KR20010023196A - Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors - Google Patents

Abstract

The present invention relates to pyridazinone compounds which are cyclooxygenase (COX) inhibitors and in particular selective inhibitors of cyclooxygenase-2 (COX-2), while COX-2 is an inducible isotype associated with inflammation Cyclooxygenase-1 (CXO-1), in contrast to its constitutive isoform, is an important "housekeeping" enzyme in several tissues, including the gastrointestinal (GI) tract and kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and kidney side effects found in currently commercially available non-sterile anti-inflammatory agents (NSAIDs).

Description

Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors as prostaglandin endoperoxide H synthase biosynthesis inhibitors

Prostaglandins are very powerful substances that often exhibit a variety of biological effects in the nanomolar to picomolar concentration ranges. The discovery of two forms of the prostaglandin endoperoxide H synthase, isoenzyme PGHS-1 and PGHS-2, which catalyzes the oxidation of arachidonic acid to biosynthesize prostaglandins. A new study was undertaken. These isozymes have been found to have different gene regulation and clearly follow different prostaglandin biosynthetic pathways. The PGHS-1 pathway is constitutively expressed in most cell types. It responds to produce prostaglandins, which play a role in regulating critical events in vascular homeostasis and also maintaining normal gastric and renal function. The PGHS-2 pathway involves induction mechanisms associated with inflammation, mitosis and ovulation.

Prostaglandin inhibitors are provided for the treatment of pain, fever and inflammation and are useful, for example, in the treatment of rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen, naproxen and phenamate inhibit both isozymes. Inhibition of constitutive enzyme PGHS-1 causes gastrointestinal side effects, including ulcers and bleeding, and kidney problems following long-term treatment. Inhibitors of PGHS-2, an inducible isozyme, can provide anti-inflammatory activity without exhibiting the side effects of PGHS-1 inhibitors.

The problem of side effects associated with NSAID administration has never been resolved in the past. In order to minimize gastric toxicity, enteric epidermal tablets and co-administration with the prostaglandin derivative misoprostol have been attempted. It is advantageous to provide compounds which are inducible isozymes, selective inhibitors of PGHS-2.

The present invention provides novel compounds that are selective inhibitors of PGHS-2.

Summary of the Invention

The present invention describes pyridazinone compounds that are selective inhibitors of cyclooxygenase-2 (COX-2). The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, halo Alkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryl Oxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C (O) R ⁵ ,-(CH ₂ ) _n C (O) R ⁵ , -R ⁶ -R ⁷ ,-(CH ₂ ) _n CH (OH) R ⁵ ,-(CH ₂ ) _n CH (OR ^d ) R ⁵ ,- (CH ₂ ) _n C (NOR ^d ) R ⁵ ,-(CH ₂ ) _n C (NR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NOR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NR ^d R ^e ) R ⁵ ,-(CH ₂ ) _n C≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ ,- (CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -R ⁸ ,-(CH ₂ ) _n (CHX') _m- (CH ₂ ) _n -CX ' ₃ ,-(CH ₂ ) _n ( CHX ') _m- (CH ₂ ) _n -R ⁸ , and-(CH ₂ ) _n -R ²⁰

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic and heterocyclic alkyl,

R ⁶ is alkylene or alkenylene, halo-substituted alkylene or halo-substituted alkenylene,

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl,

R ^d and R ^e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

X 'is halogen,

n is 0 to about 10,

m is 0 to about 5,

One or more groups of R ¹ , R ² and R ³ or ego,

X ¹ is selected from the group consisting of -SO _2- , -SO (NR ¹⁰ )-, -SO-, -SeO _2- , PO (OR ¹¹ )-and -PO (NR ¹² R ¹³ )-,

R ⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH ₂ , -N = CH (NR ¹⁰ R ¹¹ ), dialkylamino, alkoxy, thio, alkylthio, protecting group and alkyl Is selected from the group of protections attached to X ¹ by ren,

X ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl and alkynyl,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl, or R ¹² and R ¹³ are heterocyclic rings having 3 to 6 atoms together with the nitrogen to which they are attached Form the

The other two groups of R ¹ , R ² and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, ilkylthio, alkylthioalkoxy, alkoxy , Alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, Cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy , Arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, hetero Cyclic, heterocyclic alkyl, heterocyclic (alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxy Selected from the group consisting of alkylthio, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro and -YR ¹⁴ ,

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano.

The present invention relates to novel pyridazinone compounds useful for the treatment of cyclooxygenase-2 mediated diseases. More particularly, the present invention relates to a method for inhibiting prostaglandin biosynthesis, in particular induced prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) proteins.

All patents, patent applications, and documents cited herein are all incorporated by reference. In case of inconsistency, it will follow the description herein, including definitions.

The present invention describes pyridazinone compounds that are selective inhibitors of cyclooxygenase-2 (COX-2) as cyclooxygenase (COX) inhibitors. COX-2 is an inducible isoform associated with inflammation, which is a constitutive isotype of cyclooxygenase, an important "housekeeping" enzyme present in various tissues, including the gastrointestinal (GI) tract and kidneys. Contrast with 1 (COX-1).

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof:

Formula I

In the above formula,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, halo Alkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryl Oxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C (O) R ⁵ ,-(CH ₂ ) _n C (O) R ⁵ , -R ⁶ -R ⁷ ,-(CH ₂ ) _n CH (OH) R ⁵ ,-(CH ₂ ) _n CH (OR ^d ) R ⁵ ,- (CH ₂ ) _n C (NOR ^d ) R ⁵ ,-(CH ₂ ) _n C (NR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NOR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NR ^d R ^e ) R ⁵ ,-(CH ₂ ) _n C≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ ,- (CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -R ⁸ ,-(CH ₂ ) _n (CHX') _m- (CH ₂ ) _n -CX ' ₃ ,-(CH ₂ ) _n ( CHX ') _m- (CH ₂ ) _n -R ⁸ , and-(CH ₂ ) _n -R ²⁰

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic and heterocyclic alkyl,

R ⁶ is alkylene or alkenylene, halo-substituted alkylene or halo-substituted alkenylene,

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl,

R ^d and R ^e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

X 'is halogen,

n is 0 to about 10,

m is 0 to about 5,

One or more groups of R ¹ , R ² and R ³ or ego,

X ¹ is selected from the group consisting of -SO _2- , -SO (NR ¹⁰ )-, -SO-, -SeO _2- , PO (OR ¹¹ )-and -PO (NR ¹² R ¹³ )-,

R ⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH ₂ , -N = CH (NR ¹⁰ R ¹¹ ), dialkylamino, alkoxy, thiol, alkylthiol, protecting group and alkyl Is selected from the group consisting of protecting groups bonded to X ¹ by len;

X ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl and alkynyl,

R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl, or R ¹² and R ¹³ are heterocyclic rings having 3 to 6 atoms together with the nitrogen to which they are attached Form the

The other two groups of R ¹ , R ² and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, ilkylthio, alkylthioalkoxy, alkoxy , Alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, Cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy , Arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, hetero Cyclic, heterocyclic alkyl, heterocyclic (alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxy Selected from the group consisting of alkylthio, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro and -YR ¹⁴ ,

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano.

In another aspect, the present invention provides a compound of Formula II or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula,

Z is a chemical formula or ego,

X ¹ is selected from the group consisting of -SO _2- , -SO-, -SeO _2- , and -SO (NR ¹⁰ )-,

R ⁹ is a protecting group bound to X ¹ by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, —NHNH ₂ , dialkylamino, alkoxy, thiol, alkylthiol, protecting group and alkylene Selected from the group

R ¹⁰ is selected from the group consisting of hydrogen, alkyl and cycloalkyl,

X ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl and alkynyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, halo Alkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryl Oxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C (O) R ⁵ ,-(CH ₂ ) _n C (O) R ⁵ , -R ⁶ -R ⁷ ,-(CH ₂ ) _n CH (OH) R ⁵ ,-(CH ₂ ) _n CH (OR ^d ) R ⁵ ,- (CH ₂ ) _n C (NOR ^d ) R ⁵ ,-(CH ₂ ) _n C (NR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NOR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NR ^d R ^e ) R ⁵ ,-(CH ₂ ) _n CH≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ , -(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -R ⁸ ,-(CH ₂ ) _n (CHX') _m- (CH ₂ ) _n -CX ' ₃ ,-(CH ₂ ) _n (CHX ') _m- (CH ₂ ) _n -R ⁸ , and-(CH ₂ ) _n -R ²⁰

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic and heterocyclic alkyl,

R ⁶ is alkylene or alkenylene, halo-substituted alkylene or halo-substituted alkenylene,

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl,

R ^d and R ^e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

X 'is halogen,

n is 0 to about 10,

m is 0 to about 5,

R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, ilkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, Alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino , Cycloalkylamino, cycloalkyloxy, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl , Arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic (al Chy) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, Selected from the group consisting of nitro and -YR ¹⁴ ,

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano.

In another embodiment, the present invention provides a compound of Formula III or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula,

X, X ¹ , X ² , R, R ¹ , R ³ and R ⁹ are as defined in formula (I).

In a preferred embodiment, the invention is selected from the group consisting of X ¹ -SO _2- , -SO-, -SeO ₂ -and -SO (NR ¹⁰ )-,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl,-(CH ₂ ) _n C (O) R ⁵ ,-(CH ₂ ) _n C≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ and-(CH ₂ ) _n -R ²⁰ ;

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl,

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl,

R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl,

X 'is halogen,

n is from 0 to about 10,

m is 0 to about 5,

R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cyclo Alkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, aryloxy, heterocyclic, Is selected from the group consisting of heterocyclic alkyl, cyano, nitro and -YR ¹⁴ ,

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, or Pharmaceutically acceptable salts, esters or prodrugs thereof.

In another preferred embodiment the invention is selected from the group consisting of X ¹ -SO _2- , -SO-, -SeO ₂ -and -SO (NR ¹⁰ )-,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl,-(CH ₂ ) _n C (O) R ⁵ and-(CH ₂ ) _n -R ²⁰

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl,

R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl,

n is from 0 to about 10,

R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl , Haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, dia Arylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro and -YR ¹⁴ , and

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-and -NR ¹⁹ is selected from the group consisting of

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, or Pharmaceutically acceptable salts, esters or prodrugs thereof.

In another preferred embodiment the invention is selected from the group consisting of X ¹ -SO _2- , -SO-, -SeO ₂ -and -SO (NR ¹⁰ )-,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl and-(CH ₂ ) _n C (O) R ⁵ ,

R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl,

n is from 0 to about 10,

R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl , Haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, dia Arylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro and -YR ¹⁴ , and

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-and -NR ¹⁹ is selected from the group consisting of

R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of

R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, or Pharmaceutically acceptable salts, esters or prodrugs thereof.

In another preferred embodiment the invention is selected from the group consisting of X ¹ -SO _2- , -SO-, -SeO ₂ -and -SO (NR ¹⁰ )-,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ ,

R ²⁰ is aryl unsubstituted or substituted with halogen,

n is from 0 to about 10,

R ¹ is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, and -YR ¹⁴ ,

Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O)-, -C (O) O-, -NH-, -NC (O)-, and -NR ^Is selected from the group consisting of ¹⁹ ,

R ¹⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

R ³ is hydrogen,

R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano,

R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, or Pharmaceutically acceptable salts, esters or prodrugs thereof.

In another preferred embodiment, the invention is selected from the group X ¹ is -SO _2- , -SO- and -SO (NR ¹⁰ )-,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ ,

R ²⁰ is aryl unsubstituted or substituted with halogen,

n is from 0 to about 10,

R ¹ is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic and heterocyclic alkyl,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino,

X ² is selected from the group consisting of hydrogen and halogen,

X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c ,

R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl,

R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl,

R is selected from the group consisting of haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ ,

R ²⁰ is aryl unsubstituted or substituted with halogen,

n is from 0 to about 10,

Aryl wherein R ¹ is unsubstituted; And aryl substituted with one to three substituents selected from the group consisting of fluorine and chlorine (eg, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, etc.); ; But not limited to

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is selected from the group consisting of alkyl and amino,

X ² is selected from the group consisting of hydrogen and halogen,

X is O,

R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl,

R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, haloalkoxy, arylalkyl, alkyl and aryloxy,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is selected from the group consisting of alkyl and amino,

X ² is selected from the group consisting of hydrogen and fluorine,

R is selected from the group consisting of haloalkyl, aryl and alkyl,

n is from 0 to about 10,

R ¹ is isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neo Aryl (e.g. 4-fluorophenyl) substituted with one to three substituents selected from the group consisting of pentyloxy, isopentyl, aryloxy (e.g. 4-fluorophenoxy), unsubstituted aryl, and fluorine and chlorine; , 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, etc.),

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the invention is selected from the group X ¹ is -SO ₂ -and -SO (NR ¹⁰ )-,

R ⁹ is alkyl,

X ² is selected from the group consisting of hydrogen and fluorine,

X is O,

R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl,

R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl and aryloxy,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is amino,

X ² is selected from the group consisting of hydrogen and fluorine,

X is O,

R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl,

R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl and aryloxy,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is methyl,

X ² is hydrogen,

X is O,

R is selected from the group consisting of tert-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl and CF ₃ CH ₂ ,

R ¹ is aryloxy (eg 4-fluorophenoxy), isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neopentyloxy, isopentyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro- Selected from the group consisting of phenyl,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

In another preferred embodiment, the present invention provides that X ¹ is -SO _2- ,

R ⁹ is amino,

X ² is hydrogen,

X is O,

R is selected from the group consisting of tert-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl and CF ₃ CH ₂ ,

R ¹ is aryloxy (eg 4-fluorophenoxy), isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neopentyloxy, isopentyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro- Selected from the group consisting of phenyl,

Provided is a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R ³ is hydrogen.

Definition of Terms

As used throughout this specification and the appended claims, the following terms have specific meanings.

The term "protecting group" includes "carboxy protecting group" and "N-protecting group". As used herein, the term “carboxy protecting group” means a carboxylic acid protecting ester group that is used to block or protect carboxylic acid functionality during reactions involving other functional moieties of the compound. Carboxy protecting groups are described in Greene, "Protective Groups in Organic Sythesis" pp. 152-186 (1981). In addition, the carboxy protective group can be used as a prodrug such that the carboxy protective group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. tea. T. Higuchi and V. V. stella is described in detail in the context of prodrugs in the literature, incorporated herein by reference ("Pro-drugs as Novel Delivery Systems", Vol 14 of the ACS Symposium Series, American Chemical Society (1975)). It provides a discussion. Such carboxy protection groups are well known to those skilled in the art and are broadly involved in the protection of carboxy groups in the penicillin and cephalosporin fields, as described in US Pat. Nos. 3,840,556 and 3,719,667, which are incorporated herein by reference. Has been used. Examples of esters useful as prodrugs for compounds comprising carboxy groups are described in pages 14-21, of "Bioreversible Carriers in Drug Design: Theory and Application", edited by EB Roche, Pergamon Press, New York (1987). Representative carboxy protecting groups include C ₁ to C ₈ alkyl (eg methyl, ethyl or tertiary butyl, etc.); Haloalkyl; Alkenyl; Cycloalkyl and substituted derivatives thereof (eg cyclohexyl, cyclopentyl, etc.); Cycloalkylalkyl and substituted derivatives thereof (eg, cyclohexylmethyl and cyclopentylmethyl, etc.); Arylalkyl (eg phenethyl or benzyl) and substituted derivatives thereof (eg alkoxybenzyl or nitrobenzyl groups, etc.); Arylalkenyl (eg phenylethenyl, etc.); Aryl and substituted derivatives thereof such as 5-indanyl and the like; Dialkylaminoalkyl (eg, dimethylaminoethyl, etc.); Alkanoyloxyalkyl groups (e.g. acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1- (propionyloxy) -1-ethyl, 1- (p Baloyloxy) -1-ethyl, 1-methyl-1- (propionyloxy) -1-ethyl, pivaloyloxymethyl and propionyloxymethyl and the like); Cycloalkanoyloxyalkyl groups (eg cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl, etc.); Aroyloxyalkyl (eg, benzoyloxymethyl and benzoyloxyethyl, etc.); Arylalkylcarbonyloxyalkyl (eg, benzylcarbonyloxymethyl and 2-benzylcarbonyloxyethyl, etc.); Alkoxycarbonylalkyl (eg, methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, etc.); Alkoxycarbonyloxyalkyl (e.g. methoxycarbonyloxymethyl, tert-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl and 1-cyclohexyloxycarbonyloxy-1-ethyl, etc.) ); Alkoxycarbonylaminoalkyl (eg tertiary butyloxycarbonylaminomethyl, etc.); Alkylaminocarbonylaminoalkyl (eg methylaminocarbonylaminomethyl, etc.); Alkanoylaminoalkyl (eg, acetylaminomethyl, etc.); Heterocyclic carbonyloxyalkyl (eg, 4-methylpiperazinylcarbonyloxymethyl, etc.); Dialkylaminocarbonylalkyl (eg, dimethylaminocarbonylmethyl and diethylaminocarbonylmethyl, etc.); (5- (lower alkyl) -2-oxo-1,3-dioxolen-4-yl) alkyl [e.g. 5-tert-butyl-2-oxo-1,3-dioxolen-4-yl) methyl Etc.] and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl [eg, 5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like]. .

As used herein, the term "N-protecting group" or "N-protected" refers to protecting an amino group or protecting the N-terminus of an amino acid or peptide against an unwanted reaction during the synthesis process. Means a group. Commonly used N-protective groups are described in Greene, "Protective Groups In Organic Synthesis", John Wiley & Sons, New York (1981), incorporated herein by reference. Silver acyl groups (e.g. formyl, acetyl, propionyl, pivaloyl, tertiary butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxy Acetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl and 4-nitrobenzoyl, etc.) sulfonyl groups (e.g. benzenesulfonyl and p-toluenesulfonyl, etc.); carbamate forming groups (E.g. benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyl jade Carbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl , Methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyl Oxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl and phenylthiocarbonyl, etc .; alkyl groups (such as benzyl, triphenylmethyl and benzyloxymethyl, etc.) and silyl groups (such as trimethylsilyl, etc.) Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl ( Cbz).

As used herein, the term “alkanoyl” refers to an alkyl group, as defined above, attached to the parent molecular moiety through a carbonyl (—C (O) —) group. Examples of alkanoyl include acetyl, propionyl and the like.

The term "alkanoylamino" as used herein, means an alkanoyl group, as defined above, attached to an amino group. Examples of alkanoylamino include acetamido, propionylamido and the like.

As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon radical having 2 to 15 carbon atoms and also comprising one or more carbon-carbon double bonds. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkenylene" refers to a divalent group derived from a straight or branched chain hydrocarbon having 2 to 15 carbon atoms and also comprising at least one carbon-carbon double bond. Examples of alkenylene include —CH═CH—, —CH ₂ CH═CH—, —C (CH ₃ ) ═CH— and CH ₂ CH═CHCH ₂ — and the like.

As used herein, the term “alkenyloxy” refers to an alkenyl group, as defined herein, appended to the parent molecular moiety via an oxygen (—O—) bond. Examples of alkenyloxy include isopropenoxy, butenyloxy and the like.

The term "alkoxy" as used herein means R ₄₁ O-, wherein R ₄₁ is a lower alkyl group as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, isobutyloxy, isopentyloxy, tert-butoxy and the like.

The term "alkoxyalkylamino" as used herein, means alkoxy as defined herein, bonded to the parent molecular moiety through an alkylamino. Examples of alkoxyalkylamino include, but are not limited to, ethoxymethylamino, isobutyloxyethylamino and the like.

The term “alkoxyalkoxy” as used herein means R ₈₀ OR ₈₁ O—, wherein R ₈₀ is lower alkyl as defined above and R ₈₁ is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, tert-butoxymethoxy and the like.

As used herein, the term “alkoxycarbonyl” means alkoxy as defined above, attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as defined above, which is attached to the parent molecular moiety through alkenylene. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenylene, ethoxycarbonylpropenylene, and the like.

The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as defined above which is bonded to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl and the like.

The term "alkoxyalkoxyalkenyl" as used herein refers to an alkoxyalkoxy group as defined above which is bonded to an alkenyl radical. Representative examples of alkoxyalkoxyalkenyl groups include methoxyethoxyethenyl and methoxymethoxymethenyl and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group as defined above which is bonded to an alkyl radical as defined above. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

The term "(alkoxycarbonyl) thioalkoxy" as used herein means an alkoxycarbonyl group as defined above which is bonded to a thioalkoxy radical. Examples of (alkoxycarbonyl) thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy, and the like.

As used herein, the terms “alkyl” and “lower alkyl” refer to straight or branched chain alkyl radicals having 1 to 15 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The term "alkylamino" as used herein refers to R ₅₁ NH-, where R ₅₁ is a lower alkyl group, and includes, for example, ethylamino, butylamino and the like.

The term "alkylaminoalkyl" as used herein refers to a lower alkyl radical bonded to an alkylamino group.

As used herein, the term "alkylaminocarbonyl" refers to an alkylamino group as defined above, attached to the parent molecular moiety through a carbonyl (-C (O)-) bond. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.

The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which an alkylaminocarbonyl group is bonded.

The term "alkylcarbonylalkyl" as used herein means R ₄₀ -C (O) -R _41- , wherein R ₄₀ is an alkyl group and R ₄₁ is an alkylene group.

The term "alkylene" means a divalent group derived from a straight or branched chain saturated hydrocarbon having 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH _2- , -CH ₂ CH ₂ -, -CH (CH ₃ )-, -CH ₂ CH ₂ CH _2-, and -CH ₂ C (CH ₃ ) ₂ CH ₂ -and the like.

As used herein, the term “alkylsulfonyl” refers to an alkyl group as defined above, attached to the parent molecular moiety through a sulfonyl (—S (O) ₂ —) group. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.

As used herein, the term "alkylsulfonylalkyl" refers to an alkyl group as defined above, attached to the parent molecular moiety through a sulfonylalkyl (-S (O) ₂ -R-) group. Examples of alkylsulfonylalkyl include methylsulfonylmethyl, ethylsulfonylethyl, isopropylsulfonylethyl and the like.

The term "alkylsulfonylamino" as used herein refers to an alkyl group as defined above which is attached to the parent molecular moiety through a sulfonylamino (-S (O) ₂ -NH-) group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.

The term "alkylsulfonylarylalkyl" as used herein refers to sulfonylalkyl (-S (O) ₂ R ₄₅ R _43- ), where R ₄₅ is aryl and R ₃₃ is alkylene) Through an alkyl group, as defined above, attached to the parent molecular moiety through. Examples of alkylsulfonylarylalkyl include methylsulfonylphenylmethyl, ethylsulfonylphenylmethyl, isopropylsulfonylphenylmethyl and the like.

As used herein, the term "alkylthio" refers to R ₅₃ S-, wherein R ₅₃ is alkyl.

The term "alkylthioalkyl" as used herein, means an alkylthio, as defined herein, appended to the parent molecular moiety through an alkylene group.

The term "alkylthioalkoxy" as used herein means an alkylthio as defined herein, appended to the parent molecular moiety through an alkoxyl group as defined herein.

As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 15 carbon atoms and comprising one or more carbon-carbon triple bonds. Examples of alkynyl include -C≡CH, HC≡C-CH ₂ -and HC≡C-CH (CH ₃ )-and the like.

As used herein, the term "amido" means R ₅₄ -C (O) -NH-, where R ₅₄ is an alkyl group.

The term "amidoalkyl" as used herein means R ₃₄ -C (O) -NHR _35- , wherein R ₃₄ is alkyl and R ₃₅ is alkylene.

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

The term "aminoalkoxy" as used herein refers to an amino group, attached to the parent molecular moiety through an alkoxyl group as defined herein.

The term "aminocarbonyl" as used herein refers to H ₂ NC (O)-.

As used herein, the term "aminocarbonylalkyl" refers to aminocarbonyl as defined above, attached to the parent molecular moiety through alkylene.

The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which an aminocarbonyl (NH ₂ C (O)-) group is bonded.

The term "aminocarbonylalkoxy" as used herein refers to H ₂ NC (O)-bonded to an alkoxy group as defined above. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy and aminocarbonylethoxy and the like.

As used herein, the term “aroyloxyalkyl” means R ₃₂ -C (O) —OR ₃₃ —, where R ₃₂ is an aryl group and R ₃₃ is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings, including but not limited to phenyl, naphthyl, tetrahydronaphthyl , Indanyl and indenyl, and the like. The aryl group may be unsubstituted, lower alkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo (= O), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, ( Alkoxycarbonyl) thioalkoxy, thioalkoxy, alkylimino (R ^* N = where R ^* is a lower alkyl group), amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl, aminocarbonyl Alkoxy, alkanoylamino, aryl, arylalkyl, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, carboxyamide, cycloalkyl, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cya And may be substituted by one, two or three substituents independently selected from noalkoxy, heterocyclic alkoxy, —SO ₃ H, hydroxyalkoxy, phenyl and tetrazolylalkoxy. Examples of substituted aryl groups include 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4- Methylsulfonylphenyl, and pentafluorophenyl.

The term "arylalkenyl" as used herein refers to an alkenyl radical to which an aryl group is bound, including, for example, phenylethenyl and the like.

The term "arylalkynyl" as used herein refers to an alkynyl radical to which an aryl group is bound, including, for example, phenylethynyl and the like.

The term "arylalkoxy" as used herein refers to R ₄₂ O-, wherein R ₄₂ is an arylalkyl group, including, for example, benzyloxy and the like.

The term "arylalkoxyalkyl" as used herein refers to a lower alkyl radical to which an arylalkoxy group is bonded, such as benzyloxymethyl and the like.

The term "arylalkyl" as used herein refers to an aryl group as defined above, which is bonded to a lower alkyl radical, including, for example, benzyl and the like.

The term "arylalkylamino" as used herein, means an arylalkyl group as defined above, attached to the parent molecular moiety through an amino group.

The term "arylalkylthio" as used herein refers to an arylalkyl group as defined above, which is attached to the parent molecular moiety through a thiol group.

The term "arylamino" as used herein means R ₄₅ NH _2- , wherein R ₄₅ is aryl.

The term "arylcarbonylalkyl" as used herein means R ₄₅ C (O) R ₃₃ -wherein R ₄₅ is an aryl group and R ₃₃ is an alkylene group.

The term "arylhaloalkyl" as used herein, means an aryl group as defined above, attached to the parent molecular moiety through haloalkyl as defined herein. Examples of arylhaloalkyl include phenyl-2-fluoropropyl, and the like.

The term "arylhydroxyalkyl" as used herein, means an aryl group, as defined above, attached to the parent molecular moiety through hydroxyalkyl, as defined herein. Examples of arylhydrocyalkyl include phenyl-2-hydroxypropyl, and the like.

The term "aryloxy" as used herein refers to R ₄₅ O-, wherein R ₄₅ is an aryl group, including, for example, phenoxy and the like.

The term "aryloxyalkyl" as used herein, means an aryloxy group, as defined above, attached to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2-phenoxyethyl and the like.

The term "aryloxyhaloalkyl" as used herein, means an aryloxy group, as defined above, attached to the moiety of the parent molecule through haloalkyl, as defined herein. Examples of aryloxyhaloalkyl include phenyloxy-2-fluoropropyl, and the like.

The term "aryloxyhydroxyalkyl" as used herein, means an aryloxy group, as defined above, attached to the moiety of the parent molecule through hydroxyalkyl, as defined herein. Examples of aryloxyhydroxyalkyl include phenoxy-2-hydroxypropyl, and the like.

As used herein, the term "carboxaldehyde" refers to a formaldehyde radical, -C (O) H.

The term "carboxamide" as used herein means -C (O) NH ₂ .

The term "carboxy" as used herein means a carboxylic acid radical, -C (O) OH.

The term "carboxyalkyl" as used herein, means a carboxy group as defined above, bonded to an alkyl radical as defined above. Examples of carboxyalkyl include 2-carboxyethyl, 3-carboxy-1-propyl, and the like.

The term "carboxyalkenyl" as used herein, means a carboxy group as defined above, which is bonded to an alkenyl radical as defined above. Examples of carboxyalkenyl include 2-carboxytenyl, 3-carboxy-1-ethenyl and the like.

The term "carboxyalkoxy" as used herein means a carboxy group as defined above, which is bonded to an alkoxy radical as defined above. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.

The term "cyano" as used herein refers to a cyano (-CN) group.

As used herein, the term “cyanoalkyl” refers to an alkyl radical as defined above, to which a cyano (—CN) group is bonded. Examples of cyanoalkyl include 3-cyanopropyl, 4-cyanobutyl and the like.

The term "cyanoalkoxy" as used herein refers to a cyano (-CN) group, which is attached to the residue of the parent molecule via an alkoxy radacal. Examples of cyanoalkoxy include 3-cyanopropoxy and 4-cyanobutoxy and the like.

The term "cycloalkanoyloxyalkyl" as used herein refers to lower alkyl bound to a cycloalkanoyloxy group [ie, R ₆₀ -C (O) -0 (wherein R ₆₀ is a cycloalkyl group)]. Means radicals.

As used herein, the term “cycloalkyl” refers to an aliphatic ring system having 3 to 10 carbon atoms and having 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. This includes. Cycloalkyl groups are unsubstituted, hydroxy, halo, oxo (= O), alkylimino [R ^* N = (where R ^* is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, Independently selected from alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro, cyano and lower alkyl It may be substituted by one, two or three substituents.

As used herein, the term “cycloalkenyl” refers to an aliphatic ring system having 3 to 10 carbon atoms and having 1 to 3 rings containing one or more double bonds in the ring structure. Cycloalkenyl groups are unsubstituted, hydroxy, halo, oxo (= O), alkylimino [R ^* N = (where R ^* is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy Independently from alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro, cyano and lower alkyl It may be substituted by one, two or three substituents selected.

As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group bonded to a lower alkyl radical, including but not limited to cyclohexylmethyl.

The term "cycloalkylalkoxy" as used herein refers to a cycloalkyl group attached to an alkoxyl group as defined herein, including but not limited to cyclohexylmethoxy.

As used herein, the term “cycloalkylamino” refers to a cycloalkyl group, which is, but is not limited to, cyclohexylamino, bonded to the residues of the parent molecule via an amino group.

As used herein, the term “cycloalkylalkylamino” refers to a cycloalkyl group attached to a moiety of a parent molecule through an alkylamino group, including but not limited to cyclohexylmethylamino.

As used herein, the term “cycloalkylidenealkyl” refers to a cycloalkyl group, attached to the moiety of the parent molecule via a double bond linked to alkylene (= (CH ₂ ) _n −). Examples include cyclopropylideneethyl, cyclobutylidenepropyl, and the like.

As used herein, the term "cycloalkyloxy" refers to a cycloalkyl group bonded to a moiety of a parent molecule through an oxygen atom, including but not limited to cyclohexyloxy.

As used herein, the term "cycloalkenylalkyl" refers to a cycloalkenyl group attached to a lower alkyl radical, including but not limited to cyclohexenylmethyl.

As used herein, the term “cycloalkenylalkoxy” refers to a cycloalkenyl group attached to an alkoxyl group as defined herein, including but not limited to cyclohexenylmethyloxy.

The term "dialkylamino" as used herein refers to R ₅₆ R ₅₇ N-, wherein R ₅₆ and R ₅₇ are independently selected from lower alkyl, for example diethylamino and methyl Propylamino and the like.

As used herein, the term “dialkylaminoaryloxy” refers to dialkylamino as defined herein attached to the residues of the parent molecule through aryloxy as defined herein.

The term "diarylamino" as used herein refers to (R ₄₅ ) R ₄₆ ) N-, wherein R ₄₅ and R ₄₆ are independently aryl, for example diphenylamino, and the like. This includes.

The term "dialkylaminoalkyl" as used herein refers to a lower alkyl radical bonded to a dialkylamino group.

As used herein, the term “dialkylaminocarbonyl” refers to a dialkylamino group as defined above, attached to the parent molecular moiety via a carbonyl (—C (O) —) bond. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl and diethylaminocarbonyl, and the like.

The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which a dialkylaminocarbonyl group is bonded.

The term "dialkylaminocarbonylalkyl" as used herein means R ₅₀ -C (O) -R _51- , wherein R ₅₀ is a dialkylamino group and R ₅₁ is an alkylene group. do.

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

The term "haloalkyl" as used herein means an alkyl radical as defined above having one or more halogen substituents, for example chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2 , 3-difluoropentyl, and the like.

The term "haloalkenyl" as used herein means an alkenyl radical having one or more halogen substituents, for example chloromethenyl, fluoroethenyl, trifluoromethenyl or pentafluoroethenyl , 2,3-difluoropentenyl, and the like.

As used herein, the term “haloalkenyloxy” means a haloalkenyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.

The term "haloalkynyl" as used herein means an alkynyl radical having one or more halogen substituents, for example chloromethynyl, fluoroethynyl, trifluoromethynyl or pentafluoroethynyl , 2,3-difluoropentynyl, and the like.

As used herein, the term “haloalkoxy” means an alkoxy radical as defined above, which includes one or more halogen substituents, for example 2-fluoroethoxy, 2,2,2-trifluoro Roethoxy, trifluoromethoxy and 2,2,3,3,3-pentafluoropropoxy, and the like.

The term "haloalkoxyalkyl" as used herein refers to a lower alkyl radical to which a haloalkoxy group is bonded.

As used herein, the term “haloalkoxyhydrocyalkyl” means a haloalkoxy group, as defined herein, appended to the parent molecular moiety through hydroxyalkyl, as defined herein.

The term "heterocyclic ring", "heterocyclic" or "heterocycle" as used herein is a three- or four-membered ring comprising a hetero atom selected from oxygen, nitrogen and sulfur, or one, two or Three nitrogen atoms; One oxygen atom; One sulfur atom; One nitrogen and one sulfur atom; One nitrogen and one oxygen atom; Two oxygen atoms in non-adjacent positions; It means a five-membered, six-membered or seven-membered ring containing one oxygen and one sulfur atom in nonadjacent positions or two sulfur atoms in nonadjacent positions. Examples of heterocycles include, but are not limited to, thiophenene, pyrrole and furan. 5-membered rings have 0 to 2 double bonds, and 6-membered rings and 7-membered rings have 0 to 3 double bonds. The nitrogen hetero atom may be optionally quaternized. The term “heterocyclic” also means that any one of the above heterocyclic rings is a benzene ring or a cycloalkane ring, or another heterocyclic ring (eg, indolyl, dihydroindolyl, quinolyl, isoquinolyl, Acyclic groups fused to tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl, and the like. Heterocyclics include aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyri Dill, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl , Thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydro Furanyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl. Heterocyclic is also a chemical formula Where X ^* is -CH ₂ -or -O-, Y ^* is -C (O)-or [-C (R ") _2- ] _v and R" is hydrogen or C ₁ -C ₄ alkyl, v is 1, 2 or 3), and examples thereof include 1,3-benzodioxolyl and 1,4-benzodioxanyl. Heterocyclics also include bicyclic rings (eg, quinuclidinyl and the like).

Heterocyclic may be unsubstituted, hydroxy, halo, oxo (= O), alkylimino (R ^* N =), where R ^* is a lower alkyl group, amino, alkylamino, dialkylamino, alkoxy Independently from alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO ₃ H, nitro, cyano and lower alkyl It may be substituted by one, two or three substituents selected. In addition, the nitrogen containing heterocycle may be N-protected.

As used herein, the term “heterocyclic alkoxy” means a heterocyclic group as defined above bonded to an alkoxy radical as defined above. Examples of heterocyclic (alkoxy) include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.

As used herein, the term “heterocyclic amino” refers to a heterocyclic group as defined above which is attached to an amino as defined above. Examples of heterocyclic amino include 4-pyridylamino, 2-pyridylamino and the like.

As used herein, the term “heterocyclic oxy” means a heterocyclic group as defined above, bonded to the residue of the parent molecule via oxygen. Examples of heterocyclic oxys include 4-pyridyloxy, 2-pyridyloxy, and the like.

As used herein, the term “heterocyclic alkyl” means a heterocyclic group as defined above bonded to a lower alkyl radical as defined above.

The term "heterocyclic alkylamino" as used herein refers to a heterocyclic group as defined above which is bonded to an alkylamino as defined above.

The term “heterocycliccarbonyloxyalkyl” as used herein means R ₄₆ -C (O) —OR ₄₇ , wherein R ₄₆ is a heterocyclic group and R ₄₇ is an alkylene group. do.

As used herein, the term "heterocyclic thio" refers to a heterocyclic group as defined above which is attached to the residue of the parent molecule via a thiol. Examples of heterocyclic thios include 4-pyridylthio, 2-pyridylthio, and the like.

The term "hydroxy" as used herein means -OH.

The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which a hydroxy group is bound. Examples of hydroxyalkenyl include 3-hydroxypropenyl, 3,4-dihydroxybutenyl, and the like.

The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as defined above in which a hydroxy (-OH) group is bonded. Examples of hydroxyalkoxy include 3-hydroxypropoxy and 4-hydroxybutoxy, and the like.

As used herein, the term "hydroxyalkyl" refers to a lower alkyl radical to which a hydroxy group is attached. Examples of hydroxyalkyl include 1-hydroxypropyl, 4-hydroxybutyl, 1,3-dihydroxyisopentyl, and the like.

The term "hydroxyalkylamino" as used herein refers to a hydroxyalkyl group bonded to the residues of the parent molecule via amino. Examples of hydroxyalkylamino include 1-hydroxypropylamino, 4-hydroxybutylamino, 1,3-dihydroxyisopentylamino, and the like.

The term "hydroxyalkylthio" as used herein refers to a hydroxyalkyl group attached to a moiety of the parent molecule through a thiol. Examples of hydroxyalkylamino include 1-hydroxypropylthio, 4-hydroxybutylthio, 1,3-dihydroxyisopentylthio, and the like.

The term "mercapto" or "thiol" as used herein means -SH.

The term "nitro" as used herein, means -NO ₂ .

The term "oxoalkoxy" as used herein refers to a carbonyl group attached to a moiety of the parent molecule via an alkoxy group.

The term "mercaptoalkoxy" or "thiolalkoxy" as used herein means -R ₇₀ S-, where R70 is alkoxy. Examples of thiolalkoxy include, but are not limited to, methylthio, ethylthio, and the like.

The term "tetrazolyl" as used herein refers to a chemical formula Means radicals or tautomers thereof.

The term "tetrazolylalkoxy" as used herein means a tetrazolyl radical as defined above which is bonded to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.

The term "thioalkoxyalkoxy" as used herein means R ₈₀ SR ₈₁ O-, wherein R ₈₀ is lower alkyl as defined above and R ₈₁ is alkylene. Representative examples of alkoxyalkoxy groups include CH ₃ SCH ₂ O—, EtSCH ₂ O—, t-BuSCH ₂ O— and the like.

The term "thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group bonded to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH ₃ SCH ₂ CH ₂ OCH ₂ CH ₂ — and CH ₃ SCH ₂ OCH ₂ — and the like.

The compounds of 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 compounds: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, Digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroioda Id, 2-hydroxy-ethanesulfonate, lactate, malate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, Picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfo Nate and Undecanoate. In addition, basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide, and iodide, dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate, Long chain halides (eg decyl, lauryl, myristyl and stearyl chloride, bromide, and iodide), aralkyl halides (eg benzyl and phenethyl bromide) and other groups. This gives a water-soluble or fat-soluble or dispersible product.

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

Basic addition salts may be prepared in situ during the final separation and purification of the compounds of formula (I), or may be prepared by incorporating a carboxylic acid functional group and a suitable base (e.g. Or by reacting with an organic primary, secondary or tertiary amine separately. Such pharmaceutically acceptable salts are alkali and alkaline earth metal-based (eg sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc.) cations, and nontoxic ammonium, quaternary ammonium and amine cations (eg 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.

As used herein, the term "pharmaceutically acceptable ester" means an ester that can be hydrolyzed in vivo, including esters that are readily degraded in the human body to leave the parent molecule or salts thereof. Examples of suitable groups include pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acid, alkenoic acid, cycloalkanoic acid and alkanedioic acid, in which each alkyl or alkenyl moiety has advantageously 6 or less carbon atoms. Examples of specific esters include formate, acetate, propionate, butyate, acrylate and ethyl succinate.

As used herein, the term “pharmaceutically acceptable prodrug” refers to contacting tissues of humans and lower animals without involving excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment. By prodrugs of compounds of the invention, and, if appropriate, zwitterionic forms of the compounds of the invention, suitable for use, balanced with an adequate benefit / risk ratio and effective for the intended use. The term "prodrug" refers to a compound which is readily converted in vivo, for example by hydrolysis in blood, to give the parent molecule of the above formula. A detailed discussion is incorporated herein by reference. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

As used throughout this specification and the appended claims, the term “group that can be cleaved in metabolism” can be readily cleaved in vivo from a compound comprising the same and retains pharmacological activity after cleavage or By cleavage means residues that have pharmacological activity. Groups that can be cleaved during metabolism constitute a class that is reactive with the carboxyl groups of the compounds of the invention and are known to those skilled in the art. These include, but are not limited to, alkanoyl (eg, acetyl, propionyl, butyryl, etc.); Unsubstituted or substituted aroyl such as benzoyl and substituted benzoyl; Alkoxycarbonyl (eg ethoxycarbonyl); Trialkylsilyl (eg trimethyl- and triethylsilyl); Groups of dicarboxylic acids and monoesters formed (eg succinyl, etc.) are included. Since groups that can be cleaved in the metabolism of the compounds of the present invention can be cleaved in vivo easily, compounds comprising such groups act as prodrugs of other prostaglandin biosynthesis inhibitors. Compounds comprising groups that can be cleaved during metabolism can exhibit enhanced bioavailability as a result of the enhanced solubility and / or absorption rate imparted on the parent molecule thanks to the groups cleavable during metabolism. .

Asymmetric centers may be present in the compounds of the present invention. The present invention contemplates various stereoisomers and mixtures thereof. Each stereoisomer of a compound of the invention can be synthesized from a starting material comprising a chiral center, or prepared after a mixture of enantiomer products, separated, for example converted to a mixture of diastereomers and then recrystallized. Or by chromatographic techniques or by direct separation of the optical enantiomers on a chiral chromatography column. Starting compounds of certain stereochemicals are either commercially available or can be prepared by methods solved by techniques well known in the art of organic chemistry, as described below in detail.

Preferred Embodiment

Compounds useful in carrying out the invention include, but are not limited to, the following compounds:

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

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

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

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

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

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

2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Dazinon,

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

2- (tert-butyl) -4- (3-methoxybutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (tert-butyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (3,4-difluorophenyl) -4- (3-methylbutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone,

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

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

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

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

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

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

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

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

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

2- (3,4-difluorophenyl) -4- (2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

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

2- (3,4-difluorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

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

2- (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

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

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

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

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

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

2,4-bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone,

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

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

2- (3,4-difluorophenyl) -4- (2-oxopropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (3,4-difluorophenyl) -4- (2-methoxy-imino-propoxy) -5- [4- (methylsulfonyl) 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,

2- (3,4-difluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone,

2- (4-fluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, and

2,4-bis (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, or a pharmaceutically acceptable salt, ester or prodrug thereof.

More preferred compounds of the present invention include, but are not limited to, the following compounds:

2-phenyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone,

2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone,

2- (2,2,2-trifluoroethyl) -4- (4-chlorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone,

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

2- (3,4-difluorophenyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone and

2,4-bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone, or

Pharmaceutically acceptable salts, esters or prodrugs thereof.

Preparation of Compounds of the Invention

The compounds of the present invention can be prepared via various synthetic routes. Representative processes are outlined in Schemes 1-3 below.

The general route for the compounds of the invention of formula III wherein the aryl group at the 5-position of the pyridazinone ring is substituted with a sulfonyl group ring is described in Scheme 1 below. Dichloro-3- (2H) -pyridazinone is reacted with benzyl chloride and potassium carbonate in methanol. Subsequently, 2-benzyl-4-chloro-5-methoxy-3- (2H) -pyridazinone is treated with a boric acid and a palladium catalyst such as 4-fluorobenzeneboronic acid (not shown). Hydrolysis of the methoxy group with 48% hydrobromic acid yields a 5-hydroxypyridazinone compound. The 5-hydroxypyridazinone product is treated with triple anhydride, followed by substitution in the pyridazinone ring with 4-methylthiobenzeneboronic acid. This gives a methyl thioether compound, which is reacted with methylene chloride and peracetic acid in acetic acid to give methyl sulfone. Aluminum bromide or a suitable Lewis acid is used to remove the benzyl group. A suitable alkylating agent and base may be used to add the R group via substitution.

Another route for the compounds of the present invention of Formula III is described in Scheme 2 below. The 4-bromothioanisole or other suitable thioether is reacted with trialkoxy borate (eg 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 combined with a boric acid, such as 4-fluorobenzeneboronic acid (shown), and a palladium catalyst to give thioethers. This affords a methyl thioether compound, which is reacted with meta-chloroperoxybenzoic acid (MCPBA) in methylene chloride to give methyl sulfone. Aluminum bromide or other suitable Lewis acid is used to remove the benzyl group. A suitable alkylating agent and base may be used to add the R group via substitution.

A third route for the compounds of the present invention of Formula III is described in Scheme 3 below. 4-thiomethylbenzenealdehyde (Y is CH3S) is reacted with methyl (methylsulfinylmethyl) sulfide and sodium hydroxide to prepare (4-thiomethylphenyl) dimethylthioketone acetal, mono-S-oxide. The thioketene acetal and methyl 4-fluorophenylacetal or a suitable ester (X is fluorine) are treated with a strong base (eg sodium hexamethyldisilarizide) in THF to give the butyrate ester. Hydrazine and salts are used to directly cyclize dithioacetal ketene. Oxidation of pyridazinone with acetic acid peroxide gives sulfonyl pyridazone. In another route, Scheme 3A, thioacetal ketene is treated with perchloric acid to yield the ester-aldehyde as a mixture of diastereomers. The oxidation product is treated with hydrazine and then oxidized with acetic acid peroxide to give sulfonyl dihydropyridazinone. The dihydropyridazinone can be dehydrogenated by treatment with a reagent such as bromine in acetic acid to form pyridazinone. Suitable alkylating agents and bases may be used to add the R group via substitution.

Various publications are described in, for example, J. Med. Chem. 1987, 30, 239-249 and WO 96/36623 can be applied to prepare 5-hydroxy-2 (5H) -furanone, which is shown in Scheme 4.

Method IV:

The general route for the compounds of the invention of formula III wherein the aryl group at position 5 of the pyridazinone ring is substituted with a sulfonyl group ring is described in Scheme 5 below. For example, a mucohaloic acid, such as nocobromic acid or nocochloric acid, is reacted with hydrazine having the desired R group to give a dihalopyridazinone compound 5A. For example, treating the dihalo-compound with an alcohol in the presence of a base such as sodium or potassium hydride gives an alkoxide 5B (methanol is the preferred alcohol if the alkoxy group has to be removed later). The alkoxy-halide can be reacted with methylthiophenyl boronic acid to give alkoxy-pyridazinone (5C). Treatment with Grignard reagents can convert the alkoxy groups to hydrocarbyl groups to afford thioethers (5D). The thioether is oxidized with an oxidizing agent such as peracetic acid, meta-chloroperoxybenzoic acid, or the like to form sulfinyl compound (5G) or methylsulfone compound (5E). Rearrangement and hydrolysis of the sulfinyl compound (5G) yields thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to an amino-sulfonyl compound (5H). Alternatively, the methylsulfonyl compound is treated with diazodicarboxylates (e.g. DBAD, DIAD, DEAD, etc.) and disilazane anions (e.g. lithium HMDS, etc.), followed by sodium acetate and hydroxylamine-O in water. Aminosulfonyl compound (5H) can be obtained by treating with sulfonic acid to convert methylsulfonyl compound (5E) to aminosulfonyl compound (5H).

