CA2174124A1 - Pyrone derivatives as protease inhibitors and antiviral agents - Google Patents

Abstract

The present invention relates to novel tri- and tetrasubstituted pyrones and related structures which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The pyrone derivatives are useful in the development of therapies for the treatment of baterial and viral infections and diseases, including AIDS. The present invention is also directed to methods of synthesis of multifunctionalized pyrones and of related structures.

Description

~ WO95/14014 PCT~S94/12367 ~17~1~4 r~.... .....~ DERIV~rVE8 A8 ~.~A8~ I~h~ ~K~ AND A~ ~v-KA~ AGENT8 1. FIRT-n OF $9~ INVEN~IO~
S The present invention relates to ~y~ a derivatives that are inhibitors of aspartyl proteases, in part;c~ r the aspartyl prote~C~e found in ~LlGviruses including Human Immnn~A~ficiency Virus (HIV). The pyrones are expected to have utility as antiviral agents, for the treatment of 10 infection caused by HIV or other ~L~oviruses employing aspartyl prote~C~C~ and to be useful in the treatment of ~;-CD~ces caused by the LeLl~viruses, including AIDS.

2 . R~ r-~,O~ OF TB ~..V~lU..
Acquired Immunodeficiency Syl~dlume (AIDS) was coined in 1982 to describe the clinical manifestations of imml~n~ficiency. The etiological agent of AIDS was later associated with a LeL~ovirus, Human Immllno~ficiency Virus (HIV), from the lentivirus subfamily. At least two infectious 20 strains of HIV have been identified, HIV-1 and HIV-2.. Here, HIV will be used as a general term describing a variety of strains and mutants of the Human Immunodeficiency Virus. The detailed study of HIV has given rise to many appro~h~C to antiviral drug de~elopment including inhibition of the viral 2S aspartyl protease (D. Richman, Control of Virus Diseases, 45th Symposium of the Society for General Microbiology, 261-313 (1990) ) .
Aspartyl prote~s~C have been found in many l~LLuviruses including the Feline Immunodeficiency Virus, the 30 Myeloblastosis Associated Virus, HIV, and the Rous Sarcoma Virus tH. Toh et al., Nature, 315: 691 (1985); J. Ray, B. M.
Dunn, Biochlm. Biophys. Acta, 1: 1048 (1990); C. Cameron et al., J. Biological Chem., 168, 11711-720 (1993)]. Since there are structural similarities among the known ~LLvviral 35 prot~ , com~ which inhibit the HIV protease may well inhibit other leL.~viral prote~c~c.
HIV aspartyl protease is responsible for post-translational processing of ~iral ~L~ sor polyproteins such Wo95/14014 PCT~S94/12367 ~
: ` .
~7~12~ 2 -as pol and gag. (N. Graves, Structure and Function of the Aspartic P~oteases, 395-405 (l99l)). Cleavage of these polyproteins by this protease is essential for maturation of the virus, since the proteolytic activity ~PcPcs~ry for 5 polyprotein processing cannot be provided by host cellular enzymes. An important f; n~; n~ has been that viruses which lack this protease, or contain a mutation which pro~tlce~ a defective protease, lack infectivity ~C. Peng et al., ~.
Virol, 63: 2550-2556 (1989) and N. ~ohl et al., Proc. Nati.
lO Acad. sci. USA, 85: 4689-90 (1987)]. Thus, a selective HIV
protease inhibitor has been shown to inhibit viral spread and~
the production of cytopathic effects in cultures of acutely infected cells (J. C. Craig et al., Antiviral ~esearch, 16:
295-305 (l99l)). For this reason, inhibition of HIV protease 15 is believed to be a viable approach to antiviral therapy.
HIV protease inhibitors have been extensively reviewed (see for example A. Tomasselli et al., C~imica Oggi, 9: 6-27 (l99l) and T. Meek, J. Enzyme Inhibition 6: 65-98 (19g2)).
However, the majority of these inhibitors are peptides and 20 thus unsuitable as drugs, due to the well known pharmacological deficiencies exhibited by most peptide drugs (biliary e~r~Lion, low bioavailability and stability in physiological milieu, etc.) No~ idic inhibitors of HIV
protease are thus very important, since these may lead to very 25 useful therapeutic agents.
Hei 3-227923 claimed coumarins with anti-HIV activity.
However, only 4-hyd~ coumarin was specifically described without discussing its mec~ni~m of action.
World Patent 89/07939 claimed eight coumarin derivatives 30 as Hrv reverse transcriptase inhibitors with potential antiviral activity. These derivatives are hexachlorocoumarin, 7-acetoxycoumarin, and the structures shown below.

3s WO95/14014 ~ 1 7 4 1 2~ PCT/US94/12367 Br ~ N~\R~ N~N~

~`O ~O~o ." ,~.
R=H, R'=Cl; R=H, R'=CF3; R=R'=Cl ~Fe)~

OH o OH . OH

~O~o ~J ~o~ooJio~

Warfarin (3-(~-acetonylbenzyl)-4-hydLo~ycoumarin), shown 5 below, was Le~olLed by R. Nagorny et al. in AIDS, 7: 129-130 (1993) as inhibiting cell-free and cell-mediated HrV
infection. However, Warfarin was the only pyrone studied and itS ~rh~ni ~m of action in HIV inhibition was not specified.

2 0 OH Ph O

~\ Me ~0~0 Selected flavones, structurally different from the 25 pyrones of the present invention, were ~e~L Led by Fairli et al. (Biochem. Biop~ys. ~es. Comm., 188: 631-637 (1992)) to be inhibitors of HIV-l protease. These compounds are shown below.

O OH O
1'. HO~

~ OlCO2H '~~ OH
OMe OH ~

HO

WO95tl4014 PCT~S94/12367 United States Patent Number 3,206,476 describes several pyrones, specifically 3-substituted-4-hyd~o~y-6-aryl-2-pyrones, as antihypertensive agents. However, the range of substituents at the 3-position of these heterocycles is 5 limited to halo and amino yL 0~ and ~lk~noylamino derivatives.
,..
United States Patent Number 3,818,046 describes several pyrone derivatives, specifically 4-h~dko~y~yLolles with sulfur-cont~; n; n~ carbon ~hA i nc at the 3-position, as growth stunters 10 and antimicrobial agents. The substitution at the 6-position of these hetelG~ycles is limited to the methyl group. The pyrones, which are shown below, are substituted as follows: R
s Me; M = H or ~lkAl; metal; and R' = H, alkyl, phenyl, halophenyl, nitrophenyl, phenyl substituted with lower alkyl, 15 benzyl, phenethyl, naphthylmethyl, halobenzyl, benzyl substituted with lower alkyl, nitrobenzyl, propargyl, allyl, cyclohexyl substituted with lower alkyl, thioalkyl cont~;ni ng a lower alkyl group, lower alkyl, or adamantyl; and n=0 to 2.
.

OM

~,S(O)nR' R " ~`O ~ O
R--M~

A process for preparing the pyrones shown above is 30 claimed in United States Patent No. 3,931,235.

3. 8~MMARY OF ~ INVENTION
The present invention is based in great part on the extraordinary discovery of the inventors that novel tri- and 35 tetrasubstituted pyrones and related com~oullds, selected fro~
a very broad spectrum of tailored molecular stru~ es~
potently inhibit the HIV aspartyl protease blocking infection by HIV. The present invention is also based on the insights , ~ WO95/14014 2 1 7 ~ 1 ~4 PCT~Sg4/12367 of the inventors regarding the mec~ism of action of antiviral drugs, especially as revealed by their studies on structure-activity relatio~ch i rS characteristic of anti-HIV
compounds that include pyrones.
The invented pyrones are expected to be extremely useful in the development of treatments for infections caused by viruses, especially by ~eLLoviruses that rely on aspartyl protease activities for replication and infectivity. One such LeL.~irus is HIV. As virus blockers, the pyrones are also l0 expected to be very useful in the treatment of diseases and syndromes associated with viral pathogens. One such ~y~dlome is AIDS.
Efficient syntheses of the biologically active pyrones, involving either de novo assemblies of the ~L olle nucleus or ~5 modifications of suitably functio~Al;~ed pyrones, are disclosed. Furthermore, ~any working examples outlining the preparation of specific ~yLo~,as whose structures contain the desired functional yL O~p-- ' in proper geometric arrangements are given.
The testing of specific pyrones as inhibitors of the HIV
aspartyl protease, h~ on a study of the hydrolysis of an n~c~eptide enzyme substrate, and the testing of the pyrones as inhibitors of viral growth and infectivity, based on a study of infection of H9 cell lines by the HIV~ strain, 2S are also disclosed. Striking enzyme inhibitions, at nanomolar levels, with corres~o~i ng anti-~IV activities, were observed.
The present inventors contemplate the preparation of pharmaceutically useful antiviral compositions comprising one or more of the invented pyrones and related compounds and a 30 pharmaceutically acceptably carrier. They also contemplate the use of these compositions, alone or in combination with other antiviral treatments, in the treatment of infections and es caused by retroviruses, including AIDS.
The present invention relates to compounds, or the 35 pharmaceutically acceptable salts thereof, of Formula l, shown below, , 4 ~ 2 ~ PCT~Ss4tl~67 ,.
R5 W2Al(CH2 )mW3 R3 R3 Wl (CH2 )mW(CH2 )nA Y Z

wherein X is oRl, NHRl, SRl, Co2R4 or CHzORl wherein Rl is R4 or CoR4 15 wherein R4 is as defined below;
Y is oxygen or sulfur;
Z is oxygen or sulfur;
A and Al are ind~r~n~tly a chemical bond, an unsubstituted or substituted phenyl, naphthyl, a 5- or 6-20 membered heterocyclic ring, cycloalkyl, or a fused ring systemof from 8 to 10 atoms or a substituted derivative thereof wherein the substituents are one or more of F, Cl, Br, oR4, N(R4) 2, Co2R4, CoN(R4) 2, coR4~ R4, OCH2O, OCH2CH20, or C--N wherein R4 is ~ r~n~ntly hydloyen, substituted on unsubstituted 2s alkyl, cycloalkyl, alkylcycloalkyl or phenyl wherein the substituents are one or more of CO2R2, CON(R2)2, F, oR2~ SR2, N(R2)2, CN, phenyl, naphthyl, a heterocycle or CF3 wherein R2 is indep~n~ntly alkyl, cycloalkyl, or hydrogen;
Rs is hydLoyen, alkyl, cycloalkyl, alkylcycloalkyl, 30 phenyl, or the substituted derivatives thereof wherein the substituents are one or more of CO2R2, CON (R2) 2 ~ F, oR2~ phenyl, naphthyl, CF3, oRl, NHRl, SRl, or CH20Rl wherein Rl is as defined above;
R3 is ;n~F~n~ently h~dloyen, (CH2)pR4 or (CH2)iA wherein p 35 is an integer of from 0 to 2 and R4 and A are as defined above;
W, W1, and W3 are each independently a chemical bond, oxygen, NR3, C(R3) 2~ C~ CR3=CR3, C2C, CR30R3, C(=NR3)NR3, S(O)p, -~ WO95/14014 217~24 PCT/US94/12367 CR3N (R3 ) 2 ~ So2NR3, C2 ~ NR3COVgA and NCov~R3 wherein g is either or 1, and V is oxygen, sulfur, NR3, or CHR3;
W2 is an oxygen, NR3, S(O)p, So2NR3, -OCO, NR3COV~a and NCOVgR3 wherein g is either 0 or 1 and V is 0, S, NR3 or CHR3;
m and n are each in~P~ ntly an intéger of from 0 to 4 with the provision that when W and Wl are both heteroatoms or when w2 and W3 are both heteroatoms, m is an integer of from 2 to 4; and with the further proviso that R3Wl(CH2)mW(CH2~nA
cannot be methyl or ethyl.
Preferred com~o~l~s of the instant invention are those of Formula 1 shown above wherein X is hydk~yl, amino, or h~ko~ymethyl;
Z is oxygen;
Y is oxygen or sulfur;
W, W1, and W3 are each in~r~ tly oxygen, NR3, NCoV5R3, CR3=CR3, 5O2NR3, sulfur, or C(R3) 2 and w2 is selected from the group consisting of O, NR3, S, and NCov~R3~ wherein V is oxygen, NR3 or CHR3 wherein R3 is independently hyd-oyel~, (CH2)pR4 or (CH2)p A wherein p is an integer of from 0 to 2, g 20 is 0 or 1, and A is ;n~p~n~ently phenyl, naphthyl, a 5- or 6-membered hete.~y~le having one or two heteroatoms, a fused ring system of from 8 to 10 atoms, cyclopentyl, cyclohexyl or a substituted derivative thereof wherein the substituents are one or more of F, Cl, Br, oR4, N(R4)2, CO2R~, CON(R~)2, R4, 25 OCH20, or OCH2CH20 wherein R~ is i~Pr~n~tly l~Loyen, a straight or br~nçhe~ alkyl of from 1 to 5 atoms, a cycloalkyl group of 3 to 6 carbon atoms, a CH2cycloalkyl group of 4 to 8 carbons, phenyl, or a substituted derivative which substituents are of CO2R2, F, oR2~ phenyl, or CF3 wherein R2 is 30 hydrogen, methyl, ethyl, isobutyl, t-butyl, or cycloalkyl contA;~ing 3 to 6 carbon atoms, wherein Al is as previously defined; and R5 is hydrogen, methyl, ethyl, propyl, cyclo~l u~yl, hydLoxyl, carboxyl, or hy~o~ymethyl.
3s More preferred compounds of the present invention are those of Formula 1 shown above wherein X is hy~G~.yl;
Z is oxygen;

WO95/14014 ~1 7~ 2~ PCT~S94/12367 ~t Y is oxygen;
W, Wl, and W3 are each ;n~ep~n~tly oxygen, sulfur, So2NR3 ~ NR3 ~ or C(R3) 2 and w2 is O, S or NR3, wherein R3 is ~n~pen~ently hydrogen, (CH2)pR~, or (CH2)~A wherein p is an 5 integer of from 0 to 2, Rg is hydrogen, methyl, ethyl, isu~Lo~yl, isobutyl, CYC1O~L~Y1~ cyclohexyl, cyclu~lo~ylmethyl, cyclohexylmethyl, CH2CO2R2, phenyl or benzyl; R2 is H, methyl, ethyl isobutyl or t-butyl; A is phenyl, 2,3- or 4-pyridyl, 2,4- or 5-thiazolyl, morpholinyl, 2 10 or 3-furyl, cyclopentyl, cyclohexyl, indanyl, or a substituted derivative thereof wherein the substituents are one or more of F, Cl, Br, oR4 R~, Co2R4 or OCH2O, wherein Al is as previously defined; and R5 is hyd~oyen, methyl, ethyl, or hydlGxymethyl;
Some of the most preferred compounds of the present invention are included in the following:

3-[(Cyclohexylthio)phenylmethyl]-4-hy~oxy-6-phenyl-2H-pyran-2-one;
4-Hydlox~-3-[[(2-methoxyphenyl)thio]phenyl-methyl]-6-phenyl-2H-pyran-2-one;
3-(3-Methoxybenzoyl)-6-(3-methoxyphenyl)-2H-pyran-2,4(3H)-dione;

6-~4-[(3,5-Dimethyl-4-; CQYA 701yl ) methoxy]phenyl]-4-hydk~xy-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydloxy-3-~3-methyl-1-(phenylthio)butyl]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-~(2-phenylethyl)thio]-6-[4-(phenylsulfinyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[phenyl[(phenylmethyl)thio]
methyl]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydlo~y-6-(3-phenoxyphenyl)-3-[(2-3S phenylethyl)thio]-2H-pyran-2-one;
3-~2-Cyclohexyl-1-(phenylthio)ethyl]-4-hy~Gx~-6-phenyl-2H-pyran-2-one;

WO95/14014 ~74124 PCT~S9411~67 4-Hy~Lo~y-6-t3-methoxy-4-(phenylmethoXy)phenyl]-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hy& oxy-3-t(2-oxo-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one;
54-Hy~Lùxy-6-phenyl-3-[phenyl(phenylthio)methyl3-2H-pyran-2-one;
3-[Bis(2-naphthalenylmethyl)amino]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-HydLo~y-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;
(S)-l,3-Dih-y~O N-(4-hy~lGxy-2-oxo-6-phenyl-2H-pyran-3-yl)-2-(phenylmethyl)-2H-isoindol-2-acetamide;
N-(l,l-Dimethylethyl)-N'-(4-hy~loxy-2-oxo-6-phenyl-2H-pyran-3-yl)-N'-(phenylmethyl)urea;
~54-Hy~oxy-3-[(2-~h~nQYyethyl)thio]-6-phenyl-2H-pyran-2-one;
(E)-4-Hy~koxy-6-phenyl-3-t(3-phenyl-2-propenyl)thio]-2H-pyran-2-one;
4-Hydku~y-3-ph~oYy-6-phenyl-2H-pyran-2-one;
202-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-4-yl-3-methylbutanoic acid ester;
6-(3,4-Dichlorophenyl)-4-hy~L~xy-3-[(phenylmethyl)thio]-2II ~yLan-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
2-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-4-yl propanoic acid, ester;
4-Hydroxy-6-(3-methylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
304-Hydroxy-6-(3-hydroxy~henyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(2-phenylethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hyd~o~y-6-(4-hy~xy~henyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(phenylmethoxy)phenyl]-2H-pyran-2-one;

WO95/14014 2 1 ~ 4 1 2 ~ PCT~S94/12367 ~

4-Hy~loAy-6-~4-(2-phenylethoxy)phenyl]-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[3-(2-phenylethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-HY~VAY-6-(2-hYd1OAY~henY1)-3 ~(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(3-methoxyphenyl)-3-t(phenylmethyl)thio]-2~-pyran-2-one;
6-(3-Chlorophenyl)-4-hydlu~y-3-[~2-phenylethyl)thio]-2H-pyran-2-one;
4-Hy~y--6-(4-methoxy-3-methylphenyl)-3-~(phenylmethyl)thio]-2H-pyran-2-one;
6-(3-Chloro-4-methoxyphenyl)-4-1.y~o~y-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4 IIydLoAy-3-[(2-phenylethyl)thio]-6-t3-(phenylmethoxy)phenyl]-2H-pyran-2-one;
4-Hy~lo~y--3-t[2-(4-methoxyphenyl)ethyl]thio]-6-phenyl-2H-pyran-2-one;
3-[(Cyclohexylmethyl)thio]-4-hydLu~y-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Ey~lo~y-3-[(2-phenylethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
6-(2,3-Dihy~.o l,4-benzodioxin-6-yl)-4-hyd~o~y-3-t(phenylmethyl)thio]-2H-pyran-2-one;
4 -Hydl u~y - 3 - [ ( 2-phenylethyl)thio]-6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
t4-[4-Hy~koxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoAy]acetic acid;
t4-[4-Hy~Gxy-2-oxo-3-[(2-phenylethyl)thio~-2H-pyran-6-yl]phenoxy]acetic acid, ethyl ester;
4-Hydroxy-6-(4-phPnn~yphenyl)-3-~(2 phenylethyl)thio]-2H-pyran-2-one;
4-HydroAy-3-t(2-phenylethyl)thio]-6-[4-(2-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
4_HY~AY_3_[(2-PhenY1ethY1)thiO]-6-[4-(3 pyridinylmethoxy)phenyl]-2H-pyran-2-one;

~ WO9S/14014 21~4124 PCT~S94/12367 4 ~I~dl~y--6-t4-(2-methoxyphenyl)methoxy]phenyl]
3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hy~l uXy-3 - [2-naphthalenyl(phenylthio)methyl]-6-phenyl-2H-pyran-2-one;
54-H~dLoxy-3-t(2-naphthalenylthio)phenylmethyl~-6-phenyl-2H-pyran-2-one;
4-Hydloxy-3-t(2-phenylethyl)thio]-6-t4-(phenylthio)phenyl]-2H-pyran-2-one;
6-(l,3-Benzodioxol-5-yl)-4-hydroxy-3-r(phenylmethyl)thio~-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-t(phenylmethyl)thio]-2H-pyran-2-one;
4-hydLGxy-6-(2-naphthalenyl)-3 t(phenylmethyl)thio3-2H-pyran-2-one;
154-hydloxy-6-(4-hyd~y~lenyl)-3-t(phenylmethyl)thio]-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydLo~-3-t(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[2-(3-methylbutyl)phenyl]-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-(hydroxymethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
t4-t4-Hydlûxy-5-(hyd~ohy-methyl)-2-oxo-3-[(2-phenylethyl)thio~-2H-pyran-6-yl~ rh~Yy] acetic acid;
256-(3,5-Dimethylphenyl)-4-hydlo~y-5-methyl-3-[2-phenyl-l-r(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-methoxyphenoxy)phenyl]-3-[phenylr(phenylmethyl)thio]methyl]-2H-pyran-2-one;
[4-[3-r2-Cyclopentyl-l-(phenylmethoxy)ethyl~-4-hydL~xy-2-oxo-2H-pyran-6-yl]phenoxy]acetic acid;
4-Hydroxy-6-[4-t(l-methylethoxy)methyl]-2-thiazolyl~-2-oxo-3-~2-phenyl-l-[t(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
4-[4-Hydk~y-3-[l-(l-hyd~o~y-2-phenylethyl)-3-methylpentyl]-2-oxo-2H-pyran-6-yl]benzenepropanoic acid;
6-(3,5-Dimethylphenyl)-4-hydLoxy-3-[l-hydkoxy-2 methyl-l-(phenylmethyl)propyl]-2H-pyran-2-one;

WO95tl4014 PCT~S94/12367 ~
217412~
~ .~., c A ' h: -6-t3-Fluoro-4-(3-pyridinylmethoxy)phenyl]-4-hydloxy-3-[3-methyl-1-[(phenylmethyl)thio]butyl]-2H-pyran-2-one;
[2-(Hyd~oxymethyl)-4-[4-hydroXy-3-[1-(1-methylethoxy)-2-(phenylthio)ethyl]-2-oxo-2H-pyran-6-yl]ph~noxy]acetic acid;
[4-t4-~dLoxy-3-[3-methyl-2-(phenylthio)butyl]-2-oxo-2H-thiopyran-6-yl]phenoxy]acetic acid;
4-Hy~oxy-6-[(4-methoxyphenyl)methyl]-3-[[1-(phenylmethyl)butyl]thio]-2H-pyran-2-one;
t2 IIydlGxy-4-[4-h~dloxy-2-oxo-3-[2-(phenylmethylene)pentyl]-2H-pyran-6-yl]phenoxy]acetic acid;
[[5-[2-Oxo-4-hydroxy-3-[(3-methyl-1-phenylbutyl)thio]-2H-pyran-6-yl]-2-pyridinyl~oxy]acetic acid;
4-HydL-,~y-6-[5-(r~eroxymethyl)-2-furanyl]-3-t2-phenyl-1-[(phenylmethyl)thio]ethyl]-2H-pyran-2-one;
[4-t4-Hydroxy-2-oxo-3-[2-phenyl-1-[(phenyl-methyl)amino]ethyl]-2H-pyran-6-yl]phenoxy]acetic acid;
4-Hy~Gxy-3-[2-phenyl-1-tphenyl(phenyl-methyl)amino]ethyl]-6-t4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
tt4-t4-Hy~lu~y-2-oxo-3-t(phenylmethyl)thio]-2H
pyran-6-yl]cyclohexyl]oxy]acetic acid;
Cis-6-(3,5-Dimethylphenyl)-4-h~d~ ~y-3 -t 3 -methyl-1-[2, 3 -dihydro-1-hyd~oxy-lH-inden-2-yl)thio]butyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-isopropylphenyl)thio]-6-phenyl~
2H-pyran-2-one;
4 ~Iydl GXy-3 - [ [ ( 2-methylpropyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclo~opylmethyl)phenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hy~loxy-3-t(2-is~Lu~ylphenyl)thio]-6-(2, 3-dihydro-1,4-benzodioxin-6-yl)-2H-pyran-2-one;

WO9~/14014 ~ 7~2~ PCT~S94/1~67 3-~(2,5-Diis~o~ylphenyl)thio]-4-hyd~ox~-6-t(3-phenyl)phenyl]-2H-pyran-2-one;
6-t4-(3-Furanylmethoxy)phenyl]-4-hydLox~-3-t3-- methyl-l-t(phenylmethyl)thio]butyl]-2H-pyran-2-one;
56-t4-(Cyclohexylmethoxy)phenyl]-4-hy~Lo~y-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hyd~u~y-3-t(2-phenylethyl)thio]-6-t4-(phenylsulfonyl)phenyl}-2H-pyran-2-one;
4-Hyd~y-3-t(2-phenylethyl)thio]-6-t4-benzoyloxy)phenyl]-2H-pyran-2-one;
4-Hy~o~y-3-t(2-phenylethyl)thio]-6-t4 (phenylsulfinyl)phenyl]-2H-pyran-2-one;
4-~ydlGxy-3-t(2-phenylethyl)thio]-6-(4 pyridinyl)-2H-pyran-2-one;
153-tl,4-Bis(phenylthio)butyl]-4-hy& o~y-6-phenyl-2H-pyran-2-one;
4-Hy~o~-6-phenyl-3-tphenylt(phenylmethyl)thio]methyl]-2H-pyran-2-one;
4-Hydrox-y-3-tt(2-methoxyphenyl)thio]phenylmethyl]-6-phenyl-2H-pyran-2-one;
4-Hyd~o~y-3-t3-methyl-1-(phenylthio)butyl]-6-phenyl-2H-pyran-2-one;
3-t2-Cyclohexyl-1-(phenylthio)ethyl]-4-hydl uxy-6-phenyl-2H-pyran-2-one;
4-Hydloxy-6-(3-phenoxyphenyl)-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hyd~oxy-6-t3-methoxy-4-(phenylmethoxy)phenyl]-3-t~2-phenylethyl)thio]-2H-pyran-2-one;
3 06- ( 3,5-Dimethylphenyl)-4-hydroxy-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydrox-y-3-tt(3-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-t4-methyl-1-(phenylthio)pentyl]-6-phenyl-2H-pyran-2-one;
4-Hydloxy-6-PhenYl-3~t[t3~
(phenylmethoxy)phenyl]methyl]thio]-2H-pyran-2-one;

WO95/14014 PCT~S94/12367 ~1 ~1~4~

3-t(1,3-Benzodioxol-5-ylmethyl)thio]-4-h~dLu~y-6-phenyl-2H-pyran-2-one;
4-Hyd~ vXy-3- t~(2-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hy~lo~y-3-t[(2-methylphenyl)methyl]thio]-6-phenyl-2H-pyran -2-one;
4-HydlGxy-3-[[(3-methylphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-HydLo~yy-3-tt(4-methylphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
6-[1,1~-Biphenyl]-3-yl-4-hy~o~y-3-t(2-phenylethyl)thio]-2H-pyran-2-one;
4-Ey~loxy-3-t[(4-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
3-[2-cyclohexyl-l-(cyclohexylthio)ethyl]-4 h~dlv~y-6-phenyl-2H-pyran-2-one;
3-[1-[(2,6-Dimethylphenyl)thio]-3-methylbutyl]-4-h~dloxy-6-phenyl-2H-pyran-2-one;
3-[1-(Cyclohexylthio)-2-cyclo~Lo~-ylethyl]-4-hydLv~y-6-phenyl-2H-pyran-2-one;
3-[1-t(2,6-Dichlorophenyl)thio]-3-methylbutyl]-4-hy~loxy-6-phenyl-2H-pyran-2-one;
3-[1-Cyclohexylthio)-3,3-dimethylbutyl]-4-hy~lvxy-6-phenyl-2H-pyran-2-one;
[4-t4 IIy~Lv~y-2-oxo-3-t(2-phenylethyl)thio]-2H-pyran-6-yl]-2-methylph~noxy], acetic acid, ethyl ester;
6-[3,5-Dimethyl-4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-t4-(4-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
3-[1-(Cyclopentylthio)-3-methylbutyl]-4-hyd~vxy-6-phenyl-2H-pyran-2-one;
[4-[4-Ey~loxy-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-2-methylphenoxy acetic acid;
3-tl-(Cyclohexylthio)-2-(cyclopentyl)ethyl]-4-hydlo~y-6-phenyl-2H-pyran-2-one;

~ WO95/14014 2 1 7 4 L ~4 PCT~S94~12367 4-HY'~1G~Y-6-(4-hy~G~y-3,5-dimethylphenyl)-3-t(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[[~3-(2-phenylethoxy)phenyl]methyl]thio]-2H-pyran-2-one;
4-Hy~lo~y-6-[4-(2-phenylethynyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-H~dloxy--6-[4-(2-phenylethyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-[(Cyclohexylthio)phenylmethyl]-4-1~yd~o~y-6-phenyl-2H-pyran-2-one;
4 I1Y~L~Y-_3_~(phenylmethyl)thio]-6-~3-(trifluoromethoxy)phenyl]-2H-pyran-2-one;
3-t(Cyclohexylmethyl)thio]-4-hy~Loxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
6-(2,3-DihydLO l,4-benzodioxin-6-yl)-4-hydL~y-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-~ydloxy-3-[(2-phenylethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(phenylmethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-~ydloxy-3-[(phenylmethyl)thio]-6-(2,3,4-trimethoxyphenyl)-2H-pyran-2-one;
N-[4-[4-IIydL~-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]phenyl]benzenesulfonamide;
6-[4-[(3,5-Dimethyl-4-isoxazolyl)methoxy]phenyl]-4-hydLoxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-t(Cyclohexylthio)phenylmethyl]-4 hyd~ GXy -6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
2-[[(4-HydLoxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]-benzoic acid methyl ester;
3-[l-(Cyclohexylthio)-3-methylbutyl]-6-(2,3-dihydro-l,4-benzodioxin-6-yl)4-hydL~y-2H-pyran-2-one;
2-[[4-(4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]methyl-benzoic acid methyl ester;

WO 95/14014 PCT/US94/12367 ~

21741~4 - 16 ~
4-HydlGxy-3-~(2-phenylethyl)thio]-6-[4-(lH-tetrazol-5-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydlu~y-6-~3 -methyl-4-(2-pyridinylmethoxy)phenyl]-3 ~ t ( 2-phenylethyl)thio]-2H-pyran-2-one;
3 - [ 2-CyclG~Lopyl-1-t(phenylmethyl)thio]ethyl]-4-l~y~Lo~y-6-phenyl-2H-pyran-2-one;
4-Hyd~ O~y~3 ~ [ 1- t(2-methoxyphenyl)thio]-3-methylbutyl]-6-phenyl-2H-pyran-2-one;
104 ~IydLo~y-3-~ (phenylmethyl)thio]-3-methylbutyl]-6-phenyl-2H-pyran-2-one;
4-tt4-Hyd~o~y-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]ph~noYy]methyl]benzoic acid methyl ester;
3-~t4-[4-~d~u~y-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]ph~oxy]methyl]benzoic acid methyl ester;
6-[4-[(3,4-Dichlorophenyl)methoxy]phenyl]-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-[[(4-Hy~ko~y-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]benzoic acid methyl ester;
4-[[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]benzoic acid methyl ester;
6-[3,5-Bis(trifluoromethyl)phenyl]-4-h~Lo~y-3-[(phenylmethyl)thio]-2H-pyran-2-one;
253-[1-(Cyclohexylthio)-3-methylbutyl]-4-hydroxy-6-phenyl-2H-pyran-2-one;
[4-[4-Hyd~o~y-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]acetonitrile;
6-Phenyl-4-hy~ Gxy-3-[(cyclo~lo~ylmethyl)thio]-2H-pyran-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-[(4-phenylbutyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-hydroxy-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one;
356-Phenyl-4-hydroxy-5-methyl-3-(phenylthio)-2H-pyran-2-one;
t4-t4-Hydroxy-2-oxo-3-(phenylthio)-2H-pyran-6-yl ] ph~no~y ] acetic acid;

WO95/14014 ~ ~ 7 4 1 2 ~ PCT~S94112367 [4-[4-Hydlo~y-5-methyl-2-oxo-3-(phenylthio)-2H-pyran-6-yl]phP~oYy]acetic acid;
4-Hydroxy-3-t(phenylmethyl)thio]-6-(3-pyridinyl)-- 2H-pyran-2-one;
56-(2,6-Dimethyl-4-pyridinyl)-4-hydroxy-3-(phenylmethyl)thio]-2H-pyran-2-one;
4-~y~lo~y-3-t(phenylmethyl)thio]-6-(3-thienyl) 2H-pyran-2-one;
4-~y~lGxy-3-t(2-isopropylphenyl)thio]-6-tl-(2-methylpropyl)cyclopentyl]-2H-pyran-2-one;
4-HydLo~y-3-[(2-isG~Lopylphenyl)thio]-6-[l-(3 methylbutyl)cyclopentyl]-2H-pyran-2-one;
4-HydLoxy-3-[(2-iso~l~ylphenyl)thio]-6-[l-(4-methylpentyl)cyclopentyl]-2H-pyran-2-one;
lS4-~y~r~y-3~t(2 -iSv~l O~y lphenyl)thio]-6-tl-(phenylmethyl)cyclopentyl]-2H-pyran-2-one;
4 IIy~o~y-3-[(2 -iSO~l ~ylphenyl)thio]-6-tl-(2-phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-HydLoxy-3-t(2-iso~Lu~ylphenyl)thio]-6-tl- (3-phenylpropyl)cyclopentyl]-2H-pyran-2-one;
4-~ydL~xy-3-[(2 -iSO~l o~ylphenyl)thio]-6-tl-(2-methylpropyl) CyClG~ ]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2 -iSGp r ~y lphenyl)thio]-6-tl-(3-methylbutyl)cyclo~y-l]-2H-pyran-2-one;
254-Hydroxy-3-t(2-iso~Lo~ylphenyl)thio]-6-tl-(4 methylpentyl)cyclopropyl]-2H-pyran-2-one;
4-HydLoxy-3-[(2-isopropylphenyl)thio]-6-tl-(phenylmethyl)cyclo~o~yl]-2H-pyran-2-one;
4-Hyd~o~y-3-t(2-isc,~Lo~ylphenyl)thio]-6--tl-(2-phenylethyl)cyclopropyl]-2H-pyran-2-one;
4-Hyd~oxy-3-[(2-isopropylphenyl)thio]-6-[l-(3 phenylpropyl)cyclopropyl]-2H-pyran-2-one;
4-Hydluxy-6-(3-hydLuxy~henyl)-3-t(2-iso~lo~ylphenyl)thio]-2H-pyran-2-one;
354-Hydroxy-3-[(2-isopropylphenyl]thio]-6-(pyridin-4-yl)-2H-pyran-2-one;
4-Hyd~o~y-3-[(2-iso~lo~ylphenyl)thio]-6-(pyridin-2-yl)-2H-pyrân-2 -one;

WO9S/14014 ~ 1 7 ~ 1 2 ~ PCT~Ss 4 ,.ydluxy-3-t(2-isopropylphenyl)thio]-6-(4 nitrophenyl)-2H-pyran-2-one;
6-(4-Fluorophenyl)-4-hy~uxy-3-t(2-iso~v~ylphenyl)thio]-2H-pyran-2-one;
S4-Hydroxy-3-t(2-isopropylphenyl)thio]-6-(2-methylphenyl)-2H-pyran-2-one;
4-Hydl~xy-3-[(2-iso~lo~ylphenyl)thio]-6-(2 methoxyphenyl)-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydroxy-3-[(2-isu~u~lphenyl)thio]-2H-pyran-2-one;
4 -~y ~L oAy-3 - ~ ( 2-iso~u~ylphenyl)thio]-6-t4-(N,N-dimethylamino)phenyl]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2-iso~Lu~ylphenyl)thio]-6-(3-trifluoromethylphenyl)-2H-pyran-2-one;
154 II~dLo~y-3-[(2-isu~u~ylphenyl)thio]-6-[4-(l-naphthalenylmethyloxy)phenyl]-2H-pyran-2-one;
4-IIydlo~-3-[(2-iso~Lo~ylphenyl)thio]-6-t4-t2-(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~o~ylphenyl)thio]-6-[3-[2-(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
6-(4-Benzyloxy-3-methoxyphenyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(4-Benzyloxy-3-chlorophenyl)-4-hydloxy-3-t(2-is~u~ylphenyl)thio]-2H-pyran-2-one;
254-t4-~ydLo~y-2-ûxo-3-t(2-isu~L~ylphenyl)thio]
2H-pyran-6-yl]-2-methylph~no~y-acetic acid;
4-Hydroxy-6-[4-(2-hy~roxyethox-y)phenyl]-3-t(2-isopropylphenyl)thio]-2H-pyran-2-one;
2-t3-[4-Hydroxy-5-[(2-iso~lv~ylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy]acetamide;
4-HydLoxy-3-[(2-iso~Lv~ylphenyl)thio]-6-[4-(2,3-pyrazinemethoxy)phenyl]-2H-pyran-2-one;
4-Hyd~oxy-3 - t ( 2-isopropylphenyl)thio]-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
354-Hyd~oxy-3-t(2-isop~o~ylphenyl)thio]-6-[4-(pyridin-2-ylmethoxy)-3-methylphenyl]-2H-pyran-2-one;
4-~d~ u~y-3- [ ( 2-iso~Lo~ylphenyl)thio]-6-[4-(pyridin-4-ylmethoxy)phenyl]-2H-pyran-2-one;

