U.S. patent application number 09/870838 was filed with the patent office on 2002-03-07 for prostaglandin endoperoxide h synthase biosynthesis inhibitors.
Invention is credited to Basha, Anwer, Black, Lawrence A., Coghlan, Michael J., Kolasa, Teodozyj, Kort, Michael E., Liu, Huaqing, McCarty, Catherine M., Patel, Meena, Rohde, Jeffrey J., Stewart, Andrew O..
Application Number | 20020028938 09/870838 |
Document ID | / |
Family ID | 27535366 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028938 |
Kind Code |
A1 |
Black, Lawrence A. ; et
al. |
March 7, 2002 |
Prostaglandin endoperoxide H synthase biosynthesis inhibitors
Abstract
The present invention describes pyridazinone compounds of
formula I 1 which are cyclooxygenase (COX) inhibitors, and in
particular, are selective inhibitors of cyclooxygenase-2 (COX-2).
COX-2 is the inducible isoform associated with inflammation, as
opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which
is an important "housekeeping" enzyme in many tissues, including
the gastrointestinal (GI) tract and the kidneys. The selectivity of
these compounds for COX-2 minimizes the unwanted GI and renal
side-effects seen with currently marketed non-steroidal
anti-inflammatory drugs (NSAIDs).
Inventors: |
Black, Lawrence A.;
(Libertville, IL) ; Basha, Anwer; (Lake Forest,
IL) ; Kolasa, Teodozyj; (Lake Villa, IL) ;
Kort, Michael E.; (Lake Bluff, IL) ; Liu,
Huaqing; (Buffalo Grove, IL) ; McCarty, Catherine
M.; (Brookline, MA) ; Patel, Meena; (Chicago,
IL) ; Rohde, Jeffrey J.; (Evanston, IL) ;
Coghlan, Michael J.; (Grayslake, IL) ; Stewart,
Andrew O.; (Libertyville, IL) |
Correspondence
Address: |
Steven F. Weinstock
Abbott Laboratories
100 Abbott Park Road
AP6D2/377
Abbott Park
IL
60064-6050
US
|
Family ID: |
27535366 |
Appl. No.: |
09/870838 |
Filed: |
May 31, 2001 |
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Application
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09870838 |
May 31, 2001 |
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09427768 |
Oct 27, 1999 |
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09427768 |
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Current U.S.
Class: |
544/238 ;
544/239 |
Current CPC
Class: |
C07D 405/04 20130101;
C07D 409/04 20130101; C07D 237/14 20130101; A61P 35/00
20180101 |
Class at
Publication: |
544/238 ;
544/239 |
International
Class: |
C07D 43/02; C07D
237/14 |
Claims
We claim:
1. A compound of formula I: 39or a pharmaceutically acceptable
salt, ester, or prodrug thereof, wherein X is selected from the
group consisting of O, S, --NR.sup.4, --NOR.sup.a, and
--NNR.sup.bR.sup.c; R.sup.4 is selected from the group consisting
of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and
heterocyclic alkyl; R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of alkyl, aryl, arylalkyl,
cycloalkyl, and cycloalkylalkyl; R is selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy,
alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl,
arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl,
arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl,
arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl,
haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy,
heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl,
hydroxyiminoalkoxy, --(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.su- p.e)R.sup.5, --R.sup.6R.sup.7,
--(CH.sub.2).sub.nC.ident.CR.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m(CH.sub.2).sub.pR.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m(CH.sub.2).sub.pR.sup.7, and
--(CH.sub.2).sub.n(CHX').sub.m(CH.sub.2).sub.pR.sup.7; R.sup.5 is
selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl,
haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
R.sup.6 is selected from the group consisting of alkenylene,
alkylene, halo-substituted alkenylene, and halo-substituted
alkylene; R.sup.7 is selected from the group consisting of
hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
R.sup.d and R.sup.e are independently selected from the group
consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl,
cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic
alkyl; X' is halogen; m is an integer from 0-5; n is an integer
from 0-10; and p is an integer from 0-10; and R.sup.1, R.sup.2, and
R.sup.3 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy,
alkoxyiminoalkyl, alkyl, alkylcarbonylalkoxy, alkylcarbonylamino,
alkylcarbonylaminoalkyl, alkynyl, aminoalkoxy,
aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl,
arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano,
cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy,
haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy,
hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro,
phosphonatoalkoxy, Y, and W; provided that one of R.sup.1, R.sup.2,
or R.sup.3 must be W, and further provided that only one of
R.sup.1, R.sup.2, or R.sup.3 is W; W is selected from the group
consisting of 40X.sup.1 is selected from the group consisting of
S(O).sub.2, S(O)(NR.sup.10), S(O), Se(O).sub.2, P(O)(OR.sup.11),
and P(O)(NR.sup.12R.sup.13); X.sup.2 is selected from the group
consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
R.sup.9 is selected from the group consisting of alkenyl, alkoxy,
alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino,
cycloalkenyl, cycloalkyl, dialkylamino, --NHNH.sub.2, and
--NCHN(R.sup.10)R.sup.11; R.sup.10, R.sup.11, R.sup.12, and
R.sup.13 are independently selected from the group consisting of
hydrogen, alkyl, and cycloalkyl, or R.sup.12 and R.sup.13 can be
taken together, with the nitrogen to which they are attached, to
form a 3-6 membered ring containing 1 or 2 heteroatoms selected
from the group consisting of O, S, and NR.sup.7; Y is selected from
the group consisting of --OR.sup.14, --SR.sup.14,
--C(R.sup.16)(R.sup.17)R.sup.14, --C(O)R.sup.14, --C(O)OR.sup.14,
--N(R.sup.16)C(O)R.sup.14, --NC(R.sup.16)R.sup.14, and
--N(R.sup.16)R.sup.14; R.sup.14 is selected from the group
consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl,
alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic,
heterocyclic alkyl, hydroxyalkyl, and NR.sup.18R.sup.19; and
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and
heterocyclic alkyl.
2. A compound according to claim 1 wherein R.sup.2 is W; X.sup.1 is
selected from the group consisting of S(O).sub.2, S(O),
Se(O).sub.2, and S(O)(NR.sup.10); and R.sup.9 is selected from the
group consisting of alkenyl, alkoxy, alkyl, alkylamino,
alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, and
dialkylamino.
3. A compound according to claim 1 wherein, R.sup.2 is W; W is
41X.sup.1 is selected from the group consisting of S(O).sub.2,
S(O), Se(O).sub.2, and S(O)(NR.sup.10); and R.sup.9 is selected
from the group consisting of alkenyl, alkoxy, alkyl, alkylamino,
alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, and
dialkylamino.
4. A compound according to claim 3 wherein X.sup.2 is selected from
the group consisting of hydrogen and halogen; R is selected from
the group consisting of hydrogen, alkenyl, alkyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl,
arylalkyl, --(CH.sub.2).sub.nC(O)R.sup.- 5,
--(CH.sub.2).sub.nC.ident.CR.sup.7, and
--(CH.sub.2).sub.n[CH(CX'3)].su- b.m(CH.sub.2).sub.pR.sup.7; and
R.sup.1 and R.sup.3 are independently selected from the group
consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl,
alkylcarbonylamino, alkylcarbonylaminoalkyl, aminocarbonylalkyl,
aryl, cyano, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, halogen, nitro, and Y.
5. A compound according to claim 3 wherein X.sup.2 is selected from
the group consisting of hydrogen and halogen; R is selected from
the-group consisting of hydrogen, alkenyl, alkyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl,
arylalkyl, and --(CH.sub.2).sub.nC(O)R.- sup.5; and R.sup.1 and
R.sup.3 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl, nitro, and
Y.
6. A compound according to claim 3 wherein X.sup.2 is selected from
the group consisting of hydrogen and halogen; R is selected from
the group consisting of hydrogen, alkyl, aryl, haloalkyl,
heterocyclic, heterocyclic alkyl, and
--(CH.sub.2).sub.nC(O)R.sup.5; and R.sup.1 and R.sup.3 are
independently selected from the group consisting of hydrogen,
alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl, nitro, and
Y.
7. A compound according to claim 3 wherein X.sup.2 is selected from
the group consisting of hydrogen and halogen; R is selected from
the group consisting of alkyl, aryl, haloalkyl, heterocyclic,
heterocyclic alkyl, and arylalkyl wherein the aryl portion is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected
from halogen; and R.sup.1 is selected from the group consisting of
aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkoxy,
and Y.
8. A compound according to claim 3 wherein X.sup.2 is selected from
the group consisting of hydrogen and halogen; R is selected from
the group consisting of alkyl, aryl, haloalkyl, heterocyclic,
heterocyclic alkyl and arylalkyl wherein the aryl portion is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected
from halogen; R.sup.1 is selected from the group consisting of
aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkoxy,
and Y; Y is --OR.sup.14; R.sup.14 is selected from the group
consisting of alkenyl, alkyl, and aryl; and R.sup.3 is
hydrogen.
9. A compound according to claim 3 wherein X.sup.1 is S(O).sub.2;
X.sup.2 is selected from the group consisting of hydrogen and
halogen; R is selected from the group consisting of aryl,
haloalkyl, heterocyclic, heterocyclic alkyl and arylalkyl wherein
the aryl portion is optionally substituted with 1, 2, 3, 4, or 5
substituents selected from halogen; R.sup.1 is aryl optionally
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of chlorine and fluorine; and R.sup.3 is
hydrogen.
10. A compound according to claim 3 wherein X is O; X.sup.1 is
S(O).sub.2; R.sup.9 is selected from the group consisting of alkyl
and amino; X.sup.2 is selected from the group consisting of
hydrogen and halogen; R is selected from the group consisting of
alkenyl, alkyl, alkynyl, aryl, arylalkyl, and haloalkyl; R.sup.1 is
selected from the group consisting of alkyl, aryl, arylalkyl,
haloalkoxy, hydroxyalkoxy, and Y; Y is --OR.sup.14; R.sup.14 is
selected from the group consisting of alkenyl, alkyl, and aryl; and
R.sup.3 is hydrogen.
11. A compound according to claim 3 wherein X.sup.1 is S(O).sub.2;
R.sup.9 is selected from the group consisting of alkyl and amino;
X.sup.2 is selected from the group consisting of hydrogen and
fluorine; R is selected from the group consisting of haloalkyl,
aryl, and alkyl; R.sup.1 is selected from the group consisting of
isobutyloxy, isopentyloxy, 1-(3-methyl-3-butenyl)oxy,
2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methylbutoxy,
neopentyloxy, isopentyl, aryloxy, 4-fluorophenoxy, and aryl
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of chlorine and fluorine; and
R.sup.3 is hydrogen.
12. A compound according to claim 3 wherein X is O; X.sup.1 is
selected from the group consisting of S(O).sub.2 and
S(O)(NR.sup.10); R.sup.9 is alkyl; X.sup.2 is selected from the
group consisting of hydrogen and fluorine; R is selected from the
group consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl and
haloalkyl; R.sup.1 is selected from the group consisting of alkyl,
aryl, hydroxyalkoxy and Y; Y is --OR.sup.14; R.sup.14 is selected
from the group consisting of alkenyl, alkyl, and aryl; and R.sup.3
is hydrogen.
13. A compound according to claim 3 wherein X is O; X.sup.1 is
S(O).sub.2; R.sup.9 is amino; X.sup.2 is selected from the group
consisting of hydrogen and fluorine; R is selected from the group
consisting of alkenyl, alkyl, alkynyl, aryl, arylalkyl, and
haloalkyl; R.sup.1 is selected from the group consisting of alkyl,
aryl, hydroxyalkoxy and Y; Y is --OR.sup.14; R.sup.14 is selected
from the group consisting of alkenyl, alkyl, and aryl; and R.sup.3
is hydrogen.
14. A compound according to claim 3 wherein X is O; X.sup.1 is
SO.sub.2; R.sup.9 is methyl; X.sup.2 is hydrogen; R is selected
from the group consisting of t-butyl, 3-chlorophenyl,
3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluorophenyl,
3-chloro-4-fluorophenyl, and 2,2,2-trifluoroethyl; R.sup.1 is
selected from the group of consisting of isobutoxy, isopentyloxy,
(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-prop- oxy,
3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, 4-fluorophenyl,
4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy and Y; Y
is --OR.sup.14; R.sup.14 is aryl; and R.sup.3 is hydrogen.
15. A compound according to claim 3 wherein X is O; X.sup.1 is
S(O).sub.2; R.sup.9 is amino; X.sup.2 is hydrogen; R is selected
from the group of consisting t-butyl, 3-chlorophenyl,
3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluorophenyl,
3-chloro-4-fluorophenyl, and 2,2,2-trifluoroethyl; R.sup.1 is
selected from the group consisting of isobutoxy, isopentyloxy,
(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-prop- oxy,
3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, 4-fluorophenyl,
4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy and Y; Y
is --OR.sup.14; R.sup.14 is aryl; and R.sup.3 is hydrogen.
16. A compound according to claim 3 selected from the group
consisting of
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone;
2-Benzyl4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e; 2-Benzyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)-3(2H)-pyridazi-
none;
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazin-
one;
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(Phenylpropargyl)-4-(4-fluorophenyl)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,4-Difluorobenzyl)-4-(4-fluoroph-
enyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(Methyl-2-propenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Trifluoromethylbenzyl)-4-(4-fluoro-
phenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(Cycloproplymethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(4-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Pyridylmethyl)-4-(4-fluorop-
henyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(6-Fluoroquinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]3(2H)-pyridazinone;
2-(Quinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenyl)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinethione
2-Benzyl-4-(4-fluorophen-
yl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Phenyl-2-propenyl)-4-(4-flu-
orophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(5-Chlorothiazol-2-ylmethyl)-4-
-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,3,4,4,4-Hexafluorobuten-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(2,4-Difluorophenacyl)-4-(4-fluorophenyl-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(5-Chlorothien-2-ylme-
thyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(5-Methylthien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(4-Diethylaminophenacyl)-4-(4-fluorophenyl)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,4,5,6-Pentafluorobenzy-
l)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(Phenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-(4-Chlorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(Propargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(4-Cyanophenacyl)-4-(4-fluorophenyl)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2(.alpha.-Methyl-4-fluorobenz-
yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Phenethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone;
2-Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-Benzyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Trifluoromethoxyphe-
nacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Trifluoromethylphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-[2-(Benzo[b]thien-3-yl)-2-oxoethyl]-4-(4-fluoro-
phenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(3,3-Dimethyl-2-oxobutyl)-4-(4-fluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Thienylmethyl)-4-(4-fluorop-
henyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Benzo[b]thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2,4-Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-me-
thyl-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4--
(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyridazinone;
2-Benzyl-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluoro-
phenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy-
)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-
-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2,4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyrid-
azinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminos-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(2-propoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-
phenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfinyl)phenyl]--
3(2H)-pyridazinone;
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-methylphenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-flu-
orophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-Benzyl-4-(2-propylamino)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-cyclohe-
xyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-cyclopentyloxy-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-morpholino)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,3-Trifluoro-2-propen-1-yl)]-4--
(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2,4-Bis(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-cyclopropyhnethoxy-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-propen-1-oxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-flu-
oro-.alpha.-methylbenzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne;
2-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2,5-Bis[4-(methylsulfonyl)phenyl]-4-(4-fluorophenyl-
)-3(2H)-pyridazinone;
2-(3-Methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Trifluoromethyl-4-nitrophenyl)-
-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-[3-(Methylsulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-chlorop-
henyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(5-Chloro-2-thienyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-Trifluoromethylphenyl)-4-(4-chlorophenyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-c-
hlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(5-Nitro-2-thienyl)-4-(4-fluorophenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4--
(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Benzothienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(3,4-Diflorophienyl)-4-(4-fluorophenoyl)-5-[-
4-(methylsulfonyl)phe nyl]-3(2H )-pyridazinone;
2-(3-Bromophenyl)-4-(4-flu-
orophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,5-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(3-Chlorphenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(4-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Acetoxybenzyl)-4-(4-fluor-
ophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Hydroxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
2-(3-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3,4,4-Trifluoro-3-butenyl)-4-(4-fluorophenyl-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Hexynyl)-4-(4-fluo-
rophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-Cyclohexyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-Cyclopentyl-4-(4-fluorophenyl)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-Cyclobutyl-4-(4-fluorophenyl)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Methyl-2-butenyl)-4-(4-fl-
uorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2-
H)-pyridazinone,
2-(Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(3-Cyclohexenyl)-4-(4-fluorophenyl)-5-[4-
-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorobenzyl)-4-(4-fl-
uorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3-Dihydro-1H-inden-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-(2,3-Dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Tetrahydro-2H-pyran--
4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(2-Adamantyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(3-Methylcyclopentyl)-4-(4-fluorophenyl)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(1-Methylcyclopentyl)-4-(-
4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(metllylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(6-methyl-3-heptenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4--
(3-cyclopropylidenepropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone-
;
2-(3,4-Difluorophenyl)-4-(5-methyl-3-hexenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(5-methylhexyl)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-1-methyl-2E-propenyl)-4-
-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(1,1,2-Trifluoro-2-propenyl)-4-(4-fluorophen-
yl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,3-Difluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(.alpha.-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-
-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(1-Cyclohexenylmethyl)--
4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(.alpha.-Methyl-2,3,4-trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(.alpha.-Methyl-3,5-difluorobenzyl)-4-
-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(.alpha.-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(3-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-
-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorobenzyl)-4-(4-fluoro-
phenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,4,6-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,4,5-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,4-Trifluorobenzyl)-4-(4-fluo-
rophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4,4,4-Trifluoro-3-methyl-2E-butenyl)-4-(4-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Biphenyl)-4-(4-fluorophenyl)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Bromophenyl)-4-(4-fluoroph-
enyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(4-t-Butylphenyl)-4-(4-fluorophenyl)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Chlorophenyl)-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-(3-Vinylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(2-Formylphenyl)-4-(4-fluorophenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Nitrophenyl)-4-(4-fluorophenyl-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-
-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-(5-Methyl-2-thienyl))-4(4-fluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Biphenyl)-4-(4-fluorophenyl-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(5-Dimethylphenyl)-4--
(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Thienyl)-4-(4-fluorophenyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Trifluoromethylphenyl-
)-4-(4-fluorophenyl)-5-[4-(metylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[4-(1-Pyrroyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(5-Chloro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Methylphenyl)-4-(4-fluorophenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-e-
thyl-1-hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
2-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-flu-
orophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Furyl)-4-(4-fluorophenyl)-5-[.sup.4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone;
2-(3-Fluoro-4-methoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Fluorophenyl)-4-(4-fluorophenyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[4-(Aminosulfonyl)phenyl-
]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(3,5-Dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluoro-3-methylphenyl)-4-(4-f-
luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;:
2-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;:
2-(1-Adamantyloxycarbonyl)--
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fluorophen-
oxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-phenoxymethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
2-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-methylpropylthiomethyl)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2--
propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(3-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-(3-Bromophenyl)-4-(2-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4--
(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone-
;
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(benz-
oyloxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4--
(3,5-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-trifluoromethylphenyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-
-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-methylphenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-vinylphenyl)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[3-(trifl-
uoromethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methy-
lphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1-oxo-1,3-di-
hydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-propenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-buten-2-yl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzy-
l)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-
-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-b-
enzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-(4-Fluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(phenylethynyl)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-cyclohexyl-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-be-
nzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-5-[4-(m-
ethylsulfonyl)phenyl]-4-vinyl-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-
-(2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(1-propynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-(3,4-Difluorophenyl)-4-t-butyl-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-cyclohexyl-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fl-
uorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluoro-3-m-
ethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl-
)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-
-(3,5-difluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone;
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-
-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4--
(phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3,.sup.4-difluorobenzyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(-
3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-[4-Fluoro-3-(methylthio)phenyl]-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-p-
yridazinone;:
2-(2,2,2-Trifluoroethyl)-4-(2,2-ditnethylpropoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-metho-
xyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-fluoro-5-trifluoromethylphenoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-cyano-
phenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-pyridyloxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[4-(met-
hylsulfonyl)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-phenylphenoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[2-(methylthio)ethoxy]-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(-
phenyhnethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-furlmethoxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[2-(3,4-dimethoxyphenyl)etho-
xy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[2-(4-morpholino)ethoxy)]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)-
ethoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[4-(carboxamido)phenoxy)]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1-indanyloxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[-
4-(acetamido)phenoxy)]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1-methylcyclopropylmethox-
y)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3,3-dimethylbutoxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-chlorophenoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-brom-
ophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyclopentylthio)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthi-
o)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-phenylnethylthio-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenylthio)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyc-
lohexylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenylthio)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,2,2-trifluo-
roethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(tert-butylthio)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-acetamidophenylthio)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(-
2-propylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-methylprop-1-ylthio)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-amino-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-methoxypr-
opylatino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyclopentylamino)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyclobutylamino)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3,4--
dimethoxyphenethylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyclohexylamino)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethylain-
ino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-tetrahydrofurfiurylamino)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(cyclopropylmet-
hylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,3-dihydro-1H-inden-1-ylamino)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(1-piperidi-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxypropylamino)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[3-(lH-imidazol-1-yl)-
propylamino]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2R-hydroxylpropylamino)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-cyanoethylamino)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-
-4-(4-cyanoanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-[3-methoxy-5-(trifluoromethyl)anilino]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-anili-
no-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,5-dimethoxyphenylamino)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-fluoroanilino)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-
-4-(2,4-difluoroanilino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,3,5-trifluoroanilino)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(4-fluoroanilino)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(3-thienyl)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(2-benzofuranyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(1-oxo-1,3-dih-
ydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(5-chloro-2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-Benzyl-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
2-Benzyl-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone;
2-Benzyl-4-(4-trifluormethylphenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-Benzyl-4-(2-methoxyphenyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-Benzyl-4-(3,4-dimethylphenyl)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(3-fluoro-4-methoxyplienyl)-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(2-methoxypyrid-
-3-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne;
2-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyridazi-
none;
2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(t-butoxy)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(cyclo-
hexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2,2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-octyn-1-yloxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-[2-(dimet-
hylamino)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-[2-methyl-1-(1-methylethyl)propoxy]-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(phenoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-[3-(dimethylam-
ino)phenoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-methyl-1-but-
oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-
-[2-(isopropoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-methyl-3-penten-1-yloxy)--
5-[4-(methylsulfonyl)phenyl]-5-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)--
4-[3-(methoxy)butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;:
2-(4-Fluorophenyl)-4-(1-piperidinyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(1-pyrrolidinyl)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-methy-
lphenylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-pyridylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(3-Chlorophenyl)-4-(phenylmethylthio)-5-[4-(methylsulfonyl)-
phenyl]-5(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-furylmethylthio)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-]2-(methy-
lpropyl)thio]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(cyclopentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
2-(3-Chlorophenyl)-4-(2-methylpropyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(cyclopentylmethyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-cyclopenty-
lethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(3-Chlorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
2-(3-Chlorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-fluorobenzyl)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-methylphenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4--
(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(benzyloxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methylbuto-
xy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(Tetrahydro-2H-pyrano-2-yl)-4-(4-
-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-(4-Fluorophenyl)phenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-
-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorobenzyl)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5--
[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3--
fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-fl-
uoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4--
(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-methylb-
utyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-
-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-methyl-
propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-fluo-
rophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aininosulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-
-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-me-
thylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(-
aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-fluo-
rophenoxy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,3-Difluoro-2-propenyl)]-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-[2-(2-propoxy)eth-
oxy]-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-fluorophenoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-methylpropo-
xy)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-hydroxy-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-cyclopropylmetho-
xy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-cyclopropyl-1-ethoxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-cyclopropanomethoxy-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-cyclopropane-
-1-ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-(3-Chlorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-methy-
l-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-methyl-3-p-
entenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(1,5-hexadienyl-3-oxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(5-methyl-2-hex-
yloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-thioisopropyl-1-ethoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-methythhio-- 1-hexyl
oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-trifluoromethyl-1-but-
oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-ethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone;
2-(3,4-Difluorophenyl)-4-(4-methyl-1-pentyloxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-methyl-2-pentyl-
oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-cyclopentyl-1-ethoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-cyclopent-2-enyl-1-e-
thoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(2-Methoxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-
-(metylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2-Methoxyimino-2-phenylethy-
l)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimet-
hylpropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]--
3(.sup.2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4--
(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-m-
ethylpropoxy)--S-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,3,3-Trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-
-[4-(dimethylamino)methylaminosulfonylphenyl]-3(2H)-pyridazinone;
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methylamino-
sulfonylphenyl]-3(2H)-pyridazinone;
(4-Fluorophenyl)-5-[4-(methylselenonyl-
)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-fluorophenyl)-5-[-
4-(methylsulfonyl)phenyl]-.sup.3(.sup.2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-[2-(methoxyimino)-
-1-propoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone; and
2-(4-Fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone.
17. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 1 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 2 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of the
compound of claim 3 and a pharmaceutically acceptable carrier.
20. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of claim 1.
21. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of claim 2.
22. A method for inhibiting prostaglandin biosynthesis comprising
administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of claim 3.
23. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, adhesions, and cancer comprising
administering to a therapeutically effective amount of a compound
of claim 1.
24. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, adhesions, and cancer comprising
administering to a therapeutically effective amount of a compound
of claim 2.
25. A method for treating pain, fever, inflamation, rheumatoid
arthritis, osteoarthritis, adhesions, and cancer comprising
administering to a therapeutically effective amount of a compound
of claim 3.
26. A method of preparing a compound of formula III 42wherein X is
selected from the group consisting of O, S, --NR.sup.4,
--NOR.sup.a, and --NNR.sup.bR.sup.c; R.sup.4 is selected from the
group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and
heterocyclic alkyl; R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of alkyl, aryl, arylalkyl,
cycloalkyl, and cycloalkylalkyl; X.sup.1 is selected from the group
consisting of S(O).sub.2, S(O)(NR.sup.10), S(O), Se(O).sub.2,
P(O)(OR.sup.11), and P(O)(NR.sup.12R.sup.13); R.sup.9 is selected
from the group consisting of alkenyl, alkoxy, alkyl, alkynyl,
amino, cycloalkenyl, cycloalkyl, dialkylamino, --NHNH.sub.2, and
--NCHN(R.sup.10)R.sup.11; R.sup.10, R.sup.11, R.sup.12, and
R.sup.13 are independently selected from the group consisting of
hydrogen, alkyl, and cycloalkyl, or R.sup.12 and R.sup.13 can be
taken together, with the nitrogen to which they are attached, to
form a 3-6 membered ring containing 1 or 2 heteroatoms selected
from the group consisting of O, S, and NR.sup.7; X.sup.2 is
selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl and halogen; R is selected from the group consisting of
alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy,
arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy,
aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl,
carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkenyl, haloalkoxyhydroxyalkyl,
haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy,
heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5, --(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.s- up.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5, --R.sup.6R.sup.7,
--(CH.sub.2).sub.nC.ident.CR.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub- .m(CH.sub.2).sub.nR.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m(CH.sub.2).s- ub.nR.sup.7, and
--(CH.sub.2).sub.n(CHX').sub.m(CH.sub.2).sub.nR.sup.7; R.sup.5 is
selected from the group consisting of alkenyl, alkyl, alkynyl,
aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl,
haloalkynyl, heterocyclic, and heterocyclic alkyl; R.sup.6 is
selected from the group consisting of alkenylene, alkylene,
halo-substituted alkenylene, and halo-substituted alkylene; R.sup.7
is selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,
heterocyclic, and heterocyclic alkyl; R.sup.d and R.sup.e are
independently selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl,
haloalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen; n
is an integer from 0-10; m is an integer from 0-5; R.sup.1 and
R.sup.3 are independently selected from the group consisting of
hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl,
alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl,
aminoalkoxy, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl,
arylalkynyl, cyano, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl,
hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylthio, mercaptoalkoxy,
nitro, and Y; Y is selected from the group consisting of
--OR.sup.14, --SR.sup.14, --C(R.sup.16)(R.sup.17)R.sup.14,
--C(O)R.sup.14, --C(O)OR.sup.14, --N(R.sup.16)C(O)R.sup.14,
--NC(.sup.16)R.sup.14, and --N(R.sup.16)R.sup.14; R.sup.14 is
selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclic, heterocyclic alkyl and NR.sup.18R.sup.19; and
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and
heterocyclic alkyl; comprising the step of treating a compound of
formula III wherein R is hydrogen with an alkylating agent.
27. The method according to claim 26 wherein the alkylating agent
has the formula R.sup.99-Q wherein Q is a leaving group and
R.sup.99 is selected from the group consisting of methyl, ethyl,
1,1,1-trifluoroethyl, cyclopropylmethyl, 3-(2-methyl)propenyl,
4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl,
2,2-dimethyl-3-oxo-4-butyl, 2,3,3,4,4,4-hexafluorobuten-1-yl,
propargyl, phenylpropargyl, phenyl, phenethyl, 1-phenylpropen-3-yl,
benzyl, .alpha.-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl,
4-trifluomethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl,
2-trifluoromethylbenzyl, 2,4-difluorobenzyl, 2,4-difluorophenacyl,
4-trifluomethylphenacyl, phenacyl, 4-carboxyphenacyl,
4-chlorophenacyl, 4-cyanophenacyl, 4-diethylaminophenacyl,
3-thienylmethyl, 5-methylthien-2-ylmethyl,
5-chlorothien-2-ylmethyl, 2-benzo[b]thienylmethyl,
3-benzothienacyl, 5-chlorothiazol-2-ylmethyl,
5-methylthiazol-2-ylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,
4-pyridylmethyl, quinolin-2-ylmethyl, and
fluoroquinolin-2-ylmethyl.
28. The method according to claim 26 wherein the alkylating agent
has the formula R.sup.99-Q wherein Q is a leaving group and
R.sup.99 is selected from the group consisting of methyl, ethyl,
1,1,1-trifluoroethyl, cyclopropylmethyl, 3-(2-methyl)propenyl,
4-(2-methyl)but-2-enyl, 1,1-dichloropropen-3-yl,
2,3,3,4,4,4-hexafluorobuten-1-yl, propargyl, phenylpropargyl,
phenyl, phenethyl, 1-phenylpropen-3-yl, benzyl,
.alpha.-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl,
4-trifluomethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl,
2,4-difluorobenzyl, 2,4-difluorophenacyl, 4-trifluomethylphenacyl,
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.
29. The method according to claim 28 wherein the alkylating agent
has the formula R.sup.99-Q wherein Q is a leaving group and
R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, 3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl,
1,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluorobu- ten-1-yl,
propargyl, phenylpropargyl, phenyl, benzyl,
.alpha.-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.
30. The method according to claim 26 wherein the alkylating agent
has the formula R.sup.99-Q wherein Q is a leaving group and
R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, phenyl, benzyl,
.alpha.-methyl-4-fluorobenzyl, 4-fluorobenzyl, 4-fluorophenyl, and
2,4-difluorobenzyl.
31. The method according to claim 26 wherein the alkylating agent
has the formula R.sup.99-Q wherein Q is a leaving group and
R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, benzyl, and 4-fluorophenyl.
32. A method for regioselectively preparing a 4,5-disubstituted
pyridazinone comprising the steps of a) treating a compound of
formula IV 43wherein R.sup.98 is an alkyl or aryl group; and X is a
leaving group; with a nucleophilic agent to displace the X group;
b) converting the --OR.sup.98 to a leaving group; and c) treating
the copound with a second nucleophilic agent to provide the
4,5-disubstituted pyridazinone.
33. The method according to claim 32 wherein the benzyl group is
removed using a Lewis acid.
34. A method for regioselectively preparing a 4,5-disubstituted
pyridazinone comprising the steps of treating a compound of formula
V 44wherein R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl,
alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl,
aminoalkoxy, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl,
arylallynyl, cyano, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl,
hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylthio, mercaptoalkoxy,
nitro, and Y; Y is selected from the group consisting of
--OR.sup.14, --SR.sup.14, --C(R.sup.16)(R.sup.17)R.sup.14,
--C(O)R.sup.14, --C(O)OR.sup.14, --N(R.sup.16)C(O)R.sup.14,
--NC(R.sup.16)R.sup.14, and --N(R.sup.16)R.sup.14; R.sup.14 is
selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclic, heterocyclic alkyl and NR.sup.18R.sup.19; and
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and
heterocyclic alkyl; X.sup.1 is selected from the group consisting
of S(O).sub.2, S(O)(NR.sup.10), S(O), Se(O).sub.2, P(O)(OR.sup.11),
and P(O)(NR.sup.12R.sup.13); R.sup.9 is selected from the group
consisting of alkenyl, alkoxy, alkyl, alkynyl, amino, cycloalkenyl,
cycloalkyl, dialkylamino, --NHNH.sub.2, and
--NCHN(R.sup.10)R.sup.11; and R.sup.10, R.sup.11, R.sup.12, and
R.sup.13 are independently selected from the group consisting of
hydrogen, alkyl, and cycloalkyl, or R.sup.12 and R.sup.13 can be
taken together, with the nitrogen to which they are attached, to
form a 3-6 membered ring containing 1 or 2 heteroatoms selected
from the group consisting of O, S, and NR.sup.7; R.sup.7 is
selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,
heterocyclic, and heterocyclic alkyl; with a hydrazine having the
formula RNHNH.sub.2 wherein R is selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy,
arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy,
aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl,
carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkenyl, haloalkoxyhydroxyalkyl,
haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy,
heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl,
--(CH.sub.2).sub.nC(O)R.sup.5, --(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.s- up.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5, --R.sup.6R.sup.7,
--(CH.sub.2).sub.nC.ident.CR.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub- .m(CH.sub.2).sub.nR.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m(CH.sub.2).s- ub.nR.sup.7, and
--(CH.sub.2).sub.n(CHX').sub.m(CH.sub.2).sub.nR.sup.7; R.sup.5 is
selected from the group consisting of alkenyl, alkyl, alkynyl,
aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl,
haloalkynyl, heterocyclic, and heterocyclic alkyl; R.sup.6 is
selected from the group consisting of alkenylene, alkylene,
halo-substituted alkenylene, and halo-substituted alkylene; R.sup.7
is selected from the group consisting of hydrogen, alkenyl, alkyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl,
heterocyclic, and heterocyclic alkyl; R.sup.d and R.sup.e are
independently selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl,
haloalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen; n
is an integer from 0-10; m is an integer from 0-5; to furnish the
pyridazinone of formula III 45wherein X.sup.1, R, R.sup.1, R.sup.3,
and R.sup.9 are as previously defined; X is selected from the group
consisting of O, S, --NR.sup.4, --NOR.sup.a, and
--NNR.sup.bR.sup.c; R.sup.4 is selected from the group consisting
of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and
heterocyclic alkyl; R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of alkyl, aryl, arylalkyl,
cycloalkyl, and cycloalkylalkyl; and X.sup.2 is selected from the
group consisting of hydrogen, alkenyl, alkyl, alkynyl and
halogen.
35. A compound of formula VI 46or a pharmaceutically acceptable
salt, ester, or prodrug thereof, wherein R is selected from the
group consisting of alkyl, aryl, arylalkyl, haloalkyl, and
haloalkenyl; R.sup.1 is selected from the group consisting of
alkoxy, aminoalkylcarbonyloxyalk- oxy,
carboxyalkylcarbonyloxyalkoxy, hydroxyalkoxy, hydroxyalkyl, and
phosphonatoalkoxy, R.sup.9 is selected from the group consisting of
alkyl, alkylcarbonylamino, and amino.
36. A compound according to claim 35 wherein R is aryl; R.sup.1 is
hydroxyalkoxy; and R.sup.9 is selected from the group of consisting
of alkyl and amino.
37. A compound according to claim 35 wherein R is aryl; R.sup.1 is
hydroxyalkoxy; and R.sup.9 is methyl.
38. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from the group consisting of halogen and haloalkyl;
R.sup.1 is hydroxyalkoxy; and R.sup.9 is selected from the group
consisting of alkyl and amino.
39. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1 or 2 substituents independently selected from
the group of consisting chlorine and fluorine; R.sup.1 is
hydroxyalkoxy; and R.sup.9 is selected from the group consisting of
alkyl and amino.
40. A compound according to claim 38 selected from the group
consisting of
2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1--
propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-m-
ethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3,4-Difluorophenyl)-4-(3-hydrox-
y-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-hydroxy-2-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-buto-
xy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methy-
l-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(3-hydro-
xy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-buto-
xy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-pro-
poxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(2-hydr-
oxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-pro-
poxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-b-
utoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-hydroxy-3-meth-
yl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-m-
ethyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
(S)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-p-
ropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydrox-
y-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(am-
inosulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-Chloro-4-fluorophenyl)-4--
(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi-
none;
(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[-
4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-Chlorophenyl)-4-(3-h-
ydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone-
;
(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-meth-
yl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethy-
l-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dim-
ethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosu-
lfonyl)-phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(3-hydro-
xy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone-
;
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-hydroxy-2-
,2-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Dichlorophenyl)-4-(3-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[(3-Trifluoromethyl)phenyl]-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Dichlorophenyl)-4-(2-hydroxy-
-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R,
S)-2-(4-Fluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-hydroxy-1-butoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[3-(Trifluoromethyl)phenyl]-4--
(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-bu-
toxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(4-fluorophenyl)-4-(2-hydroxy-3-m-
ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-
-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-chloro-4-fluorophenyl)-4--
(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
(S)-2-(3-fluoro-4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3,4-dichlorophenyl)-4-(-
2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne;
(S)-2-(3-trifluoromethyl-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butox-
y)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3,4-Difluorophenyl)-4-(2-hyd-
roxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
(R)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-
-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-fluoro-4-chlorophenyl)-4--
(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
(R)-2-(3,4-dichlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(3-trifluoromethyl-4-fluoroph-
enyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
(R)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)--
4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
2-(4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-chlorophenyl)-4-[(S)-
-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
2-(3-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-chlorophenyl)-4-[(S)-2,3-d-
ihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e;
2-(3-bromophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-trifluoromethylphenyl)-4-[(S)-2,3-
-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
2-(3-chloro-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluoro-4-chlorophenyl-
)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
2-(3,4-dichlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-bu-
toxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-trifluoromethyl-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-buto-
xy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromo-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-[(R)-2-
,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone;
2-(4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-chlorophenyl)-4-[(R)-2,3-dih-
ydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-chlorophenyl)-4-[(R)-2,3-dihydroxy-
-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-(3-trifluoromethylphenyl)-4-[(R)-2,3-d-
ihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e;
2-(3-chloro-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluoro-4-chlorophenyl)--
4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
2-(3,4-dichlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-buto-
xy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-fluoro-3-trifluoromethylphenyl)-4-[()-2,3-dihydroxy-3-methyl-1-butox-
y]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromo-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-Difluorophenyl)-4-(4-hyd-
roxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone-
;
2-(4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
2-(4-chlorophenyl)-4-(4-hydroxy-4-methyl-1--
pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
2-(3-chlorophenyl)-4-(4-hydroxy-4-methyl-1-p-
entyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(3-trifluoromethylphenyl)-4-(4-hydroxy-4-me-
thyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-chloro-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluoro-4-chlorophenyl)-4-(4-hy-
droxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e;
2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-fluoro-3-trifluoromethylphenyl)-4-
-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone; and
2-(3-bromo-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
41. A compound according to claim 35 wherein R is haloalkyl; and
R.sup.1 is hydroxyalkoxy; and R.sup.9 is selected from the group of
consisting of alkyl and amino.
42. A compound according to claim 41 selected from the group
consisting of
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2--
methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-hydrox-
y-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hy-
droxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hy-
droxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone; and
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-
-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone.
43. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from the group consisting of halogen and haloalkyl;
R.sup.1 is aminoalkylcarbonyloxyalkoxy; and R.sup.9 is selected
from the group of consisting of alkyl and amino.
44. A compound according to claim 43 selected from the group
consisting of
2-(3,4-Difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-fluorophenyl)-4-[3-(2-amino-
acetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
2-(4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluorophenyl)-4-[3-(2-amino-
acetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
2-(3-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromophenyl)-4-[3-(2-aminoa-
cetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne;
2-(3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-chloro-4-fluorophen-
yl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(3-fluoro-4-chlorophenyl)-4-[3-(2-aminoacetyloxy)--
3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-dichlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(4-fluoro-3-trifluoromethylphe-
nyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)pheny-
1]-3(2H)-pyridazinone; and
2-(3-bromo-4-fluorophenyl)-4-[3-(2-aminoacetylo-
xy)-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
45. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from the group consisting of halogen and haloalkyl;
R.sup.1 is carboxyalkylcarbonyloxyalkoxy; and R.sup.9 is selected
from the group of consisting of alkyl and amino.
46. A compound according to claim 45 selected from the group
consisting of
2-(3,4-Difluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]ox-
y}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxyprop-
anoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
2-(4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihyd-
roxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
2-(3-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2-
,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-chlorophenyl)-4-[3-{[(2R,3R)-3-c-
arboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-bromophenyl)-4-[3-{[(2R,-
3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butox-
y]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-trifluoromethylphenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropano-
yl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-chloro-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-
-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-fluoro-4-chlorophenyl)-4-[3-{[(2R,-
3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butox-
y]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3,4-dichlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]ox-
y}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
2-(3-trifluoromethyl-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-
-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone; and
2-(3-bromo-4-fluorophenyl)-4-[3-
-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl--
1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
47. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from the group consisting of halogen and haloalkyl;
R.sup.1 is phosphonatoalkoxy; and R.sup.9 is selected from the
group of consisting of alkyl and amino.
48. A compound according to claim 47 selected from the group
consisting of
3-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-
-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-p-
yridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-p-
yridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-p-
yridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-p-
yridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-bromophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-py-
ridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-di-
hydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-di-
hydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-fluoro-4-chlorophenyl)-5-[4-(methylsulfoiyl)phenyl]-3-oxo-2,3-di-
hydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-
-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
3-({2-(3-trifluoromethyl-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-o-
xo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate; and
3-({2-(3-bromo-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-
-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate.
49. A compound according to claim 35 wherein R is phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from the group consisting of halogen and haloalkyl;
R.sup.1 is hydroxyalkoxy; and R.sup.9 is alkylcarbonylamino.
50. A compound according to claim 49 selected from the group
consisting of
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3--
on-5-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy--
3t-methyl-1-butoxy)-2H-pyridazin-3-on-5-oxy]phenyl]sulfonyl]acetamide,
sodium salt;
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propox-
y)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridaz-
in-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-py-
ridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3-Chloro-4-fluoroph-
enyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfo-
nyl]acetamide, sodium salt;
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methy-
l-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-
-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
N-[[4-[2-(2,2,2-Trifluoro-
ethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulf-
onyl]acetamide;
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-pr-
opoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium
salt;
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-p-
yridazin-3-on-5-yl]phenyl]sulfonyl]acetamide; and
N-[[4-[2-(2,2,2-Trifluor-
oethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl-
]sulfonyl]acetamide, sodium salt.
51. A compound according to claim 35 wherein R is selected from the
group consisting of haloalky and phenyl optionally substituted with
1, 2, 3, 4, or 5 substituents independently selected from the group
consisting of halogen and haloalkyl; R.sup.1 is alkoxy; and R.sup.9
is selected from the group consisting of alkyl, alkylcarbonylamino,
and amino.
52. A compound according to claim 51 selected from the group
consisting of
2-(3,4-Difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-
-3-on-5-yl]phenyl]sulfonyl]acetamide;
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-m-
ethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]-sulfonyl]acetamide,
sodium salt;
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4-(2-methyl-1-propoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(3-Chloro-4-fluorophenyl)-4--
(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(.sup.2H)-pyridazinone;
2-(3,4-Dichlorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
2-(3,4-Dichlorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-[3-(Trifluoromethyl)phenyl]-4--
(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
and
2-[3-(Trifluoromethyl)phenyl]-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone.
53. A compound according to claim 35 wherein R is tert-butyl;
R.sup.1 is selected from the group consisting of
aminoalkylcarbonyloxyalkoxy, carboxyalkylcarbonyloxyalkoxy,
hydroxyalkoxy, and phosphonatoalkoxy; and R.sup.9 is selected from
the group consisting of alkyl, alkylcarbonylamino, and amino.
54. A compound according to claim 53 selected from the group
consisting of
2-(tert-Butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
2-(tert-Butyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-b-
utoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
2-(tert-butyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-3-met-
hylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one; and
3-({2-(tert-butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-
-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate.
55.
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
Description
[0001] This application is a divisional application of U.S. Ser.
No. 09/427,768 filed Oct. 27, 1999 which is a continuation-in-part
application of U.S. Ser. No. 09/261,872 filed Mar. 3, 1999 which is
a continuation-in-part of U.S. Ser. No. 09/179,605 filed Oct. 27,
1998, which is a continuation-in-part application of U.S. Ser. No
09/129,570 filed Aug. 5, 1998, which is based in-part on
provisional application 60/056,733 filed Aug. 22, 1997.
TECHNICAL FIELD
[0002] The present invention encompasses novel pyridazinone
compounds useful in the treatment of cyclooxygenase-2 mediated
diseases. More particularly, this invention concerns a method of
inhibiting prostaglandin biosynthesis, particularly the induced
prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2,
COX-2) protein.
BACKGROUND OF THE INVNTION
[0003] The prostaglandins are extremely potent substances which
produce a wide variety of biological effects, often in the
nanomolar to picomolar concentration range. The discovery of two
forms of prostaglandin endoperoxide H synthase, isoenzymnes PGHS-1
and PGHS-2, that catalyze the oxidation of arachidonic acid leading
to prostaglandin biosynthesis has resulted in renewed research to
delineate the role of these two isozymes in physiology and
pathophysiology. These isozymnes have been shown to have different
gene regulation and represent distinctly different pro staglandin
biosynthesis pathways. The PGHS-1 pathway is expressed
constitutively in most cell types. It responds to produce
prostaglandins that regulate acute events in vascular homeostasis
and also has a role in maintaining normal stomach and renal
fuinction. The PGHS-2 pathway involves an induction mechanism which
has been linked to inflamm-ation, mitogenesis and ovulation
phenomena.
[0004] Prostaglandin inhibitors provide therapy for pain, fever,
and inflammation, and are useful therapies, for example in the
treatment of rheumatoid arthritis and osteoarthritis. The
non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen,
naproxen and fenamates inhibit both isozymes. ihibition of the
constitutive enzyme PGHS-1 results in gastrointestinal side effects
including ulcers and bleeding and incidence of renal problems with
chronic therapy. Inhibitors of the induced isozyme PGHS-2 may
provide anti-inflammatory activity without the side effects of
PGHS-1 inhibitors.
[0005] The problem of side-effects associated with NSAID
administration has never completely been solved in the past.
Enteric coated tablets and co-administration with misoprostol, a
prostaglandin derivative, have been tried in an attempt to minimize
stomach toxicity. It would be advantageous to provide compounds
which are selective inhibitors of the induced isozyme PGHS-2.
[0006] The present invention discloses novel compounds which are
selective inhibitors of PGHS-2.
SUMMARY OF THE INVENTION
[0007] The present invention discloses pyridazinone compounds which
are selective inhibitors of cyclooxygenase-2 (COX-2). The compounds
of the present invention have the formula I: 2
[0008] or a pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein
[0009] X is selected from the group consisting of O, S, --NR.sup.4,
--NOR.sup.a, and --NNR.sup.bR.sup.c;
[0010] R.sup.4 is selected from the group consisting of alkenyl,
alllyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloallrylalkyl, heterocyclic, and heterocyclic
alkyl;
[0011] R.sup.a, R.sup.b, and R.sup.c are independently selected
from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl,
and cycloalkylalkyl;
[0012] R is selected from the group consisting of alkenyl, alkoxy,
alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl,
alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy,
arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy,
aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl,
carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl,
haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic,
heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy,
hydroxyalkyl, hydroxyiminoalkoxy, --(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nCH(OH)R.sup.5,
--(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.s- up.5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5, --R.sup.6R.sup.7,
--(CH.sub.2).sub.nC.ident.CR.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub- .m(CH.sub.2).sub.pR.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m(CH.sub.2).s- ub.pR.sup.7, and
--(CH.sub.2).sub.n(CHX').sub.m(CH.sub.2).sub.pR.sup.7;
[0013] R.sup.5 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl,
haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic
alkyl;
[0014] R.sup.6 is selected from the group consisting of alkenylene,
alkylene, halo-substituted alkenylene, and halo-substituted
alkylene;
[0015] R.sup.7 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl,
haloalkyl, heterocyclic, and heterocyclic alkyl;
[0016] R.sup.d and R.sup.e are independently selected from the
group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl,
arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and
heterocyclic alkyl;
[0017] X' is halogen;
[0018] m is an integer from 0-5;
[0019] n is an integer from 0-10; and
[0020] p is an integer from 0-10; and
[0021] R.sup.1, R.sup.2, and R.sup.3 are independently selected
from the group consisting of hydrogen, alkenyl, alkoxyalkyl,
alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl,
alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaaminoalkyl,
aminoalkoxy, aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl,
arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy,
cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl,
haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic,
hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl,
mercaptoalkoxy, nitro, phosphonatoalkoxy, Y, and W; provided that
one of R.sup.1, R.sup.2, or R.sup.3 must be W, and further provided
that only one of R.sup.1, R.sup.2, or R.sup.3 is W;
[0022] W is selected from the group consisting of 3
[0023] X.sup.1 is selected from the group consisting of S(O).sub.2,
S(O)(NR.sup.10), S(O), Se(O).sub.2, P(O)(OR.sup.11), and
P(O)(NR.sup.12R.sup.13);
[0024] X.sup.2 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl and halogen;
[0025] R.sup.9 is selected from the group consisting of alkenyl,
alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino,
cycloalkenyl, cycloalkyl, dialkylamino, --NHNH.sub.2, and
--NCHN(R.sup.10)R.sup.11;
[0026] R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrogen, alkyl, and
cycloalkyl, or R.sup.12 and R.sup.13 can be taken together, with
the nitrogen to which they are attached, to form a 3-6 membered
ring containing 1 or 2 heteroatoms selected from the group
consisting of O, S, and NR.sup.7;
[0027] Y is selected from the group consisting of --OR.sup.14,
--SR.sup.14, --C(R.sup.16)(R.sup.17)R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --N(R.sup.16)C(O)R.sup.14, --NC(R.sup.16)R.sup.14,
and --N(R.sup.16)R.sup.14;
[0028] R.sup.14 is selected from the group consisting of hydrogen,
alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclic, heterocyclic alkyl, hydroxyalkyl, and
NR.sup.18R.sup.19; and
[0029] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and
heterocyclic alkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0030] All patents, patent applications, and literature references
cited in the specification are hereby incorporated by reference in
their entirety. In the case of inconsistencies, the present
disclosure, including definitions, will prevail.
[0031] In one embodiment, compounds of the present invention have
formula I wherein,
[0032] R.sup.2 is W;
[0033] X.sup.1 is selected from S(O).sub.2, S(O), Se(O).sub.2, and
S(O)(NR.sup.10);
[0034] R.sup.9 is selected from alkenyl, alkoxy, alkyl, alkylamino,
alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, and
dialkylamino; and
[0035] X, X.sup.2, R, R.sup.1, R.sup.3, and R.sup.10 are as defined
in formula I.
[0036] In another embodiment, compounds of the present invention
have formula I wherein,
[0037] R.sup.2 is W;
[0038] W is 4
[0039] X.sup.1 is selected from S(O).sub.2, S(O), Se(O).sub.2, and
S(O)(NR.sup.10);
[0040] R.sup.9 is selected from alkenyl, alkoxy, alkyl, alkylamino,
alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, ad
dialkylamino; and
[0041] X, X.sup.2, R, R.sup.1, R.sup.3, and R.sup.10 are as defined
in formula I.
[0042] In another embodiment, compounds of the present invention
have formula I wherein,
[0043] R.sup.2 is W;
[0044] W is 5
[0045] X.sup.2 is selected from hydrogen and halogen;
[0046] R is selected from hydrogen, alkenyl, alkyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl,
arylalkyl, --(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nC.ident.CR.sup.7, and
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub.m(CH.sub.2).sub.pR.sup.7;
[0047] R.sup.1 and R.sup.3 are independently selected from
hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, halogen, nitro, and Y; and
[0048] X, X.sup.1, X', R.sup.5, R.sup.7, R.sup.9, n, m, p, and Y
are as defined in formula I.
[0049] In another embodiment, compounds of the present invention
have formula I wherein,
[0050] R.sup.2 is W;
[0051] W is 6
[0052] X.sup.2 is selected from hydrogen and halogen;
[0053] R is selected from hydrogen, alkenyl, alkyl, alkynyl,
alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyalkyl, cyanoalkyl,
haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl,
arylalkyl, and --(CH.sub.2).sub.nC(O)R.sup.5;
[0054] R.sup.1 and R.sup.3 are independently selected from
hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl, nitro, and Y;
and
[0055] X, X.sup.1, R.sup.5, R.sup.9, n, and Y are as defined in
formula I.
[0056] In another embodiment, compounds of the present invention
have formula I wherein,
[0057] R.sup.2 is W;
[0058] W is 7
[0059] X.sup.2 is selected from hydrogen and halogen;
[0060] R is selected from hydrogen, alkyl, aryl, haloalkyl,
heterocyclic, heterocyclic alkyl, and
--(CH.sub.2).sub.nC(O)R.sup.5;
[0061] R.sup.1 and R.sup.3 are independently selected from
hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonylamino,
alkylcarbonylaminoalkyl, aminocarbonylalkyl, aryl, cyano,
cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, halogen, heterocyclic, heterocyclic alkyl, nitro, and Y;
and
[0062] X, X.sup.1, R.sup.5, R.sup.9, n, and Y are as defined in
formula I.
[0063] In another embodiment, compounds of the present invention
have formula I wherein,
[0064] R.sup.2 is W;
[0065] W is 8
[0066] X.sup.2 is selected from hydrogen and halogen;
[0067] R is selected from alkyl, aryl, haloalkyl, heterocyclic,
heterocyclic alkyl, and arylalkyl wherein the aryl portion is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected
from halogen; and
[0068] R.sup.1 is selected from aryl, arylalkyl, heterocyclic,
heterocyclic alkyl, hydroxyalkoxy, and Y; and
[0069] X, X.sup.1, R.sup.3, R.sup.9, and Y are as defined in
formula I.
[0070] In another embodiment, compounds of the present invention
have formula I wherein,
[0071] R is W;
[0072] W is 9
[0073] X.sup.2 is selected hydrogen and halogen;
[0074] R is selected from the group consisting of alkyl, aryl,
haloalkyl, heterocyclic, heterocyclic alkyl and arylalkyl wherein
the aryl portion is optionally substituted with 1, 2, 3, 4, or 5
substituents selected from halogen;
[0075] R.sup.1 is selected from the group consisting of aryl,
arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkoxy, and
Y;
[0076] Y is --OR.sup.14;
[0077] R.sup.14 is selected from the group consisting of alkenyl,
alkyl, and aryl;
[0078] R.sup.3 is hydrogen; and
[0079] X, X.sup.1, and R.sup.9 are as defined in formula I.
[0080] In another embodiment, compounds of the present invention
have fornula I wherein,
[0081] R.sup.2 is W;
[0082] W is 10
[0083] X.sup.1 is S(O).sub.2;
[0084] X.sup.2 is selected from hydrogen and halogen;
[0085] R is selected from aryl, haloalkyl, heterocyclic,
heterocyclic alkyl and arylalkyl wherein the aryl portion is
optionally substituted with 1, 2, 3, 4, or 5 substituents selected
from halogen;
[0086] R.sup.1 is aryl optionally substituted with 1, 2, or 3
substituents independently selected from chlorine and fluorine;
[0087] R.sup.3 is hydrogen; and
[0088] X and R.sup.9 are as defined in formula I.
[0089] In another embodiment, compounds of the present invention
have formula I wherein,
[0090] R.sup.2 is W;
[0091] W is 11
[0092] X is O;
[0093] X.sup.1 is S(O).sub.2,
[0094] R.sup.9 is selected from the group consisting of alkyl and
amino;
[0095] X.sup.2 is selected from hydrogen and halogen;
[0096] R is selected from alkenyl, alkyl alkynyl, aryl, arylalkyl,
and haloalkyl;
[0097] R.sup.1 is selected from alkyl, aryl, arylalkyl, haloalkoxy,
hydroxyalkoxy, and Y;
[0098] Y is --OR.sup.14;
[0099] R.sup.14 is selected from alkenyl, alkyl, and aryl; and
[0100] R.sup.3 is hydrogen.
[0101] In another embodiment, compounds of the present invention
have formula I wherein,
[0102] R.sup.2 is W;
[0103] W is 12
[0104] X.sup.1 is S(O).sub.2;
[0105] R.sup.9 is selected from alkyl and amino;
[0106] X.sup.2 is selected from hydrogen and fluorine;
[0107] R is selected from haloalkyl, aryl, and alkyl;
[0108] R.sup.1 is selected from isobutyloxy, isopentyloxy,
1-(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propyloxy,
3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, aryloxy,
4-fluorophenoxy, and aryl optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
chlorine and fluorine;
[0109] R.sup.3 is hydrogen; and
[0110] X is as defined in formula I.
[0111] In another embodiment, compounds of the present invention
have formula I wherein,
[0112] R.sup.2 is W;
[0113] W is 13
[0114] X is O;
[0115] X.sup.1 is selected from S(O).sub.2 and S(O)(NR.sup.10);
[0116] R.sup.9 is alkyl;
[0117] X.sup.2 is selected from hydrogen and fluorine;
[0118] R is selected from alkenyl, alky, alkynyl, aryl, arylalkyl
and haloalkyl;
[0119] R.sup.1 is selected from alkyl, aryl, hydroxyalkoxy and
Y;
[0120] Y is --OR.sup.14;
[0121] R.sup.14 is selected from alkenyl, alkyl, and aryl;
[0122] R.sup.3 is hydrogen; and
[0123] R.sup.10 is as defined in formula I.
[0124] In another embodiment, compounds of the present invention
have formula I wherein,
[0125] R.sup.2 is W;
[0126] W is 14
[0127] X is O;
[0128] X.sup.1 is S(O).sub.2;
[0129] R.sup.9 is amino;
[0130] X.sup.2 is selected from hydrogen and fluorine;
[0131] R is selected from alkenyl, alkyl, alkynyl, aryl, arylalkyl,
and haloalkyl;
[0132] R.sup.1 is selected from alkyl, aryl, hydroxyalkoxy and
Y;
[0133] Y is --OR.sup.14;
[0134] R.sup.14 is selected from alkenyl, alkyl, and aryl; and
[0135] R.sup.3 is hydrogen.
[0136] In another embodiment, compounds of the present invention
have formula I wherein,
[0137] R.sup.2 is W;
[0138] W is 15
[0139] X is O;
[0140] X.sup.1 is SO.sub.2;
[0141] R.sup.9 is methyl;
[0142] X.sup.2 is hydrogen;
[0143] R is selected from t-butyl, 3-chlorophenyl,
3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluorophenyl,
3-chloro-4-fluorophenyl, and 2,2,2-trifluoroethyl;
[0144] R.sup.1 is selected from isobutoxy, isopentyloxy,
(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propoxy,
3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, 4-fluorophenyl,
4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy and
Y;
[0145] Y is --OR.sup.14;
[0146] R.sup.14 is aryl; and
[0147] R.sup.3 is hydrogen.
[0148] In another embodiment, compounds of the present invention
have formula I wherein,
[0149] R.sup.2 is W;
[0150] W is 16
[0151] X is O;
[0152] X.sup.1 is S(O).sub.2;
[0153] R.sup.9 is amino;
[0154] X.sup.2 is hydrogen;
[0155] R is selected from t-butyl, 3-chlorophenyl,
3,4-difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluorophenyl,
3-chloro-4-fluorophenyl, and 2,2,2-trifluoroethyl;
[0156] R.sup.1 is selected consisting of isobutoxy, isopentyloxy,
(3-methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propoxy,
3-hydroxy-3-methylbutoxy, neopentyloxy, isopentyl, 4-fluorophenyl,
4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 4-fluorophenoxy, and
Y;
[0157] Y is --OR.sup.14;
[0158] R.sup.14 is aryl; and
[0159] R.sup.3 is hydrogen.
[0160] Another embodiment of the present invention relates to
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula I or a pharmaceutically acceptable
salt, ester, amide, or prodrug thereof in combination with a
pharmaceutically acceptable carrier for inhibiting prostaglandin
biosynthesis.
[0161] Another embodiment of the invention relates to a method of
inhibiting prostaglandin biosynthesis comprising administering a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt, ester, amide, or prodrug
thereof.
[0162] Another embodiment of the invention relates to a method of
treating pain, fever, inflamation, rheumatoid arthritis,
osteoarthritis, adhesions, and cancer comprising administering a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt, ester, amide, or prodrug
thereof.
[0163] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0164] R.sup.2 is W;
[0165] W is 17
[0166] and
[0167] X, X.sup.1, X.sup.2, R, R.sup.1, and R.sup.3 are as defined
in formula I; comprising the step of treating a compound of formula
I wherein R is hydrogen with an alkylating agent.
[0168] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0169] R.sup.2 is W;
[0170] W is 18
[0171] and
[0172] X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, and R.sup.3 are as
defined in formula I;
[0173] comprising the step of treating a compound of formula I
wherein R is hydrogen with an alkylating agent, wherein the
alkylating agent has the formula R.sup.99--Q wherein Q is a leaving
group and R.sup.99 is selected from the group consisting of methyl,
ethyl, 1,1,1-trifluoroethyl, cyclopropylmethyl,
3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl,
1,1-dichloropropen-3-yl, 2,2-dimethyl-3-oxo-4-but- yl,
2,3,3,4,4,4-hexafluorobuten-1-yl, propargyl, phenylpropargyl,
phenyl, phenethyl, 1-phenylpropen-3-yl, benzyl,
.alpha.-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl,
4-trifluomethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl,
2-trifluoromethylbenzyl, 2,4-difluorobenzyl, 2,4-difluorophenacyl,
4-trifluomethylphenacyl, phenacyl, 4-carboxyphenacyl,
4-chlorophenacyl, 4-cyanophenacyl, 4-diethylaminophenacyl,
3-thienylmethyl, 5-methylthien-2-ylmethyl,
5-chlorothien-2-ylmethyl, 2-benzo[b]thienylmethyl,
3-benzothienacyl, 5-chlorothiazol-2-ylmethyl,
5-methylthiazol-2-ylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,
4-pyridylmethyl, quinolin-2-ylmethyl, and
fluoroquinolin-2-ylmethyl.
[0174] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0175] R.sup.2 is W;
[0176] W is 19
[0177] and
[0178] X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, and R.sup.3 are as
defined in formula I;
[0179] comprising the step of treating a compound of formula I
wherein R is hydrogen with an alkylating agent, wherein the
alkylating agent has the formula R.sup.99--Q wherein Q is a leaving
group and R.sup.99 is selected from the group consisting of methyl,
ethyl, 1,1,1-trifluoroethyl, cyclopropylmethyl,
3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl,
1,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluorobu- ten-1-yl,
propargyl, phenylpropargyl, phenyl, phenethyl, 1-phenylpropen-3-yl,
benzyl, .alpha.-methyl-4-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl,
4-trifluomethoxyphenacyl, 4-fluorobenzyl, 4-fluorophenyl,
2,4-difluorobenzyl, 2,4-difluorophenacyl, 4-trifluomethylphenacyl,
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.
[0180] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0181] R.sup.2 is W;
[0182] W is 20
[0183] and
[0184] X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, and R.sup.3 are as
defined in formula I; comprising the step of treating a compound of
formula I wherein R is hydrogen with an alkylating agent, wherein
the alkylating agent has the formula R.sup.99--Q wherein Q is a
leaving group and R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, 3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl,
1,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluorobuten-1-yl,
propargyl, phenylpropargyl, phenyl, benzyl,
.alpha.-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.
[0185] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0186] R.sup.2 is W;
[0187] W is 21
[0188] X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, and R.sup.3 are as
defined in formula I;
[0189] comprising the step of treating a compound of formula I
wherein R is hydrogen with an alkylating agent, wherein the
alkylating agent has the formula R.sup.99--Q wherein Q is a leaving
group and R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, phenyl, benzyl,
.alpha.-methyl-4-fluorobenzyl, 4-fluorobenzyl, 4-fluorophenyl, and
2,4-difluorobenzyl.
[0190] Another embodiment of the present invention relates to a
method of preparing a compound of formula I wherein,
[0191] R.sup.2 is W;
[0192] W is 22
[0193] X, X.sup.1, X.sup.2, R, R.sup.1, R.sup.2, and R.sup.3 are as
defined in formula I;
[0194] comprising the step of treating a compound of formula I
wherein R is hydrogen with an alkylating agent, wherein the
alkylating agent has the formula R.sup.99--Q wherein Q is a leaving
group and R.sup.99 is selected from the group consisting of
1,1,1-trifluoroethyl, benzyl, and 4-fluorophenyl.
[0195] Another embodiment of the present invention relates to a
method for regioselectively preparing a 4,5-disubstituted
pyridazinone comprising the steps of
[0196] a) treating a compound of formula IV 23
[0197] wherein R.sup.98 is an alkyl or aryl group; and X is a
leaving group;
[0198] with a nucleophilic agent to displace the X group;
[0199] b) converting the --OR.sup.98 ito a leaving group; and
[0200] c) treating the compound with a second nucleophilic agent to
provide the 4,5-disubstituted pyridazinone.
[0201] Another embodiment of the present invention relates to a
method for regioselectively preparing a 4,5-disubstituted
pyridazinone comprising the steps of
[0202] a) treating a compound of formula IV 24
[0203] wherein R.sup.98 is an alkyl or aryl group; and X is a
leaving group;
[0204] with a nucleophilic agent to displace the X group;
[0205] b) converting the --OR.sup.98 to a leaving group; and
[0206] c) treating the compound with a second nucleophilic agent to
provide the 4,5-disubstituted pyridazinone wherein the benzyl group
is removed using a Lewis acid.
[0207] Another embodiment of the present invention relates to a
method for regioselectively preparing a 4,5-disubstituted
pyridazinone comprising the steps of treating a compound of formula
V 25
[0208] wherein
[0209] R.sup.1 and R.sup.3 are independently selected from the
group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl,
alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy,
alkylcarbonylalkoxy, aminocarbonylalkyl, aryl, arylalkenyl,
arylalkyl, arylalkynyl, cyano, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyloxy,
haloalkoxy, haloalkyl, halogen, heterocyclic, heterocyclic alkyl,
hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylthio, mercaptoalkoxy,
nitro, and Y;
[0210] Y is selected from the group consisting of --OR.sup.14,
--SR.sup.14, --C(R.sup.16)(R.sup.17)R.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --N(R.sup.16)C(O)R.sup.14, --NC(R.sup.16)R.sup.14,
and --N(R.sup.16)R.sup.14;
[0211] R.sup.14 is selected from the group consisting of hydrogen,
alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclic, heterocyclic alkyl and NR.sup.18R.sup.19; and
[0212] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrogen, alkenyl, alkoxy,
alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and
heterocyclic alkyl;
[0213] X.sup.1 is selected from the group consisting of S(O).sub.2,
S(O)(NR.sup.10), S(O), Se(O).sub.2, P(O)(OR.sup.11), and
P(O)(NR.sup.12R.sup.13);
[0214] R.sup.9 is selected from the group consisting of alkenyl,
alkoxy, alkyl, alkynyl, amino, cycloalkenyl, cycloalkyl,
dialkylamino, --NHNH.sub.2, and --NCHN(R.sup.10)R.sup.11; and
[0215] R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrogen, alkyl, and
cycloalkyl, or R.sup.12 and R.sup.13 can be taken together, with
the nitrogen to which they are attached, to form a 3-6 membered
ring containing 1 or 2 heteroatoms selected from the group
consisting of O, S, and NR.sup.7;
[0216] R.sup.7 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl,
haloalkyl, heterocyclic, and heterocyclic alkyl;
[0217] with a hydrazine having the formula RNHNH.sub.2 wherein R is
selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl,
arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl,
arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl,
arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkenyl,
haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic,
heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy,
hydroxyalkyl, --(CH.sub.2).sub.nC(O)R.sup.5,
--(CH.sub.2).sub.nCH(OH)R.sup.5,
(CH.sub.2).sub.nC(NOR.sup.d)R.sup.5,
--(CH.sub.2).sub.nCH(NOR.sup.d)R.sup- .5,
--(CH.sub.2).sub.nCH(NR.sup.dR.sup.e)R.sup.5, --R.sup.6R.sup.7,
--(CH.sub.2).sub.nC.ident.CR.sup.7,
--(CH.sub.2).sub.n[CH(CX'.sub.3)].sub- .m(CH.sub.2).sub.nR.sup.7,
--(CH.sub.2).sub.n(CX'.sub.2).sub.m(CH.sub.2).s- ub.nR.sup.7, and
--(CH.sub.2).sub.n(CHX').sub.m(CH.sub.2).sub.nR.sup.7;
[0218] R.sup.5 is selected from the group consisting of alkenyl,
alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl,
haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic
alkyl;
[0219] R.sup.6 is selected from the group consisting of alkenylene,
alkylene, halo-substituted alkenylene, and halo-substituted
alkylene;
[0220] R.sup.7 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl,
haloalkyl, heterocyclic, and heterocyclic alkyl;
[0221] R.sup.d and R.sup.e are independently selected from the
group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl,
arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and
heterocyclic alkyl;
[0222] X' is halogen;
[0223] n is an integer from 0-10;
[0224] m is an integer from 0-5;
[0225] to furnish the pyridazinone of formula III 26
[0226] wherein X.sup.1, R, R.sup.1, R.sup.3, and R.sup.9 are as
previously defined;
[0227] X is selected from the group consisting of O, S, --NR.sup.4,
--NOR.sup.a, and --NNR.sup.bR.sup.c;
[0228] R.sup.4 is selected from the group consisting of alkenyl,
alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic
alkyl;
[0229] R.sup.a, R.sup.b, and R.sup.c are independently selected
from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl,
and cycloalkylalkyl; and
[0230] X.sup.2 is selected from the group consisting of hydrogen,
alkenyl, alkyl, alkynyl and halogen.
