CA2333707A1 - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
CA2333707A1
CA2333707A1 CA002333707A CA2333707A CA2333707A1 CA 2333707 A1 CA2333707 A1 CA 2333707A1 CA 002333707 A CA002333707 A CA 002333707A CA 2333707 A CA2333707 A CA 2333707A CA 2333707 A1 CA2333707 A1 CA 2333707A1
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CA
Canada
Prior art keywords
alkyl
phenyl
substituted
benzyl
acid
Prior art date
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Abandoned
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CA002333707A
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French (fr)
Inventor
Melissa Egbertson
Juan C. Jaen
Linda S. Payne
Jeffrey Melamed
Mark W. Embrey
Steven D. Young
Lekhang Tran
John S. Wai
Linghang Zhuang
Julio C. Medina
Marie H. Langford
David L. Clark
Thorsten E. Fisher
James P. Guare, Jr.
Joseph P. Vacca
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Merck and Co Inc
Tularik Inc
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Individual
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Priority claimed from GBGB9815175.6A external-priority patent/GB9815175D0/en
Application filed by Individual filed Critical Individual
Publication of CA2333707A1 publication Critical patent/CA2333707A1/en
Abandoned legal-status Critical Current

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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Abstract

Certain six-membered aromatic and heteroaromatic-dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of H IV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

Description

TITLE OF THE INVENTION
HIV INTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. provisional application Serial No. 60/087,820, filed June 3, 1998.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)].
All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV
replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV
infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents &
Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-1-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). 4-phenyl-4-oxo-butenoic acid derivatives are disclosed as useful as kynurenine-3-hydroxylase inhibitors for the prevention and/or treatment of neurodegenerative diseases in PCT/EP96/04517, which published as WO 97/17316 and in PCT/EP96/04518, which published as WO 97/17317.
Applicants have discovered that certain six-membered aromatic and heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection.
SUMMARY OF THE INVENTION
Compounds of formula I, as herein defined, are disclosed.
These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
R2 R~

OR~

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms ~ substituted on carbon or nitrogen by Rl, R2, Rg, and R9;
optionally the aromatic ring may be fused with another ring system to form:
J ~ \ \ \ \
I / / / I
or or or \ O \ O \ O ( \
I / ~~ I / ~ I / /
o r N or O or O or H
N I \ ( \ ~ ( /
/ N
O or O / or H ;
R1 is selected from:
(1) -H, (2) -C1_5 alkyl, (3) -C1_6 alkyl-OR7, (4) -O-C1_6 alkyl-OR7, (5) -O-C1_6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -halo, (8) -N02, (9) -Cp_g alkyl -N(R4)(R5), (10) -R6, (11) -C2_5 alkenyl-R3, (12) -C2_5 alkynyl-R3, (13) -O-R6, (14) -O-C1_6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, . (15) -0-C1_6 alkyl-NH-C(O)-OR7;
(16) -O-C2_g alkyl-N(R4)(R5);
(17) -S-C1_g alkyl;
(18) -C(O)CH2C(O)C(O)OR7;
(19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -C1_g alkyl, (4) -C1_g alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1_g alkyl may be replaced with a fluorine atom, (5) -C2_6 alkenyl, (6) -O-R6~

(7) -O-C1_g alkyl-OR6, (8) -O-C1_g alkyl- SR6, (9) -S(O)n-R6~

(10) -C1_g alkyl (OR6)(R4) , (11) -CO_g alkyl-N(R4)(R6), (12) -C1_6 alkyl S(O)n-R6, (13) -Cp_6 alkyl C(O~RS, (14 ) -Cp_6 alkyl C(O)CH2-C(O)-OH, (15) -C1_6 alkyl C(S)-RS, (16) -C1_g alkyl NR4C(O)-R6, (17) -C1_g alkyl-C(O)N(R4)(R5), and (18) -CH2(OR7)-R6;

each R3 is independently selected from:

(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from:

(a) halogen, (b) C1_6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_g alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -Cp_6 alkyl-N(R7)2, _ 5_ (J ) -N~N-CH3 U
(k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) C1_g alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1_6 alkyl, (d) C1-g alkyloxy-, (e) -CFg, (fj -OCF3, (g) -CN, and (h) hydroxy;

(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1_6 alkyl, (c) -C1_g alkyloxy-, (d) -CFg, (e) -OCFg, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C 1-6 alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (fj -CN, (g) =O, and (h) hydroxy;
(fi) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C 1_6 alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and _ 7_ (h) hydroxy; and (7) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:

(a) halogen, (b) C1_6 alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy; and each R4 is independently selected from:

(1) -H, (2) -C1~ alkyl, (3) -CF3, (5) -C2_3 alkenyl, (6) -C1_3 alkyl-R3, (7) -C2_3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;

each R5 is independently selected from:

(1) -H, (2) -C1_3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1_3 alkyl-R3, (7) -C2_3 alkenyl-R3, (8) -S(O)n-R3, (9) -C(O)-R3, (10) -C(O)OR4, and (11) -C(O)C(O)OH;

_ g_ WO 99/b2520 PCT/US99/12093 each R6 is independently selected from:
(1) -C1_3 alkyl-R3, and (2) -R3;

each R7 is independently selected from:

(1) -H, and (2) -C1_g alkyl;

R8 is selected from:

(1) -H, (2) -O- C1_6 alkyl and (3) C1_6 alkyl;

Rg is selected from:

(1) -H, (2) -O- C1_3 alkyl, (3) -OH, and (4) oxo; and each n is independently selected from 0, 1 and 2.

Also provided for by the present invention are compounds of structural formula (I) wherein:
when A is phenyl:

(1) Rl is not R6 para to the dioxobutyric acid/ester moiety; and (2) R2 is not selected from:

(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1_6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1_g alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of Rl, R2, and R8 is not:

(a) -H, (b) C1_g alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R2 is S(O) RS
and R6 is CH2-R3 or R3 then R3 is n , , not unsubstituted phenyl.
_ g_ Also provided for by the present invention are compounds of formula (I) wherein:
WHEN A is phenyl and R1 is:
(a) H, (b) C1_5 alkyl, (c) halo, (d) N02, (e) R6 when R6 is CH2R3 or R3 and when R3 is unsubstituted phenyl, (f) -O-C 1-g alkyl, or (g) -SC1_3 alkyl;
THEN R2 is not selected from:
(a) H, (b) R3 when R3 is unsubstituted phenyl, (c) C1_g alkyl, (d) CH2R3 when R3 is unsubstituted phenyl, and (e) SORE when Rs is CH2R3 or R3 and when R3 is unsubstituted phenyl.
Also provided for by the present invention are compounds of formula (I) wherein at least one of Rl, R2, R8 and R9 is not hydrogen.
.Also provided for by the present invention are compounds of formula (I) wherein: when A is a fused ring system, the six-membered aromatic ring is substituted by the dioxobutyric acid/ester moiety Applicants hereby incorporate by reference the disclosure of U.S. provisional application Serial No. 60/087,820, filed June 3, 1998.
Also provided are compounds of formula Ia, which are defined as follows:
R~
~ O
Rz ~OR~
Rg O O
(la) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen and substituted on carbon or nitrogen by Rl ,R2 and R8; the aromatic or heteroaromatic ring may optionally be fused with a 5- or fi-membered aromatic or heteroaromatic ring to form a fused ring system, provided that when A is a fused ring system, the six-membered aromatic or heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
optionally the aromatic or heteroaromatic ring may be fused with another ring system to form:
\ \ \ \ \
or or or or N
N N , or N
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4)(R5), (7) -R6, (8) -C2_5 alkenyl-R3, (9) -C2_5 alkynyl-R3, (10) -O-R6, (11) -O-C1_g alkyl, and (12) -C(O)CH2C(O)C(0)OR7;
R2 is selected from:
(1) -H, (2) -R3~
(3) -C1_g alkyl, (4) -C1-& alkyl substituted with R3, (5) -0-R6, (6) -O-C1-g alkyl-OR6, (7) -S(O)n-RS, (8) -C1_g alkyl (OR6)(R4) , (9) -Cp_g alkyl-N(R4)(R6) , (10) -C1_6 alkyl S(O)n-R6, (11) -C1_6 alkyl C(O)-R6, (12) -C1_g alkyl C(S)-R6, (13) -C1_6 alkyl NR4C(O)-R6, and (14) -C1_g alkyl-C(O)N(R4)(R5);

each R3 is independently selected from:

(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:

(a) halogen, (b) C1_g alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:

(a) halogen, (b) C1_g alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1_g alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1_g alkyl, (c) -C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C 1_6 alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) (h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1_6 alkyl, (c) C1-g alkyloxy-, (d) -CF3, (e) -OCF3, (f~ -CN, (g) =O
(h) hydroxy;

each R4 is independently selected from:

(1) -H, (2) -C1_3 alkyl, (3) -CF3, {4) -R3~

(5) -C2_3 alkenyl, (6) -C1-3 ~kYl-R3~

(7) -C2_3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;

each R5 is independently selected from:

(1) -H, (2) -C1_3 alkyl, (3) -CF3, (4) -R3~
{5) -C2_3 alkenyl, (6) -C1_3 alkyl-R3, (7) -C2_3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;

each R6 is independently selected from:

(1) -C1_3 alkyl-R3, and (2) -R3~

R7 is selected from:

(1) -H, and (2) C 1_g alkyl;

R8 is selected from:
(1) -H, (2) -O- C1_g alkyl, and (3) C1_g alkyl; and each n is independently selected from 0, 1 and 2.
Also provided by the present invention are compounds of structural formula (Ia) wherein:
when A is phenyl, (1) Rl is not (a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) C1_3 alkyl phenyl para to the dioxobutyric acid/ester moeity, or (d) substituted -C1_3 alkyl phenyl para to the dioxobutyric acid/ester moeity; and (2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1_g alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1_g alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of Rl, R2, and R8 is not:
(a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R1 or R2 is S(O)nR6, R6 is R3.
Particular compounds of structural formula Ia include:
(1) 3-biphenyl-4-yl-2,4-dioxobutanoic acid, (2) 4-(3,5-bis-benzyloxyphenyl)-2-hydroxy-4-oxo-but-2-enoic acid, (3) 4-[3-(3,4-difluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (4) 4-[3-(4-methylbenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (5) 4-(3-benzyloxy-5-methoxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (6) 4-(3-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (7) 4-[3-(4-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (8) 4-[3-(3,4-dichlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (9) 4-[3-(4-fluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (10) 4-[3-(3-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (11) 4-[3-benzyloxy-5-(6-tent-butoxycarbonylamino-hexyloxy)phenyl]-2-hydroxy-4-oxobut-2-enoic acid, (12) 4-(3-(4-methoxybenzyloxy)phenyl)-4-oxo-2-butenoic acid, (13) 4-(3-benzyloxy-5-hydroxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (14) 4-(3-(1-phenylethoxy)phenyl)-4-oxo-2-butenoic acid, (15) 4-[3-benzyloxy-5-(6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-4-yl)pentanoylamino]hexyloxy)-phenyl]-2-hydroxy-4-oxobut-2-enoic acid, (16) 4-[3-(6-aminohexyloxy)-5-benzyloxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (17) 4-(3-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (18) 4-(3-chloro-phenyl)-2,4-dioxobutanoic acid, and (19) 4-(3-benzyl-phenyl)-2,4-dioxo-butanoic acid, (20) 4-(4-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (21) 4-(4-benzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (22) 4-(2-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (23) 4-naphthalen-1-yl-2,4-dioxobutanoic acid, and (24) 4-naphthalen-2-yl-2,4-dioxobutanoic acid, (25) 4-(6-benzyloxy-2-oxo-1,2-dihydropyridin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid, and (26) 4-(2,6-Bis benzyloxypyridin-4-yl)-2,4-dioxobutanoic acid, (27) 4-[1-(4-fluorobenzyl)-5-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, (28) 4-[1-(4-fluorobenzylr4-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, (29) 4-(4-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (30) 4-[1-(4-fluorobenzyl)-6-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, and (31) 4-biphenyl-4-yl-2,4-dioxobutanoic acid, and tautomers and pharmaceutically acceptable salts thereof.
Particular compounds of structural formula (I) include:
(1) 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid, (2) 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-dioxobutanoic acid, (3) 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)-phenyl]-2,4-dioxobutanoic acid, (4) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (5) 4-[3-(2-chlorobenzyl)phenyl]-2,4-dioxobutanoic acid, (6) 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid, (7) 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid, (8) 1-(3-benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid, (9) 1-(3-Benzyloxyphenyl)-2,4-dioxobutanoic acid, (10) 1-(2-Benzyloxyphenyl)-2,4-dioxobutanoic acid, (11) 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid, (12) 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid, (13) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (14) 4-{3-((methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (15) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (16) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (17) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (18) 4-(3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (19) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (21) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (22) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (23) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, (24) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (27) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (28) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (29) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (30) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (31) 4-(5-benzyl-3-methoxy-2-methoxyethoxypheny1~2,4-dioxobutyric acid, (32) 4-(3-Benzyl-4-methoxyphenyl)-2,4-dioxobutyric acid, (33) 4-(5-Benzyl-2-methoxyphenyl)-2,4-dioxobutyric acid, (34) 4-(3-Benzyl-4-fluorophenyl)-2,4-dioxobutyric acid, (35) 4-(3-Benzyl-4-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (36) 4-[5-(2-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid, (37) 2,4-Dioxo-4-(3-pyridin-2-ylmethylphenyl)butyric acid, (38) 4-(5-Benzyl-3-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (39) 4-(5-Benzyl-3-methoxyphenyl)-2,4-dioxobutyric acid, (40) 4-(5-Benzyl-2-benzyloxy-3-methoxyphenyl)-2,4-dioxobutyric acid, (41) 4-[5-(3-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid, (42) 4-(5-Benzyl-3-benzyloxyphenyl)-2,4-dioxobutyric acid, (43) 4-[5-Benzyl-2-(2-hydroxy)ethoxyphenyl]-2,4- dioxo-2-butanoic acid, (44) 2,4-Dioxo-4-(3-pyridin-3-ylmethylphenyl)butyric acid, (45) 4-[3-(3-Methyl-pyridin-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (46) 4-(5-Benzyl-2-methylsulfanylphenyl)-2,4-dioxobutyric acid, (47) 4-(5-Benzyl-3-N-morpholinophenyl)-2,4-dioxobutyric acid, (48) 4-(8-Benzyl-4-methyl-3,4-dihydro-2h-benzo[1,4]oxazin-6-yl)-2,4-dioxobutyric acid, (49) 4-[5-(2-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid, (50) 4-[5-(3-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid, (51) 4-(5-Benzyl-2,3,4-trimethoxyphenyl)-2,4-dioxobutyric acid, (52) 4-(6-Benzylbenzo[1,3]dioxol-4-y1~2,4-dioxobutyric acid, (53) 4-[3-Benzyl-5-(morpholine-4-carbonyl)phenyl]-2,4-dioxobutyric acid, (54) 4-(3-Benzyl-5-pyridine-2-ylmethylphenyl)-2,4-dioxobutyric acid, (55) 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid, (56) 4-(3-Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid, (57) 4-[3-Benzyl-5-(2-dimethylamino-1-hydroxy-1-methylethyl)phenyl]-2,4-dioxobutyric acid, (58) 4-(5-Benzyl-2-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (59) 4-(5-Benzyl-2-fluorophenyl)-2,4-dioxobutyric acid, (60) 4-(5-Benzyl-3-hydroxymethyl-2-methoxyphenyl)-2,4-dioxobutyric acid, (61) 4-[5-Benzyl-2-(pyrazin-2-yloxy)phenyl]-2,4-dioxobutyric acid, (62) 4-[3-Benzyl-5-(2-oxopiperidin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid, (63) 4-(5-Benzyl-2-methoxy-3-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid, (64) 4-[3-(2-Chlorobenzyl)-5-pyridin-2-ylmethylphenyl]-2,4-dioxobutyric acid, (65) 4-[5-Benzyl-2-methoxy-3-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid, (66) 4-(5-Benzyl-2-methoxymethylphenyl)-2,4-dioxobutyric acid, (67) 4-[3-(2-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (68) 4-[3-(4-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (69) 4-[3-(3-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (70) 4-(5-Benzyl-2-methoxy-3-(tert-butylcarbamoyl)phenyl]-2,4-dioxobutyric acid, (71) 4-(3-Benzyl-5-[1,2,3]triazol-1-ylmethylpheny1~2,4-dioxobutyric acid, (72) 4-[5-Benzyl-3-(N'-methyl-N-piperazinyl)phenyl]-2,4-dioxobutyric acid, (73) 4-(3-Benzyl-5-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (74) 4-(6-Benzyl-3-oxo-3,4-dihydro-2-H-benzo[1,4]oxazin-8-yl)-2,4-dioxobutyric acid, (75) 4-[5-Benzyl-2-(pyrimidin-2-yloxy)phenyl]-2,4-dioxobutyric acid, (76) 4-(5-Benzyl-3-amino-2-methoxyphenyl)-2,4-dioxobutyric acid, (77) 4-(5-Benzyl-2-ethoxyphenyl)-2,4-dioxobutyric acid, (78) 4-[5-Benzyl-2-(2-morpholin-4-yl-ethoxy)phenyl]-2,4-dioxobutyric acid, (79) 4-(5-Benzyl-2-trifluoroethoxyphenyl)-2,4-dioxobutyric acid, ($0) 4-{5-Benzyl-2-cyclobutyloxyphenyl)-2,4-dioxobutyric acid, (81) 4-(5-Benzyl-2-cyclopentyloxyphenyl)-2,4-dioxobutyric acid, (82) 4-(3-Benzyl-5-tetrazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (83) 4-(5-Benzyl-2,3-diisopropoxyphenyl)-2,4-dioxobutyric acid, (84) 4-(5-Benzyl-2-isopropoxy-3-N-methylaminophenyi)-2,4-dioxobutyric acid, (85) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminophenyl)-2,4-dioxo-butyric acid, (86) 4-[5-Benzyl-2-isopropoxy-3-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (87) 4-[5-Benzyl-2-isopropoxy-3-(morpholinomethyl)phenyl]-2,4-dioxo-butyric acid, (88) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminomethylphenyl)-2,4-dioxo-butyric acid, (89) 4-(7-Benzylbenzo[1,3]dioxol-5-yl)-2-hydroxy-4-oxobut-2-enoic acid, (90) 2-Hydroxy-4-oxo-4-(3-phenylindan-5-yl)but-2-enoic acid, (91) 4-{Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (92) 3-(3-Benzyl-5-carboxyacetylphenyl)-3-oxopropionic acid, (93) 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (94) 4-(5-Benzyl-3-methoxy-2-methylthioethoxyphenyl)-2,4-dioxobutyric acid, {95) 4-(7-Benzyl-2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,4-dioxobutyric acid, {96) (+/-) 4-(8-Benzyl-3-hydroxy-3,4-dihydro-2H-benzo[B][1,4]di-oxepin-6-yl)-2,4-dioxobutyric acid, (97) 4-(2,3-Dimethoxy-5-pent-4-enylphenyl)-2,4-dioxobutyric acid, (98) 4-(5-Cyclopropylmethyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (99) (6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid, (100) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (101) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (102) 4-[5-Benzyl-2-(3-N, N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (103) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (104) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (105) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (106) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, {107) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (108) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, (109) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid, (110) 4-[1-(2,6-Difluorobenzyl)-1H-indol-6-yl]-2,4-dioxobutyric acid, (111) 4-(1-Benzyl-1H-indol-6-yl)-2,4-dioxobutyric acid, (112) 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid, (113) 1-[1-(4-Fluorobenzyl)-4-indolyl]-2,4-dioxobutanoic acid, (114) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (115) 2,4-Dioxo-4-[3-(2,6-difluoro-benzyl)-phenyl]-butyric acid, (116) 2,4-Dioxo-4-[3-(2-4-6-trifluoro-benzyl)-phenyl]-butyric acid, (117) 2,4-Dioxo-4-[3-(2-fluoro-3-choro-benzyl)-phenyl]-butyric acid, (118) 2,4-Dioxo-4-[3-(2-methyl-4-fluoro-benzyl)-phenyl]-butyric acid, (119) 4-[3-(2,3-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (120) 4-[3-(2-Chloro-3-methylbenzyl)phenyl]-2,4-dioxobutyric acid, (121) 2,4-Dioxo-4-[3-(2,6-dichloro-benzyl)-phenyl]-butyric acid, (122) 2,4-Dioxo-4-[3-{2,3,4,5,6-penta-fluoro-benzyl)-phenyl]-butyric acid, (123) 4-[3-(2-Fluorobenzyl)phenyl]-2,4-dioxobutyric acid, (124) 2,4-Dioxo-4-[3-(2-choro-4-fluoro-benzyl)-phenyl]-butyric acid, (125) 4-[3-(2-Methylbenzyl)phenyl]-2,4-dioxobutyric acid, (126) 2,4-Dioxo-4-[3-(2-methoxybenzyl)phenyl]butyric acid, (127) 4-[3-(2-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (128) 4-[3-(2-Bromobenzyl)phenyl]-2,4-dioxobutyric acid, (129) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (130) 4-[3-(3-Chloro-2-methyl-benzyl)phenyl]-2,4-dioxobutyric acid, (131) 4-[3-(2,3-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (132) 4-(3,5-Dibenzylphenyl)-2,4-dioxo-butyric acid, (133) 2,4-Dioxo-4-[3-(2-trifluoromethylbenzyl)phenyl]butyric acid, (134) 4-[3-(4-Fluorobenzyl)phenyl]-2,4-dioxobutyric acid, (135) 4-[3-(3-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (136) 2,4-Dioxo-4-[3-(2-bromo-3-chloro-benzyl)-phenyl]-butyric acid, (137) 4-(3-Benzylphenyl)-2,4-dioxo-butyric acid, (138) 4-[3-{2-Fluoro-3-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid, {139) 4-[3-(3-Chloro-4-fluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (140) 2,4-Dioxo-4-[3-(2-bromo-4-fluoro-benzyl)-phenyl]-butyric aci d, (141) 4-[3-(3-Bromobenzyl)phenyl]-2,4-dioxobutyric acid, (142) 4-[3-(2,5-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (143) 4-[3-(5-Chloro-2-fluoro-benzyl)phenyl]-2,4-dioxobutyric acid, (144) 4-[3-(3-Methylbenzyl)phenyl]-2,4-dioxobutyric acid, (145) 4-(3-Benzyl-4-methyl-phenyl)-2,4-dioxo-butyric acid, (146) 4-[3-(3,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (147) 4-[3-(2,5-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (148) 4-[3-(2-Chloro-6-methyl-benzyl)phenyl]-2,4-dioxobutyric acid, {149) 2,4-Dioxo-4-[3-(2-trifluoromethyl-4-chloro-benzyl)-phenyl]-butyric acid, WO 99/62520 PCT/CiS99/12093 (150) 4-[3-(2-Bromo-5-chloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (151) 4-(3-Naphthalen-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (152) 2,4-Dioxo-4-[3-(3-fluorobenzyl)phenyl]butyric acid, (153) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (154) 2,4-Dioxo-4-[3-(1-phenylethyl)phenyl]butyric acid, (155) 4-(3-Benzyl-4,5-dimethylphenyl)-2,4-dioxo-butyric acid, (156) 2,4-Dioxo-4-[3-(3-methoxybenzyl)phenyl]butyric acid, (157) 4-[3-(5-Methyl-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (158) 4-[3-(5-Chloro-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (159) 4-(3-Benzyl-5-methylphenyl)-2,4-dioxo-butyric acid, (160) 4-[3-(2-Cyanobenzyl)phenyl]-2,4-dioxo-butyric acid, I5 (161) 4-[3-Benzylphenyl]-2,4-dioxobutyric acid, (162) 4-[3-(3,5-Dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (163) 4-(5-Benzyl-2,4-dimethylphenyl)-2,4-dioxo-butyric acid, (164) 4-(5-Benzyl-2-methylphenyl)-2,4-dioxo-butyric acid, (165) 4-(3-Cyclohexylmethyl-phenyl)-2,4-dioxo-butyric acid, (166) 4-(3-[(Methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (167) 4-[3-Benzyl-5-(5-hydroxy-pentyl)-phenyl]-2,4-dioxo-butyric acid, (168) 4-(3-Benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (169) 4-[3-(3-tert-Butoxy-2-hydroxy-propyl)-5-(2-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid, (170) 2,4-Dioxo-4-[3-(2,3-dimethoxy-benzyl)-phenyl]-butyric acid, (171) 4-[3-(Methoxyphenylmethyl)phenyl]-2,4-dioxobutyric acid, (172) 4-[3-[Hydroxy-(tetrahydro-furan-3-yl)-methyl]-5-(2-methyl-benzyl)-phenyl]--2,4-dioxo-butyric acid, (173) 2,4-Dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid, (174) 2,4-Dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid (175) 4-[3-Benzyl-5-(cyclopropylcarboxamido)-phenyl]-2,4-dioxobutyric acid, (176) 4-[3-Benzyl-5-(t-butoxycarbamoyl)phenyl]-2,4-dioxobutyric acid, (177) 4-[3-(Hydroxy-phenyl-methyl)-phenyl]-2,4-dioxo-butyric acid, (178) 4-(5-Benzyl-2,3-dimethylphenyl)-2,4-dioxo-butyric acid, (179) n-[3-(3,5-Dibromobenzyl)phenyl]-2,4-dioxo-butyric acid, (180) 4-[3-(2-Methyl-benzyl)-5-pyrimidin-2-yl-phenyl]-2,4-dioxo-butyric acid, (181) 4-[3-Benzyl-2-(pyrimidin-2-ylamino)-phenyl]-2,4-dioxo-butyric acid (182) 4-[3-Benzoimidazol-1-ylmethyl-5-(2-methyl-benzyl)-phenyl]--2,4-dioxo-butyric acid, (183) 2,4-Dioxo-4-[3-(3-trifluoromethylbenzyl)phenyl] butyric acid, (184) 4-(4-Phenoxy-phenyl)-2,4-dioxo-butyric acid, (185) 2,4-Dioxo-4-(3-[1,2,3]triazol-2-ylmethyl-phenyl)-butyric acid, (186) 4-[3-Benzyl-5-{6-methoxy-pyridin-2-yl)-phenyl]-2,4-dioxo-butyric acid, (187) 4-(3-Benzotriazol-2-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (188) 4-[3-Benzyl-5-(2-(4-methylpiperazin-1-yl)-pyrazin-6-yl)phenyl]-2,4-dioxobutyric acid, (189) 4-[4-(3-Phenethyl)phenyl]-2,4-dioxobutyric acid, (190) 4-[4-(3-Chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (191) 4-(3-Benzoimidazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (192) 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid, (193) 4-(3-Benzotriazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (194) 4-[3-(3,5-Dimethyl-pyrazol-1-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (195) 4-[3-Benzyloxy-5-(2-morphonin-4-yl-ethoxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid, (196) 4-(4-Methyl-3-phenoxy-phenyl)-2,4-dioxo-butyric acid (197) 4-[3-(2-Hydroxy-benzyl)-phenyl]-2,4-dioxo-butyric acid, (198) 4-[3-Benzyl-5-{6-dimethylamino-pyrazin-2-yl)-phenyl]-2,4-dioxo-butyric acid, and (199) 4-(5-Benzyl-2-methoxypyridin-3-yl)-2,4-dioxabutyric acid;

and tautomers and pharmaceutically acceptable salts thereof.
One class of compounds of structural formula (I) includes:
(1) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (2) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (3) 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (4) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (5) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (6) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (7) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (8) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (9) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (10) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (11) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (12) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, {13) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (14) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (15) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (16) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (17) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (18) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (19) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid, (21) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (22) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (24) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (27) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, (28) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (29) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, and (30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl) phenyl]-2,4-dioxo-butyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
One class of compounds of the present invention is represented by the structural formula below:
R$
R'~'I~/Rs OH
R~
O O
Another class of compounds of the present invention is represented by the structural formula below:
R
~~I~/Rs H '~'~' ' OH

Another class of compounds of the present invention is represented by the following structural formula:
R~
Rs ~I~ o H
OH
R2 ~ a O O
R
Still another class of compounds of the present invention is represented by the formula below:

O
~OH
R2 Rs O O
Another class of compounds of the present invention is represented by the following structural formula:
Yet another class of compounds of the present invention is represented by the following structural formula:
1 .~ 8 O
,, OH
..
ERs O O
Still another class of compounds of the present invention is represented by the following structural formula:

Rv ~~~1 R9 j0 ~ \J OH
' R20 O
Another class of compounds of the present invention is represented by the following structural formula:
R' R ~~~ ~/1 OH
O '\J20 O
R
Yet another class of compounds of the present invention is represented by the following structural formula:

~/1 OH
~i .\.J

Still another class of compounds of the present invention is represented by the following structural formula:
~ N ./ , ' 1 OH
~i. ~ .\.J

Another class of compounds of the present invention is represented by the following structural formula:

~1 R~~N I ,\~J ~\OH

Yet another class of compounds of the present invention is represented by the following structural formula:
R' O
H ~
'OH

Still another class of compounds of the present invention is represented by the following structural formula:
R' R8 O
H
'oH

Another class of compounds of the present invention is represented by the following structural formula:
H
'OH
R2 Rs O O
Still another class of compounds of the present invention is represented by the following structural formula:
s R
O
H OH

One class of compounds of the present invention is represented by the structural formula below:

WO 99/b2520 PCT/US99/12093 R~
R\~~ ~ O
H ' OH

Another class of compounds of the present invention is represented by the following structural formula:

/I\ O
R
OH
Is O O
R
Still another class of compounds of the present invention is represented by the formula below:
R' Rah ~ ~ ~OH

Another class of compounds of the present invention is represented by the following structural formula:
R~ O
~OH
O

Another class of compounds of the present invention is represented by the following structural formula:
R' O
R2/- ~ ~ -OH
O O

Another class of compounds of the present invention is represented by the following structural formula:
O
OH
R2~N O O
In one embodiment of the present invention, A is selected from:
(1) phenyl, (2) pyridyl, (3) naphthyl, (4) indolyl, provided that the aryl ring is substituted by the dioxobutyric acid/ester moiety in structural formula (I), (5) (6) N N
(7) (s) (9) (lo) i~

O \
N
(11) O /
(12) O \
O
(13) H
N \
C ~/
O
(14) O /
and (15) i N N
In another embodiment of the present invention, A is selected from:
(1) phenyl, (2) pyridinyl, (3) indolyl, provided that 6-membered aromatic ring is substituted by the dioxobutyric moiety in structural formula (I);
(4) 0 \
N
(5) (6) ,O \
/
O
O \
/
O
(7) H
N \
O
and (8) phenyl.
O /
In still another embodiment of the present invention, A is In one embodiment of the present invention R1 is selected from: , (1) -H, (2) -C1_5 alkyl, (3) -C1_g alkyl-OR7;

(4) -O-C1_6 alkyl-ORS, (5) -O-C1_g alkyl-SR7, (6) -CF3 or -CH2CFg, (7) -F, Cl, or Br"

(8) -N02, (9) -CO_3 alkyl -N(R4XR5), (10) -phenyl, (11) substituted phenyl substituted with 1 or 2 substituents independently selected from:

(a) halogen, (b) C1_g alkyl, (c) C1_6 alkyloxy-, (d) phenyl, (e) -CFg, (f7 -OCFg, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(12) phenyl C1_g alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) halogen, (b) C1_g alkyl, (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, (i) phenyloxy, -CO-6 ~yl-N(R?)2 ~

n -N

(k) O
and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(13) -O-R6, (14) -O-C1_g alkyl, unsubstituted or substituted with one to three fluorine atoms, (15) -O-C1_g alkyl-NH-C(O)-OR7;

(ls) -O-C2_g alkyl-N(R4)(R5);

(17) -S-C1_3 alkyl;

(18) -C(O)CH2C(O)C(O)OR7;

(19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5).

