AU2004202565B2 - Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds - Google Patents

Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds Download PDF

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Publication number
AU2004202565B2
AU2004202565B2 AU2004202565A AU2004202565A AU2004202565B2 AU 2004202565 B2 AU2004202565 B2 AU 2004202565B2 AU 2004202565 A AU2004202565 A AU 2004202565A AU 2004202565 A AU2004202565 A AU 2004202565A AU 2004202565 B2 AU2004202565 B2 AU 2004202565B2
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Australia
Prior art keywords
sulfide
ethenyl
carbonyl
phenyl
nitro
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AU2004202565A
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AU2004202565A1 (en
Inventor
Steven A Boyd
Jennifer C Freeman
Tom Von Geldern
Indrani W Gunawardana
Hwan-Soo Jae
James Link
Gang Liu
John K Lynch
Zhonghua Pei
Michael A Staeger
Martin Winn
Zhili Xin
Gui-Dong Zhu
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Abbott Laboratories
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Abbott Laboratories
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Priority claimed from US09/222,491 external-priority patent/US6110922A/en
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Publication of AU2004202565A1 publication Critical patent/AU2004202565A1/en
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Publication of AU2004202565B2 publication Critical patent/AU2004202565B2/en
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Description

AUSTRALIA
Patents Act COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Abbott Laboratories Actual Inventor(s): James Link, Gang Liu, Zhonghua Pei, Tom Von Geldern, Martin Winn, Zhili Xin, Steven A Boyd, Hwan-Soo Jae, John K Lynch, Gui-Dong Zhu, Jennifer C Freeman, Indrani W Gunawardana, Michael A Staeger Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: CELL ADHESION-INHIBITING ANTIINFLAMMATORY AND IMMUNE-SUPPRESSIVE
COMPOUNDS
Our Ref: 722193 POF Code: 457240/103086 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): CELL ADHESION-INHIBITING
ANTIINFLAMMATORY
AND IMMUNE-SUPPRESSIVE
COMPOUNDS
The present application is a divisional application from Australian patent application number 771126 (formerly 22203/00) the entire disclosure of which is incorporated herein by reference.
Technical Field 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 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.
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. and Springer, T. 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. McEnvoy, Bargatze, 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, Gaehtgens, Fennie, C., Singer, 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 (SLex), 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-a 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 selectins, 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.
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-I 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-I knockout mice have numerous abnormalities in their inflammatory responses.
The present invention discloses compounds which bind to the interactiondomain (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.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims.
Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.
Y:\M,,Nr K NO DELETE"22203-OO.do Summary of The Invention The present invention provides compounds of formula I, below,
R
1 ArS
R
R
5
R
3 R4
I
or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 3
R
4 and R, 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, .or R, is a "cis-ciinnamide." or a "transcinnamide", defined as
R
9 R10 R 9 R1io
R
8 N, RNR1 0 R 8 0 "cis-cinriamide" 441ran s-!cinnamnide", Wherein R. and R, are independently selected from a. hydrogen. and b.alkyl, c. carboxy alkyl, d. alkylaminocarbonyl alkyl, and e. dialkylaminocarbonyl alkyl.
and Rio and are independently selected from a. hydrogen, b. alkyl, c. cycloalkyl, d. alkoxycarbonylalkyl, e. hydroxyalkyl, f. heterocyclyl.
g. heterocyclylalkyl, h. heterocyclylano, i. substituted heterocyclyl, and j.substituted heterocyclylalkyl, or where NRI 0 RII is heterocyclyl or substituted heterocyclyl. where substituents are independently selected from 1) alkyl, 2) alkoxy, 3) alkoxyalkyl,.
4) cycloalkyl, aryl1, 6) heterocyclyl, 7) heterocyclylcarbolYl, 8) heterocyclylalkyamilocarbofll 9) hydroxy, 1 0).hydroxyalkyl, 11) hydroxyalkoxyalkYl, 12) carboxy, 13) carboxyalkyl, 8 14) carboxycarbonyl, carboxaldehyde, 16) alkoxycarbonyl, 17) arylalkoxycarbonyl, 18) aminoalkyl, 19) aminoalkanoyl, carboxainido, 21) alkoxycarbonylalkyl, 22) carboxamidoalkyl, 23) cyano, 24) tetrazolyl, substituted tetrazolyl,.
26) alkanoyl, 27) hydroxyalkanoyl, 28) alkanoyloxy, 29) alkanoylamino, alkanoyloxyalkyl, 31) alkanoylaminoalkyl, 32) sulfonate, 33) alkylsulfonyl, -34) alkylsulfonylaminocarbonyl, arylsulfonylamninocarbonyl, and 36) heterocyclylsulfonylamilocarboflyl, 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, 1. aminoalkyl, m. aminocarbonyl, n. alkyl(alkoxycarbonylalkyl)amiloalkyl, o. heterocyclyl, p. heterocyclylalkyl, q. substituted heterocyclylalkyl, r. carboxaldehyde, s. carboxaldehyde hydrazone, t. carboxamide, u. alkoxycarbonylalkyl, v. carboxy, w. carboxyalkyl, x. hydroxycarbonylalkyl (carboxyalkyl), y. hydroxyalkylaminocarbonyl, z. cyano, aa. amino, bb. heterocyclylalkylamino, cc. heterocyclylalkylaminocarbonyl, and dd. "trans-cinnamide".
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 1.
Still further provided are pharmaceutical compositions containing compounds of formula I.
Detailed Description The term "alkanoyl" as used herein refers to an alkyl group attached to the parent molecular group through a carbonyl group.
The term "alkanoylamino" as used herein refers to an alkanoyl group attached to the parent molecular group though an amino group.
The term "alkanoylaminoalkyl" as used herein refers to an alkanoylamino group attached to the parent molecular group through an alkyl group.
The term "alkanoyloxy" as used herein refers to an alkanoyl group attached to the parent molecular group through an oxygen radical.
The term "alkanoyloxyalkyl" as used herein refers to an alkanoyloxy group attached to the parent molecular group through an alkyl group, The term "alkoxy" as used herein refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term "alkoxyalkoxy" as used herein refers to an alkoxy group attached to the parent molecular group through an alkoxy group.
The term "alkoxyalkyl" as used herein refers to an alkoxy group attached to the parent molecular group through an alkyl group.
The term "alkoxycarbonyl" as used herein refers to an alkoxy group attached to the parent molecular group through a carbonyl group.
The term "alkoxycarbonylalkyl" as used herein refers to an alkoxycarbonyl group attached to the parent molecular group through an alkyl group.
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.
The term "alkyl(alkoxycarbonylalkyl)amino" as used herein refers to an amino group substituted with one alkyl group and one alkoxycarbonylalkyl group.
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.
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.
The term "alkylsulfonyl" as used herein refers to an alkyl radical attached to the parent molecular group through an group.
The term "alkylsulfonylaminocarbonyl" as used herein refers to an alkylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term "amino" as used herein refers to a radical of the form or to to a radical of the form where and are independently selected from hydrogen, alkyl or cycloalkyl.
The term "aminoalkanoyl" as used herein refers to to an amino group attached to the parent molecular group through an alkanoyl group.
13 The term "aminoalkyl" as used herein refers to an amino group attached to the parent molecular group through an alkyl group.
The term "aminocarbonyl" as used herein refers to an amino group attached to the parent molecular group through a carbonyl group.
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, or alkoxy substituents.
The term "arylalkoxy" as used herein refers to an aryl group attached to the parent molecular group through an alkoxy group.
The term "arylalkoxycarbonyl" as used herein refers to an arylalkoxy group attached to the parent molecular group through a carbonyl group.
The term "arylsulfonyl" as used herein refers to an aryl radical attached to the parent molecular group through an -SO- group.
The term "arylsulfonylaminocarbonyl" as used herein refers to an arylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term "carboxaldehyde" as used herein refers to the radical -CHO.
The term "carboxaldehyde hydrazone" as used herein refers to the radical
-CH=N-NR
2 0 where R 2 0 and are independently selected from hydrogen, alkyl or cycloalkyl.
14 The terms "carboxamide" or "carboxamido" as used herein refer to an amino group attached to the parent molecular group through a carbonyl group.
The term "carboxamidoalkyl" as used herein refers to a carboxamido group attached to the parent molecular group through an alkyl group.
The term "carboxy" as used herein refers to the radical -COOH.
The term "carboxyalkyl" as used herein refers to a carboxy group attached to the parent molecular group through a alkyl group.
The term "carboxycarbonyl" as used herein refers to a carboxy group attached to the parent molecular group through a carbonyl group.
The term "cyano" as used herein refers to the radical -CN.
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.
The terms "halo" or "halogen" as used herein refers to F, CI, Br, or I.
The term haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms.
The terms "heterocycle" or "heterocyclyl" represent a 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-2onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl,.
tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomnorpholinyl, triazolyl, and the like.
Heterocyclics also include bridged bicyclic groups where a.monocyclic heterocyclic group is bridged by an alkylene group such as
H
N
H ,and the like.
Heterocyclics also include compounds of the formula where X* and Z* are independently selected from -CH2-, -CH 2 -NH- and. with the proviso that at least one. of X* and Z* is not and Y* is selected from 16 and 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, 1,3benzimidazol-2-one and the like. The heterocycle groups of this invention can be optionally substituted with alkyl, halogen, hydroxy or alkoxy substituents.
The term "heterocyclylalkyl" as used herein refers to an heterocyclic group attached to the parent molecular group through an alkyl group.
The term "heterocyclylalkylamino" as used herein refers to an heterocyclylalkyl group attached to the parent molecular group through an amino group.
The term "heterocyclylalkylaminocarbonyl" as used herein refers to a heterocyclylalkylamino group attached to the parent molecular group through a carbonyl group.
The term "heterocyclylamino" as used herein refers to a heterocyclyl group attached to the parent molecular group through a amino group.
The term "heterocyclylcarbonyl" as used herein refers to a heterocyclyl group attached to the parent molecular group through a carbonyl group.
The term "heterocyclylsulfonyl" as used herein refersto a heterocyclyl radical attached to the parent molecular group through.an -SO 2 group.
The term "heterocyclylsulfonylaminocarbonyl" as used herein refers to a heterocyclylsulfonyl group attached to the parent molecular group through an aminocarbonyl group.
The term "hydroxyalkanoyl" as used herein refers to an hydroxy radical attached to the parent molecular group through an alkanoyl group.
The term "hydroxyalkoxy" as used herein refers to an hydroxy radical attached to the parent molecular group through an alkoxy group.
The term "hydroxyalkoxyalkyl" as used herein refers to an hydroxyalkoxy group attached to the parent molecular group through an alkyl group.
The term "hydroxyalkyl" as used herein refers to an hydroxy radical attached to the parent molecular group through an alkyl group.
The term "hydroxyalkylaminocarbonyl" as used herein refers to an hydroxyalkyl group attached to the parent molecular group through an aminocarbonyl group.
The term "perfluoroalkyl" as used herein refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
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.
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, 1 commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "prodrug," 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.
The term "sulfonate" as used herein refers to the radical -SO3H The term "tetrazole" or "tetrazolyl" as used herein refers to the heterocyclic radical -CNH..
The term "thioalkoxy" as used herein refers to an alkyl group attached to the parent molecular group through a sulfur atom.
Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols or 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, salt formation employing an optically active resolving agent, or direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
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 represents substituents on the same side of the carbon-carbon double bond and the term represents substituents on opposite sides of the carboncarbon 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.
As is apparent from the foregoing descriptions, the compounds of Formula 1 are useful in a variety of forms, with various substitutions as identified.
Examples of particularly desirable compounds are quite diverse, and many are mentioned herein. Included are compounds in which R, is a "icis-cinnarnide" or a "itrans-cinnamide", and R 3 is hydrogen; or where R 3 is a "cis-cinnamide" or a. "transcinnamide", and R, is hydrogen, or RI, R 2 and R 4 are each independently hydrogen or alkyl, and R. is halogen, haloalkyl or nitro. Further preferred compounds include those as above wherein and R, are each independently hydrogen, alkyl, cycloalkyl, alkoxycarbonylaalkyl, hydroxyalkyl, or heterocyclylalkyl, or where
NR
1 6R, is heterocyclyl or substituted heterocyclyl, and where At is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
Compounds of the present invention include: (2,4-Dichlorophenyl)[2-;( 6 -hydroxyhexylamino)carbonyl)ethenyl)phenyl] sulfide; (2,4-Dichiorophenyl -imidazolyl )propylaniino)carbonyl)ethenyl)phenyl] sulfide; (2,4-Dichioropheny]) [2-chloro-4-( hydroxyethylamino)carbonyi)ethenyl)phenyl] sulfide; (.2,4-Dichlorophenyl)[2-chloro.4-( E-((6hydroxyhexylamino)carbonyl)etheny)phenyl) sulfide; (2,4-Dichlorophenyl)[2-chloro-4-( E-((bis-(2-hydroxyethyl)amino)carbonyl)ethenyl) phenyl] sulfide; (2,4-Dichlorophenyl)[2-chloro-4-( 1 -pyrrolidin-2-only)propylamino)carbonyl) ethenyl)phenyl] sulfide;.
21 (2,4-Dichlorophenyl)[2-chloro-4-( I morpholinyl)carbol)ethelyl)phelyl] sulfidle; (2,4-Dichlorophenyl)[2-chloro-4-( E-((4-methylpiperazin-1 yi)carbonyl)ethenyl)phenyl] sulfide; Dichlorophenyl)[2-chloro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl)phelYll sulfide; (2,4-Dichlorophenyl)[2-chloro-4-( Em((4-(2-pyridyl)piperazifl- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2-(Hydroxymethyl)phenyl)12-chloro-4-( I -morpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2-Bromophenyl)12-chloro-4-( I-morpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl )[2-chloro-4-( E-((4-(2-hydroxyethyl)piperazifl-1I-yl)carbonyl) eihenyl)phenyll sulfide; (2,4-Dichlorophenyl,)[2-chloro-4-( .E-((4-(2-hydroxyethoxyethylpiperazifl- I yl)carbonyl) ethenyl)phenyl] sulfide; (2-Bromophenyl)12-chloro-4-( -(hydroxymethyl)piperidifl- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-chloro-4-( E-((2-(hydroxymethyl)piperidifl- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-chloro-4-( E-((3-acetamidopyrrolidiflyl)carbonyl)ethenyl)phenyl]. sulfide; 22 (2-Bromophenyl)[2-chloro-4-( E-((4-hydroxypiperidin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-chloro-4-( E-((piperidin-1I-yl)carbonyl) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-chiloro-4-( E-((3-carboxypipericlin-I yl)carbonyl)ethenyl)phenyl] sulfide; (2,4-Dicblorophenyl)[2-chloro74-( E-((4-carboxypiperidin- 1yl)carbonyl)ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-chloro-4-( E-((4-acetylhomopiperazin-1I yl)carbonyl)etheny)pheny]] sulfide; (2-Bromophenyl)[2-chloro-4-( E-((thiomorpholin- I -yl)carbonyl)ethenyl)phenyll sulfide; (2-Brornophenyl) [2-chloro-4-( I -benzimidazol-2-only)piperidin- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-chloro-4-( tetrahydroi soquinolinyl)carbonyl)etheny])phenyl] sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-( E-((4-acetylpiperazin- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-( 1 -morpholinyl)carbonyl)ethenyl)phenyl] sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-( 1 -morpholinyl)ethylamino)carbonyl) ethenyl)phenyl] sulfide; (2-Methylphenyl) [2-trifluoromethyl-4-( E-((4-phenylpiperazin- l-yl )carbonyl) ethenyl)phenyl] sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-( -pyrrolidin-2onyl)propylamino)carbonyl) ethenyl)phenyl] sulfide; (2-Methylphenyl)[2-trifluoromethyl-4-( E-((cyclopropylamino)carbonyl)ethenyl) phenyl) sulfide; (2,4-Dichlorophenyl)[2-nitro-4.( E-((4-acetylpiperazin- I -yI)carbonyl)ethenyl)phenyl] sulfide; (2,4-Dichiorophenyl) [2-nitro-4-( -pyrrolidin-2-only)propylamino)carbonyl) ethenyl)phenyl] sulfide; (2,3-Dichlorophenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (4-Bromophenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -yI)carbonyl)ethenyl)phenyl] sulfide; (4-Methylphenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl)phenyl] 'sulfide; (2,4-Dichlorophenyl)[2-nitro-4-( E-((4-(Iert-butoxycarbonyi)piperazin- I -yl)carbonyl) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-nitro-4-( E-((4-(2-fliroylcarbonyl)piperazin-1I-yl)carbony1) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-nitro-4-( E-((4-(methanesulfonyl)piperazin- I -yI)ca rbonyl) ethenyl)phenyl] sulfide; (2,4-Dichiorophenyl) [2-nitro-4-( E-((4-(diethylami nocarbonylmethyl)piperazin- I- Yl)carbonyl) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-nitro-4,-( E-((4-(diethylaminocarbonyl)piperazin- I yl)carbonyl) ethenyl)phenyli sulfidle;' (2,4-Dichlorophenyl)[2-nitro-4-( E-((4-(Iert-butoxycarbonylmethyl)pperazin-
I-
yI)carbonyi) ethenyl)phenyl] sulfide; (2,4-D)ichlorophenyl)[2-nitro-4-( E-((4-(carboxycarbonyl)piperazin- I -yl)carbohyl) ethenyl)phenyl] sulfide; (2.4-bichlorophenyi)[2-nitro-4-( -(carboxymethyl)piperazin- I -yl)carbony'l) ethenyi)phenyl] sulfide; (2Mtypey) nto E-((4-acetylpiperazin-1I-yl)carboinyl)ethenyl)phenyl] sulfide;, (2-Chiorophenyl) [2-nitro E-((4-acetylpiperazin-l I-yl)carbonyl)ethenyl)phenyl].
sulfide; (2-Aminophenyl) [2-nitro-4-( E-7((4-acetylpiperazin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (2-Hydroxymet hylphenyl)[2-nitro.4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl) *phenyl )sulfide,- (2-Ethylphenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl)phenyl1] sulfide; (2-iso-Propylphenyl) [2-nitro-4-( E-((4-acetylpiperazin-1I-yl)carbonyl)ethe nyl)phenyl] sulfide; (2-kr-Butylphenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -y I)carbohyl)ethenyl )phenyl] sulfide; (2-Chlorophenyl)[2-chloro-4-( E-((4-acetylpiperazin- I -yl)carbonyl))2propenyl)phenyl] sul fide; -Morpholinylrnethyl)phenyl)[2-chloro-4-( E-(1-morpholinyl)carbonyl) ethenyl) phenyl] sulfide; I ,3-Benzodioxolyl-5-methyl)piperazin- I-'ylmethyl)phenyl) [2-chloro-4-( 1morpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2-(4-(iso-Propylaminocarbonylmethyl)piperazin- I -ylmethyl)phenyl)[2-chloro-4-( E- -morpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2-((N-Ethoxycarbonylmethyl-N-methyl)am-inomethyl)phenyl)[2-chloro-4-( 1morpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2-Formylphenyl)[2-chloro-4-( I-morpholinyl)carbonyl)ethenyl)phenyl] sulfide; (2-(4-Eormylpiperazin- I -ylmethyl)phenyl)f12-chloro-4-( 1 -morpholinyl)carbonyl) ethenyl)phenyl] sulfide; I-Morpholinyl)carbonyl)ethenyl)phenyl)[2-chloro-4-( I-morpholinyl) carbonyl)ethenyl)phenyl] sulfide; (2-Formylphenyl) [2-nitro-4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (2-Formylphenyl)[2-chloro-4-( I -rorpholinyl)carbonyl)ethenyl)phenyl] sulfide, N,N-dimethyl hydrazone; I-Morpholinyl)propyl)-l1-amino)phenyl) [2-chloro-4-( Imorpholinyl)carbonyl) ethenyl)phenyl] sulfide; (2,4-Dichlorophenyl)[2-bromo-4-( I pyrrolidlin-2-only)propylaio)carboflyl) ethenyl)phenyl] sulfide; (2,4-Dichiorophenyl) [2-formyl-4-( I-morpholi nyl)carbonyl)ethenyl)phelyl] sulfide; (-Chloro 6-fornylphenyl .)[2-chl .oro-4-( E-((4-acetylpiperazin- I -yl)carbonyl)ethenyl) phenyl) sulfide; (2-Cyanophenyl)[2-chloro-4-7( E-((4-acetylpiperazin- I-yl )carbonyl).
ethenyl) phenyl) sulfide; (2-Isopropylphenyl)[2-cyano-4-( E-((morpholin- I -yl)carbonyl) ethenyl) phenyl] sulfide; (2-Bromophenyl)[2-nitro-4-( E-((4-acetylpiperazin-1I-yI)carbonyl) ethenyl) phenyl] sulfide; (2-(.Pyrrolidin-I -yI)phenyl) [2-thloro-4-( E-((morpholin- I-yl)carbonyl) ethenyl) phenyl] sulfide; (2-Methoxyphenyl)- [2-chl oro-4(E- [(morphol in- I -yl)carbonyl) ethenyl)pheny]sulfide; sopropylphenyl)[2-nitro- 4 -carbomethoxypiperazin- 1-yl)carbonyl) ethenyl) pheny!] sulfide; (2-Methylphenyl)12-nitro-4-( E-((3-carboxamido-4-carbobelzoxypiperazifl-I yl)carbonyl)etheny.l) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro- 4 E-((2-carbomethoxy4te1-butoxycarbofllpiperazifl- 1 -yl)carbohyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)12-nitro- 4 E-((2-carboxy-4-ter-butoxycarbonylpiperazil- I1yl)carbonyl)ethenyl) phenyl) sulfide; (2-Isopropylphenyl)[2-trifluoromethyl-4-( E-((4-acetylpiperazin- 1 -yl)carbonyl) ethenyl) phenyl) sulfide;, 5(2-Isopropylpheniy1)2-trifluormethy1-4-( E-((morpholin -1 -yl)carbonyl) ethenyl) phenyl] sulfide; (2-Isopropylpheny)[2-trifluoronethyl4-(E-((3 -(pyrrolidil- 2 -on-I -yl)prop- 1ylamino)carbonyl) ethenyl)phenyl]sulfide;.
(2-Isopropylphenyl)[2-trifluoromethyl-4-( E-((cyclobutylamino)carbonyl) ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-trifluoromethyl- 4 E-((cyclopentylamino)6arbonyl) ethenyl) phenyl) sulfide; (2-Isopropylphenyl)[2-trifluoromethyl-4-( E-((5-hydroxypent- I -ylamino)carbo nyl) ethenyl) phenyl) sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((3-carbomethoxy-4-acetylpiperazifl- I yl)carbonyl)ethenyl) phenyl] sulfide; (2-Biphenyl)[2-chloro-4-( E-((morpholin- I -yI)carbonyl) ethenyl) phenyl] sulfide; (3 ,4-Dimethylphenyl) [2-nitro-4-(E-((4-acetylpiperazin- I yl)carbonyl)ethenyl)phenyl] sulfide; (2-Bromophenyl)[2-trifluoromethyl-4-( E-((4-acetylpiperazin- I -yl)carbonyl) ethenyl) ph enyl] sulfide; (5.-lndolyl)[2-chloro-4-( E-((4-acetylpiperazin-1I -yl)carbonyl) ethenyl) phenyl] sulfide; (5-Benzodioxolyl)[2-chloro-4-( E-((4-acetyl pi perazin- I -yl)carbonyl) ethenyl).phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-,( E?-((2-carbomethoxypiperazin- I -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- I1yl)carbonyl)ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-trifluoromethyl-4-( E-((4-(reri-butoxycarbonyl)piperazin- I yI)carbonyl)ethenyl) phenyl] sulfide; (2-(Pyrrolidin- I -yI)phenyl)[2-trifluoromethvl-4-( E-((4-(Ierlbutoxycarbonyl) piperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (3-Carboxamidophenyl)[2-nitro-4-( E-((4-acetylpiperazin-I1 -yI)carbonyl) ethenyl) phenyl] sulfide; (3-(Hydroxymethyl)phenyl) [2-nitro-.4-( E-((4-acetylpiperazin- I-yl)carbonyl) ethenyl) phenyl] sulfide; Phenyl [2-irifluorornethyl-4-( E-((4-(teri-butoxycarbonyl)piperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-trifluoromethyl-4-( E-((2-carbomethoxy-4-(teributoxycarbonyl)piperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-IsopropylphenyD)[2-nitro-4-( E-((3-(pyndine4-methylamilocarb~flyl)-4-terbutoxycarbonylpiperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)- [2-chioro-4(E- [(morpholin- 1 -yl)carbonyllethenyl)phenyl ]sulfide; (2-Methoxyphenyl)[2-litro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl)phenyllsulfide; (2.-(Azetidin- I -yl)phenyl)[2-trifluoromethyl- 4 E7-((4-QIertbutoxycarbonyl)piperazin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-(Piperidin- 1 -yl)phenyl)[2-trifluoromethyl-4-( E-((4-(terf-bultoxycarbonyl)piperazlfl- 1 -yl)carbonyl)etheny1l) phenyl], sulfide; (3-Chloro-2-formylphenyl)[2-chloro-4-( E-((4-acetylpiperazin- I -yl)carbonyl) ethenyl) phenyl) sulfide; (2-Trifluoromethylphenyl)[2-trifluoromethyl- 4 E-((4-acetylpiperazin- I -yl)carbonyl) ethenyl) phenyl] sulfide; (3-Bromophenyl) [2-trifluoromethyl-4-( E-((4-acetylpiperazin-1I-yI)carbonyl) ethenyl) phenyl] sulfide; (3 ,5-Dimethylphenyl) [2-trifluoromethyl-4-( E-((4-acetylpiperazin- I -yl)carbonyl) ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro- 4 E-((3-dimethylaminocarbonyl4-(pyridifle- 4 carbonyl)piperazin-1I-yI)carbonyI)ethenyl) phenyl], sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((3-dimethylaminocarbonyl-4carbomethoxypiperazin- I -yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-dimethylaminocarbonyl-4-ac Ietylpiperazin- 1 yl)carbonyl)ethenyi) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( -morpholinocarbonyl)-4-terzbutoxycarbonylpiperazin-1 -yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylpheny]) [2-nitroj-4-( E-((3-(pyridine-4-methylaminocarbonyl)piperazin-. 1 yI)carbonyl)ethenyi) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-(((3-dimethylaminocarbonyl)piperazin- 1 yI)carbonyl)ethenyl).phenyl] sulfide; (2-I1sopropylphenyl)[2-nitro-4-( E-((3-(benztylaminocarbonyl)-4-reributoxycarbonylpiperazin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( -(dimethylaminocarbonyl)-4- teributoxycarbonylpiperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2Boohnl[-clr--E( -IShdoyety-proii--n. -yl)pr Iop- 1ylamino)carbonyl) ethenyl)phenyl) sulfide; (2-Bromnophenyl)[2-chloro-4-(E-((3 -(pyrrolidi .n-2on- I -yI)prop- I -ylamino)carbonyl)' ethenyl)phenyl] sulfide; (2-Bronophenyl) [2-chloro-4-(E-(N-methyl-N-(3 -(pyrrolidin-2-on- I -yl)prop- I yl)amino)carbonyl) ethenyl)phenyl) sulfide; (2-[2-Methoxyjethoxyphenyl)- [2-chloro-4(E-[(mhorpholin- 1yl)carbonyl]ethenyl)phenyl] sulfide; (2-lsopropylpheny])[2-nitro-4-( E-((3-(morpholinocarbonyl)piperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylpheny1A[2-flitro- 4 E-((4-tert-butoxycarbofllpiperazifl- 1y!)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylpheny1)[2-nitro- 4 E-((4-methoxycarbonylpiperazinflI yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-litro-4-( E-(4-.(pyridine-4-carbofl)piper azinl 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylpheny)[2-litro- 4 -(pyridine-3-mrethylaminocarbonyl)- 4 -IerIbutoxycarbonylpiperazifl-l-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2-nitro-4-( E-(-prdie- ehl iocroy~iainyI)carbonyl)ethenyl) phenyl] sulfide; (2-1 sopropylphenyl)[2-nitro- 4 E-((3-(pyridine-.3-methylamilocarboflyl)Piperazin.7 *yl)carbonyl)ethenyl) phenyl] sulfide; (4-Hydroxyphenyl)[2-nitro-4-( E-((4-acetylpiperazin- I1y* y)carbonyl)ethenyl)phelyl]sulfide; .5-Dichlorophenyl)[2-nitrO-4-( E-((4-acetylpiperazin- 1-.
yl)carbonyl)ethenyl)phenly]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((3 -(5S-acetoxyrnethyl-pyrrolidil- 2 -ofl I-yI)prop- 1ylamino)carbonyl) ethenyl)phenyll sulfide; (2Boohnl[-hoo4(-(-5Smto mty-yrldn2o--yl)prop- 1ylamino)carbonyl) ethenyl)phenyl] sulfide, (2-Bromophenyl)[2clr- 8('-(RhdoIehl-yrldn2o- -yl)prop- 1ylamino)carbonyl) ethenyl)phcnyl]sulfide; Phenyl[2-nitro-4-( E-((4-acetylpiperazin-1 -yl)carbonyl)ethenyl)phenyl]sulfide;, (2-Dimethylaminophenyl)[2-nitro-4-( E-((4-Acetylpiperazin- 1 -yl)carbonyl) ethenyl) phenyl] sulfide; (3-((2-Hydroxyethyl)aminocarbonyl)phenyl) [2-nitro-4-( E-((4-acetylpiperazin- 1 yl)carbonyl)ethenyl) phenl sulfide; -lmidazolyl)propyl)aniinocarbonyl)phenyl)[2-nitro-4-( acetylpiperazin- 1-yI)carbonyl)ethenyl) phenyl] sulfide; I-Morpholinyl)ethyl)aminocarbonyl)phenyl)[2-nitro-4-( acetylpiperazin- 1 -yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-hydroxymethyl-4-tertbutoxycarbonylpiperazin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro.-4-( E-((4-formnylpiperazin- I -yi)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((2-hydroxymethy]-4-teributoxycarbonylpiperazin- I -yI)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)-[2-chloro-4(E-[(3-ethoxycarbonylpiperidin-1I-yl)carbonyl]ethenyl) phenyl]sulfide; Aminophenyl) [2-nitro-4-( E-((4-acetylpiperazin- 1 yl)carbonyl)ethenyl)phenyl]sulfide; (4-Aminophenyl)[2-nitro-4-( E-((4-acetylpiperazin- I yl)carbonyl)ethenyl)phenyl]sulfide; (2,4-Dimethylphenyl)[2- nitro-4-( E-((4-acetylpiperazin- Iyl)carbonyl)ethenyl)phenyl]sulfide;.
(2,5-Dimethylphenyl)12- nitro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl)phenyl]sulfide; (4-Methoxyphenyl)[2-nitro-4-( E-((4-acetylpiperazin-1 1yl)carbonyl)ethenyl)phenyl] sulfide; (3 -Chlorophenyl)[2-nitro-4-( E-((4-acetyipiperazin- I1yl)carbonyl)ethenyl)phenyllsul fide; (2-Chioro, 4,5-diaminophenyl)[2.-chloro-4-( E-((4-acetylpiperazin- I yl)carbonyl)ethenyl) phenyl] sulfide; (3,4-Diaminophenyl)[2-chloro-4-( E-((4-acetylpiperazin- 1-yI)carbonyl)ethenyl) phenyl) (6-Chlorobenzimidazol-2-on-5-yl)[2-chloro-4-( E-((4-acetylpiperazi-n-] yl)carbohyl)ethenyl) phenyl] sulfide; (1-Methylindol-7-yl)[2-chloro-4-( E-((4-acetylpiperazin-1 -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Hydroxy. 4-aminophenyl)[2-chloro-4-( E-((4-acetylpiperazin-1yl)carbonyl)ethenyl) phenyl) sulfide; (2-I sopropylphenyl)[2-nitro-4-( E-((4-methylpiperazin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-(pyridine-2-carbonyl)piperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-(pyridine-3-carbonyl)piperazin- 1I yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((2-carboniethoxy-4-methoxycarbonylpiperazin- Iyl)carbonyl)ethenyl) phenyl] sulfide; *(2-Isopropylphenyl)[2-nitro.4-( E-((2-carboxy-4-methoxycarbonylpiperazin- 1- YI)carbonyl)ethenyl) phenyl] Sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-carbomethoxy-4-methylpiperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin-l1 yl)carbonyl]ethenyl )phenyl] sulfide; (2-Ethoxyphenyl)-[2-chloro-4(E-[(3-carboxypiperidin- I -yl)carbonyl]ethenyl)phenylj sulfide; (2-Ethoxyphenyl)-[2-chloro-4(E-[(2-ethoxycarbonylpiperidin- I yl)carbonyl]ethenyl) phenyl]sulfide.
(2-Ethoxyphenyl)[2-trifluoromethyl-4-( I -terI-butoxycarbonyl)-4hydroxypyrrolidin-3'-ylamino)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)- [2-chloro-4(E-[(2-.carboxypiperidin-1I-yl)carbonyl]ethenyl)phenyl] sulfide; (2-Ethoxyphenyl)[2-,trifluoromethyl-4-( E-(((pyrrol-3-in- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((3-(pyrrolidin-;2-on-1I-yl)prop- 1ylarnino)carbonyl) ethenyl)phenyl] sulfide; 2 -FEthoxyphenyl)[2-trifluoromethyl-4(E((4-acetylpiperazin- -yl)carboniyl)etheflyl) phenyl] sulfide; (2Ehxpey)2tilooehl4-E(4(toyabnlpprzn yI)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)[2-trfluoromethyl-4(E((4-(2-frylcabonyl)piperzin- yl)carbonyl)ethelyl) phenyl] sulfide; (2-Ethoxyphenyl)-[2-choro4(E[(3ethoxycabonylpipeidin-1-yl)carbonyllethenyl)phenyl~sulfide; (2Ehxpey)-2clr -(-[4croyie idi--yI)carbonyl] ethenyl)phell.
sulfide; (Benzodioxan-6-y1A[2-chloro-A4( E-((4-acetylpiperazifl-I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-flitro- 4 E-((4-ethoxycarbonylpiperazinfl- yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl) [2-nitro-4-( E-((4-isopropoxycarbofllpiperazifl- yl)carbonyl)ethenyl) phenyl] sulfide;.
(2-Isopropylphenyl)[ 2 -nitro- 4 -(,E-((4-isobutoxycarbonylpiperazifl 1yl)carbonyletheny1) phenyl] sulfide; (2-Isopropylpheny.1)[2-flitro-4( 1 propen-2-oxy)carbonyl)piperazifl1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-flitro- 4 E-((4-propionylpipmrzifl- I -yl)carbonyl)ethenyl).
phenyl] sulfide; 36 (2-Isopropylphenyl)[2-nitro-4-( E-((4-parboxamidopiperazin- I -yl)carbonyl)ethenyl1) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-methyl .aminocarbonylpiperazin- 1yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-(pyrimidin-2-yl)piperazin- I1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-hydroxyacetylpiperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((4-(pyrazirie-2-carbonyl)piperazin- I yl)carbonyl),ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-trifluoromethyl-4-( E-(((2-carboxypyrrol-3-in- IyJ)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-7nitro-4-( -hydroxymnethyl-4-met~hylpiperazin- I yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2- trifluoromethyl-4-( E-(((2-carboxypyrrol-3 -in-Iyl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2-trifluoromethyl-4-( E-(((2-hydroxymethylpyrrolidin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl).[2-nitro-4-( E-((3-rnethylarninocarbonyl)piperazin- 1 yl)carbonyl)ethenyl) phenyl] sulfide; (2-1 sopropylphenyl)[2-nitro-4-( E-(((3-cyclopropylaminocarbonyl)piperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((3-carboxamidopiperazin- I -yl)qarbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((3-carbomethoxy-4-oxopiperidin- I yl)carbonyl)ethcnyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4( ,5-dimethylpiperazin-. 1 -yl)carbonyl)ethenyl) phenyl]. sulfide; (1 -Ethylindol-7-yl)[2-.chloro-4-( E-((4-acetylpiperazin- 1 -yl)carbonyl)ethenyl) phenyl] sulfide; (3-[2-Methoxyjethoxyphenyl)-[2-chloro-4(E-[(morpholin-I yl)carbonyl~ethenyl)phenyl] sulfide; (2-Bromophenyl) [2-chloro-4-(E-((4,4'-S-dioxythiomorpholin-1I-yl)carbonyl) ethenyl)phenylsulfide; (2-Bromophenyl)[2-chloro-4-(E -(N-carbomethoxymethyl-N-(3-(pyrrolidin-2-on- I1yl)prop- I -yl)amino)carbonyl) ethenyl)phenyl]sulfide; (2-Bromophenyl)[2-chloro-4-(E-((4-S-oxythiomorpholin- I -yl)-2pyrrolidinone)carbonyl) ethenyl)phenyl) sulfide; -chilorophenyl) [2-nitro-4-(E-((4-acetylpiperazin- 1 -yl)carbonyl)ethenyl) .phenyl] sulfide; (2-Isopropyiphenyl) [2-nitro-4-( E-((3-acetoxymethy )piperazin- I yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( ,5-dimethyl-4acetylpiperazin-,1 y])carbonyl)ethenyl) phenyl] sulfide; (1 -Methylindol-5-yl)[2-chloro-4-( E-((4-acetylpiperazin- 1-yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-nitro-4-( F-((4-acetylpiperazin- 1 -yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-nitr'-4-(-((-(pyrrOlidil-2-ofl- I -yl)prop- 1 -ylamino)carbonyl) ethenyl)phenylsulfidle; (BenzodioxAn-6-yl)[2-nitro-4-( E-((3I-c arboethoxypiperidin- I -yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-ylM2-nitro-4-( E-((4-carboethoxypiperidin- Il-yl) 'carbonyl)'ethenyl) phenyl) sulfide; (2-Ethoxyphenyl)[2-tifluoromethyl-4-(Z-((4-acetIpiperazil- I -yl)carbojnyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)[2-trifluoromethyl-4-(E-((6-methylpyrid-2ylamino)carbonyl )ethenyl) phenyl]. sulfide; (2-MethyI..3-chlorophenyl)[2-nitro-4-(E-((4-acetylpiperazil-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl) [2-nitro-4-( E-((3-carboxamidopiperidin- I -yl)'carbonyl)etheny 1) phenyl] sulfide; (Benzodioxan-6-yi)[2-nitro-4-( E-((2-carboethoxypiperidin- l -yl) carbonyi)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI)[2-nitro-4-( E-(4-carboxamidopiperidin- 1 -yl) carbonyl)ethenyl) phenyl] sulfide; 39 (Benzodioxafl-6-yl) [2-nitro-4-( E-((4-terI-butoxycarbonylpiperazifl- -yl) carbonyl)ethenyl) phenyl] sulfide; (2-Lsopropylphenyl)[2-nitro-4-( E-((syn-3 ,5-dimethylmorpholin- 1yl)carbonyl)ethenyl) phenyl) sulfide;' (2-Isopropylphenyl)[2-nitr6-4-( E-((anti-3 ,5-dimethylmorpholin- I1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro- 4 E-((3-carboethoxypiperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-,4-( E-((3-isopropoxycarbonylpiperazilf-.
yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( )(dimethylaminocarbony1)-4-methylpiperazifl 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3)-carbomethoxy-4-hydroxypiperidifl-l yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-hydroxymethyI-4-hydroxypiperidifl- I1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)[2-trifluoromethyl-4-( E-((2-carbomethoxy-4- (methoxycarbonyl])piperazin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-EthoxyphenylMt2-trifluoromethyl-4-( E-((2-carbomethoxy-4-methyl piperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)12-trifluoromethyl-4-( E-((2.-carboxy-4-(methoxycarboflyl)piperazifl- I -yl)carbonyl)ethenyl) phenyl] sulfide; (Indol-6-yl)[2-chloro-4-( E-((4-acetylpiperazin-1 -yl)carbonyl)ethenyl) phenyl] sulfide; (1 -Ethyl,3 -(dimethylaininomethyl)indol-7-yl)[2-cloro-4-( E-((4-acetylpiperazin- I1yl)carbonyl)ethenyl) phenyl] sulfide; (5-Ethoxybenzodioxari-6-yl)[2-chloro-4-( E-((4-acetylpiperazin-1I yI)carbonyl)ethenyl) phenyl]* sulfide; (2-Ethyl-4-bromophenyl)[2-nitro-4-(E-((4-acetylpiperazin- 1 -yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl) [2-nitro-4-( E-((2-carboxypiperi din-1 -yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-nitro-4-( E-((4-carboxymethylpipe .razin- 1-Yl) carbonyl)ethenyl) pheniyl] sulfide; (3-Morpholinophenyl)[2-nitro-4-(E-((4-acetylpiperazin- I -yI)carbonyl )ethenyl) phenyl] sulfide; (5.-Ethoxybenzodioxan-8-yl)[2-chloro-4-( E-((4-acetyl piperazin- 1 yl)carbonyl)ethenyl) phenyl] sulfide;, (5-Chloro-8-ethoxyquinolin-7-yI)[2-chloro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl) phenyl] sulfidle;.
(2-Isopropylphenyl)[2-nitro-4-( E-((3)-carboethoxypiperidin-1I-yI)carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-4-( -carboxypiperidin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( -ethanesulfonylailocarboflyl) Ipiperidifl 1yl)carbonyl)ethenyl) phenyl] sulfide; sopropylphenyl)[2-nitro-.
4 E-(((3-(4-methylpiperazine) sulfonylaminocarbonyl)piperidil-lI -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitio-4-( -p-toluenesuilfonylaminocarboflyl)piperidifl 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro- 4 E-((3-methyl-4-acetylpiperazifl- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Hydroxyphenyl)- [2-chloro-4(E- [(morpholifl I -yi)carbonyl]ethnyl)phel] sulfide (1 -(Carboxymethyl)indo-5-y)[2-chlOro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)12-trifluoromethyl- 4 E-((4-acetylpiperazin- 1yI)carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro- 4 I -pyrrolidin-2-6nyl)prop- I -ylamino) carbonyl)ethenyl) phenyl] sulfide; (3(-opoiotyaiopey)2tilooehl4(-(-ceypprzn
I-
yl)carbonyl)ethenyl) phenyl] sulfide; (2-Pyrroli din- 1 -ypey)[-ir--E-(-ctlieain I -yl)carbonyl)ethenyl) phenyl] sulfide; (3-Bromophenyl)II2-nitro-4-(E-((3 -carboethoxypyrrolidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (3-Bromophenyl)[2-nitro-4-(E-((4-carboethoxypyrrolidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-(Hydroxymethyl)-benzodioxan-6-yI)[2-chloro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)12-trifluoromethyl-4-(E-((3-(pyrrolidin-2-on.- 1 -yl)prop- I1ylamino)carbonyl) ethenyl)phenyl] sulfide;.
(3-(Dimethylaminomethyl)indol-5-yl)[2-chloro-4-( E-((4.-acetylpiperazin- 1 yl)carbonyl)ethenyl) phenyl] sulfide;* (2-Isopropylphenyl)[2-nitro-4-( E-((2-carboethoxypiperi din- I -yI)carbony],)ethenyl) phenyl] sulfidle; (2-lsopropylphenyl)[2-nitro-4-( E-((2-carboxypiperidin-1I-yl)carbonyl)ethenyl) phenyl] sulfide;.
(2-Isopropylphenyl)[2-nitro-4-( E-((4-carboethoxypiperidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((4-carboxypiperidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2-nitro-4-( E-(((4-p-toluenesulfonylaminocarbonyl)piperidin-1Iyl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E+(3 -carboxy-4-hydroxypiperi din- yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI) [2-trifluoromethyl-4-( E-((3-carboethoxypiperidin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( E-((2-carboethoxypiperidin- Il-yl) carbonyl)ethenyl) phenyl]) sulfide; (Benzodioxan-6-7yI)[2-nitro-4-( E-((4-carboxypiperidin- l-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) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( E-((2-carbomethoxy-4-terl.butoxycarbonylpiperazin- 1-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI)[2-trifluoromethyl4-(E-((2-carbomethoxy-4methoxycarbonylpiperazin- I -yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( E-((2-carbomethoxypiperazin- 1-yl) carbonyl)ethenyl) phenyl] sulfide; (2-Methyl-3)-(carboethoxymethyl)indol-5-yl) [2-trifluoromethyl-4-( E-((morpholin- 1yl)carbonyl )ethenyl) phenyl] sulfide; (I -(2-Methoxyethyl)indol-5-yl) [2-chloro-4-( E-((4-acetylpiperazin- 1 yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( -acetoxymethyl -4-hydroxypiperidin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E- ((3-(dimethylaminocarbonyl)-4-hydroxypiperidin- I -yl)carbonyl)dthenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-cyanomorpholin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2-nitro-4-( E-((3-carboethoxymorpholin- I -yl)carbonyl)ethenyl) phenyl) sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-(tetrazol-5-Yl)morpholin- yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl.4-( E-((4-carboxypiperidin- Il-yl) carbonyl)ethenyl).phenyl] sulfide; (Benzodioxan-6-yl)[2-trifiuoromethyl-4-( E-((2-carboxypiperidin- Il-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( E-((4-carbomethoxypiperazin- l-yl) carbonyl)ethenyl),phenyl] sulfide; (Benzodioxan-6-yl)[2-trifl uoromethyl-4-(E-((3'-aza-6,9-diooxaspiro[5 .4]decan,- Iyl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-67Yl)[2-trifluoroA4-(E-((4-(benzimidazolon. I-yI)piperidin- IyI)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan- 6 -yJ)[ 2 -trifluorometjiyl-4-(E-((4-(methylaminocarbonyl)piperidin- I yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( E-((3)-carbomethoxy-4methoxycarbonylpiperazin- Il-yl) carbonyl )ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-carboxymorpholin-l -yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl) [2-trifluoromethyl-4-( E-((2-carboxy-4-, methoxycarbonylpiperazin-I -yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6'yl)[2-trifluoromlethyI-4-(E-((morpholin-1 -yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI)[2-trifluoromethyI-4-(E-((4{pyrrolidifl I-yl)piperidin- 1yl)carbonyl)ethenyl) phenyl] sulfide; *(2-Isopropyiphenyl) [2-nitro-4-(E-((3-aza-6,9-diooxaspiro[S .4]decan- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2Iorplhnl[-ir--E((-dmtyaioehlpprdn 1- 1 0 yl)carbonyl)ethenyl) phenyl] sulfide; *(2-Isopropylphenyl)[2-nitro-4-(E-((piperidil- I -ylamino)carbonyl)ethenyl) phenyl] sulfide; (Benodixan6-y)[2triluoomehyl4-(E-((3-carboxy-4methoxycarbonylpiperazin- 1I-yl) carbonyl)ethenyl) phenyl] sulfide;, (2-(Dimethylaminocarbonyl)-bezodioxal-6-yi)[2-chloro- 4 E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl) phehyl] sulfide;; (2-I sopropylphenyl)[2-nitro- 4 -(2-(methoxymethyl)tetrazol-5-yI) piperidin- 1yl)carbonyl)ethenyl) phenyl] sulfide (2-Isopropylphenyl)[2-nitro- 4 -(methoxyniethyl)tetrazol-5-yl) piperidin- 1yI)carbonyl)ethenyl) phenyl] sulfide; (I -Methylindol-5-yl)[2-chloro-4-( 1 -pyrrolidin-2-onyl)propylamiino) carbonyl)ethenyl) phenyl] sulfide; 46 (2-Isopropylphenyl)[2-nitro-4-( I-(tetrazol-5-yl) piperidin-1I-yl)carbonyl)ethenyl) phenyl] sulfide; (1 -Methylindol-5-yl) [2-chloro-4-( E-((3-carboethoxypiperidin- 1-yl)carbonyl)ethenyl) phenyl] sulfide (1-Methyl indol-5-yI)[2-chi bro-4-( -carboxypiperidin- 1-yI)carbonyl)ethenyl) phenyl] sulfide; (I -Methylindol-5-yi)[2-chloro-4-( E-((4-carboethoxypiperidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (1 -Methylindol-5-yl)[2-chloro-4-( E-((3-carboxypiperidin- 1-yl)c'arbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-(E-((2-(lI-methylpyrrolidin- 2- Yl)ethylamino)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-(E-((4-(pyrrolidin- I -yl)piperidin- I -yl)carbonyl)etheniyl) phenyl] sulfide; (2-Isopropylphenyl) [2-nitro-4-(E-((4-sulfopiperidin- 1 -yl)carbonyl)ethenyl) phenyl] sulfide;, (2-Isopropylphenyl)[2-nitro-4-(E-((3)-hydroxypiperidin- Il-yl )carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-trifluoromethyl-4-( ((ethanesulfonylamino)carbonyl)piperidin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl) [2-trifluoromethyl-4-( toluenesulfonylamino)carbonyl)pI peri din- 1-yl) carbonyl)ethenyl) phenyl] sulfide; 47 (Benzodioxan-6-yl)[2-trifluoromethyl-4-( ((ethanesulfonylaminio)carbonyl)piperidin- 1-yl) carbonyl)ethenyl) phenyl) sulfide; (Benzodioxan-6-yl)f12-trifluoromethyl-4-(E-((2(tetrazol-5-yl)rnorpholin- 1ylocarbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitrco-4-( E-((2-butyl, 5-(tetrazol-5-yl)morpholin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-(and 3-)(Hydroxyrnethyl)-benzodioxan-6-yl)[2-nitrO-4-( E-((4-acetylpiperazin- I1yl)carbonyl)ethenyl) phenyl) sulfide; (2-(and _3 -)(Hydroxymethyl)- be .nzodioxa-6-yl)[~2-niitro-4-(E-((3-(pyrrolidin-2-on- 1yl)prop-1I -ylamino)carbonyl) ethenyl)phenyl )sulfide;.
(2-(and 3 -)(Hydroxymethyl)-benzodioxan-6-yI)[2-trifluoromethyl-4-(E-((3)- (pyrrolidin-2-on- I -yl)prop- I -ylamino)carbony!) ethenyl)phenyl) sulfide; (3-.Hydroxymethyl)-benzodioxan-6-yl) [2-nitro-4-(E-((3-(pyrrolidin-2-on- -I-l)prop- Iylamino)carbonyl) ethenyl)phenyl] sulfide-, (Benzodioxan-6-yl)[2-chloro-4-( E-((3-carboxypiperidin- I -yl)carbonyl)ethenyl) phenyl] (2-(and 3-)(Aminomethyl)-benztodioxan-6-yl)[2-trifluoromethyl-4-(E-((3.-(pyrrolidin- 2-on-I -yl)prop-1I-ylamino)carbonyl) ethenyl)phenyl]sul fide; (2-Isopropylphenyl)[2-nitro-4-( -(methylaxninocarbonyl)morpholin-lIyl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-(hydroxymethyl)morpholin- I1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3-(acetoxymethyl)morpholin- 1.yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-( E-((3)-(aminomethyl)morpholin- 1yI)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2-nitr6-4-( E-((3-(acetamidomethyl)morpholin- 1 yl)carbonyl)ethenyl).phenyl] sulfide; (Benzodioxan-6-yl)[2-chloro-4-(E-((3-(pyrroli din-2-on-1I-yI)prop- 1 ylamino)carbonyl) ethenyl)phenylsulfide; (Benzodioxan-6-yi)[2-chloro-4-( E-((3)-carboethoxypiperidin- ,I -yI) carbonyl).ethenyl) phenyl] sulfide; (Benzodioxan-6-yi)[2-chloro-4-( E-((2-carboethoxypiperidin- I.-yl) carbonyl)ethenyl) phenyl] sulfide (2-Methoxyphenyl)-[2.3-dichloro-4(E-[(morpholin-1I-yl)carbonyljethenyl)phenyl] sulfidle; (2-Methoxyphenyl)-[2,3 -dimethyl-4(E-[(morpholin- I -yl)carbonyl]ethenyl)phenyl] sulfide; *(2-Isopropylphenyl) indol-5-ylaminio)carbonyi )ethenyl) phenyl] *sulfide; (Benzodioxan-6-yl)[2-chloro-4-( -carboxypiperidin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-chloro-4- E-((3-(tetrazol-5-yl)piperidin- 1 -yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-chloro-4-( E-((4-QIeri-butoxycarbonyl)piperazin- I -yl) carbonyl)ethenyl) phenyl) sulfide; (Benzodioxan-6-yI)[2-chloro-4-( E-((2-carboxypiperidin- Il-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2-chloro-4-( -(tetrazol-5-yl)morpholin- l-yl) carbonyl)ethenyl) phenyl] sulfide;* (Benzodioxan-6-yl)[2-chloro-4-( E-((4-(methylaminocarbonyl)pipera zin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (2-Methoxyphenyl)-.[2,3:-dichloro-4(E-[(4-carboxypiperidin- 1-yl)carbonyl]ethenyl1) phenyl] sulfide; *.(Benzodioxan-6-yl)[2-chloro-4-( E-((4-(tetrazol-5 -yl)piperi din- Il-yl) carbon yl)ethenyl) phenyl] sulfide; (2-Methoxyphenyl)- [3 -ch]orO-4(E-[ (morpholin- I -yl)carbonyl]ethenyl)phenyl] sulfide; (2-Isopropylphenyl)[2-nitro-4-(E-((4-oxopiperidin- I -yl)carbonyl)ethehyl) phenyl] sulfide; *(Benzodioxan-6-yl)[2-trifluoromethyl-4-( '-R-carboethoxypiperidin- 1yI)carbonyl)ethenyl) phenyl] sulfide; (Benzodi'oxan-6-yl )[2-trifluoromethyl-4-( -R-ciirboxypiperidin- I yl)carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2,3-dichloro-4-(E-((3 -(pyrrolidin-2-on-1I-y ])prop- I ylamino)carbonyl) ethenyl)phenyl] sulfide; (Benodixan6-y) [23 -ichoro4-(E-((4-acetylpiperazin- 1 -yl) carbonyl)ethenyl) phenyl] sulfide; (Benziodioxan-6-yl)[2,3 -dichloro-4-( E-((3-carboethoxypiperidin- i-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2,3-dichloro-4-( E-((4-carboethoxypiperidin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI)[2,3-dichloro-4-( E-((3-carboxypiperidin- carbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yl)[2.3-dichloro-4-( E-((4-carboxypiperidin- I -yl) carbonyl)ethenyl) phenyl] sulfide; (2-lsopropylpheniyl)[2,3-dichloro-4-( I-pyrrolidin-2-onyl )propylamino) carbonyl)ethenyl) phenyl) sulfide;.
(2-lsopropylphenyl)[2,3 -dichloro-4-( E-((4-acetylpiperazin- Il-yl) carbonyl)ethenyl) phenyl] sulfide; (2-I sopropylphenyl)[2,3'-dichloro-4-( -carboethoxypiperidin- l-yl) carbonyl)ethenyl) phenyl].sulfide; (2-I sopropyiphenyl) [2,3-dichloro-4-( E-((4-carboethoxypiperidin- l-yl) carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2," )-dichloro-4-( E-((3)-carboxypiperi din- I -yl) carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2,3 -di chiloro-4-( E-((4m-caLrboxypiperidin- l -yl) carbonyl)qthenyi) phenyl] sulfide; (1 -Methylindol-5-yl)[2,3 -dichloro-4-( E-((3-carboethoxypiperidin-1-I-y) carbonyl)ethenyl) phenyl) sulfide; (I -Methylindol-5-yl)[2,3 -dichloro-4-( E-((3-carboxypiperidin- 1-yl), carbonyl)ethenyl) phenyl] sulfide;.
(1 -Methylindol -5-yl) [2,3-di chiloro-4-( E-((4-carboethoxypiperidin- l-yl) carbonyl)ethenyl) Phenyl] sulfide; (1 -Methylindol-5-yl)[2.3 -dichloro-4-( E-((4-carboxypiperidin- 1-yl) carbonyl)ethenyl) phenyl] sulfide; (2-Ethoxyphenyl)-[2,3-dichloro-4(E-[(4-carboxypiperidin- 1-yl)carbonyllethenyl.) phenyl] sulfide; (2-Ethoxyphenyl)-[2,3)-dichloro-4(E-[(morpholin- I -yl)carbonyl]ethenyl)phenyl] sulfide; (2.-Ethoxyphenyl)4-2,3-dichloro-4(E- [(3-carboxypiperidin- 1 -yl)carbony]]ethenyl) phenyl] sulfide; (2-lsopropylphenyl)[2-nitro-4-( E-((3-carboethoxypyrrolidin-1I-yl)car~bonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2-nitro-4-( E-((3)-carboxypyrrolidin- 1-yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropyiphenyl) [2,3 )-difluoro-4-( -carboethoxypiperidin- 1yl)carbonyl)ethenyl) phenyl] sulfide; (2-Isopropylphenyl)[2,.3 -difluoro-4-( E-((3-carboxypiperidin- I -yl)carbonyl)ethenyl) phenyl] sulfide; (2-I sopropylphenyl)[2.-difluoro4( E-((4-carboxypiperidin- I -yl)parbonyl)ethenyl) phenyl] sulfide; (Benzodioxan-6-yI)[2-trifluoromethy-4-(E-((3etoxycabonylpyroidinyI)carbonyl)ethenyl) phenyl] sulfide (Benzodioxan-6-yl)[2-trifl'uorornethylA..(E-((3..carboxypyrrolidin 1yl)carbonyl)ethenyl) phenyl] sulfide; 2 -Methbxyphenyl)[2-chloro-3trifluoromethyl.4-( E-((4-carboethoxypiperidin-I1 yI)carbonyl)ethenyl) phenyl] sulfide; (2-Methoxyphenyl) [2-chloro->-trifluoromethyl-4-( E-((4-carboethoxypiperidin- 1yl)carbonyl)ethenyl) phenyl] sulfide;.