[0231] A preferred embodiment of the present invention relates to a
compound of formula VI 27
[0232] or a pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein
[0233] R is selected from alkyl, aryl, arylalkyl, haloalkyl, and
haloalkenyl;
[0234] R.sup.1 is selected from alkoxy,
aminoalkylcarbonyloxyalkoxy, carboxyalkylcarbonyloxyalkoxy,
hydroxyalkyl, hydroxyalkoxy, and phosphonatoalkoxy,
[0235] R.sup.9 is selected from alkyl, alkylcarbonylamino, and
amino.
[0236] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0237] R is aryl;
[0238] R.sup.1 is hydroxyalkoxy; and
[0239] R.sup.9 is selected from alkyl and amino.
[0240] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0241] R is aryl;
[0242] R.sup.1 is hydroxyalkoxy; and
[0243] R.sup.9 is methyl.
[0244] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0245] R is phenyl optionally substituted with 1, 2, 3, 4, or 5
substituents independently selected from halogen and haloalkyl;
[0246] R.sup.1 is hydroxyalkoxy; and
[0247] R.sup.9 is selected from alkyl and amino.
[0248] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0249] R is phenyl optionally substituted with 1 or 2 substituents
independently selected from chlorine and fluorine;
[0250] R.sup.1 is hydroxyalkoxy; and
[0251] R.sup.9 is selected from alkyl and amino.
[0252] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0253] R is haloalkyl; and
[0254] R.sup.1 is hydroxyalkoxy; and
[0255] R.sup.9 is selected from alkyl and amino.
[0256] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0257] R is phenyl optionally substituted with 1, 2, 3, 4, or 5
substituents independently selected from halogen and haloalyl;
[0258] R.sup.1 is aminoalkylcarbonyloxyalkoxy; and
[0259] R.sup.9 is selected from alkyl and amino.
[0260] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0261] R is phenyl optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halogen and
haloalkyl;
[0262] R.sup.1 is carboxyalkylcarbonyloxyalkoxy; and
[0263] R.sup.9 is selected from alkyl and amino.
[0264] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0265] R is phenyl optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halogen and
haloalkyl;
[0266] R.sup.1 is phosphonatoalkoxy; and
[0267] R.sup.9 is selected from alkyl and amino.
[0268] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0269] R is phenyl optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halogen and
haloalkyl;
[0270] R.sup.1 is hydroxyalkoxy; and
[0271] R.sup.9 is alkylcarbonylamino.
[0272] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0273] R is selected from haloalky and phenyl optionally
substituted with 1, 2, 3, 4, or 5 substituents independently
selected from halogen and haloalkyl;
[0274] R.sup.1 is alkoxy; and
[0275] R.sup.9 is selected from the group consisting of alkyl,
alkylcarbonylamino, and amino.
[0276] Another preferred embodiment of the present invention
relates to a compound of formula VI wherein,
[0277] R is tert-butyl;
[0278] R.sup.1 is selected from the group consisting of
aminoalkylcarbonyloxyalkoxy, carboxyalkylcarbonyloxyalkoxy,
hydroxyalkoxy, and phosphonatoalkoxy; and
[0279] R.sup.9 is selected from the group consisting of alkyl,
alkylcarbonylamino, and amino.
[0280] Another preferred embodiment of the present invention
relates to
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone or a pharmaceutically acceptable
salt, ester, or prodrug thereof.
Definitions of Terms
[0281] As used throughout this specification and the appended
claims, the following terms have the following meanings:
[0282] The term alkenyl, as used herein, refers to a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, 3-decenyl and the like.
[0283] The term "alkenylene," denotes a divalent group derived from
a straight or branched chain hydrocarbon of from 2 to 10 carbon
atoms containing at least one double bond. Representative examples
of alkenylene include, but are not limited to, --CH.dbd.CH--,
--CH.dbd.CH.sub.2CH.sub.2--, --CH.dbd.C(CH.sub.3)CH.sub.2--, and
the like.
[0284] The term "alkoxy," as used herein, refers to an alkyl group,
as defined herein, appended to the parent molecular moiety through
an oxy moiety, as defined herein. Representative examples of alkoxy
include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the
like.
[0285] The term "alkoxyalkoxy," as used herein, refers to an alkoxy
group, as defined herein, appended to the parent molecular moiety
through another alkoxy group, as defined herein. Representative
examples of alkoxyalkoxy include, but are not limited to,
tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy,
methoxymethoxy, and the like.
[0286] The term "alkoxyalkoxyalkyl," as used herein, refers to an
alkoxyalkoxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxyalkoxyalkyl include, but are not
limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl,
(2-methoxyethoxy)methyl, 2-(2-methoxyethoxy)ethyl, and the
like.
[0287] The term "alkoxyalkyl," as used herein, refers to an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
[0288] The term "alkoxyalkylcarbonyl," as used herein, refers to an
alkoxyalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkoxyalkylcarbonyl include, but are not
limited to, tert-butoxymethylcarbonyl, 2-ethoxyethylcarbonyl,
2-methoxyethylcarbonyl, methoxymethylcarbonyl, and the like.
[0289] The term "alkoxycarbonyl," as used herein, refers to an
alkoxy group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the
like.
[0290] The term "alkoxycarbonylalkenyl," as used herein, refers to
an alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkenyl group, as defined herein.
Representative examples of alkoxycarbonylalkenyl include, but are
not limited to, 3-methoxycarbonyl-1-propenyl,
4-ethoxycarbonyl-2-butenyl, and the like.
[0291] The term "alkoxycarbonylalkyl," as used herein, refers to an
alkoxycarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxycarbonylalkyl include, but are not
limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl,
2-tert-butoxycarbonylethy- l, and the like.
[0292] The term "alkoxycarbonylalkylthio," as used herein, refers
to an alkoxycarbonylalkyl group, as defined herein, appended to the
parent molecular moiety through a thio moiety, as defined herein.
Representative examples of alkoxycarbonylalkylthio include, but are
not limited to, 3-methoxycarbonylpropylsulfanyl,
4-ethoxycarbonylbutylsulfanyl, and the like.
[0293] The term "alkoxyimino," refers to a R.sub.85ON.dbd. group
wherein R.sub.85 is alkyl, as defined herein.
[0294] The term "alkoxyiminoalkoxy," as used herein, refers to an
alkoxyimino group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of alkoxyiminoalkoxy include, but are not
limited to, 2-(methoxyimino)ethoxy, 2-(ethoxyimino)-1-propoxy,
3-(isopropoxyimino)-1-butoxy, and the like.
[0295] The term "alkoxyiminoalkyl," as used herein, refers to an
alkoxyimino group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxyiminoalkyl include, but are not
limited to, 2-(methoxyimino)ethyl, 2-(ethoxyimino)-1-propyl,
3-(isopropoxyimino)-1-bu- tyl, and the like.
[0296] The term "alkyl," as used herein, refers to a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
n-decyl, and the like.
[0297] The term "alkylamino," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through an amino group, as defined herein. Representative examples
of alkylamino include, but are not limited to, methylamino,
ethylamino, propylamino, and the like.
[0298] The term "alkylaminosulfonyl," as used herein, refers to an
alkylamino group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of alkylaminosulfonyl include, but are not
limited to, methylaminosulfonyl, ethylaminosulfonyl,
propylaminosulfonyl, and the like.
[0299] The term "alkylcarbonyl," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and
the like.
[0300] The term "alkylcarbonylalkoxy," as used herein, refers to an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of alkylcarbonylalkoxy include, but are not
limited to, 2-oxopropoxy, 3,3-dimethyl-2-oxopropoxy, 3-oxobutoxy,
3-oxobutoxy, 3-oxopentyloxy, and the like.
[0301] The term "alkylcarbonylalkyl," as used herein, refers to an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylcarbonylalkyl include, but are not
limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl,
3-oxopentyl, and the like.
[0302] The term "alkylcarbonylamino," as used herein, refers to an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an amino group, as defined herein.
Representative examples of alkylcarbonylamino include, but are not
limited to, acetylamino, 1-oxopropylamino,
2,2-dimethyl-1-oxopropylamino, and the like.
[0303] The term "alkylcarbonylaminoalkyl," as used herein, refers
to an alkylcarbonylamino group, as defined herein, appended to the
parent molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylcarbonylarninoalkyl include, but
are not limited to, acetylaminomethyl, 2-(1-oxopropylamino)ethyl,
and the like.
[0304] The term "alkylcarbonyloxy," as used herein, refers to an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxy moiety, as defined herein.
Representative examples of alkylcarbonyloxy include, but are not
limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and
the like.
[0305] The term "alkylene," denotes a divalent group derived from a
straight or branched chain hydrocarbon of from 1 to 10 carbon
atoms. Representative examples of alkylene include, but are not
limited to, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--, and the like.
[0306] The term "alkylimino," as used herein, refers to
R.sub.81N.dbd. group, wherein R.sub.81 is alkyl, as defined
herein.
[0307] The term "alkylsulfinyl," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfinyl group, as defined herein. Representative
examples of alkylsulfinyl include, but are not limited,
methylsulfinyl, ethylsulfinyl, and the like.
[0308] The term "alkylsulfinylalkyl," as used herein, refers to an
alkylsulfinyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylsulfinylalkyl include, but are not
limited, methylsulfinylmethyl, ethylsulfinylmethyl, and the
like
[0309] The term "alkylsulfonyl," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited,
methylsulfonyl, ethylsulfonyl, and the like.
[0310] The term "alkylsulfonylalkyl," as used herein, refers to an
alkylsulfonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylsulfonylalkyl include, but are not
limited, methylsulfonylmethyl, 2-(ethylsulfonyl)ethyl, and the
like.
[0311] The term "alkylsulfonylamino," as used herein, refers to an
alkylsulfonyl group, as defined herein, appended to the parent
molecular moiety through an amino group, as defined herein.
Representative examples of alkylsulfonylamino include, but are not
limited, methylsulfonylamino, ethylsulfonylamino, and the like.
[0312] The term "alkylthio," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a thio moiety, as defined herein. Representative examples
of alkylthio include, but are not limited, methylsulfanyl,
ethylsulfanyl, tert-butylsulfanyl, hexylsulfanyl, and the like.
[0313] The term "alkylthioalkyl," as used herein, refers to an
alkylthio group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of alkylthioalkyl include, but are not
limited, methylsulfanylmethyl, 2-(ethylsulfanyl)ethyl, and the
like.
[0314] The term "alkylthioalkylcarbonyl," as used herein, refers to
an alkylthioalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkylthioalkylcarbonyl include, but are
not limited, methylsulfanylmethylcarbonyl,
2-(ethylsulfanyl)ethylcarbonyl, and the like.
[0315] The term "alkynyl," as used herein, refers to a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl,
1-butynyl and the like.
[0316] The term "alkynylene," denotes a divalent group derived from
a straight or branched chain hydrocarbon of from 2 to 10 carbon
atoms containing at least one triple bond. Representative examples
of alkynylene include, but are not limited to, --C.ident.C--,
--CH.sub.2C.ident.C--, --CH(CH.sub.3)CH.sub.2C.ident.C--,
--C.ident.CCH.sub.2--, --C.ident.CCH(CH.sub.3)CH.sub.2--, and the
like.
[0317] The term "amino," as used herein, refers to a --NH.sub.2
group.
[0318] The term aminoalkoxy, as used herein, refers to an amino
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of aminoalkoxy include, but are not limited to, 2-aminomethoxy,
3-aminopropoxy, 4-amino-1-methylhexyloxy, and the like.
[0319] The term "aminoalkyl," as used herein, refers to an amino
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of aminoalkyl include, but are not limited to, aminomethyl,
2-aminoethyl, 3-aminopropyl, 4-amino-1-methylhexyl, and the
like.
[0320] The term "aminoalkylcarbonyl," as used herein, refers to an
aminoalkyl group, as defined herein, appended to the parent
molecular moiety through an carbonyl group, as defined herein.
Representative examples of aminoalkylcarbonyl include, but are not
limited to, 2-amino-1-oxoethyl (2-aminoacetyl),
3-amino-1-oxopropyl, and the like.
[0321] The term "aminoalkylcarbonyloxy," as used herein, refers to
an aminoalkylcarbonyl group, as defined herein, appended to the
parent molecular moiety through an oxy moiety, as defined herein.
Representative examples of aminoalkylcarbonyloxy include, but are
not limited to, 2-amino-1-oxoethyloxy (2-aminoacetoxy),
3-amino-1-oxopropyloxy, and the like.
[0322] The term "aminoalkylcarbonyloxyalkoxy," as used herein,
refers to an aminoalkylcarbonyloxy group, as defined herein,
appended to the parent molecular moiety through an alkoxy group, as
defined herein. Representative examples of
aminoalkylcarbonyloxyalkoxy include, but are not limited to,
2-(2-amino-1-oxoethyloxy)ethoxy, 4-(3-amino-1-oxopropylox-
y)butoxy, 3-(3-amino-1-oxopropyloxy)-3-methyl-1-butoxy,
3-(2-amino-1-oxoethyloxy)-3-methyl-1-butoxy and the like.
[0323] The term "aminocarbonyl," as used herein, refers to a
H.sub.2NC(O)-group.
[0324] The term "aminocarbonylalkoxy," as used herein, refers to an
aminocarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of aminocarbonylalkoxy include, but are not
limited to, 2-(aminocarbonyl)ethoxy, 3-(aminocarbonyl)propoxy, and
the like.
[0325] The term "aminocarbonylalkyl," as used herein, refers to an
aminocarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of aminocarbonylalkyl include, but are not
limited to, 2-(aminocarbonyl)ethyl, 3-(aminocarbonyl)propyl, and
the like.
[0326] The term "aminosulfonyl," as used herein, refers to
H.sub.2NS(O).sub.2-group.
[0327] The term "aryl," as used herein, refers to a monocyclic-ring
system, or a bicyclic- or a tricyclic-fused ring system wherein one
or more of the fused rings are aromatic. Representative examples of
aryl include, but are not limited to, azulenyl, indanyl, indenyl,
naphthyl, phenyl, tetrahydronaphthyl, and the like.
[0328] The aryl groups of this invention can be substituted with 1,
2, or 3 substituents independently selected from alkenyl,
alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl,
alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkenyl,
alkoxycarbonylalkyl, alkoxycarbonylalkylthio, alkyl, alkylamino,
alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonylamino, alkylcarbonyloxy, alkylimino, alkylsulfinyl,
alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
alkylsulfonylamino, alkylthio, alkylthioalkyl,
alkylthioalkylcarbonyl, alkynyl, amino, aminocarbonyl,
aminocarbonylalkoxy, aminosulfonyl, aryl, arylalkoxy, arylalkyl,
aryloxy, arylcarbonyl, carboxy, carboxyalkenyl, carboxyalkoxy,
carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cycloalkyl,
dialkylamino, dialkylaminosulfonyl, ethylenedioxy, formyl,
formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclic,
heterocyclic alkoxy, heterocyclic alkyl, heterocyclic carbonyl,
hydroxy, hydroxyalkoxy, hydroxyalkyl, methylenedioxy, mercapto,
nitro, and sulfo. Representative examples of substituted aryl
include, but are not limited to, 3-chlorophenyl, 3-fluorophenyl,
4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl,
3-chloro-4-fluoro-phenyl, 3,4,-difluoorophenyl,
4-methylsulfonyl)phenyl, 4-aminosulfonylphenyl, pentaflurophenyl,
and the like.
[0329] The term "arylalkenyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkenyl group, as defined herein. Representative
examples of arylalkenyl include, but are not limited to,
3-phenylpropen-2-yl, 3-phenylpropen-3-yl, 2-naphth-2-ylbuten-4-yl,
and the like.
[0330] The term "arylalkoxy," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of arylalkoxy include, but are not limited to, 2-phenylethoxy,
3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
[0331] The term "arylalkoxycarbonyl," as used herein, refers to an
arylalkoxy group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of arylalkoxycarbonyl include, but are not
limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the
like.
[0332] The term "arylalkyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of arylalkyl include, but are not limited to, benzyl,
2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the
like.
[0333] The term "arylalkylthio," as used herein, refers to an
arylalkyl group, as defined herein, appended to the parent
molecular moiety through a thio moiety, as defined herein.
Representative examples of arylalkylthio include, but are not
limited to, 2-phenylethylsulfanyl, 3-naphth-2-ylpropylsulfanyl,
5-phenylpentylsulfanyland the like.
[0334] The term "arylalkynyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkynyl group, as defined herein. Representative
examples of arylalkynyl include, but are not limited to,
3-phenylpropyn-2-yl, 3-phenylpropyn-3-yl, 2-naphth-2-ylbutyn-4-yl,
and the like.
[0335] The term "arylcarbonyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of arylcarbonyl include, but are not limited to, benzoyl,
naphthoyl, and the like.
[0336] The term "arylcarbonylalkyl," as used herein, refers to an
arylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of aiylcarbonylalkyl include, but are not
limited to, 3-benzoylpropyl, 3-naphthoylpropyl, and the like.
[0337] The term "arylhaloalkyl," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through a haloalkyl group, as defined herein. Representative
examples of arylhaloalkyl include, but are not limited to,
1,1-difluoro-3-phenylpropy- l, 1,1-dibromo-3-phenylpropyl,
1,1-difluoro-2-naphth-2-ylethyl, and the like.
[0338] The term "arylhydroxyalkyl," as used herein, refers to an
aryl group, as defined herein, appended to the parent molecular
moiety through a hydroxyalkyl group, as defined herein.
Representative examples of arylhydroxyalkyl include, but are not
limited to, 1-hydroxy-3-phenylpropy- l, 2-hydroxy-3-phenylpropyl,
1-hydroxy-2-naphth-2-ylethyl, and the like.
[0339] The term "aryloxy," as used herein, refers to an aryl group,
as defined herein, appended to the parent molecular moiety through
an oxy moiety, as defined herein. Representative examples of
aryloxy include, but are not limited to, phenoxy, naphthyloxy,
3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,
3,5-dimethoxyphenoxy, and the like.
[0340] The term "aryloxyalkyl," as used herein, refers to an
aryloxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of aryloxyalkyl include, but are not limited to,
2-phenoxyethyl, 3-naphth-2-yloxypropyl, 3-bromophenoxymethyl, and
the like.
[0341] The term "aryloxyhaloalkyl," as used herein, refers to an
aryloxy group, as defined herein, appended to the parent molecular
moiety through a haloalkyl group, as defined herein. Representative
examples of aryloxyhaloalkyl include, but are not limited to,
1,1-difluoro-3-(naphth-- 2-yloxy)propyl,
1,1-difluoro-3-(4-bromophenoxy)butyl, and the like.
[0342] The term "aryloxyhydroxyalkyl," as used herein, refers to an
aryloxy group, as defined herein, appended to the parent molecular
moiety through a hydroxyalkyl group, as defined herein.
Representative examples of aryloxyhydroxyalkyl include, but are not
limited to, 1-hydroxy-3-(naphth-2-yloxy)propyl,
1-hydroxy-3-(4-bromophenoxy)butyl, and the like.
[0343] The term "arylthio," as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through a thio moiety, as defined herein. Representative examples
of arylthio include, but are not limited to, phenylsulfanyl,
naphth-2-ylsulfanyl, 5-phenylhexylsulfanyl, and the like.
[0344] The term "arylthioalkyl," as used herein, refers to an
arylthio group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of arylthioalkyl include, but are not limited to,
phenylsulfanylmethyl, 2-naphth-2-ylsulfanylethyl,
5-phenylhexylsulfanylmethyl, and the like.
[0345] The term "azido," as used herein, refers to a --N.sub.3
group.
[0346] The term "carbonyl," as used herein, refers to a
--C(O)-group.
[0347] The term "carboxy," as used herein, refers to a --CO.sub.2H
group.
[0348] The term "carboxyalkenyl," as used herein, refers to a
carboxy group , as defined herein, appended to the parent molecular
moiety through an alkenyl group, as defined herein. Representative
examples of carboxyalkenyl include, but are not limited to,
3-carboxy-1-propenyl, 4-carboxy-1butenyl, and the like.
[0349] The term "carboxyalkoxy," as used herein, refers to a
carboxy group, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein. Representative
examples of carboxyalkoxy include, but are not limited to,
3-carboxypropoxy, 4-carboxybutoxy, and the like.
[0350] The term "carboxyalkyl," as used herein, refers to a carboxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. The alkyl portion of
carboxyalkyl may contain 1 or 2 hydroxy groups, as defined herein.
Representative examples of carboxyalkyl include, but are not
limited to, carboxymethyl, 2-carboxyethyl,
1-hydroxy-3-carboxypropyl, 1,2-dihydroxy-3-carboxypropyl and the
like.
[0351] The term "carboxyalkylcarbonyl," as used herein, refers to a
carboxyalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of carboxyalkylcarbonyl include, but are
not limited to, 2-carboxy-1-oxoethyl,
3-carboxy-2,3-dihydroxy-1-oxopropyl, 3-carboxy-1-oxopropyl, and the
like.
[0352] The term "carboxyalkylcarbonyloxy," as used herein, refers
to a carboxyalkylcarbonyl group, as defined herein, appended to the
parent molecular moiety through an oxy moiety, as defined herein.
Representative examples of carboxyalkylcarbonyloxy include, but are
not limited to, 2-carboxy-1-oxoethoxy,
3-carboxy-2,3-dihydroxy-1-oxopropoxy, 3-carboxy-1-oxopropoxy, and
the like.
[0353] The term "carboxyalkylcarbonyloxyalkoxy," as used herein,
refers to a carboxyalkylcarbonyloxy group, as defined herein,
appended to the parent molecular moiety through an alkoxy group, as
defined herein. Representative examples of
carboxyalkylcarbonyloxyalkoxy include, but are not limited to,
2-(2-carboxy-1-oxoethoxy)ethoxy, 3-(3-carboxy-2,3-dihydro-
xy-1-oxopropoxy)-3-methylbutoxy,
3-(3-carboxy-1-oxopropoxy)-2-methyl-1-pro- poxy, and the like.
[0354] The term "cyano," as used herein, refers to a --CN
group.
[0355] The term "cyanoalkoxy," as used herein, refers to a cyano
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of cyanoalkoxy include, but are not limited to, 2-cyanoethoxy,
3-cyanopropoxy, and the like.
[0356] The term "cyanoalkyl," as used herein, refers to a cyano
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of cyanoalkyl include, but are not limited to, cyanomethyl,
2-cyanoethyl, 3-cyanopropyl, and the like.
[0357] The term "cycloalkenyl," as used herein, refers to a
cyclalkyl group, as defined herein, containing one double bond.
Representative examples of cycloalkenyl include, but are not
limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the
like.
[0358] The cycloalkenyl groups of this invention can be substituted
with 1, 2, or 3 substituents selected from alkoxy, alkoxyalkoxy,
alkoxycarbonyl, alkyl, alkylamino, alkylimino, alkylthio, amino,
aminocarbonyl, aryl, arylalkyl, carboxy, cyano, cycloalkyl,
dialkylamino, formyl, halogen, haloalkyl, hydroxy, oxo, mercapto,
and nitro.
[0359] The term "cycloalkenylalkyl," as used herein, refers to
cycloalkenyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkenylalkyl include, but are not
limited to, cyclopentenylmethyl, cyclohexenylmethyl, and the
like.
[0360] The term "cycloalkyl," as used herein, refers to a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons.
Representative examples of cycloalkyl include, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl.
[0361] The cycloalkyl groups of this invention can be substituted
with 1, 2, or 3 substituents selected from alkoxy, alkoxyalkoxy,
alkoxycarbonyl, alkyl, alkylamino, alkylimino, alkylthio, amino,
aminocarbonyl, aryl, arylalkyl, carboxy, cyano, cycloalkyl,
dialkylamino, formyl, halogen, haloalkyl, hydroxy, oxo, mercapto,
and nitro.
[0362] The term "cycloalkylalkyl," as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl, 4-cycloheptylbutyl, and the
like.
[0363] The term "cycloalkylcarbonyl," as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of cycloalkylcarbonyl include, but are not
limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl,
cyclohexylcarbonyl, and the like.
[0364] The term "cycloalkylidene," as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a double bond. Representative examples of
cycloalkylidene include, but are not limited to, cyclopropylidene,
cyclohexylidene, and the like.
[0365] The term "cycloalkylidenealkyl," as used herein, refers to
cycloalkylidene group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylidenealkyl include, but are
not limited to, 2-cyclopropylideneethyl, 3-cyclohexylidenepropyl,
and the like.
[0366] The term "dialkylamino," as used herein, refers to two
independent alkyl groups, as defined herein, appended to the parent
molecular moiety through an amino group. Representative examples of
dialkylamino include, but are not limited to, diethylamino,
dimethylamino, ethylmethylamino, and the like.
[0367] The term "dialkylaminosulfonyl," as used herein, refers to a
dialkylamino group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group. Representative examples
of dialkylaminosulfonyl include, but are not limited to,
diethylaminosulfonyl, dimethylaminosulfonyl,
ethylmethylaminosulfonyl, and the like.
[0368] The term "ethylenedioxy," as used herein, refers to a
--O(CH.sub.2).sub.2O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to the parent molecular moiety
through one carbon atom forming a 5 membered ring or the oxygen
atoms of the ethylenedioxy group are attached to the parent
molecular moiety through two adjacent carbon atoms forming a six
membered ring.
[0369] The term "formyl," as used herein, refers to a --C(O)H
group.
[0370] The term "formylalkyl," as used herein, refers to a formyl
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of formylalkyl include, but are not limited to, formylmethyl,
2-formylethyl, and the like.
[0371] The term "halo" or "halogen," as used herein, refers to
--Cl, --Br, --I or --F.
[0372] The term "haloalkenyl," as used herein, refers to at least
one halogen, as defined herein, appended to the parent molecular
moiety through an alkenyl group, as defined herein. Representative
examples of haloalkenyl include, but are not limited to,
2,3,3-trifluoropropen-3-yl, 2,2-difluoroethenyl, and the like.
[0373] The term "haloalkenyloxy," as used herein, refers to a
haloalkenyl group, as defined herein, appended to the parent
molecular moiety through an oxy group, as defined herein.
Representative examples of haloalkenyloxy include, but are not
limited to, 2,3,3-trifluoropropen-3-y- loxy,
2,2-difluoroethenyloxy, and the like.
[0374] The term "haloalkoxy," as used herein, refers to at least
one halogen, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein. Representative
examples of haloalkoxy include, but are not limited to,
chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy,
and the like.
[0375] The term "haloalkoxyhydroxyalkyl," as used herein, refers to
a haloalkoxy group, as defined herein, appended to the parent
molecular moiety through a hydroxyalkyl group, as defined herein.
Representative examples of haloalkoxyhydroxyalkyl include, but are
not limited to, 4-(trifluoromethoxy)-1-hydroxybutyl,
4-(difluoromethoxy)-1-hydroxybutyl, and the like.
[0376] The term "haloalkyl," as used herein, refers to at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl,
2-chloro-3-fluoropentyl, and the like.
[0377] The term "haloalkynyl," as used herein, refers to at least
one halogen, as defined herein, appended to the parent molecular
moiety through an alkynyl group, as defined herein. Representative
examples of haloalkynyl include, but are not limited to,
4,4,4-trifluorobutyn-2-yl, 3,3-difluoropropy-1-nyl, and the
like.
[0378] The term "heterocycle or heterocyclic," as used herein,
refers to a monocyclic, bicyclic, or tricyclic ring system.
Monocyclic ring systems are exemplified by any 3-or 4-membered ring
containing a heteroatom independently selected from oxygen,
nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one,
two or three heteroatoms wherein the heteroatoms are independently
selected from nitrogen, oxygen and sulfur. The 5-membered ring has
from 0-2 double bonds and the 6- and 7-membered ring have from 0-3
double bonds. Representative examples of monocyclic ring systems
include, but are not limited to, azetidinyl, azepinyl, aziridinyl,
diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl,
imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,
isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl,
morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl,
oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl,
pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl,
thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl,
thiazolinyl, thiazolidinyl, thiophenyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl, thiopyranyl, triazinyl, triazolyl,
trithianyl, and the like. Bicyclic ring systems are exemplified by
any of the above monocyclic ring systems fused to an aryl group as
defined herein, a cycloalkyl group as defined herein, or another
monocyclic ring system. Representative examples of bicyclic ring
systems include but are not limited to, for example,
benzimidazolyl, benzothiazolyl, benzothiophenyl, benzoxazolyl,
benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl,
1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl,
indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothiophenyl,
isoindolyl, isoindolinyl, isoquinolyl, phthalazinyl, pyranopyridyl,
quinolyl, quinolizinyl, quinoxalinyl, quinazolinyl,
tetrahydroisoquinolyl, tetrahydroquinolyl, thiopyranopyridyl, and
the like. Tricyclic rings systems are exemplified by any of the
above bicyclic ring systems fused to an aryl group as defined
herein, a cycloalkyl group as defined herein, or a monocyclic ring
system. Representative examples of tricyclic ring systems include,
but are not limited to, acridinyl, carbazolyl, carbolinyl,
dibenzofuranyl, dibenzothiophenyl, naphthofiiranyl,
naphthothiophenyl, oxanthrenyl, phenazinyl, phenoxathiinyl,
phenoxazinyl, phenothiazinyl, thianthrenyl, thioxanthenyl,
xanthenyl, and the like.
[0379] The heterocyclic groups of this invention can be substituted
with 1, 2, or 3 substituents independently selected from alkenyl,
alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl,
alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkenyl,
alkoxycarbonylalkyl, alkoxycarbonylalkylthio, alkyl, alkylamino,
alkylaminosulfonyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonylamino, alkylcarbonyloxy, alkylimino, alkylsulfinyl,
alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
alkylsulfonylamino, alkylthio, alkylthioalkyl,
alkylthioalkylcarbonyl, alkynyl, amino, aminocarbonyl,
aminocarbonylalkoxy, aminosulfonyl, aryl, arylalkoxy, arylalkyl,
aryloxy, arylcarbonyl, carboxy, carboxyalkenyl, carboxyalkoxy,
carboxyalkyl, cyano, cyanoalkoxy, cyanoalkyl, cycloalkyl,
dialkylamino, dialkylaminosulfonyl, ethylenedioxy, formyl,
formylalkyl, halogen, haloalkoxy, haloalkyl, heterocyclic,
heterocyclic alkoxy, heterocyclic alkyl, heterocyclic carbonyl,
hydroxy, hydroxyalkoxy, hydroxyalkyl, methylenedioxy, mercapto,
nitro, and sulfo.
[0380] The term "heterocyclic alkoxy," as used herein, refers to a
heterocyclic group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of heterocyclic alkoxy include, but are not
limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy,
5-pyrid-4-ylpentyloxy, and the like.
[0381] The term "heterocyclic alkyl," as used herein, refers to a
heterocyclic, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heterocyclic alkyl include, but are not limited to,
pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
[0382] The term "heterocyclic alkylthio," as used herein, refers to
a heterocyclic alkyl group, as defined herein, appended to the
parent molecular moiety through a thio moiety, as defined herein.
Representative examples of heterocyclic alkylthio include, but are
not limited to, 2-pyrid-3-ylethysulfanyl,
3-quinolin-3-ylpropysulfanyl, 5-pyrid-4-ylpentylsulfanyl, and the
like.
[0383] The term "heterocyclic carbonyl," as used herein, refers to
a heterocyclic, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein. Representative
examples of heterocyclic carbonyl include, but are not limited to,
pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl,
sulfanylphen-2-ylcarbonyl, and the like.
[0384] The term "heterocyclic oxy," as used herein, refers to a
heterocyclic group, as defined herein, appended to the parent
molecular moiety through an oxy moiety, as defined herein.
Representative examples of heterocyclic oxy include, but are not
limited to, pyrid-3-yloxy, quinolin-3-yloxy, and the like.
[0385] The term "heterocyclic oxyalkyl," as used herein, refers to
a heterocyclic oxy group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocyclic oxyalkyl include, but are
not limited to, pyrid-3-yloxymethyl, 2-quinolin-3-yloxyethyl, and
the like.
[0386] The term "heterocyclic thio," as used herein, refers to a
heterocyclic group, as defined herein, appended to the parent
molecular moiety through a thio moiety, as defined herein.
Representative examples of heterocyclic thio include, but are not
limited to, pyrid-3-ylsulfanyl, quinolin-3-ylsulfanyl, and the
like.
[0387] The term "heterocyclic thioalkyl," as used herein, refers to
a heterocyclic thio group, as defined herein, appended to the
parent molecular moiety through an alkyl group, as defined herein.
Representative examples of heterocyclic thioalkyl include, but are
not limited to, pyrid-3-ylsulfanylmethyl,
2-quinolin-3-ylsulfanylethyl, and the like.
[0388] The term "hydroxy," as used herein, refers to an --OH
group.
[0389] The term "hydroxyalkoxy," as used herein, refers to 1 or 2
hydroxy groups, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein. Representative
examples of hydroxyalkoxy include, but are not limited to,
hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxy-2-methylethoxy,
3-hydroxy-1-propoxy, 4-hydroxy-1-butoxy,
3-hydroxy-3-methyl-1-butoxy, 2,3-dihydroxy-1-propoxy, and the
like.
[0390] The term "hydroxyalkyl," as used herein, refers to 1 or 2
hydroxy groups, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
2-ethyl-4-hydroxyheptyl, 2,3-dihydroxypropyl, and the like.
[0391] The term "hydroxyimino," refers to a HON.dbd. group.
[0392] The term "hydroxyiminoalkoxy," as used herein, refers to a
hydroxyimino group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
Representative examples of hydroxyiminoalkoxy include, but are not
limited to, hydroxyiminomethoxy, 2-hydroxyiminoethoxy,
2-hydroxyiminopropoxy, and the like.
[0393] The term "hydroxyiminoalkyl," as used herein, refers to a
hydroxyimino group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyiminoalkyl include, but are not
limited to, bydroxyiminomethyl, 2-hydroxyiminoethyl,
2-hydroxyiminopropyl, and the like.
[0394] The term "imino," as used herein, refers to a HN.dbd.
group.
[0395] The term "iminoalkoxy," as used herein, refers to an imino
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of iminoalkoxy include, but are not limited to, 2-iminoethoxy,
2-imino-1-propoxy, 3-imino-1-butoxy, and the like.
[0396] The term "iminoalkyl," as used herein, refers to an imino
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of iminoalkyl include, but are not limited to, 2-iminoethyl,
2-imino-1-propyl, 3-imino-1-butyl, and the like.
[0397] The term "mercapto," as used herein, refers to a --SH
group.
[0398] The term "mercaptoalkoxy," as used herein, refers to a
mercapto group, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein. Representative
examples of mercaptoalkoxy include, but are not limited to,
2-mercaptoethoxy, 3-mercaptopropoxy, and the like.
[0399] The term "mercaptoalkyl," as used herein, refers to a
mercapto group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of mercaptoalkyl include, but are not limited to,
2-mercaptoethyl, 3-mercaptopropyl, and the like.
[0400] The term "methylenedioxy," as used herein, refers to a
--OCH.sub.2O-- group wherein the oxygen atoms of the methylenedioxy
are attached to the parent molecular moiety through two adjacent
carbon atoms.
[0401] The term "nitro," as used herein, refers to a --NO.sub.2
group.
[0402] The term "oxo," as used herein, refers to a .dbd.O
moiety.
[0403] The term "oxy," as used herein, refers to a --O--
moiety.
[0404] The term "phosphonato," as used herein , refers to a
(R.sub.84O).sub.2P(O)O-- group wherein R.sub.84 is selected from
hydrogen and alkyl, as defined herein.
[0405] The term "phosphonatoalkoxy," refers to a phosphonato group,
as defined herein, appended to the parent molecular moiety through
an alkoxy group, as defined herein. Representative example of
phosphonatoalkoxy include, but are not limited to, 3-hydroxypropyl
dihydrogen phosphate, 3-hydroxy-1,1-dimethylpropyl dihydrogen
phosphate, and the like.
[0406] The term "sulfinyl," as used herein, refers to a --S(O)--
group.
[0407] The term "sulfo," as used herein, refers to a --SO.sub.3H
group.
[0408] The term "sulfonyl," as used herein, refers to a
--S(O).sub.2-- group.
[0409] The term "thio," as used herein, refers to a --S--
moiety.
[0410] 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: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be
quatemized with such agents as loweralkyl halides, such as methyl,
ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides, and others. Water or oil-soluble or dispersible
products are thereby obtained.
[0411] Examples of acids which may be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulphuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid.
[0412] Basic addition salts can be prepared in situ during the
final isolation and purification of the compounds of formula I, or
separately by reacting a carboxylic acid function with a suitable
base such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia, or an
organic primary, secondary or tertiary amine. Such pharmaceutically
acceptable salts include, but are not limited to, cations based on
the alkali and alkaline earth metals, such as sodium, lithium,
potassium, calcium, magnesium, aluminum salts and the like, as well
as nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. Other representative
organic amines useful for the formation of base addition salts
include diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like.
[0413] The term "pharmaceutically acceptable ester" as used herein
refers to esters which hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters includes formates, acetates, propionates,
butyates, acrylates and ethylsuccinates.
[0414] The term "pharmaceutically acceptable prodrug" as used
herein refers to those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the invention. The term
"prodrug" refers to compounds that are rapidly transformed in vivo
to provide the parent compound having the above formula, for
example by hydrolysis in blood. A thorough discussion is provided
in T. 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, both of which are
incorporated herein by reference.
[0415] As used throughout this specification and the appended
claims, the term metabolically cleavable group denotes a moiety
which is readily cleaved in vivo from the compound bearing it,
wherein said compound, after cleavage remains or becomes
pharmacologically active. Metabolically cleavable groups form a
class of groups reactive with the carboxyl group of the compounds
of this invention are well known to practitioners of the art. They
include, but are not limited to groups such as, for example,
alkylcarbonyl, such as acetyl, propionyl, butyryl, and the like;
unsubstituted and substituted arylcarbonyl, such as benzoyl and
substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl;
trialkylsilyl, such as trimethyl- and triethysilyl; monoesters
formed with dicarboxylic acids, such as succinyl, and the like.
Because of the ease with which the metabolically cleavable groups
of the compounds of this invention are cleaved in vivo, the
compounds bearing such groups act as pro-drugs of other
prostaglandin biosynthesis inhibitors. The compounds bearing the
metabolically cleavable groups have the advantage that they may
exhibit improved bioavailability as a result of enhanced solubility
and/or rate of absorption conferred upon the parent compound by
virtue of the presence of the metabolically cleavable group.
[0416] Asymmetric centers may exist in the compounds of the present
invention. The present invention contemplates the various
stereoisomers and mixtures thereof. Individual stereoisomers of
compounds of the present invention are made by synthesis from
starting materials containing the chiral centers or by preparation
of mixtures of enantiomeric products followed by separation as, for
example, by conversion to a mixture of diastereomers followed by
separation by recrystallization or chromatographic techniques, or
by direct separation of the optical enantiomers on chiral
chromatographic columns. Starting compounds of particular
stereochemistry are either commercially available or are made by
the methods detailed below and resolved by techniques well known in
the organic chemical arts.
[0417] The present invention discloses pyridazinone compounds which
are cyclooxygenase (COX) inhibitors and are selective inhibitors of
cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated
with inflammation, as opposed to the constitutive isoform,
cyclooxygenase-1 (COX-1) which is an important "housekeeping"
enzyme in many tissues, including the gastrointestinal (GI) tract
and the kidneys.
[0418] Preferred compounds of the present invention include, but
are not limited to,
[0419]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazi-
none;
[0420]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0421]
2-Benzyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone;
[0422]
2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone;
[0423]
2-Benzyl-4-(4-fluorophenyl)-5-(trifluoromethylsulfonyloxy)-3(2H)-py-
ridazinone;
[0424]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazi-
none;
[0425]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0426]
2-Phenyl4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0427]
2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0428]
2-(Phenylpropargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0429]
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0430]
2-(Methyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0431]
2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0432]
2-(2-Trifluoromethylbenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0433]
2-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0434]
2-(2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0435]
2-(4-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0436]
2-(3-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0437]
2-(6-Fluoroquinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0438]
2-(Quinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0439]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinethione
[0440]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0441]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0442]
2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0443]
2-(3-Phenyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0444]
2-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0445]
2-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0446]
2-(5-Chlorothiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0447]
2-(2,3,3,4,4,4-Hexafluorobuten-1-yl)-4-(4-fluorophenyl)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0448]
2-(2,4-Difluorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0449]
2-(5-Chlorothien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0450]
2-(5-Methylthien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0451]
2-(4-Diethylaminophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0452]
2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0453]
2-(Phenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0454]
2-(4-Chlorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0455]
2-(Propargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0456]
2-(4-Cyanophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0457]
2-(.alpha.-Methyl-4-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0458]
2-Phenethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
[0459]
2-Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0460]
2-Benzyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0461]
2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0462]
2-(4-Trifluoromethoxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0463]
2-(4-Trifluoromethylphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0464]
2-[2-(Benzo[b]thien-3-yl)-2-oxoethyl]-4-(4-fluorophenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0465]
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0466]
2-(3,3-Dimethyl-2-oxobutyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0467]
2-(3-Thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0468]
2-(2-Benzo[b]thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0469]
2,4-Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi-
none;
[0470]
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-6-methyl-3(2H)-pyri-
dazinone;
[0471]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-6-methyl-3(2H)-pyridazinone;
[0472]
2-Benzyl-4-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0473]
2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0474]
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0475]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(amrinosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0476]
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0477]
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
[0478]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0479]
2,4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0480]
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0481]
2-Benzyl-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
[0482]
2-Benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
[0483]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0484]
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfinyl)ph-
enyl]-3(2H)-pyridazinone;
[0485]
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0486]
2-(2,2,2-Trifluoroethyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0487]
2-(2,2,2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0488]
2-(2,2,2-Trifluoroethyl)-4-(3,4-dichlorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0489]
2-Benzyl-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0490]
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0491]
2-(2,2,2-Trifluoroethyl)-4-cyclohexyloxy-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0492]
2-(2,2,2-Trifluoroethyl)-4-cyclopentyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0493]
2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0494]
2-Benzyl-4-(4-morpholino)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zillone;
[0495]
2-(2,3,3-Trifluoro-2-propen-1-yl)]-4-(4-fluorophenyl)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0496]
2,4-Bis(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazin-
one;
[0497]
2-(2,2,2-Trifluoroethyl)-4-cyclopropyhnethoxy-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0498]
2-(2,2,2-Trifluoroethyl)-4-(3-propen-1-oxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0499]
2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-.alpha.-methylbenzyloxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0500]
2-[4-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0501]
2,5-Bis[4-(methylsulfonyl)phenyl]-4-(4-fluorophenyl)-3(2H)-pyridazi-
none;
[0502]
2-(3-Methyl-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0503]
2-(2-Trifluoromethyl-4-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0504]
[3-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0505]
2-[3-(Methylsulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0506]
2-(4-Fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0507]
2-(5-Chloro-2-thienyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0508]
2-(3-Trifluoromethylphenyl)-4-(4-chlorophenyl)-5-[4-(mnethylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0509]
2-(3-Chloro-4-fluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0510]
2-(3-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0511]
2-[2-(Methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0512]
2-(5-Nitro-2-thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0513]
2-(3,4-Difluorophenyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0514]
2-(3-Benzothienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0515]
2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0516]
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0517]
2-(3-Bromophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0518]
2-(3,5-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0519]
2-(3-Chlorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0520]
2-(4-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0521]
2-(4-Acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0522]
2-(4-Hydroxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0523]
2-(3-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny
l]-3(2H)-pyridazinone;
[0524]
2-(3-Trifluoro-3-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0525]
2-(2-Hexynyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0526]
2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0527]
2-Cyclohexyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0528]
2-Cyclopentyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0529]
2-Cyclobutyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0530]
2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0531]
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0532]
2-(Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0533]
2-(3-Cyclohexenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0534]
2-(3,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0535]
2-(2,3-Dihydro-1H-inden-2-yl)-4-(4-fluorophenyt)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0536]
2-(2,3-Dihydro-1H-inden-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0537]
2-(4-Tetrahydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0538]
2-(2-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0539]
2-(2-Adamantyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
[0540]
2-(3-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0541]
2-(1-Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0542]
2-(3,4-Difluorophenyl)4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0543]
2-(3,4-Difluorophenyl)-4-(6-methyl-3-heptenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0544]
2-(3,4-Difluorophenyl)-4-(3-cyclopropylidenepropyl)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0545]
2-(3,4-Difluorophenyl)-4-(5-methyl-3-hexenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0546]
2-(3,4-Difluorophenyl)-4-(5-methylhexyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0547]
2-(3-Chloro-1-methyl-2E-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0548]
2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0549]
2-(1,1,2-Trifluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0550]
2-(3,3-Difluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0551]
2-(.alpha.-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0552]
2-(1-Cyclohexenylmethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0553]
2-(.alpha.-Methyl-2,3,4-trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
[0554]
2-(.alpha.-Methyl-3,5-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amin-
osulfonyl)phenyl]-3(2H)-pyridazinone;
[0555]
2-(.alpha.-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(amin-
osulfonyl)phenyl]-3(2H)-pyridazinone;
[0556]
2-(3-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0557]
2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0558]
2-(2,4,6-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0559]
2-(2,4,5-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0560]
2-(2,3,4-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0561]
2-(4,4,4-Trifluoro-3-methyl-2E-butenyl)-4-(4-fluorophenyl)-5-[4-(am-
inosulfonyl)phenyl]-3(2H)-pyridazinone;
[0562]
2-(4-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
[0563]
2-(4-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0564]
2-(4-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0565]
2-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0566]
2-(4-t-Butylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0567]
2-(4-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0568]
2-(3-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0569]
2-(3-Vinylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0570]
2-(2-Formylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0571]
2-(2-Nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0572]
2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0573]
2-(3-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0574]
2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0575]
2-(5-Methyl-2-thienyl))-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0576]
2-(3-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
[0577]
2-(3,5-Dimethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0578]
2-(3,4-Difluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0579]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0580]
2-(2-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0581]
2-(4-Trifluoromethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0582]
2-[4-(1-Pyrroyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0583]
2-(5-Chloro-2-thie(yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0584]
2-(4-Methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0585]
2-(4-Fluorophenyl)-4-(2-ethyl-1-hexyloxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0586]
2-(3-Thienyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0587]
2-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0588]
2-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0589]
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0590]
2-(3-Furyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
[0591]
2-(3-Fluoro-4-methoxyphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0592]
2-(2-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0593]
2-[4-(Aminosulfonyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0594]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0595]
2-(3,5-Dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0596]
2-(4-Fluoro-3-methylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0597]
2-(4-Chloro-3-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;:
[0598]
2-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;:
[0599]
2-(1-Adamantyloxycarbonyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0600]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0601]
2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0602]
2-(4-Fluorophenyl)-4-(3-fluorophenoxymethyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0603]
2-(4-Fluorophenyl)-4-phenoxymethyl-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
[0604]
2-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0605]
2-(4-Fluorophenyl)-4-(2-methylpropylthiomethyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0606]
2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyr-
idazinone;
[0607]
2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0608]
2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0609]
2-(3-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0610]
2-(3-Bromophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0611]
2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0612]
2-(3-Chloro-4-fluorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0613]
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0614]
2-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0615]
2-(3-Chlorophenyl)-4-(benzoyloxymethyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0616]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0617]
2-(2,2,2-Trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0618]
2-(2,2,2-Trifluoroethyl)-4-(3,5-dichlorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0619]
2-(2,2,2-Tnifluoroethyl)-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0620]
2-(2,2,2-Trifluoroethyl)-4-(4-trifluoromethylphenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0621]
2-(2,2,2-Trifluoroethyl)-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0622]
2-(2,2,2-Trifluoroethyl)-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0623]
2-(2,2,2-Trifluoroethyl)-4-[3-(trifluloromethyl)phenyl]-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0624] 2-(2,2,2-Trifluoroethyl)-4-(3-fluoro
-4-methoxyphenyl)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0625]
2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0626]
2-(2,2,2-Trifluoroethyl)-4-(3,5-dfluoro-4-methoxyphenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0627]
2-(2,2,2-Trifluoroethyl)-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0628]
2-(2,2,2-Trifluoroethyl)-4-(2-propenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0629]
2-(2,2,2-Trifluoroethyl)-4-(2-buten-2-yl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0630] 2-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzyl)
5-[4-(methylsulfonyl)ph- enyl]-3(2H)-pyridazinone;
[0631]
2-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0632]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0633]
2-(2,2,2-Trifluoroethyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
[0634]
2-(4-Fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0635]
2-(4-Fluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0636]
2-(4-Fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0637]
2-(4-Fluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0638]
2-(3,4-Difluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
[0639]
2-(3,4-Difluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0640]
2-(3,4-Difluorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H-pyridazinone;
[0641]
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0642]
2-(3,4-Difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-vinyl-3(2H)-p-
yridazinone;
[0643]
2-(3,4-Difluorophenyl)-4-(2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0644]
2-(3,4-Difluorophenyl)-4-(1-propynyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0645]
2-(3,4-Difluorophenyl)-4-t-butyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0646]
2-(2,2,2-Trifluoroethyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0647]
2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0648]
2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0649]
2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0650]
2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0651]
2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0652]
2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0653]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0654]
2-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0655]
2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0656]
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0657]
2-(3-Chloro-4-fluorophenyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0658]
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0659]
2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0660]
2-(3,4-Difluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0661]
2-(3,4-Difluorophenyl)-4-(3,4-difluorobenzyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0662]
2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0663]
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0664]
2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0665]
2-[4-Fluoro-3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0666]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3-
(2H)-pyridazinone;:
[0667]
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0668]
2-(2,2,2-Trifluoroethyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0669]
2-(2,2,2-Trifluoroethyl)-4-(2-fluoro-5-trifluoromethylphenoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0670]
2-(2,2,2-Ttifluoroethyl)-4-(4-cyanophenoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0671]
2-(2,2,2-Trifluoroethyl)-4-(3-pyridyloxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0672]
2-(2,2,2-Trifluoroethyl)-4-(4-n-propylphenoxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0673]
2-(2,2,2-Trifluoroethyl)-4-[4-(methylsulfonyl)phenoxy]-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0674]
2-(2,2,2-Trifluoroethyl)-4-(4-phenylphenoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0675]
2-(2,2,2-Trifluoroethyl)-4-[2-(methylthio)ethoxy]-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0676]
2-(2,2,2-Trifluoroethyl)-4-(phenyhnethoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0677]
2-(2,2,2-Trifluoroethyl)4-(2-furylmethoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0678]
2-(2,2,2-Trifluoroethyl)-4-[2-(3,4-dimethoxyphenyl)ethoxy)]-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0679]
2-(2,2,2-Trifluoroethyl)-4-[2-(4-morpholino)ethoxy)]-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0680]
2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethoxy)]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0681]
2-(2,2,2-Trifluoroethyl)-4-[4-(carboxamido)phenoxy)]-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0682]
2-(2,2,2-Trifluoroethyl)-4-(1-indanyloxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0683]
2-(2,2,2-Trifluoroethyl)-4-[4-(acetaiido)phenoxy)]-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0684]
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0685]
2-(2,2,2-Trifluoroethyl)-4-(1-methylcyclopropylmethoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0686]
2-(2,2,2-Trifluoroethyl)-4-(3,3-dimethylbutoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0687]
2-(3,4-Difluorophenyl)-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0688]
2-(3,4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0689]
2-(2,2,2-Trifluoroethyl)-4-(cyclopentylthio)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0690]
2-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthio)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0691]
2-(2,2,2-Trifluoroethyl)-4-phenylmethylthio-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0692]
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenylthio)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0693]
2-(2,2,2-Trifluoroethyl)-4-(cyclohexylthio)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0694]
2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenylthio)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0695]
2-(2,2,2-Trifluoroethyl)-4-(2,2,2-trifluoroethylthio)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0696]
2-(2,2,2-Trifluoroethyl)-4-(tert-butylthio)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0697]
2-(2,2,2-Trifluoroethyl)-4-(4-acetamidophenylthio)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0698]
2-(2,2,2-Trifluoroethyl)-4-(2-propylthio)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0699]
2-(2,2,2-Trifluoroethyl)-4-(2-methylprop-1-ylthio)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0700]
2-(2,2,2-Trifluoroethyl)-4-amino-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0701]
2-(2,2,2-Trifluoroethyl)-4-(3-methoxypropylamino)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0702]
2-(2,2,2-Trifluoroethyl)-4-(cyclopentylamino)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0703]
2-(2,2,2-Trifluoroethyl)-4-(cyclobutylamino)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0704]
2-(2,2,2-Trifluoroethyl)-4-(3,4-dimethoxyphenethylamino)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0705]
2-(2,2,2-Trifluoroethyl)-4-(cyclohexylamino)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0706]
2-(2,2,2-Trifluoroethyl)-4-[2-(1-piperidinyl)ethylainino]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0707]
2-(2,2,2-Trifluoroethyl)-4-(2-tetrahydrofurfurylamino)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0708]
2-(2,2,2-Trifluoroethyl)-4-(cyclopropylmethylamino)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0709]
2-(2,2,2-Trifluoroethyl)-4-(2,3-dihydro-1H-inden-1-ylamino)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0710]
2-(2,2,2-Trifluoroethyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0711]
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxypropylamino)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0712]
2-(2,2,2-Trifluoroethyl)-4-[3-(1H-imidazol-1-yl)propylamino]-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0713]
2-(2,2,2-Trifluoroethyl)-4-(2R-hydroxylpropylamino)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0714]
2-(2,2,2-Trifluoroethyl)-4-(2-cyanoethylamino)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0715]
2-(2,2,2-Trifluoroethyl)-4-(4-cyanoanilino)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0716]
2-(2,2,2-Trifluoroethyl)-4-[3-methoxy-5-(trifluoromethyl)anilino]-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0717]
2-(2,2,2-Trifluoroethyl)-4-anilino-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
[0718]
2-(2,2,2-Trifluoroethyl)-4-(2,5-diinethoxyphenylamino)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0719]
2-(2,2,2-Trifluoroethyl)-4-(3-fluoroanilino)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0720]
2-(2,2,2-Trifluoroethyl)-4-(2,4-difluoroanilino)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0721]
2-(2,2,2-Trifluoroethyl)-4-(2,3,5-trifluoroanilino)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0722]
2-(2,2,2-Trifluoroethyl)-4-(4-fluoroanilino)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0723]
2-Benzyl-4-(3-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazin-
one;
[0724]
2-Benzyl-4-(2-benzofuranyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0725]
2-Benzyl-4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0726]
2-Benzyl-4-(5-chloro-2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0727]
2-Benzyl-4-(3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0728]
2-Benzyl-4-(4-vinylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0729]
2-Benzyl-4-(4-trifluomethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
[0730]
2-Benzyl-4-(2-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
[0731]
2-Benzyl-4-(3,4-dimethylphenyl)-5-[4-(methylsullfonyl)phenyl]-3(2H)-
-pyridazinone;
[0732]
2-Benzyl-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0733]
2-Benzyl-4-(2-methoxypyrid-3-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0734]
2-Benzyl-4-(3-ethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0735]
2-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyrid-
azinone;
[0736]
2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone;
[0737]
2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
[0738]
2-(3-Chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
[0739]
2-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0740]
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0741]
2-(3-Chlorophenyl)-4-(t-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0742]
2-(3-Chlorophenyl)-4-(cyclohexyloxy)-5-[4-(methylsulfonyl)phenyi]-3-
(2H)-pyridazinone;
[0743]
2-(3-Chlorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0744]
2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0745]
2-(3-Chlorophenyl)-4-(3-octyn-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0746]
2-(3-Chlorophenyl)-4-[2-(dimethylamino)ethoxy]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0747]
2-(3-Chlorophenyl)-4-[2-methyl-1-(1-methylethyl)propoxy]-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0748]
2-(3-Chlorophenyl)-4-(phenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone;
[0749]
2-(3-Chlorophenyl)-4-[3-(dimethylamino)phenoxy]-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0750]
2-(3-Chlorophenyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0751]
2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0752]
2-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0753]
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0754]
2-(3,4-Difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0755]
2-(3,4-Difluorophenyl)-4-[2-(isopropoxy)ethoxy]-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0756]
2-(3,4-Difluorophenyl)-4-(3-methylpentyloxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0757]
2-(3,4-Difluorophenyl)-4-(4-methyl-3-penten-1-yloxy)-5-[4-(methylsu-
lfonyl)phenyl]-5-3(2H)-pyridazinone;
[0758]
2-(3,4-Difluorophenyl)-4-[3-(methoxy)butoxy]-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0759]
2-(3-Chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;:
[0760]
2-(4-Fluorophenyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0761]
2-(4-Fluorophenyl)-4-(1-pyrrolidinyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0762]
2-(3-Chlorophenyl)-4-(4-methylphenylthio)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0763]
2-(3-Chlorophenyl)-4-(2-pyridylthio)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0764]
2-(3-Chlorophenyl)-4-(phenylmethylthio)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0765]
2-(3-Chlorophenyl)-4-(2-furylmethylthio)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0766]
2-(3-Chlorophenyl)-4-]2-(methylpropyl)thio]-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0767]
2-(3-Chlorophenyl)-4-(cyclopentyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone;
[0768]
2-(3-Chlorophenyl)-4-(2-methylpropyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0769]
2-(3-Chlorophenyl)-4-(cyclopentylmethyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0770]
2-(3-Chlorophenyl)-4-(2-cyclopentylethyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0771]
2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0772]
2-(3-Chlorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone;
[0773]
2-(3-Chlorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0774]
2-(3-Chlorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0775]
2-(3-Chlorophenyl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0776]
2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0777]
2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0778]
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0779]
2-(3-Chlorophenyl)-4-(benzyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0780]
2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0781]
2-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0782]
2-(4-Fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0783]
2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0784]
2-(Tetrahydro-2H-pyrano-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0785]
2-(3-(4-Fluorophenyl)phenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0786]
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone;
[0787]
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0788]
2-Benzyl-4-(4-fluorobenzyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0789]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyrid-
azinone;
[0790]
2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
[0791]
2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0792]
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0793]
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0794]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0795]
2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0796]
2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2h)-pyridazinone;
[0797]
2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(-
2H)-pyridazinone;
[0798]
2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)--
pyridazinone;
[0799]
2-(3-Chlorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0800]
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
[0801]
2-(4-Fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl]-3(-
2H)-pyridazinone;
[0802]
2-(4-Fluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl]--
3(2H)-pyridazinone;
[0803]
2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone;
[0804]
2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(aniinosulfonyl)phenyl]-3(2H-
)-pyridazinone;
[0805]
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0806]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0807]
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aminosulfo-
nyl)phenyl]-3-(2H)-pyridazinone;
[0808]
2-(3,4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0809]
2-(3,4-Difluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0810]
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)p-
henyl]-3(21)-pyridazinone;
[0811]
2-(3,4-Difluorophenyl)-4-(2,2-dimethylprooyl)-5-[4-(aminosulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0812]
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0813]
2-(3,3-Difluoro-2-propenyl)]-4-(4-fluorophenyl)-5-[3-fluoro-4-(amin-
osulfonyl)phenyl]-3(2H)-pyridazinone;
[0814]
2-(3,4-Difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0815]
2-(3,4-Difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0816]
2-(3-Chlorophenyl)-4-(3-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone;
[0817]
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0818]
2-(3-Chlorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0819]
2-(4-Fluorophenyl)-4-(4-methylpentyloxy)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0820]
2-(4-Fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone;
[0821]
2-(4-Fluorophenyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0822]
2-(4-Fluorophenyl)-4-(2-cyclopropyl-1-ethoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0823]
2-(3-Chlorophenyl)-4-cyclopropanemethoxy-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[0824]
2-(3-Chlorophenyl)-4-(2-cyclopropane-1-ethoxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0825]
2-(4-Fluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0826]
2-(3-Chlorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0827]
2-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0828]
2-(3-Chlorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0829]
2-(4-Fluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0830]
2-(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0831]
2-(3-Chlorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0832]
2-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0833]
2-(4-Fluorophenyl)-4-(1,5-hexadienyl-3-oxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0834]
2-(4-Fluorophenyl)-4-(5-methyl-2-hexyloxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0835]
2-(4-Fluorophenyl)-4-(2-ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone;
[0836]
2-(4-Fluorophenyl)-4-(2-thioisopropyl-1-ethoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0837]
2-(4-Fluorophenyl)-4-(3-methylthio-1-hexyloxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0838]
2-(4-Fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone;
[0839]
2-(3,4-Difluorophenyl)-4-(3-trifluoromethyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0840]
2-(3,4-Difluorophenyl)-4-ethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[0841]
2-(3,4-Difluorophenyl)-4-(4-methyl-1-pentyloxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0842]
2-(3,4-Difluorophenyl)-4-(4-methyl-2-pentyloxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0843]
2-(3,4-Difluorophenyl)-4-(2-cyclopentyl-1-ethoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0844]
2-(3,4-Difluorophenyl)-4-(2-cyclopent-2-enyl-1-ethoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0845]
2-(2-Hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0846]
2-(2-Methoxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[0847]
2-(2-Methoxyimino-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0848]
2-(3,4-Difluorophenyl)-4-(4-methylpentyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0849]
2-(3,4-Difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0850]
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone;
[0851]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0852]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0853]
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone;
[0854]
2-(2,3,3-Trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0855]
2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0856]
2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0857]
2-(3,4-Difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[0858]
2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylam-
ino)methylaminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0859]
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)methy-
laminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0860]
(4-Fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinone;
[0861]
2-(3,4-Difluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0862]
2-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0863]
2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0864]
2-(3,4-Difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone;
[0865]
2-(3,4-Difluorophenyl)-4-[2-(methoxyimino)-1-propoxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0866]
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0867]
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0868]
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
[0869]
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
[0870]
2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0871]
2-(3,4-Difluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[0872]
2-(4-Fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone;
[0873]
2-(4-Fluorophenyl)-4-(4-hydroxy-2-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0874]
2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(amninosulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0875]
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0876]
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminos-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0877]
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0878]
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
[0879]
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0880]
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0881]
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0882]
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0883]
2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0884]
2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(-
aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0885]
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0886]
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0887]
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0888]
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone;
[0889]
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0890]
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-ditnethyl-1-propoxy)-5-[4-
-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0891]
2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0892]
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0893]
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0894]
2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0895]
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminos-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0896]
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(a-
minosulfonyl)phenyl]-3(2H)-pyridazinone;
[0897]
2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0898]
(S)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0899]
(R)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0900]
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0901]
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5--
[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0902]
(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0903]
(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5--
[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0904]
(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0905]
(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0906]
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0907]
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0908]
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0909]
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4--
(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0910]
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0911]
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4--
(aminosulfonyl)phenyl]-3(2H)-pyridazinone;
[0912]
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0913]
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0914]
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0915]
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(a-
minosulfonyl)-phenyl]-3(2H)-pyridazinone;
[0916]
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0917]
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dirnethyl-1-propoxy)-5-
-[4-(aminiosulfonyl)phenyl]-3(2H)-pyridazinone;
[0918]
2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0919]
2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(amino-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0920]
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-
-on-5-yl]phenyl]sulfonyl]acetamide;
[0921]
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-
-on-5-yl]phenyl]-sulfonyl]acetamide, sodium salt;
[0922]
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyrida-
zin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0923]
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyrida-
zin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
[0924]
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-p-
yridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0925]
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-p-
yridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
[0926]
N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-
-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0927]
N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-
-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
[0928]
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyrid-
azin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0929]
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyrid-
azin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
[0930]
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-
-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0931]
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-
-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium salt;
[0932]
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy-
)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide;
[0933]
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy-
)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, sodium
salt;
[0934]
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0935]
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(amin-
osulfonyl)phenyl]-3(2H)-pyridazinone;
[0936]
2-(3,4-Dichlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0937]
2-[(3-Trifluoromethyl)phenyl]-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0938]
2-(3,4-Dichlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone;
[0939]
(R,S)-2-(4-Fluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone;
[0940]
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone;
[0941]
2-(3-Chloro-4-fluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[0942]
2-(3-Chloro-4-fluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0943]
2-(3,4-Dichlorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0944]
2-(3,4-Dichlorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone;
[0945]
2-(3,4-Difluorophenyl)-4-(4-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone;
[0946]
2-[3-(Trifluoromethyl)phenyl]-4-(2-methyl-1-propoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[0947]
2-[3-(Trifluoromethyl)phenyl]-4-(3-methyl-1-butoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone;
[0948]
2-[3-(Trifluoromethyl)phenyl]-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0949]
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0950]
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone;
[0951]
(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0952]
(S)-2-(4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0953]
(S)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0954]
(S)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0955]
(S)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0956]
(S)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0957]
(S)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0958]
(S)-2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0959]
(S)-2-(3-fluoro-4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0960]
(S)-2-(3,4-dichlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0961]
(S)-2-(3-trifluoromethyl-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-bu-
toxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0962]
(S)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0963]
(R)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0964]
(R)-2-(4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0965]
(R)-2-(4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0966]
(R)-2-(3-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0967]
(R)-2-(3-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone;
[0968]
(R)-2-(3-bromophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[0969]
(R)-2-(3-trifluoromethylphenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0970]
(R)-2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0971]
(R)-2-(3-fluoro-4-chlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0972]
(R)-2-(3,4-dichlorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0973]
(R)-2-(3-trifluoromethyl-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-bu-
toxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0974]
(R)-2-(3-bromo-4-fluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0975]
2-(3,4-Difluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0976]
2-(4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0977]
2-(4-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0978]
2-(3-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0979]
2-(3-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0980]
2-(3-bromophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0981]
2-(3-trifluoromethylphenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0982]
2-(3-chloro-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0983]
2-(3-fluoro-4-chlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0984]
2-(3,4-dichlorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0985]
2-(3-Trifluoromethyl-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl--
1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0986]
2-(3-bromo-4-fluorophenyl)-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxy]--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0987]
2-(3,4-Difluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0988]
2-(4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0989]
2-(4-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0990]
2-(3-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0991]
2-(3-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0992]
2-(3-bromophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0993]
2-(3-trifluoromethylphenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0994]
2-(3-chloro-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0995]
2-(3-fluoro-4-chlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0996]
2-(3,4-dichlorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0997]
2-(4-fluoro-3-trifluoromethylphenyl)-4-[(R)-2,3-dihydroxy-3-methyl--
1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0998]
2-(3-bromo-4-fluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxy]--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[0999]
2-(3,4-Difluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1000]
2-(4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[1001]
2-(4-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[1002]
2-(3-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[1003]
2-(3-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone;
[1004]
2-(3-bromophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone;
[1005]
2-(3-trifluoromethylphenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1006]
2-(3-chloro-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1007]
2-(3-fluoro-4-chlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1008]
2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1009]
2-(4-fluoro-3-trifluoromethylphenyl)-4-(4-hydroxy-4-methyl-1-pentyl-
oxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1010]
2-(3-bromo-4-fluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy]-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1011]
2-(3,4-Difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1012]
2-(4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1013]
2-(4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1014]
2-(3-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1015]
2-(3-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1016]
2-(3-bromophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyfidazinone;
[1017]
2-(3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-buto-
xy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1018]
2-(3-chloro-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-buto-
xy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1019]
2-(3-fluoro-4-chlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-buto-
xyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1020]
2-(3,4-dichlorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxy]-5-
-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1021]
2-(4-fluoro-3-trifluoromethylphenyl)-4-[3-(2-aminoacetyloxy)-3-meth-
yl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1022]
2-(3-bromo-4-fluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butox-
y]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1023]
2-(3,4-Difluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropan-
oyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[1024]
2-(4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]-
oxy}-3-methylbutoxy]-3-methyl-1butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[1025]
2-(4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]-
oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[1026]
2-(3-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]-
oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[1027]
2-(3-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]-
oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone;
[1028]
2-(3-bromophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]o-
xy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone;
[1029]
2-(3-trifluoromethylphenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxyp-
ropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[1030]
2-(3-chloro-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxyp-
ropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[1031]
2-(3-fluoro-4-chlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxyp-
ropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone;
[1032]
2-(3,4-dichlorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropan-
oyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone;
[1033]
2-(3-trifluoromethyl-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-d-
ihydroxypropanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone;
[1034]
2-(3-bromo-4-fluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypr-
opanoyl]oxy}-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone;
[1035]
3-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-d-
ihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate;
[1036]
3-([2-(4-fluorophenyl)-5-[4-(mehylsulfonyl)phenyl]-3-oxo-2,3-dihydr-
o-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
[1037]
3-(2-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydr-
o-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
[1038]
3-({2-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihyd-
ro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
[1039]
3-({2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihyd-
ro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
[1040]
3-({2-(3-bromophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydr-
o-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate;
[1041]
3-({2-(3-trifluoromethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo--
2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate;
[1042]
3-({2-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo--
2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate;
[1043]
3-({2-(3-fluoro-4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo--
2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate;
[1044]
3-({2-(3,4-dichlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-d-
ihydro-4-pyridazinyl}oxy)-1,1-dirnethylpropyl dihydrogen
phosphate;
[1045]
3-({2-(3-trifluoromethyl-4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3-oxo-2,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl
dihydrogen phosphate;
[1046]
3-({2-(3-bromo-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2-
,3-dihydro-4-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen
phosphate;
[1047]
2-(tert-Butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone;
[1048]
2-(tert-Butyl)-4-[3-(2-aminoacetyloxy)-3-methyl1--butoxy]-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone;
[1049]
2-(tert-butyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy}-
-3-methylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone; and
[1050]
3-({2-(tert-butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-
-pyridazinyl}oxy)-1,1-dimethylpropyl dihydrogen phosphate; or
pharmaceutically acceptable salts or prodrugs thereof.
