CZ134396A3 - 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

Pyronic derivatives as protease inhibitors and antiviral agents _________________________

Technical field

The invention relates to pyronic derivatives which are aspartyl protease inhibitors, in particular aspartyl proteases present in retroviruses, including human immunodeficiency virus (HIV). It is contemplated that pyrones may be used as antiviral agents, for the treatment of infections caused by HIV or other aspartyl protease-using retroviruses, for 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, a retrovirus - human immunodeficiency virus (HIV) - was found by the etiological agent of AIDS from a subset of lentiviruses. At least two infectious strains of HIVHIV-1 and HIV-2 have been described. Here, HIV will be used as a general term describing a family of strains and mutants of human immunodeficiency virus. In a detailed study of HIV, research has been conducted in a variety of ways to develop an antiviral drug, including inhibition of viral aspartyl protease (D.Richman, Control of Virus Diseases, 45th Symposium Society for General Micro. 261-313 (1990).

Aspartyl proteases have been discovered in many retroviruses, including Felin immunodeficiency virus, myeloblastosis-associated virus, HIV and Rous sarcoma virus (H.Toh et al., Nature, 1985: 691, 1985; J. Kay, BMDunn, Biochim. Biophys 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 may well inhibit compounds that inhibit the HIV protease.

The HIV-aspartyl protease is responsible for the posttranslational mechanism of viral precursor proteins, e.g., pol and ........

gag (M.raves, Structure and Function of the Aspartic Proteases, pp. 395-405 (1991)). Cleavage of these proteins by this protease is essential for virus maturation, since proteolytic activity for the polyprotein process cannot be ensured by host cellular enzymes. A very important finding was that viruses that lack this protease or contain a mutation that causes a defective protease to be defective are not infectious (C. Peng et al., J. Virol, 63: p.2550-2556, 1989? and N.Kohl et al., Proc. Natl. Acad. Sci USA, 85: 4669-90, 1987). Thus, a selective HIV protease inhibitor has been shown to be capable of inhibiting virus spread and cytopathic effects in cultures of acutely infected cells (J.C.Craig et al., Antiviral Research, 16: 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.). Therefore, HIV protease inhibitors of non-peptidic origin are of increasing importance since they can be very useful therapeutic agents.

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

World Patent 89/07939 claims eight coumarin derivatives as HIV reverse transcriptase inhibitors with potential antiviral activity. These derivatives are hexachlorocoumarin, 7-acetoxycoumarin and the structures below.

Warfarin (3-fo (-acetonylbenzyl) -4-hydroxycoumarin) below was described by R. Nagorny et al. in AIDS, 7: 129-130, 1993 as an inhibitor of extracellular and cell-mediated HIV infection. However, warfarin was another studied pyron and the mechanism of its action in inhibiting HIV was not specified.

Selected flavones structurally different from the pyrons of the invention have been described by Fairlim et al., Biochem. Biophys. Res. Comm., 188: 631-637, 1992, as HIV-1 protease inhibitors. These are the following compounds:

O OH O

HO _X

HIM

OH

U.S. Pat. No. 3,206,476 discloses certain pyrones, in particular 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 several pyronic derivatives, namely 4-hydroxypyrones with sulfur-containing carbon chains at the 3-position, as growth inhibitors and antimicrobial agents. However, the substitution at the 6-position of these heterocycles refers only to the methyl group. The following pyrones 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, an allyl group, a cyclohexyl group substituted by 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

S (O) 'R ·

R

O

R = Me

A process for preparing the above-mentioned pyrons 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 antiviral 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 developing therapy for viral infections, particularly retroviruses, whose replication and infectivity is dependent on aspartyl protease activity. Pyrons are also considered to be very useful as viral blockers in the treatment of disease states and syndromes associated with viral pathogenic agents. One such syndrome is AIDS.

Effective syntheses of biologically active pyrons are described, including rebuilding pyron nuclei or modifying suitable functionalized pyrons. In addition, a number of examples are given describing the preparation of specific pyrons whose structures contain the desired functional groups in the respective geometric configurations.

Also included is testing for specific pyrons as HIV-aspartyl protease inhibitors based on research on undecapeptide enzyme substrate hydrolysis, and testing for pyrons as inhibitors of viral growth and infectivity based on HIV-1 strain infection of H9 cell lines. 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 pyrons of the invention and related compounds and a pharmaceutically acceptable carrier. 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, is also included.

The invention relates to the compounds of formula (1) below

B ⁵ W (CH ²⁾ W ³ B ³ / Z ΠΧ

ΤΎ

B ³ W ¹ (CH ₂ ) _n W (CH ₂ ) _n A ^ZX r = Z in which

X is OR ^1, NHR ^1, SR ^1, CO ₂ R ⁴ or CR-OR ¹ wherein R ¹ is R ⁴ or COR ^4, wherein R ⁴ is as defined below;

Y is O or S;

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; containing F, Cl, Br, OR, N (R) 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 'is independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl, alkylcycloalkyl or phenyl, wherein the substituent (s) is selected from the group consisting of CO-R, CON (R) -, F, OR,

2 z z

SR, N (R) n, CH, phenyl, naphthyl, heterocycle or CF, wherein R is independently alkyl, cycloalkyl, or hydrogen;

A is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylcycloalkyl group, a phenyl group or substituted derivatives thereof, wherein the substituent (s) are selected from the group consisting of CO, R,

^Z 2 CON (R) _, F, OR, phenyl, naphthyl, ²¹¹¹ 1 '' group, CF _3, OR, NHR, SR, or -CH ₂ OR, R! has the above meaning;

4

R is independently hydrogen, (CH ~) R or (CH) _A, ^J 2 P 2 ₄ p wherein p is an integer from 0 to 2 and R and A are as defined above;

W, W ^ and W ³ are independently a chemical bond, an oxygen atom, NR ³ ,

C (R ³ ) 2, co, cr ³ = cr ³ , c = c, cr ³ or ³ , c (= nr ³ ) nr ³ , s (o) p,

CR ³ N (R ³ ) -, SO-NR ³ , CO ³ , NR ³ COV a and NCOV R ³ , wherein 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 , -CO, NR ³ COV A

P ^z and NCOV g R, wherein g is 0 or 1 and V is O, S, NR or CHR ³ ;

m and n are independently integers from 0 to 4 with the proviso that

When W and W are heteroatoms or W and W are heteroatoms, then m is an integer from 2 to 4; and others

1 provided that RW (CH2) _m W _(CH2), A is not methyl or ethyl;

and pharmaceutically acceptable salts thereof.

Preferably, the compounds of the invention are of the aforementioned formula (1) in which

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

3 2

SO, NR, sulfur or C (R), and W is selected from

3 ^of 3 a set comprising 0, NR, S and NCOV R, wherein

3?. '' 3.

V is oxygen, NR or CHR pncemz R '4 independently are hydrogen, (CH _O) R or (CHJA, p 2 p wherein p is an integer from 0 to 2, g is 0 or 1 and A is independently phenyl a group, a naphthyl group, a five- or six-membered heterocycle containing one or two heteroatoms, a ring containing from 8 to 10 atoms, a cyclopentyl group, a cyclohexyl group or a substituted derivative thereof, wherein the substituent (s) is selected from 4 containing F, Cl, Br, OR, N (R) 2, COgR, CON (R ⁴ ) 2, R ⁴ , OCH ₂ O or OCH ₂ CH ₂ , wherein R ⁴ is independently hydrogen, a straight or branched alkyl group containing from 1 C 5 -C 5 -cycloalkyl, C 3 -C 6 -cycloalkyl, C 4 -C 8 -cycloalkyl, phenyl or a substituted derivative whose substituents are CO, R 2

2 F, OR, phenyl or CF, wherein R is hydrogen, methyl, ethyl, isobutyl, tert-butyl or cycloalkyl of 3 to 6 carbon atoms, wherein A 1 is as defined above; and r 5 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a hydroxyl group, a carboxyl group or a hydroxymethyl group.

More preferably, the compounds of the invention are of the aforementioned Formula 1 in which

X is a hydroxyl group;

Z is an oxygen atom;

Y is an oxygen atom;

W, W and W are independently O, S, SO_NR,

3 2 3

NR or C (R) -, and W is O, S or NR, wherein

4

R is independently hydrogen, (CH 2) R or (CH ² ) A, _v = ² P ₄ ² P wherein p is an integer from 0 to 2, R is hydrogen, methyl, ethyl, isopropyl, isobutyl , cyclopropyl, cyclohexyl, cyclopropylme. ethyl, cyclohexylmethyl,

C1-C6-phenyl or benzyl; is hydrogen, methyl, ethyl, isobutyl or tert-butyl;

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

2,4- or 5-thiazolyl, morpholinyl, 2- or 3-furyl, cyclopentyl, cyclohexyl, indanyl or a substituted derivative thereof, wherein the substituent (s) is selected from the group consisting of: F, Cl, Br, OR R, CO-R or * ^of OCH-, O, wherein A is as defined above; and

R is hydrogen, methyl, ethyl or hydroxymethyl.

The most preferred compounds of the invention are the following;

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

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

6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(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- on;

3- [Bis (2-naphthalylmethyl) 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) - yl) -2- (phenylmethyl) -2H-isoindole-2-acetamide;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

6- (2,3-Dihydro-1,4-benzodioxin-6-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-phenylethyl) thio] -S- [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) - [(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] ethyl) -2H-pyran-2- he;

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- [1-hydroxy-2-methyl-1- (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- (phenylmethylene) pentyl] -2H-pyran-6-yl] phenoxy] acetic acid;

[5- (2-Oxo-4-hydroxy-3 - [(3-methyl-1-phenylbutyl) thio] 2H-pyran-6-yl) -2-pyridinyl] oxy] acetic acid;

4-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-dihydra-1-hydroxy-1H-indett-2-yl) thio (butyl) -2H- pyran .--. _

2-on;

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- (phenylmethyl) 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) -2H-pyran-2-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-1- (phenylthio) butyl) -6-phenyl-2H-pyran-2-one;

3- (2-Cyclohexyl-1- (phenylthio) ethyl) -4-hydroxy-6-phenyl-2H-pyrah-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;

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

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

4-Hydroxy-3- (4-methyl-1- (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-phenylethyl) 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-methylphenoxyacetic 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- [(2-phenylethyl) thio] -2H-pyran-2-one;

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

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-phenylethyl) 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-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- N - (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-Chlorophenyl) -4-hydroxy-3 - [(4-phenylbutyl) thio] -2H-pyran-2-one;

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

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) cyclopropyl) -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-methylbutyl) cyclopropyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (4-methylpentyl) cyclopropyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (phenylmethyl) cyclopropyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-phenylethyl) cyclopropyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-phenylpropyl) cyclopropyl] -2H-pyran-2-one;

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

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (pyridin-4-yl) 2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (pyridin-2-yl) 2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-nitrophenyl) 2H-pyran-2-one;

6- (4-Fluorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one;

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

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

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

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (N, N-dimethylamino) phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (3-trifluoromethylphenyl) -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (1-naphthalenylmethyloxy) phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (morpholin-4-yl) ethoxyenyl] -2H-pyran-2-one; ........_ ----------------------------------------- ------------- 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [3- (2- (morpholin-4-yl) ethoxy) phenyl] -2H- pyran-2-one;

6- (4-Benzyloxy-3-methoxyphenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one;

6- (4-Benzyloxy-3-chlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one;

4- [4-Hydroxy-2-oxo-3 - [(2-isopropylphenyl) thio] -2H-pyran-6-yl] -2-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-pyrazinomethoxy) phenyl] -2H-pyran-2-one;

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

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (pyridin-2-ylmethoxy) -3-methylphenyl] -2H-pyran-2-one;

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

3- [(2-Cyclopropylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2,5-diisopropylphenyl) thio] -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (thiomorpholin-4-yl) ethoxy] phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (piperazin-1-yl) ethoxy] phenyl] -2H-pyran-2-one;

4-Hydroxy-3- [(2-isopropylphenyl) thio] -6- [4- [2- (methylpiperazin-1-yl) ethoxy] phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (1,1-dioxothiomorpholin-4-yl) ethoxy] phenyl] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (1-phenylcyclopentyl) -2H-pyran-2-one; ------------------------------------ -------------- · · ............- --------—

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-phenylpiperidin-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-2-one;

4-Hydroxy-6-phenyl-3 - [(2-tert-butylphenyl) thio] -2H-pyran

2-on;

- (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-Cyclohexylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one;

4- [4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl] thio] -2-hydroxyindane;

4-Hydroxy-3- [2-isopropyl-4- (morpholin-4-ylmethyl) phenyl] thio] -6-phenyl-2H-pyran-2-one;

4-Hydroxy-3 - [(6-isopropyl-indan-5-yl) thio] -6-phenyl-2H-pyran-2-one;

4-Hydroxy-3 - [(4-isopropyl-benzo [1,3] dioxol-5-yl) thio] 6-phenyl-2H-pyran-2-one;

. 3 - [(2-tert-butyl-4-thiomorpholin-4-ylmethylphenyl) thio] 4-hydroxy-6-phenyl-2H-pyran-2-one;

4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3 - [(2-tert-butylphenyl) thio] -2H-pyran-2-one;

3 - [(2-Cyclopropyl-5-isopropyl) phenyl] thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

3 - [(2-Cyclopentyl-5-isopropyl) phenyl] thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

3- [(Cyclohexyl-5-isopropyl) phenyl] thio] -4-hydroxy-6 (4-pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3 - [(2-tert-butyl-5-isopropylphenyl) thio] -2H-pyran-2-one;

3 - [(2,5-Di-tert-butylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

3 - [(2-Cyclopentylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

3- [(2-Cyclohexylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

4-Hydroxy-6- (4- (pyridin-3-ylmethoxy) phenyl) -3 - [(6-tert-butylindan-5-yl) thio] -2H-pyran-2-one;

4-Hydroxy-3 - [(2-isopropyl-4-morpholin-4-ylmethylphenyl) 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- [(2-1sopropylphenyl) thio] -2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-4-yl ester;

2,2-dimethylpropionic acid - [(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-isopropylbenzoyl) -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one;

- (2-tert-butylphenyl) sulfonyl] -4-hydroxy-6-phenyl-2H-pyran-2-one;

6- (1-benzylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) sulfonyl] -2H-pyran-2-one;

6- (1-benzylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one;

6- (1-benzylpropyl) -3 - [(2-tert-butylphenyl) thio] -4-hydroxy-2H-pyran-2-one;

N- [3- [6- (1-benzylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] thio] -2-isopropylphenyl] benzenesulfonamide;

6- (1-Cyclopropylmethyl-2- (tetrahydro-pyran-3-yl) ethyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one;

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-isopropylphenoxy) -2H-pyran-2-one;

6- (1-Benzylpropyl) -3- (2-tert-butylphenoxy) -4-hydroxy-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-phenylbutoxy) -2H-pyran-2-one;

6- (1-Benzylpropyl) -3- (cyclopropylphenylamino) -4-hydroxy-2H-pyran-2-one;

N- [3- [6- (1-benzylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropylamino] phenyl] benzenesulfonamide;

3- (Cyclopropylphenylamino) -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one;

3- (Bis-cyclopentylmethyl-amino) -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one;

3- (Cyclopentylmethyl- (cyclopropylmethyl) amino) -4-hydroxy-6- (pyridin-3-ylmethoxy) -2H-pyran-2-one;

6- (1-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] cyclopropanecarboxylic acid amide;

Cyclopentanecarboxylic acid cyclopentylmethyl- [4-hydroxy-2-oxo-6- [4- (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] cyclopentanesulfonamide;

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-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

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

N- [3- [6- (1-Benzencyclopropyl) -4-hydroxy-2-oxo-2H-pyran 3-yl] cyclopropylmethyl] phenyl] benzenesulfinamide;

6- (1-Benzenopropyl) -4-hydroxy-3- (2-isobutyl-5-isopropylphenyl) -2H-pyran-2-one;

6- (1-Benzylpropyl) -4-hydroxy-3- (2-methyl-5,6,7,8-tetrahydro-naphthalen-1-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-phenylpropylcyclobutyl) -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;

6- (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-isopropylphenyl) 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 (methylphenyl) 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; 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) cyclobutyl] -2H-pyran-3-yl (methyl) phenyl] benzenesulfonamide;

N- [3- [6- (1-Benzylcyclobutyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] cyclopropyl / methyl] 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) -2H-pyran-2-one;

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

6- (1-Benzyl-1-ethyl-propyl) -3- (cyclopropyl-phenylmethyl) -4-hydroxy-2H-pyran-2-one; and

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

Unless otherwise indicated, the term alkyl, usually represented by R, means a straight or branched hydrocarbon radical containing from 1 to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl a sec-butyl group, an isobutyl group, a t-butyl group, an n-pentyl group, a n-hexyl group, a n-hexyl group, an n-octyl group, a n-nonyl group, n -decyl, undecyl and dodecyl. The alkyl groups may contain one or more unsaturation sites, such as carbon-carbon double or triple bonds. The alkyl group is unsaturated or saturated with one to three substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R- , -CO-NH-, -CQ ₂ 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, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. If possible, the cycloalkyl group may contain one double bond. The cycloalkyl ring may be unsubstituted or substituted by one to three substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, formyl, carboxyl, nitrile, -NH-CO-R -CO-NHR-, -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 alkylcycloalkyl means a cycloalkyl group attached to an alkyl chain, wherein the terms cycloalkyl and alkyl are as previously defined .—-------------- -------- ---- -------------------------------------------------- -----—...... -

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 spirocycles are rings A:

or

The term "aryl" means an aromatic radical, which is a phenyl group, a benzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, anthracenyl group, a fluarenyl group or a fused ring, formed by combining any two groups of phenyl, naphthyl and five- or six-membered rings. containing from 0 to 3 heteroatoms selected from the group consisting of quinolines, isoquinolines, indoles, indanes, benzfurans, benzthiophenes, benzoxazoles, benzthiazoles, benzisoxazoles, coumarins, benzimidazoles and the like unsubstituted or substituted with one to three substituents selected from the above defined alkyl groups, the above-defined alkoxy groups, the above-defined thio alkoxy groups, hydroxy groups, thiol groups, nitro groups. amino, formyl, carboxyl, nitrile, -NHCOR, -CONHR, -CO ₂ R, -COR, aryl groups or heteroaryl groups wherein the alkyl group (RJ aryl-α-heteroaryl-group) is as defined above .

The terms heteroaryl and heterocycle, typically represented by A, mean a heteroatom containing a ring radical of 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4- or a 5-imidazolyl group, a 3-, 4- or 5-pyrazolyl group, a 2-, 4- or 5-thiazolyl group, 3-,

4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isaxazolyl skipino, 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- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 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-benzthiazolyl, 1- or 2-piperazinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl,

1- or 2- or 3-pyrrolidinyl, 2- or 3-tetrahydrofuranyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-tetrahydroquinolinyl and the like. be unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of alkyl, aryl, as defined above, alkoxy, as defined above, thioalkoxy, hydroxy, thiol, nitro, formyl, amino, carboxyl, nitrile, - NHCOR, -CC 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 such 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 such as hydrochloric acid, nitric acid, phosphorous acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphoric acid and the like, as well as salts derived therefrom from non-toxic organic acids such as aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfide, bisulfide, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, actate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, suberate, sebacate, fumarate, maleate, mandelate, benzate, chlorobenzoate nzoate, dinitrobenzoate, phthalate, benzsulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also included are amino acid salts such as arginate, gluconate, galacturonate and the like (see, e.g., 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. Examples of suitable amines are N, N'-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 the 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.

