -Ce alkylsulfonyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, formyl, CN, NO 2 , CF 3 , OH, C 1 -C 6 -alkanoyloxy, C 1 -C 6 -alkoxyimino, di-C 1 -C 6 -alkylamino, OCF 3 , aminosulfonyl , phenyl, phenoxy or pyrrolyl), heterocyclyl or heterocyclyl-Ci-C6-alkyl (where said heterocyclyl groups are selected from pyridyl, quinolyl, thiazolyl, thienyl, benzothienyl, furyl or tetrahydropyranyl and where these groups are optionally substituted with one or more groups selected among halogen, C.1-C.sub.6 alkyl or NO.sub.2); R<1> is hydroxy-C1-C8-alkylamino or hydroxy-C1-C6-alcoc sew; and R<3> is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt or ester thereof. 6. Compound according to claim 1, wherein X<1> is SO2 or SO, and R<9> is C1-C6 alkyl or amino; X<2> is hydrogen or halogen; R is C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, optionally phenyl substituted with halogen, heterocyclyl or heterocyclyl-C 1 -C 6 alkyl; R 1 is hydroxy-C 1 -C 6 -alkoxy or hydroxy-C 1 -C 6 - alkylamino; R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 7. Compound according to claim 1, wherein X<1> is SO 2 or SO, and R<9> is C 1 -C 6 alkyl or amino; X<2> is hydrogen or halogen; R is C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, optionally phenyl substituted with halogen, heterocyclyl or heterocyclyl-C 1 -C 6 alkyl; R 1 is hydroxy-C 1 -C 6 alkoxy; and R 3 is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 8. Compound according to claim 1, wherein x<1> is SO 2 , and R<9> is C 1 -C 6 alkyl or amino; X<2> is hydrogen or halogen; R is halo-Ci-Ce-alkyl, phenyl optionally substituted with halogen, heterocyclyl or heterocyclyl-C 1 -C 6 alkyl; R 1 is hydroxy-C 1 -C 8 -alkoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 9. Compound according to claim 1, wherein X<1> is SO2, and R<9> is C1-C8 alkyl or amino; X<2> is hydrogen or halogen; R is C1-C6-alkyl, C2-C8-alkenyl, C2-C9-alkynyl, halogen-Cj- C 5 -alkyl, phenyl or phenyl-C 1 -C 6 alkyl; R<1> hydroxy-C 1 -C 8 -alkoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 10. Compound according to claim 1, wherein X<1> is SO2, and R<9> is C1-C6 alkyl or amino; X<2> is hydrogen or fluorine; R is halogen C 1 -C 6 alkyl, phenyl or C 1 -C 8 alkyl; R<1> is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl- butoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 11. Compound according to claim 1, wherein X<1> is SC-2, and R9 is C1-C6 alkyl, X<2> is hydrogen or fluorine; R is C1-C8-alkyl, C2-C9-alkenylr C2-C9-alkynyl, halogen-Ci- C 1 -C 6 alkyl, phenyl or phenyl-C 1 -C 6 alkyl; R 1 is hydroxy-C 1 -C 6 alkoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 12. Compound according to claim 1, wherein X<1> is SO2, and R<9> is amino; X<2> is hydrogen or fluorine; R is C 1 -C 8 -alkyl, C 2 -C 9 -alkenyl, C 1 -C 8 -alkynyl, halo-C 1 - C8-alkyl, phenyl or phenyl-C1-C8-alkyl; R<1> is hydroxy-C1-C6-alkoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 13. Compound according to claim 1, wherein X<1> is -SO2- and R<9> is methyl; X<2> is hydrogen; R is t-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl or CF3CH2-; R 1 is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl- butoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 14. A compound according to claim 1, wherein X<x> is -SO2- and R<9> is amino; X<2> is hydrogen; R is t-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl or CF3CH2-; R 1 is 2-hydroxy-2-methyl-propoxy or 3-hydroxy-3-methyl- butoxy; and R<3> is hydrogen; or a pharmaceutically acceptable salt or ester thereof. 15. Compound according to claim 1, selected from the group consisting of of: 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; 2-(4-fluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone; 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methylpropoxy)-5-[4- (aminosulfonyl)phenyl]-3(2H)-pyridazinone; (R)-2-{3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; (S)- 2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone; (R)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone; (S)- 2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone; or a pharmaceutically acceptable salt or ester thereof. 16. A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound according to claim 2 and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound according to claim 3 and a pharmaceutically acceptable carrier. 