Preparation of Compounds of the Invention
Abbreviations
[1051] As used throughout this specification and the appended
claims, the following abbreviations have been used:
[1052] ACD for acid citrate dextrose, CAP for carrageenan induced
air pouch prostaglandin, CIP for rat carrageenan pleural
inflammation model, COX-2 for cyclooxygenase-2, CPE for carrageenan
induced paw edema in rats, DBAD for di-t-butylazodicarboxylate,
DEAD for diethyl azodicarboxylate, DIAD for
disopropylazodicarboxylate, DMAP for 4-(dimethylamino)pyridine, DME
for 1,2-dimethoxyethane, DMF for N,N-dimethylformamide, DMSO for
dimethyl sulfoxide, DMSO for dimethyl sulfoxide, EDTA for
ethylenediaminetetraacetic acid, EIA for enzyme immunoassay, FAB
for fast atom bombardment, GI for gastrointestinal, HMDS, lithium
or Li HMDS for lithium 1,1,1,3,3,3-hexamethyldisilazide, HWPX for
Human Whole Platelet Cyclooxygenase-1, MCPBA for
meta-chloroperoxybenzoic acid, NSAIDs for non-steroidal
anti-inflammatory drugs, PEG 400 for polyethyleneglycol, PGE.sub.2
for prostaglandin E.sub.2, PGHS for prostaglandin endoperoxide H
synthase, RHUCX1 for recombinant human cyclooxygenase-1, RHUCX2 for
recombinant human cyclooxygenase-2, r-hu Cox1 for recombinant human
Cox-1, TEA for triethylamine, TFA for trifluoroacetic acid, and THF
for tetrahydrofuran and WISH for human amnionic whole cell
cyclooxygenase-2. The following examples illustrate the process of
the invention, without limitation.
[1053] The compounds of the invention may be prepared by a variety
of synthetic routes. Representative procedures are outlined in
Schemes 1-10, below. 28
[1054] A general route to the compounds of the invention having
Formula III, where the aryl group at the 5-position on the
pyridazinone ring is substituted with a sulfonyl group is described
in Scheme 1. Dichloro-3(2H)-pyridazinone can be treated with benzyl
chloride and potassium carbonate in methanol to provide
2-benzyl-4-chloro-5-methoxy-3(- 2H)-pyridazinone.
2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone can be treated with
a boronic acid such as 4-fluorobenzeneboronic acid (shown) and a
palladium catalyst and the methoxy group can be hydrolyzed with 48%
hydrobromic acid to provide the 5-hydroxypyridazinone compound. The
5-hydroxypyridazinone product can be treated with triflic anhydride
followed by substitution on the pyridazinone ring using
4-methylthiobenzeneboronic acid to provide the methyl thioether
compound. The methyl thioether compound which can be treated with
peracetic acid in acetic acid and methylene chloride to provide the
methyl sulfone. The benzyl group can be removed using aluminum
bromide or another suitable Lewis acid. The R group can be added
using an appropriate alkylating agent and base. 29
[1055] An alternative route to the compounds of the present
invention having Formula III is described in Scheme 2.
4-Bromothioanisole or another suitable thioether can be treated
with a trialkoxyborate, such as trimethoxyborate or
triisopropylborate to provide 4-(methylthio)benzenebo- ronic acid.
The boronic acid can be treated with 2-benzyl-4,5-dibromo-3(2H-
)-pyridazinone using tetrakis(triphenylphosphine)palladium (0) in
dimethoxyethane and then coupled with a second boronic acid such as
4-fluorobenzeneboronic acid (shown) in the presence of a palladium
catalyst to provide the thioether. The methyl thioether compound
can be treated with meta-chloroperoxybenzoic acid (MCPBA) in
methylene chloride to provide the methyl sulfone. 30
[1056] An alternative route to the compounds of the present
invention having Formula III is described in Scheme 3.
(4-Thiomethylphenyl)dimethyl- thioketene acetal, mono-S-oxide can
be prepared by reaction of 4-thiomethylbenzaldehyde (Y is
CH.sub.3S) with methyl(methylsulfinylmethy- l)sulfide and sodium
hydroxide. The thioketene acetal and methyl 4-fluorophenylacetate
or suitable ester (X is fluorine) can be treated with a strong base
such as sodium hexamethyldisilazide in THF to provide the butyrate
ester. The dithioacetal ketene can be directly cyclized to the
N-unsubstituted pyridazinone using hydrazine and a salt. The
pyridazinone can be then be alkylated using an appropriate
alkylating agent and a base. 31
[1057] In an alternate route, shown in Scheme 4, the thioacetal
ketene (X.dbd.F and Y.dbd.CH.sub.3S) can be treated with perchloric
acid to provide an ester-aldehyde as a mixture of diastereomers.
The oxidation products can be treated with hydrazine and then
oxidized with peroxyacetic acid to provide the sulfonyl
dihydropyridazinone (Y.dbd.CH.sub.3SO.sub.2). The
dihydropyridazinone can be dehydrogenated to form the pyridazinone
by treatment with reagents such as bromine in acetic acid. The R
group may be added via substitution using an appropriate alkylating
agent and base. 32
[1058] The preparation of the 5-hydroxy-2(5H)-furanones can be
accomplished by the application of methodologies published in a
variety of sources, including: J. Med. Chem., 1987, 30, 239-249 and
WO 96/36623, hereby completely incorporated by reference. These
5-hydroxy-2(5H)-furanones can be converted to
6-substituted-4,5-diaryl-3(- 2H)pyridazinones as described in
Scheme 5. 33
[1059] A general route to the compounds of the invention having
Formula III, where the aryl group at the 5-position on the
pyridazinone ring is substituted with a para-sulfonyl group is
described in Scheme 6. A mucohalo acid, such as mucobromic or
mucochloric acid, can be treated with an hydrazine having the
desired R group to provide the dihalopyridazinone compound, 6A. The
dihalo-compound can be treated with an alcohol in the presence of a
base, such as sodium or potassium hydride, to provide an alkoxide
6B where R.sup.97 is selected from alkyl, aryl, arylalkyl,
heterocyclic, and heterocyclic alkyl. (If the alkoxy group is to be
removed at a later time then methanol is the preferred alcohol.)
The alkoxy-halide can be treated with methylthiophenylboronic acid
to provide the alkoxy-pyridazinone 6C. The alkoxy group can be
converted to a hydrocarbyl group by treatment with a Grignard
reagent to provide thioether 6D where R.sup.96 is alkyl. The
thioether 6D can be oxidized with an oxidizing agent, such as
peracetic acid, meta-chloroperoxybenzoic acid and the like, to form
the sulfinyl compound 6G, or the methylsulfone compound 6E. The
methylsulfinyl compound, 6G, can be treated with trifluoroacetic
anhydride and NaOH/MeOH followed by addition of chlorine gas and
then ammonia hydroxide to provide the aminosulfonyl compound, 6H.
Alternatively, the methylsulfonyl compound, 6E, can be treated with
a diazodicarboxylate, such as DBAD, DIAD, DEAD and the like, and a
disilazane anion, such as lithium HMDS and the like, followed by
treatment with sodium acetate and hydroxylamine-O-sulphonic acid in
water to provide the aminosulfonyl compound, 6H. 34
[1060] Methylsulfonyl alkoxy pyridazinones and aminosulfonyl alkoxy
pyridazinones can be prepared as described in Scheme 7.
Alkoxy-pyridazinone, 6C, from Scheme 6, can be oxidized using
peracetic acid to provide methyl sulfone, 7A. Methyl sulfone alkoxy
pyridazinone, 7A, can be treated as described in Scheme 6 to
provide aminosulfonyl alkoxy pyridazinone, 7B. Alternatively,
alkoxy-pyridazinone 6C, from Scheme 6, can be oxidized with one
equivalent of meta-chloroperoxybenzoic acid or one equivalent of
hydroxy(tosyloxy)iodobenzene to provide the methylsulfinyl alkoxy
pyridazinone, 7C. Methylsulfinyl alkoxy pyridazinone, 7C, can be
treated as described in Scheme 6 to provide aminosulfonyl alkoxy
pyridazinone, 7B. 35
[1061] Pyridazinones of general forml 8D and 8E, wherein R.sup.80
is hydroxyalkyl, and A and B are selected from alkenyl, alkyl,
haloalkyl, and halogen, can be prepared as described in Scheme 8.
Pyridazinones of general formula 8A can be treated with diols and a
base such as sodium hydride or potassium hydride in TMF to
selectively provide 4-substituted pyridazinones of general formula
8B. 4-Substituted pyridazinones of general formula 8B can be
treated with 4-(methylthio)phenylboronic acid, a base such as
potassium carbonate, and a palladium catalyst such as
dichlorobis(triphenylphosphine)palladium(II) in ethanol to provide
methylthio compounds of general formula 8C. Methylthio compounds of
general formula 8C can be oxidized with meta-chloroperoxybenzoic
acid or peracetic acid to provide methylsulfones of general formula
8D. Methylsulfones of general formula 8D can be processed as
described in Scheme 6 to provide aminosulfonyl compounds of general
formula 8E. Alternatively, methylthio compounds of general formula
8C can be oxidized to the sulfoxide and then processed as described
in Scheme 6 to provide aminosulfonyl compounds of general formula
8E. 36
[1062] Preparation of compounds of the invention having Formula
III, where the group at the 4-position on the pyridazinone ring is
a substituted alkyl or alkenyl group is described in Scheme 9.
Pyridazinone 9A can be treated with a halogenating reagent, such as
NBS and peroxide, to provide bromo compound 9B. The bromo compound
can be reacted with an alcohol and a weak base, such as sodium or
potassium carbonate, to provide 4-alkyl-ether, 9C where R.sup.95 is
alkyl. Alternatively, bromo compound 9B can be treated with a thio
compound in the presence of a base, such as silver carbonate, to
provide 4-alkyl-thioether, 9D where R.sup.94 is alkyl.
Alternatively, bromo compound 9B can be treated with an amine and a
weak base, such as sodium or potassium carbonate to provide
4-alkylaminoalkyl compound 9E where R.sup.93 is alkyl. 37
[1063] A general route to the compounds of the present invention
having Formula III, where the group at the 4-position on the
pyridazinone ring can be readily substituted is illustrated in
Scheme 10. Alkoxide, 10A, where R.sup.97 is methyl, can be treated
with a base, such as sodium or potassium hydroxide, to provide
4-hydroxy-pyradizinone, 10B. The alcohol can be treated with
p-toluenesulfonyl chloride to provide tosyloxy compound, 10C. The
tosyloxy compound can be readily substituted with a compound
R.sup.92Z that can undergo a S.sub.NAr reaction. Examples of these
compounds are alcohols, thiols, amines or hydrocarbyl anions.
[1064] Compounds of the present invention include, but are not
intended to be limited to, the following Examples:
EXAMPLE 1
4-(Methylthio)benzeneboronic Acid
[1065] A stirred solution of 4-bromothioanisole (5.0 g, 0.0246 mol)
in anhydrous tetrahydrofliran (THF) was chilled to -78.degree. C.
under a nitrogen atmosphere. A 2.5 M solution of n-butyl lithium
(12 mL, 0.030 mol) in hexanes was added dropwise to the chilled
solution. When the addition was complete, the reaction mixture was
stirred at -78.degree. C. for about 45 minutes. Trimethylborate
(8.5 mL, 0.0748) was introduced via syringe. The reaction mixture
was then allowed to warm to room temperature overnight. The room
temperature solution was treated successively with 10% aqueous
sodium hydroxide solution (50 mL) and water (33.5 mL) and stirred
at room temperature for 1 hour. The reaction mixture was lowered to
about pH=4-5 using 10% aqueous citric acid and the THF was removed
under reduced pressure. The aqueous residue was saturated with
sodium chloride and extracted with ethyl acetate. The organic
extract was dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure to provide a white solid which
was washed with hexanes to provide the product as a white solid
(yield: 1.5 g; 36%). mp 170.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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
[1066] Benzyl bromide (0.59 mL, 0.005 mol) was added to a stirred
solution of 4,5-dibromo-3(2H)-pyridazinone (1.27 g, 0.005 mol) and
potassium carbonate (0.76 g, 0.0055 mol) in 20 mL of anhydrous
dimethylformamide (DMF). The solution was stirred overnight at room
temperature, and partitioned between aqueous citric acid and ethyl
acetate. The aqueous layer was extracted twice with ethyl acetate.
The combined organic extracts were washed with brine, dried over
MgSO.sub.4 and filtered. The filtrate was concentrated under
reduced pressure to provide a beige solid, which was purified by
column chromatography (silica gel, 9:1 hexanes/ethyl acetate). The
product was obtained as a white solid (yield: 1.32 g, 76.7%). mp
95-96.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.31 (s,
2H), 7.29-7.37 (m, 3H), 7.41-7.47 (m, 2H), 7.79 (s, 1H). MS
(DCI/NH.sub.3) m/z 345 (M+H).sup.+. IR (KBr) 1645 cm.sup.-1.
EXAMPLE 3
2-Benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1067] A solution of the boronic acid (0.318 g, 0. mol), from
Example 1, the dibromopyridazinone (0.975 g, 0. mol), prepared
according to the method of Example 2, and
tetrakis(triphenylphosphine)palladium (0) (0.16 g, 0.0142 mol), in
dimethoxyethane (30 mL) was prepared. A 2 M aqueous solution of
sodium carbonate (2.83 mL, 0. mol) was added to the dimethoxyethane
solution and the mixture was heated at reflux. After 16 hours, a
chromatographic (TLC) check (9:1 hexanes/ethyl acetate) indicated
that both starting materials were still present and a fresh aliquot
of palladium catalyst was added. The reaction mixture was stirred
at reflux for an additional 5 hours, allowed to cool to room
temperature and stand over the weekend. The volatile materials were
removed under reduced pressure and the residue was partitioned
between water and ethyl acetate. The aqueous layer was extracted
with ethyl acetate. The combined organic extracts were washed with
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure to provide an oil which was
purified by column chromatography (silica gel, 95:5 hexanes/ethyl
acetate). Fractions containing the desired product were combined
and concentrated under reduced pressure. This material was
rechromatographed (95:5 hexanes/ethyl acetate) to furmish 0.200 g
of a beige solid. The solid was crystallized from ether/hexanes to
provide white crystals (yield: 110 mg, 15%) mp 115-118.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.53 (s, 3H), 5.40 (s,
2H), 7.30-7.42 (m, 7 H), 7.49-7.54 (m, 2H), 7.65 (s, 1H). MS
(DCI/NH.sub.3) m/z 387 (M+H).sup.+.
EXAMPLE 4
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1068] A solution of the product from Example 3, (0.100 g, 0. mol),
4-fluorobenzeneboronic acid (0.072 g, 0. mol),
tetrakis(triphenylphosphin- e)palladium (0) (0.015 g, 0. mol), and
a 2 M aqueous solution of sodium carbonate (0.64 mL, 0. mol) in 30
mL of dimethoxyethane (DME) was stirred at reflux for 16 hours. A
fresh aliquot of palladium catalyst was added with an additional
equivalent of the boronic acid. The reaction was maintained at
reflux for 24 hours. The volatile materials were removed under
reduced pressure and the residue was partitioned between water and
ethyl acetate. The aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over
MgSO.sub.4, and filtered. The filtrate was adsorbed onto silica
gel. The silica gel/product was placed at the top of a column of
silica gel and the product eluted with 93:7 hexanes/ethyl acetate.
Fractions containing product were combined and concentrated under
reduced pressure. The residue was purified fuirther by a second
column chromatography (silica gel, 95:5 hexanes/ethyl acetate).
Fractions containing product were concentrated under reduced
pressure to provide a viscous oil (yield: 0.028 g, 27%). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 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 (DCIFNH.sub.3) m/z 403 (M+H).sup.+.
EXAMPLE 5
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e
[1069] A solution of meta-chloroperoxybenzoic acid (MPCBA) (0.039
g, 0.00013 mol) in dichloromethane (5 mL) was added dropwise to a
stirred solution of the sulfide (0.027 g, 0. mol), from Example 4,
in chilled (0.degree. C.) dichloromethane (10 mL). After 5 minutes,
TLC (1:1 hexanes/ethyl acetate) indicated that the starting sulfide
had been consumed. The reaction was quenched with aqueous sodium
sulfite. The organic layer was washed twice with aqueous sodium
hydroxide and once with brine. The dichloromethane solution was
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 7:3 hexanes/ethyl acetate) to provide
the desired sulfone product. Further elution with 100% ethyl
acetate removed the sulfoxide from the column. The sulfoxide
product was re-subjected to the MCA oxidant (0.04 g, 1 hour,
0.degree. C.) and worked-up as described above. The residue
obtained was combined with the sulfone from the first column and
the mixture was purified by column chromatography (silica gel, 7:3
hexanes/ethyl acetate). Fractions containing product were combined
and concentrated under reduced pressure. The residue was
crystallized from ether/hexanes to provide the product as white
crystals (yield: 13 mg, 44.6%). mp 101-103.degree. C. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 435 (M+H).sup.+. MS (F, high res.) calculated:
m/z 435.1179 (M+H).sup.+, found: m/z 435.1184 (M+H).sup.+.
EXAMPLE 6
2-Benzyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone
[1070] To a mixture of
2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone, prepared according
to the method of (S. Cho et al. described in J. Het. Chem.,
(1996),33, 1579-1582), (2.94 g; 10 mmol), 4-fluorobenzeneboronic
acid (1.54 g; 11 mmol), and CsF (3.04 g; 22 mmol) in 25 mL of
anhydrous DME, under N.sub.2, was added Pd(Ph.sub.3P).sub.4 (347 mg
0.3 mmol). After addition, the mixture was heated at reflux for at
100.degree. C., for 18 hours. The mixture was concentrated in vacuo
and the residue partitioned between ethyl acetate and water. The
acetate layer was washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo. The solid residue was suspended in ethyl
ether-hexanes and filtered to provide a solid product (yield: 3.1
g; about 100%;>95% purity). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.90 (s, 3H), 5.36 (s, 2H), 7.09 (t, J=9 Hz, 2H), 7.31 (m,
3H), 7.50 (m, 4H), 7.91 (s, 1H). MS (DCI/NH.sub.3) m/z 311
(M+H).sup.+, 328 (M+NH.sub.4).sup.+.
EXAMPLE 7
2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone
[1071] The product from Example 6 (1.24 g; 4 mmol) in 20 mL of
acetic acid was treated with aqueous 48% HBr (25 mL). The mixture
was heated at reflux for about 5 to about 8 hours (TLC analysis).
The mixture was concentrated in vacuo. The product was dissolved in
ethyl acetate, washed with 10% bicarbonate, brine and concentrated
in vacuo. The residue was treated with diethyl ether-hexanes (2:1)
and the solid was filtered to provide an almost pure product
(yield: 1.16 g; 98%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
5.24 (2H), 7.21 (m, 2H), 7.30 (m, 5H), 7.55 (m, 2H), 7.85 (s, 1H),
11.31 (br s, 1H). MS (DCI/NH.sub.3) m/z 296 (M+H).sup.+, 314
(M+NH.sub.4).sup.+.
EXAMPLE 8
2-Benzyl-4-(4-fluorophenyl)-5-(trifluoromethylsulfopyloxy)-3(2H)-pyridazin-
one
[1072] A solution of the product from Example 7, (89 mg, 0.3 mmol)
in 2.5 mL of anhydrous pyridine under a N.sub.2 atmosphere and
maintained at 0.degree. C. was treated with triflic anhydride
(Tf.sub.2O; 0.06 mL; 0.32 mmol) dropwise. The resulting mixture was
stirred at 0.degree. C. for 5 minutes and at room temperature for
16 hours. (The pyridine and Tf.sub.2O should be pure for good
results. Occasionally an additional amount of Tf.sub.2O is
necessary to force the reaction to completion.) The mixture was
then poured to a cold solution of citric acid and extracted with
ethyl acetate to obtain an almost pure product (yield: 127 mg,
about 99%/). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.34 (s,
2H), 7.35 (mn, 7H), 7.60 (m, 2H), 8.48 (s, 1H). MS (DCI/NH.sub.3)
m/z 429 (M+H).sup.+, 446 (M+NH.sub.4).sup.+.
EXAMPLE 9
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1073] A mixture of the product from Example 8 (154 mg, 0.36 mmol),
4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et.sub.3N
(0.11 mmol; 0.8 mmol) and Pd(Ph.sub.3P).sub.4 (30 mg, 0.025 mmol)
in 15 mL of toluene was heated at reflux, about 100.degree. C. for
about 45 minutes. The mixture was concentrated in vacuo and the
residue purified by column chromatography (hexanes-ethyl acetate
3:1) to provide the title compound (yield: 98 mg, 68%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 2.47 (s, 3H), 5.38 (s, 2H), 6.98 (m,
4H), 7.12 (m, 2H), 7.20 (m, 2H), 7.35 (mn, 3H), 7.54 (m, 2H), 7.86
(s, 1H). MS (DCI/NH.sub.3) m/z 403 (M+H).sup.+, 420
(M+NH.sub.4).sup.+.
EXAMPLE 10
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e
[1074] To a solution of the product from Example 9 (140 mg, 0.348
mmol), in 10 mL of CH.sub.2Cl.sub.2, at 0.degree. C. was added
peracetic acid (CH.sub.3COOOH; 0.5 mL; 30%). The mixture was
stirred at 0.degree. C. for 90 minutes. The dichloromethane was
then removed in vacuo. The residue was dissolved in ethyl acetate,
washed with 10% NaHCO.sub.3, and brine. The ethyl acetate was
removed under reduced pressure. The residue was chromatographed
(silica gel, CH.sub.2Cl.sub.2-diethyl ether 19:1) to provide the
title compound (yield: 130 mg, 86%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 434 (M+H).sup.+, 452 (M+NH.sub.4).sup.+.
EXAMPLE 11
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
[1075] A mixture of the product from Example 10 (37 mg, 0.085 mmol)
and AlBr.sub.3 (70 mg, 0.26 mmol) in 10 mL of toluene was heated at
reflux, about 80.degree. C. for about 15 minutes and cooled to
0.degree. C. The cooled mixture was treated with 1N HCl and
extracted with ethyl acetate. The acetate layer was washed with
water, brine and concentrated in vacuo. Purification of the residue
on silica gel column (ethyl acetate as an eluent) provided the
title compound (yield: 22 mg, 76%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.07 (s, 3H), 7.00 (t, J=9 Hz, 2H), 7.20 (m,
2H), 7.56 (d, J=9 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9 Hz, 2H),
10.94 (br s, 1H). MS (DCI/NH.sub.3) m/z 345 (M+H).sup.+, 362
(M+NH.sub.4).sup.+.
EXAMPLE 12
2-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e
EXAMPLE 12A
2-Phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone
[1076] The title compound was prepared according to the method of
(S. Cho et al. described in J. Het. Chem., (1996), 33, 1579-1582),
starting with the N-phenyl-dichloropyridazinone. A mixture of
2-phenyl-4,5-dichloro-3(2- H)-pyridazinone (1 g, 4.1 mmol) and
finely powdered, anhydrous K.sub.2CO.sub.3 (580 mg, 4.2 mmol) in 50
mL of methanol was heated at reflux for 5 hours and concentrated in
vacuo. The residue was partitioned between water and ethyl acetate.
The acetate layer was washed with water, and brine to provide
2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone (yield: 920 mg,
95%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.15 (s, 3H),
7.50 (m, 5H), 8.43 (s, 1H). MS (DCI/NH.sub.3) m/z 237 (M+H).sup.+,
254 (M+NH.sub.4).sup.+.
EXAMPLE 12B
2-Phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone
[1077] The 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone product
was coupled with 4-fluorophenylboronic acid according to the method
of Example 6 to provide
2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazi- none (yield:
1.1 g; 96%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 297 (M+H).sup.+.
EXAMPLE 12C
2-Phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone
[1078] The 2-phenyl-4-(4-fluorophenyl)-5-methoxy-3(2H)-pyridazinone
product was treated with 48% HBr according to the method of Example
7 to frish 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone
(yield: 957 mg, 92%). MS (DCI/NH.sub.3) m/z 283 (M+H).sup.+, 300
(M+NH.sub.4).sup.+.
EXAMPLE 12D
2-Phenyl-4-(4-fluorophenyl
-5-trifluoromethanesulfonyloxy-3(2H)-pyridazino- ne
[1079] The 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone
product was sulfonylated according to the method of Example 8 to
furnish
2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazin-
one (yield: 1.35 g; 96%) MS (DCI/NH.sub.3) m/z 415 (M+H).sup.+, 432
(M+NH.sub.4).sup.+.
EXAMPLE 12E
2-Phenyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-3(2H)-pydazinone
[1080] The
2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-
-pyridazinone was coupled with 4-(methylthio)phenylboronic acid as
in Example 9 to provide
2-phenyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-
-3(2H)-pyridazinone (yield: 915 mg, 92%) which was immediately
oxidized with peracetic acid as in Example 9 to provide the title
compound after column chromatography (silica gel, 1:1 hexanes-ethyl
acetate) and crystallization from diethyl ether-hexanes (yield: 288
mg, 69%). mp 219-220.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 421 (M+H).sup.+, 438
(M+NH.sub.4).sup.+.
EXAMPLE 13
4-Fluorophenylacetic Acid, Methyl Ester
[1081] A catalytic amount (0.5 mL) of concentrated sulfuric acid
was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20
mol) in 500 mL of methanol. The solution was stirred at reflux for
4 hours. The volatile materials were removed under reduced pressure
to furnish a colorless oil which was dissolved in ether/ethyl
acetate and washed with 2 N aqueous Na.sub.2CO.sub.3, brine, dried
over MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure to provide an oil which was dried overnight under
high vacuum (yield: 33.6 g; 95%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J=9 Hz, 2H), 7.20-7.28
(m, 2H). MS (DCI/NH.sub.3) m/z 186 (M+NH.sub.4).sup.+.
EXAMPLE 14
[4-(Methylthio)phenyl]dimethylthioketene Acetal, Mono-S-oxide
[1082] A mixture of methyl(methylsulfinylmethyl)sulfide (50 g, 0.40
mol), and finely powdered sodium hydroxide (3.12 g, 0.078 mol) was
stirred at 70.degree. C. for 4 hours. 4-(Methylthio)benzaldehyde
(27.4 mL, 0.195 mol) was then added in one lot and the reaction
mixture was stirred at 70.degree. C. for an additional 4 hours. The
mixture was cooled to room temperature and partitioned between 10%
aqueous citric acid and dichloromethane. The organic layer was
dried over MgSO.sub.4 and filtered. The filtrate was concentrated
under reduced pressure to provide a brown oil. The oil was purified
by column chromatography (7:3 hexanes/ethyl acetate) to provide a
solid. The solid was crystallized from ether/hexanes (yield: 24.7
g; 72%). mp 52-53.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 259
(M+H).sup.+ and m/z 276 (M+NH.sub.4).sup.+.
EXAMPLE 15
2-(4-Fluorophenyl)-3-[4-(methylthio)phenyl]-4-methylthio-4-methylsulfinyl--
n-butyric Acid, Methyl Ester
[1083] A solution of the ester product from Example 13, (16.24 g,
0.0966 mol) in 50 mL of THF was added dropwise to a stirred
solution of 1.0 M sodium hexamethyldisilazide in THF (96.6 mL,
0.0966 mol), maintained at 0.degree. C., under an atmosphere of dry
nitrogen. After 30 minutes, a solution of the ketene thioacetal,
prepared according to the method of Example 14 (20.8 g, 0.0805
mol), in 50 mL of THF, was added dropwise to the reaction mixture
maintained at 0.degree. C. After 4 hours, the reaction mixture was
acidified with 10% aqueous citric acid. The aqueous layer was
washed twice with ethyl acetate. The organic extracts were
combined, washed with brine, dried over MgSO.sub.4 and filtered.
The filtrate was concentrated under reduced pressure to provide a
brown oil which was purified by column chromatography (85:15 to 1:1
dichloromethane/ethyl acetate gradient). Several products having
different Rf values and NMR spectra were isolated. These compounds
had identical mass spectra. The mixture of compounds was carried on
in the following reactions (yield: 22.4 g; 65%). MS (DCI/NH.sub.3)
m/z 444 (M+NH.sub.4).sup.+.
EXAMPLE 16
2-(4-Fluorophenyl)-3-[4-(methylthio)phenyyl]-3-formyl-n-propanoic
Acid, Methyl Ester
[1084] The mixture of compounds from Example 17, (9.0 g, 0.021 mol)
were dissolved in acetonitrile (80 mL) and cooled to 0.degree. C.
Perchloric acid (60%; 1.06 g, 0.006 mol) was added to the stirred
solution. The reaction mixture was stirred at 0.degree. C. for 8
hours, and quenched with 2 N aqueous Na.sub.2CO.sub.3. The
acetonitrile was removed under reduced pressure and the resulting
aqueous mixture was extracted with ethyl acetate. The organic
solution was dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure to give a yellow oil which was
purified by column chromatography (silica gel, 7:3 hexanes/ethyl
acetate). Fractions containing the highest Rf diastereomers from
the product mixture were concentrated in vacuo and the residue was
crystallized from methanol to furnish the title aldehyde-ester
compound as white crystals (yield: 0.27 g, 4.0%).
mp=112-113.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) m/z 333 (M+H).sup.+ and m/z 350 (M+NH.sub.4).sup.+.
Fractions containing lower Rf compounds from the product mixture
were concentrated in vacuo and the residue was identified as the
hydrate of the aldehyde-ester (yield: 2.6 g, 35.2%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 333 (M+H).sup.+ and m/z 350
(M+NH.sub.4).sup.+.
[1085] The lowest Rf compound was identified as the hydroxy lactone
formed when a hydroxy group from the hydrate displaces the methoxy
group from the ester (yield: 1.1 g, 16.4%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.45 (s, 3H), 3.54-3.71 (m, 1H), 3.98-4.21 (m,
1H), 4.61 (br s, 1H), 5.85-6.01 (m, 1H), 6.98 (t, J=9 Hz, 2H),
7.12-7.27 (m, 6H). MS (DCI/NH.sub.3) m/z 336
(M+NH.sub.4).sup.+.
EXAMPLE 17
4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-4,5-dihydro-3(2H)-pyridazinone
[1086] The aldehyde-ester, hydrate, and hydroxy lactone from
Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol.
This solution was treated with hydrazine monohydrate (0.15 mL, 30
mmol) and the resulting solution was stirred at reflux in a
Soxhelet apparatus containing molcular sieves. After 18 hours, the
reaction mixture was cooled and the volatile materials removed
under reduced pressure. The residue was partitioned between ethyl
acetate and aqueous HCl. The aqueous layer was washed twice with
ethyl acetate. The combined organic extracts were washed twice with
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by
column chromatography (4:1 hexanes/ethyl acetate) to obtain the
title compound (yield: 50 mg, 53%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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(br),
1H). MS (DCI/NH.sub.3) m/z 315 (M+H).sup.+ and m/z 332
(M+NH.sub.4).sup.+.
EXAMPLE 18
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4,5-dihydro-3(2H)-pyridazi-
none
[1087] A solution of peracetic acid, 32% in acetic acid, (0.4 mL,
1.6 mmol) was added to a stirred solution of the sulfide from
Example 17 (0.050 g, 0.16 mmol) in dichloromethane, and maintained
at 0.degree. C. The reaction mixture was stirred for 5 hours at
0.degree. C. then diluted with water. The organic layer was dried
over MgSO.sub.4 and filtered. The filtrate was concentrated under
reduced pressure to provide an oil which solidified on trituration
with ether (yield: 47 mg, 85%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 364 (M+NH.sub.4).sup.+.
EXAMPLE 19
4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
[1088] The dihydropyridazinone product from Example 18 (47 mg,
0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025
mL, 0.16 mmol) was added to the solution and the reaction mixture
was stirred at 95.degree. C. for 20 minutes. The reaction mixture
was concentrated under reduced pressure. The residue was
partitioned between ethyl acetate and water. The organic layer was
washed with brine, dried over MgSO.sub.4 and filtered. The filtrate
was concentrated under reduced pressure to provide a solid which
was eluted through a short pad of silica gel with ethyl acetate.
The title compound was crystallized from ethyl acetate/hexanes
(yield: 35 mg, 75%). mp 255-256.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 345 (M+H).sup.+ and m/z 362
(M+NH.sub.4).sup.+.
EXAMPLE 20
2-(4-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-methylsulfonyl)phenyl]-3(2H)-py-
rdazinone
[1089] A solution of the nitrogen-unsubstituted pyridazinone
product from Example 19 (160 mg, 0.465 mmol), K.sub.2CO.sub.3 (193
mg, 1.4 mmol), 4-fluorobenzylbromide (0.09 mL, 0.7 mmol) and NaI
(catalytic) in 10 mL of anhydrous N,N-dimethylformamide (DMF) was
stirred at room temperature for 18 hours. The reaction mixture was
quenched with 2N HCl, extracted with ethyl acetate (2.times.20 mL),
washed with brine and water, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography (2:2:6 ethyl acetate/dichloromethane/pentanes).
Crystallization from ether/pentanes provided white crystals (yield:
110 mg, 52%). mp 153-154.degree. C. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 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.sub.3) m/z 453 (M+H).sup.+.
EXAMPLE 21
2-(Phenylpropargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1090] The title compound was prepared according to the method of
Example 20, substituting phenylpropargyl bromide for 4-fluorobenzyl
bromide. mp 100-103.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) mi/z 459
(M+H).sup.+.
EXAMPLE 22
2-(2,4-Difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1091] The title compound was prepared according to the method of
Example 20, substituting 2,4-difluorobenzyl bromide for
4-fluorobenzyl bromide. mp 179-182.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 471 (M+H).sup.+.
EXAMPLE 23
2-(Methyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1092] The title compound was prepared according to the method of
Example 20, substituting 3-chloro-2-methylpropene for
4-fluorobenzyl bromide. mp 140-142.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 399
(M+H).sup.+.
EXAMPLE 24
2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1093] The desired compound was prepared according to the method of
Example 20 substituting 4-bromo-2-methyl-2-butene for
4-fluorobenzyl bromide. mp 169-172.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 413
(M+H).sup.+.
EXAMPLE 25
2-(2-Trifluoromethylbenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1094] The title compound was prepared according to the method of
Example 20, substituting 2-(trifluoromethyl)benzyl bromide for
4-fluorobenzyl bromide. mp 87-90.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 503 (M+H).sup.+.
EXAMPLE 26
2-(Cyclopropylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1095] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)cyclopropane for
4-fluorobenzyl bromide. mp 118-121.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 399
(M+H).sup.+ and m/z 416 (M+NH.sub.4).sup.+.
EXAMPLE 27
2-(2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1096] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)pyridine for 4-fluorobenzyl
bromide. mp 182-184.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) m/z 436 (M+H).sup.+.
EXAMPLE 28
2-(4-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1097] The title compound was prepared according to the method of
Example 20, substituting 4-(bromomethyl)pyridine for 4-fluorobenzyl
bromide. mp 153-156.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) m/z 436 (M+H).sup.+.
EXAMPLE 29
2-(3-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1098] The title compound was prepared according to the method of
Example 20, substituting 3-(bromomethyl)pyridine for 4-fluorobenzyl
bromide. mp 160-161.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) m/z 436 (M+H).sup.+.
EXAMPLE 30
2-(6-Fluoroquinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1099] The title compound was prepared according to the method of
Example 20, substituting 2-(chloromethyl)-6-fluoroquinoline for
4-fluorobenzyl bromide. mp 116-119.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 504
(M+H).sup.+.
EXAMPLE 31
2-(Quinolin-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1100] The title compound was prepared according to the method of
Example 20, substituting 2-(chloromethyl)-quinoline for
4-fluorobenzyl bromide. mp 97-100.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 386
(M+H).sup.+.
EXAMPLE 32
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pridazineth-
ione
[1101] A mixture of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone, prepared according to the method of Example
5, (109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmnol)
in 15 mL of toluene was stirred at reflux for 48 hours. The mixture
was concentrated in vacuo and the residue was chromatographed
(silica gel, ethyl acetate) to provide the title compound (yield:
100 mg, 88%). mp 88-90.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 451 (M+H).sup.+.
EXAMPLE 33
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone
[1102] Example 33 was prepared using a similar procedure as that
described in (M. De Vleeschauwer and J. V. Gauthier, Syn. Lett.,
(1997) 375).
EXAMPLE 33A
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinon-
e
[1103] A solution of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone, prepared according to the method of Example 4,
(450 mg, 1.12 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added dropwise
to a suspension of hydroxy(tosyloxy)iodobenzene (439 mg, 1.12 mmol)
in CH.sub.2Cl.sub.2 (15 mL) and the mixture was stirred until a
clear solution was obtained (about 1 hour). The reaction mixture
was then washed with water and dried with MgSO.sub.4. Removal of
solvent in vacuo provided the corresponding sulfoxide (yield: 485
mg, about 100%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H), 7.86 (s, 1H). MS (DCI/NH.sub.3) m/z 419
(M+H).sup.+, 436 (M+NH.sub.4).sup.+.
EXAMPLE 33B
2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)-3(2H)-pyridazi-
none
[1104] A suspension of the sulfoxide from Example 33A, (485 mg,
1.12 mmol) and AcONa (1.4 g) in 15 mL of Ac.sub.2O was stirred at
reflux for 2 hours and concentrated in vacuo. The residue was
distilled twice with toluene, dissolved in 25 mL of
CH.sub.2Cl.sub.2, cooled to 0.degree. C., and treated with
CH.sub.3CO.sub.3H (1 mL). After 1 hour, the mixture was washed,
successively, with saturated NaHCO.sub.3 and brine. The solvent was
removed in vacuo. The residue was chromatographed (silica gel, 1:1
hexanes-ethyl acetate) to provide the desired product,
2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)-3(2H)-pyridaz-
inone (yield: 150 mg, 27%). MS (DCI/NH.sub.3) m/z 493
(M+H).sup.+.
EXAMPLE 33C
2-Benzyl-4-(4-fluorophenyl)-5-[4-(sodiumsulfinate)phenyl]-3(2H)-pridazinon-
e
[1105] To a solution of the acetoxymethylsulfone from Example 33B
(150 mg, 0.305 mmol), in 10 mL of THF and 5 mL of methanol at
0.degree. C., was added 1 N NaOH (0.305 mL, 0.305 mmol). The
mixture was stirred at 0.degree. C. for 1 hour. The mixture was
concentrated in vacuo, the residual water was removed via an
EtOH/toluene azeotrope followed by a toluene azeotrope. The residue
was dried under high vacuum for 48 hours to provide the sodium
sulfinate (yield: 140 mg, 96%). MS (DCI/NH.sub.3) m/z 443
(M+H).sup.+
EXAMPLE 33D
2-Benzyl-4-(4-fluorophenyl)-5-[4-(chlorosulfonyl)phenyl]-3(2H)-pyridazinon-
e
[1106] The sodium sulfinate (about 0.31 mnmol) in CH.sub.2Cl.sub.2
(10 mL) was treated at 0.degree. C. with SOCl.sub.2 (0.033 mL, 0.4
mmol) for 2 hours. The mixture was washed with brine, dried with
MgSO.sub.4 and concentrated in vacuo to provide the crude sulfonyl
chloride (yield: 145 mg, about 100%). MS (DCI/NH.sub.3) m/z 455
(M+H).sup.+.
EXAMPLE 33E
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone
[1107] The crude chloride prepared according to the method of
Example 33D, in 10 mL of THE, was added to a solution of 50%
NH.sub.4OH, in 10 mL of THF, maintained at 0.degree. C. The mixture
was allowed to warm to room temperature over 3.5 hours. The THF was
removed in vacuo and the product was extracted with ethyl acetate.
The ethyl acetate was removed in vacuo and the residue was treated
with diethyl ether-hexanes 2:1 to provide the sulfonamide (yield:
113 mg, 84%). mp 188-191.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 436 (M+H).sup.+.
EXAMPLE 34
2-(2,2,2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-phenyl]--
3(2H)-pyridazinone
[1108] The title compound was prepared according to the method of
Example 20, substituting 2-iodo-1,1,1-trifluoroethane for
4-fluorobenzyl bromide. mp 177-179.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z
427 (M+H).sup.+ and m/z 444 (M+NH.sub.4).sup.+.
EXAMPLE 35
2-(3,3-Dichloro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methIsulfonyl)phenyl]-
-3(2H-pyridazinone
[1109] The title compound was prepared according to the method of
Example 20, substituting 1,1,3-trichloropropene for 4-fluorobenzyl
bromide. mp 150-152.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) m/z
453 (M+H).sup.+ and m/z 470 (M+NH.sub.4).sup.+.
EXAMPLE 36
2-(3-Phenyl-2-propenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1110] The title compound was prepared according to the method of
Example 20, substituting cinnamyl bromide for 4-fluorobenzyl
bromide. mp 165-167.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 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.sub.3) m/z 461 (M+H).sup.+
and m/z 478 (M+NH.sub.4).sup.+.
EXAMPLE 37
2-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methyylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1111] The title compound was prepared according to the method of
Example 20, substituting methyl 4-(bromomethyl)benzoate for
4-fluorobenzyl bromide and hydrolysis of the resulting ester. mp
239-241.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z
479 (M+H).sup.+ and m/z 496 (M+NH.sub.4).sup.+.
EXAMPLE 38
2-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1112] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)-5-methylthiazole for
4-fluorobenzyl bromide. mp 114-116.degree. C. .sup.1H NMR
(d.sub.6-DMSO, 300 MHz) .delta. 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.sub.3) m/z 356
(M+H).sup.+.
EXAMPLE 39
2-(5-Chlorothiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1113] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)-5-chlorothiazole for
4-fluorobenzyl bromide. mp 185-186.degree. C. .sup.1H NMR
(d.sub.6-DMSO, 300 MHz) .delta. 2.32 (s, 3H), 5.50 (s, 2H), 7.15
(m, 2H), 7.24 (m, 2H), 7.47 (m, 2H), 7.87 (m, 3H), 8.14 (s, 1H). MS
(DCI/NH.sub.3) m/z 476 (M+H).sup.+ and m/z 493
(M+NH.sub.4).sup.+.
EXAMPLE 40
2-(2,3,3,4,4,4-Hexafluorobuten-1-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone
[1114] The title compound was prepared according to the method of
Example 20, substituting 2,2,3,3,4,4,4-heptafluoro-1-iodobutane for
4-fluorobenzyl bromide. Under the alkylation conditions,
elimination of HF provided the unsaturated product. mp
167-169.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 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.sub.3) m/z 507 (M+H).sup.+ and m/z 524
(M+NH.sub.4).sup.+.
EXAMPLE 41
2-(2,4-Difluorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyrdazinone
[1115] The title compound was prepared according to the method of
Example 20, substituting 2-chloro-2',4'-difluoroacetophenone for
4-fluorobenzyl bromide. mp 191-192.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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
(DCINI.sub.3) m/z 499 (M+H).sup.+ and m/z 516
(M+NH.sub.4).sup.+.
EXAMPLE 42
2-(5-Chlorothien-2-ylmethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1116] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)-5-chlorothiophene for
4-fluorobenzyl bromide. mp 139-141.degree. C. .sup.1H NMR
(d.sub.6-DMSO, 300 MHz) .delta. 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.sub.3) m/z 474 (M+H).sup.+
and m/z 492 (M+NH.sub.4).sup.+.
EXAMPLE 43
2-(5-Methylthien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1117] The title compound was prepared according to the method of
Example 20, substituting 2-(bromomethyl)-5-methylthiophene for
4-fluorobenzyl bromide. mp 172-175.degree. C. .sup.1H NMR
(d.sub.6-DMSO, 300 MHz) .delta. 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.sub.3) m/z 441 (M+H).sup.+ and m/z 458
(M+NH.sub.4).sup.+.
EXAMPLE 44
2-(4-Diethylaminophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1118] The title compound was prepared according to the method of
Example 20, substituting 2-chloro-4'-diethylaminoacetophenone for
4-fluorobenzyl bromide. mp 105-108.degree. C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 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, 4H), 7.90 (s, 1H). MS (DCI/NH.sub.3) m/z 534
(M+H).sup.+.
EXAMPLE 45
2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1119] The title compound was prepared according to the method of
Example 20, substituting 2,3,4,5,6-pentafluorobenzyl bromide for
4-fluorobenzyl bromide. mp 115-116.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3) m/z 525 (M+H).sup.+
and m/z 542 (M+NH.sub.4).sup.+.
EXAMPLE 46
2-(Phenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-prridaz-
inone
[1120] The title compound was prepared according to the method of
Example 20, substituting 2-bromoacetophenone for 4-fluorobenzyl
bromide. mp 228-230.degree. C. .sup.1H NMR (CDCl.sub.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, 1H), 8.04 (d, J=7 Hz, 2H).
MS (DCI/NH.sub.3) m/z 463 (M+H).sup.+ and m/z 480
(M+NH.sub.4).sup.+.
EXAMPLE 47
2-(4-Chlorophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone
[1121] The title compound was prepared according to the method of
Example 20, substituting 2-bromo-4'-chloroacetophenone for
4-fluorobenzyl bromide. mp 186-188.degree. C. .sup.1NMR
(CDCl.sub.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,
1H), 7.98 (d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 497 (M+H).sup.+
and m/z 514 (M+NH.sub.4).sup.+.
EXAMPLE 48
2-(Propargyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-prrida-
zinone
[1122] The title compound was prepared according to the method of
Example 20, substituting propargyl bromide for 4-fluorobenzyl
bromide. mp 196-198.degree. C. .sup.1H NMR (CDCl.sub.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.sub.3) m/z 383
(M+H).sup.+ and m/z 400 (M+NH.sub.4).sup.+.
EXAMPLE 49
2-(4-Cyanophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1123] The title compound was prepared according to the method of
Example 20, substituting 2-bromo-4'-cyanoacetophenone for
4-fluorobenzyl bromide. mp 188-189.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3) m/z 488 (M+H).sup.+.
EXAMPLE 50
2-(.alpha.-Methyl-4-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone
[1124] The title compound was prepared according to the method of
Example 20, substituting .alpha.-methyl-4-fluorobenzyl bromide for
4-fluorobenzyl bromide. mp 162-164.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3) m/z 467 (M+H).sup.+ and
m/z 484 (M+NH.sub.4).sup.+.
EXAMPLE 51
2-Phenethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi-
none
[1125] The title compound was prepared according to the method of
Example 20, substituting (2-bromoethyl)benzene for 4-fluorobenzyl
bromide. mp 170-171.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
3.07 (s, 3H), 3.20 (t, J=9 Hz, 2H), 4.28 (t, J=9 Hz, 2H), 6.98 (t,
J=9 Hz, 2H), 7.18 (dd, J=9 Hz and 6 Hz, 2H), 7.22-37 (m, 5 H), 7.34
(d, J=9 Hz, 2H), 7.83 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS
(DCI/NH.sub.3) m/z 449 (M+H).sup.+ and m/z 466
(M+NH.sub.4).sup.+.
EXAMPLE 52
2-Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone
[1126] The title compound was prepared according to the method
described in Examples 6-10 substituting
3-chloro-4-fluorobenzeneboronic acid for 4-fluorobenzeneboronic
acid in Example 6. mp 134-136.degree. C. .sup.1H NMR (CDCl.sub.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.sub.3) m/z 469 (M+H).sup.+ and m/z
486 (M+NH.sub.4).sup.+.
EXAMPLE 53
2-Benzyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e
[1127] The title compound was prepared according to the method
described in Examples 6-10 except substituting
4-chlorobenzeneboronic acid for 4-fluorobenzeneboronic acid in
Example 6. mp 157-159.degree. C. .sup.1H NMR (CDCl.sub.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.sub.3) m/z 451
(M+H).sup.+ and m/z 468 (M+NH.sub.4).sup.+.
EXAMPLE 54
2-(2,2,2-Trifluoroethyl)-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone
[1128] The title compound was prepared by N-debenzylation of the
product, prepared in Example 52 according to the method of Example
11, followed by alkylation with 2-iodo-1,1,1-trifluoroethane
according to the method of Example 20. mp 165-166.degree. C.
.sup.1H NMR (CDCl.sub.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.sub.3) m/z 461
(M+H).sup.+ and m/z 478 (M+NH.sub.4).sup.+.
EXAMPLE 55
2-(4-Trifluoromethoxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1129] The title compound was prepared according to the method of
Example 20, substituting 2-bromo-4'-trifluoromethoxyacetophenone
for 4-fluorobenzyl bromide. mp 160-161.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3)
m/z 547 (M+H).sup.+ and m/z 564 (M+NH.sub.4).sup.+.
EXAMPLE 56
2-(4-Trifluoromethylphenacyl)-4-(4-fluorohenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1130] The title compound was prepared according to the method of
Example 20, substituting 2-bromo-4'-trifluoromethylacetophenone for
4-fluorobenzyl bromide. mp 205-206.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3) m/z 531 (M+H).sup.+ and m/z 548
(M+NH.sub.4).sup.+.
EXAMPLE 57
2-[2-(Benzo[b]thien-3-yl)-2-oxoethyl]-4-(4-fluorophenyl)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1131] The title compound was prepared according to the method of
Example 20, substituting 3-chloroacetylbenzo[b]thiophene for
4-fluorobenzyl bromide. mp 183-184.degree. C. .sup.1H NMR
(CDCl.sub.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.sub.3) m/z 519
(M+H).sup.+.
EXAMPLE 58
2-(2,2,2-Trifluoroethyl)-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1132] The title compound was prepared by N-debenzylation of the
product, prepared in Example 53 according to the method of Example
12, followed by alkylation with 2-iodo-1,1,1-trifluoroethane
according to the method of Example 20. mp 55-57.degree. C. .sup.1H
NMR (CDCl.sub.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.sub.3) m/z 443
(M+H).sup.+ and m/z 460 (M+NH.sub.4).sup.+.
EXAMPLE 59
2-(3,3-Dimethyl-2-oxobutyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1133] The title compound was prepared according to the method of
Example 20, substituting 1-bromopinacolone for 4-fluorobenzyl
bromide. mp 168-170.degree. C. .sup.1H NMR (CDCl.sub.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.sub.3) m/z 443 (M+H).sup.+ and m/z
460 (M+NH.sub.4).sup.+.
EXAMPLE 60
2-(3-Thienylmethyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone
[1134] The title compound was prepared according to the method of
Example 20, substituting 3-(chloromethyl)thiophene for
4-fluorobenzyl bromide. mp 169-172.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 3.22 (s, 3H), 5.36 (s, 2H), 7.18 (m, 5H),
7.51 (m, 4H), 7.88 (m, 2H); 8.08 (s, 1H). MS (DCI/NH.sub.3) m/z 441
(M+H).sup.+ and m/z 458 (M+NH.sub.4).sup.+.
EXAMPLE 61
2-(2-Benzo[b]thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1135] The title compound was prepared according to the method of
Example 20 substituting 2-(chloromethyl)benzo[b]thiophene for
4-fluorobenzyl bromide. mp 93-96.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 491 (M+H).sup.+ and m/z 508
(M+NH.sub.4).sup.+.
EXAMPLE 62
2,4-Bis(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
[1136] A mixture of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H )-pyridazinone
(172 mg, 0.5 mmol), prepared according to the method of Example 10,
Cu powder (32 mg), anhydrous K.sub.2CO.sub.3 (207 mg, 1.5 mmol) and
4-fluoroiodobenzene (0.12 mL, 1 mmol) was prepared in 20 mL of
pyridine. The solution was stirred at reflux for 14 hours. The
mixture was then cooled to room temperature and partitioned between
water and ethyl acetate. The ethyl acetate layer was washed with
10% citric acid, water, brine and concentrated in vacuo. Separation
by column chromatography (silica gel, CH.sub.2Cl.sub.2-diethyl
ether 15:1) provided 190 mg of crude product. Crystallization from
CH.sub.2Cl.sub.2-diethyl ether-hexanes furnished the title compound
(yield: 175 mg, 79.9%). mp 168-169.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 439 (M+H).sup.+, 456 (M+NH4).sup.+.
Anal. calc. for C.sub.23H.sub.16F.sub.2N.- sub.2O.sub.3S.0.25
H.sub.2O: 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)-pyridazinon-
e
[1137] The 5-hydroxy-5-methyl-2(5H)-furanone prepared via above
cited methods (454 mg, 1.25 mmol) was dissolved in n-butanol (10
mL) and treated with hydrazine hydrate (0.3 mL, 6.2 mmol) and
stirred at reflux for 18 hours. On cooling, white crystals (224 mg,
50%) were obtained. mp 290.degree. C. (dec.) 1HNMR (300 MHz,
d.sub.6-DMSO) .delta. 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.sub.3) 376
(+NH.sub.4).sup.+. Anal. calc. for C.sub.18H.sub.15N.sub.2FSO.sub.3
0.25 H.sub.2O: 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
[1138] The product of Example 63 (100 mg, 0.28 mmol) was dissolved
in anhydrous DMF (3 mL) and treated with
1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of
anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60.degree. C.
for 2 hours. The reaction mixture was partitioned between water and
ethyl acetate to provide the desired compound as an amorphous solid
(60 mg, 48%). 1HNMR (300 MHz, CDCl.sub.3) .delta. 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),. MS (DCI/NH.sub.3)
458 (M+NH.sub.4).sup.+ Anal. calc. for
C.sub.20H.sub.16N.sub.2F.sub.4SO.sub.3: 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)-pyridaz-
inone
[1139] The title compound was prepared by coupling
3,4-dichlorophenylboron- ic acid with
2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem.,
(1996) 33, 1579-1582) according to the method of Example 6. This
product was converted to the 5-hydroxy-derivative according to the
method of Example 7. The 5-hydroxy compound was converted to the
5-trifluoromethylsufonyloxy-derivative according to the method of
Example 8. Coupling of 4-(methylthio)phenylboronic acid to the
triflate according to the method of Example 9 provided the
5-[4-(methylthio)phenyl]-intermed- iate which was oxidized
according to the method of Example 10 to provide the final product
(yield: 780 mg, 84%). mp 161-163.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3)
m/z 485 (M+H).sup.+. Anal. calc. for
C.sub.24H.sub.18Cl.sub.2N.sub.2O.sub.3S: 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-proylphenl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1140] The title compound was prepared by coupling
4-(n-propyl)phenylboron- ic acid with
2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het. Chem., 1996,
33, 1579-1582) according to the method of Example 6. This product
was converted to the 5-hydroxy derivative according to the method
of Example 7. This product was converted to the
5-trifluoromethylsufonyloxy-- derivative according to the method of
Example 8. Coupling of 4-(methylthio)phenylboronic acid to the
triflate according to the method of Example 9 provided the
5-[4-(methylthio)phenyl]-intermediate which was oxidized according
to the method of Example 10 to provide the final product (yield:
220 mg, 70%). mp 64-66.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 451 (M+H).sup.+. Anal. calc. for
C.sub.22H.sub.21F.sub.3N.sub.2O.sub.- 3S: 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-fluorophgnl)-5-[4-(methylsulfonyl)p-
henyl]-3L2H)-pyridazinone
[1141] The title compound was prepared by first coupling
3-fluoro-4-chlorophenylboronic acid with
2-benzyl-4-chloro-5-methoxy-3(2H- )-pyridazinone according to the
method of Example 6. The product was converted to the 5-hydroxy
compound according to the method of Example 7. This 5-hydroxy
compound was converted to the 5-trifluoromethylsufonyloxy--
derivative according to the method of Example 8. Coupling of
4-(methylthio)phenylboronic acid to the triflate according to the
method of Example 9 provided the
5-[4-(methylthio)phenyl]-intermediate which was oxidized according
to the method of Example 10 to provide the final product (yield:
170 mg, 84%). mp 174-175.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 461 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.13CIF.sub.4N.sub.2O.sub.3S: 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
[1142] A solution of
2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(met-
hylsulfinyl)phenyl]-3(2H)-pyridazinone (680 mg, 1.53 mmol) in
trifluoroacetic anhydride (30 mL) was stirred at room temperature
for 1 hour. The excess solvent was evaporated in vacuo and the
residue was treated with a deoxygenated 1N solution of
methanol-NaOH (50 mL, 4:1) at 0.degree. C. The solution was stirred
at room temperature for 2 hours and quenched with dilute HCl
solution until acidic. The white suspension formed was concentrated
in vacuo to evaporate the methanol. THF was added to the resulting
suspension until a clear solution was obtained. Chlorine gas was
slowly bubbled into the solution, maintained at 0.degree. C. After
10 minutes, nitrogen gas was bubbled into the solution for a few
minutes to displace residual chlorine. Ammonium hydroxide solution
(30%, 5 to 10 mL), at 0.degree. C., was slowly added to the
solution (to consume all starting sulfonyl chloride) and stirred at
room temperature for 5 minutes The solution was partitioned between
water and ethyl acetate. The organic layer was washed first with
water, then brine, and dried over MgSO.sub.4, and filtered. The
filtrate was concentrated in vacuo. The residue was purified by
chromatography on silica gel (40:60 ethyl acetate/hexanes) to
provide the title compound (yield: 500 mg, 75%). mp 193-195.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 428 (M+H).sup.+. Anal. calc. for
C.sub.18H.sub.13F.sub.4N.sub.3O.sub.3S: 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
[1143] The title compound from Example 77 was converted to the
sulfonamide product according to the method of Example 68 (yield:
540 mg, 70%). mp 154-156.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 444 (M+H).sup.+.
Anal. calc. for C.sub.18H.sub.13ClF.sub.3N.sub.3O.sub.3S: 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-Trifluoroethel)-4-(2-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-p-
yridazinone
[1144] The methyl sulfide intermediate prepared in Example 83C was
oxidized with one equivalent of meta-chloroperoxybenzoic acid to
provide the methylsulfoxide which was converted to the sulfonamide
final product according to the method of Example 68 (yield: 396 mg,
60%). mp 158-160.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 392 (M+H).sup.+. Anal. calc. for
C.sub.15H.sub.16F.sub.3N.sub.3O.sub.- 4S: 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
[1145] The methyl sulfide intermediate of Example 76 was oxidized
with one equivalent of meta-chloroperoxybenzoic acid to provide the
methylsulfoxide which was converted to the sulfonamide final
product according to the method of Example 68 (yield: 180 mg, 37%).
mp 150-152.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) mi/z 444 (M+H).sup.+. Anal.
calc. for C.sub.18H.sub.13F.sub.4N.sub.3O.sub.4S: 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)-pyrida-
zinone
EXAMPLE 72A
2-Fluorothioanisole
[1146] A deoxygenated solution of 2-fluorothiophenol (10 g, 78
mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9
mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The
reaction mixture was stirred at room temperature for 1 hour. A thin
layer chromatography (100% hexanes) sample indicated that the
reaction had not gone to completion, so an additional equivalent of
base and iodomethane were added and the reaction mixture was
stirred overnight at room temperature. The reaction was acidified
with 10% aqueous citric acid and extracted with hexanes
(2.times.125 mL). The combined organic extracts were washed with
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated under reduced pressure to provide the desired compound
as a pale yellow oil (yield: 6.68 g; 60%).
EXAMPLE 72B
2-Fluorothioanisole
[1147] An alternative method for preparing 2-fluorothioanisole
begins with a solution of 1,2-difluorobenzene (0.79 mL, 8 mmol) in
anhydrous DMF (50 mL) was treated with sodium thiomethoxide (0.59
g, 8 mmol). The reaction mixture was stirred at room temperature
for 6 hours, and partitioned between hexanes and water. The organic
layer was washed with brine, dried over MgSO.sub.4, and filtered.
The filtrate was concentrated under reduced pressure to provide the
desired compound (1.1 g, 100%) slightly contaminated with
1,2-bis(methylthio)benzene, a lower Rf material, which was removed
by chromatography with 100% hexanes (0.9 g, 80%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.46 (s, 3H), 6.98-7.19 (m, 3H) 2.26 (dt,
J=9 Hz, 3 Hz, 1H).
EXAMPLE 72C
4-Bromo-2-fluorothioanisole
[1148] A solution of 2-fluorothioanisole (1.42 g, 10 mmol) and iron
powder (0.03 g, 0.5 mmol) in dichloromethane (20 mL) was chilled to
.degree. C. and treated dropwise with Bromine (0.5 mL, 10 mmol).
Upon completion of the Bromine treatment, the reaction was sampled
for TLC (100% hexanes). A new, higher Rf material was present but
the reaction had not gone to completion so another equivalent of
bromine was added along with a catalytic amount of aluminum
chloride. The reaction mixture was stirred overnight at room
temperature. Aqueous sodium sulfite was added to the reaction
mixture and the organic layer was isolated, dried over MgSO.sub.4,
and filtered. The filtrate was filtered through a pad of silica gel
to remove color then concentrated under reduced pressure to provide
the product as a clear, colorless oil (yield: 1.3 g; 60%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 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).
EXAMPLE 72D
3-Fluoro-4-(methylthio)benzeneboronic Acid
[1149] A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol)
in dry THF (20 mL) was chilled to -78.degree. C. under a nitrogen
atmosphere. The reaction mixture was treated with 1.6 M
n-butyl]ithium in hexanes (1.7 mL, 27.1 mmol), and the mixture was
warmed to -40.degree. C. where it was maintained for 0.5 hours. The
reaction mixture was then chilled to -78.degree. C. and three
equivalents of triisopropyl borate (1.56 mL, 67.8 mmol) were added.
The reaction mixture was allowed to warm to room temperature and
stirred for 1.5 hours. At this point, 10% aqueous KOH (200 mL, 360
mmol) was added and the mixture was stirred overnight at room
temperature. The reaction mixture was then poured into an
ice/concentrated HCl mixture with stirring to yield a white
precipitate. This solid was dried in a vacuum oven (65.degree. C.,
29 in Hg) overnight to provide the title compound (yield: 0.22 g;
52.4%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).
EXAMPLE 72E
2,4-Bis-(4-fluorophenl)-5-[3-fluoro-4-(aminosulfonyl)phenOll-3(2H)-pyridaz-
inone
[1150] 2-Benzyl-4-chloro-5-methoxy-3(2H-)-pyridazinone (J. Het.
Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog
according to the method of Example 7 and then to the
5-trifluoromethylsulfonyloxy-anal- og following the method of
Example 8. Subsequent coupling to
3-fluoro-4-(methylthio)phenylboronic acid, according to the method
of Example 9, provided
2-benzyl-4-chloro-5-[3-fluoro-4-(methylthio)phenyl]3(-
2H)-pyridazinone. This intermediate was coupled in the 4-position
with 4-fluorophenylboronic acid following the method of Example 6.
This product was 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 was oxidized with one
equivalent of meta-chloroperoxybenzoic acid to provide the
methylsulfoxide which was converted to the sulfonamide fmal product
according to the method of Example 68 (yield: 500 mg, 75%). mp
222-224 C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 458 (M+H).sup.+. Anal.
calc. for C.sub.22H.sub.14F.sub.3N.sub.3O.sub.3S: 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-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1151] The methyl sulfide intermediate prepared in Example 67 was
oxidized with one equivalent of meta-chloroperoxybenzoic acid,
according to the method of Example 68 to provide the methyl
sulfoxide. The methyl sulfoxide was converted to the sulfonamide
product according to the method of Example 68 (yield: 1.5 g, 63%).
mp 180-183.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
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.sub.3) m/z 480 (M+H).sup.+. Anal. calc. for
C.sub.18H.sub.11CIF.sub.5N.sub.3O.sub.3S: 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
[1152] 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het.
Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog
according to the method of Example 7 and then to the
5-trifluoromethylsulfonyloxy-anal- og following the method of
Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid
according to the method of Example 9 provided
2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This
4-chloro-intermediate thus prepared was treated with 2-propanol (20
mL, 261 mmol) and potassium t-butoxide (110 mg, 0.98 mmol) at
reflux for 45 minutes furnished
2-benzyl-4-(2-propoxy)-5-[4-(methylthio)pentyl]-3(2H-
)-pyridazinone This methyl sulfide was oxidized according to the
method of Example 10 to provide the title compound (yield: 180 mg,
80%). mp 109-111.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3)
m/z 399 (M+H).sup.+. Anal. calc. for
C.sub.21H.sub.22N.sub.2O.sub.4S: 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-(methlsulfonyl~phenyl]-3(2H)-pyrdazinone
[1153] The title compound was prepared according to the method of
Example 74 substituting 4-fluorophenol in place of 2-propanol
(yield: 180 mg, 99%). mp 188-190.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 451 (M+H).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.4S: 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-(mothylsulfonI)phenyl]-3-
(2H)-pyridazinone
[1154] The title compound was prepared according to the method of
Example 75 substituting
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone in place of
2-benzyl-4-chloro-5-[4-(methylsulfony- l)phenyl]-3(2H)-pyridazinone
(yield: 180 mg, 63%). mp 161-164.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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/NI.sub.3) m/z 443
(M+H).sup.+. Anal. calc. for
C.sub.19H.sub.14F.sub.4N.sub.2O.sub.4S: 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
henl -3(2H)-pyridazinone
[1155] 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het.
Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog
according to the method of Example 7 and then to the
5-trifluoromethylsulfonyloxy-anal- og according to the method of
Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid,
according to the method of Example 9, provided
2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This
intermediate was coupled with 4-chlorophenylboronic acid according
to the method of Example 6. This product was N-debenzylated
according to the method of Example 11 and N-alkylated with
2-iodo-1,1,1-trifluoroethan- e according to the method of Example
20. The resulting sulfide was oxidized to the corresponding
sulfoxide with one equivalent of meta-chloroperoxybenzoic acid,
according to the method of Example 5 to provide the title compound
(yield: 130 mg, 70%). mp 154-155.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 427 (M+H).sup.+.
Anal. calc. for C.sub.19H.sub.14CIF.sub.3N.sub.2O.sub.2S: 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
[1156] The title compound was prepared by oxidizing
2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,
(prepared as an intermediate in Example 77) according to the method
of Example 10 (yield: 180 mg, 83%). mp 166-167.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 375
(+H).sup.+. Anal. calc. for C.sub.18H.sub.15ClN.sub.2O.sub.3S: 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
[1157] 2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone (J. Het.
Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog
according to the method of Example 7 and then to the
5-(trifluoromethyl)sulfonyloxy-analog according to the method of
Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid,
according to the method of Example 9, provided
2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This
intermediate was coupled with 4-methylphenylboronic acid according
to the method of Example 6. This product was N-debenzylated
according to the method of Example 11 and N-alkylated with
2-iodo-1,1,1-trifluoroethan- e according to the method of Example
20. The resulting sulfide was oxidized to the title compound
according to the method of Example 10 (yield: 210 mg, 98%). mp
154-156.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 423 (M+H).sup.+. Anal. calc. for
C.sub.20H.sub.17F.sub.3N.sub.2O.sub.3S: 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)p-
henyl]-3(2H)-pyridazinone
[1158] 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone (J. Het.
Chem., 1996, 33, 1579-1582) was converted to the 5-hydroxy-analog
according to the method of Example 7 and then to the
5-(trifluoromethyl)sulfonyloxy-an- alog according to the method of
Example 8. Subsequent coupling to 4-(methylthio)phenylboronic acid,
according to the method of Example 9, provided
2-benzyl-4-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This
intermediate was coupled with 4-chloro-3-fluorophenylboronic acid
according to the method of Example 6. This product was
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 was oxidized to the
corresponding sulfoxide with one equivalent of
meta-chloroperoxybenzoic acid to provide the methylsulfoxide which
was converted to the sulfonamide final product according to the
method of Example 68 (yield: 500 mg, 75%). mp 214-215.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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 (DCMNH.sub.3) m/z 462 (M+H).sup.+. Anal. calc. for
C.sub.18H.sub.12F.sub.4CIN.sub.3O.sub.3S: 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)pheny-
l]-3(2H)-pyridazinone
[1159] The product described in Example 65 was N-debenzylated
according to the method of Example 11. The intermediate was
N-alkylated according to the method of Example 20, substituting
2-iodo-1,1,1-trifluoroethane in place of 4-fluorobenzyl bromide to
provide the title compound (yield: 165 mg, 55%). mp 197-198.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/NH3) m/z 477
(M+H).sup.+. Anal. calc. for
C.sub.19H.sub.13F.sub.3Cl.sub.2N.sub.2O.sub.- 3S: 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)-prdazinone
[1160] 2-Benzyl-4,5-dibromo-3(2H)-pyridazinone (2 g, 6 mmol) was
reacted with 2-aminopropane (2 mL, 23.5 mmol) and potassium
t-butoxide (910 mg, 6.6 mmol) in toluene (40 mL) at reflux for 18
hours to provide the 4-(2-propylamino) derivative after column
chromatography (silica gel, 92:8 hexanes/ethyl acetate). The
intermediate was coupled 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 provide the title compound (yield: 120 mg, 48%). mp
146-147.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 399
(M+H).sup.+. Anal. calC. for C.sub.21H.sub.23N.sub.3O.sub.3S: 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-(methlsulfonylphenyl]-3(2H)-py-
ridazinone
EXAMPLE 83A
2-(2,2,2-Trifluoroethyl-4,5-dibromo-3(2H)-pyridazinone
[1161] A solution of mucobromic acid (10 g, 38.8 mmol) and
trifluoroethyl hydrazine (70% in water, 4.88 mL, 38.8 mmol) in 100
mL of methanol was prepared and heated at reflux for 3 hours. The
reaction mixture was concentrated in vacuo and partitioned between
ethyl acetate and water. The ethyl acetate layer was dried over
MgSO.sub.4, filtered, passed through a silica gel pad, and
concentrated in vacuo. The product was obtained as yellowish solid
(yield: 8.8 g, 68%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.78
(q, J=9 Hz, 2H), 7.87 (s, 1H). MS (DCI/NH.sub.3) m/z 337
(M+H).sup.+.
EXAMPLE 83B
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone
[1162] A solution of
2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazino- ne (2 g, 6
mmol), isopropyl alcohol (3 mL) and sodium hydride (60% dispersed
in oil, 290 mg, 7.2 mmol) in toluene (40 mL) was heated at reflux
for 5 hours. The reaction mixture was partitioned between ethyl
acetate and water. The ethyl acetate layer was filtered, and
concentrated in vacuo . The residue was purified by chromatography
(95:5 hexanes/ethyl acetate) to provide the product as a greenish
oil (yield: 1.22 g, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.46 (d, J=7.5 Hz, 6H), 5.48 (h, J=6 Hz, 1H), 7.87 (s, 1H). MS
(DCI/NH.sub.3) m/z 316 (M+H).sup.+.