2 -Methoxyphenyl)[2-chlofo-3-trifluioroimethy1A4( E-(morpholin- 1yl)carbonyl)ethenyl1) phenyl] sulfide; (Benzodioxan-6-y]) E-((4-carboxypiperi din- I -yl) carbonyl)ethenyl)naphthyl] sulfide; (2-Methoxyphenyl) [2,3 -dichloro-4-( E-((4-(spiro-hydantoin-5-yl)-piperidin-
I-
yl)carbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) [2,3 -dichloro-4-( E-.(4-(2-(2-hydroxyethoxy)ethyl)piperazin- 1yl)carbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl)[ 2,3-dichloro-4-( E-((4-ethylpiperazin- I1yl)carbonyl)ethenyl)phenyl] sulfide; (2-Isopropylphenyl)[ 2,3 -dichloro-4-( E-((4-(2-(2-hydroxyethoxy) ethyl)pipdrazin- 1 yl)carbonyl)ethenyl)phenyl] sulfide; (Benzodioxan-6y1)[2,3-bis(trifluoromethyl)-4-(-((4-carboxypiperidil- I yl)carbonyl)ethenyl)phenyl]sulfide; (2-Methoxyphenyl) [2,3-dichloro-4-(E-((4-(carboxymethylamino)carboflyl-piperldifl- I -yl)carbonyl)ethenyl)phenyl] sulfide; (2-Methoxkyphenyl) [2,3-bis(trifluoromethyl)-4-(E-((4-carboxymethylpiperazifl- -yl) carbonyl)ethenyl)phenyllsulfide; (2-Methoxyphenyl) [2,3-bis(trifluoromethyl)-4-(E-((4-N-(2-hydroxyethyl)piperazil- I -yl)carbonylI)ethenyl)phenyl] sulfide; [2,3-dichloro-4-( E-((4-(carbo-2,3dihydroxypropylamino)piperidin- 1-yl)carbonyl)ethenyl)pheniyl] sulfide; (2-Methoxyphenyl) [2,3-dichloro-4-(E-(4-(2,3)-dihydroxypropionyl)piperazil-1-.
yl)carbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) [2,3-dichloro-4-( -dihydroxy-3 carboxypropionyl )piperazin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (1 -Methylindol-5-yl) [2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonylpiperidin-1I-yl)carbonyl)ethenyl)phenyl] sulfide; (I -Methylindol-5-yl) [2,3-dichloro-4-(E-((4-sulfopiperidin- 1yl)carbonyl)ethenyl)phenyl] sulfide; (I -Methylindol-5-yI) [2,3-dichloro-4-(E-(4-methylhomopiperazin- 1ylcarbonyl)ethenyl)phenyl] sulfide; (1 -Methylindol-5-yl) [2,3-dichloro-4-(E-(4-tetrohydrofuroylpiperazin- 1yl)carb6nyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) 2 3 -dichloro-4-(E-((4-amino-4-carboxypiperidin-l-1 yl)carbonyl)ethenyl)phenyl] sulfide; 2 -Methoxyphenyl)[2,,3-dichloro.4-((4.ffroylpiperazin- I -yl)carbonyl)ethenyl)phenyl] sulfide; (]I-Methylindol-5 -yl) [2,3-dichloro-4-( E-( 4 -(carbo-3-sulfopropylanino)piperadinyI)carbonyl)ethenyl)phenylJ sulfide; (2-Methoxyphenyl)[ 2.3-dichloro-4-( E-( 4 -acetylamino-4-carboxypiperidinylcarbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) 2 3 7bis(trifluoroniethyl)-4-(E-((4-carboxypiperidin-. 1 y])carbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) 5-[ 8 4 -(amninocarbonyl)piperidin-
I-*
yl )carbonyl)ethenyl)quinoiinyl) sulfide; (2-Methoxyphenyl) 2 -trifluoromethylA4-(E-((4-carboxypiperidin-.
yl )carbonyl)ethenyl)phe'nyl] sulfide; (1 -Methylindol-5-yI).[ 2,3-dichloro-4-( 1 S,4S)-2,5-diazabycyclo(2,2.I )heptan- 2 -ylcarbonyl)ethenyl)-2,3-dichlorophenyl] sulfide; (I -Methylindol-5-yl) [2,3-dichloro-4-( E-(4-hydroxy-3 -carboxypiperadin-
I-
ylcarbonyl)ethenyl)phenyl] sulfidle;; (I -Methylindol-57Y]) [2,3-dichiloro-4-( E-(S-oxothiomorpholin-1 ylcarbonyl)ethenyi)phenyl]. sulfide; (2-Methoxyphenyl) [2,3-dichloro-4-( sulfophenylamino)carbonyl)ethenyl)phenyl] sulfide; (2-Methoxyphenyl) [2,3-dichloro-4-( carboxyphenylamino)carbonyl)ethenyl)phenyl] sulfide; and [3-(4-Morpholino)phenyl] [2,3-dichloro-4-(E-[(4-carboxypiperidin- 1yl)carbonyl]ethenyl)phenyl] sulfide.
Pharmaceutical Compositions and Methods of Treatment 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.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
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, 56 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.
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.
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.
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.
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.
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-acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, binders such as. for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, humectants such as glycerol, disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, solution retarding agents such as paraffin, absorption accelerators such as quaternary ammonium compounds, wetting agents such as, for example, cetyl alcohol and glycerol monostearate, absorbents such as kaolin and bentonite clay, and lubricants such as talc, calcium stearate, magnesium stearate, solid 58 polyethylene. glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
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.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceuticallyacceptable 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 59 sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
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, agaragar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable nonirritating 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.
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 multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, 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.
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.
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- 61 toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized 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 phosphoricacid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of 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.
62 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-acceptable 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.
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 particularcompound, 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.
Generally dosage levels of about 0.1 to about 50 mg, more preferably of about 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.
Preparation of Compounds of the Invention 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.
Scheme 1 (CsHo A (.coo Ac ONR1R2 Ars CH3) "acetate Ars (HCH) A
(H.CH)
A CHOI base HO equivaleOH 1.a on CONRR 2 H solvent base.solvent 2. RRNH R R 7R" (optional 2 hydrlysis 3 4 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 2-chlorobenzaldehyde, 3-chloro,4fluorobenzaldehyde, or the like) in the presence of base sodium carbonate, triethylamine, or the like) and a polar solvent 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 64 example using thionyl chloride, or dicyclohexylcarbodiimide and Nhydroxysuccinimide, or the like) and reacted with a primary or secondary amine (for example, 6-amiinohexanol, 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.
Scheme 2 X X COOH 1. activaon X CONRR 2 ArSH ArS CONRR 2 2. 1 RR 2 NH. basesolvent Rn Rn01 ,N Rn 7 Alternatively, the order of these coupling steps may be reversed (Scheme 2).
A substituted halocinnamic acid 5 3-chloro-2-nitrocinnamic acid or the like) may be coupled with a primary or secondary amine 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.
Scheme 3
R
2
RN
activation
R,
of alcohol RR 2
NH
HO S
OR-
CONCONRRRR
2
SS
&S R2
XR
RONONRR
2 0CHO 1:'1CONRR.
R, 0 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 morpholine, N-formylpiperazine or the like) provides analogs with structures related to9. Alternatively the alcohol may be oxidized (for example using TPAP or PCC or the like) to give aldehyde Scheme 4 12 R RR R S X S(0) R CONRR2 11 13 Rs 15 NRsR, S HNR 5 R6 rY /I R SCONR,R, pd
CONRR
14 Pd(O) R 16 Cinnamides like 13 may be prepared from halo-substituted derivatives 11 by palladium-mediated coupling using tetrakis (o-tolyl phosphine) palladium Pd,(dba) 3 or the like] with acrylamide derivatives 12 (Scheme In similar manner, anilino-cinnamides like 16 can be prepared by palladium-mediated coupling of amines with halo-cinnamides 14.
N Os NO 2 S U^^-CONRR 2 17 Scheme s NH 2 S X IH] if-T- yi RONO
CONRR,
2 M+ CONRR 2 18 19 In some cases, functional groups on the aromatic rings can be modified to produce new analogs (Scheme 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.
Scheme 6 ROO ~S R3
ROOC--
CONRIR
2 x R P 2 1 I-EWG base -S R
EWG
CONRR,
21 X Pd 0 or NiO catalyst EWGjr R -1117CONR'R 2 22
CONRR
2 R4 23 It is also possible to assemble cinnamide-substituted diaryl sulfides in a "reverse" sense (Scheme Thus, for example, compound 20, prepared as described in Scheme 1, may be deprotected by treatment with base potassium t-butoxide or the like) to provide thiolate anion 21, which may be reacted with an activated haloarene 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 aryl bromide or Aryl iodides) using a metal-catalyzed Ullman coupling procedure (for example, using a palladium or nickel catalyst) to give product 23.
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 amides 31.
68 Scheme 7
YOCH-
3 RBr 2 HO~2~R~ CH HO 2 Pd 2 (dba) 3
.(TOI)
3
P
-&Br 24 25 T1 2 0 TfO ,1 Pyridine OCH 3 0
C
H1 A OCH 3 0 26.
CsF 27, ArBr, Art or ArOTf TIPS-S H. KH -0 Pd(PPh 3 4
TTHF
ArSi Ar-S OCH 3 0 29 basic Ar-St.
:R
hydrolysis -A OH 0 as In Scheme 1
R,
Y N.R4 *.0 31 A method for preparing cinnamides bearing two arylthio groups is outlined in.
Scheme 8. Commercially available difluoro cinnamic acid 32 was coupled with an aminme, using standard conditions, and this derived amide 33 was reacted with excess aryl thiol to provide the bis-sulfide 34.
F F 1. (COCI) 2
DMF
AAOH,
2. R 2
NH
0 Scheme 8 F F R ArSH 0s00 ArS
SNA
N.
R
0 34 Compounds which contain trifluoromethyl groups on the cinnamide-portion of inhibitors were made by the method shown in Scheme According to the method of.
69 XXX (Ref), Diels-Alder reaction between 1,1,1 ,4,4,4-hexafluoro-2-butyne and 2methylfuran led 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.
Scheme 9
CF
3 FC 0
BF
3 OEt 2 HO
.YCF
CH
3 F3C- CF3 F
C-
F
3 C 36 36 CF3
CF
3 1. TfzO or PhNTf 2 ArS C F 3 1. NBS HO CF 3
A
DMSO 2. ArSH, Cs2C 3
CHO
heat
CHO
37 38 as in Scheme 1
CF
3 .ArS CF 3 CONRaR 4 39 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.
Scheme amnide coupling Ar' S1
OH+
0
H
N
s -NH 41 0 *42
BOC
2 0
NI-
0
(RCO)
2 O 2K OH P. Fr NHCOR 0 NaOH A2ry OHr 0 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+ hydroyzedto afford hydroxy acid 47.
Scheme I1I
OH
0
HNKI
P0CIH A'Sj&2 amnide coupling N C0 2
CH,
0 i) LiOHITHF/H 2 0 ii) NaBH 4
CO
2
H
0 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 SScheme 12 R1 R "RI ArA KC02H RNH 2 Ar 2
'NHR
I N CO 2 H amide coupling A NJ O 0 48 49
R
48
"H
2 N OCH3 R O R 0 2 i V N'jCO2H amide couplin A N C 2
H
2. NaOH O Inhibitors bearing substituted piperazine (or homopiperazine) cinnamides may 0 10 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 with an aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride).
Scheme 13 S 0 ArS J& R 2 NH RCO 2 H, coupling ArSRN N R N^J) n or RCOCI N n 0 0 51 52 Ar' R 2 NH RCHO ArS 2 NR rNS )n NaBH(OAc) 3 Ar- n 0 0 51 51 53 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. 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.
Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-7370). The NR3R 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.
73 Scheme 14 x SH If1 aic, -CI OCH 3 catalysis .0 54 27
HNR
3
R
4
R
4 RN).S OH Pd(O) catalyst 0~ OH X ~SKR OCH 3 As in Scheme 1
SI,
Ell NRR 6 0
EXAMPLES
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)r2-( 6 -hvdroxvhexvlamino)carbonvl)ethenvl)phenvl] sulfide Example 1A 2 -r( 2 4 -Dichlorophenvl)thiolbenzaldehvde 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 2chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture was then heated under nitrogen atmosphere at 70 °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-Dichlorophenvl)thiocinnamic acid 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 0.80 mmol) in 8.0 mL of anhydrous pyridine was heated at 110 *C for 2 hours. Gas evolution ceased during this period.
Pyridine was then removed under vacuum. Water and 3N aq. HCI 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-Dichlorophenvl)r2-( E-((6-hydroxvhexvlamino)carbonvl)ethenyl)phenyl1 sulfide A suspension of the acid (284 mg, 0.87 mmol) from Example lB in 5 mL of methylene chloride was stirred with (COCl), (84 pL, 0.97 mmol), and one drop of DMF under nitrogen atmosphere for 90 minutes. The solvent was then removed under vacuum. The residue (COC1) 2 was removed with benzene (2x) in vacuo. To a separate flask, previously filled with 6-amino-1-hexanol (12 mg, 0.10 mmol), Hunig's base (22.8 pL, 0.13 mmol) and DMAP (1.1 mg, 0.008 mmol) in 2.0 mL of CHCI,, the acid chloride (30 mg, 0.087 mmol) in 1.0 mL of CH,C1l was then dropped in slowly. After 30 minutes, the reaction mixture was poured into 3N HCI and extracted with ethyl aceetate (EtOAc). The organic layer was washed with brine, dried with Na,SO,, 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. 'H NM IR (CDCI 3 300 MHz) 6 1.31-1.48 (in, 4H), 1'.48-,1.70 (mn, 4H), 3.37 J= .6.7 Hz, 2H), 3.65 J~ 6.3 Hz, 2H), 5.63 (br s, I1H), 6.3 6 J~ 15.9 Hz, I 6 .71 J 9.3 Hz, I 7.05 (dd, J 2.4, 8.7 Hz, I 7.3 1-7.49 (in, 4H), 7.65 (dd, J= 2.1, Hz, I 7.99 J= 15.9 Hz,. IH). MS (DC1/NH3) (M+NH 4 at m/z 441, 443), 445.
Example 2 (2.4-DichlorophenylM[2-( I-imidazolvl)propyvlamino)carboniyl).
ethenvl~phenyll sulfide The. title compound was prepared by the procedures described in Example IC substituting 6-amino-i -hexanol with I -(3-aininopropyl)imidazole. White powder; 1
A
NMR (d 6 -DMSO, 300 MHz) 6 1.88 J =7.7 Hz, 2H), 3.11 J= 7.7 Hz, 2H), 3.97 7..7Hz, 2H), 6.63 15.9 Hz. 1H).6.70 8.7 Hz, IN), 6.89.(d.J =0.9 Hz, 1H), 7.17 0.9 Hz, lH), 7.'3(dd. J= 2.7. 8.7 Hz, H),'7.46-7.65 (in.4H), 7.72 2.7HzIH), 7.78 15.9 Hz, 7.80 J= 8.7 Hz, lH), 8.24 (t,J =5.9 Hz, I MS (DCIJNH 3 at rnz 448. 450, 452. Analysis calculated for
C
2
,H,,N
3
,CI
2 S,-0.87 H 2 56.3 0; H, 4.67; N. 9.3 8. Found: C, 56. 30; H, 4.5 6; N, 9.27.
Example 3 (2,4-Di chi oroohenyl) )2-chl oro-4-( E-((2-hvdroxyethylanino)carbonyl) ethenyl)nhenyll sulfide The title compound was prepared by the procedures described. in Example I substituting 2-chlorobenzaldehyde with 3-chloro-4-flUOro-benzadehyde, and 6-amnino- I-hexanol with ethanolamine. Colorless oil; 'H NMR (CDCl 3 300 MHz) 8 3.57 J 7.65 Hz, 2H), 3.71 7.65 Hz, 2H), 6.06 (brs, IH), 6.40 (d,J.=15.3 HzIH), 6.9.6(d,J= 8.7 Hz, IH), 7.22-7.30(in, 4H), 7.49-7.60 (in, 7. 5(d,J= 15.3_' Ht, IH). MS (APCI) at m/z 4 02,+ 404, 406, 408. Analysis calculated for
C,
7
H,
4
N,O
2
CI
3 S,-0.25H 2 O: C, 50.14; H, 3.59; N, 3.44. Found: C, 50.16; H. 3.62; N, 3.29.
Example 4 (2..4-Dichloropjheny1'~f2-ch]6ro-4-( E-((6-hydroxyheky]Amino)carbonvl') ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde with. 3-chlo ro-4-fluoro-benzadehyde. Colorless oil; 'H NMR (CDCIj, 300 MHz) 5 1.42 (in, 4H), 1.58 (in, 4H), 3.40 J= 6.7 Hz, 2H), 3.65 (br m, 2H), 5.60 (br t, IH), 6.35 J= 15.3 Hz, IH), 6.98 J 8.7 Hz, 1H), 7.22-7.3 0 (in, 4H), 7.49-7.60 (in, I 7.5 5 J= 15.3 Hz. I MS (APCI) at rn/z 458, 460, 4162, 464. Analysis calculated for C,,H 22 NOC13S,-0.27HO: C.
54.39; H, 4.90; N, 3.02. Found: C, 54.40; H, 4.85; N, 2.71.
Example (2.4-Dichlorophenyl) r2-chloro-4-( E-((bis-(2-hydroxyethyl)amino)carbonvlI ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde, with 3)-chloro-4-fluoro-benzadehyde, and 6-amnino- I1-hexanol with diethanolamnine. Colorless oil; 'H NMR (CDCl 3 300 MHz) 6 2.99 (br s, 2H), 3.67 (hr m, 4H), 3.88 J 5.1 Hz, 2H), 3.94 J 5.1 Hz, 2H), 6.94 J 15.3 Hz, I 6.97 J1=8.7 Hz, I 7.21-7.32 (in, 3H), 7.50-7.5 4 (in, 7.58 (d, J =2.4 Hz, I 7.5 8 J 15.3 Hz, I MS. (APCI) at m/lz 446, 448, 450, 452. Analysis calculated for C, 9 H,,N,0 3 C1 3 IS~I .09H2O: C, 48.93; H, 4.36; N, 3.00.
Found: C, 48.88; H, 4.00; N, 3.01..
Example 6 (2,4-Di chi orophenyl) 2-chloro-4-( I wnrrolj di n-2- only)propvlamito)carboflyl') ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde with 3)-chloro-4-fluoro-benzadehyde, and 6-amino- 1-hexanol with 1-(3-aminopropyl)-2-pyrrolidinone. Colorless oil; NMR (CDCI13, 300 MHz) 6 1.74 (qu, J= 6.0 Hz, 2H),,2.09 (qu, J= 7.5 Hz, 2H), 2.45 J 8.25 Hz, 2H), 3.33 J= 6.0 Hz, 2H), 3.42 (qt J~ 8.25 Hz, 4H), 6.46 J 15.6 Hz, IlH), 7.02 J= 8.7 Hz, I 7.14-7.23 (mn, 2H), 7.30 (dd, J= 2.4, 8.7 Hz, I 7.51 J =2.4 Hz, I1H), 7.51 J' 15.6 Hz, I 7.60 J=2.1 Hz, I MS (DCINH 3 at m/z 483, 485, 487, 489. Analysis calculated for C 22
H,
1 N,O-,Cl 3 ,S,-0.57HO: C, 53.48; H, 4.52; N, 5.67. Found: C, 53.49; H, 4.60; N, 5.65.
79 Example 7 (2,4-DichlorophenylMr2-chloro-4-( -mnorholinyl)carbonyl)ethenvl)phenylI sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and:6-amino- I1-hexanol with morpholine. White solid; 'H NMR (CDCI 3 300 MHz) 5 3.59-3.80 (in, 8H), 6.83 J 15.6 Hz, iH), 6.97 J 8.7 Hz, I 7.16-7.32 (mn, 3H), 7.49-7.53 (in, I 7.5 9 J 2.4 Hz, I 7.5 9(d, J 15.6 Hz, I MS (DCI/N.H 3 at m/z 428, 430, 432, 434. Analysis calculated for C 19
H,
6
NOCI
3 S,0.46H 2 0: C, 52.22; H, 3.90; N, 3.20. Found: C, 52.20; H, 3.76; N, 3.12.
Example 8 (2.4-Di chi orophenyl) r2-chloro-4-( E-((4-methylpiperazin- I -yl)carbonvl) ethenyl)nhenyl] sulfide The title compound was prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino- 1 -hexanol with 1 -methylpiperazine. Colorless oil; 'H NMR (CDC,300 MHz) 5 2.37 3H), 2.51 (br in, 4H1), 3.63-3.87 (br m, 4H), 6.85 J 15.6 Hz, lH),*6.98 J= 8.7 Hz I 7.19-7.25 (mn, 2H), 7.27 (dd, J 2.1, 8.7 Hz, I 7.52 J 0.9 Hz, 7.57 J= 15.6 Hz, IlH), 7.60 J1=2.1 Hz, I1H). MIS (DCI/NH 3 at m/z 441, 443, 445, 447. Analysis calculated for C, 0
H,
9
N
2 OC1 3 S,-0.45H 2 O: C, 53.39; H, 4.46; N, 6.23. Found: C, 53.37; H, 4.46; N, 6.07.
Example 9 (2.4-Dichiorop~henyl) r2-chloro-4-( E-((4-acetvlpiperazin- 1 -l)carbonvl) ethenyl)phenvll sulfide.
The title compound was prepared by the procedures described in Example 1.
substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde. and 6-ammno- I1-hexanol with I1-acetylpiperazine. White solid; 'H NMR (CDCI 3 300 MHz) 8 2.15 3H), 3.50-3.58 (in, 2H), 3.58-3.85 (in, 6H), 6.85 J= 15.3 Hz, 18), 6.96 J 8.7 Hz, IH), 7.24-7.36 (mn, 3H), 7.54 J= 2.4 Hz, IH), 7.61 15.3 Hz, 1H), 7.61 J= 2.1 Hz, I MS (DCIINH 3 at m/z 486, 488, 490, 492! Analysis calculated for 9
N
2 Cl 3 S-0.85H,O: C, 51.99; H, 4.30; N, 5.77. Found: C, 52.03; H, 4.27; N, 5.167.
Example (2.4-Dichlorophenyl) [2-chloro-4( E-((4-(2-pyridyl)Diperazin- I -vl)carbonyl) ethenyl)phenyll sulfide The title compound was. prepared by the procedures described in Example 1 substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6.-amino- I -hexanol with 1 -(2-pyridyl)piperazine. White sol id; 'H NMR (CDCI.,, 300 MHz) 8 3.59 (br in. 2H), 3.69 (br m, 2H), 3.78 (br mn, 2H), 3.86 (br m, 2H), 6.64-6.72 (in, 2H).
6.90 J= 15.6 Hz, I 6.99 J= 8.7 Hz, I 7.22-7.25 (in, 2H), 7.3 1 (dd, J 2.4, 8.7 Hz, I1H), 7.49-7.5 7 (in, 2H), 7.61 J= 15.6 Hz, I 7.62 J= 2.4 Hz, 81 8.19-8.24(in, I MS (DCIINH 3 4 at m/z 504, 506, 508, 510. Analysis calculated for C, 4 H2 0
N
3 0IC1 3 C, 57.10; H, 3.99; N, 8.32. Found: C, 57.12; H, 4.06; N, 8.29.
Examle Il (2-(Hydroxymethylhlhenl)[2-chloro-4-( I -morpholinyl)carbonvl) ethenvl)phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-mercaptobenzyl alcohol, 2chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino-l-hexanol with morpholine. White solid; 'H NMR (CDC1 3 *3 00 MHz) 8 3.50 -3.62.(br m, 6H), 3.65-3.74 (br mn, 2H), 4.54 J 5.7 Hz, 2H), 5.3 3 J 5.7 Hz, I 6.62 J 8.7 Hz, lH), 7.28 15.0 Hz, lH), 7.36 J 7.8 Hz, I 7.42 J 15. 0 Hz, IH), 7.43 (dd, J= 1.8, 8.7 Hz, lH). 7.50 (dd. J= 2.1, 8.7 Hz, IH), 7.55 (dd. J= 2.1, 7.8 Hz,' lH), 7.68 (dd J= 1.5,.8.1 Hz, I 8.02 J 2.1 Hz, I MS (DCIJNH 3 at m/lz 390, 392. Analysis calculated for C, 0
H,
0
N
1 O3C'IS -0.09H,0: C: 61.35; H, 5.20; N, 3.5 8. Found: C, 61.3 7; H, 5.4 8; N. 38 1.
Example 12 (2-Bromophenyl) r2-chloro-4-( I-morpholinv] )carbonyl) ethenvl)phenvil sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro.-benzadehyde, and 6-ainino-l-hexanol with morpholine. White solid; 'H NMR (d 6 -DMSO, 300 MHz) 6 3.50-3.66 (br m, 6H), 3.66-3.79 (br m, 2H), 7.05 J= 8.7 Hz, lH), 7.26 (dd, J= 2.1, 8.1 Hz, I 7.33 (dd, J1 2.1. 8.1. Hz, 1H), 7.36 15.6 Hz, 1H), 7.39 (dd,J= 1.8, 12.0 Hz, IH), 7.45 (dd,J= 1.8.6.3 Hz, 1 7.48 J 15.6 Hz, IH), 7.64 (dd, J 2.1, 8.7 Hz, I 7.80 (dd, J 2.8, 8.7 Hz, I 8.09 J~ 2.1 Hz, IlH). MS (DCI/NH 3 at m/z 43 8, 440, 442.
Example 13 (2,4-Di chilorophenyl)fr2-chloro-4-( E-((4-(2-hvdroxvethyl)piperazin-1I-yl)ca rbonyl) ethenyl~phenvll sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde. and 6-amino- 1-hexanol with 1-hydroxyethylpiperazine. Colorless oil; 'H NMR (CDC1.,. 300 MHz) 8 2.85-3.20 (br m. 6H), 3.8 4-4.19 (in, 6H), 6.80 J= 15.3 Hz, I 6.94 J =8.7 Hz, I 7.22-7.38 (mn, 3H), 7.50-7.56 (in, IlH), 7.56-7.62 I 7.60 J 15.3 Hz, I1H). MS (DCI/NH.
3 at m/z 471, 473), 475, 477.
Example 14 (2,4-Dichlorophenyl) [2-chloro-4-( E-((4-(2-hydroxyethoxyethyl)piperazin- I yIhcarbonyl) ethenyl)12henvil sulfide The title compound was prepared by the procedures described in Example I substituting 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amnino- I1-hexanol with 1-[2-(2-hydroxyethoxy)ethyl]piperazine. Colorless. oil; 'H NMR (CDC13, 300 M z) 8.2.73 (br mn, 6H1), 3.58-3.68 (in, 2H4), 3.68-4.00-(in, 814), 6.84 J =15.3 Hz, I H),.6.97 J 8.7 Hz, I 7.20-7.34 (in, 3H), 7.54 J 7.5 Hz, I1H), 7.58 J~ 15.3 Hz, 1 7.5 8-7.65 (overlapping d, I1H). MS (DCT/NH 3
(M+H)
4 at, m/z 515, 517, 51.9, 52 1.
Example (2-Bromophenyl)[2-chloro-4-( -(hvdroxymnethyl)pjiperi din- I -vl)carbonyV) ethenvl)p~henyll sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde.
with 3-chloro-4-fluoro-benzadehyde, and 6-amino- I -hexanol with 3hydroxyinethylpiperidine. 'H NMR (DMSO-d 6 300OMHz) 6 8.07 J= 17.7 Hz, I1H), 7.80 J= 7.7 Hz, I 7.63 (br d, J= 7.7 Hz, I 7.44 J= 7.0 Hz, 7.40 (br s, 2H), 7.35 (in, 111), 7.25 (dd 7.7, 1.5, IH), 7.06 (dd, J= 8.1, 1lH), 4.5 7 (in, I1H), 4.45 (in, I 4.16 (brin, 2H), 1.2 1.8 (in, 8H). HIRMS calculated for
C
2 2 S ,BrCI,: 466.0243.* Observed: 466.0247.
Example 16 (2-Bromophenyl)[2-chloro-4-( E-((2-(hydroxymethyl )piteridin- 1I-vI )carbonvl) 84 ethenyl)phenyll sulfide The title compound was prepared by the procedure .s described in Example 1 substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with 2-.
hydroxymethylpiperidine. NMR (DMSO-d 6 300OMHz) 8 8.03 (in, I 7.79 J 78Hz, 1H), 7.61 (mn, I1H), 7.3 0- 7.45 (mn, 4H1), 7.23 (in, I 7.07 (in, I 4.79 (mn, 2H), 4.61 (mn, 2H), 4. 10 (in, I1H), 1.50 (in, 6H). HRMS calculated for
C.,,H
21 N OS, Br, CI1: 466.0243 Observed: 466.0247.
Examnle 17 (2-Bromophenyl)[2-chloro-4-( E-((3-acetainidopyrrolidin- I -vI)carbonyl) ethenyl')phenyll sulfide* The title compound was prepared by the procedures described in Example I.
substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-flu oro-benzadehyde, and 6-amino-1I-hexanol with 3acetarnido pyrrolidine. 'H NMR (DMSO-d 6 300MHz) 8 8.14 (in I 8.07 (dd, J 9.8, 1.7 Hz, I1H), 7.80 7.8 Hz, IH), 7.64 (dd. J=8.1, 1.7 Hz, I 7.25 -7.47 (in, 4H1), 7.10 J 7.8 Hz, iNH), 7.03 (dd, J 8.1.1.7 Hz, INH), 3.45 4.34(m, 6H), 2.02 (mn, 2H4), 1.81 (ap d, J= 1.4 Hz, IH). HRMS calculated for C,,H, 0
N
2 0 2 S,BrCl 1 479.0196. Observed: 479.0183.
Example 18 (2-Bromophenyl)[2-chloro-4-( E-((4-hydroxypiperidin- I -vI)carbonyP) ethenvl)vhenll sulfide 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-benzadphyde, and 6-amino-l -hex anol with 4hydroxypiperidine. 'H NMR (DMSO-d 6 300MHz) 8 8.08 J =1.7 Hz, 1 7.80.
(dd, J 8.0, 1.5 Hz, I 7.63 (dd. J 8.3, 1.9 Hz, I 7.44 (ap dd, J 7.5. 1.4 HzI 2H1), 7.40 (ap d, J= 3.7 Hz, 2H), 7.34. (dt, J= 1.8 Hz, I 7.25 (dd, J= 7.5'51.7 Hz I 7.05 J 8.1 Hz, I1H)7 4.76 (br s, I 4.01 (in, 2H), 3.72 (in, I1H), 3.12 (mn, IH), 1.75 (in, 2H), 1.32 (in, 2H). HRMS calculated for C,,H,4N,O,S,B rCI,: 452.0087. Observed: 452.0076.
Example 19 (2-Bromophenyl)[2-chloro-4-( E-((Piperidin-1I-vI)carbonvl) ethenyl)rphen,,, 1 sulfide The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino-1-hexanol with piperidine. 'H NMR (DMSO-d 6 300MHz) 6 8.08 J 1.7 Hz, 11H), 7.80 (dd, J 8.1, 1.4 Hz, IH), 7.63 (dd,J= 8.1, 1.7 Hz, 11H), 7.44 (ap dd, J= 7.6, 1.5 Hz, 1H), 7.39 (ap d. J= 4.8 Hz, 7.34 (dt, J 7.5, 1.6, 1 7.24 (dd. J 1.7, 1 7.05 J 8.1 Hz, I 3.65 (br in, 2H), 3.53 (br m, 2H), 1.62 (br in. 2H1), 1.50 (br in, 4H). HRMS calculated for C 20
H,
9
N,S
1 Br,Cl,: 436.0130. Observed: 436.0122.
(2,4-Dichlorophenyl)[2-chloro-4-( E-((3-carboxypiperidin- I -yl)caibonyl) ethenyl~phenyll sulfide The title compound was prepared by the procedures described in Exam ple 1 substituting 2-chlorobenzaldehyde with 3 -chloro-4-fluoro-benzadehyde, and 6-amino- I -hexanol with nipecotic acid. Colorless oil; 'H NMR (CDC1 3 300 MHz) 5, 1.44 -1.68 (br m, 1.68-2.00 (br m, 2H), 2.51-2.67 (br m, I 3.13 37 (br m, I1H), 3.8 0- 4.12 (br m, IH), 4.30-5.00 (br m, 3H), 6.86 J= 15.3I Hz, 6.99 J.=8.7 Hz, IN4), 7.16-7.24 (in,2H), 7.29 Hz, IH), .47-7.55(in. IH), 7.55 15.3 Hz, 1H), 7.60 (br d, I MS (APCI) at m/z 470,.472. 474. 476.
Example 21 Dichlorophenyl)r2-chloro-4-( E-((4-carboxypiperidin- 1 -l)carbonyl) ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 27chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino-, I -hexanol with isonipecotic acid. Colorless oil; 'H NMR (CDCI_,, 300 MHz) 8 1.68- 1.85 (in, 2H), 1.98-2.09 (in, 2H), 2.60-2.72 (in, IN), 2.90-3.13 (br in, 3.7-3.38.
(br in, I 3.93-4.12 (br in, I 4. 38-4.59 (br m, IH), 6.86 J 15.3 Hz, IH),.
6.99 (dd,J= 8.7 Hz, IH), 7.20-7.25 (in, 2H), 7.28 (dd, J= 1.8, 8.7 Hz, IH), 7.49-7.53 87 (in 7.56 J= 15.3 Hz, I 7.60 J= 1.8 Hz, I MIS (APCI) at m/z 470, 472, 474, 476.
Example 22 (2-Bromo]2henyl')[2-chloro-4-( E-((4-acetylhomopiperazifl- I -yl~carbon"l' ethenyl)phenyfl sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amino-I -hex anol with 4acetylhomnopiperazine. 'H NMR (DMSO-d 6 300MHz) 8 8. 10 (in, I1H), 7.81 J 7.7 Hz, 1H4), 7.64 (in, 11H), 7.24 -7.51 (in, 5H), 7.05 (in, IH), 3.39 -3.77 (in, 8H), 1.97 (in. 3H1), 1.68 (mn, 2H). HRMS calculated for C,,H,,N 2 0 2 S,BrCI,: 493.0352.
Observed: 493.0352.
Example 23 (2-Bromonhenyl)2-choro-4-( E-((thioinomthblin- I -yl)carbonyl)ethelyl)phenyjI, sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-broinothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehy de, and 6-amino-1I-hexanol with thiomorpholine. 'H NMR (DMSO-d 6 300MHz) 8 8. 10 J~ 1.5 Hz, I 7.80 J'8.5 Hz, I 7.64 (dd, J 8.1,.1.5 Hz, I 7.31 -7.48 (mn, 4H), 7.36 (mn. I1H).- 7.26 (dd, J 1.8 Hz, I 7.05 (d J= 8.1 Hz, I 3.96 (in, 2H), 3.82 (in, 2H), 2.62 (in, 411). FIRMS calculated for C 19
H,
7
N,O,S
2 Br,C1 1 455 9681. Observed: 455.9676.
Example 24 (2-Bromophenvl)[2-chloro-4-( I-beniimidazol-2-only)piperidin-I yl~carbonvl) ethenyi~hhenvl] sulfide The title compound was *prepared by the procedures described in Example 1 substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3-chloro-4-fluoro-benzadehyde, and 6-amnino-1I-hexanol with 4 -benziinidazol- 2-only)piperidine. 'H NMR (DMSQ-d 6 300MHz) 88.14 1.5 Hz, 1H), 7.80 (dd, J= 7.9, 1.3 Hz, 1H), 7.67 (dd, J=8.1*,1.8 Hz-, IN)7.48 (ap s,2H), 7.44 (dt.,J= 1.2, 1IH), 7.34 (dt, J 7.6, 1.6, 11H)1 7.26 (dd J= 7.7, 1.8 Hz. I H),.7.22 (in, I H)7 7.06 J= 8. 1, 1 6.97 (ap d, J= 2.6, 3 4.64 (in, I 4.48 (in, 2H), 2.79 (in, 2H), 2.29 (in. 2H1), 1.78 (in, 2H). HjRMS calculated for C,- 7 H,-3N.,OABr,C1,: 568.0,461.'Observed: 568.0477.
Example (2-Bromophenyl)[2-chloro-4-( E-((2-tetrahvdroi sociuinolinyl)carbonyl) ethenvl)phenyll sulfide 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. 'H NNIR(DMSO-d 6 300MHz) 88.12 J=7.4Hz, 1H), 7.81 (dd, J= 7.7, 1.1 Hz, I 7.67 (dd, J 8.3, 1.3 Hz, I 7.47 (in, 2H), 7.43 (dd, J 1.3 Hz, 2H), 7.34 (dt J= 7.6, 1.7 Hz, I 7.27 (d 7.7 Hz, I1H), 7 .19 (in, 4H), 7.05 J 8.1 Hz, I1H), 4.92 I1H), 4.72 I 3.95 J1 5.9 Hz, I1H), 3.78 J =5.7 Hz, 11H), 2.89 (ti J=5.3 Hz, 1H), 2.83 J=3.7, I1H). HRMvIS calculated for
C,
4
H,
9 N,0.,S,Br,C 1 484.0138. Observed:. 484.0128.
Examvle 26 (2-Methylphenyl)[2-trifluoromethvl-4-( E-((4acetylpiperazin- I -vI)carbonyl) ethenvl)phenyll sulfide The title compound was prepared by the procedures described in Example 1.
substituting 2,4-dichiorothiophenol with 2-inethyithiophenol. 2-chlorobenzaldehyde with 4-fluoro-3'-trifluoroiethylbenzadehyde.. and 6-amino-l-hexanol with Iacetylpiperazine. 'H NMR (CDC 1 300MHz) 8 7.79 I 7.63 J 15.4Hz..
1H); 7.51 J 6.8 Hz, IH), 7.41-7.333 (mn. 3H); 7.28 (in, 1H); 6.83 J =15.4 Hz, IH); 6.79 J =6.8 Hz, I 3.80-3.60 (in. 6H); 3.57-3.50 (in, 2H); 2.34 3H); 2.14 3H). MIS (ESI) m/lz 919 (2M+Na).t 897 471 449 Example 27 (2-MethylpheniMl2-trifluoromethvl-4-( -morpholinyl)carbonyl) ethenvl)iphenvll sulfide The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-methyithiophenol, 2-chlorobenzaldehyde With 4-fluoro-3)-trifluoromethylbenzadehyde, and 6-amino-1-hexanol with morpholine. 'H NMR (CDCl 3 300MHz) 8 7.79 l1H); 7.63 J =14.0 Hz, IH);.
7.52 J 7.6 Hz, I1H); 7:40-7.30 (in, 3H); 7.28 (in. I1H); 6.87 J 14.0 Hz, I H); 6.84 J 7.6 Hz, I 3 .73 (br s, 8H); 2.34 3H). MIS (ESI) ni/z 837 (2M+ Na)+, 815 408.(M+HYI.
Example 28 (2-Methylphenyl)[2-trifluoromethyl-4-( -morpholin LI)ethvlamino)carbonvl) ethenyl)phenyll sulfide The' title compound was prepared -by th e procedures described in Example. 1 substituting 2,4-dichiorothiophenol with 2-methyithiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde, and. 6-amino- I-hexanol with 2-(1 morpholinyl)ethylamine. 'H NMR (CDCI3, 300MHz) 857.80 I 7.56 J 15.8 Hz, I 7.50 J =8.1 Hz, I 7.40-7.32 (in, 3H); 7.28 (in, I 6.79 J =15.8 Hz, I 6.40 J =8.1 Hz, I1H); 3. 75 J =4.6 Hz, 4H); 3.51 J =5.5 Hz, 211), 2.57 J =5.8 Hlz, 2H); 2.55-2.48 (mn, 4H); 2.34 3H). MIS (ESI) in/z 923 473 451 Exampnle 29 (2-Methvlpheny l)r2-trifluoromethvl-4-( E-((4-phenylpi perazi n-i -yl)carbonylI 91 ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-methyithiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-I -hexanol with 4phenylpiperazine. 'H NMR (CDC1 3 300MHz) 8 7.81 IlH); 7.64 J =16.0 Hz, 1H); 7.51 8.2 Hz, 1H); 7.40-7.27 (in, 6H); 6.98-6.90 (mn, 4H); 6.8.0 J =8.2 Hz, I 3.88. (br s, 4H); 2.23 (br s, 4H); 2.34 3H). MS (ESI).nm/z 987 (2M+Na)', 965 505 483 451.
Example (2-Methylphenyl)[2-trifluoromethyl-4-( E-041( -pyrrolidin-2only)pro~ylamino)carbonyl) ethenvl)phenyll sulfide The title compound. was prepared by the procedures described in Example I substituting 2,4-dichiorothiopeo wt2-methyithiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-l-hexanol with Ipyrrolidin-2-only)propylamine. 'H NMR, (CDC13, 300MHz) 8 7.78 11H); 7.53 J =15.6 Hz, I1H); 7.49 J =7.2 Hz, I 7.40-7.3 3 (in, 3H); 7.14 (mn, I 6.80 J= 8.2 Hz, I 6.43 J 15.6 Hz, I 3.41 (in, 4H); 3.32 J 6.1 Hz, 2H); 2.43 (t, J =6.6 Hz, 2H); 2.34 3H), 2.08 (mn, 2H), 1.75 (in, 2H). MS (ESI) m/lz 947 (2M+Na) 4 925 485 463 92 Example 31 (2-Methylphenyl)[2-trifluoromethyl-4-( .E-((cycloipropylamino)carbonyl) ethenylhphenyll sulfide The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-methyithiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde. and 6-arnino-1I-hexanol with cyclopropylamine. 'H NMR (CDCI 3 300MHz) 8 7.76 I 7.56 J 15.4 Hz, IlH); 7.50 J =8.4 Hz, I 7.40- 7.30 3H); 7.28 IH);i 6.8 8 J =8.4 Hz, I1H);-;6-30 J =15.4 -Hz, I1H); 5.70 (br s, I1H), 2.95 (in, I1H); 2.34 0.85.(in, 2H); 0.57 (in, 2H). MS (ESI) rn/z 777 755 (2M+H)4, 400 378 Example 32 (2.4-Dichiorophenyl) r2-nitro-4-( E-((4-acetvlpiperazin- I -vI~carbonyl) ethenyl)]2henyll sulfide Example 32A I -Chloro-2-nitro-4-( E-((4-acetylpiperazin-1-I y)carbonyl)ethenyl) benzene To a stirred solution of trans- 4-chloro-3)-nitrocinnamic acid (1.50 g, 6.59 minol) and 1-acetylpiperazine (0.89 g, 6.94 inmol) in 20 mL of DMF at room temperature was added EDAC (1.4 g, 7.30 minol). The mixture was then stirred, at room temperature for 2 hours. TLC indicated the complete consumption of the acid. Water 93 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 OC to give 2.04 g (6.03 mmol. 91.6 of the title compound.
Example 32B (2.4-Dichlorophenvl)r2-nitro-4-( E-((4-acetylpiperazin- -yl)carbonvl) ethenyl)phenvll sulfide 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. 'H NMR (d-DMSO, 300 MHz) 8 2.05 3H), 3.42-3.50 (br m, 4H).3.50-3.64 (br m, 2H), 3.64-3.79 (br m, 2H), 6.83 J= 8.7 Hz, 1H), 7.44 J= 15.3 Hz. 1H), 7.55 J= 15.3 Hz, IH), 7.63 (dd, J= 2.7, 8.7 Hz, 1H), 7.83 8.7 Hz, 1H). 7.93 J= 8.7 Hz, 1H), 7.96 J= 2.7 Hz, 1H), 8.69 J= 1.8 Hz, 1H). MS (DCI/NH 3 at m/z 497, 499, 501. Analysis calculated for C2,H,,N.O 4 C1 2 S,-0.82HO: C, 50.94; H, 4.20; N, 8.49. Found: C, 50.91; H, 4.21; N, 8.69.
Example 33 (2,4-Di chi orophenvl) r2-njtroA-( E-041( -pvrrolidin-2-onlv)propylamino)carbonyl) ethenvl~phenyll sulfide The title compound was prepared by the procedures described in Example 32 substituting I -acetylpiperazine with I -(3-amninopropyl)-2-pyrrolidinone. Light-yellow powder; 'H NMR (d'-DMSO, 300 MI-z) 8 1.64 7.1 Hz, 1. 91 J Hz, 2H), 2.21 J= 8.3 Hz, 2H), 3.15 J= 6.3 Hz, 2H), 3.21 (dd, J~ 9.9, 17.7 Hz, 2H), 3 .3 2 (overlapping t, J 8.4 Hz, 2H), 6.72 J 15.6 Hz, I 6.86. (d9 J= 8.7 Hz, I H)7 7.46 J 15.6 Hz, I 7.63 (dd, J 2.4, 8.1 Hz, I1H); 7.79 -(dd,J 2.4, 8.7 Hz, I 7.84 (d J= 8.7 Hz, I1A), 7.96 J 2.4 Hz, I 8.18 J 6.0 Hz, I 8.46 J 2.1 Hz, I MS (DCI/NH.
3 .at m/lz 494, 496.
Example 34 (2.3-Dichlorophenyl)r2-nitro-4-( E(4-acetylpi perazin-I -Yl)carbonyl) ethenyl~p henyll sulfide The title compound was prepared by the procedures described in Example 32B substituting 2,4-dichlorothio'phenol with 2,3-dichlorothiophenol. Light-yellow powder; 'H NMR (d'-DMSO, 300 MHz) 5 2.04 3H), 3.42-3.50 (br m, 4H), 3.50- 3.64 (hr m, 2H), 3.64-3.79 (br m, 2H), 6.88. J =8.7 Hz, I 7.45 J =15.6 Hz, 1IH), 7.55 J 7.65 Hz, I 7.57 J= 15.6 Hz, I H),'7.78 (dd, J= 1.8, 8.1 Hz, I 7.8 7 (d d, J= 1. 8, 8.1 Hz, I 7.95 (dd, J 9.0 Hz, I1H), 8.69 J= 1.8 Hz, I MS (DCI/NHI) at m/z 497, 499, 50 1.
Example (4-BromophenylMf2-nitro-4-( E-((4-acetylpiperazin-1I-vI )carbonyl)ethenyl')phenvll sulfide The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichiorothiophenol with 4-bromothiophenol. Light-yellow powder; 'HA NMR (d 6 -DMSO, 300 MHz) 8 2.04 3H), 3.47 (br m, 4H), 3.52 (hr m, IH), 3.60 (br m, 3.68 (hr m, I 3.74 (hr mn, IH), 6.90 J=8.7 Hz. 1H). 7.43 J 15.0 Hz, I 7.54 J 15.0 Hz, 1 7.5 8 J 9.0 Hz, 2H), 7.78 J 9.0 Hz, 2H), 7.92 (dd, J= 2.1, 9.0 Hz, I 8.65 J=2.1 Hz, I MS (DCI/NH 3
(M+H)
4 at m/lz 507, 509.
Examplee36 (4-Methyiphenyl) r2-nitro-4-( E-((4-acetylpiperazin- I -yl)carbonvl)ethenvl)vhehyl] sulfide The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichiorothiophenol with p-thiocresol. Light-yellow powder; 'H N4MR (d 6 -DMSO, 300 MHz) 8 2.04 3H), 2.39 3H), _3 .47 (hr m. 4H1), 3.52 (hr m, IH), 3.60 (br m, IlH), 3.68 (hr m, I 6.89 J 8.7 Hz. 1 7.20 J 8.1 Hz, I H), 7.39 J 8.4 Hz, 2H), 7.40 J 15.0 Hz, 1 7.53 (di, J1 15.0 Hz, I 7.54 (di, J=8.4 Hz, 2H), 7.89 (dd,.J 2.1, 8.7 Hz, I1H), 8.64 J=2.1 Hz, I MS
(DCI/NH
3
(M+NH
4 at rn/z 443.
Example 37 (2.4-D~ichiorophenyl) r2-nitro-4-( E-((4-(tert-butoxycarbonyl)piperazin- I-yl)carbonvl) ethenyl phenyll sulfide The. title compound was prepared by the procedures described in Example 32 substituting 1 -acetylpiperazine with iert-butyl piperazine carboxylate. Light-yellow powder; 'H NMR (d 6 -DMSO, 300 MHz) 8 1.42 9H),.3.36 (overlapping m, 4H), 3.55 (br 3.70 (br m, 2H), 6.83 J= 8.7 Hz, 1H), 7.42 15.6 Hz, I H), 7.54. J 15.6 Hz, I 7.63 (dd, J 2.4, 8.4 Hz, I 7.83 J 8.7 Hz, 111), 7.92 (dd, J 2.4, 8.7 Hz, I 7.96 J= 2.7 Hz, I 8.68 J 2.4 Hz. I MS (APCI) (M+H) 4 at m/z 538, 540. 542.
Example 38 (2.4-Dichlorophenvl~r2-nitro-4-( E-((4-(2-furoylcarbonyl)pinperazin-1I-yl)carbonyl) ethenvl)phenyll sulfide Example 38A (2.4-Dichl orophenvl)[-nitro-4-( E(piperazin-l1-yl)carbonyl) ethenvl)phenyll sulfide.
Trifluoroacetic Acid Salt The compound (100 mg, 0. 186 mm ol) from Example 37 was dissolved in 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-Dichlorophenvlf2-nitro-4-( E-((4-(2-furoylcarbonyl)piperazin- I -vl~carbony]) ethenvl)phenyll sulfide to a stir-red solution of piperazine TFA salt (35 mg, 0.067 mnmol) from Example 3 8A in 2.0 mL of MH.CI, was added Et 3 N (23 pL, 0. 17 mmnol), 4dimethylaminopyri dine (D MAP) (1.0 mg, 0.0082 mmol), and furyl chloride (8.0 p.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-I 18 column, 75030 mm S-5 pM, 120 A, and a flow rate of 25 ML/min, X=2 14, 245 rn; mobile Phase A, 0.05 M NHOac, and B, CHCN; linear gradient 100% of B in 20 minutes to give the title compound (24 mg, 67%) as light-yellow powder; NMR (d'-DMSO, 300 MHz) 8 3.62-3.87. (br mn, 8H), 6.66 J1 2.1 Hz,.
I 6.84 J 8.7 Hz, I 7.04 J=.3.3 Hz, I1H), -7.44. J =15.3 Hz, IlH), 7.56 J= 15.3 Hz, I Hy. 7.63 (dd, J= 2.4, 8.1 Hz, I 7.83 J~ 8.4 Hz, I 7.8 7 (d, J= 2.1 Hz, I 7.92 (dd, J 2.1, 12.0 Hz. IlH), 7.96 J~ 2.1 Hz, IlH), 8.70 J= 2.1 Hz, I MS (APCI) at m/lz 532. 534, 536.
Example 39 (2,4-Dichlo rophenvl')r2-nitro-4-( E-((4-(methanesulfonyl)niperazin- I-vl)carbonyl) ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example 3-8B substituting furoyl chloride with methanesulfonyl chloride. Light-yelflow powder; 'H NMR (d 6 -DMSO, 300 MHz) 8 2.90 3H), 3.25 (br rn, 4H), 3.68 (br m, 2H), 3.83 (br.
mn, 2H), 6.84 J= 9.0 Hz, IH), 7.45 J= 15.6 Hz, I 7.56 J 15.6. Hz, I1-H), 7.63 (dd, J= 2.4, 8.7 Hz, IlH), 7.83 J 9.0 H-z, I 7.93 (dd, J 2.1, 9.0 Hz, 1 H), 7.95 J 2.7 Hz, IlH), 8.70 J~ 2.1 Hz, I MS (ESI) at m/z 516,:518, 520..
Example (2.4-Dichiorophen .yl) [2-nitro-4-( E-((4-(diethylaminocarbonvlniethyl)piperazin- 1 yl)carbonyl) ethenvl~phenyll sulfide The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with 2-chloro-NN-diethylacetainide. Light-yellow powder; 'H NMR (d'-DMSO, 300 MHz) 8 1.01 7.2 Hz, 3H), 1. 13 J= 7.2 Hz, 3H), 2.46 (br mn, 4H), 3.16 2H), 3.24 J= 7.2 Hz, 2H), 3.37 J= 7.2 Hz, 2H), 3.56 (br m, 2H), 3.69 (binm, 2H), 6.83 J 9.0 Hz, IlH). 7.46 J 15.3 Hz, I H), 7.52 J= ~~15.3 Hz, I 7.62 (dd, J= 2.4, 8.7 Hz, I 7.82(d 9. H,1),7 2 (dd, J= 2.1, 9.0 Hz, I 7.95 J 2.7 Hz, I 8.67 J= 2.1 Hz, IlH). MS (ESI)
(M+NH
4 y- at m/z 573, 575, 577.
Example 41 (2A4-Dichlorophenyl)[2-nitro-4-( E-((4-(diethylaminocarbonyl)piperazin- 1- Yl')carbonyl) ethenyl~phenyll sulfide The title compound was prepared by the procedures described in Example 38B substituting furoyl chloride with NN-diethylcarbamyl chloride. Light-yellow powder; 'H NMR (d 6 -DMSO, 300-MHz) 8 1.06 J= 6.9 Hz, 6H), 3.12 (hr m, 4H), 3.15.(q, J =6.9 Hz, 4H), 3.5 8 (br mn, 2H), 3 72 (hr m, 6.83 J= 8.7. Hz, I1H), 7.42 J= 15.6 Hz, INH), 7.5 3 (d3,J= 15.6 Hz, I 7.63 (dd, J 2.7, 9. 0 Hz, IlH), 7.82 J 8.7 Hz, INH), 7.92 (dd, J 2.4, 8.7 Hz, I1H), 7.95 J 2.7- Hz, IlH), 8.68 J= 2.1 Hz, I M S (APCI) at m/z 5 37, 5 39,154 1.
Example 42 (2,4-DichlorophenylYr2-nitro-4-( E-((4-(teri-butoxvcarbonylri-ethyl)pinerazin- I -VPD carbonyl)ethenyl)pbenyll sulfide The title compound was prepared by the procedures described in Example 38B substituting CH,CL, with CH 3 CN as solvent, and furoyl chloride with lert-butyl bromoacetate. Light-yellow powder; 'H NNMR (CDC13, 300 MHz) 5 1.47 9H), 2.70 (br m, 4H), 3. 21 2H), 3.74 (hr m. 2H), 3.82 (hr mn, 2H), 6.73 J= 8.7 Hz, I H), 6.92 J 15.0 Hz, I 7.39 (dd, J= 2.4, 8.7 Hz, INH), 7.47 J 8.7 Hz, IlH), 7.61 J =15.0 Hz, I 7.62 J =2.4 Hz, I 7.66 J =8.7 Hz, INH), 8.43 (hr d, 1 MS (APCI) at m/z 552, 554, 556.
Example 43 (2.4-Dichiorophenyl) r2-nitro-4-( E-((4-(carboxycarbonyl~piperazin-1I-yl)carbonyl) ethenyl)12henyl] sulfide Example 43A (2.4-Dichlorophenyl)[2-nitro-4-( E-((4-(carbethoxycarbonyl)piperazin- I -vl)carbonvl) ethenyl)vhenvll sulfide 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-(carboxvcarbonyl)piperazin- I -vl~carbonvJ) ethenyl)vhenyll sulfide.
To a stirred solution of the ethyl ester (40 mg, 0.074 mmol) from Example 43A in 2 rnL of ethanol was added saturated LiON (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 HCI. The precipitates were collected through filtration, washed with cold water, dried under vacuum to give the titled compound (30 mng, 79%) as light yellow solid. 'H NMR (d 6 -DMSO. 300 MHz) 5 3.52 (brmi, 4H), 3.62 (brmi, 2H), 3.76 (br m, 2H). 6.84 J 9.0 Hz, IN), 7.46 J= 15.3 Hz,1IH), 7.56 J 15.3 Hz. IlH). 7.63 (dd, J 8.7 Hz. I H), 7.83 J= 9.0 Hz, I1H), 7.93 J 9.0 Hz- I 7.96 J= 2.7 Hz, INH). 8.70 (br d, INH). MS (APCI) (M-COO)" at n/z 466, 468. 470.
101 Example 44 (2,4-Dichlorophenyl)[2-nitro-4-( E-((4-(carboxymethyl)piperazin- I -Vl)carbonvl) ethenvl~henyll sulfide The title compound was prepared by the procedures described in Example 38A substituting compound from Example 37 with compound from Example 42. Lightyellow powd er; 'H NMR (d'-DMSO, 3 00 MHz) 8 3.14 2H), 3.40 (overlapping br m, 4H), 3.44 (br m, I 3.51 (br m, I 3.5 7 (br m, I 3.71 (br m, I 6.82 J =8.7 Hz, IHF), 7.42 J 15.6 Hz, I 7.52 J= 15.6 Hz, 11H), 7..63 (dd,J 2.4, 8.7 Hz, I 7.83 J 8.7 Hz, I 7.92 (dd, J=2.4, 8.7 Hz, I 7.96 (d,J =2.4 Hz, I 8.68 J 2.4 Hz, I MS (APCI) at m/z 496, 498, 500.
Example (2-Methylphenyl')r2-nitro-4-( E-((4-acetylpiperazin- I -YI)carbonvl) ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example.32 substituting 2,4-di chiorothiophenol with o-thiocresol. Light-yellow powder; 'H NMR (d 6 -DMSO, 3 00 MHz) 8 2.03 3H), 2.29 3H), 3.47 (br m, 4H).3.53 (br m. -1H), 3.60 (br m, lH), 3.67 (br m, -IH1), 3.83 (br m, IH), 6.64 J= 8.7 Hz, 11H). 7.40 J =15.0 Hz, 11H), 7.36-7.42 (in, IH), 7.46-7.57 (in, 3H), 7.63 J= 6.9 Hz. IH), 7.89 (dd, J 2.4, 9. 0 Hz, I ,8.66 J= 2.4 Hz, MS(APCI) atrn/z426.
Example 46.
(2-Chlorophenyl)[2-nitro-4-( E-((4-acetylpiperazin- I -vl~carbonvl~ethenvlDhhenyll sulfide The title compound was prepared by the procedures described, in Example 32 substituting 2,4-dichiorothiophenol with 2-chiorothiophenol.. Light-yellow powder; 'H NMR (d 6 -DMSO, 300 MHz) 5 2.04 3H), 3.47 (br m, 4H), 3.52(br m, I1H), 3.60 (br m, I 3.68 (br m,l 3 .73 (brm, I 6.75: J 9.0 Hz, I 7.43 J 15.3 Hz, I1H). 7.54 1=15.3 Hz, I 7.55 (dd, J= 1.8,:8.1 Hz, I 7.64 J= 1.89,8.1 Hz, I 7.76 J 1. 8, 8.1 Hz, I1H), 7.82 J= 1. 8, 8. 1 Hz, I 7.93 (dd, J 2.4, Hz, I 8.68(d, J= 2.4 Hz., IlH). MIS (APCI) at m/z 446, 448,.450.
Example 47 (2-Aminophenyl) [2-nitro-4-( E-((4-acetylpilperazin- I -vl)carbonvl~ethenyl)Phenvll* sulfide The title compound was prepared by the pro cedures described in Example 32 substituting 2,4-dichiorothiophenol with 2-aminothiophenol. Light-yellow powder; 'H NMR (d -DMSO, 300 MHz) 6 2.04 3H), 3.47 (br m, 4H). 3.52 (br m, IH), 3.60 (br m, I 3.68 (br m, IH). 3.74 (br m, IH), 5.58 2H), 6.65 (td, J 1.5, 15.0 Hz, I H), 6.72 (dd,J= 1.5, 8.7 Hz, 1H), 7.00 (dd, J= 1.8, 8.7 Hz, I 7.27 J= 1.5,.8.6 Hz, IH), 7.36 (dd,J= 1.5, 8.7 H4z, 1H), 7.39 15.3 Hz, IH), 7.53 15.3 Hz 103 IR), 7.89 (dd,J= 1.8, 8.7 Hz, IH), 8.64 1.8 Hz, 1H). MS (APCI) at m/z 427.
Example 48 (2-Hydroxymethylphenvl')[2-nitro-4-( E-((4-acetvlpiverazin- I -vl)carbonyl) ethenvl)pbenyll sulfide The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichiorothiophenol with.2-mercaptobenzyl Alcohol. Light-yellow powdr; H NM (d-DMO, 30 Mz)5 2.03 3H), 3.47 (br m,4H), 3.52 (br m,.
1H), 3.60 (br m, I 3.67 (br m, I 3.73 (br m, I 4.53 J 5.7 Hz, I 5.34 J= 5.7 Hz, 1 6.65 J= 8.7. Hz, I 7.40 J 15.3 Hz, I 7.46 J 7.8 Hz, 11H), 7.53 (dJ= 15.3 Hz, I 7.59 J 7.5 Hz, INH)5 7.64 J= 7.5 H z, INH), 7.87 (dd, J 2.1, 8.7 Hz, INH), 8.65 J= 2.1 Hz, I MS (APCI) (M+NH 4 at. m/z 459.
Example 49 (2-Ethyin~henyl) [2-nitro-4-( E-((4-acetlliperazin- I -yl~carbonYl ethenvl~jhhenyll sulfide The title compound was prepared by the procedures described in Example 32 2,4-dichiorothiophenol wi th 2-ethylthiopheriol. Light-yellow powder; 'H NMR (d 6 -DMSO, 300 MHz) 8 .1.01 J= 7.65 Hz, 3H), 2.04 2.69 J 7.65 Hz, 2H), 3.47 (br m, 4H), 3.52 (br m, iN), 3.59 (br m, IN), 3.67 (br m, IN),3.73 104 (br m, I1H), 6.64 J 8.7 Hz, I 7.3 8 (dd, J 2.4, 7.5 Hz, I 7.40 J 15.6 Hz, I1H), 7.5 0-7.61 (in, 311), 7.5 31 J= 15.6 Hz, I 7.8 9 (dd, J 2.4. 8.7 Hz, I1H), 8.64 J 2.4 Hz, I MS (APCI) at m/z 4 74, 476.