In another embodiment of the present invention Rl is , selected from:

(1) -H, (2) -CH3, (3) -C1_g alkyl-OR7;

(4) -O-C1_g alkyl-OR7, (5) -O-C1_g alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -CO_3 alkyl -N(R4)(R5), (10) -phenyl, (11) phenyl C1_3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f7 -CN, (g) hydroxy, (h) -CO_g alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -Cp_6 alkyl-N(R7)2, (13) -O-C1_g alkyl, unsubstituted or substituted with one to three fluorine atoms, and (14) -C(O)CH2C(O)C(O)OH;

(15) -O-C1_6 alkyl-NH-C(O)-OR7;

(16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5).

In yet another embodiment of the present invention Rl is selected , fro m:

(1) -H, (2) -CH3, (3) -CH20CH3 ~
(4) -OCH2CH20H, (5) -OCH2CH20CH3, (6) -(CH2)6-OH, (7) -CF3, (8) _F~
(9) -Cl, (10) -CO-3 ~kYl -N(R4)(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f~ hydroxy, (g) -Cp_g alkyl-N(R7)2 (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f7 hydroxy, (g) -Cp_6 alkyl-N(R7)2 , , (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1_6 alkyl-NH-C(O~OR7 , (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2 NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(O)CH2C(O)C(O)OH, (27) -CH2-CH(OH)-CH2-O-R7, and (28) -C(OHKCH3)-CH2N(R4)(R~).
In another embodiment of the present invention, Rl is selected from:
(1) -H, (2) -phenyl, (3) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, selected from -F, -Br, -Cl, (b) methyl, and (c) methoxy, (4) phenyl C 1_3 alkyl-, (5) -O-R6, (6) -O-CH3, and (7) -C(O)CH2C(O)C(O)OR7.
In one embodiment of the present invention, R2 is selected from:
(1) -H, (2) -R3, (3) -C1_6 alkyl, (4) -C1_6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1_6 alkyl may be replaced with a fluorine atom, (5) _O_R6, (6) -S -R6, (7) -O-C1_g alkyl- SR6;

(8) -C 1_6 alkyl (OR6)(R4) , (9) -CO_g alkyl-N(R4)(R6) , (10) -C1_6 alkyl-S-R6, (11) -Cp_g alkyl-C(O)-R6, (12) -Cp_g alkyl-C(O)CH2-C(O)-OH

, (13) -C1_g alkyl NR4C(O)-R6 , (14) -C1_6 alkyl-C(O)N(R4)(R~), and (15) -CH2(OR7~R6.
In another embodiment of the present invention, R2 is selected from:

(1) -H, (2) _R3~

(3) -CH3, (4) -C1_g alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1_6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (?) -O-C1_g alkyl-SR6;

(8) -C1_6 alkyl (OR6)(R4) , (9) -Cp_g alkyl-N(R4)(R6) , (10) -Cp_g alkyl C(O)-R6, (Il) -CO_g alkyl C(O)CH2-C(O)-OH, (12) -C1_g alkyl NR4C(O)-R6 , (13) -C1-6 a~Yl-C(O)N(R4)(R5), and (14) -CH2(OR7)-RS.

In yet another embodiment of the present invention R2 is , selected from:

(1) -H, (2) -R3~

(3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (8) -S-phenyl, (9) -C1_g alkyl (OR6)(R4) , (10) -Cp_6 alkyl-N(R4)(R6) , (11) -C(O)-R3, (12 ) -CO_g alkyl C(O)CH2-C(O)-OH, (13) -C1_6 alkyl NR4C(O)-RS

, (14) -CH(OCH3)R3, and (15) -CH(OH)R3.
In another embodiment of the present invention, R2 is selected from:
(1) -R3, (2) -C1_g alkyl substituted with R3, (3) -0-R6, (4) -S(O)n-RS, (5) -C1_g alkyl (ORS)(R4) , (6) -CO_g alkyl-N(R4)(R6) , and (7) -C1_g alkyl-C(O)N(R4)(R5).
In one embodiment of the present invention, R3 is selected from:
(1) phenyl;

(2) subs tituted phenyl with 1, 2, 3 or 4 substituents independently selected from:

(a) halogen, (b) C 1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO_6 alkyl-N(R7)2, (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C 1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(3) thienyl, (4) subs tituted thienyl substituted on carbon with one or two subs tituents independently selected from:

(a) halogen, (b) C1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_g alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -Cp_g alkyl-N(R7)2, (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C 1_6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1_6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO_g alkyl-N(R7)2, n (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_s alkyl, (iii) -CF3, and (iv) hydroxy;

(7) imid azolyl, (8) subs tituted imidazolyl substituted on carbon with one or two subs tituents independently selected from:

(a) halogen, (b) C1_6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, (e) -S-C1_g alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2 , Ci>

(k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(9) pyrrolyl, (10) substituted pyrrolyl substituted on carbon with one or two substituents independently selected from:

(a) halogen, (b) C1_6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, (e) -S-C1_6 alkyl, -CN, (g) hydroxy, (h) phenyloxy, (i) -Cp_6 alkyl-N(R7)2, Ci) (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;
_ q4_ (11) pyrazolyl, (12) substituted pyrazolyl substituted on carbon with one or two subs tituents independently selected from:

(a) halogen, (b) C 1_6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, (e) -S-C1_6 alkyl, (f~ -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, (j ) (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy;

(15) piperidinyl, (16) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:

(a) halogen, (b) C1_g alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O

(h) benzyl, and (i) hydroxy;

(17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from:

(a) halogen, (b) C1_g alkyl, ( c ) C 1-g alkyloxy-, (d) -CF3, (e) -OCF3, -CN, (g) =O

(h) benzyl, and (i) hydroxy;

(19) hexahydrothieno[3,4-d]imidazolyl, (20) substituted hexahydrothieno[3,4-d] substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents independently selected from:

(a) oxo, (b) halogen, (c) C1_g alkyl, (d) C1-g alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy, (21) naphthyl, (22) substituted naphthyl with 1, 2, or 3 substituents independently selected from:

(a) -halogen, (b) -C1_6 alkyl, (c) -C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (23) indolyl, (24) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1_6 alkyl, (c) C1-g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(25) C3-g cycloalkyl fused with a phenyl ring;
(26) substituted C3-g cycloalkyl fused with a phenyl ring substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1_g alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, -CN, (g) =O, and (h) hydroxy;
(27) pyrazinyl;
(28) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, (b) C 1-g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_g alkyl, (i7 -CN, (g) hydroxy, (h) phenyloxy, (i) -CO_g alkyl-N(R7)2, -N

Cl ) O

(k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1-g alkyl, (iii) -CF3, and (iv) hydroxy;

(29) pyrimidinyl;

(30) subs tituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from:

(a) halogen, 1~ ~) C 1-6 ~kYl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, ( a ) -S-C 1-g alkyl, (~ -CN, (g) hydroxy, (h) phenyloxy, (i) -CO_6 alkyl-N(R~)2, -N

(j) O

(k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(31) triazolyl;

(32) subs tituted triazolyl with one or two substituents independently selected from:

(a) halogen, (b) C 1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1_g alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO_6 alkyl-N(R7)2, -N

(j ) V

, (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, (ii) C1_g alkyl, (iii) -CF3, and (iv) hydroxy;

(33) tetrazolyl;

(34) subs tituted tetrazolyl with a substituent selected from:

(a) halogen, (b) C1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) phenyl, (e) -S-C1_g alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-g alkyl-N(R7)2, (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy;
(35) C3_g cycloalkyl;
(36) substituted C3_g cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, (b) C 1-g alkyl, (c) C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(37) tetrahydrofuran;
(38) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, (b) C1_g alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, (h) benzyl, and (i) hydroxy;
(39) piperazinyl;
(40) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, (b) C 1_6 alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) -O, (h) benzyl, and (i) hydroxy;
(41) benzotriazolyl, (42) substituted benzotriazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1_6 alkyl, (c) -C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(43) benzoimidazolyl, (44) substituted benzoimidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1_g alkyl, (c) -C1_g alkyloxy-, (d) -CF3, (e) -OCF3, (f~ -CN, and (g) -hydroxy.
In another embodiment of the present invention, R3 is selected from:

(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, ~) C 1-6 ~kYl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, {c) C1_6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C 1-g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;

{5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br;

(b) C 1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) hydroxy, and (e) oxo;

(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br;

_ 52_ (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (~ hydroxy;
(11) C3_g cycloalkyl, (12) substituted C3_6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (fl =O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and (f) hydroxy;

(17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:

(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f7 -CN, and (g) -hydroxy, (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;

(23) pyrazinyl;

(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) C 1_g alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (c) C1_g alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom , (d) hydroxy, (e) phenyloxy, (f) -Cp_6 alkyl-N(R7)2, and (g) -NVN-CH3.
(25) pyrimidinyl;

(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:

(a) halogen, selected from -F, -Cl, and -Br , (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;

(28) substituted triazolyl with a substituent selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;

(30) substituted tetrazolyl with a substituent selected from:

(a) halogen, selected from -F, -Cl, and -Br , (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3_g cycloalkyl;

(32) substituted Cg_g cycloalkyl substituted with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CFg, and (e) -OCF3, (33) tetrahydrofuran;

(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;

(36) substituted piperazinyl substituted with one or two substituents independently selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) C1_g alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCFg, (f) benzyl, and (g) hydroxy;

(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:

(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CFg, and (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:

(a) -halogen, selected from -F, -Cl, and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCFg.

In yet another embodiment of the present invention, each R3 is independently selected from:

(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:

(a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CFg, (f7 -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, (J) -OCF3, (k) -CN, and (1) hydroxy;

(3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from:

(a) F, (b) C1, and (c) methyl;

(5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from:

(a) -F, (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo;

(7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:

(a) -F, (b) -Cl, (c) -CH3, and (d) -CF3;

(9) C3_6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from:

(a) methoxy-, (b) -OCF3, (c) =O, and (d) hydroxy;

(12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl;

(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:

(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3 (d) methoxy-, (e) -N(CH3)2, and -NON-CH3.
(17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl;

(21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, _ 58-(26) piperazinyl;
(27) substituted piperazinyl substituted with a substituent selected from:
(a) -F, (b) -C1, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, and (29) benzoimidazolyl.

In still another embodiment of the present invention, R3 is selected from:

(1) phenyl;

(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:

(a) halogen, selected from -F, -Cl, -Br, (b) -CHg, (c) methyloxy-, (d) phenyl, (e) -CF3, -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:

(i) halogen, selected from -F, -Cl, -Br, (ii) -CHg, (iii) -CFg, and (iv) hydroxy.

In one embodiment of the present invention, each R4 is independently selected from:

(1) -H, (2) -C1_4 alkyl, (3) -CF3 (4) -R3, (5) -C2_3 alkenyl, (6) -C1_3 alkyl-R3, (7) -C2_3 alkenyl-R3, and (8) -C(O)-R3.

In another embodiment of the present invention, each R4 is independently selected from:

(1) -H, (2) -C~_4 alkyl, (3) -CF3, (5) -C1_3 alkyl-R3, and (6) -C(O)-R3.

In one embodiment of the present invention, each R5 is independently selected from:

(1) -H, (2) -C1_3 alkyl, (5) -C2_3 alkenyl, (6) -C1_3 alkyl-R3, (7) -S(O)n-R3, (8) -C(O)-R3, (9) -C(O)OR4, and (10) -C(O)C(O)OH;

In another embodiment of the present invention, each R5 is independently selected from:

(1) -H, (2) -C1_3 alkyl, (3) -CF3, (5) -C1_3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)ON.
In another embodiment of the present invention, each R~ is independently selected from:
(1) -H, (2) -CH3 (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)ON;
In one embodiment of the present invention, R7 is independently selected from H, and -C 1_g alkyl.
In one embodiment of the present invention, R8 is selected from hydrogen, methyl and -O- C1_g alkyl.
In yet another embodiment of the present invention, R8 is hydrogen.
In one embodiment of the present invention, R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo.
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from:
(1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof' in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (IA) and (IB):

R~ 2 R~
O
R8~ 8 ORS _-- R ~ ORS

(I) (IA) O

~~ ~ ~OR~

(IB) By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (IA) and (IB) are also intended. Similarly, by referring to compound (IA), it is understood for the purposes of the present application that the tautomers (I) and (IB) are also intended. The same holds true for references to tautomer (IB).
When any variable (e.g., R3, R4, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS
related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
Schemes AI, AII, and AVI illustrate the preparation of compounds wherein A is di-aryloxy/alkyloxy substituted phenyl.
Scheme AIII illustrates the preparation of the compounds of the present invention wherein A is arylalkyl substituted phenyl. Schemes AIV and AV describe the synthesis of compounds wherein A is amino substituted phenyl. Scheme AVII describes the synthesis of compounds wherein A
is indolyl. Scheme IX illustrates the synthesis of pyridyl compounds.

Scheme AI
\
O
O \
\ I O
NaH
DME
Dimethyl oxalate O O

AI;1-1 O
\ ~ O
1 N NaOH
THF/MeOH 1:1 \ O O
O I \ OH I-2-1 / / O
\ I O
Scheme All /
\ o o \
/
/
\ ~ o H2 1 Pd /C
EtOH / Et20 \ O
O \ AII-1-1 O OH
CI~N~ O
Br(CH2)sN
Cs2 Cs2C03 O

O
O ~ I-4-1 / II- -O~N~ H O
~O
NaH
1 )NaH DME
DME dimethyl oxalate dimethyl oxalate 2) NaOH
\ ~ Ha 1 _ ~ nu AII-5-15-1 O
~4II-3_1 H O
N
~O f NaOH
O O
OH AII~6-1 O
O
O
N O
H

WO 99/b2520 PCT/US99/12093 Scheme AIII
Br ~ Br r~-BuLi Benzaldehyde Et20, -78°C

Br OH
Et3SiH
BF3~ Et20 II_2_1 \ ~ Br r~-BuLi CH3C0-N(CH3)OCH3 THF, -78°C

\ 3 O
dimethyl oxalate NaH
DME , 60°C

/I / o _ a-O O
NaOH
THF / MeOH / H20 I / O
I m- -1 OH
O O
Scheme A-IV

Br O
CS2CO3 v DMF N I
/I /
O

diethyl oxalate NaOEt N I \ O
\ off \ O OH
9,1 V-2-1 LiOH
N \ O
THF
\ OH
\
O OH
A~V-3-~

Scheme A-V
\ \ Br Cs2C03 I / + I /
H2N - [[ DMF
O
\ I I / diethyl oxalate N ~ NaOEt O
I

O
I I / LiOH
N V ~ \~ ~OEt O OH THF
I

I I~ o N v ~ \Y ~OH
O OH
I

Scheme AVI
O
O
OH
Mel / K2C03 DMF
O
O

1. diethyl oxalate NaOEt, THF
2. HCI, H20, dioxane O O
/ O ~ OH AVI3-13_1 WO 99/b2520 PCT/US99/12093 Scheme AVII
H Br N
\ I /
NaH
4-fluorobenzyl bromide DMF
F
N ~ Br /
t-BuLi, THF
O
HaC~N

F O
N

\ /

dimethyl oxalate NaH, THF
F O
N ~ OCH3 AVII-2-1 II
/ O
NaOH, H20 THF
F \ / O O
N ~ OH AVII-3-1 I I
/ O
_ 7~_ Scheme lX
HO
O
N\ / OH
HO
i. POC13, 200°C, sealed tube ii. H20 CI
O
N\
OH AIX1-11_1 CI
Bn0' Na+, DMF, reflux Bn0 O
N \ / OH AIX~2_1 Bn0 -7&

HN ~ HCI

EDC,HOAT, EtN(i-pr)2, DMF
Bn0 O
N~ ~ N-CHs Bn0 H3C0 AIX3-13-1 CH3MgBr, THF
Bn0 O
N~

Bn0 Na+OEf, (C02Et)2, THF

N. ~)---~( O
Bn0 ~--OEt AIX5-15-1 O
i. Aq NaOH, EtOH
ii. Aq HCI
B

O
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mutate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fiunarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g.
acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
_ 79_ As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15Ø 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS
antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
~iNTIVIRALS
Drug Name Manufacturer Indication 097 HoechstlBayer HIV infection, AIDS, ARC

(non-nucleoside reverse transcriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC

GW 141 (protease inhibitor) Abacavir (1592U89)Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC

(RT inhibitor) Acemannan Carrington Labs ARC

(Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT

AD-439 Tanox Biosystems HIV infection, AIDS, ARC

AD-519 Tanox Biosystems HIV infection, AIDS, ARC

Adefovir' dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL

(Los Angeles, CA) HIV positive, AIDS

Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC
neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC

beta-fluoro-ddA Nat'1 Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers Squibb/HIV infection, (CGP-73547) Novartis AIDS, ARC

(protease inhibitor) BMS-234475 Bristol-Myers Squibb/HIV infection, (CGP-61755) Novartis AIDS, ARC

(protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV

peripheral CMV

retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC

(RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV

Ind. Ltd. (Osaka, positive asymptomatic Japan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC

ddI Bristol-Myers SquibbHIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T

DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC

(protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266) AIDS, ARC

(-) 6-Chloro-4(S)- (non-nucleoside RT

cyclopropylethynyl- inhibitor) 4(S)-trifluoro-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, STOCRINE

EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith HIine herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC

(reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC

(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC

Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC

Interferon alfa-n3Interferon SciencesARC, AIDS

Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC

ISIS 2922 ISIS PharmaceuticalsCMV retinitis KNI-272 Nat'1 Cancer InstituteHIV-assoc.

diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC

(reverse transcriptase inhibitor); also with AZT

Lobucavir Bristol-Myers SquibbCMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC

(protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC

(RT inhibitor) Novapren Novaferon Labs, HIV inhibitor Inc.

(Akron, OH) Peptide T Peninsula Labs AIDS

Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV

Phosphonoformate Products, Inc infection, other CMV

infections _ 8~_ PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC

(protease inhibitor) Probucol Vyrex HIV infection, AIDS

RBC-CD4 Sheffield Med. HIV infection, Tech (Houston TX) AIDS, ARC

Ritonavir Abbott HIV infection, AIDS, ARC

(protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC

(protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC

thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV

infections Virazole VirateklICN asymptomatic HIV

Ribavirin (Costa Mesa, CA) positive, LAS, ARC

VX-478 Vertex HIV infection, AIDS, ARC

Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT

Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS
Dpi- g Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS

Bropirimine Pharmacia Upjohn advanced AIDS

Acemannan Carrington Labs, AIDS, ARC
Inc.

(/ruing, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS

Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS

Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT

Stimulating Factor HIV Core Particle Rorer seropositive HIV

Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT

IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT

IL-2 Chiron AIDS, increase in Interleukin-2 cell counts (aldeslukin) Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT

(human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL

IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL

Imuthiol Diethyl Merieux Institute AIDS, ARC

Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS

Methionine- TNI Pharmaceutical AIDS, ARC

Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT

Factor Remune Immune Response immunotherapeutic Corp.

rCD4 Genentech AIDS, ARC

Recombinant Soluble Human rCD4-IgG AIDS, ARC

hybrids Recombinant Biogen AIDS, ARC

Soluble Human Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT

SK&F106528 Smith HIine HIV infection Soluble T4 _ 88_ Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES
Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCP

Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP

Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM (Rosemont, IL) & IV) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation Spiramycin Rhone-Poulenc cryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis;

851211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP

_ 89_ _ TO HER
Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT
therapy Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc.
w/AID S
Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
The preparation of ddC, ddI and AZT are also described in EPO
0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
Indinavir is generally administered at a dosage of 800 mg three times a day.
The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: Ac represents acetyl; ACN is acetonitrile; Bn represents benzyl; Bu represents butyl; Calc'd represents calculated; DEAD is diethylazido-carboxylate; DME is dimethoxyethane; DMF is dimethyl formamide; DMSO is dimethylsulfoxide; EI represents electron impact; ES represents electrospray; Et represents ethyl; FAB represents fast atom bombardment; IPA is isopropyl alcohol; LDA is lithium diisopropylamide; L-Selectride~ is lithium tri-sec-butylborohydride; MEK is methyl ethyl ketone; Me represents methyl; NMP is 1-methyl-2-pyrrolidinone; PDA is photodiode array; rt and RT represent room temperature; THF is tetrahydrofuran; TLC is thin layer (Si02) chromatography.

4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid AI-2-1 Ste~l: 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid methyl gster AI-1-1 O O
O ~ OCH3 O
o _1_ A solution of 1-(3,5-bis-benzyloxy-phenyl)ethanone (3g, 9.0 mmole) in DME (20 mL) was treated with sodium hydride (0.54g, 60% dispersion in oil, 13.5 mmole) followed by dimethyl oxalate (L3, 9.0 mmole) and a drop of methanol and the solution was warmed to 110°C. After 0.5 hours the reaction became dark brown and homogeneous. The reaction mixture was poured into into 1N HCl and extracted with EtOAc three times, the combined organic layers were dried over MgS04, filtered and evaporated to give a yellow solid. The residue was dissolved in THF and absorbed to silica gel and added to the top of a pad of silica gel. The pad was eluted with CH2C12~ which removed non-polar impurities, then with 20%
MeOH/CH2C12, which eluted the product. The product was further purified by crystallization from EtOAc/Hexanes/Et20 to give I-1-1 as a orange foam. Rf-__0.3 (97:3:1 CH2C13 / MeOH / HOAc). 1H NMR (400 MHz, CDC13) 8 7.4 (m, lOH), 7.24 (m, 2H), 7.01 (s, 1H), 6.84 (m, 1H), 5.1 (s, 4H), 3.94, (s, 3H).
SteR_2: 4-(3.5-Bis-benzvlox -~~hen~2.4-dioxobutanoi~ acid AI-2-1 /
O O
O ~ OH
/ O
O

A solution of AI-1-11-1 (1.5g, 3.47 mmole) was dissolved in 1:1 THF / MeOH
(20 mL) and treated with 1 N NaOH (10 mL, 10 m mole) and stirred for one hour. The reaction mixture was washed with dilute ether, then acidified to pH2 with 1N HCl and extracted three times with EtOAc. The organic layers were combined, washed with 1 N HCl, dried over MgS04, filtered through a pad of CELITE diatomaceous earth and evaporated to dryness. The residue was triturated with ether to give -2-1 as bright yellow powder. 1H NMR (400 MHz, CDC13) 8 7.43-7.31 (m, lOH), 7.22 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 6.86 (m, 1H). mass spec (FAB, m+1) 405.13 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-dioxobutanoic acid AII-3-1 1-(3-Benzvloxv-5-h d~rOR,yyhenvl)ethanone AII-1-1 O
O

A solution of 1-(3,5-bis-benzyloxyphenyl)ethanone {lOg, 3.0 mmole) in 1:1 EtOH/Et20 (200 mL) was treated with 10% palladium on carbon (3.4g) and hydrogen gas at balloon pressure for one hour with vigorous stirring. The solvent was evaporated and the residue chromatographed on silica gel eluting with 20% acetone / hexanes to give AII-1-1 as a white solid. Rf--0.27 (30% acetone / hexanes). 1H NMR (400 MHz, CDC13) S 7.4 (m, 5H), 7.16 (s, 1H), 7.05 (s, 1H), 6.7 (m, 1H), 5.82 (s, 1H), 5.08 (s, 2H), 2.55 (s, 3H).
Step 2: 4-[2-(3-Acetyl-5-benzyloxy-phenoxy)-ethyl]morpholin-4-ium O
O
/
O~N
~O
An2-12-1 The free base of 4-(2-chloroethyl)morpholine hydrochloride (1.85g, 10 mmole) was formed and then combined with AII1-11-1 (0.8g, 3.3 mmole), cesium carbonate (3.25g, 10 mmole) and dioxane (40 mL) and heated to 80°C for 4.5 hours. The solution was filtered, washed with EtOAc and concentrated. Column chromatography with 10-30% acetone / hexanes gave II-2- as a brown syrup. Rf--0.39 (30% acetone / hexanes). 1H

NMR (400 MHz, CDCIg) 8 7.4 (m, 5H), 7.2 (s, 1H), 7.18 (s, 1H), 6.74 (m, 1H), 5.1 (s, 2H), 4.13 (t, J=5.6 Hz, 2H), 3.74 (t, J=4.5 Hz, 4H), 2.8 (t, J=5.6 Hz, 2H), 2.58 (m, 4H), 2.55 (s, 3H).
~teu 3: 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)phenyl]-2,4-deoxobutanoic acid AII-3-I
O O
O ~ OH
I I
I / O
O~N
v 0 AII-3-1 In a manner similar to that described for AI=1-1, AII2-1 was treated with NaH and dimethyloxate in DME to give a mixture of AII-3-1 and its methyl ester. The mixture was treated with NaOH as described for AI-2-1 to give IA I-3-1 as a yellow solid. 1H NMR (400 MHz, D20) b 7.4 (m, 5H), 6.9? (s, 1H), 6.86 (s, 1H), 6.56 (s, 1H), 5.05 (s, 2H), 4.05 (m, 2H), 3.6 (m, 5H), 2.7 (s, 2H), 2.5 (s, 4H). mass spec (m+1)=428 4-[3-Benzyloxy-5-(6-tent-butoxycarbonylamino-hexyloxy)-phenyl]-2,4-dioxobutanoic acid AII-6-1 teu 1: [6-(3-Acetyl-5-benzyloxy-phenoxy)-hexyl]carbamic acid-tert -butvl ester AII-4-1 O
O
O
O
N O

In a manner similar to that described for IAIA Ii2-11, II-1-1 was treated with (6-bromo-hexyl)-carbamic acid-tent-butyl ester (J. Med. Chem. 1994, 37, 2537-2551) to give IA I-4=1 Rf--0.41 (80% acetone / hexanes); 1H NMR
(400 MHz, CDC13) 8 7.4 (m, 5H), 7.15 (s, 1H), 7.10 (s, 1H), 6.72 (m, lh), 5.1 (s, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.12 (m, 2H), 2.56 (s, 3H), 1.8 (m, 2H), 1.5 (m, 6H), 1.45 (s, 9H), 1.40 (m, 2H).
Ste,R_2: 4-[3-Benzyloxy-5-(6-tent-butoxycarbonylamino-hexyloxy) phen 1~L4-dioxobutanoic acid methyl ester AII-5-1 /
O O
O ~ OCH3 O
O
O
N O

Freshly prepared sodium methoxide (from 0.25g sodium metal in MeOH) was suspended in toluene (5 rnL) and a solution of AII4-14-1 (0.8g, 1.8 mmole) and dimethyloxalate (0.21g, 1.8 mmole) in toluene (5 mL) was added. The mixture was stirred for 2 hours, then quenched with 3 N
HCl and extracted with EtOAc. The organic layer was dried with Na2S04, filtered and evaporated. The residue was passed through a plug of silica gel as described for AI-1-11-1 and the resulting oil crystallized from ether to give AII5-15-1 as a red solid. 1H NMR (400 MHz, CDClg) b 7.4 WO 99/62520 PCTlUS99/12093 (m, 5H), 7.2 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.75 (m, 1H), 5.10 (s, 2H), 4.5 (bs, 1H), 4.0 (t, J=6.4 Hz, 2H), 3.95 (s, 3H), 3.13 (m, 2H), 1.8 (m, 2H), 1.5 (m, 6H), 1.45 (s, 9H), 1.4 (m, 2H).
SteR 3_; 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylaminohexyloxy) ghenvll 2,4- ioxo-butanoic acid AII-6-1 O O
0 ~ OH
I I

N O

In a manner similar to that described for AI-2-1, AII-5-1 was treated with NaOH to give I~ I-6-1 as a foamy yellow solid. 1H NMR (400 MHz, CDC13) 8 7.4 (m, 5H), 7.18 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 6.72 (s, 1H), 5.08 (s, 2H), 4.5 (bs, 1H), 4.0 (m, 2H), 3.13 (m, 2H), 1.8 (m, 2H), 1.6-1.3 (m, 17H.

