U.S. patent application number 10/921965 was filed with the patent office on 2005-11-10 for cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds.
This patent application is currently assigned to Abbott Laboratories. Invention is credited to Boyd, Steven A., Freeman, Jennifer C., Geldern, Tom von, Gunawardana, Indrani W., Jae, Hwan-Soo, Link, James, Liu, Gang, Lynch, John K., Pei, ZhongHua, Staeger, Michael A., Wang, Sheldon, Winn, Martin, Xin, Zhili, Zhu, Gui-Dong.
Application Number | 20050250768 10/921965 |
Document ID | / |
Family ID | 34425529 |
Filed Date | 2005-11-10 |
United States Patent
Application |
20050250768 |
Kind Code |
A1 |
Link, James ; et
al. |
November 10, 2005 |
Cell adhesion-inhibiting antiinflammatory and immune-suppressive
compounds
Abstract
The present invention relates to novel cinnamide compounds that
are useful for treating inflammatory and immune diseases, to
pharmaceutical compositions containing these compounds, and to
methods of inhibiting inflammation or suppressing immune response
in a mammal.
Inventors: |
Link, James; (Evanston,
IL) ; Liu, Gang; (Gurnee, IL) ; Pei,
ZhongHua; (Libertyville, IL) ; Geldern, Tom von;
(Richmond, IL) ; Winn, Martin; (Deerfield, IL)
; Xin, Zhili; (Lake Bluff, IL) ; Boyd, Steven
A.; (Mundelein, IL) ; Zhu, Gui-Dong; (Gurnee,
IL) ; Freeman, Jennifer C.; (Grayslake, IL) ;
Gunawardana, Indrani W.; (Libertyville, IL) ;
Staeger, Michael A.; (Greenfield, WI) ; Jae,
Hwan-Soo; (Glencoe, IL) ; Lynch, John K.;
(Kenosha, WI) ; Wang, Sheldon; (Carmel,
IN) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
Abbott Laboratories
|
Family ID: |
34425529 |
Appl. No.: |
10/921965 |
Filed: |
August 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10921965 |
Aug 20, 2004 |
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09541795 |
Mar 31, 2000 |
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6878700 |
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09541795 |
Mar 31, 2000 |
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09474517 |
Dec 29, 1999 |
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60114097 |
Dec 29, 1998 |
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Current U.S.
Class: |
514/227.5 ;
514/232.2; 514/253.01; 514/255.01; 514/317; 514/320; 514/408;
514/618; 544/159; 544/360; 544/59; 546/199 |
Current CPC
Class: |
A61K 31/495 20130101;
C07D 217/06 20130101; C07D 213/81 20130101; C07D 231/12 20130101;
C07D 207/14 20130101; C07D 209/08 20130101; C07D 213/40 20130101;
C07D 211/20 20130101; A61K 31/54 20130101; C07D 233/56 20130101;
C07D 207/27 20130101; C07D 241/04 20130101; A61K 31/537 20130101;
C07D 401/04 20130101; C07D 211/60 20130101; C07D 295/185 20130101;
C07D 249/08 20130101; A61K 31/496 20130101; A61K 31/454 20130101;
C07C 323/62 20130101; C07D 205/04 20130101; C07D 211/46 20130101;
C07D 295/26 20130101; C07C 2601/02 20170501; C07D 207/09
20130101 |
Class at
Publication: |
514/227.5 ;
514/618; 514/232.2; 514/253.01; 514/317; 514/408; 514/320;
514/255.01; 544/059; 544/159; 544/360; 546/199 |
International
Class: |
A61K 031/54; A61K
031/537; A61K 031/496; A61K 031/495; A61K 031/454 |
Claims
1. A pharmaceutical composition comprising a compound of formula I
181or a pharmaceutically-acceptable salt or prodrug thereof,
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
independently selected from a. hydrogen, b. halogen, c. alkyl, d.
haloalkyl, e. alkoxy, f. cyano, g. nitro, h. carboxaldehyde, and
with the proviso that at least one of R.sub.1 or R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide", defined as 182wherein
R.sub.8 and R.sub.9 are independently selected from a. hydrogen,
and b. alkyl, c. carboxy alkyl, d. alkylaminocarbonyl alkyl, and e.
dialkylaminocarbonyl alkyl, and R.sub.10 and R.sub.11 are
independently selected from a. hydrogen, b. alkyl, c. cycloalkyl,
d. alkoxycarbonylalkyl, e. hydroxyalkyl, f. substituted aryl, g.
heterocyclyl, h. heterocyclylalkyl, i. heterocyclylamino, j.
substituted heterocyclyl, and k. substituted heterocyclylalkyl, or
where NR.sub.10R.sub.11 is heterocyclyl or substituted
heterocyclyl, where substituents are independently selected from 1)
alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl, 5) aryl, 6)
heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxyalkyl, 14)
carboxycarbonyl, 15) carboxaldehyde, 16) alkoxycarbonyl, 17)
arylalkoxycarbonyl, 18) aminoalkyl, 19) aminoalkanoyl, 20)
carboxamido, 21) alkoxycarbonylalkyl, 22) carboxamidoalkyl, 23)
cyano, 24) tetrazolyl, 25) substituted tetrazolyl, 26) alkanoyl,
27) hydroxyalkanoyl, 28) alkanoyloxy, 29) alkanoylamino, 30)
alkanoyloxyalkyl, 31) alkanoylaminoalkyl, 32) sulfonate, 33)
alkylsulfonyl, 34) alkylsulfonylaminocarbonyl, 35)
arylsulfonylaminocarbonyl, and 36)
heterocyclylsulfonylaminocarbonyl, and wherein Ar is a substituted
aryl or substituted heteroaryl group, where substitutions are
independently selected from a. hydrogen, b. halogen, c. alkyl, d.
aryl, e. haloalkyl, f. hydroxy, g. alkoxy, h. alkoxyalkyl, i.
alkoxycarbonyl, j. alkoxyalkoxy, k. hydroxyalkyl, l. aminoalkyl, m.
aminocarbonyl, n. alkyl(alkoxycarbonylalkyl)aminoalkyl, o.
heterocyclyl, p. substituted heterocyclyl, q. heterocyclylalkyl, r.
substituted heterocyclylalkyl, s. carboxaldehyde, t. carboxaldehyde
hydrazone, u. carboxamide, v. alkoxycarbonylalkyl, w. carboxy, x.
carboxyalkyl, y. carboxyalkoxy, z. carboxythioalkoxy, aa.
carboxycycloalkoxy, bb. thioalkyl, cc. hydroxycarbonylalkyl
(carboxyalkyl), dd. hydroxyalkylaminocarbonyl, ee. cyano, ff.
amino, gg. heterocyclylalkylamino, hh. carboxyalkylamino, ii.
heterocyclylalkylaminocarbonyl, and jj. "trans-cinnamide,"wherein
the heterocyclyl is chosen from 4-, 5-, 6- and 7-membered rings
containing 1-3 heteroatoms independently selected from nitrogen,
oxygen and sulfur; the 4- and 5-membered rings have zero to two
double bonds and the 6- and 7-membered rings have zero to three
double bonds, the heterocyclyl being optionally substituted with
alkyl, halogen, hydroxy or alkoxy substituents, further wherein the
heterocyclyl optionally comprises a group chosen from: (i)
bicyclic, tricyclic and tetracyclic groups in which any of the
above heterocyclic rings is fused to one or two rings independently
selected from an aryl ring, a cyclohexane ring, a cyclohexene ring,
a cyclopentane ring, a cyclopentene ring, and another monocyclic
heterocyclic ring; (ii) bridged bicyclic groups where a monocyclic
heterocyclic group is bridged by an alkylene group optionally
selected from 183(iii) compounds of the formula 184where X* and Z*
are independently selected from --CH.sub.2--, --CH.sub.2NH--,
--CH.sub.2O--, --NH-- and --O--, with the proviso that at least one
of X* and Z* is not --CH.sub.2--, and Y* is selected from --C(O)--
and --(C(R").sub.2).sub.v--, where R" is hydrogen or alkyl of one
to four carbons, and v is 1-3, and a pharmaceutically acceptable
carrier.
2. A pharmaceutical composition according to claim 1 wherein
R.sub.1 is a "cis-cinnamide" or a "trans-cinnamide", and R.sub.3 is
hydrogen.
3. A pharmaceutical composition according to claim 1 wherein
R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide", and R.sub.1 is
hydrogen.
4. A pharmaceutical composition according to claim 1 wherein
R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide", and R.sub.1,
R.sub.8, and R.sub.9 are hydrogen.
5. A pharmaceutical composition according to claim 4 wherein
R.sub.3 is a "cis-cinnamide".
6. A pharmaceutical composition according to claim 4 wherein
R.sub.3 is a "trans-cinnamide".
7. A pharmaceutical composition according to claim 1 wherein
R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide", R.sub.1,
R.sub.2, and R.sub.4 are each independently hydrogen or alkyl; and
R.sub.5 is selected from halogen, haloalkyl, and nitro.
8. A pharmaceutical composition according to claim 4 wherein Ar is
substituted aryl or substituted heteroaryl.
9. A pharmaceutical composition according to claim 4 wherein
R.sub.10 and R.sub.11 are each independently selected from
hydrogen, alkyl, cycloalkyl, alkoxycarbonylalkyl, hydroxyalkyl, and
heterocyclylalkyl.
10. A pharmaceutical composition according to claim 4 wherein
NR.sub.10R.sub.11 is heterocyclyl or substituted heterocyclyl.
11. A pharmaceutical composition according to claim 8 wherein Ar is
selected from substituted phenyl, 1,3-benzimidazol-2-one,
1,4-benzodioxane, 1,3-benzodioxole, 1-benzopyr-2-en-4-one, indole,
isatin, 1,3-quinazolin-4-one, and quinoline.
12. A pharmaceutical composition according to claim 1 comprising a
compound selected from the group consisting of:
(2,4-Dichlorophenyl)[2-(E-
-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)-
phenyl]sulfide; (2,4-Dichlorophenyl)[2-chloro-4-(E-((2
hydroxyethylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6
hydroxyhexylamino)carbonyl)ethenyl- )phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)-
amino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E--
((3-(1-pyrrolidin-2-only)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-ch-
loro-4-(E-((4-(2-pyridyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)-
phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethy-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-c-
hloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydro-
xymethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((piperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-
-((3-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((thi-
omorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro--
4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl)carbonyl)ethenyl)phenyl]sul-
fide;
(2-Bromophenyl)[2-chloro-4-(E-((2-etrahydroisoquinolinyl)carbonyl)et-
henyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoro-
methyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)car-
bonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4--
phenylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-onyl)propylam-
ino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-trifluoromethyl-4--
(E-((cyclopropylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-o-
nly)propylamino)carbonyl)ethenyl)phenyl]sulfide;
(2,3-Dichlorophenyl)[2-ni-
tro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-bu-
toxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(meth-
anesulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-
-((4-(diethylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)piperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E--
((4-(carboxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Chlorophenyl)[2-nitro-4-(E-((-
4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetyl-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-iso-Propylphenyl)[2-nit-
ro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl))2-propenyl)phenyl]sulfide;
(2-(1-Morpholinylmethyl)phenyl)[2-ch-
loro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4-
-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chlor-
o-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((-
1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-chloro-4-
-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)ca-
rbonyl)ethenyl)phenyl]sulfide;
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phen-
yl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide, N,N-dimethyl hydrazone;
(2-((3-(1-Morpholinyl)propyl)-
-1-amino)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide;
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylami-
no)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-
-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
(2-Chloro-6-formylphenyl)[2--
chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Cyanophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Isopropylphenyl)[2-cyano-4-(E-((morpholin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Pyrrolidin-1-yl)phenyl)[2-chloro--
4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]-
sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxypiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
(2-Methylphenyl)[2-nitro-4-(E-((3-carboxam-
ido-4-carbobenzoxypiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-tert-butoxycarbonylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro--
4-(E-((2-carboxy-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phen-
yl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluorometh-
yl-4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-
-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluor-
omethyl-4-(E-((cyclobutylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((cyclopentylamino)carbonyl)et-
henyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((5-hydro-
xypent-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-ni-
tro-4-(E-((3-carbomethoxy-4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]s-
ulfide;
(2-Biphenyl)[2-chloro-4-(E-((morpholin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(3,4-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-ac-
etylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(5-Indolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(5-Benzodioxolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbometho-
xypiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,3-Dimethoxyphenyl)-[2-
-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Fluorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarb-
onyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Pyrrolidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbon-
yl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-Carboxamidophenyl)[2-
-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-(Hydroxymethyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
Phenyl[2-trifluoromethyl-4-(E-((4-(tert-butoxycarb-
onyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-(tert-butox-
ycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-methylaminocarbonyl)-4-t-
ert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]s-
ulfide;
(2-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(2-(Azetidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((-
4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Piperidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-Chloro-2-formylphenyl-
)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Trifluoromethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(3-Bromophenyl)[2-trifluoromethyl-4-(E-(-
(4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3,5-Dimethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethyl-
aminocarbonyl-4-(pyridine-4-carbonyl)piperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-ca-
rbomethoxypiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-
-((3-(1-morpholinocarbonyl)-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-me-
thylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-dimethylaminocarbonyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(b-
enzylaminocarbonyl)-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl-
)-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-hydroxymethyl-pyrrolidin-2-on-1-yl)-
prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-
-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfi-
de;
(2-Bromophenyl)[2-chloro-4-(E-(N-methyl-N-(3-(pyrrolidin-2-on-1-yl)pro-
p-1-yl)amino)carbonyl)ethenyl)phenyl]sulfide;
(2-[2-Methoxy]ethoxyphenyl)--
[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(morpholinocarbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-tert--
butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methoxycarbonylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(4-(pyridine-4-
-carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-3-methylaminocarbonyl)-4-t-
ert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-2-methylaminocarbonyl)pipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4--
(E-((3-(pyridine-3-methylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide;
(4-Hydroxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(3,5-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(-
E-((3-(5S-acetoxymethyl-pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-methoxymethyl-pyr-
rolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((3-(4R-hydroxymethyl-pyrrolidin-2-on-1-yl)-
prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
Phenyl[2-nitro-4-(E-((4-ac-
etylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Dimethylaminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(3-((2-Hydroxyethyl)aminocarbonyl)phenyl)[2-nitro-4--
(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-((3-(1-Imidazolyl)propyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4-acetyl-
piperazin 1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-((2-(1-Morpholinyl)ethy-
l)aminocarbonyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((-
3-hydroxymethyl-4-tert-butoxycarbonylpiperazin
1-yl)carbonyl)ethenyl)pheny- l]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-formylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-hydroxyme-
thyl-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)carbonyl]-
ethenyl)phenyl]sulfide;
(3-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
(4-Aminophenyl)[2-nitro-4-(E-((4-acet-
ylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,4-Dimethylphenyl)[2-n-
itro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2,5-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(4-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(3-Chlorophenyl)[2-nitro-4-(E-((4-acetyl-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-Chloro,
4,5-diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide;
(3,4-Diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl](6-Chlorobenzimidazol-2-on-5-yl)[2-chloro-4-(E--
((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide; (2-Hydroxy,
4-aminophenyl)[2-chloro-4-(E-((4-acetylpip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-
-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyridine-2-carbonyl)piperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyr-
idine-3-carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-methoxycarbonylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-
-((2-carboxy-4-methoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfi-
de;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-methylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-car-
boxypiperidin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]ethenyl-
)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-ethoxycarbonylpiperidi-
n-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-
-4-(E-((1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-ylamino)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-carboxypiperidin-1-
-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4--
(E-(((pyrrol-3-in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1--
ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethy-
l-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-(ethoxycarbonyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-
-((4-(2-furylcarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)carbonyl]-
ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(4-carboxypiperidi-
n-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-(-
(4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-ethoxycarbonylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-isopropoxyc-
arbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-isobutoxycarbonylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-((1-prop-
en-2-oxy)carbonyl)piperazin 1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-propionylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboxamidopiper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(-
E-((4-methylaminocarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrimidin-2-yl)piperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-hydroxyac-
etylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrazine-2-carbonyl)piperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(-
E-(((2-carboxypyrrol-3-in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-methylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4--
(E-(((2-carboxypyrrol-3-in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-hydroxymethylpyrrolidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3--
methylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-cyclopropylaminocarbonyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-
-carboxamidopiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-oxopiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3,5-dimet-
hylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Ethylindol-7-yl)[2-c-
hloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-[2-Methoxy]ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethen-
yl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4,4'-S-dioxythiomorphol-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-(N--
carbomethoxymethyl-N-(3-(pyrrolidin-2-on-1-yl)prop-1-yl)amino)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Bromophenyl)[2-chloro-4-(E-((4-S-oxythiomorpholin--
1-yl)-2-pyrrolidinone)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxy-5-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethy-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-ni-
tro-4-(E-((3,5-dimethyl-4acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulf-
ide;
(1-Methylindol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpiperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((-
3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboethoxypiper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromet-
hyl-4-(Z-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((6-methylpyrid-2-ylamino)carbony-
l)ethenyl)phenyl]sulfide;
(2-Methyl-3-chlorophenyl)[2-nitro-4-(E-((4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitr-
o-4-(E-((3-carboxamidopiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((2-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxamidopiper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-
-((4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((syn-3,5-dimethylmorpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((anti-3,5-dime-
thylmorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-isopropoxycarb-
onylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-methylpipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4--
(E-((3-carbomethoxy-4-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-hydroxypiperidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4--
(E-((2-carbomethoxy-4-(methoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-me- thyl
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carboxy-4-(methoxycarbonyl)pi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Indol-6-yl)[2-chloro-4-(E-(-
(4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (1-Ethyl,
3-(dimethylaminomethyl)indol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(5-Ethoxybenzodioxan-6-yl)[2-chloro-4-(E-
-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethyl-4-bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((2-carboxypiperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-
-carboxymethylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-Morpholinophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(5-Ethoxybenzodioxan-8-yl)[2-chloro-4-(E-((4-acetylpipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(5-Chloro-8-ethoxyquinolin-7-y-
l)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypiperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E--
(((3-ethanesulfonylaminocarbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]su-
lfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-(4-methylpiperazine)sulfonyla-
minocarbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-p-toluenesulfonylaminocarbonyl)pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4--
(E-((3-methyl-4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Hydroxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]-
sulfide
(1-(Carboxymethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-
-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-onyl)prop-1-ylamino)-
carbonyl)ethenyl)phenyl]sulfide;
(3-(2-Morpholinoethylamino)phenyl)[2-trif-
luoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Pyrrolidin-1-ylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(3-Bromophenyl)[2-nitro-4-(E-((3-carboethoxypyrrol-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-Bromophenyl)[2-nitro-4-(E-((-
4-carboethoxypyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Hydroxymethyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-
-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfi-
de;
(3-(Dimethylaminomethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-
-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxypiperidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboethoxypiperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E--
((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(((4-p-toluenesulfonylaminocarbonyl)pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4--
(E-((3-carboxy-4-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboethoxypiperidin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E--
((2-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyr-
rolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluo-
romethyl-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-tert-butox-
ycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-methoxycarbo-
nylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-tr-
ifluoromethyl-4-(E-((2-carbomethoxypiperazin-1-yl)carbonyl)ethenyl)phenyl]-
sulfide;
(2-Methyl-3-(carboethoxymethyl)indol-5-yl)[2-trifluoromethyl-4-(E-
-((morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-(2-Methoxyethyl)indo-
l-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sul-
fide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethyl-4-hydroxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-(-
(3-(dimethylaminocarbonyl)-4-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-cyanomorpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxy-
morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitr-
o-4-(E-((3-(tetrazol-5-yl)morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2--
carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carbomethoxypiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-
-((3-aza-6,9-diooxaspiro[5.4]decan-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoro-4-(E-((4-(benzimidazolon-1-yl)piperidin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-
-(E-((4-(methylaminocarbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carbomethoxy-4-methoxycar-
bonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxymorpholin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboxy-4-
-methoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-(pyrrolid-
in-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-aza-6,9-diooxaspiro[5.4]decan-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(dime-
thylaminomethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((piperidin-1-ylamino)carbonyl)ethenyl)p-
henyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxy-4-met-
hoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(Dimethylaminocarbonyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4--
(E-((3-(2-(methoxymethyl)tetrazol-5-yl)piperidin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-(methoxymethyl)tetrazo-
l-5-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino)c-
arbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(tetr-
azol-5-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2-chloro--
4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(1-methylpyrroli-
din-2-yl)ethylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrrolidin-1-yl)piperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-sulfopip-
eridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-
-(E-((3-hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-((ethanesulfonylamino)carbo-
nyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-((p-toluenesulfonylamino)ca-
rbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-((ethanesulfonylamino)carbo-
nyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2(tetrazol-5-yl)morpholin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((2-bu- tyl,
5-(tetrazol-5-yl)morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpiper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide; (2-(and
3-)(Hydroxymethyl)-benz-
odioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbon-
yl)ethenyl)phenyl]sulfide; (2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2--
trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)eth-
enyl)phenyl]sulfide;
(3-Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3--
(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethen-
yl)phenyl](2-(and
3-)(Aminomethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(-
E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide-
;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(methylaminocarbonyl)morpholin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(hy-
droxymethyl)morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(acetoxymethyl)morpholin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(aminometh-
yl)morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-n-
itro-4-(E-((3-(acetamidomethyl)morpholin-1-yl)carbonyl)ethenyl)phenyl]sulf-
ide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-yla-
mino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-
-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboethoxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl-
)carbonyl]ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)-[2,3-dimethyl-4(E-[(mo-
rpholin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro--
4-(E-((indol-5-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)pip-
eridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-
-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e;
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)m-
orpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-
-4-(E-((4-(methylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulf-
ide;
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbony-
l]ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(tetrazol-5-
-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)-[3-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]-
sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((4-oxopiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-car-
boethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carboxypiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-(py-
rrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboethoxy-
piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dic-
hloro-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboxypip-
eridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichl-
oro-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino)carbonyl)ethenyl)phenyl]sulf-
ide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-acetylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carbo-
ethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carb-
oxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-
-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-ca-
rboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-ca-
rboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]eth-
enyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)c-
arbonyl]ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(3-car-
boxypiperidin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypyrrolidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypyrrol-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-difluor-
o-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((4-carboxyp-
iperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-triflu-
oromethyl-4-(E-((3-ethoxycarbonylpyrrolidin-1-yl)carbonyl)ethenyl)phenyl]s-
ulfide
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyrrolidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2-chloro-3-trifluorom-
ethyl-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((4-carboethoxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2-chloro-3-trifl-
uoromethyl-4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)naphth-
yl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(spiro-hydantoin-5-yl)-
-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dic-
hloro-4-(E-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-ethylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-
-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6yl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4--
(carboxymethylamino)carbonyl-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e;
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxymethylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-bis(triflu-
oromethyl)-4-(E-((4-N-(2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phen-
yl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-(carbo-2,3-dihydrox-
ypropylamino)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-dihydroxypropionyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E--
(4-(2,3-dihydroxy-3-carboxypropionyl)piperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)-
carbonyl-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-sulfopiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-methylhom-
opiperazin-1-ylcarbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-d-
ichloro-4-(E-(4-tetrohydrofuroylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sul-
fide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-amino-4-carboxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-((4-fu-
roylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-(carbo-3-sulfopropylamino)piper-
adin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro--
4-(E-(4-acetylamino-4-carboxypiperidin-1-ylcarbonyl)ethenyl)phenyl]sulfide-
;
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)5-[8-(E-((4-(aminocarb-
onyl)piperidin-1-yl)carbonyl)ethenyl)quinolinyl]sulfide;
(2-Methoxyphenyl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E/Z-((1S,4-
S)-2,5-diazabycyclo(2,2,1)heptan-2-ylcarbonyl)ethenyl)-2,3-dichlorophenyl]-
sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-hydroxy-3-carboxypipera-
din-1-ylcarbonyl)ethenyl)phenyl]sulfide;
(1-Methylindol-5-yl)[2,3-dichloro-
-4-(E-(S-oxothiomorpholin-1-ylcarbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-sulfophenylamino)carbonyl)ethenyl-
)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-carboxyphenylamin-
o)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Morpholino)phenyl][2,3-dichloro-4-
-(E-[(4-carboxypiperidin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4--
(E-((4-phenylcarboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(((4-hydroxylaminocarbonyl)piperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E--
((N-carboxymethyl-N-phenylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[3-chloro-6-hydroxy-4-(E-((3-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-((1-(2--
phenyl-1-carboxyethyl)amino)carbonyl)piperidin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-((1-(2-hydroxy-1-carboxy-
ethyl)amino)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-(1-(3-Carboxypiperidinyl)phenyl)[2,3-dichloro-4-(E-((1,2,5,6-tetrahydr-
opyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-(4-Pyrrolidin-1-yl)piper-
idin-1-yl)phenyl)[2,3-dichloro-4-(E-(((3-(2-pyrrolidinon-1-yl)propylamino)-
carbonyl)ethenyl)phenyl]sulfide;
[3-(4-(Spiro-2,2-dioxolanyl)piperidin-1-y-
l)phenyl][2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)phenyl]sulfid-
e;
[3-(3-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxypiper-
idin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-(2-Carboxy)ethenyl)phenyl)[2-
,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(1,2,3,6-tetrahyd-
ropyridine)-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[3-(4-Carboxylpiperidiny-
l)phenyl][2,3-dichloro-4-(E-[(4-morpholinyl)carbonyl]ethenyl)phenyl]sulfid-
e;
[2-(4-Acetylpiperazin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxypiperid-
in-1-yl)carbonyl]ethenyl)phenyl]sulfide;
3-(3-Carboxypiperidin-1-yl)phenyl-
][2,3-dichloro-4-(E-[(4-morpholinyl)carbonyl]ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-(dimethylaminos-
ulfamoyl)piperazin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((3-carboxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-bis(trifluoromethy-
l)-4-(E-((2-carboxypyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((trifluorometh-
ylsulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(piperidin-1-ylcarbonyl)ethenyl)pheny-
l]sulfide;
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)eth-
enyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((((4-carboxyphen-
yl)methyl)amino)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dic-
hloro-4-(E-(((4-pyrrolidin-1-yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sul-
fide;
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichlor-
o-4-(E-((4-((methylsulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide-
;
(2-Aminophenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)pheny-
l]sulfide;
(3-(4-carboxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-((S-oxoth-
iomorpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-
-yl)phenyl][2,3-dichloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide;
(2-Glycoxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl-
)ethenyl)phenyl]sulfide;
(2-(4-Butyroxy)phenyl)[2,3-dichloro-4-(E-((4-morp-
holino)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl-
][2,3-dichloro-4-(E-((4-hydroxyethylpiperazin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-furoyl-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-y-
l)phenyl][2,3-dichloro-4-(E-((pyrrolidin
1-yl)carbonyl)ethenyl)phenyl]sulf- ide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((diethylaminoc-
arbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-di-
chloro-4-(E-((4-ethylpiperazin-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(aminocarbonyl)-
piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-y-
l)phenyl][2,3-dichloro-4-(E-((4-(2-(ethoxyethyl)piperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
[3-((4-Carboxymethyl)piperazin-1-yl)phenyl][(2,3-dic-
hloro-4-(E-(4-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((4-mor-
pholino)carbonyl)ethenyl)phenyl]sulfide; (3-Hydroxyphenyl)
[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Butyroxy)phenyl][2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)-
phenyl]sulfide;
(2-Hydroxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpho-
lino)carbonyl)ethenyl)phenyl]sulfide;
(3-Hydroxyphenyl)[2,3-bis(trifluorom-
ethyl)-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((4-hydrox-
ypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1--
yl)phenyl][2,3-ditrifluoromethyl-4-(E-((1,2,5,6-tetrahydropyridin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[2-((4-Carboxy)butyloxy)phenyl][2,3-dichloro-
-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl]sulfide;
(2-Glycoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbonyl)e-
thenyl)phenyl]sulfide;
(2-(4-Butyroxy)phenyl)[2,3-bis(trifluoromethyl)-4-(-
E-((4-morpholino)carbonyl)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-
-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((bis-(2-ethoxyethyl)amino)carbonyl-
)ethenyl)phenyl]sulfide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trif-
luoromethyl)-4-(E-((bis-(2-hydroxypropyl)amino)carbonyl)ethenyl)phenyl]sul-
fide;
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trifluoromethyl)-4-(E-(-
(piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-(4-Butyroxy)phenyl)[2,-
3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl]sulfide-
;
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((3-(2-pyrrolidino-
n-1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide;
[2-(3-Carboxypiperidin--
1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((3-(2-pyrrolidinon
1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide;
[2-(3-Carboxypiperidin-1-
-yl)phenyl][2,3-dichloro-4-(E-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(triflu-
oromethyl)-4-(E-((1,2,5,6-tetrahydropyridin-1-yl)carbonyl)ethenyl)phenyl]s-
ulfide;
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E--
((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((4-(2--
(hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
and
(3-(3-Propioxy)phenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)-
phenyl]sulfide.
13. A pharmaceutical composition according to claim 1 comprising a
compound selected from the group consisting of:
(2-Formylphenyl)[2-nitro--
4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]s-
ulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nit-
ro-4-(E-((4-methoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carboxy-4-(methoxycarbonyl)pi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Ethyl-4-bromophenyl)[2-ni-
tro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(3-Morpholinophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2-nitro-4-(E--
((3-(1-pyrrolidin-2-onyl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
(2-(Hydroxymethyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-
-(E-((3-carboxypyrrolidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboethoxypiperidin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E--
((2-carbomethoxy-4-methoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]s-
ulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxypiperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-chloro-4-(E-(-
(4-(methylaminocarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]et-
henyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carb-
oethoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-yla-
mino)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-
-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboe-
thoxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboxypip-
eridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichl-
oro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carb-
oxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Isopropylphenyl)[2,3-
-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
(2-Methoxyphenyl)[2,3-bis(trif-
luoromethyl)-4-(E-((4-carboxymethylpiperazin-1-yl)carbonyl)ethenyl)phenyl]-
sulfide; and
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-N-(2-hydr-
oxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide.
14. A pharmaceutical composition according to claim 1 wherein Ar is
selected from the group consisting of methoxyphenyl and
isopropylphenyl.
15. A pharmaceutical composition according to claim 1 wherein Ar is
benzodioxan or substituted benzodioxan.
16. A pharmaceutical composition according to claim 1 wherein
R.sub.3 is a "trans-cinnamide"; and Ar is selected from
1,3-benzimidazol-2-one, 1,4-benzodioxane, 1,3-benzodioxole,
1-benzopyr-2-en-4-one, indole, isatin, phenyl,
1,3-quinazolin-4-one, and quinoline.
17. A pharmaceutical composition according to claim 1 wherein
R.sub.10 and R.sub.11 are independently selected from hydrogen,
alkyl, cycloalkyl, alkoxycarbonylalkyl, hydroxyalkyl, and
heterocyclylalkyl.
18. A pharmaceutical composition according to claim 1 wherein
NR.sub.10R.sub.11 is heterocyclyl or substituted heterocyclyl.
19. (canceled)
20. A method of inhibiting inflammation comprising the
administration of a pharmaceutical composition of claim 1 to a
mammal in need of treatment.
21. A method of inhibiting inflammation comprising the
administration of a pharmaceutical composition of claim 12 to a
mammal in need of treatment.
22. A method of suppressing immune response comprising the
administration of a pharmaceutical composition of claim 1 to a
mammal in need of treatment.
23. A method of suppressing immune response comprising the
administration of a pharmaceutical composition of claim 12 to a
mammal in need of treatment.
24. A compound of formula II 185wherein R.sub.1 and R.sub.2 are
independently selected from the group consisting of i. hydrogen, j.
halogen, k. alkyl, l. haloalkyl, m. alkoxy, n. cyano, o. nitro, and
p. carboxaldehyde.
25. A process for preparing a compound of formula II 186which
comprises: a) reacting a compound of formula II' 187with lithium
hydroxide, and b) cleaving the resulting methyl ether.
26. The pharmaceutical composition of claim 1 with the proviso that
when three of R.sub.1, R.sub.2, R.sub.4, and R.sub.5 are hydrogen,
then the remaining R.sub.1, R.sub.2, R.sub.4, or R.sub.5 is not
carboxyl, 5-tetrazolyl, hydroxymethyl or carboxyl derivatized in
the form of a pharmaceutically acceptable ester.
27. A compound of formula I 188or a pharmaceutically-acceptable
salt or prodrug thereof, wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, and R.sub.5 are independently selected from a. hydrogen,
b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro,
h. carboxaldehyde, and with the proviso that at least one of
R.sub.1 or R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide,"
defined as 189wherein R.sub.8 and R.sub.9 are independently
selected from f. hydrogen, and g. alkyl, h. carboxy alkyl, i.
alkylaminocarbonyl alkyl, and j. dialkylaminocarbonyl alkyl, and
R.sub.10 and R.sub.11 are independently selected from l. hydrogen,
m. alkyl, n. cycloalkyl, o. alkoxycarbonylalkyl, p. hydroxyalkyl,
q. substituted aryl, r. heterocyclyl, s. heterocyclylalkyl, t.
heterocyclylamino, u. substituted heterocyclyl, and v. substituted
heterocyclylalkyl, or where NR.sub.10R.sub.11 is heterocyclyl or
substituted heterocyclyl, where substituents are independently
selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl, 4) cycloalkyl,
5) aryl, 6) heterocyclyl, 7) heterocyclylcarbonyl, 8)
heterocyclylalkylaminocarbonyl, 9) hydroxy, 10) hydroxyalkyl, 11)
hydroxyalkoxyalkyl, 12) carboxy, 13) carboxyalkyl, 14)
carboxycarbonyl, 15) carboxaldehyde, 16) alkoxycarbonyl, 17)
arylalkoxycarbonyl, 18) aminoalkyl, 19) aminoalkanoyl, 20)
carboxamido, 21) alkoxycarbonylalkyl, 22) carboxamidoalkyl, 23)
cyano, 24) tetrazolyl, 25) substituted tetrazolyl, 26) alkanoyl,
27) hydroxyalkanoyl, 28) alkanoyloxy, 29) alkanoylamino, 30)
alkanoyloxyalkyl, 31) alkanoylaminoalkyl, 32) sulfonate, 33)
alkylsulfonyl, 34) alkylsulfonylaminocarbonyl, 35)
arylsulfonylaminocarbonyl, and 36)
heterocyclylsulfonylaminocarbonyl, and wherein Ar is a substituted
aryl group, where substitutions are independently selected from
heterocyclyl and substituted heterocyclyl.
28. A compound according to claim 27, wherein R.sub.1 and R.sub.2
are each trifluoromethyl.
29. A compound according to claim 27, wherein R.sub.3 is a
"cis-cinnamide" or a "trans-cinnamide," and R.sub.1 is
hydrogen.
30. A compound according to claim 29, wherein R.sub.3 is a
"trans-cinnamide."
31. A compound according to claim 27, wherein Ar is a phenyl group
substituted with a substituted heterocyclyl.
32. A compound according to claim 31, wherein the substituted
heterocyclyl is a substituted piperazinyl.
33. A compound according to claim 32, wherein the substituted
piperazinyl is substituted with an alkanoyl.
Description
[0001] This application is a continuation-in-part of application
Ser. No. 09/474,517, filed Dec. 29, 1999, which is a
continuation-in-part of provisional Application Ser. No.
60/114,097, filed Dec. 29, 1998.
TECHNICAL FIELD
[0002] The present invention relates to compounds that are useful
for treating inflammatory and immune diseases, to pharmaceutical
compositions comprising these compounds, and to methods of
inhibiting inflammation or suppressing immune response in a
mammal.
BACKGROUND
[0003] Inflammation results from a cascade of events that includes
vasodilation accompanied by increased vascular permeability and
exudation of fluid and plasma proteins. This disruption of vascular
integrity precedes or coincides with an infiltration of
inflammatory cells. Inflammatory mediators generated at the site of
the initial lesion serve to recruit inflammatory cells to the site
of injury. These mediators (chemokines such as IL-8, MCP-1, MIP-1,
and RANTES, complement fragments and lipid mediators) have
chemotactic activity for leukocytes and attract the inflammatory
cells to the inflamed lesion. These chemotactic mediators which
cause circulating leukocytes to localize at the site of
inflammation require the cells to cross the vascular endothelium at
a precise location. This leukocyte recruitment is accomplished by a
process called cell adhesion.
[0004] Cell adhesion occurs through a coordinately regulated series
of steps that allow the leukocytes to first adhere to a specific
region of the vascular endothelium and then cross the endothelial
barrier to migrate to the inflamed tissue (Springer, T. A., 1994,
Traffic Signals for Lymphocyte Recirculation and Leukocyte
Emigration: The Multistep Paradigm, Cell 76: 301-314; Lawrence, M.
B., and Springer, T. A., 1991, Leukocytes' Roll on a Selectin at
Physiologic Flow Rates: Distinction from and Prerequisite for
Adhesion Through Integrins, Cell. 65: 859-873; von Adrian, U.,
Chambers, J. D., McEnvoy, L. M., Bargatze, R. F., Arfos, K. E, and
Butcher, E. C., 1991, Two-Step Model of Leukocyte-Endothelial Cell
Interactions in Inflammation, Proc. Natl. Acad. Sci. USA 88:
7538-7542; and Ley, K., Gaehtgens, P., Fennie, C., Singer, M. S.,
Lasky, L. H. and Rosen, S. D., 1991, Lectin-Like Cell Adhesion
Molecule 1 Mediates Rolling in Mesenteric Venules in vivo, Blood
77: 2553-2555). These steps are mediated by families of adhesion
molecules such as integrins, Ig supergene family members, and
selectins which are expressed on the surface of the circulating
leukocytes and on the vascular endothelial cells. The first step
consists of leukocytes rolling along the vascular endothelial cell
lining in the region of inflammation. The rolling step is mediated
by an interaction between a leukocyte surface oligosaccharide, such
as Sialylated Lewis-X antigen (SLe.sup.x), and a selectin molecule
expressed on the surface of the endothelial cell in the region of
inflammation. The selectin molecule is not normally expressed on
the surface of endothelial cells but rather is induced by the
action of inflammatory mediators such as TNF-.alpha. and
interleukin-1. Rolling decreases the velocity of the circulating
leukocyte in the region of inflammation and allows the cells to
more firmly adhere to the endothelial cell. The firm adhesion is
accomplished by the interaction of integrin molecules that are
present on the surface of the rolling leukocytes and their
counter-receptors (the Ig superfamily molecules) on the surface of
the endothelial cell. The Ig superfamily molecules or CAMs (Cell
Adhesion Molecules) are either not expressed or are expressed at
low levels on normal vascular endothelial cells. The CAM's, like
the selecting, are induced by the action of inflammatory mediators
like TNF-alpha and IL-1. The final event in the adhesion process is
the extravasation of leukocytes through the endothelial cell
barrier and their migration along a chemotactic gradient to the
site of inflammation. This transmigration is mediated by the
conversion of the leukocyte integrin from a low avidity state to a
high avidity state. The adhesion process relies on the induced
expression of selectins and CAM's on the surface of vascular
endothelial cells to mediate the rolling and firm adhesion of
leukocytes to the vascular endothelium.
[0005] The interaction of the intercellular adhesion molecule
ICAM-1 (cd54) on endothelial cells with the integrin LFA-1 on
leukocytes plays an important role in endothelial-leukocyte
contact. Leukocytes bearing high-affinity LFA-1 adhere to
endothelial cells through interaction with ICAM-1, initiating the
process of extravasation from the vasculature into the surrounding
tissues. Thus, an agent which blocks the ICAM-1/LFA-1 interaction
suppresses these early steps in the inflammatory response.
Consistent with this background, ICAM-1 knockout mice have numerous
abnormalities in their inflammatory responses.
[0006] The present invention discloses compounds which bind to the
interaction-domain (I-domain) of LFA-1, thus interrupting
endothelial cell-leukocyte adhesion by blocking the interaction of
LFA-1 with ICAM-1, ICAM-3, and other adhesion molecules. These
compounds are useful for the treatment or prophylaxis of diseases
in which leukocyte trafficking plays a role, notably acute and
chronic inflammatory diseases, autoimmune diseases, tumor
metastasis, allograft rejection, and reperfusion injury. The
compounds of this invention are diaryl sulfides, which are
substituted with a cinnamide moiety. The cinnamide functionality
may be placed either ortho- or para- to the linking sulfur atom,
although para-substitution is preferable. Appropriate substitution
of both aromatic rings is tolerated, and can be used to modulate a
variety of biochemical, physicochemical and pharmacokinetic
properties. In particular the amide moiety is readily modified; a
variety of secondary and tertiary amides are active, and
alternatively a heterocyclic ring may be attached at this position.
Modifications of this amide functionality are particularly useful
in modulating physicochemical and pharmacokinetic properties.
SUMMARY OF THE INVENTION
[0007] The present invention provides compounds of formula I,
below, 1
[0008] or a pharmaceutically-acceptable salt or prodrug
thereof,
[0009] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
independently selected from
[0010] a. hydrogen,
[0011] b. halogen,
[0012] c. alkyl,
[0013] d. haloalkyl,
[0014] e. alkoxy,
[0015] f. cyano,
[0016] g. nitro,
[0017] h. carboxaldehyde, and
[0018] with the proviso that at least one of R.sub.1 or R.sub.3 is
a "cis-cinnamide" or a "trans-cinnamide", defined as 2
[0019] wherein R.sub.8 and R.sub.9 are independently selected
from
[0020] a. hydrogen, and
[0021] b. alkyl,
[0022] c. carboxy alkyl,
[0023] d. alkylaminocarbonyl alkyl, and
[0024] e. dialkylaminocarbonyl alkyl,
[0025] and R.sub.10 and R.sub.11 are independently selected
from
[0026] a. hydrogen,
[0027] b. alkyl,
[0028] c. cycloalkyl,
[0029] d. alkoxycarbonylalkyl,
[0030] e. hydroxyalkyl,
[0031] f. substituted aryl,
[0032] g. heterocyclyl,
[0033] h. heterocyclylalkyl,
[0034] i. heterocyclylamino,
[0035] j. substituted heterocyclyl, and
[0036] k. substituted heterocyclylalkyl,
[0037] or where NR.sub.10R.sub.11 is heterocyclyl or substituted
heterocyclyl, where substituents are independently selected
from
[0038] 1) alkyl,
[0039] 2) alkoxy,
[0040] 3) alkoxyalkyl,
[0041] 4) cycloalkyl,
[0042] 5) aryl,
[0043] 6) heterocyclyl,
[0044] 7) heterocyclylcarbonyl,
[0045] 8) heterocyclylalkylaminocarbonyl,
[0046] 9) hydroxy,
[0047] 10) hydroxyalkyl,
[0048] 11) hydroxyalkoxyalkyl,
[0049] 12) carboxy,
[0050] 13) carboxyalkyl,
[0051] 14) carboxycarbonyl,
[0052] 15) carboxaldehyde,
[0053] 16) alkoxycarbonyl,
[0054] 17) arylalkoxycarbonyl,
[0055] 18) aminoalkyl,
[0056] 19) aminoalkanoyl,
[0057] 20) carboxamido,
[0058] 21) alkoxycarbonylalkyl,
[0059] 22) carboxamidoalkyl,
[0060] 23) cyano,
[0061] 24) tetrazolyl,
[0062] 25) substituted tetrazolyl,
[0063] 26) alkanoyl,
[0064] 27) hydroxyalkanoyl,
[0065] 28) alkanoyloxy,
[0066] 29) alkanoylamino,
[0067] 30) alkanoyloxyalkyl,
[0068] 31) alkanoylaminoalkyl,
[0069] 32) sulfonate,
[0070] 33) alkylsulfonyl,
[0071] 34) alkylsulfonylaminocarbonyl,
[0072] 35) arylsulfonylaminocarbonyl, and
[0073] 36) heterocyclylsulfonylaminocarbonyl,
[0074] and wherein Ar is a substituted aryl or substituted
heteroaryl group, where substitutions are independently selected
from
[0075] a. hydrogen,
[0076] b. halogen,
[0077] c. alkyl,
[0078] d. aryl,
[0079] e. haloalkyl,
[0080] f. hydroxy,
[0081] g. alkoxy,
[0082] h. alkoxyalkyl,
[0083] i. alkoxycarbonyl,
[0084] j. alkoxyalkoxy,
[0085] k. hydroxyalkyl,
[0086] l. aminoalkyl,
[0087] m. aminocarbonyl,
[0088] n. alkyl(alkoxycarbonylalkyl)aminoalkyl,
[0089] o. heterocyclyl,
[0090] p. substituted heterocyclyl,
[0091] q. heterocyclylalkyl,
[0092] r. substituted heterocyclylalkyl,
[0093] s. carboxaldehyde,
[0094] t. carboxaldehyde hydrazone,
[0095] u. carboxamide,
[0096] v. alkoxycarbonylalkyl,
[0097] w. carboxy,
[0098] x. carboxyalkyl,
[0099] y. carboxy alkoxy,
[0100] z. carboxythioalkoxy,
[0101] aa. carboxycycloalkoxy,
[0102] bb. thioalkyl,
[0103] cc. hydroxycarbonylalkyl (carboxyalkyl),
[0104] dd. hydroxyalkylaminocarbonyl,
[0105] ee. cyano,
[0106] ff. amino,
[0107] gg. heterocyclylalkylamino,
[0108] hh. carboxyalkylamino,
[0109] ii. heterocyclylalkylaminocarbonyl, and
[0110] jj. "trans-cinnamide".
[0111] Additionally provided are methods of treatment or
prophylaxis in which the inhibition of inflammation or suppression
of immune response is desired, comprising administering an
effective amount of a compound of formula I.
[0112] Still further provided are pharmaceutical compositions
containing compounds of formula I.
DETAILED DESCRIPTION
[0113] The term "alkanoyl" as used herein refers to an alkyl group
attached to the parent molecular group through a carbonyl
group.
[0114] The term "alkanoylamino" as used herein refers to an
alkanoyl group attached to the parent molecular group though an
amino group.
[0115] The term "alkanoylaminoalkyl" as used herein refers to an
alkanoylamino group attached to the parent molecular group through
an alkyl group.
[0116] The term "alkanoyloxy" as used herein refers to an alkanoyl
group attached to the parent molecular group through an oxygen
radical.
[0117] The term "alkanoyloxyalkyl" as used herein refers to an
alkanoyloxy group attached to the parent molecular group through an
alkyl group.
[0118] The term "alkoxy" as used herein refers to an alkyl group
attached to the parent molecular group through an oxygen atom.
[0119] The term "alkoxyalkoxy" as used herein refers to an alkoxy
group attached to the parent molecular group through an alkoxy
group.
[0120] The term "alkoxyalkyl" as used herein refers to an alkoxy
group attached to the parent molecular group through an alkyl
group.
[0121] The term "alkoxycarbonyl" as used herein refers to an alkoxy
group attached to the parent molecular group through a carbonyl
group.
[0122] The term "alkoxycarbonylalkyl" as used herein refers to an
alkoxycarbonyl group attached to the parent molecular group through
an alkyl group.
[0123] The term "alkyl" as used herein refers to a saturated
straight or branched chain group of 1-10 carbon atoms derived from
an alkane by the removal of one hydrogen atom.
[0124] The term "alkyl(alkoxycarbonylalkyl)amino" as used herein
refers to an amino group substituted with one alkyl group and one
alkoxycarbonylalkyl group.
[0125] The term "alkyl(alkoxycarbonylalkyl)aminoalkyl" as used
herein refers to an alkyl(alkoxycarbonylalkyl)amino group attached
to the parent molecular group through an alkyl group.
[0126] The term "alkylene" as used herein refers to a divalent
group of 1-10 carbon atoms derived from a straight or branched
chain alkane by the removal of two hydrogen atoms.
[0127] The term "alkylsulfonyl" as used herein refers to an alkyl
radical attached to the parent molecular group through an
--SO.sub.2-- group.
[0128] The term "alkylsulfonylaminocarbonyl" as used herein refers
to an alkylsulfonyl group attached to the parent molecular group
through an aminocarbonyl group.
[0129] The term "amino" as used herein refers to a radical of the
form --NR.sub.18R.sub.19, or to to a radical of the form
--NR.sub.18--, where R.sub.18 and R.sub.19 are independently
selected from hydrogen, alkyl or cycloalkyl.
[0130] The term "aminoalkanoyl" as used herein refers to to an
amino group attached to the parent molecular group through an
alkanoyl group.
[0131] The term "aminoalkyl" as used herein refers to an amino
group attached to the parent molecular group through an alkyl
group.
[0132] The term "aminocarbonyl" as used herein refers to an amino
group attached to the parent molecular group through a carbonyl
group.
[0133] The term "aryl" as used herein refers to a mono- or bicyclic
carbocyclic ring system having one or two aromatic rings. The aryl
group can also be fused to a cyclohexane, cyclohexene, cyclopentane
or cyclopentene ring. The aryl groups of this invention can be
optionally substituted with alkyl, halogen, hydroxy, carboxy, or
alkoxy substituents.
[0134] The term "arylalkoxy" as used herein refers to an aryl group
attached to the parent molecular group through an alkoxy group.
[0135] The term "arylalkoxycarbonyl" as used herein refers to an
arylalkoxy group attached to the parent molecular group through a
carbonyl group.
[0136] The term "arylsulfonyl" as used herein refers to an aryl
radical attached to the parent molecular group through an
--SO.sub.2-- group.
[0137] The term "arylsulfonylaminocarbonyl" as used herein refers
to an arylsulfonyl group attached to the parent molecular group
through an aminocarbonyl group.
[0138] The term "carboxaldehyde" as used herein refers to the
radical --CHO.
[0139] The term "carboxaldehyde hydrazone" as used herein refers to
the radical --CH.dbd.N--NR.sub.2OR.sub.21, where R.sub.20 and
R.sub.21 are independently selected from hydrogen, alkyl or
cycloalkyl.
[0140] The terms "carboxamide" or "carboxamido" as used herein
refer to an amino group attached to the parent molecular group
through a carbonyl group.
[0141] The term "carboxamidoalkyl" as used herein refers to a
carboxamido group attached to the parent molecular group through an
alkyl group.
[0142] The term "carboxy" as used herein refers to the radical
--COOH.
[0143] The term "carboxyalkyl" as used herein refers to a carboxy
group attached to the parent molecular group through a alkyl
group.
[0144] The term "carboxycarbonyl" as used herein refers to a
carboxy group attached to the parent molecular group through a
carbonyl group.
[0145] The term "cyano" as used herein refers to the radical
--CN.
[0146] The term "cycloalkyl" as used herein refers to a monovalent
saturated cyclic or bicyclic hydrocarbon group of 3-12 carbons
derived from a cycloalkane by the removal of a single hydrogen
atom. Cycloalkyl groups may be optionally substituted with alkyl,
alkoxy, halo, or hydroxy substituents.
[0147] The terms "halo" or "halogen" as used herein refers to F,
Cl, Br, or I.
[0148] The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms.
[0149] The terms "heterocycle" or "heterocyclyl" represent a 4-,
5-, 6- or 7-membered ring containing one, two or three heteroatoms
independently selected from the group consisting of nitrogen,
oxygen and sulfur. The 4- and 5-membered rings have zero to two
double bonds and the 6- and 7-membered rings have zero to three
double bonds. The term "heterocycle" or "heterocyclic" as used
herein additionally refers to bicyclic, tricyclic and tetracyclic
groups in which any of the above heterocyclic rings is fused to one
or two rings independently selected from an aryl ring, a
cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a
cyclopentene ring or another monocyclic heterocyclic ring.
Heterocycles include acridinyl, benzimidazolyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,
dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,
dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,
imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,
isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,
oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,
pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl,
pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl,
pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl,
tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl,
thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl,
triazolyl, and the like.
[0150] Heterocyclics also include bridged bicyclic groups where a
monocyclic heterocyclic group is bridged by an alkylene group such
as 3
[0151] and the like.
[0152] Heterocyclics also include compounds of the formula 4
[0153] where X* and Z* are independently selected from
--CH.sub.2--, --CH.sub.2NH--, --CH.sub.2O--, --NH-- and --O--, with
the proviso that at least one of X* and Z* is not --CH.sub.2--, and
Y* is selected from --C(O)-- and --(C(R").sub.2).sub.v--, where R"
is hydrogen or alkyl of one to four carbons, and v is 1-3. These
heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl,
1,3-benzimidazol-2-one and the like. The heterocycle groups of this
invention can be optionally substituted with alkoxy, alkyl,
halogen, hydroxy, carboxy, carboxyalkyl, or alkoxycarbonyl
substituents.
[0154] The term "heterocyclylalkyl" as used herein refers to an
heterocyclic group attached to the parent molecular group through
an alkyl group.
[0155] The term "heterocyclylalkylamino" as used herein refers to
an heterocyclylalkyl group attached to the parent molecular group
through an amino group.
[0156] The term "heterocyclylalkylaminocarbonyl" as used herein
refers to a heterocyclylalkylamino group attached to the parent
molecular group through a carbonyl group.
[0157] The term "heterocyclylamino" as used herein refers to a
heterocyclyl group attached to the parent molecular group through a
amino group.
[0158] The term "heterocyclylcarbonyl" as used herein refers to a
heterocyclyl group attached to the parent molecular group through a
carbonyl group.
[0159] The term "heterocyclylsulfonyl" as used herein refers to a
heterocyclyl radical attached to the parent molecular group through
an --SO.sub.2-- group.
[0160] The term "heterocyclylsulfonylaminocarbonyl" as used herein
refers to a heterocyclylsulfonyl group attached to the parent
molecular group through an aminocarbonyl group.
[0161] The term "hydroxyalkanoyl" as used herein refers to an
hydroxy radical attached to the parent molecular group through an
alkanoyl group.
[0162] The term "hydroxyalkoxy" as used herein refers to an hydroxy
radical attached to the parent molecular group through an alkoxy
group.
[0163] The term "hydroxyalkoxyalkyl" as used herein refers to an
hydroxyalkoxy group attached to the parent molecular group through
an alkyl group.
[0164] The term "hydroxyalkyl" as used herein refers to an hydroxy
radical attached to the parent molecular group through an alkyl
group.
[0165] The term "hydroxyalkylaminocarbonyl" as used herein refers
to an hydroxyalkyl group attached to the parent molecular group
through an aminocarbonyl group.
[0166] The term "perfluoroalkyl" as used herein refers to an alkyl
group in which all of the hydrogen atoms have been replaced by
fluoride atoms.
[0167] The term "phenyl" as used herein refers to a monocyclic
carbocyclic ring system having one aromatic ring. The phenyl group
can also be fused to a cyclohexane or cyclopentane ring. The phenyl
groups of this invention can be optionally substituted with alkyl,
halogen, hydroxy or alkoxy substituents.
[0168] The term "pharmaceutically-acceptable prodrugs" as used
herein represents those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals with 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.
[0169] The term "prodrug," as used herein, represents compounds
which are rapidly transformed in vivo to the parent compound of the
above formula, for example, by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, Pro-drugs as
Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and
in Edward B. Roche, ed., Bioreversible Carriers in Drug Design,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
[0170] The term "sulfonate" as used herein refers to the radical
--SO.sub.3H The term "tetrazole" or "tetrazolyl" as used herein
refers to the heterocyclic radical --CN.sub.4H.
[0171] The term "thioalkoxy" as used herein refers to an alkyl
group attached to the parent molecular group through a sulfur
atom.
[0172] Compounds of the present invention can exist as
stereoisomers wherein asymmetric or chiral centers are present.
These compounds are designated by the symbols "R" or "S," depending
on the configuration of substituents around the chiral carbon atom.
The present invention contemplates various stereoisomers and
mixtures thereof. Stereoisomers include enantiomers and
diastereomers, and mixtures of enantiomers or diastereomers are
designated (.+-.). Individual stereoisomers of compounds of the
present invention can be prepared synthetically from commercially
available starting materials which contain asymmetric or chiral
centers or by preparation of racemic mixtures followed by
resolution well-known to those of ordinary skill in the art. These
methods of resolution are exemplified by (1) attachment of a
mixture of enantiomers to a chiral auxiliary, separation of the
resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary, (2) salt formation employing an optically active
resolving agent, or (3) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns.
[0173] Geometric isomers can also exist in the compounds of the
present invention. The present invention contemplates the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond or
arrangement of substituents around a carbocyclic ring. Substituents
around a carbon-carbon double bond are designated as being in the Z
or E configuration wherein the term "Z" represents substituents on
the same side of the carbon-carbon double bond and the term "E"
represents substituents on opposite sides of the carbon-carbon
double bond. The arrangement of substituents around a carbocyclic
ring are designated as cis or trans wherein the term "cis"
represents substituents on the same side of the plane of the ring
and the term "trans" represents substituents on opposite sides of
the plane of the ring. Mixtures of compounds wherein the
substituents are disposed on both the same and opposite sides of
plane of the ring are designated cis/trans.
[0174] As is apparent from the foregoing descriptions, the
compounds of Formula 1 are useful in a variety of forms, i.e., with
various substitutions as identified. Examples of particularly
desirable compounds are quite diverse, and many are mentioned
herein. Included are compounds in which R.sub.1 is a
"cis-cinnamide" or a "trans-cinnamide", and R.sub.3 is hydrogen; or
where R.sub.3 is a "cis-cinnamide" or a "trans-cinnamide", and
R.sub.1 is hydrogen, or R.sub.1, R.sub.2, and R.sub.4 are each
independently hydrogen or alkyl, and R.sub.5 is halogen, haloalkyl
or nitro. Further preferred compounds include those as above
wherein R.sub.10 and R.sub.11 are each independently hydrogen,
alkyl, cycloalkyl, alkoxycarbonylaalkyl, hydroxyalkyl, or
heterocyclylalkyl, or where NR.sub.10R.sub.11 is heterocyclyl or
substituted heterocyclyl, and where Ar is aryl, substituted aryl,
heteroaryl, or substituted heteroaryl.
[0175] Compounds of the present invention include:
[0176]
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)ph-
enyl]sulfide;
[0177]
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)et-
henyl)phenyl]sulfide;
[0178]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)e-
thenyl)phenyl]sulfide;
[0179]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6hydroxyhexylamino)carbonyl)et-
henyl)phenyl]sulfide;
[0180]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carb-
onyl)ethenyl)phenyl]sulfide;
[0181]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide;
[0182]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl-
)phenyl]sulfide;
[0183]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0184]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0185]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0186]
(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)et-
henyl)phenyl]sulfide;
[0187]
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phen-
yl]sulfide;
[0188]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0189]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)pipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0190]
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0191]
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0192]
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0193]
(2-Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
[0194]
(2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide;
[0195]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[0196]
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[0197]
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomopiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0198]
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide;
[0199]
(2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0200]
(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)-
ethenyl)phenyl]sulfide;
[0201]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0202]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)et-
henyl)phenyl]sulfide;
[0203]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylami-
no)carbonyl)ethenyl)phenyl]sulfide;
[0204]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0205]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-onyl)pr-
opylamino)carbonyl)ethenyl)phenyl]sulfide;
[0206]
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl-
)ethenyl)phenyl]sulfide;
[0207]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0208]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylam-
ino)carbonyl)ethenyl)phenyl]sulfide;
[0209]
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0210]
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0211]
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0212]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0213]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
[0214]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0215]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)p-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0216]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0217]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)pi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0218]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0219]
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0220]
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0221]
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0222]
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0223]
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0224]
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0225]
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0226]
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0227]
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-
-propenyl)phenyl]sulfide;
[0228]
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0229]
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-ch-
loro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0230]
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-
-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0231]
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-
-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0232]
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phe-
nyl]sulfide;
[0233]
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide;
[0234]
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-mo-
rpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0235]
(2-Formylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0236]
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phe-
nyl]sulfide, N,N-dimethyl hydrazone;
[0237]
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-mor-
pholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0238]
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylam-
ino)carbonyl)ethenyl)phenyl]sulfide;
[0239]
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl-
)phenyl]sulfide;
[0240]
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0241]
(2-Cyanophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-ylcarbonyl)ethe-
nyl)phenyl]sulfide;
[0242]
(2-Isopropylphenyl)[2-cyano-4-(E-((morpholin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide;
[0243]
(2-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0244]
(2-(Pyrrolidin-1-yl)phenyl)[2-chloro-4-(E-((morpholin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0245]
(2-Methoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)p-
henyl]sulfide;
[0246]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxypiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0247]
(2-Methylphenyl)[2-nitro-4-(E-((3-carboxamido-4-carbobenzoxypiperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0248]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-tert-butoxycarb-
onylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0249]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxy-4-tert-butoxycarbonylp-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0250]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0251]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0252]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-y-
l)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0253]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((cyclobutylamino)carbon-
yl)ethenyl)phenyl]sulfide;
[0254]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((cyclopentylamino)carbo-
nyl)ethenyl)phenyl]sulfide;
[0255]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((5-hydroxypent-1-ylamin-
o)carbonyl)ethenyl)phenyl]sulfide;
[0256]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-acetylpiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0257] (2-Biphenyl)[2-chloro-4-(E-((morpholin-1-yl)carbonyl)
ethenyl)phenyl]sulfide;
[0258]
(3,4-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0259]
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0260]
(5-Indolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide;
[0261]
(5-Benzodioxolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
[0262]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxypiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0263]
(2,3-Dimethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethen-
yl)phenyl]sulfide;
[0264]
(2-Fluorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0265]
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl)pip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0266]
(2-(Pyrrolidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxy-
carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0267]
(3-Carboxamidophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0268]
(3-(Hydroxymethyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0269]
Phenyl[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl)piperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0270]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-(tert-
-butoxycarbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0271]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-methylaminocarbony-
l)-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0272]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)ph-
enyl]sulfide;
[0273]
(2-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
[0274]
(2-(Azetidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxyca-
rbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0275]
(2-(Piperidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxyc-
arbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0276]
(3-Chloro-2-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0277]
(2-Trifluoromethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0278]
(3-Bromophenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0279]
(3,5-Dimethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0280]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-(pyrid-
ine-4-carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0281]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-carbom-
ethoxypiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0282]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-acetyl-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0283]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-morpholinocarbonyl)-4-tert--
butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0284]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-methylaminocarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0285]
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-dimethylaminocarbonyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0286]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(benzylaminocarbonyl)-4-tert-b-
utoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0287]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-tert-
-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0288]
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-hydroxymethyl-pyrrolidin-2-on-
-1-yl)prop 1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0289]
(2-Bromophenyl)[2-chloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylam-
ino)carbonyl)ethenyl)phenyl]sulfide;
[0290]
(2-Bromophenyl)[2-chloro-4-(E-(N-methyl-N-(3-(pyrrolidin-2-on-1-yl)-
prop-1-yl)amino)carbonyl)ethenyl)phenyl]sulfide;
[0291]
(2-[2-Methoxy]ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl-
]ethenyl)phenyl]sulfide;
[0292]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(morpholinocarbonyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0293]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-tert-butoxycarbonylpiperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
[0294]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methoxycarbonylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0295]
(2-Isopropylphenyl)[2-nitro-4-(E-(4-(pyridine-4-carbonyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0296]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-3-methylaminocarbony-
l)-4-tert-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0297]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-2-methylaminocarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0298]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-3-methylaminocarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0299] 1
(4-Hydroxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0300]
(3,5-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0301]
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-acetoxymethyl-pyrrolidin-2-on-
-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0302]
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-methoxymethyl-pyrrolidin-2-on-
-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0303]
(2-Bromophenyl)[2-chloro-4-(E-((3-(4R-hydroxymethyl-pyrrolidin-2-on-
-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0304]
Phenyl[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide;
[0305]
(2-Dimethylaminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0306]
(3-((2-Hydroxyethyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4-acetylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0307]
(3-((3-(1-Imidazolyl)propyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4--
acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0308]
(3-((2-(1-Morpholinyl)ethyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4--
acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0309]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-tert-butoxycar-
bonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0310]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-formylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0311]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-hydroxymethyl-4-tert-butoxycar-
bonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0312]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)car-
bonyl]ethenyl)phenyl]sulfide;
[0313]
(3-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0314]
(4-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide;
[0315]
(2,4-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0316]
(2,5-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0317]
(4-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide;
[0318]
(3-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0319] (2-Chloro,
4,5-diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0320]
(3,4-Diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]
[0321]
(6-Chlorobenzimidazol-2-on-5-yl)[2-chloro-4-(E-((4-acetylpiperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0322]
(1-Methylindol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0323] (2-Hydroxy,
4-aminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0324]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0325]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyridine-2-carbonyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0326]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyridine-3-carbonyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0327]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-methoxycarbonyl-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0328]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxy-4-methoxycarbonylpiper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0329]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-methylpiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0330]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide;
[0331]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide;
[0332]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-ethoxycarbonylpiperidin-1-yl)car-
bonyl]ethenyl)phenyl]sulfide;
[0333]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((1-(tert-butoxycarbonyl)-4-
-hydroxypyrrolidin-3-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0334]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-carboxypiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide;
[0335]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-(((pyrrol-3-in-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0336]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)p-
rop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0337]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0338]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-(ethoxycarbonyl)piperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0339]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-(2-furylcarbonyl)pipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0340]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)car-
bonyl]ethenyl)phenyl]sulfide;
[0341]
(2-Ethoxyphenyl)-[2-chloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide;
[0342]
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0343]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-ethoxycarbonylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0344]
(2-isopropylphenyl)[2-nitro-4-(E-((4-isopropoxycarbonylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0345]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-isobutoxycarbonylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0346]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-((1-propen-2-oxy)carbonyl)pipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0347]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-propionylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[0348]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboxamidopiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0349]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methylaminocarbonylpiperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
[0350]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrimidin-2-yl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0351]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-hydroxyacetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0352]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrazine-2-carbonyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0353]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-carboxypyrrol-3-in--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0354]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-methylpiperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0355]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-carboxypyrrol-3-in--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0356]
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-hydroxymethylpyrrol-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0357]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-methylaminocarbonyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0358]
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-cyclopropylaminocarbonyl)pipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0359]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxamidopiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0360]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-oxopiperidin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0361]
(2-Isopropylphenyl)[2-nitro-4-(E-((3,5-dimethylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0362]
(1-Ethylindol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0363] (3-[2-Methoxy]ethoxyphenyl)-[2-chloro-4(E-[(morpholin
1-yl)carbonyl]ethenyl)phenyl]sulfide;
[0364]
(2-Bromophenyl)[2-chloro-4-(E-((4,4'-S-dioxythiomorpholin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0365]
(2-Bromophenyl)[2-chloro-4-(E-(N-carbomethoxymethyl-N-(3-(pyrrolidi-
n-2-on-1-yl)prop-1-yl)amino)carbonyl)ethenyl)phenyl]sulfide;
[0366]
(2-Bromophenyl)[2-chloro-4-(E-((4-S-oxythiomorpholin-1-yl)-2-pyrrol-
idinone)carbonyl)ethenyl)phenyl]sulfide;
[0367]
(2-Methoxy-5-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0368]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0369]
(2-Isopropylphenyl)[2-nitro-4-(E-((3,5-dimethyl-4acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0370]
(1-Methylindol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0371]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
[0372]
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-yl-
amino)carbonyl)ethenyl)phenyl]sulfide;
[0373]
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0374]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0375]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0376]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((6-methylpyrid-2-ylamino)c-
arbonyl)ethenyl)phenyl]sulfide;
[0377]
(2-Methyl-3-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0378]
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-carboxamidopiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0379]
(Benzodioxan-6-yl)[2-nitro-4-(E-((2-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0380]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxamidopiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0381]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-tert-butoxycarbonylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0382]
(2-Isopropylphenyl)[2-nitro-4-(E-((syn-3,5-dimethylmorpholin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0383]
(2-Isopropylphenyl)[2-nitro-4-(E-((anti-3,5-dimethylmorpholin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0384]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0385]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-isopropoxycarbonylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0386]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-meth-
ylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0387]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-hydroxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0388]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-hydroxypiperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0389]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-(methoxy-
carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0390]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-methylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0391]
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carboxy-4-(methoxycarbo-
nyl)piperazin-1-ylcarbonyl)ethenyl)phenyl]sulfide;
[0392]
(Indol-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide;
[0393]
(1-Ethyl-3-(dimethylaminomethyl)indol-7-yl)[2-chloro-4-(E-((4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0394]
(5-Ethoxybenzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0395]
(2-Ethyl-4-bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0396]
(Benzodioxan-6-yl)[2-nitro-4-(E-((2-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0397]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxymethylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0398]
(3-Morpholinophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0399]
(5-Ethoxybenzodioxan-8-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide;
[0400]
(5-Chloro-8-ethoxyquinolin-7-yl)[2-chloro-4-(E-((4-acetylpiperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0401]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0402]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0403]
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-ethanesulfonylaminocarbonyl)p-
iperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0404]
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-(4-methylpiperazine)sulfonyla-
minocarbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0405]
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-p-toluenesulfonylaminocarbony-
l)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0406]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-methyl-4-acetylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0407]
(2-Hydroxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)p-
henyl]sulfide
[0408]
(1-(Carboxymethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0409]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0410]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-onyl)prop-1-yl-
amino)carbonyl)ethenyl)phenyl]sulfide;
[0411]
(3-(2-Morpholinoethylamino)phenyl)[2-trifluoromethyl-4-(E-((4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0412]
(2-Pyrrolidin-1-ylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0413]
(3-Bromophenyl)[2-nitro-4-(E-((3-carboethoxypyrrolidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0414]
(3-Bromophenyl)[2-nitro-4-(E-((4-carboethoxypyrrolidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0415]
(2-(Hydroxymethyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0416]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl-
)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0417]
(3-(Dimethylaminomethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0418]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0419]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0420]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0421]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0422]
(2-Isopropylphenyl)[2-nitro-4-(E-(((4-p-toluenesulfonylaminocarbony-
l)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0423]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxy-4-hydroxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0424]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboethoxypiperidin--
1-yl) carbonyl)ethenyl)phenyl]sulfide;
[0425]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboethoxypiperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0426]
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0427]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyrrolidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0428]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboethoxypiperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0429]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-tert-b-
utoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0430]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-methox-
ycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0431]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxypiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0432]
(2-Methyl-3-(carboethoxymethyl)indol-5-yl)[2-trifluoromethyl-4-(E-(-
(morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0433]
(1-(2-Methoxyethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0434]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethyl-4-hydroxypiperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0435]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-hydr-
oxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0436]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-cyanomorpholin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
[0437]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxymorpholin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0438]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(tetrazol-5-yl)morpholin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0439]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0440]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0441]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carbomethoxypiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0442]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-aza-6,9-diooxaspiro[5-
.4]decan-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0443]
(Benzodioxan-6-yl)[2-trifluoro-4-(E-((4-(benzimidazolon-1-yl)piperi-
din-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0444]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-(methylaminocarbonyl)-
piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0445]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carbomethoxy-4-methox-
ycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0446]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxymorpholin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0447]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboxy-4-methoxycarb-
onylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0448]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0449]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-(pyrrolidin-1-yl)pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0450]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-aza-6,9-diooxaspiro[5.4]decan--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0451]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(dimethylaminomethyl)piperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0452]
(2-Isopropylphenyl)[2-nitro-4-(E-((piperidin-1-ylamino)carbonyl)eth-
enyl)phenyl]sulfide;
[0453]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxy-4-methoxycarb-
onylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0454]
(2-(Dimethylaminocarbonyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acet-
ylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0455]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(2-(methoxymethyl)tetrazol-5-y-
l)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0456]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-(methoxymethyl)tetrazol-5-y-
l)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0457]
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-onyl)propyla-
mino)carbonyl)ethenyl)phenyl]sulfide;
[0458]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(tetrazol-5-yl)piperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0459]
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboethoxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0460]
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbon-
ylethenyl)phenyl]sulfide;
[0461]
(1-Methylindol-5-yl)[2-chloro-4-(E-((4-carboethoxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0462]
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[0463]
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(1-methylpyrrolidin-2-yl)ethyl-
amino)carbonyl)ethenyl)phenyl]sulfide;
[0464]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrrolidin-1-yl)piperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0465]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-sulfopiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide;
[0466]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxypiperidin-1-yl)carbonyl-
ethenyl)phenyl]sulfide;
[0467]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-((ethanesulfonylamino-
)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0468]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-((p-toluenesulfonylam-
ino)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0469]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-((ethanesulfonylamino-
)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0470]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2(tetrazol-5-yl)morphol-
in 1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0471] (2-Isopropylphenyl)[2-nitro-4-(E-((2-butyl,
5-(tetrazol-5-yl)morpho-
lin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0472] (2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((4-acety-
lpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0473] (2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrr-
olidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0474] (2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-
-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0475]
(3-Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2--
on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0476]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]
[0477] (2-(and
3-)(Aminomethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-(-
(3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0478]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(methylaminocarbonyl)morpholin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0479]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(hydroxymethyl)morpholin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0480]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(acetoxymethyl)morpholin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0481]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(aminomethyl)morpholin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0482]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(acetamidomethyl)morpholin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0483]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop
1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0484]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0485]
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0486]
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)carbonyl]ethen-
yl)phenyl]sulfide;
[0487]
(2-Methoxyphenyl)-[2,3-dimethyl-4(E-[(morpholin-1-yl)carbonyl]ethen-
yl)phenyl]sulfide;
[0488]
(2-Isopropylphenyl)[2-nitro-4-(E-((indol-5-ylamino)carbonyl)ethenyl-
)phenyl]sulfide;
[0489]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0490]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)piperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0491]
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(tert-butoxycarbonyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0492]
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboxypiperidin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide;
[0493]
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)morpholin-1-yl)-
carbonylethenyl)phenyl]sulfide;
[0494]
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(methylaminocarbonyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0495]
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbo-
nyl]ethenyl)phenyl]sulfide;
[0496]
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(tetrazol-5-yl)piperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0497]
(2-Methoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)p-
henyl]sulfide;
[0498]
(2-Isopropylphenyl)[2-nitro-4-(E-((4-oxopiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide;
[0499]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carboethoxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0500]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carboxypiperidin-1--
yl)carbonyl)ethenyl)phenyl]sulfide;
[0501]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-
-1-ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0502]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0503]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0504]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0505]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0506]
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0507]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-(1-pyrrolidin-2-onyl)prop-
ylamino)carbonyl)ethenyl)phenyl]sulfide;
[0508]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-acetylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide.