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 their respective mixtures.

The compounds of the invention may be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the invention may be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitoneally. The compounds of the invention may also be administered by inhalation, e.g., intranasally. The compounds of the invention may optionally be administered transdermally. One of skill in the art will recognize 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 the pharmaceutical compositions of the compounds of the invention. Solid form preparations include powders, tablets, pills - -kapsle, cachets práškem1 whose PKY ^- or split -.....

pustné granule. The solid carrier may be one or 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 a finely divided active component.

In tablets, the active component is mixed with a carrier having the necessary binding properties in suitable proportions and compressed to the desired shape and size.

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 which provides a capsule in which the active component (with or without other carriers) is surrounded by a carrier so associated with it. Similarly, wafers with powder or intradermal systems are included. Tablets, powders, capsules, pills, cachets, and powders may be used as solid dosage forms suitable for oral administration.

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

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

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 a natural or synthetic gum, a resin, 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 preparation 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 may be a preparation containing discrete quantities of preparation, such as 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 a suitable number of such dosage forms.

The amount of active component in a unit dose preparation may be adjusted in the range of 0.1 mg to 100 mg, preferably 0.5 mg to 100 mg, depending on the particular application and the efficacy of the active component. The composition may also contain, if desired, 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, for therapeutic use, the compounds of the invention are administered at an initial daily dosage of from about 0.01 mg to about 100 mg / kg. A daily dose of 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 optimal dosage in a particular situation is within the skill of the art. Generally, treatment is initiated with smaller doses that are less than optimal. Thereafter, the doses are gradually escalated until the optimum effect under the conditions is reached. Alternatively, total daily doses may be divided and administered several times a day.

4.1 General methods of synthesis of pyronic derivatives

Scheme I below illustrates the preparation of 6-substituted-3-substituted pyrons.

Scheme I

O L Ba.ze OSM ·,

2.TMS-CI

Ketone I is reacted at -78 ° C to -45 ° C in an ether or tetrahydrofuran solution with a suitable base such as 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 -78AZ to 0 Az to give the silylenol ether II. Compound (I) optionally reacts with trimethylsilyl trifluoromethanesulfonate (TMS-OTf) and triethylamine at 0 AZ in dichloromethane solution to convert to intermediate II. Compound II is then reacted with a suitably substituted malonate and 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 of the compounds of the invention, during the chemical reactions, the starting materials, reaction intermediates and reaction products may be protected by the use of protecting groups which render them substantially inert to the reaction conditions. (See, e.g., Protective Groups in Organic Synthesis, 2nd Edition, T.W. Green and P.G.

Wuts, John Wiley ' sons, New York, NY 1991). For example, the following protecting groups may serve to protect amino, hydroxyl, and other reactive groups: carboxylacyl groups, e.g., formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups such as ethoxycarbonyl, tert-butoxycarbonyl (BOC), $, R, -, - trichloroethoxycarbonyl (TCEC) -iodoethoxycarbonyl; aryloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl (TBDMS); and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl and benzyl. The protecting group may be removed after completion of the synthetic reaction by procedures known to those skilled in the art. For example, the BOC group may be removed by acidolysis, the trityl group by hydrogenolysis, the TBDMS group by reaction with fluoride ions, and the TCEC group by reaction with zinc.

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

Scheme II

The trimethylsilylenol ether II is reacted in a dry solvent such as ether or tetrahydrofuran at low temperature, preferably -78 R 2 to -35 ° C, with malonyldichloride to form pyrrone IV, which is converted using a suitably substituted p-toluenethiosulfanate to a sulfur derivative such as is described in US Pat 3,931,235 (1976).

Thiotosilate reagents can also be prepared as described by M. G. Rananasheim and P. L. Fuhs in Syn. Comm., 18 (3): 227 (1988). The desired thiols can 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); MSNewman and FWHetzel, Org. Synth.Coll.Vol.VI, 824 (1988); MSNewman and HAKarnes, J. Org.Chem. 31, 3980, (1966)) or from the corresponding iodobenzene via 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 pyrons VIII. The Rg substituent herein may be an aryl group, an alkyl group or a substituted alkyl group for compound VII.

Scheme III

O. ii.NaH

2-RLi

OEt ^R 5 ^R 3

VI poo o

CH— och ₃

->.

OH

VII vin

The substituted 6-ketoester VI is deprotonated with one equivalent of a suitable base, eg, metal hydride (sodium hydride) in a suitable solvent (ether or tetrahydrofuran). A second equivalent of a stronger base such as alkyl lithium (n-butyllithium or lithium diisopropylamide) is added to the malonate solution to form a dianion, which is subsequently reacted with a suitable acylating agent such as an amide at 0 ° C to 25 ° C to form dionester VII . Compound VII may then be cyclized to jpyron VIII in a variety of ways, e.g., using a strong acid such as HgSO ^ ^No b ^of CH ^ SO ^ H, by heating the reaction mixture in a suitable solvent with a high boiling point, such as e.g. xylene, or using a small amount of a base, preferably a sterically hindered base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene. If R 8 = H, the pyron VIII can be further derivatized, as shown in Scheme II above.

Scheme IV describes the preparation of O-acylpyrone analogs.

Scheme IV ocr ₇

OH

Base." CICRt

In m

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

Scheme V below describes the preparation of some 3-alkylpyrone derivatives.

Scheme V

OH

R

O

R ₈ CH.HSR ₉ S§H ₂ NR ₉ - ----------------.>

piperiam », HOAc

reduction ^ vm

(where Y = N, S)

XI

The intermediate pyron VIII in an alcohol medium such as ethanol is reacted with a suitable aldehyde and a suitable nucleophile such as HSRg or NHgRg in the presence of a mixture of an acid such as acetic acid and a base such as piperidine. The resulting mixture is heated at a temperature of 60 ° C to 90 ° C to form a pyrone X, which may itself be a preferred compound in -χ may be in the case that Y-S is reduced by a mechanism reducing the metal in a solvent such as sodium in liquid ammonia or using Raney nickel in a solvent such as acetone to give the desired 3-alkylpyrone XI.

Scheme VI summarizes the synthesis of certain 3-aminopyrons.

Scheme VI

1 ·

OH i

In m

HNOj, HQAc.

piperidium, HOAc

OH

OH 5

R «

ΣΠ

Sn.Ha.

«5

Re

NK,

MeN 0.

r, ₂ nco

AND

ΤΤΠ

OH

X

From NaCNBHj

X

OH

Re

1. NaH

2. R ₁₁ CQ _and H ΜβΝ O. JN .NHCR11 • ZA!

XV

Re

M-C-NEI

XVI ii. NHCNR, ₂

The nitration of the pyrone VIII is carried out with nitric acid, preferably fuming nitric acid in an acid solution, as described, for example, in U.S. Patent 3,206,476 (1965). Reduction of nitropyrone XII with tin or acid gives aminopyrone XIII. Intermediate XIII can be processed into a variety of derivatives at this stage. For example, it can 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 reaction with a mixture of a suitable carboxylic acid, N-methylmorpholine and a suitable condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 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 such as triethylamine and 4-dimethylaminopyridine; or 3. Deprotonation with sodium hydride followed by treatment with a suitable acid chloride in the presence of an excess of an amine base, usually triethylamine, at an elevated temperature, e.g., 40 ° C to 60 ° C.

From aminopyrone XIII, by reaction with a suitable isocyanate and a base such as N-methylmorpholine, they can be prepared in an inert solvent such as ethyl acetate, urea of formula XVI.

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

Scnema VII

OR with · - »xvn

OR ^ε xvm

OR OR

(E = alkyl; CC 1 H; PhCO)

6-Methylpyrrone XVII is reacted with 2 equivalents of a strong base such as sodium amide in liquid ammonia or lithium diisopropylamide in tetrahydrofuran, terminating the reaction by adding one of many electrophilic reagents such as 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 (NBS), in the presence of a free radical initiator and light, provides intermediate XIX, which can be further processed to 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 can be further derivatized using conventional reactions known in the art, such as, for example, alkylations, acyls, etc. -. ... ·

Scheme VIII below illustrates the synthesis of certain 4-substituted-pyrrone derivatives.

Scheme VIII

OH

In m

SR, ₄

XXTV

PBr ₃ / DMF

NEt 2 MeOH wa ₂ (PA 150 PSi CO

CO2CHS

XXVI

XXVII

XXV

Pyron VIII is activated, eg, by tosylation, to XXIII using p-toluenesulfonyl chloride (TsCl) in pyridine. The tosylate is then reacted with a suitable sulfur nucleophilic reagent (see -AMBittencourt et al. Tetrahedron ¹¹ , 27: 1043 (1971)) to form sulfide XXIV. In the same manner, pyron VIII is converted to the 4-bromo-analog XXV using a brominating agent such as phosphorus tribromide / dimethylformamide (DMF). Substitution of the bromine of compound XXV with an azide and subsequent reduction (preferably, for example, by hydrogenation with a palladium catalyst and a triarylphosphine in a suitable solvent) affords the 4-amino derivative XXIX.

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

Scheme IX illustrates the preparation of 2H-thiopyran-2-one derivatives.

Scheme IX

Cl

EÍO2C.

\

CH • I

Rg SH

XXX

Crayfish

OH

1. OH *

Second PňNOg / _quinolones R ₃

Rg ^S O

XXXII

Μ

A suitably substituted β-mercaptoacrylate, e.g. XXX, is condensed with a suitable malonyl dichloride in an inert solvent, e.g. toluene, at a temperature of about 0 ° C to give thiopyran-2-one XXXI. Thiopyrone XXXI can be converted to derivative XXXII under appropriate conditions, e.g., by basic hydrolysis and subsequent decarboxylation (see, e.g., F.K.Splinter and H.Arold, J.Prakt.Chem., 38: 3-4, 142-6). Thiopyrones XXXII (R 8 = H) can be converted to their substituted derivatives using the procedures outlined in Schemes II, X and VI.

W V »

Suitable protected pyrones, e.g. XVII, as well as analogs thereof, containing a sulfur atom instead of an oxygen atom in the 1-position pyron ring may be thiolated, i.e. the carbonyl group at the 2-position of the heterocycle may be substituted by a thiocarbonyl group (C = O- > C = S) using standard group modification procedures, eg using a thiating agent such as Lawesson's reagent under appropriate reaction conditions (see Monatsh. Chem., 115: 769 (1984) and Chem. Rev., 84: 17 (1984)).

General methods for preparing functionalized pyrons

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 quenched by the addition of saturated sodium bicarbonate solution and the reaction mixture is dried with 300 mL of 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 (1 hour) and used without further purification.

(ii) Condensation of trimethylsilylenol ethers with dialkyl esters of 2-substituted propanedioic acid

The crude trimethylsilylenol ether (11 mmol, 1.1 equivalents), prepared as described above, was treated with 2-substituted propanedioic acid dialkyl ester (10 mmol, 1.0 equivalents). The resulting mixture was heated to 150 ° C under a stream of nitrogen overnight. The reaction mixture was cooled to room temperature and the product purified by silica gel chromatography. Elution with 10-15% ethyl acetate / hexane removes unreacted starting materials and other impurities and elution with 30-50% ethyl acetate / 5% methylene chloride / hexanes provides further purification to give the desired pyrons 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. Malonyl dichloride (30-40 mmol) is added dropwise.

1.5-2 equivalents). The reaction mixture was gradually warmed to room temperature and stirred at room 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-pyron 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 of triethylamine followed by a suitable thiosulfonate (72 mmol, -1.04 equivalents). the mixture was heated to reflux. The solvents were evaporated, acidified with 1N hydrochloric acid and the product 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. Yield: 4080%.

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, 62 mmol, 2.6 equivalents) piperidine (0.50 mL) and acetic acid (0.50 mL). The reaction mixture was 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-2 H -pyran-2-one

The method is taken from U.S. Patent 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.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, d-TFA, delta values)

7.02 (with, 1H) 7.65 (with, 3H) 7.99 (m, 2H)

ii) 3-Amino-6-aryl-4-hydroxy-2 H -pyran-2-one

To β 6 -aryl-4-hydroxy-3-nitro-2'H-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). To obtain a homogeneous mixture, the mixture is heated to reflux. 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.

Si-Nuclear Magnetic Resonance Spectrum

(250 MHz, D ₂ O, values 6.74 (s, 1H) 7.53 (m, 3H) 7.84 (m, 2H).

iii) 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 to 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 stirred with water and concentrated in vacuo. The oily residue was 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 either by column chromatography (silica gel: 230-400 mesh) or by 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-6-aryl-4-hydroxy-2H-pyran-2-ones.

(a) To a solution of 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one hydrochloride (0784 'mmol, 1.0 equivalent) in tetrahydrofuran (10 ml) is added 60¾ of sodium hydride (0, 92 mmol, 1.1 eq). The mixture was stirred at ambient temperature for 30 minutes. In a separate flask, to the corresponding carboxylic acid (1.67 mmol, 2 equivalents) in tetrahydrofuran (20 mL) at -20 ° C was added N-methylmorpholine (0.92 mmol, 1.1 equivalents) and 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.92 mmol, 1.1 equivalents). The reaction mixture was stirred at -20 ° C for 1 hour. This solution was added to the above 3-amino-6-aryl-4-hydroxy-2H-pyran-2-one. Subsequently, additional N-methylmorpholine (0.918 mmol, 1.1 equivalents) was added and the reaction mixture was stirred at room 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 methyl chloride (8 mL) was added triethylamine (3.3 mmol). , 4.0 equivalents) followed by a catalytic amount of 4-dimethylaminopyridine (0.08 mmol, 0.1 equivalents) and the corresponding acid chloride (0.92 mmol, 1.1 equivalents). The reaction mixture was stirred at ambient temperature for 6 hours. To the reaction mixture was added 1N hydrochloric acid, and then the mixture was diluted with methylene chloride. The organic layer was washed with water and saturated sodium chloride and then dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product is recrystallized from boiling acetic acid.

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

Method F: Preparation of 3-alkyl-6-aryl-4-hydroxy-2H-pyran-2-ones (6-Aryl-4-hydroxy-2-oxo-2H-pyran-3-yl) arylthiomethanes was prepared as described in Method C. Boil Raney-Nickel (Grace 3100) in acetone for 45 minutes and replace acetone with 20 mL ethanol. (4-Hydroxy-6-substituted-2-oxo-2H-pyran-3-yl) arylthiomethane (1.0 mmol, 1 equivalent) was added and the resulting suspension was heated at reflux overnight. The mixture was filtered through Celite and washed with hot ethanol. The filtrate was concentrated in vacuo to give pure products.

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

4-Hydroxy-3-aryl (or arylalkyl) thio-6-aryl-2H-pyran-2-one (3 mmol, 1 equivalent) was dissolved in 20 mL of tetrahydrofuran and cooled to 0 ° C. 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 the 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) using ethyl acetate in hexane as eluents to give the enol ester in 70-85% yield.

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).

Example A

[(Phenylmethyl) thio] propanedioic acid diethyl ester b.p. 160 - 162 ° C / 798 Pa ^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

1.18 (t, 6H) 4.44 (s, 1H)

3.93 (s, 2H); 7.31 (m, 5H).

4.13 (q, 4H)

Example B

/ (2-Naphthalenylmethyl) thio / propanedioic acid dimethyl ester The crude product is purified by silica gel chromatography (230-400 mesh silica gel).

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values) 3.65 (s, 7H) 7.51 (m, 4H) 4.10 (s, 2H) 7.87 (m, 3H) 4.55 (s, 1H)

Example C

Diethyl ester (± (3-phenylethyl) thio) propanediol m.p. 185-190 ° C / 133 Pa;

Si-Nuclear Magnetic Resonance Spectrum;

MHz, DMSC ) -d6, delta values) 1.17 (t, 6H) 4.14 (q, 4H) 1.82 (m, 2H) 4.62 (with, IH) 2.65 (q, 4H) 7.23 (m, 5H).

Example D

[(2-Naphthalenyl) thio] propanedioic acid diethyl ester

The crude product was purified by silica gel chromatography (230-400 mesh).

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 1.09 (t, 6H) 7.58 (m, 3H) 4.12 (q, 4H) 7.90 (m, 3H) 5.27 (s, IH) 8.80 (with, IH).

Example E

[(2-Phenylethyl) thio] propanedioic acid diethyl ester b.p. 160-165 ° C / 133 Pa;

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC »-D6, delta values) 1.19 (t, 6H) 4.68 (with, IH) 2.89 (m, 2H) 7.25 (m, 5H). 4.16 (qr 4H)

Examples F-M: Preparation of p-toluenethiosulfonates

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

Example F

2-Phenoxyethyl p-toluenethiosulfonate Η-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 _Λ . "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 Η-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 S-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.43 (s, 3H) 6.93 (d, 1H) 2.80 (t, 2H) 7.02 (d, 1H) 3.19 (t, 2H) 7.21 (t, 1H) 3.75 (s, 3H) 7.49 (d, 2H) 6.83 (t, 1 H) 7.81 (d, 2H).

Example I

4-Phenylbutyl-p-toluenethiosulfonate

Si-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 1.53 (m, 3H) 7.18 (d, 2H) 2.43 (s, 3H) 7.25 (t, 2H) 2.50 (t, 2H) 7.45 (d, 2H) 3.03 (t, 2H) 7.80 (d, 2H). 7.12 (d, 1 H)

Example J

2- (3-Methoxyphenyl) ethyl-p-toluenethiosulfonate ^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.43 (s, 3H) 6.73 (m, 3H) 2.79 (t, 2H) 7.19 (m, IH) 3.25 (t, 2H) 7.49 (d, 2H) 3.73 (s, 3H) 7.83 (d, 2H)

Example K

2- (4-Methoxyphenyl) ethyl p-toluene thiosulfonate ^ ^-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.50 (s, 3H) 6.83 (t, 2H) 2.76 (t, 2H) 7.03 (d, 2H) 3.21 (t, 2H) 7.50 (t, 2H) 3.71 (s, 3H) 7.82 (d, 2H)

Example L

2- (2-Chlorophenyl) ethyl p-toluenethiosulfonate S-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values)

2.43 (with, 3H) 7.22 (m, 4H) 2.86 (t, 2H) 7.49 (d, 2H) 3.28 (t, 2H) 7.83 (d, 2H)

Example M / 4- (Phenylmethoxy) phenyl / methyl p-toluenethiosulfonate .beta.-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.41 (with, 3H) 7.13 (d, 2H) 4.28 (with, 2H) 7.37 (m, 7H) 5.06 (with, 2H) 7.72 (d, 2H) 6.87 (d, 2H)

Example N

6- (3-Chlorophenyl) -4-hydroxy-2H-pyran-2-one

A suspension of 60% sodium hydride (0.790 g, 19.7 mmol) in tetrahydrofuran (50 mL) under a nitrogen atmosphere was cooled to 0 ° C and treated with actoactate (2.51 mL, 19.7 mmol). The resulting solution was treated successively with n-BuLi (12.3 mL, 19.7 mmol) and stirred for 20 minutes at 0 ° C. The resulting orange solution was treated via cannula with a solution of 3-chloro-N-methoxy-N-methylbenzamide (δ, 50 g, 15.15 mmol) in tetrahydrofuran (5.0 mL). The mixture was allowed to warm to ambient temperature where it was stirred for 14 hours before 2N hydrochloric acid was added. The product was extracted with ethyl acetate (3 x 50 mL), the layers were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was then combined with concentrated sulfuric acid (20 mL) and the resulting mixture was stirred at ambient temperature for 18 hours before being diluted with 200 mL of water. The product was then extracted with 3 x 100 mL ethyl acetate. The layers were combined and diluted with acetone to give a homogeneous solution which was dried over sodium sulfate. The diluent was then removed in vacuo and the solid product recrystallized from acetone / hexane to give the title compound (1.33 g, mp 254-256 ° C).

