SK63996A3 - 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

Technical field

The invention relates to pyrone derivatives which are inhibitors of aspartyl proteases, in particular aspartyl proteases present in retroviruses, including human immunodeficiency virus (HIV). It is contemplated that pyrones may be used as antiviral agents in the treatment of infections caused by HIV or other aspartyl protease retroviruses, as well as in the treatment of diseases caused by retroviruses, including AIDS.

BACKGROUND OF THE INVENTION

The term Acquired Immune Deficiency Syndrome (AIDS) was created in 1982 to describe the clinical manifestations of immune deficiency. Later, it was found that the etiological agent of AIDS is a retrovirus human immunodeficiency virus (HIV) - a subset of lentiviruses. Two infectious strains of HIV have been described - HIV-1 and HIV-2. Here, HIV will be used as a generic term describing a number of strains and mutants of human immunodeficiency virus. In a detailed study of HIV, research has been conducted in different directions to develop an antiviral active ingredient, including inhibition of viral aspartyl protease (D. Richman, Control of Virus Diseases, 45th Symposium Society for General Microbiology, pp. 261-313). (1990).

Aspartyl proteases have been discovered in many viruses, including Felinovlio immunodeficiency virus, myeloblastosis-associated virus, HIV and Rous sarcoma virus (H. Toh et al., Nature, 315: 691, 1985, J. Kay, BM Dunn, Biochem. Acta, 1: 1048, 1990, C. Cameron et al., J. Biological Chem., 168, 11711-720, 1993). Since there are striking structural similarities between known retroviral proteases, other retroviral proteases can also be well inhibited by compounds that inhibit HIV protease.

HIV-aspartyl protease is responsible for the post-translational mechanism of viral precursor proteins, e.g. pol and gag (M. Graves, Structure and Function of the Aspartic Proteases, pp. 395-405 (1991)). Cleavage of these polyproteins by this protease is necessary for virus maturation, since proteolytic activity for the polyprotein process cannot be assured by host cell enzymes. A very important finding was that viruses that lack this protease or contain a mutation that results in a defective protease are not infectious (C. Peng et al., J. Virol, 63: 2550-2556, 1989, and N Kohl et al., Proc. Natl. Acad. Sci. USA, 85: 4689-90 (1987). Thus, a selective HIV protease inhibitor has been shown to be able to inhibit the spread of the virus and the development of cytopathic effects and cultures of acutely infected cells (J. C. Craig et al., Antiviral Research, 295-305, 1991). Therefore, HIV protease inhibition appears to be a promising approach to antiviral therapy.

HIV protease inhibitors have been extensively investigated (see e.g.

A. Tomasselli et al., Chimica Oggi, 9: 6-27, 1991 and T. meek, J. Enzyme Inhibition 6: 65-98, 1992). However, most of these inhibitors are peptides, making them unsuitable as active ingredients due to the pharmacological insufficiency of most peptide active ingredients (bile excretion, low bioavailability and stability in the physiological environment, etc.). For this reason, HIV protease inhibitors of non-peptidic origin are becoming increasingly important as these may be very useful therapeutic agents.

Hei 3-227923 correlated coumarins and their anti-HIV activity. However, only 4-hydroxycoumarin has been described in detail, moreover without an analysis of its mechanism of action.

World Patent 89/07939 claims coumarin derivatives here as inhibitors of HIV reverse transcriptase with a possible antiviral effect. These derivatives are: hexachlorocoumarin,

7-acetoxycoumarin and the structures below.

The below warfarin (3- (? - acetonylbenzyl) -4-hydroxycoumarin) has been described by R. Nagornny et al., In AIDS, 7: 129-130, 1993 as an inhibitor of extracellular and cell-mediated HIV infection. However, warfarin was the only pyrone studied and its mechanism of action in inhibiting HIV has not been specified.

Selected flavones structurally different from the pyrones of the invention have been described by Fairl et al., Biochem. Biophys. Res.

Comm., 188: 631-637, 1992, as HIV-1 protease inhibitors. These compounds are:

OMe

HO

U.S. Pat. No. 3,206,476 discloses certain pyrones, specifically

3-substituted-4-hydroxy-6-aryl-2-pyrones as antihypertensive agents. However, the substituents at the 3-position are limited to halides and amino groups and alkanoylamino derivatives.

U.S. Pat. No. 3,818,046 discloses derivatives, in particular 4-hydroxypyrones with several sulfur-containing pyronic carbon chains at the 3-position, as antimicrobial agents. However, the substitution of heterocycles only concerns methyl

growth inhibitors and at position 6 of these groups. The pyrones below are substituted as follows: R = Me, M = H or an alkali metal, and

R '= H, alkyl, phenyl, halophenyl, nitrifenyl, lower alkyl substituted phenyl, benzyl, phenethyl, naphthylmethyl, halobenzyl, lower alkyl benzyl, nitrobenzyl, propargyl, allyl a lower alkyl group, a cyclohexyl group substituted with a lower alkyl group, a thioalkyl group containing a lower alkyl group, a lower alkyl group or an adamantyl group, and n = 0 to 2.

OM

R = Me

A process for preparing the above-mentioned pyrones is described in U.S. Pat. 3,931,235.

The invention is largely based on the extraordinary discovery that novel tri- and tetrasubstituted pyrones and related compounds, selected from a wide variety of specific molecular structures, potentially inhibit HIV-aspartyl protease, thereby preventing HIV infection. The invention is also based on research into the mechanism of action of anti-viral drugs by studying the characteristic structure-activity relationships of anti-HIV compounds, including pyrones.

The pyrones of the invention are expected to be extremely effective in the development of therapy for infections caused by viruses, in particular retroviruses, the replication and infectivity of which depend on the activity of aspartyl protease. Pyrones as viral blockers are also considered to be very useful in the treatment of disease states and syndromes associated with viral poachogenic agents. One such syndrome is AIDS.

Effective syntheses of biologically active pyrons are described, including a new construction of pyrone nuclei or modifications of suitable functionalized pyrones. In addition, a number of examples are provided describing the preparation of specific pyrones whose structures contain the desired functional groups in the respective geometric arrangements.

Also included is the testing of specific pyrones as HIV-aspartyl protease inhibitors based on the research of undecapeptide enzyme substrate hydrolysis and the testing of pyrones as inhibitors of viral growth and infectivity based on the HIV-1 strain H9 cell line research. Unusual enzyme inhibition at nanomolar levels and corresponding anti-HIV effects have been observed.

The invention also encompasses the preparation of pharmaceutically effective antiviral compositions comprising one or more pyrones of the invention and related compounds and a pharmaceutically acceptable carrier. Also contemplated is the use of these compositions, alone or in combination with other antiviral therapies, in the treatment of infections and diseases caused by retroviruses, including AIDS.

The invention relates to compounds of formula 1 below

X

R ⁵ !

R ³ W ¹ (CH 2 in which

X is OR ¹ , NHR ¹ , SR ¹ , CO = R ⁴ or CH ² OR ¹ , wherein R ¹ is R ⁴ or

COR ⁴ , wherein R ⁴ is as defined below,

Y is an oxygen atom or a sulfur atom,

Z is an oxygen atom or a sulfur atom,

A and A ¹ are independently a chemical bond, an unsubstituted or substituted phenyl group, a naphthyl group, a five or six membered heterocyclic ring, a cycloalkyl group or a ring system containing from 8 to 10 atoms or a substituted derivative thereof, wherein the substituent (s) is from the group consisting of F, Cl, Br, OR ⁴ , N (R ⁴ ) 2, CO ² R ⁴ , CON (R ⁴ ) 2, COR ⁴ , R ⁴ , OCH 2 O, OCH 2 CH 2 O or C = N, wherein R ⁴ is independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkylcycloalkyl or phenyl, wherein the substituent (s) is / are selected from the group consisting of CO ² R ² , CON (R ² ) 2, F, OR ² , SR ² , N ( R ² ) 2, CN, phenyl, naphthyl, heterocycle or CF, wherein R ² is independently alkyl, cycloalkyl or hydrogen,

R ^p is H, alkyl, cycloalkyl, alkylcycloalkyl, phenyl or a substituted derivative thereof wherein the substituent / s is / are selected / s from the group consisting of CO 2 R ^2, CON (R ²⁾ 2, F, OR ^2, phenyl, naphthyl, CF 3, OR ¹ , NHR ¹ , SR ¹ or CH ² OR ¹ , wherein R ¹ is as defined above,

R ³ is independently hydrogen, (CH) R ⁴ or (CH) A, wherein p 2 p 2 p * is an integer from 0 to 2 and R ⁴ and A are as defined above, W, W ¹ and W ³ are independently chemical bond, oxygen atom, NR ³ , C (R ³ ), CO, cr ³ = cr ³ , C = C, CR ³ OR ³ , C (= NR ³ ) NR ³ , S (0), 2 p

CR ³ N (R ³ ), SO NR ³ , CO, NR ³ COV A and NCOV R ³ , where 2 2 2 g cj * g is 0 or 1 and V is oxygen, sulfur, NR ³ or CHR ³ ,

W ² is O, NR ³ , S (O), SO NR ³ , -OCO, NR ³ CO, and

NC0V _g R ³ , wherein g is 0 or 1 and av is 0, S, NR ³ or CHR ³ , m and n are independently integers up to 0 to 4 with the proviso that when W and W ^{1 are} heteroatoms or W ² and W ³ are heteroatoms, then m is an integer from 2 to 4, and with the further proviso that R ³ W ^x (CH ₂ ) _m W (CH ₂ ) 4 A is not a methyl or ethyl group, and pharmaceutically acceptable salts thereof.

Preferably, the compounds of the invention are of formula 1, wherein the above

W, W ¹ and W ³ are independently O, NR ³ , NCOV R ³ , CR ³ = CR ³ , sr

SO ₂ NR ³ , sulfur atom or C (R ³ ) ₂ and W ² is selected from the group consisting of O, NR ³ , S and NCOV 3 R ³ , wherein:

W is O, NR ³ or CHR ³ wherein R ³ I t is independently H, (CH) ^4, or R (CH) and,

Z-pzp wherein p is an integer from 0 to 2, g is 0 or and A is independently phenyl, naphthyl, five- or six-membered heterocycle containing one or two heteroatoms, ring system containing from 8 to 10 atoms, cyclopentyl, a cyclohexyl group or a substituted derivative thereof, wherein the substituent (s) are / are

from a set comprising

CO R ⁴ , CON (R ⁴ ), R ⁴ , OCH 2 ^R 2

R ⁴ is independently a hydrogen atom, a direct phenyl group, or a phenyl group;

F, Cl, Br, Or ⁴ ,> or OCH CH, or N (R ⁴ ) ₂ selected from 5 to 6, wherein the branched alkyl group containing from atoms, the cycloalkyl carbon atoms containing from 4 group or substituents are or or CF, a group, an ethyl group, a tert-butyl group or a 3 to 6 carbon group as defined above and a

R ⁵ is H, methyl, ethyl, propyl, cyklopropy1ová carboxyl or substituted in the 8 _CO2 R ² F wherein R ² is a group containing CH ₂ -cycloalkyl carbon atoms, derivative thereof,

OR ² , phenyl is hydrogen, methyl isobutyl, cycloalkyl atoms, wherein A ¹ has a group, a hydroxyl group, a hydroxymethyl group.

More preferably, the compounds are of formula 1, wherein according to the invention with the above

X is a hydroxyl group,

Z is an oxygen atom,

Y is an oxygen atom,

W, W ^x and W ³ are independently O, S, NR ³ , SO ² NR ³ or C (R ³ ) 2 and W ² is O, S or NR ³ , wherein R ³ is independently hydrogen, (CH) R ⁴ or (CH) A, wherein p is an integer from 0 to 2, R ⁴ is hydrogen, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl a CH ₂ CO ₂ R ² , a phenyl group or a benzyl group,

R ² is hydrogen, methyl, ethyl, isobutyl or tert-butyl,

A is phenyl, 2,3- or 4-pyridyl, 2.49

or 5-thiazolyl, morpholinyl, 2- or

3-furyl, cyclopentyl, cyclohexyl, indanyl, or a substituted derivative thereof wherein the substituent / s is / are selected / s from the group consisting of F, Cl, Br, Or ⁴ R ^4, CO 2 R ⁴ or OCH 2, wherein A ^x is as defined above, and

R ⁵ is a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group.

The most preferred compounds of the invention are:

3- [(Cyclohexylthio) phenylmethyl] ^-4-hydroxy-2 6-phenyl-2H-pyran-2-one,

4-Hydroxy-3 - [[(2-methoxyphenyl) thio] phenylmethyl] -6-phenyl-2H-pyran-2-one

3- (3-Methoxybenzoyl) -6- (3-methoxyphenyl) -2H-pyran-2,4 (3H) -dione,

6- [4 - [(3,5-Dimethyl-4-isoxazolyl) methoxy] phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one,

4-Hydroxy-3- [3-methyl-1- (phenylthio) butyl] -6-phenyl-2H-pyran-2-one;

4-hydroxy-3 - [(2-phenylethyl) ethyl] -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 - [(2-phenylmethyl) thio] -2H-pyran-2-one,

4-Hydroxy-6- (3-phenoxyphenyl) -3 - [(2-phenylethyl) thio] -2H-pyran-2-one,

3- [2-Cyclohexyl-1- (phenylthio) ethyl] -4-hydroxy-6-phenyl-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- [phenyl (phenylthio) methyl] -2H-pyran-2-one,

3- [Bis (2-naphthalenylmethyl) amino] -4-hydroxy-6-phenyl-2H-pyran-2-one;

4-Hydroxy-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-2-one; (S) -1,3-Dihydro-N- (4-hydroxy-2-oxo-6-phenyl-); 2H-pyran-3-yl) - (phenylmethyl) -2H-isoindole-2-acetamide;

N- (1,1-Dimethylethyl) -N '- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -N' - (phenylmethyl) urea,

4-Hydroxy-3 - [(2-phenoxyethyl) thio] -6-phenyl-2H-pyran-2-one, (E) -4-Hydroxy-6-phenyl-3 - [(3-phenyl-2-propenyl) ) thio] -2H-pyran-2-one,

4-Hydroxy-3-phenoxy-6-phenyl-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-hydroxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran11

2-όη

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-naphthalenyl (phenylthio) methyl] -6-phenyl-2H-pyran-2-one;

4-Hydroxy-3 - [(2-naphthalenylthio) phenylmethyl] -6-phenyl-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,

6- (3,5-Dimethylphenyl) -4-hydroxy-5-methyl-3- [2-phenyl-1 - [(phenylmethyl) thio] ethyl] -2H-pyran-2-one,

4-Hydroxy-6- [4- (2-methoxyphenoxy) phenyl] -3- [phenyl [(phenylmethyl) thio] methyl] -2H-pyran-2-one, [4- [3- [2-Cyclopentyl-1]] -Phenylmethoxy) ethyl] -4-hydroxy-2-oxo-2H-pyran-6-yl] phenoxy] acetic acid,

4-Hydroxy-6- [4 - [(1-methylethoxy) methyl] -2-thiazolyl] -2-oxo-3- [2-phenyl-1 - [[phenylmethyl) thio] thio] ethyl] -2H-pyran -2-one,

4- [4-Hydroxy-3- [1- (1-hydroxy-2-phenylethyl) -3-methylpentyl] -2-oxo-2H-pyran-6-yl] benzenepropanoic acid,

6- (3,5-dimethylphenyl) -4-hydroxy-3- [l-hydroxy-2-methyl-l- (phenylmethyl) propyl] -2H-pyran-2-one,

6- [3-Fluoro-4- (3-pyridinylmethoxy) phenyl] -4-hydroxy-3- [3-methyl-1 - [(phenylmethyl) thio] butyl] -2H-pyran-2-one, [2- (Hydroxymethyl) -4- [4-4-hydroxy-3- [1- (1-methylethoxy) -2- (phenylthio) ethyl] -2-oxo-2H-pyran-6-yl] phenoxy] acetic acid, [ 4- [4-Hydroxy-3- [3-methyl-2- (phenylthio) butyl] -2-oxo-2H-thiopyran-6-yl] phenoxy] acetic acid,

4-Hydroxy-6 - [(4-methoxyphenyl) methyl] -3 - [[1- (phenylmethyl) butyl] thio] -2H-pyran-2-one, [2-Hydroxy-4- [4-hydroxy-2] -oxo-3- [2- (phenylmethyl) 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-Hydroxy-6- [5- (phenoxymethyl) -2-furanyl] -3- [2-phenyl-1 - [(phenylmethyl) thio] ethyl] -2H-pyran-2-one, [4- [4- Hydroxy-2-oxo-3- [2-phenyl-1 - [(phenylmethyl) amino] ethyl] -2H-pyran-6-yl] phenoxy] acetic acid,

4-Hydroxy-3- [2-phenyl-1- [phenyl (phenylmethyl) amino] ethyl] -6- [4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one, [[4- [ 4-Hydroxy-2-oxo-3 - [(phenylmethyl) thio] -2H-pyran-6-yl] cyclohexyl] oxy] acetic acid,

Cis-6- (3,5-Dimethylphenyl) -4-hydroxy-3- [3-methyl-1- [2,3-dihydro-1-hydroxy-1H-inden-2-yl) thio] butyl] 2H-pyran-2-one,

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- [4- (3-Furanylmethoxy) phenyl] -4-hydroxy-3- [3-methyl-1 - [(phenyl / methyl) thio] butyl] -2H-pyran-2-one,

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- (phenylsulfonyl) phenyl] -2H-pyran-2-one,

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- (4-pyridinyl) -2 H -pyran-214

-one

3- [1,4-Bis (phenylthio) butyl] -4-hydroxy-6-phenyl-2H-pyran-2-one,

4-Hydroxy-6-phenyl-3- [phenyl [(phenylmethyl) thio] methyl] -2H-pyran-2-one;

4-hydroxy-3 - [[(2-methoxyphenyl) thio] phenylmethyl] -6-phenyl-2H-pyran-2-one,

4-Hydroxy-3- [3-methyl-l- (phenylthio) butyl] -6-phenyl-2H-pyran-2-one,

3- [2-Cyclohexyl-1- (phenylthio) ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

4-Hydroxy-6- (3-phenoxyphenyl) -3 - [(2-phenylethyl) thio] -2H-

pyran-2-όη,

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-3- [4-methyl-l- (phenylthio) pentyl] -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-Hydroxy-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 - [[(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,

3- [2-Cyclohexyl-1- (cyclohexylthio) ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

3- [1 - [(2,6-dimethylphenyl) thio] -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one,

3- [1- (Cyclohexylthio) -2-cyclopropylethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

3- [1 - [(2,6-Dichlorophenyl) thio] -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one,

3- [1- (Cyclohexylthio) -3,3-dimethylbutyl] -4-hydroxy-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-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one,

4-Hydroxy-3 - [(2-phenylmethyl) thio] -6- [4- (4-pyridinylmethoxy) phenyl] -2H-pyran-2-one,

3- [1- (Cyclopentylthio) -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

[4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] -2-methylphenoxy] acetic acid,

3- [1- (Cyclohexylthio) -2- (cyclopentyl) ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

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 - [(-phenylethyl) thio] -2H-pyran-one,

4-Hydroxy-6- [4- (2-phenylethyl) phenyl] -3 - [(phenylethyl) thio] -2H-pyran-one,

3 - [(Cyclohexylthio) phenylmethyl] -4-hydroxy-6-phenyl-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] -N- [3-methyl-4-3-pyridinyl16 methoxy) phenyl] -2H-pyran-2-one,

6- (2,3-dihydro-l, 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,

3 - [(Cyclohexylthio) phenylmethyl] -4-hydroxy-6- [3-methyl-4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one,

2 - [[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] benzoic acid methyl ester,

3- [1- (Cyclohexylthio) -3-methylbutyl] -6- (2,3-dihydro-1,4-benzodioxin-6-yl) -4-hydroxy-2H-pyran-2-one,

2 - [[4- (4-hydroxy-2-oxo-3 -] (2-phenylmethyl) thio] -2H-pyran-6-yl] phenoxy] methylbenzoic 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,

3- [2-Cyclopropyl-1 - [(phenylmethyl) thio] ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one,

4-Hydroxy-3- [1 - [(phenylmethyl) thio] -3-methylbutyl] -6-phenyl-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-Hydroxy-2-oxo-6-phenyl-2H-pyran) methyl ester 17

3-yl] thio] methyl] benzoic acid,

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,

3- [1- (Cyclohexylthio) -3-methylbutyl] -4-hydroxy-6-phenyl-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-Chloro-phenyl) -4-hydroxy-3 - [(4-phenylbutyl) thio] -2H-pyran

2-one,

4-Hydroxy-3 - [(2-hydroxy-2-phenylethyl) thio] -6-phenyl-2H-pyran-

- ón,

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 - [(phenylmethyl) thio] -6- (3-pyridinyl) -2H-pyran-2-one,

6- (2,6-dimethyl-4-pyridinyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one,

4-Hydroxy-3 - [(phenylmethyl) thio] -6- (3-thienyl) -2H-pyran-2-one,

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) 18-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-naftalénylmetyloxy) 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) 19 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-chloro-phenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one,

4- [4-Hydroxy-2-oxo-3 - [(2-isopropylphenyl) thio] -2H-pyran-6-yl] -2-methylphenoxyacetic acid,

4-Hydroxy-6- [4- (2-hydroxyethoxy) phenyl] -3 - [(2-isopropylphenyl) 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-pyrazinmetoxy) 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- (pyridine-3-)

ylmethoxy) phenyl] -2H-pyran-2-one,

4-Hydroxy-3 - [(2,5-diisopropylphenyl) thio] -6- [4- (pyridine-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- (piperazin-1-yl) ethoxy] phenyl] -2H-pyran-2-one,

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (1,1-dioxo-thiomorpholin-4-yl) ethoxy] phenyl] -2H-pyran-2-6N HCl.

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,

2-oxo-6-phenyl-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one 420

-isopentanoic acid ester,

Propanoic acid 2-oxo-6-phenyl-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one-4-yl ester,

Phenylacetic acid 2-oxo-6-phenyl-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one-4-yl ester,

4-hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6-phenyl-2H-pyran-2-one,

4-hydroxy-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-Hydroxy-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 - [(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 21

2-όη,

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-ylmethyl) 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 _z

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- (pyridine-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- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one,

Acetic acid 3 - [(2-isopropylphenyl) thio] -2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester,

Isobutyric acid 3 - [(2-isopropylphenyl) thio] -2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester,

2,2-Dimethylpropionic acid 3 - [(2-isopropylphenyl) thio] -2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester,

4-Hydroxy-3 - [(2-isopropylphenyl) sulfonyl] -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one,

4-Hydroxy-3- (2-isopropyl-benzoyl) sulfonyl) -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one,

3 - [(2-tert-butylphenyl) sulfonyl] -4-hydroxy-6-phenyl-2H22

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,

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-phenoxy) -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-isopropyl-phenoxy) -2H-pyran-2-one,

6- (1-Benzylpropyl) -3- (2-t-butylphenoxy) -2H-pyran-2-one,

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,

6- (1-Benzylpropyl) -4-hydroxy-3- (1-phenyl-butoxy) -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-323

ylmethoxy) -2H-pyran-2-one,

3- [cyclopentylmethyl- (cyclopropylmethyl) amino] -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one,

6- [l-cyclopropylmethyl-2- (tetrahydropyran-3-yl) ethyl] -3- (cyclopropylphenylamino) -4-hydroxy-2H-pyran-2-one,

Cyclopentylmethyl- [4-hydroxy-2-oxo-6 - [(pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] amide cyclopropanecarboxylic acid,

Cyclopentanecarboxylic acid cyclopentylmethyl- [4-hydroxy-2-oxo-6 - [(pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] amide,

N-Cyclopentylmethyl-N- [4-hydroxy-2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] cyklopentánsulfónamid,

3- (Cyclopropylphenylmethyl) -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

4-Hydroxy-3- (1-phenylpropyl) -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

6- (1,1-Dimethyl-3-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one,

N- [3- [Cyclopropyl [6- (1,1-dimethyl) -3-phenyl-propyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (2-phenylethyl) cyclopentyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

3- (Cyclopropylphenylmethyl) -6- (1,1-dimethyl-3-phenyl-propyl) -4-hydroxy-2H-pyran-2-one,

N- [3 - [[6- (1-Benzenocyclopropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropylmethyl] phenyl] benzenesulfonamide,

6- (1-Benzylpropyl) -4-hydroxy-3- (2-isobutyl-5-isopropyl-phenyl-2H-pyran-2-one,

6- (1-Benzylpropyl) -4-hydroxy-3- (2-methyl-5,6,7,8-tetrahydro-naphthalen-l-yl) -2H-pyran-2-one,

3- (3-Cyclopropylmethyl-5-isopropylphenyl) -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one,

3- (3,5-Diisopropylphenyl) -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -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) cyclopropyl] -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-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- [1- (3-phenylpropyl) cyclobutyl] -2H-pyran-2-one,

4-hydroxy-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-Hydroxy-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,

- (1,1-Diethyl-3-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one,

6- (1-Benzyl-1-ethylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one,

6- (1-Ethyl-1-phenylpropyl) -4-hydroxy-3 - [(2-isopropyl-25 phenyl) thio] -2H-pyran-2-one,

N- [3- [Cyclopropyl [6- (1,1-dimethyl-3-phenylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [6- (1,1-dimethyl-2-phenylethyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-6- (1-methyl-1-phenylethyl) -2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [6- (1,1-diethyl-3-phenylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [6- [1-ethyl-1- (phenylmethyl) propyl] -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [6- (1-ethyl-1-phenylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (2-phenylethyl) cyclopentyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3 - [[6- (1-Benzylcyclopentyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropylmethyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (3-phenylpropyl) cyclopentyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (2-phenylethyl) cyclopentyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3 - [[6- (1-Benzylcyclobutyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropylmethyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (3-phenylpropyl) cyclobutyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl [4-hydroxy-2-oxo-6- [1- (2-phenylethyl) cyclopropyl] -2H-pyran-3-yl] methyl] phenyl] benzenesulfonamide,

N- [3 - [[6- (1-benzylcyclopropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropylmethyl] phenyl] benzenesulfonamide,

N- [3- [Cyclopropyl] -4-hydroxy-2-oxo-6- [1- (3-phenylpropyl) cyclopropyl] -2H-pyran-3-yl [methyl] phenyl] benzenesulfonamide,

3- (Cyclopropylphenylmethyl) -6- (1,1-dimethyl-3-phenylpropyl) -4-hydroxy-2H-pyran-2-one;

3- (Cyclopropylphenylmethyl) -6- (1,1-dimethyl-2-phenylethyl) -4-hydroxy-2H-pyran-2-one,

3- (Cyclopropylphenylmethyl) -4-hydroxy-6- (1-methyl-1-phenylethyl) 26

2H-pyran-2-one,

3- (Cyclopropylphenylmethyl) -6- (1,1-diethyl-3-phenylpropyl) -4-hydroxy-2H-pyran-2-one,

6- (1-Benzyl-1-ethylpropyl) -3- (cyclopropylphenylmethyl) -4-hydroxy-2H-pyran-2-one; and

3- (Cyclopropylphenylmethyl) -6- [1-ethyl-1-phenylpropyl] -4-hydroxy-2H-pyran-2-one.

Unless otherwise stated, the term alkyl, usually represented by R, means a straight or branched hydrocarbon radical containing 1 to 12 carbon atoms and includes e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl , n-nonyl, n-decyl, undecyl and dodecyl. Acyl groups may contain one or more sites of saturation, such as double or triple bonds. The alkyl group is unsaturated with one to three substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen atoms, amino, formyl, carboxyl, nitrile, -NH-CO-R- CO-NH-, -CO _of R, -COR, aryl and heteroaryl, wherein alkyl (R) is as defined above.

Unless otherwise indicated, the term cycloalkyl, also represented by R, means a hydrocarbon ring containing from 3 to 12 carbon atoms and includes e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. If possible, the cycloalkyl group may contain one double bond. The cycloalkyl ring may be unsubstituted or substituted with one to three substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO- , -CO-NH-, -CO ₂ R, -COR, aryl and heteroaryl, wherein alkyl (R), aryl and heteroaryl are as defined above.

The terms alkoxy and thioalkoxy represent O-alkyl or S-alkyl as defined above.

The term alkoxycycloalkyl means a cycloalkyl group attached to an alkyl chain, the terms cycloalkyl and alkyl being as defined above.