~ WO 9Stl4014 PCT/US94/12367 ~17412~

3-~(2-Cyclopropylphenyl)thio]-4-hy~Lo~y-6-[4 (pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2,5-diisopropylphenyl)thio]-6-[4-(pyridin 3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~ro~lphenyl)thio]-6-t4-t2-(thiomorpholin-4-yl)ethoxy]phenyl]-2H-pyran-2-one;
., 4-Hydroxy-3-t(2-isG~ o~ylphenyl)thio]-6-~4-t2-(piperazin-l-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-HYdL u~y-3 ~ t ( 2-isu~o~ylphenyl)thio]-6-t4-t2-(methylpiperazin-1-yl)ethoxy]phenyl]-2H-pyran-2-one;
4 IIy~oxy-3-t(2-isG~Lo~ylphenyl)thio]-6-t4-t2-(1,1-dioxothiomorpholin-4-yl)ethoxy~phenyl]-2H-pyran-2-one;
4-Hy~kuxy-3-t(2-isoy~o~ylphenyl)thio]-6-(l-phenyl-cyclopentyl)-2H-pyran-2-one;
4-Hydroxy-3-t(2-isu~Lo~ylphenyl)thio]-6-(4 phenyl-piperidin-4-yl)-2H-pyran-2-one;
Isopentanoic acid 2-oxo-6-phenyl-3-t(2-isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
Propanoic acid 2-oxo-6-phenyl-3-t(2-isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
.Phenylacetic acid 2-oxo-6-phenyl-3-t(2-iso~o~ylphenyl)thio]-2H-pyran-2-one-4-ylester;
4 IIydLoxy-3-t(2-iso~Lu~yl-5-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
4-~yd~O~y-3-t(2-isu~ u~yl-4-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-t(2-isG~Lo~yl-6-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
3-[(4-Chloro-2-iso~Lu~ylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(4-hydroxy-2-iso~lu~ylphenyl)thio]-6-phenyl-2H-pyran-2-one;
3-t(2-Cyclopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[(2~5-Diisopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;

WO95/14014 ~ PCT~S94112367 ~

i 4 -HY~L oxy-6-phenyl-3-[(2-tert-butylphenyl)thio]-2H-pyran-2-one;
3-[(2-Cyclo~Lu~yl-5-isG~v~ylphenyl)thio]-4-hydLoxyy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopentyl-5-iso~Lu~ylphenyl)thio~-4-1~dL oxy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclohexyl-5-isv~Lo~ylphenyl)thio]-4-hY~L ~y-6-phenyl-2H-pyran-2-one;
4-~y~Lv~y-6-phenyl-3-[(2-tert-butyl-5-isu~Lu~ylphenyl)thio]-2H-pyran-2-one;
3-[(2,5-Di-tert-butylphenyl)thio]-4-1,~Lo~y-6-phenyl-2H-pyran-2-one;
3-~(2-Cyclopentylphenyl)thio]-4-~ o~y-6-phenyl-2H-pyran-2-one;
3-~(2-Cyclohexylphenyl)thio]-4-hyd~o~y-6-phenyl-2H-pyran-2-one;
4 ~ [ t4 IIy~lo~y-2-oxo-6-phenyl-2H-pyran-3-yl]thio]-2-hydroxy; n~An~;
4-Hydroxy-3-[[2-isop~o~yl-4-(morpholin-4-ylmethyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hy& oxy-3-[(6-iso~Lopyl-indan-5-yl)thio]-6-phenyl-2H-pyran-2-one;
4-Hy~oxy-3-[(4-iso~Lu~yl-benzo[l,3]dioxol-5-yl)thio]-6-phenyl-2H-pyran-2-one;
3-[(2-tert-Butyl-4-thiomorpholin-4-ylmethylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-3-[(2-tert-butylphenyl)thio]-2H-pyran-2-one;
3-t~(2-Cyclopropyl-5-isoplopyl)phenyl]thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[[(2-Cyclopentyl-5-iso~Lo~yl)phenyl]thio]-4-hYdL ~y-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[[(2-Cyclohexyl-5-iso~Lu~l)phenyl]thio]-4-hyd~oxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;

WO95/14014 ~1~ 4 1 2 ~ PCT~S94tl~67 4-~Iy~loxy-6-t4-(pyridin-3-ylmethoxy)phenyl]-3-t(2 tert-butyl-5-is~L~ylphenyl)thio]-2H-pyran-2-one;
3-t(2,5-Di-tert-butylphenyl)thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
53-t(2-Cyclopentylphenyl)thio]-4-hyd~x~-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-t(2-Cyclohexylphenyl)thio]-4-hy~ro~-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4 IIy~L~y-6-t4-(pyridin-3-ylmethoxy-)phenyl]-3 t(6-tert-butylindan-S-yl)thio]-2H-pyran-2-one;
4 IIydko~y-3-t(2-isopropyl-4-morpholin-4-ylmethyl-phenyl)thio]-6-~4-(pyrindin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
Acetic acid 3-t(2-iso~L~ylphenyl)thio]-2-oxo-6-lS t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
Isobutyric acid 3-t(2-iso~op~lphenyl)thio]-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
2,2-Dimethylpropionic acid 3-[(2-isopropylphenyl)thio]-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
4-~y~lo~y-3-[(2-isopropylphenyl)sulfonyl]-6-[4 (pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4 IIy-dLoxy-3-(2-iso~Lopylbenzoyl)-6-[4-(pyridin-3 ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-tert-Butylphenyl)sulfonyl]-4-hy~l~y-6 phenyl-2H-pyran-2-one;
6-(l-Benzylpropyl)-4-hyd~y-3-[(2-iso~L ~ylphenyl)sulfonyl]-2H-pyran-2-one;
306-(l-Benzylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio~-2H-pyran-2-one;
6-(l-Benzylpropyl)-3-[(2-tert-butylphenyl)thio]-4-hyd~G~y-2H-pyran-2-one;
N-[3-[[6-(l-Benzylpropyl)-4-hy~oxy-2-oxo-2H-pyran-3-yl]thio]-2-iso~o~ylphenyl]
benzenesulfonamide;

WO9Stl4014 7~ 1~4; i PCT~Ss4/12367 ~

6-tl-Cycl~lo~ylmethyl-2-(tetrahyd~o pyran-3-yl)ethyl]-4-hy~Loxy-3-[(2-iso~Lu~ylphenyl)thio]-2H-pyran-2-one;
4-~ydlo~y-3-(2-iso~ yl-rh~no~y)-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-HydLGky-3-(2-iso~Lv~yl-rh~noxy)-6-phenyl-2H
pyran-2-one;
3-(2-tert-8utyl-ph~nQxy)-4-hydLo~y-6-~4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-(2-tert-Butyl-5-methyl-rh~noYy)-4-hydLu~y-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
6-(1-Benzylplo~1)-4 1LY~1 O~Y_3_(2_ isG~l u~yl ph~noYy) -2H-pyran-2-one;
6-(1-Benzylpropyl)-3-(2-tert-butylphenoxy)-4-hyd~G~y-2H-pyran-2-one;
- 3-Benzyloxy-4-Hyd~u~y-6-~4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
2-t4-HydlO~y-2-o~O G t4-(py-ridin-3-ylmethoxy)phenyl]-2H-pyran-3-yloxy-methyl]benzoic acid methyl ester;
2-[t[6-(1-Benzylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]oxy]methyl] benzoic acid ethyl ester;
6-(1-Benzylpropyl)-4-h~dlo~y-3-(1-phenylbutoxy)-2H-pyran-2-one;
6-(1-8enzyl~ u~yl) -3-(cyclo~Lu~ylphenylamino)-4-hydroxy-2H-pyran-2-one;
N-t3-[[6-(l-Benzylpropyl)-4-hydLuxy-2-oxo-2H-pyran-3-yl] CYC1O~L u~ylamino]phenyl]benzenesulfonamide;
3-[Cyclo~lu~ylphenylamino]-4-hydroxy-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
3-(Bis-cyclopentylmethyl-amino)-4-hydroxy-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
3-[Cyclo~ell~ylmethyl(cyclo~ u~ylmethyl)amino]-4-hydlo~y-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
6-[l-cyclo~Lu~ylmethyl-2-(tetrallydLo pyran-3-yl)ethyl]-3-(cyclo~lo~ylphenylamino)-4-hyd~o~y-2H-pyran-2-one;

~ Wos5/I4014 PCT~S94/1~67 ~:~7~12~

CyclopropA~r~rboxylic acid cyclopentylmethyl-[4-hydLo~y-2-oxo-6-[(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]amide;
CyclopentAn~c~rboxylic acid cyclo~ellLylmethyl-[4-h~dlox~-2-oxo-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]amide;
N-Cyclo~ ylmethyl-N-[4-hydLoxy-2-oxo-6-~4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]
cyclopentanesulfonamide;
3-(Cyclv~L~ylphenylmethyl)-4-hyd~v~y-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
N - [3 - [CYC1V~LV~1[4 - hydlU~ - 2 ~AO G [4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]methyl]phenyl]benzenc~l f onamide;
4 ~Iy~Loxy-3-(1-phenylpropyl)-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
6-(1,1-Dimethyl-3-phenylpropyl)-4-hyd~o~y-3-[(2-iso~Lo~ylphenyl)thio]-2H-pyran-2-one;
N-[3-t CYC1G~, o~yl[6-(1,1-dimethyl-3-phenylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~l v~yl [ 4-hy~Yoxy-2 o~o G-[1-(2-phenylethyl)cyclopentyl]-2H-pyran-3-yl]methyl]phenyl]-benzenesulfonamide;
3-(Cyclo~lv~ylphenylmethyl)-6-(1,1-dimethyl-3-phenylpropyl)-4-hy~lo~y-2H-pyran-2-one;
N-[3-[~6-(1-Benzylcyclo~v~yl)-4-hydroxy-2-oxo-2H-pyran-3-yl]cycl~ o~ylmethyl]phenyl]-benzenesulfonamide;
6-(1-Benzylpropyl)-4-hydroxy-3-(2-isobutyl-5-isopropylphenyl)-2H-pyran-2-one;
6-(1-Benzylpropyl)-4-hyd~vxy-3-(2-methyl-5,6,7,8-tetr~lyd~o naphthalen-l-yl)-2H-pyran-2-one;
3-(3-Cyclopropylmethyl-5-iso~lv~ylphenyl)-4-hy~lox~-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2 one;
3-(3,5-Diiso~lv~lphenyl)-4-hydroxy-6-t4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one WOgS/14014 PCT~S94112367 ~

, 6-(Benzo[l,3]-dioxol-5-yl)-4-hydroxy-3-[(2-iso~Lu~y~lphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-t(2-isop~o~ylphenyl)thio]-6-~l-(phenylmethyl)cyclobutyl]-2H-pyran-2-one;
4-Hyd~oxy-3-t(2-is~lo~ylphenyl)thio]-6-[l-(2-phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hy~luxy-3-t(2-isopLu~ylphenyl)thio]-6-[l-( 3 ~
phenyl~o~y~l)cyclobutyl]-2H-pyran-2-one;
4-HydL vXy-3~ [ ( 2-iso~Lopyl-5-methylphenyl)thio]-6-(l-benzylcyclu~u~yl)-2H-py~an-2-one;
4-Hy~o~y-3-~(2-iso~L~l-5-methylpheny1)thio]-6-tl-(2-phenylethyl)cyclu~L u~yyl ] -2H-pyran-2-one;
4 IIyd~uxy-3-t(2-iso~Lo~yl-5-methylphenyl)thio]-6-~l-(3-phenyl~Lo~y.l)cyclo~ u~yl ] -2H-pyran-2-one;
4 IIy~loxy-3-t(2-iso~Lopyl-5-methylphenyl)thio]-6-(l-benzylcyclobutyl)-2H-pyran-2-one;
4-Hyd~uxy-3-t(2 -iSG~ o~yl-5-methylphenyl)thio]-6-tl-(2-phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hydroxy-3-t(2-iso~Lo~yl-5-methylphenyl)thio]-6-[l-(3-phenylpropyl)cyclobutyl]-2H-pyran-2-one;
4-~y~l~xy-3-t(2-isopLu~yl-5-methylphenyl)thio]-6-(l-benzylcyclopentyl)-2H-pyran-2-one;
4-Hydko~y-3-[(2-iso~Lu~yl-5-methylphenyl)thio]-6-tl-(2-phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-Hydlo~-3-t(2-isû~o~yl-5-methylphenyl)thio]-6-[l-(3-phenylpropyl)cyclopentyl]-2H-pyran-2-one;
6-(l,l-Dimethyl-3-phenylpropyl)-4-hydluxy-3-t(2-iso~L~ylphenyl)thio]-2H ~yLan-2-one;
6-(l~l-Dimethyl-2-phenylethyl)-4-hydroxy-3-[(2 iso~L~ylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(l-methyl-l-phenylethyl)-2H-pyran-2-one;
6-(l,l-Diethyl-3-phenylpropyl)-4-hydroxy-3-t(2-iso~lo~ylphenyl)thio]-2H-pyran-2-one;
3s 6-(l-Benzyl-l-èthylpropyl)-4-hydroxy-3-t(2-isoy~ylphenyl)thio]-2H-pyran-2-one;
6-(l-Ethyl-l-phenylpropyl)-4-hydroxy-3-[(2-isu~Lu~ylphenyl)thio]-2H-pyran-2-one;

WO95/14014 ~ 4 ~ ~ 4 PCT~Ss4/1~67 N-[3-tCyclo~u~lt6-(l,l-dimethyl-3-phenylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclv~.o~ylt6-(1,1-dimethyl-2-phenylethyl)-4-h~dlo~r-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-[3-tCyclo~.o~ylt4-hydroxy-6-(1-methyl-1-phenylethyl)-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclv~.v~ylt6-(~ diethyl-3-phenylpropyl)-4-hy~.~y-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-[3-tCyclo~v~yl[6-tl-ethyl-l-(phenylmethyl)propyl]-4-hy~Lu~y-2-oxo-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-t3-tCyclo~Lo~lt6-(1-ethyl-1-phenylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]methyl]phenyl~benzenesulfonamide;
N-t3-[Cyclo~ylt4-hydLo~-2-oxo-6-tl-(2-phenylethyl)cyclopentyl]-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-t3-tt6-(1-Benzylcyclopentyl)-4 hydlu~y-2-oxo-2H-pyran 3-yl]cycl~v~ylmethyl]phenyl]benzenesulfonamide;
N-t3-tCyc 1V~L V~Y 1 t4-l~y~.o~-2-oxo-6-tl-(3-phenylpropyl)cyclopentyl]-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~Lu~lt4-h~d~o~-2-oxo-6-[l-(2-phenylethyl)cyclobutyl]-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
N-[3-tt6-(1-Benzylcyclobutyl)-4-hyd~v~y-2-oxo-2H-pyran-3-yl]cyclo~.o~yl]methyl]phenyl]benzenesulfonamide;
N-[3-[cyclo~lo~l[4-hydroxy-2-oxo-6-tl-(3 phenylpropyl)cyclobutyl]-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;

W095/14014 ~ ~ 4 PCT~S94/12367 N-~3-~Cyclu~.o~ylt4-1~yd~v~y-2 - oxo-6- [ 1 - (2-phenylethyl)cyclo~lu~yl]-2H-pyran-3-yl~methyl]phenyl]benzenesulfonamide;
N-~3-[[6-(l-BenzylcyclG~lv~yl)-4-hyd~o~y-2-oxo-2H-pyran-3-yl]cyclu~u~y-lmethyl]phenyl]benzenesulfonamide;
N-[3-[Cyclo~ r u~yl~ 4-hy ~LV~y -2 oxo ~ (3-phenylpropyl)cyclo~lu~yl]-2H-pyran-3-yl]methyl]phenyl]benzenesulfonamide;
103-(Cyclo~Lv~ylphenylmethyl)-6-(1,1-dimethyl-3-phenylpropyl)-4 hy~lu~y-2H-pyran-2-one;
3-(Cyclu~u~ylphenylmethyl)-6-(l,l-dimethyl-2-phenylethyl)-4-hyd~u~y-2H-pyran-2-one;
3-(cyclf~Lu~ylphenylmethYl) -4 1~Y~1L~Y-6- (l-methyl-l-phenylethyl)-2H-pyran-2-one;
3-(cyclo~Lù~ylphenylmethyl)-6- ( 1 ~ l-diethyl-3-phenylpropyl) -4-hy~L uxy-2H-pyran-2-one;
6- (l-Benzyl-l-ethylpropyl)-3-(cyclG~Lu~lphenylmethyl)-4-hydroxy-2H-pyran-2-one and 203-(Cyclo~Lv~ylphenylmethyl)-6-[l-ethyl-l-phenylpropyl~-4-hy~Lo~y-2H-pyran-2-one.

4. ~ TT.~n n~pTpTIoN OF T~ INVENTION
Here, the term "alkyl", usually represented by an "R", means a straight or br~n~h~ dlGcarbon radical having from l to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, n-~,u~yl, iso~-u~yl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl. The alkyl ~,uu~ may contain one or more sites of unsaturation such as double or triple carbon-carbon bonds. The alkyl group is unsubstituted or substituted by from l to 3 substituents selected from alkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -N~-CO-R, -CO-NH-, -CO2R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are defined as herein.

~ WO95/14014 PCT~S94/1~67 The term "cycloalkyl", also represented by an "R", means a hydlo~arbon ring which contains from 3 to 12 carbon atoms unless otherwise specified, for example, cyclo~lo~yl~ cyclobutyl, cyclopentyl, S cyclohexyl, and adamantyl. Where possible, the cycloalkyl group may contain a single double bond.
The cycloalkyl ring may be unsubstituted or substituted by from 1 to 3 substituents selected alkyl, alkoxy, thioAlkoYy all as defined herein, ~ O~y~ thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R, -CO-NHR-, -CO2R, -COR, aryl, or ~eteroaryl wherein alkyl (R), aryl, and heteroaryl are defined as herein.
The terms "alkoxy" and '~thio~lkoxy~ are O-alkyl lS or S-alkyl as defined above for alkyl.
The term alkylcycloalkyl means a cycloalkyl attached to an alkyl chain where the terms cycloalkyl and alkyl are defined above.
The term spirocycle refers to a carbocyclic or heterocyclic ring whose ends meet at a single carbo~
in a ring or chain. Examples of such spirocycles are ring A in the following:

~O ~O ~ A~
~,S/-\Ph ~ \Ph ~ o~`O or ~ ~, A
\N~

The term "aryl" means an aromatic radical which is a phenyl group, a benzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, an anthracenyl group, a fluarenyl group or a fused ring resulting from any two of phenyl, naphthyl, and a 5- or 6- membered ring con~; n; ng from 0 to 3 heteroatoms selected from wogs/14014 ~ 7 ~ PCT~S94/12367 ~

s ,.

quinolones, isoquinolones, indoles, in~e benzofurans, benzothiorhenec, benzoxazoles, benzothiazoles, benz; ~OF~ 7oles, coumarins, benzimidazoles and the like, unsubstituted or s substituted by 1 to 3 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydlo~, thiol, nitro, halogen, amino, formyl, carboxy, nitrile, -NHCOR, -CONHR, -CO2R, -COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl are defined as above.
The terms "heteroaryl" and "hetelG~y~le", llCll~l ly represented by an "A", mean a heteroatom con~; n i ng ring radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or s-;~Y~olyl, 3- or 5- 1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl"
3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo~b]thienyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 1- or 2- piperazinyl, 2-, 3-, or 4-morpholinyl, 2-, 3-, or 4-thiomorpholinyl, 1-, 2-, or 3-pyrrolidinyl, 2- or 3-tetrahydofuranyl, 1-, 2-, -, 4-, 5-, 6-, 7- or 8-tetrahydroquinolinyl, and the like, all of which may be unsubstituted or substitut.ed by 1 to 2 substituents selected from alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, thiol, nitro, halogen, formyl, amino, carboxyl, nitrile, -NHCOR, -CO2R, -COR, wherein alkyl in as defined above or phenyl.
"Halogen" is fluorine, chlorine, bromine or ~odine.

-WO9S/14014 PCT~S94/1~67 ~17~12~

Some of the compounds of Formula 1 are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.
S Pharmaceutically acceptable acid addition salts ; of the compounds of Formula 1 include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicalbo~lic acids, phenyl-substituted A 1 kAnoic acids, hydl~y A 1kAnoic acids, alkA~; oic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydloypnphosphate~
dihydLGyenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, iso~uLyLdte, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge, S.M., et al., "Pharmaceutical Salts,~' Journal of Pharmaceutical Science, 66: 1-19 ( 1977 ) .
The acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, mag~esiU~ ~al~ium, and the like. ~xamples of W09Stl4014 ~ 24 PCT~S94/1~67 ~

suitable amines are N,N'-~;h~n7-ylethylenediamine, chlo~ u~2 ocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procA;ne (see, for example, Berge, S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1977).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are int~n~ to be encomp~se~ within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all enantiomeric and epimeric forms as well as the a~o~.iate mixLule~ thereof.
The compolln~C of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compo~n~c of the present invention can be administered by injection, that is, intravenously, intraml~cc~llArly, intracutaneously, subcutaneously, intr~ o~PnAlly, or intraperitoneally. Also, the compounds of the present invention can be administered by ;nh~l~tion, for example, intr~n~cAlly. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active comro~nt, either a compound of Formula 1 or a corr~pon~;ng pharmaceutically acceptable salt of a compound of Formula 1.
For preparing pharmaceutical compositions from the com~u~lds of the present invention, ~ WO95tl4014 ~7 ~1 2 ~ pcT~ss~/l2367 .

pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, ~o~itories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an ~nc~r~ulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the ~ece~FAry b; n~; n~ properties in suitable ~Lv~oLLions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium caL~G~ymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is inten~ to include the formulation of the active compound with ~nc~pculating material as a carrier providing a capsule in which the active component with or without other carriers, is ~uLLoul~ded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

WO95/14014 PCT~S94/1~67 ~

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water ~-o~ylene glycol solutions. For parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and ~; n~ suitable colorants, flavors, stabilizing and thiCkPn i ng agents as desired.
Aqueous suspensions suitable for oral use can be made by ~i~p~sing the finely divided active component in water with vis~o~c material, such as natural or, synthetic gums, resins, methylcellulose, sodium caL~ymethylcellulose, and other well-known 5 s~ pen~ i ng agents.
Also included are solid form preparations which are inte~ to be coll~el~ed, shortly before use, to liquid form preparations for oral administration.
Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thick~n~s, solubilizing agents, and the like.
2S The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is divided into unit doses contA; n; ng a~L O~L iate guantities of the active component. The unit dosage form can be a packaged preparation, the package con~; n; ng discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a c~pC?lles~ tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from O.l mg to lO0 mg preferably 0.5 mg to lOo mg according to the , ~ WO g5/14014 ~ ~ 7 4 ~ ~4 PCT~S94J1~67 particular application and the potency of the active comron~nt. The composition can, if desired,talso contain other compatible therapeutic agents.
In therapeutic use as antagonists of a LeL.~viral protease, as agents for the treatment of infections caused by a LeLlvvirus including HlV, or as agents for the treatment of diseases due to AIDS, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about O.O1 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg to about 10 mg/kg is preferred.
The dosages, however, may be varied ~p~n~; n~ upon the requirements of the patient, the severity of the condition being treated, the com~o~.d being employed.
Determination of the proper dosage ~or a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the optimum effect under the circumstAnr~s is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

WO9S/14014 PCT~S94/12367 ~

~7~124 .1 G~neral ~ynthetic Appr~-~h~Q
to ~6~ DQrivatives Scheme I, shown below, illustrates the S preparation of 6-substituted-3-substituted pyrones.
S~$~A~ I

O 1. B~e OSiMe3 `~ C ~ TMS-OTf ~~\_rr'RS
H ~Rs ( NEt3 ) I
OH R

CO2Et ~ ~ /
`C02Et ~\o~O
m Ketone I is treated with a suitable base, such as lithium diiso~Lu~ylamide or lithium bis(trimethylsilyl)amide, at -78 C to -45 C, in ether or THF solution and, when deprotonation is complete, quenched with chlorotrimethylsilane (TMS-Cl), at -78 C to 0 oc, producing the silyl enol ether II. Alternatively, compound I is treated with trimethylsilyltrifluorome~h~n~culfonate (TMS-OTf) and triethylamine at 0 C in dichloromethane solution, to effect transformation to intermediate II. Compound II
is then reacted with an appropriately substituted malonate and heated either neat or in xylene at 130-160 C to give the desired product III.
For ~uu~G~es of the above and other syn~h~cec of the compounds of the present invention, reactive functional yL~U~ present in starting materials, reaction intermediates, or reaction products may be WO95/14014 ~1 7 ~ ~ 2 4 PCT~S94~1~67 - 3s -protected during chemical reactions using protecting ylOU~ which render the reactive functional yl~u~
substantially inert to the reaction conditions. (See for example, Protective Groups ln Organic Synthesis, 2 ed., T. W. Green and P. G. Wuts, John Wiley & Sons, New York, NY l99l). Thus, for example, protecting y~Ou~S such as the following may be utilized to protect suitable amino, hy~ko~yl, and other groups of related reactivity: car~oxylic acyl y~Ou~S, such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl yL UU~ ~ such as ethoxycarbonyl, t-butoxycarbonyl (BOC), ~ -trichloroethoxycarbonyl (TCEC), ~-iodoethoxycarbonyl; aryloxycarbonyl yLo~, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl ylOU~, such as trimethylsilyl and t-butyldimethylsilyl (TBDMS); and yL~u~ such as trityl, tetral~ydl U~l anyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl, may all be utilized. The protecting group may be removed, after completion of the synthetic reaction of interest, by ~ r o~e~ules known to those skilled in the art. For example, the BOC group may be removed by acidolysis, the trityl group by hydLoyenolysis, TBDMS
2s by treatment with fluoride ions, and TCEC by treatment with zinc.
An alterna~ive approach to functionalized pyrones is outlined in Scheme II.

WO95/14014 2 1 ~ PCT~S94/1236 sr~ II

OH
OSiMe3 ,COCI Rs , h~
~`"``'~--S `COCI '' CH~-- so2sR2 ~ -78C

II IV
OH

R5 ~/sR2 V

The trimethyl silyl enol ether II is reacted with malonyl dichloride in a dry solvent such as ether or THF at low temperature, preferably -78 C to -35 C, to give pyrone IV, which is converted to the sulfur derivative V using an a~-o~Liately substituted p-toluenethiosulfonate, as disclosed in U.S. Patent 3,931,235 (1976). Alternatively, the thiotosylate reagents were prepared as described by M. G.
Ranasinghe and P. L. Fuchs in Syn. Comm. 18 (3): 227 (1988). The requisite thiols can be prepared ~rom the corresponding phenol via the Newman-Kwart rearrangement (see, for example, H. Kwart and H.
Omura, J. Amer. Chem. Soc. 93: 7250 (1971); M. S.
Newman and F. W. Hetzel, Org. Synth. Coll. Vol. ~I:
824 (1988); M. S. Newman and H. A. Karnes, J. Org.

~ WO95/14014 2 1 7 ~ 1 2 ~ PCT~ss4/1~67 Chem. 31: 3980 (1966)) or from the corresponding io~oh~n7ene via a nucleophilic displacement with ~hiourea in the pr~ce~ce of a nickel catalyst (~.
Takagi, Chem. Letters, 1307 (1985)).
S A synthesis of pyrones such as VIII is shown below, in Scheme III. Here, substituent R6 of structure VTI can be aryl, alkyl, or substituted alkyl.
S~ R III

!l CH 3 ~R6 i; ~1 1. NaH
OEt 2. RLi ~ OCH3 VI
OH

O 5~ ,~ 3 R6/~ `OEt R6~ O--~O
R R
VII VIII

Substituted ~-ketoester VI is deprotonated with one equivalent of a suitable base, e.g. a metal hydride such as sodium hydride, in a suitable solvent, e.g. ether or THF.. A second equivalent of a stronger base, e.g. an alkyllithium such as n-butyllithium or lithium diiso~Lu~ylamide, is added to the malonate solution to produce the dianion, which is then reacted with a suitable acylating agent, e.g. an amide, at O C to 25 C producing dione ester VII. Compound VII

WO95tl4014 I PCT~S94/12367 ~
~1 7~ 1~4 may then be cyclized to the pyrone VIII in a variety of ways, e.g. by using a sL,o~.y acid such as H2SO4 or CH3SO3H, by heating the reaction mixture in a high boiling solvent such as xylene, or by using a small s amount of a base, preferably a hindered base like l,8-~;A~hicyclo[5.4.0]undec-7-ene. If R3 = H, then pyrone VIII can be further derivatized, as shown in Scheme II above.
Scheme IV describes the preparation of O-acyl pyrone analogues.

SC~M~ IV

R5~ 1~ ,R3 R5~ ",R3 Base, CICR7 1' ~

R6' `a'~) R6' `~`O
VIII

The pyrone, e.g. VIII, is treated with a suitable base, e.g. a metal hydride such as sodium hydride, or an alkoxide, in a suitable solvent, e.g. THF, dioxane, or ether, and the resulting anion is reacted with an acyl chloride or other acylating agent producing the desired acyl derivative IS.
Scheme V, shown below, illustrates the preparation of several 3-alkyl pyrone derivatives.

WO95/14014 ~7 ~12~ PCT~S94J1~67 S~P!MF~ V

~R8CH,HSRg or H2NRg R5~,~ R
~ r., HOAc R /~0~) VIrI X
(wh~x Y= N,S) OH ~8 R6 a~
XI

Intermediate pyrone VIII in an alcoholic medium, such as ethanol, is combined with a suitable aldehyde and a suitable nucleophile, such as HSRg or NH2Rg, in the presence of a mixture of an acid, such as acetic acid, and a base, such as piperidine. The resulting mixture is heated at 60 C to 90 C to produce a pyrone X, which may itself be a preferred compound.
Alternatively, for the case of Y = S, S may be reduced via a dissolving metal reduction, e.g. by using sodium in liquid ammonia, or via a reduction employing a Raney nickel system in a solvent such as acetone, to - give desired 3-alkyl pyrones SI.
Scheme VI summarizes the synthesis of certain 3-amino pyrones.

WO95/14014 PCT~S94/12367 ~1 ~1 ~4~ ~

S~u~ Z VI

OH OH
Rs~;HNO3, HOAc Rs~ ~2 Sn, H
"HOAc jl I

R8~ ' ` R8/~ 0~0 vm OH
Rs NH2 ~
R6/l~O~'O R~2NC
1. RloCHO,D~F,/ g~ OH 1 HO~C/ R-1 CO2H Rs~ NHCNRt2 ~/~ NaCNBH3 MeN O, ~N
OH N{:~NEt ~H-- R5~/ NHCR

XV

Nitration of pyrone VIII is effected with nitric acid, preferably fuming nitric acid in acid solution, e.g. as described in US Patent 3,206,476 (1965).
Reduction of ni LL ~yL one XII with tin and acid furn;sh~s aminopyrone XIII. Intermediate 2III can now be elaborated into a variety of derivatives. For example, XIII may be treated with an a~L U~L iately substituted aldehyde in the presence of a reducing agent, such as sodium borohydride or, preferably, sodium cyanoborhydride, to give the N-alkylated analogues xrv. Acylation of compound ~III may be achieved via one of several routes: l. By treatment with sodium hydride, followed by coupling with a mixture of a suitable carboxylic acid, N-methylmorpholine, and a suitable co~n~ing agent, such as l-(3-dimethylaminu~}~yl)-3-ethylcarbodiimide, at a suitable temperature, e.g. -35 C - o oc; 2. By ~17 412A
- WO95/14014 - PCT~S94~12367 reaction with a suitable acid chloride or other acylating agent in the presence of a base, such as triethylamine, and 4-dimethylaminopyridine; or 3. By - deprotonation with sodium hydride, followed by reaction with a suitable acid chloride in the presence of excess of an amine base, usually triethylamine, at elevated temperatures, e.g. 40-60 C. Ureas such as XVI may be prepared from aminopyrone XIII by reaction with a suitable isocyanate and a base, e.g. N-methylmorpholine, in an inert solvent such as ethyl acetate.
Scheme VII ou~l ineC an alternate approach for the preparation of C-6 substituted analogs.

sr~2 VII

OR OR OR
R3 NBS ~, Rs~ ~ - R3 R13SNa ~ R5 ~ ~" R3 H C 0/~0 ~~C ~0 '~O'~O
2 0 ~ Br ~ SR~3 X$[1:

1. 2~nv.ba~l 1. N~N3 1 ~ NaOH
2. ~ 7 ~dudr~

~
OR OR OR
F~5 ~"R3 RS--~ R3 R5~ ~,R3 E ~NH2 ~ OH m 3 (E ~ alkyl groups: C~ H: PhCO) The 6-methyl pyrone XVII is treated with 2 equivalents of a strong base, e.g. sodium amide in 35 liquid ~mmonia or lithium diisopropylamide in THF
solution, followed by ~l~nch;ng with one of a great variety of electrophiles, e.g. alkyl halides, acylating agents, etc., furnishing pyrone XVIII (see _ WO 95114014 PCT/US94/12367 1ll ~17~
.

M.P. Wachter and T.M. Harris, ~etrahedron 26: 1685 tl970)). Alternatively, allylic bromination of SVII
under free radical conditions, e.g. using N-bromosuccinimide (NBS) in the presence of a free radical initiator and light, affords intermediate XIS, which can be further elaborated to amine X~ as described in Jones et al., Tetrahedron Letters, 30:
3217 (1989), converted to alcohol ~XI as described in R. Bacardit et al ., J . Heterocycl ic Chem . 19 : 157 (1982.), and ultimately transformed to sulfide ~SII as described in R. Bacardit et al., J. Heterocyclic Chem.
26: 1205 (1989). The amino and hyd~o~y substituents of structures ~ and ~SI can be further derivatized using s~n~rd reactions known in the art, e.g. via alkylation, acylation, etc..
The synthesis of several 4-substituted pyrone derivatives is shown in Scheme VIII below.

WO95114014 ~ 7 ~ ~ 2 ~ PCT~S94/1~67 St'~MF VIII

S OH OTs SR1"
R5~R3 T~CI R5~ RaRl~SNa Rs~ ~ R3 R~O~O '~
vm ~m ~v P8r3 /DMF
Br CO2C~ ~OH
R5~R3 1P50Cps~(cPora)2 R5~f; R5~RJ
l~ I NEt3, M~OH l! 11 !
R6/~O~o R~3 Rjf~O~O
lS XXV ~ ~v~
N~
t R5 ~R3 H2~d R5 2 0R6 'J~ RB
2S~V111 2~

Pyrone VIII is activated, e.g. by tosylation to YYTTT using p-toluenesulfonyl chloride (TsCl) in pyridine. The tosylate is then reacted with a suitable sulfur nucleophile (see A.M. Bittencourt et al., Tetra~edron, 27: 1043 (1971)) to give sulfide - 30 XSIV. In a similar fashion, pyrone VIII is converted to the 4-bromo analog A~V, using a brominating agent such as phosphorous-tribromide/dimethylformamide (DMF). Displacement of the bromine of X$V with azide followed by reduction (e.g. preferably hydrogenation over a palladium/triaryl-phosphine catalyst in a suitable solvent) gives 4-amino derivative SSI~.
Further functionalization of the amine moiety of X~I~
is achieved as described above in Scheme VI.

WO95/14014 PCT~S94/12367 ~

Alternatively, 4-bromo~L~l.e ~SV can be reacted with a palladium triarylphosphine catalyst and methanol in a carbon monoxide atmosphere to give ester ~XVI. The ester can be further hydrolyzed, e.g. in s acid solution at 0-25 C, to the corresponding carboxylic acid, or reduced, e.g. using a hydride t reagent such as lithium aluminum hydride in THF or ether solution at 0 C-25 C, to the alcohol (XSVII~.
Scheme IX illustrates the preparation of 2H-l0 thiopyran-2-one derivatives.
S~U~HR IX

Cl OH
~ + R3 ~ E~2C~ ~ R3 R6 SH Cl`- ~" S'~`O

OH
1. OH- ~"R3 2. PhNO2/quinolone~ ~ , 1, j ~00~11 An a~o~iately substituted ~-mercapto acrylate, e~g.
XXS, is condensed with the desired malonyl dichloride in an inert solvent, e.g. toluene, at a temperature between 0 C and the boiling point of the reaction solvent, to afford the thiopyran-2-one XS~I.
Thiopyrone ~S~I may be converted to derivative ~X~II
under suitable conditions, e.g. by basic hydrolysis followed by deca~bo~ylation (for example, see F. K.
Splinter and H. Arold, J. Prakt . Chem ., 38 : 3-4 , 142-6). Thiopyrones XS~II (R3 = H) can be converted to ~ WO95tl4014 PCT~S94/12367 ~17~12~

their substituted derivatives, using the ~oced~es of Schemes II, X, and VI for derivatization of the analogous pyrones.
Suitably protected pyrones, e.g. SVII, as well as their analogs possessing S instead of 0 at position 1 of the pyrone ring, may be thiated, i.e. the carbonyl at position-2 of the heterocycle may be replaced by a thiocarbonyl (C=O - C=S), using st~n~Ard group modification te~h~; ques, e.g. employing a thiation reagent such as Lawesson's reagent under suitable reaction conditions (see Monatsh . Chem ., 1~5: 769 (1984) and Chem. Rev. 8~: 17 (1984)).