Example (2-soPrpyphny)[-ntr.4(.E-((4-acelylpive .razin- I -vl~carbonvl)' ethenyl)rbhenyll sulfide The. title compound was prepared by the, procedures described in Example 32 substituting 2,4-dichiorothiophenol with 2-isopropyithiophenol. Light-yellow powder; 'H NMR (d 6 -DMSO, 3 00 MHz) 5 1.05 J1 6.9 Hz, 611), 2.04 3H), 3.47 (br m, 411), 3.52 (br mn, 111), 3.60 (br mr, 111), 3.67 (br m, 111), 3.72 (br mn I1H). 6.64 J 8.4 Hz. 111), 7.34-7.41 (in, 211), 7.39 1(d, J= 15.3 Hz, 11), 7.52 J= 15.3 Hz, 111), 7.56-7.73 (in, 2H), 7.90 (dd, J 2.1, 8.7 Hz. 11H), 8.64 J 2.1 Hz, 111). MS (APCI) (M+NH 4 at m/lz 47 1. Analysis calculated for C, 4
H
27 N.10 4 SrO0.
2 lHO: C, 63.03; H, 5.96; N, 9.13. Found: C, 63.03; H, 6.04; N, 9.19.
Example 51 (2-Iert-ButvILphenyl)[2-nitro-4-( E-((4-acetylpip erazin- I -yl)carbonvl) ethenyllphenyll sulfide The title compound was prepared by the procedures described in Example 32 substituting 2,4-dichlorothiophenol with 2-tert-butylthiophenol. Light-yellow powder; 'H NMR (d-DMO .30 MHz) 8 1.46 911), 2.04 311), 3.47 (br in, 411). 3.52 (br 105 m, I 3.60 (br m, I 3.67 (br m, I 3.73 (br m, I 6.68 J 8.7 Hz, I H), 7.3 5.(tt J1 7.5 Hz, I 7.3 9 (di J= 15.3 Hz,: IH), 7.45-7.57 (in, 2H), 7.50 (d3, J 15.3 Hz, I1H). 7.65 J 8.1 Hz, I 7.88 (dd, J 2.4, 8.7 Hz, 1 8. 64 J 2.4 Hz, IH). MS (APCI) (M+NH 4 at m/z 485.
Example 52.
(2-Chlorophenyl)r2-chloro-4-( E-((4-acetylpiperazin-1-I v)carbonylY)) 2-prpenv~phevllsulfide Example 52A 3 '-Chloro-4'-[(2-chlorophenyl)thiolacetonhenone.
The title compound was prepared by the procedures described in Example 1 A substituting 2,4-dichlorothiophenol with 2-chlorothiophenol, and 2chlorobenzaldehyde with 4'-fluoro.-3 -chloroacetophenone.
Example 52B (2-Chlorophenyl'42-chloro-4-( I-ethoxycarbonyl' 2-propenyl)phenvl] sulfide.
To a stirred suspension of NaH (60% in mineral oil, 12 1. mg, 3.03 inmol) in rnL of anhydrous THE under nitrogen atmosphere was added triethyl phosphonoacetate dropwise. After 20 minutes, the acetophenone (600 mng. 2.02 minol) from Example 52A in THE (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 106 EtOAc (2x20 mL) and water. The combined organic layer was washed with water and brine, dried over Na 2 SO,, concentrated in vacuo. The crude product was purified using silica gel flash column chromatography eluting with 5-10% Et,O in hexanes to give the (E)-isomer of the cinnamate (500 mg, 68%) as a white solid.
Example 52C (2-Chlorophenvl)[2-chloro-4-( E-(l-carboxv) 2-proDenvl)phenvll sulfide A mixture of the cinnamate (500 mg, 1.37 mmol) from Example 52B in 5 mL of EtOH/THF was stirred with sat. LiOH solution (0.50 mL) at 50 °C for 2 hours. The mixture was then acidified with 3N HCI and extracted with CH 2 CI, (3x 0 mL). The combined organic layer was dried over MgSO,, concentrated under reduced pressure to give the titled compound (450mg, 97%) as a white solid.
Example 52D (2-Chlorophenvl)[2-chloro-4-( E-((4-acetvlpiperazin-1 -vl)carbonvl)) 2-propenyl)phenvll sulfide The title compound was prepared using the cinnamic acid from Example 52C by the procedures described in Example 1C substituting 6-amino-l-hexanol with 1acetylpiperazine. White solid; 'H NMR (CDC13, 300 MHz) 5 2.10-2.20 3H), 2.25 3H), 3.40-3.80 8H), 6.28 1H), 7.00 J= 8.7 Hz, 1H), 7.19-7.36 4H), 7.46-7.56 2H). MS (APCI) (M+NH 4 at m/z 466, 468, 470.
.107 Example 53 -Morpholinylmetvl)]hhenl)2-chloTo-4- -morpholinvl)carbonvl) ethenyi) phenyll sulfide Example 53A -Bromomethvl)phenyP)f2-chloro-4-( E-(G -morpholinyl)carbonvl) ethenyi) phenvll sulfide 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 3 (60 jiL, 0.40 mmol) was dropped in slowly.
The ice bath was then irmoved and the mixture was stirred at room temperature for I hour. Water was then Added, the mixture was then partitioned between EtOAc and aqueous NaHCO.,. The aqueous layer was extracted with EtOAc once. The combined organic layer was washed with water and brine, dried over Na,S0 4 Concentrated on A rotavap. The crude bromide (230mg) was used directly for the alkylation without purification.
Example 53B (2-(lI-Morpholinvlmethyl~phenyl)[2-chloro-4-( I-morpholinvl)carbonyl) ethenyl) phenvll sulfide To a stirred solution of morpholine (10 4L, 0. 11 *mmol) in 0.5 mL of CH 3
ICN
was added Hunig's base (23.7 jL, 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. 'H NMR, (d 6 -DMSO, 300 MHz) 8 2.33 (br t, 4H), 3.45 (br t, 4H), 3.50-3.65 (in, 6H), 3.56 (s, 2H), 3.65-3.80 (br mn, 2H),'6.74 J= 8.7 Hz, IlH),.7.30 15.3 Hz, IH), 7.35- 7.41.(mn, 2H), 7.43, J 15.3 Hz, IH), 7.46 (td, J= 2.4, 8.1 Hz, 11H)3 7.52 (dd, J 2.1, 8.7 Hz, I 7.56 Jz 8.1 Hz, 11H). 8.02 J 2.1 Hz, I MS (DCI/NH,1) at m/z.459, 461.
Example 54 (2-(4-(1I.3-Benzodioxolyl-5-methyl)piiperazin- I -ylmethyl)phenyl)f2-chloro-4-( Imotpholinyl)carbonyl) ethenyl)vhenyll sulfide The title compound was prepared by the procedures described in Example 53B substituting inorpholine with I -piperonylpiperazine. White solid; 'H NMR (d 6 DMS0, 300 MHz) 5 2.13-2.40 (brin, 3.28 2H), 3.49-3.64 (brmi, 6H), 3.54(s, 2H), 3.70 (binm, 2H), 5.97 2H), 6.69 (dd, J= 1.8, 8.1 Hz, I1H), 6.74 J' 8.7 Hz, 1H), 6.79 1.8 Hz, IH), 6.81 8.1 Hz.. IH), 7.39 Hz. lH), 7.33-7.38 (mn, 2H), 7.38-7.50 7.43 J= 15.3 Hz, IH), 7.53 8.4 Hz, IH), 8.00 J= 2.1 Hz, IH). MS (DCI/NH.3) (M+Hy) at m/z 592, 594.
Example (2-44(1iso-Propvlaminocarbonylmethyl)piperazifl-1I-ylmethvl~lhhe vlf2-chloro- 4
E-
£0 morp~holinyl)carbonyl) ethenyl')phenyll sulfide The title compound was prepared by the procedures described in* Example 5 3B substituting morpholine with N-isopropyl- I -pipera zineacetamide. White solid; '.H NMR (d 6 -DMSO, 3 00 MHz) 8 1.04 6.3 Hz, 6H), 2.20-2.42 (hr m, 8H), 2.78 (s, 2H), 3.47-3.64 (br it, 6H), 3.56 3.64-3.76 (br mn. 2H), 3.85 (qd, J 6.3, 8.1 Hz, I 6.73 J 8.7 Hz, 1IH), 7.29 J1 15.6 Hz, I 7.3 1 -7.39 (in. 2H), 7.43 J= 15.6 Hz, I 7.45 (td, J= 2.7, 6.3 Hz, 111),'7.50 2.1, 8.7 Hz, I H), 7.55 J= 7.8 Hz, I 8.00 J= 2.1 Hz, I MS (DCI/NH 3 at m/z 557, 559.
Example 56 (2-((N-Ethoxycarbonylmethl-N-methvl~ariinomethI)phenl) 2 -chloro- 4 morrnholinyl)carbonyl) ethenyl)phenyll sulfide The title compound was prepared by the procedures described* in Example 53B substituting morpholine with, ethyl sarcosinate hydrochloride. White sol id; 'H NMR (d 6 DMSO, 300 MHz) 8 1. 16 J 7.2 Hz, 3H), 2.27 2H), -3.30 2H). 3.51-3.66 (hr m, 6H), 3.66-3.75 (hr mn, 2H), 3.78 2H), 4.05 J =7.2 Hz, 2H), 6.75 J 8.7 Hz, 1H), 7.30 J= 15.3 Hz, IH), 7.33-7.38 (in, 2H), 7.42-7.50 (in. 2H), 7.43 (d, J= 15.3 Hz, I 7.53 (dd, J= 2.1, 8.7 Hz, IH), 7.60 J~ 7.8 Hz, I1H). 8.02 J= 2.1 Hz, I MS (Del/NH 3 at ,n/z 489, 491.
Example 57 (2-Formylphenyl)[2-chloro-4-( 1-morpholinyl )carbonyl)ethenvl)phenvlI sulfide To a stirred solution of the alcohol (368 mg, 0.94 mmol) from Example I1I in mL of anhydrous acetonitrile was added activated 4A molecular sieves, TPAP 3 mg, 0.0094 mmol), and NMO (1 10 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 AiL). 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. NMR (d 6
-DMSO,
300 MHz) 8 3.60 (br m, 6H), 3.73 (br m, 2H), 7.00 J= 8.4 Hz, 1H), 7.40 J= 15.3 Hz, IH), 7.42 8.4 Hz, IH), 7.51 15.3 Hz, lH). 7.52 8.1 Hz, I 7.61. (td, J 1. 8. 8.1 Hz, I 7.71 (dd, J 2.1, 8.4 Hz, I 8.02 (dd, j 2.1.,8.4 Hz, 1H). 8.14 J=2.1 Hz, IH). MS (DCIINH 3 at 388, 390.
Example 58 (2-('4-Formylpiperazin- I -vlmethyl)phenvl )[2-chloro-4-( -morpholinyl )carbonyl) ethenvl')phenyll sulfide The title compound was prepared by the procedures described in Example 53B substituting morpholine with 1-formyl piperazine. White solid; 'H NMR (d 6
-DMSQ,
300 MHz) 8 2.20-2.32 (in. 6H), 2.74 (br m, 2H), 3.48 2H), 3.59 (mn, 6H), 3.70 (br.
m, 2H), 6.74 J= 8.7, Hz, I 7.29 J 15.6 Hz, I 7.35-7.41. (in, 2H), 7.42 J= 15.6 Hz, 1H), 7.45-7.52 3H), 7.98 J=2.1, 1H). MS (DCI/NH 3
(M+H)
at m/z 486, 488.
Example 59 -Morpholinyl)carbonvl)ethenvl)phenvl)[2-chloro-4-( E-((-morpholinvl) carbonyl)ethenvl)phenvll sulfide A mixture of bromide (80 mg, 0.18 mmol) from Example 12, acryloylmorpholine (33 mg, 0.23 mmol), Pd(OAc), (2.0 mg, 0.009 mmol), P(o-tolyl) 3 (17 mg, 0.056 mmol), Et.N (39 p.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 oC 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,SO 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, 'H NMR (d 6 -DMSO, 300 MHz) 5 3.43-3.88 (m, 16H), 6.58 8.7 Hz, 1H), 7.30 15.3 Hz, 2H), 7.43 J= 15.3 Hz, 1H), 7.47-7.64 4H), 7.86 J= 15.3 Hz, 1H), 8.06 J= 2.1 Hz, 1H), 8.14 J= Hz, 1H). MS (DCINH 3
(M+NH
4 4 at m/z 516, 518. Analysis calculated for 112
C.,
6
H,
7
N
2 0 4 C1 1 S, I0.46H,O: C, 61.56; H, .5.55; N, 5.2 1. Found: C, 61.56; H, 5.50; N, 5.43.
Example (2-Formvlphenylfl2-nitro-4-( E(4-acetylpiperazin- I -vl~carbonyl ethenyl')henvll sulfide The title compound was prepared by the procedures described in Example 5 7 substituting compound from Example I1I with co mpound from Exam~rple 48. Yellow solid; 'H NMR (d 6 -DMSO, 300 MHz) 8 2.04 3H), 3.47 (br m, 4H), 3.52 (br m.
IH), 3.60 (br m, IH). 3.68 (br m, I 3.74 (br m, 1H). 6.85 J= 8.4 Hz. 7.44 (d J= 15.6 Hz, I 7.55 J 15.6 Hz, I 7.61 J 7.5 Hz, I1H), 7.73 (t.J= Hz, I 7.80 (td, J= 2.4, 7.5 Hz, I 7.92 (dd, J= 2.1, 9.0 Hz,: IH), 8.04 (dd. J.
7.5 Hz, I 8.66 J =2.1 Hz, I 10.29 I MIS (A-PCI) (M+Cly- at m/Z 474. 476.
Example 61 (2-FormvylphenylM2-chloro-4-( -morpholinvl)carbonvl)ethenyl h2henvll sulfide.
N.N-dimethyl hvdrazone A mixture of the aldehyde (20 mg, 0.052 mmnol) from Example 57. 1,1dimethyl hydrazine (3.9 p.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.
113 as a white solid. 'H NMR (CDC13, 300 MHz) 6 2.91 6H), 3.55-3.82 (br m, 8H), 6.64 8.7 Hz, 1H), 6.76 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 J= 7.8 Hz, 1H), 7.47-7.57 2H), 7.54 2H), 8.04 (dd, J= 1.8, 8.7 Hz, 1H). MS (DCI/NH 3 at m/z 430, 432, 434, 436.
SExample 62 -Morpholinvl)propyl)-1-amino)phenvl) r2-chloro-4-( morpholinl)carbonvl) ethenvl)phenvll sulfide A mixture of bromide (60 mg, 0.14 mmol) from Example 12, aminopropylmorpholine (24 p.L, 0.17 mmol), Pd,(dba). (1.2 mg, 0.0013mmol), 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 OC over night. The S 15 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,SO,, 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, 'H NMR (d'-DMSO, 300 MHz) 8 1.62 (quintet, J= 6.5 Hz, 2H), 2.15-2.26 8H), 3.17 J= 6.5 Hz, 2H), 3.22-3.76 12 3.50 J= 6.5 Hz, 2H), 5.72 J= 5.7 Hz, 6.47 J 0 114 8.7Hz, I 6.68 J=7.2 Hz, I 6.81 (d,J1= 8.4 Hz, 1H1), 7.26 J= 15.6 Hz, 1H), 7.35-7.42 (in,2H), 7.43 15.6 Hz, 1H1), 7.44 8.4 Hz, I1H), 7.49 (d,.J =8.4 Hz, I 8.00 J =2.1 .Hz, I MS (APCI) at m/lz 502, 504.
Example 63 f2,4-:Dichloronhenvl)r2-bromo-4-( E-0(-0 I vrolidin-72-onl y~propylamino)carbonyl) ethenyi)phenyll sulfide Example 63A (2.4-D~ichlorop~henvl)[2-amino-4-( -p)Yrrolidin-2-onlv)propvylamino)carbonyl) ethenyl)6henyll sulfide A mixture of nitro compound (780 mg, 1.58 mmol) from Example 33. SnCl 2 (1.50 g, 7.91 mmol) in 25 m-L 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 3 extracted with EtOAc (2x50 The combined organic layer was washed with water and brine, dried over Na 2
SO,
condensed in vacuo to give the crude aniline as yellowish brown solid, which was converted to the bromide without purification.
Example 63B (2,4-Dichlororphenyfl[2-bromo-4-( E-043( -pv rrolidin-2-onlv)propvlarnino)carbonvl) ethenyl)phenyll sulfide To a stirred solution of t-butyl nitrite (57 p1L, 0.48 mmol), CuBr,.(87 mg, 0.39 ,mmol) in 2.0 mL of CH 3 CN at room temperatur ie was added a solution of aniline from.
Example 63A (150 mg, 0.323 mmol) in 1.0 miL of CH 3 CN. The dark green solution was then heated at 65 *C under nitrogen atmosphere for 90 minutes. The reaction mixture was then allowed to cool down to room. temperature, partitioned between.
EtOAc- and 3N HCI. The organic layer was then washed with brine,, dried over NaSO,, 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, Colorless oil; 'H NMR (d'-DMSO, 300 MHz)081.63 (quintet, J 7.2 Hz, 2H), 1.91 (quintet, J 8.4 Hz, 2H), 2.22 J 8.4 Hz, 2H), 3.09- 3.47 (in, 6H), 6.67 J 15.3 Hz, I1H), 7.07 J= 8.4 Hz,4 1H), 7.3 2 8.7 Hz, I1H), 7.3 8 (di. J= 15.3 Hz, 1IH). 7.50 (dd, J 2.4, 8.7 Hz, I 7.5 7 (dci, J= 2.1, 8.4 Hz, I 7.86 (di, J= 2.4 Hz, I 7.96 J= 2.1 Hz, I 8.13 J =6.0 Hz, I H).
MS (ESI) at m/z 527, 529, 531,533.
Example 64 (2.4-Dichiorophenvl)r2-fomyil4-( -morp~holinyl)carbonvl)ethenyl)phenvlI sulIfide Example 64A [1I -Fluoro-2-formyl-4-( 0 -morp~holinyl)carbonyl)etbenyl) benzene The title compound was prepared by the procedures describdi substituting the bromide from Example 12 with Example 64B (2A4-DichlorophenvlM[2-fornyl-4-( I moriholinyl)carbonyl)ethelyl)hhenlIl sulfide.
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; NMR (d 6 -DMSIO, 300 MHz) 5.3.60 (br m, 6H), 3.71 (br m, 2H), 6..82 J=,8.7 Hz, 1H), 7.35 J= 15.6 Hz, IH), 7.54 J= 15.6 Hz, IH), 7.55 (dd, J 2.4, 8.7 Hz, 1H), 7.61 8.7 Hz, 1H), 7.86 (dd, J= 2.4, 8.4 Hz,*1H), 7.9.1 J= 2.4 Hz-, I 8.4 1 J= 2.1 H7, I 1.0. 19 I MS (DC1/NH3) at mzz 422, 424, 426, 428.
Example (2-Chloro-6-fonnvlphenyl)r2-chloro- 4 E-((4-acetylpiperazin-w 1 -yl)carbonyl) *ethenyi) phenyll sulfide Example (2-Carbomethoxvethl)r2-chloro-4-( E-((4-acetylpiperazin- I -vi )carbonvl) ethenyl) phenyll sulfide 117 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 I-acetyl piperazine.
Example (2-Chloro-6-formvlphenvl)[2-chloro- 4 E-((4-acetyvliperazin-l-vl)carbonvl) ethenvl) phenvll sulfide To a stirred solution of the compound (105 mg, 0.26 mmol) from Example in 2 mL of THF under nitrogen atmosphere at 0 °C was added t-BuOK solution (1 281 1 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.
The yellow thiolate thus obtained was dissolved in 0.5 mL of DMF. and 2,3dichlorobenzaldehyde was then added. The mixture was then heated at 80 °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 38B to give the titled compound as a white solid (25 mg, 'H NMR (CDC13, 300 MHz) 8 2.05 3H), 3.48-3.58 2H), 3.58-3.84 6H), 6.53 J= 8.7 Hz, 1H), 6.80 15.3 Hz, 1H), 7.19 (dd, J= 1.8, 8.7 Hz, 1H), 7.51-7.62 (m, 2H), 7.60 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 4 at m/z 480, 482, 484.
Example 66 118 (2-Cvanophenyl)r2-chloro-4-( E-((4-acetvIlpiperazin- -I y)carbonyi) ethenyl) Rhenyll sulfide The title compound was prepared by the procedures described in Example substituting 2,3-dichlorobenzaldehyde with 2-fluorobenizonitrile, giving a white solid.
'H NMR (CDCl 3 300 MHz) 5 2.15 3H), 3.48-3.57 (in, 2H), 3.59-3.84.(in, 6H), 6.86 J =15.6 Hz, 1IH); 7.12 J= 8.4 Hz, I1H), 7.32 J =8.4 Hz, IlH), 7.41. J.
6.6 Hz, 7.46 (dd, J=1.8, 8.4 H, IH), 7.55 (dd, J= 1.8, 8.1 Hz, I1H), 7.61 J =15.6 Hz, I 7.64 J 8 Hz, IlH), 7.75 (dd, J 1.8, 8.4 Hz, I1H). MIS (DCI/NH,) (M+NH 4 )*at m/lz 443.
Examplee67 (2-Isopropvylphenyl)r2-cyano-4-( E-((morpholin- I -vl)carbonyl) ethenyl) phenyll sulfide Example 67A Q2-1sopropvhpheny l)(4-bromo-2-cyano]2henyl)sul fide The title compound Was prepared by the procedures described. in Example 1A substituting 2,4-dichlorothiophenol with isopropylthiophienol, and 2chlorobenzaldehyde with 2-fluorobenzonitrile.
Example 67B (2-Isopropylphenyl)[2-cyano-4-( E-((morp~holin- 1 -vl)carbonyl) ethenyl) Phenyll sulfide T Ihe title compound was prepared by the procedures described in Example 59* s ubstituting the bromide from Example 12.with the bromide from Example 67A, giving a white solid. 'H NMR (CDCl 3 3 00 MHz) 5 1. 19 J= 6.9 Hz, 6H), 3.49 (septet, J 6.9 Hz, I1H), 3.58-3.87 (in, 8H), 6.73. (d3 J= 8.4 Hz, I 6.83 J 15.6 Hz, I1H), 7.20-7.30 (mn, IlH), 7.42 (dd, J= 8.4 Hz, IlH), 7.46. J 3.0 Hz, 2H), 7.49 1. 8, 6.9 Hz, I 7.57 J 15.6 Hz, 1IH), 7.76 (d J~ 1.8 Hz, I MS (APCI') at mn/z 393 Example 68 (2-Bromnophenyl'ff-nitro-4-( E(40-acetylviverazin- I -vl)carbonyl) ethenyl) phenyll sulfide.
The title co mpound was prepared by the procedures described in Example 32B substituting 2,4-dichiorothi'ophenol with 2-bromothiophenol, providing .a light-yellow solid; 'H NMR (d 6 -DMSO, 300 MHz) 86 2.04 3H).3.40-3.65 (in, 8H), 6.75 J 8.7 Hz, I 7.42 J 15.6 H4z, I 7.51 (dd, J 2.1. 6.9 Hz 1IH), 7.54 J 15.6 Hz, I 7.55 tJ~ 2.1 Hz, I1H), 7.59 (dd, J= 2.1. 6.9 Hz IH), 7.82 (dd, J= 2.4, 7.8 Hz, I1H), 7.92(td, J= 2.4, 8.4 Hz, I 8.67 J= 2.41 Hz, I MS (APCI') atm/Lz 524, 526, 528.
Example 69 (2-(Pyrrolidiri-] -vI )phenyl)[2-chloro-4-( E-(morpholin-l1-Olcarboriyl) ethenvl) phenyll sulfide 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,(dba) 3 (3.0 mg, 0.0034mmol), BINAP (6.0 mg, 0.010mmol), followed by NaOt-Bu (26 mg, 0.27 mmol). The resulting mixture was then flushed with anhydrous N, for 2 min before it was capped and heated at 90 *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 Na2SO,, 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; 'H NMR (CDCI 3 300 MHz) 8 1.83 (br s, 4H), 3.40 (br s, 4H), 3.56-3.80 8H). 6.57 J= 8.4 Hz, 1H), 6.75 J= 15.6 Hz, IH), 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 1H), 7.32 (td, J= 1.8, 8.4 Hz. IH), 7.42 (dd, J= 1.8, 7.8 Hz, 1H), 7.50 J= 1.8 Hz, 1H), 7.55 J= 15.6 Hz. 1H). MS (APCI) at m/z 429, 431.
Example (2-Methoxvphenvl)-[2-chloro-4(E-[(morpholin- 1 -v)carbonvllethenvl)phenvl]sulfide The title compound was prepared according to the procedures of Example 1, giving a white solid, m.p. 162-164C. 'H NMR (CDCI., 300 MHz) 5 3.60-3.78 (m, 8H), 3.84 3H), 6.72 J=9Hz, 1H), 6.78 J=16Hz, 1H), 6.96-7.04 2H), 7.16 (dd, J=9Hz, 2Hz, 1H), 7.40-7.46 2H), 7.55 J=2H, 1H), 7.58 J=16Hz. 1H).
121 Anal. Calod. for C 20
,H
20 C1N0 3 S: C, 61.61;.H, 5.17; N, 3.59. Found: C, 61.53, H, 5.22; N, 3.50.
Examnie 71 (2-Isoprovylphenl1r2-nitro-4-( E-((3-carbomethoxypirierazin- 1 -v)carbonvl) ethenyi) phenyll sulfide Example 7 1 A I- teri-Butyoxvcarbonyl -2-carbomethoxyvniperazine 2-Carbomethoxypiperazine was treated with benzyl chioroformate (1.0 eq) in aqueous NaHCO, to give 1 -benzyloxycarbonyl-3-carbomethoxypiperazine. This material was treated with di-ter-butyldicarbonate (1.1 eq) and triethylamine (1.0 eq) in THF to produce I -tert-bu tyoxycarbonyl.-4-benzyloxycarbonyl-2carbomethoxypiperazine. Hydrogenation of this compound in methanol using Pd-C. gives the title compound after filtration anid solvent removal.
Example 71B (2-Isopropylphenyl")[2-nitro-4-( E-((3-carbomethoxypiperazin-1-I y)carbonvl) ethenyl) phenvil sulfide A mixture of (2-isopropylphenyl)[2-nitro-4-E-(carboxyethenyl)phenyl] sulfide (prepared according to the procedures of Example -3 the -amine from Example 71A (1.0 eq), 2-(1H-benzotria'zol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (1.0 eq), and diisopropylethylamine (2.0 eq) in DMF was stirred at ambient temp erature for 4 hr. Ethyl acetate was added, and the mixture was washed sequentially with IN HCl, bicarb, and brine. The resultant yellow solid was treated with 1:1 TFAldichloromethane at ambient temperature to give the title compound as a yellow solid. 'H NMR (DMSO-d 6 ,,300MHz) 61.15 J =6.6 Hz, 6H); 2.52-3.16.(br m, 4H); 3.25-3.47 (in, I 3.60-3.65 (br d, 3H); 3.60, 3.66 (br s, br s, 3H); 6.61-6.67 (brm, 1H); 7.30-7.62 (in,6H); 7.88-7.93 (brm, lH); 8.58-8.65 (brm, 1H). MS (APCI) at-mlz 470. Anal calcd for C, 7
N
3 S ,6.9 ,58;N Found: C, 61.51; H, 5.87; N, 8.68.
Example 72 (2-MethylvhenYl)[2-nitro-4-( E-((3-carboxamido-4-carbobenzoxvpiperazin- 1yl)carbonyl)etben'vl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H4 NMR (DMSO- 300MHz) 5 2.30 3H); 2.80-4.80 (br 5.05-5.,15 (br m, 2H); 6.61-6.67 (hr mn, I 7.02-7.64 (in, 131-); 7.80-7.90 (hr mn 1H); 8.56-8.65 (br m, 1H). MS (APCI) at m.lz 561. Anal calcd for C,4H, 8 NS,0 6 ,0.42CH 3 COOCH,CH,: C, 61.66; H, 5.29; N, 9.3 Found: C, 61.4 1; H, 5.28; N, 9.53.
Example 73 (2-Isopropylphenvl)[-nitro-4-( E-((2-carbomethoxy-4-iert-butoxN'carbonylpiperazin- I -yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 7 1, giving, a yellow solid.
'H NMR (DMSO-d,, 300OMHz) 8 1. 13 J =6.6 Hz, 6H); 1.40, 1.41 s, 9H); 2.72- 3.08 (br m, IH); 3.17-3.24 (in, IH); 3.30-3.40 (mn, lH); 3.68 (br s, 3H); 3.79-4.51 (br mn, 4H); 5.06, 5.36 (br s, br s, 1H); 6.61-6.67 (in, lH); 7.30-7.62 (in, 6H); 7.85-7.93 (br mn, IH); 8.64-8.69 (br m. lH). MS (APCI) (M+H)y at m/z 570. Anal calcd for
C,
9
H
3 NS,0 7 -0.15C 6 C, 61.66; H, 6.43; N, 7.21. Found: C, 61.69;.H, 6.3 5; N, 7.02.
Example 74 (2-Isoprop~ylphenvfl)2-nitro-4-(
E((
2 -carboxy-4- iert-butoxycarbonylpjperazin I vI)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR 300MHz) 5 1.14 J Hz, 6H); 1.45 0H); 2.72-4.75 (br in, 6H); 3 .38-3.49.(m, IH); 5.78 (br s, IH); 6.68, 6.72 s, IH); 6.88, 6.94 (br s; br,-s, lH); 7.26-7.71 (mn, 6H); 8.44 (br s, IH). MS (APCI) at m/z 554. Anal calcd for C, 60.53; H, 5.99; N4, 7.56. Found: C, 6 0.42; H, 6.2 1; N, 7.3 1.
Example (2-Isopropyiphenyl) r2-trifluoromethyl-4-( E-((4-acetylpiperazin- I-v I)carbonv1) ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCJ 3 30.0 MHz) 8 7.78 I 7.62 I H, J 15.5 Hz), 7.43-7.49 (in, 3H), 7.37 I H, J =8.1 Hz), 7.23 (mn, I 6.85 I H, J 15.5 Hz), 6.82 I H, J Hz), 3.63-3.77 (in. 6H), 3.45-3.55 (mn, 3H), 2.14 3H), 1. 17 6H, J 6.6 Hz).
MS (ESI) m'lz 477, 499, 975, 953. Anal. Calcd for C 2 5
H
2 7
F
3 N202S -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-IsopropylphenylMr2-trifluoromethvl-4-( E-((morpholin -1 -vl)carbonvl) ethenyi) phenyll sulfide The title compound was prepared acco rding to the procedures of Example 1..
IH NMR (CDCl, 300 MHz) 7.78 I 7.62 (br, I 7.33-7.48 (in, 3H), 7.22 (mn, I 6.85 (in, I 6.80 I H, J =8.5 Hz). 3.73 (br, 3.49 (dq, I H, J, J 6.9' Hz), 1. 17 6H, j 7.1 Hz). MS (ESI) inl: 436. 871.893. Anal. Calcd for
C
23
H
2 4
F
3 NI 0 2 S: C, 63.43; H, 5.55; N, 3.22. Found: C,63.12; H, 5.8 1, N, 3.10.
Example 77 (2-IsopropylphenyIMr2-trifluoroithl-4-(E-((3-(prrolidil- 2 -of 1 -Yl)prop- Iylamino)carbonvP) ethenyl)phenvil sulfide The title compound was prepared according to the procedures. of Example 1.
'H NMR (CDCI 3 300 MHz) 8 7.77 I 7.52(d, 1 H, J 15.4 Hz), 7.43-7.51 (in, 3H), 7.36 (d,11H,J3= 8.8 Hz), 7.22(in, IH). 7.10 (br, IH), 6.80 (dIH,J3= 8.4 Hz), 6.44 I H, J =15.4 Hz), 3.49 (dq, I H, J, J =6.9 Hz), 3.40 (in, 4H), 33(dd, 2H, J, 5.7 Hz, J, 12.0 Hz), 2.44 2H,J =8.1 Hz),.2.08 (tt, 2H, J, J, =7.5 Hz),.1.74 (in, 2H4), 1.18 6H, J 6.9 Hz). MIS (ESI) m/lz 491, 513, 98 1, 1 003. Anal. Calcd for
C
2 6
H
2 9
F
3
N
2 0 2 S: C. 63.66; H, 5.96; N, 5.7 1. Found: C.64.00; 6.12, N, 5.68.
Example 78 (2-Isopropylphenvl')r2-trifluoromethyl-4-( E-((cyclobutylamino)carbonyl) ethenvi) phenyil sulfide The title compound was prepared according to the procedures of Example L.
'H NMR 300 MHz) 8 7.76 114), 7.52 .1 J 15.4 Hz), 7.43-7.4 9 (in, 3H), 7.33 1H, J 7.7 Hz), 7.22 (in, 1H), 6.79 IH, J =8.1 Hz), 6.33 (d4 IH, J 15.4 Hz), 5.72 (br, 1H), 4.52 (mn, IH), 3.49 (dq, IH, J, 6.9 Hz), 2.40 (mn, 2H), 1.90 (in, 2H), 1.74 (mn, 2H4), 1. 17 6H, J =6.6 Hz). MS (ESI) m/z 420, 839. 86 1.
Anal. Calcd for C 2 3
H
2 4
F
3 NIO0 1 S: C, 65.85; H, 5.77; N. 3.34. Found: C,65.53; H,.
58,N, 3.21.
Example 79 (2-Isopropylphenvl)[2-trifluoromethyl-4-( E-((cyclopentylamino~carbonvl) ethenyl) pohenvll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCl 3 300 MHz) 8 7.77 IH), 7.52 1H, J 15.5 Hz), 7.43-7.48 (in, 7.3 3 I H, J 8.8 Hz), 7.22 (mn, I 6.79 I H, J 8.1 Hz), 6. 33 I H, J 15.5 Hz), 5.54 J 7.7, 1IH), 4.3 5 (in, I 3.49 (dq, I H, J, 6.9 Hz). 2.05 (in, 2H), 1.68 (mn, 4H), 1.44(mn. 2H), 1. 17 6H, J 7.0 Hz). MS (ESI) rn/z 43 4. 867, 889.
Anal. Calcd for C 24
H
2 6
F
3 N 1 0 1 S: C, 66.49; H4, 6.04; N, 3.23. Found: C, 66.24; H, 6.14, N, 3.06.
Example (2-Isopropyip~henvl) r2-trifluoromethyl-4-( E-((5-hydroxynent- I-vlamino)carbonyl) ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 'H NMR 3 00 MHz) 8 7.77 IlH), 7.54 I H, J =15.5 Hz), 7.43-7.49 (in, 3 7.33 I H. J 8. 0 Hz), 7.22 (in, I 6.79 I H, 8.4 Hz), 6.3 5(d, I1H, J 15.6 Hz). 5.67 (br, I 3.67 2H, J 6.4 Hz), 3.49 (dq, IlH, J, J2 6.9 Hz), 3.40 (mn, 2H), 2.40 (in, 2H), 1.45- 1.62 (in, 6H), 1. 17 6H, J 7.0 Hz). MS (ESI).m/z 452, 474, 903, 925. Anal. Calcd for C 2 4
H
2 8
F
3 N0 2 S 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-Isoprop~ylphenyl) [2-nitro-4-( E-((3-carboinethoxy-4-acetylpiperazin- 1yl)carbonvl)ethenyl) phenvil sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR 300MHz) 5 1.14 J3 6.6 Hz, 6H); 2.20 3H); 2.75-3.80 (hr in, 4H); 3.39-3.50 (in, I 3.70, 3.77 (br s, hr s, 3H); 4.49-4.75 -(br mn, 2H); 5.39 (hr s, IH); 6.71(m, 1H); 6.91-7.04 (hr mn, IH); 7.25-7.64 (mn, 6H); 8.42 (hr mn, 1H). MS 127 (APCI) at m/z 512. Anal calcd for C,,H, 9 N,S,0 6 C, 61.04; H, 5.71; N, 8.21.
Found: C, 61.40; H, 6.05; N, 7.88.
Example 82 (2-Biphenyl)l2-chl6ro-4-( E-((mornholin-lI -l)carbonyl) ethenyl) phenyll sulfide To a stirred solution of bromide from Example, 12 (60 mg, 0 .14 mmol)inlI mL.
of toluene was added 0.5 mL of sat. Na,CO 4 Pd(PPh 3 4 (8 mg, 0.007 mmol), phenylboronic acid (17 mg, 0. 14 nimol). The mixture was flushed -with nitrogen and.
heated at 100 *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 2
S
4 ftrd n ocnrtd 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); 'H NMR (CDCI,, 3 00 MHz) 5 3.5 8- 3.86 (in 8H), -6.77 J 15.6 Hz, I 6.86 J 8.4 Hz, I 7.67 (dd,J 2.1, 8.4 Hz, I 7.29-7.40 (in, 3H), 7.40-7.48 (in, 6H), 7.56 J= 15.6 Hz, I 7.65 J 1.8 Hz, I1H). MIS (APCI*) at m/lz 436, 438.
Example 83 -4-Dimethylnhenyl) r2-nitro-4-(E-((4-acgtylpiperain-..I yl~carbonyl)ethenyl~phenYI Isulfide 128 To a solution of the compound of Example 32A (40 mg, 0.12 mmole) in mL of dimethylformamnide 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 I 00 0 C for 20 h. The solvent was removed using N 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, 8 as light yellow solid.. 'H--NMR (CDCl., 400 MHz) 6 2.08 3H), 2.23 3H), 2.27 3H4), 3.45 (br, m, 2H), 3.63 (br, m, 6H4), 6.79 IH), 6.82,(d, J 19 Hz, 1H), 7.18 (dJ= 19 Hz, IH), 7.24 (dd, J=4, 19 Hz, 1H), 7.27 IH), 7.34 J 21 Hz,- IH), 7.56 J= 39 Hz, IH), 8.32 4 4Hz, IH). MS (APCI) (M+H)4 at m/.z 440.
FAB High Resolution MS calculated m/z for C,' 3
H,
6
NO
4 S O.644.
Observed mlz: 440.1646.
Example 84 (2-Brormophenvl'ff2-trifluoromethyl-4-( E-((4-acetylpiperazin- I -yI)car .bonylj ethenyl) phenyl] sulfide The title compound was prepared by the procedures described %in Example 9 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, and 3,4dichlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzaldehyde, to give a white solid. 'H NMR (d 6 -DMSO, 300 MHz) 5 2.04 3H), 3 .43 -3.80 (in, 8H), 7.21 (dd, J= 2.1, 8.4 Hz, I1H), 7.24 J= 8.4 Hz, IlH), 7.3 3 (td, J 2.1, 7.65 Hz, I 7.42 (td, J 1.8, 7.65 Hz, IH), 7.45,(d,J= 15.6 Hz, I 7.58 J 15.6 Hz, IH), 7.78 (dd, J= 129 1.8, 8.4 Hz, 1H), 7.96 (dd,J= 1.8, 8.4 Hz, 1H), 8.25 1.8 Hz, 1H). MS (APCI-) (M+NH4)' at m/z 530, 532, 534.
Example (5-Indolyl)r2-chloro-4-( E-((4-acetvlpiperazin-1-vl)carbonvl) ethenyl) phenvll sulfide 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 2
CO
3 (174 mg, 1.26 mmol), and cuprous iodide (20 mg, 0.11 mmol). The resulting mixture was then heated at 120 °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 NaSO 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 (115 mg, 25 based on the iodide) as a light-brown solid; 'H NMR (d 6 DMSO, 300 MHz) 2.03 3H), 3.40-3.78 8H), 6.51 J= 8.4 Hz, 1H), 6.53 (s, 1H), 7.23 (dd, J= 2.1, 8.4 Hz, 1H), 7.27 J= 15.6 Hz, 1H), 7.39 J= 15.6 Hz, 1H), 7.41 (dd, J= 1.8, 8.4 Hz, 1H), 7.49 J= 2.7 Hz, 1H), 7.56 J= 8.4 Hz, 1H), 7.85 J= 1.8 Hz, 1H), 7.99 J= 1.8 Hz, 1H). MS (APCI) at m/z 440, 442. Anal. Calcd for C 2 3
H
2 2 C1N 3 0 2 S 0.53 CH2C1 2 C, 58.28; H, 4.79; N, 8.66.
Found: C, 58.31; H, 4.93; N, 8.65.
Examinle 86 (5-BenzodioxolvlM[2-chloro-4-( E-((4-acetylrpiperazin- I -yl)carbonyl) ethenyl) phenvll sulfide The title compound wa's 'prepared by the procedures described in Example substituting 5-iodoindole with I -iodo-3,4-methylenedioxybenzene, providing a white solid. 'H NMR (CDCl 3 300 MHz) 8 2.14 3H), 3.48-3.60 (in, 2H), 3.60-3,84.(in.- 6H), 6.05 2H), 6.75 J= 8.4 Hz, I 6.80 J=is15.3 Hz, I1H), .6.8 8 J= 8.4 Hz, IlH), 6.98 (d J~ 2.1 Hz, I 7.08 (dd, J 2.1, 8.4 Hz, I 7.19 1.8. 8.4 Hz, I 7.52 J= 2.1 Hz, I 7.5 8 J= 15.6 Hz, IlH). MS (APICI) at m/z.445, 447.
Example 87 (2-Isopropylphenvi )[2-nitro-4-(:E-((2-ca rbomethoxypiperazin- I-vi )carbonvI)ethenvl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR (DMSO-d,, 300MHz) 8 1.14 J =6.6 Hz, 6H); 2.52-2.91 (br m, 5H); 3.30- 3.40 (1n 3 .68, 3.69 s, 3H); 4.10-4.25 (br m, I 5.00-5.21 (br m, I 6.60- 6.65(m, 7.29-7.6.2 (mn, 6H); 7.85-7.95 (in, 1H); 8.64-8.68 (in, IH). MS (APCI) at mlz 470.
Example 88 (2,3-Dimethoxyphenyl)-r2-chloro-4(E-rmo~holin- I -yl)carbonyllethenVl)Rhenyll sulfide The title compound was prepared according to the procedures of Example 1, giving a white solid, ni.p. 148-150C. 'H NMR (CDCl 3 300 MI-z) 8 3.60-3.78 (in, 8H), 3.85.(s, 3H), 3.91 311),.6.78 J=l6Hz, IH), 6.86-6.98 (in, 3H1), 7 J=9Hz, 2Hz. 1H), 7.54 J=2Hz, 111), 7.58 J=l6Hz, 1H). Anal. Calcd. for.
C
2 1 H,,ClNO 4 S: 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-acetlpipedrazil- I1yl)carbonyl)ethenyl)phenyll sulfide The title compound was prepared by the procedures described in Example 83 substituting -3 ,4-dimethylthiophenol with 2-fluorothiophenol. Yellow solid (40 ing, 'H-NMR (CDCl 3 400 MHz) 8 2.17 3H1), 3.56 (br, 2H), 3.77 (br, m, 6H), 6.88 (dd, J 21 Hz, 1H), 6.93 J =39 Hz, IH), 7.26 (dd, J 3 321 Hz, 7. 33 (dd, J 3, 19 Hz, 111), 7.49 (br, d, J =20 Hz, 111), 7.5 8 (mn, I 7.66 8.46 J =4 Hz, 111). MS (APCI) (M+Hy) at rn/z 43 0. FAB High Resolution MS calculated m/z for C,,H,N 3
O
4 FS 430.1237. Observed mlz: 430.1246.
Example (2-Bromoiphenv') r2-trifluorome thvl-4-( E-((4-(teri'-butoxvcarbonyJ)piperazin- I1yl)carbonyl)ethenyl) phenyll sulfide 132 The title compound was prepared by the procedures described in Example I substituting 2,4-dichiorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 4-fluoro-3-trifluoromethylbenzadehyde, and 6-amino-I -hexanol with t-butyl Ipiperazinecarboxylate, to give a white solid. 'H NMR (CDCl,, 300 MHz) d 1.48 (s, 9H4), 3.49 (br s, 4H), 3.56-3. 78 (in, 4H), 6.89 J= 15.6 Hz, I 7. 10 (dJ I 8.4 Hz, lH), 7.18-7.35 3H), 7.49.(d,J= 8.4Hz, IH), 7.65 15.6 Hz, 1H), 7.68 (dd, J= 8.4 IH), 7.8 5 (br s,I 1H). MIS (APCIV) at rn/z 605, 607, 609. Anal.
Calcd for C 25
H
2 6
N
2
O
3 BrF- S .0.03 H 2 0: C, 52.50; H, 4.59; N, 4.90. Found: C, 52.54; H, 4.71; N, 4.68.
Example 91, (2-(Pvrrolidin- I -vflphenyfl[2-trifluoromethvl-4-( E-((4-(ter butox ycarbonyl)piperazin- I -yl)caibonvl)ethenyl) phenyll sulfide The title compound wa .s 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. 'H NMR (CDC1 3 300 MHz) 8 1.85 9H), 1.85 (br s, 4H), 3.32-1.55 (in, 8H), 3.55-3.78 (mn, 4H), 6.76 J= 8.4 Hz, IH), 6.82 15.6 Hz, IH), 7.23- 7.45 (in, 7.61 J 15.6 Hz, I 7.75 (br s, I MIS (APCIF) at ,n/z 562.
Example 92 (3 -CarboxamidophenylMr2-nitro-4-( E-(4-acetylpiperazin-l-I -1carbonyl) ethenyl).phenyll sulfide Example 92A (3-CarboxyphenylMr2-nitro-4-( E-((4-acetvPiperazin-1 -vl~carbonyl) ethenyl) henyll sulfide The title compound was prepared by the procedures. described in Example 32B substituting 2,4-dichiorothiophenol -with 3-mercaptobenzoic acid.
Example 92B (3-CarboxamidophenylMr2-nitro-4-( E-((4-acetvlpiperazin- I -vl)carbonyl) ethenyl) p2henyll sulfide To a stirred solution of benzoic acid from Example 92A (40 mg, 0.088 mmol) in I mL of anhydrous DMF with HOBT (15 mg, 0.097 mmol) was added EDAG (19 mg, 0.097 mmcol), followed by ammonium chloride (large excess). The pH of the 'solution was adjusted to 6 withaddition 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). 'IH NMR (d 6 -DMSO, 300 MHz) 8 2.04 3H), 3.43-3.82 (in, 8H), 6.84 J 8.7 Hz, 1lH), 7.43 J 15.6 Hz, I 7. 53 J 15.6 Hz, IlH), 7.5 6 J 1. 8 Hz, INH), 7.66 J= 7.65 Hz, I 8.06 (d2 J= 7.80'Hz, I 8.12 2H), 8.67 J 2.1 Hz, I1H). MS (ESI") at. m/z 477.
Example 93 (3-(Hydroxymethyl)phenyl)r2-nitro-4-( E-((4-acetvlpiperazin- I -yl)carbonyl) ethenvi') phenyll sulfide To a stirred solution of benzoic acid from Example 92A (255 mg, 0.56 minol) in 5 mL. of anhydrous TI-IF at. 0 0 C was added in turn Et 3 N (102 mL., 0. 73 minol) and.
ethyl chioroformate (7.0 mL, 0. 73 mmol). After 60 mm n, the reaction mixture was filtered through celite plug into a stirred solution of NaBH, in water at 0 OC. The resulting reaction mixture stirred at 0 *C for 2. h before it was extracted with EtOAc (2x20 mL). The combined o rganic layers was washed with 3N*HCI, brine, dried over 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 ing, 32% yield)*as a light-yellow soli 'H N MR (d 6 -DMSO. 300 MHz) 8 2.0.4 3H), 3.40-3.79 8H), 4.56 2H), 5.38 (br s, I 6.85 J 8.7 Hz, 11-H), 7.42 J 15.6 Hz, I 7.52 (br s, 3H), 7.57 (br s, 2H), -7.91 (dd, J 2.1, 8.7.
Hz, I 8.66 J= 2.1 Hz, IlH). MS (APCI') (M+NHX) at ni/z 459., Example 94 Phenyl [2-trifluoromethyl-4-( E-((4-(ter,-butoxycarbonyl)piperazin- 1vl)carbonyl)ethenvl) Rhenyll sulfide The title compound was obtained as a reductive side product from the reaction mixture described in Example 9 1, as a colorless oil. 'H NMR (CDCI 3 300 MHz) 8 135 1.49 9H), 3.43-3.56 (br s, 4H), 3.56-3.82 (in, 4H), 6.85 J= 15.6.Hz, 1H), 7.06 8.4 Hz, 1H), 7.37-7.50 (in, 4H), 7.63 15.6 Hz, I 7.67 J 8.4 Hz, 1IH), 7276 J= 11.7 Hz, iN), 7.80 IH). MS (APCIV) at m/z 527.
Example 2 -IsopropvlpDhenvl)[2-trifluorometfhvl-4-( E-((2-carbomethoxy-4-(;ertbutoxycarbony])piperazin- I -vI)carbonvl)ethenvJ 12henyll sulfide The title compound was prepared according to the procedures 'of Example 7 1.
IH NMR (CDCI1 3 300 MHz) 5 7.79 I1H), 7.62 I H, J =15.0 Hz), 7.48 I H, J= 7.2 Hz), 7.43 (in, 2H), 7.38 IH, J =8.1 Hz), 7.22 (in, INH), 6.86 I H, J =15.4 Hz), 6.80 I H, J 8.4 Hz), 5.3 0 (br, IN), 4.62 (br d, 2H, J 14.0 Hz), 3:.89 (br m,.
I1H), 3.76 3 3.49 (dq, IH. J IJ, =6.9 Hz), 312 (in. 2H), 2.94 (hr, I1H), 1.46 (s, 9H), 1. 17 6H, J 6.6 Hz). MS (ESI) m/z -591, -627, -677.
Example 96 (2-IsopropyinhenyW) 2-nitr-(4 E-((3-(pyridine-4-methvlaminiocarbonvl )-4-tertbutoxvcarbonvilpiperazin- I -vi )carbonyl )ethenyl) phenvll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMS0-dl 6 300MHz) 8 1. 14 J =6.6 Hz, 6H); 1.38 9H); 2.83-3.85 (br in, 5H); 4.09-4.51 (hr in, 4H); 4.91-5.09 (br m, INH); 6.64 J 8.5 Hz, I 7.12- 7.62, (in, 8H); 7.82-7.96 (in, INH); 8.26-8.48 (in, 2H); 8.63 -8.75 (mn, 2H). MS. (APCI) 136 at m/z 646. Anal calcd for C 3
,H
39 C, 63.24; H, 6.09; N, 10.84. Found: C, 63.07; H, 6.43; N, 10.54.
Example 97 (2-Ethoxyphenvl)-[2-chloro-4(E-[(morpholin- -vl)carbonvllethenvl)phenvl]sulfide Example 97A 2-Ethoxvbenzenethiol To 7.82g of ethoxybenzene and 7.41g 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, (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% HCI in water until all salts. The aqueous phase was separated and washed with ether. The combined ether layers was washed with HCI, then water. After drying with Na,SO,, 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-Ethoxvphenvl)-[2-chloro-4(E-r(morpholin- -vl)carbonvl1ethenvl)phenvl1sulfide The title compound was prepared according to the procedures of Example 1, substituting the thiol of Example 97A, giving a white solid, m.p. 125-127C. 'H NMR (CDC1 3 300 MHz) 8 1.25 J=7Hz, 3H), 3.60-3.78 (in, 8H), 4.05 J=7Hz, 2H), 6.76 3=15Hz, IH), 6.82 J=9H, IH), 6.94-7.00 (mn, 2H), 7.16 (dd, 3=9Hz, 2Hz, IH), 7.34-7.45 (in, 2H), 7.54 J=2Hz, IH), 7.58 J=15Hz, IH). Anal. Calcd. for
C
2
,H
2
.,CINO
3 S: C, 62.44; H, 5.49; N, 3.47. Found: C, 62.14; H, 5.70;1 N, 3.22.
Example 98 (2-Methoxyphenflf2-nitro-4-( -acetyvipjerazin- I vl)carbonyl)ethenyl~phenyllsulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethyithiophenol with 2-methoxythiophenol, giving a yellow solid mg, 77%).11H-NMR (CDCl3, 400 MHz) 8 2.14 3H), 5 3.54 (br, m, 2H), 8 3.68 (br, i, 6H), 8 3.79 3H), 5 6.81 J =21 Hz. I1-1) 8 6.89 J =39 Hz, I H, 6 7.03 J 21 Hz, IH), 8 7.08 (mn. IH), 8 7.41 (br, di. J =21 Hz,.IH), 8 7.53 (in, IH), 8 7.60 (i IRH), 85 7.65 (br, s, IlH), 8 8.42 (br, s, I1H). MIS (APCI) at m/z 442.
Example 99 (2-(Azetidin- I -vlDphenyl)[2-trifl uoromethyl-4-( E-((4-(tert-butoxvcarbonyl)piperazin- 1 yl)carbonyl)ethenyl) phenyll sulfide 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. 'H NMR (CD1 3 300.) z 8 1.48 9H), 2.18 (pentet, J 7.43 Hz, 2H), 3.40-3.53 (in, 4H), 3.53-3.77 (in, 4H), 4.02 J= 7.43 Hz, 4H), 6.54 J~ 8.7 Hz, I 6.72 J= 8.7 Hz, I 6.78 (tt, J 7.3 5 Hz, IlH), 6.81 J 15.6 Hz, I1H), 7.29-7.42 (in, 3H), 7.61 J 15.6 Hz, I1H), 7.75 (br s, I MIS (APCI-) at m/lz 548.
Example 100 (2-(Piperidin-1I-VI )nhenyl)[2-trifluoromethyl-4-( E-((4-(Ieri-butoxvcarbonvl~piperazin- I -yl)carbonyl)ethenyl) phenyll sulfide 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. 'H NMR (CDC3, 3-00 MHz) 1.48 9H), 1.54 (br s, 6H), 2.96 (br s, 4H), 3.48 (br s, 4H), 3.55-3.78 (mn. 4H), 6.86 J 15.6 Hz, I 6.99 (td, J 1. 8, 7 .5 Hz, IlH), 7.08 J 8.4 Hz, 1. 7.19 (dd, J= 1.8, 8.1 Hz, I1H), 7.25 (br m, I1H). 7.31 (td, J 1.8, 7.5 Hz, I 7.42 (dd. J 1. 8, 8.4 Hz, I1H), 7.65 (d J= 15.6 Hz, I1H), 7.71 J 1 .8 Hz, I MS (APCI) atm/nz 5 76.
Example 10 1 (3-Chloro-2-formnylphenyl)[2-chloro-4-( E-((4-acetylr~iperazin- I -yI)carbonyl) ethenyl) Dhenv[I sulfide The title compound was prepared by the procedures described in Example substituting 2,3-dichlorobenzaldehyde with 2,6-dichlorobenzaldehyde, isolated as a white: solid. 'H NMR (CDCI 3 300 MHz) 8 2.05 3H), 3.56 (br s, 2H), 3.61-.3.86 (mn, 6H4), 6.68 J= 3.0 Hz, IRH), 6.93 J= 15.6 Hz, I 7.23 J= 3.0 Hz, I 7.25 (in, I 7.45 (dd, J 2.1, 8.4 Hz, I1H), 7.62 J 8.4 Hz, I1H), 7.67 J= 15..6 Hz, ILH), 7.69 J 2.1 Hz, I1H). MS. (APCI-) at mlz 463, 465, 467.
Example 102 (2-Trifluoromethylphenyl)[2-trifluoromethyl-4-( E-((4-acetylpiperazin-l1-vl)carbonvl) ethenyl) ]2herivfl sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 8 7.84 I 7.80 (in, I 7.66 I H, J =15.4 Hz), 7.49 (in, 3H), 7.40 (in, lH), 7.06 I1H, J =8.0 Hz), 6.87 I H, J =15.4 Hz), 3.62- 3.80 (mn, -3.53 (in, 2M. 2.15 3H). MS (ESI) m/z 503, 525.,1027.
Example 103 (3-Bromophenyl)12-trifluoromethyl E-((4-acetylp~iperazin-1I-yl)carbon-vl) ethenyl) phenyll sulfide The title compound was prepared accordi ng to the procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 8 7.83 lH), 7.66 IlH, J 15.4 Hz), 7.57 I H, J =1.9 Hz), 7.49 (mn, 2H), 7.36 (dt, IR, J 1.6, 7.8 Hz), 7.24 (in, IH), 7.18 1H. J 8.1 Hz), 6.87 I H, J 15.2 Hz), 3.62-3.82 (in, 6H), 3.54'(mn, 2H), 2.15 3H). MS (ESI) m/z 514, 515, 53 5, 53 7.
Examp~le 104 (3 .5-Dimethylrphenyl)[2-trifluoromethyl- E-((4-acetylpiperazin- I -vi )carbonyl) ethenyl) Rhenyll sulfide The title compound was prepared according to the procedures of Example. 1. 'H NMR (CDCI3, 300 MHz) 8 7.79 I1H), 7.64 I1H, J =15.1 Hz), 7.42 I H, J =8.8 Hz), 7.49 (in, 2H), 7. 13- 2H), 7.04 2H), 6.84 I H, J= 15.2 Hz). 3.62-3.82 (in, 6H), 3.54 (mn. 2H), 2.32 6H), 2.15.(s, 3H). MS (ESI) m/z 463, 485, 925, 947.
Examnle 105 2 -Isopropylphenvyl)r2-nitro-4-( E-((3dimethvaminocarbonvl-4-(pvridine-4-.
carbonyl)piperazin- I -vl~carbonvl~ethenyl) phenyll sulfide Prepared according to the procedures of Example. 71, giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 5 1.14 J =6.6 Hz, 6H); 2350-3.83 (br in, I01-H); 4.04-4.66 (br 3H); 5.32-5.43 (br m, I 6.60-6.69 (in, 1H); 7.15-7.64 (in, 8H);.
7.85-7.93 (in, IH); 8.59-8.72 (mi, 3H). MS. (APCI) at m/z 588. Anal calcd for C,,H,,NS,0 5 ,0.67H,O: C, 62.07; H, 5.77; N, 11.68. Found: C, 62.13; H, 6.01; N, 11.48 141 Example 106 (2-Isop~ronvylphenvl)r2-nitro-4-( E-((3-dimethylaminocarbony 1-4carbomethoxvpip~erazin- I -vl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 8 1.14 J =6.6 Hz, 6H); 2.50-3.83 (hr m, 14H); 4.16-.4.63 (hr m, 2H); 4.98 (br s, I 6.60-6..69 (in, I 7.20-7.6 1 6H); 7.85-7.93 IlH); 8.59-8.65 (in, 1IH). MS (APCI) atinlz 541.
Example 107 (2-lsopropylphenylfl2-nitro-4-( E-((3-dimethylaminocarbonVI-4-acetylpiperazin- 1yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 1.14 J =6.6 Hz, 6H); 1.88, 2.04 s, 314); 2.50- 3.83 (hr in, I IH); 4.16-4.59 (hr mn, 2H); 5.04-5.25. (br mn, 6.60-6.69 (in, IH); 7.21-7.62 (in, 7.85-7.93 (in, I 8.58-8.65 (mn, lH). MS (APCI at m/z 525.Ana cald fr C 7
H,
2 NS,O,: C, 61.81; H, 6.15; N, 10.68.. Found: C, 61.9;H 6.75; N, 9.67.
Example 108 (2-Isopropylphenvyjf2-nitro-4-( -morpholinocarbonyl)-4-terbutoxycarbonvlr~iperazin- 1-yl)carhonyl)ethenyl) nhenvlI sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 5 1.11-1.16 (br mn, 6H); 1.35, 1.40 (br s, br s, 9H); 2.67-5.0(br m, 16H); 6.60-6.6.9 (in, 1H); 7.28-7.62 (in, 6H); 7.87-7.92 (in, 1H); 8.63- 8.7(br mn, IH). MIS (APCI) at m/z 625. Anal calcd for C,,H, 40 0: C, 61.52; H, 6.45; N, 8.97. Found: C, 61.10; H, 6.65; N, 8.60.
Example 109 (2-Isopropy lphenyl )r-nitro-4-( -(Dvridine-4-methylaminocarbonyl)perazin 1yl)carbonyl)ethenvl) phenyl]1 sulfide Prepared according to the procedures of Example 7 1, giving a yellow solid.