[0509]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0510]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0511]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0512]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0513]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0514]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0515]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0516]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0517]
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbon-
yl]ethenyl)phenyl]sulfide;
[0518]
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)carbonyl]etheny-
l)phenyl]sulfide;
[0519]
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(3-carboxypiperidin-1-yl)carbon-
yl]ethenyl)phenyl]sulfide;
[0520]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypyrrolidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0521]
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypyrrolidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide;
[0522]
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((3-carboethoxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0523]
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((3-carboxypiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0524]
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((4-carboxypiperidin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide;
[0525]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-ethoxycarbonylpylroli-
din-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0526]
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyrrolidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0527]
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((4-carboethoxypi-
peridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0528]
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((4-carboethoxypi-
peridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0529]
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((morpholin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0530] (Benzodioxan-6-yl)[4-(E-((4-carboxypiperidin-1-v
1)carbonyl)ethenyl)naphthyl]sulfide;
[0531]
(2-methoxyphenyl)[2,3-dichloro-4-(E-((4-(spiro-hydantoin-5-yl)-pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0532] (2-methoxyphenyl-1)
[2,3-dichloro-4-(E-(4-(2-(2-hydroxyethoxy)ethen-
yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0533]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-ethyl)piperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide;
[0534]
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-(2-(2-hydroxyethoxy)ethyl-
)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0535]
(Benzodioxan-6yl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0536]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)carbony-
l-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0537]
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxymethylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0538]
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-N-(2-hydroxyeth-
yl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0539] (1-Methylindol-5-yl)
[2,3-dichloro-4-(E-((4-(carbo-2,3-dihydroxypro-
pylamino)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0540]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-dihydroxypropionyl)pipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0541]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-dihydroxy-3-carboxyprop-
ionyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0542]
(1-Methylindol-5-yl-1)[2,3-dichloro-4-(E-((4-(carboxymethylamino)ca-
rbonyl-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0543]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-sulfopiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide;
[0544] (1-Methylindol-5-yl)
[2,3-dichloro-4-(E-(4-methylhomopiperazin-1-yl-
)carbonyl)ethynyl)phenyl]sulfide;
[0545]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-tetrohydrofurylpiperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0546]
(2-Methoxyphenyl)[2.1)-dichloro-4-(E-((4-amino-4-carboxypiperidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
[0547]
(2-Methoxyphenyl)[2,3-dichloro-4-((4-furoylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide;
[0548]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-(carbo-3-sulfopropylamino-
)piperadin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0549]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-acetylamino-4-carboxypiperid-
in-1-ylcarbonyl)ethenyl)phenyl]sulfide;
[0550]
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0551]
(2-Methoxyphenyl)-5-[8-(E-((4-aminocarbonyl)piperidin-1-yl)carbonyl-
)ethenyl)quinolinyl]sulfide;
[0552]
(2-Methoxyphenyl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide;
[0553]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E/Z-((1S,4S)-2,5-diazabycyclo(-
2,2,1)heptan-2-ylcarbonyl)ethenyl)-2,3-dichlorophenyl]sulfide;
[0554]
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-hydroxy-3-carboxypiperadi-
n-1-ylcarbonyl)ethenyl)phenyl]sulfide;
[0555]
(1-Methylindol-5-yl)[2,3)-dichloro-4-(E-(S-oxothiomorpholin-1-ylcar-
bonyl)ethenyl)phenyl]sulfide;
[0556]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-sulfophenylamino)carbonyl)e-
thenyl)phenyl]sulfide;
[0557]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-carboxyphenylamino)carbonyl-
)ethenyl)phenyl]sulfide;
[0558]
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-[(4-carboxypiperidin-1-y-
l)carbonyl]ethenyl)phenyl]sulfide;
[0559]
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-((4-carboxypiperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide;
[0560]
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-phenylcarboxypi-
peridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0561]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(((4-hydroxylaminocarbonyl)pipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0562]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((N-carboxymethyl-N-phenylamino-
)carbonyl)ethenyl)phenyl]sulfide;
[0563]
(2-Methoxyphenyl)[3-chloro-6-hydroxy-4-(E-((3-carboxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide;
[0564]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-((1-(2-phenyl-1-carboxyethyl-
)amino)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0565]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-((1-(2-hydroxy-1-carboxyethy-
l)amino)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0566]
(3-(1-(3-carboxypiperidinyl)phenyl)[2,3-dichloro-4-(E-((1,2,5,6-tet-
rahydropyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0567]
(3-(4-Pyrrolidin-1-yl)piperidin-1-yl)phenyl)[2,3-dichloro-4-(E-(((3-
-(2-pyrrolidinon-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide;
[0568]
[3-(4-(Spiro-2,2-dioxolanyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(-
E-((4-morpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0569]
[3-(3-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxyp-
iperidin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[0570]
(2-(2-Carboxy)ethenyl)phenyl)[2,3-dichloro-4-(E-((4-morpholinyl)car-
bonyl)ethenyl)phenyl]sulfide;
[0571]
[3-(4-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(1,2,3,6-te-
trahydropyridine)-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[0572]
[3-(4-Carboxylpiperidinyl)phenyl][2,3-dichloro-4-(E-[(4-morpholinyl-
)carbonyl]ethenyl)phenyl]sulfide;
[0573]
[2-(4-Acetylpiperazin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxypip-
eridin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[0574] 3-(3-Carboxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-[(4
morpholinyl)carbonyl]ethenyl)phenyl]sulfide;
[0575]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-(dimethyl-
aminosulfamoyl)piperazin-1-yl)carbonyl]ethenyl)phenyl]sulfide;
[0576]
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((3-carboxypiperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0577] (2-Methoxyphenyl)
[2,3-bis(trifluoromethyl)-4-(E-((2-carboxypyrroli-
din-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0578]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((trifluo-
romethylsulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0579]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(piperidin-1-ylcarbonyl)ethenyl-
)phenyl]sulfide;
[0580]
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl-
)phenyl]sulfide;
[0581]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((((4-carboxyphenyl)methyl)amin-
o)carbonyl)ethenyl)phenyl]sulfide;
[0582]
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(((4-pyrrolidin-1-yl)piperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0583]
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide;
[0584]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((methyls-
ulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0585]
(2-Aminophenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)-
phenyl]sulfide;
[0586]
(3-(4-carboxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-((S-oxothiomo-
rpholin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0587]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-hydroxypi-
peridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0588]
(2-Glycoxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl-
)phenyl]sulfide;
[0589]
(2-(4-Butyroxy)phenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)et-
henyl)phenyl]sulfide;
[0590]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-hydroxyet-
hylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0591]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-furoylpip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0592]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-(pyrrolidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide;
[0593]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((diethylamin-
ocarbonyl)ethenyl)phenyl]sulfide;
[0594]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-ethylpipe-
razin-yl)carbonyl)ethenyl)phenyl]sulfide;
[0595]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(aminocar-
bonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0596]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(2-(ethox-
yethyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0597]
[3-((4-Carboxymethyl)piperazin-1-yl)phenyl][(2,3-dichloro-4-(E-(4-m-
orpholinyl)carbonyl)ethenyl)phenyl]sulfide;
[0598]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-(-
(4-morpholino)carbonyl)ethenyl)phenyl]sulfide;
[0599]
(3-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholinocarbonyl)ethenyl)-
phenyl]sulfide;
[0600]
[3-(4-Butyroxy)phenyl][2,3-dichloro-4-(E-((4-morpholino)carbonyl)et-
henyl)phenyl]sulfide;
[0601]
(2-Hydroxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carb-
onyl)ethenylphenyl]sulfide;
[0602]
(3-Hydroxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carb-
onyl)ethenyl)phenyl]sulfide;
[0603]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((4--
hydroxypiperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0604]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((1,-
2,5,6-tetrahydropyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0605]
[2-((4-Carboxy)butyloxy)phenyl][2,3-dichloro-4-(E-((4-morpholino)ca-
rbonyl)ethenyl)phenyl]sulfide;
[0606]
(2-Glycoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carb-
onyl)ethenyl)phenyl]sulfide;
[0607]
(2-(4-Butyroxy)phenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino-
)carbonyl)ethenyl)phenyl]sulfide;
[0608]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((bi-
s-(2-ethoxyethyl)amino)carbonyl)ethenyl)phenyl]sulfide;
[0609]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trifluoromethyl)-4-(E--
((bis-(2-hydroxypropyl)amino)carbonyl)ethenyl)phenyl]sulfide;
[0610]
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trifluoromethyl)-4-(E--
((piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0611]
(3-(4-Butyroxy)phenyl)[2,3-bis(trifluoromethyl)-4(E-((4-morpholino)-
carbonyl)ethenyl)phenyl]sulfide;
[0612]
[2-(3-Carboxypiperidin-1-yl)phenyl)][2,3-dichloro-4-(E-[(3-(2-pyrro-
lidinon-1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide;
[0613]
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-[-
(3-(2-pyrrolidinon-1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide;
[0614]
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(2-hydrox-
yethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0615]
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-(-
(1,2,5,6-tetrahydropyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0616]
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-(-
(4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
[0617]
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-(-
(4-(2-(hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide;
and
[0618] 3
(3-Propioxy)phenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)eth-
enyl)phenyl]sulfide.
[0619] Pharmaceutical Compositions and Methods of Treatment
[0620] The present invention also provides pharmaceutical
compositions which comprise compounds of the present invention
formulated together with one or more pharmaceutically-acceptable
carriers. The pharmaceutical compositions may be specially
formulated for oral administration in solid or liquid form, for
parenteral injection, or for rectal administration.
[0621] The pharmaceutical compositions of this invention can be
administered to humans and other animals orally, rectally,
parenterally, intracistemally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), bucally, or as an
oral or nasal spray. The term "parenteral" administration as used
herein refers to modes of administration which include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous and
intraarticular injection and infusion.
[0622] Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically-acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0623] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like, Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0624] In some cases, in order to prolong the effect of the drug,
it is 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.
[0625] Injectable depot forms are made by forming microencapsule
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.
[0626] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0627] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically-accept- able excipient or carrier such as sodium
citrate or dicalcium phosphate and/or (a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
(b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c)
humectants such as glycerol, (d) disintegrating agents such as
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate, (e) solution
retarding agents such as paraffin, (f) absorption accelerators such
as quaternary ammonium compounds, (g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, (h) absorbents
such as kaolin and bentonite clay, and (I) lubricants such as 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.
[0628] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0629] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. 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.
[0630] The active compounds can also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0631] Liquid dosage forms for oral administration include
pharmaceutically-acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
[0632] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0633] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[0634] 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 room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0635] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically-acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilizers, preservatives, excipients, and the like.
The preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic.
[0636] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y. (1976), p. 33 et seq.
[0637] The compounds of the present invention may be used in the
form of pharmaceutically-acceptable salts derived from inorganic or
organic acids. By "pharmaceutically-acceptable salt" is meant those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically-acceptable salts are well-known in the art.
For example, S. M. Berge, et al. Describe
pharmaceutically-acceptable salts in detail in J. Pharmaceutical
Sciences, 1977, 66: 1 et seq. The salts may be prepared in situ
during the final isolation and purification of the compounds of the
invention or separately by reacting a free base function with a
suitable acid. Representative acid addition salts include acetate,
adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate
(isethionate), lactate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups can be quaternized with such agents as
lower alkyl halides such as methyl, ethyl, propyl, and butyl
chlorides, 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; arylalkyl halides like benzyl and phenethyl bromides and
others. Water or oil-soluble 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, hydrobromic acid, sulphuric
acid and phosphoric acid and such organic acids as oxalic acid,
maleic acid, succinic acid and citric acid.
[0638] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety 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.
Pharmaceutically-acceptable basic addition salts include cations
based on alkali metals or alkaline earth metals such as lithium,
sodium, potassium, calcium, magnesium and aluminum salts and the
like and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the like. Other representative organic amines useful
for the formation of base addition salts include ethylenediamine,
ethanolamine, diethanolamine, piperidine, piperazine and the
like.
[0639] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically-accept- able carrier and any needed preservatives,
buffers, or propellants which may be required. Opthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0640] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated, and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0641] Generally dosage levels of about 0.1 to about 50 mg, more
preferably of about 5 to about 20 mg of active compound per
kilogram of body weight per day are administered orally or
intravenously to a mammalian patient. If desired, the effective
daily dose may be divided into multiple doses for purposes of
administration, e.g. two to four separate doses per day.
[0642] Preparation of Compounds of the Invention
[0643] The compounds and processes of the present invention may be
better understood in connection with the following synthetic
Schemes which illustrate the methods by which the compounds of the
invention can be prepared. 5
[0644] Scheme 1 describes the synthesis of a typical
cinnamide-substituted diaryl sulfide 4 through an aldehyde
intermediate 2. Aldehyde 2 is prepared by reaction of a thiophenol
(for example 2,4-dichlorothiophenol, 2-bromothiophenol, or the
like) with halo-substituted benzaldehyde derivative 1 (e.g.
2-chlorobenzaldehyde, 3-chloro, 4-fluorobenzaldehyde, or the like)
in the presence of base (e.g. sodium carbonate, triethylamine, or
the like) and a polar solvent (e.g. dimethylformamide,
dimethylsulfoxide, or the like). The aldehyde group is homologated
to the corresponding cinnamic acid 3, using an acetate equivalent
(for example, malonic acid, triethoxyphosphonoacetate, or the like)
in the presence of an appropriate base and solvent. In some cases,
it may be necessary to hydrolyze an intermediate ester (for example
using sodium hydroxide in alcohol). The acid group is activated
(for example using thionyl chloride, or dicyclohexylcarbodiimide
and N-hydroxysuccinimide, or the like) and reacted with a primary
or secondary amine (for example, 6-aminohexanol,
pyrrolidone-3-propylamine, or the like) to provide the desired
analog 4. In one variant, a halo-acetophenone can replace
benzaldehyde 2; the resultant cinnamides 4 are substituted with a
methyl group at the 3-position. 6
[0645] Alternatively, the order of these coupling steps may be
reversed (Scheme 2). A substituted halocinnamic acid 5 (e.g.
3-chloro-2-nitrocinnamic acid or the like) may be coupled with a
primary or secondary amine (e.g. N-acetylpiperazine or the like) as
described above to give the corresponding amide 6. The halo-group
can then be displaced with a substituted thiophenol in the presence
of base to provide the product 7. 7
[0646] A number of the compounds described herein may be prepared
from intermediate benzylic alcohols like 8 (Scheme 3) Activation of
the alcohol moiety (for example, using phosphorus tribromide or
methanesulfonyl chloride and lithium halide in dimethylformamide)
and displacement with a primary or secondary amine (e.g.
morpholine, N-formylpiperazine or the like) provides analogs with
structures related to 9. Alternatively the alcohol may be oxidized
(for example using TPAP or PCC or the like) to give aldehyde 10.
8
[0647] Cinnamides like 13 may be prepared from halo-substituted
derivatives 11 by palladium-mediated coupling [e.g. using
tetrakis(o-tolyl phosphine)palladium (0), Pd.sub.2(dba).sub.3, or
the like] with acrylamide derivatives 12 (Scheme 4). In similar
manner, anilino-cinnamides like 16 can be prepared by
palladium-mediated coupling of amines 15 with halo-cinnamides 14.
9
[0648] In some cases, functional groups on the aromatic rings can
be modified to produce new analogs (Scheme 5). For example, a nitro
group in compounds like 17 may be reduced (for example, with
tin(II) chloride, or by catalytic hydrogenation, or the like) to
the corresponding amine 18. This amine may then itself be converted
to a halogen, for example by diazotization using nitrous acid or
t-butyl nitrite in the presence of a metal halide salt like cupric
bromide, providing analog 19. 10
[0649] It is also possible to assemble cinnamide-substituted diaryl
sulfides in a "reverse" sense (Scheme 6). Thus, for example,
compound 20, prepared as described in Scheme 1, may be deprotected
by treatment with base (e.g. potassium t-butoxide or the like) to
provide thiolate anion 21, which may be reacted with an activated
haloarene (e.g. 2,3-dichlorobenzaldehyde, 3-chloro,
4-fluorobenzaldehyde or the like) to provide the corresponding
product 22. Alternatively, this same thiolate anion may be coupled
with unactivated aryl halides (e.g. aryl bromide or Aryl iodides)
using a metal-catalyzed Ullman coupling procedure (for example,
using a palladium or nickel catalyst) to give product 23.
[0650] A further method for producing (diarylsulfide cinnamides is
shown in Scheme 7, wherein the diaryl sulfide is formed through
coupling of a suitably protected aryl thiol 28 to an activated
cinnamate ester 27. Substituted phenol 24 may be brominated to give
bromophenol 25. Heck-type coupling of bromide 25 with an
appropriate olefinic substrate, for example methyl acrylate, is
effected with palladium catalysis, leading to the cinnamate ester
26. The phenol is then activated towards further reaction, for
example by conversion to the corresponding triflate 27 under
standard conditions. The required protected thiol 28 may be
prepared by the method of XXX (Tetrahedron Lett. 1994, 35,
3221-3224), by coupling an aryl halide or triflate with
triisopropylsilyl thiol under palladium catalysis. The two partners
27 and 28 are then reacted in the presence of a fluoride source,
for example cesium fluoride, to provide the diarylsulfide cinnamate
29. Hydrolysis is accomplished by basic media, such as lithium or
sodium hydroxide in water-THF, and the resulting acid 30 is coupled
to amines under standard amide-bond forming conditions (for
example, EDC/HOBt) to produce the amities 31. 11
[0651] A method for preparing cinnamides bearing two arylthio
groups is outlined in Scheme 8. Commercially available difluoro
cinnamic acid 32 was coupled with an amine, using standard
conditions, and this derived amide 33 was reacted with excess aryl
thiol to provide the bis-sulfide 34. 12
[0652] Compounds which contain trifluoromethyl groups on the
cinnamide-portion of inhibitors were made by the method shown in
Scheme 9. According to the method of XXX (Ref), Diels-Alder
reaction between 1,1,1,4,4,4-hexafluoro-2-butyne and 2-methylfuran
let to bicyclic ether 35, which was rearranged with Lewis acid (for
example, boron trifluoride etherate) to the phenol 36. The methyl
group is then converted to the corresponding aldehyde 37 by
bromination followed by reaction with dimethylsulfoxide. Using the
analogous procedures described for Scheme 1 above, the phenol was
activated and condensed with thiols under basic conditions to
afford diarylsulfide aldehydes 38, and further converted to
cinnamides 39 by the previously described procedures. 13
[0653] Cinnamides bearing more complex substituted piperidine
amides can be produced by the methods outlined in Scheme 10 and 11.
Cinnamic acids 40 are coupled to spiro-hydantoin piperidine 41, and
the derived amide 42 is first reacted with an activating reagent
(for example di-tert-butyl dicarbonate), and then hydrolyzed to the
amino acid 43. The derived amino group may then be reacted further,
for example with acid anhydrides or acid chlorides to produce
amides 44. 14
[0654] Further derivatives of piperidine amides can be obtained by
coupling of piperidinone 45 with cinnamic acids 40, as shown in
Scheme 11. Standard coupling, conditions lead to amide 46, which is
first reduced to the corresponding alcohol, then hydrolyzed to
afford hydroxy acid 47. 15
[0655] Also included in this invention are compounds derived from
coupling of amines, or amino acid derivatives (such as a-amino
esters) to the carboxylic acid group of cinnamides 48, using
standard coupling and hydrolysis methods, as outlined in Scheme 12.
Thus amides 49 are produced directly from amine coupling reactions
Amino acid esters are coupled to 48, and the derived esters are
hydrolyzed to the corresponding acids 50. 16
[0656] Inhibitors bearing substituted piperazine (or
homopiperazine) cinnamides may be produced by the methods described
in Scheme 13. The methods described may be utilized to produce
piperazine amide 51. Secondary amine 51 then serves as educt for
preparing amides 52, through standard coupling reactions.
Alternatively, 51 may be converted to tertiary amines 53 through
standard reductive alkylation methods (for example condensation
wall an aldehyde in the presence of a reducing agent such as sodium
triacetoxyborohydride). 17
[0657] A process for preparing analogs with amino substitutions of
the aryl portion of the sulfides is illustrated in Scheme 14. The
intermediate triflate 27 is reacted with halo-substituted
thiophenols 54 (X=Br, Cl, OTf, OTs) under basic catalysis, to
provide the sulfide derivative 55. The halogen or activated
hydroxyl is then substituted with an amine, using the method of
Buchwald (Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722-9723). Similar transition-metal catalyzed
reactions may be applied, for example, the method of Hartwig
(Hamann, B. C.; Hartwig, J. F. J. Chem. Soc. 1998, 120, 7369-7370).
The NR.sub.3R.sub.4, group may constitute a cyclic or acyclic,
group, optionally substituted with additional functionalities that
may enhance the activities of the compounds, and that further
synthetic transformations familiar to those skilled in the art may
be applied. For instance, ester groups may be hydrolyzed to the
corresponding carboxylic acids or amides. The derived anilino
sulfides may then be processed as described above to produce the
cinnamides 56. 18
[0658] Scheme 15 presents a synthesis of a particular class of
substituted aniline derivatives bearing a carboxylic acid. A cyclic
amino acid 58 may be converted into the corresponding t-butyl ester
61, through the intermediacy of carbamate 59 and ester 60, using
standard synthesis methods. The amino ester 61 was then reacted
with 2-fluoronitrobenzene with mild basic catalysis (for example,
cesium fluoride, potassium bicarbonate), to provide the aniline
derivative 62. The nitro group may then be transformed into an
iodo-substituted derivative 64, by first conversion to the aniline
63, followed by standard diazotization and reaction of the
diazonium salt with potassium iodide (among other similar methods
for this Sandmeyer reaction). Using the method outlined in Scheme
7, the iodide 64 may be converted to the TIPS-protected arylthiol
65. In a sequence analogous with that described in Scheme 7, silyl
thioether 65 may be reacted with cinnamide triflate 27 in the
presence of a fluoride source (for example, cesium fluoride), and
thus converted to the diarylsulfide 66. Standard synthetic
transformations (ester hydrolysis, amide coupling, and tert-butyl
ester cleavage) provides the desired acid 68, through intermediate
ester 67.
[0659] Compounds bearing elaborated ether groups on the arylsulfide
ring were made according to scheme 16. Methyl ether cinnamate
esters such as 69 were hydrolyzed to the corresponding acids, and
then the methyl ether was cleaved with boron mide (or alternatively
using similar ether cleaving agents, such as trimethylsilyl to
provide the hydroxy acids 70. Standard coupling methods provided
the 71, which were then alkylated on the phenolic group using an
appropriate halide 72 (where is a linking group consisting of an
acyclic alkyl, or heterocyclic group) or lactone (m=1,2) in the
presence of a base (such as potassium tert-butoxide, sodium
hydride, or cesium carbonate). Alternatively, the phenolic group
was alkylated with an ester-bearing alcohol 73, using Mitsunobu
conditions. The resulting ester-bearing ethers 74 were then
hydrolyzed to the corresponding acids 75 using standard hydrolysis
conditions. Alternatively, the ester of 74 may be tert-butyl, in
which case acidic deprotection to acid 75 would be employed (for
example, using trifluroacetic acid in dichloromethane, or
hydrochloric acid in dioxane). 19 20
[0660] Related compounds bearing elaborated functionalized amino
substituents were made according to Scheme 17. Triflate 27 was
reacted with an amino thiophenol to produce the diarylsulfide
cinnamide 76 in a similar manner to that described in Schemes 1, 2,
and 7. The cinnamate ester was hydrolyzed to give acid 77, which
was coupled under standard conditions to provide amide 78. The
amino group of 78 then underwent reductive alkylation with an
ester-bearing alkyl aldehyde, using standard conditions (or
alternatively using sodium triacetoxyborohydride) to provide the
secondary amine 79. The ester functionality was hydrolyzed to the
corresponding acid salt 80.
[0661] An alternative strategy for producing intermediate 78 is
shown in Scheme 18. Nitro-substituted tert-butyl ester derivative
81 (prepared according to Scheme 14, using the tert-butyl analog of
cinnamate 27) was cleaved to the carboxylic acid, converted to the
cinnamide using standard conditions, and then the nitro group was
reduced using iron powder in aqueous ammonium chloride solution. 21
22
[0662] A modified method for the preparation of analogs bearing
2,3-bis-(trifluoromethyl)cinnamides is illustrated in Scheme 19.
Commercially available acrylic acid 82 was esterified with ethyl
iodide, and the ester 83 was condensed with
1,1,1,4,4,4-hexafluoro-2-butyne at 110.degree. C. to give the
bicyclic adduct 84. The bicyclic ether was then converted to the
corresponding phenol 85 using a Lewis acid (for example boron
trifluoride-etherate). Phenol 85 was the utilized as illustrated in
Scheme 7 or Scheme 14 to prepare the desired inhibitors. 23
[0663] Scheme 20 illustrates an alternative method for preparing
substituted anilinosulfides 57. Cinnamate ester 55 was converted to
the corresponding tert-butyl ester 87, via reaction of acid 86 with
tert-butyl trichloroacetimidate under Lewis acid catalysis. The
bromide 87 was then coupled with an appropriately functionalized
amine illustrated in Scheme 20 with ethyl pyrrolidenecarboxylates)
using palladium catalysis (for example, using the conditions of
Buchwald or Hartwig noted for Scheme 14). The resultant substituted
anilines 88 were then first cleaved to acids 89 using acidic
conditions (TFA, HCl, or similar known deprotections for tert-butyl
esters), then the acids 89 were coupled to amines HNR.sub.3R.sub.4
using standard conditions to provide amides 90. The ethyl ester
group of 90 was then hydrolyzed using lithium or sodium hydroxide
in aqueous media to produce acids 91.
[0664] Compounds with a 2,6-disubstitution pattern on the cinnamide
ring systems were made according to the method of Scheme 21.
Commercially available 4,6-dichlorosalicylaldehyde was condensed
with arylthiols under basic conditions to provide the diarylsulfide
92. The phenolic group was protected with allyl bromide, providing
the O-allyl derivative 93. The method outlined in Scheme 1 was used
to prepare the corresponding cinnamic acid 94, then the allyl group
was removed using palladium(0)-catalyzed transfer to morpholine,
thus producing hydroxy cinnamic acid 95. The acid group was coupled
to a cyclic amino ester (n=0, 1, 2; R=Me, Et) under standard
conditions to yield the amide 96. Basic hydrolysis conditions
reveal the acid 97. 24 25
EXAMPLES
[0665] The compounds and processes of the present invention may be
better understood in connection with the following Examples, which
are intended as an illustration of and not a limitation upon the
scope of the invention.
Example 1
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]su-
lfide
Example 1A
2-[(2,4-Dichlorophenyl)thio]benzaldehyde
[0666] To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2
mmol) in 25 mL of anhydrous DMF was added potassium carbonate (3.09
g, 22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3
mmol). The mixture was then heated under nitrogen atmosphere at
70.degree. C. for 5 hours. The reaction mixture was then allowed to
cool to room temperature and partitioned between ether and water.
The aqueous layer was extracted with ether once and the combined
organic layer was washed with water and brine, dried over sodium
sulfate and condensed in vacuo. The crude product was purified via
silica gel flash chromatography, eluting with 5-10% ether/hexanes,
to give 2.62 g (9.25 mmol, 83%) of the desired aldehyde as a
colorless oil, which solidified slowly upon standing at room
temperature.
Example 1B
trans-2-[(2,4-Dichlorophenyl)thio]cinnamic acid
[0667] A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example
1A, malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 .mu.L, 0.80
mmol) in 8.0 mL of anhydrous pyridine was heated at 110.degree. C.
for 2 hours. Gas evolution ceased during this period. Pyridine was
then removed under vacuum. Water and 3N aq. HCl were then added
with stirring. The desired cinnamic acid was then collected through
filtration, washed with cold water and dried in a vacuum oven
overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
Example 1C
(2,4-Dichlorophenyl)[2-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)phenyl]su-
lfide
[0668] A suspension of the acid (284 mg, 0.87 mmol) from Example 1B
in 5 mL of methylene chloride was stirred with (COCl).sub.2 (84
.mu.L, 0.97 mmol), and one drop of DMF under nitrogen atmosphere
for 90 minutes. The solvent was then removed under vacuum. The
residue (COCl).sub.2 was removed with benzene (2.times.) in vacuo.
To a separate flask, previously filled with 6-amino-1-hexanol (12
mg, 0.10 mmol), Hunig's base (22.8 .mu.L, 0.13 mmol) and DMAP (1.1
mg, 0.008 mmol) in 2.0 mL of CH.sub.2Cl.sub.2, the acid chloride
(30 mg, 0.087 mmol) in 1.0 mL of CH.sub.2Cl.sub.2 was then dropped
in slowly. After 30 minutes, the reaction mixture was poured into
3N HCl and extracted with ethyl aceetate (EtOAc). The organic layer
was washed with brine, dried with Na.sub.2SO.sub.4, condensed under
reduced pressure. The crude product was purified by preparative TLC
to give 21.0 mg (90%) of the title compound as a colorless oil.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.31-1.48 (m, 4H),
1.48-1.70 (m, 4H), 3.37 (q, J=6.7 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H),
5.63 (br s, 1H), 6.36 (d, J=15.9 Hz, 1H), 6.71 (d, J=9.3 Hz, 1H),
7.05 (dd, J=2.4, 8.7 Hz, 1H), 7.31-7.49 (m, 4H), 7.65 (dd, J=2.1,
7.5 Hz, 1H), 7.99 (d, J=15.9 Hz, 1H). MS (DCI/NH.sub.3)
(M+NH.sub.4).sup.+ at m/z 441, 443, 445.
Example 2
(2,4-Dichlorophenyl)[2-(E-((3-(1-imidazolyl)propylamino)carbonyl)ethenyl)p-
henyl]sulfide
[0669] The title compound was prepared by the procedures described
in Example 1C substituting 6-amino-1-hexanol with
1-(3-aminopropyl)imidazole- . White powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.88 (p, J=7.7 Hz, 2H), 3.11 (q,
J=7.7 Hz, 2H), 3.97 (t, J=7.7 Hz, 2H), 6.63 (d, J=15.9 Hz, 1H),
6.70 (d, J=8.7 Hz, 1H), 6.89 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz,
1H), 7.33 (dd, J=2.7, 8.7 Hz, 1H), 7.46-7.65 (m, 4H), 7.72 (d,
J=2.7 Hz, 1H), 7.78 (d, J=15.9 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H),
8.24 (t, J=5.9 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 448,
450, 452. Analysis calculated for
C.sub.21H.sub.19N.sub.3O.sub.1Cl.sub.2S.sub.1.0.87 H.sub.2O: C,
56.30; H, 4.67; N, 9.38. Found: C, 56.30; H, 4.56; N, 9.27.
Example 3
(2,4-Dichlorophenyl)[2-chloro-4-(E-((2-hydroxyethylamino)carbonyl)ethenyl)-
phenyl]sulfide
[0670] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
ethanolamine. Colorless oil; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 3.57 (q, J=7.65 Hz, 2H), 3.71 (q, J=7.65 Hz, 2H), 6.06 (br
s, 1H), 6.40 (d, J=15.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.22-7.30
(m, 4H), 7.49-7.60 (m, 1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 402, 404, 406, 408. Analysis calculated for
C.sub.17H.sub.14N.sub.1O.sub.2Cl.sub.3S.sub.1.0.25H.sub.2O: C,
50.14; H, 3.59; N, 3.44. Found: C, 50.16; H, 3.62; N, 3.29.
Example 4
(2,4-Dichlorophenyl)[2-chloro-4-(E-((6-hydroxyhexylamino)carbonyl)ethenyl)-
phenyl]sulfide
[0671] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.42 (m, 4H), 1.58 (m, 4H), 3.40 (q,
J=6.7 Hz, 2H), 3.65 (br m, 2H), 5.60 (br t, 1H), 6.35 (d, J=15.3
Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.22-7.30 (m, 4H), 7.49-7.60 (m,
1H), 7.55 (d, J=15.3 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 458,
460, 462, 464. Analysis calculated for
C.sub.21H.sub.22N.sub.1O.sub.- 2Cl.sub.3S.sub.1.0.27H.sub.2O: C,
54.39; H, 4.90; N, 3.02. Found: C, 54.40; H, 4.85; N, 2.71.
Example 5
(2,4-Dichlorophenyl)[2-chloro-4-(E-((bis-(2-hydroxyethyl)amino)carbonyl)et-
henyl)phenyl]sulfide
[0672] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
diethanolamine. Colorless oil; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.99 (br s, 2H), 3.67 (br m, 4H), 3.88 (t, J=5.1 Hz, 2H),
3.94 (t, J=5.1 Hz, 2H), 6.94 (d, J=15.3 Hz, 1H), 6.97 (d, J=8.7 Hz,
1H), 7.21-7.32 (m, 3H), 7.50-7.54 (m, 1H), 7.58 (d, J=2.4 Hz, 1H),
7.58 (d, J=15.3 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 446, 448,
450, 452. Analysis calculated for
C.sub.19H.sub.18N.sub.1O.sub.3Cl.sub.3S- .sub.1.1.09H.sub.2O: C,
48.93; H, 4.36; N, 3.00. Found: C, 48.88; H, 4.00; N, 3.01.
Example 6
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-only)propylamino)ca-
rbonyl)ethenyl)phenyl]sulfide
[0673] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-(3-aminopropyl)-2-pyrrolidinone. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.74 (qu, J=6.0 Hz, 2H), 2.09 (qu,
J=7.5 Hz, 2H), 2.45 (t, J=8.25 Hz, 2H), 3.33 (q, J=6.0 Hz, 2H),
3.42 (q, J=8.25 Hz, 4H), 6.46 (d, J=15.6 Hz, 1H), 7.02 (d, J=8.7
Hz, 1H), 7.14-7.23 (m, 2H), 7.30 (dd, J=2.4, 8.7 Hz, 1H), 7.51 (d,
J=2.4 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 483, 485, 487, 489. Analysis
calculated for
C.sub.22H.sub.21N.sub.2O.sub.2Cl.sub.3S.sub.1.0.57H.sub.2O: C,
53.48; H, 4.52; N, 5.67. Found: C, 53.49; H, 4.60; N, 5.65.
Example 7
(2,4-Dichlorophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl-
]sulfide
[0674] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
morpholine. White solid; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
3.59-3.80 (m, 8H), 6.83 (d, J=15.6 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H),
7.16-7.32 (m, 3H), 7.49-7.53 (m, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.59
(d, J=15.6 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 428, 430,
432, 434. Analysis calculated for C.sub.19H.sub.16N.sub.1O.-
sub.2Cl.sub.3S.sub.1.0.46H.sub.2O: C, 52.22; H, 3.90; N, 3.20.
Found: C, 52.20; H, 3.76; N, 3.12.
Example 8
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0675] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-methylpiperazine. Colorless oil; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 2.37 (s, 3H), 2.51 (br m, 4H), 3.63-3.87 (br m, 4H),
6.85 (d, J=15.6 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 7.19-7.25 (m, 2H),
7.27 (dd, J=2.1, 8.7 Hz, 1H), 7.52 (t, J=0.9 Hz, 1H), 7.57 (d,
J=15.6 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3)
(M+H).sup.+ at m/z 441, 443, 445, 447. Analysis calculated for
C.sub.20H.sub.19N.sub.2O.sub.1Cl.sub.3S.sub.1.0.45H.sub.2O: C,
53.39; H, 4.46; N, 6.23. Found: C, 53.37; H, 4.46; N, 6.07.
Example 9
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0676] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-acetylpiperazine. White solid; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.15 (s, 3H), 3.50-3.58 (m, 2H), 3.58-3.85 (m, 6H), 6.85
(d, J=15.3 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.24-7.36 (m, 3H), 7.54
(d, J=2.4 Hz, 1H), 7.61 (d, J=15.3 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H).
MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 486, 488, 490, 492. Analysis
calculated for C.sub.21H.sub.19N.sub.2O.sub.2Cl.sub.3S.sub.-
1.0.85H.sub.2O: C, 51.99; H, 4.30; N, 5.77. Found: C, 52.03; H,
4.27; N, 5.67.
Example 10
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-pyridyl)piperazin-1-ylcarbonyl)e-
thenyl)phenyl]sulfide
[0677] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-(2-pyridyl)piperazine. White solid; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 3.59 (br m, 2H), 3.69 (br m, 2H), 3.78 (br m, 2H),
3.86 (br m, 2H), 6.64-6.72 (m, 2H), 6.90 (d, J=15.6 Hz, 1H), 6.99
(d, J=8.7 Hz, 1H), 7.22-7.25 (m, 2H), 7.31 (dd, J=2.4, 8.7 Hz, 1H),
7.49-7.57 (m, 2H), 7.61 (d, J=15.6 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H),
8.19-8.24 (m, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 504, 506,
508, 510. Analysis calculated for
C.sub.24H.sub.20N.sub.3O.sub.1Cl.sub.3S- .sub.1: C, 57.10; H, 3.99;
N, 8.32. Found: C, 57.12; H, 4.06; N, 8.29.
Example 11
(2-(Hydroxymethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
[0678] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-mercaptobenzyl alcohol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
morpholine. White solid; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
3.50-3.62 (br m, 6H), 3.65-3.74 (br m, 2H), 4.54 (d, J=5.7 Hz, 2H),
5.33 (t, J=5.7 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 7.28 (d, J=15.0 Hz,
1H), 7.36 (d, J=7.8 Hz, 1H), 7.42 (d, J=15.0 Hz, 1H), 7.43 (dd,
J=1.8, 8.7 Hz, 1H), 7.50 (dd, J=2.1, 8.7 Hz, 1H), 7.55 (dd, J=2.1,
7.8 Hz, 1H), 7.68 (dd, J=1.5, 8.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H).
MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 390, 392. Analysis calculated
for C.sub.20H.sub.20N.sub.1O.sub.3Cl.sub.1S.sub.1.0.09H.sub.2O: C,
61.35; H, 5.20; N, 3.58. Found: C, 61.37; H, 5.48; N, 3.81.
Example 12
(2-Bromophenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulf-
ide
[0679] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
morpholine. White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 3.50-3.66 (br m, 6H), 3.66-3.79 (br m, 2H), 7.05 (d, J=8.7
Hz, 1H), 7.26 (dd, J=2.1, 8.1 Hz, 1H), 7.33 (dd, J=2.1, 8.1 Hz,
1H), 7.36 (d, J=15.6 Hz, 1H), 7.39 (dd, J=1.8, 12.0 Hz, 1H), 7.45
(dd, J=1.8, 6.3 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.64 (dd, J=2.1,
8.7 Hz, 1H), 7.80 (dd, J=2.8, 8.7 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H).
MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 438, 440, 442.
Example 13
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0680] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-hydroxyethylpiperazine. Colorless oil; .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 2.85-3.20 (br m, 6H), 3.84-4.19 (m, 6H), 6.80 (d,
J=15.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 7.22-7.38 (m, 3H),
7.50-7.56 (m, 1H), 7.56-7.62 (m, 1H), 7.60 (d, J=15.3 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 471, 473, 475, 477.
Example 14
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-(2-hydroxyethoxyethyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
[0681] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
1-[2-(2-hydroxyethoxy)ethyl]piperazine. Colorless oil; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.73 (br m, 6H), 3.58-3.68 (m, 2H),
3.68-4.00 (m, 8H), 6.84 (d, J=15.3 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H),
7.20-7.34 (m, 3H), 7.54 (d, J=7.5 Hz, 1H), 7.58 (d, J=15.3 Hz, 1H),
7.58-7.65 (overlapping d, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
515, 517, 519, 521.
Example 15
(2-Bromophenyl)[2-chloro-4-(E-((3-(hydroxymethyl)piperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0682] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
3-hydroxymethylpiperidine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.07 (d, J=17.7 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 (br
d, J=7.7 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.40 (br s, 2H), 7.35 (m,
1H), 7.25 (dd 7.7, 1.5, 1H), 7.06 (dd, J=8.1, 2.9, 1 H), 4.57 (m,
1H), 4.45 (m, 1H), 4.16 (br m, 2H), 1.2-1.8 (m, 8H). HRMS
calculated for
C.sub.21H.sub.21N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 466.0243.
Observed: 466.0247.
Example 16
(2-Bromophenyl)[2-chloro-4-(E-((2-(hydroxymethyl)piperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0683] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
2-hydroxymethylpiperidine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.03 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.61 (m, 1H),
7.30-7.45 (m, 4H), 7.23 (m, 1H), 7.07 (m, 1H), 4.79 (m, 2H), 4.61
(m, 2H), 4.10 (m, 1H), 1.50 (m, 6H). HRMS calculated for
C.sub.21H.sub.21N.sub.1O.sub.2S.sub.1Br.sub.1C.sub.1: 466.0243.
Observed: 466.0247.
Example 17
(2-Bromophenyl)[2-chloro-4-(E-((3-acetamidopyrrolidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0684] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
3-acetamidopyrrolidine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
8.14 (m, 1H), 8.07 (dd, J=9.8, 1.7 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H),
7.64 (dd, J=8.1, 1.7 Hz, 1H), 7.25-7.47 (m, 4H), 7.10 (t, J=7.8 Hz,
1H), 7.03 (dd, J=8.1, 1.7 Hz, 1H), 3.45-4.34 (m, 6H), 2.02 (m, 2H),
1.81 (ap d, J=1.4 Hz, 1H). HRMS calculated for
C.sub.21H.sub.20N.sub.2O.sub.2S.sub.1Br.sub.1Cl.sub.1: 479.0196.
Observed: 479.0183.
Example 18
(2-Bromophenyl)[2-chloro-4-(E-((4-hydroxypiperidin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0685] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
4-hydroxypiperidine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
8.08 (d, J=1.7 Hz, 1H), 7.80 (dd, J=8.0, 1.5 Hz, 1H), 7.63 (dd,
J=8.3, 1.9 Hz, 1H), 7.44 (ap dd, J=7.5, 1.4 Hz, 2H), 7.40 (ap d,
J=3.7 Hz, 2H), 7.34 (dt, J=7.6, 1.8 Hz, 1H), 7.25 (dd, J=7.5, 1.7
Hz 1H), 7.05 (d, J=8.1 Hz, 1H), 4.76 (br s, 1H), 4.01 (m, 2H), 3.72
(m, 1H), 3.12 (m, 1H), 1.75 (m, 2H), 1.32 (m, 2H). HRMS calculated
for C.sub.20H.sub.19N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1:
452.0087. Observed: 452.0076.
Example 19
(2-Bromophenyl)[2-chloro-4-(E-((piperidin-1-yl)carbonyl)ethenyl)phenyl]sul-
fide
[0686] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
piperidine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.08 (d,
J=1.7 Hz, 1H), 7.80 (dd, J=8.1, 1.4 Hz, 1H), 7.63 (dd, J=8.1, 1.7
Hz, 1H), 7.44 (ap dd, J=7.6, 1.5 Hz, 1H), 7.39 (ap d, J=4.8 Hz,
2H), 7.34 (dt, J=7.5, 1.6, 1H), 7.24 (dd, J=7.5, 1.7, 1H), 7.05 (d,
J=8.1 Hz, 1H), 3.65 (br m, 2H), 3.53 (br m, 2H), 1.62 (br m, 2H),
1.50 (br m, 4H). HRMS calculated for
C.sub.20H.sub.19N.sub.1O.sub.1S.sub.1Br.s- ub.1Cl.sub.1: 436.0130.
Observed: 436.0122.
Example 20
(2,4-Dichlorophenyl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
[0687] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
nipecotic acid. Colorless oil; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.44-1.68 (br m, 1H), 1.68-2.00 (br m, 2H), 2.51-2.67 (br
m, 1H), 3.13-3.37 (br m, 1H), 3.80-4.12 (br m, 1H), 4.30-5.00 (br
m, 3H), 6.86 (d, J=15.3 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 7.16-7.24
(m, 2H), 7.29 (d, J=8.7 Hz, 1H), 7.47-7.55 (m, 1H), 7.55 (d, J=15.3
Hz, 1H), 7.60 (br d, 1H). MS (APCI) (M+H).sup.+ at m/z 470, 472,
474, 476.
Example 21
(2,4-Dichlorophenyl)[2-chloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
[0688] The title compound was prepared by the procedures described
in Example 1 substituting 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzad- ehyde, and 6-amino-1-hexanol with
isonipecotic acid. Colorless oil; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.68-1.85 (m, 2H), 1.98-2.09 (m, 2H), 2.60-2.72 (m, 1H),
2.90-3.13 (br m, 1H), 3.17-3.38 (br m, 1H), 3.93-4.12 (br m, 1H),
4.38-4.59 (br m, 1H), 6.86 (d, J=15.3 Hz, 1H), 6.99 (dd, J=8.7 Hz,
1H), 7.20-7.25 (m, 2H), 7.28 (dd, J=1.8, 8.7 Hz, 1H), 7.49-7.53 (m,
1H), 7.56 (d, J=15.3 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 470, 472, 474, 476.
Example 22
(2-Bromophenyl)[2-chloro-4-(E-((4-acetylhomolpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0689] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
4-acetylhomopiperazine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
8.10 (m, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.64 (m, 1H), 7.24-7.51 (m,
5H), 7.05 (m, 1H), 3.39-3.77 (m, 8H), 1.97 (m, 3H), 1.68 (m, 2H).
HRMS calculated for C.sub.22H.sub.22N.sub.2O.sub.1S.sub.1Br.sub.-
1Cl.sub.1: 493.0352. Observed: 493.0352.
Example 23
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide
[0690] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
thiomorpholine. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.10
(d, J=1.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.64 (dd, J=8.1, 1.5 Hz,
1H), 7.31-7.48 (m, 4H), 7.36 (m, 1H), 7.26 (dd, J=8.1, 1.8 Hz, 1H),
7.05 (d J=8.1 Hz, 1H), 3.96 (m, 2H), 3.82 (m, 2H), 2.62 (m, 4H).
HRMS calculated for
C.sub.19H.sub.17N.sub.1O.sub.1S.sub.2Br.sub.1Cl.sub.1- : 455.9681.
Observed: 455.9676.
Example 24
(2-Bromophenyl)[2-chloro-4-(E-((4-(1-benzimidazol-2-only)piperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0691] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
4-(1-benzimidazol-2-only)piperidine. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.14 (d, J=1.5 Hz, 1H), 7.80 (dd, J=7.9, 1.3 Hz, 1H),
7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.48 (ap s, 2H), 7.44 (dt, J=7.5,
1.2, 1H), 7.34 (dt, J=7.6, 1.6, 1H), 7.26 (dd, J=7.7, 1.8 Hz, 1H),
7.22 (m, 1H), 7.06 (d, J=8.1, 1H), 6.97 (ap d, J=2.6, 3H), 4.64 (m,
1H), 4.48 (m, 2H), 2.79 (m, 2H), 2.29 (m, 2H), 1.78 (m, 2H). HRMS
calculated for
C.sub.27H.sub.23N.sub.3O.sub.2S.sub.1Br.sub.1Cl.sub.1: 568.0461.
Observed: 568.0477.
Example 25
(2-Bromophenyl)[2-chloro-4-(E-((2-tetrahydroisoquinolinyl)carbonyl)ethenyl-
)phenyl]sulfide
[0692] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with
tetrahydroisoquinoline. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
8.12 (d, J=7.4 Hz, 1H), 7.81 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (dd,
J=8.3, 1.3 Hz, 1H), 7.47 (m, 2H), 7.43 (dd, J=7.5, 1.3 Hz, 2H),
7.34 (dt, J=7.6, 1.7 Hz, 1H), 7.27 (d 7.7 Hz, 1H), 7.19 (m, 4H),
7.05 (d, J=8.1 Hz, 1H), 4.92 (s, 1H), 4.72 (s, 1H), 3.95 (t, J=5.9
Hz, 1H), 3.78 (t, J=5.7 Hz, 1H), 2.89 (t, J=5.3 Hz, 1H), 2.83 (t,
J=3.7, 1H). HRMS calculated for
C.sub.24H.sub.19N.sub.1O.sub.2S.sub.1Br.sub.1Cl.sub.1: 484.0138.
Observed: 484.0128.
Example 26
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0693] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
1-acetylpiperazine. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79
(s, 1H); 7.63 (d, J=15.4 Hz, 1H); 7.51 (d, J=6.8 Hz, 1H); 7.41-7.33
(m, 3H); 7.28 (m, 1H); 6.83 (d, J=15.4 Hz, 1H); 6.79 (d, J=6.8 Hz,
1H); 3.80-3.60 (m, 6H); 3.57-3.50 (m, 2H); 2.34 (s, 3H); 2.14 (s,
3H). MS (ESI) m/z 919 (2M+Na).sup.+, 897 (2M+H).sup.+, 471
(M+Na).sup.+, 449 (M+H).sup.+.
Example 27
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
[0694] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
morpholine. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s, 1H);
7.63 (d, J=14.0 Hz, 1H); 7.52 (d, J=7.6 Hz, 1H); 7.40-7.30 (m, 3H);
7.28 (m, 1H); 6.87 (d, J=14.0 Hz, 1H); 6.84 (d, J=7.6 Hz, 1H); 3.73
(br s, 8H); 2.34 (s, 3H). MS (ESI) m/z 837 (2M+Na).sup.+, 815
(2M+H).sup.+, 408 (M+H).sup.+.
Example 28
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((2-(1-morpholinyl)ethylamino)carb-
onyl)ethenyl)phenyl]sulfide
[0695] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
2-(1-morpholinyl)ethylamine. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.80 (s, 1H); 7.56 (d, J=15.8 Hz, 1H); 7.50 (d, J=8.1 Hz,
1H); 7.40-7.32 (m, 3H); 7.28 (m, 1H); 6.79 (d, J=15.8 Hz, 1H); 6.40
(d, J=8.1 Hz, 1H); 3.75 (t, J=4.6 Hz, 4H); 3.51 (q, J=5.5 Hz, 2H),
2.57 (t, J=5.8 Hz, 2H); 2.55-2.48 (m, 4H); 2.34 (s, 3H). MS (ESI)
m/z 923 (2M+Na).sup.+, 473 (M+Na).sup.+, 451 (M+H).sup.+.
Example 29
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((4-phenylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0696] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
4-phenylpiperazine. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.81
(s, 1H); 7.64 (d, J=16.0 Hz, 1H); 7.51 (d, J=8.2 Hz, 1H); 7.40-7.27
(m, 6H); 6.98-6.90 (m, 4H); 6.80 (d, J=8.2 Hz, 1H); 3.88 (br s,
4H); 2.23 (br s, 4H); 2.34 (s, 3H). MS (ESI) m/z 987 (2M+Na).sup.+,
965 (2M+H).sup.+, 505 (M+Na).sup.+, 483 (M+H).sup.+, 451.
Example 30
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((3-(1-pyrrolidin-2-only)propylami-
nocarbonyl)ethenyl)phenyl]sulfide
[0697] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
1-pyrrolidin-2-only)propylamine. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.78 (s, 1H); 7.53 (d, J=15.6 Hz, 1H); 7.49 (d, J=7.2 Hz,
1H); 7.40-7.33 (m, 3H); 7.14 (m, 1H); 6.80 (d, J=8.2 Hz, 1H); 6.43
(d, J=15.6 Hz, 1H); 3.41 (m, 4H); 3.32 (q, J=6.1 Hz, 2H); 2.43 (t,
J=6.6 Hz, 2H); 2.34 (s, 3H), 2.08 (m, 2H), 1.75 (m, 2H). MS (ESI)
m/z 947 (2M+Na).sup.+, 925 (2M+H).sup.+, 485 (M+Na).sup.+, 463
(M+H).sup.+.
Example 31
(2-Methylphenyl)[2-trifluoromethyl-4-(E-((cyclopropylamino)carbonyl)etheny-
l)phenyl]sulfide
[0698] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-methylthiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
cyclopropylamine. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76
(s, 1H); 7.56 (d, J=15.4 Hz, 1H); 7.50 (d, J=8.4 Hz, 1H); 7.40-7.30
(m, 3H); 7.28 (m, 1H); 6.88 (d, J=8.4 Hz, 1H); 6.30 (d, J=15.4 Hz,
1H); 5.70 (br s, 1H, 2.95 (m, 1H); 2.34 (s, 3H); 0.85 (m, 2H); 0.57
(m, 2H). MS (ESI) m/z 777 (2M+Na).sup.+, 755 (2M+H).sup.+, 400
(M+Na).sup.+, 378 (M+H).sup.+.
Example 32
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
Example 32A
1-Chloro-2-nitro-4-(E-((4-acetylypiperazin-1-yl)carbonyl)ethenyl)benzene
[0699] To a stirred solution of trans-4-chloro-3-nitrocinnamic acid
(1.50 g, 6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in
20 mL of DMF at room temperature was added EDAC (1.4 g, 7.30 mmol).
The mixture was then stirred at room temperature for 2 hours. TLC
indicated the complete consumption of the acid. Water was then
added to quench the reaction and to precipitate out the product.
Cinnamide was then collected through filtration and washed with
cold water. The light yellow product was dried in vacuum oven
overnight at 40.degree. C. to give 2.04 g (6.03 mmol, 91.6%) of the
title compound.
Example 32B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0700] To a stirred solution of 4-chloro-3-nitro-cinnamide (275 mg,
0.814 mmol) from Example 32A in 1.0 mL of DMF was added potassium
carbonate (169 mg, 1.22 mmol), followed by the dropwise addition of
2,4-dichlorothiophenol (146 mg, 0.815 mmol). The mixture was then
stirred at room temperature for, 60 minutes. Completion of the
reaction was indicated by the TLC. Water was then added to
precipitate the product. Filtration, washing with cold water, and
drying in a vacuum oven afforded 350 mg (0.728 mmol, 89%) of the
titled compound as light yellow solid. .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.05 (s, 3H), 3.42-3.50 (br m, 4H), 3.50-3.64 (br
m, 2H), 3.64-3.79 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.44 (d,
J=15.3 Hz, 1H), 7.55 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz,
1H), 7.83 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.7
Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at
m/z 497, 499, 501. Analysis calculated for
C.sub.21H.sub.19N.sub.3O.sub.4- Cl.sub.2S.sub.1.0.82H.sub.2O: C,
50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
Example 33
(2,4-Dichlorophenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-only)propylaminocarb-
onyl)ethenyl)phenyl]sulfide
[0701] The title compound was prepared by the procedures described
in Example 32 substituting 1-acetylpiperazine with
1-(3-aminopropyl)-2-pyrro- lidinone. Light-yellow powder; .sup.1H
NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.64 (p, J=7.1 Hz, 2H), 1.91
(p, J=7.5 Hz, 2H), 2.21 (t, J=8.3 Hz, 2H), 3.15 (q, J=6.3 Hz, 2H),
3.21 (dd, J=9.9, 17.7 Hz, 2H), 3.32 (overlapping t, J=8.4 Hz, 2H),
6.72 (d, J=15.6 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 7.46 (d, J=15.6
Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.79 (dd, J=2.4, 8.7 Hz,
1H), 7.84 (d, J=8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.18 (t, J=6.0
Hz, 1H), 8.46 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at
m/z 494, 496.
Example 34
(2,3-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0702] The title compound was prepared by the procedures described
in Example 32B substituting 2,4-dichlorothiophenol with
2,3-dichlorothiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.42-3.50 (br m, 4H),
3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.88 (d, J=8.7 Hz, 1H),
7.45 (d, J=15.6 Hz, 1H), 7.55 (t, J=7.65 Hz, 1H), 7.57 (d, J=15.6
Hz, 1H), 7.78 (dd, J=1.8, 8.1 Hz, 1H), 7.87 (dd, J=1.8, 8.1 Hz,
1H), 7.95 (dd, J=2.7, 9.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at t/z 497, 499, 501.
Example 35
(4-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
[0703] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
4-bromothiophenol. Light-yellow powder, .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.90 (d, J=8.7
Hz, 1H), 7.43 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 7.58 (d,
J=9.0 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.92 (dd, J=2.1, 9.0 Hz,
1H), 8.65 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
507, 509.
Example 36
(4-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0704] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
p-thiocresol. Light-yellow powder, .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 2.04 (s, 3H), 2.39 (s, 3H), 3.47 (br m, 4H), 3.52 (br
m, 1H), 3.60 (br m, 1H), 3.68 (br m, 1H), 6.89 (d, J=8.7 Hz, 1H),
7.20 (d, J=8.1 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.40 (d, J=15.0 Hz,
1H), 7.53 (d, J=15.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.89 (dd,
J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3)
(M+NH.sub.4).sup.+ at m/z 443.
Example 37
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[0705] The title compound was prepared by the procedures described
in Example 32 substituting 1-acetylpiperazine with tert-butyl
piperazine carboxylate. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.42 (s, 9H), 3.36 (overlapping m,
4H), 3.55 (br m, 2H), 3.70 (br m, 2H), 6.83 (d, J=8.7 Hz, 1H), 7.42
(d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.4
Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92 (dd, J=2.4, 8.7 Hz, 1H), 7.96
(d, J=2.7 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 538, 540, 542.
Example 38
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
Example 38A
(2,4-Dichlorophenyl)[2-nitro-4-(E-((piperazin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide Trifluoroacetic Acid Salt
[0706] The compound (100 mg, 0.186 mmol) from Example 37 was
dissolved in 0.5 mL of neat trifluoroacetic acid (TFA). The mixture
was stirred at room temperature for 1 hour. The TFA was then
removed under vacuum to give the title compound (105 mg) as a
yellow solid.
Example 38B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(2-furoylcarbonyl)piperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
[0707] To a stirred solution of piperazine TFA salt (35 mg, 0.067
mmol) from Example 38A in 2.0 mL of CH.sub.2Cl.sub.2 was added
Et.sub.3N (23 .mu.L, 0.17 mmol), 4 dimethylaminopyridine (DMAP)
(1.0 mg, 0.0082 mmol), and furyl chloride (8.0 .mu.L, 0.080 mmol).
The mixture was then stirred at room temperature for 30 minutes
before the solvent was removed. The crude product was purified with
Gilson HPLC system, YMC C-18 column, 75.times.30 mm I.D., S-5
.mu.M, 120 .ANG., and a flow rate of 25 mL/min, .lambda.=214, 245
nm; mobile phase A, 0.05 M NH.sub.4Oac, and B, CH.sub.3CN; linear
gradient 20-100% of B in 20 minutes to give the title compound (24
mg, 67%) as light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 3.62-3.87 (br m, 8H), 6.66 (q, J=2.1 Hz, 1H), 6.84 (d,
J=8.7 Hz, 1H), 7.04 (d, J=3.3 Hz, 1H), 7.44 (d, J=15.3 Hz, 1H),
7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.4, 8.1 Hz, 1H), 7.83 (d,
J=8.4 Hz, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.92 (dd, J=2.1, 12.0 Hz,
1H), 7.96 (d, J=2.1 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 532, 534, 536.
Example 39
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(methanesulfonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0708] The title compound was prepared by the procedures described
in Example 38B substituting furoyl chloride with methanesulfonyl
chloride. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.90 (s, 3H), 3.25 (br m, 4H), 3.68 (br m, 2H), 3.83 (br m,
2H), 6.84 (d, J=9.0 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.56 (d,
J=15.6 Hz, 1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=9.0 Hz,
1H), 7.93 (dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.70 (d,
J=2.1 Hz, 1H). MS (ESI) (M+H).sup.+ at m/z 516, 518, 520.
Example 40
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonylmethyl)piperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0709] The title compound was prepared by the procedures described
in Example 38B substituting furoyl chloride with
2-chloro-N,N-diethylacetami- de. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.01 (t, J=7.2 Hz, 3H), 1.13 (t,
J=7.2 Hz, 3H), 2.46 (br m, 4H), 3.16 (s, 2H), 3.24 (q, J=7.2 Hz,
2H), 3.37 (q, J=7.2 Hz, 2H), 3.56 (br m, 2H), 3.69 (br m, 2H), 6.83
(d, J=9.0 Hz, 1H), 7.46 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz,
1H), 7.62 (dd, J=2.4, 8.7 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.92
(dd, J=2.1, 9.0 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.67 (d, J=2.1 Hz,
1H). MS (ESI) (M+NH.sub.4).sup.+ at m/z 573, 575, 577.
Example 41
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(diethylaminocarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0710] The title compound was prepared by the procedures described
in Example 38B substituting furoyl chloride with
N,N-diethylcarbamyl chloride. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.06 (t, J=6.9 Hz, 6H), 3.12 (br m,
4H), 3.15 (q, J=6.9 Hz, 4H), 3.58 (br m, 2H), 3.72 (br m, 2H), 6.83
(d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.6 Hz,
1H), 7.63 (dd, J=2.7, 9.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.92
(dd, J=2.4, 8.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H), 8.68 (d, J=2.1 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 537, 539, 541.
Example 42
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(tert-butoxycarbonylmethyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0711] The title compound was prepared by the procedures described
in Example 38B substituting CH.sub.2CL.sub.2 with CH.sub.3CN as
solvent, and furoyl chloride with tert-butyl bromoacetate.
Light-yellow powder; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.47
(s, 9H), 2.70 (br m, 4H), 3.21 (s, 2H), 3.74 (br m, 2H), 3.82 (br
m, 2H), 6.73 (d, J=8.7 Hz, 1H), 6.92 (d, J=15.0 Hz, 1H), 7.39 (dd,
J=2.4, 8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.61 (d, J=15.0 Hz,
1H), 7.62 (d, J=2.4 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 8.43 (br d,
1H). MS (APCI) (M+H).sup.+ at m/z 552, 554, 556.
Example 43
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
Example 43A
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carbethoxycarbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0712] The title compound was prepared by the procedures described
in Example 38B substituting furoyl chloride with ethyl oxalyl
chloride.
Example 43B
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxycarbonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0713] To a stirred solution of the ethyl ester (40 mg, 0.074 mmol)
from Example 43A in 2 mL of ethanol was added saturated LiOH (0.25
mL). The mixture was then stirred at room temperature for 2 hours.
Water (2 mL) was then added to the reaction mixture, which was then
acidified to pH=2 with concentrated HCl. The precipitates were
collected through filtration, washed with cold water, dried under
vacuum to give the titled compound (30 mg, 79%) as light yellow
solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 3.52 (br m, 4H),
3.62 (br m, 2H), 3.76 (br m, 2H), 6.84 (d, J=9.0 Hz, 1H), 7.46 (d,
J=15.3 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.63 (dd, J=2.7, 8.7 Hz,
1H), 7.83 (d, J=9.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.96 (d, J=2.7
Hz, 1H), 8.70 (br d, 1H). MS (APCI) (M-COO).sup.+ at m/z 466, 468,
470.
Example 44
(2,4-Dichlorophenyl)[2-nitro-4-(E-((4-(carboxymethyl)piperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[0714] The title compound was prepared by the procedures described
in Example 38A substituting compound from Example 37 with compound
from Example 42. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 3.14 (s, 2H), 3.40 (overlapping br m, 4H), 3.44
(br m, 1H), 3.51 (br m, 1H), 3.57 (br m, 1H), 3.71 (br m, 1H), 6.82
(d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (d, J=15.6 Hz,
1H), 7.63 (dd, J=2.4, 8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.92
(dd, J=2.4, 8.7 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 8.68 (d, J=2.4 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 496, 498, 500.
Example 45
(2-Methylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0715] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
o-thiocresol. Light-yellow powder, .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 2.03 (s, 3H), 2.29 (s, 3H), 3.47 (br m, 4H), 3.53 (br
m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.83 (br m, 1H), 6.64 (d,
J=8.7 Hz, 1H), 7.40 (d, J=15.0 Hz, 1H), 7.36-7.42 (m, 1H),
7.46-7.57 (m, 3H), 7.63 (d, J=6.9 Hz, 1H), 7.89 (dd, J=2.4, 9.0 Hz,
1H), 8.66 (d, J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 426.
Example 46
(2-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0716] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-chlorothiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.73 (br m, 1H), 6.75 (d, J=9.0
Hz, 1H), 7.43 (d, J=15.3 Hz, 1H), 7.54 (d, J=15.3 Hz, 1H), 7.55
(dd, J=1.8, 8.1 Hz, 1H), 7.64 (t, J=1.8, 8.1 Hz, 1H), 7.76 (d,
J=1.8, 8.1 Hz, 1H), 7.82 (d, J=1.8, 8.1 Hz, 1H), 7.93 (dd, J=2.4,
9.0 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z
446, 448, 450.
Example 47
(2-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
[0717] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-aminothiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H),
3.60 (br m, 1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 5.58 (s, 2H),
6.65 (td, J=1.5, 15.0 Hz, 1H), 6.72 (dd, J=1.5, 8.7 Hz, 1H), 7.00
(dd, J=1.8, 8.7 Hz, 1H), 7.27 (t, J=1.5, 8.6 Hz, 1H), 7.36 (dd,
J=1.5, 8.7 Hz, 1H), 7.39 (d, J=15.3 Hz, 1H), 7.53 (d, J=15.3 Hz,
1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8.64 (d, J=1.8 Hz, 1H). MS
(APCI) (M+H).sup.+ at m/z 427.
Example 48
(2-Hydroxymethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0718] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-mercaptobenzyl alcohol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) a 2.03 (s, 3H), 3.47 (br m, 4H), 3.52 (br
m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73 (br m, 1H), 4.53 (d,
J=5.7 Hz, 1H), 5.34 (t, J=5.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 7.40
(d, J=15.3 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.53 (d, J=15.3 Hz,
1H), 7.59 (d, J=7.5 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.87 (dd,
J=2.1, 8.7 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H). MS (APCI)
(M+NH.sub.4).sup.+ at m/z 459.
Example 49
(2-Ethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
[0719] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-ethylthiophenol. Light-yellow powder; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 1.01 (t, J=7.65 Hz, 3H), 2.04 (s, 3H), 2.69 (q,
J=7.65 Hz, 2H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.59 (br m, 1H),
3.67 (br m, 1H), 3.73 (br m, 1H), 6.64 (d, J=8.7 Hz, 1H), 7.38 (dd,
J=2.4, 7.5 Hz, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.50-7.61 (m, 3H),
7.53 (d, J=15.6 Hz, 1H), 7.89 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d,
J=2.4 Hz, 1H). MS (APCI) (M+Cl).sup.- at m/z 474, 476.
Example 50
(2-iso-Propylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0720] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-isopropylthiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.05 (d, J=6.9 Hz, 6H), 2.04 (s,
3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m,
1H), 3.72 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 7.34-7.41 (m, 2H),
7.39 (d, J=15.3 Hz, 1H), 7.52 (d, J=15.3 Hz, 1H), 7.56-7.73 (m,
2H), 7.90 (dd, J=2.1, 8.7 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H). MS
(APCI) (M+NH.sub.4).sup.+ at m/z 471. Analysis calculated for
C.sub.24H.sub.27N.sub.3O.sub.4S.sub.1.0.21H.sub.2O: C, 63.03; H,
5.96; N, 9.13. Found: C, 63.03; H, 6.04; N, 9.19.
Example 51
(2-tert-Butylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0721] The title compound was prepared by the procedures described
in Example 32 substituting 2,4-dichlorothiophenol with
2-tert-butylthiophenol. Light-yellow powder; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.46 (s, 9H), 2.04 (s, 3H), 3.47
(br m, 4H), 3.52 (br m, 1H), 3.60 (br m, 1H), 3.67 (br m, 1H), 3.73
(br m, 1H), 6.68 (d, J=8.7 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.39
(d, J=15.3 Hz, 1H), 7.45-7.57 (m, 2H), 7.50 (d, J=15.3 Hz, 1H),
7.65 (d, J=8.1 Hz, 1H), 7.88 (dd, J=2.4, 8.7 Hz, 1H), 8.64 (d,
J=2.4 Hz, 1H). MS (APCI) (M+NH.sub.4).sup.+ at m/z 485.
Example 52
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl))2-propen-
yl)phenyl]sulfide
Example 52A
3'-Chloro-4'-[(2-chlorophenyl)thiolacetophenone
[0722] The title compound was prepared by the procedures described
in Example 1A substituting 2,4-dichlorothiophenol with
2-chlorothiophenol, and 2-chlorobenzaldehyde with
4'-fluoro-3'-chloroacetophenone.
Example 52B
(2-Chlorophenyl)[2-chloro-4-(E-(1-ethoxycarbonyl)2-propenyl)phenyl]sulfide
[0723] To a stirred suspension of NaH (60% in mineral oil, 121 mg,
3.03 mmol) in 20 mL of anhydrous THF under nitrogen atmosphere was
added triethyl phosphonoacetate dropwise. After 20 minutes, the
acetophenone (600 mg, 2.02 mmol) from Example 52A in THF (5 mL) was
added in one portion. The resulting clear solution was then stirred
at room temperature for 7 hours. Reaction was then stopped, most of
the solvent was evaporated, and the residue was partitioned between
EtOAc (2.times.20 mL) and water. The combined organic layer was
washed with water and brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The crude product was purified using silica
gel flash column chromatography eluting with 5-10% Et.sub.2O in
hexanes to give the (E)-isomer of the cinnamate (500 mg, 68%) as a
white solid.
Example 52C
(2-Chlorophenyl)[2-chloro-4-(E-(1-carboxy)2-propenyl)phenyl]sulfide
[0724] A mixture of the cinnamate (500 mg, 1.37 mmol) from Example
52B in 5 mL of EtOH/THF (4:1) was stirred with sat. LiOH solution
(0.50 mL) at 50.degree. C. for 2 hours. The mixture was then
acidified with 3N HCl and extracted with CH.sub.2Cl.sub.2
(3.times.10 mL). The combined organic layer was dried over
MgSO.sub.4, concentrated under reduced pressure to give the titled
compound (450 mg, 97%) as a white solid.
Example 52D
(2-Chlorophenyl)[2-chloro-4-(E-((4-acetyl]piperazin-1-yl)carbonyl))2-prope-
nyl)phenyl]sulfide
[0725] The title compound was prepared using the cinnamic acid from
Example 52C by the procedures described in Example 1C substituting
6-amino-1-hexanol with 1-acetylpiperazine. White solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.10-2.20 (m, 3H), 2.25 (s, 3H),
3.40-3.80 (m, 8H), 6.28 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 7.19-7.36
(m, 4H), 7.46-7.56 (m, 2H). MS (APCI) (M+NH.sub.4).sup.+ at m/z
466, 468, 470.
Example 53
(2-(1-Morpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide
Example 53A
(2-(1-Bromomethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)p-
henyl]sulfide
[0726] To a stirred solution of benzyl alcohol (195 mg, 0.32 mmol)
from Example 11 in 2.0 mL of anhydrous DMF was added LiBr (48 mg,
0.35 mmol). The mixture was then cooled in an ice-water bath, and
PBr.sub.3 (60 .mu.L, 0.40 mmol) was dropped in slowly. The ice bath
was then removed and the mixture was stirred at room temperature
for 1 hour. Water was then added, the mixture was then partitioned
between EtOAc and aqueous NaHCO.sub.3. The aqueous layer was
extracted with EtOAc once. The combined organic layer was washed
with water and brine, dried over Na.sub.2SO.sub.4, concentrated on
a rotavap. The crude bromide (230 mg) was used directly for the
alkylation without purification.
Example 53B
(2-(1-Molpholinylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)eth-
enyl)phenyl]sulfide
[0727] To a stirred solution of morpholine (10 .mu.L, 0.11 mmol) in
0.5 mL of CH.sub.3CN was added Hunig's base (23.7 .mu.L, 0.14
mmol), followed by the bromide (40 mg, 0.091 mmol). The mixture was
then stirred at room temperature for 2 hours. Solvent was then
removed and the crude product was purified with Gilson Preparative
HPLC as described in Example 38B to give the titled compound as a
white solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.33 (br
t, 4H), 3.45 (br t, 4H), 3.50-3.65 (m, 6H), 3.56 (s, 2H), 3.65-3.80
(br m, 2H), 6.74 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H),
7.35-7.41 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.46 (td, J=2.4, 8.1
Hz, 1H), 7.52 (dd, J=2.1, 8.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 8.02
(d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 459,
461.
Example 54
(2-(4-(1,3-Benzodioxolyl-5-methyl)piperazin-1-ylmethyl)phenyl)[2-chloro-4--
(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
[0728] The title compound was prepared by the procedures described
in Example 53B substituting morpholine with 1-piperonylpiperazine.
White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.13-2.40
(br m, 8H), 3.28 (s, 2H), 3.49-3.64 (br m, 6H), 3.54 (s, 2H), 3.70
(br m, 2H), 5.97 (s, 2H), 6.69 (dd, J=1.8, 8.1 Hz, 1H), 6.74 (d,
J=8.7 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 7.39
(d, J=15.3 Hz, 1H), 7.33-7.38 (m, 2H), 7.38-7.50 (m, 2H), 7.43 (d,
J=15.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 592, 594.
Example 55
(2-(4-(iso-Propylaminocarbonylmethyl)piperazin-1-ylmethyl)phenyl)[2-chloro-
-4-(E-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
[0729] The title compound was prepared by the procedures described
in Example 53B substituting morpholine with
N-isopropyl-1-piperazineacetamid- e. White solid; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.04 (d, J=6.3 Hz, 6H), 2.20-2.42
(br m, 8H), 2.78 (s, 2H), 3.47-3.64 (br m, 6H), 3.56 (s, 2H),
3.64-3.76 (br m, 2H), 3.85 (qd, J=6.3, 8.1 Hz, 1H), 6.73 (d, J=8.7
Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.31-7.39 (m, 2H), 7.43 (d,
J=15.6 Hz, 1H), 7.45 (td, J=2.7, 6.3 Hz, 1H), 7.50 (dd, J=2.1, 8.7
Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H). MS
(DCI/NH.sub.3) (M+H).sup.+ at m/z 557, 559.
Example 56
(2-((N-Ethoxycarbonylmethyl-N-methyl)aminomethyl)phenyl)[2-chloro-4-(E-((1-
-morpholinyl)carbonyl)ethenyl)phenyl]sulfide
[0730] The title compound was prepared by the procedures described
in Example 53B substituting morpholine with ethyl sarcosinate
hydrochloride. White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 1.16 (t, J=7.2 Hz, 3H), 2.27 (s, 2H), 3.30 (s, 2H),
3.51-3.66 (br m, 6H), 3.66-3.75 (br m, 2H), 3.78 (s, 2H), 4.05 (q,
J=7.2 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 1H),
7.33-7.38 (m, 2H), 7.42-7.50 (m, 2H), 7.43 (d, J=15.3 Hz, 1H), 7.53
(dd, J=2.1, 8.7 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 8.02 (d, J=2.1 Hz,
1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 489,491.