~.2 General r~ ure8 for the Pre~aratson of Function~ ed PYrones Met~od A: 8ynthesis ~ia Reaction of 8ilyl Enol Bthers with 2-~ubstituted Prop~nq~;oic Acid ~sters i) Preparation of Trimethylsilyl enol ~thers To a solution of an appropriate ketone (lo mmol, 1 equivalent) in dry tetrahydrofuran (100 ml) at 7& C
was added lithium hexamethyldisilazide (11 mmol, 1.1 equivalents). The reaction mixture was stirred at -78 C for 1 hour and at -35 C for 0.5 hour.
Trimethylchlorosilane was then added dropwise at -78 C, and the resulting mixture was stirred for 1 h at -78 C and for 0.5 h at 0 C. The reaction was stirred at -78 oc for 1 h., and at o C for 0.5 h.
The reaction was interrupted by addition of saturated sodium bicarbonate solution and the reaction mixture extracted with ethyl acetate (300 ml). The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, and dried further over anhydrous sodium sulfate. The ethyl acetate solution was concentrated under reduced pressure and the material isolated was dried in vacuo for 1 hour and used without purification.

WO95/14014 2 17 ~ 12 4 PCT~S94/12367 ~

,,, !

~i) CQn~n~ation of Triuethylsilylonol ethers with Dialkyl Bsters of 2-8ubstituted Pro~ns~;oic Acid Crude trimethylsilyl enol ether (11 mmol, 1.1 equivalents), prepared as described above, was 5 combined with a dialkyl ester of a 2-substituted pro~n~;oic acid, (10 mmol, 1.O eguivalent) and the T
resulting mixture was heated at 150 C with continuous passage of nitrogen gas through the reaction mixture, overnight. The reaction mixture was cooled to room 10 temperature and the product was purified by chromatography on silica gel. Elution with 10-15%
ethyl acetate/h~An~s removed unreacted starting material and other impurities and elution with 30-50%
ethyl acetate/5% methylene chloride/h~YAnPs effected further purification furn; ~h; ng the desired pyrones in 20 - 75% yield.

~etho~ B: 8ulfenylation of 6-Aryl-~-hy~.oAy-2~-pyra~
2-one i) Preparation of 6-Aryl-4-hy~ 6~y~2 ~y~6he The trimethylsilyl enol ether (20 mmol, 1 equivalent), prepared as described in Method A (or ob~ e~
commercially), was taken in anhydrous ethyl ether and cooled to -78 C to -40 C. To it malonyl dichloride (30-40 mmol, 1.5-2 equivalents) was added dLV~ ise.
The reaction mixture was warmed up gradually to room temperature and stirred at room temperature overnight.
The solid obt~in~ was filtered and washed with anhydrous ether.
ii) 8ulfenylation of 6-Aryl-4-hydroxy-2~-pyran-2-one The 6-ary1-4-hydroxy-2-pyrone prepared as described above (1.62 mmol, 1 equivalent) was dissolved in ethanol. To this solution was added lN sodium hy~Loxide (1.72 mL, 1.04 equivalents) or 2 equivalents of triethylamine, followed by the a~ ~ iate thiolsulfonate (1.72 mmol, 1.04 equivalents). The reaction mixture was heated at reflux for overnight.

WO9S/14014 PCT~S94/12367 ~ 74~24 The solvents were evaporated, acidified with lN HCl and the product was extracted with ethyl acetate.
After evaporation of the solvents, the crude product was purified by chromatography (silica gel-230 to 400 mesh) using 30-50% of ethyl acetate in h~x~nec to yield the desired product. ~ields: 40-80%.

Mothod C: Pr~paration of ~6-Aryl~ o~y-2-oxo-2~-pyran-3-yl) ~rylthiometh~no~
To the 6 aryl-4-~1y~luxy-2H-pyran-2-one (2.16 mmol; 1 eq) in 10 mL of ethyl alcohol, the appropriate aldehyde (2.37 mmol, 1.1 equivalents), appropriate thiol (5.62 mmol, 2.6 equivalents), piperidine (0.50 mL), and acetic acid (0.50 mL) were lS added. The reaction mixture was kept at 80 oc for 24 hours. The ethyl alcohol was evaporated, acidified with lN HCl and the residue was purified by chromatography (silica gel-230 to 400 mesh) to yield 35-60% of the desired product.
~ethod D: Preparation of 6-Aryl-3-al~ylamino-~-hydroxy-2~-pyran-2-on~
i) 6-Aryl-~ dLvAy-3-nitro-2H-pyran-2-one The method used was adapted from the pro~ule described in U.S. Patent 3,206,476 (1965) for nitration and reduction. To a suspension of 6-aryl-4-hydroxy-2H-pyran-2-one (2.65 mmol, ) in acetic acid (2.77 ml) at room temperature was added fuming nitric acid (0.222 ml). After stirring for 5 minutes, the reaction mixture was cooled to 0 C and the product filtered. The product was purified by recrystallization from boiling acetic acid. lH NMR
(2S0 MHz, d-TFA) ~ 7.02 (s,lH), 7.65 (s, 3 H), 7.99 (m, 2 H).
ii) 3-A~ino-6-aryl-~-hy~roxy-2H-pyran-2-one To a suspension of 6-aryl-4-hy~,o~y-3-nitro-2H-pyran-2-one (10.5 mmol, 1 equivalent) in acetic acid (15 ml) WO95/14014 PCT~S94/12367 ~
~17~
.

and concentrated HCl (7.34 ml) was added mossy tin (20.6 mmol, l.96 equivalents). This mixture was then heated to reflux and a homogeneous mixture resulted.
The reaction mixture was refluxed for 7 minutes, and then cooled in an ice bath. Concentrated HCl was added to precipitate the 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one hydrochloride, which was collected and dried. lH NMR (250 MHz, D20) ~ 6.74 (s,lH), 7.53 (m, 3 H), 7.84 (m, 2 H).
iii) 3-Alkylamino-6-aryl-~-hydroxy-2~-pyran-2-ones To a solution of 3-amino-6-aryl-4-hy~v~y-2H-pyran-2 one hydrochloride (2 mmol, l equivalent) in dimethyl formamide cont~;n;~ 1% acetic acid (20ml) was added ~5 the aldehyde (2.l to 4.2 mmol, l.05-2.l equivalents) followed by sodium cyanoborohyride (2.1 to 4.2 mmol, l.05-2.l equivalents). The reaction was stirred for minutes, quenche~ with water and con~-~ntrated in vacuo. The oily residue was diluted with lO0 ml of ethyl acetate, washed with water, then saturated sodium chloride, and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo the crude product was either purified by column chromatography (silica gel-230 to 400 mesh) or 2S recrystallization to yield the desired product.

Method B: 3-Acylamino-6-aryl-~-hydroYy-2~-pyran-2-ones The following pLou~dures were used for amidation of the 3-amino-6-aryl-4-hydroxy-2H-pyran-2-ones.

a) To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one hydrochloride (0.84 mmol, l.0 equivalent) in THF
(10 ml) was added 60% sodium hydride (0.92 mmol, l.l equivalent) followed by stirring at room temperature for 30 min. In a separate flask, to the a~L O~L iate carboxylic acid (l.67 mmol, 2 equivalents) in THF (20 ml) at -20 C was added N-methyl morpholine (0.92 WO95/14014 PCT~S94J1~67 ~ 4~2~

mmol, 1.1 equivalent) followed by 1-(3-dimethylamino~.~yl)-3-ethylcarbodiimide hydrochloride (0.92 mmol, 1.1 equivalent). The reaction mixture was stirred at -20 C for 1 hr. This solution was added to the above 3-amino-6-aryl-4-hydlo~y-2H-pyran-2-one followed by more N-methyl morpholine (0.918 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature overnight. The reaction was qll~n~he~ by adding brine and diluting with ethyl acetate. The organic layer was washed in s~sc~c-sion with 1 N HCl, water, saturated sodium chloride, and was then dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) to yield the desired product.

~) To a suspension of 3-amino-6-aryl-4-hydko~y-2H-pyran-2-one, monohydrochloride (0.83 mmol, 1.0 equivalent) in methylene chloride (8mL) was added triethylamine (3.3 mmol, 4.0 equivalents) followed by a catalytic amount of 4-dimethylaminopyridine (0.08 mmol, o.l equivalent) and the a~Lo~iate acid chloride (0.92 mmol, 1.1 equivalent). The reaction was stirred at room temperature for 6 hours. The reaction was qll~nch~ with lN hydrochloric acid and then diluted with methylene chloride. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was recrystallized from boiling acetic acid.

c~ To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one monohydrochloride (O.63 mmol, 1.0 equivalent) in tetrahydrofuran (6mL) at 0 C was added 60% sodium hydride (0.69 mmol, 1.1 equivalents). The resulting mixture was stirred at room temperature for 15 minutes. To the reaction mixture, the corr~spo~

WO9S/14014 ~ 1 2~ PCT~S94112367 ~

acid chloride (0.69 mmol, 1.1 equivalents) was added.
The reaction mixture was heated to 50 C for 1 hour and overnight at room temperature. The reaction was quenched with lN hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydLous t magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was recrystallized from boiling nitromethane to yield the pure product.
Nethod F: Preparation of 3-Al~yl-6-aryl-~-hydrosy-2~-pyr~n-2-ones The (6-aryl-4-hyd~o~-2-oxo-2H-pyran-3-yl)arylthio-meth~nes were prepared as described in Method C.
Raney-Nickel (Grace 3100) was boiled in acetone for 45 - minutes and the acetone was replaced with ethanol (20 ml). The (4-h~d~Gxy-6-substituted-2-oxo-2H-pyran-3-yl)arylthiomethane (1.0 mmol, 1 equivalent) was added and the resulting slurry was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethanol. The filtrate was ~onc~ntrated in vacuo to yield pure products.

Method G: Preparation of ~-Acylo~y Esters of ~-~ydro~y-3-aryl(or arylal~yl)thio-6-aryl-2~-pyran-2-one The 4-hydroxy-3-aryl(or arylakyl)thio-6-aryl-2H-pyran-2-one (3 mmol, 1 equivalent) was dissolved in 20mL of tetrahydrofuran and cooled to 0 C. To this mixture was added sodium hydride ( 3.3 mmol, 1.1 equivalent) slowly and the resultant mixture was stirred at room temperature for 15 minutes. The corresponding acid chloride (6 mmol, 2 equivalents) was added drop-wise and the reaction was stirred at room temperature overnight. The reaction was ~l~nche~ with saturated sodium chloride solution and was diluted with lOOmL of ethyl acetate. The combined organic layer was washed with sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. After evaporation of ~ WO95/14014 PCT~S94/12367 ~ ~4~2~

the solvents, the crude product was purifed by column chromatography (silica gel-230 to 400 mesh) using 10 ethyl acetate in h~Y~n~ as eluents afforded the enol ester in 70-85% yields.

4.3 PreParation of 8tartin~ Materials Esamples A-B: Pr~p~r~tion of propane~ ioic Acid~
The following key intermediates were synthesized according to the proceduLe described in Comptus rendus 2S5: 2611 (1962).

ksampl~ A
Diethyl ester of l(phenylmethyl)thio3-pro~n~ ;oic acid : b.p. 160-162 C/6 mm Hg;
lH NMR (250 MHz, DMSO-d6) ~ 1.18 (t, 6 H), 3.93 (s, 2 H), 4.13 (q, 4 H), 4.44 (s, 1 H), 7.31 (m, 5 H).

Example B
D~methyl e~ter of t~2-naphthale~yl~ethyl)thio]-pro~ne~;oic ~ci~: The crude product was purified by silica gel chromatography (silica gel 230-400 mesh). lH
NMR (250 MHz, DMSO-d6) ~ 3.65 (s, 6 H), 4.10 (s, 2 H), 4.55 (s, 1 H), 7.51 (m, 3 H), 7.87 (m, 4 H).

~ s~mpl~ C
Diothyl ester of ~3-phenylpropyl)thio]-proF~ns~ioic acid: b.p. 185-190 C/1 mm Hg;
lH NMR (400 MHz, DMSO-d6) ~ 1.17 (t, 6 H), 1.82 (m, 2 H), 2.65 (q, 4 H), 4.14 (q, 4 H), 4.62 (s, 1 H), 7.23 (m, 5 H).

Example D
Diethyl ester of t~2-n~phth~lenyl)thio] ~ GL~n~;oic acid: The crude product was purified by silica gel chromatography (silica gel 230-400 mesh). lH NMR (250 MHz, DMSO-d6) ~ 1.09 (t, 6 H), 4.12 (q, 4 H), 5.27 (s, 1 H), 7.58 (m,-3 H), 7.90 (m, 3 H), 8.80 (s, 1 H).

WO95/14014 ~ 2 ~ PCT~S94/12367 ~
, ~s~ple E
Di~thyl ~st~r of t(2-ph~nyl~thyl)thio] ~ro~a~o~ioic acid: b.p.: 160-165 C/lmm of Hg.
lH NMR (400 MHz), DMSO-d6) ~ 1.19 (t, 6 H), 2.89 (m, 2 H), 4.16 (q, 4 H), 4.68 (s, 1 H), 7.25 (m, 5 H).

Es~mples F-M: Prep~r~tio~ of p-ToluenQthiosulfon~tes The following p-toluenethiosulfonates were synthesized according to the procedure described in U.S. Patent 3,931,235 (1976).

Es~mple F
2-Phe~G~y~Lhyl p-Toluenethiosulfon~te: lH NMR (400 MHz, DNSO-d6) ~ 2.41 (s, 3 H), 3.41 (t, 2 H), 4.13 (t, 2 H), 6.83 (d, 2 H), 6.94 (t, 1 H), 7.27 (t, 2 H), 7.48 (d, 2 H), 7.85 (d, 2 H).

~xample G
3-Phenyl-2-propenyl p-Toluenethiosulfon~te: lH NMR
(400 MHz, DMSO-d6) ~ 2.32 (s, 3 H), 3.93 (d, 2 H), ~.00 (dt, 1 H), 6.58 (d, 1 H), 7.29 (m, 5 H), 7.38 (d, 2 H), 7.81 (d, 2 H).

Example H
2-t2-Methosyp~nyl~thyl p-Toluenethiosulfo~atQ: lH NMR
(400 MHz, DMSO-d6) ~ 2.43 (s, 3 H), 2.80 (t, 2 H), 3.19 (t, 2 H), 3.75 (s, 3 H), 6.83 (t, 1 H), 6.93 (d, 1 H), 7.02 (d, 1 H), 7.21 (t, 1 H), 7.49 (d, 2 H), 7.81 (d, 2 H)-ExamplQ I
~-Ph~nylbutyl p-Toluenethiosulfonate: lH NMR (400 MHz, DMSO-d6) ~ 1.53 (m, 4 H), 2.43 (s, 3 H), 2.50 (t, 2 H), 3.03 (t, 2 H), 7.12 (d, 1 H), 7.18 (d, 2 H), 7.25 (t, 2 H), 7.45 (d, 2 H), 7.80 (d, 2 H).

Es~mple J

WO95/14014 ~1 7~ PCT~S94/12367 2-~3-Netho~yphenyl]ethyl p-Toluenothiosulfon~t~: lH
NMR (400 MHz, DMSO-d6) ~ 2.43 (s, 3 H), 2.79 (t, 2 H), 3.25 (t, 2 H), 3.73 (s, 3 H), 6.73 (m, 3 H), 7.19 (m, 1 H), 7.49 (d, 2 H), 7.83 (d, 2 H).

kx~mple R
2-~-~Qtho~yphenyllethyl p-Tolue~et~iosulfonate: lH
NMR (400 MHz, DMSO-d6) ~ 2.50 (s, 3 H), 2.76 (t, 2 H), 3.21 (t, 2 H), 3.71 (s, 3 H), 6.83 (t, 2 H), 7.03 (d, 2 H), 7.50 (t, 2 H), 7.82 (d, 2 H).

E~c~pl~
2-(2-Chlorophenyl)ethyl p-Toluenethio~ulfonate: lH NMR
(400 MHz, DMS0-d6) ~ 2.43 (s, 3 H), 2.86 (t, 2 H), 3.28 (t, 2 H), 7.22 (m, 4 H), 7.49 (d, 2 H), 7.83 (d, 2 H).

Esampl~ M
t~-~Phenylmetho~y)phe~yl]methyl p-Toluenethiosulfonate: lH NMR (400 MHz, DMSO-d6) ~ 2.41 (s, 3 H), 4.28 (s, 2 H), 5.06 (s, 2 H), 6.87 (d, 2 H), 7.13 (d, 2 H), 7.37 (m, 7 H), 7.72 (d, 2 H).

~x~mpl~ N
6-(3-Chlorophenyl)-~-~y~L VA~ 2E-pyran-2-one.
A slurry of 60% NaH (0.790 g, 19.7 mmol) in THF (50 mL) under a N2 atmosphere was cooled to 0 C and treated with ethyl acetoacetate (2.51 mL, 19.7 mmol).
The resulting solution was subsequently treated with n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 min. at 0 C to provide an orange solution which was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (2.50 g, 15.15 mmol) in THF (5.0 mL).
The mixture was allowed warm to ambient temperature where it was stirred for 14 h before being ~l~n~h~
with 2.0 N HCl. The product was extracted with ethylacetate (3 x 50 mL), the layers combined, dried Wos5/l4ol4 PCT~S94/12367 ~ 54 _ with Na2SO~, and the solvent removed in vacuo. The residue was then treated with conc. H2SO~ (20 mL) and the resulting mixture stirred for 18 h at room temperature before being diluted with H20 (200 mL).
The product was then extracted with ethylacetate (3 x 100 mL) being sure to collect all solids. The layers were then combined and diluted with acetone to provide a homogenous solution which was dried with Na2S0~. The solvent was then removed in vacuo and the resulting lo solid recryst~ ed from acetone-hexane to provide the title compound (1.33 g, m.p. 254 - 256 C). lH NMR
(400 NHz, DNSO-d6) ~ 11.957 (bs, 1 H), 7.889 (t, 1 H, J
= 1.5 Hz), 7.839 - 7.813 (m, 1 H), 7.598 - 7.524 (m, 2 H), 7.876 (d, 1 H, J = 2 Hz), 5.450 (d, 1 H, J = 2 Hz).

~r~mple O
6-(~-Chlorophenyl)-4-hydroxy-2H-pyran-2 -O~Q .
The title compound (1.56 g, m.p. 247 - 249 C) was prepared in a similar manner as that demol,~LLated in the preparation of Example N using the following: 60%
NaH (0.904 g, 22.6 mmol), THF (50 mL), ethyl acetoacetate (3.00 g, 22.6 mmol), lithium diis~o~ylamine in THF (39.8 mL, 24 mmol), 4-chloro-N-methoxy-N-methylbenzamide (3.73 g, 22.6 mmol), 90~
H2S04 (20 mL). H NMR (300 MHz, DMSO-d6) ~ 11.950 (bs, 1 H), 7.878 (d, 1 H, J = 9 Hz), 7.584 (d, 1 H, J = 9 Hz), 6.812 (d, 1 H, J = 2 Hz), 5.409 (d, 1 H, J = 2 Hz).
Example P
~Cy¢lopropylmethyl)-p-toluenethiosulfonate.
To a solution of methylcyclopropyl bromide (4.00 g, 29.6 mmol) in ethanol (20.0 mL) was added potassium thiotosylate (10.0 g, 44.4 mmol) and the mixture heated to 90 C for 10 h. The mixture was then ~uP~he~ into a 1 : 1 mixture of H20 (50.0 mL) and diethyl ether (50.0 mL). The layers were separated ~ WO 95/1~014 PCT/US94/12367 ~ 7~2~

and the organic layer washed with brine (50.0 mL).
The organic layer was then dried with MgS04 and concentrated in vacuo to yield the title compound as a solid (5.2 g, m.p. 46 - 48 C). lH NMR (400 MHz, s CDCl3) ~ 7.816 (d, 2 H, J = 8.8 Hz), 7.308 (d, 2 H, J
= 8.8 Hz), 2.945 (d, 2 H, J = 7.6 Hz), 2.451 (s, 3 H), 1.010 - 0.933 (m, 1 H), 0.592 - 0.545 (m, 2 H), 0.236 -0.197 (m, 2 H).

E~a~pl~ Q
~et~yl-[~-~l G~C~ Lhyl)rh~r~-~] Acetate.
A mixture of 4-hydL~Ay~io~h~nnnP (10.0 g, 60.24 mmol), CsC03 (21.6 g, 66.3 mmol), and acetone (150.0 mL) under an N2 atmosphere was treated with methylbromoacetate (7.26 mL, 78.3 mmol) and the mixture heated to reflux for 4 h. The mixture was then allowed to cool to ambient temperature, diluted with H20 (150 mL) and extracted with CHzClz (2 x 300 mL). The organic layers were combined, dried with Na2S04, and the solvent removed in vacuo to provide the title compound (12.75 g, m.p. 64 - 66 C). lH NMR (400 MHz, DMSo-d6) ~ 9.35 (d, 2 H, J = 8.9 Hz), 7.040 (d, 2 H, J = 809 Hz), 4.920 (s, 2 H), 3.715 (s, 3 H), 2.981 (q, 2 H, J = 7.2 Hz), 1.071 (t, 3 H, J = 7.2 Hz).

~7~
WO95/14014 PCT~S94/1~67 4 . 4 prQparation of SPecif ic ~y ;)~ Derivatives E:S~pl~ 1 6-(3-Chlorophenyl)-~-hy~ro~y-3-t(phenylmethyl)thio]-2~-pyr~n-2-one.
Following method A a solution of 3'-chloroacetophenone (1.50 g, 11.6 mmol) in THF (10.0 mL) was cooled to -78 C (N2 atmosphere) and treated with a 1.0 M solution of lithium hexamethyldisilazide (12.5 mL, 12.5 mmol) in THF. The solution was warmed to 0 C, allowed to stir for 15 min., then treated with trimethylsilylchloride (1.47 mL, 11.6 mmol) The reaction mixture was then allowed to stir for 0.5 h (ambient temperature) and subsequently ~lenche~ into a ~S mixture of diethyl ether (50 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic layer washed with a 1 : 1 mixture of brine :
saturated NaHCO3 (20 mL). The ethereal solution was then dried with Na2SO4 and the solvent removed in vacuo. The resulting silyl enol ether was then transferred to a flask con~in;ng diethyl -2-(thiobenzyl)propane-1,3-dioate (1.63 g, 5.80 mmol), the resulting mixture heated to 160 C for 16 h. and then allowed to cool to room temperature where it was diluted with diethyl ether (20 mL) and extracted with saturated Na2CO3 (3 x 20 mL). The aqueous layer was then acidifed with conc. HCl to pH 0 and then extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried with Na2SO4 and the solvent removed in vacuo. The resulting residue was then submitted to chromatography (SiO2-230 to 400 mesh, 100% CH2Cl2 to 1% MeOH / CH2Cl2) to provide a solid which was recrystallized from acetone / h~Y~n~c to provide 0.436 g (m.p. 136 - 137 C) of the title compound. lH NNR (400 NHz, DMSO-d6) ~ 11.950 (bs, 1 H), 7.814 (s, 1 H~, 7.761 (d, 1 H, J = 7.5 Hz), 7.616 - 7.534 (m, 2 H), 7.271 - 7.185 (m, 5 H), 6.811 (s, 1 H), 4.023 (s, 2 H).

WO951l4014 217 ~12 L~ PCT~S9411~67 ~ ~pl~ 2 6-(2-Chlorophonyl)-~-h~LG~-3-ttphQnylmeth~l)thio]-2H-pyr~n-2-one. The title compound (0.210 g, m.p. 99 -101 C) was prepared by method A using 2'-chloroacetophenone (1.50 mL, 11.6 mmol), 1.87 M
potassium hexamethyldisilazide (6.80 mL, 12.7 mmol), trimethylsilylchloride (1.47 mL, 11.6 mmol), THF (10.0 mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (1.3 g, 4.63 mmol). lH NMR (400 MHz, DMSO-d6) ~ 12.153 (bs, 1 H), 7.639 (t, 2 H, J = 9 Hz), 7.572 - 7.477 (m, 2 H), 7.276 - 7.206 (m, 5 H), 6.558 (s, 1 H), 4.029 (s, 2 H).

E~mpl~ 3 6-~3,4-Dichlorophonyl)-~ o,~ 3-t~p~enylmothyl)thio]-2~-pyran-2-on~. The title compound (0.201 g, m.p. 18S-186 oc) was prepared by method A using 3',4'-dichloroacetophenone (1.5 g, 7.9 mmol), 1.0 M lithium hexamethyldisilazide (8.7 mL, 24 8.69 mmol), trimethylsilylchloride (1.0 mL, 7.9 mmol), THF (10.0 mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (0.89 g, 3.2 mmol). lH NNR (400 MHz, DMSO-d6) 12.000 (bs, 1 H), 8.018 (s, 1 H), 7.784 (s, 2 H), 7.265 - 7.179 (m, 5 H), 6.839 (s, 1 H), 4.017 (s, 2 H).

Exa~ple ~
~-~yd ~A~ ~- (3-met~osyphenyl)-3-[(phenylmethyl)thio~-2~-pyran-2-ono. The title compound (0.400 g, m.p. 146 - 147 C) was prepared by method A using 3'-methoxyacetophenone (1.5 mL, 10.9 mmol), potassium hexamethyldisilazide (6.41 mL, 12.0 mmol), trimethylsilylchloride (1.38 mL, 10.9 mmol), THF (10.0 mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (1.23 g, 4.36 mmol). lH NMR (400 MHz, DMSO-d6) ~ 11.880 (bs, 1 H), 7.445 (t, 1 H, J = 8 Hz), 7.370 (d, 1 H, J = 8 Hz), 7.286 - 7.094 (m, 6 H), 7.109 (m, 1 H), 6.770 (s, 1 H), 4.020 (s, 2 H), 3.831 (s, 3 H).

WO95/14014 PCT~S94/12367 ES~pl~ 5 ~-~ydro~y-3-~(phenylm~t~yl)thio]-6-(3,~,5-trimethoxyphenyl)-2~-pyr~n-2-one. The title compound (0.385 g, m.p. 156 - 157 C) was prepared by method A
using 3', 4', 5'-trimethoxyacetophenone (2.0 g, 9.5 mmol), potassium hexamethyldisilazide (5.6 mL, 10.45 mmol), trimethylsilylchloride (1.2 mL, 9.5 mmol), THF
(15 mL), diethyl 2-(thiobenzyl)propane-1,3-dioate (1.07 g, 3.80 mmol). lH NMR (400 MHz, DMS0-d6) ~
11.778 (bs, 1 H), 7.265 - 7.181 (m, 5 H), 7.054 (s, 2 H), 6.792 (s, 1 H), 3.997 (s, 2 H), 3.861 (s, 6 H), 3.727 (s, 3 H).

Example 6 6-(3-Chloroph~nyl)-~-hy~rosy-3-t~2-ph~nylethyl)thiO]-2~-pyr~-2-one. The title comrolln~ (0.138 g m.p. 125 -127 C) was prepared by method B using 6-(3-chlorophenyl)-4-hy~xy-2H-pyran-2-one (0.250 g, 1.10 mmol), phenethyl-p-toluenethiosulfonate (0.43 g, 1.46 mmol), triethylamine (0.35 mL, 2.5 mmol), ethanol (5.0 mL) lH NMR (400 MHz, CDCl3) 8 7.838 (t, 1 H, J = 1.5 Hz), 7.710 (d, 1 H, J = 8 Hz), 7.530 (bs, 1 H), 7.475 -7.392 (m, 2 H), 7.308 - 7.260 (m, 2 H), 7.207 - 7.171 (m, 3 H), 6.604 ts, 1 H), 3.125 (t, 2 H, J = 7 Hz), 2.897 (t, 2 H, J z 7 Hz).

kxample 7 6-(4-Chlorophenyl)-~-hydro~y-3-tt2-phenylethyl)thio]-2~-pyr~n-2-one. The title compound (0.242 g, m.p. 161 - 163 C) was prepared by method B using 6-(4-chlorophenyl)-4-hydroxy-2H-pyran-2-one (0.250 g, 1.12 mmol), phenethyl-p-toluenethiosulfonate (0.390 g, 1.35 mmol), triethylamine (0.31 mL, 2.24 mmol), ethanol (10.0 mL). lH NMR (400 MHz, DMSO-d6) ~ 12.085 (bs, 1 H), 7.827 (d, 2 H, J = 9 Hz), 7.605 (d, 2 H, J = 9 Hz), 7.259 - 7.142 (m, 5 H), 6.830 (s, 1 H), 3.017 (t, 2 H, J = 7.5 Hz), 2.785 (t, 2 H, J = 7.5 Hz).

~ WO95/14014 PCT~S94112367 ~74~

~ mpl~ 8 ~-n~.G~ 6-phcnyl-3-t(phe~ylmethyl)~thio]-2H-pyr~-2-one: The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.00 g, 5.19 mmol) and the diethyl ester of t(phenylmethyl)thioJ-propandioic acid (0.977 g, 3.46 mmol). m.p. 155-160 C; lH NMR (250 MHz, DMSO-d6) ~ 4.00 (s, 2H), 6.74 (s, 1 H), 7.23 (m, 5 H), 7.53 (m, 3 H), 7.78 (m,2 H).

B~pl~ 9 ~-~ydlO~y 6-ph~nyl-3-t(phenylmethyl)amino]-2~-pyr~n-2-one: The title compound was prepared by method D using 3-amino-4-hydlosy-6-phenyl-2H-pyran-2-one hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in dimethylformamide (20 mL), benzaldehyde (0.233mL, 2.29 mmol), sodium cy~n~h~rohydride (0.144 g, 2.29 mmol).
m.p. dec. 205 C, 1 H NMR (250 MHZ, DMSO-d6) ~ 4.37 (s, 2 H), 6.56 (s, 1 H), 7.27 (m, 5 H), 7.45 (m, 3 H), 7.67 (m, 2 H).
E~ple 10 N-(1,1-Dimethyl~thyl)-N'-(4-hydrosy-2 G~ 6-phenyl-2H-pyran-3-yl)-N'-~phenylmethyl) ~rea: To a suspension of 4-hyd~ox~-6-phenyl-3-(phenylmethyl)amino-2H-pyran-2-one, mono~dlG~hloride (0.153 mmol) in ethyl acetate (10 ml) was added N-methylmorpholine (2.0 ml) and tert-butyl isocyanate (2.0 ml). The reaction was allowed to stir for 2.5 hrs and then quenched by dilution with ethyl acetate. The organic layer was washed with 5% citric acid and saturated sodium chloride and was dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo , the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 5%
methanol in dichloromethane as eluents.
lH NNR (250 MHz, DMSO-d6) ~ 1.24 (s, 9H), 4.47 (dd, 2 H), 5.45 (bs, 1 H), 7.23 (m, 5 H), 7.51 (m, 3 H), 7.75 (m, 2 H).

W095/14014 2 ~ PCT~S94/12367 ~

E~ample 1~
~ ~ v~-3-~2-naphthalenylmethyl)thio]-6-phenyl-2H-pyran-2-o~: The title compound was prepared by Method A using l-phenyl-1-(trimethylsilyloxy)ethylene S (0.475 g, 2.46 mmol) and dimethyl ester of t(2-naphthalenylmethyl)thio~propanedioic acid (0.500 g, 1.64 mmol). m.p. dec>250 C; lH NMR (250 MHz, DMSO-d6) 4.06 (s, 2 H), 6.47 (s, 1 H), 7.46 (m, 6 H), 7.78 (m, 6 H).
~s~mple 12 ~ 6.y 3-t(2-naphthalonylthio]-6-phonyl-2~ -2-one: The title compound was prepared by Method A using l-phenyl-1-(trimethylsilyloxy) ethylene (1.33, 6.90 mmol) and diethyl ester of [(2-naph~hAle~yl)thio]-prop~ne~;oic acid (2.00 g, 6.29 mmol). m.p. dec. 246 C; lH NMR (250 MHz, DMSO-d6) 6.95 (sl), 7.38 (m, 3 H), 7.56 (m, 4 H), 7.85 (m, 5 H).
Exampl~ 13 LG"~-3-[(phonylmethyl)thio]-6-(2,~,6-trimethylphenyl)-2~-pyran-2-ono: The title compound was prepared by Nethod A using 2',4',6'-trimethylacetoph~nnne (1.86 g, 11.5 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.65 mmol), chlorotrimethylsilane tl.60 mL, 12.65 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thioJpropAn~;oic acid (2.95 g, 10.4 mmol). m.p. 134-136 C; 'H NMR (250 MHz, DMSO-d6) 2.11 (s, 6 H), 2.26 (s, 3 H), 3.98 (s, 2 H), 6.03 (s, 1 H), 6.96 (s, 2 H), 7.25 (m, 5 H), 11.85 (bs, 1 H).

Esampl~ 1~
~-Hyarosy-6-t4-[2-(4-morpholinyl)etho~y~phe~yl]-3-~tphonylmethyl~thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using 4'-~2-(4-WO 95/14014 ~ 1 7 ~ 1 2 ~ PCT~US94/12367 morpholinyl)ethoxy]acetophenone (1.31 g, 5.29 mmol), lithium bis(trimethylsilyl)amide (0.972 g, 5.81 mmol), chlorotrimethylsilane (0.738 mL, 5.81 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]
propanedioic acid (1.35 g, 4.80 mmol). m.p. dec.
207 C; lH NMR (2S0 MHz, DMSO-d6) ~ 2.54 (s, 2 H), 6.89 (m, 4 H), 2.83 (t, 2 H), 3.55 (m, 4 H), 3.96 (s, 2 H), 4.22 (t, 2 H), 6.58 (s, 1 H), 7.08 (d, 2 H), 7.23 (m, 5 H), 7.73 (d, 2 H).
~s~mple 15 ~-~y~rosy-6-(2-naphthalenyl)-3-~(phenylmethyl)thio]-2~-pyr~n-2-ono: The title compound was prepared by Method A using 2-acetyl naphthalene (1.97 g, 11.6 mmol), lithium bis(trimethylsilyl)amide (2.13 g, 12.76 mmol), chlorotrimethylsilane (1.61 mL, 12.76 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (2.90 g, 10.5 mmol). m.p. dec. 203 C; lH NMR (250 MHz, DMSO-d6) ~
4.04 (s, 2 H), 6.89 (s, 1 H), 7.23 (m, 5 H), 7.61 ~m, 2 H), 7.84 (d, 2 H), 8.05 (m, 3 H), 8.43 (s, 1 H), 11.95 (bs, 1 H).

EKample 16 4-Hydroxy-6-phonyl-3-t(phenylthio)methyl]-2~-pyra~-2-one : The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), paraformaldehyde (0.175 g, 5.80 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. dec.
211 C; lH NMR (400 MHz, DMSO-d6) ~ 3.98 (s, 2 H), 6.73 (s, 1 H), 7.17 (m, 1 H), 7.30 (m, 2 H), 7.37 (m, 2 H), 7.54 (m, 3 H), 7.77 (m, 2 H), 12.05 (bs, 1 H).

~xample 17 ~-~y~rosy-6-(~-hy~rosyphenyl)-3-~(phenylmethyl)thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 WO95/14014 ~i 7 ~ ~ 2 ~ PCT~S94/12367 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of [(phenylmethyl)thio~prop~n~;oic acid (1.00 g, 3.54 S mmol). m.p. dec. 204 C; lH NNR t250 MHz, DMSO-d6) 8 3.96 (s, 2 H), 6.55 (s, 1 H), 6.88 (d, 2 H), 7.39 (m, 5 H), 7.63 (d, 2 H), 10.28 (s, 1 H), 11.75 (bs, 1 H).

~ample 18 ~-~ydro~y-6-~-metho~yphenyl)-3-t(phe~yl~ethyl)thio]-2~-pyr~n-2-one : The title compound was prepared by Method A using 4'-methoxyacetophenone (0.797 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 187 C; lH NMR (400 MHz, DMSO-d6) ~
3.83 (s, 3 H), 3.98 (s, 2 H), 6.62 (s, 1 H), 7.06 (m, 2 H), 7.22 (m, 5 H), 7.73 (m, 2 H), 11.76 (bs, 1 H).

13s~pl~ 9 ~-~y~rosy-6-(~-methylphenyl)-3-~phonylmethyl)thio~-2~-pyr~n-2-one : The title compound was prepared by Method A using 4'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]-prop~e~;oic acid (1.00 g, 3.54 mmol). m.p. dec. 205 oc; lH NMR (400 MHz, DMSO-d6) 8 2.37 (s, 3 H), 3.99 (s, 2 H), 6.69 (s, 1 H), 7.26 (m, 7 H), 7.68 (m, 2 H), 11.83 (bs, 1 H).

Exampl~ 20 3-[Bislphcnyl~ethyl)~cino]-~-hydroxy-6-phenyl-2~-pyr~n-2-one: The title compound was prepared by Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), 1% acetic WO 95/14014 ~ ~ 7 4 1 2~ PCT/US94/12367 acid in dimethylformamide (7 mL), benzaldehyde (0.133 mL, 1.33 mmol), sodium cyanoborohydride (0.083 g, 1.31 mmol). m.p. 130-135 C; lH NMR (400 MHz, DMSO-d6) 4.26 (s, 4 H), 6.44 (s, 1 H), 7.24 (m, 6 H), 7.44 s (m, 7 H)j 7.69 (m, 2 H).
t pl~ 21 ~-Hydroxy-6-phenyl-3-~2-phenylethyl)thio]-2~-pyr~n-2-on~: The title compound was prepared by Me~hod B using 4-hydloxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium ~yd~oxide (2.65 mL), 2-phenylethyl-p-toluenethiosulfonate (0.770 g, 2.65 mmol). m.p.
121-124 C; lH NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2 H), 2.99 (t, 2 H), 6.80 ~s, 1 H), 7.24 (m, 5 H), 7.54 (m, 3 H), 7.80 (m, 2 H).