Si-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

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

7.889 (t, 1H, J = 1.5Hz) 5.450 (d, 1H, J = 2Hz) »

7.839 - -7.813 (m, 1H)

7.598 - 7.524 (m, 2H)

Example O

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

The title compound (1.56 g, mp 247-249 ° C) was prepared in a manner analogous to Example N using the following compounds: 60% sodium hydride (0.904 g, 22.6 mmol), tetrahydrofuran (50 mL), ethyl acetate ( 3.00 g, 22.6 mmol), lithium diisopropylamine in tetrahydrofuran (39.8 mL, 24 mmol), 4-chloro-N-methoxy-N-methylbenzamide (3.73 g, 22.6 mmol), 90% acid sulfuric acid (20 ml).

^ Ι-Nuclear Magnetic Resonance Spectrum:

(300 MHz, DMSO-d6, delta values)

11.950 (bs, 1H) 6.812 (d, 1H, J = 2Hz)

7.878 (d, 1H, J = 9 Hz); 5.409 (d, 1H, J = 2 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 thiotosylate (10.0 g,

44.4 mmol) and heated at 90 ° C for 10 hours.

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 as a solid (5.2 g, mp 46-48 ° C). ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDClg, delta values)

7,816 (d, 2H, J = 8.8Hz) 1,010-0,933 (m, 1H) 7,308 (d, 2H, J = 8.8Hz) 0,592-0,545 (m, 2H) 2,945 (d, 2H, J = 7.6Hz) 0,236-0,197 (m, 2H). 2,451 (with, 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) under nitrogen was treated with methyl bromoacetate (7.26 mL, 78 mL). (3 mmol), and the mixture was heated to reflux for 4 hours. 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, 2Ή, J = 8.9Hz) 2,981 (q. 2H, J = 7.2Hz) 7,040 (d, 2H, J = 8.9 Hz) 1,071 (t, 3H, J = 7.2Hz) 4,920 (s, 2H) 3,715 (s, 3H)

________________________ Preparation of specific pyronic 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, 12.5 mmol) in tetrahydrofuran. The solution was warmed to 0 ° C, stirred for 15 min 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 diethyl ether (50 mL). 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 silylenol 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 at 160 ° C for 16 hours and then allowed to cool to ambient temperature, then diluted with 20 mL of 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 ^- is removed in vacuo. The resulting residue was subjected to chromatography (SiO ₂ : 230 400 mesh, 100% CH 2 Cl 2/1% MeOH / CH ₂ Cl ₂ ) to give a solid which was recrystallized from acetone / hexanes to give 0.436 g (mp 136-60 ° C). 137 ° C) of the title compound.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.950 (bs, 1 H)

7.814 (s, 1 H)

7.761 (d, 1H, J = 7.5 Hz) 7.616 - 7.534 (m, 2H)

-7 _r 271-7.185 (m, 5H > 6.811 (s, 1H)

4.023 (s, 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, 1 H)

7.639 (t, 2H, J = 9 Hz) 7.572-7.477 (m, 2H)

7.276 - 7.206 (m, 5H) 6.558 (s, 1H)

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 34'-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 duethyl-2- (thiobenzyl) ) Propane-1,3-dioate (0.89 g, 3.2 mmol).

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

12.00 (bs, 1 H)

8.018 (s, 1 H)

7.784 (s, 2H)

7.265-7.179 (m, 5H) 6.839 (s, 1H)

4.017 (s, 2 H).

_________________. _____ ___ Example 4 _________ ___________________________.

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

The title compound (0.400 g, mp 146-147 ° C) was treated using 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). '^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.880 (bs, 1 H) 7,109 (m, 1H) 7.445 (t, 1H, J = 8 Hz) 6,770 (with, 1H) 7.370 (d, 1H, J = 8 Hz) 4,020 (with, 2H) 7.286-7.094 (m, 6H) 3,831 (with, 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 using Method A using 3 ', 45'-trimethoxyactophenone (2.0 g, 9.5 mmol), potassium hexamethyldisilazide (5.6 mL, 10.45). 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).

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.778 (bs, 1 H) 3,997 (with, 2H) 7.265-7.181 (m, 5H) 3,861 (with, 6H) 7.054 (s, 2H) 3,727 (with, 3H).

6.792 (s, 1 H)

Example 6

6- (3-Chlorophenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one. The desired 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-toluenethiosulfanate (0.43 g, 1.46 mmol), triethylamine (0.35 mL, 2.5 mmol) and ethanol (5.0 mL).

^ Ή-Nuclear Magnetic Resonance Spectrum:

MHz, CDCl 3, delta values) 7.838 (t, -IH, J = 1.5Hz) 7.207-7.171 (m, 3H) 7.710 (d, 1H, J = 8 Hz) 6.604 (s, 1H) 7.530 (bs, IH) 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 7

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-toluenethiosulfanate (0.390 g, 1.35 mmol), triethylamine (0.31 mL, 2.24 mmol) and ethanol (10 mL).

^ Ή-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

12,085 (bs , IH) 6,830 (with, IH) 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) .

- Nuclear Magnetic Resonance Spectrum: (250 Hz, DMSO-d6, delta values)

4.00 (with, 2H) 7.53 (m, 3H) 6.74 (with, IH) 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). M.p. 205 ° C. Si-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

4.37 (with, 2H) 7.45 (m, 3H) 6.56 (with, IH) 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 monohydrochloride (0.153 mmol) in 10 mL of ethyl acetate was added N-methylmorpholine (2.0 mL) and tert-butyl isocyanate (2, 3 mL). 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 -s-Spectrum: --------------------- (250 MHz, DMSO-d6, delta values)

1.24 (s, 9H) 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). M.p. 250 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(250MHz, 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-naphthalenylthio) -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). M.p. 246 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-CL6, delta values)

6.95 (sl)

7.38 (m, 3H)

7.56 (m, 4H)

7.85 (m, 5H).

......-- - - ----------------------------- Example — 1.3.

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

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). M.p. Mp 134-136 ° C.

^ ί-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

2.11 (with. 6H) 6.96 (with, 2H) 2.26 (with, 3H) 7.25 (m, 5H) 3.98 (with, 2H) 11.85 (bs , IH). 6.03 (WITH, IH)

Example 14

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

Prepared from 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). M.p. (dec.) 207 ° C.

^ Ή-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.54 (with, 2H) 4.22 (t, 2H) 6.89 (m, 4H) 6.58 (with, IH) 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

The title compound was prepared via Method A using 2-acetyl-naphthalene (1.97 g, 11.6 mmol), lithium bis (trimethylsilyl) amide (2.13 g, 12.76 mmol), chlorotrimethylsilane (1.61 mL, 12 mL), , 76 mmol), tetrahydrofuran (127 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (2.90 g,

10.5 mmol). M.p. (dec.) 203 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 4.04 (with, 2H) 7.84 (d, 2H) 6.89 (with, IH) 8.05 (m, 3H) 7.23 (m, 5H) 8.43 (with, IH) 7.61 (m, 2H) 11.95 (bs , IH)

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 (0.5 mL) and acetic acid (0.5 mL). M.p. (dec.) 211 ° C.

^ i-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.98 (with, 2H) 7, 37 (m, 2H) 6.73 (with, IH) 7, 54 (m, 3H) 7.17 (m, IH). 7, 77 (m, 2H) • 7.30 (m, 2H) 12 , 05 (bs , IH)

Example 17

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

The title compound was prepared according to Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 mmol), 1668 thiumbis (trimethylsilyl amide (1.95 g, 11.6 mmol), chlorine).

trimethylsilane (1.48 mL, 11.6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 cf, 3.54 mmol). M.p. (dec.) 204 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

3.96 (s, 2H) 7.63 (d, 2H) 6.55 (with, 1H) 10.28 (with, 1H) 6.88 (d, 2H) 11.75 (bs , 1H) 7.39 (m, 5H)

Example 18

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

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). M.p. (dec.) 187 ° C.

Η-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 7.06 (m, 2H)

Example 19

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

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,

(54 mmol). M.p. (dec.) 205 ° C. · ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.37 (s, 3H) 7.26 (m, 7H) 3.99 (s, 2H) 7.68 (m. 2H) 6.69 (s, 1H) 11.83 (bs, 1H)

Example 20 -¾

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). M.p. (dec.) 130135 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 4.26 (with, 4H) 6.44 (with, 1H) 7.24 (m, 6H) 7.44 (m, 7H) 7.69 (m, 2H).

Example 21

4-Hydroxy-6-phenyl-3 - [(2-phenylethyl) 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), sodium hydroxide (2.65 mL), 2-Phenylethyl p-toluenethiosulfonate (0.770 g, 2.65 mmol). M.p. (dec.) 121-124 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 Jt, " 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 diethyl ester for pandioic acid (1.00 g, 3, 22 mmol). M.p. Mp 114-116 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC i-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 , 1H).

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) and 2-phenoxyethyl p-toluenethiosulfonate (0.816 g, 2.65 mmol). M.p. Mp 146-149 ° C.

Η-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, 3H) 6.81 (with, 1H) 7.81 (m, 2H) 6.88 (m, 3H) 12.04 (bs , 1H)

....................... .......- Example 24 ................ 4 -Hydroxy-6- (2-methylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran

2-on

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).

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, delta values) 2.34 (WITH, 3H) 4.01 (s, 2H) 6.32 /with, 1H) 7.32 (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-phenethylacetonophenone (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). M.p. Mp 164-166 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.75 (t, 3H) 5.92 (s, 1 H) 2.85 (t, 2H) 7.23 (m, 9H). 3.92 (s, 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'-hydroxyacetophenone (0.772 g, 5.31 mmol), lithium bis (trimethylsilyl) amide (1.95 g, 11.6) mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. (dec.) 185 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(40 ^ MHz, DMSO-d6, delta values) 4.00 (s, 2H) 6.66 (s, 1H) 6.92 (m, 1 H) 7.21 (m, 6H) 7.32 (m, 1 H).

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. N- (2-phenylethyl) thio] propanedione (1.00 g, 3.37 mmol).

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO i-d6, delta values) 2.78 (t, 2H) 7, 21 (m, 5H) 2.95 (t, 2H) 7, 65 (d, 2H) 6.62 (with, 1H) 10 , 22 (s, 1H) 6.89 (dd, 2H) 11 , 05 (bs, 1 H

Example 28

4-Hydroxy-6-phenyl-3- [3- (phenyl-2-propenyl) thio] -2H-pyran-2-one, (E) 73

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), 1N sodium hydroxide (2.65 mL). 3-phenyl-2-propenyl-p-toluenethiosulfonate (0.808 g, 2.65 mmol). M.p. Mp 133-136 ° C.

Η-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 (with, IH) 7.78 (m, 2H).

Example 29

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

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). M.p. Mp 139-142 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, delta values) 2.77 (t, 2H) 7.26 (m, 7H) 2.98 (t, 2H) 7.43 (m, 5H) 5.19 (with, 2H) ' 7.76 (d, 2H). 6.68 (WITH, IH)

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 103-106 ° C.

^ Η-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). M.p. Mp 139-142 ° C.

^ ί-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC > -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 , 1H

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). , 11.6 mmol), tetrahydrofuran (116 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. (dec.) 189 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 4.01 (s, 2H) 7, 71 (d, 1H) 6.97 (s, 1H) 10 , 75 (with, 1H) 7.25 (m, 6H) 11 , 85 (bs , 1H).

Example 33

4-Hydroxy-6- [3- (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 mL), 54 mmol), tetrahydrofuran (15 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (0.417 g, 1.40 mmol). M.p. Mp 104-106 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, delta values) 2.75 (t, 2H) 6.79 (with, 1H) 2.97 (t, 2H) 7.25 (m. 14H) 3.04 (t, 2H) 11.95 (bs , 1H) 4.25 (t, 2H)

Example 34

4-Hydroxy-6-phenyl-3- [phenyl (phenylthio) methyl] -2H-pyran-2-one, (+, -) The title compound is prepared via Method A, wherein:

76 used 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). M.p. (dec.) 220 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, 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) Tt. Mp 114-115 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.74 (t, 2H) 7.15 (m, 2H) 2.94 (t, 2H) 7.54 (m, 3H) 3.73 (s, 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 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). 4-phenyl77

- bufeyl-p-pheoluenthiosulfonate (0.851 g, 2.65 mmol). M.p. 10J 105 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC ) -d6, delta values) 1.47 (m, 2H) 6.80 (with, IH) 1.66 (m, 2H) 7.17 (m, 5H) 2.54 (t, 2H) 7.53 (m, 3H) 2.77 (t, 2H) 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) Tt. Mp 112-113 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.75 (t, 2H) 7.16 (t, IH) 3.01 (t, 2H) 7.54 (m, 3H) 3.34 (with, 3H) 7.80 (m, 2H). 6.75 (with, IH)

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) Tt. Mp 144-145 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.71 (t, 2H) 7.12 (d, 2H) 2.96 (t, 2H) 7.54 (m, 3H) 3.66 (s, 3H) 7.80 (m, 2H). 6.77 (s, IH) 6.80 (d, 2H)

•AND

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), 1N sodium hydroxide (2.65 mL). 2- (2-chlorophenyl) ethyl p-toluenethiosulfonate (0.865 g, 2.65 mmol). M.p. Mp 133-134 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.79 (t, 2H) 7.25 (m, 4H) 3.02 (t, 2H) 7.55 (m, 3H) 6.77 (s, IH) 7.81 (m, 2H).

Example 40

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). M.p. (dec.) 255 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.65 (dd, 2H); 7.52 (m, 3H)

2.71 (dd, 2H); 7.76 (m, 2H)

6.68 (s, 1H); 11.85 (bs, 1H).

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-Nickel (Grace 3100), ethanol (15 mL) and 4-hydroxy-6-phenyl-3- (3-phenyl-1- (phenylthio) propyl) -2H-pyran 2-one (0.150 g, 0.362 mmol). M.p. Mp 195-196 ° C.

¹ 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), chloro trimethylsilane (0.741 mL, 5 mL). , 84 mmol), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. Mp 140-143 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.15 (s, 6H)

3.99 (s, 2H).

6.12 (s, 1 H)

7.22 (m, 8H).

Example 43

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

The title compound is prepared by Method A, wherein:

use 4'-benzyloxy-2'-hydroxy-3'-methylacetophenone (1.29 g, 5.56 mmol), lithium bis (trimethylsilyl) amide (2.11 g, 12.6 mmol), chlorotrimethylsilane (1, 1, 2, 3, 4, 5 60 mL, 12.6 mmol), tetrahydrofuran (127 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 147-148 ° C.

,, -,

H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.14 (with, 3H) 6, 79 (d, IH) 2.77 (t, 2H) 7, 30 (rn, 13H) 2.98 (t, 2H) 9, 36 (with, IH) 5.17 (with, 2H) 11 , 85 (bs , IH) 5.29 (with, IH)

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 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 126-127 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.78 (t, 2H) 6.81 (with, IH) 3.01 (t, 2H) 7.22 (m, 6H) 5.20 (s, 2H) 7.41 (m, 7H).

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 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 152-154 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.77 (t, 2H) 7.21 (m, 7H) 2.98 (t, 2H) 7.54 (m, 2H) 5.38 (s, 2H) 7.60 (d, 1H) 6.68 (s, 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 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. (dec.) 171 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.93 (s, 3H) 7.32 (m, 6H) 3.99 (s, 2H) 7.77 (d, 1H) 6.68 (s, 1H) 7.83 (d, 1H).

Example 47

4-Hydroxy-6-phenyl-3 - [(phenylmethyl) sulfonyl] -2H-pyran-2-one The desired compound is prepared by oxidation of 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 is stirred at room temperature for 4 hours, 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.

",

H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDC1 _O , delta values)

11.34 (s, 1H); 7.8 (m, 2H)

7.5 (m, 3H) 7.37 (m, 3H)

7.27 (m, 2H).

Infrared spectrum: (KBr, cm ^-1 )

3421

3059

1726

1698

1628

Mass spectrum:

(Cl, m / e)

343 (6.8)

327 (15.54) 278 (15.99)

6.37 (with, IH) 6.23 (with, IH) 4.75 (3, IH) 4.34 (q, 2H)

1559 689

1497

1230

957

770

219 (40.99) 91 (100).

Example 48

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

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

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

11.9 (brs, 1 H) 7.2 (m, 7.6 (m. 2H) 6.7 (with, 7.39 (t, IH) 4.0 (with, 7.35 (d, IH) 7.25 (d, 4H) 2.38 (WITH, Infrared spectrum: (KBr, cm 1) 3030 1402 2585 1100 1617 787 1536 696 Mass spectrum: (Cl, m / e) 325 (64) 119 (9) 291 (1) 91 (100) 233 (3)

Example 49

2-Oxo-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran 4-ylpropanoic 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 follows G. Yield of isolated product: 72%.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.77 (m. 2H) 6.7 (s, 1H) 7.51.m (2) 3.98 (S, 2H) 7.22 (m, 4H) 2.19 (q, 2H) 7.17 (m, IH) Infrared spectrum: (KBr, cm < -1 > 0.96 (t, 3H); 3438 1528 1045 3027 1494 979 2923 1453 Λ 873 1772 1323 767 1731 1617 1153 1087 702;

Mass spectrum:

Cl, m / e) 366 (4) 105 (21) 311 (79) 91 (100) 189 Italy (26)

Example 50

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

Condensation of diethyl / (phenylethyl) thio / propadiic acid diethyl ester (1.06 g, 3.6 mmol) with trimethylsilylenol ether

3'-methoxy-4'-benzyloxyacetophenone (2.24 i g, 7 / 2 mmol) is added Yield: isolated produ ktu : 78%, m.p. Mp 147-148 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum um: (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 (s, 1 H) 2.27 (with, 3H);

5.22 (s, 1 H)

Infrared spectrum:

(KBr, cm) 3432 1626 1140 3030 1503 1024 2922 1408 696; 1717 1262 Mass spectrum: (Cl, m / e) 445 (2.12) 189 (8.33) 3553,34 156 (14.78) 309 (3.81) 137 (16.19) 105 (94.34) 91 (100); Elementary 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 diethyl / (phenylethyl) thio) propanedioate (1 g, 3.38 mmol) with the corresponding 4'-hydroxy-2'-methylacetophenone trimethylsilylenol ether (2.94 g, 10 mmol) via Method A. Isolated product yield: 52 %, mp Mp 85-87 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 11.89 (br S, 1H) 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 1541 1120 1672 1244 698; Mass spectrum: (Cl, m / e) 355 (35) 91 (30) 250 (26) 85 (100); 105 (92) Elementary analysis: C(%) H (%) calculated 67.78 5.12 found 67.53 5.40 Example 52

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

The title compound was prepared by condensation of diethyl / (phenylmethyl) thio) propanedioic acid (Ig) with the corresponding trimethylsilylenol ether 4'-methoxy-3'-methylation of tophenone by Method A. Yield of the isolated product: 68%, mp 159-106 ° C.

