AU4225499A - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
AU4225499A
AU4225499A AU42254/99A AU4225499A AU4225499A AU 4225499 A AU4225499 A AU 4225499A AU 42254/99 A AU42254/99 A AU 42254/99A AU 4225499 A AU4225499 A AU 4225499A AU 4225499 A AU4225499 A AU 4225499A
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AU
Australia
Prior art keywords
alkyl
phenyl
substituted
benzyl
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU42254/99A
Inventor
David L Clark
Melissa Egbertson
Mark W. Embrey
Thorsten E Fisher
James P. Guare
Juan Jaen
Marie Langford
Julio C. Medina
Jeffrey Melamed
Linda S Payne
Lee Tran
Joseph P. Vacca
John S. Wai
Steven D. Young
Linghang Zhuang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Tularik Inc
Original Assignee
Merck and Co Inc
Tularik Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9815175.6A external-priority patent/GB9815175D0/en
Application filed by Merck and Co Inc, Tularik Inc filed Critical Merck and Co Inc
Publication of AU4225499A publication Critical patent/AU4225499A/en
Abandoned legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/00—Carboxylic acid nitriles
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    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • 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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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
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    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
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    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Description

WO 99/62520 PCT/US99/12093 TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS 5 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 10 (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 15 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 20 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. 25 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., 30 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 35 AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants - 1- WO 99/62520 PCT/US99/12093 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 5 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 10 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 15 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 20 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 25 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 30 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 35 aromatic and heteroaromatic diketo acid derivatives are potent -2- WO 99/62520 PCT/US99/12093 inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection. SUMMARY OF THE INVENTION 5 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), 10 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. 15 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 20 deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
R
2
R
1 A
OR
7
R
9 0 0 (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: 25 A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R 2 , R8, and R9; optionally the aromatic ring may be fused with another ring system to form: -3- WO 99/62520 PCT/US99/12093 ,or or or 0 <00 or or O or O or H Sor N or H R1 is selected from: 5 (1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR 7 , (4) -0-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR7, 10 (6) -CF3 or -CH2CF3, (7) -halo, (8) -NO2, (9) -CO-3 alkyl -N(R4)(R5), (10) -R 6 , 15 (11) -C2-5 alkenyl-R 3 , (12) -C2-5 alkynyl-R 3 , (13) -O-R 6 , (14) -O-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, 20 (15) -0-C1-6 alkyl-NH-C(0)-OR7; (16) -0-C2-6 alkyl-N(R 4 )(R5); (17) -S-C1-3 alkyl; (18) -C(0)CH2C(0)C(0)OR7; (19) -CH2-CH(OH)-CH2-O-R7; and 25 (20) -C(OH)(CH3)-CH2N(R4)(R5);
R
2 is selected from: (1) -H, (2) -R 3 , -4- WO 99/62520 PCT/US99/12093 (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 (5) -C2-6 alkenyl, (6) -O-R 6 , (7) -0-C1-6 alkyl-OR 6 , (8) -0-C1-6 alkyl- SR6, (9) -S(0)n-R 6 , 10 (10) -C1-6 alkyl (OR6)(R4), (11) -C0-6 alkyl-N(R 4
)(R
6 ), (12) -C1-6 alkyl S(0)n-R 6 , (13) -CO-6 alkyl C(0)-R6, (14) -CO-6 alkyl C(0)CH2-C(0)-OH, 15 (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR4C(0)-R6, (17) -C1-6 alkyl-C(0)N(R 4 )(R5), and (18) -CH2(OR7)-R6; each R 3 is independently selected from: 20 (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, 25 (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, 30 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, -5- WO 99/62520 PCT/US99/12093 (j) -N+ N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 5 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 10 (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, 15 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 20 (g) =O, (h) benzyl, and (i) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: 25 (a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, 30 (f) -OCF3, (g) -CN, and (h) hydroxy; -6- WO 99/62520 PCT/US99/12093 (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 5 carbon atom by 1 to 3 substituents selected from: (a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, 10 (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 15 with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 20 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; 25 (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, 30 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 35 (g) =0O, and -7- WO 99/62520 PCT/US99/12093 (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 5 substituted with 1 or 2 substituents selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 10 (e) -OCF3, (f) -CN, (g) =0, and (h) hydroxy; and each R 4 is independently selected from: 15 (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, 20 (6) -C1-3 alkyl-R 3 , (7) -C2-3 alkenyl-R 3 , (8) -S(0)n-R 3 , and (9) -C(0)-R3; each R5 is independently selected from: 25 (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, 30 (6) -C1-3 alkyl-R 3 , (7) -C2-3 alkenyl-R 3 , (8) -S(0)n-R 3 , (9) -C(0)-R3, (10) -C(0)OR4, and 35 (11) -C(0)C(0)OH; - 8- WO 99/62520 PCT/US99/12093 each R 6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R 3 ; each R 7 is independently selected from: 5 (1) -H, and (2) -C1-6 alkyl;
R
8 is selected from: (1) -H, (2) -0- C1-6 alkyl and 10 (3) C1-6 alkyl;
R
9 is selected from: (1) -H, (2) -0- C1-3 alkyl, (3) -OH, and 15 (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) R1 is not R 6 para to the dioxobutyric acid/ester moiety; and 20 (2) R 2 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 25 moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R 2 , and R8 is not: (a) -H, 30 (b) C1-6 alkyl, or (c) R 3 wherein R 3 is cycloalkyl; and (4) and when R 2 is S(O)nR 6 , and R6 is CH2-R3 or R3, then R3 is not unsubstituted phenyl. -9- WO 99/62520 PCT/US99/12093 Also provided for by the present invention are compounds of formula (I) wherein: WHEN A is phenyl and R1 is: (a) H, 5 (b) C1-5 alkyl, (c) halo, (d) NO2, (e) R6 when R6 is CH2R3 or R3 and when R3 is unsubstituted phenyl, 10 (f) -O-C1-6 alkyl, or (g) -SC1-3 alkyl; THEN R 2 is not selected from: (a) H, (b) R3 when R3 is unsubstituted phenyl, 15 (c) C1-6 alkyl, (d) CH2R3 when R3 is unsubstituted phenyl, and (e) SOR6 when R6 is CH2R3 or R3 and when R3 is unsubstituted phenyl. Also provided for by the present invention are compounds of 20 formula (I) wherein at least one of R1, R 2 , 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 25 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:
"
R1 0 R
OR
7
R
8 O O (1a) and tautomers and pharmaceutically acceptable salts thereof, - 10- WO 99/62520 PCT/US99/12093 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 R1 ,R 2 and R8; the aromatic or heteroaromatic ring may 5 optionally be fused with a 5- or 6-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 10 another ring system to form: ,or or or or N, or N R1 is selected from: (1) -H, 15 (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R 4
)(R
5 ), 20 (7) -R 6 , (8) -C2-5 alkenyl-R 3 , (9) -C2-5 alkynyl-R 3 , (10) -O-R 6 , (11) -O-C1-6 alkyl, and 25 (12) -C(0)CH2C(0)C(0)OR7;
R
2 is selected from: (1) -H, (2) -R3, (3) -C1-6 alkyl, 30 (4) -C1-6 alkyl substituted with R3, (5) -O-R6, - 11- WO 99/62520 PCT/US99/12093 (6) -0-C1-6 alkyl-OR 6 , (7) -S(0)n-R 6 , (8) -C1-6 alkyl (OR 6
)(R
4 ), (9) -CO-6 alkyl-N(R4)(R 6 ), 5 (10) -C1-6 alkyl S(0)n-R 6 , (11) -C1-6 alkyl C(O)-R 6 , (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR 4 C(0)-R 6 , and (14) -C1-6 alkyl-C(0O)N(R 4 )(R5); 10 each R 3 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: 15 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, 20 (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 25 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 30 (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, 35 (b) C1-6 alkyl, - 12- WO 99/62520 PCT/US99/12093 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 5 (g) =O, (h) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, 10 (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, 15 (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 20 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-, 25 (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy; (5) a 3 to 6 membered saturated ring containing 0 or 1 30 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, -13- WO 99/62520 PCT/US99/12093 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 5 (g) =O, (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 10 substituents selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 15 (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy; each R 4 is independently selected from: 20 (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, 25 (6) -C1-3 alkyl-R 3 , (7) -C2-3 alkenyl-R 3 , (8) -S(0)n-R 3 , and (9) -C(0)-R3; each R5 is independently selected from: 30 (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, 35 (6) -C1-3 alkyl-R 3 , - 14- WO 99/62520 PCT/US99/12093 (7) -C2-3 alkenyl-R 3 , (8) -S(O)n-R 3 , and (9) -C(O)-R3; each R 6 is independently selected from: 5 (1) -C1-3 alkyl-R 3 , and (2) -R 3 ;
R
7 is selected from: (1) -H, and (2) C1-6 alkyl; 10 R 8 is selected from: (1) -H, (2) -0- C1-6 alkyl, and (3) C1-6 alkyl; and each n is independently selected from 0, 1 and 2. 15 Also provided by the present invention are compounds of structural formula (Ia) wherein: when A is phenyl, (1) R1 is not: (a) phenyl para to the dioxobutyric acid/ester moiety, 20 (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 25 acid/ester moeity; and (2) R 2 is not selected from: (a) phenyl para to the dioxobutyric acid/ester moiety, (b) substituted phenyl para to the dioxobutyric acid/ester moiety, 30 (c) -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety, and (d) substituted -C 1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R 2 , and R 8 is not: 35 (a) -H, - 15- WO 99/62520 PCT/US99/12093 (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R1 or R 2 is S(O)nR 6 , R6 is R 3 . Particular compounds of structural formula Ia include: 5 (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 10 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 15 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, 20 (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, 25 (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 30 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 35 (19) 4-(3-benzyl-phenyl)-2,4-dioxo-butanoic acid, - 16- WO 99/62520 PCT/US99/12093 (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-1l-yl-2,4-dioxobutanoic acid, and 5 (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 10 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 15 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, 20 (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, 25 (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, 30 (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, - 17- WO 99/62520 PCT/US99/12093 (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) 5 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, 10 (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 15 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 20 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, 25 (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 30 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 35 acid, - 18- WO 99/62520 PCT/US99/12093 (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 5 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 10 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, 15 (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) 20 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, 25 (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 30 acid, (55) 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid, (56) 4
-(
3 -Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid, - 19- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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, 20 (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 25 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, 30 (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 35 acid, - 20- WO 99/62520 PCT/US99/12093 (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 5 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 10 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 15 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, 20 (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, 25 (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, 30 (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, -21- WO 99/62520 PCT/US99/12093 (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) 5 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, 10 (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 15 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, 20 (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-l1H-indol-6-yl)-2,4-dioxobutyric acid, (112) 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid, 25 (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, 30 (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, - 22- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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, 20 (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 25 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, 30 (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] 35 butyric acid, - 23- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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, 20 (166) 4-{3-[(Methyl-phenyl-amino)-methyl]-phenyll-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, 25 (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 30 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, - 24- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 (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, 15 (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, 20 (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 25 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 30 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 35 (199) 4-(5-Benzyl-2-methoxypyridin-3-yl)-2,4-dioxobutyric acid; - 25- WO 99/62520 PCT/US99/12093 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 5 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- l-yl) 10 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, 15 (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 20 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 25 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, 30 (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 35 dioxobutyric acid, - 26- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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. 20 One class of compounds of the present invention is represented by the structural formula below: R 2 /- 8-1 R 9 0 R0 OH 0O Another class of compounds of the present invention is represented by the structural formula below: 25 H" OH
R
2 O O -27- WO 99/62520 PCT/US99/12093 Another class of compounds of the present invention is represented by the following structural formula:
R
9 H H - OH R2 R 8 O Still another class of compounds of the present invention is 5 represented by the formula below:
R
1
R
8 0 0 H - OH
R
2 R9 0 O Another class of compounds of the present invention is represented by the following structural formula:
R
8
R
1 0 OH
R
2 R9 0 O 10 Yet another class of compounds of the present invention is represented by the following structural formula:
R
1 I R 8 O OH 2 R 9 0 0 Still another class of compounds of the present invention is represented by the following structural formula: - 28- WO 99/62520 PCT/US99/12093
R
1 O OH R9-' \ R 20 0 Another class of compounds of the present invention is represented by the following structural formula:
R
1 0 R9 O O I\j OH R 8-- R 2 0 0 5 Yet another class of compounds of the present invention is represented by the following structural formula:
R
8
R
1 O [O 'OH RO R20 O Still another class of compounds of the present invention is represented by the following structural formula: 100 R1,N OH F61R R 20 0 Another class of compounds of the present invention is represented by the following structural formula: R 9
R
8 0O OH
R
1 N R 0 0 - 29- WO 99/62520 PCT/US99/12093 Yet another class of compounds of the present invention is represented by the following structural formula:
R
1 0 H OH
R
2 O O Still another class of compounds of the present invention is 5 represented by the following structural formula:
R
1
R
8 0 H O OH
R
2 O O Another class of compounds of the present invention is represented by the following structural formula:
R
1 0 H O OH
R
2 R8 0 0 10 Still another class of compounds of the present invention is represented by the following structural formula:
R
8
R
1
H
7 ~ 0 HOH
R
2 O O One class of compounds of the present invention is represented by the structural formula below: - 30- WO 99/62520 PCT/US99/12093 H> H OH
R
2 O O Another class of compounds of the present invention is represented by the following structural formula: OH
R
8 0 0 5 Still another class of compounds of the present invention is represented by the formula below:
R
1 j 1 \ R8 - OH R20 0 Another class of compounds of the present invention is represented by the following structural formula: 1 0 O R OH 0 0 10 R 2 Another class of compounds of the present invention is represented by the following structural formula:
R
1 R2 OH 0O -31- WO 99/62520 PCT/US99/12093 Another class of compounds of the present invention is represented by the following structural formula: 24 ROH R N 0 0 5 In one embodiment of the present invention, A is selected from: (1) phenyl, (2) pyridyl, (3) naphthyl, 10 (4) indolyl, provided that the aryl ring is substituted by the dioxobutyric acid/ester moiety in structural formula (I), (5) (6) 15 N N (7) (8) 20 (9) (10) - 32- WO 99/62520 PCT/US99/12093 (11) <0 0: (12) 5O (13) H CN c 0 (14) 0 , and 10 (15) N N In another embodiment of the present invention, A is selected from: (1) phenyl, 15 (2) pyridinyl, (3) indolyl, provided that 6-membered aromatic ring is substituted by the dioxobutyric moiety in structural formula (I); (4) 20 N (5) - 33- WO 99/62520 PCT/US99/12093 0: (6) (7) H N 5 O , and (8) 0 C)o 0 In still another embodiment of the present invention, A is phenyl. 10 In one embodiment of the present invention, R1 is selected from: (1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR 7 ; 15 (4) -O-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -F, Cl, or Br,, (8) -NO2, 20 (9) -CO-3 alkyl -N(R4)(R5), (10) -phenyl, (11) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halogen, 25 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, - 34- WO 99/62520 PCT/US99/12093 (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, 5 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 10 (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 15 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, 20 (d) phenyl, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, 25 (i) phenyloxy, (j) -CO-6 alkyl-N(R7)2, -N N-CH 3 (k) - , and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; - 35- WO 99/62520 PCT/US99/12093 (13) -O-R 6 , (14) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (15) -O-C1-6 alkyl-NH-C(0)-OR7; 5 (16) -O-C2-6 alkyl-N(R 4 )(R5); (17) -S-C1-3 alkyl; (18) -C(0)CH2C(0)C(0)OR7; (19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5). 10 In another embodiment of the present invention, R1 is selected from: (1) -H, (2) -CH3, (3) -C1-6 alkyl-OR7; 15 (4) -O-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR 7 , (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, 20 (9) -CO-3 alkyl -N(R 4 )(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: 25 (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, 30 (f) -CN, (g) hydroxy, (h) -CO-6 alkyl-N(R 7 )2, - 36- WO 99/62520 PCT/US99/12093 (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, 5 (b) -CH3, (c) -OCH3, OCH2CH 3 , OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, 10 (g) hydroxy, (h) -CO-6 alkyl-N(R 7 )2, (13) -O-CI-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, and (14) -C(0)CH2C(0)C(0)OH; 15 (15) -O-C1-6 alkyl-NH-C(0)-OR7; (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, 20 (20) -S-CH3, (21) -C(0)CH2C(0)C(0)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5). In yet another embodiment of the present invention, R1 is 25 selected from: (1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, 30 (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, - 37- WO 99/62520 PCT/US99/12093 (10) -CO-3 alkyl -N(R 4 )(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 5 independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 10 (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 15 independently selected from: (a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 20 (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2,, (14) -O-CH3, (15) -OCH2CH3, 25 (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(0)CH2C(0)C(0)OH, (20) -O-C1-6 alkyl-NH-C(0)-OR 7 , 30 (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, - 38- WO 99/62520 PCT/US99/12093 (26) -C(0)CH2C(0)C(0)OH, (27) -CH2-CH(OH)-CH2-O-R7, and (28) -C(OH)(CH3)-CH2N(R4)(R5). In another embodiment of the present invention, R1 is 5 selected from: (1) -H, (2) -phenyl, (3) substituted phenyl substituted with 1 or 2 substituents independently selected from: 10 (a) halo, selected from -F, -Br, -Cl, (b) methyl, and (c) methoxy, (4) phenyl C1-3 alkyl-, (5) -O-R 6 , 15 (6) -O-CH3, and (7) -C(0)CH2C(0)C(0)OR7. In one embodiment of the present invention, R 2 is selected from: (1) -H, 20 (2) -R 3 , (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, 25 (5) -O-R 6 , (6) -S -R 6 , (7) -O-C1-6 alkyl- SR6; (8) -C1-6 alkyl (OR6)(R4), (9) -CO-6 alkyl-N(R 4
)(R