Ex~mpl~ 22 4-~ydro~y-6-phenyl-3-tt3-phenylpropyl)thio]-2H-pyra~-2-one : The title compound was prepared by Method A using 1-Phenyl-l-(trimethylsilyloxy)ethylene (0.922 g, 4.83 ol) and diethyl ester of [(3-phenylpropyl)thio]prorAne~i~oic acid (1.00 g, 3.22 mmol). m.p. 114-116 C; lH NMR (400 MHz, DMSO-d6) ~ 1.74 (m, 2 H), 2.71 (m, 4 H), 6.82 (m, 1 H), 7.16 (m, 3 H), 7.25 (m, 2 H), 7.54 (m, 3 H), 7.81 (m, 2 H), 11.95 (bs, 1 H).

E~mple 23 ~-~y~ro~y-3-t(2-pheno~yethyl)thio]-6-phenyl-2~-pyran-2-one : The title co~ou~ld was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (o.SOO g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 mL, 2.65 mmol), 2-phenoxyethyl-p-toluenethiosulfonate (0.816 g, 2.65 mmol). m.p.
146-149 C; lH NMR (400 MHz, DMSO-d6) ~ 3.12 (t, 2 H), 4.11 (t, 2 H), 6.81 (s, 1 H), 6.88 (m, 3 H), 7.24 (m, 2 H), 7.54 (m, 3 H), 7.81 (m, 2 H)~ 12.04 (bs, 1 H).

W095tl4014 ~ PCT~S94/1~67 Illpl8 2~
~-Hyd.v~ 6-(2-methylphen~ 3-t~phenyluethyl)thio~-2H-pyran-2-one: The title compound was prepared by Method A using 2'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.S4 mmol). lH NMR (400 NHz, DMSO-d6) ~ 2.34 (s, 3 H), 4.01 (s, 2 H), 6.32 (s, 1 H), 7.32 (m, 9H).

Es~mpl~ 25 4-Ryd~o~y 6 ~2-phenylethyl)-3-[~phenylm~thyl)thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using 4-phenethylacetorh~nnn~ (0.786 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 164-166 C; lH NMR (400 MHz, DMSO-d6) 2.75 (t, 3 H), 2.85 (t, 2 H), 3.92 (s, 2 H), 5.92 (s, 1 H), 7.23 (m, 9H), 11.69 (bs, 1 H).

~mple 26 ~ d v~ 6-(3-~ v~henyl)-3-~(phenylmethyl)thio]-2~-pyra~-2-one : The title compound was prepared by Method A using 3'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 185 C; lH NMR (400 MHz, DNSO-d6) 4.00 (s, 2 H), 6.66 (s, 1 H), 6.92 (m, 1 H), 7.21 (m, 7 H), 7.32 (m, 1 H).
E~ple 27 ~-~ydrosy-6-(~-hydroxyphenyl)-3-l(phenylethyl)thio]-2H-pyran-2-one : The title compound was prepared by WO 95/14014 ~ ~ 7 4 ~ ~ 4 PCTIUS94112367 Method A using 4'-hy~lo~yacetophenone (0.688 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (1.84 g, 11.1 mmol), chlorotrimethylsilane (1.41 mL, 11.1 mmol), THF
(111 mL), and diethyl ester of [(2-phenylethyl)thio]propAne~;oic acid (1.00 g, 3.37 mmol). H NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2 H), 2.95 (t, 2 H), 6.62 (s, 1 H), 6.89 (dd, 2 H), 7.21 (m, 5 H), 7.65 (d, 2 H), 10.22 (s, 1 H), 11.05 (bs, 1 H).
Es~mple 28 4-~ydkoA~ ~-phenyl-3-[3-(phenyl-2-propenyl)thio]-2~-pyr~n 2-one, ~E)-: The title compound was prepared by Method B using 4-hyd~ -6-phenyl-2H-pyran-2-one ~5 (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 mL), 3-phenyl-2-~o~enyl-p-toluenethiosulfonate (0.808 g, 2.65 mmol). m.p.
133-136 C; lH NMR (400 MHz, DMSO-d6) ~ 3.57 (d, 2 H), 6.24 (dt, 2 H), 6.76 (s, 1 H), 7.24 (m, 5 H), 7.51 (m, 3 H~, 7.78 (m, 2 H).

- Esampl~ 29 3-tt2-phenylethyl)thio]-6-t~-~phenylm~tho~y)phe~yl]-2~-pyran-2-one : The title com~o~,d was prepared by Method A using 4'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio~propanedioic acid (1.00 g, 3.37 mmol). m.p. 139-142 C; lH NMR (400 MHz, DMSO-d6) 2.77 (t, 2 H), 2.98 (t, 2 H), 5.19 (s, 2 H), 6.68 (s, 1 H), 7.26 (m, 7 H), 7.43 (m, 5 H), 7.76 (d, 2 H).

3s Exampl~ 30 ~-Hyd.o~ 6-[~-t2-phenylethoxy)phenyl]-3-[~2-phenylethyl)thio]-2H-pyran-2-one: The title compound was prepared by Method A using 4'-(2-WO9S/14014 PCT~S94/12367 ~

phenylethoxy)acetoph~no~ (1.21 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF t57 mL), and diethyl ester of ~(2-phenylethyl)thio]propanedioic acid (l.oo g, 3.37 mmol). m.p. 103-106 C; lH NMR (400 MHz, DMSO-d6) ~ r 2.76 (t, 2 H), 2.97 (t, 2 H), 3.06 (t, 2 H), 4.27 (t, 2 H), 6.67 (s, 1 H), 7.21 (m, 12 H), 7.73 (d, 2 H).

~o E~mple 31 ~-~y~roxy-3-tt2-phe~ylethyl)thio~-6-t4-(3-phenyl~ ~o~
y)phenyl]-2~-pyr~n-2-one: The title compound was prepared by Method A using 4'-(3-phenyl~l~o~)aceto~heno~e (1.28 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of ~(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139-142 C; lH NMR (400 MHz, DMSO-d6) ~
2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t, 2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H), 11.86 (bs, 1 H).

~mple 32 ~-~y~O~ 6-t2-h~ henyl)-3-[tphenylmethyl)thio3-2~-pyran-2-one: The title compound was prepared by Method A using 2'-hydroxyacetophenone (0.722 g, S.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF
(116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 189 C; lH NMR (400 MHz, DMSO-d6) 4.01 (s, 2 H), 6.97 (s, 1 H), 7.25 (m, 7 H), 7.71 (d, 1 H), 10.75 (s, 1 H), 11.85 (bs, 1 H).
~s~pl~ 33 4-Hydrosy-6-t3-t2-phenyletho~cy)phenyl]-3-[ t2-Phen ethyl)thio~-2H-pyr~n-2-one: The title compound was ~ WO g5/14014 ~ i 7 4 1 2~ PCT~S94/1~67 prepared by Method A using 3'-(2-phenylethoxy)-acetoph~o~e (0.336 g, 1.40 mmol), lithium bis(trimethylsilyl)amide (0.257 g, 1.54 mmol), chlorotrimethylsilane (0.195 mL, 1.54 mmol), THF (15 mL), and diethyl ester of ~(2-phenylethyl)thio~-propanedioic acid (0.417 g, 1.40 mmol). m.p.
104-106 C; lH NMR (400 MHz, DMSO-d6) ~ 2.75 (t, 2 H), 2.97 (t, 2 H), 3.04 (t, 2 H), 4.25 (t, 2 H), 6.79 (s, 1 H), 7.25 (m, 14H), 11.95 (bs, 1 H).
E~mpl~ 3~
4-~ydro~y-6-phenyl-3-tphenyl~phenylthio)mQthyl~-2~-pyran-2-oue ,~/-)-: The title compound was prepared by Method E using 4-hydkuxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), thiop~nol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (O.5mL). m.p. dec. >220 C; lH NNR (400 MHz, DMS0-d6) ~ 5.80 (s, l H), 6.70 (s, 1 H), 7.23 (m, 8H), 7.54 (m, 4 H), 7.74 (m, 2 H).

E~mpl~ 35 ~-Hydro~y-3-tt2-(2-~etho~yphenyl)sthyl]thio]-6-phenyl-2H-pyran-2-one: The title compound was prepared by Method B using 4-hy~lo~y-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 mL), 2-(2-methoxyphenyl)ethyl p-toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
114-115 C; lH NMR (400 MHz, DMSO-d6) ~ 2.74 (t, 2 H), 2.94 (t, 2 H), 3.73 (s, 1 H), 6.85 (m, 3 H), 7.15 (m, 2 H), 7.54 (m, 3 H), 7.82 (m, 2 H).

Es~mpl~ 36 4-Hydroxy-6-phenyl-3-~(4-phenylbutyl)thio]-2~-pyr~n-2-one: The title compound was prepared by Method B using 4-hy~Lu~y-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 m~), 4-phenylbutyl-p--toluenethiosulfonate (0.851 g, 2.65 mmol). m.p.
103-105 C; lH NMR (400 MHz, DMSO-d6) 8 1.47 (m, 2 H), 1.66 (m, 2 H), 2.54 (t, 2 H), 2.77 (t, 2 H), 6.80 (s, 1 H), 7.17 (m, 5 H), 7.53 (m, 3 H), 7.81 (m, 2 H).
s Ex~mpl~ 37 ~-L~d~GA~-3-t~2-~3-methoxyphenyl)ethyl]thio]-6-phenyl-28-pyran-2-on~: The title compound was prepared by Method B using 4-hyd~ux~-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hy~u~ide (2.65 mL), 2-(3-methoxyphenyl)ethyl-p-toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
112-113 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.75 (t, 2 H), 3.01 (t, 2 H), 3.34 (s, 3 H), 6.75 (s, 1 H), 7.16 (t, 1 H), 7.54 (m, 3 H), 7.80 (m, 2 H).

Bx~ple 38 ~-8ydrosy-3-tt2-~-~etho~yphenyl)ethyl~thio]-6-phen~
28-pyran-2-one: The title compound was prepared by Method B using 4-hydlo~-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium h~dLGxide (2.65 mL), 2-(4-methoxyphenyl)ethyl-p-toluenethiosulfonate (0.856 g, 2.65 mmol). m.p.
144-145 C; lH NMR (400 MHz, DMSO-d6) ~ 2.71 (t, 2 H), 2.96 (t, 2 H), 3.66 (s, 3 H), 6.77 (s, 1 H), 6.80 (d, 2 H), 7.12 (d, 2 H), 7.54 (m, 3 H), 7.80 (m, 2 H).

Example 39 3-[t2-13-Chlorophenyl)ethyl~thio]-~ 6-phenyl-28-pyran-2-one: The title compound was prepared by Method B using 4-hydLo~y-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 mL), 2-(2-chlorophenyl)ethyl-p-toluenethiosulfonate (0.868 g, 2.65 mmol). m.p.
3s 133-134 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.79 (t, 2 H), 3.02 (t, 2 H), 6.77 (s, 1 H), 7.25 (m, 4 H), 7.55 (m, 3 H), 7.81 (m, 2 H).

WO95/14014 ~1 7 ~ 1 24 PCT~Sg4~1~3C7 ~plQ ~0 y~ro~y-6-ph~nyl-3-(2-ph~nyl~thyl)-2~-pyran-2-one:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (20 mL), 4-hydlo~y-6-phenyl-3-~2-phenyl-1-(phenylthio)ethyl]-2H-pyran-2-one (0.425 g, 1.06 mmol). m.p. dec. >2S5 C; lH NNR
(400 MHz, DNS0-d6) ~ Z.65 (dd, 2 H), 2.71 (dd, 2 H), 6.68 (s, 1 H), 7.23 (m, 3 H), 7.52 (m, 3 H), 7.76 (m, 2 H), 11.85 (bs, 1 H).
k~a~pl~ 41 ~ ~y~v~ 6 ~he~yl-3-(3-ph~nylpropyl)-2~-pyran-2-onQ:
The title compound was prepared by Method F using Raney-Nickel (Grace 3100), ethanol (15 mL), 4-hyd~o~-6-phenyl-3-t3-phenyl-1-(phenylthio)propyl]-2H-pyran-2-one ~( 0.150 g, 0.362 mmol). m.p. 195-196 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.73 (m, 2 H), 2.40 (t, 2 H), 2.60 (t, 2 H), 6.68 (s,,l H), 7.23 (m, 5 H), 7.52 (m, 3 H), 7.74 (m, 2 H).
Esampl~ ~2 6-~2,6-Dimethylphenyl)-~-hydroxy-3-t(phenylmethyl)thio ~-2~-pyran-2-one: The title com~o~.d was prepared by Method A using 2',6'-dimethyl acetophPnone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (~.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 140-143 C; lH NMR (400 MHz, DMSO-d6) ~
2.15 (s, 6 H), 3.99 (s, 2 H), 6.12 (s, 1 H), 7.22 (m, 8H).

Exa~plQ 43 ~-~ydro~y-6-t2-hydrosy-3-mQthyl-4-~ph~nylmothosy) phenyl]-3-[(2-phenylQthyl)thio~-2~-pyr~-2-onQ: The title compound was prepared by Method A using 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (2.11 g, WO 95/14014 ~ 1 7 4 1 2 4 PCT~S94/1~67 ~

~ - 70 12.6 mmol), chlorotrimethylsilane (1.60 mL, 12.6 mmol), THF (127 mL), and diethyl ester of t(2-phenylethyl)thio]prop~n~ioic acid (1.00 g, 3.37 mmol). m.p. 147-148 oc; lH NMR (400 MHz, DMSO-d6) 2.14 (s, 3 H), 2.77 (t, 2 H), 2.98 (t, 2 H), 5.17 (s, 2 H), 5.29 (s, 1 H), 6.79 (d, 1 H), 7.30 (m, 13H), 9.36 (s, 1 H), 11.85 (bs, 1 H).

E:~c~pl~ ~
~-n~d v~ 3-t~2-phenylethyl)thio]-6-[3-(phe~ylmetho~y) ph~nyl]-2H-pyr~n-2-onQ: The title compound was prepared by Method A using 3'-benzyloxyacetoph~no~e (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]prop~ne~;oic acid (1.00 g, 3.37 mmol). m.p. 126-127 C; lH NMR (400 MHz, DMSO-d6) 2.78 (t, 2 H), 3.01 (t, 2 H), 5.20 (s, 2 ~), 6.81 (s, 1 H), 7.22 (m, 6 H), 7.41 (m, 7 H).
Ex~mpl~ ~5 G~ 6- ~ 2-naphthalenyl~etho~y)ph~yl~-3-~2-phenylethyl)thio]-2H-pyran-2-one: The title compound was prepared by Method A using 4'-(2-naphthalenylmethoxy)acetophenone (1.39 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), ~ (57 mL), and diethyl ester of t(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 152-154 C; lH NMR (400 NHz, DNSO-d6) 2.77 (t, 2 H), 2.98 (t, 2 H), 5.38 (s, 2 H), 6.68 (s, 1 H), 7.21 (m, 7 H), 7.54 (m, 2 H), 7~60 (d, 1 H), 7.96 (m, 4 H).

3s ~sampl~ ~6 6-(3-chloro-~-~etho~yphenyl)-4-~ o~-3-~(phonyl-m~t~yl)thio]-2H-pyr~n-2-on~: The title compound was prepared by Method A using 3'-chloro-4'-methoxy ~ WO95/14014 PCT~S94/1~67 ~ ~ 7 ~

acetophenone (0.979 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of ~(phenylmethyl)-thio]prop~ne~ioic acid (1.00 g, 3.54 mmol). m.p. dec.
171 oc; lH NMR (400 MHz, DMSO-d6) ~ 3.93 (s, 3 H), 3.99 (s, 2 H), 6.68 (s, 1 H), 7.32 (m, 6 H), 7.77 (d, 1 H), 7.83 (d, 1 H).

~sampl~ ~7 ~ .6~y 6 ~snyl-3-[(phenylmethyl)su~fonyl]-2~-pyr~n-2-one: This compound was prepared by oxidation of 4-hyd~o~-6-phenyl-3-~(phenylmethyl)thio]-2H-Pyran-2-one (1 mmol, 310mg) with oxone (3 mmol, l.99g) at room temperature in lOmL of methanol and lOmL of water. After stirring the reaction mixture at room temperature for 4 hours the mixture was diluted with water and extracted with 50mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. Solvents were evaporated. The residual, a solid was pure by tlc. Isolated yield: 90%. m.p.
152-153 C lH NMR (400 MHz, CDCl3) ~ 11.34 (s, 1 H), 7.8 (m, 2 H), 7.5 (m, 3 H), 7.37 (m, 3 H), 7.27 (m, 2 H), 6.37 (s, 1 H), 6.23 (s, 1 H), 4.75 (s, 1 H), 4.34 (q, 2 H); IR (KBr) 3421, 3059, 1726, 1698, 1628, 1559, 1497, 1230, 957, 770, 689 cm~1; MS (CI) m/e 343 (6.8), 327 (15.54), 278 (15.99), 219 (40.99), 91 (100).

Es~mpl~ ~8 4-Hydroxy-6-(3-methylphenyl)-3-[~phenylmethyl)thio]-2H-pyr~n-2-one: This compound was prepared by the condensation of the diethyl ester of ~(phenylmethyl)thio]-pro~ne~ioic acid (1 g, 3.54 ~mol) with the colLe~ ding trimethylsilyl enol ether of 3~-methyl acetophenone (7.09 mmol, 1.46g) as described in general procedure A. Isolated Yield: 65%
m.p. 137-138 oc lH NMR (400 MHz, DMS0-d6) ~ 11.9 (brs, 1 H), 7.6 (m, 2 H), 7.39 (t, 1 H), 7.35 , WO9S/14014 PCT~S94/1~67 (d, 1 H), 7.25 (d, 4 H), 7.2 (m, 1 H), 6.7 (s, 1 H), 4.0 (s, 2 H), 2.38 (s, 3 H); IR (KBr) 3030, 2585, 1617, 1536, 1402, 1100, 787, 696 cm-1; MS (CI) m/e 325 (65), 291 (2), 233 (4), 119 (9), 91 (100).
s B ~mple 49 2-O~c 6 ~,henyl-3-ttphenylm~thyl)thioJ-2H-pyr~n-4-ylprop~noic aci~ ~ster: This compound was prepared by the treatment of sodium salt of 4 l-~dloxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one (310m g, 1 mmol) with propionyl chloride (2.4 mmol, 222mg) as described in the general proce~ e G. Isolated Yield: 72%. :
lH NMR (400 MHz, DMS0-d6) d 7.77 (m, 2 H), 7.51.m (3), 7.22 (m, 4 H), 7.17 (m, 1 H), 6.7 (s, 1 H), 3.98 (s, 2 H), 2.19 (q, 2 H), 0.96 (t, 3 H); IR (KBr) 3438, 3027, 2923, 1772, 1731, 1617, 1528, 1494, 1453, 1323, 1153, 1087, 1045, 979, 873, 767, 702 cm-1; MS (CI) m/e 366 (4), 311 (79), 189 (26), 105 (20), 91 (100).

Exampl~ So 4-~ydro~y-6-t3-methyl-4-(phe~yl~ethyloYy)phQ~yl]-3-~2-phenylethyl)thio]-2H-pyr~n-2-one : Co~P~cAtion of diethylester of ~(phenylethyl)thio]prop~n~;oic acid (1.06 g, 3.6 mmol) with the trimethylsilyl enol ether of 3'-methoxy-4'-benzyloxyacetorhDnone (2.24 g, 7.2 mmol) was performed as described in general procedure A. Isolated yield: 78%. m.p. 147-148 C: lH
NMR (400 MHz, DMS0-d6) ~ 7.63 (m, 2 H), 7.11-7.S3 (m, llH), 6.68 (s, 1 H), 5.22 (s, 1 H), 2.98 (t, 2 H), 2.77 (t, 2 H), 2.27 (s, 3 H); IR (KBr) 3432, 3030, 2922, 1717, 1626, 1503, 1408, 12~2, 1140, 1024, 696 cm-1; MS (CI) m/e 445 (2.12), 3553.34, 309 (3.81), 189 (8.33), 156 (14.78), 137 (16.19), 105 (94.34), 91 (100); Analysis calc'd for : C, 72.95; H, 5.44;
found: C, 72.25; H, 5.43.

Ex~mple 51 ~ WO95/14014 2 ~ ~ 4 ~ ~ PCT~S94112367 ~ .6~ 6-(~-hydrosy-2-~ethylphenyl)-3-t2-phenylethyl)thio~-2H-pyr~n-2-o~e : This compund is prepared by the condensation of diethyl ester of ~(phenylethyl)thio]propanedioic acid (1 g, 3.38 mmol) with the correspo~; ng trimethylsilyl enol ether of 4'-hyd-u~-2'-methyl acetophPno~e (2.94 g, 10 mmol) as described in the general procedure A. Isolated yield:
52% m.p. 85-87 C lH NMR (400 MHz, DMSO-d6) ~ 11.89 (brs, 1 H), 9.97 (s, 1 H), 7.35 (d, 1 H), 7.23 (m, 5 H), 6.72 (s, 2 H), 6.33 (s, 1 H), 3.o (t, 2 H), 2.78 (t, 2 H), 2.34 (s, 3 H); IR (KBr) 3300, 2926, 1672, 1604, 1541, 1244, 1194, 1120, 698 cm-1; MS (CI) m/e 355 (36), 250 (27), 105 (93), 91 (30), 85 (100);
Analysis calc'd for: C, 67.78; H, 5.12; found: C, 67.53; H, 5.40.

E~ple 52 ~-~ydrosy-6-(~-metho~y-3-m~thylphenyl)-3-~phenylmethyl)thio]-2H-pyr~n-2-one: This com~o~,d is prepared by the con~nC~tion of diethyl ester of [(phenylmethyl)thio]propAn~;oic acid (1 g, mmol) with the COL r e~ol~ding trimethylsilylenol ether of 4~-methoxy-3'-methylacetophenone as described in general pro~e~l~re A. Isolated Yield: 68%. m. p. 159-106 C lH
NMR (400 MHz, CDCl3) ~ 7.67 (dd, 1 H), 7.61 (s, 1 H), 7.2 (m, 5 H), 6.8 (d, 1 H), 6.38 (s, 1 H), 3.96 (s, 2 H), 3.89 (s, 3 H), 2.25 (s, 3 H); IR (KBr) 3432, 2945, 1613, 1507, 1402, 1262, 1142, 1030, 812, 704 cm-1; MS
(CI) m/e 355 (78.3), 263 (lg.6), 235 (11.8), 149 (12.7), 91 (100); Analysis calc'd for : C, 67.78; H, 5.12; found: C, 67.35; H, 5.17.

Ex~mple 53 2-O~ 6 ~henyl-3-~(phenylmethyl)thio]-2~-pyr~n-~-yl~cetic acid ester: This compound was prepared by the treatment of sodium salt of 4-hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one, (310 mg, 1.00 mmol) with acetyl chloride (188mg, 2.4 mmol) as WO95/14014 PCT~S94/12367 ~
~ 17 ~

described in general ~Lv~c~ e G. Isolated yield: 72~.
lH NNR (400 MHz, DMSO-d6) ~ 7.81 (m, 2 H), 7.53 (m, 3 H), 7.22 (m, 4 H), 7.16 (m, 1 H), 3.99 (s, 2 H), 1.92 (s, 3 H).

~xample 5~
2-Oso-6-phenyl-2~-pyran-~-yl-1-naphthal~nsca~lG-yliC
acid ester: This com~v~,d was prepared by Method G
using 4-h~L~y-6-phenyl-2H-pyran-2-one (0.250 g, 1.32 mmol), THF (15 mL), 60% sodium hydride (0.585 g, 1.46 mmol), 1-naphthoyl chloride (0.278 g, 1.46 mmol).
m.p. 123.5-125; lH NMR (250 MHz, DMSO-d6) ~ 6.54 (s, 1 H), 7.49 (s, 1 H), 7.65 (m, 6 H), 7.95 (m, 2 H), 8.13 (d, 1 H), 8.34 (d, 1 H), 8.50 (d, 1 H).
E~mplQ S5 3,3'-Thiobis[~-hyd.G~y 6 ~henyl-2~-pyr n-2-one~: This compound was synthesized by the following method:
4-hydroxy-6-phenyl-2H-pyran-2-one (0.250 g, 1.33 mmol) was gradually added to thionyl chloride (0.585 ml).
The reaction was allowed to stir at room temperature overnight. The unreacted thionyl chloride was removed in vacuo and residue was recrystallized from boiling methanol. m.p. >240C; lH NMR (250 MHz, d-TFA) ~ 7.03 (s, 2 H), 7.56 (m, 6 H), 7.89 (m, 4 H).

Example 56 3,3'-Dithiobis~-hyd.~y ~-phenyl-2X-pyran-2-one]:
Sul~ur monochloride (0.105 mL, 1.32 mmol) was dissolved in benzene (1 ml), and the solution was added dropwise to a suspension of 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol) in benzene (7 ml) while the 5l~cr~ncion was being refluxed. The reflux was continued for 1.5hrs. The reaction was ~l~nch~
with a few drops of water, and the light tan product was collected by filtration. The solid was recrystallization from boiling acetic acid. m.p.

W095/14014 ~ 17 ~ 1 Z4 PCT~S94/1~67 dec~280 C; lH NMR (250 MHz, DMSO-d6) ~ 6.77 (s, 2 H), 7.52 (m, 6 H), 7.81 (m, 4 H).

Es~mpl~ 57 S 3-r~n~yl-~-hyd 6Ay 6-phQnyl-2H-pyran-2-one: To a solution of ethyl benzoylacetate (150 g, 0.88 mmol) in 1,2-dichlorobenzene (150mL) was added a trace amount of sodium bicarbonate. The reaction mixture was heated to reflux. A distillate of ethanol (a~-o~imately 20mL) was collected. The reaction mixture was cooled to O C. Ether (lOOmL) was added to induce crystallization. The reaction mixture was kept in the refrigerator overnight. The solid formed was collected and washed with ether: m.p. 171-173 C;
lH NMR (250 MHz, DMSO-d6) ~ 6.91 (s, 1 H), 7.59 (m, 6 H), 7.87 (m, 4 H).

EYampl~ 58 N-~-n~ o~ 2-oxo-6-phenyl-2~-pyran-3-yl)benzene-~cot~mide: The title com~.d was prepared by Method E
using 3-amino-4-hydlGs~-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348 mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, ph~n~cetyl chloride (0.106 g, 0.626 mmol). m.p. dec. 213 C; lH NMR (250 MHz, DMSO-d6) ~ 3.69 (s, 2 H), 6.85 (s, 1 H), 7.29 (m, 4 H), 7.53 (m, 3 H), 7.83 (m, 2 H), 9.40 (bs, 1 H).

Example 59 2-oxo-6-phenyl-2~-pyran-4-yl-2-naphthal~n~c~rh~Yylic ~cid e~ter: The title compound was prepared by Method G using 4-hydlox~-6-phenyl-2H-pyran-2-one (0.200 g, 0.835 mmol), methylene chloride (8 mL), triethylamine (0.348 mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, 2-naphthoyl chloride (0.175 g, 0.918 mmol). m.p. 143.5-144 C; lH NMR (250 MHz, WO95/14014 PCT~S94/12367 DMSO-d6) ~ 6.51 (s, 1 H), 7.51 (m, 3 H), 7.72 (m, 3 H), 8.80 (m, 7 H), 8.89 (bs, 1 H).

mpl~ CO
3-r8is~2-n~phthalenylmethyl)amino]-4-hy~kG~ 6 ~henyl-2~-pyran-2-one: The title compound was prepared by Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.250 g, 1.04 mmol), 1% acetic acid in dimethylformamide (10 mL), 2-naphthaldehyde (0.407 g, 2.60 mmol), sodium cyanoborohydride (0.164 g, 2.60 mmol). m.p. dec. 209; lH NMR (250 MHz, DMSO-d6) ~ 4.46 (s, 4 H), 6.38 (s, 1 H), 7.44 (m, 8H), 7.77 (m, 13H).

Ex~mpl~ 61 N-(~-~ydroxy-2 o~o 6-phenyl-2H-pyran-3-yl)-2-naphthalenea~tamide : The title compound was prepared by Method E using 3-amino-4-hydLu~y-6-phenyl-2H-pyran-2-one hydrochloride (0.200 g, 0.835 mmol), THF (9 mL), 60 % sodium hydride (0.037 mL, 0.918 mmol), oxalyl chloride (0.080 mL, 0.918 mmol), 2-naphthalyl acetic acid (0.170 g, 0.918 mmol). m.p.
dec. 227 C; lH NMR (250 MHz, DMSO-d6) ~ 4.17 (s, 2 H), 6.84 (s, 1 H), 7.50 (m, 6 H), 7.83 (m, 4 H), 7.93 (d, 1 H), 8.17 (d, 1 H), 9.58 (s, 1 H).
Example 62 N-(~-Hydro~y-2 o~o 6-phenyl-2H-pyran-3-yl)-2-n~phth~lQn~c~-boxamide: The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), THF (6 mL), 60 ~ sodium hydride (0.028 mL, 0.688 mmol), 2-naphthoyl chloride (0.131 g, 0.688 mmol).
m.p. dec. 219 C; lH NMR (250 MHz, DMSO-d6) ~ 6.92 (s, 1 H), 7.61 (m, 5 H), 7.97 (m, 6 H), 8.62 (s, 1 H), 9.61 (s, 1 H).

Example 63 N-(4-Hydroxy-2 O~G ~-phenyl-2H-pyran-3-yl3benzene-WO g5/14014 PCTJUS94~12367 ~74~24 pror~n-~ido: The title compound was prepared by Method E using 3-amino-4-hy~ox~-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), THF (6 mL~, 60 %
sodium hydride (0.028 mL, 0.688 mmol), hydrocinnamyl S chloride (0.131 g, 0.688 mmol). m.p. 191-193 C; lH
NMR (250 MHz, DMSO-d6) ~ 2.65 (t, 2 H), 2.89 (t, 2 H), 6.86 (s, 1 H), 7.26 (m, 5 H), 7.53 (m, 3 H), 7.84 (m, 2 H), 9.28 (s, 1 H).

Bsample 6~
6~ 3-Ren~ Yol-5-yl) -4-hydro2y-3-ttphenylmethyl)thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using 3',4'-(methylenedioxy)acetophenone (0.871 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]
propanedioic acid (1.00 g, 3.54 mmol). m.p. dec.
170 C; 1H NMR (400 MHz, DMSO-d6) ~ 3.98 (s, 2 H), 6.13 (s, 2 H), 6.61 (s, 1 H), 7.0S (d, 2 H), 7.27 (m, 7 H).

E~ample 65 6-t~-(Benzoyloxy)phenyl~-~-h~GAy-3-~(phenylmethyl) thio]-2~-pyran-2-o~e: The title compound was prepared by Method A using 4'-benzoyloxyacetophPn~ne (1.27 g, 5.31 mmol), lithium bis(trimethyl-silyl)amide (0.977 g, 5.84 mmol), chlorotrimethyl-silane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of t(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 205 C; 'H NMR (400 MHz, DMSO-d6) 4.01 (s, 2 H), 6.75 (s, 1 H), 7.21 (m, 1 H), 7.25 (d, 4 H), 7.47 (d, 2 H), 7.63 (t, 2 H), 7.77 (t, 1 H), 7.90 (d, 2 H), 8.16 (d, 2 H).

~xample CC
3-tCyclohe~yl(phenylthio)methyl]-~-hyd~G~ ~-phenyl-2 -pyran-2-one: The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 WO95/14014 PCT~S94/1~67 ~
~17~1~4 g, 5.31 mmol), ethanol (10 mL), cyclnh~Y~e-carboxaldehyde (0.707 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 87-90 C; lH NMR (400 MHz, DMSO-d6) 1.46 (m, 5 H), 1.61 (m, 4 H), 2.15 (m, 1 H), 2 . 31 (d, 1 H), 4.26 (d, 1 H), 6.65 (s, 1 H), 7.16 (t, 1 H), 7.27 (t, 2 H), 7.37 (d, 2 H), 7.52 (m, 3 H), 7.74 (m, 2 H), 11 . 80 (bs , 1 H) .

IS~c~ple 67 ~-~y~ v..2~-3-[ t2-phenylethyl)thio~-6-t4-(phe~ylthio)-phe~yl]-2H-pyr~n-2-one: The title compound was prepared by Method A using 4'-(phenylthio)acetophenone (1.15 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 ,~ol), THF (56 mL), and diethyl ester of r(2-phenylethyl)thio]prop~ne~;oic acid (1.00 g, 3.37 mmol). m.p. 120-121 C; lH N~ (400 MHz, DMSO-d6) 8 2.76 (t, 2 H), 2.98 (t, 2 H), 6.72 (s, 1 H), 7.24 (m, 7 H), 7.45 (m, 5 H), 7.74 (d, 2 H).

kY~mpl~ 68 os~-6-t4-t~2-m~thox~he~yl)m~thosy]phenyl~-3-t~2-phenylethyl)thio]-2H-pyr~n-2-one: The title compound was prepared by Method A using 4'-t (2-methoxyphenyl)methoxy]phenylacetoph~none (1. 2 9 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of t(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 138-139 C; lH N~ (400 MHz, DMSO-d6) ~
2.77 (t, 2 H), 2.98 (t, 2 H), 3.83 (s, 3 H), 5.14 (s, 2 H), 6.68 (s, 1 H), 6.97 (t, 1 H), 7.08 (d, 1 H), 7 . 20 (m, 7 H), 7 . 53 (t, 1 H), 7 . 40 (d, 1 H), 7 . 76 (d, 2 H), 11.85 (bs, 1 H).

~xampl~ 69 WO95/14014 ~174:L2~ rcT/usg4J~2367 ~-~ydrosy-6-t4-~2-metho~cyp~Qnyl)metho~y]-3-methylphonyl]-3-t(2-phenylethyl)thio]-2H-pyr~n-2-ono:
The title compound was prepared by Method A using 4'-[(2-methoxyphenyl)methoxy]-3'-methylacetophenone (1.36 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]prop~n~ioic acid (1.00 g, 3.37 mmol). m.p. dec. 170 C; lH NMR (400 MHz, DMSO-d6) ~
2.25 (s, 3 H), 2.77 (t, 2 H), 2.g7 (t, 2 H), 3.84 (s, 3 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.98 (t, 1 H), 7.70 (d, 1 H), 7.27 (m, 6 H), 7.41 (t, 1 H), 7.43 (d, 1 H), 7.65 (m, 2 H), 11.81 (bs, 1 H).

E~pl~ 70 6-(3,5-Dimethylphenyl) -4-~lG_~ 3-t(phenylmethyl)-thio~-2~-pyran-2-one: The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of ~(phenylmethyl)thio]propAn~Aioic acid (1.00 g, 3.54 mmol). m.p. dec. 170 C; lH NMR (400 MHz, DMSO-d6) 2.33 (s, 6 H), 3.99 (s, 2 H), 6.67 (s, 1 H), 7.21 (m, 6 H), 7.39 (s, 2 H).

E2~mpl~ 71 4-~ydroxy-6-(4-ph~y~henyl)-3-[(2-phenylethyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 4'-phenoxyacetophenone (1.07 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 3s mmol). m.p. 127-128 C; lH NMR (400 MHz, DMSO-d6) ~
2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.18 (m, lOH), 7.46 (t, 2 H), 7.82 (d, 2 H).

WO95/14014 PCT~S94/1~67 Ex~mpl~ 72 ~-~ydrosy-6-phenyl-3-~t[4-~phenylmetho~y)phenyl]
methyl]thio]-2~-pyran-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN
sodium hyd~oxide (2.65 mL), [4-(phenylmethoxy)phenyl]methyl-p-toluenethiosulfonate (1.01 g, 2.65 mmol). m.p. 185-186 C; lH NMR (400 MHz, DMS0-d6) ~ 3.94 (s, 2 H), 5.03 (s, 2 H), 6.72 (s, 1 H), 6.89 (d, 2 H), 7.18 (d, 2 H), 7.34 (m, 5 H), 7.46 (m, 3 H), 7.80 (m, 3 H).

Example 73 ~-~ydroxy-3-~2-phenylethyl)thio]-6-~-(2-pyridinylnethoxy)phanyl]-2~-pyran-2-one: The title compound was prepared by Method A using 4'-(2-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. dec.
179 C; lH NMR (400 MHz, DMS0-d6) ~ 2.77 (t, 2 H), 2.98 (t, 2 H), 5.27 (s, 2 H), 6.68 (s, 1 H), 7.22 (m, 7 H), 7.36 (m, 1 H), 7.53 (d, 1 H), 7.77 (d, 2 H), 7.85 (t, 1 H), 8.60 (d, 2 H), 11.88 (bs, 1 H).

~xampl~ 74 ~-t~-~ydrosy-2-o~o-3-t~2-phenylethyl)thio]-2~-pyran-6-yl~phenoxy acetic acid ethyl e~ter: To a methanol solution (3 ml) of the 4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium - carbonate (0.955 g, 2.94 mmol). The reaction was stirred for 3 hrs. and is then concentrated in vacuo .
Next, dimethylformamide (15 mL) is added and the residue is reconcentrated in vacuo to dryness. The solid is then diluted with dimethylformamide (3 mL) and bromoethylacetate (0.491 mL, 2.94 mmol) is added.

~7~2~

The slurry is then stirred for 3 hrs. The reaction is quenched by dilution with ethyl acetate (100 mL). The organic layer is washed in sllcce~ion with; 1 N HCl, water, saturated sodium chloride; dried over anhydrous S magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (sioz-23o to 400 mesh) using a gradient of 15% ethyl acetate/he~n~s to 50% ethyl acetate/h~Y~nec to 30~ ethyl acetate/30~ h~Y~nP~/40%
methylene chloride.: m.p. 169-171 C; lH NMR (400 MHz, DMS0-d6) ~ 1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H), 4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d, 2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).