The term spirocycle refers to a homocyclic or heterocyclic ring whose ends meet at a single carbon atom in the ring or chain. Examples of such spirocytes may be rings Ά:

The term "aryl" means an aromatic radical by which

is phenyl, benzyl, naphthyl, biphenyl, pyrenyl, anthracenyl, fluarenyl or a fused ring formed by combining any two of the phenyl, naphthyl and five or six membered rings containing from 0 to 3 heteroatoms selected from the group containing quinolines, isoquinolines, indoles, indanes, benzfurans, benzthiophenes, benzoxazoles, benzthiazoles, benzisoxazoles, coumarins, benzimidazoles and the like, unsubstituted or substituted with one to three substituents selected from alkyl, alkoxy, thioalkoxy, thioalkoxy, thioalkoxy, nitro, amino, formyl, carboxyl, nitrile, -NHCOR, -CONHR, -CO ₂ R, -COR, aryl or heteroaryl, wherein alkyl (R), aryl and heteroaryl have the above meaning.

The terms heteroaryl and heterocycle, usually represented by A, containing a ring radical which is a group, 2- or 3-furanyl, a 2-, 4- or 5-imidazolyl group mean a 2- or 3-thienyl 2- or 3-pyrrolyl heteroatom a group, 3-, 4- or

5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-,

4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 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-, 2-, 3-, 4-, 5-, 6-, 7-

7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benz [b] thienyl, 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 or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 1-, 2- or 3-pyrrolidinyl , 2- or 3-tetrahydrofuranyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or

8-tetrahydroquinolinyl and the like. All these groups can be. unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of alkyl as defined above, aryl as defined above, alkoxy as defined above, thioalkoxy as defined, hydroxy, thiol, nitro, formyl, amino, carboxyl, nitrile, -NH, -CO 1 R, -COR, wherein the alkyl group is as defined above or represents a phenyl group.

Halogen means fluorine, chlorine, bromine or iodine.

Certain compounds of Formula 1 are capable of further forming acid addition salts and / or base salts. All of these forms are within the scope of the invention.

Pharmaceutically acceptable acid addition salts of the compounds of formula 1 include salts derived from non-toxic inorganic acids, e.g. hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydrobromic acid, hydrofluoric acid, phosphoric acid and the like, as well as salts derived from non-toxic organic acids, e.g. aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Thus, these salts include sulfate, pyrosulfate, bisulfate, sulfide, bisulfide, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, malonate , fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzsulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartate, methanesulfonate, and the like. Also included are salts of amino acids, e.g. arginate, gluconate, galacturonate and the like. (see eg Berge,

S.M. et al. Pharmaceutical Salts, Journal of Pharmaceutical Science, 66: 1-19 (1977).

The acid addition salts of the above basic compounds are prepared by reacting the free base with a sufficient amount of a suitable acid to form a salt.

Base addition salts are formed using metals or amines, e.g. alkali or alkaline earth metals or organic amines. As the cation, e.g. sodium, potassium, magnesium, calcium and the like. Examples of suitable amines include N, N ¹ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (see, e.g., Berge, SM, et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66). : 1-19 (1977).

The base addition salts of the above acidic compounds are prepared by reacting an acid with a sufficient amount of a suitable base to form a salt.

Certain compounds of the invention may exist in unsolvate as well as solsolvate forms, including hydrated forms. In general, solvate forms, including hydrated forms, are equivalent to unsolvate forms and are within the scope of the invention.

The compounds of the invention may be prepared and administered in a wide variety of oral and parenteral dosage forms.

Some of the compounds of the invention may contain one or more chiral centers, each of which may be in the R (D) or S (L) configuration. The invention encompasses all enantiomeric and epimeric forms as well as corresponding mixtures thereof.

Thus, the compounds of the invention may be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitorally. The compounds of the invention may also be administered by inhalation, e.g. intranasally. The compounds of the invention may optionally be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may contain both the compound of Formula 1 and the corresponding pharmaceutically acceptable salt of the compound of Formula 1 as the active ingredient.

Solid or liquid pharmaceutically acceptable carriers can be used to prepare pharmaceutical compositions from the compounds of the invention. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, or soluble granules. The solid carrier may be one or more substances which may also serve as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is in the form of a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is mixed with a carrier which exhibits the necessary properties in suitable proportions and is compressed to the desired shape.

The powders and tablets preferably contain from about 5% to about 70% by weight of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxycellulose, low melting wax, cocoa butter and the like.

The term formulation includes the formulation of the active compound with the encapsulating material as the carrier that provides the capsule in which the active component (with or without other carriers) is surrounded by the carrier that is associated therewith. Powder wafers or intra-skin systems are included in a similar manner. Tablets, powders, capsules, pills, cachets, and powders may be used as solid dosage forms for oral administration.

A low melting wax, such as e.g. a mixture of fatty acid glycerides or cocoa butter which is first dissolved and then the active component is mixed into it. The molten homogeneous mixture is then poured into molds of the desired dimensions, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions, or emulsions suitable for oral administration - for example, aqueous or propylene glycol aqueous solutions. For parenteral injection, liquid formulations in aqueous polyethylene glycol solution may be used.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable flavoring, coloring, stabilizing and thickening agents as desired.

Aqueous suspensions for oral administration may be prepared by dispersing the active component in finely divided form in water together with a viscous material such as e.g. natural or synthetic gums, resins, methylcellulose, sodium carboxycellulose and other suspending agents known to those skilled in the pharmaceutical art.

Also included are solid form preparations which are converted, shortly before use, to liquid formulations for oral administration.

Such liquid forms include solutions, suspensions, and emulsions.

These preparations may contain, in addition to the active component, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, thickeners, solubilizing agents and the like.

Preferably, the pharmaceutical composition is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a formulation comprising a discrete amount of formulation, e.g. tablets, capsules and powders in vials or ampoules. The unit dosage form may also be a capsule itself, a powder wafer, or a tablet, or it may be an appropriate number of such container forms.

The amount of active component in the unit dosage preparation may be adjusted in the range of from 0.1 mg to 100 mg, preferably from 0.5 mg to 100 mg, depending on the particular application and the efficacy of the active component. The composition may also, if desired, contain other compatible therapeutic agents.

As retroviral protease antagonists, as agents for the treatment of infectious diseases caused by retrovirus, including HIV, or as agents for the treatment of diseases caused by AIDS, the compounds of the invention are administered at an initial daily dose of from about 0.01 mg to about 100 mg. / kg. A daily dose of from about 0.01 mg to about 10 mg / kg is preferred. However, the dosage may be adjusted depending on the requirements of the patient, the severity of the disease being treated and the nature of the compound employed. Determination of the optimal dosage in a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages that are less than optimal. Thereafter, the doses are escalated slowly until an optimum effect is achieved under the given conditions. Alternatively, total daily doses may be divided and administered several times a day.

4.1 General methods for the synthesis of pyrone derivatives

Scheme I below shows

6-substituted-3-substituted pyrones.

training

Scheme I

O L Base OSOU-

TMS-C1 j ³

The ketone I is reacted at -78 ° C to -45 ° C in a solution of ether or tetrahydrofuran with a suitable base such as e.g. lithium diisopropylamide or lithium bis (trimethylsilyl) amide. When the deprotonation is complete, the reaction is terminated by the addition of chlorotrimethylsilane (TMS-C1) at a temperature of -78 ° C to 0 ° C to form the silylenol ether. Optionally, compound I is reacted with trimethylsilyl trifluoromethanesulfonate (TMS-OTf) and triethylamine at 0 ° C in a dichloromethane solution to transform into intermediate II. Compound II is then reacted with an appropriately substituted malonate and is either heated alone or in xylene at 130 ° C to 160 ° C to give the desired product III.

For the purposes of the above synthesis and other syntheses during chemical reactions, reaction intermediates as well as reaction products and protecting groups, which essentially make them reaction conditions.

2nd edition, NY 1991).

serve at and others eg. For example, the formyl compounds of the invention may be starting materials protected using inert groups in Organic Synthesis, John Wiley Sons, New York, protecting groups may be hydroxyl groups, carboxylacyl groups, e.g.

(BOC), -, - trichloroethoxycarbonyl

iodoethoxycarbonyl, aryloxycarbonyl groups, e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl, trialkylsilyl, e.g. trimethylsilyl and tert-butyldimethylsilyl (TBDMS) and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl and benzyl. The protective is removed after completion of the synthetic reaction known to those skilled in the art. BOC group removed by acidolysis, trityl group by hydrogenolysis, group by reaction with zinc fluoride ions.

(See, e.g., Protective TW Grenn and PG Wuts, For example, the following amino protecting groups, reactive groups: group, acetyl trifluoroacetyl group, alkoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, -trichloroethoxycarbonyl group (TCEC) may be. be, for example, a TBDMS and a TCEC group by reaction with

An alternative method of synthesizing functionalized pyrones is shown in Scheme II.

Scheme II

Trimethylsilylenol ether II is reacted in a dry solvent, e.g. ether or tetrahydrofuran at low temperature, preferably -78 ° C to -35 ° C, with malonyldichloride to form pyrone IV, which is converted using a suitably substituted p-toluenethiosulfanate into a sulfur derivative as described in U.S. Pat. 3,931,325 (1976).

Thiosilate reagents may also be prepared as described by M.G. Ranasinghom and P.L. Fuchs in Syn. Comm., 18 (3): 227 (1988). The desired thiols may also be prepared from the corresponding phenol via Newman-Kwart rearrangement (see, e.g., H. Kwart and H. Omura, J. America. Chem., 93: 7250 (1971), MS Newman and FW Hetzel, Org. Synth.Coli.Vol.VI, 824 (1988), MSNewman and HA Karnes, J. Org.Chem. 31, 3980, (1966)) or from the corresponding iodobenzene via a nucleophilic rearrangement with thiourea in the presence of a nickel-based catalyst (K Takagi, Chem. Letters, 1307 (1985).

Scheme III below shows the synthesis of pyrones VIII. R _g may be that in compound VII, aryl, alkyl or substituted alkyl.

Scheme III

wine

The substituted-ketoester VI is deprotonated with one equivalent of a suitable base, e.g. metal hydrido (sodium hydride) in a suitable solvent (ether or tetrahydrofuran). The second equivalent of a stronger base, e.g. alkyllithium (n-butyllithium or lithium diisopropylamide) is added to the malonate solution to form a dianion which is then reacted with a suitable acylating agent e.g. amide, at a temperature of 0 ° C to 25 ° C to give the dione ester VII. Compound VII can then be cyclized to pyrone VIII in various ways, e.g. using a strong acid, such as H ₂ SO ₄ or CH ₃ SO ₃ H, by heating the reaction mixture in a suitable high boiling solvent such as e.g. xylene, or using a small amount of a base, preferably a sterically hindered base, such as e.g. 1,8-diazabicyclo [5.4.0] undec-7-ene. When R ₃ = H, the pyrone VIII can be further derivatized, as shown in Scheme II above.

Scheme IV describes the preparation of O-acylpyrone analogs.

Scheme IV

OH « T 7 II ocr ₇ R s. A .R, 0 II ^R 5 '. ./R

CICR7 base

IX vm

Pyron, e.g. VIII, metal (sodium hydride) e.g. tetrahydrofuran, reacted with a suitable base, e.g. hydride or alkoxide in a suitable solvent, dioxane or ether, and the resulting anion is reacted with an acyl chloride or other acylating agent to give the desired acyl derivative IX.

The diagram below

3-alkylpyrrone derivatives.

V describes the preparation of some

Scheme V

OH

about

I: «for

RgCH.HSR ^ H ₂ NR ₉ -________>

piperidim, HOAc

in M

x.

(where Y = N, S)

XI

The intermediate pyrone Vili in an alcohol environment, e.g. ethanol, is reacted with a suitable aldehyde and a suitable nucleophilic reagent, e.g. HSR _s or NH ₂ R ₉ , in the presence of an acid mixture, e.g. acetic acid and a base, e.g. piperidine. The resulting mixture is heated at 60 ° C to 90 ° C to form pyrone X, which may itself be a preferred compound. X can be in the case where Y = S is reduced by a metal reduction mechanism in a solvent, e.g. using sodium in liquid ammonia, or using Raney nickel in a solvent, e.g. acetone, to give the desired 3-alkylpyrrone XI.

Scheme VI involves the synthesis of certain 3-aminopyrones.

Scheme VI

in M

-about

Manure. HOAc piperidine, HOAc

Sn.HCE

OH

OH i!

N H

RuCOjH

CURRENT O.

NHGRn

ZVI

ABOUT

Ii nhcnr ₁₂ i

XV

The nitration of the pyrone VIII is carried out with nitric acid, preferably fuming nitric acid in an acid solution, as described e.g. in U.S. Pat. 3,206,476 (1965). Reduction of nitropyrone XII with tin or acid affords aminopyrone XIII. Intermediate XIII can be processed into a number of derivatives at this stage. For example, it may be reacted with a suitably substituted aldehyde in the presence of a reducing agent, e.g. sodium borohydride or, preferably, sodium cyanoborohydride, to form N-alkylated analogs XIV. Acylation of compound XIII can be accomplished in several ways: 1. Reaction with sodium hydride followed by treatment with a mixture of a suitable carboxylic acid, N-methylmorpholine and a suitable condensing agent, e.g.

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide at a suitable temperature, e.g. -35 ° C to 0 ° C. 2. Reaction with a suitable acid chloride or other acylating agent in the presence of a base, e.g. triethylamine and 4-dimethylaminopyridine; or 3. Deprotonation with sodium hydride and subsequent reaction with an appropriate acid chloride in the presence of an excess of an amine base, usually triethylamine, at elevated temperature, e.g. 40 ° C to 60 ° C. From aminopyrone XIII, they may be reacted with a suitable isocyanate and a base, e.g. N-methylmorpholine prepared in an inert solvent, e.g. ethyl acetate, ureas of formula XVI.

Scheme VII illustrates an alternative method for preparing C-6-substituted analogs.

Scheme VII

(E = alkyl groups, CO _of H, PhCO)

6-Methylpyrrone XVII is reacted with 2 equivalents of a strong base, e.g. sodium amide in liquid or lithium diisopropyl amide in tetrahydrofuran, the reaction being terminated by the addition of one of a number of electrophilic agents, e.g. alkyl halides, acylating agents, etc., to form pyrone XVIII (see M.P. Wachter and T. H. Harris, Tetrahedron, 26: 1685 (1970)). Alkyl bromination of compound XVII under free radical conditions, e.g. using N-bromosuccinimide, in the presence of a free radical initiator and light, provides intermediate XIX, which can be further processed to the amine XX as described by Jones et al. in Tetrahedron Letters, 30: 3217 (1989), converted to alcohol XXI as described by R. Bacardit et al in J. Heterocyclic Chem., 19: 157 (1982) and finally converted to sulfide XXII as described by R. Bacardit et al. . in J. Heterocyclic Chem., 26: 1205 (1989). The amino and hydroxy substituents of structures XX and XXI may be. further derivatized using conventional reactions known in the art, such as e.g. alkylation, acylation, etc.

Scheme VIII below shows

-substituted-pyrone derivatives.

synthesis of certain

Scheme VIII

OH

in M

SR ,, h

XXIV

Per ₃ / DMF

Y

XXVII

Hj / Pd

Pdä ₂ (PAil>

150 psi CO

Neljas. MeOH

xxvn

Pyrone VIII is activated, e.g. tosylation, to XXIII using p-toluenesulfonyl chloride (TsCl) in pyridine. The tosylate is then reacted with a suitable sulfur nucleophilic reagent (see A.M. Bittencourt et al., Tetrahedron, 27: 1043 (1971)) to form sulfide XXIV. In the same way, the pyrone VIII is converted to the 4-bromo-analogue XXV using a grinding agent, e.g. phosphorus tribromide / dimethylformamide (DMF). Substitution of the bromine of compound XXV with an azide followed by reduction (preferably, for example, by hydrogenation with a palladium catalyst and triarylphosphine in a suitable solvent) affords the 4-amino derivative XXIX. Scheme VI above describes a further functionalization of the amine residue of compound XXIX.

4-Bromopyrone XXV can optionally be reacted with a palladium-triarylphosphine catalyst and methanol under a carbon monoxide atmosphere to form the ester XXVI. The ester may be further hydrolyzed, e.g. in an acid solution at 0 to 25 ° C to give the corresponding carboxylic acid, or reduced, e.g. using a hydride, e.g. lithium aluminum hydride, in tetrahydrofuran or an ether solution at 0-25 ° C to give alcohol XXVII.

Scheme IX derivatives.

shows the preparation of 2H-thiopyran-2-one

Scheme IX

EtO2C _x

CH

I I • i

SH 6 SH

XXX +

Cl OH ^ = A "Μν · R3- < —B ί '== 0 Cl ' r ₆ ^s o XXXI

XXXII

Suitably substituted-mercaptoacrylate, e.g. XXX, is condensed with a suitable malonyl dichloride in an inert solvent, e.g. toluene, at XXXI. Thiopyrone XXXI by alkaline hydrolysis of F.K. Splinter converted to o »-. ? LCVCUC11C AAC1 shown in Schemes II, X and VI.

a temperature of about 0 ° C to form the thiopyran-2-one may be under suitable conditions, e.g. and subsequent decarboxylation (see, e.g., Arold, J. Prakt. Chem., 38: 3-4. 142-6)

XXXII. Tiopyróny XXXII (R _a = H) can, ... r -. . . * x / “« 4 ·· r 4 · xx zxx x * —x xx Á z — xv »“ xxr 4- xrv * x z-xx x “X 4— 4 * TXX x * -x zx 4“ xxv— x zx xr

OV ^ JC 0 UJJ0 U 1 UUU V U1XC UCL1VUU./ -L U -LLLL O L- «χ ^ V and H. derivative

Suitably protected pyrones, e.g. XVII, as well as their analogs containing a sulfur atom instead of an oxygen atom in the pyrone ring at the 1-position, can be thiolated; the carbonyl group at the 2-position of the heterocycle may be substituted with a ticarbonyl group (C = O → C = S) using standard group modification procedures, e.g. using a tinting agent such as e.g. Lawesson reagent, under suitable reaction conditions (see Monatsh. Chem., 115: 769 (1984) and Chem. Rev. 84: 17 (1984)).

General methods for the preparation of functionalized pyrones

Method A: Synthesis via reaction of silylenol ethers with

2-substituted propanedioic acid esters

i) Preparation of trimethylsilylenol ethers

To a solution of the appropriate ketone (10 mmol, 1 equivalent) in dry tetrahydrofuran (100 mL) was added lithium hexamethyldisilazide (11 mmol, 1.1 equivalents) at 78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour and at -35 ° C for 0.5 hour. Trimethylchlorosilane is then added dropwise at -78 ° C and the mixture is stirred for 1 hour at -78 ° C and for 0.5 hour at 0 ° C. The reaction is interrupted by the addition of a saturated solution

4b sodium bicarbonate and the reaction mixture dried with 300 mL ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated under reduced pressure and the isolated material was dried to dryness (for 1 hour) and used without further purification.

ii) Condensation of trimethylsilylenol ether with dialkyl esters

2-substituted propanedioic acid

Crude trimethylsilylenol ether (11 mmol, 1.1 equivalents), prepared as described above, is reacted with a dialkyl ester

Of 2-substituted propanedioic acid (10 mmol, 1.0 equivalent). The resulting mixture was heated to 150 ° C under a stream of nitrogen overnight. The reaction mixture was cooled to ambient temperature and the product was purified by silica gel chromatography. Elution using 10-15% ethyl acetate / hexane removes unreacted starting materials and other impurities and eluting with 30-50% ethyl acetate / 5% methylene chloride / hexanes provides further purification to give the desired pyrones in 20-75% yield.

Method B: Sulfenylation of 6-aryl-4-hydroxy-2H-pyran-2-one

i) Preparation of 6-aryl-4-hydroxy-2-pyrone

Trimethylsilylenol ether (20 mmol, 1 equivalent), prepared as described in Method A (or commercially available), is introduced into anhydrous ethyl ether and cooled to -78 ° C to -40 ° C. Malonyldichloride (30-40 mmol, 1.5-2 equivalents) was added dropwise. The reaction mixture was gradually warmed to ambient temperature and stirred at ambient temperature overnight. The solid obtained is filtered and washed with anhydrous ether.

ii) Sulfenylation of 6-aryl-4-hydroxy-2H-pyran-2-one

6-aryl-4-hydroxy-2-pyrone, prepared as described above (1.62 mmol, 1 equivalent), was dissolved in ethanol. To this solution was added 1N sodium hydroxide (1.72 mmol, 1.04 equivalents) or 2 equivalents triethylamine followed by the appropriate thiosulfonate (1.72 mmol, 1.04 equivalents). The reaction mixture is heated at reflux overnight. The solvents were evaporated, acidified with 1N hydrochloric acid, and the product was extracted with ethyl acetate. After evaporation of the solvents, the crude product is purified by chromatography (silica gel: 200-400 mesh) using 30-50% ethyl acetate in hexanes to give the desired product. Yields: 40-80%.

Method C: Preparation of (6-aryl-4-hydroxy-2-oxo-2H-pyran-3-yl) arylthiomethanes

To 6-aryl-4-hydroxy-2H-pyran-2-one (2.16 mmol, 1 equivalent) in 10 mL of ethanol was added the appropriate aldehyde (2.37 mmol, 1.1 equivalents), the corresponding thiol (5, 10, 10, 10, 10, 10, 10). 62 mmol, 2.6 equivalents) piperidine (0.50 mL) and acetic acid (0.50 mL). The reaction mixture is stored at 80 ° C for 24 hours. The ethyl alcohol is evaporated, acidified with 1N hydrochloric acid, and the residue is purified by chromatography (silica gel: 230-400 mesh) to give the desired product in a yield of 35-60%.

Method D: Preparation of 6-aryl-3-alkylamino-4-hydroxy-2H-pyran-2-ones

i) 6-Aryl-4-hydroxy-3-nitro-2H-pyran-2-one

The method is taken from U.S. Pat. No. 3,206,476 (1965), dealing with 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 was filtered. The product is then purified by recrystallization from boiling acetic acid.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, d-TFA, delta values)

7.02 (s, 1 H)

7.65 (s, 3H).

7.99 (m, 2H); i) 3-Araino-6-aryl-4-hydroxy-2H-pyran-2-one

To a suspension of 6-Aryl-4-hydroxy-3-nitro-2H-pyran-2-one (10.5 mmol, 1 equivalent) in acetic acid (15 mL) and concentrated hydrochloric acid (7.34 mL) was added soft. tin (20.6 mmol,

1.96 equivalents). The mixture is heated to reflux to form a homogeneous mixture. The reaction mixture is thus heated for 7 minutes and then cooled in an ice bath. Concentrated hydrochloric acid was added to give a precipitate of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one hydrochloride, which was then dried.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, D _and O, delta values)

6.74 (s, 1 H)

7.53 (m. 3H)

7.84 (m, 2H) i) 3-Alkylamino-6-aryl-4-hydroxy-2H-pyran-2-ones

To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one hydrochloride (2 mmol, 1 equivalent) in dimethylformamide containing 1% acetic acid (20 mL) was added aldehyde (2.1-4, 2 mmol, 1.05 to 4.2 equivalents) followed by sodium cyanoborohydride (2.1 to 4.2 mmol, 1.05 to 2.1 equivalents). The reaction mixture was stirred for 5 minutes, then quenched with water and concentrated in vacuo. The oily residue is diluted with 100 ml of ethyl acetate, washed with water, saturated with sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product is purified by either column chromatography (silica gel: 230-400 mesh) or recrystallization to give the desired product.

Method E: 3-Acylamino-6-aryl-4-hydroxy-2H-pyran-2-ones

The procedures below are used to amidate 3-amino-648

-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, 1.0 equivalent) in tetrahydrofuran (10 mL) was added 60% sodium hydride (0.92 mmol, 1.1 equivalents). The mixture was stirred at ambient temperature for 30 minutes. In a separate flask, to the appropriate carboxylic acid (1.67 mmol, 2 equivalents) in tetrahydrofuran (20 µμ) is added N-methylmorpholine (0.92 mmQ1> 1.1 equivalents) at -20 ° C, and

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.92 mmol, 1.1 equivalents). The reaction mixture was stirred at -20 ° C for 1 µl. This solution is, for example, <34 K of the reaction

3-phenylethylamine-6-aryl-4-hydroxy-2H-pyran-2-one. Additional N-methylmorpholine (0.918 mmol, 1.1 equivalents) was added and the reaction was stirred at ambient temperature overnight. The reaction was quenched by addition of brine and dissolved in ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water, saturated sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product is purified by column chromatography (silica gel: 230-400 mesh) to give the desired product.

b) To a suspension of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one monohydrogen chloride (0.83 mmol, 1.0 equivalent) in methylene chloride (8 mL) was added triethylamine (3.3 mmol). , 4.0 equivalents) followed by a catalytic amount of 4-dimethylaminopyridine equivalent) and the corresponding acid chloride equivalent). The reaction mixture was stirred at ambient temperature for 6 hours (0.08 mmol, 0.1 (0.92 mmol, 1.1). To the reaction mixture was added 1N hydrochloric acid, and then the mixture was diluted with methylene chloride.

c) To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one monohydrogen chloride (0.63 mmol, 1.0 equivalent) in tetrahydrofuran, washed with water and saturated sodium chloride, and then dried over anhydrous. magnesium sulfate. After evaporation of the solvents in vacuo, the crude product is recrystallized from boiling acetic acid.

(6 mL) at 0 ° C was added 60% sodium hydride (0.69 mmol, 1.1 equivalents). The resulting mixture was stirred at ambient temperature for 15 minutes. To the reaction mixture was added the corresponding acid chloride (0.69 mmol, 1.1 equivalents). At room temperature, the reaction mixture is heated at 50 ° C overnight for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was then diluted with ethyl acetate. The organic layer was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After drying the solvents in vacuo, the crude product is recrystallized from boiling nitromethane to give the pure product.

Method F: Preparation of 3-alkyl-6-aryl-4-hydroxy-2H-pyran-2-ones

I (6-aryl-4-hydroxy-2-oxo-2H-pyran-3-yl) arylthiomethanes were prepared as described in Method C. Raney-Nickel (Grace 3100) was boiled in acetone for 45 minutes and replaced with acetone. ml of ethanol. (4-Hydroxy-6-substituted-2-oxo-2H-pyran-3-yl) arylthiomethane (1.0 mmol, 1 equivalent) was added and the resulting suspension was stirred overnight. heated to reflux. The mixture was filtered through Celite and washed with hot ethanol. The filtrate is concentrated in vacuo to give pure products.

Method G: Preparation of 4-acyloxyesters of 4-hydroxy-3-aryl (or arylalkyl) thio-6-aryl-2H-pyran-2-one

Dissolve 4-hydroxy-3-aryl (or arylaclyl) thio-6-aryl-2H-pyran-2-one (3 mmol, 1 equivalent) in 20 mL of tetrahydrofuran and cool to 0. To this mixture was slowly added sodium hydride (3.3 mmol, 1.1 equivalents) and the resulting mixture was stirred at ambient temperature for 15 minutes. The corresponding acid chloride (6 mmol, 2 equivalents) was then added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction is quenched by addition of saturated sodium chloride solution and the mixture is diluted with 100 mL of ethyl acetate. The combined organic layer was washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the crude product was purified by column chromatography (silica gel: 230-400 mesh) of ethyl acetate in hexane as eluents to give a yield of 70-85%.

Preparation of starting materials

Examples A-E. Preparation of Propanedioic Acids

The following key intermediates were synthesized as described in Comptus rendus, 255: 2611 (1962).

using the enol ester method

Example A

[(Phenylmethyl) thio] propanedioic acid diethyl ester, 160-162 / 798 Pa ¹ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

1.18 (T, 6H) 4.44 (WITH, 1H) 3.93 (WITH, 2H) 7.31 (M, 5H) 4.13 (Q / 4H)

Example B φ [(2-Naphthalenylmethyl) thio] propanedioic acid dimethyl ester

Crude product (silica gel: 230-400 ^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

3.65

4.10

4.55 (s, (s, (s, purified by silica gel mesh chromatography)).