Example 57
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide
[0731] To a stirred solution of the alcohol (368 mg, 0.94 mmol)
from Example 11 in 5 mL of anhydrous acetonitrile was added
activated 4 .ANG. molecular sieves, TPAP (3.3 mg, 0.0094 mmol), and
NMO (110 mg, 1.03 mmol). The mixture was then stirred at room
temperature for 3 hours. The reaction mixture was then quenched
with dimethyl sulfide (100 .mu.L). The crude product was filtered
through celite, washed with acetonitrile, condensed in vacuo. The
titled compound was purified by silica gel column chromatography to
give a white solid (216 mg, 59%). .sup.1H NMR (d.sup.6-DMSO, 300
MHz) .delta. 3.60 (br m, 6H), 3.73 (br m, 2H), 7.00 (d, J=8.4 Hz,
1H), 7.40 (d, J=15.3 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.51 (d,
J=15.3 Hz, 1H), 7.52 (td, J=1.8, 8.1 Hz, 1H), 7.61 (td, J=1.8, 8.1
Hz, 1H), 7.71 (dd, J=2.1, 8.4 Hz, 1H), 8.02 (dd, J=2.1, 8.4 Hz,
1H), 8.14 (d, J=2.1 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z
388, 390.
Example 58
(2-(4-Formylpiperazin-1-ylmethyl)phenyl)[2-chloro-4-(E-((1-morpholinyl)car-
bonyl)ethenyl)phenyl]sulfide
[0732] The title compound was prepared by the procedures described
in Example 53B substituting morpholine with 1-formyl piperazine.
White solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.20-2.32
(m, 6H), 2.74 (br m, 2H), 3.48 (s, 2H), 3.59 (m, 6H), 3.70 (br m,
2H), 6.74 (d, J=8.7 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), 7.35-7.41 (m,
2H), 7.42 (d, J=15.6 Hz, 1H), 7.45-7.52 (m, 3H), 7.98 (d, J=2.1, if
H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 486,488.
Example 59
(2-(E-((1-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-(E-((1-morpholin-
yl)carbonyl)ethenyl)phenyl]sulfide
[0733] A mixture of bromide (80 mg, 0.18 mmol) from Example 12,
acryloylmorpholine (33 mg, 0.23 mmol), Pd(OAc).sub.2 (2.0 mg, 0.009
mmol), P(o-tolyl).sub.3 (17 mg, 0.056 mmol), Et.sub.3N (39 .mu.L,
0.27 mmol), and anhydrous DMF (1.0 mL) in a pressure tube was
flushed with nitrogen for 5 minutes before it capped and heated at
110.degree. C. over night. TLC indicated almost complete
consumption of the starting bromide. The reaction mixture was then
allowed to cool down to room temperature, partitioned between EtOAc
and water. The aqueous layer was extracted once with EtOAc. The
combined organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4, condensed under reduced pressure. The crude
product was purified with Gilson Preparative HPLC as described in
Example 38B to give the titled compound as a light-brown solid (35
mg, 39%). .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 3.43-3.88 (m,
16H), 6.58 (d, J=8.7 Hz, 1H), 7.30 (d, J=15.3 Hz, 2H), 7.43 (d,
J=15.3 Hz, 1H), 7.47-7.64 (m, 4H), 7.86 (d, J=15.3 Hz, 1H), 8.06
(d, J=2.1 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H). MS (DCI/NH.sub.3)
(M+NH.sub.4).sup.+ at m/z 516, 518. Analysis calculated for
C.sub.26H.sub.27N.sub.2O.sub.4Cl.sub.1S.sub.1.0.4- 6H.sub.2O: C,
61.56; H, 5.55; N, 5.21. Found: C, 61.56; H, 5.50; N, 5.43.
Example 60
(2-Formylphenyl)[2-nitro-4-(E-((4-acetyl]piperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0734] The title compound was prepared by the procedures described
in Example 57 substituting compound from Example 11 with compound
from Example 48. Yellow solid; .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.04 (s, 3H), 3.47 (br m, 4H), 3.52 (br m, 1H), 3.60 (br m,
1H), 3.68 (br m, 1H), 3.74 (br m, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.44
(d, J=15.6 Hz, 1H), 7.55 (d, J=15.6 Hz, 1H), 7.61 (d, J=7.5 Hz,
1H), 7.73 (t, J=7.5 Hz, 1H), 7.80 (td, J=2.4, 7.5 Hz, 1H), 7.92
(dd, J=2.1, 9.0 Hz, 1H), 8.04 (dd, J=2.4, 7.5 Hz, 1H), 8.66 (d,
J=2.1 Hz, 1H), 10.29 (s, 1H). MS (APCI) (M+Cl).sup.- at m/z 474,
476.
Example 61
(2-Formylphenyl)[2-chloro-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl]sul-
fide, N,N-dimethyl hydrazone
[0735] A mixture of the aldehyde (20 mg, 0.052 mmol) from Example
57, 1,1-dimethyl hydrazine (3.9 .mu.L, 0.052 mmol) in 0.5 mL of
EtOH with a tiny amount of AcOH was stirred at room temperature
over night. The solvent was then removed and the product was
purified by preparative TLC to give the titled compound (20 mg,
90%) as a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
2.91 (s, 6H), 3.55-3.82 (br m, 8H), 6.64 (d, J=8.7 Hz, 1H), 6.76
(d, J=15.3 Hz, 1H), 7.05 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (td, J=1.8,
7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.47-7.57 (m, 2H), 7.54 (m,
2H), 8.04 (dd, J=1.8, 8.7 Hz, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at
m/z 430, 432, 434, 436.
Example 62
(2-((3-(1-Morpholinyl)propyl)-1-amino)phenyl)[2-chloro-4-(E-((1-morpholiny-
l)carbonyl)ethenyl)phenyl]sulfide
[0736] A mixture of bromide (60 mg, 0.14 mmol) from Example 12,
aminopropylmorpholine (24 .mu.L, 0.17 mmol), Pd.sub.2(dba).sub.3
(1.2 mg, 0.0013 mmol), BINAP (2.5 mg, 0.004 mmol), NaOt-Bu (19 mg,
0.20 mmol), 18-crown-6 (50 mg, 0.20 mmol), and anhydrous toluene (1
mL) in a pressure tube was flushed with nitrogen for 3 minutes
before it was capped and heated at 80.degree. C. over night. The
reaction was then stopped, and allowed to cool down to room
temperature. The reaction mixture was partitioned between EtOAc and
water, and the aqueous layer was extracted once with EtOAc. The
combined organic layer was then washed with water and brine, dried
over Na.sub.2SO.sub.4, condensed under reduced pressure. The crude
product was purified with Gilson Preparative HPLC as described in
Example 38B to give the titled compound as a light-brown oil (30
mg, 44%). .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.62
(quintet, J=6.5 Hz, 2H), 2.15-2.26 (m, 8H), 3.17 (q, J=6.5 Hz, 2H),
3.22-3.76 (m, 12H), 3.50 (t, J=6.5 Hz, 2H), 5.72 (t, J=5.7 Hz, 1H),
6.47 (d, J=8.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.81 (d, J=8.4 Hz,
1H), 7.26 (d, J=15.6 Hz, 1H), 7.35-7.42 (m, 2H), 7.43 (d, J=15.6
Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 8.00 (d,
J=2.1 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 502, 504.
Example 63
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino)car-
bonyl)ethenyl)phenyl]sulfide
Example 63A
(2,4-Dichlorophenyl)[2-amino-4-(E-((3-(1-pyrrolidin-2-only)propylamino)car-
bonyl)ethenyl)phenyl]sulfide
[0737] A mixture of nitro compound (780 mg, 1.58 mmol) from Example
33, SnCl.sub.2 (1.50 g, 7.91 mmol) in 25 mL of anhydrous EtOH was
refluxed under nitrogen atmosphere for 90 minutes. The reaction was
then allowed to cool down to room temperature, quenched with sat.
NaHCO.sub.3, extracted with EtOAc (2.times.50 mL). The combined
organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4, condensed in vacuo to give the crude aniline as
yellowish brown solid, which was converted to the bromide without
purification.
Example 63B
(2,4-Dichlorophenyl)[2-bromo-4-(E-((3-(1-pyrrolidin-2-only)propylamino)car-
bonyl)ethenyl)phenyl]sulfide
[0738] To a stirred solution of t-butyl nitrite (57 .mu.L, 0.48
mmol), CuBr.sub.2 (87 mg, 0.39 mmol) in 2.0 mL of CH.sub.3CN at
room temperature was added a solution of aniline from Example 63A
(150 mg, 0.323 mmol) in 1.0 mL of CH.sub.3CN. The dark green
solution was then heated at 65.degree. C. under nitrogen atmosphere
for 90 minutes. The reaction mixture was then allowed to cool down
to room temperature, partitioned between EtOAc and 3N HCl. The
organic layer was then washed with brine, dried over
Na.sub.2SO.sub.4, condensed in vacuo. The crude product was then
purified with Gilson Preparative HPLC as described in Example 38B
to give the titled compound as a light-brown solid (50 mg, 29%).
Colorless oil; .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.63
(quintet, J=7.2 Hz, 2H), 1.91 (quintet, J=8.4 Hz, 2H), 2.22 (t,
J=8.4 Hz, 2H), 3.09-3.47 (m, 6H), 6.67 (d, J=15.3 Hz, 1H), 7.07 (d,
J=8.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.38 (d, J=15.3 Hz, 1H),
7.50 (dd, J=2.4, 8.7 Hz, 1H), 7.57 (dd, J=2.1, 8.4 Hz, 1H), 7.86
(d, J=2.4 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 8.13 (t, J=6.0 Hz, 1H).
MS (ESI) (M+H).sup.+ at m/z 527, 529, 531, 533.
Example 64
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)phenyl-
]sulfide
Example 64A
[1
Fluoro-2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenyl)benzene
[0739] The title compound was prepared by the procedures described
in Example 59 substituting the bromide from Example 12 with
2-fluoro-5-bromobenzaldehyde.
Example 64B
(2,4-Dichlorophenyl)[2-formyl-4-(E-((1-morpholinyl)carbonyl)ethenylphenyl]-
sulfide
[0740] The title compound was prepared by the procedures described
in Example 32 substituting 4-chloro-3-nitro-cinnamide with the
compound from Example 64A. White solid; .sup.1H NMR (d.sup.6-DMSO,
300 MHz) .delta. 3.60 (br m, 6H), 3.71 (br m, 2H), 6.82 (d, J=8.7
Hz, 1H), 7.35 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.55
(dd, J=2.4, 8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (dd, J=2.4,
8.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 10.19
(s, 1H). MS (DCI/NH.sub.3) (M+H).sup.+ at m/z 422, 424, 426,
428.
Example 65
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
Example 65A
(2-Carbomethoxyethyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
[0741] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with methyl
3-mercaptopropionate, and 6-amino-1-hexanol with 1-acetyl
piperazine.
Example 65B
(2-Chloro-6-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0742] To a stirred solution of the compound (105 mg, 0.26 mmol)
from Example 65A in 2 mL of THF under nitrogen atmosphere at
0.degree. C. was added t-BuOK solution (1.0M, 281 .mu.L, 0.29
mmol). Light orange precipitates appeared immediately. After
completion of the addition, the reaction mixture was stirred at
room temperature for 1 hour before the solvent was removed on a
rotavap under reduced pressure.
[0743] The yellow thiolate thus obtained was dissolved in 0.5 mL of
DMF, and 2,3-dichlorobenzaldehyde was then added. The mixture was
then heated at 80.degree. C. under nitrogen for 2 hours. Reaction
was then stopped and the solvent was removed under vacuum. The
crude product was purified with Gilson Preparative HPLC as
described in Example 388B to give the titled compound as a white
solid (25 mg, 21%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.05
(s, 3H), 3.48-3.58 (m, 2H), 3.58-3.84 (m, 6H), 6.53 (d, J=8.7 Hz,
1H), 6.80 (d, J=15.3 Hz, 1H), 7.19 (dd, J=1.8, 8.7 Hz, 1H),
7.51-7.62 (m, 2H), 7.60 (d, J=15.3 Hz, 1H), 7.84 (dd, J=1.8, 8.4
Hz, 1H), 7.99 (dd, J=1.8, 8.4 Hz, 1H). MS (APCI) (M+NH.sub.4).sup.+
at t/z 480, 482, 484.
Example 66
(2-Cyanophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0744] The title compound was prepared by the procedures described
in Example 65B substituting 2,3-dichlorobenzaldehyde with
2-fluorobenzonitrile, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.15 (s, 3H), 3.48-3.57 (m, 2H),
3.59-3.84 (m, 6H), 6.86 (d, J=15.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H),
7.32 (d, J=8.4 Hz, 1H), 7.41 (d, J=6.6 Hz, 1H), 7.46 (dd, J=1.8,
8.4 Hz, 1H), 7.55 (dd, J=1.8, 8.1 Hz, 1H), 7.61 (d, J=15.6 Hz, 1H),
7.64 (d, J=1.8 Hz, 1H), 7.75 (dd, J=1.8, 8.4 Hz, 1H). MS
(DCI/NH.sub.3) (M+NH.sub.4).sup.+ at m/z 443.
Example 67
(2-Isopropylphenyl)[2-cyano-4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]-
sulfide
Example 67A
(2-Isopropylphenyl)(4-bromo-2-cyanophenyl)sulfide
[0745] The title compound was prepared by the procedures described
in Example 1A substituting 2,4-dichlorothiophenol with
isopropylthiophenol, and 2-chlorobenzaldehyde with
2-fluorobenzonitrile.
Example 67B
(2-Isopropylphenyl)[2-cyano-4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]-
sulfide
[0746] The title compound was prepared by the procedures described
in Example 59 substituting the bromide from Example 12 with the
bromide from Example 67A, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=6.9 Hz, 6H), 3.49 (septet,
J=6.9 Hz, 1H), 3.58-3.87 (m, 8H), 6.73 (d, J=8.4 Hz, 1H), 6.83 (d,
J=15.6 Hz, 1H), 7.20-7.30 (m, 1H), 7.42 (dd, J=2.4, 8.4 Hz, 1H),
7.46 (d, J=3.0 Hz, 2H), 7.49 (dd, J=1.8, 6.9 Hz, 1H), 7.57 (d,
J=15.6 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+
at m/z 393.
Example 68
(2-Bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
[0747] The title compound was prepared by the procedures described
in Example 32B substituting 2,4-dichlorothiophenol with
2-bromothiophenol, providing a light-yellow solid; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.40-3.65 (m, 8H),
6.75 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.51 (dd J=2.1,
6.9 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.55 (t, J=2.1 Hz, 1H), 7.59
(dd, J=2.1, 6.9 Hz, 1H), 7.82 (dd, J=2.4, 7.8 Hz, 1H), 7.92 (td,
J=2.4, 8.4 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H). MS (APCI.sup.-)
(M+Cl).sup.- at m/z 524, 526, 528.
Example 69
(2-(Pyrrolidin-1-ylphenyl)[2-chloro-4-(E-((morpholin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide
[0748] To a stirred solution of bromide (75 mg, 0.17 mmol) from
Example 12 in toluene in a sealed tube was added sequentially
pyrrolidine (18.4 mL, 0.22 mmol), Pd.sub.2(dba).sub.3 (3.0 mg,
0.0034 mmol), BINAP (6.0 mg, 0.01 mmol), followed by NaOt-Bu (26
mg, 0.27 mmol). The resulting mixture was then flushed with
anhydrous N.sub.2 for 2 min before it was capped and heated at
90.degree. C. for 24 h. The reaction mixture was then allowed to
cool down to room temperature and partitioned between ethyl acetate
and brine. The organic layer was then dried with Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude product was purified
using Gilson Preparative HPLC as described in Example 38B to give
the title compound (40 mg, 55% yield) as a white solid; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.83 (br s, 4H), 3.40 (br s, 4H),
3.56-3.80 (m, 8H), 6.57 (d, J=8.4 Hz, 1H), 6.75 (d, J=15.6 Hz, 1H),
6.81 (br t, J=8.4 Hz, 1H) 6.90 (br s, 1H), 7.15 (dd, J=2.1, 8.4 Hz,
1H), 7.18-7.27 (m, 1H), 7.32 (td, J=1.8, 8.4 Hz, 1H), 7.42 (dd,
J=1.8, 7.8 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.55 (d, J=15.6 Hz,
1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 429, 431.
Example 70
(2-Methoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]s-
ulfide
[0749] The title compound was prepared according to the procedures
of Example 1, giving a white solid, m.p. 162-164 C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.60-3.78 (m, 8H), 3.84 (s, 3H), 6.72
(d, J=9 Hz, 1H), 6.78 (d, J=16 Hz, 1H), 6.96-7.04 (m, 2H), 7.16
(dd, J=9 Hz, 2 Hz, 1H), 7.40-7.46 (, 2H), 7.55 (d, J=2H, 1H), 7.58
(d, J=16 Hz, 1H). Anal. Calcd. for C.sub.20H.sub.20ClNO.sub.3S: C,
61.61; H, 5.17; N, 3.59. Found: C, 61.53, H, 5.22; N, 3.50.
Example 71
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxypiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
Example 71A
1-tert-Butyoxycarbonyl-2-carbomethoxypiperazine
[0750] 2-Carbomethoxypiperazine was treated with benzyl
chloroformate (1.0 eq) in aqueous NaHCO.sub.3 to give
1-benzyloxycarbonyl-3-carbomethoxypipe- razine. This material was
treated with di-tert-butyldicarbonate (1.1 eq) and triethylamine
(1.0 eq) in THF to produce 1-tert-butyoxycarbonyl-4-ben-
zyloxycarbonyl-2-carbomethoxypiperazine. Hydrogenation of this
compound in methanol using 10% Pd--C gives the title compound after
filtration and solvent removal.
Example 71B
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxypiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0751] A mixture of
(2-isopropylphenyl)[2-nitro-4-E-(carboxyethenyl)phenyl- ]sulfide
(prepared according to the procedures of Example 32), the amine
from Example 71A (1.0 eq),
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylur- onium
tetrafluoroborate (1.0 eq), and diisopropylethylamine (2.0 eq) in
DMF was stirred at ambient temperature for 4 hr. Ethyl acetate was
added, and the mixture was washed sequentially with 1N HCl, bicarb,
and brine. The resultant yellow solid was treated with 1:1
TFA/dichloromethane at ambient temperature to give the title
compound as a yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz)
.delta. 1.15 (d, J=6.6 Hz, 6H); 2.52-3.16 (br m, 4H); 3.25-3.47 (m,
1H); 3.60-3.65 (br d, 3H); 3.60, 3.66 (br s, br s, 3H); 6.61-6.67
(br m, 1H); 7.30-7.62 (m, 6H); 7.88-7.93 (br m, 1H); 8.58-8.65 (br
m, 1H). MS (APCI) (M+H).sup.+ at m/z 470. Anal calcd for
C.sub.24H.sub.27N.sub.3S.sub.1O.sub.5: C, 61.39; H, 5.80; N, 8.95.
Found: C, 61.51; H, 5.87; N, 8.68.
Example 72
(2-Methylphenyl)[2-nitro-4-(E-((3-carboxamido-4-carbobenzoxypiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0752] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.30 (s,
3H); 2.80-4.80 (br m, 7H); 5.05-5.15 (br m, 2H); 6.61-6.67 (br m,
1H); 7.02-7.64 (m, 13H); 7.80-7.90 (br m, 1H); 8.56-8.65 (br m,
1H). MS (APCI) (M+H).sup.+ at m/z 561. Anal calcd for
C.sub.29H.sub.28N.sub.4S.sub.1O.su-
b.6.0.42CH.sub.3COOCH.sub.2CH.sub.3: C, 61.66; H, 5.29; N, 9.38.
Found: C, 61.41; H, 5.28; N, 9.53.
Example 73
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-tert-butoxycarbonylpip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0753] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (d,
J=6.6 Hz, 6H); 1.40, 1.41 (s, s, 9H); 2.72-3.08 (br m, 1H);
3.17-3.24 (m, 1H); 3.30-3.40 (m, 1H); 3.68 (br s, 3H); 3.79-4.51
(br m, 4H); 5.06, 5.36 (br s, br s, 1H); 6.61-6.67 (m, 1H);
7.30-7.62 (m, 6H); 7.85-7.93 (br m, 1H); 8.64-8.69 (br m, 1H). MS
(APCI) (M+H).sup.+ at m/z 570. Anal calcd for
C.sub.29H.sub.35N.sub.3S.sub.1O.sub.7.0.15C.sub.6H.sub.14: C,
61.66; H, 6.43; N, 7.21. Found: C, 61.69; H, 6.35; N, 7.02.
Example 74
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxy-4-tert-butoxycarbonylpiperazi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0754] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 1.45 (s, 9H); 2.72-4.75 (br m, 6H); 3.38-3.49 (m,
1H); 5.78 (br s, 1H); 6.68, 6.72 (s, s, 1H); 6.88, 6.94 (br s, br,
s, 1H); 7.26-7.71 (m, 6H); 8.44 (br s, 1H). MS (APCI) (M-H).sup.+
at m/z 554. Anal calcd for C.sub.28H.sub.33N.sub.3S.sub.1O.sub.7:
C, 60.53; H, 5.99; N, 7.56. Found: C, 60.42; H, 6.21; N, 7.31.
Example 75
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[0755] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.78 (s,
1H), 7.62 (d, 1H, J=15.5 Hz), 7.43-7.49 (m, 3H), 7.37 (d, 1H, J=8.1
Hz), 7.23 (m, 1H), 6.85 (d, 1H, J=15.5 Hz), 6.82 (d, 1H, J=8.5 Hz),
3.63-3.77 (m, 6H), 3.45-3.55 (m, 3H), 2.14 (s, 3H), 1.17 (d, 6H,
J=6.6 Hz). MS (ESI) m/z 477, 499, 975, 953. Anal. Calcd for
C.sub.25H.sub.27F.sub.3N.sub.2O.sub.2- S.0.5 EtOAc: C, 62.29; H,
6.00; N, 5.38. Found: C, 62.40; H, 6.21; N, 5.35.
Example 76
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0756] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) 7.78 (s, 1H), 7.62
(br, 1H), 7.33-7.48 (m, 3H), 7.22 (m, 1H), 6.85 (m, 1H), 6.80 (d,
1H, J=8.5 Hz), 3.73 (br, 8H), 3.49 (dq, 1H, J.sub.1=J.sub.2=6.9
Hz), 1.17 (d, 6H, J=7.1 Hz). MS (ESI) m/z 436, 871, 893. Anal.
Calcd for C.sub.23H.sub.24F.sub.3N- .sub.1O.sub.2S: C, 63.43; H,
5.55. N, 3.22. Found: C, 63.12; H, 5.81, N, 3.10.
Example 77
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop--
1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0757] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.77 (s,
1H), 7.52 (d, 1H, J=15.4 Hz), 7.43-7.51 (m, 3H), 7.36 (d, 1H, J=8.8
Hz), 7.22 (m, 1H), 7.10 (br, 1H), 6.80 (d, 1H, J=8.4 Hz), 6.44 (d,
1H, J=15.4 Hz), 3.49 (dq, 1H, J.sub.1=J.sub.2=6.9 Hz), 3.40 (m,
4H), 3.31 (dd, 2H, J.sub.1=5.7 Hz, J.sub.2=12.0 Hz), 2.44 (t, 2H,
J=8.1 Hz), 2.08 (tt, 2H, J.sub.1=J.sub.2=7.5 Hz), 1.74 (m, 2H),
1.18 (d, 6H, J=6.9 Hz). MS (ESI) m/z 491, 513, 981, 1003. Anal.
Calcd for C.sub.26H.sub.29F.sub.3N.sub.2O.- sub.2S: C, 63.66; H,
5.96; N, 5.71. Found: C, 64.00; H, 6.12, N, 5.68.
Example 78
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((cyclobutylamino)carbonyl)ethe-
nyl)phenyl]sulfide
[0758] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76 (s,
1H), 7.52 (d, 1H, J=15.4 Hz), 7.43-7.49 (m, 3H), 7.33 (d, 1H, J=7.7
Hz), 7.22 (m, 1H), 6.79 (d, 1H, J=8.1 Hz), 6.33 (d, 1H, J=15.4 Hz),
5.72 (br, 1H), 4.52 (m, 1H), 3.49 (dq, 1H, J.sub.1=J.sub.2=6.9 Hz),
2.40 (m, 2H), 1.90 (m, 2H), 1.74 (m, 2H), 1.17 (d, 6H, J=6.6 Hz).
MS (ESI) m/z 420, 839, 861. Anal. Calcd for
C.sub.23H.sub.24F.sub.3N.sub.1O.sub.1S: C, 65.85; H, 5.77; N, 3.34.
Found: C, 65.53; H, 5.83, N, 3.21.
Example 79
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((cyclopentylamino)carbonyl)eth-
enyl)phenyl]sulfide
[0759] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.77 (s,
1H), 7.52 (d, 1H, J=15.5 Hz), 7.43-7.48 (m, 3H), 7.33 (d, 1H, I=8.8
Hz), 7.22 (m, 1H), 6.79 (d, 1H, J=8.1 Hz), 6.33 (d, 1H. J=15.5 Hz),
5.54 (d, J=7.7, 1H), 4.35 (m, 1H), 3.49 (dq, 1H,
J.sub.1=J.sub.2=6.9 Hz), 2.05 (m, 2H), 1.68 (m, 4H), 1.44 (m, 2H),
1.17 (d, 6H, J=7.0 Hz). MS (ESI) m/z 434, 867, 889. Anal. Calcd for
C.sub.24H.sub.26F.sub.3N.sub.1O.sub.1S: C, 66.49; H, 6.04; N, 3.23.
Found: C, 66.24: H, 6.14, N, 3.06.
Example 80
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((5-hydroxypent-1-ylamino)carbo-
nyl)ethenyl)phenyl]sulfide
[0760] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.77 (s,
1H), 7.54 (d, 1H, J=15.5 Hz), 7.43-7.49 (m, 3H), 7.33 (d, 1H, J=8.0
Hz), 7.22 (m, 1H), 6.79 (d, 1H, J=8.4 Hz), 6.35 (d, 1H, J=15.6 Hz),
5.67 (br, 1H), 3.67 (t, 2H, J=6.4 Hz), 3.49 (dq, 1H,
J.sub.1=J.sub.2=6.9 Hz), 3.40 (m, 2H), 2.40 (m, 2H), 1.45-1.62 (m,
6H), 1.17 (d, 6H, J=7.0 Hz). MS (ESI) m/z 452, 474, 903, 925. Anal.
Calcd for C.sub.24H.sub.28F.sub.3NO.sub.2S.0.56 EtOAc: C, 62.92; H,
6.54; N, 2.80. Found: C, 62.86; H, 6.53; N, 2.96.
Example 81
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-acetylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0761] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.20 (s, 3H); 2.75-3.80 (br m, 4H); 3.39-3.50 (m,
1H); 3.70, 3.77 (br s, br s, 3H); 4.49-4.75 (br m, 2H); 5.39 (br s,
1H); 6.71 (m, 1H); 6.91-7.04 (br m, 1H); 7.25-7.64 (m, 6H); 8.42
(br m, 1H). MS (APCI) (M+H).sup.+ at m/z 512. Anal calcd for
C.sub.26H.sub.29N.sub.3S.sub.1O.sub.6: C, 61.04; H, 5.71; N, 8.21.
Found: C, 61.40; H, 6.05; N, 7.88.
Example 82
(2-Biphenyl)[2-chloro-4-(E-((morpholin-1-yl)carbonyl)ethenyl)phenyl]sulfid-
e
[0762] To a stirred solution of bromide from Example 12 (60 mg,
0.14 mmol) in 1 mL of toluene was added 0.5 mL of sat.
Na.sub.2CO.sub.3, Pd(PPh.sub.3).sub.4 (8 mg, 0.007 mmol),
phenylboronic acid (17 mg, 0.14 mmol). The mixture was flushed with
nitrogen and heated at 100.degree. C. for 3 h. The reaction mixture
was then allowed to cool down to room temperature and partitioned
between ethyl acetate and brine. The organic layer was then dried
with Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
crude product was purified using Gilson Preparative HPLC as
described in Example 38B to give the title compound as colorless
oil (40 mg, 67% yield); .sup.1H NMR (CDCl.sub.1, 300 MHz) .delta.
3.58-3.86 (m, 8H), 6.77 (d, J=15.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H),
7.67 (dd, J=2.1, 8.4 Hz, 1H), 7.29-7.40 (m, 3H), 7.40-7.48 (m, 6H),
7.56 (d, J=15.6 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H). MS (APCI.sup.+)
(M+H).sup.+ at m/z 436, 438.
Example 83
(3,4-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0763] To a solution of the compound of Example 32A (40 mg, 0.12
mmole) in 2.5 mL of dimethylformamide was added
3,4-dimethylthiophenol (17 mg, 0.12 mmole), followed by potassium
carbonate powder (20 mg, 0.14 mmole). The mixture was heated at
100.degree. C. for 20 h. The solvent was removed using N.sub.2 gas
flow. Water (5 mL) was then added to the residue, the resulting
precipitate was collected through filtration, washed with cold
water, and air dried to give the title compound (42 mg, 81%) as
light yellow solid. .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.08
(s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 3.45 (br, m, 2H), 3.63 (br, m,
6H), 6.79 (s, 1H), 6.82 (d, J=19 Hz, 1H), 7.18 (d, J=19 Hz, 1H),
7.24 (dd, J=4, 19 Hz, 1H), 7.27 (s, 1H), 7.34 (d, J=21 Hz, 1H),
7.56 (d, J=39 Hz, 1H), 8.32 (d, J=4 Hz, 1H). MS (APCI) (M+H).sup.+
at m/z 440. FAB High Resolution MS calculated m/z for
C.sub.23H.sub.26N.sub.3O.sub.4S (M+H).sup.+: 440.1644. Observed
m/z: 440.1646.
Example 84
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0764] The title compound was prepared by the procedures described
in Example 9 substituting 2,4-dichlorothiophenol with
2-bromothiophenol and 3,4-dichlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzaldehyde, to give a white solid.
.sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.43-3.80
(m, 8H), 7.21 (dd, J=2.1, 8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.33
(td, J=2.1, 7.65 Hz, 1H), 7.42 (td, J=1.8, 7.65 Hz, 1H), 7.45 (d,
J=15.6 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H), 7.78 (dd, J=1.8, 8.4 Hz,
1H), 7.96 (dd, J=1.8, 8.4 Hz, 1H), 8.25 (d, J=1.8 Hz, 1H). MS
(APCI.sup.+) (M+NH.sub.4).sup.+ at m/z 530, 532, 534.
Example 85
(5-Indolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl-
]sulfide
[0765] To a stirred solution of 5-iodoindole (255 mg, 1.05 mmol) in
5.0 mL of anhydrous DMF was added the potassium thiolate (457 mg,
1.26 mmol) from Example 65B, followed by K.sub.2CO.sub.3 (174 mg,
1.26 mmol), and cuprous iodide (20 mg, 0.11 mmol). The resulting
mixture was then heated at 120.degree. C. for overnight. The
reaction mixture was then allowed to cool to ambient temperature
and poured into water. The aqueous mixture was extracted twice with
25 mL of ethyl acetate. The combined organic layer was then washed
with water and brine, dried over Na.sub.2SO.sub.4, filtered,
concentrated on a rotavap under reduced pressure. The crude product
was purified using Gilson Preparative HPLC as described in Example
38B to give the title compound (15 mg, 25% based on the iodide) as
a light-brown solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta.
2.03 (s, 3H), 3.40-3.78 (m, 8H), 6.51 (d, J=8.4 Hz, 1H), 6.53 (s,
1H), 7.23 (dd, J=2.1, 8.4 Hz, 1H), 7.27 (d, J=15.6 Hz, 1H), 7.39
(d, J=15.6 Hz, 1H), 7.41 (dd, J=1.8, 8.4 Hz, 1H), 7.49 (t, J=2.7
Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.99 (d,
J=1.8 Hz, 1H). MS (APCI.sup.+) (M+NH.sub.4).sup.+ at m/z 440, 442.
Anal. Calcd for C.sub.23H.sub.22ClN.sub.3O.sub.2S.0.53
CH.sub.2Cl.sub.2: C, 58.28; H, 4.79; N, 8.66. Found: C, 58.31; H,
4.93; N, 8.65.
Example 86
(5-Benzodioxolyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
[0766] The title compound was prepared by the procedures described
in Example 85 substituting 5-iodoindole with
1-iodo-3,4-methylenedioxybenzen- e, providing a white solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.14 (s, 3H), 3.48-3.60
(m, 2H), 3.60-3,84 (m, 6H) 6.05 (s, 2H), 6.75 (d, J=8.4 Hz, 1H),
6.80 (d, J=15.3 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.1 Hz,
1H), 7.08 (dd, J=2.1, 8.4 Hz, 1H), 7.19 (d, J=1.8, 8.4 Hz, 1H),
7.52 (d, J=2.1 Hz, 1H), 7.58 (d, J=15.6 Hz, 1H). MS (APCI.sup.+)
(M+NH.sub.4).sup.+ at m/z 445, 447.
Example 87
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxypiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0767] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.52-2.91 (br m, 5H); 3.30-3.40 (m, 1H); 3.68, 3.69
(s, s, 3H); 4.10-4.25 (br m, 1H); 5.00-5.21 (br m, 1H); 6.60-6.65
(m, 1H); 7.29-7.62 (m, 6H); 7.85-7.95 (m, 1H); 8.64-8.68 (m, 1H).
MS (APCI) (M+H).sup.+ at m/z 470.
Example 88
(2,3-Dimethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phen-
yl]sulfide
[0768] The title compound was prepared according to the procedures
of Example 1, giving a white solid, m.p. 148-150 C. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.60-3.78 (m, 8H), 3.85 (s, 3H), 3.91
(s, 3H), 6.78 (d, J=16 Hz, 1H), 6.86-6.98 (m, 3H), 7.20 (dd, J=9
Hz, 2 Hz, 1H), 7.54 (d, J=2 Hz, 1H), 7.58 (d, J=16 Hz, 1H). Anal.
Calcd. for C.sub.21H.sub.22ClNO.sub.4S: C, 60.06; H, 5.28; N, 3.33.
Found: C, 59.72; H, 5.34; N, 2.97.
Example 89
(2-Fluorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0769] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
2-fluorothiophenol. Yellow solid (40 mg, 78%). .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.17 (s, 3H), 3.56 (br, m, 2H), 3.77
(br, m, 6H), 6.88 (dd, J=3, 21 Hz, 1H), 6.93 (d, J=39 Hz, 1H), 7.26
(dd, J=3.21 Hz, 1H) 7.33 (dd, J=3.19 Hz, 1H), 7.49 (br, d, J=20 Hz,
1H), 7.58 (m, 1H), 7.66 (m, 2H), 8.46 (d, J=4 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 430. FAB High Resolution MS calculated m/z for
C.sub.21H.sub.21N.sub.3O.sub.4FS (M+H).sup.+: 430.1237. Observed
m/z: 430.1246.
Example 90
(2-Bromophenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl)piperazin--
1-ylcarbonyl)ethenyl)phenyl]sulfide
[0770] The title compound was prepared by the procedures described
in Example 1 substituting 2,4-dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with
t-butyl 1-piperazinecarboxylate, to give a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) d 1.48 (s, 9H), 3.49 (br s, 4H), 3.56-3.78
(m, 4H), 6.89 (d, J=15.6 Hz 1H), 7.10 (d, J=8.4 Hz, 1H), 7.18-7.35
(m, 3H), 7.49 (d, J=8.4 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.68 (dd,
J=2.1, 8.4 Hz, 1H), 7.85 (br s, 1H). MS (APCI.sup.-) (M+Cl).sup.-
at m/z 605, 607, 609. Anal. Calcd for
C.sub.25H.sub.26N.sub.2O.sub.3BrF.sub.- 3S.0.03 H.sub.2O: C, 52.50;
H, 4.59; N, 4.90. Found: C, 52.54; H, 4.71; N, 4.68.
Example 91
(2-(Pyrrolidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0771] The title compound was prepared by the procedures described
in Example 69 substituting the bromide from Example 12 with the
bromide from Example 90, to give a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.85 (s, 9H), 1.85 (br s, 4H),
3.32-3.55 (m, 8H), 3.55-3.78 (m, 4H), 6.76 (d, J=8.4 Hz, 1H), 6.82
(d, J=15.6 Hz, 1H), 7.23-7.45 (m, 5H), 7.61 (d, J=15.6 Hz, 1H),
7.75 (br s, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 562.
Example 92
(3-Carboxamidophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
Example 92A
(3-Carboxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0772] The title compound was prepared by the procedures described
in Example 32B substituting 2,4-dichlorothiophenol with
3-mercaptobenzoic acid.
Example 92B
(3-Carboxamidophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0773] To a stirred solution of benzoic acid from Example 92A (40
mg, 0.088 mmol) in 1 mL of anhydrous DMF with HOBT (15 mg, 0.097
mmol) was added EDAC (19 mg, 0.097 mmol), followed by ammonium
chloride (large excess). The pH of the solution was adjusted to 6
with addition of triethylamine. The resulting mixture was then
stirred at ambient temperature for 6 h. Water was added to quenched
the reaction. The product precipitated out after stirring for 30
min, which was then isolated by filtration and dried in vacuum oven
to give a light yellow solid (25 mg, 63% yield). .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.43-3.82 (m, 8H),
6.84 (d, J=8.7 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.53 (d, J=15.6
Hz, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.66 (t, J=7.65 Hz, 1H), 8.06 (d,
J=7.80 Hz, 1H), 8.12 (s, 2H), 8.67 (d, J=2.1 Hz, 1H). MS
(ESI.sup.-) (M+Na).sup.+ at m/z 477.
Example 93
(3-(Hydroxymethyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0774] To a stirred solution of benzoic acid from Example 92A (255
mg, 0.56 mmol) in 5 mL of anhydrous THF at 0.degree. C. was added
in turn Et.sub.3N (102 mL, 0.73 mmol) and ethyl chloroformate (70
mL, 0.73 mmol). After 60 min, the reaction mixture was filtered
through celite plug into a stirred solution of NaBH.sub.4 in water
at 0.degree. C. The resulting reaction mixture stirred at 0.degree.
C. for 2 b before it was extracted with EtOAc (2.times.20 mL). The
combined organic layers was washed with 3N HCl, brine, dried over
Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure.
The crude product was purified using Gilson Preparative HPLC as
described in Example 38B to give the title compound (80 mg, 32%
yield) as a light-yellow solid: .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.04 (s, 3H), 3.40-3.79 (m, 8H), 4.56 (s, 2H), 5.38 (br s,
1H), 6.85 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.52 (br s,
3H), 7.57 (br s, 2H), 7.91 (dd, J=2.1, 8.7 Hz, 1H), 8.66 (d, J=2.1
Hz, 1H). MS (APCI.sup.+) (M+NH.sub.4).sup.+ at m/z 459.
Example 94
Phenyl[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0775] The title compound was obtained as a reductive side product
from the reaction mixture described in Example 91, as a colorless
oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.49 (s, 9H),
3.43-3.56 (br s, 4H), 3.56-3.82 (m, 4H), 6.85 (d, J=15.6 Hz, 1H),
7.06 (d, J=8.4 Hz, 1H), 7.37-7.50 (m, 4H), 7.63 (d, J=15.6 Hz, 1H),
7.67 (d, J=8.4 Hz, 1H), 7.76 (d, J=11.7 Hz, 1H), 7.80 (s, 1H). MS
(APCI.sup.-) (M+Cl).sup.- at m/z 527.
Example 95
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-(tert-butoxy-
carbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0776] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.62 (d, 1H, J=15.0 Hz), 7.48 (d, 1H, J=7.2 Hz), 7.43 (m, 2H),
7.38 (d, 1H, J=8.1 Hz), 7.22 (m, 1H), 6.86 (d, 1H, J=15.4 Hz), 6.80
(d, 1H, J=8.4 Hz), 5.30 (br, 1H), 4.62 (br d, 2H, J=14.0 Hz), 3.89
(br m, 1H), 3.76 (s, 3H), 3.49 (dq, 1H, J.sub.1=J.sub.2=6.9 Hz),
3.12 (m, 2H), 2.94 (br, 1H), 1.46 (s, 9H), 1.17 (d, 6H, J=6.6 Hz).
MS (ESI) m/z -591, -627, -677.
Example 96
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-methylaminocarbonyl)-4-te-
rt-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0777] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 1.38 (s, 9H); 2.83-3.85 (br m, 5H); 4.09-4.51 (br m,
4H); 4.91-5.09 (br m, 1H); 6.64 (d, J=8.5 Hz, 1H): 7.12-7.62 (m,
8H); 7.82-7.96 (m, 1H); 8.26-8.48 (m, 2H); 8.63-8.75 (m, 2H). MS
(APCI) (M+H).sup.+ at m/z 646. Anal calcd for
C.sub.34H.sub.39N.sub.5S.sub.1O.sub.6: C, 63.24; H, 6.09; N, 10.84.
Found: C, 63.07; H, 6.43; N, 10.54.
Example 97
(2-Ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]su-
lfide
Example 97A
2-Ethoxybenzenethiol
[0778] To 7.82 g of ethoxybenzene and 7.41 g of
tetramethylethylenediamine in 75 ml ether, cooled in an ice bath, a
solution of 25.6 ml of a 2.5 M n-butyllithium solution in hexane,
was added dropwise under a nitrogen atmosphere. The mixture was
stirred for 1 hour at room temperature and then cooled to -65
degrees. Sulfur (2.28 g) was added in portions. The mixture was
stirred for 3 hours at room temperature and then cooled in ice.
LiAlH.sub.4 (0.6 g) was added and the mixture was stirred 1 hour at
room temperature. The mixture was again cooled in ice while 5 ml
water was added dropwise followed by 15% HCl in water until all
salts. The aqueous phase was separated and washed with ether. The
combined ether layers was washed with HCl, then water. After drying
with Na.sub.2SO.sub.4, the ether was evaporated to give 9.66 g of
product. NMR analysis showed 70% pure material with 30% of a diaryl
sulfide impurity. This mixture was carried forward to the next
step.
Example 97B
(2-Ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]su-
lfide
[0779] The title compound was prepared according to the procedures
of Example 1, substituting the thiol of Example 97A, giving a white
solid, m.p. 125-127 C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
1.25 (t, J=7 Hz, 3H), 3.60-3.78 (m, 8H), 4.05 (q, J=7 Hz, 2H), 6.76
(d, J=15 Hz, 1H), 6.82 (d, J=9H, 1H), 6.94-7.00 (m, 2H), 7.16 (dd,
J=9 Hz, 2 Hz, 1H), 7.34-7.45 (m, 2H), 7.54 (d, J=2 Hz, 1H), 7.58
(d, J=15 Hz, 1H). Anal. Calcd. for C.sub.21H.sub.22ClNO.sub.3S: C,
62.44; H, 5.49; N, 3.47. Found: C, 62.14; H, 5.70; N, 3.22.
Example 98
(2-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0780] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
2-methoxythiophenol, giving a yellow solid (40 mg, 77%).
.sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.14 (s, 3H), .delta.
3.54 (br, m, 2H), .delta. 3.68 (br, m, 6H), 63.79 (s, 3H), 86.81
(d, J=21 Hz, 1H), 66.89 (d J=39 Hz, 1H), .delta. 7.03 (d, J=21 Hz,
1H), .delta. 7.08 (m, 1H), .delta. 7.41 (br, d. J=21 Hz, 1H),
.delta. 7.53 (m, 1H), .delta. 7.60 (m, 1H), .delta. 7.65 (br, s,
1H), .delta. 8.42 (br, s, 1H). MS (APCI) (M+H)+ at m/z 442.
Example 99
(2-(Azetidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl)-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0781] The title compound was prepared by the procedures described
in Example 69 substituting pyrrolidine with azetidine
hydrochloride, and the bromide from Example 12 with bromide from
Example 90, giving a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.48 (s, 9H), 2.18 (pentet, J=7.43 Hz, 2H), 3.40-3.53 (m,
4H), 3.53-3.77 (m, 4H), 4.02 (t, J=7.43 Hz, 4H), 6.54 (d, J=8.7 Hz,
1H), 6.72 (d, J=8.7 Hz, 1H), 6.78 (tt, J=1.5, 7.35 Hz, 1H), 6.81
(d, J=15.6 Hz, 1H), 7.29-7.42 (m, 3H), 7.61 (d, J=15.6 Hz, 1H),
7.75 (br s, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 548.
Example 100
(2-(Piperidin-1-yl)phenyl)[2-trifluoromethyl-4-(E-((4-(tert-butoxycarbonyl-
)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0782] The title compound was prepared by the procedures described
in Example 69 substituting pyrrolidine with piperidine, and the
bromide from Example 12 with bromide from Example 90, and isolated
as a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.48
(s, 9H), 1.54 (br s, 6H), 2.96 (br s, 4H), 3.48 (br s, 4H),
3.55-3.78 (m, 4H), 6.86 (d, J=15.6 Hz, 1H), 6.99 (td, J=1.8, 7.5
Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.19 (dd, J=1.8, 8.1 Hz, 1H), 7.25
(br m, 1H), 7.31 (td, J=1.8, 7.5 Hz, 1H), 7.42 (dd, J=1.8, 8.4 Hz,
1H), 7.65 (d, J=15.6 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H). MS
(APCI.sup.+) (M+H).sup.+ at m/z 576.
Example 101
(3-Chloro-2-formylphenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0783] The title compound was prepared by the procedures described
in Example 65B substituting 2,3-dichlorobenzaldehyde with
2,6-dichlorobenzaldehyde, isolated as a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.05 (s, 3H), 3.56 (br s, 2H),
3.61-3.86 (m, 6H), 6.68 (q, J=3.0 Hz, 1H), 6.93 (d, J=15.6 Hz, 1H),
7.23 (d, J=3.0 Hz, 1H), 7.25 (m, 1H), 7.45 (dd, J=2.1, 8.4 Hz, 1H),
7.62 (d, J=8.4 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H), 7.69 (d, J=2.1 Hz,
1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 463, 465, 467.
Example 102
(2-Trifluoromethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[0784] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.84 (s,
1H), 7.80 (m, 1H), 7.66 (d, 1H, J=15.4 Hz), 7.49 (m, 3H), 7.40 (m,
1H), 7.06 (d, 1H, J=8.0 Hz), 6.87 (d, 1H, J=15.4 Hz), 3.62-3.80 (m,
6H), 3.53 (m, 1H), 2.15 (s, 3H). MS (ESI) m/z 503, 525, 1027.
Example 103
(3-Bromophenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0785] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.83 (s,
1H), 7.66 (d, 1H, J=15.4 Hz), 7.57 (t, 1H, J=1.9 Hz), 7.49 (m, 2H),
7.36 (dt, 1H, J=1.6, 7.8 Hz), 7.24 (m, 1H), 7.18 (d, 1H, J=8.1 Hz),
6.87 (d, 1H, J=15.2 Hz), 3.62-3.82 (m, 6H), 3.54 (m, 2H), 2.15 (s,
3H). MS (ESI) m/z 514, 515, 535, 537.
Example 104
(3,5-Dimethylphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0786] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.64 (d, 1H, J=15.1 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.49 (m, 2H),
7.13 (s, 2H), 7.04 (s, 2H), 6.84 (d, 1H, J=15.2 Hz), 3.62-3.82 (m,
6H), 3.54 (m, 2H), 2.32 (s, 6H), 2.15 (s, 3H). MS (ESI) m/z 463,
485, 925, 947.
Example 105
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-(pyridine-4-c-
arbonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0787] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-3.83 (br m, 10H); 4.04-4.66 (br m, 3H);
5.32-5.43 (br m, 1H); 6.60-6.69 (m, 1H); 7.15-7.64 (m, 8H);
7.85-7.93 (m, 1H); 8.59-8.72 (m, 3H). MS (APCI) (M+H).sup.+ at m/z
588. Anal calcd for
C.sub.31H.sub.33N.sub.5S.sub.1O.sub.5.0.67H.sub.2O: C, 62.07; H,
5.77; N, 11.68. Found: C, 62.13; H, 6.01; N, 11.48.
Example 106
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-carbomethoxyp-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0788] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-3.83 (br m, 14H); 4.16-4.63 (br m, 2H); 4.98
(br s, 1H); 6.60-6.69 (m, 1H); 7.20-7.61 (m, 6H); 7.85-7.93 (m,
1H); 8.59-8.65 (m, 1H). MS (APCI) (M+H).sup.+ at m/z 541.
Example 107
(2-Isopropylphenyl)[2-nitro-4-(E-((3-dimethylaminocarbonyl-4-acetylpiperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0789] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 1.88, 2.04 (s, s, 3H); 2.50-3.83 (br m, 1H);
4.16-4.59 (br m, 2H); 5.04-5.25 (br m, 1H); 6.60-6.69 (m, 1H);
7.21-7.62 (m, 6H); 7.85-7.93 (m, 1H); 8.58-8.65 (m, 1H). MS (APCI)
(M+H).sup.- at m/z 525. Anal calcd for
C.sub.27H.sub.32N.sub.4S.sub.1O.sub.5: C, 61.81; H, 6.15; N, 10.68.
Found: C, 61.93; H, 6.75; N, 9.67.
Example 108
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-morpholinocarbonyl)-4-tert-butoxyc-
arbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0790] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.11-1.16
(br m, 6H); 1.35, 1.40 (br s, br s, 9H); 2.67-5.0 (br m, 16H);
6.60-6.69 (m, 1H), 7.28-7.62 (m, 6H); 7.87-7.92 (m, 1H); 8.63-8.67
(br m, 1H). MS (APCI) (M+H).sup.+ at m/z 625. Anal calcd for
C.sub.32H.sub.40N.sub.4S.sub.1O.su- b.7: C, 61.52; H, 6.45; N,
8.97. Found: C, 61.10; H, 6.65; N, 8.60.
Example 109
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-4-methylaminocarbonyl)piper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0791] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-4.46 (br m, 10H) 6.63 (d, J=8.5 Hz, 1H);
7.20-7.64 (m, 8H); 7.85-7.93 (m, 1H); 8.43-8.65 (m, 4H). MS (APCI)
(M+H).sup.+ at m/z 546. Anal calcd for
C.sub.29H.sub.31N.sub.5S.sub.1O.sub.4.0.46CH.sub.3COOCH.su-
b.2CH.sub.3: C, 63.20; H, 5.96; N, 11.95. Found: C, 63.29; H, 6.27;
N, 11.97.
Example 110
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-dimethylaminocarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0792] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-3.20 (br m, 4H); 2.82 (s, 3H); 3.04 (s, 3H);
3.26-3.49 (m, 1H); 3.52-3.59 (m, 1H); 4.08-4.47 (br m, 2H); 6.63
(d, J=8.5 Hz, 1H); 7.31-7.62 (m, 6H); 7.86-7.92 (m, 1H); 8.61 (br
m, 1H). MS (APCI) (M+H).sup.+ at m/z 483. Anal calcd for
C.sub.25H.sub.30N.sub.4S.sub.1O.su-
b.4.0.39CH.sub.3COOCH.sub.2CH.sub.3: C, 61.71; H, 6.46; N, 10.84.
Found: C, 61.96; H, 6.69; N, 10.73.
Example 111
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(benzylaminocarbonyl)-4-tert-butoxyca-
rbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0793] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 1.33, 1.42 (br s, br s, 9H), 2.75-4.77 (br m, 10H);
6.60-6.66 (br m, 1H); 7.02-7.94 (br m, 12H); 8.47-8.67 (m, 2H). MS
(APCI) (M+H).sup.+ at m/z 645.
Example 112
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-tert-butoxy-
carbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0794] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 1.35, 1.40 (br s, br s, 9H) 2.50-4.99 (br m, 14H);
6.60-6.69 (m, 1H); 7.21-7.62 (m, 6H); 7.86-7.92 (m, 1H); 8.59-8.63
(br m, 1H). MS (APCI) (M+H).sup.+ at m/z 583. Anal calcd for
C.sub.30H.sub.38N.sub.4S.su- b.1O.sub.6.0.21C.sub.6H.sub.14: C,
62.50; H, 6.87; N, 9.32. Found: C, 62.28; H, 7.15; N, 9.11.
Example 113
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-hydroxymethyl-pyrrolidin-2-on-1-yl)p-
rop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0795]
(2-Bromophenyl)[2-chloro-4-(2-carboxy-E-ethenyl)phenyl]sulfide was
prepared by the procedures described in Example 1 substituting 2,4
dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde
with 3,4 dichlorobenzaldehyde.
1-(3-aminopropyl)-5-((S)-thexyldimethylsilyloxymeth-
yl)-2-pyrrolidinone (0.2818 g, 0.8959 mmol) was added to a solution
of this cinnamic acid (0.3312 g, 0.8959 mmol),
1-[3-(dimethylamino)propyl]-3- -ethyl carbodiimide hydrochloride
(0.3435 g, 1.79 mmol), and 1-hydroxybenzotriazole hydrate (0.1816
g, 1.34 mmol) in DMF (4.0 mL). After stirring for 12 h the reaction
mixture was diluted with EtOAc (250 mL), extracted with sat.
NH.sub.4Cl (1.times.75 mL), extracted with H.sub.2O (2.times.75
mL), rinsed with brine (75 mL), and dried over Na.sub.2SO.sub.4.
The resultant thexyldimethylsilyl alcohol was purified by flash
chromatography (EtOAc) on silica gel (0.4974 g, 83%).
Tetrabutylammonium fluoride (0.68 mL of 1.0 M solution in THF) was
added dropwise to a solution of this protected alcohol (0.4544 g,
0.682 mmol) in THF (1.7 mL). After 2 h the reaction was diluted
with EtOAc (50 mL) and extracted with sat. NH.sub.4Cl (1.times.25
mL), extracted with H.sub.2O (2.times.25 mL), rinsed with brine (25
mL), and dried over Na.sub.2SO.sub.4. Flash chromatography
(EtOAc.fwdarw.9:1 CH.sub.2Cl.sub.2:MeOH) on silica gel yielded the
title compound (0.3144 g, 88 %). .sup.1H-NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.14 (t, J=5.5 Hz, 1H), 7.81 (m, 2H), 7.53 (dd, J=8.3,
1.7 Hz, 1H), 7.44 dt, J=7.7, 1.5, 1H), 7.40 (dt, J=7.7, 1.8, 1H),
7.39 (d, J=15.6 Hz, 1H), 7.28 (dd, J=7.7, 1.8 Hz, 1H), 7.05 (d,
J=8.1 Hz, 1H), 6.67 (d, J=15.6 Hz, 1H), 4.84 (t, J=5.1 Hz, 1H),
2.94-3.62 (m, 8H), 1.54-2.29 (m, 6H), MS(APCI) (M+H).sup.+ at m/z
523, 525, 527, 529.
Example 114
(2-Bromophenyl)[2-chloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)car-
bonyl)ethenyl)phenyl]sulfide
[0796] The title compound was prepared by the procedures described
in Example 1 substituting 2,4 dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with 3.4
dichlorobenzaldehyde, and 6-amino-1-hexanol with
1-(3-aminopropyl)-2-pyrrolidinone. .sup.1H-NMR (DMSO-d.sub.6, 300
MHz) .delta. 8.12 (t, J=5.9 Hz, 1H), 7.81 (m, 2H), 7.52 (dd, J=8.1,
2.0 Hz, 1H), 7.44 (dt, J=7.5, 1.4, 1H), 7.34 (dt, J=7.5, 2.0, 1H),
7.39 (d, J=15.8 Hz, 1H), 7.28 (dd, J=7.6, 1.9 Hz, 1H), 7.05 (d,
J=8.1 Hz, 1H), 6.67 (d, J=15.8 Hz, 1H), 4.02 (d, J=0.7 Hz, 1H),
3.29-3.35 (m, 2H), 3.11-3.25 (m, 4H), 2.21 (t, J=8.1 Hz, 1H), 1.94
(m, 2H), 1.64 (m, 2H), MS(APCI) (M+H).sup.+ at m/z 493, 495, 497,
499.
Example 115
(2-Bromophenyl)[2-chloro-4-(E-(N-methyl-N-(3-(pyrrolidin-2-on-1-yl)prop-1--
yl)amino)carbonyl)ethenyl)phenyl]sulfide
[0797] The title compound was prepared by the procedures described
in Example 1 substituting 2,4 dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with 3,4
dichlorobenzaldehyde, and 6-amino-1-hexanol with
1-(3methylaminopropyl)-2-pyrrolidinone. .sup.1H-NMR (DMSO-d.sub.6,
300 MHz) .delta. 8.06 (d, J=1.5 Hz, 1H), 7.80 (dd, J=7.7, 1.1 Hz,
1H), 7.64 (dd, J=8.5, 1.7 Hz, 1H), 7.25-7.46 (m, 5H), 7.04 (d,
J=8.1, 1.1, 1H), 3.14-5.30 (m, 6H), 3.14 (s, 1H), 2.91 (s, 2H),
2.19 (m, 2H), 1.92 (m, 2H), 1.68 (m, 2H), MS(APCI) (M+H).sup.+ at
m/z 507, 509, 511, 513.
Example 116
(2-[2-Methoxy]ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]etheny-
l)phenyl]sulfide
[0798] The title compound was prepared according to the procedures
of Example 97, substituting 2-methoxyethoxybenzene, giving a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.29 (s, 3H), 3.60
(t, J=7 Hz, 2H), 3.60-3.78 (m, 8H), 4.12 (t, J=7 Hz, 2H), 6.78 (d,
J=15 Hz, 1H), 6.82 (d, J=9H, 1H), 6.95-7.03 (m, 2H), 7.18 (dd, J=9
Hz, 2 Hz, 1H), 7.36-7.45 (m, 2H), 7.52 (d, J=2 Hz, 1H), 7.57 (d,
J=15 Hz, 1H). Anal. Calcd. for C.sub.22H.sub.24ClNO.sub.4S: C,
60.85; H, 5.57; N, 3.22. Found: C, 60.65; H, 5.59; N, 3.12.
Example 117
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(morpholinocarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0799] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-3.40 (br m, 6H); 3.42-3.64 (br m, 8H);
4.07-4.44 (br m, 2H); 4.08-4.47 (br m, 2H); 6.64 (d, J=8.5 Hz, 1H);
7.31-7.62 (m, 6H); 7.87-7.92 (m, 1H); 8.61 (br m, 1H). MS (APCI)
(M+H).sup.+ at m/z 525. Anal calcd for
C.sub.27H.sub.32N.sub.4S.sub.1O.sub.5.1.57H.sub.2O: C, 58.64; H,
6.41; N, 10.13. Found: C, 58.69; H, 6.36; N, 9.78.
Example 118
(2-Isopropylphenyl)[2-nitro-4-(E-((4-tert-butoxycarbonylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
[0800] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.41 (s, 9H); 3.30-3.40 (m, 1H); 3.50-3.72 (br m,
8H); 6.64 (d, J=8.5 Hz, 1H); 7.34-7.62 (m, 6H); 7.87-7.92 (dd,
J=8.5, 1.5 Hz, 1H); 8.65 (d, J=1.5 Hz, 1H). MS (APCI) (M+H).sup.+
at m/z 512. Anal calcd for C.sub.27H.sub.33N.sub.3S.sub.1O.sub.5:
C, 63.38; H, 6.50; N, 8.21. Found: C, 63.69; H, 6.62; N, 7.87.
Example 119
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methoxycarbonylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[0801] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 3.62 (s, 3H); 3.30-3.38 (m, 1H); 3.38-3.72 (br m,
8H); 6.64 (d, J=8.8 Hz, 1H); 7.34-7.62 (m, 6H); 7.87-7.92 (dd,
J=8.8, 2.0 Hz, 1H); 8.64 (d, J=2.0 Hz, 1H). MS (APCI) (M+H).sup.+
at m/z 470. Anal calcd for
C.sub.27H.sub.32N.sub.3S.sub.1O.sub.5.0.34C.sub.6H.sub.14: C,
62.77; H, 6.27; N, 8.44. Found: C, 62.70; H, 6.33; N, 8.27.
Example 120
(2-Isopropylphenyl)[2-nitro-4-(E-(4-(pyridine-4-carbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0802] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 3.30-3.40 (m, 1H); 3.52-3.86 (br m, 8H); 6.61-6.66
(br m, 1H); 7.30-7.62 (m, 8H); 7.83-7.96 (br m, 1H); 8.60-8.71 (m,
3H). MS (APCI) (M+H).sup.+ at m/z 517. Anal calcd for
C.sub.28H.sub.28N.sub.4S.sub.1O.su-
b.4.0.38CH.sub.3COOCH.sub.2H.sub.3: C, 64.46; H, 5.69; N, 10.19.
Found: C, 64.52; H, 5.94; N, 10.21.
Example 121
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-3-methylaminocarbonyl)-4-te-
rt-butoxycarbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0803] Yellow solid; .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
1.14 (d, J=6.8 Hz, 6H); 1.31-1.46 (br m, 9H); 3.30-3.41 (m, 1H);
3.15-4.78 (br m, 9H); 6.61-6.67 (br m, 1H); 7.05-7.95 (br m, 9H);
8.20-8.65 (br m, 4H). MS (APCI) (M+H).sup.+ at m/z 646. Anal calcd
for C.sub.34H.sub.39N.sub.5S.su- b.1O.sub.6.0.13H.sub.2O: C, 62.97;
H, 6.49; N, 10.79. Found: C, 62.66; H, 6.26, N, 10.60.
Example 122
(2-Isopropylphenyl)[2-nitro-4-E-((3-(pyridine-2-methylaminocarbonyl)pipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0804] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 3.30-3.41 (m, 1H); 2.50-4.46 (br m, 9H); 6.64 (d,
J=8.5 Hz, 1H); 7.21-7.93 (br m, 10H); 8.45-8.65 (br m, 3H). MS
(APCI) (M+H).sup.+ at m/z 546.
Example 123
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(pyridine-3-methylaminocarbonyl)piper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0805] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.50-4.41 (br m, 10H); 6.61-6.67 (br m, 1H);
7.26-7.70 (br m, 8H); 7.86-7.94 (br m, 1H); 8.40-8.67 (br m, 4H).
MS (APCI) (M+H).sup.+ at m/z 546.
Example 124
(4-Hydroxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0806] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
4-hydroxythiophenol. Yellow solid (23 mg, 45%). .sup.1H-NMR
(Pyridine-d.sub.5, 500 MHz) .delta. 2.08 (s, 3H), 3.42 (br, m, 2H),
3.76 (br, m, 6H), 7.01 (d, J=17 Hz, 1H), 7.26 (m, 2H), 7.37 (d,
J=31 Hz, 1H), 7.59 (m, 3H), 8.02 (d, J=31 Hz, 1H), 8.60 (d, J=4 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 428. FAB High Resolution MS
calculated m/z for C.sub.21H.sub.22N.sub.3O.sub.5S (M+H).sup.+:
428.1280. Observed m/z: 428.1296.
Example 125
(3,5-Dichlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0807] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
3,5-dichlorothiophenol. Yellow solid (12 mg, 21%); .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.04 (s, 3H), 3.43 (br, m, 2H), 3.62
(br, m, 6H), 6.82 (d, J=22 Hz, 1H), 6.82 (d, J=38 Hz, 1H), 7.37 (s,
1H), 7.38 (s, 1H), 7.40 (m, 1H), 7.43 (dd, J=3, 21 Hz, 1H), 7.55
(d, J=38 Hz, 1H), 8.29 (d, J=4 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 480. FAB High Resolution MS calculated m/z for
C.sub.21H.sub.20N.sub.3O.sub.4Cl.sub.2S (M+H).sup.+: 480.0552.
Observed m/z: 480.0553.
Example 126
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-acetoxymethyl-2-pyrrolidin-2-on-1-yl-
)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0808] To a solution of the compound of Example 113 (0.0466 g,
0.0889 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was added triethylamine
(0.024 mL, 0.18 mmol) and acetic anhydride (0.0088 mL, 0.0933
mmol). After 12 h the reaction was diluted with MeOH (1.5 mL) and
purified by preparative HPLC to provide the title compound (0.0458
g, 91%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.14 (t, J=5.7
Hz, 1H), 7.80 (m, 2H), 7.53 (dd, J=8.5, 1.5 Hz, 1H), 7.45 (dt,
J=7.7, 1.5, 1H), 7.35 (dt, J=7.7, 1.8, 1H), 7.399 (d, J=15.6 Hz,
1H), 7.29 (dd, J=7.7, 1.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.67 (d,
J=15.6 Hz, 1H), 4.20 (dd, J=11.8, 3.7 Hz, 1H), 4.03 (dd, J=11.8,
4.0 Hz, 1H), 3.85 (m, 1H), 3.45 (m, 2H), 3.15 (m, 2H), 2.95 (m,
2H), 2.00-2.48 (m, 2H), 2.02 (s, 3H), 1.51-1.82 (m, 2H), MS(APCI)
(M+H).sup.+ at m/z 565, 567, 569, 571.
Example 127
(2-Bromophenyl)[2-chloro-4-(E-((3-(5S-methoxymethyl-pyrrolidin-2-on-1-yl)p-
rop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0809] Sodium hydride (0.0088 g, 0.22 mmol, 60% dispersion) was
added to a solution of the compound of Example 113 (0.0524 g, 0.1
mmol) in DMF (0.5 mL). After 15 min, iodomethane (0.025 mL, 0.4
mmol) was added and the reaction was stirred for 12 h. The reaction
was diluted with EtOAc (7 mL) and extracted with sat. NH.sub.4Cl
(1.times.2.5 mL), extracted with H.sub.2O (2.times.2.5 mL), rinsed
with brine (2.5 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The crude products were diluted with MeOH
(1.5 mL) and purified by preparative HPLC to provide the title
compound (0.0408 g, 74%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.07 (2, 1H), 7.80 (dd, J=7.9.1.3 Hz, 1H), 7.64 (dd, J=8.3,
1.6 Hz, 1H), 7.23-7.46 (m, 5H), 7.04 (d, J=8.1, 1H), 3.74 (m, 1H),
4.4-3.52 (m, 6H), 3.27 (s, 1.5H), 3.22 (s, 1.5H), 3.14 (s, 1.5H),
2.91 (s, 1.5H), 1.5-2.3 (m, 6H), MS(APCI) (M+H).sup.+ at m/z 551,
553, 555.
Example 128
(2-Bromophenyl)[2-chloro-4-(E-((3-(4R-hydroxymethyl-pyrrol
idin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0810] The title compound was prepared by the procedures described
for Example 113 substituting
1-(3-aminopropyl)-5-((S)-thexyldimethylsilyloxym-
ethyl)-2-pyrrolidinone with
1-(3-aminopropyl)-4-((R)-thexyldimethylsilylox- y)-2-pyrrolidinone.
.sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.13 (t, J=5.5 Hz, 1H),
7.80 (m, 2H), 7.53 (dd, J=8.5, 1.7 Hz, 1H), 7.27-7.44 (m, 4H), 7.05
(d, J=8.1 Hz, 1H), 6.67 (d, J=15.8 Hz, 1H), 5.19 (d, J=3.7 Hz, 1H),
4.28 (br s, 1H), 3.10-3.62 (m, 8H), 2.06 (dd, 1H), 1.63 (m, 1H),
MS(APCI) (M+H).sup.+ at m/z 509, 511, 513.
Example 129
Phenyl[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfi-
de
[0811] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with thiophenol.
Yellow solid (36 mg, 73%); .sup.1H-NMR (CDCl.sub.3, 400 MHz)
.delta. 2.20 (s, 3H), 3.59 (br, m, 2H), 3.78 (br, m, 6H), 6.92 (d,
J=21 Hz, 1H), 6.95 (d, J=39 Hz, 1H), 7.49 (br, d, J=21 Hz, 1H),
7.56 (m, 3H), 7.65 (m, 2H), 7.69 (d, J=38 Hz, 1H), 8.46 (d, J=4 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 412. FAB High Resolution MS
calculated m/z for C.sub.21H.sub.22N.sub.3O.sub.4S (M+H).sup.+:
412.1331. Observed m/z: 412.1342.
Example 130
(2-Dimethylaminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0812] To a stirred solution of aniline from Example 47 (21 mg,
0.049 mmol) in 1 mL of ethanol was added Me.sub.2SO.sub.4 (14.0 mL,
0.15 mmol) followed by sat. Na.sub.2CO.sub.3 (25 mL). The mixture
was then refluxed for one day. The reaction mixture was allowed to
cool down to ambient temperature, partitioned between EtOAc and
water. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure.
The residue was then purified on a Gilson Preparative HPLC as
described in Example 38B to give the title compound (10 mg, 45%
yield), as a light yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.16 (s, 3H), 2.83 (s, 3H), 3.32 (br s, 3H), 3.47-3.85 (m,
8H), 6.75 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4
Hz, 1H), 6.89 (d, J=15.6 Hz, 1H), 7.40-7.51 (m, 3H), 7.64 (d,
J=15.6 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+
at m/z 454.
Example 131
(3-((2-Hydroxyethyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4-acetylpiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0813] The title compound was prepared by the procedures described
in Example 92B, substituting ammonium chloride with ethanolamine,
to give a light yellow solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.04 (s, 3H), 3.30-3.79 (m, 12H), 4.75 (t, J=5.7 Hz, 1H)
6.85 (d, J=8.7 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz
1H), 7.66 (t, J=7.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.92 (dd,
J=2.1, 8.1 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 8.62 (t,
J=5.7 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H). MS (APCI.sup.-) (M+Cl).sup.-
at m/z 533, 535.
Example 132
(3-((3-(1-Imidazolyl)propyl)aminocarbonyl)phenyl)[2-nitro-4-(E-((4-acetylp-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0814] The title compound was prepared by the procedures described
in Example 92B, substituting ammonium chloride with
3-aminopropyl-1-imidazol- e, as a light yellow solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) d 1.96 (quintet. J=6.98 Hz, 2H), 2.04 (s,
3H), 3.24 (q, J=6.98 Hz, 2H), 3.35-3.95 (m, 8H), 4.02 (t, J=6.98
Hz, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 7.19 (s, 1H), 7.41
(d, J=15.6 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.64 (s, 1H), 7.68 (d,
J=7.8 Hz, 1H), 7.79 (dt, J=1.8, 7.8 Hz, 1H), 7.91 (dd, J=1.8, 8.7
Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 8.09 (t, J=1.8 Hz, 1H), 8.65 (d,
J=1.8 Hz, 1H). MS (APCI.sup.-) (M+Cl).sup.- at m/z 597, 599.
Example 133
(3-((2-(1-Morpholinyl)ethyl)aminocarbonyl)phenyl)[2-nitro-4-(E-([4-acetylp-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0815] The title compound was prepared by the procedures described
in Example 92B, substituting ammonium chloride with
2-aminoethyl-1-morpholin- e, as a light yellow solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 2.44 (br s, 4H),
3.20-3.80 (m, 16H), 6.87 (d, J=8.4 Hz, 1H), 7.41 (d, J=15.6 Hz,
1H), 7.54 (d, J=15.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.79 (d,
J=8.4 Hz, 1H), 7.91 (dd, J=2.1, 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz,
1H), 8.07 (s, 1H), 8.58 (t, J=6.0 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H).
MS (APCI.sup.+) (M+H).sup.+ at m/z 568.
Example 134
(2-isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-tert-butoxycarbonylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0816] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.41 (s, 9H); 2.62-3.20 (br m, 4H); 3.30-3.40 (m,
1H); 3.72-4.44 (br m, 4H); 4.72-4.98 (br m, 1H); 6.62-6.66 (br m,
1H); 7.25-7.63 (m, 6H); 7.83-7.93 (br m, 1H); 8.57-8.66 (br m, 1H).
MS (APCI) (M+H).sup.+ at m/z 542. Anal calcd for
C.sub.28H.sub.35N.sub.3S.sub.1O.sub.6.0.21C.sub.6H.su- b.14: C,
62.78; H, 6.83; N, 7.51. Found: C, 62.65; H, 6.99; N, 7.36.
Example 135
(2-Isopropylphenyl)[2-nitro-4-(E-((4-formylpiperazin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide
[0817] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.1 Hz, 6H); 3.30-3.38 (m, 1H); 3.38-3.77 (br m, 8H); 6.64 (d,
J=8.5 Hz, 1H), 7.34-7.62 (m, 6H); 7.88-7.92 (dd, J=8.5, 1.7 Hz,
1H); 8.08 (s, 1H); 8.65 (d, J=1.7 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 440. Anal calcd for C.sub.23H.sub.25N.sub.3S.sub.1O.sub.4: C,
62.85; H, 5.73; N, 9.56. Found: C, 63.05; H, 5.98; N, 9.47.
Example 136
(2-Isopropylphenyl)[2-nitro-4-(E-((2-hydroxymethyl-4-tert-butoxycarbonylpi-
perazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0818] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H), 1.41 (s, 9H); 2.72-3.50 (br m, 4H); 3.30-3.40 (m,
1H); 3.85-4.52 (br m, 4H); 4.74-4.91 (br m, 1H); 6.62-6.66 (br m,
1H); 7.28-7.62 (m, 6H); 7.81-7.91 (br m, 1H); 8.57-8.66 (br m, 1H).
MS (APCI) (M+H).sup.+ at m/z 542. Anal calcd for
C.sub.28H.sub.35N.sub.3S.sub.1O.sub.6.0.17C.sub.6H.su- b.14: C,
62.65; H, 6.77; N, 7.55. Found: C, 62.54; H, 6.83; N, 7.33.
Example 137
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide
[0819] The title compound was prepared according to the procedures
of Example 97. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.25 (t,
J=7 Hz, 6H), broad peaks totaling 9 protons at 1.50-1.62,
1.65-1.92, 2.01-2.15, 2.45-2.55, 2.95-3.05, 3.13-3.30, 3.55-3.68,
3.90-4.10, 4.05 (q, J=7 Hz, 2H), 4.15 (q, J=7 Hz, 2H), 6.84 (d, J=9
Hz, 1H), 6.80-6.95 (broad, 1H), 6.94-6.99 (m, 2H), 7.18 (dd, J=9
Hz, 2 Hz, 1H), 7.34-7.41 (m, 2H), 7.52 (d, J=15 Hz, 1H), 7.55 (d,
J=2 Hz, 1H). Anal. Calcd. for C.sub.25H.sub.28ClNO.sub.4S: C,
63.35; H, 5.95; N, 2.95. Found: C, 63.17; H, 6.02; N, 26.02; N,
2.81.
