AU741317B2 - Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors - Google Patents
Arylpyridazinones as prostaglandin endoperoxide H synthase biosynthesis inhibitors Download PDFInfo
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Description
ARYLPYRIDAZINONES AS PROSTAGLANDIN ENDOPEROXIDE H SYNTHASE BIOSYNTHESIS
INHIBITORS
Technical Field 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.
10 Background of the Invention 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, isoenzymes PGHS-1 and PGHS-2, that catalyze the oxidation of arachidonic acid 15 leading to prostaglandin biosynthesis has resulted in renewed research to delineate the role of these two isozymes in physiology and pathophysiology.
These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin 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 function. The PGHS-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena.
Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and fenamates inhibit both isozymes. Inhibition 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.
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.
The present invention discloses novel compounds which are selective inhibitors of PGHS-2.
Summary of the Invention 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:
N
RN R
X
R
where X is selected from the group consisting of 0, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, .1 5 cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic,
C.N/
heterocyclic alkyl, and arylalkyl; and Ra, Rb, and Rc are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C(O)R 5 -(CH2)nC(O)R 5
-R
6
-R
7 -(CH2)nCH(OH)R 5 -(CH2)nCH(ORd)R 5 -(CH2)nC(NRd)RS, -(CH2)nCH(NORd)R5, -(CH2)nCH(NRdRe)RS, -(GH2)nC=C-R 7 -(CH2)n[C-H(CX :)Im-(CH2)n-CX'3- -(CH2)n(C _x.2)m-(CH2)n -CX'3, -(CH2)n[CH(CX'3)lm-(GH2)n
-R
8 -(0H2)n(C X'2)m-(CH2)n R 8 -(CH2)n(CHX)m-(CH2)n CX'3 -(CH2)n(GHX')m-(CH2)n -R 8 and (CH2)n-R 2 0 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl; wherein R 6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene;
R
7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, hete rocyclic, and heterocyclic alkyl; .00 R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, 0 .**ocycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; ::00:15 Rd and Re are independently selected from the group consisting of.
hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, .00.0:arylalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen: n: :is from 0to about 10, and mis 0toabout
R
2 .is 2 2 0 X or'
X-R
9
S
where X 1 is selected from the group consisting Of -S02-, -SO(NR 10 SeO2-, PO(0R 1 1 and -PO(NR1 2
R
13
R
9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH2, -N=GH(NR 1 O R 1 dialkylamino.
alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X' by an alkylene:, WO 99/10331 PCT/US98/16479
X
2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl;
R
10
R
1 1
R
12 and R 13 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 12 and R 13 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
The remaining two of the groups of R 1
R
2 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic(alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylthio, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro, and -Y-R14, wherein Y is selected from the group consisting of -C(R 16 (R1 7
-C(O)NR
2 1R 22 -N=C R 2 1
R
22 N- R 21
R
2 2 and -NR 19
R
14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl),
R
16
R
17 and R 19 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
R
21 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or their pharmaceutically acceptable salts, esters, or prodrugs thereof.
-4in one embodiment the compounds of the present invention have the formula 1, R3 R R X where N..NbRX is selected from the group consisting of 0, S, NR 4 N-0Ra, and N-N~~cwherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and Ra, Rb, and Ac are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, 15 alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,*cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryihaloalkyl, aryl hydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, S Sarylcarbonylalkyl, halolkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C(0)R 5 -(CH2)nC(0)R 5
-R
6
-R
7 -(CH2)nCH(OH)R 5 -(CH2)nCH(0Rd)R5, -(CH2)nC(N0Rd)R5, -(CH2)nCH(N0Ad)R5, -(CH2)nC-=C-R 7 -(0H2)n[CH(CX'3)]m-(CH2)n-CX'3, -(CH2)n(C X'2)m-(GH2)n -CX'3, -(CH2)n[CH(CX'3)jm-(CH2)n -R 8 -(CH2)n(C X'2)m-(CH2)n R 8 -(CH2)n(CHX')m-(CH2)n CX'3 -(CH2)n(CHX')m-(0H2)n -R 8 and (CH2)n-R 20 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, hete rocyclic, and heterocyclic alkyl; wherein R 6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene;
R
7 and R 8 are independently selected from the group consisting of 10 hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
R
20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; 15 Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen; n is from 0 to about 10, and m is 0 to about
R
2 x2 2 -R or x1R
S
where X1 is selected from the group consisting Of -S02-, -SO(NR1 -SO7-, SeO2-, PO(0R1 1 and -PO(NR1 2 Rl 3
R
9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH2, -N=GH(N R 10 R1 dialkylamino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X' by an alkylene;
X
2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl; R1,R 1 1, R 12 and R 13 are independently seleci~d from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 12 and R 13 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
At least one of R 1 or R 3 is selected from the group consisting of hydroxyalkyl, hydroxyalkoxy, mercaptoalkoxy, hydroxyalkylthio, and, hydroxyalkylamino, wherein the remaining group is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, 1 0 alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, :cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, ami nocarbonyl, ami noalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, 15 dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, hete rocyclic, heterocyclic alkyl, heterocyclic alkylamino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylthio, hydroxyalkoxy, mercaptoalkoxy, 20 oxoalkoxy, cyano, nitro, and -Y-R 1 4 wherein Y is selected from the group 9 9*consisting of -C(R1 6 (R1 7
-C(O)NR
2 1R 2 2
R
2 1
R
22 N- R 21
R
22 n -NR1 9
R
14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkytthioalkyl, alkenyl, 9lynl 99rxcclakl ylolyak cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), R 16
R
1 7 and R 1 9 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
R
2 1 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another embodiment, compounds of the present invention have the formula 11: wherein Z is a group having the formula: or/ 5 where X 1 is selected from the group consisting Of -S02-, -SeO2-- ,SO(NR10)-, and.R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -N HNH2, dialkylamnino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X' by an alkylene;
R
10 is selected from the group consisting of hydrogen, alkyl, a nd cycloalkyl;
:X
2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl; :R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalke nyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryihaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C(O)R 5 -(CH2)nC(O)R 5
-R
6
-R
7 -(CH2)nCH(OH)R 5 -(CH2)nCH(ORd)R5, -(CH2)nCH(NORd)R5, -(CH2)nC-=C-R 7 -(CH2)n[CH(CX'3)Im-(0H2)n-CX'3, -(CH2)n(C X'2)m-(CH2)n -CX'3, -(CH2)n[CH(CX'3)Im-(CH2)n -R 8 -(CH2)n(C X'2)m-(CH2)n R 8 -(GH2)n(CHX')m-(CH2)n
CX'
3 -(CH2)n(CHX')m-(CH2)n -R 8 and (CH2) n-R wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl: wherein R 6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene;,
R
7 and REI are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
R
20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, 1 0 cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;, Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, *arylalkyl, heterocyclic, and heterocyclic alkyl; Xis halogen; n istfrom 0Oto about 10, and m is 0to about-
R
1 is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, 20 alkoxyalkoxy, amido, amidloalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylAmi no, cycloalkyloxy, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthi 0, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic(alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro, and -Y-R 14 wherein Y is selected from the group consisting of -C(R 16 (R1 7 -C(0)NR 2 1
R
2 2 -N=C R 21
R
22
N-
R
21
R
22 and -NR 1 9
R
1 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl),
R
16
R
17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
R
2 1 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In yet another embodiment, compounds of the present invention have the formula III:
N
R
*N %I I-, Sf. R 9
X
1 R1
X
2 wherein X, X, 2 R, R 1
R
3 and R 9 are as defined in Formula I; or a S0 0 Spharmaceutically acceptable salt, ester, or prodrug thereof.
e: In a preferred embodiment, compounds of the present invention have the formula IIi, wherein X 1 is selected from the group consisting of -S02-, Se02-, and -SO(NR 10 and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of 0, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and R a Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl. alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl7, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, '-(CH2)nC(O)R 5 -(CH2)nC=C-
R
7 -(CH2)n[CH(CX'3)Im(CH2)n- R 8 and -(CH2)n-R 20
:I
wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
R
7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl, 1 0 R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; X' is halogen; *n is from 0 to about 10, m is from 0 to about R' is selected from the group consisting of hydroxyalkyl, hydroxyalkyith io, hydroxyalkoxy, hyd roxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkyn'yl, AlKoxy, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, 95 cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, aryloxy, heterocyclic, heterocyclic alkyl, cyano, nitro, and -Y-R 14 wherein Y is selected from the group consisting of, -C(R 16
(R
17
-C(O)NR
2 lR 2 2 -N=C R 2 1
R
22 N- R 2 1
R
22 and -NR 1 9. R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), R 16 R 17 and R 19 are independently selected from the g roup consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
R
21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano;I or a pharmaceutically acceptable salt, ester, or prodrug thereof.
-11- In another preferred embodiment, compounds of the present invention have the formula ll, wherein X 1 is selected from the group consisting of -SO 2 -SeO2-, and -SO(NR10)-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of 0, S, NR 4 N-ORa. and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, S 1 arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, -(CH2)nC(0)R 5 and (CH2)n-R 20 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
R
20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; n is from 0 to about R' is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; g R 3 is selected from the group consisting of alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and
-Y-R
14 wherein Y is selected from the group consisting of, -C(R 16
(R
17
-C(O)NR
2 1
R
2 2 and -NR19-. R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano. aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), and -12-
R
16
R
17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano;
R
21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -S02-, -SeO2-, and -SO(NR0l)-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkeryl, S20 alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, *99* cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, and -(CH2)nC(O)R 5 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and S 25 heterocyclic alkyl; and n is from 0 to about R' is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy;
R
3 is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and X, R Y-R 14, wherein Y is selected from the group consisting of, -C(R 1 6
(R
17 -13- -C(0)NR 2 1
R
2 2 and -NR1 9
R
14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl);
R
15
R
16
R
17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl or cyano;
R
2 1 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -S02-, 15 SeO2-, and -SO(NR 10 and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, S 20 cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and .Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and (CH2)n-R 2 0 where is R 20 is substituted and unsubstituted aryl wherein the 25 substituted aryl compounds are substituted with halogen; n is from 0 to about
R
1 is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy;
R
3 is hydrogen; -14-
R
15
R
16
R
17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
R
2 1 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano: or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -S02-, -SO-, and -SO(NR 1 and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, 15 wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and 20 (CH2)n-R 20 where is R 20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; Sn is from 0 to about
R
1 is hydroxyalkoxy; and oo o 25 R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is -S02- and and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
X
2 is selected from the group consisting of hydrogen and halogen; Xls selected from the group consisting of O. S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and
R
a Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and (CH2)n-R 2 0 where is R 2 0 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; n is from 0 to about
R
1 is hydroxyalkoxy; and
R
3 is hydrogen; 15 or a pharmaceutically acceptable salt, ester, or prodrug thereof.
99 In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is -SO2-,and R 9 is selected from the group consisting of alkyl and amino; 20 X 2 is selected from the group consisting of hydrogen and halogen; 9. Xis O; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl;
R
1 is hydroxyalkoxy; and
R
3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is -S02-, and R 9 is selected from the group consisting of alkyl and amino -16-
X
2 is selected from hydrogen and fluorine; R is selected from haloalkyl, aryl, and alkyl; n is from 0 to about
R
1 is selected from the group consisting of 2-hydroxy-2-methyl-propoxy; 3-hydroxy-3-methyl-butoxy; and
R
3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
in another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -S02-, and
-SO(NR
1 and R 9 is alkyl,
X
2 is selected from the group consisting of hydrogen and fluorine; Xis O; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl;
R
1 is hydroxyalkoxy; and
R
3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is -S02-, R 9 is amino;
X
2 is selected from the group consisting of hydrogen and fluorine; X is O; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl; -17-
R
1 is hydroxyalkoxy; and
R
3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have the formula III, wherein X 1 is -S02-, and R 9 is methyl;
X
2 is hydrogen; Xis O; R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, and CFCH,
R
1 is selected from the group consistina of 2-hydroxy-2-methyl-propoxy; 3-hydroxy-3-methyl-butoxy; and R3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another preferred embodiment, compounds of the present invention have 15 the formula III, wherein X 1 is -S02-, and R 9 is amino; ::i
X
2 is hydrogen; is O; R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl 20 and CF 3
CH
2
R
1 is selected from the group consisting of: S. 2-hydroxy-2-methyl-propoxy; 3-hydroxy-3-methyl-butoxy; and
R
3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof Detailed Description of the Invention 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.
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 dhousekeeping" enzyme in many tissues, including the gastrointestinal (GI) tract pd the kidneys.
-18- Definitions of Terms As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term "protecting groups includes "carboxy protecting group" and "Nprotecyting groups". "Carboxy protecting group" as used herein refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo for example by enzymatic hydrolysis, to release the biologically active parent.
T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in i "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference.
Examples of esters useful as prodrugs for compounds containing carboxyl groups 25 can be found on pages 14-21 of "Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy protecting groups are C1 to C 8 alkyl methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; -19- WO 99/10331 PCT/US98/1 6479 dialkylaminoalkyl dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionyloxy)-1 -ethyl, 1 -(pivaloyloxyl)-1 -ethyl, 1-methyl-l- (propionyloxy)-1 -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbo nyloxymethyl, cyclopentylcarbo nyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 -methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, tbutyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy-1 -ethyl, 1 -cyclohexyloxycarbonyloxy- -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (loweralkyl)-2-oxo-1 ,3-dioxolen-4-yl)alky, such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4yl)methyl and the like; and (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures.
Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichioroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, pmethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, pbromobenzyloxycarbonyl, WO 99/10331 PCT/US98/16479 3,4-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)- 1-methylethoxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).
The term "alkanoyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkanoyl include acetyl, propionyl and the like.
The term "alkanoylamino" as used herein refers to an alkanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term "alkenylene" denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH 2 CH=CH-, -C(CH 3
-CH
2
CH=CHCH
2 and the like.
The term "alkenyloxy" as used herein refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen linkage. Examples of alkenyloxy include isopropenoxy, butenyloxy and the like.
The term "alkoxy" as used herein refers to R41 0- wherein R41 is a loweralkyl group, as defined herein. Examples of alkoxy include, but are not limited to, ethoxy, isobutyloxy, isopentyloxy, tert-butoxy, and the like.
-21- WO 99/10331 PCT/US98/16479 The term "alkoxyalkylamino" as used herein refers to an alkoxy as defined herein appended to the parent molecular moiety through an alkylamino as defined herein. Examples of alkoxyalkylamino include, but are not limited to, ethoxymethylamino, isobutyloxyethylamino and the like The term "alkoxyalkoxy" as used herein refers to R800-R 8 10- wherein is loweralkyl as defined above and R81 is alkylene. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group.- Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkoxycarbonyl group as previously defined appended to the parent molecular moiety through an alkenylene. Examples of alkoxycarbonylalkenyl include methoxycarbonylethenylene, ethoxycarbonylpropenylene, and the like.
The term "alkoxyalkoxyalkyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
The term "alkoxyalkoxyalkenyl" as used herein refers to an alkoxyalkoxy group as previously defined appended to an alkenyl radical. Representative examples of alkoxyalkoxyalkenyl groups include methoxyethoxyethenyl, methoxymethoxymethenyl, and the like.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term "(alkoxycarbonyl)thioalkoxy" as used herein refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
The terms "alkyl" and "loweralkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but -22- WO 99/10331 PCT/US98/16479 not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, nhexyl and the like.
The term "alkylamino" as used herein refers to R51NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group.
The term "alkylaminocarbonyl" as used herein refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl linkage. Examples of alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
The term "alkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
The term "alkylcarbonylalkyl" as used herein refers to R40-C(0)- R41wherein R40 is an alkyl group and R41 is an alkylene group.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2
-CH
2
CH
2
-CH(CH
3
CH
2
CH
2
CH
2
-CH
2
C(CH
3 2
CH
2 and the like.
The term "alkylsulfonyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonyl group. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.
The term "alkylsulfonylalkyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl group. Examples of alkylsulfonylalkyl include methylsulfonylmethyl, ethylsulfonylmethyl, isopropylsulfonylethyl and the like.
The term "alkylsulfonylamino" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino group. Examples of alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
The term "alkylsulfonylarylalkyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl -23- WO 99/10331 PCT/US98/16479 (-S(0)2-R45R33-) group wherein R45 is aryl and R33 is alkylene. Examples of alkylsulfonylarylalkyl include methylsulfonylphenylmethyl ethylsulfonylphenylmethyl, isopropylsulfonylphenylethyl and the like.
The term "alkylthio" as used herein refers to R53S- wherein R53 is alkyl.
The term "alkylthioalkyl" as used herein refers to alkylthio as defined herein appended to the parent molecular moiety through an alkylene group.
The term "alkylthioalkoxy" as used herein refers to alkylthio as defined herein appended to the parent molecular moiety through an alkoxyl group as defined herein.
The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include H-C=C-
CH
2
H-C-C-CH(CH
3 and the like.
The term "amido" as used herein refers to R54-C(O)-NH- wherein R54 is an alkyl group.
The term "amidoalkyl" as used herein refers to R34-C(O)-NHR35- wherein R34 is alkyl and R35 is alkylene.
The term "amino" as used herein refers -NH2.
The term "aminoalkoxy" as used herein refers to an amino group appended to the parent molecular moiety through an alkoxyl group as defined herein.
The term "aminocarbonyl" as used herein refers to H2N-C(O)-.
The term "aminocarbonylalkyl as used herein refers to an aminocarbonyl as described above appended to the parent molecular moiety through an alkylene.
The term "aminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 group.
The term "aminocarbonylalkoxy" as used herein refers to H2N-C(O)appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
The term "aroyloxyalkyl" as used herein refers to R32-C(O)-O-R33- wherein R32 is an aryl group and R33 is an alkylene group. Examples of aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
-24- WO 99/10331 PCT/US98/16479 The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy, hydroxy, oxo hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl, (alkoxycarbonyl)thioalkoxy, thioalkoxy, alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, alkylsulfonyl, dialkylamino, aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, aryl, arylalkyl, arylalkoxy, aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, carboxamide, cycloalkyl, carboxyalkenyl, carboxyalkoxy, alkylsulfonylamino, cyanoalkoxy, heterocyclic alkoxy, -SO3H, hydroxyalkoxy, phenyl and tetrazolylalkoxy. In the case of halo, aryl may have up to five halo substituents. Examples of substituted aryl include 3chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, pentaflurophenyl, and the like.
The term "arylalkenyl" as used herein refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
The term "arylalkynyl" as used herein refers to an alkynyl radical to which is appended an aryl group, for example, phenylethynyl and the like The term "arylalkoxy" as used herein refers to R420- wherein R42 is an arylalkyl group, for example, benzyloxy, and the like.
The term "arylalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term "arylalkylamino" as used herein refers to an arylalkyl group as previously defined, appended to the parent molecular moiety through an amino group.
The term "arylalkylthio" as used herein refers to an arylalkyl group as previously defined, appended to the parent molecular moiety through an thiol group.
The term "arylamino" as used herein refers to R45NH 2 wherein R45 is an aryl.
WO 99/10331 PCT/US98/16479 The term "arylcarbonylalkyl" as used herein refers to R45C(O)R33- wherein is an aryl group and R33 is an alkylene group.
The term "arylhaloalkyl" as used herein refers to an aryl group as previously defined, appended to the parent molecular moiety through a haloalkyl as defined herein. Examples of arylhaloalkyl include, phenyl-2-fluoropropyl, and the like.
The term "arylhydroxyalkyl" as used herein refers to an aryl group as previously defined, appended to the parent molecular moiety through a hydroxyalkyl as defined herein. Examples of arylhydroxyalkyl include, phenyl-2hydroxypropyl, and the like.
The term "aryloxy" as used herein refers to R450- wherein R45 is an aryl group, for example, phenoxy, and the like.
The term "aryloxyalkyl" refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2phenoxyethyl and the like.
The term "aryloxyhaloalkyl" as used herein refers to an aryloxy group as previously defined, appended to the parent molecular moiety through a haloalkyl as defined herein. Examples of aryloxyhaloalkyl include, phenyloxy-2-fluoropropyl, and the like.
The term "aryloxyhydroxyalkyl" as used herein refers to an aryloxy group as previously defined, appended to the parent molecular moiety through a hydroxyalkyl as defined herein. Examples of aryloxyhydroxyalkyl include, phenyoxy-2-hydroxypropyl, and the like.
The term "carboxaldehyde" as used herein refers to a formaldehyde radical,
-C(O)H.
The term "carboxamide" as used herein refers to -C(O)NH2.
The term "carboxy" as used herein refers to a carboxylic acid radical,
-C(O)OH.
The term "carboxyalkyl" as used herein refers to a carboxy group as previously defined appended to an alkyl radical as previously defined. Examples of carboxyalkyl include 2-carboxyethyl, 3-carboxy-l-propyl and the like.
The term "carboxyalkenyl" as used herein refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined.
-26- WO 99/10331 PCT/US98/16479 Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-l-ethenyl and the like.
The term "carboxyalkoxy" as used herein refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
The term "cyano" as used herein refers a cyano group.
The term "cyanoalky" as used herein refers to an alkyl radical as previously defined to which is appended a cyano group. Examples of cyanoalkyl include 3-cyanopropyl, 4-cyanobutyl, and the like.
The term "cyanoalkoxy" as used herein refers to a cyano group appended to the parent molecular moiety through an alkoxy radical. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
The term "cycloalkanoyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group R 6 0 wherein
R
6 0 is a cycloalkyl group).
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO3H, nitro, cyano and loweralkyl.
The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings containing at least one double bond in the ring structure. Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, oxo alkylimino wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl -SO3H, nitro, cyano and loweralkyl.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
-27- WO 99/10331 PCT/US98/16479 The term "cycloalkylalkoxy" as used herein refers to a cycloalkyl group appended to an alkoxyl group as defined herein, including but not limited to cyclohexylmethyoxy.
The term "cycloalkylamino" as used herein refers to a cycloalkyl group appended to the parent molecular moiety through an amino group as defined herein, including but not limited to cyclohexylamino and the like.
The term "cycloalkylalkylamino" as used herein refers to a cycloalkyl group appended to the parent molecular moiety through an alkylamino group as defined herein, including but not limited to cyclohexylmethylamino and the like.
The term "cycloalkylidenealkyl" as used herein refers to a cycloalkyl group appended to the parent molecular moiety through a double bond which connects to an alkylene (=(CH 2 Examples include cyclopropylideneethyl, cyclobutylidenepropyl and the like.
The term "cycloalkyloxy" as used herein refers to a cycloalkyl group appended to the parent molecular moiety through an oxygen atom, including but not limited to cyclohexyloxy and the like.
The term "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to cyclohexenylmethyl.
The term "cycloalkenylalkoxy" as used herein refers to a cycloalkenyl group appended to a alkoxyl group as defined herein, including but not limited to cyclohexenylmethyoxy and the like.
The term "dialkylamino" as used herein refers to R56R57N- wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term "dialkylaminoaryloxy" as used herein refers a dialkylamino as defined herein appended to the parent molecular moiety through an aryloxy as defined herein.
The term "diarylamino" as used herein refers to (R45)(R46)N- wherein and R46 are independently aryl, for example diphenylamino and the like.
The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino group.
The term "dialkylaminocarbonyl" as used herein refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a -28-
I
WO 99/10331 PCT/US98/16479 carbonyl linkage. Examples of dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
The term "dialkylaminocarbonylalkenyl" as used herein refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
The term "dialkylaminocarbonylalkyl" as used herein refers to R50-C(0)-R51- wherein R50 is a dialkylamino group and R51 is an alkylene group.
The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.
The term "haloalkyl" as used herein refers to an alkyl radical, as defined above, which has at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2,3-difluoropentyl, and the like.
The term "haloalkenyl" as used herein refers to an alkenyl radical which has at least one halogen substituent, for example, chloromethenyl, fluoroethenyl, trifluoromethenyl or pentafluoroethenyl, 2,3-difluoropentenyl, and the like.
The term "haloalkenyloxy" as used herein refers to an haloalkenyl group as defined herein appended to the parent molecular moiety through an oxygen atom.
The term "haloalkynyl" as used herein refers to an alkynyl radical which has at least one halogen substituent, for example, chloromethynyl, fluoroethynyl, trifluoromethynyl or pentafluoroethynyl, 2,3-difluoropentynyl, and the like.
The term "haloalkoxy" as used herein refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
The term "haloalkoxyalkyl" as used herein refers to a loweralkyl radical to which is appended a haloalkoxy group.
The term "haloalkoxyhydroxyalkyl" as used herein refers to a haloalkoxy group as defined herein appended to the parent molecular moiety through a hydroxyalkyl, as defined herein.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. Examples of heterocycles include, but are not -29- WO 99/10331 PCT/US98/16479 limited to, thiophene, pyrrole, and furan. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloalkane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, furyl, tetrahydrofuranyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrimidyl and benzothienyl.
Heterocyclics also include compounds of the formula where X* is -CH2- or and Y* is or where R" is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclics can be unsubstituted or be substituted with one, two or three substituents independently selected from hydroxy, halo, oxo alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxycarbonyl, thioalkoxy, haloalkyl, mercapto, carboxy, carboxaldehyde, carboxamide, cycloalkyl, aryl, arylalkyl, -SO3H, nitro, cyano and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term "heterocyclic alkoxy" as used herein refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above. Examples of heterocyclic(alkoxy) include 4-pyridylmethoxy, 2-pyridylmethoxy and the like.
The term "heterocyclic amino" as used herein refers to a heterocyclic group as defined above appended to an amino as defined above. Examples of heterocyclic amino include 4-pyridylamino, 2-pyridylamino and the like WO 99/10331 PCT/US98/16479 The term "heterocyclic oxy" as used herein refers to a heterocyclic group as defined above appended to the parent molecular moiety through an oxygen.
Examples of heterocyclic oxy include 4-pyridyloxy, 2-pyridyloxy and the like.
The term "heterocyclic alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term "heterocyclic alkylamino" as used herein refers to a heterocyclic group as defined above appended to a alkylamino as defined above The term "heterocyclic carbonyloxyalkyl" as used herein refers to R46-C(O)-O-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
The term "heterocyclic thio" as used herein refers to a heterocyclic group as defined above appended to the parent molecular moiety through an thiol.
Examples of heterocyclic thio include 4-pyridylthio, 2-pyridylthio and the like The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkenyl" as used herein refers to an alkenyl radical to which is appended a hydroxy group. Examples of hydroxyalkenyl include 3hydroxypropenyl, 3, 4-dihydroxybutenyl and the like The term "hydroxyalkoxy" as used herein refers to an alkoxy radical as previously defined to which is appended a hydroxy group. Examples of hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is appended a hydroxy group. Examples of hydroxyalkyl include 1-hydroxypropyl, 4-hydroxybutyl, 1,3-dihydroxyisopentyl, and the like.
The term "hydroxyalkylamino" as used herein refers to a hydroxyalkyl group appenmded to the parent molecular moiety through an amino. Examples of hydroxyalkylamino include 1-hydroxypropylamino, 4-hydroxybutylamino, 1,3dihydroxyisopentylamino, and the like.
The term "hydroxyalkylthio" as used herein refers to a hydroxyalkyl group appenmded to the parent molecular moiety through an thiol. Examples of hydroxyalkylamino include 1-hydroxypropylthio, 4-hydroxybutylthio, 1,3dihydroxyisopentylthio, and the like The term "mercapto" or "thiol" as used herein refers to -SH.
-31- WO 99/10331 PCT/US98/16479 The term "nitro" as used herein refers to -N02.
The term oxoalkoxy refers to a carbonyl group attached to the parent molecular moiety through an alkoxy group.
The term "mercaptoalkoxy" or '"hioalkoxy" as used herein refers to wherein R70 is alkoxy. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
The term "tetrazolyl" as used herein refers to a radical of the formula
H,
N- N
N
or a tautomer thereof.
The term "tetrazolylalkoxy" as used herein refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above. Examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.
The term '"hioalkoxyalkoxy" as used herein refers to R80S-R810- wherein is loweralkyl as defined above and R81 is alkylene. Representative examples of alkoxyalkoxy groups include CH 3 SCH20-, EtSCH20-, t-BuSCH 2 0- and the like.
The term 'thioalkoxyalkoxyalkyl" as used herein refers to a thioalkoxyalkoxy group appended to an alkyl radical. Representative examples of alkoxyalkoxyalkyl groups include CH 3
SCH
2 CH20CH 2
CH
2
CH
3
SCH
2 0CH 2 and the like.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: 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 quaternized 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, -32- WO 99/10331 PCT/US98/16479 aralkyl halides like benzyl and phenethyl bromides, and others. Water or oilsoluble or dispersible products are thereby obtained.
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.
Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula 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.
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.
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 -33- WO 99/10331 PCT/US98/16479 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.
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, alkanoyl, such as acetyl, propionyl, butyryl, and the like; unsubstituted and substituted aroyl, such as benzoyl and substituted benzoyl; alkoxycarbonyl, such as ethoxycarbonyl; trialkylsilyl, such as trimethyl- and 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.
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.
-34- Preferred Embodiments Compounds useful in practicing the present invention include, but are not limited to: 2-(3 ,4-Dif Iuorophenyl)-4-(2-hydroxy-2-methyl-1 -propoxy)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone; Fluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylSUlfOflYl)phenYI]- 3(2H)-pyridazinone;
C
0* C.
C..
C C
C
C
C
C C
CC
C.
C
*C.C
C CC C C THIS PAGE HAS BEEN DELIBERATELY LEFT BLANK.
3.
2-(3 .4-Dif Iuorophenyl)-4-(2-hydroxy-2-methypropoxy)-5-[4-(amilosu Ito nylI) phenyll- 3 (2 H)-pyridazi none; .4-Dif luorophenyl)-4-(3-hydroxy-2- met hylpro poxy) -5-[4-(methylsulIfo nyl)phenylJ-3(2H)-pyridazinone; 2- Dif lu orophen yl)-4- hydroxy-2-met h ypropoxy)-5-[4 -(met hylsu Itonyl) phenyl]-3(2H)-pyridazinone; ,4-Difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(ami nosulfonyl)phenyl]-3(2H)-pyridazinone; Dif luorophe nyl)-4-(3 -hydroxy-2-m eth ylpro poxy) (am inosuIto ny) phenyl]-3(2H)-pyridazinone; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
300 -38- Preparation of Compounds of the Invention The compounds of the invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in Schemesl-3, below.
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, below. The dichloro-3(2H)-pyridazinone is reacted with benzyl chloride and potassium carbonate in methanol. The 2benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone is then treated with a boronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst. The methoxy group was hydrolyzed with 48% hydrobromic acid to fumish the hydroxypyridazinone compound. The 5-hydroxypyridazinone product was treated with triflic anhydride followed by substitution on the pyridazinone ring using 4methylthiobenzeneboronic acid. This furnished the methyl thioether compound which was reacted with peracetic acid in acetic acid and methylene chloride to provide the methyl sulfone. The benzyl group is removed using aluminum bromide or another suitable Lewis acid. The R group can be added via substitution using an 15 appropriate alkylating agent and base.
15 -39- WO 99/10331 WO 9910331PCTIUS98/1 6479 SCHEME 1
K
2 C0 3 PhCH 2
CI
CH
3 OH, reflux, 10 h CsF, Pd(Ph 3
P)
4
F
B(OH)
2
CH
2 Ph
CH
3 0 ci anhyd. DMVE, 100 0 C, 18 h IcH 2 Ph 48% HBr AcOH, ref lux, 7 h
(CF
3
SO
2 2 0 Pyridine, 0 OC to RT, 24 h 1. Et 3 N, Pd(Ph 3
P)
4
CH
3
B(OH)
2 Toluene,100 00, 20 min CH 3 0 2. CH- 3 00 3 H in CH 3
CO
2
H-,
CH-
2
CI
2 0 0 C, 1 h Al Br 3 Toluene, 80 00, 15 min
ICH
2 Ph WO 99/10331 PCT/US98/16479 CH30 L J- ^K 2 C0 3 RX I |j I
CH
3 o anhyd. DMF CH F
F
Another route to the compounds of the invention having Formula III is described in Scheme 2, below. The 4-bromothioanisole or other suitable thioether is reacted with a trialkoxyborate, such as trimethoxyborate or triisopropylborate to convert it to 4-(Methylthio)benzeneboronic acid The boronic acid is reacted with 2-benzyl-4,5-dibromo-3(2H)-pyridazinone using tetrakis(triphenylphosphine)palladium in dimethoxyethane. The product is then coupled with a second boronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst to provide the thioether. This furnished the methyl thioether compound which was reacted with meta-chloroperoxybenzoic acid (MCPBA) in methylene chloride to provide the methyl sulfone. The benzyl group is removed using aluminum bromide or another suitable Lewis acid. The R group can be added via substitution using an appropriate alkylating agent and base.
SCHEME 2 1) n-BuLi, (MeO) 3
B,
Br THF, -78C
B(OH)
2
CH
3 S 2) 10% NaOH, water, CH3S THF, RT N N NH K 2
CO
3 R'X NR Br O DMF Br 0 -41- WO 99/10331 PCT/US98/16479
B(OH)
2
CH
3 sS
NNR'
Pd(PPh 3 4 Na 2
CO
3 o DME, EtOH, H 2 0 r OB r N NR' CH 3
S
Br 0 Br
AN'NR'
A NR' R
B(OH)
2 0 Br o Pd(PPh 3 4 Na 2
CO
3
CH
3
S
CH
3 S DME, EtOH, H 2 0
F
N NR' A NR'
SMCPBA
CH
3 S
CH
2
CI
2 0 C CH 3 0 2 F
F
A third route to the compounds of the invention having Formula III is described in Scheme 3, below. (4-Thiomethylphenyl)dimethylthioketene acetal, mono-S-oxide was prepared by reaction of 4-thiomethylbenzaldehyde (Y is CH3S) with methyl(methylsulfinylmethyl)sulfide and sodium hydroxide. The thioketene acetal and methyl 4-fluorophenylacetate or suitable ester (X is fluorine) were treated with a strong base such as sodium hexamethyldisilazide in THF to provide the butyrate ester. The dithioacetal ketene was directly cyclized to the unsubstituted pyridazinone using hydrazine and a salt. The pyridazinone was oxidized with peroxyacetic acid to provide the sulfonyl pyridazone. In an alternate route, Scheme 3-A, the thioacetal ketene was treated with perchloric acid to provide an ester-aldehyde as a mixture of diastereomers. The oxidation products were treated with hydrazine and then oxidized with peroxyacetic acid to obtain the -42- WO 99/10331 WO 99/ 0331PCT/US9 8/16479 sulfonyl dihydropyridazinone. 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.
SCHEME 3
HO
Y.
"S,
NaOH, 70 00 0
S
NaHMDS, U'C
CO
2
CH
3
-THF
0
II
*N.
y THF, 0 0C to RT
NH
2
NH
2
HOI
8:2 DMSO/H 2 0
K
2 00 3
RX
DMF, RT 0
N,)
NR
1:11 SCHEME 3A H010 4
CH
3 CN, 0 00 56% -43- WO 99/10331 PCT/US98/16479
NH
2
NH
2 (5 eq.) EtOH, reflux, 18 h 53%
CH
3
CO
3
H
CH
2
CI
2 Br 2 AcOH, 95 °C
K
2
CO
3
RX
DMF, RT 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, and are shown in Scheme 4.
-44- WO 99/10331 PCT/US98/16479 SCHEME 4 S0 X 0 YH K2C0 3 RX R N DMF, RT Method IV: F o F o
F
NH
2
NH
2
.H
2 0I N R N- 2 ^H Na 2
CO
3 RX NR
S
OH n-BuOH ,RN DMF N MeO 2 S MeO2S MeO 2 S R 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 ring is described in Scheme 5, below. A mucohalo acid, such as, for example, mucobromic or mucochloric acid, is reacted with an hydrazine having the desired R group to provide the dihalopyridazinone compound, 5A. Treatment of the dihalo-compound with an alcohol in the presence of a base, such as, for example, sodium or potassium hydride, will provide an alkoxide, 5B. (If the alkoxy group is to be removed at a.later time then methanol is the preferred alcohol.) Reaction of the alkoxy-halide with a methylthiophenyl boronic will provide the alkoxy-pyridazinone 5C. The alkoxy group can be converted to a hydrocarbyl group by treatment with a Grignard reagent to provide the thioether 5D. The thioether can be oxidized with an oxidizing agent, such as, for example, peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G, or the methylsulfone compound 5E. Rearrangement and hydrolysis of the sulfinyl compound, 5G, provides the thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound Alternatively, the methylsulfonyl compound, 5E, can be converted to the aminosulfonyl compound by 5H by treatment of the methylsulfonyl compound with a diazodicarboxylate, such as, for example, DBAD, DIAD, DEAD and the like, and a disilazane anion, such as, for example, lithium HMDS and the like, followed by WO 99/10331 WO 9910331PCT/US98/1 6479 treatment with sodium acetate and hydroxylamine-O-sulphonic acid in water provides the aminosulfonyl compound, SCHEME 0
OH
AcOH
R-NHNH
2 0 R 97 0OH NaH 0 x
N
AcOH
R-NHNH
2 R1 7 0OH NaH
N-R
S ~B(OH) 2 Pd(PPh 3 4 CsF R 96 MgX
THF
[Ox] 0 R 96
R
S
0 [Ox]
N-
1. TFA 2. NaOH/Me.OH 3. 0 12 4. NH 4 0H H 2
N-'
I -R
A
-46- WO 99/10331 PCT/US98/16479 0 0
R
96 .R 1. DBAD/HMDS R 96 N R N 2. NaOH N 0
N
H 3. NaOAc/hydroxylamine-
S'
O0 O-sulphonic acid /H 2 0 O Alternatively, the alkoxy-pyridazinone 5C can be oxidized, as shown in Scheme 5A. The first step is employing an oxidizing agent, such as, for example, peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G', or the methylsulfone compound 5E'. Rearrangement and hydrolysis of the sulfinyl compound provides the thiophenol. The thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound Finally, the methylsulfonyl compound can be converted to the aminosulfonyl compound by 5H' by treatment of the methylsulfonyl compound 5E' with a diazodicarboxylate, such as, for example, DBAD, DIAD, DEAD and the like, and a disilazane anion, such as, for example, lithium HMDS and the like, followed by treatment with sodium acetate and hydroxylamine-O-sulphonic acid in water provides the aminosulfonyl compound, SCHEME 0 0
R
9 7 N R R97 R N O x x
N'
-N
SS
H
3 C WO 99/10331 PCT/US98/16479 S97 R R9R TFA
R
N
R [Ox] R N 2. NaOH/MeOH
R
N
.sA. .S 3. C02 12 O 4. NH 4 0H H 2
N
O
5G' 0 O R97 1. DBAD/HMDS R97 R N 2. NaOH SH3C, 3. NaOAc/hydroxylamine- S 3 0 0-sulphonic acid /H 2 0 2 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 6A, below. The thioether 5E, where R 9 6 is alkyl, methyl shown, is halogenated with a halogenating reagent, such as, for example, NBS and peroxide, to provide the bromo compound 6A. The bromo compound can be reacted with an alcohol and a weak base, such as, for example, sodium or potassium carbonate to provide the 4-alkyl-ether, 6B. The bromo compound can be reacted with a thio compound in the presence of a base, such as, for example, silver carbonate, to provide the 4-alkyl-thioether, 6C. The bromo compound can be reacted with an amine and a weak base, such as, for example, sodium or potassium carbonate to provide the 4-alkyl amino-alkyl compound 6D.
SCHEME 6 O 0
CH
3 NR NBS BrCH 2
NR
o o 4E -48- WO 99/10331 PCT/US98/16479
O
BrCH 2
N
,R
ss,,
\\J
o 0 0 BrCH 2
N
R
A N 0 0 BrCH 2
AR
0s,
R
95 0H base 1. Nal 2. R 94 SH/base 0
R
94 SCH 2R 0
N
0
R
93
NH
2 base 0 R93NHCH A NR
,N
o A general route to the compounds of the invention having Formula III, where the group at the 4-position on the pyridazinone ring can be readily substituted is illustrated in Scheme 6, above. The synthesis starts with the alkoxide, 5E', where
R
9 7 is methyl. The methoxy compound is treated with a base, such as, for example, sodium or potassium hydroxide, to provide the 4-hydroxy-pyradizinone, 6A. The alcohol is treated with p-toluenesulfonyl chloride to provide the tosyloxy compound, 6B. The tosyloxy compound can be readily substituted with a compound R 9 2 Z' that'can undergo an SN 2 reaction. Examples of these compounds are compounds such as alcohols, thiols, amines or hydrocarbyl anions.
-49- WO 99/10331 PCTIUS98/1 6479 SCHEME 6A R HO OR
SOCIS
N base 1 0j6 N O N
CH
3
SO
2 CH 3
SO
2 6A CH 3
SO
2 6B 0 O.,S'O R92Z, R92Z NR
CH
3
SO
2
CH
3
SO
2 6B 6C As used throughout this specification and the appended claims, the following abbreviations have been used: 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-tbutylazodicarboxylate, DEAD for diethyl azodicarboxylate, DIAD for disopropyl azodicarboxylate, 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 1,1,1,3,3,3hexamethyldisilazide, HWPX for Human Whole Platelet Cyclooxygenase-1, MCPBA for meta-chloroperoxybenzoic acid, NSAIDs for non-steroidal antiinflammatory drugs, PEG 400 for polyethyleneglycol, PGE2 for prostaglandin E2, PGHS for prostaglandin endoperoxide H synthase, RHUCX1 for recombinant human cyclooxygenase-1, RHUCX2 for recombinant human cyclooxygenase-2, rhu 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.
WO 99/10331 PCT/US98/16479 Compounds of the present invention include, but are not intended to be limited to, the following Examples: Example 1 4-(Methvlthio)benzeneboronic acid A stirred solution of 4-bromothioanisole (5.0 g, 0.0246 mol) in anhydrous tetrahydrofuran (THF) was chilled to -78 OC 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 °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 MgSO4 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; M.p. 170 1H NMR (300 MHz, DMSO-d 6 8 2.47 3H), 7.20 J 8 Hz, 2H), 7.71 J 8 Hz, 2H), 7.96 (br s, 2H).
Example 2 2 -Benzyl-4.5-dibromo-3(2H)-pyridazinone Benzyl bromide (0.59 mL, 0.005 mol) was added to a stirred solution of 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 MgSO4 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, M.p.
95-96 OC. 1H NMR (300 MHz, CDC 3 8 5.31 2H), 7.29-7.37 3H), 7.41-7.47 2H), 7.79 1 MS (DCI-NH 3 m/z 345 IR (KBr) 1645 cm- 1 -51- WO 99/10331 PCT/US98/16479 Example 3 2-Benzyl-4-bromo-5-[4-(methylthio)Dhenyl]-3(2H)-pyridazinone A solution of the boronic acid (0.318 g, 0.001889 mol), prepared according to the method of Example 1, the dibromopyridazinone (0.975 g, 0.002834 mol), prepared according to the method of Example 2, and tetrakis(triphenylphosphine)palladium (0.16 g, 0.0142 mol), in dimethoxyethane (30 mL) was prepared. A 2 M aqueous solution of sodium carbonate (2.83 mL, 0.005668 mol) was added to the dimethoxyethane solution and the mixture was heated 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 MgSO4, and filtered.
The filtrate was concentrated under reduced pressure to provide an oil which was purified by column chromatography (silica gel, 95:5 hexanes/ethyl acetate).
Fractions containing the desired product were combined and concentrated under reduced pressure. This material was rechromatographed (95:5 hexanes/ethyl acetate) to furnish 0.200 g of a beige solid. The solid was crystallized from ether/hexanes to provide white crystals (yield: 110 mg, 15%) M.p. 115-118 OC. 1H NMR (300 MHz, CDC13) 5 2.53 3H), 5.40 2H), 7.30-7.42 7 7.49-7.54 2H), 7.65 1H). MS (DCI-NH3) m/z 387 Example 4 2-Benzvl-4-(4-fluorophenvl)-5-4-(methylthiophenyl]-3(2H)-pyridazinone A solution of the product prepared in Example 3, (0.100 g, 0.000258 mol), 4fluorobenzeneboronic acid (0.072 g, 0.000516 mol), tetrakis(triphenylphosphine)palladium (0.015 g, 0.000013 mol), and a 2 M aqueous solution of sodium carbonate (0.64 mL, 0.001291 mol) in 30 mL of dimethoxyethane (DME) was stirred 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 MgSO4, and filtered. The filtrate was adsorbed onto silica gel. The -52- WO 99/10331 PCT/US98/16479 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 further 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, 1 H NMR (300 MHz, CDCI 3 6 2.46 (s, 3H), 5.39 2H), 6.95 J 9 Hz, 2H), 6.99 J 9 Hz, 2H), 7.11 J 9 Hz, 2H), 7.16-7.23 2H), 7.30-7.40 3H), 7.52-7.57 2H), 7.86 1 MS (DCI- NH3) m/z 403 Example 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2H)-pyridazinone A solution of meta-chloroperoxybenzoic acid (MPCBA) (0.039 g, 0.00013 mol) in dichloromethane (5 mL) was added dropwise to a stirred solution of the sulfide (0.027 g, 0.000067 mol), prepared according to the method of Example 4, in chilled (0 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 MgSO4, 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 MCPBA oxidant (0.04 g, 1 hour, 0 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, M.p.
101-103 1 H NMR (300 MHz, CDCI3) 3.05 3H), 5.40 2H), 6.95 J 9 Hz, 2H), 7.12-7.20 2H), 7.28-7.41 3H), 7.31 J 9 Hz, 2H), 7.58-7.53 (m, 2H), 7.84 1 7.87 J 9 Hz, 2H). MS (DCI-NH3) m/z 435 MS (FAB, high res.) calculated: m/z 435.1179 found: m/z 435.1184 (M+H) -53- WO 99/10331 PCT/US98/16479 Example 6 2-Benzyl-4-(4-fluorophenvl)-5-methoxy-3 (2H)-pyridazinone To a mixture of 2 -benzyl-5-methoxy-4-bromo-3(2H)-pyridazinone, prepared according to the method of S. Cho et al. described in J. Het. Chem., 1996,33, 1579-1582,, (2.94 g; 10 mmol), 4-fluorobenzeneboronic acid (1.54 g; 11 mmol), and CsF (3.04 g; 22 mmol) in 25 mL of anhydrous DME, under N2, was added Pd(Ph 3 P)4 (347 mg 0.3 mmol). After addition, the mixture was heated at reflux for at 100 OC, 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 MgSO4 and concentrated in vacuo. The solid residue was suspended in ethyl ether-hexanes and filtered to provide a solid product (yield: 3.1 g; about 100%; 95% purity). 1 H NMR (300 MHz, CDCI3) 53.90 3H), 5.36 (s, 2H), 7.09 J 9 Hz, 2H), 7.31 3H), 7.50 4H), 7.91 1H). MS (DCI-NH 3 m/z 311 328 (M+NH4)+.
Example 7 2-Benzyl-4-(4-fluorophenyl)-5-hydroxy-3 (2H)-pyridazinone A mixture of the product prepared according to the method of Example 6 (1.24 g; 4 mmol) in 20 mL of acetic acid was treated with aqueous 48% HBr 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 and the solid was filtered to provide an almost pure product (yield: 1.16 g; 1H NMR (300 MHz, DMSOd6) 5 5.24 7.21 2H), 7.30 5H), 7.55 2H), 7.85 1 11.31 (broad s, 1H). MS (DCI-NH 3 m/z 296 314 (M+NH4)+.
Example 8 2-Benzyl-44-4-fluo rophenyl)-5-(trifluoromethylsulfonyloxy)-3(2H)-pyridazinone A solution of the product prepared according to the method of Example 7, (89 mg, 0.3 mmol) in 2.5 mL of anhydrous pyridine was prepared under a N2 atmosphere and maintained at 0 oC. Triflic anhydride (Tf20; 0.06 mL; 0.32 mmol) was added to the solution, dropwise. The resulting mixture was stirred at 0 °C for minutes and at room temperature for 16 hours. (The pyridine and Tf20 should be pure for good results. Occasionally an additional amount of Tf20 is necessary to force the reaction to completion.) The mixture was then poured to a cold solution of -54- WO 99/10331 PCT/US98/16479 citric acid and extracted with ethyl acetate to obtain an almost pure product (yield: 127 mg, about 1 H NMR (300 MHz, DMSO-d6) 8 5.34 2H), 7.35 7H), 7.60 2H), 8.48 1H). MS (DCI-NH3) m/z 429 446 (M+NH4)+.
Example 9 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methvlthio)phenyll-3(2H)-pyridazinone A mixture of the product prepared according to the method of Example 8 (154 mg, 0.36 mmol), 4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et3N (0.11 mmol; 0.8 mmol) and Pd(Ph3P)4 (30 mg, 0.025 mmol) in 15 mL of toluene was heated at reflux, about 100 °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, 1 H NMR (300 MHz, CDCI3) 2.47 3H), 5.38 2H), 6.98 4H), 7.12 2H), 7.20 2H), 7.35 3H), 7.54 2H), 7.86 1 MS (DCI-NH 3 m/z 403 420 (M+NH4)+.
Example 2-Benzvl-4-(4-fluorophenvl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone To a solution of the product prepared according to the method of Example 9 (140 mg, 0.348 mmol), in 10 mL of CH2CI2, at 0 OC was added peracetic acid (CH3COOOH; 0.5 mL; The mixture was stirred at 0 °C for 90 minutes. The dichloromethane was then removed in vacuo. The residue was dissolved in ethyl acetate, washed with 10% NaHCO3, and brine. The ethyl acetate was removed under reduced pressure. The residue was chromatographed (silica gel, CH2C12diethyl ether 19:1) to provide the title compound (yield: 130 mg, 1 H NMR (300 MHz, CDCI3) 83.04 3H), 5.40 2H), 6.95 2H), 7.16 2H), 7.33 (m, 7.55 2H), 7.86 3H). MS (DCI-NH3) m/z 434 452 (M+NH4)+.
Example 11 4 -(4-Fluorophenyl)-5-[4-(methylsulfonvy)phenl]-3(2H)-pyridazinone A mixture of the product prepared according to the method of Example (37 mg, 0.085 mmol) and AIBr3 (70 mg, 0.26 mmol) in 10 mL of toluene was heated at reflux, about 80 °C for about 15 minutes and cooled to 0 OC. The cooled mixture was treated with 1N HCI 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 WO 99/10331 WO 9910331PCT[US98/1 6479 mg, 1 H NMR (300 MHz, CDCI3) 5 3.07 3H), 7.00 J 9 Hz, 2H), 7.20 (in, 2H), 7.56 J 9 Hz, 2H), 7.86 1 7.91 J 9 Hz, 2H), 10.94 (broad s, 1 H).
MS (DCI-NH3) m/z 345 362 (M+NH4)+.
Example 12 2- Phe nyl-4- (4-f luo rophenyl)-5-[ 4- (methylsu fon yl~phe nyl-3(2 H)-Pvridazi none 1 2A. 2-P henyl-4-ch loro-5-methoxy-3(2 H)-pyridazi none The 2-phenyl-4-ch lo ro-5-methoxy-3 (2 H)-pyridazi none compound was prepared according to the method of S. Cho et al. described in J. Het Chem., 1996, 33, 1579-1 582, starting with the N-phe nyl-dich loropyridazi none. A mixture of 2-phenyl-4,5-dichloro-3(2H)-pyridazinone (11 g, 4.1 mmol) and finely powdered, anhydrous K2003 (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-inethoxy-3(2H)-pyridazinone (yield: 920 mng, 1 H NMR (300 MHz, DMSO-d6) 6 4.15 3H), 7.50 (mn, 5H), 8.43 1 MS (DCI-NH3) m/z 237 254 (M+NH4)+.
1 2B. 2- Phe nyl-4-(4-f lu orophe nyl)-5- met hoxy-3 (2 H',-pyridazi none The 2-phe nyl-4-ch loro -5-inet hoxy-3 (2 H)-pyridazi none product was coupled with 4-fluorophenylboronic acid according to the method of Example 6 to provide 2phenyl-4-(4-f luorophenyl)-5-methoxy-3(2H)-pyridazi none (yield: 1.1 g; 1 H N MR (300 M Hz, C DCI13) 6 4. 00 3 7.10 J 9 Hz, 2 7.45 (in, 3 7.60 (in, 4H), 8.06 1 MS (DCI-N H3) in/z 297 1 2C. 2-Phenyl-4-(4-f luorophenyl)-5-hydroxy-3 (2 H)-pyridazi none 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 furnish 2-phenyl-4- (4-f luorophenyl)-5-hydroxy-3(2H)-pyridazi none (yield: 957 mg, MS (DCI- NH-3) m/z 283 300 (M+NH4)+.
1 2D. 2-Phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)pyridazinon The 2-phenyI-4-(4-fluorophenyl)--hydroxy-3(2H)-pyridazinone product was sulfonylated according to the method of Example 8 to furnish 2-phenyl-4-(4f luo rophe nyI)-5-trif lu oro methanesu If onyloxy-3 (2 H)-pyri dazi none (yield: 1 .35 g; 96%) MS (DCI-NH3) in/z 415 432 (M+NH4)+.
1 2E. 2 -Phenyl- 4 luorophenyl)-5-f4-(methylsulf onyl)phenyly-3(2 H)oQyridazi none -56- WO 99/10331 PCT/US98/16479 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, M.p. 219-220 1H NMR (300 MHz, DMSO-d 6 6 3.25 (s, 3H), 7.15 J 9 Hz, 2H), 7.30 2H), 7.46 1 7.56 4H), 7.64 2H), 7.90 J 9 Hz, 2H), 8.24 1H). MS (DCI-NH3) m/z 421 438 (M+NH4)+.
Example 13 4-Fluorophenylacetic acid. methyl ester A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL 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 Na2CO3, brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 1H NMR (300 MHz, CDC13) 6 3.59 2H), 3.65 3H), 7.01 J 9 Hz, 2H), 7.20-7.28 2H).
MS (DCI-NH3) m/z 186 (M+NH4)+.
Example 14 [4-(Methylthio)phenvl]dimethylthioketene acetal. mono-S-oxide A mixture of methyl(methylsulfinylmethyl)sulfide (50 g, 0.40 mol), and finely powdered sodium hydroxide (3.12 g, 0.078 mol) was stirred at 70 °C for 4 hours. 4- (Methylthio)benzaldehyde (27.4 mL, 0.195 mol) was then added in one lot and the reaction mixture was stirred at 70 °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 MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography (7:3 hexanes/ethyl acetate) to provide a solid. The solid was crystallized from ether/hexanes (yield: 24.7 g; M.p. 52- 53 OC. 1H NMR (300 MHz, CDCI3) 6 2.33 3H), 2.53 3H), 2.77 3H), 7.17 (d, WO 99/10331 PCT/US98/16479 J 9 Hz, 2H), 7.57 1 7.86 J 9 Hz, 2H). MS (DCI-NH3) m/z 259 and m/z 276 (M+NH4)+.
Example 2-(4-FluoroDhenvl)-3-[4-(methylthio)phenyl]-4-methylthio-4-methvlsulfinyl-n-butyric acid. methyl ester A solution of the ester product, prepared according to the method of Example 13, (16.24 g, 0.0966 mol) in 50 mL 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 OC, 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 oC. 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 MgSO4 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; MS (DCI-NH3) m/z 444 (M+NH4)+.
Example 16 2-(4-Fluorophenyl)-3-[4-(methythio)phenl]-3-formvl-n-proanoic acid. methyl ester The mixture of compounds, prepared according to Example 17, (9.0 g, 0.021 mol) was dissolved in acetonitrile (80 mL) and cooled to 0 OC. Perchloric acid 1.06 g, 0.006 mol) was added to the stirred solution. The reaction mixture was stirred at 0 °C for 8 hours, and quenched with 2 N aqueous Na2CO3. The acetonitrile was removed under reduced pressure and the resulting aqueous mixture was extracted with ethyl acetate. The organic solution was dried over MgSO4 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, M.p. 112-113 oC. 1H NMR (300 MHz, CDCI3) 8 2.49 3H), 2.46 (s, 3H), 4.39 2H), 7.03 J 9 Hz, 1 7.21 J 9 Hz, 1 7.25 J 9 Hz, 2H), -58- WO 99/10331 PCT/US98/16479 7.40-7.47 2H). MS (DCI-NH3) m/z 333 and m/z 350 (M+NH4)+.
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, 1 H NMR (300 MHz, CDC13) 5 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, 1 3.98 4.26 (2 d, J 12 Hz, 1 5.41 5.47 (2 d, J 6 Hz, 1 6.96 7.00 J 9 Hz, 2H), 7.11- 7.26 6H). MS (DCI-NH3) m/z 333 and m/z 350 (M+NH4)+.
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, 1 H NMR (300 MHz, CDCI3) 2.45 3H), 3.54-3.71 1 H),3.98- 4.21 1 4.61 (broad s, 1 5.85-6.01 1H), 6.98 J 9 Hz, 2H), 7.12-7.27 6H). MS (DCI-NH3) m/z 336 (M+NH4)+.
Example 17 4-(4-Fluorophenvl)-5-[4-(methylthio)phenyll-4.5-dihydro-3(2H)-pyridazinone The aldehyde-ester, hydrate, and hydroxy lactone prepared in Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred 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 HCI.
The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgSO4, 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: mg, 1 H NMR (300 MHz, CDCI3) 8 2.46 3H), 3.75 J 12 Hz, 1 3.87 J 12 Hz, 1H), 6.93-7.08 6H), 7.16 J =9 Hz, 2H), 8.71 (s(broad), 1H).
MS (DCI-NH3) m/z 315 and m/z 332 (M+NH4)+.
Example 18 4-(4-Fluorophenvl)-5-[4-(methylsulfonyl)phenyl]-4.5-dihvdro-3(2H)-pyridazinone A solution of peracetic acid, 32% in acetic acid, (0.4 mL, 1.6 mmol) was added to a stirred solution of the sulfide, prepared according to the method of Example 17, (0.050 g, 0.16 mmol) in dichloromethane, and maintained at 0 OC.
The reaction mixture was stirred for 5 hours at 0 °C then diluted with water. The organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated -59- WO 99/10331 PCT/US98/16479 under reduced pressure to provide an oil which solidified on trituration with ether (yield: 47 mg, 1 H NMR (300 MHz, CDCI3) 5 3.05 3H), 3.77 J 12 Hz, 1 4.05 J 12 Hz, 1 6.95-7.08 4H), 7.28 J 9 Hz, 2H), 7.90 J 9 Hz, 2H), 8.75 broad, 1H). MS (DCI-NH3) m/z 364 (M+NH4)+.
Example 19 4 4 -FluoroDhenyl)-5-[4-(methylsulfonyl)phenyll-3(2H)-pyridazinone The dihydropyridazinone product prepared according to the method of Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95 °C for 20 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 MgSO4 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, M.p. 255-256 °C 1 H NMR (300 MHz, CDC13) 83.07 3H), 6.98 J 9 Hz, 2H), 7.16-7.23 2H), 7.35 J 9 Hz, 2H), 7.86 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) m/z 345 and m/z 362 (M+NH4)+.
Example 2 4 -Fluorobenzyl)-4-(4-fluorophenyl-5-[4-(methylsulfonyl)phenyl-3(2
H)-
pvridazinone A solution of the nitrogen-unsubstituted pyridazinone product, prepared in Example 19 (160 mg, 0.465 mmol), K2CO 3 (193 mg, 1.4 mmol), 4-fluorobenzylbromide (0.09 mL, 0.7 mmol) and Nal (catalytic) in 10 mL of anhydrous N,N-dimethylformamide (DMF) was stirred at room temperature for 18 hours. The reaction mixture was quenched with 2N HCI, extracted with ethyl acetate (2 x mL), washed with brine and water, dried over MgSO4, 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, M.p. 153-154 1 H NMR (CDC13, 300 MHz) S3.06 3H), 5.36 2H), 6.96 J 8.4 Hz, 2H), 7.04 J 8.7 Hz, 2H), 7.16 (dd, J 9.1 Hz, J 5.4 Hz, 2H), 7.31 J 8.5 Hz, 2H), 7.54 (dd, J 8.8 Hz, 5.5 Hz, 2H), 7.84 1 7.87 J 8.8 Hz, 2H). MS (DCI-NH 3 m/z 453 WO 99/10331 WO 9910331PCT[US98/1 6479 Example 21 2-(Phenyloropargiyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenylq-3(2
H)-
prdzinone The title compound was prepared according to the method of Example substituting phenyipropargyl bromide for 4-fluorobenzyl bromide. M.p. 100-1 03 00.
1 H NMR (CDCI3, 300 MHz) 5 3.06 3H), 5.26 2H), 6.97 J 9 Hz, 2H), 7.20 (dd, J 9 Hz, J 6 Hz, 2H), 7.31 (in, 3H), 7.34 J 9 Hz, 2H), 7.48 (mn, 2H), 7.89 J 9 Hz, 2H), 7.9 1 MS (DCI-NH 3 ml/z 459 Example 22 2-(2 .4-Dif luorobenzyl)-4-(4-fluo rophenyl)-5-14-(iethvlsulfo nyl)phenyl]-3(2 H)yrdzi nn The title compound was prepared according to the method of Example substituting 2,4-difluorobenzyl bromide for 4-f luorobenzyl bromide. M.p. 179-182 1 H NMR (CDC13, 300 MHz) 6 3.06 3H), 5.45 2H), 6.87 (mn, 2H), 6.96 J= 9 Hz, 2H), 7.17 (dd, J 9 Hz, J 6 Hz, 2H), 7.32 J 9 Hz, 2H), 7.54 (in, 1 7.86 1 7.88 J 9 Hz, 2H). MS (DCI-NH3) in/z 471 Example 23 2-(Methyl-2-propenyl-4-(4-fluorophenyl)-5-4-(nethylsulfonyl)phenyll-3(2H).
The title compound was prepared according to the method of Example substituting 3-chloro-2-methylpropene for 4-fluorobenzyl bromide. M.p. 140-1 42 00 1 H NMR (CDC13, 300 MHz) 8 1.86 3H), 3.08 3H), 4.83 2H), 4.94 J 1 Hz, 1 5.05 J= 1 Hz, 1 H),6.98 J =9 Hz, 2H), 7.21 (dd, J =9 Hz, J =6Hz, 2H), 7.37 J 9 Hz, 2H), 7.89 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) in/z 399 Example 24 2-(3-Methy-2-butenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2
H)-
zi~L~a The desired compound was prepared according to the method of Example substituting 4-bromo-2-inethyl-2-butene for 4-f luorobenzyl bromide. M.p. 169- 172 00. 1 H NMR (0D013, 300 MHz) 6 1.78 3H), 1.85 3H), 3.06 3H), 4.86 J 7.5 Hz, 2H), 5.47 J 7.5 Hz, 1 6.96 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, -61 WO 99/10331 WO 99/ 0331PCTUS9816479 J 6 Hz, 2H), 7.33 J 9 Hz, 2H), 7.84 1 7.88 J 9 Hz, 2H). MS (OCi- NH3) m/z 413 Example 2-(2-Trifluoromethylbenizyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-3(2H)..
prdzinon The title compound was prepared according to the method of Example substituting 2-(trifluoromethyl)benzyl bromide for 4-fluorobenzyl bromide. M.p. 87- 00. 1 H NMR (CDCI3, 300 MHz) 8 3.07 3H), 5.66 2H), 6.97 J 9 Hz, 2H), 7.21 (dd, J 9 Hz, J 6 Hz, 2H), 7.26 J 7.7 Hz 1 7.37 J 9 Hz, 2H), 7.42 (t J 7.7 Hz, 1 7.53 J 7.7 Hz, 1 7.73 (d J 7.7 Hz, 1 7.9 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) m/z 503 Example 26 1 5 2- (Cyclopropyl meth yl)-4-(4-f lu orop1h enyl)-5-44- (met hy Isufo ny )pheny11- 3 (2 H).
The title compound was prepared according to the method of Example substituting 2- (b romo methyl)cycl opro pane for 4-f luorobenzyl bromide. M.p. 118- 121 00. 1 H NMR (00013, 300 MHz) 8 0.45-0.52 (in, 2H), 0.54-0.63 (in, 2H), 1.40- 1.52 (in, 1 3.07 3H), 4.07 J 7 Hz, 2H), 6.97 J 9 Hz, 2H), 7.19 (dd, J= 9 Hz, J 6 Hz, 2H), 7.35 J 9 Hz, 2H), 7.83 1 7.88 J 9 Hz, 2H). MS (DCI-NH3) m/z 399 and m/z 416 (M+NH4)+.
Example 27 2-(2-Pyridylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll.3(2H).
pyridazi none The title compound was prepared according to the method of Example substituting 2-(bromomethyl)pyridine for 4-fluorobenzyi bromide. M.p. 182-184 00.
1 H NMR (00013, 300 MHz) 563.07 3H), 5.56 2H), 6.95 (mn, 2H), 7.17 (in, 2H), 7.26 (in, 1 7.35 (mn, 2H), 7.46 (in, 1 7.71 (mn, 1 7.90 (in, 3H), 8.63 (in, 1 H).
MS (DCI-NH3) m/z 436 -62- WO 99/10331 WO 99/033 1PCT/US98/1 6479 Example 28 2-(L4- Pyridylmethyl)-4-(4-fluorophenyl)-5-f4-(methylsulfonyl)phenyl]-3(2
H)-
ydzin n~ The title compound was prepared according to the method of Example substituting 4-(bromomethyl)pyridine for 4-fluorobenzyl bromide. M.p. 153-1 56 00.
1 H NMR (0D013, 300 MHz) 863.07 3H), 5.40 2H), 6.97 (in, 2H), 7.17 (in, 2H), 7.34 (mn, 2H), 7.42 (in, 2H), 7.90 (in, 3H), 8.63 (in, 2H). MS (DCI-NH3) inlz 436 Example 29 2-(3-Pyridylmethyl)-4-(4-fluoropheny l)-5-[4-(inethylsulfonylphenyl-3(2H)- The title compound was prepared according to the method of Example substituting 3-(bromomethyl)pyridine for 4-fluorobenzyl bromide. M.p. 160-161 00.
1 H NMR (CD013, 300 MHz) 6 3.07 3H), 5.43 2H), 6.97 (in, 2H), 7.15 (mn, 2H), 7.34 (in, 4H), 7.35 (in, 2H), 7.87 (in, 2H), 7.97 1 8.60 (in, 1 8.81 (in, 1 H).
MS (001-N H3) m/z 436 Example 2-(6-Fluoroguinolin-2-y-methyl)-4(4-fluorophenyl)-5[4-(methylsulfonyi)phenyiL] 3(2 H) -pyridazi none The title compound was prepared according to the method of Example substituting 2-(chloromethyl)-6-fluoroquinoline for 4-fluorobenzyl bromide. M.p.