Alternatively, alkoxy-pyridazinone (5C) can be oxidized as shown in Scheme 5A. The first step is to form a sulfinyl compound (5G ') or methylsulfone compound (5E') using an oxidizing agent such as peracetic acid, meta-chloroperoxybenzoic acid, and the like. Rearrangement and hydrolysis of the sulfinyl compound yields thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to an amino-sulfonyl compound (5H '). Finally, the methylsulfonyl compound (5E ') is treated with diazodicarboxylates (e.g. DBAD, DIAD, DEAD, etc.) and disilazane anions (e.g. lithium HMDS, etc.), followed by sodium acetate and The aminosulfonyl compound (5H ') can be obtained by treatment with hydroxylamine-O-sulfonic acid to convert the methylsulfonyl compound to the aminosulfonyl compound (5H).

The preparation of the compounds of the invention of formula III wherein the 4-position group of the pyridazinone ring is substituted with an alkyl or alkenyl group is described in Scheme 6A. The thioether 5E, where R ⁹⁶ is alkyl, such as methyl as shown, is halogenated with halogenation reagents such as NBS and peroxides to afford bromo compound 6A. The bromo compound can be reacted with an alcohol and a weak base such as sodium carbonate or potassium carbonate to give 4-alkyl-ether (6B). The bromo compound can be reacted with a thio compound in the presence of a base such as silver carbonate to give 4-alkyl-thioether (6C). The bromo compound can be reacted with an amine and a weak base such as sodium carbonate or potassium carbonate to give the 4-alkyl-amino-alkyl compound (6D).

The general route for the compounds of the invention of formula III, in which the 4-position group of the pyridazinone ring can be easily substituted, is described in Scheme 6 above. Synthesis is initiated from alkoxides (5E ′), wherein R ⁹⁷ is methyl. Treatment of the methoxy compound with a base such as sodium or potassium hydroxide yields 4-hydroxy-pyridazinone (6A). The alcohol is treated with p-toluenesulfonyl chloride to give the tosyloxy compound 6B. The tosyloxy compound can be easily substituted with the compound R ⁹² Z ′ which can undergo the S _N2 reaction. Examples of these compounds are compounds such as alcohols, thiols, amines or hydrocarbyl anions.

As used throughout this specification and the appended claims, the following abbreviations may be used:

ACD: acid citrate dextrose, CAP: carrageenan induced air sac prostaglandin, CIP: rat carrageenan pleurisy model, COX-2: cyclooxygenase-2, CPE: carrageenan induced paw Edema, DBAD: di-t-butyl azodicarboxylate, DEAD: diethyl azodicarboxylate, DIAD: diisopropyl azodicarboxylate, DMAP: 4- (dimethylamino) pyridine, DME: 1,2-dimeth Methoxyethane, DMF: N, N-dimethylformamide, DMSO: dimethylsulfoxide, EDTA: ethylenediaminetetraacetic acid, EIA: enzyme immunoassay, FAB: fast atom bombardment, GI: gastrointestinal, HMDS, lithium or Li HMDS: lithium 1,1,1,3,3,3-hexamethyldisilazide, HWPX: human whole platelet cyclooxygenase-1, MCPBA: meta-chloroperoxybenzoic acid, NSAID: nonsteroidal anti-inflammatory agent, PEF400: polyethylene glycol , PGE _2: prostaglandin E _2, PGHS: prostaglandin H synthetase endo peroxide, RHUCX1: re Sum human cyclogenase-1, RHUCX2: recombinant human cyclooxygenase-2, r-hu Cox 1: recombinant human Cox-1, TEA: triethylamine, TFA: trifluoroacetic acid, THF: tetrahydrofuran, And WISH: human amnion whole cell cyclogenase-2. The following examples illustrate the manufacturing process of the present invention without limitation.

Compounds of the present invention include, but are not limited to, the compounds of 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) is cooled to -78 ° C under nitrogen atmosphere. N-butyl lithium (12 mL, 0.030 mol) 2.5 M solution in hexane is added dropwise to the cooled solution. When the addition is complete, the reaction mixture is stirred at -78 ° C for about 45 minutes. Trimethylborate (8.5 mL, 0.0748) is introduced via a syringe. The reaction mixture may then be warmed to room temperature overnight. The room temperature solution is 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 is lowered to about pH = 4-5 with 10% aqueous citric acid and THF is removed under reduced pressure. The aqueous residue is saturated with sodium chloride and extracted with ethyl acetate. The organic extract is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a white solid, which is washed with hexane to give the product of a white solid. (Yield 1.5 g; 36%). Mp 170 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 4,5-dibromo-3 (2H) -pyridazinone (1.27 g, 0.005 mol) and potassium carbonate (0.76 g, in 20 mL of anhydrous dimethylformamide (DMF). 0.0055 mol) to a stirred solution. The solution is stirred overnight at room temperature and partitioned between aqueous citric acid and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a beige solid which is purified by column chromatography (silica gel, 9: 1 hexanes / ethyl acetate). The product is obtained as a white solid. (Yield 1.32 g, 76.7%). Mp 95-96 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.31 (s, 2H), 7.29-7.37 (m, 3H), 7.41-7.47 (m, 2H), 7.79 (s, 1H). MS (DCI-NH ₃ ) m / z 345 (M + H) ⁺ . IR (KBr) 1645 cm ^-1 .

Example 3

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

Boronic acid (0.318 g, 0.001889 mol) prepared according to the method of Example 1, in dimethoxyethane (30 mL), bromopyridazinone (0.975 g, 0.002834 mol) prepared according to the method of Example 2, and Prepare a tetrakis- (tri-phenyl-phosphine) -palladium (0) (0.16 g, 0.0142 mol) solution. A 2 M aqueous solution of sodium carbonate (2.83 mL, 0.005668 mol) is added to the dimethoxyethane solution and the mixture is heated under reflux. After 16 hours, when checked by chromatography (TLC) (9: 1 hexanes / ethyl acetate), both starting materials are still present and fresh aliquots of the palladium catalyst are added. The reaction mixture is further stirred at reflux for 5 hours, cooled to room temperature and left for weekend. The volatiles are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO ₄ , and filtered. The filtrate is concentrated under reduced pressure to give an oil which is purified by column chromatography (silica gel, 95: 5 hexanes / ethyl acetate). Fractions containing the desired product are combined and concentrated under reduced pressure. This material is rechromatated (95: 5 hexanes / ethyl acetate) to yield 0.200 g of a beige solid. The solid is crystallized from ether / hexanes to give white crystals. (Yield 110 mg, 15%) Mp 115-118 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.53 (s, 3H), 5.40 (s, 2H), 7.30-7.42 (m, 7H), 7.49-7.54 (m, 2H), 7.65 (s, 1H). MS (DCI-NH ₃ ) m / z 387 (M + H) ⁺ .

Example 4

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

Product prepared in Example 3 (0.100 g, 0.000258 mol), 4-fluorobenzeneboronic acid (0.072 g, 0.000516 mol) in 30 mL of dimethoxyethane (DME), tetrakis- (tri-phenyl-phosphine ) -Palladium (0) (0.015 g, 0.000013 mol), and a 2 M aqueous solution of sodium carbonate (0.64 mL, 0.001291 mol) are stirred under reflux for 16 hours. Fresh aliquots of the palladium catalyst are combined with the same amount of additional boric acid. The reaction is kept at reflux for 24 hours. The volatiles are removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO ₄ and filtered. The filtrate is adsorbed onto silica gel. The silica gel / product is placed on top of the column of silica gel and the product is eluted with 93: 7 hexanes / ethyl acetate. Fractions containing the product are combined and concentrated under reduced pressure. The residue is further purified by second column chromatography (silica gel, 95: 5 hexanes / ethyl acetate). The fraction containing the product is concentrated under reduced pressure to give 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 (DCI-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) in sulfide in cooled (0 ° C.) dichloromethane (10 mL), prepared according to the method of Example 4. (0.027 g, 0.000067 mol) is added dropwise to the stirred solution. After 5 minutes, TLC (1: 1 hexanes / ethyl acetate) shows that the starting sulfide was consumed. The reaction is quenched with aqueous sodium sulfate solution. The organic layer is washed twice with aqueous sodium hydroxide solution and once with brine. The dichloromethane solution is dried over MgSO ₄ , and then filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, 7: 3 hexanes / ethyl acetate) to afford the desired sulfone product. Further elution with 100% ethyl acetate removes sulfoxide from the column. The sulfoxide product is reapplied to MCPBA oxidant (0.04 g, 1 hour, 0 ° C.) and then worked up as described above. The residue obtained is combined with sulfone from the first column and the mixture is purified by column chromatography (silica gel, 7: 3 hexanes / ethyl acetate). Fractions containing the product are combined and concentrated under reduced pressure. The residue is crystallized from ether / hexanes to give the product of white crystals. (Yield 13 mg, 44.6%). Mp 101-103 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (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 (DCI-NH ₃ ) m / z 435 (M + H) ⁺ . MS (FAB, high resolution) calculated: 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

Under N ₂ , in 25 mL of anhydrous DME, see S. Cho et al. described in J. Het. Chem., 1996,33, 1579-1582] 2-benzyl-5-methoxy-4-bromo-3 (2H) -pyridazinone (2.94 g; 10 mmol), 4-fluoro To the mixture of robenzeneboronic acid (1.54 g; 11 mmol), and CsF (3.04 g; 22 mmol) is added Pd (Ph ₃ P) ₄ (347 mg 0.3 mmol). After addition, the mixture is heated to reflux for 18 hours at reflux. The mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The acetate layer is washed with brine, dried over MgSO ₄ and concentrated in vacuo. The solid residue is suspended in ethyl ether-hexane and filtered to give a solid product. (Yield 3.1 g; about 100%;> 95% purity). ¹ H 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, 1 H). MS (DCI-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 product (1.24 g; 4 mmol) prepared according to the method of example 6 in 20 mL of acetic acid is treated with aqueous 48% HBr (25 mL). The mixture is heated under reflux for about 5 to about 8 hours (TLC analysis). The mixture is concentrated in vacuo. The product is dissolved in ethyl acetate, washed with 10% bicarbonate and brine and concentrated in vacuo. The residue is treated with diethyl ether-hexane (2: 1) and the solid is filtered to give an almost pure product. (Yield 1.16 g; 98%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 + H) ⁺ , 314 (M + NH ₄ ) ⁺ .

Example 8

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

A solution of the product (89 mg, 0.3 mmol) prepared according to the method of Example 7 in 2.5 mL of anhydrous pyridine is prepared under N ₂ atmosphere and maintained at 0 ° C. Triple anhydride (Tf ₂ O; 0.06 mL; 0.32 mmol) is added dropwise to the solution. The resulting mixture is stirred at 0 ° C. for 5 minutes and at room temperature for 16 hours. (For good results the pyridine and Tf ₂ O must be pure. In some cases, an additional amount of Tf ₂ O is required to complete the reaction.) The mixture is then poured into a cold solution of citric acid and extracted with ethyl acetate Yields almost pure product. (Yield 127 mg, about 99%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.34 (s, 2H), 7.35 (m, 7H), 7.60 (m, 2H), 8.48 (s, 1H). MS (DCI-NH ₃ ) m / z 429 (M + H) +, 446 (M + NH ₄ ) ⁺ .

Example 9

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

Product prepared according to the method of Example 8 in 15 mL of toluene (154 mg, 0.36 mmol), 4- (methylthio) benzeneboronic acid (67 mg, 0.4 mmol), Et ₃ N (0.11 mmol; 0.8 mmol) And a mixture of Pd (Ph ₃ P) ₄ (30 mg, 0.025 mmol) is heated at reflux at about 100 ° C. for about 45 minutes. The mixture is concentrated in vacuo and the residue is purified by column chromatography (hexane-ethyl acetate 3: 1) to afford the title compound. (Yield 98 mg, 68%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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-NH ₃ ) m / z 403 (M + H) ⁺ , 420 (M + NH ₄ ) ⁺ .

Example 10

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

At 0 ° C. peracetic acid (CH ₃ COOOH; 0.5 mL; 30%) is added to a solution of the product (140 mg, 0.348 mmol) prepared according to the method of Example 9 in 10 mL of CH ₂ Cl ₂ . The mixture is stirred at 0 ° C. for 90 minutes. Dichloromethane is then removed in vacuo. The residue is dissolved in ethyl acetate and washed with 10% NaHCO ₃ and brine. Ethyl acetate is removed under reduced pressure. The residue was purified by chromatography (silica gel, CH ₂ Cl ₂ - diethyl ether 19: 1) to give 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 (m, 3H). MS (DCI-NH ₃ ) m / z 434 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Example 11

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

A mixture of the product (37 mg, 0.085 mmol) and AlBr ₃ (70 mg, 0.26 mmol) prepared according to the method of Example 10 in 10 mL of toluene was heated at reflux for about 15 minutes at 0 ° C., followed by 0 Cool to ° C. The cooled mixture is treated with 1N HCl and extracted with ethyl acetate. The acetate layer is washed with water, brine and concentrated in vacuo. Purify the residue on a silica gel column (eluent: ethyl acetate) to afford 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, 1 H), 7.91 (d, J = 9 Hz, 2 H), 10.94 (broad s, 1 H). MS (DCI-NH ₃ ) m / z 345 (M + H) ⁺ , 362 (M + NH ₄ ) ⁺ .

Example 12

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

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

2-phenyl-4-chloro-5-methoxy-3 (2H) -pyridazinone compound is described in S. Cho et al. described in J. Het. Chem., 1996, 33, 1579-1582, starting from N-phenyldichloropyridazinone. A mixture of 2-phenyl-4,5-dichloro-3 (2H) -pyridazinone (1 g, 4.1 mmol) and finely divided anhydrous K ₂ CO ₃ (580 mg, 4.2 mmol) in 50 mL of methanol was added under reflux 5 Heat for hours and concentrate in vacuo. The residue is partitioned between water and ethyl acetate. The acetate layer is washed with water and brine to afford 2-phenyl-4-chloro-5-methoxy-3 (2H) -pyridazinone. (Yield 920 mg, 95%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.15 (s, 3H), 7.50 (m, 5H), 8.43 (s, 1H). MS (DCI-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 combined with 4-fluorophenylboronic acid according to the method of Example 6 to give 2-phenyl-4- (4-fluoro Rophenyl) -5-methoxy-3 (2H) -pyridazinone is obtained. (Yield 1.1 g; 96%). ¹ H NMR (300 MHz, CDCl ₃ ) 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 (DCI-NH ₃ ) m / z 297 (M + H) ⁺ .

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

2-phenyl-4- (4-fluorophenyl) -5-methoxy-3 (2H) -pyridazinone product was treated with 48% HBr according to the method of Example 7 to yield 2-phenyl-4- (4 -Fluorophenyl) -5-hydroxy-3 (2H) -pyridazinone is obtained. (Yield 957 mg, 92%). MS (DCI-NH ₃ ) m / z 283 (M + H) ⁺ , 300 (M + NH ₄ ) ⁺ .

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 of Example 8 to give 2-phenyl-4- (4-fluoro Rophenyl) -5-trifluoromethanesulfonyloxy-3 (2H) -pyridazinone is obtained. (Yield 1.35 g; 96%) MS (DCI-NH ₃ ) m / z 415 (M + H) ⁺ , 432 (M + NH ₄ ) ⁺ .

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

2-phenyl-4- (4-fluorophenyl) -5-trifluoromethanesulfonyloxy-3 (2H) -pyridazinone was combined with 4- (methylthio) phenylboronic acid as in Example 9 2-phenyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (yield: 915 mg, 92%) was obtained and column chromatography After crystallization from (silica gel, 1: 1 hexane-ethyl acetate) and diethyl ether-hexane, it is immediately oxidized with peracetic acid as in Example 9 to give the title compound. (Yield 288 mg, 69%). Mp 219-220 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), 7.15 (t, J = 9 Hz, 2H), 7.30 (m, 2H), 7.46 (m, 1H), 7.56 (m, 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 of concentrated sulfuric acid (0.5 mL) is added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL of methanol. The solution is stirred at reflux for 4 h. The volatiles are removed under reduced pressure to give a colorless oil which is dissolved in ether / ethyl acetate and washed with 2N aqueous Na ₂ CO ₃ , brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give an oil which is dried under high vacuum overnight. (Yield 33.6 g; 95%). ¹ 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 (DCI-NH ₃ ) m / z 186 (M + NH ₄ ) ⁺ .

Example 14

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

A mixture of methyl (methylsulfinylmethyl) sulfide (50 g, 0.40 mol) and finely divided sodium hydroxide (3.12 g, 0.078 mol) is stirred at 70 ° C. for 4 hours. Then 4- (methylthio) -benzaldehyde (27.4 mL, 0.195 mol) is added in one portion and the reaction mixture is stirred at 70 ° C. for a further 4 hours. The mixture is cooled to room temperature and partitioned between 10% aqueous citric acid and dichloromethane. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a brown oil. The oil is purified by column chromatography (7: 3 hexanes / ethyl acetate) to give a solid. The solid is crystallized from ether / hexanes. (Yield 24.7 g; 72%). Mp 52-53 ° C. ¹ 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) ⁺ and 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 ester product (16.24 g, 0.0966 mol) prepared according to the method of Example 13 in 50 mL of THF was added dropwise to a stirred solution of 1.0 M sodium hydroxide hexamethyldisilazide (96.6 mL, 0.0966 mol) in THF. And maintained at 0 ° C. under an atmosphere of anhydrous nitrogen. After 30 minutes, a solution of ketene thioacetal (20.8 g, 0.0805 mol) prepared according to the method of Example 14 in 50 mL of THF is added dropwise to the reaction mixture maintained at 0 ° C. After 4 hours, the reaction mixture is acidified with 10% aqueous citric acid. The aqueous layer is washed twice with ethyl acetate. The organic extracts are combined, washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a brown oil which is purified by column chromatography (85:15 to 1: 1 dichloromethane / ethyl acetate gradient). Several products with different R _f values and NMR spectra are separated. These compounds have the same mass spectrum. The mixture of compounds is carried out in the following reaction. (Yield 22.4 g; 65%). MS (DCI-NH ₃ ) m / z 444 (M + NH ₄ ) ⁺ .

Example 16

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

A mixture of compounds (9.0 g, 0.021 mol) prepared according to the method of Example 17 is dissolved in acetonitrile (80 mL) and cooled to 0 ° C. Perchloric acid (60%; 1.06 g, 0.006 mol) is added to the stirred solution. The reaction mixture is stirred at 0 ° C. for 8 h and quenched with 2 N aqueous Na ₂ CO ₃ . Acetonitrile is removed under reduced pressure and the resulting aqueous mixture is extracted with ethyl acetate. The organic solution is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a yellow oil which is purified by column chromatography (silica gel, 7: 3 hexanes / ethyl acetate). The fraction containing the best Rf diastereomer from the mixture of products is concentrated in vacuo and the residue is crystallized from methanol to give the title aldehyde-ester compound as white crystals. (Yield 0.27 g, 4.0%). Mp = 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) ⁺ and m / z 350 (M + NH ₄ ) ⁺ . When the fraction containing the lower R _f compound from the mixture of products was concentrated in vacuo, the residue was identified as a hydrate of the aldehyde-ester. (Yield 2.6 g, 35.2%). ¹ H NMR (300 MHz, CDCl ₃ ) 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) ⁺ and m / z 350 (M + NH ₄ ) ⁺ .

The lowest R _f compound is identified as the hydroxy lactone formed when the hydroxy group from the hydrate replaces the methoxy group from the ester. (Yield 1.1 g, 16.4%). ¹ 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

Aldehyde-ester, hydrate, and hydroxy lactone (0.10 g, 3 mmol) prepared in Example 16 are dissolved in 100 mL of ethanol. This solution is treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution is stirred in a Soxhelet apparatus with molecular sieves under reflux. After 18 hours, the reaction mixture is cooled and the volatiles are removed under reduced pressure. The residue is partitioned between ethyl acetate and aqueous HCl. The aqueous layer is washed twice with ethyl acetate. The combined organic extracts are extracted twice with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (4: 1 hexanes / ethyl acetate) to afford 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-NH ₃ ) m / z 315 (M + H) ⁺ and m / z 332 (M + NH ₄ ) ⁺ .

Example 18

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

A 32% peracetic acid (0.4 mL, 1.6 mmol) solution in acetic acid is added to a solution of sulfide (0.050 g, 0.16 mmol) in dichloromethane, prepared according to the method of Example 17 and maintained at 0 ° C. The reaction mixture is stirred for 5 h at 0 ° C. and then diluted with water. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give an oil which solidifies upon grinding with ether. (Yield 47 mg, 85%). ¹ H NMR (300 MHz, CDCl ₃ ) 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, broad, 1H). MS (DCI-NH ₃ ) m / z 364 (M + NH ₄ ) ⁺ .

Example 19

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

The hydropyridazinone product (47 mg, 0.136 mmol) prepared according to the method of Example 18 is dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) is added to the solution and the reaction mixture is stirred at 95 ° C for 20 min. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to give a solid, which is eluted through a short pad of silica gel with ethyl acetate. The title compound is determined by ethyl acetate / hexanes. (Yield 35 mg, 75%). Mp 255-256 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.07 (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-NH ₃ ) m / z 345 (M + H) ⁺ and m / z 362 (M + NH ₄ ) ⁺ .

Example 20

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

Nitrogen-unsubstituted pyridazinone product (160 mg, 0.465 mmol), K ₂ CO ₃ (193 mg, 1.4 mmol) prepared according to the method of Example 19 in 10 mL of anhydrous N, N-dimethylformamide (DMF) ), 4-fluorobenzyl-bromide (0.09 mL, 0.7 mmol) and NaI (catalytic) are stirred at room temperature for 18 hours. The reaction mixture is quenched with 2N HCl, extracted with ethyl acetate (2 × 20 mL), washed with brine and water, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is purified by column chromatography (2: 2: 6 ethyl acetate / dichloromethane / pentane). Crystallization from ether / pentane gives white crystals. (Yield 110 mg, 52%). Mp 153-154 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (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 (DCI-NH ₃ ) m / z 453 (M + H) ⁺ .

Example 21

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with phenylpropargyl bromide. Mp 100-103 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2,4-difluorobenzyl bromide. Mp 179-182 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 3-chloro-2-methylpropene. Mp 140-142 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.86 (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 (DCI-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 title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 4-bromo-2-methyl-2-butene. Mp 169-172 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.78 (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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (trifluoromethyl) benzyl bromide. Mp 87-90 ° C. ¹ 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 (DCI-NH ₃ ) m / z 503 (M + H) ⁺ .

Example 26

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) cyclopropane. Mp 118-121 ° C. ¹ 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-NH ₃ ) m / z 399 (M + H) ⁺ and m / z 416 (M + NH ₄ ) ⁺ .

Example 27

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) pyridine. Mp 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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 4- (bromomethyl) pyridine. Mp 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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 3- (bromomethyl) pyridine. Mp 160-161 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.07 (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 (DCI-NH ₃ ) m / z 436 (M + H) ⁺ .

Example 30

2- (6-fluoroquinolin-2-ylmethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (chloromethyl) -6-fluoroquinoline. Mp 116-119 ° C. ¹ 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 (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (chloromethyl) -quinoline. Mp 97-100 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (s, 3H), 5.75 (s, 2H), 6.95 (m, 2H), 7.19 (m, 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 (DCI-NH ₃ ) m / z 386 (M + H) ⁺ .

Example 32

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinthione

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone prepared according to the method of Example 5 in 15 mL of toluene ( 109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) are stirred under reflux for 48 hours. The mixture is concentrated in vacuo and the residue is purified by chromatography (silica gel, ethyl acetate) to afford the title compound. (Yield 100 mg, 88%). Mp 88-90 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (DCI-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

₂ -benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H)-, prepared according to the method of example 4, in CH ₂ Cl ₂ (10 mL). A solution of pyridazinone (450 mg, 1.12 mmol) 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 obtained a clear solution. Stir until (about 1 hour). The reaction mixture is then washed with water and dried over MgSO _{4 The} solvent is removed in vacuo to give the corresponding sulfoxide. (Yield 485 mg, about 100%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.72 (s, 3H), 5.40 (s, 2H), 6.90 (m, 2H), 7.15 (m, 3H), 7.33 (m, 3H), 7.57 (m, 3H), 7.71 (m, 1 H), 7.86 (s, 1 H). MS (DCI-NH ₃ ) m / z 419 (M + H) ⁺ , 436 (M + NH ₄ ) ⁺ .

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

Sulfoxides are described in M. De Vleeschauwer and J. V. Gauthier in Syn. Lett., 1997, 375] is converted to sulfonamides by applying the following modifications:

A suspension of sulfoxide (485 mg, 1.12 mmol) and AcONa (1.4 g) prepared according to the method of Example 33A in 15 ml of Ac ₂ O is stirred under reflux for 2 hours and concentrated in vacuo. The residue is distilled twice with toluene, dissolved in 25 mL of CH ₂ Cl ₂ , cooled to 0 ° C. and treated with CH ₃ CO ₃ H (1 mL). After 1 hour, the mixture is washed successively with saturated NaHCO ₃ and brine. The solvent is removed in vacuo. The residue was purified by chromatography (silica gel, 1: 1 hexane-ethyl acetate) to give the desired product, 2-benzyl-4- (4-fluorophenyl) -5- (acetoxymethylsulfonylphenyl) -3 (2H) -pyridazinone is obtained. (Yield 150 mg, 27%). MS (DCI-NH ₃ ) m / z 493 (M + H) ⁺ .

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

At 0 ° C. 1 N NaOH (0.305 mL, 0.305 mmol) is added to a solution of acetoxymethylsulfone (150 mg, 0.305 mmol) prepared according to the method of Example 33B in 10 mL THF and 5 mL methanol. The mixture is stirred at 0 ° C for 1 h. The mixture is concentrated in vacuo and the remaining water is removed via EtOH / toluene azeotrope followed by toluene azeotrope. The residue is dried under high vacuum for 48 hours to give sodium sulfate. (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

Sodium sulfate (about 0.31 mmol) in CH ₂ Cl ₂ (10 mL) is treated with SOCl ₂ (0.033 mL, 0.4 mmol) at 0 ° C. for 2 hours. The mixture is washed with brine, dried over MgSO ₄ and and concentrated in vacuo to afford crude sulfonyl chloride. (Yield 145 mg, about 100%). MS (DCI-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 of THF is added to a solution of 50% NH ₄ OH in 10 mL of THF and maintained at 0 ° C. The mixture can be warmed to room temperature over 3.5 hours. THF is removed in vacuo and the product is extracted with ethyl acetate. Ethyl acetate is removed in vacuo and the residue is treated with diethyl ether-hexane 2: 1 to give sulfonamide. (Yield 113 mg, 84%). Mp 188-191 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (m, 7H), 7.73 (d, J = 9 Hz, 2H), 8.11 (s, 1H). MS (DCI-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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-iodo-1,1,1-trifluoroethane. Mp 177-179 ° C. ¹ 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-NH ₃ ) m / z 427 (M + H) ⁺ and m / z 444 (M + NH ₄ ) ⁺ .

Example 35

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 1,1,3-trichloropropene. Mp 150-152 ° C. ¹ 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-NH ₃ ) m / z 453 (M + H) ⁺ and m / z 470 (M + NH ₄ ) ⁺ .

Example 36

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with cinnamil bromide. Mp 165-167 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (s, 3H), 5.01 (d, J = 7 Hz, 2H), 6.48 (dt, J = 15 Hz, 7 Hz, 1H), 6.79 (d, J = 15 Hz, 1H), 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-NH ₃ ) m / z 461 (M + H) ⁺ and m / z 478 (M + NH ₄ ) ⁺ .

Example 37

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with cinnamil bromide and hydrolysis of the resulting ester. Mp 239-241 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.06 (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, 1H), 7.89 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 479 (M + H) ⁺ and m / z 496 (M + NH ₄ ) ⁺ .

Example 38

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) -5-methylthiazole. Mp 114-116 ° C. ¹ H NMR (d ₆ -DMSO, 300 MHz) δ 2.64 (s, 3H), 3.23 (s, 2H), 5.37 (s, 2H), 7.13 (m, 2H), 7.23 (m, 2H), 7.40 ( s, 1H), 7.47 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 8.10 (s, 1H). MS (DCI-NH ₃ ) 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) -5-chlorothiazole. Mp 185-186 ° C. ¹ 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, 1 H). MS (DCI-NH ₃ ) m / z 476 (M + H) ⁺ and m / z 493 (M + NH ₄ ) ⁺ .

Example 40

2- (2,3,3,4,4,4-hexafluoro-n-buten-1-yl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2,2,3,3,4,4,4-heptafluoro-1-iodobutane. Under alkylation conditions, HF is removed to give an unsaturated product. Mp 167-169 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 3.07 (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, 1H), 7.93 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCI-NH ₃ ) m / z 507 (M + H) ⁺ and m / z 524 (M + NH ₄ ) ⁺ .

Example 41

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-chloro-2 ', 4'-difluoroacetophenone. Mp 191-192 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 7.91 (d, J = 9 Hz, 2H), 8.03-8.12 (m, 1H). MS (DCI-NH ₃ ) m / z 499 (M + H) ⁺ and m / z 516 (M + NH ₄ ) ⁺ .

Example 42

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) -5-chlorothiophene. Mp 139-141 ° C. ¹ H NMR (d ₆ -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-NH ₃ ) m / z 474 (M + H) ⁺ and m / z 492 (M + NH ₄ ) ⁺ .

Example 43

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (bromomethyl) -5-methylthiophene. Mp 172-175 ° C. ¹ H NMR (d ₆ -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-NH ₃ ) m / z 441 (M + H) ⁺ and m / z 458 (M + NH ₄ ) ⁺ .

Example 44

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-chloro-4'-diethylaminoacetophenone. Mp 105-108 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 1.23 (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, 4 H), 7.90 (s, 1 H). MS (DCI-NH ₃ ) m / z 534 (M + H) ⁺ .

Example 45

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2,3,4,5,6-pentafluorobenzyl bromide. Mp 115-116 ° C. ¹ 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) ⁺ and m / z 542 (M + NH ₄ ) ⁺ .

Example 46

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-bromoacetophenone. Mp 228-230 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 7.90 (d, J = 9 Hz, 2H), 7.91 (s, 1 H), 8.04 (d, J = 7 Hz, 2H). MS (DCI-NH ₃ ) m / z 463 (M + H) ⁺ and m / z 480 (M + NH ₄ ) ⁺ .

Example 47

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-bromo-4'-chloroacetophenone. Mp 186-188 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 7.90 (d, J = 9 Hz, 2H), 7.91 (s, 1 H), 7.98 (d, J = 9 Hz, 2 H). MS (DCI-NH ₃ ) m / z 497 (M + H) ⁺ and m / z 514 (M + NH ₄ ) ⁺ .

Example 48

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with propargyl bromide. Mp 196-198 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 383 (M + H) ⁺ and m / z 400 (M + NH ₄ ) ⁺ .

Example 49

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-bromo-4'-cyanoacetophenone. Mp 188-189 ° C. ¹ 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 (DCI-NH ₃ ) m / z 488 (M + H) ⁺ .

Example 50

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with α-methyl-4-fluorobenzyl bromide. Mp 162-164 ° C. ¹ H 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, 1H). MS (DCI-NH ₃ ) m / z 467 (M + H) ⁺ and m / z 484 (M + NH ₄ ) ⁺ .

Example 51

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with (2-bromoethyl) benzene. Mp 170-171 ° C. ¹ 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, 5H), 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) ⁺ and 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 is prepared according to the method of Examples 6-10 by replacing the 4-fluoro-benzeneboronic acid of Example 6 with 3-chloro-4-fluorobenzeneboronic acid. Mp 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, 1H), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ and m / z 486 (M + NH ₄ ) ⁺ .

Example 53

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

The title compound is prepared according to the method of Examples 6 to 10, except that the 4-fluoro-benzeneboronic acid of Example 6 is replaced with 4-chlorobenzeneboronic acid. Mp 157-159 ° C. ¹ 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 (m, 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) ⁺ and 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

Debenzylated the product prepared in Example 52 according to the method of Example 11 and then alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20 to prepare the title compound do. Mp 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) ⁺ and m / z 478 (M + NH ₄ ) ⁺ .

Example 55

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-bromo-4'-trifluoromethoxyacetophenone. Mp 160-161 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 8.11 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 547 (M + H) ⁺ and m / z 564 (M + NH ₄ ) ⁺ .

Example 56

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2-bromo-4'-trifluoromethylacetophenone. Mp 205-206 ° C. ¹ 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 (DCI-NH ₃ ) m / z 531 (M + H) ⁺ and m / z 548 (M + NH ₄ ) ⁺ .

Example 57

2- [2- (benzo [b] thien-3-yl) -2-oxoethyl] -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -Pyridazinone

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 3-chloroacetylbenzo [b] thiophene. Mp 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, 1H), 7.94 (s, 1H), 8.53 (s, 1H), 8.72 (d, J = 7 Hz, 1H). MS (DCI-NH ₃ ) m / z 519 (M + H) ⁺ .

Example 58

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

Debenzylated the product prepared in Example 54 according to the method of Example 12 and then alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20 to prepare the title compound do. Mp 55-57 ° C. ¹ H NMR (CDCl ₃ , 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, 1H), 7.92 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 443 (M + H) ⁺ and m / z 460 (M + NH ₄ ) ⁺ .

Example 59

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 1-bromopinacolone. Mp 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, 1H) 7.89 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 443 (M + H) ⁺ and m / z 460 (M + NH ₄ ) ⁺ .

Example 60

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 3- (chloromethyl) thiophene. Mp 169-172 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.22 (s, 3H), 5.36 (s, 2H), 7.18 (m, 5H), 7.51 (m, 4H), 7.88 (m, 2H); 8.08 (s, 1 H). MS (DCI-NH ₃ ) m / z 441 (M + H) ⁺ and m / z 458 (M + NH ₄ ) ⁺ .

Example 61

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

The title compound is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 2- (chloromethyl) benzo [b] thiophene. Mp 93-96 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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

4- (4-Fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (172 mg, 0.5 mmol), Cu powder, prepared according to the method of example 10 (32 mg), a mixture of anhydrous K ₂ CO ₃ (207 mg, 1.5 mmol) and 4-fluoroiodobenzene (0.12 mL, 1 mmol) is prepared in 20 mL of pyridine. The solution is stirred at reflux for 14 h. The mixture is then cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer is washed with 10% citric acid, water, brine and concentrated in vacuo. Column chromatography: The separation (silica gel, CH ₂ Cl _2, diethyl ether 15: 1) to afford 190 mg of crude product. CH ₂ Cl ₂ - Diethyl ether was crystallized from hexane to give the title compound. (Yield 175 mg, 79.9%). Mp 168-169 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.07 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.20 (m, 4H), 7.40 (d, J = 9 Hz, 2H), 7.69 (m, 2H), 7.92 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS (DCI-NH ₃ ) m / z 439 (M + H) ⁺ , 456 (M + NH 4) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ F ₂ N ₂ O ₃ S.0.25 H ₂ O

Anal: 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

5-hydroxy-5-methyl-2 (5H) -furanone (454 mg, 1.25 mmol) prepared according to the method recited above was dissolved in n-butanol (10 mL) and hydrazine hydrate (0.3 mL, 6.2 mmol) ), And then stir at reflux for 18 hours. On cooling, white crystals (224 mg, 50%) are obtained. Mp 290 ° C (dec.) ¹ HNMR (300 MHz, d ₆ -DMSO) δ 1.99 (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, 1H). MS (DCI / NH ₃ ) 376 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₅ N ₂ FSO ₃ 0.25 H ₂ O

Anal: 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

Example 63 (100 mg, 0.28 mmol) of the product was dissolved in anhydrous DMF (3 mL) and 1,1,1-trifluoro at 50-60 ^° C. in the presence of anhydrous sodium carbonate (130 mg, 1.2 mmol). Treat with rho-2-iodoethane (27.5 mL, 280 mmol) for 2 hours. The reaction mixture is partitioned between water and ethyl acetate to afford the desired compound as an amorphous solid. (60 mg, 48%). ¹ HNMR (300 MHz, CDCl ₃ ) δ 2.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J = 9 Hz, 2H), 6.90 (m, 2H), 7.10 (dd, J = 6 Hz, J = 9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J = 9 Hz, 2H). Elemental Analysis of MS (DCI / NH ₃ ) 458 (M + NH ₄ ) ⁺ C ₂₀ H ₁₆ N ₂ F ₄ SO ₃

Anal: 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

3,4-Dichlorophenylboronic acid was combined with 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone according to the method of Example 6 [J. Het. Chem., 1996, 33, 1579-1582. Prepare the title compound. This product is converted to 5-hydroxy-derivatives according to the method of Example 7. The 5-hydroxy compound is converted to 5-trifluoro-methylsulfonyloxy-derivative according to the method of Example 8. When 4- (methylthio) phenylboronic acid was bound to the triflate according to the method of Example 9, 5- [4- (methylthio) phenyl] -intermediate was obtained, which was oxidized according to the method of Example 10. Obtain the final product. (Yield 780 mg, 84%). Mp 161-163 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.90 (d, J = 9 Hz, 2H), 8.13 (s, 1H). MS (DCI-NH ₃ ) m / z 485 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ Cl ₂ N ₂ O ₃ S

Anal: 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

4- (n-propyl) phenylboronic acid was combined with 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone according to the method of Example 6 [J. Het. Chem., 1996, 33, 1579-1582. Prepare the title compound. This product is converted to 5-hydroxy-derivatives according to the method of Example 7. The 5-hydroxy compound is converted to 5-trifluoro-methylsulfonyloxy-derivative according to the method of Example 8. When 4- (methylthio) phenylboronic acid was bound to the triflate according to the method of Example 9, 5- [4- (methylthio) phenyl] -intermediate was obtained, which was oxidized according to the method of Example 10. Obtain the final product. (Yield 220 mg, 70%). Mp 64-66 ° C. ¹ 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 (DCI-NH ₃ ) m / z 451 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ F ₃ N ₂ O ₃ S

Anal: 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 is prepared by combining 3-fluoro-4-chlorophenylboronic acid with 2-benzyl-4-chloro-5-methoxy-3 (2H) -pyridazinone according to the method of Example 6. This product is converted to a 5-hydroxy-compound according to the method of Example 7. The 5-hydroxy compound is converted to 5-trifluoro-methylsulfonyloxy-derivative according to the method of Example 8. When 4- (methylthio) phenylboronic acid was bound to the triflate according to the method of Example 9, 5- [4- (methylthio) phenyl] -intermediate was obtained, which was oxidized according to the method of Example 10. Obtain the final product. (Yield 170 mg, 84%). Mp 174-175 ° C. ¹ 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, 1H), 7.30 (t, J = 9 Hz, 1H), 7.39 (d, J = 9 Hz, 2H), 7.91 (s, 1H), 7.95 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 461 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ ClF ₄ N ₂ O ₃ S

Anal: 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

2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 in trifluoroacetic anhydride (30 mL) A solution of (2H) -pyridazinone (680 mg, 1.53 mmol) is stirred at room temperature for 1 hour. Excess solvent is evaporated in vacuo and the residue is treated with 1N solution of methanol-NaOH (50 mL, 4: 1) at 0 ° C. The solution is stirred at room temperature for 2 hours and quenched with dilute HCl solution until acidic. The white suspension formed is concentrated in vacuo to evaporate methanol. THF is added to the resulting suspension until a clear solution is obtained. Chlorine gas is slowly bubbled into solution and maintained at 0 ° C. After 10 minutes, nitrogen gas is bubbled into the solution for several minutes to release residual chlorine. Ammonium hydroxide solution (30%, 5 to 10 mL) is slowly added to the solution at 0 ° C. (all starting sulfonyl chloride is consumed) and stirred at room temperature for 5 minutes. The solution is partitioned between water and ethyl acetate. The organic layer is first washed with water, then brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (40:60 ethyl acetate / hexanes) to afford the title compound. (Yield 500 mg, 75%). Mp 193-195 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.82 (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, 1H). MS (DCI-NH ₃ ) m / z 428 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₃ F ₄ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 77. The product is combined with 4-chlorophenylboronic acid according to the method of Example 6. The product was debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20 to give a sulfided compound.

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

The sulfide is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to the corresponding sulfoxide to give the corresponding methyl sulfoxide, which is converted to the sulfonamide final product according to the method of Example 68. (Yield 540 mg, 70%). Mp 154-156 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, 1H). MS (DCI-NH ₃ ) m / z 444 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₃ ClF ₃ N ₃ O ₃ S

Anal: 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 1 equivalent of meta-chloroperoxybenzoic acid to give methylsulfoxide, which was converted to the sulfonamide final product according to the method of Example 68. (Yield 396 mg, 60%). Mp 158-160 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.21 (d, J = 6 Hz, 6H), 4.83 (q, J = 7.5 Hz, 2H), 4.86 (s, 2H), 5.46 (p, J = 6 Hz , 1H), 7.72 (d, J = 9 Hz, 2H), 7.82 (s, 1H), 8.03 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 392 (M + H) ⁺ .

Elemental Analysis for C ₁₅ H ₁₆ F ₃ N ₃ O ₄ S

Anal: 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 is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to give methylsulfoxide, which is converted to the sulfonamide final product according to the method of Example 68. (Yield 180 mg, 37%). Mp 150-152 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.71 (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, 1H), 8.05 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 444 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₃ F ₄ N ₃ O ₄ S

Anal: 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) is treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture is stirred at room temperature for 1 hour. According to thin layer chromatography (100% hexane) sample, since the reaction was not completed, an additional 1 equivalent of base and iodomethane were added and the reaction mixture was stirred at room temperature overnight. The reaction is acidified with 10% aqueous citric acid and extracted with hexane (2 X 125 mL). The combined organic extracts are washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to afford the desired compound as a pale yellow oil. (Yield 6.68 g; 60%).

72A-2. 2-fluorothioanisole

Another method for preparing 2-fluorothioanisole is initiated with a solution of 1,2-difluorobenzene (0.79 mL, 8 mmol) in anhydrous DMF (50 mL) to provide sodium hydroxide thiomethoxide (0.59). g, 8 mmol). The reaction mixture is stirred at rt for 6 h and partitioned between hexane and water. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give the desired compound (1.1 g, 100%), of which 1,2-bis (methylthio) benzene, a somewhat contained R _f material, was added to 100% hexane (0.9 g, 80%). Chromatography is removed. ¹ H NMR (300 MHz, 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) is cooled to ° C and bromine (0.5 mL, 10 mmol) is added dropwise. . At the end of the bromine treatment, the reaction is collected and applied to TLC (100% hexane). A new, high R _f material is present but the reaction is not complete, so again an equal amount of bromine is added a catalytic amount of ammonium chloride. The reaction mixture is stirred overnight at room temperature. Aqueous sodium sulfate is added to the reaction mixture, the organic layer is separated, dried over MgSO ₄ and filtered. The filtrate is filtered through a pad of silica gel to decolorize and then concentrated under reduced pressure to yield the product of a clear, colorless oil. (Yield 1.3 g; 60%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.48 (s, 3H), 7.31 (t, J = 9 Hz, 1H), 7.43 (dd, J = 9 Hz, 3 Hz, 1H) 7.54 (dd, J = 9 Hz, 3 Hz, 1H).

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) is cooled to -78 ° C under nitrogen atmosphere. The reaction mixture is treated with 1.6 M n-butyllithium (1.7 mL, 27.1 mmol) in hexanes, and the mixture is warmed to −40 ° C. and maintained for 0.5 h. The reaction mixture is then cooled to -78 ° C and 3 equivalents of triisopropyl borate (1.56 mL, 67.8 mmol) are added. The reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours. At this point, 10% aqueous KOH (200 mL, 360 mmol) is added and the mixture is stirred at rt overnight. The reaction mixture is then poured into cold / concentrated HCl mixture with stirring to yield a white precipitate. This solid is dried overnight in a vacuum oven (65 ° C., 29 in Hg) to afford the title compound. (Yield 0.22 g; 52.4%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.48 (s, 3H), 7.31 (t, J = 9 Hz, 1H), 7.49 (dd, J = 12 Hz, 1.5 Hz, 1H) 7.54 (dd, J = 9 Hz, 1.5 Hz, 1H).

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] were converted to 5-hydroxy- homologues according to the method of Example 7, followed by conversion to 5-trifluoromethylsulfonyloxy- homologues according to the method of Example 8. Let's do it. Then, bound to 3-fluoro-4- (methylthio) phenyl-boronic acid according to the method of Example 9, to 2-benzyl-4-chloro-5- [3-fluoro-4- (methylthio) Phenyl] -3 (2H) -pyridazinone is obtained. This intermediate is bonded in the 4-position with 4-fluorophenylboronic acid according to the method of Example 6. This product is N-debenzylated according to the method of Example 11 and N-arylated with 4-fluoroiodobenzene according to the method of Example 62. The resulting sulfide is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methylsulfoxide, which is converted to the sulfonamide final product according to the method of Example 68. (Yield 500 mg, 75%). Mp 222-224 ° C. ¹ H 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 (d, 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, 1H), 7.95 (s, 1H). MS (DCI-NH ₃ ) m / z 458 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₁₄ F ₃ N ₃ O ₃ S

Anal: 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- (aminosulfonyl) -phenyl] -3 (2H) -pyrida Xenon

The methyl sulfide intermediate prepared in Example 67 was oxidized with 1 equivalent of meta-chloroperoxybenzoic acid according to the method of Example 68 to obtain methyl sulfoxide. Methyl sulfoxide is converted to sulfonamide product according to the method of Example 68. (Yield 1.5 g, 63%). Mp 180-183 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.39 (dd, J = 9 Hz, 3 Hz, 1H), 7.47 (dd, J = 9 Hz, 3 Hz, 1H), 7.55 (t, J = 9 Hz, 1H), 7.71 (t , J = 9 Hz, 1H), 7.78 (s, 2H), 8.37 (s, 1H). MS (DCI-NH ₃ ) m / z 480 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₁ ClF ₅ N ₃ O ₃ S

Anal: 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] were converted to 5-hydroxy- homologues according to the method of Example 7, followed by conversion to 5-trifluoromethylsulfonyloxy- homologues according to the method of Example 8. Let's do it. Then, 2-benzyl-4-chloro-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone was bound to 4- (methylthio) phenylboronic acid according to the method of Example 9. To obtain. The 4-chloro-intermediate thus prepared was treated with 2-propanol (20 mL, 261 mmol) and potassium t-butoxide (110 mg, 0.98 mmol) for 45 minutes under reflux for 2-benzyl-4- (2-pro Foxy) -5- [4- (methylthio) pentyl] -3 (2H) -pyridazinone is obtained. This methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 180 mg, 80%). Mp 109-111 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.18 (d, J = 6 Hz, 6H), 3.12 (s, 3H), 5.36 (s, 2H), 5.49 (h, J = 6 Hz, 1H), 7.35 (m, 3H), 7.47 (dd, J = 9 Hz, 3 Hz, 2H), 7.74 (d, J = 9 Hz, 2H), 7.79 (s, 1H), 8.03 (d, J = 9 Hz, 2H ). MS (DCI-NH ₃ ) m / z 399 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ N ₂ O ₄ S

Anal: C, 63.29; H, 5.56; N, 7.03.