19. Use of a therapeutically effective amount of a compound according to claim 1 for the preparation of a medicament for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer. 20. Use of a therapeutically effective amount of a compound according to claim 2 for the preparation of a medicament for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer. 21. Use of a therapeutically effective amount of a compound according to claim 3 for the preparation of a medicament for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer. 22. Process for producing a compound according to claim 3 or a pharmaceutically acceptable salt, an ester or a prodrug thereof with the formula: wherein X, X1, X<2>, R, R<1>, R<3> and R<9> are as defined in claim 1; characterized in that it comprises the step of reacting a compound of Formula III, where R is hydrogen, with an alkylating agent. 23. Method according to claim 22, characterized in that the alkylating agent has the formula R<99->Q where Q is a leaving group, and R<99> is selected from the group consisting of methyl, ethyl, 1,1,1-trifluoroethyl , cyclopropylmethyl, 3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl, 2,2-dimethyl-3-oxo-4-butyl, 2 ,3,3,4,4,4-hexafluoro-n-buten-l-yl, propargyl, phenylpropargyl, phenyl, phenethyl, 1-phenylpropen-3-yl, benzyl, α-methyl-4-fluorobenzyl, 2,3 ,4,5,6-pentafluorobenzyl, 4-trifluoromethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl, 2-trifluoromethylbenzyl, 2,4-difluorobenzyl, 2,4-di-fluorophenacyl, 4-trifluoromethylphenacyl, phenacyl, 4-carboxyphenacyl , 4-chlorophenacyl, 4-cyanophenacyl, 4-diethylamino-phenacyl, 3-thienylmethyl, 5-methylthien-2-ylmethyl, 5-chlorothien-2-ylmethyl, 2-benzo[b]thienylmethyl, 3-benzothienacyl, 5-chlorothiazole -2-ylmethyl, 5-methylthiazol-2-ylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, quinolin-2-ylmethyl and fluoroquinolin-2-ylmethyl. 24. Method according to claim 22, characterized in that the alkylating agent has the formula R<99->Q where Q is a leaving group, and R<99> is selected from the group consisting of methyl, ethyl, 1,1,1-trifluoroethyl , cyclopropylmethyl, 3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluoro-n -buten-1-yl, propargyl, phenylpropargyl, phenyl, phenethyl, 1-phenylpropen-3-yl, benzyl, α-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl, 4-trifluoromethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl, 2,4-difluorobenzyl, 2,4-difluorophenacyl, 4-trifluoromethylphenacyl, phenacyl, 4-carboxyphenacyl, 4-chlorophenacyl, 4-cyanophenacyl, 4-diethylaminophenacyl, 3- thienylmethyl, 5-methylthien-2-ylmethyl, 5-chlorothien-2-ylmethyl, 2-benzo[b]thienylmethyl and 3-benzothienacyl. 25. Method according to claim 22, characterized in that the alkylating agent has the formula R<99->Q where Q is a leaving group, and r" is selected from the group consisting of 1,1,1-trifluoroethyl, 3-(2- methyl) propenyl, 4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluoro-n-buten-1-yl, propargyl , phenylpropargyl, phenyl, benzyl, α-methyl-4-fluorobenzyl, 2,3,4,-5,6-pentafluorobenzyl, 4-fluorobenzyl, 4-fluorophenyl, 2.4-difluorobenzyl, 3-thienylmethyl, 5-methylthien-2-ylmethyl, 5-chlorothien-2-ylmethyl and 2-benzo[b]thienylmethyl. 26. Method according to claim 22, characterized in that the alkylating agent has the formula R<99->Q where Q is a leaving group, and R<99> is selected from the group consisting of 1,1,1-trifluoroethyl, phenyl, benzyl , α-methyl-4-fluorobenzyl, 4-fluorobenzyl, 4-fluorophenyl and 2,4-difluorobenzyl. 27. Method according to claim 22, characterized in that the alkylating agent has the formula R<99->Q where Q is a leaving group, and R<99> is selected from the group consisting of 1,1,1-trifluoroethyl, benzyl and 4 -fluorophenyl. 28. Process for the regioselective preparation of a 4,5-substituted pyridazone characterized in that it comprises the steps a) reacting a compound with the formula wherein R is a C 1 -C 6 alkyl or phenyl group, and X is a leaving group, with a nucleophilic agent to replace the X group; b) converting -OR<9>^ to a leaving group; and c) reacting the compound with another nucleophilic agent to provide the 4,5-substituted pyridazone. 29. Method according to claim 28, characterized in that the benzyl group is removed using a Lewis acid. 30. Process for the regioselective preparation of a 4,5-substituted pyridazone characterized in that it comprises the steps of treating a compound with the formula with a hydrazine of the formula RNHNH2 to provide the pyridazone of the formula: wherein X, X<1>, X<2>, R, R<1>, R<3> and R<9> are as defined in claim 1; or a pharmaceutically acceptable salt, ester or prodrug thereof.