'H NMR (DMS0-d,, 300MHz) 6 1. 14 J =6.6 Hz, 6H); 2.50-4.46 (br I OH); 6.6.3 J =8.5 Hz, lH); 7.20-7.64 (mn, 8H); 7.85-7.93 (in, 8.43-8.65 (mn, 4H). MS (APCI) at in/z 546. Anal. calcd for C,,H,,NS,-0.46CHCOOCH,CH,:
C,
63.20; H. 5.96; N, 11.95. Found: C, 63.29; H, 6.27; N, 11.97.
Example 2 -Isopronvlphenyl)[2-nitro-4.( 3 -dimethlaminocarbonl)piperazin-
I
yl)carbonyl)ethenvi) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H N.MR (DMSO-d,, 300MHz) 8 1.14 J =6.6 Hz, 6H- 2.50-3.20 (br m, 4H); 2.82 3H); 3.04 3H); 3.26-3.49. (in, IH)- -3.52-3.59 (mn, 1H); 4.08-4.47 (br m, 2H-); 6.63 J 8.5 Hz, I1H); 7. 3 1-7.62 (nmi 7.86-7.92 (in, I 8.61 (br m,I lH). MS 143 (APCI) at m/z .483. Anal calcd for C,,H, 0 NS,0 4 0.39CHCOOCH, 2 CH,: C, 61.71; H, 6.46; N, 10.84. Found: C, 61.96; H, 6.69; N, 10.73.
Example I111 (2-Isopropylphe-nv)[2-nitro--( E-((3-(benzlaminocarbonyl)-4-terIbutoxycarbonylrinerazin-1I-yl)carbonyl')ethenvl) phenyll sulfide Prepared according to the procedures of Example 7 1; giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 5 1.14 J =6.6 Hz, 6H); 1.33, 1.42 (br s, br's, 9H); 2.75-4.77 (br m, 101H); 6.60-6.66 (br m. IH); 7.02-7.94 (br m, 12H); 8.47-8.67 (in, 2H). MS (APCI) at nilz 645.
Example 112 Isbpropylphenylfl2-nitro- 4 E((3(dimethylaminocarbonl l- 4 -tertbutoxycarbonylpip~erazin-l1-yl)carbonyl)ethenyl) phenvil sulfide Prepared according to the procedures of Example 71,gvna yelwsid 'H NMR (DMSO-d,, 300MH z) 5 1.14 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 IH); 7.21-7.62 (in, 6H); 7.86-7.92 (in, 1H); 8.59-8.63 (br m, 111). MS (APC1) at m/z 583 Anal calcd for
C,,,H
3 NS0 6 ,0.21ICH,: C, 62.50; H, 6.87; N, 9.32. Found: C. 62.28; H, 7.15; N, 9.11.
Example 113 144 (2-Bromophenyl)[2-chloro-4-(E-((3-(5S-hvdroxymethyl-pyrrolidin-2-.on- I -yl)hronj Iylamino)carbonyl) ethenyl)phenyll sulfide (2-Bromophenyl)[2-chloro-4-(2-carboxy-E-ethenyl) pheriyl]sulfide was prepared by the procedures described in Example 1 substituting 2,4 dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3,4 dichlorobenzaldehyde. I -(3-aminopropyl)-5-((S)-thexyldimethylsilyloxymethyl)-2pyrrolidinone (0.281 8g, 0.8959 m-mol) was added to a solution of this cinnamic acid (0.33 12g, 0.8959 mmol), 1 -[3-(dimethylamino)propyl]-3-'ethyl carbodiimide hydrochlorid e (0.3435g, 1.79 mrnol), and I -hydroxybenzotriazole hydrate 181 6g, 1.34 mmnol) in DMF (4.0 rnL). After stirring for 1 2h the reaction mixture was diluted with EtOAc (250 mL), extracted with sat.. NHCl (1075 rnL), extracted with H,O (2075 mL), rinsed with brine (75mL), and dried over Na,S0 4 The resultant thexyldimethylsilyl alcohol was purified by flash chromatography (EtOAc) on silica gel (.4974 g, Tetrabutylammoniumn fluoride (.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 2h the reaction was diluted with EtOAc (50 mL) and extracted with sat. NHCl I (x25 mL), extracted with H,O (2x25 rinsed with brine and dried over Na,S0 4 Flash chromnatography (EtOAc -49:1 CH.,CI,:MeOH) on silica gel yielded the title compound (.3144g, 'H-NMR (DMSO-d 6 300MHz) 8 8.14 J 5.5 Hz, I 7.81 (in, 2H), 7.53 (dd, J 8.3 1.7 Hz, I 7.44 (dt, J 7.7, 1I-I), 7.40 (dt, J 7.7, 1.8, 1 7.39 J =15.6 Hz, I1H), 7.28 (dd,J 1.8 145 Hz, I 7.05 J 8.1 Hz, I1H), 6.67 J=15.6 Hz, I1H), 4.84 J =5.1 Hz,: .1H), 2.94-3.62 (in, 8H), 1.54-2.29 (in. 6H), MS(APCI) at m/z 523, 525, 527, 529.
Example 114 (2-Bromophenl)l2-chloo-4-(E-((3-(pyrroidin-2-onfl- -yl)1roR-1I-ylamino)carbonvl' ethenyl)phenvilsulfide 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- 'H-NMR (DMSO-d 6 300OMHz) 8 8.12 J= 5.9 Hz, 111), 7.81 (in, 211), 7.52 (dd, J 8.1, 2.0 Hz, 111), 7.44 (dt, J 7.5, 1.4, 1 7.34 (dt, J 7.5, I 7.39 J 15.8 Hz, 111), 7.28 (dd, J1 7.6, 1.9 Hz, I1H), 7.05 J 8.1 Hz, 1H),.6.67 J 15.8 Hz, I1H), 4.02 J Hz, I 3.29-3.3 5 (mn, 211), 3.11-3.25.
(mn, 411), 2.21 J 8.1 Hz, I H)7 1.94 (mn. 2H), 1.64 (in, 211), MS(APCI) (M+H)Y at mlz 493, 495, 497, 499.- Example 115 (2-Bromop~henvi) [2-chloro-4-(E-(N-methyl-N-(3-(pyrrolidin- 2 -Ofl-1-yl)prop- vl')amino)carbonyl) ethenl)pheny 11sulfide The title compound was prepared by the procedures described in Example -I substituting 2,4 dichlorothiophenol with 2-broinothiophenol, 2-chlorobenzaldehyde.
with 3,4 dichlorobenzaldehyde. and 6-amino-1-hexanol with 146 .methylaminopropyl)-2-pyrrolidinone. 'H-NMR (DMSO-d 6 300MHz) 5 8.06 J Hz, I 7.80 (dd, J 7.7, 1.1 Hz, I 7.64 (dd, J= 8.5, 1.7 Hz, I1H), 7.25-7.46 (in 7.04 J=8. 1, 1. 1, 1 3.14-5.3 0 (in, 6H), 3.14 I1H), 2.91 2H), 2.19 (in, 2H), 1.92 (nm, 2H), 1.68 (mn, 2H), MS(APCI) (M+H)Y at mlz 507, 509, 511, 51.
ExamRle 11 6 r2-Methoxylethoxyphenyl)-[2-chlor-4(E-[mompholin- I1yI)carbonyllethenyl~henyll sulfide The title compound was prepared according to the procedures of Example 97,, substituting 2-methoxyethoxybenzene, giving a white solid. 'H NMR (CDCI.,. 300 MHz) 563.29 3H), 3.60 J=7Hz, 2H), 3.60-3.78 (in, 8H), 4.12 J=.7Hz. 2H), 6.78 J=l 5Hz, 1H), 6.82 J=9H, 1H); 6.95-7.03 (in, 2H), 18 (dd, J=9Hz, 2Hz, IH), 7.36-7.45 (in,2H), 7.52 3=2Hz, IH), 7.57 J=15Hz, Anal. Calcd. for
CINO
4 S: C, 60.85; H, 5.57; N, 3.22. Found: C. 60.65; H, 5.59; N. 3.12.
Example 11 7 (2-Isbpropylphenylfl2-nitro-4-( -(morp~holinocarbonyl)piperazin- 1 yl)carbonyl)ethenvl) phenyll sulfide Prepared according to the procedures of Example 71,, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz)- 8 1. 14 J =6.6 Hz, 6H); 2.50-3.40 (br mn. 6H), 3.42- 3.64 (br m, 8H); 4.07-4.44 (br in, 2H); 4.084.47 (br in, 2H); 6.64 J 8.5 Hz,.IH); 7.3 1-7.62 (in, 6H), 7.87-7.92 (in, I1H); 8.61 (br in, I1H). MS (APCI) at in/z 525. Anal calcd for C,,H 2 N,S,0 3 -1.57H, 2 0: C,.58.64; H, 6..41; N, 10.13. Found: C, .58.69; H, 6.36; N, 9.7.8.
Example 118.
(2-Isopropyl]2henyl)f2-nitro-4:-( E-((4-teri-butoxvcarbonylpiperazin- 1 vl)carbonyl)ethenvl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NM.R (DMSO-d,, 300MHz) 8 1. 14 J =7.0 Hz', 6H); 1.41 3.30-3.40 (Mn IH); 3.50-3.72 (br mn, 6.64 J =8.5 Hz, 111);' 7.34-7.62 (mn, 6H4); 7.87-7.92 (dd, 8.5, 1.5 Hz, I 8.65 J =1.5 Hz, I1H). MS (APCI) at mlz 51.Anal calcd for C,IH 33 NS,0 5 C. 63.3 8; H, 6 .5 0; N, 8.2 1. Found: C. 63.69; H, 6..62; N, 7.8 7..
Exampnle 119 (2-I sopropyiphenvl )r2-nitro-4-( E-((4-methoxycarbonylperazin- I v')carbonyI)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 8 1.14 J 6.8 Hz. 6H); 3.62 3.30-3.38 (in, I 3.38-3.72 (br in, 6.64 J 8.8 Hz, IlH); 7.34-7.62 (in, 6H); 7.87-7.92 (dd, J 8.8, 2.0 Hz, IlH);- 8.64 J 2.0 Hz, I MS (APCI) at in/z 470. Anal calcd for C, 4
,H,
7 N,SQ,0.34C H C, 62-.77; H, 6.27; N, 8.44. Found: C, 62.70; H, 6.33; N,.8.27.
*148 Example 120 (2-lsopropylphenvl)[2-nitro-4-( E-(4-(pvridine-4-carbonvl)pipera7in- Iyl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR. (DMSO-d,, 300MHz). 8 1. 14 (di, J 6.6 Hz, 6H); 3.30-.3.40 (in, I 3.52- 3.86 (br 6.61-6.66 (br m, MH); 7.30-7.62 (in, 8H); 7.83-7.,96 (br m, 1H); 8.60- 8.71 (in, 3H). MS (APCI) at m/z. 517. Anal calcd. for C,,H,NS0 4 ,0.38-CH 3 COOCH.CH,: C, 64.46; H, 5.69; N, 10.19. Found: C, 64.52; H, 5.94; N, 10.2 1.
Example 121.
(2-Isopropylphenvl)[2-nitro-4-( E-((3-(Pyridine-3-mbethylamfinocarbonvl)-4-terlbutoxycarbonilpiperazin- 1 -yl~carbonyl~thenyl) phjenyll sulfide Yellow solid; IIH NMR (DMSO-d,, 300M.Hz) 8 1.14 (di, J =6.8 Hz, 6H4); 1.3]-1.46 (br M, 9H); 3.30-3.41. (in, IH); 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) at mlz 646.. Anal calcd fo r
C
34 H,39SO0 13 HO: C, 62.97; H, 6.49; N, 10.79. Found: C, 62.66; H, 6.26; N, 10.60.
Example 122 (2-1 sopropylphenyl)[2-nitro-4-( E-((3-.(pyridine-2-methylaminocarbonyl)piperazin- I YI)carbonvl)ethehyl) phenyll sulfide Prepared according to the procedures of Example. 7 1, giving a yellow solid.
'H NMR (DMSO-d 6 300MHz) 8 1.14 J =7.0Hz. 6H); 3.30-3.41 (mn, IH); 2.50- 4.46 (br m, 9H); 6.64 J =8.5 Hz, 1H); 7.21-7.93 (br mn, 10H); 8.45-8.65 (br mn, 3H). MS (APCI) at m/z 546.
Example 123 (2-Isopropylphenyi)[2-nitro-4-( 3 -(pyridinie-3-met1Iylaminocarbonyl)piperain-.1y1)carbohyl)ethenyl) Rhenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR (DMSO-d 6 300MHz) 8 1. 14 J =6.6 Hz, 6H); 2.50-4 .41 (br m, *1OH); 6.61 6.67 (br mn, I 7.26-7.70 (br m. 8H); 7.86-7.94 (br m, I 8.40-8.67 (br in, 4H)., MS (APCI) at m/z 546.
Example 124 (4-Hydroxyphenvl~r2-nitro-4-( E-(-acmtlpiperazin- I1yl)carbonvl)ethenvl)p~henyjlsulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethylthiophenol -with 4-hydroxythiophenol. Yellow solid (23 -mg, 'H-NMR (Pyridine-d,, 500 MHz) 5 2.08 3 3.42 (br, mn, 2H), 3.76 (br, m.' 6H). 7.01 J 17 Hz, ILH), 7.26 (mn, 2H), 7.3 7 J= 31 Hz, I 7.59 (in, 3H), 8.02 J =31 Hz, I 8.60 J 4 Hz, I MS (APCI) at mlz 428. FAB 150 High Resolution MS calculated nilz for C 21
H
22
N
3 0 5 S 428.1280. Observed mlz: 428.1296.
Example 125 (3 .5-Dichloronhenyl)M2-nitro-4-( E-((4-acetvlpiperazin- 1yl)carbonyl)ethenyl~lhhenyllsulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethylthiophenol with 3.5-dichiorothiophenol. Yellow solid (12) mg, 2 'H-NMR (CDC13, 400 MHz) 8 2.04 3H), 3.43 (br, mn, 2H), 3.62 (br, m, 6H), 6.82 J 2 2 Hz, I 6.82 J 3 8 Hz, I 7.3 7 1H1), 7.3 8 I 7.40 (in, 1H), 7.43 (dd. J ,21 Hz, 11H), 7.55 J =38 Hz, 11H), 8.29 J 4 4Hz. IH).
MS (APCI) at mlz 480. FAB High Resolution MS calculated m/z for
C
21
H
20 N3O 4 Cl 2 S 480.0552. Observed ml/z: 480.0553.
Example] 26 (2-Broinophenyl) F2-chloro-4-(E-((3-(5S-acetoxvrnethvl-12rrolidil-2-ol- I -yl)prop- 1ylamino)carbonyl) ethenyl)phenyll sulfide To a solution of. the compound of Example 113 (0.0466g, 0.0889 inmol) in
CHCI
2 mL) was added triethylamine (0.024 mL, 0. 18 mmol) and acetic anhydride (0.0088 mL, 0.093 3 minol). After 12 h the reaction was diluted with MeOH (1.5 mL) and purified by preparative HPLC to provide the title compound (.0458 g& NMR (DMSO-d 6 300M1-z) 8 8.14 J=.5.7 Hz, 1H), 7.80 (in, 2H), 7.53 (dd, J= 151 Hz, IH), 7.45 (dt,J=7.7, 1.5, I 7.35.(dt,J= 7.7, 1.8, I 7.39 15.6 Hz, I 7.29 (dd, J 7.7, 1.8 Hz, I 7.05 J= 8.1 Hz, I 6.67 J= 15.6 Hz, I1H), 4.20 (dd, J 11. 8, 3.7 Hz, I 4.03 (dd, J 11. 8, 4.0 Hz, I1H), 3.85 (in, I H), 3.45 3.15 (in, 2H), 2.95 (in, 2H), 2.00-2.48 (in, 2H), 2.02 3H), 1.5 1-1.82 (mn, 2H), MS(APCI) at in/z 565, 567, 569, 5 71.
Example 127 (2Bonpey)2clr--E(3(5-eh~r hlproii--n -vyl)pron-l ylarnino)carbonyl) ethenyl)phenyllsulfide Sodium hydride (0.0088g, 0.22 mmol, 60% dispersion) was added to a solution of the compound of Example 113 (0.0524g, 0. 1 minol) in DMF (0.5 inL).
After 15 min, iodomethane (0.025 inL, 0.4 inmol) was added and the reaction was stirred for 12 The reaction was diluted with EtOAc (7 inL) and extracted with sat.
NH
4 C1 (I1x2.5 inL), extracted with H.,O (2x2.5 mL), rinsed with brine (2.5inL), dried over Na,S0 4 filtered, and concentrated in vacuo. The crude products were diluted with MeOH (1.5 mL) and purified by preparative HPL!C to provide the title compound (0.0408 g, 'H-NMR (DMSO-d 6 300MHz) 8 8.07 1 7.80 (dd,J= 7.9, 1.3 Hz, 1H), 7.64 (dd, J 8.3 1.6 Hz, 1H), 7.23-7.46 7.04 J 8.1,I 1H), 3.74 (in, 1H), 4.4-3.52 (in, 6H), 3.27 1.5H), 3.22 1.5H), 3.14 1.5H), 2.91 (s, 1.5H), 1.5-2.3 (mn, 6H), MS(APCI) (M+H) 4 at inlz 551, 553. 555.
Example 128 152 (2-Bromo]phenyl)[2- chloro-4-(E-((3-(4R-hydroxyrmethl-vrrolidil-2-ofl- I -Xl)prop- 1 ylamino)carbonyl) etfienyl~phenyll sulfide The title compound was prepared by the procedures described for Example 113 substituting I -(3-arninopropyl)-5-((S)-thexyldimethylsilyloxymepthyl)- 2 pyrrolidinone with I -(3-aminopropyl)-4-((R)-thexyldimethylsilyloxy)-2pyrrolidinone. 'H-NMR (DMSO-d6, 300MHz) 68.13 5.5 Hz; IH), 7.80.(in, 2H), 7.53 (dd, J 8.5, 1.7 Hz. I 7.27-7.44 (mn, 4H), 7.05 J 8.1 Hz, 1H), 6.67 15.8 HzIH), 5.19 J =3.7 Hz, IH), 4.28 (br s, lH), 3.10-3).62 (in,8H), 2.06 (dd, I 1 .63 (i,1 MS(APC1) (M+H)4 at m/z 509, 511, 513.
Example 129 Phenvi [2-nitro-4-( E-((4-acetvlyiperazin- 1 -Y)carbonyl)ethenvl)phenvllsulfide The title compound was prepared by the procedures described'in Example 83 substituting 3.4-dimethyithiophenol with thiophenol. Yellow solid (36 ing, NMR (CDCI3, 400 MHz) 8 2.20 3H),.3.59 (br, m, 2H), 3.7 8 (br, m, 6H), 6.92 J =21 Hz, I 6.95 J 3 39 Hz, I 7.49 (br, d, J =21 Hz, I 7.5.6 (mn, 3H), 7.65 (mn, 2H), 7.69 J 3 38 Hz, I 8.46 J =4 Hz, I MS (APCI) (M+H)Y at mlz 412. FAB High Resolution MS calculated in/z for C-,,H22N 3 0 4 S 412.1331.
Observed m/z: 412.1l342.
Example 130 (2-Dimethvlaminojvhenvi)r2-nitro-4-( E-((4-acetylpiperazi n-I -vI)carbonyl) ethenyl) phenyl sulfide To a stirred solution of aniline from Example 47 (21 mg, 0.049 mmol) in 1 mL of ethanol was added Me 2
SO
4 (14.0 mL, 0.15 mmol) followed by sat. Na 2
CO
3 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,SO 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.
'H NMR (CDC1,, 300 MHz) 5 2.16 3H), 2.83 3H), 3.32 (br s, 3H), 3.47-3.85 8H), 6.75 J= 8.4 Hz, 1H), 6.78 J= 8.4 Hz, 1H), 6.82 J= 8.4 Hz, 1H), 6.89 15.6 Hz, 1H), 7.40-7.51 3H). 7.64 15.6 Hz, 1H), 8.45 (d,J= 1.8 Hz, 1H). MS (APCI') at m/z454.
Example 131 (3-((2-Hvdroxvethvl)aminocarbonvl)phenvl)[2-nitro- 4 E-((4-acetvlpiperazin-1vl)carbonyl)ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example 92B, substituting ammonium chloride with ethanolamine, to give a light yellow solid.
'H NMR (d 6 -DMSO, 300 MHz) 5 2.04 3H), 3.30-3.79 12H), 4.75 J 5.7 Hz, 1H), 6.85 J= 8.7 Hz, 1H), 7.42 J= 15.6 Hz, 1H), 7.54 J= 15.6 Hz, 1H), 7.66 J= 7.8 Hz, 1H), 7.79 J= 8.1 Hz, 1H), 7.92 (dd, J= 2.1, 8.1 Hz, 1H), 8.04 154 J= 8.4 Hz, I 8.11 I1H), 8.62 J 5.7 Hz, I 8.66 J 2.1 Hiz, I MS (APCIV) at m/lz 533, 535.
Example 132 (346(3-( I midazolylTropv)aminocarbonvl~hhefilV)[ 2 -fitro- 4 E(4-acetvlpiperazin- 1 -yl~carbonyl)ethenvl1) phenyll sulfide The title compound was prepared by the procedures described in Example 92B, substituting amnmonium chloride with 3-amninopropyl-1 -imidazole, as a light yellow solid. 'H NMR (d 6 -DMSO, 3 .00 MHz) d 1.96 (quintet, J 6.98 Hz, 2H), -2.04 (q,J 6.98 Hz% 2H), 3.35-3.95 (mn, 8H), 4.02 (t,J 6.98 Hz, 2H), 6.87 (d J= 8.4 Hz, 1H), 6.88 1H), 7.19 IH), 7.41 J= 15.6 Hz, LH), 7.54 J 15.6 Hz, 1H), 7.64 IH), 7.68 J 7.8 Hz, 1H), 7.79 (dt, J= 1.8, 7.8 Hz. 1 H), 7.91 (dd,J= 1.8, 8.7 Hz, I1H), 8.03 (d J= 7.8 Hz, 1H), 8.09 J= 1.8Hz, I 8.65 J =1.8 Hz, 1H). MS (APC-) (M+CI) at m/z 597, 599.
Example 133 Morpholinyl)ethyl)aminocarbonyl)phenylYr2-nitro- 4 E-(4-acetyltgiperazifl- I -vl~carbonvl)ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example 92B3, substituting ammoniumn chloride with 2-aminoethyl-1I-morpholine, as a light yellow solid. 'H NMR (d 6 -DMSO, 300 MHz) 5 2.04 3H), 2.44 (br s, 4H).3.20-3.80 16H), 6.87 J =8.4 Hz, I 7.41 J 15.6 Hz, I 7.54 J =15.6 Hz, 155 1H), 7.68 J= 8.4 Hz, I 7.79 J= 8.4Hz, 7.91 (dd, J= 2.1, 8.41Hz, IH), 8.02 J= 8.4 Hz, I1H), 8.07 1H), 8.58 J=6.0 Hz, 1H), 8.65 J= 2.1 Hz, I MS (APCI-) at m/lz 568.
Example 134 (2-Isopropylphenyl)[2-nitro-4-( E-((3-hvdroxymethyl-4-tert-butoxvcarbonylpiperazin- I -yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 711, giving a yellow solid.
-H NMR (DMS0-l 6 300MHz) 8 1.14 J =7.0 Hz, 6H); 1.41 OH); 2.62-3.20 (br m, 4H); -3 .3 0-3.40 (in, I 3.72-4.44 (hr mn, 4H); 4.72-4.98 (hr mn, I 6.62-6.66. (hr I, 1H); 7.25-7.63 (in, 16H); 7.83 -7.93 (hr m, I 8.57-8.66 (hr mn, I MS (APCI) at in/z.542. Anal calcd for C,,H,,NS,0 6 -0.21C, 6
H
4 C, 62.78; H, 6.8 3; N, 7.51. Found: C, 62.65; H, 6.99; N, 7.36.
Example 135 (2-Isopropylphenyl)F2-nitro-4-( E(40-formylpiperazin- I -vl')carbonvl)ethenyl) phenyl 1 sulfide Prepared according to the procedures of Example 71, giving a. yellow solid.
'H NMR (DMSO-l 6 300OMHz) 8 1.14 J 7.1 Hz. 6H); 3.30-3.38 (mn. lH); 3.38- 3.77 (hr mn, 8H); 6.64 J =8.5 Hz, 1H1); 7.34-7.62 (mn, 6H); 7.88-7.92 (dcl, J 1.7 Hz, 1H); 8.08 lH); 8.65 J 1.7 Hz, IH). MS (APCI) at in/z 440.
Anal calcd for C2,H, 5 NSO,: C, 62.85; H, 5.73; N, 9.56. Found: C, 63.05; H, 5.98; N, 9.47.
Example 136 (2-lsovropV1lpenyDM2-flitr6- 4 E-(2hdoyehl4tr-uoyabnliea I -yl)carbonvl)ethenvl) phenyll sulfide Prepared according to the procedures of Example 71, giviing a yellow solid. 'H NMR (DMSO-d 6 300OMHz) 8 1. 14 J =6.8 Hz, 6H): 1.41 9H); 2.72-3.50 (br m.
4H); 3.30-3.40(in, IH); 3.85-4.52 (br m, 4H); 4.74-4.91 (br m, IH); 6.62-6.66 (br m, 1 7.28-7.62 (in, 6H4); 7.81-7.91 (br m, I 8.5 7-8.66 (br m, I MS (APCI1) at m/z 542. Anal calcd for C,AHANS,0 6 -0.1I7C 6
H,
4 C, 62.65; 6.77; N, 7.55. Found: C, 62.54; H, 6.83; N, 7.33.
Example 137 (2Ehxpev)[-hoo4(-(-t yabnlie idi--vI)carbonylletheny1) phenyllsulfide The title compound was prepared according to the procedures of Example 97. 'H NMR (CDC1. 3 00 MHz) 5 1.25 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 J=7Hz, 2H), 4.15 J=7Hz, 2H), 6.84 J=9Hz, I 6.80-6.95 (broad, I 6.94-6.99 (mn, 2H), 7.18 (dd. J=9Hz, 2Hz, I 7.-3 4-7.41 (in, 2H), 7.52 1=15Hz, 1H), 7.55 J=2Hz, IH). Anal. Calcd. for
C
2 5
H
28 CINOAS. C, 63.35; H, 5.95; N, 2.95. Found: C, 63.17; H, 6.02; N, 26.02; N, .2.81.
Example 138 Aminopheny10f-nitro-4-( E-0(-acetylpipe ainl-]vl'carbonyDethenvl~phenyl Isulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethyithiophenol with 3-aminothiophenol. Yellow solid (2.9 mg, 'H-NMR (CDCl.I, 500 MHz) 5 2.20 3H), 3.60 (br. m, 2H4), 3 .77 (br, m. 6H), 4.03 (br, s, 2H), 6.85 (dd, J 16 Hz, I1H), 6.90 (in, 3 7.04 J =17 Hz, I H), 7.30 J =16 Hz, H)7.2(,J 7zH)768d, J 31 Hz, IH), 8.44 J =4 Hz, I1H). MS (APCI) (M+H)4 at m/z 427. FAB High Resolution MS calculated m/z for 3
N
4 0 4 S 427.1440. Observed m/z: 427.1440.
Example 139 (4-Aminophenyl)[2-nitro- 4 E4-acetylpiperazin-I yI~carbonvl~ethenyvphenylj sulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethylthiophenol with 4-aniinothiophenol. Yellow solid (22.5 mg, 'H-NMR (CDCI 3 500 MHz) 8 2.19 3H), 3.58 (br, mn, 2H), 3.76 (br. m, 6H), 4.03 (br, s, 2H), 6.80 (mn. I 6.93 (mn, 3H), 7.37 (in, I 7.46 J =17 Hz. I H), 7.67 J 31 Hz, 1 8.43 J 3 Hz, 1 MIS (APCI) at m/z 427. FAB High Resolution MIS calculated mlz for C 2
,H,
3 NOS 427.1440. Observed mlz: 427.1441.
Example 140 (2,4-Dimethylphenyl) nitro-4-( E-((4-acetylpiperazin-l Yl')carbonyl')ethenvl)p)henivllsulfide The title compound was'prepared by the procedures described in Example 83.
substituting 3,4-dimethyithiophenol with 2,4-dimnethylthiophenol. Yellow solid mg, 'H-NMR (CDCI 3 400 MHz) 8 1.54 (br, s, 2H), 2.14 3H), 3.53 (br, M.
2H), 3.71 (br, m, 6H), 6.5 8 J =21 Hz, I 6.76 J 3 38 Hz, I 7.03 (in, I H), 7.09 (in. I 7.28 (br, d, J= 19 Hz, I 7.33 J 20 Hz, I 7.51 J3 8 Hz, I 8.30 J =5 Hz, I MIS (APCI) at rn/z 440. FAB High Resolution MS calculated m/z for C, 3
,H
26
N
3 0 4 S 440.1644. Observed m/z: 440.1656.
Example 141 (2,5-Dimethylphenyl)r2- nitro-4-( E-((4-acetylpiperazin-1yl)carbonyl)ethenvl')phenyl Isulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethylthiophenol with 2,5-dimethylthiophenol. Yellow solid (34 mng, 'H-NMR (CDCI.3, 400 MHz) 8 2.07 3H), 2.23 3 2.28 3H),.3.46 (br, m, 2H), 3.64 (br, mn, 6H), 6.65 J =21 Hz, IH), 6.81 J 39 Hz, IH), 7.19 (in, 2H), 7.34 (in, 2H), 7.56.(d, J =38 Hz, IH), 8.35 J 5 Hz, 1H). MS (APCI) 159 at m/z 440. FAB High Resolution MS calculated ml/z for C 23
H,
6
N
3 0 4
S
440.1644. Observed m/z: 440.1656.
Example 142 (4-Methoxvnhbenyl)M2-nitro-4-( E-((4-acetvlpiperazin- 1yflcarbonyl)ethenl)Rhenyll sulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethyithiophenol with 4-methoxythiophenol. Yellow solid (44 mg, 'H-NMR 400 MHz) 5 2.09 3H), 3.48 (br, m. 2H), 3.66 (br, m, 6H), 3.83 3 6.79 J =22 Hz, I 6.83, J =40 Hz, I 6.9 5 1H), 6.98 (in, I 7.3 7 (br, d, J =20 Hz, IH), 7.43 (in, I 7.46 (in, I 7.58 J 3.8 Hz, I H), 8.3 5 J =4 Hz, I M S (APCI) at in/z 442. FAB High Resolution MS calculated m/z for C, H 24 N0S(MH: 442.1437. Observed m/z: 442.143 4.
Example 143 (3-Chlorophenyl)[2-nitro-4-( E-((4-acetyjnpeRqazin- I yl)carbonyflethenyl')phen!Lsulfide The title compound was prepared by the procedures described in Example 83 substituting 3,4-dimethylthiophenol with 3-chlorothiophenol. Yellow solid (43 mg, 'H-NMR (CDCI 3 400 MHz) 8 2.23 3H), 3.62 (br, mn. 2H), 3.80 (br, m, 6H), 6.97 J 21 Hz, I 6.99 J =39 Hz, I 7.28 J =19 Hz, IH), 7.5 7 (in, 3H), 7.675 J =4 Hz, 1H), 7.73 J =39 Hz, 1H), 8.48 J 4-Hz, IH). FAB 160 High Resolution MS calculated m/z for C,,H, 1 N3O 4 ClS 446.0941. Observed m/z: 446.0953.
Example 144 (2-Chloro. 4,5-diAmhirophenyl)r2-chloro4-( E-((4-acetylpi Iperazin- I YJ)carbonyl)ethenyl) phenyil sulfide Example 144A (2-Chloro. 4-nitro, 5-aminophenyl) [2-chloro4-( E-(W4acetylpiperazin-lIyl)carbonyl)ethenyl) phenyll sulfide The-title compound was prepared by the procedures described in Example substituting 2,3-dichlorobenzaldehyde with 4,5-dichloro-2-nitroaniline.
Example 144B (2-Chloro. 4,5-diaminophenyl)[2-chloro-4-( E-((4-acetylpiperazini-I yl)carbonyl)ethenyl) phenyll sulfide To a stirred solution of nitrobenzene from Example 1 44A (170 mg, 0.34 mmol) in 2 mnL of EtOH was added SnCI., (325 mg, 1.72 mmol)., Th e mixture was then refluxed under nitrogen atmosphere for 2 h. The reaction was allowed to co ol down to ambient. temperature, quenched with sat. NaHCO 3 extracted with EtOAc(2x20 mL). The combined organic l Ayer was washed with brine. driedover Na 2
SO
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. 'H NMR (d 6 -DMSO, 300 MHz) 8 2.04 3H), 3.42-3.80 (in, 8H), 4.84 2H), 5.3 2 2H), 6.51 J= 8.4 Hz, I 6.78 J= 8.4 Hz, 2H), 7.26 J= 15.6 Hz, I1H), 7.41 15 .6 Hz, I1H), 7.4 8 J 8.4 Hz, I 7.95 J 1.8 Hz, I MS (APCIV) at m/z 465, 467, 469, 471.
Example 145 (3 .4-Diaminophenvl)M2-chloro- 4 E-((4-acetvilniperaziflI-vl)carbony theflvl) phenyll sulfide The title compound was prepared by the procedures described in Example 144, substituting 4,5-dichloronitroaniline with 5-chioronitroaniline, resulting in A light brown solid. 'H NMR (d 6 -DMSO, 300 MHz). 5 2.04 3H), 3.3 1-3.80 (in, 8H), 4.75 2H), 5.01 6.61 J 4.2 Hz, 3H), 6.68 I 7.26 J 15.6 Hz, I1H), 7.40 J =15.6 Hz, 1 7.46 J= 8.4 Hz. 7.94 I MS (APCl') atm/z 431, 433 Example 146 (6-Chlorobenzimidazol-2-ofl-5-yl r 2 -chloro- 4 E-((4-acetylpiflRa f 1 yl)carbonyl)ethenvl) phenyll sufide A mixture of dianiline from Example 144 (35 mg, 0.075 mmol) and CDI (13 mg, 0.075 minol) in THIF was stirred at ambient temperature for one day. Solvent was then removed under reduced pressure. The crude product then purified on a Gilson 162 preparative HPLC as described in Example. 38B to give the title compound (12 mg, 32% yield) as a white solid. 'H NMR (d 6 -DMSO, 300 MHz) 8 2. 04 3H), 3.40-3.80.
(in, 8H), 6.63 J= 8.4 Hz, I 7.11 J= 2.4 Hz, I 7.12 IH), 7.23 7.32 J 15.6 Hz, IH), 7.43 J= 15.6 Hz, IH), 7.50 J 8.4 Hz, 1H), 8.03 (br s, I MS (APCID) (M-C O+H)Y at m/lz 465, 467.
Example 147 (1 -Methvlindol-7-vl)[2-chloro- 4 E-((4-acetvlpijnerazin- I -vl~carbonvlethenvl) phenyll sulfide The title compound was prepared by the procedures described in substituting 5-iodoindole with N-methyl-7-bromoindol..e, giving a light brown solid.
'H MR CD~.~,300 MHz) 8 2.14 3H), 3.47-3.56 (in, 2H), 3.56-3.83 (in, 6H), 3.96 3H), 6.142 J= 8.4 Hz, I 6.55 J= 3.6 Hz, I 6.76 J 15.6 Hz, IlH), 6.99 J 3.6 Hz, I1H), 7.09 (dd, J 2.1, 8.4 Hz, 1 7.15 J 7.65 Hz, I H), 7.42 (dd, J 0.9, 7.5 Hz, IlH), 7.53 J 1.8 Hz, I 7.55 (dd, J 15.6 Hz, I H), 7.77 (dd, J= 0.9, 7.5 Hz, I MIS (APCI-) at m/z 454, 456.
Example 148 (2-Hvdroxy. 4-aminophenyl)[2-chloro- 4 E-(4-acetylpiperazin-
I-
vl)carbonyl)ethenyl) phenylj sulfd The title compound was prepared by the procedures described in Example 1,44, substituting 4,5 -dichioronitroani line with 5-chioronitrophenol, giving a light brown solid. 'H NMR (d 6 -DMSO, 300 MHz) 5 2.04 3H), 3.4 1-3.80 5.09 2H), 6.61 J= 8.4 Hz, IlH), 6.70 J~ 7.8 Hz, IlH), 6.79 IlH), 6.80 (dd, J~ 2.1, 7.8 Hz, 1 7.26 J= 15.6 Hz, I1H), 7.40 J 15.6 Hz, I1H), 7.46 J= 8.4 Hz, 1IH), 7.94 (br s, 1H). MS (APCF) (M+H) 4 at m/z 432, 434.
Example 149 (2-1 soprop~ylphenyl) 2-nitro-4-( E-((4-methvlpip~erazin- 1 -Y)carbonvl)ethenfl) Phenvll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d 6 300MHz) 8 1.14 J =7.0 Hz, 6H); 2.19 3H); 2.25-2.36 (br m, 4H); 3.30-3.40 (in, IH); 3.51-3.72 (br 4H); 6.63 J 15 Hz, IH); 7.24-7..63 (in, 6H); 7.88-7.92 (dd, J 8.8, 1.8 Hz, IH); 8 .64 J 1.8 Hz, I MS (APCI) at m/z 4,26. Anal calcd for C,,H,,NSO,0.26H,0: C, 64.19; H, 6.45; N, 9.76.
Found: C, 64.2 1; H, 6.59; N, 9.70.
Example 150 (2-1 sopropylphenyl)[2-nitro- 4 E(4(pvyridine-2-carboflvl~pilerazin- I1yl)carbonyl)ethenyl) penyll sulfide Prepared according to the procedures of Example 71, giving a. yellow solid.
'H NMR (DMSO-.d,, 300IOMHz) 8 1.14 J =6.8 Hz, 3.30-3.40 (in, IH); 3.51- 3.83 (br mn, 8H); 6.6 1-6.66 (br mn, IH); 7.30-7.65 (in, 8H); 7.83-7.97 (mn, 2H); 8.57- 8.67 (in, 2H4). MS at m/z 517. Anal calcd for C 28 HANS,0 4 .45H,0: C, 64.07; H, 5.53; N, 10.67. Found: C, 64.04; H, 5.77; N, 10.97.
Example 151 (2-Isopropylphenyl)[2-niitro-4-( E-((4-(pvridine-3-carbonyl)piperazin- I-, yl~carbonyl)ethenyl' phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d 6 300OMHz) 6 1.14 J 7.0 Hz, 6H); 3.30-3.40 (in, 1H); 3.52- 3.87 (br m, 8H); 6.64 J 8.5 Hz, IH); 7.30-7.64 (in, 7H); 7.83-7.95 (n2H); 8.6.1- 870 (in, 3H). MS (APCI) at inlz 517. Anal calcd for -0SCV.42H 0: C, 64.16; H, 5.55; N, 10.69. Found: C, 64.18; H. 5.64; N, 10.59.
Example 152) (2-I sopRopvliihenyl )[2-nitro- E-((2-carbomethoxy-4-inethoxVcarbonylpiperazinlI yl~carbonvl~ethienvl) phenyll sulfid Prepared. according to the procedures of Example 71, giving. a yellow solid.
'H NMR (DMSO-d, 300MHz) 8 1.14 J 7.1 Hz,, 6H4); 2.70-3.95 (br mn, 4H); 3.30- 3.40 1H); 3.61, 3.61 s, 3H); 3.65, 3.67 8, 3H); 4.16-4.50 (br m, 211); 5.08- 5.39 (br m, I 6.64 (dd, J 5.1. Hz, 1H1); 730-7.63 6H); 7.83-7.94 I H); 8.62-8.67 (in, 1H). MS (APCI) at m/z 528.. Anal. calcd for
C
2 ,H,qNS0 7 ,0.19CH,,: C, 59.94; H, 5.87; N, 7.72. Found: C, 59.87; H, 5.94;.N, 7.59.
Example 153 (2-Isopropvlphenvl)[2-nitro-4-( E_((2-carboxv-4-methoxycarboflylpiperazil- I Xl~carbonyl)ethenyl) 12henyll sulfid according to the procedures of Example 71, giving a yellow solid.
IH NMR (DMSO-d 6 300OMHz) 8 1.14 (di, J 6.8,Hz, 6H); 2.70-3.95 (br m, 4H); 3.30- 3.40 (in, lH); 3.61,3.61 s, 4.16-4.51 (br m, 5.01-5.28 (br m, I 6.61 6.66 (in, I1H); 7.30-7.63 (in, 6H); 7.83-7.94 (in, I1H); 8.66 (br s, I1H). MIS (APCI) (Mat xnlz 512.
ExamRle 154 (2-Isopropylphenl)[2-flitro- 4 E((3carboinethoxy-4-rnethylpiperazinl- yl)carbonyl)ethenvl) phenyll sulfide Prepared according to the procedures of Example 7.1, giving a yellow solid..
'H1 NMR (DMSO-d 6 300MHz) 8 1. 14 (di, J 7.0 Hz, 2.25, 2.26 s, 3H). 2.20- 3.98 (br m, 8H); 3.57, 3.63 s, 3H); 6.63 (di, J 8.5 Hz, IH); 7.30-7.63 (in, 6H); 7.91 (dcl, J Hz, 8.60- 8.6 8 (br m, 1IH). M S (APCI) at mlz 4 84.
Example 155 (2-Ethoxyphenyl)- F2- chloro-4(E-r(3 -carboxyniperidin- I -yl)carbonyllethenyl)phenyvll sulfide The compound of Example 137 was hydrolyzed using an excess of aqueous 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. 166-171C. 'H-NMR (DMSO 300 MHz) 8 1.17 J=7Hz, 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 J=7Hz, 1H), 6.80 J=9Hz, 1H), 7.01 J=7Hz, 1H), 7.15 J=8Hz, 1H), 7.26-7.40 2H), 7.40-7.48 1H), 7.51 (dd, J=9Hz, 2Hz, 1H), 7.99 J=9Hz, 1H) Anal. Calcd. for
C
2 3H, 4
CINO
4 S: 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 60C to yield 307 mg of a solid, water soluble product.
Example 155 :(2-Ethoxyphenvl)-f2-chloro-4(E-[(3-carboxypiperidin- -vl)carbonvllethenvl)phenyl] sulfide The compound of Example 137 was hydrolyzed using an excess of aqueous 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. 'H NMR (DMSO,.300 MHz) 8 1.17 J=7Hz, 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 J=7Hz, I 6.80 J=9Hz, I 7.01 (t, J=7H1z, I1-H), 7. 15 J=8Hz, 7.26-7.40 (in, 2H), 7.40-7.48 (in, 1 7.51 (dd, J=9Hz, 2Hz, I 7.99 J=9Hz, I Anal. Calcd. for C 23
H,
4
C'NO
4 S: C, 61.94; H-I 5.42; N,.3.14. Found: C,61 .75; H, 5.65; N, 3.15. The resultant acid (303 mng.
0.631 inmol) was dissolved in 3 ml MeOH. A KOH solution .(38 mg, 0.595 mmol, of 87.6% KOH )in I 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 60C to yield 307 mg of a solid, water soluble product.
Example 156 (2-Ethoxyphenyl)- [2-chloro-4(E- [(2-ethoxycarbonylpiperidin- I-vl)carbonyllethenyl) phenyllsulfide The title compound was prep ared according to the procedures of Example 97.
'H NMR (CDCI 3 300 MHz) 8 1.24 J=7Hz, 3H), 1.28 J=7 Hz, 3 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 J=7Hz, 2H,4.20 J=7Hz, 2H), 6.80-6.98 (in, 4H), 7.12-7.20 (in, IH)7.35-7.43 (in, 2H), 7.50-7.58 (in, 2H). Anal. Calcd. for
C
25
H
28 C1N0,S: C, 63.35; H, 5.95; N, 2.95. Found: C,63.5 1; H. 6.22; N, 2.61.
168 Example 157 (2-Ethoxyphenyl)r2-trifluoromethyl-4-( -ert-butoxycarbonyl)-4hydroxypvrrolidin-3-lamino)carbonl)thelyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDC.I, 3 00 MHz) 8 7.76. I 7.60 1 H, J =15. 1 Hz), 7.46 (dd, 1IH, J 1.7, 7.5 7.38 7.01 IH, J 15.4 Hz), 6.98 1H, J 7.8 Hz), 6.93 I1H, J 8.3 Hz), 6.42 I H, J 15.0 Hz), 4. 30 (br, 2H), 3.98 J =7.0 Hz), 3.87 (mn, I 3.71 (in, I 3.3 3 (br, 1.47 9H), 1. 17 3H-, J 7.0 Hz). MS (ESI) m/z -551, -1103. Anal. Calcd for C 2 7 H- IF 3
N
2 0 5 S 0. 61 EtOAc: C, 5 8.32; 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-carboxvpipefl dini-I -yVcarbonylethenyl)]2henyll sulfide The compound of Example 156 was hydrolyzed, and the salt formed, according to the procedures of Example 155. m.p. 1707171 C. 'H-NMR (DMSO 300 MHz) 8 1. 16 J=7Hz, 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.,J7Hz, 2H), 6.80 J=9Hz, I 6.97-7.07 (mi, I1H), 7.15 J=9Hz, I 7.29-7.57 (in, 5H), 8.02 210 I Anal. Calcd. for C 2 3H,,ClNOS: C, 61.94; H, 5.42; N, 3.14. Found: C, 61.91; H, 5.48; N, 2.90.
169 Example 159 (2-Ethoxyphenyl'[2-trifluoromethyl-4-( E-(((pyrrol-3-in- I -yl)caibonyl)ethenvl) phenvfl sulfide The title, compound was prepared according to the procedures. of Example 1.
'H NMR (CDCl 3 3 00 MHz) 8 7.81 1IH), 7.6 8 I H, 3J 15.4 Hz), 7..35-7.47 (in, 3H), 7.04 I H, J 8.4 Hz), 6.97 (dd, I1H, J= 1.3, 7.5 Hz), 6.91 I1H, J= 8.5 Hz), 6.70 I H, J =15.4 Hz), 5.94 (in, I 5.85 (in, I1H), .4.47 (br, 2H), 4.3 8 (br, 2H), 3.98 2H7 J 7.0 Hz), 1. 19 3H, J, 7.0 Hz). MS (ESI) rn/z 420, 839, 861.
Example 160 (2-Ethoxyphenvl)[2-trifluoroinethyl-4-(E-((3-(pvrrolidin 2-on-]I-ylbhrop-l1ylainino)carbonyl) ethenyl)phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI,300 MHz) 8 7.78 1H), 7.54 I H, J 15.8 Hz), 7.42 (dd, I H, J 7.5 Hz), 7.34-7.39 (in. 2H), 7.13 (br. IlH), 7.03 I H, 3 6.97 (dd, I1H, J 1. 1, 7.7 Hz), 6.91 I H, J 8.1 Hz), 6.46 1H.H, J 15.8 Hz), 3.9 8 2H, J 7.10 Hz), 3.43 (in, 4H), 3.34 2H, J 6.0 Hz), 2.45, 2H, J 8.1 Hz), 2.08.(mn. 2H), 1.75 (mn, 2H), 1.18 3H, J 7.0 Hz). MS (ESI) nilz 493, 515, 985, 1007.
Example 161 2 -Ethoxyphenvlfl2-trifluoromethyl-4-(E-((4-acetvlpiperazin- I -yl)carbonyl)ethenvl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'IH NMR (CDCI 3 300 MHz) 8 7.79,(s, IH), 7.62 I H, J =15.6 Hz), 7.44 (dd, I1H, J 7.5 Hz), 7.3 8 (in, 2H), 7.04 I H, J 6.97 (dd, I1H, J Hz), 6.92 1H, J 8.1 Hz), 6.84 1H, J 15.6 Hz), 3.98 2H, J =7.0 Hz), 3.63)-78 (in, 6H), 3.53 (mn, 2H), 2.14 3H), 1.19 3H, J 7.0 Hz). MS (ESI) m/lz 479, 501, 95.7, 979.
Example 162 (2Ehxpey)2tilooehl4(-(-ehxc~oy)i~rzn 1yl)carbonvl)ethenvl) phenyll sulfide.
The title compound was prepared according to the procedures of Example 7 1.
'H NMR (CDCl.,, 300 MHz) 8 7.79 I H, 3J 1. 7 Hz). 7.63 I1-H, J 15. 3 H z), 7.43 (dd, I H, 3J 1.7, 7.7 Hz), 7.3 8 (mn, 2H), 7.04 I H, J 6.97 (dd,l 1H, J 1.4. 7.5 Hz), 6.92 I H, J 8.1 Hz), 6.84 I H, J 15.3 Hz), 4.18 2H. J =7.1 Hz), 3.98 2H, J 6.9 Hz), 3.68 (mn, 4H), 3.53 (in, 4H), 1.29 3H, 3 .7.1 Hz) 1. 19 3H, J 6.9 Hz). MS (ESI) m/lz 509, 531, 1017, 1039.
Example 163 (2Ehxpey~2-rfurmt 14(-(-2frlcroy~ieaiyl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 71.
'H NMR (CDCI,300 MHz) 5 7.80 IH, J 1.5 Hz), 7.66 I H, J 15.4 Hz), *7.52 I 7.45 IH, J 1.6, 7.5 Hz), 7.40 (in, 2H1), 7.08 I H, J 4.0 Hz), 7.04 IH J 6.98 (dd, I H, J 1, 7.3 Hz), 6.93 I H, J =8.5 Hz), 6.88 (d, I H, J =15.4 Hz), 6.52 (dd, IlHI 1.6, 3.5 Hz), 3.98 2H, J 7.0. Hz), 3.73-3.90 1. 19 3H, J 7.0 Hz). MIS (ESI) in/z 531, 553, 1061, 1083.
Example 164.
(-Ethoxyphenyl)-[2-chloro-4(E-[(3 -ethoxycarbonylviperidin- I-yl)crbnlehn) phenyllsulfide The title compound was prepared accordingto the procedures of Example.97.
'H-NMR (CDC1 3 8 1.25 J=7Hz, 6H), broad peaks totaling 9 protons at 1.65-1.80, 1.95-2.04,1 2.51-2.63, 2.90-3.00, 3.15-3.30, 2.95-4.05, 4.42-4.55, 4.14 J7Hz, 2H), 4.15 J=7Hz, 2H), 6.82 J= 15 Hz, I 6.84 J=9Hz, I1H), 6.93-.6.99 (in, 2H), 7.17 (dd, 1=9Hz, 2Hz, I 7.34-7.41 (mn, 2H), 7.52 J=15H4z,: IH), 7.55 J=2Hz, IH). Anal. Calcd. for C,,H, 8
CINO
4 S: C, 63 .35; H, 5.95; N, 2.95. Foun d: C, 63.0.9; H, 6.24; N, 2.77.
Example 165 (2-Ethoxyphenyl)- [2-chloro-4(E-[(4-carboxvpiperidin- I -vl)carbonvljethenYl)phenylj sulfide The compound of Example 164 was hydrolyzed, and the salt formed, according to the procedures of Example 155. m.p. 165-166C. 'H-NMR (DMSO 300 M~lz) 1.25 1=7Hz, 3110, 1.35-1.58 (in. 2H), 1.80!-1.95 (mn, 2H), 2.50-2.60 (in, I 1.78-1..91 (in, I 3.13-3.24 (in, 1iH), 4.05 J=7Hz, 4.12-4.3 5 (mn, 2H), 6.80 J=9Hz, IH), 6.96-7.05 8t J= z H,71 d .87.48 (mn, 4H), 7.51 (dd, J=9Hz, 2Hz, 1H), 8.00 J=2Hz).
Example 166 (Benzodioxan-6-yI) [2-chloro--44( E-((4-acetvlpiperazin- 1 -yI)carbonvl)ethenyl) phenvll sulfide The. title compound was prepared by the procedures described in Example substituting 5-iodoindole with 6-iodobenzenedioxane, giving a white solid. 'H NMR 300 MHz) 8 2.14 3H), 3.44-3.57 (in, 2H), 3 .57-3.86 (mn, 6H), 4.25-4.35 (in, 4H), 6.75.(d, J= 8.4 Hz, I1H), 6.7.8 J= 15.6 Hz, I1H), *6.93 J= 8.4 Hz, 1,H), 7.03 (dd, J 2. 1, 8.4 Hz, I1H), 7.08 J 2.1 Hz, I 7.18 (dd, J= 2. 1, 8. Hz, IRH), 7.51 J= 2.1 Hz, 11H), 7.57 J= 15.6 Hz, I MS (APCI 4 at m/z 45 9, 461.
Example 167 (2-1sopropylphenYl) [-nitro-4-( E-((4-ethoxycarbonylpiperazin-lI-vl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
1 H NMR (DMSO-d 6 300MHz) 8 1.14 J =7.0 Hz, 6H); 1. 19 J 7.0Hz, 3H); 330-3.40 (mn, I 3.3 0-3.73 (hr mn, 8H); 4.06 J =7.0 Hz, 2H); 6.64 J =8.5 Hz, I 7. 32-7.63 (in, 6H); 7.90 (dd, J 1. 8 Hz, I 8.65 J 8 Hz, I MS (APCI) at ml/z 484. Anal calcd, for C,,H, 9 N,S,0 5 C, 62.09; H4,.6.04; N, 8.69.
Found: C, 61.89; H, 6.13; N, 8.51.
Example 168 (2-Isopropylphenyl)l2-nitro-4-( E-((4-isopropoxycarbonvlninerazin- 1- Olcarbonvl~ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 5 1.14 J =6.8 Hz, 6H); 1.20 J 6.4 Hz, 3H); 3.30-3.40 (in, IH); 3.32-3.73 (br m, 8H); 4 .79 (hept, J =6.1 Hz, 2H); 6.64 J Hz, IH); 7.32-7.63 (mn, 6H); 7.89 (dd, J 8.5, 1.7 Hz, I :8.64 J 1. 7 Hz, I H).
MS (APCI) at m/z 498. Anal calcd for C,,HI,N 3 S,O1: C, 62.76; H, 6.28; N, 8.44. Found: C, 62.57; H, 6.43; N, 8.33.
Example 169 (2-Isopropyvlphenyl)f2-nitro-4-( E-((4-isobutoxycarbonvlpiperazin-1Iflcarbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 0.90 J =6.6 Hz, 6H); 1.14 J -7.0 Hz, 6H); 1. 88 (hept, J =6.6 Hz, I 3.3 0-3.40 (in, I 3.3 0-3.73 (br mn, 8H); 3.81 J =6.3 Hz, 2H); 6.64 J 8.5 Hz, lH); 7.32-7.63 (mn, 6H); 7.90 (dd, J 8.5, 1.5 Hz, I H); 8.65 J =1.5 Hz, IH). MS (APCI) (MWiHY at mlz 512. Anal calcd for C,,H,,NS0 3 C, 63.38; H, 6.50; N, 8.21. Found: C, 63.15; H, 6.55; N, 8.13.
Example 170 (2-Isor~ropylphenvl)[2-nitro-4-( I-propen-2-oxy)carbonyl) iperazin-1 yl)carbonyl)ethenyl) phenyll sulfide Prepared according -to, the procedures of Example 7.1, giving. a yellow solid..
IH NMR (DMSO-d 6 300MHz) 8 1.14 J 6.8 Hz, 6H); 1.88 3H4); 3.30-3,.40 (in, IH);'3.30-3.78 (br m, 8H);'4.65 4.69(in,.IH); 6.64 (dj Hz. IH); 7.32- 7.63 (in, 6H); 7.190 (dd, J 1.5 H.z, 1H); 8.65 J 5 Hz, IH). MS (APCI) at m/z 513. Anal calcd for C, 6 HqN 3
S,
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-M(-propionylniperazin- I -yl)carbonvl)ethenyl) phenvll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d 6 300MHz) 5 1.00 J1 7.3 Hz, 3H); 1.14 J =7.0 Hz, 6 H); 2.35 J 7.5 Hz, 2H); 3 .30-3.40 (n,l IH); 3.41-3.76 (br mn. 8H); 6.64 J =8.5 Hz, I 7.32-7.63 (in, 6H); 7.90 (dd, J 8.5, 1.5 Hz. I 8.64 J 1. 5 Hz, I MS (APCI) NHj- at in/z 485. Anal calcd for C,,H,,NS,0 4 C, 64.22; H, 6.25; N, 8.99. Found: C, 64.04; H, 6.44; N, 8.80.
Example 172 175 (2-Isoprop~ylphenyl) r2-nitroA--( E-((4-carboxamidopinera in- I -Yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMS0-l 6 300,MHz) 5 1.14 J 7.0 Hz, 6H1); 3.30-3.40 (in, 3.30- 3.73 (br M, 8H); 6.10 211); 6.64 J =8.5 Hz, I1H); 7.3 2-7 .63 (in, 6H1); 7.91 (dd, J 1.8 Hz, 1IH); 8.65 1.8 Hz, I MS (APCI) at mlz 470. Anal calcd for C231, 6 NS,0 4 -0.26CHCOOCHCH 3 C, 60.48; H, 5.93; N, 11.73..Found: C, 60.10; H, 5.84; N, 11.90.
Example 173 (2-Isoprop~ylphenyl)[2-nitro- 4 E((4methylamino~arbollpiper8.zin- 1vI~carbonvl~ethenvl) phenyfl sulfide Prepared according to thie procedures of Example 71, giving a yellow solid.
NH NMR (DMS0-l 6 300MHz) 8 1. 14 J 6.8 Hz, 6H); 2.58 J =4.4 Hz, 3W); 3.3 0-3.40 (in, IH); 3.28-3.70 (br mn, 8H); 6.52 J =4.4 Hz, I 6.64 J 8.5 Hz, 1W); 7.3 2-7.62 (in, 6H1); 7.90 (dd, J 1.8 Hz, 1WH); 8.64 3 =1.8 Hz,. I .MS (APCI) rn/z 486. Anal calcd for C,,H,,NS,O .36CH,COOCHCH 3
C,
61.07; H, 6.22; N, 11. 19. Found: C, 61.14;H, 6.4 1;N, 11. 19.
Example 174 (2-Isopropvlphenyl)[2-nitro- 4 E((4(pyvrimnidin-2-vl)Pi]2erazin1 yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures. of Example 7 1, giving a yellow solid.
'H NMR (DMSO-d,,, 300MHz) 8 1.15 J =6.6 Hz, 6H); 3.30-3.40 (in, IH);'3.28- 3.85 (br mn, 8H); 6.64 J Hz, I1H); 6.68 J 4.8 Hz, IH), 7.3 3-7.63 (mn, 6H); 7.92 (dd, J 8.5, 1.8 Hz, 8.40 J =4.8 Hz, 2H); 8.67 J Hz, 1H). MS (APCI) at m/z 490. Anal calcd for C,1 6 63.78; H, 5.5.6; N, 14.30..
Found: C, 63.83; H, 5.54; N, 14.11.
Exampile 175 2 -Isopropyllphenyl)[2-nitro-4-( E-((4-hydroxyaceypiperazin- I -yl)carbonyl)ethenyl) phenvll sulfide Prepared according to the procedures of Example, 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 1.15 J =6.8 Hz, 6H); 3.30-3.40 (in, lH); 3.28- .3.78 (hr m, 8H); 4.12 J =5.8 Hz, 2H); 4.61-4.69 (hr mn, 11H); 6.64 J =8.5 Hz, 1H); 7.33-7.63 (mn. 6H); 7.90 (dd, J 1. 8 Hz, I1H); 8.65 J Hz, I MS (APCI) at m/z 470. Anal calcd for C, 4 H,NS0038HCOHH:
C,
60.93);H, 6.02; N, 8.35. Found: C, 60.95; H, 6.06; N, 8.35..
Example 176 2 -1sopropylphenvl)[2-nitro-4-( E-((4-(pyrazine-2-carbonyl )pip~erazin- 1vl)carbonvl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 1.14.(d. J =6.6 Hz, 6H); 3.30-3.40 (mn, IH); 3.28- 3.88 (br m, 8H); 6.61-6.66 (br m, I 7.31-7.63 (in, 6H); 7.85-7.96 (br m, I 8.61 8.92 MS (APCI) at m/z 518. Anal* calcd for C.7H, 7 NSO,0.24CH 3 COOCH:CH,: C, 62.34; H, 5.4 1; N, 13.01. Found: C, 62.23; HI, 5.50; N, 13.10.