EXAMPLE 83C
2-(2,2,2-Trifluoroethyl
-4-(2-propoxy)-5-[4-(methylthio)phenyl1-3(2H)-pyri- dazinone
[1163] A solution of
2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-- pyridazinone
(1.2 g, 3.8 nunol), 4-(methylthio)phenylboronic acid (704 mg, 4.19
mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 5% mmol)
and cesium carbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol
dimethyl ether was heated to reflux for 5 hours. The mixture was
partitioned between ethyl acetate and water. The ethyl acetate
layer was washed with water, brine, dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (94:6 hexanes/ethyl acetate). The product was
obtained as a greenish solid (yield: 1.1 g, 81%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 83D
2-(2,2,2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl~phenyl]-3(2H)--
pyridazinone
[1164] The title compound was prepared according to the method of
Example 10, substituting
2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-[4-(methylthio)-
phenyl]-3(2H)-pyridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylthio- )phenyl]-3(2H)-pyridazinone
(yield: 220 mg, 100%). mp 152-153.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 391 (M+H).sup.+. Anal.
calc. for C.sub.16H.sub.17F.sub.3N.sub.2O.sub.4S: 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)phell-3(2H)--
pyridazinone
[1165] The title compound was prepared according to the method of
Example 83, substituting cyclohexanol in place of 2-propanol
(yield: 250 mg, 52%). mp 129-130.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 431
(M+H).sup.+. Anal. calc. for
C.sub.19H.sub.21F.sub.3N.sub.2O.sub.4S: 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(2-
H)-pyridazinone
[1166] The title compound was prepared according to the method of
Example 83, substituting cyclopentanol in place of 2-propanol
(yield: 250 mg, 52%). mp 148-150.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 417
(M+H).sup.+. Anal. calc. for
C.sub.18H.sub.19F.sub.3N.sub.2O.sub.4S: 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
EXAMPLE 86A
2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-bromo-3(2H)-pyridazinone
[1167] The title compound was prepared according method of the
Example 83B, substituting 2-propylamine in place of 2-propanol
(yield: 70%). MS (DCI/NH.sub.3) m/z 315 (M+H).sup.+.
EXAMPLE 86B
2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylthio)phenyl]-3(2H4--
pyridazinone
[1168] The title compound was prepared according method of the
Example 83C, substituting
2-(2,2,2-trifluoroethyl)-4-(2-propylamino)-5-bromo-3(2H-
)-pyridazinone in place of
2-(2,2,2-trifluoroethyl)-4-isopropoxy-5-bromo-3- (2H)-pyridazinone
(yield: 80%). MS (DCI/NH.sub.3) m/z 358 (M+H).sup.+.
EXAMPLE 86C
2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1169] The title compound was prepared according to the method of
Example 10,
substituting2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylt- hio)phenyl]-3(2H)-pyridazinone
(yield: 180 mg, 83%). mp 173-174.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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, 1H), 7.59 (d, J=9 Hz, 2H), 8.03
(d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 340 (M+H).sup.+. Anal. calc.
for C.sub.16H.sub.18F.sub.3N.sub.3O.sub.4S: 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
[1170] 2-Benzyl-4,5-dichloro-3(2H)-pyridazinone, prepared following
the procedure in Example 2, was reacted with morpholine following
the procedure of Example 86 to provide the 4-morpholino-derivative.
The morpholino intermediate was coupled at the 5-position with
4-(methylthio)phenylboronic acid according to the method of Example
6. The resulting methyl sulfide was oxidized to the title compound
according to the method of Example 10 (yield: 150 mg, 69%). mp
158-160.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 426 (M+H).sup.+. Anal. calc. for
C.sub.22H.sub.23N.sub.3O.sub.4S: 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-1-yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
EXAMPLE 88A
1-Methylsulfonyloxy-2,3,3-trifluoro-2-propene
[1171] 2,3,3-Trifluoro-2-propen-1-ol was prepared as reported in
(J. Org. Chem., (1989) 54, 5640-5642). The mesylate was obtained by
reacting 2,3,3-trifluoro-2-propen-1-ol with mesyl chloride in
diethyl ether. Standard workup provided the product, which was used
without purification.
EXAMPLE 88B
2-(2,3,3-Trifluoro-2-propen-1-yl)-4-(4-fluorophenyl)-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone
[1172]
4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone is
prepared starting with the 2-benzyl-pyridazinone from Example 9 and
debenzylating the compound according to the procedure of Example
11.
[1173] A mixture of
4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyri- dazinone
(250 mg, 0.8 mmol), Cs.sub.2CO.sub.3 (650 mg, 2 mmol), and
3-methylsufonyloxy-1,1,2-trifluoropropene (mesylate, 250 mg, 1.19
mmol) in ethyl acetate (30 mL) was stirred at 55.degree. C. for 1.5
hours. The mixture was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried with MgSO.sub.4 and
filtered. The filtrate was concentrated in vacuo. The residue was
purified by column chromatography on silica gel eluted with 15%
ethyl acetate/hexanes, to provide the methyl sulfide,
2-(2,3,3-trifluoro-2-propen-1-yl)-4-(4-fluoro-
phenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone as a greenish
oil (yield: 175 mg, 53%).
EXAMPLE 88C
2-(2,3,3-Trifluoro-2-propen-1-yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
[1174] The methyl sulfide, prepared above, was oxidized to the
title compound according to the method of Example 10 (yield: 125
mg, 68%). mp 154-156.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 111), 7.9 (d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 439
(M+H).sup.+. Anal. calc. for
C.sub.20H.sub.14F.sub.4N.sub.2O.sub.3S: 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-fluorophenl)-5-[4-(amninosulfonyl)phenyl-3(2H)-pyridazinone
[1175] The title compound was prepared according to the method of
Example 68 substituting
2,4-bis(4-fluorophenyl)-5-[4-(methyisulfinyl)phenyl]-3(2H-
)-pyridazinone in place of
2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[-
4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (yield: 118 mg, 43%/).
mp 213-216.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
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, 1H). MS (DCI/NH.sub.3) m/z 440 (M+H).sup.+,
494(M+NN.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.15FN.sub.2O.sub.3S.sub.2: 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
EXAMPLE 90A
2-(2,2,2-Trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
[1176] The title compound was prepared according method of the
Example 83B, substituting methanol in place of isopropanol (yield:
78%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.3 (s, 3H), 4.76
(q, J=9 Hz, 2H), 7.85 (s, 1H), MS (DCJ/NH.sub.3) m/z 288
(1+H).sup.+.
EXAMPLE 90B
2-(2,2,2-Trifluoroethyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazi-
none
[1177] The title compound was prepared according method of the
Example 83C, substituting
2-(2,2,2-trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyrida- zinone in
place of 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-py-
ridazinone (yield: 80%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) M/Z 331
(M+H).sup.+.
EXAMPLE 90C
2-(2,2,2-Trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazi-
none
[1178] A solution of
2-(2,2,2-Trifluoroethyl)-4-methoxy-5-[4-(methylthio)p-
henyl]-3(2H)-pyridazinone (2 g, 6.1 mmol) and hydrobrornic acid
(40% in water, 20 mL) in acetic acid (40 mL) was heated at reflux
for 3 hours. The reaction mixture was cooled to room temperature
and water (50 mL) was added. The crystals formed were filtered,
washed with water and 5% ethyl acetate in hexanes, and dried to
constant weight. The product was obtained as a white solid (yield:
1.75 g, 91%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H), 8.00 (s, 1H). MS (DCI) m/z 317
(M+H).sup.+.
EXAMPLE 90D
2-(2,2,2-Trifluoroethyl)-4-cyclopropyLmethoxy-5-[4-(methylthio)phenyl]-3(2-
H)-pyridazinone
[1179] A solution of
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)p-
henyl]-3(2H)-pyridazinone (150 mg, 0.47 mmol), cyclopropyl methanol
(43 mL, 0.52 mmol) and triphenylphosphine (124 mg, 0.47 mmol) in
freshly distilled THF was prepared and added dropwise to diethyl
azodicarboxylate (75 mL, 0.52 mmol) at 0.degree. C. The mixture was
allowed to warm to room temperature, stirred for 5 hours and
concentrated in vacuo. The residue was purified by chromatography
on silica gel (95:5 hexanes/ethyl acetate) to provide the product
as a colorless oil (yield: 140 mg, 81%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z
371 (M+H).sup.+.
EXAMPLE 90E
2-(2,2,2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1180] The title compound was prepared according to the method of
example 10, substituting
2-(2,2,2-trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone in place of
4-(4-fluorophenyl)-5-[4-(met- hylthio)phenyl]-3(2H)-pyridazinone
(yield: 130 mg, 85%). mp 133-135.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z
403 (M+H).sup.+. Anal. calc. for
C.sub.17H.sub.17F.sub.3N.sub.2O.sub.4S: C, 50.74; H, 4.25; N, 6.96.
Found: C, 50.56; H, 4.09; N, 6.88.
EXAMPLE 91
2-(2,2,2-Trifluoroethyl)-4-(3-propen-1-oxy)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1181] The title compound was prepared according to the method of
Example 90, substituting 2-propen-1-ol in place of
cyclopropylmethanol (yield: 120 mg, 77%). mp 121-123.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 389
(M+H).sup.+. Anal. calc. for
C.sub.16H.sub.15F.sub.3N.sub.2O.sub.4S: 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.-methelbenzyloxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone
[1182] The title compound was prepared according to the method of
Example 90, substituting 4-fluoro-alpha-methylbenzyl alcohol in
place of cyclopropylmethanol (yield: 155 mg, 76%). mp
133-135.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.57
(d, J=6 Hz, 3H), 3.13 (s, 13H), 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, 1H), 8.03 (d,
J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 471 (M+H).sup.+. Anal. calc. for
C.sub.21H.sub.18F.sub.4N.sub.2O.sub.4S: 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
[1183] A solution of the product from Example 11,
4-(4-Fluorophenyl)-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone (344 mg, 1.0 mmol),
4-bromothioanisole (812 mg, 4.0 mmol), and copper (70 mg, 1.1
nmmol) in 20 mL of pyridine was stirred at reflux under a nitrogen
atmosphere for 18 hours. After cooling to room temperature, the
reaction mixture was diluted with a mixture of water and ethyl
acetate. The two layers were filtered through Celite.RTM., and
separated. The organic layer was washed with 10% aqueous citric
acid, with brine, dried over MgSO.sub.4, and filtered. The filtrate
was concentrated in vacuo and the residue purified by column
chromatography (silica gel, 93:7 dichloromethane/ethyl acetate) to
provide the title compound as a foam (yield: 380 mg, 81.5%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 467 (M+H).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.3S.sub.2.0.5 H.sub.2O: 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
[1184] The title compound was prepared by oxidizing the product of
Example 93, according to the method of Example 10 (yield: 156 mg,
78%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 499 (M+H).sup.+, 516 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.19FN.sub.2O.sub.5S.sub.2.0.5
H.sub.2O: 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(2-
H)-pyridazinone
[1185] The title compound was prepared according to Example 93 ,
substituting 2-bromo-3-methylthiophene in place of
4-bromothioanisole (yield: 190 mg, 43%). mp 215-217.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 441 (M+H).sup.+, 458 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.22H.sub.17FN.sub.2O.sub.3S.sub.2.0.5
H.sub.2O: C, 58.80; H, 4.01; N, 6. 24. Found: C, 58.85; H, 3.78; N,
5.99.
EXAMPLE 96
2-(2-Trifluoromethyl-4-nitrophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1186] The title compound was prepared according to Example 93,
substituting 2-bromo-5-nitrobenzotrifluoride in place of
4-bromothioanisole (yield: 390 mg, 73%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 534 (M+H).sup.+, 551
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.15F.sub.4N.sub.3O.sub.5S.0.75 H.sub.2O: 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
[1187] The title compound was prepared according to Example 93,
substituting 3-bromothioanisole in place of 4-bromothioanisole
(yield: 355 mg, 76%). mp 196.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 467 (M+H).sup.+, 484
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.3S.sub.2: 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)pheny-
l-3(2H)-pyridazinone
[1188] The title compound was prepared by oxidizing the product of
Example 97, according to the method of Example 10 (yield: 98 mg,
65.6%). mp 141-142.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 516 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.5S.sub.- 2.H.sub.2O: C, 55.81; H,
4.07; N, 5.43. Found: C, 56.24; H, 4.29; N, 5.10.
EXAMPLE 99
2-(4-Fluorohenyl-4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone
[1189]
4-(4-Chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
is prepared starting with the 2-benzylpyridazinone from Example 53
and debenzylating the compound according to the method of Example
11.
[1190] The title compound was prepared according to the method of
Example 93, starting with
4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone and substituting 1-fluoro-4-iodobenzene in place
of 4-bromothioanisole (yield: 245 mg, 54%). mp 195-197.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 455 (M+H).sup.+, 472
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16ClFN.sub.2O.sub.3S: 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(2-
H)-pyridazinone
[1191] The title compound was prepared according to Example 93 ,
substituting
4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone and substituting 2-bromo-5-chlorothiophene in place of
4-bromothioanisole (yield: 150 mg, 45%). mp 249-251.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 477 (M+H).sup.+, 494
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.14Cl.sub.2N.sub.2O.sub.3S.sub.2.H.sub.2O: 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
[1192] The title compound was prepared according to Example 93 ,
starting with
4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone and substituting 3-iodobenzotrifluoride in place of
4-bromothioanisole (yield: 210 mg, 59.5%). mp 103-105.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 505
(M+H).sup.+, 525 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.16CIF.sub.3N.sub.2O.sub- .3S: 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
[1193] The title compound was prepared according to Example 93 ,
starting with
4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(described in Example 99) in place of
4-(4-fluorophenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone and substituting
1-bromo-3-chloro-4-fluoro- benzene in place of 4-bromothioanisole
(yield: 330 mg, 58.8%). mp 205.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 489 (M+H).sup.+, 508
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15C.sub.12N.sub.2O.sub.3S: 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)-p-
rridazinone
[1194] The title compound was prepared according to Example 93 ,
substituting 1-fluoro-3-iodobenzene in place of 4-bromothioanisole
(yield: 310 mg, 70.8%). mp 245-247.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 439
(M+H).sup.+, 456 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16F.sub.2N.sub.2O.sub.3- S.0.25 H.sub.2O: 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
[1195] The title compound was prepared according to Example 93,
substituting 2-bromothioanisole in place of 4-bromothioanisole
(yield: 280 mg, 60%). mp 206-208.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 467 (M+H).sup.+, 484 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.19FN.sub.2O.sub.3S.- sub.2.H.sub.2O: 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-(methylsulfonl)phenyl]-3(2H)-
-pyridazinone
[1196] The title compound was prepared according to Example 93,
substituting 2-bromo-5-nitrothiophene in place of
4-bromothioanisole (yield: 330 mg, 70%). mp 252-253.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 472 (M+H).sup.+, 489 (M+NH.sub.4).sup.+. Anal. caic. for
C.sub.21H.sub.14FN.sub.3O.sub.5S.sub.2.0.5 H.sub.2O: 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(2-
H)-pyridazinone
[1197] The title compound was prepared according to Example 93,
starting with
4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone and substituting 1-bromo-3,4-difluorobenzene in place of
4-bromothioanisole (yield: 310 mg, 65.7%). mp 187-188.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z
473 (M+H).sup.+, 490 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15ClF.sub.2N.sub.2O.sub- .3S.0.5 H.sub.2O: 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)-py-
ridazinone
[1198] The title compound was prepared according to Example 93,
substituting 3-bromobenzothiophene in place of 4-bromothioanisole
(yield: 185 mg, 41%). mp 265-267.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 477 (M+H).sup.+, 494
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.25H.sub.17FN.sub.2O.sub.3S.sub.2: 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
EXAMPLE 108A
4-(4-Fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
[1199] The title compound was prepared by treating
2-benzyl-4-(4-fluorophe-
noxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 75)
with AlBr.sub.3 in toluene according to the procedure in Example 11
(yield: 1.8 g, 95%).
EXAMPLE 108B
2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1200] The title compound was prepared according to Example 93,
starting with
4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
and substituting 1-fluoro-4-iodobenzene in place of
4-bromothioanisole (yield: 60 mg, 53%). mp 83-85.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 455
(M+H).sup.+, 472 (M+NH.sub.4).sup.+.
EXAMPLE 109
2-(3,4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1201] The title compound was prepared according to Example 93,
substituting 1-bromo-3,4-difluorobenzene in place of
4-bromothioanisole and
4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(Example 108A) in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178-180.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 473 (M+H).sup.+, 490 (l+NH.sub.4).sup.+.
Anal. calc. for C.sub.23H.sub.15F.sub.3N.sub.2O.sub.4S.0.5
H.sub.2O: 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)phen
11-3(2H)-pyridazinone
[1202] The title compound was prepared according to Example 93,
substituting 1,3-dibromobenzene in place of 4-bromothioanisole and
4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(Example 108A) in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone (yield: 260 mg, 50.5%). mp 208-210.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 517 (M+H).sup.+,
534 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16BrFN.sub.2O.sub.4S: 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
[1203] The title compound was prepared according to Example 93,
substituting 1-bromo-3,4-difluorobenzene in place of
4-bromothioanisole and
4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]3(2H)-pyridazinone
(Example 108A) in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone (yield: 175 mg, 37%). mp 209-211.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 473 (M+H).sup.+, 490 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.15F.sub.3N.sub.2O.sub.4S.H.sub.2O: 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
[1204] The title compound was prepared according to Example 93,
substituting 1-bromo-3-chlorobenzene in place of 4-bromothioanisole
and
4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(Example 108A) in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone (yield: 25 mg, 5.3%). mp 211-213.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 471
(M+H).sup.+, 488 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16ClFN.sub.2O.sub.4S.0.- 5 H.sub.2O: 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-(methylsulfophenyl)phenyl]-3(2H)-
-pridazinone
[1205] The title compound was prepared according to the method of
Example 20, substituting 4-nitrobenzyl bromide in place of
4-fluorobenzyl bromide (yield: 164 mg, 58.9%). mp 183-184.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 480 (M+H).sup.+,
m/z 497 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18FN.sub.3O.sub.5S: 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)--
pyrdazinone
[1206] The title compound was prepared according to the method of
Example 20, substituting 4-(chloromethyl)phenyl acetate in place of
4-fluorobenzyl bromide (yield: 220 mg, 76.9%). mp 172-174.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 510
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.26H.sub.21FN.sub.2O.sub.5S: 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)--
pyrdazinone
[1207] A solution of
2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone (0.2 g, 4.06 mmol) (Example 114)
in THF (20 mL) was treated with a solution of lithium hydroxide
monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL)
was added to provide a homogeneous solution which was stirred at
room temperature overnight. The reaction mixture was then acidified
with 10% aqueous citric acid and extracted with ethyl acetate. The
ethyl acetate layer was dried over MgSO.sub.4 and filtered. The
filtrate was concentrated in vacuo to provide a white foam which
was purified by column chromatography (silica gel, 65:35
hexanes/ethyl acetate). Product fractions were combined and
concentrated in vacuo. The residue was crystallized from ethyl
acetate/hexanes (yield: 195 mg, 70%). mp 225-226.degree. C. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 451
(M+H).sup.+. Anal. calc. for C.sub.24H.sub.19FN.sub.2O.sub.4S: 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)-py-
ridazinone
[1208] The title compound was prepared according to the method of
Example 20, substituting 3-nitrobenzyl bromide in place of
4-fluorobenzyl bromide (yield: 195 mg, 70%). mp 156-157.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 480 (M+H).sup.+, m/z 497 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.18FN.sub.3O.sub.5S: 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-(methyylsulfonyl)-ph-
enyl]-3(2H)-pyridazinone
[1209] The title compound was prepared according to the method of
Example 20, substituting 4-bromo-1,1,2-trifluoro-1-butene in place
of 4-fluorobenzyl bromide (yield: 38 mg, 14.5%). mp 131-132.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 453 (M+H).sup.+, m/z
470 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.16F.sub.4N.sub.2O.sub.3S: C, 55.75; H, 3.56; N, 6.19.
Found: C, 55.63; H, 3.62; N, 6.10.
EXAMPLE 118
2-(2-Hexyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi-
none
[1210] The title compound was prepared according to the method of
Example 20, substituting 1-chloro-2-hexyne in place of
4-fluorobenzyl bromide (yield: 170 mg, 69%). mp 79-80.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H), 7.89 (d, J=9 Hz, 2H). MS
(DCI/NH.sub.3) m/z 425 (M+H).sup.+. Anal. calc. for
C.sub.23H.sub.21FN.sub.2O.sub.3S: 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-2-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)pheny-
l)-3(2H)-pyridazinone
[1211] The title compound was prepared according to the method of
Example 20, substituting 1,1,3-trichloropropene in place of
4-fluorobenzyl bromide (yield: 1.15 g, 68%). mp 184-185.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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 (DCFNH.sub.3) m/z 454 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.14Cl.sub.2F.sub.4N.sub.3O.- sub.3S: 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)-pyridaz-
inone
[1212] The title compound was prepared according to the method of
Example 20 substituting cyclohexyl bromide in place of
4-fluorobenzyl bromide (yield: 163 mg, 76%). mp 169-171.degree. C.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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.sub.3) m/z 427 (M+H).sup.+ and m/z 444
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.23FN.sub.2O.sub.3S.0.5 H.sub.2O: 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-fluorphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridaz-
inone
[1213] The title compound was prepared according to the method of
Example 20, substituting cyclopentyl bromide in place of
4-fluorobenzyl bromide (yield: 165 g, 80%). mp 191-193.degree. C.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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.sub.3) M/z 413 (M+H).sup.+ and m/z 430
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.22H.sub.21FN.sub.2O.sub-
.3S.0.5 H.sub.2O: 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)-pyridaz-
inone
[1214] The title compound was prepared according to the method of
Example 20, substituting cyclobutyl bromide in place of
4-fluorobenzyl bromide (yield: 270 g, 68%). mp 202-203.degree. C.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.85 (m, 2H), 2.32 (m,
2H), 2.50 (m, 2H), 5.40 (quintet, 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.sub.3) m/z 399 (M+H).sup.+ and m/z 416
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.21H.sub.11FN.sub.2O.sub-
.3S.0.75 H.sub.2O: 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)phe-
nyl]-3(2H)-pyridazinone
[1215]
2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(-
2H)-pyridazinone, prepared according to the method of Example 68,
was N-debenzylated according to the method of Example 11. The
intermediate was N-alkylated according to the method of Example 20,
substituting 1-bromo-3-methyl-2-butene in place of 4-fluorobenzyl
bromide, to provide the title compound (yield: 50 mg, 300/0). mp
134-136.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 414 (M+H).sup.+. Anal. calc. for
C.sub.21H.sub.20FN.sub.3O.sub.3S: C, 61; H, 4.87; N, 10.16. Found:
C, 60.98; H, 4.66; N, 9.95.
EXAMPLE 124
2-(2,4-Difluorobenzl)-4-(4-fluorolphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H-
)-pyridazinone
[1216]
2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyrid-
azinone, prepared according to the method of Example 68, was
N-debenzylated according to the method of Example 11. The
intermediate was N-alkylated according to the method of Example 20,
substituting 2,4-difluorobenzylbromide in place of 4-fluorobenzyl
bromide to provide the title compound (yield: 65 mg, 24%). mp
236-238.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 472
(M+H).sup.+. Anal. calc. for
C.sub.23H.sub.16F.sub.3N.sub.3O.sub.3S: 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
[1217] The title compound was prepared according to the method of
Example 124, substituting 2,3,4,5,6-pentafluorobenzyl bromide in
place of 1-bromo-3-methyl-2-butene (yield: 105 mg, 35%). mp
201-203.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 526 (M+H).sup.+. Anal. calc. for
C.sub.23H.sub.13F.sub.6N.sub.3O.sub.3S: 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)-py-
ridazinone
[1218] The title compound was prepared according to the method of
Example 124, substituting 3-bromocyclohexene in place of
1-bromo-3-methyl-2-buten- e (yield: 30 mg, 10%). mp 206-208.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 426
(M+H).sup.+. Anal. calc. for C.sub.22H.sub.20FN.sub.3O.sub.3S: 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
[1219] The title compound was prepared according to the method of
Example 124, substituting 3,4-difluorobenzyl bromide in place of
1-bromo-3-methyl-2-butene and running the reaction in DMSO instead
of DMF to prevent formation of byproducts (yield: 210 mg, 62%). mp
253-255.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 472 (M+H).sup.+.
Anal. calc. for C.sub.23H.sub.16F.sub.3N.sub.3O.sub.3S: 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-fluorophenl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1220] A solution of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone (172 mg, 0.5 mmol), prepared in Example 11, 2-indanol
(67 mg, 0.5 mmol) and Ph.sub.3P (262 mg, 1 mmol) in toluene (20 mL)
and ethyl acetate (5 mL) was prepared and added dropwise a solution
of DIAD (0.2 mL, 1 mmol) in toluene (10 mL). The mixture was
stirred at room temperature for 6 hours and concentrated in vacuo.
The residue was chromatographed (silica gel, 19:1
CH.sub.2Cl.sub.2-ethyl acetate) to provide 200 mg of product
(contaminated with reduced DIAD). A second colunm chromatography
(hexanes-ethyl acetate 1:1) furmished the title product (yield: 170
mg, 74%). mp 97-100.degree. C. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 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.sub.3) m/z 461
(M+H).sup.+ and m/z 478 (M+NH.sub.4).sup.+.
EXAMPLE 129
2-(2,3-Dihydro-1H-inden-1-yl)-4-(4-fluorop,henyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1221] The title compound was prepared according to the method of
Example 128 substituting 1-indanol in place of 2-indanol (yield:
110 mg, 48%). mp 128-130.degree. C. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 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.sub.3) m/Z 461 (M+H).sup.+ and m/z 478
(M+NH.sub.4).sup.+.
EXAMPLE 130
2-(4-Tetrahydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2)-pyridazinone
[1222] The title compound was prepared according to the method of
Example 128 substituting 4-tetrahydropyranol in place of 2-indanol
(yield: 140 g, 65%). mp 230-231.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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,
1H). MS (APCI-) m/z 428 (M--H)- and m/z 463 (M+Cl)-. Anal. calc.
for C.sub.22H.sub.21FN.sub.2O.sub.4S.1.25 H.sub.2O: 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
[1223] The title compound was prepared according to the method of
Example 128 substituting 2-methylcyclopentanol in place of
2-indanol (yield: 230 g, 86%). mp 180-181.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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).sup.+ and (APCI-) m/z 461 (M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.23FN.sub.2O.sub.3S: 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)-pyri-
dazinone
[1224] The title compound was prepared according to the method of
Example 128 substituting 2-adamantanol in place of 2-indanol,
(yield: 75 g, 25%).mp 195-197.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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, 211), 7.87 (d, J=9 Hz, 2H), 8.11 (s,
1H). MS (APCI+) m/z 479 (M+H).sup.+ and (APCI-) m/z 478 (M-H)-, m/z
513 (M+Cl).sup.-. Anal. calc. for
C.sub.27H.sub.27FN.sub.2O.sub.3S.0.25 H.sub.2O: 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(2-
H)-pyridazinone
[1225] The title compound was prepared according to the method of
Example 128 substituting 3-methylcyclopentanol in place of
2-indanol (yield: 155 g, 73%). mp 169-171.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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).sup.+ and (APCI-) m/z 426 (M-H)-, m/z 461 (M+Cl).sup.-. Anal.
calc. for C.sub.27H.sub.27FN.sub.2O.sub.3S.0.25 H.sub.2O: 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)-5-14-(methylsulfonpl)phengl]-3(-
2H)-pyridazinone
[1226] A solution of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone (206 mg, 0.6 mmol), prepared according to the method
of Example 11, 1-methyl-1-cyclopentanol (60 mg, 0.6 mmol), DMAP (18
mg, 0.12 mmol) and Ph.sub.3P (262 mg, 1 mmol) in toluene (30 mL) in
ethyl acetate (5 mL) was prepared and added dropwise to a solution
of DIAD (0.2 mL, 1 mmol) in 10 mL of toluene. The mixture was
stirred at room temperature for 6 hours and then concentrated in
vacuo. The residue was chromatographed (silica gel, 19:1
CH.sub.2Cl.sub.2-ethyl acetate) to provide 80 mg of product
(contaminated with reduced DIAD). A second column chromatography
(hexanes-ethyl acetate 1:1) frnished the title product, (yield: 50
mg, 19%). mp 107-110.degree. C. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 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).sup.+ and (APCI-) m/z 426 (M--H)-, m/z 461 (M+Cl).sup.-1.
EXAMPLE 135
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
EXAMPLE 135A
5-Bromo-2-fluorostyrene
[1227] A mixture of methyltriphenylphosphonium bromide (2.14 g, 6
mmol) and potassium t-butoxide (672 mg, 6 mmol) in 50 mL of THF was
refluxed for 30 minutes under N.sub.2 and then cooled to room
temperature. 5-Bromo-2-fluorobenzaldehyde (1.02 g, 5 mmol) was
added and the resulting mixture was refluxed for 2 hours (until the
TLC showed the disappearance of starting aldehyde). The reaction
was concentrated in vacuo and partitioned between water and ethyl
acetate. The acetate layer was washed with water and brine. The
solution was dried over MgSO.sub.4 and concentrated in vacuo. The
residue was purified by chromatography (silica gel, 15:1
hexanes-diethyl ether) to provide 900 mg (90%) of
5-bromo-2-fluorostyrene.
EXAMPLE 135B
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylthio)phenyl]-
-3(2H)-pyridazinone
[1228] The bromo-styrene compound, Example 135A, in 10 mL of THF
was added dropwise to a heated mixture of magnesium turnings (120
mg, 5 mmol) and a few drops of 1,2-dibromoethane in TBF (20 mL) at
a rate to maintain a gentle reflux. The mixture was refluxed for
the next 30 minutes and cooled to room temperature. The Grignard
reagent solution was cooled to -78.degree. C. and added, dropwise,
to a solution of
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazin-
one (540 mg, 1.5 mmol) in THF (20 mL). The reaction mixture was
allowed to warm to room temperature for 12 hours. Afterwards, a
saturated solution of NH.sub.4Cl was added and the mixture was
extracted with ethyl acetate to provide 320 mg of crude
sulfide.
EXAMPLE 135C
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-vinylphenyl)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1229] The sulfide, Example 135B, was dissolved in CH.sub.2Cl.sub.2
(20 mL) and at 0.degree. C. was treated with 30% CH.sub.3CO.sub.3H
in CH.sub.3CO.sub.2H (0.5 mL). After 1.5 hours, 10% NaHCO.sub.3 was
added and the mixture extracted with CH.sub.2Cl.sub.2. The extract
was concentrated in vacuo and the residue purified by
chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide
the title compound (yield: 270 mg, 37%). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 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).sup.+ and
(APCI-) m/z 517 (M+Cl).sup.-. Anal. calc. for
C.sub.25H.sub.17F.sub.3N.sub.2O.sub.3S.0.5 H.sub.2O: 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
[1230] A Grignard, prepared as described in Example 135 ,
substituting 2-(2-bromoethyl)-1,3-dioxane (586 mg, 3 mmol) in place
of 5-bromo-2-fluorostyrene, was added to a solution of
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazin-
one (720 mg, 2 mmol) in THF (30 mL) at -78.degree. C. The mixture
was left at room temperature for 14 hours, quenched with a
saturated solution of NH.sub.4Cl and extracted with ethyl acetate
to obtain 900 mg of crude sulfide.
[1231] The intermediate sulfide product was dissolved in
CH.sub.2Cl.sub.2 (10 mL) and treated at 0.degree. C. with 33%
solution of CH.sub.3CO.sub.3H in CH.sub.3CO.sub.2H (0.7 mL) for 1
hour. The mixture was concentrated in vacuo and the residue was
partitioned between saturated NaHCO.sub.3 and ethyl acetate. The
acetate layer was dried over MgSO.sub.4 and concentrated in vacuo
to provide 950 mg of crude sulfonyl derivative.
[1232] The sulfonyl compound, prepared above, was dissolved in
acetone (50 mL) and treated with 2 N HCl (10 mL). The resulting
mixture was refluxed for 16 hours and concentrated in vacuo. The
residue was extracted with ethyl acetate to provide 900 mg of
2-(3,4-difluorophenyl)-4-(2-formylethy-
l)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (crude aldehyde,
contaminated with some unreacted starting dioxane derivative).
[1233] A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1
mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL)
was refluxed for 30 minutes and then cooled to room temperature.
The crude aldehyde was added and the mixture was refluxed for 14
hours. The reaction mixture was then cooled to room temperature and
concentrated in vacuo. The residue was dissolved in ethyl acetate
and was washed with water, 10% citric acid, brine, dried over
MgSO.sub.4 and concentrated in vacuo. Purification by column
chromatography (silica gel, 1:1 hexanes-ethyl acetate) provided the
title compound as an oil (yield: 120 mg, 13%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 0.74 (d, J=7 Hz, 6H), 1.44 (m, 1H), 1.70
(t, J=7 Hz, 2H), 2.22 (m, 2H), 2.54 (m, 2H); 3.30 (s, 3H), 5.29 (m,
2H), 7.51 (m, 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).sup.+ and (APCI-) m/z 471 (M--H)-, m/z 507 (M+Cl).sup.-.
Anal. calc. for C.sub.25H.sub.26F.sub.2N.sub.2O.sub.3S: 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-cylopropylidenepropyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1234] The title compound was prepared according to the method of
Example 136 substituting cyclopropyltriphenylphosphonium bromide in
place of isoamyltriphenylphosphonium bromide (yield: 55 mg, 12%).
mp 128-129.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
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).sup.+ and (APCI-) m/z 441 (M--H)-, m/z 477
(M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.20F.sub.2N.sub.2O.sub.3S.0.5 H.sub.2O: 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
[1235] The title compound, an oil, was prepared according to the
method of Example 136 substituting isobutyltriphenylphosphonium
bromide in place of isoamyltriphenylphosphonium bromide (yield: 170
mg, 74%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+
and (APCI-) m/z 457 (M--H)-, m/z 493 (M+Cl).sup.-. Anal. calc. for
C.sub.24H.sub.24F.sub.2N.sub.2O.sub.3S: 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-(methylsulfopyl)phenyl]-3(2H-
)-pyridazinone
[1236] The title compound, an oil, was prepared according to the
method of Example 135B , substituting 5-methylhexylmagnesium
bromide for 3-fluoro-4-vinylphenylmagnesium bromide, (yield: 28 mg,
10%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+ and (APCI) m/z 459 (M--H)-, m/z 495 (M+Cl).sup.-.
EXAMPLE 140
2-(3-Chloro-1-methyl-2E-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)p-
henyl]-3(2H)-pyridazinone
[1237] The title compound was prepared according to the method of
Example 124, substituting 1,3-dichloro-1-butene in place of
2,4-difluorobenzyl bromide (yield: 55 mg, 30%). mp 152-154.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 434 (M+H).sup.+.
Anal. calc. for C.sub.20H.sub.17ClFN.sub.3O.sub.3S: 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-1-yl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)p-
henyl]-3(2H)-pyridazinone
[1238] The title compound was prepared according to the method of
Example 124, substituting
1-methylsufonyloxy-2,3,3-trifluoro-2-propene (mesylate), prepared
in Example 88, in place of 2,4-difluorobenzyl bromide (yield: 10
mg, 4%). mp 173-175.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 440
(M+H).sup.+, MS (F, high res.) m/z calc. for
C.sub.19H.sub.14F.sub.4N.sub- .3O.sub.3S: 440.0692 (M+H).sup.+.
Found: 440.0695 (M+H).sup.+, (0.7 ppm error).
EXAMPLE 142
2-(1,1,2-Trifluoro-2-propenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phen-
yl]-3(2H)-pyridazinone
[1239] The title compound was isolated from the same reaction
mixture (Example 141) that was used to prepare
2-(2,3,3-trifluoro-2-propen-1-yl)--
4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone
(The title product is a result of an SN2' attack.) (yield: 50 mg,
20%). mp 230-232.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 1H), . MS
(DCI/NH.sub.3) m/z 440 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.13F.sub.4N.sub.3O.sub.3S: 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
[1240] The title compound was prepared according to the method of
Example 124, substituting 1,3-dibromo-1,1-difluoropropane in place
of 2,4-difluorobenzyl bromide and employing 5 equivalents of
potassium carbonate (yield: 220 mg, 65%). mp 191-194.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 422
(M+H).sup.+. Anal. calc. for
C.sub.19H.sub.14F.sub.3N.sub.3O.sub.3S: C, 54.15; H, 3.34; N, 9.97.
Found: C, 53.88; H, 3.42; N, 9.76.
EXAMPLE 144
2-(.alpha.-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)p-
henyl]-3(2H)-pyridazinone
[1241] The title compound was prepared according to the method of
Example 124, substituting 3-fluoro-.alpha.-methylbenzyl chloride in
place of 2,4-difluorobenzyl bromide (yield: 220 mg, 65%). mp
192-194.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 468 (M+H).sup.+. Anal.
calc. for C.sub.24H.sub.19F.sub.2N.sub.3O.sub.3S: 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-fluorphenyl)-5-[4-(aminosulfonyl)phenyl]-3(2-
H)-pyridazinone
[1242] The title compound was prepared according to the method of
Example 124, substituting 1-bromomethylcyclohexene in place of
2,4-difluorobenzyl bromide (yield: 70 mg, 28%). mp 192-193.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 440
(M+H).sup.+. Anal. calc. for C.sub.23H.sub.22FN.sub.3O.sub.3S: C,
62.85; H, 5.04; N, 9.56. Found: C, 62.47; H, 5.23; N, 9.14.
EXAMPLE 146
2-(.alpha.-Methyl-2,3,4-trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1243] The title compound was prepared according to the method of
Example 124, substituting 2,3,4-trifluoro-.alpha.-methylbenzyl
chloride in place of 2,4-difluorobenzyl bromide (yield: 70 mg,
50%). mp 192-194.degree. C. 1.sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 504 (M+H).sup.+. Anal. calc. for
C.sub.24H.sub.17F.sub.4N.sub.3O.sub.3S: C, 57.25; H, 3.4; N, 8.34.
Found: C, 56.84; H, 3.52; N, 7.91.
EXAMPLE 147
2-(.alpha.-Methyl-3,5-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone
[1244] The title compound was prepared according to the method of
Example 124, substituting 3,5-difluoro-.alpha.-methylbenzyl
chloride in place of 2,4-difluorobenzyl bromide (yield: 80 mg,
45%). mp 139-141.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 486 (M+H).sup.+. Anal.
calc. for C.sub.24H.sub.18F.sub.3N.sub.3O.sub.3S: C, 59.37; H,
3.73; N, 8.65. Found: C, 59.00; H, 3.70; N, 8.35.
EXAMPLE 148
2-(.alpha.-Methyl-3,4-difluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosulfon-
lI)phenyl]-3(2H)-pyridazinone
[1245] The title compound was prepared according to the method of
Example 124, substituting 3,4-difluoro-.alpha.-methylbenzyl
chloride in place of 2,4-difluorobenzyl bromide (yield: 200 mg,
58%). mp 214-215.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 486
(M+H).sup.+. Anal. calc. for
C.sub.24H.sub.18F.sub.3N.sub.3O.sub.3S: 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)-py-
rdazinone
[1246] The title compound was prepared according to the method of
Example 124, substituting 3-fluorobenzyl bromide in place of
2,4-difluorobenzyl bromide (yield: 160 mg, 61%). mp 220-222.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 454 (M+H).sup.+. Anal. calc.
for C.sub.23H.sub.17F.sub.2N.sub.3O.sub.3S: 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)-py-
ridazinone
[1247] The title compound was prepared according to the method of
Example 124, substituting 4-fluorobenzyl bromide in place of
2,4-difluorobenzyl bromide (yield: 85 mg, 34%). mp 237-239.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z
454 (M+H).sup.+. Anal. calc. for
C.sub.23H.sub.17F.sub.2N.sub.3O.sub.3S: 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
[1248] The title compound was prepared according to the method of
Example 124, substituting 2,4,6-trifluorobenzyl bromide in place of
2,4-difluorobenzyl bromide (yield: 255 mg, 73%). mp 201-203.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 490
(M+H).sup.+. Anal. calc. for
C.sub.23H.sub.15F.sub.4N.sub.3O.sub.3S: 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
[1249] The title compound was prepared according to the method of
Example 124, substituting 2,4,5-trifluorobenzyl bromide in place of
2,4-difluorobenzyl bromide (yield: 180 mg, 49%). mp 236-238.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 490 (M+H).sup.+. Anal. calc. for
C.sub.23H.sub.15F.sub.4N.sub.3O.sub.3S: 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
[1250] The title compound was prepared according to the method of
Example 124, substituting 2,3,4-trifluorobenzyl bromide in place of
2,4-difluorobenzyl bromide (yield: 220 mg, 63%). mp 218-220.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 490 (M+H).sup.+. Anal. calc. for
C.sub.23H.sub.15F.sub.4N.sub.3O.sub.3S: 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-(aminosulf-
onylphenyl]-3(2H)-pyridazinone
[1251] The title compound was prepared according to the method of
Example 124, substituting 1-bromo-3-methyl-4,4,4-trifluoro-2-butene
in place of 2,4-difluorobenzyl bromide (yield: 160 mg, 48%). mp
155-157.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 468
(M+H).sup.+. Anal. calc. for
C.sub.21H.sub.17F.sub.4N.sub.3O.sub.3S: 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)-pyida-
zinone
[1252] The title compound was prepared according to the method of
Example 62 substituting 4-bromobiphenyl in place of
4-iodo-1-fluorobenzene (yield: 0.275 g, 100%). mp 249-251.degree.
C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3)
m/z 497 (M+H).sup.+, 514 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.21FN.sub.2O.sub.3S: 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)-py-
ridazinone
[1253] The title compound was prepared according to the method of
Example 62 substituting 1,4-dibromobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.337 g, 93%). .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 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/M).sub.3) m/z 499 (M+H).sup.+, 518 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.16BrFN.sub.2O.sub.3S.0.- 75 H.sub.20: 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)-py-
ridazinone
[1254] The title compound was prepared according to the method of
Example 62 substituting 1-iodo-4-nitrobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.45 g, 100%). mp 110-116.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 466 (M+H).sup.+, 483
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16FN.sub.3O.sub.5S: 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-(mehhylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1255] The title compound was prepared according to the method of
Example 62 substituting 4-bromodiphenylether in place of
4-iodo-1-fluorobenzene (yield: 0.667 g, 22%). mp 118-125.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 513 (M+H).sup.+.
Anal. calc. for C.sub.25H.sub.21FN.sub.2O.sub.4S.0.75 H.sub.2O: 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
[1256] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-4-t-butyl-benzene in place of
4-iodo-1-fluorobenzene. No product was observed. The solution was
concentrated in vacuo. The resulting solid was dissolved in DMF (5
mL) and CuI (13.3 mg, 0.07 mmol) was added. The solution was
allowed to reflux overnight. Upon completion, the mixture was
poured into 10% citric acid and extracted with ethyl acetate. The
organic layer was washed with water, dried over MgSO.sub.4 and
concentrated in vacuo. The crude solid was purified using flash
chromatography (SiO.sub.2), eluting with 5% diethyl
ether/CH.sub.2Cl.sub.2 to provide the desired product (yield: 0.292
g, 84%). mp 132-136.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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.sub.3) m/z 477
(M+H).sup.+, 494 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.27H.sub.25FN.sub.2O.sub.3S: 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)-p-
yridazinone
[1257] The title compound was prepared according to the method of
Example 62 substituting 4-bromo-1-chlorobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.254 g, 83.5%). mp 214-216.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.24 (s, 3H), 7.16
(m, 2H), 7.29 (m, 2H), 7.52 (m, 211), 7.61 (m, 2H), 7.71 (m, 2H),
7.91 (m, 2H), 8.26 (s, 1H). MS (DCI/NH.sub.3) m/z 455 (M+H).sup.+,
472 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16ClFN.sub.2O.sub.3S: 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)-p-
yrdazinone
[1258] The title compound was prepared according to the method of
Example 62 substituting 3-bromotoluene in place of
4-iodo-1-fluorobenzene (yield: 0.262 g, 83%). mp 213-216.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 435 (M+H).sup.+, 452
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.3S: 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)-py-
ridazinone
[1259] The title compound was prepared according to the method of
Example 62 substituting 3-bromostyrene in place of
4-iodo-1-fluorobenzene (yield: 0.202 g, 62%). mp 182-183.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 447 (M+H).sup.+, 464
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.25H.sub.19FN.sub.2O.sub.3S.0.50 H.sub.2O: 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)-p-
yridazinone
[1260] The title was prepared according to the method of Example 62
substituting 2-bromobenzaldehyde in place of 4-iodo-1-fluorobenzene
(yield: 0.196 g, 60%). mp 234-236.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 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.sub.3) m/z 449 (M+H).sup.+.
Anal. calc. for C.sub.24H.sub.17FN.sub.2O.sub.4S.0.50 H.sub.2O: 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)-pyr-
idazinone
[1261] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-2-nitrobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.307 g, 90.8%). mp 236-239.degree.
C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 466 (M+H).sup.+, 483
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16FN.sub.3O.sub.5S.0.25 H20: 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-(methylsulfonylphenyl]-3(2H)-py-
ridazinone
[1262] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-3-chlorobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.255 g, 77%). mp 232-235.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 1H),
7.90 (m, 2H), 8.25 (s, 1H). MS (DCI/NH.sub.3) m/z 455 (M+H).sup.+,
472 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16CIFN.sub.2O.sub.3S: 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)-py-
ridazinone
[1263] The title compound was prepared according to the method of
Example 62 substituting 1,3 dibromobenzene in place of
4-iodo-1-fluorobenzene (yield: 0.216 g, 60%). mp 210-212.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 3H),
8.26 (s, 1H). MS (DCI/NH.sub.3) m/z 499 (M+H).sup.+, 519
(+NH.sub.4).sup.+. Anal. calc. for C.sub.23Hl6BrFN.sub.2O.sub.3S:
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-(methylsulfonylphenyl]-3(2H)-pyr-
dazinone
[1264] The title compound was prepared according to the method of
Example 62 substituting 4-bromobenzonitrile in place of
4-iodo-1-fluorobenzene (yield: 0.349 g, 100%). mp 273-278.degree.
C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 445
(M+H).sup.+. Anal. calc. for C.sub.24H.sub.16FN.sub.3O.sub.3S: 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
[1265] The title compound was prepared according to the method of
Example 62 substituting 2-bromo-5-methylthiophene in place of
4-iodo-1-fluorobenzene (yield: 0.200 g, 62%). mp 219-224.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 441 (M+H).sup.+, 458
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.17FN.sub.2O.sub.3S.sub.- 2: C, 59.99; H, 3.89; N,
6.36. Found: C, 59.90; H, 3.91; N, 6.26.
EXAMPLE 169
2-(3-Biphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phepyl]-3(2H)-pydaz-
inone
[1266] The title compound was prepared according to the method of
Example 62 substituting 3-bromobiphenyl in place of
4-iodo-1-fluorobenzene (yield: 0.28 g, 78%). mp 126-134.degree. C.
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3)
m/z 497 (M+H).sup.+, 514 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.29H.sub.21FN.sub.2O.sub.3S: 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(2-
H)-pyridazinone
[1267] The title compound was prepared according to the method of
Example 62 substituting 5-bromo-m-xylene in place of
4-iodo-1-fluorobenzene (yield: 0.152 g, 46.5%). mp 130-134.degree.
C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 449
(M+H).sup.+, 466 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.25H.sub.21FN.sub.2O.sub.3S: 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(2-
H)-pyridazinone
[1268]
4-(4-Fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrdazi-
none was prepared according to the method of Example 11, starting
with
2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone (yield: 0.3319 g, 83%).
[1269] The title compound was prepared according to the method of
Example 62 substituting
4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone and substituting 1-bromo-3,4-difluorobenzene
in place of 4-iodo-1-fluorobenzene (yield: 0.085 g, 54%). mp
157-159.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 1H), 8.12 (s, 1H). MS (DCI/NH.sub.3) m/z 471
(M+H).sup.+, 488 (N+NH.sub.4).sup.+. Anal. calc. for
C.sub.24Hl.sub.7F.sub.3N.sub.2O.sub.3S.0.25 H.sub.2O: 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)-3(2H)-pridazinone
[1270] The title compound was prepared according to the method of
Example 62 substituting
4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone and substituting
4-bromo-2-chloro-1-fluorobenzene in place of 4-iodo-1-fluorobenzene
(yield: 0.110 g, 74%). mp 153-156.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 3.30 (s, 3H), 3.89 (bs, 2H), 7.02-7.07 (m,
4H), 7.59 (m, 1H), 7.65-7.72 (m, 4H), 8.07 (m, 2H), 8.12 (s, 1H).
MS (DCI/NH.sub.3) m/z 487 (M+H).sup.+, 504 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.17CIF.sub.2N.sub.2O.sub- .3S.0.25
H.sub.2O: 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)-prrida-
zinone
[1271] The title compound was prepared according to the method of
Example 62 substituting 2-bromothiophene in place of
1-bromo-4-fluorobenzene (yield: 98 mg, 40%). mp 215-217.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 427 (M+H).sup.+, 444
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.15FN.sub.2O.sub.3S.sub.2: C, 59.14; H, 3.54; N,
6.57.
EXAMPLE 174
2-(4-Trifluoromethylphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1272] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-4-trifluoromethylbenzene in place
of 1-bromo-4-fluorobenzene (yield: 185 mg, 64%). mp 171-173.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 489 (M+H).sup.+,
506 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.16F.sub.4N.sub.2O.sub.3- S: C, 59.02; H, 3.3; N,
5.74. Found: C, 58.75; H, 3.35; N, 5.69.
EXAMPLE 175
2-[4-(1-Pyrroyl)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1273] The title compound was prepared according to the method of
Example 62 substituting 1-(4-iodophenyl)pyrrole in place of
1-bromo-4-fluorobenzene (yield:-140 mg, 50%). mp 229-231.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 486 (M+H).sup.+, 504 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.27H.sub.20FN.sub.3O.sub.3S.0.5 H.sub.2O: 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(2-
H)-pyridazinone
[1274] The title compound was prepared according to the method of
Example 62 substituting 2-bromo-5-chlorothiophene in place of
1-bromo-4-fluorobenzene (yield: 225 mg, 93%). mp 190-192.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.38 (s, 3H), 8 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.sub.3) m/z 435 (M+H).sup.+, 452
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.24H.sub.19F
N.sub.2O.sub.3S: 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)-p-
yridazinone
[1275] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-4-methylbenzene in place of
1-bromo-4-fluorobenzene (yield: 79 mg, 31%). mp 190-192.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.38 (s, 3H), 6 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.sub.3) m/z 435 (M+H).sup.+, 452
(M+NH.sub.4)+. Anal. calc. for C.sub.24H.sub.19F N.sub.2O.sub.3S:
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(2-
H)-pyridazinone
[1276] To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF
(15 mnL) at room temperature was added NaH (60% oil suspension) (20
mg, 0.5 mimol) and after 10 minutes
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone (193 mg, 0.5 mmol) was added. The
resulting mixture was stirred at room temperature for the next 2
hours. The mixture was quenched with 10% citric acid and extracted
with ethyl acetate. The extract was washed with water, brine, dried
with MgSO.sub.4, and purified by chromatography (silica gel, 2:1
hexanes-ethyl acetate) to provide the desired product (yield: 140
mg, 60%). mp 120-122.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 0.75 (m, 6H), 1.1 (m, 6H), 1.20 (quintet, 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).sup.+; (APCI-) m/z 507 (M+Cl).sup.-.
Anal. calc. for C.sub.25H.sub.29FN.sub.2O.sub.4S.0.5 H.sub.2O: 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)-pyrida-
zinone
[1277] The title compound was prepared according to the method of
Example 62 substituting 3-bromothiophene in place of
1-bromo-4-fluorobenzene (yield: 225 mg, 93%). mp 200-202.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 427 (M+H).sup.+, 444 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21H.sub.15FN.sub.2O.sub.3S.sub.- 2: 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
[1278] The title compound was prepared according to the method of
Example 62 substituting 3,5-difluorobromobenzene in place of
1-bromo-4-fluorobenzene (yield: 250 mg, 96%). mp 166-168.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.25 (s, 3H), .delta.
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.sub.3) m/z
457 (M+H).sup.+, 474 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15F.sub.3N.sub.2O.s- ub.3S: 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-fluorohephenyl)-5-4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1279] The title compound was prepared according to the method of
Example 62 substituting 2,4-difluorobromobenzene in place of
1-bromo-4-fluorobenzene (yield: 40 mg, 15%). mp 245-247.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.23 (s, 3H), .delta.
7.15 (t, 2H), 7.3 (t, 2H), 7.54 (m, 2H), 7.57 (m, 2H), 7.75 (m,
1H), 7.9 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS (DCI/NH.sub.3) m/z 457
(M+H).sup.+, 474 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.28H.sub.15F.sub.3N.sub.2O.sub.3- S: C, 60.52; H, 3.31; N,
6.03.
EXAMPLE 182
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1280] The title compound was prepared according to the method of
Example 62 substituting 3,4-difluorobromobenzene in place of
1-bromo-4-fluorobenzene (yield: 170 mg, 70%). mp 109-110.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.23 (s, 3H), .delta.
7.15 (t, 2H), 7.3 (t, 2H), 7.25 (m, 2H), 7.59 (m, 4H), 7.83 (m,
1H), 7.9 (d, J=9 Hz, 2H), 8.27 (s, 1H). MS (DCI/NH.sub.3) m/z 457
(M+H).sup.+, 474 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15F.sub.3N.sub.3O.sub.3- S: C, 60.52; H, 3.31; N,
6.14. Found 60.60; H, 3.48; N, 5.89
EXAMPLE 183
2-(3-Furyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrdazin-
one
[1281] The title compound was prepared according to the method of
Example 62 substituting 3-bromofuran in place of
1-bromo-4-fluorobenzene (yield: 175 mg, 73%). mp 239-242.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 411 (M+H).sup.+, 428 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.15F N.sub.2O.sub.4S.0.5 H.sub.2O: 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)pheny-
l]-3(2H)-pyridazinone
[1282] The title compound was prepared according to the method of
Example 62 substituting 3-fluoro-4-methoxybromobenzene in place of
1-bromo-4-fluorobenzene (yield: 230 mg, 85%). mp 97-101.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 469 (M+H).sup.+, 491
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18F.sub.2N.sub.2O.sub.4S.0.5 H.sub.2O: 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-(methlsulfonyl)phenyl]-3(2H)-py-
ridazinone
[1283] The title compound was prepared according to the method of
Example 62 substituting 2-fluorobromobenzene in place of
1-bromo-4-fluorobenzene (yield: 195 mg, 75%). mp 96-103.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.23 (s, 3H), .delta.
7.15 (t, 2H), 7.3 (m, 3H), 7.55 (m, 5H), 7.9 (d, J=9 Hz, 2H), 8.27
(s, 1H). MS (ESI) m/z 437 (M--H).sup.+). Anal. calc. for
C.sub.23H.sub.16F.sub.2N.sub.2O.sub.3S: 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
[1284] The title compound was prepared according to the method of
Example 62 substituting 4-aminosulfonyl-1-bromobenzene in place of
1-bromo-4-fluorobenzene. mp 213-216.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 499 (M+H).sup.+, 517
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.18FN.sub.3O.sub.5S.sub.2.0.5 H.sub.2O: 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
[1285] The title compound was prepared according to the method of
Example 62 substituting 3-chloro-4-fluoro-1-bromobenzene in place
of 1-bromo-4-fluorobenzene (yield: 320 mg, 78%). mp 155-157.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.23 (s, 3H),
.delta. 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.sub.3) m/z 473 (M+H).sup.+, 490
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15ClF.sub.2N.sub.2O.sub.3S: C, 58.42; H, 3.2; N,
5.92. Found 58.23; H, 2.87; N, 5.70
EXAMPLE 188
[1286]
2-(3,5-Dichlorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(-
2H)-pyridazinone
[1287] The title compound was prepared according to the method of
Example 62 substituting 3,5-dichlorobenzene in place of
1-bromo-4-fluorobenzene (yield: 360 mg, 78%). mp 289-294.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.25 (s, 3H), .delta.
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.sub.3)
m/z 490 (M+H).sup.+, 507 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.15Cl.sub.2FN.sub.2O.sub- .3S.0.5 H.sub.2O: 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
[1288] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-4-fluoro-3-methylbenzene in place
of 1-bromo-4-fluorobenzene (yield: 275 mg, 71%). mp 168-170.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.3 (s, 3H), .delta.
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.sub.3) m/z 453 (M+H).sup.+, 471
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18F.sub.2N.sub.2O.sub.3S: 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
[1289] The title compound was prepared according to the method of
Example 62 substituting 4-bromo-1-chloro-2-fluorobenzene in place
of 1-bromo-4-fluorobenzene (yield: 220 mg, 80%). mp 102-110.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H), 7.75-7.87 (m, 2H), 7.91 (d, J=5.6 Hz, 2H), 8.28
(s, 1H). MS (APCI+) m/z 473 (M+H).sup.+.
EXAMPLE 191
2-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1290] The title compound was prepared according to the method of
Example 62 substituting 1-bromo-4-chloro-2-fluorobenzene in place
of 1-bromo-4-fluorobenzene (yield: 65 mg 24%). mp 250-260.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+. Anal. calc. for
C.sub.23H.sub.15ClF.sub.2N.sub.2O.sub.3S: 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
[1291] A solution of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone, prepared according to the procedure of Example 11
(200 mg, 0.58 mmol) in CH.sub.2Cl.sub.2 (8 ml) was prepared and
stirred. 1-Adamantylfluoroformate (172 mg, 0.87 mmol),
dimethylaminopyridine (14 mg, 0.011 rnmol) and triethylamine (0.12
ml, 0.87 mmol) were added. The reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (50 ml) and washed with 10% citric acid (50 ml),
brine (50 ml) and dried over MgSO.sub.4, and concentrated in vacuo.
The resulting crude residue was purified using flash chromatography
(SiO.sub.2, eluting with 15:1 CH.sub.2Cl.sub.2:diethyl ether) to
provide the desired product (yield: 55 mg, 18%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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).sup.+. Anal. calc. for
C.sub.21H.sub.15F N.sub.2O.sub.3S.sub.2: C, 64.35; H, 5.20; N,
5.36.
EXAMPLE 193
2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
EXAMPLE 193A
2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone
[1292] 2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0
g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307
mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was
concentrated in vacuo. The crystals obtained were washed with water
and air dried (yield: 50 g; 67.5%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 4.8 (q, J=9 Hz, 2H), 7.85 (s, 1H). MS
(DCI-NH.sub.3) m/z 264 (M+NH.sub.4).sup.+.
EXAMPLE 193B
2-(2,2,2-Trifluoroethyl-4-chloro-5-hydroxy-3(2H)-pyridazinone
[1293] 2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone
(15.0 m 60.7 mmol), and potassium carbonate (10 g, 72.4 mmol.) were
mixed with water (500 mL) and stirred at reflux for 6 hours. TLC
(1:1:2 CH.sub.2Cl.sub.2/hexanes/ethyl acetate) indicated that all
starting material was consumed.) The reaction mixture was cooled to
room temperature. The pH of the reaction mixture was adjusted to
about 4 with hydrochloric acid (15%). The product was extracted
with ethyl acetate (700 mL). The organic phase was washed with
brine, dried over anhydrous MgSO.sub.4 and filtered. The filtrate
was concentrated under reduced pressure. The hydroxy compound was
obtained as a light brown solid (yield: 13.1 g, 94%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 4.92 (q, J=9 Hz, 2H), 7.9 (s, 1H).
MS (DCI/NH.sub.3) m/z 229 (M+H).sup.+.
EXAMPLE 193C
2-(2,2,2-Trifluoroethyl)-4-chloro-5-(trifluoromethylsulfonyloxy)-3(2H)-pyr-
idazinone
[1294] Anhydrous Na.sub.2CO.sub.3 (9.04 m, 85.32 mmol) was placed
in a 500 mL round bottom flask and anhydrous CH.sub.2CL.sub.2 (200
mL) was added. The reaction mixture was cooled to 0.degree. C.
under N.sub.2. The halohydroxy pyridazinone prepared in Example
193B was dissolved in CH.sub.2CL.sub.2 (100 mL) and added slowly to
the flask and stirred overnight. The reaction slowly warmed to room
temperature. (TLC (2:1 hexanes/ethyl acetate) indicated completion
of the reaction.) The reaction was quenched with H.sub.2O. The
organic phase containing the product was separated, washed with
brine and dried over MgSO.sub.4. The resulting filtrate was
concentrated under reduced pressure. The crude product was isolated
as deep red-brown residue. Purification using a silica gel column
(30:70 ethyl acetate/pentanes) provided the title compound as a
dark, reddish residue (14.3 m, 70%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 4.85 (q, J=9 Hz, 2H), 7.9 (s, 1H). MS
(DCI/NH.sub.3) m/z 378 (M+NH.sub.4).sup.+.
EXAMPLE 193D
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylthiophenyl]-3(2H)-pyridazino-
ne
[1295] A solution of the triflate prepared in Example 193C (1.56 g
4.3 mmol), 4-(methylthio)phenylboronic acid (870 mg, 5.16 mmol),
tetrakis(triphenylphosphine)palladium(0) (250 mg, 5% mmol) and
triethylamine (1.44 ml, 10.32 mmol) in toluene was heated at reflux
for 1 hour. The mixture was partitioned between ethyl acetate and
water. The ethyl acetate layer was washed with water, then brine,
followed by drying over MgSO.sub.4 and filtration. The filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 92:8 hexanes/ethyl acetate) to provide
the coupled intermediate as a pale, greenish-yellow solid (yield:
500 mg, 35%). mp 130-139.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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, 1H). MS (DCI/NH.sub.3)
m/z 335 (M+H).sup.+.
EXAMPLE 193E
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone
[1296] The title compound was prepared according to the method of
Example 10, substituting the coupled intermediate prepared in
Example 193D in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyrid-
azinone (yield: 440 mg, 81%). mp 221-222.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 367 (M+H).sup.+. X1E AH
EXAMPLE 193F
2-(2,2,2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1297] Magnesium turnings (500 mg) were placed in a dry 250 mL
round bottom flask. Anhydrous ether (20 mL) was added under N.sub.2
at room temperature then fluorobenzyl bromide (3 mL) was added and
stirred. The reaction was heated at 40.degree. C. for 2 hours. All
magnesium was consumed resulting in a pale brownish-yellow
solution. The
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone prepared in Example 193E was dissolved in dry THF (25 mL)
and transferred to the Grignard solution. The mixture was heated
for 3 hours. TLC (2:1 hexanes/ethyl acetate) indicated that the
pyridazinone starting material was consumed.) The reaction was
cooled to room temperature then quenched with a saturated
NH.sub.4Cl solution. The product was extracted with ethyl acetate
(250 mL); and the organic layer was washed with saturated
NH.sub.4Cl, and brine. The ethyl acetate solution was dried over
MgSO.sub.4 and filtered. The filtrate was concentrated under
reduced pressure. The product was isolated as an orange residue.
Purification using a silica gel column (20:80 ethyl
acetate/pentanes) provided the title compound as a pale yellow
powder (yield: 140 mg, 28%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 441
(M+H).sup.+. Anal. calc. for
C.sub.20H.sub.16F.sub.4N.sub.2O.sub.3S.0.5 H.sub.2O: 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-fluolophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone
EXAMPLE 194A
2-(4-Fluorophenyl-4,5-dibromo-3(2H)-pridazinone
[1298] Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid
(110 ImL) was treated with 4-fluorophenyl hydrazine.HCl, and the
heterogeneous mixture brought to reflux at a bath temperature of
115.degree. C. for 15 hours. During the course of reaction, the
mixture became a homogeneous deep red solution, and upon cooling to
23.degree. C., a crystalline precipitate formed. The solution was
poured into ice water (1000 mL) and stirred for 20 minutes. The
yellow/brown crystals were filtered off, washed with additional
cold water, and dried in vacuo to provide 5.8 g (86%) of product.
(J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23, 2603)
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.31-7.41 (m, 2H),
7.57-7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347
(Br.sub.79Br.sub.79M+H).sup.+, m/z 349 (Br.sub.79Br.sub.81
M+H).sup.+, m/z 364 (Br.sub.79Br.sub.79M+NH.sub.4).sup.+, and m/z
366 (Br.sub.79Br.sub.81 M+NH.sub.4).sup.+.
EXAMPLE 194B
2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
[1299] A 23.degree. C. homogeneous solution of
2-(4-fluorophenyl)-4,5-dibr- omo-3(2H)-pyridazinone (7.18 g, 20.6
mmol) prepared above in tetrahydrofuran (322 mL) was treated with
methanol (0.843 mL, 20.8 mmol) and after 5 minutes with NaH (0.833
g, 20.8 mmol, 60% oil dispersion). The reaction exothermed for
several minutes and then was continued for 8 hours at 23.degree. C.
(Note: several reactions have run to completion at this point). The
reaction did not run to completion, and so the temperature was
raised to reflux for 4 hours more. The reaction was still not
completed. An additional 0.1 equivalent of NaOMe solution was
prepared in a separate flask as above with the quantities: 32 mL of
tetrahydrofuran, 0.084 mL of methanol, and 83 mg of 60% NaH oil
dispersion. This NaOMe solution was added via syringe to the
reaction mixture cooled to 23.degree. C., and then the temperature
raised to reflux for 4 hours The reaction was still not complete,
and so another 0.1 equivalent NaOMe solution was prepared, added,
and the reaction brought to reflux, as above. After this 4 hours,
the reaction was completed. The mixture was cooled to 23.degree. C.
and diluted to 2000 mL with water. The yellow/white precipitate
that formed was filtered off, washed with additional water, and
concentrated in vacuo to provide 5.39 g (88%) of product. (J. Het.
Chem., 1988, 25, 1757) .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
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 (.sup.79Br M+H).sup.+ and m/z 301 (.sup.81Br
M+H).sup.+.
EXAMPLE 194C
2-(4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1300] The title compound was prepared according to the method of
Example 6 starting with
2-(4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of
2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting
4-(methylthio)benzeneboronic acid in place of
4-fluorobenzeneboronic acid (yield: 70 mg, 61%). .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 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).sup.+.
EXAMPLE 194D
2-(4-Fluoroohenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1301] The title compound was prepared according to the method of
Example 228 substituting methyl magnesium bromide in place of
cyclohexylmagnesium chloride (yield: 0.83 g, 87%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 194E
2-(4-Fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinon-
e
[1302] The title compound was prepared according to the method of
Example 10 substituting
2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H-
)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)ph-
enyl]-3(2H)-pyridazinone (yield: 473 mg, 86%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.24 (s, 3H), 3.14 (s, 3H), 7.19 (dd,
J=8.8, 8.8 Hz, 2H), 7.61 (d, J=8.4Hz, 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).sup.+ and
m/z 376 (M+NH.sub.4).sup.+.
EXAMPLE 194F
2-(4-Fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridaz-
inone
[1303] To a heterogeneous, refluxing solution of
2-(4-fluorophenyl)-4-meth-
yl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65
mmol) and carbon tetrachloride (24 mL) was quickly added
N-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl
peroxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run
to near 50% completion. Additional benzoyl peroxide (12 mg, 0.05
mmol) was added, and the reaction checked after another 1 hour. The
reaction was still not complete, and so more benzoyl peroxide (4
mg, 0.017 mmol) was added. After 30 minutes, the reaction was
completed. The mixture was cooled to 23.degree. C. and diluted with
ethyl acetate. The acetate solution was washed with saturated
NaHCO.sub.3, water, and brine. The solution was dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The residue was
chromatographed (flash silica gel, ethyl acetate/hexanes gradient
1:1 to 4:1) to provide the product (yield: 530 mg, 74%). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 194G
2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone
[1304] To a homogeneous solution of
2-(4-fluorophenyl)-4-bromomethyl-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone, Example 194F, (107 mg,
0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270 mmol) dissolved in
acetone (4 mL) was added powdered K.sub.2CO.sub.3 (37.3 mg, 0.270
mmol). The mixture was stirred at 23.degree. C. for 2 hours,
filtered through a bed of Celite.RTM., and concentrated in vacuo.
The residue was chromatographed (flash silica gel, ethyl
acetate/hexanes 3:2) to provide the product (yield: 83 mg, 72%). mp
65-80.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+. Anal. calc.
for C.sub.24H.sub.18F.sub.2N.sub.2O.sub.4S: 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)-pridazinone
[1305] The title compound was prepared according to the method of
Example 194G substituting 3-fluorophenol in place of 4-fluorophenol
(yield: 94 mg, 88%). mp 142-144.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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).sup.+. Anal.
calc. for C.sub.24H.sub.18F.sub.2N.sub.2O.sub.4S: 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)-pyri-
dazinone
[1306] The title compound was prepared according to the method of
Example 294G substituting phenol in place of 4-fluorophenol (yield:
67 g, 93%). mp 42-75.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.+.
EXAMPLE 197
2-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1307] A 0.degree. C. solution of the
2-(4-fluorophenyl)-4-bromomethyl-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example
194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) was treated with NaI
(35 mg, 0.233 mmol), and after 5 minutes, the cooling bath was
removed and the reaction wanned to 23.degree. C. After 30 minutes,
conversion to the
2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone was complete (thin layer chromatography, ethyl
acetate/hexanes 4:1). The NaBr and residual NaI were filtered off
through a pad of Celite.RTM.. Additional acetone (2 mL) was added
along with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol), and the
solution cooled to 0.degree. C. before addition of Ag.sub.2CO.sub.3
(63 mg, 0.227 mmol). After 5 minutes, the cooling bath was removed
and the solution warmed to 23.degree. C. for 5 hours. The reaction
mixture was filtered through Celite.RTM. and concentrated in vacuo.
The residue was chromatographed (flash silica gel, ethyl
acetate/hexanes gradient 1:1 to 3:2) to provide the product (yield:
57 mg, 60%). mp 50-70.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 1H), 7.84 (d, J=8.7 Hz, 2H), 8.13
(d, J=8.7 Hz, 2H). MS (APCI+) m/z 447 (M+H).sup.+. Anal. calc. for
C.sub.22H.sub.23FN.sub.2O.sub.3S.sub.2: C, 59.17; H, 5.19; N, 6.27.
Found: C, 59.48; H, 5.36; N, 5.90.
EXAMPLE 198
2-(4-Fluorophenyl)-4-(2-methylpropylthiomethyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1308] The title compound was prepared according to the method of
Example 197 substituting 2-methyl-1-propanethiol in place of
2-methyl-2-propanethiol (yield: 66 mg, 70%). mp 45-60.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+. Anal. calc. for
C.sub.22H.sub.23FN.sub.2O.sub.3S.sub.2: C, 59.17; H, 5.19; N, 6.27.