6 ), 30 (10) -C1-6 alkyl-S-R 6 , (11) -CO-6 alkyl-C(0)-R 6 , (12) -CO-6 alkyl-C(0)CH2-C(0)-OH, (13) -C1-6 alkyl NR 4 C(0)-R6, (14) -C1-6 alkyl-C(0)N(R4)(R5), and - 39- WO 99/62520 PCT/US99/12093 (15) -CH2(OR 7
)-R
6 . In another embodiment of the present invention, R 2 is selected from: (1) -H, 5 (2) -R 3 , (3) -CH3, (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, 10 (5) -O-R 6 , (6) -S-R6, (7) -0-C1-6 alkyl-SR6; (8) -C1-6 alkyl (OR 6
)(R
4 ), (9) -CO-6 alkyl-N(R4)(R6), 15 (10) -C0-6 alkyl C(O)-R 6 , (11) -CO-6 alkyl C(O)CH2-C(O)-OH, (12) -C1-6 alkyl NR 4
C(O)-R
6 , (13) -C1-6 alkyl-C(O)N(R 4
)(R
5 ), and (14) -CH2(OR7)-R6. 20 In yet another embodiment of the present invention, R 2 is selected from: (1) -H, (2) -R3, (3) -CH2-R3, 25 (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S-phenyl, 30 (9) -C1-6 alkyl (OR 6
)(R
4 ), (10) -CO-6 alkyl-N(R 4
)(R
6 ), (11) -C(O)-R3, (12) -CO-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR 4 C(O)-R6, - 40- WO 99/62520 PCT/US99/12093 (14) -CH(OCH3)R 3 , and (15) -CH(OH)R3. In another embodiment of the present invention, R 2 is selected from: 5 (1) -R 3 , (2) -C1-6 alkyl substituted with R 3 , (3) -O-R6, (4) -S(O)n-R 6 , (5) -C1-6 alkyl (OR 6
)(R
4 ), 10 (6) -CO-6 alkyl-N(R 4
)(R
6 ), and (7) -C1-6 alkyl-C(O)N(R4)(R5). In one embodiment of the present invention, R3 is selected from: (1) phenyl; 15 (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, 20 (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, 25 (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 30 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, -41- WO 99/62520 PCT/US99/12093 (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (3) thienyl, 5 (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, 10 (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, 15 (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) -N
N-CH
3 20 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, 25 (iii) -CF3, and (iv) hydroxy; (5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from: 30 (a) halogen, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, - 42- WO 99/62520 PCT/US99/12093 (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, 5 (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 10 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 15 (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (7) imidazolyl, (8) substituted imidazolyl substituted on carbon with one or two 20 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 25 atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, 30 (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) - 43- WO 99/62520 PCT/US99/12093 -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: 5 (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (9) pyrrolyl, 10 (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, 15 (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, 20 (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) -N
N-CH
3 25 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, 30 (iii) -CF3, and (iv) hydroxy; -44- WO 99/62520 PCT/US99/12093 (11) pyrazolyl, (12) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: (a) halogen, 5 (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, 10 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, 15 (j) -N
N-CH
3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: 20 (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (15) piperidinyl, 25 (16) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 30 (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, - 45- WO 99/62520 PCT/US99/12093 (h) benzyl, and (i) hydroxy; (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen 5 atom with 1 or 2 substituents independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 10 (e) -OCF3, (f) -CN, (g) =0, (h) benzyl, and (i) hydroxy; 15 (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, 20 (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, 25 (g) -CN, and (h) hydroxy, (21) naphthyl, (22) substituted naphthyl with 1, 2, or 3 substituents independently selected from: 30 (a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 35 (f) -CN, and - 46- WO 99/62520 PCT/US99/12093 (g) -hydroxy, (23) indolyl, (24) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: 5 (a) -halogen, (b) -C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 10 (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 15 independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 20 (e) -OCF3, (f) -CN, (g) =0, and (h) hydroxy; (27) pyrazinyl; 25 (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, 30 (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, 35 (g) hydroxy, - 47- WO 99/62520 PCT/US99/12093 (h) phenyloxy, (i) -C0-6 alkyl-N(RT)2, -N N-CH 3 (j) (k) oxo, and 5 (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and 10 (iv) hydroxy; (29) pyrimidinyl; (30) substituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from: (a) halogen, 15 (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, 20 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, -N N-CH 3 25 (j) , (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; -48- WO 99/62520 PCT/US99/12093 (31) triazolyl; (32) substituted triazolyl with one or two substituents independently selected from: (a) halogen, 5 (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, 10 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, -N N-CH 3 15 (j) , (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 20 (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (33) tetrazolyl; (34) substituted tetrazolyl with a substituent selected from: 25 (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, 30 (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, - 49- WO 99/62520 PCT/US99/12093 (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, -N N-CH 3 (j) , (k) oxo, and 5 (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and 10 (iv) hydroxy; (35) C3-6 cycloalkyl; (36) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from: (a) halogen, 15 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 20 (g) =O, (h) benzyl, and (i) hydroxy; (37) tetrahydrofuran; (38) substituted tetrahydrofuran substituted with one or two 25 substituents independently selected from: (a) halogen, (b) 01-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 30 (e) -OCF3, (f) -CN, (g) =0, (h) benzyl, and - 50- WO 99/62520 PCT/US99/12093 (i) hydroxy; (39) piperazinyl; (40) substituted piperazinyl substituted with one or two substituents independently selected from: 5 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 10 (f) -CN, (g) =0, (h) benzyl, and (i) hydroxy; (41) benzotriazolyl, 15 (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-, 20 (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy; (43) benzoimidazolyl, 25 (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-, 30 (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy. In another embodiment of the present invention, R3 is 35 selected from: -51- WO 99/62520 PCT/US99/12093 (1) phenyl; (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from: (a) halogen, selected from -F, -Cl, -Br, 5 (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, 10 (e) hydroxy, and (f) oxo; (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: 15 (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; 20 (5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br; (b) C 1-6 alkyl, wherein one or more of the hydrogen 25 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; 30 (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 35 (a) halogen, selected from -F, -Cl, and -Br; - 52- WO 99/62520 PCT/US99/12093 (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and 5 (f) hydroxy; (11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, 10 (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 15 (g) =0O, and (h) hydroxy; (13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: 20 (a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 25 (f) =0O, and (g) hydroxy; (15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from: 30 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and - 53- WO 99/62520 PCT/US99/12093 (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents 5 independently selected from: (a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 10 (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, 15 (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-, 20 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, and (h) hydroxy; 25 (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 30 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, 35 (f) -CO-6 alkyl-N(R 7 )2, and - 54- WO 99/62520 PCT/US99/12093 (g) -N
N-CH
3 (25) pyrimidinyl; 5 (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 10 (d) phenyl, (27) triazolyl; (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, 15 (c) methoxy-, and (d) hydroxy, (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, 20 (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; (32) substituted C3-6 cycloalkyl substituted with one or two 25 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and 30 (e) -OCF3, (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from: - 55- WO 99/62520 PCT/US99/12093 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and 5 (e) -OCF3, (35) piperazinyl; (36) substituted piperazinyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, 10 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and 15 (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, 20 (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, and 25 (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from: (a) -halogen, selected from -F, -C1. and -Br, (b) -methyl, (c) methoxy-, 30 (d) -CF3, and (e) -OCF3. In yet another embodiment of the present invention, each R3 is independently selected from: (1) phenyl, - 56- WO 99/62520 PCT/US99/12093 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, selected from -F, -Cl, -Br, (b) -CH3, 5 (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, 10 (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (1) hydroxy; 15 (3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from: (a) F, (b) Cl, and 20 (c) methyl; (5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from: (a) -F, 25 (b) -Cl, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, 30 (g) hydroxy, and (h) oxo; (7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 35 (a) -F, - 57- WO 99/62520 PCT/US99/12093 (b) -Cl, (c) -CH3, and (d) -CF3; (9) C3-6 cycloalkyl, 5 (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from: (a) methoxy-, (b) -OCF3, 10 (c) =0O, and (d) hydroxy; (12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, 15 (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, 20 (c) -CF3, (d) methoxy-, (e) -N(CH3)2, and (f) -N N-CH 3 25 (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl; (21) cyclopropyl, 30 (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, - 58- WO 99/62520 PCT/US99/12093 (26) piperazinyl; (27) substituted piperazinyl substituted with a substituent selected from: (a) -F, 5 (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, and 10 (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 15 selected from: (a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) phenyl, 20 (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and 25 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, selected from -F, -Cl, -Br, (ii) -CH3, (iii) -CF3, and 30 (iv) hydroxy. In one embodiment of the present invention, each R4 is independently selected from: (1) -H, (2) -C1-4 alkyl, 35 (3) -CF3, - 59- WO 99/62520 PCT/US99/12093 (4) -R 3 , (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , (7) -C2-3 alkenyl-R 3 , and 5 (8) -C(O)-R 3 . In another embodiment of the present invention, each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, 10 (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3. In one embodiment of the present invention, each R5 is 15 independently selected from: (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R 3 , 20 (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , (7) -S(O)n-R 3 , (8) -C(O)-R 3 , (9) -C(O)OR4, and 25 (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, 30 (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R 3 , (6) -C(O)-R3, (7) -C(O)OR4, and - 60- WO 99/62520 PCT/US99/12093 (8) -C(O)C(O)OH. In another embodiment of the present invention, each R5 is independently selected from: (1) -H, 5 (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and 10 (7) -C(O)C(O)OH; In one embodiment of the present invention, R7 is independently selected from H, and -C1-6 alkyl. In one embodiment of the present invention, R8 is selected from hydrogen, methyl and -0- C1-6 alkyl. 15 In yet another embodiment of the present invention, R 8 is hydrogen. In one embodiment of the present invention, R9 is selected from: (1) -H, 20 (2) -0- C1-3 alkyl, (3) -OH, and (4) oxo. Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, 25 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 30 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: 35 (1) an AIDS antiviral agent, - 61- WO 99/62520 PCT/US99/12093 (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 5 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, 10 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): R2 R 1
OR
2
R
1 O R
OR
7 - R A
OR
7
R
9 O 0 R 9 0 OH (I) (IA)
R
2
H
1
R
8 A
ROR
7
R
9 OH O (IB) By naming or referring to compound (I) and tautomers thereof, it is 15 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). 20 When any variable (e.g., R3, R 4 , 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, - 62- WO 99/62520 PCT/US99/12093 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 5 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 10 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 15 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 20 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 25 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 30 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. - 63- WO 99/62520 PCT/US99/12093 Scheme AI 0 0 010 NaH DME Dimethyl oxalate 0 0 0 O C
H
3 Al-1-1 © / o 0 1 N NaOH THF/MeOH 1:1 -64- WO 99/62520 PCT/US99/12093 O 0 0 OH AI-2-1 00 00 Scheme AII 0 O
H
2 / Pd/C EtOH / Et 2 0 - 65- WO 99/62520 PCT/US99/12093 0 0 ~All-i -1 0 OH Br(0H 2
)
6 N
CS
2 00 3 0S 2 00 3 0 - 66- WO 99/62520 PCT/US99/12093 OI O 0 0 AII-4-1 AII-2-1 N ON O NO< O" N" H OH 0 NaH 1)NaH DME DMEE DME dimethyl oxalate dimethyl oxalate 2) NaOH 0 0 0 OCH 3 O aO AII-5-1 O OH 0 H 0 NO N O7 y AII-3-1 H 0 NaOH 0 0 0 OH AII-6-1 0 N H - 67- WO 99/62520 PCT/US99/12093 Scheme AIII Bra Br n-BuLi Benzaldehyde Et 2 0, -78°C AIII-1-1 Br OH Et 3 SiH
BF
3 Et 2 0
CH
2
CI
2 - 68- WO 99/62520 PCT/US99/12093 B AIII-2-1 Br n- BuLi
CH
3
CO-N(CH
3
)OCH
3 THF, -780C
H
3 AIII-3-1 O 0 dimethyl oxalate NaH DME, 600C - 69- WO 99/62520 PCT/US99/12093 AII-4-1
OCH
3 0 0 NaOH THF / MeOH / H 2 0 OH AIII-5-1 0 0 Scheme A-IV
H
2 NBr + Br 0 CS2CO3 DMF N 6 0 AIV-1-1 - 70- WO 99/62520 PCT/US99/12093 diethyl oxalate N NaOEt O OH 0 OH AIV-2-1 LiOH N THF 0 OH O OH AIV-3-1 -71- WO 99/62520 PCT/US99/12093 Scheme A-V + Br Cs 2
CO
3
H
2 N DMF O 0 N diethyl oxalate N O NaOEt AV-1-1 N OEt LiOH NOE1 ,___ __ 0 OH THF AV-2-1 N O OH O0 OH 5 AV-3-1 - 72- WO 99/62520 PCT/US99/12093 Scheme AVI 0O OH Mel / K 2
CO
3 DMF 0 \ AVI-1-1
OCH
3 1. diethyl oxalate NaOEt, THF 2. HCI, H 2 0, dioxane 00 O OH AVI-3-1 0
OCH
3 - 73- WO 99/62520 PCT/US99/12093 Scheme AVII H N Br NaH 4-fluorobenzyl bromide DMF F F Br t-BuLi, THF O
H
3 C Nt .
CH
3 0 F \/ N 0 AVII-1-1 - 74- WO 99/62520 PCT/US99/12093 dimethyl oxalate NaH, THF F0 0 N OCH 3 AVII-2-1 NaOTHFH 2 0 THF F O O N OH AVI -3-1 0 - 75- WO 99/62520 PCT/US99/12093 Scheme IX HO - 0 OH HO i. POCl 3 , 2000C, sealed tube ii. H 2 0 Cl - 0 / OH AIX-1-1 CI BnO- Na*, DMF, reflux BnO - 0 N( OH AIX-2-1 BnO - 76- WO 99/62520 PCT/US99/12093
OCH
3 HN * HCI
CH
3 EDC,HOAT, EtN(i-pr) 2 , DMF BnO - 0
N-CH
3 BnO H 3 CO AIX-3-1
CH
3 MgBr, THF BnO N\
/CH
3 AIX-4-1 BnO Na+OEt
-
, (CO 2 Et) 2 , THF - 77- WO 99/62520 PCT/US99/12093 BnO - 0 N 0 BnO OEt AIX-5-1 O i. Aq NaOH, EtOH ii. Aq HCI BnO - 0 BnO OH AIX-6-1 O 0 The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The 5 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, mucate, carbonate, napsylate, 10 chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, 15 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 - 78- WO 99/62520 PCT/US99/12093 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, 5 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 10 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 15 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 20 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. 25 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 30 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- WO 99/62520 PCT/US99/12093 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 5 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 10 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 15 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, 20 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 25 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 30 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, 35 including oleic acid. - 80- WO 99/62520 PCT/US99/12093 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 5 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 10 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, 15.0. 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 15 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, 20 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 25 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. -81- WO 99/62520 PCT/US99/12093 ANTIVIRALS Drug Name Manufacturer Indication 097 Hoechst/Bayer 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 dipivoxil Gilead 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 - 82- WO 99/62520 PCT/US99/12093 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'l Cancer Institute AIDS-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) - 83- WO 99/62520 PCT/US99/12093 ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV 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 Kline herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBYO97 Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) - 84- WO 99/62520 PCT/US99/12093 Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddl/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc infection, other CMV infections - 85- WO 99/62520 PCT/US99/12093 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 Viratek/ICN 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 Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS - 86- WO 99/62520 PCT/US99/12093 Bropirimine Pharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, 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 CD4 Interleukin-2 cell counts (aldeslukin) - 87- WO 99/62520 PCT/US99/12093 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 CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 - 88- WO 99/62520 PCT/US99/12093 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 & IV) (Rosemont, IL) 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; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP - 89- WO 99/62520 PCT/US99/12093 OTHER 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/AIDS 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 5 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 10 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 ddl. A preferred inhibitor of HIV protease is indinavir, which is 15 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 20 and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non - 90- WO 99/62520 PCT/US99/12093 nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddl 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 5 include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl 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 10 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 15 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 20 composition useful for the treatment of AIDS. Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l1(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. 25 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 30 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 35 will readily understand that known variations of the conditions and -91- WO 99/62520 PCT/US99/12093 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 5 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; El represents electron impact; ES represents electrospray; Et represents ethyl; FAB represents fast atom 10 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 15 tetrahydrofuran; TLC is thin layer (SiO2) chromatography. EXAMPLE 1 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid AI-2-1 20 Step 1: 4-(3,5-Bis-benzyloxy-phenyl)-2,4-dioxobutanoic acid methyl ester Al-1-1 0 0 0
OCH
3 1 0 Al-1-1 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 25 oil, 13.5 mmole) followed by dimethyl oxalate (1.3, 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 - 92- WO 99/62520 PCT/US99/12093 was poured into into 1N HC1 and extracted with EtOAc three times, the combined organic layers were dried over MgSO4, 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 5 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 Al-1-1 as a orange foam. Rf=0.3 (97:3:1 CH2C13 / MeOH / HOAc). 1H NMR (400 MHz, CDC13) 5 7.4 (m, 10H), 7.24 (m, 2H), 7.01 (s, 1H), 6.84 (m, 1H), 5.1 (s, 10 4H), 3.94, (s, 3H). Ste 2: 4-(3.5-Bis-benzvloxy-phenvl)-2.4-dioxobutanoic acid Al-2-1 0 0 OOOH 0 OH O~O 0 AI-2-1 A solution of Al-1-1 (1.5g, 3.47 mmole) was dissolved in 1:1 THF / MeOH 15 (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 HC1 and extracted three times with EtOAc. The organic layers were combined, washed with 1 N HC1, dried over MgSO4, filtered through a pad of CELITE diatomaceous earth and evaporated to 20 dryness. The residue was triturated with ether to give AI-2-1 as bright yellow powder. 1H NMR (400 MHz, CDC13) 6 7.43-7.31 (m, 10H), 7.22 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 6.86 (m, 1H). mass spec (FAB, m+1) 405.13 EXAMPLE 2 25 4-[ 3 -Benzyloxy-5-( 2 -morpholin-4-yl-ethoxy)-phenyl]-2,4-dioxobutanoic acid AII-3-1 S _p 1: 1-(3-Benzvloxy-5-hydroxyphenyl)ethanone AII-1-1 - 93- WO 99/62520 PCT/US99/12093 0 0 OH AI-1-1 A solution of 1-(3,5-bis-benzyloxyphenyl)ethanone (10g, 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 5 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 NMVIR (400 MHz, CDC13) 6 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). 10 Step 2: 4
-[