4-(3-Benzylphenyl)-2,4-dioxobutanoic acid A-III-5-1 Step 1: (3 Bromophenyl)nhenvlmethanol AIII-1-1 Br OH
To an oven dried 500 ml 3-neck flask fitted with temperature probe, magnetic stir bar, and argon inlet was added a solution of 2.5M ~-butyl lithium in hexanes (20.8 ml, 0.052 mole) chilled to -78°C then diluted with diethyl ether (90 ml). To this was added dropwise by syringe over 30 minutes 1,3-dibromobenzene (11.80 g, 6.043 ml, 0.05 mole; activated basic _ 97_ alumina pretreatment) keeping the internal temperature between -74°C
and -78°C. The reaction was aged at -78°C for 2.5h before adding neat benzaldehyde (5.52 g, 5.29 ml, 0.052 mole) over 15 minutes then allowing the reaction mixture to slowly warm to room temperature as the bath discharged overnight. The reaction was quenched with 20 mL H20 then acidified with 5.4 ml cone. HCl and extracted with EtOAc three times.
The combined organic layers were washed with NaHC03, brine and dried over NaS04, filtered and evaporated in vacuo to give a clear yellow oil ~I~ -1-1 which crystallized to afford a white solid after washing with pet ether. Rf--0.14 (10% EtOAclHexanes). 1H NMR (300 MHz, CDC13) 8 7.56 (s, 1H), 7.36-7.40 (m, 3H), 7.32-7.35 (m, ~2H), 7.25-7.31 (m, 2H), 7.19 (m, 1H), 5.79 (s, 1H), 2.25 (s, 1H).
Ste~2_: ~3-Benzvl)phenyl bromide AIII-2-1 \ /

A solution of AIII-1-11-1 (4.10 g, 0.0156 mole) and triethylsilane (2.72 g, 3.71 ml, 0.0234 mole) in methylene chloride (40 ml) was chilled to 0°C under argon with stirring followed by addition of neat boron trifluoride etherate (3.32 g, 2.96 ml, 23.4 mmol). The reaction stirred at room temprature overnight. The reaction mixture was poured into 160 ml saturated NaHC03 and extracted with EtOAc three times, the combined organic layers were washed with brine and dried over Na2S04, filtered and evaporated to afford colorless oil. Chromatographic purification using 5% EtOAc/hexanes afforded pure II- -1; RF=0.44 (5% EtOAc/Hexanes) 1H NMR (400 MHz, CDCl3) S 7.27-7.33 (in, 4H), 7.09-7.23 (m, 5H),3.93 (s, 2H).
Step 3: 1-(3-Benzylphenyl)ethanone AIII-3-1 _ 98_ WO 99/62520 PC'T/US99/12093 i O
To an oven-dried 100 ml 3-neck flask fitted with temperature probe, magnetic stir bar, and argon inlet was added 1.10 g AI I2- in 26 ml THF and cooled to -78°C. Following dropwise addition of 1.6 M ~-butyl lithium in hexanes (4.90 ml, 49 mmole) over 15 minutes, the reaction was stirred for 1h at -78°C before adding neat N-methoxy-N-methylacetamide (551 mg, 53.4 mmole) over 20 minutes. The reaction mixture warmed slowly to room temperature as the bath discharged overnight. The reaction was quenched with 60 ml 10% KHS04 and extracted with Et20 three times. The combined organic layers were washed with NaHC03, brine and dried over Na2S04, filtered and evaporated in vacuo to give a clear yellow oil. Chromatographic purification using EtOAcJhexanes afforded pure_ III-3~= Rf--0.10 (5%
EtOAclhexanes); 0.40 (30 acetone, 70 hexane, 1.5 HOAc); 1H NMR (400 MHz, CDC13) 8 7.80 (m, 2H), 7.39 (m, 2H),7.29 (m, 2H), 7.19 (m, 3H), 4.05 (s, 2H), 2.6 (s, 3H).
Step 4: 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid methyl ester O

2p O O
To an oven dried 100 ml flask fitted with magnetic stir bar, and argon inlet was added freshly prepared NaOMe (485 mg, 9.2 mmole) in 10 ml toluene and cooled to 0°C. Dimethyl oxalate (951 mg, 8.1 mmole) and III- -1 (770 mg) were dissolved in dry dimethoxyethane (10 ml) and added by syringe at 0°C over 5 minutes. The flask was removed from ice bath and heated to 60°C overnight. The reaction was quenched with 60 ml saturated NH4Cl and extracted with EtOAc three times. The WO 99/62520 PC'TNS99/12093 combined organic layers were washed with H20, brine and dried over Na2S04, filtered and evaporated in vacuo to give an orange oil I-4-1.
Rf=0.26 (30 acetone, 70 hexane + 1.5 HOAc); 1H NMR (400 MHz, CDC13) 8 7.83 (m, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 7.18 (m, 2H), 7.16 (s, 1H), 4.04 (s, 2H) 3.90 (m, 3H).
Step 5: ~- -Benzy~nhenyl)-2,4-dioxobutar.~oic acid AIII-5-1 O
\ I AIII- -1 \ OH
O O
A solution of AIII-4-1 (900 mg, 2.9 mmole) was dissolved in 1:1 THF /
MeOH (20 ml) and treated with 1 N NaOH (14.6 mL, 0.0146 mole) and stirred lh. The reaction mixture was extracted with diethyl ether (2X), then acidified to pH 1-2 with 2N HCl (7.5 ml) and extracted three times with EtOAc. The organic layers were combined, washed with H20, brine and dried over Na2S04, filtered and evaporated to afford a waxy solid. The residue was recrystallized from toluene-hexane to give a light yellow solid AIII-5-15-1. mp 118-119°C (uncorrected). Rf--0.12 (5 MeOH, CH2C12, 5 HOAc). 1H NMR (400 MHz, CDC13) 8 7.84 (m, 2H), 7.45 (m, 2H), 7.31 (m, 2H), 7.24 (m, 1H), 7.18 (m, 2H), 7.14 (s, 1H), 4.06 (s, 2H).
mass spec (FAB, M+1) 283 m/e In a manner similar to that described for AIII-5-15-1, the following compound was prepared:
O
C I ~ O H AITI5-25-2 O O
mp 102-103°C (uncorrected). Rf-__0.18 (5 MeOH, 95 CH2C12, 5 HOAc) 1H NMR {400 MHz, CDC13) 8 7.85 (m, 2H), 7.44 (m, 2H), 7.25 (m, 2H), 7.15 (m, 2H), 7.06 (m, 1H), 4.03 (s, 2H). mass spec (FAB, M+1) 317 m/e 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid AIV-3-1 Step 1: 1-(4-Dibenzvlaminophenvl)ethanone AIV-1-1 N
/ I /
O

A mixture of 4-aminoacetophenone (.027 g, 2 mmol), benzyl bromide (1.71 g, .19 ml, 10 mmol), and cesium carbonate (1.63 g, 5 mmol) were combined in 20 ml DMF and heated to 60 oC for 8 hr. The solvent was then removed and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexanelEtOAc) yielded 0.238 g (38%) of AIV-1-11-1 as a clear oil. 1H NMR (400 MHz, CDClg) 8 2.51 {s, 3H), 4.76 (s, 4H), 6.77 (d, 2H, J = 8.97 Hz), 7.26 (d, 4H, J = 6.96 Hz), 7.32 (t, 2H, J =
7.14 Hz), 7.37 (t, 4H, J = 7.51 Hz), 7.86 (d, 2H, J = 9.16 Hz).
Step 2: 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester AIV-2-1 \
\ O
OEt O O

In a similar manner to example AI-1-1, 1-(4-dibenzylaminophenyl)-ethanone (0.238 g, 0.75 mmol) was reacted with diethyl oxalate (0.22 g, 0.2 ml, 1.5 mmol) and sodium ethoxide (0.1 g, 1.5 mmol) in 3 ml THF to yield 0.29 g (93%) of AIV-2_~ as a yellow solid. 1H NMR (400 MHz, CDC13) 81.39 (t, 3H, J = 7.14 Hz), 4.36 (q, 2H, J = 7.14 Hz), 4.75 (s, 4H), 6.77 (d, 2H, J = 9.15 Hz), 6.95 (s, 1H), 7.21 (d, 4H, J = 6.96 Hz), 7.29 (t, 2H, J
= 6.95 Hz), 7.35 (t, 4H, J = 7.69 Hz), 7.86 (d, 2H, J = 9.15 Hz).
step 3: ~-(4-Dibenzy~aminoRhe~vl)-2,4-dioxobutanoic acid AIV-3-1 \ O
OH
O O

In a manner similar to example AI-2-1, 4-(4-dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester (0.29 g, 0.7 mmol) was hydrolyzed using 0.58 ml l~j LiOH in 5 ml THF to afford 0.237 g (87%) of AIV-3-13-1 as an orange solid. MP = 161- 162 oC. 1H NMR (400 MHz, CDC13) 8 4.76 (s, 4H), 6.79 (d, 2H, J = 9.34 Hz), 6.99 (s, 1H), 7.20 (d, 4H, J = 6.78 Hz), 7.30 (t, 2H, J = 7.14 Hz), 7.35 (t, 4H, J = 7.33 Hz), 7.86 (d, 2H, J = 9.15 Hz).

4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid AV-3-1 to 1: 1-O3-Di enzylamino ,~henyl)ethanone AV-1-1 \
N
\ O

In a similar manner to example AIV-1-1, 3-aminoacetophenone (0.27 g, 2 mmol) was reacted with benzyl bromide (1.71 g, 1.19 ml, 10 mmol) and cesium carbonate (1.63 g, 5 mmol) in 20 ml DMF at 60oC for 4 hr to give 0.346 g (55%) of AV1-11-1 as a clear oil after purification by radial disc chromatography (4:1 hexane/CH2C12). 1H NMR (400 MHz, CDCl3) 8 2.44 (s, 3H), 4.66 (s, 4H), 6.88 (ddd, 1H, J = 8.06, 2.75, 1.10 Hz), 7.18 - 7.26 (m, 7H), 7.26 - 7.33 (m, 3H), 7.37 (dd, 1H, J = 2.74, 1.47 Hz).
SteR2_: 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester AV-2-1 \ O
N ~ OEt \ O O

In a manner similar to example AIV-1-1, 1-(3-dibenzylaminophenyl)-ethanone (0.346 g, 1.1 mmol) was reacted with diethyl oxalate (0.32 g, 0.3 ml, 2.2 mmol) and sodium ethoxide (0.15 g, 2.2 mmol) in 5 ml THF for 1 hr to give 0.48 g (100%) of AV-2-1 as a yellow oil. 1H NMR (400 MHz, CDC13) 81.37 (t, 3H, J = 7.14 Hz), 4.37 (q, 2H, J = 7.14 Hz), 4.71 (s, 4H), WO 99/62520 PC"T/US99/12093 6.93 (s, 1H), 6.95 (dd, 1H, J = 2.75, 1.47 Hz), 7.21- 7.30 (m, 7H), 7.30 -7.36 (m, 4H), 7.37 - 7.41 (m, 1H).
Step 3: 4-(3-DibenzvlaminoBhen3rl)-2.4-dioxobutanoic acid AV-3-1 O
N ~ OH
O O

In a similar manner to example AI-2-1, 4-(3-dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester (0.489 g, 1.1 mmol) was reacted with 3 ml l.~T LiOH in 10 ml THF to yield 0.4 g (94%) of V-3-1 as an orange resin.
1H NMR (400 MHz, CDC13) 8 4.71 (s, 4H), 6.96 (dt, 1H, J = 7.33, 2.20 Hz).

1-(3-benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid AVI-3-1 Step 1: 1-(3-Benzvloxv-5-methoxyphen-yl)-ethanone AVI-1-1 To a solution of 5-hydroxy-3-benzyloxyacetophenone (740 mg, 3.06 mmol) in DMF (10 mL) was added K2C03 (845 mg, 6.12 mmol) followed by methyl iodide (0.38 mL, 6.10 mmol). After stirring at rt for 3 h, the reaction mixture was poured onto water (20 mL) and extracted with Et20 (3 x 20 mL). The combined organic extracts were washed with water (20 mL), sat. NaCI (20 mL) and dried (MgS04). Concentration WO 99/b2520 PCT/US99/12093 followed by medium-pressure liquid chromatography on silica gel, eluting with 9:1/hexanes:EtOAc, afforded 0.550 g (70%) of product as a clear oil. 1H NMR (400 MHz, CDC13) 8 7.45-7.33 (m, 5H), 7.18 (t, J = 1.6 Hz, 1H), 7.11 (t, J = 1.4 Hz, 1H), 6.74 (t, J = 2.2 Hz, 1H), 5.09 (s, 2H), 3.83 (s, 3H), 2.57 (s, 3H). mass spec (EI, M+) 256 Step 2: 1-(3-Benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid H

AI-1-1 was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous HCI in dioxane to give AVI-3-1. mp 101-102 °C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 7.48-7.44 (m, 2H), 7.39 (m, 2H), 7.34 (m, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 5.19 (s, 2H), 3.81 (s, 3H). mass spec (FAB, M+H) 329 1-(3-Benzyloxyphenyl)-2,4-dioxobutanoic acid AVI-3-2 Step l: 1-(3-Benzvloxyphenvl)-ethanone AVI-1-2 O
/

To a solution of benzyl alcohol (Aldrich, 1.08 g, 10.0 mmol) in benzene (40 mL) at rt was added 3-hydroxyacetophenone (Aldrich, 1.36 g, 10.0 mmol) followed by PPh3 (2.62 g, 10.0 mmol). After cooling to 0 °C, DEAD (1.60 mL, 10.0 mmol) was added and the resulting mixture was stirred at rt.
After 4 h, the reaction mixture was poured onto hexanes (50 mL) and filtered through a pad of CELITE diatomaceous earth. The filtrate was concentrated and chromatographed on silica gel, eluting with 9:1/hexanes:EtOAc, to provide 2.01 g (89%) of product as a clear oil. 1H
NMR (400 MHz, CDC13) 8 7.60-7.54 (m, 2H), 7.47-7.32 (m, 6H), 7.21-7.17 (m, 1H), 5.12 (s, 2H), 2.59 (s, 3H). mass spec (EI, M+) 226 Ste~2: 1-(3-Benzyloxyphen3il)-2.4-dioxobutanoic acid AVI-3-2 / O \ OH
I
/ O

AVI-1-2 was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous HCl in dioxane to give AVI-3-2.
mp 109-114 °C (uncorrected) 1H NMR (400 MHz, d6_DMSO) b 7.66 (dt, J =
1.4, 8.0 Hz, 1H), 7.63 (dd, J = 1.8, 2.3 Hz, 1H), 7.52-7.47 (m, 3H), 7.43-7.38 (m, 2H), 7.09 (s, 1H), 5.22 (s, 2H).

1-(2-Benzyloxyphenyl)-2,4-dioxobutanoic acid AVI-3-3 / ~O O O
\ I \ OH
/ . O

2-benzyloxyacetophenone (Chew Service) was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous HCl in dioxane to give AVI-3-3. mp I36-138 °C (uncorrected). 1H
NMR
(400 MHz, d6-DMSO) 8 7.81 (dd, J = 1.8, 8.4 Hz, 1H), 7.62 (ddd, J = 1.8, 7.4, 8.4 Hz, 1H), 7.52 (m, 1H), 7.41-7.31 (m, 4H), 7.27 (s, 1H), 7.12 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H). mass spec (FAB, M+H) 299 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-3-5 tS~l: 1-f3-(4-Fluorobenzyloxv)Qhenvll-ethanone AVI-1-5 F ~ O
/ O
\ w /

To a solution of 3-hydroxyacetophenone (Aldrich, 680 mg, 5.00 mmol) in DMF (10 mL) at rt was added K2C03 (1.38 g, 10.0 mmol) and 4-fluorobenzyl bromide (897 mg, 4.75 mmol). After 3 h, the reaction mixture was poured onto water (20 mL) and extracted with Et20 (3 x 25 mL). The combined organic extracts were washed with 2.5 N NaOH (25 mL), sat. NaCl (25 mL) and dried (MgS04). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 9:1/hexanes:EtOAc, yielded 1.08 g (93%) of product as a clear oil. 1H
NMR (400 MHz, CDC13) 8 7.58-7.55 (m, 2H), 7.44-7.36 (m, 3H), 7.19-7.15 (m, 1H), 7.09 (m, 2H), 5.08 (s, 2H), 2.60 {s, 3H). mass spec (EI, M+) 244 Step 2: 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-F \
O \ OH
/ O

AVI-1-5 was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous HCl in dioxane to give AVI-3-5.
mp 157-158 °C (uncorrected) 1H NMR (400 MHz, dg-DMSO) 8 7.66 (d, J =
7.7 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.56-7.47 (m, 4H), 7.33 (dd, J = 1.9, 7.7 Hz, 1H), 7.23 (m, 2H), 7.08 (s, 1H), 5.20 (s, 2H). mass spec (FAB, M+H) 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-3-6 Step 1: 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid F
O O
F / O ~ OH
II
O

AVI-3-6 was prepared in a manner similar to that described for AVI-3-5 by replacing 4-fluorobenzyl bromide with 3,4-difluorobenzyl bromide.
mp 181-182 °C (uncorrected). 1H NMR (400 MHz, dg-DMSO) 8 7.68 (d, J =
7.7 Hz, 1H), 7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.53-7.43 (m, 2H), 7.36-7.33 (m, 2H), 7.09 (s, 1H), 5.21 (s, 2H). mass spec (negative mode electro-spray, M-H) 333 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid E1 to 1: (3-bromo-phenvl)-(5-methvl-thiophen-2-vl)-methanol E1-A
'S~ ~ v ~Br To an oven dried 3-neck 250 mL round bottom flask equipped with argon inlet and digital thermometer was added 2.5M nBuLi in hexanes (15.24 mL, 0.0381 mole) at -78°C. 1,3-Dibromobenzene (4.60 mL, 0.0381 mole) was then added dropwise via syringe to the solution, and this was allowed to stir for 2 hours. 5-methyl-2-thiophenecarboxaldehyde (5g, 4.27mL, 0.0396 mole) was added over one hour. After an additional hour, 50 mL of water was poured into the reaction which was then acidified with conc. HCl. Extraction with EtOAc three times followed by drying over NaS04, filtration and removal of solvent gave E1-AA as a brown oil that was taken on to the next step.
a 2: 2-(3-bromobenzyl)-5-methvlthio~hene E1-B

S Br A solution of crude ~1-A (7.0 g, 0.0247 mole) and triethylsilane (5.9 mL, 0.0371 mole) in methylene chloride (30 mL) was chilled to O° C under argon with stirnng followed by addition of boron trifluoride etherate (4.67 mL, 0.0371 mole). The reaction was stirred at room temperature for two hours. The reaction mixture was poured into 150 mL of saturated sodium bicarbonate and extracted with methylene chloride 2 times. The combined organic layers were dried over sodium sulfate. Filtration and removal of solvent afforded a brown oil. Chromatographic purification using 100% hexanes afforded _E~B as a clear oil.
Rf--0.52 (100% Hexanes) 1H NMR (400MHz, CDC13 ) 8 7.37-7.38 (m, 1H), 7.33-7.34 (m, 1H), 7.16 (s, 1H), 7.14-7.15 {m, 1H), 6.56 (m, 7.56), 4.02 (s, 2H), 2.41 (s, 3H).
Ste .~3: I-f 3-(5-methvlthiophen-2-vlmeth~phenvll-ethanone E 1-C
S

To an oven dried 3-neck flask fitted with temperature probe and argon inlet was added 1E~- (4 g, 0.0150 mole) in 40 mL of THF. The reaction was cooled to -78°C and 2.5M nBuLi in hexanes (9.OmL 0.0225 mole) was added over one hour. The lithium salt of compound precipitated out of solution. Neat N-methoxy-N-methylacetamide (2.3g, 2.3mL .0225 mole) was added slowly which caused rxn to become homogenous. Once addition was complete the reaction was allowed to stir at room temperture for two hours. The reaction was poured into 20 mL of water and acidified with concentrated HCl. Extraction with EtOAc three times followed by drying over sodium sulfate, and subsequent removal of solvent gave a brown oil. Chromatographic purification using a 88:12 mixture of Hexanes/EtOAc afforded E1-C as a clear oil.

Rf--0.42 (10% EtOAclHexanes) 1H NMR (400MHz, CDCl3 ) 8 7.84 (s, 1H), 7.82,7.80 (d, 1H), 7.37-7.45 (m, 2H), 6.58-6.55 (m, 2H), 4.12 (s, 2H), 2.58 (s, 3H), 2.41 (s, 3H).
Step 4: 4-[3-(5-methylthiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid E 1 To a solution of E1-CC (lg, 0.00446 mole) and diethyloxylate (0.67mL, 0.00491 mole) in THF (8mL) was added NaOEt (0.46g, 0.00669 mole) under an atmosphere of Argon. After two hours the reaction was poured into an aqueous solution of potassium hydrogen sulfate, extracted with EtOAc three times, dried over sodium sulfate, and the solvent removed to give the ethyl ester. Immediately following workup the ester was submitted to 3N NaOH (7.4 mL, 0.0223 mole) in a 5:2 mixture of THFlMeOH (20 mL). After one hour the reaction was poured into saturated sodium bicarbonate solution and extracted two times with ether. The aqueous layer was acidified with a solution of 10% KHS04 which caused a large amount of solids to crash out. The aqeuous layer was extracted with EtOAc eight times, the organic layer was dried over NaS04, filtered and concentrated to give a solid which was crystallized from CH2C12 and pet. ether. Collected pure ~ as a yellow solid by filtration. 1H NMR (400MHz, CDC13 ) 8 7.88-7.85 (m, 2H), 7.50-7.44 (m, 2H), 7.15 (s, 1H), 6.60-6.57 (m, 2H), 4.14 (s, 2H), 2.42, (s, 3H). Exact mass (M +NH4) = 320.0951.

4-(3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid E2 Sten 1:1: S3-bromo-benzvl) ~henvl-amine E2-A

/
N \
Br To a solution of aniline (1.268. 1.23 mL, 0.0135 mole) and 3-bromo-benzaldehyde (2.5g, 1.58 mL, 0.0135 mole) in MeOH (20mL) under argon was added HOAc to adjust pH to 5.5. After 45 minutes sodium cyanoborohydride (1.11g, 0.0176 mole) was added and pH readjusted to 5.5. After 16 hours the reaction was poured into saturated aqueous sodium bicarbonate solution, extracted 3 times with EtOAc, dried over NaS04, filtered and concentrated. Chromatographic purification with 95:5 Hexanes/EtOAc afforded E2-AA as an oil.
Rf-__0.28 (5% EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) 8 7.52 (s, 1H), 7.40-7.38 (d, 1H, j=7.33 Hz), 7.28, 7.30 (d, 1H, j=7.69 Hz), 7.21-7.14 (m, 3H), 6.75-6.71 (t, 1H, j=7.42 Hz), 6.62-6.59 (d, 2H, j=7.87 Hz) 4.31 (s, 2H), 4.06 (broad, 1H).
Step 2: (3-bromo-benzvl)-methyl-phenyl-amine E2-B
/
\ N \
Br To a solution of E2-AA (1.5 g, 0.00572 mole) in DMF (25 mL) and under argon at O°C was added NaH {0.15 g, 0.00629 mole) and this was stirred for 15 minutes followed by addition of iodomethane (0.40 mL, 0.00629 mole) which was passed through basic alu.mina. Reaction required an additional 1 equivalent each of NaH and iodomethane. After 24 hours poured into 50 mL of saturated sodium bicarbonate solution, extracted with EtOAc 3 times, dried over sodium sulfate, filtered, and concentrated. Chromatographic purification using 90:10 Hexanes/Ethyl acetate afforded E2-B.B.

Rf--0.45 (5% EtOAclHexanes) 1H NMR (400MHz, CDCl3 ) S 7.40-7.36 (m, 2H), 7.26-7.15 (m, 4H), 6.76-6.72 (m, 3H), 4.49 (s,2H), 3.02 (s, 3H).
1-(3-((methyl phenyl-amino)-methvT- henvll-ethanone E2-C
\ N \
/ O

Product from E2-B ( 1 g, 0.00361 mole), triethylamine (2mL, 0.0144 mole), thallium acetate (1.05g, 0.00937 mole), palladium acetate (0.2g, 0.000903 mole), butyl vinyl ether (1.81 mL, 0.0181 mole), and 1,3-Bis(diphenyl-phosphino)-propane (0.4g, 0.000975 mole) were combined in a pressure tube in anhydrous DMF (8 mL) under argon at 100°C overnight. Passed mixture through a pad of CELITE diatomaceous earth which was washed several times with EtOAc. Solvent was then removed and the residue dissolved in THF to which 1N HCl was added (14 mL, 0.0144 mole). After one hour poured into 20 mL of saturated sodium bicarbonate solution and extraced with EtOAc dried over NaS04 , filtered and concentrated. Chromatographic purification with 80:20 Hexanes/EtOAc afforded purified E2-C.C.
Rf_- 0.29 (10% EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) S 7.91-7.87 (m, 2H), 7.48-7.44 (m, 2H), 7.3-7.25 (m, 2H), 6.82-6.76 (m, 3H), 4.61 (s, 2H), 3.07 (s, 3H), 2.61 (s, 3H.
Step 4: 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl?-2,4-dioxo-butvric acid E2 \ N \ ( C02H
O O

To a solution of (0.4 g, 0.00167 mole) and dimethyloxylate (0.22g 0.00184 mole) in THF (5mL) was added NaOMe (0.4g, 0.00334 mole) under an atmosphere of Argon. After two hours the reaction was poured into an aqueous solution of potassium hydrogen sulfate, extracted with EtOAc three times, dried over sodium sulfate, and the solvent removed to give the methyl ester. Immediately following workup the ester was submitted to 1N NaOH (7.0 mL, 0.00167 mole) in THF (20 mL). After 1 hour the reaction was poured into saturated sodium bicarbonate solution and extracted two times with ether. The aqeuous was with 3N HCl, extracted with EtOAc three times, and the organic layers dried over NaS04, filtered and concentrated to give solid pure ~.
1H NMR (400MHz, CDC13 ) 8 7.91-7.81 (m, 2H), 7.48-7.44 (m, 2H), 7.28-7.22 (m, 2H), 7.16 (s, 1H), 6.81-6.77 (m, 3H), 4.59 (s, 2H), 3.09 (s, 3H).
Exact mass found (m+H) = 312.1230.