Found: C, 63.17; H, 5.57; N, 6.95.

Example 75

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

The title compound is prepared following the method of Example 74 by replacing 2-propanol with 4-fluorophenol. (252258) (Yield 180 mg, 99%). Mp 188-190 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12 (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-NH ₃ ) m / z 451 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₄ S

Anal: C, 63.98; H, 4. 25; N, 6.21.

Found: C, 63.74; H, 4.2; N, 6.12.

Example 76

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

2-benzyl-4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (2,2,2-trifluoroethyl) -4-chloro-5 The title compound is prepared according to the method of Example 75, replacing by-[4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 180 mg, 63%). Mp 161-164 ° C. ¹ 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, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 443 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₄ F ₄ N ₂ O ₄ S

Anal: 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] were converted to 5-hydroxy- homologues according to the method of Example 7, followed by conversion to 5-trifluoromethylsulfonyloxy- homologues according to the method of Example 8. Let's do it. Then, 2-benzyl-4-chloro-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone was bound to 4- (methylthio) phenylboronic acid according to the method of Example 9. To obtain. This intermediate is combined with 4-chlorophenylboronic acid according to the method of Example 6. This product is N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide is oxidized to the corresponding sulfoxide with 1 equivalent of meta-chloroperoxybenzoic acid according to the method of Example 5 to afford the title compound. (Yield 130 mg, 70%). Mp 154-155 ° C. ¹ 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 (DCI-NH ₃ ) m / z 427 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₄ ClF ₃ N ₂ O ₂ S

Anal: 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

Oxidation of the title compound to 2-benzyl-4-chloro-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (prepared as an intermediate in Example 77) according to the method of Example 10 To make it. (Yield 180 mg, 83%). Mp 166-167 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12 (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, 1H), 8.08 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 375 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₅ ClN ₂ O ₃ S

Anal: 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-chloro-5-methoxy-3 (2H) -pyridazinone [J. Het. Chem., 1996, 33, 1579-1582] were converted to 5-hydroxy- homologues according to the method of Example 7, followed by conversion to 5-trifluoromethylsulfonyloxy- homologues according to the method of Example 8. Let's do it. Then, 2-benzyl-4-chloro-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone was bound to 4- (methylthio) phenylboronic acid according to the method of Example 9. To obtain. This intermediate is combined with 4-methylphenylboronic acid according to the method of Example 6. This product is N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide is oxidized to the title compound according to the method of Example 10. (Yield 210 mg, 98%). Mp 154-156 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (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 (DCI-NH ₃ ) m / z 423 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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) -pyrida Xenon

2-benzyl-4-chloro-5-methoxy-3 (2H) -pyridazinone [J. Het. Chem., 1996, 33, 1579-1582] were converted to 5-hydroxy- homologues according to the method of Example 7, followed by conversion to 5-trifluoromethylsulfonyloxy- homologues according to the method of Example 8. Let's do it. Then, 2-benzyl-4-chloro-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone was bound to 4- (methylthio) phenylboronic acid according to the method of Example 9. To obtain. This intermediate is combined with 4-chlorophenylboronic acid according to the method of Example 6. This product is N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to the corresponding sulfoxide to give methylsulfoxide, which is converted to the sulfonamide final product according to the method of Example 68. (Yield 500 mg, 75%). Mp 214-215 ° C. ¹ 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, 1H ), 7.31 (d, J = 9 Hz, 1H), 7.32 (d, J = 9 Hz, 2H), 7.90 (s, 1H), 7.92 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 462 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₂ F ₄ ClN ₃ O ₃ S

Anal: 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 243196 described in Example 65 is N-debenzylated according to the method of Example 11. Replace 4-fluorobenzyl bromide with 2-iodo-1,1,1-trifluoroethane and the intermediate is N-alkylated according to the method of Example 20 to afford the title compound. (Yield 165 mg, 55%). Mp 197-198 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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 (DCI-NH ₃ ) m / z 477 (M + H) ⁺ . Elemental Analysis for C ₁₉ H ₁₃ F ₃ Cl ₂ N ₂ O ₃ S

Anal: 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 added 2-aminopropane (2 mL, 23.5 mmol) and potassium t- in toluene (40 mL). Reaction with butoxide (910 mg, 6.6 mmol) under reflux for 18 hours yields a 4- (2-propylamino) -derivative after column chromatography (silica gel, 92: 8 hexanes / ethyl acetate). The intermediate is bound in the 5-position with 4- (methylthio) phenylboronic acid according to the method of Example 6. The methyl sulfide was oxidized according to the method of Example 10 to afford the title compound. (Yield 120 mg, 48%). Mp 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, 1H) , 7.33 (m, 3H), 7.42 (s, 1H), 7.48 (dd, J = 9 Hz, 3 Hz, 2H), 7.56 (d, J = 9 Hz, 2H), 8.00 (d, J = 9 Hz , 2H). MS (DCI-NH ₃ ) m / z 399 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₂₃ N ₃ O ₃ S

Anal: 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 cocobromic acid (10 g, 38.8 mmol) and trifluoroethyl hydrazine (70% in water, 4.88 mL, 38.8 mmol) in 100 mL of methanol is prepared and heated at reflux for 3 hours. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The ethyl acetate layer is dried over MgSO ₄ , filtered through a pad of silica gel and concentrated in vacuo. The product is obtained as a yellow 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 (DCI-NH ₃ ) m / z 337 (M + H) ⁺ .

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

2-0 (2,2,2-trifluoroethyl) -4,5-dibromo-3 (2H) -pyridazinone (2 g, 6 mmol) in toluene (40 mL), isopropyl alcohol (3 mL) and a solution of sodium hydride (60% dispersion in oil, 290 mg, 7.2 mmol) are heated under reflux for 5 hours. The reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is filtered and concentrated in vacuo. The residue is purified by chromatography (95: 5 hexanes / ethyl acetate) to afford the product of a green oil. (Yield 1.22 g, 65%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46 (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

2- (2,2,2-trifluoroethyl) -4- (2-propoxy) -5-bromo-3 (2H) -pyridazinone (1.2 g, 3.8 in 20 mL of ethylene glycol dimethyl ether) 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) The solution of is heated for 5 hours. The mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with water, brine, dried over MgSO ₄ and concentrated in vacuo. The residue is purified by chromatography on silica gel (94: 6 hexanes / ethyl acetate). The product is obtained as a green solid. (Yield 1.1 g, 81%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.19 (d, J = 7.5 Hz, 6H), 2.55 (s, 3H), 4.83 (q, J = 9 Hz, 2H), 5.28 (h, J = 6 Hz , 1H), 7.32 (d, J = 9 Hz, 2H), 7.52 (d, J = 9 Hz, 2H), 7.85 (s, 1H). MS (DCI) m / z 359 (M + H) ⁺ .

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

4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (2,2,2-trifluoroethyl) -4- (2 The title compound is prepared according to the method of Example 10, replacing by -propoxy) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 220 mg, 100%). Mp 152-153 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.2 (d, J = 6 Hz, 6H), 3.13 (s, 3H), 4.84 (q, J = 9 Hz, 2H), 5.49 (p, J = 6 Hz , 1H), 7.78 (d, J = 9 Hz, 2H), 7.82 (s, 1H), 8.05 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 391 (M + H) ⁺ . Elemental Analysis for C ₁₆ H ₁₇ F ₃ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 83 by replacing 2-propanol with cyclohexane. (Yield 250 mg, 52%). Mp 129-130 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.1-1.6 (m, 8H), 1.84 (m, 2H), 3.12 (s, 3H), 4.83 (q, J = 9 Hz, 2H), 5.21 (h, J = 4.5 Hz, 1H), 7.77 (s, 1H), 7.80 (d, J = 9 Hz, 2H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 431 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₂₁ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 83 by replacing 2-propanol with cyclopentanol. (Yield 250 mg, 52%). Mp 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, 1H), 7.75 (d, J = 9 Hz, 2H), 7.83 (s, 1H), 8.04 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 417 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₉ F ₃ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 83B by replacing 2-propanol with 2-propylamine. (Yield 70%). MS (DCI-NH ₃ ) m / z 315 (M + H) ⁺ .

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

2- (2,2,2-trifluoroethyl) -4-isopropoxy-5-bromo-3 (2H) -pyridazinone 2- (2,2,2-trifluoroethyl)- The title compound is prepared according to the method of Example 83C, replacing by 4- (2-propylamino) -5-bromo-3 (2H) -pyridazinone. (Yield 80%). MS (DCI-NH ₃ ) m / z 358 (M + H) ⁺ .

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

4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (2,2,2-trifluoroethyl) -4- (2 The title compound is prepared according to the method of Example 83C, replacing by -propylamino) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 180 mg, 83%). Mp 173-174 ° C. ¹ 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 (s, 1H), 7.45 (s, 1 H), 7.59 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 340 (M + H) ⁺ .

Elemental Analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₄ S

Anal: 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 method of Example 2 was reacted with morpholine according to the method of Example 86 to obtain 4-morpholino-derivatives. . The morpholino intermediate is bound in the 5-position with 4- (methylthio) phenylboronic acid according to the method of Example 6. The resulting methyl sulfide is oxidized to the title compound according to the method of Example 10. (Yield 150 mg, 69%). Mp 158-160 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.06 (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, 1H), 8.05 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 426 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ N ₃ O ₄ S

Anal: 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-1yl)]-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 is described in J. Pat. Org. Chem., 1989, 54, 5640-5642. Mesylate is obtained by reacting mesyl chloride in diethyl ether with 2,3,3-trifluoro-2-propen-1-ol. Standard workup affords the product, which is used without purification.

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

Starting with 2-benzyl-pyridazinone from Example 9 the compound was debenzylated according to the method of Example 11 to give 4- (4-fluorophenyl) -5- [4- (methylthio) phenyl ] -3 (2H) -pyridazinone is prepared.

4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (250 mg, 0.8 mmol) in ethyl acetate (30 mL), Cs ₂ CO ₃ (650 mg, 2 mmol), and a mixture of 3-methylsulfonyloxy-1,1,2-trifluoro-propene (mesylate, 250 mg, 1.19 mmol) are stirred at 55 ° C. for 1.5 hours. The mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo. The residue was purified by column chromatography eluting with 15% ethyl acetate / hexanes on silica gel to give methyl sulfide, 2- (2,3,3-trifluoro-2-propen-1yl) -4- (4- Fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is obtained as green oil. (Yield 175 mg, 53%).

88C. 2- (2,3,3-trifluoro-2-propen-1yl)]-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -Pyridazinone

The methyl sulfide prepared above is oxidized to the title compound according to the method of Example 10. (Yield 125 mg, 68%). Mp 154-156 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 7.9 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 439 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₄ F ₄ N ₂ O ₃ S

Anal: C, 54.79; H, 3. 21; N, 6.38.

Found: C, 54.52; H, 3. 15; N, 6.21.

Example 89

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

2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2, The title compound is prepared according to the method of Example 68, replacing by 4-bis (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone. (Yield 118 mg, 43%). Mp 213-216 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.4 (m, 6H), 7.7 (dd, 2H), 7.76 (d, J = 9 Hz, 2H), 8.2 (s, 1 H). MS (DCI-NH ₃ ) m / z 440 (M + H) ⁺ , 439.44 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ FN ₂ O ₃ S ₂

Anal: 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

Isopropanol was replaced with methanol to prepare the title compound according to the method of Example 83B. (Yield 78%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.3 (s, 3H), 4.76 (q, J = 9 Hz, 2H), 7.85 (s, 1H). MS (DCI-NH ₃ ) m / z 288 (M + H) ⁺ .

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

2- (2,2,2-trifluoroethyl) -4- (2-propoxy) -5-bromo-3 (2H) -pyridazinone 2- (2,2,2-trifluoro Prepare by the method of Example 83C, replacing the ethyl) -4-methoxy-5-bromo-3 (2H) -pyridazinone to give the title compound. (Yield 80%). ¹ H 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 (s, 1H). MS (DCI-NH ₃ ) m / z 331 (M + H) ⁺ .

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

2- (2,2,2-trifluoroethyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone in acetic acid (40 mL) (2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) are stirred under reflux for 3 hours. The reaction mixture is cooled to room temperature and water (50 mL) is added. The crystals formed are filtered off, washed with 5% ethyl acetate in water and hexanes and then dried to give a constant weight. The product is obtained as a white solid. (Yield 1.75 g, 91%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.54 (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, 1 H), 8.00 (s, 1 H). MS (DCI) m / z 317 (M + H) ⁺ .

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

2- (2,2,2-trifluoroethyl) -4-hydroxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (150 mg, in freshly distilled THF 0.47 mmol), cyclopropyl methanol (43 mL, 0.52 mmol) and triphenylphosphine (124 mg, 0.47 mmol) were prepared and added dropwise to diethyl azodicarboxylate (75 mL, 0.52 mmol) at 0 ° C. do. The mixture is allowed to warm to room temperature, concentrated for 5 hours and then concentrated in vacuo. The residue is purified by chromatography on silica gel (95: 5 hexanes / ethyl acetate) to afford the product of a colorless oil. (Yield 140 mg, 81%). ¹ 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 (DCI-NH ₃ ) m / z 371 (M + H) ⁺ .

90E. 2- (2,2,2-trifluoroethyl) -4-cyclopropylmethoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

4- (4-Fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (2,2,2-trifluoroethyl) -4-cyclopropyl The title compound is prepared according to the method of Example 10, replacing by methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 130 mg, 85%). Mp 133-135 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.22 (m, 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, 1H), 7.83 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 403 (M + H) ⁺ .

Elemental Analysis for C ₁₇ H ₁₇ F ₃ N ₂ O ₄ S

Anal: 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-propene-1-oxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 90 by replacing cyclopropylmethanol with 2-propen-1-ol. (Yield 120 mg, 77%). Mp 121-123 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12 (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, 1H), 5.27 (dd, J = 15 Hz, 1 Hz, 1H), 5.85 (m, 1H), 7.25 (d, J = 9 Hz, 2H), 7.83 (s, 1H), 8.06 ( d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 389 (M + H) ⁺ .

Elemental Analysis for C ₁₆ H ₁₅ F ₃ N ₂ O ₄ S

Anal: 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) -pyrida Xenon

The title compound is prepared according to the method of Example 90 by replacing cyclopropylmethanol with 4-fluoro-alpha-methylbenzyl alcohol. (Yield 155 mg, 76%). Mp 133-135 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.57 (d, J = 6 Hz, 3H), 3.13 (s, 3H), 4.75 (q, J = 7.5 Hz, 1H), 4.87 (q, J = 7.5 Hz , 1H), 6.34 (q, J = 6 Hz, 1H), 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, 1 H), 8.03 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 471 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₁₈ F ₄ N ₂ O ₄ S

Anal: 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

Product from Example 11 in 20 mL of pyridine, 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (344 mg, 1.0 mmol ), 4-bromothioanisole (812 mg, 4.0 mmol), and a solution of copper (70 mg, 1.1 mmol) are stirred under reflux for 18 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture is diluted with a mixture of water and ethyl acetate. The two layers were separated and filtered through Celite ^{R (R} Celite). The organic layer is washed with 10% aqueous citric acid and brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography (silica gel, 93: 7 dichloromethane / ethyl acetate) to afford the title compound on the foam. (Yield 380 mg, 81.5%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (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) ⁺ .

Elemental Analysis for _{C 24 H 19 FN 2 O 3} S 2 · 0.5 H 2 O

Anal: 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 is prepared by oxidizing the product of Example 93 according to the method of Example 10. (Yield 156 mg, 78%). ¹ 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 (m, 3H). MS (DCI-NH ₃ ) m / z 499 (M + H) ⁺ , 516 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₅ S ₂ .0.5 H ₂ O

Anal: 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 is prepared following the method of Example 93 by replacing 4-bromothioanisole with 2-bromo-3-methylthiophene. (Yield 190 mg, 43%). Mp 215-217 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.21 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 441 (M + H) ⁺ , 458 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₇ FN ₂ O ₃ S ₂ .0.5 H ₂ O

Anal: 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 is prepared following the method of Example 93 by replacing 4-bromothioanisole with 2-bromo-5-nitrobenzotrifluoride. (Yield 390 mg, 73%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, 1H), 7.96 (d, J = 9 Hz, 2H), 8.02 (s, 1H), 8.61 (dd, J = 9 Hz, 3 Hz, 1H), 8.75 (d, J = 3 Hz, 1H). MS (DCI-NH ₃ ) m / z 534 (M + H) ⁺ , 551 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₅ F ₄ N ₃ O ₅ S · 0.75 H ₂ O

Anal: 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 is prepared according to the method of Example 93 by replacing 4-bromothioanisole with 3-bromothioanisole. (Yield 355 mg, 76%). Mp 196 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (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, 1H), 7.37-7.49 (m, 2H), 7.40 (d, J = 9 Hz, 2H), 7.58 (m, 1H), 7.92 (d, J = 9 Hz, 2H) , 7.99 (m, 1 H). MS (DCI-NH ₃ ) m / z 467 (M + H) ⁺ , 484 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S ₂

Anal: 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 is prepared by oxidizing the product of Example 97 according to the method of Example 10. (Yield 98 mg, 65.6%). Mp 141-142 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.95 (d, J = 9 Hz, 2H), 8.05 (m, 1H), 8.25 (t , J = 1.5 Hz, 1H), 8.33 (s, 1H). MS (DCI-NH ₃ ) m / z 516 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₅ S ₂ .H ₂ O

Anal: 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

Starting with 2-benzylpyridazinone from Example 53 and debenzylating according to the method of Example 11 4- (4-chlorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 Prepare (2H) -pyridazinone.

4- (4-chlorophenyl) -5- [4- (methylsulfonyl) instead of 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone The title compound is prepared according to the method of Example 93, starting from) phenyl] -3 (2H) -pyridazinone and replacing 4-bromothioanisole with 1-fluoro-4-iodobenzene . (Yield 245 mg, 54%). Mp 195-197 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.08 (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 ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClFN ₂ O ₃ S

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 4- (4-chlorophenyl) -5- [4- (methylsulfonyl ) Phenyl] -3 (2H) -pyridazinone and 4-bromothioanisole for 2-bromo-5-chlorothiophene to prepare the title compound according to the method of Example 93. . (Yield 150 mg, 45%). Mp 249-251 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (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, 1H), 7.94 (d, J = 9 Hz, 2 Hz, 2H), 8.04 (s, 1H). MS (DCI-NH ₃ ) m / z 477 (M + H) ⁺ , 494 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₄ Cl ₂ N ₂ O ₃ S ₂ .H ₂ O

Anal: 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

4- (4-chlorophenyl) -5- [4- (methylsulfonyl) instead of 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone The title compound is prepared according to the method of Example 93, starting from) phenyl] -3 (2H) -pyridazinone and replacing 4-bromothioanisole with 3-iodobenzotrifluoride. (Yield 210 mg, 59.5%). Mp 103-105 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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 ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ ClF ₃ N ₂ O ₃ S

Anal: 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

4- (4-chlorophenyl) -5- [4- (methylsulfonyl) instead of 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone Starting from) phenyl] -3 (2H) -pyridazinone (described in Example 99) and replacing 4-bromothioanisole with 1-bromo-3-chloro-4-fluorobenzene Prepare by the method of Example 93 to provide the title compound. (Yield 330 mg, 58.8%). Mp 205 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.10 (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, 1H), 7.85 (dd, J = 9 Hz, 3 Hz, 1H), 7.93 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCI-NH ₃ ) m / z 489 (M + H) ⁺ , 508 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ Cl ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 93 by replacing 4-bromothioanisole with 1-fluoro-3-iodobenzene. (Yield 310 mg, 70.8%). Mp 245-247 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.08 (s, 3H), 6.98 (t, J = 9 Hz, 2H), 7.14 (m, 1H), 7.24 (dd, J = 9 Hz, 6 Hz, 2H ), 7.40 (m, 2H), 7.52 (m, 3H), 7.92 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCI-NH ₃ ) m / z 439 (M + H) ⁺ , 456 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ F ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 93 by replacing 4-bromothioanisole with 2-bromothioanisole. (Yield 280 mg, 60%). Mp 206-208 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.49 (s, 3H), 3.08 (s, 3H), 6.95 (t, J = 9 Hz, 2H), 7.25 (dd, J = 9 Hz, 6 Hz, 2H ), 7.29-7.51 (m, 4H), 7.43 (d, J = 9 Hz, 2H), 7.92 (d, J = 9 Hz, 3H), 8.01 (s, 1H), 7.98 (s, 1H). MS (DCI-NH ₃ ) m / z 467 (M + H) ⁺ , 484 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S ₂ .H ₂ O

Anal: 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 is prepared according to the method of Example 93 by replacing 4-bromothioanisole with 2-bromo-5-nitrothiophene. (Yield 330 mg, 70%). Mp 252-253 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 7.95 (m, 3H), 8.14 (s, 1H). MS (DCI-NH ₃ ) m / z 472 (M + H) ⁺ , 489 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₄ FN ₃ O ₅ S ₂ .0.5 H ₂ O

Anal: 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

4- (4-chlorophenyl) -5- [4- (methylsulfonyl) instead of 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone The title compound according to the method of Example 93, starting from) phenyl] -3 (2H) -pyridazinone and replacing 4-bromothioanisole with 1-bromo-3,4-difluorobenzene To prepare. (Yield 310 mg, 65.7%). Mp 187-188 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.09 (s, 3H), 7.18 (d, J = 9 Hz, 2H), 7.29 (m, 3H), 7.41 (d, J = 9 Hz, 2H), 7.52 (m, 1H), 7.65 (m, 1H), 7.92 (d, J = 9 Hz, 2H), 8.01 (s, 1H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ ClF ₂ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 93 by replacing 4-bromothioanisole with 3-bromobenzothiophene. (Yield 185 mg, 41%). Mp 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, 1H), 7.87-7.94 (m, 2H), 7.94 (d, J = 9 Hz, 2H), 8.05 (s, 1H). MS (DCI-NH ₃ ) m / z 477 (M + H) ⁺ , 494 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₁₇ FN ₂ O ₃ S ₂

Anal: 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

Toluene was converted to 2-benzyl-4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 75) according to the method of Example 11. Treatment with AlBr ₃ in affords the title compound. (Yield 1.8 g, 95%).

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

4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and 4-bromothioanisole Substituted with iodobenzene, the title compound is prepared according to the method of Example 93. (Yield 60 mg, 53%). Mp 83-85 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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 (s, 1H). MS (DCI-NH ₃ ) m / z 455 (M + H) ⁺ , 472 (M + NH ₄ ) ⁺ .

Example 109

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

Replace 4-bromothioanisole with 1-bromo-3,4-difluorobenzene and replace 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 ( Example 2, replacing 2H) -pyridazinone with 4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 108A) Prepare the title compound according to the method of 93. (Yield 185 mg, 39%). Mp 178-180 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.11 (s, 3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45-7.52 (m, 1H), 7.61 (dt, J = 6 Hz, 3 Hz, 1H), 7.82 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₃ N ₂ O ₄ S · 0.5 H ₂ O

Anal: 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

Replace 4-bromothioanisole with 1,3-dibromobenzene and 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyrida Replace xenon with 4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 108A), following the method of Example 93. Prepare the title compound. (Yield 260 mg, 50.5%). Mp 208-210 ° C. ¹ 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, 1H ), 7.64 (br d, J = 9 Hz, 1H), 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, 1 H). MS (DCI-NH ₃ ) m / z 517 (M + H) ⁺ , 534 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₃ H ₁₆ BrFN ₂ O ₄ S

Anal: 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

Replace 4-bromothioanisole with 1-bromo-3,4-difluorobenzene and replace 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 ( Example 2, replacing 2H) -pyridazinone with 4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 108A) Prepare the title compound according to the method of 93. (Yield 175 mg, 37%). Mp 209-211 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.10 (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, 1H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₃ N ₂ O ₄ SH ₂ O

Anal: 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

Replace 4-bromothioanisole with 1-bromo-3-chlorobenzene and 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri In the method of Example 93, replacing dazinone with 4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 108A) According to the title compound. (Yield 25 mg, 5.3%). Mp 211-213 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.30 (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 (DCI-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClFN ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 4-nitrobenzyl bromide. (Yield 164 mg, 58.9%). Mp 183-184 ° C. ¹ 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, 1H), 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 ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ FN ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 4- (chloromethyl) phenyl acetate. (Yield 220 mg, 76.9%). Mp 172-174 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.30 (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 (DCI-NH ₃ ) m / z 510 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₆ H ₂₁ FN ₂ O ₅ S

Anal: 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

2- (4-acetoxybenzyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (0.2 g) in THF (20 mL) , 4.06 mmol) (Example 114) are treated with a solution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL) is added to obtain a homogeneous solution, which is stirred overnight at room temperature. The reaction mixture is then acidified with 10% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate layer is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo to give a white foam which is purified by column chromatography (silica gel, 65:35 hexanes / ethyl acetate). Product fractions are combined and concentrated in vacuo. The residue is determined from ethyl acetate / hexanes. (Yield 195 mg, 70%). Mp 225-226 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (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-NH ₃ ) m / z 451 (M + H) ⁺ . Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 3-nitrobenzyl bromide. (Yield 195 mg, 70%). Mp 156-157 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (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, 1H), 7.88 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 8.19 (br d, J = 7 Hz, 1H), 8.37 (t, J = 1.7 Hz, 1H). MS (DCI-NH ₃ ) m / z 480 (M + H) ⁺ , m / z 497 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ FN ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 4-bromo-1,1,2-trifluoro-1-butene. (Yield 38 mg, 14.5%). Mp 131-132 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.92 (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-NH ₃ ) m / z 453 (M + H) ⁺ , m / z 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₆ F ₄ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 1-chloro-2-hexine. (Yield 170 mg, 69%). Mp 79-80 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.5 Hz, 3H), 1.56 (h, J = 7.5 Hz, 2H), 2.21 (m, 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, 1 H), 7.89 (d, J = 9 Hz, 2 H). MS (DCI-NH ₃ ) m / z 425 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₂₁ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with 1,1,3-trichloropropene. (Yield 1.15 g, 68%). Mp 184-185 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.39 (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, 1H ). _{MS (DCI-NH 3) m} / z 454 (M + H) +.

Elemental Analysis for C ₁₉ H ₁₄ Cl ₂ F ₄ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with cyclohexyl bromide. (Yield 163 mg, 76%). Mp 169-171 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.23 (m, 1H), 1.41 (m, 2H), 1.71 (m, 3H), 1.87 (m, 4H), 3.23 (s, 3H), 4.85 ( m, 1H), 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, 1H). MS (DCI-NH ₃ ) m / z 427 (M + H) ⁺ and m / z 444 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ FN ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with cyclopentyl bromide. (Yield 165 g, 80%). Mp 191-193 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.67 (m, 2H), 1.85 (m, 4H), 2.05 (m, 2H), 3.23 (s, 3H), 5.36 (m, 1H), 7.12 ( t, J = 9 Hz, 2H), 7.22 (m, 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) ⁺ and m / z 430 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ FN ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 20 by replacing 4-fluorobenzyl bromide with cyclobutyl bromide. (Yield 270 g, 68%). Mp 202-203 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.85 (m, 2H), 2.32 (m, 2H), 2.50 (m, 2H), 5.40 (quartet, J = 7 Hz, 1H), 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 ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₉ FN ₂ O ₃ S · 0.75 H ₂ O

Anal: 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 of example 68 N-debenzylated according to the method of Example 11. The 4-fluorobenzyl bromide is replaced with 1-bromo-3-methyl-2-butene and the intermediate is N-alkylated according to the method of Example 20 to afford the title compound. (Yield 50 mg, 30%). Mp 134-136 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.79 (s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J = 7.5 Hz, 2H), 5.48 (t, J = 6 Hz, 1H), 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 (DCI-NH ₃ ) m / z 414 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₂₀ FN ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 123 by replacing 1-bromo-3-methyl-2-butene with 2,4-difluorobenzyl bromide. (Yield 65 mg, 24%). Mp 236-238 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.78 (s, 2H), 5.43 (s, 2H), 6.88 (m, 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 (m, 1H), 7.85 (s, 1H), 7.86 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 472 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ F ₃ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 123 by replacing 1-bromo-3-methyl-2-butene with 2,3,4,5,6-pentafluorobenzyl bromide. (Yield 105 mg, 35%). Mp 201-203 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.8 (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, 1H), 7.37 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 526 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₃ F ₆ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 123 by replacing 1-bromo-3-methyl-2-butene with 3-bromocyclohexene. (Yield 30 mg, 10%). Mp 206-208 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75-1.85 (m, 3H), 2.1-2.3 (m, 3H), 4.8 (s, 2H), 5.75 (m, 2H), 6.1 (m, 1H), 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, 1 H). MS (DCI-NH ₃ ) m / z 426 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₂₀ FN ₃ O ₃ S

Anal: 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

Replace 1-bromo-3-methyl-2-butene with 3,4-difluorobenzyl bromide and perform the reaction in DMSO instead of DMF to prevent the formation of byproducts, according to the method of Example 123 Prepare the compound. (Yield 210 mg, 62%). Mp 253-255 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.33 (s, 2H), 7.13 (t, J = 9 Hz, 2H), 7.22 (dd, J = 9 Hz, 6 Hz, 2H), 7.28 (m , 1H), 7.39 (d, J = 9 Hz, 2H), 7.42 (s, 2H), 7.47 (m, 2H), 7.73 (d, J = 9 Hz, 2H), 8.12 (s, 1H). MS (DCI-NH ₃ ) m / z 472 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ F ₃ N ₃ O ₃ S

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) prepared according to the method of Example 11 in toluene (20 mL) and ethyl acetate (5 mL) A solution of pyridazinone (172 mg, 0.5 mmol), 2-indanol (67 mg, 0.5 mmol) and Ph ₃ P (262 mg, 1 mmol) was prepared and DIAD (0.2 mL) in toluene (10 mL) , 1 mmol) is added. The mixture is stirred at rt for 6 h and concentrated in vacuo. The residue is purified by chromatography (silica gel, 19: 1 CH ₂ Cl ₂ -ethyl acetate) to give 200 mg of product (contaminated with reduced DIAD). . Purification by second column chromatography (hexane-ethyl acetate 1: 1) affords the title product. (Yield 170 mg, 74%). Mp 97-100 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.22 (s, 3H), 3.32 (m, 2H), 3.44 (dd, J = 9 Hz and 15 Hz, 2H), 5.83 (m, 1H), 7.25 (m, 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 is prepared according to the method of Example 128 by replacing 2-indanol with 1-indanol. (Yield 110 mg, 48%). Mp 128-130 ° C. ¹ H NMR (DMSO-d ₆ , 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, 1H), 7.16 (m, 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-NH ₃ ) m / z 461 (M + H) ⁺ and m / z 478 (M + NH ₄ ) ⁺ .

Example 130

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

The title compound is prepared according to the method of Example 128 by replacing 2-indanol with 4-tetrahydropyranol. (Yield 140 g, 65%). Mp 230-231 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.75 (m, 2H), 1.93 (m, 2H), 3.14 (s, 3H), 3.46 (m, 2H), 3.93 (m, 2H); 5.02 (m, 1H), 7.05 (t, J = 9 Hz, 2H), 7.15 (m, 2H), 7.40 (d, J = 9 Hz, 2H), 7.80 (d, J = 9 Hz, 2H), 8.08 (s, 1 H). MS (APCI-) m / z 428 (MH) - and m / z 463 (M + Cl ) -.

Elemental Analysis for C ₂₂ H ₂₁ FN ₂ O ₄ S.1.25 H ₂ O

Anal: 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 is prepared according to the method of Example 128 by replacing 2-indanol with 2-methylcyclopentanol. (Yield 230 g, 86%). Mp 180-181 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, J = 7 Hz, 3H), 1.60 (m, 2H), 1.89 (m, 2H), 2.10 (m, 1H), 2.21 (m, 1H), 2.40 (m, 1H), 3.23 (s, 3H), 5.37 (q, J = 7 Hz, 1H), 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 (s, 1H). MS (APCI +) m / z 427 (M + H) ⁺ and (APCI-) m / z 461 (M + Cl) ^- .

Elemental Analysis for C ₂₃ H ₂₃ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 128, replacing 2-indanol with 2-adamantanol. (Yield 75 g, 25%). Mp 195-197 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.60 (m, 2H), 1.77 (m, 2H), 1.94 (m, 6H), 2.35 (m, 4H), 3.23 (s, 3H), 4.83 ( m, 1H), 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, 1 H). MS (APCI +) m / z 479 (M + H) ⁺ and (APCI-) m / z 478 (MH) ⁻ , m / z 513 (M + Cl) ⁻ .

Elemental Analysis for C ₂₇ H ₂₇ FN ₂ O ₃ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 128 by replacing 2-indanol with 3-methylcyclopentanol. (Yield 155 g, 73%). Mp169-171 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.05 (dd, 2: 1, 3H), 1.24 (m, 1H), 1.63 (m, 1H), 2.00 (m, 3H), 2.22 (m, 2H ), 3.23 (s, 3H), 5.43 (m, 1H), 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, 1H). MS (APCI +) m / z 27 (M + H) ⁺ and (APCI-) m / z 426 (MH) ⁻ , m / z 461 (M + Cl) ⁻ . Elemental Analysis for C ₂₇ H ₂₇ FN ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H)-prepared according to the method of Example 11 in toluene (30 mL) and ethyl acetate (5 mL). A solution of pyridazinone (206 mg, 0.6 mmol), 1-methyl-1-cyclopentanol (60 mg, 0.6 mmol), DMAP (18 mg, 0.12 mmol) and Ph ₃ P (262 mg, 1 mmol) Prepare and add dropwise to a solution of DIAD (0.2 mL, 1 mmol) in 10 mL of toluene. The mixture is stirred at rt for 6 h and then concentrated in vacuo. The residue is purified by chromatography (silica gel, 19: 1 CH ₂ Cl ₂ -ethyl acetate) to give 80 mg of product (contaminated with reduced DIAD). Purification by second column chromatography (hexane-ethyl acetate 1: 1) affords the title product. (Yield 50 mg, 19%). Mp 107-110 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.55 (s, 3H), 1.70 (m, 4H), 2.08 (m, 2H), 2.32 (m, 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 (MH) ^- , 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 is stirred under N ₂ for 30 min and then cooled to room temperature. 5-Bromo-2-fluorobenzaldehyde (1.02 g, 5 mmol) is added and the resulting mixture is stirred for 2 hours (until TLC shows the disappearance of the starting aldehyde). The reaction is concentrated in vacuo and partitioned between water and ethyl acetate. The acetate layer is washed with water and brine. The solution is dried over MgSO ₄ and concentrated in vacuo. The residue is purified by chromatography (silica gel, 15: 1 hexane-diethyl ether) to give 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 bromo-styrene compound prepared above in 10 mL of THF was subjected to a predetermined rate to a heated mixture of magnesium turning (120 mg, 5 mmol) and a few drops 1,2-dibromoethane in THF (20 mL). To the proper reflux. The mixture is then refluxed for 30 minutes and then cooled to room temperature. The Grignard reagent solution was cooled to -78 ° C and 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (in THF (20 mL)). To a solution of 2H) -pyridazinone (540 mg, 1.5 mmol). The reaction mixture is warmed to room temperature for 12 hours. Then saturated NH ₄ Cl solution is added and the mixture is extracted with ethyl acetate to give 320 mg of crude sulfide.

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

The sulfide prepared above is dissolved in CH ₂ Cl ₂ (20 mL) and treated with CH ₃ CO ₃ H in 30% CH ₃ CO ₂ H (0.5 mL) at 0 ° C. After 1.5 h, 10% NaHCO ₃ is added and the mixture is extracted with CH ₂ Cl ₂ . The extract is concentrated in vacuo and the residue is purified by chromatography (silica gel, 1: 1 hexane-ethyl acetate) to afford the title compound. (Yield 270 mg, 37%). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.22 (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, 1H), 7.15 (m, 2H), 7.57 (m, 5H), 7.90 (m, 3H), 8.28 (s, 1H). MS (APCI +) m / z 483 (M + H) ⁺ and (APCI-) m / z 517 (M + Cl) ^- .

Elemental Analysis for C ₂₅ H ₁₇ F ₃ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

Grignard prepared in Example 135 (283281) was substituted with 5-bromo-2-fluorostyrene with 2- (2-bromo-ethyl) -1,3-dioxane (586 mg, 3 mmol). , 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone in THF (30 mL) at -78 ° C. 720 mg, 2 mmol) solution. The mixture is left at room temperature for 14 hours, then quenched with saturated NH ₄ Cl solution and extracted with ethyl acetate to give 900 mg of crude sulfide.

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

The sulfonyl compound prepared above is dissolved in acetone (50 mL) and treated with 2N HCl (10 mL). The resulting mixture is refluxed for 16 hours and concentrated in vacuo. The residue was extracted with ethyl acetate to give 2- (3,4-difluorophenyl) -4- (2-formylethyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyrida 900 mg of xenon (contaminated with crude aldehyde, some unreacted starting dioxane derivative) are obtained.

A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) is refluxed for 30 minutes and then cooled to room temperature. Crude aldehyde is added and the mixture is refluxed for 14 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, 10% citric acid and brine, then dried over MgSO ₄ and concentrated in vacuo. Purification by column chromatography (silica gel, 1: 1 hexane-ethyl acetate) affords the title compound in an oil. (Yield 120 mg, 13%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 2 H); 3.30 (s, 3H), 5.29 (m, 2H), 7.51 (m, 1H), 7.63 (m, 1H), 7.74 (d, J = 9 Hz, 2H), 7.82 (m, 1H), 8.02 (s , 1H), 8.10 (d, J = 9 Hz, 2H). MS (APCI +) m / z 473 (M + H) ⁺ and (APCI-) m / z 471 (MH) ⁻ , m / z 507 (M + Cl) ⁻ .

Elemental Analysis for C ₂₅ H ₂₆ F ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 136 by replacing isoamyltriphenylphosphonium bromide with cyclopropyltriphenylphosphonium bromide.

(Yield 55 mg, 12%). Mp 128-129 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.81 (m, 2H), 0.97 (m, 2H), 2.34 (m, 2H), 2.65 (m, 2H), 3.32 (s, 3H), 5.64 ( m, 1H), 7.52 (m, 1H), 7.63 (m, 1H), 7.73 (d, J = 9 Hz, 2H), 7.81 (m, 1H), 8.02 (s, 1H), 8.10 (d, J = 9 Hz, 2H). MS (APCI +) m / z 443 (M + H) ⁺ and (APCI-) m / z 441 (MH) ^- , m / z 477 (M + Cl) ^- .

Elemental Analysis for C ₂₃ H ₂₀ F ₂ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

Isoamyltriphenylphosphonium bromide is replaced with isobutyltriphenylphosphonium bromide to prepare the title compound of the oil according to the method of Example 136. (Yield 170 mg, 74%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, J = 7 Hz, 6H), 2.22 (m, 3H), 2.54 (m, 2H), 3.32 (s, 3H), 5.12 (m, 2H), 7.52 (m, 1H), 7.60 (m, 1H), 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 (MH) ⁻ , m / z 493 (M + Cl) ⁻ .

Elemental Analysis for C ₂₄ H ₂₄ F ₂ N ₂ O ₃ S

Anal: 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 of the oil is prepared following the method of Example 135B by replacing 3-fluoro-4-vinylphenylmagnesium bromide with 5-methylhexylmagnesium bromide. (Yield 28 mg, 10%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.77 (d, J = 7 Hz, 6H), 0.88 (m, 1H), 1.03 (m, 2H), 1.20 (m, 1H), 1.46 (m, 5H), 3.32 (s, 3H), 7.52 (m, 1H), 7.62 (m, 1H), 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 (MH) ⁻ , 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 1,3-dichloro-1-butene. (Yield 55 mg, 30%). Mp 152-154 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.71 (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, 1H), 5.02 (d, J = 1 Hz, 1H), 5.85 (td, J = 4 Hz, 1 Hz, 1H), 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 (DCI-NH ₃ ) m / z 434 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ ClFN ₃ O ₃ S

Anal: 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-1yl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) -phenyl] -3 (2H) -Pyridazinone

3,4-Difluorobenzyl bromide was prepared in Example 88 with 1-methylsulfonyloxy-2,2,3-trifluoro-1-propene (mesylate) 1,3-dichloro-1-butene In place of, the title compound is prepared according to the method of Example 127. (Yield 10 mg, 4%). Mp 173-175 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.39 (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, 1H), 7.78 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 440 (M + H) ⁺ , MS (FAB, high resolution)

M / z for C ₁₉ H ₁₄ F ₄ N ₃ O ₃ S

Anal: 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) -pyrida Xenon

2- (2,3,3-trifluoro-2-propen-1yl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) -phenyl] -3 (2H) The title compound is separated from the same reaction mixture (Example 141) that was used to prepare the pyridazinone (the title product is the result of the S _N 2 ′ attack). (Yield 50 mg, 20%). Mp 230-232 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.7 (s, 2H), 5.28 (dd, J = 15 Hz, 4.5 Hz, 1H), 5.39 (dd, J = 45 Hz, 4.5 Hz, 1H), 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, 1 H),. MS (DCI-NH ₃ ) m / z 440 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ F ₄ N ₃ O ₃ S

Anal: 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- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

Preparation of the title compound according to the method of Example 127 using 3,4-difluorobenzyl bromide with 1,3-dibromo-1,1-difluoropropane and 5 equivalents of potassium carbonate do. (Yield 220 mg, 65%). Mp 191-194 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.77 (d, J = 7.5 Hz, 2H), 4.95 (dtd, J = 24 Hz, 7.5 Hz, 1 Hz, 1H), 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, 1 H). MS (DCI-NH ₃ ) m / z 422 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₄ F ₃ N ₃ O ₃ S

Anal: C, 54.15; H, 3. 34; N, 9.97.

Found: C, 53.88; H, 3. 42; N, 9.76.

Example 144

2- (α-methyl-3-fluorobenzyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 3-fluoro-α-methylbenzyl chloride. (Yield 220 mg, 65%). Mp 192-194 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.76 (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) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ F ₂ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 1-bromomethylcyclohexene. (Yield 70 mg, 28%). Mp 192-193 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55 (m, 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, 1 H). MS (DCI-NH ₃ ) m / z 440 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₂₂ FN ₃ O ₃ S

Anal: C, 62.85; H, 5.04; N, 9.56.

Found: C, 62.47; H, 5. 23; N, 9.14.

Example 146

2- (α-Methyl-2,3,4-trifluorobenzyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) -phenyl] -3 (2H) -pyrida Xenon

The title compound is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 2,3,4-trifluoro-α-methylbenzyl chloride. (Yield 70 mg, 50%). Mp 192-194 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) α 1.84 (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, 1H), 7.18 (dd, J = 9 Hz, 6 Hz, 2H), 7.2 (m, 1H), 7.38 (d, J = 9 Hz, 2H), 7.86 (d, J = 9 Hz, 2H), 7.88 (s, 1H). MS (DCI-NH ₃ ) m / z 504 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₄ N ₃ O ₃ S

Anal: C, 57.25; H, 3.4; N, 8.34.

Found: C, 56.84; H, 3.52; N, 7.91.

Example 147

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

The title compound is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 3,5-difluoro-α-methylbenzyl chloride. (Yield 80 mg, 45%). Mp 139-141 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.83 (d, J = 6 Hz, 3H), 4.79 (s, 2H), 6.32 (q, J = 7 Hz, 1H), 6.84 (m, 1H), 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-NH ₃ ) m / z 486 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₃ N ₃ O ₃ S

Anal: C, 59.37; H, 3.73; N, 8.65.

Found: C, 59.00; H, 3. 70; N, 8.35.

Example 148

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

The title compound is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 3,4-difluoro-α-methylbenzyl chloride. (Yield 200 mg, 58%). Mp 214-215 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.82 (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, 1H), 7.84 (d, J = 9 Hz, 2H), 7.90 (s, 1H). MS (DCI-NH ₃ ) m / z 486 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₃ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 3-fluorobenzyl bromide. (Yield 160 mg, 61%). Mp 220-222 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.37 (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) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ F ₂ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 4-fluorobenzyl bromide. (Yield 85 mg, 34%). Mp 237-239 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.32 (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 (DCI-NH ₃ ) m / z 454 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ F ₂ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 2,4,6-trifluorobenzyl bromide. (Yield 255 mg, 73%). Mp 201-203 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 (DCI-NH ₃ ) m / z 490 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₄ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 2,4,5-trifluorobenzyl bromide. (Yield 180 mg, 49%). Mp 236-238 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.35 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 490 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₄ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 127 by replacing 3,4-difluorobenzyl bromide with 2,3,4-trifluorobenzyl bromide. (Yield 220 mg, 63%). Mp 218-220 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 (s, 1H). MS (DCI-NH ₃ ) m / z 490 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₄ N ₃ O ₃ S

Anal: 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

Replacing the 1-bromo-3-methyl-2-butene with 1-bromo-3-methyl-4,4,4-trifluoro-2-butene to prepare the title compound according to the method of Example 123. do. (Yield 160 mg, 48%). Mp 155-157 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.00 (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 (DCI-NH ₃ ) m / z 468 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₁₇ F ₄ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 4-bromobiphenyl. (Yield 0.275 g, 100%). Mp 249-251 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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-NH ₃ ) m / z 497 (M + H) ⁺ , 514 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₁ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1,4-dibromobenzene. (Yield 0.337 g, 93%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.14 (m, 2H), 7.28 (m, 2H), 7.64 (m, 2H), 7.75 (m, 2H), 7.90 (m , 2H), 8.25 (s, 1H). MS (DCI-NH ₃ ) m / z 499 (M + H) ⁺ , 518 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₃ H ₁₆ BrFN ₂ O ₃ S · 0.75 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1-iodo-4-nitrobenzene. (Yield 0.45 g, 100%). Mp 110-116 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.17 (m, 2H), 7.32 (m, 2H), 7.53 (m, 2H), 7.91 (m, 2H), 8.03 (m , 2H), 8.34 (s, 1H), 8.40 (m, 2H). MS (DCI-NH ₃ ) m / z 466 (M + H) ⁺ , 483 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ FN ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 4-bromodiphenylether. (Yield 0.667 g, 22%). Mp 118-125 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (DCI-NH ₃ ) m / z 513 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ FN ₂ O ₄ S · 0.75 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1-bromo-4-t-butyl-benzene. No product was observed at all. The solution is concentrated in vacuo. The resulting solid is dissolved in DMF (5 mL) and CuI (13.3 mg, 0.07 mmol) is added. The solution is refluxed overnight. Upon completion, the mixture is poured into 10% citric acid and extracted with ethyl acetate. The organic layer is dried with water, dried over MgSO ₄ and concentrated in vacuo. The crude solid is 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%). Mp 132-136 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.34 (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 (DCI-NH ₃ ) m / z 477 (M + H) ⁺ , 494 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₇ H ₂₅ FN ₂ O ₃ S

Anal: C, 68.05; H, 5. 29; N, 5.88.

Found: C, 67.94; H, 5.31; N, 5.67.