2 -(3-Acetyl-5-benzyloxy-phenoxy)-ethyl]morpholin-4-ium AII-2-1 00 0 N 0 AII-2-1 The free base of 4-(2-chloroethyl)morpholine hydrochloride (1.85g, 10 15 mmole) was formed and then combined with AII-1-1 (0.8g, 3.3 mmole), cesium carbonate (3.25g, 10 mmole) and dioxane (40 mL) and heated to 80 0 C for 4.5 hours. The solution was filtered, washed with EtOAc and concentrated. Column chromatography with 10-30% acetone / hexanes gave AII-2-1 as a brown syrup. Rf=0.39 (30% acetone / hexanes). 1H -94- WO 99/62520 PCT/US99/12093 NMR (400 MHz, CDC13) 6 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 (mi, 4H), 2.55 (s, 3H). 5 Step 3: 4-[3-Benzyloxy-5-(2-morpholin-4-yl-ethoxy)phenyl]-2,4 dioxobutanoic acid AII-3-1 0 0 OOOH 0 OH 0 O N O AII-3-1 In a manner similar to that discribed for Al-1-1, AII-2-1 was treated with NaH and dimethyloxate in DME to give a mixture of AII-3-1 and its 10 methyl ester. The mixture was treated with NaOH as described for Al 2-1 to give AII-3-1 as a yellow solid. 1H NMR (400 MHz, D20) 5 7.4 (m, 5H), 6.97 (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 15 EXAMPLE 3 4
-[
3 -Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy)-phenyl]-2,4 dioxobutanoic acid AII-6-1 Step 1: [6-(3-Acetyl-5-benzyloxy-phenoxy)-hexyl]carbamic acid-tert butyl ester AII-4-1 - 95- WO 99/62520 PCT/US99/12093 O o 0 N -01j H AII-4-1 In a manner similar to that described for AII-2-1, AII-1-1 was treated with (6-bromo-hexyl)-carbamic acid-tert-butyl ester (J. Med. Chem. 1994, 37, 2537-2551) to give AII-4-1. Rf=0.41 (80% acetone / hexanes); 1H NMR 5 (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 2: 4 -[3-Benzyloxy-5-(6-tert-butoxycarbonylamino-hexyloxy) 10 phenyll-2.4-dioxobutanoic acid methyl ester AII-5-1 S..0 0 0
OCH
3 0 0 O N 'O H AII-5-1 Freshly prepared sodium methoxide (from 0.25g sodium metal in MeOH) was suspended in toluene (5 mL) and a solution of AII-4-1 (0.8g, 1.8 mmole) and dimethyloxalate (0.21g, 1.8 mmole) in toluene (5 mL) was 15 added. The mixture was stirred for 2 hours, then quenched with 3 N HC1 and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was passed through a plug of silica gel as described for Al-1-1 and the resulting oil crystallized from ether to give AII-5-1 as a red solid. 1H NMR (400 MHz, CDC13) 8 7.4 - 96- WO 99/62520 PCT/US99/12093 (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). 5 Step 3: 4-[3-Benzyloxy-5-(6-tert-butoxycarbonylaminohexyloxy) phenvll-2,4-dioxo-butanoic acid AII-6-1 0 N O H AII-6-1 In a manner similar to that described for AI-2-1, AII-5-1 was treated with NaOH to give AII-6-1 as a foamy yellow solid. 1H NMR (400 MHz, 10 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. EXAMPLE 4 15 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid A-III-5-1 Step 1: (3-Bromophenyl)phenylmethanol AIII-1-1 I 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 n-butyl 20 lithium in hexanes (20.8 ml, 0.052 mole) chilled to -78 0 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- WO 99/62520 PCT/US99/12093 alumina pretreatment) keeping the internal temperature between -74 0 C and -78 0 C. The reaction was aged at -78 0 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 5 discharged overnight. The reaction was quenched with 20 mL H20 then acidified with 5.4 ml conc. HC1 and extracted with EtOAc three times. The combined organic layers were washed with NaHCO3, brine and dried over NaSO4, filtered and evaporated in vacuo to give a clear yellow oil AIII-1-1 which crystallized to afford a white solid after washing with 10 pet ether. Rf=0.14 (10% EtOAc/Hexanes). 1H NMR (300 MHz, CDC13) 6 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). Step 2: (3-Benzv1)phenv1 bromide AIII-2-1 15 Br AIII-2-1 A solution of AIII-1-1 (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 0oC under argon with stirring followed by addition of neat boron trifluoride etherate 20 (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 NaHCO3 and extracted with EtOAc three times, the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to afford colorless oil. Chromatographic purification using 25 5% EtOAc/hexanes afforded pure AIII-2-1; RF=0.44 (5% EtOAc/Hexanes) 1H NMR (400 MHz, CDC13) 8 7.27-7.33 (m, 4H), 7.09-7.23 (m, 5H),3.93 (s, 2H). Step 3: 1-(3-Benzylphenvl)ethanone AIII-3-1 - 98- WO 99/62520 PCT/US99/12093 OAIII-3-1 0 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 AIII2-1 in 26 ml THF and cooled to -78 0 C. Following dropwise addition of 1.6 M n-butyl 5 lithium in hexanes (4.90 ml, 49 mmole) over 15 minutes, the reaction was stirred for lh at -78 0 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% KHSO4 and 10 extracted with Et20 three times. The combined organic layers were washed with NaHCO3, brine and dried over Na2SO4, filtered and evaporated in vacuo to give a clear yellow oil. Chromatographic purification using EtOAc/hexanes afforded pure AIII-3-1. Rf=0.10 (5% EtOAc/hexanes); 0.40 (30 acetone, 70 hexane, 1.5 HOAc); 1H NMR (400 15 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). Ste 4: 4-(3-Benzylphenyl)-2,4-dioxobutanoic acid methyl ester AIII-4-1 \ \AIII-4-1
OCH
3 20 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 0 C. Dimethyl oxalate (951 mg, 8.1 mmole) and AIII-3-1 (770 mg) were dissolved in dry dimethoxyethane (10 ml) and 25 added by syringe at 0 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 NH4C1 and extracted with EtOAc three times. The - 99- WO 99/62520 PCT/US99/12093 combined organic layers were washed with H20, brine and dried over Na2SO4, filtered and evaporated in vacuo to give an orange oil AIII-4-1. Rf=0.26 (30 acetone, 70 hexane + 1.5 HOAc); 1H NMR (400 MHz, CDC13) 5 7.83 (m, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.24 (m, 1H), 7.18 (m, 2H), 7.16 (s, 5 1H), 4.04 (s, 2H) 3.90 (m, 3H). Step 5: 4-(3-Benzv1phenyl)-2,4-dioxobutanoic acid AIII-5-1 \ \AIII-5-1 OH 0O A solution of AIII-4-1 (900 mg, 2.9 mmole) was dissolved in 1:1 THF / 10 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 HC1 (7.5 ml) and extracted three times with EtOAc. The organic layers were combined, washed with H20, brine and dried over Na2SO4, filtered and evaporated to afford a waxy 15 solid. The residue was recrystallized from toluene-hexane to give a light yellow solid AIII-5-1. mp 118-119 0 C (uncorrected). Rf=0.12 (5 MeOH, 95 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 20 EXAMPLE 5 In a manner similar to that described for AIII-5-1, the following compound was prepared: CI OH AIII-5-2 0O 25 mp 102-103 0 C (uncorrected). Rf=0.18 (5 MeOH, 95 CH2C12, 5 HOAc) - 100- WO 99/62520 PCT/US99/12093 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 EXAMPLE 6 5 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid AIV-3-1 Step 1_: 1-(4-Dibenzvlaminophenvl)ethanone AIV-1-1 N 6 0 AIV-1-1 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 10 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 Na2SO4, filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexane/EtOAc) yielded 0.238 g (38%) of 15 AIV-1-1 as a clear oil. 1H NMR (400 MHz, CDC13) 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 20 ester AIV-2-1 - 101- WO 99/62520 PCT/US99/12093 N o OEt 0 0 AIV-2-1 In a similar manner to example Al-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 5 yield 0.29 g (93%) of AIV-2-1 as a yellow solid. 1H NMR (400 MHz, CDC13) 6 1.39 (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). 10 Step 3: 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid AIV-3-1 N N 0 OH S0 0 AIV-3-1 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 1N LiOH in 5 ml THF to afford 0.237 g (87%) of AIV-3-1 as an 15 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). EXAMPLE 7 20 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid AV-3-1 - 102- WO 99/62520 PCT/US99/12093 SteI 1: 1-(3-Dibenzvlaminophenyl)ethanone AV-1-1 N -U N N0 NO AV-1-1 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 5 cesium carbonate (1.63 g, 5 mmol) in 20 ml DMF at 600C for 4 hr to give 0.346 g (55%) of AV-1-1 as a clear oil after purification by radial disc chromatography (4:1 hexane/CH2C12). 1H NMR (400 MHz, CDC13) 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). 10 Step 2: 4-(3-Dibenzylaminophenyl)-2,4-dioxobutanoic acid ethyl ester AV-2-1 N0 N OEt N0 0 O °OO AV-2-1 In a manner similar to example AIV-1-1, 1-(3-dibenzylaminophenyl) 15 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) 6 1.37 (t, 3H, J = 7.14 Hz), 4.37 (q, 2H, J = 7.14 Hz), 4.71 (s, 4H), - 103- WO 99/62520 PCT/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-Dibenzvlaminophenvl)-2.4-dioxobutanoic acid AV-3-1 0 N OH 0 0 5 AV-3-1 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 1N LiOH in 10 ml THF to yield 0.4 g (94%) of AV-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). 10 EXAMPLE 8 1-(3-benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid AVI-3-1 O CH
OCH
3 AVI-1-1 15 Step .1: 1-(3-Benzvyloxy-5-methoxyphenvl)-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 20 with Et20 (3 x 20 mL). The combined organic extracts were washed with water (20 mL), sat. NaC1 (20 mL) and dried (MgSO4). Concentration - 104- WO 99/62520 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 5 (s, 3H), 2.57 (s, 3H). mass spec (EI, M+) 256 Ste 2: 1-(3-Benzyloxy-5-methoxyphenyl)-2,4-dioxobutanoic acid AVI-3-1 0 0 0 OH OCHH 0
OCH
3 AVI-3-1 10 Al-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 oC (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 15 EXAMPLE 9 1-(3-Benzyloxyphenyl)-2,4-dioxobutanoic acid AVI-3-2 Ste 1: 1-(3-Benzyloxvphenvl)-ethanone AVI-1-2 0 OO AVI-1-2 20 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 oC, 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 - 105- WO 99/62520 PCT/US99/12093 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 5 (m, 1H), 5.12 (s, 2H), 2.59 (s, 3H). mass spec (EI, M+) 226 Ste 2: 1-(3-Benzvloxvphenyl)-2,4-dioxobutanoic acid AVI-3-2 0 0 0 OH 0 AVI-3-2 AVI-1-2 was treated with NaOEt and diethyl oxalate to give the ethyl 10 ester which was treated with aqueous HC1 in dioxane to give AVI-3-2. mp 109-114 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 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). 15 EXAMPLE 10 1-(2-Benzyloxyphenyl)-2,4-dioxobutanoic acid AVI-3-3 0 0 0 OH 0 AVI-3-3 2-benzyloxyacetophenone (Chem Service) was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous 20 HC1 in dioxane to give AVI-3-3. mp 136-138 oC (uncorrected). 1H NMR (400 MHz, d6-DMSO) 6 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 25 EXAMPLE 11 1-[3-(4-Fluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-3-5 - 106- WO 99/62520 PCT/US99/12093 Ste 1: 1-[3-(4-Fluorobenzvloxv)phenvl]-ethanone AVI-1-5 F"O AVI-1-5 To a solution of 3-hydroxyacetophenone (Aldrich, 680 mg, 5.00 mmol) in DMF (10 mL) at rt was added K2CO3 (1.38 g, 10.0 mmol) and 4 5 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. NaC1 (25 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 10 9:1/hexanes:EtOAc, yielded 1.08 g (93%) of product as a clear oil. 1H NMR (400 MHz, CDC13) 5 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 15 3-5 F OO O O 0 OH 0 AVI-3-5 AVI-1-5 was treated with NaOEt and diethyl oxalate to give the ethyl ester which was treated with aqueous HC1 in dioxane to give AVI-3-5. mp 157-158 'C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 5 7.66 (d, J = 20 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) 317 EXAMPLE 12 25 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-3-6 - 107- WO 99/62520 PCT/US99/12093 Sten 1: 1-[3-(3,4-Difluorobenzyloxy)phenyl]-2,4-dioxobutanoic acid AVI-3-6 F:I 0 0 F 0 OH O /OH AVI-3-6 AVI-3-6 was prepared in a manner similar to that described for AVI-3-5 5 by replacing 4-fluorobenzyl bromide with 3,4-difluorobenzyl bromide. mp 181-182 'C (uncorrected). 1H NMR (400 MHz, d6-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 10 EXAMPLE 13 4-[3-(5-methyl-thiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid El Step 1: (3-bromo-phenv1)-(5-methyl-thiophen-2-vl)-methanol E1-A S Br OH E1-A 15 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 mIL, 0.0381 mole) at -78 0 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, 20 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 cone. HC1. Extraction with EtOAc three times followed by drying over NaSO4, filtration and removal of solvent gave E1-A as a brown oil that was taken on to the next step. 25 Step 2: 2-(3-bromobenzvl)-5-methy1thiophene E1-B - 108- WO 99/62520 PCT/US99/12093 S Br E1-B A solution of crude E1-A (7.0 g, 0.0247 mole) and triethylsilane (5.9 mL, 0.0371 mole) in methylene chloride (30 mL) was chilled to Oo C under argon with stirring followed by addition of boron trifluoride etherate (4.67 5 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 10 using 100% hexanes afforded E1-B as a clear oil. Rf=0.52 (100% Hexanes) 1H NMR (400MHz, CDC13 ) 6 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). 15 Step 3: 1- [3-(5-methylthiophen-2-vlmethyl)-phenvyl]-ethanone E1-C S O E1-C To an oven dried 3-neck flask fitted with temperature probe and argon inlet was added E1-B (4 g, 0.0150 mole) in 40 mL of THF. The reaction was cooled to -78oC and 2.5M nBuLi in hexanes (9.0mL 0.0225 mole) was 20 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 25 and acidified with concentrated HC1. 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. - 109- WO 99/62520 PCT/US99/12093 Rf=0.42 (10% EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) 6 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). 5 Ste 4: 4-[3-(5-methylthiophen-2-ylmethyl)-phenyl]-2,4-dioxo-butyric acid El /
CO
2 H O O E-1 To a solution of E1-C (1g, 0.00446 mole) and diethyloxylate (0.67mL, 0.00491 mole) in THF (8mL) was added NaOEt (0.46g, 0.00669 mole) 10 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 15 mixture of THF/MeOH (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% KHSO4 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 20 NaSO4, filtered and concentrated to give a solid which was crystallized from CH2Cl2 and pet. ether. Collected pure El as a yellow solid by filtration. 1H NMR (400MHz, CDC13 ) 6 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. 25 EXAMPLE 14 4-{3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo-butyric acid E2 Step 1: (3-bromo-benzvl)-phenv1-amine E2-A - 110- WO 99/62520 PCT/US99/12093 H N Br E2-A To a solution of aniline (1.26g. 1.23 mL, 0.0135 mole) and 3-bromo benzaldehyde (2.5g, 1.58 mL, 0.0135 mole) in MeOH (20mL) under argon 5 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 NaSO4, filtered and concentrated. Chromatographic purification with 10 95:5 Hexanes/EtOAc afforded E2-A 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). 15 Step 2: (3-bromo-benzv1)-methvl-phenv1-amine E2-B N Br E2-B To a solution of E2-A (1.5 g, 0.00572 mole) in DMF (25 mL) and under argon at OoC was added NaH (0.15 g, 0.00629 mole) and this was stirred 20 for 15 minutes followed by addition of iodomethane (0.40 mL, 0.00629 mole) which was passed through basic alumina. 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 25 concentrated. Chromatographic purification using 90:10 Hexanes/Ethyl acetate afforded E2-B. - 111- WO 99/62520 PCT/US99/12093 Rf=0.45 (5% EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) 6 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). Ste 3: 1- {3- [(methyl-phenvl-amino)-methyl]-phenyll-ethanone E2-C N \N. 0 5 E2-C 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 10 tube in anhydrous DMF (8 mL) under argon at 100 0 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 HC1 was added (14 mL, 0.0144 mole). After one hour poured into 20 mL of saturated sodium 15 bicarbonate solution and extraced with EtOAc dried over NaSO4 , filtered and concentrated. Chromatographic purification with 80:20 Hexanes/EtOAc afforded purified E2-C. Rf= 0.29 (10% EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) 6 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, 20 2H), 3.07 (s, 3H), 2.61 (s, 3H. Step.: 4- {3-[(methyl-phenyl-amino)-methyl]-phenyl}-2,4-dioxo butvric acid E2 I I N N 0 C 0 2 H ~0 0 E2 25 - 112- WO 99/62520 PCT/US99/12093 To a solution of E2-C (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, 5 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 10 was with 3N HC1, extracted with EtOAc three times, and the organic layers dried over NaSO4, filtered and concentrated to give solid pure E2. 1H NMR (400MHz, CDC13 ) 6 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. 15 EXAMPLE 15 4-(3-benzyl-5-pyrazin-2-yl-phenyl)-2,4-dioxo-butyric acid E3 Ste 1: (3.5-dibromo-phenyl)-phenv1-methanol E3-A Br Br OH E3-A 20 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 -780C. 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 25 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 O'C and 100 mL of HC1 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 - 113- WO 99/62520 PCT/US99/12093 was purified by chromatography with 5% EtOAc/Hexanes to afford E3-A as a colorless oil that solidified on the bench. Rf = 0.44 (5%EtOAc/Hexanes) 1H NMR (400MHz, CDC13 ) 5 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, 5 1H, j=3.48 Hz). Ste 2: 3-bromo-5-benzvl-bromobenzene E3-B Br Br E3-B A solution of E3-A (2.0 g, 0.00548 mole) and triethylsilane (1.39 mL, 10 0.00877 mole) in methylene chloride (20 mL) was chilled to 00 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. 15 The combined organic layers were dried over sodium sulfate, filtered and the solvent removed. Chromatographic purification using 1% EtOAc/Hexanes afforded E3-B. Rf=0.72 (5%EtOAc/hexanes) 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). 20 Ste 3: 2-(3-benzvl-5-bromo-phenvl)-pvrazine E3-C 1 Br E3-C To a solution of E3-B (1 g, 0.00307 mole) in THF (20 mL) under argon at -78 0 C was added 2.4M nBuLi in hexanes (1.4 mL, 0.00337 mole) - 114- WO 99/62520 PCT/US99/12093 dropwise. After 45 minutes of stirring, the solution was treated with 0.5m ZnC12 in THF (6.14 mL 0.00337 mole) and this was warmed to 0 0 C. To the reaction was added a cold mixture of chloropyrazine (0.35 mL, 0.00307 mole) and tetrakistriphenylphosphine palladium (18 mg, 5 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 10 purification with 15% EtOAc/hexanes afforded a clear oil E3-C. Rf=0.17 (20%EtOAc/hexanes) 1H NMR (400MHz, CDC13 ) 5 8.95 (s, 1H), 8.62-8.61 (m, 1H), 8.52 (m, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.32-7.20 (m, 5H), 4.04 (s, 2H). 15 Ste 4: 1-(3-benzvl-5-pyrazin-2-v1-phenvl)-ethanone E3-D ,-N O E3-D E3-C (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, 20 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 25 solvent was then removed and the residue dissolved in THF to which 1N HC1 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 NaSO4, filtered and - 115- WO 99/62520 PCT/US99/12093 concentrated. Chromatographic purification with 70:30 Hexanes/EtOAc afforded purified E3-D as a clear oil. Rf= 1H NMR (400MHz, CDC13 ) 6 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). 5 Step 5: 4-(3-benzvl-5-pvrazin-2-vl-phenvl)-2,4-dioxo-butvric acid E3 ,N / \ C02H O O E3 To a solution of E3-D (0.17 g, 0.000590 mole) and dimethyloxylate (76 mg 0.000650 mole) in THF (7mL) was added NaOMe (50 mg, 0.000884 mole) 10 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 15 hour the reaction was poured into saturated sodium bicarbonate solution and extracted three times with ether. The aqueous layer was acidified with 3N HC1, extracted with EtOAc three times, the organic layers were dried over NaSO4, 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 20 (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 EXAMPLE 16 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid 25 (isomers A and B) (G1 and G2) - 116- WO 99/62520 PCT/US99/12093 o0 OH Step 1: Synthesis of 1-(3-bromophenyl)-1,2,3.4-tetrahydronaphthalen-l1-ol Br OH To a solution of 1 g (4.2 mmol) 1,3-dibromobenzene in 10 mL 5 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 reflux for 30 min, after which the cooled reaction was quenched with a 10% HC1 solution and 10 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 vacuo to afford the crude product which was used without further purification. 15 Step 2. Synthesis of 1-(3-bromophenyl)-1,2,3,4-tetrahydronaphthalene and 4-(3-bromophenvl)- 1.2-dihydronaphthalene. Br Br H Into an ice cooled solution of .671 g (2.2 mmol) of 1-(3-bromophenyl) 1,2,3,4-tetrahydronaphthalen-1-ol and and .386 g (3.3 mmol) 20 triethylsilane in 5 mL methylene chloride was added .471 g (3.3 mmol) boron trifluoride diethyl etherate dropwise. After stirring the reaction - 117- WO 99/62520 PCT/US99/12093 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. 5 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. 10 Step 3. Synthesis of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl] ethanone and 1-[3-(1,2-dihvdronaphthalen- 1-v1)-phenyll-ethanone To a solution of .276 g of the above mixture dissolved in 10 mL of a 1:1 15 mixture of diethyl ether/tetrahydrofuran and cooled to -760C 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 20 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 25 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 30 vl)-phenvyl]butvric acid ethyl ester (isomers A and B) - 118- WO 99/62520 PCT/US99/12093 \/ 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 5 mmol) sodium ethoxide. After stirring for 1.5 hr, excess 10% citric acid solution was added and the THF removed in vacuo. 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 vacuo to afford the 10 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 15 purification. Step 5: Synthesis of 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1 vl)-phenvyl]butvric acid (isomers A and B) Isomer A: 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1 20 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 25 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 vacuo. The residue was triturated in 3:1 hexane/diethyl ether, filtered and the solvent removed in vacuo to yield the title compound as a yellow solid. 30 1H NMR (CDC13) 8 1.72 - 1.91(3H,m), 2.20(1H,m), 2.80 - 3.00(2H,m), - 119- WO 99/62520 PCT/US99/12093 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(1H,s), 7.84(1H, d, J=7.88Hz) CHN Calc. (C20H1804*.1EtOAc) 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) 8 1.72 - 1.91(3H,m), 2.20(1H,m), 2.80 - 3.00(2H,m), 10 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(1H,s), 7.84(1H, d, J=7.88Hz) CHN Calc. (C20H1804*.lEtOAc) 73.98, 5.72; Fnd. 73.68, 5.90 15 EXAMPLE 17 2,4-Dioxo-4-(3-phenylsulfanyl-phenyl)-butyric acid L1 Step 1: 1-(3-Phenvlsulfanyl-phenvl)-ethanone L1-A L1-A A mixture of potassium carbonate (1.20 g, 9.08 mmol), 0.17 M Ni(II)Br2 20 (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 gL, 9.08 mmol) and 3'-iodoacetophenone (1.88 mL, 13.6 mmol) were then introduced and 25 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 L1-A as a yellow oil. Rf = 0.49 (10% EtOAc / hexane). 1H NMR (400 MHz, CDC13) 6 7.89 (m, 1H), 7.79 (m, 1H), 7.56 (m, 1H), 7.29-7.40 (m, 6H), 2.58 (s, 3H). 30 Stei 2: 2.
