AU756826B2 - HIV integrase inhibitors - Google Patents
HIV integrase inhibitors Download PDFInfo
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- AU756826B2 AU756826B2 AU42256/99A AU4225699A AU756826B2 AU 756826 B2 AU756826 B2 AU 756826B2 AU 42256/99 A AU42256/99 A AU 42256/99A AU 4225699 A AU4225699 A AU 4225699A AU 756826 B2 AU756826 B2 AU 756826B2
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- Australia
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- alkyl
- substituted
- pyrrol
- independently selected
- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Description
TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in to human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the 1is resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transciptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., 20 Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants [I:\DayLib\LIBH]01990.doc:sxc WO 99/62513 PCT/US99/12095 demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase
II.
Zhao et al., Med Chem. vol. 40, pp. 937-941 and 1186- 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2 4 -dioxo-4-substituted-l-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4dioxobutanoic 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).
Applicants have discovered that certain nitrogen containing heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection.
SUMMARY OF THE INVENTION Compounds of formula I, as herein defined, are disclosed. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), s pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
A first embodiment the present invention provides compounds of structural formula oo* 15 I R 0 R2
OR
7
R
8 k 0 0 *O O
(I)
S: and tautomers and pharmaceutically acceptable salts thereof, wherein: A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R 2 and R 8 the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety; R' is selected from:
-H,
[I:\DayLib\LBH]0199.doc:SxC WO 99/62513 WO 9962513PCTIUS99/1 2095
-C
1 5 alkyl,
-CF
3 -halo,
-NO
2 -R6, 3
-C
2 5 alkenyl-R 3
-C
2 5 alkynyl-R -O-R6, (11) -0-Cl1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7; R2 is selected from:
-H,
-R
3 -Cl..
6 alkyl,
-C
1 6 alkyl substituted with R 3 6 -0-C 1 l.
6 alkyl-OR -S(O)n-R 6
-C
1 6 alkyl (R 6
)(R
4
-C
1 6 alkyl-N(R 6), 6 25(10) -C1..6 alkyl CS)-R 6 (13) -C 1 6 alkyl NR C(O)-R ,and (14) -C 1 6 alkyl-C(O)N(R 4 (R 5 each R 3is independently selected from: a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, WO 99/62513 PCT/US99/12095 nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; 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: halogen, C.-6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, hydroxy; unsubstituted or substituted hexahydrothieno[3,4d]imidazolyl with one or two substituents selected from: WO 99/62513 PCT/US99/12095 oxo, halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and hydroxy; a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: -halogen,
-C
1 -6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: halogen,
C
1 .6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, -6- WO 99/62513 W099/2513PCT/US99/1 2095 hydroxy; and 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: halogen,
C
1 6 alkyl,
C
1 6 alkyloxy-,
-CF
3
-OCF
3 Mf -CN, =0, hydroxy; each R 4 is (1) (2) (3) (4) (6) (7) (8) (9) eachR is (1) (2) (3) (4) independently selected from:
-H,
-C
1 3 alkyl, -C3, 3
-R,
-C
2 3 alkenyl, 3
-C
1 3 alkyl-R 3
-C
2 3 alkenyl-R 3 -S(O)n-R an&d independently selected from:
-H,
-C
1 3 alkyl,
-CF
3
-R
3
-C
2 3 alkenyl, -7- 8
-CI-
3 alkyl-R,
-C
2 3 alkenyl-R 3 3 and 3 each R 6 is independently selected from:
-C
1 3 alkyl-R 3 and -R 3 R 7 is selected from: and
C
1 6 alkyl; R 8is selected from:
-H,
CI-
6 alkyl-oxy, and
C
1 6 alkyl; and each n is independently selected from 0, 1 and 2, and further provided that when R 7 i 1 6 alkyl, then R 2is not -H or -CI- 6 alkyl.
Particular compounds of structural formula I include: 4[1 -(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester, 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4-dioxobutyric acid, 4-[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, 1-(4-methylbenzyl)-l1-H-pyrrol-2-yl] -2,4-dioxobutyric acid, 4-[i -(4-fluorobenzyl)-l1-H-pyrrol-2-yl] -2,4-dioxobutyric acid ethyl ester, 4-[l1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl. ester, 4-[1-)4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl. ester, 1-benzyl- 1H-pyrrol-2-yl)-2,4-dioxobutyric acid, 4-(1 -naphthalen-2-ylmethyl- 1H- [1:\DayLib\LIBH]01990.doc:sxc WO 99/62513 WO 9962513PCTIUS99/1 2095 pyrrol-2-yl)-2,4-dioxobutyric acid,( 10) 1-biphenyl-4ylmethyl- 1H-pyrrol -2-yl )-2,4-dioxobutyric acid, (11) 1-naphthalen- 1-ylmethyl-1H-pyrrol -2-yl ,4-dioxobutyric acid, (12) 2,4-dioxo-4-[ 1-(4-phenylbutyl 1H-pyrrol 2 -ylIbutyric acid, (13) 1-(4-chlorobenzyl 1H-pyrrol-2-yl]-2,4dioxobutyric acid, (14) 2,4-dioxo-4-( 1-phenethyl- 1H-pyrrol -2-yl)-butyric acid, 4 -[l-(2-methylbenzyl)- lJ-pyrrol-2-yHl-2,4-dioxobutyric acid, (16) 4 -[l-(3,4-difluorobenzyl).lH--pyrrolb2-y]-2,4-dioxobutyric acid, (17) 1-(4-bromobenzyl 1H-pyrrol-2-yll-2,4dioxobutyric acid, (18) 441 2-bromobenzyl)- lFJ-pyrrol-2yl]-2,4-dioxobutyric acid, (19) 1-(3-bromobenzyl)- it!pyrroll- 2 -yHl-2,4-dioxobutyric acid, (20) 4-[l -(3-chlorobenzyl lH-pyrrol-2-yl].2,4-dioxobutyrj c acid, (21) 4 -[1-(3-methylbenzyl)- iH-pyrrol-2-yJ]-2,4-dioxobutyric acid, (22) 2-fluorobenzyl lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (23) 2,4-dioxo-4-( 1-hexyl- iH-pyrrol -2-yl )-butyric acid, (24) 4- (1-biphenyl-2-ylmethyl. 1H-pyrrol 2-yl ,4-dioxobutyric acid, 2 ,4-dioxo-4-[ 1-(4-phenoxybutyl it -pyrrol-2-yl]-butyric acid, (26) 1-(3-fluorobenzyl lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (27) 4 2 -chlorobenzyl)-lm-pyrrol12y}.2,4-dcioxobutyric acid,( 28) 1-(4-fluorobenzyl )-4-iodo- lJI-pyrrol-2-yl]-2,4dioxobutyric acid (29) 44 1-(4-methoxybenzyl 1H-pyrrol- 2 -yl]-2 ,4-dioxobutyric acid,_(30) 1-(2 ,4,5-trifluorobenzyl lH-pyrrolk2-yl]-2,4-dioxobutyric acid, (31) difluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid,( 32) 4- ,5-difluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (33) 1-(2 ,5-difluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (34) 4-1 1-(2,5 ,6-difluorobenzyl ltI-pyrrol- 2 -yl]-2,4-dioxobutyric acid, (35) 1-(2-fluorobenzyl 1H-pyrrol-2-yl]-2,4clioxobutyric acid, (36) l-(4-trifluoroxnethylbenzyl). 