4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid E3 Step 1: (3.5-dibromo-phenyl)-phenyl-methanol E3-A
r \ /
Br To a solution of 1,3,5-tribromobenzene (10 g, 0.0318 mole) in ether (500g), under argon was added nBuLi in hexanes (13.4 mL, 0.0318 mole) dropwise at -78°C. During the intial cooling of the tribrombenzene in ether some solids crashed out of solution. After addition of nBuLi was complete the reaction was allowed to stir for 0.5 hours at which time neat benzaldehyde (3.55 mL, 0.035 mole) was added dropwise to the vigorously stirred reaction mixture. Once addition was complete the reaction was allowed to reach 0°C and 100 mL of HCl was added to the mixture. This was extracted with ether two times, dried with brine and over sodium sulfate and concentrated to give an oil. The crude product was purified by chromatography with 5% EtOAc/Hexanes to afford E3-AA
as a colorless oil that solidified on the bench. Rf = 0.44 (5%EtOAc/Hexanes) 1H NMR (400MHz, CDCl3 ) b 7.56-7.55 (m, 1H), 7.48-7.47 (m, 2H), 7.39-7.29 (m, 5H), 5.75 (d, 1H, j=3.48 Hz), 2.28-2.27 (d, 1H, j=3.48 Hz).
Step 2: 3-bromo-5-ben~vl-bromobenzene E3-B
Br Br E3-B
A solution of E3-AA (2.0 g, 0.00548 mole) and triethylsilane ( 1.39 mL, 0.00877 mole) in methylene chloride (20 mL) was chilled to O° C under argon with stirring followed by addition of boron trifluoride etherate ( 1.10 mL, 0.00877 mole). The reaction was stirred at room temperature overnight. The reaction mixture was poured into 75 mL of saturated sodium bicarbonate and extracted with methylene chloride two times.
The combined organic layers were dried over sodium sulfate, filtered and the solvent removed. Chromatographic purification using 1%
EtOAc/Hexanes afforded E3B. Rf--0.72 (5%EtOAcJhexanes) 1H NMR
(400MHz, CDC13 ) 8 7.50 (s, 1H), 7.37-7.21 (m, 5H), 7.16-7.14 (m, 2H), 3.91 (s, 2H).
step 3: 2-(3-benzvl-5-bromo- hen~~vrazine E3-C
Br E3-C
To a solution of~-B (1 g, 0.00307 mole) in THF (20 mL) under argon at -78°C was added 2.4M nBuLi in hexanes (1.4 mL, 0.00337 mole) dropwise. After 45 minutes of stirring, the solution was treated with 0.5m ZnCl2 in THF (6.14 mL 0.00337 mole) and this was warmed to 0°C.
To the reaction was added a cold mixture of chloropyrazine (0.35 mL, 0.00307 mole) and tetrakistriphenylphosphine palladium (18 mg, 0.0000154 mole) in THF (5 mL) and the reaction was heated to reflux for two hours. The reaction was then cooled, concentrated and treated with EtOAc and washed with 6% aqueous solution of diaminotetraacetic acid disodium salt dihydrate two times. The EtOAc layer was dried over sodium sulfate, filtered and concentrated. Chromatographic purification with 15% EtOAc/hexanes afforded a clear oil E3-C. Rf--0.17 (20%EtOAc/hexanes) 1H NMR (400MHz, CDC13 ) b 8.95 (s, 1 H), 8.62-8.61 (m, 1H), 8.52 (m, 1H), 8.02 (s, 1H), 7.77 (s, 1H), ?.43 (s, 1H), 7.32-?.20 (m, 5H), 4.04 (s, 2H).
Ste~4: 1-(3-benz~~l-5-pvrazin-2 yl-nhenvl)-ethanone E3-D
O h3-DD
E3-CC (0.29 g g, 0.000926 mole), triethylamine (0.52mL, 0.00370 mole), thallium acetate (0.27 g, 0.00102 mole), palladium acetate (52 mg, 0.000232 mole), butyl vinyl ether (0.60 mL, 0.00463 mole), and 1,3-bis(diphenylphosphino)-propane (0.1g, 0.000242 mole) were combined in a pressure tube in anhydrous DMF (4 mL) under argon at 100°C
overnight. The mixture was passed through a pad of CELITE
diatomaceous earth which was washed several times with EtOAc. The solvent was then removed and the residue dissolved in THF to which 1N
HCl was added (3.70 mL, 0.00370 mole). After one hour the reaction was poured into 15 mL of saturated sodium bicarbonate solution and extraced with EtOAc. The organic layers were dried over NaS04, filtered and concentrated. Chromatographic purification with 70:30 Hexanes/EtOAc afforded purified E3-DD as a clear oil. Rf-__ 1H NMR (400MHz, CDC13 ) 8 9.04 (s, 1H), 8.65-8.64 (m, 1H), 8.55-8.54 (m, 1H), 8.44 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.33-7.22 (m, 5H), 4.14 (s, 2H), 2.65 (s, 3H).
Step 5: 4-(3-benzvl-5-nvrazin-2-vl-phenvl)-2 4-dioxo-b Lyric acid E3 O O
To a solution of E3-DD (0.17 g, 0.000590 mole) and dimethyloxylate (76 mg 0.000650 mole) in THF (7mL) was added NaOMe (50 mg, 0.000884 mole) under an atmosphere of Argon. After one hour the reaction was poured into an aqueous solution of potassium hydrogen sulfate, extracted with EtOAc three times, dried over sodium sulfate, and the solvent removed to give the methyl ester. Immediately following workup the ester was submitted to 1N NaOH ( 1.48 mL, 0.00148 mole) in THF (10. mL). After 1 hour the reaction was poured into saturated sodium bicarbonate solution and extracted three times with ether. The aqueous layer was acidified with 3N HCl, extracted with EtOAc three times, the organic layers were dried over NaS04, filtered and concentrated to give E3 as a pure white solid. 1H NMR (400MHz, DMSO ) 8 9.41 (m, 1H), 8.76-8.75 (m, 1H), 8.67 (m, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.36-7.29 (m, 4H), 7.22-7.19 (m, 2H), 4.17 (s, 2H). Exact mass found (m+H) = 361.1196 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid (isomers A and B) (G1 and G2) \ / O
/ \
-OH
O O
Step 1: Synthesis of. l-(3-bramo henyl)-1~2 3~4-tetrahvdronaphthalen-1-of / \
Br 'OH
To a solution of 1 g (4.2 mmol) 1,3-dibromobenzene in 10 mL
diethyl ether was added .096 g (4 mmol) magnesium metal turnings.
This mixture was stirred until all of the magnesium was consumed, at which time .29 g (2 mmol) 1-tetralone was added dropwise in 2 mL
diethyl ether. The reaction was then heated to reflex for 30 min, after which the cooled reaction was quenched with a 10% HCl solution and extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in uacuo to afford the crude product which was used without further purification.
Step 2. Synthesis of 1-(3-bromophenyl)-1,2,3,4-tetrahydronaphthalene and 4-(3-bromophenvl)-1.2-dihvdronaphthalene.
/ \ / \
Br ~ -Br 'H
Into an ice cooled solution of .671 g (2.2 mmol) of 1-(3-bromophenyl)-1,2,3,4-tetrahydronaphthalen-1-of and and .386 g (3.3 mmol) triethylsilane in 5 mL methylene chloride was added .471 g (3.3 mmol) boron trifluoride diethyl etherate dropwise. After stirring the reaction for 6 hr, the solution was slowly poured into 10 mL 10% sodium carbonate solution and extracted three times with methylene chloride.
The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo.
Purification by radial chromatography (5:1 hexane/ethyl acetate) followed by a second purification (7:1 hexane/methylene chloride) a 2.5:1 mixture of 1-(3-bromophenyl)-1,2,3,4-tetrahydronaphthalene and 4-(3-bromophenyl)-1,2-dihydronaphthalene which was used without further purification.
Step 3. Synthesis of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone and 1-f3-(1.2-dihvdronaphthalen-1-vl)-phenvll-ethanone / \ / \
''Z H ~O ~O
To a solution of .276 g of the above mixture dissolved in 10 mL of a 1:1 mixture of diethyl ether/tetrahydrofuran and cooled to -76oC was slowly added .42 mL of a 2.5M solution of n-butyllithium in hexanes so the temperature did not exceed -70 oC. After the addition, the reaction was stirred for an addition 30 min, after which time .118 mL N-methoxy-N
methyl acetamide was added. This mixture was allowed to stir for 15 min, then warmed to ambient temperature and stirred for 18 hr. The reaction was then quenched by the addition of 50 mL water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in vacuo. Subsequent purification by preparative HPLC afforded three compounds: the olefin, enantiomer A
and enantiomer B. The absolute stereochemistry of the enantiomers was not determined.
Step 4: Synthesis of 2,4-dioxo-4-[3-( 1,2,3,4-tetrahydronaphthalen-1-yl~-~henvllbu~iric acid ethvl ester (isomers A and B) / O
/ ~ _ /~
H v ~ ~ O
O O
Isomer A: Into 1 mL distilled tetrahydrofuran was placed .046 g (.18 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer A), .054 g (.37 mmol) diethyl oxalate, and .025 g (.37 mmol) sodium ethoxide. After stirring for 1.5 hr, excess 10% citric acid solution was added and the THF removed in aczcuo. The residue was partitioned between water and ethyl acetate and extracted. The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and the solvent removed in va~cuo to afford the title compound which was used without further purification.
Isomer B: As described above, .048 g (.19 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer B), .056 g (.38 mmol) diethyl oxalate, and .026 g (.38 mmol) sodium ethoxide were reacted to give the title compound which was used without further purification.
Step 5: Synthesis of 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-~)-phenvllbutyric acid (isomers A and B) Isomer A: 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid ethyl ester (isomer A from above) was dissolved in 2 mLs methanol, and to it was added 1 mL of a 1M solution of sodium hydroxide in water. After stirring for 4hr, the reaction was poured into 5 mL sodium hydroxide and extracted three times with diethyl ether. The aqueous layer was then acidified via the addition of excess 10% citric acid and extracted three times with ethyl acetate. The ethyl acetate extracts were combined and washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the solvent removed in uacuo.
The residue was triturated in 3:1 hexane/diethyl ether, filtered and the solvent removed in uacuo to yield the title compound as a yellow solid.
1H NMR (CDC13) 81.72 - 1.91(3H,m), 2.20(lH,m), 2.80 - 3.00(2H,m), 4.22(1H, t, J=7.14Hz), 6.77(1H, d, J=7.69Hz), 7.03(1H, t, J=7.42Hz), 7.11-?.19(3H,m), 7.31(1H, d, J=7.69Hz), 7.41(1H, t, J=7.69Hz), 7.80(lH,s), 7.84( 1H, d, J=7.88Hz) CHN Calc. (C2pH1804~.lEtOAc) 73.98, 5.72; Fnd. 73.68, 6.04 . 5 Isomer B: In a similar manner to the above, 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid ethyl ester (isomer B from above) was reacted in 2 mL methanol with 1 mL 1M
sodium hydroxide to afford the title compound as a yellow solid.
1H NMR (CDC13) b 1.72 - 1.91(3H,m), 2.20(lH,m), 2.80 - 3.00(2H,m), 4.22(1H, t, J=7.14Hz), 6.77(1H, d, J=7.69Hz), 7.03(1H, t, J=7.42Hz), 7.11-7.19(3H,m), 7.31(1H, d, J=7.69Hz), 7.41(1H, t, J=7.69Hz), 7.80(lH,s), 7.84( 1H, d, J=7.88Hz) CHN Calc. (C2pH1804~.lEtOAc) 73.98, 5.72; Fnd. 73.68, 5.90 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid L1 Ste~l: 1-(3-Phenvlsulfanyl-nhenvl)-ethanone L1-A
\ \

A mixture of potassium carbonate (1.20 g, 9.08 mmol), 0.17 M Ni(II)Br2 (2.12 mL, 0.36 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 403 mg, 0.73 mmol), zinc powder ( 119 mg, 1.82 mmol), and N -methyl-2-pyrrolidinone (NMP, 10 mL) was stirred at room temperature for one hour in dried glassware under argon. Thiophenol (932 ~L, 9.08 mmol) and 3'-iodoacetophenone (1.88 mL, 13.6 mmol) were then introduced and the mixture was stirred for three hours. The resulting mixture was directly chromatographed using 5 % EtOAc / hexane as the elutant.
Pure fractions were combined and concentrated to afford ,~1-~ as a yellow oil. Rf = 0.49 (10% EtOAc / hexane). 1H NMR (400 MHz, CDC13) 8 7.89 (m, 1H), 7.79 (m, 1H), 7.56 (m, 1H), 7.29-7.40 (m, 6H), 2.58 (s, 3H).
Ste~2: ~4-Dioxo-4-(3-nhenylsulfanyl-nhenvl)-butyric acid L1 \ ~ \ H
O

In a manner similar to example AIV-2-_l, 2,4-dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-13-1 using 1N NaOH to afford ~-1 as a yellow solid. Rf = 0.32 (6:6:94 MeOH / AcOH / CH2Cl2).
1H NMR (400 MHz, CDC13) 8 7.91 (m, 1H), 7.81 (m, 1H), 7.48 (m, 1H), 7.43 (m, 1H), 7.33-7.43 (m, 5H), 7.09 (s, 1H).
mass spec (FAB, M+1) 301 m/e.

4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid L2 1: 1-f3-(2.4-Difluoro-benzvl)-Rhen3~11-ethanone L2-A
\ \
(/ ~/

To an oven dried three-necked 100 mL round bottom flask fitted with argon inlet, temperature probe and stir bar was added zinc powder (793 mg, 12.2 mmol), 1,2-dibromoethane (21 ~L, 0.24 mmol), and THF (2 mL).
The mixture was brought to reflux two times using a heat gun then cooled to O°C at which time a-bromo-2,4-difluorotoluene (781 ~L, 6.10 mL) in THF (3 mL) was added slowly keeping the temperature < 3°C.
To another 3-necked round bottom flask fitted as above was added bis(dibenzylideneacetone)palladium (Pd(dba)2, 234 mg, 0.41 mmol), tris(2-furyl)phosphine (tfp, 189 mg, 0.81 mmol), and THF (5 mL). The mixture was stirred 10 minutes at room temperature then cooled to O°C
at which time 3'-iodoacetophenone (562 ~L, 4.06 mmol) in THF (1 mL) was added. The flask was flushed with argon and the zinc mixture was pipetted in. After stirring 5 minutes at 0°C, the reaction was left to stir over night at room temperature. The next morning the reaction was quenched with sat. NH4C1 solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated to a brown oil. The crude product was chromatographed on silica gel using 5% EtOAc / hexane as elutant. Pure product fractions were combined and concentrated to afford L2-AA as a yellow oil. Rf = 0.22 (5% EtOAc / hexane). 1H NMR (400 MHz, CDC13) 8 7.81 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.81 (m, 2H), 4.02 (s, 2H), 2.56 (s, 3H).
Step 2: 4-f3-(2.4-Difluoro-benz~uhenyl'~2,4-dioxo-butyric acid L2 H
F / ~ V

In a manner similar to example AI-, V-2-1, 4-[3-{2,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-13-1 using 1N NaOH to afford ~ as a yellow solid. Rf = 0.60 (6:6:94 MeOH / AcOH /
CH2C12). 1H NMR (400 MHz, CDC13) 8 7.85 (m, 2H), ?.45 (m, 2H), 7.13 (m, 2H), 6.82 (m, 2H), 4.03 (s, 2H). mass spec (FAB, M+1) 319 m/e.

4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid L3 Step 1: (3-Bromo-4,5-dimethoxy-phenyl)-(4-fluoro-phenyl)-methanol In a dried round bottom flask under argon, 1.0 M 4-fluorophenyl-magnesium bromide in THF (25.5 mL, 25.5 mmol) was slowly added to 5-bromoveratraldehyde (2.5 g, 10.2 mmol) in dry THF (150 mL) at 0°C. The resulting solution was stirred for 15 minutes then allowed to stir at room temperature for 2 hours. The solvent was then removed in Uaccuo and the residue was partitioned between 10 % KHS04 solution and EtOAc.
The aqueous layer was extracted three times with EtOAc and the combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated to a yellow oil. The crude product was taken on without further purification. 1H NMR (400 MHz, CDC13) 8 7.33 (m, 2H), 7.05 (m, 3H), 6.86 (m, 1H), 5.74 (s, 1H), 3.83 (s, 6H).
Step 2: Preparation of L3-B
s~
F

To (3-bromo-4,5-dimethoxy-phenyl)-(4-fluoro-phenyl)-methanol (2.95 g, 8.65 mmol) in dry CH2C12 at 0°C was added triethylsilane (3.54 mL, 22.2 mmol) and borontrifluoride diethyl etherate (2.27 mL, 22.2 mmol). The solution was allowed to stir overnight at room temperature. The solvent was then removed in vacuo and the residue was partitioned between sat.
NaHC03 solution and CH2C12. The aqueous layer was extracted three times with CH2C12 and the combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated to a clear oil. The crude product was chromatographed on silica gel using 10 % EtOAc /
hexane as the elutant. Collected and concentrated pure product fractions to give afford ~ as a clear oil. Rf = 0.41 (10 % EtOAc /
hexane). 1H NMR (400 MHz, CDC13) 8 7.13 (m, 2H), 6.97 (m, 3H), 6.62 (m, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H).
Step 3: 1-f5-(4-Fluoro-bent ly )-2,3-dimethox~phenvll-ethanone L3-C

F
w L3-C
In dried glassware under argon, slowly added 2.5 M n -BuLi in hexane to L~B_ (2.50 g, 7.69 mmol) in distilled THF (45 mL) at -78°C. Aged solution 10 minutes then added N -methoxy-N -methylacetamide (1.11 mL, 10.8 mmol) dropwise. The reaction was stirred for 30 minutes then allowed to slowly warm to room temperature over 2 hours. The reaction was quenched with sat. NH4Cl solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 5 % EtOAc / hexane as elutant. Collected and concentrated product fractions to afford ~3-C as a clear oil. Rf = 0.27 (10 % EtOAc / hexane).
1H NMR (400 MHz, CDC13) 8 7.12 (m, 2H), 7.05 (m, 1H), 6.97 (m, 2H), 6.80 (m, 1H), 3.90 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.61 (s, 3H).
Ste~4: 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid L3 In a manner similar to example AIV-2-1,, 4-[5-(4-fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-13-1 using 1N NaOH to afford ~ as a yellow solid. Rf = 0.67 (6:6:94 MeOH /
AcOH / CH2C12). 1H NMR (400 MHz, CDC13) b 7.38 (s, 1H), 7.25 (m, 1H), WO 99/62520 PC1'/US99/12093 7.14 (m, 2H), 7.00 (m, 2H), 6.88 (m, 1H), 3.94 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H). mass spec (FAB, M+1) 361 m/e.

4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid Wl ;gyp 1: (3-Bromo-4-fluorovl)phenvlmethanol Wl A
F
/ / Br OH
To a cold (0 °C) solution of 3-bromo-4-fluorobenzaldehyde (25.5 g) in THF
(300 mL) under an atmosphere of argon, a solution of phenylmagnesium bromide in diethyl ether (3 M, 45 mL) was added. The resultant solution was stirred at room temp. for 2.5 h, and treated with aq. HCl. The resultant mixture was diluted with ethyl acetate, and neutralized with aq. HCl. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.
Ste~2: 1-Benzvl-3-bromo-4-fluorobenzene Wl-B
F
/ /
Br To a cold (0 °C) solution of (3-bromo-4-fluorophenyl)phenylmethanol (35 g) and triethylsilane (100 g) in dichloromethane (400 mL), boron trifluoride diethyl etherate (24 mL) was added dropwise over a period of 45 min. The resultant mixture was stirred at 0 °C for 1 hr, diluted with dichloromethane, and neutralized with saturated aq. sodium bicarbonate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexane. Collection and concentration of appropriate fractions provided the title bromide.

Step ~~ ~ Benz3~1-2-fluorobenzonitrile Wl-C
~ ~ ~ F
CN
To a mixture of 1-benzyl-3-bromo-4-fluorobenzene (14.7 g) and zinc cyanide (38.7 g) in dimethylformamide (55 mL), purged with a steady stream of argon for 45 min., tetrakis(triphenylphosphine)palladium(0) (7 g) was added. The resultant mixture was stirred at 95 °C for 2 days under an atmosphere of argon. The resultant mixture was diluted with ethyl acetate, washed successively with water, aq. HCI, and brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 5 - 25% ethyl acetate - hexane gradient. Collection and concentration of appropriate fractions provided the title nitrile.
t 4: 5-Benzyl-2-iso~ropoxvbenzonitrile W1-D
~ O
~ CN
To a mixture of 5-benzyl-2-fluorobenzonitrile (0.55 g) and isopropyl alcohol (0.22 mL) in THF (15 mL) at room temp., a solution of potassium bis(trimethyl-sily)amide (0.5 M, 7 mL) in toluene was added. The resultant mixture was stirred at room temp. for 2 days under an atmosphere of argon. The resultant mixture was diluted with ethyl acetate, washed successively with aq. NH4C1, and brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title nitrile.
-12&

5-Benz 1-~propoxvacetophenone Wl-E
~ O
/ /
O
To a solution of 5-benzyl-2-isopropoxybenzonitrile (0.6 g) in benzene (15 mL), a solution of methylmagnesium iodide (3 M, 1.45 mL) in ether was added. The resultant mixture was heated at 80 °C overnight under an atmosphere of argon. The resultant mixture was treated with aq. HCl and washed with brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.
step 6; 4-(5-Benzyl-2-iso~ .~oxy~henyl)-2.4-dioxobutvric acid Wl O

O O
To a solution of 5-benzyl-2-isopropoxyacetophenone (0.268 g) and dimethyl oxalate (0.315 g) in THF (10 mL) at room temp., sodium methoxide (85 mg) was added. The resultant mixture was stirred at room temp. for 2 hr. under an atmosphere of argon. The resultant mixture was treated with aq. NaOH (1M, 5.5 mL) and stirred at room temp for 1 hr. The product solution was diluted with ethyl acetate, washed successively with aq. HCl and brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residual oil was triturated with a mixture of ether and hexane. The yellow solid precipitated was filtered to provide the title product. 1H NMR (CDCl3) 8 7.8-6.8 (m, 9H), 4.6 (m, 1H), 3.95 (s, 2H), 1.43 (d, 6H).

4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid 5-Benzy~-2-(2-~ N-dimethvlami~oethoxv)benzonitrile W2-A
~ O~N~CH3 ' 3 ~ ~ CN CH
To a mixture of 5-benzyl-2-fluorobenzonitrile (0.60 g) and N,N-dimethylethanolamine (0.32 mL) in THF (20 mL) at room temp., a solution of potassium bis(trimethylsily)amide (0.5 M, 6.25 mL) in toluene was added. The resultant mixture was heated at 60 °C overnight under an atmosphere of argon. The resultant mixture was diluted with ethyl acetate, washed with brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 5%
methanol in chloroform. Collection and concentration of appropriate fractions provided the title nitrile.
4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxo-bu~vric acid W2 H3C~N~CH3 ~J

i ii O O
The title compound was prepared using the protocol described in Example W1, Step 5 - 6 substituting 5-benzyl-2-isopropoxybenzonitrile with 5-Benzyl-2-(2-N,N-dimethylaminoethoxy)benzonitrile in Step 5. 1H
NMR (DMSO-dg) 8 7.7-6.9 (m, 9H), 4.45 (br s, 2H), 3.98 (s, 2H), 3.5 (br s, 2H), 2.85 (s, 6H).

4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid W3 Step 1: 4-Benzvl-2-bromophenol W3-A
~ OH
~ Br To a solution of 4-hydroxydiphenylmethane (10 g) in chloroform (60 mL) at room temp., a solution of bromine (2.9 mL) in chloroform (20 mL) was added dropwise over a period of 2 hr. The resultant mixture was stirred at room temp. overnight, diluted with chloroform, and washed successively with sat. aq. sodium bicarbonate and brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
. tee 2: 5-B~nzy-1-~2- ~vridin-2-yloxv)phenvl bromide W3-B
~ 1 ~N
~ O
~ Br A mixture of 4-benzyl-2-bromophenol (3 g) and sodium hydride (0.3 g) in DMSO (60 mL) was stirred at room temp. until evolution of gas subsided.
The resultant mixture was treated with 2-fluoropyridine (2 mL) and stirred at 150 °C under an atmosphere of argon overnight. The product mixture was partitioned between chloroform and water. The organic extract was washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provide the title bromide.
Step 3: 5-Benzvl-2-(gyridin-2-vloxy)acetophenone W3-C
,N
~ O
/ /
O
To a cold (-78 °C) solution of 5-benzyl-2-(pyridin-2-yloxy)phenyl bromide (1.68 g) in diethyl ether (40 mL), a solution of n-BuLi in hexanes (2.5 M, 2.12 mL) was added. The resultant mixture was stirred at -?8 °C for 1 h and was treated with N-methoxy-N-methylacetamide (0.6 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at room temp. overnight. The product mixture was diluted with ether and partitioned with aq. HCl. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provide the title ketone.
Methyl 4-[5-benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyrate W3-D
,N
~ O
/ / C02Me O O

To a cold (-78 °C) solution of 5-benzyl-2-(pyridin-2-yloxy) acetophenone (0.3 g) in THF (15 mL), a solution of LDA in heptane and THF (2 M, 0.56 mL) was added. The resultant mixture was stirred at -78 °C for 1 h and was treated with a solution of dimethyl oxalate (0.213 g) in THF. The reaction mixture was allowed to warm up slowly to room temp. and was stirred at room temp. overnight. The product mixture was diluted with ethyl acetate and partitioned with aq. HCI. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residual oil was triturated with diethyl ether. The resultant ethereal solution was isolated and concentrated under vacuum to provide the title ester.
Ste~S~. 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid ,N
O

O O
To a solution of methyl 4-[5-benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyrate (0.14 g) in THF (10 mL) at room temp., aq. NaOH (1 M, 0.44.mL) was added. The resultant mixture was stirred at room temp for 6 h.
The product mixture was diluted with chloroform and partitioned with aq. HCI. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and hexane. Filtration of the resultant solid provided the title acid. 1H NMR (CDC13) 8 8.25 (m, 1H), 7.8-6.8 (m, 12H), 4.05 (s, 2H).

4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid W4 Step 1: 5-Benzvl-2-iso~ropoxv-3-methoxy-1-bromobenzene W4-A

CH3O ~CH3 O
/ / Br A mixture of 4-benzyl-2-bromo-6-methoxyphenol (0.5 g), cesium carbonate (0.84 g), and isopropyl iodide (0.51 mL) in DMF (2 mL) was stirred at room temp, overnight. The reaction mixture was diluted with ether, and washed with aq. ammonium chloride. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title bromide.
Step 2: 5-Benzyl-2-iso~ro,foxy-3-methox3~-acetonhenone W4-B

CH30 ~-CH3 ~ O
/ /
O
To a mixture of 5-benzyl-2-isopropoxy-3-methoxy-1-bromobenzene (0.4 g), thallium acetate (0.41 g), 1,3-bis(diphenylphosphino)propane (0.138 g) and triethylamine (0.67 mL) in DMF (3 mL) in a pressure tube, purged with argon for a period of 5 minute, palladium acetate (67.2 mg) and n-butyl vinyl ether (0.77 mL) was added. The reaction tube was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (5 mL) and treated with aq.
HCl (1M, 2.5 mL). The resultant mixture was stirred at rt for 1 hr., diluted with ether, and washed with brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title ketone.
Sten 3:3: 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid W4 CH30 ~-CH3 O

O O
To a solution of 5-benzyl-2-isopropoxy-3-methoxy-acetophenone (?9 mg) and dimethyl oxalate (125 mg) in THF (2 mL), sodium methoxide (30 mg) was added. The resultant mixture was stirred at room temp. for 0.5 h under an atmosphere of argon. The resultant mixture was diluted with THF (3 mL) and methanol (0.5 mL), and treated with aq. NaOH (1M, 3 mL) and stirred at room temp for 1 hr. The product solution was adjusted to pH 2 with addition of aq. HCl. The resultant mixture was concentrated under vacuum. The residue was subjected to HPLC
purification on reverse phase stationary phase. Collection and lyophilization of appropriate fractions provide the title product as light yellow solid. 1H NMR (CDC13) 8 7.58-6.89 (m, 8H), 4.53 (m, 1H), 3.97 (s, 2H), 3.81 (s, 3H), 1.26 (d, 6H).