4 -Dioxo-4-(3-phenvlsulfanvl-phenvl)-butvric acid L1 - 120- WO 99/62520 PCT/US99/12093 H 0 L1 In a manner similar to example AIV-2-1, 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-3-1 using 1N NaOH to 5 afford L-1 as a yellow solid. Rf = 0.32 (6:6:94 MeOH / AcOH / CH2C12). 1H NMR (400 MHz, CDC13) 5 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. 10 EXAMPLE 18 4-[3-(2,4-Difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid L2 Step 1: 1-[3-(2,4-Difluoro-benzyl)-phenyll-ethanone L2-A F L2-A 15 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 tL, 0.24 mmol), and THF (2 mL). The mixture was brought to reflux two times using a heat gun then cooled to OoC at which time a-bromo-2,4-difluorotoluene (781 gL, 6.10 20 mL) in THF (3 mL) was added slowly keeping the temperature < 3 0 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 OoC 25 at which time 3'-iodoacetophenone (562 giL, 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 OoC, the reaction was left to stir - 121- WO 99/62520 PCT/US99/12093 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 Na2SO4, filtered, and concentrated to a brown oil. The crude 5 product was chromatographed on silica gel using 5% EtOAc / hexane as elutant. Pure product fractions were combined and concentrated to afford L2-A as a yellow oil. Rf = 0.22 (5% EtOAc / hexane). 1H NMR (400 MHz, CDC13) 5 7.81 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.81 (m, 2H), 4.02 (s, 2H), 2.56 (s, 3H). 10 Step 2: 4-[3-(2,4-Difluoro-benzvl)-phenvll-2,.4-dioxo-butvric acid L2 H F L2 In a manner similar to example AIV-2-1, 4-[3-(2,4-difluoro-benzyl) 15 phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L2 as a yellow solid. Rf = 0.60 (6:6:94 MeOH / AcOH / CH2C12). 1H NMR (400 MHz, CDC13) 8 7.85 (m, 2H), 7.45 (m, 2H), 7.13 (m, 2H), 6.82 (m, 2H), 4.03 (s, 2H). mass spec (FAB, M+1) 319 m/e. 20 EXAMPLE 19 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo-butyric acid L3 Ste 1: (3-Bromo-4,5-dimethoxy-phenyl)-(4-fluoro-phenyl)-methanol 25 L3-A H Br F
-
L3-A - 122- WO 99/62520 PCT/US99/12093 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 OOC. The resulting solution was stirred for 15 minutes then allowed to stir at room 5 temperature for 2 hours. The solvent was then removed in vacuo and the residue was partitioned between 10 % KHSO4 solution and EtOAc. The aqueous layer was extracted three times with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to a yellow oil. The crude product was taken on 10 without further purification. 1H NMR (400 MHz, CDC13) 6 7.33 (m, 2H), 7.05 (m, 3H), 6.86 (m, 1H), 5.74 (s, 1H), 3.83 (s, 6H). Ste 2: Preparation of L3-B Br L3-B 15 To (3-bromo-4,5-dimethoxy-phenyl)-(4-fluoro-phenyl)-methanol (2.95 g, 8.65 mmol) in dry CH2C12 at 0OC 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. 20 NaHCO3 solution and CH2C12. The aqueous layer was extracted three times with CH2C12 and the combined organic extracts were washed with brine, dried over Na2SO4, 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 25 fractions to give afford L3-B 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-r5-(4-Fluoro-benzvl)-2,3-dimethoxy-phenyll-ethanone L3-C - 123- WO 99/62520 PCT/US99/12093 O F L3-C In dried glassware under argon, slowly added 2.5 M n -BuLi in hexane to L3-B (2.50 g, 7.69 mmol) in distilled THF (45 mL) at -78 0 C. Aged solution 10 minutes then added N -methoxy-N -methylacetamide (1.11 5 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. NH4C1 solution and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude 10 product was chromatographed on silica gel using 5 % EtOAc / hexane as elutant. Collected and concentrated product fractions to afford L3-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). 15 Step 4: 4-[5-(4-Fluoro-benzyl)-2,3-dimethoxy-phenyl]-2,4-dioxo butvric acid L3 H L3 In a manner similar to example AIV-2-1, 4-[5-(4-fluoro-benzyl)-2,3 20 dimethoxy-phenyl]-2,4-dioxo-butyric acid ethyl ester was formed and the crude material was hydrolyzed in a manner similar to example AIV-3-1 using 1N NaOH to afford L3 as a yellow solid. Rf = 0.67 (6:6:94 MeOH / AcOH / CH2C12). 1H NMR (400 MHz, CDC13) 6 7.38 (s, 1H), 7.25 (m, 1H), - 124- WO 99/62520 PCT/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. EXAMPLE 20 5 4-(5-Benzyl-2-isopropoxyphenyl)-2,4-dioxobutyric acid W1 Step 1: (3-Bromo-4-fluorophenyl)phenvlmethanol W1-A F Br OH To a cold (0 °C) solution of 3-bromo-4-fluorobenzaldehyde (25.5 g) in THF 10 (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. HC1. The resultant mixture was diluted with ethyl acetate, and neutralized with aq. HC1. The organic extract was dried over magnesium sulfate, 15 filtered, and concentrated under vacuum to provide the title alcohol. Step 2: 1-Benzyl-3-bromo-4-fluorobenzene Wl-B F To a cold (0 °C) solution of (3-bromo-4-fluorophenyl)phenylmethanol (35 20 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 25 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. - 125- WO 99/62520 PCT/US99/12093 Step 3: 5-Benzvl-2-fluorobenzonitrile W1-C I F CN To a mixture of 1-benzyl-3-bromo-4-fluorobenzene (14.7 g) and zinc 5 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. HC1, and brine. The 10 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. 15 Step 4: 5-Benz1vl-2-isopropoxvbenzonitrile W1-D 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 20 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 25 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. - 126- WO 99/62520 PCT/US99/12093 Step 5: 5-Benzvl-2-isopropoxvacetophenone W1-E 0 O To a solution of 5-benzyl-2-isopropoxybenzonitrile (0.6 g) in benzene (15 5 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. HC1 and washed with brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was 10 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-isopropoxvphenyl)-2,4-dioxobutvric acid W1 O
/-,CO
2 H 15 0 0 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 20 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. HC1 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 - 127- WO 99/62520 PCT/US99/12093 hexane. The yellow solid precipitated was filtered to provide the title product. 1H NMR (CDC13) 5 7.8-6.8 (m, 9H), 4.6 (m, 1H), 3.95 (s, 2H), 1.43 (d, 6H). 5 EXAMPLE 21 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4-dioxobutyric acid W2 Step 1: 5-Benzvl-2-(2-N.N-dimethvlaminoethoxy)benzonitrile W2-A 0 N"CH 3 10 ON CH3 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 15 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 20 fractions provided the title nitrile. Step 2: 4-[5-Benzyl-2-(2-N,N-dimethylaminoethoxy)phenyl]-2,4 dioxo-butvric acid W2
H
3 C.N. CH 3 OJ C0 2 H 0O 25 The title compound was prepared using the protocol described in Example W1, Step 5 - 6 substituting 5-benzyl-2-isopropoxybenzonitrile - 128- WO 99/62520 PCT/US99/12093 with 5-Benzyl-2-(2-N,N-dimethylaminoethoxy)benzonitrile in Step 5. 1H NMR (DMSO-d6) 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). 5 EXAMPLE 22 4-[5-Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid W3 Step 1: 4-Benzvyl-2-bromophenol W3-A ~OH Br 10 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 15 extract was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound. Step 2: 5-Benzyl-2-(pyridin-2-yloxy)phenvl bromide W3-B I N I Br 20 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 25 extract was washed successively with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue - 129- WO 99/62520 PCT/US99/12093 was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provide the title bromide. 5 Step 3: 5-Benzyl-2-(pvridin-2-vloxy)acetophenone W3-C ,N 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 -78 °C for 1 h 10 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. HC1. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under 15 vacuum. The residue was subjected to column chromatography on silica gel eluting with chloroform. Collection and concentration of appropriate fractions provide the title ketone. Step 4: Methyl 4-[5-benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo 20 butvrate W3-D ,N O O - 130- C 2 M 0 0 - 130- WO 99/62520 PCT/US99/12093 To a cold (-78 oC) 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 5 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. HC1. 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 10 resultant ethereal solution was isolated and concentrated under vacuum to provide the title ester. Step5: 4
-[
5 -Benzyl-2-(pyridin-2-yloxy)phenyl]-2,4-dioxo-butyric acid W3 ,N
/CO
2 H 15 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 20 aq. HC1. 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) 6 8.25 (m, 1H), 7.8-6.8 (m, 12H), 4.05 (s, 2H). 25 EXAMPLE 23 4 -(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid W4 - 131- WO 99/62520 PCT/US99/12093 Step 1: 5-Benz1vl-2-isopropoxv-3-methoxy-l1-bromobenzene W4-A
CH
3
CH
3 0 CH 3 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 5 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 10 concentration of appropriate fractions provide the title bromide. Step 2: 5-Benzyl-2-isopropoxy-3-methoxv-acetophenone W4-B
CH
3
CH
3 0 (-CH 3 O 0 To a mixture of 5-benzyl-2-isopropoxy-3-methoxy-1-bromobenzene (0.4 g), 15 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 20 bed of CELITE diatomaceous earth, and the filtrate concentrated under vacuum. The residue was dissolved in THF (5 mL) and treated with aq. HC1 (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 - 132- WO 99/62520 PCT/US99/12093 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. 5 Step 3: 4-(5-Benzyl-2-isopropoxy-3-methoxyphenyl)-2,4-dioxo-butyric acid W4
CH
3
CH
3 0 CH 3
/CO
2 H 0O To a solution of 5-benzyl-2-isopropoxy-3-methoxy-acetophenone (79 mg) and dimethyl oxalate (125 mg) in THF (2 mL), sodium methoxide (30 mg) 10 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. HC1. The resultant mixture was 15 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) 5 7.58-6.89 (m, 8H), 4.53 (m, 1H), 3.97 (s, 2H), 3.81 (s, 3H), 1.26 (d, 6H). 20 EXAMPLE 24 4-(5-Benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid W5 Step 1: (3-Bromo-4.5-dimethoxvphenvyl)phenylmethanol W5-A
OCH
3
OCH
3 Br 25 OH - 133- WO 99/62520 PCT/US99/12093 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. 5 HC1. The resultant mixture was diluted with ether, and neutralized with aq. HCL. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol. 10 Step 2: 5-Benzvl-2,3-dimethoxv- 1-bromobenzene W5-B
OCH
3
OCH
3 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 15 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. 20 Collection and concentration of appropriate fractions provided the title bromide. Step 3: 5-Benzyl-2,3-dimethoxvacetophenone W5-C
OCH
3
OCH
3 O 0- 134 - 134- WO 99/62520 PCT/US99/12093 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 5 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. HC1. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on 10 silica gel eluting with a 5 - 20% ethyl acetate gradient. Collection and concentration of appropriate fractions provide the title ketone. Step 4: Ethyl 4-(5-benzyl-2,3-dimethoxyphenyl)-2,4-dioxobutyrate W5-D
CH
3 0
OCH
3
/CO
2 Et 15 0 0 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. 20 KHSO4, 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. Step 5: 4-(5-Benzv1-2,3-dimethoxvphenvyl)-2,4-dioxobutvric acid W5 CH30
N.
O C H 3 // " CO 2 H 25 0 0 - 135- WO 99/62520 PCT/US99/12093 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 5 between ethyl acetate and aq. HC1. 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, 10 3H). EXAMPLE 25 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4-dioxobutyric acid W6 15 Step 1: 4-benzv1-2-bromo-6-nitrophenol W6-A
NO
2 OH IBr 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 20 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 25 with a gradient of 5 - 7% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title phenol. Step 2: 5-Benzyl-2-methoxv-3-nitro-l1-bromobenzene W6-B -136- WO 99/62520 PCT/US99/12093
NO
2 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 5 prepared by addition of 1-methyl-3-nitro-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 10 acetate in hexane. Collection and concentration of appropriate fractions provide the title bromide. Step 3: 5-Benzvl-2-methoxv-3-bromoaniline W6-C
NH
2 OMe Br 15 A mixture of 5-benzyl-2-methoxy-3-nitro-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 20 was concentrated under vacuum to provide the title aniline. Step 4: 5-Benzvl-2-methoxv-3-bromo-N.N-dimethylaniline W6-D NMe 2 OMe Br - 137wO 99/62520 PCT/US99/12093 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. 5 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. 10 Collection and concentration of appropriate fractions provide the title bromide. Step 5: 5-Benzyl-2-methoxy-3-N,N-dimethylaminoacetophenone W6-E Me 2 N OMe 15 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 20 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. HC1 (1M, 3 mL). The resultant mixture was stirred at rt for 1 hr., 25 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. 30 - 138- WO 99/62520 PCT/US99/12093 Step 6: 4-(5-Benzyl-3-dimethylamino-2-methoxyphenyl)-2,4 dioxobutvric acid W6 Me 2 N OCH3 C0 2 H O O To a solution of 5-benzyl-2-methoxy-3-N,N-dimethylaminoacetophenone 5 (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. KHSO4. The organic extract was washed with brine, dried over magnesium sulfate, filtered, 10 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 15 lyophilization of appropriate fractions provided the title acid. 1H NMR (CDC13) 5 7.6-7.0 (m, 8H), 4.00 (s, 2H), 3.89 (s, 3H), 3.21 (s, 6H). EXAMPLE 26 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo-butyric acid 20 W7 Step 1: 3-Benzvl-5-bromo-6-hydroxvaniline W7-A
NH
2 OH Br To a solution of 4-benzyl-2-bromo-6-nitrophenol (8.65 g) and 5% Pt on 25 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 - 139- WO 99/62520 PCT/US99/12093 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. 5 Step 2: 5-Benzvl-7-bromo-2-N,N-dimethylaminobenzoxazole W7-B
N(CH
3
)
2
N
0 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 10 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 15 on silica gel eluting with 40% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title benzoxazole. Step 3: 7-Acetvl-5-benzy1-2-N,N-dimethylaminobenzoxazole W7-C
N
( C
H
3
)
2 O 0 0 20 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 - 140- WO 99/62520 PCT/US99/12093 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. 5 HC1 (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 10 concentration of appropriate fractions provided the title ketone. Step 4: 4-[5-Benzyl-2-N,N-dimethylaminobenzoxazol-7-yl]-2,4-dioxo butyric acid W7
N
(C
H
3
)
2
N
//CO
2 H 0 0 15 To a solution of 7-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. HC1. The organic extract was 20 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 25 mixture was partitioned between ethyl acetate and aq. HC1. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with - 141- WO 99/62520 PCT/US99/12093 ether. The yellow solid precipitated was filtered to provide the title acid. 1H NMR (CDC13) 6 7.54-7.16 (m, 8H), 4.05 (s, 2H), 3.25 (s, 6H). EXAMPLE 27 5 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric acid W8 Step 1: (3,5-dibromophenyl)phenylmethanol W8-A Br Br OH To a cold (-78 'C) solution of 1,3,5-tribromobenzene (30 g) in diethyl ether 10 (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. HC1 (1M, 15 95 mL). The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol. Step 2: 1-Benzvl-3,5-dibromobenzene W8-B Br 20 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. 25 overnight. The product mixture was diluted with dichloromethane, and neutralized with saturated aq. sodium bicarbonate. The organic extract - 142- WO 99/62520 PCT/US99/12093 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. 5 Step 3: (3-benzvl-5-bromophenv1) pvrazin-2-vl ketone W8-C N 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. 10 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. 15 HC1. 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. 20 Step 4: 3-Benzyl-5-pvrazin-2-ylmethyl- 1-bromobenzene W8-D N- 143 Br - 143- WO 99/62520 PCT/US99/12093 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 5 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 10 in hexane gradient. Collection and concentration of appropriate fractions provided the title bromide. Step 5: 3-Benzvl-5-pyrazin-2-ylmethvlacetophenone W8-E N ' \N O 15 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 20 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. HC1 (3M, 4 mL). The resultant mixture was stirred at rt for 3 hr., diluted with ethyl acetate, basified with aq. sodium bicarbonate. The 25 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. - 144- WO 99/62520 PCT/US99/12093 Collection and concentration of appropriate fractions provided the title ketone. Step 6: 4-(3-Benzyl-5-pyrazin-2-ylmethylphenyl)-2,4-dioxobutyric 5 acid W8 N N /CO2H O O 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 10 '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 15 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). 20 EXAMPLE 28 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4-dioxobutyric acid W9 Step 1: 3-Benzyl-5-bromobenzaldehvde W9-A 0 H I: Br - 145- WO 99/62520 PCT/US99/12093 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 5 up slowly to room temp. and was stirred at that temp. overnight. The product mixture was diluted with ethyl acetate and partitioned with aq. HC1. 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 10 with 10% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title benzaldehyde. Step 2: 3-Benzyl-5-bromobenzyl alcohol W9-B OH Br 15 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. HC1. The organic extract was washed with brine, dried over 20 magnesium sulfate, filtered, and concentrated under vacuum to provide the title alcohol. Step 3: 3-Benzy1-5-bromobenzvl bromide W9-C Br Br - 146- WO 99/62520 PCT/US99/12093 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 5 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. 10 Step 4: 3-Benzvl-5-[1.2,3]triazol-2-ylmethyl-l1-bromobenzene W9-D
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 15 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 20 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, slica gel, eluted with 50% ethyl acetate in hexane) provided the title triazole bromide [1H NMR (CDC13) 5 7.63 (s, 2H)], and later fractions (Rf = 0.2) provided the isomeric 3-benzyl-5-[1,2,3]triazol-1 25 ylmethyl-1-bromo-benzene analog [ 1H NMR (CDC13) 8 7.76 (br s, 1H), 7.73 (br s, 1H)]. Step 5: 3-Benzvl-5-[1,2, 3 ]triazol-2-v1methylacetophenone W9-E - 147- WO 99/62520 PCT/US99/12093 N O 0 To a mixture of 3-benzyl-5-[1,2,3]triazol-2-ylmethyl-l1-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 5 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. 10 HC1 (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. 15 Collection and concentration of appropriate fractions provided the title ketone. Step 6: 4-(3-Benzyl-5-[1,2,3]triazol-2-ylmethylphenyl)-2,4 dioxobutyric acid W9 N /C02H 20 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 - 148- WO 99/62520 PCT/US99/12093 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. HC1. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated 5 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. HC1. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The 10 residue was triturated with hexane/ethyl acetate. Filtration and collection of the solid provided the title acid. 1H NMR (CDC13) 8 7.78-7.10 (m, 11H), 5.64 (s, 2H), 4.03 (s, 2H). EXAMPLE 29 15 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid W10 Step 1: 3-Chloropyridin-2-yl 3-bromophenyl ketone W10-A 1 N\ Br Cl O To a cold (-78 °C) solution of 1,3-dibromobenzene (0.8 mL) in THF (4 mL), 20 a solution of n-BuLi in hexanes (2.5 M, 3.2 mL) was added. The resultant mixture was stirred at -78 'C for 1 h and was treated with a solution of N-methoxy-N-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 25 mixture was diluted with ethyl acetate and partitioned with aq. HC1. 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 30 provided the title ketone. - 149- WO 99/62520 PCT/US99/12093 Step 2: 3-(3-Chloropyridin-2-vlmethyl)-l1-bromobenzene W10-B Br Cl 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 5 110 '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, 10 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) 8 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). 15 Step 3: 3-(3-Chloropyridin-2-vlmethy1)acetophenone W10-C 'NN Cl O CI 0 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 20 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 25 vacuum. The residue was dissolved in THF (3 mL) and treated with aq. HC1 (3M, 3 mL). The resultant mixture was stirred at room temp. overnight, diluted with ethyl acetate, basified with aq. sodium - 150- WO 99/62520 PCT/US99/12093 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 5 the title ketone. Step 4: 4-[3-(3-Chloropyridin-2-ylmethyl)phenyl]-2,4-dioxobutyric acid W10 ';N __ I C0 2 H CI 0 0 10 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 -78 '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 15 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 20 appropriate fractions provided the title acid. 1H NMR (DMSO-d6) 8 8.48 (br d, 1H), 7.92 - 7.0 (m, 7H), 4.35 (s, 2H). EXAMPLE 30 4 -[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl)phenyl]-2,4-dioxo 25 butyric acid W11 Step 1: 4-Benzv1-2,6-dibromophenol W11-A Br OH Br - 151- WO 99/62520 PCT/US99/12093 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 5 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 10 provided the title dibromophenol. Step 2: 4-Benzv1-2,6-dibromo-l1-methoxvbenzene W11-B Br OMe Br To a cold (0 °C) solution of 4-benzyl-2,6-dibromophenol (10 g) in diethyl 15 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 1-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, 20 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. 25 Step 3: 3-Benzv1-5-bromo-6-methoxvbenzvl bromide W11-C Br OMe Br - 152- WO 99/62520 PCT/US99/12093 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-l1-methoxybenzene in Step 1. 5 Step 4: 3-Benzyl- 1-bromo-5-N,N,-dimethylaminomethyl-6 methoxvbenzene W11-D NOMe Br A solution of 3-benzyl-5-bromo-6-methoxybenzyl bromide (0.65 g), dimethylamine hydrochloride (0.29 g), and diisopropylethylamine (0.61 10 mL) in acetonitrile (8 mL) was heated at 60 0 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. 15 Step5: 5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) acetophenone W11-E 0 O To a mixture of 3-benzyl-l1-bromo-5-N,N,-dimethylaminomethyl-6 20 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. - 153- WO 99/62520 PCT/US99/12093 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. HC1 (1M, 3 mL). The 5 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 10 concentration of appropriate fractions provided the title ketone. Step 6: 4-[5-Benzyl-2-methoxy-3-(N,N-dimethylaminomethyl) phenvll-2,4-dioxo-butvric acid W11 OWe /CO2H 0O 15 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. 20 The product solution was neutralized with addition of aq. HC1, 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), 25 3.97 (s, 2H),3.74 (s, 3H), 2.86 (s, 6H). EXAMPLE 31 4 -(5-Benzyl- 3 -methoxy-2-methoxyethoxyphenyl)2,4-dioxobutyric acid - 154- WO 99/62520 PCT/US99/12093 OMe "OMe O COOH O O Y-1 Step 1: 3-Bromo-4-(2-methoxvethoxy)-5-methoxvbenzaldehyde O