Found: C, 59.35; H, 5.25; N, 6.05.
EXAMPLE 199
2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazino-
ne
[1309] The title compound was prepared by the following sequence of
reactions. Mucobromic acid and 4-fluorophenylhydrazine
hydrochloride were reacted to provide
2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone following the
procedure in Example 194A.
[1310] The dibromo intermediate was reacted according to the
procedure described in Example 194B, substituting isopropanol in
place of methanol, to selectively react at the 4-position and
provide
2-(4-fluorophenyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone.
[1311] The 5-bromo-compound was coupled to
4-(methylthio)phenylboronic acid according to the method of Example
6 to provide the title compound (yield: 435 mg, 53.9%). mp
135-137.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 371 (M+H).sup.+.
EXAMPLE 200
2-(4-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone
[1312] The methyl sulfide compound prepared in Example 199 was
oxidized according to the method of Example 10 to provide the title
compound (yield: 240 mg, 92%). mp 160-162.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 403 (M+H).sup.+, 420 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.20H.sub.19FN.sub.2O.sub.4S: 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)-pyrida-
zinone
[1313]
2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H-pyri-
dazinone was prepared according to the method of Example 199,
substituting 3-chlorophenylhydrazine hydrochloride in place of
4-fluorophenylhydrazine hydrochloride, in the first step. The
resulting methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 260 mg, 80%). mp
134-136.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 419 (M+H).sup.+, 436 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.19ClN.sub.2O.sub.4S: 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)-pyrida-
zinone
[1314] The methyl sulfide intermediate was prepared according to
the method of Example 199, substituting 3-fluorophenylhydrazine
hydrochloride in place of 4-fluorophenylhydrazine hydrochloride in
the first step. The resulting methyl sulfide compound was oxidized
according to the method of Example 10 to provide the title compound
(yield: 290 mg, 72%). mp 110-112.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 403
(M+H).sup.+, 447 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.19FN.sub.2O.sub.4S: 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)-pyridaz-
inone
[1315] The methyl sulfide intermediate was prepared according to
the method of Example 199, substituting 3-bromophenylhydrazine
hydrochloride in place of 4-fluorophenylhydrazine hydrochloride.
The resulting methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 75 mg,
77.6%). mp 130-132.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 1H),
8.06 (d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 465 (M+H).sup.+, 480
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.19BrN.sub.2O.sub.4S: 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)-py-
ridazinone
[1316]
2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)-
-pyridazinone was prepared according to the method of Example 199,
substituting 2,5-difluorophenylhydrazine hydrochloride in place of
4-fluorophenylhydrazine hydrochloride.
[1317] The resulting methyl sulfide compound was oxidized according
to the method of Example 10 to provide the title compound (yield:
390 mg, 90%). mp 161-164.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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, 211), 7.92 (s,
1H), 8.07 (d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 421 (M+H).sup.+,
438 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.18F.sub.2N.sub.2O.sub.4S.0.5 H.sub.2O: 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-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1318] The title compound was prepared by the following sequence of
reactions. Mucobromic acid and 3-chloro-4-fluorophenylhydrazine
hydrochloride were reacted to provide
2-(3-chloro-4-fluorophenyl)-4,5-dib- romo-3(2H)-pyridazinone
according to the method of Example 194A.
[1319] The intermediate was selectively reacted at the 4-position
with isobutanol and base to provide
2-(4-fluorophenyl)-4-[1-(2-methylpropoxy)]-
-5-bromo-3(2H)-pyridazinone according to the method of Example
194B
[1320] The 5-bromo-compound was coupled to
3-fluoro-4-(methylthio)phenylbo- ronic acid prepared in Example
194C according to-the method of Example 6 to produce the
intermediate methyl sulfide. The sulfide compound was oxidized to
the title methyl sulfone according to the method of Example 10
(yield: 810 mg, 83.8%). mp 142-144.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 469 (M+H).sup.+, 486
(M+NH.sub.4).sup.+.
EXAMPLE 206
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
EXAMPLE 206A
2-Methylthioanisole
[1321] A solution of 2-bromothioanisole (10.53 g, 52 mmol) in
tetrahydrofuran (173 mL) was prepared and cooled to -78.degree. C.
n-BuLi (21.8 mL, 54.5 mmol, 2.5 M solution in hexanes) was slowly
added along the interior wall of the reaction vessel. The resultant
light yellow solution was stirred for 30 minutes before methyl
iodide (8.10 g, 57.1 mmol) diluted with tetrahydrofuran (6 mL) was
slowly added along the interior wall of the reaction vessel. The
mixture was stirred for another 30 minutes at -78.degree. C. The
cooling bath was removed, and the mixture stirred for 1 hour. The
solution was cooled to 0.degree. C. and a saturated aqueous
NH.sub.4Cl solution added. The resultant solution was extracted
several times with ethyl acetate, and the combined acetate layers
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was chromatographed (flash
silica gel, ethyl acetate/hexanes 1:19) to provide the product
(yield: 6.74 g, 94%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.34 (s, 3H), 2.46 (s, 3H), 7.02-7.09 (m, 1H), 7.12-7.22 (m,
3H).
EXAMPLE 206B
4-Bromo-2-methylthioanisole
[1322] To a 0.degree. C. solution of 2-methylthioanisole (0.50 g,
3.57 mmol) in methylene chloride (40 mL) was added powdered Fe (20
mg, 0.36 mmol) followed by dropwise addition of bromine (0.58 g,
3.54 rnmol). After 30 minutes, the starting material had been
consumed (thin layer chromatography, hexanes). The excess bromine
was quenched by adding a solution of NaHSO.sub.3 and stirring for
several minutes. The methylene chloride layer was separated, and
the aqueous phase extracted with additional methylene chloride. The
combined methylene chloride solution was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The resultant oil was
chromatographed (flash silica gel, ethyl acetate/hexanes 1:49) to
provide the product (yield: 0.74 g, 96%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.30 (s, 3H), 2.45 (s, 3H), 7.00 (d, J=8.4 Hz,
1H), 7.27-7.33 (m, 2H).
EXAMPLE 206C
3-Methyl-4-(methylthio)benzeneboronic Acid
[1323] 3-Methyl-4-(methylthio)benzeneboronic acid was prepared
according to the method of Example 1, substituting
4-bromo-2-(methylthio)anisole in place of 4-bromothioanisole
(yield: 5.3 g, 67%). mp 208-210. .sup.1H 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).
EXAMPLE 206D
2-(3,4-Difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone
[1324] The title compound was prepared according to the method of
Example 194A, substituting 3,4-difluorophenyl hydrazine.HCl in
place of 4-fluorophenyl hydrazine.HCl (yield: 39 g, 78%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 7.45 (m, 1H), 7.61 (m, 1H),
7.75 (m, 1H), 8.30 (s, 1H). MS (DCI/NH.sub.3) m/z 382
(M+NH.sub.4).sup.+.
EXAMPLE 206E
2-(3,4-Difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
[1325] The title compound was prepared according to the method of
Example 194B, substituting
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 15 mg,
88%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.14 (s, 3H),
7.45 (m, 1H), 7.60 (m, 1H), 7.74 (m, 1H), 8.24 (s, 1H). MS
(DCI/NH.sub.3) m/z 317 (M+H).sup.+ and m/z 334
(M+NH.sub.4).sup.+.
EXAMPLE 206F
2-(3,4-Difluorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio)phenyl]-3(2H)-p-
ridazinone
[1326] The title compound was prepared according to the method of
Example 6 starting with
2-(3,4-difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazino- ne in
place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and
substituting 3-methyl-4-(methylthio)benzeneboronic acid in place of
4-fluorobenzeneboronic acid (yield: 2.0 g, 85%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.39 (s, 3H), 2.53 (s, 3H), 4.11 (s, 3H),
7.22-7.32 (m, 2H), 7.34 (s, 1H), 7.42-7.50 (m, 2H), 7.55-7.64 (m,
1H), 7.92 (s, 1H). MS (APCI+) m/z 375 (M+H).sup.+.
EXAMPLE 206G
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl-
]-3(2H)-pyridazimone
[1327]
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio-
)phenyl]-3(2H)-pyridazinone, was prepared according to the method
of Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[3-methyl-4-
-(methylthio)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
and substituting 4-fluorophenyl magnesium bromide in place of
cyclohexylmagnesium chloride (yield: 330 mg, 56%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 2.24 (s, 3H), 2.47 (s, 3H), 6.90-7.03 (m,
6H), 7.22-7.31 (m, 2H), 7.49-7,54 (m, 1H), 7.60-7.68 (m, 1H), 8.02
(s, 1H). MS (APCI+) m/z 439 (M+H).sup.+.
EXAMPLE 206H
2-(3,4-Diflurophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1328] The title compound was prepared according to the method of
Example 10, substituting
2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4--
(methylthio)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophe-
nyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 251 mg,
82%) mp 80-100.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.+ and m/z 488
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17F.sub.3N.sub.2O.sub.3S: 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-fluorophenoxmethyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
EXAMPLE 207A
2-(3-Chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone
[1329] The title compound was prepared according to the method of
Example 194A, substituting 3-chlorophenyl hydrazine.HCl in place of
4-fluorophenyl hydrazine.HCI (yield: 24.8 g, 88%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.53-7.57 (m, 3H), 7.67-7.70 (m, 1H),
8.29 (s, 1H). MS (DCI/NH.sub.3) m/z 365 (M+H).sup.+ and m/z 382
(M+NH.sub.4+).sup.+.
EXAMPLE 207B
2-(3-Chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
[1330] The title compound was prepared according to the method of
Example 194B, substituting
2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 12.4 g,
95%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.21 (s, 3H),
7.58-7.62 (m, 3H), 7.73-7.76 (m, 1H), 8.28 (s, 1H). MS
(DCI/NH.sub.3) m/z 317 (M+H).sup.+ and ml/z 334
(M+NH.sub.4+).sup.+.
EXAMPLE 207C
2-(3-Chlorophenyl-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1331] The title compound was prepared according to the method of
Example 6 starting with
2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of
2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting
4-(methylthio)benzeneboronic acid in place of
4-fluorobenzeneboronic acid (yield: 3.3 g, 68%). .sup.1H NMR (300
MHz, DMSO-(d.sub.6) .delta. 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, 1H), 8.18 (s, 1H).
MS (DCI/NH.sub.3) m/z 359 (M+H).sup.+.
EXAMPLE 207D
2-(3-Chlorophenyl)-4-methyl-5-[3-methyl-4-(methylthio)phenyl-3(2H)-pyridaz-
inone
[1332]
2-(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phe-
nyl]-3(2H)-pyridazinone, was prepared according to the method of
Example 228, starting with
2-(3-chlorophenyl)-4-methoxy-5-[3-methyl-4-(methylthio-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4--
(methylthio)phenyl]-3(2H)-pyridazinone and substituting
4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium
chloride (yield: 180 mg, 94%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 1H). MS (APCI+) m/z 343
(M+H).sup.+ and m/z 360 (M+NH.sub.4).sup.+.
EXAMPLE 207E
2-(3-Chlorophenyl)-4-methyl-5-[4-(methylsulfonylphenyl]-3(2H)-prdazinone
[1333] The title compound was prepared according to the method of
Example 10, substituting
2-(3-chlorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2-
H)-pyridazinone for
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3-
(2H)-pyridazinone (yield: 125 mg, 67%). mp 164-168. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 2.23 (s, 3H), 3.13 (s, 3H), 7.37-7.46
(m, 2H), 7.61 (m, 3H), 7.71-7.74 (m, 1H), 7.81 (s, 1H), 8.13 (d,
J=8.7 Hz, 2H). MS (APCI+) m/z 343 (M+H).sup.+ and m/z 360
(M+NH.sub.4).sup.+.
EXAMPLE 207F
2-(3-Chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone
[1334]
2-(3-Chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone was prepared according to the method of Example 194F,
substituting
2-(3-chlorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone in place of
2-((4-fluorophenyl)-4-methyl-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyrdazinone (yield: 90 mg, 99%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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, 1H), 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).sup.+ and m/z 470 (M+NH.sub.4).sup.+.
EXAMPLE 207G
2-(3-Chlorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone
[1335] The title compound was prepared according to the method of
Example 194G, substituting
2-(3-chlorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-bromomethyl-5--
[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 30 mg, 31%).
mp 50-80.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 208
2-(3-Chlorophenyl)-4-(benzoyloxymethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone
[1336] The title compound was prepared according to the method of
Example 207 substituting benzoic acid in place of 4-fluorophenol
(yield: 33 mg, 34%). mp 50-70.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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+) ml/z 495
(M+H).sup.+.
EXAMPLE 209
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[4-(methylsulfony)phenyl]-3(2-
-pyridazinone
[1337] The title compound was prepared according to the method of
Example 193, substituting 1-bromo-3-methylbutane in place of
4-fluorobenzyl bromide (yield: 80 mg, 19%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3), m/z 403
(M+H).sup.+. Anal. calc. for
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.3S.0.25 H.sub.2O: 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
EXAMPLE 210A
4-fluoro-3-methylbenzeneboronic Acid
[1338] 5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in
dry THF (50 mL) and cooled to -78.degree. C. under N.sub.2. n-BuLi
(14 mL, 2.5M solution in THF) was added slowly using a dry syringe.
Cloudiness appeared. The reaction was stirred for 40 minutes at
-78.degree. C. Triisopropyl borate (22 mL, 95 mmol) was slowly
added while stirring. The reaction was allowed to warm to room
temperature. Stirring continued for an additional 2 hours. A pale
yellow, cloudy solution formed. (TLC (1:2 ethyl acetate /hexanes))
indicated disappearance of the starting material. The reaction was
quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45
minutes, 10% citric acid solution (300 mL) was added until,
pH.about.5.0. The product was extracted with ethyl acetate (500
mL). The organic phase was washed with brine and dried over
MgSO.sub.4, and filtered. The filtrate was concentrated under
reduced pressure to provide an off white solid (yield: 4.1 g,
84%).
EXAMPLE 2101B
2-(2,2,2-trifluoroethyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone
[1339] The boronic acid (231 mg, 1.5 mmol), prepared in example
210A,
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone (500 mg, 1.36 mmol),
tetrakis-(triphenylphosphine)-palladium(0) (47 mg, 0.041 mmol), and
CsF (413 mg, 2.72 mmol) were stirred at reflux in DME (20 mL) under
N.sub.2 for 5 hours. TLC (1:1 hexanes/ethyl acetate) indicated that
all the starting material was consumed. Volatiles were removed in
vacuo. The residue was partitioned between water and ethyl acetate.
The organic layer was washed with brine, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated in vacuo. An off white
powder was obtained (yield: 275 mg, 46%). mp 88-91.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3, a mixture of rotamers) .delta.
2.2, 2.25 (2d, J=1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92 (m, 2H)
.delta. .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.sub.3), m/z 441
(M+H).sup.+. Anal. calc. for
C.sub.20H.sub.16F.sub.4N.sub.2O.sub.3S.0.5 H.sub.2O: 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)pheny-
l]-3(2H)-pyridazinone
[1340]
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone (150 mg, 0.409 mmol) (Example 193E) was dissolved in
anhydrous DME (8 mL) and heated to reflux with
3,5-dichlorobenzeneboronic acid in presence of CsF (150 mg, 0.98
mmol) and tetrakis(triphenylphosphi- ne)-palladium (17.38 mg, 0.015
mmol) for 6 hours. After cooling to room temperature the reaction
mixture was diluted with water and extracted with ethyl acetate
(100 mL). The organic layer was washed with brine, dried over
MgSO.sub.4, and evaporated in vacuo. The compound was purified on a
silica gel column, eluting with 30% ethyl acetate in pentanes, to
provide the title compound (yield: 110 mg, 58%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 496
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.13CI.sub.2F.sub.3N.sub.2O.sub.3S: 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
[1341] The title compound was prepared according to the method of
Example 211, substituting 3-ethoxyphenylboronic acid for
3,5-dichlorobenzeneboron- ic acid (yield: 155 mg, 86%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 470 (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.21H.sub.19CI.sub.2F.sub.3N.sub.2O.sub.4S: 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)-pridazinone
[1342] The title compound was prepared according to the method of
Example 211, substituting 4-(trifluoromethyl)benzeneboronic acid in
place of 3,5-dichlorobenzeneboronic acid (yield: 85 mg, 44%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 494 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.20H.sub.14F.sub.6N.sub.- 2O.sub.3S: 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)-pridazinone
[1343] The title compound was prepared according to the method of
Example 211, substituting 3-nitrobenzeneboronic acid in place of
3,5-dichlorobenzeneboronic acid (yield: 40 mg, 22%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 471
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.14CI.sub.2F.sub.3N.sub.3O.sub.5S.0.5 EtOAc: C, 50.70;
H, 3.64; N, 8.44. Found: C, 50.61; H, 3.58; N, 8.53
EXAMPLE 215
2-(2,2,2-Tiifluoroethyl)-4-(2-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1344] The title compound was prepared according to the method of
Example 211, substituting 2-methylbenzeneboronic acid in place of
3,5-dichlorolbenzeneboronic acid (yield: 45 mg, 27%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 440 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.17F.sub.3N.sub.2O.sub.3- S: 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
[1345] The title compound was prepared according to the method of
Example 211, substituting 4-vinylbenzeneboronic acid in place of
3,5-dichlorobenzeneboronic acid (yield: 56 mg, 32%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z
452 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.17F.sub.3N.sub.2O.sub.3S: 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-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1346] The title compound was prepared according to the method of
Example 211, substituting 3-trifluoromethylbenzeneboronic acid in
place of 3,5-dichlorobenzeneboronic acid (yield: 120 mg, 63%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 494 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.14F.sub.6N.sub.2O.sub.3- S: C, 50.42; H, 2.96; N,
5.88. Found: C, 50.38; H, 2.97; N, 5.74
EXAMPLE 218
2-(2,2,2-Trifluoroethyl)-4-(3-fluoro-4-methoxyphenyl)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
[1347] The title compound was prepared according to the method of
Example 211, substituting 3-fluoro-4-methoxybenzeneboronic acid in
place of 3,5-dichlorobenzeneboronic acid (yield: 32 mg, 18%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 5H). MS (DCI/NH.sub.3) m/z 474 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.20H.sub.16F.sub.4N.sub.2O.sub.4S.0.5
H.sub.2O: 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
[1348] The title compound was prepared according to the method of
Example 211 substituting 3-fluoro-4-methylbenzeneboronic acid in
place of 3,5-dichlorobenzeneboronic acid (yield: 58 mg, 33%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 458 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.20H.sub.16F.sub.4N.sub.2O.sub.3S.0.5
H.sub.2O: 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-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1349] The title compound was prepared according to the method of
Example 211, substituting 3,5-difluoro-4-methoxybenzeneboronic acid
in place of 3,5-dichlorobenzeneboronic acid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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, 2H), 7.7-8.15
(m, 4H). MS (DCI/NH.sub.3) m/z 492 (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.20H.sub.15F.sub.5N.sub.- 2O.sub.4S: 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-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone
[1350] 6-Bromophthalide (300 mg, 1.40 mmol, Teppema et al Recl.
Trav. Chim. Pays-Bays, (1923) 42, 47) and hexamethylditin (326
.mu.L, 1.55 imuol) were dissolved in toluene (5 mL), degassed with
a nitrogen stream for 5 minutes, treated with (Ph.sub.3P).sub.4Pd
(79 mg) and heated at reflux for 1 hour. The reaction was cooled
and directly purified by chromatography on a Biotage 40S column
(pretreated with hexanes-TEA 400:1 then rinsed with hexanes) eluted
with 4:1 hexanes-ethyl acetate. The product fractions were combined
and evaporated to provide 6-(trimethyltin)phthalide (yield: 362 mg,
87%).
[1351] The tin reagent (180 mg, 0.61 mnmol), prepared above, and
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone, prepared in Example 193E, (223 mg, 0.61 mmol) were
dissolved in dry toluene (10 mL), degassed with an nitrogen stream
for 5 minutes, treated with (Ph.sub.3P).sub.4Pd (34 mg) and heated
at reflux for 1 day. The reaction was cooled and directly purified
by chromatography on a Biotage 40S column eluted with 4:1
hexanes-ethyl acetate. The product fractions were combined and
evaporated to provide the title compound along with the
4-(1,3-dihydro-1-oxo-6-isobenzofuranyl)-isomer in a 9:1 ratio.
Further manipulations to attempt to remove the minor isomer (ie
chromatography, recrystallization from ethyl acetate-hexanes)
failed (yield: 176 mg, 62%). mp 237-239.degree. C. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 3.07 (s, 3H), 4.91 (q, J=8 Hz, 2H), 5.30
(s, 2 H, major isomer), 5.33 (s, 2 H, minor isomer), 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.sub.3) m/z 482
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.15F.sub.3N.sub.2O.sub.5S: 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
[1352] A suspension of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared
according to the method of Example 193E, in THF (27 nmL) was cooled
to -78.degree. C. A solution of isopropenylmagnesium bromide (2.8
mL, 0.5 M in THF, Aldrich) was added. The reaction was warmed to
room temperature and stirred for 30 minutes. The reaction was
quenched at 0.degree. C. by the addition of saturated ammonium
chloride solution and partitioned between ethyl acetate and
additional ammonium chloride solution. The organic layer was washed
with brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure to provide a reddish brown solid. The crude
material was dissolved in methylene chlonde and adsorbed onto
silica gel (2 g). Solvent was removed under reduced pressure, the
adsorbed silica gel layered over an Extract-Clean Cartridge.RTM.
(Alltech, packing: 5 g silica gel) and the cartridge eluted with a
hexanes/acetone step gradient consisting of 40 mnL of the following
mixtures: hexanes, 8:1 hexanes/acetone, 4:1, 2:1, and 1:1.
Fractions containing desired product were combined, concentrated,
and flirther purified using HPLC (Technikrom Kromasil 60-5 sil
column, 20 mm.times.25 cm). The column was eluted with a linear
gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl
acetate at 10 mL/min over 50 minutes. Fractions containing the
title product were combined and concentrated under reduced pressure
to provide a pale yellow solid (yield: 99.3 mg, 49%). mp
192-195.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 3H), 3.11 (s, 3H), 1.98 (s, 3H). MS (DCI/NH.sub.3)
m/z 373 (M+H).sup.+, m/z 390 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.16H.sub.15F.sub.3N.sub.2O.sub.3S: 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(2-
H)-pyridazinone
[1353] The product was prepared according to the method of Example
222 substituting 1-methyl-1-propenylmagnesium bromide in place of
isopropenylmagnesium bromide to provide a mixture of geometric
isomers (.about.3:1 ratio) as an off-white solid (yield: 44.8 mg,
21%). mp 175-180.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 0.25H), 7.56 (d, J=17.4 Hz, 1.5H), 7.51 (d,
J=17.4 Hz, 0.5H), 5.55 (m, 0.75H), 5.33 (m, 0.25H), 5.86 (q, J=17.4
Hz, 2H), 3.12 (s, 2.25H), 3.11 (s, 0.75H), 2.88 (m, 2H), 2.85 (m,
1H), 1.27 (m, 3H). MS (DCFNH.sub.3) m/z 387 (M+H).sup.+, m/z 404
(M+NH.sub.4).sup.+, m/z 421 (M+2NH.sub.4-H).sup.+. Anal. calc. for
C.sub.17H.sub.17F.sub.3N.sub.2O.su- b.3S: 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
EXAMPLE 224A
3-Fluorobenzyi Magnesium Bromide
[1354] 3-Fluorobenzyl bromide (613 giL, 5 mmol), followed by
dibromoethane (10 .mu.L), was added dropwise to an oven-dried flask
containing small pieces of magnesium ribbon (134 mg, 5.5 mmol) and
diethyl ether (12 mL). Gas evolution was noted followed by gentle
reflux of the ether. The reaction was stirred until gas evolution
ceased and most of the magnesium had dissolved. The resulting pale
yellow solution of 3-fluorobenzylmagnesium bromide was used
directly in the next reaction.
EXAMPLE 224B
2-(2,2,2-Trifluoroethyl)-4-(3-fluorobenzyl)-5-[4-ethylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1355] A suspension of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared
according to the method of Example 193E, in THF (10 mL) was cooled
to 0.degree. C. A solution of 3-fluorobenzyl magnesium bromide (4.0
mL, .about.0.42 M in diethyl ether), prepared above was added. The
reaction was stirred at 0.degree. C. for 3 hours, quenched by the
addition of saturated ammonium chloride solution, and partitioned,
between ethyl acetate and additional ammonium chloride solution.
The organic layer was washed with brine, dried over sodium sulfate,
filtered, and concentrated under reduced pressure to provide a
yellow oil. The crude material was dissolved in methylene chloride
and adsorbed onto silica gel (2 g). Solvent was removed under
reduced pressure, the silica gel with the product adsorbed was
layered over an Extract-Clean Cartridge.RTM. (Alltech, packing: 10
g silica gel) and the cartridge eluted with a hexanes/acetone step
gradient consisting of 60 mL of each of the following mixtures:
hexanes, 8:1 hexanes/acetone, 4:1, 2:1, and 1:1. Fractions
containing desired product were combined, conicentrated, and
farther purified using PLC (Technikrom Kromasil 60-5 sil silica
column, 20 mm.times.25 cm). The column was eluted with a linear
gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl
acetate at 10 mL/min. for 50 minutes. Fractions containing the
title product were combined and concentrated under reduced pressure
to provide a pale yellow solid (yield: 130.9 mg, 54%). mp
58-62.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 3H). MS
(DCI/NH.sub.3) m/z 441 (M+H).sup.+, m/z 458 (M+NH.sub.4).sup.+, m/z
475 (M+2NH.sub.4-H).sup.+. Anal. calc. for
C.sub.20H.sub.16F.sub.4N.sub.2O.sub.3S: 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
EXAMPLE 225A
1-Cyclohexenyltriflate
[1356] n-Butyllithium (2.5M in hexanes, 2.20 mL, 5.50 mmol) was
added to a solution of diisopropylamine (0.77 mL, 5.50 mmol) in TBF
(20 mL) at -78.degree. C. The resulting pale yellow solution was
warmed to 0.degree. C. for 30 minutes then was cooled to
-78.degree. C. Cyclohexanone (0.52 mL, 5.0 mmol) was added and the
nearly colorless solution was warmed to 0.degree. C. for 1 hour.
N-Phenyltrifluoromethanesulfonimide (1.79 g, 5.5 mmol) was added as
a solid. The solution was stirred at room temperature for 12 hours.
The reaction mixture was then partitioned between diethyl ether and
saturated sodium bicarbonate solution. The ether layer was washed
with water then brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography (20:1 hexanes/ethyl acetate) to
provide the triflate as a pale yellow oil (yield: 0.73 g, 64%).
EXAMPLE 225B
1-Cyclohexenyltrimethyltin
[1357] A solution of 1-cyclohexenyltriflate (412 mg, 1.79 mmol),
prepared according to the method of Example 225A, and LiCl (380 mg,
8.95 mmol) in THF (9 mL) was deoxygenated by bubbling a stream of
N.sub.2 through the solution. Hexamethylditin (339 .mu.L, 1.61
mmol) and tetrakis(triphenylphosphine)palladium(0) (414 mg, 0.36
mmol) were added and the reaction heated at reflux for 12 hours.
The reaction was cooled to room temperature and partitioned between
diethyl ether and saturated sodium bicarbonate solution. The ether
layer was washed with water then brine, dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
material was dissolved in hexanes (1 mL) and loaded onto an
Extract-Clean Cartridge.RTM. (Alltech, packing: 10 g silica gel)
which had been wetted with 10% triethylamine in hexanes. The
cartridge was eluted with hexanes and fractions containing the
triflate combined and concentrated under reduced pressure to
provide 1-cyclohexenyltrimethyltin as a clear oil (yield: 150 mg,
34%).
EXAMPLE 225C
2-(2,2,2-Trifluoroethyl)-4-(1-cyclohexenyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1358] A solution of 1-cyclohexenyltrimethyltin (150 mg, 0.61
mmol), prepared according to the method of Example 225B, and
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone (172 mg, 0.47 mmol), prepared according to the method of
Example 193E, in anhydrous N-methylpyrrolidinone (1 mL) was
deoxygenated with nitrogen. Dichlorobis(triphenylphosphine)
palladium(II) (6.6 mg, 0.009 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.7
mg, 0.009 mmol) were added and the reaction heated at 80.degree. C.
for 16 hours. The reaction mixture was cooled to room temperature
and partitioned between diethyl ether and water. The ether was
washed with two additional portions water then brine, dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The crude material was dissolved in acetone and adsorbed onto
silica gel (1 g). Solvent was removed under reduced pressure, the
adsorbed silica gel layered over an Extract-Clean Cartridge.RTM.
(Alltech, packing: 10 g silica gel) and the cartridge eluted with a
hexanes/acetone step gradient consisting of the following mixtures:
hexanes (60 mL), 8:1 hexanes/acetone (80 mL), 4:1 hexanes/acetone
(150 mL). Fractions containing desired product were combined,
concentrated, and further purified using HPLC (Technikrom Kromasil
60-5 sil silica column, 20 mm.times.25 cm). The column was eluted
with a linear gradient consisting of 30% ethyl acetate/hexanes to
100% ethyl acetate at 10 mL/min. over 50 minutes. Fractions
containing the title product were combined and concentrated under
reduced pressure to provide a pale yellow foam (yield: 95.0 mg,
49%). mp 75-81.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) m/z
413 (M+H).sup.+, m/z 430 (M+NH.sub.4).sup.+, m/z 447
(M+2NH.sub.4-H).sup.+. Anal. calc. for
C.sub.19H.sub.19F.sub.3N.sub.2O.su- b.3S: 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-(aminosulfopl)phe-
n1-3(2H)-pyridazinone
EXAMPLE 226A
3-Fluoro-4-(methylthio)benzeneboronic Acid
[1359] 3-Fluoro-4-(methylthio)benzeneboronic acid was prepared
according to the method of Example 1, substituting
4-bromo-2-fluorothioanisole in place of 4-bromothioanisole.
EXAMPLE 226B
2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone
[1360] 2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone is prepared
according to the method of Example 83B starting with
2-benzyl-4,5-dibromo-3(2H)-pyr- idazinone, in place of
2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazi- none and
substituting methanol in place of isopropanol.
EXAMPLE 226C
2-Benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone
[1361] 3-Fluoro-4-(methylthio)benzeneboronic acid and
2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone were coupled
according to the method of Example 83C to provide
2-benzyl-4-methoxy-5-[3-fluoro-4-(me-
thylthio)phenyl]-3(2H)-pyridazinone as a yellow solid (yield: 4.98
g, 91%). .sup.1H NMR (300 MHz, CDCl3) ? 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
(DCNH3) m/z 357 (M+H).sup.+, m/z 374 (M+NH.sub.4).sup.+.
EXAMPLE 226D
3-Methylbutylmagnesium Bromide
[1362] An oven-dried flask containing small pieces of magnesium
ribbon (134 mg, 5.5 mmol) was charged with diethyl ether (12 mL).
1-Bromo-3-methylbutane (600 .mu.L, 5 mmol) was added dropwise,
followed by dibromoethane (10 .mu.L). The reaction required heating
at gentle reflux before gas evolution was observed. The reaction
was refluxed for 3 hours and cooled to room temperature. The pale
gray solution of 3-methylbutylmagnesium bromide was used in the
next reaction.
EXAMPLE 226E
2-Benzyl-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pydazin-
one
[1363] A solution of
2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]--
3(2H)-pyridazinone (500 mg, 1.40 mmol), prepared according to the
method of Example 226C, in THF (20 mL) was cooled to -78.degree. C.
3-Methylbutylmagnesium bromide (5 mL, 1.96 mmol), prepared in
Example 226D, was added, dropwise. Upon completion of the addition,
the reaction mixture was placed in an ice bath. After 2.5 hours,
the reaction was quenched by adding saturated ammonium chloride
solution. The crude reaction mixture was partitioned between ethyl
acetate and additional ammonium chloride solution. The organic
layer was washed with brine, dried over sodium sulfate, filtered,
and concentrated under reduced pressure to provide a yellow oil
(yield: 550 mg, 99%). .sup.1H NMR (300 MHz, CDCl3) .delta. 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/NH3) m/z 397 (M+H).sup.+, m/z 414
(M+NH.sub.4).sup.+. MS (DCI/NH.sub.3) m/z 397 (M+H).sup.+, m/z 414
(M+NH.sub.4).sup.+.
EXAMPLE 226F
4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-prdazinone
[1364]
2-Benzyl-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)--
pyridazinone (550 mg, 1.39 mmol), prepared in Example 226E, was
debenzylated according to the method of Example 11 to provide
4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone
as a pale yellow solid (yield: 375 mg, 88%). .sup.1H NMR (300 MHz,
CDCl3) .delta. 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/NH.sub.3) m/z 307
(M+H).sup.+, m/z 324 (M+NH4).sup.+ MS (DCI/NH.sub.3) m/z 307
(M+H).sup.+, m/z 324 (M+NH.sub.4).sup.+.
EXAMPLE 226G
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthio)pheny-
l]-3(2H)-pyridazinone
[1365]
4-(3-Methylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazin-
one (375 mg, 1.23 mmol), prepared in Example 226F, was alkylated
according to the method of Example 20 to provide
2-(2,2,2-trifluoroethyl)-4-(3-meth-
ylbutyl)-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a
clear oil (yield: 331 mg, 69%). .sup.1H NMR (300 MHz, CDCl3)
.delta. 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/NH3) m/z
389 (M+H).sup.+, m/z 406 (M+NH.sub.4).sup.+. MS (DCI/NH.sub.3) m/z
389 (M+H).sup.+, ml/z 406 (M+NH.sub.4).sup.+.
EXAMPLE 226H
2-(2,2,2-Trifluoroethyl-4-(3-methylbutyl-5-[3-fluoro-4-(methylsulfinyl)phe-
nyl]-3(2H)-pyridazinone
[1366]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylthi-
o)phenyl]-3(2H)-pyridazinone (331 mg, 0.85 mmol), prepared in
Example 226G, was oxidized according to the method of Example 5
using only one equivalent of MCA to provide
2-(2,2,2-trifluoroethyl)-4-(3-methylbutyl)-5-
-[3-fluoro-4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone as an
off-white solid (yield: 240 mg, 69%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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/NH3) m/z 405 (M+H).sup.+,
m/z 422 (M+NH.sub.4).sup.+. MS (DCI/NH.sub.3) m/z 405 (M+H).sup.+,
m/z 422 (M+NH.sub.4).sup.+.
EXAMPLE 226I
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1367]
2-(2,2,2-Trifluoroethyl)-4-(3-methylbutyl)-5-[3-fluoro-4-(methylsul-
finyl)phenyl]-3(2H)-pyridazinone (240 mg, 0.594 mmol), prepared in
Example 226H, was converted to the sulfonamide according to the
procedure of Example 68 to provide the title compound as a white
solid (yield: 109 mg, 44%). mp 153-156.degree. C. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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).sup.-. Anal. calc. for
C.sub.17H.sub.19F.sub.4N.sub.3O.sub.3S: 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-Trifluoroeethyl)-4-benzyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone
[1368] The title compound was prepared by adding 1.0 M
benzyhnagnesium chloride in ether (0.53 mL, 0.53 mmol) to a THF (20
mL) solution of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone (150 mg, 0.41 mmol), prepared according to the method of
Example 193E, at 0.degree. C., then allowing the mixture to warm to
room temperature over 2 hours. After an aqueous work-up, the crude
material was purified by column chromatography (silica gel, 65:35
hexanes/ethyl acetate) and crystallized from ethyl acetate/hexanes
to provide white, crystalline product (yield: 74 mg, 43%). mp
112-114.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 423 (M+H).sup.+. Anal. calc. for
C.sub.20H.sub.17F.sub.3N.sub.2O.sub.3S: 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)-pyridaz-
inone
[1369] A solution of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-
-3(2H)-pyridazinone, prepared in Example 194C, (200 mg, 0.51 mmol)
in THF (8 ml) was cooled to -78.degree. C. and treated with
cyclohexylmagnesium chloride, 2 M solution in ether (0.31 ml, 0.7
mmol). The reaction mixture was stirred at -78.degree. C. for 2
hours and then was warmed up to room temperature by removing the
cooling bath. Stirred at room temperature for 2 hours water (50 ml)
was added to the reaction mixture and extracted with ethyl acetate
(50 ml). The organic layer was dried over MgSO.sub.4 and
concentrated in vacuo. The resulting rmethyl sulfide compound was
purified by flash chromatography (SiO.sub.2, eluting with 9:1
hexanes:ethyl acetate) to provide the desired product (yield: 128
mg, 69%). MS (DCI/NH.sub.3) m/z 395 (M+H).sup.+, 412
(M+NH.sub.4).sup.+.
[1370] The methyl sulfide compound, prepared above, (122 mg, 0.3
mmol) in CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C., was treated with
CH.sub.3CO.sub.3H (0.3 ml, 1 mmol). The reaction was complete in 2
hours. The reaction mixture was diluted with CH.sub.2CI.sub.2 and
washed with saturated NaHCO.sub.3 and brine respectively. The
resulting crude residue was purified by flash chromatography
(SiO.sub.2, eluting with 1:1 hexanes:ethyl acetate) to provide the
desired product (yield: 110 mg, 93%). mp 231-233.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H),
8.1 (d, 2H). MS (DCI/NH.sub.3) m/z 427 (M+H).sup.+, 444
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.23
H.sub.23FN.sub.2O.sub.3S.0.75 H.sub.2O: 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
[1371] The title compound was prepared according to the method of
Example 228, substituting p-tolylmagnesium bromide in place of
cyclohexylmagnesium chloride (yield: 90 mg, 39%). mp
242-244.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.25
(s, 3H), 6 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.sub.3) m/z 435 (M+H).sup.+, 452 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.19FN.sub.2O.sub.3S.0.5 H.sub.2O: 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)-pyridazinon-
e
[1372] The title compound was prepared according to the method of
Example 228, substituting benzylmagnesium bromide in place of
cyclohexylmagnesium chloride (yield: 179 mg, 81%). mp
180-182.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 435 (M+H).sup.+, 452
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19FN.sub.2O.sub.3S.0.5 H20: 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-(pheylethynyl)-5-[4-(methylsulfonl)phenyl]-3(2H)-pyri-
dazinone
[1373] The title compound was prepared according to the method of
Example 228, substituting phenylacetylene magnesium bromide in
place of cyclohexylmagnesium chloride (yield: 150 mg, 55.5%). mp
203-204.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.3
(s, 3H), 7.4 (m, 8H), 7.7 (m, 2H), 8.16 (m, 4H); 8.35 (s, 1H). MS
(DCI/NH.sub.3) m/z 435 (M+H).sup.+, 452 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.25H.sub.17FN.sub.2O.sub.3S: 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)-pyr-
dazinone
[1374] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methy-
lthio)phenyl]-3(2H)-pyridazinone (yield: 245 mg, 80%). mp
80-83.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 445 (M+H).sup.+, 462 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.22F.sub.2N.sub.2O.sub.3- S: 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)-pyridaz-
inone
[1375] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-difluorophenyl)-4-methoxy-5-[4-(me-
thylthio)phenyl]-3(2H)-pyridazinone and substituting
benzylmagnesium bromide in place of cyclohexylmagnesium chloride
(yield 206 mg, 66%). mp 166-168.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 453 (M+H).sup.+, 470
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19F.sub.2N.sub.2O.sub.3S: C, 63.71; H, 4.01; N, 6.19.
Found: C, 63.53; H, 4.33; N, 5.76.
EXAMPLE 234
2-(3,4-Difluorophenl)-4-(4-methylphenyl
-5-[4-(methylsulfonyl)phenyl]-3(2H- )-pyridazinone
[1376] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-difluorophenyl)-4-methoxy-5-[4-(me-
thylthio)phenyl]-3(2H)-pyridazinone and substituting
p-tolylmagnesium bromide in place of cyclohexylmagnesium chloride
(yield: 140 mg, 56%). mp 190-192.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.28 (s, 2H), 6 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.sub.3) m/z 453 (M+H).sup.+, 470 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24F.sub.2H.sub.18N.sub.2O.sub.3- S: C, 63.71; H,
4.01; N, 6.19. Found: C, 63.69; H, 4.29; N, 5.96.
EXAMPLE 235
2-(3,4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1377] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone and substituting
4-fluoro-3-methylbenzen- emagnesium bromide in place of
cyclohexylmagnesium chloride (yield: 180 mg, 72.5%). mp
166-168.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.15
(s, 3H), 6 3.25 (s, 3H), 7.01 (m, 2H), 7.25 (d, 1H), 7.6 (m, 4H),
7.9 (m, 3H), 8.26 (s, 2H). MS (DCI/NH.sub.3) m/z 471 (M+H).sup.+,
488 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24F.sub.3H.sub.17N.sub.2O.s- ub.3S: 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)-pyridazi-
none
[1378] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone and substituting vinyl magnesium
bromide in place of cyclohexylmagnesium chloride (yield: 85 mg,
31.8%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.15 (s, 3H),
.delta. 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.sub.3) m/z 389 (M+H).sup.+, 406 (M+NH.sub.4)+.
EXAMPLE 237
2-(3,4-Difluorophenyl)-4-(2-thienyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pr-
idazinone
[1379] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone and substituting
2-thienylmagnesium bromide in place of cyclohexylmagnesium chloride
(yield: 66 mg, 28%). mp 189-191.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 445 (M+H).sup.+, 462 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21H.sub.14F.sub.2N.sub.2O.sub.3- S.sub.2: 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)-p-
yridazinone
[1380] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone and substituting
methylacetylenemagnesiu- m bromide in place of cyclohexylmagnesium
chloride (yield: 65 mg, 24%). mp 149-150.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS
(DCI/NH.sub.3) m/z 463M+H).sup.+, 480 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.20H.sub.14F.sub.2N.sub.2O.sub.3S.0.25 H20: 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)-pridaz-
inone
[1381] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(meth-
ylthio)phenyl]-3(2H)-pyridazinone and substituting t-butylmagnesium
bromide in place of cyclohexylmagnesium chloride (yield: 60 mg,
24%). mp 158-161.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 419
(M+H).sup.+, 436 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.20F.sub.2N.sub.2O.sub.3S: 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)-p-
yridazinone
[1382] The title compound was prepared according to the method of
Example 228, starting with
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylthio)phe-
nyl]-3(2H)-pyridazinone, prepared in Example 193D, in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone,
(yield: 120 mg, 53%). mp 215-218.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3)
m/z 415 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.21F.sub.3N.sub.2O.sub.3S: 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)-p-
ridazinone
[1383]
2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyi]-3(2H-
)-pyridazinone was prepared according to the method of Example 228,
starting with
2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-
-pyridazinone, prepared in Example 207C, and substituting
3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesium
chloride to provide the methyl sulfide compound.
[1384] The methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 180 mg,
55%). mp 142-143.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 469 (M+H).sup.+, 486 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.18CIF.sub.2N.sub.2O.sub- .3S.0.5 H.sub.2O:
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-(mehthylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1385]
2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]-3(2H-
)-pyridazinone was prepared according to the method of Example 228,
starting with
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-
-pyridazinone, prepared in Example 194C, and substituting
3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesiun
chloride to provide the methyl sulfide compound.
[1386] The methyl sulfide compound was oxidized according to the
method of Example 10, to provide the title compound (yield: 450 mg,
66.8%). mp 176-178.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 1H),
8.10 (d, J=9 Hz, 2H). MS (DCI/NH.sub.3) m/z 516 (N+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.19F.sub.2N.sub.- 2O.sub.5S.H.sub.2O:
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(2-
H)-pyridazinone
[1387]
2-(3,4-Difluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone was prepared according to the method of Example
228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3-
(2H)-pyridazinone, and substituting 3-fluorobenzylmagnesium
chloride in place of cyclohexylmagnesium chloride to provide the
methyl sulfide compound.
[1388] The methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 390 mg,
68%). mp 161-163.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 471
(M+H).sup.+, 488 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17F.sub.3N.sub.2O.sub.3S.0.5 H.sub.2O: 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
[1389]
2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phe-
nyl]-3(2H)-pyridazinone was prepared according to the method of
Example 228, starting with
2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone, prepared in Example 207C, and substituting
4-fluoro-3-methylphenylmagnesium bromide in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1390] The methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 620 mg,
57%). mp 228-230.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 469 (M+H).sup.+, 486 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.18CIFN.sub.2O.sub.3S: 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
[1391]
2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phe-
nyl]-3(2H)-pyridazinone was prepared according to the method of
Example 228, starting with
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone, prepared in Example 194C, and substituting
4-fluoro-3-methylphenylmagnesium bromide in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1392] The methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 590 mg,
74.4%). mp 245-247.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 453 (M+H).sup.+, 470 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.24H.sub.18F.sub.2N.sub.2O.sub.3S.0.5
H.sub.2O: 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-(methylsulfonl)phenyl]-3(2H)-
-pyridazinone
EXAMPLE 246A
2-(3-Chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pridazinone
[1393] The title compound is prepared according to the method of
Example 194A, substituting 3-chloro-4-fluorophenyl hydrazine-HCl in
place of 4-fluorophenyl hydrazine.HCl (yield: 9.1 g, 9%). .sup.1H
NMR (300 MHz, CDCl.sub.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.sub.3) m/z
383 (M+H).sup.+, 400 (+NH.sub.4).sup.+
EXAMPLE 246B
2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
[1394] The title compound is prepared according to the method of
Example 194B, substituting
2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazi- none in
place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield:
5.6 g, 84%). .sup.1H NMR (300 MHz, CDCl.sub.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.sub.3) m/z 335 (M+H).sup.+, 352
(M+NH.sub.4).sup.+.
EXAMPLE 246C
2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyrda-
zinone
[1395] The title compound is prepared according to the method of
Example 6 starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridaz- inone
in place of 2-benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone and
substituting 4-(methylthio)benzeneboronic acid in place of
4-fluorobenzeneboronic acid (yield: 3.2 g, 63%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 377 (M+H).sup.+, 394 (M+NH.sub.4).sup.+.
EXAMPLE 246D
2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylthio)phenyl]-3(2H)-py-
ridazinone
[1396] The title compound is prepared starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyri-
dazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-
-3(2H)-pyridazinone by treatment of the methoxysulfide compound
with cyclohexylmagnesium chloride according to the method of
Example 228 to provide the cyclohexyl sulfide compound.
EXAMPLE 246E
2-(3-Chloro-4-fluorophenyl
-4-cyclohexyl-5-[4-(methylsulfonyl)-phenyl]-3(2-
H)-pyridazinone
[1397] The methyl sulfide compound was oxidized according to the
method of Example 10 to provide the title compound (yield: 150 mg,
53%). mp 180-181.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 461 (M+H).sup.+, 478 (M+NH.sub.4)+.
Anal. calc. for C.sub.23H.sub.22ClFN.sub.- 2O.sub.3S: 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-mehylphenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1398]
2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methy-
lthio)phenyl]-3(2H)-pyridazinone was prepared according to the
method of Example 228, starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(me-
thylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246C, and
substituting 4-fluoro-3-methylphenylmagnesium bromide in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1399] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 118 mg, 53.7%). mp
207-208.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 487
(M+H).sup.+, 504 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17CIF.sub.2N.sub.2O.sub- .3S.0.25 H.sub.2O: 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)-py-
ridazinone
[1400]
2-(3-Chloro-4-fluorophenyl)-4-benzyl-5-[4-(methylthio)phenyl]-3(2H)-
-pyridazinone was prepared according to the method of Example 228,
starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone, prepared in Example 246C, and substituting
benzylmagnesium chloride in place of cyclohexylmagnesium chloride
to provide the methyl sulfide compound.
[1401] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 110 mg, 38.4%). mp
164-166.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 473
(M+H).sup.+, 490 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18CIFN.sub.2O.sub.3S: 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
[1402]
2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phe-
nyl]-3(2H)-pyridazinone was prepared according to the method of
Example 228, starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methyithio-
)phenyi]-3(2H)-pyridazinone, prepared in Example 246C, and
substituting 3-fluorobenzylmagnesium chloride in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1403] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 33 mg, 15%). mp
101-103.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z
487 (M+H).sup.+, 504 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17ClF.sub.2N.sub.2O.sub.3S: 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
[1404]
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylthio)phe-
nyl]-3(2H)-pyridazinone was prepared according to the method of
Example 228, starting with
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone, prepared in Example 194C, and substituting
3-fluoro-4-methylphenylmagnesium bromide in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1405] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 540 mg, 73%). mp
245-248.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 452 (M+H).sup.+, 470
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18F.sub.2N.sub.2O.sub.3S: 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-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone
[1406]
2-(3-Chloro-4-fluorophenyl)-4-(3,5-difluoro-4-methoxyphenyl)-5-[4-(-
methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the
method of Example 228, starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4--
(methylthio)phenyl]-3(2H)-pyridazinone, prepared in Example 246C,
and substituting 3,5-difluoro-4-methoxyphenylmagnesium bromide in
place of cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1407] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 590 mg, 65.7%). mp
195-197.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 487
(M+H).sup.+, 504 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.16CIF.sub.3N.sub.2O.sub- .3S.0.5 H.sub.2O: 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-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1408]
2-(3-Chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone was prepared according to the method of
Example 228, starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio-
)phenyl]-3(2H)-pyridazinone, prepared in Example 246C, and
substituting 1-(3-methylbutyl)magnesium bromide in place of
cyclohexylmagnesium chloride to provide the methyl sulfide
compound.
[1409] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 425 mg, 54.4%). mp
102-104.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 467
(M+H).sup.+, 484 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21ClF.sub.2N.sub.2O.sub- .3S: 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)-py-
ridazinone
[1410] The sulfide from Example 242,
2-(4-fluorophenyl)-4-(3-fluorobenzyl)-
-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone, was oxidized to the
methyl sulfoxide with one equivalent of meta-chloroperoxybenzoic
acid according to the procedure in Example 69B to provide the
sulfinyl compound.
[1411] The sulfoxide was converted to the title sulfonamide
according to the method of Example 68 (yield: 120 mg, 31%). mp
199-202.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 454
(M+H).sup.+, 471 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.17F.sub.2N.sub.3O.sub.3S: 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
[1412] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methy-
lthio)phenyl]-3(2H)-pyridazinone (yield: 245 mg, 80%) and
substituting phenylethynylmagnesium bromide in place of
cyclohexylmagnesium chloride (yield: 195 mg, 61%). mp
211-213.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.46
(m, SH), 7.65 (m, 2H), 8.18 (t, 4H); 8.4 (s, 1H). MS (DCI/NH.sub.3)
m/z 463 M+H).sup.+, 480 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.25H.sub.16F.sub.2N.sub.2O.sub.3S: 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
[1413] 3,4-Difluorobenzyl bromide (0.1 ml, 0.8 mmol) in ether (10
ml) was treated with magnesium turnings (19.4 mg, 0.81 mmol) and
the reaction mixture was refluxed for 1 hour. The reaction mixture
was cooled and added to a solution of
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)-
phenyl]-3(2H)-pyridazinone (0.25 g, 0.7 immol) in THF (10 ml) at
-78.degree. C. The reaction mixture was stirred at room temperature
for 18 hours. Water (50 ml) was added to the reaction mixture and
extracted with ethyl acetate (50 ml). The organic layer was dried
over MgSO.sub.4 and concentrated in vacuo. The resulting crude
residue was purified by flash chromatography (SiO.sub.2, eluting
with 9:1 hexanes:ethyl acetate) to provide 120 mg of desired
product and some starting material.
[1414] The methylthio compound (120 mg, 0.3 mmol) from above in
CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C., was treated with
CH.sub.3CO.sub.3H (0.3 ml, 1 mmol). The reaction was complete in 2
hours. The reaction mixture was diluted with CH.sub.2Cl.sub.2 and
washed with saturated NaHCO.sub.3 and brine respectively. The
resulting crude residue was purified by flash chromatography
(SiO.sub.2, eluting with 1:1 hexanes:ethyl acetate) to provide the
desired product (yield: 44 mg, 13%). mp 177-179.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 489 (M+H).sup.+, 506 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.16F.sub.4N.sub.2O.sub.3- S.0.25 H.sub.2O:
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
[1415] The title compound was prepared according to the method of
Example 228, starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phen-
yl]3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methy-
lthio)phenyl]-3(2H)-pyridazinone (yield: 245 mg, 80%) and
substituting 1-bromo-3-methylbutane in place of cyclohexylnagnesium
chloride (yield: 198 mg, 48%). mp 55-58.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 433 (M+H).sup.+, 450 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.22F.sub.2N.sub.2O.sub.3- S.0.25 H.sub.2O: 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
[1416] The title compound was prepared according to the method of
Example 228 starting with
2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)-
phenyl]-3(2H)-pyridazinone from Example 246C in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
and substituting 1-bromo-3-methylbutane in place of
cyclohexylmagnesium chloride (yield: 256 mg, 88%). mp 55-58.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 449 (M+H).sup.+, 466 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.22FN.sub.2O.sub.3SC1.0.- 25 H.sub.2O: 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)phe-
nyl]-3(2H)-pyridazinone
[1417] The title compound was prepared according to the method of
Example 228, procedure starting with
2-(3,4-difluorophenyl)-4-methoxy-5-[3-fluoro-
-4-(methylthio)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyri-
dazinone and substituting 1-bromo-3-methylbutane in place of
cyclohexyimagnesium chloride (yield: 100 mg, 20%). mp
119-121.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.75
(d, 6H), 1.4, (m, 3H), 2.48 (m, 2H), 3.4 (s, 3H), 7.51 (m, 1H), 7.8
(m, 2H), 7.81 (m, 2H). MS (DCI/NH.sub.3) m/z 451 (M+H).sup.+, 468
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21F.sub.3N.sub.2O.sub.3S: 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
[1418] To a stirred solution of
2-(3,4-difluorophenyl)-4-(4-fluorophenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (315 mg, 0.69
mmol), Example 182, in DMF (10 ml) at room temperature was treated
with sodium thiomethoxide (51 mg, 0.7 mmol). The reaction mixture
was stirred at room temperature for 3.15 hours. The reaction was
poured into water (75 ml) and extracted into ethyl acetate. The
organic layer was washed two times with brine, dried over
MgSO.sub.4, and concentrated in vacuo. The resulting crude residue
was purified using flash chromatography (SiO.sub.2, eluting with
(15:1 CH.sub.2Cl.sub.2:diethyl ether) to provide the desired
product (yield: 30 mg, 8%). mp 105-107.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.55 (s, 3H), 3.23 (s, 3H), .delta. 7.15
(m, 2H), 7.3 (m, 2H), 7.55 (m, 5H), 7.9 (d, 2H), 8.25 (s, 1H). MS
(DCI/NH.sub.3) m/z 485 (M+H).sup.+, 502 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.18F.sub.2N.sub.2O.sub.3S.sub.2: C, 59.49;
H, 3.74; N, 5.78.
EXAMPLE 260
2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-py-
ridazinone
EXAMPLE 260A
2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyrdazinone
[1419] The title compound was prepared starting with
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
and oxidizing the sulfide according to the procedure in example
69B
EXAMPLE 260B
Bis(4-(5-(2-benzyl-4-(4-fluorophenyl)-3(2H)-pyridazinone)phenyl)disulfide
[1420] A heterogeneous solution of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methy-
lsulfinyl)phenyl]-3(2H)-pyridazinone (1.0 g, 2.39 mmol) in
trifluoroacetic anhydride (10 mL, 70.8 mmol) was rapidly stirred at
reflux for 2 hours with a bath temperature of 40-43.degree. C. The
reaction solution was cooled to 23.degree. C., concentrated in
vacuo, and azeotroped with toluene (2.times.5-7 mL). The resultant
yellow/orange oil was cooled to 0.degree. C., and
methanol/triethylamine (1:1, 6 mL) was slowly added, along the
interior wall of the reaction vessel with rapid stirring. The
bright red-orange solution was stirred for 10 minutes at 0.degree.
C., the cooling bath removed, and the reaction mixture stirred an
additional 1.5 hours warming to 23.degree. C. The mixture was
cooled back to 0.degree. C., and a saturated NH.sub.4Cl solution
(200 mL) slowly added followed by enough aqueous 1 M HCl to adjust
the solution to pH 1-2. The cooling bath was removed and the
solution stirred overnight. The mixture was extracted with ethyl
acetate. The ethyl acetate solution was washed with water and
brine, and concentrated in vacuo. The resultant yellow/brown oil
(0.89 g) was a mixture of predominantly the mono-sulfide and
desired di-sulfide. Subsequent rapid stirring of a portion of the
crude reaction mixture (360 mg) in benzene (100 mL) with I.sub.2
(648 mg, 2.55 mmol) at 23.degree. C. for 30 minutes completed the
conversion of the mono-sulfide to the di-sulfide. (Chem. Pharm.
Bull., 1992, 40, 2842) The mixture was treated with a 0.1 M
Na.sub.2S.sub.2O.sub.3 solution to consume the excess 12. This
solution was extracted with ethyl acetate, and the ethyl acetate
layers dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was dissolved in CH.sub.2Cl.sub.2/hexanes and
concentrated in vacuo to provide the of product (yield: 347 mg, 90%
for partial conversion). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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).
EXAMPLE 260C
2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio)phenyl]-3(2H)-pyrida-
zinone
[1421] A rapidly stirred mixture of
bis[4-{5-[2-benzyl-4-(4-fluorophenyl)--
3(2H)-pyridazinone]}-phenyl]-disulfide (140 mg, 0.181 mmol),
potassium trifluoroacetate (55 mg, 0.361 mmol), and sulfolane (1.5
mL) was immersed in a 180.degree. C. pre-heated oil bath. The oil
bath was heated to increase the temperature to 210.degree. C., and
the reaction flask was promptly removed from the oil bath after 10
minutes from the point of first inmersion. During the course of the
reaction, the mixture changed from colorless and heterogeneous to
deep, blood red and homogeneous. After cooling to 23.degree. C.,
the mixture was diluted with ethyl acetate and washed with aqueous
1 M HCl, water, and brine. The ethyl acetate solution was dried
over MgSO.sub.4, filtered and concentrated in vacuo. The residue
was chromatographed (flash silica gel, ethyl acetate/hexanes 1:4)
to provide the product (yield: 17 mg, 41%). (Tetrahedron Lett.,
1996, 37, 9057) .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+ and m/z 474 (M+NH.sub.4).sup.+.
EXAMPLE 260D
2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)-py-
ridazinone
[1422] A solution of
2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio-
)phenyl]-3(2H)-pyridazinone (100 mg, 0.219 mmol),
3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%), and
methylene chloride (5 mL) was brought to reflux at a bath
temperature of 55.degree. C. After 1.75 hours, 3.5 hours, 5 hours,
and 6 hours, the reaction was not complete and additional
3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%) was added
each time. With the reaction completed after 7.75 hours, the
mixture was cooled to 23.degree. C. and concentrated in vacuo. The
residue was diluted with ethyl acetate and carefully shaken with a
NaHSO.sub.3 solution, 3 times, for several minutes to consume the
excess 3-chloroperoxybenzoic acid. The ethyl acetate solution was
subsequently washed with a saturated Na.sub.2CO.sub.3 solution
(3.times.), water, and brine and dried over MgSO.sub.4, filtered,
and concentrated in vacuo. The residue was chromatographed (flash
silica gel, ethyl acetate/methylene chloride/hexanes 1:2:7) to
provide of product (yield: 93 mg, 87%). (J. Med. Chem., 1990, 33,
2569) mp 80-115.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.+ and m/z 506
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.16F.sub.4N.sub.2O.sub.3- S: 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)pheny-
l]-3(2H)-pridazinone
[1423]
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone (150 mg, 0.41 mmol), prepared in Example 193E, and
neopentyl alcohol (43 mg, 0.49 mmol) were dissolved in DMF (2 mL)
and NaH (25 mg, 0.62 mmol, 60% in mineral oil) was added with
shaking and left overnight. The reaction mixture was carefully
quenched with saturated NH.sub.4Cl solution, diluted with ethyl
acetate and extracted with 1 N HCl, twice, then water, 3 times, and
then dried over MgSO.sub.4. After filtration of the drying agent
and concentration of the filtrate in vacuo, the residue was
purified by chromatography on silica gel (Biotage 40S) eluted with
2:1 hexanes-ethyl acetate. The product fractions were combined and
evaporated to provide the title compound (yield: 137 mg, 76%). mp
145-146.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 419 (M+H).sup.+, 436 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.4S: 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
[1424] The title compound was prepared according to the method of
Example 261, substituting 4-methoxyphenol in place of neopentyl
alcohol (yield: 130 mg, 54%). mp 194-195.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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). Anal. calc. for C.sub.19H.sub.17F.sub.3N.sub.2O.sub.4S:
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-(methy-
lsulfonyl)phenyl]-3(2H)-pridazinone
[1425] The title compound was prepared according to the method of
Example 261, substituting 2-fluoro-5-trifluoromethylphenol in place
of neopentyl alcohol (yield: 155 mg, 89%). mp 133-135.degree. C.
.sup.1H NMR (300 MHz, DMSO-d,) .delta. 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.sub.3)
m/z 528 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.13F.sub.7N.sub.2O.sub.4S: 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
[1426] The title compound was prepared according to the method of
Example 261, substituting 4-cyanophenol in place of neopentyl
alcohol (yield: 109 mg, 71%). mp 179-181.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 467
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.14F.sub.3N.sub.3O.sub.4S: 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(2-
H)-pyridazinone
[1427] The title compound was prepared according to the method of
Example 261, substituting 3-hydroxypyridine in place of neopentyl
alcohol (yield: 120 mg, 69%). mp 191-193.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 426
(M+H).sup.+, 443 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.18H.sub.14F.sub.3N.sub.3O.sub.4S: 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)-pridazinone
[1428] The title compound was prepared according to the method of
Example 261, substituting 4-(n-propyl)phenol in place of neopentyl
alcohol (yield: 147 mg, 77%). mp 152-153.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 484 (M+H).sup.+. Anal. calc.
for C.sub.22H.sub.21F.sub.3N.sub.2O.sub.4S: 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)phenyl]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
[1429] The title compound was prepared according to the method of
Example 261, substituting 4-(methylsulfonyl)phenol in place of
neopentyl alcohol (yield: 115 mg, 56%). mp 212-213.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 520
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20Hl.sub.7F.sub.3N.sub.2O.sub.6S.sub.2: 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
[1430] The title compound was prepared according to the method of
Example 261, substituting 4-phenylphenol in place of neopentyl
alcohol (yield: 105 mg, 51%). mp 163-165.degree. C. HNMR(300MHz,
DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 518 (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.25H.sub.19F.sub.3N.sub.2O.sub.4- S: 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)phe-
nyl]-3(2H-pyridazinone
[1431] The title compound was prepared according to the method of
Example 261, substituting 2-(methylthio)ethanol in place of
neopentyl alcohol (yield: 105 mg, 61%). mp 103-105.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 423 (M+H).sup.+, 440 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.16H.sub.17F.sub.3N.sub.2O.sub.4- S.sub.2: C, 45.49;
H, 4.06; N, 6.33. Found: C, 45.83; H1 4.1 1; N, 6.42.
EXAMPLE 270
2-(2,2,2-Trifluoroethyl)-4-(phenylmethoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1432] The title compound was prepared according to the method of
Example 261, substituting benzyl alcohol in place of neopentyl
alcohol (yield: 137 mg, 76%). mp 121-123.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z
456 (M+H).sup.+. Anal. calc. for
C.sub.20H.sub.17F.sub.3N.sub.2O.sub.4S: 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
[1433] The title compound was prepared according to the method of
Example 261, substituting 2-(hydroxymethyl)furan in place of
neopentyl alcohol (yield: 101 mg, 58%). mp 113-115.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 446
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.18H.sub.15F.sub.3N.sub.2O.sub.5S: 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-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1434] The title compound was prepared according to the method of
Example 261, substituting 2-(3,4-dimethoxyphenyl)ethanol in place
of neopentyl alcohol (yield: 118 mg, 56%). mp 133-134.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 530 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.23H.sub.23F.sub.3N.sub.2O.sub.6- S: 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-Trifluorethyl)-4-[2-(4-morpholino)ethoxy)]-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone
[1435] The title compound was prepared according to the method of
Example 261, substituting 4-(2-hydroxyethyl)morpholine in place of
neopentyl alcohol (yield: 111 mg, 59%). mp 147-148.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 462 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.22F.sub.3N.sub.3O.sub.5S: 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
[1436] The title compound was prepared according to the method of
Example 261, substituting 1-(2-hydroxyethyl)piperidine in place of
neopentyl alcohol (yield: 103 mg, 55%). mp 117-118.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 460 (M+H).sup.+. Anal.
calc. for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.4S: 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)phenoxyl)]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
[1437] The title compound was prepared according to the method of
Example 261, substituting 4-hydroxybenzamide in place of neopentyl
alcohol (yield: 50 mg, 26%). mp>250.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 468 (M+H).sup.+, 485 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.20H.sub.16F.sub.3N.sub.3O.sub.5S: 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(2-
H)-pyridazinone
[1438] The title compound was prepared according to the method of
Example 261, substituting 1-indanol in place of neopentyl alcohol
(yield: 84 mg, 44%/O). mp 113-114.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3)
m/z 482 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.19F.sub.3N.sub.2O.sub.4S: 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)ph-
enyl]-3(2H)-pyridazinone
[1439] The title compound was prepared according to the method of
Example 261, substituting 4-acetamidophenol in place of neopentyl
alcohol (yield: 45 mg, 23%). mp 215-216.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 499 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.18F.sub.3N.sub.3O.sub.5- S: 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
[1440] The title compound was prepared according to the method of
Example 261, substituting 2-methylpropanol in place of neopentyl
alcohol (yield: 111 mg, 50%0). mp 108-110.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 405 (M+H).sup.+, 422 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.17H.sub.19F.sub.3N.sub.2O.sub.4- S: C, 50.49; H,
4.74; N, 6.93. Found: C, 50.69; H, 4.89; N, 6.75.
EXAMPLE 279
2-(2,2,2-Trifluoroethyl)-4-(1-methylcyclopropylmethoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H -pyridazinone
[1441] The title compound was prepared according to the method of
Example 261, substituting 1-methylcyclopropanemethanol in place of
neopentyl alcohol (yield: 360 mg, 75.5%). mp 98-99.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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=8.5Hz, 2H), 7.84 (s, 1H), 8.06 (d, J=9 Hz, 2H). MS
(DCN.sub.3) m/z 417 M+H)+, m/z 434 (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.18H.sub.19F.sub.3N.sub.2O.sub.4- S: 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)pheny-
l]-3(2H)-pyridazinone
[1442] The title compound was prepared according to the method of
Example 261, substituting 3,3-dimethyl-1-butanol in place of
neopentyl alcohol (Yield: 270 mg, 67.4%). mp 83-85.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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 (DCI3) m/z
433 (M+H).sup.+, m/z 450 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.23F.sub.3N.sub.2O.sub.4- S: 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
[1443] A mixture of
2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-p- yridazinone
(187 mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg,
0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25
mL) was refluxed at 50.degree. C. for 3 hours and then concentrated
in vacuo. The residue was partitioned between water and ethyl
acetate. The acetate layer was washed with brine, dried over
MgSO.sub.4 and concentrated in vacuo. The residue was
chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide
2-benzyl-4-(4-chlorophenoxy)-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 200 mg, 82%).
[1444] The above derivative was dissolved in toluene (25 mL) and
was treated with AlBr.sub.3 (400 mg, 1.5 mmol) for 20 minutes at
80.degree. C. The mixture was cooled to room temperature and poured
into ice-10% citric acid-ethyl acetate. The organic layer was
separated, dried over MgSO.sub.4 and concentrated in vacuo to
provide crude desbenzyl derivative. This compound was immediately
dissolved in pyridine (50 mL) and was treated with
3,4-difluorobromobenzene (0.17 mL, 1.5 mmol), Cu (20 mg) and
K.sub.2CO.sub.3 (100 mg, 1.5 mmol) at reflux for 16 hours. After
the mixture was concentrated in vacuo, the residue was dissolved in
ethyl acetate and was washed with water, 10% citric acid and brine.
Purification by column chromatography (silica gel, 1:1
hexanes-ethyl acetate) provided the title compound (yield: 73 mg,
30%). mp 192-194.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.+ and (APCI-) m/z
523 (M+Cl).sup.-.
EXAMPLE 282
2-(3,4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1445] The title compound was prepared according to the method of
Example 281, substituting p-bromophenol in place of p-chlorophenol
(yield: 54 mg, 20%). mp 196-199.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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).sup.+ and (APCI-) m/z 569 (M+Cl).sup.-.
EXAMPLE 283
2-(2,2,2-Trifluoroethyl)-4-(cyclopentylthio)-5-4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1446] To a solution of NaH (26 mg, 1.1 mmol) in acetonitrile (3.0
mL), under nitrogen, was added cyclopentyl mercaptan (120 gL, 1.1
mmol) dropwise via syringe. The resulting solution was flushed with
nitrogen for a period of 20 minutes; after which
2-(2,2,2-trifluoroethyl)-4-chloro-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in
Example 193E, (200 mg, 0.52 mmol) was added in one portion. The
solution was stirred for an additional 20 minutes at which time,
all the 4-bromo pyridazinone was consumed. The solution was
analyzed by TLC (1:1, ethyl acetate-Hex). Water (5 mL) was
carefully added and the reaction partitioned between ethyl acetate
(125 mL) and saturated saline (50 mL). The organic layer is washed
with saturated saline (50 mL), dried over MgSO.sub.4, and
concentrated in vacuo. Silica gel chromatography (20% ethyl
acetate-80% hexanes) provided a pale yellow solid (yield: 202 mg,
83.1%). mp 149-151.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 432 (M+H).sup.+, (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.18H.sub.19F.sub.3N.sub.2O.sub.3- S.sub.2: C, 49.99; H,
4.43; N, 6.48. Found: C, 50.15; H, 4.39; N, 6.45.