116-11900. 1 H NMR (00013, 300 MHz) 83.07 3H), 5.73 2H), 6.96 (in, 2H), 7.18 (in, 2H), 7.34 (in, 4H), 7.35 (in, 2H), 7.46 (mn, 2H), 7.58 (mn, 3H), 7.90 (in, 3H), 8.12 (in, 2H). MS (DCI-NH3) m/z 504 Example 31 2-(Qui noli n-2-ylinethyl)-4-(4-f Iuorophenyfl-5-14-(methylsulfonyl)phe nyl]-3 (2H)pyridazinone The title compound was prepared, according to the method of Example substituting 2-(chloroinethyl)-quinoline for 4-fluorobenzyl bromide. M.p. 97-100 OC.
1 H NMR (00013, 300 MHz) 863.06 3H), 5.75 2H), 6.95 (in, 2H), 7.19 (in, 2H), 7.35 (in, 2H), 7.55 (in, 2H), 7.73 (in, 1 7.82 (in, 1 7.90 (in, 3H), 8.15 (in, 2H).
MS (DOI-NH3) in/z 386 -63- WO 99/10331 PCT/US98/16479 Example 32 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-3(2 H)-yridazinethione A mixture of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone, prepared according to the method of Example 5, (109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) 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, M.p. 88-90 oC. 1H NMR (300 MHz, CDCI3) 6 3.04 3H), 6.05 2H), 6.96 2H), 7.08 2H), 7.26 2H), 7.37 3H), 7.61 2H), 7.84 J 9 Hz, 2H), 8.13 1 MS (DCI-NH3) m/z 451 (M+H) Example 33 2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone 33A. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]- 3(2H)-pyridazinone A solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared according to the method of Example 4, (450 mg, 1.12 mmol) in CH2CI2 (10 mL) was added dropwise to a suspension of hydroxy(tosyloxy)iodobenzene (439 mg, 1.12 mmol) in CH2CI2 (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 MgSO4. Removal of solvent in vacuo provided the corresponding sulfoxide (yield: 485 mg, about 100%). 1H NMR (300 MHz, CDCI3) 2.72 3H), 5.40 2H), 6.90 2H), 7.15 3H), 7.33 (m, 3H), 7.57 3H), 7.71 1H), 7.86 1H). MS (DCI-NH3) m/z 419 436 (M+NH4)+.
33B. Preparation of 2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)- 3(2H)-pyridazinone The sulfoxide was transformed into the sulfonamide according to a procedure described by M. De Vleeschauwer and J. V. Gauthier in Syn. Lett., 1997,375 with the following modifications: A suspension of the sulfoxide, prepared according to the method of Example 33A, (485 mg, 1.12 mmol) and AcONa (1.4 g) in 15 mL of Ac20 was stirred at reflux for 2 hours and concentrated in vacuo. The residue was distilled twice with toluene, dissolved in 25 mL of CH2CI2, cooled to 0 and treated with CH3CO3H (1 mL). After 1 hour, the mixture was washed, successively, with saturated NaHCO 3 and brine. The solvent was removed in vacuo. The residue was WO 99/10331 PCT/US98/16479 chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, 2-benzyl-4-(4-fluorophenyl)-5-(acetoxymethylsulfonylphenyl)-3(2H)pyridazinone (yield: 150 mg, MS (DCI-NH3) m/z 493 33C. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(sodiumsulfinate)phenyl]- 3(2H)-pyridazinone To a solution of the acetoxymethylsulfone, prepared according to the method of Example 33B, (150 mg, 0.305 mmol), in 10 mL of THF and 5 mL of methanol at 0 oC, was added 1 N NaOH (0.305 mL, 0.305 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated in vacuo, the 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, MS (DCI-NH3) m/z 443 33D. Preparation of 2-Benzvl-4-(4-fluorophenyl)-5-[4-(chlorosulfony)phenvl]- 3(2H)-pyridazinone The sodium sulfinate (about 0.31 mmol) in CH2CI2 (10 mL) was treated at 0 °C with SOCI2 (0.033 mL, 0.4 mmol) for 2 hours. The mixture was washed with brine, dried with MgSO4 and concentrated in vacuo to provide the crude sulfonyl chloride (yield: 145 mg, about 100%). MS (DCI-NH3) m/z 455 33E. Preparation of 2-Benzyl-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]- 3(2H)-pyridazinone The crude chloride prepared according to the method of Example 33D, in mL of THF, was added to a solution of 50% NH40H, in 10 mL of THF, maintained at 0 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 etherhexanes 2:1 to provide the sulfonamide (yield: 113 mg, M.p. 188-191 OC.
1 H NMR (300 MHz, DMSO-d6) 5 2.70 (dd, J 15 Hz, 2H), 5.36 2H), 7.13 J 9 Hz, 2H), 7.22 2H), 7.40 7H), 7.73 J 9 Hz, 2H), 8.11 1H). MS (DCI- NH3) m/z 436 Example 34 2-(2.2.2-Trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methvlsulfonyl)phenyl]-3(2H)pvridazinone The title compound was prepared according to the method of Example substituting 2-iodo-1,1,1-trifluoroethane for 4-fluorobenzyl bromide. M.p. 177-179 WO 99/10331 WO 9910331PCTIUS98/1 6479 00. 1 H NMR (0DC13, 300 MHz) 8 3.06 3H), 4.88 J 9 Hz, 2H), 6.98 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, J 6 Hz, 2H), 7.35 J 9 Hz, 2H), 7.89 1 7.91 J 9 Hz, 2H). MS (001-N H3) m/z 427 and m/z 444 (M+NH4)+.
Example 2-(3 .3-Dich loro-2-propenvl)-4-(4-fluorophenyl)-5-f 4-(methylsu lfonyl)p2henyll-3 (2 H)pyrianDQ The title compound was prepared according to the method of Example substituting 1,1 ,3-trichloropropene for 4-fluorobenzyl bromide. M.p. 150-152 00.
1 H NMR (CDC13, 300 MHz) 6 3.06 3H), 4.98 J 7 Hz, 2H), 6.25 J 7 Hz, 1 6.98 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, J 6 Hz, 2H), 7.33 J 9 Hz, 2H), 7.85 1 7.89 J 9 Hz, 2H). MS (DCI-NH3) m/z 453 and m/z 470 (M+NH4)+.
Example 36 2-(3-Phenyl-2-propenyl)-4-(4-fluo rophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2 H)pyridazi none The title compound was prepared according to the method of Example substituting cinnamyl bromide for 4-fluorobenzyl bromide. M.p. 165-167 00. 1 H NMR (00013, 300 MHz) 6 3.06 3H), 5.01 J 7 Hz, 2H), 6.48 (dt, J 15 Hz, 7 Hz, 1 6.79 J 15 Hz, 1 6.97 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, J 6 Hz, 2H), 7.25-7.44 (in, 5H), 7.37 J 9 Hz, 2H), 7.86 1 7.89 J 9 Hz, 2H).
MS (DCI-NH3) m/z 461 and m/z 478 (M+NH4)+.
Example 37 2-(4-Carboxyphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfo nyl)pheny1]-3 (2 H)pyridazi none The title compound was prepared according to the method of Example substituting methyl 4-(bromomethyl)benzoate for 4-fluorobenzyl bromide and hydrolysis of the resulting ester. M.p. 239-241 00. 1 H NMR (00013, 300 MHz) 6 3.06 3H), 5.46 2H), 6.96 J 9 Hz, 2H), 7.17 (dd, J 9 Hz, 6 Hz, 2H), 7.33 J 9 Hz, 2H), 7.63 J 9 Hz, 2H), 7.87 1 7.89 J 9 Hz, 2H), 8.08 (d, J 9 Hz, 2H). MS (DCI-NH 3 in/z 479 and m/z 496 (M+NH4)+.
WO 99/10331 WO 99/ 0331PCT[US98/1 6479 Example 38 2-(5-Methylthiazol-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonylhphenyll- 3(2H)-pyridazi none The title compound was prepared according to the method of Example substituting 2-(bromomethyl)-5-methylthiazole for 4-f luorobenzyl bromide. M.p.
114-116 00. 1 H NMR (d6-DMSO, 300 MHz) 862.64 3H), 3.23 2H), 5.37 (s, 2H), 7.13 (in, 2H), 7.23 (in, 2H), 7.40 1 7.47 J 8 Hz, 2H), 7.87 J 8 Hz, 2H), 8.10 1 MS (DCI-N H3) in/z 356 Example 39 2-(5-Chlorothiazol-2-vlinethyl)-4-(4-fluorophenyl)-5-f4-(methvlsulfonyl)phenyl- 3 (2 H)-p2yridazi none The title compound was prepared according to the method of Example substituting 2-(broinomethyl)-5-chlorothiazole for 4-fluorobenzyl bromide. M.p.
185-18600C 1 H NMR (d6-DMSO, 300 MHz) 6 2.32 3H), 5.50 2H), 7.15 (in, 2H), 7.24 (in, 2H), 7.47 (mn, 2H), 7.87 (mn, 3H), 8.14 1 MS (DCI-NH3) inlz 476 and in/z 493 (M+NH4)+.
Example 2-(2.3.3.4.4.4-Hexafluoro-n-buten-1 -yI)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3 (2 H)-pyridazi none The title compound was prepared according to the method of Example substituting 2,2,3,3,4,4,4-heptafluoro-1 -iodobutane for 4-fluorobenzyl bromide.
Uinder the alkylation conditions, elimination of HIF provided the unsaturated product. M.p. 167-169 OC. 1 H NMR (CDCI3, 300 MHz) 6 3.07 3H), 7.00 J 9 Hz, 2H), 7.17 (dd, J 9 Hz, 6 Hz, 2H), 7.33 J 9 Hz, 2H), 7.68 J 24 Hz, 1 H), 7.93 J 9 Hz, 2H), 8.01 1 MS (DCI-NH3) m/z 507 and in/z 524 (M+N H4)+.
Example 41 2-(2 .4-Dif luorophenacyl)-4-(4-f luorophenyl)-5-14-(methylsulfonyl)phenyl]-3 (2H)pyridazinone The title compound was prepared according to the method of Example substituting 2-chloro-2',4'-difluoroacetophenone for 4-fluorobenzyl bromide. M.p.
191-192 00. 1 H NMR (CDC1 3 300 MHz) 6 3.08 3H), 5.57 J 3 Hz, 2H), 6.94- 7.07 (in, 2H), 6.96 J 9 Hz, 2H), 7.39 (dd, J 9 Hz, 6 Hz, 2H), 7.91 1 7.91 -67- WO 99/10331 WO 9910331PCTIUS98/1 6479 J 9 Hz, 2H), 8.03-8.12 (in, 1 MS (DCI-NH3) mlz 499 and m/z 516 (M+NH4)+.
Example 42 2-(5-Chlorothien-2-ylmethyl)-4-(4-fluorophenyl)-5-f4-(methylsulfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting 2-(bromomethyl)-5-chlorothiophene for 4-fluorobenzyl bromide. M.p.
139-1 41 OC0 1 H NMR (d6-DMSO, 300 MHz) 8 3.23 3H), 5.43 (s 2H), 7.03 J 4 Hz, 1 7.09-7.29 (in, 5H), 7.47 J 8 Hz, 2H), 7.87 J 8 Hz, 3H), 8.13 (s, 1 MS (001-N H3) m/z 474 and mlz 492 (M+NH4)+.
Example 43 2-(5-Methylthien-2-ylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phe nyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting 2- (bro mo met hyl)-5-methylth iophene for 4-f luorobenzyl bromide. M.p.
172-175 OC. 1 H NMR (d6-DMSO, 300 MHz) 8 3.22 3H), 5.49 2H), 7.03 (in, 1 7.14 (in, 2H), 7.23 (in, 3H), 7.48 (in, 3H), 7.86 (mn, 2H), 8.11 1 MS (DCI- NH3) mlz 441 and m/z 458 (M+NH4)+.
Example 44 2-(4-Diethylainophenacyl)-4-(4-fluorophenyl)-5-[4-(inethylsulfonyl)phenyll-3(2H)- The title compound was prepared according to the method of Example substituting 2-ch loro-4'-diethylainoacetophe none for 4-f luorobenzyl bromide.
M.p. 105-10800C 1 H NMR (CDCI3, 300 MHz) 8 1.23 J 7 Hz, 3H), 3.07 3H), 3.44 J 7 Hz, 2H), 5.61 2H), 6.66 J 9 Hz, 2H), 6.94 J 9 Hz, 2H), 7.21 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J 9 Hz, 7.87-7.94 (mn, 4H), 7.90 1 MS (DCI-NH3) in/z 534 Example 2-(2.3.4.5 Pentaf luo robe nzyl)-4- (4-flIuorophenyl)-5-44-(inethylsuIf onyl)phenyll- 3(2H)zpyridazinone The title compound was prepared according to the method of Example substituting 2,3,4,5,6-pentafluorobenzyl bromide for 4-f luorobenzyl bromide. M.p.
-68- WO 99/10331 WO 9910331PCTJUS98/1 6479 115-116 0CQ 1 H NMVR (C0013, 300 MHz) 3.06 3H), 5.50 2H), 6.96 J 9 Hz, 2H), 7.17 (dd, J 9 Hz, 6 Hz, 2H), 7.33 J 9 Hz, 2H), 7.82 1 7.89 J 9 Hz, 2H). MS (DCI-NH3) m/z 525 and mn/z 542 (M+NH4)+.
Example 46 2-(P henacyfl-4-(4-fluorophenyl)-5-[4-(methylsu lfonyl)Phenyl1-3(2H)-pyridazi none The title compound was prepared according to the method of Example substituting 2-bromoacetophe none for 4-fluorobenzyl bromide. M.p. 228-230 00.
1 H NMVR (00013, 300 MHz) 3.07 3H), 5.68 2H), 6.95 J 9 Hz, 2H), 7.20 (dd, J =9 Hz, 6 Hz, 2H), 7.38 J =9Hz, 2H), 7.53 J =7 Hz, 2H), 7.65 J =7 Hz, 1 7.90 J 9 Hz, 2H), 7.91 1 8.04 J 7 Hz, 2H). MVS (001-N H3) mlz 463 and m/z 480 (M+NH4)+.
Example 47 2-(4-Chlorophenacvl)-4-(4-fluorophenyl-5-4-(methylsulfonyl)phenyl..3(2H).
pyridazinone The title compound was prepared according to the method of Example substituting 2-bromo-4'-chloroacetophenone for 4-fluorobenzyl bromide. M.p. 186- 18800C 1 H NMR (CDC13, 300 MHz) 3.07 5.63 2H), 6.95 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J 9 Hz, 2H), 7.51 J 9 Hz, 2H), 7.65 J 7 Hz, 1 7.90 J 9 Hz, 2H), 7.91 1 7.98 J 9 Hz, 2H). MS (DCI- NH3) m/z 497 and m/z 514 (M+NH4)+.
Example 48 2 -(Proparayl)-4-(4-fluorophenyl)-5-4-(methvI ulfonyl)phenyll-3(2H)-pyridpzinone The title compound was prepared according to the method of Example substituting propargyl bromide for 4-f luorobenzyl bromide. M.p. 196-198 00. 1 H NMR (CDCI3, 300 MHz) 2.42 J 3 Hz, 1 3.06 3H), 5.04 J 3 Hz, 2H), 6.97 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.34 J 9 Hz, 2H), 7.90 (s, 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) m/z 383 and m/z 400 (M+NH4)+.
-69- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 49 2-(4-C.Yanophenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2HLJIi pyridazinone The titie compound was prepared according to the method of Example substituting 2-bromo-4'-cyanoacetophenone for 4-fluorobenzyl bromide. M.p. 188- 18900C 1 H NMR (CDCI3, 300 MHz) 3.08 3H), 5.64 2H), 6.96 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J =9 Hz, 2H), 7.84 J 9 Hz, 2H), 7.91 J -9 Hz, 2H), 7.93 1 8.14 J 9 Hz, 2H). MS (DCI-NH3) m/z 488 Example 2-(ca-Methyl-4-fluorobenzyI)-4-(4-fluorophenyl)-5-[4-(methylsu lfonyl)phenyll-3 (2 H)- The title compound was prepared according to the method of Example substituting a-methyl1-4-f lu orobe nzyl bromide for 4-fluorobenzyl bromide. M.p. 162- 164 00. 1 H NMR (CDCI3, 300 MHz) 3.06 3H), 6.40 J 9 Hz, 2H), 6.95 J 9 Hz, 2H), 7.05 J 9 Hz, 2H), 7.15 (dd, J 9 Hz and 6 Hz, 2H), 7.31 J 9 Hz, 2H), 7.53 (dd, J 9 Hz and 6 Hz, 2H), 7.87 J 9 Hz, 2H), 7.88 1 MS (DCI- NH3) m/z 467 and m/z 484 (M+NH4)+.
Example 51 2-Phenethyl-4-(4-fluorophenl)-5-4-(methylsulfonyl)henyl..3(2H)-.pyridazi none The title compound was prepared according to the method of Example substituting (2-bromoethyl)benzene for 4-fiuorobenzyl bromide. M.p. 170-171 00.
1 H NMR (CDCI3, 300 MHz) 3.07 3H), 3.20 J 9 Hz, 2H), 4.28 J 9 Hz, 2H), 6.98 J 9 Hz, 2H), 7.18 (dd, J 9 Hz and 6 Hz, 2H), 7.22-37 (in, 5 7.34 J 9 Hz, 2H), 7.83 1 7.89 J 9 Hz, 2H). MS (DCI-NH 3 m/z 449 and m/z 466 (M+NH4)+.
Example 52 2 -Benzyl-4-(3-chloro-4-fluorophenyl)-5-[4-(methylsulfonyl)phenyllI3(2H)pyrdazinone 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. M.p. 134-136 00. 1 HNMR (0D013, 300 MHz) 3.06 3H), 5.41 2H), 6.96-7.02 (in, 2H), 7.29-7.41 (mn, 3H), 7.33 J 9 Hz, WO 99/10331 WO 9910331PCTIUS98/1 6479 2H), 7.51-7.56 (in, 2H), 7.85 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) mlz 469 and m/z 486 (M+NH4)+.
Example 53 2-Benzyl-4- (4-ch lorophenyl)-544-(methylsuIfon yl)phe nyll-3 (2 H)pyridazi none 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. M.p. 157-159 00. 1 H NMR (CDCI3, 300 MHz) 3.05 3H), 5.40 2H), 7.11 J 9 Hz, 2H), 7.24 J 9 Hz, 2H), 7.28-7.40 (mn, 2H), 7.31 J 9 Hz, 2H), 7.51-7.57 (in, 2H), 7.84 1 7.88 J 9 Hz, 2H).
MS (DCI-NH3) in/z 451 and m/z 468 (M-iNH4)+.
Example 54 2-(2.2.2-TrifluoroethyI)-4-(3-chloro-4-fluoropheny)-5-[4-(methylsulfonyl)phenyll- 3(2H)-pyridazinone 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 M.p. 165-16600C 1 H NMR (CDCI3, 300 MHz) 3.07 3H), 4.89 9 Hz, 2H), 7.00-7.06 (mn, 2H), 7.31-7.35 (in, 1 7.37 J 9 Hz, 2H), 7.90 1 7.94 J= 9 Hz, 2H). MS (DCI-NH3) in/z 461 and m/z 478 (M+NH4)+.
Example 2-(4-Trifluoroinethoxyphen acyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl- 3 (2H)-pyridazi none The title compound was prepared according to the method of Example substituting 2-bromo-4'-trifluoromethoxyacetophenone for 4-fluorobenzyl bromide.
M.p. 160-161 00. 1 H NMR (CDCI3, 300 MHz) 3.08 3H), 5.65 2H), 6.96 J 9 Hz, 2H), 7.20 (dd, J 9 Hz, 6 Hz, 2H), 7.37 J 9 Hz, 2H), 7.91 J 9 Hz, 2H), 7.93 1 8.11 J 9 Hz, 2H). MS (DCI-NH3) m/z 547 and m/z 564 (M+NH4)+.
-71- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 56 2-(4-Trifluoromethylphenacyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p2henyl..
3(2 H)-pyridazi none The title compound was pr epared according to the method of Example substituting 2-bro mo-4'-trif luoro methylacetoph enone for 4-fiuorobenzyl bromide.
M.p. 205-20600C 1 H NMR (CDCI3, 300 MHz) 3.07 3H), 5.66 2H), 6.96 J= 9 Hz, 2H), 7.20 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J 9 Hz, 2H), 7.80 J 9 Hz, 2H), 7.91 J 9 Hz, 2H), 7.92 1 8.15 J 9 Hz, 2H). MVS (DCI-NH3) m/z 531 and m/z 548 (M+NH4)+.
Example 57 24[2- (Ben zo~b~t hie n-3-yi)-2-oxoeth yll-4- (4-f lu orophe nyl)-5- (meth Ylsuf on yl).
phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 1 5 substituting 3-chloroacetylbenzo[b]thiophene for 4-f luorobenzyl bromide. M.p. 183- 18400C 1 H NMR (CDCI3, 300 MHz) 3.08 3H), 5.68 2H), 6.96 J 9 Hz, 2H), 7.21 (dd, J 9 Hz, 6 Hz, 2H), 7.39 J 9 Hz, 2H), 7.42-7.54 (in, 2H), 7.91 J 9 Hz, 2H), 7.91 J 7 Hz, 1 7.94 1 8.53 1 8.72 J 7 Hz, 1 MS
(DCI-NH
3 m/z 519 Example 58 2-(2.2 .2-Trifluoroethyl)-4-(4-chlorophenyl)-5-f4-(methylsulfonyl)phenyl-3(2H).
The title compound was prepared by N-debenzylation of the product, prepared in Example 54 according to the method of Example 12, followed by alkylation with 2-iodo-1 ,1 ,1-trifluoroethane according to the method of Example M.p. 55-57 OC. 1 H NMR (CDCI3, 300 MHz) 3.07 3H), 4.88 U 9 Hz, 2H), 7.13 J 9 Hz, 7.26 J 9 Hz, 2H), 7.36 JU 9 Hz, 2H), 7.89 1 7. 92 (d, J 9 Hz, 2H). MS (DCI-NH 3 m/z 443 and m/z 460 (M+NH4)+.
Example 59 2 -(3.3-Dimethyl-2-oxobutyl)-4-(4-fluorophenyl)-5-.4-.(melhylsulfonyl)pheny11-3(2H).
The title compound was prepared according to the method of Example substituting 1 -bromopinacolone for 4-fluorobenzyl bromide. M.p. 168-170 00. 1 H NMR (00013, 300 MHz) 1.31 9H), 3.06 3H), 5.21 2H), 6.95 J 9 Hz, -72- WO 99/10331 WO 9910331PCT/US98/I 6479 2H), 7.17 (dd, J 9 Hz, 6 Hz, 2H), 7.35 J 7 Hz, 2H), 7.86 1 H) 7.89 J 9 Hz, 2H). MS (DCi-NH3) m/z 443 and mlz 460 (M+NH4)+.
Example 2-(3-Thienylmethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenl-3(2H).
pyridazi none The title compound was prepared according to the method of Example substituting 3-(chloromethyl)thiophene for 4-fluorobenzyl bromide. M.p. 169-172 00. 1 H NMR (300 MHz, DMVSO d6) 8 3.22 5.36 2H), 7.18 (in, 5H), 7.51 (in, 4H), 7.88 (mn, 2H); 8.08 1 MS (DCI-NH3) in/z 441 and m/z 458 Example 61 2-(2-Benzoiblthienylmethvl)-4-(4-fluoroohenyl)-5-[4-(methylsulfonyl)phenyl..3(2
H)-
pyridazinone The title compound was prepared according to the method of Example substituting 2-(chloromethyl)benzo[b]thiophene for 4-fluorobenzyl bromide. M.p.
93-96 00. 1 H NMR (300 MHz, COCl 3 5 3.05 3H), 5.64 2H), 6.97 (in, 2H), 7.18 (in, 2H), 7.33 (in, 5H), 7.78 (in, 2H), 7.86 (in, 3H). MS (DCI-NH 3 m/z 491 and m/z 508 (M+NH4)+.
Example 62 2 Bis(4-f luoroghenyl)-5-[4-(methylsu Ifo nyl)ph enyll.3 (2 H)-pyridazi none A mixture of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (172 mng, 0.5 inmol), prepared according to the method of Example Cu powder (32 mg), anhydrous K2003 (207 mg, 1.5 mmol) and 4fluoroiodobenzene (0.12 mL, 1 inmol) 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, CH2CI2-diethyl ether 15:1) provided 190 mg of crude product. Crystallization from CH2CI2-diethyl etherhexanes furnished the title compound (yield: 175 mng, M.p. 168-1 69 00.
1 H NMR (300 MHz, CDCI3) 5 3.07 3H), 6.98 9 Hz, 2H), 7.20 (in, 4H), 7.40 J 9 Hz, 2H), 7.69 (in, 2H), 7.92 J 9 Hz, 7.98 1 MS (DCI-NH3) -73- WO 99/10331 WO 99/ 0331PCT/US98/I 6479 m/z 439 456 Anal. caic. for C23H16F2N203S-0.25 H20: C, 62.36; H, 3.75; N, 6.32. Found: C, 62.23; H, 3.55; N, 6.26.
Example 63 4-(4-Fluorophenyfl-5-[4-(methylsulfonyl)phenyll-6-methyl-3(2H)-pyridazi none 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 ref lux for 18 hours. On cooling, white crystals (224 mg, 50%) were obtained. M.p. 290 00C (dec.) 1 HNMR (300 MHz, d6-DMSO) 861.99 3H), 3.10 3H), 7.05 J 9 Hz, 2H), 7.15 (dd, J 6 Hz, J 9 Hz, 2H), 7.48 J 9 Hz, 2H), 7.85 J 9 Hz, 2H), 13.10 (br s, 1 MS (DCI/NH3) 376 Anal. caic. for C18H15N2FSO 3 0.25 H20: C, 59.57; H, 4.30; N, 7.71. Found: 0, 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 )-pyridazi none 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 00 for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 1 HNMR (300 MHz, CDCI3) 6 2.10 3H), 3.10 3H), 4.85 J 9 9Hz, 2H), 6.90 (in, 2H), 7.10 (dd, J 6 Hz, J 9 Hz, 2H), 7.25 (in, 2H), 7.95 J =9 Hz, MS (DCI/NH3) 458 (M+NH4)+ Anal. caic. for 020H1 6N2F4S03: C, 54.54; H, 3.66; N, 6.36.
Found: C, 54.41; H, 3.56; N, 6.35.
Example 2-Benzyl-4-(3 .4-dichlorophenyl)-5-[4-(methylsu lfonyl)phenyll-3 (2H)-pyridazinone The title compound was prepared by coupling 3,4-dichlorophenylboronic acid with 2-benzyl-4-bromo-5-methoxy-3(2 H)-pyridazi none 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 compound was converted to the 5-trifluoromethylsufonyloxy-derivative according to the method of Example 8. Coupling of 4-(methylthio)phenylboronic acid to the trif late according to the method of Example 9 provided the 5-[4-(methylthio)phenyl]- -74- WO 99/10331 PCTIUS98/16479 intermediate which was oxidized according to the method of Example 10 to provide the final product (yield: 780 mg, M.p. 161-163 oC. 1 H NMR (300 MHz, DMSO-d6) 8 3.22 3H), 5.35 2H), 7.08 (dd, J 9 Hz, 3 Hz, 1 7.32-7.44 (m, 7.47 (dd, J 9 Hz, 3 Hz, 3H), 7.48 J 3 Hz, 1 7.90 J 9 Hz, 2H), 8.13 1H). MS (DCI-NH3) m/z 485 Anal. calc. for C24H18Cl2N20 3 S: C, 59.38; H, 3.73; N, 5.77. Found: C, 59.28; H, 3.92; N, 5.42.
Example 66 2-(2.2.2-Trifluoroethyl)-4-(4-n-propylpheny)-5-[4-(methylsulfonv)phenyl]-3(2H)pyridazinone The title compound was prepared by coupling 4-(n-propyl)phenylboronic acid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone 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, M.p. 64-66 OC. 1H NMR (300 MHz, CDCI3) 8 0.91 J 7.5 Hz, 3H), 1.6 J 7.5 Hz, 2H), 2.55 J 7.5 Hz, 2H), 3.05 (s, 3H), 4.88 J 9 Hz, 2H), 7.08 4H), 7.35 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 7.87 1H). MS (DCI-NH3) m/z 451 Anal. calc. for C22H21 F3N203S: C, 58.65; H, 4.69; N, 6.21. Found: C, 58.71; H, 4.72; N, 6.20.
Example 67 2-(2.2.2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-vyridazinone The title compound was prepared by first coupling 3-fluoro-4chlorophenylboronic acid with 2-benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone according to the method of Example 6. The product was converted to the 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, M.p. 174-175 1 H NMR (300 MHz, CDCI3) 3.09 3H), WO 99/10331 PCT/US98/16479 4.89 J 9 Hz, 2H), 6.87 (dm, J 9 Hz, 1 7.09 (dd, J 9 Hz, 3 Hz, 1 7.30 (t, J 9 Hz, 1 7.39 J 9 Hz, 2H), 7.91 1 7.95 J 9 Hz, 2H). MS (DCI- NH3) m/z 461 Anal. calc. for C1 9H13CIF4N203S: 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-Trifluoroethvl)-4-(4-fluorophenvl)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyridazinone A solution of 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (680 mg, 1.53 mmol) in trifluoroacetic anhydride mL) was stirred at room temperature for 1 hour. The excess solvent was evaporated in vacuo and the residue was treated with a deoxygenated 1 N solution of methanol-NaOH (50 mL, 4:1) at 0 The solution was stirred at room temperature for 2 hours and quenched with dilute HCI 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 oC. After minutes, nitrogen gas was bubbled into the solution for a few minutes to displace residual chlorine. Ammonium hydroxide solution 5 to 10 mL), at 0 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 MgSO4, 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, M.p. 193-195 1H NMR (300 MHz, CDCI3) 8 4.82 2H), 4.88 J 9 Hz, 2H), 6.98 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.30 J 9 Hz, 2H), 7.88 J 9 Hz, 2H), 7.90 1 MS (DCI- NH3) m/z 428 Anal. calc. for C18H13F4N303S: 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-chloroohenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyridazinone 69A. 2-Benzyl-4-chloro-5-14-(methylthio)phenvyl-3(2H)-pyridazinone The title compound was prepared according to the method of Example 77.
The product was coupled with 4-chlorophenylboronic acid following the method of -76- WO 99/10331 PCT/US98/16479 Example 6. The 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 to provide the sulfice compound.
69B. 2-Benzyl-4-chloro-5-r4-(methylsulfinyl)phenyll-3(2H)-pyridazinone The sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta-chloroperoxybenzoic acid to provide the corresponding methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 540 mg, M.p. 154-156 1H NMR (300 MHz, CDCI3) 8 4.86 2H), 4.87 J 9 Hz, 2H), 7.14 J 9 Hz, 2H), 7.29 J 9 Hz, 2H), 7.31 J 9 Hz, 2H), 7.89 J 9 Hz, 2H), 8.00 1H). MS (DCI-NH 3 m/z 444 Anal. calc. for C18H13CIF3N30 3 S: C, 48.71; H, 2.95; N, 9.46. Found: C, 49.05; H, 3.01; N, 9.15.
Example 2-(2.2.2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyridazinone The methyl sulfide intermediate prepared in Example 83 was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 396 mg, M.p. 158-160 1 H NMR (300 MHz, CDCI3) 1.21 J 6 Hz, 6H), 4.83 J 7.5 Hz, 2H), 4.86 2H), 5.46 J 6 Hz, 1 H), 7.72 J 9 Hz, 2H), 7.82 1 8.03 J 9 Hz, 2H). MS (DCI-NH3) m/z 392 Anal. calc. for C15H16F3N304S: 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)phenl]-3(2H)pvridazinone 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, M.p. 150-152 1 H NMR (300 MHz, CDCI3) 84.71 J 7.5 Hz, 2H), 4.72 2H), 6.88 (dd, J 9 Hz, 4.5 Hz, 2H), 7.0 J 9 Hz, 2H), 7.73 J 9 Hz, 2H), 7.98 1 8.05 J 9 Hz, 2H). MS (DCI-NH3) m/z 444 Anal. calc. for C18H13F4N 3 0 4 S: C, 48.76; H, 2.95; N, 9.47. Found: C, 48.49; H, 2.8; N, 8.95.
-77- WO 99/10331 PCT/US98/16479 Example 72 2.4-Bis-(4-fluorophenyl)-5-[3-fluo ro-4-(aminosulfonyl)phenyl-3(2 H)-pyridazi none 72A-1. 2-Fluorothioanisole A deoxygenated solution of 2-fluorothiophenol (10 g, 78 mmol) in anhydrous DMF (10 mL) was treated with iodomethane (4.9 mL, 78 mmol) and potassium carbonate (10.8 g, 78 mmol). The reaction mixture was stirred at room temperature for 1 hour. A thin layer chromotography (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 X 125 mL). The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide the desired compound as a pale yellow oil (yield: 6.68 g; 72A-2. 2-Fluorothioanisole 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 MgSO4, 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, 1H NMR (300 MHz, CDCI3) 8 2.46 3H), 6.98-7.19 3H) 2.26 (dt, J 9 Hz, 3 Hz, 1H).
72B. 4-Bromo-2-fluorothioanisole A solution of 2-fluorothioanisole (1.42 g, 10 mmol) and iron powder (0.03 g, 0.5 mmol) in dichloromethane (20 mL) was chilled to °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 WO 99/10331 PCT/US98/16479 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 MgSO4, 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; 1H NMR (300 MHz, DMSO-d 6 2.48 (s, 3H), 7.31 J 9 Hz, 1 7.43 (dd, J 9 Hz, 3 Hz, 1 H) 7.54 (dd, J 9 Hz, 3 Hz, 1 H).
72C. 3-Fluoro-4-(methylthio)benzeneboronic acid A solution of 4-bromo-2-fluorothioanisole (0.5 g, 22.6 mmol) in dry THF mL) was chilled to -78 "C under a nitrogen atmosphere. The reaction mixture was treated with 1.6 M n-butyllithium in hexanes (1.7 mL, 27.1 mmol), and the mixture was warmed to -40 0 C where it was maintained for 0.5 hours. The reaction mixture was then chilled to -780C 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 HCI mixture with stirring to yield a white precipitate. This solid was dried in a vacuum oven (65 oC, 29 in Hg) overnight to provide the title compound (yield: 0.22 g; 1 H NMR (300 MHz, DMSO-d6) 5 2.48 3H), 7.31 J 9 Hz, 1 7.49 (dd, J 12 Hz, Hz, 1 H) 7.54 (dd, J 9 Hz, 1.5 Hz, 1 H).
72D. 2.4-Bis-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)poridazinone 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone 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-analog 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 WO 99/10331 PCT/US98/16479 resulting sulfide 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: 500 mg, M.p. 222- 224 OC. 1 H NMR (300 MHz, CDCl3) 5.06 2H), 7.01 J 9 Hz, 2H), 7.06 J 9 Hz, 2H), 7.10 J 9 Hz, 2H), 7.18 J 9 Hz, 2H), 7.69 (dd, J 9 Hz, 3 Hz, 2H), 7.88 J 9 Hz, 1 7.95 1H). MS (DCI-NH3) m/z 458 Anal. calc.
for C22H14F3N303S: C, 57.76; H, 3.08; N, 9.18. Found: C, 57.5; H, 3.15; N, 8.8.
Example 73 2-(2.2.2-Trifluoroethyl)-4-(3-fluoro-4-chlorophenyl)-5-4-(aminosulfony)phenyl]- 3(2H)-pyridazinone 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%).
M.p. 180-183 1 H NMR (300 MHz, DMSO-d6) 8 5.09 J 9 Hz, 2H), 7.01 (dd, J 9 Hz, 3 Hz, 1 7.15 (dd, J 9 Hz, 3 Hz, 1 7.39 (dd, J 9 Hz, 3 Hz, 1 7.47 (dd, J 9 Hz, 3 Hz, 1 7.55 J 9 Hz, 1H), 7.71 J 9 Hz, 1 7.78 2H), 8.37 1H). MS (DCI-NH3) m/z 480 Anal. calc. for C18H1 1CIF5N303S: C, 45.05; H, 2.31; N, 8.75. Found: C, 46.19; H, 3.02; N, 7.43.
Example 74 2-Benzvl-4-(2-DroDoxy)-5-f4-(methylsulfonyl)phe nyl-3(2H)-pyridazinone 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone 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-analog 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, M.p. 109-111 OC. 1H NMR (300 MHz, CDCI3) 8 1.18 J 6 Hz, 6H), 3.12 3H), 5.36 2H), 5.49 J 6 Hz, 1 7.35 3H), 7.47 (dd, J 9 Hz, 3 Hz, 2H), 7.74 J 9 Hz, 2H), 7.79 1 8.03 J 9 Hz, 2H). MS (DCI-NH3) m/z 399 WO 99/10331 WO 99/033 1PCTIUS98/1 6479 Anal. caic. for 021 H22N204S: C, 63.29; H, 5.56; N, 7.03. Found: C, 63.17; H, 5.57; N, 6.95.
Example 2-Benzyl-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone The title compound was prepared according to the method'of Example 74 substituting 4-fluorophenol in place of 2-propanol (yield: 180 mg, M.p. 188- 190 00C. 1 H NMR (300 MHz, CDCI3) 6 3.12 3H), 5.26 2H), 6.86 (dd, J 9 Hz, 6 Hz, 2H), 6.99 J 9 Hz, 2H), 7.34 (in, 3H), 7.46 (dd, J 9 Hz, 3 Hz, 2H), 7.72 (d, J 9 Hz, 2H), 7.92 1 8.02 J 9 Hz, 2H). MS (DCI-NH3) m/z 451 Anal. calc. for C24H1 9FN204S: C, 63.98; H, 4.25; N, 6.21. Found: C, 63.74; H, 4.2; N, 6.12.
Example 76 1 5 2-(2.2.2-Trifluoroethyl)-4-(4-fluorophenoxy)-5-r4-(methylsulfonyl)phenfl1-3(2H)pyridazi none The title compound was prepared according to the method of Example substituting 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-benzyl-4-chloro-5-[4-(methylsu lfonyl)phenyl]-3(2H)pyridazinone (yield: 180 mg, M.p. 161-16400C 1 H NMR (300 MHz, CDCI3) 6 3.09 3H), 4.81 J 9 Hz, 2H), 6.88 (dd, J 9 Hz, 4.5 Hz, 2H), 7.0 J 9 Hz, 2H), 7.78 J 9 Hz, 2H), 7.79 1 8.06 J 9 Hz, 2H). MS (DCI-NH3) m/z 443 Anal. calc. for C1 9H1 4F4N204S: 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-(methylsu If inyl)phenyl]-3 (2 H)- 2-Benzyl-4-chloro-5-methoxy-3 (2H)-pyridazi none 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-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-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazi none. This intermediate was coupled with 4chlorophenylboronic 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- -81- WO 99/10331 PCT/US98/16479 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 metachloroperoxybenzoic acid, according to the method of Example 5 to provide the title compound (yield: 130 mg, M.p. 154-155 oC. 1 H NMR (300 MHz, CDCI3) 2.74 3H), 4.88 J 9 Hz, 2H), 7.14 J 9 Hz, 2H), 7.26 J 9 Hz, 2H), 7.31 J 9 Hz, 2H), 7.61 J 9 Hz, 2H), 7.82 1H). MS (DCI-NH 3 m/z 427 Anal. calc. for C19H14CIF3N202S: C, 53.46; H, 3.3; N, 6.56. Found: C, 53.58; H, 3.34; N, 6.42.
Example 78 2-Benzvl-4-chloro-5-[4-(methvlsulfonvl)phenyl-3(2H)-pyridazinone The title compound was prepared by oxidizing 2-benzyl-4-chloro-5-[4- (methylthio)phenyl]-3(2H)-pyridazinone, (prepared as an intermediate in Example 77) according to the method of Example 10 (yield: 180 mg, M.p. 166-167 OC.
1 H NMR (300 MHz, CDCI3) 5 3.12 3H), 5.41 2H), 7.37 3H), 7.53 (dd, J 9 Hz, 3 Hz, 2H), 7.68 J 9 Hz, 2H), 7.74 1 8.08 J 9 Hz, 2H). MS (DCI- NH3) m/z 375 Anal. calc. for C18H15CIN203S: 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-Trifluoroethvl)-4-(4-methylphenyl)-5-[4-(methylsulfonyl)phenyl-3 (2H)ovridazinone 2-Benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone 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 4methylphenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the title compound according to the method of Example (yield: 210 mg, M.p. 154-156 oC. 1 H NMR (300 MHz, CDCI3) 5 2.33 3H), 3.07 3H), 4.89 J 9 Hz, 2H), 7.08 4H), 7.37 J 9 Hz, 2H), 7.88 1 H), 7.89 J 9 Hz, 2H). MS (DCI-NH3) m/z 423 Anal. calc. for C20H17F3N 2 0 3 S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.59; H, 4.11; N, 6.53.
-82- WO 99/10331 PCT/US98/16479 Example 2-(22.2-Trifluoroethyl)-4-(4-chloro-3-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]- 3(2H)-pyridazinone 2-Benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone 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-chloro-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone. This intermediate was coupled with 4-chloro-3fluorophenylboronic acid according to the method of Example 6. This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2iodo-1,1,1-trifluoroethane according to the method of Example 20. The resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of metachloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 500 mg, M.p. 214-215 1 H NMR (300 MHz, CDC13) 54.82 2H), 4.88 J 9 Hz, 2H), 6.88 1 7.09 (dd, J 9 Hz, 3 Hz, 1 7.31 J 9 Hz, 1 7.32 (d, J 9 Hz, 2H), 7.90 1H), 7.92 J 9 Hz, 2H). MS (DCI-NH3) m/z 462 Anal. calc. for C18H12F4CIN 3 0 3 S: C, 46.81; H, 2.61; N, 9.09. Found: C, 46.79; H, 2.59; N, 8.86.
Example 81 2-(2.2.2-Trifluoroethyl)-4-(3.4-dichlorophenyl-5-[4-(methylsulfonyl)phenyl]-3(2H)pvridazinone 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, M.p. 197-198 1
H
NMR (300 MHz, CDCI3) 8 3.09 3H), 4.88 J 9 Hz, 2H), 6.98 (dd, J 9 Hz, 3 Hz, 1 7.37 J 9 Hz, 4H), 7.91 1H), 7.95 J 9 Hz, 2H). MS (DCI-NH3) m/z 477 Anal. calc. for-C19H13F3C12N 2 0 3 S: C, 47.81; H, 2.74; N, 5.86.
Found: C, 47.94; H, 2.87; N, 5.83.
-83- WO 99/10331 PCT/US98/16479 Example 82 2-Benzvl-4-(2-Dropylamino)-5-[4-(methvlsulfony)he nyl]-3(2 H)-yvridazinone 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%).
M.p. 146-147 C. 1 H NMR (300 MHz, CDCI3) 0.92 J= 6 Hz, 6H), 3.11 1H), 3.13 3H), 5.34 2H), 5.59 1 7.33 3H), 7.42 1 7.48 (dd, J 9 Hz, 3 Hz, 2H), 7.56 J 9 Hz, 2H), 8.00 J 9 Hz, 2H). MS (DCI-NH3) m/z 399 Anal. calc. for C21H23N303S: C, 63.45; H, 5.83; N, 10.57. Found: C, 63.31; H, 5.87; N, 10.44.
Example 83 2-(2.2.2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)pheny]-3(2H)pyvridazinone 83A. 2-(2.2.2-Trifluoroethyl)-4.5-dibromo-3(2H)-pyridazinone A solution of mucobromic acid (10 g, 38.8 mmol) and trifluoroethyl hydrazine 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 MgSO4, filtered, passed through a silica gel pad, and concentrated in vacuo.
The product was obtained as yellowish solid (yield: 8.8 g, 1 H NMR (300 MHz, CDCl3) 8 4.78 J 9 Hz, 2H), 7.87 1 MS (DCI-NH3) m/z 337 83B. 2-(2.2.2-Trifluoroethvl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone A solution of 2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone (2 g, 6 mmol), isopropyl alcohol (3 mL) and sodium hydride (60% dispersed in oil, 290 mg, 7.2 mmol) in toluene (40 mL) was heated 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, WO 99/10331 WO 9910331PCT/US98/1 6479 1 H NMR (300 MHz, CDCI3) 6 1.46 J 7.5 Hz, 6H), 5.48 J 6 Hz, 1 H), 7.87 1 MS (DCI-NH3) m/z 316 830. 2-(2.2.2-Trifluoroethyl)-4-(2-propoxy)-5-[4-(methylthio)phenyll-3(2Hy.- A solution of 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)pyridlazinone (1.2 g, 3.8 mmol), 4-(methylthio)phenylboronic acid (704 mg, 4.19 mmol), tetrakis (tri phenyl phosph ine) pall adi um (220 mg, 5% mmol) and cesium carbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol dimethyl ether was heated to ref lux for 5 hours. The mixture was partitioned between ethyl acetate and water.
The ethyl acetate layer was washed with water, brine, dried over MgSO4 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 1 H NMR (300 MHz, 00013) 8 1.19 J =7.5 Hz, 6H), 2.55 3H), 4.83 J 9 Hz, 2H), 5.28 J 6 Hz, 1 7.32 J 9 Hz, 2H), 7.52 J 9 Hz, 2H), 7.85 1 MS (DCI) mlz 359 83D. 2-(2.2.2-Trifluoroethyl)-4-(2-propoxy)-5-f4-(methylsulfonylhenyl]-3(2H)- The title compound was prepared according to the method of Example substituting 2 -(2,2,2-trifluoroethyl)-4-(2-propoxy)--[4-(methylthio)pheny]-3(2H)pyridlazinone in place of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)pyridlazinone (yield: 220 mg, 100%). M.p. 152-1 53 00. 1 H NMR (300 MHz, CDCI3) 8 1.2 J =6 Hz, 6H), 3.13 3H), 4.84 J 9 Hz, 2H), 5.49 J 6 Hz, 1 H), 7.78 J =9 Hz, 2H), 7.82 1 8.05 J 9 Hz, 2H). MS (D01-N H3) m/z 391 Anal. calc. for 016H17F3N20 4 S: 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-cyclohexylox-5-[4-(methylsulfonyl)phenyl..3(2H)..prda ion The title compound was prepared according to the method of Example 83, substituting cyclohexanol in place of 2-propanol (yield: 250 mg, M.p. 129- 13000C 1 H NMR (300 MHz, 00013) 81.1-1.6 (in, 8H), 1.84 (in, 2H), 3.12 3H), 4.83 J 9 Hz, 2H), 5.21 J 4.5 Hz, 1 7.77 1 7.80 J 9 Hz, 2H), WO 99/10331 WO 99/033 1PCTIUS98/1 6479 8.06 J 9 Hz, 2H). MS (DCI-NH 3 m/z 431 Anal. calc. for
C
1 9H21 F3N204S:0, 53.01; H, 4.91; N, 6.50. Found: C, 52.96; H, 4.84; N, 6.45.
Example 2-(2.2.2-Trifluoroethyl)-4-cyclopentyloxy-5-[4-(methylsulfonyl)phenyl-3'2H)pyridazinone The title compound was prepared according to the method of Example 83, substituting cyclopentanol in place of 2-propanol (yield: 250 mg, M.p. 1 48- 150 1 H NMR (300 MHz, CDCI 3 8 1.35-1.55 (in, 4H), 1.68-1.75 (in, 4H), 3.12 (s, 3H), 4.83 J 9 Hz, 2H), 5.89 J 4.5 Hz, 1 7.75 J 9 Hz, 2H), 7.83 (s, 1 8.04 J 9 Hz, 2H). MS (DCI-NH3) mlz 417 Anal. calc. for C18H19F3N204S:0, 51.91; H, 4.59; N, 6.72. Found: 0,52.04; H, 4.50; N, 6.65.
Example 86 1 5 2-(2.2.2-Trif luoroet hyl)-4-(2-Qroy lam ino)-5-[4- (methylsulf onyl)Phe nyl-3 (2 H)pyridazi none 86A. 2-(2.2.2-Trifluoroethyl)-4-(2-propylamino)-5-broino-3(2H)-pyridazinone The title compound was prepared according method of the Example 83B, substituting 2-propylamine in place of 2-propanol (yield: MS (DCI-NH3) in/z 315 86B. 2-(2.2.2-Trifluoroethyl)-4-(2-1propylamino)-5-'4-(inethylthio)phenyll-3(2H)pyridaznone The title compound was prepared according method of the Example 830, substituting 2-(2,2,2-trif luoroethyl)-4-(2-propylami no)-5-broino-3 (2 H)-pyridazi none in place of 2-(2,2,2-trif luoroethyl)-4-isopropoxy-5-bromo-3(2H)-pyridazi none (yield: MS (DC I-N H3) in/z 358 860. 2-(2.2.2-Trifluoroethyl)-4-(2-prop~ylamino)-5-[4-(inethylsulfonyl)phenyll-3(2H)pyridaznn The title compound was prepared according to the method of Example substituting 2-(2,2,2-Trifluoroethyl)-4-(2-propylamino)-5-(4-(methylthio)phenyl]- 3(2H)-pyridazi none in place 'of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyll-3(2H)pyridazinone (yield: 180 mg, M.p. 173-174 1 H NMR (300 MHz, 0D013) 6 0.95 J 6 Hz, 6H), 3.13 3H), 4.81 J 9 Hz, 2H), 5.97 1 7.45 1 H), -86- WO 99/10331 WO 99/ 0331PCT[US98/1 6479 7.59 J 9 Hz, 2H), 8.03 J 9 Hz, 2H). MS (DCI-NH3) m/z 340 Anal.
caic. for C16H18F3N304S: 0, 49.35; H, 4.65; N, 10.79. Found: C, 49. 29; H, 4.52; N, 10.65.
Example 87 2-Benzyl-4-(4-mo rpholino)-5-[4-(methylsulfonyl)phenyll-3(2H)-pyridazi none 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, M.p. 158-1 60 00. 1 H NMR (300 MHz, 00013) 8 3.06 J 4.5 Hz, 3H), 3.12 3H), 3.69 J 4.5 Hz, 3H), 5.33 2H), 7.35. (in, 3H), 7.5 (in, 4H), 7.58 1 8.05 J 9 Hz, 2H). MS (DCI-NH3) m/z 426 Anal. calc. for C22H23N304S: C, 62.10; H, 5.44; N, 9.87. Found: 0, 61.74; H, 5.47; N, 9.59.
Example 88 2-(2.3.3-Trifluoro-2-p2ropen-1 -yl)]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll- 3(2H)-p2yridazi none 88A. 1 -Met hyIsu If onyloxy-2.3.3-trif luo ro-2-propen e 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 2,3,3trifluoro-2-propen-1 -ol with mesyl chloride in diethyl ether. Standard workup provided the product, which was used without purification.
88B. 2-(2.3.3-Trifluoro-2-propen-1 -yl'-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]- 3 (2 H)-pyridazi none, Fluo rophe nyl)-5-4-(methylthio)phenyll-3(2H)-pyridazi none is prepared starting with the 2-benzyl-pyridazi none from Example 9 and debenzylating the compound according to the procedure of Example 11.' A mixture of 4-(4-fluorophenyl)-5-[4-(methylthio)phenynl-3(2H)-pyridazinone (250 mg, 0.8 mmol), 0s2003 (650 mg, 2(mmol), and 3-methylsufonyloxy-1 ,1 ,2trifluoropropene (mesylate, 250 mg, 1.19 mmol) in ethyl acetate (30 mL) was stirred at 55 00 for 1.5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO4 and filtered.
The filtrate was concentrated in vacuo. The residue was purified by column WO 99/10331 WO 9910331PCTIUS98/1 6479 chromatography on silica gel eluted with 15% ethyl acetate/hexanes, to provide the methyl sulfide, 2-(2,3,3-trifluoro-2-propen-1 -yl)-4-(4-fluorophenyl)-5-[4- (methylthio)phenyl]-3(2H)-pyridazinone as a greenish oil (yield: 175 mg, 53%).
880. 2-(2.3.3-Trifluoro-2-propen-1 -yl)]-4-(4-fluorophenyl)-5-f4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone The methyl sulfide, prepared above, was oxidized to the title compound according to the method of Example 10 (yield: 125 mg, M.p. 154-1 56 00. 1 H NMR (300 MHz, CDCI3) 863.07 3H), 5.1 (ddd, J 21 Hz, 3 Hz, 1.5 Hz, 2H), 6.98 J =9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.35 J =9 Hz, 2H), 7.89 1 H), 7.9 J 9 Hz, 2H). MS (D01-NH3) m/z 439 Anal. calc. for C20H14F4N203S: 0, 54.79; H, 3.21; N, 6.38. Found: C, 54.52; H, 3.15; N, 6.21.
Example 89 2 .4-Bi s(4-f luorophe nyl)-5-[4-(ami nosu If onyl)p henyll-3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 68 substituting 2,4-bis(4-f luoroph enyl)-5-[4-(methylsu If inyl)phe nyl]-3 (2H)-pyridazi none in place of 2-(2,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]- 3(2H)-pyridazi none (yield: 118 mg, M.p. 213-216 00. 1 H NMR (300 MHz, DMSO-d6) 5 7.15 2H), 7.27 (in, 2H), 7.4 (in, 6H), 7.7 (dd, 2H), 7.76 J =9 Hz, 2H), 8.2 1 MS (DCI-NH3) m/z 440 439.44 Anal. caic. for 021 H15FN203S2: 0, 60.13; H, 3.44; N, 9.56. Found: 0, 59.94; H, 3.37; N, 9.46.
Example 2-(2.2.2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyl)phe nylI-3(2H)pyridzinon 2-(2.2.2-Trifluoroethyl)-4-methoxy-5-bromo-3(2H)-pyridazinone The title compound was prepared according method of the Example 83B3, substituting methanol in place of isopropanol (yield: 1 H NMR (300 MHz, 0D013) 6 4.3 3H), 4.76 J 9 Hz, 2H), 7.85 1 MS (D01-NH3) m/z 288 2- (2.2.2-T rif luo roethyl)-4,-methox y-54f4- (met hylthi o)p he nyll-3 (2H) pyridazinone The title compound was prepared according method of the Example 830, substituting 2 -(2,2,2-trif luoroethyl)-4-methoxy-5-bromo-3(2 H)-pyridazi none in place -88- WO 99/10331 WO 9910331PCT/US98/1 6479 of 2- (2,2,2-trif luoroethyl)-4-(2-propoxy)-5-bro mo-3(2 H)-pyridazi none (yield: 1 H NMR (300 MHz, CDCI3) 6 2.54 3H), 4.11 3H), 4.82 J 9 Hz, 2H), 7.33 J 9 Hz, 2H), 7.48 J 9 Hz, 2H), 7.84 1 MS (DCl-N.H3) m/z 331 900. 2-(2.2.2-Trifluoroethyl)-4-hydroxy-5-[4-(methylthio'phenyll-3(2H)pyridazi none A solution of 2-(2,2,2-Trifluoroethyl)-4-methoxy-5-[4-(methylthio)phenyl- 3 (2 H)-pyridazi none (2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) in acetic acid (40 mL) was heated at ref lux 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 1 H NMR (300 MHz, CDC13) 6 2.54 3H), 4.82 J 9 Hz, 2H), 7.47 J 9 Hz, 2H), 7.65 J 9 Hz, 2H), 7.73 (br s, 1 8.00 1 MS (DCI) m/z 317 90D. 2-(2.2.2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylthio)p2heny]-3(2H)pyridazi none A solution of 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone (150 mg, 0.47 mmol), cyclopropyl methanol (43 mL, 0.52 mmol) and triphenylphosphine (124 mg, 0.47 mmol) in freshly distilled THIF was prepared and added dropwise to diethyl azodicarboxylate (75 mL, 0.52 mmol) at 0 OC The mixture was allowed to warm to room temperature, stirred for 5 hours and concentrated in vacuc. 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 1 H NMR (300 MHz, 00013) 860.22 (in, 2H), 0.48 (mn, 2H), 1.6 (in, 1 H), 2.53 3H), 4.26 J 7.5 Hz, 2H), 4.72 J 9 Hz, 2H), 7.32 J 9 Hz, 2H), 7.55 J 9 Hz, 2H), 7.87 1 MS (DCI-NH3) m/z 371 2-(2.2.2-Trifluoroethyl)-4-cyclopropylmethoxy-5-[4-(methylsulfonyflphenyll- 3(2 H) -py rid azi none The title compound was prepared according to the method of example substituting 2- (2,2,2-t rif luo roeth y )-4-cyclopropyImet hoxy-5-[4- (met hylth io) phe nyl] 3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone (yield: 130 mg, M.p. 133-135 00. 1 H NMR (300 MHz, CDCl 3 6 0.22 (in, 2H), 0.5 (in, 2H), 1.07 (in, 1 3.12 3H), 4.4 J 9 Hz, 2H), 4.83 J -89- WO 99/10331 WO 9910331PCT/US98/1 6479 9 Hz, 2H), 7.79 1 7.83 J 9 Hz, 8.07 J 9 Hz, 2H). MS (DCI- NH3) m/z 403 Anal. caic. for C17H17F3N20 4 S: 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-Trifluoroethyfl-4-(3-propen-1 -oxy)-5-[4-(methylsulfonyfl~henyll-3'2
H)-
gyridazinone The title compound was prepared according to the method of Example substituting 2-propen-1-ol in place of cyclopropylmethanol (yield: 120 mg, 77%).
M.p. 121-12300C 1 H NMR (300 MHz, CDCI3) 8 3.12 3H), 4.84 J 12 Hz, 5.07 J 6 Hz, 2H), 5.21 (dd, J 13.5 Hz, 1 Hz, 1 5.27 (dd, J 15 Hz, 1 Hz, 1 5.85 (in, 1 7.25 J 9 Hz, 2H), 7.83 1 8.06 J 9 Hz, 2H). MS (DCI-NH3) m/z 389 Anal. calc. for C1 6H1 5F3N204S: 0, 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-a/Dha-methylbenzyloxy)-5-4.(methylsulfonyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example substituting 4-fluoro-a/pha-methylbenzyl alcohol in place of cyclopropyl methanol (yield: 155 mg, M.p. 133-135 00. 1 H NMR (300 MHz, CDCI3) 8 1.57 J =6 Hz, 3H), 3.13 3H), 4.75 J 7.5 Hz, 1 4.87 J 7.5 Hz, 1 6.34 J =6 Hz, 1 6.83 J 9 Hz, 2H), 6.98 (dd, J 9 Hz, 6 Hz, 2H), 7.59 J 9 Hz), 7.70 1 8.03 J 9 Hz, 2H). MS (DCI-NH3) m/z 471 Anal. calc. for 021 H18F4N20 4 S: C, 53.61; H, 3.85; N, 5.95. Found: C, 53.54; H, 3.73; N, 5.86.
Example 93 2-[4-(Methylthio)p2henyll-4-(4-fluorophenyl)-5-14-(methylsulfonyl)phe nylI-3(2H)- 12yrdaznone A solution of the product from Example 11, Fluo rophe nyl) (m ethylsulfo nyl)phenyl]-3(2H)-pyridazi none (344 mg, 1.0 mmol), 4-bromothioanisole (812 mg, 4.0 mmol), and copper (70 mg, 1.1 mmol) in 20 mL of pyridine was stirred at ref lux 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®D, and separated. The organic layer was washed with 10% aqueous citric acid, with brine, dried over MgSQ4, and WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 filtered. The filtrate was concentrated in vacua 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, 1 H NMR (300 MHz, ODC1 3 6 2.55 (s, 3H), 3.05 3H), 6.98 J 9 Hz, 2H), 7.22 (dd, J 9 Hz, 6 Hz, 2H), 7.38 (dd, J 8 Hz, 2 Hz, 4H), 7.64 J 9 Hz, 2H), 7.91 J 9 Hz, 2H), 7.98 1 MS (DCI- NH3) m/z 467 Anal. calc. for C24Hj9FN203S2-0.5 H20: C, 60.63; H, 4.21; N, 5.90. Found: 0, 60.72; H, 3.96; N, 5.70.
Example 94 2 Bisf 4-(methylsu lfo nyflohenyllj-4-(4-f luorophenyl-3 (2H)-pyridazi none The title compound was prepared by oxidizing the product of Example 93, according to the method of Example 10 (yield: 156 mg, 1 H NMR (300 MHz, CDCI3) 863.10 3H), 3.12 3H), 7.02 (in, 2H), 7.24 (mn, 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 (in, 3H). MS (DCI-NH3) m/z 499 516 Anal. calc. for C24H19FN205S 2 C, 56.80; H, 3.94; N, 5.53. Found: C, 56.50; H, 3.88; N, 5.38.
Example 2 -(3-Methyl- 2-thi eny (4-f Iuo rophe (met hylsu fon y) phe ny11- 3 (2H)- 12rdznn The title compound was prepared according to Example 93, substituting 2bromo-3-inethylthiophene in place of 4-bromothioanisole (yield: 190 ing, 43%).
M.p. 215-21700C 1 H NMR (300 MHz, CDCI3) 862.21 3.08 3H), 6.90 J 9 Hz, 1 6.98 J 9 Hz, 2H), 7.24 (dd, J 9 Hz, 6 Hz, 3H), 7.41 J 9 Hz, 2H), 7.94 J 9 Hz, 2H), 7.98 1 MS (DCI-NH3) m/z 441 458 Anal. calc. for 022H17FN203S2-0.5 H20: C, 58.80; H, 4.01; N, 6. 24.
Found: 0, 58.85; H, 3.78; N, 5.99.
Example 96 2 2 -Trifluoroinethyl-5-nitrophenyl)-4-(4-fluorophenyl).s.r4-(ethylsulfonyl)phenyL- 3(2H):-pyridazi none The title compound was prepared according to Example 93, substituting 2in place of 4-bro moth ioaniso le (yield: 390 mng, 73%).
1 H NMR (300 MHz, CDC13) 863.08 3H), 6.98 J 9 Hz, 2H), 7.21 (dd, J 9 Hz, 6 Hz, 2H), 7.43 J 9 Hz, 2H), 7.80 J 9 Hz, 1 7.96 J 9 Hz, 2H), 8.02 1 8.61 (dd, J 9 Hz, 3 Hz, 1 8.75 J 3 Hz, 1 MS (DCI-NH3) m/z 534 -91 WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 551 Anal. caic. for 024H-15F4N\30 5 S-0.75 H20: C, 52.70; H, 3.02; N, 7.69. Found: 0, 52.42; H, 3.04; N, 6.82.
Example 97 2-E3-(Methylthio~phenyll-4-(4-fluorophenyfl-5-(4-(methylsulfonyl)ohenyll-3(2H).
pyridazi none The title compound was prepared according to Example 93, substituting 3bromothioanisole in place of 4-bromothioanisole (yield: 355 mg, M.p. 196 00. 1 H NMR (300 MHz, CDCI3) 8 2.55 3H), 3.08 3H), 6.99 J =9 Hz, 2H), 7.23 (dd, J =9 Hz, 6 Hz, 2H), 7.28-7.33 (in, 1 7.37-7.49 (in, 2H), 7.40 J 9 Hz, 2H), 7.58 (in, 1 7.92 J 9 Hz, 2H), 7.99 (in, 1 MS (DCI-NH3) mlz 467 484 Anal. calc. for C24H19FN203S2: 0, 61.80; H, 4.08; N, 6.01. Found: 0, 61.56; H, 3.93; N, 5.86.
Example 98 2-[3-(Methylsulfonyl)phenyll-4-(4-fluorophenyl)-5-[4-(inethylsulfonyl)phenyll-3(2
H)-
pyridazi none The title compound was prepared by oxidizing the product of Example 97, according to the method of Example 10 (yield: 98 mng, M.p. 141 -1 42 OQ.
1 H NMR (300 MHz, DMSO-d6) 863.25 3H), 3.35 3H), 7.18 J 9 Hz, 2H), 7.32 (dd, J 9 Hz, 6 Hz, 2H), 7.52 J 9 Hz, 2H), 7.83 J 9 Hz, 1 7.95 J 9 Hz, 2H), 8.05 (in, 1 8.25 J 1.5 Hz, 1 8.33 1 MS (DCI-NH3) in/z 516 Anal. caic. for C24Hj9FN205S2*H20: 0, 55.81-; H, 4.07; N, 5.43.
Found: C, 56.24; H, 4.29; N, 5.10.
Example 99 2-(4-Fluorophenyl)-4- (4-chlorop~henyl)-5-[4-(methylsu lfonyl)phenyll-3(2H)pyridazi none 4-(4-C hlorophenyl)-5-[4-(inethylsuIf onyl)phenyl]-3(2H)-pyridazi none is prepared starting with the 2-benzylpyridazi none from Example 53 and debenzylating the compound according to the method of Example 11.
The title compound was prepared according to the method of Example 93, starting with 4-(4-chlo rophenyl)-5-[4-(methylsulIfonyl)phenyl]-3(2 H)-pyridazi none in place of 4 4 -f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3 (2H)-pyridazi none and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 245 mng, M.p. 195-19700C 1 H NMR (300 MHz, CDCI 3 863.08 3H), 7.19 (in, 4H), -92- WO 99/10331 WO 9910331PCTIUS98/1 6479 7.25 (in, 2H), 7.41 J 9 Hz, 2H), 7.70 (in, 2H), 7.95 J 9 Hz, 2H), 8.01 (s, 1 MS (DCI-NH 3 m/z 455 472 Anal. calc, for 023H1601FN20 3 S: 0, 60.78; H, 3.52; N, 6.17. Found: 0, 60.81; H, 3.53: N, 5.93.
Example 100 2-(5-Chloro-2-thienyl)-4-(4-ch lorophenyl)-5-f 4-(methylsu lfonyl)phenyll-3 (2LH)- 12ridainone The title compound was prepared according to Example 93, substituting 4- (4-chlorop henyl)-5-[4-(methylsulIfonyl)phe nyl]-3(2 H)-pyridazi none in place of 4-(4f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none and substituting 2in place of 4-bro moth ioan isole (yield: 150 mng, M.p. 249-251 00. 1 H NMR (300 MHz, 0D013) 8 3.05 3H), 6.92 J 9 Hz, 1 H), 7.18 J 9 Hz, 2H), 7.31 J 9 Hz, 2H), 7.39 J 9 Hz, 2H), 7.58 J 6 Hz, 1 7.94 J 9 Hz, 2 Hz, 2H), 8.04 1 MS (DCI-NH3) m/z 477 494 Anal. calc. for 021 H14012N203S2-H20: C, 50.9; H, 3.03; N, 5.60.
Found: 0, 50.5; H, 2.79; N, 5.26.
Example 101 2-(3-Trifluoromethylphenyl)-4-(4-chlorophenyl)-5-4-(methylsulfony)phenyll.3(2
H)-
pyiaznn The title compound was prepared according to Example 93, starting with 4- 4 -chlorophenyl)-5-[4-(methylsulIfonyl)phe nyl]-3(2H)-pyridazi none in place of 4-(4f luorophenyl)-5-f4-(methylsulfonyl)phenyl] -3(2 H)-pyridazi none and substituting 3iodobenzotrif luo ride in place of 4-bromothioanisole (yield: 210 mng, M.p.