~xa~ple 75 ~-~ydroxy-3-~2-~aphth~le~yl~phenylthio)methyl]-6-phenyl 2H-pyran-2-one: The title compound was prepared by Method ~ using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 2-naphthaldehyde (0.912 g, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 98-101 C; lH NMR (400 MHz, DMSO-d6) 5.96 (s, 1 H), 6.73 (s, 1 H), 7.18 (t, 1 H), 7.36 (m, 4 H), 7.52 (m, 5 H), 7.88 (m, 3 H), 8.07 (s, 1 H).
Example 76 ~-Hydroxy-3-t~2-naphth-l~nylthio)phenylmethyl]-6-phe~yl-2~-Pyran-2-one: The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), 2-naphthalenethiol (2.21 gL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL).
m.p. dec. 200 C; lH NMR (400 MHz, DMSO-d6) ~ 5.9 (s, 1 H), 6.71 (s, 1 H), 7.20 (m, 5 H), 7.44 (m, 7 H), 7.75 (m, 3 H), 7.82 (m, 2 H).

~xample 77 WO95114014 PCT~S94/12367 ~-t~ ~y~v~ 2-oso-3-[(2-phenylethyl)thio]-2~-pyr~n-6-yl]ph~o~c~tic acid: To a tetrahydrofuran (10 ml) solution of 4-[4-hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]ph~noxyacetic s acid, ethyl ester (0.939 mmol) was added lN sodium hydroxide (2.34 mmol). The reaction was stirred for 5 hrs, and then quenched by addition of water (lo ml) followed by acidification with conc. hydrochloric acid to pH 2. The aqueous layer was then extracted with 2X
with ethyl acetate (100 ml). The combined organic extracts were then washed with saturated sodium chloride and dried over anhy~Luus magnesium sulfate.
After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p.
182-183 C; lH NMR (400 MHz, DNSO-d6) ~ 2.76 (t, 2 H), 2.97 (t, 2 H), 4.78 (s, 2 H), 6.67 (s, 1 H), 7.06 (d, 2 H), 7.21 (m, 5 H), 7.75 (d, 2 H).
E~mple 78 ~-~ydroxy-3-~t2-phe~ylethyl)thio]-6-[~-(3-pyridinylmethoxy)phenyl]-2~-pyran-2-o~e:
The title compound was prepared by Method A using 4'-(3-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]pro-p~ne~;oic acid (1.00 g, 3.37 mmol). m.p. 178-179 C;
lH NMR (400 MHz, DMSO-d6) ~ 2.76 (t, 2 H), 2.98 (t, 2 H), 5.25 (s, 2 H), 6.69 (s, 1 H), 7.21 (m, 7 H), 7.45 (q, 1 H), 7.77 (d, 2 H), 7.91 (d, 1 H), 8.57 (bs, 1 H), 8.70 (bs, 1 H).

Example 79 6-r~-(Cyclohe~ylmethoxy)phenyl]-~-hydro~y-3-[(2-phenylcthyl)thio]-2~-pyran-2-o~e: The title com~o~,ld was prepared by Method A using 4'-(cyclohexylmethoxy) ~WO95/14014 2~7~ PCT~S94/12367 , - 83 -acetophenone (2.50 g, 10.77 mmol), lithium bis(trimethylsilyl)amide (2.70 g~ 16.16 mmol), chlorotrimethylsilane (2.05 mL,16.16 mmol), THF (107 mL), and diethyl ester of t(2-phenylethyl)thio]prop~n~;oic acid (1.00 g, 3.37 mmol). m.p. 130-132 C; lH NMR (400 MHz, DMS0-d5) ~
1.15 (m, 5 H), 1.81 (m, 6 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 3.85 (d, 2 H), 6.67 (s, 1 H), 7.21 (m, 5 H), 7.45 (q, 1 H), 7.74 (d, 2 H).
Example 80 ~-~ydro~y-3-t~2-pheuylethyl)thio]-6-t~-~phe~ylsul~onyl)phenyl]-2~-pyran-2-one: The title compound was prepared by Method A using 4 ' -(phenylsulfonyl)acetophenone (2.50 g, 9.61 mmol), lithium bis(trimethylsilyl)amide (2.41 g, 14.42 mmol), chlorotrimethylsilane (1.83 mL, 14.42 mmol), THF (96 mL), and diethyl ester of [(2-phenylethyl)thio]pror~n~ioic acid (1.00 g, 3.37 mmol). m.p. 194-195 C; lH NMR (400 MHz, DMS0-d6) 2.76 (t, 2 H), 3.01 (t, 2 H), 6.87 (s, 1 H), 7.19 (m, 5 H), 7.68 (m, 3 H), 8.04 (m, 6 H), 12.05 (bs, 1 H).

~sa~pl~ 81 J. -~ydrosy-3 - ~ ~ 2 -phenylethyl ) thio 1 -6- t ~ ~
be~zoyloxy) phenyl ~ -2~-pyr~n-2 -ono: The title compound was prepared by Method A using 4'-benzoyloxyacetophenone (2.50 g, 10.41 mmol), lithium bis(trimethylsilyl)amide (2.61 g, 15.62 mmol), chlorotrimethylsilane (1.98 mL,15.62 mmol), THF (100 mL), and diethyl ester of [~2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 164-166 C; lH NMR (400 MHz, DMSO-d6) 2.78 (t, 2 H), 3.01 (t, 2 H), 6.81 (s, 1 H), 7.21 (m, S H), 7.49 (d, 2 H), 7.63 (t, 2 H), 7.77 (t, 1 H) ,7.92 (d, 2 H) ,12.00 (bs, 1 H) wos5/14014 ~7~ PCT~S94/12367 kX~pl~ 82 d.~-3-t(2-phonylethyl)thio]-6-t~-~ph~nylsulfinyl)phenyl]-2H-pyran-2-one: The title compound was prepared by Method A using 4'-(phenylsulfinyl)acetophenone (2.50 g, 10.24 mmol), lithium bis(trimethylsilyl)amide (2.57 g,15.36 mmol), chlorotrimethylsilane (1.94 mL,15.36 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propAnP~ioic acid (1.00 g, 3.37 mmol). m.p. 171-173 C; lH NMR (400 MHz, DMSO-d6) S 2.76 (t, 2 H), 3.01 (t, 2 H), 6.83 (s, 1 H), 7.19 (m, 5 H), 7.54 (m, 3 H), 7.75 (d, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H), 12.05 (bs, 1 H).

k~ample 83 ~-Hydrosy-3-[~2-phenylethyl)thio]-6-~-pyridinyl)-2H-pyran-2-one: The title compound was prepared by Method A using 4-acetylpyridine (2.50 g, 20.63 mmol), lithium bis(trimethylsilyl)amide (5.17 g, 30.94 mn ol), chlorotrimethylsilane (3.92 mL, 30.94 mmol), THF (200 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 149-152 C; lH NMR (400 MHz, DMSO-d6) S 2.78 (t, 2 H), 3.04 (t, 2 H), 6.98 (s, 1 H), 7.20 (m, 5 H), 7.74 (d, 2 H), 8.74 (d, 2 H).

~x~mple 8~
3-[1,4-Bis(phenylthio)butyl]-4-hydrosy-6-phQnyl-2H-pyran-2-one, (~/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 ml), cycl~yl~yl carboxaldehyde (0.436 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 75-77 C; 7H NMR (400 MHz, DMS0-d6) S 5.9 (s, 1 H), 6.71 (s, 1 H), 7.20 (m, 5 H), 7.44 (m, 7 H), 7.75 (m, 3 H), 7.82 (m, 2 H).

Esa~pl~ 85 WO95/14014 ~ 24 PCT~S94112367 -L~ dlv~-6-phenyl-3-~phenyl~tph~nylmothyl)thio]methyl]-2H-pyran-2-one, ~+/-): The title compound was prepared by Method C
using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), benzylmercaptan (1.62 mL, 13.8 mmol), pipe~dine (0.5 mL), acetic acid (0.5mL). m.p. 189-191 C; lH NMR
(400 MHz, DMSO-d6) S 3.70 (dd, 2 H), 5.29 (s, 1 H), 6.65 (s, 1 H), 7.23 (m, 8H), 7.50 (m, 5 H), 7.73 (m, 2 H), 11.96 (bs, 1 H).

E~mple 86 ~-~yd~v~y~3~~ t~2-metho~yphenyl)thiolphenylmethyl]-6-phenyl-2H-pyr~n-2-onQ, (I/-) The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), 2-methoxythiophenol (1.93 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 165-170 C; lH NMR (400 MHz, DMSO-d6) S 3.870 (s, 3 H), 5.81 (s, 1 H), 6.70 (s, 1 H), 6.84(t, 1 H), 7.19 (m, 3 H), 7.28 (t, 2 H), 7.53 (m, 3 H), 7.75 (m,2H), 12.13 (bs, 1 H).

Es~mple 87 4-Hyaroxy-3-t3-mQthyl-l-(phenylthio)butyl]-6-phenyl-2~-pyran-2-o~e, (~/-) The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.626 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (O.S mL), acetic acid (O.SmL). m.p.
154-156 C; lH NMR (400 MHz, acetone-d6) S O.89 (d, 3 H), 0.93 (d,3H), 1.63 (m,lH), 1.80 (m, 1 H), 2.32 (m,lH), 4.82 (dd, 2 H), 6.70 (s, 1 H), 7.24 (m, 3 H), 7.82 (m, 2 H), 10.49 (bs, 1 H).
3~
~xample 88 3-t2-Cyclohexyl-l-(phenylthio)ethyl]-~-h~ -6-phenyl-2~-pyran-2-one, ~/-) The title compound was wos5ll4ol4 PCT~S94/12367 ~1 ~ 4 - 86 -prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclohexylmethyl carboxaldehyde (0.735 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), S acetic acid (0.5mL). m.p. dec. 205 C; lH NNR (400 MHz, acetone-d6) ~ 0.91 (d, 3 H), 1.25 (m, 5 H), 1.73 (m, 5 H), 2.58 (m, 1 H), 4.83 (dd, 1 H), 6.69 (s, 1 H), 7.22 (m, 3 H), 7.48 (m, 5 H), 7.82 (m, 2 H).
Exa~ple 89 ~ ~d~o~ 6-~3-rhn-o-~he~yl)-3-[~2-phenylethyl)thio~-2~-pyran-2-one: The title compound was prepared by Method A using 3'-rh~Yyacetophenone (2.00 g, 9.43 mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-prop~e~;oic acid (1.00 g, 3.37 mmol). m.p. 114-115 C; lH NMR (400 MHz, DMS0-d6) 2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09 (m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).

I~pl~ 90 ~-n~d,v~y~6-t3-metho~y~ phe~ylmetho~y)phenyl]-3-~2-phenylethyl)thio]-2H-pyran-2-o~e: The title compound was prepared by Method A using 4'-benzyloxy-3'-methoxyacetophenone (2.00 g, 7.81 mmol), lithium bis(trimethylsilyl)amide (1.96 g, 11.71 mmol), chlorotrimethylsilane (1.48 mL, 11.71 mmol), THF (80 mL), and diethyl ester of [(2-phenylethyl)thio3propanedioic acid (1.00 g, 3.37 mmol). m.p. 114-115 C; lH NMR (400 MHz, DMSO-d6) 2.77 (t, 2 H), 2.98 (t, 2 H), 3.86 (s, 1 H), 6.75 (s, 1 H), 7.21 (m, 7 H), 7.40 (m, 6 H).

~ pl~ 91 6-S3,5-Dimethylphenyl)-~-hy~ro~y-3-t~2-phenylethyl)thio~-2~-pyr~-2-one: The title compound WO95/14014 ~ ~q~ ~ PcT~S94112367 was prepared by Method A using 3',5'-dimethyl acetophenone (1.75 g, 11.82 mmol), lithium diisopropylamide (1.89 g, 17.73 mmol), chlorotrimethylsilane (2.25 mL, 17.73 mmol), THF (120 mL), and diethyl ester of [(2-phenylethyl)thio]-prop~n~;oic acid (1.00 g, 3.37 mmol). m.p. 155-157 C; lH NMR (400 MHz, DMSO-d6) ~ 2.34 (s, 6 H), 2.77 (t, 2 H), 2.99 (t, 2 H), 6.72 (s, 1 H), 7.21 (m, 6 H), 7.41 (s, 2 H), 8.74 (d, 2 H).
~mple 92 ydroYy-3-ttt3-metho~cyphenyl)methyl]thio]-6-phenyl-2~-pyran-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide (5.31 mL), ~3-(methoxy)phenyl]methyl p-toluenethiosulfonate (2.12 g, 6.90 mmol). m.p.
134-136 C; lH NMR (400 MHz, DMSO-d6) ~ 3.69 (s, 3 H), 3.99 (s,2H), 6.75 (m, 2 H), 6.83 (m, 2 H), 7.16 (t, 1 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

Example 93 ~-~ydroxy-3-~-methyl-1-(phenylthio)pentyl]-6-phQnyl-2~-pyran-2-one, (~/-) The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 4-methylpentanal (0.584 mL, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (O.SmL). m.p. 144-145 C; lH NMR (400 MHz, DMSO-d6) 0.80 (d, 3 H), 0.81 (d, 3 H), 1.07 (m, 1 H), 1.18 (m, 1 H), 1.49 (m, 1 H), 1.89 (m, 1 H), 2.19 (m, 1 H), 4.51 (dd, 1 H), 6.68 (s, 1 H), 7.19 (t, 1 H), 7.29 (t, 2 H), 7.35 (d, 2 H), 7.53 (m, 3 H), 7.76 (m, 2 H).

3s Example 9 ~-Hydro~y-6-ph~nYl-3~[[t3~
(ph~nylmethoxy)phenyl]methyl]thio]-2~-pyran-2-one: The title compound was prepared by Method B using 4-WO95/14014 PCT~S94/1~67 hydl~y-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hy~Loxide (5.31 mL), [3-(benzoxyl)phenyl]methyl p-toluenethiosulfonate (2.65 g, 6.90 mmol). m.p. 140-141 C; lH NMR (400 MHz, DMSO-d6) ~ 3.98 (s, 2 H), 5.01 (s, 2 H), 6.75 (s, 1 H), 6.83 (m, 2 H), 6.91 (m, 1 H), 7.28 (t, 1 H), 7.34 (m, 4 H), 7.52 (m, 3 H), 7.80 (m, 2 H).

E~mpl~ 95 3-t~1,3~ n7~i~1-5-ylm~thyl)thio]-4-hydroxy-6-phenyl-2~-pyr~n-2-one : The title compound was prepared by Method B using 4-hydL~xy-6-phenyl-2H-pyran-2-one (l.00 g, 5.31 mmol), ethanol (15 mL), lN
sodium hyd~oxide (5.31 mL), 1,3-benzodioxoyl-5-yl methyl p-toluenethiosulfonate (2.22 g, 6.90 mmol).
m.p. 162-164 C; lH NMR (400 MHz, DMSO-d6) ~ 3.92 (s, 2 H), 5.95 (s, 2 H), 6.75 (m, 4 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

E~mpl~ 96 ~-~ydroxy-3-t~2-methoxyphenyl~methyl]thio]-6-phenyl-2~-pyran-2-on~: The title compound was prepared by Method B using 4-hy~L~y-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), lN sodium hydroxide (2.65 mL), [(2-methoxyphenyl)methyl] p-toluenethiosulfonate (0.816 g, 2.65 mmol). m.p.
152-153 C; lH NMR (400 MHz, DMSO-d6) ~ 3.73 (s, 3 H), 3.95 (s, 2 H), 6.71 (s, 1 H), 6.81 (t, l H), 6.91 (d, 1 H), 7.13 (d, l H), 7.17 (t, 1 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

Exampl~ 97 4-Hydrosy-3-[t(2-methylphenyl)methyl]thio]-6-phenyl-2H-pyr~n-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide (5.31 mL), [(2-methylphenyl)methyl] p-toluenethiosulfonate (1.55 g, 5.31 mmol). m.p. 176-~ W095rl4014 ~17 ~ ~ 2~ PCT~Ss4/l2367 178 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.42 (s, 3 H), 3.99 (s, 2 H), 6.74 (s, 1 H), 709 (m, 4 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

Esample 98 4-ny~lG~-3-t[~3-methylphenyl)methyl]thio]-6-phenyl-2~-pyran-2-one: The title compound was prepared by Me~hod B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (lS mL), lN sodium hyd~o~ide (5.31 mL), t(3-methylphenyl)methyl~ p-toluenethiosulfonate (1.55 g, 5.31 mmol). m.p. 139-140 C; lH NMR (400 MHz, DMSO-d6) ~ 2.23 (s, 3 H), 3.96 (s, 2 H), 6.74 (s, 1 H), 7.07 (m, 4 H), 7.54 (m, 3 H), 7.79 (m, 2 H).
~sample 99 4-~y~6~y-3-tt(~-mQthylphenyl)m~thyl]thio~-6-phen 2~-pyr~n-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide (5.31 mL), [(4-methylphenyl)methyl] p-toluenethiosulfonate (1.5S g, 5.31 mmol). m.p. 164-165 C; lH NMR (400 MHz, DMSO-d6) ~ 2.23 (s, 3 H), 3.g6 (s, 2 H), 6.74 (s, 1 H), 7.06 (d, 2 H), 7.14 (d, 2 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

~ xa~ple 100 6-t1,1'-Biphenyl]-3-yl-~-hydro~y-3-~(2-phenylethyl)thio~-2H-pyran-2-one : The title compound was prepared by Method A using 3~-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL, 1~.24 mmol), triethylamine (2.84 mL, 20.40 mmol), methylene chloride (26 mL), and diethyl ester of ~(2-phenylethyl)thio]prop~n~ ;oic acid (1.00 g, 3.37 mmol). m.p. 93-94 oc; lH NMR (400 MHz, DMSO-d6) ~ 2.79 (t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H), 7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d, 2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).

~17~ 12~1 WO 9Stl4014 PCI/US94112367 E~a~plQ 101 ~-~ydroxy-3-~ -~Qthosyphenyl)methyl]thio]-6-phenyl-2~-pyr~n-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide (5.31 mL), [(4-methox~phenyl)methyl] p-toluenethiosulfonate (2.21 g, 6.90 mmol). m.p. 168-170 C; lH NMR (400 MHz, DMSO-d6) ~ 3.96 (s, 3 H), 3.95 (s, 2 H), 6.73 (s, 1 H), 6.81 (d, 2 H), 7.17 (d, 2 H), 7.53 (m, 3 H), 7.79 (m, 2 H).

E~mpl~ 102 3-t2-Cyclohexyl-l-(cyclohe~ylthio)ethyl]-4-~ -6-phenyl-2H-pyr~n-2-one, (~ : The title compound was lS prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclohexylmethyl carboxaldehyde (0.735 g, 5.84 mmol), cyclohexylmercaptan (1.60 g, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. dec. 220 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.86 (m, 2 H), 1.18 (m, 9H), 1.66 (m, lOH), 2.03 (m, 2 H), 2.58 (m, 2 H), 4.25 (m, 1 H), 6.68 (s, 1 H), 7.53 (m, 3 H), 7.75 (m,2H).

Esampl~ 103 3-[1- r (2,6-Dimethylphenyl)thio3-3-methylbutyl]-4-~y~y 6-phenyl-2H-pyran-2-one, ~/-) : The title compound was prepared by Method C using 4-hydk oxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.63 mL, 5.84 mmol), 2,6-dimethylthiophenol (1.90 g, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 166-167 C; lH NMR (400 MHz, DMSO-d6) ~ 0.78 (d, 3 H), 0.83 (d, 3 H), 1.42 (m, 1 H), 1.47 (m, 1 H), 2.46 (m, 1 H), 2.51 (s, 6 H), 4.37 (m, 1 H), 6.51 (s, 1 H), 7.70 (m, 3 H), 7.52 (m, 3 H), 7.74 (m,2H).

E~C~pl~ 10 WO 95tl4014 PCT/US94J12367 3-t1-(Cycloh y lthio~-2-cyclopropylethyl~-4-Ly~ ~y~6~
pho~yl-2H-pyr~n-2-o~ The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cycl~u~ylmethyl carboxaldehyde (0.67 g, 5.84 mmol), cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 69-71 C; lH NMR
(400 MHz, DMS0-d6) ~ -0.02 (m, 1 H), 0.05 (m, 1 H), 0.34 (m, 2 H), 0.64 (m, 2 H), 1.22 (m, 5 H), 1.52 (m, 1 H), 1.67 (m, 3 H), 1.84 (m, 1 H), 1.97 (m, 2 H), 2.64 (m, 1 H), 4.21 (t, 1 H), 6.69 (s, 1 H), 7.52 (m, 3 H), 7.75 (m, 2 H).

E~P1Q 105 3-~1-t(2,6-~ichlorophenyl)thio~-3-methylbutyl]-~-hydro~y-6-phenyl-2H-pyran-2-one, (+/-) : The title com~o~-d was prepared by Method C using 4-hy~ y-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.62 mL, 5.84 mmol), 2,6-dichlorothiophenol (2.74 g, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 158-162 C; lH NMR (400 NHz, DMSO-d6) ~ 0.83 (d, 3 H), 0.87 (d, 3 H), 1.49 (m, 1 H), 1.74 (m, 1 H), 2.39 (m, 1 H), 4.68 (m, 1 H), 6.769 (s, 1 H), 7.49 (m, S H), 7.74 (m, 3 H).

Es~mpl~ 106 3-tl-(Cyclohexylthio)-3,3-dLmethylbutyl]-~-hydroxy-6-phenyl-2~-pyr~n-2-one, ~+/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), 3,3-dimethylbutanal (0.73 mL, 5.84 mmol), cyclohexylmercaptan (1.86 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (O.SmL). m.p. >225 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.85 (s, 9H), 1.25 (m, 5 H), 1.65 (m, 7 H), 4.30 (m, 1 H), 6.69 (s, 1 H), 7.54 (m, 3 H), 7.75 (m, 2 H).

wossll40l4 PCT~S94/1~67 \
~7~1~4 E~ample 107 t4~ ydrosy-2-oso-3-~t2-phenylethyl)thio]-2~-pyr~n-6-yl]-2-methylphenosy], acQtic acid, ethyl ester: The title compound was prepared by Method A
using ethyl (4-acetyl-2-methylph~noxy)acetate (2.00 g, 8.47 mmol), trimethyl silyltriflate (3.92 mL, 20.33 mmol), triethylamine (4.72 mL, 33.88 mmol), methylene chloride (22 mL), and diethyl ester of [(2-phenylethyl)thio]propAnP~;oic acid (1.00 g, 3.37 mmol). m.p. 154-156 C; lH NMR (400 MHz, DMSO-d6) ~
1.22 (t, 3 H), 2.26 (s, 3 H), 2.77 (t, 2 H), 2.97 (t, 2 H), 4.17 (t, 2 H), 4.91 (s, 2 H), 6.66 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.61 (m, 2 H).

~xample 108 6-t3,5-Dimethyl~ dimethyl I 1, 1-~imethyl~thyl)silyl]oxy]phenyl]-~-hydrosy-3-ttphenylmethyl)thiol-2~-pyra~-2-one: The title compound was prepared by Method A using 3',5'-dimethyl-4'-t[dimethyl(1,1-dimethylethyl)silyl]oxy]
acetophenone (1.50 g, 5.39 mmol), trimethylsilyltriflate (1.24 mL, 6.47 mmol), triethylamine (1.50 mL, 10.78 mmol), methylene chloride (13 mL), and diethyl ester of [(phenylmethyl)thio]propAn~;oic acid (1.00 g, 3.54 mmol). m.p. 137-139 C; lH NMR (400 MHz, DMSO-d6) ~
0.21 (s, 6 H), 0.99 (s, 9H), 2.22 (s, 6 H), 3.96 (s, 2 H), 6.54 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.44 (m, 2 H).
E~ample 109 4-~ydroxy-3-t(2-phenylethyl)thio]-6[4-(4-pyridinylmethoxy)phenyl]-2~-pyran-2-one: The title compound was prepared by Method A using 4'-(4-pyridinylmethoxy)acetophenone (2.00 g, 8.81 mmol), trimethylsilyltriflate (2.04 mL, 10.57 mmol), triethylamine (2.45 mL, 17.62 mmol), methylene chloride (22 mL), and diethyl ester of [(2-WO95/14014 PCT~S94/12367 ~7 412~

phenylethyl~thio~prop~n~;oic acid (1.00 g, 3.37 mmol). m.p. dec. 212 C; lH NMR (400 MHz, DMSO-d6) 2.73 (t, 2 H), 2.88 (t, 2 H), 5.29 (s, 2 H), 6.48 (s, 1 H), 7.18 (m, 5 H), 7.45 (d, 2 H), 7.74 (d, 2 H), 8.90 (d, 2 H).

~ c~mpl~ 110 3-tl-~Cyclopentylthio)-3-methylbutyl~ y~ v~-6-phe~yl-2~-pyr~n-2-o~e (~ The title compound was prepared by Method C using 4-h~ y-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.62 mL, 5.84 mmol), cyclopentylmercaptan (1.43 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 146-149 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.85 (d, 2 H), 0.87 (d, 2 H), 1.32 (m, 1 H), 1.54 (m, 7 H), 1.85 (m, 1 H), 2.00 (m, 2 H), 3.04 (m, 1 H), 4.20 (dd, 1 H), 6.69 (s, 1 H), 7.53 (m, 3 H), 7.76 (m,2H), 11.69 (bs, 1 H).

E~mpl~
t4-t4-Hydro2y-2-oxo-3t(2-phenylethyl)thio]-2H-pyran -6-yl]-2-methylrho~ acetic acia: To a tetrahydrofuran (10 ml) solution of ~4-~4-llyd~o~y-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-2-methylphenoxy]-, acetic acid, ethyl ester (0.20 g.
o.45 mmol) was added lN sodium hydroxide (1.13 mL, 1.13 mmol). The reaction was stirred for 5 hrs, and then quenched by addition of water (10 ml) followed by acidification with conc. hydrochloric acid to pH 2.
The aqueous layer is then extracted with 2X with ethyl acetate (100 ml). the com~ined organic extracts were then washed with saturated~sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/511 methylene chloride/methanol/acetic acid as the eluent. m.p. dec. 210 C; lH NMR (400 MHz, DMS0-d6) ~ 2.26 (S, 3 H), 2.78 (t, 2 H), 2.98 (t, 2 Hl, WO95tl4014 PCT~S94112367 ~
~7~

4.81 (s, 2 H), 6.67 (s, 1 H), 6.97 (d, 2 H), 7.21 (m, 5 H), 7.61 (d, 2 H).

BY~mpl~ 112 3-ll-(cycloherylthio)-2-cyclope~tylQthyl]-~-h~GAy-6 phenyl-28-pyran-2-one, (I/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclopentylmethylcarboxaldehyde (0.65 g, 5.84 mmol), cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5mL). m.p. 157-160 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.44 (m, 18H), 2.01 (m, 1 H), 2.19 (m, 1 H), 2.60 (m, 1 H), 4.16 (m, 1 H), 6.68 (s, 1 H), 7.53 (m, 3 H), 7.75 (m,2H), 11.66 (bs, 1 H).
E~a~pl~ 113 v~y 6-(~-hy~roxy-3~5-diuethylphenyl)-3-t~phenyl~ethyl)thio]-2~-pyra~-2-one: To a THF (10 mL) solution of 6-~3,5-dimethyl-4- r [ dimethyl(1,1-dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-~(phenylmethyl)thio]-2H-pyran-2-one at 0 C is added 3 N HCl (9.0 mL). The reaction is stirred for 48 hrs.
at room temperature. The reaction is ~l~nch~ by pouring onto ethyl acetate and washed in succession with water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2-230 to 400 mesh) using S0 % ethyl acetate/ h~ es. m.p. 174-176 C; lH
NMR (250 MHz, DMSO-d6) ~ 2.21 (s, 6 H), 2.60 (m, 1 H), 3.96 (s, 2 H), 6.52 (s, 1 H), 7.23 (s, 5 H), 7.38 (s, 2 H), 9.06 (s, 1 H).

~xample 11 ~-~y~ VAy ~-phenyl-3-t~t3-(2-phenylethoxy)phe~yl]methyl]thio]-2~-pyran-2-one : The title compound was prepared by Method B using 4-hydl~xy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ~ WO gS114014 PCT~US94~23C7 ~7gl~

ethanol (15 mL), lN sodium hy~oxide (5.31 mL), t3-(2-(phenylethoxy)phenyl]methyl p-toluenethiosulfonate (2.11 g, 5.31 mmol). m.p. 85-90 C; lH NMR (400 MHz, DMSO-d6) ~ 2.96 (t, 2 H), 3.96 (s, 2 H), 4.09 (t, 2 H), 6.77 (m, 4 H), 7.19 (m, 5 H), 7.53 (m, 3 H), 7.77 (m, 2 H).

~amplo 115 ~ ~v~y~6~ t ~- (2-phenylethyllyl) phenyl] -3-1 ~2-ph~ylethyl)thio]-2~-pyr~n-2-on~: The title compound was prepared by Method A using 4'-(2-phenethynyl)acetophenone (1.50 g, 6.81 mmol), trimethylsilyltriflate (1.57 mL, 8.17 mmol), triethylamine (1.89 mL, 13.62 mmol), methylene chloride (17 mL), and diethyl ester of [(2-phenylethyl)thio]propAn~ioic acid (1.00 g, 3.37 mmol). m.p. 181-182 C; lH NMR (400 MHz, DMSO-d6) 2.78 (t, 2 H), 3.02 (t, 2 H), 6.85 (s, 1 H), 7.21 (m, 5 H), 7.45 (m, 3 H), 7.59 (d, 2 H), 7.86 (d, 2 H).
~xample 116 ~ G~-6-t~-(2-phenylethyl)ph~nyl]-3-tt2-phenylethyl)thio]-2~ ~ ~n-2-one: The title compound was prepared by Method A using 4'-(2-phenethyl)acetoph~nnn~ (1.50 g, 6.68 mmol), trimethylsilyltriflate (1.55 mL, 8.02 mmol), triethylamine (1.86 mL, 13.36 mmol), methylene chloride (17 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 122-123 C; lH NMR (400 MHz, DMSO-d6) 2.77 (t, 2 H), 2.93 (m, 4 H), 2.99 (t, 2 H), 6.75 (s, 1 H), 7.26 (m, 5 H), 7.38 (d, 2 H), 7.71 (d, 2 H).

~s~mpl~ 117 3-~(Cyclohe~ylthio)pheuylmethyl]-~-hydroxy-6-phenyl-2~-pyran-2-one, (~/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1. 00 g, 5 . 31 mmol), ethanol (10 mI ), WO95114014 PCT~S94/1~67 ~

217 ~
^ - 96 -benzaldehyde (0.593 mL, 5.84 mmol), cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (O.SmL). m.p. 189-191 C; lH NMR
(400 MHz, DMSO-d6) ~ 1.21 (m, 5 H), 1.52 (m, 1 H), 1.91 (m, 2 H), 2.58 (m, 2 H), 5.37 (s, 1 H), 6.70 (s, 1 H), 7.17 (t, 1 H), 7.53 (m, 5 H), 7.74 (m, 2 H), 11.96 (bs, 1 H).

~mple 118 ~ ~y~ 3-~phenylmathyl)thio]-6-~3-(trifluorom~thoxy)phenyll-2~-pyr~n-2-on~: The title com~.d was prepared by Method A using 3'trifluoromethoxyacetophenone (3 g, 14.7 mmol), lithium bis(trimethylsilylamide (2.45 g, 14.7 mmol), chlorotrimethylsilane (2.47 g, 14.7 mmol) and diethyl ester Of t(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 128-132 C; lH NMR (400 MHz, DMSO-d6) ~ 4.03 (s, 2 H), 6.81 (s, 1 H), 7.2 (m, 2 H), 7.28 (m, 3 H), 7.56 (dd, 1 H), 7.69 (t, 1 H), 7.75 (s, 1 H), 7.86 (d, 1 H); IR (KBr) 2963, 1651, 1550, 1394, 1369, 1395, 1263, 1098, 1024, 800 cm~1; MS (CI):
m/e 395 (M+H, 37), 309 (8), 273 (7), 205 (3), 119 (10); Analysis calc'd for ClgHl304SlF3.H2O: C, 55.34; H, 3.67; found: C, 54.94; H, 4.03.
Example 119 3-t(Cyclohexylm~thyl)thio]-~-hydroxy-6-phe~yl-28-pyran-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.5 g, 2.66 mmol), ethanol (7 mL), lN sodium hydroxide (2.66 mL), cyclohexylmethyl-p-toluenethiosulfonate (0.756 g, 2.66 mmol). m.p. 141-143 C; lH NMR (400 MHz, DMSO-d6) ~ 0.92 (m, 2 H), 1.14 (m, 3 H), 1.19 (m, l H), 1.61 (m, 3 H), 1.83 (m, 2 H), 2.64 (d, 2 H), 6.78 3S (s, 1 H), 7.53 (m, 3 H), 7.81 (m, 2 H); IR (RBr) 3106, 2922, 1651, 1547, 1396, 1099, 766 cm~l; MS (CI) m/e 317 (M+H, 16), 279 (83), 242 (77), 201 (27), 177 (19), 134 (54), 105 ~65), 97 (100).

WO95/14014 ~7~ PCT~S94112367 2s~ple 120 4-Xy~roxy-3-t~2-ph~ylethyl)thio]-6-[3-methyl-4-(3-pyridinylmethoxy)phe~yl~-2~-pyr~n-2-one: The title compound was prepared by Method A using 3r-methyl-4~-(3-pyridinylmethoxy)acetoph~no~ (2.0 g, 8.29 mmol), lithium bis(trimethylsilylamide (1.53 g, 9.13 mmol), chlorotrimethylsilane (1.54 g, 9.13 mmol) and diethyl ester of [2-(phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 149-151 C; lH NMR (400 MHz, DMSO-d6) ~ 2.25 (s, 3 H), 2.78(t, 2 H), 2.97 (t, 2 H), 5.28 (s, 2 H), 6.69 (s, 1 H), 7.22 (m, 6 H), 7.44 (dd, 1 H), 7.67 (s + d, 2 H), 7.92 (d, 1 H), 8.58 (brs, 1 H), 8.72 (brs, 1 H); IR (KBr) 3430, 2926, 1713, 1626, 1505, 1263, 1136, 1028, 808, 705 cm-l; MS
(CI): m/e 446 (M+H), 341 (15), 200 (6), 105 (100);
Analysis calc'd for C26H23O4SlNl: C, 70.09; H, 5.20; N, 3.14; found: C, 70.31; H, 5.27; N, 2.95.

Example 121 6-~2,3-Dihydro~ ben~o~; OY; n-6-yl) -4-hydro~y-3-t~phenylmethyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2.5 g, 14.25 ol), lithium bis(trimethylsilylamide (2.35 g, 14.25 mmol), chlorotrimethylsilane (2.47 g, 14.25 mmol) and diethyl ester of t(phenylmethyl)thio]propAne~;oic acid (l.oo g, 3.55 mmol). m.p. 192-193 C; lH NMR (400 MHz, DMSO-d6) ~ 3.99 (s, 2 H), 4.17 (m, 4 H), 6.8 (s, 1 H), 7.0 (d, 1 H), 7.2 (m, 1 H), 2.28 (m, 7 H); IR (KBr) 3435, 2924, 1649, 1624, 1508, 1288, 1066, 698 cm~l; MS
(CI): m/e 369 (M+H,), 277 (12), 233 (12), 163 (9), 107 (10), 91 (76); Analysis calc'd for C20Hl6OsS1: C, 65.21;
H, 4.38; found: C, 64.80; H, 4.17.

$~mple 122 o~y-3-t~2-phenylethyl)thio]-6-t3-(trifluoromethyl)phenyl]-2~-pyran-2-one: The title compound was prepared by Method A using the woss/140l4 ~ 4 PCT~S94/12367 corres~on~;ng trimethylsilyl enol ether (4.5 mmol) and diethyl ester of t(2-phenylethyl)thio]prop~e~;oic acid (1.33 g, 4.55 mmol). m.p. 117-118(C); lH NMR
(400 MHz, DMSO-d6) ~ 2.8 (t, 2 H), 3.03 (t, 2 H), 6.94 (s, 1 H), 7.2 (m, 5 H), 7.8 (t, 1 H), 7.94 (t, 1 H), 8.08 (s, 1 H), 8.14 (d, 1 H); IR (KBr) 3435, 3026, 2924, 1720, 1635, 1543, 1327, 1171, 1130, 696 cm~l; MS
(CI): m/e 393 (M+H, 100), 373 (9), 288 (38), 256 (20), 224 (11), 105 (62); Analysis calc'd for C20H~5S,O3F3.H2O: C, 58.53; H, 4.18; found: C, 59.28;
H, 3.81.