EXAMPLE 284
2-(2,2,2-Trifluoroethyl)-4-(1H-1,2,4-triazole-3-ylthio)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone
[1447] The title compound was prepared according to the method of
Example 283, substituting 1H-1,2,4-triazole-3-thiol in place of
cyclopentyl mercaptan (yield: 164 mg, 93%). mp 197-200.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/NH.sub.3) m/z 431
(M+H).sup.+, (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.15H.sub.12F.sub.3N.sub.2O.sub.3S.sub.2: 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
[1448] The title compound was prepared according to the method of
Example 283, substituting benzyl mercaptan in place of cyclopentyl
mercaptan (yield: 141 mg, 76%). mp 108-111.degree. C. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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/NH.sub.3) m/z 454 (M+H).sup.+,
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.17F.sub.3N.sub.2O.sub.3S.sub.2, 0.75 EtOAc: 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)pheny-
l]-3(2H-pyridazinone
[1449] The title compound was prepared according to the method of
Example 283, substituting 4-fluorophenylmethyl mercaptan in place
of cyclopentyl mercaptan (yield: 184 mg, 73.5%). mp 182-185.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.08 (s, 3H), 4.82 (q,
J=8.5 Hz, 2H), 6.87-6.81 (m, 2H), 7.19-7.11 (m, 2H), 7.48 (d, J=9.0
Hz, 2H), 7.68 (s, 1H), 7.93 (d, J=8.5 Hz, 2H). MS (DCI/NH.sub.3)
m/z 458 (M+H).sup.+, (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.14F.sub.4N.sub.2O.sub.3- S.sub.2: 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
[1450] The title compound was prepared according to the method of
Example 283, substituting cyclohexyl mercaptan in place of
cyclopentyl mercaptan (yield: 189 mg, 78%). mp 165-167.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/NH.sub.3) m/z 446 (M+H).sup.+,
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.21F.sub.3N.sub.2O.sub.3S.sub.2: 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-fluorolphenylthio)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1451] The title compound was prepared according to the method of
Example 283, substituting 3-chloro-4-fluorothiophenol in place of
cyclopentyl mercaptan (yield: 190 mg, 65%). mp 142-145.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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+1).sup.+,
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.19H.sub.13ClF.sub.-
4N.sub.2O.sub.3S.sub.2.0.25 C.sub.6H.sub.6.H.sub.2O: 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-trfuoroethylthio)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone
[1452] The title compound was prepared according to the method of
Example 283, substituting 2,2,2-trifluoroethyl mercaptan in place
of cyclopentyl mercaptan (yield: 175 mg, 66%). mp 155-158.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/NH.sub.3) m/z 446 (M+H)+,
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.15H.sub.12F.sub.6N.sub.2O.sub.3S.sub.2: 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
[1453] The title compound was prepared according to the method of
Example 283, substituting tert-butyl mercaptan in place of
cyclopentyl mercaptan (yield: 212 mg, 85%). mp 186-189.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+, (M+Na).sup.+.
Anal. calc. for C.sub.17H.sub.19F.sub.3N.sub.2O.sub.3S.sub.2: 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-acetainidolphenlthio)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pridazinone
[1454] The title compound was prepared according to the method of
Example 283, substituting 4-acetamidothiophenol in place of
cyclopentyl mercaptan (yield: 100 mg, 37%). mp 191-193.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+, (+NH.sub.4).sup.+. Anal. calc.
for C.sub.21H.sub.18F.sub.3N.sub.3O.sub.4S- .sub.2.0.25H.sub.2O,
0.25 C.sub.6H.sub.6: 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-proylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1455] The title compound was prepared according to the method of
Example 283, substituting isopropyl mercaptan in place of
cyclopentyl mercaptan (yield: 180 mg, 81%). mp 165-167.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 406 (M+H).sup.+, (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.16H.sub.17F.sub.3N.sub.2O.sub.3- S.sub.2, 0.75H.sub.2O:
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)ph-
enyl-3(2H)-pyridazinone
[1456] The title compound was prepared according to the method of
Example 283, substituting 2-methyl-1-propyl mercaptan in place of
cyclopentyl mercaptan (yield: 100 mg, 83%). mp 135-138.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/NH.sub.3) m/z 420 (M+H).sup.+, (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.17H.sub.19F.sub.3N- .sub.2O.sub.3S.sub.2: 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)-pyrida-
zinone
[1457]
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone, prepared according to Example 193E, (500 mg, 1.36
mrnmol) was dissolved in DMF (10 mL) and treated with NaN.sub.3
(100 mg, 1.5 mmol). After 2 hours at room temperature, the reaction
was diluted with ethyl acetate and washed with water, 4 times, and
dried over MgSO.sub.4. After filtration of the drying agent and
concentration of the filtrate in vacuo, the residue was purified by
chromatography on silica gel (Biotage 40S) eluted with 2:1
hexanes-ethyl acetate. The product fractions were combined and
evaporated to provide the azido intermediate,
2-(2,2,2-Trifluoroethyl)-4-azido-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone (yield: 481 mg, 95%).
[1458] The 4-azido-compound above (39 mg, 0.105 mmol) was dissolved
in THF (3 mL) and MeOH (2 mL) and treated with excess NaBH.sub.4.
After 15 minutes, the reaction was quenched with saturated
NH.sub.4Cl solution and the product was extracted into ethyl
acetate. The organic layer was washed with water, 3 times, and
dried over MgSO.sub.4. Filtration of axis the drying agent and
evaporation of the solvent provided the title compound (yield: 26
mg, 71%). mp>260.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.-. Anal. calc. for
C.sub.13H.sub.12F.sub.3N.sub.3O.sub.3S: 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-methoxylpropylamino)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1459] A solution of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared
according to the method of Example 193E, and 3-methoxypropylamine
(145 mg, 1.64 mmol) in pyridine (4 mL) was heated at 100.degree. C.
for 16 hours. The reaction mixture was cooled to room temperature,
mixed with silica gel (2 g), and the solvent removed under reduced
pressure. The adsorbed silica gel was layered over an Extract-Clean
Cartridge.RTM. (Alltech, packing: 10 g silica gel) and the
cartridge eluted with a hexanes/acetone step gradient consisting of
60 mL of each of the following mixtures: hexanes, 8:1
hexanes/acetone, 4:1, 2:1, and 1:1. Fractions containing desired
product were combined, concentrated, and further purified using
HPLC (Technikrom Kromasil 60-5 sil silica column, 20 mm.times.25
cm). The column was eluted with a linear gradient consisting of 30%
ethyl acetate/hexanes to 100% ethyl acetate at 10 mL/min over 50
minutes. Fractions containing product were combined and
concentrated under reduced pressure to provide the product as
off-white crystals (yield: 215 mg, 95%). mp 110-113.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 211), 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.sub.3) m/z 420 (M+H).sup.+, m/z 437
[M+NH.sub.4]+. Anal. calc. for
C.sub.17H.sub.20F.sub.3N.sub.3O.sub.4S: 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
[1460] The product was prepared according to the method of Example
295, substituting cyclopentylamine in place of 3-methoxypropylamine
to provide brown crystals (yield: 195 mg, 86%). mp 134-139.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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 (brm, 8H). MS (DCI/NH.sub.3) m/z 416 (M+H).sup.+, m/z 433
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.18H.sub.20F.sub.3N.sub.3O.sub.3S: 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-Trfluoroethyl)-4-(cyclobutylamino)-5-[4-(methylsulfonyl)phenyl]-3-
(2H-pyridazinone
[1461] The product was prepared according to the method of Example
295, substituting cyclobutylamine in place of 3-methoxypropylamine
to provide an off-white solid (yield: 206 mg, 94%). mp
169-172.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 402 (M+H).sup.+, m/z 419 (M+NH.sub.4).sup.+. Anal calc. for
C.sub.17H.sub.18F.sub.3N.sub.3O.sub.3S.0.25 CH.sub.3COCH.sub.3: 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-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1462] The product was prepared according to the method of Example
295, substituting 3,4-dimethoxyphenethylamine in place of
3-methoxypropylamine to provide an off-white solid (yield: 206 mg,
94%). mp 163-165.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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,
H), 4.79 (q, J=17.4 Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.11 (s,
3H), 2.91 (dt, J=12.6, 12.6 Hz, 2H), 2.60 (t, J=13.8 Hz, 2H). MS
(DCI/NH.sub.3) m/z 529 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.24F.sub.3N.sub.3O.sub.5S: 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
[1463] The product was prepared according to the method of Example
295 , substituting cyclohexylamine in place of 3-methoxypropylamine
to provide an off-white solid (yield: 103 mg, 42%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 430
(M+H).sup.+, m/z 447 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.22F.sub.3N.sub.3O.sub.3- S: 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-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1464] The product was prepared according to the method of Example
295, substituting 2-(1-piperdinyl)ethylamine in place of
3-methoxypropylamine to provide an off-white solid (yield: 210 mg,
84%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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=18.0Hz, 2H), 3.13 (s, 3H), 2.64 (br, 2H), 2.32 (br, 4H), 1.58
(br, 6H), 1.42 (br, 2H). MS (DCI/NH.sub.3) m/z 459 (M+H).sup.+.
Anal. calc. for C.sub.19H.sub.22F.sub.3N.sub.3O.sub.- 3S: 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-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1465] The product was prepared according to the method of Example
295, substituting tetrahydrofurfurylamine in place of
3-methoxypropylamine to provide an off-white solid (yield: 150 mg,
64%). mp 128-129.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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, 3H), 1.34 (m, 1H). MS (DCI/NH.sub.3) m/z 432 (M+H).sup.+, m/z
449 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.18H.sub.20F.sub.3N.sub.3O.sub.3S: 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-(cyclopropylmethylamino)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone
[1466] The product was prepared according to the method of Example
295, substituting cyclopropylmethylamine in place of
3-methoxypropylamine to provide an off-white solid (yield: 130 mg,
59%). mp 145-146.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 402 (M+H).sup.+, m/z 419 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.17H.sub.18F.sub.3N.sub.3O.sub.3- S: 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-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1467] The product was prepared according to the method of Example
295, substituting 1-indanylamine in place of 3-methoxypropylamine
to provide an off-white solid (yield: 82 mg, 32%). mp
155-158.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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)-. Anal. calc. for
C.sub.22H.sub.20F.sub.3N.sub.3O.sub.3S: 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
[1468] The product was prepared according to the method of Example
295, substituting piperidine in place of 3-methoxypropylamine to
provide an off-white solid (yield: 180 mg, 79%). mp 160-161.degree.
C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 416 (M+H).sup.+. Anal. calc. for
C.sub.18H.sub.20F.sub.3N.sub.3O.sub.3S.H.sub.2O: 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)phe-
nyl]-3(2H)-pyridazinone
[1469] The product was prepared according to the method of Example
295, substituting 3-hydroxypropylamine in place of
3-methoxypropylamine to provide a white solid (yield: 109.6 mg,
50%). mp 152-154.degree. C. .sup.1H NMR (300 MHz, CDCl3) .delta.
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.sub.3) m/z 406 (M+H).sup.+, m/z 423
(M+NH.sub.4).sup.+. Anal. calc. for C.sub.16H.sub.18F.sub.3N.sub.-
3O.sub.4S: 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-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone
[1470] The product was prepared according to the method of Example
295, substituting 1-(3-aminopropyl)imidazole in place of
3-methoxypropylamine. The reaction mixture was concentrated to
dryness and the residue purified using RP-HPLC (Rainin Dynamax C-18
column, 60 .ANG. pore size, 21.4 mm i.d.). The column was eluted
with a linear gradient consisting of 20% acetonitrile (containing
0.1 % TFA)/80% water (containing 0.1 % TFA) to 100% acetonitrile
(containing 0.1% TFA) at 15 mL/min over 70 minutes. The peak
corresponding to the title product was collected and lyophilized to
provide a tan hygroscopic foam (yield: 70.2 mg, 28%). .sup.1H NMR
(300 MHz, DMSO) .delta. 8.95 (br s, 1H), 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 (brt, 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, 3H), 2.69 (m, 2H), 1.81 (tt, J=13.2, 13.2
Hz, 2H). MS (DCI/NH.sub.3) m/z 456 (M+H).sup.+. Anal. calc. for
C.sub.19H.sub.20F.sub.3N.sub.5O.sub.- 3S.1.4 CF.sub.3COOH: C,
42.57; H, 3.51; N, 11.39. Found: C, 42.78; H, 3.58; N, 11.24.
EXAMPLE 307
2-(2,2,2-Trifluoroethyl)-4-(2R-hydroxylpropylamino)-5-[4-(methylsulfonyl)p-
henyl]3(2H)-pyridazinone
[1471] The product was prepared according to the method of Example
295, substituting (R)-(-)-2-propanolamine in place of
3-methoxypropylamine to provide an off-white solid (yield: 109.6
mg, 50%). M.p .=140-142.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3)
m/z 406 (M+H).sup.+, m/z 423 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.16H.sub.18F.sub.3N.sub.3O.sub.4S: 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
[1472] The product was prepared according to the method of Example
295, substituting 2-cyanoethylamine in place of
3-methoxypropylainine to provide an off-white solid (yield: 27 mg,
12%). mp 172-174.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 418 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.16H.sub.15F.sub.3N.sub.4O.sub.3S: 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]-2-
(2H)-pyridazinone
[1473] A suspension of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (300 mg, 0.820 mmol), prepared
according to the method of Example 193E, 4-aminobenzonitrile (290
mg, 2.46 mmol), and silver oxide (760 mg, 3.28 mmol) in pyridine
(1.5 mL) was stirred at 80.degree. C. for 24 hours. The reaction
was cooled to room temperature, adsorbed onto silica gel (2 g) and
solvent removed under reduced pressure. The adsorbed silica gel was
layered over an Extract-Clean Cartridge.RTM. (Alltech, packing: 10
g silica gel) and the cartridge eluted with a hexanes/acetone step
gradient consisting of 60 mL of each of the following mixtures:
hexanes, 8:1 hexanes/acetone, 4:1, 2:1, and 1:1. Fractions
containing desired product were combined, concentrated, and further
purified using PLC (Technikrom Kromasil 60-5sil column, 20
mm.times.25 cm). The column was eluted with a linear gradient
consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10
mL/min over 50 minutes. Fractions containing product were combined
and concentrated under reduced pressure to provide the product as a
tan solid (yield: 149.9 mg, 41%). mp>230.degree. C. .sup.1H NMR
(300 MHz, DMSO) .delta. 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.sub.3) m/z 466
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.15F.sub.3N.sub.4O.sub.3S: 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-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone
[1474] The product was prepared according to the method of Example
309, substituting 3-methoxy-5-(trifluoromethyl)aniline in place of
4-aminobenzonitrile to provide a brown solid (yield: 226.5 mg,
80%). mp 206-208.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 539 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.17F.sub.6N.sub.3O.sub.4S: C, 48.37; H, 3.29; N, 8.06.
Found: C, 48.60; H, 3.33; N, 7.94.
EXAMPLE311
2-(2,2,2-Trifluoroethyl)-4-anilino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone
[1475] The product was prepared according to the method of Example
309, substituting aniline in place of 4-aminobenzonitrile to
provide a tan solid (yield: 90 mg, 53%). mp 154-156.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 424 (M+H).sup.+, m/z 441
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.16F.sub.3N.sub.3O.sub.3S: 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
[1476] The product was prepared according to the method of Example
309, substituting 2,5-dimethoxyaniline in place of
4-aminobenzonitrile to provide a tan solid (yield: 140 mg, 53%). mp
95-96.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.78 (br
s, 1H), 7.72 (s, 1H), 7.63 (d, J=18.0 Hz, 2H), 7.18 (d, J=18.0 Hz,
2H), 6.54 (d, J=18.0 Hz, 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, 3H). MS
(DCI/NH.sub.3) m/z 484 (M+H).sup.+, m/z 501 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.21H.sub.20F.sub.3N.sub.3O.sub.5- S: 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)-pridazinone
[1477] The product was prepared according to the method of Example
309, substituting 3-fluoroaniline in place of 4-aminobenzonitrile
to provide a tan solid (yield: 151.3 mg, 42%). mp 156-158.degree.
C. .sup.1H NMR (300 MHz, DMSO) .delta. 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/NH3) m/z 442 (M+H).sup.+, m/z 459
(M+NH.sub.4).sup.+, m/z 476 (N+2NH.sub.4--H).sup.+. Anal. calc. for
C.sub.19H.sub.15F.sub.4N.sub.3O.sub.3S.0.5 CH.sub.3COCH.sub.3: 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-meth
Isulfonyl)phenyl]-3(2H)-pyridazinone
[1478] The product was prepared according to the method of Example
309, substituting 2,4-difluoroaniline in place of
4-aminobenzonitrile to provide a tan solid (yield: 63.1 mg, 17%).
mp 170-175.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta. 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.sub.3) m/z 460 (M+H)+, m/z 477 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.19H.sub.14F.sub.5N.sub.3O.sub.3- S: 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)p-
henyl]-3(2H)-pyridazinone
[1479] The product was prepared according to the method of Example
309, substituting 2,3,5-trifluoroaniline in place of
4-aminobenzonitrile to provide a pale purple solid (yield: 85.3 mg,
22%). mp 190-194.degree. C. .sup.1H NMR (300 MHz, DMSO) .delta.
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.sub.3) m/z 495 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.19H.sub.13F.sub.6N.sub.3O.sub.3- S: 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
[1480] The product was prepared according to the method of Example
309, substituting 4-fluoroaniline in place of 4-aminobenzonitrile
to provide a tan solid (yield: 15.8 mg, 4%). mp 158-160.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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/N1.sub.3) m/z 459 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.19H.sub.15F.sub.4N.sub.3O.sub.3- S.1.25 H.sub.2O: 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
[1481]
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
prepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid
(66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol), and
tetrakis-(triphenylphosphi- ne)-palladium(0) (13.9 mg, 0.012 mmol)
in DME (25 mL) were stirred at reflux for 6 hours TLC
(1CH.sub.2Cl.sub.2:1 hexanes: 1.5 ethyl acetate) indicated that all
starting materials were consumed. The reaction mixture was cooled
to room temperature and concentrated under reduced pressure. The
residue was partitioned between water and ethyl acetate. The
organic layer was washed with brine, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated under reduced pressure. The
residue was purified using a silica gel column (0.5:2.5:0.5
CH.sub.2Cl.sub.2/hexanes/- ethyl acetate). A yellow powder was
obtained (yield: 50 mg, 31%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.09 (s, 3H), 5.41 (s, 211), 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.sub.3) m/z 423
(M+H).sup.+. Anal. calc. for C.sub.22
H.sub.18N.sub.2O.sub.3S.sub.2. 0.5 H.sub.2O: 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)-pyridazinon-
e
[1482] The title compound was prepared according to the method of
Example 317, substituting 2-benzofuranboronic acid for
3-thiopheneboronic acid (yield: 46 mg, 25%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3), m/z 457
(M+H).sup.+. Anal. calc. for
C.sub.26H.sub.20N.sub.2O.sub.4S.H.sub.2O: 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-oxo-1,3-dihydro-2-benzofuran-5-yl)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone
[1483] The title compound was prepared according to the method of
Example 221, substituting
2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone, prepared in Example 78, in place of
2-(2,2,2-trifluoroethyl)-4-
-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 112
mg, 44%). mp>250.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 473
(M+H).sup.+, 490 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.26H.sub.20N.sub.2O.sub.5S: 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)-pyrdazi-
none
[1484] The title compound was prepared according to the method of
Example 317, substituting 5-chloro-2-thiopheneboronic acid in place
of 3-thiopheneboronic acid (yield: 21 mg, 17%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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.sub.3), m/z 457
(M+H).sup.+. Anal. calc. for C.sub.18H.sub.15ClN.sub.2O.sub.3S: 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
[1485] The title compound was prepared according to the method of
Example 317, substituting 3-nitrobenzeneboronic acid in place of
3-thiopheneboronic acid (yield: 20 mg, 11%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3),
m/z 462 (M+H).sup.+. Anal. calc. for C.sub.24
H.sub.19N.sub.3O.sub.5S. 0.75 H.sub.2O: 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)-pridazinone
[1486] The title compound was prepared according to the method of
Example 317, substituting 4-vinylbenzeneboronic acid in place of
3-thiopheneboronic acid (yield: 40 mg, 23%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3), m/z
443 (M+H).sup.+. Anal. calc. for C.sub.26H.sub.22N.sub.2O.sub.3S:
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-trifluormethylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone
[1487] The title compound was prepared according to the method of
Example 317, substituting 4-(trifluoromethyl)benzeneboronic acid in
place of 3-thiopheneboronic acid (yield: 101 mg, 52%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.05 (s, 3H), 5.42 (s, 2H), 7.3-7.5
(m, 8H), 7.55-7.6 m, 3H), 7.85 (s, 2H), 7.9 (s, 1H). MS
(DCI/NH.sub.3) m/z 485 (M+H).sup.+. Anal. calc. for
C.sub.25H.sub.19F.sub.3N.sub.2O.sub.3S.0.25 H.sub.2O: 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)-pyridazino-
ne
[1488] The title compound was prepared according to the method of
Example 317, substituting 2-methoxybenzeneboronic acid in place of
3-thiopheneboronic acid (yield: 75 mg, 42%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 447 (M+H).sup.+.
Anal. calc. for C.sub.25H.sub.22N.sub.2O.sub.4S.0.5 H.sub.2O: 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-dimethylphenl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi-
none
[1489]
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(150 mg, 0.4 mmol) prepared in Example 78 was dissolved in
anhydrous DME (10 mL) and heated to reflux with
3,4-dimethylbenzeneboronic acid in presence of CsF (146 mg, 0.96
mmol) and tetrakis(triphenylphosphine)palla- dium (14 mg, 0.012
mmol) for 6 hours. After cooling to room temperature the reaction
mixture was diluted with water and extracted with ethyl acetate
(100 mL). The organic layer was washed with brine, dried over
MgSO.sub.4, and evaporated in vacuo. The compound was purified on a
silica gel column, eluting with 30% ethyl acetate in pentanes,
providing the desired compound (yield: 100 mg, 56%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 445 (M+H).sup.+. Anal. calc. for
C.sub.26H.sub.24N.sub.2O.sub.3S.H.sub.2O: 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)-p-
yridazinone
[1490] The title compound was prepared according to the method of
Example 325, substituting 3-fluoro-4-methoxybenzeneboronic acid in
place of 3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 465 (M+H).sup.+. Anal. calc. for
C.sub.25H.sub.21N.sub.2O.sub.4S.0.25 H.sub.2O: C, 64.02; H, 4.62;
N, 5.97. Found: C, 63.93; H, 4.54; N, 5.43
EXAMPLE 327
2-Benzyl-4-(2-methoxypyrid-3-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone
[1491] The title compound was prepared according to the method of
Example 325, substituting 2-methoxy-3-pyridylboronic acid in place
of 3,4-dimethylbenzeneboronic acid (yield: 35 mg, 19%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 448 (M+H).sup.+. Anal. calc. for
C.sub.24H.sub.21N.sub.3O.sub.4S: 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-ethoxylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne
[1492] The title compound was prepared according to the method of
Example 325, substituting 3-ethoxybenzeneboronic acid in place of
3,4-dimethylbenzeneboronic acid (yield: 115 mg, 67%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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
(DCLNH.sub.3) m/z 461 (M+H).sup.+. Anal. calc. for
C.sub.26H.sub.24N.sub.2O.sub.4S.0.5H.sub.2O: 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
EXAMPLE 329A
2-Benzyl-4,5-dibromo-3(2H)-pyridazinone
[1493] The title compound was prepared according to the method of
Example 194A, substituting benzyl hydrazine hydrochloride in place
of 4-fluorophenyl hydrazine hydrochloride (yield: 7.86 g, 60%).
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 5.27 (s, 2H), 7.26-7.41
(m, 5H), 8.19 (s, 1H). MS (DCI.sub.3) m/z 345 (M+H).sup.+, 362
(M+H).sup.+.
EXAMPLE 329B
2-Benzyl-5-bromo-4-methoxy-3(2H)-pyridazinone
[1494] The title compound was prepared according to the method
described in Example 194B, substituting
2-benzyl-4,5-dibromo-3(2H)-pyridazinone for
2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 2.877 g;
85%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.14 (s, 3H),
5.23 (s, 2H), 7.26-7.38 (m, 5H), 8.11 (s, 1H). MS (DCl-NH.sub.3)
m/z 295 (M+H).sup.+, 312 M+NH.sub.4).sup.+.
EXAMPLE 329C
2-Benzyl-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1495] The title compound was prepared according to the method
described in Example 6, substituting
2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone for
2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone (yield: 3.705 g).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.52 (s, 3H), 3.99 (s,
3H), 5.28 (s, 2H), 7.26-7.41 (m, 7H), 7.55 (m, 2H), 8.02 (s, 1H).
MS (DCl-NH.sub.3) m/z 339 (M+H).sup.+, 356 (M+NH.sub.4).sup.+.
EXAMPLE 329D
2-Benzyl-4-(4-fluorobenzyl-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
[1496] The title compound was prepared according to the method of
Example 228, substituting 4-fluorobenzyl magnesium chloride in
place of cyclohexylmagnesium chloride and
2-benzyl-4-methoxy-5-[4-(methylthio)phen- yl]-3(2H)-pyridazinone
was substituted in place of 2-(4-fluorophenyl)-4-me-
thoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone.
EXAMPLE 329E
2-Benzyl-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-(2H)-pyridazinone
[1497] The sulfide compound, Example 329D, was oxidized to the
methyl sulfonyl compound according to the method of Example 10. mp
186-189.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 3.27
(s, 3H), 3.83 (s, 2H), 5.31 (s, 2H), 6.94-7.05 (m, 4H), 7.27-7.40
(m, 5H), 7.67 (m, 2H), 7.94 (s, 1H), 8.03 (m, 2H). MS
(DCI/NH.sub.3) m/z 449 (M+H).sup.+, 466 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.25H.sub.21FN.sub.2O.sub.3S: 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)-pyrid-
azinone
EXAMPLE 330A
2-(tert-Butyl)-4,5-dichloro-3(2H)-pyridazinone
[1498] A solution of mucochloric acid (33.8 g, 200 mmol) and
tert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol
(400 mL) was stirred at reflux overnight. Methanol was removed in
vacuo and the residue was partitioned between ether and water. The
organic layer was dried over MgSO.sub.4 and filtered. The filtrate
was concentrated in vacuo and the residue was purified by column
chromatography (silica gel, 100% hexanes). Product-containing
fractions were combined and the title compound was crystallized
from ether/hexanes (yield: 10.0 g, 22.6%). mp 63-64.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.65 (s, 9H), 7.73 (s,
1H). MS (DCI/NH.sub.3) m/z 221 (M+H).sup.+, 238
(M+NH.sub.4).sup.+.
EXAMPLE 330B
2-(tert-Butyl)-4-(3-methylbutoxy)-5-chloro-3(2H)-pyridazinone
[1499] A stirred, room temperature solution of 3-methyl-1-butanol
(0.5 mL, 4.52 mmol) in tetrahydrofuran (10 mL) was treated with a
60% oil suspension of sodium hydride (0.24 g, 5.88 mmol). After 5
minutes, hydrogen gas evolution had subsided, so the
dichloro-intermediate from Example 330A (1.0 g, 4.52 mmol) was
added and the reaction mixture was stirred at room temperature for
20 hours. The reaction was quenched with 10% aqueous citric acid
and extracted with ethyl acetate. The organic layer was washed with
brine, dried over MgSO.sub.4, and filtered. The filtrate was
concentrated in vacuo, and the residue was purified by column
chromatography (silica gel, 100% hexanes). The title compound was
obtained as a pale yellow oil (yield: 0.7 g, 56.7%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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 (DCIm.sub.3) m/z 273 (M+H).sup.+, 290
(M+NH.sub.4).sup.+.
EXAMPLE 330C
2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridzino-
ne
[1500] A solution of the intermediate from Example 330B (700 mg,
2.57 mmol), 4-(methylthio)benzeneboronic acid (560 mg, 3.34 mmol),
cesium carbonate (2.17 g, 6.67 mmol), and
tetrakis(triphenylphosphine)palladium(- 0) (210 mg, 0.18 mmol) in
dimethoxyethane (40 mL) was heated at reflux for 5 hours. The heat
source was then removed and the reaction mixture was stirred at
room temperature for 64 hours. The reaction mixture was filtered
and the filtrate was concentrated in vacuo to provide a brown oil.
This oil was purified by column chromatography twice (silica gel,
97:3 hexanes/ethyl acetate, then 96:4 hexanes/ethyl acetate) to
provide a semi-solid product (yield: 270 mg, 29.2%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 330D
2-(tert-Butyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrid-
azinone
[1501] The title compound was prepared according to the method of
Example 10, substituting
2-(tert.-butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phen-
yl]-3(2H)-pyridazinone for
4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2- H)-pyridazinone
(yield: 188 mg, 63.9%). mp 138-139.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 393 (M+H).sup.+. Anal. calc. for
C.sub.20H.sub.28N.sub.2O.sub.4S: 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)-pyridazino-
ne
[1502] The title compound was prepared according to the method of
Example 10, substituting
2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(-
2H)-pyridazinone (Example 207C) in place of
2-benzyl-4-(4-fluorophenyl)-5--
[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 3.31 g, 96%). mp
112-114.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 2H), 8.21 (s, 1H). MS (DCI/NH.sub.3) m/z 391
(M+H).sup.+, 408 (M+NH.sub.4).sup.+. Anal. calc. for:
C.sub.18H.sub.15ClN.sub.2O.sub.4S.0.- 25 H.sub.2O: 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)-pyridazin-
one
[1503] A suspension of
2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone (6.26 g, 16 mmol) in 5% NaOH (54 mL)
dioxane (39.4 mL) was heated at reflux and stirred for 1.5 hours.
As the reaction proceeds, the solution becomes orange and
homogeneous. The mixture was cooled and poured into IN HC1, with
constant stirring. The resulting white solid was filtered and
rinsed with H.sub.2O and left to dry overnight. The mostly dry
product was taken up in CH.sub.2Cl.sub.2 and azeotroped with
toluene to remove any remaining H.sub.2O, to provide the desired
product as a white solid (yield: 6.79 g, >100%). .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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, 1H). MS
(DCI/NH.sub.3) m/z 377 (M+H).sup.+, 396 (M+NH.sub.4).sup.+.
EXAMPLE 333
2-(3-Chlorophenyl)-4-tosyloxy-5-[4-(methylsulfony)phenyl]-3(2H)-pyridazino-
ne
[1504] To a 0.degree. C. solution of
2-(3-chlorophenyl)-4-hydroxy-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332,
(6.79 g, 16 mmol) in pyridine (160 mL) was added p-toluenesulfonyl
chloride (3.06 g, 16 mmol). The solution was left to warm slowly to
room temperature with stirring under nitrogen. After 2.5 hours, the
mixture was poured into H.sub.2O with constant stirring. The
resulting off-white solid was filtered, rinsed with H.sub.2O and
dried to provide the desired product (yield: 6.26 g, 79%). mp
198-200.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 2.35
(s, 3H), 3.28 (s, 3H), 7.20 (m, 2H), 7.52-7.64 (M, 5H), 7.70 (m,
3H), 7.89 (m, 2H), 8.32 (s, 1H). MS APCI+531 (N+H).sup.+, 548
(M+H.sub.2O).sup.+, APCI-493 (M+35).sup.-. Anal. calc. for
C.sub.24H.sub.19ClN.sub.2O.sub.6S.sub.2: C, 54.29; H, 3.61; N,
5.28. Found: C, 54.55; H, 3.46; N, 5.57.
EXAMPLE 334
2-(3-Chlorophenyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrdazinone
[1505] A solution of
2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone, prepared in Example 332, in POCl.sub.3 was
heated to reflux for 3 hours while stirring under nitrogen. The
mixture was cooled to room temperature and poured into ice with
constant swirling. The resulting white solid was extracted with
ethyl acetate. The combined organics were washed with H.sub.2O,
dried over MgSO.sub.4, and concentrated to a solid. The crude
product was purified using flash chromatography (SiO.sub.2, eluting
with 1:1 ethyl acetate/hexanes) to provide the desired product
(yield: 0.151 g, 29%). mp 203-204.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 3.29-3.36 (3H, obstructed by H.sub.2O), 7.60
(m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.14 (m, 2H), 8.25 (s, 1H). MS
(DCILNH.sub.3) m/z 395 (M+H).sup.+, 412 (N+NH.sub.4).sup.+. Anal.
calc. for C.sub.17H.sub.12Cl.sub.2N.sub.2O.sub.3S: 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
[1506] To a stirred suspension of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333,
(0.175 g, 0.33 mmol) in THF (3.3 mL) was added isobutanol (0.03 mL,
0.33 nimol), and NaH (0.0132 g, 0.33 mmol). The resulting solution
was stirred under nitrogen for 1 hour. The reaction was poured into
H.sub.2O and extracted with ethyl acetate. The combined organics
were dried over MgSO.sub.4 and concentrated in vacuo. The crude
solid was purified using flash chromatography (SiO.sub.2, 2:1
hexanes:ethyl acetate) to provide the desired product (yield:
0.1088 g 76%). mp 166-169.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 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.sub.3) m/z 433
(M+H).sup.+, 450 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21ClN.sub.2O.sub.4S- : 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)-pyrdazi-
none
[1507] The title compound was prepared according to the method of
Example 335, substituting t-butanol in place of isobutanol (yield:
0.093 g, 66%). mp 232-235.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 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, 2H), 8.20 (s, 1H). MS
(DCI/NH.sub.3) m/z 433 (M+H).sup.+, 450 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21H.sub.21ClN.sub.2O.sub.4S: C, 58.26; H, 4.89; N,
6.47. Found: C, 58.21; H, 4.88; N, 6.28.
EXAMPLE 337
2-(3-Chlorphenyl)-4-(cyclohexyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
dazinone
[1508] The title compound was prepared according to the method of
Example 335, substituting cyclohexanol in place of isobutanol
(yield: 0.139 g, 92%). semi-solid; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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).sup.+, 476 (M+H.sub.2O).sup.+, APCI-458 (M)-, 493
(M+35).sup.-. Anal. calc. for
C.sub.23H.sub.23ClN.sub.2O.sub.4S.0.25 H.sub.2O: 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
[1509] The title compound was prepared according to the method of
Example 335, substituting neopentyl alcohol in place of isobutanol
(yield: 0.109 g, 74%). mp 151-153.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 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, 2H), 8.07 (m, 2H), 8.20
(s, 1H). MS (DCI/NH.sub.3) m/Z 447 (M+H).sup.+, 464
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.23ClN.sub.2O.sub.4S: 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)-p-
yridazinone
[1510] The title compound was prepared according to the method of
Example 335, substituting 3-methyl-1-butanol in place of isobutanol
(yield: 0.229 g, 80.5%). mp 134-135.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 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.sub.3)
m/z 447 (M+H).sup.+, 464 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.23ClN.sub.2O.sub.4S: c, 59.12; H, 5.19; N, 6.27.
Found: C, 58.91; H, 5.12; N, 6.01.
EXAMPLE 340
2-(3-Chlorophenyl)-4-(3-octyn-1-yloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)--
pyridazinone
[1511] The title compound was prepared according to the method of
Example 335, substituting 3-octyn-1-ol in place of isobutanol
(yield: 0.128 g, 77%). Oil. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 485
(M+H).sup.+. Anal. calc. for C.sub.25H.sub.25ClN.sub.2O.sub.4S: 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)ethoxyl-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1512] The title compound was prepared according to the method of
Example 335, substituting N,N-(dimethyl)ethanolamine in place of
isobutanol (yield: 0.111 g, 75%). mp 110-113.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 448 (M+H).sup.+.
Anal. calc. for C.sub.21H.sub.22ClN.sub.3O.sub.4S.0.50 H.sub.2O: 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-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1513] The title compound was prepared according to the method of
Example 335, substituting 2,4-dimethyl-3-pentanol in place of
isobutanol (yield: 0.075 g, 48%). Semi-solid; .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 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.sub.3) m/z 475
(M+H).sup.+, 492 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.27ClN.sub.2O.sub.4S (0.75 H.sub.2O): 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)-pyridazi-
none
[1514] The title compound was prepared according to the method of
Example 335, substituting phenol in place of isobutanol (yield:
0.053 g, 35%). mp 205-207.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 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.sub.3) m/z 453 (M+H).sup.+, 470 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.17ClN.sub.2O.sub.4S- : 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)phenoxy]-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1515] The title compound was prepared according to the method of
Example 335, substituting 3-(dimethylamino)phenol in place of
isobutanol (yield: 0.057 g, 60%). mp 191-193; .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 2.85 (s, 6H), 3.27 (s, 3H), 6.36 (m, 3H),
7.05 (m, 1H), 7.51-7.63 (m, 3H), 7.72 (m, 1H), 7.90 (m, 2H), 8.05
(m, 2H), 8.39 (s, 1H). MS APCI+ 495 (M+H).sup.+, APCI-, 495 (M)-,
590 (M+35).sup.-. Anal. calc. for
C.sub.25H.sub.22ClN.sub.3O.sub.4S: C, 60.54; H, 4.47; N, 8.47.
Found: C, 60.04; H, 4.49; N, 8.26.
EXAMPLE 345
2-(3-Chloroophenyl)-4-(4-methoxyphenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1516] The title compound was prepared according to the method of
Example 335, substituting 4-methoxyphenol in place of isobutanol
(yield: 0.080 g, 69%). mp 182-184.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 3.27 (s, 3H), 3.70 (s, 3H)i 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.sub.3) m/z 483 (M+H).sup.+, 500
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19ClN.sub.2O.sub.5S: 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
[1517] The title compound was prepared according to the method of
Example 335, substituting
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 150 mg, 61%). mp
116-117.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 435 (M+H).sup.+, 452 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21F.sub.2H.sub.20N.sub.2O.sub.4S: 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
[1518] The title compound was prepared according to the method of
Example 346 substituting 3-methyl-1-butanol in place of isobutanol
(yield: 63 mg, 23%). mp 121-123.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z
449 (M+H).sup.+, 466 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.22F.sub.2N.sub.2O.sub.4S: 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)l-
phenyl]-3(2H)-pyridazinone
[1519] The title compound was prepared according to the method of
Example 346, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4--
tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and
substituting 4-fluorophenol in place of isobutanol mp
168-170.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H). MS (DCI/NH.sub.3) m/z 491 (M+H).sup.+, 508
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.14F.sub.4N.sub.2O.sub.4S: 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-(me
hylsulfonyl)pheny1-3(2H)-pyridazinone
[1520] The title compound was prepared according to the method of
Example 346 substituting neopentyl alcohol in place of isobutanol
(yield: 1.18 g, 94%). mp 126-128.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 449 (M+H).sup.+,
466 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.22F.sub.2N.sub.2O.sub.4S: 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-(ispropoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1521] The title compound was prepared according to the method of
Example 346 substituting 2-(isopropoxy)ethanol in place of
isobutanol (yield: 432 mg, 72%). mp 105-107.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 465
(M+H).sup.+, 482 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.22F.sub.2N.sub.2O.sub.5S: 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
[1522] The title compound was prepared according to the method of
Example 346 substituting 3-methylpentyl-1-ol in place of isobutanol
(yield: 400 mg, 80%). mp 100-102.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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, 1H). MS
(DCI/NH.sub.3) m/z 463 (M+H).sup.+, 480 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.24F.sub.2N.sub.2O.sub.4S: 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
[1523] The title compound was prepared according to the method of
Example 346 substituting 4-methyl-3-pentene-1-ol in place of
isobutanol (yield: 405 mg, 67.8%). mp 88-90.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z
461 (M+H).sup.+, 478 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.22F.sub.2N.sub.2O.sub.4- S: 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
[1524] The title compound was prepared according to the method of
Example 346 substituting 3-methoxybutyl-1-ol in place of isobutanol
(yield: 350 mg, 68%). mp 99-101.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.97 (d, 3H), 1.7 (m, 2H), 3.05 (s, 3H), 3.2
(m, 1) 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, 1H). MS
(DCI/NH.sub.3) m/z 465 (M+H).sup.+, 482 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.22F.sub.2N.sub.2O.s- ub.5S: 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-methylbenzylamnino)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone
[1525] To a rapidly stirred 0.degree. C. mixture of
N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7
nmL) was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59
mmol, 2.5 M in hexanes). The reaction mixture was stirred for 10
minutes at 0.degree. C. and 1 hour at 23.degree. C. The solution
was cooled to -78.degree. C., and a tetrahydrofuran (10-15 mL)
solution of the 2-(3-chlorophenyl)-4-methoxy-5-
-[4-(methylthio)phenyl]-3(2H)-pyridazinone (200 mg, 0.56 mmol)
slowly added along the interior wall of the reaction vessel. This
reaction mixture was stirred overnight, slowly warming to
23.degree. C. as the cooling bath evaporated. The reaction was
quenched with water and diluted with a large excess of ethyl
acetate. The layers were separated, and the ethyl acetate layer
washed with additional water and brine and dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was
chromatographed (flash silica gel, ethyl acetate/hexanes 1:9) to
provide 2-(3-chlorophenyl)-4-(N-methyl
benzylamino)-5-[4-(methylthio)phenyl]-3(2H- )-pyridazinone (yield:
145 mg, 58%).
[1526] The title compound was prepared according to the method of
Example 10, substituting
2-(3-chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylt-
hio)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[-
4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 143 mg, 95%). mp
60-85.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 355
2-(4-Fluorophenyl)-4-(1-piperidinyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone
[1527] To a slightly heterogeneous solution of piperidine (99.7 mg,
1 .17 mmol) and toluene (8 mL) cooled to -78.degree. C. was slowly
added dropwise an n-BuLi solution (0.235 imL, 0.59 mmol, 2.5 M in
hexanes). After stirring at -78.degree. C. for 10 minutes, the
cooling bath was removed and the mixture stirred an additional 1
hour at 23.degree. C. The
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
(400 mg, 1.17 mmol) was dissolved in portions in toluene
(3.times.6-7 mL aliquots) with a heat gun and cooled to 0.degree.
C. prior to transfer via syringe to the lithium amide solution
(cooled to -78.degree. C.). The addition was made slowly along the
interior wall of the reaction vessel. This reaction mixture was
stirred overnight, slowly warming to 23.degree. C. as the cooling
bath evaporated. The reaction was quenched with water and diluted
with a large excess of ethyl acetate. The layers were separated,
and the ethyl acetate layer washed with additional water and brine
and dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
residue was chromatographed (flash silica gel, ethyl
acetate/hexanes 1:2) to provide 440 mg (95%) of
2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4--
piperidino-3(2H)-pyridazinone.
[1528] The title compound was prepared according to the method of
Example 10, substituting
2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-
-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone (yield: 165 mg, 98%). mp
80-100.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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).sup.+. Powdered out in
CH.sub.2Cl.sub.2/C.sub.6H.sub.14. Anal. calc. for
C.sub.22H.sub.22FN.sub.3O.sub.3S.0.25C.sub.6Hl.sub.4: 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)-p-
yridazinone
[1529] The title compound was prepared according to the method of
Example 355, substituting pyrrolidine for piperidine (yield: 107
mg, 82%). mp 192-195.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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).sup.+. Anal. calc. for
C.sub.21H.sub.20FN.sub.3O.sub.3S: 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(2-
H)-pyridazinone
[1530] To a stirred suspension of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333,
(0.0802 g, 0.15 mmol) in EtOH (1.5 mL) was added thiocresol (0.019
g, 0.15 mmol) and K.sub.2CO.sub.3 (0.0203 g, 0.15 mmol). The
suspension was heated to 50.degree. C. with stirring for 2.5 hours.
The mixture was poured into H.sub.2O with constant stirring. The
resulting precipitate was filtered, rinsed with H.sub.2O and dried
to provide the desired product (yield: 0.060 g, 83%). mp
178-178.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 1H), 7.88 (m, 2H), 8.08 (s, 1H). MS (DCI/NH.sub.3)
m/z 483 (M+H).sup.+, 500 (M+NH.sub.4).sup.+. Anal. calc. for:
C.sub.24H.sub.19ClN.sub.2O.sub.3S.sub.2.0.75 H.sub.2O: 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)-py-
ridazinone
[1531] The title compound was prepared according to the method of
Example 357, substituting 2-mercaptopyridine in place of thiocresol
(yield: 0.061 g, 39%). mp 110-114.degree. C. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 3.28 (s, 3H), 7.16 (m, 1H), 7.37 (m, 1H),
7.51-7.71 (m, 5H), 7.81 (m, 2H), 8.03 (m, 2H), 8.27 (s, 1H), 8.34
(m, 1H). MS (DCI/NH.sub.3) m/z 470 (M+H).sup.+. Anal. calc. for
C.sub.22H.sub.16ClN.sub.3O.sub.3S.sub.2.- 0.50 H.sub.2O: 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
[1532] To a stirred suspension of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(meth-
ylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333,
(0.175 g, 0.33 mmol) in THF (3.3 mL) was added benzyl mercaptan
(0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). The resulting
solution was stirred at room temperature under nitrogen for 1 hour.
The mixture was poured into H.sub.2O and extracted with ethyl
acetate. The combined organics were dried over MgSO.sub.4 and
concentrated in vacuo. The resulting crude product was purified
using flash chromatography (SiO.sub.2, 2:1 hexanes:ethyl acetate)
to provide the desired product (yield: 0.136 g 85%). mp
142-145.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 3H), 7.74 (m, 1H), 8.01 (m, 2H). MS
(DC17NH.sub.3) m/z 483 (M+H).sup.+, 500 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.24H.sub.19ClN.sub.2O.sub.3S.sub.2: C, 59.68; H,
3.96; N, 5.80. Found: C, 59.40; H, 4.11;N,5.71.
EXAMPLE 360
2-(3-Chlorophenyl)-4-(2-furylmethylthio)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1533] The title compound was prepared according to the method of
Example 359, substituting furfuryl mercaptan in place of benzyl
mercaptan (yield: 0.162 g, 100%). mp 140-149.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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, 1H), 8.03 (m,
2H), 8.08 (s, 1H). MS (DCI/NH.sub.3) m/z 473 (M+H).sup.+, 490
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.17ClN.sub.2O.sub.4S.sub.2: C, 55.87; H, 3.62; N,
5.92. Found: C, 55.84; H, 3.61; N, 5.82.
EXAMPLE 361
2-(3-Chlorophenyl)-4-[2-(methylpropyl)thiol]-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone
[1534] The title compound was prepared according to the method of
Example 359, substituting 2-methyl-1-propanethiol in place of
benzyl mercaptan (yield: 0.134 g, 91%). Oil. .sup.1H NMR (300 MHz,
DMSO d.sub.6) .delta. 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.sub.3) m/z 449 (M+H).sup.+,
466 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21ClN.sub.2O.sub.3S.sub.2 (0.50 H.sub.2O): 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-(methylonylsulfonyl)phenyl]-(2H)-p-
yridazinone
[1535] To a -78.degree. C. solution of
2-(3-chlorophenyl)-4-tosyloxy-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example
333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentyl
magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting
solution was stirred under nitrogen less than 1 hour with warming
to room temperature. The reaction was poured into water and
extracted with ethyl acetate. The combined organics were dried over
MgSO.sub.4 and concentrated in vacuo. The resulting crude product
was purified using flash chromatography (SiO.sub.2, 2:1 ethyl
acetate:hexanes) to provide the desired product (yield: 0.1328 g,
94%). mp 155-157.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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 (3H, obstructed by H.sub.20),
7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS
(DCI/NH.sub.3) m/z 429 (M+H).sup.+, 446 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.21ClN.sub.2O.sub.3S: 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-(2-methylpropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone
[1536] The title compound, an oil, was prepared according to the
method of Example 362, substituting isobutyl magnesium chloride in
place of cyclopentylmagnesium chloride, (yield: 0.132 g, 96%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3)
m/z 417 (M+H).sup.+, 434 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21ClN.sub.2O.sub.3S.0.5- 0 H.sub.2O: 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-(cyclopentylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1537] The title compound, an oil, was prepared according to the
method of Example 362, substituting cyclopentylmethyl magnesium
bromide in place of cyclopentyl magnesium chloride (yield: 0.0579
g, 38%). .sup.1H NM (300 MHz, DMSO d.sub.6) .delta. 0.66 (m, 2H),
1.03 (m, 3H), 1.50 (m, 6H), 1.61 (m, 1H), 2.46 (m, 1H), 3.27-3.42
(3H, obstructed by H.sub.20), 7.50-7.66 (m, 3H), 7.75 (m, 3H), 7.99
(s, 1H), 8.10 (m, 2H). MS (DCI/NH.sub.3) m/z 457 (M+H).sup.+, 474
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.25ClN.sub.2O.sub.3S: 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-cyclopentylethyl)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1538] The title compound was prepared according to the method of
Example 362, substituting cyclopentylethyl magnesium bromide in
place of cyclopentyl magnesium chloride (yield: 0.165 g, 94%/).
.sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 0.76 (m, 3H), 0.99-1.21
(m, 5H), 1.31-1.62 (m, 8H), 2.42-2.56 (lH, obstructed by DMSO),
3.25-3.34 (2H, obstructed by H.sub.2O), 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
(DCNH.sub.3) m/z 471 (M+H).sup.+, 488 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.25H.sub.27ClN.sub.2O.sub.3S: C, 63.75; H, 5.78; N,
5.95. Found: C, 63.48; H, 5.70; N, 5.67.
EXAMPLE 366
2-(3-Chloropenyl)-4-(3-methylbutyl)-5-[4-(methysulfonyl)phenyl]-3(2H)-pyda-
zinone
[1539] The title compound was prepared according to the method of
Example 362, substituting 3-methylbutyl magnesium bromide in place
of cyclopentylmagnesium chloride (yield: 0.0221 g, 16%). mp
60-65.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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, 1H), 8.11 (m, 2H). MS (DCI/NH.sub.3)
m/z 431 (M+H).sup.+, 448 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.23ClN.sub.2O.sub.3S.0.2- 5 H.sub.2O: 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)-pyridazinon-
e
[1540] The title compound was prepared according to the method of
Example 362, substituting benzyl magnesium chloride in place of
cyclopentylmagnesium chloride. mp 174-177.degree. C. (yield: 25.9
g, 57%). .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 451
(M+H).sup.+, 468 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19ClN.sub.2O.sub.3S: 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)-pyridaz-
inone
[1541] The title compound was prepared according to the method of
Example 362 substituting cyclohexylmagnesium chloride in place of
cyclopentylmagnesium chloride (yield: 0.099 g, 68%). mp
85-90.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) m/z 443 (M+H).sup.+,
460 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.23ClN.sub.2O.sub.3S (1.25 H.sub.20): 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)-p-
yridazinone
[1542] The title compound was prepared according to the method of
Example 228 using the product from Example 207C and substituting
4-fluorobenzyl magnesium chloride in place of cyclohexyl magnesium
chloride (yield: 0.1895 g, 41%). mp 183-185.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 3.25-3.36 (3H, obstructed by
H.sub.20), 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.sub.3) m/z 469
(M+H).sup.+, 486 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18ClFN.sub.2O.sub.3S: 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)-p-
yridazinone
[1543] The title compound was prepared according to the method of
Example 362 substituting p-tolylmagnesium bromide in place of
cyclopentylmagnesium chloride (yield: 65 mg, 40.9%). mp
222-224.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 451
(M+H).sup.+, 468 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19ClN.sub.2O.sub.3S.0.25 H.sub.2O: 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)ph-
enyl]-3(2H)-pyridazinone
[1544]
2-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone was prepared according to the
method of Example 362, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone and substituting
3-fluoro-4-methylphenylmagnesium bromide in place of
cyclopentylmagnesium chloride to provide the methyl sulfide
compound.
[1545] The methyl sulfide was oxidized according to the method of
Example 10 to provide the title compound (yield: 265 mg, 85.4%). mp
204-206.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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, 1H), 7.93 (d, J=9
Hz, 2H), 7.99 (s, 1H). MS (DCI/NH.sub.3) m/z 471 (M+H).sup.+, 488
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17F.sub.3N.sub.2O.sub.3S: 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)-pyrida-
zinone
[1546] The title compound was prepared according to the method of
Example 228, starting with
2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]--
3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone and substituting phenethyl magnesium
chloride in place of cyclohexylmagnesium chloride then oxidizing by
the method of Example 10 (yield: 0.100 g, 39%). mp 142-145.degree.
C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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,
1H), 7.78 (m, 1H), 8.03 (m, 3H). MS (DCI/NH.sub.3) m/z 465
(M+H).sup.+, 482 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.25H.sub.21ClN.sub.2O.sub.3S: 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
EXAMPLE 373A
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyridazinone
[1547] The title compound was prepared according to the method of
Example 194B, starting with
2-(3-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone (Example 207A) in
place of 2-(4-fluorophenyi)-4,5-dibromo-3(2H)-pyridazin- one and
substituting 2-methyl-1-propanol in place of methanol.
EXAMPLE 373A
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluro-4-methylthio)phenyl]-3(2-
H)-pyridazione
[1548] The title compound was prepared according to the method of
Example 6, starting with
2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-bromo-3(2H)-pyr- idazinone
in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and
substituting 3-fluoro-4-(methylthio)benzeneboronic acid (Example
72D) in place of 4-fluorobenzeneboronic acid.
EXAMPLE 373C
2-(3-Chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methysulfonyl)phenyl-
]-3(2H)-pyridazinone
[1549] Example 373B was oxidized according to the method of Example
10 to provide the title compound (yield: 0.73 g, 100%). mp
180-183.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 0.82
(d, J=6 Hz, 2H), 3.30-3.39 (3H, obstructed by H.sub.20) 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.sub.3) m/z 451 (M+H).sup.+, 468
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.20ClFN.sub.2O.sub.4S: 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)-pyrida-
zinone
[1550] To a stirred solution of
2-(3-chlorophenyl)-4-hydroxy-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone (Example 332) (0.100 g, 0.28
mmol) in DMF (2.8 mL) was added benzyl chloride (0.32 mL, 0.28
mmol). The resulting solution was stirred with heating to
60.degree. C. overnight. The solvent was removed in vacuo and the
resulting residue partitioned between ethyl acetate and 10% citric
acid. After extracting with ethyl acetate, the combined organics
were dried over MgSO.sub.4 and concentrated in vacuo. The crude
product was purified using flash chromatography (SiO.sub.2, 1:1
ethyl acetate:hexanes) to provide the desired product (yield: 0.096
g, 76%). mp 110-113.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 3.39 (s, 3H), 5.48 (s, 2H), 7.29 (m, 4H), 7.59-7.71 (m,
3H), 7.76 (m, 3H), 8.00 (m, 2H), 8.21 (s, 1H). MS (DCI/NH.sub.3)
m/z 467 (M+H).sup.+, 484 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.19ClN.sub.2O.sub.4S: 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)-p-
yridazinone
[1551] 2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone
(Example 194B) was converted into
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)ph-
enyl]-3(2H)-pyridazinone according to the method of Example 194C
followed by the oxidation method in Example 10. The methoxy
compound was converted to the
2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone, by treatment with NaOH according to the procedure of
Example 332. The hydroxy compound was treated with
p-toluenesulfonyl chloride according to the procedure of Example
333, to funmish
2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazi-
none.
[1552] The title compound was prepared according to the method of
Example 335,, starting with
2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tos-
yloxy-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-4-tosyloxy-3(2H)-pyridazinone substituting
3-methyl-1-butanol in place of isobutanol (yield: 0.3932 g, 94%).
mp 117-120.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta.
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.sub.3) m/z 431 (M+H).sup.+, 448
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.23FN.sub.2O.sub.4S: 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
[1553] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyl-
oxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375)
in place of
2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-
-pyridazinone (yield: 0.486 g, 100%). mp 121-128.degree. C. .sup.1H
NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3)
m/z 417 (M+H).sup.+, 434 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21FN.sub.2O.sub.4S.0.50 H20: 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)-p-
yridazinone
[1554] The title compound was prepared according to the method of
Example 62, starting with
4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3-
(2H)-pyridazinone and reacting with 1-iodo-4-fluorobenzene (yield:
0.0881 g, 78%). mp 175-177.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 3.27-3.36 (3H, obstructed by H20), 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.sub.3) m/z 453 (M+H).sup.+, 470
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.18F.sub.2N.sub.2O.sub.3S: 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-pyr-
idazinone
[1555] The title compound was prepared according to the method of
Example 228, substituting 3-methylbutyl magnesium bromide in place
of cyclohexylmagnesium chloride (yield: 0.325 g, 69%). mp
151-154.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 415 (M+H).sup.+, 432 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.23FN.sub.2O.sub.3S.- 0.50 H.sub.2O: C,
62.39; H, 5.71; N, 6.61. Found: C, 62.04; H, 5.78; N, 6.46.
EXAMPLE 379
2-(Tetahdro-2H-pyrano-2-yl)-4-(4-fluorophenyl)-5-4-(methylsulfonyl)phenyl--
3(2H)-pyridazinone
[1556] To the solution of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone prepared according to Example 11 (172 mg, 0.5
nmuol) and p-toluenesulfonic acid hydrate (19 mg, 0.1 mmol) in
dioxane (10 mL) was added 2,3-dihydropyran (2 mL). The mixture was
stirred at room temperature for 6 hours. The mixture was then
poured into a solution of saturated NaHCO.sub.3 and extracted with
ethyl acetate. The ethyl acetate was concentrated in vacuo and the
residue was chromatographed (silica gel, 1: 1 hexanes-ethyl
acetate) to provide the title compound (yield: 25 mg, 11 %).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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.sub.3)
m/z 429 (M+H).sup.+.
EXAMPLE 380
2-(3-(4-Fluorophenyl)phenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-
l]-3(2H-pyridazinone
[1557] The title compound was prepared according to the method of
Example 4, starting with
2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone (Example 166) in place of
2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and
substituting cesium fluoride for sodium carbonate (yield: 0.62 g,
62%). mp 222-225.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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, 3H), 7.93 (m, 3H), 8.27 (s, 1H). MS
(DCI/NH.sub.3) m/z 515 (M+H).sup.+, 532 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.29H.sub.20F.sub.2N.sub.2O.sub.3S.0.25 H.sub.2O: 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-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1558]
2-(2,2,2-Trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[3-fluoro-4-(met-
hylthio)phenyl]-3(2H)-pyridazinone was prepared according to the
method of Example 261, substituting
2-(2,2,2-trifluoroethyl)-4-chloro-5-[3-fluoro-4-
-(methylthio)phenyl]-3(2H)-pyridazinone in place of
2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri-
dazinone.
[1559] The methyl sulfide was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to give the methyl sulfoxide. The
sulfoxide was converted to the title compound according to the
method of Example 68 (yield: 196 mg, 28%). mp 144-145.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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,
1H), 7.79 (s, 1H), 8.03 (t, J=8 Hz, 1H). MS (DCI/NH.sub.3) m/z 438
(M+H).sup.+. Anal. calc. for
C.sub.17H.sub.19F.sub.4N.sub.3O.sub.4S: C, 46.68; H, 4.38; N, 9.61.
Found: C, 46.76; H, 4.30; N, 9.52.
EXAMPLE 382
2-(2,2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(aminosulfonyl)-
phenyl]-3(2H)-pyridazinone
[1560] The title compound was prepared according to the method of
Example 68 substituting
2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(methyl-
sulfinyl)phenyl]-3(2H)-pyridazinone in place of
2-(2,2,2-trifluoroethyl)-4-
-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone
(yield: 260 mg, 26%). mp 163-164.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 424
(M+H).sup.+, m/z 441 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.16H.sub.17F.sub.4N.sub.3O.sub.4- S: 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
[1561] The title compound was prepared according to the method of
Example 384, substituting
2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(4-fluorop-
henyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield:
0.5723 g 34%). mp 120-123.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 3.83 (bs, 2Hj, 5.30 (bs, 2H), 6.95-7.06 (m, 4H),
7.28-7.40 (m, 5H), 7.48 (m, 2H), 7.60 (m, 2H), 7.91 (m, 2H), 7.95
(s, 1H). MS (DCI/NH.sub.3) m/z 450 (M+H).sup.+, 467
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.20FN.sub.3O.sub.3S: 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
[1562] To a solution of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone (130 mg, 0.3 mmol) and
di-t-butylazodicarboxylat- e (DBAD) (69 mg, 0.3 mmol) in THF (30
mL) at -78.degree. C. was added dropwise a 1 N solution of lithium
1,1,1,3,3,3-hexamethyldisilazide (0.9 mL, 0.9 mmol) in THF
[1563] After addition, the reaction was stirred an additional 45
minutes at -78.degree. C. (or until the TLC indicated a
disappearance of starting material). The reaction was quenched with
a saturated solution of NH.sub.4Cl and extracted with ethyl
acetate. The acetate extract was dried over MgSO.sub.4 and
concentrated in vacuo to obtain 220 mg of crude adduct.
[1564] The above adduct was dissolved in THF (30 ML) and was
treated at room temperature with 1 N NaOH (3 mL) for 5 hours.
Sodium acetate (NaOAc.3 H.sub.2O, 1.38 g, 10 mmol) was added
followed by addition of hydroxylamine-O-sulfonic acid (1.13 g, 10
mmol) and H.sub.2O (30 mL). The resulting mixture was stirred at
room temperature for 18 hours and then extracted with ethyl
acetate. The extract was washed with water, brine, dried over
MgSO.sub.4 and concentrated in vacuo. The residue was purified by
chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide
the desired product (yield: 70 mg, 54%). mp 185-189.degree. C.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 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,
1H). MS (DCI/NH.sub.3) m/z 436 (M+H).sup.+. Anal. caic. for
C.sub.23H.sub.18FN.sub.3O.sub.3S.0.75 H.sub.2O: 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)-p-
yridazinone
[1565] The product from Example 108 was converted to the title
sulfonamide according to the method of Example 384, (yield: 65 mg,
28.8%). mp 227-229.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 469 (M+H).sup.+, 486
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.15F.sub.2N.sub.3O.sub.4S: 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)phe-
nyl]-3(2H)-pyridazinone
[1566] The product from Example 371 was converted to the title
sulfonamide according to the method of Example 384 (yield: 45 mg,
28%). mp 198-200.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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, 1H), 8.25
(s, 1H). MS (DCI/NH.sub.3) m/z 472 (M+H).sup.+, 489
(M+NH.sub.4).sup.+.
EXAMPLE 387
2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonylphenyl]--
3(2H)-pridazinone
[1567] The product from Example 250 was converted to the title
sulfonamide according to the method of Example 384 (yield: 185 mg,
46%). mp 187-188.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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, 1H). MS
(DCI/NH.sub.3) m/z 454 (M+H).sup.+, 471 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.17F.sub.2N.sub.3O.sub.3- S.0.25 H.sub.2O:
C, 60.36; H, 3.87; N, 9.19. Found: C, 60.30; H, 4.26; N. 8.83.
EXAMPLE 388
2-(3,4-Difluophenyl)-4-(4-fluorophenoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-
-pyridazinone
[1568] The product from Example 109 was converted to the title
sulfonamide according to the method of Example 384 (yield: 110 mg,
45.7%). mp 224-226.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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.sub.3) m/z 474
(M+H).sup.+, 491 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.14F.sub.3N.sub.3O.sub.4S.0.25 H.sub.2O: 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-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone
[1569] The product from Example 247 was converted to the title
sulfonamide according to the method of Example 384 (yield: 230 mg,
38%). mp 243-245.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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, 1H). MS
(DCI/NH.sub.3) m/z 469 (M+H).sup.+, 486 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.16ClF.sub.2N.sub.3O.sub.3S: 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
[1570] The methyl sulfone product of Example 245 was converted to
the title sulfonamide according to the method of Example 384
(yield: 78 mg, 28.3%). mp 202-204.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 454
(M+H).sup.+, 471 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23Hl.sub.7F.sub.2N.sub.30.sub.3S.0.25 H.sub.2O: 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-(aminosulfonpl)phenyl]-
-3(2h)-pyridazinone
[1571] The methyl sulfone product of Example 244 was converted to
the title sulfonamide according to the method of Example 384
(yield: 125 mg, 39%). mp 187-188.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 470 (M+H).sup.+, 487 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.17ClFN.sub.3O.sub.3S.0.25 H.sub.2O: 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)-pyr-
idazinone
[1572] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 366) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.0756 g, 16%). mp 167-170.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 0.78 (d, J=6 Hz, 6H), 1.47 (5H,
obstructed by hexanes), 7.51-7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m,
1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH.sub.3)
m/z 432 (M+H).sup.+, 449 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.22ClN.sub.3O.sub.3S (0.25 H.sub.2O): 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)-pyridaz-
inone
[1573] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone (Example 372) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.075 g, 17%). semi-solid; .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 2.80 (m, 4H), 3.29-3.42 (3H, obstructed by
H.sub.2O), 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.sub.3) m/z 466
(M+H).sup.+, 483 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.20ClN.sub.2O.sub.3S.0.2- 5 H.sub.2O: 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)-py-
ridazinone
[1574] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (Example 339) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.575 g, 18%). mp 137-139.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 448
(M+H).sup.+, 465 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.22ClN.sub.3O.sub.4S: 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)-p-
yridazinone
[1575] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone (Example 335) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.0458 g, 25%). mp 80-85.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 434
(M+H).sup.+, 451 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.20ClN.sub.3O.sub.4S: 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)-pyr-
idazinone
[1576] The title compound was prepared according to the method of
Example 384, substituting
2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 378) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (0.090 g 21%). mp 180-183.degree. C. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 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.sub.3)
m/z 416 (M+H).sup.+, 433 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.22FN.sub.3O.sub.3S: 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)-p-
yridazinone
[1577] The title compound was prepared according to the method of
Example 384, substituting
2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone (Example 376) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.024 g, 6%). mp 132-136.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 418
(M+H).sup.+, 435 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.20H.sub.20FN.sub.3O.sub.4S: 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)-py-
rdazinone
[1578] The title compound was prepared according to the method of
Example 384, substituting
2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (Example 375) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.051 g, 18%). Yellow oil. .sup.1H NMR (300 MHz, DMSO
d.sub.6) .delta. 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.sub.3) m/z
432 (M+H).sup.+, 449 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.22FN.sub.3O.sub.4S: 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)-pyrida-
zinone
[1579]
2-(t-Butyl)-4-(3-methyl-1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-py-
ridazinone prepared in Example 330C was oxidized with one
equivalent of meta-chloroperoxybenzoic acid to the corresponding
methyl sulfoxide. The sulfoxide was converted to the title
sulfonamide by the method of Example 68 (yield: 1.25 g, 54%). mp
153-155.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 394
(M+H).sup.+. Anal. calc. for C.sub.19H.sub.27N.sub.3O.sub.4S: 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)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl
phenyl]-3(2H)-pyridazinone
[1580] The title compound was prepared according to Example 384
substituting
2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyrdazinone (Example 182) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 950 mg, 54%). mp 177-181.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 458 (M+H).sup.+, 475
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.14F.sub.3N.sub.3O.sub.3S: 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
[1581] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 380 mg, 47%). mp 208-210.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 474 (M+H).sup.+, 491 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.14F.sub.2Cl.sub.2N.sub.- 3O.sub.3S.0.5
H.sub.2O: 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)phe-
nyl]-3(2H)-pyridazinone
[1582] The title compound was prepared according to the method of
procedure Example 384, substituting
2-(3,4-difluorophenyl)-4-(4-fluoro-3--
methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in
place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 105 mg, 27%). mp 243-245.degree. C. .sup.H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 472 (M+H).sup.+, 489
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.24H.sub.17F.sub.3N.sub.2O.sub.3S.0.5 H.sub.2O: 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(2-
H)-pyridazinone
[1583] The title compound was prepared according to the method of
Example 384, substituting
2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl-
)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg,
42%). mp 169-171.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6
(m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS
(DCI/NH.sub.3) m/z 436 (M+H).sup.+, 453 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.20H.sub.19F.sub.2N.sub.3O.sub.4- S.0.25 H.sub.2O:
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
[1584] The title compound was prepared according to the method of
Example 384, substituting
2-(3,4-difluorophenyi)-4-(3-methylbutyl)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 58 mg,
52%). mp 171-173.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 434 (M+H).sup.+,
451 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21F.sub.2N.sub.3O.sub.3S.0.25 H.sub.2O: 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
[1585] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 102
mg, 61.8%). mp 154-156.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.75 (d, 6H), 1.4, (m, 3H), 2.48 (m, 2H),
7.54 (s, 2H), 7.6 (m, 1H), 7.69 (m, 2H), 7.93 (dd, 1H), 8.05 (m,
2H). MS (DCI/NH.sub.3) m/z 450 (M+H).sup.+, 468 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.22H.sub.22FN.sub.2O.sub.3SCl.0.25 H.sub.2O:
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
[1586] The title compound was prepared according to the method of
Example 384 substituting
2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 310
mg, 38%). mp 173-175.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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.sub.3) m/z 450 (M+H).sup.+, 467 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21H.sub.21F.sub.2N.sub.3O.sub.4S: 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-(aminosulfonylphe-
nyl]-3(2H)-pyridazinone
[1587] The title compound was prepared according to the method of
Example 384 substituting
2-(3,4-difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 125 mg, 31%). mp 224-226.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.15 (d, 4H), 7.51 (m, 1H), 7.6 (m, 2H)
7.75 (m, 4H), 7.9 (t, 1H); 8.4 (s, 1H). MS (DCI/NH.sub.3) m/z 492
(M+H).sup.+, 509 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.13F.sub.4N.sub.3O.sub.4- S: 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-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone
[1588] The intermediate,
2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(methyl-
thio)phenyl]-3(2H)-pyridazinone prepared according to the method of
Example 72, was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which
was converted to the sulfonamide according to the method of Example
68. The sulfonamide material was N-debenzylated according to the
method of Example 11 and N-alkylated according to the method of
Example 20, substituting 1,3-dibromo-1,1-difluoropropane in place
of 4-fluorobenzyl bromide and employing 4 equivalents of potassium
carbonate to provide the title compound (yield: 120 mg, 27%). mp
180-183.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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 (DCILNH.sub.3) m/z 440 (M+H).sup.+. Anal. calc.
for Cl.sub.9Hl.sub.3F.sub.4N.sub.30.sub.3S: 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)ethoxyl
-5-[4-(aminosulfonyl)phenyl- ]-3(2H)-pyridazinone
[1589] The title compound was prepared according to the method of
Example 384, substituting
2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 110 mg, 34%). mp 54-56.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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.sub.3) m/z 466 (M+H).sup.+, 483
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21F.sub.2N.sub.30.sub.5S: C, 54.19; H, 4.55; N, 9.03.