6H)

2H)

1H)

7.51 (m, 3H)

7.87 (m. 4H)

Example C

[(3-Phenylpropyl) thio] propanedioic acid diethyl ester

bp 185-190 / 133 Pa, 1 H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.17 (t, 6H) 4.14 (q, 4H) 1.82 (m, 2 H) 4.62 (s, 1H) 2.65 (q, 4H)

Example D

The diethyl ester of [(2-naphthalenyl) thio] propanedioic product is purified by silica gel chromatography

230-400 mesh).

Crude (silica gel: ¹ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

1.09 (T, 6H) 7.58 (M, 3H) 4.12 (Q, 4H) 7.90 (M, 3H) 5.27 (with, 1H) 8.80 (with, 1H)

Example E

[(2-Phenylethyl) thio] propanedioic acid diethyl ester b.p. 160 - 165/133 Pa ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.19 (t, 6H) 4.68 (s, 1H)

2.89 (m, 2H) 7.25 (m, 5H)

4.16 (q, 4H)

Examples F-M: Preparation of p-toluenethiosulfonates

The following p-toluenethiosulfonates are synthesized as described in U.S. Pat. 3,931,235 (1976).

Example F

2-Phenoxyethyl-β-1-toluenesulfonate ^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.41 (WITH, 3H) 6.94 (T, 1H) 3.41 (T, 2H) 7.27 (T, 2H) 4.13 (T, 2H) 7.48 (D, 2H) 6.83 (D, 2H) 7.85 (D, 2H)

Example G

3-Phenyl-2-propenyl-p-toluenethiosulfonate ^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.32 (with, 3H) 7 29 (M, 5H) 3.93 (D, 2H) 7 38 (D, 2H) 6.00 (Dt, 1H) 7 81 (D, 2H) 6.58 (D, 1H)

Example H

2- [2-Methoxyphenyl] ethyl p-toluenethiosulfonate ^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.43 (WITH, 3H) 6.93 (D, 1H) 2.80 (T, 2H) 7.02 (D, 1H) 3.19 (T, 2H) 7.21 (T, 1H) 3.75 (with, 3H) 7.49 (D, 2H) 6.83 (T, 1H) 7.81 (D, 2H)

Example I

4-Phenylbutyl-p-toluenethiosulfonate ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.53 (m, 4H)

2.43 (s, 3H)

7.18 (d, 2H).

7.25 (t, 2H).

2.50 (T, 2H) 7.45 (D, 2H) 3.03 (T, 2H) 7.80 (D, 2H) 7.12 (D, 1H)

Example J

2- [3-Methoxyphenyl] ethyl-p-toluenethiosulfonate ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.43 (with, 3H) 6.73 (M, 3H) 2.79 (T, 2H) 7, 19 (M, 1H) 3.25 (T, 2H) 7.49 (D, 2H) 3.73 (WITH, 3H) 7.83 (D, 2H)

Example K

2- [4-Methoxyphenyl] ethyl p-toluenethiosulfonate ¹ H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.50 (s, 3H)

6.83 (t, 2 H)

2.76 (t, 2 H)

7.03 (t, 2H).

3.21 (t, 2H).

7.50 (t, 2 H)

3.71 (s, 3H)

7.82 (d, 2 H)

Example L

2- (2-Chlorophenyl) ethyl p-toluenethiosulfonate ¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.43 (s, 3H)

7.22 (m, 4H)

2.86 (t, 2 H)

7.49 (d, 2H).

3.28 (t, 2H).

7.83 (d, 2 H)

Example M [4- (Phenylmethoxy) phenyl] methyl-p-toluenethiosulfonate. @ 1 H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.41 (WITH, 3H) 7.13 (D, 2H) 4.28 (WITH, 2H) 7,3 7 (M, 7 H) 5.06 (with, 2H) 7.72 (D, 2H) 6.78 (D, 2H)

Example N

6- (3-Chloro-phenyl) -4-hydroxy-2H-pyran-2-one

19.7 mmol) v

A suspension of 60% sodium hydride (0.790 tetrahydrofuran (50 mL) under nitrogen atmosphere) was cooled to 0 and treated with acetoacetate (2.51 mL, 19.7 mmol) and the resulting solution was gradually treated with n-BuLi (12.3 mL). , 19.7 mmol) and stirred for 20 min at 0 ° C. The resulting solution was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (2.50 g, 15.15 mmol) in tetrahydrofuran. (5.0 mL) The mixture was allowed to warm to ambient temperature when stirred for 14 hours before 2N hydrochloric acid was added, the product was extracted with 3 NaOH and combined with x 50 mL of ethyl acetate, the layers were combined, dried with sulfate solvent The residue is then left with concentrated sulfuric acid (20 ml) and stirred for 18 hours at ambient temperature before 200 ml of water, the product is then extracted 3, combined and diluted with acetone which is dried over sodium sulfate. The diluent removes and solid product recrystallizes (1.33 g, diluted with x100 mL ethyl acetate) to give a homogeneous solid, m.p. 254 Layers of solution, vacuum acetone / hexane to give the title compound

256 ° C).

@ 1 H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta)

11.957 (bs, 1 H)

7.889 (t, 1H, J = 1.5Hz)

7.839 - 7.813 (m, 1H)

7.598 - 7.524 (m, 2H)

7.876 (d, 1H, J = 2 Hz)

5.450 (d, 1H, J = 2 Hz)

Example O

6- (4-Chlorophenyl) -4-hydroxy-2H-pyran-2-one

The title compound (1.56 g, mp 247-249 ° C) was prepared N using the following compounds: 60% mmol), tetrahydrofuran (50 mL), mmol), lithium diisopropylamine in mL, 24 mmol), (3.73 g, 22.6 mmol), 90% sulfuric acid (20 mL).

'H-Nuclear Magnetic Resonance Spectrum:

6.812 (d, 1H, J = 2 Hz) 5.409 (d, 1H, J = 2 Hz) in a manner similar to that of sodium hydride (0.904 g, 22.6 ethyl acetoacetate (3.00 g, 22.6 tetrahydrofuran (39.8))

4-chloro-N-methoxy-N-methylbenzamide (300 MHz, DMSO-d6, delta) 11.950 (bs, 1H)

7.878 (d, 1H, J = 9 Hz)

7.584 (d, 1 H, J = 9 Hz)

Example P (Cyclopropylmethyl) -p-toluenethiosulfonate

To a solution of methylcyclopropyl bromide (4.00 g, 29.6 mmol) in ethanol (20 mL) was added potassium thiosylate (10.0 g, 44.4 mmol) and the mixture was heated at 90 ° C for 10 h. The mixture was then partitioned into a 1: 1 mixture of water (50.0 mL) and diethyl ether (50 mL). The layers were separated and the organic layer was washed with brine (50.0 mL). The organic layer was then dried over magnesium sulfate and concentrated in vacuo to give the title compound and concentrated in vacuo to give the title compound as a solid (5.2 g, mp 46-48 ° C).

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.816 (d, 2H, J = 8.8 Hz) 1.010-0.933 (m, 1H)

7.308 (d, 2H, J = 8.8 Hz) · 0.592-0.545 (m, 2H)

2.945 (d, 2H, J = 7.6 Hz) 0.236-0.197 (m, 2H)

2.451 (S, 3H)

Example Q

Methyl [4- (1-oxoethyl) phenoxy] -acetate

A mixture of 4-hydroxypropiophenone (10.0 g, 60.24 mmol), cesium carbonate (21.6 g, 66.3 mmol) and acetone (150.0 mL) is treated with methyl bromoacetate (7.26 mL, 78) under a nitrogen atmosphere. (3 mmol) and the mixture was heated to reflux for 4 h. The mixture was then allowed to cool to ambient temperature, diluted with 150 mL of water and extracted with dichloromethane (2 x 300 mL). The organic layers were combined, dried over sodium sulfate and the solvent removed in vacuo to give the title compound (12.75 g, mp. 64-66 ° C). 'H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

9.35 (d, 2H, J = 8.9 Hz) 2.981 (q, 2H, J = 7.2 Hz)

7,040 (d, 2H, J = 8.9 Hz) 1.071 (t, 3H, J = 7.2 Hz)

4.920 (s, 2H); 3.715 (s, 3H)

Preparation of Specific Pyrone Derivatives

Example 1

6- (3-Chlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

Using Method A, a solution of 3'-chloroacetophenone (1.50 g, 11.6 mmol) in tetrahydrofuran (10.0 mL) was cooled to -78 ° C (nitrogen atmosphere) and treated with a 1.0 M solution of lithium hexamethyldisilazide (12.5 mL). mL, 12.5 mmol) in tetrahydrofuran. The solution was warmed to 0 ° C, stirred for 15 minutes and then treated with trimethylsilyl chloride (1.47 mL, 11.6 mmol). The reaction mixture was stirred for 0.5 h (ambient temperature) and gradually poured into a mixture of diethyl ether (50 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated and the organic layer was washed with a 1: 1 mixture of brine and saturated sodium bicarbonate (20 mL). The ether solution was dried over sodium sulfate and the solvent was removed in vacuo. The resulting silylene ether was then transferred to a flask containing diethyl 2- (thiobenzyl) propane-1,3-dioate (1.63 g, 5.80 mmol). The resulting mixture was heated to 160 ° C for 16 hours and then allowed to cool to ambient temperature, then diluted with 20 mL diethyl ether and extracted with saturated sodium carbonate (3 x 20 mL). The aqueous layer was acidified with concentrated hydrochloric acid to pH 0 and then extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate and the solvent was removed in vacuo. The resulting residue was chromatographed (SiO ₂ : 230-400 mesh, 100% CH ₂ Cl ₂ , 1% MeOH / CH ₂ Cl _a ) to give a solid which was recrystallized from acetone / hexanes to give 0.436 g (m.p. 136-137 ° C) of the desired compound. ¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 11.950 (bs, 1 H) 7.271-7.185 (m, 5H) 7.814 (s, 1 H) 6.811 (s, 1 H) 7.761 (d, 1H, J = 7.5 Hz) 4.023 (S, 2H) 7.616 - 7.534 (m, 2H) Example 2

6- (2-Chlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound (0.210 g, mp 99-101 ° C) was prepared via Method A using 2'-chloroacetophenone (1.50 mL, 11.6 mmol), 1.87 M potassium hexamethyldisilazide (6.80 mL, 12.7 mmol) , trimethylsilyl chloride (1.47 mL, 11.6 mmol), tetrahydrofuran (10.0 mL) and diethyl 2- (thiobenzyl) propane-1,3-dioate (1.3 g, 4.63 mmol).

^ Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

12.153 (bs, 1H) 7.276-7.206 (m, 5H)

7.639 (t, 2H, J = 9 Hz) 6.558 (s, 1H) 7.572-7.477 (m, 2H) 4.029 (s, 2H) Example 3

6- (3,4-Dichlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound (0.201 g, mp 185-186 ° C) was prepared via Method A using 3 ^L , 4'-dichloroacetophenone (1.5 g, 7.9 mmol), 1.0 M lithium hexamethyldisilazide (8.7 mL, 8.69). mmol), trimethylsilyl chloride (1.0 mL, 7.9 mmol), tetrahydrofuran (10.0 mL) and diethyl 2- (thiobenzyl) propane-1,3-dioate (0.89 g, 3.2 mmol). ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

12.00 (bs, 1H) 7.265-7.179 (m, 5H)

8.018 (s, 1 H) 6.839 (s, 1 H)

7.784 (s, 2H); 4.017 (s, 2H)

Example 4

4-hydroxy-6- (3-methoxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The desired compound (0.400 g, mp 146-147 ° C) was prepared via Method A using 3'-methoxyacetophenone (1.5 mL, 10.9 mmol), potassium hexamethyldisilazide (6.41 mL, 12.0 mmol), trimethylsilyl chloride ( 1.38 mL, 10.9 mmol), tetrahydrofuran (10.0 mL) and diethyl 2- (thiobenzyl) propane-1,3-dioate (1.23 g, 4.36 mmol).

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.880 (bs, 1 H) 7.109 (m, IH) 7.445 (t, 1H, J = 8 Hz) 6.770 (s, 1 H) 7.370 (d, 1H, J = 8 Hz) 4.020 (s, 2H) 7.286-7.094 (m, 6H) 3.831 (s, 3H)

Example 5

4-hydroxy-3 - [(phenylmethyl) thio] -6- (3,4,5-trimethoxyphenyl) -2H-pyran-2-one

The title compound (0.385 g, mp 156-157 ° C) was prepared via Method A using 3 ', 4', 5'-trimethoxyacetophenone (2.0 g, 9.5 mmol), potassium hexamethyldisilazide (5.6 mL, 10 mL), 45 mmol), trimethylsilyl chloride (1.2 mL, 9.5 mmol), tetrahydrofuran (15 mL) and diethyl 2- (thiobenzyl) propane-1,3-dioate (1.07 g, 3.80 mmol). ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.778 (be, 1H); 3.997 (s, 2H)

7.265-7.181 (m, 5H) 3.861 (s, 6H)

7.054 (S, 2H); 3.727 (s, 3H)

6.792 (s, 1 H)

Example 6

6- (3-Chlorophenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound (0.138 g, mp 125-127 ° C) was prepared via Method B using 6- (3-chlorophenyl) -4-hydroxy-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) and ethanol (5.0 mL).

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDCl _a , delta values)

7.838 (t, 1H, J = 1.5Hz) 7.207-7.171 (m, 3H) 7.710 (d, 1H, J = 8 Hz) 6.604 (s, 1 H) 7.530 (bs, 1 H) 3.125 (t, 2H, J = 7 Hz) 7.475-7.392 (m, 2H) 2.897 (t, 2H, J = 7 Hz) 7.308-7.260 (m, 2H)

Example

6- (4-Chlorophenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound (0.242 g, mp 161-163 ° C) was prepared via 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) and ethanol (10 mL).

'H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

12.085 (bs, 1H) 6,830 (with, 1H) 7.827 (d, 2H, J = 9 Hz) 3,017 (T, 2H, J = 7.5Hz) 7.605 (d, 2H, J = 9 Hz) 2,785 (T, 2H, J = 7.5Hz) 7.259 - 7.142 (m, 5H)

Example 8

4-hydroxy-6-phenyl-3 - ((phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.00 g, 5.19 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (0.977 g, 3.46 mmol) .

¹ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMS0-d6, delta values)

• 4.00 (with, 2H) 7.53 (M, 3H) 6.74 (WITH, 1H) 7.78 (M, 2H) 7,23 (M, 5H)

Example 9

4-hydroxy-6-phenyl-3 - [(phenylmethyl) amino] -2H-pyran-2-one

The title compound was prepared via Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in dimethylformamide (20 mL) , benzaldehyde (0.233 mL, 2.29 mmol) and sodium cyanoborohydride (0.144 g, 2.29 mmol). MP: 205 ° C.

1 H-Nuclear Magnetic Resonance Spectrum: (250 MHz, DMSO-d6, delta values)

4.37 (WITH, 2H) 7.45 (M, 3H) 6.56 (with, 1H) 7.67 (M, 2H) 7.27 (M, 5H)

Example 10

N- (1,1-Dimethylethyl) -N '- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -N' - (phenylmethyl) urea

To a suspension of 4-hydroxy-6-phenyl-3 (phenylmethyl) amino-2H-pyran-2-one, monochloride (0.153 mmol) in 10 mL of ethyl acetate was added N-methylmorpholine (2.0 mL) and tert-butyl isocyanate (2). , 0 mL). The reaction mixture was stirred for 2.5 hours and then diluted with ethyl acetate. The organic layer was washed with 5% citric acid and 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: 230-400 mesh) using 5% methanol in dichloromethane as eluents.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

1.24 (S, 8H) 7,23 (M, 5H) 4.47 (dd, 2H) 7.51 (M, 3H) 5.45 (bs, 1 H) 7.75 (M, 2H)

Example 11

4-hydroxy-3 - [(2-naphthalenylmethyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (0.475 g, 2.46 mmol) and [(2-naphthalenylmethyl) thio] propanedioic acid dimethyl ester (0.500 g, 1.64 mmol) . MP: 250 ° C.

'H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.06 (WITH, 2H) 6.47 (WITH, 1H) 7.46 (M, 6H) 7.78 (M, 6H)

Example 12

4-hydroxy-3 - [(2-naphthalenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.33 g, 6.90 mmol) and [(2-naphthalenyl) thio] propanedioic acid diethyl ester (2.00 g,

6.29 mmol). MP: 246 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.95 (Sl) 7.38 (M, 3H) 7.56 (M, 4H) 7.85 (M, 5H)

Example 13

4-hydroxy-3 - [(phenylmethyl) thio] -6- (2,4,6-trimethyl-phenyl) -2H-pyran-2-

-one

2.11 (s, 6H)

6.96 (s, 2H).

2.26 (s, 2H)

3.98 (s, 2H)

7.25 (m, 5H)

11.85 (bs, lH)

The title compound was prepared via Method A using 2 ', 4', 6 '- trimethylacetophenone (1.86 g, 11.5 mmol), lithium bis (trimethylsilyl) amide (2.11 g, 12.65 mmol), chlorotrimethylsilane (1.60 mL, 12.65 mmol), tetrahydrofuran (127 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (2.95 g,

10.4 mmol). MP: Mp 134-136 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.03 (S, 1 H)

Example 14

4-Hydroxy-6- [4- [2- (4-morpholinyl) ethoxy] phenyl] -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4- [2- (4-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), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.35 g,

4.80 mmol). MP: (decomposition) 207 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

2.54 (WITH, 2H) 4.22 (T, 2H) 6.98 (M, 4H) 6.58 (with, 1H) 2.83 (T, 2H) 7.08 (D, 2H) 3.55 (M, 4H) 7,23 (M, 5H) 3.96 (with, 2H) 7.73 (D, 2H)

Example 15

4-Hydroxy-6- (2-naphthalenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

2-acetylnaphthalen

(2.13 method A, with g, 11.6 mmol), lithium bis (trimethylsilyl) amide

12.76 mmol), chlorotrimethylsilane (1.61 mL,

12.76 mmol), tetrahydrofuran (127 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (2.90 g,

10.5 mmol). MP: (decomposition) 203 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.04 (S, 2H) 7.84 (D, 2H) 6.89 (S, 1 H) 8.05 (M, 3H) 7,23 (m, 5H) 8.43 (with, 1H)

7.61 (m. 2H)

11.95 (bs, 1 H)

Example 16

4-Hydroxy-6-phenyl-3 - [(phenylthio) methyl] -2H-pyran-2-one

The title compound was prepared via 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), piperidine (0.50 mL) and acetic acid (0.5 mL).

MP: (decomposition) 211 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO ~ d6, delta values)

3.98 (WITH, 2H) 7.37 (m, 2H) 6.73 (with, 1H) 7.54 (m, 4H) 7.17 (M, 1H) 7.77 (m, 2H) 7.30 (M, 2H) 12.05 (bs, 1 H)

Example 17

4-Hydroxy-6- (4-hydroxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11 mL), m.p. , 6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 204 ° C.

^X H-Nuclear magnetic resonance spectrum:

(250 MHz, DMSO-d6, delta values)

3.96 (WITH, 2H) 7.63 (d, 2 H) 6.55 (with, 1H) 10.28 (s, IH) 6.88 (D, 2H) 11.75 (bs, 1 H) 7.39 (M, 5H)

Example 18

4-Hydroxy-6- (4-methoxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via 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). , tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 187 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 3.83 (with, 3H) 7.22 (m, 5H) 3.98 (with, 2H) 7.73 (m, 2H) 6.62 (with, 1H) 11, 76 (bs, 1 H) 7.06 (M, 2H)

Example 19

4-Hydroxy-6- (4-methylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-6N HCl

The title compound was prepared via 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) , tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 205 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 2.37 (with, 3H) 7.26 (m, 6H) 3.99 (with, 2H) 7.68 (m, 2H) 6.69 (with, 1H) 11.83 (bs, 1 H)

Example 20

3- [Bis (phenylmethyl) amino] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), 1% acetic acid in dimethylformamide (7 mL) , benzaldehyde (0.133 mL, 1.33 mmol), sodium cyanoborohydride (0.083 g, 1.31 mmol). MP: (decomposition) 130-135 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.26 (with, 4H) 6.44 (with, 1H) 7.24 (M, 6H) 7.44 (M, 7 H) 7.69 (M, 2H)

Example 21

4-Hydroxy-6-phenyl-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (7 mL), 1 N hydroxide

2-phenylethyl p-toluenethiosulphonate (0.77 <

decomposition) 121-124 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta) Method B, (0.500 sodium 2.65 with g, 2.65 mmol), (2.65 mL), mmol. MP: (at

2.78 (T, 2H) 7.24 (M, 5H) 2.99 (T, 2H) 7.54 (M, 3H) 6.80 (with, 1H) 7.80 (M, 2H)

Example 22

4-Hydroxy-6-phenyl-3 - [(3-phenylpropyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (0.922 g, 4.83 mmol) and [(3-phenylpropyl) thio] propanedioic acid diethyl ester (1.00 g,

3.22 mmol). MP: Mp 114-116 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

1.73 (M, 2H) 7.25 (m. 2H) 2.71 (M, 4H) 7.54 (m. 3H) 6.82 (M, 1H) 7.81 (m. 2H) 7.16 (M, 3H) 11.95 (bs, 1 H)

Example 23

4-Hydroxy-3 - [(2-phenoxyethyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL, 2.65 mmol)

2-Phenoxyethyl p-toluenethiosulfonate (0.816 g, 2.65 mmol). MP: 146-149 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3 12 (T, 2H) 7.24 (m, 2H) 4. 11 (T, 2H) 7.54 (m, 4H) 6. 81 (T, 2H) 7.81 (m, 2H) 6. 88 (M, 3H) 12.04 (bs, 1 H)

Example 24

4-Hydroxy-6- (2-methylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via 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) , tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.34 (s, 3H)

4.01 (s, 2H).

6.31 (s, 1H)

7.33 (m, 9H)

Example 25

4-Hydroxy-6- (2-phenylethyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4-phenethylacetophenone (0.786 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: Mp 164-166 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.75 (T, 3H) 5.92 (S, 1 H) 2.85 (T, 2H) 7,23 (m, 8H) 3.92 (with, 2H) 11.69 (bs, 1 H)

Example 26

4-Hydroxy-6- (3-hydroxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3 ^1- hydroxy-acetophenone (0.772 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11 mL), m.p. 6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). Mp (dec.) 185 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

4.00 (with, 2H) 6.66 (WITH, 1H) 6.92 (M, 1H) 7.21 (M, 7 H) 7.32 (M, 1H)

Example 27

4-Hydroxy-6- (4-hydroxyphenyl) -3 - [(phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4'-hydroxyacetophenone (0.688 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (1.84 g, 11.1 mmol), tetrahydrofuran (111 mL), and diethyl ester. [(2-phenylethyl) thio] propanedioic acid (1.00 g, 3.37 mmol).

^X H-Nuclear Magnetic Resonance Spectrum:

7.21 (m, 5H)

7.65 (d, 2H).

10.22 (s, 1H)

11.05 (bS, 1H) (400 MHz, DMSO-d6, delta values)

2.78

2.95

6.62

6.89

2H)

2H)

1H) (dd, 2H) (t, (t, (S,

Example 28

4-Hydroxy-6-phenyl-3- [3- (phenyl-2-propenyl) thio] -2H-pyran-2-one, (E) The desired compound was prepared via Method B using 4-hydroxy-6- phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL), 3-phenyl-2-propenyl-p-toluenethiosulfonate (0.808 g, 2.65 mmol). Mp 133-136 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3 57 (d, 2H) 7.24 (M, 5H) 6. 24 (dt, 2H) 7.51 (M, 3H) 6. 76 (S, 1 H) 7.78 (M, 2H)

Example 29

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylmethoxy) phenyl] -2H-pyran-2-one

ΊΟ

The title compound was prepared via 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), tetrahydrofuran (57 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 139-142 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.77 (T, 2H) 7.26 (M, 7 H) 2.98 (T, 2H) 7.43 (M, 5H) 5.19 (WITH, 2H) 7.76 (D, 2H) 6.68 (WITH, 1H)

Example 30

4-Hydroxy-6- [4- (2-phenylethoxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 (2-phenylethoxy) acetophenone (1.21 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), tetrahydrofuran (57 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP:

Mp 103-106 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.76 (T, 2H) 6.67 (with, 1H) 2.97 (T, 2H) 7.21 (M, 12H) 3.06 (T, 2H) 7.73 (D, 2H) 4.27 (T, 2H)

Example 31

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (3-phenylpropoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using 4 '- (3-phenylpropoxy) acetophenone (1.28 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.750 mL, 5.56 mmol), tetrahydrofuran (57 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 139-142 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.04 (M, 2H) 6.68 (WITH, 1H) 2.84 (M, 4H) 7.18 (M, 12H) 2.98 (T, 2H) 7.75 (D, 2H) 4.40 (T, 2H) 11.86 (bs, 1 H)

Example 32

4-Hydroxy-6- (2-hydroxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 2'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11 mL). 6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 189 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

4.01 (with, 2H) 7.71 (d, IH) 6.97 (WITH, 1H) 10.75 (s, 1H) 7.25 (M, 7 H) 11.85 (bs, 1 H)

Example 33

4-Hydroxy-6 - [(2-phenylethoxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3 '- (2-phenylethoxy) acetophenone (0.336 g, 1.40 mmol), lithium bis (trimethylsilyl) amide (0.257 g, 1.54 mmol), chlorotrimethylsilane (0.195 mL, 1.54 mmol), tetrahydrofuran (15 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (0.417 g, 1.40 mmol). MP: Mp 104-106 ° C.

'H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.75 (t, 2H) 6.79 (s, 1H) 2.97 (t, 2H) 7.25 (m, 14H) 3.04 (t, 2H) 11.95 (bs, 1 H) 4.25 (t, 2H)

Example 34

4-Hydroxy-6-phenyl-3- [phenyl (phenylthio) methyl] -2H-pyran-2-one, (+, -) The desired compound was prepared via Method A 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), thiophenol (1.40 mL, 13.8 mmol), piperidine ( 0.5 ml) and acetic acid (0.5 ml). MP: (decomposition) 220 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

5.80 (with, 1H) 6.70 (WITH, 1H) 7,23 (M, 8H) 7, 54 (M, 4H) 7.74 (M, 2H)

Example 35

4-hydroxy-3 - [[2- (2-methoxyphenyl) ethyl] thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL). and

2- (2-methoxyphenyl) ethyl p-toluenethiosulfonate (0.856 g, 2.65 mmol). MP: Mp 114-115 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.74 (T, 2H) 7.15 (M, 2H) 2.94 (T, 2H) 7.54 (M, 3H) 3.73 (WITH, 1H) 7.82 (M, 2H) 6.85 (M, 3H)

Example 36

4-Hydroxy-6-phenyl-3 - [(4-phenylbutyl) thio] -2H-pyran-2-one,

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (7 mL), 1 N hydroxide by method B, with (0.500 g, 2.65 mmol) sodium (2.65 mL). )

4-Phenylbutyl-p-toluenethiosulfonate (0.851 g, 2.65 mmol). MP: 103

105 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.47 (M, 2H) 6.80 (with, 1H) 1.66 (M, 2H) 7.17 (M, 5H) 2.54 (T, 2H) 7.53 (M, 3H)

2.77 (t, 2 H)

7.81 (m. 2H)

Example 37

4-Hydroxy-3 - [[2- (3-methoxyphenyl) ethyl] thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL). and

2- (3-methoxyphenyl) ethyl p-toluenethiosulfonate (0.865 g, 2.65 mmol). MP: Mp 112-113 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.75 (t, 2 H)

7.16 (t, 1 H)

3.01 (t, 2 H)

7.54 (m. 3H)

3.34 (s, 3H)

7.80 (m, 2H).

6.75 (s, 1 H)

Example 38

4-hydroxy-3 - [[2- (4-methoxyphenyl) ethyl] thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL). and

2- (4-methoxyphenyl) ethyl p-toluenethiosulfonate (0.865 g, 2.65 mmol). MP: Mp 144-145 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.71 (T, 2H) 7.12 (D, 2H) 2.96 (T, 2H) 7.54 (M, 3H) 3.66 (with, 3H) 7.80 (M, 2H) 6.77 (WITH, 1H) 6.80 (D, 2H)

Example 39

3 - [[2- (3-Chlorophenyl) ethyl] thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL). and

2- (2-chlorophenyl) ethyl p-toluenethiosulfonate (0.865 g, 2.65 mmol). MP: Mp 134-134 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMS0-d6, delta values)

2.79 (t, 2 H)

3.02 (t, 2H).