4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid W5 step 1: (3-Bromo-4,5-dimethoxvphenyl)phenylmethanol W5-A

~ OCH3 ~ Br 2,5 OH

To a cold (0 °C) solution of 3-bromo-4,5-dimethoxybenzaldehyde (5.42 g) in THF (25 mL) under an atmosphere of argon, a solution of phenylmagnesium bromide in THF (1 M, 25 mL) was added. The resultant solution was stirred at room temp. for 1 h, and treated with aq.
HCl. The resultant mixture was diluted with ether, and neutralized with aq. HCI. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.
a 2: 5-Benzvl-2.3-dimethoxy-1-bromobenzene W5-B

~ OCH3 / / Br To a cold (0 °C) solution of the (3-Bromo-4,5-dimethoxyphenyl)phenyl-methanol (5 g) and triethylsilane (3.7 g) in dichloromethane (80 mL), boron trifluoride diethyl etherate (3 mL) was added dropwise over a period of 5 min. The resultant mixture was stirred at room temp. for 1 hr, diluted with dichloromethane, and neutralized with saturated aq.
sodium bicarbonate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel.
Collection and concentration of appropriate fractions provided the title bromide.
~.gp ~'. 5-Benz~,~-dimethox av ceto~hPnnnP W5-C

~ OCH3 / /
O

To a cold (-78 °C) solution of 5-benzyl-2,3-dimethoxy-1-bromobenzene (3.1 g) in THF (46 mL), a solution of n-BuLi in hexanes (2.5 M, 4.2 mL) was added. The resultant mixture was stirred at -78 °C for 1 h and was treated with N-methoxy-N-methylacetamide ( 1.1 g). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at room temp. 1 h. The product mixture was diluted with ethyl acetate and partitioned with aq. HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 5 - 20% ethyl acetate gradient. Collection and concentration of appropriate fractions provide the title ketone.
Ste~4: Ethyl4-(5-benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyrate / / C02Et O O
To a solution of 5-benzyl-2,3-dimethoxyacetophenone (0.55 g) and diethyl oxalate (0.48 g) in THF (8 mL), sodium ethoxide (0.22 g) was added. The resultant mixture was stirred at room temp. for 1 hr under an atmosphere of argon. The reaction mixture was quenched with aq.
KHS04, and diluted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title ester.
Ste~S: 4-(5-Benzvl-2.3-dimethoxyphenvl)-2.4-dioxobutyric acid W5 ~5 O O

To a solution of ethyl 4-(5-benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyrate (0.59 g) in ethanol (8 mL), aq. NaOH (1 M, 6.4 mL) was added. The resultant mixture was stirred at room temp for 2 h. The product mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and aq. HCI. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and hexane. Filtration of the resultant solid provided the title acid. 1H NMR
(CDC13) 8 7.4-7.2 (m, 7H), 6.92 (br s, 1H), 3.97 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).

4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid W6 4-benzvl-2-bromo-6-nitrophenol W6-A

OH
Br To a solution of 4-benzyl-2-bromophenol (7.2 g) in glacial acetic acid (65 mL) at room temp., a solution of conc. nitric acid (15.8 M, 1.7 mL) in glacial acetic acid (10 mL) was added dropwise over a period of 1 hr. The resultant solution was stirred at room temp. for 2 hr., poured into ice-water, and neutralized with aq. ammonia. The mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 5 - 7% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title phenol.
a 2: 5-Benz3~1-2-methoxv-3-nitro-1-bromobenzene Wfi-B
-13&

OMe Br To a cold (0 °C) solution of 4-benzyl-2-bromo-6-nitrophenol (1.3 g) in diethyl ether (50 mL), a solution of diazomethane in diethyl ether was added over a period of 15 minute. The diazomethane solution was prepared by addition of 1-methyl-3-vitro-1-nitrosoguanidine (2.0 g) portionwise into a mixture of 40% aq. KOH (50 mL) and ether (50 mL) at 0 °C over a period of 15 min. The resultant solution was stirred at room temp. overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 4% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title bromide.
5-Benzvl-2-methoxy-3-bromoaniline W6-C

OMe Br A mixture of 5-benzyl-2-methoxy-3-vitro-1-bromobenzene (2.0 g) and 5%
Pt on charcoal (0.2 g) in a mixture of ethanol ( 100 mL) and acetic acid (5 mL) was shaken in a Parr hydrogenator under an atmosphere of hydrogen gas (56 psi) at room temp. for 45 min. The resultant mixture was filtered through a plug of CELITE diatomaceous earth. The filtrate was concentrated under vacuum to provide the title aniline.
,$teu 4:4: 5-Benzvl-2-methox~-3-bromo-N,N-dimethylaniline W6-D
NMe2 OMe Br WO 99/62520 PCT/(JS99/12093 To a solution of 5-benzyl-2-methoxy-3-bromoaniline ( 1.9 g), formaldehyde (37%, 5.3 g), and sodium cyanoborohydride (1.25 g) in acetonitrile (40 mL) at room temp, glacial acetic acid (2 mL) was added dropwise over a period of 3 hr. The reaction mixture was stirred at room temp.
overnight. The resultant solution was adjusted to pH ~6 with addition of aq sodium bicarbonate and partitioned with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 3% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provide the title bromide.
step 5: 5-Benzyl-2-methoxy-3-N,N-dimethylaminoacetophenone Me2N
OMe / /
O
To a mixture of 5-benzyl-2-methoxy-3-bromo-N,N-dimethylaniline (0.33 g), thallium acetate (0.3 g), 1,3-bis(diphenylphosphino)propane (0.106 g) and triethylamine (0.42 mL) in DMF (2.5 mL) in a pressure tube, purged with argon for a period of 5 minute, palladium acetate (56 mg) and n-butyl vinyl ether (0.67 mL) was added. The reaction tube was sealed and stirred at 100 °C for 1 hr. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (10 mL) and treated with aq.
HCl (1M, 3 mL). The resultant mixture was stirred at rt for 1 hr., diluted with ether, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 4% ethyl acetate in hexane. Collection and concentration of appropriate fractions provide the title ketone.

Step 6: 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-~iioxobutvric acid W6 Me2N

O O
To a solution of 5-benzyl-2-methoxy-3-N,N-dimethylaminoacetophenone (75 mg) and diethyl oxalate (57 mg) in THF (2 mL), sodium ethoxide (36 mg) was added. The resultant mixture was stirred at room temp. for 1 hr. under an atmosphere of argon. The reaction mixture was diluted with ethyl acetate and partitioned with 5% aq. KHS04. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in ethanol (3 mL) and treated with aq. NaOH (1M, 1 mL) and stirred at room temp for 1 hr. The product solution was concentrated under vacuum. The residue was dissolved in acetonitrile and acidified with aq TFA, and subjected to HPLC purification on reverse phase. Collection and lyophilization of appropriate fractions provided the title acid. 1H NMR
(CDC13) 8 7.6-7.0 (m, 8H), 4.00 (s, 2H), 3.89 (s, 3H), 3.21 (s, 6H).

4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid Step 1: 3-Benzvl-5-bromo-6-hvdroxvaniline W7-A

OH
Br To a solution of 4-benzyl-2-bromo-6-nitrophenol (8.65 g) and 5% Pt on charcoal (0.15 g) in a mixture of ethanol (100 mL) and acetic acid (8 mL) was shaken in a Parr hydrogenator under an atmosphere of hydrogen gas (43 psi) at room temp. for 1 hr. The resultant mixture was filtered through a plug of CELITE diatomaceous earth. The filtrate was concentrated under vacuum to provide the title aniline.
Ste~2~. 5-Benzvl-7-bromo-2-N.N-dimethvlaminobenzoxazole W7-B
N(CH3)2 N=
O
/ / Br A mixture of 3-benzyl-5-bromo-6-hydroxyaniline ( 1.0 g) and anhydrous (dichloromethylene)dimethylammonium chloride (0.6 g; dried by repetitive concentration from toluene under vacuum) in anhydrous chloroform (30 mL) was heated under reflux overnight under an atmosphere of argon. The reaction mixture was diluted with chloroform, and washed successively with aq. KOH and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title benzoxazole.
ate .~3~. 7-Acetyl-5-benzvl-2-N.N-dimethylaminobenzoxazole W7-C
N(CH3)2 N
O
/ /
O
To a mixture of 5-benzyl-7-bromo-2-N,N-dimethylaminobenzoxazole (0.8 g), thallium acetate (0.695 g), 1,3-bis(diphenylphosphino)propane {0.25 g) and triethylamine (0.98 mL) in DMF (5 mL) in a pressure tube, purged with argon for a period of 15 minute, palladium acetate ( 130 mg) and n-butyl vinyl ether ( 1.55 mL) was added. The reaction tube was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (20 mL) and treated with aq.
HCl (1M, 6 mL). The resultant mixture was stirred at rt for 1 hr., diluted with ether, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.
SteR4: 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid W7 To a solution of ?-acetyl-5-benzyl-2-N,N-dimethylaminobenzoxazole (200 mg) and diethyl oxalate (150 mg) in THF (7 mL), sodium ethoxide (138 mg) was added. The resultant mixture was stirred at room temp. for 3 hr. under an atmosphere of argon. The reaction mixture was diluted with ethyl acetate and partitioned with aq. HCI. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was obtained by filtration. A solution of this intermediate ester (125 mg) in THF (4 mL) was treated with aq.
NaOH (1M, 2.7 mL) and stirred at room temp for 1 hr. The product mixture was partitioned between ethyl acetate and aq. HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with O O

ether. The yellow solid precipitated was filtered to provide the title acid.
1H NMR (CDC13) 8 7.54-7.16 (m, 8H), 4.05 (s, 2H), 3.25 (s, 6H).

4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid W8 Ste~l~. (3.5-dibromo h~envl)phenylmethanol W8-A
Br Br OH
To a cold (-78 °C) solution of 1,3,5-tribromobenzene (30 g) in diethyl ether (500 mL), a solution of n-BuLi in hexanes (2.5 M, 38.1 mL) was added.
The resultant mixture was stirred at -78 °C for 1 h and was treated with benzaldehyde (10.2 mL). The reaction mixture was allowed to warm up slowly to 0 °C. and was stirred at that temp. for 1.5 hr. The product mixture was diluted with ethyl acetate and partitioned with aq. HCl (1M, 95 mL). The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.
to - 1-Benzvl-3.5-dibromobenzene W8-B
Br Br To a cold (0 °C) solution of (3,5-dibromophenyl)phenylmethanol (32.5 g) and triethylsilane (27.7 g) in dichloromethane (500 mL), boron trifluoride diethyl etherate (30 mL) was added dropwise over a period of 45 min.
The resultant mixture was stirred at 0 °C for 1 hr, and at room temp.
overnight. The product mixture was diluted with dichloromethane, and neutralized with saturated aq. sodium bicarbonate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexane. Collection and concentration of appropriate fractions provided the title dibromide.
Step 3: (3-benzvl-5-bromo~henyl) Dvrazin-2-yl ketone W8-C
N
I
O ~ N
\ \
Br To a cold (-78 °C) solution of 1-benzyl-3,5-dibromobenzene (1.5 g) in diethyl ether (20 mL), a solution of n-BuLi in hexanes (2.5 M, 2 mL) was added.
The resultant mixture was stirred at -78 °C for 1 h and was treated with a solution of N-methoxy-N-methylpyrazinecarboxyamide (0.84 g) in diethyl ether (5 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at that temp. overnight. The product mixture was diluted with ethyl acetate and partitioned with aq.
HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title pyrazine.
to 4: 3-Benzyl-5-pvrazin-2-vlmethyl-1-bromobenzene W8-D
N
I
\ N
\ \
Br A mixture of (3-benzyl-5-bromophenyl) pyrazin-2-yl ketone (0.97 g) and anhydrous hydrazine (2 mL) in ethylene glycol (6 mL) was heated at 110 °C for 4 hr. Excess hydrazine was removed under reduced pressure.
The residue ethylene glycol solution was treated with powdered solid KOH (0.4 g) and heated under an atmosphere of argon for 4 h. The product mixture was partitioned between benzene and water. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20-30% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title bromide.
a 5: 3-Benzvl-5-gvrazin-2-vlmethylacetophenone 'lV8-EE
N
O
To a mixture of 3-benzyl-5-pyrazin-2-ylmethyl-1-bromobenzene (0.77 g), thallium acetate (0.66 g), 1,3-bis(diphenylphosphino)propane (0.263 g) and triethylamine (1.27 mL) in DMF (5 mL) in a pressure tube, purged with argon for a period of 10 minute, palladium acetate (128 mg) and n-butyl vinyl ether (1.5 mL) was added. The reaction tube was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (5 mL) and treated with aq.
HCl (3M, 4 mL). The resultant mixture was stirred at rt for 3 hr., diluted with ethyl acetate, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane.

Collection and concentration of appropriate fractions provided the title ketone.
a 6: 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric arid W8 N'~~, To a cold (-78 °C) solution of 3-benzyl-5-pyrazin-2-ylmethylacetophenone {0.595 g) in THF (4 mL), a solution of lithium bis{trimethylsilyl)amide in THF (1 M, 1.2 mL) was added. The resultant mixture was stirred at -78 °C for 1 h and was treated with diethyl oxalate (0.18 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at room temp. overnight. The product mixture was treated with aq.
NaOH {1 M, 2 mL) and stirred at room temp for 4 h. The product solution was concentrated under vacuum. The residue was dissolved in acetonitrile and acidified with aq TFA, and subjected to HPLC
purification on reverse phase. Collection and lyophilization of appropriate fractions provided the title acid. 1H NMR (CDC13) 8 8.7-7.0 (m, 12H), 4.22 (s, 2H) , 4.02 (s, 2H).

4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid W9 Ste~l: ,~- en yl-5-bromobenzaldeh~~de W9-A
O H
\ \
Br O O

To a cold (-78 °C) solution of 1-benzyl-3,5-dibromobenzene (1.15 g) in THF
(30 mL), a solution of n-BuLi in hexanes (2.5 M, 2 mL) was added. The resultant mixture was stirred at -78 °C for 1 h and was treated with anhydrous DMF (0.3 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at that temp. overnight. The product mixture was diluted with ethyl acetate and partitioned with aq.
HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title benzaldehyde.
SteR 2: 3-Benzvl-5-bromobenzvl alcohol W9-B
OH
\ \
/ I / gr To a cold (0 °C) solution of 3-benzyl-5-bromobenzaldehyde (0.465 g) in methanol (5 mL), sodium borohydride (0.123 g) was added. The reaction mixture was stirred at room temp. for 3 hr. The product mixture was concentrated, and the residue partitioned between ethyl acetate and aq.
HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol.
Steg3: 3-Benzvl-5-bromobenzvl bromide W9-C
Br \ ( \
/ / Br -14&

To a cold (0 °C) solution of 3-benzyl-5-bromobenzyl alcohol (0.32 g) and carbon tetrabromide (0.57 g) in dichloromethane (6 mL), a solution of triphenylphosphine (0.45 g) in dichloromethane (4 mL) was added dropwise. The reaction mixture was stirred at room temp. for 2 hr. The product mixture was concentrated, and the residue was subjected to column chromatography on silica gel eluting with 15% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title dibromide.
t 4: 3-Ben~yl-5-f 1.2.31triazol-2-ylinethvl-1-bromobenzene W9-D
N-N
~N
Br A mixture of sodium hydride (28 mg, 60% dispersion in mineral oil, washed with hexane) and 1,2,3-triazole (0.38 mL) in DMF was stirred at room temp. for 10 min. The resultant mixture was treated with a solution of 3-benzyl-5-bromobenzyl bromide in DMF. The reaction mixture was stirred at room temp. overnight. The product mixture was concentrated, and the residue partitioned between ethyl acetate and aq.
ammonium chloride. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of earlier fractions (Rf = 0.8, slices gel, eluted with 50% ethyl acetate in hexane) provided the title triazole bromide [1H NMR (CDC13) 8 7.63 (s, 2H)], and later fractions (Rf = 0.2) provided the isomeric 3-benzyl-5-[1,2,3]triazol-1-ylmethyl-1-bromo-benzene analog [ 1H NMR (CDC13) 8 7.76 (br s, 1H), 7.73 (br s, 1H)].
Step 5: 3-Benz 1-~,2.31triazol-2-vlmethvlacetophenone W9-E

N
N
~N
I\ I\
i To a mixture of 3-benzyl-5-[1,2,3]triazol-2-ylmethyl-1-bromobenzene (0.4 g), thallium acetate (0.35 g), 1,3-bis(diphenylphosphino)propane (0.13 g) and triethylamine (0.68 mL) in DMF (4 mL) in a pressure tube, purged with argon for a period of 10 minute, palladium acetate (55 mg) and n-butyl vinyl ether (0.8 mL) was added. The reaction tube was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (5 mL) and treated with aq.
HCl (3M, 4 mL). The resultant mixture was stirred at rt for 3 hr., diluted with ethyl acetate, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane.
Collection and concentration of appropriate fractions provided the title ketone.
Ste~6~. 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylpheny1~2,4-dioxobutvric acid W9 N
N
~N
\ \

I li O O
To a solution of 3-benzyl-5-[1,2,3]triazol-2-ylmethylacetophenone (60 mg) and diethyl oxalate (89 mg) in THF (3 mL), sodium ethoxide (21 mg) was added. The resultant mixture was stirred at room temp. for 1 hr. under an atmosphere of argon. The reaction mixture was diluted with ethyl acetate and partitioned with aq. HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in THF (1 mL) and treated with aq. NaOH (1M, 1 mL) and stirred at room temp for 3 hr. The product mixture was diluted with ethyl acetate and partitioned with aq.
HCl. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with hexane/ethyl acetate. Filtration and collection of the solid provided the title acid. 1H NMR (CDC13) S 7.78-7.10 (m, 11H), 5.64 (s, 2H), 4.03 (s, 2H).

4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid W10 ten 1: ,~ Chloropvridin-2-yl 3-bromophenvl ketone W10-A
~~ N
Br n CI O
To a cold (-78 °C) solution of 1,3-dibromobenzene (0.8 mL) in THF
(4 mL), a solution of n-BuLi in hexanes (2.5 M, 3.2 mL) was added. The resultant mixture was stirred at -?8 °C for 1 h and was treated with a solution of N-methoxy-N-methyl-3-chloropyridine-2-carboxyamide in THF (4 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at that temp. overnight. The product mixture was diluted with ethyl acetate and partitioned with aq. HCl.
The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.

Step 2: 3-(3-Chloronvridin-2-vlmeth3il)-1-bromobenzPne W10-B
I ~_N i w A mixture of 3-chloropyridin-2-yl 3-bromophenyl ketone (0.2 g) and anhydrous hydrazine (1 mL) in ethylene glycol (2.5 mL) was heated at 110 °C for 4 hr. Excess hydrazine was removed under reduced pressure.
The residue ethylene glycol solution was treated with powdered solid KOH (0.1 g) and heated under an atmosphere of argon for 1 h. The product mixture was partitioned between benzene and water. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25% ethyl acetate Collection and concentration of appropriate fractions provided the title bromide. 1H NMR (CDC13) b 8.47 (br dd, 1H), 7.66 (br dd, 1 H), 7.44 (br s, 1H), 7.35 (br d, 1 H), 7.22 {br d, 1H), 7.16-7.12 (m 2 H), 4.28 (s, 2H).
Step 3: 3-(3-ChloroRvridin-2-ylmeth_vOa~Ptonhenone W10-C
~~ N
I I
CI Q
To a mixture of 3-(3-chloropyridin-2-ylmethyl)-1-bromobenzene (0.76 g), thallium acetate (0.87 g), 1,3-bis(diphenylphosphino)propane (0.27 g) and triethylamine (1.67 mL) in DMF (6 mL) in a pressure tube, purged with argon for a period of 10 minute, palladium acetate (134 mg) and n-butyl vinyl ether (1.96 mL) was added. The reaction tube was sealed and stirred at 100 °C for 2 days. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (3 mL) and treated with aq.
HCl (3M, 3 mL). The resultant mixture was stirred at room temp.
overnight, diluted with ethyl acetate, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title ketone.
te~4~. 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid W10 ~~ N
/ l / C02H
ii ii CI O O
To a cold (-78 °C) solution of 3-(3-chloropyridin-2-ylmethyl)acetophenone (0.19 g) in THF (3 mL), a solution of lithium bis(trimethylsilyl)amide in hexane ( 1 M, 1.54 mL) was added. The resultant mixture was stirred at -?8 °C for 1 h and was treated with diethyl oxalate (0.22 mL). The reaction mixture was allowed to warm up slowly to room temp. and was stirred at room temp. for 1.5 hr. The product mixture was treated with aq. NaOH ( 1 M, 3.2 mL) and stirred at room temp overnight. The product solution was concentrated under vacuum. The residue was dissolved in acetonitrile and acidified with aq TFA, and subjected to HPLC purification on reverse phase. Collection and lyophilization of appropriate fractions provided the title acid. 1H NMR (DMSO-d6) b 8.48 (br d, 1H), 7.92 - 7.0 (m, 7H), 4.35 (s, 2H).

4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl)phenyl]-2,4-dioxo-butyric acid W11 4-Benzvl-2,6-dibromophenol W11-A
Br OH
/ / Br To a solution of 4-hydroxydiphenylmethane ( 15.3 g) in glacial acetic acid (200 mL) at room temp., a solution of bromine (8.6 mL) in acetic acid (20 mL) was added dropwise over a period of half an hour. The resultant mixture was stirred at room temp. for 3 hr, poured into ice water, and partitioned with toluene. The organic extract was washed successively with 10% aq. sodium hydrogensulfite and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 7% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title dibromophenol.
SteQ2: 4-Benzvl-2.6-dibromo-1-methoxvben~Pne W11-B
Br OMe Br To a cold (0 °C) solution of 4-benzyl-2,6-dibromophenol (10 g) in diethyl ether (100 mL), a solution of diazomethane in diethyl ether was over a period of 20 minute. The diazomethane solution was prepared by addition of I-methyl-3-nitro-1-nitrosoguanidine (8.5 g) portionwise into a mixture of 40% aq. KOH (100 mL) and ether (50 mL) at 0 °C over a period of 15 min. The resultant solution was stirred at room temp. for two days, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1-2 % ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title dibromide.
~,3-Benzvl-5-bromo-6-methoxvbenzvl bromide Wll-C
Br OMe Br The title compound was prepared using the protocol described in Example W9, Step 1- 3 substituting 1-benzyl-3,5-dibromobenzene with 4-benzyl-2,6-dibromo-1-methoxybenzene in Step 1.
t 4~ 3-Benzyl-1-bromo-5-N,N,-dimethylaminomethyl-6-~nethoxvbenzene Wll-D
N~
OMe Br A solution of 3-benzyl-5-bromo-6-methoxybenzyl bromide (0.65 g), dimethylamine hydrochloride (0.29 g), and diisopropylethylamine (0.61 mL) in acetonitrile (8 mL) was heated at 60 °C overnight. The resultant solution was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 4 % methanol in chloroform. Collection and concentration of appropriate fractions provided the title bromide.
Step 5: 5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl)-acetonhenone W 11-E
N~
OMe O
To a mixture of 3-benzyl-1-bromo-5-N,N,-dimethylaminomethyl-6-methoxybenzene (0.30 g), thallium acetate (0.28 g), 1,3-bis(diphenyl-phosphino)propane (0.80 g) and triethylamine (0.39 mL) in DMF (2 mL) in a pressure tube, purged with argon for a period of 5 minute, palladium acetate (43 mg) and n-butyl vinyl ether (0.62 mL) was added.

The reaction tube was sealed and stirred at 100 °C overnight. The reaction mixture was filtered through a bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (10 mL) and treated with aq. HCl (1M, 3 mL). The resultant mixture was stirred at room temp. for 1 h, diluted with ethyl acetate, basified with aq. sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 7% methanol in chloroform. Collection and concentration of appropriate fractions provided the title ketone.
a 6' 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl)-nhenvll-2.4-dioxo-butyric acid Wl1 N~
OMe O O
To a solution of 5-benzyl-2-methoxy-3-(N,N-dimethylaminomethyl)-acetophenone (0.26 g) and diethyl oxalate (0.19 g) in THF (8 mL), sodium ethoxide (118 mg) was added. The resultant mixture was stirred at room temp. for 1 hr. under an atmosphere of argon. The resultant solution was treated with aq. NaOH (1M, 5 mL) and stirred at room temp for 1 hr.
The product solution was neutralized with addition of aq. HCl, and concentrated under vacuum. The residue was dissolved in acetonitrile and acidified with aq TFA, and subjected to HPLC purification on reverse phase. Collection and lyophilization of appropriate fractions provided the title acid. 1H NMR (CDC13) 8 7.67-7.11 (m, 8H), 4.26 (s, 2H), 3.97 (s, 2H),3.74 (s, 3H), 2.86 (s, 6H).

4-(5-Benzyl-3-methoxy-2-methoxyethoxyphenyl)2,4-dioxobutyric acid H

Step 1: 3-Bromo-4-(2-methoxyethoxy)-5-methoxybenz l~dehyde Me Me CHO
To a 500 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 5-bromovanillin (10 g, 43.28 mmol), DMF
(125 mL), powdered Cs2COg (28.2 g, 86.56 mmol) and 2-bromoethylmethyl ether ( 5.08 mL, 54.10 mmol). This well stirred mixture was heated at 75oC for 24h. The cooled mixture was filtered through a frit to remove the cesium salts and the filtrate was concentrated in aacuo. The residue was dissolved in EtOAc and washed with water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. 1H NMR (CDC13): b 3.44 (s, 3H); 3.77 (t, j=4 Hz, 2H); 3.92 (s, 3H); 4.27 (t, j=4 Hz, 2H); 7.38 (d, j=2 Hz, 1H); 7.65 (d, j=2Hz, 1H); 9.84 (s, 1H).
t 2: 1-(3-Bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenvlmethanol.

WO 99/b2520 PCT/US99/12093 n To a 11 round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.OOg, 41.50 mmol) and dry THF {150 mL). This solution was cooled in an ice bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.OM
solution, 49.81 mmol) was added with a syringe. The resulting solution was stirred for lh at OoC. The reaction was quenched with aqueous NH4C1 solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgS04), filtered and concentrated in vacuo. This material was chromatographed on 400g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol as an oil. 1H NMR (CDC13): b 2.29 (d, j=4Hz, 1H); 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.82 (s, 3H); 4.13 (t, j=4 Hz, 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H).
~gp~ 1-(3-Bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenvlmethane.
Me To a 500 mL round bottomed Mask with a stirring bar and a nitrogen inlet was added of 1-(3-bromo-4-{2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol (12.83g, 34.94 mmol), dry methylene chloride (200 mL) and triethylsilane (13.87 mL, 87.34 mmol). This solution was cooled in an ice bath and borontrifluoride etherate (4.43 mL, 34.94 mmol) was added with a syringe over 5 min. The mixture was aged 2h at OoC. The reaction was quenched with saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform. The chloroform fraction was washed with brine, dried (MgS04), filtered and concentrated in uacuo. This material was chromatographed on 400g of silica gel using 20/80 EtOAc-hexane as eluant to give 9.45g of 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethane as an oil. 1H
NMR (CDC13): 8 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.77 (s, 3H); 3.88 (s, 2H);
4.13 (t, j=4 Hz, 2H); 6.64 (d, j=2Hz, 1H); 6.94 (d, j=2Hz, 1H); 7.26 (m, 5H).
Step 4: 1-(2-(2-Methoxyethoxy)-3-methoxy-5-phenylmethyl)-1-ethanone.
~OMe To a 25 mL glass pressure vessel with a stirring bar was added 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethane (1.95g, 5.55 mmol) and 12 mL of DMF. This solution was degassed with a stream of nitrogen for 10 min. Palladium {II) acetate (0.25g, 1.11 mmol), DPPP (0.50g, 1.20 mmol), thallium (I) acetate (1.61g, 6.11 mmol), butylvinyl ether (3.62 mL, 27.75 mmol) and triethylamine (3.09 mL, 22.20 mmol) were added and the mixture was degassed for another 10 min.
The vessel was sealed and heated at 100oC for 18h with vigorous stirring.
The cooled mixture was filtered through a CELITE diatomaceous earth pad and the filtrate was concentrated in vacuo. The residue was dissolved in THF (30 mL) and 1~T HCl (30 mL) was added. This solution was stirred at ambient temperature 20h. The mixture was extracted with two portions of EtOAc. The combined EtOAc extracts were washed with water and brine. Drying (MgS04), filtration and removal of the solvent in Uczcuo gave a yellow oil. This material was chromatographed on 90g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(2-(2-methoxyethoxy)-3-methoxy-5-phenylmethyl)-1-ethanone as an oil. 1H NMR (CDC13): 8 2.64 (s, 3H);3.37 (s, 3H); 3.63 (t, j=4 Hz, 2H);
3.80 (s, 3H); 3.93 (s, 2H); 4.17 (t, j=4 Hz, 2H); 6.82 (d, j=2Hz, 1H); 7.04 (d, j=2Hz, 1H); 7.26 (m, 5H).
Step 5: Ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutvrate.
To a 50 mL round bottomed flask with a stirring bar and a nitrogen inlet was added 1-(2-(2-methoxyethoxy)-3-methoxy-5-phenylmethyl)-1-ethanone (1.35g, 4.29 mmol), THF (30 mL), diethyl oxalate (1.75 mL, 12.88 mmol) and sodium ethoxide (0.41g, 6.00 mmol). This solution was stirred 2h at ambient temperature. The reaction was quenched with saturated aqueous NH4C1 solution and extracted with EtOAc. The organic phase was washed with water and brine. Drying (MgS04), filtration and removal of the solvent in va~cuo gave an oil. This material was exposed to high vacuum for 2 days to remove the excess diethyl oxalate giving 1.48g of ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyrate as an oil. 1H NMR (CDC13): 8 1.38 (t, j=7Hz, 3H), 3.36 (s, 3H); 3.66 (t, j=4 Hz, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.16 (t, j=4 Hz, 2H); 4.82 (q, j=7Hz, 2H); 6.87 (d, j=2Hz, 1H); 7.26 (m, ?H).