O
Me MeO Br CHO 5 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 Cs2CO3 (28.2 g, 86.56 mmol) and 2 bromoethylmethyl ether ( 5.08 mL, 54.10 mmol). This well stirred mixture was heated at 750C for 24h. The cooled mixture was filtered 10 through a frit to remove the cesium salts and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. 1H NMR (CDC13): 6 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, 15 j=2Hz, 1H); 9.84 (s, 1H). Step 2: 1-(3-Bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)- 1 phenvylmethanol. - 155- WO 99/62520 PCT/US99/12093 0,--
O
M
e Meo Br OH To a 11 round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.00g, 41.50 mmol) and dry THF (150 mL). This solution was cooled in an ice 5 bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.0M 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 10 (MgSO4), 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): 8 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, 15 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H). Step 3: 1-(3-Bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)- 1 phenylmethane. 0
*,-
O
M
e MeO Br - 156- WO 99/62520 PCT/US99/12093 To a 500 mL round bottomed flask 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 5 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 (MgSO4), filtered and 10 concentrated in vacuo. 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): 5 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). 15 Step 4: 1-(2-(2-Methoxyethoxy)-3-methoxy-5-phenylmethyl)- 1 ethanone. OMe rOMe O To a 25 mL glass pressure vessel with a stirring bar was added 1-(3 20 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 25 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 1N HC1 (30 mL) was added. This solution - 157- WO 99/62520 PCT/US99/12093 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 (MgSO4), filtration and removal of the solvent in vacuo gave a yellow oil. This material was chromatographed 5 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). 10 Step 5: Ethyl 4-(benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4 dioxobutvrate. Me rl OMe 0 COOEt 0 0 To a 50 mL round bottomed flask with a stirring bar and a nitrogen inlet 15 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 20 organic phase was washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo 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 25 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, 7H). - 158- WO 99/62520 PCT/US99/12093 Step 6: 4-(Benzyl-3-methoxy-2-methoxyethoxyphenyl)-2,4 dioxobutvric acid. OMe "OMe O COOH O O To a 200 mL round bottomed flask with a stirring bar and a nitrogen 5 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 N solution in water, 18 mmol). This mixture was stirred 2h at ambient temperature. The organic solvents were removed in vacuo and the aqueous residue was diluted 10 with 30 mL of water. This solution was washed with ethyl ether (2 X 50 mL) then acidified with 1N HC1. This mixture was extracted with ethyl ether (100 mL). The ether solution was washed with water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a yellow oil. This material was crystallized by dissolving in 1:1 ether 15 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: 83-850C. Anal. Calc'd for C21H2207: C, 65.28; H, 5.74; Found: C, 65.28; H, 6.05. 1H NMR (CDC13): 20 6 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). EXAMPLES 32-108 The following examples (32-108) may be prepared according to the 25 general procedures outlined in the Schemes and in Examples 1 to 31. 32. 4-(3-Benzyl-4-methoxyphenyl)-2,4-dioxobutyric acid - 159- WO 99/62520 PCT/US99/12093 CH30 / CO2H Anal. Calcd for C18H1605 0.30 toluene: C, 71.01; H, 5.46. Found: C, 71.05; H, 5.68. 5 33. 4-(5-Benzyl-2-methoxyphenyl)-2,4-dioxobutyric acid O C H 3 /CO2H Anal. Called for C18H1605: C, 69.22; H, 5.16. Found: C, 68.89; H, 5.10. 10 34. 4-(3-Benzyl-4-fluorophenyl)-2,4-dioxobutyric acid F / CO2H OO Anal. Called for C17H13FO4 0.15 H20: C, 67.38; H, 4.42. 15 Found: C, 67.31; H, 4.16. 35. 4-(3-Benzyl-4-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid - 160- WO 99/62520 PCT/US99/12093 Anal. Called for C19H19NO4 1.42 TFA: C, 55.61; H, 4.41; N, 3.03. Found: C, 55.51; H, 4.22; N, 2.95. 5 36. 4-[5-(2-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid Anal. Called for C20H2006: C, 67.41; H, 5.66. Found: C, 67.42; H, 5.57. 10 37. 2,4-Dioxo-4-(3-pyridin-2-ylmethylphenyl)butyric acid Anal. Called for C16H13NO4 0.7 TFA: C, 57.55; H, 3.80; N, 3.86. 15 Found: C, 57.73; H, 3.84; N, 3.79. 38. 4-(5-Benzyl-3-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid 20 Anal. Called for C19H19NO4 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 25 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 30 - 161- WO 99/62520 PCT/US99/12093 Anal. Calcd for C25H2206 0.30 H20: C, 70.84; H, 5.37. Found: C, 70.82; H, 5.22. 5 41. 4-[5-(3-Methylbenzyl)-2,3-dimethoxyphenyl]-2,4-dioxobutyric acid Anal. Called for C20H2006: C, 67.41; H, 5.66. Found: C, 67.33; H, 5.18. 10 42. 4-(5-Benzyl-3-benzyloxyphenyl)-2,4-dioxobutyric acid Anal. Called for C24H2005 0.15 H20: C, 73.69; H, 5.23. 15 Found: C, 73.65; H, 5.30. 43. 4-[5-Benzyl-2-(2-hydroxy)ethoxyphenyl]-2,4- dioxo-2-butanoic acid 20 Anal. Calcd for C19H1806: C, 66.66; H, 5.30. Found: C, 66.69; H, 5.51. 44. 2,4-Dioxo-4-(3-pyridin-3-ylmethylphenyl)butyric acid 25 Anal. Calcd for C16H13NO4 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. 30 45. 4-[3-(3-Methyl-pyridin-2-ylmethyl)phenyl]-2,4-dioxo-butyric acid - 162- WO 99/62520 PCT/US99/12093 Anal. Calcd for C16H13NO4 1 TFA: C, 55.48; H, 3.92; N, 3.41. Found: C, 55.20; H, 4.01; N, 3.58. 5 46. 4-(5-Benzyl-2-methylsulfanylphenyl)-2,4-dioxobutyric acid Anal. Caled for C18H1605 0.05 H20 0.20 HCI: C, 64.23; H, 4.88. 10 Found: C, 64.16; H, 4.76. 47. 4-(5-Benzyl-3-N-morpholinophenyl)-2,4-dioxobutyric acid 15 Anal. Called for C21H21NO5 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 20 Anal. Calcd for C20H19NO5 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. 25 49. 4-[5-(2-Chlorobenzyl)-3-N,N-dimethylaminophenyl]-2,4-dioxobutyric acid - 163- WO 99/62520 PCT/US99/12093 Anal. Calcd for C19H18C1NO4 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 5 acid Anal. Calcd for C19H18C1N04 0.65 Et20: C, 58.37; H, 5.78; N, 3.15. Found: C, 58.12; H, 5.45; N, 2.77. 10 51. 4-(5-Benzyl-2,3,4-trimethoxyphenyl)-2,4-dioxobutyric acid Anal. Called for C20H2007 0.15 H20: C, 64.04; H, 5.46. 15 Found: C, 63.98; H, 5.29. 52. 4-(6-Benzylbenzo[1,3]dioxol-4-yl)-2,4-dioxobutyric acid 20 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 25 Anal. Calcd for C22H21NO6 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. 30 54. 4-(3-Benzyl-5-pyridine-2-ylmethylphenyl)-2,4-dioxobutyric acid - 164- WO 99/62520 PCT/US99/12093 Anal. Called for C23H19NO4 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. 5 55. 4-[3-Benzyl-5-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid Anal. Caled for C22H23NO5 : C, 58.18; H, 4.88; N, 2.83. 10 Found: C, 58.26; H, 4.76; N, 2.77. 56. 4-(3-Benzyl-5-pyridine-3-ylmethylphenyl)-2,4-dioxobutyric acid 15 Anal. Calcd for C23H19NO4 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 20 Anal. Called for C22H25NO5 1.20 H20: C, 55.53; H, 5.51; N, 2.70. Found: C, 55.55; H, 5.23; N, 2.55. 25 58. 4-(5-Benzyl-2-N,N-dimethylaminophenyl)-2,4-dioxobutyric acid Anal. Calcd for C19H19NO4 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. 30 - 165- WO 99/62520 PCT/US99/12093 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. 5 Found: C, 67.83; H, 4.46. 60. 4-(5-Benzyl-3-hydroxymethyl-2-methoxyphenyl)-2,4-dioxobutyric acid 10 Anal. Calcd for C19H1806: 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 15 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. 20 62. 4-[3-Benzyl-5-(2-oxopiperidin-1-ylmethyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C23H23NO5 : C, 70.22; H, 5.89; N, 3.56. 25 Found: C, 69.86; H, 5.55; N, 3.40. 63. 4-[5-Benzyl-2-methoxy-3-(morpholinomethyl)phenyl]-2,4-dioxobutyric acid 30 - 166- WO 99/62520 PCT/US99/12093 Anal. Called for C23H25NO6: 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 5 acid Anal. Calcd for C23H18C1NO4 1.0 H20: C, 64.86; H, 4.73; N, 3.29. Found: C, 64.89; H, 4.37; N, 2.97. 10 65. 4-[5-Benzyl-2-methoxy-3-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4 dioxobutyric acid 15 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 20 Anal. Calcd for C19H1805 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 25 acid Anal. Calcd for C22H22NO5F 2.25 TFA 0.15 H20: C, 48.32; H, 3.76; N, 2.13. 30 Found: C, 48.30; H, 3.77; N, 1.82. - 167- WO 99/62520 PCT/US99/12093 68. 4-[3-(4-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid 5 Anal. Called for C22H22NO5F 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. 10 69. 4-[3-(3-Fluorobenzyl)-5-morpholinomethylphenyl]-2,4-dioxobutyric acid Anal. Called for C22H22NO5F 1.45 TFA 0.50 H20: C, 52.12; H, 4.30; N, 2.44. 15 Found: C, 52.11; H, 4.29; N, 2.24. 70. 4-[5-Benzyl-2-methoxy-3-(tert-butylcarbamoyl)phenyl]-2,4 dioxobutyric acid 20 Anal. Calcd for C23H25NO7 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. 25 71. 4-(3-Benzyl-5-[1,2,3]triazol-1-ylmethylphenyl)-2,4-dioxobutyric acid Anal. Called for C20H17N304 0.1 hexane: C, 66.51; H, 4.99; N, 11.30. Found: C, 66.87; H, 4.87; N, 11.65. 30 - 168- WO 99/62520 PCT/US99/12093 72. 4-[5-Benzyl-3-(N'-methyl-N-piperazinyl)phenyl]-2,4-dioxobutyric acid Anal. Calcd for C22H24N30 4 : C, 63.38; H, 6.04; N, 6.72. 5 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 10 Anal. Calcd for C20H17N 3 0 4 : 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 15 Anal. Calcd for C19H15NO6 0.30 H20: C, 63.61; H, 4.38; N, 3.90. Found: C, 63.69; H, 4.51; N, 3.89. 20 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. 25 Found: C, 60.51; H, 3.96; N, 6.31. 76. 4-(5-Benzyl-3-amino-2-methoxyphenyl)-2,4-dioxobutyric acid - 169- WO 99/62520 PCT/US99/12093 FAB MS M+1 = 345 77. 4-(5-Benzyl-2-ethoxyphenyl)-2,4-dioxobutyric acid 5 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 10 Anal. Calcd for C23H25NO6 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. 15 79. 4-(5-Benzyl-2-trifluoroethoxyphenyl)-2,4-dioxobutyric acid Anal. Called for C19H15F305 0.05 Et20: C, 60.05; H, 4.07. 20 Found: C, 60.00; H, 4.08. 80. 4-(5-Benzyl-2-cyclobutyloxyphenyl)-2,4-dioxobutyric acid 25 Anal. Called 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 30 - 170- WO 99/62520 PCT/US99/12093 Anal. Called 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 5 Anal. Called for C19H16N404: C, 61.99; H, 4.59; N, 14.91. Found: C, 62.00; H, 4.74; N, 14.88. 10 83. 4-(5-Benzyl-2,3-diisopropoxyphenyl)-2,4-dioxobutyric acid Anal. Called for C23H2606 0.2 hexane: C, 69.92; H, 6.98. Found: C, 69.86; H, 6.99. 15 84. 4-(5-Benzyl-2-isopropoxy-3-N-methylaminophenyl)-2,4-dioxobutyric acid 20 Anal. Called for C21H23NO5 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 25 butyric acid Anal. Caled for C22H25NO5 0.10 TFA: C, 57.95; H, 5.27; N, 2.82. Found: C, 58.09; H, 5.10; N, 2.83. 30 - 171- WO 99/62520 PCT/US99/12093 86. 4-[5-Benzyl-2-isopropoxy-3-(2-N,N-dimethylaminoethoxy)phenyl]-2,4 dioxobutyric acid 5 Anal. Called for C24H29NO6 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 10 butyric acid Anal. Calcd for C25H29NO6 1.0 HCI: C, 63.09; H, 6.35; N, 2.94. Found: C, 63.43; H, 6.46; N, 2.65. 15 88. 4-(5-Benzyl-2-isopropoxy-3-N,N-dimethylaminomethylphenyl)-2,4 dioxo-butyric acid 20 Anal. Calcd for C23H27NO5 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 / -0 0 0 OH 25 0 0 Anal calc for C18H1406 .1 ethyl acetate C, 65.94 ; H, 4.45 - 172- WO 99/62520 PCT/US99/12093 Found C, 65.95; H, 4.84 90. 2-Hydroxy-4-oxo-4-(3-phenylindan-5-yl)but-2-enoic acid OH 000 5 Anal calc for C19H1604.05 H20 C, 73.79; H, 5.25 Found C, 73.48 ; H, 5.33 10 91. 4-(Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid 0 i~oH N O 0 Anal calc for C24H21NO4 .1 ethyl acetate C, 73.95; H, 5.55; N, 3.54 Found C, 73.69 ; H, 5.90; N, 3.22 15 92. 3-(3-Benzyl-5-carboxyacetylphenyl)-3-oxopropionic acid - 173- WO 99/62520 PCT/US99/12093 OH O0 0 OH O O Anal calc for C19H1606 1.5 H20 C, 62.12; H, 5.21 Found C, 61.98; H, 5.28 5 93. 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid O 0 0 0H Anal calc for C24H21NO4 .05 ethyl acetate C, 74.17 ; H, 5.51; N, 3.57 Found C, 74.05 ; H, 5.38; N, 3.29 10 94. 4-(5-Benzyl-3-methoxy-2-mtethylthioethoxyphenyl)-2,4-dioxobutyric acid -1 C 0 2 H OMe T
SCH
3 - 174- WO 99/62520 PCT/US99/12093 Anal. Calc'd for C21H2206S: C, 62.67; H, 5.51 Found: C, 62.26; H, 5.65 mp: 99-1000C 5 95. 4-(7-Benzyl-2,3-dihydrobenzo[1,4]dioxin-5-yl)-2,4-dioxobutyric acid O O C 0 2 H O o\ ) Anal. Calc'd for C19H1606: C, 67.05; H, 4.74 Found: C, 66.35; H, 4.87 mp: 154-1550C 10 96. (+/-) 4-(8-Benzyl-3-hydroxy-3,4-dihydro-2H-benzo[B][1,4]di-oxepin-6 yl)-2,4-dioxobutyric acid OO C 0 2 H (+/-) OH Anal. Calc'd for C20H1807: C, 64.06; H, 4.90 15 Found: C, 64.06; H, 5.14 mp: 182-183oC 97. 4-(2,3-Dimethoxy-5-pent-4-enylphenyl)-2,4-dioxobutyric acid - 175- WO 99/62520 PCT/US99/12093 C02H OMe OMe Anal. Calc'd for C17H2006: C, 63.74; H, 6.29 Found: C, 64.05; H, 6.05 mp: 75-760C 5 98. 4-(5-Cyclopropylmethyl-2,3-dimethoxyphenyl)-2,4-dioxobutyric acid C02H OMe OMe Anal. Calc'd for C16H1806: C, 62.74; H, 5.92 10 Found: C, 62.75; H, 5.79 mp: 101-1030C 99. 4-(5-Benzyl-2-isopropoxy-3-[1,2,3]triazol-1-ylmethylphenyl)-2,4 dioxobutyric acid 15 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). 20 100. 4-(5-Benzyl-2-isopropoxy-3-[1,2,4]triazol-1-ylmethylphenyl)-2,4 dioxobutyric acid - 176- WO 99/62520 PCT/US99/12093 1H NMR (CDC13) 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 5 dioxobutyric acid Anal. Calcd for C23H27NO6 0.40 HC1 0.25 Et20: C, 64.54; H, 6.75; N, 3.14. 10 Found: C, 64.42; H, 6.76; N, 3.11. 102. 4-[3-(Phenyldifluoromethyl)phenyl]-2,4-dioxobutyric acid 15 Anal. Calcd for C17H12F204: C, 64.15; H, 3.80. Found: C, 64.29; H, 3.73. 103. 4-(5-Benzyl-2-cyclopropyloxyphenyl)-2,4-dioxobutyric acid 20 Anal. Called for C20H1805 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 25 butyric acid TFA salt Anal. Calcd for C26H31NO5 1.15 TFA: C, 59.77; H, 5.70; N, 2.46. Found: C, 59.68; H, 5.70; N, 2.33. 30 - 177- WO 99/62520 PCT/US99/12093 105. 4-[5-Benzyl-2-(2-dimethylamino- 1-methylethoxy)phenyl]-2,4-dioxo butyric acid 5 Anal. Called for C22H25NO 5 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 10 acid Anal. Called for C23H25N0 5 1.7 H20 0.30 EtOAc: C, 64.23; H, 6.86; N, 3.10. 15 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 20 Anal. Called for C28H29N204 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 25 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. 30 Found: C, 66.58; H, 6.09; N, 5.43. - 178- WO 99/62520 PCT/US99/12093 EXAMPLE 109 (6-Benzyloxy-l1-oxo-indan-2-ylidene)-hydroxyacetic acid AVIII-3-1 Ste 1: 6-Benzvloxvindan-1-one AVIII-1-1 AVIII-1-1 5 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 K2CO3 (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 10 into water, extracted with CH2C12, the organic layer was separated and dried with MgSO4, the solvent evaporated and the product purified by chromatography over silica to obtain AVIII-1-1 as a yellowish solid. 1H NMR (400 MHz, CDC13) 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+), 15 91 (100). Step 2: (6-Benzyloxy-l1-oxo-indan-2-ylidene)-hydroxyacetic acid ethyl ester AVIII-2-1
OCH
2
CH
3 AVIII-2-1 20 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 CH2C12, quenched with saturated NaHCO3 (aq), the organic 25 layer was separated and dried with MgSO4, the mixture was filtered, the solvent evaporated and the crude purified by preparative silica HPLC - 179- WO 99/62520 PCT/US99/12093 eluting with 10:30:60 EtOAc / CH2C12 / Hexanes to afford the product as a yellow solid, melting point 118-1190C (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), 3.91 (s, 2H), 1.43 (t, J=7.24 Hz, 3H). mass spec EI: m/z (relative abundance) 338 5 (M+), 91 (100). Step 3: (6-Benzyloxy- 1-oxo-indan-2-ylidene)-hydroxyacetic acid AVIII-3-1 0 OH Avm-3-1 10 A solution of AVIII-2-1 (500mg, 1.47 mmole) in 1,4-dioxane (3 mL) and 3N HC1 (3 mL) was heated in a sealed tube at 700C overnight. The reaction was then allowed to cool to ambient temperature and poured into 1N HC1 (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 / hexanes to afford AVIII-3-1 15 as a yellow solid, melting point 188-1890C (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 EXAMPLE 110 20 1-[1-(4-Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid AVII-3-1 - 180- WO 99/62520 PCT/US99/12093 Ste 1: 6-Bromo-1-(4-fluorobenzv1)indole F N Br 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% 5 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 1N HC1 and extracted with EtOAc (3x), the combined organic layers were dried (MgSO4) and concentrated. Chromatography of the residue (4:1/hexanes:EtOAc) 10 provided the product. 1H NMR (400 MHz, CDC13) 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 15 Step 2: 1-[ 1-( 4 -Fluorobenzv1)-6-indolyll-ethanone AVII-1-1 F 0 \No AVII-1-1 To a solution of 6 -bromo-1-(4-fluorobenzyl)indole (2.50 g, 8.20 mmol) in THF (40 mL) at -78 oC was added t-butyllithium (10.6 mL of a 1.7 M solution in pentane, 18.0 mmol) dropwise. After stirring at -78 oC for 30 20 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. NaC1 and dried (MgSO4). Concentration followed by 25 chromatography of the residue (4:1/hexanes:EtOAc) provided 750 mg (34%) of product.. - 181- WO 99/62520 PCT/US99/12093 1H NMR (400 MHz, CDCl3) 8 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). 5 Step 3: 1-[1-(4-Fluorobenzyl)-6-indolyl]- 2,4-dioxobutanoic acid methyl ester AVII-2-1 F@ 0 0 F \/ N 'OCH 3 0 AVII-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% 10 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 HC1 (20 mL) was added and the mixture was extracted with CH2C12 (3 x 15 mL). The combined organic extracts were washed with sat. NaC1 (20 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid 15 chromatography on silica gel, eluting with 5:5:1/ CH2C12:hexanes:EtOAc, afforded 597 mg (65%) of product. 1H NMR (400 MHz, CDCl3) 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), 7.11 (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, 20 3H). Ste 4: 1-[1-( 4 -Fluorobenzyl)-6-indolyl]-2,4-dioxobutanoic acid AVII 3-1 F- 0 0 F OH SAVII-3-1 25 To a solution of AVII-2-1 (597 mg, 1.69 mmol) in THF (10 mL) was added 1 N 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 - 182- WO 99/62520 PCT/US99/12093 extracts were discarded. The aqueous phase was treated with 3 N HCI (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 aC 5 (uncorrected). 1H NMR (400 MHz, d6-DMSO) 5 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 10 EXAMPLE 111 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 - - 0 0 \ OH 15 AVII-3-2 mp 156-157 oC (uncorrected). 1H NMR (400 MHz, d6-DMSO) 5 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 20 EXAMPLE 112 4-[1-(2.6-Difluorobenzyl)- 1H-indol-6-yl]-2,4-dioxobutyric acid F N
CO
2 H 0 0 F 25 ES MS Exact Mass Calcd. for C19H13F2NO 4 +H 358.0885 - 183- WO 99/62520 PCT/US99/12093 Found 358.0887 EXAMPLE 113 4-(1-Benzyl-1H-indol-6-yl)-2,4-dioxobutyric acid 5 N o CO 2 H 0 0 Anal. Calcd for C19H15NO4 0.75 HC1 0.05 H20: C, 65.27; H, 4.57; N, 4.01. Found: C, 65.26; H, 4.25; N, 3.87. 10 EXAMPLE 114 4-(5-Benzyl-2-methoxypyridin-3-yl)-2,4-dioxobutyric acid 15 Anal. Called 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. EXAMPLE 115 20 The Compounds in the following Table were made according to the procedures outlined in the Schemes and in Examples 1 to 31. - 184- WO 99/62520 PCT/US99/12093 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 - 185- WO 99/62520 PCT/US99/12093 4-[3-(2,3-dichloro-benzyl)- C17H12C1204.NH 4 + 368.0443 phenyl]-2,4-dioxo-butyric 368.0451 acid 4-[3-(2-chloro-3- C18H15C104.NH 4 + 348.1015 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- C17H13FO4.NH4 318.1133 fluorobenzyl)phenyl]-2,4- 318.1136 dioxobutyric acid 2,4-dioxo-4-[3-(2-choro-4- NH4+ 352.0752 fluoro-benzyl)-phenyl]- 352.0746 butyric acid -186- WO 99/62520 PCT/US99/12093 4-[3-(2- C18H1604.NH 4 + 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- C17H13C10 4
.NH