Example 160

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

The title compound is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 4-bromo-1-chlorobenzene. (Yield 0.254 g, 83.5%). Mp 214-216 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.29 (m, 2H), 7.52 (m, 2H), 7.61 (m, 2H), 7.71 (m , 2H), 7.91 (m, 2H), 8.26 (s, 1 H). MS (DCI-NH ₃ ) m / z 455 (M + H) ⁺ , 472 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClFN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 3-bromotoluene. (Yield 0.262 g, 83%). Mp 213-216 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.39 (s, 3H), 3.24 (s, 3H), 7.14 (m, 2H), 7.28 (m, 3H), 7.43 (m, 3H), 7.53 (m , 2H), 7.80 (m, 2H), 8.22 (s, 1H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 3-bromostyrene. (Yield 0.202 g, 62%). Mp 182-183 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.25 (s, 3H), 5.35 (d, J = 12 Hz, 1H), 5.92 (d, J = 15 Hz, 1H), 6.82 (m, 1H), 7.15 (m, 2H), 7.30 (m, 2H), 7.50-7.60 (m, 4H), 7.74 (m, 1H), 7.91 (m, 2H), 8.24 (s, 1H). MS (DCI-NH ₃ ) m / z 447 (M + H) ⁺ , 464 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₁₉ FN ₂ O ₃ S · 0.50 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 2-bromobenzaldehyde. (Yield 0.196 g, 60%). Mp 234-236 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1H), 8.29 (s, 1H), 10.02 (s, 1H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ FN ₂ O ₄ S · 0.50 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1-bromo-2-nitrobenzene. (Yield 0.307 g, 90.8%). Mp 236-239 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.12-7.27 (m, 4H), 7.56 (m, 2H), 7.7-8.01 (m, 5H), 8.18 (m, 1H) , 8.35 (s, 1 H). MS (DCI-NH ₃ ) m / z 466 (M + H) ⁺ , 483 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ FN ₃ O ₅ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1-bromo-3-chlorobenzene. (Yield 0.255 g, 77%). Mp 232-235 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.23 (s, 3H), 7.14 (m, 2H), 7.29 (m, 2H), 7.49-7.58 (m, 4H), 7.66 (m, 1H), 7.79 (m, 1 H), 7.90 (m, 2 H), 8.25 (s, 1 H). MS (DCI-NH ₃ ) m / z 455 (M + H) ⁺ , 472 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClFN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 1,3 dibromobenzene (yield: 0.216 g, 60%). Mp 210-212 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.23 (s, 3H), 7.15 (m, 2H), 7.29 (m, 2H), 7.48-7.55 (m, 3H), 7.69 (m, 2H), 7.90 (m, 3 H), 8.26 (s, 1 H). MS (DCI-NH ₃ ) m / z 499 (M + H) ⁺ , 519 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ BrFN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 4-bromobenzonitrile. (Yield 0.349 g, 100%). Mp 273-278 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.11-7.21 (m, 2H), 7.25-7.35 (m, 2H), 7.52 (m, 2H), 7.88-7.96 (m, 4H), 8.04 (m, 2H), 8.31 (s, 1H). MS (DCI-NH ₃ ) m / z 445 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ FN ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 2-bromo-5-methylthiophene. (Yield 0.200 g, 62%). Mp 219-224 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.45 (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-NH ₃ ) m / z 441 (M + H) ⁺ , 458 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₇ FN ₂ O ₃ S ₂

Anal: C, 59.99; H, 3.89; N, 6.36.

Found: C, 59.90; H, 3.91; N, 6.26.

Silsingme 169

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

The title compound is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 3-bromobiphenyl. (Yield 0.28 g, 78%). Mp 126-134 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (DCI-NH ₃ ) m / z 497 (M + H) ⁺ , 514 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₉ H ₂₁ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 4-iodo-1-fluorobenzene with 5-bromo-m-xylene. (Yield 0.152 g, 46.5%). Mp 130-134 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.34 (s, 6H), 3.23 (s, 3H), 7.07-7.12 (m, 2H), 7.15 (m, 1H), 7.21-7.32 (m, 4H) , 7.52 (m, 2H), 7.90 (m, 2H), 8.29 (s, 1H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ FN ₂ O ₃ S

Anal: 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

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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 4- (4-fluorophenylmethyl) -5- [4- (methyl Sulfonyl) phenyl] -3 (2H) -pyridazinone and 4-iodo-1-fluorobenzene with 1-bromo-3,4-difluorobenzene The title compound is prepared according to the method. (Yield 0.085 g, 54%). Mp 157-159 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.30 (s, 3H), 3.88 (bs, 2H), 7.04 (m, 4H), 7.49-7.66 (m, 2H), 7.70 (m, 2H), 7.81 (m, 1 H), 8.12 (s, 1 H). MS (DCI-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₃ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 4- (4-fluorophenylmethyl) -5- [4- (methyl Sulfonyl) phenyl] -3 (2H) -pyridazinone and 4-iodo-1-fluorobenzene by 4-bromo-2-chloro-1-fluorobenzene, Example 62 The title compound is prepared according to the method of. (Yield 0.110 g, 74%). Mp 153-156 ° C. ¹ 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, 2 H), 8.12 (s, 1 H). MS (DCI-NH ₃ ) m / z 487 (M + H) ⁺ , 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ ClF ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 2-bromothiophene. (Yield 98 mg, 40%). Mp 215-217 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (DCI-NH ₃ ) m / z 427 (M + H) ⁺ , 444 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ FN ₂ O ₃ S ₂

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1-bromo-4-trifluoro-methylbenzene. (Yield 185 mg, 64%). Mp 171-173 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (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 (DCI-NH ₃ ) m / z 489 (M + H) ⁺ , 506 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ F ₄ N ₂ O ₃ S

Anal: C, 59.02; H, 3.3; N, 5.74.

Found: C, 58.75; H, 3. 35; N, 5.69.

Example 175

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

The title compound is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1- (4-iodophenyl) -pyrrole. (Yield 140 mg, 50%). Mp 229-231 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (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, 1H). MS (DCI-NH ₃ ) m / z 486 (M + H) ⁺ , 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₇ H ₂₀ FN ₃ O ₃ S0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1-bromo-5-chlorothiophene. (Yield 225 mg, 93%). Mp 190-192 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), d 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m, 4H), 7.5 (D, 4H) 7.91 ( d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1-bromo-4-methylbenzene. (Yield 79 mg, 31%). Mp 190-192 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), d 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m, 4H), 7.5 (D, 4H) 7.91 ( d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S

Anal: 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), after 10 minutes, 2- ( 4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (193 mg, 0.5 mmol) is added. The resulting mixture is stirred at room temperature for 2 hours. The mixture is quenched with 10% citric acid and extracted with ethyl acetate. The extract is washed with water and brine, dried over MgSO ₄ and purified by chromatography (silica gel, 2: 1 hexane-ethyl acetate) to afford the desired product. (Yield 140 mg, 60%). Mp 120-122 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quartet, J = 7 Hz, 2H), 1.44 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₅ H ₂₉ FN ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3-bromothiophene. (Yield 225 mg, 93%). Mp 200-202 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), 7.15 (t, 2H), 7.29 (m, 2H), 7.5 (d, J = 9 Hz, 2H), 7.6 (M, 1H) 7.66 (dd, 1H), 7.91 (d, J = 9 Hz, 2H), 8.13 (dd, 1H), 8.25 (s, 1H). MS (DCI-NH ₃ ) m / z 427 (M + H) ⁺ , 444 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ FN ₂ O ₃ S ₂

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3,5-difluorobromobenzene. Mp 166-168 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), d 7.15 (t, 2H), 7.27 (m, 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, 1H). MS (DCI-NH ₃ ) m / z 457 (M + H) ⁺ , 474 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₃ N ₂ O ₃ S

Anal: 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 is prepared following the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 2,4-difluorobromobenzene. (Yield 40 mg, 15%). Mp 245-247 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (s, 3H), d 7.15 (t, 2H), 7.3 (t, 2H), 7.54 (m, 2H), 7.57 (m, 2H), 7.75 (m, 1 H), 7.9 (d, J = 9 Hz, 2 H), 8.27 (s, 1 H). MS (DCI-NH ₃ ) m / z 457 (M + H) ⁺ , 474 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₈ H ₁₅ F ₃ N ₂ O ₃ S

Anal: C, 60.52; H, 3.31; N, 6.03.

Example 182

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

The title compound is prepared following the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3,4-difluorobromobenzene. (Yield 170 mg, 70%). Mp 109-110 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (s, 3H), d 7.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H), 7.59 (m, 4H), 7.83 (m, 1 H), 7.9 (d, J = 9 Hz, 2 H), 8.27 (s, 1 H). MS (DCI-NH ₃ ) m / z 457 (M + H) ⁺ , 474 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ F ₃ N ₃ O ₃ S

Anal: C, 60.52; H, 3.31; N, 6.14.

Found: C, 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3-bromofuran. (Yield 175 mg, 73%). Mp 239-242 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), 7.09 (d, 1H), 7.15 (t, 2H), 7.29 (m, 2H), 7.5 (d, J = 9 Hz 2H ), 7.8 (t, 1H) 7.91 (d, J = 9 Hz, 2H), 8.3 (s 1H), 8.58 (s, 1H). MS (DCI-NH ₃ ) m / z 411 (M + H) ⁺ , 428 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ FN ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3-fluoro-4-methoxybromobenzene. (Yield 230 mg, 85%). Mp 97-101 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 1H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 491 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 2-fluorobromobenzene. (Yield 195 mg, 75%). Mp 96-103 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (s, 3H), δ 7.15 (t, 2H), 7.3 (m, 3H), 7.55 (m, 5H), 7.9 (d, J = 9 Hz , 2H), 8.27 (s, 1 H). MS (ESI) m / z 437 (MH) ⁺ ).

Elemental Analysis for C ₂₃ H ₁₆ F ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 4-aminosulfonyl-1-bromobenzene. Mp 213-216 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (DCI-NH ₃ ) m / z 499 (M + H) ⁺ , 517 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₈ FN ₃ O ₅ S ₂ .0.5 H ₂ O

Anal: 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 is prepared following the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3-chloro-4-fluoro-1-bromobenzene. (Yield 320 mg, 78%). Mp 155-157 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (s, 3H), δ 7.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H), 7.53 (d, J = 9 Hz , 2H), 7.59 (t, 1H), 7.73 (m, 1H), 7.9 (d, J = 9 Hz, 2H) 7.96 (m, 1H), 8.27 (s, 1H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ ClF ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 3,5-dichlorobenzene. (Yield 360 mg, 78%). Mp 289-294 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), δ 7.15 (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 (DCI-NH ₃ ) m / z 490 (M + H) ⁺ , 507 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ Cl ₂ FN ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1-bromo-4-fluoro-3-methylbenzene. (Yield 275 mg, 71%). Mp 168-170 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.3 (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 (DCI-NH ₃ ) m / z 453 (M + H) ⁺ , 471 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 4-bromo-1-chloro-2-fluorobenzene. (Yield 220 mg, 80%). Mp 102-110 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (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, 1 H), 7.75-7.87 (m, 2 H), 7.91 (d, J = 5.6 Hz, 2H), 8.28 (s, 1 H). 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 is prepared according to the method of Example 62 by replacing 1-bromo-4-fluorobenzene with 1-bromo-4-chloro-2-fluorobenzene. (Yield 65 mg 24%). Mp 250-260 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.21 (s, 3H), 7.12-7.19 (m, 2H), 7.25-7.32 (m, 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) ⁺ .

Elemental Analysis for C ₂₃ H ₁₅ ClF ₂ N ₂ O ₃ S

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone in CH ₂ Cl ₂ (8 ml) prepared according to the method of Example 11 200 mg, 0.58 mmol) is prepared and stirred. 1-adamantylfluoroformate (172 mg, 0.87 mmol), dimethylamino-pyridine (14 mg, 0.011 mmol) and triethylamine (0.12 ml, 0.87 mmol) are added. The reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with CH ₂ Cl ₂ (50 ml), washed with 10% citric acid (50 ml) and brine (50 ml), dried over MgSO ₄ , and concentrated in vacuo. The resulting crude residue is purified using flash chromatography (SiO ₂ , eluted with 15: 1 CH ₂ Cl ₂ : diethyl ether) to afford the desired product. (Yield 55 mg, 18%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.66 (bs, 6H), 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) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ FN ₂ O ₃ S ₂

Anal: 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) is treated with cocochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. . The solvent is concentrated in vacuo. The crystals obtained are washed with water and air dried. (Yield 50 g; 67.5%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.8 (q, J = 9 Hz, 2H), 7.85 (s, 1H). MS (DCl-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.) mL) and reflux for 6 hours. TLC (1: 1: 2 CH ₂ Cl ₂ / hexanes / ethyl acetate) shows that all the starting material was consumed. The reaction mixture is cooled to room temperature. The pH of the reaction mixture is adjusted to about 4 with hydrochloric acid (15%). The product is extracted with ethyl acetate (700 mL). The organic phase is washed with brine, dried over anhydrous MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The hydroxy compound is 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) is placed in a 500 mL round bottom flask and anhydrous CH ₂ CL ₂ (200 mL) is added. The reaction mixture is cooled to 0 ^o C under N ₂ . Dissolve in halohydroxy pyridazinone CH ₂ CL ₂ (100 mL) prepared in Example 193B, slowly add to the flask and stir overnight. The reaction is slowly warmed to room temperature. (TLC (2: 1 hexanes / ethyl acetate) indicates the reaction is complete.) The reaction is quenched with H ₂ O. The organic phase containing the product is separated, washed with brine and dried over MgSO ₄ . The resulting filtrate is concentrated under reduced pressure. Crude product is obtained as a dark reddish brown residue. Purification using a silica gel column (30:70 ethyl acetate / pentane) affords the title compound as a dark red residue. (14.3 m, 70%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.85 (q, J = 9 Hz, 2H), 7.9 (s, 1H). MS (DCI-NH ₃ ) m / z 378 (M + NH ₄ ) ⁺ .

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

Triflate (1.56 g 4.3 mmol), 4- (methylthio) phenyl-boronic acid (870 mg, 5.16 mmol), tetrakis- (triphenyl-phosphine), prepared according to the method of Example 193C, in toluene A solution of palladium (0) (250 mg, 5% mmol) and triethylamine (1.44 ml, 10.32 mmol) is heated under reflux for 1 hour. The mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is washed with water followed by brine, then dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo. The residue is purified by column chromatography (silica gel, 92: 8 hexanes / ethyl acetate) to afford the combined intermediate as a pale green yellow solid. (Yield 500 mg, 35%). Mp 130-139 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (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, 1 H). MS (DCI-NH ₃ ) m / z 335 (M + H) ⁺ .

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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone was replaced by the above linked intermediate prepared in Example 193D. The title compound is prepared according to the method of Example 10. (Yield 440 mg, 81%). Mp 221-222 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.33 (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, 1H). 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 turning (500 mg) is placed in a dry 250 mL round bottom flask, anhydrous ether (20 mL) is added under N ₂ at room temperature, then fluorobenzyl bromide (3 mL) is added and stirred. The reaction is heated at 40 ^° C. for 2 hours. All magnesium is consumed to produce a light brown-yellow solution. 2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone prepared in Example 193E was replaced with anhydrous THF ( 25 mL) and transfer to Grignard solution. The mixture is heated for 3 hours. TLC (2: 1 hexanes / ethyl acetate) shows that pyridazinone starting material was consumed.) The reaction was cooled to room temperature and then quenched with saturated NH ₄ Cl solution. The product is extracted with ethyl acetate (250 mL) and the organic layer is washed with saturated NH ₄ Cl and brine. The ethyl acetate solution is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The product is obtained as an orange residue. Purification using a silica gel column (20:80 ethyl acetate / pentane) affords 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) ⁺ .

Elemental analysis for C ₂₀ H ₁₆ F ₄ N ₂ O ₃ S0.5 H ₂ O

Anal: 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

The cocobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) is treated with 4-fluorophenyl hydrazine-HCl and the heterogeneous mixture is refluxed for 15 h in a bath at 115 ° C. During the course of the reaction, the mixture turns into a homogeneous dark red solution and upon cooling to 23 ° C. a crystalline precipitate is formed. The solution is poured into cold water (1000 mL) and stirred for 20 minutes. The yellow / brown crystals are filtered off, washed further with cold water and concentrated in vacuo to yield 5.8 g (86%) of product. References [J. Het. Chem .., 1993, 30, 1501; Heterocycles 1985, 23, 2603] ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.31-7.41 (m, 2H), 7.57-7.64 (m, 2H), 8.29 (s, 1H). MS (DCI +) m / z 347 (Br ₇₉ Br ₇₉ M + H) ⁺ , m / z 349 (Br ₇₉ Br ₈₁ M + H) ⁺ , m / z 364 (Br ₇₉ Br ₇₉ M + NH ₄ ) ⁺ , And m / z 366 (Br ₇₉ Br ₈₁ M + NH ₄ ) ⁺ .

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

23 ° C. of 2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone (7.18 g, 20.6 mmol) prepared above in tetrahydrofuran (322 mL), The homogeneous solution is treated with methanol (0.843 mL, 20.8 mmol) and after 5 minutes with NaH (0.833 g, 20.8 mmol, 60% oil dispersion). The reaction is exothermic for a few minutes and then continued at 23 ° C. for 8 hours (note: at this point several reactions are completed and completed). Since the reaction is not complete, the temperature is raised to further reflux for 4 hours. The reaction is still not complete. In addition, 0.1 equivalent of NaOMe solution is prepared as above using quantification of 32 mL of tetrahydrofuran, 0.084 mL of methanol, and 83 mg of 60% NaH oil dispersion in a separate flask. This NaOMe solution is added to the reaction mixture via a syringe, cooled to 23 ° C. and then raised to reflux for 4 hours. Since the reaction is still not complete, an additional 0.1 equivalent of NaOMe solution is prepared as above, added and the reaction is refluxed. After 4 hours, the reaction is complete. The mixture is cooled to 23 ° C. and diluted to 2000 mL with water. The yellow / white precipitate formed is filtered off, washed further with water and concentrated in vacuo to give 5.39 g (88%) of product. References [J. Het. Chem., 1988, 25, 1757] ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.13 (s, 3H), 7.30-7.40 (m, 2H), 7.56-7.62 (m, 2H), 8.22 (s , 1H). MS (APCI +) m / z 299 (Br ₇₉ M + H) ⁺ and m / z 301 (Br ₈₁ M + H) ⁺ .

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

2- (4-fluorophenyl) -4-methoxy-5-bromo-3 (2H) -pyrida instead of 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone Starting from xenon and replacing 4-fluorobenzeneboronic acid with 4- (methylthio) -benzeneboronic acid, the title compound is prepared according to the method of Example 6. (Yield 70 mg, 61%). ¹ H NMR (500 MHz, DMSO-d ₆ ) 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 (s, 1H). MS (APCI +) m / z 343 (M + H) ⁺ .

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

The title compound is prepared according to the method of Example 228, replacing cyclohexylmagnesium chloride with methyl magnesium bromide. (Yield 0.83 g, 87%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.25 (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, 1H). MS (APCI +) m / z 327 (M + H) ⁺ .

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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-methyl-5 The title compound is prepared according to the method of Example 10, replacing by-[4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 473 mg, 86%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (m, 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 + NH ₄ ) ⁺ .

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

2- (4-fluorophenyl) -4-methyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) To the heterogeneous, refluxing solution of N-bromosuccinimide (yield: 308 mg, 1.73 mmol) is added quickly followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour, the reaction proceeds and only about 50% complete. In addition, benzoyl peroxide (12 mg, 0.05 mmol) is added and after 1 h the reaction is checked. Since the reaction is still not complete, additional benzoyl peroxide (4 mg, 0.017 mmol) is added. After 30 minutes, the reaction is complete. The mixture is cooled to 23 ° C. and diluted with ethyl acetate. The acetate solution is washed with saturated NaHCO ₃ , water, and brine. The solution is dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is chromatographed (flash silica gel, ethyl acetate / hexane gradient 1: 1 to 4: 1) to afford the product. (Yield 530 mg, 74%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.16 (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

2- (4-fluorophenyl) -4-bromomethyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, prepared above, dissolved in acetone (4 mL) To a homogeneous solution of (107 mg, 0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270 mmol) is added powdered K ₂ CO ₃ (37.3 mg, 0.270 mmol). The mixture is stirred at 23 ° C. for 2 hours, filtered through a pad of Celite ^R and then concentrated in vacuo. The residue is chromatographed (flash silica gel, ethyl acetate / hexane 3: 2) to afford the product. (Yield 83 mg, 72%). Mp 65-80 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12 (s, 3H), 4.94 (s, 2H), 6.78-6.86 (m, 2H), 6.91-7.00 (m, 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) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 194G by replacing 4-fluorophenol with 3-fluorophenol. (Yield 94 mg, 88%). Mp 142-144 ° C. ¹ 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, 1H), 8.07 (d, J = 8.7 Hz, 2H). MS (APCI +) m / z 469 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O _{4 /} S

Anal: C, 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 is prepared following the method of Example 194G by replacing 4-fluorophenol with phenol. (Yield 67 g, 93%). Mp 42-75 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.28 (s, 3H), 4.92 (s, 2H), 6.83-6.90 (m, 2H), 6.91-6.99 (m, 1H), 7.22-7.30 (m , 2H), 7.35-7.44 (m, 2H), 7.66-7.73 (m, 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

2- (4-fluorophenyl) -4-bromomethyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone prepared in Example 194F in acetone (2.5 mL) ( 92.5 mg, 0.212 mmol) of a 0 ° C. solution is treated with NaI (35 mg, 0.233 mmol) and after 5 minutes the cooling bath is removed and the reaction is warmed to 23 ° C. After 30 minutes, the conversion of 2- (4-fluorophenyl) -4-iodomethyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone is complete (thin layer chromatography, Ethyl acetate / hexane 4: 1). NaBr and residual NaI are filtered through the paddle of Celite ^R. In addition, acetone (2 mL) was added together with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol), the solution was cooled to 0 ° C., and then further Ag ₂ CO ₃ (63 mg, 0.227 mmol). ) After 5 minutes, the cooling bath is removed and the solution is heated to 23 ° C. for 5 hours. The reaction mixture is filtered through Celite ^R and concentrated in vacuo. The residue is chromatographed (flash silica gel, ethyl acetate / hexane gradient 1: 1 to 3: 2) to afford the product. (Yield 57 mg, 60%). Mp 50-70 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.34 (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, 1 H), 7.84 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H). MS (APCI +) m / z 447 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₃ S ₂

Anal: 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 is prepared following the method of Example 197 by replacing 2-methyl-2-propanethiol with 2-methyl-1-propanethiol. (Yield 66 mg, 70%). Mp 45-60 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.95 (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) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₃ S ₂

Anal: 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 is prepared according to the following reaction sequence. Mucobromic acid and 4-fluorophenylhydrazine hydrochloride were reacted according to the method of Example 194A to give 2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone do. Methanol was replaced with isopropanol to react the dibromo-intermediates selectively at the 4-position according to the method of Example 194B, resulting in 2- (4-fluorophenyl) -4- (2-propoxy) -5 -Bromo-3 (2H) -pyridazinone is obtained.

The 5-bromo-compound is bound to 4- (methylthio) phenylboronic acid according to the method of Example 6 to afford the title compound. (Yield 435 mg, 53.9%). Mp 135-137 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.21 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 371 (M + H) ⁺ .

Example 200

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

Example (264970) The methyl sulfide compound prepared in 199 is oxidized according to the method of Example 10 to afford the title compound. (Yield 240 mg, 92%). Mp 160-162 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (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-NH ₃ ) m / z 403 (M + H) ⁺ , 420 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₉ FN ₂ O ₄ S

Anal: 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

In the first step, 4-fluorophenylhydrazine hydrochloride is replaced with 3-chlorophenylhydrazine hydrochloride, following the method of Example 199 to 2- (3-chlorophenyl) -4- (2-propoxy) -5 -[4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared. The resulting methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 260 mg, 80%). Mp 134-136 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.24 (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, 1H), 7.70 (br s, 1H), 7.84 (d, J = 9 Hz, 2H), 7.93 (s, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 419 (M + H) ⁺ , 436 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₉ ClN ₂ O ₄ S

Anal: 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

In a first step, methyl sulfide intermediate is prepared according to the method of Example 199 by replacing 4-fluorophenylhydrazine hydrochloride with 3-fluorophenylhydrazine hydrochloride. The resulting methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 290 mg, 72%). Mp 110-112 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.31 (d, J = 6 Hz, 6H), 3.11 (s, 3H), 5.47 (sept, J = 6 Hz, 1H), 7.09-7.18 (m, 1H) , 7.41-7.52 (m, 3H), 7.83 (d, J = 9 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 403 (M + H) ⁺ , 447 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₀ H ₁₉ FN ₂ O ₄ S

Anal: 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

In a first step, methyl sulfide intermediate is prepared according to the method of Example 199 by replacing 4-fluorophenylhydrazine hydrochloride with 3-bromophenylhydrazine hydrochloride. The resulting methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 75 mg, 77.6%). Mp 130-132 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) d 1.23 (d, J = 6 Hz, 6H), 3.15 (s, 3H), 5.48 (sept, J = 6 Hz, 1H), 7.38 (t, J = 9 Hz , 1H), 7.55 (br d, J = 7 Hz, 1H), 7.65 (br d, J = 7 Hz, 1H), 7.79-7.87 (m, 1H), 7.83 (d, J = 9 Hz, 2H) , 8.13 (s, 1 H), 8.06 (d, J = 9 Hz, 2 H). MS (DCI-NH ₃ ) m / z 465 (M + H) ⁺ , 480 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₉ BrN ₂ O ₄ S

Anal: 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

4-Fluorophenylhydrazine hydrochloride was replaced with 2,5-difluorophenylhydrazine hydrochloride, following 2- (2,5-difluorophenyl) -4- (2-propoxy according to the method of Example 199 ) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared.

The resulting methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 390 mg, 90%). Mp 161-164 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.23 (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-NH ₃ ) m / z 421 (M + H) ⁺ , 438 (M + NH ₄ ) ⁺ .

Elemental analysis for C ₂₀ H ₁₈ F ₂ N ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the following reaction sequence. Mucobromic acid and 3-chloro-4-fluorophenylhydrazine hydrochloride were reacted according to the method of Example 194A to give 2- (3-chloro-4-fluorophenyl) -4,5-dibromo-3 ( 2H) -pyridazinone is obtained. The intermediate was reacted selectively with isobutanol and a base at the 4-position according to the method of Example 194B to give 2- (4-fluorophenyl) -4- [1- (2-methyl-propoxy)]-5- Obtain bromo-3 (2H) -pyridazinone. The 5-bromo-compound was attached to the 3-fluoro-4- (methylthio) phenylboronic acid prepared in Example 194C according to the method of Example 6 to yield an intermediate methyl sulfide. The sulfide compound is oxidized to the title compound methyl sulfone according to the method of example 10. (Yield 810 mg, 83.8%). Mp 142-144 ° C. ¹ 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, 1H), 7.52-7.61 (m, 3H), 7.75 (dd, J = 9 Hz, 3 Hz, 1H), 7.89 (s, 1H), 8.10 (t , J = 9 Hz, 1H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Example 206

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 hexane) is added slowly along the inner wall of the reaction vessel. The resulting pale yellow solution is stirred for 30 minutes, and then methyl iodide (8.10 g, 57.1 mmol) diluted with tetrahydrofuran (6 mL) is slowly added along the inner wall of the reaction vessel. The mixture is stirred for further 30 min at -78 ° C. The cold bath is removed and the mixture is stirred for 1 hour. The solution is cooled to 0 ° C. and saturated aqueous NH ₄ Cl solution is added. The resulting solution is extracted several times with ethyl acetate and the combined acetate layers are washed with brine, then dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is chromatographed (flash silica gel, ethyl acetate / hexane 1:19) to afford the product. (Yield 6.74 g, 94%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.34 (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 further bromine (0.58 g, 3.54 mmol). Add. After 30 minutes the starting material is consumed (thin layer chromatography, hexane). NaHSO ₃ is added and stirred for a few minutes to quench excess bromine. The methylene chloride layer is separated and the aqueous phase is further extracted with methylene chloride. The combined methylene chloride solution is dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting oil is chromatographed (flash silica gel, ethyl acetate / hexane 1:49) to afford the product. (Yield 0.74 g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.30 (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.

4-Bromothioanisole is replaced with 4-bromo-2- (methylthio) -anisole to prepare 3-methyl-4- (methylthio) -benzeneboronic acid according to the method of Example 1. (Yield 5.3 g, 67%). Mp 208-210. ¹ 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, 1H).

206D. 2- (3,4-Difluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone.

The title compound is prepared according to the method of Example (264970) 194A, replacing 4-fluorophenyl hydrazine.HCl with 3,4-difluorophenyl hydrazine.HCl. (Yield 39 g, 78%). ¹ 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 (DCI-NH ₃ ) m / z 382 (M + NH ₄ ) ⁺ .

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

2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone to 2- (3,4-difluorophenyl) -4,5-dibromo-3 ( Substituted by 2H) -pyridazinone, the title compound is prepared according to the method of Example 194B. (Yield 15 mg, 88%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.14 (s, 3H), 7.45 (m, 1H), 7.60 (m, 1H), 7.74 (m, 1H), 8.24 (s, 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.

2- (3,4-difluorophenyl) -4-methoxy-5-bromo-3 (2H) instead of 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone Starting with pyridazinone and replacing 4-fluorobenzeneboronic acid with 3-methyl-4- (methylthio) -benzeneboronic acid, the title compound is prepared according to the method of Example 6. (Yield 2.0 g, 85%). ¹ 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, 2 H), 7.55-7.64 (m, 1 H), 7.92 (s, 1 H). 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 instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Starting from -methoxy-5- [3-methyl-4- (methylthio) phenyl] -3 (2H) -pyridazinone, carried out by replacing cyclohexyl magnesium chloride with 4-fluorophenyl magnesium bromide 2- (3,4-difluorophenyl) -4- (4-fluorophenyl) -5- [3-methyl-4- (methylthio) phenyl] -3 (2H)-according to the method of example 228 To prepare pyridazinone. (Yield 330 mg, 56%). ¹ 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, 1 H), 8.02 (s, 1 H). MS (APCI +) m / z 439 (M + H) ⁺ .

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

2- (3,4-difluorophenyl) -4- to 2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone The title compound is prepared according to the method of Example 10, replacing by (4-fluorophenyl) -5- [3-methyl-4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 251 mg, 82%) Mp 80-100 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.59 (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, 1H), 7.81-7.90 (m, 1H), 8.27 (s, 1H). MS (APCI +) m / z 471 (M + H) ⁺ and m / z 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 194A by replacing 4-fluorophenyl hydrazine.HCl with 3-chlorophenyl hydrazine.HCl. (Yield 24.8 g, 88%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53-7.57 (m, 3H), 7.67-7.70 (m, 1H), 8.29 (s, 1H). MS (DCI-NH ₃ ) m / z 365 (M + H) ⁺ and m / z 382 (M + NH ₄ ⁺ ) ⁺ .

207B. 2- (3-Chlorophenyl) -4-methoxy-5-bromo-3 (2H) -pyridazinone.

2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone to 2- (3-chlorophenyl) -4,5-dibromo-3 (2H) -pyri Substituted with dazinone, the title compound is prepared according to the method of Example 194B. (Yield 12.4 g, 95%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.21 (s, 3H), 7.58-7.62 (m, 3H), 7.73-7.76 (m, 1H), 8.28 (s, 1H). MS (DCI-NH ₃ ) m / z 317 (M + H) ⁺ and m / z 334 (M + NH ₄ ⁺ ) ⁺ .

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

2- (3-chlorophenyl) -4-methoxy-5-bromo-3 (2H) -pyridazinone instead of 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone Starting from and replacing 4-fluorobenzeneboronic acid with 4- (methylthio) -benzeneboronic acid, the title compound is prepared according to the method of Example 6. (Yield 3.3 g, 68%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (m, 1 H), 8.18 (s, 1 H). 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- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone instead of 2- (3-chlorophenyl) -4-methoxy- The method of Example 228, starting from 5- [3-methyl-4- (methylthio) phenyl] -3 (2H) -pyridazinone and replacing cyclohexylmagnesium chloride with 4-fluorophenyl magnesium bromide To 2- (3-chlorophenyl) -4- (4-fluorophenyl) -5- [3-methyl-4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 180 mg, 94%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.25 (s, 3H), 2.56 (s, 3H), 7.28-7.45 (m, 6H), 7.58-7.63 (m, 1H), 7.71-7.74 (m, 1H ), 7.82 (s, 1 H). MS (APCI +) m / z 343 (M + H) ⁺ and m / z 360 (M + NH ₄ ) ⁺ .

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

2-Benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4-methyl-5- The title compound is prepared according to the method of Example 10, replacing by [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 125 mg, 67%). Mp 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, 1 H), 8.13 (d, J = 8.7 Hz, 2 H). MS (APCI +) m / z 343 (M + H) ⁺ and m / z 360 (M + NH ₄ ) ⁺ .

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

2- (4-fluorophenyl) -4-methyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4-methyl-5 2- (3-chlorophenyl) -4-bromomethyl-5- [4, following the method of Example 194F, replacing with-[4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone -(Methylsulfonyl) phenyl] -3 (2H) -pyridazinone is prepared. (Yield 90 mg, 99%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, 1H), 7.76-7.78 (m, 1 H), 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) ⁺ and m / z 470 (M + NH ₄ ) ⁺ .

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

2- (4-fluorophenyl) -4-bromomethyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone to 2- (3-chlorophenyl) -4-bro The title compound is prepared according to the method of Example 194G, replacing by mother methyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 30 mg, 31%). Mp 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 is prepared following the method of Example 207, replacing 4-fluorophenol with benzoic acid. (Yield 33 mg, 34%). Mp 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, 1H), 7.61-7.68 (m, 3H ), 7.75-7.78 (m, 1H), 7.83-7.88 (m, 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 is prepared according to the method of Example 193 by replacing 4-fluorobenzyl bromide with 1-bromo-4-methylpentane. (Yield 80 mg, 19%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.81 (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, 1H), 8.1 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ), m / z 403 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₂₁ F ₃ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

210A. Preparation of Boric Acid:

2-fluorotoluene-5-bromo (6 g, 31.7 mmol) is dissolved in anhydrous THF (50 mL) and cooled to -78 C under N ₂ . n-BuLi (14 mL, 2.5M solution in THF) is added slowly using a dry syringe. Turbidity appears. The reaction is stirred for 40 min at -78 ° C. Triisopropyl borate (22 mL, 95 mmol) is added slowly with stirring. The reaction is allowed to warm to room temperature. Stirring is continued for an additional 2 hours. A pale yellow, cloudy solution is produced. (TLC (1: 2 ethyl acetate / hexane) shows the disappearance of starting material. The reaction is quenched by addition of 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution until about pH 5.0 (300 mL) is added The product is extracted with ethyl acetate (500 mL) The organic phase is washed with brine, dried over MgSO ₄ and filtered The filtrate is concentrated under reduced pressure to give a gray solid. Yield: 4.1 g, 84%).

210B. Suzuki Coupling:

Boronic acid (231 mg, 1.5 mmol), 2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (prepared in Example 210A) 2H) -pyridazinone (500 mg, 1.36 mmol), tetrakis- (triphenylphosphine) -palladium (0) (47 mg, 0.041 mmol), and CsF (413 mg, 2.72 mmol) under N ₂ , Stir at reflux for 5 h in DME (20 mL). TLC (1: 1 hexanes / ethyl acetate) shows that all starting material was consumed. The volatiles are removed in vacuo. The residue is partitioned between water and ethyl acetate. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo. Gray powder is obtained. (Yield 275 mg, 46%). Mp 88-91 ° C; ¹ H NMR (300 MHz, CDCl ₃ , mixture of rotamers) δ 2.2, 2.25 (2d, J = 1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92 (m, 2H) 6.61-6.8 ( m, 1H) 6.82-6.98 (m, 1H) 7.35 (d, J = 9 Hz, 1H) 7.78 (d, J = 9 Hz, 1H) 7.86-8.09 (m, 4H). MS (DCI-NH ₃ ), m / z 441 (M + H) ⁺ .

Elemental analysis for C ₂₀ H ₁₆ F ₄ N ₂ O ₃ S0.5 H ₂ O

Anal: 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) is dissolved in anhydrous DME (8 mL) and 3,5-dimethylbenzeneboron in the presence of CsF (150 mg, 0.98 mmol) and tetrakis (triphenylphosphine) -palladium (17.38 mg, 0.015 mmol) Heat reflux for 6 hours with acid. After cooling to rt, the reaction mixture is diluted with water and extracted with ethyl acetate (100 mL). The organic layer is washed with brine, dried over MgSO ₄ and concentrated in vacuo. The compound is purified by eluting with 30% ethyl acetate in pentane on a silica gel column to afford the title compound. (Yield 110 mg, 58%). ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 7.36 (d, J = 9 Hz, 2H), 7.94 (s, 1H), 7.96 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 496 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ CI ₂ F ₃ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 3-ethoxyphenylboronic acid. (Yield 155 mg, 86%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.42 (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, 1H), 6.75 (t, J = 1.5 Hz, 1H), 6.85 (dd, J = 1.5 Hz, 9 Hz, 1H), 7.15 (t, J = 9 Hz, 1H), 7.38 (d, J = 9 Hz, 2H), 7.88 (d, J = 9 Hz, 2H), 7.90 (s, 1H). MS (DCI-NH ₃ ) m / z 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₉ CI ₂ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 4- (trifluoromethyl) benzeneboronic acid. (Yield 85 mg, 44%). ¹ H NMR (300 MHz, CDCl ₃ ) 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-NH ₃ ) m / z 494 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₄ F ₆ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 3-nitrobenzeneboronic acid. (Yield 40 mg, 22%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (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, 1H), 8.05 (m, 1H), 8.15-8.21 (m, 1H). MS (DCI-NH ₃ ) m / z 471 (M + NH ₄ ) ⁺ .

Elementary Analysis for C ₁₉ H ₁₄ CI ₂ F ₃ N ₃ O ₅ S.0.5 EtOAc

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 2-methylbenzeneboronic acid. (Yield 45 mg, 27%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.05, 2.12 (2s, 3H), 3.01 (s, 3H), 4.75-5.05 (m, 2H), 6.88 (d, J = 9 Hz, 1H), 7.03- 7.25 (m, 3H), 7.31 (d, J = 9 Hz, 2H), 7.85 (d, J = 9 Hz, 2H), 7.95 (s, 1H). MS (DCI-NH ₃ ) m / z 440 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 4-vinylbenzeneboronic acid. (Yield 56 mg, 32%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.06, 3.08 (2s, 3H), 4.78-4.95 (m, 2H), 5.30 (t, J = 6 Hz, 1H), 5.65, 5.75 (2d, J = 18 Hz, 1H), 6.58-6.92 (m, 1H), 7.1-7.4 (m, 6H), 7.75-8.08 (m, 3H). MS (DCI-NH ₃ ) m / z 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 3-trifluoromethylbenzeneboronic acid. (Yield 120 mg, 63%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.03, 3.08 (2s, 3H), 4.75-4.98 (m, 2H), 7.30-7.60 (m, 6H), 7.75-8.10 (m, 3H). MS (DCI-NH ₃ ) m / z 494 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₄ F ₆ N ₂ O ₃ S

Anal: 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) -pyrida Xenon

The title compound is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 3-fluoro-4-methoxybenzeneboronic acid. (Yield 32 mg, 18%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05, 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, 5 H). MS (DCI-NH ₃ ) m / z 474 (M + NH ₄ ) ⁺ .

Elemental analysis for C ₂₀ H ₁₆ F ₄ N ₂ O ₄ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 211 by replacing 3,5-dimethylbenzeneboronic acid with 3-fluoro-4-methylbenzeneboronic acid. (Yield 58 mg, 33%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.21, 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 (DCI-NH ₃ ) m / z 458 (M + NH ₄ ) ⁺ .

Elemental analysis for C ₂₀ H ₁₆ F ₄ N ₂ O ₃ S0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 211, replacing 3,5-dimethylbenzeneboronic acid with 3,5-difluoro-4-methoxybenzeneboronic acid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.9, 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, 2 H), 7.7-8.15 (m, 4 H). MS (DCI-NH ₃ ) m / z 492 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₅ F ₅ N ₂ O ₄ S

Anal: 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-1-oxo-5-isobenzofuranyl) -5- [4- (methylsulfonyl) phenyl]- 3 (2H) -pyridazinone

6-bromophthalide [300 mg, 1.40 mmol, Teppema et al Recl. Trav. Chim. Pays-Bays, 1923, 42, 47] and hexamethylditin (326 μl, 1.55 mmol) were dissolved in toluene (5 mL), degassed with a stream of nitrogen for 5 minutes, (Ph ₃ P) ₄ Pd (79 mg) After treatment with, it is heated under reflux for 1 hour. The reaction is cooled and eluted with 4: 1 hexane-ethyl acetate on a Biotage 40S column (pretreated with hexane-TEA 400: 1 and then washed with hexane) and purified directly by chromatography. The product fractions are combined and evaporated to give intermediate, 6- (trimethyltin) phthalide. (Yield 362 mg, 87%).

Tin reagent (180 mg, 0.61 mmol) prepared above and 2- (2,2,2-trifluoro-ethyl) -4-chloro-5- [4- (methylsulfonyl) prepared in Example 193E Phenyl] -3 (2H) -pyridazinone (223 mg, 0.61 mmol) was dissolved in anhydrous toluene (10 mL), degassed with a stream of nitrogen for 5 minutes and treated with (Ph ₃ P) ₄ Pd (34 mg). Then, it is heated under reflux for 1 day. The reaction is cooled and eluted with 4: 1 hexane-ethyl acetate on a Biotage 40S column and purified directly by chromatography. The product fractions are combined and evaporated to yield the title compound and 4- (1,3-dihydro-1-oxo-6-isobenzofuranyl) -isomer in a ratio of 9: 1. Further work to remove the minor isomers (ie chromatography, recrystallization from ethyl acetate-hexane) failed. (Yield 176 mg, 62%). Mp 237-239 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.07 (s, 3H), 4.91 (q, J = 8 Hz, 2H), 5.30 (s, 2H, major isomers), 5.33 (s, 2H, minor isomers ), 7.20 (dd, J = 1 Hz, 7 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 7.52 (s, 1H), 7.79 (d, J = 7 Hz, 1H), 7.92 ( d, J = 8 Hz, 2H), 7.96 (s, 1H). MS (DCI-NH ₃ ) m / z 482 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₅ F ₃ N ₂ O ₅ S

Anal: 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

2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3, prepared according to the method of Example 193E, in THF (27 mL). A suspension of 2H) -pyridazinone (200 mg, 0.546 mmol) is cooled to -78 ° C. A solution of isopropenyl-magnesium bromide (2.8 mL, 0.5 M in THF, Aldrich) is added. The reaction is allowed to warm to room temperature and stirred for 30 minutes. Saturated ammonium chloride solution is added to quench the reaction at 0 ° C. and partition between ethyl acetate and additional ammonium chloride solution. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a reddish brown solid. The crude material is dissolved in methylene chloride and adsorbed onto silica gel (2 g). The solvent was removed under reduced pressure, the adsorbed silica gel was layered with Extract-Clean Cartridge ^R (Alltech, packing: 5 g silica gel) and 40 mL of the next mixture (hexane, 8: 1 hexanes / acetone, 4: 1 Elute the cartridge with a hexane / acetone step gradient consisting of 2: 1, and 1: 1). Fractions containing the desired product are combined, concentrated and further purified using HPLC (Technikrom Kromasil 60-5sil column, 20 mm x 25 cm). The column is eluted at 10 mL / min for 50 minutes with a linear gradient of 30% ethyl acetate / hexanes to 100% ethyl acetate. Fractions containing the title product are combined and concentrated under reduced pressure to give a pale yellow solid. (Yield 99.3 mg, 49%). Mp 192-195 ° C. ¹ 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 (m, 3 H), 3.11 (s, 3 H), 1.98 (s, 3 H). MS (DCI-NH ₃ ) m / z 373 (M + H) ⁺ , m / z 390 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₅ F ₃ N ₂ O ₃ S

Anal: 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) -4- (2-buten-2-yl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

Isopropenyl magnesium bromide was replaced with 1-methyl-1-propenyl magnesium bromide to prepare the product according to the method of Example 222 to give a mixture of geometric isomers (˜3: 1 ratio) as a gray solid. (Yield 44.8 mg, 21%). Mp 175-180 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (d, J = 18.0 Hz, 1.5H), 8.01 (d, J = 18.0 Hz, 0.5H), 7.29 (s, 0.75H), 7.28 (s, 0.25 H), 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 ) m / z 387 (M + H) ⁺ , m / z 404 (M + NH ₄ ) ⁺ , m / z 421 (M + 2NH ₄ -H) ⁺ .

Elemental Analysis for C ₁₇ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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), an oven containing small pieces of magnesium (134 mg, 5.5 mmol) and diethyl ether (12 mL) Add drop wise to the dried flask. After observing gas evolution, the ether is gently refluxed. Stir the reaction until gas evolution ceases and most of the magnesium is dissolved. The pale yellow solution of the resulting 3-fluorobenzyl magnesium bromide is used directly in the next reaction.

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

2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H, prepared according to the method of example 193E in THF (10 mL) The suspension of) -pyridazinone (200 mg, 0.546 mmol) is cooled to 0 ° C. A solution of 3-fluorobenzyl magnesium bromide (4.0 mL, ˜0.42 M in diethyl ether) prepared above is added. The reaction is stirred at 0 ° C. for 3 hours, quenched by addition of saturated ammonium chloride solution and then partitioned between ethyl acetate and additional ammonium chloride solution. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. The crude material is dissolved in methylene chloride and adsorbed onto silica gel (2 g). The solvent was removed under reduced pressure, and the silica gel containing the adsorbed product was layered with Extract-Clean Cartridge ^R (Alltech, packing: 10 g silica gel) and 60 mL of each next mixture (hexane, 8: 1 hexane The cartridge is eluted with a hexane / acetone step gradient consisting of acetone, 4: 1, 2: 1, and 1: 1). Fractions containing the desired product are combined, concentrated and further purified using HPLC (Technikrom Kromasil 60-5sil column, 20 mm x 25 cm). The column is eluted at 10 mL / min for 50 minutes with a linear gradient of 30% ethyl acetate / hexanes to 100% ethyl acetate. Fractions containing the title product are combined and concentrated under reduced pressure to give a pale yellow solid. (Yield 130.9 mg, 54%). Mp 58-62 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 18.0 Hz, 2H), 7.73 (s, 1H), 7.47 (d, J = 17.4 Hz, 2H), 7.18 (m, 1H), 6.88 (m, 1H), 6.76 (br d, J = 15.6 Hz, 1H), 6.68 (br d, J = 18.6 Hz, 1H), 4.86 (q, J = 17.4 Hz, 2H), 3.93 (s, 2H) , 3.12 (s, 3 H). MS (DCI-NH ₃ ) m / z 441 (M + H) ⁺ , m / z 458 (M + NH ₄ ) ⁺ , m / z 475 (M + 2NH ₄ -H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₆ F ₄ N ₂ O ₃ S

Anal: 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-cyclohexenyltriplate.

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

225B. 1-cyclohexenyltrimethyltin.