~xa~pl~ 123 ~ d.o~ 3-[~phenylmethyl)thio]-6-[3-~trifluoromethyl)phenyl]-2H-pyran-2-one: The title compound was prepared by Method A using the correspo~;ng trimethylsilyl enol ether (9.8 mmol) and diethyl ester of [(phenylmethyl)thio]prop~n~;oic acid (2.76 g, 9.88 mmol).
m.p. 152-153 C; lH NMR (400 MHz, DMSO-d6) ~ 3.97 (s, 2 H), 6.53 (s, 1 H), 7.25 (m, 5 H), 7.61 (t, 1 H), 7.75 (d, 1 H), 8.03 (d, 1 H), 8.08 (s, 1 H); IR (KBr) 3434, 3244, 1678, 1628, 1535, 1522, 1435, 1341, 1316, 1192, 1132, 936, 706 cm~l; MS (CI) m/e 379 (M+H,), 257 (1), 91 (100); Analysis calc'd for ClgHl3O3SlF3: C, 60.31; H, 3.46; found: C, 60.53; H, 3.57.

~xample 12~
4-nydl6~y-3-tlp~enylmethyl)thio]-6-(2,3,4-trimethoxyphenyl)-2H-pyran-2-one: The title compound was prepared by Method A using 2',3',4'-trimethoxyacetophenone (1.5 g, 7.13 mmol), lithium bis(trimethylsilyl)amide (1.43 g, 8.56 mmol), chlorotrimethylsilane (1.8 mL, 10.67 mmol) and diethyl ester of [(phenylmethyl)thio]prop~ne~;oic acid (1.00 g, 3.54 mmol).

~xampl~ ~25 WO95/14014 PCT~S9411~67 ~ 74~

N-t~-t~-~y~Lv~ 2-oso-3-~(2-ph~nylothyl)thio3-2~-pyran-C-yl~phenyl]-b~nzonQsulfonamide: The title compound was prepared by Method A using the correspon~;ng benzenesulfonamide (3.0 g, 10.91 mmol), S lithium bis(trimethylsilylamide (3.65 g, 21.82 mmol), chlorotrimethylsilane (3.68 mL, 21.82 mmol) and diethyl ester Of t(phenylethyl)thio]propanedioic acid (1.00 g, 3.37 ol). m.p. 89-91 C; lH NMR (400 MHz, DMS0-d6) ~ 2.78 (t, 2 H), 3.03 (t, 2 H), 6.86 (s, 1 H), 7.25 (m, 6 H), 7.72 (t, 3 H), 7.86 (m, 5 H); IR (KBr) 3443, 3335, 1725, 1632, 1543, 1383, 1171, 912, 729, 581, 552 cm~1; Analysis calc'd ~or C2sH21N1S205. H20: C, 60.35; H, 4.66; N, 2.81; found: C, 60.13; H, 4.47;
N, 3.23.
~5 ~sample 126 6-~4-~3,5-Dimethyl~ s~lyl)metho~y]phenyl]-~-h~,G~-3-t~2-phenylethyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 4'-(3,5-dimethyl-4-isoxazolyl)acetophenone (1.65 g, 6.74 mmol), lithium bis(trimethylsilylamide (1.13 g, 6.74 mmol), chlorotrimethylsilane (1.14mL, 6.74 mmol) and diethyl ester of t(2-phenylethyl)thio]prop~n~;oic acid (1.00 g, 3.37 mmol). m.p. 152-154 C; lH NMR
(400 MHz, DMS0-d6) ~ 2.22 (s, 3 H), 2.31 (s, 3 H), 2.78 (t, 2 H), 2.99 (t, 2 H), 5.03 (s, 2 H), 6.69 (s, 1 H), 7.17 (d, 3 H), 7.25 (m, 4 H), 7.78 (d, 2 H); IR (KBr) 2936, 2979, 1640, 1510, 1406, 1182, 988, 820, 764 cm~l;
MS (CI) m/e 450 (M+H), 341 (10), 236 (9), 112 (76), 105 (100); Analysis calc'd for C2sHz3NlOsS1: C, 66.80;
H, 5.16; N, 3.12; found: C, 66.42; H, 5.20; N, 2.74.

~xample 127 3s (~/-) 3-l(cyclohexylthio)phenylmethyl]-~-hydroxy-6-t3 mcthyl-4-(3-pyridinylmQthoxy)phenyl]-2~-pyran-2 -O~Q:
The title compound was prepared by Method C using 4-hydroxy-6-~3-methyl-4-(3-pyridinylmethoxy)phenyl~-2H-WO9S/14014 ~ 7~ PCT~S94/12367 ~

pyran-2-one (0.5 g, 1.62 mmol), benzaldehyde (0.189 g, 1.78 mmol), cyclohexylmercaptan (0.489 g, 4.212 mmol), piperidine, (0.5 mL), acetic acid (0.5 mL). m.p.
84-87 C (d); IR (KBr) 3059, 2930, 2853, 1676, 1601, 1449, 1260, 1134, 700 cm-l; MS (CI) m/e 446 (2), 331 (9), 226 (61), 205 (24), 135 (44).

E~a~pl~ 128 2~ -hydrosy-2-oxo-6-phenyl-2~-pyr~n-3-yl)thio]methyl]-be~zoic acid methyl ester : The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (2.0 g, 10.63 mmol), [2-(carbomethoxy)phenyl]methyl p-toluenethiosulfonate (3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol (20mL). m.p. 122-123 C; lH NMR (400 MHz, DMSO-d6) 3.81 (s, 3 H), 4.31 (s, 2 H), 6.67 (s, 1 H), 7.25 (d, 1 H), 7.31 (t, 1 H), 7.44 (t, 1 H), 7.44 (m, 3 H), 7.53 (d, 1 H), 7.99 (m, 3 H); IR (KBr) 3005, 2951, 1721, 1653, 1543, 1400, 1267, 1078, 966, 766, 711, 520 cm-1; MS (CI) m/e 397 (M+29, 4), 369 ((M+H), 40), 3~7 (34), 191 (26), 149 (100), 105 (14).

Exa~ple 129 3-[1-(Cyclohexylthio)-3-methylbutyl]-6-(2,3-dihydro-1~ ~-b~n70~; ~Yi n-6-yl) ~-hydroxy-2~-pyr~n-2-on~
The title compound was prepared by Method C using 4-hydroxy-6-[1,4-benzodioxin-6-yl]-2H-pyran-2-one (1.0 g, 4.06 mmol), isovaleraldehyde (0.35 g, 4.06 mmol), cyclohexylmercaptan (0.944 g, 8.12 mmol), piperidine, (0.5 mL), acetic acid (0.5 mL). m.p. 161-162 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.85 (d, 3 H), 0.88 (d, 3 H), 1.2 (m, 5 H), 1.39 (m, 1 H), 1.53 (m, 2 H), 1.65 (m, 2 H), 1.81 (brm, 1 H), 2.04 (m, 2 H), 4.2 (q, 1 H), 4.32 (brq, 4 H), 6.53 (s, 1 H), 6.99 (d, 1 H), 7.2 (d, 1 H), 7.25 (dd, 1 H); IR (KBr) 1099, 2930, 2853, 1649, 1564, 1510, 1397, 1314, 1289, 1260, 1140, 106g, 891, 771, 608 cm~l.

~ Wos5/14014 ~ 2~ PCT~S94)~67 k~a~pl~ 130 2 t~4-t4-L~ G~ -2-oxo-3-[(2-phenyl~thyl)t~io]-2~-pyran-6-yl] phn~ y]~othyl]-b~zoic ~cid methyl ~ster:
The title compound was prepared by Method A using 2-[[(4-acetyl)phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), trimethylsilyltrifluoromethylsulfonate (1.57 g, 7.04 mmol), triethylamine (1.42 g, 14.08mmol) and diethyl ester of ~(2-phenylethyl)thio]prop~ne~;oic acid (1.04 g, 3.52 mmol). m.p. 161-162 C; lH NMR (400 MHz, DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.81 (s, 3 H), 5.5 (s, 2 H), 6.69 (s, 1 H), 7.14 (m, 3 H), 7.25 (m, 4 H), 7.5 (m, 2 H), 7.78 (m, 2 H), 7.78 (d, 2 H), 7.94 (d, 1 H); IR (KBr) 3028, 2949, 2909, 2675, 1715, lS 1638, 1510, 1402, 1291, 1267, 1181, 1030, 828, 747 cm-l; MS (CI) m/e 489 (M+H, 51), 384 (3), 353 (1), 149 (100), 135 (47), 105 (33).

~x~mple 131 ~-~ydrosy-3-t~2-ph~nylethyl)thio]-6-t~ -tetr~sol-5-ylmethoxy)phenyl]-2~-pyran-2-o~e: The title compound was prepared by using example 143 (0.5 g, 1.32 mmol) and trimethyltin azide (0.543 g, 2.64 mmol), toluene (lOmL) and ethanol (lOmL) at its reflux temperature for 24hours. The solvents were evaporated. The residue was treated with lN HCl and stirred at room temperature for 2 hours. The residue was taken up in methanol, the solvents were then evaporated and the solid obtained was washed with ethyl acetate to obtain pure compound. m.p. 195-196 C (dec); lH NMR (400 MHz, DMS0-d6) ~ 2.78 (t, 2 H), 2.99 (t, 3 H), 5.6 (s, 2 H), 6.72 (s, 1 H), 7.22 (m, 7 H), 7.81 (d, 2 H); IR (KBr) ~ 3121, 3028, 1657, 1549, 1512, 1410, 12S6, 1186, 1059, 831, 696 cm~~; MS (CI) m/e 423 (N+H, 8), 341 (3), 137 (11), 105 (100).

WO95/14014 PCT~S94/12367 ~
~17~12~

2~aple 132 ~-~ydrosy-6-[3-methyl-~-[(2-pyridinyl)methoxy]phenyl]-3-~2-phenylethyl)thio]-2~-pyran-2-ono: The title compound was prepared by Method A using 4-(2-pyridinylmethoxy)-3-methylacetophenone (2.0 g, 8.29 mmol), trimethylsilyltrifluoromethylsulfonate (1.84 g, 8.29 mmol), triethylamine (1.68 g, 16.58mmol) and diethyl ester of t(2-phenylethyl)thio]propanedioic acid (1.22 g, 4.15 mmol). m.p. 75-77 C; lH NMR (400 MHz, DMSO-d6) 8 2.32 (s, 3 H), 2.78 (t, 3 H), 2.97 (t, 2 H), 5.29 (s, 2 H), 6.67 (s, 1 H), 7.14-7.29 (m, 4 H), 7.38 (m, 1 H), 7.56 (m, 2 H), 7.67 (m, 2 H), 7.86 (t, 2 H), 8.61 (d, 1 H); IR (KBr) 3063, 2924, 1719, 1603, 1505, 1267, 1138, 1039, 760 cm~l; MS (CI) m/e 446 (M+H, 90), 341 (16), 279 (17), 242 (21), 151 (25), 105 (100); Analysis calc'd for C26H2304NlS1: C, 70.09; H, 5.2; N, 3.4; found: C, 70.68; H, 5.28; N, 3.14.

EsamplQ 133 3-t2-CYC1~1G~Y1-1-~(phenyl~thyl)thio~ethyl]-~-hydrosy-6-phenyl-2~-pyr~n-2-one ~l/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), 2-cyclopropylmethylcarboxaldehyde (0.67 g, 7.98 mmol), benzylmercaptan (1.98 g, 15.96 mmol), piperidine, (0.5 mL), acetic acid (0.5 mL). m.p. 59-61 c; lH NMR (400 MHz, DMSO-d6) ~ -0.97 (m, 2 H), 0.28 (m, 2 H), 0.58 (m, 1 H), 1.61 (m, 1 H), 2.01 (m, 1 H), 3.72 (ABXq, 2 H), 4.22 (q, 1 H), 6.67 (s, 1 H), 7.18 (t, 1 H), 7.25 (d, 2 H), 7.31 (t, 2 H), 7.53 (m, 3 H), 7.75 (m, 2 H);
IR (KBr) 3061, 2919, 2631, 1649, 1564, 1404, 1267, 766, 691 cm~1; MS (CI) m/e 255 ((M-SBzl), 19), 201 (5), 147 (2); Analysis calc'd for C23H2203Sl: C, 72.99; H, 5.86; found: C, 72.31; H, 6.08.

Esauple 134 WO95114014 Z ~CT~S9411~67 ~ ~ 7~12a~

~-~ydroxy-3-tl-t(2-m~tho~yph~nyl)thio~-3-mQthylbUtyl]-C-phenyl-2~-pyran-2-onQ (+/-) : The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69 s g, 7.98 mmol), 2-methoxythiophenol (2.24 g, 15.96 mmol), piperidine, (1.0 mL), acetic acid (1.0 mL) and ethanol (15mL). m.p. 75-78 C; lH NMR (400 MHz, DMSO-d6) ~ 0.86 (d, 3 H), 0.89 (d, 3 H), 1.53 (m, 1 H), 1.69 (m, 1 H), 2.19 (m, 1 H), 3.64 (s, 3 H), 4.69 (g, 1 H), 6.64 (s, 1 H), 6.89 (t, 1 H), 6.94 (d, 1 H), 7.17 (t, 1 H), 7.33 (d, 1 H), 7.53 (m, 3 H), 7.78 (m, 2 H); IR (KBr) 3063, 2955, 2635, 1649, 1564, 1406, 1242, 1026, 768, 750, 691 cm~1; MS (CI) m/e 257 ((M-SPh(OMe), 11), 201 (3), 169 (5), 141 (88);
Analysis calc'd for C23H2404Sl: C, 69.67; H, 6.10;
found: C, 69.63; H, 5.92.

~x~mplQ 135 4-Hydroxy-3-t1-t(phenyln~thyl)thio]-3-methylbutyl]-6-phenyl-2H-pyran-2-one ~ The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69 g, 7.98 mmol), benzylmercaptan (1.98 g, 15.96 mmol), piperidine, (1.0 mL), acetic acid (1.0 mL). m.p.
153-155 C; lH NMR (400 MHz, DMSO-d6) ~ 0.64 (d, 3 H), 0.81 (d, 3 H), 1.25 (m, 1 H), 1.53 (m, 1 H), 2.04 (m, 1 H), 3.69 (ABXq, 2 H), 4.22 (q, 1 H); IR (KBr) 3086, 2955, 1651, 1566, 1497, 1404, 1311, 1127, 912, 766, (8).
- ~sample 136 ~-[t~-[4-hydro~y-2-oso-3-tl2-phQnylQthyl)thio]-2~-- pyran-C-yl~phQnoxy]m~thyl]bQnzoic aci~ methyl ester :
The title compound was prepared by Method A using 4-~t(4-acetyl)phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), lithium hexamethyldisilazide (2.36 g, 14.08 mmol), chlorotrimethylsilane (2.38 g, 14.08 mmol) and diethyl ester of [(2-WO 95/1401~ ~ 7 4 1 2 ~ PCT/US94/12367 phenylethyl)thio]propanedioic acid (1.0 g, 3.05 mmol).
m.p. 157-158 C; lH NMR (400 MHz, DMSO-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.86 (s, 2 H), 5.31 (s, 2 H), 6.67 (s, 1 H), 7.17 (q, 4 H), 7.25 (m, 3 H), 7.61 (d, 2 H), s 7.78 (d, 2 H), 8.0 (d, 2 H); IR (KBr) 3023, 2936, 2581, 1632, 1510, 1404, 1258, 1184, 1098, 1009, 818, 718 cm~1; MS (CI) m/e 517 (M+29, 7), 489 (M+H, 55), 384 (19), 149 (40), 105 (100).

Es~mple 137 Methyl ester of 3-[t~-~4-hydroxy-2-oxo-3-t~2 phonylethyl)thio]-2H-pyra~-6-yl]rhP~-yl~ethyll-benzoic acid: The title compound was prepared by Method A using 3-[[(4-acetyl)phenoxy]methyl]benzoic acid methyl ester (2.0 g, 7.04 mmol), lithiumhexamethyldisilazane (2.36 g, 14.08 mmol), chlorotrimethylsilane (2.38 g, 14.08 mmol) and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.0 g, 3.05 mmol). m.p. 147-149 C; lH NMR (400 MHz, DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 3.86 (s, 2 H), 5.31 (s, 2 H), 6.69 (s, 1 H), 7.2 (m, 7 H), 7.58 (t, l H), 7.75 (m, 3 H), 7.78 (d, 1 H), 7.94 (d, 1 H), 8.08 (s, 1 H); IR (KBr) 3081, 2950, 1726, 1632, 1609, 1512, 1406, 1345, 1406, 1290, 1209, 1098, 1004, 820, 748, 696 cm~l; MS (CI) m/e 489 (M+H, 48), 384 (16), 341 (7), 236 (6), 149 (39), 119 (11), 105 (100).

gx~mple 138 6l~-[3,4-Dichlorophenylmetho~y]ph~yl]-~-hydro~y-3-t~2-phenylethyl)thio]-2X-pyran-2-one: The title compound was prepared by Method A using 4-[(3,4-dichlorophenyl)methoxy]acetophenone (2.0 g, 6.80 mmol), lithium hexamethyldisilazide (2.28 g, 13.61 mmol), chlorotrimethylsilane (2.3 g, 13.61 mmol) and diethyl ester of ~(2-phenylethyl)thio]propanedioic acid (1.0 g, 3.40 mmol). m.p. 168-169 C; lH NMR (400 MHz, DMS0-d6) ~ 2.78 (t, 2 H), 2.97 (t, 2 H), 5.22 (s, 2 H), 6.69 (s, 1 H), 7.17 (m, 8H), 7.47 (dd, 1 H), WO9Stl4014 ~174~ ~L~ PCT~Ss4/12367 7.69 (d, 1 H), 7.78 (d, 1 H); IR (KBr) 3054, 2602, 1713, 1611, 1512, 1399, 1291, 1179, 1109, 1042, 818, 754 cm~l; MS (CI) m/e 501 (17), 499 (24), 394 (12), 353 (1), 161 (20), 159 (27), 105 (100).

E~ple 139 3-tt(~-hydrosy-2-oso-6-phenyl-2~-pyran-3-yl)thio]methyl]-be~zoic aci~ mQthyle~ter: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (2.0 g, 10.63 mmol), ~3-(carbomethoxy)phenyl]methyl p -toluenethiosulfonate (3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol (20mL). m.p. 170-171 C; lH NMR (400 MHz, DMSO-d6) 3.78 (s, 3 H), 4.06 (s, 2 H), 6.72 (s, 1 H), 7.42 (t, 1 H), 7.53 (m, 4 H), 7.78 (m, 3 H), 7.83 (s, 1 H);
IR (KBr) 3108, 2947, 1716, 1644, 1549, 1400, 1302, 1100, 770, 713, 523 cm~l; MS (CI) m/e 369 (M+H, 7), 337 (8), 235 (6), 189 (4), 149 (11), 85 (100).

~s~pl~ 1~0 Methylester of ~-t~(4-hy~roxy-2-oxo-6-phenyl-2~-pyran-3-yl)thio]methyl~benzoic aci~: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (2.0 g, 10.63 mmol), [4-(carbomethoxy)phenyl~methyl p -toluenethiosulfonate (3.57 g, 10.63 mmol), lN NaOH (10.63mL), ethanol (20mL). m.p. 215-216 C; lH NMR (400 MHz, DMSO-d6) 3.81 (s, 3 H), 4.06 ts, 2 H), 6 (69, J=s Hz, 1 H), 7.39 (d, 2 H), 7.67 (m, 3 H), 7.81 (m, 2 H), 7.86 (d, 2 H); IR (RBr) 3110, 3038, 1717, 1644, 1547, 1402, ~ 1279, 1103, 720, 526 cm~l; MS (CI) m/e 369 (M+H, 22), 235 (100), 207 (18), 189 (37), 151 (55), 119 (20), 105 (21), 85 (28).

3s ~xample 1~1 6-~3,5-Bi~(trifluoromQthyl)phenyl]-~-hydrosy-3-~phenyl-ethyl)thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using trimethylsilyl WO95/14014 PCT~S94/1~67 ether of 3~,5/-trifluoromethylacetophenone (2.16 g, 7.1 mmol) [prepared using 3,5-ditrifluoromethylacetophenone (15 g, 58.55 mmol) and trimethylsilyltrimethylsulfonate (13.01 g, 58.55 mmol) and triethylamine (11.84 g, 117.10 mmol) and distilled], and diethyl ester of [(phenylmethyl)thio]prop~ne~ioic acid (1.0 g, 3.55 mmol). m.p. 80-82 C; lH NMR (400 MHz, CDCl3) ~ 4.0 (s, 2 H), 6.61 (s, 1 H), 7.22 (m, 2 H), 7.28 (m, 3 H), 7.97 (s, 1 H), 8.25 (s, 2 H); IR (KBr) 3090, 1726, 1682, 1638, 1549, 1530, 1385, 1281, 1182, 1138, 902, 700 cm~l; MS (CI) m/e 475 (M+29, 3), 447 (M+H, 21), 213 (1), 149 (2), 91 (100).

Es~mple 1~2 3-tl-(Cyclohesylthio)-3-methylbutyl]-~-hy~roxy-6-phenyl-2~-pyran-2-one ~l/-) :
The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (076 g, 8.78 mmol), cyclohexylmercaptan (2.04 g, 17.56 mmol), piperidine, (1.0 mL), acetic acid (1.0 mL) and ethanol (20mL).m.p.
210-212 C; lH NMR (400 MHz, DMSO-d6) 8 0.89 (t, 6 H), 1.36 (m, 6 H), 1.44 (m, 1 H), 1.56 (m, 2 H), 1.69 (m, 2 H), 1.81 (m, 1 H), 2.08 (m, 2 H), 2.61 (brm, 1 H), 4.22 (m, 1 H), 6.67 (s, 1 H), 7.53 (m, 3 H), 7.78 (m, 2 H); IR (KBr) 3106, 2928, 2851, 1659, 1568, 1404, 1125, 766, 569 cm~l; MS (CI) m/e 259 (50), 257 (49), 201 (46), 189 (16), 147 (8), 105 (28), 83 (100).
Ex~mpl~ 1~3 1~-t~-~y~roxy-2-oso-3-t(2-phenylethyl)thio]-2~-pyra~-6-yl]phenoYy]acetonitrile:
The title compound was prepared by Method A using the appropriate acetophenone (3.0 g, 17.12 mmol), trimethylsilyltrifluoromethylsulfonate (3.8 g, 17.12 mmol), triethylamine (3.46 g, 34.24mmol) and diethyl ester of [2-(phenylethyl)thio]prop~nP~;oic acid (2.53 WO95114014 ~1 7~ PCT~S94/12367 g, 8.56 mmol). m.p. 157-159 C; lH NMR (400 MHz, DMS0-d6) ~ 2.92 (t, 2 H), 3.11 (t, 2 H), 4.86 (s, 2 H), 6.56 (s, 2 H), 7.08 (d, 2 H), 7.19 (t, 3 H), 7.3 (m, 3 H), 7.86 (d, 2 H); IR (KBr) 2993, 2577, 1634, 1510, 1404, 1342, 1302, 1226, 1188, 1098, 1051, 833, 717, sos cm~l; MS (CI) m/e 380 (lO0), 275 (60), 205 (8), 105 )-~pl~
4-Hydroxy-3-[~2-isG~!o~lph~nyl)thio]-6-phenyl-2H-pyran-2-one:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.24 g, 6.45 mmol),and diethyl ester of (2-iso~Lo~ylphenyl)thio pro~Ane~ioic acid (1.0 g, 3.23 mmol). lH NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6 H), 3.42 (m, l H), 6.89 (s, 1 H), 6.92 (dd, 1 H), 7.06 (t, 1 H), 7.13 (t, 1 H), 7.28 (d, 1 H), 7.56 (m, 3 H), 7.85 (m, 2 H) ; IR (KBr) 3117, 2962, 1661, 1551, 1406, 1365, 1101, 760 cm~l; MS (CI) m/e 339(100), 305 (4), 219 (25), 189 (11), 147 (9), 105 (9); Analysis calc'd for C20H1803S1: C, 70.98; H, 5.36; found: C, 70.82; H, 5.24.

E~pl~ l~S
3-t(Cycl~ lnethyl)thio]-4-hydroxy-6-phenyl-2H-py~n-2-one.
The title compound (0.053 g, m.p. 136-137 C) was prepared by method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.250 g, 1.33 mmol), cyclo~-o~ylmethyl-p-- toluenethiosulfonate (0.585 g, 2.261 mmol), triethylamine (0.158 g, 1.46 mmol), sodium bicarbonate (0.110 g, 1.33 mmol), ethanol (10.0 mL). ~H NMR (250 MHz, CDCl3) ~ 7.994 - 7.726 (m, 2 H), 7.683 - 7.406 (m, 3 H), 6.665 (s, 1 H), 2.724 - 2.694 (d, 2 H, J = 7.3 Hz), 1.063 - 0.903 (m, 1 H), 0.608 - 0.533 (m, 2 H), 0.270 - 0.208 (m, 2 H).

4`
WO95/14014 PCT~S94tl2367 ~
:.

Ex~mpl~ 1~6 6-(3-Chlorophenyl)-4-hydroxy-3-t~-phenylbutyl)thio]-2H-pyran-2-one.
The title compound (0.024 g, m.p. 123-124 C) was prepared by method B using 6-(3-chlorophenyl)-4-hydroxy-2H-pyran-2-one (0.250 g, 1.13 mmol), 4-phenyl-butyl-p-toluenethiosulfonate (0.45 g, 1.93 mmol), triethylamine (0.115 g, 1.13 mmol), sodium bicarbonate (0.094 g, 1.13 mmol), ethanol (5.0 mL). lH NMR (400 MHz, CDC13) ~ 7.848 - 7.839 (m, 1 H), 7.729 (m, 1 H), 7.479 - 7.392 (m, 2 H), 7.276 - 7.239 (m, 2 H), 7.174 -7.137 (m, 3 H), 6.631 (s, 1 H), 2.831 - 2.794 (t, 2 H), 2.633 - 2.596 (t, 2 H), 1.747 - 1.689 (m, 2 H), 1.649 - 1.591 (m, 2 H).
Exa~ple 1~7 ~-Hy~roxy-3-~t2-o~o-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one. A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in R.F. Harris, J.E. Dunbar, U.S. 3,818,046) in CH2Cl2 (3.0 mL) under an N2 atmosphere was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetorh~n~ne (0.167 g, 0.840 mmol). The mixture was allowed to stir for 30 min. at ambient temperature then the solvent removed in vacuo. The residue was then diluted with diethyl ether and extracted with saturated Na2CO3 (3 x 50 mL). The aquous layers were then combined, acidifed with conc. HCl, and extracted with CH2Cl2 (3 x 100 mL). The organic layers were combined, dried with Na2S04, and the solvent removed in vacuo to give the title compound (0.066 g, m.p. 164 -166 C) which was dried in vacuo. lH NMR (300 MHz, CDCl3) ~ 9.900 (bs, 1 H), 7.970 (d, 2 H, J = 7.1 Hz), 7.810 (d, 2 H, J = 8 Hz), 7.615 (t, 1 H, J = 4 Hz), 7.505 - 7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2 H).

kx~mplQ 1~8 Wo95/14014 2 ~ PCT~S94/12367 ~-~ydroxy-3-t(2-phQnylethan-2-ol)thio]-6-pho~yl-2 pyr~n-2-on~.
To a stirred solution of 4-hydroxy-3-[(2-oxo-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one (0.021 g, 5 o.060 mmol) in THF (1.0 mL) cooled to O oc (N2 atmosphere) was a 1.0 M solution of BH3-DMS (0.05 mL, O.05 mmol) in THF added via syringe. The mixture was allowed to stir for 1 h then quenched with a 1 : 1 mixture of 4 N HCl : MeOH. The mixture was then lo extracted with diethyl ether. The layers were combined, dried with Na2SO4, and the solvent removed in vacuo to provide the title compound (0.015 g) as an oil. lH NMR (200 MHz, CDCl3) 8 7.873 - 7.777 (m, 4 H), 7.516 - 7.153 (m, 6 H), 6.667 (s, 1 H), 4.820 - 4.755 (dd, 1 H, J = 9.8 Hz, 3.2 Hz), 3.212 - 3.127 (dd, 1 H, J = 13.8 Hz, 3.2 Hz), 2.920 (dd, 1 H, J = 9.8 Hz, 13.8 Hz).

E~mple 149 ~ ~ydroxy-5-methyl-6-phenyl-3-~phe~ylthio]-2~-pyran-2 one.
A solution of propiophenone (1.50 mL, 11.3 mmol) in CH2Cl2 (40.0 mL) was cooled to O oc (N2 atmosphere) and treated with triethylamine (3.14 mL, 22.6 mmol) followed by trimethylsilyltriflate (2.60 mL, 13.5 mmol). The solution was then warmed to ambient temperature, allowed to stir for 15 min., and subsequently quenched into a mixture of diethyl ether (50 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic layer washed with a 1 : l mixture of brine : saturated NaHCO3 (20 mL). The ethereal solution was then dried with Na2SO4 - and the solvent removed in vacuo. The resulting silyl enol ether was then transferred to a flask cont~;n;ng diethyl -2-(thiophenyl)propane-1,3-dioate (1.00 g, 3.76 mmol), the mixture heated to 140 C for 16 h.
then allowed to cool to room temperature where it was diluted with diethylether and extraced with saturated W095/14014- 2~ 7~124 PCT~S94/12367 ~

. ` -- 110 --Na2CO3 (3 x 20 mL). The aqueous layers were combined, washed with diethylether (3 x 75 mL), then carefully acidified with conc. HCl. The mixture was then extracted with CH2C12 (3 x 200 mL), the organic layers combined, dried with Na2SO4, and the solvent removed in vacuo to provide the title compound (0.350 g, m.p. 166 - 167 oc). lH NMR (400 MHz, DMSO-d6) 8 6.309 - 6.285 ( m, 2 H), 6.227 - 6.211 (m, 3 H), 5.983 (t, 2 H, J = 8 Hz), 5.862 (d, 3 H, J = 8 Hz), 0.705 (s, 3 H).

~ C~IIpl~ 150 t ~- t ~-~y~G~~2~0X0~3~ ~phenylthio)-2~-pyran-6-yl]pheno~y]-acetic acid.
A solution of methyl-~4-(1-oxoethyl)phenoxy]-acetate (2.S0 g, 10.86 mmol) in CH2Cl2 (25.0 mL) was cooled to o oc (N2 atmosphere) and treated with triethylamine (3.03 mL, 21.7 mmol) followed by trimethylsilyltriflate (2.52 mL, 13.0 mmol). The solution was then warmed to ambient temperature, allowed to stir for 15 min., and subsequently qu~nche~
into a mixture of diethyl ether (50 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic layer washed with a 1 : 1 mixture of brine : saturated NaHCO3 (20 mL). The ethereal solution was then dried with Na2SO4 and the solvent removed in vacuo. The resulting silyl enol ether was then transferred to a flask cont~i n; ng diethyl 2-(thiophenyl)propane-1,3-dioate (0.97 g, 3.6 mmol). The mixture was then heated to 140 C for 16 h. and allowed to cool to room temperature where it was submitted to chromatography (SiO2-230 to 400 mesh, 100%
CH2Cl2 to 2.0% MeOH / CH2Cl2) to provide an impure solid which was diluted with diethyl ether (20 mL) and extracted with saturated Na2CO3 (3 x 20 mL). The 3s combined aqueous extracts were washed with diethyl ether (3x100 mL) and then acidifed with conc. HCl to pH 0. The mixture was then extracted with ethyl acetate (3 x 100 mL), the organic layers combined, WO95/14014 PCT~S94JI~67 2 ~

dried with Na2SO4 and the solvent removed in vacuo. to provide the title compound (0.695 g, m.p. 186 - 188 C). lH NMR (300 MHz, DMSO-d6) ~ 13.175 (bs, 1 H), 12.425 (bs, 1 H), 7.809 (d, 2 H, J = 9 Hz), 7.298 -s 7.247 (m, 2 H), 7.149 - 7.004 (m, 5 H), 6.785 (s, 1 H), 4.804 (s, 2 H).

~s~mple 151 t~-t~-~ydro~y-5-methyl-2-oxo-3-~phenylthio)-2H-pyr~n-lo ~-yl]~h~ ]-aoeti¢ acid. The title compound (0.691 g, m.p. 194 - 197 C) was prepared in a similar manner to that demonstrated in the preparation of [4-~4-hydroxy-2-oxo-3-(phenylthio)-2H-pyran-6-yl]phenoxy]-acetic acid using the following: Methyl-[4-(l-oxoethyl)phenoxy]-acetate (2.00 g, 8.81 mmol), triethylamine (3.68 mL, 26.4 mmol), trimethylsilyltriflate (2.38 mL, 12.3 mmol), dichloromethane (20.0 mL), diethyl 2-(thiophenyl)propane-1,3-dioate (1.34 g, 5.00 mmol.).
lH NMR (400 MHz, DMSO-d6) ~ 7.585 (d, 2 H, J = 9 Hz), 7.325 - 7.286 (m, 2 H), 7.178 (d, 3 H, J = 7.5 Hz), 7.063 (d, 2 H, J = 9 Hz), 4.784 (s, 2 H), 2.042 (s, 3 H).

Es~ple 152 ~-~ydrosy-3-phc~o~y-6-phenyl-2H-pyra~-2-one. To a pressure reactor was added 2-phenoxyprop~ne~;oicacid diethylester 8.11 g (0.032 moles) and 1-phenyl-1-(trimethylsilyloxy)ethylene 12.35 g (0.064 moles).
The vessel was pressurized to 600 psi with N2. The mixture was heated at 100 C for 8 hours then an additional 63.5 hours at 147 - 154 C. The vessel was cooled to room temperature and rinsed with ethyl acetate. Crude flash chromatography (hexane/ethyl acetate 1/1) afforded partially purified material which was then flashed on silica gel using hexane /
ethyl acetate 95/5 - 40/60 as eluents. The resulting solid was recrystallized from diethyl ether and ethyl WO95/14014 ~7~ PCT~S94/12367 acetate to afford 1.64g (18%) of the title compound (mp = 215-219 C). lH NMR (400 MHz, DMSO-d6) ~ 6.90 (s, 1 H), 6.95 (dd, 2 H), 7.02 (t, 1 H), 7.28 - 7.33 (m, 2 H), 7.52 - 7.56 (m, 3 H), 7.80 - 7.856 (m, 2 H), 12.0 (bs, 1 H).

E~ample 153 ~-Hydroxy-3-~phcnylmethyllthio]-6-~3-pyridinyl)-2~-pyran-2-on~. The title compound was prepared from the lo condensation of the trimethylsilyl enol ether of 3-acetyl pyridine and diethyl ester of [(phenylmethyl)thio]prop~ne~;oic acid following the same procedure outlined in Method A; m.p. 183-184 C.
NMR (DMS0-d6) ~ 4.02 (s, 2 H), 6.83 (s, 1 H), 7.20 (m, 1 H), 7.26 (d, 4 H), 7.55 (m, 1 H), 8.16 (m, 1 H), 8.69 (m, 1 H), 8.98 (d, 1 H).

~sample 154 6-(2~6-DLmethyl-~-pyridinyl)-~-hydroxy-3-t(phenylmethyl)thio]-2~-pyran-2-one. The title compound was prepared from the condensation of the trimethylsilyl enol ether of 4-acetyl-2,6-dimethylpyridine and the diethyl ester of ~(phenylmethyl)thio~prop~e~;oic acid following the same procedure outlined in Method A; m.p. 88-90 C.
NMR (DMSO-d6) ~ 2.55 (s, 6 H), 4.02 (s, 2 H), 6.85 (s, 1 H), 7.16-7.28 (m, 5 H), 7.40 (s, 2 H).

ksample 155 ~-~ydroxy-3-ttphenylmethyl)thio~-6-~3-thienyl)-2H-pyran-2-one. The title compound was prepared from the condensation of the trimethylsilyl enol ether of 3-acetylthiophene and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the 3s same procedure outlined in Method A; m.p. 150-151 C.
NMR (DMSO-d6) ~ 3.98 (s, 2 H), 6.58 (s, 1 H), 7.24 (m, 5 H), 7.48 (m, 1 H), 7.72 (m, 1 H), 8.13 (d, 1 H).

WO95/14014 217~4 PCT~S94/1~67 E~ple 156 3-t(2,6-Di~thylpho~yl)mothyl]thio]-~-hydroxy-6-phenyl-2H-pyran-2-onQ: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN
sodium hydroxide (5.31 mL), (2,6-dimethylphenyl)methyl p-toluenethiosulfonate (1.62 g, 5.31 mmol). m.p. 231-233 C; lH NMR (400 MHz, DMSO-d6) ~ 2.34 (6H, s), 4.01 (s, 2H), 6.81 (m, 2H), 7.03 (m, 3H), 7.53 (m, 3H), 7.82 (m, 2H).

Ex~mple 157 ~-~y~6~y-6-phenyl-3-tt(3-ph~ henyl)methyl]thio]
2H-pyran-2-one: The title compound was prepared by Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), lN sodium hydroxide (5.31 mL), (3-phenoxyphenyl)methyl p-toluenethiosulfonate (1.96 g, 5.31 mmol). m.p. 131-133 C; lH NMR (400 MHz, DMSO-d6) ~ 3.97 (s, 2H) 6.73 (s, lH), 6.87 (m, 4H), 7.03 (m, 2H), 7.27 (m, 3H), 7.53 (m, 3H), 7.78 (m,2H).