Example 138
(3-Aminophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)phe-
nyl]sulfide
[0820] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
3-aminothiophenol. Yellow solid (2.9 mg, 5.6%); .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 2.20 (s, 3H), 3.60 (br, m, 2H), 3.77
(br, m, 6H), 4.03 (br, s, 2H), 6.85 (dd, J=4, 16 Hz, 1H), 6.90 (m,
3H), 7.04 (d, J=17 Hz, 1H), 7.30 (t, J=16 Hz, 1H), 7.52 (d, J=17
Hz, 1H), 7.68 (d, J=31 Hz, 1H), 8.44 (d, J=4 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 427. FAB High Resolution MS calculated m/z for
C.sub.21H.sub.23N.sub.4O.sub.4S (M+H).sup.+: 427.1440. Observed
m/z: 427.1440.
Example 139
(4-Aminophenyl)[2-nitro-4-(E-((4-acetyl]piperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0821] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
4-aminothiophenol. Yellow solid (2.5 mg, 4.9%): .sup.1H-NMR
(CDCl.sub.3, 500 MHz) .delta. 2.19 (s, 3H), 3.58 (br, m, 2H), 3.76
(br, m, 6H), 4.03 (br, s, 2H), 6.80 (m, 1H), 6.93 (m, 3H), 7.37 (m,
1H), 7.46 (d, J=17 Hz, 1H), 7.67 (d, J=31 Hz, 1H), 8.43 (d, J=3 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 427. FAB High Resolution MS
calculated m/z for C.sub.21H.sub.23N.sub.4O.sub.4S (M+H).sup.+:
427.1440. Observed m/z: 427.1441.
Example 140
(2,4-Dimethylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0822] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
2,4-dimethylthiophenol. Yellow solid (40 mg, 76%); .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 1.54 (br, s, 2H), 2.14 (s, 3H), 3.53
(br, m, 2H), 3.71 (br, m, 6H), 6.58 (d, J=21 Hz, 1H), 6.76 (d, J=38
Hz, 1H), 7.03 (m, 1H), 7.09 (m, 1H), 7.28 (br, d, J=19 Hz, 1H),
7.33 (d, J=20 Hz, 1H), 7.51 (d, J=38 Hz, 1H) 8.30 (d, J=5 Hz, 1H).
MS (APCI) (M+H).sup.+ at m/z 440. FAB High Resolution MS calculated
m/z for C.sub.23H.sub.26N.sub.3O.sub.4S (M+H).sup.+: 440.1644.
Observed m/z: 440.1656.
Example 141
(2,5-Dimethylphenyl)[2-nitro-4-(E-((4-acetyl]piperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0823] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
2,5-dimethylthiophenol. Yellow solid (34 mg, 64%); .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.07 (s, 3H), 2.23 (s, 3H), 2.28 (s;
3H), 3.46 (br, m, 2H), 3.64 (br, m, 6H), 6.65 (d, J=21 Hz, 1H),
6.81 (d, J=39 Hz, 1H), 7.19 (m, 2H), 7.34 (m, 2H), 7.56 (d, J=38
Hz, 1H), 8.35 (d, J=5 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 440.
FAB High Resolution MS calculated m/z for
C.sub.23H.sub.26N.sub.3O.sub.4S (M+H).sup.+: 440.1644. Observed
m/z: 440.1656.
Example 142
(4-Methoxyphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0824] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
4-methoxythiophenol. Yellow solid (44 mg, 83%); .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.09 (s, 3H), 3.48 (br, m, 2H), 3.66
(br, m, 6H), 3.83 (s, 3H), 6.79 (d, J=22 Hz, 1H), 6.83 (d, J=40 Hz,
1H), 6.95 (m, 1H), 6.98 (m, 1H), 7.37 (br, d, J=20 Hz, 1H), 7.43
(m, 1H), 7.46 (m, 1H), 7.58 (d, J=38 Hz, 1H), 8.35 (d, J=4 Hz, 1H).
MS (APCI) (M+H).sup.+ at m/z 442. FAB High Resolution MS calculated
m/z for C.sub.22H.sub.24N.sub.3O.sub.5S (M+H).sup.+: 442.1437.
Observed m/z: 442.1434.
Example 143
(3-Chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[0825] The title compound was prepared by the procedures described
in Example 83 substituting 3,4-dimethylthiophenol with
3-chlorothiophenol. Yellow solid (43 mg, 80%). .sup.1H-NMR
(CDCl.sub.3, 400 MHz) .delta. 2.23 (s, 3H), 3.62 (br, m, 2H), 3.80
(br, m, 6H), 6.97 (d, J=21 Hz, 1H), 6.99 (d, J=39 Hz, 1H), 7.28 (d,
J=19 Hz, 1H), 7.57 (m, 3H), 7.675 (t, J=4 Hz, 1H), 7.73 (d, J=39 Hz
1H), 8.48 (d, J=4 Hz, 1H). FAB High Resolution MS calculated m/z
for C.sub.21H.sub.21N.sub.3O.sub.4ClS (M+H).sup.+: 446.0941.
Observed m/z: 446.0953.
Example 144
(2-Chloro
4,5-diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
Example 144A
(2-Chloro, 4-nitro,
5-aminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[0826] The title compound was prepared by the procedures described
in Example 65B substituting 2,3-dichlorobenzaldehyde with
4,5-dichloro-2-nitroaniline.
Example 144B
(2-Chloro,
4,5-diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0827] To a stirred solution of nitrobenzene from Example 144A (170
mg, 0.34 mmol) in 2 mL of EtOH was added SnCl.sub.2 (325 mg, 1.72
mmol). The mixture was then refluxed under nitrogen atmosphere for
2 h. The reaction was allowed to cool down to ambient temperature,
quenched with sat. NaHCO.sub.3, extracted with EtOAc (2.times.20
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The residue was then
purified on Gilson preparative HPLC as described in Example 38B to
give the title compound (70 mg, 44% yield) as a light yellow solid.
.sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.42-3.80
(m, 8H), 4.84 (s, 2H), 5.32 (s, 2H), 6.51 (d, J=8.4 Hz, 1H), 6.78
(d, J=8.4 Hz, 2H), 7.26 (d, J=15.6 Hz, 1H), 7.41 (d, J=15.6 Hz,
1H), 7.48 (d, J=8.4 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H). MS
(APCI.sup.+) (M+H).sup.+ at t/z 465, 467, 469, 471.
Example 145
(3,4-Diaminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0828] The title compound was prepared by the procedures described
in Example 144, substituting 4,5-dichloronitroaniline with
5-chloronitroaniline, resulting in a light brown solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.31-3.80 (m, 8H),
4.75 (s, 2H), 5.01 (s, 2H), 6.61 (t, J=4.2 Hz, 3H), 6.68 (s, 1H),
7.26 (d, J=15.6 Hz 1H), 7.40 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.4 Hz,
1H), 7.94 (s, 1H), MS (APCI.sup.+) (M+H).sup.+ atm/z 431, 433.
Example 146
(6-Chlorobenzimidazol-2-on-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0829] A mixture of dianiline from Example 144 (35 mg, 0.075 mmol)
and CDI (13 mg, 0.075 mmol) in THF was stirred at ambient
temperature for one day. Solvent was then removed under reduced
pressure. The crude product then purified on a Gilson preparative
HPLC as described in Example 38B to give the title compound (12 mg,
32% yield) as a white solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.04 (s, 3H), 3.40-3.80 (m, 8H), 6.63 (d, J=8.4 Hz, 1H),
7.11 (d, J=2.4 Hz, 1H), 7.12 (s, 1H), 7.23 (s, 1H), 7.32 (d, J=15.6
Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 8.03 (br
s, 1H). MS (APCI.sup.+) (M-CO+H).sup.+ at m/z 465, 467.
Example 147
(1-Methylindol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0830] The title compound was prepared by the procedures described
in 85, substituting 5-iodoindole with N-methyl-7-bromoindole,
giving a light brown solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.14 (s, 3H), 3.47-3.56 (m, 2H), 3.56-3.83 (m, 6H), 3.96
(s, 3H), 6.42 (d, J=8.4 Hz, 1H), 6.55 (d, J=3.6 Hz, 1H), 6.76 (d,
J=15.6 Hz, 1H), 6.99 (d, J=3.6 Hz 1H), 7.09 (dd, J=2.1, 8.4 Hz,
1H), 7.15 (t, J=7.65 Hz, 1H), 7.42 (dd, J=0.9, 7.5 Hz, 1H), 7.53
(d, J=1.8 Hz, 1H), 7.55 (dd, J=15.6 Hz, 1H), 7.77 (dd, J=0.9, 7.5
Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 454, 456.
Example 148
(2-Hydroxy,
4-aminophenyl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0831] The title compound was prepared by the procedures described
in Example 144, substituting 4,5-dichloronitroaniline with
5-chloronitrophenol, giving a light brown solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.41-3.80 (m, 8H),
5.09 (s, 2H), 6.61 (d, J=8.4 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.79
(s, 1H), 6.80 (dd, J=2.1, 7.8 Hz, 1H), 7.26 (d, J=15.6 Hz, 1H),
7.40 (d, J=15.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.94 (br s, 1H).
MS (APCI.sup.+) (M+H).sup.+ at m/z 432, 434.
Example 149
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methylpiperazin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide
[0832] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 2.19 (s, 3H); 2.25-2.36 (br m, 4H); 3.30-3.40 (m,
1H); 3.51-3.72 (br m, 4H); 6.63 (d, J=8.5 Hz, 1H); 7.24-7.63 (m,
6H); 7.88-7.92 (dd, J=8.8, 1.8 Hz, 1H); 8.64 (d, J=1.8 Hz, 1H). MS
(APCI) (M+H).sup.+ at m/z 426. Anal calcd for
C.sub.23H.sub.27N.sub.3S.sub.1O.sub.3.0.26H.sub.2O: C, 64.19; H,
6.45; N, 9.76. Found: C, 64.21; H, 6.59; N, 9.70.
Example 150
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyridine-2-carbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0833] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 3.30-3.40 (m, 1H); 3.51-3.83 (br m, 8H); 6.61-6.66
(br m, 1H); 7.30-7.65 (m, 8H), 7.83-7.97 (m, 2H); 8.57-8.67 (m,
2H). MS (APCI) (M+H).sup.- at m/z 517. Anal calcd for
C.sub.28H.sub.28N.sub.4S.sub.1O.su- b.4.0.45H.sub.2O: C, 64.07; H,
5.53; N, 10.67. Found: C, 64.04; H, 5.77; N, 10.97.
Example 151
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyridine-3-carbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0834] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 3.30-3.40 (m, 1H); 3.52-3.87 (br m, 8H); 6.64 (d,
J=8.5 Hz, 1H); 7.30-7.64 (m, 7H); 7.83-7.95 (m, 2H); 8.61-8.70 (m,
3H). MS (APCI) (M+H).sup.+ at m/z 517. Anal calcd for
C.sub.28H.sub.28N.sub.4S.sub.1O.su- b.4.0.42H.sub.2O: C, 64.16; H,
5.55; N, 10.69. Found: C, 64.18; H, 5.64; N, 10.59.
Example 152
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carbomethoxy-4-methoxycarbonylpiperaz-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0835] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.1 Hz, 6H); 2.70-3.95 (br m, 4H); 3.30-3.40 (m, 1H); 3.61, 3.61
(s, s, 3H); 3.65, 3.67 (s, s, 3H); 4.16-4.50 (br m, 2H); 5.08-5.39
(br m, 1H), 6.64 (dd, J=8.5, 5.1 Hz, 1H); 7.30-7.63 (m, 6H);
7.83-7.94 (m, 1H); 8.62-8.67 (m, 1H). MS (APCI) (M+H).sup.+ at m/z
528. Anal calcd for
C.sub.26H.sub.29N.sub.3S.sub.1O.sub.7.0.19C.sub.6H.sub.14: C,
59.94; H, 5.87; N, 7.72. Found: C, 59.87; H, 5.94; N, 7.59.
Example 153
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxy-4-methoxycarbonylpiperazin-1--
ylcarbonyl)ethenyl)phenyl]sulfide
[0836] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.70-3.95 (br m, 4H); 3.30-3.40 (m, 1H); 3.61.3.61
(s, s, 3H); 4.16-4.51 (br m, 2H); 5.01-5.28 (br m, 1H); 6.61-6.66
(m, 1H); 7.30-7.63 (m, 6H); 7.83-7.94 (m, 1H); 8.66 (br s, 1H). MS
(APCI) (M-H).sup.+ at m/z 512.
Example 154
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-methylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0837] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 2.25, 2.26 (s, s, 3H); 2.20-3.98 (br m, 8H), 3.57,
3.63 (s, s, 3H); 6.63 (d, J=8.5 Hz, 1H); 7.30-7.63 (m, 6H); 7.91
(dd, J=8.5, 1.5 Hz, 1H); 8.60-8.68 (br m, 1H). MS (APCI)
(M-H).sup.+ at m/z 484.
Example 155
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]ethenyl)-
phenyl]sulfide
[0838] The compound of Example 137 was hydrolyzed using an excess
of aqueous 10% NaOH in methanol, stirring overnight. The reaction
mixture was concentrated in vacuo, water was added, and the
solution was extracted with ether. The mixture was acidified; the
resultant solid was collected by filtration and dried overnight in
a vacuum oven, giving a while solid, m.p. 166-171 C. .sup.1H-NMR
(DMSO 300 MHz) .delta. 1.17 (t, J=7 Hz, 3H), broad peaks totaling 9
protons at 1.32-1.48, 1.51-1.78, 1.90-2.04, 2.25-2.50, 2.80-2.90,
2.95-3.17, 3.45-3.51, 3.95-4.19, 4.41-4.51, 4.06 (q, J=7 Hz, 1H),
6.80 (d, J=9 Hz, 1H), 7.01 (t, J=7 Hz, 1H), 7.15 (d, J=8 Hz, 1H),
7.26-7.40 (m, 2H), 7.40-7.48 (m, 1H), 7.51 (dd, J=9 Hz, 2 Hz, 1H),
7.99 (d, J=9 Hz, 1H). Anal. Calcd. for C.sub.23H.sub.24ClNO.sub.4S:
C, 61.94; H, 5.42; N, 3.14. Found: C, 61.75; H, 5.65; N, 3.15. The
resultant acid (303 mg, 0.631 mmol) was dissolved in 3 ml MeOH. A
KOH solution (8 mg, 0.595 mmol, of 87.6% KOH) in 1 ml MeOH was
added. The resulting solution was concentrated in vacuo, and 5 ml.
ether was added. The mixture was stirred for one hour to form a
powder, which was filtered and dried in the vacuum oven at 60 C to
yield 307 mg of a solid, water soluble product.
Example 155
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]ethenyl)-
phenyl]sulfide
[0839] The compound of Example 137 was hydrolyzed using an excess
of aqueous 110% NaOH in methanol, stirring overnight. The reaction
mixture was concentrated in vacuo, water was added, and the
solution was extracted with ether, giving a white solid, m.p.
166-171. .sup.1H NMR (DMSO, 300 MHz) .delta. 1.17 (t, J=7 Hz, 3H),
broad peaks totaling 9 protons at 1.32-1.48, 1.51-1.78, 1.90-2.04,
2.25-2.50, 2.80-2.90, 2.95-3.17, 3.45-3.51, 3.95-4.19, 4.41-4.51,
4.06 (q, J=7 Hz, 1H), 6.80 (d, J=9 Hz, 1H), 7.01 (t, J=7 Hz, 1H),
7.15 (d, J=8 Hz, 1H), 7.26-7.40 (m, 2H), 7.40-7.48 (m, 1H), 7.51
(dd, J=9 Hz, 2 Hz, 1H), 7.99 (d, J=9 Hz, 1H). Anal. Calcd. for
C.sub.23H.sub.24ClNO.sub.4S: C, 61.94; H, 5.42; N, 3.14. Found: C,
61.75; H, 5.65; N, 3.15. The resultant acid (303 mg, 0.631 mmol)
was dissolved in 3 ml MeOH. A KOH solution (38 mg, 0.595 mmol, of
87.6% KOH) in 1 ml MeOH was added. The resulting solution was
concentrated in vacuo, and 5 ml. ether was added. The mixture was
stirred for one hour to form a powder, which was filtered and dried
in the vacuum oven at 60 C to yield 307 mg of a solid, water
soluble product.
Example 156
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-ethoxycarbonylpiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide
[0840] The title compound was prepared according to the procedures
of Example 97. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.24 (t,
J=7 Hz, 3H), 1.28 (t, J=7 Hz, 3H), broad peaks totaling 9 protons
at 1.35-1.55, 1.65-1.80, 2.25-2.38, 3.33-3.45, 3.95-4.05,
4.15-4.28, 4.60-4.80, 5.44-5.50, 4.05 (q, J=7 Hz, 2H), 4.20 (q, J=7
Hz, 2H), 6.80-6.98 (m, 4H), 7.12-7.20 (m, 1H) 7.35-7.43 (m, 2H),
7.50-7.58 (m, 2H). Anal. Calcd. for C.sub.25H.sub.28ClNO.sub.4S: C,
63.35; H, 5.95; N, 2.95. Found: C, 63.51. H, 6.22; N, 2.61.
Example 157
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((1-(tert-butoxycarbonyl)-4-hydrox-
ypyrrolidin-3-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0841] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76 (s,
1H), 7.60 (d, 1H, J=15.1 Hz), 7.46 (dd, 1H, J=1.7, 7.5 Hz), 7.38
(m, 2H), 7.01 (d, 1H, J=15.4 Hz), 6.98 (d, 1H, J=7.8 Hz), 6.93 (d,
1H, J=8.3 Hz), 6.42 (d, 1H, J=15.0 Hz), 4.30 (br, 2H), 3.98 (q, 2H,
J=7.0 Hz), 3.87 (m, 1H), 3.71 (m, 1H), 3.33 (br, 2H), 1.47 (s, 9H),
1.17 (t, 3H, J=7.0 Hz). MS (ESI) m/z -551, -1103. Anal. Calcd for
C.sub.27H.sub.31F.sub.3N.sub.2O.sub.5S.0- .61 EtOAc: C, 58.32; H,
5.96; N, 4.62. Found: C, 58.07; H, 5.88; N, 4.76.
Example 158
(2-Ethoxyphenyl)-[2-chloro-4(E-[(2-carboxypiperidin-1-yl)carbonyl]ethenyl)-
phenyl]sulfide
[0842] The compound of Example 156 was hydrolyzed, and the salt
formed, according to the procedures of Example 155. m.p. 170-171 C.
.sup.1H-NMR (DMSO 300 MHz) .delta. 1.16 (t, J=7 Hz, 3H), broad
peaks totaling 9 protons at 1.20-1.49, 1.51-1.75, 2.10-2.27,
2.55-2.65, 3.10-3.21, 4.20-4.29, 4.35-4.45, 5.13-5.25, 4.05 (q, J=7
Hz, 2H), 6.80 (d, J=9 Hz, 1H), 6.97-7.07 (m, 1H), 7.15 (d, J=9 Hz,
1H), 7.29-7.57 (m, 5H), 8.02 (s, 1H). Anal. Calcd. for
C.sub.23H.sub.24ClNO.sub.4S: C, 61.94; H, 5.42; N, 3.14. Found: C,
61.91; H, 5.48; N, 2.90.
Example 159
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-(((pyrrol-3-in-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0843] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.81 (s,
1H), 7.68 (d, 1H, J=15.4 Hz), 7.35-7.47 (m, 3H), 7.04 (d, 1H, J=8.4
Hz), 6.97 (dd, 1H, J=1.3, 7.5 Hz), 6.91 (d, 1H, J=8.5 Hz), 6.70 (d,
1H, J=15.4 Hz), 5.94 (m, 1H), 5.85 (m, 1H), 4.47 (br, 2H), 4.38
(br, 2H), 3.98 (q, 2H, J=7.0 Hz), 1.19 (t, 3H, J=7.0 Hz). MS (ESI)
m/z 420, 839, 861.
Example 160
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-y-
lamino)carbonyl)ethenyl)phenyl]sulfide
[0844] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.78 (s,
1H), 7.54 (d, 1H, J=15.8 Hz), 7.42 (dd, 1H, J=1.7, 7.5 Hz),
7.34-7.39 (m, 2H), 7.13 (br, 1H), 7.03 (d, 1H, J=8.5), 6.97 (dd,
1H, J=1.1, 7.7 Hz), 6.91 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=15.8
Hz), 3.98 (q, 2H, J=7.0 Hz), 3.43 (m, 4H), 3.34 (q, 2H, J=6.0 Hz),
2.45 (t, 2H, J=8.1 Hz), 2.08 (m, 2H), 1.75 (m, 2H), 1.18 (t, 3H,
J=7.0 Hz). MS (ESI) m/z 493, 515, 985, 1007.
Example 161
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0845] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.62 (d, 1H, J=15.6 Hz), 7.44 (dd, 1H, J=1.7, 7.5 Hz), 7.38
(m, 2H), 7.04 (d, 1H, J=8.1), 6.97 (dd, 1H, J=1.4, 7.5 Hz), 6.92
(d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=15.6 Hz), 3.98 (q, 2H, J=7.0 Hz),
3.63-78 (m, 6H), 3.53 (m, 2H), 2.14 (s, 3H), 1.19 (t, 3H, J=7.0
Hz). MS (ESI) m/z 479, 501, 957, 979.
Example 162
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-(ethoxycarbonyl)piperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0846] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (d,
1H, J=1.7 Hz), 7.63 (d, 1H, J=15.3 Hz), 7.43 (dd, 1H, J=1.7, 7.7
Hz), 7.38 (m, 2H), 7.04 (d, 1H, J=8.5), 6.97 (dd, 1H, J=1.4, 7.5
Hz), 6.92 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=15.3 Hz), 4.18 (q, 2H,
J=7.1 Hz), 3.98 (q, 2H, J=6.9 Hz), 3.68 (m, 4H), 3.53 (m, 4H), 1.29
(t, 3H, J=7.1 Hz) 1.19 (t, 3H, J=6.9 Hz). MS (ESI) m/z 509, 531,
1017, 1039.
Example 163
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((4-(2-furylcarbonyl)piperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
[0847] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.80 (d,
1H, J=1.5 Hz), 7.66 (d, 1H, J=15.4 Hz), 7.52 (s, 1H), 7.45 (dd, 1H,
J=1.6, 7.5 Hz), 7.40 (m, 2H), 7.08 (d, 1H, J=4.0 Hz), 7.04 (d, 1H,
J=8.1), 6.98 (dd, 1H, J=1.1, 7.3 Hz), 6.93 (d, 1H, J=8.5 Hz), 6.88
(d, 1H, J=15.4 Hz), 6.52 (dd, 1H, J=1.6, 3.5 Hz), 3.98 (q, 2H,
J=7.0 Hz), 3.73-3.90 (m, 8H), 1.19 (t, 3H, J=7.0 Hz). MS (ESI) m/z
531, 553, 1061, 1083.
Example 164
(2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1-yl)carbonyl]e-
thenyl)phenyl]sulfide
[0848] The title compound was prepared according to the procedures
of Example 97. .sup.1H-NMR (CDCl.sub.3) .delta. 1.25 (t, J=7 Hz,
6H), broad peaks totaling 9 protons at 1.65-1.80, 1.95-2.04,
2.51-2.63, 2.90-3.00, 3.15-3.30, 2.95-4.05, 4.42-4.55, 4.14 (q, J=7
Hz, 2H), 4.15 (q, J=7 Hz, 2H), 6.82 (d, J=15 Hz, 1H), 6.84 (d, J=9
Hz, 1H), 6.93-6.99 (m, 2H), 7.17 (dd, J=9 Hz, 2 Hz, 1H), 7.34-7.41
(m, 2H), 7.52 (d, J=15 Hz, 1H), 7.55 (d, J=2 Hz, 1H). Anal. Calcd.
for C.sub.25H.sub.28ClNO.sub.4S: C, 63.35; H, 5.95; N, 2.95. Found:
C, 63.09; H, 6.24; N, 2.77.
Example 165
(2-Ethoxyphenyl)-[2-chloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]ethenyl)-
phenyl]sulfide
[0849] The compound of Example 164 was hydrolyzed, and the salt
formed, according to the procedures of Example 155. m.p. 165-166 C.
.sup.1H-NMR (DMSO 300 MHz) .delta. 1.25 (t, J=7 Hz, 3H0, 1.35-1.58
(m, 2H), 1.80-1.95 (m, 2H), 2.50-2.60 (m, 1H), 1.78-1.91 (m, 1H),
3.13-3.24 (m, 1H), 4.05 (q, J=7 Hz, 2H), 4.12-4.35 (m, 2H), 6.80
(d, J=9 Hz, 1H), 6.96-7.05 (t, J=8 Hz, 1H), 7.15 (d, J=9 Hz, 1H),
7.28-7.48 (m, 4H), 7.51 (dd, J=9 Hz, 2 Hz, 1H), 8.00 (d, J=2
Hz).
Example 166
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide
[0850] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with 6-iodobenzenedioxane,
giving a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
2.14 (s, 3H), 3.44-3.57 (m, 2H), 3.57-3.86 (m, 6H), 4.25-4.35 (m,
4H), 6.75 (d, J=8.4 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 6.93 (d,
J=8.4 Hz, 1H), 7.03 (dd, J=2.1, 8.4 Hz, 1H), 7.08 (d, J=2.1 Hz,
1H), 7.18 (dd, J=2.1, 8.4 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.57 (d,
J=15.6 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 459, 461.
Example 167
(2-Isopropylphenyl)[2-nitro-4-(E-((4-ethoxycarbonylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0851] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.19 (t, J=7.0 Hz, 3H); 3.30-3.40 (m, 1H); 3.30-3.73
(br m, 8H), 4.06 (q, J=7.0 Hz, 2H); 6.64 (d, J=8.5 Hz, 1H);
7.32-7.63 (m, 6H); 7.90 (dd, J=8.8, 1.8 Hz, 1H); 8.65 (d, J=1.8 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 484. Anal calcd for
C.sub.25H.sub.29N.sub.3S.sub.1O.sub.5: C, 62.09; H, 6.04; N, 8.69.
Found: C, 61.89; H, 6.13; N, 8.51.
Example 168
(2-Isopropylphenyl)[2-nitro-4-(E-((4-isopropoxycarbonylpiperazin-1-yl)carb-
onylethenyl)phenyl]sulfide
[0852] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.20 (d, J=6.4 Hz, 3H); 3.30-3.40 (m, 1H); 3.32-3.73
(br m, 8H); 4.79 (hept, J=6.1 Hz, 2H); 6.64 (d, J=8.5 Hz, 1H);
7.32-7.63 (m, 6H); 7.89 (dd, J=8.5, 1.7 Hz, 1H); 8.64 (d, J=1.7 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 498. Anal calcd for
C.sub.26H.sub.31N.sub.3S.sub.1O.su- b.5: C, 62.76; H, 6.28; N,
8.44. Found: C, 62.57; H, 6.43; N, 8.33.
Example 169
(2-Isopropylphenyl)[2-nitro-4-(E-((4-isobutoxycarbonylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0853] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.90 (d,
J=6.6 Hz, 6H); 1.14 (d, J=7.0 Hz, 6H); 1.88 (hept. J=6.6 Hz, 1H);
3.30-3.40 (m, 1H); 3.30-3.73 (br m, 8H); 3.81 (d, J=6.3 Hz, 2H);
6.64 (d, J=8.5 Hz, 1H); 7.32-7.63 (m, 6H); 7.90 (dd, J=8.5, 1.5 Hz,
1H); 8.65 (d, J=1.5 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 512. Anal
calcd for C.sub.27H.sub.33N.sub.3S.sub.1O.sub.5: C, 63.38; H, 6.50;
N, 8.21. Found: C, 63.15; H, 6.55; N, 8.13.
Example 170
(2-Isopropylphenyl)[2-nitro-4-(E-((4-((1-propen-2-oxy)carbonyl)piperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide
[0854] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.88 (s, 3H); 3.30-3.40 (m, 1H), 3.30-3.78 (br m,
8H); 4.65 (s, 1H); 4.69 (m, 1H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.63
(m, 6H); 7.90 (dd, J=8.5, 1.5 Hz, 1H); 8.65 (d, J=1.5 Hz, 1H). MS
(APCI) (M+NH.sub.4).sup.+ at m/z 513. Anal calcd for
C.sub.26H.sub.29N.sub.3S.sub.1O.sub.5: C, 63.01; H, 5.90; N, 8.48.
Found: C, 62.98; H, 6.06; N, 8.27.
Example 171
(2-Isopropylphenyl)[2-nitro-4-(E-((4-propionylpiperazin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
[0855] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.00 (t,
J=7.3 Hz, 3H); 1.14 (d, J=7.0 Hz, 6H); 2.35 (q, J=7.5 Hz, 2H);
3.30-3.40 (m, 1H); 3.41-3.76 (br m, 8H); 6.64 (d, J=8.5 Hz, 1H);
7.32-7.63 (m, 6H); 7.90 (dd, J=8.5, 1.5 Hz, 1H); 8.64 (d, J=1.5 Hz,
1H). MS (APCI) (M+NH.sub.4).sup.+ at m/z 485. Anal calcd for
C.sub.25H.sub.29N.sub.3S.su- b.1O.sub.4: C, 64.22; H, 6.25; N,
8.99. Found: C, 64.04; H, 6.44; N, 8.80.
Example 172
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboxamidopiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0856] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 3.30-3.40 (m, 1H); 3.30-3.73 (br m, 8H); 6.10 (s,
2H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.63 (m, 6H); 7.91 (dd, J=8.5,
1.8 Hz, 1H); 8.65 (d, J=1.8 Hz, 1H). MS (APCI) (M+NH.sub.2).sup.+
at m/z 470. Anal calcd for
C.sub.23H.sub.26N.sub.4S.sub.1O.sub.4.0.26CH.sub.3COOCH.sub.2CH.sub.3:
C, 60.48; H, 5.93; N, 11.73. Found: C, 60.10; H, 5.84; N,
11.90.
Example 173
(2-Isopropylphenyl)[2-nitro-4-(E-((4-methylaminocarbonylpiperazin-1-yl)car-
bonyl)ethenyl)phenyl]sulfide
[0857] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.58 (d, J=4.4 Hz, 3H); 3.30-3.40 (m, 1H); 3.28-3.70
(br m, 8H); 6.52 (q, J=4.4 Hz, 1H); 6.64 (d, J=8.5 Hz, 1H);
7.32-7.62 (m, 6H); 7.90 (dd, J=8.5, 1.8 Hz, 1H); 8.64 (d, J=1.8 Hz,
1H). MS (APCI) (M+NH.sub.4).sup.+ at m/z 486. Anal calcd for
C.sub.24H.sub.28N.sub.4S.su-
b.1O.sub.4.0.36CH.sub.3COOCH.sub.2CH.sub.3: C, 61.07. H, 6.22; N,
11.19. Found: C, 61.14; H, 6.41; N, 11.19.
Example 174
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrimidin-2-yl)piperazin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[0858] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.15 (d,
J=6.6 Hz, 6H); 3.30-3.40 (m, 1H); 3.28-3.85 (br m, 8H), 6.64 (d,
J=8.5 Hz 1H); 6.68 (d, J=4.8 Hz, 1H): 7.33-7.63 (m, 6H); 7.92 (dd,
J=8.5, 1.8 Hz, 1H); 8.40 (d, J=4.8 Hz, 2H); 8.67 (d, J=1.8 Hz, 1H).
MS (APCI) (M+H).sup.+ at m/z 490. Anal calcd for
C.sub.26H.sub.27N.sub.5S.sub.1O.sub.3: C, 63.78; H, 5.56; N, 14.30.
Found: C, 63.83; H, 5.54; N, 14.11.
Example 175
(2-Isopropylphenyl)[2-nitro-4-(E-((4-hydroxyacetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0859] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.15 (d,
J=6.8 Hz, 6H); 3.30-3.40 (m, 1H); 3.28-3.78 (br m, 8H); 4.12 (d,
J=5.8 Hz, 2H); 4.61-4.69 (br m, 1H); 6.64 (d, J=8.5 Hz, 1H);
7.33-7.63 (m, 6H); 7.90 (dd, J=8.5, 1.8 Hz, 1H); 8.65 (d, J=1.8 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 470. Anal calcd for
C.sub.14H.sub.21N.sub.3S.sub.1O.sub.5.0.38CH.sub.-
3COOCH.sub.2CH.sub.3: C, 60.93; H, 6.02; N, 8.35. Found: C, 60.95;
H, 6.06; N, 8.35.
Example 176
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrazine-2-carbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0860] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 3.30-3.40 (m, 1H); 3.28-3.88 (br m, 8H); 6.61-6.66
(br m, 1H); 7.31-7.63 (m, 6H); 7.85-7.96 (br m, 1H); 8.61-8.92 (m,
4H). MS (APCI) (M+H).sup.+ at m/z 518. Anal calcd for
C.sub.27H.sub.27N.sub.5S.sub.1O.su-
b.4.0.24CH.sub.3COOCH.sub.2CH.sub.3: C, 62.34; H, 5.41; N, 13.01.
Found: C, 62.23; H, 5.50; N, 13.10.
Example 177
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-carboxypyrrol-3-in-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0861] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.68 (d, 1H, J=15.4 Hz), 7.48 (d, 1H, J=7.4 Hz), 7.45 (m, 2H),
7.38 (d, 1H, J=8.3 Hz), 7.23 (m, 1H), 6.80 (d, 1H, J=8.5 Hz), 6.70
(d, 1H, J=15.4 Hz), 6.04 (m, 1H), 5.88 (m, 1H), 5.31 (m, 1H), 4.60
(m, 1H), 4.50 (m, 1H), 3.76 (s, 3H), 3.50 (m, 1H), 1.22 (d, 6H,
J=7.0 Hz). MS (ESI) m/z 476, 498, 951, 973. Anal. Calcd for
C.sub.25H.sub.24F.sub.3NO.sub.3S.0.38 EtOAc: C, 62.58; H, 5.35; N,
2.75. Found: C, 62.53; H, 5.27; N, 2.76.
Example 178
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-methylpiperazin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[0862] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.22 (s, 3H); 1.82-4.63 (br m, 9H); 3.30-3.40 (m,
1H) 6.62-6.66 (br m, 1H); 7.25-7.63 (m, 6H); 7.86-7.92 (br m, 1H);
8.57-8.65 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 456.
Example 179
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-carboxypyrrol-3-in-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0863] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.72 (d, 1H, J=15.5 Hz), 7.49 (d, 1H, J=7.4 Hz), 7.36-7.46 (m,
3H), 7.23 (m, 1H), 6.82 (d, 1H, J=8.5 Hz), 6.74 (d, 1H, J=15.4 Hz),
6.00 (br, 2H), 4.48 (br, 1H), 4.51 (br, 2H), 3.48 (m, 1H), 1.18 (d,
6H, J=7.0 Hz). MS (ESI) m/z -460, -492, -921.
Example 180
(2-Isopropylphenyl)[2-trifluoromethyl-4-(E-(((2-hydroxymethylpyrrolidin-1--
yl)carbonyl)ethenyl)phenyl]sulfide
[0864] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H), 7.68 (d, 1H, J=15.4 Hz), 7.48 (d, 1H, J=7.4 Hz), 7.45 (m, 2H),
7.38 (d, 1H, J=8.3 Hz), 7.23 (m, 1H), 6.80 (d, 1H, J=8.5 Hz), 6.70
(d, 1H, J=15.4 Hz), 5.82 (m, 1H), 5.70 (m, 1H), 4.92 (m, 1H), 4.18
(br s, 2H), 3.76 (s, 3H), 3.78 (d, 1H, J=11.5 Hz), 3.50 (m, 2H),
3.01 (t, 2H, J=7.5 Hz), 2.58 (t, 2H, J=7.6 Hz), 1.19 (d, 6H, J=7.1
Hz). MS (ESI) m/z 450, 472, 921.
Example 181
(2-Isopropylphenyl)[2-nitro-4-(E-((3-methylaminocarbonyl)piperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0865] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 2.60 (d, J=4.4 Hz, 3H); 2.50-4.45 (br m, 7H);
3.30-3.40 (m, 1H); 6.62-6.66 (br m, 1H); 7.32-7.62 (m, 6H);
7.81-7.92 (m, 2H); 8.59-8.65 (br m, 1H). MS (APCI) (M+H).sup.+ at
m/z 469.
Example 182
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-cyclopropylaminocarbonyl)piperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide
[0866] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.40-0.62
(br m, 4H); 1.14 (d, J=6.8 Hz, 6H); 2.50-4.41 (br m, 8H); 3.30-3.40
(m, 1H); 6.62-6.67 (br m, 1H); 7.32-7.62 (m, 6H); 7.87-7.92 (m,
2H); 8.59-8.64 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 495.
Example 183
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxamidopiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0867] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 2.50-4.42 (br m, 7H); 3.30-3.40 (m 1H); 6.62-6.67
(br m, 1H); 7.12-7.62 (m, 8H); 7.87-7.92 (m, 1H); 8.60-8.65 (br m,
1H). MS (APCI) (M+H).sup.+ at m/z 455.
Example 184
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-oxopiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0868] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.32-2.55 (br m, 2H); 3.30-3.40 (m, 1H); 3.64, 3.76
(s, s, 3H); 3.68-4.58 (br m 5H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.63
(m, 6H); 7.88-7.96 (m, 1H); 8.60-8.68 (m, 1H). MS (APCI)
(M+H).sup.+ at m/z 483. Anal calcd for
C.sub.25H.sub.26N.sub.2S.sub.1O.sub.6.0.17C.sub.6H.sub.14: C,
62.86; H, 5.75; N, 5.63. Found: C, 62.81; H, 5.83; N, 5.60.
Example 185
(2-Isopropylphenyl)[2-nitro-4-(E-((3,5-dimethylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0869] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.96-1.06
(m, 6H); 1.14 (d, J=6.8 Hz, 6H); 2.07-4.39 (br m, 7H); 6.63 (d,
J=8.5 Hz, 1H); 7.30-7.63 (m, 6H); 7.92 (dd, J=8.5, 1.7 Hz, 1H);
8.60 (d, J=1.7 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 440. Anal
calcd for C.sub.26H.sub.29N.sub.3S- .sub.1O.sub.3: C, 65.58; H,
6.65; N, 9.56. Found: C, 65.36; H, 6.87; N, 9.27.
Example 186
(1-Ethylindol-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0870] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
N-ethyl-7-bromoindole, white solid; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.30 (t, J=7.05 Hz, 3H), 2.14 (s, 3H), 3.52 (br s,
2H), 3.58-3.84 (m, 6H), 4.42 (q, J=7.05 Hz, 2H), 6.42 (d, J=8.4 Hz,
1H), 6.59 (d, J=3.0 Hz, 1H), 6.76 (d, J=15.6 Hz, 1H), 7.08 (d,
J=8.4 Hz, 1H), 7.10 (d, J=3.0 Hz, 1H), 7.16 (t, J=7.65 Hz, 1H),
7.42 (dd, J=0.9, 7.5 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.54 (d,
J=15.6 Hz, 1H), 7.78 (dd, J=0.9, 7.5 Hz, 1H). MS (APCI.sup.+)
(M+H).sup.+ at m/z 468, 470.
Example 187
(3-[2-Methoxy]ethoxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]etheny-
l)phenyl]sulfide
[0871] The title compound was prepared according to the procedures
of Example 85. .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta. 3.45 (s,
3H), 3.65-3.80 (m, 10H), 4.09-4.13 (m, 2H), 6.82 (broad d,
J=15.1H), 6.88 (d, J=9 Hz, 1H), 6.87 (dd, J=9 Hz, 2 Hz, 1H),
7.03-7.10 (m 2H), 7.20 (d, J=9 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.52
(s, 1H), 7.56 (broad d, J=15, 1H).
Example 188
(2-Bromophenyl)[2-chloro-4-(E-((4,4'-S-dioxythiomorpholin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0872] 4-Methylmorpholine N-oxide (0.0935 g, 0.798 mmol) and 4
.ANG. molecular sieves (0.0333 g) were added to a solution of
(2-Bromophenyl)[2-chloro-4-(E-((thiomorpholin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide (0.1230 g, 0.27 mmol: prepared according to the
procedures described in Example 1). After 15 min,
tetrapropylammonium perruthenate (0.0058 g, 0.0166 mmol) was added
and after 4 h had elapsed the starting material was consumed by TLC
and the crude products were passed through a plug of silica with
5:2 hexane:ethyl acetate.fwdarw.9:1 CH.sub.2Cl.sub.2:MeOH. The
mixture was then purified by preparative HPLC to provide the title
compound (0.0138 g, 10%). .sup.1H-NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.12 (d, J=1.47 Hz, 1H), 7.81 (dd, J=7.9, 1.3, 2H), 7.65
(dd, J=8.0, 1.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.27-7.53 (m, 4H),
7.03 (d, J=9.0 Hz, 1H), 4.12 (br s, 2H), 3.98 (br s, 2H), 3.26 (br
s, 2H), 3.19 (br s, 2H), 1.54-2.29 (m, 6H), MS(APCI) (M+H).sup.+ at
m/z 486, 488, 490.
Example 189
(2-Bromophenyl)[2-chloro-4-(E-(N-carbomethoxymethyl-N-(3-(pyrrolidin-2-on--
1-yl)prop-1-yl)amino)carbonyl)ethenyl)phenyl]sulfide
Example 189A
N-Carbomethoxymethyl-N-(3-(pyrrolidin-2-on-1-yl)prop-1-yl)amine
[0873] Methyl bromoacetate (1.35 mL, 14.3 mmol) was added dropwise
to a solution of 3-aminopropyl-2-pyrrolidinone (2.0 mL, 14.3 mmol)
and diisopropylethylamine (2.7 mL) in CH.sub.2Cl.sub.2. The
reaction was stirred for 12 h and was then concentrated in vacuo,
and carried forward without further purification.
Example 189B
(2-Bromophenyl)[2-chloro-4-(E-(N-carbomethoxymethyl-N-(3-(pyrrolidin-2-on--
1-yl)prop-1-yl)amino)carbonyl)ethenyl)phenyl]sulfide
[0874] The title compound was prepared by the procedures described
for Example 113, substituting 2,4 dichlorothiophenol with
2-bromothiophenol, 2-chlorobenzaldehyde with 3,4
dichlorobenzaldehyde, and
1-(3-aminopropyl)-5-((S)-hydroxymethyl)-2-pyrrolidinone with the
compound from Example 189A. .sup.1H-NMR (DMSO-d.sub.6, 300 MHz)
.delta. 8.07 (dd, J=9.4, 1.7 Hz, 1H), 7.81 (m, 1H), 7.64 (m, 1H),
7.24-7.49 (m, 5H), 7.05 (m, 1H), 4.53 (s, 1H), 4.14 (s, 1H), 3.68
(s, 1H), 3.64 (s, 2H), 3.54 (m, 2H), 3.13-3.43 (m, 4H), 2.39 (m,
2H), 1.91 (m, 2H), 1.72 (m, 2H), MS(APCI) (M+H).sup.+ at m/z 565,
567, 569.
Example 190
(2-Bromophenyl)[2-chloro-4-(E-((4-S-oxythiomorpholin-1-yl)-2-pyrrolidinone-
)carbonyl)ethenyl)phenyl]sulfide
[0875] The title compound (0.0178 g, 14%) was isolated from the
same reaction mixture as described in Example 188. .sup.1H-NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.12 (d, J=1.8 Hz, 1H), 7.81 (dd,
J=7.9, 1.3 Hz, 1H), 7.65 (dd, J=8.3, 1.7 Hz 1H), 7.46 (d, J=7.4 Hz,
1H), 7.26-7.48 (m, 4H), 7.04 (d, J=7.4 Hz, 1H), 4.29 (br m, 2H),
3.97 (br m, 1H), 3.61 (br m, 1H), 2.80 (br m, 4H), MS(APCI)
(M+H).sup.+ at m/z 470, 472, 474.
Example 191
(2-Methoxy-5-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0876] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.44 (s,
1H), 7.66 (d, 1H, J=15.1 Hz), 7.58 (d, 1H, J=2.6 Hz), 7.48 (dd, 1H,
J=2.6, 8.8 Hz), 7.44 (m, 1H), 6.97 (d, 1H, J=8.8 Hz), 6.92 (d, 1H,
J=15.5 Hz), 6.82 (d, 1H, J=8.5 Hz), 3.78 (s, 3H), 3.70 (m, 6H),
3.54 (m, 2H), 2.15 (s, 3H). MS (ESI) m/z 476, 498, 951, 973. Anal.
Calcd for C.sub.22H.sub.22ClN.sub.3O.- sub.5S.0.48 EtOAc: C, 55.44;
H, 5.03; N, 8.11. Found: C, 54.36; H, 4.90; N, 8.50.
Example 192
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethyl)piperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0877] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.04 (s, 3H); 3.30-3.40 (m, 1H); 2.50-4.46 (br m,
9H); 6.64 (d, J=8.8 Hz, 1H); 7.30-7.62 (m, 6H); 7.87-7.93 (m, 1H);
8.58-8.63 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 484. Anal calcd
for C.sub.25H.sub.29N.sub.3S.sub.1O.sub.5.0.2H.sub.2O: C, 61.60; H,
6.09; N, 8.62. Found: C, 61.63; H, 6.21; N, 8.41.
Example 193
(2-Isopropylphenyl)[2-nitro-4-(E-((3,5-dimethyl-4acetylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0878] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.00-1.20
(br m, 6H); 1.15 (d, J=6.8 Hz, 6H); 2.04 (s, 3H); 2.76-4.58 (br m,
7H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.63 (m, 6H); 7.94 (dd, J=8.5,
1.8 Hz, 1H); 8.66 (d, J=1.8 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z
482. Anal calcd for
C.sub.26H.sub.31N.sub.3S.sub.1O.sub.4.0.3H.sub.2O: C, 64.13; H,
6.54; N, 8.63. Found: C, 64.15; H, 6.61; N, 8.50.
Example 194
(1-Methylindol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0879] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
N-methyl-5-bromoindole, giving a white solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.40-3.80 (m, 8H),
3.86 (s, 3H), 6.49 (d, J=8.4 Hz, 1H), 6.52 (d, J=3.0 Hz, 1H), 7.27
(d, J=15.6 Hz, 1H), 7.31 (dd, J=2.4, 8.4 Hz, 1H), 7.39 (d, J=15.6
Hz, 1H), 7.41 (dd, J=1.8, 8.4 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.63
(d, J=8.4 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.99 (br s, 1H). MS
(APCI.sup.-) (M+H).sup.- at m/z 454, 456.
Example 195
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
Example 195A
6-Mercaptobenzodioxane
[0880] The title compound was prepared by the procedures described
in Example 97A, substituting 2-ethoxybenzene with
6-iodobenzenedioxane.
Example 195B
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
[0881] The title compound was prepared by the procedures described
in Example 32, substituting 2,4-dichlorobenzenethiol with
6-mercaptobenzenedioxane, to give a light-yellow solid; .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s, 3H), 3.41-3.80 (m, 8H),
4.28-4.38 (m, 4H), 6.86 (d, J=8.4 Hz, H), 7.05 (d, J=8.4 Hz, 1H),
7.10 (dd, J=2.1, 8.4 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 7.40 (d,
J=15.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.91 (dd, J=1.8, 8.4 Hz,
1H), 8.62 (d, J=1.8 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z
470. Anal. Calcd for C.sub.23H.sub.23N.sub.3O.sub.6S.0.17 H.sub.2O:
C, 58.46; H, 4.98; N, 8.89. Found: C, 58.47; H, 4.88; N, 8.78.
Example 196
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)c-
arbonyl)ethenyl)phenyl]sulfide
[0882] The title compound was prepared by the procedures described
in Example 32, substituting 2,4-dichlorobenzenethiol with
6-mercaptobenzenedioxane, and 1-acetylpiperazine with
3-aminopropyl-1-pyrrolidin-2-one, giving a light-yellow solid.
.sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.64 (p, J=7.2 Hz, 2H),
1.92 (p, J=7.8 Hz, 2H), 2.21 (t, J=7.8 Hz, 2H), 3.13 (t, J=7.2 Hz,
2H), 3.19 (t, J=7.2 Hz, 2H), 3.38-3.46 (overlapping t, J=7.8 Hz,
2H), 4.27-4.37 (m, 4H), 6.70 (d, J=15.6 Hz, 1H), 6.90 (d, J=8.4 Hz,
1H), 7.05 (d, J=8.4 Hz, 1H), 7.09 (dd, J=2.1, 8.4 Hz, 1H), 7.16 (d,
J=2.1 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 7.77 (dd, J=2.1, 8.4 Hz,
1H), 8.16 (t, J=6.0 Hz 1H), 8.41 (d, J=2.1 Hz, 1H). MS (APCI.sup.+)
(M+H).sup.+ at m/z 484. Anal. Calcd for
C.sub.24H.sub.25N.sub.3O.sub.6S.0.51 CH.sub.2Cl.sub.2.0.24 MeOH: C,
55.61; H, 5.09; N, 7.86. Found: C, 55.39; H, 5.48; N, 8.26.
Example 197
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0883] The title compound was prepared by the procedures described
in Example 196 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
ethyl nipecotate, giving a yellow solid, mp 73-75.degree. C.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.26 (t, J=7.0 Hz, 3H),
1.74 (br, 1H) 1.78 (br, 1H), 210 (br, 1H), 2.54 (br, 1H), 2.95-3.70
(br, 2H), 3.90-4.10 (br, 2H), 4.15 (q, J=7.0 Hz, 2H), 4.30-4.40 (m,
4H), 4.65 (br, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H),
7.06 (dd, J=2.0, 8.0 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.40-7.50 (m,
1H), 7.58 (d, J=15.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H). MS (APCI) m/z
499 (M+H).sup.+. Anal. calcd. for C.sub.25H.sub.26N.sub.2O.sub.7S:
C, 60.23; H, 5.26; N, 5.62. Found: C, 60.09; H, 5.43; N, 5.47.
Example 198
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0884] The title compound was prepared by the procedure described
as in example 196 substituting N-(3'-aminopropyl)-2-pyrrolidinone
with ethyl isonipecotate, giving a yellow solid, mp 78-88.degree.
C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.27 (t, J=7.0 Hz,
3H), 1.65 (m, 2H), 2.00 (m, 2H), 2.60 (m, 1H), 2.80-3.50 (br, 2H,
4.15 (br, 1H), 4.16 (q, J=7.0, 2H), 4.34 (m, 4H), 4.54 (br, 1H),
6.90 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H) 7.05 (dd, J=2.0, 8.0
Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.12 (br, 1H), 7.44 (d, J=8.0 Hz,
1H), 7.60 (br, 1H), 8.40 (s, 1H). MS (Cl/NH.sub.3) m/z 499
(M+H).sup.+. Anal. calcd. for C.sub.25H.sub.26N.sub.2O.sub.7S 0.03
H.sub.2O: C, 60.16; H, 5.26; N, 5.61. Found: C, 60.15; H, 5.65; N,
5.40.
Example 199
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-acetylpiperazin-1-yl)carbonyle-
thenyl)phenyl]sulfide
Example 199A
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-carbomethoxyethenyl)phenyl]sul-
fide
[0885] Bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate
(1.20 g, 3.77 mmole), and 18-crown-6 (3.56 g, 13.48 mmol) were
dissolved in 22 ml of dry THF. The mixture was cooled to
-78.degree. C. and KN(SiMe.sub.3).sub.2 (0.5 M in THF, 4.04 mmol)
was added and stirred for 30 min.
(2-Ethoxyphenyl)[2-trifluoromethyl-4-formyl phenyl]sulfide (1.10 g,
3.77 mmol, prepared according to the procedure of example 1) in 13
ml of THF was added via cannulation. After 1 hr at that
temperature, the cooling bath was removed and the mixture allowed
to warm to ambient temperature. Saturated NH.sub.4Cl soln. was
added and the mixture was extracted with ethyl acetate three times.
The combined organics were dried over sodium sulfate, concentrated
in vacuo and purified by medium pressure chromatography on silica
gel to give 772 mg (60% yield) of the cis-isomer
(J.sub.olefinic=12.5 Hz) along with 322 mg (25% yield) of the
trans-isomer (J.sub.olefinic=12.5 Hz).
Example 199B
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-acetylpiperazin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0886] The compound of Example 199A was converted to the
corresponding amide according to the procedures of Example 1.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.64 (d, 1H. J=16.9 Hz),
7.32-7.4 (m, 2H), 6.98 (m, 2H), 6.93 (m, 2H), 6.65 (d, 1H, J=12.1
Hz), 6.08 (d, 1H, J=12.2 Hz), 3.98 (q, 2H, J=7.0 Hz), 3.68 (m, 2H),
3.62 (m, 2H), 3.44-3.54 (m, 4H), 2.11 and 2.05 (s, 3H), 1.20 (t,
3H, J=7.0 Hz). MS (ESI)s m/z 479, 501.
Example 200
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((6-methylpyrid-2-ylamino)carbonyl-
)ethenyl)phenyl]sulfide
[0887] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.12 (d,
1H, J=8.1 Hz), 7.78 (s, 1H, J=1.7 Hz), 7.70 (d, 1H, J=15.6 Hz),
7.63 (t, 1H, J=7.8 Hz), 7.46 (dd, 1H, J=1.6, 7.8 Hz), 7.36-7.42 (m,
2H), 7.04 (d, 1H, J=8.1), 6.99 (dd, 1H, J=1.2, 7.6 Hz), 6.92 (m,
2H), 6.50 (d, 1H, J=15.6 Hz), 3.99 (q, 2H, J=6.9 Hz), 2.47 (s, 3H),
1.19 (t, 3H, J=7.0 Hz). MS (ESI)s m/z 459, 481. Anal. Calcd for
C.sub.24H.sub.21F.sub.3N.sub.2O.sub.- 2S.1.1 H.sub.2O: C, 60.27; H,
4.89; N, 5.86. Found: C, 60.28; H, 5.05; N, 5.94.
Example 201
(2-Methyl-3-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0888] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.1, 300 MHz) .delta. 8.46 (d,
1H, J=1.5 Hz), 7.64 (d, 1H, J=15.4 Hz), 7.56 (d, 1H, J=2.6 Hz),
7.54 (d, 1H, J=2.2 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.27 (m, 1H), 6.92
(d, 1H, J=15.4 Hz), 6.68 (d, 1H, J=8.5 Hz), 3.63-3.78 (m, 6H), 3.53
(m, 2H), 2.45 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z 460, 482, 919.
Anal. Calcd for C.sub.22H.sub.22Cl.sub.1N.sub.3O.sub.4S: C, 57.45,
H, 4.82, N, 9.14. Found: C, 75.54, 5.08, N, 8.82.
Example 202
(Benzodioxan-6-yl)[2-nitro-4-(E-((3-carboxamidopiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0889] The title compound was prepared by the procedures described
in Example 196, substituting N-(3'-aminopropyl)-2-pyrrolidinone
with nipecotamide, giving a llight yellow solid, mp 243-245.degree.
C. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.38-1.50 (m, 2H),
1.77-2.00 (m, 2H), 2.38 (m, 1H), 2.70 (m, 1H), 3.11 (m, 1H), 4.22
(m, 1H), 4.28-4.30 (m, 2H), 4.32-4.36 (m, 2H), 4.42 (m, 1H), 6.85
(d, J=8.5 Hz, 1H), 7.04-7.16 (m, 2H), 7.35 (s, 1H), 7.40 (d, J=13.0
Hz, 1H), 7.48 (d, J=15.5 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 8.58 (s,
1H). MS (APCI) m/z 470 (M+H).sup.+. Anal. calcd. for
C.sub.23H.sub.23N.sub.3O.sub.6S.0.37 H.sub.2O: C, 58.01; H, 5.03;
N, 8.82. Found: C, 58.02; H, 5.13; N, 8.61.
Example 203
(Benzodioxan-6-yl)[2-nitro-4-(E-((2-carboethoxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0890] The title compound was prepared by the procedures described
in Example 196, substituting N-(3'-aminopropyl)-2-pyrrolidinone
with ethyl pipecolinate, producing a light yellow solid, mp
74-75.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz) d 1.28 (t, J=7.0
Hz, 3H), 1.32-1.55 (m, 2H), 1.60-1.82 (m, 3H), 2.33 (m, 1H), 3.40
(m, 1H), 3.98 (m, 1H), 4.23 (q, J=6.5 Hz, 2H), 4.32 (q, J=5.0 Hz,
4H), 5.45 (m, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H),
7.0-7.10 (m, 3H), 7.44, (d, H=7.5 Hz, 1H), 7.60 (d, J=15.0 Hz, 1H),
8.38 (m, 1H). MS (APCI) m/z 499 (M+H).sup.-. Anal. calcd. for
C.sub.25H.sub.26N.sub.2O.sub.7S.0.11 H.sub.2O: C, 59.99; H, 5.28;
N, 5.60. Found: C, 59.98. H, 5.42; N, 5.91.
Example 204
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxamidopiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0891] The title compound was prepared by the procedures described
in Example 196, substituting N-(3'-aminopropyl)-2-pyrrolidinone
with isonipecotamide, giving a light yellow solid.
mp>230.degree. C. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.35
(m, 1H), 1.60 (m, 1H), 1.72 (m, 1H), 1.68 (m, 1H), 2.20 (m, 1H),
2.75 (m, 1H), 3.04 (m, 1H), 3.20 (m, 1H), 4.20 (m, 1H), 4.32 (m,
4H), 6.85 (d, J=8.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 7.09 (dd,
J=2.0, 8.5 Hz, 1H), 7.26 (s, 1H), 7.37 (d, J=16.0 Hz, 1H), 7.47 (d,
J=16.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H). MS (APCI) m/z 470
(M+H).sup.+. Anal. calcd. for C.sub.23H.sub.23N.sub.3O.sub-
.6S.0.13 H.sub.2O: C, 58.55; H, 4.97; N, 8.91. Found: C, 58.41; H,
5.14; N, 9.30.
Example 205
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-tert-butoxycarbonylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0892] The title compound was prepared by the procedures described
in Example 196, substituting N-(3'-aminopropyl)-2-pyrrolidinone
with Boc-piperazine, giving a light yellow solid. mp
165-167.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.48
(s, 9H), 3.50 (m, 4H), 3.65 (br, m, 4H), 4.32 (m, 4H), 6.89 (d,
J=5.0 Hz, 1H), 6.92 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.05 (dd,
J=2.0, 8.5 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 7.45 (m, 1H), 7.63 (d,
J=15.5 Hz, 1H), 8.40 (m, 1H). MS (APCI) M/z 528 (M+H).sup.+. Anal.
calcd. for C.sub.26H.sub.19N.sub.3O.sub.7S: C, 59.19; H, 5.54; N,
7.96. Found: C, 58.85; H, 5.69; N, 8.20.
Example 206
(2-Isopropylphenyl)[2-nitro-4-(E-((syn-3,5-dimethylmorpholin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0893] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.10-1.18
(m, 12H); 2.29-2.39 (m, 1H); 2.67-2.78 (m, 1H); 3.30-3.53 (m, 3H);
4.17-4.38 (m, 2H); 6.63 (d, J=8.8 Hz, 1H); 7.32-7.63 (m, 6H); 7.92
(dd, J=8.8, 1.5 Hz, 1H); 8.66 (d, J=1.8 Hz, 1H). MS (APCI)
(M+H).sup.+ at m/z 441. Anal calcd for
C.sub.24H.sub.28N.sub.2S.sub.1O.sub.4: C, 65.43; H, 6.41; N, 6.36.
Found: C, 65.69; H, 6.70; N, 6.17.
Example 207
(2-Isopropylphenyl)[2-nitro-4-(E-((anti-3,5-dimethylmorpholin-1-ylcarbonyl-
)ethenyl)phenyl]sulfide
[0894] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.07-1.12
(m, 6H); 1.15 (d, J=6.6 Hz, 6H); 3.32-3.48 (m, 3H); 3.60-3.83 (br
m, 2H); 3.87-3.98 (m, 2H); 6.63 (d, J=8.5 Hz, 1H); 7.32-7.63 (m, 6
Hr, 7.93 (dd, J=8.8, 1.8 Hz, 1H); 8.64 (d, J=1.8 Hz, 1H). MS (APCI)
(M+H).sup.- at m/z 441.
Example 208
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0895] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.08-1.26 (m, 3H); 2.52-3.16 (br m, 4H); 3.25-3.40
(m, 1H); 3.41-4.26 (br m, 5H); 6.61-6.67 (br m, 1H); 7.30-7.62 (m,
6H); 7.87-7.93 (br m, 1H); 8.58-8.64 (br m, 1H). MS (APCI)
(M+H).sup.+ at m/z 484. Anal calcd for
C.sub.25H.sub.29N.sub.3S.sub.1O.sub.5: C, 62.09; H, 6.04; N, 8.69.
Found: C, 61.96; H, 6.28; N, 8.49.
Example 209
(2-Isopropylphenyl)[2-nitro-4-(E-((3-isopropoxycarbonylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0896] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.07-1.21
(br m, 6H); 1.14 (d, J=7.0 Hz, 6H), 2.52-3.16 (br m, 4H); 3.30-3.40
(m, 1H); 3.41-4.24 (br m, 3H); 4.81-4.97 (m, 1H); 6.61-6.68 (br m,
1H); 7.32-7.63 (m, 6H), 7.87-7.94 (br m, 1H); 8.60-8.66 (br m, 1H).
MS (APCI) (M+H).sup.+ at m/z 498. Anal calcd for
C.sub.26H.sub.31N.sub.3S.sub.1O.su- b.5: C, 62.76; H, 6.28; N,
8.44. Found: C, 62.51; H, 6.52; N, 8.14.
Example 210
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-methylpiper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0897] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.14 (s, 3H); 2.82, 2.84 (s, s, 3H); 3.12 (s, 3H);
2.12-4.24 (br m, 8H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.62 (m, 6H);
7.87-7.94 (br m, 1H); 8.60-8.66 (br m, 1H). MS (APCI) (M+H).sup.+
at m/z 497. Anal calcd for
C.sub.26H.sub.32N.sub.4S.sub.1O.sub.4.042H.sub.2O: C, 61.94; H,
6.56; N, 11.11. Found: C, 62.00; H, 6.78; N, 10.89.
Example 211
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carbomethoxy-4-hydroxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[0898] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.59-1.75 (br m, 2H); 2.50-3.14 (br m, 1H);
3.30-3.40 (m, 1H); 3.60, 3.61 (s, s, 3H); 4.01-4.44 (br m, 4H);
5.05-5.10 (br m, 1H); 6.63 (d, J=8.5 Hz, 1H); 7.34-7.62 (m, 6H);
7.87-7.94 (br m, 1H); 8.60-8.66 (br m, 1H). MS (APCI) (M+H).sup.+
at m/z 485.
Example 212
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxymethyl-4-hydroxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0899] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.49-1.90 (br m, 2H); 2.75-3.14 (br m, 1H);
3.30-3.40 (m, 1H); 3.40-4.23 (br m, 5H); 4.38-4.52 (m, 1H);
4.60-4.73 (m, 1H); 6.61-6.66 (m, 1H); 7.27-7.61 (m, 6H); 7.84-7.93
(br m, 1H) 8.54-8.63 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 457.
Anal calcd for C.sub.24H.sub.28N.sub.2S.su- b.1O.sub.5.047H.sub.2O:
C, 61.97; H, 6.27; N, 6.02. Found: C, 62.02; H, 6.49; N, 5.90.
Example 213
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-(methoxycarbony-
l)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0900] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.80 (s,
1H), 7.66 (d, 1H, J=15.4 Hz), 7.45 (dd, 1H, J=1.6, 7.5 Hz), 7.48
(m, 2H), 7.01 (d, 1H, J=6.6 Hz), 6.95 (d, 1H, J=6.8 Hz), 6.90 (m,
2H), 5.34 (br s, 1H), 4.66 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H),
3.18 (m, 1H), 3.00 (m, 3H). MS (ESI) m/z 553, 575.
Example 214
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-methyl
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0901] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.79 (s,
1H) 7.64 (d, 1H, J=15.3 Hz), 7.45 (dd, 1H, J=1.7, 7.8 Hz), 7.4-7.35
(m, 2H), 7.01 (d, 1H, J=8.1 Hz), 6.97 (dd, 1H, J=1.2, 7.6 Hz),
6.87-7.91 (m, 2H), 5.36 (br s, 1H), 3.98 (q, 2H, J=6.9 Hz), 3.90
(m, 1H), 3.78 (s, 3H), 3.65 (m, 1H), 3.42 (m, 1H), 2.85 (m, 1H),
2.32 (s, 3H), 2.24 (m, 1H), 2.19 (m, 1H), 1.18 (t, 3H, J=6.9 Hz).
MS (ESI) m/z 509, 531.
Example 215
(2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((2-carboxy-4-(methoxycarbonyl)pip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0902] The title compound was prepared according to the procedures
of Example 71. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.10 (m,
1H), 7.68 (m, 1H), 7.42 (m, 2H), 7.30 (m, 1H), 7.20 (d, 1H, J=15.6
Hz), 7.10 (d, 1H, J=8.1 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.98 (d, 1H,
J=7.5 Hz), 4.65 (br s, 1H), 4.53 (m, 2H), 4.05 (m, 2H), 4.00 (q,
2H, J=6.9 Hz), 3.57 (s, 3H), 1.09 (t, 3H, J=6.9 Hz). MS (ESI) m/z
-537, -569.
Example 216
(Indol-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)ethenyl)pheny-
l]sulfide
[0903] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with 6-bromoindole,
isolated as a white solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz)
.delta. 2.03 (s, 3H), 3.40-3.77 (m, 8H), 6.52-6.55 (m, 1H), 6.60
(d, J=8.4 Hz, 1H), 7.13 (dd, J=1.8, 8.4 Hz, 1H), 7.27 (d, J=15.6
Hz, 1H), 7.40 (d, J=15.6 Hz, 1H), 7.43 (dd, J=1.8, 8.4 Hz, 1H),
7.51 (t, J=3.0 Hz, 1H), 7.64 (m, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.99
(d, J=1.8 Hz, 1H). MS (APCI.sup.-) (M+H).sup.+ at m/z 440, 442.
Example 217
(1-Ethyl,3-(dimethylaminomethyl)indol-7-yl)[2-chloro-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0904] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
7-bromo-3-N,N-dimethylmethyl-N- -ethyl indole, and isolated as a
light-brown solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.30
(t, J=7.05 Hz, 3H), 2.14 (s, 3H), 2.41 (s, 6H), 2.93-3.05 (m, 2H),
3.47-3.55 (m, 2H), 3.55-3.87 (m, 6H), 6.42 (d, J=8.4 Hz, 1H), 6.85
(d, J=15.6 Hz, 1H), 7.09 (dd, J=2.1, 8.4 Hz, 1H), 7.17 (d, J=8.4
Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.43 (dd, J=0.9, 7.8 Hz, 1H), 7.52
(d, J=2.1 Hz, 1H), 7.54 (d, J=15.6 Hz, 1H), 7.81 (dd, J=0.9, 7.8
Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 525, 527.
Example 218
(5-Ethoxybenzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0905] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
6-bromo-5-ethoxybenzodioxane, as s white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.28 (t J=7.2 Hz, 3H), 2.14 (s, 3H),
3.54 (br s, 2H), 3.60-3.88 (m, 6H), 4.06 (q, J=7.2 Hz, 2H), 4.33
(s, 4H), 6.70 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.78 (d,
J=15.6 Hz, 1H0, 6.98 (d, J=8.4 Hz, 1H), 7.17 (dd, J=1.8, 8.4 Hz,
1H), 7.50 (d, J=1.8 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H). MS
(APCI.sup.+) (M+H).sup.+ at m/z 503, 505.
Example 219
(2-Ethyl-4-bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[0906] The title compound was prepared according to the procedures
of Example 32. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.43 (d,
1H, J=2.0 Hz), 7.64 (d, 1H, J=15.6 Hz), 7.58 (d, 1H, J=2.0 Hz),
7.40-7.48 (m, 3H), 6.90 (d, 1H, J=15.2 Hz), 6.90 (d, 1H, J=8.5 Hz),
3.63-3.77 (m, 6H), 3.54 (m, 2H), 2.72 (q, 2H, J=7.5 Hz), 2.15 (s,
3H), 1.18 (t, 3H, J=7.5 Hz). MS (ESI) m/z 518, 520, 542, 627. Anal.
Calcd for C.sub.23H.sub.24Br.sub.1N.s- ub.3O.sub.4S: C, 53.08; H,
4.60; N, 7.93. Found: C, 53.29, H, 4.67, N, 8.11.
Example 220
(Benzodioxan-6-yl)[2-nitro-4-(E-(2-carboxypiperidin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
[0907] The title compound was prepared by the hydrolysis of the
compound of Example 203 under basic conditions (aq. NaOH/EtOH),
producing a light yellow solid: mp 165.degree. C. (dec.). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.15-1.52 (m, 3H), 1.46-1.62
(m, 2H), 2.32 (m, 1H), 2.80 (m, 1H), 3.45 (br, 1/2H), 4.00 (br,
1/2H), 4.44 (br, 1/2H), 4.800 (br, 1/2H), 6.83 (d, J=8.0 Hz, 1H)
7.03 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.0, 14.0 Hz, 1H), 7.15 (d,
J=2.0 Hz, 1H), 7.20 (d, J=15.5 Hz, 1H), 7.35 (d, J=15.5 Hz, 1H),
7.73 (m, 1H), 8.52 (m, 1H). MS (ESI) m/z 469 (M-H).sup.-, 471
(M+H).sup.-. Anal. calcd. for
C.sub.23H.sub.21N.sub.2O.sub.7SNa.NaOH.2.7 H.sub.2O: C, 47.54; H,
4.75; N, 4.82. Found: C, 47.18; H, 4.36; N, 4.89.
Example 221
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxymethylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0908] The title compound was prepared by deprotection of the
compound 33 with TFA in CH.sub.2Cl.sub.2. The resultant free amine
was treated with tert-butyl bromoacetate and TEA in acetonitrile at
room temperature, and followed by deprotection with TFA in
CH.sub.2Cl.sub.2, giving a light solid. mp 120.degree. C. (dec.).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.20-3.45 (m, 4H), 4.20
(s, 2H), 3.50-3.80 (m, 4H), 4.28-4.46 (m, 4H), 6.86 (d, J=8.5 Hz,
1H), 7.04 (m, J=8.0 Hz, 1H), 7.09 (dd, J=2.08.0 Hz, 1H) 7.15 (d,
J=2.0 Hz, 1H), 7.40 (d, J=15.5 Hz, 1H), 7.56 (d, J=15.0 Hz, 1H),
7.90 (dd, J=2.0, 8.5 Hz, 1H), 8.63 (m 1H). MS (ESI) m/z 484
(M-H).sup.+, 486 (M+H).sup.+. Calcd. Anal for
C.sub.23H.sub.21N.sub.3O.su- b.7S.1.19CF.sub.3COOH.1.34 H.sub.2O:
47.63; H, 4.11; N, 6.89. Found: C, 47.93; H, 4.51; N, 6.49.
Example 222
(3-Morpholinophenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0909] The title compound was prepared according to the procedures
of Example 62, employing the compound of Example 103 as starting
material. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.80 (s, 1H),
7.64 (d, 1H, J=15.4 Hz), 7.43 (m, 1H), 7.32 (t, 1H, J=8.1 Hz), 7.08
(m, 2H), 6.99 (m, 2H), 6.84 (d, 1H, J=15.4 Hz), 3.87 (t, 4H, J=4.8
Hz), 3.63-3.79 (m, 6H), 3.50-3.55 (m, 2H), 3.18 (t, 4H, J=4.8 Hz),
2.10 (s, 3H). MS (ESI) m/z 520, 542, 1061.
Example 223
(5-Ethoxybenzodioxan-8-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl-
)ethenyl)phenyl]sulfide
[0910] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
8-bromo-5-ethoxybenzodioxane, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.52 (t, J=7.2 Hz, 3H), 2.15 (s, 3H),
3.48-3.59 (m, 2H), 3.59-3.85 (m, 6H), 4.16 (q, J=7.2 Hz, 2H),
4.22-4.30 (m, 2H), 4.30-4.40 (m, 2H), 6.59 (d, J=8.7 Hz, 1H), 6.63
(d, J=8.7 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H),
7.17 (dd, J=2.1, 8.7 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.58 (d,
J=15.6 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 503, 505.
Example 224
(5-Chloro-8-ethoxyquinolin-7-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0911] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
5-chloro-8-ethoxy-7-iodoquinol- ine, giving a white solid. .sup.1H
NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.37 (t, J=7.2 Hz, 3H), 2.04
(s, 3H), 3.41-3.82 (m, 8H), 4.46 (q, J=7.2 Hz, 2H), 7.29 (s, 1H),
7.37 (dd, J=8.4 Hz, 1H), 7.42 (d, J=15.6 Hz, 1H), 7.51 (d, J=15.6
Hz, 1H), 7.68 (dd, J=1.8, 8.4 Hz, 1H), 7.74 (dd, J=3.9, 8.4 Hz,
1H), 8.15 (s, 1H), 8.55 (dd, J=1.8, 8.4 Hz, 1H) 9.05 (dd, J=1.8,
3.9 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 530, 532, 534.
Example 225
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
Example 225A
(2-Isopropylphenyl)[2-nitro-4-(E-(carboxy)ethenyl)phenyl]sulfide
[0912] To a stirred mixture of 4-chloro-3-nitrocinnamic acid (500
mg, 2.2 mmol) in 5 mL of anhydrous DMF with K.sub.2CO.sub.3 (911
mg, 6.6 mmol) was added 2-isopropylbenzenethiol (372 mL, 2.2 mmol)
in 1 mL of DMF dropwise. The resulting mixture was then heated at
70.degree. C. under nitrogen atmosphere over night. Water (25 mL)
was then added and the reaction mixture was acidified to pH=4 with
3N HCl. The cloudy mixture was extracted with EtOAc (2.times.20
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give the title compound
as viscous light-yellow oil, which was used for coupling with
further purification.