7.25 (m, 4H)

7.55 (m. 3H)

Example 40

6.77 (s, 1H)

7.81 (m. 2H)

4-Hydroxy-6-phenyl-3- (2-phenylethyl) -2H-pyran-2-one

The title compound was prepared via Method F using Raney-Nichel (Grace 3100), ethanol (20 mL), 4-hydroxy-6-phenyl-3- [2-phenyl-1- (phenylthio) ethyl] -2H-pyran -2-one (0.425 g, 1.06 mmol). MP: (decomposition) 255 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.65 (dd, 2 H) 7.52 (m, 4H) 2.71 (dd, 2H) 7.76 (m, 2H) 6.68 (s, 1H) 11.85 (bs, 1 H) 7.23 (m, 3H)

Example 41

4-Hydroxy-6-phenyl-3- (3-phenylpropyl) -2H-pyran-2-one

The title compound was prepared via Method F using Raney-Nichel (Grace 3100), ethanol (15 mL), 4-hydroxy-6-phenyl-3- [3-phenyl-1- (phenylthio) ethyl] -2H-pyran -2-one (0.150 g, 0.362 mmol). MP: Mp 195-196 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.73 (M, 2H) 7 23 (M, 5H) 2.40 (T, 2H) 7 52 (M, 3H) 2.60 (T, 2H) 7 74 (M, 2H) 6.68 (with, 1H)

Example 42

6- (2,6-dimethylphenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 2 ', 6'-dimethylacetophenone (0.785 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5 mL), 84 mmol), tetrahydrofuran (58 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: Mp 140-143 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.15 (with, 6H) 3.99 (with, 2H) 6,12 (with, 1H) 7.22 (M, 8H)

Example 43

4-Hydroxy-6- [2-hydroxy-3-methyl-4- (phenylmethoxy) phenyl] -3-4 (2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.56 mmol), lithium bis (trimethylsilyl) amide (2.11 g, 12, 6 mmol), chlorotrimethylsilane (1.60 mL, 12.6 mmol), tetrahydrofuran (127 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 147-148 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.14 (with, 3H) 6.79 (d, 1 H) 2.77 (T, 2H) 7.30 (m, 12H) 3.98 (T, 2H) 9.36 (S, 1 H) 5.17 (with, 2H) 11.85 (bs, 1 H) 5.29 (with, 1H)

Example 44

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [3- (phenylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56) mmol), tetrahydrofuran (57 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 126-127 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 6.81 (with, 1H) 3.01 (T, 2H) 7.22 (M, 6H) 5.20 (WITH, 2H) 7.41 (M, 7 H)

Example 45

4-Hydroxy-6- [4- (2-naphthalenylmethoxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (57 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 152-154 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 77 (T, 2H) 7.21 (M, 7 H) 2 98 (T, 2H) 7.54 (M, 2H) 5 38 (WITH, 2H) 7, 60 (D, 1H) 6. 68 (WITH, 1H) 7.96 (M, 4H)

Example 46

6- (3-Chloro-4-methoxyphenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-chloro-4'-methoxyacetophenone (0.979 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), tetrahydrofuran (58 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 171 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.93 (with, 3H) 7.32 (M, 6H) 3.99 (with, 2H) 7, 77 (D, 1H) 6.68 (with, 1H) 7.83 (D, 1H)

Example 47

4-Hydroxy-6-phenyl-3 - [(phenylmethyl) sulfonyl] -2H-pyran-2-one

The title compound was prepared by oxidizing 4-hydroxy-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-2-one (1 mmol, 310 mg) with oxone (3 mmol, 1.99 g) at ambient temperature. in 10 ml of methanol and 10 ml of water. The reaction mixture was stirred at ambient temperature for 4 hours and then diluted with water and extracted with 50 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and the solvents were evaporated. The resulting solid was purified by thin layer chromatography. Isolated yield: 90%, m.p. Mp 152-153 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDCl ₃ , delta values)

11.34 (s, 1 H) 6.37 (s, 1 H) 7.8 (m. 2H) 6.23 (s, 1H) 7.5 (m, 3H) 4.75 (s, 1H) 7.37 (m, 3H) 4.34 (q, 2H)

7.27 (m, 2H).

Infrared spectrum:

(KBr, cm ^-1 )

3421 1559 689

3059 1497

17261230

1698957

1628770

Mass spectrum:

(CI, m / e)

343 (6.8)

327 (15.54)

278 (15.99)

219 (40.99) (100)

Example 48

4-Hydroxy-6- (3-methylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared by condensation of [(phenylmethyl) thio] propanedioic acid diethyl ester (1 g, 3.54 mmol) with the corresponding trimethylsilylenol ether of 3'-methylacetophenone (7.09 mmol, 1.46 g) via Method A. Yield of the isolated product 65%, tt Mp 137-138 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.9 (brs, 1 H) 7.2 (M, 1H) 7.6 (m, 2H) 6.7 (with, 1H) 7.39 (t, 1 H) 4.0 (with, 2H) 7.35 (d, 1 H) 2.38 (with, 3H) 7.25 (d, 3H)

Infrared spectrum:

(KBr, cm ^x ) 3030 1402 2585 1100 1617 787 1536 696 Mass MS: (Cl, m / e) 325 (64) 291 (1) 233 (3)

119 (9)

Example 49

2-Oxo-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-4-ylpropanedioic acid ester

The title compound was prepared by reacting 4-hydroxy-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-2-one sodium salt (310 mg, 1 mmol) with propionyl chloride (2.4 mmol, 222 mg) as described above. G. Yield of isolated product: 72%.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.77 (m. 2H)

7.51.m (3)

7.22 (m, 4H)

7.17 (m, 1H).

(KBr,

6.7 (s, 1 H)

3.98 (s, 2H)

2.19 (q, 2H)

cm ^x ) 3438 1528 1045 3027 1494 979 2923 1453 873 1772 1153 702 1617 1087

Mass spectrum:

(CI, m / e) 366 (4) 105 (20) 311 (79) 91 (100) 189 (26)

Example 50

4-Hydroxy-6- [3-methyl-4- (phenylmethyloxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

Condensation of [(phenylmethyl) thio] propanedioic acid diethyl ester (1.06 g, 3.6 mmol) with trimethylsilylenol ether 3'-methoxy-4 '

-benzyloxyacetophenone (2.24 g, 7.2 mmol) was carried out via Method A. Yield of the isolated product: 78%, m.p. Mp 147-148 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.63 (M, 2H) 2.98 (T, 2H) 7,11- 7.53 (m, 11H) 2.77 (T, 2H) 6.68 (with, 1H) 2.27 (with, 3H) 5.22 (with, 1H)

Infrared spectrum:

(KBr, cm ^x ) 3432 1626 1140 3030 1503 1024 2922 1408 696 1717 1262 weight MS: (Cl, m / e) 445 (2.12) 189 (8.33) 3,553.34 156 (14.78) 309 (3.81) 137 (16,19) 105 (94.34) 91 (100) Elemental analysis: C (%) H (%) calculated 72.95 5.44 found 72.25 5.43

Example 51

4-Hydroxy-6- (4-hydroxy-2-methylphenyl) -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared by condensation of [(phenylethyl) thio] propanedioic acid diethyl ester (1 g, 3.38 mmol) with the corresponding trimethylsilylenol ether 4'-hydroxy-2'-methylacetophenone (2.94 g, 10 mmol) by Method A.

Isolated product yield: 52%, mp 85-87 ° C. ¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11, 89 (brs, 1 H) 6.33 (WITH, 1H) 9.97 (with, 1H) 3.0 (T, 2H) 7.35 (D, 1H) 2.78 (T, 2H) 7,23 (M, 5H) 2.34 (with, 3H) 6.72 (with, 2H)

Infrared spectrum:

(KBr, cm ^-1 ) 3300 1604 1194 2926 1514 1120 1672 1244 698

Mass spectrum:

(Cl, m / e)

355 (35) 250 (26) 91 85 (30) (100) 105 (93) Elementary calculated calculated . analysis: C (%) 67,78 67.53 H (%) 5.12 5.40

Example 52

4-Hydroxy-6- (4-hydroxy-3-methylphenyl) -3 - [(2-phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared by the condensation of diethyl ester of [(phenylmethyl) thio] propanedioic acid (1 g) with the corresponding trimethylsilyl enol ether of 4'-hydroxy-3 ¹ - -metylacetofenónu way

A. Yield of isolated product: 68%, mp 159-106 ° C. ¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDCl ₃ , delta values)

7.67 (dd, IH) 6.38 (S, 1 H) 7.61 (s, 1 H) 3.96 (s, 2H) 7.2 (m, 5H) 3.89 (S, 3H) 6.8 (d, IH) 2.25 (S, 3H)

Infrared spectrum:

(KBr, cm ^-1 )

3432 1507 1142 2945 1402 1030 1613 1262 812 704 Mass spectrum: (CI, m / e) 355 (78.3) 149 (12.7) 263 (19.6) 91 (100) 235 (11.8) Elemental analysis: C (%) H (%) calculated 67,78 5.12 found 67.35 5.17

Example 53

2-Oxo-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-4-ylacetic acid ester

The title compound was prepared by reacting 4-hydroxy-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-2-one sodium salt (310 mg, 1.00 mmol) with acetyl chloride (188 mg, 2.4 mmol) ) by method G. Yield of isolated product: 72%.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.81 (m, 2H) 3.99 (s, 2H) 7.53 (m, 4H) 1, 92 (S, 3H) 7.22 (m, 3H) 7.16 (m, 1 H)

Example 54

2-Oxo-6-phenyl-2H-pyran-4-yl-1-naphthalenecarboxylic acid ester

The title compound was prepared via Method G using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.250 g, 1.32 mmol), tetrahydrofuran (15 mL), 60% sodium hydride (0.585 g, 1M). , 46 mmol)

1-naphthoyl chloride (0.278 g, 1.46 mmol). Mp 123.5-125 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

6.54 (WITH, 1H) 8.13 (D, 1H) 7.49 (WITH, 1H) 8.34 (D, 1H) 7.65 (M, 6H) 8.50 (D, 1H) 7.95 (M, 2H)

Example 55

3,3'-thiobis [4-hydroxy-6-phenyl-2H-pyran-2-one]

The title compound was synthesized as follows: 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 mixture was stirred at ambient temperature overnight. Unreacted thionyl chloride was removed in vacuo and the residue was recrystallized from boiling methanol. MP: 240 DEG.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, d-TFA, delta values)

7.03 (s, 2H).

7.56 (m, 6H)

7.89 (m. 4H)

Example 56

3,3'-Dithiobis [4-hydroxy-6-phenyl-2H-pyran-2-one] 1

Sulfuric chloride (0.105 mL, 1.32 mmol) was dissolved in 1 mL of benzene and this reaction mixture was added dropwise to a suspension of 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol). ) in 7 ml of benzene, the suspension being previously heated to reflux. The reflux was continued for a further 1.5 hours. The reaction mixture is enriched with a few drops of water and a light brown-brown product is isolated by filtration. The solid product is recrystallized from boiling acetic acid. MP: 280 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.77 (with, 2H) 7.52 (M, 6H) 7.81 (M, 4H)

Example 57

3-Benzoyl-4-hydroxy-6-phenyl-2H-pyran-2-one

To a solution of ethylbenzoylacetate (150 g, 0.88 mmol) in ethyl acetate

1,2-Dichlorobenzene (150 mL) was added sodium bicarbonate. The reaction mixture was refluxed. Isolate about a trace amount to 20 mL of ethanol distillate. The reaction mixture was cooled to 0 ° C. Ether (100 ml) was added for crystallization. The reaction mixture is placed in a refrigerator overnight. The resulting solid was washed with ether. MP: Mp 171-173 ° C.

¹ H-Nuclear. Magnetic Resonance Spectrum: (250 MHz, DMSO-d6, delta values)

6.91 (s, IH)

7.59 (m, 6H)

7.87 (m. 4H)

Example 58

N- (4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) benzeneacetamide

The title compound was prepared via Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one anhydride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348) mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, phenylacetyl chloride (0.106 g, 0.626 mmol). MP: (decomposition) 213 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

3.69 (WITH, 2H) 7.53 (M, 3H) 6.85 (WITH, 1H) 7.83 (M, 2H) 7.29 (M, 4H) 9.40 (Bs, 1H)

Example 59

2-Oxo-6-phenyl-2H-pyran-4-yl-2-naphthalenecarboxylic acid ester

The title compound was prepared via Method G using 4-hydroxy-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), mp 143.5-144 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.51 (with, 1H) 8.80 (M, 7 H) 7.51 (M, 3H) 8.89 (Bs, 1H) 7.72 (M, 3H)

Example 60

3- [Bis (2-naphthalenylmethyl) amino] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via 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) and sodium cyanoborohydride (0.164 g, 2.60 mmol). MP: (decomposition) 209 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.46 (s, 4H) · ’

6.38 (s, IH)

7.44 (m, 8H).

7.77 (m, 13H).

Example 61

N- (4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -2-naphthaleneacetamide

The title compound was prepared via Method E, substituting 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.835 mmol), tetrahydrofuran

0.918 mmol), oxalyl chloride

2-Naphthalylacetic acid (0.170 g, ° C).

(9 mL), (0.080

0,918

60% sodium hydride (0.918 mmol) and mmol). Mp (using (0.200 g, (0.037 mL, decomp. Acid)) 227 ^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.17 (WITH, 2H) 7.93 (D, 1H) 6.84 (WITH, 1H) 8.17 (Á, 1H) 7.50 (M, 6H) 9.58 (with, 1H) 7.83 (M, 4H)

Example 62

N- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -2-naphthalenecarboxamide

The title compound was prepared via Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), tetrahydrofuran (6 mL), 60% sodium hydride (0.028). mL, 0.688 mmol), 2-naphthoyl chloride (0.131 mL, 0.688 mmol) mp (decomposition) 219 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.92 (with, 1H) 8.62 (S, 1 H) 7.61 (M, 5H) 9.61 (S, 1 H) 7.97 (M, 6H)

Example 63

N- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) benzenepropanamide

The title compound was prepared via Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), tetrahydrofuran (6 mL), 60% sodium hydride (0.028). mL, 0.688 mmol), and hydrocinamyl chloride (0.131 g, 0.688 mmol). MP: (decomposition) 191-193 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

2.65 (T, 2H) 7.53 (M, 3H) 2.89 (T, 2H) 7.84 (M, 2H) 6.86 (with, 1H) 9.28 (with, 1H) 7.26 (M, 5H)

Example 64

6- (1,3-benzodioxol-5-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.54 mmol). MP: (decomposition) 170 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.98 (WITH, 2H) 7.27 (M, 7 H) 6.13 (WITH, 2H) 7.05 (D, 2H) 6.61 (WITH, 1H)

Example 65

6- [4- (Benzoyloxy) phenyl] -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran

-2-one

The title compound was prepared via Method A using 4'-benzoyloxyacetophenone (1.27 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84) mmol), tetrahydrofuran (58 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 205 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

4.01 (with, 2H) 7.63 (T, 2H) 6.75 (WITH, 1H) 7.77 (T, 1H) 7.21 (M, 1H) 7.90 (D, 2H) 7.25 (D, 4H) 8.16 (D, 2H) 7.47 (D, 2H)

Example 66

3- [Cyclohexyl (phenylthio) methyl] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclohexanecarboxaldehyde (0.707 mL, 5 mL), 84 mmol), thiophenyl (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: 87-90 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.46 (M, 5H) 7.27 (T, 2H) 1.61 (M, 4H) 7.37 (D, 2H) 2.15 (M, 1H) 7.52 (M, 3H) 2.31 (D, 1H) 7.74 (M, 2H) 4.26 (D, 1H) 11, 80 (B! 5, 1H)

Example 67

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylthio) phenyl] -2H-pyran 90

-2 - όη

The title compound was prepared via Method A using 4 '- (phenylthio) acetophenone (1.15 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.750 mL, 5.56 mmol), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 120-121 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.76 (T, 2H) 7.24 (M, 7 H) 2.98 (T, 2H) 7.45 (M, 5H) 6.72 (with, 1H) 7.74 (D, 2H)

Example 68

4-Hydroxy-6- [4 - [(2-methoxyphenyl) methoxy] phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 '- [(2-methoxyphenyl) methoxy] phenylacetophenone (1.29 g, 5.56 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.06 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: 138-139 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.77 (T, 2H) 7.08 (D, 1H) 2.98 (T, 2H) 7.20 (M, 7 H) 3.83 (with, 3H) 7.53 (T, 1H) 5.14 (with, 2H) 7.40 (D, 1H) 6.68 (WITH, 1H) 7.76 (D, 2H) 6.97 (T, 1H) 11.85 (bs, 1H)

Example 69

4-Hydroxy-6- [4 - [(2-methoxyphenyl) methoxy] -3-methylphenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 ¹ - [(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), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: (decomposition) 170 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 25 (with, 3H) 7.70 (D, 1H) 2 77 (T, 2H) 7.27 (M, 6H) 2 97 (T, 2H) 7.41 (T, 1H) 3 84 (WITH, 3H) 7.43 (D, 1H) 5 17 (WITH, 2H) 7.65 (M, 2H) 6. 67 (WITH, 1H) 11, 81 (bs, 1 H) 6. 98 (T, 1H)

Example 70

6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via 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 mL), 84 mmol), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). MP: (decomposition) 170 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.33 (WITH, 6H) 7.21 (M, 6H) 3.99 (with, 2H) 7.39 (with, 2H) 6.67 (with, 1H)

Example 71

4-hydroxy-6- (4-phenoxyphenyl) -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 ^1- phenoxyacetophenone (1.07 g, 5.06 mmol), lithium bis (trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56) mmol), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). Mp 127-128 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.77 (T, 2H) 7.18 (M, 10H) 2.99 (T, 2H) 7.46 (T, 2H) 6.72 (WITH, 1H) 7.82 (D, 2H)

Example 72

4-hydroxy-6-phenyl-3 - [[[4- (phenylmethoxy) phenyl] methyl] thio] -2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.500 g, 2.65 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.65 mL). and [4- (phenylmethoxy) phenyl] methyl p-toluenesulfonate (1.01 g, 2.65 mmol). MP: Mp 185-186 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3 94 (WITH, 2H) 7.18 (D, 2H) 5 03 (with, 2H) 7.34 (M, 5H) 6. 72 (with, 1H) 7.46 (M, 3H) 6. 89 (D, 2H) 7, 80 (M, 3H)

Example 73

4-hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (2-pyridinylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: (decomposition) 179 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.77 (T, 2H) 7.53 (D, 1H) 2.98 (T, 2H) 7.77 (D, 2H) 5.27 (WITH, 2H) 7.85 (T, 1H) 6.68 (with, 1H) 8.60 (D, 2H) 7.22 (M, 7 H) 11.88 (BI s, 1H) 7,36 (M, 1H)

Example 74

4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxyacetic acid ethyl ester

To a methanol solution (3 mL) of 4-hydroxy-6- (4-hydroxyphenyl) -3 - [(2-phenylethyl) thio] -2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium carbonate. (0.995 g, 2.94 mmol). The reaction mixture was stirred for 3 hours and then concentrated in vacuo. 15 ml of dimethylformamide are then added and the solid is again concentrated to dryness under vacuum. The solid was then diluted with 3 mL of dimethylformamide and bromoacetate (0.491 mL, 2.94 mmol). The suspension is stirred for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 mL). The organic layer was washed successively with 1N hydrochloric acid, water, and saturated sodium chloride. It is then dried over anhydrous magnesium sulfate. of solvents, the crude product is purified

After vacuum evaporation by flash column chromatography (SiO ₂ : 230-400 mesh) using 15¾ ethyl acetate / hexanes, 50% ethyl acetate / hexanes to 30% ethyl acetate / 30% hexanes / 40% methyl chloride. Mp 169-171 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.20 (T, 3H) 4.87 (with, 2H) 2.75 (T, 2H) 6.69 (with, 1H) 2.96 (T, 2H) 7.06 (D, 2H) 4.16 (Q, 2H) 7.19 (M, 5H) 7.73 (D, 2H) 11.85 (B; 5, 1H)

Example 75

4-Hydroxy-3- [2-naphthalenyl (phenylthio) methyl] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method C 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), thiophenyl (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 98-101 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

5.96 (with, 1H) 7.52 (M, 5H) 6.73 (with, 1H) 7.88 (M, 3H) 7.18 (T, 1H) 8.07 (with, 1H) 7,36 (M, 4H)

Example 76

4-Hydroxy-3 - [(2-naphthalenylthio) phenylmethyl] -6-phenyl-2H-pyran-2-one

The title compound was prepared via 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 mL), 84 mmol),

2-Naphthalethiol (2.21 g, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). Mp (dec.) 200 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

5.9 (S, 1H); 7.44 (m, 7H)

6.71 (WITH, 1H) 7.75 (m. 3H) 7.20 (M, 5H) 7.82 (m. 2H) Example 77

4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxyacetic acid

To a tetrahydrofuran solution (10 mL) of 4- [4-hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxyacetic acid ethyl ester (0.939 mmol) was added 1 N sodium hydroxide ( 2.34 mmol). The reaction mixture was stirred for 5 hours and then 10 mL of water was added, followed by acidification to pH 2 with concentrated hydrochloric acid. The aqueous layer was then extracted with 2 x 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: 230-400 mesh) eluting with 94/5/1 methylene chloride / methanol / acetic acid. MP: 182-183 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 76 (T, 2H) 7.06 (D, 2H) 2 97 (T, 2H) 7.21 (M, 5H) 4. 78 (with, 2H) 7.75 (D, 2H) 6. 67 (with, 1H)

Example 78

4-hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: (decomposition) 178 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 76 (T ·, 2H) 7.45 (q, 1 H) 2 98 (T, 2H) 7.77 (d, 2H) 5 25 (with, 2H) 7.91 (d, 1 H) 6. 69 (with, 1H) 8.57 (bs, 1 H) 7 21 (M, 7 H) 8.70 (bs, 1 H)

Example 79

6- [4- (Cyclohexylmethoxy) phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 ^1- (cyclohexylmethoxy) acetophenone (2.50 g, 10.77 mmol), lithium bis (trimethylsilyl) amide (2.70 g, 16.16 mmol), chlorotrimethylsilane (2). , 05 mL, 16.16 mmol), tetrahydrofuran (107 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). Mp 130-132 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.15 (M, 5H) 6.67 (WITH, 1H) 1.81 (M, 6H) 7.21 (M, 5H) 2.77 (T, 2H) 7.45 (Q, 1H) 2.97 (T, 2H) 7.74 (D, 2H) 3.85 (D, 2H)

Example 50

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylsulfonyl) phenyl] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (96 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 194-195 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.76 (T, 2H) 7.68 (m. 3H) 3.01 (T, 2H) 8.04 (m, 6H) 6.87 (WITH, 1H) 21.05 (bs, 1 H) 7.19 (M, 5H)

Example 81

4-hydroxy-3 - [(2-phenylethyl) thio] -6 - [(4-benzoyloxy) phenyl] -2H-pyran-2-one

The title compound was prepared via 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), tetrahydrofuran (100 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 164-166 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7.63 (t, 2H) 3.01 (T, 2H) 7.77 (t, 1 H) 6.81 (with, 1H) 7.92 (d, 2H) 7.21 (M, 5H) 12,00 (bs, 1 H) 7.49 (D, 2H)

Example 82

4-Hydroxy-3 - [(2-phenylethyl) thio] -6 - [(4- (phenylsulfinyl) phenyl] -2H-pyran-2-one)

The title compound was prepared via 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), tetrahydrofuran (100 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 171-173 ° C.

^ -Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.76 (T, 2H) 7.75 (d, 2H) 3.01 (T, 2H) 7.86 (d, 2H) 6.83 (with, 1H) 7.95 (d, 2H) 7.19 (M, 5H) 12.05 (bs, 1 H) 7.54 (M, 3H)

Example 83

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- (4-pyridinyl) -2H-pyran-2-one

The title compound was prepared via Method A using 4-acetylpyridine (2.50 g, 20.63 mmol) lithium bis (trimethylsilyl) amide (5.17 g, 30.94 mmol), chlorotrimethylsilane (3.92 mL, 30 mL). , 94 mmol), tetrahydrofuran (200 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: (decomposition) 149-152 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7.20 (M, 5H) 3.04 (T, 2H) 7.74 (D, 2H) 6.98 (with, 1H) 8.74 (D, 2H)

Example 84

3- [1,4-Bis (phenylthio) butyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclopropylcarboxaldehyde (0.436 mL, 5 mL), 84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 75-77 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

5.9 (S, 1 H) 7.44 (M, 7 H) 6.71 (S, 1 H) 7.75 (M, 3H) 7.20 (m, 5H) 7.82 (M, 2H)

Example 85

4-Hydroxy-6-phenyl-3- [phenyl [(phenylmethyl) thio] methyl] -2H-pyran-2-one, (+, -)

The title compound was prepared via 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 mL), 84 mmol), benzyl mercaptan (1.62 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 189-191 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.70 (Dd, 2H) 7.50 (m, 5H) 5.29 (with, 1H) 7.73 (m, 2H) 6.65 (with, 1H) 11.96 (bs, 1 H) 7,23 (M, 8H)

Example 86

4-Hydroxy-3 - [[(2-methoxyphenyl) thio] phenylmethyl] -6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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 mL), 84 mmol),

2-methoxythiophenol (1.93 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 165-170 ° C.

100 ¹ H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

3,870 (WITH, , 3H) 7.28 (T, 2H) 5.81 (WITH, 1H) 7.53 (M, 3H) 6.70 (with, 1H) 7.75 (M, 2H) 6.84 (T, 1H) 12,13 (B! 5, 1H) 7.19 (M, 3H)

Example 87

4-Hydroxy-3- [3-methyl-1- (phenylthio) butyl) -6-phenyl-2H-pyran-2-one • (+, -)

The title compound was prepared via 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 mL), 84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 154-156 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, acetone-d ₆ , delta values)

0.89 (D, 3H) 4.82 (dd, 2H) 0.93 (D, 3H) 6.70 (s, 1H) 1.63 (M, 1H) 7.24 (m, 4H) • 1.80 (M, 1H) 7.82 (m, 2H) 2.32 (M, 1H) 10.49 (bs, 1 H)

Example 88

3- [2-Cyclohexyl-1- (phenylthio) ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclohexylmethylcarboxaldehyde (0.735 mL, 5 mL), 84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: 205 ° C.

101 ^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, acetone-d _g , delta values)

0.91 (D, 3H). 6.69 (with, 1H) 1.25 (M, 5H) 7.22 (M, 3H) 1.73 (M, 5H) 7.48 (M, 5H) 2.58 (M, 1H) 7.82 (M, 2H) 4.83 (Dd, 1H)

Example 89

4-hydroxy-6- (3-phenoxyphenyl) -3 - [(phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4-hydroxy-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), 3'-phenoxyacetophenone (2.00 g, 9.43 mmol) , lithium bis (trimethylsilyl) amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), tetrahydrofuran (100 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester ( 1.00 g, 3.37 mmol). MP: Mp 114-115 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.76 2.99 (T, (T, 2H) 2H) 7.34 7.44 (with, (T, 1H) 2H) • 6.76 (with, 1H) 7.65 (M, 2H) 7.09 (M, 7 H)

Example 90

4-Hydroxy-6- [3-methoxy-4- (phenylmethoxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 ¹ -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), tetrahydrofuran (80 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

102

3.37 mmol). MP: Mp 114-115 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2, ‘77 (T, 2H) 6.75 (WITH, 1H) 2.98 (T, 2H) 7.21 (M, 7 H) 3.86 (with, 1H) 7.40 (M, 6H)

Example 91

6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3 ', 5'-dimethylacetophenone (1.75 g, 11.82 mmol), lithium diisopropylamide (1.89 g, 17.73 mmol), chlorotrimethylsilane (2.25 mL, 17.73 mmol), tetrahydrofuran (120 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 155-157 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.34 (WITH, 6H) 7.21 (M, 6H) 2.77 (T, 2H) 7.41 (with, 2H) 2.99 (T, 2H) 8.74 (D, 2H) 6.72 (with, 1H)

Example 92

4-Hydroxy-3 - [[(3-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N hydroxide by method B, with (1.00 g, 5.31 mmol) sodium (5 mL). 31 mL), [3- (methoxy) phenyl] methyl p-toluenethiosulfonate (2.12 g, 6.90 mmol).