A solution of 1-cyclohexenyltriplate (412 mg, 1.79 mmol) and LiCl (380 mg, 8.95 mmol) prepared according to the method of Example 225A, in THF (9 mL), was streamed through this solution in an N ₂ stream. Bubble to deoxygenate. Hexamethylditin (339 μl, 1.61 mmol) and tetrakis (triphenylphosphine) palladium (0) (414 mg, 0.36 mmol) are added and the reaction is heated at reflux for 12 hours. The reaction is stirred to room temperature and partitioned between diethyl ether and saturated sodium bicarbonate solution. The ether layer is washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material is dissolved in hexane (1 mL) and charged onto Extract-Clean Cartridge ^R (Alltech, packing: 10 g silica gel) already wetted with 10% triethylamine in hexane. The catirizil is eluted with hexane, the fractions comprising triflate are combined and concentrated under reduced pressure to give 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.

1-cyclohexenyltrimethyltin (150 mg, 0.61 mmol) prepared according to the method of Example 225B in anhydrous N-methylpyrrolidinone (1 mL) and 2- (2, prepared according to the method of Example 193E) A solution of 2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (172 mg, 0.47 mmol) is 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, The reaction is heated at 80 ° C for 16 h. The reaction mixture is cooled to room temperature and partitioned between diethyl ether and water. The ether is washed twice with water followed by brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material is dissolved in acetone and adsorbed onto silica gel (1 g). The solvent was removed under reduced pressure, and the adsorbed silica gel was layered with Extract-Clean Cartridge ^R (Alltech, packing: 10 g silica gel), followed by the following mixture (hexane (60 ml), 8: 1 hexanes / acetone (80 ml) The cartridge is eluted with a hexane / acetone step gradient consisting of 4: 1 hexanes / acetone (150 ml). Fractions containing the desired product are combined, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil silica column, 20 mm x 25 cm). The column is eluted at 10 mL / min for 50 minutes with a linear gradient of 30% ethyl acetate / hexanes to 100% ethyl acetate. Fractions containing the title product are combined and concentrated under reduced pressure to give a pale yellow foam. (Yield 95.0 mg, 49%). Mp 75-81 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, J = 17.4 Hz, 2H), 7.76 (s, 1H), 7.55 (d, J = 17.4 Hz, 2H), 5.51 (br s, 1H), 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-NH ₃ ) m / z 413 (M + H) ⁺ , m / z 430 (M + NH ₄ ) ⁺ , m / z 447 (M + 2NH ₄ -H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₉ F ₃ N ₂ O ₃ S

Anal: 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) -pyrida Xenon

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

4-Fromothioanisole is replaced with 4-bromo-3-fluorothioanisole to prepare 3-fluoro-4- (methylthio) benzeneboronic acid according to the method of Example 1.

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

2- (2,2,2-trifluoroethyl) -4,5-dibromo-3 (2H) -pyridazinone instead of 2-benzyl-4,5-dibromo-3 (2H) -py Starting from dazinone and replacing isopropanol with methanol, 2-benzyl-4-methoxy-5-bromo-3 (2H) -pyridazinone is prepared according to the method of Example 83B.

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 combined according to the method of Example 83C to give 2 as a yellow solid. -Benzyl-4-methoxy-5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone is obtained. (Yield 4.98 g, 91%). ¹ H NMR (300 MHz, CDCl 3) δ 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-methylbutylmagnesium bromide

Fill an oven-dried flask containing small pieces of magnesium (134 mg, 5.5 mmol) with diethyl ether (12 mL). 1-bromo-3-methylbutane (600 μl, 5 mmol) is added dropwise followed by dibromoethane (10 μl) dropwise. When the reaction is heated under gentle reflux, gas evolution is observed. The reaction is refluxed for 3 hours and cooled to room temperature. A light gray solution of 3-methylbutylmagnesium bromide is used in the next reaction.

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

2-benzyl-4-methoxy-5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared according to the method of Example 226C in THF (20 mL) (500 mg, 1.40 mmol) is cooled to -78 ° C. 3-methylbutylmagnesium bromide (5 mL, 1.96 mmol) prepared in Example 226D is added dropwise. Upon complete addition, the reaction mixture is placed in a cold bath. After 2.5 h, saturated ammonium chloride solution is added to quench the reaction. The crude reaction mixture is partitioned between ethyl acetate and additional ammonium chloride solution. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. (Yield 550 mg, 99%). ¹ H NMR (300 MHz, CDCl 3) δ 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 (m, 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-NH ₃ ) m / z 397 (M + H) ⁺ , m / z 414 (M + NH ₄ ) ⁺ .

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) ) Is debenzylated according to the method of Example 11 to obtain 4- (3-methylbutyl) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyrida as a pale yellow solid. Obtain xenon. (Yield 375 mg, 88%). ¹ H NMR (300 MHz, CDCl 3) d 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-NH ₃ ) m / z 307 (M + H) ⁺ , m / z 324 ( M + NH ₄ ) ⁺ .

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

Example 4- (3-methylbutyl) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone (375 mg, 1.23 mmol) prepared in Example 226F Alkylation according to the method of 20, 2- (2,2,2-trifluoroethyl) -4- (3-methylbutyl) -5- [3-fluoro-4- (methylthio) phenyl in clear oil ] -3 (2H) -pyridazinone is obtained. (Yield 331 mg, 69%). ¹ H NMR (300 MHz, CDCl 3) δ 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 (m, 3H), 0.85 (d, 6H, J = 12.0 Hz). MS (DCI-NH 3) m / z 389 (M + H) ⁺ , m / z 406 (M + NH 4) ⁺ . MS (DCI-NH ₃ ) m / z 389 (M + H) ⁺ , m / z 406 (M + NH ₄ ) ⁺ .

226H. 2- (2,2,2-trifluoroethyl) -4- (3-methylbutyl) -5- [3-fluoro-4- (methylsulfinyl) -phenyl] -3 (2H) -pyrida Xenon.

2- (2,2,2-trifluoroethyl) -4- (3-methylbutyl) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H, prepared in Example 226G ) -Pyridazinone (331 mg, 0.85 mmol) was oxidized according to the method of Example 5 using only 1 equivalent of MCPBA to give 2- (2,2,2-trifluoroethyl)-as a gray solid. 4- (3-methylbutyl) -5- [3-fluoro-4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone is obtained. (Yield 240 mg, 69%). ¹ H NMR (300 MHz, CDCl 3) δ 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, 1H , 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 ) ⁺ .

226I. 2- (2,2,2-trifluoroethyl) -4- (3-methylbutyl) -5- [3-fluoro-4- (aminosulfonyl) -phenyl] -3 (2H) -pyrida Xenon

2- (2,2,2-trifluoroethyl) -4- (3-methylbutyl) -5- [3-fluoro-4- (methylsulfinyl) -phenyl] -3 prepared in Example 226H (2H) -pyridazinone (240 mg, 0.594 mmol) is converted to sulfonamide according to the method of Example 68 to afford the title compound as a white solid. (Yield 109 mg, 44%). Mp 153-156 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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 (m, 2H), 1.55 (m, 1H), 1.41 (m, 2H), 0.85 (d, J = 12.6 Hz, 6H). MS (ESI (−)) m / z 420 (M ⁻ H) ⁻ .

Elemental Analysis for C ₁₇ H ₁₉ F ₄ N ₃ O ₃ S

Anal: 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

1.0 M benzyl magnesium chloride in ether (0.53 mL, 0.53 mmol) was prepared at 0 ° C. according to the method of Example 193E, according to the method of Example 193E 2- (2,2,2-trifluoroethyl) -4-chloro-5- After addition to a THF (20 mL) solution of [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (150 mg, 0.41 mmol), the mixture was allowed to warm to room temperature over 2 hours and the title Prepare the compound. After aqueous workup, the crude material is purified by column chromatography (silica gel, 65:35 hexanes / ethyl acetate) and crystallized from ethyl acetate / hexanes to give a white, crystalline product. (Yield 74 mg, 43%). Mp 112-114 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.12 (s, 3H), 3.94 (s, 2H), 4.85 (q, J = 12 Hz, 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, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 423 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S

Anal: C, 56.86; H, 4.05; N, 6.63.

Found: C, 56.60; H, 4.13; N, 6.57.

Example 228

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 in THF (8 ml) (200 mg, 0.51 mmol) is cooled to -78 ° C and treated with cyclohexyl magnesium chloride, 2 M solution in ether (0.31 ml, 0,7 mmol). The reaction mixture is stirred at -78 ° C for 2 hours, then the cold bath is removed and warmed to room temperature. The water is stirred for 2 hours at room temperature, water (50 ml) is added to the reaction mixture and extracted with ethyl acetate (50 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo. The resulting methyl sulfide compound is purified by flash chromatography (eluted with SiO ₂ , 9: 1 hexanes: ethyl acetate) to afford the desired product. (Yield 128 mg, 69%). MS (DCI-NH ₃ ) m / z 395 (M + H) ⁺ , 412 (M + NH ₄ ) ⁺ .

At 0 ° C., the methyl sulfide compound (122 mg, 0.3 mmol) prepared above in CH ₂ Cl ₂ (10 ml) is treated with CH ₃ CO ₃ H (0.3 ml, 1 mmol). The reaction is complete after 2 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ and brine, respectively. The resulting crude residue is purified by flash chromatography (SiO ₂ , eluted with 1: 1 hexanes: ethyl acetate) to afford the desired product. (Yield 110 mg, 93%). Mp 231-233 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.1 (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, 1 H), 8.1 (d, 2H). MS (DCI-NH ₃ ) m / z 427 (M + H) ⁺ , 444 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ FN ₂ O ₃ S · 0.75 H ₂ O

Anal: C, 64.77; H, 5. 44; N, 6.57.

Found: C, 62.86; H, 5.53; N, 5.78.

Example 229

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

The title compound is prepared according to the method of Example 228 by replacing cyclohexylmagnesium chloride with p-tolylmagnesium bromide. (Yield 90 mg, 39%). Mp 242-244 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.25 (s, 3H), d 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, 1H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 228, replacing cyclohexylmagnesium chloride with benzylmagnesium bromide. (Yield 179 mg, 81%). Mp 180-182 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (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 (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ FN ₂ O ₃ S · 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 228, replacing cyclohexyl magnesium chloride with phenylacetylene magnesium bromide. (Yield 150 mg, 55.5%). Mp 203-204 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (s, 3H), 7.4 (m, 8H), 7.7 (m, 2H), 8.16 (m, 4H); 8.35 (s, 1 H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₁₇ FN ₂ O ₃ S

Anal: 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

2- (4-fluorophenyl) -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting with 4-methoxy-5- [4- (methylthio) phenyl] 3 (2H) -pyridazinone, the title compound is prepared according to the method of Example 228. (Yield 245 mg, 80%). Mp 80-83 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.1 (m, 3H), 1.6 (m, 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-NH ₃ ) m / z 445 (M + H) ⁺ , 462 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₂ F ₂ N ₂ O ₃ S

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone The method of Example 228, starting from) -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, replacing cyclohexylmagnesium chloride with benzylmagnesium bromide To yield the title compound. (Yield 206 mg, 66%). Mp 166-168 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (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 ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ F ₂ N ₂ O ₃ S

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Example 228 starting from) -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing cyclohexylmagnesium chloride with p-tolylmagnesium bromide The title compound is prepared according to the method of. (Yield 140 mg, 56%). Mp 190-192 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 2H), d 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 ) ⁺ .

Elemental Analysis for C ₂₄ F ₂ H ₁₈ N ₂ O ₃ S

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone ), Starting from 4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, and cyclohexylmagnesium chloride with 4-fluoro-3-methylbenzenemagnesium bromide Alternatively, the title compound is prepared according to the method of Example 228. (Yield 180 mg, 72.5%). Mp 166-168 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 2.15 (s, 3H), d 3.25 (s, 3H), 7.01 (m, 2H), 7.25 (d, 1H), 7.6 (m, 4H), 7.9 (m, 3 H), 8.26 (s, 2 H). MS (DCI-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₄ F ₃ H ₁₇ N ₂ O ₃ S: 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

2- (3,4-difluorophenyl) -4 instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Starting from -methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing cyclohexyl magnesium chloride with vinyl magnesium bromide, according to the method of Example 228 Prepare the compound. (Yield 85 mg, 31.8%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.15 (s, 3H), d 3.3 (s, 3H), 5.7 (dd, 1H), 6.4 (dd, 1H), 6.7 (dd, 1H) 7.01 ( m, 2H), 7.5 (m, 1H), 7.65 (m, 1H), 7.8 (m, 3H), 8.1 (s, 3H). MS (DCI-NH ₃ ) m / z 389 (M + H) ⁺ , 406 (M + NH ₄ ) ⁺ .

Example 237

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

2- (3,4-difluorophenyl) -4 instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone The method of Example 228, starting from -methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, replacing cyclohexyl magnesium chloride with 2-thienyl magnesium bromide To yield the title compound. (Yield 66 mg, 28%). Mp 189-191 ° C ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 (DCI-NH ₃ ) m / z 445 (M + H) ⁺ , 462 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₄ F ₂ N ₂ O ₃ S ₂

Anal: 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

2- (3,4-difluorophenyl) -4 instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Starting from -methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing cyclohexyl magnesium chloride with methylacetylene magnesium bromide according to the method of Example 228 Prepare the title compound. (Yield 65 mg, 24%). Mp 149-150 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.1 (s, 3H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.8 (m, 1H), 8.1 ( m, 4H); 8.3 (s, 1 H). MS (DCI-NH ₃ ) m / z 463M + H) ⁺ , 480 (M + NH ₄ ) ⁺ .

Elemental analysis for C ₂₀ H ₁₄ F ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

2- (3,4-difluorophenyl) -4 instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Starting from -methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing cyclohexyl magnesium chloride with t-butylmagnesium bromide in the method of Example 228 According to the title compound. (Yield 60 mg, 24%). Mp 158-161 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21, (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 (DCI-NH ₃ ) m / z 419 (M + H) ⁺ , 436 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₀ F ₂ N ₂ O ₃ S

Anal: 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

2- (2,2,2 prepared in Example 193E instead of 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone The title compound is prepared according to the method of Example 228, starting from -trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 120 mg, 53%). Mp 215-218 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.1 (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, 1H), 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, 1H), 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 (DCI-NH ₃ ) m / z 415 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₂₁ F ₃ N ₂ O ₃ S

Anal: 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

Cyclohexyl magnesium chloride was prepared starting from 2- (3-chlorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 331. 2- (3-chlorophenyl) -4- (3-fluorobenzyl) -5- [4- (methylthio) phenyl] -3 following the method of Example 228, replacing 3-fluorobenzylmagnesium chloride (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 180 mg, 55%). Mp 142-143 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.14 (s, 3H), 3.98 (s, 2H), 6.75 (br d, J = 9 Hz, 1H), 6.82 (br d, J = 9 Hz, 1H) , 6.88 (br t, J = 9 Hz, 1H), 7.15-7.23 (m, 1H), 7.37-7.47 (m, 2H), 7.54 (d, J = 9 Hz, 2H), 7.63 (dt, J = 9 Hz, 2 Hz, 1H), 7.75 (t, J = 2 Hz, 1H), 7.82 (s, 1H), 8.10 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ ClF ₂ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

Cyclohexyl magnesium chloride, starting from 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 194C Is substituted with 3-fluorobenzylmagnesium chloride and 2- (4-fluorophenyl) -4- (3-fluorobenzyl) -5- [4- (methylthio) phenyl] according to the method of Example 228 -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 450 mg, 66.8%). Mp 176-178 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.14 (s, 3H), 3.95 (s, 2H), 6.75 (br d, J = 9 Hz, 1H), 6.82 (br d, J = 9 Hz, 1H) , 6.88 (br t, J = 9 Hz, 1H), 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, 1 H), 8.10 (d, J = 9 Hz, 2 H). MS (DCI-NH ₃ ) m / z 516 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ F ₂ N ₂ O ₅ SH ₂ O

Anal: 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

Starting from 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 206E, cyclo Hexylmagnesium chloride is replaced with 3-fluorobenzylmagnesium chloride, following the method of Example 228 to 2- (3,4-difluorophenyl) -4- (3-fluorobenzyl) -5- [4- (Methylthio) phenyl] -3 (2H) -pyridazinone is prepared to obtain a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 390 mg, 68%). Mp 161-163 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.14 (s, 3H), 3.95 (s, 2H), 6.74 (br d, J = 9 Hz, 1H), 6.82 (br d, J = 9 Hz, 1H) , 6.89 (br t, J = 9 Hz, 1H), 7.15-7.33 (m, 2H), 7.48-7.57 (m, 1H), 7.53 (d, J = 9 Hz, 2H), 7.59-7.67 (m, 1H), 7.83 (s, 1H), 8.10 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₃ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

Cyclohexyl magnesium chloride was prepared starting from 2- (3-chlorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 207B. Substituted with 4-fluoro-3-methylphenylmagnesium bromide, following the method of Example 228 2- (3-chlorophenyl) -4- (4-fluoro-3-methylphenyl) -5- [4- (methyl Thio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 620 mg, 57%). Mp 228-230 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.20 (s, 3H), 3.06 (s, 3H), 6.83-6.93 (m, 2H), 7.19 (br d, J = 9 Hz, 1H), 7.37-7.47 (m, 2H), 7.40 (d, J = 9 Hz, 2H), 7.65 (dt, J = 7 Hz, 3 Hz, 1H), 7.68 (t, J = 3 Hz, 1H), 7.91 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ ClFN ₂ O ₃ S

Anal: 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- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

Cyclohexyl magnesium chloride, starting from 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 194C Is replaced by 4-fluoro-3-methylphenylmagnesium bromide, following the method of Example 228 to 2- (4-fluorophenyl) -4- (4-fluoro-3-methylphenyl) -5- [4- (Methylthio) phenyl] -3 (2H) -pyridazinone is prepared to obtain a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 590 mg, 74.4%). Mp 245-247 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.01 (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 (DCI-NH ₃ ) m / z 453 (M + H) ⁺ , 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₃ S · 0.5 H ₂ O

Anal: C, 62.47; H, 3. 90; N, 6.08.

Found: C, 62.11; H, 4.11; N, 5.81.

Example 246

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 of Example 194A by replacing 4-fluorophenyl hydrazine.HCl with 3-chloro-4-fluorophenyl hydrazine.HCl. (Yield 9.1 g, 9%). ¹ 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-NH ₃ ) m / z 383 (M + H) ⁺ , 400 (M + NH ₄ ) ⁺

246B. 2- (3-Chloro-4-fluorophenyl) -4-methoxy-5-bromo-3 (2H) -pyridazinone.

2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone to 2- (3-chloro-4-fluorophenyl) -4,5-dibromo-3 Substituted by (2H) -pyridazinone, the title compound is prepared according to the method of Example 194B. (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-NH ₃ ) m / z 335 (M + H) ⁺ , 352 (M + NH ₄ ) ⁺ .

246C. 2- (3-Chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone.

2- (3-chloro-4-fluoro instead of 2-benzyl-5-methoxy-4-bromo-3 (2H) -pyridazinone and substituting 3-methyl-4- (methylthio) -benzeneboronic acid Starting from Phenyl) -4-methoxy-5-bromo-3 (2H) -pyridazinone, replacing 4-fluorobenzeneboronic acid with 3-methyl-4- (methylthio) -benzeneboronic acid The title compound is prepared according to the method of Example 6. (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, 1H), 7.78 (dd, J = 9 Hz, 3 Hz, 1H), 7.93 (s, 2H). MS (DCI-NH ₃ ) m / z 377 (M + H) ⁺ , 394 (M + NH ₄ ) ⁺ .

246D. 2- (3-Chloro-4-fluorophenyl) -4-cyclohexyl-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone

2- (4-chlorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone instead of 2- (3-chloro-4-fluorophenyl)- Starting from 4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone, the methoxy-sulfide compound was treated with cyclohexyl magnesium chloride according to the method of Example 228. The title compound is prepared to yield a cyclohexyl sulfide compound.

246E. 2- (3-Chloro-4-fluorophenyl) -4-cyclohexyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 150 mg, 53%). Mp 180-181 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.02-1.36 (m, 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, 1H), 3.17 (s, 3H), 7.25 (t, J = 9 Hz, 1H), 7.53 (d, J = 9 Hz, 1H), 7.53-7.61 (m, 2H), 7.69 (s, 1H), 7.78 (dd, J = 9 Hz, 3 Hz, 1H), 8.12 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 461 (M + H) ⁺ , 478 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₂ ClFN ₂ O ₃ S

Anal: 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

Starting from 2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 246D, Replace cyclohexylmagnesium chloride with 4-fluoro-3-methylphenylmagnesium bromide, following the method of Example 228, following 2- (3-chloro-4-fluorophenyl) -4- (4-fluoro-3- Methylphenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 118 mg, 53.7%). Mp 207-208 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.21 (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, 1H), 7.85 (dd, J = 9 Hz, 3 Hz, 1H), 7.93 (d, J = 9 Hz, 2H), 7.99 (s, 1H). MS (DCI-NH ₃ ) m / z 487 (M + H) ⁺ , 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ ClF ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

Starting from 2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 246D, Cyclohexylmagnesium chloride was replaced with benzylmagnesium chloride, following the method of Example 228 2- (3-chloro-4-fluorophenyl) -4-benzyl-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 110 mg, 38.4%). Mp 164-166 ° C. ¹ 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, 1H), 7.81 (s, 1H), 7.82 (dd, J = 6 Hz, 3 Hz, 1H), 8.09 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ ClFN ₂ O ₃ S

Anal: C, 61.54; H, 3. 85; N, 5.99.

Found: C, 61.40; H, 3. 82; N, 5.54.

Example 249

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

Starting from 2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 246D, Replace cyclohexyl magnesium chloride with 3-fluorobenzyl-magnesium chloride, following the method of Example 228 to 2- (3-chloro-4-fluorophenyl) -4- (3-fluorobenzyl) -5- [4- (Methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 33 mg, 15%). Mp 101-103 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.15 (s, 3H), 3.95 (s, 2H), 6.73 (br d, J = 9 Hz, 1H), 6.81 (br d, J = 9 Hz, 1H) , 6.88 (br t, J = 9 Hz, 1H), 7.15-7.28 (m, 2H), 7.51 (d, J = 9 Hz, 2H), 7.53 (ddd, J = 9 Hz, 3 Hz, 1.5 Hz, 1H), 7.83 (dd, J = 6 Hz, 3 Hz, 1H), 7.83 (s, 1H), 8.10 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 487 (M + H) ⁺ , 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ ClF ₂ N ₂ O ₃ S

Anal: 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

Cyclohexyl magnesium chloride, starting from 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 194C Is substituted with 3-fluoro-4-methylphenylmagnesium bromide, following the method of Example 228 to 2- (4-fluorophenyl) -4- (3-fluoro-4-methylphenyl) -5- [4- (Methylthio) phenyl] -3 (2H) -pyridazinone is prepared to obtain a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 540 mg, 73%). Mp 245-248 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.22 (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, 1H), 7.06 (t, J = 9 Hz, 1H), 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-NH ₃ ) m / z 452 (M + H) ⁺ , 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₃ S

Anal: 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

Starting from 2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 246D, Replace cyclohexylmagnesium chloride with 3,5-difluoro-4-methoxyphenylmagnesium bromide, following 2- (3-chloro-4-fluorophenyl) -4- (3, 5-Difluoro-4-methoxyphenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 590 mg, 65.7%). Mp 195-197 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.10 (s, 3H), 4.12 (s, 3H), 6.81 (br d, J = 9 Hz, 2H), 7.27 (t, J = 9 Hz, 1H), 7.43 (d, J = 9 Hz, 2H), 7.60-7.67 (m, 1H), 7.83 (br d, J = 9 Hz, 1H), 7.98 (d, J = 9 Hz, 2H), 7.98 (s, 1H). MS (DCI-NH ₃ ) m / z 487 (M + H) ⁺ , 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ ClF ₃ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

Starting from 2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 246D, Replace cyclohexylmagnesium chloride with 1- (3-methylbutyl) -magnesium bromide, following 2- (3-chloro-4-fluorophenyl) -4- (3-methylbutyl)-according to the method of Example 228. 5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide compound is oxidized according to the method of Example 10 to give the title compound. (Yield 425 mg, 54.4%). Mp 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 (m, 2H), 3.30 (s, 3H), 7.22- 7.38 (m, 3H), 7.57-7.64 (m, 1H), 7.72 (br s, 1H), 7.80 (br d, J = 6 Hz, 1H), 8.15 (t, J = 9 Hz, 1H). MS (DCI-NH ₃ ) m / z 467 (M + H) ⁺ , 484 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ ClF ₂ N ₂ O ₃ S

Anal: 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 (275624) is oxidized to methyl sulfoxide using 1 equivalent of meta-chloroperoxybenzoic acid according to the method of Example 69B to afford a sulfinyl compound.

The sulfoxide is converted to the title sulfonamide according to the method of Example 68 (yield: 120 mg, 31%). Mp 199-202 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.92 (s, 2H), 6.85 (br t, J = 9 Hz, 2H), 6.99 (br t, J = 9 Hz, 1H), 7.26 (q, J = 7 Hz, 1H), 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, 1 H). MS (DCI-NH ₃ ) m / z 454 (M + H) ⁺ , 471 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ F ₂ N ₃ O ₃ S

Anal: 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 is prepared following the method of Example 228, replacing chloride with phenylethynylmagnesium bromide. (Yield 195 mg, 61%). Mp 211-213 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.46 (m, 5H), 7.65 (m, 2H), 8.18 (t, 4H); 8.4 (s, 1 H). MS (DCI-NH ₃ ) m / z 463M + H) ⁺ , 480 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₁₆ F ₂ N ₂ O ₃ S

Anal: 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) is treated with magnesium turning (19.4 mg, 0.81 mmol) and the reaction mixture is refluxed for 1 hour. The reaction mixture was cooled down and at -78 ° C., 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H in THF (10 ml) To a solution of) -pyridazinone (0.25 g, 0.7 mmol). The reaction mixture is stirred at rt for 18 h. Water (50 ml) is added to the reaction mixture and extracted with ethyl acetate (50 ml). The organic layer is dried over MgSO ₄ and concentrated in vacuo. The resulting crude residue is purified by flash chromatography (eluted with SiO ₂ , 9: 1 hexanes: ethyl acetate) to afford 120 mg of desired product and some starting material.

The methylthio compound (120 mg, 0.3 mmol) from above in CH ₂ Cl ₂ (10 ml) is treated with CH ₃ CO ₃ H (0.3 ml, 1 mmol) at 0 ° C. The reaction is over 2 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ and brine respectively The resulting crude residue is purified by flash chromatography (SiO ₂ , eluted with 1: 1 hexanes: ethyl acetate). Obtain the desired product (yield: 44 mg, 13%) Mp 177-179 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.3 (s, 3H), 3.9 (s, 2H), 6.85 (m, 1H), 7.15 (m, 1H), 7.25 (m, 2H), 7.6 (m, 7H), 8.15 (m, 3H) .MS (DCI-NH ₃ ) m / z 489 (M + H ) ⁺ , 506 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ F ₄ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone ), 3-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, and 3,4-difluorobenzyl bromide to 1-bromo-3- Substituted with methylbutane, the title compound is prepared according to the method of Example 233. (Yield 198 mg, 48%). Mp 55-58 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J = 9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 433 (M + H) ⁺ , 450 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ F ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3,4-difluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone ), 3-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, and 3,4-difluorobenzyl bromide to 1-bromo-3- Substituted with methylbutane, the title compound is prepared according to the method of Example 233. (Yield 256 mg, 88%). Mp 55-58 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (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 (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ FN ₂ O ₃ SCl.0.25 H ₂ O

Anal: 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

2- (3-chloro-4-fluorophenyl) -4-methoxy-5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone instead of 2- (3, 3,4-difluorobenzyl bromide starting from 4-difluorophenyl) -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone; Substituted by bromo-3-methylbutane, the title compound is prepared according to the method of Example 233. (Yield 100 mg, 20%). Mp 119-121 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.4 (s, 3H), 7.51 (m, 1H), 7.8 (m, 2 H), 7.81 (m, 2 H). MS (DCI-NH ₃ ) m / z 451 (M + H) ⁺ , 468 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ F ₃ N ₂ O ₃ S

Anal: 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

At room temperature, 2- (3,4-difluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H)-in DMF (10 ml) A stirred solution of pyridazinone (315 mg, 0.69 mmol) is treated with sodium thiomethoxide (51 mg, 0.7 mmol). The reaction mixture is stirred at room temperature for 3.15 hours. The reaction is poured into water (75 ml) and extracted with ethyl acetate. The organic layer is washed twice with brine, dried over MgSO ₄ and concentrated in vacuo. The resulting crude residue is purified using flash chromatography (SiO ₂ , eluted with 15: 1 CH ₂ Cl ₂ : diethyl ether) to afford the desired product. (Yield 30 mg, 8%). Mp 105-107 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.55 (s, 3H), 3.23 (s, 3H), d 7.15 (m, 2H), 7.3 (m, 2H), 7.55 (m, 5H), 7.9 (d, 2 H), 8.25 (s, 1 H). MS (DCI-NH ₃ ) m / z 485 (M + H) ⁺ , 502 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₃ S ₂

Anal: 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

Oxidation of the sulfides following the method of Example 69B starting from 2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone To give the title compound.

260B. Bis (4- (5- (2-benzyl-4- (4-fluorophenyl) -3 (2H) -pyridazinone) -phenyl) disulfide:

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone in trifluoroacetic anhydride (10 mL, 70.8 mmol) ( 1.0 g, 2.39 mmol) of the heterogeneous solution is rapidly stirred at a bath temperature of 40 to 43 ° C. under reflux for 2 hours. The reaction solution is cooled to 23 ° C., concentrated in vacuo and azeotropic with toluene (2 × 5-7 mL). The resulting yellow / orange oil is cooled to 0 ° C. and methanol / triethylamine (1: 1, 6 mL) is added slowly along the inner wall of the reaction vessel with rapid stirring. The bright red-orange solution is stirred for 10 min at 0 ° C, the cold bath is removed and the reaction mixture is stirred for an additional 1.5 h while warming to 23 ° C. The mixture is cooled to 0 ° C. again, saturated NH ₄ Cl solution (200 mL) is added slowly, then sufficient aqueous 1 M HCl is added to adjust the solution to pH 1-2. The cold bath is removed and the solution is stirred overnight. The mixture is extracted with ethyl acetate. The ethyl acetate solution is washed with water and brine and concentrated in vacuo. The resulting yellow / brown oil (0.89 g) is a mixture in which monosulfide and the desired disulfide predominate. Then, the crude reaction mixture (360 mg) in benzene (100 mL) was stirred rapidly at 23 ° C. for 30 minutes with I ₂ (648 mg, 2.55 mmol) to complete conversion of monosulfide to disulfide [ Chem. Pharm. Bull., 1992, 40, 2842]. The mixture is treated with 0.1 M Na ₂ S ₂ O ₃ solution to consume excess I ₂ . The solution is extracted with ethyl acetate and the ethyl acetate layer is dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is dissolved in CH ₂ Cl ₂ / hexanes and concentrated in vacuo to afford the product. (Yield 347 mg, partial conversion 90%). ¹ 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 (s, 2H).

260C. 2-benzyl-4- (4-fluorophenyl) -5- [4- (trifluoromethylthio) phenyl] -3 (2H) -pyridazinone:

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 a rapidly stirred mixture of sulfolane (1.5 mL) are immersed in a preheated oil bath at 180 ° C. The oil bath is heated to raise the temperature to 210 ° C., and after 10 minutes from the initial immersion time, the reaction flask is quickly removed from the oil bath. During the course of the reaction, the mixture changes from a colorless, heterogeneous mixture to a dark red homogeneous mixture. After cooling to 23 ° C., the mixture is diluted with ethyl acetate and washed with aqueous 1 M HCl, water and brine. The ethyl acetate solution is dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is chromatographed (flash silica gel, ethyl acetate / hexane 1: 4) to afford the product. (Yield 17 mg, 41%). (Tetrahedron Lett .., 1996, 37, 9057) ¹ H NMR (300 MHz, CDCl ₃ ) d 5.41 (s, 2H), 6.94 (dd, J = 8.2, 8.2 Hz, 2H), 7.11-7.20 (m, 4H), 7.31-7.42 (m, 3H), 7.52-7.61 (m, 4H), 7.86 (s, 1H). MS (APCI +) m / z 457 (M + H) ⁺ and m / z 474 (M + NH ₄ ) ⁺ .

260D. 2-benzyl-4- (4-fluorophenyl) -5- [4- (trifluoromethylsulfonyl) phenyl] -3 (2H) -pyridazinone:

2-benzyl-4- (4-fluorophenyl) -5- [4- (trifluoromethylthio) phenyl] -3 (2H) -pyridazinone (100 mg, 0.219 mmol), 3-chloroperoxy A solution of benzoic acid (380 mg, 1.3 mmol, 57-86%) and methylene chloride (5 mL) is refluxed at a bath temperature of 55 ° C. After 1.75 hours, 3.5 hours, 5 hours and 6 hours, the reaction is not complete, so additional 3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%) is added at each time point. When the reaction is complete after 7.75 hours, the mixture is cooled to 23 ° C and concentrated in vacuo. The residue is diluted with ethyl acetate and shaken three times carefully for several minutes with NaHSO ₃ solution to consume excess 3-chloroperoxybenzoic acid. The ethyl acetate solution is then washed with saturated Na ₂ CO ₃ solution (3 ×), water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography of the residue (flash silica gel, ethyl acetate / methylene chloride / hexane 1: 2: 7) afforded the product [J. Med. Chem., 1990, 33, 2569]. (Yield 93 mg, 87%). Mp 80-115 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.36 (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 (s, 1H). MS (APCI +) m / z 489 (M + H) ⁺ and m / z 506 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₆ F ₄ N ₂ O ₃ S

Anal: 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, prepared in Example 193E) 0.41 mmol), and neopentyl alcohol (43 mg, 0.49 mmol) are dissolved in DMF (2 mL) and NaH (25 mg, 0.62 mmol, 60% in mineral oil) is added with shaking and left overnight. The reaction mixture is quenched with saturated NH ₄ Cl solution, diluted with ethyl acetate, extracted twice with 1 N HCl and then three times with water, then dried over MgSO ₄ . The desiccant is filtered, the filtrate is concentrated in vacuo, and the residue is purified by chromatography eluting with 2: 1 hexane-ethyl acetate on silica gel (Biotage 40S). The product fractions are combined and evaporated to give the title compound. (Yield 137 mg, 76%). Mp 145-146 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (DCI-NH ₃ ) m / z 419 (M + H) ⁺ , 436 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₂₁ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4-methoxyphenol. (Yield 130 mg, 54%). Mp 194-195 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (s, 1H). MS (ESI-) m / z 439 (M ⁻ H) ⁻ .

Elemental Analysis for C ₁₉ H ₁₇ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 2-fluoro-5-trifluoromethylphenol. (Yield 155 mg, 89%). Mp 133-135 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.28 (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 (DCI-NH ₃ ) m / z 528 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₃ F ₇ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 261, replacing neopentyl alcohol with 4-cyanophenol. (Yield 109 mg, 71%). Mp 179-181 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.26 (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, 1H). MS (DCI-NH ₃ ) m / z 467 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₄ F ₃ N ₃ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 3-hydroxypyridine. (Yield 120 mg, 69%). Mp 191-193 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.26 (s, 3H), 5.01 (q, J = 9 Hz, 2H), 7.36 (dd, J = 3 Hz, 8 Hz, 1H), 7.55 (ddd , J = 1 Hz, 3 Hz, 8 Hz, 1H), 7.88 (d, J = 8 Hz, 2H), 8.04 (d, J = 8 Hz, 2H), 8.31 (dd, J = 1 Hz, 5 Hz , 1H), 8.36 (s, 1H), 8.38 (d, J = 3 Hz, 1H). MS (DCI-NH ₃ ) m / z 426 (M + H) ⁺ , 443 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₄ F ₃ N ₃ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4- (n-propyl) phenol. (Yield 147 mg, 77%). Mp 152-153 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.87 (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 Hz , 2H), 8.32 (s, 1H). MS (DCI-NH ₃ ) m / z 484 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4- (methylsulfonyl) phenol. (Yield 115 mg, 56%). Mp 212-213 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.21 (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-NH ₃ ) m / z 520 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₆ S ₂

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4-phenylphenol. (Yield 105 mg, 51%). Mp 163-165 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 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, 1 H). MS (DCI-NH ₃ ) m / z 518 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₁₉ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 2- (methylthio) ethanol. (Yield 105 mg, 61%). Mp 103-105 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.01 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 423 (M + H) ⁺ , 440 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₇ F ₃ N ₂ O ₄ S ₂

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with benzyl alcohol. (Yield 137 mg, 76%). Mp 121-123 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.28 (s, 3H), 5.06 (q, J = 9 Hz, 2H), 5.48 (s, 2H), 7.20-7.25 (m, 2H), 7.27- 7.81 (m, 3H), 7.76 (d, J = 8 Hz, 2H), 7.98 (d, J = 8 Hz, 2H), 8.12 (s, 1H). MS (DCI-NH ₃ ) m / z 456 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 2- (hydroxymethyl) furan. (Yield 101 mg, 58%). Mp 113-115 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.28 (s, 3H), 5.07 (q, J = 9 Hz, 2H), 5.52 (s, 2H), 6.41 (dd, J = 2 Hz, 3 Hz , 1H), 6.45 (d, J = 4 Hz, 1H), 7.62 (d, J = 2 Hz, 1H), 7.69 (d, J = 8 Hz, 2H), 7.97 (d, J = 8 Hz, 2H ), 8.13 (s, 1 H). MS (DCI-NH ₃ ) m / z 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₅ F ₃ N ₂ O ₅ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 2- (3,4-dimethoxyphenyl) ethanol. (Yield 118 mg, 56%). Mp 133-134 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 6.74 (d, J = 2 Hz, 1H), 6.77 (d , J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 2H), 7.93 (d, J = 8 Hz, 2H), 8.11 (s, 1H). MS (DCI-NH ₃ ) m / z 530 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ F ₃ N ₂ O ₆ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4- (2-hydroxyethyl) morpholine. (Yield 111 mg, 59%). Mp 147-148 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.23 (m, 4H), 2.46 (t, J = 5 Hz, 2H), 3.28 (s, 3H), 3.40 (m, 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-NH ₃ ) m / z 462 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₂₂ F ₃ N ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 1- (2-hydroxyethyl) piperidine. (Yield 103 mg, 55%). Mp 117-118 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (DCI-NH ₃ ) m / z 460 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₂₄ F ₃ N ₃ O ₄ S

Anal: C, 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) -pyri Dazinon

The title compound is prepared according to the method of Example 261 by replacing neopentyl alcohol with 4-hydroxybenzamido. (Yield 50 mg, 26%). Mp> 250 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.26 (s, 3H), 5.02 (q, J = 8 Hz, 2H), 7.08 (d, J = 9 Hz, 2H), 7.30 (s, 1H) , 7.82 (d, J = 9 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 7.92 (s, 1H), 8.03 (d, J = 8 Hz, 2H), 8.47 (s, 1H) . MS (DCI-NH ₃ ) m / z 468 (M + H) ⁺ , 485 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₆ F ₃ N ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 1-indanol. (Yield 84 mg, 44%). Mp 113-114 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.07-2.14 (m, 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, 1H), 7.12-7.24 (m, 2H), 7.21-7.28 (m, 2H), 7.44 (d, J = 8 Hz, 2H), 7.87 (d, J = 8 Hz, 2H), 8.09 (s, 1H). MS (DCI-NH ₃ ) m / z 482 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₉ F ₃ N ₂ O ₄ S

Anal: 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) -pyrida Xenon

The title compound is prepared following the method of Example 261, replacing neopentyl alcohol with 4-acetamidophenol. (Yield 45 mg, 23%). Mp 215-216 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.02 (s, 3H), 3.26 (s, 3H), 5.02 (q, J = 8 Hz, 2H), 6.61-6.65 (m, 1H), 7.17- 7.20 (m, 2H), 7.34 (br s, 1H), 7.88 (d, J = 9 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 8.36 (s, 1H), 9.97 (s, 1H). MS (DCI-NH ₃ ) m / z 499 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S

Anal: 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 is prepared according to the method of Example 261 by replacing neopentyl alcohol with 2-methylpropanol. (Yield 111 mg, 50%). Mp 108-110 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.77 (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 (DCI-NH ₃ ) m / z 405 (M + H) ⁺ , 422 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₇ H ₁₉ F ₃ N ₂ O ₄ S

Anal: C, 50.49; H, 4. 74; N, 6.93.

Found: C, 50.69; H, 4.89; N, 6.75.

Example 279

(2,2,2-trifluoroethyl) -4- (1-methylcyclopropylmethoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 261 by replacing neopentyl alcohol with 1-methylcyclopropanemethanol. (Yield 360 mg, 75.5%). Mp 98-99 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.35 (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, 1H), 8.06 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 417 (M + H) ⁺ , m / z 434 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₉ F ₃ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 261 by replacing neopentyl alcohol with 3,3-dimethyl-1-butanol. (Yield 270 mg, 67.4%). Mp 83-85 ° C. ¹ 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, 1H), 8.05 (d, J = 8.5 Hz, 2H). MS (DCI-NH ₃ ) m / z 433 (M + H) ⁺ , m / z 450 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₂₃ F ₃ N ₂ O ₄ S

Anal: 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

2-benzyl-4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (187 mg, 0.5 mmol) prepared in Example 78 in THF (25 mL), A mixture of p-chlorophenol (129 mg, 0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) is refluxed at 50 ° C. for 3 hours and then concentrated in vacuo. The residue is partitioned between water and ethyl acetate. The acetate layer is washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed (silica gel, 1: 1 hexane-ethyl acetate) to give 2-benzyl-4- (4-chlorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Obtain dazinone. (Yield 200 mg, 82%).

The derivative is dissolved in toluene (25 mL) and treated with AlBr ₃ (400 mg, 1.5 mmol) at 80 ° C. for 20 minutes. The mixture is cooled to room temperature and poured into cold-10% citric acid-ethyl acetate. The organic layer is separated, dried over MgSO ₄ and concentrated in vacuo to afford the crude desbenzyl derivative. This compound was immediately dissolved in pyridine (50 mL) and refluxed with 3,4-difluorobromobenzene (0.17 mL, 1.5 mmol), Cu (20 mg) and K ₂ CO ₃ (100 mg, 1.5 mmol). Process for 16 hours. After the mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate and washed with water, 10% citric acid and brine. Purification by column chromatography (silica gel, 1: 1 hexane-ethyl acetate) affords the title compound. (Yield 73 mg, 30%). Mp 192-194 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.22 (s, 3H), 7.13 (m, 2H), 7.35 (m, 2H), 7.50 (m, 1H), 7.60 (m, 1H), 7.75 ( m, 1H), 7.87 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.41 (s, 1H). 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 is prepared according to the method of Example 281 by replacing p-chlorophenol with p-bromophenol. (Yield 54 mg, 20%). Mp 196-199 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.25 (s, 3H), 7.09 (d, J = 9 Hz, 2H), 7.47 (d, J = 9 Hz, 2H), 7.52 (m, 1H) , 7.62 (m, 1H), 7.78 (m, 1H), 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

Under nitrogen, cyclopentyl mercaptan (120 μl, 1.1 mmol) is added dropwise via syringe to a solution of NaH (26 mg, 1.1 mmol) in acetonitrile (3.0 mL). Flush the resulting solution with nitrogen for 20 minutes; Thereafter, 2- (trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (200 mg, 0.52 mmol) prepared in Example 193E was obtained. Add at once. If the solution is stirred for a further 20 minutes, then all 4-bromo pyridazinone is consumed. The solution is analyzed by TLC (1: 1, ethyl acetate-Hex). Water (5 mL) is added carefully and the reaction is partitioned between ethyl acetate (125 mL) and saturated brine (50 mL). The organic layer is washed with saturated brine (50 mL), dried over MgSO ₄ and concentrated in vacuo. Silica gel chromatography (20% ethyl acetate-80% hexanes) yields a pale yellow solid. (Yield 202 mg, 83.1%). Mp 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 , 1H), 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-NH ₃ ) m / z 432 (M + H) ⁺ , (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₉ F ₃ N ₂ O ₃ S ₂

Anal: C, 49.99; H, 4. 43; N, 6.48.

Found: C, 50.15; H, 4. 39; N, 6.45.

Example 284

(2,2,2-trifluoroethyl) -4- (1H-1,2,4-triazol-3-ylthio) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -Pyridazinone.

The title compound is prepared according to the method of Example 283 by replacing cyclopentyl mercaptan with 1H-1,2,4-triazole-3-thiol. (Yield 164 mg, 93%). M.p. 197-200 ℃.^OneH NMR (300 MHz, CDCl₃) δ 3.14 (s, 3H), 4.84 (q, J = 8.1 Hz, 2H), 7.41 (s, 1H), 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 (DCI-NH₃) m / z 431 (M + H)⁺, (M + NH₄)⁺.

Elemental Analysis for C ₁₅ H ₁₂ F ₃ N ₂ O ₃ S ₂

Anal: 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.

Replace the cyclopentyl mercaptan with benzyl mercaptan to prepare the title compound according to the method of Example 283. (Yield 141 mg, 76%). M.p. 108-111 ℃.^OneH NMR (300 MHz, CDCl₃) δ 3.01 (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)⁺.

Elemental analysis for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S ₂ , 0.75 EtOAc

Anal: C, 53.06; H, 4. 45; N, 5.38.

Found: C, 53.55; H, 4. 16; N, 5.84.

Example 286

2- (2,2,2-trifluoroethyl) -4- (4-fluorophenylthio) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 283 by replacing cyclopentyl mercaptan with 4-fluorophenylmethyl mercaptan. (Yield 184 mg, 73.5%). M.p. 182-185 ℃.^OneH NMR (300 MHz, CDCl₃) δ 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, 1 H), 7.93 (d, J = 8.5 Hz, 2 H). MS (DCI-NH₃) m / z 458 (M + H)⁺, (M + NH₄)⁺.

Elemental Analysis for C ₁₉ H ₁₄ F ₄ N ₂ O ₃ S ₂

Anal: 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

Replace the cyclopentyl mercaptan with cyclohexyl mercaptan to prepare the title compound according to the method of Example 283. (Yield 189 mg, 78%). M.p. 165-167 ℃.^OneH NMR (300 MHz, CDCl₃) 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, 1H), 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 (DCI-NH₃) m / z 446 (M + H)⁺, (M + NH₄)⁺.

Elemental Analysis for C ₁₉ H ₂₁ F ₃ N ₂ O ₃ S ₂

Anal: 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) -pyrida Xenon

The title compound is prepared following the method of Example 283, replacing cyclopentyl mercaptan with 3-chloro-4-fluorothiophenol. (Yield 190 mg, 65%). Mp 142-145 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.18 (s, 3H), 4.85 (q, J = 8.4 Hz, 2H), 6.96 (ov.t, J = 8.5 Hz, 1H), 7.14-7.10 (m, 1H), 7.18 (dd, J = 2.1, 6.5 Hz, 1H,), 7.53 (d, J = 8.4 Hz, 2H), 7.77 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H). MS (CI) m / z 493 (M + l) ⁺ , (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ ClF ₄ N ₂ O ₃ S ₂ .0.25 C ₆ H ₆ .H ₂ O

Anal: C, 47.36; H, 2.92; N, 5.41.