103-105 OC. 1 H NMR (300 MHz, ODC1 3 6 3.08 3H), 7.18 J 9 Hz, 2H), 7.28 J 9 Hz, 2H), 7.41 J 9 Hz, 2H), 7.65 (mn, 2H), 7.95 (in, 3H), 8.04 (in, 2H).
MS (D01-NH3) m/z 505 525 Anal. calc. for C24H16ClF3N20 3 S: 0, 57.14; H, 3.17; N, 5.56. Found: 0, 56.61; H, 3.28; N, 5.38.
Example 102 2-(3-C hloro-4-f luorophenyl)-4-(4-chlorophe nyl)-5-f 4-(methylsu lfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to Example 93, starting with 4- (4-chlorophenyl)-5-[4-(inethylsu Ifonyl)phenyl]-3 (2H)-pyridazi none (described in Example 99) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone and substituting l-bromo-3-chloro-4-fluorobenzene in place of 4- -93- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 bromothioanisole (yield: 330 mg, M.p. 205 IC. 1 H NMR (300 MHz, CDCI3) 563.10 3H), 7.17 J 9 Hz, 2H), 7.23-7.31 (in, 1 7.28 J =9 Hz, 2H), 7.41 J 9 Hz, 2H), 7.65 (ddd, J 9 Hz, 3 Hz, 1.5 Hz, 1 7.85 (dd, J 9 Hz, 3 Hz, 1 7.93 J 9 Hz, 2H), 8.01 1 MS (DCI-NH3) mn/z 489 508 Anal. caic. for 023H1 5012N203S: 0, 56.44; H, 3.17; N, 5.73. Found: 0, 56.37; H, 3.19; N, 5.64.
Example 103 2-(3-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)pheny-3 (2 H)pyridazinone The title compound was prepared according to Example 93, substituting 1 fluoro-3-iodobenzene in place of 4-bromothioanisole (yield: 310 mg, M.p.
245-247 00. 1 H NMR (300 MHz, CDCI3) 563.08 3H), 6.98 J 9 Hz, 2H), 7.14 (in, 1 7.24 (dd, J 9 Hz, 6 Hz, 2H), 7.40 (in, 2H), 7.52 (in, 3H), 7.92 J 9 Hz, 2H), 8.01 1 MS (DCI-NH3) m/z 439 456 Anal. calc. for C23H16F2N2O3S-0.25 H20: 0, 62.34; H, 3.67; N, 6.38. Found: C, 62.33; H, 3.68; N, 6.22.
Example 104 2-[2-(Methylthio)phenyll-4-(4-fluorophenyl)-5-f4-(inethylsulfonyl)phenyl1-3(2H)pyridazi none The title compound was prepared according to Example 93, substituting 2bromothioanisole in place of 4-bromothioanisole (yield: 280 mng, M.p. 206- 208 00. 1 H NMR (300 MHz, CDCI3) 6 2.49 3H), 3.08 3H), 6.95 J 9 Hz, 2H), 7.25 (dd, J 9 Hz, 6 Hz, 2H), 7.29-7.51 (in, 4H), 7.43 J 9 Hz, 2H), 7.92 (d, J 9 Hz, 3H), 8.01 1 7.98 1 MS (DCI-NH 3 mn/z 467 484 Anal. calc. for C24H19FN2O3S2-H 2 O: 0, 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-(methylsu lfonyl)pheny11-3(2 H)p2yridazi none The title compound was prepared according to Example 93, substituting 2in place of 4-broinothioanisole (yield: 330 ing, M.p.
252-2530 -C IH NMR (300 MHz, ODC1 3 6 3.06 3H), 7.05 J 9 Hz, 2H), 7.25 (dd, J 9 Hz, 6 Hz, 2H), 7.40 J 9 Hz, 2H), 7.71 J 6 Hz, 1 7.95 (in, 3H), -94- WO 99/10331 WO 9910331PCT/US98/1 6479 8.14 1 MVS (DCI-NH3) mlz 472 489 Anal. calc, for 021 H1 4FN3O5S2-0.5 H20: 0, 52.50; H, 3.02; N, 8.75. Found: 0, 52.79; H, 3.18; N, 8.74.
Example 106 pyridazinone The title compound was prepared according to Example 93, starting with 4- (4-chlorophenyl)-5-[4-(methylsulfonyl)phenylj-3 (2H)-pyridazi none in place of 4-(4f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none and substituting 1 bromo-3,4-difluorobenzene in place of 4-bromothioanisole (yield: 310 mg, 65.7%).
M.p. 187-18800)C 1 H NMVR (300 MHz, CDC13) 563.09 3H), 7.18 J 9 Hz, 2H), 7.29 (in, 3H), 7.41 J =9 Hz, 2H), 7.52 (in, 1 7.65 (in, 1 7.92 J 9 Hz, 2H), 8.01 1 MS (DCI-NH3) m/z 473 490 Anal. calc. for C23115CIF2N20 3 S*0.5 H20: 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-(methylsu lfonyl)phenyl]-3(2 H)- 12rdznn The title compound was prepared according to Example 93, substituting 3-bromobenzothiophene in place of 4-bromothioanisole (yield: 185 mg, M.p.
265-267 00. 1 H NMVR (300 MHz, CDCI3) 563.09 3H), 7.0 J 9 Hz, 2H), 7.27 (dd, J 9 Hz, 6 Hz, 2H), 7.39-7.47 (in, 2H), 7.44 J 9 Hz, 2H), 7.75-7.82 (in, 1 H), 7.87-7.94 (in, 2H), 7.94 J 9 Hz, 2H), 8.05 1 MS (DCI-NH3) m/z 477 494 Anal. caic. for 025H17FN20 3 S2: C, 63.03; H, 3.57; N, 5.88. Found: 0, 62.89; H, 3.55; N, 5.71.
Example 108 2 4 -Fluorophenyl)-4-(4-fluorophenoxy)-5-[4-(methlsulfonyl)phenl-3(2H).
12yrdaznn 108BA. 4 4 -Fiuo rophenoxy)-5-f 4-(methylsulfo nyl)phenyI1.3(2H)-Pyridazi none The title compound was prepared by treating 2-benzyl-4-(4-fluorophenoxy)- 4 (methylsuIto nyl)phe nyl]-3 (2 H)-py ridazi none (Example 75) with AlBr3 in toluene according to the procedure in Example 11 (yield: 1.8 g, WO 99/10331 WO 9910331PCTIUS98/1 6479 1 08B. 2-(4-Fluorophenyl)-4-(4-fluorophenoxy)-5-14-(methylsulfonyrp1henyl].3(2H)- 12yrid The title compound was prepared according to Example 93, starting with 4- (4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2 H)-pyridazi none and substituting 1-fluoro-4-iodobenzene in place of 4-bromothioanisole (yield: 60 mg, M.p.
83-85 00. 1 H NMR (300 MHz, CDCI3) 63.10 3H), 6.89-7.03 (in,4H), 7.15 J= 9 Hz, 2H), 7.65 (dd, J 9 Hz, 6 Hz, 2H), 7.83 J 6 Hz, 2H), 8.07 J 9 Hz, 2H), 8.08 1 MS (DCI-NH3) m/z 455 472 (M+NH 4 Example 109 2-(3 .4-Dif luorop~henyl)-4-(4-fluorophenoxy)-5-r4-(methylsu lfonyflphe nyll-3(2 H)pyridazinone The title compound was prepared according to Example 93, substituting 1 bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4- 1 5 fluorophenoxy)-5-[4-(methylsu lfonyl)phenyl]-3(2H)-pyridazinone (Example 108BA) in place of 4-(4-f luorophenyl)-5-[4-(methylIsulfonyl)phenyll-3(2 H)-pyridazi none (yield: 185 mg, M.p. 178-180 0C. 1 H NMR (300 MHz, 0D013) 6 3.11 3H), 6.89- 7.04 (in, 4H), 7.45-7.52 (in, 1 7.45-7.52 (in, 1 7.61 (dt, J 6 Hz, 3 Hz, 1 H), 7.82 J =9 Hz, 2H), 8.07 J 9 Hz, 8.08 1 MS (DCI-NH3) in/z 473 490 Anal. calc. for C23115F 3
N
2
O
4 S.0.5 H20: 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-fluorohenoxy)--4-(methylsulfonyl)p2henyl].3(2
H)-
pyridazinone The title compound was prepared according to Example 93, substituting 1,3dibroinobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4- (met hylsu If onyl) phe nyl]-3 (2 H)-pyridazi none (Example 108A) in place of 4-(4f luo ro phe nyl)-5-[4- (iethylsuIf onyl) phe nyl]-3 (2 H)-pyridazi none (yield: 260 mg, M.p. 208-210 00. 1 H NMR (300 MHz, CDCI3) 863.09 3H), 6.89-7.04 (in, 4H), 7.34 J 9 Hz, 1 7.53 (br d, J 9 Hz, 1 7.64 (br d, J 9 Hz, 1 7.82 (d, J 9 Hz, 2H), 7.87 J 1.5 Hz, 1 8.08 J 9 Hz, 2H), 8.09 1 MS (DCI- NH3) in/z 517 534 Anal. calc. for C23H16BrFN2O4S: 0, 53.7; H, 3.11; N, 5.45. Found: 0, 53.46; H, 2.88; N, 5.18.
-96- WO 99/10331 WO 9910331PCTIUS98/ 16479 Example I11 2-(3 .5-Dif luorophenyl)-4-(4-fluorophenoxy)-5-[4- (methylsu Ifonyl)p2henyl]-3(2 H)pyrdaLDQ' The title compound was prepared according to Example 93, substituting 1bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 1 08A) in place of 4-(4-f luo rophenyl)-5- (methylsuIf onyl) phe nyl]-3(2 H)-pyridlazi none (yield: 175 mg, M.p. 209-211 00. 1 H NMVR (300 MHz, 0D013) 8 3.10 3H), 6.85 (tt, J 9 Hz, 3 Hz, 1 6.90-7.04 (in, 4H), 7.38 (dd, J 9 Hz, 3 Hz, 2H), 7.81 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.10 1 MS (DCI-NH3) m/z 473 490 Anal. calc. for C23H15F3N2O4S-H2O: C, 58.47; H, 3.18; N, 5.94.
Found: 0, 58.31; H, 3.15; N, 5.82.
Example 112 1 5 2-(3-Chlorophenyl)-4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyll-3(2
H)-
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-(methylsulf onyl) phenyl]-3(2 H)-pyridazi none (Example 108A) in place of 4-(4f luorophenyl)-5-[4- (methylsuIf onyl)phenyl]-3(2 H)-pyridazi none (yield: 25 mg, M.p. 211-213 00. 1 H NMR (300 MHz, DMSO-d6) 8 3.30 3H), 7.15 J 9 9Hz, 4H), 7.51-7.64 (in, 3H), 7.71 -7.75 (in, 1 7.91 J =9 Hz, 2H), 8.06 J 9 9Hz, 2H), 8.41 1 MS (DCI-NH3) m/z 471 488 Anal. caic. for C23H16CIFN 2
O
4 S-0.5 H20: 0, 57.62; H, 3.44; N, 5.85. Found: C, 57.62; H, 3.52; N, 5.48.
Example 113 2- (4-N itrobe nzyl)-4- (4-f Iuo rophenyl)-5[4- (met hylsuf onyl) ph en Yq.13 (2H).
p2yridazinone The title compound was prepared according to the method of Example substituting 4-nitrobenzyl bromide in place of 4-fluorobenzyl bromide (yield: 164 mg, M.p. 183-1 84 OC. 1 H NMVR (300 MHz, CDCI3) 8 3.05 3H), 5.47 (s, 2H), 6.96 J 9 Hz, 2H), 7.16 (dd, J 9 Hz, 3 Hz, 2H), 7.32 J 9 Hz, 2H), 7.70 J 9 Hz, 2H), 7.87 1 7.88 J 9 Hz, 2H), 8.22 J 9 Hz, 2H). MS (DCI-NH3) m/z 480 mlz 497 Anal. calc. for C24H18FN305S: C, 60.12; H, 3.78; N, 8.76. Found: 0, 59.89; H, 3.83; N, 8.61.
-97- WO 99/10331 PCT/US98/16479 Example 114 2-(4-Acetoxybenzyl)-4-(4-fluorophenyl)-5-4- (methylsulfonyl)phenyll-3(2 Hpyridazinone The title compound was prepared according to the method of Example substituting 4-(chloromethyl)phenyl acetate in place of 4-fluorobenzyl bromide (yield: 220 mg, M.p. 172-174 C. 1 H NMR (300 MHz, CDCI3) 2.30 (s, 3H), 3.05 3H), 5.38 2H), 6.95 J 9 Hz, 2H), 7.06 J 9 Hz, 2H), 7.16 (dd, J 9 Hz, 5 Hz, 2H), 7.31 J 9 Hz, 2H), 7.60 J 9 Hz, 2H), 7.81 1 7.87 J 9 Hz, 2H). MS (DCI-NH 3 m/z 510 Anal. calc. for C26H21FN205S: C, 63.40; H, 4.30; N, 5.69. Found: C, 63.28; H, 4.41; N, 5.39.
Example 115 2-(4-Hydroxvbenzvl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenvl]-3(2H)pyridazinone A solution of 2-(4-acetoxybenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.2 g, 4.06 mmol) (Example 114) in THF (20 mL) was treated with a solution of lithium hydroxide monohydrate (0.05 g, 1.22 mmol) in water (5 mL). Methanol (2 mL) was added to provide a homogeneous solution which was stirred at room temperature overnight. The reaction mixture was then acidified with 10% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO4 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, M.p. 225-226 1 H NMR (300 MHz, CDCI3) 8 3.05 3H), 4.86 1H), 5.33 2H), 6.80 J 8.5 Hz, 2H), 6.95 J 9 Hz, 2H), 7.15 (dd, J 9 Hz, 5 Hz, 2H), 7.30 J 8.5 Hz, 2H), 7.46 J 8.5 Hz, 2H), 7.83 1 7.87 J 8.5 Hz, 2H). MS (DCI-NH3) m/z 451 Anal. calc. for C24H19FN 2 0 4 S: C, 63.99; H, 4.25; N, 6.22. Found: C, 63.73; H, 4.16; N, 6.11.
Example 116 2 -(3-Nitrobenzyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting 3-nitrobenzyl bromide in place of 4-fluorobenzyl bromide (yield: 195 mg, M.p. 156-157 1 H NMR (300 MHz, CDC13) 8 3.05 3H), 5.48 (s, WO 99/10331 WO 9910331PCTIUS98/1 6479 2H), 6.96 J 9 Hz, 2H), 7.16 (dd, J 9 Hz, 5 Hz, 2H), 7.33 J 8.5 Hz, 2H), 7.54 J 7 Hz, 1 7.88 1 7.90 J 8.5 Hz, 2H), 8.19 (br d, J 7 Hz, 1 H), 8.37 J 1.7 Hz, 1 MS (DCI-NH3) mlz 480 m/z 497 Anal.
calc. for 024H18FN305S: 0, 60.12; H, 3.78; N, 8.76. Found: 0, 59.98; H, 3.73; N, 8.67.
Example 117 2-(3 .4.4-Trifluoro-3-butenyl)-4-(4-f luorophenyl)-5-[4- (methvlsultonyl)phenyll-3 (2H)pydzinone The title compound was prepared according to the method of Example substituting 4-bromo-1 ,1 ,2-trifluoro-1 -butene in place of 4-fluorobenzyl bromide (yield: 38 mg, M.p. 131-132 OC0 1 H NMR (300 MHz, CDCI3) 82.92 (br d, J -21.7 Hz, 2H), 3.06 3H), 4.47 J =6.6 Hz, 2H), 6.98 J 9 Hz, 2H), 7.17 (dd, J 9 Hz, 5 Hz, 2H), 7.35 J 8.5 Hz, 2H), 7.85 1 7.89 J 8.5 Hz, 2H).
MS (DCI-NH3) m/z 453 m/z 470 Anal. calc. for 021 H1 6F4N203S: 0, 55.75; H, 3.56; N, 6.19. Found: 0, 55.63; H, 3.62; N, 6.10.
Example 118 2-(2-Hexynyfl-4-(4-f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2 H)-pyridazi none The title compound was prepared according to the method of Example substituting 1-chloro-2-hexyne in place of 4-fluorobenzyl bromide (yield: 170 mg, M.p. 79-80 'C0 1 H NMR (300 MHz, 0D013) 8 0.99 J 7.5 Hz, 3H), 1.56 (h, J 7.5 Hz, 2H), 2.21 (in, 2H), 3.06 3H), 5.01 J 3 Hz, 2H), 6.96 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.34 J 9 Hz, 2H), 7.88 1 7.89 J 9 Hz, 2H). MS (DCI-NH3) m/z 425 Anal. calc. for 023H21 FN2O3S: 0, 65.07; H, 4.98; N, 6.59. Found: 0, 64.87; H, 4.90; N, 6.58.
Example 119 2- Dich lo ro-2-p rope nyl)-4- (4-f luo rophe ny (ami nosu Ifon yl)Phe nyll-3 (2H) pyridazinone The title compound was prepared according to the method of Example substituting 1,1 ,3-trichloropropene in place of 4-fluorobenzyl bromide (yield: 1.15 g, M.p. 184-185 00. 1 H NMR (300 MHz, DMSO-d6) 8 4.39 J 7.5 Hz, 2H), 6.43 J 7.5 Hz, 1 7.14 J 9 Hz, 2H), 7.23 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J 9 Hz, 2H), 7.43 2H), 7.73 J 9 Hz, 2H), 8.11 1 MS (DCI-NH3) m/z -99- WO 99/10331 WO 9910331PCTIUS98/1 6479 454 Anal. cab,. for C19H14CI2F4N3O3S: C, 50.23; H, 3.1; N, 9.24.
Found: C, 50.28; H, 3.29; N, 9.19.
Example 120 2-Cyclohexyl-4-(4-f luorophenyl)-5-44- (methylsu If onyl)phenyll-3 (2 H)-pyridazi none The title compound was prepared according to the method of Example substituting cyclohexyl bromide in place of 4-fluorobenzyl bromide (yield: 163 mg, M.p. 169-171 O0. 1 H NMR (DMSO-d6, 300 MHz) 6 1.23 (in, 1 1 .41 (mn, 2H), 1.71 (mn, 3H), 1.87 (mn, 4H), 3.23 3H), 4.85 (in, 1 7.11 (in, 2H), 7.22 (mn, 2H), 7.46 J 9 Hz, 2H), 7.85 J 9 Hz, 2H), 8.11 1 MS (DCI-NH 3 m/z 427 and m/z 444 Anal. calc. for C23H23FN20 3 S.0.5 H20: 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-f luorophenyl)-5-[4- (methylsu If onyl)phenyll-3 (2 H)-pyridazi none The title compound was prepared according to the method of Example substituting cyclopentyl bromide in place of 4-fluorobenzyl bromide (yield: 165 g, M.p. 191-193 00. 1 H NMR (DMSO-d6, 300 MHz) 5 1.67 (in, 2H), 1.85 (in, 4H), 2.05 (in, 2H), 3.23 3H), 5.36 (in, 1 7.12 J 9 Hz, 2H), 7.22 (in, 2H), 7.45 J =9 Hz, 2H), 7.85 J 9 Hz, 2H), 8.13 1 MS (DCI-NH 3 in/z 413 and in/z 430 Anal. calc. for C22H21 FN2O3S-0.5 H20: 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-f luorophenyl)-5-[4-(methylsuIf onyl)phe nyl]-3(2 pyridazi none The title compound was prepared according to the method of Example substituting cyclobutyl bromide in place of 4-fluorobenzyl bromide (yield: 270 g, M.p. 202-203 00. 1 H NMR (DMSO-d6, 300 MHz) 8 1.85 (in, 2H), 2.32 (in, 2H), 2.50 (in, 2H), 5.40 (quintet, J 7 Hz, 1 7.11 J 9 Hz, 2H), 7.21 (in, 2H), 7.47 J =9Hz, 2H), 7.86 J =9Hz, 2H), 8.16 1H). MS (DCI-NH3)mi/z 399 and inlz 416 Anal. caic. for 021 H1 9FN2O3S-0.75 H20: C, 61.22; H, 5.01; N, 6.80. Found: C, 61.19; H, 4.62; N, 6.73.
0- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 123 2-(3-Methyl-2-butenyl)-4-(4-fluorophenyl)-5-[3-fluoro-4-(ami nosulfonyl,)phenyl]- 3(2H)-pyridazi none 2-Benzyl-4-(4-fluo rophenyl)-5-[3-f luoro-4-(am inosulfonyl)phenyl]-3(2H)pyridazinone prepared according to the method of Example 68 was Ndlebenzylated according to the method of Example 11. The intermediate was Nalkylated according to the method of Example 20, substituting 1-bromo-3-methyl-2butene in place of 4-fluorobenzyl bromide, to provide the title compound (yield: mg, M.p. 134-136 OC. 1H NMR (300 MHz, 00013) 8 1.79 3H), 1 .86 (s, 3H), 4.78 2H), 4.85 J 7.5 Hz, 2H), 5.48 J =6 Hz, 1 6.96 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.28 J 9 Hz, 2H), 7.83 1 7.85 J 9 Hz, 2H). MS (D01-NH3) m/z 414 Anal. calc. for 021 H20FN30 3 S: C, 61: H, 4.87; N, 10.16. Found: C, 60.98; H, 4.66; N, 9.95.
Example 124 2-(2 .4-Dif luorobenzyl)-4-(4-f luo rophenyl)-5-f 4-(ami nosu lfonyl)phenyl]-3(2H)pyrdanofl The title compound was prepared according to the method of Example 123, substituting 2,4-difluorobenzyl bromide in place of 1-bromo-3-methyl-2-butene (yield: 65 mg, M.p. 236-23800C 1 H NMR (300 MHz, CDCI3) 864.78 2H), 5.43 2H), 6.88 (in, 2H), 6.97 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.38 J 9 Hz, 2H), 7.55 (in, 1 7.85 1 7.86 J 9 Hz, 2H). MS (DCI-NH3) m/z 472 Anal. calc. for C23H1 6F3N 3 0 3 S: 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- (ami nosulfonyl)phenyll-3(2 H)pyriaioQD The title compound was prepared according to the method of Example 123, substituting 2,3,4,5,6-pentafluorobenzyl bromide in place of 1-bromo-3-methyl-2butene (yield: 105 mng, M.p. 201 -203 OC. 1 H NMR (300 MHz, CDCI3) 6 4.8 2H), 5.5 2H), 6.98 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.28 J 9 Hz, 2H), 7.32 1 7.37 J 9 Hz, 2H). MS (DCI-NH3) m/z 526 Anal.
calc. for C23H13F6N303S: 0, 52.57; H, 2.49; N, 7.99. Found: C, 52.66; H, 2.68; N, 7.8.
-101- WO 99/10331 PCT/US98/16479 Example 126 2-(3-Cyclohexenyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 123, substituting 3-bromocyclohexene in place of 1 -bromo-3-methyl-2-butene (yield: mg, M.p. 206-208 1 H NMR (300 MHz, CDC3) 8 1.75-1.85 3H), 2.1- 2.3 3H), 4.8 2H), 5.75 2H), 6.1 1 6.97 J 9 Hz, 2H), 7.20 (dd, J 9 Hz, 6 Hz, 2H), 7.28 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 7.90 1H). MS (DCI- NH3) m/z 426 Anal. calc. for C22H20FN303S: 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)phenvl]-3(2H)pvridazinone The title compound was prepared according to the method of Example 123, 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, M.p. 253-255 0C. 1H NMR (300 MHz, DMSO-d6) 5 5.33 (s, 2H), 7.13 J= 9 Hz, 2H), 7.22 (dd, J 9 Hz, 6 Hz, 2H), 7.28 1 7.39 J 9 Hz, 2H), 7.42 2H), 7.47 2H), 7.73 J 9 Hz, 2H), 8.12 1 MS (DCI- NH3) m/z 472 Anal. calc. for C23H16F3N 3 0 3 S: 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-1 H-inden-2-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone A solution of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (172 mg, 0.5 mmol), prepared in Example 11, 2-indanol (67 mg, mmol) and Ph3P (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 mL). The mixture was stirred at room temperature for 6 hours and concentrated in vacuo. The residue was chromatographed (silica gel, 19:1 CH2CI2-ethyl acetate) to provide 200 mg of product (contaminated with reduced DIAD). A second column chromatography (hexanes-ethyl acetate 1:1) furnished the title product (yield: 170 mg, M.p. 97-100 OC. 1H NMR (DMSO-d6, 300 MHz) 5 3.22 3H), 3.32 (m, 2H), 3.44 (dd, J 9 Hz and 15 Hz, 2H), 5.83 1 7.25 4H), 7.34 4H), -102- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 7.46 J 9 Hz, 2H), 7.85 J 9 Hz, 2H), 8.06 I1H). MS (DCI-NH3) m/z 461 and m/z 478 (M+NH4)+.
Example 129 2-(2.3-Dihydro-1 H-inden-1 -yl'-4-(4-fluorophenyl)-5-f4-(methylsuI fonyl)phenyll- 3 (2H)-pvridazinone The title compound was prepared according to the method of Example 128 substituting 1 -indanol in place of 2-indanol (yield: 110 mg, M.p. 128-1 30 OC.
1 H NMR (DMSO-d6, 300 MHz) 5 2.40 (in, 1 2.60 (in, 1 3.00 (in, 1 3.22 4H), 6.60 (dd, J 9 Hz, 6 Hz, 1 7.16 (in, 4H), 7.27 (in, 4H), 7.47 J 9 Hz, 2H), 7.85 J 9 Hz, 2H), 8.02 1 MS (DCI-NH3) in/z 461 and inlz 478 (M+NH4)+.
Example 130 1 5 2-(4-Tetrahydro-2H-pyran-4-yl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll- 3(2 H)-pyridazi none The title compound was prepared according to the method of Example 128 substituting 4-tetrahydropyranol in place of 2-indanol (yield: 140 g, M.p. 230- 231 00. 1 H NMR (300 MHz, DMSO-d6) 6 1.75 (in, 2H), 1.93 (mn, 2H), 3.14 3H), 3.46 (in, 2H), 3.93 (in, 2H); 5.02 (in, 1 7.05 J 9 Hz, 2H), 7.15 (in, 2H), 7.40 (d, J 9 Hz, 2H), 7.80 J 9 Hz, 2H), 8.08 1 MS (APO m/z 428 and m/z 463 Anal. caic. for 022H21 FN2O4S*1 .25 H20: 0, 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-(inethylsulfonyl)phenyll-3 (2 H)pyridazi none The title compound was prepared according to the method of Example 128 substituting 2-inethylcyclopentanol in place of 2-indanol (yield: 230 g, M.p.
180-181 00. 1 H NMR (300 MHz, DMSO-d6) 860.75 J 7Hz, 3H), 1.60 (in, 2H), 1.89 (in, 2H), 2.10 (in, 1 2.21 (in, 1 2.40 (in, 1 3.23 3H), 5.37 J 7 Hz, 1 7.12 J 9 Hz, 2H), 7.21 (in, 2H), 7.47 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 8.11 1 MS (APCI+) m/z 427 and (APOI-) in/z 461 Anal.
calc. for C23H23FN203S: 0, 64.77; H, 5.43; N, 6.56. Found: C, 64.71; H, 5.34; N, 6.28.
-103- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 Example 132 2-(2-Adamantyl)-4-(4-fluorophenyl)-5-4-(methylsufonyl)p2henyl-3(2H)pyridazinone The title compound was prepared according to the method of Example 128 substituting 2-adamantanol in place of 2-indanol, (yield: 75 g, 195-1 97 1 H NMR (300 MHz, DMSO-d6) 5 1.60 (in, 2H), 1.77 (mn, 2H), 1.94 (in, 6H), 2.35 (in, 4H), 3.23 3H), 4.83 (in, 1 7.11 J 9 Hz, 2H), 7.22 (mn, 2H), 7.47 J 9 Hz, 2H), 7.87 J 9 Hz, 2H), 8.11 1 MS (APCI+) m/z 479 and (APOI-) in/z 478 m/z 513 Anal. calc. for 027H27FN203S.0.25 H20: 0, 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- (Methylsulfonyflphenyll-3(2 H)pyrdazinon The title compound was prepared according to the method of Example 128 substituting 3-methylcyclopentanol in place of 2-indanol (yield: 155 g, 73%).
M.p. 169-1 71 00. 1 H NMR (300 MHz, DMSO-d6) 561.05 (dd, 2:1, 3H), 1.24 (in, 1 1.63 (in, 1 2.00 (in, 3H), 2.22 (in, 2H), 3.23 3H), 5.43 (in, 1 7.1 J 9 Hz, 2H), 7.21 (in, 2H), 7.46 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 8.12 (two s, 2:1, 1 MS (APCI+) in/z 27 and (APOI-) mn/z 426 m/z 461 Anal. calc. for C27H27FN2O 3 S.0.25 H20: C, 64.09; H, 5.49; N, 6.49. Found: C, 64.27; H, 5.62; N, 6.46.
Example 134 2-(1 -Methylcyclopentyl)-4-(4-fluorophenyl)-5-[4-(inethylsulfonynphenyl]-3(2H)- A solution of 4-(4-f Iuorophe nyl)-5-[4- (met hylsuIfony1) ph enyl]-3 (2 H)pyridazinone (206 ing, 0.6 inmol), prepared according to the method of Example 11, 1 -iethyl-1 -cyclopentanol (60 mg, 0.6 rmol), DMAP (18 mg, 0. 12 iniol) and Ph3P (262 ing, 1 minol) in toluene (30 mL) in ethyl acetate (5 inL) was prepared and added dropwise to a solution of DIAD (0.2 inL, 1 inmol) 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 CH2CI2-ethyl acetate) to provide 80 mng of product (contaminated with reduced DIAD). A second column chromatography (hexanes-ethyl acetate 1 furnished the title product, (yield: ing, M.p. 107-110 00. 1 H NMR (DMSO-d 6 300 MHz) 8 1.55 3H), 1 .70 (in, -104- WO 99/10331 PCT/US98/16479 4H), 2.08 2H), 2.32 2H), 3.22 3H), 7.10 J 9 Hz, 2H), 7.20 2H), 7.45 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 8.03 1 MS (APCI+) m/z 427 and (APCI-) m/z 426 m/z 461 Example 135 2-(3.4-Difluorophenvl)-4-(4-fluoro-3-vinvlphenvl)-5-[4-(methvlsulfonvy)phenvl]- 3(2H)-pyridazinone.
135A. 5-Bromo-2-fluorostyrene.
A mixture of methyltriphenylphosphonium bromide (2.14 g, 6 mmol) and potassium t-butoxide (672 mg, 6 mmol) in 50 mL of THF was refluxed for minutes under N2 and then cooled to room temperature. 5-Bromo-2fluorobenzaldehyde (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 MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 15:1 hexanes-diethyl ether) to provide 900 mg of 5-bromo-2-fluorostyrene.
135B. 2-(3.4-Difluorophenyl)-4-(4-fluoro-3-vinvlphenyl)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone.
The bromo-styrene compound, prepared above, 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 THF (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 °C and added, dropwise, to a solution of 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone (540 mg, 1.5 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature for 12 hours. Afterwards, a saturated solution of NH4CI was added and the mixture was extracted with ethyl acetate to provide 320 mg of crude sulfide.
135C. 2-(3.4-Difluorophenvyl-4-(4-fluoro-3-vinvylhenvl)-5-[4-(methvlsulfonvl)phenyl]-3(2H)-pyridazinone.
The sulfide, prepared above, was dissolved in CH2CI2 (20 mL) and at 0 °C was treated with 30% CH3CO3H in CH3CO2H (0.5 mL). After 1.5 hours, NaHCO3 was added and the mixture extracted with CH2C12. The extract was concentrated in vacuo and the residue purified by chromatography (silica gel, 1:1 -105- WO 99/10331 PCT/US98/16479 hexanes-ethyl acetate) to provide the title compound (yield: 270 mg, 1 H NMR (DMSO-d6, 300 MHz) 83.22 3H), 5.37 J 12 Hz, 1H), 5.65 J 18 Hz, 1H), 6.77 (dd, J 12 Hz and 18 Hz, 1H), 7.15 2H), 7.57 5H), 7.90 (m, 3H), 8.28 1H). MS (APCI+) m/z 483 and (APCI-) m/z 517 Anal.
calc. for C25H17F3N203S-0.5 H20: 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)phenyll-3(2H)pyridazinone 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)-pyridazinone (720 mg, 2 mmol) in THF (30 mL) at -78 The mixture was left at room temperature for 14 hours, quenched with a saturated solution of NH4CI and extracted with ethyl acetate to obtain 900 mg of crude sulfide.
The intermediate sulfide product was dissolved in CH2CI2 (10 mL) and treated at 0 °C with 33% solution of CH3CO3H in CH3CO2H (0.7 mL) for 1 hour.
The mixture was concentrated in vacuo and the residue was partitioned between saturated NaHCO3 and ethyl acetate. The acetate layer was dried over MgSO4 and concentrated in vacuo to provide 950 mg of crude sulfonyl derivative.
The sulfonyl compound, prepared above, was dissolved in acetone (50 mL) and treated with 2 N HCI (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-formylethyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (crude aldehyde, contaminated with some unreacted starting dioxane derivative).
A mixture of isoamyltriphenylphosphonium bromide (414 mg, 1 mmol) and potassium t-butoxide (112 mg, 1 mmol) in toluene (25 mL) was refluxed for 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 MgSO4 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%).
1 H NMR (300 MHz, DMSO-d6) 8 0.74 J 7 Hz, 6H), 1.44 1 1.70 J 7 -106- WO 99/10331 WO 99/ 0331PCT/US98/16479 Hz, 2H), 2.22 (in, 2H), 2.54 (in, 2H); 3.30 3H), 5.29 (in, 2H), 7.51 (in, 1 7.63 (in, 1 7.74 J 9 Hz, 2H), 7.82 (in, 1 8.02 1 8.10 J 9 Hz, 2H). MS (APCI+) m/z 473 and (APCI-) mlz 471 m/z 507 Anal. calc.
for 02 5 H26F2N203S: C, 63.54; H, 5.54; N, 5.92. Found: C, 63.74; H, 5.67; N, 5.58.
Example 137 2 Dif luo rop heny (3-cyclo propyliden ep2ropyl)-5-[4-(m ethyl su IfonyI)p he nyll- 3 (2H)-pyridazi none The title compound was prepared according to the method of Example 136 substituting cyclopropyltriphenylphosphonium bromide in place of isoainyltriphenyiphosphonium bromide (yield: 55 ing, M.p. 128-129 OQ* 1
H
NMR (300 MHz, DMSO-d6) 8 0.81 (in, 2H), 0.97 (in, 2H), 2.34 (in, 2H), 2.65 (in, 2H), 3.32 3H), 5.64 (in, 1 7.52 (in, 1 7.63 (in, 1 7.73 J 9 Hz, 2H), 7.81 (in, 1 8.02(s, 1 8.10 J 9 Hz, 2H). MS (APCI+) m/z 443 and (APCI-) in/z 441 in/z 477 Anal. caic. for C23H20F2N2O3S-0.5 0, 61.18; H, 4.68; N, 6.20. Found: C, 61.48; H, 4.60; N, 6.02.
Example 138 2-(3 .4-Dif luorop~henyl)-4-(5-inethyl-3-hexenyl)-5-[4-(inethylsulfonvl)phenyll-3(2
H)-
pyridazinone The title compound, an oil, was prepared according to the method of Example 136 substituting isobutyltriphenylphosphonium bromide in place of isoainyltriphenylphosphoniuin bromide (yield: 170 mg, 1 H NMR (300 MHz, DMSO-d6) 850.75 J 7 Hz, 6H), 2.22 (in, 3H), 2.54 (in, 2H), 3.32 3H), 5.12 (in, 2H), 7.52 (in, 1 7.60 (in, 1 7.72 J 9 Hz, 2H), 7.80 (in, 1 8.02 1 H), 8.10 J 9 Hz, 2H). MS (APCI+) m/z 459 and (APOI-) in/z 457 m/z 493 Anal. calc. for C24H24F2N 2 0 3 S: 0, 62.86; H, 5.27; N, 6.10.
Found: C, 62.57; H, 5.32; N, 5.81.
Example 139 2-(3 Dif luorophenyl)-4-(5-inethylhexyl)-5-f 4-(methylsu lfonyl)p2henyll-3(2 H)priclaione The title compound, an oil, was prepared according to the method of Example 13513, substituting 5-inethylhexylmagnesium bromide for 3-fluoro-4vinylphenylinagnesium bromide, (yield: 28 mg, 1 H NMR (300 MHz, DMSOd6) 5 0.77 J 7 Hz, 6H), 0.88 (in, 1 1.03 (in, 2H), 1.20 (in, 1 1.46 (in, -107- WO 99/10331 WO 99/ 0331PCTIUS98/l 6479 3.32 3H), 7.52 (in, 1 7.62 (in, 1 7.75 J 9 Hz, 2H), 7.82 (in, 1 8.02 (s, 1 8.11 J 9 Hz, 2H). MS (APCI+) mlz 461 and (APOI-) m/z 459 (Mmlz 495 Example 140 2-(3-Chloro-1 -methyl-2E-propenyl)-4-(4-fluorophenyl)-5-4-(aminosulfonyl)phenyl.
3(2H)-pyridazi none The title compound was prepared according to the method of Example 127, substituting 1 ,3-dichloro-1 -butene in place of 3,4-difluorobenzyl bromide (yield: mng, M.p. 152-1 54 OC. 1 H NMR (300 MHz, CDCI3) 5 4.71 (dt, J 15 Hz, Hz, 2H), 2.28 J 1.5 Hz, 3H), 4.8 2H), 4.99 J 1 Hz, 1 5.02 J 1 Hz, 1 5.85 (td, J 4 Hz, 1 Hz, 1 6.98 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.28 J 9 Hz, 2H), 7.86 1 7.87 J 9 Hz, 2H). MS (DCI-NH3) m/z 434 Anal. calc. for C2OH17CIFN 3
O
3 S: 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-(ami nosulfonyl)phenyl]- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 127, substituting 1 -met hylsuf onyloxy-2,2,3-trif luo ro- 1 -pro pe ne (mesylate), prepared in Example 88, in place of -3,4-difluorobenzyl bromide (yield: 10 mng, M.p. 173- 175 00. 1 H NMR (300 MHz, CDCI3) 8 4.39 2H), 5.09 (ddd, J 26 Hz, J 3 Hz, J Hz, 2H), 6.98 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, J 6 Hz, 2H), 7.29 J 9 Hz, 2H), 7.78 1 7.78 J 9 Hz, 2H). MS (DCI-NH3) m/z 440 MS (FAB, high res.) m/z calc. for C19H14F4N 3 0 3 S: 440.0692 Found: 440.0695 (0.7 ppm error).
Example 142 2-(1 .1 2 -Trifluoro-2-propenyl)-4-(4-fluorop~henyl)-5-[4-(aminosulfonyl)phenyln- 3(2 H)-pyridazi none 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-(ami nosulf onyl)phenyl]-3(2H)-pyridazi none (The title product is a result of an
SN
2 attack.) (yield: 50 mg, M.p. 230-232 00. 1 H NMR (300 MHz, CDCI3) 6 4.7 2H), 5.28 (dd, J 15 Hz, 4.5 Hz, 1 5.39 (dd, J 45 Hz, 4.5 Hz, 1 6.98 (t, -108- WO 99/10331 WO 9910331PCT[US98/1 6479 J 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.31 J 9 Hz, 2H), 7.9 J 9 Hz, 2H), 7.92 1 MS (DCI-NH3) m/z 440 Anal. calc, for C1 9H1 3F4N303S: 0, 51.93; H, 2.98; N, 9.56. Found: 0, 51 .88; H, 3.01; N, 9.15.
Example 143 2-(3 .3-Dif luoro-2-propenyl)-4-(4-f luorop~henyl)-5-[4-(ami nosulfonyl)phenyl]-3(2 H)pyridazinone The title compound was prepared according to the method of Example 127, substituting 11,3-dibromo-1 ,11 -dif luo ropro pane in place of 3,4-dif luo robe nzylI bromide and employing 5 equivalents of potassium carbonate (yield: 220 mg, M.p.
191-194 1 H NMR (300 MHz, DMSO-d6) 8 4.77 J 7.5 Hz, 2H), 4.95 (dtd, J= 24 Hz, 7.5 Hz, 1 Hz, 1 7.12 J 9 Hz, 2H), 7.23 (dd, J 9 Hz, 6 Hz, 2H), 7.49 (d, J 9 Hz, 2H), 7.50 2H), 7.74 J 9 Hz, 2H), 8. 1 1 MS (DCI-NH3) m/z 422 Anal. calc. for 019H14F3N303S: C, 54.15; H, 3.34; N, 9.97. Found: 0, 53.88; H, 3.42; N, 9.76.
Example 144 2-Qi-Methyl-3-fluorobenzyl)-4-(4-fluorophenyl)-5-44- (aminosulfonyl)phenyl]-3(2 H)pyridazinone The title compound was prepared according to the method of Example 127, substituting 3-fluoro-cx-methylbenzyl chloride in place of 3,4-difluorobenzyl bromide (yield: 220 mg, M.p. 192-194 00. 1 H NMVR (300 MHz, DMSO-d6) 1.76 6 Hz, 3H), 6.27 J 7 Hz, 1 7.1 J 9 Hz, 2H), 7.22 (dd, J 9 Hz, 6 Hz, 2H), 7.49 J 9 Hz, 2H), 7.51 2H), 7.72 J 9 Hz, 2H), 8.18 1 MS (DCI-NH3) m/z 468 Anal. calc. for C24H1 9F2N303S: C, 61.66; H, 4.09; N, 8.98. Found: C, 61.36; H, 3.96; N, 8.86.
Example 145 2-(1 -Cyclohexenylmethyl)-4-(4-fluorophenyl)-5-[4-(aminosulfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 127, substituting 1-bromomethylcyclohexene in place of 3,4-dif luo robe nzyl bromide (yield: 70 mg, M.p. 192-193 00. 1 H NMR (300 MHz, DMSO-d6) 8 1 .55 (in, 4H), 1.98 (in, 4H), 4.64 2H), 5.53 1 7.12 J 9 Hz, 2H), 7.22 (dd, J 9 Hz, 6 Hz, 2H), 7.39 J 9 Hz, 2H), 7.39 2H), 7.72 J 9 Hz, 2H), 8.07 1 H).
-109- WO 99/10331 WO 9910331PCTJUS98/1 6479 MS (DCI-NH 3 mlz 440 Anal. cab,. for C23H22FN 3 0 3 S: 0, 62.85; H, 5.04; N, 9.56. Found: C, 62.47; H, 5.23; N, 9.14.
Example 146 2-(a-Methvl-2 .3,4-trifluorobenzvr)-4-(4-fluorolhenvb)-5-f4-(aminosulfonyl)ohenvll.
3(2 pyridazi none The title compound was prepared according to the method of Example 127, substituting 2,3,4-trifluoro-ca-methylbenzyl chloride in place of 3,4-difluorobenzyl bromide (yield: 70 mg, M.p. 192-194 00. 1 H NMR (300 MHz, CDCI3) 5 1.84 J 6 Hz, 3H), 4.8 2H), 6.54 J 7 Hz, 1 6.96 J 9 Hz, 2H), 6.99 (in, 1 7.18 (dd, J =9Hz, 6Hz, 2H), 7.2 1H), 7.38 J =9 Hz, 2H), 7.86 J =9 Hz, 2H), 7.88 1 MS (DCI-NH3) m/z 504 Anal. calc. for 024H17F4N30 3 S: 0, 57.25; H, 3.4; N, 8.34. Found: 0, 56.84; H, 3.52; N, 7.91.
Example 147 2-hx-Methyl-3,5-difluorobenzyl)-4-(4-fluorogh enyl)-5-[4-(aminosulfonyl'ohenyll- 3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 127, substituting 3,5-difluoro-a-methylbenzyl chloride in place of 3,4-difluorobenzyl bromide (yield: 80 mng, M.p. 139-141 00. 1 H NMR (300 MHz, CDCI3) 6 1 .83 J 6 Hz, 3H), 4.79 2H), 6.32 J 7 Hz, 1 6.84 (in, 1 6.97 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 J 9 Hz, 2H), 7.85 1 7.9 J 9 Hz, 2H). MVS (DCI-NH3) m/z 486 Anal. calc.
for C24H18F3N30 3 S: C, 59.37; H, 3.73; N, 8.65. Found: C, 59.00; H, 3.70; N, 8.35.
Example 148 2-(ca-Methyl-3 .4-difluorobenzyl)-4-(4-fluoroohenvb-5-[4-(ami nosulfonvfl~henyll- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 127, substituting 3,4-difluoro-cx-methylbenzyl chloride in place of 3,4-diflIuo robe nzyl bromide (yield: 200 mg, M.p. 21 4-215 00. 1 H NMR (300 MHz, CDCI3) 6 1.82 J 6 Hz, 3H), 4.7 2H), 6.35 J 7 Hz, 1 6.96 J 9 Hz, 2H), 7.16 (mn, 4H), 7.28 J 9 Hz, 2H), 7.37 (mn, 1 7.84 J 9 Hz, 2H), 7.90 1 MS
(DCI-NH
3 m/z 486 Anal. calc. for C24H18BF3N30 3 S: C, 59.37; H, 3.73; N, 8.65. Found: 0, 59.13; H, 3.73; N, 8.54.
110- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 149 2-(3-Fluorobenzyl)-4-(4-fluorophenyl)-5-[4-(aminosu Ifonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 127, substituting 3-fluorobenzyl bromide in place of 3,4-difluorobenzyl bromide (yield: 160 mg, M.p. 220-222 00. 1 H NMR (300 MHz, DMSO-d6)6 5.37 (s,2H), 7.12 J 9 Hz, 2H), 7.22 (in, 5H), 7.39 (in, 5H), 7.73 J 9 Hz, 2H), 8.11 1 H).
MVS (D01-NH3) m/z 454 Anal. caic. for C23H17F2N303S: 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-r4-(aminosulfonylbphenyll-3(2H)pyrdzinone The title compound was prepared according to the method of Example 127, substituting 4-fluorobenzyl bromide in place of 3,4-d if luo robe nzyl bromide (yield: mg, M.p. 237-239 00. 1 H NMVR (300 MHz, DMSO-d6) 865.32 2H), 7.12 J 9 Hz, 2H), 7.22 (in, 4H), 7.38 (in, 7.47 J 9 Hz, 6 Hz, 2H), 7.72 J 9 Hz, 2H), 8.10 1 MS (DCI-NH3) mlz 454 Anal. calc. for 023H17F2N303S: 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-Trifluo robenzyl)-4-(4-fluorophenyl)-5-[4-(ami nosulfonyl)phenyl]-3(2H)pyridazinon The title compound was prepared according to the method of Example 127, substituting 2,4,6-trif lu orobe nzyl bromide in place of 3,4-difluorobenzyl bromide (yield: 255 mng, M.p. 201 -203 00. 1 H NMR (300 MHz, DMSO-d6) 6 5.38 (s, 2H), 7.13 J =9 Hz, 2H), 7.23 (in, 4H), 7.38 J 9 Hz, 2H), 7.42 2H), 7.70 (d, J 9 Hz, 2H), 8.08 1 MS (DCI-NH3) m/z 490 Anal. calc. for 023H1 5F4N303S: 0, 56.44; H, 3.08; N, 8.58. Found: 0, 56.31; H, 3.09; N, 8.40.
Example 152 2-(2 .4.5-Trifluorobenzyl)-4-(4-fluorophenyl)-5-[4-(ain nsu lfonyl)phenyl]-3(2H)pyidznone The title compound was prepared according to the method of Example 127, substituting 2,4,5-trifluorobenzyl bromide in place of 3,4-dif luo robe nzyl bromide (yield: 180 mg, M.p. 236-238 OQ. 1 H NMR (300 MHz, DMSO-d6) 6 5.35 (s, -111- WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 2H), 7.13 J 9 Hz, 2H), 7.23 (dd, J 9 Hz, 6 Hz, 2H), 7.39 J 9 Hz, 2H), 7.41 2H), 7.6 (in, 2H), 7.72 J =9 Hz, 2H), 8.11 1 MS (DCI-NH3) mlz 490 Anal. caic. for C23H15F4N30 3 S: 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-f luorophenyl)-5-[4-(ami nosulfonyl)Dhenyll-3(2H)- The title compound was prepared according to the method of Example 127, substituting 2,3,4-trif luo robe nzyl bromide in place of 3,4-dif luo robe nzyl bromide (yield: 220 mng, M.p. 218-220 OC. 1 H NMR (300 MHz, DMSO-d 6 5 5.40 (s, 2H), 7.13 J 9 Hz, 2H), 7.22 (dd, J 9 Hz, 6 Hz, 2H), 7.34 (mn, 2H), 7.39 J 9 Hz, 2H), 7.42 2H), 7.73 J 9 Hz, 2H), 8.12 1 MS (DCI-NH3) m/z 490 Anal. calc. for C23H15F4N 3 0 3 S: 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-Trif lu oro-3- methyl-2 E-butenyl)-4-(4-f Iuo roph eny1) (am inosuIto nyl)phenyll-3(2 H)-Dyridazi none The title compound was prepared according to the method of Example 123, substituting 1-bromo-3-methyl-4,4,4-trifluoro-2-butene in place of 1-broino-3inethyl-2-butene (yield: 160 mg, M.p. 155-157 OC. 1 H NMR (300 MHz, CDCI3) 5 2.00 3H), 4.8 2H), 4.96 J 7.5 Hz, 2H), 6.33 (in, 1 6.99 J= 9 Hz, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.29 J 9 Hz, 2H), 7.95 1 7.97 (d, J 9 Hz, 2H). MS (DCI-NH3) m/z 468 Anal. calc. for C21 H1 7F4N303S: 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-f luorophenyl)-5-?4-(methylsulfonyI)phenyll-3(2H)-pyridazi none The title compound was prepared according to the method of Example 62 substituting 4-broinobiphenyl in place of 4-iodo-1-fluorobenzene (yield: 0.275 g, 100%). M.p. 249-251 DC. 1 H NMR (300 MHz, DM50S d6) 8 3.24 3H), 7.16 (in, 2H), 7.30 (in, 2H), 7.42 (mn, 1 7.48-7.58 (in, 4H), 7.75 (in, 4H), 7.84 (in, 2H), 7.91 (in, 2H), 8.27 1 MS (DCI-NH3) mlz 497 514 Anal. calc.
for C23H21 FN203S: C, 70.15; H, 4.26; N, 5.64. Found: C, 69.81; H, 4.42; N, 5.41.
-112- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 156 2-(4-Bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2Hypyridazinone 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, 1 H NMR (300 MHz, DMS0 d6) 563.24 3H), 7.14 (in, 2H), 7.28 (in, 2H), 7.64 (in, 2H), 7.75 (in, 2H), 7.90 (mn, 2H), 8.25 1 MVS (DCI-NH3) mlz 499.
518 Anal. calc. for C23H16BrFN2O3S*0.75 H20: 0, 53.86; H, 3.43; N, 5.46. Found: 0, 53.92; H, 3.16; N, 5.34.
Example 157 2-(4-Nitrophenyl)-4-(4-fluoroo~henyl)-5-r4-(inethylsu lfonyl)phenyl]-3(2H)pyridaz non 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%). M.p. 110-11600. 1 H NMR (300 MHz, DM50 d6)83.24 7.17 (mn, 2H), 7.32 (mn, 2H), 7.53 (mn, 2H), 7.91 (mn, 2H), 8.03 (in, 2H), 8.34 1 8.40 (in, 2H). MS (DCI-NH3) m/z 466 483 Anal. calc. for 023H16FN305S: 0, 59.35; H, 3.46; N, 9.03. Found: 0, 59.02; H, 3.62; N, 8.82.
Example 158 2-(4-Phenoxyphenyl)-4-(4-fluorophenyl)-5-f4-(methylsulfonyl)phenyl-3 (2H)- 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, M.p. 118-12500C 1 H NMR (300 MHz, DMSO d6) 6 3.24 3H), 7.12 (in, 7.15-7.33 (in, 4H), 7.46 (mn, 2H), 7.52 (in, 765 (mn, 2H), 7.90 (in, 2H), 8.23 1 MS (DCI-NH3) m/z 513 Anal. calc. for 025H21 FN204S-0.75 C, 66.21; H, 4.31; N, 5.32. Found: C, 65.98; H, 4.25; N, 5.27.
Example 159 t-Butylphenyl)-4-(4-fluorophenyl)-5-4-(methylsulfonyl)phenyl].3 (2H)pyrida non The title compound was prepared according to the method of Example 62 substituting 1-broino-4-t-butyl-benzene in place of 4-iodo-1-fluorobenzene. No product was observed. The solution was concentrated in vacuo. The resulting -113- WO 99/10331 PCT/US98/16479 solid was dissolved in DMF (5 mL) and Cul (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 MgSO4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO 2 eluting with 5% diethyl ether/CH2Cl2 to provide the desired product (yield: 0.292 g, M.p. 132-136 1H NMR (300 MHz, DMSO d6) 6 1.34 9H), 3.24 3H), 7.14 2H), 7.29 2H), 7.54 6H), 7.90 2H), 8.23 1 MS (DCI-NH3) m/z 477 494 (M+NH4)+.
Anal. calc. for C27H25FN20 3 S: 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-fluorohenyl)-5-[4-(methylsulfonvy)phenyl]-3(2H)pvridazinone The title compound was prepared according to the method of Example 62 substituting 4-bromo-l-chlorobenzene in place of 4-iodo-l-fluorobenzene (yield: 0.254 g, M.p. 214-216 1 H NMR (300 MHz, DMSO d6) 3.24 3H), 7.16 2H), 7.29 2H), 7.52 2H), 7.61 2H), 7.71 2H), 7.91 2H), 8.26 1H). MS (DCI-NH3) m/z 455 472 Anal. calc. for C23H16CIFN20 3 S: C, 60.73; H, 3.55; N, 6.16. Found: C, 60.45, H, 3.41; N, 6.05.
Example 161 2-(3-MethvlDhenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfony)phenyl]-3(2H)vpridazinone The title compound was prepared according to the method of Example 62 substituting 3-bromotoluene in place of 4-iodo-l-fluorobenzene (yield: 0.262 g, M.p. 213-216 1 H NMR (300 MHz, DMSO d6) 62.39 3H), 3.24 3H), 7.14 2H), 7.28 3H), 7.43 3H), 7.53 2H), 7.80 2H), 8.22 1 H).
MS (DCI-NH3) m/z 435 452 Anal. calc. for C24H19FN203S: 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)v henvl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 62 substituting 3-bromostyrene in place of 4-iodo-l-fluorobenzene (yield: 0.202 g, -114- WO 99/10331 WO 99/ 0331PCTIUS9816479 M.p. 182-183 0 C. 1 H NMR (300 MHz, DMS0 d6) 863.25 3H), 5.35 J 12 Hz, 1 5.92 J 15 Hz, 1 6.82 (in, 1 7.15 (in, 2H), 7.30 (in, 2H), 7.50- 7.60 (in, 4H), 7.74 (in, 1 7.91 (in, 2H), 8.24 1 MVS (DCI-NH3) m/z 447 464 Anal. caic. for C25H19FN2O3S-0.50 H20: 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-(methlsulfonyl)phenyll-3(2H>I prdaznone The title was prepared according to the method of Example 62 substituting 2broinobenzaldehyde in place of 4-iodo-1-fluorobenzene (yield: 0.196 g, M.p.
234-236 00. 1 H NMR (300 MHz, DM50S d6) 863.24 3H), 7.15 (in, 2H), 7.27 (in, 2H), 7.54 (in, 2H), 7.64-7.75 (in, 2H), 7.86-7.95 (mn, 3H), 8.01 (in, 1 8.29 1 H), 10.02 1 MS (DCI-NH 3 in/z 449 Anal. cab,. for C24H17FN204S-0.50 H20: 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-(methylsu lfonyl)phenyll-3(2H)pyidznon The title compound was prepared according to the method of Example 62 substituting 1l-bromo-2-nitrobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.307 g, M.p. 236-239 00. 1 H NMR (300 MHz, DM50S d6) 6 3.24 3H), 7.12-7.27 (in, 4H), 7.56 (in, 2H), 7.7-8.01 (in, 5H), 8.18 (in, 1 8.35 1 MS (DCI-NH3) m/z 466 483 Anal. calc. for 023H16FN305S.0.25 C, 58.78; H, 3.53; N, 8.94. Found: C, 58.63; H, 3.54; N, 8.88.
Example 165 2-(3-Ch borophenyl)-4-(4-fluorophenyl)-5-[4-(methvlsulfonyl)phenyll-3(2)pyrdanone 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, M.p. 232-235 00. 1 H NMR (300 MHz, DM50S d6) 6 3.23 3H), 7.14 (mn, 2H), 7.29 (in, 2H), 7.49-7.58 (in, 4H), 7.66 (mn, 1 7.79 (mn, 1 7.90 (in, 2H), 8.25 1 MS (DCI-NH3) in/z 455 472 (M+NH 4 Anal. calc. for C23H16CIFN 2 0 3 S: C, 60.73; H, 3.55; N, 6.16. Found: C, 60.40; H, 3.43; N, 5.98.
-115- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 166 2-(3-Bromophenvl)-4-(4-fluorophenfl)-5-[4-(methylsulfonylbphenyl]-3 (2 H)pyridazinone 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, M.p. 210-212 00. 1 H NMR (300 MHz, DM50S d6) 8 3.23 3H), 7.15 (in, 2H), 7.29 (mn, 2H), 7.48-7.55 (in, 3H), 7.69 (mn, 2H), 7.90 (in, 3H), 8.26 1 MS
(DCI-NH
3 m/z 499 519 Anal. calc. for C23H16BrFN 2
O
3 S: C, 55.32; H, 3.23; N, 5.61. Found: 0, 55.12; H, 3.12; N, 5.51.
Example 167 2-(4-Cyan ophe nvl)-4- (4-f Iuo rophe nyl)- 5-4- (met hy suf onyl) ph e nl-3 (2 H)- The title compound was prepared according to the method of Example 62 substituting 4-broinobenzonitrile in place of 4-iodo-1-fluorobenzene (yield: 0.349 g, 100%). M.p. 273-27800C 1 H NMR (300 MHz, DM50S d6) 5 3.24 3H), 7.11-7.21 (in, 2H), 7.25-7.35 (in, 2H), 7.52 (mn, 2H), 7.88-7.96 (in, 4H), 8.04 (in, 2H), 8.31 (s, 1 MS (DCI-NH3) m/z 445 Anal. calc. for C24H16FN303S: C, 64.71; H, 3.62; N, 9.43. Found: 0, 64.50; H, 3.53; N, 9.35.
Example 168 2- Methyl-2-thi enyl))-4- (4-f luorop heny 1)-54[4- (met hylsuIf on yl) phen Yll-3 (2 H)pyrida none The title compound was prepared according to the method of Example 62 substituting 2-broino-5-inethylthiophene in place of 4-iodo-1-fluorobenzene (yield: 0.200 g, M.p. 219-224 00. 1 H NMR (300 MHz, DM50S d6) 8 2.45 3H), 3.23 3H), 6.80 (mn, 1 7.17 (mn, 2H), 7.29 (in, 2H), 7.52 (in, 3H), 7.89 (mn, 2H), 8.33 1 MS (DCI-NH3) m/z 441 458 Anal. caic. for C22H17FN 2 0 3
S
2 0, 59.99; H, 3.89; N, 6.36. Found: 0, 59.90; H, 3.91; N, 6.26.
Example 169 2 -(3-Birphenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]..3(2H)..pyridazinone 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, M.p. 126-134 00. 1 H NMR (300 MHz, DM50S d6) 8 3.24 3H), 7.15 (in, -116- WO 99/10331 WO 9910331PCTIUS98/1 6479 2H), 7.31 (in, 2H), 7.37-7.45 (in, 1 7.51 (in, 7.64 (in, 7.68-7.79 (in, 3H), 7.92 (in, 8.27 1 MS (DCI-NH3) mlz 497 514 Anal.
caic. for C291-21 FN2O3S: 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-f luorophenyl)-5-[4-(methylsu lfonyl)phenyl]-3 (2 H)- The title compound was prepared according to the method of Example 62 5-bromo-in-xylene in place of 4-iodo-1-fluorobenzene (yield: 0.152 g, M-p. 130-134 00. 1 H NMVR (300 MHz, DIMS0 d6) 8 2.34 3.23 (s, 3H), 7.07-7.12 (mn, 2H), 7.15 (mn, 1 7.21-7.32 (in, 4H), 7.52 (mn, 2H), 7.90 (in, 2H), 8.29 1 MS (DCI-NH 3 in/z 449. 466 Anal. calc. for C251-21 FN2O3S: C, 66.95; H, 4.72; N, 6.25. Found: C, 66.81; H, 4.57; N, 6.07.
Example 171 2- (3.
4 Dif luorop henyl)-4- (4-f Iuo robe nzy )-54[4-(metylsu fo nyl)p he nyll -3 (2hk.
prida '~n 4-(4-Fluorophenylmethyl)-5-[4- (iethylsulfonyl)phenyl]-3(2 H)-pyridazinone was prepared according to the method of Example 11, +starting with 2-benzyl-4-(4f luo rophenylmethyl)-5-[4-(methylsulIf onyl)phenyl]-3(2 H)-pyridazi none in place of 2benzyl- 4 luorophenyl)-5-[4-(methylsulf ony)phenyl..3(2 H)..pyridazi none (yield: 0.3319 g, 83%).
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylinethyl)--[4-(methylsulfonyl)phenyl]-3(2H).
pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(inethylsulfonyl)phenyl]-3(2H)pyridazinone and substituting 1-bromo-3,4-difluorobenzene in place of 4-iodo-1fluorobenzene (yield: 0.085 g, M.p. 157-159 00. 1 H NMVR (300 MHz, DMVSO d6) 563.30 3H), 3.88 (bs, 2H-1), 7.04 (in, 4H), 7.49-7.66 (mn, 7.70 (in, 2H), 7.81 (in, 1 8.12 1 MS (DCI-NH3) in/z 471 488 (M+NH 4 Anal. calc.
for C24H17F3N 2 0 3 S.0.25 H20: C, 60.69; H, 3.71; N, 5.84. Found: C, 6.39; H, 3.76; N, 5.81.
-117- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 172 2-(3-Chloro-4-fluorophenyl)-4-(4-fluorobenzyl)-5-[4-(methylsu Ifonyl)phenyl]-3(2 H)pyridazi none The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsufonyl)phenyl]-3(2H)pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridlazinone and substituting 4-bromo-2-chloro-1-fluorobenzene in place of 4iodo-1-fluorobenzene (yield: 0.110 g, M.p. 153-156 00. 1 H NMR (300 MHz, d6) 5 3.30 3H), 3.89 (bs, 2H), 7.02-7.07 (in, 4H), 7.59 (in, 1 7.65-7.72 (in, 4H), 8.07 (in, 2H), 8.12 1 MS (DCI-NH3) m/z 487 504 Anal. caic. for C24H1701F2N20 3 S-0.25 H20: 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-f luorop~henyl)-5-[4-(methylsulf onyl)phenyll-3 (2 H)pyridazi none The title compound was prepared according to the method of Example 62 substituting 2-broimoth iophene in place of 1 -bromrno-4-f luo robe nzene (yield: 98 mg, M.p. 215-21700C 1 H NMR (300 MHz, DMSO-d6) 863.25 3H), 7.18 (mn, J 9 Hz, 3H), 7.29 (in, 2H), 7.42 2H), 7.75 1 7.93 J 9 Hz), 8.4 1 H).
MS (DCI-NH3) m/z 427 444 Anal. caic. for 021 H15FN203S2: C, 59.14; H, 3.54; N, 6.57.
Example 174 2-(4-Trifluoromethylphenyl)-4-(4-fluorophenyl)-5-f4-(methylsu lfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 62 substituting 1 -bromo-4-trifluoromethylbenzene in place of 1 -broino-4fluorobenzene (yield: 185 mg, M.p. 171-17300C 1 H NMR (300 MHz, DMSOd6) 6 3.25 3H), 7.18 2H), 7.29 (in, 2H), 7.52 J 9 Hz 2H), 7.91 J 9 Hz, 2H), 7.93 4H), 8.32 1 MS (DCI-NH3) m/z 489 506 (M+NH4)+.
Anal. caic. for C24H16F4N203S: 0, 59.02; H, 3.3; N, 5.74. Found: C, 58.75; H, 3.35; N, 5.69.
-11 8- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 Example 175 24[4-(1 -Pvrroyflphenyll-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p2henyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 62 substituting 1-(4-iodophenyl)pyrrole in place of 1-bromo-4-f luo robe nze ne (yield: 140 mg, M.p. 229-231 OQ. 1 H NMVR (300 MHz, DMSO-d6) 8 3.25 3H), 6.3 2H), 7.18 2H), 7.29 (in, 2H), 7.46 2H) 7.53 J 9 Hz 2H), 7,75 4H), 7.91 J 9 Hz, 2H), 8.27 1 MS (DCl-NH 3 m/z 486 504 (M+NH4)+.
Anal. calc. for 027H20FN30 3 S-0.5 H20: C, 66.79; H, 4.15; N, 8.65. Found: C, 65.21; H, 4.29; N, 8.12.
Example 176 hNoro-2-t hie nyl)-4- (4-f luo roph enyfl-5-[4-(methylsu If o nyl)phe nyl]-3(2 H) pyridazinone The title compound was prepared according to the method of Example 62 substituting 1 -bromo-5-chlorothiophene in place of 1 -bromo-4-fluorobenzene (yield: 225 mg, M.p. 190-19200C 1 H NMVR (300 MHz, DMVSO-d 6 8 2.38 (s, 3H), 8 3.25 3H), 7.15 2H), 7.29 (in, 4H), 7.5 4H) 7.91 J 9 Hz, 2H), 8.21 1 MS (DCI-NH 3 m/z 435 452 Anal. calc. for C24H19F N203S: 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)pheny]-3(2H)p2yridazinone 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 M.p. 190-192 00. 1 H NMR (300 MHz, DMSO-d6) 8 2.38 3H), 8 3.25 3H), 7.15 2H), 7.29 (mn, 4H), 7.5 4H) 7.91 J 9 Hz, 2H), 8.21 (s, 1 MS (DCI-NH 3 in/z 435 452 Anal. calc. for 024H1 9F N203S: C, 66.35; H, 4.41; N, 6.45. Found: C, 66.15; H, 4.37; N, 6.3.