",

H-Nuclear Magnetic Resonance Spectrum:

(400MHz, CDClg)

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

Infrared spectrum:

cm) 3432 1507 1142 2945 1402 1030 1613 1262 812 704;

Mass spectrum: ’(Cl, m / e) 355 (78.3) 149 (12.7 263 (19.6) 235 (11.8) 91 (100); Elementary 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) Yield of the isolated product: 72%.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, delta values) 7.81 (m, 2H) 3.99 (s, 2H) 7.53 (m, 3H) 1.92 (s, 3 H). 7.22 (m, 4H) 7.16 (m, 1H) Example 54 Acid ester 2-oxo-6-phenyl-2 H -pyran-4 -yl-1- • not talenkarbo

xylové

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) and 1-naphthoyl chloride (0.278 g, 1.46 mmol). M.p.

123.5-125 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.54 (with, IH) 8.13 (d, IH) 7.49 (with, IH) 8.34 (d, IH) 7.65 (m, 6H) 8.50 (d, IH). 7.95 (m, 2H)

Example 55

3,3'-Thiobis (4-hydroxy-6-phenyl-2H-pyran-2-one)

The desired 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 room temperature overnight. The unreacted thionyl chloride was removed in vacuo and the residue was recrystallized from boiling methanol. M.p. Mp 240 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, d-TFA, delta values)

7.03 (s, 2H).

7.56 (m, 6H)

7.89 (m, 4 H).

Example 56

3,3'-Dithiobis (4-hydroxy-6-phenyl-2H-pyran-2-one)

Dissolve sulfuric chloride (0,105 ml,

1.32 mmol) and this reaction mixture is 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, which is pre-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 the pale yellow-brown product is isolated by filtration. The solid product is recrystallized from boiling acetic acid. M.p. 280 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

6.77 (s, 2H); 7.52 (m, 6H); 7.81 (m, 4H).

Example 57

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

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

1,2-dichlorobenzene (150 ml) was added with a trace amount of sodium bicarbonate. The reaction mixture is heated to reflux. About 20 ml of ethanol distillate are isolated. 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. M.p. Mp 171-173 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250MHz, DMSC i-d6, delta values) 6.91 (with, 1H) 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 hydrochloride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348 mL, 50 mmol), catalytic 4-dimethylaminopyridine, phenacetyl chloride (0.106 g, 0.626 mmol). M.p. (dec.) 213 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(250MHz, DMSO-d6, delta values) 3.69 (s, 2H) 7, 53 (m, 3H) 6.85 (s, 1H) 7, 83 (m, 2H) 7.29 (m, 3H) 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). M.p. 143.5-144 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250MHz, DMSO-d6, delta values) 6.51 (s, IH) 8.80 (m, 7H) 7.51 (m, 4H) 8.89 (bs, IH) 7.72 (m, 4H)

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). mL), 2-naphthaldehyde (0.407 g, 2.60 mmol) and sodium cyanoborohydride (0.164 g, 2.60 mmol). M.p. (decomp.) 209 ° C «^ Η-Nuclear Magnetic Resonance Spectrum:

(250MHz, DMSO-d6, delta values) 4.46 (with, 4H) 6.38 (with, 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 is prepared via Method E using 3-amino-4-hydroxy-6-phenyl-2H -pyran-2-one hydrochloride (0.200 g, 0.835 mmol), tetrahydrofuran (9 mL), 60% sodium hydride (0.037 mL, 0.918 mmol), oxalyl chloride (0.080 mL),

0.918 mmol) and 2-naphthalylacetic acid (0.170 g, 0.918 mmol). M.p. (dec.) 227 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC ) -d6, delta values) 4.17 (with, 2H) 7.93 (d, 1H) 6.84 (WITH, 1H) 8.17 (d, 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 g, 0.688 mmol). M.p. (dec.) 219 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

250 MHz, DMSO-d6, delta values) 6.92 (s, 1H) 8.62 (s, 1H) 7.61 (m, 5H) 9.61 (s, 1H) 7.97 (m, 6 H).

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 hydroxide (60%). 0.028 mL, 0.688 mmol) and hydrocinnamyl chloride (0.131 g, 0.688 mmol). M.p. Mp 191-193 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

2.65 (t, 2H) 7.53 (m, 3H) 2.89 (t, 2Hj 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). M.p. (dec.) 170 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 3.98 (s, 2H) 7.27 (m, 6H) 6.13 (s, 2H) 7.05 (d, 2H) 6.61 (s, 1H)

Example 65

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

Prepared from 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 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. (dec.) 205 ° C.

^ Ή-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), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. 87-90 ° C.

^ Ή-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 (bs , 1H)

Example 67

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

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), chlor94 trimethylsilane (0.750_ml, 5.56) mmol), tetrahydrofuran (56 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 120-121 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC > —D6, delta values) 2.76 (t, 2H) 7.24 (m, 7H) 2.93 (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). M.p. 138-139 ° C. 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, 7H) 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 '- ((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). M.p. (dec.) 170 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.25 (with, 3H) 7.70 (d, IH) 2.77 (t, 2H) 7.27 (m, 6H) 2.97 (t, 2H) 7.41 (t, IH) 3.84 (with, 3H) 7.43 (d, IH) 5.17 (with, 2H) 7.65 (m, 2H) 6.67 (with, IH) 11.81 (bs , 1 6.98 (t, IH)

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), chloro thimethylsilane (0.741 mL, 5 mL). , 84 mmol), tetrahydrofuran (58 mL) and [(phenylmethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.54 mmol). M.p. (dec.) 170 ° C.

- H-Nuclear magnetic resonance spectrum:

(400MHz, DMSC i-d6, delta values) 2.33 (with, 6H) 7.21 (m, 7H) 3.99 (with, 2H) 7.39 (s, 2H) 6.67 (with, IH)

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'-phenoxyacetophenone (1.07 g, 5.06 mmol), lithium bis (trimethylsilyl) amide ((γ, 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.

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.77 (t, 2H) 7.18 (m, 10H) 2.99 (t, 2H) 7.46 (t, 2H) 6.72 (s, 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-toluenethiosulfonate (1.01 g, 2.65 mmol). M.p. Mp 185-186 ° C.

,.

H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.94 (s, 2H) 7.18 (d, 2H) 5.03 (s, 2H) 7.34 (m, 5H) 6.72 (s, 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 179 ^DEG C. (dec.)

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.77 (t, 2H) 7.53 (d, IH) 2.98 (t, 2H) 7.77 (d, 2H) 5.27 (s, 2H) 7.85 (t, IH) 6.68 (s, IH) 8.60 (d, 2H) 7.22 (m, 6H) 11, ^ 88 (bs , 1 7.36 (m, lH)

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. Then 15 ml of dimethylformamide are added and the solid is again concentrated to dryness under vacuum. The solid was then diluted with 3 mL of dimethylformamide and bromoethyl acetate (0.491 mL, 2.94 mmol). The suspension was 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 was 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 mash) using 15% ethyl acetate / hexanes, 50% ethyl acetate / hexanes to 30% ethyl acetate / 30% hexanes / 40% methyl chloride. M.p. Mp 169-171 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-d6, delta values) 1.20 (t, 3H) 4.87 (with, 2H) 2.75 (t, 2H) 6.69 (s, IH) 2.96 (t, 2H) 7.06 (d, 2H) 4.16 (q, 2H) 7.19 (m, 5H)

7.73 (d, 2H).

11.85 (bs, 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 (* §, 912) g, 5.84 mmol), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 98-101 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

5.96 (with, IH) 7.52 (m, 5H) 6.73 (with, IH) 7.88 (m, 3H) 7.18 (t, IH) 8.07 (with, IH) 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, 5.84) mmol), 2-naphthalenethiol (2.21 mL, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). M.p. (dec.) 200 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

5.9 (s, 1H) 7.44 (m, 6H) 6.71 (s, 1H) 7.75 (m, 4H) 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 and ethyl ester (0.939 mmol) was added 1N sodium hydroxide (2N). , 34 mmol). The reaction mixture was stirred for 5 hours, 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. M.p. Mp 182-183 ° C. ^ Η-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 (s, 1 H)

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). M.p. (dec.) 178 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.76 (t, 2H) 7.45 (q, 1H) 2.98 (t, 2H) 7.77 (d, 2H) 5.25 (s, 2H) 7.91 (d, 1H) 6.69 (3, 1H) 8.57 (bs , 1H 7.21 (m, 7H) 8.70 (bs , 1H

100 ALIGN!

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 (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] propanoic acid diethyl ester (1.00 g, 3.37 mmol). M.p. 130-132 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC ) -d6, delta values) 1.15 (m, 5H) 6.67 (with, IH) 1.81 (m, 6H) 7.21 (m, 5H) 2.77 (t, 2H) 7.45 (q. IH) 2.97 (t, 2H) 7.74 (d, 2H). 3.85 (d, 2H)

Example 80

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

Prepared from Method A using 4 (phenylsulfonyl) acetophenone (2.50 g, 9.61 mmol) lithium bis (trimethylsilyl) amide (2.41 g, 14.42 mmol), chloro trimethylsilane (1.83). mL, 14.42 mmol), tetrahydrofuran (96 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 194-195 ° C.

^ Nuclear Magnetic Resonance Spectrum:

MHz, DMSC »-D6, delta values) · 2.76 (t, 2H) 7, 68 (m, 3H) 3.01 (t, 2H) 8, 04 (m, 6H) 6.87 (with, IH) 12 , 05 (bs , IH) 7.19 (m, 5H)

101

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). M.p. Mp 164-166 ° C.

^ Η-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, 1H) 6.81 (with, 1H) 7.92 (d, 2H) 7.21 (m, 5H) 12.00 (bs , 1H). 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). M.p. Mp 171-173 ° C.

H-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 (s, 1H) 7.95 (d, 2H) 7.19 (m, 5H) 12.05 (bs , 1H) 7.54 (m, 3H)

102 _____________________________ 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), chlorotrimethyl silane (3.92 mL, 30.94 mmol), tetrahydrofuran (200 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. (dec.) 149-152 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.78 (t, 2H) 7.20 (m, 5H) 3.04 (t, 2H) 7.74 (d, 2H) 6.98 (s, IH) 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). M.p. Mp 75-77 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 5.9 (s, IH) 7.44 (m, 7H) 6.71 (s, IH) 7.75 (m, 3H) 7.20 (m, 5H) 7.82 (m, 2H).

103

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). M.p. Mp 189-191 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.70 (dd, 2H) 7.50 (m, 5H) 5.29 (s, 1H) 7.73 (m, 2H) 6.65 (s, 1H) 11.96 (bs , 1H) 7.23 (m, 9H)

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). M.p. Mp 165-170 ° C.

^ 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 (bs , 1H) 7.19 (m, 3H)

Example 87

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

104

Prepared from Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol) ethanol (10 mL), isovaleraldehyde (0.626 mL, 5.84) mmol), thiophenol (1.40 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 154-156 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, acei ton-dg delta value) 0.89 (d, 3H) 4.82 (dd, 2H) 0.93 (d, 3H) 6.70 . · <* (S, IH) 1.63 (m, IH) 7.24 (m, 3H) 1.80 (m, IH) 7.82 (m, 2H) 2.32 (m, IH) 10.49 (bs , IH)

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). M.p. (dec.) 205 C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, ace ton-dg delta values) 0.91 (d, 3H) ' 6.69 (with, IH) 1,25 (m, 5H) 7.22 (m, 3H) 1.73 (m, 5H) 7.48 (m, 5H) 2.58 (m, IH) 7.82 (m, 2H). 4.83 (dd , IH)

Example 89

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

105

Prepared according to Method A using 4-hydroxy-6-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 diethyl ester of ((2-phenylethyl) thio) propanedione (1.00 g, 3.37 mmol). M.p. Mp 114-115 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 2.76 (t, 2 H) 7.34 (s, 1 H) 2.99 (t, 2 H) 7.44 (t, 2H). 6.76 (s, 1 H) 7.56 (m, 2 H). 7.09 (m, 7H) Example 90 4-Hydroxy-6- (3-methoxy-4- (phenylmethoxy)) 1 phenyl-3 - [(2-phenyl) ethyl) thio] -2H-pyran-2-one

The title compound was prepared via Method A using 4'-benzyloxy-3'-methoxyacetophenone (2.00 g, 7.81 mmol), lithium bis (trimethylsilyl) amide (1.96 g, 11.71 mmol) chlorotrimethylilan ( 1.48 mL, 11.71 mmol), tetrahydrofuran (80 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 114-115 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.77 (t, 2H) 6.75 (with, 1H) 2.98 (t, 2H) 7.21 (m, 7H) 3.86 (s, 1H) 7.40 (m, 6H).

Example 91

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

106

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), chlorotrimethyl silane (2.25 mL, 17.73 mmol), tetrahydrofuran (120 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 155-157 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

-¾

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 via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), 1N sodium hydroxide (5.31). ml), [3- (methoxy) phenyl] methyl p-toluenethiosulfonate (2.12 g, 6.90 mmol). M.p. Mp 134-136 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC > -d6, delta values) 3.69 (with, 3H) 7.16 (t, 1H) 3.99 (s, 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, (+ -)

107

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), 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). M.p. Mp 144-145 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

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 via Method B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), 1N sodium hydroxide (5.31). mL) and [3- (benzoxyl) phenyl] methyl p-toluenethiosulfonate (2.65 g, 6.90 mmol). M.p. Mp 140-141 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-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, 1H)

108 __ ____ 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), 1N sodium hydroxide (5.31). mL) and 1,3-benzodioxoyl-5-ylmethyl-p-toluenethiosulfonate (2.22 g, 6.90 mmol). M.p. Mp 162-164 ° C.

",

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-on

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), 1N sodium hydroxide (2.65 mL). and (2-methoxyphenyl) methyl p-toluenethiosulfonate (0.816 g, 2.65 mmol). M.p. Mp 152-153 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.73 (with, 3H) 7.13 (d, IH) 3.95 (with, 2H) 7.17 (t, IH) 6.71 (with, IH) 7.53 (m, 3H) 6.81 (t, IH) 7.79 (m, 2H). 6.91 (d, IH)

Example 97

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

109

The title compound was prepared - in a manner --přičemž _R B using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (15 mL), IN sodium hydroxide ( 5.31 mmol) and [(2-methylphenyl) methyl] -p-toluenethiosulfonate (1.55 g, 5.31 mmol) mp 176-178 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.42 (s, -3H) 7.09 (m, 4H) 3.99 (s, 2H) 7.53 (m, 3H) 6.74 (s, 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 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 [(3-methylphenyl) methyl] -p-toluenethiosulfonate (1.55 g, 5.31 mmol). M.p. Mp 139-140 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-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

4-hydroxy-3 - [(4-methylphenyl) methyl] thio] -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 / (4—

110 methylphenylmethyl-.beta.-tolxrenthiosulfonate ¢ 1.55 g, 5.31. Mp 164-165 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, values delta) 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 ALIGN!

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). M.p.

- 94 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 values delta) 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

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 / (4111 methoxyphenyl) methyl p-toluenethiosulfonate (2.21 g, 6.90 mmol). M.p. Mp 168-170 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 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)

g, 5.84 mmol), cyclohexylmercaptan (1.60 g, 13.8 mmol perdin (0.5 ml) and acetic acid (0.5 mL). M.p. (for mp 220 ° C. ^ H-Nuclear Magnetic Resonance spectrum: (400MHz, 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, (+, -)

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),

112

2,6-dimethylthiophenol (1.90 g, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 166-167 ° C. ^ Η-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). M.p. Mp 69-71 ° C.

^ Η-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 (ra, 2H) 2.64 (ra, 1H) 0.64 (ra, 2H) 4.21 (t, 1H) 1,22 (m, 5H) 6.69 (with, 1H) 1.52 (m, 1H) 7.52 (m, 3H) 1.67 (m, 3H) 7.75 (ra, 2H).

Example 105

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 158 - l ^of 62 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.83 (d, 3H) 4.68 (m, IH) 0.87 (d, 1 * 3H) 6.76 (with, IH) 1.49 (m, IH) 7.49 (m, 5H) 1.74 (m, IH) 7.74 (m, 3H). 2.39 (m, IH)

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 t, 5.31 mmol), ethanol (10 mL), 3,3-dimethylbutanal (0). , 73 mL, 5.84 mmol), cyclohexylmercaptan (1.86 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. 225 [deg.] C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.85 (with, 9H) 6.69 (with, IH) 1,25 (m, 5H) 7.54 (m, 3H) 1.65 (m, 7H) 7.75 (m, 2H). 4.30 (m, IH)

Example 107

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

The title compound was prepared via Method A wherein:

114

- ethyl (4-acetyl-2-methylphenoxy) acetate (2.00 g) is used;

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). M.p. Mp 154-156 ° C.