MP: Mp 134-136 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

103

3.69 (WITH, 3H) 7.16 (T, 1H) 3.99 (with, 2H) 7.53 (M, 3H) 6.75 (M, 2H) 7.79 (M, 2H) 6.83 (M, 2H)

Example 93

4-Hydroxy-3- [4-methyl-1- (phenylthio) pentyl] -6-phenyl-2H-pyran-2-one, (+, -)

Prepared from 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), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 144-145 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

0.80 (D, 3H) 4.51 (Dd, 1H) 0.81 (D, 3H) 6.68 (with, 1H) 1.07 (M, 1H) 7.19 (T, 1H) 1.18 (M, 1H) 7.29 (T, 2H) 1.49 (M, 1H) 7.35 (D, 2H) 1.89 (M, 1H) 7.53 (M, 3H) 2.19 (M, 1H) 7.76 (M, 2H)

Example 94

4-Hydroxy-6-phenyl-3 - [[[3- (phenylmethoxy) phenyl] methyl] thio] -2H-pyran-2-one

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1N hydroxide by Method B, with (1.00 g, 5.31 mmol) sodium ( 5.31 mL) and [3- (benzoxy) phenyl] methyl p-toluenethiosulfonate (2.65 g, 6.90 mmol). MP: Mp 140-141 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

104 (400 MHz, DMSO-d6, delta values)

3.98 (with, 2H) 7.28 (T, 1H) 5.01 (with, 2H) 7.34 (M, 4H) 6.75 (with, 1H) 7.52 (M, 3H) 6.83 (M, 2H) 7.80 (M, 2H)

6.91 (m, IH)

Example 95

3 - [(1,3-benzodioxol-5-ylmethyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-Hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), 1 N sodium hydroxide (5.31) mL) and 1,3-benzodioxol-5-ylmethyl-p-toluenethiosulfonate (2.22 g, 6.90 mmol). MP: Mp 162-164 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.92 (WITH, 2H) 7.53 (M, 3H) 5.95 (with, 2H) 7.79 (M, 2H) 6.75 (M, 4H)

Example 96

4-hydroxy-3 - [[(2-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one,

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (7 mL), 1 N hydroxide by method B, with (0.500 g, 2.65 mmol) sodium (2.65 mL). ) a

MP: Mp 152-153 ° C.

3.73 (s, 3H)

3.95 (s, 2H).

7.13 (d, IH)

7.17 (t, 1H) [(2-methoxyphenyl) methyl] p-toluenethiosulfonate (0.816 g, 2.65 mmol).

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMS0-d6, delta values)

105

6.71 (WITH, 1H) 7.53 (M, 3H) 6.81 (T, 1H) 7.79 (M, 2H) 6.91 (D, 1H)

Example 97

4-hydroxy-3 - [[(2-methylphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one,

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N hydroxide and [(2-methylphenyl) methyl] p-toluenethiosulfonate (1.55 Tt). 178 ° C.

(1.00 g, sodium

B

5.31 (5.31

9, 5.31 (mmol), mL) mmol).

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.42 (with, 3H) 7.09 (M, 4H) 3.99 (with, 2H) 7.53 (M, 3H) 6.74 (WITH, 1H) 7.79 (M, 2H)

Example 98

4-hydroxy-3 - [[(3-methylphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one,

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1N hydroxide by Method B, with (1.00 g, 5.31 mmol) sodium (5 mL). 31 mL) and [(3-methylphenyl) methyl] p-toluenethiosulfonate (1.55 g, 5.31 mmol).

MP: Mp 139-140 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.23 (WITH, 3H) 7.07 (M, 4H) 3.96 (WITH, 2H) 7.54 (M, 3H) 6.74 (with, 1H) 7.79 (M, 2H)

Example 99

106

4-Hydroxy-3 - [[(4-methylphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one, Method B (1.00 g, sodium)

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N hydroxide and [(4-methylphenyl) methyl] -p-toluenethiosulfonate (1.55 Tt 164-165 °). C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) g,

5.31 (5.31

5.31 (mmol), ml) mmol).

2.23 (with, 3H) 7.14 (D, 2H) 3.96 (WITH, 2H) 7.53 (M, 3H) 6.74 (with, 1H) 7.79 (M, 2H) 7.06 (D, 2H)

Example 100

6- [1,1'-Biphenyl] -3-yl-4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyl triflate (2.36 mL, 12.24 mmol), triethylamine (2.84 mL, 20.40 mmol) ), methyl chloride (26 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 93-94 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.79 (T, 2H) 7.52 (T, 2H) 3.01 (T, 2H) 7.64 (T, 1H) 6.92 (WITH, 1H) 7.75 (D, 2H) 7.21 (M, 5H) 7.82 (T, 2H) 7.42 (T, 1H) 8.02 (WITH, 1H)

Example 101

4-Hydroxy-3 - [[(4-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one

107 method (1.00 g, sodium

B

5.31 (5.31

The title compound was prepared using 4-Hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N hydroxide and [(4-methoxyphenyl) methyl] p-toluenethiosulfonate (2.21 g, 6.90) Mp 168-170 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta) (mmol), ml) mmol).

3 96 (WITH, 3H) 7.17 (D, 2H) 3 95 (with, 2H) 7.53 (M, 3H) 6. 73 (WITH, 1H) 7.79 (M, 2H) 6. 81 (D, 2H)

Example 102

3- [2-Cyclohexyl-1- (cyclohexylthio) ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclohexylmethylcarboxaldehyde (0.735 mL, 5 mL), 84 mmol), cyclohexyl mercaptan (1.60 g, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). Mp (dec.) 220 ° C. ¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.86 (M, 2H) 4.25 (M, 1H) 1.18 (M, 9H) 6.68 (with, 1H) 1.66 (M, 10H) 7.53 (M, 3H) 2.03 (M, 2H) 7.75 (M, 2H) 2.58 (M, 2H)

Example 103

3- [1 - [(2,6-Dimethylphenyl) thio] -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

108

The title compound was prepared via Method C using 4-Hydroxy-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), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 166-167 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.78 (D, 3H) 4.37 (M, 1H) 0.83 (D, 3H) 6.51 (with, 1H) 1.42 (M, 1H) 7.70 (M, 3H) 1.47 (M, 1H) 7.52 (M, 3H) 2.46 (M, 1H) 7.74 (M, 2H) 2.51 (with, 6H)

Example 104

3- [1- (Cyclohexylthio) -2-cyclopropylethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-Hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclopropylmethylcarboxaldehyde (0.67 g, 5.84 mmol), cyclohexyl mercaptan (1.68 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 69-71 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

-0.02 (M, 1H) 1.84 (M, 1H) 0.05 (M, 1H) 1.97 (M, 2H) 0.34 (M, 2H) 2.64 (M, 1H) 0.64 (M, 2H) 4,21 (T, 1H) 1.22 (M, 5H) 6.69 (with, 1H) 1.52 (M, 1H) 7.52 (M, 3H) 1.67 (M, 1H) 7.75 (M, 3H)

Example 105

109

3- [1 - [(2,6-Dichlorophenyl) thio] -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-Hydroxy-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), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 158-162 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.83 (D, 3H) 4.68 (M, 1H) 0.87 (D, 3H) 6.76 (WITH, 1H) 1.49 (M, 1H) 7.49 (M, 5H) 1.74 (M, 1H) 7.74 (M, 3H) 2.39 (M, 1H)

Example 106

3- [1- (Cyclohexylthio) -3,3-dimethylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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), cyclohexyl mercaptan (1.86 g, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: 225 [deg.] C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.85 (WITH, 9H) 6.69 (with, 1H) 1.25 (M, 5H) 7.54 (M, 3H) 1.65 (M, 7 H) 7.75 (M, 2H) 4.30 (M, 1H)

[4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H ethyl ester Example 107

110

pyran-6-yl] -2-methylphenoxyacetic

The title compound was prepared via Method A using ethyl (4-acetyl-2-methyl-phenoxy) acetate (2.00 g, 8.47 mmol), trimethylsilyl triflate (3.92 mL, 20.33 mmol), triethylamine (4). , 72 mL, 33.88 mmol), methylene chloride (22 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 154-165 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.22 (T, 3H) 4.91 (WITH, 2H) 2.26 (with, 3H) 6.66 (WITH, 1H) 2.77 (T, 2H) 6.99 (D, 1H) 2.97 (T, 2H) 7.21 (M, 5H) 4.17 (T, 2H) 7.61 (M, 2H)

Example 108

6- [3,5-Dimethyl-4 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] phenyl] -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3 ', 5'-dimethyl-4' - [[dimethyl (1,1-dimethylethyl) silyl] oxy] acetophenone (1.50 g, 5.39 mmol), trimethylsilyl triflate ( 1.24 mL, 6.47 mmol), triethylamine (1.50 mL, 10.78 mmol), methylene chloride (13 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol) . MP: Mp 137-139 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.21 (with, 6H) 6.99 (D, 1H) 0.99 (WITH, 9H) 7.21 (M, 5H) 2.22 (WITH, 6H) 7.44 (M, 2H) 3.96 (with, 2H)

Example 109

111

4-Hydroxy-3 - [(2-phenylethyl) thio] -6 - [(4- (pyridinylmethoxy) phenyl) -2H-pyran-2-one

The title compound was prepared via Method A using 4 ^1- (pyridinylmethoxy) acetophenone (2.00 g, 8.81 mmol), trimethylsilyl triflate (2.04 mL, 10.57 mmol), triethylamine (2.45 mL, 17 mL), m.p. , 26 mmol), methylene chloride (22 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). Mp 212 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.73 (t, 2H) 7.18 (M, 5H) 2.88 (t, 2H) 7.45 (D, 2H) 5.29 (S, 2H) 7.74 (D, 2H) 6.48 (s, 1H) 8.90 (D, 2H)

Example 110

3- [1- (Cyclopentylthio) -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-Hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.62 mL, 5.84 mmol), cyclopentyl mercaptan (1.43 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 146-149 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.85 (D, 2H) 3.04 (m, 1 H) 0.87 (D, 2H) 4.20 (dd, 1 H) 1.32 (M, 1H) 6.69 (S, 1 H) 1.54 (M, 7 H) 7.53 (m, 4H) 1.85 (M, 1H) 7.76 (m, 2H) 2.00 (M, 1H) 11.69 (bs, 1 H)

Example 111

112

[4- [4-Hydroxy-2-iso-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] -2-methylphenoxyacetic acid

To a tetrahydrofuran solution (10 mL) of [4- [4-hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] -2-methylphenoxy] acetic acid ethyl ester (0, 20 g, 0.45 mmol) was added 1 N sodium hydroxide (1.13 mmol). The reaction mixture was stirred for 5 hours and then 10 mL of water was added. This is followed by acidification with concentrated hydrochloric acid to pH 2. The aqueous layer is then extracted twice with ethyl acetate (100 mL). The combined organic layers were 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: 230-400 mesh) using 94/5/1 methylene chloride / methanol / acetic acid as eluent. MP: (decomposition) 210 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.26 (WITH, 3H) 6.67 (WITH, 1H) 2.87 (T, 2H) 6.97 (D, 2H) 2.98 (T, 2H) 7.21 (M, 5H) 4.81 (with, 2H) 7.61 (D, 2H)

Example 112

3- [1- (Cyclopentylthio) -3-cyclopentylethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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), cyclohexyl mercaptan (1.68 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 157-160 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

113 (400 MHz, DMSO-C16, delta values)

1.44 (M, 18H) 6.68 (with, 1H) 2.01 (M, 1H) 7.53 (M, 3H) 2.19 (M, 1H) 7.75 (M, 2H) 2.60 (M, 1H) 11.66 (B: S, 1H) 4.16 (M, 1H)

Example 113

4-Hydroxy-6- (4-hydroxy-3,5-dimethylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one

To a tetrahydrofuran (10 mL) solution of 6- [3,5-dimethyl-4 - [[dimethyl (1,1-dimethylethyl) silyl] oxy] phenyl] -4-hydroxy-3 - [(phenylmethyl) thio] -2H- 1 N hydrochloric acid (9.0 mL) was added at 0 ° C to the pyran-2-one. The reaction mixture was stirred at ambient temperature for 48 hours. Ethyl acetate was then added to the reaction mixture, and the mixture was washed successively with water and saturated sodium chloride. It is then dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography. (SiO ₂ : 230-400 mesh) using 50% ethyl acetate / hexanes. Mp 174-176 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

2.21 (with, 6H) 7,23 (WITH, 5H) 2.60 (M, 1H) 7.38 (WITH, 2H) 3.96 (with, 2H) 9.06 (with, 1H) 6.52 (WITH, 1H)

Example 114

4-Hydroxy-6-phenyl-3 - [[[3- (2-phenylethoxy) phenyl] methyl] thio] -2H-pyran-2-one

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol).

114 ethanol (15 mL), 1 N sodium hydroxide (5.31 mL), [3- (2-phenylethoxy) phenyl] methyl p-toluenethiosulfonate (2.11 g, 5.31 mmol). MP: 85-90 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.96 (T, 2H) 7.19 (M, 5H) 3.96 (WITH, 2H) 7.53 (M, 3H) 4.09 (T, 2H) 7.77 (M, 2H) 6.77 (M, 4H)

Example 115

4-Hydroxy-6- [4- (2-phenylethynyl) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 '- (2-phenethynyl) acetophenone (1.50 g, 6.81 mmol), trimethylsilyl triphthalate (1.57 mL, 8.17 mmol), triethylamine (1.89 mL). , 13.62 mmol), methylene chloride (17 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 181-182 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 78 (T, 2H) 7.45 (M, 3H) 3 02 (T, 2H) 7.59 (D, 2H) 6. 85 (with, 1H) 7.86 (D, 2H) 7 21 (M, 5H)

Example 116

4-Hydroxy-6- [4- (2-phenylethyl) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 (2-phenethyl) acetophenone (1.50 g, 6.68 mmol), trimethylsilyl triphthalate (1.55 mL, 8 ”, 2 mmol), triethylamine (1.86).

115 mL, 13.36 mmol), methylene chloride (17 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 122-123 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2 77 (T, 2H) 7.26 (M, 5H) 2 93 (M, 4H) 7.38 (D, 2H) 2 99 (T, 2H) 7.71 (D, 2H) 6. 75 (with, 1H)

Example 117

3 - [(Cyclohexylthio) phenylmethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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 mL), 84 mmol), mmol), cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 189-191 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.21 (M, 5H) 6.70 (with, 1H) 1.52 (M, 1H) 7.17 (T, 1H) 1.91 (M, 2H) 7.53 (M, 5H) 2.58 (M, 2H) 7.74 (M, 2H) 5.37 (with, 1H) 11.96 (B: S, 1H)

Example 118

4-hydroxy-3 - [(2-phenylmethyl) thio] -6 - [(3- (trifluoromethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-trifluoromethoxyacetophenone (3.00 g, 14.7 mmol), lithium

116 bis (trimethylsilyl) amide (2.45 g, 14.7 mmol), chlorotrimethylsilane (2.47 g, 14.7 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol) ). MP: Mp 128-132 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

4.03 (with, 2H) 7.56 (Dd, 1H) 6.81 (with, 1H) 7.69 (T, 1H) 7.2 (M, 2H) 7.75 (WITH, 1H) 7.28 (M, 3H) 7.86 (D, 1H)

Infrared spectrum: (KBr,

cm ¹ ) 2963 1369 1098 1651 1395 1024 1550 1263 800 1394

Mass spectrum: (CI, m / e)

395

309

273

37)

205

119 (3) (10) (M + H)

Elemental analysis for C C _{£ £} H:

With F .H

3 calculated calculated

H

3.67

4.03 (%)

Example 119

3 - [(Cyclohexylmethyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method B using 4-Hydroxy-6-phenyl-2H-pyran-2-one (0.5 g, 2.66 mmol), ethanol (7 mL), 1 N sodium hydroxide (2.66) ml), cyclohexylmethyl p-toluenesulfonate (0.756 g, 2.66 mmol). MP: Mp 141-143 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

117

0.92 (M, 2H) 2.64 (D, 2H) 1.14 (M, 3H) 6.78 (with, 1H) 1.19 (M, 1H) 7.53 (M, 3H) 1.61 (M, 3H) 7.81 (M, 2H) 1.83 (M, 2H)

Infrared spectrum:

(KBr, cm ^T ) 3106 1547 1099

2922

1651

Mass spectrum: 4 ^ (Cl, m / e) 317 (M + H). 279 (83) 242 (77) 201 (27)

1396 766 16) 177 (19) 134 (54) 105 (65) 97 (100)

Example 120

4-Hydroxy - [(2-phenylethyl) thio] -6 - [(3-methyl-4- (3-pyridinylmethoxy) phenyl) -2H-pyran-2-one

The title compound was prepared via Method A using 3 ^1- methyl-4 '- (3-pyridinylmethoxy) acetophenone (2.00 g, 8.29 mmol), lithium bis (trimethylsilyl) amide (1.53 g, 9, 13 mmol), chlorotrimethylsilane (1.54 g, 9.13 mmol) and [2- (phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). Mp 149-151 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.25 (WITH, 3H) 7.44 (dd, 1 H) 2.78 (T, 2H) 7.67 (S + d, 2 H) 2.97 (T, 2H) 7.92 (d, 1 H) 5.28 (WITH, 2H) 8.58 (brs, 1 H) 6.69 (WITH, 1H) 8.72 (brs, 1 H) 7.22 (M, 6H)

118

Infrared spectrum:

(KBr,

cm ^x ) 3430 1505 1028 2926 1263 808 1713 1136 705 1326

Mass spectrum: (CI, m / e)

445 (M + H)

341 (14)

Elemental Analysis for

C H

200

105 (6) (100) calculated found

ABOUT

2 4

C (%)

70.09

70,31

H (%)

5.20

5.27

N (%)

3.14

2.95

Example 121

6- (2,3-Dihydro-4-benzodioxin-6-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

Prepared from Method A using 1,4-benzodioxin-6-ylmethyl ketone (2.5 g, 14.25 mmol), lithium bis (trimethylsilyl) amide (2.35 g, 14.25 mmol), chlorotrimethylsilane (2.47 g, 14.25 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.55 mmol). MP: 192

- 193 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 3.99 (s, 2H). 7.0 (d, IH) 4.17 (m, 4H) 7.2 (m, IH) 6.8 (s, 1H) 2.28 (m, 7H)

Infrared spectrum:

(KBr, cm ^x ) 3435 1624 1066 2924 1508 698 1649 1288

119

Mass spectrum:

(CI, m / e) 369 (M + H) 163 277 (12) 107 233 (12) 91

Calcd

C (%) calculated 65.21 found 64.80

H (%)

4.38

4.17

Example 122 e

4-hydroxy-3 - [(2-phenylethyl) thio] -6 - [(3- (trifluoromethyl) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using the corresponding trimethylsilylenol ether (4.5 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.33 g, 4.55 mmol). MP: Mp 117-118 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.8 (T, 2H) 7.49 (T, 1H) 3.03 (T, 2H) 8.08 (with, 1H) 6.94 (with, 1H) 8.14 (D, 1H) 7.2 (M, 5H)

Infrared spectrum: (KBr, cm ^-1 )

3435 1635 1171 3026 1543 1130 2924 1327 696 1720 Mass spectrum: (CI, m / e) 393 (M + H) 100) 256 (19) 373 (8) 224 (12) 288 (37) 10 * 5 (63)

120

Elemental Analysis for CHSOF .HO ^{J c} 2015133 2

C (%)

H (%) calculated found

58.53

59.28

4.18

3.81

Example 123

4-Hydroxy-3 - [(phenylmethyl) thio] -6 - [(3- (trifluoromethyl) phenyl) -2H-pyran-2-one

The title compound was prepared via Method A using the corresponding trimethylsilylenol ether (9.8 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (2.76 g,

9.88 mmol). MP: Mp 152-153 ° C.

delta) ^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, data)

3.97 (with, 2H) 7.75 (D, 1H) 6.53 (WITH, 1H) 8.03 (D, 1H) 7.25 (M, 5H) 8.08 (with, 1H) 7.61 (T, 1H)

Infrared spectrum:

(KBr,

cm ^x ) 3434 1522 1192 3244 1435 1132 1678 1341 936 1535 1316 706 1522

(M + H) (100)

Mass spectrum: (CI, m / e) 379 257 91

Elemental Analysis for

CH calcd found x ₃ ° ₃

C (%)

60.31

60,53

H

3.46

3.57 (%)

121

Example 124

4-Hydroxy-3 - [(phenylmethyl) thio] -6 - [(2,3,4-trimethoxyphenyl) -2H-pyran-2-one

The title compound was prepared via 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 [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol).

Example 125

N- [4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenyl] benzenesulfonamide

The title compound was prepared via Method A using the corresponding benzenesulfonamide (3.0 g, 10.91 mmol), lithium bis (trimethylsilyl) amide (3.65 g, 21.82 mmol), chlorotrimethylsilane (3.68 mL, 21 mL), , 82 mmol) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: Mp 89-91 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7.25 (M, 6H) 3.03 (T, 2H) 7.72 (T, 3H) 6.86 (WITH, 1H) 7.86 (M, 5H)

Infrared spectrum:

cm- ¹ ) 3443 1543 729 3335 1383 581 1725 1171 552 1632 912

H (%)

N (%)

H, CHNS 0: 0 ^C 25 H 2 5 2XX ,. 2

C (%)

122 calculated found

60.35 4.66 2.81

60.13 4.47 3.23

Example 126

6- [4 - [(3,5-Dimethyl-4-isoxazolyl) methoxy] phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 '- (3,5-dimethyl-4-isoxazolyl) -acetophenone (1.65 g, 6.74 mmol), lithium bis (trimethylsilyl) amide (1.13 g, 6). , 74 mmol), and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: Mp 152-154 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.22 (WITH, 3H) 6.69 (WITH, 1H) 2.31 (with, 3H) 7.17 (D, 3H) 2.78 (T, 2H) 7.25 (M, 4H) 2.99 (T, 2H) 7.78 (D, 2H) 5.03 (WITH, 2H)

Infrared spectrum:

(KBr, cm ^x ) 2936 1510 988 2979 1406 820 1640 1182 764 weight MS: (Cl, m / e) 450 (M + H) 236 341 (9) 112 105 (99) Elemental analysis for CHN 0 ^c 2 5 2 3 X WITH : 5 X

C (%)

66.80

66.42 calculated found

H (%)

5.16

5.20

N (%)

3.12

2.74

Example 127

123 (2 / -)

3 - [(Cyclohexylthio) phenylmethyl] -4-hydroxy-6- [3-methyl-4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via Method C using 4-hydroxy-6- [3-methyl-4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one (0.5 g, 1.62 mmol). benzaldehyde (0.189 g, 1.78 mmol), cyclohexyl mercaptan (0.489 g, 4.212 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 84-87 ° C.

Infrared spectrum:

cm ^x ) 3059 1676 1260 2930 1601 1134 2853 1449 700

Mass spectrum:

(Cl, m / e) 446 (2) 205 (24) 331 (9) 135 (44) 226 (61)

Example 128

2 - [[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] benzoic acid methyl ester

The title compound was prepared via 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), 1 N sodium hydroxide (10.63 mL) and ethanol (20 mL). MP: Mp 122 123 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.81 (S, 3H) 7.44 (T, 1H) 4.31 (S, 2H) 7.44 (M, 3H) 6.67 (s, 1H) 7.53 (D, 1H)

124

7.25 (d, IH)

7.31 (t, IH)

Infrared spectrum: (KBr,

cm ^x ) 3005 1543 966 2951 1400 766 1721 1267 711 1653 1078 520

Mass spectrum:

(Cl, m / e) 397 (M + 29,4) 191 (26) 369 40 (M + H) 149 (100) 337 (34) 105 (14)

Example 129

3- [1- (Cyclohexylthio) -3-methylbutyl] -6- (2,3-dihydro-1,4-benzodioxin-6-yl) -4-hydroxy-2H-pyran-2-one {+, -)

The title compound was prepared via Method C using 4-hydroxy-6- [1,4-benzodioxin-6-yl] -2H-pyran-2-one 4.06 mmol), isovaleraldehyde (0.35 g, 4, Cyclohexyl mercaptan (0.944 g, 8.12 mmol), piperidine (0.5 acetic acid (0.5 mL), mp 161-162 ° C. ^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) (1.0 g, mmol), mL) a

0.85 (D, 3H) 2.04 (m, 2H) 0.88 (D, 3H) 4.2 (q, 1 H) 1.2 (M, 5H) 4.32 (brq, 4H) 1.39 (M, 1H) 6.53 (S, 1 H) 1.53 (M, 2H) 6.99 (d, 1 H) 1.65 (M, 2H) 7.2 (d, 1 H) 1.81 (brm, lH) 7.25 (dd, 1 H)

Infrared spectrum: (KBr, cm ^-1 ) 1099

1510

1140

125

2930 1397 1069 2853 1314 891 1649 1289 771 1564 1260 608 Example 130

2 - [[4- [4-hydroxy-2-oxo-3 - [(2-phenylethyl) thio] methyl ester

-2H-pyran-6-yl] phenoxy] methyl] benzoic acid

The title compound was prepared via Method A using 2 - [[(4-acetyl) phenoxy] methyl] benzoic acid methyl ester (7.04 mmol), trimethylsilyltrifluoromethylsulfonate (1.57 g, mmol), triethylamine (1.42 g, 14 g). , 08 mmol) and diethyl ester g, 3.52 mmol). MP:

(2.0 g,

7.04 mmol), triethylamine (1.42 g, 14.08 [(2-phenylethyl) thio] propanedioic acid (1.04 161-162 ° C).

^X H-Nuclear Magnetic Resonance Spectrum:

(400

MHz, 1 DMSO -d6, delta values) 2.78 (T, 2H) 7.14 (M, 3H) 2.97 (T, 2H) 7.25 (M, 4H) 3.81 (WITH, 3H) 7,5 ( im, 2H) 5.5 (WITH, 2H) 7.78 (M, 2H) 6.69 (with, 1H) 7.78 (D, 2H) 7.94 (D, 1H)

Infrared spectrum:

(KBr,

cm ^x ) 3028 1638 1181 2949 1510 .... 1030 2909 1402 828 2675 1291 747 1715 1267

Mass Spectrum: (CI, m / e)

489 (mih,

384 mm (3)

149 (99)

135 (46)

51)

126

353 mm (1)

105 (34)

Example 131

4-hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (lH-tetrazol-5-ylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared using the compound of Example 143 (0.5 g, 1.32 mmol), trimethyltin azide (0.543 g, 2.64 mmol), toluene (10 mL), and ethanol (10 mL) with heating to reflux. 24 hours. The solvents were evaporated, the solid residue was treated with 1N hydrochloric acid, and the mixture was stirred at ambient temperature for 2 hours. The solid residue is retained in methanol, the solvents are evaporated and the solid product is washed with ethyl acetate to give the title compound. MP: 195-196 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 6.72 (with, 1H) 2.99 (T, 3H) 7.22 (M, 7 H) 5.6 (with, 2H) 7.81 (D, 2H)

Infrared spectrum: (KBr, cm ^-1 )

3121 1512 1059 3028 1410 831 1657 1256 696 1549 1186

Mass spectrum:

(Cl, m / e)

423 (M + H 8) 137 (11) 341 (3) 105 (100)

Example 132

4-Hydroxy-6- [3-methyl-4 - [(2-pyridinyl) methoxy] phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

127

The title compound was prepared via Method A using 4- (2-pyridinylmethoxy) -3-methylacetophenone (2.0 g, 8.29 mmol), trimethylsilyltrifluoromethylsulfonate (1.84 g, 8.29 mmol), triethylamine (1, 1, 2, 3, 2, 3, 3, 2 68 mL, 16.58 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.22 g, 4.15 mmol). MP: Mp 75-77 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO- d6, delta values) 2.32 (with, 3H) 7.38 (M, 1H) 2.78 (T, 3H) 7.56 (M, 2H) 2.97 (T, 2H) 7.67 (M, 2H) 5.29 (WITH, 2H) 7.86 (T, 2H) 6.67 (with, 1H) 8.61 (D, 1H) 7.14 - 7, , 29 (m, 3H)

Infrared spectrum: (KBr, cm ³ -)

3063

2924

1719

Mass spectrum:

1603

1505

1267

1138

1039

760

(CI, m / e) 446 (M + H 90) 242 (21) 341 (16) 151 (25) 279 (17) 105 (100)

C H

6

Elemental Analysis for

X

N S: i O

4

C (%) H (%) N (%) calculated 70.09 5.2 3.4 found 70.68 5.28 3.14

Example 133

3- [2-Cyclopropyl-1 - [(phenylmethyl) thio] ethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one (+, -)

The title compound was prepared via Method C, whereby

128 uses 4-hydroxy-6-phenyl-2H-pyran-2-one 2-cyclopropylmethylcarboxaldehyde benzyl mercaptan (1.98 g, 15.96 acetic acid (0.5 mL). Tt 59 ^T H-Nuclear Magnetic Resonance (400 MHz, DMSO-d6, values (0.67 mmol),

- 61 ° C.