1H-pyrrol-2-yl] -2,4dioxobutyric acid, (37) 4-[l -(4-cyanobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, -9- WO 99/62513 WO 9962513PCT/US99/1 2095 (38) 3-methoxybenzyl )-llH -pyrrol-2-yl] -2 ,4-dioxobutyric acid, (39) 2-hydroxy-4-[ 1-(4-hydroxybenzyl 1H-pyrrol-2-yl] -2,4dioxobutyric acid, (40) l-cyclopentylmethy- 1H-pyrrol- 2-yl) 2 ,4-dioxobutyric acid, (41) l-[3-(4-fluorophenyl)propyl]- 1H-pyrrol-2-y)-2,4dioxobutyric acid, (42) 4- 2 -(4-fluorophenyl )ethyl]- lH-pyrrol-2-yl)-2,4-dioxobutyric acid, (43) l-(3-phenylpropyl lH-pyrrol-2-y]-2,4-dioxobutyric acid, (44) 4-Q1-ethyl- 1H-pyrrol-2.yl) -2,4-dioxobutyric acid, 4-[1-(3-fluoro-benzyl> 1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (46) 4-[1-(2-chloro-benzyl 1-H -pyrrol-2-ylJ- 2,4-dioxobutyric acid, (47) l-(3-benzoylan-iinopropyi 1H-pyrrol-3-yl] -2,4-dioxobutyric acid, (48) 4-1 l-1 3 4 -fluorophenoxy)benzyl]- 1H-pyrrol-2-ylfl -2,4dioxobutyric acid, (49) 1-cyclohexylmethyl- 1-H -pyrrol-2-yl ,4-dioxo-butyric acid methyl ester (50) 1-cyclohexylmethyl- 1-H -pyrrol- 2 -yl)-2,4-dioxo-butyric acid, (51) 4- [1-(4-fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl-2 ,4dioxobutyric acid ethyl ester, (52) 4- [1-(4-fluorobenzyl )-4-phenylethynyl- 1H-pyrrol-2-yl] -2,4dioxobutyric acid, (53) 1-(4-fluorobenzyl )-4-phenethyl- 1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester, (54) l-(4-fluorobenzyl )-4-phenethyl- lJ-pyrrol-2-yl]-2,4dioxobutyric acid, (55) 4
-II-(
4 -fluorobenzyl)- 1-methyl- 1H -pyrrol-2-yl]-2,4dioxobutyric acid methyl ester, (56) 4 4 -fluorobenzyl 1-methyl-llH -pyrrol-2-yl]-2,4dioxobutyric acid, (57) 3-chlorobenzyfl- 1-methyl-lH -pyrrol-2-yl]-2 ,4dioxobutyric acid, 10 WO 99/62513 WO 9962513PCTIUS99/12095 (58) 4-[5-(4-fluorobenzyl 1H -pyrrol-2-yl]-2,4-dioxobutyrc acid, (59) 4 -[5-(3-chlorobenzyl)- 1ff -pyrrol-2-yl]-2,4-dioxobutvrc acid, 4-[5-(benzyl 1ff -pyrrol-2-yl]-2 ,4-dioxobutyric acid.
(61) 4 -[S-3-fluorobenzyl 1f -pyrrol-2-yl]-2,4-dioxobutvrjc acid, (62) 4 -[5-(4-fluorobenzyl 1-(4-fluorobenzyl )-I1f -pyrrol-2-yH-2 ,4dioxobutyric acid, 4 -[5-(3-chlorobenzyb- 1-(4-fluorobenzyl)- 1f -pyrrol-2-yl]-2,4dioxobutyric acid, (64) 4-[5-(benzyl 1-(4-fluorobenzyl )-I1f -pyrrol-2-yl]-2 ,4dioxobutyric acid, 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- 1ff -pyrrol-2 -yl] -2,4dioxobutyric acid, (66) 4 -15-(4-fluorobenzyl 1-methyl- 1H -pyr-rol-3-yl]-2 ,4dioxobutyric acid, (67) 3-chlorobenzyl)- 1-methyl- LU -pyrrol-3-yl]-2,4dioxobutyric acid, (68) 4-[5-(benzyl)- 1-methyl- 1H -pyrrol-3-yl]-2 ,4-dioxobutyric acid, (69) 4-15-(3-fluorobenzyl)- 1-methyl- 1H -pyrrol-3-yl]-2,4clioxobutyric acid, (70) 4-(5-benzyl- 1f -pyrrol-3-yl)-2 ,4-dioxobutyric acid, (71) 4-[2 ,5-bis-(3-chlorobenzyl 1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (72) l-(4-Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2 ,4dioxobutyric acid ethyl ester, (73) l-( 4 -Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4dioxobutyric acid, (74) 4 -[4-Dimethylamino-1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester, 4-[4-Dimethylainino- l-(4-fluorobenzyl 1H-pyrrol-2-yl]-2,4dioxobutyric acid, (76) l-(4-Fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)- 1-(4-fluorobenzyl)- lH-pyrrol-2-yl]-2 ,4dioxobutyric acid, (78) 4-[5-Nitro- 1-(4-fluorobenzyl lH-pyrrol-2-yl-2,4-dioxobutyric -11 WO 99/62513 WO 9962513PCT[US99/12095 (79) 4-[1-benzyl- 1H-pyrrolb3-yl]-2 ,4-dioxobutyric acid methyl ester, 4-[1-benzyl- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[1-(4-fluorobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-Il-(3-bromoIbenzyl lF-pyrrol-3-yHj-2,4-dioxobutyric acid, (83) 4-fluorobenzyl )-4-methyl- 1H-pyrrol-3-yl]-2,4dioxobutyric acid, (84) 4-[2 ,4-dimethyl- 1-(4-fluorobenzyl 1H-pyrrol-3-yl]-2 ,4dioxobutyric acid, (85) 1-(3 ,4-difluorobenzyl 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (86) 1-(3-chlorobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 1-(4-chlorobenzyl lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[l1-(4-bromobenzyl lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_.
(89) 4 3 4 -dichlorobenzyl)-m..-pyrrol3.yl].24ioxobutyrc acid, 4-[1-(2-methylbenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (91) 4 3 -chlorobenzyl)-4-methyl-lHpyrrol3yl..2,4.
dioxobutyric acid, (92) l-(3-trifluoromethylbenzyl 1H-pyrrol-3-yl]-2 ,4dioxobutyric acid, (93) 44 1-(4-methylbenzyl). 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (94) 1-(4-methoxybenzyl lH-pyrrol-3-yll-2,4-dioxobutyric acid, 1-(3-methylbenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (96) l-[3-(4-fluorophenyl)-propyl.. 1H-pyrrol-3-yl}-2,4dioxobutyric acid, (97) 4-[1-(4-bromobenzyl)- l-H-pyrrol-3-yll-2,4-dioxobutyric acid, (98) 4-lIl-(4-chlorobenzyl)- 1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (99) 4-[4-Benzylmethylamino..l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid, ethyl ester, (100) 4-[4-Benzylmethylamino. -(4-fluorobenzyl 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid, (101) 4-[4-Phenyl- l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester, 12 WO 99/62513 WO 9962513PCTLUS99/1 2095 (102) 4-14-Phenyl- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]- 2,4dioxobutyric acid, (103) 4 4 -fluorobenzyl)-4-methanesulfonylamino.1Hpyrrol.3yl]-2,4-dioxo-butyric acid ethyl ester, (104) 4-[l1-(4-fluorobenzyl )-4-methanesulfonylamino. H-pyrrol-3yl]-2,4-dioxo-butyric acid, (105) 1-(4-Fluorobenzyl )-3-acetylamino- 1H-pyrrol-2-yl]-2 ,4dioxobutyric acid, (106) 4 -[4-acetylamino-l1-(4-fluorobenzyl 1H-pyrrol-2-yl] -2,4dioxobutyric acid, (108) 4-14-(4-fluorobenzyl 1-H -pyrrol-3-yHl-2,4-dioxobutyric acid, (109) 1,4-bis-(4-fluorobenzyl LU -pyrrol- 3 -yl]-2,4-dioxobutyric acid, (110) 4
-II-(
3 -ethoxycarbonyl-3-oxopropionyl l-(4-fluorohenzyl 1Hpyrazol-3-yl]-2 ,4-dioxobutyric acid ethyl ester, (111) 4-1 1-(4-fluorobenzyl 1H-pyrazol-4-yl]-2 ,4-dioxobutyric acid ethyl ester, (112) 4-[1-(4-fluorobenzyl 1H-pyrazol-4-yl]-2 ,4-dioxobutyric acid, (113) 4-[4-Dimethylamino- 1-(4-fluorobenzyl IH-pyrrol-3-yl] -2,4dioxobutyric acid, (114) 4-[Il-( 4 -Fluorobenzyl)-5-methyl- lH-pyrazol-4-yl]-2-hydroxy.4 oxobut-2-enoic acid, (115) 4-[2-(4-fluorobenzyl )-2H-pyrazol-3-yl]-2 ,4-dioxo-butyric acid ethyl ester, (116) 4-2(-looezl-Hprao--l-,-ix-uyi acid, (117) 4 -fluorobenzyl)-3-methyl- 1tI-pyrazol-4-yl]-2,4dioxobutyric acid ethyl ester, (118) l-(4-fluorobenzyl)-3-methyl..1F-pyrazol-4-yl]-2 ,4dioxobutyric acid, (119) 4-13-methyl- 3-chlorobenzyl )-1I-pyrazol-4-yl]-2,4dioxobutyric acid ethyl ester, (120) 44[3 -methyl- l-(3-chlorobenzyl lH-pyrazol-4-yl]-2,4dioxobutyric acid, 13 WO 99/62513 WO 9962513PCTIUS99/1 2095 (121) 4-[5 -methyl- l-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4dioxobutyric acid, (122) 4-[5 -methyl- l-(3-chlorobenzyl 1H-pyrazol-4-yl]-2,4.