Sl-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 1,22 (t, 3H) 4.91 (with, 2H) 2.26 (with, 3H) 6.66 (with. IH) 2.77 (t, 2H) 6.99 (d, IH) 2.97 (t, 2H) 7.21 (m. 5H) 4.17 (t, 2H) 7.61 (n, 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 (actophenone (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 137-139 ° C Si-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC > —D6, delta values) 0.21 (with, 6H) 6.99 (d, IH) 0.99 (WITH, 9H) 7.21 (m, 5H) 2.22 (with, 6H) 7.44 (m, 2H). 3.96 (with, 2H) 6.54 (WITH, IH)

Example 109

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

The desired compound was prepared via Method A using 4- (4-pyridinylmethoxy) acetophenone (2.00 g, 8.81 mmol), trimethylsilyl triflate (2.04 mL, 10.57 mmol), triethyl amine (2, 4, 4-pyridinylmethoxy) acetophenone. 45 mL, 17.26 mmol), methylene chloride (22 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. (dec.) 212 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 values delta) 2.73 (t, 2H) 7.18 (m, 5H) 2.88 (t, 2H) 7.45 (d, 2H) 5.29 (with, 2H) 7.74 (d, 2H) 6.48 (with, IH) 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). M.p. Mp 146-149 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 values delta) 0.85 (d, 2H) 3.04 (m, lH) 0.87 (d, 2H) ' 4.20 (dd, IH) 1.32 (m, IH) 6.69 (s, IH) 1.54 (m, 7H) 7.53 (m, 4H) 1.85 (m, IH) 7.76 (m, 2H) 2.00 (m, 2H) 11.69 (bs, IH) Example 111

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

116

-------- _{To a} tetrahydrofuran (10 mL) solution of [4- (4-hydroxy) -2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl] 1-Sodium hydroxide (1.13 mL, 1.13 mmol) was added to (2-methylphenoxy) acetic acid ethyl ester (0.20 g, 0.45 mmol). The reaction mixture was stirred for 5 hours and then 10 mL of water was added. This is followed by acidification to pH 2 with concentrated hydrochloric acid. 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) eluting with 94/5/1 methylene chloride / methanol / acetic acid. Mp (dec.) 210 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.26 (s, 3H) 6.67 (with, 1H) 2.78 (t, 2H) 6.97 (d, 2H) 2.98 (t, 2H) 7.21 (m, 5H) 4.81 (s, 2H) 7.61 (d, 2H).

Example 112

3- [1- (Cyclohexylthio) -2-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). M.p. 157-160 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

- 117

1.44 Cm, 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 (bs , 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-pyran-2 1N hydrochloric acid (9.0 ml) was added at 0 ° C. 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 sequentially 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.

Η-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 (s, IH)

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)

118 mmol), ethanol (1.5 mL), 1 N sodium hydroxide (5.31 mL), [3- (2 (phenylethoxy) phenyl) methyl p-toluenethiosulfonate (2.11 g, 5.31 mmol). 90 ° C.

^ Η-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, 2.H) 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 triflate (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). M.p. 181-182 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC ) -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).

119 trimethylsilyl triflate (1.55 mL, 8.2 mmol), triethylamine (1.86 mL, 13.36 mmol), methylene chloride (17 mL), and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol).

M.p. Mp 122-123 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6 delta values) 2.77 (t, 2H) 7.26 (m, 5H) 2.93 (m, 3H) 7.38 (d, 2H) 2.99 (t, 2H) 7.71 (d, 2H). 6.75 (s, IH)

(O r-t

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), cyclohexylmercaptan (1.68 mL, 13.8 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). M.p. Mp 189-191 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 1,21 (m, 5H) 6.70 (with, IH) 1.52 (m, lH) 7.17 (t, IH) 1.91 (m, 2H) 7.53 (m, 5H) 2.58 (m, 2H) 7.74 (m, 2H) 5.37 (s, IH) ' 11.96 (bs , IH).

Example 118

4-Hydroxy-3 - [(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).

120 lithium bis (trimethylsilyl) amide (2.45 g, ... 14.7 mmol), chlorotrimethylsilane (2.47 g, 14.7 mmol) and diethyl ester of ((phenylmethyl) thio) propanedioic acid (1.00 g, 3.54 mmol). M.p. 128-132 ° C.

^ Ή-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 4.03 (s, 2H) 7.56 (dd , 1H) 6.81 (s, 1H) 7,6í (t, 1H) 7.2 (m, 2H) 7.75 (with, 1H) 7.28 (m, 4H) 7.86 (d, 1H)

Infrared spectrum:

(KBr, cm ^-1 ) 2963 1651 1550 1394 1369 1395 1263 1098 1024 800 Mass spectrum: (Cl, m / e) 395 (M + H) 37) 205 (3) 309 (7) 119 (10) 273 (6) Elementary analysis for ^C 19 ^H 13 ° 4 ^N 1 ^F 3 ' ^H 2 ° C(%) H (%) calculated 55.34 3.67 found 54.94 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), cyclo121 hexylmethyl-p-toluenethiosulfonate (0.756 g, 2.66 mmol). M.p. Mp 141-143 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 0.92 (m, 2H) 2.64 (d, 2H) 1.14 (m, 4H) 6.78 (with, IH) 1.19 (m, lH) 7.53 (m, 3H) 1.61 (m, 4H) 7.81 (m, 2H); 1.83 (m, 2H)

Infrared spectrum:

(KBr, cm 1)

3106 1547 1099

2922 1396 766

1651

Mass spectrum:

(Cl, m / e)

317 (M + H 16) 177 (18) 279 (83) 134 (55) 242 (77) 105 (64) 201 Italy (27) 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'-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). M.p. Mp 149-151 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

122

2.25 (s. 3H) 7.44 (dd, IH) 2.78 (t, 2 H) 7.67 (s + d, 2H) 2.97 (t, 2 H) 7.92 (d, IH) 5.28 (s, 2H). 8.58 (brs, IH) 6.69 (s, 1H) 8.72 (brs, 1H); 7.22 (m, 6H) Infrared spectrum: (KBr, cm ^) 3430 1505 1028 2926 1263 808 1713 1136 705; 1626

Mass spectrum: (CI, m / e)

446 (M + H)

Elemental analysis calculated

200 (5)

105 (99) 26 ^H 23 ° 4 ^N E C (%) H (%) N (%) 70.09 5.20 3.14 70.31 5.27 2.95

Example 121

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

Prepared from Method A using 1,4-benzodioxin-6-ylmethylketone (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). M.p.

192-193 ° C:

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

123 ...... 3.99 ...... (s, 2H)

4.17 (m, 4H); 6.8 (s, 1H)

Infrared spectrum:

(KBr, cm ^)

7.0 (d, 1H); 7.2 (m, 1H); 2.28 (m, 7H).

3435 1624 2924 1508 1649 1288 Mass spectrum: (Cl, m / e) 368 (M + H) 163 (9) 277 (11) 107 (9) 233 (11) 91 (76). Elementary analysis P ^{ro C} 20 ^H 16 O5 ^{S L:} C(%) H (%) calculated 65.21 4.38 found 64.80 4.17

Example 122

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 [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.33 g, 4.55 mmol). M.p. Mp 117-118 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.8 (t, 2 H) 7.94 (t, 1 H) 3.03 (t, 2H) 8.08 (s, 1H) 6.94 (s, 1 H) 8.14 (d, 1 H). 7.2 (m, 5H)

Infrared Spectrum: (KBr, cm -1)

124

3435 1635 1171 3026 ............  1543 1130 2924 1327 696 1720 spectrum: , m / e) 393 (M + H, 100). 256 (19) 373 (8) 224 (12) 288 (37) 105, 62.

Elemental analysis for? 20 ^H 15 ^S 1 ° 3? 3 * ^H 2 °

H (%)

calculated 58.53 4.18 found 59.28 3.81 Example 123

4-Hydroxy-3 - [(phenylmethyl) thio] -6- [3- (trifluoromethylphenyl) 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). M.p. Mp 152-153 ° C.

^ Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.97 (with, 2H) 6.53 (with, 1H) 7.25 (m, 5H) 7.61 (t, 1H)

7.75 (d, 1H) 8.03 (d, 1H) 8.08 (with, 1H)

Infrared spectrum: (KBr, cm ^-1 )

3434

3244

1678

1535

1522

1522 1192 1435 1132 1341 936 1316 706.

125

Mass spectrum: __________________________________________________ (Cl, m / e)

378 (M + H)

257 (1) (99)

Elemental analysis for ^C] _9 ⁱⁱ J.3 ° 3 and ^F 3 ^S:

C (%) calculated

H (%)

3.46

3.57

60.31

60.53

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), and the desired compound. , 82 mmol) and [(phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. 89-91 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.78 (t, 2H) 3.03 (t, 2H) 6.86 (s, 1H)

7.25

7.72

7.86 (m, 6H) (t, 3H) (m, 5H).

126

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

3443 1543 729

3335 1333 581

1725 1171 552

1632 912

Elemental Analysis for ^C 25 ^H 21 ^N 1 ^S 2 ° 5 · ^H 2 ^0:

C (%) H (%) calculated 60.35 4.66 found 60.13 4.47

N (%)

2.81

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). M.p. Mp 152-154 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, 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:

cm) 2936 1510 988 2979 1406 820 1640 1182 764.

Mass spectrum: (CI, m / e)

127

450 (M + H) 341 (10); 105 (100).

236 (9)

Elemental analysis calculated for ^C 25 ^H 23 ^N 1 ° 5 ^S 1

C(%)

66.80

66.42

H (%)

5.16

5.20

N (%)

3.12

2.74

Example 127 (1R) -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), cyclohexylmercaptan (0.489 g, 4.212 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. 84-87

Infrared spectrum:

cm) 3059 1676 1260 2930 1601 1134 2853 1449 700;

Mass spectrum:

(Cl, m / e) 446 (1) 205 (24) 331 (8) 135 (44) 226 (60)

Example 128

2 - [(4-Hydroxy-2-oxo-6-phenyl-2H-pyrazin-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).

128 2-Carbomethoxybenzyl / methyl p-toluenethiosulfonate (3.57 g, 10.63 mmol), 1 N sodium hydroxide (10.63 mL) and ethanol (20 mL). M.p. Mp 122-123 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.81 (with, 3H) 7.44 (t, 1H) 4.31 (with, 2H) 7.44 (m, 3H) 6.67 (with, 1H) 7.53 (d, 1H) 7.25 ** (d, 1H) 7.99 (m, 3H); 7.31 (t, 1H)

Infrared spectrum: (KBr, cm &lt; -1 &gt;

3005 1543 966 2951 1400 766 1721 1267 711 1653 1078 520

Mass spectrum:

me) 397 (M + 29.4) 191 Italy (26) 369 (M + H), 40 149 (100) 337 (33) 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 (1.0 g, 4.06 mmol), isovaleraldehyde (0). , 35 g, 4.06 mmol), cyclohexylmercaptan (0.944 g, 8.12 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 161-162 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

129

0.85 (d. 3H) 2.04 (m, 2H) 0.88 (d, 3H) 4.2 (q, 1H) 1.2 (m, 5H) 4.32 (brq, 4H) 1.39 (m, 1H) 6.53 (s, 1H). 1.53 (m, 2 H) 6.99 (d, 1H) 1.65 (m, 2H) 7.2 (d, 1H). 1.81 (brm, IH) 7.25 (dd, IH): spectrum: (KBr, cm 1) 1099 1510 1140 2930 1397 1069 2853 1314 891 1649 1289 771 1564 1260 608.

Example 130

2- [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 2 - [(4-acetyl) phenoxy / methyl / benzoic acid methyl ester (2.0 g, 7.04 mmol), trimethylsilyltrifluoromethylsulfonate (1.57 g, 7.04 mmol) , triethylamine (1.42 g, 14.08 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.04 g, 3.52 mmol). M.p. Mp 161-162 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 2.78 (t, 2 H) 7.14 (m, 4H) 2.97 (t, 2 H) 7.25 (m, 3H) 3.81 (s, 3H) 7.5 (m, 2H) 5.5 (s, 2H) 7.78 (m, 2H) 6.69 (s, 1H) 7.78 (d, 2H) 7.94 (d, 1H); Infrared spectrum:

(KBr, cm 1)

130

3028 _____________ '1638 ........... ... ............... 1181 2949 1510 1030 2909 1402 828 2675 1291 747;

1715 1267

Mass spectrum:

(Cl, m / e)

489 (M + H, .51) 149 (100) 384 (3) 135 (47) 353 (1) 105 (33).

Example 131

4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (1H-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 are evaporated, the solid residue is treated with 1N hydrochloric acid, and the mixture is stirred at room 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. M.p. Mp 195-196 ° C.

^ Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 2.78 (t, 2 H) 6.72 (S, 1 H) 2.99 (t, 3H) 7.22 (m, 6H) 5.6 (s, 2H). 7.81 (d, 2 H). Infrared spectrum: (KBr, cm ^-1 ) 3121 1512 1059 3028 1410 831 1657 1256 696; 1549 1186

131

Mass spectrum: ..... _ (Cl, m / e)

423 (M + H, .delta.) 341 (3)

137 (11) 105 (100).

Example 132

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

The title compound was prepared via Method A using 4- (2-pyridinylmethoxy) -3-methyl-acetophenone (2.0 g, 8.29 mmol), trimethylsilyltrifluoromethylsulfonate (1.84 g, 8.29 mmol), triethylamine (1.0 g, 8.29 mmol). 68 g, 16.58 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.22 g, 4.15 mmol) Tt Mp 75-77 ° C.

^ Η-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:

cm) 3063 1603 1138 2924 1505 1039 1719 1267 760;

Mass spectrum: (CI, m / e)

446 (M + H 90) 242 Italy (21) 341 (16) 151 Italy (25) 279 (17) 105 (100);

132

-Elementary analysis for_:

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 (+, -)

Prepared from Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), 2-cyclopropylmethylcarboxaldehyde (0.67 g, 7.98 mmol) ), benzyl mercaptan (1.98 g, 15.96 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 59-61 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) -0.97 (m, 2H) 6.67 (with, IH) 0.28 (m, 2H) 7.18 (t, IH) 0.58 (m, lH) 7.25 (d, 2H) 1.61 (m, lH) 7.31 (t, 2H) 2.01 (m, lH) 7.53 (m, 3H) 3.72 (ABXq, 2 H) 7.75 (m, 2H);

Infrared spectrum:

cm) 3061 1649 1267 2919 1564 766 2613 1404 691;

Mass spectrum:

me) 255 ((M-SBzl) 201 (5) 147 (2);

133

Elemental analysis calculated found PRA C ₂ ^H 3 3 22 ° C ^with 1 ^L (%)

72.99

72.31

H (%) 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 wherein

4-hydroxy-6-phenyl-2H-pyran-2-one (1.5 g, 7.98 was used) isovaleraldehyde (0.69 g, 7.98 mmol), 2 -methoxythi phenol (2.24 g, 15.96 mmol), piperidine (1.0 mL), acid (1 mL) and ethanol (15 mL). M.p. Mp 75-78 ° C Η-Nuclear Magnetic Resonance Spectrum: (400 MHz, DMSO-d6, delta values) 0.86 (d, 3H) 6.64 (s, 1H) 0.89 (d, 3H) 6.89 (t, 1 H) 1.53 (m, 1H) 6.94 (d, 1 H) 1.69 (m, 1H) 7.17 (t, 1 H) 2.19 (m, IH) 7.33 (d, 1 H) 3.64 (s, 3H) 7.53 (m, 4H) 4.69 (q, 1H) 7.78 (m, 2H); Infrared spectrum: (KBr, cm ^-1 ) 3063 1649 1026 2955 1564 768 2635 1406 750 1649 1242 691;

Mass spectrum:

(Cl, m / e)

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

134

Elemental analysis for ^C 21 ^H 24 ° 4 ^S 1 ^: C (%) H (%) calculated 69.67 6.10 found 69.63 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 (1.0 mL). M.p. 153-155 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

(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, 1 H) 4.22 (q, 1 H);

1.53 (m, 1H).

(KBr, cm ¹ )

3086 1566 1311 2955 1497 1127 1651 1404 912 766

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

135

(2.36 g, 14.08 mmol), chlorotrimethylsilane (2.38 g, 14.08). mmol) and diethyl ester of [(2-phenylethyl) thio] propanedioic acid (1.0 g, 3.05 mmol). M.p. . Mp 157-158 ° C. Η-Nuclear Magnetic Resonance Spectrum: (400MHz, DMSO-d6, delta values) 2.78 (t, 2 H) 7.17 (q, 4H) 2.97 (t, 2 H) 7.25 (m. 3H) 3.86 (s, 2H) 7.61 (d, 2 H) 5.3N (s, 2H) 7.78 (d, 2H). 6.67 (s, 1H) 8.0 (d, 2 H); Infrared spectrum: (KBr, cm ^) 3023 1510 1098 2936 1404 1009 2581 1258 818 1632 1184 718; Mass spectrum: (Cl, m / e) 517 (M + 29.7) 149 (39) 488 (M + H, 55) 105 (100); 384 (18) Example 137

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

Prepared via Method A using 3 - [(4-acetyl) phenoxy / methyl / benzoic acid methyl ester (2.0 g, 7.04 mmol), lithium hexamethyldisilazane (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). M.p. Mp 147-149 ° C.

136 ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMS O-d6 7 Kodnoty delta) 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 < Im, 7H)

Infrared spectrum:

cm) 3081 .1512 1098 ' 2950 1406 1004 1726 1345 820 1632 1406 748 1609 1290 696;

Mass spectrum:

(Cl, m / e) 488 (M + H, 48) 236 (6) 384 (15) 149 Italy (39) 341 (6) 119 Italy (11)

105 (100).

Example 138

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

The title compound was prepared via Method A using 4 - [(3,4-dichloro-phenyl) -methoxy] -acetone-phenone (2.0 g, 6.80 mmol), lithium hexamethyldisilazide (2.28 g, 13.61 mmol), chlorotrimethylsilane (2, 3, 6, 7 mmol). 3 g, 13.61 mmol) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.0 g, 3.40 mmol), mp 168-169 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

137

2.78 (t, 2 H) 2.97 (t, 2H) 5.22 (with, 2H) 6.69 (with, 1H)

7.17 (m, 8H) 7.47 (dd , 1H) 7.69 (d, 1H) 7.78 (d, 1H);

Infrared spectrum: (KBr, cm ^-1 )

3054

2602

1713

1611

Mass spectrum:

me) 501 (17) 499 (24) 394 (12) 353 (1)

1512 1109 1399 1042 1291 818 1179 754;

161 (20) 159 Italy (27) 105 (100).

Example 139

3 - [(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), [3- (carbomethoxy) phenyl] methyl p-toluenethiosulfonate (3.57 g, 10.63 mmol), 1 N sodium hydroxide (10.63 mL), ethanol (20 mL). M.p. Mp 170-171 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, 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 ^-1 )

138

3108 1549 770 2947 1400 713 1716 1302 523; 1644 1100 Mass spectrum: (Cl, m / e) 369 (M + H +, 7) 189 (3) 337 (7) 149 (12) 235 (5) 85 (100).

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), 1N sodium hydroxide (10.63 mL), ethanol (20 mL). M.p. Mp 215-216 ° C.

^ Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.81 (with, 3H) 7.67 (m, 3H) 4.06 (with, 2H) 7.81 (m, 2H) 6 (69 , J = ^: with Hz, IH) 7.86 (d, 2H);

7.39 (d, 2H).

cm) 3110 1547 1103 3038 1402 720 1717 1279 526; 1644

Mass spectrum:

(Cl, m / e) 151 (55) 369 (M + H, 21) 119 (20) 235 (100) 105 Italy (21)

(28).