Found: C, 47.88; H, 2.95; N, 5.24.

Example 289

2- (2,2,2-trifluoroethyl) -4- (2,2,2-trifluoroethylthio) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Dazinon.

The title compound is prepared according to the method of Example 283 by replacing cyclopentyl mercaptan with 2,2,2-trifluoroethyl mercaptan. (Yield 175 mg, 66%). M.p. 155-158 ℃.^OneH NMR (300 MHz, CDCl₃) 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 (DCI-NH₃) m / z 446 (M + H)⁺, (M + NH₄)⁺.

Elemental Analysis for C ₁₅ H ₁₂ F ₆ N ₂ O ₃ S ₂

Anal: 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 is prepared according to the method of Example 283, replacing cyclopentyl mercaptan with tert-butyl mercaptan. (Yield 212 mg, 85%). M.p. 186-189 ℃.^OneH NMR (300 MHz, CDCl₃) δ 1.25 (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)⁺.

Elemental Analysis for C ₁₇ H ₁₉ F ₃ N ₂ O ₃ S ₂

Anal: 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 is prepared following the method of Example 283, replacing cyclopentyl mercaptan with 4-acetamidothiophenol. (Yield 100 mg, 37%). Mp 191-193 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.16 (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, 1H), 7.78 (d, J = 8.1 Hz, 2H). MS (CI) m / z 497 (M + H) ⁺ , (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₈ F ₃ N ₃ O ₄ S ₂ .0.25H ₂ O, 0.25 C ₆ H ₆

Anal: 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 is prepared following the method of Example 283, replacing cyclopentyl mercaptan with isopropyl mercaptan. (Yield 180 mg, 81%). Mp 165-167 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.17 (d, J = 6.8 Hz, 6H), 3.13 (s, 3H), 4.33 (p, J = 6.8 Hz, 1H), 4.86 (q, J = 8.5 Hz , 2H), 6.59 (d, J = 8.5 Hz, 2H), 7.68 (s, 1H), 8.07 (d, J = 8.1 Hz, 2H). MS (DCI-NH ₃ ) m / z 406 (M + H) ⁺ , (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₇ F ₃ N ₂ O ₃ S ₂ , 0.75H ₂ O

Anal: 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-methylprop-1-ylthio) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone .

The title compound is prepared following the method of Example 283, replacing cyclopentyl mercaptan with 2-methyl-1-propyl mercaptan. (Yield 100 mg, 83%). M.p. 135-138 ℃.^OneH NMR (300 MHz, CDCl₃) δ 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, 1H), 8.08 (d, J = 8.5 Hz, 2H). MS (DCI-NH₃) m / z 420 (M + H)⁺, (M + NH₄)⁺.

Elemental Analysis for C ₁₇ H ₁₉ F ₃ N ₂ O ₃ S ₂

Anal: 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 (500 mg, prepared according to Example 193E) 1.36 mmol) is dissolved in DMF (10 mL) and treated with NaN ₃ (100 mg, 1.5 mmol). After 2 h at rt, the reaction is diluted with ethyl acetate, washed four times with water and dried over MgSO ₄ . The drying agent is filtered off, the filtrate is concentrated in vacuo, and the residue is chromatographed by elution with 2: 1 hexane-ethyl acetate on silica gel (Biotage 40S). Product fractions are combined and evaporated to azido intermediate, 2- (2,2,2-trifluoroethyl) -4-azido-5- [4- (methylthio) phenyl] -3 (2H) -pyrida Obtain xenon. (Yield 481 mg, 95%).

The 4-azido-compound (39 mg, 0.105 mmol) is dissolved in THF (3 mL) and MeOH (2 mL) and treated with excess NaBH ₄ . After 15 minutes, the reaction is quenched with saturated NH ₄ Cl solution and the product is extracted with ethyl acetate. The organic layer is washed three times with water and dried over MgSO ₄ . The desiccant is filtered and the solvent is evaporated to afford the title compound. (Yield 26 mg, 71%). Mp> 260 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.26 (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) ⁻ .

Elemental Analysis for C ₁₃ H ₁₂ F ₃ N ₃ O ₃ S

Anal: 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

2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3, prepared according to the method of Example 193E, in pyridine (4 mL) A solution of 2H) -pyridazinone (200 mg, 0.546 mmol), and 3-methoxypropylamine (145 mg, 1.64 mmol) is heated at 100 ° C. for 16 hours. The reaction mixture is cooled to room temperature, mixed with silica gel (2 g), and the solvent is removed under reduced pressure. The adsorbed silica gel was layered with Extract-Clean Cartridge ^R (Alltech, packing: 10 g silica gel) and then 60 mL of each of the following mixtures (hexane, 8: 1 hexane / acetone, 4: 1, 2: The cartridge is eluted with a hexane / acetone step gradient consisting of 1, and 1: 1). Fractions containing the desired product are combined, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil silica column, 20 mm x 25 cm). The column is eluted at 10 mL / min for 50 minutes with a linear gradient of 30% ethyl acetate / hexanes to 100% ethyl acetate. Fractions containing the product are combined and concentrated under reduced pressure to yield the product of gray crystals. (Yield 215 mg, 95%). Mp 110-113 ° C. ¹ 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, 1H), 6.57 (br t, 1H, 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-NH ₃ ) m / z 420 (M + H) ⁺ , m / z 437 [M + NH ₄ ] ⁺ .

Elemental Analysis for C ₁₇ H ₂₀ F ₃ N ₃ O ₄ S

Anal: 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

By replacing 3-methoxypropylamine with cyclopentylamine, the product was prepared according to the method of Example 295 to give brown crystals. (Yield 195 mg, 86%). Mp 134-139 ° C. ¹ 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, 1H), 6.12 (br d, J = 16.8 Hz, 1H), 4.79 (q, J = 17.4 Hz, 2H), 3.33 (br m, 1H), 3.12 (s, 3H), 1.64-1.23 (br m, 8H). MS (DCI-NH ₃ ) m / z 416 (M + H) ⁺ , m / z 433 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₂₀ -F ₃ N ₃ O ₃ S

Anal: 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 3-methoxypropylamine is replaced with cyclobutylamine to prepare the product according to the method of Example 295 to give a gray solid. (Yield 206 mg, 94%). Mp 169-172 ° C. ¹ 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, 1H), 6.28 (br d, J = 16.2 Hz, 1H), 4.81 (q, J = 17.4 Hz, 2H), 3.42 (m, 1H), 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 ) ⁺ .

Elemental Analysis for C ₁₇ H ₁₈ F ₃ N ₃ O ₃ S · 0.25 CH ₃ COCH ₃

Anal: 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 of Example 295 by replacing 3-methoxypropylamine with 3,4-dimethoxyphenethylamine to give a gray solid. (Yield 206 mg, 94%). Mp 163-165 ° C. ¹ 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 , 1H), 6.50 (m, 2H), 6.16 (br d, J = 11.4 Hz, 1H), 4.79 (q, J = 17.4 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.11 (s, 3 H), 2.91 (dt, J = 12.6, 12.6 Hz, 2H), 2.60 (t, J = 13.8 Hz, 2H). MS (DCI-NH ₃ ) m / z 529 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₄ F ₃ N ₃ O ₅ S

Anal: 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

Replacing 3-methoxypropylamine with cyclohexylamine gave the product according to the method of Example 295 to give a gray solid. (Yield 103 mg, 42%). ¹ 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, 1H), 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 ) ⁺ .

Elemental Analysis for C ₁₉ H ₂₂ F ₃ N ₃ O ₃ S

Anal: 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) -pyri Dazinon

The 3-methoxypropylamine is replaced with cyclopentylamine to prepare the product according to the method of Example 295 to give a gray solid. (Yield 210 mg, 84%). ¹ 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, 1H), 6.91 (br, 1H), 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-NH ₃ ) m / z 459 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₂₂ F ₃ N ₃ O ₃ S

Anal: 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 3-methoxypropylamine is replaced with tetrahydrofurfurylamine to prepare the product according to the method of Example 295 to give a gray solid. (Yield 150 mg, 64%). Mp 128-129 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (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, 1H), 4.81 (q, J = 18.0 Hz, 2H), 3.84 (m, 2H), 3.72 (m, 1H), 3.12 (s, 3H), 2.83 (m, 1H), 2.64 (m, 1H ), 1.84 (m, 3 H), 1.34 (m, 1 H). MS (DCI-NH ₃ ) m / z 432 (M + H) ⁺ , m / z 449 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₂₀ F ₃ N ₃ O ₃ S

Anal: 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 3-methoxypropylamine is replaced with cyclopropylmethylamine to prepare the product according to the method of Example 295 to give a gray solid. (Yield 130 mg, 59%). Mp 145-146 ° C. ¹ 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, 1H), 6.20 (br, 1H), 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 (DCI-NH ₃ ) m / z 402 (M + H) ⁺ , m / z 419 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₇ H ₁₈ F ₃ N ₃ O ₃ S

Anal: 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 of Example 295 by replacing 3-methoxypropylamine with 1-indanylamine to give a gray solid. (Yield 82 mg, 32%). Mp 155-158 ° C. ¹ H 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, 1H), 7.27-7.14 (m, 4H) , 6.30 (br d, J = 18.0 Hz, 1H), 4.81 (q, J = 18.0 Hz, 2H), 4.57 (m, 1H), 3.09 (s, 3H), 2.89 (m, 1H), 2.60 (m , 1H), 1.85 (m, 1H), 1.68 (m, 1H). MS (ESI (−) m / z 462 (M ⁻ H) ⁻ .

Elemental Analysis for C ₂₂ H ₂₀ F ₃ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 295 by replacing 3-methoxypropylamine with piperidine to give a gray solid. (Yield 180 mg, 79%). Mp 160-161 ° C. ¹ 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-NH ₃ ) m / z 416 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₂₀ F ₃ N ₃ O ₃ SH ₂ O

Anal: 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 of Example 295 by replacing 3-methoxypropylamine with 3-hydroxypropylamine to give a white solid. (Yield 109.6 mg, 50%). Mp 152-154 ° C. ¹ 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, 1H), 6.48 (br, 1H), 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-NH ₃ ) m / z 406 (M + H) ⁺ , m / z 423 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₄ S

Anal: 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 is prepared according to the method of Example 295 (271065), replacing 3-methoxypropylamine with (3-aminopropyl) imidazole. The reaction mixture is concentrated to dryness and the residue is purified using RP-HPLC (Rainin Dynamax C-18 column, 60 μs pore size, 21.4 mm id). The column is eluted at 15 mL / min for 70 minutes 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). Peaks corresponding to the title product are collected and lyophilized to give a brown hygroscopic foam. (Yield 70.2 mg, 28%). ¹ H NMR (300 MHz, DMSO) δ 8.95 (br s, 1 H), 7.97 (d, J = 16.8 Hz, 2H), 7.66 (d, J = 16.2 Hz, 2H), 7.61 (s, 1H), 7.58 (d, J = 15.0 Hz, 2H), 6.99 (br t, 1H, 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, 3 H), 2.69 (m, 2 H), 1.81 (tt, J = 13.2, 13.2 Hz, 2H). MS (DCI-NH ₃ ) m / z 456 (M + H) ⁺ .

C ₁₉ H ₂₀ F ₃ N ₅ O ₃ S.1.4 Elemental Analysis for CF ₃ COOH

Anal: 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-hydroxypropylamino) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The 3-methoxypropylamine is replaced with (R)-(-)-2-propanolamine to prepare the product according to the method of Example 295 to give a gray solid. (Yield 109.6 mg, 50%). Mp. = 140-142 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.04 (d, J = 18.0 Hz, 2H), 7.56 (d, J = 18.0 Hz, 2H), 7.49 (s, 1H), 6.42 (br, 1H), 4.79 (m, 2H), 3.80 (m, 1H), 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 ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₄ S

Anal: 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 of Example 295 by replacing 3-methoxypropylamine with 1-cyanoethylamine to give a gray solid. (Yield 27 mg, 12%). Mp 172-174 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 18.0 Hz, 2H), 7.63 (d, J = 18.0 Hz, 2H), 7.51 (s, 1H), 6.08 (br t, 1H), 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 (DCI-NH ₃ ) m / z 418 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₅ F ₃ N ₄ O ₃ S

Anal: 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

2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3, prepared according to the method of Example 193E, in pyridine (1.5 mL) A suspension of 2H) -pyridazinone (300 mg, 0.820 mmol), 4-aminobenzonitrile (290 mg, 2.46 mmol), and silver oxide (760 mg, 3.28 mmol) is stirred at 80 ° C. for 24 hours. The reaction is cooled to room temperature, adsorbed onto silica gel (2 g) and the solvent is removed under reduced pressure. The adsorbed silica gel was layered with Extract-Clean Cartridge ^R (Alltech, packing: 10 g silica gel) and then 60 mL of each of the following mixtures (hexane, 8: 1 hexane / acetone, 4: 1, 2: The cartridge is eluted with a hexane / acetone step gradient consisting of 1, and 1: 1). Fractions containing the desired product are combined, concentrated and further purified using HPLC (Technikrom Kromasil 60-5 sil column, 20 mm x 25 cm). The column is eluted at 10 mL / min for 50 minutes with a linear gradient of 30% ethyl acetate / hexanes to 100% ethyl acetate. Fractions containing the product are combined and concentrated under reduced pressure to give the product as a brown solid. (Yield 149.9 mg, 41%). Mp> 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 (DCI-NH ₃ ) m / z 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₁₅ F ₃ N ₄ O ₃ S

Anal: 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 4-aminobenzonitrile is replaced with 3-methoxy-5- (trifluoromethyl) aniline to prepare the product according to the method of Example 309 to give a brown solid. (Yield 226.5 mg, 80%). Mp 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, 1H), 6.46 (br s, 1H), 6.31 (br s, 1H), 4.90 (q, J = 17.4 Hz, 2H), 3.72 (s, 3H), 2.94 (s, 3H). MS (DCI-NH ₃ ) m / z 539 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₇ F ₆ N ₃ O ₄ S

Anal: 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

Replacing 4-aminobenzonitrile with aniline gives the product according to the method of Example 309 to give a brown solid. (Yield 90 mg, 53%). Mp 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 ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₆ F ₃ N ₃ O ₃ S

Anal: 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 4-aminobenzonitrile is replaced with 2,5-dimethoxyaniline to prepare the product according to the method of Example 309 to give a brown solid. (Yield 140 mg, 53%). Mp 95-96 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.78 (br s, 1 H), 7.72 (s, 1 H), 7.63 (d, J = 18.0 Hz, 2H), 7.18 (d, J = 18.0 Hz, 2H), 6.54 (d, J = 18.0 Hz, 1H), 6.38 (dd, J = 6.0, 18.0 Hz, 1H), 4.89 (q, J = 18.0 Hz, 2H), 3.73 (s, 3H), 3.47 (s, 3H ), 2.96 (s, 3 H). MS (DCI-NH ₃ ) m / z 484 (M + H) ⁺ , m / z 501 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₀ F ₃ N ₃ O ₅ S

Anal: 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 4-aminobenzonitrile is replaced with 3-fluoroaniline to prepare the product according to the method of Example 309 to give a brown solid. (Yield 151.3 mg, 42%). Mp 156-158 ° C. ¹ H NMR (300 MHz, DMSO) δ 9.18 (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, 1H), 6.56 (m, 1H), 6.49 (m, 2H), 5.04 (q, J = 18.0 Hz, 2H), 3.08 (s, 3H). MS (DCI-NH ₃ ) m / z 442 (M + H) ⁺ , m / z 459 (M + NH ₄ ) ⁺ , m / z 476 (M + 2NH ₄ -H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₅ F ₄ N ₃ O ₃ S · 0.5 CH ₃ COCH ₃

Anal: 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 4-aminobenzonitrile is replaced with 2,4-difluoroaniline to prepare the product according to the method of Example 309 to give a brown solid. (Yield 63.1 mg, 17%). Mp 170-175 ° C. ¹ 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, 1H), 6.75 (m, 2H), 5.05 (q, J = 18.0 Hz, 2H), 3.09 (s, 3H). MS (DCI-NH ₃ ) m / z 460 (M + H) ⁺ , m / z 477 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₄ F ₅ N ₃ O ₃ S

Anal: 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) -pyri Dazinon

The 4-aminobenzonitrile is replaced with 2,3,5-trifluoroaniline to prepare the product according to the method of Example 309 to give a pale orange solid. (Yield 85.3 mg, 22%). Mp 190-194 ° C. ¹ H NMR (300 MHz, DMSO) δ 9.27 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 17.4 Hz, 2H), 7.39 (d, J = 17.4 Hz, 2H), 7.03 ( m, 1H), 6.76 (m, 1H), 5.06 (q, J = 18.0 Hz, 2H), 3.14 (s, 3H). MS (DCI-NH- ₃ ) m / z 495 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ F ₆ N ₃ O ₃ S

Anal: 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 4-aminobenzonitrile is replaced with 4-fluoroaniline to prepare the product according to the method of Example 309 to give a brown solid. (Yield 15.8 mg, 4%). Mp 158-160 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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-NH ₃ ) m / z 459 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₉ H ₁₅ F ₄ N ₃ O ₃ S.1.25 H ₂ O

Anal: 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 (150 mg, 0.4 mmol) prepared in Example 78 in DME (25 mL), Thiophen-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) under reflux 6 Stir for hours. TLC (1CH ₂ Cl ₂ : 1 hexanes: 1.5 ethyl acetate) shows that all the starting material was consumed. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure. The residue is purified using a silica gel column (0.5: 2.5: 0.5 CH ₂ Cl ₂ / hexanes / ethyl acetate). Yellow powder is obtained. (Yield 50 mg, 31%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.09 (s, 3H), 5.41 (s, 2H), 6.72 (dd, J = 1.5 Hz, 9 Hz, 1H), 7.13 (dd, J = 3 Hz, 3 Hz, 1H), 7.3-7.45 (m, 5H), 7.5-7.6 (m, 3H), 7.78 (s, 1H), 7.92 (d, 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 423 (M + H) ⁺ .

C ₂₂ H ₁₈ N ₂ O ₃ S ₂ . Elemental Analysis of 0.5 H ₂ O

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenboboric acid with 2-benzofuranboronic acid. (Yield 46 mg, 25%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.13 (s, 3H), 5.5 (s, 2 H,), 6.85-6.92 (m, 1H), 7.15-7.25 (m, 3H), 7.3-7.42 (m , 3H), 7.45-7.7 (m, 5H), 7.79 (s, 1H) 8.0 (d, J = 9 Hz, 2H), 8.08 (s, 1H). MS (DCI-NH ₃ ), m / z 457 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₀ N ₂ O ₄ SH ₂ O

Anal: 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-1-oxo-5-isobenzofuranyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

2-benzyl prepared from Example 78 with 2- (2,2,2-trifluoroethyl) -4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone The title compound is prepared according to the method of Example 221, replacing with 4-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 112 mg, 44%). Mp> 250 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.73 (d, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 2H), 8.17 (s, 1H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₆ H ₂₀ N ₂ O ₅ S

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenboronic acid with 4-chloro-2-thiophenboronic acid. (Yield 21 mg, 17%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.15 (s, 3H), 5.45 (s, 2H), 6.51 (d, J = 4.5 Hz, 1H), 6.7 (d, J = 4.5 Hz, 1H), 7.3 -7.4 (m, 3H), 7.5 = 7.6 (m, 4H), 7.6 (s, 1H), 8.05 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ), m / z 457 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₁₅ ClN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenoboronic acid with 3-nitrobenzeneboronic acid. (Yield 20 mg, 11%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.0 (s, 3H), 5.93 (s, 2H), 7.6-7.8 (m, 9H), 7.8 (t, J = 4.5 Hz, 3H), 8.04 (s, 1H), 8.15 (m, 1H). MS (DCI-NH ₃ ), m / z 462 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ N ₃ O ₅ S. 0.75 H ₂ O

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenoboronic acid with 4-vinylbenzeneboronic acid. (Yield 40 mg, 23%). ¹ 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, 1H) 6.65 ( dd, J = 12 Hz, 18 Hz, 1H), 7.1-7.6 (m, 11H) 7.83 (d, J = 3 Hz, 2H), 7.85 (s, 1H). MS (DCI-NH ₃ ), m / z 443 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenoboronic acid with 4- (trifluoromethyl) benzeneboronic acid. (Yield 101 mg, 52%). ¹ H 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, 1 H). MS (DCI-NH ₃ ) m / z 485 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₁₉ F ₃ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 317 by replacing 3-thiophenboronic acid with 2-methoxybenzeneboronic acid. (Yield 75 mg, 42%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.01 (s, 3H), 3.5 (s, 3H), 5.40 (dd, J = 12 Hz, 18 Hz, 2H), 6.76 (d, J = 9 Hz, 1H ), 6.85-6.95 (m, 1H), 7.09 (dd, J = 1.5 Hz, 9 Hz, 1H), 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-NH ₃ ) m / z 447 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₂₂ N ₂ O ₄ S · 0.5 H ₂ O

Anal: 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). Dissolve and heat reflux with 3,4-dimethylbenzeneboronic acid for 6 hours in the presence of CsF (146 mg, 0.96 mmol) and tetrakis (triphenylphosphine) palladium (14 mg, 0.012 mmol). After cooling to rt, the reaction mixture is diluted with water and extracted with ethyl acetate (100 mL). The organic layer is washed with brine, dried over MgSO ₄ and evaporated in vacuo. The compound is purified by eluting with 30% ethyl acetate in pentane on a silica gel column to afford the desired compound. (Yield 100 mg, 56%). ¹ H NMR (300 MHz, CDCl ₃ ) 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-NH ₃ ) m / z 445 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₄ N ₂ O ₃ SH ₂ O

Anal: 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 is prepared according to the method of Example 325 by replacing 3,4-dimethylbenzeneboronic acid with 3-fluoro-4-methoxybenzeneboronic acid. (Yield 35 mg, 19%). ¹ 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 (DCI-NH ₃ ) m / z 465 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ N ₂ O ₄ S · 0.25 H ₂ O

Anal: 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 is prepared according to the method of Example 325 by replacing 3,4-dimethylbenzeneboronic acid with 2-methoxy-3-pyridylboronic acid. (Yield 35 mg, 19%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.05 (s, 3H), 3.58 (s, 3H), 5.4 (dd, J = 15 Hz, 18 Hz; 2H), 6.88 (m, 1H), 7.28-7.40 (m, 5H), 7.5-7.6 (dd, J = 1.5 Hz; 7.5 Hz, 3H), 7.82 (s, 1H), 7.85 (d, J = 18 Hz, 2H), 8.15 (br s, 1H). MS (DCI-NH ₃ ) m / z 448 (M + H) ⁺ .

Elemental Analysis for C ₂₄ H ₂₁ N ₃ O ₄ S

Anal: 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 is prepared according to the method of Example 325 by replacing 3,4-dimethylbenzeneboronic acid with 3-ethoxybenzeneboronic acid. (Yield 115 mg, 67%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.31 (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, 1H), 6.72 (t, J = 1.5 Hz, 1H), 6.8 (dd, J = 1.5 Hz, 9 Hz, 1H), 7.15 (t, J = 9 Hz, 1H), 7.3-7.4 (m, 5H), 7.5-7.6 (m, 2H), 7.85 (d, J = 9 Hz, 3H). MS (DCI-NH ₃ ) m / z 461 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₄ N ₂ O ₄ S · 0.5H ₂ O

Anal: 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 is prepared according to the method of Example 194A by replacing 4-fluorophenyl hydrazine hydrochloride with benzyl hydrazine hydrochloride. (Yield 7.86 g, 60%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 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

2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone by replacing 2-benzyl-4,5-dibromo-3 (2H) -pyridazinone The title compound is prepared according to the method of Example 194B. (Yield 2.877 g; 85%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.14 (s, 3H), 5.23 (s, 2H), 7.26-7.38 (m, 5H), 8.11 (s, 1H). MS (DCl-NH ₃ ) m / z 295 (M + H) ⁺ , 312 (M + NH ₄ ) ⁺ .

329C. 2-benzyl-4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone

By replacing 2-benzyl-4-methoxy-5-bromo-3 (2H) -pyridazinone with 2-benzyl-4-methoxy-5-bromo-3 (2H) -pyridazinone The title compound is prepared according to the method of Example 6. (Yield 3.705 g). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1 H). MS (DCl-NH ₃ ) m / z 339 (M + H) ⁺ , 356 (M + NH ₄ ) ⁺ .

329D. 2-benzyl-4- (4-fluorobenzyl-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

Replace cyclohexyl-magnesium chloride with 4-fluorobenzyl magnesium chloride, 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyri The title compound is prepared according to the method of Example 233 by replacing dazinone with 2-benzyl-4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone.

329C. 2-benzyl-4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The sulfide compound (Example 329D) is oxidized to a methyl sulfonyl compound according to the method of Example 10. Mp 186-189 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 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, 2 H), 7.94 (s, 1 H), 8.03 (m, 2 H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ FN ₂ O ₃ S

Anal: 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 cocochloric acid free (33.8 g, 200 mmol) and tert-butyl-hydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) is stirred under reflux overnight. Methanol is removed in vacuo and the residue is partitioned between ether and water. The organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography (silica gel, 100% hexane). The product-containing fractions are combined and the title compound is crystallized from ether / hexanes. (Yield 10.0 g, 22.6%). Mp 63-64 ° C. ¹ 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-1-butanol (0.5 mL, 4.52 mmol) in tetrahydrofuran (10 mL) is treated with a 60% oil suspension of sodium hydride (0.24 g, 5.88 mmol). After 5 minutes, when the hydrogen gas evolution subsides, dichloro-intermediate from Example 330A (1.0 g, 4.52 mmol) is added and the reaction mixture is stirred at room temperature for 20 hours. The reaction is quenched with 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO ₄ , and filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography (silica gel, 100% hexane). The title compound is obtained as a pale yellow oil. (Yield 0.7 g, 56.7%). ¹ H NMR (300 MHz, CDCl ₃ ) 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 , 1H), 4.49 (t, J = 6 Hz, 2H), 7.64 (s, 1H). MS (DCI-NH ₃ ) m / z 273 (M + H) ⁺ , 290 (M + NH ₄ ) ⁺ .

330C. 2- (tert-butyl) -4- (3-methylbutoxy) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone

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) in dimethoxyethane (40 mL) And a solution of tetrakis (triphenylphosphine) palladium (0) (210 mg, 0.18 mmol) is heated under reflux for 5 hours. The heat source is then removed and the reaction mixture is stirred at room temperature for 64 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give a brown oil. This oil is purified twice by column chromatography (silica gel, 97: 3 hexanes / ethyl acetate, followed by 96: 4 hexanes / ethyl acetate) to give 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 (s, 1H). MS (DCI) m / z 361 (M + H) ⁺ .

330D. 2- (tert-butyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

4- (4-Fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (tert-butyl) -4- (3-methylbutoxy)- The title compound is prepared according to the method of Example 10, replacing by 5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 188 mg, 63.9%). Mp 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, 1H), 1.69 (s, 9H) , 3.10 (s, 3H), 4.38 (t, J = 6 Hz, 2H), 7.71 (s, 1H), 7.74 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H) . MS (DCI-NH ₃ ) m / z 393 (M + H) ⁺ .

Elemental Analysis for C ₂₀ H ₂₈ N ₂ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4-methoxy-5 The title compound is prepared according to the method of Example 10, replacing by-[4- (methylthio) phenyl] -3 (2H) -pyridazinone (Example 207C).

(Yield 3.31 g, 96%). Mp 112-114 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.31 (m, 3H), 4.10 (m, 3H), 7.52-7.65 (m, 3H), 7.75 (m, 1H), 7.90 (m, 2H), 8.07 (m, 2 H), 8.21 (s, 1 H). MS (DCI-NH ₃ ) m / z 391 (M + H) ⁺ , 408 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₅ ClN ₂ O ₄ S · 0.25 H ₂ O

Anal: 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

2- (3-chlorophenyl) -4- (methoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri in 5% NaOH (54 mL) and dioxane (39.4 mL) A suspension of dazinone (6.26 g, 16 mmol) is heated under reflux and stirred for 1.5 h. As the reaction proceeds, the solution becomes a homogeneous orange solution. The mixture is cooled and poured into 1N HCl with constant stirring. The resulting white solid is filtered, washed with H ₂ O and left to dry overnight. The nearly dried product is dissolved in CH ₂ Cl ₂ and azeotropic with toluene to remove all remaining H ₂ O to give the desired product as a white solid. (Yield 6.79 g,> 100%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.27 (s, 3H), 7.51-7.62 (m, 2H), 7.68 (m, 1H), 7.79 (m, 1H), 8.03 (m, 4H), 8.24 (s, 1 H). MS (DCI-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

2- (3-chlorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (6.79 g) in pyridine (160 mL) prepared in Example 332 , 16 mmol) is added p-toluenesulfonyl chloride (3.06 g, 16 mmol). The solution is left to stir under nitrogen and gradually warmed to room temperature. After 2.5 hours, the mixture is poured into H ₂ O with constant stirring. The resulting gray solid is filtered off, washed with H ₂ O and dried to give the desired product. (Yield 6.26 g, 79%). Mp 198-200 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 2 H), 8.32 (s, 1 H). MS APCI ⁺ 531 (M + H) ⁺ , 548 (M + H ₂ 0) ⁺ , APCI ^- 493 (M + 35) ^- .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₆ S ₂

Anal: 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

Manufactured by POCl ₃ in the _Example 332 2- (3-chlorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) - pyrido Dodge discussed solution, under nitrogen While stirring, the mixture is heated to reflux for 3 hours. The mixture is cooled to room temperature and poured onto ice with constant stirring. The resulting white solid is extracted with ethyl acetate. The combined organics are washed with H ₂ O, dried over MgSO ₄ and filtered to give a solid. The crude product is purified using flash chromatography (SiO ₂ , eluted with 1: 1 ethyl acetate / hexanes) to afford the desired product. (Yield 0.151 g, 29%). Mp 203-204 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.29-3.36 (interrupted by 3H, H ₂ O), 7.60 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m , 2H), 8.25 (s, 1H). MS (DCI-NH ₃ ) m / z 395 (M + H) ⁺ , 412 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₇ H ₁₂ Cl ₂ N ₂ O ₃ S

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (0.175) prepared in Example 333 in THF (3.3 mL) g, 0.33 mmol) isobutanol (0.03 mL, 0.33 mmol) and NaH (0.0132 g, 0.33 mmol) are added. The resulting solution is stirred under nitrogen for 1 hour. The reaction is poured into H ₂ O and extracted with ethyl acetate. The combined organics are dried over MgSO ₄ and concentrated in vacuo. The crude solid is purified using flash chromatography (SiO ₂ , 2: 1 hexanes: ethyl acetate) to afford the desired product. (Yield 0.1088 g 76%). Mp 166-169 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.78 (d, J = 6 Hz, 6H), 1.84 (m, 1H), 3.29 (s, 3H), 4.20 (d, J = 6 Hz, 2H), 7.51-7.63 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 433 (M + H) ⁺ , 450 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ ClN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 335, replacing isobutanol with t-butanol. (Yield 0.093 g, 66%). Mp 232-235 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.18 (s, 9H), 3.30 (s, 3H), 7.52-7.64 (m, 3H), 7.74 (m, 1H), 7.92 (m, 2H), 8.08 (m, 2 H), 8.20 (s, 1 H). MS (DCI-NH ₃ ) m / z 433 (M + H) ⁺ , 450 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₁ H ₂₁ ClN ₂ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with cyclohexanol. (Yield 0.139 g, 92%). Semi-solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.09-1.50 (m, 6H), 1.57 (m, 2H), 1.88 (m, 2H), 3.13 (s, 3H), 5.19 (m, 1H), 7.38- 7.48 (m, 2H), 7.59 (m, 1H), 7.70 (m, 1H), 7.83 (m, 2H), 7.92 (s, 1H), 8.07 (m, 2H). MS APCI ⁺ 459 (M + H) ⁺ , 476 (M + H ₂ 0) ⁺ , APCI ^- 458 (M) ^- , 493 (M + 35) ^- .

Elemental Analysis for C ₂₃ H ₂₃ ClN ₂ O ₄ S · 0.25 H ₂ O

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with neopentyl alcohol. (Yield 0.109 g, 74%). Mp 151-153 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.78 (s, 9H), 3.29 (s, 3H), 4.10 (s, 2H), 7.52-7.64 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2 H), 8.07 (m, 2 H), 8.20 (s, 1 H). MS (DCI-NH ₃ ) m / z 447 (M + H) ⁺ , 464 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ ClN ₂ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 3-methyl-1-butanol. (Yield 0.229 g, 80.5%). Mp 134-135 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.79 (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, 1H), 7.90 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 447 (M + H) ⁺ , 464 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ ClN ₂ O ₄ S

Found: 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-octin-1-yloxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared following the method of Example 335, replacing isobutanol with 3-octin-1-ol. (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 (m, 2H), 4.68 (t, J = 6 Hz, 2H), 7.43 (m, 2H), 7.59 (m, 1H), 7.70 (m, 1H), 7.86 (m, 2H), 7.92 (s, 1H). MS (DCI-NH ₃ ) m / z 485 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₂₅ ClN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 335, replacing isobutanol with N, N- (dimethyl) ethanolamine. (Yield 0.111 g, 75%). Mp 110-113 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.29 (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-NH ₃ ) m / z 448 (M + H) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ ClN ₃ O ₄ S · 0.50 H ₂ O

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 2,4-dimethyl-3-pentanol. (Yield 0.075 g, 48%). Semi-solid; ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.79 (m, 12H), 1.78-1.92 (m, J = 6 Hz, 2H), 3.29 (s, 3H), 5.40 (t, J = 6 Hz, 1H ), 7.57 (m, 3H), 7.72 (m, 1H), 7.91 (m, 2H), 8.07 (m, 2H), 8.17 (m, 1H). MS (DCI-NH ₃ ) m / z 475 (M + H) ⁺ , 492 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₂₇ ClN ₂ O ₄ S (0.75 H ₂ 0)

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with phenol. (Yield 0.053 g, 35%). Mp 205-207 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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-NH ₃ ) m / z 453 (M + H) ⁺ , 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ ClN ₂ O ₄ S

Anal: C, 60.99; H, 3.78; N, 6.19.

Found: C, 60.79; H, 3.65; N, 5.87.

Example 344

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

The title compound is prepared following the method of Example 335, replacing isobutanol with 3- (dimethylamino) phenol. (Yield 0.057 g, 60%). Mp 191-193; ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1 H), 7.90 (m, 2 H), 8.05 (m, 2 H), 8.39 (s, 1 H). MS APCI ⁺ 495 (M + H) ⁺ , APCI ⁻ , 495 (M) ⁻ , 590 (M + 35) ⁻ .

Elemental Analysis for C ₂₅ H ₂₂ ClN ₃ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 4-methoxyphenol. (Yield 0.080 g, 69%). Mp 182-184 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.27 (s, 3H), 3.70 (s, 3H), 6.84 (m, 2H), 7.00 (m, 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 ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₅ S

Anal: C, 59.64; H, 3.97; N, 5.80.

Found: C, 59.86; H, 3.94; N, 5.62.

Example 346

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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound is prepared according to the method of Example 335, replacing by -tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 150 mg, 61%). Mp 116-117 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78 (d, 6H), 1.84, (m, 1H), 3.3 (s, 3H), 4.2 (d, 2H), 7.54 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H), 7.91 (d, 2H), 8.07 (d, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 435 (M + H) ⁺ , 452 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ F ₂ H ₂₀ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 346, replacing isobutanol with 3-methyl-1-butanol. (Yield 63 mg, 23%). Mp 121-123 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78 (d, 6H), 1.48, (m, 3H), 3.3 (s, 3H), 4.43 (t, 2H), 7.54 (m, 1H), 7.6 (m, 1H), 7.82 (m, 1H), 7.91 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.2 (s, 1H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ F ₂ N ₂ O ₄ S

Anal: 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

2- (3,4-difluorophenyl) instead of 2- (3-difluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone Start with -4-tosyloxy-5- [3-fluoro-4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replace isobutanol with 4-fluorophenol The title compound is prepared according to the method of Example 346. Mp 168-170 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (s, 1 H). MS (DCI-NH ₃ ) m / z 491 (M + H) ⁺ , 508 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₄ F ₄ N ₂ O ₄ S

Anal: C, 56.33; H, 2.88; N, 5.71.

Found :, C, 56.07; H, 2.94; N, 5.33.

Example 349

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

The title compound is prepared following the method of Example 346, replacing isobutanol with neopentyl alcohol. (Yield 1.18 g, 94%). Mp 126-128 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78 (s, 9H), 3.3 (s, 3H), 4.1 (s, 2H), 7.51 (m, 1H), 7.6 (m, 1H), 7.82 ( m, 1H), 7.91 (d, J = 9 Hz, 2H), 8.07 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ F ₂ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 346, replacing isobutanol with 2- (isopropoxy) ethanol. (Yield 432 mg, 72%). Mp 105-107 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.95 (d, 6H), 3.3 (s, 3H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.54 ( m, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 8.01 (m, 4H), 8.2 (s, 1H). MS (DCI-NH ₃ ) m / z 465 (M + H) ⁺ , 482 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ F ₂ N ₂ O ₅ S

Anal: 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 is prepared following the method of Example 346, replacing isobutanol with 3-methylpentyl-1-ol. (Yield 400 mg, 80%). Mp 100-102 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, J = 9 Hz, 2H) 8.05 (d, J = 9 Hz, 2H), 8.2 ( s, 1 H). MS (DCI-NH ₃ ) m / z 463 (M + H) ⁺ , 480 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₄ F ₂ N ₂ O ₄ S

Anal: 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-1-yloxy) -5- [4- (methylsulfonyl) phenyl] -5-3 (2H)- Pyridazinone

The title compound is prepared following the method of Example 346, replacing isobutanol with 4-methyl-3-penten-1-ol. (Yield 405 mg, 67.8%). Mp 88-90 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.5 (d, 6H), 2.27 (m, 2H) 3.3 (s, 3H), 4.43 (t, 2H), 4.95 (m, 1H), 7.5 (m , 1H), 7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, 2H), 8.06 (d, 2H), 8.2 (s, 1H). MS (DCI-NH ₃ ) m / z 461 (M + H) ⁺ , 478 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₂ F ₂ N ₂ O ₄ S

Anal: 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 is prepared following the method of Example 346, replacing isobutanol with 3-methoxybutyl-1-ol. (Yield 350 mg, 68%). Mp 99-101 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 7.9 (d, J = 9 Hz, 2H) 8.01 (d, J = 9 Hz, 2H), 8.2 ( s, 1 H). MS (DCI-NH ₃ ) m / z 465 (M + H) ⁺ , 482 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₂ F ₂ N ₂ O ₅ S

Anal: 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-methylbenzylamino) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone:

To the rapidly stirred 0 ° C. mixture of N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7 mL) is slowly added dropwise n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexane). The reaction mixture is stirred at 0 ° C. for 10 minutes and at 23 ° C. for 1 hour. The solution was cooled to -78 ° C and 2- (3-chlorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (200 mg, 0.56 mmol A tetrahydrofuran (10-15 mL) solution of) is slowly added along the inner wall of the reaction vessel. While stirring the reaction mixture overnight, the reaction mixture is slowly warmed to 23 ° C. to allow the cold bath to evaporate. The reaction is quenched with water and diluted with excess ethyl acetate. The layer is separated and the ethyl acetate layer is washed with additional water and brine, then dried over MgSO ₄ , filtered and then concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate / hexane 1: 9) to give 2- (3-chlorophenyl) -4- (N-methyl benzylamino) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone is obtained. (Yield 145 mg, 58%).

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (N-methyl The title compound is prepared according to the method of Example 10, replacing by benzylamino) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. (Yield 143 mg, 95%). Mp 60-85 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, 1H), 7.67 (s, 1H), 7.70 (dd, J = 1.8, 1.8 Hz, 1H), 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 the somewhat heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL), cooled to −78 ° C., slowly add dropwise n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexane). After stirring at −78 ° C. for 10 minutes, the cold bath is removed and the mixture is stirred at 23 ° C. for an additional hour. 2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone (400 mg, 1.17 mmol) was heated with several guns. Divided into fractions, dissolved in toluene (3 × 6-7 mL aliquots), cooled to 0 ° C. and transferred to a lithium amide solution (cooled to −78 ° C.) via a syringe. It is slowly added along the inner wall of the reaction vessel. While stirring the reaction mixture overnight, the reaction mixture is slowly warmed to 23 ° C. to allow the cold bath to evaporate. The reaction is quenched with water and diluted with excess ethyl acetate. The layer is separated and the ethyl acetate layer is washed with additional water and brine, then dried over MgSO ₄ , filtered and then concentrated in vacuo. Chromatography of the residue (flash silica gel, ethyl acetate / hexane 1: 2) gave 2- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -4-piperidino-3 (2H) -pyridine 440 mg (95%) of dazinone are obtained.

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -5- [4- The title compound is prepared according to the method of Example 10, by replacing with (methylthio) phenyl] -4-piperidino-3 (2H) -pyridazinone. (Yield 165 mg, 98%). Mp 80-100 ° C. ¹ 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, 1H), 8.06 (d, J = 8.7 Hz, 2H). MS (APCI +) m / z 428 (M + H) ⁺ . Formation of powder in CH ₂ Cl ₂ / C ₆ H ₁₄ .

Elemental Analysis for C ₂₂ H ₂₂ FN ₃ O ₃ S · 0.25C ₆ H ₁₄

Anal: 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 is prepared according to the method of Example 355 by replacing piperidine with pyrrolidine. (Yield 107 mg, 82%). Mp 192-195 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71-1.80 (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) ⁺ .

Elemental Analysis for C ₂₁ H ₂₀ FN ₃ O ₃ S

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (0.0802) prepared in Example 333 in EtOH (1.5 mL). g, 0.15 mmol) is added to thicresol (0.019 g, 0.15 mmol) and K ₂ CO ₃ (0.0203 g, 0.15 mmol). The suspension is heated to 50 ° C. with stirring for 2.5 h. The mixture is poured into H ₂ O with constant stirring. The resulting precipitate is filtered off, washed with H ₂ O and dried to afford the desired product. (Yield 0.060 g, 83%). Mp 178-178 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.19 (s, 3H), 3.23 (s, 3H), 6.95 (m, 2H), 7.08 (m, 2H), 7.52-7.66 (m, 3H), 7.72 (m, 1 H), 7.88 (m, 2 H), 8.08 (s, 1 H). MS (DCI-NH ₃ ) m / z 483 (M + H) ⁺ , 500 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₃ S ₂ .0.75 H ₂ O

Anal: 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

Thiocresol is replaced with 2-mercaptopyridine to prepare the title compound according to the method of Example 357. (Yield 0.061 g, 39%). Mp 110-114 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 2 H), 8.27 (s, 1 H), 8.34 (m, 1 H). MS (DCI-NH ₃ ) m / z 470 (M + H) ⁺ .

Elemental Analysis for C ₂₂ H ₁₆ ClN ₃ O ₃ S ₂ .0.50 H ₂ O

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (0.175) prepared in Example 333 in THF (3.3 mL) g, 0.33 mmol) is added benzyl mercaptan (0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). The resulting solution is stirred under nitrogen at room temperature for 1 hour. The mixture is poured into H ₂ O and extracted with ethyl acetate. The combined organics are dried over MgSO ₄ and concentrated in vacuo. The resulting crude product is purified using flash chromatography (SiO ₂ , 2: 1 hexanes: ethyl acetate) to afford the desired product. (Yield 0.136 g 85%). Mp 142-145 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.31 (s, 3H), 4.36 (s, 2H), 7.17 (m, 2H), 7.21-7.33 (m, 3H), 7.51 (m, 2H), 7.57 -7.64 (m, 3 H), 7.74 (m, 1 H), 8.01 (m, 2 H). MS (DCI-NH ₃ ) m / z 483 (M + H) ⁺ , 500 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₃ S ₂

Anal: 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) phenyl] -3 (2H) -pyridazinone

The title compound is prepared according to the method of Example 359 by replacing benzyl mercaptan with furfuryl mercaptan. (Yield 0.162 g, 100%). Mp 140-149 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.31 (s, 3H), 4.46 (s, 2H), 6.20 (m, 1H), 6.37 (m, 1H), 7.50-7.67 (m, 6H), 7.77 (m, 1 H), 8.03 (m, 2 H), 8.08 (s, 1 H). MS (DCI-NH ₃ ) m / z 473 (M + H) ⁺ , 490 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₇ ClN ₂ O ₄ S ₂

Anal: 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 is prepared following the method of Example 359 by replacing benzyl mercaptan with 2-methyl-1-propanethiol. (Yield 0.134 g, 91%). oil. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (m, 1H), 7.79 (m, 2H), 8.04 (m, 3H). MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ ClN ₂ O ₃ S ₂ (0.50 H ₂ 0)

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (0.175) prepared in Example 333 in THF (3.3 mL) g, 0.33 mmol) is added cyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution is stirred under nitrogen while warming to room temperature. The reaction is poured into water and extracted with ethyl acetate. The combined organics are dried over MgSO ₄ and concentrated in vacuo. The resulting crude product is purified using flash chromatography (SiO ₂ , 2: 1 ethyl acetate: hexanes) to afford the desired product. (Yield 0.1328 g, 94%). Mp 155-157 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09 (m, 2H), 2.90 (m, J = 8 Hz, 1H ), 3.26-3.37 (interfered with 3H, H ₂ O), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS (DCI-NH ₃ ) m / z 429 (M + H) ⁺ , 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ ClN ₂ O ₃ S

Anal: 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

Cyclohexyl magnesium chloride is replaced with isobutyl magnesium chloride to prepare the title compound of the oil according to the method of Example 362. (Yield 0.132 g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 (DCI-NH ₃ ) m / z 417 (M + H) ⁺ , 434 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ ClN ₂ O ₃ S · 0.50 H ₂ O

Anal: 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

Cyclopentyl magnesium chloride is replaced with cyclohexylmethyl magnesium bromide to prepare the title compound of the oil according to the method of Example 362. (Yield 0.0579 g, 38%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.66 (m, 2H), 1.03 (m, 3H), 1.50 (m, 6H), 1.61 (m, 1H), 2.46 (m, 1H), 3.27-3.42 (Interfered by 3H, H ₂ O), 7.50-7.66 (m, 3H), 7.75 (m, 3H), 7.99 (s, 1H), 8.10 (m, 2H). MS (DCI-NH ₃ ) m / z 457 (M + H) ⁺ , 474 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₂₅ ClN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 362 by replacing cyclopentyl magnesium chloride with cyclohexylethyl magnesium bromide. (Yield 0.165 g, 94%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.76 (m, 3H), 0.99-1.21 (m, 5H), 1.31-1.62 (m, 8H), 2.42-2.56 (1H, disturbed by DMSO), 3.25 -3.34 (interrupted by 2H, H ₂ O), 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-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₂₇ ClN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 362 by replacing cyclohexyl magnesium chloride with 3-methylbutyl magnesium bromide. (Yield 0.0221 g, 16%). Mp 60-65 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.75 (d, J = 7 Hz, 6H), 1.32-1.52 (m, 3H), 3.31 (s, 3H), 7.50-7.65 (m, 3H), 7.77 (m, 3H), 8.03 (s, 1 H), 8.11 (m, 2H). MS (DCI-NH ₃ ) m / z 431 (M + H) ⁺ , 448 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ ClN ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

Replace the cyclohexyl magnesium chloride with benzyl magnesium chloride to prepare the title compound according to the method of Example 362. Mp 174-177 ° C (yield: 25.9 g, 57%). ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (DCI-NH ₃ ) m / z 451 (M + H) ⁺ , 468 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₃ S

Anal: 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 is prepared following the method of Example 362, replacing cyclopentylmagnesium chloride with cyclohexylmagnesium chloride. (Yield 0.099 g, 68%). Mp 85-90 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.01-1.30 (m, 3H), 1.48-1.69 (m, 3H), 1.75 (m, 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 (DCI-NH ₃ ) m / z 443 (M + H) ⁺ , 460 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ ClN ₂ O ₃ S (1.25 H ₂ 0)

Anal: 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 is prepared according to the method of Example 362 by replacing cyclopentylmagnesium chloride with 4-fluorobenzyl magnesium chloride. (Yield 0.1895 g, 41%). Mp 183-185 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.25-3.36 (interrupted by 3H, H ₂ O), 3.89 (bs, 2H), 6.97-7.09 (m, 4H), 7.50-7.64 (m, 3H) , 7.71 (m, 3H), 8.06 (m, 2H), 8.11 (s, 1H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ ClFN ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 362, replacing cyclopentylmagnesium chloride with p-tolylmagnesium bromide. (Yield 65 mg, 40.9%). Mp 222-224 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28 (s, 3H), 3.25 (s, 3H), 7.12 (t, 4H), 7.6 (m, 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 ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

Starting from 2- (3,4-difluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and cyclohexyl magnesium chloride 2- (3,4-difluorophenyl) -4- (3-fluoro-4-methylphenyl) -5- [4, according to the method of Example 362, replacing with -fluoro-4-methylphenylmagnesium bromide -(Methylthio) phenyl] -3 (2H) -pyridazinone is prepared to give a methyl sulfide compound.