SteR 6: 4-(Benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutvric acid.
OOH
To a 200 mL round bottomed flask with a stirring bar and a nitrogen inlet was added ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyrate (1.48g, 3.57 mmol), THF (30 mL), methanol (30 mL), and sodium hydroxide solution (18 mL of a 1 ~T solution in water, 18 mmol).
This mixture was stirred 2h at ambient temperature. The organic solvents were removed in uacuo and the aqueous residue was diluted with 30 mL of water. This solution was washed with ethyl ether (2 X 50 mL) then acidified with 1N HCI. This mixture was extracted with ethyl ether (100 mL). The ether solution was washed with water and brine.
Drying (MgS04), filtration and removal of the solvent in uacuo gave a yellow oil. This material was crystallized by dissolving in 1:1 ether-hexane (~5mL) and storing in a freezer over night. The crystalline product was collected by filtration on a frit and dried in vacuo at ambient temperature to give 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid as yellow needles. MP: 83-85oC. Anal. Calc'd for C21H2207~ C, 65.28; H, 5.74; Found: C, 65.28; H, 6.05. 1H NMR (CDC13):
8 3.39 (s, 3H); 3.71 (t, j=4 Hz, 2H); 3.82 (s, 3H); 3.96 (s, 2H); 4.21 (t, j=4 Hz, 2H); 6.90 (d, j=2Hz, 1H); 7.28 (m, 6H); 9.60 (br s, 1H).

The following examples (32-108) may be prepared according to the general procedures outlined in the Schemes and in Examples 1 to 31.
32. 4-(3-Benzyl-4-methoxyphenyl)-2,4-dioxobutyric acid Cf Anal. Calcd for C18H1605 0.30 toluene: C, 71.01; H, 5.46.
Found: C, 71.05; H, 5.68.
33. 4-(5-Benzyl-2-methoxyphenyl)-2,4-dioxobutyric acid -"." , Anal. Calcd for C18H1605: C, 69.22; H, 5.16.
Found: C, 68.89; H, 5.10.
34. 4-(3-Benzyl-4-fluorophenyl)-2,4-dioxobutyric acid r Anal. Calcd for C17H13FO4 0.15 H20: C, 67.38; H, 4.42.
Found: C, 67.31; H, 4.16.
35. 4-(3-Benzyl-4-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid Anal. Calcd for ClgH1gN04 1.42 TFA: C, 55.61; H, 4.41; N, 3.03.
Found: C, 55.51; H, 4.22; N, 2.95.
36. 4-[5-(2-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid Anal. Calcd for C2pH2p06: C, 67.41; H, 5.66.
Found: C, 67.42; H, 5.57.
37. 2,4-Dioxo-4-(3-pyridin-2-ylmethylphenyl)butyric acid Anal. Calcd for C16H13N04 0.7 TFA: C, 57.55; H, 3.80; N, 3.86.
Found: C, 57.73; H, 3.84; N, 3.79.
38. 4-(5-Benzyl-3-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid Anal. Calcd for ClgH1gN04 1.35 TFA: C, 57.40; H, 4.59; N, 3.19.
Found: C, 57.66; H, 4.87; N, 3.03.
39. 4-(5-Benzyl-3-methoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C18H1605 0.15 H20: C, 68.62; H, 5.22.
Found: C, 68.59; H, 5.04.
40. 4-(5-Benzyl-2-benzyloxy-3-methoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C25H220g 0.30 H20: C, 70.84; H, 5.37.
Found: C, 70.82; H, 5.22.
41. 4-[5-(3-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid Anal. Calcd for C2pH20~6: C, 67.41; H, 5.66.
Found: C, 67.33; H, 5.18.
42. 4-(5-Benzyl-3-benzyloxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C24H20~5 O.IS H20: C, 73.69; H, 5.23.
Found: C, 73.65; H, 5.30.
43. 4-[5-Benzyl-2-(2-hydroxy)ethoxyphenyl]-2,4- dioxo-2-butanoic acid Anal. Calcd for C1gH1806: C, 66.66; H, 5.30.
Found: C, 66.69; H, 5.51.
44. 2,4-Dioxo-4-(3-pyridin-3-ylmethylphenyl)butyric acid Anal. Calcd for C16H13N04 1.1 TFA & 0.35 MeCN:
C, 53.65; H, 3.61; N, 4.47.
Found: C, 53.56; H, 3.79; N, 4.47.
45. 4-[3-(3-Methyl-pyridin-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C16H13N04 1 TFA: C, 55.48; H, 3.92; N, 3.41.
Found: C, 55.20; H, 4.01; N, 3.58.
46. 4-{5-Benzyl-2-methylsulfanylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C18H1605 0.05 H20 0.20 HCl: C, 64.23; H, 4.88.
Found: C, 64.16; H, 4.76.
47. 4-(5-Benzyl-3-N-morpholinophenyl)-2,4-dioxobutyric acid Anal. Calcd for C21H21N05 1 TFA 0.2 H20: C, 56.95; H, 4.66; N, 2.89.
Found: C, 56.96; H, 5.18; N, 3.00.
48. 4-( 8-Benzyl-4-methyl-3,4-dihydro-2h-benzo [ 1,4] oxazin-6-yl )-2,4-dioxobutyric acid Anal. Calcd for C2pH1gN05 0.15 MeCN 0.1 TFA:
C, 66.37; H, 5.31; N, 4.34.
Found: C, 66.41; H, 5.58; N, 4.41.
49. 4-[5-(2-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid Anal. Calcd for C1gH18C1N04 0.15. hexane: C, 64.12; H, 5.44; N, 3.76.
Found: C, 64.02; H, 5.43; N, 3.56.
50. 4-[5-(3-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid Anal. Calcd for C1gH18C1N04 0.65 Et20: C, 58.37; H, 5.78; N, 3.15.
Found: C, 58.12; H, 5.45; N, 2.77.
51. 4-(5-Benzyl-2,3,4-trimethoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C2pH20O7 0.15 H20: C, 64.04; H, 5.46.
Found: C, 63.98; H, 5.29.
52. 4-(6-Benzylbenzo[1,3]dioxol-4-yl)-2,4-dioxobutyric acid Anal. Calcd for C18H1406 0.3 H20 0.1 Et20: C, 65.16; H, 4.64.
Found: C, 65.25; H, 4.65.
53. 4-[3-Benzyl-5-(morpholine-4-carbonyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H21N06 0.25 CHC13 0.15 hexane:
C, 63.45; H, 5.37; N, 3.20.
Found: C, 63.42; H, 5.30; N, 3.20.
54. 4-(3-Benzyl-5-pyridine-2-ylmethylphenyl)-2,4-dioxobutyric acid WO 99/62520 PG"T/US99/12093 Anal. Calcd for C23H1gN04 1.0 TFA 0.2 hexane:
C, 62.39; H, 4.19; N, 2.46.
Found: C, 62.35; H, 4.55; N, 2.78.
55. 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H23N05 : C, 58.18; H, 4.88; N, 2.83.
Found: C, 58.26; H, 4.76; N, 2.77.
56. 4-(3-Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C23H1gN04 1.0 TFA: C, 61.60; H, 4.14; N, 2.87.
Found: C, 61.65; H, 4.43; N, 2.92.
57. 4-[3-Benzyl-5-(2-dimethylamino-1-hydroxy-1-methylethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H25N05 1.20 H20: C, 55.53; H, 5.51; N, 2.70.
Found: C, 55.55; H, 5.23; N, 2.55.
58. 4-(5-Benzyl-2-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid Anal. Calcd for ClgH1gN04 1.0 TFA 0.55 H20: C, 56.13; H, 4.73; N, 3.12.
Found: C, 56.11; H, 4.67; N, 3.11.

59. 4-(5-Benzyl-2-fluorophenyl)-2,4-dioxobutyric acid Anal. Calcd for C17H13FO4 0.05 H20 0.05 Et20: C, 67.75; H, 4.50.
Found: C, 67.83; H, 4.46.
60. 4-(5-Benzyl-3-hydroxymethyl-2-methoxypheny1~2,4-dioxobutyric acid Anal. Calcd for C1gH1806 : C, 66.66; H, 5.30.
Found: C, 66.91; H, 5.39.
61. 4-[5-Benzyl-2-(pyrazin-2-yloxy)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C21H16N205 0.45 TFA 1.15 H20:
C, 58.66; H, 4.21; N, 6.25.
Found: C, 58.67; H, 4.15; N, 6.55.
62. 4-[3-Benzyl-5-(2-oxopiperidin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C23H23N05 : C, 70.22; H, 5.89; N, 3.56.
Found: C, 69.86; H, 5.55; N, 3.40.
63. 4-[5-Benzyl-2-methoxy-3-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C23H25N06~ C, 57.14; H, 4.99; N, 2.67.
Found: C, 57.57; H, 5.34; N, 2.47.
64. 4-[3-(2-Chlorobenzyl)-5-pyridin-2-ylmethylphenyl]-2,4-dioxobutyric acid Anal. Calcd for C23H18C1N04 1.0 H20: C, 64.86; H, 4.73; N, 3.29.
Found: C, 64.89; H, 4.37; N, 2.97.
65. 4-[5-Benzyl-2-methoxy-3-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C24H28N205 2.2 TFA: C, 51.01; H, 4.57; N, 4.22.
Found: C, 51.03; H, 4.52; N, 4.12.
66. 4-(5-Benzyl-2-methoxymethylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C1gH1805 0.10 hexane: C, 70.27; H, 5.84.
Found: C, 70.40; H, 5.48.
67. 4-[3-(2-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H22N05F 2.25 TFA 0.15 H20:
C, 48.32; H, 3.76; N, 2.13.
Found: C, 48.30; H, 3.77; N, 1.82.

68. 4-[3-(4-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H22N05F 1.05 TFA 0.15 H20:
C, 55.46; H, 4.51; N, 2.68.
Found: C, 55.48; H, 4.53; N, 2.43.
69. 4-[3-(3-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H22N05F 1.45 TFA 0.50 H20:
C, 52.12; H, 4.30; N, 2.44.
Found: C, 52.11; H, 4.29; N, 2.24.
70. 4-[5-Benzyl-2-methoxy-3-(tert-butylcarbamoyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C23H25N07 0.25 EtOAc 0.05 Et20:
C, 64.13; H, 6.12; N, 3.09.
Found: C, 64.13; H, 6.10; N, 3.13.
71. 4-(3-Benzyl-5-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C20H17N304 0.1 hexane: C, 66.51; H, 4.99; N, 11.30.
Found: C, 66.87; H, 4.87; N, 11.65.

72. 4-[5-Benzyl-3-(N'-methyl-N-piperazinyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H24N304: C, 63.38; H, 6.04; N, 6.72.
Found: C, 63.34; H, 6.12; N, 6.56.
73. 4-(3-Benzyl-5-(1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C2pH17N3O4: C, 66.11; H, 4.72; N, 11.56.
Found: C, 66.26; H, 4.99; N, 11.59.
74. 4-(6-Benzyl-3-oxo-3,4-dihydro-2-H-benzo[1,4]oxazin-8-yl)-2,4-dioxobutyric acid Anal. Calcd for C1gH15N06 0.30 H20: C, 63.61; H, 4.38; N, 3.90.
Found: C, 63.69; H, 4.51; N, 3.89.
75. 4-[5-Benzyl-2-(pyrimidin-2-yloxy)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C21H16N205 0.40 H20 0.45 TFA:
C, 60.48; H, 4.00; N, 6.44.
Found: C, 60.51; H, 3.96; N, 6.31.
76. 4-(5-Benzyl-3-amino-2-methoxyphenyl)-2,4-dioxobutyric acid FAB MS M+1= 345 77. 4-(5-Benzyl-2-ethoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C18H1605 0.15 hexane: C, 70.44; H, 5.97.
Found: C, 70.62; H, 5.62.
78 . 4-[5-Benzyl-2-(2-morpholin-4-yl-ethoxy)phenyl~-2,4-dioxobutyric acid Anal. Calcd for C23H25N06 0.65 CH2C12 0.10 Et20:
C, 60.93; H, 5.80; N, 2.95.
Found: C, 61.11; H, 5.78; N, 2.75.
79. 4-(5-Benzyl-2-triffuoroethoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C1gH15F305 0.05 Et20: C, 60.05; H, 4.07.
Found: C, 60.00; H, 4.08.
80. 4-(5-Benzyl-2-cyclobutyloxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C21H2005 0.05 H20 0.15 Et20: C, 71.19; H, 5.97.
Found: C, 71.20; H, 5.99.
81. 4-(5-Benzyl-2-cyclopentyloxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C22H2205 0.20 toluene 0.15 Et20: C, 72.80; H, 6.39.
Found: C, 72.81; H, 6.40. .
82. 4-(3-Benzyl-5-tetrazol-2-ylmethylphenyl)-2,4-dioxobutyric acid Anal. Calcd for C1gH16N404: C, 61.99; H, 4.59; N, 14.91.
Found: C, 62.00; H, 4.74; N, 14.88.
83. 4-(5-Benzyl-2,3-diisopropoxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C23H2606 0.2 hexane: C, 69.92; H, 6.98.
Found: C, 69.86; H, 6.99.
84. 4-(5-Benzyl-2-isopropoxy-3-N-methylaminophenyl)-2,4-dioxobutyric acid Anal. Calcd for C21H23N05 0.10 TFA 0.90 H20:
C, 55.28; H, 5.20; N, 2.80.
Found: C, 55.26; H, 5.12; N, 2.82.
85. 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminophenyl)-2,4-dioxo-butyric acid Anal. Calcd for C22H25N05 0.10 TFA: C, 57.95; H, 5.27; N, 2.82.
Found: C, 58.09; H, 5.10; N, 2.83.
86. 4-[5-Benzyl-2-isopropoxy-3-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C24H2gN06 1.70 TFA 0.05 H20:
C, 52.89; H, 4.99; N, 2.25.
Found: C, 52.92; H, 5.02; N, 2.01.
87. 4-[5-Benzyl-2-isopropoxy-3-(morpholinomethyl)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C25H2gN06 1.0 HCl: C, 63.09; H, 6.35; N, 2.94.
Found: C, 63.43; H, 6.46; N, 2.65.
88. 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminomethylphenyl)-2,4-dioxo-butyric acid Anal. Calcd for C23H27N05 0.10 TFA: C, 58.70; H, 5.52; N, 2.74.
Found: C, 58.42; H, 5.27; N, 2.45.
89. 4-(7-Benzylbenzo[1,3]dioxol-5-yl)-2-hydroxy-4-oxobut-2-enoic acid /- O
O

OH
~r O O
Anal talc for C18H1406 .1 ethyl acetate C, 65.94 ; H, 4.45 Found C, 65.95 ; H, 4.84 90. 2-Hydroxy-4-oxo-4-(3-phenylindan-5-yl)but-2-enoic acid OH
Anal talc for C1gH1604 .05 H20 C, 73.79 ; H, 5.25 Found C, 73.48 ; H, 5.33 91. 4-(Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid O
OH
O O
Anal talc for C24H21N04 .1 ethyl acetate C, 73.95 ; H, 5.55 ; N, 3.54 Found C, 73.69 ; H, 5.90; N, 3.22 92. 3-(3-Benzyl-5-carboxyacetylphenyl)-3-oxopropionic acid OH
O O
Anal talc for C1gH160g 1.5 H20 C, 62.12 ; H, 5.21 Found C, 61.98 ; H, 5.28 93. 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid O
~OH
O O
Anal talc for C24H21N04 .05 ethyl acetate C, 74.17 ; H, 5.51 ; N, 3.57 Found C, 74.05 ; H, 5.38; N, 3.29 94.4-(5-Benzyl-3-methoxy-2-mtethylthioethoxyphenyl)-2,4-dioxobutyric acid Anal. Calc'd for C21H22~6S~ C, 62.67; H, 5.51 Found: C, 62.26; H, 5.65 mp: 99-100oC
95. 4-(7-Benzyl-2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,4-dioxobutyric acid ~ ~C02H
/ /
O
Anal. Calc'd for C 1gH 1606: C, 67.05; H, 4.74 Found: C, 66.35; H, 4.87 mp: 154-155oC
96. (+/-) 4-(8-Benzyl-3-hydroxy-3,4-dihydro-2H-benzo[B][1,4]di-oxepin-6-yl)-2,4-dioxobutyric acid Anal. Calc'd for C2pH1807: C, 64.06; H, 4.90 Found: C, 64.06; H, 5.14 mp: 182-183oC
97. 4-(2,3-Dimethoxy-5-pent-4-enylphenyl)-2,4-dioxobutyric acid v ~C02H
OMe OMe Anal. Calc'd for C17H2006: C, 63.74; H, 6.29 Found: C, 64.05; H, 6.05 mp: 75-76oC
98. 4-(5-Cyclopropylmethyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid ~ ~COzH
OMe OMe Anal. Calc'd for C 16H 1806: C, 62.74; H, 5.92 Found: C, 62.75; H, 5.79 mp: 101-103oC
99. 4-( 5-Benzyl-2-isopropoxy-3-[ 1,2, 3]triazol-1-ylmethylphenyl )-2,4-dioxobutyric acid 1H NMR (CDC13) 8 7.75 (s, 1H), 7.59 (s, 1H), 7.31-7.12 (m, 7H), 5.63 (s, 2H), 4.19 (m, 1H), 3.92 (s, 2H), 1.29 (d, J = 6 Hz, 6H).
100. 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid 1H NMR (CDCl3) 8 8.42 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.34-7.14 (m, 7H), 5.37 (s, 2H), 4.23 (m, 1H), 3.95 (s, 2H), 1.31 (d, J = 6 Hz, 6H).
101. 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid Anal. Calcd for C2gH27N~6 0.40 HCl 0.25 Et20:
C, 64.54; H, 6.75; N, 3.14.
Found: C, 64.42; H, 6.76; N, 3.11.
102. 4-[3-(Phenyldifluoromethyi)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C17H12F2~4: C, 64.15; H, 3.80.
Found: C, 64.29; H, 3.73.
103. 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid Anal. Calcd for C2pH1805 0.2 hexane: C, 71.60; H, 5.90.
Found: C, 71.78; H, 5.55 104. 4-[5-Benzyl-2-isopropoxy-3-( 1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid TFA salt Anal. Calcd for C26H31N~5 1.15 TFA: C, 59.77; H, 5.70; N, 2.46.
Found: C, 59.68; H, 5.70; N, 2.33.
105 . 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C22H25N05 0.80 H20 0.20 EtOAc:
C, 65.91; H, 6.84; N, 3.37.
Found: C, 65.91; H, 6.91; N, 3.41.
106. 4-[5-Benzyl-2-( 1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C23H25N05 1.7 H20 0.30 EtOAc:
C, 64.23; H, 6.86; N, 3.10.
Found: C, 64.23; H, 6.62; N, 3.08.
107. 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C28H2gN204 0.5 HCl:
C, 70.83; H, 6.00; N, 5.62.
Found: C, 70.73; H, 6.00; N, 5.62.
108. 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid Anal. Calcd for C26H26N205 1.25 H20 0.15 methyl t-butyl ether:
C, 66.62; H, 6.33; N, 5.81.
Found: C, 66.58; H, 6.09; N, 5.43.

(6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid AVIII-3-1 Step 1: 6-Benzvloxvindan-1-one AVIII-1-1 ~ i To a solution of 6-hydroxy-indan-1-one (J. Chem. Soc. Perkin Trans. 1, 1984, 4, 687-695) (29g, 196 mmole) in DMF (250 mL), was added under a N2 atmosphere at ambient temperature K2C03 (69.1g, 500 mmole) and benzyl bromide (27.7 mL, 250 mmole). The reaction was set to reflux for 4 hours. The mixture was allowed to cool to room temperature, poured into water, extracted with CH2Cl2, the organic layer was separated and dried with MgS04, the solvent evaporated and the product purified by chromatography over silica to obtain AVIII-1-1 as a yellowish solid. 1H
NMR (400 MHz, CDCl3) 8 7.45-7.3 (m, 6H), 7.24 (m, 2H), 5.17 (s, 2H), 3.05 (m, 2H), 2.7 (m, 2H). mass spec EI: m/z (relative abundance) 238 (M+), 91 (100).
to ~ (6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid ethyl ester AVIII-2-1 ~OCH2CH3 To a solution of AVIII-1-1 (1.9, 8 mmole) and diethyl oxalate (Aldrich, 2.17 mL, 16 mmole) in THF (8 mL) was added in portions NaOEt (Aldrich, 1.088g, 16 mmole). The reaction was stirred at ambient temperature under a N2 atmosphere for 1.5 hours. The reaction was diluted with CH2Cl2, quenched with saturated NaHC03 (aq), the organic layer was separated and dried with MgS04, the mixture was filtered, the solvent evaporated and the crude purified by preparative silica HPLC

eluting with 10:30:60 EtOAc / CH2Cl2 / Hexanes to afford the product as a yellow solid. melting point 118-119oC (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.48-7.30 (m, 8H), 5.12 (s, 2H), 4.41 (q, J=7.24 Hz, 2H), 3.9I (s, 2H), 1.43 (t, J=7.24 Hz, 3H). mass spec EI: m/z (relative abundance) 338 (M+), 91 (100).
S~,p~: (6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid i off A solution of AVIII-2-1 (500mg, 1.47 mmole) in 1,4-dioxane (3 mL) and 3~T HCl (3 mL) was heated in a sealed tube at 70oC overnight. The reaction was then allowed to cool to ambient temperature and poured into 1N HCl (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 / hexanes to afford AVIII-3-1 as a yellow solid. melting point 188-189oC (uncorrected). 1H NMR {400 MHz, DMSO) 8 7.56 (d, J=8.4, 1H), 7.47 (m, 2H), 7.42-7.33 {m, 5H), 5.21 (s, 2H), 3.77 (s, 2H). mass spec (FAB, m+1) 311 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid AVII-3-1 Stegl_: 6-Bromo-1-(4-fluorobenzvl)indole F \ /
Br \ I , A solution of 6-bromoindole (J. Org. Chem. 1986, 51, 5106) (3.00 g, 15.3 mmol) in DMF (65 mL) was treated with NaH (734 mg of a 60°l0 suspension in mineral oil, 18.4 mmol). After 30 min, 4-fluorobenzyl bromide (1.90 mL, 15.3 mmol) was added. When starting material was consumed, the reaction mixture was poured into 1~T HCl and extracted with EtOAc (3x), the combined organic layers were dried (MgS04) and concentrated. Chromatography of the residue (4:1/hexanes:EtOAc) provided the product.
1H NMR (400 MHz, CDCl3) 8 7.49 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.21 (dd, J = 8.4, 1.0 Hz, 1H), 7.08-7.04 (m, 3H), 7.15-6.96 (m, 2H), 6.52 (d, J = 3.2 Hz, 1H), 5.24 (s, 2H). mass spec (EI, M+) 303, 305 Step 2: 1.-f 1-(4-Fluorobenzvl)-6-indolvll-ethanone AVII-1-1 F \ / o Iw To a solution of 6-bromo-1-(4-fluorobenzyl)indole (2.50 g, $.20 mmol) in THF (40 mL) at -78 °C was added t-butyllithium ( 10.6 mL of a 1.7 M
solution in pentane, 18.0 mmol) dropwise. After stirring at -78 °C for min, N-methoxy-N-methylacetamide (1.20 g, 12.3 mmol) was added and the mixture was stirred at -78 °C for 2 h and rt for 1 h before adding sat.
NH4C1 (5 mL). The reaction mixture was poured onto water and extracted with EtOAc (3x). The combined organic extracts were washed with sat. NaCl and dried (MgS04). Concentration followed by chromatography of the residue (4:1/hexanes:EtOAc) provided 750 mg (3410) of product.

WO 99/b2520 PCTNS99/12093 1H NMR (400 MHz, CDCl3) b 8.00 (s, 1H), 7.74 (dd, J = 8.3, 1.5 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 3.1 Hz, 1H), 7.12-7.07 (m, 2H), 7.00 (m, 2H), 6.60 (d, J = 3.1 Hz, 1H), 5.38 (s, 2H), 2.63 (s, 3H).
Sin : 1-[1-(4-Fluorobenzyl)-6-indolyl]- 2,4-dioxobutanoic acid methyl ester AVII-2-1 O
Avn-2-1 To a solution of AII-1-1 (700 mg, 2.60 mmol) in THF (10 mL) was added dimethyl oxalate (460 mg, 3.90 mmol) followed by NaH (156 mg of a 60%
suspension in mineral oil, 3.90 mmol). Methanol (2 drops) was added and the reaction mixture was heated to reflux. After 1 h, 1 N HCl (20 mL) was added and the mixture was extracted with CH2Cl2 (3 x 15 mL).
The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgS04). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 5:5:1/
CH2C12:hexanes:EtOAc, afforded 597 mg (65%) of product. 1H NMR (400 MHz, CDC13) 8 8.05 (s, 1H), 7.76 (dt, J = 8.4, 1.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 3.1, 1.1 Hz, 1H), 7.14 (s, 1H), ?.I1 (dd, J = 8.4, 5.2 Hz, 2H), 7.01 (t, J = 8.4 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 5.38 (s, 2H), 3.95 (s, 3H).
Step 4: 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid AVII-H
O

To a solution of AVII-2-1 (597 mg, 1.69 mmol) in THF (10 mL) was added 1 ~T NaOH (5 mL). After stirring for 14 h at rt, the mixture was poured into 1 N NaOH (20 mL) and extracted with Et20 (3 x 20 mL). The Et20 extracts were discarded. The aqueous phase was treated with 3 N HCl (30 mL), extracted with CH2C12 (3 x 20 mL) and the combined organic extracts dried (MgSO4). Concentration provided a bright red solid which was triturated with Et20 to provide the product. mp 173-174 °C
(uncorrected). 1H NMR (400 MHz, d6_DMSO) 8 8.37 (s, 1H), 7.79 (d, J =
3.0 Hz, 1H), 7.75 (dt, J = 8.4, 1.3 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.7, 5.6 Hz, 2H), 7.25 (s, 1H), 7.15 (t, J = 8.2 Hz, 2H), 6.63 (d, J = 3.0 Hz, 1H), 5.62 (s, 2H). mass spec (negative mode electrospray, M-H) 338 1-[1-(4-Fluorobenzyl)-4-indolyl]-2,4-dioxobutanoic acid AVII-3-2 Compound AVII-3-2 was prepared in a manner similar to that described for AVII-3-1 by replacing 6-bromoindole with 4-bromoindole (J. Org. Chem. 1986, 51, 5106).
F
O O
~OH
v ll ~ O AVB-3-2 mp 156-157 °C (uncorrected). 1H NMR (400 MHz, dg-DMSO) 8 7.88 (d, J =
8.3 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.30-7.25 (m, 1H), 7.17-7.11 (m, 4H), 5.52 (s, 2H). mass spec (negative mode electrospray, M-H) 338 4-[1-(2.6-Diffuorobenzyl~lH-indol-6-yl]-2,4-dioxobutyric acid N ~' / ~ 0 0 F
ES MS Exact Mass Calcd. for C1gH13F2NO4+H 358.0885 Found 358.0887 4-( 1-Benzyl-1H-indol-6-yl)-2,4-dioxobutyric acid ~\

O O
Anal. Calcd for C1gH15N04 0.75 HC10.05 H20:
C, 65.27; H, 4.57; N, 4.01.
Found: C, 65.26; H, 4.25; N, 3.87.

4-(5-Benzyl-2-methoxypyridin-3-yl)-2,4-dioxobutyric acid Anal. Calcd for C17H15N05 0.05 Et20 0.05 H20:
C, 64.98; H, 4.95; N, 4.41.
Found: C, 64.91; H, 4.89; N, 4.15.

The Compounds in the following Table were made according to the procedures outlined in the Schemes and in Exa~pnples 1 to 31.