MS:

delta) (1/5 g, piperidine g, 7.98

7.98 (0.5 mmol, mmol), ml) a

-0.97 (M, 2H) 6.67 (with, 1H) 0.28 (M, 2H) 7.18 (T, 1H) 0.58 (M, 1H) 7.25 (D, 2H) 1.61 (M, 1H) 7.31 (T, 2H) 2.01 (M, 1H) 7.53 (M, 3H) 3.72 (ABXq, 2 H) 7.75 (M, 2H)

Infrared spectrum:

(KBr,

cm ^x ) 3061 1649 1267 2919 1564 766 2613 1404 691

Mass Spectrum: (CI, m / e)

255 (M-SBzl

201 (4)

147 (1)

Elemental Analysis for

C H Calcd

C (%)

72.99

72.31 (%)

5.86

6.08

Example 134

4-Hydroxy-3- [1 - [(2-methoxyphenyl) thio] -3-methylbutyl] -6-phenyl-2H-pyran-2-one (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69 g, 7.98 mmol), 2-methoxythiophenol (2.24 g,

15.96 mmol), piperidine (1.0 mL), acetic acid (1 mL) and ethanol

129 (15 mL). MP: Mp 75-78 ° C.

^ -Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.86 (D, 3H) 6.64 (with, 1H) 0.89 (D, 3H) 6.89 (T, 1H) 1.53 (M, 1H) 6.94 (D, 1H) 1.69 (M, 1H) 7.17 (T, 1H) 2.19 (M, 1H) 7.33 (D, 1H) 3.64 (with, 3H) 7.53 (M, 3H) 4.69 (Q, 1H) 7.78 (M, 2H)

Infrared spectrum:

cm ^χ ) 3063 1649 1026 2955 1564 768 2635 1406 750 1649 1242 691

Mass spectrum:

(CI, m / e)

257 ((M-SPh (OMe), 11)) 169 (5) 201 (3) • 141 (88)

Elemental analysis for C H O S:

* ^c 2 3 24 4 X -

e calculated calculated C (%) 69.67 69.63 H (%) 6.10 5.92 Example 135

4-Hydroxy-3- [1 - [(phenylmethyl) thio] -3-methylbutyl] -6-phenyl-2H-pyran-2-one (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.69 g, 7.98 mmol), benzyl mercaptan (1.98 g,

15.96 mmol), piperidine (1.0 mL) and acetic acid (1 mL). MP: 153-155 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

130 (400 MHz, DMSO-d6, delta values)

0.64 (d. 3H) 2.04 (m, 1 H) 0.81 (d, 3H) 3.69 (ABXq, 2 H) 1.25 (m, IH) 4.22 (q, 1 H) 1.53 (m, IH)

Infrared spectrum:

cm ^x ) 3086 1566 1311 2955 1497 1127 1651 1404 912 766 (8

Example 136

4 - [[4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxy] methyl] benzoic acid methyl ester

The title compound was prepared via Method A using 4 - [[(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 [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.0 g, 3.05 mmol). MP: Mp 157-158 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7.17 (Q, 4H) 2.97 (T, 2H) 7.25 (M, 3H) 3.86 (WITH, 2H) 7.61 (D, 2H) 5.31 (with, 2H) 7.78 (D, 2H) 6.67 (WITH, 1H) 8.0 (D, 2H)

Infrared spectrum:

cm ^x ) 3023 1510 1098 2936 1404 1009 2581 1258 ⁸¹⁸ 1632 1184 718

131

Mass spectrum: (CI, m / e) 517 (M + 29, 7) 149 489 (M + H, 55) 105 (99) 384 (19)

Example 137

Acid methyl ester

3 - [[4- [4-hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxy] methyl] benzoic acid

Prepared via Method A using 3 - [[(4-acetyl) phenoxy] methyl] benzoic acid methyl ester (2.0 g, 7.04 mmol), lithium hexamethyldisilazane (2.38 g, 14.08 mmol) ) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.0 g, 3.05 mmol). MP: Mp 147-149 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7 58 (T, 1H) 2.97 (T, 2H) 7 75 (M, 3H) 3.86 (WITH, 2H) 7 78 (D, 1H) 5.31 (WITH, 2H) 7 94 (D, 1H) 6.69 (WITH, 1H) 8 08 (with, 1H) 7.2 (M, 7 H)

Infrared spectrum:

(KBr,

cm ^x ) 3081 1512 1098 2950 1406 1004 1726 1345 820 1632 1406 748 1609 1290 696

Mass spectrum:

132

(Cl, m / e) 489 (M + H 48) 236 (6) 384 (16) 149 (39) 341 (7) 119 (11) 105 (100)

Example 138

6- [4- [3,4-Dichlórfenylmetoxy] phenyl-4-hydroxy-3 - [(3-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using [4- (3,4-dichlorophenyl) methoxy] acetophenone (2.0 g, 6.80 mmol), lithium hexamethyldisilazane (2.28 g, 13.61 mmol), chlorotrimethylsilane ( 2.3 g, 13.61 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.0 g, 3.40 mmol). MP: Mp 168-169 ° C.

^X H-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.78 (T, 2H) 7 17 (M, 8H) 2.97 (T, 2H) 7 47 (Dd, 1H) 5.22 (with, 2H) 7 69 (D, 1H) 6.69 (with, 1H) 7 78 (D, 1H)

Infrared spectrum:

cm ^x ) 3054 1512 1109 2602 1399 1042 1713 1291 818 1611 1179 754

Mass spectrum:

(Cl, m / e)

501 (17) 161 (20) 499 (24) 159 (27) 394 (12) 105 (100) 353 (D

133

Example 139

3 - [[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] benzoic acid methyl ester with g, 10.63 mmol) (3.57 g, 10, 63 (20 mL), mp 170

The title compound was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (2,0 [3- (carbomethoxy) phenyl] methyl-p-toluenethiosulfonate mmol), 1N sodium hydroxide (10.63) ml), ethanol

- 171 ° C.

^X H-Nuclear Magnetic Resonance Spectrum:

(400

(Hz, DMSO-d6, delta values) 3.78 (with, 3H) 7.53 (M, 4H) 4.06 (with, 2H) 7.78 (M, 3H) 6.72 (WITH, 1H) 7.83 (WITH, 1H) 7.42 (T, 1H)

Infrared spectrum:

(KBr,

cm ^x ) 3108 1549 770 2947 1400 713 1716 1302 523 1644 1100

(M + H, 8)

Mass spectrum: (CI, m / e)

369

337

235

189 (3)

149 (12) (100)

7)

134

Example 140

4 - [[(4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] benzoic acid methyl ester

The title compound was prepared via 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), 1 N sodium hydroxide (10.63 mL), ethanol (20 mL). MP: 215-216 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

3.81 (with, 3H) 7.67 (M, 3H) 4.06 (with, 2H) 7.81 (M, 2H) 6 (6S ), J = = S Hz, 1H) 7.86 (D, 2H) 7.39 (D, 2H)

Infrared spectrum:

(KBr, cm ^-1 )

3110 1547 1103

3038 1403 720 1717 1279 526 1644 Mass spectrum: (Cl, m / e) 151 (55) 369 (M + H) 22) 119 (20) . 235 (99) 105 (21) 207 (17) 85 (28) 189 (36)

Example 141

6- [3,5-Bis (trifluoromethyl) phenyl] -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared by Method A using trimethylsilyl ether 3 ^1, 5 &apos; trifíuórmetylacetofenónu (2.16 g,

135

7.1 mmol) (preparation using 3,5-ditrifluoromethyl acetophenone (15 g, 58.55 mmol), trimethylsilyltrimethylsulfonate (13.01 g, 58.55 mmol) and triethylamine (11.84 g, 117.10 mmol)) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.0 g, 3.55). MP: 80 82 ° C.

^X H-NMR (400 MHz, CDC1 ₃₎ delta 4.0 (s, 2H) 6.61 (s, 1H) 7.22 (m. 2H) 7.28 (m, 3H) 1H) 2H) 7.97 8.25 (WITH, (with, ♦ Infrared spectrum: (KBr, cm ^-1 ) 3090 1549 1182 1726 1530 1138 1682 1385 902 1638 1281 700

Mass spectrum:

(Cl, m / e) 151 (55) 475 (M + 29.3) 149 (2) 447 (M + H, 21). ⁹¹ (100) 213 mm (1)

Example 142

3- [1- (Cyclohexylthio) -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (0.76 g, 8.78 mmol), cyclohexylmercaptan (2.04 g,

17.56 mmol), piperidine (1.0 mL) and acetic acid (1.0 mL) and ethanol (20 mL). MP: Mp 210-212 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.89 (t, 6H) 1.81 (m, 1H)

1.36 (m, 6H) 2.08 (m, 2H)

136

1.44 (M, 1H) 2.61 (brm, lH) 1.56 (M, 2H) 4.22 (m, 1 H) 1.69 (M, 2H) 6.67 (s, 1H) 7.53 (M, 3H)

Infrared spectrum:

(KBr, cm ^-1 ) 3106 1659 1125 2928 1568 766 2851 1404 569 Mass MS: (Cl, m / e) 259 (49) 147 (8) 257 (48) 105 (28) 201 (45) 83 (100)

189 (15)

Example 143 [4- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxy] acetonitrile

The title compound was prepared via Method A using appropriate acetophenone (3.0 g, 17.12 mmol), trimethylsilyltrifluoromethylsulfonate (3.8 g, 17.12 mmol), triethylamine (3.46 g, 34.24 mmol), and [2- (phenylethyl) thio] propanedioic acid diethyl ester (2.53 g, 8.56 mmol). MP: 157-159 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.92 (T, 2H) 7.08 (D, 2H) 3.11 (T, 2H) 7.19 (T, 3H) 4.86 (WITH, 2H) 7.3 (M, 3H) 6.56 (WITH, 2H) 7.86 (D, 2H)

Infrared spectrum:

(KBr, cm ^-1 )

2993 1342 1051

137

2577 1302 833 1543 1226 717 1510 1188 505 1404 1098 Mass spectrum: (Cl, m / e) 380 (99) 205

275 (60) 105

Example 144

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.24 g, 6.45 mmol) and (2-isopropylphenyl) -thiopropanedioic acid diethyl ester (1.0 g, 3.23 mmol). ).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.13 (T, 1H) 3.42 (M, 1H) 7.28 (D, 1H) 6.89 (with, 1H) 7.56 (M, 3H) 6.92 (Dd, 1H) 7.85 (M, 2H) 7.06 (T, 1H)

Infrared spectrum: (KBr, cm ^-1 )

3117 1551 1101 2962 1406 760 1661 1365

Mass spectrum:

(Cl, m / e) 339 (100) 189 (11) 305 (4) 147 (9) 219 (25) 105 (9)

Analysis for C _2o H _s 0 _{i 3} S:

C (%)

H (%)

138

70,98

70.82

Example 145

5.36

5.24 calculated found

3 - [(cyclopropylmethyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound (0.053 g, mp 136-137 ° C) was prepared via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (0.250 g, 1.33 mmol), cyclopropylmethyl-p- toluene thiosulfonate (0.585 g, 2.261 mmol), triethylamine (0.158 g,

1.46 mmol), sodium bicarbonate (0.110 g, 1.33 mmol) and ethanol (10.0 mL).

^X H-NMR (250 MHz, CDC1 ₃₎ delta

7,994 - 7,726 (M, 2H) 1,063 - - 0,903 (m, 1 H) 7,683 - 7,406 (M, 3H) 0.608 - - 0,533 (m, 2H) 6,665 (s, 1H) 0,270 - 0.208 (m, 2H) 2,724 - 2,694 (D, 2H, J = 7.3Hz)

Example 146

6- (3-Chlorophenyl) -4-hydroxy-3 - [(4-phenylbutyl) thio] -2H-pyran-2-one

The title compound was prepared via Method B using 6- (3-chloro-phenyl) -4-hydroxy-2H-pyran-2-one (0.250 g, 1.13 mmol), 4-phenyl-butyl-p-toluenethiosulfonate (0.45 g). g, 1.93 mmol), triethylamine (0.115 g, 1.13 mmol), sodium bicarbonate (0.094 g, 1.13 mmol) and ethanol (5.0 mL). MP: Mp 123-124 ° C.

^X H-NMR (400 MHz, CDC1 ₃₎ delta

7,848 - 7,839 (M, 1H) 6,631 (S, 1 H) 7,729 (m, 1 H) 2,831 -2.794 (t, 2H) 7,479 - 7,392 (M, 2H) 2,633 - 2.596 (t, 2H) 7,276 - 7,239 (M, 2H) 1,747 - 1.689 (m, 2H) 7,174 - 7,137 (M, 3H) 1,649 - 1.591 (m, 2H)

139

Example 147

4-Hydroxy-3 - [(2-oxo-2-phenylethyl) thio] -6-phenyl-2H-pyran-2-one

A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175 g, 0.840 mmol), prepared as described by R.F. Harris and J.E. Dunbar in U.S. Pat. 3,818,046, in dichloromethane (3.0 mL) under a nitrogen atmosphere, was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was stirred at ambient temperature for 30 minutes and then the solvents were removed in vacuo. The solid was diluted with diethyl ether and extracted with saturated sodium carbonate (3 x 50 mL). The aqueous layers were then combined, acidified with concentrated hydrochloric acid and extracted with dichloromethane (3 x 100 mL). The organic layers were combined, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (0.066 g, mp.164-166 ° C) which was dried in vacuo.

'H NMR (400 MHz, CDCl _a) delta

9,900 (bs, 1 H) 7,505 - 7,443 7,970 (d, 2H) J 7 , 1 Hz) 6,619 (s, 1H) 7,810 (d, 2H) J 8 Hz) 4,334 (S, 2H) 7,615 (t, 1 H, J = 4 Hz)

Example 148

4-Hydroxy-3 - [(2-phenylethan-2-ol) thio] -6-phenyl-2H-pyran-2-one

To a stirred solution of 4-hydroxy-3 - [(2-oxo-2-phenylethyl) thio] -6-phenyl-2H-pyran-2-one (0.021 g, 0.060 mmol) in tetrahydrofuran (1.0 mL) cooled to 0 (nitrogen atmosphere), a 1.0 M solution of BH ₃ .DMS (0.05 mL, 0.05 mmol) was added via syringe. The mixture was stirred for 1 hour and then treated with 1: 1 4N HCl: MeOH. The mixture was then extracted with diethyl ether. The layers merge

140 was dried over sodium sulfate and the solvents removed in vacuo to give the title compound (0.015 g) as an oil. ^ H NMR (200 MHz, CDC1 ₃₎ delta

7,873 - 7,777 (M, 4H) 7,516 - 7,153 (M, 6H) 6,667 (s, 1H) 4,820 - 4,755 (Dd, 1H, J = 9.8 Hz, 3.2 Hz) 3,212 - 3,127 (Dd, 1H, J = 13.8 Hz, 3.2 Hz) 2,920 (dd, 1 H, J = ; 9.8 Hz, 13.8 Hz)

Example 149

4-hydroxy-5-methyl-6-phenyl-3- [phenylthio] -2H-pyran-2-one

A solution of propiophenone (1.50 mL, 11.3 mmol) in dichloromethane (40 mL) was cooled under a nitrogen atmosphere to 0 ° C and treated first with triethylamine (3.14 mL, 22.6 mmol) and then with trimethylsilyl triflate (2.60 mL, 13.5 mmol). at room temperature, stirred for 15 minutes with a mixture of diethyl ether (50 mL) and sodium bicarbonate solution (20 mL). dried over sodium sulfate and the solvent was dried

The mixture was warmed to and then saturated aqueous ether was removed in vacuo.

The resulting silylenol ether was then transferred to a flask containing diethyl 2- (thiophenyl) propane-1,3-dioate (1.00 g, 3.76 mmol) and the mixture was heated at 140 ° C for 16 h. It was then cooled to ambient temperature while being diluted with diethyl ether and extracted with saturated sodium carbonate (3 x 20 mL). The aqueous layers were combined, washed with diethyl ether (3 x 75 mL), and then slightly acidified with concentrated hydrochloric acid. The mixture was then extracted with dichloromethane (3 x 200 mL), the organic layers were combined, dried over sodium sulfate and the solvent removed in vacuo to give the title compound (0.350 g, mp 166-167 ° C).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

6.309 - 6.285 (m, 2H) 5.862 (d, 3H, J = 8 Hz)

141

6.227 - 6.211 (m, 3H) 0.705 (S, 3H)

5.983 (t, 2H, J = 8 Hz)

Example 150

[4- [4-Hydroxy-2-oxo-3- (phenylthio) -2H-pyran-6-yl] phenoxy] acetic acid

A solution of methyl [4- (1-oxoethyl) phenoxy] acetate (2.50 g, 10.86 mmol) in dichloromethane (25.0 mL) was cooled under a nitrogen atmosphere to

0 ° C and treated first with triethylamine (3.03 mL, 21.7 mmol) and then with mmol). The solution was warmed for minutes and sequentially added with trimethylsilylflate (2.52 mL, 13.0 rt), stirred for 15 to a mixture of diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (20 mL). The resulting silylenol ether was transferred to a flask containing diethyl 2- (thiophenyl) propane-1,3-dioate (0.97 g, 3.6 mmol) and heated at 140 ° C for 16 h. C and then subjected to chromatography (SiO ₂ : 230-400 mesh, 100% CH ₂ Cl ₂ ,

2.0% MeOH / CH ₂ Cl ₂ ) to give an impure solid which was diluted with diethyl ether (20 mL) and extracted with saturated sodium carbonate (3 x 20 mL). The combined aqueous extracts were washed with diethyl ether (3 x 100 mL) and acidified with concentrated hydrochloric acid to pH 0. The mixture was then extracted with ethyl acetate (3 x 100 mL), the organic layers were combined, dried over sodium sulfate and the solvent removed in vacuo to give the desired product. compound (0.695 g, mp 186-188 ° C).

^X H-Nuclear Magnetic Resonance Spectrum (300 MHz, DMSO-d _s , delta values)

13.175 (bs, 1H) 7.298-7.247 (m, 2H)

12.425 (bs, 1H) 7.149-7.004 (m, 5H)

7.809 (d, 2H, J = 9 Hz) 6.785 (s, 1H)

4.804 (s, 2H).

Example 151

142

[4- [4-Hydroxy-5-methyl-2-oxo-3- (phenylthio) -2H-pyran-6-yl] phenoxy] -acetic acid

The title compound (0.691 g, mp 194-197 ° C) was prepared in a similar manner as in the preparation of [4- [4-hydroxy-2-oxo-3- (phenylthio) -2H-pyran-6-yl] phenoxy] acetic acid. using methyl [4- (1-oxoethyl) phenoxy] acetate (2.00 g, 8.81 mmol) triethylamine (3.68 mL, 26.4 mmol), trimethylsilyl triflate (2.38 mL,

12.3 mmol), dichloromethane (20.0 mL) and diethyl 2- (thiophenyl) propane-1,3-dioate (1.34 g, 5.00 mmol).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

7,585 (d, 2H) J = 9 Hz) 7,063 (D, 2H, J = 9 Hz) 7,325 - 7,286 (m, 2H) 4,784 (with, 2H) 7,178 (d, 3H, J = 7.5Hz) 2,042 (with, 3H)

Example 152

-Hydroxy-3-phenoxy-6-phenyl-2H-pyran-2-one

2-Phenoxypropanedioic acid is added to the pressure reactor

- diethyl ester (8.11 g, 0.032 mol) and 1-phenyl-1- (trimethylsilyloxy) ethylene (12.35 g, 0.064 mol). The vessel was pressurized to 600 psi with nitrogen. The mixture was heated at 100 ° C for 8 hours and then at 147-154 ° C for 63.5 hours. Cool the vessel to ambient temperature, rinsing with ethyl acetate. Flash chromatography (hexane / ethyl acetate 1/1) gave the purified material which was then loaded onto silica gel using hexane / ethyl acetate 95/5 as eluent.

- 40/60. The resulting solid was recrystallized from diethyl ether and ethyl acetate to give 1.64 g (18%) of the title compound. MP: Mp 215-219 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

6.90 (S, 1H) 7.52-7.56 (m, 3H)

6.95 (dd, 2H); 7.80-7.856 (m, 2H)

143

7.02 (t, 1H); 12.0 (bS, 1H)

7.28 - 7.33 (m, 2H)

Example 153

4-hydroxy-3 - [(phenylmethyl) thio] -6- (3-pyridinyl) -2H-pyran-2-one

The title compound was prepared via Method A using condensation of 3-acetylpyridine trimethylsilylenol ether and [(phenylmethyl) thio] propanedioic acid diethyl ester. MP: 183-184 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

4.02 (WITH, 2H) 7.55 (M, 1H) 6.83 (with, 1H) 8.16 (M, 1H) 7.20 (M, 1H) 8.69 (M, 1H) 7.26 (D, 4H) 8.98 (D, 1H)

Example 154

6- (2,6-dimethyl-4-pyridinyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A by condensation of 4-acetyl-2,6-dimethylpyridine trimethylsilylenol ether and [(phenylmethyl) thio] propanedioic acid diethyl ester. MP: 88-90 ° C.

Η-Nuclear Magnetic Resonance Spectrum (400MHz, DMSO-d6, delta values) 3.98 (s, 2H) 7.48 (m, IH) 6.58 (s, 1H) 7.72 (m, IH) 7.24 (m, 5H) 8.13 (d, IH)

Example 155

4-Hydroxy-3 - [(phenylmethyl) thio] -6- (3-thienyl) -2H-pyran-2-one

144 was prepared according to Method A, namely 3-acetylpyridine trimethylsilylenol ether and [(phenylmethyl) thio] propanedioic acid. Tt 150 Required by condensation of diethyl ester 151 ° C. ^X H-Nuclear Magnetic Resonance Spectrum

2.55 (s, 6H) 7.16 - 7.28 (m, 5H) 4.02 (s, 2H) 7.40 (s, 2H) 6.85 (s, 1H)

Example 156

3 - [(2,6-Dimethylphenyl) methyl] thio] -4-hydroxy-6-phenyl-2H-pyran-2-one via Method B, with (1.00 g, 5.31 mmol) sodium (5 , 31 mL) and 5.31 mmol).

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N (2,6-dimethylphenyl) methyl p-toluenethiosulfonate (1.62 Tt 231-233 ° C). C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.34 (with, 6H) 7.03 (M, 3H) 4.01 (with, 2H) 7.53 (M, 3H) 6.81 (M, 2H) 7.82 (M, 2H)

Example 157

4-Hydroxy-6-phenyl-3 - [[(3-phenoxyphenyl) methyl] thio] -2H-pyran-2-one

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (15 mL), 1 N (3-phenoxyphenyl) methyl p-toluenethiosulfonate, m.p. Mp 131-133 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d 6, δ values) by method B (mmol), mL) and mmol).

(1.00 sodium (1.96 g, 5.31 (5.31 g, 5.31

145

3 97 (with, 2H) 7.27 (M, 3H) 6, 73 (with, 1H) 7.53 (M, 3H) 6. 87 (M, 4H) 7.78 (M, 2H)

7.03 (m. 2H)

Example 158

3- [1 - [(Cyclohexylmethyl) thio] -3-methylbutyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, ethanol (10 mL), isovaleraldehyde (0.462 mL,

C, taking

5.31 mmol),

5.84 mmol), cyclohexylmethylthiol (1.79 g, 13.8 mol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 146-148 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.58 (d, 5H) 4.17 (dd, 1 H) 1.11 (m, 5H) 6.69 (S, 1 H) 1.57 (m, 9H) 7.54 (m, 4H) 2.07 (m, 1 H) 7.75 (m, 2H) 2.28 (dd, 1 H) 11.71 (bs, 1 H) 2.38 (dd, 1 H)

Example 159

3- [1 - [(Cyclohexylmethyl) thio] phenylmethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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 mL), 84 mmol), cyclohexylmethylthiol (1.79 g, 13.8 mol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: 138-141 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

146

0.89 (M, 2H) 5.30 (with, 1H) 1.21 (M, 3H) 6.71 (WITH, 1H) 1.42 (M, 1H) 7.26 (T, 1H) 1.61 (M, 3H) 7.28 (T, 2H) 1.75 (M, 2H) 7.53 (M, 5H) 2.39 (M, 2H) 7.74 (M, 2H)

Example 160

4-Hydroxy-6- [4- (2-hydroxyethoxy) phenyl] -3 - [(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 2.0M lithium borohydride (0.5 mL, 1.00 mmol). The reaction mixture was stirred overnight. The reaction was quenched by the addition of 1N 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: 230-400 mesh) eluting with 50% ethyl acetate / hexanes to 100% ethyl acetate. MP: Mp 123-125 ° C.

1 H-Nuclear Magnetic Resonance Spectrum

2.77 (T, 2H) 7.09 (D, 2H) 2.97 (T, 2H) 7.19 (M, 5H) 3.37 (M, 2H) 7.75 (D, 2H) 4.07 (T, 2H) 4.92 (Bs, 1H) 6.68 (WITH, 1H)

Example 161

[3- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] phenoxy] acetic acid ethyl ester

147

The title compound was prepared via Method A using ethyl (3-acetylphenoxy) acetate (2.00 g, 9.00 mmol), trimethylsilyl triflate (4.18 mL, 21.62 mmol), triethylamine (5.01 mL, 36.00 mmol), methylene chloride (23 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: 116-119 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.22 (T, 3H) 6.80 (WITH, 1H) 2.77 (T, 2H) 7.20 (M, 7 H) 3.05 (T, 2H) 7.44 (M, 2H) 4.89 (D, 2H)

Example 162

4-Hydroxy-6- [4 - [(5-methyl-3-phenyl-4-isoxazolyl) methoxy] phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4 '- [(5-methyl-3-phenyl-4-isoxazolyl) methoxy] acetophenone (2.00 g, 6.51 mmol), trimethylsilyl triflate (1.51 mL, 7 mL). , 81 mmol), triethylamine (1.81 mL, 13.02 mmol), methylene chloride (16 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g,

3.37 mmol). MP: Mp 126-128 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.54 (WITH, 3H) 7.21 (M, 7 H) 2.77 (T, 2H) 7.49 (M, 3H) 2.98 (T, 2H) 7.71 (M, 2H) 5.08 (WITH, 2H) 7.77 (D, 2H) 6.69 (WITH, 1H)

Example 163

6- (3,5-dimethylphenyl) -4-hydroxy-3- (phenylthio) -2H-pyran-2-one

148

The title compound was prepared via 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 mL), m.p. , 40 mmol), methylene chloride (24 mL) and (phenylthio) propanedioic acid diethyl ester (1.00 g, 7.46 mmol). MP: Mp 210-211 ° C. @ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

2.35 (WITH, 6H) 7.21 (WITH, 1H) 6.83 (with, 1H) 7.27 (t, 2H) 7.12 (M, 3H) 7.46 (WITH, 2H)

Example 164

3- [1- [Cyclopentylthio] -2-cyclopropylethyl] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method C using. 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), cyclopropylmethylcarboxaldehyde (0.892 g, 10.62 mmol), cyclopentylthiol (1.43 mL) , 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). MP: 75-80 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.04 (M, 2H) 3.19 (M, 1H) 0.07 (M, 2H) 4,21 (Dd, 1H) 0.66 (M, 1H) 6.71 (with, 1H) 1.53 (M, 7 H) 7.54 (M, 3H) 1.94 (M, 3H) 7.76 (M, 2H)

Example 165

N- [3- [4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-6-yl] phenyl] -4-methylbenzenesulfonamide

The title compound was prepared via Method A, whereupon

149 uses 3 '- (p-toluenesulfonamide) acetophenone (1.38 g, 5.06 mmol), trimethylsilyl triflate (2.34 mL, 12.41 mmol), triethylamine (2.82 mL,

20.42 mmol), methylene chloride (18 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). MP: 133-135 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.32 (with, 3H) 7.40 (m, 3H) 2.77 (T, 2H) 7.53 (S, 1 H) 3.09 (T, 2H) 7.67 (d, 2H) 6.68 (WITH, 1H) 10.50 (S, 1 H) 7.19 (M, 6H) 21.03 (bs, 1 H)

Example 166

3- [Cyclopentyl (cyclopentylthio) methyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared using 4-hydroxy-6-phenyl-2H-pyran-2-one ethanol (10 mL), cyclopentylthiol via Method C, with (1.00 g, 5.31 mmol) cyclopentanecarboxaldehyde (0.780 g, 7). , 96 mmol), (1.43 mL, 13.8 mmol), piperidine (0.5 mL)

and acid acid (0.5 ml). MP: 139 - 142 ° C. ^X H-Nuclear Magnetic Resonance Spectrum (400 1 MHz,] DMSO d6, values delta) 1.03 (M, 1H) 6. 69 (WITH, 1H) 1.64 (M, 15H) 7 52 (M, 3H) 2.64 (M, 1H) 7 76 (M, 2H) 3.00 (M, 1H) 11 55 (bs, 1 H) 3.84 (D, 1H)

6- (1,1'-Biphen-3-yl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

Example 167

150

The title compound was prepared via Method A using 3 ^1- phenylacetophenone (0.946 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL,

9.66 mmol), methylene chloride (17 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g, 3.22 mmol). MP: Mp 193-195 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.28 (D, 1H) 3.43 (M, 1H) 7.42 (T, 1H) 6.95 (D, 1H) 7.51 (T, 2H) 7.02 (with, 1H) 7.66 (T, 1H) 7.06 (T, 1H) 7.75 (D, 2H) 7.13 (T, 1H) 7.85 (T, 2H) 8.07 (with, 1H)

Example 168

4-Hydroxy-6-phenyl-3 - [(2-propylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (0.990 mL, 4.83 mmol) and [(2-propylphenyl) thio] propanedioic acid diethyl ester (1.00 g,

3.22 mmol). MP: Mp 158-160 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0,972 (T, 3H) 7.06 (M, 2H) 1.64 (M, 2H) 7.16 (M, 1H) 2.71 (T, 2H) 7.55 (M, 3H) 6.87 (WITH, 1H) 7.85 (M, 2H)

6.92 (m, IH)

The title compound was prepared via Method A using 3 ', 5'-dimethylacetophenone (0.714 g, 4.83 mmol).