-119- WO 99/10331 PCT/US98/16479 Example 178 2-(4-Fluorophenyl)-4-(2-ethyl-1 -hexvloxy)-5-4-(methylsulfonvl)phenvll-3(2H)pyridazinone To a solution of 2-ethyl-1-hexanol (65 mg, 0.5 mmol) in THF (15 mL) at room temperature was added NaH (60% oil suspension) (20 mg, 0.5 mmol) and after minutes 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (193 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for the next 2 hours. The mixture was quenched with 10% citric acid and extracted with ethyl acetate. The extract was washed with water, brine, dried with MgSO4, and purified by chromatography (silica gel, 2:1 hexanes-ethyl acetate) to provide the desired product (yield: 140 mg, M.p. 120-122 OC. 1H NMR (300 MHz, DMSO-d6) 8 0.75 6H), 1.1 6H), 1.20 (quintet, J 7 Hz, 2H), 1.44 1 3.27 3H), 4.30 J= 6 Hz, 2H), 7.37 J= 9 Hz, 2H), 7.65 2H), 7.89 J 9 Hz, 2H), 8.06 J 9 Hz, 2H), 8.18 1H). MS (APCI+) m/z 473 (APCI-) m/z 507 Anal. calc. for C25H29FN204S-0.5 H20: C, 62.35; H, 6.27; N, 5.87. Found: C, 62.22; H, 6.14; N, 6.22.
Example 179 2-(3-Thienvyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl-3 (2H)-pyridazinone 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, M.p. 200-202 C. 1 H NMR (300 MHz, DMSO-d6) 3.25 3H), 7.15 2H), 7.29 2H), 7.5 J 9 Hz, 2H), 7.6 1H) 7.66 (dd, 1H), 7.91 J 9 Hz, 2H), 8.13 (dd, 1H), 8.25 1H). MS (DCI-NH3) m/z 427 444 Anal.
calc. for C21 H15FN203S2: 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-f luorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 62 substituting 3,5-difluorobromobenzene in place of 1-bromo-4-fluorobenzene (yield: -120- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 250 mg, M.p. 166-168 OC. 1 H NMR (300 MHz, DMSO-d6) 863.25 3H), 6 7.15 2H), 7.27 (in, 2H), 7.4 (in, 1 7.41 (in, 2H), 7.51 J 9 Hz, 4H), 7.9 J= 9 Hz, 2H), 8.3 1 MS (DCI-NH3) m/z 457 474 Anal. calc.
for 023H15F3N 2 0 3 S: 0, 60.13; H, 3.31; N, 6.14. Found: C, 60.49; H, 3.31; N, 6.03.
Example 181 2-(2 Difluorophenyl)-4-(4-f luorophenyl)-5-f4-(methylsulfonyl)phenyll-3 (2 H)pyridazinone The title compound was prepared according to the method of Example 62 substituting 2,4-difluorobroinobenzene in place of 1 -broino-4-f luo robe nze ne (yieid: mg, M.p. 245-24700C 1 H NMR (300 MHz, DMSO-d6) 563.23 3H), 8 7.15 2H), 7.3. 2H), 7.54 (in, 2H), 7.57 (in, 7.75 (in, 1 7.9 J 9 Hz, 2H), 8.27 1 MS (DCI-NH3) m/z 457 474 Anal. caic. for 028H1 5F3N203S: 0, 60.52; H, 3.31; N, 6.03.
Example, 182 2-(3 .4-Difluorophenyl)-4-(4-f luorophenyl)-5-[4-(methylsulfo nyl)12henyll-3 (2 H)pyridazinQDe The title compound was prepared according to the method of Example 62 substituting 3,4-difluorobroinobenzene in place of 1 -broino-4-f Iuo robe nze ne (yield: 170 ing, M.p. 109-110 00. 1 H NMR (300 MHz, DMSO-d6) 5 3.23 3H), 8 7.15 2H), 7.3 2H), 7.25 (in, 2H), 7.59 (in, 4H), 7.83 (in, 1 7.9 J 9 Hz, 2H), 8.27 1 MS (DOI-NH3) in/z 457 474 Anal. calc. for 023H15F3N 3 0 3 S: 0, 60.52; H, 3.31; N, 6.14. Found 60.60; H, 3.48; N, 5.89 Example 183 Furyl)-4-(4-fluorophenyl)-5-[4-(inethylsu If onyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 62 substituting 3-broinofuran in place of 1-broino-4-fluorobenzene (yield: 175 ing, M.p. 239-242 00. 1 H NMR (300 MHz, DMSO-d 6 6 3.25 3H), 7.09 1 H), 7.15 2H), 7.29 (in, 2H), 7.5 J 9 Hz 2H), 7.8 1 H) 7.91 J 9 Hz, 2H), 8.3 (s 1 8.58 1 *MS (001-N H3) in/z 411 428 Anal. calc. for 021 Hi 5F N2O4S-Q.5 H20: C, 61.46; H, 3.68; N, 6.83. Found: 0, 59.91; H, 3.54; N, 6.54.
-121- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 184 2-(3-Fluoro-4-methoxyphenyb)-4-(4-f luorophenyl)-54[4-(methylsulfoyl)Dhenyll- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 62 substituting 3-fluoro-4-methoxybromobenzene in place of 1 -bromo-4fluorobenzene (yield: 230 mg, M.p. 97-101 0 C. 1 H NMR (300 MHz, DMS0d6) 5 3.25 3H), 3.9 3H), 7.16 1 7.29 (in, 3H), 7.5 (in, 4H), 7.91 J 9 Hz, 2H), 8.23 (s 1 MS (DCI-NH3) m/z 469 491 Anal. calc.
for C24H1 BF2N204S*0.5 H20: 0, 61.53; H, 3.87; N, 5.98. Found: C, 61.18; H, 4.01; N, 5.58.
Example 185 2-(2-Fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenll-3'2
H)-
The title compound was prepared according to the method of Example 62 substituting 2-fluorobromobenzene in place of 1 -bromo-4-fluorobenzene (yield: 195 mng, M.p. 96-103 00. 1 H NMR (300 MHz, DMSO-d6) 8 3.23 3H), 6 7.15 2H), 7.3 (mn, 3H), 7.55 (mn, 5H), 7.9 J 9 Hz, 2H), 8.27 1 MS (ESI) m/z 437 Anal. calc. for 023H1 6F2N20 3 S: 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(2
H)-
The title compound was prepared according to the method of Example 62 substituting 4-aminosulfonyl-1-broinobenzene in place of 1-bromo-4fluorobenzene. M.p. 213-2160 OC 1H NMR (300 MHz, DMSO-d6) 6 3.25 3H), 7.15 2H), 7.29 (in, 2H), 7.53 2H) 7.55 1 7.7 (dd, 2H) 7.91 4H), 7.98 (d, 2H), 8.3 1 MS (DCI-NH3) m/z 499 517 Anal. caic. for C23H18FN305S2.0.5 H20: C, 55.30; H, 3.63; N, 8.41. Found: 0, 54.4; H, 3.79; N, 7.78.
-122- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 187 2-(3-Chloro-4-fluorophenyl)-4-(4-fluorophe nyl)-5-[4-(methylsulfonyl~phenyl H)- The title compound was prepared according to the method of Example 62 substituting 3-chloro-4-fluoro-1-bromobenzene in place of 1-bromo-4fluorobenzene (yield: 320 mg, M.p. 155-1 57 0C. 1 H NMR (300 MHz, DMSOd6) 5 3.23 3H), 567.15 2H), 7.3 2H), 7.25 (in, 2H), 7.53 J 9 Hz, 2H), 7.59 1 7.73 (mn, 1 7.9 J 9 Hz, 2H) 7.96 (in, 1 8.27 1 MS (DCl- NH3) m/z 473 (M 490 Anal. caic. for 023H15ClF2N20 3 S: C, 58.42; H, 3.2; N, 5.92. Found 58.23; H, 2.87; N, 5.70 Example 188 2-(3 .5-Dichlorophenyl)-4-(4-f luorophenyl).5-[4-(inethylsu lfonyl)phenyll-3(2H)- The title compound was prepared according to the method of Example 62 substituting 3,5-dichlorobenzene in place of 1-broino-4-fluorobenzene (yield: 360 mg, M.p. 289-294 00. 1 H NMVR (300 MHz, DMSO-d6) 6 3.25 3H), 6 7.15 2H), 7.27 (mn, 2H), 7.51 J 9 Hz, 7.75 1 7.83 2H), 7.9 J 9 Hz, 2H), 8.3 1 MS (DCI-NH3) in/z 490 507 Anal. calc. for 023H15Cl2FN20 3 S*0.5 H20: 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-(inethylsulfonyI)phe nvll-3(2H)pyidao The title compound was prepared according to the method of Example 62 substituting 1-broino-4-fluoro-3-inethylbenzene in place of 1-bromo-4fluorobenzene (yield: 275 mg, M.p. 168-17000C 1 H NMR (300 MHz, DMSOd6) 6 2.3 3H), 6 3.25 3H), 7.15 2H), 7.3 (in, 3H), 7.56 (in, 4H), 7.9 2H), 8.23 2H). MS (DCI-NH3) in/z 453 471 Anal. calc. for C24H1 8F2N203S: C, 63.71; H, 4.01; N, 6.01. Found: C, 63.53; H, 4.06; N, 5.92.
-123- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 Example 190 2-(4-Chloro-3-fluorophenyl)-4-(4-fluorophe nyl)-5-[4-(methylsulfo nyl)phenyl]-3 (2 H)pyridazinone: The title compound was prepared according to the method of Example 62 substituting 4-bromo-1 -chloro-2-fluorobenzene in place of 1 -bromo-4fluorobenzene (yield: 220 mg, M.p. 102-110 00. 1 H NMR (300 MHz, DMS0d6) 8 3.23 3H), 7.11-7.19 (in, 2H), 7.25-7.32 (in, 2H), 7.51 J 5.6 Hz, 2H), 7.58-7.64 (mn, 1 7.75-7.87 (in, 2H), 7.91 J 5.6 Hz, 2H), 8.28 1 MS (APCI+) m/z 473 Example 191 2-(4-Chloro-2-fluorophenyl)-4-(4-fluorophenyl)-5-4-(methylsulfo nyl)phenyt]-3(2 H)pyridazi none: The title compound was prepared according to the method of Example 62 substituting 1 -bromo-4-chloro-2-fluorobenzene in place of 1 -bromo-4fluorobenzene (yield: 65 mg M.p. 250-260 00. 1 HNMR (300 MHz, DMS0d6) 8 3.21 3H), 7.12-7.19 (in, 2H), 7.25-7.32 (in, 2H), 7.49-7.58 (in, 3H), 7.68- 7.78 (in, 2H), 7.91 J 8.7 Hz, 2H), 8.29 1 MS (APCI+) m/z 473 Anal. calc. for 023H15ClF2N20 3 S: 0, 58.41; H, 3.19; N, 5.92. Found: C, 58.69; H, 3.45; N, 5.78.
Example 192 2-(1 -Adainantyloxycarbonyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyI)phenyl-3(2H)pyridazi none A solution of 4-(4-fluorophenyl)-5-[4-(m'ethylsulfonyl)phenyl]-3(2H)pyridazinone, prepared according to the procedure of Example 11 (200 mng, 0.58 mmol) in 0H2012 (8 ml) was prepared and -stirred. 1 -Adamantylfluoroforinate (172 mng, 0.87 inmol), dimethylaminopyridine (14 mg, 0.011 minol) and triethylamine (0.12 ml, 0.87 inmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 0H2C12 (50 ml) and washed with 10% citric acid (50 ml), brine (50 ml) and dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiO 2 eluting with 15:1 0H2C12:diethyl ether) to provide the desired product (yield: 55 mg, 1 H NMR (300 MHz, DMSO-d6) 8 1.66 (bs, 6H), 2.25 (bd, 1 OH), 3.21 3H), 7.15 2H), 7.24 (in, 2H), 7.6 (dd, 2H), 7.88 J -124- WO 99/10331 PCT/US98/16479 9 Hz, 2H), 8.15 1H). MS (ESI) m/z 521 Anal. calc. for C21 N203S2: C, 64.35; H, 5.20; N, 5.36.
Example 193 2-(2.2.2-Trifluoroethyl)-4-(4-fluorobenzvl)-5-[4-(methylsulfonyl)phenyl]-3(2 H)pyridazinone 193A. 2-(2.2.2-Trifluoroethyl)-4.5-dichloro-3(2H)-pyridazinone 2,2,2-Trifluoroethylhydrazine (70% solution in water, 35.0 g, 0.307 mol) was treated with mucochloric acid (51.88 g, 0.307 mol) in ethanol (300 mL) and refluxed for 5 hours. The solvent was concentrated in vacuo. The crystals obtained were washed with water and air dried (yield: 50 g; 1H NMR (300 MHz, CDCI3) d 4.8 J 9 Hz, 2H), 7.85 1 MS (DCI-NH3) m/z 264 (M+NH4)+.
193B. 2-(2.2.2-Trifluoroethyl)-4-chloro-5-hydroxv-3(2H)-pyridazinone 2-(2,2,2-Trifluoroethyl)-4,5-dichloro-3(2H)-pyridazinone (15.0 m 60.7 mmol), and potassium carbonate (10 g, 72.4 mmol.) were mixed with water (500 mL) and stirred at reflux for 6 hours. TLC (1:1:2 CH2CI2/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 The product was extracted with ethyl acetate (700 mL).
The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The hydroxy compound was obtained as a light brown solid (yield: 13.1 g, 1 H NMR (300 MHz, DMSO-d6) 8 4.92 J 9 Hz, 2H), 7.9 1H). MS (DCI-NH3) m/z 229 193C. 2-(2.2.2-Trifluoroethyl)-4-chloro-5-(trifluoromethylsulfonyloxy)-3(2H)pyridazinone Anhydrous Na2CO3 (9.04 m, 85.32 mmol) was placed in a 500 mL round bottom flask and anhydrous CH2CL2 (200 mL) was added. The reaction mixture was cooled to 0 °C under N2. The halohydroxy pyridazinone prepared in Example 193B was dissolved in CH2CL2 (100 mL) and added slowly to the flask and stirred overnight. The reaction slowly warmed to room temperature. (TLC 1 hexanes/ethyl acetate) indicated completion of the reaction.) The reaction was quenched with H20. The organic phase containing the product was separated, washed with brine and dried over MgSO4. The resulting filtrate was concentrated under reduced pressure. The crude product was isolated as deep red-brown -125- WO 99/10331 PCT/US98/16479 residue. Purification using a silica gel column (30:70 ethyl acetate/pentanes) provided the title compound as a dark, reddish residue (14.3 m, 1H NMR (300 MHz, CDCI3) 8 4.85 J 9 Hz, 2H), 7.9 1H). MS (DCI-NH 3 m/z 378 (M+NH4)+.
193D. 2-(2.2.2-Trifluoroethyl)-4-chloro-5-[4-(methylthio)phenvl]-3(2H)vridazinone 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 MgSO4 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, greenishyellow solid (yield: 500 mg, M.p. 130-139 OC. 1 H NMR (300 MHz, CDCI3) 8 2.55 3H), 4.87 J 9 Hz, 2H), 7.37 J 9 Hz, 2H), 7.48 J 9 Hz, 2H), 7.82 1 MS (DCI-NH3) m/z 335 (M+H) 193E. 2-(2.2.2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting the coupled intermediate prepared in Example 193D in place of 2benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 440 mg, M.p. 221-222 1 H NMR (300 MHz, DMSO-d6) 3.33 3H), 5.10 (q, J 9 Hz, 2H), 7.90 J 9 Hz, 2H), 8.12 J 9 Hz, 2H), 8.20 1 MS (DCI- NH3) m/z 367 193F. 2-(2.2.2-Trifluoroethyl)-4-(4-fluorobenzyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone Magnesium turnings (500 mg) were placed in a dry 250 mL round bottom flask. Anhydrous ether (20 mL) was added under N2 at room temperature then fluorobenzyl bromide (3 mL) was added and stirred. The reaction was heated at 0 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)pyridazinone prepared in Example 193E was dissolved in dry THF (25 mL) and transferred to the Grignard solution. The mixture was heated for 3 hours. TLC (2:1 S 35 hexanes/ethyl acetate) indicated that the pyridazinone starting material was consumed.) The reaction was cooled to room temperature then quenched with a -126- WO 99/10331 PCT/US98/16479 saturated NH4CI solution. The product was extracted with ethyl acetate (250 mL); and the organic layer was washed with saturated NH4CI, and brine. The ethyl acetate solution was dried over MgSO4 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, 1 H NMR (300 MHz, CDCI3) 3.13 3H), 4.85 2H), 6..93 4H), 7.49 J 9 Hz, 2H) 7.72 (s, 1H), 8.08 J 9 Hz, 2H). MS (DCI-NH3) m/z 441 Anal. calc. for C20H16F4N203S-0.5 H20: C, 53.45; H, 3.81; N, 6.23. Found C, 53.45; H, 3.81; N, 6.23.
Example 194 2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazinone 194A. 2-(4-Fluorophenyl)-4.5-dibromo-3(2H)-pyridazinone Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenyl hydrazine.HCI, and the heterogeneous mixture brought to reflux at a bath temperature of 115 OC for 15 hours. During the course of reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23 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 of product. Het. Chem.., 1993, 30, 1501; Heterocycles 1985, 23, 2603) 1 H NMR (300 MHz, DMSO-d6) 8 7.31-7.41 2H), 7.57-7.64 2H), 8.29 1 MS (DCI+) m/z 347 (Br79Br79 m/z 349 (Br79Br81 m/z 364 (Br79Br79 M+NH4)+, and m/z 366 (Br79Br81 M+NH4)+.
194B. 2-(4-Fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone A 23 OC homogeneous solution of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)pyridazinone (7.18 g, 20.6 mmol) prepared above in tetrahydrofuran (322 mL) was treated with methanol (0.843 mL, 20.8 mmol) and after 5 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 °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 -127- WO 99/10331 PCT/US98/16479 methanol, and 83 mg of 60% NaH oil dispersion. This NaOMe solution was added via syringe to the reaction mixture cooled to 23 OC, 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 OC and diluted to 2000 mL with water. The yellow/white precipitate that formed was filtered off, washed with additional water, and concentrated in vacuoto provide 5.39 g of product. Het. Chem., 1988, 25, 1757) 1 H NMR (300 MHz, DMSO-d6) 4.13 3H), 7.30-7.40 2H), 7.56-7.62 2H), 8.22 (s, 1H). MS (APCI+) m/z 299 (Br79 and m/z 301 (Br81 194C. 2-(4-Fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone 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%).
1 H NMR (500 MHz, DMSO-d 6 5 2.54 3H), 4.02 3H), 7.35 (dd, J 9.0, 9.0 Hz, 2H), 7.39 J 8.5 Hz, 2H), 7.61 J 8.5 Hz, 2H), 7.65 (dd, J 9.0, 5.0 Hz, 2H), 8.14 1H). MS (APCI+) m/z 343 194D. 2-(4-Fluorophenyl)-4-methyl-5-[4-(methylthio)phenyvl-3(2H)-pyridazinone 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, 1 H NMR (300 MHz, CDC3) 8 2.25 3H), 2.55 3H), 7.17 (dd, J 8.8, 8.8 Hz, 2H), 7.31 J 8.7 Hz, 2H), 7.38 J 8.7 Hz, 2H), 7.61-7.68 2H), 7.82 1 MS (APCI+) m/z 327 194E. 2-(4-Fluorophenvl)-4-methyl-5-[4-(methylsulfonylphenvl]-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting 2-(4-fluorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone (yield: 473 mg, 1H NMR (300 MHz, CDCI3) 5 2.24 (s, 3H), 3.14 3H), 7.19 (dd, J 8.8, 8.8 Hz, 2H), 7.61 J 8.4 Hz, 2H), 7.63-7.69 2H), 7.80 1 8.12 J 8.4 Hz, 2H). MS (APCI+) m/z 359 and m/z 376 (M+NH4)+.
-128- WO 99/10331 PCT/US98/16479 194F. 2-(4-Fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyll-3(2H)ovridazinone To a heterogeneous, refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was 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 OC and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO3, water, and brine. The solution was dried over MgSO4, 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, 1 H NMR (300 MHz, CDCI3) 8 3.16 3H), 4.34 2H), 7.20 (dd, J 8.8, 8.8 Hz, 2H), 7.67-7.74 2H), 7.82 J 8.7 Hz, 2H), 7.86 1 8.17 J 8.7 Hz, 2H). MS (APCI+) m/z 437 194G. 2-(4-Fluorophenyl)-4-(4-fluorophenoxymethyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone To a homogeneous solution of 2-(4-fluorophenyl)-4-bromomethyl-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared above, (107 mg, 0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270 mmol) dissolved in acetone (4 mL) was added powdered K2CO3 (37.3 mg, 0.270 mmol). The mixture was stirred at 23 °C for 2 hours, filtered through a bed of Celite®, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 3:2) to provide the product (yield: 83 mg, M.p. 65-80 OC. 1H NMR (300 MHz, CDC13) 5 3.12 3H), 4.94 2H), 6.78-6.86 2H), 6.91-7.00 2H), 7.15-7.24 2H), 7.65-7.72 2H), 7.74 J 8.7 Hz, 2H), 7.93 1H), 8.08 J 8.7 Hz, 2H). MS (APCI+) m/z 469 Anal. calc. for C24H18F2N204S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.22; H, 3.63; N, 5.64.
-129- WO 99/10331 PCT/US98/16479 Example 195 2-(4-Fluorophenvyl)-4-(3-fluorophenoxymethyl)-5-r4-(methylsulfonvl)Dhenvyl-3(2H)pyridazinone The title compound was prepared according to the method of Example 194G substituting 3-fluorophenol in place of 4-fluorophenol (yield: 94 mg, M.p.
142-144 1H NMR (300 MHz, CDCI3) 3.12 3H), 4.98 2H), 6.49-6.56 (m, 1 6.60-6.73 2H), 7.15-7.25 3H), 7.65-7.75 4H), 7.93 1 8.07 J 8.7 Hz, 2H). MS (APCI+) m/z 469 Anal. calc. for C24H18F2N 2 0 4 S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.20; H, 3.92; N, 5.86.
Example 196 2-(4-Fluorophenyl)-4-phenoxymethyl-5-4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 294G substituting phenol in place of 4-fluorophenol (yield: 67 g, M.p. 42-75 OC.
1 H NMR (300 MHz, DMSO-d 6 8 3.28 3H), 4.92 2H), 6.83-6.90 2H), 6.91- 6.99 1H), 7.22-7.30 2H), 7.35-7.44 2H), 7.66-7.73 2H), 7.81-7.88 (m, 2H), 8.02-8.08 2H), 8.21 1 MS (APCI+) m/z 451 Example 197 2-(4-Fluorophenyl)-4-(t-butylthiomethyl)-5-4-(methylsulfonyl)phe nyl-3(2H)pyridazinone A 0 °C solution of the 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 194F (92.5 mg, 0.212 mmol) in acetone (2.5 mL) was treated with Nal (35 mg, 0.233 mmol), and after minutes, the cooling bath was removed and the reaction warmed to 23 After minutes, conversion to the 2-(4-fluorophenyl)-4-iodomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone was complete (thin layer chromatography, ethyl acetate/hexanes The NaBr and residual Nal were filtered off through a pad of Celite®. Additional acetone (2 mL) was added along with 2-methyl-2-propanethiol (20.5 mg, 0.227 mmol), and the solution cooled to 0 °C before addition of Ag2CO3 (63 mg, 0.227 mmol). After 5 minutes, the cooling bath was removed and the solution warmed to 23 °C for 5 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 3:2) to provide the product (yield: 57 mg, M.p. 50-70 C. 1 H NMR (300 MHz, CDC13) 8 1.34 9H), 3.14 3H), 3.65 -130- WO 99/10331 PCT/US98/16479 2H), 7.13-7.21 2H), 7.63-7.70 2H), 7.79 1H), 7.84 J 8.7 Hz, 2H), 8.13 J 8.7 Hz, 2H). MS (APCI+) m/z 447 Anal. calc. for C22H23FN203S2: C, 59.17; H, 5.19; N, 6.27. Found: C, 59.48; H, 5.36; N, 5.90.
Example 198 2-(4-Fluorophenvy-4-(2-methylpropylthiomethvl)-5-[4-(methylsulfonyl)phenyll- 3(2H)-pyridazinone The title compound was prepared according to the method of Example 197 substituting 2-methyl-l-propanethiol in place of 2-methyl-2-propanethiol (yield: 66 mg, M.p. 45-60 1H NMR (300 MHz, CDCI3) 5 0.95 J 6.6 Hz, 6H), 1.67-1.82 1H), 2.62 J 6.6 Hz, 2H), 3.15 3H), 3.61 2H), 7.19 (dd, J 8.2, 8.2 Hz, 2H), 7.62-7.71 2H), 7.75 J 8.4 Hz, 2H), 7.79 1 8.13 J 8.4 Hz, 2H). MS (APCI+) m/z 447 Anal. calc. for C22H23FN203S2: 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)phenyll-3(2H)-pyridazinone 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. 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-(2propoxy)-5-bromo-3(2H)-pyridazinone.
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, M.p. 135-137 OC. 1H NMR (300 MHz, CDCI3) 1.21 J 6 Hz, 6H), 2.55 3H), 5.26 (sept, J 6 Hz, 1 7.17 J 9 Hz, 2H), 7.34 J 9 Hz, 2H), 7.57 J 9 Hz, 2H), 7.58-7.66 2H), 7.95 1H). MS (DCI-NH3) m/z 371 Example 200 2 4 -Fluorophenyl-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyll-3(2H)-pyridazinone 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, M.p. 160-162 1 H NMR (300 MHz, DMSO-d6) 1.30 J 6 Hz, 6H), 3.41 3H), 5.41 1 7.48 J 9 Hz, 2H), 7.77 (dd, J 9 Hz, 6 Hz, 2H), -131- WO 99/10331 PCT/US98/16479 8.05 J 9 Hz, 2H), 8.19 J 9 Hz, 2H), 8.31 1H). MS (DCI-NH3) m/z 403 420 Anal. calc. for C20H19FN204S: C, 59.70; H, 4.73; N, 6.97. Found: C, 59.40; H, 4.86; N, 6.69.
Example 201 2-(3-Chlorophe nyl)-4-(2-propoxy)-5-[4-(methvlsulfonyl)phenyl]-3(2 H-pyridazinone 2-(3-Chlorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone 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, M.p. 134-136 1 H NMR (300 MHz, CDCI3) 5 1.24 J 6 Hz, 6H), 3.13 3H), 5.48 (sept, J 6 Hz, 1 7.37-7.48 2H), 7.59 (dt, J 7 Hz, 1.5 Hz, 1H), 7.70 (br s, 1 7.84 J 9 Hz, 2H), 7.93 1 8.06 J 9 Hz, 2H). MS (DCI-NH3) m/z 419 436 Anal. calc. for C20H19CIN204S: C, 57.42; H, 4.55; N, 6.70. Found: C, 57.08; H, 4.59; N, 6.44.
0 Example 202 2 -(3-Fluorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyl-3(2 H)-pyridazinone 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, M.p. 110-112 1 H NMR (300 MHz, CDCI3) 8 1.31 J 6 Hz, 6H), 3.11 3H), 5.47 (sept, J 6 Hz, 1H), 7.09-7.18 1H), 7.41-7.52 3H), 7.83 J 9 Hz, 2H), 7.93 1 8.08 J 9 Hz, 2H). MS (DCI-NH3) m/z 403 447 Anal. calc. for C20H19FN204S: C, 59.70; H, 4.73; N, 6.97. Found: C, 59.54; H, 4.87; N, 6.70.
Example 203 2 3 -Bromophenvl)-4-(2-propoxvy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone 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, M.p. 130-132 OC. 1H NMR (300 MHz, CDCI3) 1.23 J -132- WO 99/10331 WO 9910331PCTIUS98/1 6479 6 Hz, 6H), 3.15 3H), 5.48 (sept, J 6 Hz, 1 7.38 J 9 Hz, 1 7.55 (br d, J =7 Hz, 1 7.65 (br d, J 7 Hz, 1 7.79-7.87 (in, 1 7.83 J 9 Hz, 2H), 8.13 1 8.06 J 9 Hz, 2H). MS (DCI-NH3) m/z 465 480 (M+NH4)+.
Anal. calc, for C20Hj9BrN20 4 S: C, 51.84; H, 4.10; N, 6.05. Found: 0, 51.95; H, 4.18; N, 5.74.
Example 204 2-(2 .5-Dif luorophenyl)-4-(2-propoxy)-5-[4-(methylsulfonyl)phenyll-3 (2H)pyidnone 2-(2,5-Difluorophenyl)-4-(2-propoxy)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone was prepared according to the method of Example 199, substituting 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: 390 mng, M.p.
161 -164 00. 1 H NMR (300 MHz, 0D013) 8 1.23 J 6 Hz, 6H), 3.12 3H), 5.55 (sept, J 6 Hz, 1 7.12-7.29 (in, 3H), 7.82 J 9 Hz, 2H), 7.92 1 8.07 J 9 Hz, 2H). MS (DCI-NH3) m/z 421 438 Anal. calc. for 020H18 F2N204S-0.5 H20: 0, 55.94; H, 4.31; N, 6.53. Found: 0, 55.86; H, 4.19; N, 6.38.
Example 205 2 -(3-Chloro-4-fluoropheny)-4-(2-methylpropoxy)-5-3-fluoro-4-(methylsulfonL).
phenylI-3 (2 H)-pyridazi none 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-f luorophenyl)-4,5-dibromo-3(2H)-pyridazi none according to the method of Example 1 94A. 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)-pyridazi none according to the method of Exa mple 194B. The 5-bromo-compound was coupled to 3-fluoro-4-(methylthio)phenylboronic acid prepared in Example 1940 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, M.p. 142-14400. 1 H NMR (300 MHz, CDCI3)80.90 J=6 Hz, 6H), 1.95 (sept, J 6 Hz, 1 3.30 3H), 4.37 J 6 Hz, 2H), 7.26 J 9 Hz, -133- WO 99/10331 PCT/US98/16479 1 7.52-7.61 3H), 7.75 (dd, J 9 Hz, 3 Hz, 1 7.89 1 8.10 J 9 Hz, 1H). MS (DCI-NH3) m/z 469 486 (M+NH4)+.
Example 206 2-(3.4-Difluorophenvl)-4-(4-fluorophenvl)-5-[3-methvl-4-(methvlsulfonvylphenyl]- 3(2H)-pyridazinone 206A. 2-Methylthioanisole A solution of 2-bromothioanisole (10.53 g, 52 mmol) in tetrahydrofuran (173 mL) was prepared and cooled to -78 oC. 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 OC. The cooling bath was removed, and the mixture stirred for 1 hour. The solution was cooled to 0 OC and a saturated aqueous NH4CI solution added. The resultant solution was extracted several times with ethyl acetate, and the combined acetate layers washed with brine, dried over MgSO4, 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, 1 H NMR (300 MHz, CDCI3) 6 2.34 3H), 2.46 3H), 7.02-7.09 1 7.12-7.22 3H).
206B. 4-Bromo-2-methylthioanisole.
To a 0 °C solution of 2-methylthioanisole (0.50 g, 3.57 mmol) in methylene chloride (40 mL) was added powdered Fe (20 mg, 0.36 mmol) followed by dropwise addition of bromine (0.58 g, 3.54 mmol). After 30 minutes, the starting material had been consumed (thin layer chromatography, hexanes). The excess bromine was quenched by adding a solution of NaHSO3 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 MgSO4, 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, 1 H NMR (300 MHz, CDCI3) 5 2.30 3H), 2.45 (s, 3H), 7.00 J 8.4 Hz, 1H), 7.27-7.33 2H).
C 206C. 3-Methyl-4-(methylthio)benzeneboronic acid.
3-Methyl-4-(methylthio)benzeneboronic acid was prepared according to the method of Example substituting 4 -bromo-2-(methylthio)anisole in place of 4- -134- WO 99/10331 WO 9910331PCTJUS98/I 6479 bromoth ioan isole (yield: 5.3 g, M.p. 208-210 1 H NMR 2.28 3H), 2.46 3H), 7.20 J 8.4 Hz, 1 7.62 1 7.70 J 8.4 Hz, 1 H).
2060. 2-(3.4-Dif luo rophenyl)-4.5-dibromo-3(2 H)-pyridazi none.
The title compound was prepared according to the method of Example 1 94A, substituting 3,4-difluorophenyl hydrazine.HCl in place of 4-fluorophenyl hydrazine.HCl (yield: 39 g, 1 H NMR (300 MHz, DMSO-d6) 8 7.45 (in, 1 H), 7.61 (mn, 1 7.75 (in, 1 8.30 1 MS (DCI-NH3) in/z 382 (M+NH4)+.
206E. Dif luorophenyl)-4-inethoxy-5-bromo-3(2H)-pyridazi none.
The title compound was prepared according to the method of Example 194B, 1 0 substituting 2-(3,4-difluorophen yl)-4,5-dibroino-3 (2H)-pyridazi none in place of 2-(4f luoropheny I)-4,5-dibromo-3(2 H)-pyridazi none (yield: 15 ing, 1 H NMR (300 MHz, DMSO-d6) 6 4.14 3H), 7.45 (in, 1 7.60 (in, 1 7.74 (in, 1 8.24 (s, 1 MS (DCI-NH3) in/z 317 and m/z 334 (M+NH4)+.
206F. 2-(3 .4-Difluorophenyl)-4-methoxy-5-[3-inethyl-4-(inethylthio)phenyql-3(2H).
pyridazinone.
The title compound was prepared according to the method of Example 6 starting with 2- (3,4-dif luo rophe nyl)-4-methoxy-5-broino-3 (2H)-pyridazi none in place of 2-benzyl-4-bro mo-5-inethoxy-3 (2H)-pyridazi none and substituting 3methyl-4-(inethylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 2.0 g, 1 H NMR (300 MHz, 00013) 5 2.39 3H), 2.53 3H), 4.11 (s, 3H), 7.22-7.32 (in, 2H), 7.34 1 7.42-7.50 (in, 2H), 7.55-7.64 (in, 1 7.92 (s, 1 MS (APCI+) in/z 375 206G. 2-34Dfurpey)4(-loohny)5[-ehl4(ehlhopeyl 3 (2 H)-pyridazi none.
2-(3,4-Difluorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(inethylthio)phenyl]- 3(2 H)-pyridazi none, was prepared according to the method of Example 228, starting with 2- (3,4-dif Iuorophenyl)-4-inethoxy-5- [3-met hyl-4- (met hylth io) phe nyl].
.3(2 H)-py ridazi none in place of 2-(4-fluorophenyl)-4-inethoxy-5-[4-(inethylthio)phenyl]-3(2 H)-pyridazi none and substituting 4-fluorophenyl magnesium bromide in place of cyclohexylinagnesiuin chloride (yield: 330 mg, 1 H NMR (300 MHz,.
00013) 6 2.24 3H), 2.47 3H), 6.90-7.03 (in, 6H), 7.22-7.31 (in, 2H), 7.49-7.54 (in, 1 7.60-7.68 (in, 1 8.02 1 MS (APCi+) inlz 439 206 H. 2 Di uorlhenl--(- u oheyl-4-mthl4 mth s f L phenyll-3(2 H)-pyridazi none.
The title compound was prepared according to the method of Example substituting 2-34dfurpey)4(-loohnl--3m ty--m tyti) -13 WO 99/10331 WO 9910331PCTIUS98/1 6479 phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 251 mg, 82%) M.p. 80-1 00 00. 1 H NMR (300 MHz, DMSO-d6) 562.59 3H), 3.25 3H), 7.13-7.34 (in, 5H), 7.45 1 H), 7.52-7.69 (in, 2H), 7.81 J 8.4 Hz, 1 7.81-7.90 (mn, 1 8.27 1 MS (APCI+) m/z 471 and mlz 488 Anal. calc, for C24H17F3N203S: 0, 61.27; H, 3.64; N, 5.95. Found: C, 61.53; H, 3.92; N, 5.67.
Example 207 2-(3-Ch Iorophenyl)-4-(4-f luorophe noxymethyl)-5-i4- (methylsulfonyl)phenyl]-3 (2 H)pyrdanone 207A. 2-(3-Chboroohenyl)-4.5-dibromo-3(2H)-pyridazinone.
The title compound was prepared according to the method of Example 1 94A, substituting 3-chlorophenyl hydrazine*HCI in place of 4-fluorophenyl hydrazine. HOI (yield: 24.8 g, 1 H NMR (300 MHz, DMSO-d6) 8 7.53-7.57 (in, 3H), 7.67-7.70 (in, 1 8.29 1 MS (DCl-NH 3 mlz 365 and in/z 382 207B. 2-(3-C hlorophenyl)-4-methoxy-5-bro mo-3 (2 H)-pyri dazi none.
The title compound was prepared according to the method of Example 1 94B, substituting 2- (3-chlorophenyl)-4,5-di bromo-3(2 H)-pyridazi none in place of 2-(4fluorophenyl)-4,5-dibroino-3(2H)-pyridazi none (yield: 12.4 g, 1 H NMR (300 MHz, DMSO-d6) 5 4.21 3H), 7.58-7.62 (in, 3H), 7.73-7.76 (in, 1 8.28 1 H).
MS (DCI-NH3) m/z 317 and mlz 334 2070. 2 -(3-Chlorophenyl)-4-inethoxy-5-T4-(inethylthio)phenyll-3(2 H)-12yridazi none.
The title compound was prepared according to the method of Example 6 starting with 2-(3-chlorophenyl)-4-methoxy-5-bromo-3(2 H)-pyridazi none in place of 2-be nzyl-4-b roino-5-imet hoxy-3 (2 H)-pyri dazi none and substituting 4-(methylthio)benzeneboronic acid in place of 4-f luorobenzeneboronic acid (yield: 3.3 g, 68%).
1 H NMR (300 MHz, DMSO-d6) 6 2.54 3H), 4.03 3H), 7.40 J 9.0 Hz, 2H), 7.50-7.64 (in, 5H), 7.73-7.77 (in, 1 8.18 1 MS (DCI-NH3) m/z 359 207D. 2-(3-Chlorophenyl)-4-m-ethyl-5-r3-methyl-4-(inethylthio)phenvll-3(2H)pyridazi none.
2 -(3-Chlorophenyl)-4-(4-fluorophenyl)-5-[3-methyl-4-(methylthio)phenyl].
3(2H)-pyridazi none, was prepared according to the method of Example 228, starting with 2- (3-ch lo rophe ny methoxy--[3- met hyl-4- (met hylthi o)ph enyl]- 3(2H)-pyridazi none in place of 2-(4-fluorophenyl)-4-inethoxy-5-[4-(inethylthio)phenyl]-3(2H)-pyridazi none and substituting 4-f luorophenyl magnesium bromide in place of cycbohexyimagnesiuin chloride (yield: 180 mg, 1 H NMR (300 MHz, -136- WO 99/10331 WO 9910331PCT/US98/1 6479 00013) 8 2.25 3H), 2.56 3H), 7.28-7.45 (in, 6H), 7.58-7.63 (in, 1 7.71-7.74 (in, 1 7.82 1 MS (APCI+) m/z 343 and mlz 360 (M+NH4)+.
207E. 2-(3U-Chlorophenyl-4-methyl-5-f4-(methylsulfonylphenyI1-3(2H)- The title compound was prepared according to the method of Example substituting 2-(3-chlorophenyl)-4-methyl-5-[4-(methylthio)phenyl]-3(2H)pyridazinone for 2-be nzyl-4- (4-flIu oroph enyl)-5-[4- (met hylth io)ph enyl]-3 (2 H)pyridazinone (yield: 125 mg, M.p. 164-168. 1 H NMR (300 MHz, 00013) 8 2.23 3H), 3.13 3H), 7.37-7.46 (mn, 2H), 7.61 (in, 3H), 7.71-7.74 (mn, 1 7.81 1 8.13 J 8.7 Hz, 2H). MS (APCI+) m/z 343 and m/z 360 (M+NH4)+.
207F. 2 -(3-Chlorophenyl)-4-bromonetyl-5-[4-(methylsulfonyphenl-3(2H)pyridzinone 2-(3-COhlo rop he nyl)-4-b romo meth yl-5-[4- (met hyl su Ifo nylI)phe nyl]-3 (2 H)pyridazinone was prepared according to the method of Example 194F, substituting 2- (3-ch lorophe ny1)-4- met hy1-5-[4- (methysu f onyl) phen yl]-3 (2 H)-pyridazi none in place of 2-(4-fluorophenyl)-4-inethyl-5-[4-(methylsulfonyl)phenyl].3(2H).
pyridazinone (yield: 90 mg, 1 H NMVR (300 MHz, 00013) 8 3.13 3H), 4.33 2H), 7.40-7.47 (in, 2H), 7.66 (ddd, J 2.4, 2.4, 7.2 Hz, 1 7.76-7.78 (in, 1 H), 7.81 J 8.7 Hz, 2H), 7.86 1 8.17 J 8.7 Hz, 2H). MS (APCI+) m/z 453 and m/z 470 (M+NH4)+.
207G. 2 3 -Chloro~henyl)-4-(4-fluorophenoxynethyl)--[4-(nethylsulfonyl)phenyl..
3(2 H)-pyridazi none The title compound was prepared according to the method of Example 1 94G, substituting 2-(3-chlorophenyl)-4-bromomnethyl-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, M.p. 50-80 00.
1 H NMR (300 MHz, 00013) 8 3.11 3H), 4.94 2H), 6.78-6.85 (in, 2H), 6.91 6.99 (in, 2H), 7.39-7.48 (in, 2H), 7.64 (ddd, J 7.5, 1.9, 1.9 Hz, 1 7.71-7.77 (in, 3H), 7.93 1 8.08 J 8.7 Hz,- 2H). MS (AP0I+) m/z 485 Example 208 2-(3-Chlorophe nvl)-4-(be nzoyloxymethyl)-5-[4-(methylsu lfonyl)p2henyll-3(2H)pyrdzinone The title compound was prepared according to the method of Example 207 substituting benzoic acid in place of 4-fluorophenol (yield: 33 mng, M.p. 50-70 -137- WO 99/10331 PCT/US98/16479 oc. 1 H NMR (300 MHz, CDCI 3 6 3.00 3H), 5.36 2H), 7.36-7.48 4H), 7.52- 7.59 1 7.61-7.68 3H), 7.75-7.78 1 7.83-7.88 2H), 7.89 1 H), 8.02 J 8.7 Hz, 2H). MS (APCI+) m/z 495 Example 209 2 -(2.2.2-Trifluoroet hyl)-4-(3-methylbutyl)-5-[4-(methylsul fonvl)phenyl-3(2H)pyvridazinone The title compound was prepared according to the method of Example 193 substituting 1-bromo-4-methylpentane in place of 4-fluorobenzyl bromide (yield: mg, 1H NMR (300 MHz, CDCI3) 6 0.81 J 7.5 Hz, 6H), 1.3-1.6 3H), 2.52 2H), 3.14 (3 H, s) 4.85 J 9 Hz, 2H), 7.55 J 9 Hz, 2H) 7.67 1 H), 8.1 J 9 Hz, 2H). MS (DCI-NH 3 m/z 403 Anal. calc. for C18H21F3N203S.0.25 H20: 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-(methysulfonyl)phenyl]- 3(2H)-pyridazinone 210A. Preparation of boronic acid: (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to -78 C under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for minutes at -78 oC. 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 minutes, 10% citric acid solution (300 mL) was added until, pH The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%).
210B. Suzuki Couplinga: The boronic acid (231 mg, 1.5 mmol), prepared in example 210A, 2-(2,2,2trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (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 N2 for hours. TLC (1:1 hexanes/ethyl acetate) indicated that all the starting material was -138- WO 99/10331 PCT/US98/16479 consumed. Volatiles were removed in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. An off white powder was obtained (yield: 275 mg, M.p. 88-91 1H NMR (300 MHz, CDCl3, a mixture of rotamers) 8 2.2, 2.25 (2d, J 1.5 Hz, 3H) 3.05, 3.09 (2 s, 3H) 4.78-4.92 2H) 6.61-6.8 1 H) 6.82-6.98 1 H) 7.35 J 9 Hz, 1 H) 7.78 (d, J 9 Hz, 1 H) 7.86-8.09 4H). MS (DCI-NH3), m/z 441 Anal. calc. for C20H16F4N203S-0.5 H20: 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-dichlorophenvl)-5-[4-(methylsulfonvl)phenyl]-32 H)pvridazinone 2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (150 mg, 0.409 mmol) (Example 193E) was dissolved in anhydrous DME (8 mL) and heated to reflux with 3,5-dimethylbenzeneboronic acid in presence of CsF (150 mg, 0.98 mmol) and tetrakis(triphenylphosphine)-palladium (17.38 mg, 0.015 mmol) for 6 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo.
The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, to provide the title compound (yield: 110 mg, 1 H NMR (300 MHz, CDCI3) 8 3.08 3H), 4.88 J 9 Hz, 2H), 7.06 J 1.5 Hz, 9 Hz, 2H), 7.31 J 1.5 Hz, 1 7.36 J 9 Hz, 2H), 7.94 1 7.96 J 9 Hz, 2H).
MS (DCI-NH3) m/z 496 Anal. calc. for C19H13Cl2F3N203S: 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)pvridazinone The title compound was prepared according to the method of Example 211, substituting 3-ethoxyphenylboronic acid for 3,5-dimethylbenzeneboronic acid (yield: 155 mg, 1 H NMR (300 MHz, CDCI3) 1.42 J 7.5 Hz, 3H), 3.06 (s, 3H), 3.90 J 7.5 Hz, 2H), 4.88 J 9 Hz, 2H), 6.65 J 7.5 Hz, 1 6.75 (t, J 1.5 Hz, 1 6.85 (dd, J 1.5 Hz, 9 Hz, 1 7.15 J 9 Hz, 1H), 7.38 J 9 Hz, 2H), 7.88 J 9 Hz, 2H), 7.90 1 MS (DCI-NH3) m/z 470 (M+NH4)+.
-139- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 Anal. cab,. for C21 H1 9012F3N204S: 0, 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-trifluoromethylphenI)-5-[4-(methylsulfony1)p2henYl..
3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 211, substituting 4-(trifluoromethyl)benzeneboronic acid in place of 3,4-dimethylbenzeneboronic acid (yield: 85 mg, 1 H NMR (300 MHz, CDCI3) 5 3.08 (s, 3H), 4.90 J 9 Hz, 2H), 7.35 J 9 Hz, 4H), 7.58 J 9 Hz, 2H), 7.90 J= 9 Hz. 3H). MS (DCI-NH3) m/z 494 Anal. caic. for C20H14F6N203S: C, 50.42; H, 2.96; N, 5.88. Found: C, 50.20; H, 3.02; N, 5.70 Example 214 1 5 2-(2.2,2-Trifluoroethyl)-4-(3-nitrop~henyl)-5-[4-(methylsulfonyl)pheny]-3(2H).
pyridazi none The title compound was prepared according to the method of Example 211, substituting 3-nitrobenzeneboronic acid in place of 3,4-dimethylbenzeneboronic acid (yield: 40 mg, 1 H NMR (300 MHz, GDCI3) 863.05 3H), 4.92 J 9 Hz, 2H), 7.36 J 9 Hz, 2H), 7.45-7.60 (in, 2H), 7.91 J 9 Hz, 2H), 7.95 (s, 1 8.05 (mn, 1 8.15-8.21 (in, 1 MS (DCI-NH3) in/z 471 Anal.
caic. for 019H14012F3N305S-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-Trifluoroethyl)-4-(2-inethylphenyl)-5-[4-(methylsulfonyl)phenylp.3(2
H)-
pyridazinone The title compound was prepared according to the method of Example 211, substituting 2-inethylbenzeneboronic acid in place of 3,4-dimethylbenzeneboronic acid (yield: 45 mg, 1 H NMR (300 MHz, CDCI3) 6 2.05, 2.12 (2s, 3H), 3.01 (s, 3H), 4.75-5.05 (in, 2H), 6.88 J 9 Hz, 1 7.03-7.25 (in, 3H), 7.31 J 9 Hz, 2H), 7.85 J 9 Hz, 2H), 7.95 1 MS (DCI-NH3) m/z 440 Anal.
calc. for C20H17F3N203S: 0, 55.10; H, 4.27; N, 6.42. Found: C, 55.17; H, 4.18; N, 6.10 -140- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 216 2-(2.2.2-Trifluoroethyl)-4-(4-Vinylphenyfl-5-[4-(methylsulfonyl)phenyll-3(2
H)-
pyrdnone The title compound was prepared according to the method of Example 211, substituting 4-vinylbenzeneboronic acid in place of 3,4-dimethylbenzeneboronic acid (yield: 56 mg, 1 H NMR (300 MHz, CDCI3)8a3.06, 3.08 (2s, 3H), 4.78- 4.95 (in, 2H), 5.30 J 6 Hz, 1 5.65, 5.75(2d, J 18 Hz, 1 6.58-6.92 (in, 1 H), 7.1-7.4 (in, 6H), 7.75-8.08 (mn, 3H). MS (DCI-NH3) m/z 452 Anal. calc.
for 021 H17F3N20 3 S: 0, 58.06; H, 3.94; N, 6.45. Found: 0, 57.82; H, 4.01; N, 6.09 Example 217 2-(2.2 .2-Trif lu oroet hyl)-4[3 (trif luo romethy1) phe nvll-5-[4- (met hyl su Ifo ny I)phe nyL]- 3(2 H)-pyridazi none The title compound was prepared according to the method of Example 211, substituting 3-trifluoromethylbenzeneboronic acid in place of 3,4-dimethylbenzeneboronic acid (yield: 120 mng, 1 H NMR (300 MHz, CDCI3) 5 3.03, 3.08 (2s, 3H), 4.75-4.98 (mn, 2H), 7.30-7.60 (mn, 6H), 7.75-8.10 (mn, 3H). MS (DCI-NH3) in/z 494 Anal. calc. for C20H14F6N203S: 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-methoxyphenl)-5-[4-(inethylsulfonyl)phenyl..
3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 211, substituting 3-fluoro-4-methoxybenzeneboronic acid in place of 3,4-diinethylbenzeneboronic acid (yield: 32 mg, 1 H NMR (300 MHz, CDCI3) a 3.05, 3.09 (2s, 3H), 3.85, 3.87 (2s, 3H), 4.78-4.90 (mn, 2H), 6.60-7.10 (in, 3H), 7.30-8.15 (in, MS (DCI-NH3) inlz 474 Anal. calc. for C20H16F4N 2 04S-0.5 C, 51.61; H, 3.68; N, 6.01. Found: 0, 51.52; H, 3.65; N, 5.93 Example 219 2-(2.2.2-Trif luoroethyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(inethylsu lfonvl)phenyL- 3 (2 pyri dazi none The title compound was prepared according to the method of Example 211 substituting 3-fluoro-4-methylbenzeneboronic acid in place of 3,4-diinethylbenzeneboronic acid (yield: 58 mg, 1 H NMR (300 MHz, CDC13) 6 2.21, 2.25 -141- WO 99/10331 PCT/US98/16479 (2d, J 1.5 Hz, 3H), 3.50, 3.55 (2s, 3H), 4.75-4.95 2H), 6.56-7.15 3H), 7.30- 8.10 5H). MS (DCI-NH3) m/z 458 Anal. calc. for C20H16F4N203S.0.5 H20: 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-methoxyphenvl)-5-[4-(methlsulfony)phenvl]-3(2H)-pyridazinone The title compound was prepared according to the method of Example 211, substituting 3,5-difluoro-4-methoxybenzeneboronic acid in place of 3,4dimethylbenzeneboronic acid. 1H NMR (300 MHz, CDCI3) 5 2.9, 3.1 (2s, 3H), 3.92, 4.01 (2s, 3H), 4.78-4.95 2H), 6.25-6.80 1H), 7.30-7.5 2H), 7.7-8.15 (m, 4H). MS (DCI-NH3) m/z 492 Anal. calc. for C20H15F5N204S: C, 50.64; H, 3.19; N, 5.90. Found: C, 50.542; H, 3.41; N, 5.67 Example 221 2-(2.2.2-Trifluoroethyl)-4-(1.3-dihvdro-1-oxo-5-isobenzofuranyl)-5-[4-(methylsulfonvl)phenyl]-3(2 H)-pyridazinone 6-Bromophthalide (300 mg, 1.40 mmol, Teppema et al Recl. Trav. Chim.
Pays-Bays,1923, 42, 47) and hexamethylditin (326 giL, 1.55 mmol) were dissolved in toluene (5 mL), degassed with a nitrogen stream for 5 minutes, treated with (Ph3P)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 the intermediate, 6-(trimethyltin)phthalide (yield: 362 mg, 87%).
The tin reagent (180 mg, 0.61 mmol), prepared above, and 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 193E, (223 mg, 0.61 mmol) were dissolved in dry toluene (10 mL), degassed with an nitrogen stream for 5 minutes, treated with (Ph3P)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, M.p. 237- -142- WO 99/10331 PCT/US98/16479 239 1H NMR (300 MHz, CDC13) 5 3.07 3H), 4.91 J 8 Hz, 2H), 5.30 2 H, major isomer), 5.33 2 H, minor isomer), 7.20 (dd, J 1 Hz, 7 Hz, 1H), 7.36 (d, J 8 Hz, 2H), 7.52 1 7.79 J 7 Hz, 1 7.92 J 8 Hz, 2H), 7.96 1 H).
MS (DCI-NH3) m/z 482 Anal. calc. for C21H15F3N205S: 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-Trifluoroethvl)-4-(2-propenvl)-5-[4-(methylsulfonvl)phenvl]-3(2H)vpridazinone A suspension of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (200 mg, 0.546 mmol), prepared according to the method of Example 193E, in THF (27 mL) was cooled to -78 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 °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 chloride and adsorbed onto silica gel (2 g).
Solvent was removed under reduced pressure, the adsorbed silica gel layered over an Extract-Clean Cartridge® (Alltech, packing: 5 g silica gel) and the cartridge eluted with a hexanes/acetone step gradient consisting of 40 mL 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 60-5sil column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 mL/min over 50 minutes. Fractions containing the title product were combined and concentrated under reduced pressure to provide a pale yellow solid (yield: 99.3 mg, M.p. 192-195 OC. 1 H NMR (300 MHz, CDCI3) 8.03 J 17.4 Hz, 2H), 7.76 1H), 7.55 2H, J 17.4 Hz), 5.23 (br s, 1H), 4.84 3H), 3.11 3H), 1.98 3H). MS (DCI-NH3) m/z 373 m/z 390 (M+NH4)+.
Anal. calc. for C16H15F3N203S: C, 51.61; H, 4.06; N, 7.52. Found: C, 51.72; H, 4.24; N, 7.35.
-143- WO 99/10331 PCT/US98/16479 Example 223 2-(2.2.2-Trifluoroethyl)-4-(2-buten-2-yl)-5-[4-(methylsulfonyl)phenyl]-3(2H)- Dvridazinone The product was prepared according to the method of Example 222 substituting 1-methyl-l-propenylmagnesium bromide in place of isopropenylmagnesium bromide to provide a mixture of geometric isomers ratio) as an offwhite solid (yield: 44.8 mg, M.p. 175-180 1 H NMR (300 MHz, CDCI3) 8.03 J 18.0 Hz, 1.5H), 8.01 J 18.0 Hz, 0.5H), 7.29 0.75H), 7.28 (s, 0.25H), 7.56 J 17.4 Hz, 1.5H), 7.51 J 17.4 Hz, 0.5H), 5.55 0.75H), 5.33 0.25H), 5.86 J 17.4 Hz, 2H), 3.12 2.25H), 3.11 0.75H), 2.88 (m, 2H), 2.85 1H), 1.27 3H). MS (DCI-NH3) m/z 387 m/z 404 m/z 421 (M+2NH4-H)+. Anal. calc. for C17H17F3N203S: 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)phenyll-3(2H)pvridazinone 224A. 3-Fluorobenzvl maanesium bromide.
3-Fluorobenzyl bromide (613 p-L, 5 mmol), followed by dibromoethane pL), 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.
224B. 2-(2.2.2-Trifluoroethyl)-4-(3-fluorobenzvl)-5-[4-(methylsulfonyl)phenvl]- 3(2H)-pyridazinone.
A suspension of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)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 OC. A solution of 3-fluorobenzyl magnesium bromide (4.0 mL, -0.42 M in diethyl ether), prepared above was added. The reaction was stirred at 0 °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 -144- WO 99/10331 PCT/US98/16479 adsorbed onto silica gel (2 Solvent was removed under reduced pressure, the silica gel with the product adsorbed was layered over an Extract-Clean Cartridge® (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 x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 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, M.p. 58-62 1 H NMR (300 MHz, CDCI3) 88.07 J 18.0 Hz, 2H), 7.73 1 7.47 J 17.4 Hz, 2H), 7.18 1 6.88 1 6.76 (br d, J 15.6 Hz, 1H), 6.68 (brd, J 18.6 Hz, 1H), 4.86 J 17.4 Hz, 2H), 3.93 2H), 3.12 3H). MS (DCI-NH3) m/z 441 m/z 458 m/z 475 (M+2NH4-H)+. Anal. calc. for C20H16F4N20 3 S: 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 -cvclohexenvl)-5-[4-(methvlsulfonyl)phenvll-3(2H)pyridazinone 225A. 1-Cvclohexenvltriflate.
n-Butyllithium (2.5M in hexanes, 2.20 mL, 5.50 mmol) was added to a solution of diisopropylamine (0.77 mL, 5.50 mmol) in THF (20 mL) at-78 oC. The resulting pale yellow solution was warmed to 0 OC for 30 minutes then was cooled to -78 oC. Cyclohexanone (0.52 mL, 5.0 mmol) was added and the nearly colorless solution was warmed to 0 oC 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%).
225B. 1-Cvclohexenvltrimethvltin.
A solution of 1-cyclohexenyltriflate (412 mg, 1.79 mmol), prepared according to the method of Example 225A, and LiCI (380 mg, 8.95 mmol) in THF (9 mL) was -145- WO 99/10331 PCT/US98/16479 deoxygenated by bubbling a stream of N2 through the solution. Hexamethylditin (339 gL, 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® (Alltech, packing: 10 g silica gel) which had been wetted with 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%).
225C. 2-(2.2.2-Trifluoroethyl)-4-(1-cyclohexenyl-5-[4-(methylsulfonylphenyl]- 3(2H)-pyridazinone.
A solution of 1-cyclohexenyltrimethyltin (150 mg, 0.61 mmol), prepared according to the method of Example 225B, and 2-(2,2,2-trifluoroethyl)-4-chloro-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172 mg, 0.47 mmol), prepared according to the method of Example 193E, in anhydrous N-methylpyrrolidinone (1 mL) was deoxygenated with nitrogen. Dichlorobis(triphenylphosphine) palladium(ll) (6.6 mg, 0.009 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (7.7 mg, 0.009 mmol) were added and the reaction heated at °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 Solvent was removed under reduced pressure, the adsorbed silica gel layered over an Extract-Clean Cartridge® (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 x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 mL/min. over 50 minutes. Fractions containing the title product were combined and concentrated under reduced pressure to provide a pale yellow foam (yield: 95.0 mg, M.p. 75-81 OC. 1H NMR (300 MHz, CDCI3) 8 8.02 J 17.4 Hz, 2H), 7.76 1 7.55 J 17.4 Hz, 2H), 5.51 (br s, 1 4.83 (br q, J -146- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 16.2 Hz, 3H), 3.11 3H), 2.18 (br, 2H), 1.96 (br, 2H), 1.70-1.50 (in, 4H). MS (DCI- NH3) mlz 413 m/z 430 m/z 447 (M+2NH4-H)+. Anal. calc, for Cj9H19F3N20 3 S: 0, 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-(aminosu lfonyl)phenyll- 3(2H)-pyridaznn 226A. 3-Fluoro-4-('methylthio)benzeneboronic acid.
3-Fluoro-4-(methylthio)benzeneboronic acid was prepared according to the method of Examplel, substituting 4-bromo-3-fluorothioanisole in place of 4-bromothioanisole.
226B. 2- Benzyl-4-methoxy-5-bromo-3 (2H) -pyridazi none 2-Benzyl-4-methoxy-5-bromo-3(2 H)-pyridazi none is prepared according to the method of Example 83B starting with 2-benzyl-4,5-dibromo-3(2H)-pyridazinone, in place of 2- (2,2,2-triflIuo roeth yl)-4,5-di bro mo-3 (2 H)-pyrid azi none and substituting methanol in place of isopropanol.
226C. 2-Benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)p2henyll-3(2 H)-pyridaznn 3-Fluoro-4-(methylthio)benzeneboronic acid and 2-be nzyl-4- met bromo-3(2 H)-pyridazi none were coupled according to the method of Example 83C to provide 2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)pyridazinone as a yellow solid (yield: 4.98 g, 91 1 H NMR (300 MHz, CDCI3) a 7.76 1 7.47 (mn, 2H), 7.39-7.21 (in, 7H), 5.34 2H), 4.13 3H), 2.51 3H).
MS (DCI-NH3) in/z 357 m/z 374 (M+NH4)+.
226D. 3-Methylbutylinagnesium bromide An oven-dried flask containing small pieces of magnesium ribbon (134 mg, iniol) was charged with diethyl ether (12 mL). 1 -Broino-3-methylbutane (600 p.L, 5 minol) was added dropwise, followed by dibroinoethane (10 pgL). The reaction required heating at gentle ref lux before gas evolution was observed. The reaction was ref luxed for 3 hours and cooled to room temperature, The pale gray solution of 3-methylbutylinagnesiuin bromide was used in the next reaction.
226E. 2- Ben zy 1-4-(3-inethyl butyl)-5-[3-f luo ro-4- (met hylth io) Ph=11-3 (2 H).
pyridazi none A solution of 2-ezl4mtoy5[-loo4(ehlhopey]32) pyridazinone (500 mg, 1.40 inmol), prepared according to the method of Example 2260, in THF (20 mL) was cooled to-78 00. 3-Methylbutylmagnesium bromide -147- WO 99/10331 WO 9910331PCT/US98/I 6479 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 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, 1 H NMVR (300 MHz, CDCI3) a 7.67 (s, 1 7.49 (in, 2H), 7.39-7.25 (in, 4H), 7.02 (in, 2H), 5.35 2H), 2.57-2.49 (in, 2H), 2.52 3H), 1.62-1.36 (in, 3H), 0.83 6H, J 12.0 Hz). MS (DCI-NH3) m/z 397 in/z 414 MS (DCI-NH3) m/z 397 m/z 414 (M+NH4)+.
226F. 4- Q-Methylbutyl)-5-43-f luoro-4-(methylthio)phe nyl]-3 (2 H)-pyridazi none.
2 -Be nzy 1-4- met hylbuty lu oro-4- (m ethylth io)ph enyl] -3(2 H)pyridazinone (550 mng, 1.39 inmol), prepared in Example 226E, was debenzylated according to the method of Example 11 to provide 4-(3-inethylbutyl)-5-[3-fluoro-4- (inethylth io)phenyl]-3(2 H)-pyridazi none as a pale yellow solid (yield: 375 mng, 1 H NMR (300 MHz, CDCI3)867.65 1 7.34 (dd, 1 H, J =16.2, 16.2 Hz), 7.11-6.98 (in, 2H), 2.60-2.50 (in, 2H), 2.54 3H), 1.65-1.37 (mn, 3H), 0.83 6H, J 12.0 Hz). MS (DCI-NH3) in/z 307 in/z 324 (M+NH4)+ MS (DCI-NH3) m/z 307 in/z 324 (M+NH4)+.
226G. 2-(2.2.2-Trifluoroethyl)-4-(3-inethylbutyl)-5-[3-fluoro-4-(methylthio)phenyll- 3 (2 H)-pyridazi none.
Methylbutyl)-5-[3-f luoro-4-(methylthio)phenyl]-3(2 H)-pyridazi none (375 ing, 1.23 iniol), prepared in Example 226F, was alkylated according to the method of Example 20 to provide 2-(2,2,2-trifluoroethyl)-4- (3-inethylbutyl)-5-[3-fluoro-4- (methylthio)phenyl]-3(2H)-pyridazinone as a clear oil (yield: 331 mg, 1 H NMVR (300 MHz, CDC13) 567.67 1 7.34 (dd, 1 H, J 16.8, 16.8 Hz), 7.11-6.98 (in, 2H), 4.82 (dd, 2H, J 17.4, 17.4 Hz), 2.60-2.51 (in, 2H), 2.53 3H), 1.61-1.32 (in, 3H), 0.85 6H, J 12.0 Hz). MS (DCI-NH3) in/z 389 in/z 406 MS (DCI-NH3) in/z 389 m/z 406 (M+NH4)+.
226H. 2-(2.2.2-Trifluoroethyl)-4-(3-methvlbutyl)-5-3-fluoro-4-(methylsulfinyphenyI]-3(2H)-pyridazinone.
2- (2,2,2-T rif luo roethyl)-4- (3-methy lbuty luo ro-4- (met hyIth io) phenyl]- 3(2H)-pyridazinone (331 ing, 0.85 iniol), prepared in Example 226G, was oxidized according to the method of Example 5 using only one equivalent of MORBA to provide 2- (2 ,2,2-trif luoroet hyl)-4- inethy lbutyl)-5-[3-flIuo ro-4- (met hylsu If i nylI)phenyl]-3(2H)-pyridazi none as an off-white solid (yield: 240 mng, 1 H INMR -148- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 (300 MHz, CDCI3) 868.02 (dd, 1 H, J 15.0, 15.0 Hz), 7.67 1 7.37 (dd, 1 H, J 17.4, 3.0 Hz), 7.11 (dd, 1 H, J 18.6, 3.0 Hz), 4.84 (dd, 2H, J 17.4, 17.4 Hz), 2.91 3H), 2.53 (in, 2H), 1.60-1.35 (in, 3H), 0.57 6H, J 12.0 Hz). MS (DCI-NH3) m/z 405 m/z 422 MS (DCI-NH3) mlz 405 m/z 422 (M+NH4)+.
2261. 2-(2.2.2-Trifluoroethyl)-4-(3-methvlbutyl-5-r3-fluoro-4-(aminosulfonyl)phenyll-3(2 H)-pyridazi none 2- (2,2 ,2-Trif luo roethyl)-4- (3-methylbutyl) -5-[3-flIuo ro-4- (met hylsuf inyI)phenyl]-3(2H)-pyridazi none (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, M.p. 153-1 56 00.
1 H NMR (300 MHz, CDCI3) 6 8.07 (dd, J 15.0,15.0 Hz, 1 7.74 1 7.27- 7.19 (in, 2H), 5.14 (br s, 2H), 4.83 J 18.0 Hz, 2H), 2.52 (in, 2H), 1.55 (in, 1 H), 1.41 (in, 2H), 0.85 J 12.6 Hz, 6H). MS (ESI m/z 420 Anal. calc. for C17H19F4N303S: 0, 48.45; H, 4.54; N, 9.97. Found: 0, 48.24; H, 4.56; N, 9.80.
Example 227 2-(2.2.2-Trif luoroethyb)-4-benzvl-5-[4-(inethvlsu lfonvlkhenvll-3(2 H)-gyridazi none The title compound was prepared by adding 1.0 M benzylmagnesium chloride in ether (0.53 inL, 0.53 mmol) to a THF (20 mL) solution of 2-(2,2,2trif luoroethyl)-4-chloro-5-[4-(methylsuIf onyl)phenyl]-3(2 H)-pyridazi none (150 mg, 0.41 iniol), prepared according to the method of Example 193E, at 0 00, 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, M.p. 112-114 00. 1 H NMR (300 MHz, CDCI3) 6 3.12 3H), 3.94 2H), 4.85 J 12 Hz, 2H), 6.99 (dd, J Hz, 3 Hz, 2H), 7.2 (in, 3H), 7.48 J 9 Hz, 2H), 7.72 1 8.06 J 9 Hz, 2H).