The methyl sulfide is oxidized according to the method of Example 10 to afford the title compound. (Yield 265 mg, 85.4%). Mp 204-206 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 7.08 (t, J = 9 Hz, 1H), 7.23-7.33 (m, 1H), 7.41 (d, J = 9 Hz, 2H), 7.49-7.56 (m, 1H), 7.61- 7.69 (m, 1 H), 7.93 (d, J = 9 Hz, 2 H), 7.99 (s, 1 H). MS (DCI-NH ₃ ) m / z 471 (M + H) ⁺ , 488 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₃ N ₂ O ₃ S

Anal: 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

2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone instead of 2- (3-chlorophenyl) -4-methoxy- Starting from 5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone, cyclohexylmagnesium chloride is replaced with phenethyl magnesium chloride and then oxidized according to the method of Example 10, followed by The title compound is prepared according to the method of Example 228. (Yield 0.100 g, 39%). Mp 142-145 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.80 (m, 4H), 3.30 (s, 3H), 7.01 (m, 2H), 7.21 (m, 3H), 7.51-7.60 (m, 4H), 7.63 (m, 1 H), 7.78 (m, 1 H), 8.03 (m, 3 H). MS (DCI-NH ₃ ) m / z 465 (M + H) ⁺ , 482 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ ClN ₂ O ₃ S

Anal: 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.

2- (3-chlorophenyl) -4,5-dibromo-3 (2H) -pyri instead of 2- (4-fluorophenyl) -4,5-dibromo-3 (2H) -pyridazinone Starting from dazinone (Example 207A) and replacing methanol with 2-methyl-1-propanol, the title compound is prepared according to the method of Example 194B.

373B. 2- (3-Chlorophenyl) -4- (2-methylpropoxy) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone

2- (3-chlorophenyl) -4- (2-methylpropoxy) -5-bromo-3 (2H instead of 2-benzyl-4-bromo-5-methoxy-3 (2H) -pyridazinone Title compound according to the method of Example 6 starting from) -pyridazinone and replacing 4-fluorobenzeneboronic acid with 3-fluoro-4- (methylthio) benzeneboronic acid (Example 72C) To prepare.

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 of Example 10 to obtain the title compound. (Yield 0.73 g, 100%). Mp 180-183 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.82 (d, J = 6 Hz, 2H), 3.30-3.39 (interrupted by 3H, H ₂ 0) 4.25 (d, J = 6 Hz, 2H), 7.57 (m, 3H), 7.75 (m, 1H), 7.85 (m, 1H), 8.00 (m, 1H), 8.23 (s, 1H). MS (DCI-NH ₃ ) m / z 451 (M + H) ⁺ , 468 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₀ ClFN ₂ O ₄ S

Anal: C, 55.94; H, 4. 47; N, 6.21.

Found: C, 55.73; H, 4.58; N, 6.01.

Example 374

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

2- (3-chlorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 332) in DMF (2.8 mL) (0.100 g, To the stirred solution of 0.28 mmol) is added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution is stirred while heating to 60 ° C. overnight. The solvent is removed in vacuo and the resulting residue is partitioned between ethyl acetate and 10% citric acid. After extraction with ethyl acetate, the combined organics are dried over MgSO ₄ and concentrated in vacuo. The crude product is purified using flash chromatography (SiO ₂ , 1: 1 ethyl acetate: hexanes) to afford the desired product. (Yield 0.096 g, 76%). Mp 110-113 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 2 H), 8.21 (s, 1 H). MS (DCI-NH ₃ ) m / z 467 (M + H) ⁺ , 484 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₉ ClN ₂ O ₄ S

Anal: 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) was subjected to 2- (4-fluorophenyl) according to the method of Example 194C. It is converted to -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and then oxidized according to the method of Example 10. The methoxy compound was treated with NaOH according to the method of Example 332 to give 2- (3-chlorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Switch to Dazinon. The hydroxy compound was treated with p-toluenesulfonyl chloride according to the method of Example 333 to give 2- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -4-tosyloxy- 3 (2H) -pyridazinone is obtained.

2- (3-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -4-tosyloxy-3 (2H) -pyridazinone instead of 2- (4-fluorophenyl) -5- [4 Title compound according to the method of Example 335, starting from-(methylsulfonyl) phenyl] -4-tosyloxy-3 (2H) -pyridazinone and replacing isobutanol with 3-methyl-1-butanol To prepare. (Yield 0.3932 g, 94%). Mp 117-120 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI-NH ₃ ) m / z 431 (M + H) ⁺ , 448 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₄ S

Anal: 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

2- (3-chlorophenyl) -5- [4- (methylsulfonyl) phenyl] -4-tosyloxy-3 (2H) -pyridazinone 2- (4-fluorophenyl) -5- [4 The title compound is prepared according to the method of Example 335, replacing by-(methylsulfonyl) phenyl] -4-tosyloxy-3 (2H) -pyridazinone (prepared as an intermediate in Example 375). (Yield 0.486 g, 100%). Mp 121-128 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1H). MS (DCI-NH ₃ ) m / z 417 (M + H) ⁺ , 434 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ FN ₂ O ₄ S · 0.50 H ₂ O

Anal: 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

Starting from 4- (4-fluorophenylmethyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and reacted with 1-iodo-4-fluorobenzene , The title compound is prepared according to the method of Example 62. (Yield 0.0881 g, 78%). Mp 175-177 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.27-3.36 (interrupted by 3H, H ₂ O), 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-NH ₃ ) m / z 453 (M + H) ⁺ , 470 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₈ F ₂ N ₂ O ₃ S

Anal: 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 is prepared according to the method of Example 228 by replacing cyclohexylmagnesium chloride with 3-methylbutyl magnesium bromide. (Yield 0.325 g, 69%). Mp 151-154 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.75 (d, J = 7 Hz, 6H), 1.32-1.51 (m, 3H), 3.31 (s, 3H), 7.37 (m, 2H), 7.66 (m , 2H), 7.77 (m, 2H), 8.00 (s, 1H), 8.10 (m, 2H). MS (DCI-NH ₃ ) m / z 415 (M + H) ⁺ , 432 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₃ S · 0.50 H ₂ O

Anal: 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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (172 mg, prepared in Example 11 in dioxane (10 mL) 0.5 mmol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) are added 2,3-dihydropyran (2 mL). The mixture is stirred at room temperature for 6 hours. The mixture is then poured into a solution of saturated NaHCO ₃ and extracted with ethyl acetate. Ethyl acetate is concentrated in vacuo and the residue is chromatographed (silica gel, 1: 1 hexane-ethyl acetate) to afford the title compound. (Yield 25 mg, 11%). ¹ H NMR (DMSO-d ₆ , 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, 1H), 4.00 (m, 1H), 5.98 (m, 1H), 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, 1H). 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

2- (3-bromophenyl) -4- (4-fluorophenyl)-instead of 2-benzyl-4-bromo-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Starting with 5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 166) and replacing sodium carbonate with cesium fluoride, the title compound was prepared according to the method of Example 4. Manufacture. (Yield 0.62 g, 62%). Mp 222-225 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.36 (m, 3H), 7.53 (m, 2H), 7.64 (m, 2H), 7.73-7.81 (m, 3 H), 7.93 (m, 3 H), 8.27 (s, 1 H). MS (DCI-NH ₃ ) m / z 515 (M + H) ⁺ , 532 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₉ H ₂₀ F ₂ N ₂ O ₃ S · 0.25 H ₂ O

Anal: 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-chloro-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (2,2,2- 3- (2) following the method of Example 261, replacing with trifluoroethyl) -4-chloro-5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone Prepare 2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H) -pyridazinone do.

The methyl sulfide is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methyl sulfoxide. The sulfoxide is converted to the title compound according to the method of Example 68. (Yield 196 mg, 28%). Mp 144-145 ° C. ¹ 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, 1H) , 7.48 (br s, 1 H), 7.79 (s, 1 H), 8.03 (t, J = 8 Hz, 1 H). MS (DCI-NH ₃ ) m / z 438 (M + H) ⁺ .

Elemental Analysis for C ₁₇ H ₁₉ F ₃ N ₃ O ₄ S

Anal: 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) -pyrida Xenon

2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2- Replaced by (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone Prepare by the method of Example 68 to give the title compound. (Yield 260 mg, 26%). Mp 163-164 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.6 Hz, 6H), 1.91 (septet, 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, 1H), 8.02 (t, J = 8 Hz, 1H). MS (DCI-NH ₃ ) m / z 424 (M + H) ⁺ , m / z 441 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₆ H ₁₇ F ₄ N ₃ O ₄ S

Anal: 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

2- (3,4-Difluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2-benzyl-4 The title compound is prepared according to the method of Example 384, replacing by-(4-fluorophenylmethyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 0.5723 g 34%). Mp 120-123 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.83 (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, 2 H), 7.91 (m, 2 H), 7.95 (s, 1 H). MS (DCI-NH ₃ ) m / z 450 (M + H) ⁺ , 467 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₂₀ FN ₃ O ₃ S

Anal: 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

At −78 ° C., 2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (130 mg, in THF (30 mL) 0.3 mmol) and di-t-butylazodicarboxylate (DBAD) (69 mg, 0.3 mmol) in lithium 1,1,1,3,3,3-hexamethyldisilazide (0.9 mL, 0.9 mmol) of 1 N solution is added. After addition, the reaction is further stirred at −78 ° C. for 45 minutes (or until disappearance of the starting material by TLC). The reaction is quenched with saturated solution of NH ₄ Cl and extracted with ethyl acetate. The acetate extracts are dried over MgSO ₄ and concentrated in vacuo to give 220 mg of crude adduct.

The adduct is dissolved in THF (30 mL) and treated with 1 N NaOH (3 mL) at room temperature for 5 hours. Sodium hydroxide acetate (NaOAc.3H ₂ O, 1.38 g, 10 mmol) is added followed by hydroxylamine-O-sulfonic acid (1.13 g, 10 mmol) and H ₂ O (30 mL). The resulting mixture is stirred at rt for 18 h and then extracted with ethyl acetate. The extract is washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue is purified by chromatography (silica gel, 1: 1 hexane-ethyl acetate) to afford the desired product. (Yield 70 mg, 54%). Mp 185-189 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 5.33 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.40 (m, 7H), 7.83 (d, J = 9 Hz, 2H), 8.10 (s, 1 H). MS (DCI-NH ₃ ) m / z 436 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₈ FN ₃ O ₃ S · 0.75 H ₂ O

Anal: 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 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 65 mg, 28.8%). Mp 227-229 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.08-7.17 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₅ F ₂ N ₃ O ₄ S

Anal: 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 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 45 mg, 28%). Mp 198-200 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.87 (dd, J = 9 Hz, 3 Hz, 1H), 7.13 (dt, J = 9 Hz, 3 Hz, 1H), 7.19 (t, J = 7 Hz, 1H), 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, 1 H), 8.25 (s, 1 H). MS (DCI-NH ₃ ) m / z 472 (M + H) ⁺ , 489 (M + NH ₄ ) ⁺ .

Example 387

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

The product from Example 259 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 185 mg, 46%). Mp 187-188 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (m, 2H), 7.77 (d, J = 9 Hz, 2H) , 8.22 (s, 1 H). MS (DCI-NH ₃ ) m / z 454 (M + H) ⁺ , 471 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ F ₂ N ₃ O ₃ S · 0.25 H ₂ O

Anal: 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- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

The product from Example 109 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 110 mg, 45.7%). Mp 224-226 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.86 (br s, 2H), 6.89-7.03 (m, 4H), 7.19-7.30 (m, 1H), 7.45-7.52 (m, 1H), 7.56-7.66 ( m, 1H), 7.79 (d, J = 9 Hz, 2H), 8.04 (d, J = 9 Hz, 1H), 8.08 (s, 1H). MS (DCI-NH ₃ ) m / z 474 (M + H) ⁺ , 491 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₄ F ₃ N ₃ O ₄ S · 0.25 H ₂ O

Anal: C, 55.32; H, 2.93; N, 8.80.

Found: C, 55.26; H, 3.11; N, 8.58.

Example 389

2- (3-Chloro-4-fluorophenyl) -4- (4-fluoro-3-methylphenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

The product from Example 247 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 230 mg, 38%). Mp 243-245 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.17 (br s, 3H), 6.94-7.09 (m, 2H), 7.25 (dd, J = 9 Hz, 3 Hz, 1H), 7.41-7.48 (m , 4H), 7.60 (t, J = 9 Hz, 1H), 7.68-7.75 (m, 1H), 7.77 (d, J = 9 Hz, 2H), 7.95 (dd, J = 6 Hz, 3 Hz, 1H ), 8.25 (s, 1 H). MS (DCI-NH ₃ ) m / z 469 (M + H) ⁺ , 486 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClF ₂ N ₃ O ₃ S

Anal: 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- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

The methyl sulfone product of Example 245 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 78 mg, 28.3%). Mp 202-204 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.22 (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, 1H). MS (DCI-NH ₃ ) m / z 454 (M + H) ⁺ , 471 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ F ₂ N ₃ O ₃ S · 0.25 H ₂ O

Anal: 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 methyl sulfone product of Example 244 is converted to the title compound sulfonamide according to the method of Example 384. (Yield 125 mg, 39%). Mp 187-188 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.21 (s, 3H), 4.71 (s, 2H), 6.85-6.92 (m, 2H), 7.21 (d, J = 9 Hz, 1H), 7.32-7.47 ( m, 2H), 7.37 (d, J = 9 Hz, 2H), 7.64 (dt, J = 7 Hz, 3 Hz, 1H), 7.77 (br s, 1H), 7.91 (d, J = 9 Hz, 2H ). MS (DCI-NH ₃ ) m / z 470 (M + H) ⁺ , 487 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₇ ClFN ₃ O ₃ S · 0.25 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (3- The title compound is prepared according to the method of Example 384, replacing by methylbutyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 366). (Yield 0.0756 g, 16%). Mp 167-170 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.78 (d, J = 6 Hz, 6H), 1.47 (5H, interrupted by hexanes), 7.51-7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m, 1 H), 7.98 (m, 2 H), 8.03 (s, 1 H), 8.60 (bs, 1 H). MS (DCI-NH ₃ ) m / z 432 (M + H) ⁺ , 449 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ ClN ₃ O ₃ S (0.25 H ₂ 0)

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (phenethyl The title compound is prepared according to the method of Example 384, replacing by) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 372). (Yield 0.075 g, 17%). Semi-solid; ¹ H NMR (300 MHz, DMSO d ₆ ) δ 2.80 (m, 4H), 3.29-3.42 (interrupted by 3H, H ₂ O), 6.96 (m, 2H), 7.14-7.28 (m, 3H), 7.46 -7.68 (m, 7H), 7.78 (m, 1H), 7.92 (m, 2H), 8.01 (s, 1H). MS (DCI-NH ₃ ) m / z 466 (M + H) ⁺ , 483 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₂₀ ClN ₂ O ₃ S · 0.25 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (3- The title compound is prepared according to the method of Example 384, replacing by methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 339). (Yield 0.575 g, 18%). Mp 137-139 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1H), 7.84 (m, 2H), 7.94 (m, 2H), 8.20 (s, 1H). MS (DCI-NH ₃ ) m / z 448 (M + H) ⁺ , 465 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ ClN ₃ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (2- The title compound is prepared according to the method of Example 384, replacing by methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 335). (Yield 0.0458 g, 25%). Mp 80-85 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (m, 1H), 7.85 (m, 2H), 7.95 (m, 2H), 8.21 (m, 1H). MS (DCI-NH ₃ ) m / z 434 (M + H) ⁺ , 451 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₂₀ ClN ₃ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4- (3 The title compound is prepared according to the method of Example 384, replacing by -methylbutyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 378). (0.090 g 21%). Mp 180-183 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.78 (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 (DCI-NH ₃ ) m / z 416 (M + H) ⁺ , 433 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ FN ₃ O ₃ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4- (2 The title compound is prepared according to the method of Example 384, replacing by -methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 376). (Yield 0.024 g, 6%). Mp 132-136 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 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, 1H). MS (DCI-NH ₃ ) m / z 418 (M + H) ⁺ , 435 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₀ H ₂₀ FN ₃ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4- (3 The title compound is prepared according to the method of Example 384, replacing by -methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 375). (Yield 0.051 g, 18%). Yellow oil. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.80 (d, J = 5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J = 6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, 1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs, 1H). MS (DCI-NH ₃ ) m / z 432 (M + H) ⁺ , 449 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₂ FN ₃ O ₄ S

Anal: 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

1 equivalent of 2- (t-butyl) -4- (3-methyl-1-butoxy) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone prepared in Example 330C Is oxidized to the corresponding methyl sulfoxide using meta-chloroperoxybenzoic acid. This sulfoxide is converted to the title compound sulfonamide by the method of Example 68. (Yield 1.25 g, 54%). Mp 153-155 ° C. ¹ 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, 1H), 1.70 (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-NH ₃ ) m / z 394 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₂₇ N ₃ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound was prepared according to the method of Example 384, replacing by-(4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 182) do. (Yield 950 mg, 54%). Mp 177-181 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (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, 1H), 8.27 (s, 1H). MS (DCI-NH ₃ ) m / z 458 (M + H) ⁺ , 475 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₄ F ₃ N ₃ O ₃ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chloro-4-fluorophenyl)- The title compound is prepared according to the method of Example 384, replacing by 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 380 mg, 47%). Mp 208-210 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.7 (m, 1H), 7.75 (d, J = 9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s, 1H). MS (DCI-NH ₃ ) m / z 474 (M + H) ⁺ , 491 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₄ F ₂ Cl ₂ N ₃ O ₃ S · 0.5 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound was prepared according to the method of Example 384, replacing by-(4-fluoro-3-methyl-phenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone do. (Yield 105 mg, 27%). Mp 243-245 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.2 (s, 3H), 7.01 (m, 2H), 7.25 (m, 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-NH ₃ ) m / z 472 (M + H) ⁺ , 489 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₄ H ₁₇ F ₃ N ₂ O ₃ S · 0.5 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound is prepared according to the method of Example 384, replacing by-(2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 35 mg, 42%). Mp 169-171 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3 H), 7.91 (d, 2 H), 8.21 (s, 1 H). MS (DCI-NH ₃ ) m / z 436 (M + H) ⁺ , 453 (M + NH ₄ ) ⁺ .

Elemental analysis for C ₂₀ H ₁₉ F ₂ N ₃ O ₄ S · 0.25 H ₂ O

Anal: C, 55.17; H, 4.40; N, 9.65.

Found: C, 54.19; H, 4. 25; N, 9.35

Example 404

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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound is prepared according to the method of Example 384, replacing by-(3-methylbutyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 58 mg, 52%). Mp 171-173 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.3 (s, 3H), 7.51 (m, 1H), 7.65 (m, 1H), 7.75 (d, J = 9 Hz, 2H), 7.81 (m, 1H) 8.05 (s, 1H), 8.12 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 434 (M + H) ⁺ , 451 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ F ₂ N ₃ O ₃ S · 0.25 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chloro-4-fluorophenyl)- The title compound is prepared according to the method of Example 384, replacing by 4- (3-methylbutyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 102 mg, 61.8%). Mp 154-156 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2 H), 7.93 (dd, 1 H), 8.05 (m, 2 H). MS (DCI-NH ₃ ) m / z 450 (M + H) ⁺ , 468 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₂ H ₂₂ FN ₂ O ₃ SCl.0.25 H ₂ O

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound is prepared according to the method of Example 384, replacing by-(2,2-dimethylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 310 mg, 38%). Mp 173-175 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 (DCI-NH ₃ ) m / z 450 (M + H) ⁺ , 467 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₁ H ₂₁ F ₂ N ₃ O ₄ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [3-fluoro-4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluoro The title compound was prepared according to the method of Example 400, replacing by rophenyl) -4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone Manufacture. (Yield 125 mg, 31%). Mp 224-226 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 2H) 7.75 (m, 4H), 7.9 (t, 1H); 8.4 (s, 1 H). MS (DCI-NH ₃ ) m / z 492 (M + H) ⁺ , 509 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₁₃ F ₄ N ₃ O ₄ S

Anal: C, 53.77; H, 2.67; N, 8.55.

Found:,; C, 53.33; H, 2. 84; N, 8.22

Example 408

2- (3,3-difluoro-2-propenyl)]-4- (4-fluorophenyl) -5- [3-fluoro-4- (aminosulfonyl) phenyl] -3 (2H) -Pyridazinone

Example 72 (264192), prepared as an intermediate, 2-benzyl-4- (4-fluorophenyl) -5- [3-fluoro-4- (methylthio) phenyl] -3 (2H)- Pyridazinone is oxidized with monosaccharide meta-chloroperoxybenzoic acid to afford methyl sulfoxide, which is converted to sulfonamide according to the method of Example 68. Replace 3,4-difluorobenzyl bromide with 1,3-dibromo-1,1-difluoropropane and use 4 equivalents of potassium carbonate to prepare the sulfonamide material according to the method of Example 11 N-debenzylation and N-alkylation according to the method of Example 127 afford the title compound. (Yield 120 mg, 27%). Mp 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, 1H), 7.87 (t, J = 7.5 Hz, 2H). MS (DCI-NH ₃ ) m / z 440 (M + H) ⁺ .

Elemental Analysis for C ₁₉ H ₁₃ F ₄ N ₃ O ₃ S

Anal: 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- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound was prepared according to the method of Example 384, replacing by [-(2- (2-propoxy) ethoxy] -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone do. (Yield 110 mg, 34%). Mp 54-56 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.0 (d, 6H), 3.43 (m, 1H), 3.54 (m, 2H), 4.63 (m, 2H), 7.5 (m, 3H), 7.6 ( m, 1H), 7.8 (m, 1H), 7.95 (m, 4H), 8.2 (s, 1H). MS (DCI-NH ₃ ) m / z 466 (M + H) ⁺ , 483 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ F ₂ N ₃ O ₅ S

Anal: 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

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 The title compound is prepared according to the method of Example 384, replacing by-(4-methyl-3-pentenyloxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone . Mp 70-73 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.5 (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 (DCI-NH ₃ ) m / z 462 (M + H) ⁺ , 479 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ F ₂ N ₃ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 3-fluorophenol. (Yield 0.034 g, 22%). Mp 178-180 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.27 (s, 3H), 6.88-7.00 (m, 2H), 7.10 (m, 1H), 7.36 (m, 1H), 7.59 (m, 3H), 7.74 (m, 1 H), 7.90 (m, 2 H), 8.06 (m, 2 H), 8.43 (s, 1 H). MS (DCI-NH ₃ ) m / z 488 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ ClFN ₂ O ₄ S · 0.25 H ₂ O

Anal: 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- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3-chlorophenyl) -4- (2- The title compound is prepared according to the method of Example 384, replacing by methylpropoxy) -5- [3-fluoro-4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 0.019 g, 10%). Mp 157-159 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.81 (d, J = 6 Hz, 6H), 1.86 (m, 1H), 4.24 (d, J = 6 Hz, 2H), 7.75 (m, 3H), 7.66 (m, 1 H), 7.73 (m, 2 H), 7.83 (m, 2 H), 7.91 (m, 1 H), 8.23 (s, 1 H).

Elemental Analysis for C ₂₁ H ₁₉ ClFN ₃ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 4-methyl-1-pentanol. (Yield 0.137 g, 90%). Mp 139-140 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1H), 7.90 (m, 2H), 8.07 (m, 2H), 8.20 (s, 1H) . MS (DCI-NH ₃ ) m / z 461 (M + H) ⁺ , 478 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₅ ClN ₂ O ₄ S

Anal: 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

2- (4-fluorophenyl) -4-tosyloxy instead of 2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone Starting from -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing isobutanol with 4-methyl-1-pentanol, titled according to the method of Example 335 Prepare the compound. (Yield 0.128 g, 85%). Mp 123-125 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.74 (d, J = 6 Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 (m, 2H), 3.28 (s, 3H ), 4.39 (t, J = 6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.91 (m, 2H), 8.07 (m, 2H), 8.18 (s, 1H). MS (DCI-NH ₃ ) m / z 445 (M + H) ⁺ .

Elemental Analysis for C ₂₃ H ₂₅ FN ₂ O ₄ S

Anal: 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

2- (3-chlorophenyl) -4-methoxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-methoxy The title compound is prepared according to the method of Example 332, replacing by 5-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone. (Yield 2.022 g, 97%). ¹ H NMR (300 MHz, DMSO d ₆ ) δ 3.28 (s, 3H), 7.38 (m, 2H), 7.70 (m, 2H), 8.03 (m, 4H), 8.22 (s, 1H). MS (APCI- + Q1 MS) 361 (M + H) ⁺ , (-Q1MS) 359 (MH) ^- .

Example 416

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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy The title compound is prepared according to the method of Example 335 by replacing -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing isobutanol with cyclopropylmethanol. (Yield 0.117 g, 83%). Mp 166-167 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.22 (m, 2H), 0.46 (m, 2H), 1.10 (m, 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 (s, 1H). MS (DCI-NH ₃ ) m / z 415 (M + H) ⁺ , 432 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₅ ClN ₂ O ₄ S

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy The title compound is prepared according to the method of Example 335 by replacing -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and isobutanol with 2-cyclopropane ethanol . (Yield 0.1472 g, 100%). Mp 111-117 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ -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-NH ₃ ) m / z 429 (M + H) ⁺ , 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ FN ₂ O ₄ S

Anal: 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 is prepared following the method of Example 335 by replacing isobutanol with cyclopropane methanol. (Yield 0.0917 g, 64%). Mp 158-161 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.22 (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, 1H), 7.96 (m, 2H), 8.08 (m, 2H), 8.23 (s, 1H). MS (DCI-NH ₃ ) m / z 431 (M + H) ⁺ , 448 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₉ ClN ₂ O ₄ S · 0.25 H ₂ O

Anal: 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

Isobutanol was replaced with 2-cyclopropane ethanol to prepare the title compound according to the method of Example 335. (Yield 0.114 g, 78%). Mp 124-128 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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 (m, 3H), 7.76 (m, 1H), 7.91 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 445 (M + H) ⁺ , 462 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ ClN ₂ O ₄ S

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy In the method of Example 362, replacing 5-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and cyclopropyl magnesium chloride with 4-methylpentane-1-magnesium bromide According to the title compound. (Yield 0.165 g, 99%). Mp 112-115 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 0.75 (d, J = 7 Hz, 6H), 1.07 (q, J = 7 Hz, 2H), 1.32-1.53 (m, 3H), 2.45 (t, 2H ), 3.31 (s, 3H), 7.37 (m, 2H), 7.66 (m, 2H), 7.76 (m, 2H), 8.00 (s, 1H), 8.10 (m, 2H). MS (DCI-NH ₃ ) m / z 429 (M + H) ⁺ . 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₅ FN ₂ O ₃ S

Anal: 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 is prepared following the method of Example 362, replacing cyclopropyl magnesium chloride with 4-methylpentane-1-magnesium bromide. (Yield 165 mg, 98%). oil. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 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-NH ₃ ) m / z 445 (M + H) ⁺ , 462 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₅ ClN ₂ O ₃ S

Anal: 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-buteneoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and isobutanol with 3-methyl-2-buten-1-ol according to the method of Example 335 Prepare the title compound. (Yield 0.1284 g, 88%). Mp 128-132 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.58 (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 (s, 1H). MS (DCI-NH ₃ ) m / z 429 (M + H) ⁺ , 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ FN ₂ O ₄ S

Anal: 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-buteneoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared following the method of Example 335, replacing isobutanol with 3-methyl-2-buten-1-ol. (Yield 0.119 g, 81%). Mp 113-115 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.58 (s, 3H), 1.67 (s, 3H), 3.31 (s, 3H), 4.96 (m, 2H), 5.32 (m, 1H), 7.58 (m , 3H), 7.75 (m, 1H), 7.89 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (APCI + Q1MS) 445 (M + H) ⁺ , (APCI-Q1MS) 479 (M + 35) ^- .

Elemental Analysis for C ₂₂ H ₂₁ ClN ₂ O ₄ S

Anal: 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

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and isobutanol with 4-methyl-2-penten-l-ol, according to the method of Example 335 Prepare the title compound. (Yield 0.1165 g, 77%). Mp 111-114 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.46 (s, 3H), 1.56 (s, 3H), 2.26 (m, 2H), 3.30 (s, 1H), 4.43 (t, J = 7 Hz, 2H ), 4.96 (m, 1H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.18 (s, 1H). MS (DCI-NH ₃ ) m / z 443 (M + H) ⁺ , 460 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ FN ₂ O ₄ S

Anal: 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-buteneoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

2- (3-chlorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-tosyloxy -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and isobutanol with 3-methyl-3-buten-1-ol according to the method of Example 335 Prepare the title compound. (Yield 0.1327 g, 91%). Mp 109-111 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) 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, 1H), 4.68 (bs, 1H), 7.37 (m, 2H), 7.66 (m, 2H), 7.90 (m, 2H), 8.05 (m, 2H), 8.19 (s, 1H). MS (DCI-NH ₃ ) m / z 429 (M + H) ⁺ , 446 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ FN ₂ O ₄ S

Anal: 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 is prepared following the method of Example 335, replacing isobutanol with 4-methyl-3-penten-l-ol. (Yield 0.1149 g, 76%). Mp 110-111 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.47 (s, 3H), 1.55 (s, 3H), 2.27 (m, 2H), 3.30 (s, 3H), 4.44 (t, J = 6 Hz, 2H ), 4.96 (m, 1H), 7.52-7.64 (m, 3H), 7.75 (m, 1H), 7.91 (M, 2H), 8.06 (m, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 459 (M + H) ⁺ , 476 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₂₃ ClN ₂ O ₄ S

Anal: 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-buteneoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared following the method of Example 335, replacing isobutanol with 3-methyl-3-buten-1-ol. (Yield 0.1159 g, 79%). Mp 110-112 ° C. ¹ H NMR (300 MHz, DMSO d ₆ ) δ 1.62 (s, 3H), 2.32 (t, J = 7 Hz, 2H), 3.30 (s, 3H), 4.57 (t, J = 6 Hz, 2H), 4.63 (bs, 1H), 4.68 (bs, 1H), 7.51-7.64 (m, 3H), 7.76 (m, 1H), 7.90 (m, 2H), 8.05 (m, 2H), 8.21 (s, 1H) . MS (DCI-NH ₃ ) m / z 445 (M + H) ⁺ , 462 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₂ H ₂₁ ClN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 178 by replacing 2-ethyl-1-hexanol with 1,5-hexadien-3-ol. (Yield 150 mg, 85%). Mp 104-105 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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) ^- .

Elemental Analysis for C ₂₃ H ₂₁ FN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 178 by replacing 2-ethyl-1-hexanol with 5-methyl-2-hexanol. (Yield 150 mg, 82%). Mp 102-103 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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, 1H), 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) ^- .

Elemental Analysis for C ₂₄ H ₂₇ FN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 178 by replacing 2-ethyl-1-hexanol with 2-ethyl-1-butanol. (Yield 140 mg, 80%). Mp 107-108 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.73 (t, J = 7 Hz, 6H), 1.20 (quartet, 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) ^- .

Elemental Analysis for C ₂₃ H ₂₅ FN ₂ O ₄ S

Anal: 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 is prepared according to the method of Example 178 by replacing 2-ethyl-1-hexanol with 2- (isopropylthio) ethanol. (Yield 138 mg, 74%). Mp 137-139 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.13 (d, J = 7 Hz, 6H), 2.77 (t, J = 7 Hz, 2H), 2.88 (quadrant, J = 7 Hz, 1H), 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) ⁺ .

Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₄ S ₂

Anal: 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-1-hexyloxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared following the method of Example 178 by replacing 2-ethyl-1-hexanol with 3- (methylthio) -1-hexanol. (Yield 155 mg, 79%). Mp 90-92 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.78 (t, J = 7 Hz, 3H), 1.30 (m, 4H), 1.76 (m, 2H), 2.82 (s, 3H), 2.38 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₄ H ₂₇ FN ₂ O ₄ S ₂

Anal: 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-1-oxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

The title compound is prepared following the method of Example 178 by replacing 2-ethyl-1-hexanol with 2-methyl-4-penten-1-ol. (Yield 135 mg, 76%). Mp 106-107 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ0.76 (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, 1H), 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 443 (M + H) ⁺ ; (APCI-) m / z 477 (M + Cl) ^- .

Elemental Analysis for C ₂₃ H ₂₃ FN ₂ O ₄ S

Anal: 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

2- (3,4-difluorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pidazinone (189 mg, 0.5 mmol) in THF (25 mL) To a solution of Ph ₃ P (262 mg, 1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) was added a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL) The resulting mixture is stirred for 8 hours at room temperature. The mixture is concentrated in vacuo and the residue is chromatographed (silica gel, 1: 1 hexane-ethyl acetate) to afford the desired product. (Yield 180 mg 71%). Mp 126-128 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.96 (d, J = 7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m, 1H), 3.29 (s, 3H), 4.46 (m, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI +) m / z 503 (M + H) ⁺ ; (APCI-) m / z 537 (M + Cl) ^- .

Elemental Analysis for C ₂₂ H ₁₉ F ₅ N ₂ O ₄ S

Anal: 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

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- The method of Example 178, starting from 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing 2-ethyl-1-hexanol with ethanol To yield the title compound. (Yield 25 mg, 12%). Mp 121-123 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (t, J = 7 Hz, 3H), 3.30 (s, 3H), 4.51 (q, J = 7 Hz, 2H), 7.52 (m, 1H) , 7.62 (m, 1H), 7.81 (m, 1H), 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) ^- .

Elemental Analysis for C ₁₉ H ₁₆ F ₂ N ₂ O ₄ S · 0.25 H ₂ O

Anal: 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

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting from 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, replacing 2-ethyl-1-hexanol with 4-methyl-1-pentanol The title compound is prepared according to the method of Example 178. (Yield 120 mg, 52%). Mp 98-99 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.73 (d, J = 7 Hz, 6H), 1.02 (m, 2H), 1.29 (m, 1H), 1.54 (m, 2H), 3.30 (s, 3H), 4.40 (t, J = 7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₃ H ₂₄ F ₂ N ₂ O ₄ S

Anal: C, 59.72; H, 5. 23; N, 6.05.

Found: C, 59.57; H, 5. 28; N, 6.01.

Example 438

2- (3,4-difluorophenyl) -4- (4-methyl-2-pentyloxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting from 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, replacing 2-ethyl-1-hexanol with 4-methyl-2-pentanol The title compound is prepared according to the method of Example 178. (Yield 115 mg, 50%). Mp 132-133 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.80 (d, J = 7 Hz, 3H), 0.87 (d, J = 7 Hz, 3H), 1.10 (d, J = 7 Hz, 3H), 1.26 (m, 1H), 1.50 (m, 1H), 1.63 (m, 1H), 3.30 (s, 3H), 5.31 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 ( m, 1H), 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) ^- .

Elemental Analysis for C ₂₃ H ₂₄ F ₂ N ₂ O ₄ S

Anal: 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

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting from 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, replacing 2-ethyl-1-hexanol with 2-cyclopentyl-1-ethanol The title compound is prepared according to the method of Example 178. (Yield 115 mg, 60%). Mp 100-101 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.00 (m, 2H), 1.38 (m, 2H), 1.57 (m, 7H), 3.30 (s, 3H), 4.42 (t, J = 7 Hz, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 ( s, 1 H). MS (APCI +) m / z 475 (M + H) ⁺ ; (APCI-) m / z 509 (M + Cl) ^- .

Elemental Analysis for C ₂₄ H ₂₄ F ₂ N ₂ O ₄ S · 0.25 H ₂ O

Anal: 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-cyclopent-2-enyl-1-ethoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Dazinon

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting with 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2-ethyl-1-hexanol is 2-cyclopent-2-enyl-1 Substituted by ethanol, the title compound is prepared according to the method of Example 178. (Yield 95 mg, 48%). Mp 126-127 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (m, 1H), 1.57 (sextet, J = 7 Hz, 1H), 1.69 (sextet, J = 7 Hz, 1H), 1.87 (m, 2H) , 2.57 (m, 1H), 3.30 (s, 3H), 4.45 (m, 2H), 5.60 (m, 1H), 5.68 (m, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1 H), 7.90 (d, J = 9 Hz, 2H), 8.08 (d, J = 9 Hz, 2H), 8.22 (s, 1H). MS (APCI +) m / z 473 (M + H) ⁺ ; (APCI-) m / z 507 (M + Cl) ^- .

Elemental Analysis for C ₂₄ H ₂₂ F ₂ N ₂ O ₄ S

Anal: 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

Product from Example 46, 2-phenacyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyrida in ethanol (200 mL) A mixture of xenon (700 mg, 1.5 mmol) and sodium borohydride (69 mg, 1.8 mmol) is stirred at 40 ° C. for 2 hours. The reaction mixture is then concentrated in vacuo and the residue is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo to give a pale yellow solid which is crystallized from ethyl acetate / hexanes to give the title compound as white crystals. (Yield 540 mg, 78%). Mp 205-207 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.07 (s, 3H), 3.75 (br s, 1H), 4.63-4.47 (m, 2H), 5.33 (dd, J = 9 Hz, 3 Hz, 1H), 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, 1 H), 7.91 (d, J = 9 Hz, 2H). MS (DCI-NH ₃ ) m / z 465 (M + H) ⁺ .

Elemental Analysis for C ₂₅ H ₂₁ FN ₂ O ₄ S

Anal: C, 64.64; H, 4.55; N, 6.03.

Found: C, 64.34; H, 4. 66; N, 5.93.

Example 442

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

Product from Example 441 (241636), anhydrous DMF (16 mL), 2- (2-hydroxy-2-phenyl-ethyl) -4- (4-fluorophenyl) -5- [4- ( Of a 80% oil dispersion of methylsulfonyl) phenyl] -3 (2H) -pyridazinone (210 mg, 0.45 mmol), iodomethane (56 μl, 0.90 mmol), and sodium hydride (18 mg, 0.59 mmol) The mixture is stirred at rt for 18 h. The reaction mixture is partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer is washed with brine, dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo to give a yellow oil which is purified by column chromatography (silica gel, 70:30 hexanes / ethyl acetate). Fractions containing the product are combined, concentrated in vacuo and the residue is triturated with hexane to afford the title compound. (Yield 75 mg, 34.7%). Mp 135-137 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.07 (s, 3H), 3.26 (s, 3H), 4.33-4.52 (m, 2H), 4.91 (dd, J = 9 Hz, 3 Hz, 1H), 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-NH ₃ ) m / z 479 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₃ FN ₂ O ₄ S

Anal: C, 65.25; H, 4. 84; N, 5.85.

Found: C, 64.98; H, 4.83; N, 5.81.

Example 443

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

Product from Example 46, 2-phenacyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyrida in methanol (100 mL) A mixture of xenon (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol) and sodium hydroxide acetate (518 mg, 3.8 mmol) is refluxed for 48 hours under reflux. The reaction mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer is washed with brine, then dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo to give a brown oil which is purified by column chromatography (silica gel, 70:30 hexanes / ethyl acetate). Fractions containing product are combined and concentrated in vacuo. The residue is crystallized from methanol / water to give the title compound as a mixture of E and Z oximes. (Yield 82 mg, 35%). Mp 95-99 ° C. ¹ H 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 (DCI-NH ₃ ) m / z 492 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₂ FN ₃ O ₄ S

Anal: 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 is prepared according to the method of Example 255 by replacing 3,4-difluorobenzyl bromide with 1-bromo-4-methylpentane. (Yield 145 mg, 58%). Mp 111-113 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 8.02 (s, 1H), 8.1 (d, 2H). MS (DCI-NH ₃ ) m / z 447 (M + H) ⁺ , 464 (M + NH ₄ ) ⁺ . Elemental Analysis for C ₂₃ H ₂₄ F ₂ N ₂ O ₃ S

Anal: C, 61.87; H, 5. 42; N, 6.27.

Found: C, 61.76; H, 5.55; N, 6.11.

Example 445

2- (3,4-Difluorophenyl) -4- (3-methyl-1-butoxy) -5- [4- (aminosulfonyl) -phenyl] -3 (2H) -pyridazinone

2-benzyl-4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 2- (3,4-difluorophenyl) -4 Substituted according to the method of Example 384, replacing by-(3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (Example 347) Prepare the compound. (Yield 248 mg, 42%). Mp 149-151 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 7.85 (m, 3H), 7.95 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (DCI-NH ₃ ) m / z 450 (M + H) ⁺ , 467 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₂₁ F ₂ N ₃ O ₄ S

Anal: 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

Intermediate prepared in Example 90C, 2- (2,2,2-trifluoroethyl) -4-hydroxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone Reaction with 2,2-dimethyl-propanol according to the method of example 90D resulted in 2- (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (methyl Thio) phenyl] -3 (2H) -pyridazinone is obtained. The product is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methyl sulfoxide. 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2- Replaced by (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (methylsulfinyl) phenyl] -3 (2H) -pyridazinone The sulfoxide is converted to the title compound according to the method of Example 68. (Yield 125 mg, 53%). Mp 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 (DCI-NH ₃ ) m / z 420 (M + H) ⁺ .

Elemental Analysis for C ₁₇ H ₂₀ F ₃ N ₃ O ₄ S

Anal: 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 is prepared following the method of Example 83 by isopropanol replacing 3-methyl-1-butanol. (Yield 65 mg, 85%). Mp 111-113 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.84 (d, J = 6 Hz, 6H), 1.51 (m, 2H), 1.63 (m, 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-NH ₃ ) m / z 419 (M + H) ⁺ .

Elemental Analysis for C ₁₈ H ₂₁ F ₃ N ₂ O ₄ S

Anal: 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

Intermediate prepared in Example 90C, 2- (2,2,2-trifluoroethyl) -4-hydroxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone By reacting with 3-methyl-1-butanol according to the method of Example 90D, 2- (2,2,2-trifluoroethyl) -4- (3-methylbutoxy) -5- [4- (methylthio) Phenyl] -3 (2H) -pyridazinone is obtained. The product is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methyl sulfoxide. 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2- Example substituted by (2,2,2-trifluoroethyl) -4- (3-methylbutoxy) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone The sulfoxide is converted to the title compound according to the method of 68. (Yield 65 mg, 50%). Mp 123-124 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.84 (d, J = 6 Hz, 6H), 1.52 (q, J = 6 Hz, 2H), 1.60 (h, J = 7.5 Hz, 1H), 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 (DCI-NH ₃ ) m / z 420 (M + H) ⁺ .

Elemental Analysis for C ₁₇ H ₂₀ F ₃ N ₃ O ₄ S

Anal: C, 48.68; H, 4.80; N, 10.01.

Found: C, 48.86; H, 4.83; N, 9.92.

Example 449

2- (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone

Intermediate prepared in Example 90C, 2- (2,2,2-trifluoroethyl) -4-hydroxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone By reacting with 2-methyl-1-propanol according to the method of Example 90D, 2- (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (methylthio) Phenyl] -3 (2H) -pyridazinone is obtained. The product is oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methyl sulfoxide. 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4- (methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2- Example 68 replacing by (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (methylsulfinyl) phenyl] -3 (2H) -pyridazinone The sulfoxide is converted to the title compound according to the method. (Yield 120 mg, 40%). Mp 170-172 ° C. ¹ 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-NH ₃ ) m / z 406 (M + H) ⁺ .

Elemental Analysis for C ₁₆ H ₁₈ F ₃ N ₃ O ₄ S

Anal: 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, according to the method of Example 11 was subjected to N- Debenzylation yields 4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone. The intermediate is mixed with 1 equivalent of 1-methylsulfonyl-oxy-2,3,3-trifluoro-2-propene (Example 88A) followed by 1 equivalent of cesium carbonate. The reaction mixture is heated to 50 ° C. for 5 hours. Aqueous workup was followed by chromatography to give 2- (2,3,3-trifluoro-propenyl) -4- (4-fluorophenyl) -5- [4- (methylthio) phenyl] -3 ( 2H) -pyridazinone (650 mg, 63%) is obtained. The product was oxidized with 1 equivalent of meta-chloroperoxybenzoic acid to afford methyl sulfoxide, 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- [4 -(Methylsulfinyl) -phenyl] -3 (2H) -pyridazinone 2- (2,3,3-trifluoropropenyl) -4- (4-fluorophenyl) -5- [4- (Methylsulfinyl) -phenyl] -3 (2H) -pyridazinone was converted to the title compound according to the method of Example 68. (Yield 65 mg, 35%). Mp 190-193 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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, 1H), 7.87 (t, J = 7.5 Hz, 1H). MS (ESI-NH ₃ ) m / z 456 (M−H) ⁺ . Elemental Analysis for C ₁₉ H ₁₂ F ₅ N ₃ O ₃ S

Anal: 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 is prepared according to the method of Example 178 by replacing 2-ethyl-1-hexanol with 3-methyl-1,3-butanediol. (Yield 110 mg, 61%), Mp 133-134 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.04 (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, 1 H). MS (APCI +) m / z 447 (M + H) ⁺ ; (APCI-) m / z 481 (M + Cl) ^- .

Elemental Analysis for C ₂₂ H ₂₃ FN ₂ O ₅ S · 0.25 H ₂ O

Anal: C, 58.59; H, 5. 25; N, 6.21.

Found: C, 58.42; H, 5.00; N, 6.02.