Example 225B
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0913] The title compound was prepared by the procedures described
in Example 92, substituting the benzoic acid with cinnamic acid
from 225A, and ammonium chloride with ethyl nipecotate, giving a
light-yellow solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.18
(d, J=6.6 Hz, 6H), 1.27 (t, J=7.2 Hz, 3H), 1.69-1.82 (m, 1H),
1.82-1.99 (m, 1H), 1.99-2.20 (m, 1H), 2.45-2.62 (m, 2H), 3.45
(septet, J=6.6 Hz, 1H), 3.56-3.80 (m, 1H), 3.80-4.10 (m, 2H), 4.16
(q, J=7.2 Hz, 2H), 4.65-4.81 (m; 1H), 6.69 (d, J=8.4 Hz 1H), 7.00
(br s, 1H) 7.31 (dd, J=2.4, 6.9 Hz, 1H), 7.42 (br d, J=8.4 Hz, 1H),
7.51 (d, J=15.6 Hz, 1H), 7.52 (overlapping d, 2H), 7.58 (d, J=15.6
Hz, 1H), 8.43 (s, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 483.
Example 226
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0914] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
the ethyl ester from Example 225B, and KOH with NaOH, to give a
light-yellow solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta.
1.15 (d, J=6.9 Hz, 6H), 1.30-1.50 (m, 1H), 1.50-1.80 (m, 2H),
1.88-2.04 (m, 2H), 2.95-3.17 (m, 1H), 3.94-4.06 (m, 1H), 4.06-4.22
(m, 2H), 4.40-4.52 (m, 1H), 6.63 (d, J=8.7 Hz, 1H), 7.33-7.53 (m,
3H), 7.56-7.68 (m, 3H), 7.91 (dd, J=1.8, 8.4 Hz, 1H), 8.63 (d,
J=8.4 Hz, 1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 455.
Example 227
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-ethanesulfonylaminocarbonyl)piperidi-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0915] To a stirred solution of free acid (50 mg, 0.11 mmol) from
Example 226 in 1 mL of methylene chloride was added ethyl
sulfonamide (18 mg, 0.17 mmol), EDAC (25 mg, 0.13 mmol), and DAMP
(2.7 mg, 0.022 mmol) sequentially. The mixture was stirred at
ambient temperature for 16 h. The solvent was then removed on a
rotavap under reduced pressure and the residue was purified on an
Alltech sep-pak, eluting with 1% MeOH in EtOAc to give 30 mg (50%
yield) the title compound as a light yellow solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.18 (d, J=6.3 Hz, 6H), 1.34 (t,
J=7.5 Hz, 3H), 1.61-1.74 (m, 2H), 1.84-2.04 (m, 1H), 2.13-2.35 (m,
1H), 2.60-2.75 (m, 2H), 3.44 (p, J=7.5 Hz, 2H), 3.53-3.66 (m, 1H),
3.66-3.85 (m, 2H), 4.00-4.18 (m, 0.1H), 6.71 (d, J=8.7 Hz, 1H),
6.88 (d, J=15.6 Hz, 1H), 7.31 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (d,
J=1.8, 8.4 Hz, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H),
7.67 (d, J=15.6 Hz, 1H), 8.43 (s, 1H). MS (ESI.sup.+) (M+H).sup.+
at m/z 546.
Example 228
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-(4-methylpiperazine)sulfonylaminocar-
bonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0916] The title compound was prepared by the procedures described
in Example 228, substituting ethyl sulfonamide with
N-methylpiperazine sulfonamide, giving a light yellow solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.18 (d, J=6.5 Hz, 6H),
1.40-2.10 (m, 9H), 2.60 (s, 3H), 2.60-2.76 (m, 4H), 2.90 (br s,
3H), 3.44 (septet, J=6.5 Hz, 1H), 3.52-4.08 (m, 4H), 6.71 (d, J=8.4
Hz, 1H), 6.95 (d, J=15.6 Hz, 1H), 7.31 (d, J=2.1, 8.4 Hz, 1H),
7.43-7.57 (m, 4H), 7.64 (d, J=15.6 Hz, 1H), 8.44 (s, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 616. Anal. Calcd for
C.sub.29H.sub.37N.sub.5O.sub.6S.sub.2.1.13 H.sub.2O: C, 54.76; H,
6.22; N, 11.01. Found: C, 54.78; H, 6.11; N, 10.87.
Example 229
(2-Isopropylphenyl)[2-nitro-4-(E-(((3-n-toluenesulfonylaminocarbonyl)piper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0917] The title compound was prepared by the procedures described
in Example 228, substituting ethyl sulfonamide with
p-toluenesulfonamide, giving a light yellow solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=6.5 Hz, 6H), 1.75-1.94 (m,
2H), 2.05-2.24 (m, 1H), 2.40 (s, 3H), 2.48-2.60 (m, 2H), 3.45
(septet, J=6.5 Hz, 1H), 3.50-3.85 (m, 3H), 3.85-4.12 (m, 1H), 6.72
(d, J=8.4 Hz, 1H), 6.86 (d, J=15.6 Hz, 1H), 7.27-7.34 (m, 2H), 7.43
(dd, J=2.1, 8.4 Hz, 1H), 7.50 (overlapping d, 1H), 7.53 (d, J=8.4
Hz, 2H), 7.55 (d, J=8.4 Hz 1H), 7.92 (d, J=8.4 Hz, 2H), 8.44 (s,
1H). MS (ESI.sup.+) (M+H).sup.- at m/z 608.
Example 230
(2-Isopropylphenyl)[2-nitro-4-(E-((3-methyl-4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[0918] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.94-1.18
(m, 3H); 1.14 (d, J=7.0 Hz, 6H); 1.98-2.08 (br m, 3H); 2.69-3.74
(br m, 4H); 4.02-4.65 (br m, 4H); 6.64 (d, J=8.5 Hz, 1H) 7.31-7.63
(m, 6H); 7.88-7.96 (br m, 1H); 8.65 (br s, 1H). MS (APCI)
(M+H).sup.+ at m/z 468. Anal calcd for
C.sub.25H.sub.29N.sub.3S.sub.1O.sub.4.0.1H.sub.2O: C, 63.91; H,
6.70; N, 8.94. Found: C, 63.54; H, 6.41; N, 8.67.
Example 231
(2-Hydroxyphenyl)-[2-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]s-
ulfide
[0919] The title compound was prepared according to the procedures
of Example 1, giving a white solid, m.p. 157-158 C. .sup.1H-NMR
(CDCl.sub.3 300 MHz) .delta. 3.60-3.76 (m, 8H), 6.42 (s, 1H), 6.57
(d, J=9 hz, 1H), 6.76 (d, J=15 Hz, 1H), 6.99-7.04 (m, 1H),
7.10-7.20 (m, 2H), 7.42-7.55 (m, 4H). Anal. Calcd. for
C.sub.19H.sub.18ClNO.sub.3S: C, 60.71; h, 4.83; N, 3.73. Found: C,
60.48; H, 5.05; N, 3.69.
Example 232
(1-(Carboxymethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0920] To a stirred solution of indole compound from Example 85 (35
mg, 0.080 mmol) in 1 mL of anhydrous DMSO was added crushed KOH (18
mg, 0.32 mmol). After 45 min t-butyl bromoacetate (23.5 mL, 0.16
mmol) was added. The resulting mixture was stirred at ambient
temperature for 10 h. Water was then added and the reaction mixture
was acidified with 3 N HCl to pH=3. The title compound (25 mg, 63%)
was collected through filtration and dried in vacuum oven, giving a
white solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 2.04 (s,
3H), 3.38-3.80 (m, 8H), 4.59 (s, 2H), 6.45 (d, J=3.0 Hz, 1H), 6.52
(d, J=8.7 Hz, 1H), 7.21 (dd, J=2.1, 8.7 Hz, 1H), 7.25 (d, J=15.6
Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 7.40 (d, J=3.0 Hz, 1H), 7.47 (d,
J=8.4 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.97 (s, 1H). MS (ESI.sup.+)
(M-H).sup.+ at m/z 496, 498.
Example 233
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-acetylpiperazin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[0921] The title compound was prepared by the procedures described
in Example 84, substituting 2-bromothiophenol with
6-mercaptobenzenedioxane, white solid. .sup.1H NMR (CDCl.sub.1, 300
MHz) .delta. 2.15 (s, 3H), 3.46-3.89 (m, 8H), 4.30 (dd, J=2.1, 6.0
Hz, 4H), 6.84 (d, J=15.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.97-7.10
(m, 3H), 7.42 (d, J=8.4 Hz, 1H), 7.64 (d, J=15.0 Hz, 1H), 7.77 (s,
1H). MS (ESI.sup.+) m/z 493 (M+H).sup.+.
Example 234
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-pyrrolidin-2-onyl)prop-1-ylamino)c-
arbonyl)ethenyl)phenyl]sulfide
[0922] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.1 Hz, 6H); 1.58-1.68 (m, 2H): 1.85-1.97 (m, 2H); 2.18-2.24 (m,
2H); 3.10-3.22 (m, 4H); 3.30-3.39 (m, 3H); 6.65-6.72 (m, 2H);
7.32-7.45 (m, 2H); 7.57-7.62 (m, 3H); 7.76 (dd, J=8.8, 2.0 Hz, 1H);
8.11-8.17 (m, 1H); 8.44 (d, J=2.0 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 468. Anal calcd for
C.sub.25H.sub.29N.sub.3S.sub.1O.sub.4.0.26CH.sub.3COOCH.sub.2CH.sub.3:
C, 63.77; H, 6.39; N, 8.57. Found: C, 63.46; H, 6.37; N, 8.90.
Example 235
(3-(2-Morpholinoethylamino)phenyl)[2-trifluoromethyl-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0923] The title compound was prepared according to the procedures
of Example 62, employing the compound of Example 103 as starting
material. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.78 (d, 1H,
J=1.4 Hz), 7.64 (d, 1H, J=15.4 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21
(t, 1H, J=7.9 Hz), 7.12 (d, 1H, J=8.5 Hz), 6.84 (d, 1H, J=15.4 Hz),
6.82 (m, 1H), 6.76 (t, 1H, J=1.8 Hz), 6.66 (m, 1H), 3.72 (m, 10H),
3.51-3.55 (m, 2H), 3.16 (t, 2H, J=5.9 Hz), 2.64 (t, 2H, J=5.9 Hz),
2.50 (m, 4H), 2.15 (s, 3H). MS (ESI) m/z 563.
Example 236
(2-Pyrrolidin-1-ylphenyl)[2-nitro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[0924] The title compound was prepared according to the procedures
of Example 62, employing the compound of Example 103 as starting
material. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.77 (s, 1H),
7.64 (d, 1H, J=15.4 Hz), 7.40 (m, 1H), 7.22 (d, 1H, J=7.8 Hz), 7.10
(d, 1H, J=8.8 Hz), 6.82 (d, 1H, J=15.3 Hz), 6.76 (d, 1H, J=7.8 Hz),
6.70 (t, 1H, J=2.0 Hz), 6.59 (dd, 1H, J=2.4, 8.1 Hz), 3.61-3.79 (m,
6H), 3.51-3.54 (m, 2H), 3.28 (m, 4H), 2.14 (s, 3H), 2.01 (m, 4H).
MS (ESI) m/z 504.
Example 237
(3-Bromophenyl)[2-nitro-4-(E-((3-carboethoxypyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0925] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.40 (d,
11, J=1.5 Hz), 7.75 (m, 1H), 7.45 (m, 1H), 7.48-7.56 (m, 2H), 7.38
(t, 1H, J=7.9 Hz), 7.00 (br, 1H), 6.87 (d, 1H, J=9.5 Hz), 4.16 (q,
2H, J=7.1 Hz), 3.99 (br, 2H), 3.70 (br, 1H), 3.30 (br, 1H), 3.00
(br, 1H), 2.55 (s, 1H), 2.10 (m, 1H), 1.89 (br, 1H), 1.85 (br, 1H),
1.27 (t, 3H, J=7.0 Hz). MS (ESI) m/z 519, 521. Anal. Calcd for
C.sub.23H.sub.23BrN.sub.2O.sub.5S.0.19 H.sub.2O: C, 52.84; H, 4.51;
N, 5.36. Found: C, 52.85; H, 4.55; N, 5.28.
Example 238
(3-Bromophenyl)[2-nitro-4-(E-((4-carboethoxypyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0926] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.41 (s,
1H), 7.75 (m, 1H), 7.62-7.67 (m, 2H), 7.53 (m, 1H), 7.48 (d, 1H,
J=8.8 Hz), 7.38 (t, 1H, J=7.9 Hz), 6.98 (br, 1H), 6.88 (d, 1H,
J=8.5 Hz), 4.18 (q, 2H, J=7.1 Hz), 3.64-78 (br, 4H), 3.55 (br, 4H),
1.29 (t, 3H, J=7.0 Hz). MS (ESI) m/z 520, 522.
Example 239
(2-(Hydroxymethyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
[0927] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with a mixture of
2-hydroxymethyl-6-bromobenzodioxane and
2-hydroxymethyl-7-bromobenzodioxa- ne, giving a white solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz, mixture of 3:2 regioisomers)
.delta. 2.15 (s, 3H), 3.46-3.83 (m, 8H), 3.83-4.01 (m, 2H),
4.10-4.42 (m, 4H), 6.75 (d, J=8.4 Hz, 1H), 6.79 (d, J=15.9 Hz, 1H),
[6.95 (d), 6.98 (d), J=4.8 Hz, 1H in total], [7.04 (t), 7.07 (t),
J=1.5 Hz, 1H in total], [7.10 (d), 7.11 (d), J=2.4 Hz, 1H in
total], 7.19 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=15.6 Hz,
1H). MS (APCI.sup.+) (M+H).sup.+ at m/z 489.
Example 240
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-
-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0928] The title compound was prepared by the procedures described
in Example 233, substituting 1-acetylpiperazine with
3-aminopropyl-1-pyrroli- din-2-one, giving a white solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.69-1.80 (m, 2H), 2.08 (p, J=7.5
Hz, 2H), 2.44 (t, J=7.5 Hz, 2H), 3.27-3.48 (m, 6H), 4.24-4.34 (m,
4H), 6.44 (d, J=15.6 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 7.00 (d,
J=8.4 Hz, 1H), 7.01 (dd, J=2.7, 8.4 Hz, 1H), 7.06 (d, J=2.7 Hz,
1H), 7.08 (s, 1H), 7.40 (dd, J=2.1, 8.4 Hz, 1H), 7.53 (d, J=15.6
Hz, 1H), 7.75 (d, J=2.1 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z
507.
Example 241
(3-(Dimethylaminomethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0929] The title compound was prepared by the procedures described
in Example 217, substituting the indole from 186 with the indole
from Example 85, resulting in a white solid. .sup.1H NMR (CDCl, 300
MHz) .delta. 2.15 (s, 3H), 2.54 (s, 6H), 3.47-3.85 (m, 8H), 4.05
(s, 2H), 6.56 (d, J=8.7 Hz, 1H), 6.77 (d, J=15.6 Hz, 1H), 7.09 (d,
J=8.7 Hz, 1H), 7.36 (dd, J=1.5, 8.7 Hz, 1H), 7.50 (d, J=8.7 Hz,
1H), 7.52 (s, 2H), 7.56 (d, J=15.6 Hz 1H), 7.88 (s, 1H), 9.27 (s,
1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 497, 499. Anal. Calcd for
C.sub.26H.sub.29ClN.sub.4O.sub.2S.0.46 TFA.1.72 MeOH: C, 56.89; H,
6.06; N, 9.27. Found: C, 56.83; H, 6.15: N, 9.46.
Example 242
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0930] The title compound was prepared by the procedures described
in Example 225, substituting ethyl nipecotate with ethyl
pipecolinate, giving a light-yellow solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.18 (d, J=6.9 Hz, 6H), 1.28 (t, J=7.35 Hz, 3H),
1.34-1.62 (m, 2H), 1.62-1.84 (m, 3H), 2.32 (br d, J=13.2 Hz, 1H),
3.33-3.54 (m, 1H), 3.45 (septet, J=6.9 Hz, 1H), 3.99 (br d, J=13.2
Hz, 1H), 4.21 (q, J=7.35 Hz, 2H), 5.46 (br s, 1H), 6.69 (d, J=8.7
Hz, 1H), 7.01 (d, J=15.6 Hz, 1H), 7.25-7.34 (m, 1H), 7.42 (d, J=8.7
Hz, 1H), 7.46-7.60 (m, 3H), 7.58 (d, J=15.6 Hz, 1H), 8.44 (s, 1H).
MS (ESI.sup.+) (M+H).sup.+ at m/z 483.
Example 243
(2-Isopropylphenyl)[2-nitro-4-(E-((2-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0931] The title compound was prepared by the procedures described
in Example 226, substituting the ethyl ester from Example 225 with
the ethyl ester from Example 242, giving a light-yellow solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.18 (d, J=6.9 Hz, 6H),
1.40-1.89 (m, 5H), 2.34 (br d, J=11.7 Hz, 1H), 3.31-3.51 (m, 1H),
3.44 (septet, J=6.9 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 5.42 (br s,
1H), 6.70 (d, J=7.8 Hz, 1H), 6.99 (br d, J=15.6 Hz, 1H), 7.29 (td,
J=2.7, 6.9 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.45-7.58 (m, 3H), 7.64
(d, J=15.6 Hz, 1H), 8.43 (s, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z
455. Anal. Calcd for C.sub.24H.sub.26N.sub.2O.sub.5S.0.08 H.sub.2O:
C, 63.22; H, 5.78; N, 6.14. Found: C, 63.21; H, 5.65; N, 6.00.
Example 244
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0932] The title compound was prepared by the procedures described
in Example 225, substituting ethyl nipecotate with ethyl
isonipecotate, to give a light-yellow solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.18 (d J=6.9 Hz, 6H), 1.27 (t, J=7.5
Hz, 3H), 1.64-1.86 (m, 2H), 1.94-2.09 (m, 2H), 2.90-3.15 (m, 1H),
3.15-3.39 (m, 1H), 3.44 (septet, J=6.9 Hz, 1H), 3.95-4.14 (m, 1H),
4.16 (q, J=7.5 Hz, 2H), 4.40-4.63 (m, 1H), 6.69 (d, J=8.7 Hz, 1H),
6.98 (d, J=15.6 Hz, 1H), 7.29 (td, J=2.7, 6.9 Hz, 1H), 7.41 (d,
J=8.4 Hz, 1H), 7.46-7.60 (m, 3H), 7.58 (d, J=15.6 Hz, 1H), 8.43 (s,
1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 483.
Example 245
(2-Isopropylphenyl)[2-nitro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0933] The title compound was prepared by the procedures described
in Example 226, substituting the ethyl ester from Example 225 with
the ethyl ester from Example 244, producing a light-yellow solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.18 (d, J=6.9 Hz, 6H),
1.65-1.89 (m, 2H), 1.97-2.14 (m 2H), 2.59-2.74 (m, 1H), 2.93-3.20
(m, 1H), 3.20-3.42 (m, 1H), 3.44 (septet, J=6.9 Hz, 1H), 3.97-4.18
(m, 1H), 4.40-4.65 (m, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.97 (d, J=15.6
Hz, 1H), 7.30 (td. J=2.7, 6.9 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H),
7.46-7.65 (m, 3H), 7.60 (d, J=15.6 Hz, 1H), 8.43 (s, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 455.
Example 246
(2-Isopropylphenyl)[2-nitro-4-(E-(((4-p-toluenesulfonylaminocarbonyl)piper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0934] The title compound was prepared by the procedures described
in Example 229, substituting the acid from Example 226 with the
acid from Example 245, light-yellow solid: .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.14 (d, J=6.9 Hz, 6H), 1.18-1.39
(m, 2H), 1.67-1.79 (m, 2H), 2.39 (s, 3H), 2.60-2.75 (m, 1H),
2.96-3.14 (m, 1H), 3.26-3.42 (m, 1H), 3.34 (septet, J=6.9 Hz, 1H),
4.10-4.42 (m, 2H), 6.62 (d, J=8.4 Hz, 1H), 7.32-7.43 (m, 4H), 7.45
(d, J=15.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.60 (d, J=3.6 Hz, 1H),
7.78 (d, J=8.4 Hz, 2H), 7.87 (dd, J=2.7, 8.4 Hz, 1H), 8.60 (d,
J=2.7 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 606. Anal. Calcd
for C.sub.31H.sub.33N.sub.3O.sub.6S.sub.2.0.26 H.sub.2O: C, 60.80:
H, 5.52; N, 6.86. Found: C, 60.85; H, 5.84; N, 6.61.
Example 247
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxy-4-hydroxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0935] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.53-1.70 (br m, 2H); 2.92-3.52 (br m, 1H);
3.30-3.40 (m, 1H); 3.98-4.44 (br m, 4H); 4.90-5.20 (br m, 1H); 6.63
(d, J=8.5 Hz, 1H); 7.34-7.62 (m, 6H); 7.87-7.94 (br m, 1H);
8.58-8.64 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 471. Anal calcd
for C.sub.24H.sub.26N.sub.2S.sub.1O.su- b.6: C, 61.26; H, 5.57; N,
5.95. Found: C, 61.05; H, 5.85; N, 5.73.
Example 248
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboethoxypiperidin-1-yl)
carbonyl)ethenyl)phenyl]sulfide
[0936] The title compound was prepared by the procedures described
in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
ethyl nipecotate, giving a white hygroscopic solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.26 (t, J=7.0 Hz, 3H), 1.54 (m, 1H)
1.65-1.80 (m, 2H), 2.10 (m, 1H), 2.54 (m, 1H), 2.92-3.40 (m, 2H),
3.60-4.10 (m, 2H), 4.14 (q, J=7.0 Hz, 2H), 4.25-4.32 (m, 4H), 6.91
(d, J=7.5 Hz, 1H), 7.00 (dd, J=2.0, 15.0 Hz, 3H), 7.05 (d, J=2.0
Hz, 1H), 7.40 (d, J=8.0, 1H), 7.56 (d, J=15.0 Hz, 1H), 7.76 (s,
1H). MS (CI/NH.sub.3) m/z 522 (M+H).sup.+. Anal. calcd. for
C.sub.26H.sub.26F.sub.3NO.sub.5S: C, 59.88; H, 5.02; N, 2.69.
Found: C, 59.92; H, 5.39; N, 2.56.
Example 249
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboethoxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0937] The title compound was prepared by the procedures described
in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
ethyl pipecolinate. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.28
(t, J=7.0 Hz, 3H), 1.35-1.54 (m, 2H), 1.64-1.82 (m, 3H), 2.30 (m,
1H), 3.40 (m, 1H), 4.00 (m, 1H), 4.22 (q, J=7.0 Hz, 2H), 4.26-4.34
(m, 4H), 5.48 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.98 (m, 1H), 7.02
(dd, J=2.0, 8.0 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.0 Hz,
1H), 7.57 (d, J=15.0 Hz, 1H), 7.77 (s, 1H). MS (CI/NH.sub.3) m/z
522 (M+H).sup.+. Anal. calcd for C.sub.26H.sub.26F.sub.3NO.sub.5S:
C, 59.88; H, 5.02; N, 2.69. Found: C, 60.25; H, 5.12; N, 2.55.
Example 250
(Benzodioxan-6-yl)[2-nitro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl-
)phenyl]sulfide
[0938] The title compound was prepared by the hydrolysis of
compound 198 under basic condition (aq. NaOH/EtOH), and purified by
reversed-phase HPLC. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
1.44 (m, 2H), 1.78 (m, 2H), 2.04 (m, 2H), 2.82 (m, 1H), 4.02-4.20
(m, 2H), 4.4.20-4.35 (m, 4H), 6.90 (d, J=8.0 Hz, 1H), 6.97 (d,
J=8.0 Hz, 1H), 7.05 (dd, J=2.0, 8.0 Hz, 1H), 7.10 (d, J=2.0 Hz,
1H), 7.15 (br, 1H), 7.44 m 1H), 7.60 (br, 1H), 8.40 (s, 1H). MS
(ESI) m/z 469 (M-1).sup.-.
Example 251
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyrrolidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0939] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.75 (s,
1H), 7.60 (d, 1H, J=15.0 Hz) 7.40 (br, 1H), 7.06 (d, 1H, J=2.2 Hz),
6.96-7.02 (m, 3H), 6.90 (d, 1H, J=8.5 Hz), 4.30 (m, 5H), 3.99 (br,
2H), 3.29 (br, 2H), 2.60 (br, 2H), 1.85 (br, 2H). MS (ESI) m/z
-492.
Example 252
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboethoxypiperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0940] The title compound was prepared by the procedures described
in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
ethyl isonipecotate, giving a white sticky solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.26 (t, J=7.0 Hz, 3H), 1.68-1.80 (m,
2H), 1.98-2.10 (, 2H), 2.54-2.70 (m, 2H), 3.00-3.30 (br, 2H), 4.15
(m, 3H), 4.26-4.34 (m, 4H), 6.90 (d, J=8.0 Hz, 2H), 7.00 (dd,
J=2.0, 8.0 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H), 7.41 (m, 1H), 7.50 (br,
1H), 7.75 (s, 1H). MS (CI/NH3) m/z 522 (M+H).sup.+. Anal. calcd.
for C.sub.24H.sub.22F.sub.3NO.sub.5S.0.1 H.sub.2O: C, 58.20; H,
4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Example 253
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-tert-butoxyca-
rbonylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0941] The title compound was prepared by the procedures described
in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
1-Boc-3-carbomethoxypiperazine, giving a white solid. mp
85-87.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.46 (s,
9H), 2.90-3.00 (m, 2H), 3.08-3.20 (m, 2H), 3.76 (s, 3H), 3.90 (m,
1H) 4.25-4.34 (m, 4H), 4.58-4.66 (m, 2H), 6.92 (d, J=8.0 Hz, 1H),
6.98 (m, 1H), 7.02 (dd, J=2.0, 8.0 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H),
7.40 (m, 1H), 7.62 (br, 1H), 7.76 (s, 1H). MS (APCI) m/z 609
(M+H).sup.+. Anal. calcd. for
C.sub.29H.sub.31F.sub.3N.sub.2O.sub.7S: C, 57.23; H, 5.13; N, 4.60.
Found: C, 57.09; H, 5.25; N, 4.37.
Example 254
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxy-4-methoxycarbon-
ylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0942] The title compound was prepared by treating the compound of
Example 255 with methyl chloroformate and pyridine in
CH.sub.2Cl.sub.2 at room temperature, producing a white foam.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.00 (m, 1H), 3.18 (m,
1H), 3.60 (m, 1H), 3.72 (s, 3H), 3.76 (s, 3H), 3.90 (m, 1H), 4.10
(br, 1H), 4.28-4.34 (m, 4H), 4.64 (m, 1H), 5.32 (m, 1H), 6.85 (d,
J=15.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.98 (m, 1H), 7.02 (dd,
J=2.0, 8.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H),
7.64 (d, J=15.0 Hz, 1H), 7.77 (s, 1H). MS (CI/NH.sub.3) m/z 567
(M+H).sup.+. Anal. calcd. for
C.sub.26H.sub.25F.sub.3N.sub.2O.sub.7S: C, 55.12; H, 4.45; N, 4.94.
Found: C, 55.18; H, 4.70; N, 4.68.
Example 255
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carbomethoxypiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0943] The title compound was prepared by deprotection of compound
253 with TFA in CH.sub.2Cl.sub.2, resulting in a light yellow
solid. mp 70-72.degree. C. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.90 (m, 1H), 3.05 (m, 1H), 3.35 (m, 1H), 3.68 (m, 1H),
3.80 (s, 3H), 400 (m, 1H), 4.25-4.34 (m, 4H), 4,70 (br, 1H), 5.46
(m, 1H), 6.84 (d, J=15.5 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.96-7.04
(m, 2H), 7.06 (m, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.65 (d, J=15.5 Hz,
1H), 7.77 (s, 1H). MS (CI/NH.sub.3) m/z 509 (M+H).sup.+. Anal.
calcd. for C.sub.24H.sub.23F.sub.3N.sub.2O.sub.5S.1.55 H.sub.2O: C,
53.74; H, 4.90; N, 5.22. Found: C, 54.04; H, 4.59; N, 4.82.
Example 256
(2-Methyl-3-(carboethoxymethyl)indol-5-yl)[2-trifluoromethyl-4-(E-((morpho-
lin-1-yl)carbonyl)ethenyl)phenyl]sulfide
Example 256A
(4-Bromophenyl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl)ethenyl)p-
henyl]sulfide
[0944] The bromide was prepared by the procedure described in
Example 12, substituting 2-bromothiophenol with 4-bromothiophenol,
and 3,4-dichlorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzaldehyde.
Example 256B
(4-Hydrazinophenyl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide, benzophenone hydrazone
[0945] To a stirred solution of above-described bromide (1.0 g,
2.12 mmol) in 10 mL of toluene with Pd(OAc).sub.2 (9.5 mg, 0.04
mmol), BINAP (40 mg, 0.06 mmol), and benzophenone hydrazone (437
mg, 2.12 mmol) was added NaOt-Bu (285 mg, 2.97 mmol). The reaction
mixture was bubbled with N.sub.2 for 2 min before it was heated at
80.degree. C. for 4 h. The reaction mixture was then allowed to
cool down to ambient temperature. Ether was then added and the
mixture was filtered through celite, washed with diethyl ether. The
filtrate was concentrate in vacuo and the residue was purified on a
SiO.sub.2 flash column chromatography eluting with 10-30%
EtOAc/hexanes to give 170 mg (13%) of the title compound as light
brown foamy solid.
Example 256C
(2-Methyl-3-(carboethoxymethyl)indol-5-yl)[2-trifluoromethyl-4-(E-((morpho-
lin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0946] To a stirred solution of hydrazone (90 mg, 0.15 mmol) in 2
mL of ethanol was added levunilic acid (24 mL, 23 mmol) and p-TsOH
(146 mg, 0.75 mmol). The mixture was then refluxed for 2 days.
After cooled down to ambient temperature, the reaction mixture was
partitioned between EtOAc and sat. NaHCO.sub.3. The organic layer
was then washed with brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was then purified on Gilson
preparative HPLC as described in Example 38B to give 6.0 mg (7%) of
the title compound, light-brown solid. .sup.1H NMR (CDCl.sub.3,
1300 MHz) .delta. 1.20 (t, J=7.4 Hz, 3H), 2.46 (s, 3H), 3.55-3.83
(br m, 8H), 3.67 (s, 2H), 4.12 (q, J=7.4 Hz, 2H), 6.79 (d, J=15.3
Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 7.23-7.31 (m, 2H), 7.34 (d, J=8.4
Hz, 1H), 7.60 (d, J=15.3 Hz, 1H), 7.76 (s, 1H), 7.80 (s, 1H), 8.04
(s, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 533.
Example 257
(1-(2-Methoxyethyl)indol-5-yl)[2-chloro-4-(E-((4-acetylpiperazin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[0947] The title compound was prepared by the procedures described
in Example 232, substituting 1-butyl bromoacetate with
bromoethylmethyl ether, white solid; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 2.14 (s, 2H), 3.35 (s, 3H), 3.46-3.56 (m, 2H),
3.56-3.80 (m, 6H), 3.75 (t, J=5.6 Hz, 2H), 4.33 (t, J=5.6 Hz, 2H),
6.54 (d, J=3.3 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 6.75 (d, J=15.3 Hz,
1H), 7.09 (dd, J=2.1, 11.7 Hz, 1H), 7.26 (overlapping d, 1H), 7.36
(dd, J=2.1, 8.7 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.51 (d, J=2.1 Hz,
1H), 7.56 (d, J=15.3 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 498, 500.
Example 258
(2-Isopropylphenyl)[2-nitro-4-(E-((3-acetoxymethyl-4-hydroxypiperidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0948] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) 1.14 (d, J=7.0
Hz, 6H), 1.51-1.90 (br m, 2H); 1.92-2.06 (m, 3H); 2.50-3.21 (br m,
2H); 3.30-3.40 (m, 1H), 3.40-4.44 (br m, 5H); 4.88-4.97 (br m, 1H);
6.63 (d, J=8.5 Hz, 1H); 7.31-7.62 (m, 6H); 7.87-7.94 (br m, 1H);
8.58-8.64 (br m, 1H). MS (APCI) (M+H).sup.+ at m/z 499. Anal calcd
for C.sub.26H.sub.30N.sub.2S.su- b.1O.sub.6.0.29H.sub.2O: C, 61.98;
H, 6.12; N, 5.56. Found: C, 62.00; H, 6.35; N, 5.55.
Example 259
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(dimethylaminocarbonyl)-4-hydroxypipe-
ridin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0949] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H), 1.54-1.75 (br m, 2H); 2.81, 2.82 (br s, br s, 3H),
3.00, 3.04 (br s, br s, 3H); 2.75-3.60 (br m, 3H), 3.30-3.40 (m,
1H); 3.90-4.28 (br m, 2H); 4.95-5.28 (br m, 1H); 6.61-6.66 (m, 1H);
7.34-7.62 (m, 6H); 7.87-7.94 (br m, 1H); 8.58-8.63 (br m, 1H). MS
(ESI) (M+H).sup.+ at m/z 498. Anal calcd for
C.sub.26H.sub.31N.sub.3S.sub.1O.sub.5.0.34H.sub.2O: C, 61.99; H,
6.34; N, 8.34. Found: C, 61.96; H, 6.37; N, 8.56.
Example 260
(2-Isopropylphenyl)[2-nitro-4-(E-((3-cyanomorpholin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
[0950] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 3.30-3.40 (m, 1H); 3.30-4.16 (br m, 5H); 4.20-4.29
(br m, 1H); 5.07 (t, J=3.5 Hz, 1H); 6.65 (d, J=8.8 Hz, 1H);
7.32-7.44 (m, 2H); 7.54-7.62 (m, 4H); 7.91 (dd, J=8.8, 2.0 Hz, 1H);
8.67 (d, J=2.0 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z 438. Anal
calcd for C.sub.23H.sub.23N.sub.3S.sub.1O.su-
b.4.0.25C.sub.6H.sub.14: C, 64.11; H, 5.82; N, 9.15. Found: C,
63.99; H, 6.00; N, 9.12.
Example 261
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboethoxymorpholin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[0951] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.12-1.27 (m, 3H); 3.30-3.40 (m, 1H); 3.15-4.33 (br
m, 9H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.42 (m, 2H); 7.50-7.62 (m,
4H); 7.88-7.96 (br m, 1H), 8.65 (br s, 1H). MS (APCI) (M+H).sup.+
at m/z 485. Anal calcd for C.sub.25H.sub.28N.sub.2S.sub.1O.sub.6:
C, 61.97; H, 5.82; N, 5.78. Found: C, 61.83; H, 6.07; N, 5.74.
Example 262
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(tetrazol-5-yl)morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[0952] The compound of Example 260 (160 mg, 0.336), sodium azide
(56.6 mg, 0.872 mmol), n-Bu.sub.3SnCl and THF were mixed in a
reaction tube, flushed with nitrogen and heated to reflux
overnight. The mixture was then cooled to ambient temperature and
1N HCl soln. was added. The mixture was extracted with ethyl
acetate three times and the combined organics were dried over
MgSO.sub.4. The mixture was filtered through a short silica gel
plug to give 96 mg (56% yield) of the desired material. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d, J=6.8 Hz, 6H); 2.96-4.62
(br m, 7H); 4.77 (dd, J=10.5, 2.7 Hz, 1H); 6.58-6.67 (m, 1H);
7.32-7.62 (m, 614); 7.92 (dd, J=8.8, 2.0 Hz, 1H); 8.62-8.67 (br m,
1H). MS (APCI) (M+H) at m/z 481. Anal calcd for
C.sub.23H.sub.24N.sub.6S.sub.1- O.sub.4.1.2H.sub.2O: C, 54.93; H,
5.31; N, 16.71. Found: C, 54.97; H, 5.12; N, 16.50.
Example 263
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[0953] The title compound was prepared by hydrolysis of the
compound of Example 252 under basic conditions (aq. NaOH/EtOH),
giving a white solid, mp 88.degree. C. (dec.). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.40 (m, 2H), 1.98 (m, 2H), 2.95
(m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 4.20 (m, 2H), 4.35 (m, 4H),
7.00 (m, 4H), 7.20 (m, 2H), 7.90 (m, 1H), 8.20 (m, 1H), 12.30 (s,
1H). MS (APCI) m/z 494 (M+H).sup.+. Anal. calcd. for
C.sub.24H.sub.22F.sub.3NO.sub.5S.0.1 H.sub.2O: C, 58.20; H, 4.52;
N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Example 264
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[0954] The title compound was prepared by hydrolysis of the
compound of Example 249 under basic conditions (aq. NaOH/EtOH),
resulting in a white solid, mp 90.degree. C. (dec.). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.15-1.50 (m, 2H), 1.50-1.70 (m,
2H), 2.16 (m, 1H), 2.56 (m, 1H), 3.15 (m, 1H), 4.30 (s, 4H), 4.32
(m, 1H), 5.20 (m, 1H), 7.02 (m, 4H), 7.30-7.52 (m, 2H), 7.84 (m,
1H), 8.15 (s, 1H). MS (APCI) m/z 494 (M+H).sup.+. Anal. calcd. for
C.sub.24H.sub.22F.sub.3NO.sub.5.0.3 H.sub.2O: C, 57.78; H, 4.57; N,
2.81. Found: C, 57.87; H, 4.57; N, 2.76.
Example 265
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-carbomethoxypiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0955] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76 (s,
1H), 7.62 (d, 1H, J=15.0 Hz), 7.40 (d, 1H, J=8.6 Hz) 7.06 (d, 1H,
J=2.1 Hz), 6.98-7.04 (m, 2H), 6.91 (d, 1H, J=8.4 Hz), 6.84 (d, 1H,
J=15.6 Hz), 4.31 (m, 4H), 4.18 (q, 2H, J=7.1 Hz), 3.68 (br, 4H),
3.54 (br s, 4H), 1.29 (t, 3H, J=7.2 Hz). MS (ESI) m/z 523, 545,
1045, 1067.
Example 266
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-aza-6,9-diooxaspiro[5.4]deca-
n-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0956] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.13 (s,
1H), 7.84 (d, 1H, J=9.0 Hz), 7.48 (d, 1H, J=15.4 Hz) 7.38 (d, 1H,
J=15.4 Hz), 6.98-7.06 (m, 4H), 4.30 (m, 4H), 3.92 (s, 4H), 3.74
(br, 2H), 2.62 (br, 2H), 1.63 (br, 4H). MS (ESI) m/z 508, 1015.
Example 267
(Benzodioxan-6-yl)[2-trifluoro-4-(E-((4-(benzimidazolon-1-yl)piperidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
[0957] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.32 (s,
1H), 7.79 (s, 1H), 7.66 (d, 1H, J=15.4 Hz), 7.44 (d, 1H, J=8.5 Hz),
7.0-7.12 (m, 6H), 6.94 (d, 1H, J=9.9 Hz), 6.90 (d, 1H, J=2.6 Hz),
4.98 (m, 1H), 4.59 (m, 1H), 4.20 (m, 5H), 3.31 (br, 1H), 2.83 (br,
1H), 2.40 (m, 2H), 1.98 (m, 2H). MS (ESI) m/z 582, 604, 1163,
1185.
Example 268
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-(methylaminocarbonyl)piperid-
in-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0958] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.75 (s,
1H), 7.67 (d, 1H, J=15.4 Hz) 7.40 (d, 1H, J=8.1 Hz), 7.06 (d, 1H,
J=2.4 Hz), 6.96-7.02 (m, 2H), 6.90 (d, 1H, J=8.2 Hz), 4.28 (m, 4H),
3.95 (br, 2H), 3.50 (m, 1H), 2.82 (s, 3H), 2.40 (m, 1H), 2.15 (br,
1H), 1.88 (br, 1H), 1.73 (br, 2H). MS (ESI) m/z 507,529, 1035.
Example 269
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carbomethoxy-4-methoxycarbon-
ylpiperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0959] The title compound was prepared by the procedures described
in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with
2-carbomethoxy-1-methoxycarbonylpiperazine, producing a light
yellow solid. mp 56.degree. C. (dec.). .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 2.70-3.50 (br, 4H), 3.70 (s, 3H), 3.76 (d, J=9.0 Hz,
3H), 4.00 (m, 1H), 4.20 (m, 4H), 4.50-5.00 (br, 2H), 6.91 (d, J=8.5
Hz, 1H), 6.92-7.02 (m, 2H), 7.07 (d, J=2.0 Hz, 1H), 7.25 (m, 1H),
7.40 (m, 1H), 7.60 (m, 1H), 7.72 (s, 1H). MS (APCI) m/z 567
(M+H).sup.+. Anal. calcd. for
C.sub.26H.sub.25F.sub.3N.sub.2O.sub.7S: C, 55.12; H, 4.45; N, 4.94.
Found: C, 55.33; H, 4.74; N, 4.76.
Example 270
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxymorpholin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0960] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 3.08-4.33 (br m, 7H); 3.30-3.40 (m, 1H); 6.58-6.68
(m, 1H); 7.32-7.66 (m, 6H); 7.87-7.94 (m, 1H); 8.53-8.65 (m, 1H).
MS (APCI) (M+H).sup.- at m/z 457. Anal calcd for
C.sub.23H.sub.24N.sub.2S.sub.1O.su- b.6: C, 60.51; H, 5.30; N,
6.14. Found: C, 60.33; H, 5.54; N, 5.80.
Example 271
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2-carboxy-4-methoxycarbonylpip-
erazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0961] The title compound was prepared by treating the compound of
Example 255 with methyl chloroformate and pyridine in
CH.sub.2Cl.sub.2 at room temperature, and followed by hydrolysis
under basic conditions (aq. NaOH/EtOH), producing a white solid. mp
102.degree. C. (dec.). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.
2.85 (m, 1H), 3.02 (m, 1H), 3.20 (m, 1H) 3.40 (m, 1H), 3.62 (s,
3H), 3.88 (m, 1H), 4.29 (s, 4H), 4.35 (m, 1H) 5.15 (m, 1H),
6.90-7.10 (m, 3H), 7.30 (d, J=15.0 Hz, 1H), 7.40 (d, J=15.0 Hz,
1H), 7.54 (d, J=15.0 Hz, 1H), 7.82 (m, 1H), 8.15 (m, 1H). MS
(ESI)/z 553 (M+H).sup.+. Anal. calcd. for
C.sub.25H.sub.23F.sub.3N.sub.2O.sub.7S.- 0.25 H.sub.2O: C, 53.91;
H, 4.25; N, 5.03. Found: 53.91; H, 4.35; N, 5.05.
Example 272
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((morpholin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0962] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76 (s,
1H), 7.62 (d, 1H, J=15.6 Hz), 7.40 (dd, 1H, J=1.8, 8.2 Hz), 7.04
(d, 1H, J=2.1 Hz), 6.98-7.03 (m, 2H), 6.91 (d, 1H, J=8.1 Hz), 6.81
(d, 1H, J=15.3 Hz), 4.30 (m, 4H), 3.65-3.74 (br m, 8H). MS (ESI)
m/z 452, 474, 925.
Example 273
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-(pyrrolidin-1-yl)piperidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide
[0963] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.75 (s,
1H), 7.65 (d, 1H, J=15.3 Hz), 7.40 (dd, 1H, J=1.4, 8.3 Hz), 7.06
(d, 1H, J=2.4 Hz), 6.98-7.02 (m, 2H), 6.90 (d, 1H, J=8.1 Hz), 6.85
(d, 1H, J=15.3 Hz), 4.68 (m, 1H), 4.20 (m, 4H), 3.10 (m, 1H), 3.14
(m, 1H), 2.81 (s, 4H), 2.58 (br, 1H), 2.02 (s, 4H), 1.88 (s, 4H),
1.64 (m, 1H). MS (ESI) m/z 519, 1037.
Example 274
(2-Isopropylphenyl)[2-nitro-4-(E-((3-aza-6,9-diooxaspiro[5.4]decan-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[0964] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.44 (s,
1H), 7.50-7.62 (m, 4H), 7.41 (d, 1H, J=8.0 Hz), 7.30 (m, 1H), 6.96
(br d, 1H, J=15.6 Hz), 6.69 (d, 1H, J=9.4 Hz), 4.00 (s, 4H), 3.75
(br m, 4H), 3.44 (m 1H), 1.75 (br s, 4H), 1.18 (d, 6H, J=7.0 Hz).
MS (ESI) m/z 439, 937.
Example 275
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(dimethylaminomethyl)piperidin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[0965] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.40 (d,
1H, J=1.8 Hz), 7.50-7.58 (m, 4H), 7.42 (d, 1H, J=8.1 Hz), 7.30 (dd,
1H, J=1.9, 7.0 Hz), 7.00 (d, 1H, J=15.4 Hz), 6.68 (d, 1H, J=8.5
Hz), 5.10 (br, 1H), 3.92 (br, 1H), 3.44 (quintet, 1H, J=6.9 Hz),
3.20 (m, 1H), 2.26-2.50 (m, 7H), 1.62-1.85 (m, 7H), 1.48 (m, 1H),
1.18 (d, 6H, J=7.0 Hz). MS (ESI) m/z 468.
Example 276
(2-Isopropylphenyl)[2-nitro-4-(E-((piperidin-1-ylamino)carbonyl)ethenyl)ph-
enyl]sulfide
[0966] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.44 (d,
1H, J=1.8 Hz), 7.66 (d, 1H, J=16.2 Hz), 7.55 (d, 1H, J=7.4 Hz),
7.47-7.51 (m, 3H), 7.30 (m, 2H), 6.72 (d, 1H, J=8.5 Hz), 6.37 (s,
1H), 3.48 (m, 2H), 3.10 (m, 2H), 2.63 (m, 1H), 1.81-1.89 (m, 2H),
1.62-1.77 (m, 4H), 1.19 (d, 6H, J=7.0 Hz). MS (ESI) m/z 426,
851.
Example 277
(Benzodioxan-6-yl)[2-trifluoromethyl-4
E-((3-carboxy-4-methoxycarbonylpipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0967] The title compound was prepared by hydrolysis of the
compound of Example 269 under basic conditions (aq. NaOH/EtOH).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.60-3.30 (m, 3H),
3.40-3.50 (m, 1H), 3.62 (d, J=12.0 Hz, 1H), 3.80 (m, 1H), 4.25-4.35
(m, 4H), 4.55 (m, 1H), 7.00 (s, 2H), 7.00-7.06 (m, 1H), 7.25 (m,
2H), 7.5 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H). MS (APCI) m/z 553
(M+H).sup.+. Calcd. Anal.
C.sub.24H.sub.33F.sub.3N.sub.2O.sub.5.1.55 H.sub.2O: C, 54.35; H,
4.20; N, 5.07. Found: C, 54.16; H, 4.19; N, 4.96.
Example 278
(2-(Dimethylaminocarbonyl)-benzodioxan-6-yl)[2-chloro-4-(E-((4-acetylpiper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0968] The title compound was prepared by the procedures described
in Example 85, substituting 5-iodoindole with
2-N,N-dimethylcarboxamide-6-br- omobenzenedioxane and
3-N,N-dimethylcarboxamide-6-bromobenzenedioxane, giving a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz, mixture of regioisomers)
.delta. 1.93 (s, 3H), 2.15 (s, 6H), 3.53 (br s, 2H), 3.59-3.90 (br
m, 8H), 4.86-5.01 (m, 1H), 6.74-6.81 (m, 1H), 6.80 (d, J=15.3 Hz
1H), 6.93 (d, J=8.7 Hz, 1H), 7.02 (d, CDCl.sub.31.8 Hz, 1H), 7.13
(dd, J=1.8, 8.4 Hz, 1H), 7.16-7.25 (m, 1H), 7.54 (s, 1H), 7.58 (d,
J=15.6 Hz, 1H). MS (ESI.sup.+) (M+Na).sup.- at m/z 552, 554.
Example 279
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(2-(methoxymethyl)tetrazol-5-yl)piper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0969] The title compound was prepared by the procedures described
in Example 225, substituting ethyl nipecotate with
3-N-methoxymethyltetrazol- ylpiperidine, to give a light-yellow
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=6.9 Hz,
6H), 1.62-1.80 (br m, 2H), 1.80-2.20 (br m, 2H), 2.20-2.39 (br m,
2H), 3.12-3.38 (br m, 2H), 3.46 (s, 3H), 4.11 (septet, J=6.9 Hz,
1H), 4.17-4.34 (br m, 1H), 5.79 (s, 2H), 6.70 (br s, 1H), 7.05 (d
J=15.3 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.35-7.68 (m, 5H), 8.42 (br
s, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 523.
Example 280
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(1-(methoxymethyl)tetrazol-5-yl)piper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0970] The title compound was prepared by the procedures described
in Example 279 and separated from the same reaction mixture via
SiO.sub.2 flash column chromatography, to give a light-yellow
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=6.9 Hz,
6H), 1.62-1.80 (br m, 2H), 1.80-2.20 (br m, 2H), 2.20-2.39 (br m,
2H), 3.12-3.38 (br m, 2H), 3.46 (s, 3H), 4.11 (septet, J=6.9 Hz,
1H), 4.17-4.34 (br m, 1H), 5.79 (s, 2H), 6.70 (br s, 1H), 7.05 (d,
J=15.3 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.35-7.68 (m, 5H), 8.42 (br
s, 1H). MS (ESI.sup.+) (M+H).sup.- at m/z 523.
Example 281
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino)ca-
rbonyl)ethenyl)phenyl]sulfide
Example 281A
Triisopropylysilyl(1-methylindol-5-yl)sulfide
[0971] To a stirred solution of 5-bromo-N-methyl indole (300 mg,
1.43 mmol) in 5 mL of benzene in a sealed tube was charged with
Pd(PPh.sub.3).sub.4 (82 mg, 0.072 mmol), followed by KSTIPS (326
mg, 1.43 mmol). The mixture was flushed with N.sub.2, the tube was
capped, and the reaction mixture refluxed for 2 h. The reaction
mixture was then allowed to cool down, partitioned between
Et.sub.2O and water. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, concentrated in vacuo. The residue was
purified on a SiO.sub.2 flash column chromatography eluting with 5%
EtOAc/hexanes to give 400 mg (88%) of the title compound as
colorless oil.
Example 281B
3-Chloro-4-((1-methylindol-5-yl)thio)benzaldehyde
[0972] To a stirred solution of thiolsilyl ether (1.0 g, 3.13 mmol)
in 5 mL of DMF with 3-chloro-4-flurobenzaldehyde (500 mg, 3.13
mmol) at ambient temperature was added CsF (5.7 mg, 0.38 mmol). The
mixture was stirred over night before it was poured in water and
extracted with Et.sub.2O (2.times.25 mL). The combined organic
layer was washed with water and brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was purified on a SiO.sub.2
flash column chromatography eluting with 5-10% EtOAc/hexanes to
give 650 mg (71%) of the title compound as white solid.
Example 281C
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino)ca-
rbonyl)ethenyl)phenyl]sulfide
[0973] The title compound was prepared by the procedures described
in Example 92, substituting the benzoic acid with cinnamic acid
prepared from the above-described aldehyde, and ammonium with
3-aminopropyl-1-pyrrolidin-2-one, to give a white solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.74 (br m, 2H), 2.07 (br m, 2H),
2.44 (br m, 2H), 3.32 (br m, 2H), 3.40 (br m, 4H), 3.85 (s, 3H),
6.36 (d, J=15.3 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.36 (dd, J=1.5,
9.0 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.89 (d, J=1.5
Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 468, 470. Anal. Calcd
for C.sub.25H.sub.26ClN.sub.3O.s- ub.2S.1.37 H.sub.2O: C, 60.95; H,
5.88; N, 8.53. Found: C, 60.97; H, 5.98; N, 8.46.
Example 282
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(tetrazol-5-yl)piperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[0974] The compound from Example 279 (75 mg, 0.14 mmol) was
dissolved in 1 mL of neat TFA and left at ambient temperature for
overnight. The reagent was then removed in vacuo and the residue
was evaporated twice with benzene. The crude product was purified
using Gilson Preparative HPLC as described in Example 38B to give
the title compound as a light-yellow solid (50 mg, 72%); .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.17 (d, J=6.5 Hz, 6H), 1.25-1.39
(m, 1H), 1.69-1.81 (m, 1H), 2.09 (br s, 1H), 2.14-2.30 (m, 1H),
2.57-2.71 (m, 1H), 3.35-3.66 (m, 3H), 3.90-4.03 (m, 1H), 4.66-4.78
(m, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.86 (d, J=15.3 Hz, 1H), 7.32 (dd,
J=2.1, 6.9 Hz, 1H), 7.42 (dd, J=2.1, 8.7 Hz, 1H), 7.47-7.57 (m,
3H), 7.76 (d, J=15.3 Hz, 1H) 8.46 (d, J=2.1 Hz, 1H). MS (ESI.sup.+)
(M+H).sup.+ at m/z 479. Anal. Calcd for
C.sub.24H.sub.26N.sub.6O.sub.3S.0- .28 H.sub.2O: C, 59.61; H, 5.54;
N, 17.38. Found: C, 59.71; H, 5.44; N, 16.99.
Example 283
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0975] The title compound was prepared by the procedures described
in Example 281C. substituting aminopropyl pyrrolidinone with ethyl
nipecotate, giving a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.26 (t, J=7.5 Hz, 3H), 1.65-1.96 (m, 2H), 2.00-2.20 (m,
1H), 2.04 (s, 1H), 2.54 (br m, 1H), 3.12-3.34 (m, 1H), 3.85 (s,
3H), 3.92-4.07 (m, 1H), 4.07-4.20 (m, 1H), 4.15 (q, J=7.5 Hz, 2H),
4.65-4.90 (m, 1H), 6.53 (d, J=3.0 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H),
6.85 (d, J=15.3 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 7.14 (d, J=3.0 Hz,
1H), 7.37 (dd, J=1.5, 8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.51 (s,
1H), 7.51 (d, J=15.3 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 483, 485.
Example 284
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)ethe-
nyl)phenyl]sulfide
[0976] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
ethyl ester from Example 283, and KOH with NaOH, to provide a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.45-1.69 (m, 1H),
1.69-1.98 (m, 2H), 1.98-2.22 (m, 1H), 2.51-2.70 (m, 1H), 3.05-3.47
(m, 1H), 3.80-4.20 (m, 2H), 3.85 (s, 3H), 4.47-4.68 (m, 1H), 6.53
(d, J=3.0 Hz, 1H) 6.57 (d, J=8.1 Hz, 1H), 6.87 (d, J=15.3 Hz, 1H),
7.08 (d, J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.37 (d, J=9.0 Hz,
1H), 7.42 (d, J=9.0 Hz, 1H), 7.51 (s, 1H), 7.52 (d, J=15.3 Hz 1H),
7.89 (br s, 1H). MS (ESI (M-H+ H) at m/z 453, 455.
Example 285
(1-Methylindol-5-yl)[2-chloro-4-(E-((4-carboethoxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0977] The title compound was prepared by the procedures described
in Example 281C, substituting aminopropyl pyrrolidinone with ethyl
isonipecotate, giving a white solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) d 1.26 (t, J=7.5 Hz, 3H), 1.64-1.83 (m, 2H), 1.88-2.08 (m,
2H), 2.48-2.67 (m, 1H), 2.86-3.40 (m, 2H), 3.85 (s, 3H), 3.89-4.24
(m, 1H), 4.15 (q, J=7.5 Hz, 2H), 4.24-4.65 (m, 1H), 6.53 (d, J=3.0
Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 6.81 (d, J=15.3 Hz, 1H), 7.07 (d,
J=8.1 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.37 (dd, J=1.5, 9.0 Hz,
1H), 7.50 (d, J=9.0 Hz, 1H), 7.50 (d, J=15.3 Hz, 1H), 7.88 (d,
J=1.5 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 483, 485.
Example 286
(1-Methylindol-5-yl)[2-chloro-4-(E-((3-carboxypiperidin
1-yl)carbonyl)ethenyl)phenyl]sulfide
[0978] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
ethyl ester from Example 285, and KOH with NaOH, giving a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.60-1.90 (m, 2H),
1.90-2.10 (m, 2H), 2.57-2.72 (m, 1H), 2.80-3.40 (m, 2H), 3.85 (s,
3H), 3.91-4.20 (m, 1H), 4.30-4.68 (m, 1H), 6.53 (d, J=3.0 Hz, 1H),
6.57 (d, J=8.1 Hz, 1H), 6.80 (d, J=15.3 Hz, 1H), 7.07 (d, J=8.1 Hz,
1H), 7.15 (d, J=3.0 Hz, 1H), 7.37 (dd, J=1.5, 9.0 Hz, 1H), 7.51 (d,
J=9.0 Hz, 1H), 7.51 (s, 1H), 7.51 (d, J=15.3 Hz, 1H), 7.89 (br s,
1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 455, 457. Anal. Calcd for
C.sub.24H.sub.23ClN.sub.2O.sub.3S.0.42 H.sub.2O: C, 62.32; H, 5.20;
N, 6.06. Found: C, 62.35; H, 5.30; N, 5.87.
Example 287
(2-Isopropylphenyl)[2-nitro-4-(E-((2-(1-methylpyrrolidin-2-yl)ethylamino)c-
arbonyl)ethenyl)phenyl]sulfide
[0979] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.1, 300 MHz) .delta. 8.44 (d,
1H, J=1.8 Hz), 7.56 (d, 1H, J=3.7 Hz), 7.50-7.58 (m, 3H), 7.43 (DD,
1H, J=1.84, 8.4 Hz), 7.30 (dd, 1H, J=2.2, 6.8 Hz), 6.78 (d, 1H,
J=8.5 Hz), 6.52 (d, 1H, J=15.8 Hz), 3.63 (m, 2H), 3.42 (m, 3H),
3.00 (m, 1H), 3.78 (m, 1H), 2.59 (s, 3H), 2.05 (m, 1H), 2.00 (m,
5H), 1.18 (d, 6H, J=7.0 Hz). MS (ESI) m/z 454, 490.
Example 288
(2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[0980] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.43 (d,
1H, J=1.8 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.51-7.55 (m, 3H), 7.41 (dd,
1H, J=1.84, 8.8 Hz), 7.31 (dd, 1H, J=2.4, 7.5 Hz), 6.92 (d, 1H,
J=15.4 Hz), 6.70 (d, 1H, J=8.5 Hz), 4.70 (m, 1H), 4.10 (m, 1H),
3.44 (pent. 1H, J=6.8 Hz), 3.16 (m, 1H), 2.80 (br, 4H), 2.55 (br,
1H), 2.03 (m, 4H), 1.90 (m, 4H), 1.65 (m, 1H), 1.18 (d, 6H, J=7.0
Hz). MS (ESI) m/z 480, 959.
Example 289
(2-Isopropylphenyl)[2-nitro-4-(E-((4-sulfopiperidin-1-yl)carbonyl)ethenyl)-
phenyl]sulfide
[0981] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.63 (d,
1H, J=1.8 Hz), 7.92 (dd, 1H, J=1.8, 8.8 Hz), 7.60 (m, 3H), 7.47 (d,
1H, J=14.2 Hz), 7.42 (d, 1H, J=14.2 Hz), 6.62 (d, 1H, J=8.5 Hz),
4.45 (m, 2H), 4.38 (m, 2H), 3.34 (m, 1H), 3.00 (m, 2H), 2.70 (m,
1H), 2.60 (m, 2H), 1.14 (d, 6H, J=6.9 Hz). MS (ESI) m/z 491,
981.
Example 290
(2-Isopropylphenyl)[2-nitro-4-(E-((3-hydroxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[0982] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.43 (s,
1H), 7.50-7.62 (m, 4H), 7.41 (d, 1H, J=8.1 Hz), 6.97 (m, 1H), 6.69
(d, 1H, J=8.1 Hz), 3.85 (m, 2H), 3.65 (m, 1H), 3.50 (m, 3H), 1.93
(m, 2H), 1.65 (m, 2H), 1.18 (d, 6H, J=6.6 Hz). MS (ESI) m/z 427,
449, 853, 875.
Example 291
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-((ethanesulfonylamino)carbon-
yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0983] The title compound was prepared by the procedures described
in Example 227. The product was purified by reversed-phase HPLC.
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.34 (t, J=7.0 Hz, 2H),
1.44 (t, J=7.0 Hz, 3H), 1.95 (br, 1/2H), 2.20 (br, 1/2H), 2.68 (br,
1H), 3.14 (q, J=7.0 Hz, 2H), 3.45 (m, 1H), 3.65 (m, 1H), 3.93 (m,
1H), 4.30 (m, 4H), 4.50-4.60 (br, 2H), 6.92 (d, J=8.0 Hz, 1H),
6.98-7.04 (m, 3H), 7.06 (m 1H), 7.40 (d, J=8.0 Hz, 1H), 7.65 (m,
1H), 7.75 (s, 1H). MS (APCI) m/z 585 (M+H).sup.+.
Example 292
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(p-toluenesulfonylamino)carb-
onyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0984] The title compound was prepared by the same procedure
described in Example 229. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
1.25 (m, 2H), 1.55 (m, 1H), 1.70-2.25 (br, 1H), 2.41 (d, J=13.0 Hz,
3H), 2.55 (br, 1H), 3.50-3.80 (br, 2H), 4.20-4.35 (m, 4H),
4.68-4.75 (m, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.00-7.10 (m, 2H), 7.30
(d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.91 (m, 1H). MS
(CI/NH.sub.3) m/z 647 (M+H).sup.+. Anal. calcd. for
C.sub.31H.sub.29F.sub.3N.sub.2O.sub.6S.sub.2.0.5 H.sub.2O: C,
56.78; H, 4.61; N, 4.27. Found: C, 56.86; H, 4.69; N, 4.35.
Example 293
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((4-((ethanesulfonylamino)carbon-
yl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0985] The title compound was prepared by the procedures described
in Example 227, giving a white foam. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.35-1.40 (m, 2H), 1.44 (t J=7.0 Hz, 3H), 1.76 (m,
1H), 2.0 (m, 1H), 2.50-3.20 (br, 1H), 3.15 (q, J=7.0 Hz, 2H),
3.40-3.55 (m, 2H), 4.25-4.32 (m, 4H), 4.52 (br, 2H), 6.90 (d, J=8.0
Hz, 1H), 6.98-7.05 (dd, J=2.0, 8.0 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H),
7.40 (m, 1H), 7.60 (m, 1H), 7.75 (s, 1H), 8.22 (br, 1H). MS (APCI)
m/z 585 (M+H).sup.+. Anal. calcd. for
C.sub.26H.sub.27F.sub.3N.sub.2O.sub.6S.sub.2.0.8 H.sub.2O: C,
52.13; H, 4.81; N, 4.68. Found: C, 52.14; H, 4.80; N, 4.66.
Example 294
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((2(tetrazol-5-yl)morpholin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0986] The corresponding nitrile (160 mg, 0.336 mmol, prepared via
the procedures of Example 1), sodium azide (56.6 mg, 0.872 mmol),
n-Bu.sub.3SnCl and THF were mixed in a reaction tube, flushed with
nitrogen and heated to reflux overnight. The mixture was then
cooled to ambient temperature, and 1N HCl soln. was added. The
mixture was extracted with ethyl acetate three times and the
combined organics were dried over MgSO.sub.4. The mixture was
filtered through a short silica gel plug to give 96 mg (56% yield)
of the desired material. .sup.1H NMR (DMSO-d.sub.6, 500 MHz,
100.degree. C.) .delta. 7.99 (d, 1H, J=1.7 Hz), 7.79 (dd, 1H,
J=2.0, 8.6 Hz), 7.50 (d, 1H, J=15.3 Hz), 7.24 (d, 1H, J=15.6 Hz),
7.14 (d, 1H, J=8.2 Hz), 6.96 (m, 1H), 6.94 (d, 1H, J=2.1 Hz), 6.92
(m, 1H), 4.60 (dd, 1H, J=3.0, 9.8 Hz), 4.50 (br d, 1H, J=12.2 Hz),
4.26 (m, 5H), 4.17 (m, 1H), 4.00 (dt, 1H, J=3.2, 11.6 Hz), 3.72
(td, 1H, J=3.0, 11.0 Hz), 3.43 (br m, 1H), 3.29 (br m, 1H). MS
(ESI) m/z -518. Anal. Calcd for
C.sub.23H.sub.20F.sub.3N.sub.5O.sub.4S. 1.83 HOAc: C, 50.88; H,
4.38; N, 11.13. Found: C, 50.61; H, 4.46; N, 11.4.
Example 295
(2-Isopropylphenyl)[2-nitro-4-(E-((2-butyl,
5-(tetrazol-5-yl)morpholin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
Example 295A
2-Butyl-5-cyanomorpholine
[0987] The title compound was prepared by the procedures described
in Example 260A, substituting ethanolamine with 2-aminohexanol.
Example 295B
(2-Isopropylphenyl)[2-nitro-4-(E-((2-butyl-5-cyanomorpholin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[0988] The title compound was prepared by the procedures described
in Example 260B, substituting the morpholine from Example 260A with
the compound of Example 295A.
Example 295C
(2-Isopropylphenyl)[2-nitro-4-(E-((2-butyl-5-(tetrazol-5-yl)morpholin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[0989] The title compound was prepared by the procedures described
in Example 262, substituting the nitrile compound from Example 260
with the compound of Example 295B, giving a light-yellow solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz, 3:2 mixture of diastereomers)
.delta. 0.89 (t, J=7.5 Hz, 1H), 1.01 (br m, 1H), 1.19 (d, J=6.5 Hz,
6H), 1.23-1.43 (m, 4H), 1.68-1.84 (m, 1H), 3.10-3.61 (m, 2H),
3.83-4.17 (m, 2H), 4.40-5.26 (m, 2H), 6.67-6.77 (m, 1H), [6.91 (d),
7.02 (d), J=15.3 Hz 1H in total], 7.25-7.37 (m, 2H), 7.44-7.60 (m,
3H), [7.67 (d), 7.79 (d), J=15.3 Hz, 1H in total], 8.43-8.50 (m,
1H). MS (ESI.sup.+) (M-H).sup.+ at m/z 535.
Example 296
(2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
Example 296A
Triisopropylsilyl(2-(and
3-)hydroxymethylbenzodioxan-6-yl)sulfide
[0990] The title compound was prepared by the procedures described
in Example 281A, substituting 5-bromo-N-methyl indole with a
mixture of 6-bromo-2-hydroxymethylbenzenedioxane and
6-bromo-3-hydroxymethylbenzened- ioxane.
Example 296B
(2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((4-acetylpipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[0991] The title compound was prepared by the procedures described
in Example 281B, substituting 3-chloro-4-flurobenzaldehyde with
4-chloro-3-nitrocinnamide, giving a light yellow solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz, 3:2 mixture of diastereomers) .delta. [2.11
(s), 2.15 (s), 3H in total], 3.48-3.83 (m, 8H), 3.83-4.04 (m, 2H),
4.20 (dd, J=8.4, 11.4 Hz, 1H), 4.26-4.44 (m, 2H), 6.89 (d, J=5.7
Hz, 1H), 6.92 (s, 1H), 6.97-7.11 (m, 1H), 7.04 (d, J=15.0 Hz, 1H),
7.14 (d, J=2.1 Hz, 1H), 7.46 (br d, J=9.0 Hz, 1H), 7.65 (d, J=15.0
Hz, 1H), 8.41 (d, J=2.1 Hz, 1H). MS (ESI.sup.+) (M+H).sup.- at m/z
500.
Example 297
(2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin--
2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0992] The title compound was prepared by the procedures described
in Example 296B, substituting the acetylpiperazine
4-chloro-3-nitrocinnamide with 3-aminopropyl-1-pyrrolidin-3-one
4-chloro-3-nitrocinnamide, giving a light-yellow solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz, 3:2 mixture of diastereomers) .delta. 1.75
(br m, 2H), 2.08 (p, J=7.5 Hz, 2H), 2.45 (t, J=7.5 Hz, 2H),
3.27-3.48 (m, 6H), 3.82-4.03 (m, 2H), 4.13-4.44 (m, 3H), 6.49 (d,
J=15.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), [6.99 (d), 7.01 (d), J=8.4
Hz, 1H in total], [7.06 (dd), 7.08 (dd), J=1.5, 2.4 Hz, 1H in
total], [7.13 (d), 7.14 (d), J=2.4 Hz, 1H in total], 7.17 (br s,
1H), 7.46 (d, J=8.4 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 8.36 (d,
J=1.5 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 514.
Example 298
(2-(and
3-)(Hydroxymethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(p-
yrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0993] The title compound was prepared by the procedures described
in Example 281, substituting 6-thiolsilyl indole with the
thiolsilyl ether described in Example 296A, and
3-chloro-4-fluorobenzaldehyde with
4-fluoro-3-trifluoromethylbenzaldehyde, producing a white solid.
.sup.1H NMR (CDCl.sub.3, 300 MHz, 3:2 mixture of diastereomers)
.delta. 1.75 (br m, 2H), 2.09 (br m, 2H), 2.45 (br m, 2H),
3.25-3.60 (m, 6H), 3.80-4.43 (m, 5H), 6.46 (d, J=15.3 Hz, 1H),
[6.92 (d), 6.95 (d), J=6.8 Hz, 1H in total], [7.03 (d), 7.04 (d),
J=8.1 Hz, 1H in total], 7.06-7.10 (m, 1H), 7.13 (br s, 1H), 7.42
(d, J=8.1 Hz, 1H), 7.54 (d, J=15.3 Hz, 1H), 7.77 (s, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 537.
Example 299
(3-Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2-on-1-yl-
)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
Example 299A
3-(Hydroxymethyl)-6-bromo-benzodioxane
[0994] To a stirred solution of 5-bromosalicylaldehyde (5.0 g, 24.9
mmol), and epichlorohydrin (5.6 mL, 72.1 mmol) in 20 mL of DMF at
80.degree. C. was added K.sub.2CO.sub.3 slowly in portions. The
resulting mixture was then heated at 90.degree. C. for 3 h.
Reaction was then stopped, water was added, extracted with diethyl
ether. The organic extracts were washed with water, brine, dried
over Na.sub.2SO.sub.4, concentrated in vacuo. The residue was
purified on a SiO.sub.2 flash column chromatography eluting with
15-30% EtOAc/hexanes to give 2.82 g (44%) of the title compound as
colorless oil.
[0995] To a stirred solution of the aldehyde (2.82 g, 11 mmol) in
35 mL of CHCl.sub.3 was added mCPBA (2.27 g, 13 mmol). The mixture
was stirred at ambient temperature for 30 min and then heated at
50.degree. C. for 2 h. The reaction was then quenched with aq.
Na.sub.2S.sub.2O.sub.5, extracted with Et.sub.2O (2.times.50 mL).
The combined organic layer was washed with aq. NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, concentrated in vacuo to give 2.92 g
of crude product which was proceeded to the next step without
purification.
[0996] To a stirred solution of the above-described crude formate
(2.92 g) in 5 mL of THF was added 3N aq. NaOH (3.9 mL, 11.7 mmol).
The reaction mixture was then heated at 70.degree. C. for 4 h. The
reaction mixture was then partitioned between EtOAc and water. The
organic layer was then washed with brine, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give 2.50 g (93% over
two steps) of the title compound.
Example 299B
Triisopropyl(3-(hydroxymethyl)-benzodioxan-6-yl)sulfide
[0997] The title compound was prepared by the procedures described
in Example 281A, substituting 5-bromo-N-methyl indole with the
bromide from Example 299A.
Example 299C
(3-Hydroxymethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pyrrolidin-2-on-1-yl-
)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[0998] The title compound was prepared by the procedures described
in Example 297, substituting the mixture of thiolsilyl ethers from
Example 296A with the compound of Example 299B, giving a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.74 (br m, 2H),
2.08 (t, J=7.5 Hz, 2H), 2.44 (t, J=7.5 Hz, 2H), 3.25-3.53 (m, 6H),
3.88 (dd, J=4.8, 16.8 Hz 1H), 3.97 (dd, J=4.8, 16.8 Hz, 1H), 4.21
(dd, J=3.1, 12.9 Hz, 1H), 4.26-4.36 (m, 1H), 4.40 (dd, J=2.4, 12.9
Hz, 1H), 6.49 (d, J=15.3 Hz, 1H), 6.88 (d, J=8.7 Hz, 1H), 7.00 (d,
J=8.7 Hz, 1H), 7.07 (dd, J=2.4, 8.7 Hz, 1H), 7.14 (d J=2.4 Hz, 1H),
7.20 (br s, 1H), 7.46 (dd, J=0.9, 8.7 Hz, 1H), 7.54 (d, J=15.3 Hz,
1H), 8.36 (s, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 514. Anal.
Calcd for C.sub.25H.sub.27N.sub.3O.sub.7S.0.82 H.sub.2O: C, 56.83;
H, 5.46; N, 7.95. Found: C, 56.84; H, 5.18; N, 7.74.
Example 300
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxylpiperidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[0999] The title compound was prepared by the procedures described
in Example 263, substituting 4-fluoro-3-trifluoromethylbenzaldehyde
with 3-chloro-4-fluorobenzaldehyde, giving a white solid. .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.64-1.88 (br m, 1H), 1.95-2.09
(br m, 2H), 2.57-2.73 (m, 1H), 2.90-3.17 (m, 1H) 3.17-3.50 (m 1H),
3.90-4.19 (m, 1H), 4.25-4.36 (m, 4H), 4.39-4.66 (m, 1H), 6.75 (d,
J=8.4 Hz, 1H), 6.84 (d, J=15.3 Hz 1H), 6.93 (d, J=8.7 Hz, 1H), 7.03
(dd, J=2.4, 8.7 Hz, 1H) 7.08 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.4 Hz,
1H), 7.51 (s, 1H), 7.54 (d, J=15.3 Hz, 1H). MS (ESI+) (M+H).sup.+
at m/z 460, 462.
Example 301
(2-(and
3-)(Aminomethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(pyr-
rolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
Example 301A
(2-(and
3-)(Mesyloxymethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(-
pyrrolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[1000] To a stirred solution of alcohol from Example 298 (200 mg,
0.37 mmol)) in 2 mL of methylene chloride with Et.sub.3N (104 mL,
0.74 mmol)) was added methanesulfonyl chloride (35 mL, 0.56 mmol)
dropwise. The mixture was then stirred at ambient temperature for
one hour. The reaction mixture was then poured into 3N HCl,
extracted with EtOAc (2.times.10 mL). The combined organic layer
was washed with aq. NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, concentrated in vacuo to give 275 mg of crude
product which was proceeded to the next step without
purification.