4 + 334.0854 chlorobenzyl)phenyl]-2,4- 334.0841 dioxobutyric acid 4-[3-(2- C17H13BrO4.NH4+ 378.034 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 - 187- WO 99/62520 PCT/US99/12093 4-[3-(2,3-difluoro-benzyl)- C17H12F204.NH4+ 336.1044 phenyl]-2,4-dioxo-butyric 336.1042 acid 4-(3,5-dibenzylphenyl)-2,4- C24H2004.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- C17H13F04 301.0885 fluorobenzyl)phenyl]-2,4- 301.0876 dioxobutyric acid 4-[3-(3- C17H13C104.NH4+ 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 - 188- WO 99/62520 PCT/US99/12093 4-(3-benzylphenyl)-2,4- C17H1404.NH4+ 300.124 dioxo-butyric acid 300.123 4-[3-(2-fluoro-3-methyl- 315.1027 315.1034 benzyl)-phenyl]-2,4-dioxo butyric acid sodium salt 4-[3-(3-chloro-4-fluoro- C17H12C1FO4.NH4 352.0733 benzyl)-phenyl]-2,4-dioxo- + 352.0746 butyric acid 2,4-dioxo-4-[3-(2-bromo-4- NH4+ 396.0247 fluoro-benzyl)-phenyl]- 396.0241 butyric acid 4-[3-(3- C17H13BrO4 361.0101 bromobenzyl)phenyl]-2,4- 361.0075 dioxobutyric acid 4-[3-(2,5-difluoro-benzyl)- C17H12F204.NH4+ 336.1046 phenyl]-2,4-dioxo-butyric 336.1042 acid - 189- WO 99/62520 PCT/US99/12093 4-[3-(5-chloro-2-fluoro- C17H12CIFO 4
.NH
4 352.0753 benzyl)phenyl]-2,4- + 352.0746 dioxobutyric acid 4-[3-(3- C18H1 6 0 4 297.112 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-difluoro-benzyl)- 319.0776 319.078 phenyl]-2,4-dioxo-butyric acid 4-[3-(2,5-dichloro-benzyl)- C17H12C120 4
.NH
4 + 368.0465 phenyl]-2,4-dioxo-butyric 368.0451 acid 4-[3-(2-chloro-6-methyl- C18H15C10 4
.NH
4 + 348.1012 benzyl)phenyl]-2,4- 348.0997 dioxobutyric acid - 190- WO 99/62520 PCT/US99/12093 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.NH 4 411.9966 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 phenylsulfanyl-phenyl) butyric acid 2,4-dioxo-4-[3-(1- NH4+ 314.1401 phenylethyl)phenyl]butyric 314.1387 acid - 191- WO 99/62520 PCT/US99/12093 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- 340.0405 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 - 192- WO 99/62520 PCT/US99/12093 Methyl 4-[3-benzylphenyl]- C18H1 6 0 4 297.113 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] -phenyll 2,4-dioxo-butyric acid - 193- WO 99/62520 PCT/US99/12093 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-tert-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- C18H 1605.NH4+ 330.1344 methyl)phenyl]-2,4- 330.1336 dioxobutyric acid - 194- WO 99/62520 PCT/US99/12093 4-[3-[hydroxy-(tetrahydro- C23H240 6
.NH
4 + 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- C21H9NO5.NH 4 + 383.1601 (cyclopropylcarboxamido)- 383.1601 phenyl]-2,4-dioxobutyric acid 4-[3-benzyl-5-(t- C22H23NO6.NH 4 + 415.1867 butoxycarbamoyl)phenyl]- 415.1863 2,4-dioxobutyric acid - 195- WO 99/62520 PCT/US99/12093 4-[3-(hydroxy-phenyl- C17H140 5 299.0905 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- C17H12Br204 NH4+ 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 - 196- WO 99/62520 PCT/US99/12093 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 HC1 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- C13H11N304.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 - 197- WO 99/62520 PCT/US99/12093 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- l-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.NH 4 + 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 - 198- WO 99/62520 PCT/US99/12093 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- C16H16N20 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 - 199- WO 99/62520 PCT/US99/12093 4-[3-(2-hydroxy-benzyl)- 316.118 316.1177 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 - 200- WO 99/62520 PCT/US99/12093 EXAMPLE 116 HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were 5 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 10 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. EXAMPLE 117 15 Assay for 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. 20 Representative compounds tested in the present assay demonstrated IC95s of less than 10 micromolar. EXAMPLE 118 Oral Composition 25 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. 30 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. 35 -201-

Claims (24)

1. A compound of structural formula (I): R 2 R ROR 7 R 9 O O (i) and tautomers and pharmaceutically acceptable salts thereof, 5 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 10 form: ,or or or orN or Oor O or H (N~N Sor 0 or H R1 is selected from: 15 (1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR 7 , (4) -O-C1-6 alkyl-OR 7 , (5) -0-C1-6 alkyl-SR 7 , 20 (6) -CF3 or -CH2CF 3 , (7) -halo, (8) -NO2, - 202- WO 99/62520 PCT/US99/12093 (9) -CO-3 alkyl -N(R 4 )(R5), (10) -R6, (11) -C2-5 alkenyl-R 3 , (12) -C2-5 alkynyl-R 3 , 5 (13) -O-R 6 , (14) -0-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, (15) -0-C1-6 alkyl-NH-C(0)-OR7; (16) -O-C2-6 alkyl-N(R 4 )(R5); 10 (17) -S-C1-3 alkyl; (18) -C(0)CH2C(0)C(0)OR7; (19) -CH2-CH(OH)-CH2-O-R7; and (20) -C(OH)(CH3)-CH2N(R4)(R5); R2 is selected from: 15 (1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a 20 fluorine atom, (5) -C2-6 alkenyl, (6) -O-R 6 , (7) -O-C1-6 alkyl-OR 6 , (8) -O-C1-6 alkyl- SR 6 , 25 (9) -S(0)n-R 6 , (10) -C1-6 alkyl (OR 6 )(R 4 ), (11) -CO-6 alkyl-N(R 4 )(R 6 ), (12) -C1-6 alkyl S(0)n-R 6 , (13) -C0-6 alkyl C(0)-R6, 30 (14) -CO-6 alkyl C(0)CH2-C(0)-OH, (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR 4 C(0)-R6, (17) -C1-6 alkyl-C(0)N(R 4 )(R5), and (18) -CH2(OR7)-R6; - 203- WO 99/62520 PCT/US99/12093 each R 3 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 5 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 10 atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, 15 (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 20 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 25 (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, 30 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, - 204- WO 99/62520 PCT/US99/12093 (f) -CN, (g) =0, (h) benzyl, and (i) hydroxy; 5 (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, (b) halogen, (c) C1-6 alkyl, 10 (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy; 15 (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: 20 (a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 25 (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 30 substituents selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 35 (e) -OCF3, - 205- WO 99/62520 PCT/US99/12093 (f) -CN, (g) =0O, and (h) hydroxy; (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms 5 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, 10 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and 15 (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: 20 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 25 (f) -CN, (g) =0, and (h) hydroxy; and each R4 is independently selected from: (1) -H, 30 (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , 35 (7) -C2-3 alkenyl-R 3 , - 206- WO 99/62520 PCT/US99/12093 (8) -S(O)n-R 3 , and (9) -C(O)-R3; each R 5 is independently selected from: (1) -H, 5 (2) -C1-3 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , 10 (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; 15 each R6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: (1) -H, and 20 (2) -C1-6 alkyl; R8 is selected from: (1) -H, (2) -0- C1-6 alkyl and (3) C1-6 alkyl; 25 R9 is selected from: (1) -H, (2) -0- C1-3 alkyl, (3) -OH, and (4) oxo; and 30 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: - 207- WO 99/62520 PCT/US99/12093 (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 5 moiety, and (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R 2 , and R8 is not: (a) -H, 10 (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and (4) and when R 2 is S(O)nR 6 , and R6 is CH2-R3 or R3, then R3 is not unsubstituted phenyl. 15
2. The compound according to Claim 1 of structural formula: R 2 R1 0 R 8 A OH R 9 0 0 (1) and tautomers and pharmaceutically acceptable salts thereof, wherein: 20 A is selected from: (1) phenyl, (2) pyridyl, (3) naphthyl, (4) indolyl, provided that the aryl ring is substituted by the 25 dioxobutyric acid/ester moiety in structural formula (I), (5) - 208- WO 99/62520 PCT/US99/12093 (6) InN (7) CCO 5 (8) (9) (10) 10 N (11) 0:0 (12) 15 (13) H (14) 0 , and - 209- WO 99/62520 PCT/US99/12093 (15) N N; R1 is selected from: (1) -H, 5 (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR 7 ; (4) -O-C1-6 alkyl-OR7, (5) -O-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, 10 (7) -F, Cl, or Br,, (8) -NO2, (9) -CO-3 alkyl -N(R4)(R5), (10) -phenyl, (11) substituted phenyl substituted with 1 or 2 substituents 15 independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, 20 (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and 25 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and 30 (iv) hydroxy; (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from: -210- WO 99/62520 PCT/US99/12093 (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, 5 (d) phenyl, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, 10 (i) phenyloxy, (j) -CO-6 alkyl-N(R7)2, (k) -N N-CH 3 , and (1) substituted phenyloxy with 1, 2, or 3 substituents 15 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 20 (13) -O-R 6 , (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(R 4 )(R5); 25 (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); R 2 is selected from: 30 (1) -H, (2) -R 3 , (3) -C1-6 alkyl, -211- WO 99/62520 PCT/US99/12093 (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, 5 (6) -S-R6, (7) -0-C1-6 alkyl- SR 6 ; (8) -C1-6 alkyl (OR 6 )(R4), (9) -CO-6 alkyl-N(R 4 )(R6), (10) -C1-6 alkyl S -R 6 , 10 (11) -CO-6 alkyl C(0)-R6, (12) -CO-6 alkyl C(0)CH2-C(0)-OH, (13) -C1-6 alkyl NR 4 C(0)-R6, (14) -C1-6 alkyl-C(0)N(R 4 )(R5), and (15) -CH2(OR7)-R6; 15 each R3 is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from: (a) halogen, 20 (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (c) C 1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) phenyl, 25 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, 30 (j) -N N-CH 3 (k) oxo, and -212- WO 99/62520 PCT/US99/12093 (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, 5 (iii) -CF3, and (iv) hydroxy; (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: 10 (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, 15 (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, 20 (i) -CO-6 alkyl-N(RT)2, (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 25 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 30 (5) pyridyl, (6) substituted pyridyl substituted on carbon with one or two substituents independently selected from: (a) halogen, -213- WO 99/62520 PCT/US99/12093 (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, 5 (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, 10 (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 15 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 20 (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 25 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, 30 (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -C0-6 alkyl-N(R 7 )2, -214- WO 99/62520 PCT/US99/12093 (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 5 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 10 (9) pyrrolyl, (10) substituted pyrrolyl substituted on carbon with one or two substituents independently selected from: (a) halogen, (b) C 1-6 alkyl, wherein one or more of the hydrogen 15 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, 20 (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 25 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; - 215- WO 99/62520 PCT/US99/12093 (11) pyrazolyl, (12) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: (a) halogen, 5 (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, 10 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, 15 (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: 20 (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (15) piperidinyl, 25 (16) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 30 (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, -216- WO 99/62520 PCT/US99/12093 (h) benzyl, and (i) hydroxy; (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen 5 atom with 1 or 2 substituents independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 10 (e) -OCF3, (f) -CN, (g) =0, (h) benzyl, and (i) hydroxy; 15 (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, 20 (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, 25 (g) -CN, and (h) hydroxy, (21) naphthyl, (22) substituted naphthyl with 1, 2, or 3 substituents independently selected from: 30 (a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 35 (f) -CN, and -217- WO 99/62520 PCT/US99/12093 (g) -hydroxy, (23) indolyl, (24) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: 5 (a) -halogen, (b) -C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 10 (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 15 independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 20 (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; (27) pyrazinyl; 25 (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, 30 (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, 35 (g) hydroxy, -218- WO 99/62520 PCT/US99/12093 (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, (j) -N N-CH 3 5 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, 10 (iii) -CF3, and (iv) hydroxy; (29) pyrimidinyl; (30) substituted pyrimidinyl substituted on nitrogen or carbon with one or two substituents independently selected from: 15 (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, 20 (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, 25 (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 30 selected from: (i) halogen, (ii) C1-6 alkyl, -219- WO 99/62520 PCT/US99/12093 (iii) -CF3, and (iv) hydroxy; (31) triazolyl; (32) substituted triazolyl with one or two substituents 5 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 10 atoms may be replaced with a fluorine atom, (d) phenyl, (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, 15 (h) phenyloxy, (i) -CO-6 alkyl-N(R7)2, (j) /-- -N N-CH 3 (k) oxo, and 20 (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and 25 (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 30 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, - 220- WO 99/62520 PCT/US99/12093 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, 5 (i) -CO-6 alkyl-N(R 7 )2, (j) -N N-CH 3 (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; 15 (35) C3-6 cycloalkyl; (36) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from: (a) halogen, (b) C1-6 alkyl, 20 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, 25 (h) benzyl, and (i) hydroxy; (37) tetrahydrofuran; (38) substituted tetrahydrofuran substituted with one or two substituents independently selected from: 30 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, -221- WO 99/62520 PCT/US99/12093 (e) -OCF3, (f) -CN, (g) =0, (h) benzyl, and 5 (i) hydroxy; (39) piperazinyl; (40) substituted piperazinyl substituted with one or two substituents independently selected from: (a) halogen, 10 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 15 (g) =0, (h) benzyl, and (i) hydroxy; (41) benzotriazolyl, (42) substituted benzotriazolyl substituted on a carbon atom with 20 one or two substituents independently selected from: (a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, 25 (e) -OCF3, (f) -CN, and (g) -hydroxy; (43) benzoimidazolyl, (44) substituted benzoimidazolyl substituted on a carbon atom 30 with one or two substituents independently selected from: (a) -halogen, (b) -C1-6 alkyl, (c) -C1- 6 alkyloxy-, (d) -CF3, - 222- WO 99/62520 PCT/US99/12093 (e) -OCF 3 , (f) -CN, and (g) -hydroxy; each R 4 is independently selected from: 5 (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, 10 (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R 3 , and (8) -C(O)-R3; each R 5 is independently selected from: (1) -H, 15 (2) -C1-3 alkyl, (3) -CF3, (4) -R 3 , (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, 20 (7) -S(O)n-R 3 , (8) -C(O)-R3, (9) -C(O)OR4, and (10) -C(O)C(O)OH; each R 6 is independently selected from: 25 (1) -C1-3 alkyl-R 3 , and (2) -R 3 ; each R 7 is independently selected from: (1) -H, and (2) -C1-6 alkyl; 30 R8 is selected from hydrogen, methyl and -0- C1-6 alkyl; and R 9 is selected from: (1) -H, (2) -0- C1-3 alkyl, (3) -OH, and - 223- WO 99/62520 PCT/US99/12093 (4) oxo; and each n is independently selected from 0, 1 and 2; PROVIDED THAT when A is phenyl: 5 (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 10 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, 15 (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 20 acid/ester moiety; and (3) at least one of R1, R 2 , and R8 is not: (a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and 25 (4) and when or R 2 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: 30 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 35 (I); - 224- WO 99/62520 PCT/US99/12093 (4) o (5) 0:0 5 (6) (7) H (N O , and (8) 10 0 R1 is selected from: (1) -H, (2) -CH3, (3) -C1-6 alkyl-OR 7 ; 15 (4) -O-C1-6 alkyl-OR7, (5) -0-Cl1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, 20 (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: 25 (a) -F, -Cl, or -Br, - 225- WO 99/62520 PCT/US99/12093 (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF 3 , (d) -CF3, (e) -SCH3, 5 (f) -CN, (g) hydroxy, and (h) -CO-6 alkyl-N(R 7 )2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 10 independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF 3 , (d) -CF3, 15 (e) -SCH3, (f) -CN, (g) hydroxy, and (h) -CO-6 alkyl-N(R 7 )2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three 20 fluorine atoms, (14) -C(0)CH2C(0)C(0)OH; (15) -O-C1-6 alkyl-NH-C(0)-OR7; (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, 25 (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(0)CH2C(0)C(0)OH, (22) -CH2-CH(OH)-CH2-O-R7, and 30 (23) -C(OH)(CH3)-CH2N(R4)(R5); R 2 is selected from: (1) -H, (2) -R3, (3) -CH3, - 226- WO 99/62520 PCT/US99/12093 (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R 6 , 5 (6) -S-R6, (7) -O-C1-6 alkyl- SR6; (8) -C1-6 alkyl (OR 6 )(R 4 ), (9) -CO-6 alkyl-N(R 4 )(R 6 ), (10) -C0-6 alkyl C(0)-R6, 10 (11) -C0-6 alkyl C(0)CH2-C(0)-OH, (12) -C1-6 alkyl NR 4 C(0)-R6, (13) -C1-6 alkyl-C(0)N(R 4 )(R5), and (14) -CH2(OR 7 )-R 6 ; each R 3 is independently selected from: 15 (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 20 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 25 (f) oxo; (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from F, C1, and Br, 30 (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, - 227- WO 99/62520 PCT/US99/12093 (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 5 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; 10 (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 15 (a) halogen, selected from -F, -Cl, and -Br; (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and 20 (f) hydroxy; (11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, 25 (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 30 (g) =0O, and (h) hydroxy; (13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: 35 (a) halogen selected from -F, -Cl, and -Br, - 228- WO 99/62520 PCT/US99/12093 (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 5 (f) =0O, and (g) hydroxy; (15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from: 10 (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and 15 (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from: 20 (a) -halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 25 (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on 30 carbon with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 35 (e) -OCF3, - 229- WO 99/62520 PCT/US99/12093 (f) -CN, (g) =0, and (h) hydroxy; (23) pyrazinyl; 5 (24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, 10 (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -CO-6 alkyl-N(R 7 )2, and 15 (g) -N N-CH 3 (25) pyrimidinyl; (26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from: 20 (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl; 25 (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, 30 (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, - 230- WO 99/62520 PCT/US99/12093 (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; (32) substituted C3-6 cycloalkyl substituted with one or two 5 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and 10 (e) -OCF3, (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, 15 (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl; 20 (36) substituted piperazinyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 25 (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy; (37) benzotriazolyl, 30 (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-, 35 (d) -CF3, and -231- WO 99/62520 PCT/US99/12093 (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from: 5 (a) -halogen, selected from -F, -C1. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3; 10 each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R 3 , 15 (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R 3 ; each R5 is independently selected from: (1) -H, (2) -C1-3 alkyl, 20 (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R 3 , (6) -C(O)-R 3 , (7) -C(O)OR 4 , and 25 (8) -C(O)C(O)OH; each R 6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R 3 ; each R 7 is independently selected from: 30 (1) -H, and (2) -C1-6 alkyl; R8 is selected from hydrogen, methyl and -0- C1-6 alkyl; and R 9 is selected from: (1) -H, - 232- WO 99/62520 PCT/US99/12093 (2) -0- C1-3 alkyl, (3) -OH, and (4) oxo; and 5 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, 10 (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) R 2 is not selected from: 15 (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 20 (d) substituted -C1-6 alkyl phenyl para to the dioxobutyric acid/ester moiety; and (3) at least one of R1, R 2 , and R 8 is not: (a) -H, (b) C1-6 alkyl, or 25 (c) R3 wherein R3 is cycloalkyl; and (4) and when R 2 is SR6, R 6 is R 3 .