Example 177.
(2-Isopropylphenyl)M2-trifluoromethvl-4-( E-(((2-6arboxyrivrol-3-in- 1 yl)carbonyl)ethenyl) phenyil sulfide The title compound was prepared according 'to the procedures of-Example 71.
1H NMR (CDC1,, 300 MHz) 8 7.79 1IH), 7.68 I H, J 15.4 Hz), 7.48 I H, J 7.4 Hz), 7.45 (in, 2H), 7.38 I-I, J =8.3 Hz), 7.23 (in, IH), 6.80 IH, J 8.5 Hz), 6.70 I H, J 15.4 Hz), 6.04 (mn, 1 5.88 (in. I1H),.5.31 I 4.60 (mn, I H), 4.50 (in, I1H), 3.76 3H), 3.50 (in, I 1.22 6H, J 7.0 Hz). MS (ESI) m/z 476, 498, 951, 973. Anal. Calcd for C 2 5
H
2 4
F
3 N0 3 S 0.38 Et OAc: C, 62.58; H, 5.35; N, 2.75. Found: C, 62.53; H, 5.27; N, 2.76.
Example 178 (2-Isopropylphenyl)12-nitro-4-(- E-((3-hydroxvmethvl -4-methylpiperazin- 1yl'carbonyflethenvl) phenvil sulfide Prepared according to- the procedures of Example 71, giving a yellow solid.
-H NMR (DMS0-l,. 300OMHz) 8 1. 14 J 6.8 Hz, 6H); 2.22 3H); 1.82-4.63 (br m,9H); 3.30-3.40 (in. I1H); 6.62-6.66 (hr mn, I 7.25-7.63 (in, 6H); 7.86-7.92 (br m, 1H); 8.57-8.65 (hr m, IH). MS'(APCI) at m/z 456.
Example 179 (2-I sopropylphenyl)f2-trifluoromethyl-4-( E-(((2-carboxypvrrol-3-in- Ivl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI.,, 3 00 MHz) 8 7.79 I 7.72 IlH, J =15.5. Hz), 7.49 IlH, J 7.4 Hz), 7.36-7.46 (in, 3H), 7.23 (in, IH), 6.82 I1H, J =8.5 Hz), 6.74 1H, J= 15.4 Hz), 6.00 (br, 2H), 4.48 1H), 4.51 (br, 2H), 3.48 (in, IH), 1. 18 6H, J= Hz). MS (ESI) W/-7-460, -492, -921.
Example 180 (2-Isopropvlphenyi)r2-trifluoromethvl-4-( E-(((2-hvdroxymethvlpvrrolidin- 1vl)carbonyl~etbenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI 1 300 MHz) 8 7.79 IH), 7.68 IH, J =15.4 Hz). 7.48 1H, J= 7.4 Hz), 7.45 (in, 2H), 7.3 8 I H, J 8.3 Hz), 7.23 (in, I 6.80 I H! J =8.5 Hz), 6.70 I H, J 15.4 Hz), 5.82 (in, IlH), 5.70 (mn, I1H), 4.92 (mn, I 4.18 (br s, 2H), 3.76 3H), 3.78 IH, J 11.5 Hz), 3.50 (mn, 2H), 3.01 2H, J 7.5 Hz). 2.58 (t, 2H,,.J 7.6 Hz), 1. 19 6H. J 7.1 Hz). MS (ESI) m/lz 450,472, 92 1.
179 Example 181 (2-Isopropylphenyl)r2-nitro-4-( E-((3-methvlaminocarbonyl)niperazin- 1yl)carbonflethenvl) rphenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NM.R (DMSO-d,, 300M1-z) 5 1.14 J 7.0 Hlz, 6H); 2.60 J =4.4 Hz, 3H); 2.504.45 (br m, 7H); 3.30-3.40 (in, 1H); 6.62-6.66 (br mn, 7.32-7.62 (mn, 6H); 7.8 1-7.92 (mn, 2H); 8.59-8.65 (br mn, IH). MS (APCI) at inlz 469.
Example 182.
(2-Isoptopyl]phenyl)[2-nitro-4-( -cyclopropvylaminocarbonyl)piperazin- 1yl)carbonvl)ethenyl) phenvll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 0.40-0.62 (br mn, 4H); 1. 14 J =6.8 Hz,- 6H); 2.50- 4.41 (br mn, 8H); 3.30-3.40 (in, IH); 6.62-6.67 (br in, IH); 7.32-7.62 (in, 6H); 7.87- 7.92 2H); 8.59-8.64 (br.m, I MS (APCI) (M+H)4at m/z 495.
Example 183 (2-Isopropylphenyl'ff2-nitro-4-( -carboxamidorpinerazin-1I-yl)carbonyl)ethenyl) phenvllsulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d 6 300MHz) 8 1. 14 J 7.0 Hz, 6H); 2.50-4.42 (br m, 7H); 3.30- 3.40 (in, 6.62-6.67 (br m, IH); 7.12-7.62 (in, 8H); 7.87-7.92 (in, 1H); 8.60-8.65 (br mn, I1H).. MS (APCI) at m/z 455.
Example 184 (2-I sopropylphenyl)[2-nitro-4-( E-((3-carbomethoxy-4-oxopiperidin- 1yI)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d,, 300OMHz) 5 1. 14.(d, J 6.8 Hz, 6H); 232-2.55 (binm, 2H); 3.30- 3.40 (in, IHi); 3.64,3.76 s, 3H); 3.68-4.58 (br m, 51H); 6.64 J 8.5 Hz, 11H); 7.32-7.63 (mn, 7.88-7.96 (in, lH); 8.60-8.68 (in, I MS (APCI) at m/z 483. Anal calcd for C,H, N,S O.lI7C 6 C. 62.86; H, 5.75; N, 5.6.3. Found: C, 62.8 1; H, 5.83; N, 5.60.
Examnle 185 (2-Isopronylp~henyl) [2-nitro-4- 5-dirmethylpiperazin-1I-yl~carbonyI)ethenyl) p2henyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR (DMSO-d,. 300MHz) 560.96-1.06 (in, 6H); 1. 14 J 6.8Hz, 6H); 2.0.7-4.39( br mn, 7H); 6.63 J 8.5 Hz, I 7.30-7.63 6H); 7.92 (dd, J 8.5, 1.7 Hz, I H); 8.60 J 1.7 Hz, I MS (APCI) at mlz 440. Anal calcd for H, 6.65; N, 9.56. Found: C, 65.36; H, 6.87; N, 9.27.
Example 186 0I -E thylind6l-7-ylr2-chloro-44. E-((4-acetylpiperazin-1-I-l)carbonvl)ethenyl) phenill sulfide The title compound was prepared by the procedures described in Example substituting 5-jodoindole with N-ethyl-7-bromoindole. white solid; 'H NMR (CDC1 3 300 MHz) 5 1.30 J1 7.05 Hz, 2.14 3.52 (br s, 2H), 3.58-3.84 (i,6H), 4.42 J 7.05 Hz,.2H), 6.42 J 8.4 Hz, IH), 6.59 J= 3.0 Hz, lH), 6.76 J =15.6 Hz, I1H), 7.08 J 8.4 Hz, lH), 7.10 J 3.0 Hz, I 7.16 J 7.65 Hz.
I 7.42 (dd, J 0. 9, 7.5 Hz, I1H),7.53 J 1.8 Hz, I 7.54 (di J= 15.6 Hz. I H), 7.78 (dd, J= 0.9, 7.5 Hz, I MS (APCI*) at m/z.468. 470.
Example 187 [2-Methoxylethoxyphenvi )-r2-chloro-4(E-I (mornholin- 1yl)carbonyllethenvl)phenyl sulfide The title compound was prepared. according to the procedures of Example 'H-NMR (CDC,3 300 MHz) 8 3.45 3H), 3.65-3.80 (in, I OH), 4.09-4.13 (in. 2H), 6.82 (broad d, J=l 5, 1 6.88 J=9Hz, IlH), 6.87 (dd, J=9Hz, 2Hz, I 7.03 7.20 J=9- I IH), 7.31 1=8 Hz, I 7.52 I 7.56 (broad d, J= I I H).
Example 188 2 -Bromophenv)2-chloro4(E((44'-Sdioxythiomho~holin- I -vI)carbonvl) ethenyl)Rhenyl Isulfide 4-Methylmorpholine N-oxide (0.0935 g, 0.798 mmol) and 4A molecular sieves (0.0333g) were added to a solution of (2-Bromophenyl)[2-chloro-4-(E,- ((thiomorpholin-lI-yl)carbonyl) ethenyl)phenyl]sulfide (0.1230g.1 0.27 mmol; prepared.
according to the procedures described in Example After 15 min, tetrapropylammoniuin perruthenate (0,0058g, 0.0166 mmol) was added and after 4h 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-* 9:1 CHICI,: MeOH.
The mixture was then purified- by preparative HPLC to provide the title compound (0.0138 'H-NMR (DMSO-d6, 300MHz) 8 8.12 J= 1.47 Hz, 7.81 (dd 13,2H), 7.65 (dd, J= 8.0, 1.5 Hz, IH), 7.47 J--9.0 Hz, IH),.27 7.3(in, 4H), 7.03. J= 9.0 Hz, I 4.12 (br s, 2H), 3.98 (br ,2).32 b ,2) 3.19 (br s. 2H), 1.54-2.29 (in, 6H), MS(APCI) at m/z 486, 488, 490.
Example 189 (2-Bromophenyl 2 -chloro-4-(E-(N-carbomethoxymethvN(3(Pvrrolidin2on- 1vI )tron- I -yl)amino)carbonvi) ethenyl)phenyllsulfide Example 1 89A N-Carbomethoxvnmethyl-N-(3-(prroidin2on I -vl)prob-- Iv)amine 183 Methyl bromoacetate (1.35 mL, 14..3 mmol) was added dropwise to. a solution of 3aminopropyl-2-pyrrolidinone (2.0 mL, 14.3 mmol) and diisopropylethylamine (2.7 mL) in CH 2
CI
2 The reaction was stirred for 12h and was then concentrated in vacuo, and carried forward without further purification.
Example 1 89B (2-Bromorphenyl)l2-chloro-4-(E-(N-carbomethoxymethyl-N-(3-(pyrrolidin-2-on- I1- Yl~prop)- I -yl)amino)carbonyl) ethenvl)phenyllsulfide The title compound was prepared by the procedures described for Example 113, substituting 2,4 dichlorothiophenol with 2-bromothiophenol, 2chlorobenzaldehyde with 3,4 dichlorobenzaldehyde, and 1-(.3-amninopropyl)-5-((S)hydroxymethyl)-2-pyrrolidinone with the compound. from Example 1 89A. 'H-NMR (DMSO-d6, 300MHz) 5 8.07 (dd, J 1.7 Hz, I 7.81 (in, I 7.64 (in, I H), 7.24-7.49 (in, 7.05 (in, I 4.53 I1H), 4.14 I -3.68 I 3.64 2H), 3.54 (mn, 2H), 3.13-3.43 (in, 4H), 2.39 (mn, 2H), 1.91 (in, 2H), 1.72 (in, 2H), MS(APCI) at m/z 5 65, 567, 5.69.
Example 190 (2-Broinophenyl) r2-chloro-4-(E-((4-S-oxythioinorpholin- I -yl)-2vrrolidin one)carbonyl) ethenyl)ohenyllsulfide The title compound (0.01 78g, 14%) was isolated from the same reaction m .ixture as described in Example 188. 'H-NMR (DMSO-d6, 300OMHz) 58.12 (dJ= 184 1.8 Hz, I 7.81 (dd, J= 7.9, 1.3 .Hz, I 7.65 (dd, J= 8.3, 1.7 Hz, I 7.46 J= 7.4 Hz, I 7.26-7.48 (in, 4H), 7.04 J 7.4 Hz, I1H), 4.29 (hr mn, 2H), 3.97 .(br m, 114), 3.61 (br mn, I 2.80 (hr m, 4H), MS(APCI) at mlz,4.70, 472, 474.
Example 191 (2-Methoxv-5-chldrophenylMr2-nitro-4-(E-((4-acetylpiperazin- I -Yl~crbonyl)ethenyl) phenvll sulfide.
The title compound was prepared according to -the procedures of Example 1.
'H NMR 300 MHz) 8 8.44 IH), 7.66 IH, J =15.1 Hz), 7.58 IR, J= 2.6 Hz), 7.48 (dd, I H, J 8.8 Hz), 7.44 (in, I 6.97 I H, J =8.8 Hz), 6.9.2 (d, I1H, J =15.5 Hz), 6.82 11H, J 8.5 Hz), 3.78 3H). 3.70 (in, 6H), 3.54 (in, 2H), 2.15 3H1). MIS (ESI) m/lz 476, 498, 95.1, 973. Anal. Calcd for C 2 2H22C1N 3 0 5
S
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-I sopropvlp~henvlfl2-nitro-4-( -acetoxymethyl~hiperazin- 1-vyl)carbonyI)ethenyl) p2henyil sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d 6 300MHz) 8 1.14 J =6.8 Hz,,6H); 2.04 3H); 3.30-3.40 (in, 1 2.50-4.46 (binm, 9H); 6.64 J =8.8 Hz, I 7.30-7.62 (mn, 6H); 7.87-7.93 (in, IH); 8.58-8.63 (hr in, lH). MS (APCI (M+H) 4 at inlz 484. Anal calcd for C,,H,NS0 5 C, 61.60; H, 6.09; N. 8.62. Found:. C, 61.63 H, 6.2 1; N, 8.4 1.
Example 193 (2-Isopropvi]phenyl) [2-nitro-4-( .5-dirmethyl-4acetylp2iperazin- 1yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d, 300MHz) 81.00-1.20 (br m, 6H); 1.15 J =6.8Hz, 6H); 2.04 2.76-4.58 (br m, 7H); 6.64 J 8.5 Hz, 1H); 7.32-7.63 (in, 6H); 7.94 (dd, J 1.8 Hz, lH); 8.66 J =1.8 Hz, IH). MS (APCI) at m/z 482. Anal calcd for C, H 31 N S 0 C, 64.13; H, 6.54; N, 8.63. Found:: C, 64.15; H, 6.61; N, 8.50.
Example 194 (1 -Methvlindol-5-vl~r2-chloro-4-( E-((4-acetylp~iperazin-1I-yl)carbonyl)ethenvl) phenyl] sulfide The title compound was prepare d by the procedures described in Example substituting 5-iodoindole with N-methyl-5 -bromoindole,. giving a white solid. 'H4 NMR (d'-DMSO, 300 MHz) 8 2.04 3H). 3.40-3.80 (in, 8H), 3.86 3H4), 6.49 J 8.4 Hz,11), 6.52 (dJ=3.0 Hz, IH), 7.27 J=:15.6 Hz, IH), 7.31 (dd,J=2.4, 8.4 Hz, IH), 7.39 15.6 Hz, IH), 7.41 (dd,7= 1.8, 8.4 Hz, 11), 7.48 Hz, I1H), 7.63 J 8.4 Hz, I1H), 7.85 J1= 1.8 Hz, I 7.99 (br s, 111). MS (APCI') atnm/z 454, 456.
Example 195 (Benzodioxan-6-vl)[2-nitro- 4 E-((-acetylpiperazin- 1 -yl')carbonyl)ethenyl) phenOl sulfide Example 195A 6-Mercaptobenzodioxafle The title compound was prepared by the procedures described in Example 97A, substituting 2-ethoxybenzene with 67iodobenzenedioxane.
Example 195B (Benzodioxan-6-yl)[2 -nitro-4-( E-((4-acetylpiperazin- I -vl')carbonvl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 32, substituting 2,4-di chilorobenzenethiol with 6-mercaptobenzenedioxale, to give a lightyellow solid; 'H NMR (d 6 -DMSO, 300 MH) 8 2.04 3H), 3.41 80 (in, 8H), 4.28- 4.38 (mn, 4H1), 6.86 J= 8.4 Hz, I1H), 7.05 J 8.4 Hz, I 710 (dd, J 2.1, 8.4.
Hz, I H),7.15 J 2.1 Hz, I 7.40 J 15.6 Hz, I H),.7.53 J~ 15.6 Hz, I H), 7.91 (dd,J=1.8, 8.4 Hz, H),8.62 1.8 Hz, IH). MS (APCE) atni/z: 470. Anal. Calcd for C 2 3
H
2 3
N
3 06S -0.17 H 2 0: C, 58.46; H, 4.98; N, 8.89. Found: C, 5 8.4 7; H, 4.8 8; N, 8.7 8.
Example 196 (Benz .odioxan-6-vlI f2-nitro-4-(E-((3-(pvrrolidil-2-ofl- I -yl)12rop- I -ylamino)carbonvl) ethenyl)pbenyllsulfide The title compound was prepared by the procedures described in Example 32, s ubstituting 2,4-dichlorobenzenethiol with 6-mercaptobenzenediox'afe, and 1-.
acetylpiperazine with 3-aminopropyl-1-pyrrolidin- 2 -ofle, giving a light-yellow solid.
'H NMR (d'-DMSO, 300 MHz) 8 1.64 J 7.2 Hz, 2H), 1.92.(p, J= 7.8 Hz, 2H), 2.21 J 7.8 Hz, 2H), 3.13 J= 7.2 Hz, 2H), 3.19 J= 7.2 Hz, 2H), 3.3 8-3.46 (overlapping t, J= 7.8 1-z, 2H), 4.27-4.37 (in, 4H), 6.70 J= 15.6 Hz, 1H), 6.90 (d, J= 8.4 Hz, I 7.05 J 8.4 Hz, IH), 7.09 (dd, J 2.1, 8.4 Hz, I1H), 7.16 (di.J 2.1 Hz, I 7.46 J 15.6 Hz, I 7.77 (dd, J 2.1, 8.4 Hz' I 8.16 J Hz, I 8.41 J 2.1 Hz, I Ms (APCi-) at rn/Lz 484. Anal. Calcd for
C
2 4
H
2 5 N 306S 0.51 CH 2 Cl 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-vi)[2-nitro- 4 -carboethoxypirberi din- I -yP) carbonvl~ethenyl) phenvll sulfide -The title compound was prepared by the procedures described in. Example 196 substituting 'aminopropyl)-2-pyrrolidinofle with ethyl nipecotate, giving a yellow solid, mp 73-75 0 C. 'H NMR (CDCI 3 300 MHz) 1.26 J=7.0 Hz, 3H), 1.74 (br, I 1.78 (br, I1H), 2.10 (br, I 2.54 (br, I 2.95-3.70 (br, 2H), 3.90-4.10 (br, .15 q, J70 Hz 2H) 4.3-4.40 (in, 4H). 4.65 (br, IH), 6.90 I 6.98 J=8.5 Hz, I 7.06 (dd, J=2.0, 8.0 Hz, I 7.10 J=2.0 Hz, I H), 7.40-7.50 (in, lH), 7.58 J=15.0 Hz, IH), 8.40. J=2.0 Hz, IlH). MIS (APCI) rnlz 499 Anal. calcd. for C, 5
H
26
N
2 0 7 S: C, 60.23; H, 5.26; N, 5.62. Found: C, 60.09; H, 5.43; N, 5.47.
Example 198 (Benzodioxan-6-vlMr2-nitro-4-( E-((4-carboethoxypiperidin- I carbonvl~ethenyl) phenyll sulfide 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 0 C. 'H NMR (CDCI 3 300 MHz) 8 1.27 (tj J=r7.0 Hz, 3H), 1.65 (in, 2H), 2.00 (mn, 2H), 2.60 (mn, I1H), 2.80-3.50 (br, 2H), 4.15 (br, I 4.16 (q, 4.34 (in, 4H), 4.54 (br, I 6.90 J=8.0. Hz, I 6.98. J=8.0 Hz, I-IH), 7.05 (dd, J=2.0, 8.0 Hz, I 7. 10 J=2.0 Hz, I 7.12. (br, 1 7.44 Hz, I 7.60 (br, I 8.40 I M S (CI/NH3) m/z Anal. calcd. for
C
2 5
H,
6
N
2 01S 0.03 H,O: C, 60.16; H, 5.26; N. 5.6 1. Found: C, 60.15; H, 5.65; N, 5.40.
Example 199 (2-Ethoxyp~henyl')r2-triflubromethvl-4-(Z-((4-acetvlpiperazin- 1 -YI)carbonyl)ethenyl) phenyll sulfide Example 1 99A (2-Ethoxyphenyl)'2-trifiuoromethl-4-(Z-((4-carboinethoxyethenyl) phenyll sulfide 189 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 °C and KN(SiMe 3 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
4 C1 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 yield) of the cis- isomer (Joer,,c 12.5 Hz) along with 322 mg (25% yield) of the trans- isomer (Joe,,fi 12.5 Hz).
Example 199B (2-Ethoxvphenyl)[2-trifluoromethvl-4-(Z-((4-acetylpiperazin-l-vl)carbonvl)ethenvl) phenvll sulfide The compound of Example 199A was converted to the corresponding amide according to the procedures of Example 1. 'H NMR (CDCI., 300 MHz) 5 7.64 1H, J 16.9 Hz), 7.32-7.4 2H), 6.98 2H), 6.93 2H), 6.65 1H, J 12.1 Hz), 6.08 1H, J 12.2 Hz), 3.98 2H, J 7.0 Hz), 3.68 2H), 3.62 2H), 3.44- 3.54 4H), 2.11 and 2.05 3H), 1.20 3H, J =7.0 Hz). MS (ESI)s m/z 479, 501.
Example 200 190 (2-Ethoxvphenyl )[2-trifluoromethyl-4-(E-((6-methvlpyrid-2ylamino)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR. (CDCl 3 300 MHz) 5 8.12 I H, J 8.1 Hz), 7.78 11H, J =1.7 Hz), 7.70 I1H, J =15.6 Hz), 7.63 1]H, J 7.8 Hz), 7.46 (dd, I H, J 1.6, 7.8 Hz), 7.36-7.42 (in, 2H), 7.04 I H, J 6.99 (dd, I H, J 1 7.6 Hz), 6.92 (in, 2H), 6.50 (d, 1H, J 15.6 Hz), 3.99 2H, J =6.9 Hz), 2.47 119 (t3H, J 7.0 Hz). MS (ESI)s nt/z 45 9, 48 1. Anal. Calcd for C 2 4
H
2
IF
3
N
2 0 2 S 1. 1 H 2 0: C, 60.27; 4.89; N, 5.86. Found: C, 60.28; H, 5.05; N, 5.94.
Example 201 2 -Methyl-3-chlorophenvl')[2-nitro-4-(E-((4-acetylpiyerazin. I -yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the. procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 6 8.46 IH, I 1.5 Hz), 7.64 H.1= 15.4 Hz), 7.56 I H, J =2.6 Hz), 7.54 I H, J 2.2 Hz), 7.47 I1H, J 8.5 Hz), 7.2 7 (mn, I H), '6.92 I H, J =15.4 Hz), 6.68 I H, .1J 8.5 Hz), 3.6-3-3.78 (in, 3.53 (in, 2H), 2.45 3H), 2.15. 3H). MS (ESI) m/z 460, 482, 919. Anal. Calcd for C22H 2 2 C1 1
N
3 0 4 S: 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-((-carboxamidopiperidin- I -yi) carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 196, substituting N-(3 '-aininopropyl)-2-pyrrolidinone with nipecotamide, giving a. Ilight yellow solid, mp 243-245 'H NMR (CDCI.
3 500 MHz) 8 1.38-1.50 (in, 2H), 1.77- 2.00 (mn, 2H), 2.38 (mn, lH), 2.70 (in, IH), 3.11 (mn, IH), 4.22 (in, IH), 4.28-4.30 (in, 2H), 4 .'324.36 (mn, 2H), 4.42 (in, I1H), 6.85 J=8.5 Hz, ILH), 7.04-7.16 (mn, 2H), 7.35 IH), 7.40 J=13.0 Hz, IH), 7.48 J=15.5 Hz, IH),.7.91 J=8.5 Hz, 1H), 8.58 I1-H). MS (APCI) mlz 470 Anal. calcd. for C., 3 H,3N 3 10 6 S- .0.37 H20: C, 58.01; H, 5.03; N, 8.82. Found: C, 58.02; H, 5.13; N, 8.61.
Example 203.
(Benzodioxan-6-yi)M2-nitro-4-( E-((2-carboethoxyipeiridin-lI-vi) carbonyl)ethenyl) phenvil sulfide The title compound was. prepared by the procedures described in Example] 196, substituting N-(3'-aninopropyl)-2-pyrrolidinone with ethyl pipecolinate, producing a light yellow solid, mp 74-75 0 C. 'H NMR (CDCI 3 ,'300 MHz) d 1.28 J=7.0 Hz, 3H), 1.32-1.55 (mn. 2H), 1.60-1.82 (mn, 3H), 2.33 (mn, lH), 3.40 (mn, IH), 3.98 (in, 1H), 4.23 J= 6.5 Hz, 2H), 4.32 J=5.0 Hz, 4H), 5.45 (mn, I 6.90 J=8.0 Hz, I1H), 6.97 J=8.0 Hz, IH), 7.0-7.10 (in, 3H), 7.44, H=7.5 Hz, 1H), 7.60 J=15.0 Hz, IH), 8.3 8 (mn, I MS (APCI) ml/z 499 Anal. calcd. for C, 5
H
2
,N
2 0 7 S*0. 11
H
2 0: 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-carboxamidogiperidin- I -vi) carbonyl)ethenyl) pfienyll sulfide The title compound was prepared by the. procedures described in Example 1 96, substituting N-(3'-aminopropyl)-2-pyrrolidinone with isonipecotamide, giving a light yellow solid, mp >230 0 C. NMR (CDC'I 3 500 MHz) 5 1.3 5 I 1.60 (in, I1H).
1.72(in, I1H), 1.68 (in. I 2.20 (mn, I 2.75 (in, IlH). 3.04 (in, I 3.20 (mn, :1H), 4.20(in, 1H) 4.32 (i.41-1, 6.85 J8.5 Hz, lH),.7.04 J8.5Hz, IH), 7.09 (dd, J=2.0, 8.5 Hz, IH), 7.26 IH), 7.37.(d, J=16 .0 Hz, IH), 7.47 J=16.0 Hz, IH), 8.58 J=2.0 Hz, I MS (APCI) in/z 470 Anal. calcd. for C,.IH2 3
N
3
O
6 S*0.l3 H,O: C, 58.55; H, 4.97; N, 8.91. Found: C, 58.41; H, 5.14; N, 9.30.
Example 205 (Benzodioxan-6-vl)r2-nitro-4-( E-((4-iert-butoxycarbonylpiperazin- I -yi) carbonvl)ethenyl) phenvil sulfide The title compound was prepared by the procedures described in Examplel 96, substituting N-(3'-aminopropyl)-2-pyrrolidinone with Boc-piperazi ne, giving a light yellow solid, mp 165-1 67 0 C. 'H NMR (CDCl 3 300 MHz) 5 1.48 (s, 9H), 3.50(in, 4H), 3.65 (br,mi, 4H), 4.32 (in,4H). 6.89 J=5.0 Hz, IH), 6.92(in, 1H), 6.97 J=8.0 Hz, IlH), 7.05 (dd, J=2.0, 8.5 Hz,lIH), 7.10 J=2.0. Hz, I 7.45 193 In 7.63 J= 15.5 Hz, I 8.40 (mn, IlH). MS (APCI) M/z. 528 (M+H) 4 Anal.
calcd. for C., 6
H_,
9
N
3 0,S: C, 59.19; H, 5.54; N, 7.96. Found: C, 58.85; H, 5.69; N,8.20.
Example 206 (2-IsopropNvlphenyl) r2-nitro-4-( E-((svn-3 .5-diniethylinorpholin- 1vlbcarbonvl~ethenvl) phenvil sulfide Prepared according to the procedures of Example 7 1, giving a. yellow solid.
'H NMR (DMSO-d,. 300MIz) 5 1.10-1.18 (in, 12H); 2.29-2.39 (mn, 1H); 2.67-2.78 (mn, IH); 3.30-3.53 4.17-4.38 (mn, 2H); 6.63 J =8.8 Hz, IH); 7.32-7.63 (mn, 6H); 7.92 (dd, J 1.5 Hz, I 8.66 J 8 Hz,: I MS (APCI) at ni/z 44 1. Anal calcd for C.
4 C, 65.43;.H, 6.41; N,'6.36. Found: C, 65.69; H, 6.70; N, 6.17.
Example 207 (2-lsopropvlPhenYl)[2-nitro-4-( E-((anii-3 .5,-dimethylniorpholin- I1vl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR.(DMSO-d,. 300MHz) 5 1.07-1.12 (mn, 6H); 1.15 J =6.6 Hz, 6H); 3.32- 3.48 (in, 3H); 3.60-3J.83 (br in, 3.87-3.98 (mn, 2H); 6.63 J 8.5 Hz, 1I-H); 7.32- 7.63 (in, 6H); 7.93 (dd, J 1.8 Hz, 11H); 8.64 J =1.8 Hz, IH). MS (APCI) at mlz 44 1.
194 Example 208 (2-Isopropyvlphenvl)[2-nitro-4-( E-((3-carboethoxypiperazin- I -yl')carbonyl')ethenyl) phenyll sulfide Prepared according to the procedures of Exa mple 71, giving a yellow solid.
'H NMR (DMS0-l 6 300MHz) 8 1.14. J =6.8 Hz, 61-4); 1.08-1.26 (in, 3H); 2.52- 3.16 (br mn, 4H); 3.25-3.40 (in, I -3 .41-4.26 (br mn, 5H); 6.61-6.67 (br m, I 7.30- 7.62 (in, 6H4); 7.87-7.93 (br m, 111); 8.5 8-8.64 (br in, IH). MS (APCI) at m/z 484. Anal calcd for Cj-1 29 N,S,0 5 C, 62.09; H, 6.04; N, 8.69. Found: C, 61.96; H, 6.28; N, 8.49.
Examp~le 209 (2 -IsopropyljhenvlI[-nitro-4-( -isopropoxyc ronvlninerazin- 1vl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example -71, giving a yellow solid.
'H.NMR (DMSO-d 6 300MHz) 5 1.07-1421 (br m, 6H); 1. 14 J =7.0 Hz, 6H); 2.52- 3.16 (br mn, 414); 3.30-3.40 (in, I 3.41-4.24 (br 3H4); 4.81-4.97 (mn, IH); 6.61 6.68 (br mn, 11H); 7.32-7.63 (mn, 6H); 7.87-7.94 (br mn, 114); 8.60-8.66 (br mn, 1H). MS (APCI) at m/z 498. Anal calcd for C,,H,,N 3 C, 62.76; H, 6.28; N, 8.44.
Found: C, 62.5 1; H, 6.52; N, 8.14.
Example 210 195 (2-Isopropvylphenyl) [2-nitro-4-( -(dimethylaminocarbonvl)-4-methylpiperazin- 1 yl)carbonyl~etbenyl) 12henyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMS0-l 6 300MHz) 8 1. 14 J =6.8 Hz, 6H4); 2.14 3H); 2.82, 2.84 (s, s, 3H); 3.12 2.124.24 (br m, 8H); 6.64 J 8.5.Hz,, 1H); 7.32-7.62 (MI 6H); 7.87-7.94 (br m, 11H); 8.60-8.66 (br m, 11H). MS (APCI) at mlz 497.
Anal caled for C,6H, 2 NS0 4 ,042H,0: C, 61.94; H, 6.56; N, 11.11. Found: C, 62.00; H, 6.78; N, 10.89.
ExaRnle 211I (2-isopropylp~henyl) r2-nitro-4-( -carbomethoxv-4-hvdroxvpipei din- I1vl)carbonyl)ethenvl) 12henyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d., 300MHz) 8 1.14 J 7.0 HIz, 6H); 1.59-1 .75 (br m, 2H); 2.50- 3.14 (br mn, 111); 3.30-3.40 (in, IH); 3.60, 3 .61 s, 3H); 4.01-4.44 (br m, 4H);* 5.05-5. 10 (br mn, I 6.63 J 8.5 Hz, I .7.34-7.62 (mn, 6H); 7.87-7.94 -(br rn, I1H); 8.60-8.66 (br mn, I MS (APCI) at in/z 485.
Example 212 (2-Isopropylphenyl)[2-nitro-4( E-((3-hydroxyrnethyl-4-hydroxvpineri din- I1vl~carb onyl~ethenOl phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. IH NMR (DMS0-l 6 300MHz) 5 1. 14 J =6.8 Hz, 6H); 1.49-1.9.0 (hr mn, 2H); 2.75- 3.14 (binm, I1H); 3.30-3.40 (mn, I 3.40-4.23 (binm, 5H); 4.3 8-4.52 (mn, 1IH); 4.60- 4.73 (in, I 6.61-6.66 (mn, I 7.27-7.61 (mn, 6H); 7.84-7.93 (hr mn, I 8.54-8. 63 (hr mn, I MS (APCI) at in/z 457. Anal calcd for C, 4
H,
2 S,O,-047H,0: C, 61.97; H, 6.27; N, 6.0.2. Found: C, 62.02; H, 6.49; N, 5.90.
Example 213 2 -Ethoxynhenyl)r2-trifluoromethl.4( E-((2-cArbonethoxy-4.
(methoxycarbonyl )piperazin- I -vl)carbonylDethenyl)'pbhiyll sulfide The title comnpound was prepared according to the procedures of Example 71.
'H NMR (CDCI 3 300 MHz) 8 7.80 1H) 7.66 I H J =15.4 Hz),.7.45 (dd, I H, J.
7.5 Hz), 7.48 7.01 I1Hi J =6.6 Hz), 6.95 I H, J 6.8 6.90 5.34 (hr s, I 4.66 (in, 2H), 3.76. 3 3.73 3H), 3.18 (in, I 3. 00 3H). MIS (ESI) ni/z 553, 575..
Example 214 (2-Ethoxyp Thenyl) [2-trifluoromethyl E-((2-carbomeihoxy-4-methyl pperazin- 1vl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 71L.
'HNMR (CDC] 3 300 MHz) 8 7.79 IH), 7.64 IH, J= 15.3 Hz), 7.45 (dd, IH, J 7.8.Hz), 7.4-7.35 2H), 7.01 I.J =8.1 Hz), 6.97 (dl, IH, J= 1.2, 7.6 Hz), 6.87-7.91 (in, 2H), 5.36 (br s, 1H), 3.98 2H, J 6.9 Hz), 3.90,(mn, 1H), 3.78 3H), 3.65 (in, I 3.42 (in, IH), 2.85 (in, I 2.32 3H), 2.24 (in, 1H), 2119 (n I1H), 1. 18 3H, J 6.9 Hz). MIS (ESI) n/z 509, 53 1.
Example 215 (2-EthoxyphenyV)[2-trifluoroinethyl-4-( E-((2-carboxy-4-(methoxycarbonyl)piperazin- 1 -Olcarbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Examp le 7 1.
'H MR DMS -,300 MHz) 8 8.10 (in, I1H), 7.68 (m,1IH), 7.42 (in, 7.30 lH), 7.20 I H, J =15.6 Hz), 7. 10 I1H, J 8.1 Hz), 7.04 I H, J 8.5 Hz), 6.98 I H, J =7.5 Hz), 4.65 (br s, I1H), 4.53 (mn, 2H), 4.05 (in, 2H), 4.00 2H, J= 6.9 Hz), 3.57 1.09 3H-, J =6.9 Hz). MIS (ESI) m/lz -537, -569.
Example 216 (Indol-6-vflr-chloko-4-( E-((4-acetvlpiperazin- I -yl)carbonyl)ethenyi) p2henvll sulfide The title compound was prepared by the procedures described in Example substituti ng 5-iodoindole with 6-bromoindole, isolated as a white solid. 'H NMR (d 6 DMSO, 300 M~z) 8 2.03 3H), 3.40-3.77 (in, 8H), 6.52-6.55 (mn, I 6.60 J 8.4 Hz, I H)I 7.13 (dd,J 1.8, 8.4 Hz, I1H), 7.27 J 15.6. Hz, I1H), 7.40 J 15.6 Hz, I 7.43 (dd, J 8.4 Hz, I1H), 7.51 (tJ 3.0 Hz, I 7.64 (in, IH)j 7.70 (d, J 8.4 Hz, I 7.99 J 1. 8 Hz, I MIS (APCI) at m/lz 440, 442.
Example 217 (1-Ethyl .3-(dimethylaminomethY] )indol-7-yl)[2-chioro-4-( E-((4-acetyl viperazin- Iyl)carbonyl)ethenyl) phenyll sulfide The, title compound-was prepared by the procedures described in Example substituting 5-iodoindole with 7-bromo-3-NN-dimethylmnethyl-N-ethyl *indole, and isolated as a light-brown solid.,'H, NMR (CDGI 3 300 MHz) 5 1.-30 J 7 7.05 Hz, 3H), 2.14 3H), 2.41 6H),,2.93-3.05 (in, 2H), 3.47-3.55 87 (in.
6H), 6.42 J=8.4 Hz, IH), 6.85 J =15.6,Hz, IH), 7.09 (dd,J =2.1,8.4 Hz,.
1IH), 7.17 J 8.4 Hz, I 7.23 8.4 Hz, IH), 7.43 (dd,J= 0.9, 7.8 Hz, IR), 7.52 J2.1 Hz, IH), 7.54 J= 15.6 Hz, IH). 7.8-1(dd J= 0.9, 7..8 HzIH1).MS (ESI-) at m/z 525, 527..
Example 218 (5-Ethoxvbenzodioxan-6-yl)[2-chloro-4-( E-((4-acetylpiperazin- 1vl~carbonyl)6thenyl) phenyll sulfide The title compound was prepared by the procedures described in Example substituting 5-iodoindole with 6-bromo-5-ethoxybenzodioxane, as s white solid. 'H NMR (CDCI3, -300 MHz) 8 1.28 J= 7.2 Hz, 3H), 2.14 3H), 3.54 (br s. 2H), .3.60-3.88(in, 6H), 4.06 J= 7.2 Hz, 2H), 4.33 4H), 6.70 J 8.4 Hz, I H), 6.73 J= 8.4 Hz, I1H), 6.78 J 15.6 Hz, I HO, 6.98 J= 8.4 Hz, I 7.17 (dd, 199 J= 1.8, 8.4 Hz, IH), 7.50.(d,J= 1.8 Hz, I 7.57 15.6 Hz, lI-H). MS (APCI") at m/lz 503, 505.
Example 219 2 -Ethyl- 4 -bromophenvl)r2-nitr..4-(E.((4.acetlpiperazin- I -yl)carbonyl~ethenyl) pheinyll sulfide The title compound was prepared according to the procedures of Example. 32.
'H NMR (CDC1 3 300 MHz) 5,8.43 11-, J 2.0 Hz), 7.64 IH, J =15.6 Hz), .7.58.
I H, J =2.0 Hz), 7.40-7.48 (in, 3H1), 6.90 I1H, J =15.2 Hz), 6.90 I1H, 3 Hz), 3.63-3.77 (mn, 3.54 (in, 2H), 2.72 2H-, J =7.5 Hz). 2.15 1. 18 (t, 3H-, J.=7.5 Hz). MS (EST) m/z 518, 520,542, 627. Anal. Calcd for C 2 3
H
2 4 Br 1
N
3
O
4
S
C, 53.08; H, 4.60; N, 7.93. Found: C, 53 .29, H,.4.67, N, 8.11.
Example 220 (Benzodioxan-6-l)2-nitr.4-( E-((2-carboxvpiperidin-1I-yi) carbonvl)ethenvl) pheny]1 sulfide The title compound was prepared by the hydrolysis of the compound of Example 203 under basic conditions (aq. NaOIEtOH), producing a light yellow solid:, mp 165 6 C(dec.). 'H NMR (DMSO-d 6 300 MHz) 6 1. 15-1.52 (mn, 3H), 1.46- '1.62 (in, 2H), 2.32 (in, I1H), 2.80 (in, I 3.45(br, 1/2H4), 4.00 (br, 1/2H), 4.44 (br, 1/2H),5 4.800 (br, 1/2H), 6.83 J=8. OHz, IH), 7.03 J=8.0 Hz,,IH), 7.09 (dd,+ J=12.0, 14.0 Hz, I 7.15 J=2.0 Hz, 7.20 (d J= 15.5 Hz. 1I-H), 7.3 5 11.I5.5 200 Hz, I 7.73 (in, I 8.52 (mn, I MS (ESI1) m/z 469 471 Anal.
calcd. for C 2 3
H
2 1
N
2
O
7 SNa -NaOH*2.7 H 2 0: C, 47.54; H, 4.75; N, 4.82. Found: C, 47.18; HI, 4.36; N, 4.89.
Examnle 221 (Benzodioxan--6-vl)f2-nitro-4-( carboxymethylpiperazin-lI-vi) carbonyl)ethenyl)' phenvll sulfide The title compound was prepared by deprotection of the compound 33 with TEA in CH,C1 2 The resultant free amine was trea Ited w ith t'ert-butyl bromoacetate and TEA in acetonitrile at room temperature, and followed by deprotection-with TFA in CH 2 Cl 2 giving a light solid, mp 120 0 C 'H NMR .(DMSO-d,, 300 MHz).8 .3.20-3.45 (in, 4H), 4.20 2H), 3.50-3.80 (mn, 4H), 4.28-4.46 (mn, 4H), 6.86 Hz, 1H), 7.04 (mn, J=8.0 Hz, 11H), 7.09 (dd, J=2.0 8.0 Hz, 11H), 7.15 J=2.0 Hz, IIH),- 7.40 J=15.5 Hz, 1H), 7.56 J=15.0 Hz, 11H), 7.90 (dd, J=2.0, 8.5 Hz, IH), 8.63 (mn, I MS (ESI) m/z 484 (M-H),486 Calcd. Anal for
C
2 3
H
2
N
3 0 7 Sl .19CF 3 COOH'1.34 H2O: 47.63; H, 4.1 1; N, 6.89. Found: C, 47.93; H, 1; N, 6.49.
Example 222 (3-Morphbolinophenyl)[2-nitro-4-(E-((4-acetvlpiperazin-1I -l)carbonvl )ethenyl) Phenyll sulfide The title compound was prepared according to the procedures of Example 62, employing the compound of Example 103 as starting material. 'H NMR (CDC 3 300 MHz) 8 7.80 I1H), 7.64 I1H, J 15.4 Hz), 7.43 (in, I1H), 7.32 I1H, J =8.1 Hz), 7.08 (in, 2H), 6.99 (in, 2H), 6.84 IH, J =15.4 Hz), 3.87 4H, J 4.8 Hz), 3.63- 3.79.(Mn, 6H), 3.50-3.55 (in, 2H), 3.18 4H, J 4.8 Hz), 2.10 MS (ESI) m/z 520, 542, 1061.
Example 223 (5-Ethoxybenzodioxan-8-ylM2-chloro-4-( E-((4acetylyiperazin- yl)carbonyl)ethmnvl phenyl] sulfide The title compound was prepared by the procedures described in Example substituting 5-iodoindole with 8-bromo-5-ethoxybenzodioxane, giving a white solid.
'H NMR 300 MHz) 8 1.52 J= 7.2 Hz, 3H), 2.15 3H), 3.48-3.59 (in, 2H), 3.59-3.85 (in, 6H), 4.16 J 7.2 Hz, 2H), 4.22-4.30 (mn, 2H), 4.30-4.40 (i, 2H), 6.59 J1 8.7 Hz, I 6.63 (d,J 8.7 Hz, I 6.78 15.6 Hz, I1H), 7.08 J 8.7 Hz, I 7.17.(dd,J 2.1, 8.7 Hz, I1H), 7.51 J 2.1 Hz, I 7.5 8 J =15.6 Hz, I1H). MS (APG1+) (M+H) 4 at m/z 503, 505.
Example 224 (5-Chloro-8-ethoxycjuinol in-7-yl)[2-chloro-4-( E-((4-acetylpinerazin- I yl)carbonflethenyl) phenyll sulfide 202 The title compound was prepared. by the procedures -described in Example substituting 5-iodoindole with 5-chloro-8-ethoxy-7-iodoquinoline, giving a* white solid. 'H NMR (d'-DMSO, 3 00 M4Hz) 8 1.37 (t J~ 7.2 Hz, 3H), 2.04 3H), 3.41 3.82 (in, 8H), 4.46 J1 7.2 Hz, 2H), 7.29 I1H), 7.3 7 J= 8.4 Hz, I 7.42 (d, J= .15.6 Hz, IH), 7.51 (dJ= 15.6 Hz, 1IH), 7.68 1.8, 8.4 Hz, I 7.74 (dd, J 8.4 Hz, IH), 8.15 1H1), 8.55 (dd, J= 1.8, 8.4 Hz, IH), 9.05 (dd, J= 1.8, 3.9, Hz, IlH). MIS (APCI') (M+H) 4 at' m/z 530, 532, 534.
Example 225 (2-Isop2ropylphenyl)r2-nitro-4-( E-((-carboethoxvrpiperidin- I -yl)carbonyl)ethenyl) pelsulfide, Examnile 225A (2-Ilsoprop~ylphenyl)r2,nitro-4-( E-(carboxv)ethenyl) phenyll sulfide To a'stirred mixture of 4-chloro-3-nitrocinnamic acid (500 mg. 2.2 inmol) in mL of anhydrous DMF with K 2 C0 3 (911 mg, 6.6 inmol).was added 2isopropylbenzenethiol (372 mL, 2.2 inmol) in I ml, of DMF dropwise. The resulting mixture was then heated at 70 'C under nitrogen atmosphere over night. Water mL) was then added and the reaction mixture was acidified to pH =4 with 3N HC1.
The cloudy mixture was extracted with EtOAc (2x20 mL). The -combined organic layer was washed with brine, dried over Na 2
SO
4 concentrated in vacuo to give the 203 title comnpound as viscous light-yellow oil, which was used for coupling with further purification.
Example 225B (2-Iso-propylphenyl) [2-nitro-4-( E-0(-carboethoxypiperidin- I -yl)carbonyl)ethenyl) phenvil sulfide The title compound was prepared by the procedures described in Example 92, substituting the benzoic acid with cinnamic, acid from 225A, and ammoniumi chloride with ethyl nipecotate, giving a light-yellow solid. 'H NMR (CDCI 3 300 MHz) 5 1. 18 J 6.6 Hz, 1.27 J 7.2 Hz, 3H), 1.69-1.82 (in, I 1.82-1.99 (in, I1H),.
1.99-2.20 (in, I1H), 2.45-2.62 (mn, 2H), 3.45 (septet, J= 6.6 Hz, I 3.56-3.80 (mn, I 3.80-4. 10 (in, 2H), 4.16 J= 7.2 Hz, 2H), 4.65-4.81 (in, I 6.69 J= 8.4 Hz, IlH), 7.00 (br s, I 7.31 (dd, J= 2.4, 6.9 Hz, 1 7.42 (br d, J~ 8.4 Hz, I H), 7.51 J 15.6 Hz, I 7.52 (overlapping d, 2H), 7.5 8 J 15.6 H4z, I 8.43 (s, 1IH). MS (APCI-) at. mn/z483.
Example 226 (2-lsopropylphenvlMr2-nitro-4-( E-0(-carboxypiperidin- I -yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester fromn Example 137 with the ethyl *ester from Example 225B, and KOH with NaOH, to give a light-yellow solid. 'H NMR (d'-DMSO, 300 204 MHz) 5 1.15 J= 6.9 Hz, 6H), 1.30-1.50(in, 1WH), 1.50-1.80(in, 2H), 1.88-2.04(mn, 2H), 2.95-3.17 (in, IH), 3.94-4.06 (mn, IH), 4.06-4M2 (in, 2H), 4.40-4.52 1H), 6.63 J= 8.7 Hz, 1H), 7.33-7.53 (in, 3H), 7.56-7.68 (mn, 3H), 7.91 (dd, J= 1.8, 8.4 Hz, IH), 8.63 J=8.4 Hz, 1H). MS (APCI') (M+H) 4 atnm/z 455.
Example 227 (2-Isop~ropvlphenvfl r2-nitro-4-( E-(((3-ethanesulfonylariniocarbonyl)pineridin-. 1 yl)carbonyl)ethenvl) phenYll sulfide To a stirred solution of free acid (5 0 mg, 0. 11 in=6o) from Example 226. in 1 mL of methylene chloride was added ethyl sulfonamnide (18 mng, 0. 17 inmol), EDAC mng, 0. 13 inmol), and DAMP (2.7 mng, 0.022 iniol) 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% MeON in EtOAc to give 30 mg (50 yield) the title compound as a light yellow solid. 'H NMR (CDCl 3 3 00 MHz) 6 1. 18 J =6.3 Hz, 6H), 1.34 J Hz, 3H), 1.61-1.74 (mn, 2H), 1. 84-2.04 (mn. I 2. 13-2.35 (mn, I 2.60-2.75 (in, 2H),.
3.44 J= 7.5 Hz, 2H), 3.53-3.66 (in, I 3.66-3.85 (in, 2H), 4.00-4.18 (mn, I1H), 6.71 J 8.7 Hz, I 6.88 J1= 15.6 Hz, I1H), 7.31 (dd, J 2.4, 8.4 Hz,- I 7.41 1. 8, 8.4 Hz, INH), 7.51 J 1. 8 Hz, I 7.54 J=8.4.Hz, I 7.67 J 15.6 Hz, I 8.43 IlH). MS (ES1') (M+H)4 at m/lz 546.
Example 228 (2-Isopropylphenyl)F2-nitro-4-( E-W(3-(4-methylpiperazine) sul fonylaminocarbonyl)piperidin-1-I-l)carbonvl)ethenvl) phenyil sulfide The title compound was prepared by the procedures described- in Example 228,' substituting ethyl sulfonamide with N-methyl piperazine sulfonamide, giving a light yellow solid. 'HNMR (CD'CI 3 ,300 MHz) 8 1.18 6.5 Hz, 6H), 1.40-2.10 (in, 9H4), 2.6 0 3H), 2.60-2.76 (in, 4H), 2.90 (br. s, 31-1), 3.44 (septet, J= 6.5 Hz, IlH), 3.52-4.0 8 (mn, 4H), 6.71 8.4 Hz, I 6.95 J 15.6 Hz, 1H4), 7.31 J 2.1, 8.4 Hz, IH), 7.43-7.57(in, 4H), 7.64 J= 15.6 Hz, 1H), 8.44_(s, 1H). MS (ESI-) at m/lz 616. Anal. Calcd for C 2 qH 37
N
5
O
6
S
2 1.13 H 2 0: C, 54.76; H, 6.22; N, 11.01. Found: C, 54.78; H, 6.11; N, 10.87.
Example 229 (2-1 sopropylp~henylMf2-nitro-4-( E-(((-p-toluenesul fonyl aminocarbonylDyiperi din- I1yI)carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 228, substituting* ethyl sulfonamide with p-toluenesulfonaiide, giving a light yellow solid.
'H NMR (CDCl 3 300 MHz) 8 1.19 J= 6.5 Hz, 6H), 1.75-1.94 (in, 2H), 2.05-2.24 (mn, IH)) 2.40 3H), 2.48-2.60 (in, 2H), 3.45 (septet, J 6.5 Hz, I 3.50-3.85 (in, 3H), 3.85-4.12 (in, IH), 6.72 8.4 Hz, 1H), 6.86 (d2 J= 15.6 Hz, IH), 7.27-7.34 (in, 2H), 7.43 (dd,J 2.1, 8.4 Hz, I 7.50 (overlapping d, IlH), 7.53 J =8.4 Hz, 2H), 7.5 5 J 8.4 Hz, I 7.92 J 8.4 Hz, 2H), 8.44 11-1). MS (ESI*) at m/z 608.
206 Example 230 (2-Isopropylphenyl)[2-nitro-4-( E-((3-methyl-4-acetylniperazin- 1vl)carbonvl)ethenjl) 12henyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d, 300MHz) 5 0.94-1.18 (mn, 3H); 1.14 J =7.0 Hz, 1.98- 2.08 (br mn, 3H); 2.6973.74. (br mn, 4H); 4.02-4.65 (br m, 4H);'6.64 J =8.5 Hz, I 7.3 1-7.63 (in, 6H); 7.88-7.96 (br m, lH); 8.65 (hr s, 114I). MS (APCI) at mlz 468. Anal calcd for C 2
.,H
9 NS0 4 0.I-lH,O: C, 63.91;, H, 6.70; N, 8.94. Found: C, 63.54; H, 6.41; N, 8.67.
Examnle 231 (2-Hvdroxvphenyl)-12-chloro-4(E-r(morpholin-1I-yflcarbonyllethenyl)phenyllsulfide The title compound was prepared according to the procedures of Example 1,.
giving a white solid, m.p. 157-158C. 'H-NMR (CDCI 3 300 MHz) 8 3.60-3.76 (in, 8H), 6.42 I 6.5 7 3=9hz, I 6.76 J=1I5Hz, 1IH), 6.99-7.04. (mn, I H),9 7. 7.20 (mn, 2H), 7.42-7.55 (in, 4H). Anal. Calcd. for C 19
H
13 C1N0 3 S: C,*60.71; h, 4.83; N, 3.73. Found: C, 60.48;'H, 5.05; N, 3.69.
Example 232 (1 -(Carboxymethvl)indol-5-ylfl2-chloro-4-( E-((4-acetylpiperazin- 1yl)carbonvl)ethenyl) phenyil sulfide 207 To a stirred solution of indole compound from Example 85 (35 mg, 0.080 mmol) in I ML of anhydrous DMS0 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 NHCI to pH The title compound (25 mg, 63 was collected through filtration and dried in vacuum oven, giving a white -solid.
'H NMR d 6 -DMSO, 300 MHz) 5 2.04 3H), 3.38-3.80 (in,81),45(s2H,65 3.0 Hz, I 6.52 J~ 8.7 Hz, I 7.21 (dd, J= 2.1, 8.7 Hz, IlH), 7.2.5 J =15.6 Hz, I 7.3 8 J 15.6 H-z, I 7.40 J 3.0 Hz, I 7.47 J 8.4 Hz, I 7.80 J 2.1 Hz, I1H)3 7.97 I MS (ES1") at m/z 496, 498.
Example 233 (Benzodioxan-6-vJ)r2-trifluoromethyl-4-( E-((4-ace tvlpiperazin-1 yj)carbonyl)ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example 84, substituting 2-bromothiophenol with 6-mercaptobenzenedioxane. white solid; 'H NMR (CDCI 3 300 MHz) 5'2.15, 3H), 3.46-3.89 (in, 8H), 4.30 (dd, J= 2.1, 6.0 Hz, 4H), 6.84 J 15.0 Hz, I 6.92 (d,J 8.4 Hz, IlH), 6.97-7.1 0 (in, 3 7.42 J =8.4 Hz, I 7.64 J= 15.0 Hz, I1H), 7.77 I1H). MS (ESI') rn/z 493 Example 234 208 (2-lsopropylphenyl)[2-nitro-4-( -Pyrrolidin-2-onvl)prop-1I-yiamino) carbonvl~ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR (DMSO-d,, 300MHz) 5 1.14 J =7.1 Hz, 6H); 1.58-1.68 (in, 211); 1.85-.1.97 2H); 2.18-2.24 (m,2H);-3.10-3.22 (mn, 411); 3.30-3.39 (mn, 3H); 6.65-6.72 (in, 2H); 7.32-7.45 (in, 2H1); 7.57-7.62 (in, 3H); 7.76 (dd, J 2.0 Hz, 1H); 8.11-8.17 (mn, 11H); 8.44 J =2.0 Hz, I1H). MS (APCI) (M+H)t at mlz 468. Anal calcd for C,,H,NS0 4 .,0.26CH 3
COOCH,CH
3 C, *63.717; H, 6.39; N, 8.57. Found: C, 63.46; H, 6.37; N, 8.90.
I0 Example 235 (3-(2-Morpholinoethylainino)phenylMr2-trifluoromethyl-4-(E-((4-Acetylpiperazin- 1- Yl)carbonvl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 62, employing the compound of Example 103 as starting material. IH NMR (CDCl 3 300 MHz) 5 7.78 111,3 1.4Hz), 7.64 1H, J =15.4 Hz), 7.42.(d, 111, J= 8.8 Hz), 7.21 (t,l11,3 =7.9 Hz), 7.12 11, 8.5 Hz), 6.84 11,J3= 15.4 Hz), 6.82 (i, 111), 6.76 I11,3 J1. 8 Hz), 6.66 (in, 111), 3.72 (mn, 1011), 3.51-3.55 (in, 211), 3.16 (t, 211, 3J 5.9 Hz), 2.64 2H, J =5.9 Hz), 2.50 (in, 411), 2.15 311). MIS (ESI) m/z 563.
Example 236 (2-Pyrrolidin- I -vlphenyl)2-nitro-4-(E-((4-acetylTviperazin- I -vl)carbonyl)ethenyl) phenvll sulfide The title compound was prepared according to the procedures of Example 62, employing the compound of Example 103 as starting material. 'H NqMR (CDCI 3 300 MHz) 8 7.7.7 I 7.64 I H, J =15.4 Hz), 7.40 (in, I1H), 7.22 I1H, J =7.8 Hz), 7. 10 I1H, J =8.8 Hz), 6.82 I H, J =15.3 Hz), 6.7 6 I H, J 7.8 Hz), 6.70 (t, I H, J =2.0 Hz). 6.59 (dd, I H, J 8.1 Hz), 3.61-3.79 (in, 6H), 3.51-3.54 2H), 3.28 (in, 4H), 2.14 2.01 (mn, 4H). MS (EqT' m/z 504.
Example 237 3 -Broinop~henvl)r2-nitro-4-(E-((3-carboethoxypyrrolidin-1 -yl~carbonvl)ethenyl) phenvI] sulfide The title compound was prepared according to the procedures of, Example 1.
'H NMR (CDCl.I, 300 MHz) 8 8.40 1H, J 1.5 Hz), 7.75 (in, 1H), 7.45 (in, I H), 7.48-7.56 (in, 2H), 7.3 8 I H, J 7.9 7.00 (br, I1H), 6.87 I H, J =9.5 Hz), 4.16 2H4 J =7.1 Hz), 3.99 (br, 2H), 3.70 (br, I 3.3 0 (hr, 11H),.3.00 (hr, I 2.55 IH), 2.10 (in, IH), 1.89 (br, 1H), 1.85 (br, IH), 1.27 3H, J 7.0 Hz). MS (ESI) m/z 519, 521. Anal. Calcd for C 2 3
H
2 3 BrN 2
O
5 S 0.19 H 2 0: C, 52.84; 4.51; N, 5.36. Found: C, 52.85; H, 4.55; N, 5.28.
Example 238 210 (3-Bromophenyl)I'2-nitro-4-(E-( (4-carboethoxypyrrolid i-1 -yl)carbonyl)ethenvP) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCl 3 ,3 300 MHz) 8 8.41 I1H), 7.75 (in, I 7.62-7.67 (in, 7.5 3 (in, 11H), 7.48.(d, 1H, J =8.8 Hz), 7.38 (ti IH, J 6.98 (br, IH), 6.88 IH, J= Hz), 4.18 2H, J =7.1 Hz), 3.64-78 (br, 3.55 (hr, 4H), 1'.29 (t 3H, J 7.
Hz). MS (ESI) m/lz 520, 522.
Examp~le 239 (2-(Hydroxvmnethyfl-benzodioxan-6-Yil)2-chloro-4-( E-((4-acety lpinerazin-I yl)carbonvl)ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example substituting 5-iodoindole with a. mixture of 2-hydrox yiethyl-6-bromobenzodioxane and 2-hydroxymethyl-7-bromobenzodioxane, giving a white solid. 'H NMR (CDCl 3 300 MHz, mixture of 3:2 regioisomers) 8 2.15 3H), 3.46-3.83 (in, 8H), 3.83-4.01 (mn, 2H), 4.10-4.42 (in, 4H), 6.75 J= 8.4 Hz, 6.79 J= 15.9 Hz, I1H), [6.95.