Found, C, 54.29; H, 4.67; N, 8.95.
EXAMPLE 410
2-(3,4-Difl ro
henyl)-4-(4-meth-1-3-penteloxy)-5-[4-(aminosulfonyl3phenyl]- -3(2H
pyrdazinone
[1590] The title compound was prepared according to the method of
Example 384 substituting
2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(-
methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne. mp 70-73.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
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=2 H, 2H), 8.2 (s, 1H). MS
(DC1rNH.sub.3) m/z 462 (M+H).sup.+, 479 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.22H.sub.21F.sub.2N.sub.3O.sub.4S: C, 57.26; H,
4.59; N, 9.1 1. 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
[1591] The title compound was prepared according to the method of
Example 335,, substituting 3-fluorophenol in place of isobutanol
(yield: 0.034 g, 22%). mp 178-180.degree. C. .sup.1H NMR (300-MHz,
DMSO d.sub.6) .delta. 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, 1H), 7.90 (m, 2H), 8.06
(m, 2H), 8.43 (s, 1H). MS (DCI/NH.sub.3) m/z 488 (M+H).sup.+. Anal.
calc. for C.sub.23H.sub.16ClFN.sub.2O.sub.4S.0.25 H.sub.2O: 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
[1592] The title compound was prepared according to the method of
Example 384, substituting
2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 0.019 g, 10%). mp 157-159.degree. C. .sup.1H NMR (300
MHz, DMSO d.sub.6) .delta. 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, 1H), 7.73 (m, 2H), 7.83 (m,
2H), 7.91 (m, 1H), 8.23 (s, 1H). Anal. calc. for
C.sub.21H.sub.19ClFN.sub.3O.sub.4S: 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-methylpentyoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H--
pyridazinone
[1593] The title compound was prepared according to the method of
Example 335, substituting 4-methyl-1-pentanol in place of
isobutanol (yield: 0.137 g, 90%). mp 139-140.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 461 (M+H).sup.+, 478
(M+NH.sub.4).sup.+. Anal. caic. for
C.sub.23H.sub.25ClN.sub.2O.sub.4S: 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
[1594] The title compound was prepared according to the method of
Example 335, starting with
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phe- n
I]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-methyl-1-pentanol in place of isobutanol (yield: 0.128 g, 85%).
mp 123-125.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta.
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.sub.3) m/z 445
(M+H).sup.+. Anal. calc. for C.sub.23H.sub.25FN.sub.2O.sub.4S: 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)-pyridazino-
ne
[1595] The title compound was prepared according to the method of
Example 332, substituting
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone for
2-(3-chlorophenyl)-4-methoxy-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone (yield: 2.022 g, 97%). .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 3.28 (s, 3H), 7.38 (m, 2H), 7.70
(m, 2H), 8.03 (m, 4H), 8.22 (s, 1H). MS (APCI-+Q1MS) 361
(M+H).sup.+, (-Q1MS) 359 (M-H).sup.-.
EXAMPLE 416
2-(4-Fluorophenyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-
-pyridazinone
[1596] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
cyclopropylmethanol in place of isobutanol (yield: 0.117 g, 83%).
mp 166-167.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6) .delta.
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.sub.3) m/z 415 (M+H).sup.+, 432
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.25ClN.sub.2O.sub.4S: 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
[1597] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
2-cyclopropane ethanol in place of isobutanol (yield: 0.1472 g,
100%). mp 111-117.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. -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.sub.3)
m/z 429 (M+H).sup.+, 446 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21FN.sub.2O.sub.4S: 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
[1598] The title compound was prepared according to the method of
Example 335, substituting cyclopropane methanol in place of
isobutanol (yield: 0.0917 g, 64%). mp 158-161.degree. C. .sup.1H
NMR (300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 431 (M+H).sup.+, 448 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.21H.sub.19ClN.sub.2O.sub.4S.0.25 H.sub.2O: 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
[1599] The title compound was prepared according to the method of
Example 335, substituting 2-cyclopropane ethanol in place of
isobutanol (yield: 0.114 g, 78%). mp 124-128.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 445 (M+H).sup.+, 462 (M+NH.sub.4).sup.+.
Anal. calc. for C.sub.22H.sub.21ClN.sub.2O.sub.4S- : 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)-p-
yridazinone
[1600] The title compound was prepared according to the method of
Example 362, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-methylpentane-1-magnesium bromide for cyclopentyl magnesium
chloride (yield: 0.165 g, 99%). mp 112-115.degree. C. .sup.1H NMR
(300 MHz, DMSO d.sub.6) .delta. 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.sub.3) m/z 429 (M+H).sup.+. 446 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.25FN.sub.2O.sub.3S: 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)-p-
yridazinone
[1601] The title compound was prepared according to the method of
Example 362, substituting 4-methylpentane-1-magnesium bromide in
place of cyclopentyl magnesium chloride (yield: 165 mg, 98%). oil.
1H NMR (300 MHz, DMSO d.sub.6).delta. 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.sub.3) m/z 445 (M+H).sup.+, 462 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.23H.sub.25ClN.sub.2O.sub.3S: C, 62.06; H, 5.66; N,
6.30. Found: C, 61.86; H, 5.64; N, 6.18.
EXAMPLE 422
2-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H-pyridazinone
[1602] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.1284 g,
88%). mp 128-132.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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.sub.3) m/z 429 (M+H).sup.+, 446
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21FN.sub.2O.sub.4S: C, 61.67; H, 4.94; N, 6.54.
Found: C, 61.41; H, 4.95; N, 6.47.
EXAMPLE 423
2-(3-Chlorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1603] The title compound was prepared according to the method of
Example 335, substituting 3-methyl-2-buten-1-ol in place of
isobutanol (yield: 0.1 19 g, 81%). mp 113-115.degree. C. .sup.1H
NMR (300 MHz, DMSO d.sub.6) .delta. 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).sup.-. Anal. calc. for
C.sub.22H.sub.21CIN.sub.2O.sub.4S: 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
[1604] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-methyl-3-penten-1-ol in place of isobutanol (yield: 0.1165 g,
77%). mp 111-114.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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.sub.3) m/z 443
(M+H).sup.+, 460 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.23FN.sub.2O.sub.4S: C, 62.43; H, 5.24; N, 6.33.
Found: C, 62.32; H, 5.30; N, 6.25.
EXAMPLE 425
2-(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1605] The title compound was prepared according to the method of
Example 335, substituting
2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone in place of
2-(3-chlorophenyl)-4-tosyloxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
3-methyl-3-butene-1-ol in place of isobutanol (yield: 0.1327 g,
91%). mp 109-111.degree. C. .sup.1H NMR (300 MHz, DMSO d.sub.6)
.delta. 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.sub.3)
m/z 429 (M+H).sup.+, 446 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21FN.sub.2O.sub.4S: 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)-pyridaznone
[1606] The title compound was prepared according to the method of
Example 335, substituting 4-methyl-3-pentene-1-ol in place of
isobutanol (yield: 0.1149 g, 76%). mp 110-111.degree. C. .sup.1H
NMR (300 MHz, DMSO d.sub.6) .delta. 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 (DCENH.sub.3) m/z 459 (M+H).sup.+, 476
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.23ClN.sub.2O.sub.4S: C, 60.19; H, 5.05; N, 6.10.
Found: C, 60.06; H, 4.90; N, 5.96.
EXAMPLE 427
2-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1607] The title compound was prepared according to the method of
Example 335, substituting 3-methyl-3-butene-1-ol in place of
isobutanol (yield: 0.1159 g, 79%). mp 110-112.degree. C. .sup.1H
NMR (300 MHz, DMSO d.sub.6) .delta. 1.62 (s, 3H), 2.32 (t, J=7Hz,
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.sub.3) m/z 445 (M+H).sup.+, 462
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.22H.sub.21ClN.sub.2O.sub.4S: 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
[1608] The title compound was prepared according to the method of
Example 178, substituting 1,5-hexadien-3-ol in place of
2-ethyl-1-hexanol (yield: 150 mg, 85%). mp 104-105.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+; (APCI-) m/z 475
(M+Cl).sup.-. Anal. calc. for C.sub.23H.sub.21FN.sub.2O.sub.4S: 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
[1609] The title compound was prepared according to the method of
Example 178, substituting 5-methyl-2-hexanol in place of
2-ethyl-1-hexanol (yield: 150 mg, 82%). mp 102-103.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+; (APCI-) m/z 493 (M+Cl).sup.-. Anal. calc. for
C.sub.24H.sub.27FN.sub.2O.sub.4S: 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
[1610] The title compound was prepared according to the method of
Example 178, substituting 2-ethyl-1-butanol in place of
2-ethyl-1-hexanol (yield: 140 mg, 80%). mp 107-108.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.73 (t, J=7 Hz, 6H),
1.20 (quintet, J=7 Hz, 4H), 1.40 (m, 1H), 3.29 (s, 3H), 4.29 (d,
J=7 Hz, 2H), 7.37 (t, J=9 Hz, 2H), 7.66 (m, 2H), 7.90 (d, J=9 Hz,
2H), 8.07 (d, J=9 Hz, 2H), 8.19 (s, 1H). MS (APCI+) m/z 445
(M+H).sup.+; (APCI-) m/z 479 (M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.25FN.sub.2O.sub.4S: 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)pheny-
l]-3(2H)-pyridazinone
[1611] The title compound was prepared according to the method of
Example 178, substituting 2-(isopropylthio)ethanol in place of
2-ethyl-1-hexanol (yield: 138 mg, 74%). mp 137-139.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.13 (d, J=7 Hz, 6H),
2.77 (t, J=7 Hz, 2H), 2.88 (quintet, 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).sup.+. Anal. calc. for
C.sub.22H.sub.23FN.sub.2O.sub.4S.sub.2: 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
[1612] The title compound was prepared according to the method of
Example 178, substituting 3-(methylthio)-1-hexanol in place of
2-ethyl-1-hexanol (yield: 155 mg, 79%). mp 90-92.degree. C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+;
(APCI-) mn/z 525 (M+Cl).sup.-. Anal. calc. for
C.sub.24H.sub.27FN.sub.2O.sub.4S.sub.2: C, 58.75; H, 5.54; N, 5.70.
Found: C, 58.66; H, 5.54; N, 5.66.
EXAMPLE 434
2-(4-Fluorophenyl)-4-(2-methyl-4-pentenyl-1-oxy)-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone
[1613] The title compound was prepared according to the method of
Example 178, substituting 2-methyl-4-penten-1-ol in place of
2-ethyl-1-hexanol (yield: 135 mg, 76%). mp 106-107.degree. C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.76 (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).sup.+; (APCI-) m/z 477 (M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.23FN.sub.2O.sub.4S: 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
[1614] To a solution of
2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyidazinone (189mg, 0.5 mmol), Ph.sub.3P (262 mg,
1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF
(25 mL) was added dropwise a solution of DIAD (0.2 mL, 1 mmol) in
THF (5 mL) and the resulting mixture was stirred at room
temperature for 8 hours. The mixture was concentrated in vacuo and
the residue was chromatographed (silica gel, 1:1 hexanes-ethyl
acetate) to provide the desired product, (yield: 180 mng 71%). mp
126-128.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+; (APCI-) ni/z 537 (M+Cl).sup.-. Anal. calc. for
C.sub.22H.sub.19F.sub.5N.sub.2O.sub.4S: 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)-pyridaz-
inone
[1615] The title compound was prepared according to the method of
Example 178, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
ethanol in place of 2-ethyl-1-hexanol (yield: 25 mg, 12%). mp
121-123.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+; (APCI-) m/z 441
(N+Cl).sup.-. Anal. caic. for
C.sub.19H.sub.16F.sub.2N.sub.2O.sub.4S.0.25 H.sub.2O: 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)pheny-
l]-3(21)-pyridazinone
[1616] The title compound was prepared according to the method of
Example 178, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-methyl-1-pentanol in place of 2-ethyl-1-hexanol (yield: 120 mg,
52%). mp 98-99.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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).sup.+; (APCI-) m/z 497
(M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.24F.sub.2N.sub.2O.sub.4S: 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-pentyoxy-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1617] The title compound was prepared according to the method of
Example 178, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-methyl-2-pentanol for 2-ethyl-1-hexanol (yield: 115 mg, 50%). mp
132-133.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+;
(APCI-) m/z 497 (M+Cl).sup.-. Anal. calc. for
C.sub.23H.sub.24F.sub.2N.sub.2O.sub.4S: 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)phe-
nyl]-3(2H)-pyridazinone
[1618] The title compound was prepared according to the method of
Example 178, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
2-cyclopentyl-1-ethanol in place of 2-ethyl-1-hexanol (yield: 115
mg, 60%). mp 100-101.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 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, 1H). MS
(APCI+) m/z 475 (M+H).sup.+; (APCI-) m/z 509 (M+Cl).sup.-. Anal.
calc. for C.sub.24H.sub.24F.sub.2N.sub.2O.sub- .4S.0.25 H.sub.2O:
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-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1619] The title compound was prepared according to the method of
Example 178, starting with
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
2-cyclopent-2-enyl-1-ethanol in place of 2-ethyl-1-hexanol (yield:
95 mg, 48%). mp 126-127.degree. C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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, 1H), 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).sup.+; (APCI-) m/z 507
(M+Cl).sup.-. Anal. calc. for C.sub.24H.sub.22F.sub.2N.sub.2O.sub-
.4S: 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
[1620] A mixture of the product from Example 46,
2-phenacyl-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (700 mg, 1.5
mmol), and sodium borohydride (69 mg, 1.8 mmol) in ethanol (200
mL), was stirred at 40.degree. C. for 2 hours. The reaction mixture
was then concentrated in vacuo and the residue was partitioned
between ethyl acetate and 2 N aqueous hydrochloric acid. The
organic layer was washed with brine, dried over MgSO.sub.4, and
filtered. The filtrate was concentrated in vacuo to provide a pale
yellow solid which was crystallized from ethyl acetate/hexanes to
provide the title compound as white crystals (yield: 540 mg, 78%).
mp 205-207.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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, 1H), 7.91 (d, J=9
Hz, 2H). MS (DCI/NH.sub.3) m/z 465 (M+H).sup.+. Anal. calc. for
C.sub.25H.sub.21FN.sub.2O.sub.4S: 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
[1621] A mixture of the product from Example 441,
2-(2-hydroxy-2-phenyleth-
yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(210 mg, 0.45 mmol), iodomethane (56 .mu.L, 0.90 mmol), and an 80%
oil dispersion of sodium hydride (18 mg, 0.59 mmol) in anhydrous
DMF (16 mL) was stirred at room temperature for 18 hours. The
reaction mixture was partitioned between ethyl acetate and 2 N
aqueous hydrochloric acid. The organic layer was washed with brine,
dried over MgSO.sub.4, and filtered. The filtrate was concentrated
in vacuo to provide a yellow oil which was purified by column
chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions
containing product were combined and concentrated in vacuo , and
the residue was triturated with hexanes to provide the title
compound (yield: 75 mg, 34.7%). mp 135-137.degree. C. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 479 (M+H).sup.+. Anal. calc. for
C.sub.26H.sub.23FN.sub.2O.sub.4S: 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)p-
henyl]-3(2H)-pyridazinone
[1622] A mixture of the product from Example 46,
2-phenacyl-4-(4-fluorophe-
nyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476
mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol), and sodium
acetate (518 mg, 3.8 mmol) in methanol (100 mL) was stirred at
reflux for 48 hours. The reaction mixture was concentrated in vacuo
, and the residue was partitioned between ethyl acetate and
saturated aqueous anumonium chloride. The organic layer was washed
with brine then dried over MgSO.sub.4, and filtered. The filtrate
was concentrated in vacuo to provide a brown oil which was purified
by column chromatography (silica gel, 70:30 hexanes/ethyl acetate).
Fractions containing product were combined and concentrated in
vacuo . The residue was crystallized from methanol/water to provide
the title compound as a mixture of E and Z oximes (yield: 82 mg,
35%). mp 95-99.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.3) m/z 492 (M+H).sup.+. Anal. calc. for
C.sub.26H.sub.22FN.sub.3O.sub.4S: 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-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1623] The title compound was prepared according to the method of
Example 255, substituting 1-bromo-4-methylpentane in place of
3,4-difluorobenzyl bromide (yield: 145 mg, 58%). mp 111-113.degree.
C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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.sub.3)
m/z 447 (M+H).sup.+, 464 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.24F.sub.2N.sub.2O.sub.3- S: 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
[1624] The title compound was prepared as described in Example 384,
substituting
2-(3,4-difluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone (Example 347) in place of
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazino-
ne (yield: 248 mg, 42%). mp 149-151.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 450
(M+H).sup.+, 467 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.21F.sub.2N.sub.3O.sub.4- S: 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)pheny-
l]-3(2H-pyridazinone
[1625] The intermediate,
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted
with 2,2-dimethylpropanol to provide
2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylp-
ropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to
the method of Example 90D.
[1626] The product was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The
sulfoxide was converted to the title compound according to the
method of Example 68, substituting
2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-
-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone for
2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]--
3(2H)-pyridazinone (yield: 125 mg, 53%). mp 123-124.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 420
(M+H).sup.+. Anal. calc. for
C.sub.17H.sub.20F.sub.3N.sub.3O.sub.4S: 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
[1627] The title compound was prepared according to the method of
Example 83, substituting 3-methyl-1-butanol in place of isopropanol
(yield: 65 mg, 85%). mp 111-113.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 419 (M+H).sup.+. Anal. calc. for
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.4S: 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-Trfluoroethyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)pheenyl]-3(-
2H)-pyridazinone
[1628] The intermediate,
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted
with 3-methyl-1-butanol to provide
2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-
-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the
method of Example 90D.
[1629] The product was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The
sulfoxide was converted to the title compound according to the
method of Example 68, substituting
2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-
-(methylsulfinyl)phenyl]-3(2H)-pyridazinone for
2-(2,2,2-trifluoroethyl)-4-
-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone
(yield: 65 mg, 50%). mp 123-124.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 420 (M+H).sup.+. Anal. calc. for
C.sub.17H.sub.20F.sub.3N.sub.3O.sub.4S: 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
[1630] The intermediate,
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted
with 2-methyl-1-propanol to provide
2-(2,2,2-trifluoroethyl)-4-(2-methylpropox-
y)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the
method of Example 90D.
[1631] The product was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The
sulfoxide was converted to the title compound according to the
method of Example 68, substituting
2-(2,2,2-trifluoroethyl)-4-(2-methylpropoxy)-5-[-
4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone for
2-(2,2,2-trifluoroethyl)--
4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone
(yield: 120 mg, 40%). mp 170-172.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 406 (M+H).sup.+. Anal.
calc. for C.sub.16H.sub.18F.sub.3N.sub.3O.sub.4S: 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-Trifluorophenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3-
(2H)-pyridazinone
[1632] The product of Example 4,
2-benzyl-4-(4-fluorophenyl)-5-[4-(methylt-
hio)phenyl]-3(2H)-pyridazinone, was N-debenzylated by the method of
Example 11 to provide
4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-p- yridazinone.
The intermediate was mixed with one equivalent of
1-methylsufonyloxy-2,3,3-trifluoro-2-propene, (Example 88A) in
ethyl acetate, followed by one equivalent of cesium carbonate. The
reaction mixture was heated to 50.degree. C. for 5 hours. Aqueous
work-up, followed by chromatography provided
2-(2,3,3-trifluoropropenyl)-4-(4-fluo-
rophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (650 mg,
63%). The product was oxidized with one equivalent of
meta-chloroperoxybenzoic acid to provide the methyl sulfoxide which
was converted to the title compound according to the method of
Example 68, substituting
2-(2,3,3-trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)pheny-
l]-3(2H)-pyridazinone for
2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-
-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (yield: 65 mg, 35%). mp
190-193.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 456 (M--H).sup.+. Anal. calc. for
C.sub.19H.sub.12F.sub.5N.sub.3O.sub.3S: 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)ph-
enyl]-3(2H)-pyridazinone
[1633] The title compound was prepared according to the method of
Example 178, substituting 3-methyl-1,3-butanediol in place of
2-ethyl-1-hexanol (yield: 110 mg, 61%). mp 133-134.degree. C.;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 1H); MS (APCI+) m/z 447 (M+H).sup.+; (APCI-) m/z
481 (M+Cl).sup.-; Anal. calc. for
C.sub.22H.sub.23FN.sub.2O.sub.5S.0.25 H.sub.2O: C, 58.59; H, 5.25;
N, 6.21. Found: C, 58.42; H, 5.00; N, 6.02.
EXAMPLE
4522-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyrridazinone
[1634] The title compound was prepared according to the method of
Example 178, substituting
2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone in place of
2-(4-fluorophenyl)-4-tosyloxy-5-[4--
(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
2-methyl-1,2-propanediol in place of 2-ethyl-1-hexanol (yield: 55
mg, 31%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 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).sup.+; (APCI-) m/z 485
(M+Cl).sup.-; Anal. calc. for
C.sub.21H.sub.20F.sub.2N.sub.2O.sub.5S: 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)-pyrida-
zinone
[1635] The title compound was isolated from the reaction mixture in
Example 233, as a product of oxidation of unreacted starting
material (yield: 22 mg, 8%). mp 113-115.degree. C. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 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.sub.3) m/z 393 (M+H).sup.+, 410 (M+NH.sub.4).sup.+. Anal.
calc. for C.sub.18H.sub.14F.sub.2N.sub.2O.sub.4S: C, 55.10; H,
3.60; N, 7.14.
EXAMPLE 454
2-(2,3,4,5,6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-(dimethylamino)met-
hylaminosulfonylphenyl]-3(2H)-pyridazinone
[1636] The title compound was isolated from the reaction mixture in
Example 125, as a product resulting from a reaction with the
solvent, N,N-dimethylformamide (yield: 53 mg, 16%). mp
194-196.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.05
(s, 3H), 3.17 (s, 3H), 5.49 (s, 2H), 6.97 (t, J=9Hz, 2H), 7.18 (dd,
J=9Hz, 6Hz, 2H), 7.20 (d, J=9Hz, 2H), 7.81 (s, 1H), 7.82 (d, J=9
Hz, 2H), 8.14 (s, 1H). MS (DCI/NH.sub.3) m/z 581 (M+H).sup.+. Anal.
calc. for C.sub.26H.sub.18F.sub.6N.sub.4O.sub.3S: 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)methylaminos-
ulfonylphenyl]-3(2H)-pyridazinone
[1637] The title compound was isolated from the reaction mixture in
Example 124, as a product resulting from a reaction with the
solvent, N,N-dimethylformamide (yield: 55 mg, 18%). mp
193-195.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 527 (M+H).sup.+. Anal. calc. for
C.sub.26H.sub.21F.sub.3N.sub.4O.sub.3S: C, 59.30; H, 4.02; N,
10.64. Found: C, 59.08; H, 3.97; N, 10.48.
EXAMPLE 456
(4-Fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinone
EXAMPLE 456A
4-Bromoselenoanisole
[1638] Freshly crushed magnesium turmings (6.1 g, 0.25 mol) were
suspended with vigorous stirring in a solution of diethyl ether
(360 mL) and 1,4-dibromobenzene (10 g, 0.04 mol). The solution was
brought to reflux for 30 minutes, without initiation. Several
crystals of iodine were added which initiated the reaction to a
self-sustained reflux. The reflux was maintained as the remainder
of the 1,4-dibromobenzene (49 g, 0.21 mol) was slowly added. The
reaction was refluxed for an additional 2 hours after addition of
the 1,4-dibromobenzene was completed. When nearly all of the
magnesium turnings had been consumed, the yellow/gray heterogeneous
solution was cooled to 23.degree. C., and selenium (19 g, 0.24 mol)
was added in small portions via spatula so as to maintain a gentle
reflux. The selenium that became stuck to the sides of the flask
was washed in with additional diethyl ether. After addition, the
solution was stirred for 20 minutes at 23.degree. C. and then was
cooled to 0.degree. C. A diethyl ether (20 mL) solution of methyl
iodide (35.5 g, 0.25 mol) was slowly added dropwise to the reaction
mixture. Upon completion of addition, the cooling bath was removed,
and the solution stirred for 3 hours at 23.degree. C. The reaction
solution was slowly poured into ice water/i M HCl, and then the
biphasic solution filtered through a glass wool plug. The ethereal
layer was separated and the aqueous phase extracted twice more with
diethyl ether. The combined ethereal extracts were dried over
MgSO.sub.4, filtered, and concentrated in vacuo to provide a
semi-viscous orange oil. On standing overnight at -20.degree. C.,
large yellow needles formed. The residual oil was drawn off via
pipette to provide 17 g (27%) of crystalline product. (J. Org.
Chem., 1983, 48, 4169) .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
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.sub.76 M+H).sup.+, m/z 250 (Se.sub.78
M+H).sup.+, m/z 252 (Se.sub.80M+H).sup.+, and m/z 254 (Se.sub.82
M+H).sup.+.
EXAMPLE 456B
2,4-Bis(4-fluorophenyl)-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone
[1639] The title compound was prepared according to the method of
Example 228, substituting
2-(4-fluorophenyl)-4-methoxy-5-[4-(methylseleno)phenyl]-
-3(2H)-pyridazinone (prepared according to the method of Example
194C, substituting 4-(methylseleno)benzeneboronic acid from Example
1 in place of 4-(methylthio)benzeneboronic acid) in place of
2-(4-fluorophenyl)-4-me-
thoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting
4-fluorophenyl magnesium bromide in place of cyclohexylmagnesium
chloride (yield: 44 mg, 69%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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).sup.+.
EXAMPLE 456C
2,4-Bis(4-fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2H)-pyridazinone
[1640] A stirred solution of the
2,4-bis(4-fluorophenyl)-4-(4-fluorophenyl-
)-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone (40 mg, 88.1
mrnmol) in methylene chloride (2 mL) was treated with
3-chloroperoxybenzoic acid (100 mg, 342 mmol, 57-86%) at 23.degree.
C. After 2 hours, the reaction appeared to be only slightly more
than 50% completed. Additional 3-chloroperoxybenzoic acid (80 mg,
274 mmol, 57-86%) was added. The reaction ran to completion over
the next 16 hours of stirring at 23.degree. C. The solution was
diluted with ethyl acetate and carefully shaken with a NaHSO.sub.3
solution (two times) for several minutes to consume the excess
3-chloroperoxybenzoic acid. The ethyl acetate solution was
subsequently washed with a saturated Na.sub.2CO.sub.3 solution (two
times), water, and brine and dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was chromatographed (flash
silica gel, acetone/methylene chloride/hexanes 2:2:1) to provide
the product (yield: 40 mg, 93%). (J. Chem. Soc., Chem. Commun.,
1985, 569). mp 110-150.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 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).sup.+ and m/z 504
(M+NH.sub.4).sup.+. Anal. calc. for
C.sub.23H.sub.16F.sub.2N.sub.2O.sub.3Se.0.5 H.sub.2O: C, 55.88; H,
3.46; N, 5.66. Found: C, 55.60; H, 3.61; N, 5.29.
EXAMPLE 457
2-(3,4-Difluorohenyl)-4-(3-fluorophenol)-5-[4-(methylsulfonyl)phenyl]-3(2H-
)-pyridazinone
[1641] The title compound was prepared as described in Example 62,
starting with
4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone and substituting 3,4-difluorobromobenzene in place
of 1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). mp
182-185.degree. C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.23
(s, 3 H), 6.98 (d, J=9 Hz, 11), 7.18 (m, 2H), 7.32 (m, 1H), 7.52
(d, J=9 Hz, 2 H), 7.6 (m, 2H), 7.85 (m, 1 H), 7.9 (d, J=9 Hz, 2H),
8.3 (s, 1 H). MS (DCI/NH.sub.3) m/z 457 (M+H).sup.+, 474
(M+NH.sub.4).sup.+.
EXAMPLE 458
2-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone
[1642] The title compound was prepared as described in Example 62,
substituting
4-(3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyrida-
zinone in place of
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone (yield: 135 mg, 34%). mp 199-201.degree. C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 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, 2 H),
7.71 (m, 2H), 7.91(d, J=9 Hz, 2 H), 8.27 (s, 1 H). MS
(DCI/NH.sub.3) m/z 439 (M+H).sup.+, 456 (M+NH.sub.4).sup.+.
EXAMPLE 459
2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfony-
lphenyl]-3(2H)-pyridazinone
[1643] To a solution of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-pro-
poxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (139 mg,
0.309 mmol) and di-t-butylazodicarboxylate (71.2 mg, 0.309 mmol) in
THF (25 mL) at -78.degree. C. was added dropwise a 1M solution of
NaHMDS (0.93 mL, 0.928 mmol) in THF. After addition the reaction
was stirred another 45 min at -78.degree. C. (or until TLC
indicated a disappearance of starting material) and then was
treated with 1N NaOH (20 mL). The reaction mixture was stirred at
room temperature for the next 18 h. Sodium acetate trihydrate (758
mg, 5.57 mmol) was added followed by addition of
hydroxylamine-O-sulphonic acid (630 mg, 5.57 mmol) and H.sub.2O (50
mL). The resulting mixture was stirred at ambient temperature for
the next 18 hours and then extracted with EtOAc. The extract was
washed with water, brine, dried over MgSO.sub.4 and concentrated in
vacuo. The residue was purified by chromatography (silica gel, 1:1
hexanes-EtOAc) to provide the title compound (yield: 25 mg; 18%).
mp 65-69.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.0 (s, 6H), 4.2 (s, 2H), 4.56 (s, 1H), 7.51 (m, 3H), 7.6 (m, 1H),
7.85 (m, 1H), 7.95 (s, 4H), 8.21 (s, 1H); MS (DCI/NH.sub.3) m/z 451
(M+H).sup.+, 467 (M+NH.sub.4).sup.+.
EXAMPLE 460
2-(3,4-Difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(-
2H)-pyridazinone
[1644] A solution of
2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone (378 mg, 1 mmol), Ph.sub.3P (524 mg, 2
mmol) and acetol (74 mg, 1 mmol) in THF (25 mL) at room temperature
was treated dropwise with a solution of DIAD (0.4 mL, 2 mmol) in
THF (5 mL). The mixture was stirred at room temperature for 6 hours
and concentrated in vacuo. The residue was chromatographed (silica
gel, 1:1 hexanes-ethyl acetate) to provide the desired product
(yield: 205 mg, 48%). mp 169-170.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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).sup.+, (APCI-) m/z 469 (M+Cl)-; Anal. calc. for
C.sub.20H.sub.16F.sub.2N.sub.2O.sub.5S.0.75H.sub.2O: C, 53.62; H,
3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08. 38
EXAMPLE 461
2-(3,4-Difluorophenyl)-4-[2-(methoxyimino)-1-propoxy]-5-[4-(methylsulfonyl-
)phenyl]-3(2H)-pyridazinone
[1645] A mixture of
2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone from Example 460 (150 mg, 0.3
mmnol) in H.sub.2O (10 mL) and dioxane (20 mL) was treated with
methoxyamine hydrochloride (84 mg, 1 mmol) and sodium acetate
trihydrate (138 mg, 1 mmol). The mixture was stirred at room
temperature for 6 hours. The reaction mixture was extracted with
ethyl acetate and purified by column chromatography (silica gel,
1:1 hexanes-ethyl acetate) to provide the title compound (yield: 20
mg, 15%). mp 143-145.degree. C.; .sup.1 H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H),
4.93 (s, 2H), 7.54 (mi, 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).sup.+; (APCI-) m/z 498 (M+Cl).sup.-. Anal.
calc. for C.sub.21H.sub.19F.sub.2N.sub.3OS: 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-methyl-1-propoxy)-5-[4-(methylsu-
lfonl)phenyl]-3(2H)-pridazinone
EXAMPLE 462A
(R)-3-t-Butoxy-2-methyl-1-propanol
[1646] 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.sub.4 (0.1 mL) and the reaction mixture was left at room
temperature in a tightly closed flask for 24 hours. The mixture was
then poured into a saturated solution of NaHCO.sub.3 and extracted
with ethyl ether. The ether was removed in vacuo and the residue
was dissolved in THF (50 mL). To the resulting solution was added
NaBH.sub.4 (925 mg, 25 mmol) and at 55.degree. C. dropwise methanol
(10 mL). The reaction was continued at 55.degree. C. for 1 hours,
then it was cooled to ambient temperature, acidified with 10%
citric acid to pH 5 and extracted with ethyl acetate. The acetate
extract was washed with water, brine, dried with MgSO.sub.4 and
concentrated in vacuo. The residue was chromatographed (silica gel,
2:1 hexane-ethyl acetate) to provide
(R)-3-t-butoxy-2-methyl-1-propanol (yield: 1 g, 68%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 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=4.5 Hz, 12 Hz,
1H), 3.70 (m, 2 H); MS (DCI/NH.sub.3) m/z 164
(M+NH.sub.4).sup.+.
EXAMPLE 462B
(S)-2-(3,4-Difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-(4-methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1647] To a solution
2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl-
)phenyl-3(2H)-pyridazinone (378 mg, 1 mmol), Ph.sub.3P (524 mg, 2
mmol) and Example 462A (146 mg, 1 mmol) in THF (25 mL) at room
temperature was added dropwise a solution of DIAD (0.4 mL, 2 mmol)
in THF (5 mL). The mixture was then stirred at room temperature for
6 hours and concentrated in vacuo. The residue was passed through a
silica gel pad (hexane-ethyl acetate as an eluent) to provide 550
mg of roughly purified
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone, still contaminated with
reduced DIAD. MS (APCI+) m/z 507 (M+H).sup.+; (APCI-) m/z 541
(M+Cl).sup.-.
EXAMPLE 462C
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1648] A mixture of Example 462B (100 mg, 0.2 mmol) in TFA (5 mL)
was left at ambient temperature for 24 hours. The mixture was then
concentrated in vacuo, the residue was neutralized with saturated
solution of NaHCO.sub.3 and extracted with ethyl acetate.
Purification on a column (silica gel, 1:2 hexanes-EtOAc) gave a
foamy product (yield: 51 mg, 56%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.75 (d, J 7 Hz, 3H), 1.81 (sextet (J=7 Hz,
1H), 3.21 (d, J=6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J=6 Hz, 12 Hz,
1H), 4.40 (dd, J=6 Hz, 12 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).sup.+; (APCI-) m/z 485
(M+Cl)-; Anal. calc. for C.sub.21H.sub.20F.sub.2N.sub.2O.sub.5S: 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-methyl-1-propoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1649] The title compound was prepared by the method described in
Example 462, substituting (R)-(-)-methyl
3-hydroxy-2-methylpropionate in place of (S)-(+)-methyl
3-hydroxy-2-methylpropionate (yield: 65 mg, 61%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 0.75 (d, J=7 Hz, 3H), 1.81 (sextet, 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, 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).sup.+;
(APCI-), m/z 485 (M+Cl)-. Anal. calc. for
C.sub.21H.sub.20F.sub.2N.sub.2O.sub.5S: 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-methyl-1-propoxy)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1650] To a solution of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl--
1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example
462B, 450 mg, 0.9 mmol) and DBAD (207 mg, 0.9 mmol) in THF (25 mL)
at -78.degree. C. was added dropwise a 1M solution of LiHMDS (3 mL,
3 mmol) and the resulting mixture was stirred at -78.degree. C. for
2 hours. The mixture was warmed to room temperature and 1N NaOH (5
mL, 5 mmol) was added. After 12 hours at ambient temperature,
sodium acetate trihydrate (2.76 g, 20 mmol) and water (10 mL)
followed by hydroxylainine-O-sulfonic acid (2 g, 15 mmol) were
added and the mixture was stirred at room temperature for 5 hours.
The product was extracted with ethyl acetate and purified by
chromatography (silica gel, 1:2 hexanes-EtOAc) to afford crude
intermediate (yield: 160 mg, 35%). MS (APCI+) m/z 508 (M+H).sup.+;
(APCI-) m/z 542 (M+Cl)-.
[1651] TFA (5 mL) was added to the above intermediate and the
resulting solution was left at room temperature for 24 hours. The
TFA was removed in vacuo, then the residue was neutralized with
saturated NaHCO.sub.3 and extracted with ethyl acetate. The organic
layer was dried over MgSO.sub.4 then filtered. The filtrate was
concentrated in vacuo and the residue was purified by column
chromatography (silica gel, 1:2 hexane-ethyl acetate) to provide
the title compound (yield: 50 mg, 33%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 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, 12 Hz, 1H), 4.40 (dd,
J=6 Hz, 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).sup.+; (APCI-) m/z 486
(M+Cl)-.
EXAMPLE 465
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1652] The desired material was prepared according to the procedure
of Example 464 substituting
(R)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methy-
l-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in
place of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone (yield: 30 mg, 20%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 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, 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)-. Anal. calc. for
C.sub.20H.sub.19F.sub.2N.sub.3O.sub.5S: 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-methyl-1-butoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1653] The title compound was prepared according to the method of
Example 178, substituting 2-methyl-1,4-butandiol in place of
2-ethyl-1-hexanol and separating the regioisomeric products by
multiple preparative thin layer chromatography runs, eluting with
4:1 ethyl acetate/hexanes (yield: 65 mg, 19%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 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).sup.+.
EXAMPLE 467
2-(3,4-Difluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2-
H)-pyridazinone
[1654] The title compound was prepared according to the method of
Example 460 substituting 4-hydroxy-2-butanone in place of acetol.
(yield: 95.0 mg, 21%). mp 134-135.degree. C.; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 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.sub.3) m/z 449 (M+H), 466 (M+NH.sub.4).sup.+. Anal. calc.
for C.sub.21H.sub.18F.sub.2N.sub.2O.sub.5- S: 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-oxo-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-p-
yridazinone
[1655] The title compound was prepared according to the method of
Example 460 starting with
2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(m-
ethylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting
4-hydroxy-2-butanone in place of acetol. (yield: 85.0 mg, 20%). mp
133-136.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 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.sub.3) m/z 431 (M+H).sup.+,
448 (M+NH.sub.4).sup.+. Anal. calc. for
C.sub.21H.sub.19FN.sub.2O.sub.5S: C, 58.60; H, 4.42; N, 6.52.
Found: C, 58.87; H, 4.55; N, 6.51.
EXAMPLE 469
2-(4-Fluorophenyl)-4-(4-hydroxy-2-methyl-1-butoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1656] The title compound was prepared according to the method of
Example 178, substituting 2-methyl-1,4-butandiol in place of
2-ethyl-1-hexanol and separating the regioisomeric pr-ducts by
multiple preparative thin layer chromatography runs, eluting with
4:1 ethyl acetate/hexanes (yield: 43 mg, 12%). .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 0.87 (d, J=8.1 Hz, 3H), 1.33-1.46 (m, 1H),
1.50-1.67 (m, 2H), 1.93-2.04 (m, 1H), 3.13 (s, 3H), 3.54-3.72 (m,
2H), 4.29 (dd, J=6.0, 9.3 Hz, 1H), 4.43 (dd, J=6.0, 9.3 Hz, 1H),
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).sup.+.
EXAMPLE 470
2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1657] The title compound was prepared according to the method of
Example 459, substituting
2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (yield: 600 mg, 60%). mp
163-164.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.05 (s, 6H), 1.73 (t, J=6 Hz, 2H), 4.30 (s, 1H), 4.52 (t, J=6 Hz,
2H), 7.37 (t, J=9 Hz, 1H), 7.47 (s, 2H), 7.65 (dd, J=9 Hz, J=3 Hz,
2H), 8.83 (d, J=9 Hz, 2H), 8.95 (d, J=9 Hz, 2H), 8.18 (s, 1H); MS
(DCI/NH.sub.3) m/z 448 (M+H).sup.+. Anal. calcd. for
C.sub.21H.sub.22FN.sub.3O.sub.5S: C, 56.36; H, 4.95; N, 9.39.
Found: C, 55.96; H, 4.89; N, 9.09.
EXAMPLE 471
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
EXAMPLE 471A
3,4-Difluorophenylhydrazine
[1658] A stirred mixture of 3,4-difluoroaniline (12.9 g, 0.1 mol)
in concentrated hydrochloric acid (60 mL) was chilled to
-10.degree. C. with an ice/methanol bath. A solution of sodium
nitrite (6.9 g, 0.1 mol) in water (30 mL) was added at a rate which
maintained the temperature of the reaction mixture below 10.degree.
C. After stirring for 2 hours, the reaction mixture was cooled to
0.degree. C. and a solution of tin(II) chloride (56.88 g, 0.3 mol)
in concentrated hydrochloric acid (50 mL) was added dropwise with
vigorous stirring. Additional concentrated hydrochloric acid (150
mL) was added to the reaction mixture and stirring was continued
for 2 hours. The reaction mixture was filtered to collect the
precipitated hydrochloride salt of the title compound. This
precipitate was dissolved in water (75 mL) and the resulting
solution was basified with 50% aqueous sodium hydroxide and
extracted with ethyl acetate. The organic extracts were dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated in
vacuo to provide the title intermediate as a brown oil (8.11 g,
57.4%).
EXAMPLE 471B
2-(3,4-Difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone
[1659] The title intermediate was prepared by the method of Example
194A, substituting 3,4-difluorophenylhydrazine (Example 471 A) for
4-fluorophenylhydrazine hydrochloride.
EXAMPLE 471C
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-bromo-3(2H)-pyrid-
azinone
[1660] The dibromo-intermediate from Example 471B was reacted
according to the procedure described in Example 194B, substituting
3-methyl-1,3-butanediol in place of methanol, to selectively react
at the 4-position and provide the title intermediate.
EXAMPLE 471D
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylthio)ph-
enyl]-3(2H)-pyridazinone
[1661] The product from Example 471C (12.79 g, 32.86 mmol) was
coupled to 4-(methylthio)phenylboronic acid (6.07 g, 36.15 mmol)
with K.sub.2CO.sub.3 (10 g, 72.3 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (1.15 g, 1.64 mmol) in ethanol (200 mL)
at 60-65.degree. C. for 40-70 minutes to provide the title
intermediate (yield: 9.16 g, 64.5%).
EXAMPLE 471E
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1662] The sulfide from Example 471D was oxidized to the title
compound by the method of Example 10 (yield: 7.46 g, 76%). m.p.
131-133.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.04 (s, 6H), 1.73 (t, J=6 Hz, 2H), 3.29 (s, 3H), 4.43 (s, 1H),
4.54 (t, J=6 Hz, 2H), 7.52 (m, 1H), 7.62 (ddd, J=9 Hz, J=9 Hz,
J=1.5 Hz, 1H), 7.82 (ddd, J=9 Hz, J=9 Hz, J=3Hz, 1H), 7.91 (d, J=9
Hz, 1H), 8.08 (d, J=9 Hz, 2H), 8.20 (s, 1H); MS (DCI-NH.sub.3) m/e
465 (M+H).sup.+. Anal. calcd. for
C.sub.22H.sub.22F.sub.2N.sub.2O.sub.5S: C, 56.88; H, 4.77; N, 6.03.
Found: C, 56.92; H, 4.88; N, 5.94.
EXAMPLE 472
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl-
)phenyl]-3(2H)-pyridazinone
[1663] The title compound was prepared according to the method of
Example 459, substituting
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)--
5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone (yield: 300 mg, 50%). mp
181-181.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.04 (s, 6H), 1.72 (t, J=6 Hz, 2H), 4.43 (s, 1H), 4.53 (t, J 6 Hz,
2H), 7.49 (s, 2H), 7.53 (m, 1H), 7.63 (ddd, J=9 Hz, J=9 Hz, J=1.5
Hz, 1H), 7.79 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz,
1H), 7.95 (d, J=9 Hz, 2H), 8.19 (s, 1H); MS (DCI/NH.sub.3) m/z 466
(M+H).sup.+. Anal. calcd. for C.sub.21H.sub.21F2N.sub.2O.sub.5S: C,
54.12; H, 4.66; N, 8.81. Found: C, 54.19; H, 4.55; N, 9.03.
EXAMPLE 473
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1664] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3-chloro-4-fluorophenylh- ydrazine in place of
3,4-difluorophenylhydrazine (yield: 200 mg, 89%). mp
108-110.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.24
(s, 6H), 1.89 (t, 2H, J=6 Hz), 2.34 (s, 1H), 3.12 (s, 3H), 4.57 (t,
J=6 Hz, 2H), 7.25 (t, J=9 Hz, 1H), 7.60 (m, 1H), 7.78 (d, J=6 Hz,
1H), 7.79 (d, J=9 Hz, 2H), 7.92 (s, 1H), 8.08 (d, J=9 Hz, 2H); MS
(DCI/NH.sub.3) m/z 4-81 (M+H).sup.+; Anal. calcd. for
C.sub.22H.sub.22FClN.sub.2O.sub.5S: C, 54.94; H, 4.61; N, 5.82.
Found: C, 54.87; H, 4.65; N, 5.72.
EXAMPLE 474
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1665] The title compound was prepared according to the method of
Example 459, substituting
2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-but-
oxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 473)
in place of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 160 mg, 45%). mp
59-62.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.05
(s, 6H), 1.73 (t, 2H, J=6 Hz), 4.32 (s, 1H), 4.54 (t, J=6 Hz, 2H),
7.50 (s, 2H), 7.60 (t, J=9 Hz, 1H), 7.66 (m, 1H), 7.73 (d, J=9 Hz,
2H), 7.74 (d, J=9 Hz, 2H), 7.75 (m, 1H), 8.22 (s, 1H); MS
(DCI/NH.sub.3) m/z 482 (M+H).sup.+. Anal. calcd. for
C.sub.21H.sub.21FClN.sub.3O.sub.5S: C, 52.33; H, 4.39; N, 8.71.
Found: C, 52.30; H, 5.03; N, 8.10.
EXAMPLE 475
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1666] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3-chlorophenylhydrazine in place of 3,4-difluorophenylhydrazine
(yield: 200 mg, 89%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.04 (d, J=8.5 Hz, 2H), 7.91 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.67
(m, 1H), 7.57 (m, 1H), 7.40 (t, J=8.8 Hz, 1H), 7.36 (m, 1H), 4.54
(t, J=6.3 Hz, 2H), 3.10 (s, 3H), 2.56 (s, 1H), 1.86 (t, J=6.3 Hz,
2H), 1.20 (s, 6H), MS (DCI/NH.sub.3) m/z 462(M+H).sup.+.
EXAMPLE 476
2-(3-Chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1667] The title compound was prepared according to the method of
Example 459, substituting
2-(3-chlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-
-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 475) in place
of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl--propoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.03 (d, J=8.7 Hz, 2H), 7.91 (s, 1H), 7.70 (d, J=8.7 Hz,
2H), 7.68 (m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.38 (m, 1H), 5.65
(s, 2H), 4.51(t, J=6.6 Hz, 2H), 2.70 (br s, 1H), 1.87 (t, J=6.6 Hz,
2H), 1.20 (s, 6H); MS (DCI/NH.sub.3) m/z 463 (M+H).sup.+.
EXAMPLE 477
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-peridazinone
[1668] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
4-fluorophenylhydrazine in place of 3,4-difluorophenylhydrazine and
substituting 2-methyl-1,2-propanediol (prepared by the LAH
reduction of methyl 2-hydroxyisobutyrate) in place of
3-methyl-1,3-butanediol. mp 152-154.degree. C., .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.10 (d, 2H, J=18 Hz), 7.95 (s, 1H), 7.83
(d, 2H, J=18 Hz), 7.63 (d, 1H, J=18 Hz), 7.61 (d, 1H, J=18 Hz),
4.18 (s, 2H), 3.13 (s, 3H), 1.19 (s, 6H), MS (DCI/NH.sub.3) m/z 433
(M+H).sup.+, 450 (M+NH.sub.4).sup.+. Analysis for
C.sub.21H.sub.21FN.sub.2O.sub.5S, Calcd: C, 58.32; H, 4.89; N,
6.48. Found: C, 58.42; H, 5.05; N, 6.43.
EXAMPLE 478
2-(4-Fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1669] The title compound was prepared according to the method of
Example 459, substituting
2-(4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 477) in place
of
2-(3,4-difluoro-phenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone. mp 155-158.degree. C.; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.17 (s, 1H), 7.92 (s, 4H), 7.67
(d, 1H, J=18 Hz), 7.64 (d, 1H, J=18 Hz), 7.49 (s, 2H), 7.38 (d, 1H,
J=18 Hz), 7.35 (d, 1H, J=18 Hz), 4.54 (s, 1H), 4.19 (s, 2H), 1.00
(s, 6H), MS (ESI+): m/z 434 (M+H), 456 (M+Na).sup.+, 889
(2M+Na).sup.+; Analysis for C.sub.20H.sub.20FN.sub.3O.sub.5S,
Calcd: C, 55.42; H, 4.65; N, 9.69. Found: C, 55.64; H, 4.85; N,
9.53.
EXAMPLE 479
2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone
[1670] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3-chloro-4-fluorophenylh- ydrazine in place of
3,4-difluorophenylhydrazine and substituting
2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl
2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol. mp
122-124.degree. C., .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.98
(s, 6H), 3.29 (s, 3H), 4.21 (s, 2H), 4.56 (s, 1H), 7.61 (dd, 1H,
J=7,17 Hz), 7.67 (ddd, 1H, J=2,4,7 Hz), 7.93 (dd, 1H, J=2,7 Hz),
7.98 (d, 2H, J=8 Hz), 8.06 (d, 2H, J=8 Hz), 8.22 (s, 1H); MS
(DCI/NH.sub.3) m/z 465(M--H).sup.-; Anal. Calcd for
C.sub.21H.sub.20ClFN.sub.2O.sub.5S: C 54.02, H 4.32, N 6.00. Found:
C 54.06, H4.57, N 5.95.
EXAMPLE 480
2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1671] The title compound was prepared according to the method of
Example 459, substituting
2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-pro-
poxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 479)
in place of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(me-
thylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 176-178.degree. C.,
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.00 (s, 6H), 4.19 (s,
2H), 4.54 (s, 1H), 7.49 (s, 2H), 7.62 (t, 1H, J=9Hz), 7.66 (ddd,
1H, J=2,5,9 Hz), 7.92 (s, 4.5H), 7.94 (d, 0.5H, J=2 Hz), 8.20 (s,
1H); MS (DCIJNH.sub.3) m/z 468 (M+H)+; 1 Cl, 490 (M+Na).sup.+; 1Cl;
Anal. Calcd for C.sub.20H.sub.19ClFN.sub.2O.sub.5S: C 51.34, H
4.09, N 8.98. Found: C 51.33, H 4.23, N 8.76.
EXAMPLE 481
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone
[1672] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3-chlorophenylhydrazine in place of 3,4-difluorophenylhydrazine and
substituting 2-methyl-1,2-propanediol (prepared by the LAH
reduction of methyl 2-hydroxyisobutyrate) in place of
3-methyl-1,3-butanediol. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.15 (m, 2H), 7.98 (s, 1H), 7.85 (m, 2H), 7.76 (m, 1H), 7.62 (m,
1H), 7.43 (m, 2H), 4.22 (s, 2H), 3.15 (s, 3H), 1.21 (s, 6H); MS
(DCI/NH.sub.3) m/z 449 (M+H).sup.+; Anal. Calcd for
C.sub.21H.sub.21ClN.sub.2O.sub.5S: C 56.18, H 4.72, N 6.24. Found:
C 56.08, H 4.67, N 6.23.
EXAMPLE 482
2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1673] The title compound was prepared according to the method of
Example 459, substituting
2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 481) in place
of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.19 (s, 1H), 7.93 (m, 4H), 7.75 (m, 1H), 7.61-7.48 (m,
5H), 4.53 (s, 2H), 4.20 (s, 3H), 1.00 (s, 6H); MS (ESI-) m/z 448
(M--H).sup.-; Anal. Calcd for C.sub.20H.sub.20CIN.sub.3O.sub.5S: C
53.39, H 4.48, N 9.34. Found: C 53.11, H 4.82, N 9.24.
EXAMPLE 483
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1674] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
2,2,2-trifluoroethylhydr- azine in place of
3,4-difluorophenylhydrazine and substituting
2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl
2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 1.18 (s, 6H), 2.62 (br s, 1H),
3.15 (s, 3H), 4.20 (s, 2H), 4.85 (q, J=9 Hz, 2H), 7.78 (d, J=9 Hz,
2H), 7.85 (s, 1H), 8.08 (d, J=9 Hz, 2H); MS (DCLNH.sub.3) m/z 421
(M+1).sup.+; Analysis calculated for
C.sub.17H.sub.19F.sub.3N.sub.2O.sub.5S: C, 48.57; H, 4.56; N, 6.66.
Found: C, 48.72; H, 4.78; N, 6.56.
EXAMPLE 484
2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1675] The title compound was prepared by the following sequence of
reactions. Mucobromic acid and 2,2,2-trifluoroethylhydrazine
hydrochloride were reacted to provide
2-(2,2,2-trifluoroethyl)-4,5-dibrom- o-3(2H)-pyridazinone following
the procedure in Example 194A. The dibromo-intermediate was reacted
according to the procedure described in Example 194B, substituting
2-methyl-1,2-propanediol in place of methanol, to selectively react
at the 4-position and provide
2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-bromo-3(2H)-p-
yridazinone. This 5-bromo-compound was coupled to
4-[2-(tetrahydropyranyl)- thio]phenylboronic acid (prepared from
THP-protected 4-bromothiophenol and triisopropyl borate) with
K.sub.2CO.sub.3 and PdCl.sub.2(PPh.sub.3).sub.2 in ethanol at
60-65.degree. C. for 40-70 minutes to provide
2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-[2-(tetrah-
ydropyranyl)thio]phenyl]-3(2H)-pyridazinone. This intermediate
THP-sulfide was then converted to the title compound by treatment
with N-chlorosuccinimide (3.5 equivalents) at 0.degree. C. in
THF/H.sub.2O for 15 minutes to an hour followed by addition of
excess ammonium hydroxide at 0.degree. C. and stirring at ambient
temperature for 3 hours. Aqueous work-up and column chromatographic
purification (80:20 pentane/ethyl acetate) provided the title
compound. .sup.1H NMR (300MHz, CDCl.sub.3) .delta. 1.18 (s, 6H),
2.65 (br s, 1H), 4.15 (s, 2H), 4.85 (q, J=9 Hz, 2H), 4.9 (s, 2H),
7.75 (d, J=9 Hz, 2H), 7.85 (s, 1H), 8.05 (d, J=9 Hz, 2H); MS
(DCFNH.sub.3) m/z 422 (M+H)+; Analysis calculated for
C.sub.16H.sub.18F.sub.3N.sub.3O.sub.5S: C, 45.60; H, 4.30; N, 9.97.
Found: C, 45.86; H, 4.63; N, 9.81.
EXAMPLE 485
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone
[1676] The title compound may be prepared according to the method
of Example 483, substituting neopentyl glycol in place of
2-methyl-1,2-propanediol.
EXAMPLE 486
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminos-
ulfonyl)phenyl]-3(2H)-pyyddazinone
[1677] The title compound may be prepared according to the method
of Example 484, substituting neopentyl glycol in place of
2-methyl-1,2-propanediol.
EXAMPLE 487
2-(4-Fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy
-5-[4-(aminosulfonyl)phe- nyl]-3(2H)-pyridazinone
[1678] The title compound may be prepared according to the method
of Example 459, substituting
2-(4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-buto-
xy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 466)
for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 488
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1679] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
2-methyl-1,4-butanediol for 3-methyl-1,3-butanediol, then
separating the regioisomeric products by multiple preparative thin
layer chromatography runs.
EXAMPLE 489
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1680] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
3-chloro-4-fluorophenylh- ydrazine for 3,4-difluorophenylhydrazine
and substituting 2-methyl-1,4-butanediol for
3-methyl-1,3-butanediol, then separating the regioisomeric products
by multiple preparative thin layer chromatography runs.
EXAMPLE 490
2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1681] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
3-chlorophenylhydrazine for 3,4-difluorophenylhydrazine and
substituting 2-methyl-1,4-butanediol for 3-methyl-1,3-butanediol,
then separating the regioisomeric products by multiple preparative
thin layer chromatography runs.
EXAMPLE 491
2-(3,4-Difluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl-
)phenyl]-3(2H)-pyridazinone
[1682] The title compound may be prepared according to the method
of Example 459, substituting
2-(3,4-difluorophenyl)-4-(4-hydroxy-3-methyl-1--
butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example
488) for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 492
2-(3-Chloro-4-fluorophenyl)-4-(4-hydroxy-3-methyl-1-butoxv)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1683] The title compound may be prepared according to the method
of Example 459, substituting
2-(3-chloro-4-fluorophenyl)-4-(4-hydroxy-3-meth-
yl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(Example 489) for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 493
2-(3-Chlorophenyl)-4-(4-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1684] The title compound may be prepared according to the method
of Example 459, substituting
2-(3-chlorophenyl)-4-(4-hydroxy-3-methyl-1-buto-
xy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 490)
for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 494
(S)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxv)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone
[1685] The title compound may be prepared according to the method
of Example 464, substituting
(S)-2-(4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-
-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone for
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 495
(R)-2-(4-Fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfony-
l)-phenyl]-3(2H)-pyridazinone
[1686] The title compound may be prepared according to the method
of Example 465, substituting
(R)-2-(4-fluorophenyl)-4-(3-t-butoxy-2-methyl-1-
-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone for
(R)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 496
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxv)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone
[1687] The title compound may be prepared according to the method
of Example 462, substituting
2-(3-chloro-4-fluorophenyl)-4-hydroxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)--
4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.
EXAMPLE 497
(S)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone
[1688] The title compound can be prepared according to the method
of Example 464, substituting
(S)-2-(3-chloro-4-fluorophenyl)-4-(3-t-butoxy-2-
-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
in place of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 498
(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone
[1689] The title compound may be prepared according to the method
of Example 463, substituting
2-(3-chloro-4-fluorophenyl)-4-hydroxy-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)--
4-hydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.
EXAMPLE 499
(R)-2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(ami-
nosulfonyl)phenyi]-3(2H)-pyridazinone
[1690] The title compound may be prepared according to the method
of Example 464, substituting
(R)-2-(3-chloro-4-fluorophenyl)-4-(3-t-butoxy-2-
-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
in place of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[-
4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 500
(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone
[1691] The title compound may be prepared according to the method
of Example 462, substituting
2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-hydroxy-
-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.
EXAMPLE 501
(S)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxv)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pridazinone
[1692] The title compound may be prepared according to the method
of Example 464, substituting
(S)-2-(3-chlorophenyl)-4-(3-t-butoxy-2-methyl-1-
-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place
of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 502
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfon-
yl phenyl]-3(2H)-pyridazinone
[1693] The title compound can be prepared according to the method
of Example 463, substituting
2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-hydroxy-
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 503
(R)-2-(3-Chlorophenyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone
[1694] The title compound can be prepared according to the method
of Example 464, substituting
(R)-2-(3-chlorophenyl)-4-(3-t-butoxy-2-methyl-1-
-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place
of
(S)-2-(3,4-difluorophenyl)-4-(3-t-butoxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 504
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl
1-propoxy)-5-[4-(methyl- sulfonyl)phenyl]-3(2H)-pyridazinone
[1695] The title compound may be prepared according to the method
of Example 462, substituting
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-h-
ydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.
EXAMPLE 505
(S)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxv-2-methyl-1-propoxy)-5-[4-(aminos-
ulfonyl)phenyl]-3(2H)-pyridazinone
[1696] The title compound may be prepared according to the method
of Example 484, substituting (R)-3-t-butoxy-2-methyl-1-propanol
(Example 462A) in place of 2-methyl-1,2-propanediol. After Suzuki
coupling with 4-[2-(tetrahydropyranyl)thio]phenylboronic acid, the
resulting intermediate is treated with NCS and NH.sub.4OH as in
Example 484. This sulfonamide product is then treated with TFA (as
in Example 462C) to cleave the t-butyl ether and provide the title
compound.
EXAMPLE 506
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone
[1697] The title compound may be prepared according to the method
of Example 463, substituting
2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-h-
ydroxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazinone.
EXAMPLE 507
(R)-2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2-methyl-1-propoxy-5-[4-(aminosu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1698] The title compound may be prepared according to the method
of Example 505, substituting (S)-3-t-butoxy-2-methyl-1-propanol in
place of (R)-3-t-butoxy-2-methyl-1-propanol.
EXAMPLE 508
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone
[1699] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
4-fluorophenylhydrazine in place of 3,4-difluorophenylhydrazine and
substituting neopentyl glycol in place of
3-methyl-1,3-butanediol.
EXAMPLE 509
2-(4-Fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone
[1700] The title compound may be prepared according to the method
of Example 459, substituting
2-(4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1--
propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 510
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsu-
lfonyl)phenyl]-3(2H)-pyridazinone
[1701] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting neopentyl
glycol-in place of 3-methyl-1,3-butanediol (yield: 300 mg, 71%). mp
161-162.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
0.72 (s, 6H), 3.05 (d, J=6 Hz, 2H), 3.30 (s, 3H), 4.19 (s, 2H),
4.54 (t, J=6 Hz, 1H), 7.52 (m, 1H), 7.62 (dd, J=9 Hz, J=9 Hz, 1H),
7.82 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 8.08
(d, J=9 Hz, 2H), 8.21 (s, 1H); MS (DCI/NH.sub.3) m/z 465
(M+H).sup.+; Anal. calcd. for C.sub.22H.sub.22F2N.sub.2O.sub.5S: C,
56.88; H, 4.77; N, 6.03. Found: C, 56.84; H, 4.83; N, 5.99.
EXAMPLE 511
2-(3,4-Difluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(aminosul-
fonyl)phenyl]-3(2H)-pyridazinone
[1702] The title compound may be prepared according to the method
of Example 459, substituting
2-(3,4-difluorophenyl)-4-(3-hydroxy-2,2-dimethy-
l-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 512
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(met-
hylsulfonyl)phenyl]-3(2H)-pyridazinone
[1703] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
3-chloro-4-fluorophenylh- ydrazine in place of
3,4-difluorophenylhydrazine and substituting neopentyl glycol in
place of 3-methyl-1,3-butanediol.
EXAMPLE 513
2-(3-Chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(ami-
nosulfonyl)phenyl]-3(2H)-pyridazinone
[1704] The title compound may be prepared according to the method
of Example 459, 20 substituting
2-(3-chloro-4-fluorophenyl)-4-(3-hydroxy-2,2-
-dimethyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 514
2-(3-Chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pridazinone
[1705] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
3-chlorophenylhydrazine in place of 3,4-difluorophenylhydrazine and
substituting neopentyl glycol in place of
3-methyl-1,3-butanediol.
EXAMPLE 515
2-(3-Chlorophenyl)-4-(3-hydroxv-2,2-dimethyl-1-propoxy)-5-[4-(aminosulfony-
l)phenyl]-3(2H)-pyridazinone
[1706] The title compound may be prepared according to the method
of Example 459, substituting
2-(3-chlorophenyl)-4-(3-hydroxy-2,2-dimethyl-1--
propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone for
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone.
EXAMPLE 516
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-y-
l]phenyl]sulfonyl]acetamide
[1707] A mixture of
2-(3,4-difluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(am-
inosulfonyl)phenyl]-3(2H)-pyridazinone (Example 403, 1 equivalent),
acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3
equivalents), and triethylamine (1.2 equivalents) is stirred at
room temperature for 16 hours. The reaction mixture is partitioned
between ethyl acetate and water. The organic layer is washed with
brine then dried over MgSO.sub.4 and filtered. The filtrate is
concentrated in vacuo to give the title compound.
EXAMPLE 517
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-propoxy)-2H-pyridazin-3-on-5-y-
l]phenyl]-sulfonyl]acetamide, Sodium Salt
[1708] To a suspension of
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-methyl-1-prop-
oxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide (Example 516,
1 equivalent) in absolute ethanol is added a solution of sodium
hydroxide (I equivalent) in absolute ethanol. The mixture is
stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 518
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-o-
n-5-yl]phenyl]sulfonyl]acetamide
[1709] A mixture of
2-(4-fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[-
4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 470, 1
equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 519
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-2H-pyridazin-3-o-
n-5-yl]phenyl]sulfdnyl]acetamide, Sodium Salt
[1710] To a suspension of
N-[[4-[2-(4-Fluorophenyl)-4-(3-hydroxy-3-methyl--
1-butoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide (Example
518, 1 equivalent) in absolute ethanol is added a solution of
sodium hydroxide (1 equivalent) in absolute ethanol. The mixture is
stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 520
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazi-
n-3-on-5-yl]phenyl]sulfonyl]acetamide
[1711] A mixture of
2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy-
)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 459, 1
equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 521
N-[[4-[2-(3,4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1-promoxy)-2H-pyridazi-
n-3-on-5-yl]phenyl]sulfonyl]acetamide, Sodium Salt
[1712] To a suspension of
N-[[4-[2-(3,4-difluorophenyl)-4-(2-hydroxy-2-met-
hyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
(Example 520, 1 equivalent) in absolute ethanol is added a solution
of sodium hydroxide (1 equivalent) in absolute ethanol. The mixture
is stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 522
N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyr-
idazin-3-on-5-yl-phenyl]sulfonyl]acetamide
[1713] A mixture of
2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-pr-
opoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 480,
1 equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 523
N-[[4-[2-(3-Chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyr-
idazin-3-on-5-yl]phenyl]sulfonyl]acetamide, Sodium Salt
[1714] To a suspension of
N-[[4-[2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy--
2-methyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
(Example 522, 1 equivalent) in absolute ethanol is added a solution
of sodium hydroxide (1 equivalent) in absolute ethanol. The mixture
is stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 524
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyridazin-3--
on-5-yl]phenyl]sulfonyl]acetamide
[1715] A mixture of
2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5--
[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 482, 1
equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 525
N-[[4-[2-(3-Chlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-piridazin-3--
on-5-yl]phenylsulfonyl]acetamide, Sodium Salt
[1716] To a suspension of
N-[[4-[2-(3-chlorophenyl)-4-(2-hydroxy-2-methyl--
1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
(Example 525, 1 equivalent) in absolute ethanol is added a solution
of sodium hydroxide (1 equivalent) in absolute ethanol. The mixture
is stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 526
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyrida-
zin-3-on-5-yl]phenyl]sulfonyl]acetamide
[1717] A mixture of
2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propo-
xy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 484, 1
equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 527
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(2-hydroxy-2-methyl-1-propoxy)-2H-pyrida-
zin-3-on-5-yl]phenyl]sulfonyl]acetamide, Sodium Salt
[1718] To a suspension of
N-[[4-[2-(2,2,2-trifluoroethyl)-4-(2-hydroxy-2-m-
ethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
(Example 526, 1 equivalent) in absolute ethanol is added a solution
of sodium hydroxide (1 equivalent) in absolute ethanol. The mixture
is stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 528
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-propoxy)-2H-py-
ridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
[1719] A mixture of
2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-dimethyl-1-p-
ropoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example
486, 1 equivalent), acetic anhydride (3 equivalents),
4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2
equivalents) is stirred at room temperature for 16 hours. The
reaction mixture is partitioned between ethyl acetate and water.
The organic layer is washed with brine then dried over MgSO.sub.4
and filtered. The filtrate is concentrated in vacuo to give the
title compound.
EXAMPLE 529
N-[[4-[2-(2,2,2-Trifluoroethyl)-4-(3-hydroxv-2,2-dimethyl-1-propoxy)-2H-py-
ridazin-3-on-5-yl]phenyl]sulfonyl]acetamide, Sodium Salt
[1720] To a suspension of
N-[[4-[2-(2,2,2-trifluoroethyl)-4-(3-hydroxy-2,2-
-dimethyl-1-propoxy)-2H-pyridazin-3-on-5-yl]phenyl]sulfonyl]acetamide
(Example 528, 1 equivalent) in absolute ethanol is added a solution
of sodium hydroxide (1 equivalent) in absolute ethanol. The mixture
is stirred at room temperature for 10 minutes and concentrated in
vacuo. The residue is dried at high vacuum to provide the title
compound.
EXAMPLE 530
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl]-3(2H)-pyridazinone
[1721] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
2,2,2-trifluoroethylhydr- azine in place of
3,4-difluorophenylhydrazine. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 1.25 (s, 6H), 1.88 (t, 2H, J=9 Hz), 2.35 (br s, 1H), 3.15
(s, 3H), 4.55 (t, 2H, J=7.5 Hz), 4.85 (q, 2H, J=9 Hz), 7.75(d, 2H
J=9 Hz), 7.65 (s, 1H), 8.05 (d, 2H J=9 Hz); MS (DCI/NH.sub.3) M/z
435 (M+H).sup.+; Analysis calculated for
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.- 5S: C, 49.77; H, 4.87; N,
6.45. Found: C, 49.71; H, 4.90; N, 6.45.
EXAMPLE 531
2-(2,2,2-Trifluoroethyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(aminosulfon-
yl)phenyl]-3(2H)-pyridazinone
[1722] The title compound was prepared according to the method of
Example 484, substituting 3-methyl-1,3-butanediol in place of
2-methyl-1,2-propanediol. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.85 (t, 2H, J=6 Hz), 2.78 (s, 6H), 4.55 (t, 2H, J=6 Hz), 4.85 (q,
2H, J=9 Hz), 5.3 (s, 2H), 7.68 (d, 2H J=9 Hz), 7.85 (s, 1H), 8.05
(d, 2H J=9Hz), 8.45 (br s, 1H); MS (DC/NH.sub.3) m/z 436 (M+H)+;
Analysis calculated for C.sub.17H.sub.20F.sub.3N.sub.3O.sub.5S: C,
46.89; H, 4.62; N, 9.65. Found: C, 47.18; H, 4.93; N, 9.86.