Example 301B
(2-(and
3-)(Azidomethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(pyr-
rolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[1001] To a stirred solution suspension of NaN.sub.3 (44 mg, 0.68
mmol) in 1 mL of DMSO was added mesylate (275 mg) in 0.5 mL of DMSO
solution. The reaction mixture was then heated at 70.degree. C. for
2 h, then cooled down to room temperature, water was added,
extracted with EtOAc (2.times.10 mL). The combined organic layer
was washed with water, brine, dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The residue was purified on a SiO.sub.2
flash column chromatography eluting with 5-10% MeOH/EtOAc to give
35 (17%, two steps) mg of the title compound as light brown
oil.
Example 301C
(2-(and
3-)(Aminomethyl)-benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-(pyr-
rolidin-2-on-1-yl)prop-1-ylamino)carbonyl)ethenyl)phenyl]sulfide
[1002] To a stirred solution of azide (230 mg, 0.41 mmol) in 1 mL
of THF was added PPh.sub.3 (118 mg, 0.45 mmol), followed by one
drop of water. The mixture was then stirred at room temperature for
one hour. The volatile solvent was then removed in vacuo and the
crude product was purified using Gilson Preparative HPLC as
described in Example 38B to give 25 mg (11%) of the title compound.
Light brown oil; .sup.1H NMR (CDCl.sub.3, 300 MHz, 3:2 mixture of
diastereomers) .delta. 1.74 (br m, 2H), 1.96-2.16 (m, 2H),
2.35-2.50 (m, 2H), 3.23-3.47 (m, 6H), 3.92-4.63 (m, 5H), 6.41-6.55
(m, 1H), 6.83-7.10 (m, 3H), 7.36-7.58 (m, 3H), 7.67-7.67 (m, 2H).
MS (ESI.sup.+) (M+H).sup.+ at m/z 536. Anal. Calcd for
C.sub.26H.sub.28F.sub.3N.sub.3O.sub.4S.0 H2O: C, 58.31; H., 5.27;
N, 7.85. Found: C, 58.34; H, 5.48; N, 7.78.
Example 302
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(methylaminocarbonyl)morpholin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[1003] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.6 Hz, 6H); 2.61 (d, J=4.8 Hz, 3H); 3.14-4.62 (br m, 7H);
3.30-3.40 (m, 1H); 6.63 (d, J=8.8 Hz, 1H); 7.32-7.62 (m, 6H);
7.80-7.97 (m, 2H); 8.66 (d, J=1;5 Hz, 1H). MS (APCI) (M+H).sup.+ at
m/z 470. Anal calcd for
C.sub.24H.sub.27N.sub.3S.sub.1O.sub.5.0.8H.sub.2O: C, 59.58; H,
5.96; N, 8.68. Found: C, 59.57; H, 5.94; N, 8.72.
Example 303
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(hydroxymethyl)morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1004] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 2.70-3.51 (br m, 5H); 3.30-3.40 (m, 1H); 3.83-3.93
(m, 1H); 4.03-4.47 (br m, 2H) 4.74-4.82 (m, 1H); 6.64 (d, J=8.5 Hz,
1H); 7.30-7.62 (m, 6H); 7.86-7.94 (m, 1H); 8.59-8.65 (m, 1H). MS
(APCI) (M+H)+at m/z 443. Anal calcd for
C.sub.11H.sub.11N.sub.2S.sub.1O.sub.5: C, 62.43; H, 5.92; N, 6.33.
Found: C, 62.12; H, 6.20; N, 6.06.
Example 304
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(acetoxymethyl)morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1005] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.1 Hz, 6H); 2.04 (s, 3H); 3.30-3.40 (m, 1H); 2.58-4.41 (br m,
9H); 6.64 (d, J=8.5 Hz, 1H); 7.30-7.62 (m, 6H); 7.90 (dd, J=8.5,
1.8 Hz, 1H); 8.59-8.65 (m, 1H). MS (APCI) (M+H).sup.+ at m/z 485.
Anal calcd for C.sub.25H.sub.28N.sub.2S.sub.1O.sub.6: C, 61.97; H,
5.82; N, 5.78. Found: C, 61.85; H, 5.84; N, 5.68.
Example 305
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(aminomethyl)morpholin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[1006] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d, 300 MHz) .delta. 1.14 (d, J=7.0
Hz, 6H); 2.61 (d, J=5.5 Hz, 2H); 2.49-3.60 (br m, 5H); 3.82-3.93
(m, 1H); 4.13-4.45 (m, 2H); 6.64 (d, J=8.5 Hz, 1H); 7.32-7.62 (m,
6H); 7.88-7.95 (m, 1H); 8.59-8.67 (m, 1H). MS (APCI) (M+H).sup.+ at
m/z 442. Anal calcd for
C.sub.23H.sub.27N.sub.3S.sub.1O.sub.4.0.4H.sub.2O: C, 61.55; H,
6.25; N, 9.36. Found: C, 61.60; H, 6.25; N, 9.00.
Example 306
(2-Isopropylphenyl)[2-nitro-4-(E-((3-(acetamidomethyl)morpholin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1007] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.82 (s, 3H); 2.70-3.50 (br m, 7H); 3.85-3.94 (m,
1H); 4.13-4.40 (m, 2H); 6.64 (d, J=8.5 Hz, 1H), 7.32-7.62 (m, 6H);
7.88-8.06 (m, 1H); 8.59-8.67 (m, 1H). MS (APCI) (M+H).sup.+ at m/z
484. Anal calcd for
C.sub.25H.sub.29N.sub.3S.sub.1O.sub.5.0.27H.sub.2O: C, 61.47. H,
6.10; N, 8.60. Found: C, 61.50; H, 6.34; N, 8.53.
Example 307
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylamino)-
carbonyl)ethenyl)phenyl]sulfide
[1008] The title compound was prepared by the procedures described
in Example 300 substituting ethyl isonipecotate with
N-(3'-aminopropyl)-2-py- rrolidinone. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.75 (br s, 2H), 2.02-2.34 (m, 2H), 2.40-2.50 (m, 2H),
3.30-3.50 (m, 6H), 4.28-4.33 (m, 4H), 6.40 (br, 1H), 6.75 (d, J=8.0
Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 7.02 (dd, J=2.0, 8.0 Hz, 1H), 7.08
(d, J=2.0 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.45 (m, 1H), 7.50 (s,
1H). MS (ESI) m/z 473 (M+H). Anal. calcd. for
C.sub.24H.sub.25ClN.sub.2O.sub.4S.0.5 H2O: C, 59.81; H, 5.44; N,
5.81. Found: C, 59.76; H, 5.80; N, 5.43.
Example 308
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1009] The title compound was prepared by the procedures described
in Example 300 substituting ethyl isonipecotate with ethyl
nipecotate. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.25 (t,
J=7.0 Hz, 3H), 1.60-1.90 (br, 2H), 2.10 (br, 1H), 2.52 (br, 1H),
3.00-3.50 (br, 2H), 3.80 (br, 1H), 4.10-4.20 (m, 4H), 4.28-4.35 (m,
4H), 6.74 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.02 (dd,
J=2.0, 8.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.18 (m, 1H), 7.50-7.03
(m, 3H). MS (ESI) m/z 488 (M+H).sup.+. Anal. calcd. for
C.sub.25H.sub.26ClNO.sub.5SNa.0.5 H.sub.2O: C, 60.42; H, 5.48; N,
2.82. Found: C, 60.61; H, 5.51; N, 2.42.
Example 309
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboethoxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1010] The title compound was prepared by the same procedure
described in Example 300 substituting ethyl isonipecotate with
ethyl pipecolinate. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.30
(t, J=7.0 Hz, 3H), 1.30-1.50 (br, 3H), 1.55-1.85 (br, 3H), 2.30 (m,
1H), 4.00 (m, 1H), 4.20 (m, 2H), 4.30 (m, 4H), 5.44 (br, 1H), 6.85
(d, J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 7.00 (dd, J=2.0, 8.0 Hz,
1H), 7.07 (d, J=2.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.22 (m, 1H), 7.50
(s, 1H). MS (ESI) m/z 488 (M+H).sup.+. Anal. calcd. for
C.sub.25H.sub.26ClNO.sub.5S: C, 61.53; H, 5.37; N, 2.87. Found: C,
61.86; H, 5.63; N, 2.56.
Example 310
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phen-
yl]sulfide
Example 310A
2,3-Dichloro-4-trifluoromethanesulfonyloxy-benzaldehyde
[1011] 2,3-Dichloro-4-hydroxy-benzaldehyde (9.10 g., J. Med. Chem.
19 (4), 534, 1994) was dissolved in 45 ml. pyridine at room
temperature. The solution was placed in an ice bath and
immediately, 15.63 g. of trifluoromethanesulfonic anhydride was
added slowly. [Note: If the pyridine solution is cooled to zero
before addition of triflic anhydride the aldehyde crystallizes out
and the mixture cannot be stirred.] After the addition is complete
the dark mixture was stirred for 1 hour at room temperature. It was
then poured into a stirred mixture of ice water, 100 ml. of
concentrated HCl and ether. [Note: Not everything is soluble in
this mixture] The ether layer was separated, dried over sodium
sulfate, and the solvent removed. Warm heptane was added to this
residue, and any insoluble material was filtered. The solution was
concentrated to give 8.74 g. (57% yield) of product as an orange
oil which solidified in the refrigerator.
Example 310B
2,3-Dichloro-4-(2-methoxyphenylthio)-benzaldehyde
[1012] 2,3-Dichloro-4-trifluoromethanesufonyloxy-benzaldehyde (2.50
g.) was dissolved in 6 ml. acetonitile. 2-Methoxybenzenethiol (2.55
g. of, 70% pure material, 50% excess) was added. With cooling 2.50
g. diisopropylethylamine was added slowly. The solution was removed
from the ice bath, whereon a solid formed. The solution was warmed
in a 50 C waterbath for 5 minutes. More acetonitrile (5 ml.) was
added and the mixture was cooled in ice, and then filtered to get
2.047 g. of product, m.p. 137-139 C.
Example 310C
2,3-Dichloro-4-(2-methoxyphenylhio)-cinnamic acid
[1013] A mixture of
2,3-dichloro-4-(2-methoxyphenylthio)-benzaldehyde (2.03 g.), 1.44
g. malonic acid, 5 ml. pyridine, and 0.100 g piperidine was heated
to 115 degrees for 1.5 hours. The mixture was cooled, and ice and
HCl were added. The resulting solid was filtered, washed with water
and dissolved in tetrahydrofuran. This solution was dried over
sodium sulfate, the solvent removed and ether added to give 1.733 g
of product, m.p. 187-188 C.
Example 310D
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phen-
yl]sulfide
[1014] The title compound was prepared according to the procedure
of Example 1, substituting the cinnamic acid of Example 310C,
giving a white solid, m.p. 161-162 C. .sup.1H-NMR (CDCl.sub.3 300
MHz) .delta. 3.83 (s, 3H), 6.55 (d, J=9 Hz, 1H), 6.70 (broad d,
J=15 Hz, 1H), 6.99-7.05 (m, 2H), 7.26 (d, J=9 Hz 1H), 7.43-7.50 (m,
2H), 8.07 (broad d, J=15 Hz, 1H) Anal. Calcd. for
C.sub.20H.sub.19Cl.sub.2NO.sub.3S: C, 56.61; H, 4.51; N, 3.30.
Found: C, 56.75; H, 4.57; N, 2.61.
Example 311
(2-Methoxyphenyl)-[2,3-dimethyl-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phen-
yl]sulfide
[1015] The title compound was prepared according to the procedures
of Example 310. .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.39 (s,
3H), 2.42 (s, 3H), 3.60-3.80 (m, 8H), 3.90 (s, 3H), 6.69 (d, J=15
Hz, 1H), 6.82-6.94 (m, 3H), 7.05 (d, J=9 Hz, 1H), 7.20-7.30 (m,
2H), 8.06 (d, J=15 Hz, 1H). Anal. Calcd. for
C.sub.22H.sub.25NO.sub.3S: C, 68.91; H, 6.57; N, 3.65. Found: C,
68.75; H, 6.67; N, 3.24.
Example 312
(2-Isopropylphenyl)[2-nitro-4-(E-((indol-5-ylamino)carbonyl)ethenyl)phenyl-
]sulfide
[1016] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 11.04 (s,
1H), 10.10 (s, 1H), 8.52 (d, 1H, J=1.5 Hz), 8.02 (s, 1H), 7.81 (dd,
1H, J=1.8, 8.5 Hz), 7.53-6.63 (m, 4H7.39 (m, 1H), 7.25-7.35 (m,
3H), 6.94 (d, 1H, J=15.8 Hz), 7.72 (d, 1H, J=8.5 Hz), 6.40 (m, 1H),
3.33 (m, 1H), 1.16 (d, 6H, J=6.6 Hz). MS (ESI) m/z 458, 480, 915.
Anal. Calcd for C.sub.26H.sub.23N.sub.3O.sub.3S.0.22 H.sub.2O: C,
67.67; H, 5.12; N, 9.10. Found: C, 67.68; H, 5.19; N, 9.08.
Example 313
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[1017] The title compound was prepared by hydrolysis of the
compound of Example 308 under basic condition (aq. NaOH/EtOH).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.10-1.40 (m, 2H), 1.60
(m, 1H), 1.76-1.96 (m, 3H), 2.88 (m, 1H), 3.98 (m, 1H), 3.98 (m,
1H), 4.30 (m, 4H), 6.72 (d, J=8.0 Hz, 1H), 7.02 (m, 3H), 7.30 (m,
2H), 7.48 (m, 1H), 7.92 (m, 1H). MS (ESI) m/z 458 (M+H).sup.+.
Anal. calcd. for C.sub.23H.sub.21ClNO.sub.5SNa: C, 55.76: H, 4.58;
N, 2.83. Found: C, 55.76; H, 4.78; N, 2.63.
Example 314
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)piperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1018] The title compound was prepared by the procedures described
in Example 282, producing a white solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.66-1.80 (m, 2H), 2.10-2.30 (m, 2H), 2.64 (m,
1H), 3.55 (m, 2H), 3.98 (m, 1H), 4.25 (m, 1H), 4.30-4.36 (m, 4H),
6.72 (dd, J=3.0, 12.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 1H), 7.03 (dd,
d=2.0, 8.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H),
7.52 (s, 1H), 7.70 (d, J=15.0 Hz, 1H). MS (ESI) m/z 484
(M+H).sup.+. Anal. calcd. for C.sub.23H.sub.22ClN.sub.5O-
.sub.3S.0.38 H.sub.2O: C, 56.28; H, 4.67; N, 14.27. Found: C,
56.46; H, 4.58; N, 13.94.
Example 315
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(tert-butoxycarbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[1019] The title compound was prepared by the procedures described
in Example 300 substituting ethyl isonipecotate with
1-Boc-piperazine. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.50
(s, 9H), 3.50 (br, s 4H), 3.70 (br, 4H), 4.28-4.35 (m, 4H), 6.74
(d, J=8.0 Hz, 1H), 6.82 (m, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.02 (dd,
J=2.0, 8.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H),
7.50 (s, 2H), 7.58 (m, 1H). MS (ESI) m/z 517 (M+H).sup.+. Anal.
calcd. for C.sub.26H.sub.29ClN.sub.2O.sub.5S.0.1 H.sub.2O: C,
60.19; H, 5.67; N, 5.40. Found: C, 60.20; H, 5.97; N, 5.11.
Example 316
(Benzodioxan-6-yl)[2-chloro-4-(E-((2-carboxypiperidin-1-yl)carbonyl)etheny-
l)phenyl]sulfide
[1020] The title compound was prepared by hydrolysis of the
compound of Example 309 under basic conditions (aq. NaOH/EtOH).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) a 1.10-1.40 (m, 3H), 1.45-1.60
(m, 2H), 2.25-2.45 (m, 2H), 2.55-2.80 (m, 1H), 4.30 (m, 4H), 4.50
(m, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.00 (m, 3H), 7.10 (m, 1H), 7.25
(d, J=16.0 Hz, 1H), 7.48 (d, J=8.0 15.5 Hz, 1H), 7.90 (d, J=15.5
Hz, 1H). MS (ESI) m/z 458 (M+H).sup.+. Anal. calcd. for
C.sub.23H.sub.21ClNO.sub.5SNa.1.3 H.sub.2O: C, 54.69; H, 4.73; N,
2.45. Found: C, 54.67; H, 4.71; N, 2.77.
Example 317
(Benzodioxan-6-yl)[2-chloro-4-(E-((3-(tetrazol-5-yl)morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1021] The title compound was prepared by the procedures described
in Example 262. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.50-1.70
(m, 2H), 3.15 (br, 1H), 3.70-3.90 (m, 2H), 4.25-4.35 (m, 4H), 4.55
(m, 1H), 5.04 (br, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz,
1H), 7.03 (dd, J=2.0, 8.0 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H),
7.20-7.30 (m, 2H), 7.50 (m, 1H), 7.65 (m, 1H). MS (ESI) m/z 486
(M+H).sup.+. Anal. calcd. for
C.sub.22H.sub.20ClN.sub.5O.sub.4S.H.sub.2O: C, 52.43; H, 4.40; N,
13.90. Found: C, 52.34; H, 4.35; 13.62.
Example 318
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(methylaminocarbonyl)piperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[1022] The title compound was prepared by deprotection of the of
Example 315 compound using anhydrous TFA in dichloromethane,
followed by treatment with methyl isocyanate. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.88 (s, 3H), 3.50 (br, 4H), 3.72
(br, 4H), 4.30 (m, 4H), 6.74 (d, J=8.0 Hz, 1H), 6.82 (d, J=15.0 Hz,
1H), 6.92 (d, J=8.0 Hz 1H), 7.03 (dd, J=2.0, 8.0 Hz, 1H), 7.08 (d,
J=2.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.60 (m, 1H).
MS (ESI) m/z 474 (M+H). Anal. calcd. for
C.sub.23H.sub.24ClN.sub.3O.sub.4S: C, 57.63; H, 5.17; N, 8.77.
Found: C, 57.53; H, 5.02; N, 8.58.
Example 319
(2-Methoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]eth-
enyl)phenyl]sulfide
[1023] The title compound was prepared according to the procedures
of Example 310. .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta. 1.66-1.83
(m, 2H), 1.95-2.09 (m, 2H), 2.57-2.69 (m, 1H), 2.94-3.08 (m, 1),
3.15-3.31 (m, 1H), 3.72 (s, 3H), 3.90-4.05 (m, 1H), 4.41-4.55 (m,
1H), 6.55 (d, J=9 Hz, 1H), 6.73 (d, J=5 Hz, 1H), 7.00-7.05 (m, 2H),
7.27 (d, J=8 Hz, 1H), 7.44-7.50 (m, 2H), 7.92 (d, J=15 Hz, 1H).
Anal. Calcd. for C.sub.22H.sub.21Cl.sub.2NO.sub.4S: C, 56.66; H,
4.54; N, 3.00. Found: C, 56.89; H, 4.84; N, 2.64.
Example 320
(Benzodioxan-6-yl)[2-chloro-4-(E-((4-(tetrazol-5-yl)piperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1024] The title compound was prepared by the procedures described
in Example 314 substituting 3-(tetrazol-5-yl)piperidine with
4-(tetrazol-5-yl)piperidine. The crude reaction product was
purified by reversed-phase HPLC. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 1.22 (m, 1H), 1.55-1.75 (m, 2H), 2.06 (m, 1H), 2.45
(m, 1H), 4.22 (m, 4H), 4.30 (m, 4H), 6.70 (m, 1H), 7.00 (dd, J=2.0,
8.0 Hz, 2H), 7.25-7.40 (m, 4H), 7.50 (m, 1H). MS (ESI) m/z 484
(M+H).sup.+.
Example 321
(2-Methoxyphenyl)-[3-chloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)phenyl]s-
ulfide
[1025] The title compound was prepared according to the procedures
of Example 1, giving a white solid, m.p. 124-125 C. .sup.1H-NMR
(CDCl.sub.3 300 MHz) .delta. 3.60-3.80 (m, 8H), 3.85 (s, 3H), 6.80
(d, J=15 Hz, 1H), 6.95-7.01 (m, 2H), 7.05 (dd, J=9 Hz 2 Hz, 1H),
7.15 (d, J=2 Hz, 1H), 7.35-7.48 (m, 3H), 7.75 (d, J=15 Hz, H).
Anal. Calcd. for C.sub.20H.sub.20ClNO.sub.3S: C, 61.61; H, 5.17; N,
3.59. Found: C, 61.43. H, 5.30; N, 3.73.
Example 322
(2-Isopropylphenyl)[2-nitro-4-(E-((4-oxopiperidin-1-yl)carbonyl)ethenyl)ph-
enyl]sulfide
[1026] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.45 (s,
1H), 7.50-7.57 (m, 3H), 7.42 (br d, 1H, J=8.1 Hz), 7.30 (m, 1H),
7.02 (br, 1H), 6.72 (d, 1H, J=8.4 Hz), 4.01 (br s, 4H), 3.44
(quintet, 1H, J=6.8 Hz), 2.56 (br m, 4H), 1.18 (d, 6H, J=7.1 Hz).
MS (ESI) m/z 425, 457. Anal. Calcd for
C.sub.23H.sub.24N.sub.2O.sub.4S: C, 65.07; H, 5.70; N, 6.60. Found:
C, 64.92; H, 5.67; N, 6.62.
Example 323
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carboethoxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[1027] The title compound was prepared by the procedures described
in Example 248, substituting ethyl(.+-.)nipecotate with ethyl
nipecotate tartrate, giving a white solid. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.26 (t, J=7.4 Hz, 3H), 1.46-1.67 (m, 1H),
1.67-1.98 (m, 2H), 1.98-2.23 (m, 1H), 2.46-2.63 (m, 1H), 3.10-3.42
(m, 1H), 3.53-4.13 (m, 2H), 4.16 (q, J=7.4 Hz, 2H), 4.25-4.40 (m,
4H), 4.60-4.88 (m, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.93 (d, J=15.3 Hz,
1H) 6.97-7.05 (m, 2H), 7.07 (d, J=2.7 Hz, 1H), 7.42 (d, J=8.4 Hz,
1H), 7.59 (d, J=15.3 Hz, 1H), 7.77 (s, 1H). MS (ESI+) (M+H) at m/z
522.
Example 324
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-R-carboxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[1028] The title compound was prepared by the procedures described
in Example 251, substituting the ethyl ester from Example 248 with
ethyl ester from Example 323, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.48-1.71 (m, 1H), 1.71-2.01 (m, 2H),
2.01-2.20 (m, 1H), 2.53-2.70 (m, 1H), 3.18-3.54 (m, 1H), 3.86-4.20
(m, 2H), 4.20-4.33 (m, 4H), 4.45-4.75 (m, 1H), 6.90 (d, J=8.7 Hz,
1H), 6.95-7.04 (m, 3H), 7.06 (d, J=2.4 Hz, 1H), 7.35-7.45 (br m,
1H), 7.60 (d, J=15.3 Hz, 1H), 7.75 (s, 1H). MS (ESI.sup.+)
(M+H).sup.+ at m/z 494.
Example 325
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-(pyrrolidin-2-on-1-yl)prop-1-ylam-
ino)carbonyl)ethenyl)phenyl]sulfide
[1029] The title compound was prepared by the procedures described
in Example 240, substituting 4-fluoro-3-trifluoromethylbenzaldehyde
with 2,3-dichloro-4-trifluoromethanesulfoxybenzaldehyde, giving a
white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.71-1.82
(m, 2H), 2.08 (p, J=7.5 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H), 3.2603.50
(m, 6H), 4.23-4.36 (m, 4H), 6.36 (t, J=15.6 Hz, 1H), 6.60 (d, J=8.7
Hz, 1H) 6.44 (d, J=8.7 Hz, 1H), 7.03 (dd, J=2.4, 8.7 Hz, 1H), 7.09
(d, J=2.4 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.94 (d, J=15.6 Hz, 1H).
MS (ESI.sup.+) (M+H).sup.+ at m/z 507, 509, 511. Anal. Calcd for
C.sub.24H.sub.24Cl.sub.2N.sub.2O.sub.4S.1.87 H.sub.2O: C, 53.27; H,
5.17; N, 5.18. Found: C, 53.30; H, 5.17; N, 4.83.
Example 326
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-acetylpipiperazin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[1030] The title compound was prepared by the procedures described
in Example 325, substituting aminopropyl pyrrolidinone with
1-acetylpiperazine, white solid; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 2.17 (s, 3H), 3.50-3.94 (m, 8H), 4.26-4.40 (m, 4H), 6.61
(d, J=8.7 Hz, 1H), 6.71 (d, J=15.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),
7.04 (dd, J=2.4, 8.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.30 (d,
J=8.7 Hz, 1H), 7.99 (d, J=15.6 Hz, 1H). MS (ESI.sup.+) (M+Na).sup.+
at m/z 515, 517, 519. Anal. Calcd for
C.sub.23H.sub.22Cl.sub.2N.sub.2O.sub.4S.0.52 CH.sub.2Cl.sub.2: C,
52.55; H, 4.32; N, 5.21. Found: C, 52.63; H, 4.16; N, 4.82.
Example 327
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1031] The title compound was prepared by the procedures described
in Example 325, substituting aminopropyl pyrrolidinone with ethyl
nipecotate, giving a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.26 (t, J=7.0 Hz, 3H), 1.66-1.96 (m, 2H), 1.96-2.21 (m,
1H), 2.44-2.60 (m, 1H), 2.85-3.40 (m, 2H), 3.50-3.70 (m, 1H),
3.80-4.10 (m, 2H), 4.15 (q, J=7.0 Hz, 2H), 4.26-4.40 (m, 4H), 6.66
(d, J=8.7 Hz, 1H), 6.74 (d, J=15.3 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),
7.03 (dd, J=2.4, 8.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.25-7.38 (m,
1H), 7.93 (d, J=15.3 Hz, 1H). MS (ESI.sup.+) (M+Na).sup.+ at m/z
544, 546, 548.
Example 328
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1032] The title compound was prepared by the procedures described
in Example 325, substituting aminopropyl pyrrolidinone with ethyl
isonipecotate, giving a white solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.26 (t, J=7.2 Hz, 3H), 1.69 (td, J=3.9, 10.8 Hz, 1H),
1.74 (td, J=3.9, 10.8 Hz, 1H), 1.82-2.05 (m, 2H), 2.50-2.63 (m, 1H)
2.84-3.31 (m 2H), 3.81-4.06 (m, 1H), 4.15 (q, J=7.2 Hz, 2H),
4.24-4.34 (m, 4H), 4.34-4.59 (m, 1H), 6.61 (d, J=8.7 Hz, 1H), 6.74
(d, J=15.6 Hz, 1H), 6.94 (d, J=8.7 Hz 1H), 7.03 (dd, J=2.7, 8.7 Hz,
1H), 7.08 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.90 (d,
J=15.6 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 522, 524, 526.
Anal. Calcd for C.sub.25H.sub.25Cl.sub.- 2NO.sub.5S: C, 57.48; H,
4.82; N, 2.68. Found: C, 57.82; H, 4.96; N, 2.28.
Example 329
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1033] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
the ethyl ester from Example 327, and KOH with NaOH, providing a
white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.70-2.0 (m,
2H), 2.0-2.20 (m, 1H), 2.54-2.68 (m, 1H), 3.03-3.46 (m, 2H),
3.80-4.11 (m, 2H), 4.27-4.40 (m, 4H), 4.50-4.70 (m, 1H), 6.60 (d,
J=8.9 Hz, 1H), 6.79 (d, J=15.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H),
7.03 (dd, J=2.1, 8.5 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 7.30 (d,
J=8.9 Hz, 1H), 7.93 (d, J=15.3 Hz, 1H). MS (ESI.sup.+) (M-2H).sup.-
at m/z 492, 494, 496. Anal. Calcd for
C.sub.23H.sub.21Cl.sub.2NO.sub.5S.0.73 H.sub.2O: C, 54.43; H, 4.46;
N, 2.76. Found: C, 54.43; H, 4.39; N, 2.49.
Example 330
(Benzodioxan-6-yl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1034] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
the ethyl ester from Example 328, and KOH with NaOH, to produce a
white solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.33-1.55
(m, 2H), 1.62-1.78 (m, 2H), 1.93-2.07 (m, 1H), 2.90 (brt, J=10.5
Hz, 1H), 3.16 (brt, J=10.5 Hz, 1H), 3.96 (br d, J=13.5 Hz, 1H),
4.09 (br d, J=13.5 Hz, 1H), 4.26-4.42 (m, 4H), 6.60 (d, J=9.0 Hz,
1H), 7.04-7.08 (m, 2H), 7.13 (d, J=1.5 Hz, 1H), 7.22 (d, J=15.3 Hz,
1H), 7.70 (d, J=15.3 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 516, 518, 520. Anal. Calcd for
C.sub.23H.sub.20Cl.sub.2N.sub.1NaO.sub.5S.0.36 Et.sub.2O: C, 54.06:
H, 4.38; N, 2.58. Found: C, 53.99; H, 4.37; N, 2.22.
Example 331
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-(1-pyrrolidin-2-onyl)propylamino-
)carbonyl)ethenyl)phenyl]sulfide
[1035] The title compound was prepared by the procedures described
in Example 325, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, to give a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=7.2 Hz, 6H), 1.76 (p,
J=5.8 Hz, 2H), 2.08 (p, J=7.65 Hz, 2H), 2.46 (t, J=7.65 Hz, 2H),
3.32 (q, J=5.8 Hz, 2H), 3.36-3.51 (m, 5H), 6.35 (d, J=15.3 Hz, 1H),
6.40 (d, J=8.7 Hz, 1H), 7.10 (brt, J=7.5 Hz, 1H), 7.20-7.30 (m,
2H), 7.42-7.53 (m, 2H), 7.94 (d, J=15.3 Hz, 1H). MS (ESI.sup.+)
(M+H).sup.+ at m/z 491, 493, 495. Anal. Calcd for
C.sub.25H.sub.28Cl.sub.2N.sub.2O.sub.2S.0.7 CH.sub.2Cl.sub.2: C,
56.03; H, 5.38; N, 5.08. Found: C, 56.06; H, 5.22; N, 5.01.
Example 332
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-acetylpiperazin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1036] The title compound was prepared by the procedures described
in Example 326, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, providing a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=7.2 Hz, 6H), 2.17 (s, 3H),
3.46 (septet, J=7.2 Hz, 1H), 3.50-3.90 (m, 8H), 6.41 (d, J=8.7 Hz,
1H), 6.71 (d, J=15.3 Hz, 1H), 7.21-7.35 (m, 2H), 7.44-7.57 (m, 3H),
7.99 (d, J=15.3 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 477,
479, 481. Anal. Calcd for
C.sub.24H.sub.26Cl.sub.2N.sub.2O.sub.2S.0.32 CH.sub.2Cl.sub.2: C,
57.89; H, 5.32; N, 5.55. Found: C, 57.85; H, 5.25; N, 5.74.
Example 333
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[1037] The title compound was prepared by the procedures described
in Example 327, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.20 (d, J=7.2 Hz, 6H), 1.20-1.35 (m,
5H), 1.65-1.93 (m, 1H), 1.93-2.16 (m, 1H), 2.43-2.58 (m, 1H),
3.06-3.35 (m, 1H), 3.47 (septet, J=7.2 Hz, 1H), 3.77-4.23 (m, 4H),
4.50-4.77 (m, 1H), 6.41 (d, J=8.4 Hz, 1H), 6.80 (d, J=15.3 Hz, 1H),
7.18-7.32 (m, 2H), 7.40-7.55 (m, 2H), 7.93 (d, J=15.3 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 506, 508, 510.
Example 334
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[1038] The title compound was prepared by the procedures described
in Example 328, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, to give a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=7.2 Hz, 6H), 1.26 (t,
J=7.05 Hz, 3H), 1.69 (td, J=3.9, 10.8 Hz, 1H), 1.74 (td, J=3.9,
10.8 Hz, 1H), 1.88-2.06 (m, 2H), 2.50-2.63 (m, 1H), 2.84-3.08 (m,
1H), 3.08-3.32 (m, 1H), 3.47 (septet, J=7.2 Hz, 1H), 3.86-4.06 (m,
1H), 4.15 (q, J=7.05 Hz, 2H), 4.37-4.61 (m, 1H), 6.40 (d, J=8.7 Hz,
1H), 6.73 (d, J=15.6 Hz, 1H), 7.22-7.35 (m, 2H), 7.44-7.57 (m, 3H),
7.92 (d, J=15.6 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 506,
508, 510. Anal. Calcd for C.sub.26H.sub.29Cl.sub.2NO.sub.3S.0.01
H.sub.2O: C, 61.64; H, 5.77; N, 2.76. Found: C, 61.64; H, 5.90; N,
2.70.
Example 335
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[1039] The title compound was prepared by the procedures described
in Example 329, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, giving a white solid. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.19 (d, J=7.2 Hz, 1H), 1.43-1.67 (m,
1H), 1.67-1.97 (m, 2H), 1.97-2.19 (m, 1H), 2.52-2.64 (m, 1H),
3.04-3.38 (m, 1H), 3.47 (septet, J=7.2 Hz, 1H), 3.75-4.10 (m, 2H),
4.44-4.70 (m, 1H), 6.40 (d, J=8.4 Hz, 1H), 6.79 (d, J=15.3 Hz, 1H),
7.18-7.29 (m, 2H), 7.41-7.53 (m, 3H), 7.93 (d, J=15.3 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 478, 480, 482. Anal. Calcd for
C.sub.24H.sub.25Cl.sub.2NO.sub.3S.0.05 H.sub.2O.0.01 EtOH: C,
60.13; H, 5.29; N, 2.92. Found: C, 60.14: H, 5.11; N, 2.52.
Example 336
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[1040] The title compound was prepared by the procedures described
in Example 330, substituting 6-mercaptobenzodioxane with
2-isopropylbenzenethiol, giving a white solid. .sup.1H NMR
(d.sup.6-DMSO, 300 MHz) .delta. 1.16 (d, J=7.2 Hz, 6H), 1.33-1.53
(m, 2H), 1.64-1.78 (m, 2H), 1.97-2.10 (m, 1H), 2.88 (brt, J=10.5
Hz, 1H), 3.15 (brt, J=10.5 Hz, 1H), 3.97 (br d, J=13.2 Hz, 1H),
4.11 (br d, J=13.2 Hz, 1H), 6.41 (d, J=9.0 Hz, 1H), 7.22 (d, J=15.6
Hz, 1H), 7.31-7.42 (m, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.56-7.64 (m,
2H), 7.71 (d, J=15.6 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 478, 480, 482. Anal. Calcd for
C.sub.24H.sub.24Cl.sub.2NNaO.sub.3S.0.95 H.sub.2O: C, 55.70; H,
5.04; N, 2.71. Found: C, 55.69; H, 4.90; N, 2.57.
Example 337
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1041] The title compound was prepared by the procedures described
in Example 283, substituting 4-fluoro-3-chlorobenzaldehyde with
2,3-dichloro-4-trifluoromethanesulfoxybenzaldehyde, giving a white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.23 (t, J=7.5 Hz,
3H), 1.46-1.67 (m, 1H), 1.67-1.95 (m, 2H), 1.95-2.17 (m, 1H),
2.43-2.60 (m, 1H), 3.02-3.42 (m, 1H), 3.67-3.92 (m, 2H), 3.86 (s,
3H), 4.13 (q, J=7.5 Hz, 2H), 4.59-4.80 (m, 1H), 6.46 (d, J=8.7 Hz,
1H), 6.54 (d, J=3.0 Hz, 1H), 6.77 (d, J=15.3 Hz, 1H), 7.15 (d,
J=3.0 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 7.42
(d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.92 (d, J=15.3 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 517, 519, 521.
Example 338
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[1042] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
ethyl ester from Example 337, and KOH with NaOH, to give a white
solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.29-1.45 (m,
1H), 1.45-1.78 (m, 2H), 1.78-2.02 (m, 1H), 2.20-2.40 (m, 1H), 2.82
(brt, J=10.5 Hz 1H) 3.08 (brt, J=10.5 Hz, 1H), 3.80-4.07 (m, 2H),
3.86 (s, 3H), 4.38-4.50 (m, 1H), 6.42 (d, J=8.4 Hz. H), 6.54 (d
J=3.0 Hz, 1H), 7.19 (d, J=15.3 Hz, 1H), 7.32 (dd, J=1.8, 8.7 Hz,
1H), 7.48 (d, J=3.0 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.67-7.77 (m,
2H), 7.87 (d, J=1.8 Hz, 1H). MS (ESI.sup.+) (M+H).sup.+ at m/z 489,
491, 493. Anal. Calcd for C.sub.24H.sub.22Cl.sub.2N.sub.2O.sub.3-
S.0.56 CH.sub.2Cl.sub.2: C, 54.94; H, 4.34; N, 5.22. Found: C,
54.89; H, 4.44; N, 5.32.
Example 339
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboethoxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1043] The title compound was prepared by the procedures described
in Example 285, substituting 4-fluoro-3-chlorobenzaldehyde with
2,3-dichloro-4-trifluoromethanesulfoxybenzaldehyde, providing a
white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.25 (t,
J=7.2 Hz, 3H), 1.62-1.79 (m, 2H), 1.87-2.04 (m, 2H), 2.41-2.63 (m,
1H), 2.85-3.41 (m, 2H), 3.85 (s, 3H), 3.87-4.10 (m, 1H), 4.15 (q,
J=7.2 Hz, 2H), 4.32-4.60 (m, 1H), 6.46 (d, J=8.7 Hz, 1H), 6.54 (d,
J=3.0 Hz, 1H), 6.71 (d, J=15.3 Hz, 1H), 7.15 (d, J=3.0 Hz, 1H),
7.17 (d, J=8.7 Hz 1H), 7.36 (dd, J=2.4, 8.4 Hz, 1H), 7.42 (d, J=8.4
Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.90 (d, J=15.3 Hz, 1H). MS
(ESI.sup.+) (M+H).sup.+ at m/z 517, 519, 521. Anal. Calcd for
C.sub.26H.sub.26Cl.sub.2N.sub.2O.sub.3S.0.12 H.sub.2O: C, 60.10; H,
5.09; N, 5.39. Found: C, 60.09; H, 5.21; N, 5.54.
Example 340
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide
[1044] The title compound was prepared by the procedures described
in Example 155, substituting the ethyl ester from Example 137 with
ethyl ester from Example 339, and KOH with NaOH, to give a white
solid. .sup.1H NMR (d.sup.6-DMSO, 300 MHz) .delta. 1.31-1.53 (m,
2H), 1.62-1.76 (m, 2H), 1.94-2.09 (m, 1H), 2.88 (brt, J=10.5 Hz,
1H), 3.13 (brt, J=10.5 Hz, 1H), 3.86 (s, 3H), 3.93 (br d, J=13.2
Hz, 1H), 4.09 (br d, J=13.2 Hz, 1H), 6.41 (d, J=8.7 Hz, 1H), 6.53
(dd, J=0.9, 3.0 Hz, 1H), 7.04 (d, J=15.3 Hz, 1H), 7.32 (dd, J=2.1,
8.7 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H) 7.69
(d, J=15.3 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H).
MS (ESI.sup.+) (M+H).sup.+ at m/z 489, 491, 493. Anal. Calcd for
C.sub.24H.sub.21C.sub.1N.sub.2NaO.sub.3S.0 H.sub.2O: C, 56.37; H,
4.14; N, 5.48. Found: C, 56.44; H, 4.38; N, 5.20.
[1045] An alternative method for preparing Example 340 is given
below. 26
Example 340A
1-Methyl-5-iodoindole
[1046] To a solution of 5-iodoindole (75 g, 0.31 mmol) in dry THF
(750 mL), at -78.degree. C. was added sodium hydride (60% in
mineral oil, 14.85 g, 0.37 mol) in one portion. The suspension was
stirred at -78.degree. C. for 1 hour after which iodomethane (38.3
mL, 0.46 mmol) was added. The reaction mixture was stirred
overnight with a slow elevation on temperature to room temperature
(no more dry ice was added). Ether (600 mL) and hexane (1.2 L) were
added and the mixture was washed with brine (1.6 L) and water (1.5
L), dried over Na.sub.2SO.sub.4 and filtered. The solution was
concentrated and the residual brown solid was recrystallized from
hexane to give the title compound (66 g). The impure fraction from
the mother liquor was flash chromatographed (8% EtOAc in hexane) to
give an additional quantity of desired product (12.5 g, combined
yield of 99%). MS (DCI/NH.sub.3) m/e 258 (M+H).sup.+. 27
Example 340B
1-Methyl-5-triisopropylsilyl-5-indolethiol
[1047] Potassium hydride (35% in mineral oil, 12.03 g, 0.105 mol)
was charged to a 250 mL RBF and was washed with dry THF (2.times.50
mL). The resultant KH powder was then suspended in dry THF (75 mL),
and cooled to 5.degree. C. Triisopropylsilylthiol (20.0 g, 0.105
mol) was slowly added via syringe over a period of 15 minutes.
Vigorous escape of hydrogen as was observed with addition of the
thiol. The suspension was stirred at 5.degree. C. for 1 our and
became homogenous. After another hour stirring at room temperature,
this solution was calculated to a THF solution (10 mL) containing
Example 340A (24.5 g, 95.5 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.2 g, 1.91 mmol). The
yellow suspension was stirred at 70.degree. C. for 1 hour. After
cooled ether and hexane were added, and the mixture was washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. The residual oil
was purified by flash chromatography (silica gel, 3% EtOAc in
hexane) to give the title compound (26.7 g 88%). MS (DCI/NH.sub.3)
m/e 320 (M+H).sup.+. 28
Example 340C
4-Bromo-2,3-dichlorophenol
[1048] To a solution of 2,3-dichlorophenol (200 g, 1.227 mmol) in
dichloromethane (800 mL), at 0.degree. C. was added dropwise
bromine (196.1 g, 1.227 mmol) from a dropping funnel within 1 hour.
The red solution was stirred overnight (0.degree. C.--rt), and
washed with 10% NaHSO.sub.3. The organic phase was dried over
Na.sub.2SO.sub.4, and concentrated. The residual white solid was
recrystallized from hexane to give example 340C as white needles
(207 g, 70%). MS (DCI/NH.sub.3) m/e 241 (M+H).sup.+. 29
Example 340D
Methyl 2,3-(dichloro-4-hydroxyphenylacrylate
[1049] A 1 L RBF was charged with Example 340C (48.4 g, 0.2 mol).
Pd.sub.2(dba).sub.3 (4.6 g, 5 mmol). (Tol).sub.3P (4.66 g, 15.2
mmol), and purged with nitrogen. Dry DMF (300 mL), methyl acrylate
(51.66 g, 0.6 mmol) and triethylamine (84 mL, 0.6 mmol) were then
added. The reaction mixture was pureed with nitrogen and stirred at
100.degree. C. (oil bath) for 16 hours. After cooled to room
temperature, a lot of white crystalline material stirred. Ethyl
acetate (500 mL) and brine (not saturated, 800 mL) were added and
stirred. The white crystalline material dissolved. A little
insoluble black solid (Pd) was filtered off. To the solution was
then added, with stirring, saturated NaCl solution (2 L) and hexane
(500 mL). The mixture was stirred for 1 hour. The formed yellowish
solid was collected by filtration, washed with water (400 mL),
acetonitrile (50 mL) and 1:1 ethyl acetate/hexane (500 mL), and
dried to give pure desired compound (44.99 g, 91%). MS
(DCI/NH.sub.3) m/e 247 (M+H).sup.+. 30
Example 340E
Methyl 2,3-dichloro-4-trifluoromethane
sulfonyloxyphenylacrylate
[1050] To a suspension of Example 340D (18.62 g, 75.4 mmol) in
pyridine (150 mL) at 5.degree. C. was added trifluoromethylsulfonyl
anhydride (25.53 g, 90 mmol) very slowly. The suspension was
stirred at 5.degree. C. for 1 hour and became homogeneous. The
solution was kept at 5.degree. C. for 2 hours and at room
temperature for 20 minutes. Ether (700 mL) was added and the
mixture was washed 10% HCl (700 mL)/brine (300 mL), 10% HCl (100
mL)/brine (900 mL), and brine (500 mL). The organic phase was dried
Na.sub.2SO.sub.4) and concentrated to five the title compound
(24.86 g, 87%). MS (DCI/NH.sub.3) m/e 379 (M+H).sup.+. 31
Example 340F
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(carboxyethenyl)phenyl]sulfide
[1051] To a solution of Example 340B (38.5 g, 0.12 mol) and Example
340E (30.3 g, 0.08 mmol) in di N-methylpyrrolidinone (300 mL) was
added CsF (18.2 g, 0.12 mmol) 5.degree. C. under nitrogen
atmosphere. After 1 hour stirring at the same temperature, the
cooling bath was removed, and the mixture was stirred at room
temperature for 0.5 hour. Ethyl acetate (800 mL) was added, and the
mixture was washed with brine and water, and concentrated. The
residual oil was separated by flash chromatography (20%
EtOAc/hexane) to give a yellow solid (30 g).
[1052] This yellow solid was dissolved in THF (150 mL), and was
added a solution of LiOH (4.0 g, 0.16 mol) in H.sub.2O (50 mL). The
mixture was stirred at room temperature for 1 hour and more water
(100 mL) was added to form a transparent solution. After overnight
stirring, the solution was acidified with 10% aq. HCl. The mixture
was concentrates under reduced pressure to about 100 mL. The formed
solid material was collected by filtration, washed with water (200
mL), acetonitrile (30 mL) 1:1 ether/hexane, and dried to give the
title compound (22.3 g, overall 74%). MS (DCI/NH.sub.3) m/e 378
(M+H).sup.+. 32
Example 340G
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carbomethoxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[1053] To a solution of Example 340F (9.5 g, 25.1 mmol) and methyl
isonipecotate (7.19 g, 50.2 mmol) in DMF (70 mL) was added EDC
(9.64 g, 50.2 mmol), HOBt (6.78 g, 50.2 mmol) and triethylamine
(7.0 mL, 50.2 mmol). The reaction mixture was stirred at room
temperature for 15 hours. Ethyl acetate (800 mL) was added, and the
mixture was washed with brine, and concentrated. The residue was
purified by flash chromatography (60% EtOAc in hexane) to give
example 340G as white powder (10.86 g, 94%). MS (ESI.sup.+) m/z 503
(M+H).sup.+. 33
Example 340
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)-
ethenyl)phenyl]sulfide, sodium salt
[1054] To a suspension of Example 340G (11.8 g, 23.6 mmol) in THF
(150 mL) was added a solution of lithium hydroxide monohydrate
(1.98 g, 47.2 mmol) in H.sub.2O (30 mL). The mixture was stirred at
room temperature overnight. Water (120 mL) was added and formed
transparent solution was stirred for another hour before 10% HCl
(30 mL) was added. The mixture was concentrated under reduced
pressure to about 120 mL. The formed solid material was collected
by filtration, washed with water, acetonitrile, and dried to give a
white solid (11.0 g).
[1055] 10.50 grains of the solid was suspended in methanol (60 mL),
and was treated with a solution NaOH (0.859 g) in methanol (20 mL).
After all of the solid material went into solution, the solvent was
removed under reduced pressure. The residual yellow oil was
triturated with ether, and dried to give the title compound as
yellow powder (11.33 g, 95%).
Example 341
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin-1-yl)carbonyl]ethe-
nyl)phenyl]sulfide
[1056] The title compound was prepared according to the procedures
of Example 310, substituting 2-ethoxybenzenethiol prepared
according to the procedures of Example 97A. .sup.1H-NMR
(CD.sub.3OD, 300 MHz) Potassium salt .delta. 1.20 (t, J=7 Hz, 3H),
1.55-1.72 (m, 2H), 1.88-1.98 (m, 2H), 2.32 (m, 1H), 2.88 (t, J=12
Hz, 1H), 3.20 (t, J=12 Hz, 1H), 4.05 (q, J=7 Hz, 2H), 4.14 (d, J=12
Hz, 1H), 4.48, (d, J=12 Hz, 1H), 6.64 9d, J=9 Hz, 1H), 7.00-7.15
(m, 3H), 7.44-7.50 (m, 2H), 7.56 (d, J=9 Hz, 1H), 7.90 (d, J=15 Hz,
1H) Anal. Calcd. for C.sub.23H.sub.22KCl.sub.2NO.sub.4S 0.5
H.sub.2O: C, 52.37, H, 4.39, N, 2.66. Found: C, 52,23; H, 4.56; N,
2.49.
Example 342
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(morpholin-1-yl)carbonyl]ethenyl)pheny-
l]sulfide
[1057] The title compound was prepared according to the procedures
of Example 310, substituting 2-ethoxybenzenethiol prepared
according to the procedures of Example 97A. .sup.1H-NMR
(CDCl.sub.3, 300 MHz) .delta. 1.25 (t, J=7 Hz, 3H), 3.55-3.80 (m,
8H), 4.05 (q, J=7 Hz, 2H), 6.63 (d, J=9 Hz, 1H), 6.71 (d, J=15 Hz,
1H), 6.95-7.03 (m, 2H), 7.26 (d, J=9 Hz, 1H), 7.39-7.50 (m, 2H),
7.99 (d, J=15 Hz, 1H) Anal. Calcd. for
C.sub.21H.sub.21Cl.sub.2NO.sub.3S: C, 57.54; H, 4.82; N, 3.20.
Found: C, 57.55; H, 4.77; N, 3.14.
Example 343
(2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(3-carboxypiperidin-1-yl)carbonyl]ethe-
nyl)phenyl]sulfide
[1058] The title compound was prepared according to the procedures
of Example 310, substituting 2-ethoxybenzenethiol prepared
according to the procedures of Example 97A. .sup.1H-NMR (CD.sub.3OD
300 MHz) .delta. 1.20 (t, J=7 Hz, 3H), broad peaks totaling 9
protons at 1.4-1.95, 2.0-2.14, 2.22-2.35, 2.75-3.134.10-4.34,
4.69-4.76, 4.05 (q, J=7 Hz, 2H), 6.64 (d, J=9 Hz, 1H), 7.03 (t, J=8
Hz, 1H), 7.10 (d, J=9 Hz, 1H), 7.22 (d, J=15 Hz, 1H), 7.45-7.50 (m,
2H), 7.62 (d, J=9 Hz, 1H), 7.80 (d, J=15 Hz, 1H). The acid (303 mg,
0.63 mmol) was dissolved in 3 mL of methanol. A solution of KOH
(0.60 mmol) in 1 mL of methanol was added. The resultant solution
was stirred for 5 min and concentrated in vacuo. Ether (5 mL) was
added, and the mixture was stirred for 1 hr. The resultant powder
was collected by filtration and dried under vacuum at 60 C to give
307 mg of a solid, water-soluble product. Anal. Calcd. for
C.sub.23H.sub.22KC.sub.1- 2NO.sub.4S 0.5 H.sub.2O; C, 52.37; H,
4.39; N, 2.66. Found: C, 52.20; H, 4.65, N, 3.04.
Example 344
(2-isopropylphenyl)[2-nitro-4-(E-((3-carboethoxypyrrolidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[1059] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=7.0 Hz, 6H); 1.20 (t, J=7.0 Hz, 3H); 1.92-2.30 (m, 2H); 3.10-4.01
(m, 6H); 4.06-4.17 (m, 2H); 6.64 (d, J=8.5 Hz, 1H); 7.06-7.17 (m,
1H), 7.34-7.62 (m, 5H); 7.88-7.96 (m, 1H); 8.62 (dd, J=1.5, 8.5 Hz,
1H). MS (APCI) (M+H).sup.+ at m/z 469. Anal calcd for
C.sub.25H.sub.28N.sub.2S.sub.1O.su- b.5: C, 64.08; H, 6.02; N,
5.98. Found: C, 64.12; H, 5.98; N, 5.89.
Example 345
(2-Isopropylphenyl)[2-nitro-4-(E-((3-carboxypyrrolidin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[1060] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (d,
J=6.8 Hz, 6H); 1.92-2.24 (m, 2H); 3.01-3.92 (m, 6H); 6.64 (dd,
J=1.7, 8.5 Hz, 1H); 7.04-7.16 (m, 1H), 7.33-7.61 (m, 5H); 7.87-7.95
(m, 1H); 8.61 (dd, J=1.7, 8.5 Hz, 1H). MS (APCI) (M+H).sup.+ at m/z
441. Anal calcd for C.sub.23H.sub.24N.sub.2S.sub.1O.sub.5: C,
62.71; H, 5.49; N, 6.36. Found: C, 62.47; H, 5.39; N, 6.09.
Example 346
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((3-carboethoxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[1061] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.18 (d,
J=7.0 Hz, 6H); 1.10-1.22 (m, 3H); 1.30-2.07 (br m, 4H); 2.50-3.45
(br m, 3H); 3.55-4.47 (br m, 5H); 6.62-6.72 (m, 1H); 7.23-7.73 (m,
7H). MS (APCI) (M+H).sup.+ at m/z 474.
Example 347
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((3-carboxypiperidin-1-yl)carbonyl)e-
thenyl)phenyl]sulfide
[1062] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.18 (d,
J=7.0 Hz, 6H); 1.30-2.03 (br m, 4H) 2.25-3.50 (br m, 4H); 3.87-4.51
(br m, 2H); 6.62-6.72 (m, 1H); 7.23-7.73 (m, 7H). MS (APCI)
(M+H).sup.+ at m/z 446.
Example 348
(2-Isopropylphenyl)[2,3-difluoro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)e-
thenal)phenyl]sulfide
[1063] Prepared according to the procedures of Example 71, giving a
yellow solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.18 (d,
J=6.8 Hz, 6H); 1.30-1.91 (br m, 4H); 2.50-3.50 (br m, 4H);
4.02-4.34 (br m, 2H); 6.62-6.72 (m, 1H); 7.23-7.73 (m, 7H). MS
(APCI) (M+H).sup.+ at m/z 446.
Example 349
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-ethoxycarbonylpyrrolidin-1-y-
l)carbonyl)ethenyl)phenyl]sulfide
[1064] The title compound was prepared according to the procedures
of Example 1. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.77 (s,
1H), 7.62 (d, 1H, J=15.4 Hz) 7.42 (d, 1H, J=8.5 Hz), 7.06 (d, 1H,
J=2.1 Hz), 6.98-7.04 (m, 2H), 6.91 (d, 1H, J=8.1 Hz), 6.68 (dd, 1H,
J=3.3, 15.3 Hz), 4.30 (m, 4H), 4.19 (q, 2H, J=7.0 Hz), 3.56-3.92
(m, 4H), 3.06-3.24 (m, 1H), 2.10-2.35 (m, 2H), 1.28 and 1.29 (two
t, 3H, J=7.2 Hz). MS (ESI) m/z 508, 1015.
Example 350
(Benzodioxan-6-yl)[2-trifluoromethyl-4-(E-((3-carboxypyrrolidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1065] The title compound was prepared by hydrolysis of the
compound of Example 349 according to standard procedures. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.10 (d, 1H, J=9.9 Hz), 7.84
(t, 1H, J=7.8 Hz), 7.46 (d, 1H, J=15.3 Hz), 7.10 (d, 1H, J=15.3
Hz), 6.97-7.06 (m, 4H), 4.30 (m, 4H), 3.50 (br, overlapped with
water residue peak), 3.00 (m, 1H), 2.10 (m, 1H), 2.00 (m, 1H). MS
(ESI) m/z -478, -957.
Example 351
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((4-carboethoxypiperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
Example 351A
3-Chloro-4-hydroxy-2-(trifluoromethyl)benzaldehyde
[1066] Chloroform (6.7 g, 2.0 eq.) was added dropwise to a stirred
mixture of Ca(OH).sub.2 (8.95 g, 120 mmol.), K.sub.2CO.sub.3 (13.5
g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol (5.0 g, 22 mmol.),
and H.sub.2O (50 mL) at 60.degree.-70.degree. over 2 h. The
reaction mixture was cooled, and acidified with conc. HCl. The
product was extracted into EtOAc and dried over Na.sub.2SO.sub.4.
Solvent was evaporated, the crude product was separated and
purified through a silica column, eluting with hexane and EtOAc
(3:2) to give 580 mg (10%) of the title compound.
Example 351B
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-carboxyethenyl)phenyl]su-
lfide
[1067] The title compound was prepared according to the procedures
described in Example 310, substituting the compound of Example 351A
for 4-hydroxy-2,3-dichlorobenzaldehyde.
Example 351C
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-E-((4-carboethoxypiperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1068] To the acyl chloride (37 mg, 0.1 mmol) prepared from the
compound of Example 351B, as a solution in CH.sub.2C.sub.2 was
added 1.2 eq. of ethyl isonipecotate and 1.2 eq. of Hunig's base.
The mixture was stirred at room temperature for 20 min., .about.90%
of the solvent was removed in vacuo, and the resultant solution was
loaded on a silica column to elute with hexane and EtOAc (3:2) to
give 51 mg (98%) of the title compound. .sup.1H-NMR (CDCl.sub.3,
300 MHz) .delta. 1.25 (t, J=7.5 Hz, 3H), 1.65-1.78 (m, 2H),
1.92-2.02 (br, 2H), 2.51-2.60 (m, 1H), 2.93-3.24 (br, 2H), 3.82 (s,
3H), 3.88-3.96 (m, 1H), 4.15 (q, J=7.5 Hz, 2H), 4.40-4.50 (br, 1H),
6.48 (d, J=15 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 7.02 (d, J=7.5 Hz,
2H), 7.12 (d, J=9 Hz, 1H), 7.49 (t, J=9 Hz, 2H), 7.86 (qq, J=4.5
Hz, 1H). MS (DCI/NH.sub.3) m/e 528 (M+H).sup.+.
Example 352
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((4-carboethoxypiperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1069] The compound of Example 351 was hydrolyzed by aq. NaOH in
EtOH at rt. to give 90% yield of the title compound. .sup.1H NMR
(DMSO, 300 MHz) .delta. 1.37-1.52 (br, 2H), 1.78-1.86 (br, 2H),
2.45-2.55 (m, 1H), 2.83 (t, J=12 Hz 1H), 3.17 (t, J=13.5 Hz, 1H),
3.80 (s, 3H), 4.07 (d, J=12 Hz, 1H), 4.26 (d, J=13.5 Hz, 1H), 6.75
(d, J=9 Hz, 1H), 6.98 (d, J=15 Hz, 1H), 7.11 (t, J=9 Hz, 1H), 7.26
(d, J=9 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.62 (d, J=9 Hz, 2H), 7.70
(qq, J=4.5 Hz, 1H). MS (DCI/NH.sub.3) m/e 500 (M+H).sup.+.
Example 353
(2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-(E-((morpholin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1070] Prepared according to the procedures of Example 351, giving
50 mg (91%) of the title compound. .sup.1H-NMR (CDCl.sub.3, 300
MHz) .delta. 3.56-3.62 (br m, 2H), 3.67-3.77 (br m, 6H), 3.85 (s,
3H), 6.45 (d, J=15 Hz, 1H), 6.73 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz,
2H), 7.09 (t, J=9 Hz, 1H), 7.52 (d, J=9 Hz, 2H), 2.93 (qq, J=6 Hz,
1H). MS (DCI/NH.sub.3) m/z 458 (M+H).sup.+.
Example 354
(Benzodioxan-6-yl)[4-(E-((4-carboxypiperidin-1-yl)carbonyl)ethenyl)naphthy-
l]sulfide
[1071] The methods of Example 310 and 311 were used to convert
4-hydroxy-2-naphthaldehyde and 6-benzodioxanethiol to the desired
product as a yellow solid. .sup.1H NMR (DMS-d.sub.6, 300 MHz)
.delta.1.50 (br s, 2H) 1.83-1.92 (m, 2H), 2.5-2.6 (m, 1H) 2.85-2.95
(m, 1H), 3.18-3.29 (m, 1H), 4.22 (br s, 5H), 4.30-4.38 (m, 1H),
6.87-6.92 (m, 3H), 7.38 (d, J=15 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H),
7.64-7.70 (m, 2H), 7.93 (d, J=7.5 Hz, 1H), 8.2-8.45 (m, J=3H).
MS(ESI.sup.+) m/z 476 (M+H).sup.-. Anal calcd for
C.sub.27H.sub.25NO.sub.5S.0.67H.sub.2O: C, 66.50; H, 5.44; N, 2.87.
Found: C, 66.56; H, 5.81; N, 2.49. 34
Example 355
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(spiro-hydantoin-5-yl)-piperidin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide
[1072] The title compound was prepared from Example 310C, using the
procedures described in Example 340 and substituting, methyl
isonipecotate with piperadine-4-spiro-5'-hydantoin, which was
prepared according to a literature method (Wysong, C., et al, J.
Org. Chem. 1996, 7650). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.65 (m, 2H), 1.75 (m, 2H), 3.05 (m, 1H), 3.50 (m, 1H), 4.12 (m,
1H), 4.20 (m, 1H), 6.56 (d, J=6.5 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H),
7.22 (d, J=8.0 Hz 1H), 7.28 (d, J=15.6 Hz, 1H), 7.49 (dd, J=8.0,
1.7 Hz, 1H), 7.56 (t, J=8.21 Hz, 1H), 7.76 (d, J=15.61 Hz, 1H),
7.84 (d, J=8.6 Hz, 1H), 8.58 (s, 1H), 10.73 (s, 1H). MS (ESI.sup.-)
m/z 504 (M-H).sup.-. 35
Example 356
(2-methoxyphenyl)[2,3-dichloro-4-(E-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1073] The title compound was prepared from Example 310C by the
procedures described in Example 340 and substituting methyl
isonipecotate with N-[2-(2-hydroxyethoxy)ethyl]piperazine. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.3.10 (m, 2H), 3.50 (m, 4H), 4.50
(m, 2H), 4.70 (s, 1H), 6.57 (d, J=8.5 Hz, 1H) 7.09 (t, J=8.0 Hz,
1H), 7.23 (d, J=8.0 Hz, 1H), 7.26 (d, J=15.5 Hz 1H), 7.49 (dd,
J=7.8, 1.7 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 7.78 (d, J=15.6 Hz,
1H), 7.80 (d, J=7.8 Hz, 1H). MS (ESI.sup.-) m/z 545 (M-H).sup.-.
36
Example 357
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-ethylpiperazin-1-yl)carbonyl)ethen-
yl)phenyl]sulfide
[1074] The title compound was prepared from Example 310C by the
procedure described in Example 340 and substituting methyl
isonipecotate with 1-ethylpiperazine. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.09 (t, J=7.1 Hz, 3H), 2.42 (q, J=7.1 Hz, 2H),
2.47 (m, 4H), 3.60 (m, 2H), 3.75 (m, 2H), 3.82 (s, 3H), 6.56 (d,
J=8.5 Hz, 1H), 6.74 (d, J=15.3 Hz, 1H), 7.02 (m, 2H), 7.26 (d,
J=8.5 Hz, 1H), 7.46 (m, 2H), 7.94 (d, J=15.5 Hz, 1H). MS
(ESI.sup.+) m/z 451 (M+H).sup.+. 37
Example 358
(2-Isopropylphenyl)[2,3-dichloro-4-(E-((4-(2-(2-hydroxyethoxy)ethyl)pipera-
zin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1075] The title compound was prepared from the cinnamide acid of
Example 331, using the procedures described in Example 340 and
substituting methyl isonipecotate with
N-[2-(2-hydroxyethoxy)ethyl]piperazine. .sup.1H NMR (300 MHz
DMSO-d.sub.6) .delta. 1.18 (d, 6H), 3.0 (m, 3H), 3.30 (m, 2H), 3.50
(m, 10H), 3.80 (m, 2H), 4.50 (t, 1H), 6.45 (d, 1H), 7.30 (d, 1H),
7.35 (dd, 1H), 7.55 (d, 1H), 7.60 (m, 2H), 7.75 (d, 1H), 7.80 (d,
1H). MS (ESI.sup.-) m/z 523 (M+H).sup.+.
Example 359
(Benzodioxan-6yl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
Example 359A
1-Methyl-2,3-bis(trifluoromethyl)-7-oxabicyclo[2.2.1]hepta-2,5-diene
[1076] Hexafluoro-2-butyne (21.0 g, 0.13 mol) was transferred into
a reaction bottle and added 2-methylfuran (12.86 g, 0.157 mol).
This resulting mixture bottle was scaled and heated for 15 hr. at
120.degree. C. After cooling the excess 2-methylfuran was
rotoevaporated in vacuo at rt. to give crude title product (29 g,
92%), which was used directly.
Example 359B
4-Methyl-2,3-bis(trifluoromethyl)phenol
[1077] A mixture of Example 359A (12.0 g, 0.05 mol) and boron
trifluoride-diethyl ether complex (150 ml) was stirred at room temp
overnight, then neutralized carefully with 20% aqueous potassium
carbonate, then the mixture was extracted with ether. The ether
layer was dried over MgSO.sub.4 and evaporated under reduced
pressure to afford 10.4 g (85%) of the title compound.
Example 359C
4-[4-Bromobenzene
sulfonyloxy-2,3-bis(trifluoromethyl)benzylbromide
[1078] The phenol compound of Example 359B (10 g, 0.04 mol) was
treated with 4bromobenzenesulfonyl chloride (11.0 g, 0.043 mol) and
Hunig's base (5.56 g, 0.043 mol) in CH.sub.2Cl.sub.2 (150 ml). The
solution was washed with water, brine and dried over MgSO.sub.4.
After evaporating the solvent, N-bromosuccinimide (7.3 g, 0.04 mol)
and benzoyl peroxide 200 mg) were added and the mixture was
suspended in CCl.sub.4 (100 ml). The resulting mixture was refluxed
for 13 hr. When the reaction was cooled, the white solid was
filtered and washed with CCl.sub.4 to afford the crude title
compound. This crude product was used for next step without further
purification.
Example 359D
4-Hydroxy-2,3-bis(trfluromethyl)benzaldehyde
[1079] The crude product of Example 359C was dissolved in 60 ml of
DMSO and 20 ml of CH.sub.2Cl.sub.2, and 12 g of trimethylamine
N-oxide added. The resulting mixture was stirred at rt for 2.5 hr.
The reaction mixture was poured into an ice cold 50% saturated
aqueous NaCl solution (200 ml) and extracted with ether
(3.times.100 ml). The combined organic layer was washed with brine
and dried over Na.sub.2SO.sub.4. After evaporation of solvent, die
product was purified by column chromatography, eluted with
hexane:EtOAc (3:2) to provide 3.0 g of the title compound plus 4.0
g of recovered
4-[4-bromobenzenesulfonyloxy-2,3-bis(trfluoromethyl)]toluene.
Example 359E
(Benzodioxan-6-yl)-[2,3-bis(trfluoromethyl)-4-(E-carboethenyl)phenyl]sulfi-
de
[1080] The title compound was prepared according to the procedures
described in Example 330, substituting the compound of Example 359D
for 4-hydrox-2,3-dichlorobenzaldehyde.
Example 359F
(Benzodioxan-6yl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[1081] The title compound was prepared from Example 359E by the
procedures described in Example 330, giving a white solid. .sup.1H
NMR (CD.sub.3OD, 300 MHz) .delta. 1.65 (br s, 2H), 1.93-2.04 (m,
2H), 2.57-2.65 (m, 1H), 2.95-3.05 (m, 1H), 3.25 (m, 1H), 4.12 m,
1H), 4.28 (m, 4H), 4.41 (m, 1H), 6.92-7.03 (m, 4H), 7.25 (d, J=9
Hz, 1H), 7.72 (d, J=9 Hz, 1H), 7.72-7.81 (m, 1H). MS (ESI) m/e 562
(M+H).sup.+. Anal calcd for C.sub.25H.sub.21NO.sub.5F.sub.6S: C,
53.48; H, 3.77: N, 2.49. Found: C, 53.42; H, 69; N, 2.25. 38
Example 360
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-piper-
din-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1082] 39
Example 360A
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(methylaminomethylcarboxylate)carb-
onyl-piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1083] The title compound was prepared by the procedure described
in Example 363 using glycine methyl ester as the coupling
substrate. HPLC (Supelco C-18 column, water:acetonitrile
50:90-90:50, 9 minute elution, flow rate 1.5 mL/min. rt=6.11 min.
MS (APCI m/e 537 (M+H).sup.-;
[1084] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.46 (m, 3H),
1.78 (br d, 2H), 2.79 (m, 1H), 3.15 (m, 1H), 3.62 (s, 3H), 3.80 (s,
3H), 3.83 (d, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 6.58 (d, 1H), 7.09
(t, 1H), 7.22 (d, 1H), 7.25 (dd, 1H), 7.48 (d, 1H), 7.56 (t, 1H),
7.72 (d, 1H), 7.81 (d, 1H), 8.28 (t, 1H). Anal calcd for
C.sub.25H.sub.26Cl.sub.2N.sub.2O.sub.5S- .1.3 H.sub.2O: C, 53.54;
H, 5.14: N, 4.99. Found: C, 53.49: H, 4.88: N, 4.75. 40
Example 360B
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-piper-
idin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1085] The title compound was hydrolyzed as described in Example
340H. HPLC (Supelco C-18 column, water:acetonitrile 90:0-0:90, 30
minute elution, flow rate 0.8 mL/min) rt 26.14 min. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.46 (m, 2H), 1.75 (m, 2H), 2.73
(m, 1H), 3.12 (m, 1H), 3.70 (m, 2H), 3.79 (s, 3H), 4.02 (m, 1H),
4.20 (m, 1H), 4.41 (m, 1H), 6.65 (d, 1H), 7.09 (dt, 1H), 7.22 (d,
1H), 7.25 (dd, 1H), 7.48 (dd, 1H), 7.58 (m, 1H), 7.72 (d, 1H), 7.8
(d, 1H), 8.11 (m, 1H). MS (APCI) m/e 523 (M+H).sup.-.
Example 361
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxymethylpiperazin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1086] The title compound was prepared according to the procedures
of Example 22, employing the compound of Example 359D as starting
material, to give a white solid. .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta. 3.07-3.12 (m, 4H), 3.48 (s, 2H), 3.74 (s, 3H), 3.89 (br s,
4H), 6.99-7.18 (m, 4H), 7.53 (d, J=9 Hz, 2H), 7.72 (d, J=9 Hz, 1H),
7.78-7.88 (m, 1H), MS (ESI) m/z 549 (M+H).sup.-. Anal calcd for
C.sub.26H.sub.26F.sub.6N.sub- .2O.sub.4S.0.9HAc: C, 51.43; H, 4.28;
N, 4.65. Found: C, 51.48; H, 4.12; N, 4.45.
Example 362
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-N-(2-hydroxyethyl)pipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1087] The title compound was prepared by the procedures described
in Example 356, employing the compound of Example 359D as starting
material to Live an oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
2.68 (br s 6H), 3.71 (br s, 4H), 3.80 (br S, 5H), 6.55 (d, J=15 Hz,
1H), 6.93-7.02 (m, 2H), 7.10 (d, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 1H),
7.41-7.50 (m, 2H), 7.82 (qq. J=15 Hz, 1H). MS (ESI) m/z 535
(M+H).sup.+. Anal calcd for
C.sub.24H.sub.24F.sub.6N.sub.2O.sub.3S.HCl: C, 50.49; H, 4.41; N,
4.91. Found: C, 50.72; H, 4.70; N, 4.55.
Example 363
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-(carbo-2,3-dihydroxypropylamino-
)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1088] To 3 solution of Example 340H (10 mg, 0.2 mmol) and
3-amino-1,2-propanediol (37.4 mg, 0.41 mmol) in DMF (3 mL) was
added EDC (78 mg, 0.41 mmol). HOBt (55 mg, 0.41 mmol) and
triethylamine (0.057 mL, 0.41 mmol). The reaction mixture was
stirred at room temperature for 15 hours. Ethyl acetate (60 mL) was
added, and the mixture was washed with brine. The aqueous phase was
extracted with 10%; MeOH in methylene chloride. The combined
organic phases were concentrated to dry. The residual material was
triturated with water, filtered, washed with water, acetonitrile
and ethyl acetate, and dried to give example 363 (0.92 mg, 80%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.44 (m, 1H), 1.72 (m,
1H), 2.41 (m, 1H), 2.70 (t, 1H), 3.00 (m, 2H), 3.20 (m, 2H), 3.27
(m, 2H), 3.50 (m, 2H), 3.90 (s, 3H), 4.18 (br d, 1H), 4.40 (br d,
1H), 4.50 (t, 1H), 4.77 (d, 1H), 6.40 (d, 1H), 6.58 (d, 1H), 7.19
(d, 1H), 7.35 (d, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.70 (m, 2H),
7.80 (t, 1H), 7.88 (s, 1H). MS (ESI.sup.+) m/z 562 (M+H).sup.+.
Anal. calcd for
C.sub.27H.sub.29Cl.sub.2N.sub.3SO.sub.4.0.25H.sub.2O: C, 57.19; H,
5.24; N, 7.41. Found: C, 57.07; H, 5.22; N, 7.13. 41
Example 364
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-(dihydroxypropionyl)piperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1089] 42
Example 364A
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((piperazin-1-yl)carbonyl)ethenyl)phen-
yl]sulfide
[1090] The title compound was prepared by the procedures described
in Example 340G substituting methyl isonipecotate with piperazine.