dioxobutyric acid ethyl ester, (123) 4-[5 -methyl- l-(.3-chlorobenzyl 1H-pyrazol-4-yl]-2,4dioxobutyric acid, (124) 4 -[l-4-fluoro-benzyl)- lH-imidazol-2-yl]-2,4-dioxo.butrc acid, (125) 4-l(-looezl-Hiriao--l-,-ix-uyi acid ethyl ester, (126) l-(4-fluorobenzyl lH-imidazol-2-yl]-2,4-dioxo..butyric acid, (127) 1-Benzyl- 1H-imidazol-2-yl )-2,4-dioxobutyric acid, (128) l-(4-fluorobenzyl 1H-imridazol-4-yl]-2 ,4-dioxo-butyric acid ethyl ester, (129) 1-(4-fluorobenzyl lI-imidazol-4-y]-2,4-dioxo-.butyric acid, (130) 4 -II1-(4-fluorobenzyl)- 1-H -indol 2 -yl]-2,4-dioxobutyric acid methyl ester, (131) 4-[Il-(4-fluorobenzyl 1H -indol 2 -yl]-2,4-dioxobutyric acid, (132) 2-hydroxy-4-( 1-methyl- 1-H -indol-2-yl) -2 ,4-dioxobutyric acid, (133) 4 -[1-(4-fluorobenzyl 1H-indol-3-yl]-2 ,4-dioxobutyric acid, (134) l-I[l-(4-fluorobenzyl)-lHJ-indol-3-yl]-2 ,4-dioxobutyric acid ethyl ester, (135) 1 -(4-fluorobenzyl 1I-indol-3-yl]-2 ,4-dioxobutyric acid,( 136) 3-fluorobenzyl)- 1-H-pyrrol-3-yl]-2,4dioxobutyric acid, (137) 4 -[4-(3-chlorobenzyl 1-H-pyrrol-3-yl]-2 ,4-dioxo-butyric acid, (138) 4 -[4-(4-fluorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (139) 4-[2,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-pyrrol-3-yl] -2 ,4-dioxobutyric acid, (140) 1-(3 ,5-dichlorobenzyl l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (141) 4- [l-(3-thiophenemethyl l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, 14 WO 99/62513 WO 9962513PCTIUS99/1 2095 (142) 4-li -2,4-dimethylbenzyl )-l-H-pyrrol-3-yl]-2,4-clioxobutyric acid, (143) 4 -[l-(3-chloro-5-methyl-benzyl 1-H-pyrrol-3-yl]-2,4-dioxo.
butyric acid, (144) 1-naphthalenemethyl l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (145) 1-(2-thiophenemethyl l-H-pyrrole-3-yl-2,4-dioxobutyric acid, and (146) 4 4 -(3-chlorobenzyl)-1-methyl-l-H..pyrrol3yl.2,4.
dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention are compounds of structural formula: N O R
R
2 0 Another embodiment of the present invention are compounds of structural formula: 0 N O H
R
2 0 0 Still another embodiment of the present invention are compounds of structural formula: R 8 0 OR 7 N 0 20R2 15 WO 99/62513 PCT/US99/12095 Another embodiment of the present invention are compounds of structural formula:
R
8 0
R
1
OH
N O 0
R
2 Another embodiment of the present invention are compounds of structural formula: 00 A OR 7 K N 0
N
R
2 Another embodiment of the present invention are compounds of structural formula: 00
OR
7
R
1 N O
R
2 Another embodiment of the present invention are compounds of structural formula:
R
1 0 NN OH R2 0 0 Another embodiment of the present invention are compounds of structural formula: -16- WO 99/62513 PCT/US99/12095 N f Y
OH
R
2 O
O
In one class of compounds of the present invention, A is selected from: pyrrolyl, imidazolyl, pyrazolyl, and indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula In another class of compounds of the present invention, A is pyrazolyl.
In yet another class of compounds of the present invention, A is imidazolyl.
In still another class of compounds of the present invention, A is pyrrolyl.
In another class of compounds of the present invention, A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indole.
In one class of compounds of the present invention, R1 is selected from:
-H,
-CH
3
-CF
3 -halo,
-NO
2 -N(R4 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halogen, -17- WO 99/62513 WO 9962513PCTIUS99/1 2095
C
1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, phenyl
C
1 3 alkyl-, substituted phenyl CI- 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen,
C
1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, 18- WO 99/62513 PCT/US99/12095 (11) -C2- 5 alkenyl-R 3 (12) -C 2 5 alkynyl-R 3 and (13) -C(O)CH2C(O)C(O)OR7.
In another class of compounds of the present invention, R1 is selected from:
-H,
-CH
3
-CF
3 -halo, .0
-NO
2
-N(R
4 R 5 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 -3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 0 substituents independently selected from: halo, methyl, and methoxy, (11) -C 2 5 alkenyl-R 3 and (12) -C(O)CH2C(0)C(O)OR7 In yet another class of compounds of the present invention, R1 is selected from:
-H,
-C1- 5 alkyl, 0
-CF
3 -halo,
-NO
2 19- WO 99/62513 PCT/US99/12095
-N(R
4 -phenyl, substituted phenyl substituted with 1 substituent independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, substituted phenyl C 1 -3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, (11) -C 2 5 alkenyl-R 3 and (12) -C(O)CH2C(O)C(O)OR7 In yet another class of compounds of the present invention, R1 is selected from:
-H,
-C1- 5 alkyl, -CF3, -halo, wherein halo is selected from: Cl, -Br, and -I;
-NO
2
-N(R
4 -phenyl, phenyl C 1 -3 alkyl-, substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br;
-C
2 5 alkynyl-R 3 and (11) -C(O)CH2C(O)C(O)OR7 In another class of compounds of the present invention, R1 is selected from:
-H,
WO 99/62513 PCT/US99/12095 -C1- 5 alkyl,
-CF
3 -halo, wherein halo is selected from: Cl, -Br, and -I;
-NO
2 -phenyl, phenyl C1- 3 alkyl-, substituted phenyl C 1 -3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and
-C
2 5 alkynyl-R 3 In one class of compounds of the present invention, R 2 is selected from:
-H,
-R
3 -C1- 6 alkyl,
-C
1 -6 alkyl substituted with R 3
-O-R
6
-O-C
1 .6 alkyl-OR 6 -S(O)n-R 6
-C
1 6 alkyl (OR 6
)(R
4 -C1- 6 alkyl-N(R 4 -C1 6 alkyl S(O)n-R 6 (11) -C1- 6 alkyl C(O)-R 6 (12) -C 1 -6 alkyl C(S)-R 6 (13) -C1- 6 alkyl.NR4C(O)-R 6 and (14) -C1- 6 alkyl-C(O)N(R 4
)(R
5 In another class of compounds of the present invention, R 2 is selected from:
-H,
-21 WO 99/62513PCUS/129 PCT/US99/12095 3
-R,
-C
1 6 alkyl,
-C
1 6 alkyl substituted with R 3 6 -0-Cl 1 6 alkyl-OR 64
-C
1 6 alkyl (OR
-C
1 6 alkyl-N(R 4)(R6), 6
-C
1 6 alkyl S(0)n-R (11) -C 1 6 alkyl NR 4
C(O)_R
6 and (12) -C 1 6 alkyl-C(O)N(R 4)(R In yet another class of compounds of the present invention, R2 is selected from:
-H,
3
-R,
-C 1 6 alkyl,
-C
1 6 alkyl substituted with R, 6
-O-R
6 -0-C 1 6 alkyl-OR
-C
1 6 alkyl (OR 46
-C
1 6 alkyl C(O)-R, 4 6
-C
1 6 alkyl NR4C(0)-R and (11) -C 1 6 alkyl-C(0)N(R )(XR In still another class of compounds of the present invention, R2 is selected from:
-H,
-R,
-C
1 6 alkyl,
-C
1 6 alkyl substituted with R, 6 -0-R 22 WO 99/62513 PCT/US99/12095 (6) (7) (8) (9) selected fro (1) (2)
-O-C
1 6 alkyl-OR 6
-C
1 6 alkyl (OR 6
)(R
4 -C1- 6 alkyl-N(R 4
-C
1 -6 alkyl C(O)-R 6 and -C1-6 alkyl NR 4
C(O)-R.