MS (DCI-NH3) m/z 423 Anal. calc. for C20H17F3N203S: C, 56.86; H, 4.05; N, 6.63. Found: C, 56.60; H, 4.13; N, 6.57.
Example 228 Fluorophenfl)-4-cvclohexvl-5-[4-(methvlsulfo nyflhenyll-3(2H)-ovridazinone A solution of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared in Example 1940, (200 mg, 0.51 minol) in THF (8 ml) was cooled to -78 OQ and treated with cyclohexylinagnesium chloride, 2 M solution in -149- WO 99/10331 PCT/US98/16479 ether (0.31 ml, 0,7 mmol). The reaction mixture was stirred at -78 °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 MgSO4 and concentrated in vacuo. The resulting methyl sulfide compound was purified by flash chromatography (Si02, eluting with 9:1 hexanes:ethyl acetate) to provide the desired product (yield: 128 mg, MS (DCI-NH3) m/z 395 412 (M+NH4)+.
The methyl sulfide compound, prepared above, (122 mg, 0.3 mmol) in CH2CI2 (10 ml) at 0 oC, was treated with CH3CO3H (0.3 ml, 1 mmol). The reaction was complete in 2 hours. The reaction mixture was diluted with CH2CI2 and washed with saturated NaHCO3 and brine respectively. The resulting crude residue was purified by flash chromatography (Si0 2 eluting with 1:1 hexanes:ethyl acetate) to provide the desired product (yield: 110 mg, M.p. 231-233 1 H NMR (300 MHz, DMSO-d6) 1.1 3H), 1.6 6H), 2.15 2H), 7.35 2H), 7.65 2H), 7.73 (dd, 2H) 7.93 1 8.1 2H). MS (DCI-NH3) m/z 427 444 Anal. calc. for C23 H23FN203S.0.75 H20: C, 64.77; H, 5.44; N, 6.57. Found: C, 62.86; H, 5.53; N, 5.78.
Example 229 Fluorophenyl)-4-(4- methylphenyl)-5-[4-(methylsulfonyl)phenvl]-3(2 H)pyridazinone The title compound was prepared according to the method of Example 228, substituting p-tolylmagnesium bromide in place of cyclohexylmagnesium chloride (yield: 90 mg, M.p. 242-244 1 H NMR (300 MHz, DMSO-d6) 5 2.25 (s, 3H), 5 3.25 3H), 7.1 4H), 7.35 2H), 7.5 J 9 Hz, 2H), 7.7 (dd, 2H) 7.9 (d, J 9 Hz, 2H), 8.2 1H). MS (DCI-NH3) m/z 435 452 Anal.
calc. for C24H19FN203S-0.5 H20: 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-(methylsulfonylohenyl]-3(2 H)-pyridazinone The title compound was prepared according to the method of Example 228, substituting benzylmagnesium bromide in place of cyclohexylmagnesium chloride (yield: 179 mg, M.p. 180-182 OC. 1 H NMR (300 MHz, DMSO-d6) 5 3.3 (s, 3H), 7.0 2H), 7.2 3H), 7.35 2H), 7.65 2H)7.72 2H) 8.05 3H). MS -150- WO 99/10331 WO 99/033 1PCTJUS98/1 6479 (DCI-NH3) m/z 435 452 Anal. caic. for C24H1 9FN20 3 C, 66.34; H, 4.41; N, 6.45. Found: 0, 66.48; H, 4.17; N, 6.36.
Example 231 2-(4-Fluorophenyl)-4-(phenylethynyl)-5-[4-(methylsulfonyl)phenyll-3(2H)prdzinon The title compound was prepared according to the method of Example 228, substituting phenylacetylene magnesium bromide in place of cyclohexylmagnesiumn chloride (yield: 150 mg, M.p. 203-204 OQ. 1 H NMR (300 MHz, DMSO-d6) 6 3.3 3H), 7.4 (in, 8H), 7.7 (in, 2H), 8.16 (mn, 4H) :.8.35 (s, 1 MS (DCI-NH3) mlz 435 452 Anal. caic. for 025H17FN203S: C, 67.56; H, 3.86; N, 6.30. Found: C, 67.63; H, 3.86; N, 6.30.
Example 232 1 5 2-(3.4-Difluorophenyl)-4-cyclohexyl-5-[4-(methylsulfonyl)phenyll-3(2
H)-
The title compound was preparedl according to the method of Example 2.28, starting with 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(inethylthio)phenylj3(2H)pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(inethylsulfonyl)phenyl]- 3(2 H)-pyridazi none (yield: 245 mng, M.p. 80-83 00. 1 H NMR (300 MHz, DMSO-d6) 861.1 (in, 3H), 1.6 (in, 6H), 2.15 (in, 2H), 7.5 (in, 1 7.6 (in, 2H), 7.7 (d, 2H), 7.78 (in, 2H), 7.93 1 8.1 2H). MS (DCI-NH3) m/z 445 462 Anal. calc. for C23H22F2N203S: 0, 62.15; H, 4.99; N, 6.30. Found: C, 62.65; H, 5.25; N, 5.97.
Example 233 2-(3 .4-Dif luorophenyl)-4-benzyl-5-[4-(methylsulfonyl)phenyll-3 (2H)-pyridazi none The title compound was prepared according to the method of Example 228, starting with 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(inethylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(rhethylthio)phenyl]- 3(2H)-pyridazi none and substituting benzylmagnesiuin bromide in place of cyclohexylmagnesium chloride (yield 206 mg, MUp. 166-168 0 C. 1 H NMR (300 MHz, DMSO-d6) 6 3.3 3H), 3.9 2H), 7.0 2H), 7.2 (in, 3H), 7.6 (mn, 2H), 7.72 2H), 7.8 1 8.05 2H), 8.12 1 MS (DCI-NH3) mlz 453 470 (M+NH 4 Anal. calc. for 024H19F2N 2 0 3 S: C, 63.71; H, 4.01; N, 6.19.
Found: C, 63.53; H, 4.33; N, 5.76.
-151- WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 Example 234 2-(3 .4-Dif luorophenyl)-4-(4-methylphenyl)-5-[4-(methylsufo nvl)phenyll-3(2H)- The title compound was prepared according to the method of Example 228, starting with 2- (3,4-d ifiu o rophen yl)-4- methoxy-5-[4- (met hylsu fon yl) phe nyl]-3 (2 H)pyridazinone in place of 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone and substituting cyclohexylmagnesium chloride in place of ptolylmagnesium bromide (yield: 140 mg, 56%) M.p. 190-192 0 C. 1 H NMR (300 MHz, DMSO-d6) 862.28 2H), 6 3.25 3H), 7.1 4H), 7.5 (in, 4H), 7.89 (in, 3H), 8.05 2H), 8.23 1 MS (DCI-NH3) m/z 453 470 Anal.
calc. for C24F2H18N203S: C, 63.71; H, 4.01; N, 6.19. Found: 0, 63.69; H, 4.29; N, 5.96.
Example 235 2-(3 .4-Dif luorophenyl)-4-(4-f luoro-3-methylphenyl)-5-14-(methylsu lfonyl)phenyl]- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 228, starting with 2- (3,4-d if luo rophenyl)-4-met hoxy-5-[4- (met hylsu Ifo nyl)phe nyl]-3 (2 H)pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazi none and substituting 4-fluoro-3-methylbenzeneinagnesiuin bromide in place of cyclohexylinagnesiuin chloride (yield: 180 ing, 72.5%) M.p. 166-1 68 00. 1 H NMR (300 MHz, DMSO-d6) 6 2.15 3H), 6 3.25 3H), 7.01 (in, 2H), 7.25 1 7.6 (in, 4H), 7.9 (in, 3H), 8.26 2H). MS (DCI-NH3) inlz 471 488 Anal. calc. for C24F3H17N20 3 S: 0, 61.27; H, 3.64; N, 5,95. Found: C, 61.47; H, 3.84; N, 5.67.
Example 236 2-(3 .4-Dif luorophenyl)-5-[4-(inethylsulfonyl)phenyll-4-vi nyl-3(2 H)-pyridazi none The title compound was prepared- according to the meth 'od of Example 228, starting with 2- (3,4-d if luorop hen yl)-4-methoxy--[4- (methylsulfonyl)phe nyl] -3(2 H)pyridazinone in place of 2-(4-fluorophenyl)-4-inethoxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazi none and substituting vinyl magnesium bromide in place of cyclohexylinagnesium chloride (yield: 85 ing, 1 H NMR (300 MHz, DMSOd6) 6 2.15 3H), 6 3.3 3H), 5.7 (dd, 1 6.4 (dd, 1 6.7 (dd, 1 H) 7.01 (in, 2H), -152- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 (in, 1 7.65 (in, 1 7.8 (in, 3H), 8.1 MVS (DCI-NH3) mlz 389 406 (M+NH4)+.
Example 237 2-(3.4-Difluorophenyl)-4-(2-thienyl)-5-[4-(methylsulfonyl)phenyll-3(2H)- The title compound was prepared according to the method of Example 228, starting with 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]- 3(2 H)-pyridazi none and substituting 2-thienylmagnesium bromide in place of cyclohexylmagnesium chloride (yield: 66 mg, M.p. 189-191 00 1 H NMR (300 MHz, DMSO-d6) 8 3.3 3H), 6.95 (in, 2H), 7.55 (mn, 1 7.7 (in, 5H), 7.85 (in, 1 H), 8.03 J 9 Hz, 2H), 8.13 1 MS (DCI-NH 3 mlz 445 462 Anal. calc. for 021 H14F2N203S 2 0, 56.75; H, 3.17; N, 6.30. Found: 0, 56.92, H, 3.92, N, 5.79.
Example 238 2-(3.4-Difluorophenyl)-4-(l -progynyl)-5-f4-(methylsulfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 228, starting with 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone and substituting inethylacetylenemnagnesium bromide in place of cyclohexylmagnesiuin chloride (yield: 65 mng, M.p. 149-1 50 00. 1 H NMR (300 MHz, DMSO-d6) 8 2.1 3H), 3.3 3H), 7.51 (in, 1 7.65 (in, 1 7.8 (in, 1 8.1 (in, 4H) 8.3 1 MS (DCI-NH3) in/z 463M+H)+, 480 Anal.
calc, for C20H14F2N203S-0.25 H20: C, 59.94; H, 3.52; N, 7.00. Found: 0, 59.49; H, 3.63; N, 6.34.
Example 239 Dif luorophenyl)-4-t-butyl-5-t4-(methylsulfonyl)phenyll-3 (2H)-pyridazi none The title compound was prepared according to the method of Example 228, starting with 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(inethylsulfonyl)phenyq]-3(2H)pyridazinone in place of 2-(4-fluorophenyl)-4-inethoxy-5-[4-(inethylthio)phenyl]- 3(2H)-pyridazinone and substituting t-butyl magnesium bromide in place of cycbohexylinagnesiuin chloride (yield: 60 mg, M.p. 158-161 -C0 1 H NMR -153- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 (300 MHz, DMSO-d6) 8 1.21, 9H), 3.3 3H), 7.51 (in, 1 7.45 (in, 1 7.75 (in, 4H), 8.02 J 9 Hz, 2H). MS (DCI-NH 3 mlz 419 436 (M+NH4)+.
Anal. calc, for 021 H20F2N203S: 0, 60.27; H, 4.82; N, 6.69. Found: 0, 60.15; H, 5.10; N, 6.39 Example 240 2-(2.2 .2-Trifluoroethyl)-4-cyclohexyl-5-r4-(methylsu lfonyI)phenyll-3 (2 H)- The title compound was prepared according to the method of Example 228, 1 0 starting with 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfony)phenyl]-3(2H)pyridazinone, prepared in Example 193E, in place of 2-(4-fluorophenyl)-4-methoxy- 5-[4-(methylthi o)phe nyl]-3 (2 H)-pyri dazi none, (yield: 120 mng, M.p. 215-218 00. 1 HNMR (300 MHz, CDC1 3 81 .1 (tt, J =9Hz, J =4.5 Hz, 2H), 1.25 (tt,J 9Hz, Hz, 1 1.49 J 12 Hz, 2H), 1.63 J 12 Hz, 1 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, 1 3.17 3H), 4.83 J 12 Hz, 2H), 7.49 J 9 Hz, 2H), 7.6 1 8.09 J 9 Hz, 2H). MS (DCI-NH3) m/z 415 Anal. cab,. for 019H21 F3N203S: 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)-5-14-(methylsulfonyl)phenl-3(2
H)-
idzna 2-(3-Chlorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]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 331, and substituting 3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 180 mng, M.p. 142-1 43 OC.
1 H NMR (300 MHz, CDCI3) 8 3.14 3H), 3.98 2H), 6.75 (br d, J 9 Hz, 1 H), 6.82 (br d, J 9 Hz, 1 6.88 (br t, J =9 Hz, 1 7.15-7.23 (in, 1 7.37-7.47 (in, 2H), 7.54 J 9 Hz, 2H), 7.63 (dt, J =9 Hz, 2 Hz, 1 7.75 J 2 Hz, 1 7.82 1 8.10 J 9 Hz, 2H). MS (DCI-NH3) m/z 469 486 (M+NH4)+.
Anal. calc. for C 24 H18ClF2N20 3 S.0.5 H20: C, 60.38; H, 3.88; N, 5.87. Found: C, 60.62; H, 3.89; N, 5.82.
-154- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 242 2-(4-Fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfonyflphenyl]:-32H.)- 2- Fl uo rop he nyl)-4- (3-flIuo robe nzyl)-5-[4-(met hylth io)phe nyl]-3 (2H) pyridazinone was prepared according to the method of Example 228, starting with 2- (4-f luorophenyl)-4-methoxy-5-[4-(methylthio) phenyl]-3(2H)-pyridazi none, prepared in Example 194C, and substituting 3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide compound was oxidized according to the method of Example 10, to provide the title compound (yield: 450 mg, M.p. 176-178 00. 1 H NMR (300 MHz, 0DC13) 863.14 3H), 3.95 2H), 6.75 (br d, J 9 Hz, 1 6.82 (br d, J 9 Hz, 1 6.88 (br t, J 9 Hz, 1 7.14-7.23 (in, 3H), 7.54 J= 9 Hz, 2H), 7.67 (dd, J 9 Hz, 6 Hz, 2H), 7.81 1 8.10 J 9 Hz, 2H). MS (DCI-NH3) m/z 516 Anal. calc. for C24Hj9F2N205S-H 2 0: C, 61.28; H, 4.04; N, 5.96. Found: 0, 61.24; H, 4.09; N, 5.77.
Example 243 2-(3 .4-Difluorophenyl)-4-(3-fluorobenzyl)-5-4-(methylsulfonyl)phenyll-3t'2H)- 2-(3 Dif Iuo rophe ny1) (3-f luo robe nzylI)-5-[4-(methylthio) ph enyl]-3 (2 H)pyridazinone was prepared according to the method of Example 228, starting with 2-(3 ,4-dif luorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazi none prepared in Example 206E, and substituting 3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesiumn chloride to provide the methyl sulfide compound.
The methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 390 mg, M.p. 161-163 00.
1 H NMR (300 MHz, CDCI3) 863.14 3H), .3.95 2H), 6.74 (br d, J 9 Hz, 1 H), 6.82 (br d, J 9 Hz, 1 6.89 (br t, J 9 Hz, 1 7.15-7.33 (in, 2H), 7.48-7.57 (mn, 1 7.53 J 9 Hz, 2H), 7.59-7.67 (in, 1 7.83 1 8.10 J 9 Hz, 2 H).
MS (DCI-NH 3 m/z 471 488 Anal. calc. for 024H17F3N20 3 S.0.5 H20: 0, 60.13; H, 3.65; N, 5.85. Found: 0, 60.08; H, 3.81; N, 5.54.
-155- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 244 2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphenyl)-5-f4-(methvlsulfonyl)phenyll-3(2H)- 2-(3-Chlorophenyl)-4-(4-fluoro-3-methylphe nyl)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazi none 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 207B, and substituting 4-fluoro-3methyiphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 620 mg, M.p. 228-230 00.
1 H NMR (300 MHz, CDCI3) 562.20 3H), 3.06 3H), 6.83-6.93 (in, 2H), 7.19 (br d, J 9 Hz, 1 7.37-7.47 (in, 2H), 7.40 J 9 Hz, 2H), 7.65 (dt, J 7 Hz, 3 Hz, 1 7.68 J 3 Hz, 1 7.91 J 9 Hz, 2H), 7.98 1 MS (DCI-NH3) m/z 469 486 Anal. calc. for C24H1 BCIFN203S: C, 61.54; H, 3.85; N, 5.99. Found: C, 61.39; H, 3.84; N, 5.82.
Example 245 2-(4-Fluorophe nyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyll-3(2H)pyiaznn 2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(methylthio)phenyl]- 3(2 H)-pyridazi none was prepared according to the method of Example 228, starting with 2-(4-f Iuorophenyl)-4-methoxy-5-[4- (met hylthio)phe nyl]-3 (2 H)pyridazinone, prepared in Example 1940, and substituting 4-fluoro-3-methylphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 590 mg, M.p. 245-247 00. 1 H NMR (300 MHz, 00013) 8 2.01 3H), 3.07 3H), 6.87 (in, 2H), 7.21 (mn, 3H), 7.41 J 9 Hz, 7.68 (in, 2H), 7.92 J 9 Hz, 2H), 7.97 1 MS (DCI-NH3) m/z 453 470 Anal. calc. for C24H1 8F2N203S*0.5 C, 62.47; H, 3.90; N, 6.08. Found: 0, 62.11; H, 4.11; N, 5.81.
6- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 246 2 hlo ro- 4-f Iuo rop he nyl)-4-cyclohexy1-5414-(methylIsufto nyl)2h e nyl]-3 (2 H)pyridazinone.
246A. 2-(3-Chloro-4-f luorophenyl)-4.5-dibromo-3(2H)-pyridazi none, The title compound is prepared according to the method of Example 194A, substituting 3-chloro-4-fluorophenyl hydrazine*HCI in place of 4-fluorophenyl hydrazine. HCI (yield: 9.1 g, 1 H NMR (300 MHz, CDCI3) 7.22 J 9 Hz, 1 7.53-7.58 (in, 1 7.73 (dd, J 9 Hz, 3 Hz, 1 7.94 1 MVS (DCI-NH3) m/z 383 400 (M+NH4)+ 246B. 2-(3-Ch loro-4-f luorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazi none.
The title compound is prepared according to the method of Example 194B, substituting 2- (3-ch loro-4-f luorophenyl)-4,5-dibromo-3(2 H)-pyridazi none in place of 2-(4-fluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (yield: 5.6 g, 1 H NMR (300 MHz, CDCI3) 4.32 3H), 7.22-7.30 (in, 1 7.45-7.55 (in, 1 7.64-7.74 (in, 1 7.94 J 9 Hz, 1 MS (DCI-NH3) m/z 335 352 (M+NH4)+.
246C. 2-(3-Chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl-3(2H)pyrdanone 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)-pyridazinone in place of 2-benzyl-5-methoxy-4-bromo-3( 2 H)-pyridazi none and substituting 3methyl-4-(methylthio)benzeneboronic acid in place of 4-fluo robe nze nebo roni c acid (yield: 3.2 g, 1 H NMR (300 MHz, CDCI3) 8 2.53 3H), 4.13 3H), 7.25 (t, J 9 Hz, 1 7.35 J 9 Hz, 2H), 7.52 J 9 Hz, 2H), 7.55-7.64 (in, 1 7.78 (dd, J 9 Hz, 3 Hz, 1 7.93 2H). MS (DCI-NH3) m/z 377 394 (M+NH4)+.
246D. 2-(3-Chloro-4-fluorophenyl)-4-cyclohexyl-5-[4-(methylthio)phenyll-3(2H)pyridazinone The title compound is prepared starting with 2-(3-chloro-4-fluorophenyl)-4methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazi none in place of 2-(4- 1fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazi none by treatment of the methoxy-sulfide compound with cyclohexylmagnesium chloride according to the method of Example 228 to provide the cyclohexyl sulfide compound.
246E. 2-(3-Chloro-4-fluoroph-enyl)-4-cyclohexyl-5-[4-(methylsulfonyl)pheyL-.
32 "2)-pyridazi none, The methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 150 mng, M.p. 180-181 0
C.
-157- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 1 H NMR (300 MHz, CDCI3) 5 1.02-1.36 (in, 2H), 1.49-1.68 (in, 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, 1 3.17 (s, 3H), 7.25 J 9 Hz, 1 7.53 J 9 Hz, 1 7.53-7.61 (in, 2H), 7.69 1 H), 7.78 (dd, J 9 Hz, 3 Hz, 1 8.12 J 9 Hz, 2H). MS (DCI-NH3) m/z 461 478 Anal. caic. for C23H22CIFN20 3 S: C, 60.01; H, 4.78; N, 6.09. Found: C, 59.85; H, 4.97; N, 5.79.
Example 247 2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-r4- (methylsuIf onyl)phe nyll-3 (2 H)-pyridazi none 2-(3-Chloro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-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-(inethylthio)phenyl]- 3(2H)-pyridazinone, prepared in Example 246D, and substituting 4-fluoro-3methylphenyl magnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 118 mg, M.p. 207-208 00. 1 H NMR (300 MHz, 0D013) 8 2.21 (br s, 3H), 3.08 3H), 6.81-6.93 (in, 2H), 7.15-7.30 (in, 2H), 7.41 J 9 Hz, 2H), 7.60-7.68 (mn, 1 7.85 (dd, J 9 Hz, 3 Hz, 1 7.93 J 9 Hz, 2H), 7.99 1 MS (DCI-NH3) m/z 487 504 Anal. calc.
for 024H17ClF2N203S*0.25 H20: 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-r4-(methylsu lfonyl)phenyll-3(2H)pyiaznn 2-(3-C hloro-4-fluorophenyl)-4-benzyl-5-[4-(inethylthio)phenyl]-3(2H)pyridazinone was prepared according to the method of Example 228, starting with 2-(3-chloro-4-fluorophenyl)-4-inethoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared in Example 246D, and substituting benzylmagnesiuin chloride in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 110 ing, M.p. 164-166 0C. 1 H NMR (300 MHz, CDCI3) 8 3.11 3H), 3.99 2H), 7.01-7.06 (in, 2H), 7.17-7.28 (in, 4H), 7.53 8- WO 99/10331 WO 9910331PCTIUS98/1 6479 J 9 Hz, 2H), 7.59-7.66 (in, 1 7.81 1 7.82 (dd, J 6 Hz, 3 Hz, 1 8.09 J 9 Hz, 2H). MVS (DCI-NH3) m/z 473 490 Anal. cab,. for C24Hl8CIFN2O3S: C, 61.54; H, 3.85; N, 5.99. Found: 0, 61.40; H, 3.82; N, 5.54.
Example 249 2-(3-Chloro-4-fluorophenyl)-4-(3-fluorobenzyl)-5-[4-(methylsulfony)phenyl-3(2H)pidnn 2-(3-Chlo ro-4-f luorophe nyl)-4-(3-fluorobenzyl)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone was prepared according to the method of Example 228, 1 0 starting with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared in Example 246D, and substituting 3-fluorobenzylmagnesium chloride in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 33 mng, M-p. 101-1 03 00. 1 H NMR (300 MHz, CDCI3) 8 3.15 3H), 3.95 2H), 6.73 (br d, J 9 Hz, 1 6.81 (br d, J 9 Hz, 1 6.88 (br t, J 9 Hz, 1 7.15-7.28 (in, 7.51 J 9 Hz, 2H), 7.53 (ddd, J 9 Hz, 3 Hz, 1.5 Hz, 1 7.83 (dd, J 6Hz, 3 Hz, 1 7.83 1 8.10 (d, J 9 Hz, 2H). MS (DCI-NH 3 m/z 487 504 Anal. calc. for C24H17ClF2N203S: 0, 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-inethylphenvl)-5-[4-(methylsulfonyl)phenyl-3(2H)- 2-(4-Fluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(inethylthio)phenyl]- 3 (2 H)-pyridazi none was prepared according to the method of Example 228, starting with 2-(4-fluorophenyl)-4-inethoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared in Example 1940, and substituting 3-fluoro-4-methylphenylinagnesium bromide in place of cyclohexylmagnesiuin chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 540 mng, M.p. 245-248 00. 1 H NMR (300 MHz, CDCI3) 5 2.22 (br s, 3H), 3.05 3H), 6.83 (dd, J 9 Hz, 1.5 Hz, 1 6.96 (dd, J 9Hz, 1.5 Hz, 1 7.06 J 9Hz, 1 7.18 J 9Hz, 2H), 7.41 J 9 Hz, 2H), 7.65-7.72 (mn, 2H), 7.91 J 9 Hz, 2H), 7.95 1 MS (DCI-NH 3 m/z -159- WO 99/10331 WO 9910331PCTJUS98/1 6479 452 470 Anal. caic. for C24H18F 2
N
2 0 3 S: C, 63.86; H, 3.99; N, 6.21. Found: C, 63.49; H, 4.13; N, 5.98.
Example 251 2-(3-C hlo ro-4-f Iu oro phe nyl)-4- (3.5-dif luoro-4- met hoxyphenyl) -s[4- (methylsulfonyl)phe nyll-3(2H)-pyridazi none 2- C hlo ro-4-f lu orophe n y)-4-13,5-dif lu oro-4-methoxyph enyl) (met hyIthio) phe nyl1]-3(2 H)-pyri dazi none was prepared according to the method of Example 228, starting with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]- 3 (2H)-pyridazi none, prepared in Example 246D, and substituting 3,5-difluoro-4methoxyphenylmagnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 590 mg, M.p. 195-197 00. 1 H NMR (300 MHz, CDCI3) 863.10 3H), 4.12 3H), 6.81 (br d, J 9 Hz, 2H), 7.27 J 9 Hz, 1 7.43 J 9 Hz, 2H), 7.60-7.67 (in, 1 7.83 (br d, J 9 Hz, 1 7.98 J 9 Hz, 2H), 7.98 1 MS (DCI-NH3) m/z 487 504 Anal. calc.
for C24H1 6CIF3N203S-0.5 H20: 0, 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-methylbuty)--[3-fluoro-4-(methylsulfonyl)phenYI].
3(2H)-pyridazi none 2- (3-C hloro-4-f luo rop he nyl)-4- (3-m ethylbutyl)-5-[4- (met hylth io) phe ny I]- 3(2H)-pyridazinone was prepared according to the method of Example 228, starting with 2-(3-ch loro-4-f luo rophe nyl)-4-methoxy-5-[4- (methylthio)phenyl]-3(2H)pyridazinone, prepared in Example 2460, and substituting 1-(3-methylbutyl)magnesium bromide in place of cyclohexylmagnesium chloride to provide the methyl sulfide compound.
The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 425 mg, M.p. 102-104 00. 1 H NMR (300 MHz, 00013) 860.85 J 9 Hz, 6H), 1.41-1.62 (in, 1 2.50-2.63 (in, 2H), 3.30 (s, 3H), 7.22-7.38 (in, 3H), 7.57-7.64 (in, 1 7.72 (br s, 1 7.80 (br d, J 6 Hz, 1 H), 8.15 J 9 Hz, 1 MS (DCI-NH3) m/z 467 484 Anal. calc.
for C22H21 CIF2N2O3S: C, 56.65; H, 4.51; N, 6.01. Found: 0, 56.25; H, 4.49; N, 6.06.
-160- WO 99/10331 PCT/US98/16479 Example 253 2-(4-Fluorophenvl)-4-(3-fluorobenzyl)-5-[4-(aminosulfonvl)phenyl]-3(2H)pyridazinone The methyl sulfide intermediate from Example 242 was oxidized to the methyl sulfoxide with one equivalent of meta-chloroperoxybenzoic acid according to the procedure in Example 69B to provide the sulfinyl compound.
The sulfoxide was converted to the title sulfonamide according to the method of Example 68 (yield: 120 mg, M.p. 199-202 1 H NMR (300 MHz, DMSOd6) 5 3.92 2H), 6.85 (br t, J 9 Hz, 2H), 6.99 (br t, J 9 Hz, 1 7.26 J 7 Hz, 1 7.35 J 9 Hz, 2H), 7.50 2H), 7.62-7.71 4H), 7.95 J 9 Hz, 2H), 8.11 1H). MS (DCI-NH3) m/z 454 471 Anal. calc. for C23H17F2N303S: C, 60.86; H, 3.75; N, 9.27. Found: C, 60.99; H, 3.76; N, 9.02.
Example 254 2-(3.4-Difluorophenvl)-4-(phenvlethvnvyl-5-[4-(methvlsulfonvl)phenvl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 232 substituting phenylethynylmagnesium bromide in place of chloride (yield: 195 mg, M.p. 211-213 oC. 1H NMR (300 MHz, DMSO-d6) 8 7.46 5H), 7.65 (m, 2H), 8.18 4H) 8.4 1H). MS (DCI-NH3) m/z 463M+H)+, 480 Anal.
calc. for C25H16F2N203S: C, 64.56; H, 3.49; N, 6.06. Found: C, 64.49; H, 3.68; N, 5.86.
Example 255 2-(3.4-Difluo rophenvl)-4-(3.4-difluorobenzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone 3,4-Difluorobenzyl bromide (0.1 ml, 0.8 mmol) in ether (10 ml) was treated with magnesium 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 mmol) in THF (10 ml) at -78 oC. 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 MgSO4 and concentrated in vacuo. The resulting crude residue was purified by flash -161- WO 99/10331 WO 9910331PCTIUS98/1 6479 chromatography (SiO2, eluting with 9:1 hexanes:ethyl acetate) to provide 120 mg of desired product and some starting material.
The methylthio compound (120 mg, 0.3 mmol) from above in CH2012 (10 ml) at 0 OC, was treated with CH3CO3H (0.3 ml, 1 mmol). The reaction was complete in 2 hours. The reaction mixture was diluted with 0H2CI2 and washed with saturated NaHCO3 and brine respectively. The resulting crude residue was purified by flash chromatography (SiO2, eluting with 1:1 hexanes:ethyl acetate) to provide the desired product (yield: 44 mg, M.p. 177-179 00. 1 H NMR (300 MHz, DMSO-d6) 563.3 3H), 3.9 6.85 (in, 1 7.15 (in, 1 7.25 (mn, 2H), 7.6 (mn, 7H), 8.15 (in, 3H). MS (DCI-NH3) in/z 489 506 Anal. calc. for C24H16F4N2O3S-0.25 H20: C, 59.01; H, 3.30; N, 5.74. Found: 0, 58.16; H, 3.56; N, 4.51.
Example 256 1 5 2-(3.4-Difluorophenyl)-4-(3-inethylbutyl)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazi none The title compound was prepared according to the method of Example 233, starting with 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(inethylsulfonyl)phenyl]-3(2H)pyridlazinone in place of 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(inethylthio)phenyl]- 3(2 H)-pyridazi none and substituting 1-broino-3-inethylbutane in place of 3,4-difluorobenzyl bromide (yield: 198 mg, M.p. 55-5800C 1 H NMR (300 MHz, DMSO-d6) 860.75 6H), 1.4, (in, 3H), 2.48 (in, 2H), 3.3 3H), 7.51 (in, 1 H), 7.65 (mn, 1 7.75 J 9 Hz, 2H), 7.81 (in, 1 H) 8.05 1 8.12 J 9 Hz, 2H).
MS (DCI-NH3) in/z 433 450 Anal. calc. for C22H22F2N2O3S-0.25 H20: 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-inethylbutyl)-5-[4-(methylsulfonyl)phenyll..3(2
H)-
pyridazinone The title compound was prepared according to the method of Example 233, procedure starting with 2-(3,4-difluorophenyl)-4-inethoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone with 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[4- (inethylthio)phenyl]-3 (2H)-pyridazin one and substituting 1 -broino-3-inethylbutane in place of 3,4-difluorobenzyl bromide (yield: 256 ing, M.p. 55-58 00. 1 H NMR (300 MHz, DMSO-d6) 6 0.75 6H), 1.4, (in, 3H), 2.48 (in, 2H), 3.3 3H), -16 2- WO 99/10331 WO 9910331PCT/US98/1 6479 7.62 (in,2H), 7.75 2H), 7.93 (dd, 1H), 8.05 1H), 8.12 J =9Hz, 2H). MS (DC I-N H3) m/z 449 466 Anal. cab,. for C22H22FN203SCI.0.25 H20: C, 58.86; H, 4.94; N, 6.24. Found: 0, 59.23; H, 5.12; N, 6.00.
Example 258 Difluorophenyl)-4-(3-methylbutyl)-5-[3-fluo ro-4-(methylsulfonyluphe nyll- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 233, procedure starting with 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chloro-4-fluorophenyl)-4-methoxy-5-[3f luoro-4-(methylthio)phenyl]-3(2 H)-pyridazi none and substituting 1 -bromo-3methyibutane in place of 3,4-difluorobenzyl bromide (yield: 100 mg, 20%) M.p.
119-121 O0. 1 H NMR (300 MHz, DMSO-d6) 860.75 6H), 1.4, (in, 3H), 2.48 (in, 2H), 3.4 3H), 7.51 (mn, 1 7.8 (mn, 2H), 7.81 (in, 2H). MS (DCI-NH3) in/z 451 468 Anal. calc. for 022H21 F3N203S: C, 58.66; H, 4.7; N, 6.22.
Example 259 2-[4-Fluoro-3-(methylthio)phenyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenLI]- 3(2H)-pyridazi none To a stirred solution of 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazi none (315 mg, 0.69 mmol) in DMF (10 ml) at room temperature was treated with sodium thioinethoxidle (51 mg, 0.7 minol). 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 MgSO4, and concentrated in vacuo. The resulting crude residue was purified using flash chromatography (SiO2, eluting with (15:1 CH2CI2:diethyl ether) to provide the desired product (yield: 30 ing, M.p. 105-107 OC. 1 H NMR (300 MHz, DMSO-d6) 82.55 3H), 3.23 3H), 87.15 (in, 2H), 7.3 (mn, 2H), 7.55 (in, 5H), 7.9 2H), 8.25 1 MS (DCI-NH3) m/z 485 502 Anal. calc. for C24H 18F2N203S2: C, 59.49; H, 3.74; N, 5.78.
-163- WO 99/10331 PCT/US98/16479 Example 260 2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyll-3(2H)pyridazinone: 260A. 2-Benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinvl)phenyl]-3(2H)-pyridazinone 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.
260B. Bis(4-(5-(2-benzyl-4-(4-fluorophenvl)-3(2H)-pyridazinone)phenyl)disulfide: A heterogeneous solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazinone (1.0 g, 2.39 mmol) in trifluoroacetic anhydride mL, 70.8 mmol) was rapidly stirred at reflux for 2 hours with a bath temperature of 40-43 OC. The reaction solution was cooled to 23 OC, concentrated in vacuo, and azeotroped with toluene (2 x 5-7 mL). The resultant yellow/orange oil was cooled to 0 and methanol/triethylamine 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 the cooling bath removed, and the reaction mixture stirred an additional 1.5 hours warming to 23 oC. The mixture was cooled back to 0 and a saturated NH4CI solution (200 mL) slowly added followed by enough aqueous 1 M HCI 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 12 (648 mg, 2.55 mmol) at 23 °C for 30 minutes completed the conversion of the mono-sulfide to the disulfide. (Chem. Pharm. Bull., 1992, 40, 2842) The mixture was treated with a 0.1 M Na2S203 solution to consume the excess 12. This solution was extracted with ethyl acetate, and the ethyl acetate layers dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in CH2CI2/hexanes and concentrated in vacuo to provide the of product (yield: 347 mg, 90% for partial conversion). 1 H NMR (300 MHz, CDCI3) 5 5.38 4H), 6.91 (dd, J 8.8, 8.8 Hz, 4H), 7.02 J 8.7 Hz, 4H), 7.11-7.20 4H), 7.28-7.39 10H), 7.54 (dd, J 6.9, 1.5 Hz, 4H), 7.83 2H).
-164- WO 99/10331 PCT/US98/16479 260C. 2-Benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio)phenyll-3(2H)pyridazinone: A rapidly stirred mixture of bis[4-{5-[2-benzyl-4-(4-fluorophenyl)-3(2H)pyridazinone]}-phenyl]-disulfide (140 mg, 0.181 mmol), potassium trifluoroacetate (55 mg, 0.361 mmol), and sulfolane (1.5 mL) was immersed in a 180 °C pre-heated oil bath. The oil bath was heated to increase the temperature to 210 and the reaction flask was promptly removed from the oil bath after 10 minutes from the point of first immersion. During the course of the reaction, the mixture changed from colorless and heterogeneous to deep, blood red and homogeneous. After cooling to 23 the mixture was diluted with ethyl acetate and washed with aqueous 1 M HCI, water, and brine. The ethyl acetate solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:4) to provide the product (yield: 17 mg, (Tetrahedron Lett.., 1996, 37, 9057) 1 H NMR (300 MHz, CDCI3) 8 5.41 (s, 2H), 6.94 (dd, J 8.2, 8.2 Hz, 2H), 7.11-7.20 4H), 7.31-7.42 3H), 7.52-7.61 4H), 7.86 1H). MS (APCI+) m/z 457 and m/z 474 (M+NH4)+.
260D. 2-Benzvl-4-(4-fluorophenyl)-5-[4-(trifluoromethylsulfonyl)phenyl]-3(2H)pyridazinone: A solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(trifluoromethylthio)phenyl]- 3(2H)-pyridazinone (100 mg, 0.219 mmol), 3-chloroperoxybenzoic acid (380 mg, 1.3 mmol, 57-86%), and methylene chloride (5 mL) was brought to reflux at a bath temperature of 55 oC. 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 °C and concentrated in vacuo. The residue was diluted with ethyl acetate and carefully shaken with a NaHSO3 solution, 3 times, for several minutes to consume the excess 3-chloroperoxybenzoic acid. The ethyl acetate solution was subsequently washed with a saturated Na2CO3 solution water, and brine and dried over MgSO4, 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, Med. Chem., 1990, 33, 2569) M.p. 80-115 oC. 1H NMR (300 MHz, DMSO-d6) 5.36 2H), 7.11 (dd, J 9.0, 9.0 Hz, 2H), 7.18-7.26 2H), 7.29-7.46 5H), 7.66 J 8.7 Hz, 2H), 8.10 J= 8.7 Hz, 2H), 8.18 1H). MS (APCI+) m/z 489 and m/z -165- WO 99/10331 PCT/US98/16479 506 Anal. calc. for C24H16F4N20 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-(methylsulfonvy)phenvl-3(2H)pyridazinone 2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (150 mg, 0.41 mmol), prepared in Example 193E, and neopentyl alcohol (43 mg, 0.49 mmol) 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 NH4CI solution, diluted with ethyl acetate and extracted with 1 N HCI, twice, then water, 3 times, and then dried over MgSO4. 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, M.p. 145-146 1 H NMR (300 MHz, DMSO-d6) 5 0.76 9H), 3.28 3H), 4.06 2H), 5.02 J 9 Hz, 2H), 7.88 J 8 Hz, 2H), 8.04 J 8 Hz, 2H), 8.13 1H). MS (DCI-NH3) m/z 419 436 Anal. calc. for C18H21F3N204S: 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-methoxvphenoxy)-5-[4-(methylsulfonylphenyl]-3(2H pyridazinone The title compound was prepared according to the method of Example 261, substituting 4-methoxyphenol in place of neopentyl alcohol (yield: 130 mg, 54%).
M.p. 194-195 oC. 1 H NMR (300 MHz, DMSO-d6) 6 2.24 3H), 3.26 3H), 5.00 J 9 Hz, 2H), 6.88 J 8 Hz, 2H), 7.09 J 8 Hz, 2H), 7.37 J 8 Hz, 2H), 8.03 J 8 Hz, 2H), 8.33 1H). MS (ESI-) m/z 439 Anal. calc. for C19H17F3N204S: 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-trifluoromethvlphenoxy)-5-[4-(methylsulfonyl)- Dhenyll-3(2H)-pyridazinone The title compound was prepared according to the method of Example 261, substituting 2-fluoro-5-trifluoromethylphenol in place of neopentyl alcohol (yield: -166- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 155 mg, M.P. 133-135 00. 1 H NMR (300 MHz, DMSO-d6) 5 3.28 3H), 5.03 J 9 Hz, 2H), 7.10-7.53 (in, 2H), 7.72 (dd, J 1 Hz, 7 Hz 1 7.92 J 8 Hz, 2H), 8.07 J 8 Hz, 2H), 8.38 1 MS (DCI-NH3) m/z 528 (M+NH4) Anal. caic. for 020H1 3F7N204S: 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)Y4-(4-cyanoohenoxv)-5-(4-(methylsulfonfl)1henvll-3 (2 H- D2yridazi none The title compound was prepared according to the method of Example 261, substituting 4-cyanophenol in place of neopentyl alcohol (yield: 109 mg, 71%).
M.p. 179-181 00. 1 H NMR (300 MHz, DMSO-d6) 6 3.26 3H), 5.02 J 9 Hz, 2H), 7.25 J 9 Hz, 2H), 7.81 J 9 Hz,'2H), 7.86 J 8 Hz, 2H), 8.03 J 8 Hz, 2H), 8.37 1 MS (DCI-NH3) m/z 467 (M+NH4). Anal. calc. for C20H14F3N304S: 0, 53.45; H, 3.14; N, 9.35. Found: 0, 53.19; H, 3.01; N, 9.09.
Example 265 2-(2.2.2-Trifluoroethyl')-4-(3-pyridyloxy)-5-14-(methvlsulfonyl)Dhenyll-3(2H)p2yridazinone The title compound was prepared according to the method of Example 261, substituting 3-hydroxypyridine in place of neopentyl alcohol (yield: 120 mng, 69%).
M.p. 191-193 OC. 1 H NMR (300 MHz, DMSO-d6) 5 3.26 3H), 5.01 J 9 Hz, 2H), 7.36 (dd, J 3 Hz, 8 Hz, 1 7.55 (ddd, J. 1 Hz, 3 Hz, 8 Hz, 1 7.88 J 8 Hz, 2H), 8.04 J 8 Hz, 2H), 8.31 (dd, J 1 Hz, 5 Hz, 1 8.36 1 8.38 J 3 Hz, 1 MS (DCI-NH3) m/z 426 443 Anal. calc. for C18H14F3N304S: 0,50.82; H, 3.32; N, 9.88. Found: 0,50.95; H, 3.57; N, 9.71.
Example 266 2 -(2.2.2-Trifluoroethyl)-4-(4-n-propylphenoxy)-5-[4-(methylsulfony)phenyl-3(2
H)-
pyridazinone The title compound was prepared according to the method of Example 261, substituting 4-(n-propyl)phenol in place of neopentyl alcohol (yield: 1 47 mng, 77%).
M-p. 152-153 00. 1 H NMR (300 MHz, DMSO-d6) 8 0.87 J 7 Hz, 3H), 1.54 J 7 Hz, 2H), 3.25 3H), 5.00 J 9 Hz, 2H), 6.88 J 9 Hz, 2H), 7.09 J 9 Hz, 2H), 7.87 J 8 Hz, 2H), 8.02 J 8 Hz, 2H), 8.32 1 MS (DCI-NH3) -167- WO 99/10331 WO 9910331PCTJUS98/1 6479 m/z 484 Anal. calc, for C22H21 F3N204S: 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-Trifluoroethyfl-4-[4-(methylsulfonyl)phenoxyl-5-[4-(methylsulfonyl)phen I 3(2 H)-pyridazi none The title compound was prepared according to the method of Example 261, substituting 4-(methylsulfonyl)phenol in place of neopentyl alcohol (yield: 115 mg, M.p. 212-213 00. 1 H NMR (300 MHz, DMSO-d6) 863.21 3H), 3.27 3H), 5.03 J 9 Hz, 2H), 7.31 J 9 Hz, 2H), 7.83-7.89 (in, 4H), 8.04 J 8 Hz, 2H), 8.40 1 MS (DCI-NH3) m/z 520 Anal. calc. for C20H17F3N206S2: 0, 47.81; H, 3.41; N, 5.58. Found: C, 47.92; H, 3.18; N, 5.52.
Example 268 1 5 2- (2.2.2-Trif Iu oroethyl)-4- (4-p henvl he noxy)-5-[4-(m et hylsu Ifo nyl)p2he nyl] 3(2H pyridazi none The title compound was prepared according to the method of Example 261, substituting 4-phenylphenol in place of neopentyl alcohol (yield: 105 mg, 51%).
M.p. 163-16500C 1 H NMR (300 MHz, DMSO-d6) 863.26 3H), 5.02 J 9 Hz, 2H), 7.10 J 8 Hz, 2H), 7.33 (br t, J 7 Hz, 1 7.44 J 7 Hz, 7.57-7.63 (in, 4H), 7.92 J 8 Hz, 2H), 8.04 J 8 Hz, 2H), 8.37 1 MS (DCI-NH3) m/z 518 Anal. calc. for C25H19qF3N204S: 0, 60.00; H, 3.83; N, 5.60.
Found: C, 60.18; H, 3.66; N, 5.52.
Example 269 2- (2.2.2-Trif luo roeth yl)-4-[r2- (met hylt hio)ethoxyl-5-[4- (methylsuIf on yl) ph enyll -3 (2 H)pyridazi none 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 M.p. 103-105 00. 1 H NMR (300 MHz, DMSO-d6) 6 2.01 3H), 2.72 J 7 Hz, 2H), 3.29 3H), 4.59 J 7 Hz, 2H), 5.03 J 9 Hz, 2H), 7.91 J 8 Hz, 2H), 8.04 J 8 Hz, 2H), 8.15 1 MS (DCI-NH3) m/z 423 440 Anal. caic. for 016H17F3N20 4
S
2 C, 45.49; H, 4.06; N, 6.33. Found: C, 45.83; H, 4.11; N, 6.42.
-168- WO 99/10331 WO 99/ 0331PCTIUS98/I 6479 Example 270 2- (2.2 .2-Trif Iuoroeth (p heny Imethoxy)-5-[4- (met hylsu Ifo nyj)phenyll-3 (2 H)pyridazi none The title compound was prepared according to the method of Example 261, substituting benzyl alcohol in place of neopentyl alcohol (yield: 137 mg, M.p.
121 -1 23 00. 1 H NMR (300 MHz, DMSO-d6) 563.28 3H), 5.06 J 9 Hz, 2H), 5.48 2H), 7.20-7.25 (in, 2H), 7.27-7.81 (in, 3H), 7.76 J 8 Hz, 2H), 7.98 J= 8 Hz, 2H), 8.12 1 MS (DCI-NH3) m/z 456 Anal. calc. for C20H17F3N204S: 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-furyl methoxy)-5-r4-(methylsulfonyl)phenyll-3(2H)- Wydazinone The title compound was prepared according to the method of Example 261, substituting 2-(hydroxymethyl)furan in place of neopentyl alcohol (yield: 101 mg, M.p. 113-115 00. 1 H NMR (300 MHz, DMSO-d6) 6 3.28 3H), 5.07 J 9 Hz, 2H), 5.52 2H), 6.41 (dd, J 2 Hz, 3 Hz, 1 6.45 J 4 Hz, 1 7.62 (d, J 2 Hz, 1 7.69 J 8 Hz, 2H), 7.97 J 8 Hz, 2H), 8.13 1 MS (DCI- NH3) m/z 446 Anal. caic. for C18H15F3N205S: 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)1-5-[ 4-(methylsu Ifonyl- Uhenyll-3(2 H)-pyridazi none 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 mng, M.p. 133-134 00. 1 H NMR (300 MHz, DMSO-d6) 6 2.82 J 7 Hz, 2H), 3.28 3H), 3.63 3H), 3.70 3H), 4.68 J 7 Hz, 2H), 5.01 J 9 Hz, 2H), 6.61 (dd, J 2 Hz, 8 Hz, 1 6.74 J 2 Hz, 1 6.77 J 8 Hz, 1 7.74 J 8 Hz, 2H), 7.93 J 8 Hz, 2H), 8.11 1 MS (DCI-NH 3 m/z 530
(M+NH
4 Anal. calc. for C23H23F3N 2 0 6 S: C, 53.90; H, 4.52; N, 5.47. Found: C, 53.87; H, 4.48; N, 5.45.
-169- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 273 2-(2.2 .2-Trif luoroethyl)-4-r2-(4-morpholi no)ethoxy)I-5-[4-(methylsulfonyl)phenyll- 3 (2 H)-pyri dazi none 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, M.p. 147-14800C 1 H NMR (300 MHz, DMSO-d6) 8 2.23 (in, 4H), 2.46 (t, J 5 Hz, 2H), 3.28 3H), 3.40 (in, 4H), 4.60 J 5 Hz, 2H), 5.02 J 8 Hz, 2H), 7.96 J 8 Hz, 2H), 8.03 J 8 Hz, 2H), 8.17 1 MS (DCI-NH3) m/z 462 Anal. calc. for C1 9H22F3N305S: 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)-4-12-(1 -pipe ridi nyl) ethoxy)]-5-[4- (met hylsuIto nyI)p he nyl]- 3 (2 H )-pyri dazi none 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, M.p. 117-118 OC. 1 H NMR (300 MHz, DMSO-d6) 8 1.30 (br s, 6H), 2.20 (br s, 4H), 2.41 J 4 Hz, 2H), 3.28 3H), 4.60 J 5 Hz, 2H), 5.02 J 9 Hz, 2H), 7.97 J 8 Hz, 2H), 8.03 J 8 Hz, 2H), 8.15 1 MS (DCI-NH3) m/z 460 Anal. calc. for C20H24F3N304S: 0, 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)-4-14-(carboxamido)phenoxy)1-5-4-(methylsulfonyl)pheyl 3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 261, substituting 4-hydroxybenzamide in place of neopentyl alcohol (yield: 50 mng, 26%).
M.p. 250 00. 1 H NMR (300 MHz, DMSO-d6) 8 3.26 3H), 5.02 J 8 Hz, 2H), 7.08 J 9 Hz, 2H), 7.30 1 7.82 J 9 Hz, 2H), 7.88 J 8 Hz, 2H), 7.92 1 8.03 J 8 Hz, 2H), 8.47 1 MS (DCI-NH3) m/z 468 485 Anal. calc. for C20H16F 3 N30 5 S: 0, 51.39; H, 3.45; N, 8.99.
Found: C, 51.31; H, 3.28; N, 8.77.
-170- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 276 2-(2-2.2-Trifluoroethy)-4-(1 -indanyloxy)-5-[4-(Methylsulfonyl)phenyl]-3(2H)- The title compound was prepared according to the method of Example 261, substituting 1-indanol in place of neopentyl alcohol (yield: 84 mg, M.p. 113- 114 00. 1 H NMR (300 MHz, DMSO-d6) 8 2.07-2.14 (in, 1 2.22-2.35 (in, 1 H), 2.73 (dd, J 5 Hz, 7 Hz, 2H), 3.24 3H), 5.00-5.22 (mn, 2H), 6.48 (dd, J 2 Hz, 6 Hz, 1 7.12-7.24 (mn, 2H), 7.21-7.28 (in, 2H), 7.44 J 8 Hz, 2H), 7.87 J 8 Hz, 2H), 8.09 1 MS (DCI-NH 3 m/z 482 Anal. calc. for C22H19F3N204S: 0, 57.19; H, 4.48; N, 5.80. Found: C, 57.36; H, 4.30; N, 5.78.
Example 277 2- (2.2 .2-Trif uoro ethyl)-4-[ 4- (acetamni do) phe noxy)1- 5-[r4- (met hylsu lfo nyI)p henYL- 3(2 H)-pyridazi none The title compound was prepared according to the method of Example 261, substituting 4-acetamidophenol in place of neopentyl alcohol (yield: 45 mg, 23%).
M.p. 215-216 00. 1 HNMR (300 MHz, DMSO-d 6 6 2.02 3H), 3.26 3H), 5.02 J 8 Hz, 2H), 6.61-6.65 (in, 1 7.17-7.20 (in, 2H), 7.34 (br s, 1 7.88 J 9 Hz, 2H), 8.03 J 8 Hz, 2H), 8.36 1 9.97 1 MS (DCI-NH3) in/z 499 Anal. calc. for 021 H18F3N305S: 0, 52.39; H, 3.77; N, 8.73. Found: C, 52.57; H, 4.02; N, 8.37.
Example 278 27o(2.2 .2-Trif luoro ethyl)-4- methylpropoxy)-5-[4-(methylsuIf onyMl) Qhen Ylp-3 (2Hpyiaznn The title compound was prepared according to the method of Example 261, substituting 2-inethylpropanol in place of neopentyl alcohol (yield: 111 mg, M.p. 108-110 00. 1 HNMR (300 MHz, DMSO-d6) 6 0.77 J 6.4 Hz, 6H), 1.52 (sept, J 6.4 Hz, 1 3.28 3H), 4.17 J 6 Hz, 2H), 5.02 J 9 Hz, 2H), 7.88 J =9 Hz, 2H), 8.04 J 9 Hz, 2H), 8.14 1 MVS (DCI-NH3) in/z 405 422 Anal. calc. for C17H19F 3
N
2 0 4 S: 0, 50.49; H, 4.74; N, 6.93. Found: 0, 50.69; H, 4.89; N, 6.75.
Example 279 2- (2.2.2-Trif Iuo roethyl)-4--( methylcyc lo propyl met hoxy)-5-14- (methyl suIf onyl) phenyll-3 (2 H)-o2vridazi none -171- WO 99/10331 PCT/US98/16479 The title compound was prepared according to the method of Example 261, substituting 1-methylcyclopropanemethanol in place of neopentyl alcohol (yield: 360 mg, M.p. 98-99 OC. 1H NMR (300 MHz, CDCI3) 8 0.35 (dt, J 40 Hz, Hz, 4H), 0.91 3H), 3.11 3H), 4.32 2H), 4.82 J 8.5 Hz, 2H), 7.80 J 8.5 Hz, 2H), 7.84 1 8.06 J 9 Hz, 2H). MS (DCI-NH3) m/z 417 m/z 434 Anal. calc. for C18H19F3N204S: C, 51.92; H, 4.60; N, 6.73.
Found: C, 51.87; H, 4.72; N, 6.69.
Example 280 2-(2.2.2-Trifluoroethyl)-4-(3.3-dimethylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 261, substituting 3,3-dimethyl-1-butanol in place of neopentyl alcohol (yield: 270 mg, M.p. 83-85 1 H NMR (300 MHz, CDCI3) 8 0.88 9H), 1.56 J 8 Hz, 2H), 4.60 J 8 Hz, 2H), 4.83 J 8.5 Hz, 2H), 7.73 J 8.5 Hz, 2H), 7.81 (s, 1 8.05 J 8.5 Hz, 2H). MS (DCI-NH3) m/z 433 m/z 450 (M+NH4)+.
Anal. calc. for C19H23F3N204S: C, 52.77; H, 5.36; N, 6.48. Found: C, 52.95; H, 5.29; N, 6.35.
Example 281 2-(3.4-Difluorophenvl)-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenvl]-3(2
H)-
pyridazinone A mixture of 2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (187 mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg, 0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25 mL) was refluxed at 50 °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 MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 2-benzyl-4-(4chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 200 mg, 82%).
The above derivative was dissolved in toluene (25 mL) and was treated with AIBr3 (400 mg, 1.5 mmol) for 20 minutes at 80 OC. The mixture was cooled to room temperature and poured into ice-10% citric acid-ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to provide crude desbenzyl derivative. This compound was immediately dissolved in pyridine -172- WO 99/10331 PCT/US98/16479 mL) and was treated with 3,4-difluorobromobenzene (0.17 mL, 1.5 mmol), Cu mg) and K2C03 (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, M.p. 192-194 1 H NMR (300 MHz, DMSO-d6) 3.22 3H), 7.13 2H), 7.35 2H), 7.50 1 7.60 1 7.75 1H), 7.87 J 9 Hz, 2H), 8.05 J 9 Hz, 2H), 8.41 1 MS (APCI+) m/z 488 and (APCI-) m/z 523 Example 282 2-(3.4-Difluorophenyl)-4-(4-bromophenoxy)-5-[4-(methylsulfonyl)phenyl-3(2H)pyridazinone.
The title compound was prepared according to the method of Example 281, substituting p-bromophenol in place of p-chlorophenol (yield: 54 mg, M.p.
196-199 OC. 1 H NMR (300 MHz, DMSO-d6) 8 3.25 3H), 7.09 J 9 Hz, 2H), 7.47 J 9 Hz, 2H), 7.52 1 7.62 1 7.78 1 7.89 J 9 Hz, 2H), 8.05 J 9 Hz, 2H), 8.41 1 MS (APCI+) m/z 533 and (APCI-) m/z 569 Example 283 2-(2.2.2-Trifluoroethyl)-4-(cyclopentylthio)-5-[4-(methylsulfonyl)phenyl-3(2H)pyridazinone To a solution of NaH (26 mg, 1.1 mmol) in acetonitrile (3.0 mL), under nitrogen, was added cyclopentyl mercaptan (120 pL, 1.1 mmol) dropwise via syringe. The resulting solution was flushed with nitrogen for a period of 20 minutes; after which 2-(trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone, prepared in Example 193E, (200 mg, 0.52 mmol) was added in one portion. The solution was stirred for an additional 20 minutes at which 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 MgSO4, and concentrated in vacuo. Silica gel chromatography (20% ethyl acetate-80% hexanes) provided a pale yellow solid (yield: 202 mg, M.p. 149-151 1 H NMR (300 MHz, CDCI3) 8 1.40-1.34 2H), 1.62-1.54 4H), 1.93-1.88 2H), 3.13 3H), 4.40-4.35 1 4.85 J 8.2 Hz, 2H), 7.58 J 8.5 Hz, 2H), 7.66 1 H), -173- WO 99/10331 WO 9910331PCTIUS98/1 6479 8.06 J 8.4 Hz, 2H). MS (DCI-NH3) m/z 432 Anal. caic. for C18H19F3N20 3
S
2 0, 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--(1 H-i .2.4-triazole-3-ylthio)-5-!4-(,methylsulfonyI)phenyl]- 3(2H)-pyridazinone.
The title compound was prepared according to the method of Example 283, substituting 1 H-i ,2,4-triazole-3-thiol in place of cyclopentyl mercaptan (yield: 164 mg, M.p. 197-200 00. 1 H NMR (300 MHz, CDCI3) 5 3.14 3H), 4.84 J= 8.1 Hz, 2H), 7.41 1 7.68 J 6.8 Hz, 2H), 7.83 1 8.00 J 7.1 Hz, 2H), 8.05 1 MS (DCI-NH 3 m/z 431 Anal. calc. for C15H12F3N203S2: C, 41.76; H, 2.80 N, 16.23. Found: C, 41.68; H, 2.85; N, 15.99.
Example 285 2 -(42.2.2-Trif Iuoro ethyl J-4-2he nyl met hylth io-5-[4- (methylsu fon Yl) Phen Yll-3 (2 H)- The title compound was prepared according to the method of Example 283, substituting benzyl mercaptan in place of cyclopentyl mercaptan (yield: 141 mg, M.p. 108-1 11 1 H NMR (300 MHz, CDCI3) 5 3.01 3H), 4.38 2H), 4.87 J Hz, 2H), 7.10-7.06 (in, 2H), 7.22-7.20 (in, 5H), 7.59 1 7.95 J Hz, 2H). MS (DC I-N H3) in/z 454 Anal. caic. for C20H17F3N20 3
S
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-.(methylsuIf onyl)phe nyII-3(2H)pyridaziflQD The title compound was prepared according to the method of Example 283, substituting 4-fluorophenylmethyl mercaptan in place of cyclopentyl mercaptan (yield: 184 mng, M.p. 182-185 00. 1 H NMR (300 MHz, ODC1 3 8 3.08 (s, 3H), 4.82 J 8.5 Hz, 2H), 6.87-6.81 (mn, 2H), 7.1 9-7.11 (in, 2H), 7.48 J Hz, 2H), 7.68 1 7.93 J 8.5 Hz, 2H). MS (DCI-NH3) m/z 458 Anal. calc. for C19qH1 4F4N 2 0 3
S
2 C, 49.78; H, 3.08 N, 6.11. Found: 0, 49.89 H, 3.18 N, 5.86 -17 4- WO 99/10331 WO 9910331PCT[US98/1 6479 Example 287 2-(2.2 .2-Trifluoroethyl)-4-(cyclohexylthio)-5-[4-(methylsulfonyl)phe nyl]-3 (2H)flziflfn The title compound was prepared according to the method of Example 283, substituting cyclohexyl mercaptan in place of cyclopentyl mercaptan (yield: 1 89 mg, M.p. 165-167 OC. 1 H NMR (300 MHz, CDCI3) 861.28-1.17 (in, 5H), 1.64-1.56 (mn, 3H), 1.82-1.79 (in, 2H), 3.13 3H), 4.08-4.05 (mn, 1 4.86 J 8.5 Hz, 2H), 7.58 J 8.4 Hz, 2H), 7.67 1 8.06 J 8.5 Hz, 2H). MS (DCI-NH3) inlz 446 Anal. calc. for C1 9H21 F3N203S2: 0, 51.11; H, 4.74 N, 6.27. Found: C, 51.39 H, 4.72 N, 5.91.
Example 288 2-(2 .2.2-Trifluoroethyfl-4-(3-chloro-4-fluorophienylthio)-5-[4-(methylsulfony)rphenyll.
3(2 H)-pyridazi none The title compound was prepared according to the method of Example 283, substituting 3-chloro-4-fluorothiophenol in place of cyclopentyl inercaptan (yield: 190 mg, M.p. 142-1 45 00. 1 H NMR (300 MHz, CDCI3) 6 3.18 3H), 4.85 J 8.4 Hz, 2 6.96 (ov. t, J 8.5 Hz, 1 7.14-7.10 (in, 1 7.18 (dd, J 2. 1, Hz, 1 7.53 J 8.4 Hz, 2H), 7.77 1 7.96 J 8.0 Hz, 2H). MS (Cl) in/z 493 Anal. calc. for C19H1301F4N20 3
S
2 .0.25 C6H6-H2O: 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-Trif luoroethyfl-4-(2.2.2-trifluoroethylthio)-5-f 4-(inethylsu lfonyl)phenyfl- 3 (2 H)-pyridazi none.
The title compound was prepared according to the method of Example 283, substituting 2,2,2-trifluoroethyl mercaptan in place of cyclopentyl inercaptan (yield: 175 mg, M.p. 155-15800C 1 H NMR (300 MHz, CDCI3) 6 3.14 3H), 3.98 J 9.8 Hz, 2H), 4.86 J 8.1 Hz, 2H), 7.58 J 8.4 Hz, 2H), 7.75 1 H), 8.10 J 8.4 Hz, 2H). MS (DCI-NH3) in/z 446 Anal. caic. for Ci SHi2F6N20 3
S
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-Trif luo roethyl)-4-(tert-butylth io)--[4-i(met hylsuf on yl) ph e nyl].312 H)pyridazinone.
-175- WO 99/10331 WO 9910331PCTIUS98/1 6479 The title compound was prepared according to the method of Example 283, substituting tert-butyl mercaptan in place of cyclopentyl mercaptan (yield: 212 mg, M.p. 186-1 89 OC. 1 H NMR (300 MHz, CDCI3) 51.25 9H), 3.13 3H), 4.87 J 8.1 Hz, 2H), 7.62 J 8.5 Hz, 2H), 7.67 1 8.05 J 8.1 Hz, 2H). MS (ESI) m/z 420 Anal. calc. for C1 7H1 9F3N20 3
S
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-Trif uo roethyF) (4-acetamidop hen ylth io)-54[4- (met hylsu If onyl) ph enyL- 3 (2 H)pyridazi none.
The title compound was prepared according to the method of Example 283, substituting 4-acetamidlothiophenol in place of cyclopentyl mercaptan (yield: 100 mg, M-p. 191-193 1 H NMR (300 MHz, CDC13) 5 2.16 3H), 3.08 (s, 3H), 4.83 J 8.2 Hz, 2H), 7.00 J 8.8 Hz, 2H), 7.19 J 8.8 Hz, 2H), 7.31 J 8.1 Hz, 2H), 7.58 1 7.78 J =8.1 Hz, 2H). MS (Cl) m/z 497 Anal. calc. for 02j1i8F3N3O4S2-0.25H 2 O, 0.25 C6H6: C, 52.83; H, 4.06; N, 7.70. Found: C, 52.97; H, 3.85; N, 7.65.
Example 292 2- (2.2.2-Trif luo roet hyl)-4- (2-pro pylth io) -54[4-(met hylsufo nyI)p he ny1 3 (2 H) prdzinoe The title compound was prepared according to the method of Example 283, substituting isopropyl mercaptan in place of cyclopentyl mercaptan (yield: 180 mg, M.p. 165-16700C 1 H NMR (300 MHz, CDCI3) 61.17 J 6.8 Hz, 6H), 3.13 3H), 4.33 J 6.8 Hz, 1 4.86 J 8.5 Hz, 2H), 6.59 J 8.5 Hz, 2H), 7.68 1 8.07 J 8.1 Hz, 2H). MS (DCI-NH3) mlz 406 (M+NH4)+.
Anal. calc. for C1 6H1 7F3N20 3
S
2 0.75H20: 0, 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)phenyll- 3(2 H) -pyri dazi none, The title compound was prepared according to the method of Example 283, substituting 2-methyl-i -propyl mercaptan in place of cyclopentyl mercaptan (yield: 100 mg, M.p. 135-138 00. 1 H NMR (300 MHz, CDCI3) 6 0.87 J 6.4 Hz, 6H), 1.67-1.60 (in, 1 3.00 J 6.7 Hz, 2H), 3.14 3H), 4.84 J 8.5 Hz, -176- WO 99/10331 PCT/US98/16479 2H), 7.61 J 8.4 Hz, 2H), 7.67 1H), 8.08 J 8.5 Hz, 2H). MS (DCI-NH3) m/z 420 Anal. calc. for C17H19F3N203S2: C, 48.56 H, 4.55; N, 6.66. Found: C, 47.86; H, 4.57; N, 6.51.
Example 294 2-(2.2.2-Trifluoroethyl)-4-amino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone 2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylthio)phenyl]-3(2H)pyridazinone, prepared according to Example 193E, (500 mg, 1.36 mmol) was dissolved in DMF (10 mL) and treated with NaN3 (100 mg, 1.5 mmol). After 2 hours at room temperature, the reaction was diluted with ethyl acetate and washed with water, 4 times, and dried over MgSO4. 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-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 481 mg, The 4-azido-compound above (39 mg, 0.105 mmol) was dissolved in THF (3 mL) and MeOH (2 mL) and treated with excess NaBH4. After 15 minutes, the reaction was quenched with saturated NH4CI solution and the product was extracted into ethyl acetate. The organic layer was washed with water, 3 times, and dried over MgSO4. Filtration of the drying agent and evaporation of the solvent provided the title compound (yield: 26 mg, M.p. 260 1H NMR (300 MHz, DMSO-d6) 8 3.26 3H), 4.93 J 9 Hz, 2H), 6.71 2H), 7.72 1 H), 7.76 J 8 Hz, 2H), 8.02 J 8 Hz, 2H). MS (ESI-) m/z 346 Anal. calc.
for C13H12F3N303S: C, 44.96; H, 3.48; N, 12.10. Found: C, 44.59; H, 3.52; N, 11.93.