EXAMPLE 532
2-(3,4-Dichlorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfony-
l)phenyl]-3(2H)-pyridazinone
[1723] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3,4-dichlorophenylhydraz- ine in place of
3,4-difluorophenylhydrazine. mp 118-120.degree. C.; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.25 (s, 6H), 1.92 (t, J=6 Hz, 2H),
3.13 (s, 3H), 4.07 (t, J=6Hz, 2H), 7.58 (d, J=9 Hz, 1H), 7.59 (dd,
J=9 Hz, J=2 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.87 (d, J=2 Hz, 1H),
7.84 (s, 1H), 8.19 (d, J=9 Hz, 2H); MS (DCI/NH.sub.3) m/z 497
(M+H).sup.+. Anal. calcd. for
C.sub.22H.sub.22Cl.sub.2N.sub.2O.sub.5S: C, 53.12; H, 4.45; N,
5.63. Found: C, 52.80; H, 4.53; N, 5.35.
EXAMPLE 533
2-[(3-Trifluoromethyl)phenyl]-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone
[1724] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3-(trifluoromethyl)pheny- lhydrazine in place of
3,4-difluorophenylhydrazine and substituting
2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl
2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol (yield:
200 mg, 75%). mp 143-144.degree. C.; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.20 (s, 6H), 3.13 (s, 3H), 4.11 (s, 2H), 7.64
(m, 2H), 7.84 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 1H), 7.97 (d, J=9
Hz, 1H), 7.98 (s, 1H), 8.13 (d, J 9 Hz, 2H); MS (DCI/NH.sub.3) m/z
483 (M+H).sup.+; Anal. calcd. for
C.sub.22H.sub.21F.sub.3N.sub.2O.sub.5S0.5C.sub.4H.sub.10O.sub.2: C,
54.75; H, 4.79; N, 5.32. found: C, 55.15; H, 4.77; N, 5.09.
EXAMPLE 534
2-(3,4-Dichlorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pridazinone
[1725] The title compound was prepared according to the sequence of
reactions described in Example 471, substituting
3,4-dichlorophenylhydraz- ine in place of
3,4-difluorophenylhydrazine and substituting
2-methyl-1,2-propanediol (prepared by the LAH reduction of methyl
2-hydroxyisobutyrate) in place of 3-methyl-1,3-butanediol (yield:
1.7 g, 75%). mp 108-110.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.96 (s, 6H), 3.38 (s, 3H), 4.20 (s, 2H),
4.52 (s, 1H), 7.68 (dd, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz, 1H),
7.78 (d, J=9 Hz, 2H), 7.79 (d, J=3 Hz, 1I1), 8.04 (d, J=9 Hz, 2H),
8.22 (s, 1H); MS (DCI/NH.sub.3) m/z 483 (M+H).sup.+; Anal. calcd.
for C.sub.21H.sub.20Cl.sub.2N.sub.2O.sub.5S: C, 52.18; H, 4.17; N,
5.79. Found: C, 52.41; H, 4.22; N, 5.53.
EXAMPLE 535
(R,S)-2-(4-Fluorophenyl)-4-(3-hydroxy-1-butoxv)-5-[4-(methylsulfonyl)pheny-
l]-3(2H)-pyridazinone
[1726] The title compound was prepared by reacting the product from
Example 468,
2-(4-fluorophenyl)-4-(3-oxo-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone (20 mg, 0.05 mmol) in methanol (5 nL) at
0.degree. C. with sodium borohydridre (4 mg, 0.1 mmol). The
reaction mixture was allowed to warn to room temperature, then
volatile components were removed under reduced pressure. The
residue was treated with water and 10% aqueous citric acid solution
was added to bring the pH to 7. The resulting precipitate was
collected by filtration and dried to provide the title compound as
an off-white solid (11 mg, 50.9%). mp 63-66.degree. C.; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.21 (d, J=6 Hz, 3H), 1.60-1.73 (m,
1H), 1.84-1.96 (m, 1H), 3.14(s, 3H), 4.01-4.14 (m, 1H), 4.20-4.28
(m, 1H), 4.64 (dt, J=3 Hz, J=9 Hz, 1H), 7.20 (t, J=9 Hz, 2H),
7.43-7.55 (m, 2H), 7.81 (d, J=9 Hz, 2H), 7.96 (s, 1H), 8.10 (d, J=9
Hz, 2H); MS (DCI/NH.sub.3) m/z 433 (M+H).sup.+.
EXAMPLE 536
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone
EXAMPLE 536A
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-chloro-3(2H)-pyridazinone
[1727] To a stirred, room temperature solution of n-butanol (0.81
g, 10.93 mmol, 1.1 equiv.) in THF (20 mL) was slowly added 1.0 M
sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol, 1.2
equiv.). The reaction mixture was stirred for 0.5 hours, then it
was transferred to a solution of
2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone (2.88 g,
10.4 mmol, 1.0 equiv.) in THF (80 mL). The resulting reaction
mixture was stirred for 0.5 hours at room temperature to provide
the title compound (2.5 g, 79.4%).
EXAMPLE 536B
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridaz-
inone
[1728] A slurry of palladium(II) acetate (9.0 mg, 0.04 mmol),
triphenylphosphine (21.0 mg, 0.08 mmol) and isopropanol (1 mL) was
stirred at room temperature for 10 minutes. To this mixture was
added
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-chloro-3(2H)-pyridazinone
(Example 536A, 0.63 g, 2 mmol), 4-(methylthio)benzeneboronic acid
(0.403 mg, 2.4 mmol) and isopropanol (4 mL). A solution of
K.sub.3PO.sub.4 (0.66 g, 3 mmol) in water (1 mL) was also added and
the resulting reaction mixture was deoxygenated by bubbling
nitrogen through it for 2 minutes. The reaction mixture was then
stirred under a nitrogen atmosphere for 15 hours at 70.degree. C.
The reaction mixture was then cooled to room temperature and water
(15 mL) was added to provide a precipitate. The precipitate was
collected by filtration and rinsed with water then hexane to give
after drying the title compound (0.77 g, 95%).
EXAMPLE 536C
2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyr-
idazinone
[1729] To a solution of
2-(3,4-difluorophenyl)-4-(1-butoxy)-5-[4-(methylth-
io)phenyl]-3(2H)-pyridazinone (Example 536B, 0.6 g, 1.5 mmol) in
acetone (10 mL) at -20.degree. C. was slowly added over 5 minutes a
32% solution of peracetic acid in acetic acid (3.75 mmol). The
reaction mixture was allowed to warm to room temperature at which
point water (30 mL) was added. Stirring was continued for 0.5
hours, then the precipitate was collected by filtration and washed
with water to provide the title compound (0.61 g, 94%). mp
129-132.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.88
(t, J=6 Hz, 3H), 1.20-1.36 (m, 2H), 1.54-1.68 (m, 2H), 3.14 (s,
3H), 4.52 (t, J=6 Hz, 2H), 7.25-7.34 (m, 1H), 7.44-7.50 (m, 1H),
7.55-7.62 (m, 2H), 7.77-7.82 (m, 2H), 7.92 (s, 1H), 8.05-8.10 (m,
2H); MS (DCI/NH.sub.3) m/z 435 (M+H).sup.+; Anal. calcd. for
C.sub.21H.sub.20F.sub.2N.sub.2O.sub.4S: C, 58.06; H, 4.64; N, 6.44.
Found: C, 57.82; H, 4.53; N, 6.31.
EXAMPLE 537
2-(3-Chloro-4-fluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)ph-
enyl]-3(2H)-pyridazinone
[1730] The title compound was prepared according to the method of
Example 536 substituting 2-methyl-1-propanol in place of n-butanol
and substituting
2-(3-chloro-4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone for
2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone in Example
536A. The resulting intermediate was subjected to the conditions in
Example 536B, substituting the catalyst PdCl.sub.2(PPh.sub.3).sub.2
in place of the palladium(II) acetate-triphenylphosphine slurry.
The resulting intermediate was then oxidized by the method of
Example 536C to provide the title compound (0.58 g, 92%). mp
116-120.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.86
(d, J=6 Hz, 6H), 1.85-1.94 (m, 1H), 3.14 (s, 3H), 4.32 (d, J=6 Hz,
2H), 7.24-7.30 (m, 1H), 7.56-7.62 (m, 1H), 7.77-7.83 (m, 3H), 7.86
(m, 1H), 7.92 (s, 1H), 8.05-8.10 (m, 2H); MS (DCI/NH.sub.3) m/z 451
(M+H).sup.+; Anal. calcd. for C.sub.21H.sub.20ClFN.sub.2O.sub.4S:
C, 55.94; H, 4.47; N, 6.21. Found: C, 55.81; H, 4.38; N, 6.18.
EXAMPLE 538
2-(3-Chloro-4-fluorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1731] The title compound was prepared according to the method of
Example 536 substituting 3-methyl-1-butanol in place of n-butanol
to provide the title compound (0.62 g, 92%). mp 148-152.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6 Hz, 6H),
1.50-1.70 (m, 3H), 3.14 (s, 3H), 4.54 (t, J=6 Hz, 2H), 7.24-7.30
(m, 1H), 7.56-7.62 (m, 1H), 7.77-7.83 (m, 3H), 7.86 (m, 1H), 7.92
(s, 1H), 8.05-8.10 (m, 2H); MS (DCI/NH.sub.3) m/z 465 (M+H).sup.+;
Anal. calcd. for C.sub.22H.sub.22ClFN.sub.2O.sub.4S: C, 56.83; H,
4.77; N, 6.02. Found: C, 56.70; H, 4.77; N, 6.11.
EXAMPLE 539
2-(3,4-Dichlorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1732] The title compound was prepared according to the method of
Example 536 substituting 2-methyl-1-propanol in place of n-butanol
and substituting
2-(3,4-dichlorophenyl)-4,5-dibromo-3(2H)-pyridazinone for
2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to provide
the title compound (0.63 g, 98%). mp 127-129.degree. C.; .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6 Hz, 6H), 1.82-1.94
(m, 1H), 3.14 (s, 3H), 4.30 (d, J=6 Hz, 2H), 7.56-7.62 (m, 2H),
7.77-7.82 (m, 2H), 7.86 (m, 1H), 7.92 (s, 1H), 8.06-8.10 (m, 2H);
MS (DCI/NH.sub.3) m/z 467 (M+H).sup.+; Anal. calcd. for
C.sub.21H.sub.20Cl.sub.2N.sub.2O.sub.4S: C, 53.97; H, 4.31; N,
5.99. Found: C, 53.82; H, 4.29; N, 5.89.
EXAMPLE 540
2-(3,4-Dichlorophenyl)-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]--
3(2H)-pyridazinone
[1733] The title compound was prepared according to the method of
Example 536 substituting 3-methyl-1-butanol in place of n-butanol
to provide the title compound (0.63 g, 98%). mp 130-134.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.86 (d, J=6 Hz, 6H),
1.50-1.68 (m, 3H), 3.14 (s, 3H), 4.51 (t, J=6 Hz, 2H), 7.56-7.62
(m, 2H), 7.77-7.82 (m, 2H), 7.86 (m, 1H), 7.92 (s, 1H), 8.06-8.10
(m, 2H); MS (DCI NH.sub.3) m/z 481 (M+H).sup.+; Anal. calcd. for
C.sub.22H.sub.22Cl.sub.2N.sub.2O.sub.4S: C, 54.89; H, 4.61; N,
5.82. Found: C, 54.72; H, 4.56; N, 5.73.
EXAMPLE 541
2-(3,4-Difluorophenyl)-4-(4-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-
-3(2H)-pyridazinone
[1734] The title compound was prepared according to the method of
Example 536 substituting 1,4-butanediol in place of n-butanol and
substituting 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone
for 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to
provide the title compound (0.61 g, 95%). mp 110-113.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.52-1.60 (m, 2H),
1.72-1.82 (m, 2H), 3.15 (s, 3H), 3.62 (t, J=6 Hz, 2H), 4.52 (t, J=6
Hz, 2H), 7.25-7.34 (m, 1H), 7.44-7.50 (m, 1H), 7.55-7.62 (m, 1H),
7.77-7.82 (m, 2H), 7.92 (s, 1H), 8.05-8.10 (m, 2H); MS
(DCI/NH.sub.3) m/z 468 (M+H).sup.+; Anal. calcd. for
C.sub.21H.sub.20F.sub.2N.sub.2O.sub.5S: C, 55.99; H, 4.48; N, 6.22.
Found: C, 55.79; H, 4.41; N, 5.96.
EXAMPLE 542
2-[3-(Trifluoromethyl)phenyl]-4-(2-methyl-1-propoxy)-5-[4-(methylsulfonyl)-
phenyl]-3(2H)-pyridazinone
[1735] The title compound was prepared according to the method of
Example 536 substituting 2-methylpropanol for n-butanol and
substituting
2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in
place of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to
provide the title compound (0.58 g, 90%). mp 125-127.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.84 (d, J=6 Hz, 6H),
1.86-1.98 (m, 1H), 3.14 (s, 3H), 4.30 (d, J=6 Hz, 2H), 7.60-7.70
(m, 2H), 7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m, 2H),
8.06-8.12 (m, 2H); MS (DCI/NH.sub.3) m/z 484 (M+H).sup.+; Anal.
calcd. for C.sub.22H.sub.21F.sub.3N.sub.2O.sub.4S: C, 56.65; H,
4.54; N, 6.00. Found: C, 56.49; H, 4.56; N, 5.81.
EXAMPLE 543
2-[3-(Trifluoromethyl)phenyl]-4-(3-methyl-1-butoxy)-5-[4-(methylsulfonyl)p-
henyl]-3(2H)-pyridazinone
[1736] The title compound was prepared according to the method of
Example 536 substituting 3-methyl-1-butanol in place of n-butanol
and substituting
2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in
place of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to
provide the title compound (0.53 g, 74%). mp 82-85.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.95 (d, J=6 Hz, 6H),
1.52-1.64 (m, 3H), 3.14 (s, 3H), 4.52 (d, J=6 Hz, 2H), 7.60-7.70
(m, 2H), 7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m, 2H),
8.06-8.12 (m, 2H); MS (DCI/NH.sub.3) m/z 498 (M+H).sup.+; Anal.
calcd. for C.sub.23H.sub.23F.sub.3N.sub.2O.sub.4S: C, 57.49; H,
4.82; N, 5.83. Found: C, 57.47; H, 4.94; N, 5.60.
EXAMPLE 544
2-[3-(Trifluoromethyl)phenyl]-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl-
sulfonyl)phenyl]-3(2H)-pyridazinone
[1737] The title compound was prepared according to the method of
Example 536 substituting 3-methyl-1,3-butanediol in place of
n-butanol and substituting
2-[3-(trifluoromethyl)phenyl]-4,5-dibromo-3(2H)-pyridazinone in
place of 2-(3,4-difluorophenyl)-4,5-dichloro-3(2H)-pyridazinone to
provide the title compound (1.2 g, 75%). mp 90-93.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.14 (s, 6H), 1.90 (t,
J=6 Hz, 2H), 3.14 (s, 3H), 4.58 (t, J=6 Hz, 2H), 7.60-7.70 (m, 2H),
7.79-7.84 (m, 2H), 7.94 (s, 1H), 7.88-7.98 (m, 2H), 8.06-8.12 (m,
2H); MS (DCI/NH.sub.3) m/z 514 (M+H).sup.+; Anal. calcd. for
C.sub.23H.sub.23F.sub.3N.sub.2O.sub.5S: C, 55.64; H, 4.67; N, 5.64.
Found: C, 56.01; H, 4.83; N, 5.06.
EXAMPLE 545
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
EXAMPLE 545A
Ethyl (R)-3-(tert-butyldimethylsiloxy)butanoate
[1738] To a stirred, room temperature solution of ethyl
(R)-3-hydroxybutanoate (5.00 g, 37.8 mmol) and
tert-butyldimethylsilyl chloride (6.85 g, 45.5 mmol) in DMF (90 mL)
was added imidazole (3.87 g, 56.9 mmol). This reaction mixture was
stirred at room temperature for 18 hours. The reaction mixture was
partitioned between hexane (300 mL) and water (100 mL). The organic
layer was washed with water (2.times.100 mL) then dried
(MgSO.sub.4) and filtered. The filtrate was concentrated under
reduced pressure to give the title compound.
EXAMPLE 545B
(R)-3-(tert-Butldimethylsiloxy)-1-butanol
[1739] The crude product from Example 545A (.about.37 mmol) was
dissolved in dichloromethane (100 mL). To this stirred solution,
chilled to -78.degree. C., was added dropwise a 1M solution of
diisobutylaluminum hydride in dichloromethane (185 mL, 185 mmol).
The reaction mixture was stirred at -78.degree. C. for two hours,
then it was allowed to warm to -30.degree. C. and stirred an
additional 0.5 hours. Methanol was then added carefully at
-20.degree. C. to quench any remaining hydride. The reaction
mixture was then diluted with methyl tert-butylether (200 mL) and
washed with aqueous sodium tartrate solution (4.times.100 mL) and
brine (2.times.100 mL). The organic layer was dried (MgSO.sub.4)
and filtered. The filtrate was concentrated under reduced pressure
to give the crude title compound (6.3 g, 83%).
EXAMPLE 545C
(R)-2-(3,4-Difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxyl-5-bro-
mo-3(2H)-pyridazinone
[1740] To a stirred, 0.degree. C. solution of the product from
Example 545B (3.4 g, 10 mmol) in THF (20 mL) was added 1M sodium
bis(trimethylsilyl)amide in THF (12 iL, 12 mmol). The reaction
mixture was stirred at room temperature for 0.5 hours, then it was
transferred to a stirred, -30.degree. C. solution of
2-(3,4-difluorophenyl)-4,5-dibromo-- 3(2H)-pyridazinone (3.66 g, 10
mmol) in THF (100 mL). The reaction mixture was stirred at
-30.degree. C. for 1 hour, then overnight while warming to room
temperature. The reaction was quenched with saturated aqueous
ammonium chloride solution (100 mL) and extracted with ethyl
acetate (2.times.100 mL). The organic layer was washed with brine
(2.times.20 mL), then dried (MgSO.sub.4), and filtered. The
filtrate was concentrated under reduced pressure and the residue
was purified by column chromatography (silica gel, 90:10
hexane/ethyl acetate) to provide the title intermediate (2.5 g,
51%).
EXAMPLE 545D
(R)-2-(3,4-Difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxyl-5-[4--
(methylthio)phenyl]-3(2H)-pyridazinone
[1741] Under a nitrogen atmosphere, a mixture of the product from
Example 545C (0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid
(0.4 g, 2.4 mmol), K.sub.3PO.sub.4 (1.2 g, 6 mmol),
PdCl.sub.2(PPh.sub.3).sub.2 (28 mg, 0.04 mmol), isopropanol (9 mL),
and water (1 mL) was stirred at 70.degree. C. for 4 hours. The
reaction mixture was then cooled to room temperature, water (30 mL)
was added and stirring was continued for 2 hours. The crude black
precipitate was collected by filtration then washed with water (10
mL) and hexane (10 mL). This title intermediate was used without
further purification in the following oxidation/deprotection
step.
EXAMPLE 545E
(R)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1742] A stirred solution of the product from step Example 545D
(.about.2 mmol) in acetone (10 mL) was chilled to 0.degree. C. To
this was added 32% peracetic acid in acetic acid solution (1.42 mL,
6 mmol). The reaction mixture was stirred for 1 hour while warming
to room temperature. At this point the oxidation was complete, but
some of the products hydroxy group was still silylated so 1M
tetrabutylammonium fluoride in THF (4 mL, 4 mmol) was added and
stirring was continued for 0.5 hours. The reaction mixture was then
treated with 5% aqueous sodium thiosulfate solution (30 mL) for 2
hours. The precipitated product was collected by filtration, washed
with water (10 mL) and hexane (10 mL). The solid was stirred in
isopropanol (5 mL) for 6 hours then collected by filtration and
dried to provide the title compound (0.78 g, 87%). mp
126-129.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.22
(d, J=6 Hz, 3H), 1.62-1.74 (m, 1H), 1.84-1.94 (m, 1H), 3.16 (s,
3H), 3.30 (s br, 1H), 4.00-4.10 (m, 1H), 4.20-4.30 (m, 1H), 4.63
(td, J=9.6 Hz, J=4 Hz, 1H), 7.25-7.34 (m, 1H), 7.46-7.52 (m, 1H),
7.56-7.64 (m, 1H), 7.78-7.84 (m, 2H), 7.97 (s, 1H), 8.06-8.12 (m,
2H); MS (DCI/NH.sub.3) m/z 468 (M+NH.sub.4).sup.+.
EXAMPLE 546
(S)-2-(3,4-Difluorophenyl)-4-(3-hydroxy-1-butoxy)-5-[4-(methylsulfonyl)phe-
nyl]-3(2H)-pyridazinone
[1743] The title compound was prepared according to the method of
Example 545 substituting ethyl (S)-3-hydroxybutanoate in place of
ethyl (R)-3-hydroxybutanoate (0.72 g, 80%). mp 128-130.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.22 (d, J=6 Hz, 3H),
1.62-1.74 (m, 1H), 1.84-1.94 (m, 1H), 3.16 (s, 3H), 3.30 (s br,
1H), 4.00-4.10 (m, 1H), 4.20-4.30 (m, 1H), 4.63 (td, J=9.6 Hz, J=4
Hz, 1H), 7.25-7.34 (m, 1H), 7.46-7.52 (m, 1H), 7.56-7.64 (m, 1H),
7.78-7.84 (m, 2H), 7.97 (s, 1H), 8.06-8.12 (m, 2H); MS
(DCI/NH.sub.3) m/z 468 (M+NH.sub.4).sup.+.
EXAMPLE 547
(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone
EXAMPLE 547A
Methyl (S)-2-hydroxy-3-methylbutanoate
[1744] The title compound (CAS Registry # [17392-84-6]) is prepared
by literature procedures (e.g. Journal of Organic Chemistry, (1994)
59(7), 1933-1936).
EXAMPLE 547B
Methyl (S)-2-(tert-butyldimethylsiloxy)-3-methylbutanoate
[1745] The title compound is prepared by the method of Example
545A, substituting methyl (S)-2-hydroxy-3-methylbutanoate (Example
547A) in place of ethyl (R)-3-hydroxybutanoate.
EXAMPLE 547C
(S)-2-(tert-Butyldimethylsiloxy)-3-methyl-1-butanol
[1746] The title compound is prepared by the method of Example
545B, substituting methyl
(S)-2-(tert-butoxydimethylsiloxy)-3-methylbutanoate (Example 547B)
in place of ethyl (R)-3-(tert-butyldimethylsiloxy)butanoat- e
(Example 545A).
EXAMPLE 547D
(S)-2-(3
4-Difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-methYl-1-buto-
xyl-5-bromo-3(2H)-pyridazinone
[1747] The title compound is prepared by the method of Example
545C, substituting
(S)-2-tert-butyldimethylsiloxy-3-methyl-1-butanol (Example 547C) in
place of (R)-3-(tert-butyldimethylsiloxy)-1-butanol (Example
545B).
EXAMPLE 547E
2-(3,4-Difluorophenyl)-4-[(S)-2-(tert-butyldimethylsiloxy)-3-methyl-1-buto-
xyl -5-[4-methylthio)phenyl]3(2H)-pyridazinone
[1748] The title intermediate is prepared by the method of Example
545D, substituting
(S)-2-(3,4-difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-
-methyl-1-butoxy]-5-bromo-3(2H)-pyridazinone (Example 547D) in
place of
(R)-2-(3,4-difluorophenyl)-4-[3-(tert-butyldimethylsiloxy)-1-butoxy]-5-br-
omo-3(2H)-pyridazinone (Example 545C).
EXAMPLE 547F
(S)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1749] The title compound is prepared by the method of Example
545E, substituting
(S)-2-(3,4-difluorophenyl)-4-[2-(tert-butyldimethylsiloxy)-3-
-methyl-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone
(Example 547E) in place of
(R)-2-(3,4-difluorophenyl)-4-[3-(tert-butyldimethylsilo-
xy)-1-butoxy]-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (Example
545D).
EXAMPLES 548-558
[1750] The following compounds may be prepared according to the
sequence of reactions described in Example 547, substituting the
appropriate 2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.
1 Example Number X 548 4-F 549 4-Cl 550 3-F 551 3-Cl 552 3-Br 553
3-CF.sub.3 554 3-C1-4-F 555 4-Cl-3-F 556 3,4-di-Cl 557
4-F-3-CF.sub.3 558 3-Br-4-F
EXAMPLE 559
(R)-2-(3,4-Difluorophenyl)-4-(2-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsul-
fonyl)phenyl]-3(2H)-pyridazinone
[1751] The title compound may be prepared according to the sequence
of reactions described in Example 547, substituting methyl
(R)-2-hydroxy-3-methyl-butanoate [17392-84-6] prepared as described
in (Tetrahedron, 1995, 51(38), 10513-10522) in place of methyl
(S)-2-hydroxy-3-methylbutanoate.
EXAMPLES 560-570
[1752] The following compounds can be prepared according to the
sequence of reactions described in Example 559, substituting the
appropriate 2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.
2 Example Number X 560 4-F 561 4-Cl 562 3-F 563 3-Cl 564 3-Br 565
3-CF.sub.3 566 3-Cl-4-F 567 4-Cl-3-F 568 3,4-di-Cl 569
4-F-3-CF.sub.3 570 3-Br-4-F
EXAMPLE 571
2-(3,4Difluorophenyl-4-[(S)-2,3-dihydroxy-3-methyl-1-butoxyl
-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
[1753] The title compound may be prepared according to the sequence
of reactions described in Example 547, substituting methyl
(R)-2,3-dihydroxy-3-methylbutanoate [37504-90-8] (Australian
Journal of Chemistry, (1986) 39(11), 1907-1909) in place of methyl
(S)-2-hydroxy-3-methylbutanoate.
EXAMPLES 572-582
[1754] The following compounds may be prepared according to the
sequence of reactions described in Example 571, substituting the
appropriate 2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.
3 Example Number X 572 4-F 573 4-Cl 574 3-F 575 3-Cl 576 3-Br 577
3-CF.sub.3 578 3-Cl-4-F 579 4-Cl-3-F 580 3,4-di-Cl 581
4-F-3-CF.sub.3 582 3-Br-4-F
EXAMPLE 583
2-(3,4-Difluorophenyl)-4-[(R)-2,3-dihydroxy-3-methyl-1-butoxyl-5-[4-(methy-
lsulfonyl))phenyl]-3(2H)-pyridazinone
[1755] The title compound may be prepared according to the sequence
of reactions described in Example 547, substituting methyl
(S)-2,3-dihydroxy-3-methylbutanoate [75347-92-1] (Journal of
Organic Chemistry, 1980, 45(25), 5218-5220) in place of methyl
(S)-2-hydroxy-3-methylbutanoate.
EXAMPLES 584-594
[1756] The following compounds may be prepared according to the
sequence of reactions described in Example 571, substituting the
appropriate 2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.
4 Example Number X 584 4-F 585 4-Cl 586 3-F 587 3-Cl 588 3-Br 589
3-CF.sub.3 590 3-Cl-4-F 591 4-Cl-3-F 592 3,4-di-Cl 593
4-F-3-CF.sub.3 594 3-Br-4-F
EXAMPLE 595
2-(3,4-Difluorophenyl)-4-(4-hydroxy-4-methyl-1-pentyloxy)-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1757] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
4-methyl-1,4-pentanediol [1462-10-8] (Journal of Organic Chemistry,
(1972) 37, 3310-3322) in place of methyl
3-methyl-1,3-butanediol.
EXAMPLE 596-606
[1758] The following compounds may be prepared according to the
sequence of reactions described in Example 471, substituting
4-methyl-1,4-pentanediol [1462-10-8] (Journal of Organic Chemistry,
(1972) 37, 3310-3322) in place of methyl 3-methyl-1,3-butanediol
and substituting the appropriate
2-(X-phenyl)-4,5-dibromo-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone.
5 Example Number X 596 4-F 597 4-Cl 598 3-F 599 3-Cl 600 3-Br 601
3-CF.sub.3 602 3-Cl-4-F 603 4-Cl-3-F 604 3,4-di-Cl 605
4-F-3-CF.sub.3 606 3-Br-4-F
EXAMPLE 607
2-(3,4-Difluorophenyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxyj-5-[4-(me-
thylsulfonpl)phenyl]-3(2H)-pyridazinone
[1759] The title compound may be prepared by a
carbodiimide-mediated coupling (method described in Angew. Chem.,
Int. Ed. Engl., (1979)18(9), 686)
of2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methy-
lsulfonyl)phenyl]-3(2H)-pyridazinone (Example 471) with an
N-protected-glycine (such as N-Fmoc-glycine); followed by an amino
group deprotection step (such as treatment at room temperature with
tetrabutylammonium fluoride in DMF).
EXAMPLES 608-618
[1760] The following compounds may be prepared by the method of
Example 607, substituting the appropriate
2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-bu-
toxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 471).
6 Example Number X 608 4-F 609 4-Cl 610 3-F 611 3-Cl 612 3-Br 613
3-CF.sub.3 614 3-Cl-4-F 615 4-Cl-3-F 616 3,4-di-Cl 617
4-F-3-CF.sub.3 618 3-Br-4-F
EXAMPLE 619
2-(3,4-Difluorophenyl)-4-[3-{[(2R,3R)-3-carboxy-2,3-dihydroxyjpropanoyl]ox-
y}-3-meethylbutoxy]-3-methyl-1-butoxy]-5-[4-(methylsulfopyl)phenyl]-3(2H)--
pyridazinone
[1761] The title compound may be prepared in a manner similar to
that described in J. Chem. Soc., Chem Commun., (1993) 410-412,
reacting
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 471) with an appropriately
protected L-tartaric acid diester (such as below), followed by
deprotection.
EXAMPLE 619A
Dibenzyl
(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}butanedioate
[1762] The alcohol groups of (+)-dibenzyl-L-tartrate can be
protected as the tert-butyldiphenylsilyl ethers by standard methods
as described in (Greene, T W, Wuts, P G M; Protective Groups in
Organic Synthesis; 3.sup.rd Edition; 1999; John Wiley & Sons,
Inc.; NY, N.Y.; 141-144) to provide the title intermediate.
EXAMPLE 619B
(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}butanedioic Acid
[1763] The dibenzyl ester of Example 619A can be cleaved by
standard hydrogenolysis procedures as described in (Greene, T W,
Wuts, P G M; Protective Groups in Organic Synthesis; .sub.3rd
Edition; 1999; John Wiley & Sons, Inc.; NY, N.Y.; 415-419) to
provide the title intermediate.
EXAMPLE 619C
(3R,4R)-3,4-bis{[tert-butyl(dilphenyl)silyl]oxy}dihydro-2,5-furandione
[1764] Example 619B may be reacted by standard methods as described
in (Journal of Organic Chemistry, (1987) 52(3), 455-457) with
trifluoroacetic anhydride to provide the title intermediate.
EXAMPLE 619D
(2R,3R)-2,3-bis{[tert-butyl(diphenyl)siyl]oxy}-4-methoxy-4-oxobutanoic
Acid
[1765] Example 619C may be reacted with anhydrous methanol by
standard methods as described in (Organic Syntheses, Collective
Volume III, (1955) 169-171) to provide the title intermediate.
EXAMPLE 619E
1-isopropenyl 4-methyl
(2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]oxy}buta- nedioate
[1766] Example 619D may be reacted with isopropenyl acetate in the
presence of catalytic bor d ribn tuoride etherate and mercury()
acetate as described in (J. Chem. Soc., Chem Commun., (1993)
410-412) to provide the title intermediate.
EXAMPLE 619F
2-(3,4-Difluorophenyl)-4-{3-[((2R,3R)-2,3-bis{[tert-butyl(diphenyl)silyl]o-
xy}-4-methoxy-4-oxobutanoyl)oxy]-3-methylbutoxy}-5-[4-(methylsulfonyl)phen-
yl]-3(2H)-pyridazinone
[1767] Example 619E maybe coupled to
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-
-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone
(Example 471) in the presence of catalytic 4-toluene sulfonic acid
by the method described in (J. Chem. Soc., Chem Commun., (1993)
410-412) to provide the title intermediate.
EXAMPLE 619G
2-(3,4-Difluorophenyl)-4-[3-{[(2R,3R)-3-carboxv-2,3-dihydroxypropanoyl]oxy-
}-3-methylbutoxy]-3-methyl-1-butoxyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-py-
ridazinone
[1768] Example 619F can be treated with aqueous sodium hydroxide in
methanol as described in (J. Chem. Soc., Chem Commun., (1993)
410-412) to provide the title compound.
EXAMPLE 620-630
[1769] The following compound may be prepared by the method of
Example 619F, substituting the appropriate
2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-b-
utoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 471), followed by treatment
with aqueous sodium hydroxide in methanol as in Example 619G.
7 Example Number X 620 4-F 621 4-Cl 622 3-F 623 3-Cl 624 3-Br 625
3-CF.sub.3 626 3-Cl-4-F 627 4-Cl-3-F 628 3,4-di-Cl 629
4-F-3-CF.sub.3 630 3-Br-4-F
EXAMPLE 631
3-({2-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro--
4-pyridazinyl}oxy)-1,1-dimethylpropyl Dihydrogen Phosphate
[1770] The title compound may be prepared as described in
(Kosolapoff, G M and Maier, L, Organic Phosphorus Compounds, (1973)
Volume 6, John Wiley & Sons, NY, N.Y.); such as reacting
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-m-
ethyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone
(Example 471) with 2-cyanoethylphosphate (Fieser, L F and Fieser,
M, Reagents for Organic Synthesis, 1967, Volume 1, 172-173, John
Wiley & Sons, NY, N.Y.) in the presence of DCC and pyridine.
Mild alkaline hydrolysis of the cyanoethyl ester selectively
provides the title compound.
EXAMPLE 632-642
[1771] The following compounds may be prepared by the method of
Example 631, substituting the appropriate
2-(X-phenyl)-4-(3-hydroxy-3-methyl-1-bu-
toxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl]-3(2H)-pyridazinone (Example 471).
8 Example Number X 632 4-F 633 4-Cl 634 3-F 635 3-Cl 636 3-Br 637
3-CF.sub.3 638 3-Cl-4-F 639 4-Cl-3-F 640 3,4-di-Cl 641
4-F-3-CF.sub.3 642 3-Br-4-F
EXAMPLE 643
2-(tert-Butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl-
]-3(2H)-pyridazinone
[1772] The title compound may be prepared according to the sequence
of reactions described in Example 471, substituting
2-tert-butyl-4,5-dichlor- o-3(2H)-pyridazinone (Example 330A) in
place of 2-(3,4-difluorophenyl)-4,5-
-dibromo-3(2H)-pyridazinone.
EXAMPLE 644
2-(tert-Butyl)-4-[3-(2-aminoacetyloxy)-3-methyl-1-butoxyl-5-[4-(methylsulf-
onyl)phenyl]-3(2H)-pyridazinone
[1773] The title compound may be prepared by the method of Example
607, substituting
2-(tert-butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)phenyl]-3(2H)-pyridazinone (Example 643) in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)phenyl -3(2H)-pyridazinone (Example 471).
EXAMPLE 645
2-(tert-Butyl)-4-[3-{r(2R,3R)-3-carboxy-2,3-dihydroxypropanoyl]oxy]-3-meth-
ylbutoxyl-3-methyl-1-butoxyl-5-[4-(methylsulfonyl)-phenyl]-3(2H)-pyridazin-
one
[1774] The title compound may be prepared by the method of Example
619, substituting
2-(tert-butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)-phenyl]-3(2H)-pyridazinone (Example 643) in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)-phenyl]-3(2H)-pyridazinone (Example 471).
EXAMPLE 646
3-([2-(tert-Butyl)-5-[4-(methylsulfonyl)phenyl]-3-oxo-2,3-dihydro-4-pyrida-
zinyl}oxy)-1,1-dimethylpropyl Dihydrogen Phosphate
[1775] The title compound may be prepared by the method of Example
631, substituting
2-(tert-butyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyls-
ulfonyl)-phenyl]-3(2H)-pyridazinone (Example 643) in place of
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfon-
yl)-phenyl]-3(2H)-pyridazinone (Example 471).
Prostaglandin Inhibition Determination Compound Preparation and
Administration
[1776] For oral administration, test compounds were suspended on
the day of use in 100% polyethyleneglycol (PEG 400) with a
motorized homogenizer equipped with a Teflon-coated pestle (TRI-R
Instrument, Jamaica, N.Y.).
[1777] To compare the mean responses of the treatment groups,
analysis of variance was applied. Percent inhibition values were
determined by comparing the individual treatment mean values to the
mean of the control group. Linear regression was used to estimate
IC.sub.50's/ED.sub.50's in appropriate assays.
EIA Determination of Prostaglandins
[1778] EIA reagents for prostaglandin determination were purchased
from Perseptive Diagnostics, (Cambridge, Mass.). Prostaglandin
E.sub.2 (PGE.sub.2) levels in lavage fluids were determined after
the samples were dried under nitrogen and reconstituted with assay
buffer. PGE.sub.2 levels in enzyme assays or cell culture media
were measured against standards prepared in the same milieu. The
immunoassays were conducted as recommended by the manufacturer. The
EIA was conducted in 96 well microtiter plates (Nunc Roskilde,
Denmark) and optical density was measured using a microplate reader
(Vmax, Molecular Devices Corp., Menlo Park, Calif.).
Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays
[1779] Inhibition of prostaglandin biosynthesis in vitro was
evaluated using recombinant human Cox-1 (r-hu Cox1) and Cox-2 (r-hu
Cox-2) enzyme assays. Representative compounds dissolved in DMSO
(3.3% v/v) were preincubated with microsomes from recombinant human
PGHS-1 or PGHS-2 expressed in the baculovirus/Sf9 cell system
(Gierse, J. K., Hauser, S. D., Creely, D. P., Koboldt, C.,
Rangwala, S., H., Isakson, P. C., and Seibert, K. Expression and
selective inhibition of the constituitive and inducible forms of
cyclooxygenase, Biochem J. 1995, 305: 479.), together with the
cofactors phenol (2 mM) and hematin (1 .mu.M) for 60 minutes prior
to the addition of 10 .mu.M arachidonic acid. The reaction was
allowed to run for 2.5 minutes at room temperature prior to
quenching with HCl and neutralization with NaOH. PGE.sub.2
production in the presence and absence of the drug was determined
by EIA analysis. The EIA was conducted in 96 well microtiter plates
(Nunc Roskilde, Denmark) and optical density was measured using a
microplate reader (Vmax, Molecular Devices Corp., Menlo Park,
Calif.). EIA reagents for prostaglandin determination were
purchased from Perseptive Diagnostics (Cambridge, Mass.). PGE.sub.2
levels were measured against standards prepared in the same milieu.
The immunoassays were conducted as recommended by the
manufacturer.
[1780] The data illustrating the inhibition of prostaglandin
biosynthesis in vitro by compounds of this invention is shown in
Table 1. The compounds are designated by the Example Number. Column
2 shows Cox-1 percent inhibition at the particular micromolar dose
level and Column 3 shows Cox-2 percent inhibition at the particular
nanomolar dose level. Values for Cox-1 and Cox-2 inhibition that
are parenthetical indicate IC.sub.50 values.
9 TABLE 1 RHUCX1 RHUCX2 Example % Inh. at % Inh. at Number Dose
(.mu.M) Dose (.mu.M) 10 2 @ 100 (0.014) 12 0 @ 100 97 @ 10 77 @ 1 9
@ 0.1 20 10 @ 100 86 @ 0.1 9 @ 0.01 21 19 @ 100 (0.92) 22 25 @ 100
91 @ 0.03 35 @ 0.01 23 0 @ 100 68 @ 0.1 27 @ 0.01 24 60 @ 100 99 @
1 0 @ 10 61 @ 0.1 45 @ 0.01 25 1 @ 100 93 @ 1 66 @ 0.1 26 10 @ 100
91 @ 1 44 @ 0.1 44 @ 0.01 32 20 @ 100 96 @ 1 83 @ 0.1 34 16 @ 100
(0.92) 35 34 @ 10 (0.017) 36 21 @ 10 (0.57) 39 0 @ 100 (0.44) 40 76
@ 10 97 @ 1 69 @ 1 89 @ 0.1 41 13 @ 100 49 @ 1 17 @ 0.1 42 0 @ 100
99 @ 1 92 @ 0.1 43 8 @ 100 100 @ 1 96 @ 0.1 45 5 @ 100 85 @ 1 63 @
0.1 48 0 @ 100 73 @ 1 2 @ 0.1 50 23 @ 100 99 @ 1 59 @ 0.1 52 32 @
10 99 @ 1 83 @ 0.1 53 10 @ 100 99 @ 1 77 @ 0.1 54 0 @ 100 95 @ 1 58
@ 0.1 58 0 @ 100 (0.95) 60 7 @ 100 100 @ 1,000 62 6 @ 100 (0.624)
64 68 @ 1 34 @ 1 36 @ 0.1 65 13 @ 100 98 @ 1 65 @ 0.1 68 32 @ 100
(0.297) 69 2 @ 100 88 @ 1 29 @ 0.1 30 @ 0.01 72 0 @ 100 65 @ 1 18 @
0.1 73 9 @ 100 (1.34) 74 11 @ 100 86 @ 1 75 @ 0.1 77 35 @ 100 82 @
10 39 @ 1 80 41 @ 10 (0.064) 37 @ 1 81 6 @ 100 97 @ 1 44 @ 0.1 84
49 @ 10 87 @ 0.3 9 @ 1 88 0 @ 100 97 @ 1,000 35 @ 0.1 89 62 @ 30
(0.35) 40 @ 10 97 35 @ 100 (0.332) 100 62 @ 10 100 @ 10 65 @ 1 61 @
0.1 105 85 @ 1 98 @ 1 52 @ 0.1 106 19 @ 200 (0.135) 107 88 @ 10 86
@ 1 50 @ 1 36 @ 0.1 108 0 @ 100 (0.279) 109 6 @ 100 (0.147) 110 5 @
100 93 @ 1 50 @ 0.1 111 13 @ 100 (0.052) 112 5 @ 100 (0.136) 118 31
@ 100 72 @ 0.1 17 @ 0.01 119 (0.178) (0.027) 120 15 @ 100 97 @ 1 45
@ 0.1 121 0 @ 100 (0.005) 122 1 @ 100 (0.285) 124 26 @ 100 (0.044)
127 50 @ 10 74 @ 1 30 @ 1 51 @ 0.1 128 14 @ 100 (0.477) 132 93 @ 1
88 @ 1 43 @ 0.1 133 23 @ 100 (0.358) 134 54 @ 100 (0.053) 35 @ 10
140 (3.06) (0.022) 141 55 @ 100 99 @ 1 62 @ 10 95 @ 0.1 142 80 @ 10
96 @ 1 53 @ 1 45 @ 0.1 32 @ 0.01 143 62 @ 100 (0.076) 43 @ 10 144
(0.058) 88 @ 1 78 @ 0.1 65 @ 0.01 145 (0.238) 86 @ 0.1 56 @ 0.01
146 82 @ 10 100 @ 1 53 @ 1 73 @ 0.1 147 (0.067) 100 @ 1 64 @ 0.1 0
@ 0.03 149 45 @ 10 (0.003) 40 @ 1 150 56 @ 100 100 @ 0.1 39 @ 10
153 54@ 100 (0.062) 35 @ 10 154 (0.126) (0.018) 165 0 @ 100 (1.08)
166 3 @ 100 (0.199) 168 0 @ 100 85 @ 1 93 @ 0.1 171 0 @ 100 82 @ 10
74 @ 1 61 @ 0.1 178 6 @ 100 92 @ 1,000 34 @ 10 180 8 @ 100 78 @ 1
48 @ 0.1 182 (5.01) (0.07) 183 25 @ 100 97 @ 1 51 @ 0.1 187 2 @ 100
(0.094) 188 18 @ 100 (0.526) 190 (1.88) (0.134) 194 35 @ 100 90 @
10 73 @ 1 72 @ 0.1 198 10 @ 100 68 @ 1 23 @ 0.1 207 97 @ 1 81 @ 0.1
209 0 @ 100 79 @ 1 55 @ 0.1 40 @ 0.01 213 0 @ 100 (0.812) 219 20 @
100 90 @ 1 75 @ 0.1 220 51 @ 100 96 @ 1 38 @ 1 90 @ 0.1 226 0 @ 100
(1.09) 228 7 @ 100 (0.209) 230 4 @ 100 (0.215) 231 7 @ 100 90 @ 1
68 @ 0.1 232 23 @ 100 (0.024) 234 0 @ 100 (0.328) 235 22 @ 100
(0.21) 237 54 @ 10 89 @ 0.1 44 @ 1 240 14 @ 100 (0.297) 241 0 @ 100
(0.028) 245 9 @ 100 (1.38) 246 0 @ 100 (0.054) 247 72 @ 10 99 @ 10
55 @ 1 71 @ 1 51 @ 0.1 248 13 @ 100 (0.08) 249 6 @ 100 98 @ 1 68 @
0.1 43 @ 0.01 252 0 @ 100 87 @ 0.1 26 @ 0.01 253 77 @ 100 (0.272)
29 @ 10 254 7 @ 100 84 @ 1 48 @ 0.1 256 0 @ 100 (0.134) 257 0 @ 100
(0.04) 260 8 @ 100 2 @ 10 261 0 @ 200 (0.161) 262 15 @ 100 (0.432)
263 1 @ 100 85 @ 10 76 @ 1 53 @ 0.1 265 8 @ 100 53 @ 10 48 @ 1 33 @
0.1 272 0 @ 100 70 @ 1 55 @ 0.1 273 16 @ 100 54 @ 10 42 @ 1 278 36
@ 100 96 @ 1 91 @ 0.1 279 0 @ 100 60 @ 1 31 @ 0.1 281 7 @ 100 71 @
1 52 @ 0.1 47 @ 0.01 283 0 @ 100 90 @ 10 71 @ 1 54 @ 0.1 287 0 @
100 93 @ 10 79 @ 1 25 @ 0.1 314 7 @ 100 51 @ 10 4 @ 1 318 23 @ 100
97 @ 1 77 @ 0.1 321 4 @ 100 (0.192) 322 39 @ 100 (0.058) 54 @ 10
323 1 @ 100 (0.365) 325 (0.199) 330 15 @ 100 85 @ 1 72 @ 0.03 5 @
0.01 335 5 @ 100 (0.001) 338 0 @ 100 100 @ 1 83 @ 0.1 339 2 @ 100
(0.088) 344 16 @ 100 (0.897) 345 0 @ 100 (0.242) 346 14 @ 100 94 @
1 76 @ 0.1 48 @ 0.01 347 11 @ 100 (0.075) 349 0 @ 100 (0.086) 351 3
@ 100 91 @ 1 63 @ 0.1 42 @ 0.01 352 0 @ 100 (0.154) 353 6 @ 100
(0.826) 354 .angle.@ 100 45 @ 10 45 @ 1 36 @ 0.1 355 0 @ 100 79 @
10 66 @ 1 46 @ 0.1 358 30 @ 100 (2.45) 361 3 @ 100 (0.011) 362 1 @
100 84 @ 10 49 @ 1 364 0 @ 100 86 @ 1 0 @ 0.1 366 0 @ 100 (0.03)
367 0 @ 100 (0.077) 368 13 @ 100 96 @ 1 65 @ 0.1 369 0 @ 100 70 @ 1
48 @ 0.1 370 8 @ 100 (0.048) 371 8 @ 100 (0.166) 372 0 @ 100 94 @
10 88 @ 1 59 @ 0.1 374 2 @ 100 (0.02) 375 46 @ 100 (0.18) 31 @ 10
376 12 @ 100 (0.027) 381 0 @ 100 (0.188) 384 82 @ 100 99 @ 1 49 @
10 78 @ 0.1 386 58 @ 100 83 @ 1 47 @ 1 63 @ 0.1 58 @ 0.01 387 57 @
10 76 @ 1 60 @ 1 65 @ 0.1 56 @ 0.01 388 74 @ 10 (0.049) 36 @ 1 390
88 @ 10 99 @ 10 45 @ 1 72 @ 1 60 @ 0.1 392 56 @ 100 82 @ 0.1 35 @
10 65 @ 0.01 393 15 @ 100 85 @ 1 58 @ 0.1 394 86 @ 100 94 @ 1 38 @
10 64 @ 0.1 20 @ 0.01 395 91 @ 100 93 @ 1 35 @ 10 77 @ 0.1 34 @
0.01 396 22 @ 100 (0.059) 397 25 @ 100 93 @ 1 58 @ 0.1 39 @ 0.01
398 26 @ 100 (0.202) 400 27 @ 100 (0.142) 401 (0.753) 96 @ 1 62 @
0.1 48 @ 0.01 402 89 @ 1 (0.221) 403 (150.76) 92 @ 1 64 @ 0.1 36 @
0.01 404 77 @ 100 92 @ 0.1 47 @ 10 57 @ 0.01 405 90 @ 100 (0.198)
61 @ 10 406 23 @ 100 100 @ 1 64 @ 0.1 18 @ 0.01 407 32 @ 100 (0.17)
408 0 @ 100 (0.279) 410 48 @ 100 67 @0 .035 1 @ 10 47 @ 0.017 411
96 @ 10 (0.009) 81 @ 1 412 31 @ 100 (0.002) 413 0 @ 100 (0.11) 414
0 @ 100 87 @ 1 76 @ 0.1 418 33 @ 100 85 @ 1 52 @ 0.1 53 @ 0.025 419
12 @ 100 (0.1) 420 29 @ 100 (0.323) 421 (0.269) 92 @ 1 81 @ 0.1 38
@ 0.01 422 53 @ 100 52 @ 1 82 @ 10 37 @ 0.1 76 @ 1 423 0 @ 100 87 @
1 68 @ 0.1 36 @ 0.01 424 7 @ 100 75 @ 1 58 @ 0.1 33 @ 0.01 425 12 @
100 69 @ 0.1 31 @ 0.01 426 1 @ 100 (0.057) 434 0 @ 100 (0.081) 437
16 @ 100 (0.124) 438 0 @ 100 (0.127) 440 20 @ 100 84 @ 1 59 @ 0.1
22 @ 0.01 442 55 @ 100 90 @ 0.1 56 @ 0.01 443 35 @ 100 86 @ 0.1 74
@ 0.01 444 0 @ 100 83 @ 1 62 @ 0.1 14 @ 10 445 (56.62) (0.069) 446
0 @ 200 (0.373) 447 0 @ 100 90 @ 1 57 @ 0.1 35 @ 0.01 449 5 @ 200
(0.129) 450 29 @ 100 87 @ 1 40 @ 0.1 22 @ 0.01 451 10 @ 100 (0.470)
452 14 @ 100 15 @ 1 467 4 @ 100 (1.96) 475 0 @100 (0.71) 471 (3.68)
(0.49) 478 33 @ 100 (0.81) 528 (3.4) (0.72)
IL-1.beta. Induced PGE.sub.2 Production in WISH Cells
[1781] Human amnionic WISH cells were grown to 80% confluence in 48
well plates. Following removal of the growth medium and two
washings with Geys Balanced Salt Solutn, 5 ng IL-1.beta. /ml (UBI,
Lake Placid, N.Y.) was added to the cells with or without test
compound in DMSO (0.01% v/v) in Neuman-Tytell Serumless Medium
(GIBCO, Grand Island, N.Y.). Following an 18 hour incubation to
allow for the maximal induction of PGHS-2, the conditioned medium
was removed and assayed for PGE.sub.2 content by EIA analysis as
described above.
[1782] Monocyte U937 (ATCC, Rockville, Md.) cells were grown in a
similar fashion to the WISH cells. After incubation, the
conditioned medium was removed and assayed for Cox-1 content by EIA
analysis as described above.
[1783] The data illustrating the inhibition of prostaglandin
biosynthesis in vitro by compounds of this invention is shown in
Table 2. U937 values indicate Cox-1 percent inhibition at the
particular micromolar dose level while partenthetical values
indicate IC.sub.50 values. WISH cell values indicate percent
inhibition at the particular micromolar dose level while
parenthetical values indicate IC.sub.50 values.
Human Whole Platelet Cyclooxygenase-1 Assay (HWCX)
[1784] Blood from normal healthy volunteers is collected into tubes
containing ACD (acid citrate dextrose) as the anticoagulant. This
blood is centrifuged at 175.times.g to prepare platelet rich
plasma. The platelet rich plasma is then centrifuged at 100.times.g
to pellet the white blood cells, leaving the platelets in the
supernatant. The supernatant is layered on a cushion of 0.7 mL of
10% bovine serum albumin in Tyrodes solution (Gibco; Grand Island,
N.Y.) and then centrifuged at 1000.times.g. The resulting
supernatant from this centrifuigation is then removed and 11 mL of
Tyrodes solution is added to the remaining pellet of platelets. The
platelets are then aliquoted at 120 .mu.l into a 96 well plate.
Experimental compounds are added and allowed to pre-incubate for 10
minutes. At the end of this pre-incubation period, the calcium
ionophore A23187 is added to a final concentration of 8.8 .mu.M and
the incubation is continued for ten minutes. The reaction is
stopped by adding cold 6 mM EDTA, the incubation mixture is
centrifuged at 220.times.g, and the supernatants are then analyzed
for thromboxane using a commercial kit from Cayman Chemical (Ann
Arbor, Mich.
10TABLE 2 U937 HWPX Wish Example % Inhib. at % Inhib. at % Inhib.
at Numbers Dose (.mu.M) Dose (.mu.M) Dose (.mu.M) 10 (4.1) (0.014)
20 33 @ 1 (0.001) 24 (0.19) (0.007) 43 86 @ 10 (0.008) 9 @ 1 53 78
@ 10 90 @ 0.1 8 @ 1 44 @ 0.01 65 (0.02) 69 (1.14) (0.02) 72 (25)
(0.072) 75 84 @ 10 (0.001) 0 @ 3 77 (8.8) (0.126) 85 (0.47) 86 52 @
1 47 @ 0.01 89 (3.8) (2.1) (0.05) 100 (0.13) (0.02) 102 (0.05) 105
62 @ 1 (0.018) 106 (17.5) (0.03) 108 (8) (0.097) 109 (2.693)
(0.018) 119 (0.076) (0.001) 120 74 @ 3 (0.025) 58 @ 1 121 (0.041)
123 90 @ 1 (0.001) 29 @ .1 126 (0.05) 129 (0.04) 132 100 @ 0.1 36 @
0.01 140 (0.773) (0.01) 141 56 @ 0.3 (0.004) 142 (7.53) (0.088) 143
(0.007) 145 72 @ 1 (0.009) 30 @ .3 146 84 @ 10 (0.044) 46 @ 3 147
84 @ 0.3 (0.029) 148 51 @ 0.3 (0.042) 149 89 @ 10 (0.03) 34 @ 3 152
(0.029) 153 (2.95) (0.046) 154 81 @ .3 100 @ 0.1 48 @ .1 69 @ 0.01
160 (7.2) (0.03) 162 (0.034) 165 (1.9) (0.030) 166 (9.4) (0.02) 168
47 @ 1 (0.009) 171 90 @ 1 56 @ 0.1 187 (12.6) (0.015) 189 31 @ 100
(0.041) 190 (9.96) (0.03) 191 (0.06) 194 (28.09) (0.069) 198
(0.184) 203 77 @ 1 23 @ 0.1 207 (0.068) 228 (19.6) (0.086) 241
(0.0474) 243 (0.03) 244 (3.67) (0.019) 245 (0.046) 246 (0.02) 247
(7.76) (0.02) 248 82 @ 30 (0.005) 17 @ 10 252 (0.044) 256 (4.7)
(0.028) 261 (34) (0.099) 271 52 @ 1 15 @ 0.1 278 (0.07) 279 (0.391)
287 (0.16) 317 (0.027) 320 29 @ 3 78 @ .1 15 @ .01 321 50 @ 0.01
322 (0.026) 323 57 @ 0.01 324 (0.047) 325 (2.3) (0.04) 326 (0.05)
330 (16.7) (0.005) 335 (0.023) 338 (14.93) (0.004) 339 (0.393)
(0.026) 343 (0.191) (0.016) 344 (0.1) 345 (0.03) 349 34 @ 100
(0.041) 352 (5.5) (6.048) 358 69 @ 1 0 @ 0.1 366 (1.615) (0.002)
367 50 @ 1 (0.018) 8 @ .3 368 (13.7) 64 @ 0.03 33 @ 0.01 370 (8.4)
(0.02) 375 (2.04) (0.089) 381 31 @ 30 (0.075) 91 @ 100 385 (2.18)
(0.023) 388 0 @ .3 (0.032) 392 (1.95) (0.02) 394 (0.019) 396 (12.7)
(0.02) 397 (13.8) (0.04) 399 82 @ 0.1 39 @ 0.03 400 (0.3) (0.026)
401 (0.32) (0.017) 403 (0.902) (0.018) 404 (0.337) 96 @ 0.1 58 @
0.01 406 (1.61) (0.026) 408 (0.029) 410 (0.053) 414 54 @ 1 46 @ 0.1
418 (14.25) (0.25) 430 34 @ 10 (0.054) 89 @ 100 442 (0.42) 445 100
@ 100 (0.025) 22 @ 10 446 (24.4) (0.02) 449 (40) (0.089) 450 (0.05)
451 (22.4) (0.15) 452 56 @ 1 1 @ 0.1 475 50 @ 100 (0.44) 467
(0.135) 471 (0.32) (0.04) 478 (0.5) (0.108) 528 (3.5) (0.054)
Carrageenan Induced Paw Edema (CPE) in Rats
[1785] Hingpaw edema was reduced in male rats as described by
Winter et al., Proc. Soc. Exp. Biol. Med., 1962, 111, 544. Briefly,
male Sprague-Dawley rats weighing between 170 and 190 g were
administered test compounds orally 1 hour prior to the subplantar
injection of 0.1 ml of 1% sodium carrageenan (lambda carrageenan,
Sigma Chemical Co., St Louis, Mo.) into the right hindpaw. Right
paw volumes (ml) were measured immediately following injection of
carrageenan for baseline volume measurements using a Buxco
plethysmograph (Buxco Electronics, Inc., Troy, N.Y.). Three hours
after the injection of carrageenan, right paws were remeasured and
paw edema calculated for each rat by subtracting the zero time
reading from the 3 hour reading. Data are reported as mean percent
inhibition +/-SEM. Statistical significance of results was analyzed
by Dunnetts multiple comparison test where p<0.05 was considered
statistically significant.
Rat Carrageenan Pleural Inflammation (CIP) Model
[1786] Pleural inflammation was induced in male adrenalectomized
Sprague-Dawley rats following the method of Vinegar et al., Fed.
Proc. 1976, 35, 2447-2456. Animals were orally dosed with
experimental compounds, 30 minutes prior to the intrapleural
injection of 2% lambda carrageenan (Sigma Chemical Co., St. Louis
Mo.). Four hours later the animals were euthanized and the pleural
cavities lavaged with ice cold saline. The lavage fluid was then
added to two volumes of ice cold methanol (final methanol
concentration 66%) to lyse cells and precipitate protein.
Eicosanoids were determined by EIA as described above.
[1787] The data illustrating the inhibition of prostaglandin
biosynthesis in vivo by the compounds of this invention is shown in
Table 3. Values reported are percent inhibition at 10 milligrams
per kilogram body weight.
[1788] Carrageenan induced air pouch prostaglandin biosynthesis
model (CAP) Air pouches are formed in the backs of male Sprague
Dawley rats by injecting 20 mL of sterile air on day 0. Three days
later the pouch was reinflated with an additional 10 mL of sterile
air. On day 7, 1 mL of saline containing 0.2 % lambda carrageenan
(Sigma Chemical Co.) is injected into the pouch to induce the
inflammatory reaction that is characterized by the release of
prostaglandins. Test compounds are dosed at 0.1 to 10 mg/kg 30
minutes prior to carrageenan. Four hours after the carrageenan
injection the pouch is lavaged and levels of prostaglandins are
determined by enzyme immuno-assay using commercially available
kits. Percent inhibitions are calculated by comparing the response
in animals which have received vehicle to those which received
compound. Values for Cox-2 inhibition that are parenthetical
indicate ED.sub.50 values.
[1789] The data illustrating the inhibition of prostaglandin
biosynthesis in vivo by the compounds of this invention is shown in
Table 3. Values reported are percent inhibition at 10 milligrams
per kilogram body weight for CIP and CPE tests and at 3 milligrams
per kilogram body weight for CAP testing.
11 TABLE 3 Example CIP % Inhib. CPE % Inhib. CAP % Inhib. Numbers @
10 mpk @ 10 mpk @ 3 mpk 10 44 12 42 25 34 36 31 54 31 30 58 42 14
67 62 57 21 66 59 7 0 67 40 @ 3 mpk 68 64 40.3 69 61 45.5 87
ED.sub.30 = 5.4 72 73 46 29 74 46.5 18 34 77 51 21 80 60 28.5 91 89
68.3 45.5 94 ED.sub.50 = 3.4 106 47 109 13 71 112 21 42.5 119 82 27
76 120 5 11 121 19 8 123 23 143 59 153 51 160 56 35 166 40 59 168 0
6 180 34.5 182 59 27 98 185 59 20 53 187 51 28 30 190 60 28 71 205
54 226 21 40.5 243 7 245 47 246 48 248 49 256 47 257 60 261 28 79
330 4.5 335 45 339 43 90.5 ED.sub.50 = 0.58 346 49.5 347 27 66.5
349 63 351/64 0 352 89 ED.sub.50 = 5.0 353/63 0 361 65 366 63
ED.sub.50 = 1.5 367 48 375 47 77.5 ED.sub.50 = 0.57 376 17 77.5 378
59 384/33 51 15 51 385 65 388 28 80 390 60 391 61 392 60 394 70 395
71 396 23 85 397 70 400 65 41 82.5 403 43 68.5 ED.sub.50 = 0.35 405
53 406 23 66.5 407 61 419 48 427 78 445 15 73 446 44 92 ED.sub.50 =
0.5 449 23 76 ED.sub.50 = 1.8 450 86 451 ED.sub.30 = 0.82 80.5
ED.sub.50 = 0.7 452 71 459 45 464 70 475 33 ED.sub.50 = 1.4 467
ED.sub.30 = 1.7 ED.sub.50 = 0.4 471 41 ED.sub.50 = 0.9 478 26 75
528 40 ED.sub.50 = 1.4
Human Whole Blood Assays Cyclooxygenase-1
[1790] Heparin anticoagulated blood was incubated with drugs
dissolved in DMSO. The samples are incubated at 37 degrees Celsius
for 4.5 hours after which calcium ionophore at a final
concentration of 30 .mu.M was added and the mixture allowed to
incubate for 30 minutes. The reaction was stopped with the addition
of EGTA and cold methanol (50% final concentration). After 18 hours
at -70 degrees Celsius, the plates were centrifuged and
supernatants analyzed for TXB.sub.2.
Cyclooxygenase-2
[1791] Heparin anticoagulated blood was incubated with drugs
dissolved in DMSO. The samples are incubated at 37 degrees Celsius
for 15 minutes. E. coli lipopolysaccaride (LPS) 5 .mu.g/ml dded and
the samples incubated for 5 hours. The reaction was stopped with
the addition of EGTA and cold methanol (50% final concentration).
After 18 hours at -70 degree Celsius, the plates were centrifuged
and supernatants analyzed for TXB.sub.2.
[1792] Example 451-Human whole blood Cox-1 IC.sub.50=29.12
micromolar
[1793] Example 451-Human whole blood Cox-2 IC.sub.50=0.47
micromolar
[1794] Example 471-Human whole blood Cox-1=55.5% at 30
micromolar
[1795] Example 471-Human whole blood Cox-2 =85% at 0.03
micromolar
[1796] The 4-hydroxyalkoxy-3(2H)-pyridazinone Cox-2 inhibition and
in vivo activity has been found to be suprisingly good. In
addition, when compared to the 4-alkoxy-3(2H)-pyridazinones, the
hydroxyalkoxy compounds typically possess a superior oral
pharmacokinetic profile, such as better plasma half-life, plasma
concentration maxima, and area under the curve. For example,
Example 375 shows a 14 day plasma micromolar concentration (based
on 10 mg/kg dosage) of 0.0 while Example 451 shows a 3.43
micromolar level. In addition, the half life of Rat IV (3mg/kg) for
Example 375 was 2.9 while Example 451 showed 5.2. The AUC value
(micromolar/hour) for Example 375 was 1.8 while Example 451 was
69.
[1797] It is anticipated that the 4-hydroxyalkoxy compounds are
preferred to parent alkoxy compounds with regard to once-a-day
dosing to achieve predictable exposure levels across a wide range
of doses while producing an antiinflammatory effect.
Pharmaceutical Compositions
[1798] The present invention also provides pharmaceutical
compositions which comprise compounds of the present invention
formulated together with one or more non-toxic pharmaceutically
acceptable carriers. The pharmaceutical compositions of the present
invention comprise a therapeutically effective amount of a compound
of the present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; 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 a propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringers solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the procedures and
judgements well known to one skilled in the art. The pharmaceutical
compositions of this invention can be administered to humans and
other animals orally, rectally, parenterally, intracistemally,
intravaginally, intraperitoneally, topically (as by powders,
ointments, or drops), bucally, or as an oral or nasal spray.
[1799] The compounds of the present invention may be potentially
useful in the treatment of several illness or disease states such
as inflammatory diseases, dysmennorhea, asthma, premature labor,
adhesions and in particular pelvic adhesions, osteoporosis, and
ankylosing spondolitis. Current Drugs Ltd, ID Patent Fast Alert,
AG16, May 9, 1997.
[1800] The compounds of the present invention may also be
potentially useful in the treatment of cancers, and in particular,
colon cancer. Proc. Natl. Acad. Sci., 94, pp. 3336-3340, 1997.
[1801] The compounds of the present invention may be useful by
providing a pharmaceutical composition for inhibiting prostaglandin
biosynthesis comprising a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable salt, ester,
or prodrug thereof, and a pharmaceutically acceptable carrier.
[1802] In addition, the compounds of the present invention may be
useful by providing a method for inhibiting prostaglandin
biosynthesis comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
[1803] In addition, the compounds of the present invention may be
useful by providing a method for treating pain, fever, inflamation,
rheumatoid arthritis, osteoarthritis, adhesions, and cancer
comprising administering to a mammal in need of such teratment a
therapeutically effective amount of a compound of formula I.
[1804] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (such as, for example, cottonseed,
groundnut, corn, germ, olive, castor, sesame oils, and the like),
glycerol, tetrahydrofurfuryl alcohol, poly-ethyl-ene glycols and
fatty acid esters of sorbitan, and mixtures thereof. Besides inert
diluents, the oral compositions can also include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and perfuming agents.
[1805] Injectable preparations, such as, 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. The sterile injectable preparation
may also be a sterile injectable solution, suspension or emulsion
in a nontoxic parenterally acceptable diluent or solvent, such as,
for example, a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringers
solution, isotonic sodium chloride solution, and the like. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
can be employed including synthetic mono-or diglycerides. In
addition, fatty acids such as oleic acid are used in the
preparation of injectable preparations.
[1806] The injectable formulations can be sterilized by any method
known in the art, such as, for example, by filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents
in the form of sterile solid compositions which can be dissolved or
dispersed in sterile water or other sterile injectable medium prior
to use.
[1807] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsulated matrices of the
drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides) Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions which are compatible with body tissues.
[1808] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and thus melt in the rectum or vaginal cavity
and release the active compound.
[1809] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is usually mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as, for
example, sodium citrate or dicalcium phosphate and/or a) fillers or
extenders such as, for example, starches, lactose, sucrose,
glucose, mannitol, and silicic acid, b) binders such as, for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as,
for example, glycerol, d) disintegrating agents such as, for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents such as, for example, paraffin, f) absorption
accelerators such as, for example, quaternary ammonium compounds,
g) wetting agents such as, for example, cetyl alcohol and glycerol
monostearate, h) absorbents such as, for example, kaolin and
bentonite clay, and) lubricants such as, for example, talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering
agents.
[1810] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients such as, for example, lactose or milk sugar as well as
high molecular weight polyethylene glycols and the like.
[1811] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using excipients
such as, for example, lactose or milk sugar as well as high
molecular weight polethylene glycols and the like.
[1812] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulation art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as, for example, sucrose, lactose or starch. Such dosage forms may
also comprise, as is normal practice, additional substances other
than inert diluents, e.g., tableting lubricants and other tableting
aids such as, for example, magnesium stearate and microcrystalline
cellulose. In the case of capsules, tablets and pills, the dosage
forms may also comprise buffering agents. They may optionally
contain opacifying agents and can also be of a composition that
they release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[1813] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[1814] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as, for example, animal and vegetable fats, oils, waxes, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene glycols,
silicones, bentonites, silicic acid, talc and zinc oxide, or
mixtures thereof.
[1815] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as, for example, lactose, talc,
silicic acid, aluminum hydroxide, calcium silicates and polyamide
powder, or mixtures of these substances. Sprays can additionally
contain customary propellants such as chlorofluorohydrocarbons.
[1816] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage fonms
can be made by dissolving or dispensing the compound in a suitable
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[1817] According to the methods of treatment of the present
invention, a patient, such as a human or mammal, is treated by
administering to the patient a therapeutically effective amount of
a compound of the invention, in such amounts and for such time as
is necessary to achieve the desired result. By a therapeutically
effective amount of a compound of the invention is meant a
sufficient amount of the compound to provide the relief desired, at
a reasonable benefit/risk ratio applicable to any medical
treatment. It will be understood, however, that the total daily
usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of
sound medical judgment. The specific therapeutically effective dose
level for any particular patient will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in
combination or coincidental with the specific compound employed;
and like factors well known in the medical arts.
[1818] The total daily dose of the compounds of this invention
administered to a human or other mammal in single or in divided
doses can be in amounts, for example, from 0.001 to about 1000
mg/kg body weight daily or more preferably from about 0.1 to about
100 mg/kg body weight for oral administration or 0.01 to about 10
mg/kg for parenteral administration daily. Single dose compositions
may contain such amounts or submultiples thereof to make up the
daily dose.
[1819] The amount of active ingredient that may be combined with
the carrier materials to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration.
[1820] The reagents required for the synthesis of the compounds of
the invention are readily available from a number of commercial
sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma
Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp.
(Ronkonkoma, N.Y., USA); Alfa Aesar (Ward Hill, Mass. 01835-9953);
Eastman Chemical Company (Rochester, N.Y. 14652-3512); Lancaster
Synthesis Inc. (Windham, N.H. 03087-9977); Spectrum Chemical
Manufacturing Corp. (Janssen Chemical) (New Brunswick, N.J. 08901);
Pfaltz and Bauer (Waterbury, Conn. 06708). Compounds which are not
commercially available can be prepared by employing known methods
from the chemical literature.
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