6.98 J =4.8 Hz, I H in total], [7.04 7.07 J =1.5 Hz, 1 H in total], 7.11 J= 2.4 Hz, I H in total], 7.19 J= 8.4 Hz, I 7.5 3 11H)*, 7.5 8 J 15.6 Hz, IH). MS (APCV) at m/z 489.
Example 240 (Benzodioxan-6-vl)f2-trifluoromethl-4-(E-((3-(Pvrrolidil- 2 -ol- I -v])proR- 1ylamino)carbonyl) ethenyl)phenyllsulfide The title compound was prepared by the procedures described in Example 233, substituting 1-acetylpiperazine with 3-aminopropyl-1 -pyrrolidin-2-one, giving a white solid. 'H NMR (CDC1 3 300 MHz) 8 1.69-1.80 (in, 2H), 2.08 J= 7.5 Hz, 2H), 2.44 i 7.5 Hz, 2H), 3.27-3.48 (in, 6H), 4.24-4.34 (in, 4H), 6.44 (d,J 15.6 Hz, I H), 6.90 J 8.4 Hz, I 7.00 J= 8.4 Hz, I 7.01 (dd, J= 2.7, 8.4. Hz, 1IH), 7.06 J= 2.7 Hz, I1H), 7.08 I1-H), 7.40 (dd, J 8.4 Hz, I 7.53 J= 15.6 Hz, I1H), 7.75 J= 2.1, Hz, I1H). MS (ESIY) at m/z 507.
Example 241 (3-(Dimethylaminomethl)indol-5-v1)r2-chloro-4-( E-((4-acetylpiperazin- 1yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared-by the procedures described in Example 217, substituting the indole from. 186 with the i ndole from Example 85, resulting -in a white solid. 'H NMR (CDC13, 300 MHz) 82-.15 3H), 2.54 6H), 3.47-3.85 (in, 8H), 4.05 2H), 6.56 J= 8.7 Hz, IH), 6.77 J 15.6 Hz, I1H), 7.09 8.7 Hz, I 7.36 (dd, J 1.5, 8.7 Hz, I 7.50 J= 8.7 H4z, I1H), 7.52 2H), 7.56 J 15.6 Hz, I1H),7.8 8 I 9.27 I1H). MS (ESI*) at m/lz 497, 499. Anal.
Calcd for C 2 6
H
2 9 C1N 4 0 2 S 0.46 TFAM 1.72 MeOR: C, 56.89; H, 6.06; N, 9.27.
Found: C, 56.83; H, 6.15; N, 9.46.
212 Example 242 (2-Isopropvylphenyl)r2-nitro-4-( E-((2-carboethoxypiperidin- I -Yl)carbonyl)ethenvyl) phenyI1 sulfide The title compound was prepared by the procedures described in Example 2.25, substituting ethyl nipecotate wkith ethyl pipecolinate, giving a light-yellow so -lid. 'H NMR (CDCI3, 300 MHz) 8 1.18 J= 6.9 Hz, 6H), 1.28 J=.7.35 Hz, 3H), 1.34- 1.62 (in,2H), 1.62-1.84 (in,3H), 2.32 (br d, J=13. 2 Hz, 1H), 3.33-3.54 (in, IH), 3 (septet, J 6.9 Hz, 1IH), 3.99 (br d, J= 13.2 Hz, IlH), 4.21 J 7.3 5 Hz, 2H), 5.46 (br s, 1H), 6.69 J= 8.7 Hz7, IH), 7.01 J= 15.6 Hz, IH), 7.25-7.34 (in, IH), 7.42 J= 8.7 Hz, I 7.46-7.60 (mn, 3 7.5 8 J= 15.6 Hz, I 8.44 I MIS
(ESI
4 at ?n/z 483..
Example 243 (2-Is opropylphenyl'ff2-nitro-4-( E((2-carboxyperidin- I -Yl)carbonyl)ethenyl) phenyll sulfide 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. 'H NMR (CDC13, 300 MHz) 8 1. 18 J= 6.9 Hz, 6H), 1.40-1.89 (in, 5H), 2.34 (br d, J= 11.7Hz, IlH)q 3.3 1-3.51 (mn, I 3.44 (septet, J 6.9 Hz, 4.01 J= 11.7 Hz, I 5.42 (br s, IlH), 6.70 J 7.8 Hz, I 6.99 (br d, J1= 15.6 Hz, I 7.29 (td, J 2.7, 6.9 Hz, I1H), 7.41 J1= 7.8 Hz, I 7.45- 8 (in, 3 7.64 15.6 Hz, I 8.43 I MS (ESI+) at m/z 455.
213 Anal. Calcd for C 2 4
H
2 6
N
2 0 5 S 0.08 H 2 0: C, 63.22; H, 5.78; N, 6.14. Found: C, 63.21; H, 5.65; N, 6.00.
Example 244 (2-Isopropvylphenylfl2-nitro-4-( E-((4-carboethoxypiperidin- I -yl)carbonyl)ethenvl) phenvil sulfide The title compound. was prepared by the procedures described in Example 225, substituting ethyl nipecotate with ethyl isonipecotate, to give a light-yellow solid. 'H NMR (CDCl 3 3 00 MHz) 5 1.18 J =6.9 Hz,! 1.27 J 7.5 Hz, 1.64- 1.86 1.94-2.09 (mn, 2H), 2.90-3.15 (in, IH), 3.15-3.39 (in, 1H), 3.44 (septet,Ji 6.9 Hz, 11H), 3.95-4.14 (mn, I1H), 4.16 J 7.5 Hz, 2H), 4.40-4.63 (in 6.69 (d, J 8.7 Hz, I1H), 6.98 J 15.6 Hz, I 7.29 (td, J 2.7, 6.9 Hz, I 7.41 J 8.4Hz, I1H), 7.46-7.60 (in, 3H), 7.5 8 J 15.6 Hz, I 8.43 (s,l IH). MS (ESIE) (M+H4) at m/lz 483.
Exampe 245 (2-lsopropvlphenvlfl2-nitro-4-( E4-carboxypiperidin- I -yl)carbonyl)ethenyl) Phenyll sulfide 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. 'H NMR (CDCl 3 30 0 MHz) 5 1.18 J= 6.9 Hz, 6H), 1.65-1.89 (in, 2H), 1.97-2.14 (mn, 2H), 2.59-2.74.(in, IH), 2.93-3.20 (mn, 1H), .214 3.20-3.42 (in, I 3.44 (septet, J 6.9 Hz, IlH),, 3.97-4.18 (in, I1H), 4.40-4.65 (mn, I 6.70 J= 8.7 Hz, I1H), 6.97 J= 15.6 Hz, I1H), 7.30 (td, J= 2.7, 6.9 Hz, I H), 7.41 J1=8.7 Hz, I 7.46-7.65 (in, 3H), 7.60 (d,.IJ 15.6 Hz, I 8.43 11H).
MS (ESI-) at nhz 455.
Example 246 2 -lsoo~ropylphenyl)[2-nitro-4-( E-f(4ff ounflfnimiopbnv~ieidn1 yl)carbonvl)ethenyJ) phenyll sulfide 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; 'H NMR (d'-DMSO, 300 MHz) 5 1.14 J1=6.9 Hz, 6H), 1. 18-1.39 (in, 2H), 1.67-1.7.9 (mn, 2H), 2.39 3H), 2.60-2.75 (in, 2.96-3.14 (mn, I 3.26-3.42 (in, I 3.34 (septet, J1 6.9 Hz, I 4.10-4.42 (mn, 2H), 6.62 J 8.4 Hz, INH), 7.3 2- 7.43 (in, 4H), 7.45 15.6 Hz, INH), 7.5 8 1=8.4 Hz, 2H), 7.60 J1=3.6 Hz, 1 7.78 J1 8.4 Hz, 2H), 7.87 (dd,J 8.4 Hz, iN), 8.60 J 2.7 HziN).' MS (ESI-) at mhz 606. Anal. Calcd for C 3 lH 3 3
N
3 0 6
S
2 0.26 H 2 0: C, 60.80; H, 5.52; N, 6.86. Found: C, 60.8.5; H, 5.84; N, 6.6 1.
Example 247 (2-lsopropylp~henyl)[2-nitro-4-( E-((3-carboxy-4-hvdroxyiperidin- 1vl~carbonvl~ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid. 'H NMR (DMSO-d 6 300MHz) 8 1. 14 J =6.8 Hz, 6H4); 1.53-1.70 (br m. 2H); 2.92-' 3.52 (hr m. IH); 3.30-3.40 (in, IH1); 3.98-4.44 (br m, 4H); 4.90-5.20 (br mn, I1H); 6.63 J 8.5 Hz, I 7.34-7.62 (mn, 6H); 7.87-7.94 (hr mn, I1H); 8.58-8.64 (hr m, 111).
MS (APCI) at ink, 471. Anal calcd for C,,H,6N,$S 6 61.26; H, 5.57; N, 5.95. Found: C, 61.05; H, 5.85; N, 5.73.
Example 248.
(Benzodioxan-6-vl) r2-trifluoromethvl-4-( E-((-carboethoxypiperidin-1- 1 v) carbonyl)ethenyl) phen 11 sulfide The titlecoinpound was prepared by the procedures described in Example 240 substituting N-(3'-aminopropyl)-2-pyrrolidinone with ethyl nipecotate, giving a white hygroscopic solid. 'H NMR (CDCI 3 300 MI-z) 5 1.26 J=7.0 Hz, 1L54 (in, IlH), 1.65-1.80 (in, 2H), 2. 10 (in, I1H), 2.54 (mn, I 2.92-3.40. 2H), 3.60-4.10 (in, 2H), 4.14 J=7.0 Hz, 214), 4.25-4.32 (mn, 4H), 6.91 J=7.5 Hz, IH), 7.00 (dd, 15.0 Hz, 3H), 7.05 J=2.0 Hz, IlH), 7.40 J=8.0, I 7.56 J=15.0 Hz, I 7.76 IlH). M S (CI/NH 3 )mn/z 522 Anal. calcd. for C, 6
H
26
F
3 N0 5
S:
C, 59.88; H, 5.02; N, 2.69. Found: C; 59.92;,H, 5.39; N, 2.56.
Example 249 (Benzodioxan-6-yi)(2- trifluoromethvl- 4 E-((2-carboethoxypiperidin- I -VI) carbonvl')ethenvl) phenyll sulfide 216 The title compound was prepared by the procedures described in Example 240 substituting N-(3 '-aniinopropyl)-2-pyrrolidinone with ethyl pipecolinate. 'H NMR (CDCl 3 300 MHz) 8 1.28 J=7.0 Hz, 3H), 1.35-1.54 (in, 2H), 1.64-1.82 (in, 3H), 2.30 (in, lH), 3.40 (mn, 111), 4.00 (in, IH), 4.22 J=7.0 Hz, 2H), 4.26-4.34 (mn, 4H), 5.48 (in, 1H), 6.91.(d, J=83 Hz, IH), 6.98 (mn, 111), 7.02 (dd, J=2.0, 8.0 Hz, 2H), 7.06.
J=2.0 Hz, I H),,7.41 J=8.0 Hz, I 7.57 J=1 5.0 Hz,l IH), 7.77 I MS (Cl/NH 3 m/z 522 Anal. calcd for C 26
H
26
F
3 N0 5 S: C; 59.88; H, 5.02; N, 2.69. Found: C, 60.25; H, 5.12; N, 2.55.
Example 250 (Benzodioxan-6-vI')[2-nitro-4-( E-((4-carboxypiperidin- 1 -vi) carbonyl~ethenvl) Rhenvil sulfide The title compound was prepared by the hydrolysis of compound 198 under basic condition (aq. NaOHIEtOH), and purified by reversed-phase HPLC. 'H NMR (DMSO-d 6 300 MHz) 8 1.44 1.78 (mn, 2H), 2.04 (in, 2H), 2.82 (mn, IH), 4.02-4.20 (mn, 2H), 4.4.20-4.35 (mn, 4H), 6.90 J=8.0 HzIH), 6.97 J=8.0 Hz, I 7.05(dd, J=2.0, 8.0 Hz, I1H), 7.10O(d, J=2.0 Hz, I 7.15 (br, I 7,44 (in IH), 7.60 (br, I 8.40 I1H). MS (ESI) in/z 469 I).
Example 251 (Benzodioxan-6-yI)[2-trifluoromethvl-4-(E-((3 -carboxyp~yrrolidin- 1vl~carbonvl~ethenvl) phenyll sulfide 217 The title compound was prepared according to the procedures of Example I. 'HNMR (CDCl 3 300 MHz) 5 7.75 lH), 7.60 1H, J =15.0 Hz) 7.40 (br, INH), 7.06 I H, J 2.2 Hz), 6.96-7.02 (in, 3H), 6.90 IH, J 8.5 Hz), 4. 30 (in, 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-vl)[2-trifluoromethvl-4-( E-((4-carboethoxvypiperidin-l1-VI) carbonyl~ethenyl) Rheniyll sulfide The title compound was prepared by the procedures de scribed in Example 240 substituting N-(3 '-aininopropyl)-2-pyrrolidinone with ethyl isonipecotate, giving a white sticky solid. 'H NMR (CDCI 3 300 MHz) 5 1.26 J=7.0 Hz, 3H), 1.68-1.8 0 (in, 2H), 1.98-2.10 C,2H), 2.54-2.70 (mn, 2H), 3.00-3.30 (br, 2H), 4.1.5 (mn, 3H), 4.26- 4.34 (in, 4H), 6.90 J=8.0 Hz, 2H), 7.00 (dd, J=2.0, 8.0 Hz, 2H4),'7.06 J=2.0 Hz, IH), 7.41 (mn, 1H), 7.50 1H), 7.75 I1H). MS (CIINH3) inlz 522 An al.calcd. for C 24
H
2
.,F
3 N0 5 S- 0.1 H,O: C, 58.20; H, 4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Example'253 (Benzodioxan-6-ylM[2-trifluoromethyl-4-( E-((2-carbomethoxv-4-iertbutoxycarbonylp2iperazin- 1 -yl) carbonvl~etheny 1) phenvll sulfide The title compound was prepared by the procedures described in Example 240 substituting N-(3 '-aminopropyl)-2-pyrrolidinone with. I -Boc-3-, carbomethoxypiperazine, giving a white solid, nip 85-87 0 C. 'H NMR (CDC1 3 3 00 MHz) 5 1.46 9H), 2.,90-3.00 (mn, 2H), 3.08-3.20.(in, 214I), 3.76 3H), 3.90 (in, IH), 4.25-4.34 (in, 4H), 4.58-4.66 (in, 2H), 6.92 J=8.0 Hz, IH), 6.98 (in, 7.02 (dd, J=2.0, 8.0 Hz, 2H), 7.06 J=2.0 Hz, I 7.40 (in, I 7.62 (br, INH), 7.76 (s, I1H). MS (APCI) m/z 609 Anal. calcd. for C 29
H
3
,F
3 NI0 7 S: C5 57.23; H 5.13; N, 4.60. Found: C, 57.09; H, 5.25; N, 4.37.
.Example 254 (Benzodioxan-6-vl)r2-trifluoromethvlA E-(2-arbomethoxyA4 methoxvcarbonyvlieain- I -vi) carbonyl)ethenvl) henvil sulfide The. title compound was prepared by treating the compound of Example 255 with methyl chlorofommiate and pyridine in CH 2 CI., at room temperature, producing a white foam. 'H NMR (CDCI 3 300 MHz) 5.3.00 (mn, 1H), 3.18 (in, 3.60.(in, 1W), 3.72 3H1), 3.76 3H), 3.90.(in, IH), 4.10 (br, IN), 4.28-4.34 (in, 4H), 4.64 (in, IlH), 5.32 (mn, I1H), 6.85 J=1 5.5 Hz, 1WH), 6.92 J= 8.0 Hz, I 6.98 (in, I H), 7.02. (dd, J=2.0, 8.0 Hz, I1H), 7.08 J=2.0 Hz, I1W), 7.40 J=8.0 Hz, 1WH), 7.64 (d, J=15.0 Hz, 1W), 7.77 1W). MS (CT/NH 3 m/z 567 Anal. calcd. for
C,-
6
H.,
5
F
3
N
2 07S. C, 55.12; H, 4.4 5; N, 4.94.. Found: C, 55.18; H, 4.70; N, 4.68.
Example 255 219 (Benzodioxan-6-ylMr2-trifluoromethyi-4-( E-((2-carbomethoxylniperazin- I -YD' carbonvlbethenyl) Rhenyll sulfide The title compound was prepared by deprotection of compound 253 with TEA in CH 2
CI
2 resulting in a light yellow solid, mp 70-72 0 C. IH NMR (CDCL 3 ,.300 MHz) 5 2. 90 (mn, I 3.05 (1n 3.3 5 (in, I1H), 3.68 (mn, I 3.80 3H), 4 00 (in, I H), 4.25-4.34 (in, 4H),,4,70 (br, I 5.46 (in, I 6.84 J=1 5.5 Hz, I 6.90 (d, Hz, 1H), 6.96-7.04 (mn, 2H), 7.06 (in, 114), 7.40 J=8.0 Hz, IH), 7.65 J= 155 Hz, IlH), .7.77 I MS (Cl/NH 3 m/z 5 09 Anal. calcd. or
C
24
H
23
F
3
N
2 0 5 S1.55,H2O: C, 53.74; H,4.90; N, 5.22. Found: C, 54.04; H, 4.59; N,.
4.82.
Example 256 (2-Methyl-3 -(carboethoxymethvl)indol-5-v14r2-trifluoromethvi-4-( E-((morpholin- 1yl)carbonvl)ethenyl) phenyll sulfide ExamRle 256A (4-Bromophenyl4r2-trifluoromethyl-4-( E-((molpholin- I -vl)carbonyl) ethenyl) phenyll sulfide The bromide was prepared by the procedure described in Example 12, substituting 2-bromothiophenol with 4-bromothiophenol, and 3,4dichlorobenzaldehyde with 4-fluoro-3-trifluoroinethylbenzaldehyde.
220 Example 256B 4 -Hvdrazinophenvl)[2-trifluoromethvl-4-( E-((morpholin-1-yl)carbonvl ethenvl) phenyll sulfide, benzophenone hydrazone To a stirred solution of above-described bromide (1.0 g, 2.12 mmol) in 10 mL of toluene with Pd(OAc) 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 2 for 2 min before it was heated at OC 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, flash column chromatography eluting with 10-30% EtOAc/hexanes to give 170 mg of the title compound as light brown foamy solid.
Example 256C 2 -Methyl-3-(carboethoxvmethyl)indol-5-vl) 2-trifluoromethvl-4- E-((morpholin-1vl)carbonyl)ethenyl) phenyll sulfide 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 3 The organic layer was then washed with brine, dried over Na 2 SO,, concentrated in vacuo. The residue was then purified on Gilson preparative HPLC as described in Example 38B to give 221 mg of the title compound. light-brown solid. 'H NMR (CDC 3 300 MHz) 1.20 J= 7.4 Hz, 3H), 2.46 3H), 3.55-3.83 (br m, 8H), 3.67 2H), 4.12 J 7.4 Hz, 6.79 J= 15.3 Hz, I 6.84 J= 8.4 Hz, I1H), 7M2-7.31 (in, 2H), 7.34 J= 8.4 Hz, I1H), 7.60 J 15.3 Hz, I 7.76 I 7.80 I1H)7 8.04 (s, JH). MS (ESI-) atm/z 533.
Example 257 (I -(2-Methoxyethyl)indol-5-ylM2-chloro-4-( E-((4-acetvlpiperazin- 1- Yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 232, substituting t-butyl bromoacetate with bromoethylmethyl ether. white solid; 'H NMR
(CDCI
3 ,,300 MHz) 8 2.14 2H), 3.35 3H), 3.46.-3.56 (in, 2H), 3.56-3.80 (mn, 6H),, 3.75 J= 5.6 Hz, 2H), 4.33 J= 5.6 Hz, 2H), 6.54 3.3 Hz, IH), 6.61, J= 8.7Hz, IH),6.75(d,J=15.3Hz, IH),7.09(dd,J=2.l, 11.7Hz, IH),7.26 (overlapping d, IH), 7.36 (dd,i= 2.1, 8.7 Hz, 1H), 7.44 J= 8.7 Hz, IH). 7.51 J =2.1 Hz, IH), 7.56 15.3 Hz, 7.88 1.5 Hz,1W. MS (ESIfl(M+H) at m/z 498, 500.
Examnle 258 (2-IsopropylphenylO[-nitro-4-( E-((3-acetoxymethyl-4-hydroxypiperidin- I vl~carbonyl)ethenvl) phenyll sulfide Prepared according to the procedures of Example .71, giving a yellow solid.
IH NMR (D)MS0-l, 300MHz) 5 1. 14 J =7.0 Hz, 6H); 1.5 1-1.90 (br mn, 2H) ;"1.92- 2.0.6 (in, 3H); 2.50-3.21 (br m, 2H); 3.30-3.40 (in, 1K); 3.404.440 mb i, 5H); 4.88- 4.97 (br m, I 6.63 J =8.5 Hz, lH); 7.3 1-7.62 7.,87-7.94 (br.in, 1K); 8.58-8.64 (br m, A1H). MS, (APCI) at i/z 49.9. Anal calcd. for.
C.
6 HNS,0 6 0.29H1,o: C, 61..98; H 6.12; 5.56. Found: C, 62.00; H, 6.35; N, 5.55.
Example 259 2 -Isopropvlbhenyl) r2-niitro-4-( 3 -(dimethylaminocarbonyl).4.hvdroxypipei din- 1 -l)carbonvl~ethenyl) henyll sulfide Prepared according to the procedures of Example 7 1, giving a yellow solid.
'H NMR (DMS0-d, 6 300MHz) 8 1.14 J =6.8 Hz, 6H); 1.54-1.75 (hr in, 2H); 2.81, 2,.82 (hr s, br s, 3H); 3.00, 3.04 (br s, hr s, 3H); 2.75-3.60 (hr in, 3H4); 3.30-3.40 (in, 1H); 3.90-4.28 (br mn, 2H); 4.95-5.28 (hr m, 1H); 6.61'-6'.66 (mn, 1K); 7.34-7.62.(in, 6H); 7.87-7.94 (br mn, 114); 8.58-8.63 (hr m, I MS (ESI) at m/z 498. Anal.
calcd for Cz 6 KH,,NSO,0.34H,O: C, 61.99; H, 6.34; N, 8 .34. Found: C, 61.96; H, 6.37; N, 8.56..
Example 260 2 -1sorroplheny)2-nitro4-(E-((3-cyanomopholin..I -yl)carhonvl)ethenvi) phenyil sulfide 223 Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 8 1.14 J 6.8 Hz, 6H); 3.30-3.40 (in, IH); 3.30- 4.16 (br m, 5H); 4.20-4.29 (br mn, I 5.07 J =3.5 Hz, I 6.65(d, J =8.8 Hz, I 7.32-7.44 (in, 2H); 7.54-7.62 (in, 4H); 7.91 (dd, J 2.0 Hz, I1H); 8.67 J 2.0 Hz, IlH). MS (APCI) at rn/z 438. Anal calcd for C,,HNS 1
O,
4 0.25CH,,:.
C, 64.11; H, 5.82; N, 9.15. Found: C, 63.99; H, 6.00; N, 9.12..
Example 261 (2-Isopropvlpheny1) [2-nitro-4-( E-((3-carboethoxymornholin- I -vyl)carbonyl)ethenyl) phenvll sulfide Prepared according to the procedures of Example 7 1, giving a yellow solid.
'H NMR (DMSO-1 6 300MHz) 8 1.14 J 7.0 Hz, 6H); 1.12-1.27 (mn, 3H); 3.30- 3.40 (in, IH); 3.15-4.33 (br m, 9H); 6.64 J 8.5 Hz, 7.32-7.42 (mn, 2H); 7.50- 7.62 (mn, 4H); 7.88-7.96 (br mn, 8.65 (br s, IH). MIS (APCI) at in/z 485.
Anal calcd for 6 C, 61.97; H, 5.82; N, 5.78. Found: C, 61.83; H, 6.07; N, 5.74.
Example 262 (2-Isopropvylphenyl)f2-nitro-4-( -(tetrazol-5-vI)morpholin- 1 -l)carbonyl)ethenyl) phenyll sulfide The compound of Example 260 (160 mg, 0.336), sodium azide (56.6 ing, 0.872 inmol), n-Bu_ 3 SnCl and THF were mixed in a reaction tube, flushed with 224 nitrogen and heated to reflux overnight. The mixture was then cooled to ambient temperature and IN HCl soin. was added. The mixture. was extracted with ethyl acetate three times and the combined organics were dried over MgSO 4 The mixture was filtered through a short silica gel plug to give 96 mg (56%X yield) of the desired material. UHNMR (DMSO-d, 6 300MHz) 8 1.14 J =6.8 Hz, 6H); 2.96-4.62 (br m, 7H); 4.77 (dd, J =10.5, 2.7 Hz, I 6.58-6.67 (in, I1H); 7.32-7.62 (in, 6H); 7.92 (dd, J 2.0 Hz, I 8.62-8.67 (br m, I MS (APCI at im/z 48 1. Anal calcd for C,,H, 4
N
6 S,QI.l.2H,O: C, 54.93; H, 5.31; N, 16.71. Found: C, 54.97; H, 5.12;N, 6.50.
Example 263 (Benzodioxan-6-vlIr2-trifluoromthl.4( E-((4-carboxypiperidin-lI-vI) carbonyl )ethenyl) henv Fl sulfide The title compound was prepared by hydrolysis of the compound of Example 252 under basic conditions (aq. NaOHIEtOH), giving a white solid, mp 8 8 'C (dec.).
'H NMR (DMSO-d 6 300 MHz) 8 1.40 (in, 2H), 1.98 (in, 2H), 2.95 (in, IH), 3.15 (in, I 3.45 (mn, I 4.20 (in, 2H), 4.3 5 (in, 4H), 7.00 (in, 4H), 7.20 (mn, 2H), 7.90 (in, I1H), 8.20 (in, I 12.3 0 IlH). MS (APCI) m/z 4.94 Anal. calcd. for
C
24
H
2 2F 3
NO
5 S-0.1 H 2 0: C, 58.20; H, 4.52; N, 2.83. Found: C, 58.14; H, 4.69; N, 2.76.
Example 264 225 (Benzodioxan-6-yl)r2-trifluoromethyl-4-( E-((2-carboxvpiperidin- 1 -vi) carbonyl)eihenyl) phenyll sulfide The title compound was prepared by hydrolysis of the compound of Example 249 under basic conditions (aq. NaOHIEtOH), resulting in a white solid, mp 90 'C 'H NMR (DMSO-d 300 MHz) 8 1. 15-1.50 (mn, 2H), 1.50-1.70 (in, 2H), 2.16 (in, 2.56 IN), 3.15(in, IN), 4.30 4H), 4.32(in, IH),.5.20(in, IH), 7.02 7.3 0-7.52 (mn, 2H), 7.84 (in, I11), 8.15 I MS (APCI) in/z 494 Anal. calcd. for C 24 1HIrF 3
NO
5 *0.3 H 2 0: C, 57.78; H, 4.57; N, 2.8 1. Found: C, 57.87; H, 7; N, 2.76.
Examp~le 265 (Benizodioxan-6-yl) f2-trifluoromethyl-4-( arbomethoxYpiperazin- I -VP) carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCl 3 300 MHz) 8 7.76 I 7.62 (d3 I H, J 15.0 Hz), 7.40 INH, J= 8.6 Hz) 7.06 INH, J =2.1 Hz), 6.98-7.04 (in, 2H), 6.91 I1H, J =8.4 Hz), 6.84 (d, I H, J =15.6 Hz), 4.31 (mn, 4H), 4.18 2H, J 7.1 Hz), 3.68 (br, 4H), 3. 54 (br s, 4H), 1.29 3H, J. 7.2 Hz). MIS (ESI) rn/z 523, 545, 1045, 1067.
Example* 266 226 (Benzodioxan-6-Yl) r2-trifliuoromethyl-4-(E-((3-az-69-diooxasiro5.4decan. Yl~carbonyl)etheniYl phenyll sulfide The title compound was prepared according to the procedures of Example 1.
1H NMR, (DMS0-l 6 300 MHz) 8 8.13 I 7.84 IlHI J =9.0 Hz), 7.48 I1H, J =15.4 Hz) 7.38 IH, J ='15.4 Hz), 6.98-7.06 (in, 4H), 4.30 (in, 4H), 3.92 4H), 3.74 (br, 2H), 2.62 (br, 1.63.(br, 4H). MS (ESI) rn/z 508, 10151.
Example 267 (Benz .odioxan-6-yl)[2-trifiuoro-4-(E-((4-(benzimiclazolon I -yl)piperidin- 1yllcarbonyl)ehenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDC1 3 3 00 MHz) 8 8.3 2 I 7.79 1IH), 7.66 I H, J 15.4 Hz), 7.44 I H, J =8.5 Hz), 7.0-7.12 (mn, 6H), 6.94 I1H, J =9.9 Hz), 6.9.0 IlH, J= 2.6 Hz), 4.98 (mn, I1H), 4.59 (m,lIH), 4.20 (in, 5H), 3.31 (br, I 2.83 (br, I1H), 2.40 (mn, 2H), 1.98 (mn, 2H). MS (ESI) m/lz 582, 604, 1163, 1185.
Example 268 (Benzodioxan- 6 -yI)[2-trifluoromethyI-4(E-((4(methylaninocarbovl)piperidin 1yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 8 7.75 I1H), 7.67 I H, J =15.4 Hz) 7.40 1IH, J 8.1 Hz), 7.06 I H, J 2.4 Hz), 6.96-7.02 (mn, 2H), 6.90 I1H, J =8.2 Hz), 4.28 (in, 4H), 3.95 (br, 2H), 3.50 (in, IH),2.82 3H), 2.40 (in, 1H), .2.15 (br, IH), 1.88.
(br, IH), 1.73 (br, 2H). MIS (ESI) m/lz 507, 529, 1035.
Example 269 (Benzodioxan-6-ylM2-trifluoromethyl-4-( E-0(-carboinethoxy-4inethoxycarbonylpiperazin-lI-vi) carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example. 240 substituting N-(3 '-aminopropyl)-2-pyrrolidinone with 2-carboinethoxy- I methoxycarbonylpiperazine, producing a light yellow solid, mp 56 0 C 'H NMR (CDCI 3 300 MHz) 5 2.70-3.50 (br, 4H),.3.70 3H), 3.76 J=9.0 Hz, IH), 4.00(m, I 4.20 (in, 4H), 4.50-5.00 (br, 2H), 6.91 J=8.5 Hz,, IH),,6.92-7.02 (in, 2H), 7.07 J=2.0 Hz, I 7.25 (mn, I 7.40 I 7.60 (in, 7.72 I H).
MS (APCI) in/z 567 (M+Hy Anal. calcd. for C 26
H
25
F
3
N
2 0 7 S: 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-carboxvinornholin-1-I-l)carbonv!)ethenyl) p2henyll sulfide Prepared according to the procedures of Example 71, giving-a yellow solid. IH NMR (DMSO-d 6 300MHz) 8 1. 14 J =6.8 Hz, 6H); 3.08-4.33 (br in, 7H); 3.30- 3.40 (mn, IA); 6.58-6.68 (mn, IH); 7.32-7.66 (mn, 6H); 7.87-7.94 (in, lH); 8.53-8.65.
228 I MS (APCI) at m/z 45 7. Anal calcd for C,,H,,NS,0 6 C, 60.5 H, 5.30; N, 6.14. Found: C, 60.33; H, 5.54; N, 5.80.
Example 271 (Benzodioxan-6-yI)[2-trifluoromethyl4-(E-((2-carboxv-4-.
methoxvcarbonvlojperazin-I-vi) carbonvl)ethenyl) 2henyll sulfide The title compound was prepared by treating the compound of Example 255 with methyl chloroformate and pyridine in CH 2 CI., at room temperature, and followed by hydrolysis under basic conditions (aq. NaOH/EtOH), producing a white solid, mp 102 0 C 'H NMR (DMSO-d 6 300 MHz) 8 2.85 (mn, lH), 3.02 (in, IH), 3.20 (in, IH), 3.40 (in, IH), 3.62 3H), 3.88 (in, IH), 4.29 4H), 4.35 5.15 (in, I 6.90-7. 10 (in, 3H), 7.30 J=l 5.0 Hz, I 7.40 3=1 5.0 Hz, IH), 7.54 (d, J=15.0 Hz, IH), 7.82 (in, IH), 8.15 (in, I MS (ESI) m/z 553 Anal. calcd.
for C,H 23 F3N 2
O
7 S- 0.25 H 2 0: C, 53.91; H, 4.25; N, 5.03. Found: 53.9.1; H, 4.35; N, 5.05.
Example 272 (Benzodioxan-6-l)r2trifluoromeihyl4E((inorrholin- I -yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
1H NMR (CDCI 3 300 MHz) 5 7.76 I 7.62 I H, J 15.6 Hz), .7.40 (dd,l lH, J 8.2 Hz), 7.04 I H, J =2.1 Hz), 6.98-7.03 (in, 2H), 6.91 I H, J 8.1 Hz), 229 6.81 I H, J =15.3 Hz), 4.30 (mn, 4H), 3.65-3.74 (br m, 8H). MS (ESI) m/z 452, 474, 925.
Example 273 (Benzodioxan-6-ylM[24rifluoromethvl-4-(E-((4-(pvrrolidin- 1 -vl)piper idin- 1yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example.
'H NMR (CDCI 3 3 00 MHz) 8 7.75 I .7.65 IlH,. J =15.3 Hz), 7.40 (dd, IlH, J 8.3 Hz), 7.06 I H, JT= 2.4 Hz), 6.98-7.02 (in, 2H), 6.90 IRH, J 8.1 Hz), 6.85 I H, J =15.3 Hz), 4.68 IH), 4.20 (mn, 4H), 3. 10 IH), 3.14 IH), 2.81 4H), 2.58 (br, IH), 2.02 4H), 1.88 4H), 1.64 MS (ESI) m/z 519, 103 7.
Exampnle 274 (2-Isopropylphenyl)M2-nitro-4-(E-((3-aza-6,9-diooxaspiro [5 .41decan-lIyl)carbonyI)ethenl) phenvl1 sulfide The title compound was prepared according to the proce dures of Example 1.
'H NMR (CD.Cl 3 300 MHz) 8 8.44 I 7.50-7.62 (in, 4H), 7.41 I H7 J Hz), 7.30 (mn, IH), 6.96 (br d, I H, J 15.6 Hz), 6.69 ILH, J =9.4 Hz), 4.00 4H), 3 .75 (br in, 4H), 3.44 (mn, I 1.75 (br s, 4H), 1. 18 6H, J =7.0 Hz). MS (ESI) m/z 439, 937.
Example 275 2 -lsopropylphenyl)M2-nitro-4-(E-((2-(dimethvlami nomethyl~piveridin- 1vl)carbonyl~ethenyl) phenvll sulfide The title compound was prepared according to the procedures of Example 1.
'H NM R (CDCl 3 300 MIHi) 8 8.40 1 H, J =1.8 Hz), 7.50-7.58 7.42 (d, IH1, J =8.1 H4z), 7.30 (dd, IIH, J 7.0 Hz), 7.00 I H, J =15.4 Hz), 6.68 I H, J 8.5 Hz), 5. 10 (br, IlH), 3.92 (br, I 3.44 (quintet, I H, J 6.9 Hz), 3.20 IH), 2.26-2.5 0 (in, 1.62-1.85 (mn, 7H), 1.48 IH), 1. 18 6.H, J =7.0 Hz). MS.
(ESI) m/z 468.
Example 276 (2-lsopropylvhenyl) 2- nitro-4-(E-((piperidin- I -ylamino)cgibonyl~etheny) D'henvll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCl 3 300 MHz) 5 8.44 I1H, J 1.8 Hz), .7.66 11H, J 16.2 Hz), .7.55 IH7 J =7.4 Hz), 7.47-7.51 (nm, 3H), 6.721(d, IH, 3J 8.5 Hz), 6.37 (s, IH), 3.48 2H), 3. 10 (m,2H1), 2.63 IH), 1. 81-1.89 (m,211), 1.62-1.77 (m,4H), 1. 19 6H, J 7.0 Hz). MS (ESI). m/z 426, 85 1.
Example 277 (Benzodioxan-6-yl)r2-trifluoromnethyl-4-( E-(-carboxY-4methoxycarbonylpiperazin- I -viD carbonl) ethenyl) phenvil sulfide 231 The title compound was prepared by hydrolysis of the compound of Example 269 under basic conditions (aq. NaOHIEtOH). 'H NMR (DMSO-d 6 300 MHz) 8 2.60-3.30 (in, 3H),.3.40-3.50 (mn, 1H), 3.62 J= 12.0 Hz, IH),3.80 (mn, IH), 4.25- 4.35 (mn, 4H), 4.55 (in, IH), 7.00 2H), 7.00-7.06 (in, 1H4), 7.25 7.5 (in, 1H), 7.80 (mn, IH), 8.10 (mn, IH). MS (APCI) rn/z 553 (M+H) 4 Calcd. Anal..
C
24
H
23
F
3
N
2 0 3 *1.55 H20: C, 54.35; H, 4.20; N, 5.07. Found: C, 54.16; H, 4.19; N, .4.96.
Example 278 (2-(Dimethylaminocarbonvl)-benzodioxan-6-yl)[2-chloro-4-( E-((4-acetylpiperazin-l YI)carbonyl)ethenl) Rheniyll sulfide The title compound was prepared by the procedures described in Example substituting 5-jodoindole with 2-NN-dimethylcarboxamide-6-bromobenzenedioxane and 3-NN-dimiethyicarboxainide-6-bromobenzenedioxane, giving a white solid. 'H NMVR (CDC] 3 300 MHz, mixture of regl~oisomers) 8 1.93 3H), 2.15 6H), 3.53.
(br s, 2H), 3.59-3.90 (br in, 8H), 4.86-5.01 (mn, I1H), 6.746.81 (in, I1H), 6.80 J 15.3 Hz, I 6.93 J= 8.7 Hz, I1H), 7.02 CDCI 3 1.8 Hz, I 7.13 (dd, J 1.8, 8.4 Hz, IH), 7.16-7.25 (mn, I1H), 7.54 I 7.58 J 15.6 Hz 1H). MS (ESI") (M+Na 4 at m/z 552, 554.
Example 279 232 (2-Isopronvlphenyl)[2-niitro-(- E-((3-(2-(methoxymethvl)tetrazol-5-vl) rpineridin- 1yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 225, substituting ethyl nipecotate with 3-N-methoxymethyltetrazolylpiperidine, to give a, light-yellow solid. 'H N4MR (CDCI 3 300 MHz) 5. 1.19 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 2H), 3.46 (s, 3 4.11 (septet, J= 6.9 Hz, I 4.17-4.34 (br m, IH), 5.79 2H), 6.70 (br s, IH),.
7.05 J 15.3 Hz, I 7.3 1 J 7.8 Hz, IH), 7.35-7.68 (in, 5H), 8.42 (br s, H).
MS (ESI+) at m/lz 523.
Example 280.
(2-lsopropylvhenyl)l2-nitro-4- E-O(3( -(methoxvmethyl)tetrazol-yv) piperidin- 1 yl~carbonvl~ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example 279 and separated from the same reaction mixture via.SiO 2 flash column chromatography, to give a light-yello'w solid. 'H NMR (CDCI 3 300 MHz) I 1 .19 J =6.9 Hz, 6H), 1.62-1.80 (br mn, 2H), 1.80-2.20 (br m, 2H), 2.20-2.39 (br mn, 2H), 3.12-3.3.8 (br in.
2H), 3.46 3H),*4.11 (septet, J= 6.9 Hz, I 4.17-4.34 (br mn, I 5.79 2H), 6.70 (br s, I 7.05 J= 15.3 Hz, IlH), 7.31 J= 7.8 Hz, IH), 7.35-7.68 (mn. 8.42 (br s, IlH). MS'(ESI-) at m/z 523.
Example 281 (1 -Methylindol-5-yl)[2-chloro-4-( -pyrrolidin-2-onyl)propvlamino) carbonvl)ethenvl) phenvl] sulfide Example 281A Triisopropvlsilvl(I -methylindol-5-vl) sulfide To a stirred solution of 5-bromo-N-methyl indole (300 mg, 1.43 mmol) in mL of benzene in a sealed tube was charged with Pd(PPh 3 4 (82 mg, 0.072 mmol), followed by KSTIPS (326 mg, 1.43 mmol). The mixture was flushed with N 2 the tube was capped, and the reaction mixture refluxed for 2 h. The reaction mixture was then allowed to cool down, partitioned between EtzO and water. The organic layer was washed with brine, dried over NaSO 4 concentrated in vacuo. The residue was purified on a SiO, 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-(( -methvlindol-5-vl)thio) benzaldehvde To a stirred solution of thiolsilyl ether (1.0 g, 3.13 mmol) in5 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,O (2x25 mL). The combined organic layer was washed with water and brine, dried over Na 2
SO
4 concentrated in vacuo. The residue 234 was purified on a SiO 2 flash column chromatography eluting with 5-10 EtOAc/hexanes to give 650 mg- (71 of the title compound as white solid.
Example 281C (0 -Methylinidol-5-Yl'ff2-chloro-4-( I-pvrrolidin-2-onyl )propylamino) carbonyl)ethenyl) phenyll sulfide 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 anmo~nium with 3-aminopropyl-l-pyrrolidini-2- one, to give a white.
solid. 'H N4MR (CDCl 3 300 MHz) 8 1.74 (br mn, 2H), 2.07 (br in, 21H), 2.44 (br in, 2H), 3.32 (br in, 2H), 3.40 (br n, 4H),.3.85 6.36 j= 15.3 Hz, 1H), 7.14.(0, J~ 3.0: Hz, IlH)3 7.36. (dd, J= 1. 5, 9. 0 Hz, IH), 7.41 J 9. 0 Hz, I 7.50 11H), 7.8 9 J 1. 5 Hz, I M S (ESl+) (M+H) 4 at m/z 46 8, 4 70. Anal. Cal cd for
C
2 5
H
2 6 C1N 3 0 2 S. 1.37 H 2 0: C, 60.95; H, 5.88; N, 8.53. Found: C, 60.97; H, 5.98; N, 8.4+6.
Example 282 (2-Isopropylphenyl)r2-nitro-4-( E- -(tetrazol-5-vl) piperidin-1I-vi )carbonyl)ethenvl) phenyll sulfide The compound from Example 279 (75 mg, 0. 14 mimol) 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 235 product was purified using Gilson Preparative. J-PLC as described in Example 38B to give the title compound as a light-yellow solid (50 mg, 72 'H NMR (CDCI 3 300 MHz) 8 1.17 J= 6.5 Hz, 6H), 1.25-1.39 (in, I 1.69-1.81 (in, I 2.09 (br s, IH), 2.14-2.30 (in, IH4), 2.57-2.7 1 (in, 1H), 3.35-3.66 (in, 3H), 3.90-4.0 (in, 1H), 4.66-4.78.(in, I 6.73 J 8.7 Hz, IlH), 6.86 J 15.3 Hz, IJH), 7.32 (dd, J 2.1, 6.9 Hz, I 7.42 (dd, J 2.1. 8.7 Hz, IlH), 7.47-7.57 (mn, 3H1), 7.76 J 15.3 Hz, I 8.46 J 2.1 Hz, I1H). MS (ESI') at m/nz 479. Anal. Calcd for
C
2 4
H
2 6
N
6 0 3 S 0.28 H 2 0: C, 59.6 1; H, 5.54;. N, 17.38. Found: C, 59.71; H, 5.44; N, 16.99.
Example 283 (I -Methvlindol-5-Yl )[2-chloro-4-( E-(-scarboethoxypiperidin- I -v 1 )carbonvl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 281 C, substituting aininopropyl pyrrolidinone with ethyl nipecotate, giving a white solid. 'H NMR (CDCI 3 300 MHz) 8 1.26 J=.7.5 Hz, 3H), 1.65-1.96 (in, 2H4), 2.00- 2.20 (in, I 2.04 I 2.54 (br in, 1WH), 3.12-3.34 (in, I1H), 3.85 3H), 3.92-4.07 (in, 1WH), 4.07-4.20 (in, 1WH), 4.15 J= 7.5 Hz, 2H), 4.65-4.90 (in, I1H), 6.53 J Hz, I1W), 6.5 7(d, J= 8.1 Hz, I 6.8 5 J= 15.3 Hz, I1H), 7.0 J= 8.7 Hz, 1WH), 7.14 J= 3. 0 Hz, I1H), 7.3 7 (dd, J 1. 5, 8.7 Hz, I 7.42 J 8.7 Hz, 1WH), 7.51 1WH), 7.51 J 15.3 Hz, 1WH), 7.89 1.5 Hz, 1WH). MS (ESI") at ni/z 483, 485.
Example 284 (1 -Methylindo]-5-yl)[2-chl oro-4-( E-((3-carboxypiperidin- I -yl)carbonyl)ethenyl) p2henyll sulfide The title compound was prepared by the procedures described in Example 155, substituting the ethyl ester from Example 1.37 with ethyl ester from Example 283, and KOH with NaOH, to provide a white solid. 'H NMR (Dl,30MHz) 5 1.45-1.69.
(in, 1H), 1.69-1.98 (mn, 2H), 1.98-2.22, (in, lH),.2.5 1-2.70 (mn, lH), 3.05-3.47 (in, lH), 3.80-4.20 (in, 2H),'3.85 3H), 4.47-4.68 (in, I 6.53 J 3.0 Hz, I 6.57 J =8.1 Hz, IH), 6.87 J= 15.31-z, IH), 7.08 J=8.1 Hz, H),7.14 IH),-7.37 J= 9.0 Hz, 1H), 7.42 J= 9..0 Hz, IH), 7.51 IlH), 7.52 J 15.3 Hz, I 7.89 (br s, I MS (ESI') at m/lz 453, 455.
Example 285 (1 -Methvlirndol-5-vl)[2-chloro-4-( E-((4-carboethoxypiperidin-1l -yl)carbon l)ethenvl) phenvll sulfide The title compound was prepared by the procedures described in Example 281 C, substituting aininopropyl pyrrolidinone with ethyl isonipecotate, giving a white solid. 'H NMR (CD.CJ 3 300 MHz) d 1.26 J= 7.5 Hz, 3H), 1.64-1.83 (in, 2H), 1.88- 2.08 (in, 2H), 2.48-2.67 (mn, 1H), 2.86-3.40 (in, 2H), 3.85 3H), 3.89-4.24 (in, I H), 4.15 7.5 Hz±,2H), 4.24-4.65 lH), 6.53 (d,J=3.0 Hz, IH), 6.58 (d,J=8.1 Hz,. I 6.81 J 15.3 Hz, I 7.07 J 8.1 Hz, IH), 7.1 4 J 3.0 Hz, IlH), 237 7.37 (dd,J1 1.5, 9.0 Hz, I 7.50 J=9.0 Hz, I 7.50 1= 15.3 Hz, 1I), 7.88 J= 1.5 Hz, I MS (IESI') at in/z 483, 485.
Example 286 (1 -Methvlindol-5-vl)r2-chloro-4-( -carboxyperidin-1I-yl)carbonvl )ethenyl) phenyll sulfide The title compound was prepared by the procedures. described in Example, 155, substituting the ethyl ester from Example 13 7 with ethyl ester from Exampl e.28 5, and KOH with NaOH, giving a white solid. 'H NMR 300 MHz) 8 1.60-1.90 (in, 2H), 1.90-2.10 2.57-2.72 (mn, IH), 2.80-3.40 2H),.3.85 3H), 3.91-4.20 In 4.3 0-4.68 (in, I 6.53 J= 3. 0 Hz, I 6.5 7 J= 8.1 Hz, I 6.80 (d, J= 15.3 Hz, I 7.07 J 8.1 Hz, I 7.15 J 3.0 Hz, I 7.3 7 (dd, J= 9. 0Hz, I1H), 7.51 J 9. 0 Hz, I 7.51 I 7.5 1 J 15.3 Hz, I 7.8 9(br s, 1H). MS (ESIE) at m/z 455, 457. Anal. Calcd for C2 4
H
2 3
CIN
2 0 3 S 0.42
H
2 0: C, 62.32; H, 5.20; N, 6.06. Found: C, 62.35; H, 5.30; N, 5.87.
Example 287 2 -Isoprop~ylphenyl I -inethylpyrrolidin-2yl)ethylamino)carbonyl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 8 8.44 I H, J =1.8 Hz), 7.56 I H, J 3.7 Hz), 7.50-7.58 (in, 3H), 7.43 (DD, I H, J =1.84, 8.4 Hz), 7.30 (dd, 1 HI J 2.12, 6.8 Hz), 238 6.78 I1H, J =8.5 Hz), 6.52 I1H, J =15.8 Hz), 3.63 3.42 (in, 3H), 3.00 3.78 2.59 3H), 2.05 (mjlH), 2.00 (mn, 511), 1.18 6H, J Hz). MS (ESI) m/z. 454, 490.
Example 288 (2-Isopropylphenyl)r2-nitro-4-(E-((4-(Dvrrolidin- I -vl12iiperidin- I -vl~carbonvl~ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (CDCI 3 300 MHz) 8 8.43 1H,1 J 1.8 Hz), 7.57.(d, 111, J 8.5 Hz), 7.51 7.55 (in, 311), 7.41 (dd, 111, J= 1.84, 8.8 Hz),7.31 (dd, 111, 7.5 Hz),6.92 I11, J =15.4 Hz), 6.70 1H4, J =8.5 Hz), 4.70 (in, I 4.10 (m,1IH), 3'.44 (pent, I H, J 6.8 Hz), 3.16,(mn, I1-I). 2.80 (br, 411), 2.55 (br, I 2.03 1.90 (in, 411), 1.65(in, 11), 1.18 611, J=7.0 Hz). MS (ESI)m/z 480, 959.
Example 289 (2-Isopiopylphenyl) r2-nitro-4-(E-(f4-sulfopiperi din- I -vl)carbonvl)ethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR (DMSO-d 6 3 00 MHz) 8 8.63 I11,1 J1. 8 Hz), 7.92 (dd, I11,1 J 1. 8, 8.8 Hz), 7.60 (in, 311), 7.47 11H, J 14.2 Hz), 7.42 I1H, J 14.2 Hz), 6.62 (di, 111, J Hz), 4.45 (in, 211), 4.3 8 (in, 211), 3.34 (in, 111), 3.00 (in, 211), 2.70 (in, 111), 2.60 (in,2H), 1. 14 611, J =6.9 Hz). MS (ESI) m/z 491, 98 1.
239 Example 290 (2-Ioprnvihenl )r 2 -nitro-4-(E-((3-hydroXVpjeridin- I -yl)carbonyehen) en] sulfide The title compound was prepared according to the procedures of.Example 1.
'H NMR (CDC1 3 300 MHz) 8 8.43, I1H), 7.50-7.62 (in, 4H), 7.41 I H, J 8.1 Hz), 6.97 (in, I1H), 6.69 I H, J =8.1 Hz), 3.85 (in, 2H4), 3.65 (in, I1H), 3.50 (m,3H), 1.93 1.65 (in, 2H), 1. 18 6H, J=6.6 Hz). MS (ESI). m/z 427, 449, 853 875.
Example 291 (Benzodioxan-6-y)[2-trifluoromethv-4-( ((ethanesulfonvlamino)carbonvl )pip~eridin- I -vi) carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 227.
The product was purified by reversed-phase HPLC. NMR (CDCI 3 300 MHz) 1.34 J= 7.0 Hz, 2H), 1.44 J=7.0 Hz, 1.95 (br, 1/2H), 2.20 (br, 1/2H), 2.68 (br, iH), 3.14 J=7.0 Hz, 2H), 3.45 (in, 3.65 3.93(in, iM), 4.30(in, 4H), 4.50-4.60 (br, 2H), 6.92 J1=8.0 Hz, I 6.98-7.04 (in, 3H), 7.06 (in, IMH), 7.40 J=8.0 Hz, IM), 7.65 (in, 1H), 7.75 IM). MS (APCI) m/z 585 Example 292 240 (Benzodioxan-6-yvIM2-trifluoromethyl- 4 .toluenesulfonylamino)carbonyl)piperidin- I -yi) carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the same procedure described in Example 229. 'H NMR 300 MHz) 8 1.25 (in, 2H), 1.55 (in, 1 1.70-2.25 (br, IH), 2.4 1 J=13.0 Hz, 3H), 2'55 (br, IH), 3.50-3.80 (br, 2H), 4.20-4.35 (in, 4H), 4.68- 4.75 (in, 2H), 6.90 J=8.0 Hz, 1H), 7.00-7..10 (in, 2H), 7.30 1=8.0 Hz, 1H), 7.81 fr4.0 Hz, 1IH), 7.91 (in, IH) MS (Cl/NH 3 m-/z 647 Anal. calcd. for
C
3 jH 2 qF 3 N,0 6
S
2 .0.5 H,O: 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-( ((ethanesulfonvlamino)carbonyl)Riperi din- I -vi) carbonvl~ethenyl) phenvil sulfide The title compound was prepared by the procedures described in Example 227, giving a white foam. 'H NMR (CDC1 3 00 MHz) 8 1.35-1.40 (in, 2H), 1.44 Hz, 3H4), 1.76 (mn, I 2.0 (in, I 2.50-3.20 (br, I 3.15 J=7.0 Hz, 2H), 3.40-.
3.55 2H), 4.25-4.32 (mn, 4H), 4.52 6.90 J=r8.0 Hz, I1H), 6.98-7.05 (dd, 8.0 Hz, 2H), 7.06 (di J=2.0 Hz, I1H), 7.40 (mn, I1H), 7.60 (in, I 7 .75 I H), 8.22 (br, iH). MS (APCI) inlz 585 Anal. calcd. for C 2
,H
2 7
F.
3
N
2 0 6
S
2 *0.8
H
2 0: C, 52.13; H, 4.8 1; N, 4.6 8. Found: C; 52.14; H, 4.8 0; N, 4.66.
Example 294 (Benzodioxan-6-yl)[2-trifluoromethyl (E((2(tezoI-5-v)orhoin 1vl)carbonyi)ethenyl) phenvil sulfide The corresponding nitrile (160 mg, 0.33 6 mmol, prepared via the procedures of Example sodium azide (56.6 mg, 0.872 minol), n-BU 3 SnCI 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 IN HCI. soin. Was added. The mixture was extracted with ethyl acetate three times and the combined organics were dried over. MgSO,. The mixture was filtered through a short silica gel plug to give. 9.6 ng (56% yield) of the desired material. 'H NMR (DMSO-d 6 500 MHz,. 100 8 7.99 I H5,J 1. 7Hz), 7.79 (dd, I HJ2.0, 8.6 Hz), 7.50 I H, J 15.3 Hz), 7.24 (d, I H, J =15.6 Hz), 7.14 IHf, J =8.2 Hz), 6.96 (in, I 6.94 1 2.1 Hz), 6.2(in, I 4.60 (dd, I H9 J 9.8 Hz), 4.50 (br d, I H, J =12.2 Hz), 4.26 (in, 4.17 (in 4.00 (dt, I1H, J 3.2, 11.6 Hz), 3.72 (td, I H, J 1 30, 11.0 Hz), 3.43 (br mn, I 3.29 (br m, I MS (ESI) m.z -518. Anal. Calcd for C 2 3
H
2 0
F
3
N
5 0 4
S.
1.83 HOAc: C, 50.88; H, 4.38; N, 11. 13. Found: C, 50.6 1; H, 4.46; N, 11.4.
Example 295 2 -Isopronvlphenvl'ff2-nitro-4-( E-((2-butvl. 54terazol-5-yft)ornholin-lIvl'carbonvflethenvl) henvll sulfide Example 295A 242 The title compound was prepared by the procedures described in Example 260A, substituting ethanolamnine with 2-aminohexanol.
Example 295B (2-1sopropylphenyl)[2-nitro-4-( E-((2-butyl-5-cyanomorp~holin- 1 -yl)carbonyl)ethenyl) phenyll sulfide 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-IsoproPvlphenylfl2-nitro-4-( E-((2-butvl 5-(tetrazol-5-flmorI pho lin- 1yl)carbonyl)ethenyl) phenyil sulfide The title compound was prepared by the procedures described in* Example 262, substituting the nitrile compound from Example. 260 with the compound of Example 29513, giving a light-yellow solid. 'H NMR (CDCl 3 300 MHz, 3:2 mixture of.
diastereomers) 6 0.89 J 7.5 Hz, I 1.01 (br mn, 1 1.19 J= 6.5 Hz, 6H), 1.23-1.43 (in, 4H), 1.68-1.84 (in, IlH), 3.10-3.61 (in, 2H), 3.83 -4.17 2H), 4.40- 5.26 (mn, 2H), 6.67-6.77 (in, IH), [6.91 7.02 15.3 Hz, IH. in total], 7.25- 7.37 (in, 2H), 7.44-7.60 (mn, 3H), [7.67 7.79 (d),1J 15.3 Hz, I1H in total], 8.43- 8.50 (in, IH). MIS (ESI-) at m/z 535.
243 Example 296 (2-(and 3 -)(Hvydroxvmethv1)-benzodioxan6vl)r2..nitm-4-( 4 -acetylPiperazjn-
I-
vl)carbonyl')ethenvl) vhenyll sulfide Example 296A Triisopropylsilyl (2-and 3-)hvdroxymethylbenzodioxan-6-yl) sulfide The title compound was prepared by the procedures described in Example 28 1 A, substituting 5-bromo-N-methyl indole with a mixture. of 6-brorno-2hydroxymethylbenzenedioxane and 6- bromo-3 -hydroxymethylbenzenedioxne.
Example 296B (2-(and 3 -)(HdroxvmethvI)-benzodioxan-6-l)r2nitro-4-( E-(Wacetlpiperazin- 1vl)carbonvl)ethenyl), henyll sulfide The title compound was prepared by the procedures described in Example 281 B, substituting 3 -chloro- 4 -flurobenzaldehyde with 4 -chloro-3-nitrocinnamide, giving a light yellow solid. 'H NMR (CDCI 3 3 00 MHz,. 3:2 mixture of diastereomers) 8 2 .11 2.15 3H in total],.: 3.48-3.83 (in, 8H), 3.83-4.04 (in, 2H), 4.20 (dd, J 8.4, 11.4 Hz, I 4.26-4.44 (in, 2H), 6.89 J= 5.7 Hz, lI 6.92 I 6.97-7.11 (in, IH), 7.04 J 15.0 Hi, I 7.14 J=2.1 Hz, I 7.46 (br d, J= 9.0 Hz, I 7.65 J= 15.0 Hz, I 8.41 J= 2.1 Hz, IlH). MS (ESI-) at m/lz 500.
244 Example 297 (2 (and .3-)(Hydroxymethyl)-benzodiojxan-6-yP) f2-flitro-4-(E-((3-(pyrrolidil- 2 -on- 1 yl)p~ro2- I -ylamino)carbonyl) ethenyl~phenyl sulfide The title compound was prepared by the procedures described in Example 296B3, substituting the acetylpi perazine 4-chloro.-3-nitrocinnamide with 3-.
aminopropyl-lI -pyrrolidin-3-one 4w-chloro-3-nitrocinnamier ivnn lgtyelo solid. 'H NMR (CDCI 3 300 MHz, 3:2 mixture of diastereomers) 81.75 (br m, 2H), 2.08 J 7.5 Hz, 2H), 2.45 (t,J 7.5 Hz, 2H), 3.27-3.48 (in, 6H), 3.824.03 (n 2H), 4.13-4.44 (in, 3H), 6.49 J 15.0 Hz, I 6.88 J 8.4 Hz, I1H), [6.99 7.01 J =8.4 Hz, I H in total], [7.06 7.08 1.5, 2.4 Hz IHitoal],* [7.13 7.14 J 2.4 Hz, I H in total], 7.17 (br S, I 7.46 8.4 Hz, IlH), 7.54 J= 15.0 Hz, I 8.36 J= 1.5 Hz, IlH). MS (ESI 4 at m/lz 514.