Example 295 2-(2.2.2-Trifluoroethyl)-4-(3-methoxypropylamino)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone A solution of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)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 °C for 16 hours. The reaction mixture was cooled to room temperature, mixed with silica gel (2 and the solvent removed under reduced pressure. The adsorbed silica gel was layered over an Extract-Clean Cartridge® -177- WO 99/10331 PCT/US98/16479 (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 x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 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, M.p. 110-113 1H NMR (300 MHz, CDCI3) 8.02 J 18.0 Hz, 2H), 7.55 2H, J 18.0 Hz), 7.48 1 6.57 (br t, 1 H, J 9.0 Hz), 4.81 J 17.4 Hz, 2H), 3.33 J 12.0 Hz, 2H), 3.28 3H), 3.12 3H), 2.76 (dt, J 12.0, 12.0 Hz, 2H), 1.65 (tt, J 12.0, 12.0, Hz, 2H). MS (DCI-NH3) m/z 420 m/z 437 Anal. calc. for C17H20F3N304S: C, 48.68; H, 4.81; N, 10.02.
Found: C, 48.74; H, 4.69; N, 9.84.
Example 296 2-(2.2.2-Trifluoroethyl)-4-(cyclopentylamino)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The product was prepared according to the method of Example 295, substituting cyclopentylamine in place of 3-methoxypropylamine to provide brown crystals (yield: 195 mg, M.p. 134-139 OC. 1 H NMR (300 MHz, CDCI3) 5 8.03 J 18.0 Hz, 2H), 7.56 J 18.0 Hz, 2H), 7.45 1H), 6.12 (br d, J 16.8 Hz, 1H), 4.79 J 17.4 Hz, 2H), 3.33 (br m, 1H), 3.12 3H), 1.64-1.23 (br m, 8H).
MS (DCI-NH3) m/z m/z 433 Anal. calc. for C18H20- F3N 3 0 3 S: C, 52.04; H, 4.85; N, 10.11. Found: C, 52.40; H, 4.93; N, 10.03.
Example 297 2-(2.2.2-Trifluoroethyl)-4-(cyclobutylamino)-5-[4-(methlsulfonyl)phenlnv-3(2H)pyvridazinone The product was prepared according to the method of Example 295, substituting cyclobutylamine in place of 3-methoxypropylamine to provide an offwhite solid (yield: 206 mg, M.p. 169-172 1 H NMR (300 MHz, CDCI3) 6 8.03 J 17.4 Hz, 2H), 7.54 J 17.4 Hz, 2H), 7.45 1 6.28 (br d, J 16.2 Hz, 1H), 4.81 J 17.4 Hz, 2H), 3.42 1H), 3.13 3H), 1.79 4H), 1.64 (m, 1H), 1.39 1H). MS (DCI-NH 3 m/z 402 m/z 419 Anal calc.
-178- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 for 017H18F3N30 3 S-0.25 CH3000H 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-f4-(metysulfony)..
phenyll-3 (2 H)-pyri dazi none 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, M.p. 163-165 OQ. 1 H NMR (300 MHz, CDCI3) 8 8.02 J 18.0 Hz, 2H), 7.52 J 18.0 Hz, 2H), 7.45 1 6.75 J 16.2 Hz, 1 6.50 (in, 2H), 6.16 (br d, J 11.4 Hz, 1 4.79 J 17.4 Hz, 2H), 3.84 3H), 3.83 3H), 3.11 3H), 2.91 (dt, J 12.6, 12.6 Hz, 2H), 2.60 J 13.8 Hz, 2H). MS (DCI-NH3) m/z 529 Anal. caic. for C23H24F3N305S: C, 54.01; H, 4.73; N, 8.21. Found: C, 54.30; H, 4.69; N, 8.1 6.
Example 299 2-(2.2.2-Trifluoroethyl)-4-(cyclo hexylamino)-5-[4-(methylsulfonyl)phenyl]-3(2
H-
The product was prepared according to the method of Example 295, substituting cyclohexylamine in place of 3-methoxypropylamine to provide an offwhite solid (yield: 103 mg, 1 H NMR (300 MHz, CDCI3) 8 8.04 J 18.0 Hz, 2H), 7.58 J 18.0 Hz, 2H), 7.44 1 6.06 (br d, J 18.6 Hz, 1 4.81 J= 18.0 Hz, 2H), 3.11 3H), 2.70 (mn, 1 1.66-1.48 (mn, 4H), 1.42 (in, 1 1.07 (in, 3H), 0.76 (in, 2H). MS (DCI-NH3) m/z 430 m/z 447 Anal. calc.
for C19H22F3N30 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 -giperidinyl)ethylaminol-5-[4-(methylsulfonyl)phenyll- 3 (2 pyridazi none The product was prepared according to the method of Example 295, substituting cyclopentylainine in place of 3-methoxypropylamine to provide an offwhite solid (yield: 210 mg, 1 HNMR (300 MHz, CDCI3) 88.02 J =18.0 Hz, 2H), 7.56 J 18.0 Hz, 2H), 7.49 1 6.91 (br, 1 4.82 J 18.0 Hz, 2H), 3.13 3H), 2.64 (br, 2H), 2.32 (br, 4H), 1.58 (br, 6H), 1.42 (br, 2H). MS (DCl- NH3) in/z 459 Anal. calc. for C1 9H22F3N30 3 S: 0, 52.39; H, 5.50; N, 12.22. Found: 0, 52.64; H, 5.59; N, 12.00.
-179- WO 99/10331 WO 99/ 0331PCT1US98/1 6479 Example 301 2- (2.2.2-T rif luo roethyl)-4- (2-tetra hydrof urf urylam i no) (met hYlsu lfo nYl)2he n Yll- 3(2H)-pyridazi none The product was prepared according to the method of Example 295, substituting tetrahydrofurfurylamnine in place of 3-methoxypropylamine to provide an off-white solid (yield: 150 mg, M.p. 128-129 -C 1 H NMR (300 MHz, 00013) 8 8.03 J 18.0 Hz, 2H), 7.56 J 18.0 Hz, 2H), 7.47 1 6.48 (br t, J 9.0 Hz, 1 4.81 J 18.0 Hz, 2H), 3.84 (in, 2H), 3.72 (in, 1 3.12 3H), 2.83 (in, 1 2.64 (in, 1 1.84 (in, 3H), 1.34 (in, 1 MVS (DCI-NH3) m/z 432 mn/z 449 Anal. calc. for C1 8H20F3N30 3 S: 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-(cyclop~rooylamino)-5-[4-(methylsulfonyl)phenyln-3(2H)pyrid The product was prepared according to the method of Example 295, substituting cyclopropylinethylamnine in place of 3-inethoxypropylamine to provide an off-white solid (yield: 130 mg, M.p. 145-1 46 00. 1 H NMR (300 MHz, 00013) 5 8.01 J 18.0 Hz, 2H), 7.53 J 18.0 Hz, 2H), 7.48 1 6.20 (br, 1 4.82 J 18.0 Hz, 2H), 3.12 3H), 2.45 (br d, J 13.2 Hz, 2H), 0.88 (in, 1 0.51 (mn, 2H), 0.10 (in, 2H). MS (DCI-NH3) in/z 402 m/z 419 Anal. calc. for C17H18F3N303S: 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-1 H-inden-1 -ylamino)-5-[4-(methylsulfonyl)p2henyll-3(2H)-p2yridazi none The product was prepared according to the method of Example 295, substituting 1-indanylamine in place of 3-methoxypropylamine to provide an offwhite solid (yield: 82 ing, M.p. 155-158 00C 1 H NMR (300 MHz, 00013) 8 8.04 J 18.0 Hz, 2H), 7.68 J 18.0 Hz, 2H), 7.49 1 7.27-7.14 (mn, 4H), 6.30 (br d, J 18.0 Hz, 1 4.81 J 18.0 Hz, 2H), 4.57 (in, 1 3.09 3H), 2.89 (in, 1 2.60 (in, 1 1.85 (in, 1 1.68 (in, 1 MS (ESI in/z 462 Anal. calc. for 022H2ciF3N3O3S: C, 57.01; H, 4.35; N, 9.07. Found: C, 57.30; H, 4.45; N, 8.86.
-18 0- WO 99/10331 PCT/US98/16479 Example 304 2-(2.2.2-Trifluoroethvl)-4-(1-piperidinyl)-5-[4-(methylsulfonvl)phenyl]-3(2H)pyridazinone 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, M.p. 160-161 1H NMR (300 MHz, CDCI3) 8.04 (d, J 18.0 Hz, 2H), 7.58 1H), 7.46 J 18.0 Hz, 2H), 4.80 J 18.0 Hz, 2H), 3.13 3H), 2.96 4H), 1.65-1.52 6H). MS (DCI-NH3) m/z 416 Anal. calc. for C18H20F3N303S-H20: 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-Trifluoroethvl)-4-(3-hyd roxypropylami no)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone 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, M.p. 152-154 oC. 1 H NMR (300 MHz, CDCI3) 8 8.02 J 18.0 Hz, 2H), 7.56 J 18.0 Hz, 2H), 7.48 1 6.48 (br, 1 4.79 J 17.4 Hz, 2H), 3.63 J 12.0 Hz, 2H), 3.12 3H), 2.81 (dt, J 12.0, 12.0 Hz, 2H), 1.65 (tt, J 12.0, 12.0 Hz, 2H). MS (DCI-NH3) m/z 406 m/z 423 Anal. calc. for C16H18F3N304S: 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-(1 H-imidazol-1-vyl)propvlamino]-5-[4-(methvlsulfonvl)- Dhenyll-3(2H)-pyridazinone The product was prepared according to the method of Example 295, substituting (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 A pore size, 21.4 mm The column was eluted with a linear gradient consisting of 20% acetonitrile (containing 0.1% 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%).
1H NMR (300 MHz, DMSO) 5 8.95 (br s, 1H), 7.97 J 16.8 Hz, 2H), 7.66 J -181- WO 99/10331 WO 9910331PCTIUS98/1 6479 16.2 Hz, 2H), 7.61 1 7.58 J 15.0 Hz, 2H), 6.99 (br t, 1 H, J 13.2 Hz), 4.97 (dt, J =18.0, 18.0 Hz, 2H), 3.97 J 13.2 Hz, 2H), 3.28 3H), 2.69 (in, 2H), 1.81 (tt, J =13.2, 13.2 Hz, 2H). MS (DCI-NH3) mlz 456 Anal. calc. for C19H20F3N503S*1.4 CF3000H: C, 42.57; H, 3.51; N, 11.39. Found: 0, 42.78; H, 3.58; N, 11.24.
Example 307 2- (2.2.2-Trif lu oroethyl)-4- (2 R-hyd roxyl prop1ylami no)-5-{4-(methylsulffonYl) ph eny]- 3 (2 H)-pyridazi none 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, M.p. 140-14200C 1 H NMR (300 MHz, CDCI3) 6 8.04 J 18.0 Hz, 2H), 7.56 J 18.0 Hz, 2H), 7.49 1 6.42 (br, 1 4.79 (in, 2H), 3.80 (mn, 1 3.12 3H), 2.68 (in, 2H), 1.02 J 12.0 Hz, 3H).
MS (DCI-NH3) in/z 406 m/z 423 Anal. calc. for 016H18F3N304S: 0, 47.41; H, 4.48; N, 10.37. Found: 0, 47.56; H, 4.41; N, 10.25.
Example 308 2-(2.2.2-Trifluoroethyl)-4-(2-cyanoethylamino)-5-f4-(inethylsulfony)phenYlp-3(2H).
pyridazinone The product was prepared according to the method of Example 295, substituting 1 -cyanoethylamine in place of 3-methoxypropylainine to provide an offwhite solid (yield: 27 mng, M.p. 172-174 00. 1 H NMVR (300 MHz, CDCI3) 6 8.09 J 18.0 Hz, 2H), 7.63 J =18.0 Hz, 2H), 7.51 1 6.08 (br t, 1 H), 4.87 J 18.0 Hz, 2H), 3.17 (dt, J =13.2,13.2 Hz, 2H), 3.13 3H), 2.39 J 13.2 Hz, 2H). MS (DCI-NH3) in/z 418 Anal. caic. for C16H15F3N40 3 S: 0, 48.00; H, 3.78; N, 13.99. Found: 0, 48.28; H, 3.77; N, 13.80.
Example 309 2-( 2 .2.2-Trifluoroethyl)-4-(4-cyanoanilino)-5-[4-(inethylsulfonvl)p2heny1]-3(2H)pyrdaziona A suspension of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(inethylsulfonyl)phenyl].
3(2H)-pyridazi none (300 ing, 0.820 minol), prepared according to the method of Example 193E, 4-aininobenzonitrile (290 ing, 2.46 inmol), and silver oxide (760 ing, 3.28 minol) in pyridine (1.5 mL) was stirred at 80 00 for 24 hours. The reaction was cooled to room temperature, adsorbed onto silica gel (2 g) and solvent -18 2- WO 99/10331 PCT/US98/16479 removed under reduced pressure. The adsorbed silica gel was layered over an Extract-Clean Cartridge® (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 60-5sil column, 20 mm x 25 cm). The column was eluted with a linear gradient consisting of 30% ethyl acetate/hexanes to 100% ethyl acetate at 10 mL/min over 50 minutes. Fractions containing product were combined and concentrated under reduced pressure to provide the product as a tan solid (yield: 149.9 mg, M.p.>230 OC. 1 H NMR (300 MHz, DMSO) 8 9.49 1H), 8.00 1H), 7.69 J 17.4 Hz, 2H), 7.43 J 16.8 Hz, 2H), 7.32 J 18.0 Hz, 2H), 6.78 J 18.0 Hz, 2H), 5.06 J 18.0 Hz, 2H), 3.13 3H), 2.68 2H), 1.02 J 12.0 Hz, 3H). MS (DCI-NH3) m/z 466 Anal.
calc. for C20H15F3N403S: 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-(methvlsulfonyl)phenyll-3(2H)-pyridazinone 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, M.p. 206-208 1H NMR (300 MHz, CDCI3) 8 7.90 1 7.77 1H), 7.71 J 18.0 Hz, 2H), 7.28 J 17.4 Hz, 2H), 6.61 (br s, 1 6.46 (br s, 1H), 6.31 (br s, 1H), 4.90 J 17.4 Hz, 2H), 3.72 3H), 2.94 3H). MS (DCI-NH3) m/z 539 Anal. calc. for C21H17F6N304S: C, 48.37; H, 3.29; N, 8.06. Found: C, 48.60; H, 3.33; N, 7.94.
Example 311 2-(2.2.2-Trifluoroethyl)-4-anilino-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone The product was prepared according to the method of Example 309 substituting aniline in place of 4-aminobenzonitrile to provide a tan solid (yield: mg, M.p. 154-156 OC. 1 H NMR (300 MHz, CDCI3) 8 7.89 (br s, 1 7.72 (s, 1H), 7.62 J 18.0 Hz, 2H), 7.19 J 18.0 Hz, 2H), 7.96-7.82 3H), 6.61 (d, J 14.4 Hz, 2H), 4.90 J 18.0 Hz, 2H), 2.94 3H). MS (DCI-NH3) m/z 424 m/z 441 Anal. calc. for C 19H16F3N303S: C, 53.90; H, 3.81; N, 9.92. Found: C, 53.87; H, 3.73; N, 9.89.
-183- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 312 2-(2.2.2-Trifluoroethyl)-4-(2 .5-dimethoxyphenylamino)-5-[4-(methylsufonyl)phenyl- 3 (2 H)-pyridazi none 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, M.p. 95-96 00. 1 H NMR (300 MHz, CDCI3) 6 7.78 (br s, 1 7.72 1 7.63 J 18.0 Hz, 2H), 7.18 J 18.0 Hz, 2H), 6.54 J 18.0 Hz, 1 6.38 (dd, J 6.0, 18.0 Hz, 1 4.89 J 18.0 Hz, 2H), 3.73 3H), 3.47 3H), 2.96 MS (DCI-NH3) m/z 484 m/z 501 Anal. calc. for 021 H20F3N 3 05S: 0, 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)pheny1-3(2H)pyridazi none The product was prepared according to the method of Example 309 substituting 3-fluoroaniline in place of 4-aminobenzonitriie to provide a tan solid (yield: 151.3 mg, M.p. 156-158 00. 1 H NMVR (300 MHz, DMS0) 6 9.18 (s, 1 7.91 1 7.62 J 17.4 Hz, 2H), 7.36 J 17.4 Hz, 2H), 6.88 (dd, J 15.0, 15.0 Hz, 1 6.56 (in, 1 6.49 (in, 2H), 5.04 J 18.0 Hz, 2H), 3.08 (s, 3H). MS (DCI-NH3) m/z 442 m/z 459 m/z 476 (M+2NH4-H)+.
Anal. calc. for C19qH1 5F4N3O3S.0.5 CH3C00H3: 0, 52.33; H, 3.85; N, 8.93.
Found: 0, 52.51; H, 3.58; N, 8.81.
Example 314 2-(2.2.2-Trifluoroethyl)-4-(2.4-difluoroanilino)-5-r4-(methylsu lfonyl)phenyll-3(2H)J- 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, M.p. 170-175 00. 1 H N MR (300 MHz, DMSO) 6 9.00 1 H), 7.80 1 7.57 J 17.4 Hz, 2H), 7.26 J 17.4 Hz, 2H), 7.05 (in, 1 6.75 (mn, 2H), 5.05 J 18.0 Hz, 2H), 3.09 3H). MVS (DCI-NH3) m/z 460 mlz 477 Anal. calc. for C19qH1 4F5N30 3 S: 0, 49.68; H, 3.07; N, 9.15; found: 0, 50.00; H, 2.95; N, 9.10.
-184- WO 99/10331 PCT/US98/16479 Example 315 2-(2.2.2-Trifluoroethyl)-4-(2.3.5-trifluoroanilino)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazinone 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, M.p. 190-194 1 H NMR (300 MHz, DMSO) 6 9.27 1 7.90 1 7.70 J 17.4 Hz, 2H), 7.39 J 17.4 Hz, 2H), 7.03 1H), 6.76 1H), 5.06 J 18.0 Hz, 2H), 3.14 3H). MS (DCI-NH 3 m/z 495 Anal. calc. for C19H13F6N303S: 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)phenvl]-3(2 Hpyridazinone 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, M.p. 158-160 C. 1 H NMR (300 MHz, CDCI3) 87.80 (br s, 1H), 7.69 1H), 7.65 J 18.0 Hz, 2H), 7.18 J 18.0 Hz, 2H), 6.63 J 3.6 Hz, 2H), 6.61 2H), 4.89 J 17.4 Hz, 2H), 2.96 3H). MS (DCI-NH3) m/z 459 Anal. calc. for C19H15F4N303S-1.25 H20: 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)phenyll-3 (2H)-pyridazinone 2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid (66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol), and tetrakis-(triphenylphosphine)-palladium(0) (13.9 mg, 0.012 mmol) in DME (25 mL) were stirred at reflux for 6 hours TLC (1CH2CI2:1 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 MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (0.5:2.5:0.5 CH2CI2/hexanes/ethyl acetate). A yellow powder was obtained (yield: 50 mg, 1H NMR (300 MHz, CDCI3) 6 3.09 3H), 5.41 (s, 2H), 6.72 (dd, J 1.5 Hz, 9 Hz, 1 7.13 (dd, J 3 Hz, 3 Hz, 1 7.3-7.45 -185- WO 99/10331 WO 9910331PCTIUS98/1 6479 7.5-7.6 (in, 3H), 7.78 1 7.92 9 Hz, 2H). MS (DCI-NH 3 m/z 423 Anal. caic. for 022 H18N203S2. 0.5 H20: 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-(methylsu If onyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 317, substituting 2-benzofuranboronic acid 3-thiopheneboronic acid (yield: 46 mg, 1 H NMR (300 MHz, CDCI3) 6 3.13 3H), 5.5 2 6.85-6.92 (in, 1 H), 7.15-7.25 (in, 3H), 7.3-7.42 (in, 3H), 7.45-7.7 (mn, 5H), 7.79 1 H) 8.0 J 9 Hz, 2H), 8.08 1 MS (DCI-NH3), in/z 457 Anal. calc. for C26H20N2O4S-H2O: 0, 65.80; H, 4.67; N, 5.90. Found 0, 65.44; H, 4.42; N, 6.14.
Example 319 2-Benzyl-4-(1 .3-dihydro-1 -oxo-5-isobenzofuranyl)-5-[4-(inethylsulfonyl)p2henyll- 3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 221 substituting 2-benzyl-4-ch lo ro-5-[4-(methylsulIfo nyl) phe nyl]-3(2 H)-pyridazi none, prepared in Example 78, in place of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4- (inethylsuIf onyl)- phe nyl]-3 (2 H)-py ridcazi none (yield: 112 mng, M.p. 250 00.
1 H NMR (300 MHz, DMSO-d6) 6 3.20 3H), 5.34 2H), 5.36 2H), 7.30-7.44 (in, 6H), 7.48 J 8 Hz, 2H), 7.57 1 7.73 J 8 Hz, 1 7.85 J 8 Hz, 2H), 8.17 1 MS (DCI-NH3) m/z 473 490 Anal. calc. for 026H20N205S: C, 65.46; H, 4.33; N, 5.87. Found: C, 65.56; H, 4.48; N, 5.75.
Example 320 2-Be nzy 1-4- (5-ch lo ro-2-thi enyl)-5-[4-(m ethyl suIfo nyl)ph en Yll-3 (2 H)-pyri dazi no ne The title compound was prepared according to the method of Example 317, substituting 4-chloro-2-thiopheneboronic acid in place of 3-thiopheneboronic acid (yield: 21 mg, 1 H NMVR (300 MHz, CDCI3) 863.15 3H), 5.45 2H), 6.51 J 4.5 H z, 1 6.7 J 4.5 H z, 1 7.3 -7.4 (mn, 3 7.5 7.6 (in, 4 7.6 (s, 1 8.05 J 9 Hz, 2H). MS (DCI-NH3), m/z 457 Anal. calc. for C18H15CIN203S: C, 57.68; H, 4.03; N, 7.47. Found C, 57.61; H, 3.84; N, 7.14.
-18 6- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 321 2-Benzyl-4-(3-nitrophenyl)-5-[4-(methylsu lfonyl)phenyl]-3 (2H)-pyridazinone 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 1 H NMR (300 MHz, CDCI3) 5 3.0 3H), 5.93 2H), 7.6-7.8 (in, 9H), 7.8 J 4.5 Hz, 3H), 8.04 1 8.15 (mn, 1 MS (DCI-NH3), in/z 462 Anal. calc. for 024 H1 9N305S. 0.75 H20: 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)phenyll-3(2H)-pyridazi none The title compound was prepared according to the method of Example 317, substituting 4-vinylbenzeneboronic acid in place of 3-thiopheneboronic acid (yield: mng, 1 H NMR (300 MHz, 0D013) 8 3.05 3H), 5.28 J 12 Hz, 1 H), 5.41 2H), 5.74 J 18 Hz, 1 H) 6.65 (dd J 12 Hz, 18 Hz, 1 7.1-7.6 (in, 11 H) 7.83 J 3 Hz, 2H), 7.85 1 -MS (DCI-NH3), in/z 443 Anal.
calc. for C26 H22N203S: 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)-5-14-(methylsulfonyl)phenyll-3(2H).
pyrifldaznn The title compound was prepared according to the method of Example 317, substituting 4-(trifluoroinethyl)benzeneboronic acid in place of 3-thiopheneboronic acid (yield: 101 ing, 1 HNMR (300 MHz, CDCI3) 8 3.05 3H), 5.42 2H), 7.3-7.5 (mn, 8H), 7.55-7.6 m, 3H), 7.85 2H), 7.9 1 MS (DCI-NH3) in/z 485 Anal. calc. for 025H1 9F3N2O3S-0.25 H20: 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-inethoxyphe nyl)-5-[4-(inethylsu lfonyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 317, substituting 2-methoxybenzeneboronic acid in place of 3-thiopheneboronic acid *(yield: 75 ing, 1 H NMR (300 MHz, CDCI3) 8 3.01 3H), 3.5 3H), 5.40 (dd, J 12 Hz, 18 Hz, 2H), 6.76 J 9 Hz, 1 6.85-6.95 (mn, 1 7.09 (dd, J Hz, 9 Hz, 1 7.26-7.41 (in, 6H), 7.55 (dd, J 1.5 Hz, 9 Hz, 2H), 7.82 J -9 -187- WO 99/10331 WO 9910331PCTIUS98/16479 Hz, 3H). MS (DCI-NH3) m/z 447 Anal. caic. for 025H22N20 4 S*0.5 C, 65.91; H, 5.08; N, 6.14. Found C, 65.86; H, 5.08; N, 5.58.
Example 325 2-Benzyl-4-(3 .4-dimethylphenyl)-5-(4-(methylsulfonyl)phenyll-3(2H)-p2yridazinone 2-Benzyl-4-chloro-5-[4-(methylsulIfonyl)phenyl]-3(2H)-pyridazi none (1 50 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)palladium (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 MgSO4, 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, 1 H NMR (300 MHz, CDCI3) 8 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 (in, 3H), 7.30-7.40 (in, 4H), 7.42-7.60 (in, 2H), 7.70-8, 02 (in, 4H). MS (DCI-NH3) m/z 445 Anal. caic. for C26H24N203S.H20: C, 67.51; H, 5.66; N, 6.05. Found: C, 67.45;H, 5.56; N, 5.85.
Example 326 2- Ben zyl-4- (3-f luo ro-4-methoxypheny (met hylsuIf on yl)phen Yll-3 (2 H)- The title compound was prepared according to the method of Example 325, substituting 3-fluoro-4-methoxybenzeneboronic acid in place of 3 ,4-di methylbenzeneboronic acid (yield: 35 ing, 1 H NMR (300 MHz, CDCI3) 6 3.05 (s, 3H), 3.85 3H), 5.3, 5.4 (2s, 2H), 6.75-7.03 (in, 3H), 7.3-7.40 (in, 5H), 7.4-7.55 (dd, J 1.5 Hz; 7.5 Hz, 2H), 7.8-7.95 (mn, 3H). MS (DCI-NH3) in/z 465 Anal.
calc. for C25H21 N2O4S-0.25 H20: C, 64.02; H, 4.62; N, 5.97. Found: C, 63.93; H, 4.54; N, 5.43 Example 327 2-BenzyI-4-f3-(2-inethoxypyridyl)1-5-f4-(inethylsulfonyl)phenyll-3(2H)-pyridazi none The title compound was prepared according to the method of Example 325, substituting 2-methoxy-3-pyridylboronic acid in place of 3 ,4-dimiethylbenzeneboronic acid (yield: 35 ing, 1 H NMR (300 MHz, CDC13) 863.05 3H), 3.58 3H), 5.4 (dd, J 15 Hz, 18 Hz; 2H), 6.88 (in, 1 7.28-7.40 (mn, 5H), 7.5-7.6 (dd, -188- WO 99/10331 WO 9910331PCT/US98/1 6479 J 1.5 Hz; 7.5 Hz, 3H), 7.82 1 7.85 J 18 Hz, 2H), 8.15 (br s, 1 MS (DCI-NH3) m/z 448 Anal. caic. fo *r 024H21 N304S: 0, 64.42; H, 4.73; N, 9.39. Found: C, 64.17; H, 5.11; N, 9.04 Example 328 2-Benzvl-4-(3-ethoxyphenyl)-5-[4-(methylsu lfo nyl)phenyll-3 (2 H)-pyridazi none 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, 1 H NMR (300 MHz, CDCI3) 861.31 J 7.5 Hz, 3H), 3.05 3H), 3.89 J =7.5 Hz, 2H), 5.14 2H), 6.65 J 9 Hz, 1 6.72 J Hz,'1 6.8 (dd, J =1.5 Hz, 9 Hz,. 1 7.15 J 9 Hz, 1 7.3-7.4 (in, 7.5-7.6 (in, 2H), 7.85 J 9 Hz, 3H). MS (DCl-NH3) m/z 461 Anal. calc.
for 026H24N204S-0.5H20: C, 66.50; H, 5.36; N, 5.96. Found: 0, 66.39; H, 5.02; N, 5.77 Example 329 2-BenzyI-4-(4-f luorobenzyl)-5-f4-(methylsulfo nyl)phenyIl-(2 H)-pyridazi none 329A. 2-Benzyl-4.5-dibromo-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 1 94A, substituting benzyl hydrazine hydrochloride in place of 4-fluorophenyl hydrazine hydrochloride (yield: 7.86 g, 1 H NMR (300 MHz, DM50S d6) 6 5.27 2H), 7.26-7.41 (mn, 5H), 8.19 1 MS (DCI-NH 3 m/z 345 362 329B. 2-Benzyl-5-bro mo-4-methoxy-3 (2H)-pyridazi none The title compound was prepared according to the method described in Example 194B, substituting 2-be nzyl-4,5-dibroino -3(2 H)-pyridazi none for 2-(4f luorophenyl)-4,5-dibromo-3(2 H)-pyridazi none (yield: 2.877 g; 1 H NMVR (300 MHz, DMSO-d 6 6 4.14 3H), 5.23 2H), 7.26-7.38 (in, 5H), 8.11 1 MS
(DCI-NH
3 m/z 295 312 (M+NH4)+.
329C. 2 Benzyl-4- met hoxy-5[4- (m eth ylthi o) phe ny 1-3 (2H) -pyridazi none The title compound was prepared according to the method described in Example 6, substituting 2-benzyl-4-methoxy-5-bromo-3(2 H)-pyridazinone for 2- -189- WO 99/10331 WO 9910331PCTIUS98/1 6479 be nzyl-4-methoxy-5-bromo-3 (2 H)-pyri dazi none (yield: 3.705 1 H NMR (300 MHz, DMSO-d6) 8 2.52 3H), 3.99 3H), 5.28 2H), 7.26-7.41 (in, 7H), 7.55 (in, 2H), 8.02 1 MS (DCI-NH3) m/z 339 356 (M+NH4)+.
3290. 2-Benzyl-4-(4-f luorobenzyl-5-[4-(methylsu lfonyl)phenyl]-3(2 H)-pvridazi none The title compound was prepared according to the method of Example 233, substituting 4-fluorobenzyl magnesium chloride in place of cyclohexylinagnesiuin chloride and 2-benzyl-4-inethoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone was substituted in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(inethylthio)phenyl]- 3 (2 H)-pyridazi none.
3290. 2-Benzyl-4-methoxy-5-14-(methvlsulfonyl)phenyl]-3(2H)-pyridazinone The sulfide compound (Example 329D) was oxidized to the methyl sulfonyl compound according to the method of Example 10. M.p. 186-189 00. 1 H NMR (300 MHz, DM50S d6) 863.27 3H), 3.83 2H), 5.31 2H), 6.94-7.05 (nn, 4H), 7.27-7.40 (mn, 5H), 7.67 (in, 2H), 7.94 1 8.03 (in, 2H). MS (DCI-NH3) in/z 449 466 Anal. calc. for 025H21 FN2O3S: 0, 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-(inethylsuIf onyl)phe nyl1-3(2 H)-pyridazi none 330A. 2-(tert.-Butyl)-4.5-dichloro-3(2H)-pyridazi none A solution of mucochloric acid (33.8 g, 200 minol) and tert.-butylhydrazine hydrochloride (24.9 g, 200 inmol) in methanol (400 mL) was stirred at reflux overnight. Methanol was removed in vacua and the residue was partitioned between ether and water. The organic layer was dried over MgSO4 and filtered.
The filtrate was concentrated in vacua 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, M.p. 63-6400C 1 H NMR (300 MHz, 00013) 51.65 9H), 7.73 1 H).
MS (DCI-NH3) m/z 221 238 (M+NH4)+.
330B. 2 -(tert.-Butyl)-4-(3-inethylbutoxy)-5-chloro-3 (2 H)-pyridazi none A stirred, room temperature solution of 3-methyl-i -butanol (0.5 inL, 4.52 inmol) in tetrahydrofuran (10 inL) was treated with a 60% oil suspension of sodium hydride (0.24 g, 5.88 iniol). After 5 minutes, hydrogen gas evolution had subsided, so the dichloro-intermediate from Example 330A (1.0 g, 4.52 inmol) was -190- WO 99/10331 PCT/US98/16479 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 MgSO4, 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, 1H NMR (300 MHz, CDCI3) 8 0.95 J 6 Hz, 6H), 1.63 9H), 1.64 J 6 Hz, 2H), 1.85 (nonet, J 6 Hz, 1 4.49 J 6 Hz, 2H), 7.64 1 MS (DCI-NH 3 m/z 273 290 (M+NH4)+.
330C. 2-(tert.-Butvl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenvl]-3(2H)pyridazinone A solution of the intermediate from Example 330B (700 mg, 2.57 mmol), 4- (methylthio)benzeneboronic acid (560 mg, 3.34 mmol), cesium carbonate (2.17 g, 6.67 mmol), and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.18 mmol) in dimethoxyethane (40 mL) was heated 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, 1 H NMR (300 MHz, CDCI3) 5 0.81 J 6 Hz, 6H), 1.49 J 6 Hz, 2H), 1.63 (nonet, J 6 Hz, 1H), 1.69 9H), 2.52 (s, 3H), 7.32 J 9 Hz, 2H), 7.50 J 9 Hz, 2H), 7.73 1H). MS (DCI) m/z 361 330D. 2-(tert.-Butvl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example substituting 2-(tert.-butyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone for 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 188 mg, M.p. 138-139°C. 1 H NMR (300 MHz, CDCI3) 5 0.81 J 6 Hz, 2H), 1.48 J 6 Hz, 2H), 1.48-1.68 1 1.69 9H), 3.10 3H), 4.38 J 6 Hz, 2H), 7.71 1 7.74 J 9 Hz, 2H), 8.03 J 9 Hz, 2H). MS (DCI-NH3) m/z 393 (M+H) Anal. calc. for C20H28N204S: C, 61.20; H, 7.19; N, 7.14. Found: C, 61.13; H, 7.23; N, 6.89.
-191- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 331 2-(3-Chlorophenyl)-4-methoxy-5-[4-(methylsu lfonyflphenyfl-3(2 H)-pyridaine The title compound was prepared according to the method of Example substituting 2-(3-chlorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)pyridazinone (Example 2070) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 3.31 g, M.p. 112-114 00. 1 H NMR (300 MHz, DMVSO d6) 8 3.31 (in, 3 4.10 (in, 3H), 7.52-7.65 (mn, 3H), 7.75 (in, 1 H), 7.90 (in, 2H), 8.07 (mn, 2H), 8.21 1 MS (DCI-NH3) m/z 391 408 Anal. calc. for: C18H15CIN2O4S.0.25 H20: 0, 54.68; H, 3.95; N, 7.08.
Found: 0, 54.59; H, 3.65; N, 6.98.
Example 332 2-(3-Chlorophenyl)-4-hydroxy-5-[4-(methylsulfonvl)phenyll-3 (2H)-pyridaznn A suspension of 2-(3-chlorophenyl)-4-(methoxy)-5-[4-(methylsulfonyl)phenyl]-3(2 H)-pyridazi none (6.26 g, 16 mmol) in 5% NaOH (54 inL) 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 1 N HOI, with constant stirring. The resulting white solid was filtered and rinsed with H20 and left to dry overnight. The mostly dry product was taken up in 0H2CI2 and azeotroped with toluene to remove any remaining H20, to provide the desired product as a white solid (yield: 6.79 g, >1 1 H NMR (300 MHz, DMSO d6) 6 2.27 3H), 7.51-7.62 (mn, 2H), 7.68 (in, 1 7.79 (in, 1 8.03 (in, 4H), 8.24 (s, 1 MS (DC l-NH3) m/z 377 396 (M+NH4)+.
Example 333 2-(3-Chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl-3(2H)-pyridazi none To a 0 00 solution of 2-(3-ch lorophenyl)-4-hydroxy-5-[4-(methylsu Ifonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 332, (6.79 g, 16 minol) in pyridine (160 mL) was added p-toluenesulfonyl chloride (3.06 g, 16 minol). The solution was left to warm slowly to room temperature with stirring under nitrogen.
After 2.5 hours, the mixture was poured into H20 with constant stirring. The resulting off-white solid was filtered, rinsed with H20 and dried to provide the desired product (yield: 6.26 g, M.p. 198-20000C 1 H NMR (300 MHz, d6) 5 2.35 3H), 3.28 3H), 7.20 (mn, 2H), 7.52-7.64 5H), 7.70 (in, 3H), 7.89 (in, 2H), 8.32 1 MS AP0I+ 531 548 APCI-493 -192- WO 99/10331 PCT/US98/16479 Anal. calc. for C24H19CIN206S2: C, 54.29; H, 3.61; N, 5.28. Found: C, 54.55; H, 3.46; N, 5.57.
Example 334 2-(3-Chlorophenyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone A solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone, prepared in Example 332, in POC13 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 H20, dried over MgSO4, and concentrated to a solid. The crude product was purified using flash chromatography (SiO2, eluting with 1:1 ethyl acetate/hexanes) to provide the desired product (yield: 0.151 g, M.p. 203-204 1 H NMR (300 MHz, DMSO d6) 8 3.29-3.36 (3H, obstructed by H20), 7.60 3H), 7.76 1 7.92 2H), 8.14 2H), 8.25 1H). MS (DCI-NH3) m/z 395 412 (M+NH4)+.
Anal. calc. for C17H12Cl2N203S: 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)phenyll-3(2H)pyridazinone To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added isobutanol (0.03 mL, 0.33 mmol), and NaH (0.0132 g, 0.33 mmol). The resulting solution was stirred under nitrogen for 1 hour.
The reaction was poured into H20 and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.1088 g M.p. 166-169 1 H NMR (300 MHz, DMSO d6) 8 0.78 J 6 Hz, 6H), 1.84 1H), 3.29 3H), 4.20 J 6 Hz, 2H), 7.51-7.63 3H), 7.76 1H), 7.92 2H), 8.07 2H), 8.21 1H). MS (DCI- NH3) m/z 433 450 Anal. calc. for C21 H21 CIN204S: C, 57.07; H, 5.01; N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.
-193- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 336 2-(Q3-Ch loro ph en (t-butoxy)-5-[4- (met hylsu Ifonvl) Qhe nyll-3 (2 H)-pyrdazi noneg The title compound was prepared according to the method of Example 335, substituting t-butanol in place of isobutanol (yield: 0.093 g, M.p. 232-235 00.
1 H NMR (300 MHz, DMS0 d6) 6 1.18 9H), 3.30 3H), 7.52-7.64 (in, 3H), 7.74 (in, 1 7.92 (mn, 2H), 8.08 (in, 2H), 8.20 1 MS (DOI-NH3) in/z 433 450 Anal. cab,. for C21 H21 CIN2O4S: C, 58.26; H, 4.89; N, 6.47.
Found: 0, 58.21; H, 4.88; N, 6.28.
Example 337 1 0 2-(3-Chlorophenyl)-4-(cyclohexyloxy)-5-[4-(methylsulfonyl)phenyli-3(2H)pyridazi none The title compound was prepared according to the method of Example 335, substituting cyclohexanol in place of isobutanol (yield: 0.139 g, semi-solid; 1 H NMR (300 MHz, 00013) 81.09-1.50 (in, 6H), 1.57 (in, 2H), 1.88 (in, 2H), 3.13 (s, 3H), 5.19 (in, 1 7.38-7.48 (mn, 2H), 7.59 (in, 1 7.70 (in, 1 7.83 (in, 2H), 7.92 1 8.07 (in, 2H). MS APCI+ 459 476 APCI-458 493 Anal. calc. for C23H23ClN204S-O.25 H20: 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-di methylpropoxy)-14-(inethylsu lfonyl)Dhenyl]-3(2H)pyridazi none The title compound was prepared according to the method of Example 335, substituting neopentyl alcohol in place of isobutanol (yield: 0.109 g, M.p.
151-153 00. 1 H NMR (300 MHz, DMVSO d6) 6 0.78 9H), 3.29 3H), 4.10 (s, 2H), 7.52-7.64 (in, 3H), 7.76 (mn, 1 7.92 (in, 2H), 8.07 (in, 2H), 8.20 1 MS (DCI-NH3) m/z 447 464 Anal. calc. for C22H23CIN204S: 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-nethylbutoxy)--4-(methylsulfonyl)phenyll-3(2
H)-
pyridz non The title compound was prepared according to the method of Example 335, substituting 3-methyl-i -butanol was substituted in place of isobutanol (yield: 0.229 g, M.p. 134-135 OQ. 1 H NMR (300 MHz, DM50S d6) 6 0.79 J 6 Hz, 6H), 1.42-1.64 (in, 3H), 3.30 3H), 4.43 J 6 Hz, 2H), 7.52-7.65 (in, 3H), 7.76 -194- WO 99/10331 WO 99/033 1PCTIUS98/1 6479 (in, 1 7.90 (in, 2H), 8.07 (in, 2H), 8.21 1 MVS (DCI-NH3) m/z 447 464 Anal. calc. for C22H2301N204S: C, 59.12; H, 5.19; N, 6.27. Found: C, 58.91; H, 5.12; N, 6.01.
Example 340 2-(3-Chlorop~henyl)-4-(3-oQctyn-1 -yloxv'-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridaziona 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, Oil. 1 H NMR (300 MHz, CDCI3) 6 0.88 (in, 3H), 1.25-1.44 (in, 4H), 2.05 (in, 2H), 2.52 (in, 2H), 4.68 J 6 Hz, 2H), 7.43 (in, 2H), 7.59 (mn, 1 7.70 (in, 1 7.86 (in, 2H), 7.92 (s, 1 MS (DCI-NH3) m/z 485 Anal. caic. for C25H25CIN2O4S: C, 61 .94; H, 5.20; N, 5.78. Found: 0, 61.82; H, 4.99; N, 5.57.
Example 341 2-(3-C hlorophe nyl)-4-(2-(dimethylami no)ethoxyl-5-f 4-(inethylsulfonyl)phe nyl]- 3 (2H)-pyridazi none 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, M.p. 110-113 OC. 1 H NMR (300 MHz, DMSO d6) 8 2.29 (bs, 6H), 2.68 (bs, 2H), 4.68 J 5 Hz, 2H), 7.38-7.48 (in, 2H), 7.57 (in, 1 7.68 (in, 1 7.89 (in, 2H), 8.07 (mn, 2H). MS (DCI-NH 3 m/z 448 Anal. calc. for 021 H22CIN 3 0 4 S.0.50 H20: 0, 55.19; H, 5.07; N, 9.19. Found: 0, 55.24; H, 4.97; N, 9.07.
Example 342 2-(3-Chlorophenyl)-4-[2-methyl-1 -methylethvl)p2ropoxyl-5-f4-(methylsulfonyl)phenyll]-3(2H)-pyridazi none 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; 1 H NMR (300 MHz, DMS0 d6) 80.79 (in, 12H), 1.78-1.92 (in, J 6 Hz, 2H), 3.29 3H), 5.40 J 6 Hz, 1 7.57 (in, 3H), 7.72 (in, 1 7.91 (mi, 2H), 8.07 (mn, 2H), 8.17 (mn, 1 MS (DOI-NH 3 in/z 475 492 Anal.
caic. for C24H2701N204S (0.75 H20): 0, 59.00; H, 5.88; N, 5.78. Found: C, 58.83; H, 5.74; N, 5.52.
-195- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 343 2-(3-Ch lorophenyl)-4-(phenoxy)-5-[4- (methylsulfonyl)phenyl]-3(2H)vpyridazi none The title compound was prepared according to the method of Example 335, substituting phenol in place of isobutanol (yield: 0.053 g, M.p. 205-207 00.
1 H NMR (300 MHz, DMVSO d6) 8 3.28 3H), 7.08 (in, 7.31 (m 2H), 7.50-7.64 (in, 3H), 7.73 (in, 1 7.90 (in, 2H), 8.05 (in, 2H), 8.40 1 MS (DCI-NH3) m/z 453 470 Anal. calc. for 023 H17CIN2O4S: C, 60.99; H, 3.78; N, 6.19. Found: 0, 60.79; H, 3.65; N, 5.87.
Example 344 2-(3-Chlorophenyl)-4-[3-(dimiethylainino)phenvl]-5-[4-(inethylsulfony1)o2henyl- 3(2H)-pyridazinone The title compound was prepared according to the method of Example 335, substituting 3-(diinethylainino)phenol in place of isobutanol (yield: 0.057 g, M.p. 191-1 93; 1 H NMR (300 MHz, DM50S d6) 6 2.85 3.27 3H), 6.36 (in, 3H), 7.05 (in, 1 7.51 -7.63 (in, 3H), 7.72 (in, 1 7.90 (in, 2H), 8.05 (in, 2H), 8.39 1 MS APCI+ 495 APCI-, 495 590 Anal. calc. for C25H22C1N304S: 0, 60.54; H, 4.47; N, 8.47. Found: C, 60.04; H, 4.49; N, 8.26.
Example 345 2-(3-Chlorophe nyl)-4-(4-methoxyphenoxy)-5-[4-inethylsulfonyl)pheny1]-3(2H)pyriazion The title compound was prepared according to the method of Example 335, substituting 4-methoxyphenol in place of isobutanol (yield: 0.080 g, M.p.
182-1 84 00. 1 H NMVR (300 MHz, DM50S d6) 6 3.27 3H), 3.70 3H), 6.84 (in, 2H), 7.00 (in, 2H), 7.56 (in, 3H), 7.72 (in, 1 7.90 (in, 2H), 8.04 (in, 2H), 8.38 (s, 1 MS (DCI-NH3) m/z 483 500 Anal. calc. for C24H-1901N20 5 S: 0, 59.64; H, 3.97; N, 5.80. Found: C, 59.86; H, 3.94; N, 5.62.
Example 346 2-(3 Dif luorophenyl)-4-(2-methylpropoxy)-5-[4-(inethylsulfonyl)phenyll-3 (2H)pyridazi none The title compound was prepared according to the method of Example 335, substituting 2- (3,4-dif luoro phe nyl)-4-tosyloxy-5-[4- (mnethyIsuIto nyl) ph eny l]-3 (2H) pyridazinone in place of 2-(3-ch lo rophe nyl)-4-tosyloxy-5-[4- (met hyl su Ifony1) phenyl]-3(2H)-pyridazinone (yield: 150 mg, 61%) M.p. 116-11700C 1 H NMR (300 -196- WO 99/10331 WO 9910331PCT/US98/1 6479 MHz, DMSO-d6) 860.78 6H), 1.84, (in, 1 3.3 3H), 4.2 2H), 7.54 (in, 1 H), 7.6 (in, 1 7.82 (in, 1 7.91 2H), 8.07 2H), 8.21 1 MS (DCI-NH3) m/z 435 452 Anal. caic. for C21 F2H-20N\204S: C, 58.06; H, 4.64; N, 6.45.
Example 347 2-(3.4-Difluorophenyl)-4-(3-methyl-1 -butoxy)-5-[4-(methylsulfonyl)p2henyll-3(2 HpyLidznne The title compound was prepared according to the method of Example 346 substituting 3-methyl-i -butanol in place of isobutanol (yield: 63 mng, M.p.
121-123 C. 1 H NMR (300 MHz, DMSO-d6) 560.78 6H), 1.48, (mn, 3H), 3.3 (s, 3H), 4.43 2H), 7.54 (in, 1 7.6 (in, 1 7.82 (in, 1 7.91 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.2 1 MS (DCI-NH3) m/z 449 466 (M+NH4)+.
Anal. calc. for C22H22F2N204S: C, 58.92; H, 4.94; N, 6.25. Found, C, 59.22; H, 4.97; N, 6.07.
Example 348 2-(3 .4-Difluorophenyl)-4-(4-fluorophenoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]- 3 (2H)-pyridazi none The title compound was prepared according to the method of Example 346, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[3-fluoro-4-(methylsulfonyl)phenyl]- 3 (2H)-pyridazi none in place of 2-(3-difluorophenyl)-4-tosyloxy-5-[4-(methylsuIf onyl)phenyl]-3(2H)-pyridazi none and substituting 4-fluorophenol in place of isobutanol M.p. 168-1 70 0 C. 1 H NMR (300 MHz, DMSO-d6) 6 3.39 3H), 7.15 (d, 4H), 7.51 (in, 1 7.6 (in, 1 H) 7.75 (in, 3H), 7.97 1 8.4 1 MS (DCI-NH3) mlz 491 508 Anal. calc. for 023H14F4N204S: C, 56.33; H, 2.88; N, 5.71. Found, C, 56.07; H, 2.94; N, 5.33.
Example 349 2-Q3.4- Dif luorophe nyl)-4- (2.2-di methylpropoxy)-5-[ 4- (met hylsu IfonYl)phe nyl-3(2H)pyridazi none The title compound was prepared according to the method of Example 346 substituting neopentyl alcohol in place of isobutanol (yield: 1.18 g, M.p. 126- 128 00. 1 H NMVR (300 MHz, DMSO-d 6 6 0.78 9H), 3.3 3H), 4.1 2H), 7.51 (in, 1 7.6 (in, 1 7.82 (in, 1 7.91 J 9 Hz, 8.07 J 9 Hz, 2H), 8.21 -197- WO 99/10331 WO 9910331PCTJUS98/1 6479 1 MS (DC I-NH3) mlz 449 466 Anal. calc, for C22H22F2N204S: 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-f2-(isopropoxy)ethoxyl-5-[4-(methylsulfony)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 346 substituting 2-(isopropoxy)ethanol in place of isobutanol (yield: 432 mg, M.p.
105-107 0 C. 1 H NMR (300 MHz, DMSO-d6) 8 0.95 6H), 3.3 3H), 3.43 (in, 1 3.54 (in, 2H), 4.63 (in, 2H), 7.54 (in, 1 7.6 (in, 1 7.8 (in, 1 8.01 (in, 4H), 8.2 1 MVS (DCI-NH3) m/z 465 482 Anal. calc. for C22H22F2N205S: C, 56.89; H, 4.77; N, 6.03. Found, C, 57.03; H, 4.65; N, 5.83.
Example 3.51 2-(3.4-Difluorophenyl)-4-(3-inethylpentyloxy)-5-f4-(nethylsulfonyl)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 346 substituting 3-methylpentyl-1-ol in place of isobutanol (yield: 400 mg, M.p.
100-102 0 C. 1 H NMR (300 MHz, DMSO-d6) 8 0.75 (mn, 6H), 1.05 (in, 1 1.28 (mn, 3H) 1.6 (in, 1 3.3 3H), 4.45 (in, 2H), 7.5 (in, 1 7.6 (in, 1 7.8 (in, 1 7.9 J 9 Hz, 2H) 8.05 J 9 Hz, 2H), 8.2 1 MS (DCI-NH3) in/z 463 480 Anal. calc. for C23H24F2N204S: 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-inethyl-3-penten-1 -yloxy)-5-[4-(methylsulfonyl)pheyL]- 5-3(2 H)-pyridazi none 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 mng, 67.8%).
M.p. 88-90 00. 1 H NMR (300 MHz, DMSO-d6) 5 1.5 6H), 2.27 (in, 2H) 3.3 (s, 3H), 4.43 2H), 4.95 (in, 1 7.5 (mn, 1 7.6 (in, 1 7.8 (mn, 1 7.9 2H), 8.06 2H), 8.2 1 MS (DCI-NH3) m/z 461 478 Anal. calc. for C23H22F2N204S: C, 59.99; H, 4.82; N, 6.08. Found, C, 59.88; H, 4.76; N, 5.84.
-198- WO 99/10331 PCT/US98/16479 Example 353 2-(3.4-Difluorophenyl-4-[3-(methoxy)butoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 346 substituting 3-methoxybutyl-l-ol in place of isobutanol (yield: 350 mg, 68%) M.p.
99-101 1H NMR (300 MHz, DMSO-d6) 5 0.97 3H), 1.7 2H), 3.05 3H), 3.2 1 H) 3.3 3H), 4.45 2H), 7.54 1 7.6 1 7.8 1 7.9 J 9 Hz, 2H) 8.01 J 9 Hz, 2H), 8.2 1H). MS (DCI-NH3) m/z 465 482 Anal. calc. for C22H22F2N205S: C, 56.89; H, 4.77; N, 6.03. Found, C, 56.60; H, 4.83; N, 5.96.
Example 354 2-(3-Chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylsulfonyl)phenl]-3(2H)pyridazinone: To a rapidly stirred 0 °C mixture of N-methylbenzylamine (67.5 mg, 0.56 mmol) and tetrahydrofuran (3.7 mL) was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). The reaction mixture was stirred for minutes at 0 OC and 1 hour at 23 OC. The solution was cooled to -78 OC, 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 °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 MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:9) to provide 2-(3chlorophenyl)-4-(N-methyl benzylamino)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone (yield: 145 mg, 58%).
The title compound was prepared according to the method of Example substituting 2-(3-chlorophenyl)-4-(N-methylbenzylamino)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (yield: 143 mg, M.p. 60-85 1H NMR (300 MHz, CDCI 3 8 2.46 3H), 3.09 3H), 4.63 2H), 7.19 J 8.7 Hz, 2H), 7.24- 7.29 2H), 7.32-7.48 5H), 7.60 (ddd, J 7.2, 1.8, 1.8 Hz, 1 7.67 1 H), 7.70 (dd, J 1.8, 1.8 Hz, 1H), 7.91 J 8.7 Hz, 2H). MS (APCI+) m/z 480 -199- WO 99/10331 PCT/US98/16479 Example 355 2-(4-Fluorophenyl)-4-(1 -pieridinvl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to -78 °C was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at -78 °C for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23 oC.
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 x 6-7 mL aliquots) with a heat gun and cooled to 0 oC prior to transfer via syringe to the lithium amide solution (cooled to -78 The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23 °C as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg of 2-(4-fluorophenyl)-5-[4- (methylthio)phenyl]-4-piperidino-3(2H)-pyridazinone.
The title compound was prepared according to the method of Example substituting 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-4-piperidino-3(2H)pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone (yield: 165 mg, M.p. 80-100 1 H NMR (300 MHz, CDCI3) 8 1.59 (br s, 6H), 2.59 (br s, 4H), 3.14 3H), 7.17 (dd, J 8.7, 8.7 Hz, 2H), 7.51 J 8.7 Hz, 2H), 7.55-7.62 2H), 7.68 1H), 8.06 J 8.7 Hz, 2H).
MS (APCI+) m/z 428 Powdered out in CH2CI2/C6H14. Anal. calc. for C22H22FN303S-0.25C6H14: C, 62.85; H, 5.72; N, 9.35. Found: C, 62.46; H, 5.77; N, 9.13.
Example 356 2-(4-Fluorophenyl)-4-(1-pvrrolidinyl)-5-f4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound was prepared according to the method of Example 355, substituting pyrrolidine for piperidine (yield: 107 mg, M.p. 192-195 1 H NMR (300 MHz, CDCI3) 1.71-1.80 4H), 3.13 3H), 3.40-3.49 4H), 7.16 (dd, J 8.7, 8.7 Hz, 2H), 7.47-7.60 5H), 7.99 J 8.7 Hz, 2H). MS (APCI+) -200- WO 99/10331 WO 9910331PCT/US98/I 6479 mlz 414 Anal. caic. for 021 H2OFN3O 3 S: 0, 61.00; H, 4.87; N, 10.16.
Found: 0, 60.95; H, 4.94; N, 10.07.
Example 357 2-(3-Chlorophenyl)-4-(4-methylphenylthio)-5-[4-(methylsulfonyl)phenyll-3(2H)- To a stirred suspension of 2- (3-ch loro phe nyl)-4-tosyloxy-5-[4- (met hylsulIfonyl)phenyl]-3(2 H)-pyridazin one, 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 K2C03 (0.0203 g, 0.15 mmol). The suspension was heated to 5000C with stirring for hours. The mixture was poured into H20 with constant stirring. The resulting precipitate was filtered, rinsed with H20 and dried to provide the desired product (yield: 0.060 g, M.p. 178-17800C 1 H NMR (300 MHz, DMVSO d6) 8 2.19 (s, 3H), 3.23 3H), 6.95 (in, 2H), 7.08 (in, 2H), 7.52-7.66 (in, 3H), 7.72 (in, 1 7.88 (mn, 2H), 8.08 1 MS (DC l-NH3) mlz 483 500 Anal. calc.
for: C24H-19C1N203S2-0.75 H20: 0, 58.05; H, 4.16; N, 5.64. Found: 0, 57.99; H, 3.69; N, 5.76.
Example 358 2-(3-Chlorophenyl)v4-(2-pyridylthio)-5-44-(methylsulfonyl)Qhenyll-3(2H)- The title compound was prepared according to the method of Example 357, substituting 2-inercaptopyridine in place of thiocresol (yield: 0.061 g, M.p.
110-114 00C. 1 H NMR (300 MHz, DMVSO d6) 6 3.28 3H), 7.16 (in, 1 7.37 (in, 1 7.51-7.71 (mn, 5H), 7.81 (mn, 2H), 8.03 (mn, 2H), 8.27 1 8.34 (in, 1 MS (DCI-NH3) m/z 470 Anal. calc. for 022H16CIN303S2*0.50 H20: 0, 55.16; H, 3.57; N, 8.77. Found: 0, 54.88; H, 3.19; N, 8.59.
Example 359 2-(3-Chlorophenyl)-4-(phenylnethylthio).5-[4-(methylsulfonyl)phenylI-3(2H)pydzinone To a stirred suspension of 2-(3-chlo rophe nyl)-4-tosyloxy-5-[4-(inethylsuIf onyl)phenyl]-3(2H)-pyridazi none, prepared in Example 333, (0.175 g, 0.33 inmol) in THF (3.3 ml-) was added benzyl mercaptan (0.04 inL, 0.33 minol) and TEA (0.046 mL, 0.33 minol). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The mixture was poured into H20 and extracted with -201- WO 99/10331 PCT/US98/16479 ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.136 g M.p. 142-145 1H NMR (300 MHz, DMSO d6) 53.31 3H), 4.36 2H), 7.17 2H), 7.21-7.33 3H), 7.51 2H), 7.57-7.64 3H), 7.74 1 8.01 2H). MS (DCI-NH3) m/z 483 500 Anal. calc. for C24H19CIN203S2: 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)phenyll-3(2H)pyridazinone 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%).
M.p. 140-149 1 H NMR (300 MHz, DMSO d6) 83.31 3H), 4.46 2H), 6.20 1 6.37 1H), 7.50-7.67 6H), 7.77 1 8.03 2H), 8.08 1 H).
MS (DCI-NH3) m/z 473 490 Anal. calc. for C22H17CIN204S2: C, 55.87; H, 3.62; N, 5.92. Found: C, 55.84; H, 3.61; N, 5.82.
Example 361 2-(3-Chlorophenyl)-4-12-(methylpropyl)thio]-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone 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, Oil. 1H NMR (300 MHz, DMSO d6) 8 0.61 J 6 Hz, 6H), 1.54-1.69 (m, 1 2.91 J 6 Hz, 2H), 3.33 3H), 7.52-7.64 3H), 7.74 1 7.79 (m, 2H), 8.04 3H). MS (DCI-NH3) m/z 449 466 Anal. calc. for C21 H21 CIN203S2 (0.50 H20): C, 55.07; H, 4.84; N, 6.11. Found: C, 54.70; H, 4.64; N, 5.85.
Example 362 2-(3-Chlorophenyl)-4-(cyclopentyl)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazinone To a -78 °C solution of 2 -(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution was stirred under nitrogen less than 1hour with -202- WO 99/10331 PCT/US98/16479 warming to room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics were dried over MgS04 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.1328 g, M.p. 155-157 1H NMR (300 MHz, DMSO d6) 1.50 (m, 2H), 1.66 2H), 1.79 2H), 2.09 2H), 2.90 J 8 Hz, 1 3.26-3.37 (3H, obstructed by H20), 7.49-7.63 3H), 7.71 3H), 7.97 1 8.10 2H). MS (DCI-NH3) m/z 429 446 Anal. calc. for C22H21CIN203S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.
Example 363 2-(3-Chlorophenyl)-4-(3-methvlpropyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone The title compound, an oil, was prepared according to the method of Example 362, substituting isobutyl magnesium chloride in place of cyclohexylmagnesium chloride, (yield: 0.132 g, 1 H NMR (300 MHz, CDCI3) 0.77 J 6 Hz, 6H), 2.08 1 2.54 J 7 Hz, 2H), 7.36-7.46 2H), 7.56 2H), 7.62 1H), 7.73 2H), 8.11 2H). MS (DCI-NH3) m/z 417 434 Anal. calc. for C21 H21 CIN203S-0.50 H20: C, 59.21; H, 5.20; N, 6.57. Found: C, 59.27; H, 5.40; N, 6.12.
Example 364 2-(3-Chlorophenyl)-4-(cyclohexylmethyl)-5-[4-(methylsulfonvl)phenyll-3(2H)pvridazinone The title compound, an oil, was prepared according to the method of Example 362, substituting cyclohexylmethyl magnesium bromide in place of cyclopentyl magnesium chloride (yield: 0.0579 g, 1H NMR (300 MHz, DMSO d6) 0.66 2H), 1.03 3H), 1.50 6H), 1.61 1 2.46 1 3.27-3.42 (3H, obstructed by H20), 7.50-7.66 7.75 3H), 7.99 1H), 8.10 2H).
MS (DCI-NH3) m/z 457 474 Anal. calc. for C24H25CIN203S: C, 63.08; H, 5.51; N, 6.13. Found: C, 63.08; H, 5.47; N, 6.04.
-203- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 365 2-(3-Chlorophenyl)-4-(2-cyclohexylethyl)-5-[4-(methylsulfonyl)phenyl-3(2
H)-
pyridazi none The title compound was prepared according to the method of Example 362, substituting cyclohexylethyl magnesium bromide in place of cyclopentyl magnesium chloride (yield: 0.165 g, 1 HNMR (300 MHz, DM50 d6) 60.76 (in, 3H), 0.99-1.21 (mn, 5H), 1.31-1.62 (in, 8H), 2.42-2.56 (1 H, obstructed by DMS0), 3.25-3.34 (2H, obstructed by H20), 7.48-7.65 (in, 3H), 7.48-7.65 (in, 3H), 7.76 (in, 3H), 8.01 1 8.10 (in, 2H). MS (DCI-NH3) m/z 471 488 (M+NH4)+.
Anal. calc. for C25H27C1N20 3 S: C, 63.75; H, 5.78; N, 5.95. Found: C, 63.48; H, 5.70; N, 5.67.
Example 366 2-(3-Chlorophenyl)-4-(3- methylbutyl)-5-44-(methylsulfonyl)phenyl]-3(2H)- 12rdznn The title compound was prepared according to the method of Example 362, substituting 3-methylbutyl magnesium bromide in place of cyclohexylmagnesiuin chloride (yield: 0.0221 g, M.p. 60-65 00. 1 H NMR (300 MHz, DMSO d6) 6 0.75 J 7 Hz, 6H), 1.32-1.52 (in, 3H), 3.31 3H), 7.50-7.65 (in, 3H), 7.77 (in, 3H), 8.03 1 8.11 (in, 2H). MS (DOI-NH3) m/z 431 448 (M+NH4)+.
Anal. calc. for C22H2301N203S*0.25 H20: 0, 60.68; H, 5.43; H, 6.43. Found C, 60.29; H, 5.60; N, 6.17.
Example 367 2-(3-Ch lorophenyl)-4-benzyl-5-[4-(inethylsulfonyl)Qhenyll-3(2 H)-p2Yridazi none The title compound was prepared according to the method of Example 362, substituting benzyl magnesium chloride in place of cyclohexylmagnesiuin chloride.
M.p. 174-1 77 00 (yield: 25.9 g, 1 H NMR (300 MHz, DMSO d6) 6 3.30 3H), 3.91 (bs, 2H), 7.02 (in, 2H), 7.12-7.25 (in, 3H), 7.51-7.64 (in, 3H), 7.72 (in, 3H), 8.07 (in, 2H), 8.12 1 MS (DCI-NH 3 m/z 451 468 Anal. calc.
for C24H19CIN 2 0 3 S: 0, 63.92; H, 4.25; N, 6.21. Found: 0, 63.69; H, 4.28; N, 6.02.
Example 368 2-(3-C hlorophe nyl)-4-cyclo hexyl-5-[4- (methylsulf onyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the method of Example 362 substituting cyclohexylinagnesiuin chloride in place of cyclopentylmagnesiumn -204- WO 99/10331 WO 99/033 1PCT/US98/1 6479 chloride (yield: 0.099 g, M.p. 85-90 00. 1 HNMR (300 MHz, ODC 3 )861.01- 1.30 (in, 3H), 1.48-1.69 (in, 3H), 1.75 (in, 2H), 2.28 (in, 2H), 2.57 (in, 1 3.16 (s, 3H), 7.35-7.46 (in, 2H), 7.50-7.62 (in, 3H), 7.68 (in, 2H), 8.11 (in, 2H). MS (DCI- NH3) mlz 443 460 Anal. calc, for C23H2301N20 3 S (1.25 H20): 0, 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-fluorobe-rzyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazi none The title compound was prepared according to the method of Example 228, substituting 4-f luorobenzyl magnesium chloride in place of cyclopentyl magnesium chloride (yield: 0.1895 g, M.p. 183-185 00. 1 H NMR (300 MHz, DM50 d6) 6 3.25-3.36 (3H, obstructed by H20), 3.89 (bs, 2H), 6.97-7.09 (in, 4H), 7.50-7.64 (mn, 3H), 7.71 (in, 3H), 8.06 (in, 2H), 8.11 1 MS (DCI-NH3) mlz 469 486 Anal. calc. for C24H18CIFN2O3S: 0, 61.47; H, 3.87; N, 5.97. Found: C, 61.23; H, 3.84; N, 5.77.
Example 370 2-(3-C hlorophenyl')-4-.(4-inethylphenyl)-5-[4-(inethylsulfonyl)phenvl]-3(2
H)-
pyridazinone The title compound was prepared according to the method of Example 362 substituting p-tolylinagnesiumn bromide in place of cyclopentylmagnesium chloride (yield: 65 mg, M.p. 222-224 00. 1 H NMVR (300 MHz, DMSO-d6) 6 2.28 (s, 3H), 3.25 3H), 7.12 4H), 7.6 (in, 5H), 7.79 1 H) 7.9 J 9 Hz, 2H), 8.22 (s, 1 MVS (DCI-NH3) in/z 451 468 Anal. cab,. for C24H19CIN20 3 S.0.25 H20: 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-methylphenvl)--[4-(nethylsulfony)phenl].