Example 452

2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Dazinon

2- (4-fluorophenyl) -4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 2- (3,4-difluorophenyl)- Starting with 4-tosyloxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2-ethyl-1-hexanol is 2-methyl-1,2-propanediol The title compound is prepared according to the method of Example 178 by substituting for. (Yield 55 mg, 31%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.97 (s, 6H), 3.30 (s, 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7.52 (m, 1H), 7.62 ( m, 1H), 7.81 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₁ H ₂₀ F ₂ N ₂ O ₅ S

Anal: 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 is separated from the reaction mixture in Example (275567) 233 as the oxidation product of the unreacted starting material. (Yield 22 mg, 8%). Mp 113-115 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 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 (DCI-NH ₃ ) m / z 393 (M + H) ⁺ , 410 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₁₈ H ₁₄ F ₂ N ₂ O ₄ S

Anal: 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 is separated from the reaction mixture in Example 125 in the product resulting from reaction with a solvent, N, N-dimethylformamide. (Yield 53 mg, 16%). Mp 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, 1H), 7.82 (d, J = 9 Hz, 2H), 8.14 (s, 1H). MS (DCI-NH ₃ ) m / z 581 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₁₈ F ₆ N ₄ O ₃ S

Anal: C, 53.79; H, 3. 12; N, 9.65.

Found: C, 53.50; H, 3. 24; N, 9.56.

Example 455

2- (2,4-Difluorobenzyl) -4- (4-fluorophenyl) -5- [4-[(dimethylamino) methylene] -aminosulfonylphenyl] -3 (2H) -pyridazinone

The title compound is separated from the reaction mixture in Example 124 as product resulting from reaction with solvent, N, N-dimethylformamide. (Yield 55 mg, 18%). Mp 193-195 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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-NH ₃ ) m / z 527 (M + H) ⁺ .

Elemental Analysis for C ₂₆ H ₂₁ F ₃ N ₄ O ₃ S

Anal: C, 59.30; H, 4.02; N, 10.64.

Found: C, 59.08; H, 3.97; N, 10.48.

Example 456

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

446A. 4-bromoselenoanisole

Freshly ground magnesium turning (6.1 g, 0.25 mol) is suspended by vigorous stirring in a solution of diethyl ether (360 mL) and 1,4-dibromobenzene (10 g, 0.04 mol). The solution is refluxed for 30 minutes with the phase not starting the reaction. Several iodine crystals are added to initiate the reaction to semi-maintain reflux. Reflux is maintained while slowly adding a residue of 1,4-dibromobenzene (49 g, 0.21 mol). After the addition of 1,4-dibromobenzene is complete, the reaction is refluxed for an additional 2 hours. If nearly all of the magnesium turning is consumed, the heterogeneous yellow / grey solution is cooled to 23 ° C. and selenium (19 g, 0.24 mol) is added in small portions using a snow blower to maintain gentle reflux. Selenium adhering to the side of the flask is further washed with diethyl ether. After addition, the solution is stirred at 23 ° C. for 20 minutes and then cooled to 0 ° C. A solution of methyl iodide (35.5 g, 0.25 mol) of diethyl ether (20 mL) is slowly added dropwise to the reaction mixture. Upon completion of the addition, the cold bath is removed and the solution is stirred at 23 ° C. for 3 hours. The reaction solution is poured slowly into cold water / 1 M HCl, and then the biphasic solution is filtered through a glass wool plug. The ethereal layer is separated and the aqueous phase is extracted two more times with diethyl ether. The combined etheric extracts are dried over MgSO ₄ , filtered and concentrated in vacuo to give a semi-viscous orange oil. If left overnight at -20 [deg.] C., large yellow worms are formed. The residual oil is extracted with a pipette to give 17 g (27%) of crystalline product [J. Org. Chem., 1983, 48, 4169]. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.46 (s, 3H), 7.12 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H). MS (APCI +) m / z 248 (Se ₇₆ M + H) ⁺ , m / z 250 (Se ₇₈ M + H) ⁺ , m / z 252 (Se ₈₀ M + H) ⁺ , and m / z 254 (Se ₈₂ M + H) ⁺ .

446B. 2,4-bis (4-fluorophenyl) -5- [4- (methylseleno) phenyl] -3 (2H) -pyridazinone

2- (4-fluorophenyl) -4-methoxy-5- [4- (methylthio) phenyl] -3 (2H) -pyridazinone 2- (4-fluorophenyl) -4-methoxy -5- [4- (methylseleno) phenyl] -3 (2H) -pyridazinone [4- (methylthio) benzeneboronic acid to 4- (methylseleno) benzeneboronic acid (4-bromothioani Manufactured according to the method of Example 194, replacing the sol with 4-bromoselenoanisole), and cyclohexyl magnesium chloride being replaced with 4-fluorophenyl magnesium Substituted with bromide, the title compound is prepared according to the method of Example 228. (Yield 44 mg, 69%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.37 (s, 3H), 6.98 (dd, J = 8.8, 8.8 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.17 (dd, J = 8.7, 8.7 Hz, 2H), 7.23-7.31 (m, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.65-7.72 (m, 2H), 8.00 (s, 1H). MS (APCI +) m / z 455 (M + H) ⁺ .

446C. 2,4-bis (4-fluorophenyl) -5- [4- (methylselenyl) phenyl] -3 (2H) -pyridazinone

2,4-bis (4-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (methyl-seleno) phenyl] -3 (2H) -pyri in methylene chloride (2 mL) A stirred solution of dazinone (40 mg, 88.1 mmol) is treated with 3-chloroperoxybenzoic acid (100 mg, 342 mmol, 57-86%) at 23 ° C. After 2 hours, the reaction seems to have completed slightly over 50%. In addition, 3-chloroperoxybenzoic acid (80 mg, 274 mmol, 57-86%) is added. Then it is stirred for 16 hours at 23 ° C to complete the reaction. The solution is diluted with ethyl acetate and carefully shaken (twice) with NaHSO ₃ solution for several minutes to consume excess 3-chloroperoxybenzoic acid. The ethyl acetate solution is then washed with saturated Na ₂ CO ₃ solution (twice), water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography of the residue (flash silica gel, acetone / methylene chloride / hexane 2: 2: 1) afforded the product [J. Chem. Soc., Chem. Commun., 1985, 569]. (Yield 40 mg, 93%). Mp 110-150 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.32 (s, 3H), 6.91 (dd, J = 8.7, 8.7 Hz, 2H), 7.14-7.27 (m, 4H), 7.48 (d, J = 8.4 Hz, 2H), 7.65-7.73 (m, 2H), 7.97 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H). MS (APCI +) m / z 487 (M + H) ⁺ and m / z 504 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₃ H ₁₆ F ₂ N ₂ O ₃ Se.0.5 H ₂ O

Anal: C, 55.88; H, 3. 46; N, 5.66.

Found: C, 55.60; H, 3.61; N, 5.29.

Example 457

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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone instead of 4- (3-fluorophenyl) -5- [4- (methylsul Starting from phonyl) phenyl] -3 (2H) -pyridazinone and replacing 1-bromo-4-fluoro-benzene with 3,4-difluorobromobenzene described in the method of Example 62 Prepare the title compound as described. (Yield 185 mg, 46.5%). Mp 182-185 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) d 3.23 (s, 3 H), 6.98 (d, J = 9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.52 (d , J = 9 Hz, 2H), 7.6 (m, 2H), 7.85 (m, 1H), 7.9 (d, J = 9 Hz, 2H), 8.3 (s, 1H). MS (DCI-NH ₃ ) m / z 457 (M + H) ⁺ , 474 (M + NH ₄ ) ⁺ .

Example 458

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

4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone 4- (3-fluorophenyl) -5- [4- (methylsulfonyl) The title compound is prepared as described in the method of Example 62 by replacement with phonyl) phenyl] -3 (2H) -pyridazinone. (Yield 135 mg, 34%). Mp 199-201 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.24 (s, 3H), 6.98 (d, J = 9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.39 (t, 1H), 7.54 (d, J = 9 Hz, 2H), 7.71 (m, 2H), 7.91 (d, J = 9 Hz, 2H), 8.27 (s, 1H). MS (DCI-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 compound sulfonamide according to the method of Example 384.

Example 460

2- (3,4-difluorophenyl) -4- (2-oxo-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone

At room temperature, 2- (3,4-difluorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (378) in THF (25 mL). To a solution of mg, 1 mmol), Ph ₃ P (524 mg, 2 mmol) and acetol (74 mg, 1 mmol) were added dropwise a solution of DIAD (0.4 mL, 2 mmol) in THF (5 mL). The mixture is stirred at rt for 6 h and concentrated in vacuo. The residue is chromatographed (silica gel, 1: 1 hexane-ethyl acetate) to afford the desired product. (Yield 205 mg, 48%). Mp 169-170 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.08 (s, 3H), 3.30 (s, 3H), 5.30 (s, 2H), 7.48 (m, 1H), 7.62 (q, J = 10 Hz, 1H), 7.75 (m, 1H), 7.94 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 8.21 (s, 1H). MS (APCI +) m / z 435 (M + H) ⁺ , (APCI-) m / z 469 (M + Cl) ⁻ .

Elemental Analysis for C ₂₀ H ₁₆ F ₂ N ₂ O ₅ S · 0.75H ₂ O

Anal: C, 53.62; H, 3.93; N, 6.25.

Found: C, 53.26; H, 3.61; N, 6.08.

Example 461

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

2- (3,4-difluorophenyl) -4- (2-oxo-1-propoxy) -5- from Example 460 in H ₂ O (10 mL) and dioxane (20 mL) A mixture of [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (150 mg, 0.3 mmol) was added to methoxylamine hydrochloride (84 mg, 1 mmol) and sodium acetate trihydrate (138 mg, 1 mmol). The mixture is stirred at room temperature for 6 hours. The reaction mixture is extracted with ethyl acetate and purified by column chromatography (silica gel, 1: 1 hexane-ethyl acetate) to afford the title compound. (Yield 20 mg, 15%). Mp 143-145 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, 1H), 7.65 ( q, J = 10 Hz, 1H), 7.82 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₁ H ₁₉ F ₂ N ₃ O ₅ S

Anal: C, 54.42; H, 4.13; N, 9.06.

Found: C, 54.33; H, 3.93; N, 8.92.

Example 462

(S) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H)- Pyridazinone

462A (R) -3-t-butoxy-2-methyl-1-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% HClO ₄ (0.1 mL) The reaction mixture is left for 24 hours in a completely sealed flask at room temperature. The mixture is poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The ether is removed in vacuo and the residue is dissolved in THF (50 mL). To the resulting solution is added sodium borohydride (925 mg, 25 mmol) and methanol (10 mL) is added dropwise at 55 ° C. The reaction is continued at 55 ° C. for 1 hour, then cooled to room temperature, acidified to pH 5 with 10% citric acid and then extracted with ethyl acetate. The acetate extract is washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The residue is chromatographed (silica gel, 2: 1 hexane-ethyl acetate) to give (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, 1H), 3.53 (dd, J = 12 Hz, 4.5 Hz, 1H), 3.70 (m, 2H). MS (DCI-NH ₃ ) m / z 164 (M + NH ₄ ) ⁺ .

462B (S) -2- (3,4-difluorophenyl) -4- (3-t-butoxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 ( 2H) -pyridazinone

At room temperature, 2- (3,4-difluorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (378) in THF (25 mL). mg, 1 mmol), Ph ₃ P (524 mg, 2 mmol) and THF in a solution of the above alcohol, (R) -3-t-butoxy-2-methyl-1-propanol (146 mg, 1 mmol) A solution of DIAD (0.4 mL, 2 mmol) in 5 mL) is added dropwise. The mixture is then stirred at rt for 6 h and concentrated in vacuo. The residue was crudely purified by passing through a pad of silica gel (eluent: hexane-ethyl acetate) (S) -2- (3,4-difluorophenyl) -4- (3-t-butoxy-2-methyl 550 mg of propoxy) -5- [4- (methyl-sulphonyl) -phenyl] -3 (2H) -pyridazinone, which is still contaminated with reduced DIAD, is obtained. 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 this product (100 mg, ˜0.2 mmol) in TFA (5 mL) is stirred at rt for 24 h and then concentrated in vacuo. The residue is neutralized with saturated NaHCO ₃ and extracted with ethyl acetate. Purification by column chromatography (silica gel, 1: 2 hexane-ethyl acetate) affords the title compound. (Yield 51 mg, 56%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, J = 7 Hz, 3H), 1.81 (septet, J = 7 Hz, 1H), 3.21 (d, J = 6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 12 Hz, 6 Hz, 1H), 4.40 (dd, J = 12 Hz, 6 Hz, 1H), 4.48 (br s, 1H), 7.52 (m, 1H) , 7.61 (m, 1H), 7.80 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₁ H ₂₀ F ₂ N ₂ O ₅ S

Anal: C, 55.99; H, 4. 47; N, 6.21.

Found: C, 55.65; H, 4.65; N, 5.92.

Example 463

(R) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] pyridazinone

Example starting from (R)-(-)-methyl 3-hydroxy-2-methyl-propionate instead of (S)-(-)-methyl 3-hydroxy-2-methyl-propionate The desired material is prepared according to the method of 462. (Yield 65 mg, 61%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.75 (d, J = 7 Hz, 3H), 1.81 (septet, J = 7 Hz, 1H), 3.21 (t, J = 6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J = 6 Hz and 12 Hz, 1H), 4.40 (dd, J = 6 Hz and 12 Hz, 1H), 4.49 (t, J = 6 Hz, 1H), 7.52 ( m, 1H), 7.61 (m, 1H), 7.80 (m, 1H), 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) ^- .

Elemental Analysis for C ₂₁ H ₂₀ F ₂ N ₂ O ₅ S

Anal: C, 55.99; H, 4. 47; N, 6.21.

Found: C, 55.62; H, 4.52; N, 6.06.

Example 464

(S) -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-methyl-propoxy) from Example 462 in THF (25 mL) at -78 ° C. THF (3 mL, 3 mmol) in a solution of -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone (450 mg, ˜0.9 mmol) and DBAD (207 mg, 0.9 mmol) A solution of 1 M lithium bis (trimethylsilyl) amide in water is added dropwise. The resulting mixture is stirred at -78 ° C for 2 hours. The mixture is warmed to room temperature and 1N NaOH (5 mL, 5 mmol) is added. After 12 h at room temperature, sodium acetate trihydrate (2.76 g, 20 mmol) and H ₂ O (10 mL) were added followed by hydroxylamine-O-sulfonic acid (2 g, 15 mmol) and the mixture was added. Stir at room temperature for 5 hours. The product is extracted with ethyl acetate and purified by chromatography (silica gel, 1: 2 hexane-ethyl acetate) to afford the desired intermediate. (Yield 160 mg, 35%). MS (APCI +) m / z 508 (M + H) ⁺ ; (APCI-) m / z 542 (M + Cl) ^- .

TFA (5 mL) is added to the intermediate and the resulting solution is stirred at room temperature for 24 hours. TFA is removed in vacuo and the residue is neutralized with saturated NaHCO ₃ and extracted with ethyl acetate. The organic extract is dried over MgSO ₄ and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed (silica gel, 1: 2 hexane-ethyl acetate) to afford the title compound. (Yield 50 mg, 33%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 = 12 Hz, 6 Hz, 1H), 4.40 (dd, J = 12 Hz, 6 Hz, 1H), 4.50 (t, J = 6 Hz, 1H), 7.51 (m, 3H), 7.61 ( m, 1H), 7.80 (m, 1H), 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 465

(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- (methylsulfonyl) phenyl] -3 (2H)- (R) -2- (3,4-difluorophenyl) -4- (3-hydroxy-2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 instead of pyridazinone Prepare for the title compound according to the method of Example 464 starting from (2H) -pyridazinone. (Yield 30 mg, 20%). ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H), 4.40 (dd, J = 6 Hz and 12 Hz, 1H), 4.50 (t, J = 6 Hz, 1H), 7.51 (m, 3H), 7.61 ( m, 1H), 7.80 (m, 1H), 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) ⁻ .

Elemental Analysis for C ₂₀ H ₁₉ F ₂ N ₃ O ₅ S

Anal: C, 53.21; H, 4. 24; N, 9.30.

Found: C, 53.45; H, 5.53; N, 9.50.

Example 466

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

2-ethyl-1-hexanol was replaced with 2-methyl-1,4-butanediol, and the regio isomer product was separated by preparative TLC using ethyl acetate: hexane (4/1) and silica gel, Prepare by the method of Example 178 to give the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) d 0.87 (d, J = 8.1 Hz, 3H), 1.48-1.87 (m, 4H), 3.13 (s, 3H), 3.41 (dd, J = 6.3, 13.5 Hz, 1H), 3.46 (dd, J = 6.3, 13.5 Hz, 1H), 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, 1H), 8.07 (d, J = 10.5 Hz, 2H). MS (APCI +) m / z 447 (M + H) ⁺ .

Example 467

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

Β-replacement of acetol with 4-hydroxy-2-butanone to prepare the title compound according to the method of Example 460. (Yield 95.0 mg, 21%). Mp 134-135 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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, 1H), 7.45 (m, 1H), 7.58 (m, 1H), 7.73 (d, J = 9 Hz, 2H), 7.89 (s, 1H), 8.05 (d, J = 9 Hz, 2H) . MS (DCI-NH ₃ ) m / z 449 (M + H) ⁺ , 466 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₈ F ₂ N ₂ O ₅ S

Anal: C, 56.25; H, 4.02; N, 6.25.

Found: C, 55.97; H, 4. 17; N, 6.11.

Example 468

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

2- (3-fluorophenyl)-instead of 2- (3,4-difluorophenyl) -4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone Example 46 Starting from 4-hydroxy-5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and replacing acetol with 4-hydroxy-2-butanone, Example 46 The title compound is prepared according to the method of. (Yield 85.0 mg, 20%). Mp 133-136 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) 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-NH ₃ ) m / z 431 (M + H) ⁺ , 448 (M + NH ₄ ) ⁺ .

Elemental Analysis for C ₂₁ H ₁₉ FN ₂ O ₅ S

Anal: C, 58.60; H, 4. 42; N, 6.52.

Found: C, 58.87; H, 4.55; N, 6.51.

Prostaglandin Inhibition Measurement

Compound Preparation and Administration

For oral administration test compounds are suspended in 100% polyethylene glycol (PEG 400) with a Teflon-coated mortar (TRI-R Instument, Jamaica, NY) on the day of use.

To compare the average response of treatment groups, various analyzes are applied. The percent inhibition value is determined by comparing the mean value of each treatment group with the control. Linear regression is used to evaluate IC ₅₀ / ED ₅₀ with a suitable analysis.

EIA measurement of prostaglandins

EIA reagents for prostaglandin measurements are purchased from Perseptive Diagnostics (Cambridge, Mass.). Prostaglandin E ₂ (PEG ₂ ) levels in the washes are measured after the sample is dried under nitrogen and reconstituted with assay buffer. PEG ₂ levels in enzyme assays or cell culture media are measured compared to standards prepared under the same conditions. Immunoassays are performed as recommended by the manufacturer. EIA is performed on 96-well microtiter plates (Nunc Roskilde, Denmark) and absorbance is measured using a microplate reader (Vmax, Molecular Devices Corp., Menlo Park, CA).

Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays

In vitro prostaglandin biosynthesis inhibition is assessed using recombinant human Cox-1 (r-hu Cox-1) and Cox-2 (r-hu Cox-2) enzyme assays. Representative compounds dissolved in DMSO (3.3% v / v) were treated with a baculovirus / Sf9 cell system with cofactors phenol (2 ml) and hematin (1 μM) for 60 minutes prior to addition of 10 μM arachidonic acid. Gierse, JK Hauser, SD, Creely, DP, Koboldt, C., Rangwala, S., H., Isakson, PC, and Seibert, K. Expression and selective inhibition of the constitutive and inducible forms of cyclooxygenase, Biochem J. 1995 , 305: 479, preincubated with microsomes from recombinant human PGHS-1 or PGHS-2. The reaction is carried out for 2.5 minutes at room temperature, then quenched with HCl and neutralized with NaOH. PGE ₂ production in the presence or absence of drug is measured by EIA analysis. EIA is performed on 96-well microtiter plates (Nunc Roskilde, Denmark) and absorbance is measured using a microplate reader (Vmax, Molecular Devives Corp., Menlo Park, CA). EIA reagents for prostaglandin crystals are purchased from Perseptive Diagnostics (Cambridge, Mass.). PGE ₂ levels are measured in comparison to standards prepared under the same conditions. Immunoassays are performed as recommended by the manufacturer.

Data describing the inhibition of in vitro prostaglandin biosynthesis by the compounds of the present invention are shown in Table 1. Compounds are indicated by example number. Column 2 shows the percentage of Cox-1 inhibition at a certain μM dose level and column 3 shows the percentage of Cox-2 inhibition at a particular nM dose level. Cox-2 inhibition values in parentheses represent IC ₅₀ values.

IL-1β-induced PGE ₂ Production in WISH Cells

Human amnion WISH cells are grown to 80% confluence in 48-well plates. After removing the growth medium and washing twice with a balanced salt solution of Gey, 5 ng IL-1β / ml (UBI, Lake Placid, NY) was added to Neuman-Tytell serum-free medium (GIBCO, Grand Island, NY) Is added to the cells in the presence or absence of test compound in DMSO (0.01% v / v). After 18 hours of incubation for maximal induction of PGHS-2, the condition-conditioned medium is removed and the PGE ₂ content is assayed by EIA analysis as described above.

Monocyte U937 (ATCC, Rockville, MD) cells are grown in a fashion similar to that of WISH cells. After incubation, the condition-conditioned medium is removed and the Cox-1 content is assayed by EIA analysis as described above.

Data describing the inhibition of in vitro prostaglandin biosynthesis by the compounds of the present invention are shown in Table 2. U937 values represent percent Cox-1 inhibition at specific μM dose levels, and values in parentheses represent IC ₅₀ values. WISH cell values represent percent inhibition at specific μM dose levels, and values in parentheses represent IC ₅₀ values.

Human Whole Platelet Cyclooxygenase-1 Assay (HWCX)

Blood from normal healthy volunteers is collected in a tube containing ACD (Acid citrate Dextrose) as an anticoagulant. The blood is centrifuged at 175 × g to produce platelet-rich plasma. Platelet-enriched plasma is centrifuged at 100 × g to pellet the white blood cells and retain platelets in the supernatant. The supernatant is deposited on a cushion of 0.7 ml of 10% bovine serum albumin in Tyrodes solution (Gibco; Grand Island, NY) and then centrifuged at 1000 × g. After removing the supernatant resulting from centrifugation, 11 ml of Tyrodes solution is added to the remaining pellets of platelets. Platelets are dispensed in 120 μl each in a 96-well plate. Add test compound and preincubate for 10 minutes. At the end of the preincubation period, calcium ionophore A23187 is added to a final concentration of 8.8 μM and incubated for 10 minutes. The reaction is stopped by addition of cooled 6 mM EDTA, the incubation mixture is centrifuged at 220xg and the supernatant is analyzed for thromboxane using a commercial kit from Cayman Chemical (Ann Arbor, MI).

Carrageenan Induced Foot Edema (CPE) in Rats

See Winter et al., Proc. Soc. Exp. Biol. Med., 1962, 111, 544, induces hind edema in male rats. Briefly, 0.1 ml of 1% sodium carrageenan (Sigma Chemical Co., St Louis, MO) was injected into the sole of the foot on the right hind foot of a male Sprague-Dawley rat, weighing 170-190 g. The test compound is administered orally 1 hour prior to injection. The volume of the right foot (ml) is measured after carrageenan injection for baseline volume measurements using a Buxco flowmeter (Buxco Electronics, Inc., Troy, NY). After 3 hours of carrageenan injection, the right foot is re-measured and the foot edema for each rat is calculated by subtracting the 0 hour reading from the reading at 3 hours. Data are expressed as mean percent inhibition ± SEM. Statistical significance for the results is analyzed by Dunnetts' multiple comparison test where p <0.05 is considered statistically significant.

Rat Carrageenan Pleural Inflammation (CIP) Model

See Vinegar et al., Fed. Proc. 1976, 35, 2447-2456 to induce pleural inflammation in adrenalectomized male Sprague-Dawley rats according to the methods of The test compound is orally administered 30 minutes prior to intrapleural injection of 2% lambda carrageenan (Sigma Chemical Co., St. Louis MO). After 4 hours, the rats are euthanized and the pleural cavity is washed with ice cooled saline. The wash is added to twice the volume of ice-cold methanol (final methanol concentration 66%) to lyse the cells and precipitate the protein. Eicosanoids are measured by EIA as described above.

Data indicating in vivo inhibition of prostaglandin biosynthesis by the compounds of the present invention are shown in Table 3. The reported value is% inhibition at 10 mg / kg body weight.

Carrageenan-induced air pouch prostaglandin biosynthesis model (CAP)

An air sac is formed by injecting 20 ml of sterile air into the back of a male Sprague Dawley rat (day 0). After 3 days, inflate the air bag again with 10 ml of additional sterile air. On day 7, 1 ml of saline containing 0.2% lambda carrageenan (Sigma Chemical Co.) is injected into the air sac to induce an inflammatory response characterized by prostaglandin release. Test compounds are administered at a dose of 0.1 to 10 mg / kg 30 minutes prior to carrageenan injection. Four hours after carrageenan injection, the air sac is washed and the level of prostaglandin is measured by an enzyme immuno-assay using a commercial kit. The percent inhibition is calculated by comparing the response in the rats to which the vehicle was administered with the response in the rats to which the test compound was administered. Cox-2 inhibition values in parentheses represent ED ₅₀ values.

Data showing inhibition of prostaglandin biosynthesis in vivo by the compounds of the present invention are shown in Table 3. Reported values are% inhibition at 10 mg / kg body weight for CIP and CPE tests and% inhibition at 3 mg / kg body weight for CAP tests.

Pharmaceutical composition

The invention also provides pharmaceutical compositions containing a compound of the invention formulated with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical composition of the invention contains a therapeutically effective amount of a compound of the invention formulated with one or more pharmaceutically acceptable carriers. As used herein, "pharmaceutically acceptable carrier" means a nontoxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or any type of formulation aid. Examples of materials that can be used as pharmaceutically acceptable carriers include sugars (eg, lactose, glucose and sucrose); Starch (eg corn starch and potato starch); Cellulose or derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethyl alcohol; And phosphate buffers as well as other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, skinning agents, sweeteners, flavoring agents, fragrances and antioxidants are processes well known to the person skilled in the art. And depending on the judgment. The pharmaceutical compositions of the present invention are administered to humans and other animals by oral, rectal, parenteral, subretinal alveolar, intravaginal, intraperitoneal, topical (as powders, ointments or drops), or oral or oral or nasal sprays. Can be.

Compounds of the invention may be potentially useful for the treatment of several diseases or pathological conditions (eg, inflammatory diseases, dysmenorrhea, asthma, premature birth, adhesions and certain pelvic adhesions, osteoporosis and ankylosing spondylitis). Current Drugs Ltd . ID Patent Fast Alert, AG 16, May 9, 1997].

The compounds of the present invention may be potentially useful for the treatment of cancer and in particular colon cancer. See Proc. Natl. Acad. Sci., 94, pp. 3336-3340, 1997].

The compounds of the present invention are useful for providing pharmaceutical compositions for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof and a pharmaceutically acceptable carrier. Can be represented.

Compounds of the invention are useful for providing pharmaceutical compositions for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, ester or prodrug thereof and a pharmaceutically acceptable carrier. Can be represented.

Compounds of the present invention are useful for providing pharmaceutical compositions for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt, ester or prodrug thereof and a pharmaceutically acceptable carrier. Can be represented.

The compounds of the invention also provide a method of inhibiting prostaglandin biosynthesis, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof Can be useful.

Compounds of the present invention are useful for providing methods of inhibiting prostaglandin biosynthesis, including administering a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, ester, or prodrug thereof to a mammal in need of inhibition of prostaglandin biosynthesis. Can be represented.

Compounds of the present invention are useful for providing methods of inhibiting prostaglandin biosynthesis, including administering a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof to a mammal in need of inhibition of prostaglandin biosynthesis Can be represented.

In addition, the compounds of the present invention may be administered to a mammal by administering to a mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, including pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and May be useful in providing a method for treating cancer.

Compounds of the present invention can be used for treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, including administering to a mammal a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt, ester or prodrug thereof. May be useful in providing a method of treatment.

Compounds of the present invention can be used for the treatment of pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, including administering to a mammal a therapeutically effective amount of a compound of formula III or a pharmaceutically acceptable salt, ester or prodrug thereof May be useful in providing a method of treatment.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms, in addition to the active compounds, are inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol , Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil, etc.), glycerol, tetrahydrofurfuryl Fatty acid esters of alcohols, polyethylene glycol and sorbitan and mixtures thereof. In addition to inert diluents. Oral compositions may also contain auxiliaries such as wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and fragrances.

Injectables, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. In addition, sterile injectables can be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, for example solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution and the like. In addition, sterile, nonvolatile oils can conventionally be employed as a solvent or suspending medium. For this purpose, all blended nonvolatile oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations may be sterilized by inserting a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or sterile injection media prior to use or by any method known in the art, for example, filtration through a bacterial-retaining filter. Can be.

In order to sustain the effect of the drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of absorption of the drug depends on the rate of dissolution followed by crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms can be prepared by forming the drug into microencapsulated matrices in biodegradable polymers such as polyactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable formulations in the form of deposits are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are suitable non-inflammatory excipients or carriers, such as cocoa butter, polyethylene glycol or suppository waxes, which melt the compound of the present invention in the rectum or vaginal cavity as a solid at room temperature or as a liquid at body temperature to release the active compound. Preference is given to suppositories which can be prepared by mixing together).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules. In such solid dosage forms, the active compound is usually one or more inert, pharmaceutically acceptable excipients or carriers 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 carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants, such as glycerol, d) disintegrants E.g. agar-agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants, e.g. paraffins, f) absorption accelerators, e.g. quaternary ammonium compounds, g) Humectants, such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, mag Syum stearate, La solid polyethylene glycols, sodium lauryl sulfate are mixed and the mixture thereof. In the case of capsules, tablets, pills, the dosage forms may also contain buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

The active compound may also be present in microencapsulated form with one or more excipients as described above. Specific dosage forms of tablets, dragees, capsules, pills, and granules can be prepared to have a coating and skin such as enteric coating, controlled release coating and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with one or more diluents, for example sucrose, lactose or starch. Such dosage forms also typically contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. For capsules, tablets and pills, the dosage form may also contain a buffer. These may optionally contain opacifying agents and may also be compositions which only or preferentially release the active ingredient in any delayed manner at specific sites of the intestinal tract. Examples of insertion compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers that may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated for inclusion in the present invention.

Ointments, pastes, creams and gels, in addition to the active compounds of the present invention, include excipients such as animal and vegetable fats, oils, wax paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids , Talc and zinc oxide or mixtures thereof.

Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. Sprays may further contain conventional propellants, such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of regulating-delivering the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the influx of compounds through the skin. This rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the treatment method of the present invention, the patient can be treated by administering to the patient, such as a human or a mammal, a therapeutically effective amount of a compound of the present invention in the amount and time necessary to achieve the desired result. A “therapeutically effective amount” of a compound of the invention means an amount of the compound that is sufficient to provide the desired level of remission, at a suitable benefit / risk ratio applicable to the medical treatment. However, the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of appropriate medical judgment. The level of a particular therapeutically effective amount for a particular patient can include the disorder being treated and the severity of the disorder; Activity of the specific compound employed; The specific composition employed; Age, weight, general health status; The sex and diet of the patient; Dosing time; Route of administration and rate of excretion of the specific compound employed; Treatment duration; Drugs used in combination or coincidental with the specific compound employed; And other elements well known in the art of pharmacy.

The total daily dose of a compound of the invention administered to humans or other mammals at once or in divided doses is from 0.001 to about 1000 mg / kg body weight per day, for example oral administration, or more preferably about 0.1 To about 100 mg / kg body weight, and from parenteral administration to 0.01 to about 10 mg / kg body weight. A single dosage composition may comprise such amounts or submultiples thereof which constitute a daily dosage.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will depend on the host treated and the particular mode of administration.

Reagents required for the synthesis of the compounds of the present invention are readily available from various commercial sources [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); Specturm Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT 06708). Compounds which are not commercially available can be prepared using the methods disclosed in the chemical literature.

Claims (35)

A compound of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof. Formula I In the above formula, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, halo Alkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryl Oxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C (O) R ⁵ ,-(CH ₂ ) _n C (O) R ⁵ , -R ⁶ -R ⁷ ,-(CH ₂ ) _n CH (OH) R ⁵ ,-(CH ₂ ) _n CH (OR ^d ) R ⁵ ,- (CH ₂ ) _n C (NOR ^d ) R ⁵ ,-(CH ₂ ) _n C (NR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NOR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NR ^d R ^e ) R ⁵ ,-(CH ₂ ) _n C≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ ,- (CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -R ⁸ ,-(CH ₂ ) _n (CHX') _m- (CH ₂ ) _n -CX ' ₃ ,-(CH ₂ ) _n ( CHX ') _m- (CH ₂ ) _n -R ⁸ , and-(CH ₂ ) _n -R ²⁰ R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic and heterocyclic alkyl, R ⁶ is alkylene or alkenylene, halo-substituted alkylene or halo-substituted alkenylene, R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl, R ^d and R ^e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, X 'is halogen, n is 0 to about 10, m is 0 to about 5, One or more groups of R ¹ , R ² and R ³ or ego, X ¹ is selected from the group consisting of -SO _2- , -SO (NR ¹⁰ )-, -SO-, -SeO _2- , PO (OR ¹¹ )-and -PO (NR ¹² R ¹³ )-, R ⁹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH ₂ , -N = CH (NR ¹⁰ R ¹¹ ), dialkylamino, alkoxy, thiol, alkylthiol, protecting group and alkyl Is selected from the group consisting of protecting groups bonded to X ¹ by len; X ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl and alkynyl, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl, or R ¹² and R ¹³ are heterocyclic rings having 3 to 6 atoms together with the nitrogen to which they are attached Form the The other two groups of R ¹ , R ² and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, ilkylthio, alkylthioalkoxy, alkoxy , Alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, Cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy , Arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, hetero Cyclic, heterocyclic alkyl, heterocyclic (alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxy Selected from the group consisting of alkylthio, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro and -YR ¹⁴ , Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano. A compound of formula II or a pharmaceutically acceptable salt, ester or prodrug thereof. Formula II In the above formula, Z is a chemical formula or ego, X ¹ is selected from the group consisting of -SO _2- , -SO-, -SeO _2- , and -SO (NR ¹⁰ )-, R ⁹ is a protecting group bound to X ¹ by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, —NHNH ₂ , dialkylamino, alkoxy, thiol, alkylthiol, protecting group and alkylene Selected from the group R ¹⁰ is selected from the group consisting of hydrogen, alkyl and cycloalkyl, X ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl and alkynyl, R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, halo Alkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryl Oxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C (O) R ⁵ ,-(CH ₂ ) _n C (O) R ⁵ , -R ⁶ -R ⁷ ,-(CH ₂ ) _n CH (OH) R ⁵ ,-(CH ₂ ) _n CH (OR ^d ) R ⁵ ,- (CH ₂ ) _n C (NOR ^d ) R ⁵ ,-(CH ₂ ) _n C (NR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NOR ^d ) R ⁵ ,-(CH ₂ ) _n CH (NR ^d R ^e ) R ⁵ ,-(CH ₂ ) _n CH≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -CX' ₃ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ , -(CH ₂ ) _n (CX ' ₂ ) _m- (CH ₂ ) _n -R ⁸ ,-(CH ₂ ) _n (CHX') _m- (CH ₂ ) _n -CX ' ₃ ,-(CH ₂ ) _n (CHX ') _m- (CH ₂ ) _n -R ⁸ , and-(CH ₂ ) _n -R ²⁰ R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic and heterocyclic alkyl, R ⁶ is alkylene or alkenylene, halo-substituted alkylene or halo-substituted alkenylene, R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl, R ^d and R ^e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, X 'is halogen, n is 0 to about 10, m is 0 to about 5, R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, ilkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, Alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino , Cycloalkylamino, cycloalkyloxy, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl , Arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic (al Chy) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, Selected from the group consisting of nitro and -YR ¹⁴ , Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano. A compound of formula III or a pharmaceutically acceptable salt, ester or prodrug thereof. Formula III In the above formula, X, X ¹ , X ² , R, R ¹ , R ³ and R ⁹ are as defined in claim 1. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ —, —SO—, —SeO ₂ —, and —SO (NR ¹⁰ ) —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl,-(CH ₂ ) _n C (O) R ⁵ ,-(CH ₂ ) _n C≡CR ⁷ ,-(CH ₂ ) _n [CH (CX ' ₃ )] _m- (CH ₂ ) _n -R ⁸ and-(CH ₂ ) _n -R ²⁰ ; R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl, R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl, R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl, X 'is halogen, n is from 0 to about 10, m is 0 to about 5, R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cyclo Alkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, aryloxy, heterocyclic, Is selected from the group consisting of heterocyclic alkyl, cyano, nitro and -YR ¹⁴ , Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-, -N = CR ²¹ R ²² , -NR ²¹ R ²² and -NR ¹⁹ , and R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano or a pharmaceutical thereof Acceptable salts, esters or prodrugs. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ —, —SO—, —SeO ₂ —, and —SO (NR ¹⁰ ) —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl,-(CH ₂ ) _n C (O) R ⁵ and-(CH ₂ ) _n -R ²⁰ R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl, R ²⁰ is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic and heterocyclic alkyl, n is from 0 to about 10, R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl , Haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, dia Arylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro and -YR ¹⁴ , and Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-and -NR ¹⁹ is selected from the group consisting of R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano or a pharmaceutical thereof Acceptable salts, esters or prodrugs. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ —, —SO—, —SeO ₂ —, and —SO (NR ¹⁰ ) —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl , Arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl and-(CH ₂ ) _n C (O) R ⁵ , R ⁵ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic and heterocyclic alkyl, n is from 0 to about 10, R ¹ and R ³ are independently hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl , Haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, dia Arylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro and -YR ¹⁴ , and Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O) NR ²¹ R ^22- , -C (O)-, -C (O) O-, -NH -, -NC (O)-and -NR ¹⁹ is selected from the group consisting of R ¹⁴ is hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl , Heterocyclic and heterocyclic (alkyl) selected from the group consisting of R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano or a pharmaceutical thereof Acceptable salts, esters or prodrugs. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ —, —SO—, —SeO ₂ —, and —SO (NR ¹⁰ ) —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ , R ²⁰ is aryl unsubstituted or substituted with halogen, n is from 0 to about 10, R ¹ is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, and -YR ¹⁴ , Y is -O-, -S-, -C (R ¹⁶ ) (R ¹⁷ )-, -C (O)-, -C (O) O-, -NH-, -NC (O)-, and -NR ^Is selected from the group consisting of ¹⁹ , R ¹⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, R ³ is hydrogen, R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁹ are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano, R ²¹ and R ²² are independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl and cyano or a pharmaceutical thereof Acceptable salts, esters or prodrugs. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ —, —SO— and —SO (NR ¹⁰ ) —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ , R ²⁰ is aryl unsubstituted or substituted with halogen, n is from 0 to about 10, R ¹ is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic and heterocyclic alkyl, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino and dialkylamino, X ² is selected from the group consisting of hydrogen and halogen, X is selected from the group consisting of O, S, NR ⁴ , N-OR ^a and N-NR ^b R ^c , R ⁴ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic and arylalkyl, R^a, R^bAnd R^cIs independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl, R is selected from the group consisting of haloalkyl, aryl, heterocyclic, heterocyclic alkyl and-(CH ₂ ) _n -R ²⁰ , R ²⁰ is aryl unsubstituted or substituted with halogen, n is from 0 to about 10, Aryl wherein R ¹ is unsubstituted; And aryl substituted with one to three substituents selected from the group consisting of fluorine and chlorine (eg, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, etc.); ; But not limited to A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is selected from the group consisting of alkyl and amino, X ² is selected from the group consisting of hydrogen and halogen, X is O, R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl, R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, haloalkoxy, arylalkyl, alkyl and aryloxy, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is selected from the group consisting of alkyl and amino, X ² is selected from the group consisting of hydrogen and fluorine, R is selected from the group consisting of haloalkyl, aryl and alkyl, n is from 0 to about 10, R ¹ is isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neo Aryl (e.g. 4-fluorophenyl) substituted with one to three substituents selected from the group consisting of pentyloxy, isopentyl, aryloxy (e.g. 4-fluorophenoxy), unsubstituted aryl, and fluorine and chlorine; , 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, etc.), A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is selected from the group consisting of —SO ₂ — and —SO (NR ¹⁰ ) —, R ⁹ is alkyl, X ² is selected from the group consisting of hydrogen and fluorine, X is O, R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl, R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl and aryloxy, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is amino, X ² is selected from the group consisting of hydrogen and fluorine, X is O, R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl and arylalkyl, R ¹ is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl and aryloxy, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is methyl, X ² is hydrogen, X is O, R is tert-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF _Is selected from the group consisting of ₃ CH ₂ , R ¹ is aryloxy, isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyl Oxy, neopentyloxy, isopentyl, 4-fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The compound of claim 3, wherein X ¹ is —SO ₂ —, R ⁹ is amino, X ² is hydrogen, X is O, R is tert-butyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF _Is selected from the group consisting of ₃ CH ₂ , R ¹ is aryloxy, isobutyloxy, isopentyloxy, 1- (3-methyl-3-butenyl) oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyl Is selected from the group consisting of oxy, neopentyloxy, isopentyl, 4-fluorofe, 4-chlorofe, 4-chloro-3-fluoro-pe, 4-fluorophenoxy, A compound or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R ³ is hydrogen. The method of claim 3, wherein the 2- (2,2,2-trifluoroethyl) -4- (4-chlorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyrida Xenon, 2- (4-fluorophenyl) -4- (3-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3-chlorophenyl) -4- (3-methyl-3-butenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (4-chloro-3-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone , 2- (4-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (3-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methyl-1-propoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyri Dazinon, 2- (4-fluorophenyl) -4- (3-hydroxy-3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (tert-butyl) -4- (3-methoxybutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (tert-butyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (3-methylbutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-methylbutyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3-chlorophenyl) -4- (3-methylbutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3-chlorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3-chlorophenyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-methylbutoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-methylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (4-fluorophenoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (4-fluorophenoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (2,2-dimethylpropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-chloro-3-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (4-fluorophenoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (4-fluorophenyl) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2,4-bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-hydroxy-2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-oxopropoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-methoxy-imino-propoxy) -5- [4- (methylsulfonyl) 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, 2- (3,4-difluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-oxo-butoxy) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone and A compound selected from the group consisting of 2,4-bis (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3 (2H) -pyridazinone or a pharmaceutically acceptable salt thereof, Esters or prodrugs. 18. The compound of claim 16 wherein 2-phenyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone, 2- (2,2,2-trifluoroethyl) -4- (4-chlorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone, 2- (4-fluorophenyl) -4- (3-methylbutoxy) -5- [4- (methylsulfonyl) phenyl) -3 (2H) -pyridazinone, 2- (3,4-difluorophenyl) -4- (2-methylpropoxy) -5- [4- (aminosulfonyl) phenyl] -3 (2H) -pyridazinone and A compound selected from the group consisting of 2,4-bis (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) -pyridazinone or a pharmaceutically acceptable salt, ester or Prodrugs. A pharmaceutical composition for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of the compound of claim 2 and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibiting prostaglandin biosynthesis containing a therapeutically effective amount of the compound of claim 3 and a pharmaceutically acceptable carrier. A method of inhibiting prostaglandin biosynthesis, characterized by administering a therapeutically effective amount of the compound of claim 1 to a mammal in need of inhibition of prostaglandin biosynthesis. A method of inhibiting prostaglandin biosynthesis, characterized by administering a therapeutically effective amount of the compound of claim 2 to a mammal in need of inhibition of prostaglandin biosynthesis. A method of inhibiting prostaglandin biosynthesis, characterized by administering a therapeutically effective amount of the compound of claim 3 to a mammal in need of inhibition of prostaglandin biosynthesis. A method of treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, characterized by administering a therapeutically effective amount of the compound of claim 1. A method for treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, characterized by administering a therapeutically effective amount of the compound of claim 2. A method of treating pain, fever, inflammation, rheumatoid arthritis, osteoarthritis, adhesions and cancer, characterized by administering a therapeutically effective amount of the compound of claim 3. A method of preparing a compound of claim 3 or a pharmaceutically acceptable salt, ester or prodrug thereof, characterized in that the compound of formula III wherein R is hydrogen is reacted with an alkylating agent. Formula III In the above formula, X, X ¹ , X ² , R, R ¹ , R ³ and R ⁹ are as defined in claim 1. The compound of claim 27, wherein the alkylating agent is a compound of Formula R ⁹⁹ -Q, Q is a leaving group, and R ⁹⁹ is 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-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-trifluoromethylbene, 2 , 4-difluorobene, 2,4-difluorophenacyl, 4-trifluoromethylphenacyl, phenacyl, 4-carboxyphenacyl, 4-chlorophenacyl, 4-cyanophenacyl, 4-di Ethylaminophenacyl, 3-thienylmethyl, 5-methylthien-2-ylmethyl, 5-chlorothien-2-ylmethyl, 2-benzo [b] thienylmethyl, 3-benzothienacyl, 5-chlorothia Zol-2-ylmethyl, 5-meth Is selected from thiazol-2-ylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, quinolin-2-ylmethyl, and the group consisting of a fluoro-quinolin-2-ylmethyl. The compound of claim 27, wherein the alkylating agent is a compound of Formula R ⁹⁹ -Q, Q is a leaving group, and R ⁹⁹ is 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-butene -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-trifluoro Romethylphenacyl, 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. The compound of claim 27, wherein the alkylating agent is a compound of Formula R ⁹⁹ -Q, Q is a leaving group, and R ⁹⁹ is 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. The alkylating agent of claim 27 wherein the alkylating agent is a compound of Formula R ⁹⁹ -Q, Q is a leaving group, and R ⁹⁹ is 1,1,1-trifluoroethyl, phenyl, benzyl, α-methyl-4-fluorobenzyl , 4-fluorobenzyl, 4-fluorophenyl and 2,4-difluorobenzyl. The alkylating agent of claim 27 wherein the alkylating agent is a compound of formula R ⁹⁹ -Q, Q is a leaving group and R ⁹⁹ is selected from the group consisting of 1,1,1-trifluoroethyl, benzyl and 4-fluorophenyl Way. a) reacting a compound of Formula IV with a nucleophilic agent to replace the X group, b) converting group-OR ⁹⁸ to an exit group, and c) reacting this compound with a second nucleophile to obtain 4,5-substituted pyridazone, wherein the 4,5-substituted pyridazone is regioselectively prepared. Way. In the above formula, R ⁹⁸ is an alkyl or aryl group, X is an exit group. The method of claim 33, wherein the benzyl group is removed using Lewis acid. Treating a 4,5-substituted pyridazone or a pharmaceutically acceptable salt, ester or prodrug thereof by treating the compound of Formula V with a hydrazine of Formula RNHNH ₂ to provide a pyridazone of Formula III. Optionally manufacturing method. Formula III In the above formula X, X ¹ , X ² , R, R ¹ , R ³ and R ⁹ are as defined in claim 1.