207 (18)

139

Example 141

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

The title compound was prepared via Method A using 3 ', 5'-trifluoromethyl-acetophenone trimethylsilyl ether (2.16 g, 7.1 mmol) / preparation using 3,5-ditrifluoromethyl-acetophenone (15 g, 58.55 mmol), trimethylsilyltrimeth ylsulfonate (13.01 g, 58.55 mmol) and triethylamine (11.84 g, 117.10 mmol) and diethyl ester of ((phenylmethyl) thio) propanedioic acid (1.0 g, 3.55 mmol). M.p. 80-82 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDClg, delta values)

4.0 (s, 2H) 6.61 (s, 1 H) 7.22 (m. 2H) 7.28 (m, 3H) 7.97 (s, IH) 8.25 (s, 2 H); Infrared spectrum:

cm) 3090 1549 1182 1726 1530 1138 1682 1385 902 1638 1281 700;

Mass spectrum:

(Cl, m / e) 475 (M + 29.3) 149 (2) 447 (M + H, 20) 91 (100) 213 (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), cyclohexylmer140 captan (2.04 g, 17.56 mmol), piperidine (1.0 mL) and acetic acid (1.0 mL) and ethanol (20 mL). M.p. Mp 210-212 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 0.89 (t, 6H) 1.81 (m, lH) 1.36 (m, 7H) 2.08 (m, 2H) 1.44 (m, 1 H) 2.61 (brm, IH) 1.56 (m, 2H) 4.22 (m, lH) 1.69 (m, 2H) 6.67 (s, IH) 7.53 (m, 4H) 7.78 (m, 2H);

Infrared spectrum:

(KBr, cm) 3106 1659 1125 2928 1568 766 2851 1404 569; Mass spectrum: (Cl, m / e) 259 (49) 147 (8) 257 (48) 105 (28) 201 (45) 189 (15) 83 (100).

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). M.p. Mp 157-159 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

141

2.92 (t, 2H) ............ 7.08 (d, 2H) 3.11 (t, 2H) 7.19 (t, 3H) 4.86 (with, 2H) 7.3 (m, 4H) 6.56 (with, 2H) 7.86 (d, 2H);

Infrared spectrum:

(KBr

cm) 2993 1342 1051 2577 1302 833 1543 1226 717 1510 1188 505; 1404 1098

-¾

Mass spectrum: (CI, m / e)

380 (100)

205 (8) 105 (94).

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). ).

. , ~ *

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

2962

1661

1551

1406

1365

1101

760;

142

Mass spectrum:

(Cl, m / e) 339 (99) 189 Italy (11) 305 (3) 147 (9) 219 (24) 105 (9); Elemental analysis for ^C 20 ^H 18 ° 3 ^S 1 ^: C(%) H (%) calcd 5.36

found 70.82 ’5.24.

Example 145

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-toluenethiosulfonate (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).

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, CDCl3, delta values)

7,994 - 7,726 (m, 2H) 1,063 - - 0,903 (m, IH) 7,683 - 7,406 (m, 3H) 0.608 - - 0,533 (m, 2H) 6,665 (s, IH) 0,270 - • 0.208 (m, 2H).

2.724-2.694 (d, 2H, J = 7.3 Hz)

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), hydrogen143 sodium carbonate (0.094 g, 1.13 nunol) and methanol (5, G-mi). M.p. Mp 123-124 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, CDCl ^, delta values)

7,848-7,839 (m, 1H) 6.631 (s, 1 H) 7.729 (m, IH) ) 2,831-2,794 (t, 2H) 7,479-7,392 (m, 2H) 2,633-2,596 (t, 2H) 7,276-7,239 2H) 1,747-1,689 (m, 2H) 7,174-7,137 (m, 3H) 1,649-1,591 (m, 2H).

Example 147

4-Hydroxy-3 - [(2-oxo-2-phenylethyl) thio] -6-phenyl-2H-pyran-2-one 4-hydroxy-3-mercapto-6-phenyl-2-pyrone solution (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 nitrogen, was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was stirred at room 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 evaporated in vacuo to give the title compound (0.066 g, mp 164-166 ° C) which was dried in vacuo.

Η-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDClCl, delta values)

9,900 (bs , 1H) 7,505- 7, 443 (m. 5H) 7,970 (d, 2H, J = 7, , 1 Hz) 6,619 (with , 1H) 7,810 (d, 2H, J = 8 Hz) 4,334 (with , 2H). 7,615 (t, 1H, J = 4 Hz)

144

......... 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] T-6-phenyl-2H-pyran-2-one (0.021 g, 0.060 mmol) in tetrahydrofuran (1.0 mL) cooled to 0 ° C (nitrogen atmosphere) was added a 1.0 M solution of BHg.DMS ( 0.05 ml, 0.05 mmol) 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 were combined, dried over sodium sulfate and the solvents removed in vacuo to give the title compound (0.015 g) as an oily product.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, ' CDCl 3, hc idnot .y delta) 7,873 - 7,777 (m, 4H) 7,516 - 7,153 (m, 6H) 6,667 (s, IH) 4,820 - 4,755 (dd, IH, J = 9.8 Hz, 3.2 Hz) 3,212 - 3,127 (dd, IH, J = 13.8 Hz, 3.2 Hz 2,920 (dd, IH, 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 to 0 ° C under nitrogen and treated first with triethylamine (3.14 mL,

22.6 mmol) followed by trimethylsilyl triflate (2.60 mL, 13.5 mmol). The mixture was warmed to ambient temperature, stirred for minutes and then treated with a mixture of diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (20 mL). The ether solution was dried over sodium sulfate and the solvent 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 to 140 ° C for hours. It is then cooled to ambient pulse

145 mL, 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).

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

6.309-6.285 (m, 2H) 5.862 (d, 3H, J = 8 Hz)

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 to 0 ° C under a nitrogen atmosphere and treated first with triethylamine. (3.03 mL, 21.7 mmol) followed by trimethylsilylflate (2.52 mL, 13.0 mmol). The solution was warmed to room temperature, stirred for 15 minutes and added gradually to a mixture of diethyl ether (50 mL) and saturated aqueous sodium bicarbonate (20 mL). The ether solution was dried over sodium sulfate and the solvent removed in vacuo. The resulting silylenol ether was transferred to a flask containing diethyl 2- (thiophenyl) propane-1,3-dioate (0.97 g, 3.6 mmol). The mixture is heated at 140 ° C for 16 hours 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 10dml) and acidified to pH 0 with concentrated hydrochloric acid. 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 of the title compound (0.695 g, mp 186-188 ° C).

Η-Nuclear Magnetic Resonance Spectrum:

(300 MHz, DMSO-dg, 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, 2 H).

Example 151

[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).

Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

7.585 (d, 2H, J = 9 Hz) 7,063 (d, 2H) 7.325-7.286 (m, 2 H) 4,784 (s, 2H) 7.178 (d, 3H, J = 7.5 Hz) 2,042 (s, 3 H).

Example 152

4-Hydroxy-3-phenoxy-6-phenyl-2 H -pyran-2-one

2-Phenoxypropanedioic acid diethyl ester (8.11 g, 0.032 mol) and 1-phenyl-1- (trimethylsilyloxy) ethylene (12.35 g, 0.064 mol) were added to the pressure reactor. The vessel was pressurized to 600 psi with nitrogen. The mixture was heated at room temperature for 8 hours

147 ° C and then 83.5 hours at 147-154 ° C. ......

Cool the vessel to room temperature, rinsing with ethyl acetate. Flash chromatography (hexane / ethyl acetate 1/1) gave a partially purified material which was then loaded onto silica gel eluting with hexane / ethyl acetate 95/5 - 40/60. The resulting solid was recrystallized from diethyl ether and ethyl acetate to give 1.64 g (18%) of the title compound. M.p. Mp 215-219 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

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) 7.02 (t, 1 H) 12.0 (bs, 1 H). 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 diethyl ((phenylmethyl) thio) propanedioate. M.p. 183-184 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -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

- 148

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. M.p. Mp 88-90 ° C.

'H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.98 (with, 2H) 7.48 (m, 1H) 6.58 (with, 1H) 7,72 ·, (m, 1H) 7.24 (m, 5H) 8.13 (d, 1H).

Example 155

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

The title compound was prepared via Method A by condensation of 3-acetylthiophene trimethylsilyleneol ether and ((phenylmethyl) thio) propanedioic acid diethyl ester. M.p. Mp 150-151 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

2.55 (5, 6H) 7.16 - 7.28 (m, 5H) 4.02 (with, 2H) 7.40 (s, 2 H). 6.85 (with, 1H)

Example 156

3 - [(2,6-Dimethylphenyl) methyl] 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 (2,6-dimethylphenyl) methyl p-toluenethiosulfonate (1.62 g, 5.31 mmol). M.p. Mp 231-233 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO -d6, delta values) 2.34 (s, 6H) 7.03 (m, 3H) 4.01 (with, 2H) 7.53 (m, 4H) 6.81 (m, 2H) 7.82 (m, 2H).

149

Example 157

4-Hydroxy-6-phenyl-3 - [(3-phenoxyphenyl) 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), ethanol (15 mL), 1 N sodium hydroxide (5.31) mL) and (3-phenoxyphenyl) methyl p-toluenethiosulfonate (1.96 g, 5.31 mmol). M.p. Mp 131-133 ° C. V ^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC > -d6, delta values) 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 via Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), isovaleraldehyde (0.462 mL, 5 mL), 84 mmol) cyclohexylmethylthiol (1.79 g, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 146-148 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.58 (d, 6H) 4.17 (dd, 1 H) 1.11 (m, 5H) 6.69 (s, 1H) 1.57 (m, 8H) 7.54 (m, 4H) 2.07 (m, 1H) 7.75 (m, 2H) 2.28 (dd, 1H) 11.71 (bs, 1 H) 2.38 (dd, 1H)

Example 159

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

- 150

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 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. 138-141 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 0.89 (m, 2H) 5.30 (with, 1H) 1,21 (m, 4H) 6.71 (with, 1H) 1.42 (m, 1 H) 7.26 (t, 1H) 1.61 (m, 4H) 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 ethyl 4- (4-hydroxy-2-oxo-3-) - (2-phenylethyl) thio/ 2 H -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. M.p. Mp 123-125 ° C. ^ Η-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)

151

Example 161 -.....

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

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). M.p. Mp 116-119 ° C.

^ 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, 7H) 3.05 (t, 2H) 7.44 (m, 2H).

4.89 (d, 2 H)

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-isoxazoles) methoxy) acetophenone (2.00 g, 6.51 mmol), trimethylsilyl triflate (1.51 mL,

7.81 mmol), triethylamine (1.81 mL, 13.02 mmol), methylene chloride (16 mL) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 126-128 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC ) -d6, delta values) 2.54 (with, 3H) 7.21 (m, 7H) 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

152

The title compound was prepared via Method A using 35'-dimethylacetophenone (1.43 g, 9.70 mmol), trimethylsilyl triflate (2.24 mL, 11.64 mmol), triethylamine (2.70 mL, 19.40 mmol) ), methylene chloride (24 mL) and (phenylthio) propanedioic acid diethyl ester (1.00 g, 7.46 mmol). M.p. Mp 210-211 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.35 (s, 7H) 7.21 (with, IH) 6.83 (s, IH) 7.27 (t, 2H) 7.12 (m, 4H) 7.46 (with, 2H).

Example 164

3- (1- (Cyclopentylthio) -2-cyclopropylethyl) -4-hydroxy-6-phenyl-12H-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 : 1,43 ml, 13 , 8 mmol) peridine (0.5 mL), acetic acid (0,5 ml). T .t. 75 - Si-Nuclear magnetic resonance spectrum: (400 MHz, DMSO-d6, delta values) 0.04 (m. 2H) 3.19 (m, lH) 0.07 (m, 2 H). 4.21 (dd, IH) 0.66 (m, 1H) 6.71 (s, IH) 1.53 (m, 7H) 7.54 (m, 4H) 1.94 (m, 3H) 7.76 (m, 2H).

Example 165

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

The title compound was prepared via Method A using 3 '- (p-toluenesulfonamide) acetophenone (1.38 g, 5.06 mmol), trimethylsilyl triflate (2.34 mL, 12.41 mmol), triethyl153 amine (2.82) ml, 20.24 mmol), methylene chloride (18 ml) and [(2-phenylethyl) thio] propanedioic acid diethyl ester (1.00 g, 3.37 mmol). M.p. Mp 133-135 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 2.32 (with, 3H) 7, 40 (m, 4H) 2.77 (t, 2H) 7, 53 (with, 1H) 3.09 (t, 2H) 7, 67 (d, 2H) 6.68 (with, 1H) 10 , 50 (with, 1H) 7.19 (m, 6H) 12 , 03 (bs , 1H)

Example 166

3- (Cyclopentyl (cyclopentylthio) 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), cyclopentanecarboxaldehyde (0.780 g, 7, 96 mmol), cyclopentylthiol (1.43 mL, 13.8 mmol), piperidine (0.5 mL) and acetic acid (0.5 mL). M.p. Mp 139-142 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

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 , 1H) 3.84 (d, 1H)

Example 167

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

The title compound was prepared via Method A using 3'-phenylacetophenone (0.946 g, 4.83 mmol), trimethyl

154 silyl 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). M.p. Mp 193-195 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 values delta) 1,25 (d, 6H) 7.28 (d, IH) 3.43 (m, IH) 7.42 (t, IH) 6.95 (d, IH) 7.51 (t, 2H) 7.02 (with, IH) 7.66 (t, • IH) 7.06 (t, IH) 7.75 (d, 2H) 7.13 (t, IH) 7.85 (t, 2H) 8.07 (with, IH) 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 diethyl ester for pandioic acid (1.00 g, 3, 22 mmol). M.p. Mp 158-160 ° C.

1-H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0,972 (i.e. , 3H) 7.06 (m, 2H) 1.64 (m, 2H) 7.16 (m, IH) 2.71 (t, 2H) 7.55 (m, 3H) 6.87 (with, IH) 7.85 (m, 2H). 6.92 (m, IH)

Example 169

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

The title compound was prepared via Method A using 3 ', 5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine

155 (1/34 mL, 9.66 mmol), methyl chloride (17 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g, 3.22 mmol). M.p. Mp 154-155 ° C.

^ Η-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, IH) 3.40 (m, IH) 7.27 (d, IH) 6.90 (d, IH) 7.45 (with, 2H). 7.05 (t, IH)

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'-hydroxyacetophenone (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). M.p. (decomposition) 250 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.24 (d, 6H) 7.05 (t, IH) 3.40 (m, IH) 7.10 (t, IH) 6.70 (with, lH) 7.26 (d, IH) 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 using 1-phenyl-1- (trimethylsilyloxy) ethylene (0.990 mL, 4.83 mmol) and diethyl ester of 2- (cyclopropylmethyl) phenyl / thio / propanedioic acid (1.00 g, 3.10 mmol). M.p. Mp 165-167 ° C.

156 ¹ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, 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) 7.56 (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, 1, 2, 4, 7 mmol). 34 ml, 9.66 mmol), methylene chloride (17 ml) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.00 g,

3.22 mmol). M.p. 225 [deg.] C.

'.

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)

Example 173

4- (4-Hydroxy-5 - [(2-isopropylphenyl) thio] 6-oxo-6H-pyran-2-yl) phenoxyacetic acid ethyl ester

The title compound was prepared via Method A using ethyl (4-acetylphenoxy) acetate (2.14 g, 9.67 mmol).

157 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). M.p. Mp 194-196 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1.57 (m, 9H) 6.90 (d, IH) 3.41 (m, IH) ^{7 '05} (m, 4H) 4.81 (qr 2H) 7.26 (d, IH) 4.89 (with, 2H) 7.79 (d, 2H). 6.75 (with, IH)

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] phenoxyacetyl ethyl ester (0.319 g, 0.75 mmol) was added 1N sodium hydroxide. (1.80 mL, 1.81 mmol). The reaction mixture was stirred for 1.5 hours, then 10 mL of water was added, followed by acidification with concentrated hydrochloric acid to pH 2. 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. M.p. (dec.) 217 ° C.

Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-d6, delta values) 1,25 (d, 6H) 6.90 (d, IH) 3.42 (m, IH) 7.06 (m, 4H) 4.79 (with, 2H) 7.26 (d, IH) 6.75 (with, IH) 7.79 (d, 2H).

158

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), trimethylsilyltrifine (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol). mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol). Mp 221-223 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 1,25 (d, 6H) 7.10 (m, 4H) 3.40 (m, IH) 7.27 (m, IH) 3.85 (with, 3H) 7.81 (d, 2H) 6.78 (with, IH) 12.38 (brs, IH) 6.92 (m, IH)

Example 176

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

The title compound was prepared via Method A using 4'-methylacetophenone (2.02 mL, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol). mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol). Mp 191-193 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 1,25 (d, 6H) 7.10 (m, 2H) 2.39 (with, 3H) 7.27 (m, IH) 3.41 (m, IH) 7.37 (m, 2H) 6.84 (s, IH) 7.75 (d, 2H). 6.92 (m, IH)

159

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). M.p. Mp 204-207 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, 1.33 CDC1_, delta values) 7.30 (m, 1 H) (d, 6H) 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 title compound was prepared via Method A using 4'-chloroacetophenone (2.33 g, 15.1 mmol), trimethyl silyl 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).

M.p. Mp 148-151 ° C.

Si-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).

160

..................... Example 179 - 4- (4-Hydroxy-5 - [(2-isopropylphenyl) thio] ethyl ester)

6-oxo-6H-pyran-2-yl / benzoic acid

Prepared from Method A using 4-acetyl benzoate (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). M.p. Mp 201-203 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 values delta) 1,25 (d, 5H) 6.94 (m, IH) 1.35 (t, 3H) 7.00 (with, IH) 3.42 (m, lH) 7.10 (m, 2H) 4.35 (q, 2H) 7.28 (m, IH) 6.94 (m, lH) 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), trimethylsilyltrifine (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1). mmol), methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol) Mp 201-204 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

1,25 (d, 6H) 7.09 (m, 2H) 3.41 (m, IH) 7.30 (m, 4H) 6.82 (with, IH) 9.91 (br, , IH) 6.93 (m, 2H)

161

Example 181

4-Hydroxy-3 - [(2-isopropylphenyl) thio] -2H-6- (2-phenylethyl-1en) -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), 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). M.p. Mp 190-192 ° C.

¹ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 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'-Biphen-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) , methylene chloride (30 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.11 g, 10.0 mmol). M.p.

Mp 203-206 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(250 MHz, DMSO-d6, delta values)

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).

162

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 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL) and [2- (naphthalen-2-yl) thio] propanedioic acid diethyl ester (1.62 g, 5.1 mmol). 183185 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 7.07 (s, 1H) 7.69 (d, 1H) 7.33 (dd, 1 H) 7.78 (d, 1H) 7.39 - 7.58 (m, 5H) 7.81 - 7, , 92 m 7.66 (s, 1H) 8.11 (with, 1H).

Example 184

4-Hydroxy-3 - [(naphthalen-1-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). M.p. Mp 242-243 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

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, 1H)

Example 185

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

163

The title compound was prepared via Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL) and [2- (cyclopropylmethyl) phenyl] thio / propanedioic acid diethyl ester (1.14 g, 5.1 mmol). M.p. 88 ° C.