ExamplIe 298 (2-(and 3-)(Hydroxymethyl)-benzodioxan-6-flr2-trifluoromflthyl-4-(E-((3- (pyrrolidin-2-on- I-vl)p2rop-1I-ylamino)carbonvl) ethenyl)phenyllIsulfide 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. 'H1 NMR (CDC1 3 3 00 MHz, 3:2 mixture. of diastereomers) 8 1.75 (br m, 2H), 2.09 (br m, 2H), 2.45 (br mn 2H), 3.25-3.60 (in, 6H), 3.80-4.43 (in, 6.46 J= 15.3 Hz, I1H), [6.92 6.95 J= 6.8 Hz, I H in total], [7.03 245 7.04 J= 8.1 Hz, III in total], 7.06-7.10 (in, IH), 7.13 (br s, 7.42 J= 8.1 Hz, I 7.54 J 1 .5.3 Hz, IH), 7.77 1H). M4S (ESI-) at m/z 537.
Example 299 3 -Hvdroxymethyl)-benzodioxan-6-yl)[2nitro4(E((3.(pyrrolidin-2.on1 -vI)p2rop- Ivlamino)carbonyl) ethenvl)phenyll sulfide Example 299A 3 -(Hydroxymethyl)-6-bromo-benzodioxane, To a stirred solution of 5-brornosalicylaldehyde (5.0 g, 24.9 minol). and epichlorohydrin (5.6 mL, 72.1 inmol) in 20 mL of DMF at 80 *C "was added K 2 C0 3 slowly in portions. The resulting mixture was then heated at 9.0 '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 NaSO 4 concentrated in vacuo. The residue was purified on a Si0 2 flash column chromatography eluting with 15-30 EtOAc/hexanes to give 2.82 g (44 of the title compound as colorless oil.
To a stirred solution of the aldehyde (2.82 g& I1 I mol) in 35 m L of CHC1 3 was. added mCPBA (2.27 g, 13 minol). The mixture was stirred at ambient temperature for 30 min and then heated at 50 'C for 2 h. The reaction was then quenched with aq. Na 2
S
2
O
5 extracted with Et 2 O (2x50 mL). The combined organic layer was washed with aq. NaHCO 3 brine, dried over Na 2
SO
4 concentrated in vacuo 246 to give 2.92 g of crude product which was proceeded to the next step without purification.
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 °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 2
SO
4 concentrated in vacuo to give 2.50 g (93% over two steps) of the title compound.
Example 299B Triisopropyl (3-(hvdroxvmethvl)-benzodioxan-6-yl) sulfide The title compound was prepared by the procedures described in Example 281 A, substituting 5-bromo-N-methyl indole with the bromide from Example 299A.
Example 299C (3-Hydroxvmethyl)-benzodioxan-6-yl)[2-nitro-4-(E-((3-(pvrrolidin-2-on-1-vl)prop-1vlamino)carbonvl) ethenvl)phenyllsulfide 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. 'H NMR (CDCl 3 300 MHz) 5 1.74 (br m, 2H), 2.08 J= 7.5 Hz, 2H), 2.44 J= 7.5 Hz, 2H), 3.25-3.53 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 1H), 4.40 (dd, J= 2.4, 12.9 Hz, 1H), 6.49 J= 15.3 Hz, 1H), 6.88 J= 247 8.7 HzIH), 7.00 J= 8.7 Hz, 1H), 7.07 (dd, J= 2.4, 8.7 HzIH), 7.14 J=2.4 Hz, INH), 7.20 (br s, I 7.46 (dd, J= 0. 9, 8.7 Hz, INH), 7.54 J= 15.3 Hz, I H), 8.6(s, IH). MIS (ESI+) at m/z 514. Anal. Calcd for C 2 5
H
2 7
N
3 0 7 S -0.82
H
2 0: C, 56.83; H, 5.46; N, 7.95. Found: C, 56.84; H, 5.18; N, 7.74.
Exampnle 300 (Benzodioxan-6-yl)[2-cbloro.4-( E-((3-carboxypiperid in- I -vI~carbonyl~ethenyli phenyll sulfide The title compound was prepared by the procedures described in Example 263, substituting 4-fluoro-3 -trifluoromethylbenzaldehyde with 3 -chloro-4fluorobenzaldehyde, giving a white solid. 'H NMR (CCI,300 MHz) 8. 1.64-1.88 (br m, 2H), 1.95-2.09 (br m, 2H), 2.57-2.73 (in, 1H). 2.90-3.1 7 (in, 1H), 3.17-3.50 (in, 1H), 3.90-4.19 (in, IH), 4.25-4.36 (in. 4H), 4.39-4.66 (in, 1H), 6.75 J= 8.4 Hz, INH), 6.84 J= 15.3 Hz, I 6.93 J~ 8.7 Hz, I 7.03 2.4, 8.7 Hz, INH), 7.08 J= 2.4 Hz, 1IH), 7.18 J 8.4 Hz, I 7.51 (s,1IH), 7.54 J 15.3 Hz, I MS (ESI*) at rn/z 460, 462.
Example 301 (2-(and 3 -)(Aminomethyl)-benzodioxan-6-yl) [2-trifl uoroinethyl..z-(E((3 (pvnroli din- 2-on-I -vl)prop-1I-ylamino)carbonyl) et enl~hhenvl Isulfide Examol e 3 01 A (2-fand 3-)(Mesyloxymethyl)-benzodioxani-6-yi) [2-trifluoromethyl-4-(E-((3- (pvyrrolidin-2-on- I -yI)vrop- I -ylamino)carbonyl) ethenvl~hhenyll sulfide To a stirred solution of alcohol from Example 298 (200 mg, 0.37 mmol)) in 2 mL of methylene chloride with Et 3 N(0104 mL, 0.74 mmol)) was added mnethanesulfonyl 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.
HCI, extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with aq. NaHCO 3 brine, dried over Na 2
SO
4 concentrated in vacuo to give 275 mng of crude product which was proceeded to the next step without purification..
Example 301B.
(24and 3-)(Azidomethyll-beznzodioxan-6-yi)M2-tri fluoromethyl- 4-(E-((3-(pyrrolidin-2on-I -yl)Vrop- I -ylamino)carbonvl) ethenyl)phenyll sulfide To a stirred solution suspension of NaN 3 (44, mg, 0.68 mmol) in]I mL of DMSO was added-mesylate (275.mg) In 0.5 mL of DMSO solution. The reaction mixture was then heated at 70 'C for 2 h, then cooled down to room temperature, water was added, extracted with EtOAc (2.x 10 mL). The combined organic layer was washed with water, brine, dried over Na,S0 4 concentrated in vacuo. The residue was purified on a SiO 2 flash column chromatography eluting with 5-10% MeOH!EtOAc to give 35 two steps) mg of the title compound as light brown oil.
249 Example 301C (2-(and 3 -)(Aminomethv)benzodioxan6vl)r2trifluoromethv4(-(3-(pUOlidin- 2-on- I -vl)prop- I -ylamino)carbonvl) ethenyl)phenyllsulfide To a stirred solution of azide (230 mg, 0.41 mmol) in I mL of THF was added PPh 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 of the title. compound. Light brown oil; 'H NMR (CDCI 3 300 MI-k, 3:2 mixture of diastereomers) 8 1.74 (br m, 2H), 1.96-2.16 (in, 2.35-2.50 (in, 2H), 3.23-3.47 (in, 6H), 3.92-4.63 (in, 5H), 6.4 1-6.55 (in, I H), 6.83-7. 10 (in, 3H), 7.3 6-7.58 (in, 3H), 7.67-7.67 (mn, 2H). MS (ESI') at m/lz 536. Anal. Calcd for C2 6
H
2 8
F
3
N
3 0 4 S -0 H20: C, 58.31; H, 5.27; N, 7.85. Found: C, 58.34; H, 5.48; N, 7.78.
Example 302 2 -IsoiropylphenyI)[2-nitro-4-( -((3-(methylaminocarbonyl )iorpholin- I YI)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'-HNMR (DMSO-d 6 ,,300MHz) 51.14 16.6 Hz, 2.61 J =4.8 Hz, 3H); 3.14-4.62 (br m, 7H); 3.30-3.40 (mn, I 6.63 J =8.8 Hz, I 7.32-7.62 (in, 6H); 7.80-7.97 (in, 2H); 8.66(d, J1 1.5 Hz, I MS (APCI) at inlz 470.
250 Aia] calcd for C,,H,,NS 1 0 5 0.8H,O: C, 59.58; H, 5.96; N, 8.68. Found: C, 5 9.5 7; H, 5.94; N, 8.72.
Example 303 (2-lsopropylphenvl)[2-nitro- 4 E3-4hydroxymethyl~morpholifl- I yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MI-z) 8 1. 14 J =6.8 Hz, 6H4); 2.70-3,51 (br mn, 5H); 3.30- 3.40 (in, 11-1); 3.83-3.93 I 4.03-4..47 (br mn, 2H); 4.74-4.82:(mn, I 6.64 J 8.5 Hz, 11H); 7.30-7.62 (mn, 6H); 7.86-7.94 (in, 11H); 8.59- 8.65 I MIS (APCI) at m/z 443. Anal calcd for N SO0,- C, 62.43; H, 5.92; N, 6.33.
Found: C, 62.12; H, 6.20; N, 6.06.
Example 304 (2-lsopropylphenyl)42-nitro-4-( E-((3-(aceioxymethvl)morholif- I1yl)carbonyl)ethenyl) ph enyli sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d,, 300MHz) 5 1.14 J 7.1 Hz, 6H); 2.04.(s, 3H4); 3.30-3.40 (mn, 11H); 2.58-4.41 (br m, 9H); 6.64 J 8.5 Hz, IH); 7.30-7.62 (mn, 6H); 7.90 (dd, J= 8.5, 1.8 Hz, IH); 8.59-8.65 11H). MS (APCI) (M+H)*at inz 485. Anal calcd for
C,,H
28
NS,O
6 C, 61.97; H, 5.82; N, 5.78. Found: C, 61.85; H,5.84; N, 5.68.
251 Example 305 2 -1sopropylphenvl)[2-nitro.4( 3 -(aminomnethyl)morpholin-. 1 yl)carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving. a yellow solid.
11H NMR (DMSO-d 6 300MHz).8 1.14 J =7.0 Hz, 6H); 2 .61 J =5.5 Hz, 2H); -2.49-3.60 (br m, 5H); 3.82-3.93 (in, 114); 4.13-4.45 (mn, 2H); 6.64 J =8.5 H z, I H); 7.32-7.62 (in, 6H); 7.88-7.95 (in, lIH); 8 5 9 IH). MS (APCI) at mlz 442. Anal cal cd for C, 3
H,
7
N
3 5,0.04H,0: C, 61.55; H4, 6.25; N, 9.36. Found:. C, 61.60; H, 6.25; N, 9.00.
Example 306 2 -lsonronvlphenvl)[2-nitro-4( E-((3-(acetamiomethy)o-njjhol.
I-
yl)carbonvl)dthenyl) phenyll sulfide Prepared According to the procedures of Example 71, giving a yellow solid.
-H NMR (DMSO-d 6 300MHz) 8 1. 14 J =6.8 Hz, 6H); 1.82 3H); 2.70-3.50 (br mn, 7H); 3.85-3.94 (mn, 4.13-4.40 (mn, 2H); 6.64 J =8.5 Hz, IH); 7.32-7.62 (in, 6H); 7.88-8.06 (in, I 8 59 -8.67(m, IlH). MS (APCI) at m./z 484. Anal calcd for C,sH, 9 NS,O,O0.27H 2 0: C, 61.47; H, 6.10; N, 8.60. Found: C, 61.50; H, 6.34; N, 8.53.
Exam~le 307 252 (Benzodioxan-6-yl) r2-chloro-4-(E-((3-(lpyrolidin-2-on- I -vI)Tnrov- 1ylamino)carbonyl) ethenyl)phenyl Isulfide The title compound was. prepared by the procedures described in Example 300 substituting ethyl isonipecotate with N-(3 '-aminopropyl)-2-pyrrolidinone.
NMR
(CDC1 3 300 MHz) 8 1.75 (br s, 2H1), 2.02-2.34 2H), 2.40-2.5.0 (mn, 2H), 3.30-3.50 (in, 6H1), 4.28-4.33 (mn, 4H1), 6.40 (br, 1H), 6.75 J=8.0 Hz, 111), 6.93 J=8.5 Hz,.
7.02 (dd, J=2.0O, 8.0 Hz, I 7.08 J=2.0 Hz, I 7.18 J1=8.5 Hz, I 7.45 (in, I1H), 7.50 1IH). MIS (ESI) m./z 473 Anal. calcd. for
C
24
H
2 ,.ClN 2
O
4 S.0.5. H20: C, 59.8 1; H, 5.44; N, 5.8 1. Found: C, 59.76; H, 5.80;, N, 5.43.
Example 308 (Benzodioxan-6-YDR[-chloro-4-( E-((3-carboethoxypineridin- I carbonyl~ethenyl) phenvll sulfide The title compound was prepared by the procedures described in Example 300 substituting ethyl isonipecotate with ethyl nipecotate. NMR (CDCI 3 300 MHz) 1.25 J=7.0. Hz, 3H), 1.60-1.90 (bn, 2H), 2. 10 (br, I 2.52 (bn, I 3.00-3.50 (bn, 2H), 3.80 (br, 1 4.10-4.20 (in, 4H), 4.28-4.35 (in, 4H), 6.74 J=8.0 Hz, I H), 6.92 J1=8.0 Hz, I 7.02 (dd, J1=2.0, 8.0 Hz, I 7.08 J=2.0 Hz, I 7.18 (in, 7.50-7.03 (mn, 311). MS (ESI) in/z 488 Anal. calcd. for
C
2 5
H
26 ClN0sSNa-0.5 H,O: C, 60.42; H, 5.48; N, 2.82. Found: C, 60.61; H, 5.5 1; N, 2142.
Example 309 (Benzodioxan-6-yl)r2-chloro-4-( E-((2-carboethoxypiperidin- I -vI) carbonyl)ethenvl) phenvil sulfide The title compound was prepared by the same procedure described in Example 300 substituting ethyl isonipecotate with ethyl pipecolinate. 'HNMR (CDC1 3 300 MHz) 5 1.30 J=7.0 Hz, 3H), 1.30-1.50 (br,3H4), 1.55-1.85 (br, 314), 2.30 (in, 111), 4.00 (in, I 4.20 (in, 2H), 4.30 (in, 4H), 5.44 (br, I 6.85 J=8.0 Hz, IlH), 6.90 J=8.0. Hz, I1H), 7.00 (dd, J=2.0, 8.0 Hz, I 7.07 J=2.0 Hz, I1H), 7.10-7.20 (mn, 2H4), 7.22 (in, 1H), 7.50 1H1). MS (ESI) m/z 488 Anal. calcd. for
C
25
H
26 C1N0 5 S: C, 61.53; H, 5.37; N, 2.87. Found: C, 61.86;BH, 5.63; N, 2.56.
Exaple (2-Methoxvphenyl)-[2.3-dichloro-4(E..[(momhoI in- I -yi )carbonyllethenyl)6henyil sulfide Example 31 OA 2 3 -Dichloro4-trifluoronethanesulfonyloxybenzldehvde 2,3-Dichloro-4-hydroxy-benzaldehyde 10 g. J. Med. Chem. 19 534, 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.] 254 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 HCI 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-methoxvphenvlthio)-benzaldehyde 2,3-Dichloro-4-trifluoromethanesufonyloxy-benzaldehyde (2.50 was dissolved in 6 ml. acetonitile. 2-Methoxybenzenethiol (2.55 g. of 70% pure material, 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 50C 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. 137-139C.
Example 310C 2.3-Dichloro-4-(2-methoxyphenvthio)-cinnamic acid A mixture of 2,3-dichloro-4-(2-methoxyphenylthio)-benzaldehyde (2.03 1.44 g. malonic acid, 5 ml. pyridine, and 0.100 g piperidine was heated to 115 degrees 255 for 1.5 hours. The mixture was cooled, and ice and HCI 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. 187-188C.
Example 3 (2-Methoxvphenyl)-[2..3-dichloro-4(E- [(morpholin- 1 -Y)carbonyllethenvl)Dhenvll sulfide The title compound was prepared according to the procedure of Example 1, substituting the cinnamic acid of Example 3 1lOG, giving a white solid, m.p. 161-162C.
'H-NMR (GDCI 3 300.MHz) 5 3.83 3H), 6.55 Jr9Hz, 11H), 6 .70 '(broad d, Hz, I 6.99-.7.05 (in, 214), 7.26.(d, J=9 Hz,; I 7.43-7.50 (mn, 2H), 8.07 (broad d, Hz, IH) Anal. Calcd. for C 20
,H
19
CJ
2 NO3S: C, 56.61; H, 4.5;N,3.30. Found: C, 56.75; H, 4.57; N, 2.61.
Example 311 (2-Methoxy]2henyl )-2.3-dimethyl-4(E-[(mornholin. I-vl)carbbnvllethenyl)DhenylI sulfide The title compound was prepared according to the procedures of Example 3 1H-NMR (CDC 3 300 MHz) 8 2.39 3H), 2.42 3H), 3.60-3.80 (in, 8H), 3.90 (s, 3H),.6.69 J=15 Hz, 1H4), 6.82-6.94 (mn, 3H), 7.05 J=9Hz, IH), 7.20-7.30 (in, 256 2H), 8.06 J=15 Hz, IH). Anal. Calcd. for C 2 A11 5 N0 3 S: C, 618.91; H, 6.57; N, 3.65.
Found: C, 68.75; H, 6.67;.N, 3.24.
Examnle 312 (2-Isoprop-vliphenvl)[2-nitro-4-(E-((indol-5-ylamino)carbonyl)ethenyl) phenyl] sulfide The title compound was prepared according to the procedures, of Example 1.
'H NMR (DMS0-l 6 300 MHz) 8 11.04 IH), 10.10 lH), 8.52 IH, I Hz), 8.02 I1H), 7.81 (dcl, I H, J 1.8, 8.5 Hz), 7.53-6.63 (in, 4H-7.39 (in, I1H),. 7.25- 7.35 (in, 3H), 6.94 (d9 I H, J 15.8 Hz), 7.72 I1H, J 8.5 Hz), 6.40 (in, 1H), 3.33 1 (I1H), 1.116.(d, 6H, J 6.6 Hz). MIS (ESI) m/z 458, 480, 915. Anal. Calcd for,
C
2 6
H-
2 3
N
3 0 3 S 0.22 H-20: C, 67.67; H, 5.12; N, 9.10. Found: C, 67.68; H, 5.19; N, 9.08.
Example 313 (Benzo dioxan-6-vlDr2-chloro-4-( E-((-carboxypiperidin-1 -vI) carbonylethenvl) phenyll sulfide The title compound was prepared by hydrolysis of the compound of Example 308 under basic condition (aq. Na0HIEtOH). 'H NMR (DM50-l 6 300 MHz) 81.10- 1.40 (in, 2H4), 1.60 (mn, INH), 1.76-1.96 (in, 3H), 2.88 (mn, INH), 3.98 (in, INH), 3.98 (in, 1 4.30 6.72 J=8.0 Hz, INH), 7.02 (3 3H), 7.30 7.48 (mn, IH), 7.92 (1 IH). MS (ESI) in/z 458 (M+H) 4 Anal. calcd. for.C23H 21
CINO
5 SNa: C, 55.76; H, 4.58; N, 2.83. Found: C, 55.76;.H, 4.78; N, 2.63.
257 Example,314 (Benzodioxan-6-yl)[2-chloro-4-( -(tefl-azol-5-vl)piperidin- I -yi) carbonyl)etbenyl) rhenvll sulfide The title compound was prepared by the procedures described in Exa mple 282, producing a white solid. 'H NMR (CDCI 3 300 MHz) 8 1.66-1.80 (in, 2H), 2. 10-2.30 (in, 2H), 2.64 (in, I 3.55 (in, 3.98 (mn, IlH), 4.25 (in, I '4.30-4.36 (mn, 41-I), 6.72 (dd, J=3.0, 12.0 Hz, 2H), 6.93 J8.O Hz, 7.03 (dd, d2.O, 8.0 Hz, IH), 7.09 J=2.0 Hz, IH), 7.20 J=8.5 Hz, IH), 7.52 1H), 7.70 J=15.0 Hz, IH).
MS (ESI) m/z 484 Anal. calcd. for C 23 Hj 2 C1N03S.O.38 H 2 0: C, 56.28; H, 4.67; N, 14.27. Found: C, 56.46; H,,4.58; N, 13.94.
Example 315 (Benzodioxan-6-yl)r2-chloro-4-( 4 -(Iert-butoxycarbonyl)piperazin- I-yi) carbonyl)ethenyl) Dhenyll sulfide The title compound was prepared by the procedures described in Example 300, substituting ethyl isonipecotate with 1-Boc-piperazine. 'H NMR (CDCl 3 300 MHz) 8 1.50 9H), 3.50 (br, s 4H), 3.70 (br, 4H), 4.28-4.35 (in, 4H), 6.74 J=8.0 Hz, IH), 6.82 (in, IH), 6.92 J=8.0 Hz, IH), 7.02 (dd, J=2.0, 8.0 Hz, 1H); 7.17 J=2.0 Hz, IH), 7.28 J=8.0 Hz, IH), 7.50 2H), 7.58 (mn, IH). MS (ESI) m/z 517 Anal. calcd. for C 26
H
29 C1N 2 0 5
H
2 0: C, 60.19; H, 5.67; N, 5.40. Found: C, 60.20; H, 5.97; N, 5.11.
258 Example 316 (Benzodioxan-6--Yl) r2-chloro-4-( E-((2-carboxyiperidin- I -vi) cafbonyl)ethenyl) p2henvil sulfide The title. compound was prepared by hydrolysis of the compou..nd of Example 309 under basic conditions (aq. NaOHIEtOH). 'H NMR (DMSO-d 6 300 IMHz) 1.10-1.40 (mn, 3H), 1.45-1.60 (in, 2.25-2.45 2H), 2.55-2.80 (in, IH), 4.30 (in, 4H), 4.50 (in, I 6.70 J=8.0 Hz, I 7.00 3H),7. 10 (in, I11), 7..25 (di, J=1 Hz,. IH), 7.48 (d2, J=8.0 15.5 Hz, I 7.90 (di, J=1 5.5 Hz, I1H). MS (ESI) in/z, 45 8 Anal.calcd. for C 2 H 2 1
CINO
5 Sa3 H 2 0: 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)mornholin-1 -vI) carbonyl)ethenyl) phenyll sulfide The title compound was prepared b Iy the procedures described in Example 262.
'H NMR (CDC1,300 MHz) 8 1.50-1 .70 (mn, 2H), 3.15 (br, 1H), 3.70-3.90 (mn, 2H), 4.25-4.35 (in, 4H), 4.55 (in, lH), 5.04 (br, 1H), 6.72 (ci, J=8.0 Hz, lH), 6.93 (ci, Hz, I 7.03 (dci, J=2.0, 8.0 Hz, I 7.07 (ci, J=2.0 Hz, I 7.20-7.30 (in, 2H), 7.50, (mn, I1H), 7.65 (in, I MS (ESI) m/iz 48.6 Anal. calcci. for C 22
H,
0 C1N 5 0,S C, 52.43; H, 4.40; N, 13.90. Found: C, 52.34; H, 4.35; 13.62.
Example 318 259 (Benzodioxan 6-vIDf2-chIloro-4-( E-((4-(methylaminocarbonvl)lpinerazjin- I -yi) carbonyl)ethenvl) phenvfl sulfide The title compound was prepared by deprotection. of the of Example 315 compound using anhydrous TFA in dichioromethane, followed by treatment with methyl isocyanate. 'H NMR (CDCl 3 3.00 MHz) 5 2.88 3H), 3.50 (br, 4H), 3.72 (br, 4.30 (in, 4H), 6.74 J=8.0 Hz, I1H), 6.82 J=1 5.0 Hz, IlH), 6.92 Hz, I 7.03 (dd, J=2.0, 8.0 Hz, I 7.08 J=2.0 Hz, IlH), 7.20 J=8.0 Hz, I H), 7.50 I 7.60 (in, IH). MS (ESI) m/z 474 Anal.. calcd. for C23H 24 ClN 3
O
4 S: 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-carboxypipeidin I -vl)carbonyllethenyl) phenyli sulfide The title compound was prepared according to, the procedures of Example 3 'H-NMR (CDCI 3 300 MHz) 5 1.66-1.83 (in, 2H), 1.95-2.09 (mn, 2H), 2.57-2.69 (in, 1H), 2.94-3.08 (in, 3.15-3.31 (in, 1H), 3.72 3H), 3.90-4.05 (in, 1H), 4.41-4.55 (in, IH), 6.55 J=9Hz, lH), 6.73 J=15Hz, IH), 7.00-7.05 (mn, 2H), 7.27 (d, J=8Hz, IH), 7.44-7.50 (in, 2H), 7.92 J=15Hz, IH). Anal. Calcd. for
C
22
H
2 1 C1 2 N0 4 S: C, 56 .66; H, 4.54; N, 3.00. Found: C, 56,89; H, 4.84; N, 2.64.
Example 320 (Benzodioxan-6-yWf2-chloro- 4 E-((4-(tetrazol-5-yl)piperidin-1 -vI) carbonyl)ethenyl) phenyl] sulfide The title'compound was prepared by the procedures described in Example 31.4 substituting 3 -(tetrazol-5-yl)piperi dine with 4-(tetrazol-5-yl)piperid ine. The crude reaction product was purified by reversed-phase HPLC. 'H NMR (DMSO-d 6 300 MHz) 8 1.22 (in, 1H), 1.55-1.75 (in, 2H), 2.06 (in, 114), 2.45 (in, 114), 4.22 (in, 4H), 4.30 6.70- IH), 7.00 (dd, J-2.0, 8.0 Hz, 2H), 7.25-7.40 (in, 4H4), 7.50 (in, I1H). MS (ESI) mn/z 484 Example 321 (2-Methoxyphenvl)-r3-chloro-A(E-(norholin- 1 -yl)carbonyljethenyl')phenylj sulfide The title compound was prepared according to the procedures of.Example 1, giving a white. solid, Imp. 124-125C. 'H-NMR (CDCl3 300 MHz) 5 3.60-3.80 (in, 8H4), 3.85 3H), 6.80 J= 15 Hz, 11H), 6.95-7.01 (in, 214), 7.05 (dd, J=9Hz, 2 Hz, 7.15 J=2Hz, 114), 7.35-7.48 (in, 314), 7.75 J=15,Hz, 114). Anal..Calcd. for
C,
0 1 2 C10S C, 61.61; 14, 5.17; N, 3.59. Found: C, 61.43;, H, 5.30; N, 3.73.
Example 322 (2-1 soprop~ylphenyl) r2-nitr-4-(E-((4-oxopiperi din I -yl)carbonyl)ethenvl) phenyll sulfide The title compound was prepared according to the procedures of Example 1.
'H NMR. (CDCl 3 ,-300 MHz) 8 8.45 114), 7.50-7.57 (in, 314), 7.42(br. d, 114, J 8.1 Hz), 7.30 (in, I 7.02 (br, I 6.72 (d 1.H, J =8.4 Hz), 4.01 (br s, 4H), 3.44 (quintet, I1H, J =6.8 Hz), 2. 56 (br. m, 4H), 1. 18 6H, J =7.1 Hz). MS (ESI) m/z 425, 457. Anal. Calcd for C 2 3
H
24
N
2 0 4 S C, 65.07; H, 5.70; N, 6.60. Found: C, 64.912; H,- 5.67; N, 6.62.
(Benzodioxan-6-vl)F2-trifluoromethyl-4-( E-((3-R-carboethoxypiperidin-1Ivl~carbonyl)ethenvl) p2henXll sulfide The title compound was prepared by the procedures described in Example 248,* substituting ethyl (±)nipecotate with ethyl nipecotate tartrate, giving a white solid. 'H NMR (CDCl 3 300 MHz) 8 1.26 J 7.4 Hz, 3H), 1.46-1.67 (in, I1H), 1.67-1.98 (in, 2H), 1.98-2.23 (mn, IH), 2.46-2.63 (in, 1H), 3.10-3.42 (in, IH), 3.53-4.13 (in, 2H), 4.16 J= 7.4 Hz, 2H), 4.25-4.40 (in, 4H), 4.60-4.88 (mn, IH), 6.91 Hz, I1H), 6.93 J 15.3 Hz, I 6.97-7.05 (mn, 2H), 7..07 2.7 Hz,- 1H), 7.42 J =8.4 Hz, I 7.5 9 15.3 Hz, 1IH), 7.77 I1H). MS.(ESI~) atm/Wz 522.
Example 324 (Benzodioxan-6-yl) [2-trifluoromethyl-4-( E-((3-R-carboxypiperidin- 1yl)carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 25 1, substituting the ethyl ester from Example 248 with ethyl ester from Example 323, giving a white solid. NMR (CDCI 3 300 MHz) 8 1.48-1.71 (in, 1H), 1.7 1-2.01 (in, 262 2H),.2.01-2.20 (in, 2.53-2.70(in, 3.18-3.54 (rn, IH), 386-4.20 (in,2H), 4.20-4.33 (ml, 4H), 4.454'.75 (in, I 6.90 J~ 8.7 Hz, I 6.9*5-7.04 (in, 3H), 7.06 J 2.4 Hz, I 7.3 5-7.45 (br mn, I1H), 7.60 J= 15.3 Hz, I1H), 7.75 I11).' MS (ESI+) at m/lz 494.
Example 325.
(Benzodioxan-6-yl)[2.3-dichoro-4(E((3-(p2yl,.Oldn-2-on-1 -vl)prop- 1ylamino)ca rbonyl) ethenyl)p2henvllsulfide The title compound was prepared by the procedures described. in Example 240, substituting 4 -fluoro-3-trifluoromethylbenzaldehyde with 2,3-dichloro-4trifluoromethanesulfoxybenzaldehyde, giving a white solid. 'H NMR (CDC 3 300.
MHz) 6 1.7 1-1 .82(in, 2H), 2.08 J= 7.5 Hz, 2H), 2.46 J= 7.5:Hz, 2H), 3.2603.50 (in, 6H), 4.2.3-4.36 (mn, 6.36 J 15.6 Hz, I 6.60 J 8.7 Hiz, I 6.44 J 8.7 Hz, I 7.0 (dd, J 2.4, 8.7 Hz, I 7.09 (d3 J= 2.4 Hz, I H), 7.31 J=8.7 Hz, I 7.94 J 15.6 Hz, I MS (ESI') (M±+H)*atm~z 507, 509, 511. Anal. Calcd for C 2 4
H
2 4 C1 2
N
2 0 4 S 1.87 H 2 0: C, 53.27; H, 5.17; N, 5.18..
Found: C, 53.30; H, 5.17; N, 4.83.
Examle 326 (Benzodioxan-6-vi) F2,3-dichloro-4-(
E-(
4 -acevppzn I v)croy~tey) Phenyll sulfide The title compound was prepared by the procedures described in Example 325, 263 substituting aminopropyl pyrrolidinone with I -acetylpiperazine. white solid; 'H NMR
(CDCI
3 300 MHz) 8 2.17 3H), 3.50-3.94 (in, 8H), 4.26-4.40 (in, 4H), 6.61 (d,J= 8.7 Hz, I 6.71 J1 15.6 Hz, I1H), 6.95 J1 8.4 Hz, I1H) 7.04 (dd, J= 2.4, 8.4 Hz, I 7.09 J1=2.4 Hz, I 7.30 (d J= 8.7 Hz, I 7.99 J1=15.6 Hz, 1 H).
MS (ES1-) at m/z-515, 517, 519. Anal.. Calcd for C 2 3
H
2 2 C1 2
N
2 0 4 S -0.52
CH
2
CI
2 C, 52.55; H, 4.32; N, 5.2 1. Found: C, 52.63; H, 4.16; N, 4.82.
Example 327 (Benzodioxan-6-vl) [2.3-di ch oro-( E4(3-carboethoxypiperidin- I -vi) carbonyl)ethenyl) phenvil sulfide The title compound was prepared by the procedures described in Example 325, substituting aininopropyl pyrrolidinone with ethyl nipecotate, giving a white solid. 'H NMR (CDCI 3 300 MHz) 8 1.26 J1= 7.0 H4z, 3H), 1.66-1.96 (mn, 2H), 1.96-2.21 (in, I 2 .44-2.60 (mn, I 2.85-3.40 (in, 2H), 3.50-3.70 (in, I1H), 3.80-4.10 (in, 2H), 4.15 J1 7.0 Hz, 2H), 4.26-4.40 (in, 4H), 6.66 J1 8.7 Hz, I 6.74 J1 15.3 Hz, I1H), 6.95 J= 8.4 Hz, I 7.03 (dd, J 124, 8.4 Hz, I1H), 7.09 J1=2.4 Hz, I 7.25-7.3 8 (mn, I1H, 7.93 J1 15.3 Hz, I1H). MS (ESI*) at m/z 544, 546, 548.
Example 328 (Benzodioxan-6-v)[23 -di chloro-4-( E-((4-catboethoxypiperi din- I -vi) carbonyl~ethenyl) Dhenvll sulfide 264 The title compound was prepared by the procedures. described in Example 325, substituting aminopropyl pyrrolidinone with ethyl isonipecotate, giving a white solid.
'H NMR (CDC1 3 j, 300 MI-Iz) 8 1.26 J= 7.2 Hz, 3H), 1.69 (td, J= 3.9, 10.8 Hz, I1H), 1.74 (td, J 3.9, 10.8 Hz, I 1.82-2.05 (in, 2H), 2.50-2.63 (in, I 2.84-3.31 (mn, 2H), 3.81-4.06 (in, I1H), 4.15 7.2 Hz, 2H), 4.244.34 (mn, 4H), 4.34-4.59 (in, INH), 6.61 J= 8.7 Hz, INH), 6.74 J~ 15.6 Hz, INH), 6.94 J= 8.7 Hz, INH), 7.03 (dd, J1 2.7, 8.7 Hz, INH), 7.08 J= 2.7 Hz, INH), 7.29 J= 8.7 Hz, I 7.90 J1 =15.6 Hz, INH). MS (ESI') (M+H) 4 at m/~z 522, 524, 526. Anal. Calcd for
C
2 5
H
2 5 C1 2 N0 5 S: C, 5.7.48;.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-carboxvrpiperidin- I -yl) cArbonvl)ethenyl) Rhenyll sulfide 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. 'H NMR (CDCI 3 300 MH z) 8 1.70- (in, 2H), 2.0-2.20 (in, IH), 2.54-2.68 (in, IN), 3.03-3.46 (in, 2H), 3.80-4.1,1 (in, 2H), 4.27-4.40 (in, 4H), 4.50-4.70 IN), 6.60 J= 8.9 Hz, iN), 6.79 J= 1 5.3.
Hz, INH), 6.94 J= 8.5 Hz, INH), 7.03 (dd,J 2.1, 8.5 Hz, INH), 7.08 J= 2.1 Hz, IN), 7.30 J=8.9 Hz, 7.93 J= 15.3 Hz,IN). MS (ESI-) (M-2H)-at n/z 492,494, 496. Anal. Calcd for C23H2ICI 2 NOS- 0.73 H 2 0: C, 54.43; H, 4.46;,N, 2.76. Found: C, 54.43; H, 4.39; N, 2.49.
ExampIle330 (Benzodioxan-6-ylf2,3-dichlo-4-( E-((4-carboxypiperidin-1I-yi) carbonyl)ethenyl) phenyll sulfide 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 32 8, And KOH withNaOH, to produce a whi te solid. 'H NMR (d 6 -DMSO, 300 MHz) 8 1.33-1.55 (in, 2H), 1.62-1.78,(m, 2H), 1.93-2.07 IH), 2.90 (brt,J= 10.5 Hz, I H), 3.16 (brt, J= 10.5 Hz, 1H), 3.96 (br d, J= 13.5 Hz, IH), 4.09 (br 13.5 Hz, IH), 4.26-4.42 (in, 4H), 6.60 J Hz, I 7.04-7.08 (mn, 2H), 7.13 J 1.5 Hz, lH), 7.22 J= 15.3 Hz, 1H), 7.70 (d J= 15.3 Hz, 7.86 9.0 Hz, IH). MS (ESIV) (M+H) 4 at m/z 516, 518, 520. Anal. Calcd for C 2 3
H
2 0 C1 2 NINaO 5 S 0.36 Et 2 O: C,54.06; H, 4.38; N, 2.58. Found: C, 53.99; H, 4.37; N, 2.22.
Exampl1e 331 (2-Isopropylphenyl)2.3-dichloo- 4 E-((3-(1I-pyrrolidin-2-onvl~hropylamino) carbonyl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 325, substituting 6-mercaptobenzodioxane with 2-isopropylbenzenethiol, to give a white solid. 'H NMR (CDCl 3 300 MHz) 8 1.19 J= 7.2 Hz, 6H), 1.76 (p J 5.8 Hz, 2H), 2.08 J= 7.65 Hz, 2H), 2.46 J 7.65 Hz, 2H), 3.32 5.8 Hz, 2H), 3.36-3.5 1 6.35 J=15.3 Hz,lH),6.40 J=8.7 Hz,1H), 7.10 (biJ= Hz, I 7.20-7.30(in, 2H), 7.42-7.53 (in,2H), 7.94 15.3 Hz, IH). MS at m/z 491, 403, 495. Anal. Calcd for C 2 5
H
2 8 C1 2
N
2 0 2 S 0.7
CH
2
CI
2 C, 56.03; H, 5.3 8; N, 5.08. Found: C, 56.06; H, 5.22; N, 5.0 1.
Example 332 (2-1SOrODVRoyhenyl )[2,3-dichloro-4-( E-((4-acetylpinerazin-1I-vil) carbony~ethenyl) p~henyil sulfide The title compound was prepared,.by the procedures described* in Example 326, substituting 6 -mercaptobenzodioxane with 2 -isopropylbenzenethiol, providing a white solid. 'H NMR 300 MHz) 8 1. 19 J =7.2 Hz, 6H), 2.17 3H), 3.46 (septet, J= 7.2 Hz, I 3.50-3.90 (in, 8H),.6.41 J= 8.7 Hz, 1H), 6.71- 15.3 Hz, IH), 7.21-7.35 (in, 2H), 7.44-7.57 (in, 3H), 7.99 J= 15.3.Hz,: IH). MS (ESI') at m/z 477, 479, 48 1. Anal. Calcd for C 2 4
H
2 6 C1 2
N
2 0 2 S 0.32 CH 2
CI
2
C,
57.89; H, 5.32; N, 5.55. Found: C, 57.85; H, 5.25; N, 5.74.
Example 333 2 -Is opropylphenyl)[23.dichlor-4-( E-(-carboethoxypiperid in.. I -vi) carbonyl~ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 327, substituting 6 -mercaptobenzodioxane with 2 -isopropylbenzenethiol, giving a white solid. 'H NMR (CDCI 3 300 MHz) 8 1.20 J 7.2 Hz, 6H), 1.20-1.35 (mn, 1.65-1.93 (in, 1.93-2.16 (mn, I 2.43-2.58 (in, I 3.06-3.35 (mn,lIH), 3.47 267 (septet, J= 7.2 Hz, I 3.77-4.23 (in, 4H), 4.5 0-4.7 7 (in, I1H), 6.41 J= 8.4 Hz, I1H), 6.80 J 15.3 Hz, 1 7.18-7.32 (in, 2H), 7.40-7.55 (in, 2H), 7.93 (d,J= 15.3,Hz, I1H). MS (ESI-) (M+H) 4 at tn/z 506, 508, 5 Examrle 334 (2-Isop~ropylphenvl)r2.3-dichloro-4-( E-;((4-carboethoxyriperidin- -yI) carbonyl)ethenvl) phenyll sulfide The title compound was prepared by the procedures described in Example 328, substituting 6-mercaptobenzodioxane with 2-isopropylbenzenethiol, to give a white solid. 'H NMR (CDCl 3 300 MHz) 8 1.19 J= 7.2 Hz, 6H), 1.26 J =7.05 Hz, 3H), 1.69 (td, J=3.9, 10.8 Hz, IlH), 1.74 (td, J3.9, 10.8 Hz, I 1.88-2.06 (m, 2H), 2.50-2.63 (in, I 2.84-3.08 (in, 1IH), 3.08-3.32 (in, I1H)7 3.47 (septet, J= 7.2 Hz, IH), 3.86-4.06 1H), 4.15 J=7.05 Hz, 2H), 4.37-4.61 IH), 6.40 J= 8.7 Hz, IH), 6.73 J= 15.6 Hz, 1H), 7.22-7.35 (in, 2H), 7.44-7.57 (mn, 3H), 7.92 J= 15.6 Hz, IRH). MS (ESIE) at m/z 506, 508, 510. Anal. Calcd for
C
2 6
H
2 9 Cl 2 N0 3 S -0.01-H 2 0: C, 61.64; H, 5.77; N, 2.76. Found: C, 61.64; H, 5.90; N, 2.70.
Example 335 (2-Isop~ropyliphenylfl2,3-dichloro-4-( E-((-carboxypiperidin- I -vl) carbonvl)ethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 329, 268 substituting 6 -mercaptobenzodioxane with 2-isopropylbenzenethiol, giving a white solid. 'H NMR-(CDCI 3 ,-300 MHz) 8 1. 19 (d J 7.2 H-z, I1H), 1.43-1.67 (in, I1H), 1.67-1.97 (mn, 1.97-2.19 (in, IH), 2.52-2.64 (in, lH), 3.04-3.38 (mn, 1H), 3.47 (septet, J= 7.2 Hz, I 3.75-4.10 (in, 2H), 4.44-4.7 0 (in, I 6.40 J= 8.4. Hz, 1iH), 6.79 J 15.3 Hz, I 7.18-7.29. (in, 2H), 7.41-7. ,53 (in, 3H), 7.93 J 15.3 Hz, i1H). MS (ESI 4 at m/lz 478, 480, 482. Anal. Calcd for
C
2 4
H
2 5 C1 2 N0 3 S -0.05 H 2 0 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 -Isopropylrphenvl)r2,3-dichloro-4( E((4-carboxypiperidin- I -yi) cabonl)ethenvl) phenyll sulfide.
The itle compound was prepared by the procedures described in Example 33.0, substituting 6 -mercaptobenzodioxane with 2-isopropylbenzenethiol, giving a white solid. 'H NMR (d 6 -DMSO, 300 MHz) .5 1. 16 J 7.2 Hz, 6H), 1.33-1.53 (in, 2H), 1.64-1.78 (in, 2H), 1.97-2. 10 (in, I 2.88 (brt, J 10.5 Hz, I1H), 3.15 (brt, J 10.5 Hz, I1H), 3.97 (br d, J= 13.2 Hz, IlH), 4.11 (br d, J 13.2 Hz. I 6.41 J=9. 0 H7, I 7.22 J= 15.6 Hz, I 7.3 1-7.42 (mn, I 7.53 (d,J 7.8.Hz, I 7.56- 7.64 (in, 2H), 7.71 J= 15.6 Hz, I 7.85 (di, J= 9.0 Hz, I MS (ESI*) atm/z 478, 480, 482. Anal. Calcci for C2 4
H
24 Cl 2 NNaO 3 S 0.95 H 2 0: 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-dichlioo4-( E-((3-carboethoxypiperi din- I -yl) carbonyl)ethenvl) 12henyll sulfide The title compound was prepared by the procedures described in Example 283, substituting 4-fluoro-3-chlorobenzaldehyde with 2,3-dichloro-4trifluoromethanesulfoxybenzaldehyde, giving a white solid. 'H NMR (CDCl 3 300 MHz) 8 1.23 J 7.5 Hz, 3H), 1.46-1.67 (in, I 1.67-1.95 (in, 2H), 1.95-2.17 (mn, I1H), 2.43-2.60 (mn, I1H), 3.02-3.42 (mn, I1H), -3 .67-3.92 (in, 2H), 3.86 3H), 4.13 J Hz, 2H), 4.59-4.80 IH), 6.46 (d,J=8.7 HzI1H), 6.54 (d,J=3.0Hz, IH), 6.77 J= 15.3 Hz, IH), 7.15 J 3.0 Hz, IH), 7.19 J= 8.7 Hz, lH), 7.37 J -8.7 Hz, IH), 7.42 8.7 Hz, IH), 7.89 lH), 7.92 (d,J='15.3 Hz, MS (ES1 at m/z 517, 519, 52 1.
Example 338 (1 -Meth-ylindol-5-ylfl2,3-dichloro-4-( E-((3-carboxypiperidin-l1-yP) carbonvlethenyl) phenyll sulfide The title compound was prepared by the procedures described in Example 155, .substituting the ethyl ester from Example 137 with ethyl ester from Example 3 37, and KOH with NaOH, to give a white solid. 'H NMR (d'-DMSO, 300 MHz) 8 1.29-1.45 (in, IH), 1.45-1.78 (in, 2H), 1.78-2.02 (in, 1H), 2.20-2.40 (mn, IH), 2.82 (brt, J= 10.5 Hz, IH), 3.08 (brt, J= 10.5 Hz, lH), 3.80-4.07. (in, 2H), 3.86 3H), 4.38-4.50 (in, I 6.42 J= 8.4 Hz, I 6.54 J= 3. 0 Hz, I 7.19 J 15.3 Hz, I 2 270 (dd, J= 1.8, 8.7 Hz, 1H), 7.48 J=,3.0 Hz, I 7.64 8.7 Hz, 1H), 7.67-7.77 (in,2H), 7.87 J= 1.8 Hz, I MS (ESI') at m/z 489, 491, 493. Anal.
Calcd for C24H 2 2 C1 2
N
2 0 3 S -0.56 CH 2
CI
2 C, 54.94; H, 4.34; N, 5.22. Found: C, 54.89; H, 4.44; N, 5.32.
Example 339 (1-Methvlindol-5-yl)r2.3-dichloro4-( E-((4-cairboethoxypiperid in- -I -i carbonvi)ethenyl) phenvil sulfide The title compound was prepared by the procedures -described in Example,285, substituting 4 -fluoro-3'-chlorobenzaldehyde with 2,3-dichloro-4trifluoromethanesulfoxybenzaldehyde, providing a white solid. 'H NMR,(CDC1.
3 3.00 MHz) 8 1.25 J 7.2 Hz, 3H), 1.62-1.79 (mn, 2H), 1.87-2.04 (in, 2H), 2.41-2.63 (in, I 2.8-5-3.41 (mn, 2H), 3.85 3H), 3.87-4.10 (in, l 4.15 J 7.2 Hz, 2H), 4.32-4.60 (mn, I 6.46 J 8.7 Hz, I 6.54 J 3.0 Hz, I 6.7 1 J 15.3 Hz, IlH), 7.15 J1= 3.0 Hz, I 7.17 J= 8.7 Hz, I 7.36 (dd, J 2.4, 8.4 Hz, I 7.42 J= 8.4 Hz, IlH), 7.88 J= 2.4 Hz, IlH), 7.90 J= 15.3 Hz, IlH).- MS.
(ESI') (M+H) 4 at m/lz 517, 519, 521. Anal. Calcd for C 2 6
H
2 6 Cl 2
N
2 0 3 S 0.12 H 2 0: C, 60. 10; H, 5.09; N, 5.3 9. Found: C, 60.09; H, 5.2 1; N, 5.54.
Example 340 (1 -Miethylindol-5-vI)[2,3-dichloro-4-( E-((4-carboxvpieridin- I -vI) carbonl)ethenyl) phenyll sulfi de 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. 'H NMR (d 6 -DMSO, 300 MHz) 5 1.31-1.53 2H), 1.62-1.76 2H), 1.94-2.09 1H), 2.88 (brt, J= 10.5 Hz, 1H), 3.13 (brt, J= 10.5 Hz, 1H), 3.86 3H), 3.93 (br d, J= 13.2 Hz, 1H), 4.09 (br d, J= 13.2 Hz, 1H), 6.41 J= 8.7 Hz, 1H), 6.53 (dd, J= 0.9, 3.0 Hz, 1H), 7.04 J= 15.3 Hz, 1H), 7.32 (dd,J= 2.1, 8.7 Hz, 1H), 7.48 J 3.0 Hz, 7.64 J= 8.7 Hz, 1H), 7.69 15.3 Hz, 1H), 7.73 J= 8.7 Hz, 1H), 7.88 J=2.1 Hz, 1H). MS (ESI') at m/z 489, 491, 493. Anal. Calcd for C 2 4
H
2 1 Cl 2
N
2 Na03S 0 C, 56.37; H, 4.14; N, 5.48. Found: C, 56.44; H, 4.38; N, 5.20.
An alternative method for preparing Example 340 is given below.
N
Example 340A 1 To a solution of 5-iodoindole (75 g, 0.31 mol) in dry THF (750mL), at -78 0
C
was added sodium hydride (60% in mineral oil, 14.85 g, 0.37 mol) in one portion.
The suspension was stirred at -78°C for 1 hour after which iodomethane (28.8 mL, 0.46 mol) was added. The reaction mixture was stirred overnight with a slow elevation on temperature to room temperature(no more dry ice was added). Ether (600mL) and hexane (1.2L) were added and the mixture was washed with brine (1.6L) and water dried over Na 2
SO
4 and filtered. The solution was concentrated and a the residual brown solid was recrystallized from hexane to give the title compound (66 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 MS (DCI/NH3) m/e 258 (M+H) Example 340B 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 (2x50mL). The resultant KH powder was then suspended in dry THF (75 mL), and cooled to 5 Triisopropylsilylthiol (20.0 g, 0.105 mol) was slowly added via syringe over a period of 15 minutes.
Vigorous escape of hydrogen gas was observed with addition of the thiol. The suspension was stirred at 5°C for I our and became homogenous. After another hour stirring at room temperature, this solution was cannulated to a THF solution (100mL) containing Example 340A (24.5 g, 95.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.91 mmol). The yellow suspension was stirred at 70 0 C for 1 hour. After cooled, ether and hexane were added, and the mixture was washed with brine, dried (Na 2
SO
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, MS (DCI/NH3) m/e 320 (M+H) 273 Cl HO C- CI Br Example 340C 4-Bromo-2.3-dichlorophenol To a solution of 2,3-dichlorophenol (200 g, 1.227 mol) in dichloromethane (800 mL), at 0 °C was added dropwise bromine (196.1g, 1.227 mol).from a dropping funnel within 1 hour. The red solution was stirred overnight (0°C rt), and washed with 10% NaHSO 3 The organic phase was dried over Na 2
SO
4 and concentrated. The residual white solid was recrystallized from hexane to give example 340C as white needles (207g, MS (DCI/NH 3 mle 241 (M+H)
CI
HO CI
HOIOCH
3 0 Example 340D Methyl 2,3-dichloro-4-hydroxyphenvlacrvlate A 1 L RBF was charged with Example 340C (48.4 g, 0.2 mol), Pd,(dba) 3 (4.6 g, 5 mmol), (Tol) 3 P (4.66 g, 15.2 mmol), and purged with nitrogen. Dry DMF (300 mL), methyl acrylate (51.66 g, 0.6 mol) and triethylamine (84 mL, 0.6 mol) were then added. The reaction mixture was purged with nitrogen and stirred at 100 0 C (oil bath) for 16 hours. After cooled to room temperature, a lot of white crystalline material formed. 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) 274 was filtered off. To the solution was then added, with stirring, saturated NaCI 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 mL) and 1:1 ethyl acetate/hexane (500 mL), and dried to give pure desired compound (44.99g, MS (DCI/NH3) m/e 247 (M+H) Cl TfO CH
-OCH
3 Example 340E Methyl 2 ,3-dichloro-4-trifluoromethane sulfonvloxyphenvlacrvlate To a suspension of Example 340D(18.62 g, 75.4 mmol) in pyridine (150 mL) at 5 0 C was added trifluoromethylsulfonyl anhydride (25.53 g, 90 mmol) very slowly.
The suspension was stirred at 5 oC for 1. hourand became homogeneous. The solution was kept at 5 °C for 2 hours and at room temperature for 20 minutes. Ether (700mL) was added and the mixture was washed 10%HCI (700 mL)/brine (300 mL), (100 mL)/brine (900 mL), and brine (500 mL). The organic phase was dried (Na2SO 4 and concentrated to give the title compound (24.86 g, MS (DCI/NH 3 m/e 379 Cl S NC OH 0 Example 340F (1 -Methvlindol-5-vl)[2.3-dichloro-4-( E-(carboxvethenyl)phenyl sulfide To a solution of Example 340B (38.5 g, 0.12 mol) and Example 340E (30.3 g, 0.08 mol) in dry N-methylpyrrolidinone (300 mL) was added CsF (18.2 g, 0.12 mol) at 5°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 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 EtOAc/hexane) to give a yellow solid (30 g).
This yellow solid was dissolved in THF (150 mL), and was added a solution of LiOH (4.0 g, 0.16 mol) in H,O (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. HCI. The mixture was concentrated 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 MS (DCI/NH3) m/e 378 o
C
1 0 S C N OCH 3 0 Example 340G 276 -Methylindol-5-vl) 2.3-dichloro-4-( E-((4-carbomethoxypiperidin- 1 vl)carbonvl)ethenyl)phenvll sulfide 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, MS m/z 503 (M+H) CI 0 S ONa 0 Example 340 (1-Methvlindol-5-vl)r2.3-dichloro-4-( E-((4-carboxypiperidin-1vl)carbonvl)ethenvl)phenyll sulfide, sodium salt 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 HO 2 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% HCI 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).
277 10.50 grams of the solid was suspended in methanol (60 mL), and was treated with a solution NaOH (0.85 9g) 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, Example 341 (2-Ethoxyphenyl)-[2.3-dichloro-4(E-f(4-carboxVpiperidifil- -l)carbonyllethenyl) phenyll sulfide The title compound was prepared according to the procedures of Example 3 substituting 2-ethoxybenzenethiol prepared according to the procedures of Example 97A. 'H-NMR (CD 3 OD, 300 MHz) Potassium salt 8 1.20 J=7Hz, 3H), 1.55-1.72 (in, 2H), 1.88-1.98 (in, 2H), 2.32 (in, IH), 2.88 1=12Hz, IH), 3.20 J=12 Hz, IH), 4.05 1=7Hz, 2H), 4.14 1=1 2 Hz, I 4.48, J= 12 Hz, I 6.64 9d, J=9Hz, IH), 7.00-7.15 3H), 7.44-7.50 2H), 7.56 J=9Hz, 7.90 1=15 Hz, I H) Anal. Calcd. for C 23
H
22 KC1 2 N0 4 S 0.5 H 2 0: C, 52.37, H, 4.39, N,-2.66. Found: C, 52,23; H, 4.56; N, 2.49.
Example 342 (2-Ethoxynhenl)-F2.3-dichloro-4(E (iorpholin- I -yl)carbonyljethenyl)p~henvlj sulfide The title compound was prepared according to the proc edures of Example 3 substituting 2 -ethoxybenzenethiol prepared according to the procedures of Example.
97A; '1--NMR (CDC 3 300 MHz) 5 1.25 J=7Hz, 3H), 3.55-3.80 (in, 8H), 4.05 (q, J=7Hz1, 2H), 6.63 J=9Hz, IH), 6.71 J=l15 Hz, I 6.95-7.03 (mn, 2H4), 7.26 (d, J =9Hz, l 7.3 9-7.5 0 (in, 2H), 7.99 J= 15 Hz, IlH) Anal. Caldd. for
C
2
,H
2 1 C1 2 N0 3 S: C, 57.54; 4.82; N, 3.20. Found: C, 57.55; H, 4.77; N, 3.14.
Example 343 (2-Ethoxy-nhenyl)- 2 .3-dichloro-4(E-r(3-carboxvpiperid in-I -yl)carbonyllethenyl) phenvil sulfide.
The title compound was prepared according to. the-procedures of Example. 310, substituting 2-ethoxybenzenethjol prepared according to the procedures of Example 97A. 'H-NMR (CD 3 OD 300MHz) 8 1.20 J=7Hz, 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=7Hz, 2H), 6.64 J=9Hz,. Il-H), 7.03 J=8Hz, I 7. 10 J=9Hz, I 7.22 (d, J=1 5 Hz, I 7.45-7.50 (in, 2H), 7.62 J=9Hz, I 7'.80 J=1 5 Hz, I The acid (-303 mg, 0.63 mmol).was dissolved in 3 mL of methanol. A solution of KOH (0.60 minol) in 1 mL of methanol was added. The resultant solution was stirred for min and concentrated in vacuo. Ether (5 inL) was added, and the mixture was stirred for I hr. The resultant powder was collected by filtration and dried under vacuum at 60C to give 307 mng of a solid, water-soluble product. Anal. Calcd. for C23HKC 1 2
NO
4 S 0.5 H 2 0; C, 52.37; H, 4.39; N, 2.66. Found: C, 52.20; H, 4..65 N, 3.04.
2.79 Example 344 (2-Isop~ropylphenyl)l2-nitro-4-( E-((3-carboethoxvYTYrrolidin- I -vlbcarbonyl'ethenyl) phenyil sulfide Prepared according -to the proced ures of Example. 71, giving a yellow solid.
'H NMR (DMSO-d., 300MHz) 8 1. 14 J =7.0 Hz, 6H); 1.20 7.0 Hz, 3H); 1.92-2.30 2H); 3.10-4.01 (in, 6H); 4.06-4.17 (in, 2H1); 6.64 (di, J =8.5 Hz, I1H); 7.06-7.17 (in, IH), 7.34-7.62 (mn, 5H); 7.88-7.96 (in, IH); 8.62 (dci, J 1.5, 8.5 Hz, I MS (APCI) at m/z 469. Anal calcd for C,6.8 H, 6.02; N, 5.98. Found: C, 64.12; H, 5.98; N, 5.89.
Example 345 (2-Isop~ropylphenylMf2-nitro-4-( -carboxypyrrolidin- I I')carbonyl)ethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300OMHz) 8 1. 14 (di, J =6.8 Hz, 6H); 1.92-2.24 2H); 3.01 3.92 (in, 6H); 6.64 (dd, J 1.7, 8.5 Hz, 1H); 7.04-7.16 (mn, 1H), 7.33-7.61 (mn, 7.87-7.95 (mn, IH); 8.61 (dci, J 8.5 Hz, I MIS (APCI) (M+H) 4 at rn/z 441.
Anal calcd for C, 3
H,
4 N,S,0 4 C, 62.71; H, 5.49; N, 6.36. Foun d: C, 62.47; H, 5.39; N, 6.09.
Example 346 280 (2-Isopropyiphenyl) [2.3-difluoro-4-( E-((3-carboethoxypiperidin- 1 Yl)carbonyl)ethenyl) phenyll sulfide.
Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSQ-d 6 300MHz) 8 1.18 J =7.0 Hz, 6H); 1.10-1.22 (in, 3H); 1.30- 2.07( br mn, 4H); 2.50-3.45 (br mn, 3H); 3.55-4.47 (br mn, 5H4); 6.62-6.72 7.23- 7.73 (in, 7H). MS (APCI) at m./z 474., Example 347 (2-Isopronylphenvl)r2.3-difiuoro-4-( E-((3-carboxylpi]eri din- I -y]I)carbonvi)ethenyl) phenyil sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-d,, 300MHz) 5 1.18 J 7.0 Hz, 6H); 1.30-2.03 (br in, 2.25- 3.50 (br mn, 4H); 3.87-4.51 (br in, 2H); 6.62-6.72 (in, I .7.23-7.73 (mn, 7H). MS (APCI) at m/z 446.
Example 348 (2-1 sopropylphenyl) [2,3 -di f!uoro-4-( E(40-carboxypineri din- I -yl)carbonyflethenyl) phenyll sulfide Prepared according to the procedures of Example 71, giving a yellow solid.
'H NMR (DMSO-1 6 300MHz) 8 1. 18 .J 6.8Hz, 6H); 1.30-1.91 (brin, 4H4); 2.50- 3.50 (br in, 4H); 4.02-4.34 (br mn, 2H); 6.62-6.72 (mn, 11H); 7.23-7.73 (mn, 7H). MS (APCI) at in/z 446.
Example 349 (Bnoixn6y)2tilooeh E(3ehxcroypioiiyl)carbonyl)ethenyl) phenyil sulfide The title compoun~d was prepared according to the procedures of Example 1.