In one class of compounds of the present invention, R 3 is m: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl, -23- WO 99/62513 PCT/US99/12095 -CF3,
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 .6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, -24- WO 99/62513 WO 9962513PCTIUS99/1 2095
C
1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1..
6 alkyl, (iii) -CF 3 and (iv) hydroxy; 25 WO 99/62513 PCT/US99/12095 (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 -6 cycloalkyl; (14) substituted C 3 -6 cycloalkyl with 1 or 2 substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, -26- WO 99/62513 PCT/US99/12095 Ci_6 alkyl, C1-6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=O,
hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C1-6 alkyl, C1-6 alkyloxy-,
-CF
3
-OCF
3
-CN,
=0, hydroxy; (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C1.
6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: -halogen, -27- WO 99/62513 PCT/US99/12095 -CI-6 alkyl,
-C
1 -6 alkyloxy-,
-CF
3
-OCF
3 -CN, and -hydroxy; (23) C 3 .6 cycloalkyl fused with a phenyl ring; (24) substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen,
C
1 -6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy.
In another class of compounds of the present invention, R3 is selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen,
C
1 .6 alkyl,
C
1 6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and 28- WO 99/62513 PCT/US99/12095 substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1.6 alkyl, (iii) -CF 3 and (iv) hydroxy, thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl,
C
3 -6 cycloalkyl, substituted C 3 -6 cycloalkyl with 1 or 2 substituents independently selected from: halogen,
C
1 .6 alkyl,
C
1 -6 alkyloxy-,
-CF
3
-OCF
3
-CN,
and hydroxy; piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and (14) C3-6 cycloalkyl fused with a phenyl ring.
In still another class of compounds of the present invention, R3 is selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, -29- WO 99/62513 PCT/US99/12095 (3) (4) (6)
C
1 -6 alkyl,
C
1 -6 alkyloxy-, phenyl,
-CF
3
-OCF
3
-CN,
hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from C1, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy;
C
3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo; and naphthyl.
In one class of compounds of the present invention, R4 is )m:
-H,
-C
1 3 alkyl, and
-CF
3 In another class of compounds of the present invention, R4 from:
-H,
-C
1 3 alkyl, -CF3,
-R
3
-C
2 .3 alkenyl,
-C
1 3 alkyl-R 3 selected fr (1) (2) (3) is selected (1) (2) (3) (4) (6) WO 99/62513 PCT/US99/12095
-C
2 3 alkenyl-R 3 -S(O)n-R 3 and
-C(O)-R
3 In still another class of compounds of the present invention, R4 is selected from:
-H,
-C1.
3 alkyl,
-CF
3
-R
3
-C
1 -3 alkyl-R 3 -S(O)n-R 3 and
-C(O)-R
3 In yet another class of compounds of the present invention, R4 is selected from: and -C1- 3 alkyl.
In one class of compounds of the present invention, R5 is selected fr (1) (2) (3) (4) (6) (7) (8) (9) is selected (1) (2) om:
-H,
-C
1 3 alkyl, -CF3,
-R
3
-C
2 .3 alkenyl,
-C
1 3 alkyl-R 3
-C
2 3 alkenyl-R 3 -S(O)n-R 3 and
-C(O)-R
3 In another class of compounds of the present invention, from:
-H,
-C1.
3 alkyl, -31 WO 99/62513 PCT/US99/12095
-CF
3 and
-R
3 In yet another class of compounds of the present invention, is selected from:
-H,
-C1- 3 alkyl,
-CF
3 3
-R
3 3
-C
1 3 alkyl-R -S(O)n-R 3 and
-C(O)-R
3 In one class of compounds of the present invention, R7 is hydrogen.
In another class of compounds of the present invention, R7 is selected from: and C1-4 alkyl.
In one class of compounds of the present invention, R8 is selected from:
-H,
-OCH3, and -CH3.
In another class of compounds of the present invention, R8 is selected from: and CH3.
In yet another class of compounds of the present invention, R8 is selected from: and C1-6 alkyl.
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a -32- WO 99/62513 PCT/US99/12095 pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from: an AIDS antiviral agent, an anti-infective agent, and an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof' in describing compounds of structural formula Applicants also intend the following tautomeric forms of the same compound (Ia) and (Ib):
R
1 0 R 1 0 R 7 O R OR
R
8 0 0 R 8 0 OH (la)
R
R 1 0 R2-'
OR
7
R
8 OH O (Ib) -33- WO 99/62513 PCT/US99/12095 By naming or referring to compound and tautomers thereof, it is understood for the purposes of the present application that the tautomers (Ia) and (Ib) are also intended. Similarly, be referring to compound (Ia), it is understood for the purposes of the present application that the tautomers and (Ib) are also intended. The same holds true for references to tautomer (Ib).
When any variable 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, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HTV integrase, 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 to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
-34- WO 99/62513 PCT/US99/12095 Compounds of structural formula wherein A is pyrrolyl may be made according to the procedures in Schemes AI-AXI.
Compounds of structural formula wherein A is pyrazolyl may be prepared according to the procedures in Schemes BI-BV. Compounds of structural formula wherein A is imidazolyl are prepared according to the procedures in Schemes CI-CII. Schemes DI-D2 illustrate the preparation of the indolyl compounds of the present invention.