^ Η-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), trimethylsilyl triflate (3 g, 13.1 mmol), triethylamine (2.73 g, 27.02 mmol), methylene chloride (20 mL) and [2- (cyclopropylmethyl) phenyl] thio / propanedioic acid diethyl ester (2.18 g, 6.76 mmol). M.p. Mp 168 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.28 (d, 2H) 6.92 (m, 1H) 0.39 (dd , 2H) 7.11 (m, 2H) 1.13 (m, 1H) 7.22 (with, 1H) 2.36 (with, 6H) 7.33 (m, 1H) 2.67 (d, 2H) 7.47 (with, 2H). 6.85 (with, 1H)

164

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'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyltrifine (2.27 g, 10.20 mmol), triethylamine (2.06 g,

20.40 mmol), methyl dichloride (20 mL) and diethyl ester

N- (2-isobutylphenyl) thio / propanedione (1.14 g, 5.1 mmol). M.p. Mp 187-188 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.83 (d, 5H) 7.53 (t, 2H) 1.78 (m, 1 H) 7.67 (t, 1H) 2.4 (d, 2H) 7.75 (with, 1H) 7.03 (s, 1H) 7.78 (WITH, 1H) 7.8 (s, 4H) 7.86 (m, 2H) 7.44 (t, 1 H) 8.08 (with, 1H).

Example 188

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

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyoxy) ethylene (1.96 g, 10.20 mmol) and [(2-isobutylphenyl) thio] propanedioic acid diethyl ester (1.64 g, 5H). , 1 mmol). M.p. 195 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC > -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

165

The title compound was prepared using diethyl 2- (isopropylphenyl) thio) propanedioate (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). M.p. Mp 145-147 ° C. Si-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 1,23 (d, 5H) 7.69 (t, IH) 3.4 (m, lH) 7.89 (d, 2H) 6.89 (s, IH) 8.14 (with, IH) 6.92 (d, IH) 8.22 (d, IH) 7.06 (m, 2H) 8.61 (brs , IH) 7.25 (d, IH) 8.97 (brs , IH) 7.53 (m, lH)

Example 190

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

The title compound was prepared via Method A using 3'-methylacetophenone (0.87 g, 6.46 mmol), trimethyl silyl triflate (1.44 g, 6.46 mmol), triethylamine (0.653 g,

6.46 mmol), methylene chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.0 g, 3.23 mmol). M.p. Mp 161-162 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 1,25 (d, 6H) 7.13 (t, IH) 2.39 (with, 3H) 7.28 (d, IH) 3.42 (m, IH) 7.39 (d, IH) 6.86 (with, IH) 7.4 (t, IH) 6.92 (d, IH) 7.64 (d, IH) 7.07 (t, IH) 7.67 (with, IH)

166

--------------------------------.................. ..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).

Si-Nuclear Magnetic Resonance Spectrum:

(250MHz, DMS O-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 using 3'-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (3.0 g, 9.71 mmol).

Isolated. Yield: 70%. M.p. Mp 177-178 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

MHz, 0.28 3.42 6.92 6.94 7.06 7.13 DMSO-d6 values delta) 7.28 7.58 7.63 7.83 7.89 (d, 1 H) (t, 1 H) (t, 1 H) (d, 1 H) (s, 1 H). (d, (m, (d, (with, (t, (t, 6H) 1H) 1H) 1H) 1H) 1H) Example 193

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

167

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) methyl methyl chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.64 g, 5.29 mmol). Isolated yield 70%. M.p. Mp 168-169 ° C.

^ 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) 6.92 (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

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). M.p. Mp 248-249 ° C.

L Η-Nuclear Magnetic Resonance Spectrum:

400 MHz, DMSC i-d6, values delta) 2.47 (s, 6H) 7.39 (m, 4H) 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). M.p. Mp 210-211 ° C.

168

-Η-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). M.p. Mp 264-265 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values) 6.75 (s, 1H) 7.56 (m, 4H) 7.31 (t, 1 H) 7.78 (m, 2H) 7.49 (d, 2H)

Example 197

4- / 5- (1-Cyclopentylthio-3-methylbutyl) -4-hydroxy-6-oxo-6H-pyran-6-yl] benzoic 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). M.p. Mp 174-176 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 , delta values) 1.05 - 0,72 (m, 10H) 4.36 (q, 2H) 1.81 - 1,14 (m, 7H) 6.8 (s, 1H) 2.13 - 1,81 (m, 3H) 7.90 (d, 1 H) 3.04 (t, 1 H) 7.97 (q, 1 H) 4.22 (m, 1 H) 8.15 (m, 2H).

169

EXAMPLE 198 3 - [(Benzylthio) pyridin-3-yl] methyl] -4-hydroxy-6-phenyl-2H-pyran -2-on (+, -)

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). M.p. Mp 103-106 ° C. Si-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.75 (q, 2H) 7.36 (m, 4H) 5.31 (S, IH) 7.72 (m, 2H) 6.33 (s, IH) 7.89 (d, IH) 7.2 (m, lH) 8.38 (dd, IH) 7.28 (m, 5H) 8.57 (s, 1H). Example 199 Cyclopentylthio-2-cyclopropylethyl) -6- (2 , 3-dihydroben 4 / dioxin- 6-yl) -4-hydroxy-2 H -pyran-2 -he, (+, -)

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), cyclopropylmethylcarboxaldehyde (0.34 g, 4.06 mmol), cyclopentylthiol (0.83 g, 8.12 mmol), piperidine (1.0 mL) and acetic acid (1.0 mL) . M.p. 80-82 ° C.

Si-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6 , delta values) 0.03 (m, 2H) 4.2 (m, IH) 0.33 (m, 2H) 4.31 (m, 4H) 0.64 (m, lH) 6.53 (with, IH) 1,28 - 1,74 (m, 6H) 7.0 (d, IH) 1.83 - 2,06 (m, 4H) 7.24 (d, IH) 3.06 (m, lH) 7.24 (dd , 2H)

170

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) was added. 2 H sodium hydroxide 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. M.p. 227 ° C.

^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC »-D6, values delta) 2.78 (t, 2H) 7.14 - 7 , 32 m 2.97 (t, 2H) 7.58 (d, 2H) 5.29 (with, 2H) 7.78 (d, 2H) 6.72 (with, 1H) 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), trimethylsilyltrifine (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.

^ i-Nuclear Magnetic Resonance Spectrum:

400 MHz, DMSC i-d6, delta values) 1.36 (t, 3H) 6.86 (with, 1H) 2.78 (t, 2H) 7.11 - 7, , 28 m 3.01 (t, 2H) 7.92 (d, 2H) 4.35 (G, 2H) 8.08 (d, 2H).

..Ml

- 171 ____________________________________ - 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.

¹ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

2.94 (t, 2H) 7.92 (d, 1H) 3.03 (t, 2H) 7.99 (d, 1H) 6.64 (with, 1H) 8.05 (d, 1H) 7.11 - 7 .33 (m, 5H) 8.08 (d, 1H).

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 using 1,4-benzodioxin-6-ylmethylketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22 g). , 44 mmol), methylene chloride (20 mL) and [(2-isopropylphenyl) thio] propanedioic acid diethyl ester (1.73 g, 5.61 mmol). M.p. Mp 246-248 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

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, (+, -)

172

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) . ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

0.78 (t, 6H) 4.31 (brm, 6 1.36 (m, 1 H) 6.56 (s, 1H) 1.5 (m, 1 H) 7.03 (d, 2H) 2.06 (m, 1 H) 7.36 - 7.25 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.

^ H-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6, delta values) 1,25 (m, 5H) 5.33 (with, 1H) 1.53 (m, 1H) 6.69 (with, 1H) 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-12H-pyran-2-one, (+, -)

173

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).

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1,25 (m, 5H) 7.33 (m, IH) 1.53 (m, IH) 7.53 (m, 3H) 1.67 (m, 2H) 7.73 (m, 2H) 1.92 (m, 2H) 7.97 (d, IH) 2.69 (m, IH) 8.39 (d, IH) 5.39 (with, IH) 8.67 (d, IH).

6.72 (s, 1H).

Example 207

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

The title compound was prepared by saponification of 4 - [(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl / benzoic acid methyl ester (0.1 g) as described in Example 200.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-d6, delta values) 4.06 (with, 2H) 7.58 (m, 3H) 6.72 (with, IH) 7.86 (m, 4H) 7.36 (d, 2H)

Example 208

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

The title compound was prepared by saponification of methyl 3 - [(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl] benzoic acid methyl ester (0.1 g) as described in Example 200.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

4.4 (d, 1H) 7.4 (t, 1H)

4.72 (d, 1H) 7.44-7.61 (m, 5H)

6.72 (s, 1H); 7.74-7.92 (m, 4H)

Example 209

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

The title compound was prepared by saponification of 2 - [(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl / benzoic acid methyl ester (0.2 g) as described in Example 200.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 4.36 (with, 2H) 7.39 (t, IH) 6.69 (with, IH) 7.53 (m, 3H) 7.18 (d, IH) 7.79 (m, 3H). 7.29 (t, IH)

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, 5.07 mmol). M.p. 275-280 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO -d6, delta values) 6.78 (s, IH) 7.42 (dd, , IH). 6.89 (dd, IH) 7.56 (m, 3H) 7.08 (tt, IH) 8.06 (m, 2H). 7.19 (tt, IH)

175 —--------------------------- '' Example 211 ------- ---------- 4-Hydroxy-3 - [(2-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 [(2-methoxyphenyl) thio] propanedioic acid diethyl ester (1.51 g, 5.07 mmol). M.p. Mp 208-209 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

3.83 (with, 3H) 6.97 (d, 1H) 6.74 (dd, , 1H) 7.08 (t, 1H) 6.82 (d, 1H) 7.56 (m, 3H) 6.86 (with, 1H) 7.86 (m, 2H).

Example 212

4- (4-Benzyloxyphenyl) -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). mL) and 2 - [(isopropylphenyl) thio] propanedioic acid diethyl ester (0.210 g, 0.675 mmol). M.p. 163-165 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

1,28 (d, 5H) 7.19 (d, 1H) 3.4 (m, 1 H) 7.28 (d, 1H) 5.22 (s, 2H) 7.36 (qr 2H) 6.64 (s, 1H) 7.42 (d, 2H) 6.92 (d, 1 H) 7.49 (d, 2H) 7.06 (t, 1 H) 7.83 (d, 2H). 7.11 (t, 1 H)

Example 213

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

176

The title compound was prepared via Method A using 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). M.p. 181-182 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 6.88 (s, IH) 7.29 (t, IH) 7.13 (dt, 2H) 7.56 (m, 3H) 7.19 (dt, IH) 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- (trimethylsilyoxy) ethylene (1.95 g, 10.14 mmol) and [(3-methoxyphenyl) thio] propanedioic acid diethyl ester (1.51 g, 5H). , 07 mmol). M.p. 130-131 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 3.69 (s, 3H) 7.2 (dt, 2H) 6.63 (dd, IH) 7.58 (m, 3H) 6.72 (dd, IH) 7.88 (m, 2H). 6.89 (s, IH)

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- (trimethylsilyoxy) ethylene (1.95 g,

10.14 mmol) and [(3-methylphenyl) thio] propanedioic acid diethyl ester (1.43 g, 5.07 mmol). M.p. Mp 197-198 ° C. 1 H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

177

2.24 (-S, 3H). ........... 7,14 (t, 2H) 6.89 (with, 1H) 7.56 (m, 3H) 6.93 (t, 1H) 7.86 (m, 2H). 6.97 (with, 1H)

Example 216

3 - [(2-Ethylphenyl) 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 g). , 86 mmol). M.p. Mp 190-192 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC i-d6, delta values) 1,25 (t, 3H) 7.08 (m, 2H) 2.78 (qr 2H) 7.2 (m, 1 H) 6.89 (with, 1H) 7.58 (m, 4H) 6.92 (m, 1H) 7.86 (m, 2H)

Example 217

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

The title compound is prepared by reacting 4hydroxy-3- (2-isopropylphenyl) thio] -6-phenyl-2H-pyran-2-one sodium salt (0.2 g, 0.59 mmol) with acetyl chloride (0.09 g, 1M). (18 mmol) as described in General Procedure GTt Mp 113-115 ° C.

^ i-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSC »- <3.6, 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).

V i:

178

--------- Example 218

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). M.p. Mp 223-229 ° C. ^ H-Nuclear Magnetic Resonance Spectrum:

(400 MHz, DMSO-d6, delta values)

6.89 (s, 1H).

7.4 - 7.61 (m, 7H)

7.89 (m. 2H).

Example 219

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

The title compound was prepared via Method A using 1-phenyl-1- (trimethylsilyoxy) ethylene (1.3 g, 6.76 mmol) and [(3,5-dimethylphenyl) thio] propanedioic acid diethyl ester (1.0 g) , 3.38 mmol). M.p. Mp 214-216 ° C.

^ 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, 1 H)

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 acid - [(2-isopropylphenyl) thio] propanedioate (4.0 g, 12.92 mmol)

M.p. Mp 187-188 ° C.

- Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSO-d6 values delta) 0.96 - 1.33 (m + 1.24 d, , 11H) 6.92 (dd, , IH) 1.61 - 1.87 (m, 6H) 7.11 (m, 4H) 3.4 (m, lH) 7.29 (dd, , IH) 3.86 (d, 2H) 7.81 (d, 2H). 6.76 (s, IH)

Example 221

6- (3-Benzyloxyphenyl) -4-hydroxy-3- (2-isopropylphenyl) thio [2H-pyran-2-one]

Prepared via Method A using 3-benzyloxyacetophenone (2.0 g, 8.84 mmol), trimethylsilyltrifine (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). M.p. Mp 162-164 ° C. ^ Η-Nuclear Magnetic Resonance Spectrum:

MHz, DMSC ) -d6, delta values) 1,25 (d, 6H) 7.06 (dt, IH) 3.42 (m, IH) 7.11 (dt, IH) 5.35 (with, 2H) 7.22 (dd, IH) 6.89 (with, IH) 7.28 (dd, IH) 6.92 (d, IH) 7.39 - 7, 51 (m,

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).

180 g (15-72 mmol) and diethyl ester of [(2-isopropylphenyl) thio] propanedioic acid (3.66 g, 11.79 mmol). M.p. 132-133 ° C.

^ Η-Nuclear Magnetic Resonance Spectrum:

(400MHz, DMSO-d6, delta values) 1,25 (d, 5H) 6.90 (d, 1 H) 2.06 (m, 2H) 7.05 (dt, 2H) 2.75 (t, 2H) 7.08 (q, 2H) 3.39 (m, 1Ή) 7.11 7.31 (m 4.08 (t, 2H) 7.81 (d, 2 H). 6.78 (s, 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 diethyl ester of (2-sec-butylphenyl) thio/propanedioic acid (1.0). g, 3.09 mmol). M.p. Mp 170-171 ° C.

¹ 'H-Nuclear Magnetic Resonance Spectrum:

(400MHz, 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).

181 -. Determination of HIV protease inhibition

Starting materials

DTT buffer: 1.0 mM dithiothreitol (DTT) is prepared daily in 0.1% polyethylene glycol (mw 8000) 80 mM NaOAc,

160 mM NaCl, 1.0 mM EDTA and hydrochloric acid lowered the pH to 4.7.

HIV-I Protease: The enzyme is obtained from Bachem Bioscience Inc. The undiluted enzyme thawed from -80 ° C and diluted 50 times with DTT buffer. The solution is still maintained at 0 ° C (ice water) and used for testing within 20 minutes of thawing.

Enzyme substrate: Substrate III from Bachem Bioscience Inc. is the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-p-NitrophenylalanineGlu-Ala-Norleucine-Ser-NHg (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 a final (1) = 100, 50, 20,

10, 5, 2, 1, 0.5 and 0 Ms2% DMSO in DTT buffer in each reaction well (total inhibition volume 50 L).

Test

Add 20 L of substrate (40 Μ final concentration), 50 L of inhibitor (at such a concentration that the final dilution corresponds to the test concentration) to each reaction well, and 20 L

DTT buffer. The reaction plate (96 wells) is incubated for at least 5 minutes at 37 ° C.

While the reaction plate is shaken, 10 L of diluted protease is added to the reaction well. After 10 seconds of shaking, the plate is returned to the heater (100 L final reaction volume)

182

At 37 ° C, the reaction is incubated for 5 minutes and interrupted 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 separation of the undigested substrate and the two digested products by high pressure liquid chromatography, and absorbance at 220 nm is measured to determine the relative peak area of the 3 components. Relative peak areas are used to calculate% conversion to product as a function of inhibitor concentration. The data are in% relative to the control (ratio of% conversion in the presence and absence of inhibitor x 100) versus inhibitor concentration and well coincides with the equation Y = 100 / l + (X / IC 50), where IC 50 is inhibitor concentration at 50% inhibition; A is the slope of the inhibition curve.

Table 1

Results of HIV protease inhibition

Example Inhibitory Concentration 50 (Mean) / M /

1 0.47 1 3 ! .O I 4 0.9 I 6 0.4 I 8 i.7 17 0.69 1 23 1.7 i 26 1.2 I 27 Mar: O · ⁵ j 28 1.9 1 29 0.33 I 33 i.97 I 34 0.8 1 44 0.75 | 48 0.86

183

Example _. Inhibitive.

concentration 50 (average) / M /

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

184

Anti-HIV-1 activity

Using the general procedures of Pauwels et al., (J. Virol. Methods, 16, 171-185, 1987) and Mann-et al., (AIDS Research and Human Retroviruses, 253-255, 1989), the H9 cell line performs antivirus testing of acute HIV-1 infection. The cultures are batches of cell cultures infected in 1 ml of culture medium RPM1 1640/10% fetal calf serum containing 75 cells containing 10 infectious doses of HIV-1 ... for an effective mb -y multiplication of infection of 0.01. After two hours of viral absorption, cells are washed once and transferred to a 96-well microtiter plate at a density of 10 cells per well. In order to obtain the required active substance concentration and 0.2%

DMSO at a final volume of 200 L test compounds were added. Uninfected control cultures are maintained for 7 days after infection for the XTT-cytotoxicity assay.

and 7 days after infection, cultures are tested for viral replication by reverse transcriptase.

Table 2

Antiviral activity in the H9 cell line

Example Concentration for

50% protection (M)

29 17 70 29 78 3 87 15 Dec 121 15 Dec 166 14 169 31 172 0.65

185

Combinations of a protease inhibitor with other AIDS treatments, eg (not only) reverse transcriptase inhibitors AZT or ddC, may show 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 and 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.

Antibacterial activity g / ml

Ex. 172 Ex. 29 Ex. 167 '.. Ex. 2 Staphylococcus aureus H228 50 25 6.2 12.5 D staphylococcus 1 UC-76 aureus 50 25 6.2 12.5 1 Enterccoccus I foecalis MGH2 100 ALIGN! 50 12.5 25 Streptococcus pneuaonia 5V-1 50 25 6.2 12.5 Streptococcus i pyogenes C203 50 25 6.2 12.5

186 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 by the description of specific embodiments, but only by the definition of the following claims.

77 // strength?