'H NMR (CDCI.,, 300 MHz) 8 7.77 I 7.62 I H, J 15.4 Hz) 7.42 1H, 3 Hz), 7.06 1H,.J 2.1 Hz), 6.98-7 .04 (in, 2H), 6.91 I H, J 8.1 Hz), 6.68 (dd, IlH, J 3.3, 15.3 Hz), 4.30 (in, 4H), 4.19 2H, J 7.0 Hz), 3.56-3.92 (mn, 4H), 3.06-3.24 (in, I H),2.10-2.3 5 (in, 2H), 1.28 and 1.29 (two t, 3H7 J1 7.2 Hz). MS (ESI) ,z 508,l1015.
Example 350 (Benzodioxan-6-ylM[2-trifluoromethyl-4(E((3carboxypyrolidin-lIyI)carbonyl~etbenvl) phenyll sulfide The title compound was prepared by hydrolysis of the compound of Example 349 according to standard procedures. 'H NMR (DMSO-d,, 300 MHz) 5 8.10 (d7 1 H, J 9.9 Hz), 7.84 I H, J 7.8 Hz), 7.46 I H, J 15.3 Hz), 7. 10 1iA, J1 15.3 Hz), 6.97-7.06 (in, 4H), 4.30 (mn, 4H), 3.50 (br, overlapped with water residue peak), 3.00 (mn, I 2. 10 (mn, I 2.00 (in, I MS (ESI) m/z -478, -957.
Example 351 (2-Methoxyphenll2-chloro-3-trifluoromethyl-4-( E-((4-carboethoxypiperi din- I1yl)carbonyl)ethenyl) phenyll sulfide Example 35 1A 3-Chloro-4-hydroxy-2-(trifluoromethyl)benzaldehyde Chloroform (6.7g, 2.0 eq.) was added dropwise to A stirred mixture of Ca(QH) 2 (8.95g, 120 mmol.), K 2 C0 3 (13.5g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol 22 mmol.), and H,O (50 mL) at 60'-70" over 2 h. The reaction mixture was cooled, and acidified with conc. HCI. The product was extracted into EtOAc and dried over Na 2
SO
4 Solvent was evaporated, the crude product was sep arated and purified through a silica column, eluting with hexane and EtOAc to give 5 80 mg of the title compound.
Example 351 B (2-Methoxyphenyl)[2-chloro-3-tfifluoromethyl-4-( E-carboxyethenyl) phenyll sulfide The title compound was prepared according to the procedures described in Example 3 10, substituting the compou nd of Example 3 51 A for 4-hydroxy-2,3dichlorobenzaldehyde.
Exampl e 3 5 1C (2-Methoxyphenyl)[2-chloro-3-trifluoromethyl-4-( E-((4-carboethoxypiperi din- 1 yl)carbonyl~hthenyl) phenyll sulfide 283 To the acyl chloride (3 7 mg, 0. 1 mmol) prepared from the compound of Example 351IB, as a solution in CH,C1 2 was added 1.2 eq.. of ethyl isonipecotate and 1.2 eq. of 1-unig's base. The mixture was stirred at room temperature for 20 min., of the solvent was removed in vacuo, and the resultant solution was loaded on a silica column to elute with'hexane and EtOAc to give 5 1mg of the title compound. 'H-NMR (CDCl3, 300MHz) 8 1.25 J=7.5Hz, 3H), 1.65-1.78 (in, 211), 1.92-2.02 (br, 2H-),.2.51-2.60 (in, IH), 2.93-3.24 (br, 211), 3.82 3.88-3.96 (m,1I 4.15 (q,J=7.5Hz, 2H), 4.40-4.50 (br, I 6.48 J=lI5Hz, I 6.72 (d, J=91-z, I 7.02 J=7.5Hz, 2H), 7.12 J=9Hz, 11H), 7.49 J=9Hz, 7.86 (qq, J=4.5Hz, I MS (DCIINH 3 m/e 528 Example 352 (2-MethoxyphenlMf2-chloro-3 -trifluoromethvl-4-( E-((4-carboethoxypiperi dinl- I yJ)carbonyl')ethenyl) phenyil sulfide The compound of Example 351 was hydrolyzed by aq. NaOH in EtOH at rt. to give 90% yield of the title compound. 'H NMR(DMSO, 300MHz) 8. 1.37-1.52 (br..
2H), 1 .78-1.86 (hr. 2H), 2.45-2.55 (in, 11H), 2.83 3=12Hz, IH), 3.17 J=13.5 Hz, 1H), 3.80 3H), 4.07 3=12Hz, 1H1), 4.26 J=13.5Hz, 1H1), 6.75 (d,3J9Hz, 11H), 6.98 3=15Hz, 1H), 7.1 1(t, 3=9Hz, 1H), 7.26 3=9Hz, 1H), 7.53 3=7.5Hz, 1H), 7.62 J=9Hz, 2H), 7.70 (qq, 3=4.5Hz 111). MS (DCIINH 3 m/e Example 353 2 -Methoxyphenyl)[2-chloro-3tifluoromethylA.4( E-((morpholin-I1 yl)carbonyl)ethenyl) nhenylj sulfide Prepared according to the procedures of Example 3 51, giving 50 mg (91 of the title compound. 'H-NMR (CDCI 3 300MHz) 5 3.56-3.62 (br m r, 2H), 3.6 7-3.77 (br m, 3.85 3H), 6.45 J I5Hz, I 6.73 J-9Hz, I 7.03 J=9Hz, 2H), 7.09 (t,;J=9Hz, 1 7.52 J=9Hz, 2H), 2.93 (qq, J=6Hz,. I MS (DCIINH 3 m/z 458 Example 354 (Benzodioxan-6-vJ) E-((4-carbxypierdin- I -yI) carbonl)ethenyl)naiphthyll sulfide The methods of Example 3 10 and 311 were used to convert 4-hydroxy-2naphthaldehyde and 6- benzodioxanethiol to the desired product as a yellow solid. 'H- NMR (DMS-d 6 300MHz) 8 1.50 (br s, 2H), 1.83-1.92 (in, 2H), 2.5-2.6 (in, IH), 2.85- 2.95 (in, lH), 3.18-3.29 (in, IH), 4.22 (br s, 5H), 4.30-4.38(in, 1H), 6.87-6.92 (in, 3 7.3 8 J=1I5Hz, 1H). 7.45 J=7.5Hz, lH), 7.64-7.70 (in, 2H), 7.93 (d, 1=7.5Hz, I 8.20-8.45 (in, J=3H). MS( ESI* m/z 476 Anal calcd for
C
27
H
2 sNOS0.67H,O: C, 66.50; H, 5.44; N, 2.87. Found: C, 66.56; H, 5.81; N, 2.49.
CH
3 0 CI
NH
&sq?NH~ 285 Example 355 (2-Methoxyphenyl) r2,3 -dichloro-4-( E-((4-(spiro-hydantoin-5-yl)-piperidin- I yl)'carbonyl)ethenyl)phenylj sulfide The title compound was prepared from Example 3 1 OC, using the p rocedures described in Example 340 and substituting methyl isonipecotate with piperadine-4spiro-S '-hydantoin, which was prepared according to a literature method (Wysong, C., et al, J Org. Chem. 1996, 7650). 1H NMvR (300 MHz, DMSO-d6) 8 1.65 (in, 2H-), 1.75 3.05 (mn, 1H), 3.50 (in, lH), 4,12 (in, 1H), 4.20 (mn, 1H), 6.56 (d, I 7. 10 J=8.0Hz. 1lH), 7.22 J=8.0 Hz, I 7.28 J=15.6 Hz, I H), 7.49 (dd, J=8.0, 1.7Hz, 1IH), 7.5 6 J=8.2Hz, IlH), 7.76 J=1I5.6Hz, I 7.84(d, J=8.6Hz, 1H), 8.58 IH), 10.73(s, IH). MS (ESIV) m/z 504
CH
3 0 C1 0 Example 356 (2-MethoxyphenDl [2.3-dichloro-4-( E-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-l1yl)carbonyl)ethenyl)phenyll sulfide The title compound was prepared from Example 31 OC by the procedures described in Example 340 and substituting methyl isonipecotate with .hydroxyethoxy)ethyl]piperazine. lH NMR (300 MHz, DMSO-d6) 53.10 2H), 3.50 (mn, 4H), 4.50 (in, 2H), 4.70 IH), 6.57 J=8.Hz, IH), 7.09 J=8.OHz, I 7.23 J=8.OHz, lH), 7 .26 J=1I5.5Hz, I 7.49 (dd, J=7 1.7Hz, I1H). 7.5 7 (t, J=8.2Hz, 1H), 7.78 J1l5.6Hz, I1-H), 7.80. J=7.8Hz, I1H). MS (ESI-) m/z 545 (M-
CH
3 0 CI 0 Example 357 (2-Methxyphenyl) 2,3-dichloro-4-( E-((4-ethylpiperazin- 1yl~carbonyl~ethenylDphenyll sulfide The title comp ound was prepared fromh Example 3 1 OC by the proced .ures described in Example 340 and substituting methyl isonipecotate with Iethylpiperazine. 1 H NMR (300 MHz, CDCI 3 6 1.09 J=7.lHz,.3H), 2.42 J=7.lIHz, 2H), 2.47 (in, 4H), 3.60.(in, 2H), .3.75 (in, MH), 3.82 3H), 6.56 (d, 1H), 6.74(d, J=15.3Hz, IH), 7.02 (in, 2H), 7.26 J=8.5Hz,'IH), 7.46 (in, 2H), 7.94 J=1I5.5Hz, I MS (ESE') m/z 451 0 Example 358 (2-Isopropylphenyj)[ 2,3-dich]6ro-4-( E-((4-(2-(2-hydroxyethoxy)etbyl)piperazin- 1 yl)carbonyl)ethenyl)phenyll sulfide The title compound was prepared from the cinnamide acid of Example 3 31, using the procedures described in Example 3 40 and substituting methyl isonipecotate with N-[2.-(2-hydroxyethoxy)ethyl]piperazine. IH NMR (300 MHz, DMSO-d6) 8 1. 18 6H), 3.0 (in, 3H), 3.30 (in, 2H), 3.50 (in, I OH), 3.80 (mn, 2H), 4.50 1t 1H), 6.45 1H), 7.30 1H), 7.35 (dd, 11H), 7.55 IH), 7.60 (in, 2H), 7.75 7.80 I MS (ESIE) nt 523 Example 359 (Benzodioxan-6y1)[2.3-bis(trifluoromethvl)-4-(E-((4-carboxvpiperidin- I yl)carbonyl~ethenyl)phenylsul fide Examplie 359A I -Methyl-2.3 -bis(trifluoromethvl)-7-oxabicvclof2.2.lIlhepta-2.5-diene Hexafluoro-2-butyne (2 1.0 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 sealed and heated for 15 hr. at 120 0 C. After cooling, the excess 2-methylfuran was rotoevaporated in vacuo at rt, to give crude title product (29 which was used directly.
Example 359B 4-Methyl-2,3-bis(trifluoromethyl)phenoI A mixture of Example 359A (12.0 g, 0.05 mol) and boron trfluoride-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, and evaporated under reduced pressure to afford 10.4g of the title compound.
Example 359C 4-r4-Bromobenzene sufonvloxy-2,3-bis(trifluoromethyl)]benzvlbromide 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 CH2C1 (150 ml). The solution was washed with water, brine and dried over MgSO 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 CC1 4 (100ml). The resulting mixture was refluxed for 13 hr. When the reaction was cooled, the white solid was filtered and washed with CC1 4 to afford the crude title compound. This crude product was used for next step without further purification.
Example 359D 4 -Hvdroxv-2.3-bis(trfluoromethvl)benzaldehvde The crude product of Example 359C was dissolved in 60 ml of DMSO and ml of CHC1 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 NaCI solution (200 ml) and extracted with ether (3XI 00 ml). The combined organic layer was washed with brine and dried over Na,S0 4 After evaporation of solvent, the product was purified by column chromatography, eluted with hexane:EtOAc 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')- r2,3-bis(tr-fluoromethyl)-4-(E-carboethe nyl)phenyllsulfide 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-6y1) [2,3-bis(trifluoromethyl)-4-(E-((4-carboxypiperidin-lIvl)carbonyl)ethenvl)phenyllsulfide The title conmpound was prepared from Example 359E by the procedures described in Example 330, giving a white solid. 'H NMR (CD 3 OD, 300MHz) 8 1.65(br s, 2H),l1.93 -2.04 (in, 2H), 2.57-2.65 (in, I 2.95-3.05 IH), 3.25 (in, I H), 4.12 (in, 1H), 4.28 (in, 4H), 4.41 (in, 111), 6.92-7.03 (mn, 4H), 7.25 J=9Hz, IH), 7.72 J=9Hz, I 7.72-7.81 (mn, IlH). MS (ESI) m/e 562 (M-4H) 4 Anal calcd for
C
25
H
21 N0 5 FS: C, 53.48; H, 3.77; N, 2.49. Found: C, 53.42; H, 3.69; N, 2.25.
290 I N OH 0 Example 360, (2-Methoxyphenyl) r2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-piperidin I -yl)carbonvl~ethenYl)phenyfl sulfide 0 0 0 Example 360A (2-MethoxYphenyl)[2,3-dichloro-4-(E-((4-(methylaminomethlcarboxylate)carbonvlp2iperidin- I -flcarbon-y )ethdnyl)pheftyl Isulfide The title compound was prepared by the procedure described in Example 363 using glycine methyl ester as the coupling substrate. HPLC (Supelco C-I 8 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 'H NMR (300 MHz, DMSO-d 6 8 1.46(m, 3H), 1.78(br d, 2H), 2.79(m, I 3.15(m, IH), 3.62(s, 3H), 3.80(s, 3H), 3.83(d, 2H),.4.20(m, IlH), 4.40(m, 1IH), 6.58(d, I.H), 7.09(t,.1H), 7.22(d, IH), 7.25(dd, 1H), 7.48(d, 11-I), 7.56(t, IH), 7.72(d, IH), 7.81(d, I 8.28(t, I Anal calcd for C 25
H
26
C
2
N
2 0,S 1.3 H20: C, 53.54; H, 5. 14; N, 4.99.
Found: C, 53.49; H, 4.88; N, 4.75.
N H0 0 Example 360B (2-Methokyphenyl) [2,3-dichloro-4-(E-((4-(carboxymethylamino)carbonyl-piperidin- 1 -yI)carbonyl)ethenYl~phenyll sulfide The title compound was hydrolyzed as described in Example 340H. HPLG (Supelco C-i 18 column, wateracetonitrile 90:0- 0:90, 30 minute elution, flow rate 0.8 mL/min) rt 26.14 min. 'H NMR (300 MHz, DMSO-d 6 )5 L146 (in, 2H), 1.75 (in, 2H), 2.73 (in, I 3.12 1 3.70 (in, 2H), 3.79 3 4.02 (in, I 4.20 (in, I 4.4 1 (in, I1H), 6.65 I 7.09 (dt, I1H), 7.22 I 7.25 (dd, 7.48 (dd, I 7.5,8 (in, 1 0 1IH), 7.72 I 7.82 IlH), 8.11 (in, I MS (APCI) mle 523 Example 361 (2-Methoxyphenyl) [2.3 -bis(trifluoroinethvl )-4-(E-((4-carboxvmethylpiperazin-l1-yi) carbonyl~ethenyl~phenyll sulfide The title c ompound was prepared according to the procedures of Example 22, employing the compound of Example 359D as starting material, to give a white solid.
'H NMR (CD 3 OD, 300 MHz) 8 3.07-3.12 (in, 4H), 3.48 2H), 3.74 3H), 3.89 (br s, 4H), 6.99-7.18 (in, 4H), 7.53 J=9Hz, 2H), 7.72 J=9Hz,IH), 7.78-7.88 (in, I MS (ESI) m/z 549 Anal calcd for C,' 6
H
26
F
6 N0 4 S0.9HAc: C, 51.43, H, 4.28, N,94.65. Found: C,.51.48, H, 4.12, N,4.45.
292 Example 362 (2-Methoxyphenyl) [2,3-bis(trifluoromethyl)-4-(E-((4-N-(2-hydroxyethyl)piperazin- 1yl)carbonyl)ethenyl)phenyllsulfide 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. 'H NMR (CDCI 3 300. MHz) 8 2.68 (br s, 6H), 3.71 (br s, 3-.80 (br s, 5H), 6.55 (d, J= I5Hz, I1H), 6.93-7.02 (in, 2H), 7.10 J=9Hz, I 7.35 J=9Hz, I 7.41-7.50 (mn, 2H), 7.82 (qq, J= 5Hz, I MS (ESI) mz.535 Anal calcd for
C
24
H
2 4
F
6 N4 2 0 3 S-TCl: C,50.49; H, 4.41; N, 4.91. Found: C, 50.72; H, 4.70; N, 4.5 Example 363 (I -Methylindol-5-Yl) r2,3-dichloro-4-( E-((4-(carbo-2,3dihydroxypropylamino)pirperidin- I .y)carbonyl)ethenyl)phenylj sulfide To a solution of Example 340H (1 00mg. 0.2 mmol) and 3-amino- 1,2propanediol (37.4 mg, 0.41 mmol) in DMF (3 mL) was added EDC (78 mg, 0.41 inmol), HOBt (55 mg, 0.41 mimol) and triethylamine (0.05 7 imL, 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 (92 mng, 1 H NMR (3 00 MHz, DMSO-d6) 8 1.44 (in, I1H), 1. 72 (in, I 2.41 (in, INH), 293 2.70 3.00 3.20 (in, 2H), 3.27 (in, 2H), 3.50 (in, 211), 3.90 311), .4.18 (br d, I 4.40 (br d, 111), 4.50(t, 1H), 4.77 114), 6.40 1H), 6.58 111), 7.19 I1H), 7.3 5 I1H), 7.5 O(d, I 7.66 11H), 7.70 (i,2H),.7.80 I1H), 7.88 11H). MS (ESI-) m/lz 562 Anal. caled for C27H29C1 2
N
3 S04-0.25H20: 57.19; H, 5.24; N, 7.41. Found: C, 57.07; H, 5.22; N, 7.13.
CH
3 0 CI 0 N, OH 0 Example 364 (2-Methoxyphenvi [2.3-dichloro-4-(E-(4-(2,3 -dihvdroxvvronionyl)piperazin- 1- Yl)carbonYl)ethenYl )phenYil sulfide
*CH
3 0 CI CI KNH Example 364A (2-Methoxylphenyl )I 2,3-dichloro-4-( E-((pinperazin-1I-yI)carbonyl)ethenyl)phenylI sulfide The title compound was prepared by the procedures described in Example 340G substituting methyl isonipecotate with piperazine. MS (DCI/NH3) mle 423 294
CH
3 0 C1 o6s NQ OH 0 Example 364B3 (2--Methoxyphenl) [2 3-dichloro-4-( E-( 4 /A '-Ihyr rninJ )piverin. I yl)carbonvl)ethenvl)nhenvlI sulfide Thie title compound was prepared by the procedures described in Example 340, substituting methyl isonipecotate wkith Example 3,64A and substituting Example 340G with DL-glyceric acid.Ca salt. IN NMR (300 MHz, DMSO-d 6 5 3.2-38 (i,12H), 4.38 IH), 6.58 IH), 7.10 1H), 7.27 IH), 7.28 IH), 7.50 IH), 7.60 It IH), 7.79 I 7.83 I MS (ESI-) m/z 5.11
CH
3 0 CI 0 OH SNQ, OHO0 0 Example 365 (2-Methoxyphenyl) r23-dichloro-4-( E(4-(2.3-dihydroxy-3 carboxvpropionyl)piperazin. I -yl)carbonyl)ethenyJ)phenyll sulfide The title compound was prepared by the procedures described in Example 340, substituting methyl isonipecotate with Example 364A and substituting Example. 340G with meso-tartaric acid. 1 H NMR (300 MHz, CDCI3) 8 3.70 (in, 8H), 4.33 (br s, IN), 4.72 (br s, 1H), 6.58 1H), 6.77 IH), 7.03 (in, 2H), 7.25(d, IH), 7.50 IH), 7.52 I 8.00 I MS (ESI) m/lz 55.5 C1 0 N H 0H I 0 Example 366 (0 -Methylindol-5-yl) [2,3-dichloro-4-(E-((4-(carboxymethlaio)carboflylpiperidin- 1 -y)carbonyl~ethenyl)]2henvlI sulfide Th e title compound was prepared by the procedures described in Example. 363 substituting 3-amino-I ,2-propanediol with glycijne methyl ester hydrochloride.
followed by hydrolysis. 'H NMR (300 MHz, DMSO-d6) 8 1.42 (in, 2H), 1.75. (in, 2H), 2.4 5 (in, I 2.7 8 (in, IlH), 3. 10 (in, I 3.72 2H), 3.90 3 4.18 (br d, IH), 4.40 (br d, lH), 6.42 IH), 6.57 1H), 7.18 7.32 IH), 7.50 (d, I1-H), 7.65 7.67 (di- IH), 7.70 (in IlH), 7.8 8 IlH), .8.18 I MS (ESI) in/z 546, Anal. calcd for C 26
H
25
N
3 C1 2 S0 4 C, 57.15; H, 4.61; N, 7.69.
Found: C, 57.17; H, 4.64; N, 7.39.
C1 S SOH I0 Example 367 (1 -Methylindol-5-Yl) [2.3 -dichloro-4-(E-((4-sulfopiperidin- 1yl)carbonyl)ethenvl)phenyll sulfide 296 The title compound was prepared from Example 340F, by the procedures described in Example 340G, substituting methyl isonipecotate. with piperadine-4sulfonic acid: H NMR (300, MHz, DMSO-d6) 8 1.40 (in, 2H), 1.90 (in, 2H), 3.03 (in, 1H), 4.10 (in, 3H), 4.42 (br d, 6.40 J=8.8Hz, IH), 6.53 J=3.1IHz, IH), 7.15 J=15.3Hz, IH), 7.33 (dd, J=8.5, 1.7Hz, IH), 7.48 J=3.lHZ, 1H), 7.65.(d, I 7.67 J1I5.2Hz, IH), 7.174 3.=8..8Hz, 1H), 7.87 J=1.5Hz).. MS (ES1) m/z 525 Anal.calcd for C23H22N2C1 2
S
2 O4-0. TFA: C, 47.91; H, 3.73; N, 4.54. Found: C, 47.71; H, 3.84; N, 4.73..
C1 S I~
N-
0 Example 368 (1 -Methylindol-5-vi) r2.3-dichloro-4-(E-(4-inethylhomopiperazin-- Ylcarbonyl)ethenYl~jjhenvlj sulfide The title compound was prepared by th e procedures described in Example 340G substituting methyl isonipecotate with N-methyl hoinopiperazine. 'H NMR.
(300. MHz, DMSO-d6) 6 2.06 2H), 2.81 (mn, 2H), 3.17 (ri, 2H), 3.55 (in 3.70 3H), 3.86 3H), 4.05 (in, 1H), 6.42 (dd, J=8.4,3.3Hz, IH), 6.54 J3.OHz, IH), 7.08 (dd, 3=15.4,7.5Hz, IH), 7.35 (dd, J=8.8,2.OHz, 7.49 3=-:3.0Hz, IH), 7.65 3=8.5Hz, I 7.73 3=8.8Hz, I 7.8,0 31I5.2Hz, I 7.88 J=2.OHz, IH). MS (ESI-) m/z 474 Anal. calcd for C2 6
H
2 ANC12SF7 3 0 3 *0.75 TFA: C, 49.0 1; FH, 4.00; N, 6.23. Found: C, 48.7 1; H, 4.09; N, 6.13.
C1 0 0 Example 369 [2,3-dichloro-4-(E-(4-tetrohydrofuroylpiperazin- 1vI)carbonvl)ethenl~hhenlj sulfide The title compound was prepared by the procedures described in Example 340G substituting methyl isonipeco tate with I -tetrahydrofuroylpiper-azine.- I MR (300 MHz, DMSO-d6) 8 1.80 (in, 214), 2.00 (in, 2H4), 3.50 (in, 8H), 3.75 (in,*2H),.3.88 3H), 4.68 114), 6.42 IH), 6.57 IH), 7.19 IH), 7.32 lH), 7.48 (d, 1IH), 7.65 I 7.70 I 7.75 I 7.87 I MS,(ESI*) m/~z 544 Anal calcd for C 27
H
27
N
3 C1,S0 3 C, 59.56; H, 4.99;.N, 7.71. Found: C, 59.40; H, 4.94;.N, 7.61.
0 cr S 0 Example 370 (Benz odiokan-6-y!) r2-(benzodioxan-6-thioxy)-4-(E-((4morpholino)carbonyl)ehenyl~phenylI sulfide 298 Example 370A (E)-Morpholino 2,4-difluorocinnamide The title compound was processed as reported in Example I C'substituting morpholine (1.04 mL, 11.9 rnmol) for the amine and trans-2,4-difluorocinnaniic acid.
(1.00 g, 5.4 inmol) for the carboxylic acid. The title compound was obtained as an off-white foam (1.4 g, 100%). 'HNMR (DMS0-dl, 300 MHz) d 8.04.(dd, J=15.26,.
8.82 Hz, IH), 7.53*(d, J=14.91 Hz, IH), 7.38-7.30 (in, IH), 3.61-3.48 (mn, 8H). M.S (APCI) m/z 254 Example 370B M 6r-holinyl-(E)-2,4-bis( I,4-benzodioxane-6-mercaptan)cinniamic amide Example 370A (233 mg, 1.00 minol) was combined with cesium carbonate (652 mng, 2.00 inmol), 1,4-benzodioxane-6-thiol (370 mg, 2.20 mmol), and DMF ML). The mixture Was processed as reported in Example I A to provide the title compound (220 mg, 40%) as a White foam. 'H NMAR (DmsO-d 6 300 MHz) 8 7.83(d J= 15.20. Hz, I 7.80 (d2- J=8.20 Hz, I1H)) 7.17 J= 15.3 Hz, IH), 7.02 (dd, IH), 6.87-6.75-(in, 6H), 6.48 IH), 4.33-4.25 (in, 8H), 3.6 1-3.48 8H).* MS (APCI) m/lz 550
CH
3 0 C1 0 O 0rsi7 NH52 0 Example 371 299 (2-Methoxyphenyl) [2,3-dichloro-4-(E-((4-amino-4-carboxypinperidin- I1- YlDcarbonyvbethenYl~heyl1 sulfide To a suspension of Example 3 55 (700 mg, 1.4 mmol) in DME (10 mL) was added a solution of (BOC) 2 0 (1.51 g, 6.9 mmol) in DME (5 mL),'triethylamine (0.23 mnL, 1.7 mimol) and DMAP (9 mg, 0.07 mmol). The reaction mixture was stirred at room temper ature overnight. Additional triethylarnine (0.23 mL) and DMAP (30 mg).
were added, and the mixture was heated at 60 *C for 6 hours. After aqueous work up, the crude product was suspended in DME (5 rnL) and water (5 mL) containing 200 mug of NaOH.. The suspension was stirred for 5 hours at room temperature, and separated by HPLC to give, the title compound (300 mg, IHNMR (300 MHz, .DMSO-d6)8~1.78 (in,2H), 2.10 (in,2H), 3.60 (in,2H), 3.80 3H), 3.86 6.58 (di, IH), 7.10 1H), 7.25 1H), 7.28 (di, IH), 7.50 IH), 7.58 1H), 7.77 (di, 11-1). 7.80 I 8.50 (br s, 2H). MS (ESIE) m/z 481 Anal calcci for C22H22N2C1,S0 4 *0.7S C, 47.34; H, 4.06; N, 4.60. Found: C, 47.3 1; H,4.05; 4.43..
N
0 c4 N N 0 Example 372 (2-Methoxyphenylfl2.3-dichloro-4-((4-fijroylpjerazin I -yl)carbonyl)ethenyl)phenylI sulfide To a solution of Example 364A (100mg, 0.24 mmol) and 2-furfural (30mg, 0.24 nimol) in dichloroethane (2 mL) was added NaBH(OAC) 3 (142 mg, 0.67 mmol) under nitrogen atmosphere.' The mixture was stirred for 16 hours at room temperature.
Dichioromethane (20 mL) was added and the mixture was washed with 5% Na .HCO 3 then with brine, and the organic phase was separated and concentrated. The residual solid was chromatographed by flash chromatography. MeOI3/CH 2
CL
2 and desired fractions were combined, concentrated and dried to afford the. title compound as an off-white solid (84 mg, HPLC (Supelco. C-i 8 column, water: acetonitril e 100:0- 0:100, 15 minute elution, flow rate 1.5 mL/rnin) rt 11.90 min. 'H NMR (300.
MHz, DMSO-d 6 5 2.39 (in, 4H), 3.52 2H), 3.55 (in, 2H), 3.63 (mn, 2H), 3.79 (s, 3H), 6.29 111), 6.40 (mn, 1IH), 6.5 7 I1H), 7.08 (dt, I1H), 7.21 I 7.23 (dd, I 7.4 8 (dd, I 7.5 7 (mn, 2H), 7.72 I 7.8 0 I MS (ESI) nile 503 C1 0 CI S 3
H
N' N
H
I0 Example 373 (1 -Methylindol-5-vl') [2.3 -dichloro-4-( E-(4-(carbo-3 -sulfonropylamino)piperadin- I- Yl)carbohyl)ethenlhphenvll sulfide The title compound was prepared from Example 340H by the procedures described in Example 363 substituting 3 -amino-I ,2-propanediol with 3-"amino-Ipropanesulfonic acid. 1 NMR (3 00 MHz, DMSO-d6) 5 1.40 (in, 2H), 1.70 (in, 4H), 2.38 (in, 11-1),2.42(in, 2H),2.70 (in, I 3.05 3.86(s, 3H),4.18(br d, H), ,4.40 (br d, IH), 6.40 IH), 6.55 1H), 7.20 IH), 7.35 1H), 7.50 1-H), 7.65( I 7.70 7.77 I 7.87 I1H). MS (ESI-) m/lz 610 Anal calcd for C 27
H,
9
N
3 Cl 2
S
2
O
5 -1.5 TFA: C, 46.10; H,3.93; N, 5.38. Found: C, 46.52; H, 4.03; N, 5.66.
C1 0O Example 374 (2-Methoxyphenyl)[ 2.3 -dichloro-4-( E.-(4-acetylAmino-4-carboxypiperidinI Ivlcarbonvl)ethenyl)phenyll sulfide To a suspension of Example 371 (90 mg, 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-I18, CH 3
CN/H
2 0).to give example 374 (56 mng, 57%).
IH NMR (300 MHz, DMSO-d6) 8 1.78 (in, 2H), 1.82 3H), 1.98 (in, 2H), 3.05 (t, IH), 3.38 (tlH), 3.80 4.00 (br d, IH), 4.12 (br d, lH), 6.58 IH), 7.08 (t, I 7.23 I 7.25 I1H), 7.50 I 7.5 8 I 7.78 IJH), 7.80 I H), 8.18 1H). MS (ES1+) rn/z 523 Anal calcd for C 2
,H
2
,N
2
CI
2 SO5-0.35TFA: C, 52.80; H, 4.40; N, 5.05. Found: C, 52.74; H, 4.42; N, 5.11.
Example 375 (2-Methoxyphenyl) 2 ,.-bis(trifluoromethyl)-4-(E-((4-carboxypieridin-.1 yl)carbonyl)ethenvl)p2henyllsulfide The title compound was prepared by the, procedures described inExample 3 52, employing the compound of Example 359D to give a white solid. 'H NMR(CD OD, 300 MI-z) 8 1.65 (br s, 2H), 1.94-2.03 (in, 2H), 2.57-2.67 (in, IlH), 2.95-3.05. (i, I -3.23-3.32 (mn, I1H), 3.75 3H), 4.12 (br s, I1H), 4.40. (hr s, I1H), 7.00 J=I I1H), 7.03-7.20 (in, 3H), 7.47-7.53 (mn, 2H), 7.68 J=9Hz, I 7.77 (qq, 1IH). MS (ESI) m/1z 534 Anal calcd for C 4 H 2
,NF
6 0 4 S: CI 54.03; H, 3.97; N, 2.63. Found:, C, 54.11; H, 4.04; N, 1. 76.
Example 376 (2-Methoxyphenyl) 5- 8 -(E-((4-(aminocarbonvl)piperidin- I yl)carbonyl)etbenyl)puinolinyll sulfide Example 376A 5-Chloro-8-(trifluoroffethanesulfonyloxy)guinoline 5-Chloro-8-hydroxyquinoline was treated as described in Example 340E to provide the title compound. 'H NMR (DMSO-d 6 300 MHz) 5 7.59 (7.5Hz, I 7.65-7.69 8.63 (dd, J,=9Hz, J,=1.5Hz, IlH), 9.21 (dd, J,=6Hz,JI 1.5Hz, IH). MS (APCI-NH3) mn/e 312, 3.14 303 Example 376B 5-Chloro-8-[E-(metboxycarboiy)ethenyllciuinolineI 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, 'H NMR (DMSO-d 6 300 MHz) 8 3.78 3H), 6.98 J=16.SHz, IH), 7.78-7.83 (in, 1H), 7.88 J=9Hz, IH), 8.32 (d, J=9Hz, IH), 8.65 (dd, J,=9Hz, J 2 =l1.5Hz, IH), 8.85 J=16.5 Hz, 1H), 9.12 (dd, J,=1.5Hz, 1H). MS (APCI-NI-3) mle 248, 250 Example 376C (2-Methoxyphenyl) 5-r8-(E-(methoxycarbonyl)ethenl)ciuinolinyllsulfide The method of Example 340F was used, substituting the produc from Example 376B for Example 340OE. Thus, Example 376B (2.19 g, 8.84 mmol) was conver Ited to the title compound '(1.07 g, 'H NMR (DMSO-d 6 300 MHz) 8 3.83 3H), 6.80 J=1I6.5Hz, I1H), 6.86-6.99 2H), 7.16 J=6Hz, I1H), 7.3 3- 7.38, (in, IH), 7.44 J=7.5Hz, IH), 7.67-7.72 8.22 J=7.5Hz, 1H), 8.63 (dd, J,==9Hz, J,=1.5Hz, IH), 8.82 J=16.5Hz, 1H), 9.07 (dd, J,=6Hz, 12.48 IH). MS (APCI-NH3) nile 3.38 Example 376C (2-Methoxyphenvi) 5-[8-(E-((4-(aminocarbonylhpiperidin- 1yl)carbonyl)ethenyl)guinol inyll sulfide The method of Example 340G was used, substituting the product from Example 376B for Example 340F, and substituting 4 -piperidinecarboxamide for methyl isonipecotate. 'H NMR (DMSO-d 6 300 MHz) 8 1.71-2.82 (mn, 2H), .2.96-2.03 (in, 2H),.2.44-2.52 (in, I1H), 2.81-2.94 and 3.16-3.30 (mn, 11H), 3.37-3.54 (in, 2H), 3.88 (s, 3H), 4.17-4.34 and 4.60-4.80 (in, I 5.72 2H1), 6.82 4.5Hz,I1H), 6.90 (dd,
J
1 =4.5Hz, J 2 =0.75Hz, I1H), 6.93 6Hz, I 7.23 -7.28 (in, I 7.40 J--9Hz, I H), 7.47-7.50 (mn, I 7.51 (d,,J=6Hz, I H),.7.82 J=4.5 Hz, 11-1), 8.5 7 J=9,Hz, I1-H), 8.74 (dd, J,=4.5H 2
J
2 =0.75Hz, 111), 9.00 (in, lH).
Example 377 (2-Methoxyphenyl) r 2 -trifluoromethyl-4-(E.((4-carboxvpipeid in- I yJ)carbonvl)ethenyl)p~henyllsulfide O~aS CF~ 0.
Example 377A 2 -Trifluoromethvl-4-(thiobenzodioxan.6y)cinramic acid A solution, of commercially available 4 -fluoro-2-(trifluoroinethyl)cinnainic acid. (5 g, 21.4 inmol) in ethyl acetate (200 inL) under nitrogen at ambient temperature was treated with a solution of diazoinethane 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 3 brine, dried (MgSO 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 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 NaQH, distilled water, brine, dried (MgSO 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 (21 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 H 2 SO4, extracted with diethyl ether, washed with brine, dried (MgSO 4 and concentrated to give 2.7 g (7.1 mmol) of the title compound as an off-white powder 'H NMR (300 MHz, d6-DMSO) 7.97 1H), 7.72 (dq, 1H), 7.47 1H), 7.31 (dd, 1H), 7.05 3H), 6.58 IH), 4.3 4H). MS (APCI-NH 3 nm/e 383 (M+H) 400 (M+NH 4 (o CO2H 0 CO 2
H
Example 377B 306 (Benzodioxan-6-l)[3trifluoromethv-4(E((2-caboxvpipeidin- 1yl)carbonvl)ethenyl)phenyll sulfide 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 y ellow foam Analytical HPLC: 4.6X250 mm C1 8 column, 0.8 mL/min, 254 nmn, CH 3
CN:H
2 0 with 0.1 TFA, 0: 100 (0 mmn),-ramp to 90: 10 (0-10 min), 90: (10-1.8 min), ramp to 0:100 (18-20 min), rt 11.29 mi (98..2 area%). 'H NMR (300 MHz, d6-DMSO) 8 8.07 1H), 7.65 (dq, IH), 7.38 (in, 3H), 7.03 (in, 3H), 5.15 (in, 1 4.4 (mn, 11-1), 4.29 (in, 4H), 4.1 (mn, IlH), 3.2 (in, I 2.2 (in, I 1. 68 2H-), 1.3 (in, 2H). MS (APCI-NH 3 m/e 494 511 (M+NH 4
CI
0 0 Example 378 (1 -Methylindol-5-yi) r23-dichloro--4-( S,4S)-5-tert-butvloxycarbonyl-2 diazabycyclo(2,2 I )heptan-2-yl)carbonvl)ethenvl)ph enyl1 sulfide The title compound was prepared by the procedures described in Example 340 substituting methyl isonipecotate with t-butyl (I diazabicyclo(2,2, I)heptane-2-carboxylate. IHNMR (300 MHz, DMSO-d6)851.40 (s, 9H), 1.82(in, 2H), 3.17 (in, 3.30.(in,2H), 3.58 IH), 3.82 3H), 4.05.(in, I 4.40 (in, IlH), 4.75 (br s, IlH), 4.92 (br s, I 6.42 (dd, I 6.5 8 I 6.75 IH), 7.05 1H), 7.351(d, 7.50 lH), 7.65 IH), 7.68 1H), 7.78 (t, 7.77 I MS (ESI') m/z 558 Anal calcd for C 2 8
H
29
N
3 C1 2
SO
3
C,
60.21; H, 5.23; N, 7.52. Found: C, 60.23; H, 5.36; N, 7.41.
C1 0 Example 379 (0 -Methylindol-5-yi) 23-dichloro-4-( I S.4S)-2,5-diazabycyclo(2.2 I )heptan- 2-ylcarbonyl)ethenyl)-2,3-dichlorophenylI sulfide To a solution of Example 378 (820 mg, 1.47 mmol) in CH 2
CI
2 (20 mL) was added trifluoroacetic acid (2mL) at.0 0 C. The yellow solution was stirred at the same temperature for 2 hours. More CH 2
CI
2 (50 mL) was added and the solution was poured into water (100 mL) containing NaHCO 3 (4.5 The insoluble material was collected by filtration, washed with water and methanol. The CH 2 CI, solution was concentrated, and the residual solid was filtered, washed with water, methanol and CH,C1 2 The combined solid was dried to give the title compound (650 mng, IH NMR (300 MHz, DMSO-d6) 8 1.70 (mn, 2H), 2.90 (in, I 3.50 (in, 4H), 3.88 (s, 3H), 4.85 (in, I1H)2 6.45 I 6.60 (dd, I1H), 6.77 I 7.05 (dd, IlH), 7.25 (s, IH), 7.35 (dd, IH), 7.65 1H), 7.70 11), 7.80 lH). MIS (ESI-) in/z 4S8(M+H)+.
Cl N^ 'OH S N2 OH 0 0 Example 380 (1 -Methylindol-5-vl) [2.3-dichloro-4-( E-(4-hvdroxv-3-carboxvpiperadin-1ylcarbonvl)ethenv])phenvl] sulfide 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 EtOAc in hexane) to give a white solid (220 mg).
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, (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). 1 H NMR (300 MHz DMSO-d6) 6 1.60 (m, 2H), 3.00 1H), 3.40 1H), 3.85(1H, 4.05 1H), 4.20 1H), 4.35 1H), 5.00 1H), 6.42 1H), 6.58 1H), 7.20 (dd, 1H), 7.35 1H), 7.50 1H), 7.6-7.8 3H), 7.90 1H). MS (ESI') m/z 505 (M+H) Anal calcd for
C
2
,H,
2 N,C1,SO 4 C, 57.03; H, 4.38; N, 5.54. Found: C, 56.77; H, 4.17; N, 5.34.
309
C,
0 Example 381 (I -Methylindol-5-vl) 2.3-dichloro-4-( E-(S-oxothiomompholin- I1vlcarbonYl)ethenyl)phenjlj sulfide The title compound was prepared by the procedures described in Examrple 340 substituting methyl isonipecotate with thiomorpholine S-oxide. 1 H NMR (3 00 MHz,
CDCI
3 2.70 (in, 2H), 2.85 (in, 2H), 3.185 3H), -3.90 (in, 2H), 4.20 (in, I 4.60 (in, 6.45 lH), 6.55 1H), 6.70 lH), 7.18 lH), 7.20 (dIlH), 7.38 1 7.41 1 7.77 I 7.98 I MS (ESY) m/lz 479
CH
3 0 C1
HO
3 Example 382 (2-Methoxyphenyl) r2.3-dichloro-4-( sulfophenylamino)carbonyl)ethenyl)phenylI sulfide The title compound was prepared by the procedures described in Example I C substituting Example I B with (2-methoxy) [2,3-dichloro-4-( E-(2carboxyethenyl)phenyl] sulfide and substituting 6-amino-I1 -hexanol with sulfanilic acid. IH NMR (300 MHz- DMSO-d6) 8 3.82 3H), 6.65 lH), 6.82 lH), 7.12 310 (t 7.25 I 7.5-7.7 (in, 7H), 7.85 IRH), 10.40 I MS (ESI-) m/z 510 Anal calcd for C 22
H,
7
C
2
NS
2 0 5 .0.65TFA: C, 50.80; H, 3.25; N, 2.55.
Found: C, 50.75; H, 3.43; N, 2.65.
CH
3 0 C1
H
CO H Example 383 (2-Methoxyphenyl) [2.3-dichloro-4-( carboxyphenylamino)carbohvl)ethenyl)phenylI sulfide The title compound was prepared by the procedures described in Example I C substituting Example I B with (2-mrethoxy) [2,3-dichloro-4- E-(2carboxyethenyl)phenyl] sulfide and substituting 6-amino- I -hexanol with 4aminobenzoic acid. 1 HNMR (300 MHz, DMSO-d6) 5 3.82 3 6.65 I H), 6.82.(d, 111), 7.10.(t, IH), 7.30 1H), 7.60 (in, 3H),,7.82 3H), 7.90 IH), 7.92 1H), 10.65 111), 12.75 IH). MS (ESI") rnz 4.74 Example 384.
r3-(4-MorpholinomphenVll r2.3 -dich]oro-4-(E-[(4-carboxvpiperidin- I- Yl)carbonylletherivD1nhenyll sulfide Example 384A (3-Bromophenyl) r2.3-dichloto-4-(E-[methoxyca rbonylletherivhenll sulfide 311
CI
Br ySN 0 Example 384A To a solution of the resultant compound from Example 340E (12.0 g, 31.7 mmol) in N-methylpiperidinone (63 mL) at 0 'C (under dry N 2 was added 3-.
bromothiophenol (4.0 mL, 7.3 g, 3 8..8 mmol) and a solution of lithiuim tert-butoxide (3.1 g, 38.8 mmol), and the resulting solution was stirred for 3 hr at 0 The reaction was diluted with.500 mL EtOAc and extracted sequentially with 100 ML water, 3 x 60 mL of I N aq. NaOH, then 2 x 100 mL brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to produce the crude title.
compound (9.2 'HNMR (DMSO-d,, 300 MHz) 5 3.75 6.67 11-1), 6.83 J-9Hz, I 7.46-7.5 9 (in, 2H), 7.72-7.76 (in, 2H), 7.80 J=2.5Hz, I H), 7.85 J=9Hz, IH), 7.88 J=l5Hz, 1H). MS (APCI) m/e 419
CI
0.
Example 384B [3-(4-Morpholino)phenflI [2,3-dichloro-4.(E-methoxycarbonyllethnyl)phen~l1 sulfide The procedure of Old, D. Wolfe, JI Buchwald, S. L. J1 Am. Chem.. Soc.
1998, 120,.9722-9723, was. adapted. To a stirred solution of Example 384A (200 mg, 312 0.479 mmol) in ethylene glycol dimethyl ether (1 mL) with I -(N,N-dimethylami .no)- I '-(dicyclohexylphophino)biphenyl (14 mg,: 7.5 mol%), Pd,(dba) 3 (II mg, 2.5 mol%), and morpholine (0.05 ml, 0.5 74 mrnol) was added powdered K 3 P0 4 (142 mg, 0.67 mmol). The reaction mixture was bubbled with N 2 for 5 minutes and heated at 90 PC in sealed tube for 18 hours.. This was allowed to cool to ambient temperature, -diluted.
with ethyl acetate (5 mL) and washed with brine.(2x3 mL). The dried (Na 2
SO
4 organic layer was evaporated under reduced pressure to obtain the crude product (260 mg). The title compound (80 mg, 39%) was isolated by flash chromatography. on silica gel eluting with 7.5 %acetone hexane., 'H NMR (DMSO-d 6 300 MHz) 5 3.04 3.07 (in, 2H4), 3.13-3.14 (in, 2H), 3.69-3.78, in, 6.60-6.70 (in, 2H), 6. 96-7.01 (in, IN) 7.11-7.21 in, 2H), 7.36-7.44 (in, INH), 7.78-7-94 MS (ESI) m/e 424, 426 0 C1 (D.N
S,~C
SOH
0 Examle 384C [3-(4-Momjholin6)p~henvl 1 r23-dichloro-4-(E-rcarboxvlethernvl)phenylI s .ulfide The, title compound (42 ing, 55%) was prepared by treatment of Example 384B (80 mng, 0.189 iniol)v with LiOH (27 ing, 0.566 ininl) as described for Example 340H. 'H NMR (DMSO-d 6 300 MHz) 8 3.04-3.08 (in, 2H), 3.13-3.19 3.70-3.78 (in, 4H), 6.53 J=I5Hz,.lH), 6.55 J=15.75Hz, 1H), 6.67 (d, J=8.25Hz, IH), 7.10-7.20 (in, 2H), 7.77-7.91 (in, 3H). MS (ESI) ml/e 410, 412 0ThCI 0 030 -Example 384D [3-(-Morrpho66n)phenyll [2,3 -dichloro-4-(E-[(4-ethoxvcarbonvlpiperidin-I yl)carbonyllethenyl)phenyll sulfide To stirred a solution of Example 384C (40 mg, 0.098 minol) in N,N-* dimethylforinaiide (1 rnL) containing HOBt-H 2 O (23 mg, 0.146 inmol), N4methylmorpholine (0.032 mL, 0.293 mmol) and ethyl isonipecotate (0.018 inL, 0. 117 minol) was added EDCI (28 mg, 0. 146 mmol) at 0 'C and stirred at ambient temperature for 12 hours. The reaction mixture was diluted with ethyl acetate mL), washed. with brine (2x6 inL), dried (Na,S0 4 and evaporated to dryness under reduced pressure. The title compound (40 mng, 78%) was obtained by flash chromatography on silica gel+ eluting with 20 %acetone hexane.. 'H NMR (DMSO-d 6 500 MHz) 8 1. 18 (mn, 3H), 1.40-1.53 (mn, 2H), 1.82-1.93 (mn, 2H4), 2.60-2.68 (in, I H), 2.82-2.91,(2H-), 3.05 J=5Hz, 2H), 3.15 J=5Hz,+ 2H), 3.73 J=5Hz, 2H), 3.78 (t, 2H), 4.02-4.10 (in, 2H), 4.12-4.35. (mn, 2H), 6.72 J=IOHz, I1H), 6.97"(in, IH), 7.10-7.27 (mn, 2H), 7.38 (in, IH), 7.73-7.80 (in, IH), 7.85 J=8.75 Hz, 111), .7.96 J-lOHz, H).
314 O' CI 0
SO
Example 384E [3-(4-Morholino)phenll [2,3-dichloro-4-(E-r(4-carboxvpiperidin-1 vl)carbonvylethenyl)phenyll sulfide Using the procedure of Example 340H, Example 384D is hydrolyzed to the title compound.
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-!, as described below: ICAM-I LFA-1 Biochemical Interaction Assay In the biochemical assay, 100 pL of anti-LFA-1 antibody (ICOS Corporation) at a concentration of 5 pg/ml in Dulbecco's phosphate-buffered saline (D-PBS) is used to coat wells of a 96-well microtiter plate overnight at 4°C. The wells are then washed twice with wash buffer (D-PBS w/o Ca" or Mg 0.05% Tween 20) and blocked by addition of 200 pL of D-PBS, 5% fish skin gelatin. Recombinant LFA-1 (100 pL of 0.7 pg/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-i/LFA-1 antagonists, prepared as 10 mM stock solutions in dimethyl sulfoxide (DMSO), are diluted in D-PBS, 2mM MgCI 2 1% fish skin gelatin and 50 pL of each dilution added to duplicate wells. This is followed by addition of 50 pL of 0.8 .g/ml biotinylated recombinant ICAM-I/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 pL 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 pL 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: S average OD w/ compound minus background average OD w/o compound minus background where "background" refers to wells that are not coated with anti-LFA-1 antibody.
316 Compounds of the present invention exhibit inhibitory activity in the above assay as follows: Compound inhibition of Example 4tM 1 2 73 3 4 72 73 6 7 87 8 74 9 93 79 11 87 12 13 79 14 82 88 16 86 17 84 317 18. 86 19 93 82 21 22 23 24 .82 26 94 27 94 28 87 29 84 93 31 92 32 92 33 9 34 9 8 36 37 91 38 91 39 86 41 83 42 56 43 82 44 78 88.
46. 87 47 82 48 89 49 93 94 51 84 52 86 53 87 54 86 82 56 83 57 0'.
319 58 59 92 61 88 62 92 63 82 64 81 86 66 82 67 84 68 92 69 92 92 71 72 88 73 89 74 92 91 76 92 77 92 320 78 92 79 81 92 82 86 83 92 84 92 86 92 87 88 86 89 91 92 82 93 82 94 88 96 97 94 98 99 100 92 101 86 102 92 103 93 104 92 105 88 106 86 107 96 108 29 109 110 94 111 84 112 93 113 88 114 89 115 86 116 92 117 94 118 94 119 120 94 121 94 122 94 123 94 124 91 125 94 126 127 89 128 84 129 92 130 91 131 84 132 81 133 83 134 94 135 136 94 137 94 S138 88 139 92 140 94 141 93 142 94 143 92 144 92 145 92 146 81 147 94 148 92 149 93 150 94 151 92 152 94 153 92 154 94 155 93 156 94 157 158 92 159 160 94 161 94 162 163 .94 164 92 165 92 166 167 94 .168 93 169 92 170 93 171 94 172 94 173 94 174 92 175 94 176 94 117 325 178 93 179 93 180 88 181 93 182 92 183 92 184 94 185 93 186 83 187 86 188 81 189 76 190 86 191 93 192 193 92 194 86 195 196 92 197 94 326 198 93 199 87 200. 83 201. 92 202 203 92 204 92 2.05 94 .206 94 207 94 208 93 209 92 210 93 211 94 212 94 213 94 214 92 215 98 216 86 217 94 327.
218 94 219 98 220 91 221 222 98 223 96 224 86 225 98 226 96 227 96 228 96 229 96 230 92 231 88 232 233 93 234 98 235 92 236 237 92 238 97 239 98 240 97 241 91 242 58 243 244 96 245 96 246 97 247 93 248 96 249 96 250 92 251 98 252 97 253 96 254 98 255 97 256 94 257 94 329 258 96 259 96 260 92 261 96 262 96 263 94 264 94 265 96 266 .86 267 94 268 96 269 ~94 270 271 272 94 273 93.
274 96 275 94 276 86 277 94 278 88 279 94 280 94 281 96 282 96 283 284 94 285 94 286 96 287 92 288 92 289 290 291 96 292 96 293 96 294 96 295 94 296 94 297 94 298 94 299 92 300 92 301 91 302 92 303 94 304 94 305 92 306 93 307 93 308 94 309 94 310 92 311 92 312 86 313 314 96 315 96 316 94 317 92 318 98 319 98 320 89 321 94 322 96 323 98 324 96 325 98 326 98 327 98.
328 98 329 98 330 98 331 97 332 98 333 98 334 94 335 98 336 98 337 93 338 93 339 92 340 93 341 94 342 94 343 94 344 93 345 92 346 347 92 348 349 92 350 91 351 94 352 94 353 92 354 91 355 96 356 96 357 97 358 97 359 96 360 98 361 98 362 98 363 96 364 96 365 96 366 96 367 97 368 93 369 96 370 73 371 93 372 93 373 97 374 96 376 377 96 378 97 379 380 97 381 99 382 97 383 97 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: ICAM-1 /JY-8 cell adhesion assay For measurement of inhibitory activity in the cell-based adhesion assay, 96well microtiter plates are coated with 70 pL of recombinant ICAM-1/I g (ICOS Corporation) at a concentration of 5 pg/mL in D-PBS w/o Ca or Mg" overnight at 4°C. The wells are then washed twice with D-PBS and blocked by addition of 200 .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 pL at 2 x 106 cells/ml in RPMI 1640/1% fetal bovine serum) are added to the wells. For fluorescent labeling of JY-8 cells, 5 x 106 cells washed once in RPMI 1640 are resuspended in 1 mL of RPMI 1640 containing 2 pM Calceiun AM (MolecularProbes), are incubated at 37 0 C for 30 minutes and 336 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 10mM stock solutions in DMSO and 50 jtL 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: average OD w/ compound inhibition 100 X 1 average OD w/o compound and these concentration/inhibition data are used to generate dose response curves, from which IC 5 o values are derived.
337 Compounds of the present invention exhibit blocking activity in the above assay as follows: Compound inhibition of Example 4tpM 1 17 2 49 3 67 4 69 54 6 77 7 69 8 62.
9 72 11 12 72 13 63 14 67 72 16 67 17 72 18 62 19 84 61 21 22 78 23 24 38 26 27 28 29 64 31 82 32 33 67 34 76 71 36 72 37 78 38 73 39 82 87 41 79 42 43 66 44 69 62 46. 61 47 57 48 78 49 84 51 52 53 74 54 76 73 56 57 84 339 58 64 59 77 61 82 62 74 63 69 84 66 67 71 68 66 67 71 74 78 76 77 83 78 81 79 81 82 67 84 81 86 71 88 69 89 71 91 72 92 73 93 69 94 73 71 96 82 340 97 6 98 68 99 100 62 101 66 102 77 103 71 104 7 105 .63.
106 64.
107 62~ 108 59 109 110 72 111 64 112 77 .116 6 117 36 118 71 119 82 120 7 121 74 122 79 123 54 134 83 135 74 136 137 140 142 76 144 63 147 77 150 151 76 152 74 154 68 155 69 158 66 159 76 161 84 162 82 163 83 165 74 166 72 167 78 168 170 78 171 72 172 66 173 68 174 67 175 63 176 66 184 74 191 192 73 193 74 194 76 197 76 204 74 205 74 206 207 208 209 64 210 211 62 212 215 58 218 74 219 68 222 225 74 226 54 227 68 228 67 229 73 230 78 233 68 234 235 74 238 74 239 78 240 69 243 76 244 78 245 247 248 251 72 252 66 253 76 254 255 72 257 258 81 259 74 261 74 262 74 263 61 264 265 72 266 69 268 63 270 64 271 66 272 68 274 279 51 281 58 284 54 286 41 289 8 290 77 319 62 325 78 326 61 327 73 329 330 79 332 82 333 334 81 335 66 336 77 340 83 341 88 352 81 344 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 EBVtransformed B cell line expressing LFA-I on its surface) to immobilized ICAM-3, as follows: ICAM-3 JY-8 cell adhesion assay For measurement of inhibitory activity in the cell-based adhesion assay, 96well microtiter plates are coated with 50 pL of recombinant ICAM-3/Ig (ICOS Corporation) at a concentration of 10 pg/mL in D-PBS w/o Ca" or Mg" overnight at 4 0 C. The wells are then washed twice with D-PBS, blocked by addition of 100 pL 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 tpL are added to duplicate wells. JY-8 cells (a human EBV- 345 transformed B cell line expressing LFA-1 on its surface; 100 pL at 0.75 x 106 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 gL of 14% glutaraldehyde/D-PBS and incubated for an additional 90 minutes.
The wells are washed gently with dHO; 50 PL of dH 2 0 is added, followed by 1.L of 1% crystal violet. After 5 minutes the plates are washed 3X with dH20; pL of dH20 and 225 piL 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: average OD w/ compound inhibition 100 X 1 averageOD ompound average OD w/o compound 346 Compounds of the present invention exhibit blocking activity in the above assay as follows: Compound inhibition Of Example 0.6pM 9 100 12 100 100 16 100 17 100 18 100 26 100 27 100 100 32 100 34 100 100 41 100 100 46 100 49 100 100 54 100 59 100 100 62 100 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., JImmunol 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.
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.
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., AmJ Respir Crit Care Med 153:521-529, 1996.
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 complexinduced lung injury model according to the method of Mulligan et al., Jlmmunol 154:1350-1363, 1995, or in a murine acid-induced lung injury model according to the method ofNagase, et al., Am J Respir Crit Care Med 154:504-510, 1996.
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.
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.
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., Jlmmunol 151:5088-5095, 1993.
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., JImmunol 150:1074-1083, 1993.
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., Gastroenterolog 108:1761-1769, 1995.
349 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 US A 94:6432-6437, 1997.
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.
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 265): H1578-H1584, 1991.
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 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.
350 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.
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 ofTalento et al., Transplantation 55: 418-422, 1993, in a cynomolgus monkey renal allograft model according to the method of Cosimi et al., JImmunol 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, JImmunol 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.
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.
351 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., Jmmunol 161:2333-2338, 1998.

Claims (4)

1. A process for preparing a compound of formula I R1 Ar S R2 Rs R4 O wherein R 1 R 2 R 4 and R 5 are independently selected from a. hydrogen, b. halogen, c. alkyl, d. haloalkyl, e. alkoxy, f. cyano, g. nitro, h. carboxaldehyde, 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, I. aminoalkyl, m. aminocarbonyl, Y:\Mary\NKINoDelete\2004202565.doc 1 353 n. alkyl(alkoxycarbonylalkyl)aminoalkyl, o. heterocyclyl, p. heterocyclylalkyl, q. substituted heterocyclylalkyl, r. carboxaldehyde, s. carboxaldehyde hydrazone, t. carboxamide, u. alkoxycarbonylalkyl, v. carboxy, w. carboxyalkyl, x. hydroxycarbonylalkyl (carboxyalkyl), y. hydroxyalkylaminocarbonyl, z. cyano, aa. amino, bb. heterocyclylalkylamino, cc. heterocyclylaminocarbonyl, dd. "trans-cinnamide", which comprises homologating a compound of formula I' using an acetate equivalent R1 -S 2 Ar RS yCHO R, I'.
2. A process according to claim 1, wherein R 1 and R 2 are trifluoromethyl, and R 4 and R 5 are hydrogen.
3. A process according to claim 1, wherein the homologating comprises hydrolysis of an intermediate ester of formula I. Y:\MaryNKINoDelete\2004202565.doc 354
4. A process according to claim 1, wherein Ar is a substituted aryl group, where the substitution is selected from aa. amino. DATED: 21 December 2004 PHILLIPS ORMONDE FITZPATRICK Attorneys for: Abbott Laboratories Y:\MaryNKINoDelete2004202565.doc
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