SCHEME AI
CH
3 r C H 0 4-fluorobenzyl bromide NaH
DMF
N C H3 NIS N Al-1-1 1O acetone F "F& dimethyl oxalate NaH
DME
heat WO 99/62513 WO 9962513PCTIUS99/12095 0 N
OCH
3 AJ-2-1 0 0 tO NaOH RsOH ITHF /MeOH /H 2 0 0 N OH 0 0 Al31 36 WO 99/62513 WO 9962513PCTIUS99/12095 Scheme All
N
H
I
0 LiHMDS cyciohexanecarbonyl chloride
THF
All-1-1
BH
3 -Me 2
S
THF
heat AII-2- 1 n -butyllithiumn
THF
N methoxy-N methylacetamide 37 WO 99/62513 WO 9962513PCTIUS99/1 2095 11 All-3-1 0 Idimethyi oxalate NaH
DME
heat 0 N
OCH
3 AIJ-4-1 0 0 I NaOH THF MeOH/ H 2 0 0 N OH &0 0 38 WO 99/62513 WO 9962513PCT/US99/12095 Scheme AiI Gui
[(C
6
H
5 3
P]
4 Pd
TEA
CH
3
CN
Pd/C EtOH Allj-i1 1 Diethyl oxalate NaOEt
THF
39 WO 99/62513 WO 9962513PCTIUS99/12095 A111-4- 1 -OEt 0 0 AIII-2-1 1N LIOH
THF
Diethyl oxalate NaQEt
THF
AlII-- 0 AIII-31 OEt 00 1N NaOH
THF
0 0
OH
AIII-6-1 WO 99/62513 WO 9962513PCTIUS99/12095 Scheme AIV pI
N
H
MeMgCl 50:50 THF:MeOH benzyl bromide F AJV-1-1
N
H
MeMgCI
THF
acetic anhydride
F
OH
3
H
3 C 0 -41 WO 99/62513 WO 9962513PCTJUS99/I 2095 dimethyl oxylate NaH
DME
ref lux cat. MeOH
TA
rief lux IN-6- I AIV-4-1 0C H 3 'C H 3 0 0 H 3
C
dimethyl oxylate NaH
OME
ref lux cat. MeOH I1 N NaOH
THF
F
0 N OH H3C 0 AIV-7-1
IH
AIV-5- I 1 NNaOH
THF
AIV-8- I 0
H
3
C
Scheme AV
COOH
(+1-)NH 0 EtOH (abs) SOCi 2 (cat) RT -42 WO 99/62513 WO 9962513PCTIUS99/1 2095 COGEt
~NH
0 Boc 2 0 Et 3 N DMF 4-DMAP
CHCI
3 AV-1-1 OOEt 0 PhMgBr [VHF -40'C 30 mmn AV-2-1 0 Ph
H
1. TFA/CH 2
CI
2
/RT
2. Et 3 N /CH 2 CI RT AV-3-1 \N COOEt 1. DDQ /CH 2
CI
2
/RT
2. NaOH H 2 0 ref lux AV-4-1 43 WO 99/62513 WO 9962513PCTIUS99/12095
NCOOH
H
MeON HMe-HCI
EDC*HCI
HOBt-H 2 0 DMF /Et 3
N
AV-5-1 F
CH
2 Br
OCH
3 N NCH 3 H 0 NaH DMF AV-6-1 MeLi THF -78'C AV-7-1 0 Eto~r-O-t 0 NaOEt /THF /RT AV-8-1 -44- WO 99/62513 WO 9962513PCT/US99/1 2095 1N NaOH MeOH /RT AV-9-1 AV-1 0-1 Scheme A-VI I 0
HNO
3
AC
2 0 Al-i -1 WO 99/62513 WO 9962513PCTIUS99/12095 K 10% Pd-C 0 EtOH
H
2 (1Atm)
F"
A VI-1-1
NH
2
N
0
N
F
CH
3 I /DMF /ICs 2 00 3 0
(CH
3 2 N Et0, A k.
0
N
0 Na0Et /THF /RT
F
AVI-3- 46 WO 99/62513 WO 9962513PCTIUS99/I 2095 (0H 3 2 CEt 0 0 AVI-4-1 1N NaOH MeOH /RT 0OH 0 0 AVI-5-1 SCHEME AVII 0
IOH
3
N
4-f Iuorobenzyl bromide NaH
DMF
47 WO 99/62513 WO 9962513PCTIUS99/12095 0 N e C3AVII-1-1 I dimethyl oxalate I NaH I DME Iheat AVII-2-1 THF MeOH
H
2 0 AVII-3-1 48 WO 99/62513 WO 9962513PCTIUS99/1 2095
NH
2 Scheme AVIII PhOHO NaCNBH 3 MeGH HOAc A VI-2-1
H
2 CHO NaCNBH 3 MeOH HOAc AVIII-1 -1 0 y H3 0 EtC~rJ 0 NaOEt /THF RT AVIII-2-1 49 WO 99/62513 WO 9962513PCTIUS99/1 2095 QOEt 1N NaOH MeOH /RT 0 0 AVIII-3-1
OH
3
'OH
0 0 AVIII-4-1 Scheme AIX PhB(OH) 2 Pd(Ph 3
P)
4 Et 3 N DMF 9000 AIIIl-1-1 50 WO 99/62513 WO 9962513PCTIUJS99/12095 0 EtC-KF: 0 Na0Et /THF RT AIX-i-i 1N NaOH /MeOH /RT AIX-3-1 SCHEME AX -51- WO 99/62513 WO 9962513PCT/US99/12095
.CH
3 AVI-2- 1 methylsulfonylchloride TEA/C
H
2 C1 2 O H 3
H
3 s AX-1-1 diethyioxalate NaOEtfTH
F
H
3
C
CO
2 Et 0 0 AX-2-1 1N NaOH
CH
3
OH/THF
52 WO 99/62513 WO 9962513PCT[US99/12095 Scheme AXI 0F
N
I Ad
CH
2
CI
2 4-fluorobenzoyl chloride 0 Si Pr) 3
BH
3 -Me 2
S
THF
heat 53 WO 99/62513 WO 9962513PCT/US99/I 2095 AXI-2-
I
Si(i-Pr) 3 AI01 3 0H 2 C1 2 acetyl chloride AXI-3-] Si(i- Pr) 3 [Bu]NF THF
I
F
N
H
1) dimethyl oxalate NaH
DMEI
heat 2) NaOH THF /MeOH
H
2 0 54 WO 99/62513PCUS9125 PCT/US99/12095 AXI-5-1I
OH
N
H
Scheme AXI(b) 0 DMF NaH -e-k4-f Iuorobenzyl bromide AXJ-4-1I AXI-4-2 1) dimethyl oxalate NaH
DME
heat 2) NaOH THF /MeOH
H
2 0 55 WO 99/62513 WO 9962513PCT/US99/1 2095 AXI-5-2 Scheme BI 0 0 k OEt EtO
N
H
Br
TEA
DMF
BI-1-1 1N LIOH
THF
-56- WO 99/62513 WO 9962513PCT[US99/1 2095 BI-2-1
F
MeO, NH. HOI EDO, HOBT, TEA
DMF
0 MeO-N eN
F
MeLi
THF
57 WO 99/62513 WO 9962513PCTIUS99/12095 B 1-4-1 jDiethyl oxalate NaOEt
THF
Scheme BI (cont.) 0 Bi-5-1 1N LiOH
THF
58 WO 99/62513 WO 9962513PCTIUS99/12095 090 0 BI-6-1 Scheme Bi Br N
H
I- I B r Fj~ NaH
DMF
Br
N
J BI1-1-1 MeO 0 n-BuLi Et 2
O
59 WO 99/62513 WO 9962513PCTIUS99/12095 0
N
BII-2-1 iethyl oxalate 0 0 B1I-3-1 1M NaOH MeOH BII-4- 1 60 WO 99/62513 WO 9962513PCTIUS99/12095 Scheme Bill
N
H 0 Br
F'
NaH
DMF
B1l1-1 -1 Diethyl oxalate NaOEt
THF
61 WO 99/62513 WO 9962513PCTIUS99/1 2095 0
N,
I BTII-2-1 1M NaOH
THF
'OH
BIII-3-1 Scheme BIV 0
N
1 M NaGH
THF
62 WO 99/62513 WO 9962513PCTIUS99/12095 J, BIV-1-1 Fj NaH/DMF 0 4",N BIV-2-1 IDiethyl oxalate NaOEt
THF
BIV-3-1 1M NaGH
THF
63 WO 99/62513 WO 9962513PCTIUS99/1 2095
OH
N\ 0
N
F BIV-4-1 Scheme BY 0 Br
N
H C I BIV-1 -1 NaH
DMF
64 WO 99/62513PCIS9125 PCT/US99/12095 0
N
'T B-1-1C Diethyl oxalate NaQEt
THF
BV-2-1 Diethyl oxalate NaOEt
THF
BV-3-1 BV-5-1 1M NaOH MeOH 1M NaOH MeOH 65 WO 99/62513 WO 9962513PCTIUS99/12095 yn
OH
0 BV-6- 1 BV-4- 1 Scheme Ci
N
tCN
H
4-F-benzylbromid, TEA!