3(2H)-pyridaz6 none 2- Dif Iluorophen yl)-4- (3-f luo ro-4- met hyl phenyl)-5-[4- (iethylth io) phen yl] 3(2H)-pyridazinone was prepared according to the method of Example 362, starting with 2-(3,4-difluorophenyl)-4-tosyboxy-5-[4-(inethylsulfonyl)phenyl]-3(2H)pyridazinone and substituting 3 -fluoro-4-inethylphenylmagnesium bromide in place of cyclohexyinagnesium chloride to provide the methyl sulfide compound.
-205- WO 99/10331 WO 9910331PCT[US98/1 6479 The methyl sulfide was oxidized according to the method of Example 10 to provide the title compound (yield: 265 mg, M.p. 204-206 1 H NMR (300 MHz, CDCI3) 8 2.25 (br s, 3H), 3.08 6.83 (dd, J 9 Hz, 1.5 Hz, 1 6.96 (dd, J 9 Hz, 1.5 Hz, 1 7.08 J 9 Hz, 1 7.23-7.33 (in, 1 7.41 J 9 Hz, 2H), 7.49-7.56 (in, 1 7.61-7.69 (mn, 1 7.93 J 9 Hz, 2H), 7.99 1 MS (DCI-NH3) in/z 471 488 Anal. calc. for C24H17F3N 2 0 3 S: C, 61.28; H, 3.62; N, 5.96. Found: C, 61.07; H, 3.95; N, 5.56.
Example 372 1 0 2-(3-C h lo rophenyl)-4- (Qhenethyfl-5-[ 4- (met hylsuIf onyl)Ph enyll-3 (2H)L--pyridazi none The title compound was prepared according to the method of Example 228, starting with 2-(3-chlorophenyl)-4-inethoxy-5-[4-(methylthio)phenyl]-3(2H)pyridlazinone in place of 2-(4-fluorophenyl)-4-methoxy-5-[4-(inethylthio)phenyl]- 3(2H)-pyridazi none and substituting phenethyl magnesium chloride in place of cyclohexylmagnesium chloride then oxidizing by the method of Example 10 (yield: 0.100 g, M.p. 142-145 00. 1 H NMVR (300 MHz, DM50S d6) 862.80 (in, 4H), 3.30 3H), 7.01 (in, 2H), 7.21 (in, 3H), 7.51 -7.60 (mn, 4H), 7.63 (mn, 1 7.78 (in, 1 8.03 (in, 3H). MS (DCI-NH3) in/z 465 482 Anal. calc. for C25H2101IN203S: 0, 64.58; H, 4.55; N, 6.02. Found: C, 64.24; H, 4.50; N, 5.90.
Example 373 2-(3-Ch Iorophenvl)-4-(2-methylpropoxy)-5-[3-f luoro-4-(methylsulfo nyl)phenyl]- 3(2H)-pyridazi none 373A. 2-(3-C hlorophenyl)-4-(2-inethylpropoxy)- 5-broino-3(2 H)-pyridazi none.
The title compound is prepared according to the method of Example 194B, starting with 2-(3-ch lorophenyl)-4,5-dibromo-3(2 H)-pyridazi none (Example 207A) in place of 2-(4-f luorophenyl)-4,5-dibro mo-3 (2H)-pyridazi none ans substituting 2methyl-1-propanol in place of methanol.
373B. 2 hlo rophe ny met hyl prooxy)- 543-f luo ro-4-(mgt hylt hio)p he ny 11 3 (2H)-pyridazi none The title compound is prepared according to the method of Example 6, starting with 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-broino-3(2 H)-pyridazi none in place of 2-benzyl-4-broino-5-inethoxy-3(2 H)-pyridazi none and substituting 3fluoro-4-(inethylthio)benzeneboronic acid (Example 72C) in place of 4fluorobenzeneboronic acid.
-206- WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 3730. 2-(3-Ch Iorophenyl)-4-(2-methyloropoxy)-5-r3-fluoro-4-(methylsulfonyl)p2henyll-3(2H)-pvridazi none The -methyl sulfide compound was oxidized according to the method of Example 10 to provide the title compound (yield: 0.73 g, 100%). M.p. 180-183 00.
1 H NMR (300 MHz, DMVSO d6) 6 0.82 J 6 Hz, 2H), 3.30-3.39 (3H, obstructed by H20) 4.25 J 6 Hz, 2H), 7.57 (in, 3H), 7.75 (in, 1 7.85 (in, 1 8.00 (in, 1 8.23 1 MS (DCI-NH3) m/z 451 468 Anal. calc. for 021 H2001FN 2 04S: 0, 55.94; H, 4.47; N, 6.21. Found: C, 55.73; H, 4.58; N, 6.01.
Example 374 2-(3-C h lorophenyl)-4-(benzyloxv)-5-[4-(methylsulf onyl)ph e nylI-3 (2 H)-pyridazi none To a stirred solution of 2-(3-chlorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none (Example 332) (0.100 g, 0.28 inmol) in DMF (2.8 ml-) was added benzyl chloride (0.32 mL, 0.28 mmol). The resulting solution was stirred with heating to 60 00 overnight. The solvent was removed in vacuc and the resulting residue partitioned between ethyl acetate and 10% citric acid. After extracting with ethyl acetate, the combined organics were dried over MgSO4 and concentrated in vacuo. The crude product was purified using flash chromatography (SiO 2 1:1 ethyl acetate: hexanes) to provide the desired product (yield: 0.096 g, M.p. 110-11300C 1 H NMR (300 MHz, DMSO d6) 83.39 3H), 5.48 2H), 7.29 (mn, 4H), 7.59-7.71 (in, 3H), 7.76 (in, 3H), 8.00 (mn, 2H), 8.21 1 MS (DCI- NH3) in/z 467 484 Anal. calc. for 024H1 901N204S: 0, 61.73; H, 4.10; N, 6.00. Found: 0, 62.00; H, 4.18; N, 5.93.
Example 375 2-(4-Fluorophenyl)-4-3-nethylbutoxy)-5-[4-(methylsulfonyl)phenyl-3(2H).
pyridazinone Fluorophenyl)-4-inethoxy-5-bromo-3 (2 H)-pyridazi none (Example 1 94B) is converted into 2-(4-fluorophenyl)-4-inetho xy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone according to the method of Example 1940 followed by the oxidation method in Example 10. The methoxy compound is convert ed to the 2-(3chlorophenyI)-4-hydroxy-5-[4-(nethylsulfonyl)phenyl]-3(2H)-pyridazinone, by treatment with NaOH according to the procedure of Example 332. The hydroxy compound is treated with p-toluenesulfonyl chloride according to the procedure of Example 333, to furnish 2 4 -fluorophenyl)-5-[4-(inethylsulfonyl)phenyl]-4-tosyloxy- 3(2 H)-pyridazi none.
-207- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 The title compound was prepared according to the method of Example 335, starting with 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)pyridazinone in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4tosyloxy-3(2H)-pyridazinone substituting 3-methyl-i -butanol in place of isobutanol (yield: 0.3932 g, M.p. 117-120 00. 1 HNMR (300 MHz, DM50S d6) 5 0.79 (d, J 6 Hz, 6H), 1.41 -1 .59 (in, 3H), 3.30 3H), 4.42 J 5 Hz, 2H), 7.36 (in, 2H), 7.65 (in, 2H), 7.90 (in, 2H), 8.06 (in, 2H), 8.18 1H). MS (DCl-NH3) in/z 431 448 Anal. calc. for 022H23FN204S: 0, 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-miethylpropoxy)-5-[4-(miethylsulfonyl)phenyl]-3(2
H)-
pyridazi none The title compound was prepared according to the method of Example 335, 1 5 substituting 2-(4-fluorophenyl)-5-14-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3chlorophenyl)-5-[4- (iethylsuIf onyl)phenyl]-4-tosyloxy-3(2 H)-pyridlazi none (yield: 0.486 g, 100%). M.p. 121-128 00. 1 H NMVR (300 MHz, DM50S d6) 850.78 J 7 Hz, 6H), 1.84 (in, 1 3.30 3H), 4.20 J 6 Hz, 2H), 7.37 (in, 2H), 7.66 (in, 2H), 7.92 (in, 2H), 8.07 (in, 2H), 8.19 1 MVS (DCI-NH3) in/z 417 434 Anal. calc. for 021 H21 FN204S-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-(methylsulfonvl'phenyll-3(2H)- -nQid-zio The title compound was prepared according to the method of Example 62, starting with 4-(4-fluorophenylinethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone and reacting with 1-iodo-4-fluorobenzene (yield: 0.0881 g, 78%).
M.p. 175-177 00. 1 H NMR (300 MHz, DM50S d6) 8 3.27-3.36 obstructed by 3.88 (bs, 2H), 6.98-7.09 (in, 4H), 7.34 (in, 2H), 7.65 (mn, 2H), 7.71 (in, 2H), 8.06 (in, 3H). MS (DCI-NH3) m/z 453 470 Anal. calc. for C24H1I8F2N203S: 0, 63.71; H, 4.01; N, 6.19. Found: 0, 63.61; H, 4.26; N, 6.03.
-208- WO 99/10331 WO 9910331PCT/US98/1 6479 Example 378 Flu oro phe nyl)-4-(3-methylbutyl)-5- [4-(methylsulf onyl)Phenyl..3( H)pyridazi none The title compound was prepared according to the method of Example 228, substituting 3-methylbutyl magnesium bromide in place of cyclohexylmagnesiumn chloride (yield: 0.325 g, M.p. 151-154 1 H NMR (300 MHz, DMS0 d6) 8 0.75 J 7 Hz, 6H), 1 .32-1.51 (in, 3H), 3.31 3H), 7.37 (in, 2H), 7.66 (mn, 2H), 7.77 (in, 2H), 8.00 1 8.10 (in, 2H). MS (DCI-NH3) mlz 415 432 Anal. calc. for C22H23FN203S-0.50 H20: C, 62.39; H, 5.71; N, 6.61.
Found: 0, 62.04; H, 5.78; N, 6.46.
Example 379 2-(Tetrahydro-2H-pyrano-2-yl)-4(-fluorophenyl)-5-14-(inethylsu lfonyflphenvl]- 3(2 py ridazi none 1 5 To the solution of 4- (4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone prepared according to Example 11 (172 mg, 0.5 minol) and ptoluenesulfonic acid hydrate (19 mg, 0.1 inmol) in dioxane (10 mL) was added 2,3dihydropyran (2 mL). The mixture was stirred at room temperature for 6 hours. The mixture was then poured into a solution of saturated NaHCO3 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 mng, 11 1 H NMVR (DMSO-d6, 300 MHz) 8 1.54 (mn, 2H), 1.74 (in, 2H), 2.00 (in, 1 2.17 (in, 1 3.23 31H), 3.62 (in, 1 4.00 (mn, 1 5.98 (in, 1 7.13 J 9 Hz, 2H), 7.23 (in, 2H), 7.47 J 9 Hz, 2H), 7.86 J 9 Hz, 2H), 8.12 1 MS (DCI-NH 3 in/z 429 Example 380 2-(3-(4-Fluorophenyl) pjenyl)-4-(4-fluorophenyl)--4-(nethylsulfonyl)phenyll 3 (2H)-pyridazi none The title compound was prepared according to the method of Example 4, starting with 2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(inethylsulfonyl)phenyl]- 3(2 H)-pyridazi none (Example 166) in place of 2-benzyl-4-broino-5-[4-(methylthio)phenylj-3(2 H)-pyridazi none and substituting cesium fluoride for sodium carbonate (yield: 0.62g, M.p. 222-225 OC. 1 H NMVR (300 MHz, DMS0 d6) 6 3.24 (s, 3H), 7.16 (in, 2H), 7.36 (mn, 3H), 7.53 (in, 7.64 (in, 2H), 7.73-7.81 (in, 3H), 7.93 (in, 3H), 8.27 1 MS (DCI-NH 3 m/z 515 532 (M+NH 4 Anal. calc.
-209- WO 99/10331 WO 9910331PCTIUS98/1 6479 for 029H20F2N203S-0.25 H20: C, 67.10; H, 3.98; N, 5.35. Found: 0, 66.93; H, 3.99; N, 5.17.
Example 381 2-(2.2.2-Trif luoroethyl)-4-(2.2-dimethylpropoxy)-5-[3-f luoro-4- (ami nosu lfonyl)phenyll- (2 H)-p2yridazi none 2-(2,2,2-Trif luoroethyl)-4-(2,2-di methylpropoxy)-5-[3-f luoro-4-(methylthio)phenyl]-3(2H)-pyridazinone was prepared according to the method of Example 261, substituting 2-(2,2,2-trifluoroethyl)-4-chloro-5-[3-fiuoro-4-(methylthio)phenyl]- 3(2H)-pyridazinone in place of 2-(2,2,2-trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none.
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, M.p. 144- 145 OQ* 1 H NMR (300 MHz, 00013) 5 0.86 9H), 4.23 2H), 4.82 J 8 Hz, 2H), 5.10 2H), 7.46 1 7.48 (br s, 1 7.79 1 8.03 J 8 Hz, 1 H).
MS (DCI-NH3) m/z 438 Anal. calc. for C17119F3N304S: 0, 46.68; H, 4.38; N, 9.61. Found: 0, 46.76; H, 4.30; N, 9.52.
Example 382 2-(2.2.2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(ami nosulfonyl)phen I]- 3 (2 H)-pyri dazi none The title compound was prepared according to the method of Example 68 substituting 2 2 2 2 -t rif luo roethyl1)-4- met hyl pro poxy)-5-[4- (methyIsuIf in yl) phe nyl] 3(2H)-pyridazinone in place of 2-(2 ,2,2-trifluoroethyl)-4-(4-fluorophenyl)-5-[4- (methylsulf inyl)phenyl]-3 (2H)-pyri dazi none (yield: 260 mg, M.p. 163-164 00.
1 H NMR (300 MHz, 00013) 8 0.86 J 6.6 Hz, 6H), 1.91 (septet, J 6.6 Hz, 1 H), 4.34 J 6.6 Hz, 2H), 5.11 (br s, 2H), 7.43-7.52 (in, 2H), 7.80 1 8.02 J 8 Hz, 1 MS (DCI-NH3) m/z 424 m/z 441 Anal. calc. for 016H17F4N30 4 S: 0, 45.39; H, 4.05; N, 9.92. Found: 0, 59.89; H, 3.83; N, 8.61.
Example 383 2-Be nzvl-4- (4-f luoroben zyl)-5-14-(ami nosu If onyl)phenyl]-3 (2 H)-pyridazi none The title compound was prepared according to the method of Example 384, substituting 2-benzyl-4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2
H)-
pyridazinone in place of 2 3 4 -difluorophenyl)-4-(4.fluorophenyl)..s.[4.(methyl.
-2 WO 99/10331 PCT/US98/16479 sulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.5723 g M.p. 120-123 oC. 1
H
NMR (300 MHz, DMSO d6) 5 3.83 (bs, 2H), 5.30 (bs, 2H), 6.95-7.06 4H), 7.28- 7.40 5H), 7.48 2H), 7.60 2H), 7.91 2H), 7.95 1H). MS (DCI-NH3) m/z 450 467 Anal. calc. for C24H20FN303S: 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)phenyll-3(2H)-pyridazinone To a solution of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (130 mg, 0.3 mmol) and di-t-butylazodicarboxylate (DBAD) (69 mg, 0.3 mmol) in THF (30 mL) at -78 °C was added dropwise a 1 N solution of lithium 1,1,1,3,3,3-hexamethyldisilazide (0.9 mL, 0.9 mmol) in THF. After addition, the reaction was stirred an additional 45 minutes at -78 °C (or until the TLC indicated a disappearance of starting material). The reaction was quenched with a saturated solution of NH4CI and extracted with ethyl acetate. The acetate extract was dried over MgSO4 and concentrated in vacuo to obtain 220 mg of crude adduct.
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 1.38 g, 10 mmol) was added followed by addition of hydroxylamine-O-sulfonic acid (1.13 g, 10 mmol) and H20 (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 MgSO4 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, M.p. 185-189 OC. 1 H NMR (DMSO-d6, 300 MHz) 8 5.33 2H), 7.11 2H), 7.22 2H), 7.40 7H), 7.83 J 9 Hz, 2H), 8.10 1H). MS (DCI-NH3) m/z 436 Anal. calc. for C23H18FN303S-0.75 H20: 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)phenyll-3(2H)pyridazinone The product from Example 108 was converted to the title sulfonamide according to the method of Example 384, (yield: 65 mg, M.p. 227-229 °C.
1 H NMR (300 MHz, DMSO-d6) 67.08-7.17 4H), 7.36 J 3 Hz, 2H), 7.47 (br s, -211- WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 2H), 7.61 -7.69 (in, 2H), 7.83 J =9 Hz, 2H), 7.93 J 9 Hz, 2H), 8.40 1 H).
MS (DCI-NH3) m/z 469 486 Anal. caic. for 024H1 5 F2N304S: 0, 58.02; H, 3.30; N, 9.24. Found: C, 57.84; H, 3.34; N, 9.01.
Example 386 2-(3 .4-Difluorophenyl)-4-(3-fluoro-4-methylphenyl)-5-[4-(aminosulfonyl)phenyl- 3 (2 H)-pyridazi none The product from Example 371 was converted to the title sulfonamidle according to the method of Example 384 (yield: 45 mg, M.p. 198-200 00. 1 H NMR (300 MHz, DMSO-d6) 8 6.87 (dd, J 9 Hz, 3 Hz, 1 7.13 (dt, J 9 Hz, 3 Hz, 1 7.19 J 7 Hz, 1 7.46 J 9 Hz, 2H), 7.47 (br s, 2H), 7.52-7.69 (in, 2H), 7.79 J 9 Hz, 2H), 7.82-7.89 (in, 1 8.25 1 MS (001-N H3) m/z 472 489 (M+NH4)+.
Example 387 2-(4-Fluorophenyl)-4- (3-f Iu oro-4- met hylphe nyl)-5-[4- (aiinosulfonyl)phenyl-3 (2 H)pyridazi none The product from Example 250 was converted to the title sulfonamidle according to the method of Example 384 (yield: 185 mg, M.p. 187-1 88 00.
1 H NMR (300 MHz, DMSO-d6) 8 2.22 (br s, 3H), 6.87 (dd, J 9 Hz, 3 Hz, 1 7.16 J 9 Hz, 2H), 7.38 J 9 Hz, 2H), 7.46 (br s, 2H), 7.47 J 9 Hz, 2H), 7.67- 7.73 (in, 2H), 7.77 J 9 Hz, 2H), 8.22 1 MS (DCI-NH3) m/z 454 471 Anal. calc. for 023H17F2N 3 0 3 S.0.25 H20: 0, 60.36; H, 3.87; N, 9.19. Found: 0, 60.30; H, 4.26; N, 8.83.
Example 388 2-(3.4-Difluorophenyl)-4-(4-fluorophenoxv)-5-[4-(aminosulfonyflohenyll-3(2)- 12dzinone The product from Example 109 was converted to the title sulfonamide according to the method of Example 384 (yield: 110 mg, M.p. 224-226 00.
1 H NMR (300 MHz, 00013) 864.86 (br s, 2H), 6.89-7.03 (in, 4H), 7.19-7.30 (in, 1 H), 7.45-7.52 (in, 1 7.56-7.66 (in, 1 7.79 J 9 Hz, 2H), 8.04 J 9 Hz, 1 H), 8.08 1 MS (DC I-N H3) in/z 474 491 Anal. cab,. for C22H1 4 F3N304S-0.25 H20: C, 55.32; H, 2.93; N, 8.80. Found: 0, 55.26; H, 3.11; N, 8.58.
-2 12- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 389 2-(3-Ch loro-4-fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4- (aminosulfonyl)p~henyl]32H)-p2yridazinone The product from Example 247 was converted to the title sulfonamide -according to the method of Example 384 (yield: 230 mg, M.p. 243-245 00.
1 H NMR (300 MHz, DMSO-d 6 562.17 (br s, 3H), 6.94-7.09 (in, 2H), 7.25 (dd, J 9 Hz, 3 Hz, 1 7.41-7.48 (in, 4H), 7.60 J 9 Hz, 1 7.68-7.75 (mn, 1 7.77 J 9 Hz, 2H), 7.95 (dd, J 6 Hz, 3 Hz, 1 8.25 1 MS (DCI-NH 3 m/z 469 486 Anal. caic. for C23H16ClF2N30 3 S: C, 56.67; H, 3.29; N, 8.63. Found: C, 56.81; H, 3.35; N, 8.95.
Example 390 2-(4-Fluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-[4-(aninosulfonvl)phenynl-3(2H)- The methyl sulfone product of Example 245 was converted to the title sulfonamide according to the method of Example 384 (yield: 78 mg, M.p.
202-204 00. 1 H NMR (300 MHz, CDCI3) 8 2.22 3H), 4.86 2H), 6.83-6.91 (in, 2H), 7.14-7.25 (in, 3H), 7.36 J 9 Hz, 2H), 7.65-7.72 (in, 2H), 7.91 J =9 Hz, 2H), 8.0 1 MS (DCI-NH3) m/z 454 471 Anal. calc. for C23H17F2N303S.0.25 H20: C, 60.36; H, 3.77; N, 9.19. Found: 0, 60.24; H, 3.93; N, 9.25.
Example 391 2-(3-Chlorop~henyl)-4-(4-fluoro-3-methylphenyl)-5-4-(ami nosulfonyl)phenyl]-3(2h)pyridazinone The methyl sulfone product of Example 244was converted to the title sulfonamide according to the method of Example 384 (yield: 125 mg, M.p.
187-1 88 00. 1 H NMR (300 MHz, 00013) 62.21 3H), 4.71 2H), 6.85-6.92 (in, 2H), 7.21 J 9 Hz, 1 7.32-7.47 (in, 2H), 7.37 J 9 Hz, 2H), 7.64 (dt, J 7 Hz, 3 Hz, 1 7.77 (br s, 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) in/z 470 487 Anal. calc. for 023H-17CIFN303S.0.25 H20: C, 58.32; H, 3.65; N, 8.88. Found: C, 58.27; H, 3.91; N, 8.62.
-2 13- WO 99/10331 WO 99/ 0331PCTfUS98/1 6479 Example 392 2-(3-Chlorophenyl)-4-(3-methylbutyl)-5-[4-(aminosulfonyl)phenyll-3(2
H)-
pyridazinone The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]- 3(2 H)-pyridazi none (Example 366) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylIsuIfo nyl) phe nyl]-3(2 H)-pyridazi none (yield: 0.0756 g, M.p. 167-170 00. 1 H NMR (300 MHz, DMS0 d6) 5 0.78 J 6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51-7.65 (in, 4H), 7.68 (in, 2H), 7.75 (in, 1 7.98 (in, 2H), 8.03 1H), 8.60 (bs, 1 MS (DCI-NH3) m/z 432 449 Anal. calc. for 021 H22CIN303S (0.25 H20): C, 57.79; H, 5.19; N, 9.62. Found: 0, 57.78; H, 5.02; N, 9.40.
Example 393 1 5 2-(3-Chlorophenyl)-4-(phenethyl)-5-[4-(aminosulfonyl)Dhenyll-3(2H)-pyridazinone The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(phenethyl)-5-[4-(methylsulfonyl)pheny]-3(2H)pyridlazinone (Example 372) in place of 2-benzyl1-4- (4-f luorop henyl)-5-[4- (met hylsulIfonyl)phenyl]-3(2 H)-pyridazi none (yield: 0.075 g, semi-solid; 1 H NMR (300 MHz, DM50S d6) 8 2.80 (in, 4H), 3.29-3.42 (3H, obstructed by H20), 6.96 (in, 2H), 7.14-7.28 (in, 3H), 7.46-7.68 (in, 7H), 7.78 (in, 1 7.92 (in, 2H), 8.01 1 H).
MS (D01-NH3) m/z 466 483 Anal. calc. for C24H20CIN2O3S.0.25 H20: 0, 61.27; H, 4.39; N, 8.93. Found: 61.18; H, 4.68; N, 8.58.
Example 394 2-(3-C hlorophenyl)-4-(3-methylbutoxy)-5-[4-(ami nosulfonyl)phenyll-3(2 H)pyridazi none The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (Example 339) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulIfonyl)p henyl]-3 (2 H)-pyridazi none (yield: 0.575 g, M.p. 137-139 OC0 1 H NMR (300 MHz, DMVSO d6) 6 0.81 J =7 Hz, 6H), 1.49 (in, 2H), 1.57 (in, 1 4.42 J 7 Hz, 2H), 7.44-7.65 (in, 5H), 7.76 (in, 1 7.84 (in, 2H), 7.94 (in, 2H), 8.20 1 MS (DCI-NH3) in/z 448 465 Anal. calc. for 021 H22CIN30 4 S: 0, 56.31; H, 4.95; N, 9.38. Found C, 56.02; H, 4.82; N, 9.31.
-2 14- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 395 2-(3-C hlorop~henyl)-4-(2-methylpropoxy)-5-[4- (ami nosulfonyl)phenyl1-3 (2H)pyridaz none 5 The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (Example 335) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2 H)-pyridazi none (yield: 0.0458 g, M.p. 80-85 00.
1 HNMR (300 MHz, DM30 d6) 860.80 J 6 Hz, 6H), 1.74-1.92 (in, 3H), 4.20 J 6 Hz, 2H), 7.49-7.64 (in, 5H), 7.76 (in, 1 7.85 (in, 2H), 7.95 (in, 2H), 8.21 (in, 1H). MS (DCI-NH3) in/z 434 451 Anal. calc. for C20H2001N304S: 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)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 384, substituting 2- (4-f luo ro phe nyl)-4- met hylbutyl)-5-[4-(methylsuIfo ny)phe nyl]- 3(2H)-pyridazinone (Example 378) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (inethylsulfonyl)phenyll-3(2 H)-pyridazi none (0.090 g 21 M.p. 180-183 00. 1 H NMVR (300 MHz, DMS0 d6) 6 0.78 J 6 Hz, 6H), 1.49 (in, 5H), 7.36 (in, 2H), 7.53 (mn, 2H), 7.62-7.73 (mn, 4H), 7.98 (in, 3H). MS (DCI-NH3) m/z 416 433 Anal. calc. for 021 H22FN30 3 S: 0, 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-(am nosulfonyl)phe nyll-3(2H)pydzinone The title compound was prepared according to the method of Example 384, substituting 2- (4-f lu orop henyl)-4- (2-m ethylpro poxy) -5-[4-(inet hylsuIf ony1) phenyl]- 3(2 H)-pyridazi none (Example 376) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazi none (yield: 0.024 g, M.p. 132-1 36 00.
1 H NMR (300 MHz, DM30 d6) 6 0.79 J 6 Hz, 6H), 1.83 (mn, 1 4.19 J 6 Hz, 2H), 7.36 (in, 2H), 7.50 (in, 2H), 7.66 (mn, 2H), 7.84 (in, 2H), 7.95 (in, 2H), 8.18 1 MS (DCI-NH3) in/z 418 435 (M+NH 4 Anal. calc. for C20H20FN 3 0 4 S: C, 57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.
-2 WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 398 2-(4-Fluorophenyl)-4-(3-methylbutoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)pyrdaione The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4.(methylsulfonyl)phenyl]- 3(2 H)-pyridazi none (Example 375) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylIsuIf onyl) phenyl]-3 (2 H)-pyridazi none (yield: 0.051 g, Yellow oil. 1
H
NMVR (300 MHz, DM50S d6) 8 0.80 J 5 Hz, 6H), 1.47 (in, 3H), 4.42 J 6 Hz, 2H), 7.37 (in, 2H), 7.50 (in, 1 7.65 (mn, 2H), 7.83 (in, 2H), 7.93 (in, 2H), 8.18 (s, 1 8.60 (bs, 1 MS (DCI-NH3) m/z 432 449 Anal. calc. for C21 H22FN304S: 0, 58.46; H, 5.14; N, 9.74. Found: 0, 58.16; H, 5.21; N, 9.57.
Example 399 1 5 2-(tLButvl)k4-(3-inethyl-1 -butoxy)-5-[4-(aminosulfonyl)phenyll-3(2H)-pyridazinone 2-(t-Butyl)-4- methyl- 1 -butoxy)-5-[4-(inethylthio)phenyl]-3(2H)pyridazinone prepared in Example 3300 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, M.p. 153-155-C. 1 H NMR (300 MHz, CDCI3) a 0.82 J 6 Hz, 2H), 1.48 J 6 Hz, 2H), 1.49-1.69 (in, 1 1.70 9H), 4.37 J 6 Hz, 2H), 4.32 2H), 7.70 J 9 Hz, 2H), 7.72 1 8.01 J 9 Hz, 2H). MS (DCI- NH-3) in/z 394 Anal. calc. for C1 9H27N304S: 0, 57.99; H, 6.91; N, 10.67.
Found: C, 58.11; H, 6.71; N, 10.58.
Example 400 2-(3.4-Difluorophenyl)-5-[4-(aininosulfo nyl)phenyl]-4-(4-fluorophenyl)-3(2H)pyridazi none The title compound was prepared according to Example 384 substituting 2- (3, 4 -difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H).
pyridazinone (Example 182) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(inethylsulIfonyl)phenyl] -3(2 H)-pyridazi none (yield: 950 mg, M.p. 177-181 00. 1 H NMR (300 MHz, DMSO-d 6 a 7.15 2H), 7.29 (in, 2H), 7.43 1 7.45 (bs, 2H), 7.59 (mn, 2H), 7.76 J 9 Hz, 2H), 7.85 (in, 1 8.27 1 MS (DCI-NH3) m/z 458 475 Anal. calc. for C22H14F3N 3 0 3 S: C, 57.77; H, 3.08; N, 9.19. Found, 0, 57.22; H, 3.28; N, 8.99.
-2 16- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 Example 401 2-(3-Ch Ioro-4-f Luorophenyl)-4-(4-f luorophenyl)-5-[4-(aminosu If onyl)phenvl]-3(2H)pyrdanQne The title compound was prepared according to the method of Example 384, substituting 2- (3-ch lo ro-4-f lu oro ph enyl)-4-(4-flIuo rophe nyl)-5-[4- (met hylsuf onyl) phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3 (2H)-pyridazi none (yield: 380 mg, M.p. 208-210 OC0 1 H NMR (300 MHz, DMSO-d6) 8 7.15 2H), 7.27 (in, 2H), 7.4.3 1 7.45 (bs, 2H) 7.51 J 9 Hz, 4H), 7.6 1 7.7 (in, 1 7.75 J 9 Hz, 2H), 7.94 (dd, 1 8.25 1 MS (DCI-NH3) mlz 474 491 Anal. cabc.
for C22H14F2C12N303S*O.5 H20: 0, 55.76; H, 2.98; N, 8.87. Found: 0, 56.05; H, 3.42; N, 8.65.
Example 402 2-(3 .4-Difluorophenyl)-4-(4-fluoro-3-methylphenyl)-5-F4-(aminosulfonyl)phenyl- 3(2H)-pyridazi none The title compound was prepared according to the method of procedure Example 384, substituting 2- (3,4-dif luo rophe nyl)-4-(4-f luo ro-3-imet hyl phe nyl)-5-[4- (inethylsulfonyl)phenyl]-3(2H)-pyridazi none in place of 2-benzyl-4-(4-fluorophenyl)- 5-[4-(inethylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 105 ing, M.p. 243- 245 00. 1 H NMR (300 MHz, DMSO-d6) 8 2.2 3H), 7.01 (in, 2H), 7.25 (in, 1 H), 7.45 1 7.47 (bs, 2H), 7.6 (mn, 2H), 7.77 J 9 Hz, 2H), 7.85 (in, 1 8.26 (s, 2H). MS (DCI-NH3) m/z 472 489 Anal. calc. for C24H17F3N2O3S-0.5 H20: 0, 58.59; H, 3.42; N, 8.91. Found: 0, 57; H, 4.23; N, 8.89.
Example 403 2-(3 .4-Difluorophenyl)-4-(2-methylpropoxy)-5-[4-(aininosulfonyl)phenyl]-3(2H)pyiaznn The title compound was prepared according to the method of Example 384, substituting 2- (3 ,4-dif luorophenyl)-4- (2-inethylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazi none (yield: 35 mg, M. p. 169-171 00.
1 H NMR (300 MHz, DMSO-d6) 860.78 6H), 1.84, (in, 1 4.2 2H), 7.54 (in, 3H), 7.6 (in, 1 7.82 (in, 3H), 7.91 2H), 8.21 1 MS (DCI-NH3) in/z 436 -2 17- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 453 Anal. caic. for C20Hj9F2N30 4 S-0.25 H20: 0, 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-f4-(aminosulfonyl)phenyl]-3(2H)pyridazi none The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]- 3(2 H)-pyridazi none in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulf onyl)phenyl]-3 (2 H)-pyridazi none (yield: 58 mg, M.p. 171 -173 00. 1 H NMR (300 MHz, DMSO-d6) 8 0.75 6H), 1 (in, 3H), 2.48 (in, 2H), 3.3 3H), 7.51 (in, 1 7.65 (mn, 1 7.75 J 9 Hz, 2H), 7.81 (in, 1 H) 8.05 1 8.12 (d, J 9 Hz, 2H). MS (DCI-NH3) m/z 434 451 Anal. caic. for 021 H21 F2N 3 0 3 S.0.25 H20: 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-methylbuty)-5-[4-(aminosufonyl)phenyll-3(2H)pridaziono The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyri dazi none in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazi none (yield: 102 mg, M.p. 154-156 C. 1 H NMR (300 MHz, DMSO-d6) 5 0.75 6H), 1.4, (in, 3H), 2.48 (in, 2H), 7.54 2H), 7.6 (in, 1 7.69 (in, 2H), 7.93 (dd, 1 8.05 (in, 2H). MS (DCI-NH3) m/z 450 468 Anal. calc. for C22H22FN203S01'0.25 H20: C, 58.86; H, 4.94; N, 6.24. Found: 0, 59.23; H, 5.12; N, 6.00.
Example 406 Dif luo rophe nyl)-4-(2.2-dimethylpropoxy)-5-[4- (aninosuIto nyl)phenyll-3 (2H).
pyridazinone The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylsufonyl).
phenyl]-3(2 H)-pyridazi none in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulIfonyl) phenyl]-3 (2 H)-pyridazi none (yield: 310 mng, M.p. 173-175 00. 1 H NMR (300 MHz, DMSO-d6) 8 0.8 9H), 3.3 3H), 4.1 2H), 7.51 (in, -2 18- WO 99/10331 WO 9910331PCT/US98/16479 3H), 7.6 (in, 1 7.85 (in, 3H), 7.95 J 9 Hz, 2H), 8.21 1 MS (DCI-NH3) m/z 450 467 Anal. caic. for 021 H21 F2N304S: 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-f luorophenoxy)-5-[3-fluo ro-4-(ami nosu lfonyl)phenyil- 3(2H)-pyridazi none The title compound was prepared according to the method of Example 400 substituting 2-(3 ,4-difluorophenyl)-4-(4-fluorophenoxy)-5-[4-(inethylsulfonyl)phenyl]-3(2 H)-pyridazi none in place of 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4- (methylsulIfonyl)phenyl]-3 (2 H)-pyridazi none (yield: 125 ing, 31 M.p. 224-226 1 H NMR (300 MHz, DMSO-d6) 8 7.15 4H), 7.51 (in, 1 7.6 (in, 2H) 7.75 (in, 4H), 7.9 1 8.4 1 MS (001-N H3) mn/z 492 509 (M+NH4)+.
Anal. calc. for C22H13F4N304S: 0, 53.77; H, 2.67; N, 8.55. Found,; 0, 53.33; H, 2.84; N, 8.22 Example 408 2-(3 .3-Dil luoro-2-propenyl)1-4-(4-fluorophenyl)-5-3-f luoro-4- (ami nosu If onyl)phe nyl]-3 (2 H)-pyridazi none The intermediate, 2-benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(inethylthio)phenyl]-3(2H)-pyridazinone prepared according to the method of Example 72, was oxidized with one equivalent of meta-ch lo rope roxybenzoic 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 127, substituting 1 ,3-dibroino-1 ,1-difluoropropane in place of 3,4-difluorobenzyl bromide and employing 4 equivalents of potassium carbonate to provide the title compound (yield: 120 mg, M.p. 180-183 O0. 1 H NMR (300 MHz, CDCI3) 864.71 (dt, J Hz, 7.5 Hz, 2H), 4.75 J 7.5 Hz, 2H), 5.06 2H), 7.02 (in, 2H), 7.19 (dd, J 9 Hz, 6 Hz, 2H), 7.81 1 7.87 J 7.5 Hz, 2H). MS (DCI-NH3) in/z 440 Anal. calc. for 019H13F4N303S: C, 51.93; H, 2.98; N, 9.56. Found: C, 51.71; H, 3.15; N, 9.28.
-219- WO 99/10331 WO 99/ 0331PCT/US98/I 6479 Example 409 2-(3 Difluorophenyl)-4-[2-(2-propoxy)ethoxyI-5-[4-(aminosulfonyl)phenyl-3(2H)pyridazinone The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-[2-(2-propoxy)ethoxy]-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-be nzyl-4- (4-f lu orophe nyl)-5-[4- (met hyl sulfonyl)phenyl]-3(2H)-pyridazinone (yield: 110 mg, M.p. 54-56 00. 1 H NMR (300 MHz, DMSO-d6) 8 1 .0 6H), 3.43 (in, 1 3.54 (in, 2H), 4.63 (mn, 2H), 7.5 (in, 3H), 7.6 (in, 1 7.8 (in, 1 7.95 (mn, 4H), 8.2 1 MS (DCI-NH3) in/z 466 483 Anal. caic. for C21 H21 F2N305S: C, 54.19; H, 4.55; N, 9.03. Found, C, 54.29; H, 4.67; N, 8.95.
Example 410 2-(3 .4-Difluorophenyl)-4-(4-inethyl-3-pentenyloxy)-5-f 4-(ainosu lfonyl)phe nyu- 3(2 H)-pyridazi none The title compound was prepared according to the method of Example 384 substituting 2-(3 ,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(inethylsulfonyl)phenyl]-3(2H)-pyridazi none in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (inethylsulfonyl)phenyl]-3(2 H)-pyridazi none. M.p. 70-73 00. 1 H NMR (300 MHz, DMSO-d6) 1 .5 6H), 2.27 (in, 2H) 4.43 2H), 4.5 (in, 1 7.5 (mn, 2H), 7.6 (in, 1 7.8 (mn, 2H), 7.92 J 2 H, 2H), 8.2 1 MS (DCI-NH3) in/z 462 479 Anal. calc. for C22H21 F2N304S: C, 57.26; H, 4.59; N, 9.11.
Found, 56.96; H, 4.70; N, 9.01.
Example 411 2-(3-C hlorophenvl)-4-(3-fluorophenoxy)-5-[4-(methylsulfonynphenyl1-3(2
H)-
pyrdazinon The title compound was prepared according to the method of Example 335, substituting 3-fluorophenol in place of isobutanol (yield: 0.034 g, M.p. 178- 18000C 1 H NMR (300 MHz, DMVSO d6) 863.27 3H), 6.88-7.00 (in, 2H), 7.10 (in, 1 7.36 (in, 1 7.59 (in, 3H), 7.74 (in, 1 7.90 (in, 2H), 8.06 (in, 2H), 8.43 (s, 1 MS -(DCI-NH3) in/z 488 Anal. caic. for C23H1 6CIFN2O4S-0.25 0, 58.10; H, 3.49; N, 5.89. Found 0, 58.04; H, 3.59; N, 5.80.
-220- WO 99/10331 PCTIUS98/16479 Example 412 2-(3-C hlo rophenyl)-4-(2-methylproooxy)-5-[3-f luoro-4- (aminosu lfonvhp1henyll- 3 (2 H)-p2yridazi none The title compound was prepared according to the method of Example 384 substituting 2-(3-chlorophenyl)-4-(2-methylpropoxy)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-3 (2 H)-pyridazi none in place of 2-be nzyl-4-(4-f lu orophe nyl)-5-[4- (met hyIsu lfonyl)phenyl]-3 (2 H)-pyridazi none (yield: 0.019 g, M.p. 157-159 0C. 1
H
NMR (300 MHz, DM50S d6) 5 0.81 J 6 Hz, 6H), 1.86 (in, 1 4.24 J 6 Hz, 2H), 7.75 (in, 3H), 7.66 (in, 1 7.73 (mn, 7.83 (in, 2H), 7.91 (in, 1 8.23 (s, 1 Anal. calc. for 021 Hl 9CIFN3O 4 S: 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-inethyilpentyloxy)-5-[4-'methylsu Ifonyl)phenyll-3 (2H)- The title compound was prepared according to the method of Example 335, substituting 4-inethyl-1-pentanol in place of isobutanol (yield: 0.137 g, M.p.
139-14000C 1 H NMR (300 MHz, DM50S d6) 5 0.74 J 6 Hz, 6H), 1.03 (in, 2H), 1.39 (in, 1 1.54 (mn, 2H), 3.29 3H), 4.40 J 5 Hz, 2H), 7.51 -7.60 (in, 3H), 7.75 (in, 1 7.90 (mn, 2H), 8.07 (mn, 2H), 8.20 1 MS (DCI-NH3) m/z 461 478 Anal. calc. for C23H25C1N204IS: C, 59.95; H, 5.97; N, 6.08. Found: C, 59.62; H, 5.63; N, 5.86.
Example 414 2-4-Fl uorophenyl)-4-(4-m ethyl Pentyloxy)-5f4-(m ethyl su fonyl)ph enyl-3 pyridazinone The title compound was prepared according to the method of Example 335, starting with 2-4furpey)4tslx--[-m tysloy hnl-(H)pyridazinone in place of 2- (3-ch lo rophe nyl)-4-tosyloxy-5-[4- (met hyl su If onylI)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-i -pentanol in place of isobutanol (yield: 0.128 g, M.p. 123-1 25 0 1 H NMR (300 MHz, DM50S d6) 8 0.74 J 6 Hz, 6H), 1.03 (in, 2H), 1.39 (mn, 1 1.54 (mn, 2H), 3.28 3H), 4.39 J 6 Hz, 2H), 7.37 (in, 2H), 7.66 (in, 2H), 7.91 (in, 2H), 8.07 (in, 2H), 8.18 1 H).
-22 1- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 MS (DCI-NH3) m/z 445 Anal. calc, for C23H25FN204S: C, 62.14; H, 5.67; N, 6.30. Found: C, 62.28; H, 5.59; N, 6.25.
Example 415 Fl uorophenyI)-4-hydroxy-5-[4-(methylsu fonyl)phenyll-3 (2 H)-ryridazi none The title compound was prepared according to the method of Example 332, substituting 2-(4-fluorophenyI)-4-methoxy-5-[4-(methylsulfony)phenyl]-3(2H)pyridazinone for 2-(3-chlorophenyl)-4-methoxy-5-[4-(methylsulfonyl)phenyl].3(2H)pyridazinone (yield: 2.022 g, 1 H NMR (300 MHz, DMS0 d6) 8 3.28 3H), 7.38 (in, 2H), 7.70 (mn, 2H), 8.03 (mn, 4H), 8.22 1 MS (APCI-+Q1 MS) 361 (-QiMS) 359 Example 416 2-(4-Fluorophenyl)-4-cycloprop~ylmethoxy-5-[4-(methylsu lfonyl)phenyll-3(2H)pyrdzinone The title compound was prepared according to the method of Example 335, substituting 2 -(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsufonyl)phenyl]-3(2H)pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none and substituting cyclopropylmethanol in place of isobutanol (yield: 0.117 g, M.p. 166-16700C 1 H NMR (300 MHz, DM30S d6) 6 0. 22 (in, 2 0. 46 (mn, 2 1. 10 (in, 1 3.31 3 4.30 J 7 Hz, 2 7.36 (in, 2H), 7.66 (in, 2H), 7.96 (in, 2H), 8.07 (in, 2H), 8.20 1 MS (DCI-NH3) in/z 415 432 Anal. calc. for C23H25CIN204S: 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)phenyll-3(2H)pyridazinone The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)- -222- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 pyridazinone in place of 2-(3-chlorophe 'nyl) -4-tosyloxy-5 (met hylsuIf onyI)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopropane ethanol in place of isobutanol (yield: 0.1472 g, 100%). M.p. 111-11700C 1 H NMVR (300 MHz, d6) 56-0.01 (in, 2H), 0.31 (in, 2H), 0.60 (in, 1 1.49 J 6 Hz, 2H), 3.29 3H), 4.48 J 6 Hz, 2H), 7.37 (in, 2H), 7.65 (mn, 2H), 7.91 (in, 2H), 8.06 (in, 2H), 8.17 (s, 1 MS (DCI-NH3) mlz 429 446 Anal. cab,. for C22H-21 FN2O4S: 0, 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)phenyll-3(2Hrill pyridazi none The title compound was prepared according to the method of Example 335, substituting cyclopropane methanol in place of isobutanol (yield: 0.0917 g, 64%).
M.p. 158-161 00. 1 H NMVR (300 MHz, DM50S d6) 860.22 (in, 2H), 0.46 (mn, 2H), 1. 13 (in, 1 3.31 3H), 4.31 J 7 Hz, 2H), 7.57 (in, 3H), 7.75 (in, 1 7.96 (mn, 2H), 8.08 (in, 2H), 8.23 1 MS (DCI-NH 3 mlz 431 448 Anal.
calc. for 021 Hi 9CIN204S.0.25 H20: 0, 57.92; H, 4.51; N, 6.43. Found: C, 57.86; H, 4.35; N, 6.27.
Example 419 2-(3-Chlorop~henyl)-4-(2-cyclopropane-1 -ethoxy)-5-[4-(inethylsulfony)phenyl]- 3 (2 H)-pyridazi none 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%).
M.p. 124-1 28 00. 1 H NMVR (300 MHz, DM50S d6) 6 0.00 (in, 2H), 0.32 (in, 2H), 0.61 (in, 1 1.49 J 6 Hz, 2H), 3.30 3H), 4.50 J 6 Hz, 2H), 7.58 (in, 3H), 7.76 (in, 1 7.91 (in, 2H), 8.07 (in, 2H), 8.21 1 MS (DCI-NH3) in/z 445 462 (M+iNH 4 Anal. calc. for 022H2101N204S: 0,.59.39; H, 4.76; N, 6.30.
Found: C, 58.92; H, 4.94; N; 6.15.
-223- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 420 2-(4-Fluorophenyfl-4-(4-methylpentyb)-5-f4-(methylsulfonyl)1henvlj-3(2Hypyridazinone The title compound was prepared according to the method of Example 362, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2- (3-ch lo rophe nyl)-4-tosyloxy-5-[4- (met hylsuIf o nyl)phenyl] -3 (2H)-pyridazi none and substituting 4-methylpentane-1 -magnesium bromide for cyclopropyl magnesium chloride (yield: 0. 165 g, M.p. 112-115 00. 1 H NMR (300 MHz, DM50S d6) 8 0.75 J 7 Hz, 6H), 1.07 J 7 Hz, 2H), 1.32-1.53 (in, 3H), 2.45 2H), 3.31 3H), 7.37 (in, 2H), 7.66 (in, 2H), 7.76 (in, 2H), 8.00 1 8.10 (in, 2H). MS (DCI-NH3) inlz 429 446 (M+NH4)+.
Anal. calc. for 023H25FN20 3 S: C, 64.47; H, 5.88; N, 6.54. Found: C, 64.44; H, 5.90; N, 6.49.
Example 421 2-(3-Chlorophenyl)-4-(4-methylpentl)--4-(nethylsulfonyl)phenyl.3 (2H)pyridazi none The title compound was prepared according to the method of Example 362, substituting 4-inethylpentane-1 -magnesium bromide in place of cyclopropyl magnesium chloride (yield: 165 mg, oil. 1 H NMR (300 MHz, DM50S d6) 8 0.76 J 6 Hz, 6H), 1.07 (mn, 2H), 1.33-1.55 (mn, 3H), 2.45 (in, 2H), 3.32 3H), 7.51-7.65 (in, 4H), 7.76 (in, 2H), 8.03 1 8.11 (in, 2H). MS (DCI-NH3) in/z 445 462 Anal. calc. for 023H25CIN203S: 0, 62.06; H, 5.66; N, 6.30. Found: C, 61.86; H, 5.64; N, 6.18.
-224- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 422 2-(4-Fluorophenyl)-4-(3-methyl-2-butenoxy)-5-[4-(methylsulfonyl)p2heny]-3 (2H)pyridazinone The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3-methyl-2-buten-1-ol in place of isobutanol (yield: 0.1284 g, M.p. 128-132 00. 1 H NMR (300 MHz, DMS0 d6) 6 1.58 3H), 1.67 3H), 3.30 3H), 4.95 J 7 Hz, 2H), 5.31 (in, 1 H), 7.38 (in, 2H), 7.65 (mn, 2H), 7.89 (in, 2H), 8.06 (in, 2H), 8.18 1 MS (DCI-NH3) mn/z 429 446 Anal. calc. for C22H21 FN2O4S: 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)phenyll-3(2H)pyridazi none The title compound was prepared according to the method of Example 335, substituting 3-methyl-2-buten-1 -ol in place of isobutanol (yield: 0.119 g, 81 M.p.
113-115 00. 1 H NMR (300 MHz, DMVSO d6) 8 1.58 3H), 1.67 3H), 3.31 (s, 3H), 4.96 (in, 2H), 5.32 (mn, 1 7.58 (in, 31H), 7.75 (in, 1 7.89 (in, 2H), 8.07 (in, 2H), 8.21 1 MS (APCI+Q1 MS) 445 (APCI-Q1 MS) 479 Anal. calc. for C22H21 CIN204S: 0, 59.39; H, 4.76; N, 6.30. Found: 0, 59.14; H, 4.66; N, 6.16.
Example 424 2-(4-Fluorophenyl)-4-(4-methyl-3-12entenyloxy)-5-4-(methylsulfonyl)phenylp.3(2H).
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-L4-(methylsulfonyl)phenyl)-3(2H)pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)- -225- WO 99/10331 WO 9910331PCT/US98/1 6479 phenyl]-3 (2H)-pyridazi none and substituting 4-methyl-2-penten-1 -ol in place of isobutanol (yield: 0.1165 g, M.p. 111-114 00. 1 H NMR (300 MHz, d6) 8 1.46 3H), 1.56 3H), 2.26 (in, 2H), 3.30 1 4.43 J 7 Hz, 2H), 4.96 (in, 1 7.37 (in, 2H), 7.65 (in, 2H), 7.91 (in, 2H), 8.06 (in, 2H), 8.18 1 MS (DCI-NH3) m/z 443 460 Anal. cab,. for C23H23FN 2 0 4 S: C, 62.43; H, 5.24; N, 6.33. Found: C, 62.32; H, 5.30; N, 6.25.
Example 425 2-(4-Fluorophenyl)-4-(3-methyl-3-butenoxy)-5-[4-(methylsulfonyl)p2henyll-3 (2H)pyridazinone The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4- (inethylsulfonyl)phenyl]-3(2H)-pyridazi none and substituting 3-methyl-3-butene-1 ol in place of isobutanol (yield: 0.1327 g, M.p. 109-111 00. 1 H NMR (300 MHz, DM50S d6) 5 1.61 3H), 2.32 J 7 Hz, 2H), 3.30 3H), 4.56 J 7 Hz, 2H), 4.63 (bs, 1 4.68 (bs, 1 7.37 (mn, 2H), 7.66 (in, 2H), 7.90 (mn, 2H), 8.05 (in, 2H), 8.19 1 MS (DCI-NH 3 mlz 429 446 Anal. caic. for C22H21 FN204S: 0, 61.67; H, 4.94; N, 6.54. Found: 0, 61.50; H, 5.00; N, 6.45.
Example 426 2-(3-Chlorophenyl)-4-(4-inethyl-3-p2entenyloxy)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridazi none The title compound was prepared according to the method of Example 335, substituting 4-inethyl-3-pentene-1 -ol in place of isobutanol (yield: 0. 1149 g, 76%).
M.p. 110-111 00. 1 H NMR (300 MHz, DMVSO d6) 5 1.47 3H), 1.55 3H), 2.27 (in, 2H), 3.30 3H), 4.44 J 6 Hz, 2H), 4.96 (mn, 1 7.52-7.64 (in, 3H), 7.75 (in, 1 7.91 2H), 8.06 (mn, 2H), 8.21 1 MS (DCI-NH3) in/z 459 476 Anal. calc. for C23H23CIN20 4 S: C, 60.19; H, 5.05; N, 6.10. Found: C, 60.06; H, 4.90; N, 5.96.
-226- WO 99/10331 WO 99/ 0331PCTIUS98/16479 Example 427 2-(3-Chlorophenyl)-4-(3-methyl-3-butenoxy)-5-4-(methylsu Ifonyl)phenvl]-3 (2 H'pyridazinone 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%).
M.p. 110-112 00. 1 H NMR (300 MHz, DMSO d6)861.62 3H), 2.32 J =7 Hz, 2H), 3.30 3H), 4.57 J 6 Hz, 2H), 4.63 (bs, 1 4.68 (bs, 1 7.51-7.64 (in, 3H), 7.76 (mn, 1 7.90 (in, 2H), 8.05 (mn, 2H), 8.21 1 MS (DCI-NH3) in/z 445 462 Anal. caic. for 022H21 C1N204S: C, 59.39; H, 4.76; N, 6.30. Found: 0, 59.27; H, 4.68; N, 6.18B.
Example 428 2- Fluo rophe ny .5-hexadi e n y-3-oxy)-5-[4- (met hylsuIfo ny1) ph e nyl-3(2HL)pyridazinone The title compound was prepared according to the method of Example 178, substituting 1,5-hexadien-3-ol in place of 2-ethyl-i -hexanol (yield: 150 ing, M.p. 104-105 00. 1 H NMR (300 MHz, DMSO-d6) 562.42 (in, 2H), 3.30 3H), 5.00 (mn, 2H), 5.17 (in, 2H), 5,64 (in, 2H), 7.36 J 9 Hz, 2H), 7.64 (in, 2H), 7.92 J 9 Hz, 2H), 8.06 J 9 Hz, 2H), 8.19 1 MS (APOI+) mlz 441 (APCI-) in/z 475 Anal. calc. for 023H21 FN2O4S: 0, 62.71; H, 4.80; N, 6.35.
Found: C, 62.96; H, 4.93; N, 5.85.
Example 429 2-4Furpey)4(-ehl2hxlxy--4(ehlufnlpeyl32) py rid azi none 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%).
M.p. 102-10300C 1 H NMR (300 MHz, DMSO-d 6 6 0.73 J 7 Hz, 6H), 1.04 (in, -227- WO 99/10331 WO 9910331PCTIUS98/1 6479 2H), 1. 14 J 7 Hz, 1.40 (in, 3H), 3.29 3H), 5.12 (in, 1 7.36 J 9 Hz, 2H), 7.66 (in, 2H), 7.92 J 9 Hz, 8.07 J 9 Hz, 8.19 1 MVS (APCI+) m/z 459 (APCI-) mlz 493 Anal. cab,. for C24H27FN 2 04S: 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-ethvl-1 -butoxy)-5-[4-(methvlsulfonyl)phenyl-3(2H)- 12riadinone 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, M.p. 107-108 0 C. 1 H NMR (300 MHz, DMSO-d6) 8 0.73 J 7 Hz, 6H), 1.20 (quintet, J 7 Hz, 1.40 (mn, 1 3.29 3H), 4.29 J 7 Hz, 2H), 7.37 J 9 Hz, 2H), 7.66 (mn, 7.90 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.19 1 MS (APCI+) m/z 445 (APOI-) m/z 479 Anal. caic. for C23H25FN204S: C, 62.14; H, 5.66; N, 6.30. Found: C, 62.05; H, 5.86; N, 6.30.
Example 432 2-(4-Fluorophenyl)-4-(2-thioisopropyl-1 -ethoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazilnn The title compound was prepared according to the method of Example 178, substituting 2-(isopropylthio)ethanol in place of 2-ethyl-i -hexanol (yield: 138 ing, M.p. 137-139 1 H NMR (300 MHz, DMSO-d6) 6 1.13 J 7 Hz, 6H), 2.77 J 7 Hz, 2H), 2.88 (quintet, J 7 Hz, 1 3.29 3H), 4.58 J 7 Hz, 2H), 7.37 J 9 Hz, 2H), 7.66 (mn, 2H), 7.92 J 9 Hz, 2H), 8.06 J 9 Hz, 2H), 8.18 1 MS (APCI+) m/z 463 Anal. calc. for C22H23FN204S2: C, 57.12; H, 5.01; N, 6.05. Found: C, 56.82; H, 4.91; N, 5.99.
-228- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 433 2,-(4-Fluorophenyl)-4-(3-methylthio-1 -hexyloxy)-5-[4-(methylsulfonyl)phenyll-3(2H)pyridaziDno The title compound was prepared according to the method of Example 178, substituting 3-(methylthio)-1-hexanol in place of 2-ethyl-i -hexanol (yield: 155 mg, M-p. 90-92 OC. 1 H NMR (300 MHz, DMSO-d6) 5 0.78 J 7 Hz, 3H), 1.30 (in, 4H), 1.76 (in, 2H), 2.82 3H), 2.38 (in, 1 3.29 3H), 4.55 (in, 2H), 7.37 J 9 Hz, 2H), 7.66 (in, 2H), 7.92 J 9 Hz, 2H), 8.06 J 9 Hz, 2H), 8.18 1 H).
MS (APCI+) in/z 491 (ARCI-) m/z 525 Anal. calc. for C24H27FN204S2: 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-inethyl-4-pentenyl-1 -oxy)-5-[4-(inethylsulfonyl)Phenyl 3 (2 H)-pyri dazi none 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 ing, M.p. 106-107 00. 1 H NMR (300 MHz, DMSO-d6) 8 0.76 J 7 Hz, 3H), 1.78 (in, 2.00 (in, 1 3.29 3H), 4.25 (mn, 2H), 4.90 (in, 2H), 5.67 (in, 1 H), 7.37 J 9 Hz, 2H), 7.66 (in, 2H), 7.92 J 9 Hz, 2H), 8.06 J 9 Hz, 2H), 8.18 1 MS (APCI-i) in/z 443 (APOI-) in/z 477 Anal. calc. for C23H23FN204S: C, 62.42; H, 5.23; N, 6.33. Found: C, 62.13; H, 5.12; N, 6.22.
Example 435 2-(3.4-Difluorophenl)-4-(3-trifluoromethyl-1 -butoxy)-5-[4-(methylsulfonyl)phenyll- 3 (2 H)-pyridazi none To a solution of 2-(3,4-difluorophe nyl)-4-hydroxy-5-[4- (methylsulIfonyl) phe nyl]-3 (2 H)-pyidazi none (1 89mg, 0.5 inmol), Ph3P (262 ing, 1 mmol) and 3-trifluoromethyl-1-butanol (66 ing, 0.5 minol) in THE (25 inL) was added dropwise a solution of DIAD (0.2 inL, 1 inmol) in THF (5 ml-) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was -229- WO 99/10331 WO 9910331PCT[US98/1 6479 concentrated in vacuo and the residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, (yield: 180 mg M.p.
126-128 OC. 1 H NMR (300 MHz, DMSO-d6) 6 0.96 J 7 Hz, 3H), 1.55 (in, 1lH), 1.97 (in, 1 2.30 (in, 1 3.29 3H), 4.46 (in, 2H), 7.52 (in, 1 7.62 (in, 1 H), 7.81 (in, 1 7.90 J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MS (APCI+) m/z 503 (APOI-) m/z 537 Anal. calc. for C22H1 9F5N 2 0 4 S: C, 52.59; H, 3.81; N, 5.57. Found: C, 52.70; H, 3.73; N, 5.63.
Example 436 Dif luorophe nyl)-4-ethoxy-5-[4-(methylsu lfonyl)phenyll-3 (2H) -pyridazi none The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(inethylsulfonyl)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-i -hexanol (yield: mng, M.p. 121 -123 OC. 1 H NMR (300 MHz, DMSO-d6) 81.23 J 7 Hz, 3H), 3.30 3H), 4.51 J 7 Hz, 2H), 7.52 (mn, 1 7.62 (in, 1 7.81 (in, 1 7.90 (d, J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MVS (APCI+) m/z 407 (APCI-) m/z 441 Anal. calc. for C19H16F2N2O4S-0.25 H20: C, 55.53; H, 4.04; N, 6.81. Found: C, 55.58; H, 4.21; N, 6.61.
Example 437 2-(3 .4-Difluorop~henyl)-4-(4-inethyl-1 -pentyloxy)-5-f4-(inethylsulfonyl)phenyll-3(2H)pyridazi none 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-(nethylsulfonyl)phenyl]j- 3(2H)-pyridazi none and substituting 4-methyl-i -pentanol in place of 2-ethyl-ihexanol (yield: 120 mg, M-p. 98-99 1 H NMR (300 MHz, DMSO-d6) 8 0.73 J 7 Hz, 6H), 1.02 (in, 2H), 1.29 (in, 1 1 .54 (in, 2H), 3.30 3H), 4.40 (t, J 7 Hz, 2H), 7.52 (in, 1 7.62 (in, 1 7.81 (in, 1 7.90 J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MS (APCI+) in/z 463 (APCI-) m/z 497 -230- WO 99/10331 WO 9910331PCTIUS98/1 6479 Anal. calc. for 023H24F2N20 4 S: 0, 59.72; H, 5.23; N, 6.05. Found: C, 59.57; H, 5.28; N, 6.01.
Example 438 Dif Iuo roph enyl1)-4- methby-2-pe ntyloxy)-5-[4- (methylsu If o nl)phenyl1-3(2H)-pyridazi none The title compound was prepared according to the method of Example 178, starting with 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyll-3(2H)pyridlazinone 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, M.p. 132-133 00. 1 H NMR (300 MHz, DMSO-d6) 860.80 J =7 Hz, 3H), 0.87 J 7 Hz, 3H), 1.10 J 7 Hz, 3H), 1.26 (in, 1 1.50 (in, 1 H), 1.63 (in, 1 3.30 3H), 5.31 (in, 1 7.52 (in, 1 7.62 (in, 1 7.81 (in, 1 H), 7.90 J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MS (APCI+) m/z 463 (APCI-) in/z 497 Anal. calc. for C23H24F2N204S: C, 59.72; H, 5.23; N, 6.05. Found: 0, 59.44; H, 5.26; N, 5.99.
Example 439 2-(3.4-Difluorophenyl)-4-(2-cyclopentyl-1 -ethoxy)-54[4- (inethylsulfonvl)phenyl1-3(2H)-pyridazinone The title compound was prepared according to the method of Example 178, starting with 2-(3 ,4-dif luorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2
H)-
pyridlazi none in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]- 3(2-H)-pyridazi none and substituting 2-cyclopentyl-1 -ethanol in place of 2-ethyl-i hexanol (yield: 115 mg, M.p. 100-101 00. 1 H NMR (300 MHz, DMSO-d6) 6 1 .00 (mn, 2H), 1.38 (mn, 2H), 1.57 7H), 3.30 3H), 4.42 J 7 Hz, 2H), 7.52 (in, 1 7.62 (in, 1 7.81 (in, 1 7.90 J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MS (APCI+) m/z 475 (APOI-) mn/z 509 Anal. caic. for C24H24F2N 2 0 4 S-0.25 H20: C, 60.17; H, 5.15; N, 5.84. Found: C, 60.12; H, 5.14; N, 5.76.
-23 1- WO 99/10331 PCT/US98/16479 Example 440 2-(3.4-Difluorophenyl)-4-(2-cyclopent-2-enyl-1 -ethoxy)-5-[4- (methvlsulfonvl)phenvl]-3(2H)-pyridazinone 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 2ethyl-1-hexanol (yield: 95 mg, M.p. 126-127 1 H NMR (300 MHz, DMSOd6) 5 1.30 1 1.57 (sextet, J 7 Hz, 1H), 1.69 (sextet, J 7 Hz, 1 1.87 (m, 2H), 2.57 1H), 3.30 3H), 4.45 2H), 5.60 1H), 5.68 1H), 7.52 (m, 1 7.62 1 7.81 1H), 7.90 J 9 Hz, 2H), 8.08 J 9 Hz, 2H), 8.22 1 MS (APCI+) m/z 473 (APCI-) m/z 507 Anal. calc. for C24H22F2N204S: C, 61.00; H, 4.69; N, 5.92. Found: C, 60.76; H, 4.65; N, 5.80.
Example 441 2-(2-Hvdroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (700 mg, 1.5 mmol), and sodium borohydride (69 mg, 1.8 mmol) in ethanol (200 mL), was stirred at 40 °C for 2 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 MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a pale yellow solid which was crystallized from ethyl acetate/hexanes to provide the title compound as white crystals (yield: 540 mg, M.p. 205-207 1 H NMR (300 MHz, CDC13) 6 3.07 3H), 3.75 (br s, 1 4.63-4.47 2H), 5.33 (dd, J 9 Hz, 3 Hz, 1 7.00 J 9 Hz, 2H), 7.20 (dd, J 9 Hz, 3 Hz, 2H), 7.30-7.45 5H), 7.52 J 9 Hz, 2H), 7.91 1 7.91 J 9 Hz, 2H). MS (DCI-NH3) m/z 465 Anal. calc. for C25H21 FN204S: C, 64.64; H, 4.55; N, 6.03. Found: C, 64.34; H, 4.66; N, 5.93.
-232- WO 99/10331 PCT/US98/16479 Example 442 2-(2-Methoxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyll-3(2H)vpridazinone A mixture of the product from Example 441, 2-(2-hydroxy-2-phenylethyl)-4- (4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (210 mg, 0.45 mmol), iodomethane (56 gL, 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 MgSO4, 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, M.p. 135-137 1 H NMR (300 MHz, CDCI3) 8 3.07 3H), 3.26 3H), 4.33-4.52 2H), 4.91 (dd, J 9 Hz, 3 Hz, 1 H), 6.99 J 9 Hz, 2H), 7.20 (dd, J 9 Hz, 3 Hz, 2H), 7.31-7.50 7H), 7.87 1 H), 7.89 J 9 Hz, 2H). MS (DCI-NH3) m/z 479 Anal. calc. for C26H23FN204S: C, 65.25; H, 4.84; N, 5.85. Found: C, 64.98; H, 4.83; N, 5.81.
Example 443 2-(2-Methoxvimino-2-phenvlethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonv)phenvll]- 3(2H)-pyridazinone A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol), and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) 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 ammonium chloride. The organic layer was washed with brine then dried over MgSO4, 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 -233- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 from methanol/water to provide the title compound as a mixture of E and Z oximes (yield: 82 mg, M.p. 95-99 00. 1 H NMR (300 MHz, CDCI3) 8 3.03 3H), 4.07 3H), 5.57 2H), 6.94 J 9 Hz, 2H), 7.07 (dd, J 9 Hz, 3 Hz, 2H), 7.24 J 9 Hz, 2H), 7.31-7.37 (in, 3H), 7.60-7.67 (in, 2H), 7.74 1 7.83 J 9 Hz, 2H). MS (DCI-NH3) m/z 492 Anal. calc. for C26H22FN30 4 S: C, 63.53; H, 4.51; N, 8.54. Found: C, 63.40; H, 4.51; N, 8.31.