MS (DCI/NH.sub.3) m/e 423 (M-H).sup.+. 43
Example 364B
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-dihydroxypropionyl)piperazin-1-
-yl)carbonyl)ethenyl)phenyl]sulfide
[1091] The title compound was prepared by the procedures described
in Example 340, substituting methyl isonipecotate with Example 364A
and substituting Example 340G with DL-gylceric acid Ca salt.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.2-3.8 (m, 12H), 4.38
(t, 1H), 6.58 (d, 1H), 7.10 (t, 1H), 7.27 (d, 1H), 7.28 (d, 1H),
7.50 (d, 1H), 7.60 (t, 1H), 7.79 (d, 1H), 7.83 (d, 1H). MS
(ESI.sup.+) m/z 511 (M+H).sup.+. 44
Example 365
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-(2,3-dihydroxy-3-carboxypropionyl)p-
iperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1092] The title compound was prepared by the procedures described
iii Example 340 substituting methyl isonipecotate with Example 364A
and substituting Example 340G with meso-tartaric acid, .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.70 (m, 8H), 4.33 (br s, 1H), 4.72
(hr s, 1H), 6.58 (d, 1H), 6.77 (d, 1H), 7.03 (m, 2H), 7.25 (d, 1H),
7.50 (d, 1H), 7.52 (d, 1H), 8.00 (d, 1H). MS (ESI.sup.+) m/z 555
(M+H).sup.+. 45
Example 366
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-pi-
peridin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1093] The title compound was prepared by the procedures described
in Example 363 substituting 3-amino-1,2-propanediol with glycine
methyl ester hydrochloride followed by hydrolysis. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.42 (m, 2H), 1.75 (m, 2H), 2.45 (m,
1H), 2.78 (m, 1H), 3.0 (m, 1H), 3.72 (d, 2), 3.90 (s, 3H), 4.18 (br
d, 1H), 4.40 (br d, 1H), 6.42 (d, 1H), 6.57 (d, 1H), 7.18 (d, 1H),
7.32 (d, 1H), 7.50 (d, 1H), 7.65 (5 (d, 1H), 7.67 (d, 1H), 7.70 (m,
1H), 7.88 (s, 1H), 8.18 (t, 1H). MS (ESI.sup.-) m/z 546
(M+H).sup.+. Anal. calcd for
C.sub.26H.sub.25N.sub.3Cl.sub.2SO.sub.4: C, 57.15; H, 4.61; N,
7.69. Found: C, 57.17; H, 4.64: N, 7.39. 46
Example 367
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-((4-sulfopiperidin-1-yl)carbonyl)et-
henyl)phenyl]sulfide
[1094] The title compound was prepared from Example 340F, by the
procedures described in Example 340G, substituting methyl
isonipecotate with piperadine-4-sulfonic acid. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.40 (m, 2H), 1.90 (m, 2H), 3.03 (m,
1H), 4.10 (m, 3H), 4.42 (br d, 1H), 6.40 (d, J=8.8 Hz, 1H), 6.53
(d, J=3.1 Hz, 1H), 7.15 d, J=15.3 Hz, 1H), 7.33 (dd, J=8.5, 1.7 Hz,
1H) 7.48 (d, J=3.1 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.67 (d, J=15.2
Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.87 (d, J=1.5 Hz). MS (ESI.sup.-)
m/z 525 (M+H).sup.+. Anal. calcd for
C.sub.23H.sub.22N.sub.2Cl.sub.2S.sub.2O.sub.4.0.8 TFA: C, 47.91; H,
3.73; N, 4.54. Found: C, 47.71; H, 3.84; N, 4.73. 47
Example 368
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-methylhomopiperazin-1-ylcarbonyl-
)ethenyl)phenyl]sulfide
[1095] The title compound was prepared by the procedures described
in Example 340G substituting methyl isonipecotate with N-methyl
Homopiperazine. .sup.1H NMR 300 MHz, DMSO-d.sub.6) .delta. 2.06 (m,
2H), 2.81 (m, 2H), 3.17 (m, 2H), 3.55 (m 3H), 3.70 (s, 3H), 3.86
(s, 3H), 4.05 (m, 1H), 6.42 (dd, J=8.4, 3.3 Hz, 1H), 6.54 (d, J=3.0
Hz, 1H), 7.08 (dd, J=15.4, 7.5 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz,
1H), 7.49 (d, J=3.0 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.8
Hz, 1H), 7.80 (d, J=15.2 Hz 1H), 7.88 (d, J=2.0 Hz 1H). MS
(ESI.sup.-) m/z 474 (M+H).sup.+. Anal. calcd for
C.sub.26H.sub.26N.sub.3Cl.sub.2SF.sub.3O.sub.3.0.75 TFA: C, 49.01;
H, 4.00; N, 6.23. Found: C, 48.71; H, 4.09; N, 6.13. 48
Example 369
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-tetrohydrofuroylpiperazin-1-yl)c-
arbonyl)ethenyl)phenyl]sulfide
[1096] The title compound was prepared by the procedures described
in Example 340G substituting methyl isonipecotate with
1-tetrahydrofuroylpiperazine. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.80 (m, 2H), 2.00 (m, 2H), 3.50 (m, 8H), 3.75 (m, 2H) 3.88
(s, 1H), 4.68 (t, 1H) 6.42 (d, 1H), 6.57 (d, 1H), 7.19 (d, 1H),
7.32 (d, 1H) 7.48 (d, 1H), 7.65 (d, 1H), 7.70 (d, 1H), 7.75 (d, 1H)
7.87 (s, 1H). MS (ESI.sup.-) m/z 544 (M+H).sup.+. Anal calcd for
C.sub.27H.sub.27N.sub.3Cl- .sub.2SO.sub.3: C, 59.56; H, 4.99; N,
7.71. Found: C, 59.40; H, 4.94; N, 7.61. 49
Example 370
(Benzodioxan-6-yl)[2-(benzodioxan-6-thioxy)-4-(E-((4-morpholino)carbonyl)e-
thenyl)phenyl]sulfide
Example 370A
(E)-Morpholino 2,4-difluorocinnamide
[1097] The title compound was processed as reported in Example 1C
substitution morpholine (1.04 mL, 11.9 mmol) for the amine and
trans-2,4-difluorocinnammic acid (1.00 g, 5.4 mmol) for the
carboxylic acid. The title compound was obtained as an off-white
foam (1.4 g, 100%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) d 8.04 (dd,
J=15.26, 8.82 Hz, 1H), 7.53 (d, J=14.91 Hz, 1H), 7.38-7.30 (m, 1H),
3.61-3.48 (m, 8H). MS (APCI) m/z 254 (M+H).sup.+.
Example 370B
Morpholinyl-(E)-2,4-bis(1,4-benzodioxane-6-mercaptan)cinnamic
amide
[1098] Example 370A (233 mg, 1.00 mmol) was combined with cesium
carbonate (652 m, 2.00 mmol). 1,4-benzodioxane-6-thiol (370 mg,
2.20 mmol), and DMF (5 mL). The mixture was processed as reported
in Example 1A to provide the title compound (220 mg, 40%) as a
white foam. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.83 (d,
J=15.20 Hz, 1H), 7.80 (d, J=8.20 Hz 1H), 7.17 (d, J=15.3 Hz 1H),
7.02 (dd, J=8.5, 2.0 Hz, 1H), 6.87-6.75 (m, 6H), 6.48 (S, 1H),
4.33-4.25 (m, 8H), 3.61-3.48 (m, 81-1). MS (APCI) m/z 550
(M+H).sup.+. 50
Example 371
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-amino-4-carboxypiperidin-1-yl)carb-
onyl)ethenyl)phenyl]sulfide
[1099] To a suspension of Example 355 (700 mg, 1.4 mmol) in DME (10
mL) was added a solution of (BOC).sub.2O (1.51 g 6.9 mmol) in DME
(5 mL), triethylamine (0.23 ml, 1.7 mmol) and DMAP (9 mg, 0.07
mmol). The reaction mixture was stirred at room temperature
overnight. Additional triethylamine (0.23 mL) and DMAP (30 mg) were
added, and the mixture was heated at 60.degree. C. for 6 hours.
After aqueous work up, the crude product was suspended in DME (5
mL) and water (5 mL) containing 200 mg of NaOH. The suspension was
stirred for 5 hours at room temperature, and separated by HPLC to
give the title compound (300 mg, 45%) .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.78 (m, 2H), 3.60 (m, 2), 3.60 (m, 2H), 3.80
(s, 3H), 3.86 (m, 2H), 6.58 (d, 1H), 7.10 (d, 1H), 7.25 (d, 1H),
7.28 (d, 1H), 7.50 (d, 1H), 7.58 (t, 1H), 7.77 (d, 1H), 7.80 (d,
1H), 8.50 (br s, 2H). MS (ESI.sup.+) m/z 481 (M+H).sup.+. Anal
calcd for C.sub.22H.sub.22N.sub.2Cl.sub.2SO.sub.4.0.75 H.sub.2O: C,
47.34; H, 4.06; N, 4.60. Found: C, 47.31; H, 4.05; N, 4.43. 51
Example 372
(2-Methoxyphenyl)[2,3-dichloro-4-((4-furoylpiperazin-1-yl
carbonyl)ethenyl)phenyl]sulfide
[1100] To solution of Example 364A (100 mg, 0.24 mmol) and
2-furfural (30 mg, 0.24 mmol) in dichloroethane (2 mL) was added
NaBH(OAc).sub.3 (142 mg, 0.67 mmol) under nitrogen atmosphere. The
mixture was stirred for 16 hours at room temperature.
Dichloromethane (20 mL) was added and the mixture was washed with
5% NaHCO.sub.3, then with brine, and the organic phase was
separated and concentrated. The residual solid was chromatographed
by flash chromatography (5% MeOH/CH.sub.2CL.sub.2) and desired
fractions were combined, concentrated and dried to afford the title
compound as an off-white solid (84 m, 69%). HPLC (Supelco C-18
column, water:acetonitrile 100:0-0:100, 15 minute elution, flow
rate 1.5 mL/min) rt 11.90 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.39 (m, 4H), 3.52 (s, 2H), 3.55 (m, 2H), 3.63 (m, 2H),
3.79 (s, 3H), 6.29 (d, 1H), 6.40 (m, 1H), 6.57 (d, 1H), 7.08 (dt,
1), 7.21 (d, 1H), 7.23 (dd, 1H), 7.48 (dd, 1H), 7.57 (m, 1H), 7.72
(d, 1H), 7.80 (d, 1H). MS (ESI) m/e 503 (M+H).sup.+. 52
Example 373
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-(carbo-3-sulfopropylamino)pipera-
din-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1101] The title compound was prepared from Example 340H by the
procedures described in Example 363 substituting
3-amino-1,2-propanediol with 3-amino-1-propanesulfonic acid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.40 (m, 2H), 1.70 (m,
4H), 2.38 (m, 1H), 2.42 (m, 2H), 2.70 (m, 1H), 3.0 (m, 3H), 3.86
(s, 3H), 4.18 (br d, 1H), 4.40 (br d, 1H), 6.40 (d, 1H), 6.55 (d,
1H), 7.20 (d, 1H), 7.35 (d, 1H) 7.50 (d, 1) 7.65 (d, 1H), 7.70 (d,
1H) 7.77 (d, 1H), 7.87 (d, 1H). MS (ESI.sup.+) m/z 610 (M+H).sup.+.
Anal calcd for C.sub.27H.sub.29N.sub.3Cl.sub.2S.sub.2O.sub.5- .1.5
TFA: C, 46.10; H, 3.93; N, 5.38. Found: C, 46.52; H, 4.03; N, 5.66.
53
Example 374
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-acetylamino-4-carboxypiperidin-1-yl-
carbonyl)ethenyl)phenyl]sulfide
[1102] To a suspension of Example 371 (90 nm, 0.187 mmol) and
triethylamine (0.08 mL, 0.57 mmol) in DMF (3 mL) was added acetyl
chloride (0.1 mL) at room temperature. The mixture was stirred for
3 hours. Ethyl acetate (60 mL) was added, and the mixture was
washed with brine. The organic phase was dried, filtered and
concentrated. The residue was separated by HPLC (C-18,
CH.sub.3CN/H.sub.2O) to give example 374 (56 mg, 57%).
[1103] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.78 (m, 2H),
1.82 (s, 3H), 1.98 (m, 2H), 3.05 (t, 1H) 3.38 (t, 1H), 3.80 (s,
3H), 4.00 (br d, 1H), 4.12 (br d, 1H), 6.58 (d, 1H), 7.08 (t, 1H),
7.23 (d, 1H), 7.25 (d, 1H), 7.50 (d 1H), 7.58 (t, 1H), 7.78 (d,
1H), 7.80 (d, 1H), 8.18 (s, 1H), MS (ESI.sup.-) m/z 523
(M+H).sup.+. Anal calcd for
C.sub.24H.sub.24N.sub.2Cl.sub.2SO.sub.5.0.35TFA: C, 52.80; H, 4.40;
N 5.05. Found: C, 52.74; H, 4.42; N, 5.11.
Example 375
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[1104] The title compound was prepared by the procedures described
in Example 352, employing the compound of Example 359D to give a
white solid. .sup.1H NMR(CD.sub.3OD, 300 MHz) .delta. 1.65 (br s,
2H), 1.94-2.03 (m, 2H), 2.57-2.67 (m, 1H), 2.95-3.05 (m, 1H)
3.23-3.32 (m, 1H), 3.75 (s, 3H), 4.12 (br s, 1H), 4.40 (br s, 1H),
7.00 (d, J=15 Hz, 1H), 7.03-7.20 (m, 3H) 7.47-7.53 (m, 2H), 7.68
(d, J=9 Hz 1H), 7.77 (qq, J=15 Hz, 1H). MS (ESI) m/z 534 (M+H)+.
Anal calcd for C.sub.24H.sub.21NF.sub.6O.sub.4S: C, 54.03; H, 3.97;
N, 2.63. Found: C, 54.11H, 4.04; N, 1.76.
Example 376
(2-Methoxyphenyl)5-[8-(E-((4-(aminocarbonyl)piperidin-1-yl)carbonyl)etheny-
l)quinolinyl]sulfide
Example 376A
5-Chloro-8-(trifluoromethanesulfonyloxy)quinoline
[1105] 5-Chloro-8-Hydroxyquinoline was treated as described in
Example 340E to provide the title compound. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 7.59 (7.5 Hz, 1H), 7.65-7.69 (m,
2H), 8.63 (dd, J.sub.1=9 Hz, J.sub.2=1.5 Hz, 1H), 9.21 (dd,
J.sub.1=6 Hz, J.sub.2=1.5 Hz, 1H). MS (APCI-NH.sub.3) m/e 312, 314
(M+H).sup.+.
Example 376B
5-Chloro-8-[E-(methoxycarbonyl)ethenyl]quinoline
[1106] The method of Example 340D was used, substituting the
product from Example 376A for Example 340C. Thus, Example 376A
(6.23 g, 20.0 mmol) was converted to the title compound (2.22 g,
45%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.78 (s, 3H),
6.98 (d, J=16.5 Hz, 1H), 7.78-7.83 (m, 1H), 7.88 (d, J=9 Hz, 1H),
8.32 (d, J=9 Hz, 1H), 8.65 (dd, J.sub.1=9 Hz, J.sub.2=1.5 Hz 1H),
8.85 (d, J=16.5 Hz, 1H), 9.12 (dd, J.sub.1=4.5 Hz, J.sub.2=1.5 Hz
1H). MS (APCI-NH.sub.3) m/e 248, 250 (M+H).sup.+.
Example 376C
(2-Methoxyphenyl)
5-[8-(E-(methoxycarbonyl)ethenyl)quinolinyl]sulfide
[1107] The method of Example 340F was used, substituting the
product from Example 376B for Example 340E. Thus, Example 376B
(2.19 g, 8.84 mmol) was converted to the title compound (1.07 g,
36%). .sup.1H NMR (DMSO-d, 300 MHz) .delta. 3.83 (s, 3H), 6.80 (d,
J=16.5 Hz, 1H), 6.86-6.99 (m, 2H), 7.16 (d, J=6 Hz, 1H), 7.33-7.38
(m, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.67-7.72 (m, 1H), 8.22 (d, J=7.5
Hz, 1H), 8.63 (dd, J.sub.1=9 Hz J.sub.2=1.5 Hz 1H), 8.82 (d, J=16.5
Hz, 1H), 9.07 (dd, J.sub.1=6 Hz, J.sub.2=1.5 HZ), 12.48 (s, 1H). MS
(APCI-NH.sub.3) m/e 338 (M+H).sup.+.
Example 376C
(2-Methoxyphenyl)5-[8-(E-((4-(aminocarbonyl)piperidin-1-yl)carbonyl)etheny-
l)quinolinyl]sulfide
[1108] The method of Example 340G was used substituting the product
from Example 376B for Example 340F, and substituting
4-piperidinecarboxamide for methyl isonipecotate. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 1.71-2.82 (m, 2H), 2.96-2.03 (m,
2H), 2.44-2.52 (m, 1H), 2.81-2.94 and 3.16-3.30 (m, 1H), 3.37-3.54
(m, 2H), 3.88 (s, 1H), 4.17-4.34 and 4.60-4.80 (m, 1H), 5.72 (s,
2H), 6.82 (t, 4.5 Hz, 1H), 6.90 (dd, J.sub.1=4.5 Hz, J.sub.2=0.75
Hz 1H), 6.93 (d, 6 Hz, 1H), 7.23-7.28 (m, 1H), 7.40 (d, J=9 Hz,
1H), 7.47-7.50 (m, 1H), 7.51 (d, J=6 Hz, 1H), 7.82 (d, J=4.5 Hz,
1H), 8.57 (d, J=9 Hz, 1H), 8.74 (dd, J.sub.1=4.5 Hz J.sub.2=0.75
Hz, 1H), 9.00 (m, 1H).
Example 377
(2-Methoxyphenyl)[2-trifluoromethyl-4-(E-((4-carboxypiperidin-1-yl)carbony-
l)ethenyl)phenyl]sulfide
[1109] 54
Example 377A
2-Trifluoromethyl-4-(thiobenzodioxan-4-yl)cinnamic acid
[1110] A solution of commercially available
4-fluoro-2-(trifluoromethyl)ci- nnamic acid (5 g, 21.4 mmol) in
ethyl acetate (200 mL) under nitrogen at ambient temperature was
treated with a solution of diazomethane in diethyl ether to a
persistent yellow color, stirred an additional ten minutes, then
quenched by dropwise addition of glacial acetic acid. The resultant
clear solution was washed with saturated NaHCO.sub.3, brine, dried
(MgSO.sub.4), filtered through a plug of silica, rinsed with ethyl
acetate and concentrated to give 5.4 grams of a yellow oil. A
solution of this methyl ester (2.5 g, 10 mmol) and
6-mercaptobenzodioxane (1.9 g, 11 mmol) in 40 mL of
dimethylformamide was treated with cesium carbonate (3.9 g, 12
mmol), and stirred at room temperature for 20 hours. The resultant
orange heterogeneous solution was diluted with diethyl ether and
water, washed with 1 M NaOH, distilled water, brine, dried
(MgSO.sub.4), filtered through a plug of silica, concentrated and
then flash chromatographed with 20% ethyl acetate/hexane followed
by 33% ethyl acetate/hexane to give 2.8 g of a light yellow syrup.
A solution of this diaryl sulfide ester (2.8 g, 7.1 mmol) in THF
(2.1 mL) and distilled water (7 mL) was treated with lithium
hydroxide hydrate (450 mg, 10.7 mmol) and stirred 67 hours at
ambient temperature. The resultant solution was diluted with
distilled water, washed with diethyl ether, acidified to pH 1-2
with 3 M SO.sub.4, extracted with diethyl ether, washed with brine,
dried (MgSO.sub.4) and concentrated to give 2.7 g (7.1 mmol) of the
title compound as an off-white powder (71%). .sup.1H NMR (300 MHz,
d6-DMSO) .delta. 7.97 (d, 1H), 7.72 (dq, 1H), 7.47 (d, 1H), 7.31
(dd, 1H), 7.05 (m, 3H), 6.58 (d, 1H), 4.3 (m, 4H), MS
(APCI-NH.sub.3) m/e 383 (M+H).sup.+, 400 (M+NH.sub.4).sup.+. 55
Example 377B
(Benzodioxan-6-yl)[3-trifluoromethyl-4-(E-((2-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[1111] Example 377A (382 mg, 1 mmol) was coupled with (d,l)-ethyl
pipicolinate according to the procedure of Example 340G. The
derived ethyl ester was hydrolyzed using the method of Example 340H
to give 280 mg of the title compound as a light yellow foam (84%).
Analytical HPLC: 4.6.times.250 mm C18 column, 0.8 mL/min, 254 nm,
CH.sub.3CN:H.sub.2O with 0.1% TFA, 0:100 (0 min), ramp to 90:10
(0-10 min), 90:10 (10-18 min), ramp to 0:100 (18-20 min), rt 11.29
min (98.2 area %). .sup.1H NMR (300 MHz, d6-DMSO) .delta. 8.07 (t,
1H), 7.65 (dq, 1H), 7.38 (m, 3H), 7.03 (m, 1H), 5.15 (m, 1H), 4.4
(m, 1H), 4.29 (m, 4H), 4.1 (m, 1H) 3.2 (m, 1H), 2.2 (m, 1H), 1.68
(m, 2H), 1.3 (m, 2H). MS (APCI-NH.sub.3) m/e 494 (M+H).sup.+, 511
(M+NH.sub.4).sup.+. 56
Example 378
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(((1S,4S)-5-tert-butyloxycarbonyl-2-
,5-diazabycyclo(2,2,1)heptan-2-yl)carbonyl)ethenyl)phenyl]sulfide
[1112] The title compound was prepared by the procedures described
in Example 340 substituting methyl isonipecotate with
t-butyl(1S,4S)-(-)2,5-diazabycyclo(2,2,1)heptane-2-carboxylate.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.40 (s, 9H), 1.82 (m,
2H), 3.17 (m, 1H), 3.30 (m, 2H), 3.58 (m, 1H), 3.82 (s, 3H), 4.05
(m, 1H), 4.40 (m, 1H), 4.75 (br s, 1H), 4.92 (br s, 1H), 6.42 (dd,
1H), 6.58 (d, 1H), 6.75 (d, 1H), 7.05 (d, 1H), 7.35 (d, 1H), 7.50
(d, 1H), 7.65 (d, 1H), 7.68 (d, 1H), 7.78 (t, 1H), 7.77 (s, 1H). MS
(ESI.sup.+) m/z 558 (M+H).sup.+. Anal calcd for
C.sub.28H.sub.29N.sub.3Cl.sub.2SO.sub.3: C, 60.21; H, 5.23; N,
7.52. Found: C, 60.23; H, 5.36; N, 7.41. 57
Example 379
(1-Methylindol-5-yl)[2,3-dichloro-4-(E/Z-((1S,4S)-2,5-diazabycyclo(2,2,1)h-
eptan-2-ylcarbonyl)ethenyl)-2,3-dichlorophenyl]sulfide
[1113] To a solution of Example 378 (820 mg, 1.47 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added trifluoroacetic acid (2 mL) at
0.degree. C. The yellow solution was stirred at the same
temperature for 2 hours. More CH.sub.2Cl.sub.2 (50 mL) was added
and the solution was poured into water (100 mL) containing
NaHCO.sub.3 (4.5 g). The insoluble material was Collected by
filtration, washed with water and methanol. The CH.sub.2Cl.sub.2
solution was concentrated, and the residual solid was filtered,
washed with water, methanol and CH.sub.2Cl.sub.2. The combined
solid was dried to give the title compound (650 mg, 91%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.70 (m, 2H), 2.90 (m, 1H),
3.50 (m, 4H), 3.88 (s, 3H), 4.85 (m, 1H), 6.45 (d, 1H), 6.60 (dd,
1H), 6.77 (d, 1H), 7.05 (dd, 1H), 7.25 (s, 1H), 7.35 (dd, 1H), 7.65
(C, 1H), 7.70 (d, 1H), 7.80 (d, 1H). MS (ESI.sup.+) m/z 458
(M+H).sup.+. 58
Example 380
(1-Methylindol-5-yl)[2,3-dichloro-4-(E-(4-hydroxy-3-carboxypiperadin-1-ylc-
arbonyl)ethenyl)phenyl]sulfide
[1114] To a suspension of Example 340G (300 mg, 0.794 mmol) and
methyl 4-oxo-3-piperadine carboxylate hydrochloride (307 mg, 1.59
mmol) in DMF (10 mL) was added EDC (305 mg, 1.59 mmol). HOBt (215
mg, 1.59 mmol) and triethylamine (0.443 ml, 1.59 mmol). The
suspension was stirred at room temperature overnight. Ethyl acetate
(100 mL) was added and the mixture was washed with brine, water and
was concentrated. The residual oil was separated by flash
chromatography (60% EtOAc in hexane) to give a white solid (220
mg).
[1115] 180 mg of this solid was dissolved in THF (10 mL). A
solution of lithium hydroxide monohydrate (29 mg, 0.68 mmol) in
water (10 mL) was added. The mixture was stirred at room
temperature 2 hours. NaBH.sub.4 (50 mg) was then added. After 4
hours stirring, the solution was acidified and concentrated to 5
mL. The formed white solid was collected by filtration, washed with
water, acetonitrile, and dried to give the title compound (92 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.10 (m, 2H), 3.00 (m,
1H), 3.40 (m, 1H), 3.85 (1H), 4.05 (m, 1H), 4.20 (m, 1H), 4.35 (m,
1H), 5.00 (m, 1H), 6.42 (d, 1H), 6.58 (d, 1H), 7.20 (dd, 1H), 7.35
(d, 1H), 7.50 (d, 1H), 7.6-7.8 (m, 3H), 7.90 (s, 1H). MS (ESI) m/z
505 (M+H).sup.+. Anal calcd for
C.sub.24H.sub.27N.sub.2Cl.sub.2SO.sub- .4: C, 57.03; H, 4.38; N,
5.54. Found: C, 56.77; H, 4.17; N, 5.34. 59
Example 381
(1-Methylindol-1-yl)[2,3-dichloro-4-(E-(S-oxothiomorpholin-1-ylcarbonyl)et-
henyl)phenyl]sulfide
[1116] The title compound was prepared by the procedures described
in Example 340 substituting methyl isonipecotate with
thiomorpholine S-oxide. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
2.70 (m, 2H), 2.85 (m, 2H), 3.85 (s, 3H), 3.90 (m, 2H), 4.20 (m,
1H), 4.60 (m, 1H), 6.45 (d 1H), 6.55 (d, 1H), 6.70 (d, 1H), 7.18
(d, 1H), 7.20 (d, 1H), 7.38 (d, 1H), 7.41 (d, 1H), 7.77 (s, 1H),
7.98 (d, 1H), MS (ESI.sup.+) m/z 479 (M+H).sup.+. 60
Example 382
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-sulfophenylamino)carbonyl)ethenyl)-
phenyl]sulfide
[1117] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with
(2-methoxy)[2,3-dichloro-4-(E-(2-- carboxyethenyl)phenyl]sulfide
and substituting 6-amino-1-hexanol with sulfanilic acid. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 3.82 (s, 3H), 6.65 (d, 1H),
6.82 (d, 1H), 7.12 (t, 1H), 7.25 (d, 1H), 7.5-7.7 (m, 7H), 7.85 (d,
1H), 10.40 (s, 1H), MS (ESI) m/z 510 (M+H).sup.+. Anal calcd for
C.sub.22H.sub.17Cl.sub.2NS.sub.2O.sub.5.0.65TFA: C, 50.80; H, 3.25;
N, 2.55. Found: C, 50.75; H, 3.43; N, 2.65. 61
Example 383
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((4-carboxyphenylamino)carbonyl)etheny-
l)phenyl]sulfide
[1118] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with
(2-methoxy)[2,3-dichloro-4-(E-(2-- carboxyethenyl)phenyl]sulfide
and substituting 6-amino-1-hexanol with 4-aminobenzoic acid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.82 (s, 3H), 6.65 (d,
1H), 6.82 (d, 1H), 7.10 (t, 1H), 7.60 (d, 1H), 7.60 (m, 3H), 7.82
(t, 3H), 7.90 (d, 1H), 7.92 (d, 1H), 10.65 (s, 1H), 1-0.75 (s, 1H).
MS (ESI.sup.+) m/z 474 (M+H).sup.+. 62
Example 384
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1119] 63
Example 384A
(3-Bromophenyl)[2,3-dichloro-4-(E-[methoxycarbonyl]ethenyl)phenyl]sulfide
[1120] To a solution of the resultant compound from Example 340E
(12.0 g, 31.7 mmol) in N-methylpyrrolidinone (63 mL) at 0.degree.
C. (under dry N.sub.2) was added 3-bromothiophenol (4.0 mL, 7.3 g,
38.8 mmol) and a solution of lithium tert-butoxide (3.1 g, 38.8
mmol), and the resulting solution was stirred for 3 h at 0.degree.
C. The reaction was diluted with 500 mL EtOAc and extracted
sequentially with 100 mL water, 3.times.60 mL of 1 N aq. NaOH, then
2.times.100 mL brine. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to produce
the crude title compound (9.2 g). .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 3.75 (s, 3H), 6.67 (d, J=15 Hz, 1H), 6.83 (d, J=9 Hz,
1H), 7.46-7.59 (m, 2H), 7.72-7.76 (m, 2H), 7.80 (t, J=2.5 Hz, 1H),
7.85 (d, J=9 Hz, 1H), 7.88 (d, J=15 Hz, 1H); MS (APCI) m/e 419
(M+H).sup.+. 64
Example 384B
(3-Bromophenyl)[2,3-dichloro-4-(E-carboxyethenyl)phenyl]sulfide
[1121] Using the procedure for Example 340H, Example 348A was
hydrolyzed to the title compound. .sup.1H NMR (DMSO-d.sub.6, 300
MHz) .delta. 6.56 (d, J=16.5 Hz, 1H), 6.84 (d, J=9 Hz, 1H),
7.45-7.58 (m, 2H), 7.72 (m, 1H), 7.77-7.86 (m, 4H), 12.75 (br s,
1H); (ESI) m/e 401, 403 (M-H).sup.-. 65
Example 384C
(3-bromophenyl)[2,3-dichloro-4-(E-[(4-ethoxycarbonylpiperidin-1-yl)carbony-
l]ethenyl)phenyl]sulfide
[1122] The title compound (750 mg, 58%) was prepared from Example
384B (1.0 g, 2.48 mmol), using the procedures described in Example
340G substituting methyl isonipecotate with ethyl isonipecotate.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.18 (t, J=7.5 Hz, 3H),
1.38-1.56 (m, 2H), 1.82-1.92 (m, 2H), 2.50-2.69 (m, 1H), 2.80-2.93
(m, 1H), 3.14-3.27 (m, 1H), 4.07 (t, J=7.5 Hz, 2H), 4.10-4.35 (m,
2H), 6.92 (d, J=9 Hz, 1H), 7.30 (d, J=15 Hz, 1H), 7.43-7.52 (m,
2H), 7.67-7.77 (m, 3H), 7.92 (d, J=9 Hz, 1H). 66
Example 384D
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-[(4-ethoxycarbonylpiperidin-1-y-
l)carbonyl]ethenyl)phenyl]sulfide
[1123] The procedure of D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 9722-9723, was adapted. To a stirred solution
of Example 384D. (180 mg, 0.331 mmol) in ethylene glycol dimethyl
ether (1 mL) containing
1-(N,N-dimethylamino)-1'-(dicyclohexylphophino)biphenyl (7 mg, 5
mol %), Pd.sub.2(dba).sub.3 (8 mg, 2.5 mol %), and morpholine
(0.058 ml, 0.663 mmol) was added powdered K.sub.3PO.sub.4 (141 mg,
0.663 mmol). The reaction mixture was bubbled with N.sub.2 for 5
min and heated at 90.degree. C. in sealed tube for 18 h. Then the
solvent was removed under reduced pressure and residue was diluted
with methylene chloride (1 mL). The title compound (90 mg, 50%) was
isolated by flash chromatography on silica gel eluting with 20%
acetone-hexane. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.18
(t, J=7.5 Hz, 3H), 1.35-1.55 (m, 2H), 1.79-1.91 (m, 2H), 2.58-2.69
(m, 1H), 2.70-2.94 (m, 2H), 3.16 (t, J=4.5 Hz, 2H), 3.15 (t, J=5
Hz, 4H), 3.73 (t, J=4.5 Hz, 4H), 3.78 (t, J=5 Hz, 2H), 4.08 (q,
J=7.5 Hz, 2H), 4.11-4.36 (m, 2H), 6.70 (d, J=8.25 Hz, 1H), 6.97 (m,
1H), 7.10-7.27 (m, 2H), 7.24 (d, J=15 Hz, 1H), 7.39 (m, 1H), 7.73
(d, J=15 Hz, 1H), 7.86 (d, J=8.25 Hz, 1H); MS (ESI) m/e 549, 551
(M+H).sup.+. 67
Example 384E
[3-(4-Morpholino)phenyl][2,3-dichloro-4-(E-[(4-carboxypiperidin-1-yl)carbo-
nyl]ethenyl)phenyl]sulfide
[1124] The title compound (38 mg, 67%) was prepared from Example
384D (60 mg, 0.11 mmol) using the procedures described in Example
340H. .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.37-1.55 (m,
2H), 1.81-1.90 (m, 2H), 2.52-2.58 (m, 1H), 2.80-2.94 (m, 1H),
3.10-3.15 (r, 3H), 3.67-3.75 (m, 3H), 3.76-3.99 (m, 3H), 4.04-4.16
(m, 1H), 4.22-4.33 (m, 1H), 6.71 (d, J=8 Hz, 1H), 6.96 (d, J=7 Hz,
1H), 7.07 (m, 1H), 7.12 (s, 1H), 7.24 (d, J=15 Hz, 1H), 7.38 (t,
j=7 Hz, 1H), 7.73 (d, J=15 Hz, 1H), 7.85 (d, J=8 Hz, 1H). MS (ESI)
m/e 521, 523 (M+H).sup.+, 519, 521 (M-H).sup.-. 68
Example 385
(2-Methoxyphenyl)[2,3-bis(trfluoromethyl)-4-(E-((4-phenylcarboxypiperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1125] 69
Example 385A
4-Phenylpiperidine-4-carboxylic acid
[1126] 4-Cyano-4-phenylpiperidine hydrochloride (2.0 g, 0.11 mol)
was dissolved in 8 mL of conc. H.sub.2SO.sub.4 and 4 mL of
H.sub.2O, then the solution was heated at reflux for 4 h. The
solution was cooled and then NaOH was added to precipitate a white
solid. The solid was collected, then dissolved in methanol, and the
solution was filtered and concentrated to obtain a white solid.
This dried solid was used for without purification for Example
385B. 70
Example 385B
Methyl 4-phenylpiperidine-4-carboxylate hydrochloride
[1127] Dissolved the 4-phenylpiperidinecarboxylic acid in 10 mL of
methanol and added 2 mL of thionyl chloride dropwise at room
temperature. The resulting mixture was stirred overnight at room
temperature. Evaporated solvent in vacuo, added toluene and
evaporated excess thionyl chloride in vacuo. This white powder salt
was used for next step without further purification. 71
Example 385C
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-phenylcarboxypiperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1128] The methyl ester of the title compound was prepared by the
procedures described in Example 356, employing the compound of
Example 359D as starting material, to give an oil. The resultant
methyl ester was hydrolyzed with aq. NaOH in methanol at 60.degree.
C. for 4 h to give a white solid. .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta. 1.88 (br t, J=13.5 Hz, 2H), 2.59 (br d, J=13.5 Hz, 2H),
3.13 (br t, J=13.5 Hz, 1H), 3.75 (s, 3H), 3.44 (br t, J=13.5 Hz,
1H), 4.12 (br d, J=13.5 Hz, 1H), 4.42 (br d, J=13.5 Hz, 1H), 6.35
(d, J=15 Hz, 1H), 7.0-7.46 (m, 7H), 7.43-7.55 (m, 3H), 7.62-7.85
(m, 2H); MS(ESI) m/z 610 (M+H).sup.+. Anal calcd for
C.sub.30H.sub.25F.sub.6NO.sub.4S.H.sub.2O: C, 57.49; H, 4.13; N,
2.20. Found: C, 57.12; H, 3.93; N, 1.77. 72
Example 386
(2-Methoxyphenyl)
[2,3-dichloro-4-(E-(((4-hydroxylaminocarbonyl)piperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1129] To a suspension of Example 319 (300 mg, 0.64 mol) in
CH.sub.2Cl.sub.2 (10 mL) was added oxalyl chloride (67 .mu.L) and 2
drops of DMF. The yellow suspension was stirred at room temperature
for 2 h to give an orange solution which was then concentrated
under reduced pressure, and dried under vacuum. An aliquot of the
resulting acid chloride solution (2 mL) was added to a solution
containing o-trimethylsilyloxyamine (101 mg, 0.96 mmol), Hunig's
base (122 .mu.L, 0.7 mmol) and DMAP (2 mg) in CH.sub.2Cl.sub.2 (3
mL). After the solution was stirred at room temperature for 1 h,
TBAF (1.0 M solution in THF, 1.5 mL) was then added. The brown
solution was stirred at room temperature for another h, then it was
purified by HPLC (Zorbax, C-18) to give the title compound as white
solid (71 mg). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.50 (m,
2H), 1.70 (m, 2H), 2.28 (m, 1H), 2.70 (m, 1H), 3.09 (m, 1H), 3.79
(s, 3H), 4.23 (m, 1H), 4.45 (m, 1H), 6.55 (d, J=8.8 Hz, 1H), 7.08
(t, J=7.4 Hz, 1H), 7.25 (m, 2H), 7.48 (d, J=7.2 Hz, 1H), 7.54 (t,
J=8.2 Hz, 1H), 7.73 (d, J=15.3 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H),
8.55 (br s, 1H), 10.46 (s, 1H). MS (ESI.sup.+) m/z 481 (M+H).sup.+.
73
Example 387
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((N-carboxymethyl-N-phenylamino)carbon-
yl)ethenyl)phenyl]sulfide
[1130] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with
(2-methoxy)[2,3-dichloro-4-(E-(2-- carboxyethenyl)phenyl]sulfide
and substituting 6-amino-1-hexanol with N-phenylglycine ethyl ester
following by hydrolysis. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.76 (s, 3H), 4.40 (s, 2H), 6.35 (d, J=15.5 Hz, 1H), 6.46
(d, J=8.4 Hz, 1H), 7.05 (t, J=7.3 Hz, 1H), 7.22 (m, 2H), 7.35 (t,
J=7.5 Hz, 3H), 7.44 (t, J=7.2 Hz, 3H), 7.55 (t, J=7.4 Hz, 1H), 7.76
(d, J=15.4 Hz, 1H); MS (ESI.sup.+) m/z 488, 490 (M+H).sup.+. Anal.
calcd for C.sub.24H.sub.19NCl.sub.2O.sub.4S: C, 59.02; H, 3.92; N,
2.87. Found: C, 58.71; H, 4.10; N, 2.58. 74
Example 388
(2-Methoxyphenyl)
[3-chloro-6-hydroxy-4-(E-((3-carboxypiperidin-1-yl)carbo-
nyl)ethenyl)phenyl]sulfide
[1131] 75
Example 388A
(2-Methoxyphenyl) ((3-chloro-6-hydroxy-4-formyl)phenyl)sulfide
[1132] 2-Methoxythiophenol (3.5 mL, 28.9 mmol) and
2,4-dichloro-6-hydroxyb- enzaldehyde (5.00 g, 26.3 mmol) were
processed as described in Example 1 to provide the title disulfide
(6.71 g, 87%) as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 10.18 (s, 1H), 7.61 (dd, J=7.4 Hz, J=1.7 Hz, 1H),
7.56 (dd, J=7.7 Hz, J=1.9 Hz, 1H), 7.25 (d, 7.3 Hz, 1H), 7.11 (dt,
J=7.7 Hz, J=1.5 Hz, 1H), 6.69 (d, J=1.8 Hz, 1H), 6.38 (d, 1.5 Hz,
1H), 3.80 (s, 3H); MS (APCI) m/z 294 (M+H).sup.+. 76
Example 388B
(2-Methoxyphenyl)(3-chloro-6-allyloxy-4-benzaldehyde)sulfide
[1133] Allyl bromide (2.0 mL, 22.8 mmol) was added to a stirred
solution of Example 388A (6.71 g, 22.8 mmol), cesium carbonate
(14.86 g, 45.6 mmol), and DMF (45 mL). After 21 h, the pale yellow
solution was diluted with 1 N aqueous HCl (100 mL) and extracted
with Et.sub.2O (2.times.75 mL). The ether extracts were combined,
dried (MgSO.sub.4), filtered, and concentrated to a yellow solid
(7.20 g, 94%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.28
(s, 1H), 7.58 (dd, J=8.4 Hz, J=1.7 Hz, 1H), 7.52 (dd, J=7.8 Hz,
J=1.7 Hz, 1H), 7.23 (d, J=8.1 Hz, J=1.0 Hz, 1H), 7.08 (dt, J=7.8
Hz, J=1.4 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 6.52 (d, J=1.7 Hz, 1H),
5.97 (m, 1H), 5.33 (d, J=17.3 Hz, 1H), 5.28 (d, J=10.8 Hz, 1H),
4.61 (m, 2H), 3.80 (s, 3H); MS (APCI) m/z 335 (M+H).sup.+. 77
Example 388C
(2-Methoxyphenyl)[3-chloro-6-allyloxy-4-((carboxy)ethenyl)phenyl]sulfide
[1134] Example 388B was processed as detailed in Example 1B.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.77 (d, J=16.3 Hz,
1H), 7.51 (dd, J=7.4 Hz, J=1.7 Hz, 1H), 7.43 (dd, J=7.4 Hz, J=1.7
Hz, 1H), 7.19 (dd, J=8.1 Hz, J=1.0 Hz, 1H), 7.05 (dt, J=7.4 Hz,
J=1.4 Hz, 1H), 6.82 (d, J=1.3 Hz, 1H), 6.72 (d, J=15.9 Hz; 1H),
6.66 (d, J=1.7 Hz, 1H), 6.00 (m, 1H), 5.30 (d, J=9.8 Hz, 1H), 5.26
(d, J=3.1 Hz, 1H), 4.63 (m, 2H), 3.80 (s, 3H). MS (APCI) m/z 377
(M+H.sup.+) 394 (M+NH.sub.4.sup.+). 78
Example 388D
(2-Methoxyphenyl)[3-chloro-6-hydroxy-4-(E-((3-carboxypiperidin-1-yl)carbon-
yl)ethenyl)phenyl]sulfide
[1135] The allyl group of Example 388C was removed as reported in
the literature (Honda, M.; Morita, H.; Nagakura, I. J. Org. Chem.
1997, 62, 8932.) and the carboxylic acid was converted to the amide
as reported in Example 165 to provide the title compound as a white
solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.73 (d, J=16.3
Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.19 (d,
J=7.9 Hz, 1H), 7.05 (dt, J=7.8 Hz, 1.1 Hz, 1H), 6.70 (d, J=1.8 Hz,
1H), 6.59 (d, J=6.59 Hz, 1H), 4.30 (m, 1H), 3.95 (m, 2H), 3.80 (s,
3H), 2.85 (m, 2H), 1.87 (m, 2H), 1.45 (m, 2H). MS (APCI) m/z 448
(M+H.sup.+). 79
Example 389
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(4-((1-(2-phenyl-1-carboxyethyl)amino)-
carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1136] The methyl ester of the title compound was prepared by the
procedure described in Example 363 using L-phenylalanine methyl
ester as the coupling substrate. The methyl ester was then
hydrolyzed as described in Example 340 to provide the title
compound. HPLC (Supelco C-18 column, water:acetonitrile
100:0-0:100, 20 minute elution, flow rate 1.5 mL/min, RT=13.97 min;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.45 (m, 2H), 1.56 (m,
1H), 1.68 (m, 1H), 2.41 (m, 1H), 2.71 (m, 1H), 2.83 (m, 2H), 3.08
(m, 2H), 3.79 (s, 3H), 4.12 (m, 1H), 4.30 (m, 1H), 4.41 (m, 1H),
6.55 (d, 1H), 7.09 (t, 1H), 7.22 (m, 6H), 7.48 (dd, 1H), 7.57 (m,
1H), 7.72 (d, 1H), 7.81 (d, 1H), 8.11 (m, 1H), 12.64 (br s, 1H); MS
(ESI) m/e 613 (M+H).sup.+. 80
Example 390
(2-Methoxyphenyl)
[2,3-dichloro-4-(E-(4-((1-(2-hydroxy-1-carboxyethyl)amin-
o)carbonyl)piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1137] The methyl ester of the title compound was prepared by the
procedure described in Example 363 using L-serine methyl ester as
the coupling substrate. The methyl ester was then hydrolyzed as
described in Example 340 to give the title compound. HPLC (Supelco
C-18 column, water:acetonitrile 100:0-0:100, 20 minute elution,
flow rate 1.5 mL/min, RT=11.79 min; .sup.1H NMR (300 MHz,
DMSO-d.sub.4) .delta. 1.48 (m, 2H), 1.72 (m, 2H), 2.55 (m, 2H),
2.71 (m, 1H), 3.10 (m, 1H), 3.62 (m, 2H), 3.79 (s, 3H), 4.22 (m,
2H), 4.41 (m, 1H), 6.55 (d, 1H), 7.09 (t, 1H), 7.34 (m, 2H), 7.48
(m, 1H), 7.57 (m, 1H), 7.71 (d, 1H), 7.81 (d, 1H), 7.96 (br d, 1H);
MS (ESI) m/e 553 (M+H).sup.+. 81
Example 391
(3-(1-(3-Carboxypiperidinyl)phenyl)[2,3-dichloro-4-(E-((1,2,5,6-tetrahydro-
pyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1138] 82
Example 391A
(3-bromophenyl)[2,3-dichloro-4-(E-[(1,2,3,6-tetrahydropyridin-1-yl)carbony-
l]ethenyl)phenyl]sulfide
[1139] The title compound (1.2 g, 103%) was prepared from Example
384B (1.00 g, 2.48 mmol), using the procedures described in Example
340G substituting methyl isonipecotate with
1,2,3,6-tetrahydropyridine. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.09-2.2 (m, 2H), 3.61-3.68 (m, 1H), 3.70-3.77 (m, 1H),
4.03 (m, 1H), 4.18 (m, 1H), 5.69-5.78 (M, 1H), 5.80-5.93 (m, 1H),
6.93 (d, J=9 Hz, 1H), 7.20-7.37 (m, 1H), 7.43-7.56 (m, 3H),
7.67-7.79 (m, 2H), 7.88-7.97 (m, 1H); MS (ESI) m/e 470, 472
(M+H).sup.+. 83
Example 391B
[3-(3-ethoxycarbonylpiperidine)][2,3-dichloro-4-(E-[(1,2,3,6-tetrahydropyr-
idin-1-yl)carbonyl]ethenyl)phenyl]sulfide
[1140] The title compound (50 mg, 46%0 was prepared by the
procedures described in Example 384D, substituting morpholine with
ethyl nipecotate. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.17
(t, J=6.8 Hz, 3H), 1.5-1.76 (m, 3H), 1.82-1.95 (m, 1H), 2.06-2.19
(m, 2H), 2.56-2.67 (m, 1H), 2.84-2.96 (m, 1H), 3.06-3.13 (m, 1H),
3.43-3.52 (m, 1H), 3.61-3.74 (m, 2H), 3.99-4.18 (m, 4H), 5.66-5.91
(m, 2H), 6.73 (d, J=9 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 7.06-7.12
(m, 2H), 7.31-7.39 (m, 2H), 7.75 (d, J=15 Hz, 1H), 7.80-7.91 (m,
1H); MS (ESI) m/e 545, 547 (M+H).sup.+. 84
Example 391C
[3-(3-carboxypiperidine)][2,3-dichloro-4-(E-[(1,2,3,6-tetrahydropyridine)--
1-yl)carbonyl]ethenyl)phenyl]sulfide
[1141] The title compound (20 mg, 49%) was prepared from Example
391B (43 mg, 0.08 mmol) using the procedures described in Example
340H. .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.51-1.64 (m,
2H), 1.68-1.73 (m, 1H), 1.87-1.94 (m, 1H), 2.07-2.19 (m, 2H),
2.51-2.57 (m, 1H), 2.83-2.89 (m, 1H), 2.99-3.04 (m, 1H), 3.61-3.73
(m, 4H), 4.02 (br s, 1H), 4.15 (br s, 1H), 5.67-5.76 (m, 1H),
5.79-5.90 (m, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.92 (J=6.25 Hz, 1H),
7.10-7.13 (m, 2H), 7.14-7.30 (m, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.74
(d, J=15 Hz, 1H), 7.80-7.90 (m, 1H); MS (ESI) m/e 517, 519
(M+H).sup.+. 85
Example 392
(3-(4-Pyrrolidin-1-yl)piperidin-1-yl)phenyl)[2,3-dichloro-4-(E-(((3-(2-pyr-
rolidinon-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide
[1142] 86
Example 392A
(3-bromophenyl)
[2,3-dichloro-4-(E-(((3-(2-pyrrolidinon-1-yl)propylamino)c-
arbonyl)ethenyl)phenyl]sulfide
[1143] The title compound (1.25 g, 95%) was prepared from Example
384B (1.00 g, 2.475 mmol), using the procedures described in
Example 340G substituting methyl isonipecotate with
3-aminopropylpyrrolidine. MS (ESI) m/e 529, (M+H).sup.+, 527,
(M-H).sup.-. 87
Example 392B
(3-(4-Pyrrolidin-1-yl)piperidin-1-yl)phenyl)[2,3-dichloro-4-(E-(((3-(2-pyr-
rolidinon-1-yl)propylamino)carbonyl)ethenyl)phenyl]sulfide
[1144] The title compound (32 mg, 27%) was prepared from Example
392A as described in Example 384D, substituting morpholine with
4-(1-pyrrolidinyl)piperidine. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.60-1.67 (m, 4H), 1.84-2.90 (m, 5H), 2.91-2.03 (m, 1H),
2.04-2.11 (m, 3H), 2.20 (t, J=7.5 Hz, 2H), 2.75 (br t, J=12.5 Hz,
2H), 3.00-3.16 (m, 1H), 3.21 (t, J=7.5 Hz, 1H), 3.33 (m, 1H),
3.46-3.64 (m, 1H), 3.87 (br d, J=10 Hz, 2H), 6.59 (d, J=15 Hz, 1H),
6.80 (d, J=8.75 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 7.12-7.18 (m, 2H),
7.33 (t, J=7.5 Hz, 1H), 7.57 (d, J=8.75 Hz, 1H), 7.68 (d, J=15 Hz,
1H), 8.24 (t, J=5 Hz, 1H); MS (ESI) m/e 601, 603, (M+H).sup.+; 599,
601 (M-H).sup.-. 88
Example 393
[3-(4-(Spiro-2,2-dioxolanyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-m-
orpholinyl)carbonyl)ethenyl)phenyl]sulfide
[1145] 89
Example 393A
(3-bromophenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl]s-
ulfide
[1146] The title compound (980 mg, 84%) was prepared from Example
384B (1.00 g, 2.48 mmol), using the procedures described in Example
340G substituting methyl isonipecotate with morpholine. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) 3.53-3.63 (m, 6H), 3.68 (br s, 2H), 6.93
(d, J=8 Hz, 1H), 7.27 (d, J=15 Hz, 1H), 7.44-7.52 (m, 2H),
7.67-7.74 (m, 2H), 7.78 (d, J=15 Hz, 1H), 7.80 (d, J=8 Hz, 1H); MS
(ESI) m/e 474 (M+H).sup.+. 90
Example 393B
[3-(4-(Spiro-2,2-dioxolanyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-m-
orpholinyl)carbonyl)ethenyl)phenyl]sulfide
[1147] The title compound (32 mg, 27%) was prepared from Example
393A as described in Example 384D, substituting morpholine with,
4-dioxa-8-azaspiro[4,5]decane. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.68 (t, J=5 Hz, 4H), 3.52-3.60 (m, 7H), 3.66 (br s, 2H),
3.91 (s, 4H), 6.71 (d, J=8.75 Hz, 1H), 6.91 (m, 1H), 7.11-7.13 (m,
2H), 7.22 (d, J=15 Hz, 1H), 7.35 (m, 1H), 7.76 (d, J=15 Hz, 1H),
7.85 (d, J=8.75 Hz, 1H); MS (ESI) m/e 535, 537 (M+H).sup.+. 91
Example 394
[3-(3-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxypiperidi-
n-1-yl)carbonyl]ethenyl)phenyl]sulfide
[1148] The title compound (51 mg, 41%) was prepared from Example
384C as described in Example 384D, substituting morpholine with
ethyl nipecotate followed by hydrolysis with LiOH as described in
Example 340H. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.39-1.60
(m, 4H), 1.67-1.76 (m, 1H), 1.82-1.96 (m, 3H), 2.52-2.59 (m, 3H),
2.81-2.93 (m, 2H), 2.99-3.07 (m, 1H), 3.14-3.25 (m, 1H), 3.47-3.54
(m, 1H), 3.69 (dd, J.sub.1=4 Hz, J.sub.2=12 Hz, 1H), 4.05-4.17 (m,
1H), 4.24-4.34 (m, 1H), 6.72 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H),
7.11 (m, 2H), 7.23 (d, J=15 Hz, 1H), 7.34-7.40 (m, 1H), 7.73 (d,
J=15 Hz, 1H), 7.85 (d, J=8 Hz, 1H); MS (ESI) m/e 563, 565
(M+H).sup.+. 92
Example 395
(2-(2-Carboxy)ethenyl)phenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)e-
thenyl)phenyl]sulfide
[1149] 93
Example 395A
(2-(2-Tert-butyloxycarbonyl)ethenyl)phenyl)[2,3-dichloro-4-(E-((4-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide
[1150] A solution of Example (2-bromophenyl) (50 mg, 0.11 mmol),
tris(benzylidineacetone)dipalladium[0] (5.1 mg, 0.0056 mmol), and
tri-o-tolylphosphine (11 mg, 0.035 mmol) in 0.2 mL DMF was degassed
with nitrogen gas for 10 min, then triethylamine (50 .mu.L, 36 mg,
0.36 mmol) and tert-butyl acrylate (50 .mu.L, 44 mg, 0.34 mmol)
were added to the solution, and the vessel was sealed under
nitrogen and heated in a 100.degree. C. oil bath for 17 h. The
reaction was concentrated under hi-vacuum, and the residue was
partially purified by preparative TLC eluting with 10%
acetone-CH.sub.2Cl.sub.2 to provide 42 mg (0.080 mmol, 73%) of the
title compound as a crude material. The compound was further
purified by preparative HPLC (30-100% MeCN in 0.1% aqueous TFA, 40
min elution, C-18 reverse-phase Sorbax 10 mm column, producing 26
mg (0.051 mmol, 47%) of the title compound as a glass. .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 1.47 (s, 9H), 2.3-2.7 (v br s, 5H),
3.54-3.90 (2 br m, 8H>, 6.32 (d, J=16 Hz, 1H), 6.46 (d, J=8 Hz,
1H), 6.69 (br d, J=15 Hz, 1H), 7.24 (br d, partially overlapped
with CHCl.sub.3, approx. 1H), 7.40-7.54 (m, 2H), 7.59 (dd, J=2.8
Hz, 1H), 7.75 (dd, J=2.8 Hz, 1H), 7.94 (br d, J=15 Hz, 1H), 7.98
(d, J=16 Hz, 1H); MS (ESI) m/e 520, 522 (M+H).sup.+. 94
Example 395B
(2-(2-Carboxy)ethenyl)phenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)e-
thenyl)phenyl]sulfide
[1151] Example 395A (26 mg, 0.050 mmol) was dissolved in 1 mL
chloroform and 1 mL TFA and the solution was stirred at ambient
temperature for 1 h. The solvent was concentrated under reduced
pressure to provide 25 mg (109%) of the title compound as an 85:15
mixture of E- and Z-cinnamide isomers. Data for major isomer:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.55-3.85 (2 br m, 9H),
6.42 (d, J=16 Hz, 1H), 6.47 (d, J=8 Hz, 1H), 6.69 (d, J=15 Hz, 1H),
7.24 (d, partially overlapped with CHCl.sub.3, approx. 1H),
7.43-7.56 (m, 2H), 7.78 (dd, J=2.8 Hz, 2H), 7.93 (d, J=15 Hz, 1H),
8.23 (d, J=16 Hz, 1H); MS (ESI) m/e 464, 466 (M+H).sup.+. 95
Example 396
[3-(4-Carboxylpiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(1,2,3,6-tetrahydr-
opyridine)-1-yl)carbonyl]ethenyl)phenyl]sulfide
[1152] The title compound (22 mg, 58%) was prepared from Example
391A as described in Example 384D, substituting morpholine with
ethyl isonipecotate followed by hydrolysis with LiOH as described
in Example 340H. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.59-1.70 (m, 2H), 1.87-1.93 (m, 2H), 2.07-2.19 (m, 2H), 2.39-2.47
(m, 1H), 2.80-2.90 (m, 2H), 4.03 (br s, 1H), 4.16 (br s, 1H),
5.68-5.76 (m, 1H), 5,79-5.90 (m, 1H), 6.72 (d, J=8 Hz, 1H), 6.93
(d, J=7 Hz, 1H), 7.13 (m, 2H), 7.17-7.3 (m, 1H), 7.36 (t, J=7 Hz,
1H), 7.75 (d, J=15 Hz, 1H), 7.80-7.90 (m, 1H); MS (ESI) m/e 517,
519 (M+H).sup.+. 96
Example 397
[3-(4-Carboxylpiperidinyl)phenyl][2,3-dichloro-4-(E-[(4-morpholinyl)carbon-
yl]ethenyl)phenyl]sulfide
[1153] The title compound (39 mg, 79%) was prepared from Example
393A as described in Example 384D, substituting morpholine with
ethyl isonipecotate followed by hydrolysis with LiOH as described
in Example 340H. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
1.56-1.68 (m, 2H), 1.86-1.92 (m, 2H), 2.38-2.46 (m, 1H), 2.77-2.86
(m, 2H), 3.52-3.61 (m, 6H), 3.65-3.72 (m, 4H), 6.71 (d, J=8 Hz,
1H), 6.91)d, J=7 Hz, 1H), 7.10 (m, 2H), 7.21 (d, J=15 Hz, 1H), 7.34
(t, J=8 Hz, 1H), 7.76 (d, J=15 Hz, 1H), 7.83 (d, J=8 Hz, 1H); MS
(ESI) m/e 521, 523 (M+H).sup.+. 97
Example 398
[2-(4-Acetylpiperazin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-carboxypiperidin--
1-yl)carbonyl]ethenyl)phenyl]sulfide
[1154] The title compound (19 mg, 83%) was prepared from Example
384C as described in Example 384D, substituting morpholine with
4-acetylpiperazine, followed by hydrolysis with LiOH as described
in Example 340H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.38-1.54 (m, 2H), 1.82-11.92 (m, 2H), 2.00 (s, 3H), 2.51-2.60 (m,
1H), 2.87-3.00 (m, 5H), 3.13-3.27 (m, 1H), 3.36-3.46 (m, 4H),
4.06-4.18 (m, 1H), 4.22-4.36 (m, 1H), 6.91 (d, J=7.5 Hz, 1H),
7.10-7.17 (m, 1H), 7.20-7.25 (m, 2H), 7.28 (d, J=15 Hz, 1H),
7.39-7.45 (m, 1H), 7.77 (d, J=15 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H);
MS (ESI) m/e 562, 564 (M+H).sup.+. 98
Example 399
[3-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-morpholinyl)carb-
onyl]ethenyl)phenyl]sulfide
[1155] The title compound (30 mg, 60%) was prepared from Example
393A as described in Example 384D, substituting morpholine with
ethyl nipecotate followed by hydrolysis with LiOH as described in
Example 340H. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.51-1.60
(m, 1H), 1.66-1.72 (m, 1H), 1.87-1.94 (m, 1H), 2.79-2.87 (m, 1H),
2.96-3.02 (m, 1H), 3.44-3.72 (m, 12H), 6.71 (d, J=8 Hz, 1H), 6.90
(d, J=7 Hz, 1H), 7.09 (m, 2H), 7.21 (d, J=15 Hz, 1H), 7.32-7.38 (m,
1H), 7.76 (d, J=15 Hz, 1H), 7.84 (d, J=8 Hz, 1H); MS (ESI) m/e 521,
523 (M+H).sup.+. 99
Example 400
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-(dimethylaminosu-
lfamoyl)piperazin-1-yl)carbonyl]ethenyl)phenyl]sulfide
[1156] 100
Example 400A
N,N-Dimethyl piperazinylsulfamide
[1157] To a solution of tert-butyl 1-piperazinecarboxylate (2.5 g,
13.42 mmol) in tetrahydrofuran (21.5 ml, 0.25 M) at 0.degree. C.
was added triethylamine (2.25 mL, 16.11 mmol) followed by
dimethylsulfamoyl chloride (1.73 mL, 16.11 mmol). The reaction
mixture was stirred at 0.degree. C. for 1 h, diluted with ethyl
acetate (100 mL) and washed with saturated NaHCO.sub.3 solution
(2.times.30 mL), followed by brine (2.times.30 mL). The dried
(Na.sub.2SO.sub.4) organic layer was evaporated to dryness under
reduced pressure and the residue obtained was treated with 10%
trifluoroacetic acid in methylene chloride (20 mL) at ambient
temperature. After 48 h, methylene chloride was evaporated in vacuo
to obtain a colorless syrup. This crude material was made basic (1
N NaOH, 50 mL), and the mixture was extracted sequentially with
ethyl acetate (2.times.20 mL) and methylene chloride (2.times.30
mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and
evaporated to dryness under reduced pressure to obtain the title
compound in quantitative yield. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.77 (s, 3H), 2.79 (s, 3H), 3.12-3.20 (m, 7H), 3.3 (m, 1H),
8.86 (br s, 1H); MS (ESI) m/e 194 (M+H).sup.+. 101
Example 400B
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-[(4-(dimethylaminosu-
lfamoyl)piperazin-1-yl)carbonyl]ethenyl)phenyl]sulfide
[1158] The title compound was prepared from Example 384B as
described in Example 340G, substituting methy isonipecotate with
Example 400A, followed by amination with ethyl isonipecotate as
described in Example 396. .sup.1H NMR (500 MHz, MeOH-d.sub.4)
.delta. 2.79-2.88 (m, 2H), 2.01-2.08 (m, 2H), 2.48-2.53 (m, 1H),
2.84 (s, 6H), 2.91-2.99 (m, 2H), 3.24-3.29 (m, 2H), 3.66-3.73 (m,
2H), 3.77 (m, 6H), 6.80 (d, J=7.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H),
7.11 (d, J=15 Hz, 1H), 7.16-7.22 (m, 2H), 7.39 (t, J=7.5 Hz, 1H),
7.62 (d, J=7.5 Hz, 1H), 7.95 (d, J=15 Hz, 1H); MS (ESI) m/e 625,
627 (M-H).sup.-. 102
Example 401
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((3-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[1159] 103
Example 401A
Ethyl 2-Furylacrylate
[1160] Ethyl iodide (64 mL, 0.796 mol) was added to furylacrylic
acid (100 g, 0.724 mol), diisopropylethyl amine (140 mL, 0.796
mmol), in acetonitrile (1100 mL), and the mixture was heated to
60.degree. C. After 18 h, the dark solution was cooled to room
temperature and concentrated in vacuo. The resulting brown sludge
was diluted with Et.sub.2O (500 mL), washed with 1 N aqueous HCl
(2.times.250 mL), washed with 0.2 N aqueous NaOH (2.times.250 mL),
washed with saturated aqueous NaHCO.sub.3 (1.times.250 mL), dried
(MgSO.sub.4), filtered, and concentrated to a black oil (114 g,
95%). .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.84 (d, J=1.7
Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 6.97 (d, J=3.4 Hz, 1H), 6.33 (dd,
J=3.4 Hz, J=1.7 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 4.17 (q, J=7.1
Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); MS (APCI) m/z 167 (M+H).sup.+.
104
Example 401B
Ethyl E-2,3-bis(trifluoromethyl)-4-hydroxycinnamate
[1161] A solution of Example 401A (20 g, 0.12 mol) in
tetrahydrofuran (40 mL) at -50.degree. C. in a 600 mL Parr stirred
reactor was treated with hexafluoroacetylene (24.4 g, 0.15 mol),
the reactor sealed and heated to 110.degree. C. for 22 hours,
allowed to slowly cool to room temperature, and then concentrated
to a brown oil (36 g). This oil was then treated with boron
trifluoride etherate (33 mL, 0.275 mol) at room temperature for 17
hours, additional boron trifluoride etherate (16 mL, 0.135 mol)
added, stirred six hours, cooled to 0.degree. C., diethyl ether
(200 mL) added, followed by slow addition of 150 mL of 2M potassium
carbonate (vigorous gas evolution). This mixture was diluted with
additional diethyl ether, layers separated, organic layer washed
with brine, dried (MgSO.sub.4) and concentrated to give 39 grams of
a brown semi-solid. This semi-solid was diluted with 75 mL of
dichloromethane and then flash chromatographed on silica gel with
10-50% ethyl acetate/hexane to provide the title compound (22.8 g,
58%). mp 138-140.degree. C.; .sup.1H NMR (300 MHz, d6 DMSO) .delta.
11.64 (bs, 1H), 7.95 (d, 1H), 7.78 (dq, 1H), 7.33 (d, 1H), 6.47 (d,
1H), 4.21 (q, 2H), 1.26 (t, 3H); MS (APCI-NH.sub.3) m/e 329
(M+H).sup.+, 346 (M+NH.sub.4).sup.+, 327 (M-H).sup.-. Analytical
HPLC: 4.6.times.250 mm Zorbax C18 column, 1.5 mL/min, 254 nm,
CH.sub.3CN:H.sub.2O with 0.1% TFA, 0:100 ramp to 90:10 (0-10 min),
90:10 (10-18 min), ramp to 0:100 (18-20 min), Rt=10.6 min (98.3
area %). 105
Example 401C
Ethyl
E-4-(trifluoromethanesulfonyl)-2,3-bis(trifluoromethyl)cinnamate
[1162] Triflic anhydride (670 .mu.L, 3.97 mmol) was added to a
mixture of Example 401B (1.00 g, 3.05 mmol) and pyridine (6.5 mL).
After 2 h, the dark solution was diluted with Et.sub.2O (75 mL),
washed with 1 N aqueous HCl (2.times.50 mL), washed with saturated
aqueous NaHCO.sub.3 (1.times.75 mL), dried (MgSO.sub.4), filtered,
and concentrated to a dark amber oil (1.35 g, 96%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.33 (d, J=8.8 Hz, 1H), 8.11 (d,
J=8.8 Hz, 1H), 7.87-7.78 (m, 1H), 6.67 (d, J=16.0 Hz, 1H), 4.24 (q,
J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H); MS (APCI) m/z 478
(M+NH.sub.4).sup.+, 495 (M+Cl).sup.-. 106
Example 401D
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-(ethoxycarbonyl)ethenyl)ph-
enyl]sulfide
[1163] 2-Methoxythiophenol (524 .mu.L, 4.30 mmol) was added to
Example 401C (1.69 g, 3.90 mmol), cesium carbonate (3.18 g, 9.75
mmol), and DMF (8 mL). After 15 h, the dark solution was diluted
with Et.sub.2O (100 mL), washed with water (1.times.50 mL), washed
with 1 N aqueous HCl (2.times.100 mL), washed with saturated
aqueous NaHCO.sub.3 (1.times.100 mL), dried (MgSO.sub.4), filtered,
and concentrated to a dark oil. Flash silica gel column
chromatography (85:15 hexane:ethyl acetate) provided the ethyl
ester (1.16 g, 66%) as a yellow oil. The ester (858 mg) was
subsequently hydrolyzed as previously detailed in Example 155 to
provide the title compound (670 mg, 84%) as a white solid. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.89 (d, J=8.8 Hz, 1H),
7.74-7.67 (m, 1H), 7.55 (dd, J=7.5 Hz, J=1.7 Hz, 1H), 7.50 (dd,
J=9.9 Hz, 1.7 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.19 (t, J=7.1 Hz,
1H), 7.07 (dt, J=7.5 Hz, J=1.3 Hz, 1H), 6.44 (d, 15.6 Hz, 1H), 3.75
(s, 3H). MS (APCI) m/z 421 (M-H.sup.+). 107
Example 401E
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((3-carboxypiperidin-1-yl)-
carbonyl)ethenyl)phenyl]sulfide
[1164] Example 401D was processed as detailed in Examples 137 and
155 to provide the title compound (168 mg, 86%) as a white solid.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.95 (d, 1H), 7.57 (m,
1H), 7.50 (t, 1H), 7.46 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 7.14
(d, 1H), 7.06 (t, 1H), 4.4 (m, 1H), 4.01 (m, 2H), 3.75 (s, 3H),
1.93 (m, 2H), 1.63 (m, 2H), 1.42 (m, 2H). MS (APCI) m/z 534
(M+H.sup.+). Anal. calcd for C.sub.24H.sub.21F.sub.6NO.sub.4S+0.75M
H.sub.2O: C, 52.70; H, 4.15; N, 2.56. Found: C, 53.01; H, 3.78; N,
2.17. 108
Example 402
(2-Methoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((2-carboxypyrrolidin-1-yl-
)carbonyl)ethenyl)phenyl]sulfide
[1165] Example 401D was processed as reported in Example 401E,
substituting L-proline methyl ester hydrochloride for the amine.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.98 (d, J=8.2 Hz, 1H),
7.64 (m, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.21
(d, 1H), 7.19 (d, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.95 (d, J=15.0 Hz,
1H), 4.34 (m, 1H), 3.70 (m, 2H), 3.76 (s, 3H), 2.08 (m, 2H), 1.91
(m, 2H); MS (APCI) m/z 520 (M+H.sup.+). Anal. calcd for
C.sub.23H.sub.19F.sub.6NO.sub.4S: C, 53.18; H, 3.69; N, 2.70.
Found: C, 52.88; H, 3.86; N, 2.43. 109
Example 403
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((trifluoromethy-
lsulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1166] 110
Example 403A
Piperazine-1-trifluoromethylsulfonamide
[1167] The title compound (1.65 g, 72%) was prepared as described
in Example 400A, substituting dimethylsulfamoyl chloride with
trifluoromethanesulfonyl chloride (1.26 ml, 11.81 mmol). MS (ESI)
m/e 219 (M+H).sup.+. 111
Example 403B
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((trifluoromethy-
lsulfonyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1168] Example 403B (51 mg, 38%) was prepared from Example 384B as
described in Example 340G, substituting methy isonipecotate with
Example 403A followed by amination with ethyl isonipecotate as
described in Example 396. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.56-1.66 (m, 2H), 2.84-2.91 (m, 2H), 2.37-2.45 (m, 1H),
2.77-2.86 (m, 2H), 3.63-3.70)m, 7H), 3.72-3.85 (m, 3H), 6.72 (d,
J=8.75 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 7.09 (m, 1H), 7.11 (s, 1H),
7.21 (d, J=15 Hz, 1H), 7.34 (t, J=7.5 Hz, 1H), 7.76 (d, J=15 Hz,
1H), 7.81 (d, J=8.75 Hz, 1H); MS (ESI) m/e 650, 652 (M-H).sup.-.
112
Example 404
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(piperidin-1-ylcarbonyl)ethenyl)phenyl-
]sulfide
[1169] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with
(2-methoxy)[2,3-dichloro-4-(E-(2-- carboxyethenyl)phenyl]sulfide
and substituting 6-amino-1-hexanol with piperidine. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.48 (m, 4H), 1.59 (m, 2H), 3.55
(m, 4H), 3.79 (s, 3H), 6.55 (d, J=8.4 Hz, 1H), 7.08 (t, J=7.4 Hz,
1H), 7.21 (d, J=6.0 Hz, 1H), 7.25 (s 1H), 7.48 (dd, J=7.8, 1.7 Hz,
1H), 7.56 (m, 1H), 7.72 (d, J=15.6 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H);
MS (ESI.sup.+) m/z 422, 424 (M+H).sup.+. Anal. calcd for
C.sub.21H.sub.21NCl.sub.2SO.sub.2: C, 59.72; H, 5.01; N, 3.32.
Found: C, 59.52; H, 4.94; N, 3.05. 113
Example 405
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl-
]sulfide
[1170] 114
Example 405A
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-(carboxy)ethenyl)phenyl]sulfide
[1171] Boron tribromide (84 mL of a 1.0M solution in
CH.sub.2Cl.sub.2) was added to a suspension of Example 310C in
CH.sub.2Cl.sub.2 (85 mL) at 0.degree. C. After addition was
completed, the ice-water bath was removed, and the homogeneous dark
solution was stirred for 2 h before the mixture was poured into 1 N
aqueous HCl (100 mL) and ice (100 g), and extracted with EtOAc
(3.times.100 mL). The organic layers were combined, washed with
brine (1.times.50 mL), dried (MgSO.sub.4), filtered, and
concentrated to a white solid (11.3 g). .sup.1H NMR (DMSO-d.sub.6,
300 MHz) .delta. 10.26 (s, 1H), 7.82 (d, J=15.6, 1H), 7.74 (d,
J=8.5 Hz, 1H), 7.44 (dt, J=7.8 Hz, J=1.7 Hz, 1H), 7.41 (dd, J=7.4
Hz, J=1.7 Hz, 1H), 7.05 (dd, J=8.4 Hz, J=1.3 Hz, 1H), 6.94 (dt,
J=7.8 Hz, J=1.4 Hz, 1H), 6.52 (d, J=8.2 Hz, 1H), 6.50 (d, J=16.0
Hz, 1H); MS (APCI) m/z 339 (M-H).sup.-, 375 (M+Cl).sup.-. 115
Example 405B
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl-
]sulfide
[1172] Example 405A (11.3 g) was processed as reported in Example
310D to provide the title product (8.47 g, 62%) as a white solid.
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) 10.24 (s, 1H), 7.81 (d, J=8.9,
1H), 7.77 (d, J=14.9 Hz, 1H), 7.44 (dt, J=6.4 Hz, J=1.7 Hz, 1H),
7.39 (dd, J=8.2 Hz, J=1.7 Hz, 1H), 7.05 (dd, J=8.1 Hz, J=1.0 Hz,
1H), 6.94 (dt, J=7.8 Hz, J=1.0 Hz, 1H), 6.52 (d, J=8.8 Hz, 1H),
6.53 (d, J=8.8 Hz, 1H); MS (APCI) m/z 410 (M+H).sup.+, 446
(M+Cl).sup.-. 116
Example 406
(2-Methoxyphenyl)[2,3-dichloro-4-(E-((((4-carboxyphenyl)methyl)amino)carbo-
nyl)ethenyl)phenyl]sulfide
[1173] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with (2-methoxy)
[2,3-dichloro-4-(E-(2-carboxyethenyl)phenyl]sulfide and
substituting 6-amino-1-hexanol with methyl 4-(aminomethyl)benzoate
hydrochloride following by hydrolysis. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) 83.79 (s, 3H), 4.46 (s, 2H), 6.60 (d, J=8.1 Hz, 1H),
6.66 (d, J=15.6 Hz, 1H), 7.08 (t, J=8.4 Hz, 1H), 7.25 (d, J=8.5 Hz,
1H), 7.39 (d, J=8.5 Hz, 2H), 7.51 (m, 3H), 7.75 (d, J=15.6 Hz, 1H),
7.90 (d, J=8.4 Hz, 2H), 8.83 (t, J=5.7 Hz, 1H), 12.90 (brs, 1H); MS
(ESI.sup.+) m/z 488, 490 (M+H).sup.+. Anal. calcd for
C.sub.24H.sub.19NCl.sub.2O.sub.4S: C, 59.02; H, 3.92; N, 2.87.