DMF
CIL1i 1) nBuLi/THF/-78oC 2) 002 66 WO 99/62513 WO 9962513PCTIUS99/12095 N. CI-2-1
IEDC/HOBT/TEA/DM~F
IN OCH3 N
CH
3 0 CI-3-1 C H 3 Li/TH F/-78 0
C
CI-4-1 diethyloxalate NaOEt/THF 67 WO 99/62513 WO 9962513PCTIUS99/1 2095 0 0 CI-5-1 1N NaOH
CH
3
OHFFHF
C1-6-1 Scheme Cli N 00 2
H
N
H
4-F-benzylbromidi
CS
2 00 3 I DMF 68 WO 99/62513 WO 9962513PCTIUS99/1 2095 0
N
'd CI-1 -1
SCH
3 LiITH F -780C F Nx
H
011-1 -lb 0 N-
H
3
N
CII-2-1 diethyloxalate NaOEt/THF
CO
2 Et CII-3-1 1iN NaOH
CH
3 0HiTHF 69 WO 99/62513 WO 9962513PCTIUS99/1 2095 C0 2
H
CII-4-1 Scheme DI
,OH
MeLi Et 2
O
ref lux
OCH
3 DI-1-1 4-f Iuorobenzyl bromidt NaH
DMF
WO 99/62513 WO 9962513PCTIUS99/12095 DI-2-1 dimethyi oxalate NaH
DME
heat 0 r OCH 3 0 0 DI-3-1 NaOH THF /Me0H
/H
2 0
OH
0 0 DI-4-1 -71 WO 99/62513 WO 9962513PCT/US99/1 2095 Scheme DII Br INaH
DMF
0 DII-1 -1 Diethyl oxalate NaOEt
THF
72 WO 99/62513 PCT/US99/12095 SDII-2-1
F
1M LiOH
THF
O
0 OH F\ o I0
N
F DII-3-1 The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, 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, -73- WO 99/62513 PCT/US99/12095 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 prodrug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, Nbenzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g.
acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles.
The terms "administration of' and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
-74- WO 99/62513 PCT/US99/12095 Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
WO 99/62513 PCT/US99/12095 The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterallyacceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 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 for the symptomatic adjustment of the dosage to the patient to be treated.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS -76- WO 99/62513 PCTIUS99/12095 antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
ANTIVIRALS
Drug Name 097 Amprenivir 141 W94 GW 141 Abacavir (1592U89) GW 1592 Acemannan Acyclovir AD-439 AD-519 Adefovir dipivoxil AL-721 Alpha Interferon Manufacturer Hoechst/Bayer Glaxo Wellcome Glaxo Wellcome Carrington Labs (Irving,
TX)
Burroughs Wellcome Tanox Biosystems Tanox Biosystems Gilead Sciences Ethigen (Los Angeles, CA) Glaxo Wellcome Indication HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase
(RT)
inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (RT inhibitor)
ARC
HIV infection,
AIDS,
ARC, in combination with
AZT
HIV infection,
AIDS,
ARC
HIV infection,
AIDS,
ARC
HIV infection ARC, PGL HIV positive, AIDS Kaposi's sarcoma, HIV in combination w/Retrovir -77- WO 99/62513 PCT/US99/12095 Ansamycin LM 427 Antibody which neutralizes pH labile alpha aberrant Interferon AR177 beta-fluoro-ddA BMS-232623 (CGP-73547) BMS-234475 (CGP-61755) CI-1012 Cidofovir Curdlan sulfate Cytomegalovirus immune globin Cytovene Ganciclovir Delaviridine Dextran Sulfate Adria Laboratories ARC (Dublin, OH) Erbamont (Stamford, CT) Advanced Biotherapy AIDS, ARC Concepts (Rockville, MD) Aronex Pharm Nat'l Cancer Institute Bristol-Myers Squibb/ Novartis Bristol-Myers Squibb/ Novartis Warner-Lambert Gilead Science AJI Pharma USA MedImmune Syntex Pharmacia-Upjohn Ueno Fine Chem.
Ind. Ltd. (Osaka, Japan) HIV infection,
AIDS,
ARC
AIDS-associated diseases HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV-1 infection CMV retinitis, herpes, papillomavirus HIV infection CMV retinitis sight threatening
CMV
peripheral CMV retinitis HIV infection, AIDS, ARC (RT inhibitor) AIDS, ARC, HIV positive asymptomatic -78- WO 99/62513 PCT/US99/12095 ddC Dideoxycytidine ddl Dideoxyinosine DMP-450 Efavirenz (DMP 266) 6-Chloro-4(S)cyclopropylethynyl- 4(S)-trifluoromethyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one)
STOCRIN,
Famciclovir
FTC
GS 840 HBY097 Hoffman-La Roche Bristol-Myers Squibb
AVID
(Camden, NJ) DuPont Merck Elan Corp, PLC (Gainesville,
GA)
Smith Kline Emory University Gilead Hoechst Marion Roussel HIV infection,
AIDS,
ARC
HIV infection,
AIDS,
ARC; combination with AZT/d4T HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (non-nucleoside
RT
inhibitor) HIV infection herpes zoster, herpes simplex HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) -79- WO 99/62513 PCT/US99/12095 Hypericin Recombinant Human Interferon Beta Interferon alfa-n3 Indinavir ISIS 2922 KNI-272 Lamivudine, 3TC Lobucavir Nelfinavir Nevirapine Novapren Peptide T Octapeptide Sequence Trisodium Phosphonoformate VIMRx Pharm.
Triton Biosciences (Almeda,
CA)
Interferon Sciences Merck ISIS Pharmaceuticals Nat'1 Cancer Institute Glaxo Wellcome Bristol-Myers Squibb Agouron Pharmaceuticals Boeheringer Ingleheim Novaferon Labs, Inc.
(Akron, OH) Peninsula Labs (Belmont,
CA)
Astra Pharm.
Products, Inc HIV infection,
AIDS,
ARC
AIDS, Kaposi's sarcoma, ARC ARC, AIDS HIV infection,
AIDS,
ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC CMV retinitis HIV-assoc.
diseases HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT CMV infection HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (RT inhibitor) HIV inhibitor
AIDS
CMV retinitis, HIV infection, other CMV infections 80 WO 99/62513 PCT/US99/12095 PNU-140690 Probucol RBC-CD4 Ritonavir Saquinavir Stavudine; d4T Didehydrodeoxythymidine Valaciclovir Virazole Ribavirin VX-478 Zalcitabine Zidovudine; AZT Pharmacia Upjohn Vyrex Sheffield Med.
Tech (Houston TX) Abbott Hoffmann- LaRoche Bristol-Myers Squibb Glaxo Wellcome Viratek/ICN (Costa Mesa, CA) Vertex Hoffmann-La Roche Glaxo Wellcome HIV infection, AIDS, ARC (protease inhibitor) HIV infection,
AIDS
HIV infection, AIDS, ARC HIV infection, AIDS, ARC (protease inhibitor) HIV infection, AIDS, ARC (protease inhibitor) HIV infection,
AIDS,
ARC
genital HSV CMV infections asymptomatic HIV positive, LAS, ARC HIV infection,
AIDS,
ARC
HIV infection,
AIDS,
ARC, with AZT HIV infection,
AIDS,
ARC, Kaposi's sarcoma, in combination with other therapies
IMMUNO-MODULATORS
Drug Name AS-101 Manufacturer Wyeth-Ayerst Indication
AIDS
-81 WO 99/62513 PCT/US99/12095 Bropirimine Acemannan CL246,738 FP-21399 Gamma Interferon Granulocyte Macrophage Colony Stimulating Factor Granulocyte Macrophage Colony Stimulating Factor Granulocyte Macrophage Colony Stimulating Factor HIV Core Particle Immunostimulant IL-2 Interleukin-2 IL-2 Interleukin-2 IL-2 Interleukin-2 (aldeslukin) Pharmacia Upjohn Carrington Labs, Inc.