4. The compound according to Claim 3 and tautomers and pharmaceutically acceptable salts thereof, wherein: 30 R1 is selected from: (1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, - 233- WO 99/62520 PCT/US99/12093 (5) -OCH2CH2OCH 3 , (6) -(CH2)6-OH, (7) -CF3, (8) -F, 5 (9) -Cl, (10) -CO-3 alkyl -N(R 4 )(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 10 independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF 3 , (d) -CF3, 15 (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 20 independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 25 (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R7)2, (14) -O-CH3, (15) -OCH2CH3, 30 (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, (19) -C(O)CH2C(O)C(O)OH, (20) -O-C1-6 alkyl-NH-C(0)-OR7, - 234- WO 99/62520 PCT/US99/12093 (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH 3 ) 2 , (23) -O-CH2CH2 NH2, (24) -O-CH(CH3)CH2NH 2 , 5 (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); R 2 is selected from: 10 (1) -H, (2) -R 3 , (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, 15 (6) -CH(CH3)-R3, (7) -O-R 6 , (8) -S-phenyl, (9) -C1-6 alkyl (OR6)(R4), (10) -CO-6 alkyl-N(R4)(R6), 20 (11) -C(O)-R 3 , (12) -CO-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR4C(O)-R6, (14) -CH(OCH3)R3, and (15) -CH(OH)R3; 25 each R 3 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, 30 (b) -CH3, (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, - 235- WO 99/62520 PCT/US99/12093 (g) -CF3, (h) -CH2CF3, (i) -CF2CH 3 , (j) -OCF3, 5 (k) -CN, and (1) hydroxy; (3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from: 10 (a) F, (b) Cl, and (c) methyl; (5) pyridyl, (6) substituted pyridyl substituted on a carbon with a 15 substituent selected from: (a) -F, (b) -Cl, (c) -CH3, (d) -CF3, 20 (e) -OCH3, (f) -OCF3, (g) hydroxy, and (h) oxo; (7) pyrazolyl 25 (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: (a) -F, (b) -C1, (c) -CH3, and 30 (d) -CF3; (9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from: -236- WO 99/62520 PCT/US99/12093 (a) methoxy-, (b) -OCF3, (c) =0O, and (d) hydroxy; 5 (12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl; (16) substituted pyrazinyl substituted on nitrogen or carbon with 10 a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) -CF3, (d) methoxy-, 15 (e) -N(CH3)2, and (F) -N N-CH 3 (17) pyrimidinyl, (18) [1,2,3]-triazolyl, 20 (19) [1,2,4]-triazolyl, (20) tetrazolyl; (21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, 25 (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl, (27) substituted piperazinyl substituted with a substituent selected from: 30 (a) -F, (b) -Cl, (c) methyl, (d) -CF3, and - 237- WO 99/62520 PCT/US99/12093 (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R 4 is independently selected from: 5 (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R3, and 10 (6) -C(O)-R3; each R5 is independently selected from: (1) -H, (2) -CH3, (3) -CF3, 15 (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)OH; each R6 is independently selected from: 20 (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: (1) -H, and (2) -C1-6 alkyl; 25 R8 is selected from: (1) -H, (2) methoxy, and (3) -C1-6 alkyl, and R9 is selected from: 30 (1) -H, (2) -0- C1-3 alkyl, (3) -OH, and (4) oxo; and PROVIDED THAT: when A is phenyl, 35 (1) R1 is not: - 238- WO 99/62520 PCT/US99/12093 (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 5 moeity, or (d) substituted -C1-3 alkyl phenyl para to the dioxobutyric acid/ester moeity; and (2) R 2 is not selected from: (a) phenyl para to the dioxobutyric acid/ester moiety, 10 (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 15 acid/ester moiety; and (3) at least one of R1, R 2 , R8 and R9 is not: (a) -H, (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl. 20
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. 25
6. The compound according to Claim 1 of structural formula: R 1 H 0 H- OH R 2 O O and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: 30 (1) -H, - 239- WO 99/62520 PCT/US99/12093 (2) -CH3, (3) -C1-6 alkyl-OR7; (4) -0-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR7, 5 (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -CO-3 alkyl -N(R4)(R5), (10) -phenyl, 10 (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, 15 (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (e) -CF3, (f) -SCH3, (g) -CN, (h) hydroxy, 20 (i) -CO-6 alkyl-N(R 7 )2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from: (a) -F, -C1, or -Br, 25 (b) CH3, (c) -OCH3, -OCH2CH3, -OCF3, or -OCH2CF3, (e) -CF3, (f) -SCH3, (g) -CN, 30 (h) hydroxy, (i) -CO-6 alkyl-N(R 7 )2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(0)CH2C(0)C(0)OH, - 240- WO 99/62520 PCT/US99/12093 (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, 5 (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); 10 R 2 is selected from: (1) -H, (2) -R 3 , (3) -CH3, (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the 15 hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, (6) -S-R6, (7) -0-C1-6 alkyl- SR6, 20 (8) -C1-6 alkyl (OR 6 )(R 4 ), (9) -CO-6 alkyl-N(R4)(R6), (10) -CO-6 alkyl C(O)-R6, (11) -CO-6 alkyl C(O)CH2-C(O)-OH, (12) -C1-6 alkyl NR 4 C(O)-R6, 25 (13) -C1-6 alkyl-C(O)N(R 4 )(R5), and (14) -CH2(OR 7 )-R6; each R3 is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, 3 or 4 substituents 30 independently selected from: (a) halogen, selected from -F, -Cl, -Br, (b) C 1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, - 241- WO 99/62520 PCT/US99/12093 (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom,-, (d) -CN, (e) hydroxy, and 5 (f) oxo; (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from F, C1, and Br, 10 (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, 15 (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, 20 (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, 25 (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; 30 (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy; - 242- WO 99/62520 PCT/US99/12093 (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, 5 (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 10 (g) =0O, and (h) hydroxy; (13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: 15 (a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 20 (f) =0O, and (g) hydroxy; (15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen with 1 or 2 substituents independently selected from: 25 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and 30 (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from: - 243- WO 99/62520 PCT/US99/12093 (a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 5 (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, 10 (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-, 15 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; 20 (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 25 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, 30 (f) -CO-6 alkyl-N(R7)2, and (g) /- -N N-CH 3 (25) pyrimidinyl; -244- WO 99/62520 PCT/US99/12093 (26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, 5 (c) methoxy-, and (d) phenyl, (27) triazolyl; (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -C1, and -Br, 10 (b) methyl, (c) methoxy-, and (d) hydroxy, (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: 15 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; 20 (32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, 25 (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from: 30 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, 35 (35) piperazinyl; - 245- WO 99/62520 PCT/US99/12093 (36) substituted piperazinyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, 5 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy; 10 (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, 15 (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, (40) substituted benzoimidazolyl substituted on carbon with one 20 or two substituents independently selected from: (a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and 25 (e) -OCF3, each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, (3) -CF3, 30 (4) -R3, (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; each R5 is independently selected from: (1) -H, 35 (2) -C1-3 alkyl, -246- WO 99/62520 PCT/US99/12093 (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R3, (6) -C(O)-R3, 5 (7) -C(O)OR 4 , and (8) -C(O)C(O)OH; each R 6 is independently selected from: (1) -C1-3 alkyl-R3, and (2) -R 3 ; 10 each R 7 is independently selected from: (1) -H, and (2) -C1-6 alkyl; PROVIDED THAT: (1) at least one of R1 and R 2 is not: 15 (a) H, (b) C1-6 alkyl, or (c) R 3 wherein R 3 is cycloalkyl; and (2) when R 2 is SR 6 , R 6 is R3. 20
7. The compound according to Claim 1 of structural formula: R 1 R 8 H H- OH R 2 O O and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: 25 (1) -H, (2) -CH3, (3) -C1-6 alkyl-OR 7 ; (4) -O-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR 7 , 30 (6) -CF3 or -CH2CF3, - 247- WO 99/62520 PCT/US99/12093 (7) -Cl, (8) -F, (9) -CO-3 alkyl -N(R4)(R5), (10) -phenyl, 5 (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, 10 (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, and 15 (h) -CO-6 alkyl-N(R 7 )2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from: (a) -F, -C1, or -Br, 20 (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, 25 (g) hydroxy, and (h) -CO-6 alkyl-N(R 7 )2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(0)CH2C(0)C(0)OH, 30 (15) -O-C1-6 alkyl-NH-C(0)-OR7, (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3) 2 , (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, 35 (20) -S-CH3, - 248- WO 99/62520 PCT/US99/12093 (21) -C(O)CH2C(O)C(O)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5); R 2 is selected from: 5 (1) -H, (2) -R 3 , (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 10 fluorine atom, (5) -O-R 6 , (6) -S -R 6 , (7) -0-C1-6 alkyl- SR6; (8) -C1-6 alkyl (OR6)(R4), 15 (9) -CO-6 alkyl-N(R 4 )(R6), (10) -CO-6 alkyl C(O)-R6, (11) -CO-6 alkyl C(O)CH2-C(O)-OH, (12) -CI-6 alkyl NR4C(O)-R6, (13) -C1-6 alkyl-C(O)N(R4)(R5), and 20 (14) -CH2(OR7)-R6; each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, 3 or 4 substituents independently selected from: 25 (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,-, 30 (d) -CN, (e) hydroxy, and (f) oxo; (3) thienyl, - 249- WO 99/62520 PCT/US99/12093 (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from F, C1, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen 5 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 10 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 15 atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo; (7) imidazolyl, (8) pyrrolyl, 20 (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br; (b) -CH3, 25 (c) -CF3, (d) -OCH3, (e) -OCF3, and (f) hydroxy; (11) C3-6 cycloalkyl, 30 (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) CH3, (c) methyloxy-, 35 (d) -CF3, - 250- WO 99/62520 PCT/US99/12093 (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; 5 (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, 10 (c) methoxy-, (d) -CF3, (e) -OCF3, (f) =0O, and (g) hydroxy; 15 (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, 20 (c) methoxy-, (d) -CF3, (e) -OCF3, and (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, 25 (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, 30 (c) methoxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy, -251- WO 99/62520 PCT/US99/12093 (20) indolyl, (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on carbon with a substituent selected from: 5 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 10 (f) -CN, (g) =0O, and (h) hydroxy; (23) pyrazinyl; (24) substituted pyrazinyl substituted on nitrogen or carbon with 15 one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (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 20 atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -CO-6 alkyl-N(R7)2, and (g) -N N-CH 3 25 (25) pyrimidinyl; (26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, 30 (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl; - 252- WO 99/62520 PCT/US99/12093 (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and 5 (d) hydroxy, (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, 10 (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; (32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from: 15 (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, 20 (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, 25 (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl; (36) substituted piperazinyl substituted with one or two 30 substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, 35 (e) -OCF3, -253- WO 99/62520 PCT/US99/12093 (f) benzyl, and (g) hydroxy; (37) benzotriazolyl, (38) substituted benzotriazolyl substituted on carbon with one or 5 two substituents independently selected from: (a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and 10 (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from: (a) -halogen, selected from -F, -C1. and -Br, 15 (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3; each R 4 is independently selected from: 20 (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R 3 , and 25 (6) -C(O)-R3; each R5 is independently selected from: (1) -H, (2) -C1-3 alkyl, (3) -CF3, 30 (4) -R3, (5) -C1-3 alkyl-R 3 , (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH; 35 each R6 is independently selected from: - 254- WO 99/62520 PCT/US99/12093 (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: (1) -H, and 5 (2) -C1-6 alkyl; R 8 is selected from methyl and -0- C1-6 alkyl; and PROVIDED THAT: (1) at least one of R1, R2, and R8 is not: (a) C1-6 alkyl, or 10 (b) R3 wherein R3 is cycloalkyl; and (2) when R 2 is SR6, R6 is R3.
8. The compound according to Claim 1 of structural formula: R 1 0 HOH - OH 15 R 2 RO 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: (1) -H, (2) -CH3, 20 (3) -C1-6 alkyl-OR 7 ; (4) -O-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR 7 , (6) -CF3 or -CH2CF3, (7) -Cl, 25 (8) -F, (9) -CO-3 alkyl-N(R 4 )(R5), (10) -phenyl, (11) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 30 independently selected from: - 255- WO 99/62520 PCT/US99/12093 (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 5 (e) -SCH3, (f) -CN, (g) hydroxy, (h) -CO-6 alkyl-N(R7)2, (12) -O-CH2-phenyl, wherein the phenyl group may be 10 unsubstituted or substituted with 1 to four substituents independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, 15 (d) -CF3, (e) -SCH3, (f) -CN, (g) hydroxy, (h) -CO-6 alkyl-N(R 7 )2, 20 (13) -0-01-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, (14) -C(0)CH2C(0)C(0)OH, (15) -O-C1-6 alkyl-NH-C(0)-OR7, (16) -O-CH2CH2 N(CH3)2, 25 (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(0)CH2C(0)C(0)OH, 30 (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5); R2 is selected from: (1) -H, (2) -R3, 35 (3) -CH3, - 256- WO 99/62520 PCT/US99/12093 (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R6, 5 (6) -S-R6, (7) -0-C1-6 alkyl-SR6, (8) -C 1-6 alkyl-(OR 6 )(R 4 ), (9) -CO-6 alkyl-N(R 4 )(R 6 ), (10) -C0-6 alkyl-C(O)-R 6 , 10 (11) -CO-6 alkyl-C(O)CH2-C(O)-OH, (12) -C1-6 alkyl-NR 4 C(O)-R 6 , (13) -C1-6 alkyl-C(O)N(R 4 )(R5), and (14) -CH2(OR 7 )-R 6 ; each R3 is independently selected from: 15 (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 20 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 25 (f) oxo; (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from F, C1, and Br, 30 (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, - 257- WO 99/62520 PCT/US99/12093 (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 5 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; 10 (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 15 (a) halogen, selected from -F, -Cl, and -Br; (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and 20 (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, 25 (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 30 (g) =0O, and (h) hydroxy; (13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: 35 (a) halogen selected from -F, -Cl, and -Br, - 258- WO 99/62520 PCT/US99/12093 (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 5 (f) =0O, and (g) hydroxy; (15) morpholinyl, (16) substituted morpholinyl substituted at carbon or nitrogen with 1 or 2 substituents independently selected from: 10 (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, and 15 (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents independently selected from: 20 (a) -halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, 25 (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, (22) substituted 1,2,3,4-tetrahydronaphthalenyl substituted on 30 carbon with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 35 (e) -OCF3, - 259- WO 99/62520 PCT/US99/12093 (f) -CN, (g) =0, and (h) hydroxy; (23) pyrazinyl; 5 (24) substituted pyrazinyl substituted on nitrogen or carbon with one or two substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, (b) C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, 10 (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, (e) phenyloxy, (f) -CO-6 alkyl-N(R 7 )2, and 15 (g) -N N-CH 3 (25) pyrimidinyl; (26) substituted pyrimidinyl substituted on nitrogen or carbon with a substituent selected from: 20 (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, (27) triazolyl; 25 (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) hydroxy, 30 (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, - 260- WO 99/62520 PCT/US99/12093 (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; (32) substituted C3-6 cycloalkyl substituted with one or two 5 substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and 10 (e) -OCF3, (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, 15 (b) methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (35) piperazinyl; 20 (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-, 25 (d) -CF3, (e) -OCF3, (f) benzyl, and (g) hydroxy; (37) benzotriazolyl, 30 (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-, 35 (d) -CF3, and - 261- WO 99/62520 PCT/US99/12093 (e) -OCF3, (39) benzoimidazolyl, and (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from: 5 (a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3; 10 each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R 3 , 15 (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; each R5 is independently selected from: (1) -H, (2) -C1-3 alkyl, 20 (3) -CF3, (4) -R 3 , (5) -C1-3 alkyl-R 3 , (6) -C(O)-R3, (7) -C(O)OR 4 , and 25 (8) -C(O)C(O)OH; each R 6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R 3 ; each R 7 is independently selected from: 30 (1) -H, and (2) -C1-6 alkyl; R8 is selected from methyl and -0- C1-6 alkyl; and each n is independently selected from 0, 1 and 2; PROVIDED THAT: - 262- WO 99/62520 PCT/US99/12093 (1) at least one of R1, R 2 , and R 8 is not: (a) C1-6 alkyl, or (b) R 3 wherein R 3 is cycloalkyl; and (2) when R 2 is SR 6 , R 6 is R 3 . 5
9. The compound according to Claim 1 of structural formula: R 8 R 1 H H-OH R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: 10 R1 is selected from: (1) -H, (2) -CH3, (3) -C1-6 alkyl-OR 7 , (4) -O-C1-6 alkyl-OR7, 15 (5) -0-C1-6 alkyl-SR7, (6) -CF3 or -CH2CF3, (7) -Cl, (8) -F, (9) -CO-3 alkyl -N(R 4 )(R 5 ), 20 (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, 25 (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, (f) -CN, 30 (g) hydroxy, - 263- WO 99/62520 PCT/US99/12093 (h) -CO-6 alkyl-N(R 7 )2, (12) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents independently selected from: 5 (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -SCH3, 10 (f) -CN, (g) hydroxy, (h) -CO-6 alkyl-N(R 7 )2, (13) -O-C1-6 alkyl, unsubstituted or substituted with one to three fluorine atoms, and 15 (14) -C(0)CH2C(0)C(0)OH, (15) -O-C1-6 alkyl-NH-C(0)-OR 7 , (16) -O-CH2CH2 N(CH3)2, (17) -O-CH(CH3)CH2N(CH3)2, (18) -O-CH2CH2 NH2, 20 (19) -O-CH(CH3)CH2NH2, (20) -S-CH3, (21) -C(0)CH2C(0)C(0)OH, (22) -CH2-CH(OH)-CH2-O-R7, and (23) -C(OH)(CH3)-CH2N(R4)(R5); 25 R 2 is selected from: (1) -H, (2) -R3, (3) -CH3, (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the 30 hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -O-R 6 , (6) -S -R6, (7) -O-C1-6 alkyl- SR6, - 264- WO 99/62520 PCT/US99/12093 (8) -C1-6 alkyl (OR 6 )(R 4 ), (9) -CO-6 alkyl-N(R 4 )(R 6 ), (10) -CO-6 alkyl C(O)-R 6 , (11) -CO-6 alkyl C(O)CH2-C(O)-OH, 5 (12) -C1-6 alkyl NR 4 C(O)-R 6 , (13) -C1-6 alkyl-C(O)N(R 4 )(R 5 ), and (14) -CH2(OR 7 )-R6; each R 3 is independently selected from: (1) phenyl; 10 (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, 15 (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; 20 (3) thienyl, (4) substituted thienyl substituted on carbon with one or two substituents independently selected from: (a) halogen, selected from F, C1, and Br, (b) C1-6 alkyl, wherein one or more of the hydrogen 25 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 30 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, - 265- WO 99/62520 PCT/US99/12093 (c) C1-6 alkyloxy- wherein one or more of the hydrogen atoms may be replaced with a fluorine atom, (d) hydroxy, and (e) oxo; 5 (7) imidazolyl, (8) pyrrolyl, (9) pyrazolyl (10) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 10 (a) halogen, selected from -F, -Cl, and -Br; (b) -CH3, (c) -CF3, (d) -OCH3, (e) -OCF3, and 15 (f) hydroxy; (11) C3-6 cycloalkyl, (12) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, selected from -F, -C1, and -Br, 20 (b) CH3, (c) methyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, 25 (g) =0, and (h) hydroxy; (13) piperidinyl, (14) substituted piperidinyl substituted on carbon with one or two substituents independently selected from: 30 (a) halogen selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, (e) -OCF3, - 266- WO 99/62520 PCT/US99/12093 (f) =0O, and (g) hydroxy; (15) morpholinyl, (16) substituted morpholinyl substituted on carbon or nitrogen 5 with 1 or 2 substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 10 (e) -OCF3, and (f) hydroxy; (17) hexahydrothieno[3,4-d]imidazolyl, (18) naphthyl, (19) substituted naphthyl with 1, 2, or 3 substituents 15 independently selected from: (a) -halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, 20 (e) -OCF3, (f) -CN, and (g) -hydroxy, (20) indolyl, and (21) 1,2,3,4-tetrahydronaphthalenyl, 25 (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-, 30 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, and (h) hydroxy; 35 (23) pyrazinyl; - 267- WO 99/62520 PCT/US99/12093 (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 5 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, 10 (f) -CO-6 alkyl-N(R 7 )2, and (g) -N N-CH 3 (25) pyrimidinyl; (26) substituted pyrimidinyl substituted on nitrogen or carbon 15 with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, and (d) phenyl, 20 (27) triazolyl; (28) substituted triazolyl with a substituent selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, (c) methoxy-, and 25 (d) hydroxy, (29) tetrazolyl; (30) substituted tetrazolyl with a substituent selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, 30 (c) methoxy-, and (d) hydroxy, (31) C3-6 cycloalkyl; - 268- WO 99/62520 PCT/US99/12093 (32) substituted C3-6 cycloalkyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, 5 (c) methoxy-, (d) -CF3, and (e) -OCF3, (33) tetrahydrofuran; (34) substituted tetrahydrofuran substituted with one or two 10 substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, (b) methyl, (c) methoxy-, (d) -CF3, and 15 (e) -OCF3, (35) piperazinyl; (36) substituted piperazinyl substituted with one or two substituents independently selected from: (a) halogen, selected from -F, -Cl, and -Br, 20 (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) benzyl, and 25 (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, 30 (b) -methyl, (c) methoxy-, (d) -CF3, and (e) -OCF3, (39) benzoimidazolyl, - 269- WO 99/62520 PCT/US99/12093 (40) substituted benzoimidazolyl substituted on carbon with one or two substituents independently selected from: (a) -halogen, selected from -F, -Cl. and -Br, (b) -methyl, 5 (c) methoxy-, (d) -CF3, and (e) -OCF3, each R4 is independently selected from: (1) -H, 10 (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; 15 each R5 is independently selected from: (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, 20 (5) -C1-3 alkyl-R 3 , (6) -C(O)-R3, (7) -C(O)OR4, and (8) -C(O)C(O)OH; each R6 is independently selected from: 25 (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: (1) -H, and (2) -C1-6 alkyl; 30 R8 is selected from methyl and -0- C1-6 alkyl; and PROVIDED THAT: (1) at least one of R1, R 2 , and R8 is not: (b) C1-6 alkyl, or (c) R3 wherein R3 is cycloalkyl; and 35 (2) when R 2 is SR6, R6 is R3. - 270- WO 99/62520 PCT/US99/12093
10. The compound according to Claim 1 of structural formula: RK 0 ) DOH R 2 5 and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: (1) -H, (2) -CH3, (3) -CH2OCH3, 10 (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, (8) -F, 15 (9) -Cl, (10) -CO-3 alkyl -N(R 4 )(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 20 independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 25 (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2, (13) -O-CH2-phenyl, wherein the phenyl group may be unsubstituted or substituted with 1 to four substituents 30 independently selected from: -271- WO 99/62520 PCT/US99/12093 (a) -F, -Cl, or -Br, (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, 5 (e) -CN, (f) hydroxy, (g) -C0-6 alkyl-N(R 7 )2,, (14) -O-CH3, (15) -OCH2CH3, 10 (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, 15 (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2NH2, (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, 20 (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, 25 (2) -R3, (3) -CH2-R3, (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, 30 (7) -O-R6, (8) -S-phenyl, (9) -C1-6 alkyl (OR6)(R4), (10) -CO-6 alkyl-N(R 4 )(R6), (11) -C(O)-R3, 35 (12) -CO-6 alkyl C(O)CH2-C(O)-OH, - 272- WO 99/62520 PCT/US99/12093 (13) -C1-6 alkyl NR 4 C(O)-R 6 , (14) -CH(OCH3)R3, and (15) -CH(OH)R3; each R3 is independently selected from: 5 (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, selected from -F, -Cl, -Br, (b) -CH3, 10 (c) methyloxy-, (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, 15 (h) -CH2CF3, (i) -CF2CH3, (j) -OCF3, (k) -CN, and (1) hydroxy; 20 (3) thienyl, (4) substituted thienyl substituted on a carbon atom with a substituent selected from: (a) F, (b) C1, and 25 (c) methyl; (5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from: (a) -F, 30 (b) -C1, (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, - 273- WO 99/62520 PCT/US99/12093 (g) hydroxy, and (h) oxo; (7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two 5 substituents independently selected from: (a) -F, (b) -Cl, (c) -CH3, and (d) -CF3; 10 (9) C3-6 cycloalkyl, (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from: (a) methoxy-, 15 (b) -OCF3, (c) =0O, and (d) hydroxy; (12) morpholinyl, (13) naphthyl, 20 (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, 25 (b) methyl, (c) -CF3, (d) methoxy-, (e) -N(CH3)2, and -N N-CH 3 30 (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl; - 274- WO 99/62520 PCT/US99/12093 (21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, 5 (25) tetrahydrofuran, (26) piperazinyl; (27) substituted piperazinyl substituted with a substituent selected from: (a) -F, 10 (b) -C1, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, 15 (29) benzoimidazolyl, each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, (3) -CF3, 20 (4) -R3, (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; each R5 is independently selected from: (1) -H, 25 (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and 30 (7) -C(O)C(O)OH; each R6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: 35 (1) -H, and - 275- WO 99/62520 PCT/US99/12093 (2) -C1-6 alkyl.