Claims (18)

Claims PATENTOVÉ 1. A compound of Formula ¹ RSW (CH _{2) m} W _{(CH2) I1} A- 'Ύ W2A ^l (CH ₂ yF3K3 Y in which X is OR ¹ , NHR ¹ , SR ¹ , CO ⁴ or CH ¹ , wherein 1 4 4 '' '4 R is R or COR, wherein R is as defined below; Y is O or S; Z is oxygen or sulfur; 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; are selected from the group consisting of F, Cl, Br, OR, 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, II W, W ^X and W ³ man or an alkylcycloalkyl group or phenyl group thereof. pina, wherein the substituent (s) is / are selected from, 2 2 2 from the group consisting of CO R, CON (R) 2, F, OR, 2 ^{Z 2} SR, N (R) 2, CN, phenyl, naphthyl ^of 2, heterocycle and CF, wherein R is independently alkyl, cycloalkyl or hydrogen; is hydrogen, alkyl, cycloalkyl, alkylcycloalkyl, phenyl or derived substituted derivatives, wherein the substituent (s) is / are selected from CO ₂ R, CON (R) ₂ , F, OR ^3, phenyl, naphthyl, CF ₃ , OR ¹ , NHR ¹ , SR ¹ or CH ¹ R ¹ , wherein R ¹ 'is as defined above; is independently hydrogen, (CH ₂ ) p R or (CH ₂ ) A, wherein p is an integer from 0 to 2 and 4 P R and A are as defined above; are independently a chemical bond, an oxygen atom, NR ³ , C (R ³ ) ₂ , CO, CR ³ = CR ³ , C = C, CR ³ OR ³ , C (= NR ³ ) NR ³ , CR ³ N (R ³ ) 2, S (O), SO ² NR ³ , CO 2, 3 3 P NR COV A or NCOV R, wherein g is 0 or 1 3 3 and V is oxygen, sulfur, NR or CHR; and are independently integers from 0 to 4 with the proviso that when W and W are ¹ heteroatoms or are 23 if W and W are heteroatoms, m is an integer from 2 to 4, and with the further proviso that R ³ W ¹ (CH ₂ ) W (CH ₂ ) _n A cannot be methyl or ethyl; a pharmaceutically acceptable salt. 2. A compound according to claim 1 of the formula wherein: 2 3 '' W is SO- NR or S (O), wherein p is an integer of 2 p a number from 0 to 2. III A compound according to claim 2, wherein A ¹ is not a bond. A compound according to claim 3 of the 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 - [(3phenyl) phenyl] -2H-pyran-2-one; 6-Phenyl-4-hydroxy-5-methyl-3- (phenylthio) -2H-pyran-2-one; [4- (4-Hydroxy-2-oxo-3- (phenylthio) -2H-pyran-6-yl) phenoxy] acetic acid; [4- (4-Hydroxy-5-methyl-2-oxo-3- (phenylthio) 2H-pyran-6-yl) phenoxy] acetic acid; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-methylpropyl) cyclopentyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-methylbutyl) cyclopentyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (4-methylpentyl) cyclopentyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (phenylmethyl) cyclopentyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-phenylethyl) cyclopentyl] -2H-pyran-2-one; IV 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-phenylpropyl) cyclopentyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-methylpropyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-methylbutyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (4-methylpentyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (phenylmethyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-phenylethyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-phenylpropyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-6- (3-hydroxyphenyl) -3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (pyridin-4-yl) -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (pyridin-2-yl) -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-nitrophenyl) -2H-pyran-2-one; 6- (4-Fluorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (2-methylphenyl) -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (2-methoxyphenyl) -2H-pyran-2-one; 6- (2-Chlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; in 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-naphthalenylmethyioxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (2-morpholin-4-yl) ethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [3- (2-morpholin-4-yl) ethoxy) phenyl] -2H-pyran-2-one; 6- (4-Benzyloxy-3-methoxyphenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 6- (4-Benzyloxy-3-chlorophenyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 4- (4-Hydroxy-2-oxo-3 - [(2-isopropylphenyl) thio] -2H-pyran-6-yl) -2-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-pyrazinomethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-pyridine) · 3-ylmethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (pyridin-2-ylmethoxy) -3-methylphenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- (pyridin-4-ylmethoxy) phenyl] -2H-pyran-2-one; 3- [(2-Cyclopropylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; VI 4-Hydroxy-3 - [(2,5-diisopropylphenyl) thio] -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyphah-2-oh; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (thio morphiolin-4-yl) ethoxy] phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (piperazin-1-yl) ethoxy] phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (methylpiperazin-1-yl) ethoxy] phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [4- [2- (1,1-dioxothiomorpholin-4-yl) ethoxy] phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (1-phenylcyclopentyl) -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- (4-phenylpiperidin-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; VII 3 - [(2-Cyclopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 3- [(2,5-Diisopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 4-Hydroxy-6-phenyl-3 - [(2-tert-butylphenyl) thio] -2H-pyran-2-one; 3 - [(2-cyclopropyl-5-isopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 3 - [(2-Cyclopentyl-5-isopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 3- [(2-Cyclohexyl-5-isopropylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 4-Hydroxy-6-phenyl-3 - [(2-tert-butyl-5-isopropylphenyl) thio] -2H-pyran-2-one; 3 - [(2,5-Di-tert-butylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 3 - [(2-Cyclopentylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 3 - [(2-Cyclohexylphenyl) thio] 4-hydroxy-6-phenyl-2H-pyran-2-one; 4- [4-Hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl] thio] -2-hydroxyindane; 4-Hydroxy-3- [2-isopropyl-4- (morpholin-4-ylmethyl) phenyl] thio] -6-phenyl-2H-pyran-2-one; 4-Hydroxy-3 - [(6-isopropyl-indan-5-yl) thio] -6-phenyl-2H-pyran-2-one; 4-Hydroxy-3 - [(4-isopropyl-benzo [1,3] dioxol-5-yl) thio] -6-phenyl-2H-pyran-2-one; 3 - [(2-tert-butyl-4-thiomorpholin-4-ylmethylphenyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; VIII 4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3- [(tert-butylphenyl) thio] -2H-pyran-2-one; 3 - [(2-Cyclopropyl-5-isopropyl) phenyl] thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 3 - [(2-Cyclopentyl-5-isopropyl) phenyl] thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 3- [(2-Cyclohexyl-5-isopropyl) phenyl] thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3 - [(2-tert-butyl-5-isopropylphenyl) thio] -2H-pyran-2-one; 3 - [(2,5-Di-tert-butylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 3 - [(2-Cyclopentylphenyl) thio] -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 3- [(2-Cyclohexylphenyl) thio-4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -3 - [(6-tert-butylindan-5-yl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropyl-4-morpholin-4-ylmethylphenyl) 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-7-ylmethoxy) phenyl] -2H-pyran-4-yl ester; 4-Hydroxy-3 - [(2-isopropylphenyl) sulfonyl] -6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; IX _________ 3- (2-tert-butylphenyl) sulfonyl-4-hydroxy-6-phenyl-2H-pyran-2-one; 6- (1-Benzylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) sulfonyl] -2H-pyran-2-one; 6- (1-Benzylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 6- (1-Benzylpropyl) -3 - [(2-tert-butylphenyl) thio] -4-hydroxy-2H-pyran-2-one; N- [3- [6- (1-Benzylpropyl) -4-hydroxy-2-oxo-2H-pyran 3-yl] thio] -2-isopropylphenyl] benzenesulfonamide; 6- (1-Cyclopropylmethyl-2- (tetrahydro-pyran-3-yl) ethyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2one; 6- (1,1-Dimethyl-3-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 6- (Benzo [1,3] dioxol-5-yl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (phenylmethyl) cyclobutyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (2-phenylethyl) cyclobutyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropylphenyl) thio] -6- [1- (3-phenylpropyl) cyclobutyl-2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- (1-benzylcyclopropyl) -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- [1- (2-phenylethyl) cyclopropyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-isopropyl-5-methylphenyl) thio] -6- 1- (3-phenylpropyl) cyclopropyl-2H-pyran-2-one; X 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; 6- (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; and 6- (1-Ethyl-1-phenylpropyl) -4-hydroxy-3 - [(2-isopropylphenyl) thio] -2H-pyran-2-one. 5. A compound according to claim 2 of the formula wherein: A ¹ · is a bond and (CH_) is not a bond. 1 m XI A compound according to claim 5 selected from the group consisting of 6 - [- (3,5-Dimethyl-4-isoxazolyl) methoxy] phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylsulfinyl) phenyl] -2H-pyran-2-one; 6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-6- (3-phenoxyphenyl) -3 - [(2-phenylethyl) thio] 2H-pyran-2-one; 4-Hydroxy-6- [3-methoxy-4- (phenylmethoxy) phenyl] -3- (2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-oxo-2-phenylethyl) thio] -6-phenyl-2H-pyran-2-one; 4-Hydroxy-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenoxyethyl) thio] -6-phenyl-2H-pyran-2-one; (E) -4-Hydroxy-6-phenyl-3 - [(3-phenyl-2-propenyl) thio] -2H-pyran-2-one; 2-Oxo-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-4-yl-3-methylbutanoic acid ester; 6- (3,4-Dichlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 6- (3-Chlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 2-Oxo-6-phenyl-3 - [(phenylmethyl) thio] -2H-pyran-4-yl propanoic acid ester; 4-Hydroxy-6- (3-methylphenyl) -3- [(phenylmethyl) thio] 2H-pyran-2-one; XII 4-Hydroxy-6- (3-phenylethyl) -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; XIII 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [3- (trifluoromethyl) phenyl] -2H-pyran-2-one; 6- (2,3-Dihydro-1,4-benzodioxin-6-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [3-methyl-4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one; [4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) phenoxy] acetic acid; [4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) phenoxy] acetic acid ethyl ester; 4-Hydroxy-6- (4-phenoxyphenyl) -3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (2-pyridinylmethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-6- [4- (2-methoxyphenyl) methoxy] phenyl] -3- [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylthio) phenyl] -2H-pyran-2-one; 6- (1,3-Benzodioxol-5-yl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-6- (2-naphthalenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-6- (4-hydroxyphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one; 6- (2-Chlorophenyl) -4-hydroxy-3 - [(phenylmethyl) thio] 2H-pyran-2-ene; XIV (4-Bydroxy + 6-y2-nCz2-methylbutyl) phenyl] -3 - [(phenylmethyl) thio] -2H-pyran-2-one; 6- (3,5-Dimethylphenyl) -4- (hydroxymethyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one; [4- (4-Hydroxy-5- (hydroxymethyl) -2-oxo-3) (2-phenylethyl) thio] -2H-pyran-6-yl (phenoxy) acetic acid; 4-Hydroxy-6 - [(4-methoxyphenyl) methyl] -3- [1- (phenylmethyl) butyl] thio] -2H-pyran-2-one; [5- (2-Oxo-4-hydroxy-3 - [(3-methyl-1-phenylbutyl) thio] -2H-pyran-6-yl) 2-pyridinyl] oxy] acetic acid; [4- (4-Hydroxy-2-oxo-3 - [(phenylmethyl) thio] -2H-pyran-6-yl] cyclohexyl] oxy] acetic acid; 6- [4- (Cyclohexylmethoxy) phenyl] -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylsulfonyl) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- (4-benzoyloxy) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (phenylsulfinyl) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- (4-pyridinyl) 2H-pyran-2-one; 4-Hydroxy-6- (3-phenoxyphenyl) -3 - [(2-phenylethyl) thio] 2H-pyran-2-one; 4-Hydroxy-6- [3-methoxy-4- (phenylmethoxy) phenyl] -3- (2-phenylethyl) thio] -2H-pyran-2-one; 6- (3,5-Dimethylphenyl) -4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(3-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one; XV 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-12H-pyran-2-one; 6- (1,1'-Biphenyl) -3-yl-4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(4-methoxyphenyl) methyl] thio] -6-phenyl-2H-pyran-2-one; [4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) -2-methylphenoxy] acetic acid ethyl ester; 6- (3,5-Dimethyl-4- [dimethyl (1,1-dimethylethyl) silyl] oxy / phenyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (4-pyridinylmethoxy) phenyl] -2H-pyran-2-one; [4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) -2-methylphenoxy acetic acid; 4-Hydroxy-6- (4-hydroxy-3,5-dimethylphenyl) -3 - [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-6-phenyl-3- [3- (2-phenylethoxy) phenyl] methyl] thio] -2H-pyran-2-one; XVI 4-Hydroxy-6- [4- (2-phenylethynylphenyl) -3- [(2-phenyl ethynyl) thio] -2H-pyran-2-one; 4-Hydroxy-6- [4- (2-phenylethyl) phenyl] -3- [(2-phenylethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(phenylmethyl) thio] -6- [3- (trifluoromethoxy) phenyl] -2H-pyran-2-one; 3- [(Cyclohexylmethyl) thio] -4-hydroxy-6-phenyl-2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [3-methyl-4- (3-pyridinylmethoxy) phenyl] -2H-pyran-2-one; 6- (2,3-Dihydro-1,4-benzodioxin-6-yl) -4-hydroxy-3 [(phenylmethyl) thio] -2H-pyran-2-one; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [3- (trifluoromethyl) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(phenylmethyl) thio] -6- [3- (trifluoromethyl) phenyl] -2H-pyran-2-one; 4-Hydroxy-3 - [(phenylmethyl) thio] -6- (2,3,4-trimethoxyphenyl) -2H-pyran-2-one; N- (4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio) -2H-pyran-6-yl) phenyl] benzenesulfonamide; 6- [4- ((3,5-Dimethyl-4-isoxazolyl) methoxy) phenyl] 4-hydroxy-3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 2 - [(4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) thio] methyl / benzoic acid methyl ester; 2- [4- (4-Hydroxy-2-oxo-3 - [(2-phenylethyl) thio] -2H-pyran-6-yl) phenoxy] methylbenzoic acid methyl ester; 4-Hydroxy-3 - [(2-phenylethyl) thio] -6- [4- (1H-tetrazol-5-ylmethoxy) phenyl] -2H-pyran-2-one; XVII 4-Hydroxy-6- (3-methyl-4- (2-pyridinylmethoxy) phenyl) 3 - [(2-phenylethyl) thio] -2H-pyran-2-one; 4- [4-Hydroxy-2-oxo-3 - [(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] methylbenzoic 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-Chlorophenyl) -4-hydroxy-3 - [(4-phenylbutyl) thio] 2H-pyran-2-one; 4-Hydroxy-3 - [(2-hydroxy-2-phenylethyl) thio] -6-phenyl-2H-pyran-2-one; 4-Hydroxy-3 - [(phenylmethyl) thio] -6- (3-pyridinyl) 2H-pyran-2-one; 6- (2,6-Dimethyl-4-pyridinyl) -4-hydroxy-3 - [(phenylmethyl) thio] -2H-pyran-2-one; and 4-Hydroxy-3 - [(phenylmethyl) thio] -6- (3-thienyl) -2H-pyran-2-one; XVIII - A compound according to claim 7. 1 of the general formula in which 2 W represents an oxygen atom. A compound according to claim 7, wherein A ^{1 is} not a bond. A compound according to claim 8 of the formula selected from the group consisting of 4-Hydroxy-3-phenoxy-6-phenyl-2 H -pyran-2-one; 4-Hydroxy-3- (2-isopropylphenoxy) -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-methylphenoxy) -4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 6- (1-Benzylpropyl) -4-hydroxy-3- (2-isopropylphenoxy) 2H-pyran-2-one; and 6- (1-Benzylpropyl) -3- (2-tert-butylphenoxy) -4-hydroxy-2H-pyran-2-one. A compound according to claim 7, wherein A ¹ is a bond and (C 1-6) W ^{3 is} not a bond. A compound according to claim 10, selected from the group consisting of XIX 12. 13. 14. 3-Benzyloxy-4-hydroxy-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-2-one; 2- (4-Hydroxy-2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl) -2H-pyran-3-yloxymethyl] benzoic acid methyl ester 2- [6- (1-Benzylpropyl) -4-hydroxy-2-oxo-2H-pyran-3-yl] oxy / methyl] benzoic acid ethyl ester; and 6- (1-Benzylpropyl) -4-hydroxy-3- (1-phenylbutoxy) -2H-pyran-2-one. A compound according to claim 1 of the formula wherein: 2 ~ ... W is selected from the group consisting of NR; NR ³ COV A; § NCOV R; and 9 ₃ SO ₂ NR, wherein in each case nitrogen is bonded to the carbon at the 3-position of the pyron ring. A compound according to claim 12 of the formula wherein: 2. 3 W is NR. A compound according to claim 13 of the 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; XX 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; and 6- (1-Cyclopropylmethyl-2- (tetrahydropyran-3-yl) ethyl) -3- (cyclopropylphenylamino) -4-hydroxy-2H-pyran-2-one. A compound according to claim 12 of the general formula wherein 2 - - W is selected from the group consisting of NR ³ COV NCOV Ri i ^ 3 SO ₂ NR, wherein in each case nitrogen is bonded to the carbon at the 3-position of the pyron ring. A compound according to claim 15, selected from the group consisting of (S) -1,3-Dihydro-N- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -2- ( phenylmethyl) -2H-isoindole-2-acetamide; N- (1,1-Dimethylethyl) -1 '- (4-hydroxy-2-oxo-6-phenyl-2H-pyran-3-yl) -1' - (phenylmethyl) urea; Cyclopentylmethyl- [4-hydroxy-2-oxo-6 - [(pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] cyclopropanecarboxylic acid amide; Cyclopentanecarboxylic acid cyclopentylmethyl- [4-hydroxy-2-oxo-6- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] amide; and XXI N-Cyclopentylmethyl-N- [4-hydroxy-2-oxo-β- [4- (pyridin-3-ylmethoxy) phenyl] -2H-pyran-3-yl] cyclopentanesulfonamide. 17. Compounds with the names: 2- Cyclopentylbenzenethiol; 3-Methoxy-2- (1-methylethyl) benzenethiol; r 2- (1,1-Dimethylethyl) -4-methoxybenzenethiol; 2- (Cyclopenten-2-yl) benzenethiol; 2-Cyclohexylbenzenethiol; 2- (1,1-Dimethylethyl) -5-methoxybenzenethiol; 2- (1,1-Dimethyl-2-hydroxyethyl) benzethiol and 2- (1,1-Dimethylethyl) -4,5- (methylenedioxy) benzethiol. 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; [(2-Isopropyl-5-methylphenyl) thio] propanedioic acid diethyl ester; /( 2,4-Di-tert-butylbenyl) thio/propanedioic acid diethyl ester; Propanedio diethyl ester; /( 2-sec. butylphenyl) thio/XXII [(2-Cyclohexylphenyl) thio] propanedioic acid diethyl ester; [(2-Cyclopentylphenyl) thio] propanedioic acid diethyl ester; (( 2- tert -Butyldimethylsilyloxymethylphenyl) thio) propanedioic acid diethyl ester and Child ^ hylester acid / (3- ^(p-4 toluensulfonylami- amino) phenyl) thio / propanedioic.