(Irving, TX) American Cyanamid Lederle Labs Elan Corp, PLC (Gainesville, GA) Fuki ImmunoPharm Genentech Genetics Institute Sandoz Hoeschst-Roussel Immunex Schering-Plough Rorer Cetus Hoffman-La Roche Immunex Chiron advanced AIDS AIDS, ARC AIDS, Kaposi's sarcoma HIV infection blocks HIV fusion with CD4+ cells ARC, in combination w/TNF (tumor necrosis factor)
AIDS
AIDS
AIDS, combination w/AZT seropositive HIV AIDS, in combination w/AZT AIDS, ARC, HIV, in combination w/AZT AIDS, increase in CD4 cell counts -82- WO 99/62513 PCT/US99/12095 Immune Globulin Intravenous (human) IMREG-1 IMREG-2 Imuthiol Diethyl Dithio Carbamate Alpha-2 Interferon Methionine- Enkephalin
MTP-PE
Muramyl-Tripeptide Granulocyte Colony Stimulating Factor Remune rCD4 Recombinant Soluble Human CD4 rCD4-IgG hybrids Recombinant Soluble Human CD4 Interferon Alfa 2a SK&F106528 Soluble T4 Cutter Biological (Berkeley,
CA)
Imreg (New Orleans, LA) Imreg (New Orleans, LA) Merieux Institute Schering Plough TNI Pharmaceutical (Chicago, IL) Ciba-Geigy Corp.
Amgen Immune Response Corp.
Genentech Biogen Hoffman-La Roche Smith Kline pediatric AIDS, in combination w/AZT AIDS, Kaposi's sarcoma, ARC, PGL AIDS, Kaposi's sarcoma, ARC, PGL AIDS, ARC Kaposi's sarcoma w/AZT, AIDS AIDS, ARC Kaposi's sarcoma AIDS, in combination w/AZT immunotherapeutic AIDS, ARC AIDS, ARC AIDS, ARC Kaposi's sarcoma AIDS, ARC, in combination w/AZT HIV infection -83- WO 99/62513 WO 9962513PCT/US99/1 2095 Thymopentin Tumor Necrosis Factor; TNF Immunobiology Research Institute (Annandale,
NJ)
Genentech HTV infection ARC, in combination w/gamma Interferon Druff Name Clindamycin with Primaquine Fluconazole Pastille Nystatin Pastille Ornidyl Eflornithine Pentamidine Isethionate (IM IV) Trimethoprim, Trimethoprimisulfa Piritrexim Pentamidine isethionate for inhalation Spiramycin Intraconazole- 12 11 Trimetrexate
ANTI-INFECTVES
Manufacturer Pharmacia Upjohn Pfizer Squibb Corp.
Merrell Dow Indication
PCP
cryptococcal meningitis, candidiasis prevention of oral candidiasis
PCP
LyphoMed (Rosemont,
IL)
Burroughs Wellcome Fisons Corporation Rhone-Poulenc Janssen Pharm.
Warner-Lambert PCP treatment antibacterial antibacterial PCP treatment PCP prophylaxis cryptosporidjal diarrhea histoplasmosis; cryptococcal meningitis
PCP
84 WO 99/62513 PCT/US99/12095
OTHER
Drug Name Daunorubicin Recombinant Human Erythropoietin Recombinant Human Growth Hormone Megestrol Acetate Testosterone Total Enteral Nutrition Manufacturer NeXstar, Sequus Ortho Pharm. Corp.
Serono Bristol-Myers Squibb Alza, Smith Kline Norwich Eaton Pharmaceuticals Indication Karposi's sarcoma severe anemia assoc. with AZT therapy AIDS-related wasting, cachexia treatment of anorexia assoc.
w/AIDS AIDS-related wasting diarrhea and malabsorption related to AIDS It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- 4 -(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non- WO 99/62513 PCT/US99/12095 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 include those with the following indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (1-(4-(3-pyridyl-methyl)- 2 (S)-N'-(t-butylcarboxamido)-piperazinyl))pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
Indinavir is generally administered at a dosage of 800 mg three times a day.
The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed.
Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the ocmpounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variatioons of the conditions and processes of the following -86- WO 99/62513 PCT/US99/12095 preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: Ac represents acetyl; ACN is acetonitrile; Bn represents benzyl; DME is dimethoxy ethane; DMF is dimethyl formamide; DMSO is dimethyl sulfoxide; EDC represents 1-(3dimethylaminopropyl-3-ethyl carbodiimide; Et represents ethyl; HOBT represents 1-hydroxybenzotriazole; LiHMDS represents IPA is isopropyl alcohol; Me represents methyl; sat. is saturated; THF is tetrahydrofuran; TLC is thin layer (SiO 2 chromatography.
EXAMPLE 1 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1 Step 1: 1-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone AI-1-1
CH
3 0 F AI-1-1 A solution of 2-acetyl pyrrole (1.09g, 0.01 mole) in 20 mL of DMF was treated with sodium hydride (0.48g 60 dispersion in oil, 0.012 mole) followed by 4-fluorobenzyl bromide (1.73g, 0.012 mole) and stirred overnight at room temperature. The solution was poured into 300 mL saturated NaHCO3 and extracted with EtOAc three times, the combined organic layers were washed with NaHCO3 and dried over MgSO4, filtered and evaporated to give a clear yellow oil that was taken on to the next step without further purification. Rf=0.58 (20% EtOAc/Hexanes).
1H NMR (400 MHz, CDC13) d 7.1 2H), 7.0 3H), 6.9 1H), 6.2 (m, 1H), 5.52 2H), 2.4 3H).
Step 2: 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AI-2-1 -87- WO 99/62513 PCT/US99/12095 N OCH 3
OO
F AI-2-1 A solution of l-[1-(4-fluorobenzyl)- 1H -pyrrol-2-yl]ethanone (AI-1-1) (2.17g, 0.01 mole) in DME (20 mL) was treated with sodium hydride (0.48g, 60% dispersion in oil) followed by dimethyl oxalate (1.42g, 0.012 mole) and a drop of methanol and the solution was warmed to reflux overnight. The reaction mixture was poured into 300 mL saturated NaHCO3 and extracted with EtOAc three times, the combined organic layers were washed with NaHCO3 and dried over MgSO4, filtered and evaporated. The residue was crystallized with diethyl ether to give AI-2- 1 as yellow -orange crystals. Rf=0.39 (97:3:1 CHC13 MeOH HOAc). 1H NMR (400 MHz, CDC13) 6 7.15, (dd, J 1.65, 4.21 Hz, 1H), 7.10 2H), 3H), 6.84 1H), 6.28 (dd, J 2.57, 4.11 Hz, 1H), 5.6 2H), 3.9 (s, 3H).
Step 3: 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1
OH
N O H 0 0 F AI-3-1 A solution of Al-1-2 (1.35g, 0.0045 mole) was dissolved in 1:1 THF MeOH mL) and treated with 1 N NaOH (22.5 mL, 0.0225 mole) and stirred overnight. 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, 88 WO 99/62513 PCT/US99/12095 filtered and evaporated to dryness. The residue was crystallized from CHC1 3 to give AI-3-1 as bright orange-yellow crystals. mp 172 0
C
decomposed (uncorrected). TLC Rf=0.37 (94:6:6 CHC13 MeOH HOAc).
1H NMR (400 MHz, CDC13) 5 7.2 (dd,J 1.65, 4.21 Hz,1H), 7.09 3H), 7.0 2H), 6.86 1H), 6.3 (dd, J 2.56, 4.21 Hz, 1H), 5.58 2H). mass spec (FAB, m+1) 290.08 EXAMPLE 2 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-9 Step 1: 1-[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]ethanone AI-1-3 N -Y
H
3 C AI-1-3 To a solution of 2-acetyl pyrrole (1.09g, 10 mmole) in acetone (5 mL) was added 10 N NaOH(aq) (1 mL) and 4-methylbenzyl bromide (1.85g, mmole). The reaction was stirred at ambient temperature for 12 hours, then the mixture was diluted with Et20, washed with water, dried with MgSO4, and the solvent evaporated. The residue was purified by preparative silica HPLC using 20% EtOAc/Hex to afford the product as a thick clear oil that solidified upon standing. melting point 52-53°C (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.11 J=7.8 Hz, 2H), 7.04 J=7.72 Hz, 2H), 7.01 1H), 6.18 5.55 2H), 2.42 3H), 2.32 3H). mass spec (EI, m/z) 213 105.