11. The compound according to Claim 1 of structural formula: R 1 N R2 OH 5 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: (1) -H, (2) -CH3, 10 (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, (6) -(CH2)6-OH, (7) -CF3, 15 (8) -F, (9) -Cl, (10) -CO-3 alkyl -N(R 4 )(R5), (11) -phenyl, (12) phenyl C1-3 alkyl-, wherein the phenyl group may be 20 unsubstituted or substituted with 1 to four substituents independently selected from: (a) -F, -Cl, or -Br, (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, 25 (d) -CF3, (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2, -276- WO 99/62520 PCT/US99/12093 (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, 5 (b) CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, 10 (g) -CO-6 alkyl-N(R 7 )2,, (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, 15 (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, 20 (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 25 (28) -C(OH)(CH3)-CH2N(R4)(R5); R 2 is selected from: (1) -H, (2) -R 3 , (3) -CH2-R3, 30 (4) -CH2CH2-R3, (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R 6 , (8) -S -phenyl, - 277- WO 99/62520 PCT/US99/12093 (9) -C1-6 alkyl (OR 6 )(R 4 ), (10) -CO-6 alkyl-N(R 4 )(R 6 ), (11) -C(O)-R3, (12) -CO-6 alkyl C(O)CH2-C(O)-OH, 5 (13) -C1-6 alkyl NR 4 C(O)-R 6 , (14) -CH(OCH3)R3, and (15) -CH(OH)R3; each R3 is independently selected from: (1) phenyl; 10 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, 15 (d) ethyloxy-, (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, 20 (i) -CF2CH3, (j) -OCF3, (k) -CN, and (1) hydroxy; (3) thienyl, 25 (4) substituted thienyl substituted on a carbon atom with a substituent selected from: (a) F, (b) C1, and (c) methyl; 30 (5) pyridyl, (6) substituted pyridyl substituted on a carbon with a substituent selected from: (a) -F, (b) -Cl, - 278- WO 99/62520 PCT/US99/12093 (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, 5 (g) hydroxy, and (h) oxo; (7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: 10 (a) -F, (b) -Cl, (c) -CH3, and (d) -CF3; (9) C3-6 cycloalkyl, 15 (10) piperidinyl, (11) substituted piperidinyl substituted on carbon with a substituent selected from: (a) methoxy-, (b) -OCF3, 20 (c) =0O, and (d) hydroxy; (12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, 25 (15) pyrazinyl; (16) substituted pyrazinyl substituted on nitrogen or carbon with a substituent selected from: (a) halogen, selected from -F, -C1, and -Br, (b) methyl, 30 (c) -CF3, (d) methoxy-, (e) -N(CH3)2, and (f) - 279- WO 99/62520 PCT/US99/12093 -N N-CH 3 (17) pyrimidinyl, (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, 5 (20) tetrazolyl; (21) cyclopropyl, (22) cyclobutyl, (23) cyclopentyl, (24) cyclohexyl, 10 (25) tetrahydrofuran, (26) piperazinyl; (27) substituted piperazinyl substituted with a substituent selected from: (a) -F, 15 (b) -Cl, (c) methyl, (d) -CF3, and (e) benzyl, (28) benzotriazolyl, 20 (29) benzoimidazolyl, each R 4 is independently selected from: (1) -H, (2) -C1-4 alkyl, (3) -CF3, 25 (4) -R 3 , (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; each R 5 is independently selected from: (1) -H, 30 (2) -CH3, (3) -CF3, (4) phenyl, (5) -benzyl, - 280- WO 99/62520 PCT/US99/12093 (6) -C(O)OR 4 , and (7) -C(O)C(O)OH; each R 6 is independently selected from: (1) -C1-3 alkyl-R 3 , and 5 (2) -R 3 ; each R 7 is independently selected from: (1) -H, and (2) -C1-6 alkyl. 10
12. The compound according to Claim 1 of structural formula: R24 OH R2 N 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R1 is selected from: 15 (1) -H, (2) -CH3, (3) -CH2OCH3, (4) -OCH2CH2OH, (5) -OCH2CH2OCH3, 20 (6) -(CH2)6-OH, (7) -CF3, (8) -F, (9) -Cl, (10) -CO-3 alkyl-N(R 4 )(R5), 25 (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, 30 (b) -CH3, (c) -OCH3, OCH2CH3, OCF3, or OCH2CF3, -281- WO 99/62520 PCT/US99/12093 (d) -CF3, (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2, 5 (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, 10 (c) -OCH3, OCH2CH 3 , OCF3, or OCH2CF3, (d) -CF3, (e) -CN, (f) hydroxy, (g) -CO-6 alkyl-N(R 7 )2,, 15 (14) -O-CH3, (15) -OCH2CH3, (16) -OCH2CF3, (17) -OCF3, (18) -OCH(CH3)2, 20 (19) -C(0)CH2C(0)C(0)OH, (20) -O-C1-6 alkyl-NH-C(0)-OR7, (21) -O-CH2CH2 N(CH3)2, (22) -O-CH(CH3)CH2N(CH3)2, (23) -O-CH2CH2NH2, 25 (24) -O-CH(CH3)CH2NH2, (25) -S-CH3, (26) -C(0)CH2C(0)C(0)OH; (27) -CH2-CH(OH)-CH2-O-R7; and (28) -C(OH)(CH3)-CH2N(R4)(R5); 30 R 2 is selected from: (1) -H, (2) -R 3 , (3) -CH2-R3, (4) -CH2CH2-R3, - 282- WO 99/62520 PCT/US99/12093 (5) -CF2-R3, (6) -CH(CH3)-R3, (7) -O-R6, (8) -S-phenyl, 5 (9) -C1-6 alkyl (OR 6 )(R 4 ), (10) -CO-6 alkyl-N(R 4 )(R 6 ), (11) -C(O)-R3, (12) -CO-6 alkyl C(O)CH2-C(O)-OH, (13) -C1-6 alkyl NR 4 C(O)-R6, 10 (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 15 selected from: (a) halogen, selected from -F, -Cl, -Br, (b) -CH3, (c) methyloxy-, (d) ethyloxy-, 20 (e) -OCH2CF3, (f) -OCF2CH3, (g) -CF3, (h) -CH2CF3, (i) -CF2CH3, 25 (j) -OCF3, (k) -CN, and (1) hydroxy; (3) thienyl, (4) substituted thienyl substituted on a carbon atom with a 30 substituent selected from: (a) F, (b) Cl, and (c) methyl; (5) pyridyl, -283- WO 99/62520 PCT/US99/12093 (6) substituted pyridyl substituted on a carbon with a substituent selected from: (a) -F, (b) -Cl, 5 (c) -CH3, (d) -CF3, (e) -OCH3, (f) -OCF3, (g) hydroxy, and 10 (h) oxo; (7) pyrazolyl (8) substituted pyrazolyl substituted on carbon with one or two substituents independently selected from: (a) -F, 15 (b) -C1, (c) -CH3, and (d) -CF3; (9) C3-6 cycloalkyl, (10) piperidinyl, 20 (11) substituted piperidinyl substituted on carbon with a substituent selected from: (a) methoxy-, (b) -OCF3, (c) =0O, and 25 (d) hydroxy; (12) morpholinyl, (13) naphthyl, (14) 1,2,3,4-tetrahydronaphthalenyl, (15) pyrazinyl; 30 (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, 35 (d) methoxy-, - 284- WO 99/62520 PCT/US99/12093 (e) -N(CH3)2, and (f)-N N-CH 3 (17) pyrimidinyl, 5 (18) [1,2,3]-triazolyl, (19) [1,2,4]-triazolyl, (20) tetrazolyl; (21) cyclopropyl, (22) cyclobutyl, 10 (23) cyclopentyl, (24) cyclohexyl, (25) tetrahydrofuran, (26) piperazinyl; (27) substituted piperazinyl substituted with a substituent 15 selected from: (a) -F, (b) -Cl, (c) methyl, (d) -CF3, and 20 (e) benzyl, (28) benzotriazolyl, (29) benzoimidazolyl, each R 4 is independently selected from: (1) -H, 25 (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R 3 , and (6) -C(O)-R3; 30 each R5 is independently selected from: (1) -H, (2) -CH3, (3) -CF3, - 285- WO 99/62520 PCT/US99/12093 (4) phenyl, (5) -benzyl, (6) -C(O)OR4, and (7) -C(O)C(O)OH; 5 each R6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R3; each R 7 is independently selected from: (1) -H, and 10 (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, 15 (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 20 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 25 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, 30 (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, 35 (14) 4-(3-(l1-phenylethoxy)phenyl)-4-oxo-2-butenoic acid, - 286- WO 99/62520 PCT/US99/12093 (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 5 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, 10 (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-1l-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 15 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 20 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, 25 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 30 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, 35 (6) 4-(4-Dibenzylaminophenyl)-2,4-dioxobutanoic acid, - 287- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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 20 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 (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 30 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, - 288- WO 99/62520 PCT/US99/12093 (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, 5 (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, 10 (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, 15 (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, 20 (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 25 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, 30 (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, 35 (52) 4-(6-Benzylbenzo[1,3]dioxol-4-yl)-2,4-dioxobutyric acid, - 289- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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 15 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 20 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, 25 (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, 30 (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 35 dioxobutyric acid, - 290- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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, 20 (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 25 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, 30 (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, 35 (93) 4-(4-Dibenzylaminophenyl)-2-hydroxy-4-oxobut-2-enoic acid, - 291- WO 99/62520 PCT/US99/12093 (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, 5 (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, 10 (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, 15 (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 20 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, 25 (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)-lH-indol-6-yl]-2,4-dioxobutyric acid, 30 (111) 4-(1-Benzyl-l1H-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, 35 (116) 2, 4 -dioxo- 4 -[3-(2-4-6-trifluoro-benzyl)-phenyl]-butyric acid, - 292- WO 99/62520 PCT/US99/12093 (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, 5 (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, 10 (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, 15 (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, 20 (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, 25 (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, 30 (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, 35 (146) 4-[3-(3,4-difluoro-benzyl)-phenyl]-2,4-dioxo-butyric acid, - 293- WO 99/62520 PCT/US99/12093 (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, 5 (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, 10 (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, 15 (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, 20 (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 25 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) 30 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, 35 (173) 2,4-dioxo-4-(3-phenoxymethyl-phenyl)-butyric acid, - 294- WO 99/62520 PCT/US99/12093 (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 5 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 10 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, 15 (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, 20 (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, 25 (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, 30 (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 35 (197) 4-[3-(2-hydroxy-benzyl)-phenyl]-2,4-dioxo-butyric acid, - 295- WO 99/62520 PCT/US99/12093 (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. 5
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, 10 (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, 15 (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, 20 (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, 25 (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, 30 (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 35 acid, - 296- WO 99/62520 PCT/US99/12093 (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, 5 (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 10 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, 15 (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 20 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. 25
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 30 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 35 (1) an AIDS antiviral agent, - 297- WO 99/62520 PCT/US99/12093 (2) an anti-infective agent, and (3) an immunomodulator.
19. The composition of Claim 18 wherein the antiviral 5 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) 10 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 15 therapeutically effective amount of a compound of structural formula (I): R2 R OR7 R 9 0 0 (1) and tautomers and pharmaceutically acceptable salts thereof, 20 wherein: A is a six-membered aromatic or heteroaromatic ring containing 0, 1, or 2 nitrogen heteroatoms substituted on carbon or nitrogen by R1, R 2 , R8, and R9; optionally the aromatic ring may be fused with another ring system to 25 form: - 298- WO 99/62520 PCT/US99/12093 or or or orN or or O or H Sor 0 or H R1 is selected from: 5 (1) -H, (2) -C1-5 alkyl, (3) -C1-6 alkyl-OR 7 , (4) -0-C1-6 alkyl-OR 7 , (5) -O-C1-6 alkyl-SR7, 10 (6) -CF3 or -CH2CF3, (7) -halo, (8) -NO2, (9) -CO-3 alkyl -N(R4)(R5), (10) -R 6 , 15 (11) -C2-5 alkenyl-R 3 , (12) -C2-5 alkynyl-R 3 , (13) -O-R 6 , (14) -0-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, 20 (15) -0-C1-6 alkyl-NH-C(0)-OR7; (16) -O-C2-6 alkyl-N(R 4 )(R5); (17) -S-C1-3 alkyl; (18) -C(0)CH2C(0)C(0)OR7; (19) -CH2-CH(OH)-CH2-O-R7; and 25 (20) -C(OH)(CH3)-CH2N(R4)(R5); R 2 is selected from: (1) -H, (2) -R 3 , - 299- WO 99/62520 PCT/US99/12093 (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 (5) -C2-6 alkenyl, (6) -O-R 6 , (7) -0-C1-6 alkyl-OR 6 , (8) -0-C1-6 alkyl- SR6, (9) -S(0)n-R 6 , 10 (10) -C1-6 alkyl (OR6)(R4), (11) -CO-6 alkyl-N(R 4 )(R 6 ), (12) -C1-6 alkyl S(0)n-R 6 , (13) -CO-6 alkyl C(0)-R6, (14) -CO-6 alkyl C(0)CH2-C(0)-OH, 15 (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR4C(0)-R6, (17) -C1-6 alkyl-C(0)N(R 4 )(R5), and (18) -CH2(OR7)-R6; each R 3 is independently selected from: 20 (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, 25 (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, 30 (e) -S-C1-6 alkyl, (f) -CN, (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, - 300- WO 99/62520 PCT/US99/12093 -N N-CH 3 (j) (k) oxo, and (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: 5 (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0, 1 or 2 10 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from: (a) halogen, (b) C1-6 alkyl, 15 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, 20 (h) benzyl, and (i) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, 25 (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, 30 (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, -301- WO 99/62520 PCT/US99/12093 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, 5 (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and 10 (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: 15 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 20 (f) -CN, (g) =0O, 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 25 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 30 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; and - 302- WO 99/62520 PCT/US99/12093 (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: 5 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 10 (f) -CN, (g) =0O, and (h) hydroxy; and each R4 is independently selected from: (1) -H, 15 (2) -C1-4 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , 20 (7) -C2-3 alkenyl-R 3 , (8) -S(0)n-R 3 , and (9) -C(0)-R3; each R5 is independently selected from: (1) -H, 25 (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , 30 (7) -C2-3 alkenyl-R 3 , (8) -S(0)n-R 3 , (9) -C(0)-R3, (10) -C(0)OR4, and (11) -C(0)C(0)OH; 35 each R6 is independently selected from: - 303- WO 99/62520 PCT/US99/12093 (1) -C1-3 alkyl-R 3 , and (2) -R3; each R7 is independently selected from: (1) -H, and 5 (2) -C1-6 alkyl; R 8 is selected from: (1) -H, (2) -0- C1-6 alkyl and (3) C1-6 alkyl; 10 R 9 is selected from: (1) -H, (2) -0- C1-3 alkyl, (3) -OH, and (4) oxo; and 15 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, 20 (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, 25 (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 30 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, - 304- WO 99/62520 PCT/US99/12093 (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 5 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, 10 (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) 15 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, 20 (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 (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, 30 (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 - 305- WO 99/62520 PCT/US99/12093 (30) 4-[5-Benzyl-2-isopropoxy-3-(pyridin-2 ylaminomethyl)phenyl]-2,4-dioxo-butyric acid;and tautomers and pharmaceutically acceptable salts thereof. 5
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): R 2 R 1 A OR 7 R 9 0 0 (1) 10 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, R 2 , R8, and R9; 15 optionally the aromatic ring may be fused with another ring system to form: / \ I K K K ,or or or or Nor O or O or H Sor 0 or H 20 R1 is selected from: (1) -H, (2) -Cl1-5 alkyl, - 306- WO 99/62520 PCT/US99/12093 (3) -C1-6 alkyl-OR 7 , (4) -O-C1-6 alkyl-OR 7 , (5) -0-C1-6 alkyl-SR 7 , (6) -CF3 or -CH2CF3, 5 (7) -halo, (8) -NO2, (9) -CO-3 alkyl -N(R4)(R5), (10) -R6, (11) -C2-5 alkenyl-R 3 , 10 (12) -C2-5 alkynyl-R 3 , (13) -O-R6, (14) -0-C1-6 alkyl, wherein one or more of the hydrogen atoms may be replaced with fluorine atoms, (15) -0-C1-6 alkyl-NH-C(0)-OR7, 15 (16) -0-C2-6 alkyl-N(R 4 )(R5), (17) -S-C1-3 alkyl, (18) -C(0)CH2C(0)C(0)OR7, (19) -CH2-CH(OH)-CH2-O-R7, and (20) -C(OH)(CH3)-CH2N(R4)(R5); 20 R2 is selected from: (1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R 3 , wherein one or more of the 25 hydrogen atoms on C1-6 alkyl may be replaced with a fluorine atom, (5) -C2-6 alkenyl, (6) -O-R6, (7) -0-C1-6 alkyl-OR 6 , 30 (8) -0-C1-6 alkyl- SR 6 , (9) -S(O)n-R6, (10) -C1-6 alkyl (OR 6 )(R4), (11) -CO-6 alkyl-N(R 4 )(R 6 ), (12) -C1-6 alkyl S(O)n-R 6 , - 307- WO 99/62520 PCT/US99/12093 (13) -C0-6 alkyl C(O)-R 6 , (14) -CO-6 alkyl C(O)CH2-C(O)-OH, (15) -C1-6 alkyl C(S)-R6, (16) -C1-6 alkyl NR 4 C(O)-R6, 5 (17) -C1-6 alkyl-C(O)N(R 4 )(R5), and (18) -CH2(OR 7 )-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, 10 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, 15 (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, 20 (g) hydroxy, (h) phenyloxy, (i) -CO-6 alkyl-N(R 7 )2, -N N-CH 3 (j) , (k) oxo, and 25 (1) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and 30 (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, - 308- WO 99/62520 PCT/US99/12093 unsubstituted or substituted with 1 to 5 substituents selected from: (a) halogen, (b) C1-6 alkyl, 5 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0, 10 (h) benzyl, and (i) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, 15 (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, 20 (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 25 ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: (a) -halogen, (b) -Cl1-6 alkyl, (c) -C1-6 alkyloxy-, 30 (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy; (5) a 3 to 6 membered saturated ring containing 0, 1 or 2 35 heteroatoms selected from oxygen, nitrogen or sulfur, fused - 309- WO 99/62520 PCT/US99/12093 with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C1-6 alkyl, 5 (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and 10 (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: 15 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, 20 (f) -CN, (g) =0O, 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 25 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-, 30 (d) -CF3, (e) -OCF3, (f) -CN, (g) =0O, and (h) hydroxy; and 35 each R4 is independently selected from: - 310- WO 99/62520 PCT/US99/12093 (1) -H, (2) -C1-4 alkyl, (3) -CF3, (4) -R3, 5 (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R 3 , (7) -C2-3 alkenyl-R 3 , (8) -S(O)n-R 3 , and (9) -C(O)-R3; 10 each R5 is independently selected from: (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, 15 (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R 3 , (8) -S(O)n-R3, (9) -C(O)-R3, 20 (10) -C(O)OR4, and (11) -C(O)C(O)OH; each R6 is independently selected from: (1) -C1-3 alkyl-R 3 , and (2) -R3; 25 each R7 is independently selected from: (1) -H, and (2) -C1-6 alkyl; R8 is selected from: (1) -H, 30 (2) -0- C1-6 alkyl and (3) C1-6 alkyl; R9 is selected from: (1) -H, (2) -0- C1-3 alkyl, 35 (3) -OH, and -311- WO 99/62520 PCT/US99/12093 (4) oxo; and each n is independently selected from 0, 1 and 2.
24. The method according to Claim 23 wherein the 5 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 10 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, 15 (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 20 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, 25 (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 30 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, -312- WO 99/62520 PCT/US99/12093 (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, 5 (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-yhnlmethylphenyl) 2,4-dioxobutyric acid, (23) 4-[5-Benzyl-2-(3-N,N-dimethylaminopropoxy)-3 10 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, 15 (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 20 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. - 313-
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