Example 169

151 trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL,

9.66 mmol), methylene chloride (17 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g, 3.22 mmol). MP: Mp 154-155 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.24 (D, 6H) 7.11 (Dt, 2H) 2.35 (with, 6H) 7.20 (with, 1H) 3.40 (M, 1H) 7.27 (D, 1H) 6.90 (D, 1H) 7.45 (with, 2H) 7.05 (T, 1H)

Example 170

4-Hydroxy-6- (4-hydroxyphenyl) -3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4'-dimethylacetophenone (0.657 g, 4.83 mmol), trimethylsilyl triflate (2.05 mL, 10.62 mmol), triethylamine (2.69 mL,

19.32 mmol), methylene chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g, 3.22 mmol). MP: (decomposition) 250 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.24 (D, 6H) 7.05 (T, 1H) 3.40 (M, 1H) 7.10 (T, 1H) 6.70 (with, 1H) 7.26 (D, 1H) 6.90 (T, 3H) 7.70 (D, 2H)

Example 171

3 - [[2- (cyclopropylmethyl) phenyl] thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A, whereupon

152 uses 1-phenyl-1- (trimethylsilyloxy) ethylene (0.990 mL, 4.83 mmol) and [[2- (cyclopropylmethyl) phenyl] thio] propanedioic acid diethyl ester (1.00 g, 3.10 mmol). MP: Mp 165-167 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.25 (dd, 2H) 6.92 (M, 1H) 0.52 (dd, 2H) 7.05 (M, 2H) 1.21 (m, 1 H) 7.32 (M, 1H) 2.50 (d, 2H) 7.65 (M, 3H) 6.87 (s, 1H) 7.86 (M, 2H)

Example 172

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via 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 [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g, 3.22 mmol). MP: 225 [deg.] C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.23 (D, 6H) 7 29 (D, 1H) 3.41 (M, 1H) 7 45 (Dd, 1H) 5.26 (with, 2H) 7 82 (D, 2H) 6.78 (with, 1H) 7 91 (D, 1H) 6.90 (D, 1H) 8 56 (D, 1H) 7.08 (Dt, 2H) 8 71 (with, 1H) 7.21 (D, 2H)

4- [4-Hydroxy-5 - [(2-isopropylphenyl) thio] -6-oxo-6H-pyran-2-yl] phenoxyacetic acid ethyl ester

Example 173

153

The title compound was prepared via Method A using ethyl (4-acetyl-phenoxy) -acetophenone (2.14 g, 9.67 mmol), trimethylsilyl triflate (4.48 mL, 23.20 mmol), triethylamine (12.93 mL, 38.6 mmol), methylene chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (2.00 g, 6.45 mmol). MP: Mp 194-196 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

1.57 (M, 9H) 6.90 (D, 1H) 3.41 (M, 1H) 7.05 (M, 4H) 4.81 (Q, 2H) 7.26 (D, 1H) 4.89 (WITH, 2H) 7.79 (D, 2H) 6.75 (with, 1H)

Example 174

4- [4-Hydroxy-5 - [(2-isopropylphenyl) thio] -6-oxo-6H-pyran-2-yl] phenoxyacetic acid

To a tetrahydrofuran (10 mL) solution of 4- [4-Hydroxy-5 - [(2-isopropylphenyl) thio] -6-oxo-6H-pyran-2-yl] phenoxyacetic acid ethyl ester (0.319 g, 0.75 mmol) 1 N sodium hydroxide (1.80 mL, 1.81 mmol) was added. The reaction mixture was stirred for 1.5 hours, then 10 mL of water was added, and then the mixture was acidified to pH 2 with concentrated hydrochloric acid. The aqueous layer was then extracted with 2 x ethyl acetate (100 mL). The combined organic layers were 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: 230-400 mesh) eluting with 94/5/1 methylene chloride / methanol / acetic acid. MP: (decomposition) 217 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

1.25 (d, 6H)

3.42 (m, IH)

6.90 (d, IH)

7.06 (m, 4H)

154

4.79 (s, 2H)

6.75 (s, 1H)

7.26 (d, IH)

7.79 (d, 2 H)

Example 175

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-methoxyphenyl) -2H-pyran

2-one

The title compound was prepared via Method A using

4'-methoxyacetophenone (2.26 g, 15.1 mmol),

trimethylsilyl triflate (3.5 mL, 18.1 mmol), 30.6 mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid (3.11 triethylamine (4.26 mL, diethyl ester g, 10) 0 mmol)

Mp 121-223 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

I 25 (D, 6H) 7.10 (m, 3H) 3 40 (M, 1H) 7.27 (m, 1 H) 3 85 (with, 3H) 7.81 (d, 2H) 6. 78 (with, 1H) 12.38 (brs, 1 H) 6. 92 (M, 1H)

Example 176

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-methoxyphenyl) -2H-pyran-2-one

The title compound was prepared via Method A using 4'-methylacetophenone (2.02 trimethylsilyl triflate (3.5 mL, 18.1 mmol), 30.6 mmol), methylene chloride (30 mL) and 15.1 mmol). triethylamine (4.26 mL, [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol).

Mp 191-193 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

1.25 (d, 6H); 7.10 (m, 2H)

155

2.39 (WITH, 3H) 7.27 (M, 1H) 3.41 (M, 1H) 7.37 (M, 2H) 6.84 (with, 1H) 7.75 (D, 2H) 6.92 (M, 1H)

Example 177

6- (3,4-Dichlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via 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 mL). , 0 mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (4.0 g, 12.8 mmol). MP: Mp 204-207 ° C.

^X H-NMR (400 MHz, CDC1 ₃₎ delta

1.33 (D, 6H) 7.30 (M, 1H) 3.55 (M, 1H) 7.56 (D, 1H) 6.71 (with, 1H) 7.69 (M, 1H) 7.00 (M, 1H) 7.74 (Br, 1H) 7.08 (M, 1H) 7.98 (with, 1H) 7.20 (M, 1H)

Example 178

6- (4-Chlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The desired compound was used 4'-chloroacetophenone trimethylsilyl triflate (3.5 mL, 18.1 30.6 mmol), methylene chloride (30 [(2-isopropylphenyl) thio] propanedione 148-151 ° C.

prepared according to Method A, with (2.33 g, 15.1 mmol), mmol), triethylamine (4.26 mL, mL) and acid diethyl ester (3.11 g, 10.0 mmol). MP:

156 ^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.08 (M, 2H) 3.41 (M, 1H) 7.27 (M, 1H) 6.86 (with, 1H) 7.62 (M, 2H) 6.92 (M, 1H) 7.86 (M, 2H), and

Example 179

4- [4-Hydroxy-5 - [(2-isopropylphenyl) thio] -6-oxo-ethyl ester

6H-pyran-2-yl] benzoic acid

The title compound was prepared via Method A using 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 [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol). MP: Mp 201-203 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 6.94 (M, 1H) 1.35 (T, 3H) 7.00 (with, 1H) 3.42 (M, 1H) 7.10 (M, 2H) 4.35 (Q, 2H) 7.28 (M, 1H) 6.94 (M, 1H) 7.99 (M, 2H) 8.11 (M, 2H)

Example 180

4-Hydroxy-6- (3-hydroxyphenyl) -3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-hydroxyacetophenone (2.06 g, 15.1 mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL,

61.1 mmol), methylene chloride (30 mL) and diethyl ester

157 [(2-isopropylphenyl) thio] propanedioic acid (3.11 g, 10.0 mmol). MP: Mp 201-204 ° C.

^ H-Nuclear Magnetic Resonance Spectrum (250 MHz, DMSO-d6, delta)

1.25 (D, 6H) 7.09 (m, 2H) 3.41 (M, 1H) 7.30 (m, 3H) 6.82 (with, 1H) 9.91 (br, 1H) 6.93 (M, 2H)

Example 181

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -2H-6- (2-phenylethyl-1-ene) -pyran-2-one

The title compound was prepared via Method A using trans-4-phenyl-3-buten-2-one (2.23 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol),

30.6 mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid (3.11 triethylamine (4.26 mL, g diethyl ester, 10.0 mmol).

Mp 190-192 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

1.25 (D, 6H) 7.27 (M, 1H) 3.40 (M, 1H) 7.40 (M, 4H) 6.44 (with, 1H) 7.71 (D, 2H) 6.89 (M, 1H)

7.10 (m. 3H)

Example 182

6- (1,1'-Bifen-4-yl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4-acetylbiphenyl (3.06 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol) .

158 methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol). MP: Mp 203-206 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (250 MHz, DMSO-d6, delta)

1.26 (D, 6H) 7.28 (M, 1H) 3.40 (M, 1H) 7.51 (M, 3H) 6.94 (M, 2H) 7.77 (M, 2H) 7.10 (M, 2H) 7.91 (Q, 4H)

Example 183

6- (1,1'-Biphenyl-3-yl) -4-hydroxy-3 - [(naphthalen-2-yl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 mL, 10.20 mmol), triethylamine (2.06 mL, 20.40 mmol), methylene chloride (20 mL) and [(naphthalen-2-yl) thio] propanedioic acid diethyl ester (1.62 g, 5.1 mmol). MP: 183-185 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

7.07 (s, 1 H)

7.69 (d, IH)

7.33 (dd, IH)

7.78 (d, IH)

7.39 - 7.58 (m, 5H)

7.81 - 7.92 (m, 6H)

7.66 (s, 1 H)

8.11 (s, 1 H)

Example 184

4-hydroxy-3 - [(naphthalen-l-yl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(1-naphthyl) thio] propanedioic acid diethyl ester (1.61 g, 5H). , 07 mmol). MP: Mp 242-243 ° C.

159 @ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

6.83 (WITH, 1H) 7.83 (M, 2H) 7.19 (D, 1H) 7.94 (D, 1H) 7.39 (T, 1H) 8.28 (D, 1H)

7.64 - 7.42 (m, 5H)

7.69 (d, IH)

Example 185

6- (1,1'-Biphenyl-3-yl) -3 - [[2- (cyclopropylmethyl) phenyl] thio] -4-hydroxy-2H-pyran-2-one

The title compound was prepared via Method A using 3 ^1- phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 mL, 10.20 mmol), triethylamine (2.06 mL, 20.40 mmol), methylene chloride (20 mL) and [[2- (cyclopropylmethyl) phenyl] thio] propanedioic acid diethyl ester (1.14 g, 5.1 mmol). Mp 88 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.25 (D, 2H) 7.33 (M, 1H) 0.53 (Dd, 2H) 7.44 (D, 1H) 1.14 (M, 1H) 7.53 (T, 2H) 2.67 (D, 2H) 7.67 (T, 1H) 6.94 (M, 1H) 7.75 (D, 2H) 7.03 (with, 1H) 7.86 (M, 2H) 7.11 (M, 2H) 8.08 (with, 1H)

Example 186

3 - [[2- (Cyclopropylmethyl) phenyl] thio] -6- (3,5-dimethylphenyl) -4-

-hydroxy-2H-pyran-2-one

The title compound was prepared via Method A using 3,3'-dimethylacetophenone (2 g, 13.51 mmol), trimethyl

160 silyl triflate (3 g, 31.1 mmol), triethylamine (2.73 mL, 27.02 mmol), methylene chloride (20 mL) and [[2- (cyclopropylmethyl) phenyl] thio] propanedioic acid diethyl ester (2.18 g) , 6.76 mmol).

MP: Mp 168 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.28 (D, 2H) 6.92 (m, 1 H) 0.39 (Dd, 2H) 7.11 (m, 2H) 1.13 (M, 1H) 7.22 (S, 1 H) 2.36 (with, 6H) 7.33 (m, 1 H) • 2.67 (D, 2H) 7.47 (S, 2H) 6.85 (with, 1H)

Example 187

6- (1,1'-biphenyl-3-yl) -4-hydroxy-3- [2-isobutylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 3 ^1- phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 mL, 10.20 mmol), triethylamine (2.06 mL, 20.40 mmol), methylene chloride (20 mL) and [2-isobutylphenyl) thio] propanedioic acid diethyl ester (1.14 g, 5.1 mmol). Mp 187-188 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.83 (D, 6H) 7 53 (T, 2H) 1.78 (M, 1H) 7 67 (T, 1H) 2.4 (D, 2H) 7 75 (with, 1H) 7.03 (with, 1H) 7 78 (WITH, 1H) 7.8 (with, 4H) 7 86 (M, 2H) 7.44 (T, 1H) 8 08 (WITH, 1H)

Example 188

4-hydroxy-3 - [(2-isobutylphenyl) thio] -6-phenyl-2H-pyran-2-one

161

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.96 g, 10.20 mmol) and [(2-isobutylphenyl) thio] propanedioic acid diethyl ester (1.64 g, 5H). , 1 mmol). MP: 195.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.83 (D, 6H) 7 06 (with, 4H) 1.64 (M, 1H) 7 56 (M, 3H) 2.39 (D, 2H) 7 86 (M, 2H) 6.89 (with, 1H)

Example 189

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (pyridin-3-yl) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using [2- (isopropylphenyl) thio] propanedioic acid diethyl ester (1 g, 3.22 mmol), trimethylsilyl triflate (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). MP: Mp 145-147 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.69 (T, 1H) 3.4 (M, 1H) 7.89 (D, 2H) 6.89 (with, 1H) 8.14 (with, 1H) 6.92 (D, 1H) 8.22 (D, 1H) 7.06 (M, 2H) 8.61 (Br: S, 1H) 7.25 (D, 1H) 8.97 (Br: S, 1H) 7.53 (M, 1H)

Example 190

4-hydroxy-3 - [(2-isopropylphenyl) thio] -6- (3-methylphenyl) -2H-pyran-2-one

162

The title compound is used 3 ^1- methylacetophenone trimethylsilyl triflate (1.44 g,

6.46 mmol), methylene chloride was prepared according to Method A, with g, 6.46 mmol), triethylamine (0.653 g, diethyl ester)

3.23 mmol). MP: 161 spectrum (0.87

6.46 mmol), (20 mL) and [(2-isopropylphenyl) thio] propanedioate (1.0 g, -162 ° C. ^X H-Nuclear Magnetic Resonance (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.13 (T, 1H) 2.39 (with, 3H) 7.28 (D, 1H) 3.42 (M, 1H) 7.39 (D, 1H) 6.86 (with, 1H) 7.4 (T, 1H) 6.92 (D, 1H) 7.64 (D, 1H) 7.07 (T, 1H) 7.67 (with, 1H)

Example 191

4-Hydroxy-3- (2-isopropyl-phenoxy) -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1-trimethylsilyloxyethylene (2.62 g, 13.6 mmol) and 2- (isopropyl) phenoxypropanedioic acid diethyl ester (2.0 g, 6.8 mmol).

^X H-Nuclear Magnetic Resonance Spectrum (250 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.09 (T, 1H) 3.44 (M, 1H) 7.29 (D, 1H) 6.67 (D, 1H) 7.53 (M, 3H) 6.89 (with, 1H) 7.83 (M, 2H) 7.0 (T, 1H)

Example 192

6- (3-Chlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A, whereupon

163 used 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 [(2-isopropylphenyl) thio] propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70%. MP: Mp 177-178 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.28 (D, 6H) 7.28 (D, 1H) 3.42 (M, 1H) 7.58 (T, 1H) 6.92 (D, 1H) 7.63 (T, 1H) 6.94 (with, 1H) 7.83 (D, 1H) 7.06 (T, 1H) 7.89 (with, 1H) 7.13 (T, 1H)

Example 193

6- (3,5-Dichlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

Prepared from 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

[(2-isopropylphenyl) thio] propanedioic acid (1.64

Isolated yield: 70%. MP: Mp 168-169 ° C.

^X H-NMR (400 MHz, DMSO-d6) g, 5.29 mmol).

1.25 (D, 6H) 7.13 (T, 1H) 3.42 (M, 1H) 7.28 (D, 1H) 6.92 (D, 1H) 7.83 (M, 1H) 7.01 (with, 1H) 7.88 (M, 2H) 7.06 (T, 1H)

Example 194

3 - [(2,6-dimethylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

164

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(2,6-dimethylphenyl) thio] propanedioic acid diethyl ester (2.0 g) .

6.8 mmol). MP: Mp 248-249 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.47 (with, 6H) 7.39 (M, 3H) 6.75 (with, 1H) 7.78 (M, 2H) 7.08 (M, 3H)

Example 195

4-hydroxy-3 - [(2-methylphenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(2-methylphenyl) thio] propanedioic acid diethyl ester (1.43 g, 5H). , 07 mmol). MP: Mp 210-211 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.47 (WITH, 3H) 7.17 (D, 1H) 6.82 (with, 1H) 7.56 (M, 3H) 6.86 (D, 1H) 7.86 (M, 2H) 7.04 (M, 2H)

Example 196

3 - [(2,6-dichlorophenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.72 g, 8.93 mmol) and [(2,6-dichlorophenyl) thio] propanedioic acid diethyl ester (1.5 g). .

4.46 mmol). MP: Mp 264-265 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

165

6.75 (WITH, 1H) 7.56 (M, 3H) 7.31 (T, 1H) 7.78 (M, 2H) 7.49 (d, 2H)

Example 197

4- [5- (1-Cyclopentylthio-3-methylbutyl) -4-hydroxy-6-oxo-6H-pyran-6-ylbenzoic acid ethyl ester, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6- (4'-carbethoxyphenyl) -2H-pyran-2-one (1.50 g, 5.77 mmol), ethanol (15 mL), isovaleraldehyde ( 0.497 g, 5.77 mmol), cyclopentylthiol (1.18 g, 11.54 mmol), piperidine (1.0 mL), acetic acid (1.0 mL). MP: Mp 174-176 ° C.

^X H-Nuclear Magnetic Resonance Spectrum

(400MHz,] DMSO-d 6, delta values) 1.05 - 0,72 (M, 10H) 4.36 (Q » 2H) 1.81 - 1,14 (M, 7 H) 6.8 (WITH, 1H) 2.13 - 1,81 (M, 3H) 7.90 (D, 1H) 3.04 (t, 1 H) 7.97 (Q, 1H) 4.22 (rn, 1 H) 8.15 (M, 2H)

Example 198

3 - [[(Benzylthio) pyridin-3-yl] methyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via 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), benzyl mercaptan (1.98 g, 15.96 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). MP: Mp 103-106 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

3.75 (q, 2 H)

5.31 (s, 1 H)

7.36 (m, 3H)

7.72 (m. 2H)

166

6.33 (s, 1H)

7.2 (m, IH)

7.28 (m, 5H)

7.89 (D, 1H) 8.38 (Dd, 1H) 8.57 (with, 1H)

Example 199

3- (1-Cyclopentylthio-2-cyclopropylethyl) -6- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -4-hydroxy-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -2H-pyran-2-one (1.00 g, 4.06) mmol), cyclopropylmethylcarboxaldehyde (0.34 ethanol (15 mL), g, 4.06 mmol), cyclopentylthiol (0.83 g, 8.12 mmol), piperidine and acetic acid (1.0 mL). MP: 80-82 ° C.

^X H-NMR (1.0 ml) (400 MHz, DMSO-d6)

0.03 (M, 2H) 4.2 (m, 1 H) 0.33 (M, 2H) 4.31 (m, 3H) 0 '64 (M, 1H) 6.53 (s, 1H) 1.28 - 1, 74 (M, 7 H) 7.0 (d, 1 H) 1.83 - 2, 06 (M, 3H) 7.24 (d, 1 H) 3.06 (M, 1H) 7.24 (dd, 2H)

Example 200

4 - [[(4-Hydroxy-6-oxo-5 - [(phenylethyl) thio] -6H-pyran-2-yl) phenoxy] methyl] benzoic acid

To a dioxane (20 mL) solution of 4 - [[(4-hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) phenoxy] methyl] benzoic acid (0.25 g) 2H NaOH and methanol were added to keep the reaction mixture homogeneous. The reaction mixture was stirred at ambient temperature for 24 hours. The solvents were evaporated. The solid was acidified with 3N hydrochloric acid. The resulting precipitate was filtered, washed with ether and dried in vacuo. MP: 227 ° C.

167 ^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.78 (t, 2 H) 7.14 - 7.32 (m, 7H) 2.97 (t, 2 H) 7.58 (d, 2 H) 5.29 (s, 2H) 7.78 (d, 2H).

6.72 (s, IH)

7.97 (d, 2H).

Example 201

4- (4-Hydroxy-6-oxo-5 - [(2-phenylethyl) thio] -6H-pyran-2-yl) benzoic acid ethyl ester

The title compound was prepared via Method A using 4-carboethoxyacetophenone (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 [(2-phenylethyl) thio] propanedioic acid diethyl ester (2.31 g, 7.81 mmol). MP: 156-158 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.36 (t, 3H) 6.86 (S, 1 H) 2.78 (t, 2 H) 7.11 - 7.28 (m, 5H) 3.01 (t, 2 H) 7.92 (d, 2H) 4.35 (q, 2H) 8.08 (d, 2H)

Example 202

4- (4-Hydroxy-6-oxo-5 - [(2-phenylethyl) thio] -6H-pyran-2-yl) benzoic acid

4- (4-Hydroxy-6-oxo-5- (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.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.94 (t, 2 H)

7.92 (d, IH)

168

3.03 (T, 2H) 7.99 (D, 1H) 6. 64 (WITH, 1H) 8.05 (D, 1H) 7 11 - 7, 33 (m, 4H)

Example 203

6- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A, whereupon

use 1,4-benzodioxin-6-ylmethylketone (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 [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.73 246-248 ° C).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

5.61 mmol).

MP:

1.25 (D, 6H) 7.06 (T, 1H) 3.4 (M, 1H) 7.11 (T, 1H) 4.32 (M, 4H) 7.26 (D, 1H) 6.72 (with, 1H) 7.31 (D, 1H) 6.89 (D, 1H) 7.35 (Dd, 1H) 7.01 (D, 1H)

Example 204

3- (1-Benzylthio-3-methylbutyl) -6- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -4-hydroxy-2H-pyran-2-one, (+, -)

The title compound was prepared via 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), benzyl mercaptan (1.0 g, 8.12 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL) ).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

169

0.78 (t, 6H) 4.31 (brm, 5H) 1.36 (m, IH) 6.56 (s, 1H) 1.5 (m, IH) 7.03 (d, 2H) 2.06 (m, IH) 7,36 7.25 (m, 6H)

4.2 (m, 1 H)

Example 205

3 - [[(Cyclohexylthio) pyridin-4-yl] methyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-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) and acetic acid (0.5 mL).

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (M, 5H) 5.33 (s, 1H) 1.53 (M, 1H) 6.69 (S, 1 H) 1.67 (M, 2H) 7.5 (m, 5H) 1.92 (M, 2H) 7.75 (m, 2H) 2.71 (M, 1H) 8.47 (d, 2H)

Example 206

3 - [[(Cyclohexylthio) pyridin-3-yl] methyl] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), ethanol (10 mL), pyridine-3-carboxaldehyde (0). , 86 g, 7.98 mmol), cyclohexylthiol (1.86 g, 7.98 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL).

^X H-Nuclear Magnetic Resonance Spectrum

170 (400 MHz, DMSO-d6, delta values)

1.25 (M, 5H) 7.33 (M, 1H) 1.53 (M, 1H) 7.53 (M, 3H) 1.67 (M, 2H) 7.73 (M, 2H) 1.92 (M, 2H) 7.97 (D, 1H) 2.69 (M, 1H) 8.39 (D, 1H) 5.39 (with, 1H) 8.67 (D, 1H) 6.72 (with, 1H)

Benzoic acid

Example 207

4 - [[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] The title compound is prepared by saponification of 4 - [[(4-hydroxy-2-oxo-6) methyl ester. -phenyl-2H-pyran-3-yl) thio] methyl] benzoate (0.1 g) as described in Example 200. ^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

4.06 (with, 2H) 7.58 (M, 3H) 6.72 (WITH, 1H) 7.86 (M, 4H) 7,36 (D, 2H) 7.86 (M, 4H)

Benzoic acid

Example 208

3 - [[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] The desired compound is prepared by saponification of 3 - [[(4-hydroxy-2-oxo-6) methyl ester. -phenyl-2H-pyran-3-yl) thio] methyl] benzoate (0.1 g) as described in Example 200. ^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

4.4 (d, 1 H)

4.73 (d, 1H)

6.71 (s, 1H)

7.4 (t, 1 H)

7.44 - 7.61 (m, 5H)

7.74 - 7.92 (m, 4H)

171

Example 209

2 - [[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thiomethyl] benzoic acid

The title compound was prepared by saponification of 2 - [[(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thiomethyl] benzoic acid methyl ester (0.2 g) as described in Example 200. ^X H- Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

4.36 (with, 2H) 7.39 (T, 1H) 6.69 (with, 1H) 7.53 (M, 3H) 7.18 (D, 1H) 7.79 (M, 3H) 7.29 (T, 1H)

Example 210

3 - [(2-chlorophenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(2-chlorophenyl) thio] propanedioic acid diethyl ester (1.53 g, 5H). , 07 mmol). MP: 275-280 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

6.78 (with, 1H) 7.42 (Dd, 1H) 6.89 (Dd, 1H) 7.56 (M, 3H) 7.08 (Tt, 1H) 8.06 (M, 2H) 7.19 (Tt, 1H)

Example 211

4-hydroxy-3 - [(2-methoxyphenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A, whereupon

172 uses 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(2-methoxyphenyl) thio] propanedioic acid diethyl ester (1.51 g, 5.07 mmol). MP: Mp 208-209 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

3.83 (S, 3H) 6.97 (D, 1H) 6.74 (dd, 1 H) 7.08 (T, 1H) 6.82 (d, 1 H) 7.56 (M, 3H) 6.86 (S, 1 H) 7.86 (M, 2H)

Example 212

4- (4-Benzyloxy-phenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4-benzyloxyacetophenone (0.3 g, 0.675 mmol), trimethylsilyl triflate (0.15 g, 0.675 mmol), trimethylamine (0.14 g,

1.35 mmol), methylene chloride (20 mL) and diethyl ester

Of 2 - [(isopropylphenyl) thio] propanedioic acid (0.210 g, 0.675 mmol). MP: 163-165 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.28 (D, 6H) 7.19 (D, 1H) 3.4 (M, 1H) 7.28 (D, 1H) 5.22 (with, 2H) 7,36 (Q, 2H) 6.64 (with, 1H) 7.42 (D, 2H) 6.92 (D, 1H) 7.49 (D, 2H) 7.06 (T, 1H) 7.83 (D, 2H) 7.11 (T, 1H)

Example 213

3 - [(3-chlorophenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A, whereupon

173 used 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(3-chlorophenyl) thio] propanedioic acid diethyl ester (1.53 g, 5.07 mmol). MP: Mp 181-182 ° C.