Example 444 2-(3 Difluorophenyl)-4-(4-methylpe ntyl)-5-[3-fluoro-4-(methylsu lfonvl)ohenyl]- 3 (2 H)-pyridazi none 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, M.p. 111-113 00. 1 H NMVR (300 MHz, DMSO-d6) 5 0.75 6H), 1.09 (in, 2H), 1.4 (in, 3H), 2.48 (mn, 2H), 3.4 3H), 7.61 (in, 2H), 7.75 2H), 7.81 (in, 1 8.02 1 8.1 2H). MS (DCI-NH3) m/z 447 464 (M+NH4)+.
Anal. caic. for C23H24F2N20 3 S: 0, 61.87; H, 5.42; N, 6.27. Found: C, 61.76; H, 5.55; N, 6.11.
Example 445 2-(3.4-Difluorop~henyl)-4-(3-methyl-1 -butoxy)-5-f4-(aminosulfonyl)pheny1I-3(2H)- 12rdznn The title compound was prepared as described in Example 384,-substituting 2- (3,4-dif luo roph enyl)-4- met hyl- 1 -butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone (Example 347) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4- (methylsulfonyl)phenyl]-3(2 H)-pyridazi none (yield: 248 mg, M.p. 149-1 51 00. 1 H NMR (300 MHz, DMSO-d6) 8 0.8 J 6 Hz, 6H), 1.48 (mn, 2H), 1.54 (in, 1 4.4 2H), 7.51 (in, 3H), 7.6 (in, 1 7.85 (in, 3H), 7.95 J 9 Hz, 2H), 8.21 1 MS (DCI-NH3) m/z 450 467 Anal. calc. for 021 H21 F2N 3 04S: C, 56.12; H, 4.71; N, 9.35. Found, C, 56.12; H, 4.67; N, 9.15.
-234- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 446 2-(2.2.2-Trifluoroethyl)-4-(2.2-dimethylpropoxy)-5-[4-(aminosulfonyl)phenyql-3(2H)py- Uizinone The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone prepared in Example 90C was reacted with 2,2-dimethylpropanol to provide 2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4- (methylthio)phenyl]-3 (2H)-pyridazi none according to the method of Example The product was oxidized with one equivalent of meta-ch lo rope roxybe nzoic 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-(2,2dimethylpropoxy)-5-[4-(methylsulf inyl)phenyll-3(2H)-pyridazi none for 2-(2,2,2trif luoroethyl)-4-(4-f luorophenyl)-5-[4-(methylsulfi nyl)phenyl]-3 (2H)-pyridazi none (yield: 125 mg, M.p. 123-1 24 0 C. 1 H NMR (300 MHz, 0D013) 860.82 9H), 4.18 2H), 4.82 J 9 Hz, 2H), 4.84 2H), 7.70 J 9 Hz, 2H), 7.81 1 H), 8.04 J 9 Hz, 2H). MS (DCI-NH3) m/z 420 Anal. calc. for C1 7H20F3N304S: 0, 48.68; H, 4.80; N, 10.01. Found: 0, 48.76; H, 4.77; N, 9.94.
Example 447 2-(2.2.2-Trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyll-3 (2H)pyriazione The title compound was prepared according to the method of Example 83, substituting 3-methyl-1-butanol in place of isopropanol (yield: 65 mg, M.p.
111-113 00. 1 H NMR (300 MHz, CDCI3) 8 0.84 J 6 Hz, 6H), 1.51 (in, 2H), 1.63 (in, 1 3.11 3H), 4.54 J 6 Hz, 2H), 4.83 J 9 Hz, 2H), 7.73 J 9 Hz, 2H), 7.82 1 8.05 J 9 Hz, 2H); MVS (DC I-N H3) m/z 419 Anal.
calc. for C1 8H21 F3N204S: 0, 51.66; H, 5.05; N, 6.69. Found: C, 51.91; H, 5.06; N, 6.56.
-235- WO 99/10331 WO 9910331PCTIUJS98/1 6479 Example 448 2-(2.2.2-Trifluoroethyl)-4-(3-methylbutoxy)-5-4-(aminosuIfonyl)phenyl]-3(2
H)-
The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone prepared in Example 900 was reacted with 3-methyl-i -butanol to provide 2-(2,2,2-trifluoroethyl)-4-(3-methylbutoxy)-5-[4-(methylthio)phenyl]- 3(2H)-pyridazi none according to the method of Example 90D. The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The sulfoxide was converted to the title compound according to the method 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-(4f luorophenyl)-5-[4-(methylsulfinyl)phenyl]-3(2H)-pyridazi none (yield: 65 mg, M.p. 123-12400C 1 H NMR (300 MHz, 00013) 860.84 J 6 Hz, 6H), 1.52 J 6 Hz, 2H), 1.60 J =7.5 Hz, 1 4.52 J 6 Hz, 2H), 4.83 J 9 Hz, 2H), 4.90 2H), 7.69 J =9 Hz, 2H), 7.82 1 8.04 J 9 Hz, 2H). MS (DCI-NH3) m/z 420 Anal. calc. for C1 7H20F3N 3 04S: 0, 48.68; H, 4.80; N, 10.01.
Found: 0, 48.86; H, 4.83; N, 9.92.
Example 449 2-(2.2,2-Trifluoroethyl)-4-(2-methylpropoxy)-5-[4-(aminosulfonyl)phenyl1-3(2H)pyridazinone The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]- 3(2H)-pyridazinone prepared in Example 900 was reacted with 2-methyl-i propanol to provide 2-(2,2,2-trifluoroethyl)-4-(2-methyipropoxy)-5-[4-(methylthio)phenyl]-3 (2 H)-pyridazi none according to the method of Example 90D. The product was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methyl sulfoxide. The sulfoxide was converted to the title compound according to the method of Example 68, substituting 2- (2 ,2,2-trifluoroethyl)-4-(2-methylpropoxy)- 5-[4-(methylsu Ifi nyl)phenyl]-3(2 H)-pyridazi none for 2-(2,2,2-trifluoroethyl)-4-(4fluorophenyI)-5-[4-(methylsulfinyl)phenyl].3(2H)-pyridazinone (yield: 120 mg, M.p. 170-17200C 1 H NMR (300 MHz, 00013) 80.83 J 6 Hz, 6H), 1.9 (in, 1 H), 4.3 (in, 2H), 4.82 2H), 4.88 (mn, 2H), 7.70 J 9 Hz, 7.79 1 8.03 J 9 Hz, 2H); MS (DC l-NH3) m/z 406 Anal. calc. for 016H18F3N304S: 0, 47.4; H, 4.47; N, 10.36. Found: 0, 47.48; H, 4.36; N, 10.25.
-236- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 Example 450 2-(2.3 .3-Trifluoropropenyl)-4-(4-f luorophenyl)-5-[4-(aminosulfonyl)phenyll-3(2H)pyrdanone The product of Example 4, 2-benzyl-4-(4-fluorophenyl)-5-14- (methylth io) pheny l]-3 (2 H)-pyridazi none, was N-debenzylated by the method of Example 11 to provide 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)pyridazinone. The intermediate was mixed with one equivalent of 1-methylsufonyloxy-2,3,3-t riflIuo ro-2- prope ne, (Example 88A) in ethyl acetate, followed by one equivalent of cesium carbonate. The reaction mixture was heated to 50 00 for hours. Aqueous work-up, followed by chromatography provided 2-(2,3,3-trifluoropropenyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)-pyridazi none (650 mg, 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-triflIuorop rope nyl) -4- 1 5 (4-f luorophenyl)-5-[4-(methylsulIf inyl)phenyl]-3 (2 H)-pyridazi none for 2-(2,2,2trifluoroethyl)-4-(4-f lu orophenyl)-5-[4- (methylsulfi nyl)phenyl]-3 (2H)-pyridazi none (yield: 65 mg, M.p. 190-1930C. 1 H NMR (300 MHz, CDOI3) 6 5.07 2H), 5.10 (dt, J 21 Hz, J 3 Hz, 2H), 7.05 (in, 4H), 7.19 (dd, J 9 Hz, J 6 Hz, 2H), 7.84 1 7.87 J 7.5 Hz, 1 MS (ESI-NH3) m/z 456 Anal. caic. for 019H12F5N303S: 0, 49.89; H, 2.64; N, 9.18. Found: 0, 49.89; H, 2.73; N, 9.03.
Example 451 2- Flu oro phe nyl)-4- hyd roxy-3-methyl- 1 -butoxy)-5-[4- (m ethyl su If onyl) PhenyL]- 3(2H)-pyridaz'non The title compound was prepared according to the method of Example 178, substituting 3-methyl-i ,3-butandiol in place of 2-ethyl-1 -hexanol (yield: 110 mg, M.p. 133-134 00 1 H NMR (300 MHz, DMSO-d6)861.04 6H), 1.72 J =7 Hz, 2H), 3.29 3H), 4.32 1 4.53 J 7 Hz, 2H), 7.37 J 9 Hz, 2H), 7.66 (in, 2H), 7.90 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.19 1 MS (APCI+) m/z 447 (APO m/z 481 Anal. calc. for 022H23FN205S*0.25 C, 58.59; H, 5.25; N, 6.21. Found: 0, 58.42; H, 5.00; N, 6.02.
-237- WO 99/10331 WO 9910331PCTIUS98/1 6479 Example 452 2-(3 .4-Difluorophenyl)-4-(2-hydroxy-2-methyl-1 -p2ropoxy)-5-[4 (methylsu If onyl)phenyll-3(2 H)-pyridazi none 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)pyridlazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]- 3(2 H)-pyridazi none and substituting 2-methyl-i ,2-propandiol in place of 2-ethyl-ihexanol (yield: 55 mg, 31%) H NMR (300 MHz, DMVSO-d6) 8 0.97 6H), 3.30 (s, 3H), 4.20 2H), 4.54 1 7.52 (in, 1 7.62 (mn, 1 7.81 (in, 1 7.98 J 9 Hz, 2H), 8.05 J 9 Hz, 2H), 8.21 1 MVS (APCI+) mlz 451 (APOI-) m/z 485 Anal. calc. for 021 H20F2N205S: C, 55.99; H, 4.47; N, 6.21.
Found: C, 56.00; H, 4.48; N, 5.87.
uExample 453 2- Dif luo rophenyl)-4-methoxy-5-(4-(methylsulf onyl)phenyll-3 (2 H)-pyridazi none The title compound was isolated from the reaction mixture in Example 233, as a product of oxidation of unreacted starting material (yield: 22 mg, M.p.
113-115 00. 1 H NMR (300 MHz, DMSO-d6) 583.3 3H), 4.1 3H), 7.53 (in, 1 H), 7.63 (in, 1 7.8 (in, 1 8.15 2H), 8.2 2H). MS (DCI-NH3) m/z 393 410 Anal. calc. for C18H14F2N204S: 0, 55.10; H, 3.60; N, 7.14.
Example 454 2-(2.3.4.5 .6-Pentafluorobenzyl)-4-(4-fluorophenyl)-5-[4-f(diinethylamino)methylenelami nosulfonylphenyll-3(2 H)-pyridazi none 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, M.p. 194-19600C 1 H NMR (300 MHz, CDCI3) 8 3.05 3H), 3.17 3H), 5.49 2H), 6.97 J 9 Hz-, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.20 J 9 Hz, 2H), 7.81 1 7.82 J 9 Hz, 2H), 8.14 1 MS (DCI-NH3) mlz 581 Anal. calc. for C26H18F6N 4 0 3 S: C, 53.79; H, 3.12; N, 9.65.
Found: 0, 53.50; H, 3.24; N, 9.56.
238-- WO 99/10331 PCT/US98/16479 Example 455 2-(2.4-Difluorobenzyl)-4-(4-fluorophenvl)-5-[4-(dimethvlamino)methylene]aminosulfonvlphenyll-3(2H)-pyridazinone 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, M.p. 193-195 1H NMR (300 MHz, CDCI3) 8 3.03 3H), 3.16 3H), 5.43 2H), 6.88 2H), 6.95 J 9 Hz, 2H), 7.18 (dd, J 9 Hz, 6 Hz, 2H), 7.20 J 9 Hz, 2H), 7.52 1 7.81 J 9 Hz, 2H), 7.84 1 H), 8.13 1H). MS (DCI-NH3) m/z 527 Anal. calc. for C26H21F3N403S: C, 59.30; H, 4.02; N, 10.64. Found: C, 59.08; H, 3.97; N, 10.48.
Example 456 2-(4-Fluorophenyl)-5-[4-(methylselenonylphenvl]-3(2H)-Dvridazinone 446A. 4-Bromoselenoanisole Freshly crushed magnesium turnings (6.1 g, 0.25 mol) were suspended with vigorous stirring in a solution of diethyl ether (360 mL) and 1,4-dibromobenzene 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 1,4dibromobenzene (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 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 °C and then was cooled to 0 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 oC. The reaction solution was slowly poured into ice water/1 M HCI 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 MgSO4, filtered, and concentrated in vacuo to provide a semi-viscous orange oil. On standing overnight at -20 large yellow needles formed. The residual oil was drawn off via pipette to provide 17 g of -239- WO 99/10331 PCT/US98/16479 crystalline product. Org. Chem., 1983, 48, 4169) 1 H NMR (300 MHz, CDCI3) 6 2.46 3H), 7.12 J 8.7 Hz, 2H), 7.39 J 8.7 Hz, 2H). MS (APCI+) m/z 248 (Se76 m/z 250 (Se78 m/z 252 (Se80 and m/z 254 (Se82 446B. 2.4-Bis(4-fluorophenyl)-5-[4-(methylseleno)phenyl]-3(2H)-pyridazinone 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, (prepared according to the method of Example 1, substituting 4-bromoselenoanisole in place of 4-bromothioanisole) in place of 4-(methylthio)benzeneboronic acid] in place of 2-(4-fluorophenyl)-4methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting 4fluorophenyl magnesium bromide in place of cyclohexylmagnesium chloride (yield: 44 mg, 1 H NMR (300 MHz, CDC13) 2.37 3H), 6.98 (dd, J 8.8, 8.8 Hz, 2H), 7.05 J 8.7 Hz, 2H), 7.17 (dd, J 8.7, 8.7 Hz, 2H), 7.23-7.31 2H), 7.32 J 8.7 Hz, 2H), 7.65-7.72 2H), 8.00 1 MS (APCI+) m/z 455 446C. 2.4-Bis(4-fluorophenyl)-5-[4-(methylselenonyl)phenyl]-3(2 H)-pridazinone A stirred solution of the 2,4-bis(4-fluorophenyl)-4-(4-fluorophenyl)-5-[4- (methylseleno)phenyl]-3(2H)-pyridazinone (40 mg, 88.1 mmol) in methylene chloride (2 mL) was treated with 3-chloroperoxybenzoic acid (100 mg, 342 mmol, 57-86%) at 23 OC. 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 The solution was diluted with ethyl acetate and carefully shaken with a NaHSO3 solution (two times) for several minutes to consume the excess 3chloroperoxybenzoic acid. The ethyl acetate solution was subsequently washed with a saturated Na2CO3 solution (two times), water, and brine and dried over MgSO4, 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, Chem. Soc., Chem. Commun., 1985, 569). M.p. 110-150 OC. 1H NMR (300 MHz, CDC3) 8 3.32 3H), 6.91 (dd, J 8.7, 8.7 Hz, 2H), 7.14- 7.27 4H), 7.48 J 8.4 Hz, 2H), 7.65-7.73 2H), 7.97 1 8.00 J 8.4 Hz, 2H). MS (APCI+) m/z 487 and m/z 504 Anal. calc. for -240- WO 99/10331 WO 9910331PCTIUS98/1 6479 C23H16F2N2O3SeO.5 H20: C, 55.68; H, 3.46; N, 5.66. Found: 0, 55.60; H, 3.61; N, 5.29.
Example 457 2-(3 .4-Dif luorophenyl)-4-(3-f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2
H)-
-Qriaznon The title compound was prepared as described in Example 62, starting with 4-(3-f luorophenyl)-5-[4-(methylsulIfonyl)phenyl]-3(2 H)-pyridazi none in place of 4-(4- 1 0 f luorophe nyl)-5-[4-(methylsulfonyl) phenyl]-3(2 H)-pyridazi none and substituting 3,4difluorobromobenzene in place of 1 -bro mo-4-f luo robe nzene (yield: 185 mg, M.p. 182-18500C 1 H NMR (300 MHz, DMVSO-d6) 863.23 3 6.98 J 9 Hz, 1 7.18 (in, 2H), 7.32 (in, 1 7.52 J 9 Hz, 2 7.6 (mn, 2H), 7.85 (in, 1 7.9 J 9 Hz, 2H), 8.3 1 MS (DCI-NH 3 in/z 457 474 (M+NH4)+.
Example 458 2-(4-Fluorophenyl)-4-(3-fluorophenyl)-5-[4-(methylsu lfonyl)phenyl]-3(2H)pyridainone The title compound was prepared as described in Example 62, substituting 4-(3-f luorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazi none in place of 4-(4f luorophenyl)-5-[4-(methylsulf onyl)phenyl]-3 (2H)-pyridazi none (yield: 135 mg, M.p. 199-201 00. I H NMR (300 MHz, DMSO-d6) 8 3.24 3H), 6.98 J= 9 Hz, 1 7.18 (in, 2H), 7.32 (in, 1 7.39 1 7.54 J 9 Hz, 2 7.71 (in, 2H), 7.91 J 9 Hz, 2 8.27 1 MS (DCI-NH3) in/z 439 456 (M+NH4)+.
-24 1- WO 99/10331 WO 9910331PCT/US98/I 6479 Example 459 2-(3 .4-Dif luorophenyl)-4-(2-hydroxy-2-m-ethylpropoxy)-5-[4-(aminosu Ifonfl)phenyll-3 (2 H)-pyridazi none 2-(3 ,4-Dif luorophenyl)-4-(2-hydroxy-2-methylpropoxy)-5-[4-(methylsu Ifonyl)phenyll-3(2 H)-pyridazi none (Example 452) is converted to the title sulfonamide according to the method of Example 384.
Example 460 2-(3.4-Difluorophenyl)-4-(2-oxo-1 -prop~oxvy)5-[4-(methylsulfonyl)phenyll-3(2H)p2yridazinone A solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazi none (378 mg, 1 mmol), Ph3P (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 THE (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, M.p. 169-170 00. 1 H NMR (300 MHz, DMSO-d6) 6 2.08 3H), 3.30 3H), 5.30 7.48 (in, 1 7.62 J 10 Hz, 1 7.75 (in, 1 7.94 J 9 Hz, 2H), 8.05 J 9 Hz, 2H), 8.21 1 MS (APCI+) m/z 435 (APOI-) m/z 469 Anal. calc. for C2cjH1 6F2N2O5S-0.75H2O: C, 53.62; H, 3.93; N, 6.25. Found: C, 53.26; H, 3.61; N, 6.08.
Example 461 2-(3.4-Difluorophenyl)-4-[2-(methoxyimino)propoxyl-5-[4-(methylsulfonyl)pheny-L 3(2H)-pyridazinone A mixture of 2-(3,4-difluorophenyl)-4-(2-oxo-1 -propoxy)-5-[4- (methylsulfonyl)phenyl]-3 (2H)-pyridazi none from Example 460 (150 mg, 0.3 minol) in H20 (10 mL) and dioxane (20 mL) was treated with methoxylamine -242- WO 99/10331 PCT/US98/16479 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, M.p.
143-145 OC. 1 H NMR (300 MHz, DMSO-d6) 5 1.63 3H), 3.30 3H), 3.74 (s, 3H), 4.93 2H), 7.54 1 7.65 J 10 Hz, 1 7.82 1 7.92 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.24 1 MS (APCI+) m/z 464 (APCI-) m/z 498 Anal. calc. for C21 H19F2N305S: 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-Difluorophenvl)-4-(3-hydroxv-2-methylpropoxy)-5-[4-(methylsulfonvl)phenvyl-3 (2 H)-vyridazinone 462A (R)-3-t-Butoxv-2-methyl-1-propanol A solution of (S)-(+)-methyl 3-hydroxy-2-methylpropionate (1.18 g, 10 mmol) in t-butyl acetate (30 mL) was treated with 70% HCI04 (0.1 mL), and the reaction mixture was left at room temperature in a tighthly closed flask for 24 hours. The mixture was poured into a saturated solution of sodium bicarbonate and extracted with diethyl ether. The ether was removed in vacuo and the residue was dissolved in THF (50 mL). To the resulting solution was added sodium borohydride (925 mg, mmol) and at 55 °C dropwise methanol (10 mL). The reaction was continued at °C for 1 hour, then cooled to room temperature, acidified with 10% citric acid to pH 5 and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 2:1 hexanes-ethyl acetate) to provide (R)-3-t-butoxy-2methyl-1-propanol (yield: 1 g, 1 H NMR (300 MHz, CDCI3) 6 0.85 J 7 Hz, 3H), 1.20 9H), 2.03 1H), 3.30 J 12 Hz, 1H), 3.53 (dd, J 12 Hz, Hz, 1 3.70 2H). MS (DCI-NH3) m/z 164 (M+NH4)+.
462B 2 -(3.4-Difluoroohenvl)-4-(3-t-butoxv-2-methylpropoxy)-5-[4- (methylsulphonyl)phenyll-3(2H)-pyridazinone To a solution 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (378 mg, 1 mmol), Ph3P (524 mg, 2 mmol) and the above -243- WO 99/10331 PCT/US98/16479 alcohol, (R)-3-t-butoxy-2-methyl-1-propanol (146 mg, 1 mmol) in THF (25 mL) at room temperature was added dropwise a solution of DIAD (0.4 mL, 2 mmol) in THF 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 (hexanesethyl acetate as an eluent) to provide 550 mg of roughly purified difluorophenyl)-4-(3-t-butoxy-2-methylpropoxy)-5-[4-(methylsulphonyl)phenyl]- 3(2H)-pyridazinone, still contaminated with reduced DIAD. MS (APCI+) m/z 507 (APCI-) m/z 541 462C (S)-2-(3.4-Difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)phenvl]-3(2H)-pyridazinone A mixture of the above product (100 mg, -0.2 mmol) in TFA (5 mL) was stirred at room temperature for 24 hours and then concentrated in vacuo. The residue was neutralized with saturated NaHCO3 and extracted with ethyl acetate.
Purification by column chromatography (silica gel, 1:2 hexanes-ethyl acetate) provided the title compound (yield: 51 mg, 1 H NMR (300 MHz, DMSO-d6) 0.75 J 7 Hz, 3H), 1.81 (septet, J 7 Hz, 1 3.21 J 6 Hz, 2H), 3.30 (s, 3H), 4.29 (dd, J 12 Hz, 6 Hz, 1 4.40 (dd, J 12 Hz, 6 Hz, 1H), 4.48 (br s, 1 H), 7.52 1 7.61 1 7.80 1 7.91 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.20 1H). MS (APCI+) m/z 451 (APCI-) m/z 485 Anal.
calc. for C21 H20F2N205S: 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-DifluoroDhenvl)-4-(3-hydroxv-2-methylpropoxy)-5-[4-(methylsu Ifonyl- Dhenvl]pyridazinone The desired material was prepared according to the procedure of Example 462 starting with (R)-(-)-methyl 3-hydroxy-2-methylpropionate in place of methyl 3-hydroxy-2-methylpropionate (yield: 65 mg, 1H NMR (300 MHz, DMSO-d6) 8 0.75 J 7 Hz, 3H), 1.81 (septet, J 7 Hz, 1 3.21 J 6 Hz, 2H), 3.30 3H), 4.29 (dd, J 6 Hz and 12 Hz, 1 4.40 (dd, J 6 Hz and 12 Hz, 1 H), 4.49 J 6 Hz, 1 7.52 1 7.61 1 7.80 1 7.91 J 9 Hz, 2H), 8.07 J 9 Hz, 2H), 8.20 1 MS (APCI+) m/z 451 (APCI-) m/z -244- WO 99/10331 PCT/US98/16479 485 Anal. calc. for C21 H20F2N205S: 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-hydroxv-2-methylpropoxy)-5-[4-(aminosulfonyl)phenvl]-3(2H)-pvridazinone To a solution of (S)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5- [4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 462 (450 mg, -0.9 mmol) and DBAD (207 mg, 0.9 mmol) in THF (25 mL) at -78 °C was added dropwise 1 M lithium bis(trimethylsilyl)amide solution in THF (3 mL, 3 mmol). The resulting mixture was stirred at -78 °C for 2 hours. The mixture was warmed to room temperature and 1N NaOH was added (5 mL, 5 mmol). After 12 hours, at room temperature, sodium acetate trihydrate (2.76 g, 20 mmol) and H20 (10 mL) followed by hydroxylamine-O-sulphonic 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-ethyl acetate) to provide the desired intermediate (yield: 160 mg, MS (APCI+) m/z 508 (APCI-) m/z 542 TFA (5 mL) was added to the above intermediate and the resulting solution was stirred at room temperature for 24 hours. The TFA was removed in vacuo, and the residue was neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic extract was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed (silica gel, 1:2 hexanes-ethyl acetate) to provide the title compound (yield: 50 mg, 1H NMR (300 MHz, DMSO-d6) 5 0.76 J 7 Hz, 3H), 1.81 (sextet, J 7 Hz, 1 3.22 J 6 Hz, 2H), 4.28 (dd, J 12 Hz, 6 Hz, 1 4.40 (dd, J 12 Hz, 6 Hz, 1 4.50 J 6 Hz, 1 7.51 3H), 7.61 1 7.80 1 7.84 J 9 Hz, 2H), 7.95 J 9 Hz, 2H), 8.20 1 MS (APCI+) m/z 452 (APCI-) m/z 486 -245- WO 99/10331 WO 99/ 0331PCTLUS98/1 6479 Example 465 2- DiflIuo rop he nyl)-4- hydroxy-2-m ethyl propoxy)-5-[ 4- (am ino su If onyl)phenyll-3(2 H)-pyridazi none The title compound was prepared according to the procedure of Example 464 starting with (R)-2-(3,4-difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4- (methylsulfonyl) phenyl]-3 (2 H)-pyridazi none in place of (S)-2-(3,4-difluorophenyl)hyd roxy-2- methylpropoxy)-5-[4-(methylsuIf onyl)phenyll-3 (2H) -pyridazi none (yield: 30 mg, 1 H NMVR (300 MHz, DMSO-d6) 8 0.76 J 7 Hz, 3H), 1.81 (sextet (J 7 Hz, 1 3.22 J 6 Hz, 2 4.28 (dd, J 6 Hz and 12 Hz, 1 4.40 (dd, J 6 Hz and 12 Hz, 1 4.50 J 6 Hz, 1 7.51 (in, 3H), 7.61 (in, 1 7.80 (in, 1 7.84 J 9 Hz, 2H), 7.95 J 9 Hz, 2H), 8.20 1 MS (APCI+) m/z 452 (APOI-) m/z 486 Anal. caic. for C20HjqF2N305S: 0, 53.21; H, 4.24; N, 9.30. Found: C, 53.45; H, 5.53; N, 9.50.
Example 466 Fluo rophe n hyd roxy- 3- methyl butoxy)-5-[4-(methylsu IPh onyl)2h e nyll- 3 (2H)-pyridazi none.
The title compound was prepared according to the method of Example 178, substituting 2-methyl-i ,4-butanediol in place of 2-ethyl-i -hexanol and separating the regiolsomeric products by preparative TLC using Silica Gel with ethyl acetate:hexanes 1 H NMR (300 MHz, 0D013) 8 0.87 J 8.1 Hz, 3H), 1.48- 1.87 (in, 4H), 3.13 3H), 3.41 (dd, J 6.3, 13.5 Hz, 1 3.46 (dd, J 6.3, 13.5 Hz, 1 4.48-4.63 (mn, 2H), 7.15-7.24 (in, 2H), 7.58-7.66 (in, 2H), 7.79 J=1 0.5 Hz, 2H), 7.91 1 8.07 J 10.5 Hz, 2H). MS (APCI+) in/z 447 Example 467 2-(3 .4-difluorophenyl)-4- (3-oxobutoxy)-5-[4-(inethylsulfonyl)pheny11-3(2H)pydziann The title compound is prepared according to the method of Example 460 I3substituting 4-hydroxy-2-butanone in place of acetol. (yield: 95.0 ing, 21 M.p.
134-1 35 OC. 1 H NMR (300 MHz, 00013) 82.06 3H), 2.81 J 9 Hz, 2H), 3.13 3H), 4.75 J 9 Hz, 2H), 7.30 (in, 1 7.45 (in, 1 7.58 (in, 1 7.73 J 9 -246- WO 99/10331 PCT/US98/16479 Hz, 2H), 7.89 1 8.05 J 9 Hz, 2H) MS (DCI-NH3) m/z 449 466 Anal. calc. for C21H18F2N20 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-FluoroDhenvl)-4-(3-oxobutoxy)-5-[4-(methylsulfonl)phenl]-3(2 H)pyridazinone The title compound is prepared according to the method of Example 460 starting with 2-(4-fluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)pyridazinone in place of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-hydroxy-2-butanone in place of acetol. (yield: 85.0 mg, M.p. 133-136 OC. 1 H NMR (300 MHz, CDCI3) 8 2.04 3H), 2.80 J 9 Hz, 2H), 3.13 3H), 4.76 J 9 Hz, 2H), 7.20 J 9 Hz, 2H), 7.55 2H), 7.75 J 9 Hz, 2H), 7.91 1 8.05 J 9 Hz, 2H). MS (DCI-NH3) m/z 431 448 Anal. calc. for C21H19FN205S: C, 58.60; H, 4.42; N, 6.52. Found: C, 58.87; H, 4.55; N, 6.51.
Prostaglandin Inhibition Determination Compound Preparation and Administration 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, NY).
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 IC50's/ED50's in appropriate assays.
EIA Determination of Prostaglandins EIA reagents for prostaglandin determination were purchased from Perseptive Diagnostics, (Cambridge, MA). Prostaglandin E2 (PGE2) levels in lavage fluids were determined after the samples were dried under nitrogen and -247- WO 99/10331 PCT/US98/16479 reconstituted with assay buffer. PGE2 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, CA).
Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays Inhibition of prostaglandin biosynthesis in vitro was evaluated using recombinant human Cox-1 (r-hu Cox1) and Cox-2 (r-hu Cox2) enzyme assays.
Representative compounds dissolved in DMSO v/v) were preincubated with microsomes from recombinant human PGHS-1 or PGHS-2 expressed in the baculovirus/Sf9 cell system (Gierse, J. Hauser,S. Creely, D. Koboldt, C., Rangwala, Isakson, P. and Seibert, K. Expression and selective inhibition of the constituitive and inducible forms of cyclooxyvenase Biochem J.
1995, 305: 479.), together with the cofactors phenol (2 mM) and hematin (1 pIM) for minutes prior to the addition of 10 iM arachidonic acid. The reaction was allowed to run for 2.5 minutes at room temperature prior to quenching with HCI and neutralization with NaOH. PGE2 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, CA). EIA reagents for prostaglandin determination were purchased from Perseptive Diagnostics (Cambridge, MA). PGE2 levels were measured against standards prepared in the same milieu. The immunoassays were conducted as recommended by the manufacturer.
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-2 inhibition that are parenthetical indicate IC50 values.
SEE ATTACHED TABLE -248- WO 99/10331 WO 9910331PCT[US98/I 6479 Table 1 Example RIIUCX1 RI-UCX2 Numbers Inh. at lnh. at (tM) Doe(W 2 @100 (0.014) 12 0 @100 97@ 77 1 10 @100 86 @0.1 0.01 21 19 @100 (0.92) 22 ~25 @100 91 @0.03 0.01 23 0 @100 68 @0.1 27 0.01 24 60 @100 99@ 1 0 @10 61 @0-1 @0.01 1 @100 93@ 1 66 0.1 26 10 @100 91@ 1 44 @0.1 44 0.01 32 20 @100 96@ 1 3 0.1 34 16 100 (0.92) -249- WO 99/10331 WO 99/ 0331PCT/US98/1 6479 34 @100 (0.017) 36 21 10 (0.57) 39 0 @100 (0.44) 76@ 10 97@ 1 69 @1 89 @0.1 41 13 @100 49@ 1 0.1 42 0@ 100 99@ 1 92 0.1 43 8 @100 100@ 1 96 0.1 5 @100 85@ 1 63 @0.1 48 0 @100 73@ 1 2 0.1 23 @100 99@ 1 59 0.1 52 32@ 10 99@ 1 83 0.1 53 10 @100 99@ 1 0.1 54 0 @100 95@ 1 58 0.1 58 0 @100 (0.95) -250- WO 99/10331 WO 9910331PCTJUS98/I 6479 7@ 100 100 1,000 62 6 100 (0.624) 64 68@P1 34@ 1 36@ 0.1 13 @100 98 @1 0.1 68 32 100 (0.297) 69 2 @100 88@1l 29 0.1 30 0.01 72 0 @100 65@ 1 18 @0.1 73 9 @100 (1.34) 74 11 @100 86@ 1 77 35 @100 82@ 39 1 41 10 (0.064) 37 1 81 6 @100 97@ 1 44 0.1 84 49@10 87 @0.3 9@_-b1 1- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 88 0 @.100 97 1,000 35 0.1 89 62 30 (0.35) 97 35 100 (0.332) 100 62@ 10 100 1 61 @0.1 105 85@ 1 98@ 1 0.1 106 19 @200 (0.135) 107 88@ 10 86@ 1 5091 36 @0.1 108 0 100 (0.279) 109 6 @100 (0.147) 110 5 @100 93@ 1 0.1 111 13 @100 (0.052) 112 5 @100 (0.136) 118 31 @100 72 @0.1 0.01 119 (0.178) (0.027)- 120 15 @100 97@ 1 0.1 121 0 100 (0.005) 2- WO 99/10331 WO 9910331PCT/US98/1 6479 122 1 100 (0.285) 124 26 @100 (0.044) 127 50 @10 74@1 @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) 10 140 (3.06) (0.022) 141 55 @100 99@ 1 62 @10 95 @0.1 142 80@ 10 9 6@C)1 53@1 45 @0.1 32 0.01 143 62 100 (0.076) 43 144 (0.058) 88 1 78 0.1 0.01 145 (0.238) 86 @0.1 56 0.01 146 82@10 100 @1 53 @1 73 @0.1 3- WO 99/10331 WO 9910331PCT/US98/1 6479 147 (0.067) 100@c-b1 64 0.1 0.03 149 45 @c 10 (0.003) 40 P 1 150 56@100 100 @0.1 39@ 153 54@C- 100 (0.062) 154 (0.126) (0.018) 165 0@C-)100 (1.08 166 3@100 (0.199) 168 0@ 100 8 5@C)1 0.1 171 0@CD100 82@1 0 74 1 61 @0.1 178 6@ 100 92 @1,000 349@10 180 8@C-b100 78@1 48 0.1 182 (0.07) 183 25 @100 97@ 1 51 0.1 187 2 100 (0.094) -254- WO 99/10331 WO 9910331PCT/US98/I 6479 188 18@9100 (0.526) 190 (1.88) (0.134) 194 3 5@C)10 0 90@ 73 1 72 0.1 198 10@c-b100 68@ 1 23 0.1 207 97@ 1 81 0.1 209 0 @100 79@ 1 @0.1 0.01 213 0 @100 (0.812) 219 20@C-)100 90@ 1 0.1 220 51 @100 96@ 1 38 @1 90 @0.1 226 0 @100 (1.09) 228 100 (0.209) 230 4@C-)100 (0.215) 231 7 @100 90@ 1 68 0.1 232 23 100 (0.024) 234 0 100 _(0.328) -255- WO 99/10331 WO 9910331PCT[US98/1 6479 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 @1 71 @1 51 @0.1 248 13 100 (0.08) 249 6 @100 9 8@C)1 68@0.1 43 0.01 252 0@C)10 0 87 @0.1 @E 0.01 253 77 100 (0.272) 29 254 7@100 84@ 1 489@0.1 256 0@c)100 (0.134) 257 0 100 (0.04) 260 8 @100 2@C-b10 261 0 @200 161)_ -256- WO 99/10331 WO 9910331PCTIUS98/1 6479 262 15 @100 (0.432) 263 1 @100 85 76 1 53 0.1 265 8 @100 53 48 1 0.1 272 0 @100 70@ 1 0.1 273 16 @100 54 42 1 278 36 @1l0 96@ 1 91 0.1 279 0 @100 60@ 1 0.1 281 7 @100 71@ 1 52 @0.1 47 0.01 283 0 @100 90@ 71 1 54 0.1 287 0 @100 93 79 1 0.1 314 7 @100 51 -257- WO 99/10331 WO 9910331PCTJUS98/1 6479 318 23 @100 97@ 1 S77 0.1 321 4 @100 (0.192) 322 39 @100 (0.058) 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 -258- WO 99/10331 WO 99/ 0331PCTJUS98/1 6479 352 0 @100 (0.154) 353 6 100 (0.826) 354 0 @100 45 1 36 0.1 355 0 @100 79 66 1 46 0.1 358 30 100 (2.45) 361 3 @100 (0.011) 362 1 @100 84@ 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) 371 372 8 100 0 100 (0.166).
94 88 1 59 @0.1 -259- WO 99/10331 WO 9910331PCT/US98/1 6479 374 2 100 (0.02) 375 46 @100 (0.18) 31 376 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 @1 65 @0.1 56 0.01 388 74 10 (0.049) 36 1 390 88 @10 99 @1 72@ 1 0.1 392 56 @100 82 @0.1 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 -260- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 395 91@()100 93@ 1 35@910 77@O.1 34 0.01 396 229@100 (0.059) 397 25@P100 93@ 1 58 @0.1 39 0.01 398 269@100 (0.202) 400 27@P100 (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 0.01 404 77 Ca@ 100 92 0.1 47@C-)10 57 @0.01 405 90 100 (0.198) 61 @cb10 406 23@C-)100 100 @1 64 @0.1 18 0.01 407 32 100 (0.17) 408 0 100 (0.279) -26 1- WO 99/10331 WO 9910331PCTIUS98/1 6479 410 48@9100 67 @0.035 )110 47 @0.017 411 96@C)10 (0.009) 81 1 412 31 @100 (0.002) 413 0@100 (0.11) 414 0@100 8 7@C)1 76 @0.1 418 33 @100 85@ 1 52 @0.1 53 0.025 419 12@CD100 (0.1) 420 29 100 (0.323) 421 (0.269) 92@ 1 81 0.1 38 0.01 422 53@C)100 52@CD1 82 @10 37 @0.1 76 1 423 0@100 87@ 1 68 @0.1 0.01 424 7 @100 75@ 1 58 0.1 33 0.01 425 12 @100 69 @0.1 319@ 0.01, -262- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 426 1 Ca- 10 0 (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 @0.1 445 (56.62) (0.069) 446 0 200 (0.373) 447 0 @100 90@ 1 57 @0.1 0.01 449 5 @200 (0.129) 450 29 @100 87@ 1 0.1 451 10 @100 43@ 1 @0.1 -263- WO 99/10331 PCT/US98/16479 452 14 100 15 @1 IL-1B Induced PGE2 Production in WISH Cells Human amnionic WISH cells were grown to 80% confluence in 48 well plates. Following removal of the growth medium and two washings with Gey's Balanced Salt Solutn, 5 ng IL-1 1/ml (UBI, Lake Placid, NY) was added to the cells with or without test compound in DMSO (0.01% v/v) in Neuman-Tytell Serumless Medium (GIBCO, Grand Island, NY). Following an 18 hour incubation to allow for the maximal induction of PGHS-2, the conditioned medium was removed and assayed for PGE2 content by EIA analysis as described above.
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.
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 IC50 values. WISH cell values indicate percent inhibition at the particular micromolar dose level while parenthetical values indicate IC50 values.
Human Whole Platelet Cyclooxygenase-1 Assay (HWCX) Blood from normal healthy volunteers is collected into tubes containing ACD (acid citrate dextrose) as the anticoagulant. This blood is centrifuged at 175 x g to prepare platelet rich plasma. The platelet rich plasma is then centrifuged at 100 x g to pellet the white blood cells, leaving the platelets in the supernatant. The supernatant is layered on a cushion of 0.7 mL of 10% bovine serum albumin in Tyrodes solution (Gibco; Grand Island, NY) and then centrifuged at 1000 x g. The resulting supernatant from this centrifugation is then removed and 11 mL of Tyrodes solution is added to the remaining pellet of platelets. The platelets are then aliquoted at 120 !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 gM 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 x g, and the -264- WO 99/10331 WO 9910331PCTIUS98/1 6479 supernatants are then analyzed for thromboxane using a commercial kit from Cayman Chemical (Ann Arbor, MI).
SEE ATTACHED TABLE Table 2 Example U937 I-WPX Wish Numbers Inhib. at Inhib. at Inhib. at Dose Dose (jiM) (0.014) 33@1 (0.001) 24 (0.19) (0.007) 43 86@ 10 (0.008) 9@ 1 53 78 @10 90 @0.1 8P1 44@g0.01 (0.02) 69 (1.14) (0.02) 72 (25) (0.072) 84@P10 (0.001) 77 (0.126 (0.47) 86 52 1 0.01 89 (0.05) 100 (0.13) (0.02) 102 (0.05) 105 62@ 1 (0.018) 106 (17.5) (0.03) 108 (0.097) 109 (2.693) (0.018) 119 (0.076) (0.001) -26 WO 99/10331 WO 9910331PCT/US98/1 6479 120 74 @3 (0.025) 58 1 121 (0.041) 123 90@ 1 (0.001) 29 .1 126 129 (0.04) 132 100 0.1 36 0.01 140 (0.773) (0.01) 141 @0.3 (0.004) 142 (7.53) (0.088) 143 _(0.007) 145 72 @1 (0.009) .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) 3 152 (0.029) 153 (2.95) (0.046) 154 81 100 @0.1 69 @0.01 160 (0.03) 162 (0.034) 165 (0.030) 166 (0.02) 168 47 1 (0.009) 171 90 1 0.1 187 (12.6) (0.015 -266- WO 99/10331 WO 99/ 0331PCTIUS98/1 6479 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 2.52 256 (0.028) 261 (34) (0.099) 271 52 1 @0.1 278 (0.07) 279 (0.391) 287 (0.16) 317 (0.027) 320 29 @3 78 @.l 15 .01 321 50 0.01 322 (0.026) 323 57 0.01 324 (0.047) -267- WO 99/10331 WO 9910331PCT/US98/1 6479 325 (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 (6.048) 358 69 1 0 0.1 366 (1.615) (0.002) 367 50 1 (0.018) 8 368 (13.7) 64 @0.03 @E 0.0 1 370 (0.02) 374 (0.03) 381 319@30 (0.075) 91 385 (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 0.03 400 (0.026) 401 (0.32) (0.017) -268- WO 99/10331 PCT/US98/16479 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 1 0 446 (24.4) (0.02) 449 (40) (0.089) 450 (0.05) 451 (25.6) (0.15) 452 56 1 1 0.1 Carrageenan Induced Paw Edema (CPE) in Rats Hindpaw edema was induced in male rats as described by Winter et 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, NY).
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 -269- WO 99/10331 PCT/US98/16479 significance of results was analyzed by Dunnetts multiple comparison test where p< 0.05 was considered statistically significant.
Rat Carrageenan Pleural Inflammation (CIP) Model Pleural inflammation was induced in male adrenalectomized Sprague- Dawley rats following the method of Vinegar et 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.
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.
Carrageenan induced air pouch prostaglandin biosynthesis model (CAP) Air pouches are formed in the backs of male Sprague Dawley rats by injecting 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 ED50 values.
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.
See attached table -270- WO 99/10331 WO 9910331PCTIUS98/1 6479 3 Example CIP CPE CAP Numbers Inhib. Inhib. Inhib.
mpk 10 mpk @3mpk 44 12 42 34 36 31 54 31 58 42 14 67 62 57 21 66 59 7 0 67 40 @3mpk 68 64 40.3 69 61 45.5 87 ED30 5.4 72 73 46 29 74 46.5 18 34 77 51 21 60 28.5 91 89 68.3 45.5 94 ED0= 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 -27 1- WO 99/10331 WO 9910331PCTIUS98/1 6479 160 56 166 40 59 168 0 .6 180 34.5 182 59 27 98 185 59 20 53 187 51 28 190 60 28 71 205 54 226 21 40.5 243 7 245 47 246 48 248 49 256 47 257 261 28 79 330 335 339 43 90.5 0.58 346 49.5 347 27 66.5 349 63 351/64 0 352 89 353/63 0 361 366 63 367 48 -272- WO 99/10331 WO 9910331PCTIUS98/1 6479 375 47 91 0.30 376 17 77.5 378 59 384/33 51 15 51 385 388 28 390 391 392 394 395 71 396 23 397 400 65 41 403 43 68.5 0.35 405 53 406 23 66.5 407 61 419 48 427 78 445 15 73 446 44 92 ED0= 449 23 76 1.8 450 86 451 80.5 1 452 71 -273- WO 99/10331 PCT/US98/16479 Pharmaceutical Compositions 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; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as 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, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
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.
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.
-274- WO 99/10331 PCT/US98/16479 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 pharmaceutrically acceptable carrier.
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 II or a pharmaceutically acceptable salt, ester, or prodrug thereof, and a pharmaceutrically acceptable carrier.
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 III or a pharmaceutically acceptable salt, ester, or prodrug thereof, and a pharmaceutrically acceptable carrier.
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.
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 a compound of formula II or a pharmaceutically acceptable salt, ester, or prodrug thereof.
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 compound of formula III or a pharmaceutically acceptable salt, ester, or prodrug thereof.
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.
In addition, the compounds of the present invention may be useful by providing a method for treating pain, fever, inflamation, rheumatoid arthritis, -275- WO 99/10331 PCT/US98/16479 osteoarthritis, adhesions, and cancer comprising administering to a mammal in need of such teratment a therapeutically effective amount of a compound of formula
II.
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
III.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
In addition to the active compounds, the liquid dosage forms 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, 1,3butylene 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.
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, Ringer's 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.
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 -276- WO 99/10331 PCT/US98/16479 be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
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.
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.
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 -277- WO 99/10331 PCT/US98/1 6479 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.
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.
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.
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, 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.
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.
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, poly- -278- WO 99/10331 PCT/US98/16479 ethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
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.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms 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.
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.
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 -279parenteral administration daily. Single dose compositions may-contain such amounts or submultiples thereof to make up the daily dose.
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.
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, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652- 3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense, except where the context requires otherwise.
It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general 20 knowledge in the art, in Australia or in any other country.
oo* *o -280-
Claims (19)
1. A compound of formula 1: N R 2 X where X is selected from the group consisting of 0, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of. alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and Ra, Rb, and RC are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; 10 R is selected from the group consisting of.alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, aryihydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxylhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C(0)R 5 -(CH2)nC(0)R 5 -R 6 -R 7 :-(CH2)nCH(OH)R 5 -(CH2)nCH(ORd)R5, -(CH2)nC(NRd)R5, -(CH2)nC-=C-R 7 -(CH2)nICH(CX'3)Im-(CH2)n-CX'3, -(CH2)n(C X'2)m-(CH2)n CX'3, -(CH2)n[CH(CX'3)]m-(CH2)n -R 8 -(CH2)n(C X'2)m-(CH2)n R8 H2)n(CHX')m-(CH2)n CX'3 -(CH2)n(CHX')m-(CH2)n -R 8 and (CH2)n-R 2 0 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl; -28 1- wherein R 6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene; R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; R 2 0 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; R d and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen; n is from 0 to about 10, and m is 0 to about R 2 is X2 X2 where X 1 is selected from the group consisting of -S02-, -SO(NR 1 0 SeO2-, PO(OR 1 1 and -PO(NR1 2 R 1 R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, :'ii cycloalkyl, cycloalkenyl, amino, -NHNH 2 -N=CH(N R 1 0R 11 dialkylamino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X' by an alkylene; X 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl; R 1 0 R 1 1 R 1 2 and R 1 3 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 1 2 and R 1 3 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms. at least one of R 1 or R 3 is selected from the group consisting of hydroxyalkyl, hydroxyalkoxy, mercaptoalkoxy, hydroxyalkylthio, and, hydroxyalkylamino, wherein the remaining group is Sselected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, I halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, -282- WO 99/10331 WO 9910331PCTIUS98/1 6479 alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamnino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic(alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylami no, hydroxyalkoxy ,hydroxyalkylthio, me roaptoalkoxy, oxoalkoxy, cyano, nitro, and -Y-R 1 4 wherein Y is selected from the group consisting of -C(R 16 (R1 7 -C(0)NR 2 lR 2 2 -N=C RZ 1 R 2 2 N- R 21 R 22 and -NR 19 R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, hete rocyclic, and heterocyclic(alkyl), R 16 R 17 and R 19 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and R 21 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
2. A compound having the formula 11: R3 N R wherein Z is a group having the formula: -283- where X 1 is selected from the group consisting Of -S02-, -SeO2- and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH2, dialkylamino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to XV by. an alkylene; R 10 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl; X 2 is selected from the group consisting of hydrogen, halogen, alkyl, 1 0 alkenyl, and alkynyl; is selected from the group consisting ofa-plkyl, alkenyW-- alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, 15 haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, aryihydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heteroc yclic oxy, -C(O)R 5 -(C.H2)nC(O)R 5 -R 6 -R 7 -(CH2)flCH(OH)R 5 -(CH2)nCH(ORd)R5, 20 -(CH2)nC(NRd)R5, -(CH2)nCH(NORd)R5, -(CH2)nCaC-R 7 -(CH2)n[CH(CX'3)lm-(CH2)n-CX'3, -(CH2)n(C X 2)m-(CH2)n -CX'3, -(CH2)n[CH(CX'3)]m-(CH2)n -R 8 -(CH2)n(C X'2)m-(CH2)n R 8 H2)n(CHX')m-(CH2)n CX'3 -(CH2)n(CHX')m-(CH2)n -R 8 and (CH2) nR 2 0 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl; wherein R 6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene; -284- R 7 and R 8 are- independently selected fronithe-group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; Rd and Re are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; X' is halogen; n is from0 toabout 10, and mis 0to about R 1 is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hvdroxValkoxy, hydroxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamnino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamnino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, 15 cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylami no, cycloalkylami no, cycloalkyloxy, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamnino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthi o, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic(alkyl) amino, heterocyclic alkoxy, heterocyclic :amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, *..*hydroxyalkylamino, hydroxyalkoxy, mercaptoalkoxy, oxoalkoxy, cyano, nitro, and -Y-R 1 4 wherein Y is selected from the group consisting of -0(R 1 6 (R1 7 -C(0)NR 2 1 R 2 2 -N=C R 21 R 2 2 N- R 2 1 R 22 and -NR 1 R 1 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl) 1 R 16 R 17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and R 2 1 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, _______heterocyclic, heterocyclic alkyl, or cyano; -285- or a pha~rmaceutically acceptable salt, ester, or prodrug-tbereof.
3. A compound having the formula Ill: R 3 N ,R R 9 X' R x 2 I wherein X, X1, X 2 R, R 1 R 3 and R 9 are as defined in claim 1; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
4. A compound of claim 3 wherein X 1 is selected from the group :a 10 consisting Of -S02-, -SeO2-, and -SO(NRi and R 9 is selected from the 0 ae *:*agroup consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, 00a 0 alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of 0, S, NR 4 N-ORa, and 15 N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cyclo- a alkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic :alkyl, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; 0* R is selected from the group consisting of alkyl, alkenyl, 20 alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, -(CH2)nC(O)R 5 -(CH2)nCEC- R 7 -(CH2)n[CH(CX'3)]m(CH2)n- R 8 and -(CH2)n-R 20 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; -286- R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl, R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; X' is halogen; n is from 0 to about 10, m is from 0 to about R' is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, aryloxy, 15 heterocyclic, heterocyclic alkyl, cyano, nitro, and -Y-R 1 4, wherein Y is selected from the group consisting of, -C(R16) -C(0)NR 2 1R 22 -N=C R 2 1 R 22 N- R 2 1 R 22 and -NR 1 R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkyIthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, 20*cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl); cnin R 16 R 17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof. A compound of claim 3 wherein X 1 is selected from the group consisting of -S02-, -SeO2-, and -SO(NR10)-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and gRZRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cyclo- -287- alkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and. arylalkyl; and Ra, Rb, and RC.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryi, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalky I, aryl, arylalkeny I, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, -(CH2)nC(O)R 5 and (CH2)n-R 20 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; n is from 0 to about R 1 is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,. cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and -Y-R 14 wherein Y is selected from the group consisting of, -C(R 16 (R1 7 -C(0)NR 2 l A 22 and -NA 1
9. R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), and A 16 A 17 and R 19 are independently selected f romn the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; R 2 1 and R 22 are indepe ndently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof. -28 8- 6. A compound of claim 3 wherein X 1 is selected from the group consisting of -S02-, -SeO2-, and-SO(NR 1 and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cyclo- alkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, and 15 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; and n is from 0 to about R' is selected from the group consisting of hydroxyalkyl, 20 hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; R 3 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, 25 aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and -Y-R 14 wherein Y is selected from the group consisting of, -C(R1 6 (R1 7 -C(O)NR 2 1 R 22 and -NR 19 R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl); R 15 R16, R 17 and R 19 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl or cyano; -289- R 2 1 and R 2 2 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof. 7. A compound of claim 3 wherein X 1 is selected from the group consisting of -S02-, -SeO2-, and -SO(NR10)-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, 15 cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and (CH2)n-R 20 where is R 2 0 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; Sn is from 0 to about 20 R 1 is selected from the group consisting of hydroxyalkyl, hydroxyalkylthio, hydroxyalkoxy, hydroxyalkylamino and mercaptoalkoxy; R3 is hydrogen; R 15 R 16 R 17 and R 1 9 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and R 2 1 and R22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; heterocyclic, heterocyclic alkyl, or cyano; -290- -or a pharmaceutically acceptable salt, ester, or prodrug thereof. 8. A compound of claim 3 wherein X 1 is selected from the group consisting of -SO2-, and -SO(NR10)-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and Ra, Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and (CH2)n-R 2 0 where is R 20 is substituted and unsubstituted aryl wherein the 15 substituted aryl compounds are substituted with halogen; n is from 0 to about R 1 is hydroxyalkoxy; and SR 3 is hydrogen; 20 or a pharmaceutically acceptable salt, ester, or prodrug thereof. 9 e* *9*e 9. A compound of claim 3 wherein X 1 is -SO2- and and R 9 is selected i from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen; X is selected from the group consisting of O, S, NR 4 N-ORa, and N-NRbRc, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cyclo- alkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a Rb, and Rc.are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl; -291- R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and -(CH2)n-R 20 where is R 20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; n is from 0 to about R 1 is hydroxyalkoxy; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof. A compound of claim 3 wherein X 1 is -S02-,and R 9 is selected from the group consisting of alkyl and amino; X 2 is selected from the group consisting of hydrogen and halogen; XisO; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl; R 1 is hydroxyalkoxy; and 20 R 3 is hydrogen; S. or a pharmaceutically acceptable salt, ester, or prodrug thereof.
11. A compound of claim 3 wherein X 1 is -SO2-, and R9 is selected from the group consisting of alkyl and amino; X2 is selected from hydrogen and fluorine; R is selected from haloalkyl, aryl, and alkyl; n is from 0 to about R 1 is selected from the group consisting of 2-hydroxy-2-methyl-propoxy; 3-hydroxy-3-methyl-butoxy; arid -292- R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof. 9 9 9* 9 9 9* 9 20 99 9 *9*9 9
12. A compound of claim 3 wherein X 1 is selected from the group consisting of -S02-, and -SO(NR 1 0 and R 9 is alkyl, X 2 is selected from the group consisting of hydrogen and fluorine; Xis O; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl; R 1 is hydroxyalkoxy; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
13. A compound of claim 3 wherein X 1 is -S02-, R 9 is amino; X 2 is selected from the group consisting of hydrogen and fluorine; Xis O; R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl; R 1 is hydroxyalkoxy; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
14. A compound of claim 3 wherein X 1 is -SO 2 and R 9 is methyl; X 2 is hydrogen; -293- X isO0; R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4- difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, and CF 3 CH,2'; R 1 is selected from the group consisting of. 2-hyd roxy-2-methyl-propoxy; 3-hyd roxy-3-methyl-butoxy; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof. A compound of claim 3 wherein X 1 is -S02-, and R 9 is amino; X2is hydrogen; X isO0; 1 5 R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4- difluorophenyl, 4-fluorophenyl, 4-chloro'3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF 3 CH 2 R 1 is selected from the group consisting of 2 -hydroxy-2-methyl-propoxy; 3-y oy3mety-buoy and :R 3 is hydrogen; *:or a pharmaceutically acceptable salt, ester, or prodrug thereof.
16. A compound according to claim 3, selected from the group consisting of: -294- 2-(3,4-Dif lu oroph enyl)-4-(2- hyd roxy-2- met hyl- 1 -propoxy)-5-[4- (methylsulIfonyl)phe nyl]-3(2 H)-pyridazi none; Flu orophe nyl)-4-(3-hyd roxy-3-methylbutoxy)-5-[4-(m ethylsuIf onyl) phenyl]- 3 (2 H)-pyridazi none; 5* -29 THIS PAGE HAS BEEN DELIBERATELY LEFT BLANK. -296- 2-(3 ,4-Dif luorophenyl)-4-(2-hydroxy-2-methylpropoxy)-5-[4-(aminosulfonyl)phe nyl]- 3 (2 H)-pyridazi none; ,4-Difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(methylsulfonyl)- 5phenyl]-3(2H)-pyridazinone; 2-(3,4-Difluorophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4-(ethysufofl)- phenyl]-3(2H)-pyridazinone; -297- Dif Iuo rophenyl)-4-(3-hydroxy-2-methylpropoxy)-5-[4. (aminosu Ifonyl)- phenyl]-3(2H)-pyridazinone; 2-(3 4 -Difluorophenyl)-4-(3-hydroxy-2-methylpropoxy).5[4..(aminosufony)- phenyl]-3(2H)-pyridazinone; or a pharmaceutically acceptable salt, ester, or prodrug thereof. 2 0* ,::So P 254 1 -298-
17. A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound of any one of claims 1 to 16 and a pharmaceutically acceptable carrier.
18. A method for inhibiting prostaglandin biosynthesis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 16.
19. A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, adhesions, and cancer comprising administering to a therapeutically effective amount of a compound of any one of claims 1 to 16. o S -299- A method for the preparation of a compound of claim 3 or a pharmaceutically acceptable salt, ester, or prodrug thereof having the formula R 3 NNIR x R 9 X R wherein X, X1, X 2 R, R 1 R 3 and R 9 are as defined in claim 1; comprising the step of reacting a compound having formula [Lwhere R is hydrogen, with an alkylating agent. *21. The method according to claim 20 wherein the alkylating agent has the formula R 99 -0 where Q is a leaving group and R 99 is selected from the group consisting of methyl, ethyl, 1 ,1 ,1-trifluoroethyl, cyclopropylmethyl, 3-(2-methyl)- propenyl, 4-(2-methyl)but-2-enyl, 1,1 -dichloroprope n-3-yl, 2,2-dimethyl-3-oxo- 4-butyl, 2,3,3,4 ,4,4-hexafluoro-n-buten-1 -yI, propargyl, phenylpropargyl, phenyl, phenethyl, 1 -phenylpropen-3-yi, benzyl, a-methyl-4-fluorobenzyl, 2,3,4,5,6-pe ntaf luo robe nzyl, 4-trifluomethoxyphenacyl, 4-fluorobenzyl, 4-fluoro- phenyl, 2-trifluoromethylbenzyl, 2,4-dif lu orobe nzyl, 2 ,4-difluorophenacyl, 4-trifluomethyiphenacyl, phenacyl, 4-carboxyphenacyl, 4-chlorophenacyl, 4-cyanophenacyl, 4-diethylaminophenacyl, 3-thienylmethyl, 2-ylmethyl, 5-chlorothien-2-ylmethyl, 2-benzo[b]thienylmethyl, 3-benzothienacyl, 5-chlorothiazol-2-ylmethyl, 5-methylthiazol-2-ylmethyl, 2-pyridylmethyl, 3-pyridyl- methyl, 4-pyridylmethyl, quinolin-2-ylmethyl, and fluoroquinolin-2-ylmethyl. -300-
22. The method according to claim 20 wherein the alkylating agent has the formula R 99 -Q where Q is a leaving group and R 99 is selected from the group consisting of methyl, ethyl, 1,1 .1-trifluoroethyl, cyclopropylmethyl, 3-(2-methyl)- propenyl, 4-(2-methyl)but-2-enyl, 1,1 -dichloropropen-3-yl, 2,3,3,4,4,4-hexafluoro-n- buten-1 -yl, propargyl, phenyipropargyl, phenyl, phenethyl, 1 -phenylpropen-3-yl, benzyl, oc-methyl-4-f luo robe nzyl, 2,3,4,5,6-pentafluorobenzyl, 4-trifluomethoxy- phenacyl, 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-yl- methyl, 5-chlorothien-2-ylmethyl, 2-benzofblthienylmethyl, and 3-benzothienacyl.
23. The method according to claim 20 wherein the alkylating agent has :the formula R 99 -Q where Q is a leaving group and R 99 is selected from the group 000 15 consisting of 1,1,1 -trifluoroethyt, 3-(2-methyl)propenyl, 4-(2-methyl)but-2-enyl, 000 1 ,1-dichloropropen-3-yl, 2,3,3,4,4,4-hexafluoro-n-buten-1 -yl, propargyl, phenyl- 0* propargyl, phenyl, benzy1, a-methyl-4-fluorobenzyl, 2,3,4,5,6-pe ntaflu orobe nzyl, luorobenzyl, 4-fluorophenyl, 2,4-dif luo robe nzyl, 3-thienylmethyl, 2-ylmethyl, 5-chlorothien-2-ylmethyl, and 2-be nzo[blthienylmethyl.
24. The method according to claim 20 wherein the alkylating agent has *the formula R 99 -Q where Q is a leaving group and R 99 is selected from the group consisting of 1,1,1 -trifluoroethyl, phenyl, benzyl, a-methyl-4-fluorobenzyl, 4-fluoro- So:: benzyl, 4-fluorophenyl, and 2,4-difluorobenzyl. h mthdaccording tcli20weinthe alkylating agent has the formula R 9 9 -Q where Q is a leaving group and R 9 9 is selected from the group consisting of 1,1,1-trifluoroethyl, benzyl, and 4-fluorophenyl.
26. A method for regioselectively preparing a 4,5- substituted pyridaz inone comprising the steps of a) reacting a compound with the formula 1- NCH 2 Ph R 98 0 x where R 98 is an alkyl or aryl group and X is a leaving group, with a nucleophilic agent to displace the X group and introduce R 1 as defined in claim 1; b) converting the -OR 9 8 to a leaving group; and c) reacting the compound with a second nucleophilic agent to introduce R 2 as defined in claim 1 and thereby provide the 4,5- substituted pyridazinone of general formula I as defined in claim 1 in which R is CH 2 Ph, R 3 is hydrogen and X is 0.
27. The method according to claim 26 wherein the benzyl group is removed using a Lewis acid.
28. A method for regioselectivly preparing a 4,5- substituted pyridazinone comprising the steps of treating a compound having the formula S. 0o 0@Se @0* S S S* 00* 5 0 5* S.* S 0 6* Oe Be S 5 See S S.* 0 'OH R 9 X with a hydrazine having the formula RNHNH2 to furnish the pyridazinone, having the formula: Ill wherein X, Xl, X 2 R, R 1 R 3 and R 9 are as defined in claim 1; or a pharmaceutically acceptable salt, ester, or prodrug thereof. -302-
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| AU65230/99A AU773237B2 (en) | 1997-08-22 | 1999-10-27 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
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| US08/129570 | 1998-08-05 | ||
| PCT/US1998/016479 WO1999010331A1 (en) | 1997-08-22 | 1998-08-10 | Arylpyridazinones as prostaglandin endoperoxide h synthase biosynthesis inhibitors |
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| CN1279026C (en) * | 1998-10-27 | 2006-10-11 | 艾博特公司 | Prostaglandin endoperoxide H synthase biosynthesis inhibitors |
| FR2969606B1 (en) * | 2010-12-22 | 2013-01-11 | Pf Medicament | DERIVATIVES OF DIARYLPYRIDAZINONES, THEIR PREPARATION AND THEIR APPLICATION IN HUMAN THERAPEUTICS |
| CN107334767B (en) * | 2017-06-08 | 2019-03-05 | 中国医学科学院医药生物技术研究所 | A kind of application of pyridazinone compound in oncotherapy |
| JP7147444B2 (en) * | 2018-10-03 | 2022-10-05 | 株式会社島津製作所 | Sample injection device and sample injection system |
| CN114560814B (en) * | 2022-03-02 | 2023-10-20 | 天津理工大学 | Synthesis method of substituted 2, 3-naphthyridine ketone compound |
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| US4238490A (en) * | 1979-02-12 | 1980-12-09 | Diamond Shamrock Corporation | Antihypertensive pyridazin(2H)-3-ones |
| WO1982000402A1 (en) * | 1980-08-07 | 1982-02-18 | Shamrock Corp Diamond | Herbicidal and plant growth regulant diphenylpyridazinones |
| US4404203A (en) * | 1981-05-14 | 1983-09-13 | Warner-Lambert Company | Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents |
| WO1988009675A1 (en) * | 1987-06-05 | 1988-12-15 | Medicis Corporation | Inhibition of arachidonic acid metabolism |
| AU691673B2 (en) * | 1994-11-14 | 1998-05-21 | Dow Agrosciences Llc | Pyridazinones and their use as fungicides |
| US5622948A (en) * | 1994-12-01 | 1997-04-22 | Syntex (U.S.A.) Inc. | Pyrrole pyridazine and pyridazinone anti-inflammatory agents |
| US6342510B1 (en) * | 1995-06-12 | 2002-01-29 | G. D. Searle & Co. | Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist |
| WO1998041511A1 (en) * | 1997-03-14 | 1998-09-24 | Merck Frosst Canada & Co. | Pyridazinones as inhibitors of cyclooxygenase-2 |
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| KR20010023196A (en) | 2001-03-26 |
| HUP0400909A3 (en) | 2004-10-28 |
| NZ501808A (en) | 2002-12-20 |
| PL194175B1 (en) | 2007-05-31 |
| JP2003516925A (en) | 2003-05-20 |
| CN1167687C (en) | 2004-09-22 |
| IL133552A (en) | 2005-12-18 |
| BG64675B1 (en) | 2005-11-30 |
| SK286972B6 (en) | 2009-08-06 |
| KR100675028B1 (en) | 2007-01-29 |
| CZ2000446A3 (en) | 2000-05-17 |
| NO315423B1 (en) | 2003-09-01 |
| PL355418A1 (en) | 2004-04-19 |
| BG104241A (en) | 2000-10-31 |
| CN1277605A (en) | 2000-12-20 |
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