EXACT MASS FOUND
COMPOUND NAME CALC (m/z): (m/z):
4-[3-(2,4-difluoro-benzyl)- 319.0776 319.0781 phenyl]-2,4-dioxo-butyric acid 2,4-dioxo-4-[3-(2,6-difluoro- NH4+ 336.1063 benzyl)-phenyl]-butyric 336.1042 acid 2,4-dioxo-4-[3-(2-4-6- NH4+ 354.0955 trifluoro-benzyl)-phenyl]- 354.0948 butyric acid (sodium salt) 2,4-dioxo-4-[3-(2-fluoro-3- C17H12C1F04 352.0763 choro-benzyl)-phenyl]- NH4+
butyric acid 352.0746 2,4-dioxo-4-[3-(2-methyl-4- NH4+ 332.1307 fluoro-benzyl)-phenyl]- 332.1293 butyric acid 4-[3-{2,3-dichloro-benzyl)- C17H12C1204.NH4+ 368.0443 phenyl]-2,4-dioxo-butyric 368.0451 acid 4-[3-(2-chloro-3- C18H15C104.NH4+ 34$.1015 methylbenzyl)phenyl]-2,4- 348.0997 dioxobutyric acid 2,4-dioxo-4-(3-(2,6-dichloro- NH4+ 368.046 benzyl)-phenyl]-butyric 368.0451 acid 2,4-dioxo-4-[3-(2,3,4,5,6- NH4+ 390.0775 penta-fluoro-benzyl)- 390.0759 phenyl]-butyric acid 4-[3-(2- C17H13F04.NH4 318.1133 fluorobenzyl)phenyi]-2,4- 318.1136 dioxobutyric acid 2,4-dioxo-4-[3-(2-choro-4- NH4+ 352.0752 fluoro-benzyl )-phenyl]- 352.0746 butyric acid 4-[3-(2- C18H1604.NH4+ 314.1395 methylbenzyl)phenyl]-2,4- 314.1387 dioxobutyric acid 2,4-dioxo-4-[3-(2- NH4+ 330.135 methoxybenzyl)phenyl]buty 330.1336 ric acid 4-[3-(2- C17H13C104.NH4+ 334.0854 chlorobenzyl)phenyl]-2,4- 334.0841 dioxobutyric acid 4-[3-(2- C17H13BrC4-~4+ 37$.034 bromobenzyl)phenyl]-2,4- 378.0335 dioxobutyric acid 4-[5-(4-fluoro-benzyl)-2,3- 361.1082 361.109 dimethoxy-phenyl]-2,4-dioxo-butyric acid 4-[3-(3-chloro-2-methyl- C18H15C104.NH4+ 348.1013 benzyl)phenyl]-2,4- 348.0997 dioxobutyric acid 4-[3-(2,3-difluoro-benzyl)- C17H12F2~4.~4+ 336.1044 phenyl]-2,4-dioxo-butyric 336.1042 acid 4-(3,5-dibenzylphenyl)-2,4- C2~i2004.NH4+ 390.171 dioxo-butyric acid 390.1700 2,4-dioxo-4-[3-(2- NH4+ 368.1111 trifluoromethylbenzyl)phen 368.1104 yl]butyric acid 4-[3-(4- Cl?H13F~4 301.0885 fluorobenzyl)phenyl]-2,4- 301.0876 dioxobutyric acid 4-[3-(3- C17H13C104.NFi4+ 334.0847 chlorobenzyl)phenyl]-2,4- 334.0841 dioxobutyric acid 2,4-dioxo-4-[3-(2-bromo-3- NH4+ 411.9944 chloro-benzyl)-phenyl]- 411.9946 butyric acid WO 99!62520 PGT/US99/12093 4-(3-benzylphenyl)-2,4- C17H1404.~4+ 300.124 dioxo-butyric acid 300.123 4-[3-(2-ffuoro-3-methyl- 315.1027 315.1034 benzyl)-phenyl]-2,4-dioxo-butyric acid sodium salt 4-[3-(3-chloro-4-ffuoro- C17H12C1F04.IVH4 352.0733 benzyl)-phenyl]-2,4-dioxo- + 352.0746 butyric acid 2,4-dioxo-4-[3-(2-bromo-4- NH4+ 396.0247 ffuoro-benzyl)-phenyl]- 396.0241 butyric acid 4-[3-(3- C 17H13B~4 361.0101 bromobenzyl)phenyl]-2,4- 361.0075 dioxobutyric acid 4-[3-(2,5-diffuoro-benzyl)- C17H12F204.NH4+ 336.1046 phenyl]-2,4-dioxo-butyric 336.1042 acid 4-[3-(5-chloro-2-ffuoro- C17H12C1F04.NH4 352.0753 benzyl)phenyl]-2,4- + 352.0746 dioxobutyric acid 4-[3-(3- C18H1604 297.112 methylbenzyl)phenyl]-2,4- 297.1121 dioxobutyric acid 4-(3-benzyl-4-methyl- 297.1121 297.1142 phenyl)-2,4-dioxo-butyric acid 4-[3-(3,4-diffuoro-benzyl)- 319.0776 319.078 phenyl]-2,4-dioxo-butyric acid 4-[3-(2,5-dichloro-benzyl)- C17H12C1204.NH4+ 368.0465 phenyl]-2,4-dioxo-butyric 368.0451 acid 4-[3-{2-chloro-6-methyl- C18H15C104.NH4+ 348.1012 benzyl)phenyl]-2,4- 348.0997 dioxobutyric acid 2,4-dioxo-4-[3-(2- NH4+ 386.1010 386.1009 trifluoromethyl-4-chloro-benzyl)-phenyl]-butyric acid 4-[3-(2-bromo-5-chloro- C17H12BrC104.NH4 411.9966 benzyl)-phenyl]-2,4-dioxo- + 411.9947 butyric acid 4-( 3-naphthalen-1- 333.1121 333.1121 ylmethyl-phenyl)-2,4-dioxo-butyric acid 2,4-dioxo-4-[3-(3- NH4+ 318.1136 318.114 fluorobenzyl)phenyl]butyric acid 2,4-dioxo-4-(3- 301.0535 301.0524 phenyl sulfanyl-phenyl )-butyric acid 2,4-dioxo-4-[3-( 1- 1VH4+ 314.1401 phenylethyl)phenyl]butyric 314.1387 acid 4-( 3-benzyl-4,5- 311.1278 311.1293 dimethylphenyl )-2,4-dioxo-butyric acid 2,4-dioxo-4-[3-(3- NH4+ 330.1341 methoxybenzyl)phenyl]buty 330.1336 ric acid 4-[3-(5-methyl-thiophen-2- NH4+ 320.0967 ylmethyl)phenyl]-2,4-dioxo- 320.0951 butyric acid 4-[3-(5-chloro-thiophen-2- NH4+ 340.0418 ylmethyl)phenyl]-2,4-dioxo- 3øp.p405 butyric acid 4-(3-benzyl-5- 297.1121 297.1127 methylphenyl)-2,4-dioxo-butyric acid 4-[3-(2- NH4+ 325.1157 cyanobenzyl)phenyl]-2,4- 325.1183 dioxo-butyric acid Methyl 4-[3-benzylphenyl]- C18H1604 29?.113 2,4-dioxobutyrate 297.1121 4-[3-(3,5-dichloro-benzyl)- 351.0185 351.0167 phenyl]-2,4-dioxo-butyric acid 4-(5-benzyl-2,4- 311.1278 311.1298 dimethylphenyl )-2,4-dioxo-butyric acid 4-(5-benzyl-2- 297.1121 297.1123 methylphenyl )-2,4-dioxo-butyric acid 4-( 3-cyclohexylmethyl- 289.1434 289.1449 phenyl)-2,4-dioxo-butyric acid 4-(3-[(methyl-phenyl- 312.123 312.1235 amino)-methyl]-phenyl}-2,4-dioxo-butyric acid 4-[3-benzyl-5-(5-hydroxy- 369.1696 369.1688 pentyl)-phenyl]-2,4-dioxo-butyric acid 4-(3-benzyl-5-pyrazin-2-yl- NH4+ 378.1455 phenyl)-2,4-dioxo-butyric 378.1448 acid 4-[3-(3-tent-butoxy-2- 427.2115 427.213 hydroxy-propyl )-5-(2-methyl-benzyl )-phenyl]-2,4-dioxo-butyric acid 2,4-dioxo-4-[3-(2,3- NH4+ 360.1451 dimethoxy-benzyl)-phenyl]- 360.1442 butyric acid 4-[3-(methoxyphenyl- C18H1605.NH4+ 330.1344 methyl )phenyl]-2,4- 330.1336 dioxobutyric acid 4-[3-[hydroxy-(tetrahydro- C23H2406.NH4+ 414.1911 furan-3-yl)-methyl]-5-(2- 414.1917 methyl-benzyl )-phenyl]-2,4-dioxo-butyric acid 2,4-dioxo-4-(3- 299.0914 299.0924 phenoxymethyl-phenyl)-butyric acid 2,4-dioxo-4-( 3- 313.107 313.1096 phenoxymethyl-phenyl )-butyric acid methyl ester 4-[3-benzyl-5- C21HgN05.NH4+ 383.1601 (cyclopropylcarboxamido)- 383.1601 phenyl]-2,4-dioxobutyric acid 4-[3-benzyl-5-(t- C22H23N06.~4+ 415.1867 butoxycarbamoyl)phenyl]- 415.1863 2,4-dioxobutyric acid 4-[ 3-(hydroxy-phenyl- C 17H 145 299.0905 methyl)-phenyl]-2,4-dioxo- 299.0919 butyric acid 4-(5-benzyl-2,3- 311.1278 311.1275 dimethylphenyl)-2,4-dioxo-butyric acid sodium salt N-[3-(3,5- C17H12Br'2C4 ~4+ 455.9461 dibromobenzyl)phenyl]-2,4- 455.9440 dioxo-butyric acid 4-[3-(2-methyl-benzyl)-5- 389.1496 389.149 pyrimidin-2-yl-phenyl]-2,4-dioxo-butyric acid methyl ester 4-[3-benzyl-2-(pyrimidin-2- C21H20N304 376.1292 ylamino)-phenyl]-2,4-dioxo- 376.1306 butyric acid hydrochloride 4-[3-benzoimidazol-1- 427.1652 427.1648 ylmethyl-5-( 2-methyl-benzyl)-phenyl]--2,4-dioxo-butyric acid TFA salt 2,4-dioxo-4-[3-(3- CHN +0.75 HCl C: 57.38;
trifluoromethylbenzyl)phen C:57.24; H: 3.67 H, 4.03 yl]butyric acid 4-(4-phenoxy-phenyl)-2,4- 285.0757 285.0763 dioxo-butyric acid 2,4-dioxo-4-(3-[1,2,3]triazol- C13H11N3~4.Na 296.0645 2-ylmethyl-phenyl)-butyric 296.0642 acid 4-[3-benzyl-5-(6-methoxy- 390.1336 390.1361 pyridin-2-yl)-phenyl]-2,4-dioxo-butyric acid 4-( 3-benzotriazol-2- 324.0984 324.0978 ylmethyl-phenyl)-2,4-dioxo-butyric acid 4-[3-benzyl-5-(2-(4- 459.2027 459.2014 methylpiperazin-1-yl)-pyrazin-6-yl)phenyl]-2,4-dioxobutyric acid 4-[4-(3-phenethyl)phenyl]- 297.1121 297.1124 2,4-dioxobutyric acid 4-[4-(3- C17H13C104.NH4+ 334.0854 chlorobenzyl)phenyl]-2,4- 334.0841 dioxobutyric acid 4-(3-benzoimidazol-1- 323.1026 323.1033 ylmethyl-phenyl )-2,4-dioxo-butyric acid trifluoracetic acid salt 4-[3-benzyloxy-5-(6-tert- 528.2604 528.2592 butoxycarbonylamino-hexyloxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid methyl ester 4-( 3-benzotriazol-1- 274.0822 274.0825 ylmethyl-phenyl)-2,4-dioxo-butyric acid 4-[3-(3,5-dimethyl-pyrazol- C16H16N2~4 301.1196 1-ylmethyl)-phenyl]-2,4- 301.1183 dioxo-butyric acid 4-[3-benzyloxy-5-(2- 428.1704 428.1695 morphonin-4-yl-ethoxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid TFA
salt 4-(4-methyl-3-phenoxy- 299.0914 299.0914 phenyl)-2,4-dioxo-butyric acid 4-[3-(2-hydroxy-benzyl)- 316.118 316.iI77 phenyl]-2,4-dioxo-butyric acid 4-[3-benzyl-5-(6- 404.1605 404.162 dimethylamino-pyrazin-2-yl)-phenyl]-2,4-dioxo-butyric acid HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, C.M. and Bushman F.D. (1997) Cell; 88, 483 for recombinant integrase and preintegration complexes, respectively, hereby incorporated by reference for these purposes.
Representative compounds tested in the integrase assay demonstrated IC50's less than 1 micromolar. Further, representative compounds tested in the preintegration complex assay also demonstrated IC50's of less than 1 micromolar.

Assay fox inhibition of HIV replication Assays for the inhibition of acute HIV infection of T-lymphoid cells was conducted according to Vacca, J.P. et al., (1994), Proc. Natl. Acad. Sci. USA 91, 4906, herein incorporated by reference for these purposes.
Representative compounds tested in the present assay demonstrated ICgSs of less than 10 micromolar.

Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as come within the scope of the following claims and their equivalents.

Claims (24)

WHAT IS CLAIMED:
1. A compound of structural formula (I):

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R2, R8, and R9;
optionally the aromatic ring may be fused with another ring system to form:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR7, (4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -halo, (8) -NO2, (9) -Co-3 alkyl -N(R4)(R5), (10) -R6, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, (13) -O-R6, (14) -O-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, (15) -O-C1-6 alkyl-NH-C(O)-OR7;
(16) -O-C2-6 alkyl-N(R4)(R5);
(17) -S-C1-3 alkyl;
(18) -C(O)CH2C(O)C(O)OR7;
(19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -C2-6 alkenyl, (6) -O-R6, (7) -O-C1-6 alkyl-OR6, (8) -O-C1-6 alkyl- SR6, (9) -S(O)n-R6, (10) -C1-6 alkyl (OR6)(R4), (11) -C0-6 alkyl-N(R4)(R6), (12) -C1-6 alkyl S(O)n-R6, (13) -C0-6 alkyl C(O)R6, (14 ) -C0-6 alkyl C(O)CH2-C(O)-OH, (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR4C(O)-R6, (17) -C1-6 alkyl-C(O)N(R4)(R5), and (18) -CH2(OR7)-R6;

each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN,and (h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0,1,2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O,and (h) hydroxy; and (7) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O,and (h) hydroxy; and each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R5 is independently selected from:

(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, (9) -C(O)-R3, (10) -C(O)OR4, and (11) -C(O)C(O)ON;
each R6 independently selected from:

(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from:
(1) -H, (2) -O- C1-6 alkyl and (3) C1-6 alkyl;

R9 is selected from:

(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and each n is independently selected from 0, 1 and 2;

PROVIDED THAT when A is phenyl:
(1) R1 is not R6 para to the dioxobutyric acid/ester moiety; and (2) R2 is not selected from:

(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R2, and R8 is not:
(a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R2 is S(O)n R6, and R6 is CH2-R3 or R3, then R3 is not unsubstituted phenyl.
2. The compound according to Claim 1 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) phenyl, (2) pyridyl, (3) naphthyl, (4) indolyl, provided that the aryl ring is substituted by the dioxobutyric acid/ester moiety in structural formula (I), (5) R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR7;
(4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -F, Cl, or Br,, (8) -NO2, (9) -C0-3 alkyl -N(R4)(R5), (10) -phenyl, (11) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -CF3, (f) -SCH3, (g)-CN, (h)hydroxy, (i)phenyloxy, (j)-C0-6 alkyl-N(R7)2, (k) (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(13) -O-R6, (14) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (15) -O-C1-6 alkyl-NH-C(O)-OR7;
(16) -O-C2-6 alkyl-N(R4)(R5);
(17) -S-C1-3 alkyl;
(18) -C(O)CH2C(O)C(O)OR7;
(19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S-R6, (7) -O-C1-6 alkyl- SR6;
(8) -C1-6 alkyl (OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C1-6 alkyl S -R6, (11) -C0-6 alkyl C(O)-R6, (12) -C0-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6 (14) -C1-6 alkyl-C(O)N(R4)(R5), and (15) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen.
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f)~-CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl, (8) substituted imidazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (i) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii ) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl, (10) substituted pyrrolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;

(11) pyrazolyl, (12) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(15) piperidinyl, (16) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(19) hexahydrothieno[3,4-d]imidazolyl, (20) substituted hexahydrothieno[3,4-d] substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents independently selected from:
(a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (fl -OCF3, (g) -CN, and (h) hydroxy, (21) naphthyl, (22) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (23) indolyl, (24) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(25) C3-6 cycloalkyl fused with a phenyl ring (26) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(27) pyrazinyl;
(28) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(29) pyrimidinyl;
(30) substituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(31) triazolyl;
(32) substituted triazolyl with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (j) (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(33) tetrazolyl;
(34) substituted tetrazolyl with a substituent selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(35) C3-6 cycloalkyl;
(36) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(37) tetrahydrofuran;
(38) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) -O
(h) benzyl, and (i) hydroxy;
(39) piperazinyl;
(40) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(41) benzotriazolyl, (42) substituted benzotriazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(43) benzoimidazolyl, (44) substituted benzoimidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
each R4 is independently selected (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3 (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, and (8) -C(O)-R3;
each R5 independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -S(O)n-R3, (8) -C(O)-R3, (9) -C(O)OR4, and (10) -C(O)C(O)OH;

each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from hydrogen, methyl and -O- C1-6 alkyl; and R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and each n is independently selected from 0, 1 and 2;
PROVIDED THAT when A is phenyl:

(1) R1 is not (a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity, or (d) substituted -C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity; and (2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R2, and R8 is not:
(a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when or R2 is SR6, and R6 is CH2-R3 or R3, then R3 is not unsubstituted phenyl.
3. The compound according to Claim 2 , and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) phenyl, (2) pyridinyl, (3) indolyl, provided that 6-membered aromatic ring is substituted by the dioxobutyric moiety in structural formula (I);

and R1 is selected from:
(1)-H, (2)-CH3, (3)-C1-6 alkyl-OR7;
(4)-O-C1-6 alkyl-OR7, (5)-O-C1-6 alkyl-SR7, (6)-CF3 or -CH2CF3, (7)-Cl, (8) -F, (9)-C0-8 alkyl -N(R4)(R5), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, and (h) -C0-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, and (h) -C0-6 alkyl-N(R7)2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(O)CH2C(O)C(O)OH;
(15) -O-C1-6 alkyl-NH-C(O)-OR7;
(16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S-R6, (7) -O-C1-6 alkyl- SR6;
(8) -C1-6 alkyl (OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C0-6 alkyl C(O)-R6, (11) -C0-6 alkyl C(O)CH2-C(O)-OH, (12) -C1-6 alkyl NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and (14) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo;
(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy;
(11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3 (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) =O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and (f) hydroxy;
(17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) pyrazinyl;
(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -C0-6 alkyl-N(R7)2, and (g) ;
(25) pyrimidinyl;
(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;
(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl;
(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;
(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy;
(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3;
each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from hydrogen, methyl and -O- C1-6 alkyl; and R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and PROVIDED THAT: when A is phenyl, (1) R1 is not:
(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity, or (d) substituted -C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity; and (2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R2, and R8 is not:
(a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R2 is SR6, R6 is R3.
4. The compound according to Claim 3 and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, (10) -C0-3 alkyl -N(R4)(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, {f) hydroxy, (g) -C0-6 alkyl-N(R7)2, (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1-6 alkyl-NH-C(O)-OR7, (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2 NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(O)CH2C(O)C(O)OH, (27) -CH2-CH(OH)-CH2-O-R7, and (28) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S-phenyl, (9) -C1-6 alkyl (OR6)(R4), (10) -C0-6 alkyl-N(R4)(R6), (11) -C(O)-R3, (12) -C0-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6, (14) -CH(OCH3)R3, and (15) -CH(OH)R3;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (l) hydroxy;
(3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from:
(a) F, (b) Cl, and (c) methyl;
(5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from:
(a) -F, (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo;
(7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) -F, (b) -Cl, (c) -CH3, and (d) -CF3;
(9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from:

(a) methoxy-, (b) -OCF3, (c) =O, and (d) hydroxy;
(12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl;
(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3, (d) methoxy-, (e) -N(CH3)2, and (f) (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl;
(21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl, (27) substituted piperazinyl substituted with a substituent selected from:
(a) -F, (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (s) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (s) -C(O)OR4, and (7) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from:
(1) -H, (2) methoxy, and (3) -C1-6 alkyl, and R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and PROVIDED THAT: when A is phenyl, (1) R1 is not:

(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity, or (d) substituted -C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity; and (2) R2 is not selected from:
(a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, (c) -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R2, R8 and R9 is not:
(a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl.
5. The compound according to Claim 4, wherein A is phenyl, and at least one of R1, R2, R8 and R9 is not hydrogen, and tautomers and pharmaceutically acceptable salts thereof.
6. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -C1-6 alkyl-OR7;
(4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -C0-3 alkyl -N(R4)(R5), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, (i) -C0-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, -OCH2CH3, -OCF3, or -OCH2CF3, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, (i) -C0-6 alkyl-N(R7)2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(O)CH2C(O)C(O)OH, (15) -O-C1-6 alkyl-NH-C(O)-OR7, (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S-R6, (7) -O-C1-6 alkyl- SR6, (8) -C1-6 alkyl (OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C0-6 alkyl C(O)-R6, (11) -C0-6 alkyl C(O)CH2-C(O)-OH, (12) -C1-6 alkyl NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and (14) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo;
(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a} halogen, selected from -F, -Cl, and -Br;
(b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy;

(11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) =O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and (f) hydroxy;
(17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:

(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) pyrazinyl;
(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -C0-6 alkyl-N(R7)2, and (g) (25) pyrimidinyl;

(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;
(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl;
(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;

(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy;
(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
PROVIDED THAT:
(1) at least one of R1 and R2 is not:
(a) H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (2) when R2 is SR6, R6 is R3.
7. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -C1-6 alkyl-OR7;
(4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -C0-3 alkyl -N(R4)(R5), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
{a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, and (h) -C0-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) -CH3, {c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, and (h) -C0-6 alkyl-N(R7)2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(O)CH2C(O)C(O)OH, (15) -O-C1-6 alkyl-NH-C(O)-OR7, (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH
(22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S -R6, (7) -O-C1-6 alkyl- SR6;
(8) -C1-6 alkyl (OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C0-6 alkyl C(O)-R6, (11) -C0-6 alkyl C(O)CH2-C(O)-OH
(12) -C1-6 alkyl NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and (14) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo;
(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy;
(11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f)~-CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) =O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and (f) hydroxy;
(17) hexahydrothieno(3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) pyrazinyl;
(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -C0-6 alkyl-N(R7)2, and (g) (25) pyrimidinyl;
(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;

(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl;
(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;
(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy;
(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3;
each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH;
each R6 is independently selected from:

(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from methyl and -O- C1-6 alkyl; and PROVIDED THAT:
(1) at least one of R1, R2, and R8 is not:
(a) C1-6 alkyl, or (b) R3 wherein R3 is cycloalkyl; and (2) when R2 is SR6, R6 is R3.
8. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -C1-6 alkyl-OR7;
(4) -O-C 1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -C0-3 alkyl-N(R4)(R5), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -C0-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -C0-6 alkyl-N(R7)2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(O)CH2C(O)C(O)OH, (15) -O-C1-6 alkyl-NH-C(O)-OR7, (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S-R6, (7) -O-C1-6 alkyl-SR6, (8) -C1-6 alkyl-(OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C0-6 alkyl-C(O)-R6, (11) -C0-6 alkyl-C(O)CH2-C(O)-OH, (12) -C1-6 alkyl-NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and (14) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo;
(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy;
(11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) =O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted at carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and hydroxy;
(17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) pyrazinyl;
(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (fl -C0-6 alkyl-N(R7)2, and (g) (25) pyrimidinyl;
(26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, {b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;
(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl;
(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;
(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy;
(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3;
each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from methyl and -O- C1-6 alkyl; and each n is independently selected from 0, 1 and 2;
PROVIDED THAT:

(1) at least one of R1, R2, and R8 is not:
(a) C1-6 alkyl, or (b) R3 wherein R3 is cycloalkyl; and (2) when R2 is SR6, R6 is R3.
9. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -C1-6 alkyl-OR7, (4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -CO-3 alkyl -N(R4)(R6), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -C0-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -C0-6 alkyl-N(R7)2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, and (14) -C(O)CH2C(O)C(O)OH, (15) -O-C1-6 alkyl-NH-C(O)-OR7, (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S -R6, (7) -O-C1-6 alkyl- SR6, (8) -C1-6 alkyl (OR6)(R4), (9) -C0-6 alkyl-N(R4)(R6), (10) -C0-6 alkyl C(O)-R6, (11) -C0-6 alkyl C(O)CH2-C(O)-OH, (12) -C1-6 alkyl NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and (14) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and (f) oxo;
(3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from F, Cl, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, and (c) C 1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom;
(5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo;
(7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br;
(b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy;
(11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from:
(a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f)~=O, and (g) hydroxy;
(15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and (f)~hydroxy;
(17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) pyrazinyl;

(24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, {e) phenyloxy, (f) -C0-6 alkyl-N(R7)2, and (g) {25) pyrimidinyl;
{26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl;
(28) substituted triazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl;
(30) substituted tetrazolyl with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl;

(32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran;
(34) substituted tetrahydrofuran substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl;
(36) substituted piperazinyl substituted with one or two substituents independently selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy;
(37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or two substituents independently selected from:
{a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from:
(a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from methyl and -O- C1-6 alkyl; and PROVIDED THAT:
(1) at least one of R1, R2, and R8 is not:
(b) C 1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (2) when R2 is SR6, R6 is R3.
10. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, (10) -C0-3 alkyl -N(R4)(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, , (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1-6 alkyl-NH-C(O)-OR7, (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(O)CH2C(O)C(O)OH;
(27) -CH2-CH(OH)-CH2-O-R7; and (28) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S-phenyl, (9) -C1-6 alkyl (OR6)(R4), (10) -C0-6 alkyl-N(R4)(R6), (11) -C(O)-R3, (12) -C0-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6, (14) -CH(OCH3)R3, and (15) -CH(OH)R3;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (l) hydroxy;
(3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from:
(a) F, (b) Cl, and (c) methyl;
(5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from:
(a) -F, (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo;
(7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) -F, (b) -Cl, (c) -CH3, and (d) -CF3;
(9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from:
(a) methoxy-, (b) -OCF3, (c) =O, and (d) hydroxy;
(12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl;
(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3, (d) methoxy-, (e) -N(CH3)2, and (f) (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl;

(21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl;
(27) substituted piperazinyl substituted with a substituent selected from:
(a) -F, (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl.
11. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, (10) -C0-3 alkyl -N(R4)(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, , (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1-6 alkyl-NH-C(O)-OR7, (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(O)CH2C(O)C(O)OH;
(27) -CH2-CH(OH)-CH2-O-R7; and (28) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S -phenyl, (9) -C1-6 alkyl(OR6)(R4), (10) -C0-6 alkyl-N(R4)(R6), (11) -C(O)-R3, (12) -C0-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6, (14) -CH(OCH3)R3, and (15) -CH(OH)R3;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (l) hydroxy;
(3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from:
(a) F, (b) Cl, and (c) methyl;
(5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from:
(a) -F, (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo;
(7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) -F, (b) -Cl, (c) -CH3, and (d) -CF3;
(9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from:
(a) methoxy-, (b) -OCF3, (c) =O, and (d) hydroxy;
(12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl;
(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3 (d) methoxy-, (e) -N(CH3)2, and (f) (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl;
(21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl;
(27) substituted piperazinyl substituted with a substituent selected from:
(a) -F, (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R4 is independently selected from:

(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)OH;

each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1 alkyl.
12. The compound according to Claim 1 of structural formula:

and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, (10) -C0-3 alkyl-N(R4)(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:
(a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from:

(a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R7)2, , (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1-6 alkyl-NH-C(O)OR7, (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(O)CH2C(O)C(O)OH;
(27) -CH2-CH(OH)-CH2-O-R7; and (28) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S-phenyl, (9) -C1-6 alkyl (OR6)(R4), (10) -C0-6 alkyl-N(R4)(R6), (11) -C(O)-R3, (12) -C0-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6, (14) -CH(OCH3)R3, and (15) -CH(OH)R3;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (l) hydroxy;
(3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from:

(a) F, (b) Cl, and (c) methyl;
(5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from:
(a) -F, (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo;
(7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from:
(a) -F, (b) -Cl, (c) -CH3, and (d) -CF3;
(9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from:
(a) methoxy-, (b) -OCF3, (c) =O, and (d) hydroxy;
(12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl;
(16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from:
(a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3 (d) methoxy-, (e) -N(CH3)2, and (f) (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl;
(21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl;
(27) substituted piperazinyl substituted with a substituent selected from:
(a) -F, (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, and (6) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl.
13. A compound according to Claim 1, selected from:
(1) 3-biphenyl-4-yl-2,4-dioxobutanoic acid, (2) 4-(3,5-bis-benzyloxyphenyl)-2-hydroxy-4-oxo-but-2-enoic acid, (3) 4-[3-(3,4-difluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (4) 4-[3-(4-methylbenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (5) 4-(3-benzyloxy-5-methoxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (6) 4-(3-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (7) 4-[3-(4-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (8) 4-[3-(3,4-dichlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (9) 4-[3-(4-fluorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (10) 4-[3-(3-chlorobenzyl)oxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (11) 4-[3-benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)phenyl]-2-hydroxy-4-oxobut-2-enoic acid, (12) 4-(3-(4-methoxybenzyloxy)phenyl)-4-oxo-2-butenoic acid, (13) 4-(3-benzyloxy-5-hydroxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (14) 4-(3-(1-phenylethoxy)phenyl)-4-oxo-2-butenoic acid, (15) 4-[3-benzyloxy-5-(6-[5-(2-oxohexahydrothieno[3,4-d]imidazol-4-yl)pentanoylamino]hexyloxy)-phenyl]-2-hydroxy-4-oxobut-2-enoic acid, (16) 4-[3-(6-aminohexyloxy)-5-benzyloxyphenyl]-2-hydroxy-4-oxobut-2-enoic acid, (17) 4-(3-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (18) 4-(3-chloro-phenyl)-2,4-dioxobutanoic acid, and (19) 4-(3-benzyl-phenyl)-2,4-dioxo-butanoic acid, (20) 4-(4-dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (21) 4-(4-benzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (22) 4-(2-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (23) 4-naphthalen-1-yl-2,4-dioxobutanoic acid, (24) 4-naphthalen-2-yl-2,4-dioxobutanoic acid, (25) 4-(6-benzyloxy-2-oxo-1,2-dihydropyridin-4-yl)-2-hydroxy-4-oxobut-2-enoic acid, (26) 4-(2,6-Bis benzyloxypyridin-4-yl)-2,4-dioxobutanoic acid, (27) 4-[1-(4-fluorobenzyl)-5-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, (28) 4-[1-(4-fluorobenzyl)-4-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, (29) 4-(4-benzyloxyphenyl)-2-hydroxy-4-oxobut-2-enoic acid, (30) 4-[1-(4-fluorobenzyl)-6-indolyl]-2-hydroxy-4-oxo-2-butenoic acid, and (31) 4-biphenyl-4-yl-2,4-dioxobutanoic acid, and tautomers and pharmaceutically acceptable salts thereof.
14. A compound selected from the group consisting of:
(1) 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid, (2) 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)-phenyl]-2,4-dioxobutanoic acid, (3) 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)-phenyl]-2,4-dioxobutanoic acid, (4) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (5) 4-[3-(2-chlorobenzyl)phenyl]-2,4-dioxobutanoic acid, (6) 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid, (7) 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid, (8) 1-(3-benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid, (9) 1-(3-Benzyloxyphenyl)-2,4-dioxobutanoic acid, (10) 1-(2-Benzyloxyphenyl)-2,4-dioxobutanoic acid, (11) 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid, (12) 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid, (13) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (14) 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (15) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (16) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (17) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (18) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (19) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (21) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (22) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (23) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, (24) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (27) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (28) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (29) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (30) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (31) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid, (32) 4-(3-Benzyl-4-methoxyphenyl)-2,4-dioxobutyric acid, (33) 4-(5-Benzyl-2-methoxyphenyl)-2,4-dioxobutyric acid, (34) 4-(3-Benzyl-4-fluorophenyl)-2,4-dioxobutyric acid, (35) 4-(3-Benzyl-4-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (36) 4-[5-(2-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid, (37) 2,4-Dioxo-4-(3-pyridin-2-ylmethylphenyl)butyric acid, (38) 4-(5-Benzyl-3-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (39) 4-(5-Benzyl-3-methoxyphenyl)-2,4-dioxobutyric acid, (40) 4-(5-Benzyl-2-benzyloxy-3-methoxyphenyl)-2,4-dioxobutyric acid, (41) 4-[5-(3-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid, (42) 4-(5-Benzyl-3-benzyloxyphenyl)-2,4-dioxobutyric acid, (43) 4-[5-Benzyl-2-(2-hydroxy)ethoxyphenyl]-2,4- dioxo-2-butanoic acid, (44) 2,4-Dioxo-4-(3-pyridin-3-ylmethylphenyl)butyric acid, (45) 4-[3-(3-Methyl-pyridin-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (46) 4-(5-Benzyl-2-methylsulfanylphenyl)-2,4-dioxobutyric acid, (47) 4-(5-Benzyl-3-N-morpholinophenyl)-2,4-dioxobutyric acid, (48) 4-(8-Benzyl-4-methyl-3,4-dihydro-2h-benzo[1,4]oxazin-6-yl)-2,4-dioxobutyric acid, (49) 4-[5-(2-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid, (50) 4-[5-(3-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid, (51) 4-(5-Benzyl-2,3,4-trimethoxyphenyl)-2,4-dioxobutyric acid, (52) 4-(6-Benzylbenzo[1,3]dioxol-4-yl)-2,4-dioxobutyric acid, (53) 4-[3-Benzyl-5-(morpholine-4-carbonyl)phenyl]-2,4-dioxobutyric acid, (54) 4-(3-Benzyl-5-pyridine-2-ylmethylphenyl)-2,4-dioxobutyric acid, (55) 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid, (56) 4-(3-Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid, (57) 4-[3-Benzyl-5-(2-dimethylamino-1-hydroxy-1-methylethyl)phenyl]-2,4-dioxobutyric acid, (58) 4-(5-Benzyl-2-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid, (59) 4-(5-Benzyl-2-fluorophenyl)-2,4-dioxobutyric acid, (60) 4-(5-Benzyl-3-hydroxymethyl-2-methoxyphenyl)-2,4-dioxobutyric acid, (61) 4-[5-Benzyl-2-(pyrazin-2-yloxy)phenyl]-2,4-dioxobutyric acid, (62) 4-[3-Benzyl-5-(2-oxopiperidin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid, (63) 4-[5-Benzyl-2-methoxy-3-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid, (64) 4-[3-(2-Chlorobenzyl)-5-pyridin-2-ylmethylphenyl]-2,4-dioxobutyric acid, (65) 4-[5-Benzyl-2-methoxy-3-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid, (66) 4-(5-Benzyl-2-methoxymethylphenyl)-2,4-dioxobutyric acid, (67) 4-[3-(2-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (68) 4-[3-(4-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (69) 4-[3-(3-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid, (70) 4-[5-Benzyl-2-methoxy-3-(tert-butylcarbamoyl)phenyl]-2,4-dioxobutyric acid, (71) 4-(3-Benzyl-5-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (72) 4-[5-Benzyl-3-(N'-methyl-N-piperazinyl)phenyl]-2,4-dioxobutyric acid, (73) 4-(3-Benzyl-5-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (74) 4-(6-Benzyl-3-oxo-3,4-dihydro-2-H-benzo[1,4]oxazin-8-yl)-2,4-dioxobutyric acid, (75) 4-[5-Benzyl-2-(pyrimidin-2-yloxy)phenyl]-2,4-dioxobutyric acid, (76) 4-(5-Benzyl-3-amino-2-methoxyphenyl)-2,4-dioxobutyric acid, (77) 4-(5-Benzyl-2-ethoxyphenyl)-2,4-dioxobutyric acid, (78) 4-[5-Benzyl-2-(2-morpholin-4-yl-ethoxy)phenyl]-2,4-dioxobutyric acid, (79) 4-(5-Benzyl-2-trifluoroethoxyphenyl)-2,4-dioxobutyric acid, (80) 4-(5-Benzyl-2-cyclobutyloxyphenyl)-2,4-dioxobutyric acid, (81) 4-(5-Benzyl-2-cyclopentyloxyphenyl)-2,4-dioxobutyric acid, (82) 4-(3-Benzyl-5-tetrazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (83) 4-(5-Benzyl-2,3-diisopropoxyphenyl)-2,4-dioxobutyric acid, (84) 4-(5-Benzyl-2-isopropoxy-3-N-methylaminophenyl)-2,4-dioxobutyric acid, (85) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminophenyl)-2,4-dioxo-butyric acid, (86) 4-[5-Benzyl-2-isopropoxy-3-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (87) 4-[5-Benzyl-2-isopropoxy-3-(morpholinomethyl)phenyl]-2,4-dioxo-butyric acid, (88) 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminomethylphenyl)-2,4-dioxo-butyric acid, (89) 4-(7-Benzylbenzo[1,3]dioxol-5-yl)-2-hydroxy-4-oxobut-2-enoic acid, (90) 2-Hydroxy-4-oxo-4-(3-phenylindan-5-yl)but-2-enoic acid, (91) 4-(Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (92) 3-(3-Benzyl-5-carboxyacetylphenyl)-3-oxopropionic acid, (93) 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, (94) 4-(5-Benzyl-3-methoxy-2-mtethylthioethoxyphenyl)-2,4-dioxobutyric acid, (95) 4-(7-Benzyl-2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,4-dioxobutyric acid, (96) (+/-) 4-(8-Benzyl-3-hydroxy-3,4-dihydro-2H-benzo[B][1,4]di-oxepin-6-yl)-2,4-dioxobutyric acid, (97) 4-(2,3-Dimethoxy-5-pent-4-enylphenyl)-2,4-dioxobutyric acid, (98) 4-(5-Cyclopropylmethyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (99) (6-Benzyloxy-1-oxo-indan-2-ylidene)-hydroxyacetic acid, (100) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (101) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (102) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (103) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (104) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (105) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (106) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, (107) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (108) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, (109) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid, (110) 4-[1-(2,6-Difluorobenzyl)-1H-indol-6-yl]-2,4-dioxobutyric acid, (111) 4-(1-Benzyl-1H-indol-6-yl)-2,4-dioxobutyric acid, (112) 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid, (113) 1-[1-(4-Fluorobenzyl)-4-indolyl]-2,4-dioxobutanoic acid, (114) 4-[3-(2,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (115) 2,4-dioxo-4-[3-(2,6-difluoro-benzyl)-phenyl]-butyric acid, (116) 2,4-dioxo-4-[3-(2-4-6-trifluoro-benzyl)-phenyl]-butyric acid, (117) 2,4-dioxo-4-[3-(2-fluoro-3-choro-benzyl)-phenyl]-butyric acid, (118) 2,4-dioxo-4-[3-(2-methyl-4-fluoro-benzyl)-phenyl]-butyric acid, (119) 4-[3-(2,3-dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (120) 4-[3-(2-chloro-3-methylbenzyl)phenyl]-2,4-dioxobutyric acid, (121) 2,4-dioxo-4-[3-(2,6-dichloro-benzyl)-phenyl]-butyric acid, (122) 2,4-dioxo-4-[3-(2,3,4,5,6-penta-fluoro-benzyl)-phenyl]-butyric acid, (123) 4-[3-(2-fluorobenzyl)phenyl]-2,4-dioxobutyric acid, (124) 2,4-dioxo-4-[3-(2-choro-4-fluoro-benzyl)-phenyl]-butyric acid, (125) 4-[3-(2-methylbenzyl)phenyl]-2,4-dioxobutyric acid, (126) 2,4-dioxo-4-[3-(2-methoxybenzyl)phenyl]butyric acid, (127) 4-[3-(2-chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (128) 4-[3-(2-bromobenzyl)phenyl]-2,4-dioxobutyric acid, (129) 4-[5-(4-fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (130) 4-[3-(3-chloro-2-methyl-benzyl)phenyl]-2,4-dioxobutyric acid, (131) 4-[3-(2,3-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (132) 4-(3,5-dibenzylphenyl)-2,4-dioxo-butyric acid, (133) 2,4-dioxo-4-[3-(2-trifluoromethylbenzyl)phenyl]butyric acid, (134) 4-[3-(4-fluorobenzyl)phenyl]-2,4-dioxobutyric acid, (135) 4-[3-(3-chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (136) 2,4-dioxo-4-[3-(2-bromo-3-chloro-benzyl)-phenyl]-butyric acid, (137) 4-(3-benzylphenyl)-2,4-dioxo-butyric acid, (138) 4-[3-(2-fluoro-3-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid, (139) 4-[3-(3-chloro-4-fluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (140) 2,4-dioxo-4-[3-(2-bromo-4-fluoro-benzyl)-phenyl]-butyric acid, (141) 4-[3-(3-bromobenzyl)phenyl]-2,4-dioxobutyric acid, (142) 4-[3-(2,5-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (143) 4-[3-(5-chloro-2-fluoro-benzyl)phenyl]-2,4-dioxobutyric acid, (144) 4-[3-(3-methylbenzyl)phenyl]-2,4-dioxobutyric acid, (145) 4-(3-benzyl-4-methyl-phenyl)-2,4-dioxo-butyric acid, (146) 4-[3-(3,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (147) 4-[3-(2,5-dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (148) 4-[3-(2-chloro-6-methyl-benzyl)phenyl]-2,4-dioxobutyric acid, (149) 2,4-dioxo-4-[3-(2-trifluoromethyl-4-chloro-benzyl)-phenyl]-butyric acid, (150) 4-[3-(2-bromo-5-chloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (151) 4-(3-naphthalen-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (152) 2,4-dioxo-4-[3-(3-fluorobenzyl)phenyl]butyric acid, (153) 2,4-dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (154) 2,4-dioxo-4-[3-(1-phenylethyl)phenyl]butyric acid, (155) 4-(3-benzyl-4,5-dimethylphenyl)-2,4-dioxo-butyric acid, (156) 2,4-dioxo-4-[3-(3-methoxybenzyl)phenyl]butyric acid, (157) 4-[3-(5-methyl-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (158) 4-[3-(5-chloro-thiophen-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid, (159) 4-(3-benzyl-5-methylphenyl)-2,4-dioxo-butyric acid, (160) 4-[3-(2-cyanobenzyl)phenyl]-2,4-dioxo-butyric acid, (161) 4-[3-benzylphenyl]-2,4-dioxobutyric acid, (162) 4-[3-(3,5-dichloro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (163) 4-(5-benzyl-2,4-dimethylphenyl)-2,4-dioxo-butyric acid, (164) 4-(5-benzyl-2-methylphenyl)-2,4-dioxo-butyric acid, (165) 4-(3-cyclohexylmethyl-phenyl)-2,4-dioxo-butyric acid, (166) 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (167) 4-[3-benzyl-5-(5-hydroxy-pentyl)-phenyl]-2,4-dioxo-butyric acid, (168) 4- (3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (169) 4-[3-(3-tert-butoxy-2-hydroxy-propyl)-5-(2-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid, (170) 2,4-dioxo-4-[3-(2,3-dimethoxy-benzyl)-phenyl]-butyric acid, (171) 4-[3-(methoxyphenylmethyl)phenyl]-2,4-dioxobutyric acid, (172) 4-[3-[hydroxy-(tetrahydro-furan-3-yl)-methyl]-5-(2-methyl-benzyl)-phenyl]--2,4-dioxo-butyric acid, (173) 2,4-dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid, (174) 2,4-dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid, (175) 4-[3-benzyl-5-(cyclopropylcarboxamido)-phenyl]-2,4-dioxobutyric acid, (176) 4-[3-benzyl-5-(t-butoxycarbamoyl)phenyl]-2,4-dioxobutyric acid, (177) 4-[3-(hydroxy-phenyl-methyl)-phenyl]-2,4-dioxo-butyric acid, (178) 4-(5-benzyl-2,3-dimethylphenyl)-2,4-dioxo-butyric acid, (179) n-[3-(3,5-dibromobenzyl)phenyl]-2,4-dioxo-butyric acid, (180) 4-[3-(2-methyl-benzyl)-5-pyrimidin-2-yl-phenyl]-2,4-dioxo-butyric acid, (181) 4-[3-benzyl-2-(pyrimidin-2-ylamino)-phenyl]-2,4-dioxo-butyric acid (182) 4-[3-benzoimidazol-1-ylmethyl-5-(2-methyl-benzyl)-phenyl]-2,4-dioxo-butyric acid, (183) 2,4-dioxo-4-[3-(3-trifluoromethylbenzyl)phenyl] butyric acid, (184) 4-(4-phenoxy-phenyl)-2,4-dioxo-butyric acid, (185) 2,4-dioxo-4-(3-[1,2,3]triazol-2-ylmethyl-phenyl)-butyric acid, (186) 4-[3-benzyl-5-(6-methoxy-pyridin-2-yl)-phenyl]-2,4-dioxo-butyric acid, (187) 4-(3-benzotriazol-2-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (188) 4-[3-benzyl-5-(2-(4-methylpiperazin-1-yl)-pyrazin-6-yl)phenyl]-2,4-dioxobutyric acid, (189) 4-[4-(3-phenethyl)phenyl]-2,4-dioxobutyric acid, (190) 4-[4-(3-chlorobenzyl)phenyl]-2,4-dioxobutyric acid, (191) 4-(3-benzoimidazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (192) 4-[3-benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid, (193) 4-(3-benzotriazol-1-ylmethyl-phenyl)-2,4-dioxo-butyric acid, (194) 4-[3-(3,5-dimethyl-pyrazol-1-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (195) 4-[3-benzyloxy-5-(2-morphonin-4-yl-ethoxy)phenyl]-2-hydroxy-4-oxo-but-2-enoic acid, (196) 4-(4-methyl-3-phenoxy-phenyl)-2,4-dioxo-butyric acid (197) 4-[3-(2-hydroxy-benzyl)-phenyl]-2,4-dioxo-butyric acid, (198) 4-[3-benzyl-5-(6-dimethylamino-pyrazin-2-yl)-phenyl]-2,4-dioxo-butyric acid, and (199) 4-(5-benzyl-2-methoxypyridin-3-yl)-2,4-dioxobutyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
15. The compound according to Claim 14 selected from:
(1) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (2) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (3) 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl)-2,4-dioxo-butyric acid, (4) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (5) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (6) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (7) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (8) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (9) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (10) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4 dioxobutyric acid, (11) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (12) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, (13) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (14) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (15) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (16) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (17) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (18) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (19) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid, (21) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (22) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (24) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (27) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, (28) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (29) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, and (30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to Claim 1.
17. The pharmaceutical composition of Claim 16, useful for treating infection by HIV, or for treating AIDS or ARC.
18. The pharmaceutical composition according to Claim 17 additionally comprising a therapeutically effective amount of an AIDS
treatment agent selected from (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator.
19. The composition of Claim 18 wherein the antiviral agent is an HIV protease inhibitor.
20. The composition of Claim 19 wherein the HIV
protease inhibitor is N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide or a pharmaceutically acceptable salt thereof.
21. A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of structural formula (I):
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R2, R8, and R9;
optionally the aromatic ring may be fused with another ring system to form:

R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR7, (4)~ -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -halo, (8) -NO2, (9) -C0-3 alkyl-N(R4)(R5), (10) -R6, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, (13) -O-R6, (14) -O-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, (15) -O-C1-6 alkyl-NH-C(O)-OR7;
(16) -O-C2-6 alkyl-N(R4)(R5);
(17) -S-C1-3 alkyl;
(18) -C(O)CH2C(O)C(O)OR7;
(19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) ~-H, (2)~-R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -C2-6 alkenyl, (6) -O-R6, (7) -O-C1-6 alkyl-OR6, (8) -O-C1-6 alkyl-SR6, (9) -S(O)n-R6, (10) -C1-6 alkyl (OR6)(R4) (11) -C0-6 alkyl-N(R4)(R6), (12) -C1-6 alkyl S(O)n-R6, (13) -C0-6 alkyl C(O)-R6, (14) -C0-6 alkyl C(O)CH2-C(O)-OH, (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR4C(O)-R6, (17) -C1-6 alkyl-C(O)N(R4)(R5), and (18) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R7)2, (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O
(h) benzyl, and (i) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy; and (7) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy; and each R4 is independently selected from:
(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, (9) -C(O)-R3, (10) -C(O)OR4, and (11) -C(O)C(O)OH;
each R6 is independently selected from:

(1) -C1-3 alkyl-R3, and (2) -R3, each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from:
(1) -H, (2) -O- C1-6 alkyl and (3) C1-6 alkyl;
R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and each n is independently selected from 0, 1 and 2.
22. The method according to Claim 21, wherein the compound of structural formula (I) is selected from:
(1) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (2) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (3) 4-(3-[(methyl-phenyl-amino)-methyl]-phenyl)-2,4-dioxo-butyric acid, (4) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (5) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (6) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (7) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (8) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (9) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (10) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (11) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (12) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, (13) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (14) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (15) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (16) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (17) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (18) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (19) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid, (21) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (22) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (24) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (27) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, (28) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (29) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, and (30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid;and tautomers and pharmaceutically acceptable salts thereof.
23. A method of treating infection by HIV, or of treating AIDS or ARC, comprising the administration to a human in need of such treatment a therapeutically effective amount of a compound of structural formula (I):
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R2, R8, and R9;
optionally the aromatic ring may be fused with another ring system to form:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR7, (4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -halo, (8) -NO2, (9) -CO-3 alkyl -N(R4)(R5), (10) -R6, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, (13) -O-R6, (14) -O-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, (15) -O-C1-6 alkyl-NH-C(O)-OR7 (16) -O-C2-6 alkyl-N(R4)(R5), (17) -S-C1-3 alkyl, (18) -C(O)CH2C(O)C(O)OR7, (19) -CH2-CH(OH)-CH2-O-R7, and (20) -C(OH)(CH3)-CH2N(R4)(R5);
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -C2-6 alkenyl, (6) -O-R6, (7) -O-C1-6 alkyl-OR6, (8) -O-C1-6 alkyl- SR6, (9) -S(O)n-R6, (10) -C1-6 alkyl (OR6)(R4), (11) -C0-6 alkyl-N(R4)(R6), (12) -C1-6 alkyl S(O)n-R6, (13) -C0-6 alkyl C(O)-R6, (14) -C0-6 alkyl C(O)CH2-C(O)-OH, (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR4C(O)-R6, (17) -C1-6 alkyl-C(O)N(R4)(R5), and (18) -CH2(OR7)-R6;
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on nitrogen or carbon by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, (k) oxo, and (l) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b> C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) benzyl, and (i) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy; and (7) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy; and each R4 is independently selected from:

(1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R5 independently selected is from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, (9) -C(O)-R3, (10) -C(O)OR4, and (11) -C(O)C(O)OH;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H, and (2) -C1-6 alkyl;
R8 is selected from:
(1) -H, (2) -O- C1-6 alkyl and (3) C1-6 alkyl;
R9 is selected from:
(1) -H, (2) -O- C1-3 alkyl, (3) -OH, and (4) oxo; and each n is independently selected from 0, 1 and 2.
24. The method according to Claim 23 wherein the compound of structural formula (I) is selected from:
(1) 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid, (2) 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid, (3) 4-{3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid, (4) 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid, (5) 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid, (6) 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid, (7) 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, (8) 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid, (9) 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid, (10) 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid, (11) 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid, (12) 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid, (13) 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid, (14) 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid, (15) 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid, (16) 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid, (17) 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid, (18) 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid, (19) 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenyl]-2,4-dioxo-butyric acid, (20) 4-(5-benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4-dioxobutyric acid, (21) 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (22) 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid, (23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3-methoxyphenyl]-2,4-dioxobutyric acid, (24) 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid, (25) 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid, (26) 4-[5-Benzyl-2-isopropoxy-3-(1-piperidinylmethyl)phenyl]-2,4-dioxo-butyric acid, (27) 4-[5-Benzyl-2-(2-dimethylamino-1-methylethoxy)phenyl]-2,4-dioxo-butyric acid, (28) 4-[5-Benzyl-2-(1-methylpiperidin-4-yloxy)phenyl]-2,4-dioxo-butyric acid, (29) 4-[3-Benzyl-5-(4-benzylpiperazin-1-yl)phenyl]-2,4-dioxo-butyric acid, and (30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2-ylaminomethyl)phenyl]-2,4-dioxo-butyric acid;
and tautomers and pharmaceutically acceptable salts thereof.
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Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ506435A (en) 1998-03-26 2002-08-28 Shionogi & Co 3-Indoly-2-hydroxy-4-oxo-2-butanoic acid useful as antiviral activity
ES2244204T3 (en) 1998-07-27 2005-12-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. DERIVATIVES OF DICETOACIDES AS POLYMERASE INHIBITORS
US6620841B1 (en) 1998-12-25 2003-09-16 Shionogi & Co., Ltd. Aromatic heterocycle compounds having HIV integrase inhibiting activities
MXPA02012405A (en) * 2000-06-16 2003-06-06 Bristol Myers Squibb Co Hiv integrase inhibitors.
WO2002070486A1 (en) 2001-03-01 2002-09-12 Shionogi & Co., Ltd. Nitrogen-containing heteroaryl compounds having hiv integrase inhibitory activity
RU2302411C2 (en) * 2001-05-09 2007-07-10 Байер Кропсайенс Аг Substituted arylketones and a herbicide agents based thereon
KR100959356B1 (en) 2001-06-12 2010-05-20 웰스테트 테라퓨틱스 코포레이션 Compounds for the Treatment of Metabolic Disorders
KR20100087209A (en) 2001-08-10 2010-08-03 시오노기세이야쿠가부시키가이샤 Antiviral agent
WO2003016266A1 (en) * 2001-08-16 2003-02-27 Japan Tobacco Inc. β-KETOAMIDE COMPOUNDS AND MEDICINAL USE THEREOF
US7232819B2 (en) 2001-10-26 2007-06-19 Istituto Di Ricerche Di Biologia P. Angeletti S.P.A. Dihydroxypyrimidine carboxamide inhibitors of HIV integrase
EP1441735B1 (en) 2001-10-26 2006-02-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase
EP1463741A4 (en) * 2001-12-07 2006-07-05 Us Gov Health & Human Serv Compounds to treat hiv infection and aids
US7323460B2 (en) 2002-03-15 2008-01-29 Merck & Co., Inc. N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors
US7358249B2 (en) 2002-08-13 2008-04-15 Shionogi & Co., Ltd. Heterocyclic compounds having inhibitory activity against HIV integrase
WO2004035577A2 (en) 2002-10-16 2004-04-29 Gilead Sciences, Inc. Pre-organized tricyclic integrase inhibitor compounds
AU2004274493A1 (en) 2003-09-19 2005-03-31 Gilead Sciences, Inc. Aza-quinolinol phosphonate integrase inhibitor compounds
DE602005023717D1 (en) 2004-03-10 2010-11-04 Usa CHINOLIN-4-ONE AS INHIBITORS OF THE RETROVIRAL INTEGRASE FOR THE TREATMENT OF HIV, AIDS AND AIDS-RELATED COMPLEX (ARC)
EP1732541A4 (en) 2004-04-07 2008-03-05 Takeda Pharmaceutical Cyclic compounds
AU2007254190A1 (en) 2006-05-16 2007-11-29 Gilead Sciences, Inc. Integrase inhibitors
JP2009543865A (en) 2006-07-19 2009-12-10 ユニバーシティ オブ ジョージア リサーチ ファウンデーション， インコーポレーテッド Pyridinone diketo acids: inhibitors of HIV replication in combination therapy
CN101977610B (en) 2008-01-25 2012-05-16 奇默里克斯公司 Methods of treating viral infections
US8664255B2 (en) 2008-10-20 2014-03-04 The Texas A&M University System Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof
WO2011071849A2 (en) 2009-12-07 2011-06-16 University Of Georgia Research Foundation, Inc. Pyridinone hydroxycyclopentyl carboxamides: hiv integrase inhibitors with therapeutic applications
US8283366B2 (en) 2010-01-22 2012-10-09 Ambrilia Biopharma, Inc. Derivatives of pyridoxine for inhibiting HIV integrase
PT2534150T (en) 2010-02-12 2017-05-02 Chimerix Inc Methods of treating viral infection
CN103420894A (en) * 2012-05-22 2013-12-04 中国科学院上海药物研究所 2- butane-1,4-diketone compounds, preparation method and applications
CN106905244B (en) * 2017-02-27 2019-08-16 武汉工程大学 Diaryl pyrimidine-diketone acid heterozygous HIV-1 inhibitor and preparation method thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899508A (en) * 1974-04-12 1975-08-12 Lilly Co Eli 5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof
SE7605371L (en) * 1975-05-14 1976-11-15 Fisons Ltd PROCEDURE FOR THE PREPARATION OF CHROMON-2-CARBOXYLIC ACIDS
US4336397A (en) * 1980-12-29 1982-06-22 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis
US4423063A (en) * 1980-12-29 1983-12-27 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butaoic acid derivatives useful in treating urinary track calcium oxalate lithiasis
JPS61134346A (en) * 1984-12-03 1986-06-21 Shionogi & Co Ltd 4-oxocarboxylic acid derivative and antiulcer agent
PH27357A (en) * 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
ES2039301B1 (en) * 1991-11-20 1994-05-16 Genesis Para La Investigacion PROCEDURE FOR OBTAINING NEW USEFUL SYNTHESIS INTERMEDIATES FOR THE PREPARATION OF FLUOROQUINOLONS.
IL111613A0 (en) * 1993-11-12 1995-01-24 Rhone Poulenc Rorer Ltd Substituted phenyl compounds, their preparation and pharmaceutical compositions containing them
US5475109A (en) * 1994-10-17 1995-12-12 Merck & Co., Inc. Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease
GB9522617D0 (en) * 1995-11-03 1996-01-03 Pharmacia Spa 4-Phenyl-4-oxo-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
NZ506435A (en) * 1998-03-26 2002-08-28 Shionogi & Co 3-Indoly-2-hydroxy-4-oxo-2-butanoic acid useful as antiviral activity

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