E~a~pl~ 158 - 3-tl-t~Cyclohexyl~ethyl)thio]-3-methylbutyl]-4-~ydh~ 6 ~henyl-2~-pyran-2-one, ~/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.462 mL, 5.84 mmol), cyclohexylmethylthiol (1.79 g, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). m.p. 146-148 C; lH
NMR (400 MHz, DMSO-d6) ~ 0.58 (d, 6H), 1.11 (m, 5H), 1.57 (m, 8H), 2.07 (m, lH), 2.28 (dd, lH), 2.38 (dd, lH), 4.17 (dd, lH), 6.69 (s, lH), 7.54 (m, 3H), 7.75 (m, 2H), 11.71 (bs, lH).
Ex~mpl~ 159 3-tl-~Cyclohexyl~ethyl)thio]phenylmethyl]-~-hydroxy-6-phenyl-2H-pyr~n-2-on~, (I/-): The title compound WO95/14014 ;' PCT~S94/12367 ~
2~7 4 ~ 2~
^ - 114 -was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one ~1.00 g, 5.31 mmol), ethanol (10 mL), benzaldehyde (0.593 mL, 5.84 mmol), cyclohexylmethylthiol (1.79 g, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5mL). m.p. 138-141 C; lH NMR
(400 MHz, DMSO-d6) ~ 0.89 (m, 2H), 1.21 (m, 3H), 1.42 (m, lH), 1.61 (m, 3H), 1.75 (m, 2H), 2.39 (m, 2H), 5.30 (s, lH), 6.71 (s,lH), 7.26 (t,lH), 7.28 (t, 2H), 7.S3 (m, 5H), 7.74 (m, 2H).
kS~pl~ 160 ~-~ydroxy-6-t~-(2-hydroxyethoxy)ph~nyl]-3-t(2-phenylethyl)thio]-2H-pyran-2-one: To a tetrahydrofuran (7 mL) solution of [4-[4-hydroxy-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-phenoxy]acetic acid, ethyl ester (0.30 g, 0.70 mmol) was added 2.0 M lithium borohydride (0.5 mL, 1.00 mmol). The reaction was stirred overnight. The reaction was then quenched by addition of lN
hydrochloric acid (2.0 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated and washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 50% ethyl acetate/hex~e~ to 100% ethyl acetate as the eluent. m.p. 123-125 C; lH NMR (400 MHz, DMSO-d6) ~ 2.77 (t, 2H), 2.97 (t, 2H), 3.37 (m, 2H), 4.07 (t, 2H), 4.92 (bs, lH), 6.68 (s, lH), 7.09 (d,2H), 7.19 (m, 5H), 7.75 (d, 2H).

Exampl~ 161 ~3-~-Hydro~y-2-oxo-3-~(2-phenylethyl)thio]-2H-pyran -6-yl]rh~ y] acetic acid, ethyl ester: The title compound was prepared by Method A using ethyl (3-acetylphenoxy)acetate (2.00 g, 9.00 mmol), trimethyl silyltriflate (4.18 mL, 21.62 mmol), triethylamine (5.01 mL, 36.00 mmol), methylene chloride (23 mL), and W095/14014 ~1 7~12~ PCT~S94112367 diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 116-119 C; lH NMR (400 MHz, DMSO-d6) ~ 1.22 (t, 3H), 2.77 (t, 2H), 3.05 (t, 2H), 4.89 (d, 2H), 6.80 (s, lH), 7.20 (m, 7H), 7.44 (m, 2H).

Ex~mple 162 ~-~ydrosy-6-[~-t(5-methyl-3-phenyl-~-isoYasolyl)metho~y]phenyl]-3-t~2-phenylethyl)thio]-2H-p~ran-2-one: The title compound was prepared by Method A using 4'-[(5-methyl-3-phenyl-4-isoxaoly)methoxy]acetophenone (2.00 g, 6.51 mmol), trimethylsilyl triflate (1.51 mL, 7.81 mmol), triethylamine (1.81 mL, 13.02 mmol), methylene chloride (16 mL), and diethyl ester of ~(2-phenylethyl)thio]prop~ne~;oic acid (l.OOg, 3.37 mmol).
m.p. 126-128 C; lH NNR (400 MHz, DMSO-d6) ~ 2.54 (s, 3H), 2.77 (t, 2H), 2.98 (t, 2H), 5.08 (s, 2H), 6.69 (s, lH), 7.21 (m, 7H), 7.49 (m, 3H), 7.71 (m, 2H), 7.77 (d, 2H).

B Iple lC3 6-(3,5-Di~ethylphenyl)-~-hydroYy-3-(phenylthio)-2~-pyr~n-2-one: The title compound was prepared by Method A using 3',5'-dimethylacetophenone (1.43 g, 9.70 mmol), trimethylsilyl triflate (2.24 mL, 11.64 mmol), triethylamine (2.70 mL, 19.40 mmol), methylene chloride (24 mL), and diethyl ester of (phenylthio)-propanedioic acid (1.00 g, 7.46 mmol). m.p. 210-211 C; H NMR (400 MHz, DMSO-d6) ~ 2.35 (s, 6H), 6.83 (s, lH), 7.12 (m, 3H), 7.21 (s, lH), 7.27 (t, 2H), 7.46 (s, 2H).

E2~mpl~ 16~
3-tl-tCyclopentylthio]-2-cyclopropylethyl]-4-hydro~y-6-phenyl-2~-pyran-2-one, (+/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), WO95/14014 21 r7 41~ PCT~S94/12367 ~

cyclo~ylmethylcarboxaldehyde (0.892 g, 10.62 mmol), cyclopentylthiol (1.43 mL, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). m.p.75-80 C; lH NMR (400 MHz, DMSO-d6) ~ 0.04 (m, 2H), 0.07 tm, 2H), 0.66 (m, lH), 1.53 (m, 7H), 1.94 (m, 3H), 3.19 (m, lH), 4.21 (dd, lH), 6.71 (s,lH), 7.54 (m, 3H), 7.76 (m, 2H).

E~ample 165 N-t3-t4-~y~ 6a~ 2-oxo-3-t~2-phenylethyl)thio]-2~-pyr~n-C-yl]phenyl]-4-methyl-bensenesulfon~mide: The title compound was prepared by Method A using 3'-(p-toluenesulfonamide)acetophenone (1.38 g, 5.06 mmol), trimethylsilyl triflate (2.34 mL, 12.41 mmol), triethylamine (2.82 mL, 20.24 mmol), methylene chloride (18 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 133-135 C; lH NMR (400 MHz, DMSO-d6) 2.32 (s, 3H), 2.77 (t, 2H), 3.09 (t, 2H), 6.68 (s, lH), 7.19 (m, 6H), 7.40 (m, 4H), 7.53 (s, lH), 7.67 (d, 2H), 10.50 (s, lH), 12.03 (bs, lH).

E~ample lC6 3-tCyclopentyl(cyclopentylthio)methyl]-~-hy~roxy-6-phenyl-2~-pyran-2-one, (~ The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclopentanecarboxaldehyde (0.780 g, 7.96 mmol), cyclopentylthiol(1.43 mL, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). m.p.139-142 C; lH NMR (400 MHz, DMS0-d6) ~ 1.03 (m, lH), 1.64 (m, 15H), 2.64 (m, lH), 3.00 (m, lH), 3.84 (d, lH), 6.69 (s, lH), 7.52 (m, 3H), 7.76 (m, 2H), 11.55 (bs, lH).

~ample 167 6-(1,1'-Biphen-3-yl)-~-h~o~-3-~(2-isopropylphenyl) thio~-2H-pyran-2-one: The title compound was prepared by Method A using 3'-phenylacetophenone (0.946 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), W095/14014 - ~ 7~1 2~ PCT~S94/l~67 triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of t(2-isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22 mmol). m.p. 193-195 C; ; lH NMR (400 MHz, DMSO-d6) 1.25 (d, 6H), 3.43 (m, lH), 6.95 (d, lH), 7.02 (s, r lH), 7.06 (t, lH), 7.13 (t, lH), 7.28 (d, lH), 7.42 (t, lH), 7.51 (t, 2H), 7.66 (t, lH), 7.75 (d,2 H), 7.85 (t, 2H), 8.07 (s, lH).

Es~mpl~ 168 ~-~ydroYy-6-phenyl-3-t~2 ~G~lphenyl)thio]-2~-pyran-2-on~: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol) and diethyl ester of t(2-propylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 158-160 C; lH NMR (400 MHz, DMSO-d6) 0.972 (t, 3H), 1.64 (m, 2H), 2.71 (t, 2H), 6.87 (s, lH), 6.92 (m, lH), 7.06 (m, 2H), 7.16 (m, lH), 7.55 (m, 3H), 7.85 (m, 2H).
Ex~ple 169 6-(3,5-Dimethylphenyl)-~-hydroxy-3-t(2-isopropylphenyl)-thio]-2~-pyr~n-2-one: The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of t(2-isopropylphenyl)thio]propanedioic acid (l.OOg, 3.22 mmol) m.p. 154-155 C; lH NMR (400 MHz, DMSO-d6) ~ 1.24 (d, 6H), 2.35 (s, 6H), 3.40 (m, lH), 6.90 (d, lH), 7.05 (t, lH), 7.11 (dt, 2H), 7.20 (s, lH), 7.27 (d, lH), 7.45 (s, 2H).

~s~mple 170 ~-Hydro~y-6-(~-hy~roxyphenyl)-3-t~2-isopropylphenyl) thio]-2~-pyr~-2-one: The title compound was prepared by Method A using 4~-hydlo~y~cetophenone (0.657 g, 4.83 mmol), trimethylsilyl=~riflate (2.05 mL, 10.62 WO95/14014 ~ PCT~S94/12367 ~
~ ~ 7~

mmol), triethylamine (2.69 mL, 19.32 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (l.OOg, 3.22 mmol) m.p. 250 C; (dec.) ; lH NMR (400 MHz, DMS0-d6) 1.24 (d, 6H), 3.40 (m, lH), 6.70 (s, lH), 6.90 (t, 3H), 7.05 (t, lH), 7.10 (t, lH), 7.26 (d, lH), 7.70 (d, 2H).

~xampl~ 171 3-tt2-~Cyclopropyl~ethyl)phenyl]thio]-~-hydroxy-6-phsnyl-2~-pyran-2-one: The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol), and diethyl ester of tt2-(cyclopropylmethyl)phenyl]thio]
propanedioic acid (l.OOg, 3.10 mmol) m.p. 165-167 C;
H NMR (400 MHz, DMSO-d6) ~ 0.25 (dd, 2H), 0.52 (dd, 2H), 1.21 (m, lH), 2.50 (d, 2H), 6.87 (s, lH), 6.92 (m, lH), 7.05 (m, 2H), 7.32 (m, lH), 7.56 (m, 3H), 7.86 (m,2H).
E~mple 172 4-~ydro~y-3-t~2-isG~v~lphenyl)thio]-6-t~-(pyridin-3-yl~ethoxy)ph~nyl]-2~-pyr~n-2-on~: The title compound was prepared by Method A using 4'-(pyridin-3-ylmethoxy)acetophenone (1.09 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (1.00 g, 3.22 mmol) m.p. 225 C; ; lH NMR (400 MHz, DMSO-d6) ~ 1.23 (d, 6H), 3.41 (m, lH), 5.26 (s, 2H), 6.78 (s, lH), 6.90 (d, lH), 7.08 (dt, 2H), 7.21 (d, 2H), 7.2g (d, lH), 7.45 (dd, lH), 7.82 (d, 2H), 7.91 (d, lH), 8.56 (d, lH), 8.71 (s, lH).
E~ampl~ 173 ~-[~-HyaroYy-5-[~2-isopropylphenyl)thio]-6-oYo-6H-pyr~n-2-yl]~h~ ~cetic ~cid ethyl e~tQr: The title ~ WO95/14014 ~ 7 ~ 12 4 PCT~S94/l~67 com~ound was prepared by Method A using ethyl (4-acetyl-phenoxy)acetate (2.14g, 9.67 mmol), trimethylsilyl triflate (4.48 mL, 23.20 mmol), triethylamine (12.93 mL, 38.6 mmol), methylene S chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (2.00g, 6.45 mmol) m.p. 194-196 C; ; lH NMR (400 MHz, DMSO-d6) l.S7 (m, 9H), 3.41 (m, lH), 4.81 (q, 2H), 4.89 (s, 2H), 6.75 (s, lH), 6.90 (d, lH), 7.05 (m, 4H), 7.26 lo (d~ lH), 7.79 (d, 2H).

Ex~mple 17~
~-[4-Hydrosy-5-t (2-iSG~ o~lphenyl)thio]-6-oso-6H-pyran-2-yl~-phe~o~ acetic acid: To a tetrahydrofuran (10 ml) solution of 4-t4-Hydroxy-5-t(2-isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy acetic acid ethyl ester (0.319 g. 0.75 mmol) was added lN sodium hydroxide (1.80 mL, 1.81 mmol). The reaction was stirred for 1.5 h, and then water (10 ml) was added followed by acidification with conc.
hydrochloric acid to pH 2. The aqueous layer was then extracted 2X with ethyl acetate (100 ml). the combined organic extracts were then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p. 217 C; (dec.); 1H NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.42 (m, lH), 4.79 (s, 2H), 6.75 (s, lH), 6.90 (d, lH), 7.06 (m, 4H), 7.26 (d, lH), 7.79 (d, 2H).

Es~mple 175 4-~ydrosy-3-t~2-isopropylphenyl)thio]-6-(~-methoxyphenyl)-2~-pyran-2-one:
The title compound was prepared by Method A using 4'-methoxyacetoph~non~ (2.26 g, 15.1 mmol), WO 95tl4014 ' PCT/US94/12367 ~l 2174~2~

trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 S mmol) m.p. 221-223 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.40 (m, lH), 3.85 (s, 3H), 6.78 (s, lH), 6.92 (m, lH), 7.10 (m, 4H), 7.27 (m, lH), 7.81 (d, 2H), 12.38 (brs, lH).

E~mpl~ 17C
~-nyd,6.y-3-tl2-isopropylphenyl)thio]-6-(~-methylphenyl)-2~-pyran-2-one:
The title compound was prepared by Method A using 4'-methylacetoph~none ( 2.02 mL, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of t(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 191-193 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6H), 2.39 (s, 3H), 3.41 (m, lH), 6.84 (s, lH), 6.92 (m, lH), 7.10 (m, 2H), 7.27 (m, lH), 7.37 (m, 2H), 7.75 (d, 2H).

E~pl~ 177 6-t3,~-Dichlorophenyl)-4-~yd.6~ 3-[~2-isopropylphenyl)thio]-2~-pyran-2-one:
The title compound was prepared by Method A using 3',4'-dichloroacetophenone ( 2.46 g, 12.8 mmol), trimethylsilyl triflate (3.0 mL, 15.4 mmol~, triethylamine (3.6 mL, 26.0 mmol), methylene chloride (30 mL), and diethyl ester of ~(2-isopropylphenyl)thio] prop~ne~;oic acid (4.0 g, 12.8 mmol) m.p. 204-207 C; lH NMR (400 MHz, CDCl3) ~ 1.33 (d, 6H), 3.55 (m, lH), 6.71 (s, lH), 7.00 (m, lH), 7.08 (m, lH), 7.20 (m, lH), 7.30 (m, lH), 7.56 (d, lH), 7.69 (m, lH), 7.74 (br, lH), 7.98 (s, lH).

EK~pl~ 178 WO95/14014 ~ 2~1 PCT~S94112367 6~ Chlorophenyl)-~-hydrosy-3-t(2-~o~ o~lphenyl)thio]-2~-pyran-2-o~e:
The title compound was prepared by Method A using 4~-chloroacetoph~no~e ( 2.33 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 ~L, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of t(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 148-151 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.41 (m, lH), 6.86 (s, lH), 6.92 (m, lH), 7.08 (m, 2H), 7.27 (m, lH), 7.62 (m, 2H), 7.86 (m, 2H).

~Yample 179 4-~-Hydro~y-5-t(2-i~opropylphenyl)thio]-6 o~o 6~-pyr~n-2-yl~benzoic acid ethyl e~ter: The title compound was prepared`by Method A using ethyl 4-acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-iso~ ylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-203 C; lH NMR (400 MHz, DMS0-d6) ~ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, lH), 4.35 (q, 2H), 6.94 (m, lH), 7.00 (s, lH), 7.10 (m, 2H), 7.28 (m, lH), 7.99 (m, 2H), 8.11 (m, 2H).

E~a~pl~ 180 ~ ~G~-6-(3-h~G~y~h~yl)-3-t(2-is~L~ylphenyl)thio]-2~-pyra~-2-one:
The title compound was prepared by Method A using 3'-hydroxyacetophenone ( 2.06 g, lS.l mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1 mmol), methylene chloride (30 mL), and diethyl ester of [(2-iso~ ylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-204 C; lH NMR (250 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.41 (m, 1~), 6.82 (s, lH), 6.93 (m, 2H), 7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, lH).

WO95tl4014 2 ~ 7 ~ PCT~S94/1~67 EX~pl~ 181 ~-Hydrosy-3-t~2-isG~,G~lp~onyl)thio]-2H-6-(2-phenylethyl-1-ene)-pyra~-2-one:
The title compound was prepared by Method A using trans-4-phenyl-3-buten-2-one ( 2.23 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 190-192 C; lH NMR (400 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.40 (m, lH), 6.44 (s, lH), 6.89 (m, lH), 7.10 (m, 3H), 7.27 (m, lH), 7.40 (m, 4H), 7.71 (d, 2H).

~x~pl~ 182 6-(1,1'-Biphen-4-yl)-~-hydro~y-3-t~2-isopropylphenyl) thio]-2H-pyr~n-2-one:
The title compound was prepared by Method A using 4-acetylbiphenyl ( 3.06 g, lS.l mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of ~(2-is~v~ylphenyl)thio]prop~n~ioic acid (3.11 g, 10.0 mmol) m.p. 203-206 C; lH NMR (250 MHz, DMSO-d6) ~ 1.26 (d, 6H), 3.40 (m, lH), 6.94 (m, 2H), 7.10 (m, 2H), 7.28 (m, lH), 7.51 (m, 3H), 7.77 (m, 2H), 7.91 (q, 4H).

~x~pl~ 183 6-(1,1~-Biphenyl-3-yl)-~-hydroxy-3-t~naphthalen-2-yl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene t chloride (20 mL), and diethyl ester of [2-(naphthalen-2-yl)thio]-propanedioic acid (1.62 g, 5.1 mmol). m.p.
183-185 C; lH NMR (400 MHz, DMS0-d6) ~ 7.07 (s, lH), 7.33 (dd, lH), 7.39-7.58 (m, 5H), 7.66 (s, lH), 7.69 .

~ WO95/14014 PcT~S941~67 21~41~

(d, lH), 7.78 (d, lH), 7.81-7.92 (m, 6H), 8.11 (s, lH).

EX~pl~ 184 S ~-~ydroxy-3-[~naphthalen-1-yl)thio]-6-phenyl-2~-pyran-2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(1-naphthyl)thio]prop~n~;oic acid (1.61g, 5.07 mmol).
m.p. 242-243 C; lH NMR (400 MHz, DMSO-d6) ~ 6.83 (s, lH), 7.19 (d, lH), 7.39 (t, lH), 7.64-7.42 (m, 5H), 7.69 (d, lH), 7.83 (m, 2H), 7.94 (d, lH), 8.28 (d, lH).

Ex~mple 185 6-(1,1~-Biphenyl-3-yl)-3-t~2-(cyclopropylmethyl)phenyl]thio]-~-hydrosy-2H-pyran-2-o~e: The title compound was prepared by Method A
using 3'-phenyl acetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27g, 10.20 mmol), triethylamine (2.06g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [[2-( CYC10~L u~ylmethyl)phenyl]thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 88 oc; lH NMR (400 MHz, DMSO-d6) 0.25 (d, 2H), 0.53 (dd, 2H), 1.14 (m, lH), 2.67 (d, 2H), 6.94 (m, lH), 7.03 (s, lH), 7.11 (m, 2H), 7.33 (m, lH), 7.44 (d, lH), 7.53 (t, 2H), 7.67 (t, lH), 7.75 (d, 2H), 7.86 (m, 2H), 8.08 (s, lH).

~x~mple 186 3-tt2-(Cyclo~.o~lnethyl1phenyl]thio]-6-(3,5-~imethyl-phe~yl)-~-hydrosy-2~-pyran-2-one: The title compound was prepared by Method A using 3,3'-dimethyl acetophenone (2 g, 13.51 mmol), trimethylsilyl 3s triflate (3 g, 13.1 mmol), triethylamine (2.73 g, 27.02 mmol), methylene chloride (20 mL), and diethyl ester of tt2-( CYC10~L v~ylmethyl)phenyl]thio]prop~ne~;oic acid (2.18 21~2~
WO9S/14014 PCT~S94/12367 g, 6.76 mmol). m.p. 168 C; lH NMR (400 MHz, DMSO-d6) 0.28 (d, 2H), 0.39 (dd, 2H), l.i3 (m, lH), 2.36 (s, 6H), 2.67 (d, 2H), 6.85 (s, lH), 6.92 (m, lH), 7.11 (m, 2H), 7.22 (s, lH), 7.33 (m, lH), 7.47 (s, 2H).

~xample 187 6-(l,lJ-Biphenyl-3-yl)-~-hydroxy-3-[~2-isobutylphe~yl) thio]-2H-pyran-2-one: The title compound was prepared by Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester Of t(2-isobutylphenyl)thio~propanedioic acid (1.14 g, 5.1 mmol). m.p. 187-188 C lH NMR (400 MHz, DMSO-d6) ~ 0.83 (d, 6H), 1.78 (m, lH), 2.4 (d, 2H), 7.03 (s, lH), 7.08 (s, 4H), 7.44 (t, lH), 7.53 (t, 2H), 7.67 (t, lH), 7.75 (s, lH), 7.78 (s, lH), 7.86 (m, 2H), 8.08 (s, lH).

E~ample 188 ~ G~-3- ~t2-isobutylphenyl)t~io]-6-phenyl-2~-pyr~n-2-one: The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.96 g, 10.20 mmol) and diethyl ester of [(2-isobutylphenyl)thio]propanedioic acid (1.64 g, 5.1 mmol). m.p. 195 oc lH NMR (400 MHz, DMSO-d6) ~ 0.83 (d, 6H), 1.64 (m, lH), 2.39 (d, 2H), 6.89 (s, lH), 7.06 (s, 4H), 7.56 (m, 3H), 7.86 (m, 2H).

Esample 189 4-~ydrosy-3-[(2-isopropylphenyl)thio]-6-t4-(pyridin-3- -yl)phenyl]-2~-pyran-2-one: The title compound was prepared by using diethyl ester of [2-(isopropylphenyl)thio]-propanedioic acid (1 g, 3.22 mmol), trimethylsilyltriflate (1.18 g, 5.31 mmol), triethylamine (0.98 g, 9.66 mmol) and 3-(pyridin-3-yl)acetophenone (0.95 g, 4.83 mmol) as described by Method A. m.p.145-147 C lH NMR (400 MHz, DMSO-d6) WOg~/14014 ~ 2 4 PCT~S94/12367 1.25 (d, 6H), 3.4 (m, lH), 6.89 (s, lH), 6.92 (d, lH), 7.06 (m, 2H), 7.25 (d, lH), 7.53 (m, lH), 7.69 (t, lH), 7.89 (d, 2H), 8.14 (s, lH), 8.22 (d, lH), 8.61 (brs, lH), 8.97 (brs, lH).

pl~ 190 ~-Hydroxy-3-t(2-isopropylph~nyl)thio]-6-(3-methylphenyl)-2~-pyran-2-one: The title compound was prepared by Method A using 3'-methylacetophenone (O.87 lo g, 6.46 mmol), trimethylsilyl triflate (1.44g, 6.46 mmol), triethylamine (0.653 g, 6.46 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.0 g, 3.23 mmol). m.p. 161-162 oc; lH NMR (400 MHz, DMSO-d6) 1.25 (d, 6H), 2.39 (s, 3H), 3.42 (m, lH), 6.86 (s, lH), 6.92 (d, lH), 7.07 (t, lH), 7.13 (t, lH), 7.28 (d, lH), 7.39 (d, lH), 7.4 (t, lH), 7.64 (d, lH), 7.67 (s, lH).

~a~pl~ 191 4-~yaroxy-3-(2-i~opropylph~Ay)-6-phenyl-2~-pyran-2 one: The title compound was prepared by Method A
using 1-phenyl-1-trimethylsilyloxy)ethylene (2.62g, 13.6 mmol) and diethyl ester of 2-(is~Lo~yl)phenoxy propanedioic acid (2.0g, 6.8 mmol). lH NMR (250 MHz, DMSO-d6) ~ 1.25 (d, 6H), 3.44 (m, lH), 6.67 (d, lH), 6.89 (s, lH), 7.0 (t, lH), 7.09 (t, lH), 7.29 (d, lH), 7.53 (m, 3H), 7.83 (m, 2H).

Example 192 6-(3-Chlorophenyl)-~-hydrosy-3-t(2-isopropylphenyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 3~-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL), and diethyl ester of t(2-isopropylphenyl)thio]-propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177-178 -2 1 7 4 1 2~ PCT~S94112367 ~

C; lH NMR (400 MHZ, DMSO-d6) ~ 0.28 (d, 6H), 3.42 (m, lH), 6.92 (d, lH), 6.94 (s, lH), 7.06 (t, lH), 7.13 (t, lH), 7.28 (d, lH), 7.58 (t, lH), 7.63 (t, lH), 7.83 (d, lH), 7.89 (s, lH).

~x~ple 193 6-~3,5-Dichlorophenyl)-~-hydrosy-3-[~2-isopropylphenyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 3,5-dichloroacetophenone (2 g, 10.58 mmol), trimethylsilyl triflate (2.35 g, 10.58 mmol), triethylamine (2.14 g, 21.16 mmol), methylene chloride (20 mL), and diethyl ester of [(2-iso~rG~ylphenyl)thio]propanedioic acid (1.64 g, 5.29 mmol). Isolated yield: 70% m.p.l68-16s C; lH NMR (400 NHz, DMSO-d6) ~ 1.25 (d, 6H), 3.42 (m, lH), 6.92 (d, lH), 7.01 (s, lH), 7.06 (t, lH), 7.13 (t, lH), 7.28 (d, lH), 7.83 (m, lH), 7.88 (m, 2H).

B ~ple 19~
3-t(2,6-Dimethylphenyl)thio]-4-hydrosy-6-phenyl-2~-pyran-2-one: The title compound was prepared by Method A using l-phenyl-l-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2,6-dimethylphenyl)thio]prop~n~;oic acid (2.0 g, 6.8 mmol). m.p. 248-249 oc; lH NMR (400 MHz, DMSO-d6) 2.47 (s, 6H), 6.75 (s, lH), 7.08 (m, 3H), 7.39 (m, 3H), 7.78 (m, 2H).

Ex~ple 195 ~-Hydrosy-3-[(2-methylphenyl)thio]-6-phenyl-2~-pyran-2-one: The title compound was prepared by Method A
using l-phenyl-l-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of t(2-methylphenyl)thio]prop~ne~;oic acid (1.43 g, 5.07 3s mmol). m.p. 210-211 C; lH NMR (400 MHz, DMSO-d6) 2.47 (s, 3H), 6.82 (s, lH), 6.86 (d, lH), 7.04 (m, 2H), 7.17 (d, lH), 7.56 (m, 3H), 7.86 (m, 2H).

~ WO95/14014 2 ~ ~ 1 1 2 ~ PCT~S94/12367 Bx~ple 196 3-(2,6-Dichloroph~nyl)thio] ~-hydrosy-6-phenyl-2~-pyr~n-2-on~: The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.72 g, 8.93 mmol) and diethyl ester of [(2,6-dichlorophenyl)thio]propanedioic acid (1.5 g, 4.46 mmol). m.p. 264-26S C; ~H NMR (400 MHz, DMSO-d6) ~
6.75 (s, lH), 7.31(t, lH), 7.49 (d, 2H), 7.56 (m, 3H), 7.78 (m, 2H).
g~ample 197 ~-tS-~1-Cyclopentylthio-3-methylbutyl)-~-hy~roxy-6-oxo-6H-pyr~n-2-yl]b~nzoic ~cid ethyl e~ter (~ The title compound was prepared by Method C using 4-hydroxy-6-(4'-carbethoxyphenyl)-2H-pyran-2-one (1.50 g, 5.77 mmol), ethanol (15 mL), isovalaraldehyde (0.497 g, 5.77 mmol), cyclopentylthiol (1.18 g, 11.54 mmol), piperidine (1.0 mL), acetic acid (1.0 mL). m.p.
174-176 C; lH NMR (400 MHz, DMSO-d6) ~ 1.05-0.72 (m, lOH), 1.81-1.14(m, 7H), 2.13-1.81(m, 3H), 3.04 (t, lH), 4.22 (m, lH), 4.36 (q, 2H), 6.8 (s, lH), 7.90 (d, lH), 7.97 (~, lH), 8.15 (m, 2H).

E~pl~ 198 3-tt~Bensylthio)pyridin-3-yl]m~thyl]-~-hy~roxy-6-phenyl-2H-pyr~n-2-one ~/-): The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.50 g, 7.98 mmol), ethanol (10 mL), pyridine-3-carboxaldehyde (0.86 g, 7.98 mmol), benzylmercaptan (1.98g, 15.96 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). m.p. 103-106 C; lH NMR (400 MHz, DMS0-d6) ~ 3.75 (q, 2H), 5.31 (s, lH), 6.33 (s, lH), 7.2 (m, lH), 7.28 (m, 5H), 7.36 (m, 3H), 7.72 (m, 2H), 7.89 (d, lH), 8.38 (dd, lH), 8.57 (s, lH).
Es~mple 199 3-~1-Cyclopentylthio-2-cyclopropyl~thyl)-6-(2,3-di~ydrobenzotl,~]dioxin-6-yl)-~-hydrosy-2~-pyr~n-2-one woss/l4014 PCT~S94112367 ~
~ 7~

~ The title compound was prepared by Method C
using 4-hydroxy-6-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2H-pyran-2-one (l.oo g, 4.06 mmol), ethanol (15 mL), cyclu~L~ylmethylcarboxaldehyde (0.34 g, 4.06 mmol), cyclopentylthiol (0.83 g, 8.12 mmol), piperidine (1.0 mL), acetic acid (1.0 mL). m.p. 80-82 C; lH NMR (400 MHz, DMSO-d6) ~ 0.03 (m, 2H), 0.33 (m, 2H), 0.64 (m, lH), 1.28-1.74 (m, 7H), 1.83-2.06 (m, 3H), 3.06 (m, lH), 4.2 (m, lH), 4.31 (m, 4H), 6.53 (s, lH), 7.0 (d, lH), 7.24 (d, lH), 7.24 (dd, 2H).

~s~ple 200 ~-tt(~-~ydroxy-6-o~o-5-t(phenylethyl)thio]-6H-pyran-2-yl)-pheno~y]m~thyl]benzoic acid: To a dioxane (20 mL) solution of 4-t[4-hydroxy-2-oxo-3-t(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]methyl]benzoic acid methyl ester (0.25 g) was added 2N sodium hydroxide, followed by methanol to keep the reaction homogeneous. Reaction was stirred at room temperature for 24h. Solvents were evaporated. The residue w s acidified with 3N hydrochloric acid. The precipitate formed was filtered and washed with ether and dried under vacuum. m.p. 227 C; lH NMR (400 MHz, DMSO-d6) 2.78 (t, 2H), 2.97 (t, 2H), 5.29 (s, 2H), 6.72 (s, lH), 7.14-7.32(m, 7H), 7.58 (d, 2H), 7.78 (d, 2H), 7.97 (d, 2H).

~xample 201 ~ -~ydroxy-6-oso-5-t~2-phenylethyl)thio]-6H-pyran-2-yl)benzoic acid ethyl ester: The title compound was prepared by Method A using 4-carboethoxy acetophenone (3 g, 15.61 mmol), trimethylsilyl triflate (3.47 g, 15.61 mmol), triethylamine (3.16 g, 31.22 mmol), methylene chloride (20 mL), and diethyl ester of [2-(phenylethyl)thio]-propanedioic acid (2.31 g, 7.81 mmol). m.p. 156-158 C lH NMR (400 MHz, DMSO-d6) ~ 1.36 (t, 3H), 2.78 (t, 2H), 3.01 (t, 2H), 4.35 (q, 2H), 14 ~ 2 ~ PCT~S94/12367 6.86 (s, lH), 7.11-7.28 (m, 5H), 7.92 (d, 2H), 8.08 (d, 2H).

Ex~ple 202 ~ -Hydro~y-6-oxo-S-t(2-phenylethyl)thio~-6H-pyran-2-yl)benzoic acid: The compound 4-(4-hydroxy-6-oxo-5-r (2-phenylethyl)thio-6H-pyran-2-yl)benzoic acid ethyl ester (0.2 g) was saponified as described in example 200. m.p. 231 C lH NMR (400 MHz, DMSO-d6) ~ 2.94 (t, 2H), 3.03 (t, 2H), 6.64 (s, lH), 7.11-7.33 (m, 5H), 7.92 (d,lH), 7.99 (d,lH), 8.05 (d,lH), 8.08 (d,lH).

Bx~ple 203 6-l2,3-Dihydrobenso~1,4]dio~in-6-yl)-~-hydroxy-3-t(2-isopropylph~nyl)thio]-2H-pyran-2-one: The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22.44 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.73 g, 5.61 mmol). m.p. 246-248 C; lH NNR (400 MHz, DMSO-d6) ~
1.2S (d, 6H), 3.4 (m, lH), 4.32 (m, 4H), 6.72 (s, lH), 6.89 (d, lH), 7.01 (d, lH), 7.06 (t, lH), 7.11 (t, lH), 7.26 (d,lH), 7.31 (d, lH), 7.35 (dd, lH).

E~ample 20~
3~ Benzylthio-3-methylbutyl)-6-(2,3-dihydrobenzo[1,4]~ioxin-6-yl)-~-hydro~y-2~-pyran-2-one (I/-): The title compound was prepared by Method C
using 4-hydroxy-6-(2,3-dihydrobenzo~1,4]dioxin-6-yl)-2H-pyran-2-one (1.00 g, 4.06 mmol), ethanol (15 mL), isovaleraldehyde (0.35 g, 4.06 mmol), benzylmercaptan (1.0 g, 8.12 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). lH NMR (400 MHz, DMSO-d6) ~ 0.78 (t, 6H), 1.36 (m, lH), 1.5 (m, lH), 2.06 (m, lH), 4.2 (m, lH), 4.31 (brm, 6H), 6.56 (s, lH), 7.03 (d, 2H), 7.36-7.2s (m, 6H).

WO95/14~14 ~17~124 PCT~S94/12367 ~

~a~ple 205 3-tt(Cyclo~exylthio)pyridin-~-yl]methyl]-~-hydrosy-6-phenyl-2H-pyran-2-one(~ The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-s pyran-2-one (1.5 g, 7.98 mmol), ethanol (10 mL), pyridine-4-carboxaldehyde (0.86 g, 7.98 mmol), cyclohexylthiol (1.86 g, 7.98 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). lH NMR (400 MHz, DMSO-d6) 1.25 (m, SH), 1.53 (m, lH), 1.67 (m, 2H), 1.92 (m, 2H), 2.71 (m, lH), 5.33 (s, lH), 6.69 (s, lH), 7.5 (m, 5H), 7.75 (m, 2H), 8.47 (d, 2H).

Ex~mple 206 3-tt(Cyclohesylthio)pyridin-3-yl~methyl]-4-hydro~y-6-phenyl-2~-pyran-2-one (~ The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), ethanol (10 mL), pyridine-3-carboxaldehyde (0.86g, 7.98 mmol), cyclohexylthiol (1.86g, 7.98 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). lH NMR (400 MHz, DMSO-d6) 1.25 (m, 5H), 1.53 (m, lH), 1.67 (m, 2H), 1.92 (m, 2H), 2.69 (m, lH), 5.39 (s, lH), 6.72 (s, lH), 7.33 (m, lH), 7.53 (m, 3H), 7.73 (m, 2H), 7.97 (d, lH), 8.39 (d, lH), 8.67 (d, lH).
Esampl~ 207 ~-t~ ydrosy-2-oso-6-phenyl-2~-pyran-3-yl)thio]methyl]benzoic acid: The title compound was prepared by the saponification of methyl ester of 4-[t(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]benzoic acid (0.1 g) as described in Example 200. lH NMR (400 MHz, DMSO-d6) ~ 4.06 (s, 2H), 6.72 (s, lH), 7.36 (d, 2H), 7.58 (m, 3H), 7.86 (m, 4H)-~mple 208 3-ll ~4-A~ 6~y~2 o~o 6 ~henyl-2H-pyran-3-yl)~hio]methyl~bensoic acid: The title compound was -2 1 7 4 :1 2 i P,~,US94,l2367 WO g5/14014 prepared by the saponification of methyl ester of 3-[[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl~benzoic acid (0.1 g) as described in Example 200. lH N~ (400 MHz, DMSO-d6) ~ 4.4 (d, lH), 4.72 (d, lH), 6.72 (s, lH), 7.4 (t, lH), 7.44-7.61(m, SH), 7.74-7.92 (m, 4H).

Ex~ple 209 2-[tt~-~ydro~cy-2-oxo-6-phenyl-2~l-pyr~-3-10 yl)thio]-lethyl]bellsoic acid: The title compound was prepared by the saponification of methyl ester of 2-~ t (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio~methyl~benzoic acid (0.2 g) as described in Example 200. lH N~ (400 ~z, DMSO-d6) ~ 4.36 (s, 2H), 6.6g (s, lH), 7.18 (d, lH), 7.29 (t, lH), 7.39 (t, lH), 7.53 (m, 3H), 7.79 (m, 3H).