Found: C, 58.97; H, 4.07; N, 2.71. 117
Example 407
(2-Methoxyphenyl)[2,3-dichloro-4-(E-(((4-pyrrolidin-1-yl)piperidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[1174] The title compound was prepared by the procedures described
in Example 1C substituting Example 1B with
(2-methoxy)[2,3-dichloro-4-(E-(2-- carboxyethenyl)phenyl]sulfide
and substituting 6-amino-1-hexanol with 4-(pyrrolidinyl)piperidine.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.48 (m, 2H), 1.84 (m,
2H), 2.00 (m, 2H), 2.10 (m, 2H), 2.65 (m, 1H), 3.10 (m, 3H), 3.35
(m, 1H), 3.50 (m, 1H), 3.80 (s, 3H), 4.38 (m, 2H), 4.52 (m, 1H),
6.56 (d, J=8.5 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H) 7.22 (d, J=7.8 Hz,
1H), 7.26 (d, J=15.2 Hz, 1H), 7.48 (dd, J=7.8, 1.7 Hz, 1H), 7.57
(t, J=8.2 Hz, 1H), 7.76 (d, J=15.3 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H);
MS (ESI.sup.+) m/z 491, 493 (M+H).sup.+. Anal. calcd for
C.sub.25H.sub.28N.sub.2Cl.sub.2O.sub.2S 1.8 TFA: C, 49.30; H, 4.31;
N, 4.02. Found: C, 49.08; H, 4.31; N, 3.97. 118
Example 408
(2-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-carboxypiperidin-1-yl)carbonyl)eth-
enyl)phenyl]sulfide
[1175] Example 405A (119 mg) was processed as detailed in Example
165 to provide the title compound as a white solid (43 mg, 28%).
.sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 10.23 (s, 1H), 7.81 (d,
8.8, 1H), 7.72 (d, J=15.2 Hz, 1H), 7.42 (dt, J=7.8 Hz, J=1.7 Hz,
1H), 7.39 (dd, J=7.1 Hz, J=1.7 Hz, 1H), 7.21 (d, J=15.3 Hz, 1H),
7.05 (dd, J=8.2 Hz, J=1.0 Hz, 1H), 6.93 (dt, J=7.4 Hz, J=1.0 Hz,
1H), 6.53 (d, J=8.5 Hz, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 2.85 (m,
2H), 1.87 (m, 2H), 1.44 (m, 2H). MS (APCI) m/z 452 (M+H.sup.+), 450
(M-H.sup.+), 486 (M+Cl.sup.-). Anal. calcd for
C.sub.21H.sub.19Cl.sub.2NO.sub.4S+0.25M H.sub.2O: C, 55.21; H,
4.30; N, 3.07. Found: C, 55.26; H, 4.29; N, 2.72. 119
Example 409
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((methylsulfonyl-
)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1176] 120
Example 409A
Piperazine methylsulfonamide
[1177] The title compound (1.65 g, 72%) was prepared as described
in Example 400A, substituting dimethylsulfamoyl chloride with
methanesulfonyl chloride (1.26 ml, 11.81 mmol). 121
Example 409B
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-((methylsulfonyl-
]piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1178] Example 409B (48 mg, 72%) was prepared from Example 384B as
described in Example 340G, substituting methy isonipecotate with
Example 409A followed by amination with ethyl isonipecotate as
described in Example 396. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.55-1.71 (m, 2H), 1.83-1.94 (m, 2H), 2.36-2.48 (m, 1H),
2.77-2.86 (m, 21H), 2.88 (s, 3H), 3.10-3.18 (m, 4H), 3.66-3.84 (m,
6H), 6.73 (d, J=8 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 7.11 (m, 1H),
7.13 (s, 1H), 7.25 (d, J=15 Hz, 1H), 7.32-7.41 (m, 1H), 7.78 (d,
J=15 Hz, 1H), 7.85 (d, J=8 Hz, 1H); MS (ESI) m/e 598, 600
(M+H).sup.+; 596, 598 (M-H).sup.-. 122
Example 410
(2-Aminophenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)phenyl]-
sulfide
[1179] 123
Example 410A
tert-Butyl
2,3-dichloro-4-((trifluoromethyl)sulfonyloxy)cinnamate
[1180] The title compound was constructed according to the
procedure for Example 340D and 340E, except using tert-butyl
acrylate instead of methyl acrylate. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.11 (d, 1H), 7.78 (d, 1H), 7.72 (d, 1H),
6.72 (d, 1H), 1.5 (s, 9H); MS (APCI-NH.sub.3) m/e 456 (M+Cl).sup.-.
124
Example 410B
tert-Butyl 2,3-dichloro-4-((triisopropylsilyl)thio)cinnamate
[1181] Sodium hydride (3.05 g of 60% dispersion, 76 mmol) that had
been rinsed with dry tetrahydrofuran (2.times.), was suspended in
128 mL of THF, cooled to -5.degree. C., and slowly treated with
triisopropylsilyl thiol (12.2 mL, 57 mmol), maintaining an internal
temperature below 4.degree. C., stirred at 0.degree. C. for 1.5 h,
then added to a second flask containing Example 410A (20 g, 47.4
mmol) and tetrakistriphenylphosphine palladium (4.4 g, 3.8 mmol) in
95 mL of THF. The reaction was heated at reflux for 8 h, then
allowed to cool to ambient temperature and concentrated. The
resultant slurry was diluted with ethyl acetate, filtered through
celite, washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated. The resultant black residue was flash chromatographed
on silica gel with 2.5-5% acetone/hexane to provide the title
compound (18.2 g, 83%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
7.82 (d, 1H), 7.78 (d, 1H), 7.0 (d, 1H), 6.5 (d, 1H), .delta. 1.5
(s, 9H), 1.35 (m, 3H), 1.09 (d, 18H); MS (APCI-NH.sub.3) m/e 462
(M+H).sup.+. 125
Example 410C
(2-Nitrophenyl)[2,3-dichloro-4-(E-((tert-butyloxycarbonyl)ethenyl)phenyl]s-
ulfide
[1182] A solution of Example 410B in toluene (40 mL) was treated
with cesium fluoride (600 mg, 4 mmol) followed by
2-fluoronitrobenzene (5.03 mL, 47.4 mmol), then heated at reflux
for 2 h, then allowed to cool and the mixture was concentrated
under reduced pressure. The resultant dark brown slurry was diluted
with ethyl acetate, washed with water (2.times.), 1 M NaOH,
(2.times.), water (2.times.), dried (Na.sub.2SO.sub.4) and
concentrated. The 21.2 grams of crude product was flash
chromatographed on silica gel with 10% acetone/hexane to provide
the title compound (8.92 g, 53%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.17 (dd, 1H), 7.95 (d, 1H), 7.83 (d, 1H),
7.78 (m, 1H), 7.48 (m, 1H), 7.3 (dd, 1H), 7.17 (d, 1H), 6.6 (d,
1H), 1.5 (s, 3H); MS (APCI-NH.sub.3) m/e 427 (M+H).sup.+. 126
Example 410D
(2-Nitrophenyl)[2,3-dichloro-4-(E-((carboxy)ethenyl)phenyl]sulfide
[1183] A solution of Example 410C (3.2 g, 7.5 mmol) in
dichloromethane (12 mL) at room temperature was treated with
trifluoroacetic acid (4 mL), stirred 30 minutes, and concentrated
to give the title compound (2.8 g, 100%) as an off-white solid.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.16 (dd, 1H), 7.94 (d,
1H), 7.86 (d, 1H), 7.76 (m, 1H), 7.48 (m, 1H), 7.29 (dd, 1H), 7.11
(d, 1H), 6.61 (d, 1H); MS (APCI-NH.sub.3) m/e 371 (M+H).sup.+.
127
Example 410E
(2-Nitrophenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)phenyl]-
sulfide
[1184] A solution of Example 410D (2.7 g, 7.29 mmol) in
dimethylformamide (32 mL) was treated with hydroxybenzotriazole
hydrate (1.2 g, 8.0 mmol), morpholine (1.4 mL, 16 mmol) and then
1-(3-dimethylaminopropyl)-3-ethylca- rbodiimide hydrochloride (1.53
g, 8.0 mmol), stirred at room temperature for 64 hours. The
heterogeneous mixture was filtered, the white solid washed with
water, and then dried in a vacuum oven at 50.degree. C. for 24
hours to provide 2.8 g (88%) of the title compound as a white
powder. mp 210-213.degree. C.; .sup.1H NMR (300 MHz, d6 DMSO)
.delta. 8.15 (dd, 1H), 8.03 (d, 1H), 7.82 (d, 1H), 7.74 (m, 1H),
7.45 (m, 1H), 7.32 (d, 1H), 7.2 (m, 2H), 3.7 (m, 2H), 3.6 (m, 6H);
MS (APCI-NH.sub.3) m/e 440 (M+H).sup.+. 128
Example 410F
(2-Aminophenyl)[2,3-dichloro-4-(E-((4-morpholinyl)carbonyl)ethenyl)phenyl]-
sulfide
[1185] A solution of iron powder (1.3 g, 22.8 mmol) and ammonium
chloride (292 mg, 5.46 mmol) in ethanol (9 mL) and distilled water
(9 mL) at 105.degree. C. was treated with example 410F (2 g, 4.55
mmol) in ethanol (20 mL), stirred for one hour and then allowed to
cool to room temperature. The resultant heterogeneous black mixture
was filtered through a plug of Celite, rinsed through with ethyl
acetate (100 mL), the filtrate washed with 1 M potassium carbonate,
brine, dried (Na.sub.2SO.sub.4) and concentrated to give 1.9 g
(100%) of the title compound as an off-white powder. mp
230-240.degree. C. (dec); .sup.1H NMR (300 MHz, d6 DMSO) .delta.
7.9 (d, 1H), 7.8 (d, 1H), 7.2 (d, 1H), 6.95 (dt, 1H), 6.84 (m, 2H),
6.68 (d, 1H), 6.58 (dt, 1H), 5.05 (bs, 2H), 3.7 (m, 2H), 3.6 (m,
6H); MS (APCI-NH.sub.3) m/e 410 (M+H).sup.+; Analytical HPLC:
4.6.times.250 mm Zorbax C18 column, 1.5 mL/min, 254 nm,
CH.sub.3CN:H.sub.2O with 0.1% TFA, 0:100 ramp to 90:10 (0-10 min),
90:10 (10-18 min), ramp to 0:100 (18-20 min), Rt=9.2 min. 129
Example 411
(3-(4-carboxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-((S-oxothiomorpholin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1186] 130
Example 411A
[3-(4-Ethoxycarbonyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-(thiomorphol-
in-ylcarbonyl)ethenyl)phenyl]sulfide
[1187] The title compound was prepared by the procedures described
in Example 397B substituting morpholine with thiomorpholine. MS
(APCI.sup.+) m/z 565, 567 (M+H).sup.+. 131
Example 411B
(3-(4-carboxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-((S-oxothiomorpholin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1188] To a solution of Example 411A (107 mg, 0.189 mmol) in
CH.sub.2Cl.sub.2 (6 mL) was added mCPBA (80%, 41 mg, 0.189 mmol) at
0.degree. C. After stirring at the same temperature for 2 h, THF (2
mL) was added. The solution was concentrated to 1 mL, and was
diluted with THF to 3 mL. Lithium hydroxide monohydrate (24 mg) in
water (1 mL) was then added. The mixture was stirred at room
temperature for 3 hours. The formed transparent solution was
separated by HPLC (Zorbax C-18) to give the title compound (68 mg).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.64 (m, 2H), 1.90 (m,
2H), 2.41 (m, 1H), 2.86 (m, 4H), 3.62 (m, 2H), 3.95 (m, 1H), 4.18
(m, 1H), 4.3 (m, 4H), 6.71 (d, J=8.4 Hz, 1H), 6.93 (d, J=7.5 Hz,
1H), 7.12 (d, J=7.5 Hz, 1H), 7.13 (s, 1H), 7.28 (d, J=15.3 Hz, 1H),
7.36 (t, J=8.8 Hz, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.88 (d, J=8.8 Hz,
1H); MS (APCI.sup.+) m/z 553, 555 (M+H).sup.+. Anal. calcd for
C.sub.25H.sub.26N.sub.2Cl.sub.2S.sub.2O.sub.4 2 TFA: C, 44.57; H,
3.61; N, 3.58. Found: C, 44.34; H, 3.76; N, 3.51. 132
Example 412
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-hydroxypiperidin-
-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1189] 133
Example 412A
(3-Bromophenyl)[2,3-dichloro-4-(E-((tert-butyloxycarbonyl)ethenyl)phenyl]s-
ulfide
[1190] To a solution of Example 384B (2.35 g, 5.82 mmol) in THF (23
mL) at -5.degree. C. was added tert-butyl trichloroacetimidate (2.6
mL, 14.54 mmol) and boron trifluoride-etherate (2.35 mL, 18.54
mmol). The solution was stirred at the same temperature for 10
minutes, and was then warmed up to room temperature for 5 h. The
yellow solution was poured into aq. NaHCO.sub.3 solution, and the
mixture was extracted with ethyl acetate. The combined organic
phases were washed with water, dried over anhydrous MgSO.sub.4, and
concentrated. The residual white solid was dissolved in
CH.sub.2Cl.sub.2 and was precipitated by adding hexane. The formed
suspension was filtered through silica gel, and washed with 1:8
EtOAc/hexane. The solution was concentrated and was further
purified by flash chromatography (silica gel, 1:20EtOAc/hexane) to
give the title compound (2.50 g, 94%). MS (APCI.sup.+) m/z 461
(M+H).sup.+. 134
Example 412B
(3-(4-carboethoxypiperidin-1-yl)phenyl)[2,3-dichloro-4-(E-(carbo-t-butoxye-
thenyl)phenyl]sulfide
[1191] A pressure tube was charged with Example 412A (589 mg, 1.28
mmol), Pd.sub.2(dba).sub.3 (30 mg, 0.032 mmol),
2-dicyclohexylphosphanyl-2'-dime- thylaminobiphenyl (26 mg, 0.064
mmol), and anhydrous K.sub.3PO.sub.4 (382 mg, 1.8 mmol), and was
purged with nitrogen. DME (4 mL) and ethyl isonipecotate (242 mg,
1.54 mmol) were added via syringe, and the mixture was purged with
nitrogen again. The red reaction mixture was stirred at room
temperature for 0.5 h and at 95.degree. C. for 15 h. After the
reaction mixture was cooled, the it was diluted with ethyl acetate,
and washed with brine. The aqueous phase was extracted with ethyl
acetate. The combined ethyl acetate solution was concentrated and
the residual oil was separated by flash chromatography (silica gel,
1:6 EtOAc/hexane) to give the title compound (523 mg, 76%). MS
(APCI.sup.+) m/z 536 (M+H).sup.+. 135
Example 412C
[3-(4-(Ethoxycarbonyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-(carboxy)et-
henyl)phenyl]sulfide
[1192] To a solution of Example 412B (510 mg, 0.95 mmol) in
CH.sub.2Cl.sub.2 (8 mL) at 0.degree. C. was added trifluoroacetic
acid (1.6 mL). The yellow solution was stirred at 0.degree. C. for
1 h, and was warmed to room temperature for 3 h. After diluting
with CH.sub.2Cl.sub.2, the solution was poured into aq. NaHCO.sub.3
solution. The inorganic phase was acidified to pH 5, and was
extracted with 10% MeOH in CH.sub.2Cl.sub.2. The combined organic
phases were washed with water, concentrated under vacuum and dried
to give the title compound (472 mg, 100%). MS (APCI.sup.+) m/z 480
(M+H).sup.+. 136
Example 412D
[3-(4-carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-(4-hydroxypiperidin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1193] To a suspension of Example 412C (150 mg, 0.31 mmol) in DMF
(3 mL) was added 4-hydroxypiperidine (63 mg, 0.62 mmol),
1-(3-dimethylaminopropy- l)-3-ethylcarbodimide (120 mg, 0.62 mmol),
HOBt (84 mg, 0.62 mmol) and triethylamine (87 .mu.L, 0.62 mmol) at
room temperature. The mixture was stirred at the same temperature
for 15 h. Ethyl acetate was added, the mixture was washed with
brine, water, and was concentrated. The residual oil was dissolved
in THF (3 mL), and was added lithium hydroxide monohydrate (26 mg,
0.62 mmol) in water (1.5 mL). After stirring for 15 hours, the
solution was separated by HPLC (Zorbax C-18) to give the title
compound (132 mg, 55%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.32 (m, 2H), 1.65 (m, 2H), 1.75 (m, 2H), 1.92 (m, 2H), 2.43 (m,
1H), 2.86 (t, J=10.6 Hz, 2H), 3.15 (m, 1H), 3.32 (m, 1H), 3.71 (m,
3H), 3.95 (m, 2H), 6.73 (d, J=8.5 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H),
7.13 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.24 (d, J=15.2 Hz, 1H), 7.37
(t, J=8.1 Hz, 1H), 7.72 (d, J=15.2 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H);
MS (ESI+) m/z 535, 537 (M+H).sup.+. Anal. calcd for
C.sub.26H.sub.28N.sub.2Cl.sub.2SO.sub.4 0.25 TFA: C, 56.43; H,
5.05; N, 4.97. Found: C, 56.37; H, 5.00; N, 4.91. 137
Example 413
(2-Glycoxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl-
]sulfide
[1194] Diethyl azodicarboxylate (270 .mu.L, 1.47 mmol) was added to
a suspension of Example 405 (400 mg, 0.95 mmol), triphenylphosphine
(386 mg, 1.47 mmol), and THF (2.0 mL). After 16 h, the dark orange
solution was diluted with EtOAc (40 mL), washed with 1 N aqueous
HCl (1.times.20 mL), washed with 0.2 N aqueous NaOH (1.times.20
mL), washed with brine (1.times.20 mL), dried (MgSO.sub.4),
filtered, and concentrated. Flash silica gel column chromatography
(9:1 hexane:ethyl acetate) provided a mix of desired ester and
triphenyl phosphine oxide. The mixture (200 mg) was combined with
lithium hydroxide, monohydrate (34 mg, 0.81 mmol), THF (0.5 mL),
and H.sub.2O (0.5 mL). After 21 h, the cloudy solution was diluted
with 0.2 N aqueous NaOH (30 mL), washed with CH.sub.2Cl.sub.2
(2.times.15 mL), combined with 1 N aqueous HCl until pH<2, and
extracted with EtOAc (2.times.20 mL). The EtOAc extracts were
combined, washed with brine (1.times.20 mL), dried (MgSO.sub.4),
filtered, and concentrated to a white solid (87 mg, 47%). .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.80 (d, J=7.8, 1H), 7.77 (d,
J=15.3 Hz, 1H), 7.51 (dt, J=8.1 Hz, J=2.0 Hz, 1H), 7.48 (d, J=8.1
Hz, 1H), 7.22 (d, J=15.3 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.08 (dt,
J=7.1 Hz, J=1.0 Hz, 1H), 6.71 (d, J=8.9 Hz, 1H), 4.77 (s, 2H), 3.66
(s, 2H), 3.58 (s, 6H); MS (APCI) m/z 468 (M+H).sup.+; 466
(M-H).sup.-, 502 (M+Cl).sup.-. Anal. calcd for
C.sub.21H.sub.19Cl.sub.2NO.sub.5S: C, 53.85; H, 4.09; N, 2.99.
Found: C, 54.07; H, 4.28; N, 2.69. 138
Example 414
(2-(4-Butyroxy)phenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)p-
henyl]sulfide
[1195] Ethyl 4-bromobutyrate was added to a mixture of Example 405
(300 mg, 0.731 mmol), cesium carbonate (358 mg, 1.10 mmol), and DMF
(1.5 mL). After 16 h, the pale milky solution was diluted with
EtOAc (30 mL), washed with 1 N aqueous HCl (2.times.25 mL), washed
with brine (1.times.25 mL), dried (MgSO.sub.4), filtered, and
concentrated to a white solid (326 mg, 85%) as the ethyl ester. The
ethyl ester (312 mg, 0.595 mmol), THF (1.5 mL), and H.sub.2O (1.5
mL) were combined with lithium hydroxide, monohydrate (63 mg, 1.50
mmol). After 18 h, the clear solution was poured into 1 N aqueous
HCl (25 mL) and extracted with EtOAc (2.times.25 mL). The organic
layers were combined, dried (MgSO.sub.4), filtered, and
concentrated to a white solid (247 mg, 85%). .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 7.79 (d, J=8.5, 1H), 7.77 (d,
J=15.6 Hz, 1H), 7.51 (dt, J=7.5 Hz, J=1.7 Hz, 1H), 7.48 (dd, J=7.5
Hz, J=1.0 Hz, 1H), 7.20 (d, J=14.9 Hz, 1H), 7.19 (d, J=9.5 Hz, 1H),
7.06 (t, J=7.5 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 4.01 (t, J=6.1 Hz,
2H), 3.65 (s, 2H), 3.58 (s, 6H), 2.10 (t, J=7.4 Hz, 2H), 1.75 (m,
2H); MS (APCI) m/z 496 (M+H).sup.+. 139
Example 415
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-hydroxyethylpipe-
razin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1196] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with
1-hydroxyethylpiperazin- e. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.70 (m, 2H), 1.94 (m, 2H), 2.98 (m, 2H), 3.05 (m, 2H),
3.18 (m, 2H), 3.54 (m, 2H), 3.65 (m, 3H), 3.78 (m, 2H), 6.77 (d,
J=8.8 Hz, 1H), 7.03 (d, J=6.8 Hz, 1H), 7.28 (d, J=14.9 Hz, 1H),
7.29 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.78 (d, J=15.3 Hz, 1H), 7.86
(d, J=8.8 Hz, 1H); MS (ESI.sup.+) m/z 564, 566 (M+H).sup.+. 140
Example 416
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-furoylpiperazin--
1-yl)carbonyl)ethenyl)phenyl]sulfide
[1197] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with
1-furoylpiperazine. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.64 (m, 2H), 1.91 (m, 2H), 2.43 (m, 1H), 2.87 (m, 2H), 3.70 (m,
10H), 6.43 (m, 1H), 6.72 (d, J=8.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H),
7.03 (d, J=3.3 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.26
(d, J=15.2 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.77 (d, J=15.2 Hz,
1H), 7.86 (m, 2H); MS (ESI+) m/z 614, 616 (M+H).sup.+. Anal. calcd
for C.sub.30H.sub.29N.sub.3Cl.sub.2SO.sub.5 1.5 TFA: C, 50.45; H,
3.91; N, 5.35. Found: C, 50.53; H, 3.96; N, 5.35. 141
Example 417
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((pyrrolidin-1-yl)ca-
rbonyl)ethenyl)phenyl]sulfide
[1198] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with pyrrolidine.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.63 (m, 2H), 1.79 (m,
2H), 1.88 (m, 4H), 2.43 (m, 1H), 2.82 (m, 2H), 3.39 (t, J=6.7 Hz,
2H), 3.59 (t, J=6.8 Hz, 2H), 3.68 (m, 2H), 6.71 (d, J=8.5 Hz, 1H),
6.92 (d, J=7.5 Hz, 1H), 6.96 (d, J=15.3 Hz, 1H), 7.12 (d, J=6.8 Hz,
1H), 7.13 (s, 1H), 7.35 (t, J=8.8 Hz, 1H), 7.72 (d, J=15.3 Hz, 1H),
7.80 (d, J=8.5 Hz); MS (ESI.sup.+) m/z 505, 507 (M+H).sup.+. Anal.
calcd for C.sub.25H.sub.26N.sub.2Cl.sub.2SO.sub.3 0.8 TFA: C,
53.54; H, 4.53; N, 4.69. Found: C, 53.74; H, 4.40; N, 4.64. 142
Example 418
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((diethylaminocarbon-
yl)ethenyl)phenyl]sulfide
[1199] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with diethylamine.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.06 (t, J=6.7 Hz, 3H),
1.11 (t, J=6.7 Hz, 3H), 1.63 (m, 2H), 1.88 (m, 2H), 2.43 (m, 1H),
2.82 (m, 2H), 3.35 (q, J=6.7 Hz, 2H), 3.47 (q, J=6.7 Hz, 2H), 3.70
(m, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 7.07 (d,
J=15.2 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 7.13 (s, 1H), 7.35 (t,
J=8.8 Hz, 1H), 7.75 (d, J=15.3 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H); MS
(ESI.sup.+) m/z 507 (M+H).sup.+. Anal. calcd for
C.sub.25H.sub.28N.sub.2Cl.sub.2SO.sub.3 0.2 TFA: C, 57.53; H, 5.36;
N, 5.28. Found: C, 57.68; H, 5.38; N, 5.33. 143
Example 419
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-ethylpiperazin-y-
l)carbonyl)ethenyl)phenyl]sulfide
[1200] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with
1-ethylpiperazine. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.22
(t, J=7.5 Hz, 3H), 1.63 (m, 2H), 1.87 (m, 2H), 2.42 (m, 1H), 2.81
(t, J=10.5 Hz, 2H), 3.00 (m, 2H), 3.15 (m, 2H), 3.40 (m, 1H), 3.51
(m, 2H), 3.67 (m, 2H), 4.50 (m, 2H), 6.73 (d, J=8.8 Hz, 1H), 6.89
(d, J=7.8 Hz, 1H), 7.11 (m, 2H), 7.28 (d, J=15.2 Hz, 1H), 7.36 (m,
1H), 7.80 (d, J=15.2 Hz, 1H), 7.86 (d, J=8.5 Hz); MS (APCI.sup.+)
m/z 548, 550 (M+H).sup.+. Anal. calcd for
C.sub.27H.sub.31N.sub.3Cl.sub.2SO.sub.3 2.2 TFA: C, 47.18; H, 4.19;
N, 5.26. Found: C, 47.27; H, 4.27; N, 5.30. 144
Example 420
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(aminocarbonyl)p-
iperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1201] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with
isonipecotamide. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.45
(m, 2H), 1.63 (m, 2H), 1.73 (m, 2H), 1.87 (m, 2H), 2.43 (m, 2H),
2.78 (m, 2H), 3.10 (m, 2H), 3.7 (m, 3H), 4.30 (m, 1H), 4.40 (m,
1H), 6.70 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.92 (d, J=7.5 Hz, 1H),
7.12 (m, 2H), 7.25 (d, J=15.2 Hz, 1H), 7.27 (s, 1H), 7.35 (m, 1H),
7.73 (d, J=15.2 Hz, 1H), 7.86 (d, j=8.6 Hz, 1H); MS (APCI.sup.+)
m/z 562 (M+H).sup.+. Anal. calcd for
C.sub.27H.sub.29N.sub.3Cl.sub.2SO.sub.4 0.2 TFA: C, 56.23; H, 5.03;
N, 7.18. Found: C, 56.41; H, 4.96; N, 6.98. 145
Example 421
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(2-(ethoxyethyl)-
piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1202] The title compound was prepared by the procedures described
in Example 412 substituting 4-hydroxypiperidine with
1-(2-ethoxyethyl)pipera- zine. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.15 (t, J=6.8 Hz, 3H), 1.63 (m, 2H), 1.90 (m, 2H), 2.42
(m, 1H), 2.81 (t, J=10.2 Hz, 2H), 3.09 (m, 2H), 3.32 (m, 2H), 3.50
(q, J=6.8 Hz, 2H), 3.51 (m, 2H), 3.68 (m, 4H), 4.45 (m, 2H), 6.73
(d, J=8.6 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 7.11 (m, 2H), 7.26 (d,
J=15.3 Hz, 1H), 7.36 (m, 1H), 7.80 (d, J=15.2 Hz, 1H), 7.83 (d,
J=8.5 Hz, 1H); MS (APCI.sup.+) m/z 592 (M+H).sup.+. Anal. calcd for
C.sub.29H.sub.35N.sub.3Cl.sub.2SO.sub.4 2.5 TFA: C, 46.53; H, 4.31;
N, 4.79. Found: C, 46.51; H, 4.31; N, 4,77. 146
Example 422
[3-((4-Carboxymethyl)piperazin-1-yl)phenyl][(2,3-dichloro-4-(E-(4-morpholi-
nyl)carbonyl)ethenyl)phenyl]sulfide
[1203] The title compound (24 mg, 42%) was prepared from Example
393A as described in Example 384D, substituting morpholine with
1-((ethoxycarbonyl)methyl)piperazine, followed by hydrolysis with
LiOH as described in Example 340H. .sup.1H NMR (300 MHz,
MeOH-d.sub.4) 3.54 (s, 8H), 3.69 (s, 8H), 4.11 (s, 2H), 6.77 (d,
J=8.5 Hz, 1H), 7.06 (d, J=15 Hz, 1H), 7.08 (m, 1H), 7.42 (t, J=7.5
Hz, 1H), 7.59 (d, J=8.25 Hz, 1H), 7.93 (d, J=15 Hz, 1H); MS (ESI)
m/e 536, 538 (M+H).sup.+. 147
Example 423
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((4-morp-
holino)carbonyl)ethenyl)phenyl]sulfide
[1204] 148
Example 423A
[3-Bromophenyl][2,3-bis(trifluoromethyl)-4-(E-(2-carboxy)ethenyl)phenyl]su-
lfide
[1205] The title compound was prepared from Example 401C using the
procedures described in Example 384A, followed by hydrolysis with
LiOH as given in Example 340H. 149
Example 423B
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((4-morp-
holino)carbonyl)ethenyl)phenyl]sulfide
[1206] The title compound was prepared from Example 423A as
described in Example 340G, substituting methy isonipecotate with
morpholine, followed by amination with ethyl isonipecotate as
described in Example 396, and subsequent hydrolysis according to
the procedure of Example 340H. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 1.5-1.64 (m, 2H), 1.67-1.75 (m, 1H), 1.87-1.96 (m, 1H),
2.49-2.57 (m, 2H), 2.82-2.91 (m, 1H), 2.99-3.06 (m, 1H), 3.46-3.54
(m, 2H), 3.54-3.62 cm, 5H), 3.63-3.72 (m, 3H), 6.87 (d, J=8 Hz,
1H), 7.06-7.13 (m, 2H), 7.16 (d, J=15 Hz, 1H), 7.25-7.36 (m, 2H),
7.66 (dd, J.sub.1=15 Hz, J.sub.2=4 Hz, 1H), 8.00 (d, J=8 Hz, 1H);
MS (ESI) m/e 589 (M+H).sup.+. 150
Example 424
(3-Hydroxyphenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)phenyl-
]sulfide
[1207] Example 310B was processed as described in Examples 310 and
405, substituting 3-methoxythiophenol for the thiol. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 9.88 (s, 1H), 7.86 (d, J=8.8, 1H),
7.77 (d, J=14.9 Hz, 1H), 7.33 (dt, J=7.4 Hz, J=1.0 Hz, 1H), 7.24
(d, J=14.8 Hz, 1H), 6.96 (dd, J=8.8 Hz, J=1.0 Hz, 1H), 6.90 (dd,
J=8.8 Hz, J=1.0 Hz, 1H), 6.89 (s, 1H), 6.79 (d, J=8.5 Hz, 1H), 3.67
(s, 2H), 3.58 (s, 6H); MS (APCI) m/z 410 (M+H).sup.+, 427
(M+NH.sub.4).sup.+; 408 (M-H).sup.-, 446 (M+Cl).sup.-. Anal. calcd
for C.sub.19H.sub.17Cl.sub.2NO.sub.3S.0.25 H.sub.2O: C, 55.01; H,
4.25, N, 3.38. Found: C, 55.15; H, 4.25; N, 3.51. 151
Example 425
[3-(4-Butyroxy)phenyl][2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)p-
henyl]sulfide
[1208] Example 424 was processed as described in Example 414 to
provide the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 7.86 (d, J=8.8 Hz, 1H), 7.77 (d,
J=15.3 Hz, 1H), 7.43 (dt, J=7.5 Hz, J=1.7 Hz, 1H), 7.24 (d, 15.2
Hz, 1H), 7.11 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.73 (d, J=8.5 Hz,
1H), 4.02 (t, J=6.5 Hz, 2H), 3.67 (s, 2H), 3.58 (s, 6H), 2.37 (t,
J=7.5 Hz, 2H), 1.95 (m, 2H); MS (APCI) m/z 410 (M+H.sup.+), 494
(M-H).sup.-, 530 (M+Cl).sup.-. 152
Example 426
(2-Hydroxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbonyl)et-
henyl)phenyl]sulfide
[1209] Example 401D was processed as described in Example 405 to
provide the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 10.26 (s, 1H), 7.96 (d, J=8.5, 1H),
7.67 (m, 1H), 7.46 (dd, J=7.4 Hz, J=1.3 Hz, 1H), 7.38 (dt, J=7.5
Hz, J=1.3 Hz, 1H), 7.16 (d, J=15.2 Hz 1H), 7.13 (d, J=8.5 Hz, 1H),
7.00 (d, 8.2 Hz, 1H), 6.90 (t, J=7.4 Hz, 2H), 3.65 (s, 2H), 3.57
(s, 6H). MS (APCI) m/z 478 (M+H).sup.+, 495 (M+NH.sub.4).sup.+; 476
(M-H).sup.-, 512 (M+Cl).sup.-. 153
Example 427
(3-Hydroxyphenyl)[2,3-bis(trifluoromethyl)-4-((4-morpholino)carbonyl)ethen-
yl)phenyl]sulfide
[1210] Example 401C was processed as described in Example 401D,
substituting 3-methoxythiophenol for the thiol, and in Example 405
to provide the title compound as a white solid. .sup.1HNMR
(DMSO-d.sub.6, 300 MHz) .delta. 9.86 (s, 1H), 8.02 (d, J=8.8, 1H),
7.67 (m, 1H), 7.35 (d, J=9.5 Hz, 1H), 7.30 (dt, J=7.8 Hz, J=0.7 Hz,
1H), 7.19 (d, J=15.2 Hz 1H), 6.95 (d, J=8.8 Hz, 1H), 6.88 (d, J=7.5
Hz, 1H), 6.85 (s, 1H), 3.67 (s, 2H), 3.58 (s, 6H). MS (APCI) m/z
478 (M+H.sup.+), 495 (M+NH4.sup.+), 476 (M-H.sup.+), 512
(M+Cl.sup.-). 154
Example 428
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((4-hydroxy-
piperidin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1211] The title compound was prepared by the procedures described
in Example 412 substituting Example 384B with Example 423A. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.31 (m, 2H), 1.63 (m, 2H),
1.71 (m, 2H), 1.91 (m, 2H), 2.42 (m, 1H), 2.82 (t, J=10.5 Hz, 2H),
3.16 (m, 1H), 3.31 (m, 1H), 3.70 (m, 3H), 3.93 (m, 2H), 6.88 (d,
J=7.1 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.14 (t, J=7.1 Hz, 1H), 7.23
(d, J=8.8 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H),
7.60 (dq, J=15.2, 4.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H); MS
(APCI.sup.+) m/z 603 (M+H).sup.+. Anal. calcd for
C.sub.28H.sub.28F.sub.6N.sub.2O.sub.4S 1.15 TFA: C, 49.60; H, 4.00;
N, 3.82. Found: C, 49.65; H, 3.80; N, 3.81. 155
Example 429
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((1,2,5,6-t-
etrahydropyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1212] The title compound was prepared by the procedures described
in Example 412 substituting Example 384B with Example 423A, and
substituting 4-hydroxypiperidine with 1,2,5,6-tetrahydropyridine.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.63 (m, 2H), 1.90 (m,
2H), 2.12 (m, 2H), 2.43 (m, 1H), 2.81 (t, J=10.5 Hz, 2H), 3.75 (m,
4H), 4.01 ((s, 1H), 4.15 (s, 1H), 5.73 (m, 1H), 5.84 (m, 1H), 6.87
(d, J=7.5 Hz, 1H), 7.10 (m, 2H), 7.30 (m, 3H), 7.62 (m, 1H), 8.01
(t, J=6.5 Hz, 1H); MS (APCI.sup.+) m/z 585 (M+H).sup.+. Anal. calcd
for C.sub.28H.sub.26F.sub.6N.sub.2O.sub.3S 0.1 TFA: C, 56.83; H,
4.41; N, 4.70. Found: C, 56.91; H, 4.44; N, 4.60. 156
Example 430
[2-((4-Carboxy)butyloxy)phenyl][2,3-dichloro-4-(E-((4-morpholino)carbonyl)-
ethenyl)phenyl]sulfide
[1213] Example 405 was processed as described in Example 414,
substituting ethyl 5-bromovalerate for the alkyl halide. .sup.1H
NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.79 (d, J=8.5, 1H), 7.77 (d,
J=715.3 Hz, 1H), 7.51 (dt, J=8.2 Hz, J=1.7 Hz, 1H), 7.48 (dd, J=7.5
Hz, J=1.7 Hz, 1H), 7.20 (dd, J=7.5 Hz, J=1.7 Hz, 1H), 7.20 (d,
J=15.6 Hz, 1H), 7.05 (dt, J=7.5 Hz, J=11.0 Hz, 1H), 6.63 (d, J=8.5
Hz, 1H), 3.99 (t, J=6.1 Hz, 2H), 3.65 (s, 2H), 3.58 (s, 6H), 2.10
(t, J=7.1 Hz, 2H), 1.56 (m, 2H), 1.39 (m, 2H). MS (APCI) m/z 510
(M+H).sup.+. Anal. calcd for C.sub.24H.sub.25Cl.sub.2NO.su-
b.5S.0.75 H.sub.2O: C, 55.02; H, 5.10; N, 2.67. Found: C, 54.72; H,
4.82; N, 2.77. 157
Example 431
(2-Glycoxyphenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbonyl)et-
henyl)phenyl]sulfide
[1214] Example 426 was processed as detailed in Example 414,
substituting ethyl bromoacetate for the alkyl bromide. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 7.94 (d, 8.4, 1H), 7.66 (m, 1H),
7.50 (m, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 7.16
(d, J=14.9 Hz, 1H), 7.07 (m, 2H), 4.74 (s, 2H), 3.65 (s, 2H), 3.57
(s, 6H); MS (APCI) m/z 536 (M+H).sup.+, 553 (M+NH.sub.4).sup.+; 534
(M-H).sup.+. Anal. calcd for C.sub.23H.sub.19F.sub.6NO.sub.5S: C,
51.59; H, 3.58; N, 2.62. Found: C, 51.31; H, 3.63; N, 2.33. 158
Example 432
(2-(4-Butyroxy)phenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbon-
yl)ethenyl)phenyl]sulfide
[1215] Example 426 was processed as described in Example 414 to
provide the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 7.92 (d, 8.5, 1H), 7.65 (m, 1H),
7.59 (d, J=7.8 Hz, J=1.7 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.15 (d,
J=8.2 Hz, 1H), 7.12 (d, J=15.6 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H),
7.07 (t, J=7.2 Hz, 1H), 3.92 (t, J=6.1 Hz, 2H), 3.65 (s, 2H), 3.57
(s, 6H), 1.99 (t, J=7.1 Hz, 2H), 1.63 (m, 2H); MS (APCI) m/z 562
(M-H).sup.-, 598 (M+Cl).sup.-. 159
Example 433
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-ditrifluoromethyl-4-(E-((bis-(2-et-
hoxyethyl)amino)carbonyl)ethenyl)phenyl]sulfide
[1216] The title compound was prepared by the procedures described
in Example 412 substituting Example 384B with Example 423A, and
substituting 4-hydroxypiperidine with bis(2-ethoxyethyl)amine.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.99 (t, J=6.8 Hz, 3H),
1.09 (t, J=6.8 Hz, 3H), 1.63 (m, 2H), 1.90 (m, 2H), 2.44 (m, 1H),
2.82 (t, J=10.8 Hz, 2H), 3.40 (m, 4H), 3.50 (m, 6H), 3.68 (m, 4H),
6.88 (d, J=7.5 Hz, 1H), 7.11 (m, 3H), 7.32 (m, 2H), 7.62 (dq,
J=15.2, 4.5 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H); MS (APCI.sup.+) m/z
663 (M+H).sup.+. Anal. calcd for
C.sub.31H.sub.36F.sub.6N.sub.2O.sub.5S 0.7 TFA: C, 52.41; H, 4.98;
N, 3.77. Found: C, 52.38; H, 4.94; N, 3.68. 160
Example 434
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trifluoromethyl)-4-(E-((bis-(-
2-hydroxylpropyl)amino)carbonyl)ethenyl)phenyl]sulfide
[1217] The title compound was prepared by the procedures described
in Example 412 substituting Example 384B with Example 423A, and
substituting 4-hydroxypiperidine with diisopropanolamine. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.04 (m, 6H), 1.63 (m, 2H),
1.90 (m, 2H), 2.42 (m, 1H), 2.83 (t, J=10.5 Hz, 2H), 3.04 (m, 1H),
3.26 (m, 1H), 3.45 (m, 2H), 3.67 (m, 2H), 3.75 (m, 1H), 3.90 (m,
1H), 6.90 (d, J=7.5 Hz, 1H), 7.11 (m, 3H), 7.28 (d, J=8.5 Hz, 1H),
7.33 (t, J=8.2 Hz, 1H), 7.63 (m, 1H), 7.95 (dd, J=8.5, 2.1 Hz, 1H);
MS (APCI.sup.+) m/z 635 (M+H).sup.+. Anal. calcd for
C.sub.29H.sub.32F.sub.6N.sub.2O.sub.5S 1.5 TFA: C, 47.71; H, 4.19;
N, 3.48. Found: C, 47.52; H, 4.28; N, 3.40. 161
Example 435
[3-(4-Carboxypiperidin-1-yl)phenyl][2,3-bis-(trifluoromethyl)-4-(E-((piper-
azin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1218] The title compound was prepared by the procedures described
in Example 412 substituting Example 384B with Example 423A, and
substituting 4-hydroxypiperidine with
1-(1,2,3,4-tetrahydrofuroyl)piperazine. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.62 (m, 2H), 1.88 (m, 2H), 2.43 (m, 1H),
2.82 (t, J=10.5 Hz, 2H), 3.15 (br s, 4H), 3.71 (m, 2H), 3.75 (m,
2H), 3.86 (m, 2H), 6.87 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H),
7.12 (d, J=7.5 Hz, 1H), 7.20 (d, J=15.2 Hz, 1H), 7.28 (d, J=8.5 Hz,
1H), 7.35 (d, J=7.8 Hz, 1H), 7.70 (dt, J=15.2, 4.5 Hz, 1H), 7.98
(d, J=8.5 Hz, 1H), 8.85 (br s, 1H); MS (APCI.sup.+) m/z 588
(M+H).sup.+. Anal. calcd for C.sub.27H.sub.27F.sub.6N.sub.3O.sub.3S
3.3 TFA: C, 41.87; H, 3.17; N, 4.36. Found: C, 41.78; H, 3.26; N,
4.43. 162
Example 436
(3-(4-Butyroxy)phenyl)[2,3-bis(trifluoromethyl)-4-(E-((4-morpholino)carbon-
yl)ethenyl)phenyl]sulfide
[1219] Example 427 was processed as described in Example 414 to
provide the title compound as a white solid. .sup.1H NMR
(DMSO-d.sub.6, 300 MHz) .delta. 8.02 (d, J=8.5, 1H), 7.65 (m, 1H),
7.40 (t, J=7.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (d, J=14.9 Hz,
1H), 7.09 (m, 3H), 4.02 (t, J=6.4 Hz, 2H), 3.67 (s, 2H), 3.58 (s,
6H), 2.37 (t, J=7.1 Hz, 2H), 1.95 (m, 2H); MS (APCI) m/z 564
(M+H).sup.+; 562 (M-H).sup.-, 598 (M+Cl).sup.-. 163
Example 437
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((3-(2-pyrrolidinon--
1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide
[1220] 164
Example 437A
N-Benzyoxycarbonyl nipecotic acid
[1221] To a solution of nipecotic acid (10 g, 63.6 mmol) in 1 N
NaOH (2.5 g in 64 ml water, 63.6 mmol) at 0.degree. C. was
alternately added benzyloxycarbonyl chloride (10.9 mL, 76.5 mmol)
in diethyl ether (50 mL) and 1 N NaOH (5 g in 128 ml water, 127.2
mmol) in five portions. The reaction mixture was stirred at
0.degree. C. for 2 h, and at ambient temperature for 24 h. Then
this was made acidic with 10% HCl and the solid formed was filtered
and dried (vacuum oven, 45.degree. C.) to obtain the title compound
(18.9 g, 113%). MS (ESI) n/e 264 (M+H).sup.+. 165
Example 437B
tert-Butyl N-benzyoxycarbonyl nipecotate
[1222] A solution of Example A (18 g, 62 mmol) in THF (250 mL, 0.25
M) was treated with trichloroacetimidate (28 mL, 15 5 mmol) and
BF.sub.3.Et.sub.2O (18 mL, 1 mL/g) at ambient temperature. After 18
h the reaction mixture was quenched with solid NaHCO.sub.3 followed
by water and stirred vigorously. Then the solvent was removed, and
partitioned with ethyl acetate (250 mL). The organic layer was
separated and washed with brine (3.times.80 mL), dried
(Na.sub.2SO.sub.4) and evaporated to dryness under reduced pressure
to obtain the crude product. The title compound (19.2 g, 96%) was
obtained by flash chromatography on silica gel eluting with 20%
acetone:hexane. MS (ESI) m/e 320 (M+H).sup.+. 166
Example 437C
tert-Butyl nipecotate
[1223] Example 437B (19 g, 59.5 mmol) was treated with 10% Pd on
carbon (2 g, 10 wt %) in ethanol (237 mL, 0.25 M) to obtain the
title compound (10.4 g, 94%). MS (ESI) m/e 186 (M+H).sup.+. 167
Example 437D
2-Nitro-(3-(tert-butyloxycarbonyl)piperidin-1-yl)benzene
[1224] To a solution of Example 437C (10.4 g, 56.1 mmol) in toluene
(112 mL) was added 2-fluoronitrobenzene (6.0 ml, 56 mmol) and CsF
(852 mg, 5.6 mmol). The reaction mixture was stirred under reflux
conditions for 18 h, and allowed to cool to ambient temperature.
The mixture was diluted with ethyl acetate (100 ml), washed with
10% HCl (2.times.50 ml), followed by brine (3.times.100 ml), then
dried (Na.sub.2SO.sub.4) and evaporated in vacuo to obtain the
title compound (16.5 g, 94%). MS (ESI) m/e 307 (M+H).sup.+. 168
Example 437E
2-Amino-(3-(tert-butyloxycarbonyl)piperidin-1-yl)benzene
[1225] Example 437E (16.4 g, 53.5 mmol) was treated with 10% Pd on
carbon (1.65 g, 10 wt %) in ethanol (215 ml, 0.5 M) at ambient
temperature for 2 hours. The reaction mixture was filtered through
celite and the filtrate was evaporated to dryness under reduced
pressure to obtain the title compound (13.45 g, 91%). MS (ESI) m/e
277 (M+H).sup.+. 169
Example 437F
2-Iodo-(3-(tert-butyloxycarbonyl)piperidin-1-yl)benzene
[1226] Example 437E was dissolved in 3 N H.sub.2SO.sub.4 (195 mL,
0.25 M), cooled to 0.degree. C. and treated with NaNO.sub.2 (3.35
g, 48.6 mmol) in water (20 mL). After 30 minutes at 0.degree. C.
potassium iodide (12.01 g, 72.8 mmol) and urea (583 mg, 9.7 mmol)
in water (10 mL) were added and stirred for 1 h. The reaction
mixture was quenched with 10% NaHCO.sub.3 (50 mL) and partitioned
with ethyl acetate (450 mL). The organic layer was separated and
washed with 10% NaHCO.sub.3 (2.times.100 mL), brine (2.times.100
mL), dried (Na.sub.2SO.sub.4) and evaporated to dryness under
reduced pressure. The title compound (17.2 g, 91%) was obtained by
flash chromatography on silica gel eluting with 10% acetone:hexane.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.39 (s, 9H), 6.85 (tt,
J.sub.1=1.5 Hz, J.sub.2=7.5 Hz, 1H), 7.14 (dd, J.sub.1=1.5 Hz,
J.sub.2=7.5 Hz, 1H), 7.37 (tt, J.sub.1=1.5 Hz, J.sub.2=7.5 Hz, 1H),
7.84 (dd, J.sub.1=1.5 Hz, J.sub.2=7.5 Hz, 1H); MS (ESI) m/e 388
(M+H).sup.+. 170
Example 437G
[2-(3-tert-Butyloxycarbonyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-(2-me-
thoxycarbonyl)ethenyl)phenyl]sulfide
[1227] Example 437F was converted to the corresponding
triisopropylsilyl thiol analogue by the method describe d for the
preparation of Example 340B. Then this intermediate was reacted
with Example 340E (2.94 g, 7.75 mmol) at -20.degree. C. as
described in Example 340F to obtain the title compound (2.5 g,
63%). MS (ESI) m/e 522, 524 (M+H).sup.+. 171
Example 437H
[2-(3-tert-Butyloxycarbonyl)piperidin-1-yl)phenyl][2,3-dichloro-4-(E-(2-ca-
rboxy)ethenyl)phenyl]sulfide
[1228] Using the procedure for Example 340H, Example 437H was
hydrolyzed to the title compound. MS (ESI) m/e 508, 510
(M+H).sup.+. 172
Example 437I
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((3-(2-pyrrolidinon--
1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide
[1229] The title compound (66 mg) was prepared from Example 437H
(90 mg, 0.177 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with
3-aminopropyl-2-pyrrolidinone followed by treatment with 20% TFA in
methylene chloride as described in Example 412C. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 1.27-2.43 (m, 2H), 2.60-2.72 (m, 3H),
2.84 (m, 3H), 2.17-2.30 (m, 3H), 2.62-2.73 (m, 2H), 3.08-3.23 (m,
5H), 3.29-3.38 (m, 3H), 6.62 (d, J=15 Hz, 1H), 6.92 (d, J=8.5 Hz,
1H), 7.12 (t, J=7.5 Hz, 1H), 7.41 (m, 1H), 7.58 (d, J=8.75 Hz, 1H),
7.70 (d, J=15 Hz, 1H), 8.21 (t, J=5 Hz, 1H); MS (ESI) m/e 576, 578
(M+H).sup.+. 173
Example 438
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((3-(2-p-
yrrolidinon-1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide
[1230] 174
Example 438A
[2-(3-tert-Butyloxycarbonyl)piperidin-1-yl)phenyl][2,3-bis(trifluoromethyl-
)-4-(E-(2-carboxy)ethenyl)phenyl]sulfide
[1231] The title compound (445 mg, 71%) was prepared from the
reaction of Example 401C (500 mg, 1.08 mmol) with Example 437F,
using the procedures described in Example 437G followed by
hydrolysis as described in Example 340G. MS (ESI) m/e 604
(M+H).sup.+. 175
Example 438B
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((3-(2-p-
yrrolidinon-1-yl)propylaminocarbonyl)ethenyl)phenyl]sulfide
[1232] The title compound was prepared from Example 438A (110 mg,
0.191 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with
3-aminopropyl-2-pyrrolidinone followed by treatment with 20% TFA in
methylene chloride as described in Example 412C. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 1.11-1.21 (m, 1H), 1.28-1.38 (m, 1H),
1.60-1.70 (m, 3H), 1.79-1.86 (m, 1H), 1.87-1.94 (m, 2H), 2.05-2.12
(m, 1H), 2.00 (t, J=7.5 Hz, 2H), 2.58-2.66 (m, 2H), 2.96-3.01 (m,
1H), 3.11-3.18 (m, 2H), 3.19 (t, J=6.25 Hz, 2H), 3.26 (m, 1H), 3.32
(t, J=6.25 Hz, 2H), 6.46 (d, J=15 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H),
7.33 (m, 2H), 7.43 (m, 1H), 7.62 (m, 1H), 7.75 (d, J=7.5 Hz, 1H),
8.22 (t, J=5 Hz, 1H); MS (ESI) m/e 644 (M+H).sup.+. 176
Example 439
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-dichloro-4-(E-((4-(2-hydroxyethyl)-
piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1233] The title compound was prepared from Example 437H (90 mg,
0.177 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with 1-(2-hydroxyethyl)piperazine
followed by treatment with 20% TFA in methylene chloride as
described in Example 412C. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.31-1.45 (m, 2H), 1.67-1.74 (m, 1H), 1.86-1.92 (m, 1H),
2.24-2.31 (m, 1H), 2.66 (t, J=10 Hz, 1H), 2.73 (t, J=10 Hz, 1H),
3.02-3.24 (m, 5H), 3.33-3.38 (m, 1H), 3.52 (m, 3H), 3.75 (t, J=5
Hz, 2H), 4.31-4.60 (m, 3H), 6.90 (d, J=9 Hz, 1H), 7.11 (t, J=7.5
Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.30 (d,
J=15 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.83 (d, J=15 Hz, 1H), 7.85
(d, 9 Hz, 1H); MS (ESI) m/e 564, 566 (M+H).sup.+. 177
Example 440
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((1,2,5,-
6-tetrahydropyridin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1234] The title compound was prepared from Example 438A (110 mg,
0.191 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with 1,2,5,6-tetrahydropyridine
followed by treatment with 20% TFA in methylene chloride as
described in Example 412C. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.19-1.27 (m, 1H), 1.30-1.40 (m, 1H), 1.64-1.70 (m, 1H),
1.80-1.86 (m, 1H), 2.04-2.18 (m, 2H), 2.60 (t, J=10 Hz, 1H), 2.68
(t, J=0 Hz, 1H), 3.03 (br d, J=10 Hz, 1H), 3.23 (br d, J=10 Hz,
1H), 3.60-3.74 (m, 2H), 3.91-4.20 (m, 3H), 5.68-5.74 (m, 1H),
5.80-5.90 (m, 1H), 7.06-7.19 (m, 2H), 7.20-7.28 (m, 2H), 7.36 (m,
1H), 7.44 (t, J=7.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.94-8.04 (m, 1H);
MS (ESI) m/e 585 (M+H).sup.+. 178
Example 441
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-4-(4-(2--
hydroxyethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1235] The title compound was prepared from Example 438A (110 mg,
0.191 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with 1-(2-hydroxyethyl)piperazine
followed by treatment with 20% TFA in methylene chloride as
described in Example 412C. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.17-1.27 (m, 1H), 1.17-1.27 (m, 1H), 1.31-1.41 (m, 1H),
1.64-1.71 (m, 1H), 1.80-1.88 (m, 1H), 2.07-2.15 (m, 1H), 2.61 (t,
J=10 Hz, 1H), 2.09 (t, J=10 Hz, 1H), 2.91-3.13 (m, 3H), 3.18-3.28
(m, 3H), 3.44-3.58 (m, 3H), 3.75 (t, J=5 Hz, 2H), 4.29-4.58 (m,
3H), 7.15 (d, J=7.5 Hz, 1H), 7.19 (d, J=10 Hz, 1H), 7.28 (d, J=7.5
Hz, 2H), 7.37 (d, J=7.5 Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 7.69-7.77
(m, 1H), 7.98 (d, J=7.5 Hz, 1H), 9.77 (br s, 1H); MS (ESI) m/e 632
(M+H).sup.+. 179
Example 442
[2-(3-Carboxypiperidin-1-yl)phenyl][2,3-bis(trifluoromethyl)-4-(E-((4-(2-(-
hydroxyethoxy)ethyl)piperazin-1-yl)carbonyl)ethenyl)phenyl]sulfide
[1236] The title compound was prepared from Example 438A (110 mg,
0.191 mmol), using the procedures described in Example 340G
substituting methyl isonipecotate with
1-[2-(2-hydroxyethoxy)ethyl]piperazine followed by treatment with
20% TFA in methylene chloride as described in Example 412C. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 1.17-1.27 (m, 1H), 1.31-1.40
(m, 1H), 1.64-1.70 (m, 1H), 1.80-1.86 (m, 1H), 2.08-2.16 (m, 1H),
2.61 (t, J=10 Hz, 1H), 2.68 (t, J=10 Hz, 1H), 3.03 (br d J=10 Hz,
1H), 3.06-3.18 (m, 2H), 3.25 (br d, J=10 Hz, 1H), 3.33 (m, 2H),
3.42-3.51 (m, 2H), 3.53-3.60 (m, 2H), 3.70-3.80 (m, 5H), 4.32-4.56
(m, 3H), 7.13-7.21 (m, 2H), 7.27 (d, J=9 Hz, 2H), 7.35 (d, J=7.5
Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.68-7.77 (m, 1H), 7.44-8.01 (m,
1H), 9.81 (br sp 1H); MS (ESI) m/e 676 (M+H).sup.+. 180
Example 443
(3-(3-Propioxy)phenyl)[2,3-dichloro-4-(E-((4-morpholino)carbonyl)ethenyl)p-
henyl]sulfide
[1237] .beta.-Propiolactone (50 .mu.L, 0.75 mmol) was added to a
mixture of Example 405 (308 mg, 0.75 mmol), potassium tert-butoxide
(750 mL, 1 M in THF), and THF (1.0 mL). After 18 h, the reaction
was diluted with EtOAc, washed with 1 M aqueous HCl, washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. Purification
by preparative HPLC provided the title compound (72 mg, 20%) as a
white solid. .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 7.80 (d,
J=8.4 Hz, 1H), 7.78 (d, J=15.8 Hz, 1H), 7.52 (dt, J=8.8 Hz, J=1.7
Hz, 1H), 7.46 (dd, J=7.8 Hz, J=17 Hz, 1H), 7.23 (d, 0.1 Hz, 1H),
7.22 (d, J=15.3 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 6.58 (d, J=8.5 Hz,
1H), 4.22 (m, 2H), 4.05 (m, 2H), 3.66 (s, 2H), 3.58 (s, 6H); MS
(APCI) m/z 482 (M+H).sup.+; 480 (M-H).sup.-.
[1238] Compounds that antagonize the interaction between ICAM-1 and
LFA-1 can be identified, and their activities quantitated, using
both biochemical and cell-based adhesion assays. A primary
biochemical assay measures the ability of the compound in question
to block the interaction between the integrin LFA-1 and its
adhesion partner ICAM-1, as described below:
[1239] ICAM-1/LFA-1 Biochemical Interaction Assay
[1240] In the biochemical assay, 100 .mu.L of anti-LFA-1 antibody
(ICOS Corporation) at a concentration of 5 .mu.g/ml in Dulbecco's
phosphate-buffered saline (D-PBS) is used to coat wells of a
96-well microtiter plate overnight at 4.degree. C. The wells are
then washed twice with wash buffer (D-PBS w/o Ca.sup.++ or
Mg.sup.++, 0.05% Tween 20) and blocked by addition of 200 .mu.L of
D-PBS, 5% fish skin gelatin. Recombinant LFA-1 (100 .mu.L of 0.7
.mu.g/ml, ICOS Corporation) in D-PBS is then added to each well.
Incubation continues for 1 hour at room temperature and the wells
are washed twice with wash buffer. Serial dilutions of compounds
being assayed as ICAM-1/LFA-1 antagonists, prepared as 10 mM stock
solutions in dimethyl sulfoxide (DMSO), are diluted in D-PBS, 2 mM
MgCl.sub.2, 1% fish skin gelatin and 50 .mu.L of each dilution
added to duplicate wells. This is followed by addition of 50 .mu.L
of 0.8 .mu.g/ml biotinylated recombinant ICAM-1/Ig (ICOS
Corporation) to the wells and the plates are incubated at room
temperature for 1 hour. The wells are then washed twice with wash
buffer and 100 .mu.L of Europium-labeled Streptavidin (Wallac Oy)
diluted 1:100 in Delfia assay buffer (Wallac Oy) are added to the
wells. Incubation proceeds for 1 hour at room temperature. The
wells are washed eight times with wash buffer and 100 .mu.L of
enhancement solution (Wallac Oy, cat. No. 1244-105) are added to
each well. Incubation proceeds for 5 minutes with constant mixing.
Time-resolved fluorimetry measurements are made using the Victor
1420 Multilabel Counter (Wallac Oy) and the percent inhibition of
each candidate compound is calculated using the following equation:
1 % inhibition = 100 .times. { 1 - average OD w / compound minus
background average OD w / o compound minus backgroud }
[1241] where "background" refers to wells that are not coated with
anti-LFA-1 antibody.
[1242] Compounds of the present invention exhibit inhibitory
activity in the above assay. % inhibition at 4 .mu.M was
demonstrated.
[1243] Biologically relevant activity of the compounds in this
invention is confirmed using a cell-based adhesion assay, which
measures their ability to block the adherence of JY-8 cells (a
human EBV-transformed B cell line expressing LFA-1 on its surface)
to immobilized ICAM-1, as follows:
[1244] ICAM-1/JY-8 Cell Adhesion Assay
[1245] For measurement of inhibitory activity in the cell-based
adhesion assay, 96-well microtiter plates are coated with 70 .mu.L
of recombinant ICAM-1/Ig (ICOS Corporation) at a concentration of 5
.mu.g/mL in D-PBS w/o Ca.sup.++ or Mg.sup.++ overnight at 4.degree.
C. The wells are then washed twice with D-PBS and blocked by
addition of 200 .mu.L of D-PBS, 5% fish skin gelatin by incubation
for 1 hour at room temperature. Fluorescent tagged JY-8 cells (a
human EBV-transformed B cell line expressing LFA-1 on its surface;
50 .mu.L at 2.times.10.sup.6 cells/ml in RPMI 1640/1% fetal bovine
serum) are added to the wells. For fluorescent labeling of JY-8
cells, 5.times.10.sup.6 cells washed once in RPMI 1640 are
resuspended in 1 mL of RPMI 1640 containing 2 .mu.M Calceiun AM
(MolecularProbes), are incubated at 37.degree. C. for 30 minutes
and washed once with RPMI-1640/1% fetal bovine serum. Dilutions of
compounds to be assayed for ICAM-1/LFA-1 antagonistic activity are
prepared in RPMI-1640/1% fetal bovine serum from 10 mM stock
solutions in DMSO and 50 .mu.L are added to duplicate wells.
Microtiter plates are incubated for 45 minutes at room temperature
and the wells are washed gently once with RPMI-1640/1% fetal bovine
serum. Fluorescent intensity is measured in a fluorescent plate
reader with an excitation wavelength at 485 nM and an emission
wavelength at 530 nM. The percent inhibition of a candidate
compound at a given concentration is calculated using the following
equation: 2 % inhibition = 100 .times. { 1 - average OD w /
compound average OD w / o compound }
[1246] and these concentration/inhibition data are used to generate
dose response curves, from which IC.sub.50 values are derived.
[1247] Compounds of the present invention exhibit blocking activity
in the above assay. Inhibition at 4 .mu.M was demonstrated.
[1248] Compounds of the present invention have been demonstrated to
act via interaction with the integrin LFA-1, specifically by
binding to the interaction domain (I-domain), which is known to be
critical for the adhesion of LFA-1 to a variety of cell adhesion
molecules. As such, it is expected that these compounds should
block the interaction of LFA-1 with other CAM's. This has in fact
been demonstrated for the case of ICAM-3. Compounds of the present
invention may be evaluated for their ability to block the adhesion
of JY-8 cells (a human EBV-transformed B cell line expressing LFA-1
on its surface) to immobilized ICAM-3, as follows:
[1249] ICAM-3/JY-8 Cell Adhesion Assay
[1250] For measurement of inhibitory activity in the cell-based
adhesion assay, 96-well microtiter plates are coated with 50 .mu.L
of recombinant ICAM-3/Ig (ICOS Corporation) at a concentration of
10 .mu.g/mL in D-PBS w/o Ca.sup.++ or Mg.sup.++ overnight at
4.degree. C. The wells are then washed twice with D-PBS, blocked by
addition of 100 .mu.L of D-PBS, 1% bovine serum albumin (BSA) by
incubation for 1 hour at room temperature, and washed once with
RPMI-1640/5% heat-inactivated fetal bovine serum (adhesion buffer).
Dilutions of compounds to be assayed for ICAM-3/LFA-1 antagonistic
activity are prepared in adhesion buffer from 10 mM stock solutions
in DMSO and 100 .mu.L are added to duplicate wells. JY-8 cells (a
human EBV-transformed B cell line expressing LFA-1 on its surface;
100 .mu.L at 0.75.times.10.sup.6 cells/ml in adhesion buffer) are
then added to the wells. Microtiter plates are incubated for 30
minutes at room temperature; the adherent cells are then fixed with
50 .mu.L of 14% glutaraldehyde/D-PBS and incubated for an
additional 90 minutes. The wells are washed gently with dH.sub.2O;
50 .mu.L of dH.sub.2O is added, followed by 50 .mu.L of 1% crystal
violet. After 5 minutes the plates are washed 3.times. with
dH.sub.2O; 75 .mu.L of dH.sub.2O and 225 mL of 95% EtOH are added
to each well to extract the crystal violet from the cells.
Absorbance is measured at 570 nM in an ELISA plate reader. The
percent inhibition of a candidate compound is calculated using the
following equation: 3 % inhibition = 100 .times. { 1 - average OD w
/ compound average OD w / o compound }
[1251] Compounds of the present invention exhibit blocking activity
in the above assay. 100% inhibition at 0.6 .mu.M was
demonstrated.
Additional JY-8 (ICAM/LFA-1) Cell Adhesion Assay Protocol
[1252] Reagents
[1253] ICAM-1/Ig, ICOS
[1254] D-PBS, Dulbecco's w/o Ca & Mg
[1255] D-PBS, Dulbecco's w/ Ca & Mg
[1256] Blocking Solution: 1% non-fat dried milk in PBS w/o Ca &
Mg
[1257] RPMI 1640 media
[1258] RPMI 1640 media with 1% FBS (RPMI-1% FBS)
[1259] RPMI 1640 media with 50% FBS (RPMI-50% FBS)
[1260] 1 mM Calcein AM, Molecular Probes, cat. C-1430 or C-3099
[1261] DMSO
[1262] JY-8 cells
[1263] Procedure
[1264] 1. Coat plate (70 ul/well) with 5 ug/ml in D-PBS w/ Ca &
Mg of ICAM-1/Ig. Cover and incubate overnight at 4.degree. C.
[1265] 2. Make compound and control dilutions using RPMI-1% FBS and
RPMI-50% FBS as the diluents.
[1266] 3. Decant ICAM-1/Ig coated plate(s), and wash 3.times. with
D-PBS w/o Ca & Mg.
[1267] 4. Block entire plate(s) with 150 ul/well of Blocking
solution. Cover and incubate for approximately 1 hour at room
temperature.
[1268] 5. Count the number of viable JY-8 cells using standard
methodology. Need approximately 10-15.times.10E6 cells per 96 mw
tray.
[1269] 6. Wash cells 1.times. in RPMI 1640 media without
serum--centrifuging for 5 minutes at approximately 1400 rpms.
Remove supernate and resuspend cell pellet to 5.times.10E6 cells
per ml in RPMI 1640 media without serum.
[1270] 7. Add 2 ul of 1 mM Calcein AM for every 1 ml of cell
suspension. Mix. Incubate for 30-60 minutes at 37 degrees C. in a
CO.sub.2 incubator (keeping cap of centrifuge tube loose for gas
exchange).
[1271] 8. Add approximately 10 mls of RPMI-1% FBS, aliquot into two
equal pools and centrifuge for 5 minutes at 1400 rpms.
[1272] 9. Remove supernate from each pool and resuspend each cell
pellet to 2.times.10E6 cell per ml with RPMI-1% FBS or RPMI-50%
FBS.
[1273] 10. Decant blocked 96 mw plate(s) and wash 3.times. with
D-PBS w/o Ca & Mg.
[1274] 11. Add 50 ul/well of each compound dilution or control. Add
50 ul of Calcein labeled JY-8 cells to all wells. Centrifuge
plate(s) briefly (2-5 seconds) at 100-150 rpms. Cover and incubate
for 30-60 minutes at 37 degrees C.
[1275] 12. Gently wash wells 1.times. with approximately 150 ul per
well of PBS w/Ca & Mg. Remove all liquid from wells.
[1276] 13. Read absorbence using reader with an excitation of
485/20 and an emission of 530/25.
[1277] 14. Calculate % inhibition using the following equation: 4 %
inhibition = 100 .times. { 1 - average OD w / compound average OD w
/ o compound }
[1278] The ability of the compounds of this invention to treat
arthritis can be demonstrated in a murine collagen-induced
arthritis model according to the method of Kakimoto, et al., Cell
Immunol 142: 326-337, 1992, in a rat collagen-induced arthritis
model according to the method of Knoerzer, et al., Toxicol Pathol
25:13-19, 1997, in a rat adjuvant arthritis model according to the
method of Halloran, et al., Arthitis Rheum 39: 810-819, 1996, in a
rat streptococcal cell wall-induced arthritis model according to
the method of Schimmer, et al., J Immunol 160: 1466-1477, 1998, or
in a SCID-mouse human rheumatoid arthritis model according to the
method of Oppenheimer-Marks et al., J Clin Invest 101: 1261-1272,
1998.
[1279] The ability of the compounds of this invention to treat Lyme
arthritis can be demonstrated according to the method of Gross et
al., Science 281, 703-706, 1998.
[1280] The ability of compounds of this invention to treat asthma
can be demonstrated in a murine allergic asthma model according to
the method of Wegner et al., Science 247:456-459, 1990, or in a
murine non-allergic asthma model according to the method of Bloemen
et al., Am J Respir Crit Care Med 153:521-529, 1996.
[1281] The ability of compounds of this invention to treat
inflammatory lung injury can be demonstrated in a murine
oxygen-induced lung injury model according to the method of Wegner
et al., Lung 170:267-279, 1992, in a murine immune complex-induced
lung injury model according to the method of Mulligan et al., J
Immunol 154:1350-1363, 1995, or in a murine acid-induced lung
injury model according to the method of Nagase, et al., Am J Respir
Crit Care Med 154:504-510, 1996.
[1282] The ability of compounds of this invention to treat
inflammatory bowel disease can be demonstrated in a rabbit
chemical-induced colitis model according to the method of Bennet et
al., J Pharmacol Exp Ther 280:988-1000, 1997.
[1283] The ability of compounds of this invention to treat
autoimmune diabetes can be demonstrated in an NOD mouse model
according to the method of Hasagawa et al., Int Immunol 6:831-838,
1994, or in a murine streptozotocin-induced diabetes model
according to the method of Herrold et al., Cell Immunol
157:489-500, 1994.
[1284] The ability of compounds of this invention to treat
inflammatory liver injury can de demonstrated in a murine liver
injury model according to the method of Tanaka et al., J Immunol
151:5088-5095, 1993.
[1285] The ability of compounds of this invention to treat
inflammatory glomerular injury can be demonstrated in a rat
nephrotoxic serum nephritis model according to the method of
Kawasaki, et al., J Immunol 150:1074-1083, 1993.
[1286] The ability of compounds of this invention to treat
radiation-induced enteritis can be demonstrated in a rat abdominal
irradiation model according to the method of Panes et al.,
Gastroenterology 108:1761-1769, 1995.
[1287] The ability of compounds of this invention to treat
radiation pneumonitis can be demonstrated in a murine pulmonary
irradiation model according to the method of Hallahan et al., Proc
Natl Acad Sci USA 94:6432-6437, 1997.
[1288] The ability of compounds of this invention to treat
reperfusion injury can be demonstrated in the isolated rat heart
according to the method of Tamiya et al., Immunopharmacology 29(1):
53-63, 1995, or in the anesthetized dog according to the model of
Hartman et al., Cardiovasc Res 30(1): 47-54, 1995.
[1289] The ability of compounds of this invention to treat
pulmonary reperfusion injury can be demonstrated in a rat lung
allograft reperfusion injury model according to the method of
DeMeester et al., Transplantation 62(10): 1477-1485, 1996, or in a
rabbit pulmonary edema model according to the method of Horgan et
al., Am J Physiol 261(5): H1578-H1584, 1991.
[1290] The ability of compounds of this invention to treat stroke
can be demonstrated in a rabbit cerebral embolism stroke model
according the method of Bowes et al., Exp Neurol 119(2): 215-219,
1993, in a rat middle cerebral artery ischemia-reperfusion model
according to the method of Chopp et al., Stroke 25(4): 869-875,
1994, or in a rabbit reversible spinal cord ischemia model
according to the method of Clark et al., Neurosurg 75(4): 623-627,
1991.
[1291] The ability of compounds of this invention to treat
peripheral artery occlusion can be demonstrated in a rat skeletal
muscle ischemia/reperfusion model according to the method of Gute
et al., Mol Cell Biochem 179: 169-187, 1998.
[1292] The ability of compounds of this invention to treat graft
rejection can be demonstrated in a murine cardiac allograft
rejection model according to the method of Isobe et al., Science
255: 1125-1127, 1992, in a murine thyroid gland kidney capsule
model according to the method of Talento et al., Transplantation
55: 418422, 1993, in a cynomolgus monkey renal allograft model
according to the method of Cosimi et al., J Immunol 144: 4604-4612,
1990, in a rat nerve allograft model according to the method of
Nakao et al., Muscle Nerve 18: 93-102, 1995, in a murine skin
allograft model according to the method of Gorczynski and Wojcik, J
Immunol 152: 2011-2019, 1994, in a murine corneal allograft model
according to the method of He et al., Opthalmol Vis Sci 35:
3218-3225, 1994, or in a xenogeneic pancreatic islet cell
transplantation model according to the method of Zeng et al.,
Transplantation 58:681-689, 1994.
[1293] The ability of compounds of this invention to treat
graft-vs.-host disease (GVHD) can be demonstrated in a murine
lethal GVHD model according to the method of Harning et al.,
Transplantation 52:842-845, 1991.
[1294] The ability of compounds of this invention to treat cancers
can be demonstrated in a human lymphoma metastasis model (in mice)
according to the method of Aoudjit et al., J Immunol 161:2333-2338,
1998.
* * * * *