H -H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

6.88 (with, 1H) 7.29 (T, 1H) 7.13 (Dt, 2H) 7.56 (M, 2H) 7.19 (Dt, 1H) 7.86 (M, 2H)

Example 214

4-hydroxy-3 - [(3-methoxyphenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(3-methoxyphenyl) thio] propanedioic acid diethyl ester (1.51 g, 5H). , 07 mmol). MP: 130-131 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

3.69 (with, 3H) 7.2 (Dt, 2H) 6.69 (Dd, 1H) 7.58 (M, 3H) 6.72 (Dd, 1H) 7.88 (M, 2H) 6.89 (with, 1H)

e

Example 215

4-Hydroxy-3 - [(3-methylphenyl) thio] -6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.95 g, 10.14 mmol) and [(3-methylphenyl) thio] propanedioic acid diethyl ester (1.43 g, 5H). , 07 mmol). MP: Mp 197-198 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

2.24 (s. 3H)

6.89 (s, 1H)

7.14 (t. 2H)

7.56 (m, 3H)

174

7.86 (m. 2H)

6.93 (t, IH)

6.97 (s, IH)

Example 216

3 - [(2-Ethyl-phenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (4.17 g, 21.71 mmol) and [(2-ethylphenyl) thio] propanedioic acid diethyl ester (1.5 g,

10.86 mmol). MP: Mp 190-192 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (T, 3H) 7.08 (M, 2H) 2.78 (Q, 2H) 7.2 (M, 1H) 6.89 (WITH, 1H) 7.58 (M, 3H) 6.92 (M, 1H) 7.86 (M, 2H)

Example 217

Acetic acid 3 - [(2-isopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-4-yl ester

The title compound is prepared by reacting 4-hydroxy-3 - [(2-Isopropylphenyl) thio] -6-phenyl-2H-pyran-2-one sodium salt (0.2 g, 0.59 mmol) with acetyl chloride (0.09) g, 1.18 mmol) as described in the general procedure GTt Mp 113-115 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.26 (D, 6H) 7.04 (Dt, 1H) 1.89 (WITH, 3H) 7.13 (Dt, 1H) 3.42 (M, 1H) 7.28 (Dd, 1H) 6.89 (with, 1H) 7.58 (M, 3H) 6.94 (Dd, 1H) 7.86 (M, 2H)

Example 218

175

4-Hydroxy-6-phenyl-3 - [(3-trifluoromethylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.72 g, 8.92 mmol) and [[(3-trifluoromethylphenyl) phenyl] thio] propanedioic acid diethyl ester (1.5 g, 4.46 mmol). MP: Mp 228-229 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

6.88 (s, 1H)

7.4 - 7.61 (m, 7H)

7.89 (m. 2H)

Example 219

3 - [(3,5-dimethylphenyl) thio] 4-4-hydroxy-6-phenyl-2H-pyran-2-one

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.3 g, 6.76 mmol) and [(3,5-dimethylphenyl) thio] propanedioic acid diethyl ester (1.0 g) .

3.38 mmol). MP: Mp 214-216 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

2.2 (s, 6H) 7.56 (m, 3H)

6.75 (brs, 3H); 7.86 (m, 2H)

6.89 (s, 1H)

Example 220

6- [4- (cyclohexylmethoxy) phenyl] -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4-cyclohexylmethoxyacetophenone (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

176 [(2-isopropylphenyl) thio] propanedioic acid (4.0 g, 12.92 mmol). MP: Mp 187-188 ° C.

^X H-Nuclear Magnetic Resonance Spectrum (400

Hz,] DMSO-d 6, delta values) 0.96 - 1,33 (m + 1.24d, 11H) 6.92 (Dd, 1H) 1.61 - 1,87 (m, 7H) 7.11 (M, 4H) 3.4 (m, 1 H) 7.29 (Dd, 1H) 3.86 (d, 2H) 7.81 (D, 2H) 6.76 (S, 1 H)

6- (3-Benzyloxyphenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one

The title compound was prepared via 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 [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (0.210 g, 0.675 mmol). Mp 162-164 ° C. ¹ H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

1.25 (D, 6H) 7.06 (Dt, 1H) 3.42 (M, 1H) 7.11 (Dt, 1H) 5.35 (with, 2H) 7.22 (Dd, 1H) 6.89 (with, 1H) 7.28 (Dd, 1H) 6.92 (D, 1H) 7.39 - 7, 51 (

Example 222

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (3-phenylpropoxy) phenyl] -2H-pyran-2-one

The title compound was prepared via Method A using 4-phenylpropyloxyacetophenone (2.0 g, 7.86 mmol), trimethylsilyl triflate (1.75 g, 7.86 mmol), triethylamine (1.59 g,

177

15.72 mmol) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.66 g, 11.79 mmol). MP: 132-133 ° C.

@ 1 H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta)

1.25 (D, 6H) 6.90 (d, 1 H) 2.06 (M, 2H) 7.05 (dt, 2H) 2.75 (T, 2H) 7.08 (q, 2H) 3.39 (M, 1H) 7.11 - 7.31 (m, 4.08 (T, 2H) 7.81 (d, 2H) 6.78 (with, 1H)

Example 223

3 - [(2-sec-butylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one, (+, -)

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyloxy) ethylene (1.0 g, 6.17 mmol) and [(2-sec-butylphenyl) thio] propanedioic acid diethyl ester (1.0 g) , 3.09 mmol). MP: Mp 170-171 ° C.

^T H-Nuclear Magnetic Resonance Spectrum (400 MHz, DMSO-d6, delta values)

0.86 (T, 3H) 6.97 (D, 1H) 1.22 (T, 3H) 7.06 (T, 1H) 1.57 (M, 1H) 7.13 (T, 1H) 1.67 (M, 1H) 7.22 (T, 1H) 3.22 (M, 1H) 7.56 (M, 3H) 6.89 (with, 1H) 7.86 (M, 2H)

178

Determination of HIV protease inhibition Starting materials

DTT buffer: 1.0 mM dithiothreitol (DTT) is freshly prepared daily in 0.1% polyethylene glycol (mw 8000) 80 mM NaOAc, 160 mM NaCl, 1.0 mM EDTA, and the pH is reduced to 4.7.

HIV-I Protease: The enzyme is obtained from Bachem Bioscience Inc. The undiluted enzyme is thawed from -80 ° C and diluted 50 times with DTT buffer. The solution is still maintained at 0 ° C (ice water) and used in experiments within 20 minutes of thawing.

Enzyme Substrate: Substrate III by Bachem Bioscience Inc. is the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-p-Nitrophenylalanine-Glu-Ala-Norleucine-Ser-NH ₂ (purity &gt; 97%). A 200 M solution in DTT buffer is stored on ice. The substrate solution is prepared fresh daily.

Test compound: Dilute 10 mM inhibitor (I) in dimethylsulfoxide (DMSO) to 200 m DTT buffer. A 10 M solution of 2% DMSO in DTT buffer was prepared from a 200 M solution. Two inhibitor solutions are used to prepare final [I] = 100, 50, 20, 10, 5, 2, 1, 0.5 and 0 M with 2% DMSO in DTT buffer in each reaction well (total inhibition volume 50 L) .

Test

While the reaction plate is shaken, 10 L of diluted protease is added to the reaction well. After 10 seconds of shaking, the plate will return to the heater (Final

20 L of substrate (40 M final concentration), 50 L of inhibitor (at such a concentration that the final dilution corresponds to the test concentration) and 20 L of DTT buffer are added to each reaction well. The reaction plate (96 wells) is incubated for at least 5 minutes at 37 ° C.

179 reaction volume 100 L).

At 37 ° C, the reaction is incubated for 5 minutes and is discontinued by placing the reaction plate on a shaker and adding 20 L of 10% trifluoroacetic acid. Shaking is continued for 10 seconds. The degree of proteolysis is then given by the separation of the uncleaved substrate and the two cleavage products by high pressure liquid chromatography, with the aim of determining the relative

the peak areas of these components are 220 nm in length. The relative areas of conversion to product as a function are in% relative to the control absorbance at the wave peak used to calculate the% inhibitor concentration. Experiment data (ratio of% conversion in the presence and absence of inhibitor x 100) versus inhibitor concentration and well coincides with the equation Y = 100 / + (X / IC50) ^A , where IC50 is the inhibitor concentration at 50% inhibition and A is the slope of the inhibition curve. .

Table 1

Results of inhibition. HIV protease

Example

Inhibitory concentration 50 (mean (M))

1 0.47 3 1.0 4 0.9 6 0.4 8 1.7 17 0.69 23 1.7 26 1.2 27 0.5 28 1.9 29 0.33 33 1.97 34 0.8

180

Example

Inhibitory concentration 50 (mean (M))

44 0.75 48 0.86 49 1.6 52 0.7 64 0.6 68 0.45 70 0.13 71 1.9 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

181

Anti-HIV-1 activity

Using the general procedures of Pauwels et al., (J. Virol.

Methods, 16, 171-185, 1987) and Manna et al., (AIDS Research and Human Retroviruses, 253-255, 1989), an antiviral assay for acute HIV-1 infection is performed in the H9 cell line.

The cultures are batches of cell cultures infected in 1 ml culture medium RPM1 1640/10% fetal calf serum containing 10 ^v cells and 10 ^s infectious doses of HIV-1 _{± it} for a purposeful multiplication of infection of 0.01. After two hours of viral uptake, cells are washed and transferred to a 96-well microtiter plate at a density of 10 ⁴ cells per well. Test compounds were added to produce the desired drug concentration and 0.2% DMSO at a final volume of 200 L.

Uninfected control cultures are maintained for 7 days post infection for the purpose of the XTT-cytotoxicity assay. At 4 and 7 days post infection, the cultures are tested for viral replication by reverse transcriptase.

Table 2

Antiviral activity in the H9 cell line

Example

Concentration at 50% protection (M)

29 17 70 29 78 3 87 15 121 15 166 14 169 31 172 0.65

182

Combinations of a protease inhibitor with other treatments for AIDS, e.g. (not only) AZT or ddC reverse transcriptase inhibitors may exhibit synergistic results. J.C. Craig et al .: Antiviral 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 Res., 21: 327-34 (1993), A.M. Caliendo et al., Clin. Infect. Dis., 18/4: 516-524 (1994).

In the microtiter dilution method described by Heifetz et al., Antimicr. Agents Chemoth., 6: 124 (1974), the compounds of the invention exhibit antibacterial activity.

Using the above method, the following minimum inhibitory concentration values are obtained for representative compounds of the invention. These data are related to clinically relevant Gram-positive pathogens that have become highly resistant to conventional therapy in recent years.

183

Antibacterial activity g / ml

Pr. 172 Pr. 29 Pr. 167 Pr. Staphylococcus aureus H228 50 25 6.2 12.5 Staphylococcus aureus UC-76 50 25 6.2 12.5 Enterococcus foecalis MGH2 100 50 12.5 25 Streptococcus pneumonia 50 25 6.2 12.5 Streptococcus pyogenes C203 50 25 6.2 12.5

It should be understood by those skilled in the art that other, not specifically described, compositions also fall within the scope of the invention. Thus, the invention is not limited to the description of specific embodiments, but only by the definition of the following claims.

Claims (18)

PATENT CLAIMS A compound of the general formula X _R S WAHHCHg ^ SR ³ i I R ³ W ¹ (CH ₂ ) _m W (CH ₂ ) _n A ^of 'Y' 2 Z wherein X is OR ¹ , NHR ¹ , SR ¹ , CO ² R ⁴ or CH ² OR ¹ , wherein R ¹ is R ⁴ or COR ⁴ , wherein R ⁴ is as defined below, Y is an oxygen atom or a sulfur atom, Z is an oxygen atom or a sulfur atom, A and A ¹ are independently a chemical bond, an unsubstituted or substituted phenyl group, a naphthyl group, a five or six membered heterocyclic ring, a cycloalkyl group, an alkylcycloalkyl group or a ring system containing from 8 to 10 atoms or a substituted derivative thereof; / s from the group consisting of F, Cl, Br, oR ^4, N (R ⁴⁾ 2, CO 2 R ^4, CON (R ⁴⁾ 2, COR ^4, R ^4, OCH ₂ O, OCH ₂ CH ₂ O or C = N wherein R ⁴ is independently hydrogen> substituted or unsubstituted alkyl, cycloalkyl, alkylcycloalkyl or phenyl, wherein the substituent (s) is / are selected from the group consisting of CO ₂ R ² , CON (R ² ) 2, F , OR ² , SR ² , N (R ² ) 2, CN, phenyl, naphthyl, heterocycle or CF, wherein R ² is independently alkyl, cycloalkyl, or hydrogen, 185 R ^s R ³ W W ^x is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, a phenyl group or a derived substituted derivative, wherein the substituent (s) is / are selected from the group consisting of CO 2 R ² , CON (R ² ) ₂ , F, OR ² , phenyl, naphthyl, CF 4, OR ^x , NHR ^X , SR ¹ or CH OR ^X , is and CO ₂ R ² , a naphthyl group, wherein R ^x is as defined above, independently of a hydrogen atom, (CH) R ⁴ 2] p an integer from 0 to 2 and R ⁴ W ³ are independently chemical C (R ³ ) ₂ , CO, CR ³ N (R ³ ) ₂ , SO ₂ NR ³ , g is 0 or 1 and or CHR ³ , are independently integers W ^x heteroatoms or an integer from 2 CR ³ = CR ^3, C≡C, WHAT , V is or (CH 2) A, wherein p and A are as defined above, a bond, an oxygen atom, NR ³ , CR ³ OR ³ , C (= NR ³ ) NR ³ , S (O), P NR ³ COA or NCOV 4 R ³ , wherein the oxygen atom, the sulfur atom, NR ^{3 thereof} is to 4 with the proviso that if they are heteroatoms, then they have a further proviso, R ³ W ^X (CH ₂ ) _m W (CH ₂ ) _n A cannot be a methyl or ethyl group, pharmaceutically acceptable salts. 2. W ² to 0 W ² and W ³ to 4, W and is that A compound according to claim 1 having the general formula wherein SO _{2 is} NR ³ or S (O) 2, wherein p is an integer from 0 to 2. A compound according to claim 2 having the general formula wherein And ^x is not a bond. A compound according to claim 3 of the general formula 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] 186 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] acid 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) cyklopenty1-2H-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) cyklopropy1-2H-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, 187 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-naftalenylmetyloxy) 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-isopropyl | phenyl) thio] -2H-pyran-2-one, 4- [4-Hydroxy-2-oxo-3 - [(2-isopropylphenyl) thio] -2H-pyran-6-yl] -2-methylphenoxyacetic acid, 4-Hydroxy-6- [4- (2-hydroxyethoxy) phenyl] -3 - [(2-isopropylphenyl) 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-pyrazinmetoxy) 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, 188 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-dioxo-thiomorpholin-4-yl) ethoxy] phenyl] -2H-pyran-2-one, 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (1-phenylcyclopentyl) -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-yl ester, Propanoic acid 2-oxo-6-phenyl-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one-4-yl ester, Phenylacetic acid 2-oxo-6-phenyl-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one-4-yl ester, 4-hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6-phenyl-2H-pyran-2-one, 4-hydroxy-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-Hydroxy-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- 189 a. . - {. '' · «' -2-6n, '7 4-Hydroxy-6-phenyl-3 - [(2-tert-butylphenyl) thio] -2H-pyran-2-one; 3 - [(2-Cyclopropyl-5-isopropylphenyl) thio] -4-hydroxy-6-phenyl-1 H- -2B.-pyraj) .- _2-t OZL £ 3- (5-CyklopeíLtyl, -izopropylfenyl) thio] r 4-hydroxy-6-phenyl-2H-pyran-2-RON _/ 3 - [(2-Cyclohexyl-5-isopropylphenyl) thiyl] -4-hydroxy-6-phenyl- -2H-pyran-2-one; 4-Hydroxy-6-phenyl-3- (2-tert-butyl-5-isopropylphenyl) thio] - 2H-pyran-2-ou, £ 3 '(2,5-Di-tert-butyl-phenyl) -thi] -4-hydroxy-6- phenyl-2H-pyran-i / -2-one, 3-I (2-Cyclopentylphenyl) thio-4-hydroxy-5-phenyl-2H-pyran-2-yne 3 - [(2-Cyclphexylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 4 - [[4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl] thio] -2-hydroxy-indane; 4-Hydroxy-3 - [[2-isopropyl-4- (morpholin-4-ylmethyl) phenyl] thio] -. - * 'à ·' -6-phenyl-2H-pyran-2-one, / j 4-Hydroxy-3- Ĺ (6-isopropyl-indan-5-yl} thio-6-phenyl-2H-pyran-y -2-one, y 4-Hydroxy-3 - [(4-isopropyl-benzyl [1,3] dioxol-5-yl) -thio] -6-y phenyl-2H-pyr $-2-Ox, Jy 3- [(2-tert-butyl-4-thiomorpholine-4-vimethylphenyl) thio] -4-ol; -bydroxY-6-phenyl-2H-pyran-2-one _of y 4-Hydroxy-6- [4- (pyridin-3-ylsezoxy) phenyl] -3 - [(2-tert-butyl-phenyl) thio] -2H-pyran-2-one, • '> Λ · 3-Π (2-Cyclopropyl-5-isopropyl-phenyl) -thio] -4-hydroxy-6- [4- / -pyridin-3-ylmethyl) phenyl] -2H-pyran-2-one, y 3- Π (2-cyclopentyl-5-isopropyl-phenyl) -thio] -4-hydroxy-6- [4- pyridin-3-yÍTnetyl ·) phenyl] -2-pyrar_-2-one, / 3- [E (2-Cyclohexyl-5-isopropyl} phenyl] thio] -4-hydroxy-6- [4-pyridin-3-ylmethyl) phenyl] -2H-pyran-2-one, 4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3 - [(2-tert-butyl-5-isopropylphenyl) thio] -2H-pyran-2-cr. _; 3-1 (2,5-Di-tert-butylphenyl) thi] -4-hydroxy-6- [4- (pyridine-3-); -ylmethoxy) phenyl] -2H-pyran-2-one; I 3- [(2-Cyclopentylphenyl) thio] -4-hyôroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one _/ 3 - [(2-Cyclohexylphenyl) thio] -4-hydroxy-, 6- [4- (pyridin-3-ylwethoxy) phenyl] 4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3-1 (6-tert-butylindan-5-yl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropyl-4-morpholin-4-ylinethylphenyl) thio] -6- [4- (pyridin-3-ylraethoxy) phenyl] -2H-pyran-2-one, Acetic acid 3 - [(2-isopropylphenyl) thio] -2-oxo-5- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyrrol-4-yl ester, Isobutyric acid 3-1 (2-isopropylphenyl) thio] -2-oxo-N- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester, 2,2-Dimethylpropionic acid 3 - [(2-isopropylphenyl) thio] -2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester, 4-Hydroxy-3 - [(2-isopropylphenyl) sulfonyl] -6- [4- (pyridin-3-ylniethoxy) phenyl] -2H-pyran-2-one, 3- [(2-Terc.bntylfenyl) sulfonyl-4-hydroxy-6-phenyl-2H-pyran-2-one _yl 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-2-6n, n- [3-1 (6- (1-benzylpropyl) -4- hydroxy-2-oxo-2S-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, U 190 6- (1,1-dimethyl-3-phenyl-propyl) -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-benzyl) cyclopropyl) -2H-pyran-2-one, 4-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- [1- (2-phenylethyl) cyclopropyl] -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-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- [1- (3-phenylpropyl) cyclobutyl] -2H-pyran-2-one, 4-hydroxy-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-hydroxy-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-l-phenylethyl) -2H-pyran-2-one, 6- (1,1-Diethyl-3-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one, 191 6- (1-Benzyl-1-ethylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; and 6- (1-ethyl-l-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one. A compound according to claim 2 of the formula wherein A is a bond and (CH) W ³ is not a bond. 1 ^J 2 m ^J A compound of the general formula according to claim 5 selected from the group consisting of J 6 - [- [(3,5-Dimethyl-4-isoxazolyl) methoxy] phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one, 4-Hydroxy-3 - [(2-phenylethyl) ethyl] -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- [phenyl (phenylmethyl) thio] -2H-pyran-2-one, 4-Hydroxy-3 - [(2-phenoxyethyl) thio] -6-phenyl-2H-pyran-2-one, (E) -4-Hydroxy-6-phenyl-3 - [(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-Chloro-phenyl) -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, 192 4-Hydroxy-6- (3-hydroxyethyl) -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 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] -1H-pyran-2-one, 4-Hydroxy-6- (4- (2-methoxyphenyl) methoxy] phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one, 4-Hydroxy-3 - [(2-phenylethyl) thioc] -6- [4- (phenylphenyl) phenyl] -2H-pyran-2-one, 6- (1 _and 3-Benzodioxol-5-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one, 6- (3,5-Methylphenyl) -4-hydroxybenzyl-3 - [(phenylenylmethy1) thi. o] - 2H-pyran-2-one, 4-Hydroxy-6- {2-naphthyl} -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-D-methylphenyl) -4- (hydroxymethyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one, [4- [4-Hydroxy-5- (hydroxymethyl) -2-oxo-3 - [(2-phenylethyl) tib] -2K-pyran-6-yl] phenoxy] acetic acid> 4-Kydroxy-6- [4-methoxy-phenyl) methyl] -3 - [[Ϊ- (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-cis-3 - [(phenylmethyl) thio] -2 H -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- (3-phenylethylthio) -6- [4- (phenylsulfonyl) phenyl] 193 b 2H-pyran-2-one, 4-Hydroxy-3- [2- (3-phenylethyl) thio] -6- [4- (benzoyloxy) phenyl] pyran-2-one 4-Hydroxy-3- [2- (3-fenylety1) the] * 6- [4- (phenylsulfinyl) phenyl] -2H-pyran-2-one, 4-Hydroxy-3- [2- (3-phenylethyl ·; thio] -6- (4-pyridyl) -2H-pyran-2-one, 4-Hydroxy-6- (3-phenoxyphenyl ·) -3 - [(2-phenylethyl) thio] -2H-pyran-2-unit, 4-Hydroxy-6- [3-inethoxy-4- (phenylmethoxy) phenyl] -3 - [(2-phenylethyl) thio] -2H-pyran-2-one, 6- (3,5-dimethylphenyl) -4-hydroÄy-3 - [(2-phenylethyl) thio] -2H-pyran-2-όη, 4-Hydroxy-3 - [[(3-methoxyphenyl. Methyl) thio] -6-phenyl-2H-pyran-2-one; 4-Hydroxy-6-phenyl-3 - [[[3- (phenyl-tetoxy) phenyl] methyl] thio] -2H-pyran-2-one, 3 - [(1,3-Benzodioxol-5-ylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one, 4-Hydroxy-3 - [[(2-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one, 4-hydroxy-3 - [[(2-mety1fenyl) mety1] thio] -6-feny1-2H-pyran-2-one, 4-hydroxy-3 - [[(3-methylphenyl) metylJtiq] -6-phenyl-2H-pyran-2-OA, 4-hydroxy-3 - [[(4-methylphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one, 6-11.1-Biphenyl] -3-yl-4-hydroxy-3-r- (2-phenylethyl) thio] -2H-pyran-2-one, 4-hydroxy-3 - [[(4-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran 194 -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-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one, 4-hydroxy-3 - [(2-phenylmethyl) 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 - [(- phenylethyl) thio] -2H-pyran-one 4-Hydroxy-6- [4- (2-phenylethyl) phenyl] -3 - [(- phenylethyl) thio] -2H-pyran-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, 195 2 - [[4- (4-Hydroxy-2-oxo-3 - [(2-phenylmethyl) thio] -2H-pyran-6-yl] phenoxy] methylbenzoic acid methyl ester, 4-hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (lH-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-hydroxy-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-Chloro-phenyl) -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; 4-Hydroxy-3 - [(phenylmethyl) thio] -6- (3-thienyl) -2H-pyran-2-one. A compound according to claim 1 having the general formula wherein W ² represents an oxygen atom. A compound according to claim 7 having the general formula wherein A ^{1 is} not a bond. 196 A compound according to claim 8 having the general formula selected from the group consisting of 4-Hydroxy-3-phenoxy-6-phenyl-2H-pyran-2-one 4-Hydroxy-3- (2-isopropylphenoxy) -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one, 4-Hydroxy-3- (2-isopropylphenoxy) -6-phenyl-2H-pyran-2-one; 3- (2-t-butylphenoxy) -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; 6- (1-Benzylpropyl) -3- (2-t-butylphenoxy) -2H-pyran-2-one, A compound according to claim 7 having the general formula wherein A ^x represents a bond and (CH ₂ ) _m W ³ does not represent a bond. A compound according to claim 10 of the general formula selected from the group consisting of 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-ylmethoxy] 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. A compound according to claim 1 of the formula wherein W ² is selected from the group consisting of NR ³ NR ³ COV A g NCOV R ³ ag 197 SO NR ³ wherein in each case nitrogen is bonded to the carbon at the 3-position of the pyrone ring. A compound according to claim 12 having the general formula wherein W ² is NR ³ A compound according to claim 13 of the general formula selected from the group consisting of 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-cyclopentylmethylamino) -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one, 3- [Cyclopentylmethyl (cyclopropylmethyl) amino] -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one, 6- [l-cyclopropylmethyl-2- (tetrahydropyran-3-yl) ethyl] -3- (cyclopropylphenylamino) -4-hydroxy-2H-pyran-2-one. A compound according to claim 12 having the general formula wherein W ² is selected from the group consisting of NR ³ COV WITH NCOV R ³ a S ^- SO NR ³ wherein in each case nitrogen is bonded to the carbon at the 3-position of the pyrone ring. 198 A compound according to claim 15 having the general formula selected from the group consisting of (S) -1,3-Dihydro-N- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) - (phenylmethyl) ) -2H-isoindole-2-acetamide; N- (1,1-Dimethylethyl) -N '- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -N' - (phenylmethyl) urea, Cyclopentylmethyl- [4-hydroxy-2-oxo-6 - [(pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] amide cyclopropanecarboxylic acid, Cyclopentanecarboxylic acid cyclopentylmethyl- [4-hydroxy-2-oxo-6 - [(pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] amide, N-Cyclopentylmethyl-N- [4-hydroxy-2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] cyklopentánsulfónamid, 17. Compounds with the names: 2- Cyclopentylbenzenethiol, 3-Methoxy-2- (1-methylethyl) benzenethiol, 2- (1,1-Dimethylethyl) -4-methoxybenzenethiol, 2- (cyclopenten-2-yl) benzenethiol. 2-Cyklohexylbenzéntiol, 2- (1,1-Dimethylethyl) -5-methoxybenzenethiol, 2- (1,1-Dimethyl-2-hydroxyethyl) benzenethiol a 2- (1,1-Dimethylethyl) -4,5- (methylenedioxy) benzenethiol. 18. Compounds with the names: [(2-Isopropylphenyl) thio] propanedioic acid diethyl ester, [(2-cyclopropylmethylphenyl) thio] propanedioic acid diethyl ester, [(2,5-Diisopropylphenyl) thio] propanedioic acid diethyl ester, Diethyl ester, [(2-Isopropyl-5-methylphenyl) thio] propanoic acid [(2,4-di-tert-butylbenzyl) thio] propanedioic acid diethyl ester, 199 [(2-sec-butylphenyl) thio] propanedioic acid diethyl ester, [(2-cyclohexylphenyl) thio] propanedioic acid diethyl ester, [(2-cyclopentylphenyl) thio] propanedioic acid diethyl ester, [(2-tert-Butyldimethylsilyloxymethylphenyl) thio] propanedioic acid diethyl ester and [(3- (p-toluenesulfonylamino) phenyl) thio] propanedioic acid diethyl ester.