~ ~pl~ 210 3-t(2-Chlorophenyl)thio]-4-hy~ A~-6-phenyl-2~-pyra~-20 2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.9S g, 10.14 mmol) and diethyl ester of [(2-chlorophenyl)thio]propanedioic acid (1.53 g, 5.07 mmol). m.p. 275-280 C; lH N~ (400 NHz, DMSO-d6) ~
6.78 (s, lH), 6.89 (dd, lH), 7.08 (tt, lH), 7.19 (tt, lH), 7.42 (dd, lH), 7.56 (m, 3H), 8.06 (m, 2H).

ample 211 ~-~y~ro~cy-3-~(2-metho~ enyl)thio3-6-phenyl-2~-pyran-30 2-o~e: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.9~ g, 10.14 mmol) and diethyl ester of ~(2-methoxyphenyl)thio]propAn~;oic acid (1.51 g, 5.07 mmol). m.p.208-209 C; lH N~ (400 MHz, DMSO-d6) ~ 3.83 (s, 3H), 6.74 (dd, lH), 6.82 (d, lH), 6.86 (s, lH), 6.97 (d, lH), 7.08 (t, lH), 7.56 (m, 3}I), 7.86 (m, 2H).

_ _ WO 95/14014 PCT/US94/12367 ~1 ~ 7~2~

~mplo 212 6-(~-Benzyloxyphenyl)-~-hydroYy-3-t~2-isopropyl-phenyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 4-benzyloxyacetophenone (0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g, 0.675 mmol), triethylamine (0.14 g, 1.35 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isG~lo~ylphenyl)thio]propanedioic acid (0.210 g, 0.675 mmol). m.p. 163-165 C; lH NMR (400 MHz, DMSO-d6) ~
1.28 (d, 6H), 3.4 (m, lH), 5.22 (s, 2H), 6.64(s,1H), 6.92 (d, lH), 7.06 (t, lH), 7.11(t, lH), 7.19 (d, lH), 7.28 (d, lH), 7.36 (q, 2H), 7.42 (d, 2H), 7.49 (d, 2H), 7.83 (d, 2H).

Es~ple 213 3-[~3-Chlorophenyl)thio]-~-hydroxy-6-phenyl-2H-pyran-2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-chlorophenyl)thio]prop~ne~;oic acid (1.53 g, 5.07 mmol). m.p.l81-182 C; lH NMR (400 MHz, DMSO-d6) ~ 6.88 (s, lH), 7.13 (dt, 2H), 7.19 (dt, lH), 7.29 (t, lH), 7.56 (m, 3H), 7.86 (m, 2H).

Exa~pl~ 2 ~-~yd~vAy~3~ t ~3-metho~ enyl) thio] -6-phenyl-2~-pyran 2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p. 130-131 C lH NMR (400 MHz, DMSO-d6) ~ 3.69 (s, 3H), 6.69 (dd, lH) , 6.72 (dd, lH), 6.89 (s, lH), 7.2 (dt, 2H), 7.58 (m, 3H), 7.88 (m, 2H).

Eg~mpl~ 215 ~-~ydro~y-3-[~3-methylphenyl)thio]-6-ph~nyl-2~-pyr~n-2-one: The title compound was prepared by Method A
using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, Wo95/14014 ~ 7 4 1 2 i PCT~S94/1~67 10.14 mmol) and diethyl ester of [(3-methylphenyl)thio]propanedioic acid (1.43 g, 5.07 mmol). m.p. 197-198 C; lH NMR (400 MHz, DMSO-d6) 2.24 (s, 3H), 6.89 (s, lH), 6.93 (t, lH), 6.97 (s, lH), 7.14 (t, 2H), 7.56 (m, 3H), 7.86 (m, 2H).

~ample 216 3-t~2-~thylphenyl)thio]-~-hydroSy-6-phe~yl-2H-pyran-2-one: The title compound was prepared by Method A using l-phenyl-l-(trimethylsilyloxy)ethylene (4.17 g, 21.72 mmol) and diethyl ester of [(2-ethylphenyl)thio]propanedioic acid (1.5 g, 10.86 mmol). m.p. 190-192 C; lH NMR (400 MHz, DMSO-d6) 1.25 (t, 3H), 2.78 (q, 2H), 6.8g (s, lH), 6.92 (m, lH), 7.08 (m, 2H), 7.2 (m, lH), 7.58 (m, 3H), 7.86 (m, 2H).

Ex~mpl~ 217 Acetic ~cid 3-~2-iso~L~ylphenyl)thio]-2-o~o-6-phcnyl-2R-pyran-4-yl e5tQr: This compound was prepared by the treatment of sodium salt of 4-hydroxy-3-t2-isopropylphenyl)thio]-6-phenyl-2H-pyran-2-one (0.2 g, 0.59 mmol) with acetyl chloride (0.09 g, 1.18 mmol) as described in general proce~uLe G. m.p. 113-115C; lH
NMR (400 MHz, DMSO-d6) ~ 1.26 (d, 6H), 1.89 (s, 3H), 3.42 (m, lH), 6.89 (s, lH), 6.94 (dd, lH), 7.04 (dt, lH), 7.13 (dt, 1~), 7.28 (dd, lH), 7.58 (m, 3H), 7.86 (m, 2H).

Example 218 ~-~ydroxy-6-phenyl-3-~(3-trifluoromethylphenyl)thio]-2~-pyran-2-one: The title compound was prepared by Method A using 1-phenyl-l-(trimethylsilyloxy)ethylene (1.72 g, 8.92 mmol) and diethyl ester of [~3-(trifluoromethyl)phenyl]thio]propanedioic acid (1.5 g, 4.46 mmol). m.p. 228-229 C; lH NMR (400 MHz, DMSO-d6) ~ 6.89 (s, lH), 7.4-7.61 (m, 7H), 7.89 (m, 2H).

WO95tl4014 PCT~S94/12367 ~
~17~124 ~ ~mpl~ 219 3-t3,5-Di~ethylphenyl)thio]-4-h~dro~y-6-phenyl-2H-pyran-2-one: The title compound was prepared by Method A using l-phenyl-l-(trimethylsilyloxy)ethylene (1.3 g, 6.76 mmol) and diethyl ester of t(3,5-dimethylphenyl)thio]propanedioic acid (1.0 g, 3.38 mmol). m.p. 214-216 C; lH NMR (400 MHz, D~SO-d6) S 2.2 (s, 6H), 6.75 (brs, 3H), 6.89 (s, lH), 7.56 (m, 3H), 7.86 (m, 2H).
Exampl~ 220 6-t~-(Cyclo~eYyl~etho-y)p~enyl]-~-hy~rosy-3-t(2-is~ lphenyl~thio]-2H-pyr~n-2-one: The title compound was prepared by Method A using 4-cyclohexylmethoxy acetophenone (2.0 g, 8.61 mmol), trimethylsilyl triflate (1.91 g, 8.61 mmol), triethylamine (1.74 g, 17.22 mmol), methylene chloride (20 mL), and diethyl ester of t(2-iso~lu~ylphenyl)thio]propanedioic acid (4.0 g, 12.92 mmol). m.p. 187-188 C; 'H NMR (400 MHz, DMSO-d6) ~
0.96-1.33 (m + 1.24 d llH), 1.61-1.87 (m, 6H), 3.4 (m, lH), 3.86 (d, 2H), 6.76 (s, lH), 6.92 (dd, lH), 7.11 (m, 4H), 7.29 (dd, lH), 7.81 (d, 2H).

kxa~pl~ 221 6-~3-Benzylo~yphenyl)-4-hydro~y-3-~2-isopropylphenyl)thio]-2H-pyr~n-2-o~e: The title compound was prepared by Method A using 3-benzyloxyacetophenone (2.0 g, 8.84 mmol), trimethylsilyl triflate (1.96 g, 8.84 mmol), triethylamine (1.79 g, 17.68 mmol) and diethyl ester f t(2-isopropylphenyl)thio] propanedioic acid (0.210 g, 0.675 mmol). m.p. 162-164 C; lH NMR (400 MHz, DMS0-d6) ~ 1.25 (d, 6H), 3.42 (m, lH), 5.35 (s, 2H), 6.89 (s, lH), 6.92 (d, lH), 7.06 (dt, lH), 7.11 (dt, lH), 7.22 (dd, lH), 7.28 (dd, lH), 7.39-7.51(m, 8H).

E~mple 222 WO95/14014 2 1 7 ~ 1 2 4 PCT~S94Jl~67 ~-~ydro~y-3-tt2-~sopropylphenyl3thio]-6-t~-~3-phenylp.~)phenyl]-2~-pyr~n-2-one: The title compound was prepared by Method A using 4-phenylpropyloxy acetophenone ~2.0 g, 7.86 mmol), trimethylsilyl triflate (1.75 g, 7.86 mmol), triethylamine (1.59 g, 15.72 mmol) and diethyl ester ~ of [(2-iso~Lo~ylphenyl)thio]-propanedioic acid (3.~6 g, 11.79 mmol). m.p. 132-133 C; lH NMR (400 MHz, DMSO-d~) ~ 1.25 (d, 6H), 2.06 (m, 2H), 2.75 (t, 2H), 3.39 (m, lH), 4.08 (t, 2H), 6.78 (s, lH), 6.90 (d, lH), 7.05 (dt, 2H), 7.08 (q, 2H), 7.11-7.31 (m, 6H), 7.81 (d, 2H).

~xampl~ 223 3-[~2-sec-Butylphenyl)thio]-~-hydroxy-6-phenyl-2~-pyr~n-2-one (l/-): The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.0 g, 6.17 mmol) and diethyl ester of [(2-sec-butylphenyl)thio]propanedioic acid (1.0 g, 3.09 mmol).
m.p. 170-171 C; lH NMR (400 MHz, DMSO-d6) ~ O.86(t, 3H), 1022 (d, 3H), 1.57 (m, lH), 1.67 (m, lH), 3.22 (m, lH), 6.89 (s, lH), 6.97 (d, lH), 7.06 (t, lH), 7.13 (t, lH), 7.22 (d, lH), 7.56 (m, 3H), 7.86 (m, 2H).
4.5 Deter~ination of ~IV Protea~e Inhibition ~.5.1 ~tartin~ Materials DTT Buffer: 1.0 mM dithiothreitol (DTT) was prepared fresh daily in 0.1% polyethylene glycol (mw 8000) 80 mM NaOAc, 160 mM NaCl, 1.0 mM EDTA, and brought to pH 4.7 with HCl.
!
~IV-I Protease: The enzyme is obtained from Bachem Bioscience Inc. The undiluted enzyme is thawed from -80 C and diluted 50-fold with DTT buffer. The solution is always kept at O C on ice water and used in the experiment within 20 minutes after thawing.

W095/14014 ~1 7~12~ PCT~S94/12367 Enzy~e 8ubstrate: Substrate III from Bachem Bioscience Inc. is the und~c~r~ptide H-His-Lys-Ala-Arg-Val-Leu-p-NitrophenylAl ~n; n~-Glu-Ala-Norleucine-Ser-N}I2 (> 97 %
purity). A 200 ~M stock solution in DTT buffer is s prepared and stored on ice. Substrate solution is prepared fresh daily.

Test Compound: l0 mM inhibitor (I) in dimethyl sulfoxide (DMSO) is diluted to 200 ~M with DTT buffer.
From the 200 ~M stock solution is made a l0 ~M stock solution with 2% DMSO in DTT buffer. The two inhibitor solutions are used to make final [I] = l00, 50, 20, l0, 5, 2, l, 0.5 and 0 ~M with 2% DMSO in DTT
buffer in each reaction well (total inhibitor volume of 50 ~l).

~.5.2 Ass~Y

To each reaction well is added 20 ~l of substrate (final concentration of 40 ~M), 50 ~l of inhibitor (at a concentration such that final dilution will produce the test concentration) and 20 ~l of DTT buffer. The reaction plate (96 wells) is incubated at 37 oc for at least 5 minutes.
10 ~1 of the diluted protease is added to the reaction well while the reaction plate is shaking. Once shaken for l0 seconds, the plate is returned to the heating block at 37 C. (Final reaction volume = 100 ~1.
The reaction is incubated for 5 minutes at 37 C. The reaction is stopped by placing the reaction plate on the shaker and adding 20 ~l of 10% trifluoroacetic acid (TFA) and shAking for l0 seconds. The amount of proteolysis is then determined by separation of noncleaved substrate and two cleaved products with reverse-phase HPLC, while measuring absorbance at 220 nm to determine the relative peak areas of the three WO95/14014 PCT~S94/1~67 ~ 7~4 components. The relative peak areas are used to calculate % conversion to product as a function of inhibitor concentration. The data is plotted as %
Control (the ratio of % conversion in the presence and 5 absence of inhibitor x loO) versus inhibitor concentration and fit with the equation Y=
100/l+(X/IC50) A, where IC50 is the inhibitor concentration at 50% inhibition and A is the slope of the inhibition curve.
lo Table 1 HIV Protease Inhibition Results Example # 50% Inhibition Concentration (Averaged) [~M]
1 0.47 3 1.0 4 0.9 6 0.4 20 8 1.7 17 0.69 23 1.7 26 1.2 28 1.9 29 0.33 33 1.97 34 0.8 3044 0.75 48 0.86 49 1.6 52 0.7 3564 0.6 68 0.45 0.13 71 1.9 WO95/14014 ; PCT~S94/12367 ~

2~ - 138 -73 0.77 74 0.61 77 0.14 78 1.5 87 0.41 110 0.07 113 0.24 121 0.48 129 0.20 133 0.06 144 0.037 160 0.36 163 0.63 164 0.055 166 0.23 169 0.015 172 0.068 183 0.41 193 0.026 4.6 Anti-~IV-l ActivitY
Using the general methods of Pauwels et al., (J.
Vlrol. Met~ods, 16, 171-185, 1987) and Mann et al.
(AIDS Research and Human ~etroviruses, 253-255, 1989) anti-viral assays of acute HIV-1 infection were performed in the H9 cell line. Cultures were batch infected in 1 ml of RPM1 1640 media/10% fetal calf serum con~i n; ng 107 cells and 105 infectious doses of HIV-liiib for an effective multiplicity of infection of 0.01. After 2 hours of viral absorption, cells were washed once and plated in 96-well microtiter plates at a density of 10~ cells per well. Test compounds were added to ~L ~d~ce the desired concentration of drug and 0.2% DMSO in a final volume of 200 ~l. Uninfected parallel cultures were maint~; n~ for XTT cytotoxicity assay at 7 days post infection. Cultures were tested WO 95/14014 21 7 ~ ~ 2 4 PCT~S94/12367 for viral replication by reverse transcriptase assay at 4 and 7 days post infection.

Table 2 Antiviral ActivitY in H9 Cells ~onrentration for 50%
Example # Protection ~M]

lS78 3 172 0.65 Combinations of prot,ease inhibitor with other AIDS treatments, such as (but not limited to) the HIV
reverse transcriptase inhibitors AZT or ddC, may produce synergistic results. J. C. Craig et al., Antivlral Chem. Chemother., 4/3: 161-166 (1993); E. V.
Connell et al., Antimicrob. Agents Chemother., 38:
348-352 (1994); D. M. Lambert et al., Antiviral ~es., 21: 327-342 (1993); A. M. Caliendo et al., Clin.
Infect. Dis., 18/4: 516-524 (1994) .
The compounds of the invention display antibacterial activity when tested by the microtitration dilution method as described in Heifetz, et al., Antimicr. Agents. & Chemoth. 6 : 124 (1974) which is incorporated herein by reference.
By use of the above referenced method, the following minimum inhibitory concentration values wo gSI14014 ~ 7 ~ PCT~S94/1~67 ~l (MICs in ~g/mL) were obtained for representative compounds of the invention vs. clinically relevant gram positive pathogens which have become highly resistant to conventional therapy in recent years.
Antibacterial Activity ~g/ml Ex. 172 Ex. 29 Ex. 167 Ex.
Staphylococcus 50 25 6.2 12.5 aureus H228 Staphylococcus 50 25 6.2 12.5 aureus UC-76 Enterococcus 100 50 12.5 25 foecalis MGH2 Streptococcus 50 25 6.2 12.5 pneumonia 5V-l ~e~Lococcus 50 25 6.2 12.5 pyogenes C203 It should be apparent to those skilled in the art that other compositions not specifically disclosed in the instant specification are, nevertheless, contemplated thereby. Such other compositions are considered to be within the scope and spirit of the present invention. Hence, the invention should not be limited by the description of the specific embodiments disclosed herein but only by the following claims.

Claims (30)

WHAT IS CLAIMED IS:

1. A compound or a pharmaceutically acceptable salt thereof of formula wherein X is OR1, NHR1, SR1, CO2R4 or CH2OR1 wherein R1 is R4 or COR4 wherein R4 is as defined below;
Y is oxygen or sulfur;
Z is oxygen or sulfur;
A and A1 are each independently a chemical bond, an unsubstituted or substituted phenyl, naphthyl, a 5-or 6-membered heterocyclic ring, cycloalkyl, alkylcycloalkyl or a fused ring system of from 8 to 10 atoms or a substituted derivative thereof wherein the substituents are one or more of F, Cl, Br, OR4, N(R4)2, CO2R4, CON(R4) 2, COR4, R4, OCH2O, OCH2CH2O, or CN wherein R4 is independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkylcycloalkyl or phenyl wherein the substituents are one or more of CO2R2, CON(R2)2, F, OR2, SR2, N(R2)2, CN, phenyl, naphthyl, a heterocycle or CF3 wherein R2 is independently alkyl, cycloalkyl, or hydrogen;
R5 is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, phenyl, or the substituted derivatives thereof wherein the substituents are one or more of CO2R2, CON(R2)2, F, OR2, phenyl, naphthyl, CF3, OR1, NHR1, SR1, or CH2OR1 wherein R1 is as defined above;

R3 is independently hydrogen, (CH2)pR4 or (CH2 )pA
wherein p is an integer of from 0 to 2 and R4 and A are as defined above;
W, W1, and W3 are each independently a chemical bond, oxygen, NR3, C(R3)2, CO, CR3=CR3, CC, CR3OR3, C(=NR3)NR3, CR3N(R3)2, S(O)p SO2NR3, CO2, NR3COVgA or NCOVgR3 wherein g is either 0 or 1, and V is oxygen, sulfur, NR3, or CHR3;
W2 is oxygen, NR3, S(O)p, SO2NR3, -OCO, NR3COVgA or NCOVgR3 wherein g is either 0 or 1, and V is oxygen, sulfur, NR3, or CHR3; and m and n are each independently an integer of from 0 to 4 with the provision that when W and W1 are both heteroatoms or when W2 and W3 are both heteroatoms, m is an integer of from 2 to 4, and with the further proviso that R3W1(CH2)mW(CH2)nA cannot be methyl or ethyl.

2. A compound of the formula of claim 1 wherein We is SO2NR3 or S(O)p, wherein p is an integer from 0 to 2.

3. A compound of the formula of claim 2 wherein A1 is not a bond.

4. A compound of the formula of claim 3 selected from the group consisting of 4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[[(2-methylpropyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopropylmethyl)phenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(2,3-dihydro-1,4-benzodioxin-6-yl)-2H-pyran-2-one;
3-[(2,5-Diisopropylphenyl)thio]-4-hydroxy-6-[(3-phenyl)phenyl]-2H-pyran-2-one;

6-Phenyl-4-hydroxy-5-methyl-3-(phenylthio)-2H-pyran-2-one;
[4-[4-Hydroxy-2-oxo-3-(phenylthio)-2H-pyran-6-yl]phenoxy]acetic acid;
[4-[4-Hydroxy-5-methyl-2-oxo-3-(phenylthio)-2H-pyran-6-yl]phenoxy]acetic acid;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(2-methylpropyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(3-methylbutyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(4-methylpentyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(phenylmethyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(2-phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(3-phenylpropyl)cyclopentyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(2-methylpropyl) cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(3-methylbutyl)cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(4-methylpentyl)cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(phenylmethyl) cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(2-phenylethyl)cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(3-phenylpropyl)cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-6-(3-hydroxyphenyl)-3-[(2 isopropylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl]thio]-6-(pyridin-4-yl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(pyridin-2-yl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(4-nitrophenyl)-2H-pyran-2-one;

6-(4-Fluorophenyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(2-methylphenyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(2-methoxyphenyl)-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(N,N-dimethylamino)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[( 2 -isopropylphenyl)thio]-6-(3-trifluoromethylphenyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(1-naphthalenylmethyloxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-[2-(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[3-[2-(morpholin-4-yl)ethoxy)phenyl]-2H-pyran-2-one;
6-(4-Benzyloxy-3-methoxyphenyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(4-Benzyloxy-3-chlorophenyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
4-[4-Hydroxy-2-oxo-3-[(2-isopropylphenyl)thio]-2H-pyran-6-yl]-2-methylphenoxy-acetic acid;
4-Hydroxy-6-[4-(2-hydroxyethoxy)phenyl]-3-[(2-isopropyphenyl)thio]-2H-pyran-2-one;
2-[3-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy]acetamide;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(2,3-pyrazinemethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(pyridin-2-ylmethoxy)-3-methylphenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-(pyridin-4-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-Cyclopropylphenyl)thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;

4-Hydroxy-3-[(2,5-diisopropylphenyl)thio]-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-[2-(thiomorpholin-4-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-[2-(piperazin-1-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-[2-(methylpiperazin-1-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[4-[2-(1,1-dioxothiomorpholin-4-yl)ethoxy]phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(1-phenyl-cyclopentyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(4-phenyl-piperidin-4-yl)-2H-pyran-2-one;
Isopentanoic acid 2-oxo-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
Propanoic acid 2-oxo-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
Phenylacetic acid 2-oxo-6-phenyl-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one-4-ylester;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydloxy-3-[(2-isopropyl-4-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-6-methylphenyl)thio]-6-phenyl-2H-pyran-2-one;
3-[(4-Chloro-2-isopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydloxy-3-[(4-hydroxy-2-isopropylphenyl)thio]-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[(2,5-Diisopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[(2-tert-butylphenyl)thio]-2H-pyran-2-one;

3-[(2-Cyclopropyl-5-isopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopentyl-5-isopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[2-Cyclohexyl-5-isopropylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[(2-tert-butyl-5-isopropylphenyl)thio]-2H-pyran-2-one;
3-[(2,5-Di-tert-butylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclopentylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
3-[(2-Cyclohexylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-[[4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl]thio]-2-hydroxyindane;
4-Hydroxy-3-[[2-isopropyl-4-(morpholin-4-ylmethyl)phenyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(6-isopropyl-indan-5-yl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(4-isopropyl-benzo[1,3]dioxol-5-yl)thio]-6-phenyl-2H-pyran-2-one;
3-[(2-tert-Butyl-4-thiomorpholin-4-ylmethylphenyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-3-[(2-tert-butylphenyl)thio]-2H-pyran-2-one;
3-[[(2-Cyclopropyl-5-isopropyl)phenyl]thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[[(2-Cyclopentyl-5-isopropyl)phenyl]thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[[(2-Cyclohexyl-5-isopropyl)phenyl]thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-3-[(2-tert-butyl-5-isopropylphenyl)thio]-2H-pyran-2-one;

3-[(2,5-Di-tert-butylphenyl)thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-Cyclopentylphenyl)thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-Cyclohexylphenyl)thio]-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-3-[(6-tert-butylindan-5-yl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-4-morpholin-4-ylmethyl-phenyl)thio]-6-[4-(pyrindin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
Acetic acid 3-[(2-isopropylphenyl)thio]-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
Isobutyric acid 3-[(2-isopropylphenyl)thio]-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
2,2-Dimethylpropionic acid 3-[(2-isopropylphenyl)thio]-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-4-ylester;
4-Hydroxy-3-[(2-isopropylphenyl)sulfonyl]-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-[(2-tert-Butylphenyl)sulfonyl]-4-hydroxy-6-phenyl-2H-pyran-2-one;
6-(1-Benzylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)sulfonyl]-2H-pyran-2-one;
6-(1-Benzylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(1-Benzylpropyl)-3-[(2-tert-butylphenyl)thio]-4-hydroxy-2H-pyran-2-one;
N-[3-[[6-(1-Benzylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]thio]-2-isopropylphenyl]
benzenesulfonamide;
6-[1-Cyclopropylmethyl-2-(tetrahydro-pyran-3-yl)ethyl]-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(1,1-Dimethyl-3-phenylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;

6-(Benzo[1,3]-dioxol-5-yl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(phenylmethyl)cyclobutyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(2-phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-[1-(3-phenylpropyl)cyclobutyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-(1-benzylcyclopropyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-[1-(2-phenylethyl)cyclopropyyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-[1-(3-phenylpropyl)cyclopropyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-(1-benzylcyclobutyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-[1-(2-phenylethyl)cyclobutyl]-2H-pyran-2-one;
4-Hyd,oxy-3-t(2-isopropyl-5-methylphenyl)thio]-6-[1-(3-phenylpropyl)cyclobutyl]-2H-pyran-2-one;
4-Hydloxy-3-[(2-isopropyl-5-methylphenyl)thio]-6 (1-benzylcyclopentyl)-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-[1-(2-phenylethyl)cyclopentyl]-2H-pyran-2-one;
4-Hydloxy-3-[(2-isopropyl-5-methylphenyl)thio]-6-[1-(3-phenylpropyl)cyclopentyl]-2H-pyran-2-one;
6-(1,1-Dimethyl-3-phenylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(1,1-Dimethyl-2-phenylethyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-isopropylphenyl)thio]-6-(1-methyl-1-phenylethyl)-2H-pyran-2-one;
6-(1,1-Diethyl-3-phenylpropyl)-4-hydroxy-3-r(2-isopropylphenyl)thio]-2H-pyran-2-one;
6-(1-Benzyl-1-ethylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one and 6-(1-Ethyl-1-phenylpropyl)-4-hydroxy-3-[(2-isopropylphenyl)thio]-2H-pyran-2-one.

5. A compound of the formula of claim 2 wherein Al is a bond and (CH2)mW3 taken together is not a bond.

6. A compound of the formula of claim 5 selected from the group consisting of 6-[4-[(3,5-Dimethyl-4-isoxazolyl)methoxy]phenyl]-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4 (phenylsulfinyl)phenyl]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(3-phenoxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[3-methoxy-4-(phenylmethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-oxo-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenoxyethyl)thio]-6-phenyl-2H-pyran-2-one;
(E)-4-Hydroxy-6-phenyl-3-t(3-phenyl-2-propenyl)thio]-2H-pyran-2-one;
2-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-4-yl-3-methylbutanoic acid ester;
6-(3,4-Dichlorophenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
2-Oxo-6-phenyl-3-[(phenylmethyl)thio]-2H-pyran-4-yl propanoic acid, ester;
4-Hydroxy-6-(3-methylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(3-hydroxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(2-phenylethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;

4-Hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4 (phenylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-phenylethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[3-(2-phenylethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(2-hydroxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(3-methoxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3-Chlorophenyl)-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(4-methoxy-3-methylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3-Chloro-4-methoxyphenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-(phenylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[[2-(4-methoxyphenyl)ethyl]thio]-6-phenyl-2H-pyran-2-one;
3-[(Cyclohexylmethyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
6-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]acetic acid;
[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]acetic acid, ethyl ester;
4-Hydroxy-6-(4-phenoxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(2-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-methoxyphenyl)methoxy]phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(phenylthio)phenyl]-2H-pyran-2-one;
6-(1,3-Benzodioxol-5-yl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(2-naphthalenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-(4-hydroxyphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(2-Chlorophenyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[2-(3-methylbutyl)phenyl]-3-[(phenylmethyl)thio]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-(hydroxymethyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
[4-[4-Hydroxy-5-(hydroxymethyl)-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl] phenoxy] acetic acid;
4-Hydroxy-6-[(4-methoxyphenyl)methyl]-3-[[1-(phenylmethyl)butyl]thio]-2H-pyran-2-one;
[[5-[2-Oxo-4-hydroxy-3-[(3-methyl-1-phenylbutyl)thio]-2H-pyran-6-yl]-2-pyridinyl]oxy]acetic acid;
[[4-[4-Hydroxy-2-oxo-3-[(phenylmethyl)thio]-2H-pyran-6-yl]cyclohexyl]oxy]acetic acid;
6-[4-(Cyclohexylmethoxy)phenyl]-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(phenylsulfonyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-benzoyloxy)phenyl]-2H-pyran-2-one;

4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(phenylsulfinyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-(4-pyridinyl)-2H-pyran-2-one;
4-Hydroxy-6-(3-phenoxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[3-methoxy-4-(phenylmethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
6-(3,5-Dimethylphenyl)-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[[(3-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[[[3-(phenylmethoxy)phenyl]methyl]thio]-2H-pyran-2-one;
3-[(1,3-Benzodioxol-5-ylmethyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydloxy-3-[[(2-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[[(2-methylphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-tt(3-methylphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[[(4-methylphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
6-[1,1'-Biphenyl]-3-yl-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[[(4-methoxyphenyl)methyl]thio]-6-phenyl-2H-pyran-2-one;
[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]-2-methylphenoxy], acetic acid, ethyl ester;
6-[3,5-Dimethyl-4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]phenyl]-4-hydloxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(4-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
[4-[4-Hydroxy-2-oxo-3[(2-phenylethyl)thio]-2H-pyran-6-yl]-2-methylphenoxy acetic acid;

4-Hydroxy-6-(4-hydroxy-3,5-dimethylphenyl)-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-phenyl-3-[[[3-(2-phenylethoxy)phenyl]methyl]thio]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-phenylethynyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-6-[4-(2-phenylethyl)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-[3-(trifluoromethoxy)phenyl]-2H-pyran-2-one;
3-[(Cyclohexylmethyl)thio]-4-hydroxy-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3-methyl-4-(3-pyridinylmethoxy)phenyl]-2H-pyran-2-one;
6-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[3 (trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-[3-(trifluoromethyl)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-(2,3,4-trimethoxyphenyl)-2H-pyran-2-one;
N-[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]phenyl]benzenesulfonamide;
6-[4-[(3,5-Dimethyl-4-isoxazolyl)methoxy]phenyl]-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
2-[[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]-benzoic acid methyl ester;
2-[[4-(4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]methyl-benzoic acid methyl ester;
4-Hydroxy-3-[(2-phenylethyl)thio]-6-[4-(1H-tetrazol-5-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-6-[3-methyl-4-(2-pyridinylmethoxy)phenyl]-3-[(2-phenylethyl)thio]-2H-pyran-2-one;

4-[[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]phenoxy]methyl]benzoic acid methyl ester;
3-[[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxy]methyl]benzoic acid methyl ester;
6-[4-[(3,4-Dichlorophenyl)methoxy]phenyl]-4-hydroxy-3-[(2-phenylethyl)thio]-2H-pyran-2-one;
3-[[(4-Hydkoxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]benzoic acid methyl ester;
4-[[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)thio]methyl]benzoic acid methyl ester;
6-[3,5-Bis(trifluoromethyl)phenyl]-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one;
[4-[4-Hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H
pyran-6-yl]phenoxy]acetonitrile;
6-Phenyl-4-hydroxy-3-[(cyclopropylmethyl)thio]-2H-pyran-2-one;
6-(3-Chlorophenyl)-4 hydroxy-3-[(4-phenylbutyl)thio]-2H-pyran-2-one;
4-Hydroxy-3-[(2-hydroxy-2-phenylethyl)thio]-6-phenyl-2H-pyran-2-one;
4-Hydroxy-3-[(phenylmethyl)thio]-6-(3-pyridinyl)-2H-pyran-2-one;
6-(2,6-Dimethyl-4-pyridinyl)-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one and 4-Hydroxy-3-[(phenylmethyl)thio]-6-(3-thienyl)-2H-pyran-2-one.

7. A compound of the formula of claim 1 wherein W2 is oxygen.

8. A compound of the formula of claim 7 wherein A1 is not a bond.

9. A compound of the formula of claim 8 selected from the group consisting of 4-Hydroxy-3-phenoxy-6-phenyl-2H-pyran-2-one;

4-Hydroxy-3-(2-isopropyl-phenoxy)-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
4-Hydroxy-3-(2-isopropyl-phenoxy)-6-phenyl-2H-pyran-2-one;
3-(2-tert-Butyl-phenoYy)-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
3-(2-tert-Butyl-5-methyl-phenoxy)-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
6-(1-Benzylpropyl)-4-hydroxy-3-(2-isopropylphenoxy)-2H-pyran-2-one and 6-(1-Benzylpropyl)-3-(2-tert-butylphenoxy-4-hydroxy-2H-pyran-2-one.

10. A compound of the formula of claim 7 wherein A1 is a bond and (CH2)mW3 taken together is not a bond.

11. A compound of the formula of claim 10 selected from 3-Benzyloxy-4-hydroxy-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-2-one;
2-[4-Hydroxy-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yloxymethyl]benzoic acid methyl ester;
2-[[[6-(1-Benzylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]oxy]methyl) benzoic acid ethyl ester and 6-(1-Benzylpropyl)-4-hydroxy-3-(1-phenylbutoxy)-2H-pyran-2-one.

12. A compound of formula of claim 1 wherein W2 is selected from NR3;
NR3COVgA;
NCOV5R3; or SO2NR3, wherein for each choice of W2 the nitrogen is bonded to the carbon at the 3 position of the pyrone ring.

13. A compound of formula of claim 12 wherein W2 is NR3.

14. A compound of formula of claim 13 selected from 3-[Bis(2-naphthalenylmethyl)amino]-4-hydroxy-6-phenyl-2H-pyran-2-one;
6-(1-Benzylpropyl)-3-(cyclopropylphenylamino)-4-hydroxy-2H-pyran-2-one;
N-[3-[[6-(1-Benzylpropyl)-4-hydroxy-2-oxo-2H-pyran-3-yl]cyclopropylamino]phenyl]benzenesulfonamide;
3-[Cyclopropylphenylamino]-4-hydroxy-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
3-(Bis-cyclopentylmethyl-amino)-4-hydroxy-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one;
3-[Cyclopentylmethyl(cyclopropylmethyl)amino]-4-hydroxy-6-(pyridin-3-ylmethoxy)-2H-pyran-2-one and 6-[1-Cyclopropylmethyl-2-(tetrahydro-pyran-3-yl)ethyl]-3-(cyclopropylphenylamino)-4-hydroxy-2H-pyran-2-one.

15. A compound of formula of claim 12 wherein W2 is selected from the group NR3COVgA; NCoVgR3;
or SO2NR3, wherein for each choice of W2 the nitrogen is bonded to the carbon at the 3 position of the pyrone ring.

16. A compound of formula of claim 15 selected from (S)-1,3-Dihydro-N-(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl)-2-(phenylmethyl)-2H-isoindol-2-acetamide;
N-(1,1-Dimethylethyl)-N'-(4-hydLoxy-2-oxo-6-phenyl-2H-pyran-3-yl)-N'-(phenylmethyl)urea;
Cyclopropanecarboxylic acid cyclopentylmethyl-[4 hydroxy-2-oxo-6-[(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]amide;
Cyclopentanecarboxylic acid cyclopentylmethyl-[4 hydroxy-2-oxo-6-[4-(pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]amide and N-Cyclopentylmethyl-N-[4-hydroxy-2-oxo-6-[4 (pyridin-3-ylmethoxy)phenyl]-2H-pyran-3-yl]
cyclopentanesulfonamide.

17. The compounds named:
2-Cyclopentylbenzenethiol;
3-Methoxy-2-(1-methylethyl)benzenethiol;
2-(1,1-Dimethylethyl)-4-methoxybenzenethiol;
2-(Cyclopenten-2-yl)benzenethiol;
2-Cyclohexylbenzenethiol;
2-(1,1-Dimethylethyl)-5-methoxybenzenethiol;
2-(1,1-Dimethyl-2-hydroxyethyl)benzenethiol and 2-(1,1-Dimethylethyl)-4,5-(methylenedioxy)benzenethiol.

18. The compounds named:
Diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-cyclopropylmethylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2,5-diisopropylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-isopropyl-5-methylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2,4-ditert-butylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-sec-butylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-cyclohexylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-cyclopentylphenyl)thio]-propanedioic acid;
Diethyl ester of [(2-tert-butyldimethylsilyloxymethylphenyl)thio]-propanedioic acid and Diethyl ester of [(3-(p-toluenesulfonylamino)phenyl)thio]-propanedioic acid.

19. A pharmaceutical composition for the treatment of infection or disease caused by a bacterium, which comprises an amount of the compound of claim 1 sufficient to provide an antibacterially effective dosage of the compound in the range of about 1 to about 50 mg/kg-day and a pharmaceutically acceptable carrier .

20. A pharmaceutical composition for the treatment of infection or disease caused by a retrovirus, which comprises an amount of the compound of claim 1 sufficient to provide an antivirally effective dosage of the compound in the range of about 1 to about 50 mg/kg-day and a pharmaceutically effective carrier.

21. A pharmaceutical composition for the treatment of infection or disease caused by a retrovirus, which comprises an amount of the compound of claim 2 sufficient to provide an antivirally effective dosage of the compound in the range of about 1 to about 50 mg/kg-day and a pharmaceutically effective carrier.

22. A pharmaceutical composition for the treatment of infection or disease caused by a retrovirus, which comprises an amount of the compound of claim 4 sufficient to provide an antivirally effective dosage of the compound in the range of about 1 to about 50 mg/kg-day and a pharmaceutically effective carrier.

23. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 1.

24. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 1 in combination with an HIV reverse transcriptase inhibitor.

25. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 1 in combination with AZT.

26. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 1 in combination with ddC.

27. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 2.

28. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 2 in combination with a HIV reverse transcriptase inhibitor.

29. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 4.

30. A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a composition of claim 4 in combination with a HIV reverse transcriptase inhibitor.