Step 2: 4-[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-2 -89- WO 99/62513 PCT/US99/12095 N OCH 2
CH
3 0 O
H
3 C AI-2-2 To a solution of AI-1-3 (639mg, 3 mmole) and diethyl oxalate (0.814 mL, 6 mmole) in THF (3 mL) was added in portions NaOEt (408mg, 6 mmole).
The reaction was stirred at ambient temperature under a N2 atmosphere for 1.5 hours. The reaction was poured into hexanes mL) and the yellow precipitate was filtered and dried under vacuum.
The crude solid was triturated with 1M HC1 (50 mL), filtered, and dried under vacuum. The product was further purified by crystallization from EtOAc Hexanes Et20 to obtain the product as a yellow powder.
melting point 94-97°C (uncorrected). 1H NMR (400 MHz, CDCl3) 8 7.15 1H), 7.12 J=8.04 Hz, 2H), 7.03 J=8.08 Hz, 2H), 7.01 1H), 6.85 1H), 6.26 (dd, J=2.48, 4.08Hz, 1H), 5.61 2H), 4.37 J=7.12 Hz, 2H), 2.33 3H), 1.40 J=7.12 Hz, 3H). mass spec (EI, m/z) 331 105.
Step 3: 4 -[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid N OH 00o AI-3-9 H 3 C AI-3-9 A solution of AI-2-2 (240mg, 1mmol) in 1,4-dioxane (3 mL) and 3N HCI (3 mL) was heated in a sealed tube at 70°C overnight. The reaction was then allowed to cool to ambient temperature and poured into 1H HC1 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 hexanes to afford AI-3-9 as a yellow solid, melting point 179-181'C (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 1H), 7.41 J=4.28 Hz, 1H), 7.10(d, J=7.68 Hz, 2H), 6.98 (d, WO 99/62513 WO 9962513PCTIUS99/12095 J=7.68 Hz, 2H), 6.83 1H), 6.30 (dd, J=2.5, 4.1 Hz, 1H), 5.58 2H), 2.24 3H).
mass spec (FAB, rn-i1) 286 EXAMPLE 3 4 4 -fluorobenzyl)--H-pyolb2yl].2,4-dijoxobutyri acid ethyl ester Al- 2-3 Step 1: 14-[ -4-fluorobenzyl )-4-iodo- 11 -pyrrol-2-ylilethanone Al. 1-2 I OH 3
IN\
0 Al-1-2 A solution of i-[1-(4-fluorobenzyl)-I11 -pyrrol-2-yllethanone (Al-i-i) (3g, 13.8 mmole) in acetone (75 mL) was cooled to -78'C and treated with Niodosuccinimide (3.73g, 16.6 mmole). The reaction was slowly warmed and stirred for four days, then evaporated and the residue redissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and evaporated. Silica gel chromatography in 13:87 EtOAc/Hexane gave the title compound as a white crystalline solid.
Rf 0.62 (20% EtOAc Hexanes). IR NMR (400 MHz, CDCl3) 5 7.15 (in, 2H), 7.08 (mn, 1H1), 7.0 (in, 2H), 6.93 (mn, 1H), 5.5 2H), 2.4 3H).
Step 2: 4-II-(4-fluorobenzyl)- l-H-pyrrol- 2 -yl].2,4-dioxobutyric acid ethyl ester AI-2-3 N 1-rOCH 2
CH
3 0 0 FAl-2-3 -91 WO 99/62513 PCT/US99/12095 AI-2-3 was synthesized from AI-1-2 in a manner similar to that described for AI-2-2 to afford the product as a yellow solid, melting point 87-90°C (uncorrected). 1H NMR (400 MHz, CDC13) 6 7.15 (dd, J=1.6, 4.16 Hz, 1H), 7.09 2H), 7.01-6.96 3H), 6.83 1H), 6.27 (dd, J=2.52, 4.20 Hz, 1H), 5.60 2H), 4.36 J=7.16 Hz, 2H), 1.38 J=7.16 Hz, 3H).
mass spec (EI, m/z) 317 109.
EXAMPLE 4 4-[l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester AI-2-4 0 0 F Al-2-4 To a solution of AI-2-3 (317mg, 1 mmole) in 2-propanol (anhydrous, mL) was added p-toluenesulfonic acid (19mg, 0.1 mmole) and the mixture was set to reflux for 72 hours. The reaction mixture was then allowed to cool to ambient temperature, diluted with Et20, washed with a solution of saturated NaHCO3, the organic layer separated and dried with MgSO4, the solvent evaporated and the crude was purified by preparative silica HPLC eluting with 30% EtOAc hexanes to afford the product as yellow solid, melting point 87-88 0 C (uncorrected). 1H NMR (400 MHz, CDC13) 6 7.15-7.08 3H), 7.00-6.95 3H), 6.80 1H), 6.27 (dd, J=2.52, 4.10 Hz, 1H), 5.60 2H), 5.19 1H), 1.36 J=6.24 Hz, 6H). mass spec (FAB, m+1) 332 EXAMPLE 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester -92- WO 99/62513 PCT/US99/12095 N O(C H 2 3
CH
3 O O F was synthesized from AI-2-3 by refluxing for 24 hours in nbutanol in a manner similar to that described for the synthesis of AI-2-4 to afford the product as a yellow solid, melting point 64-65 C (uncorrected). 1H NMR (400 MHz, CDC13) 6 7.14-7.08 3H), 7.00-6.95 3H), 6.81 1H), 6.26 (dd, J=2.52, 4.12 Hz, 1H), 5.59 2H), 4.29 (t, J=6.76 Hz, 2H), 1.72 2H), 1.42 2H), 0.96 J=7.52 Hz, 3H). mass spec (FAB, m+1) 346 EXAMPLE 6 4-(1-benzyl- 1H-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-2 N OH AI-3-2 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with benzyl bromide and carried through the sequence to yield AI-3-2. mp 150-151 0 C (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.55 1H), 7.41 1H), 7.25 3H), 7.06 2H), 6.82 1H), 6.3 1H), 5.63 2H).
EXAMPLE 7 -93- WO 99/62513 WO 9962513PCT/US99/1 2095 1-naphthalen-2-ylmethy- lH-pyrrol-2-yl)-2,4-dioxobutynic acid Al-3-3 0 N OH 0 0 Al-3-3 In a manner similar to that described for AL-3-1, 2-acetyl pyrrole was treated with 2-bromomethylnapthylene and carried through the sequence to yield mp 160-162TC (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.82 (in, 3H), 7.6 1H), 7.45 (mn, 4H), 7.3 (mn, 1H), 6.83 (s, 1H), 6.88 (in, 1H), 5.8 2H).
EXAMPLE 8 1-biphenyl-4-ylinethyl- 1H-pyrrol -2-yl ,4-dioxobutyric acid A-1-3-4 0 N OH 0 0 AI-3-4 In a manner similar to that described for ALI-1, 2-acetyl pyrrole was treated with 4-phenyl benzyl bromide and carried through the sequence to yieldA-3-4. mp 189-191TC (uncorrected). 1H NMR (300 MHz, DMSO) 5 7.75 (mn, 5H), 7.58 (mn, 3H), 7.48 (mn, 1H), 7.3 (mn, 2H), 7.0 1H), 6.45 (in, 1H), 5.8 2H).
EXAMPLE 9 94 WO 99/62513 WO 9962513PCTIUS99/1 2095 1-naphthalen- 1-ylmethyl- 1H-pyrrol -2-yl )-2,4-dioxobutyric acid 0 N OH In a manner similar to that described for AL-3-, 2-acetyl pyrrole was treated with 1-bromomethyl napthalene and carried through the sequence to yield.AI1-3-5. mp 172-174'C (uncorrected). 1H NiVR (300 MV~Hz, DMSO) 5 8.1 (in, 1H), 8.0 (in, 1H), 7.83 (in, 1H), 7.6 (mn, 3H), 7.4 (in, 2H), 6.9 1H), 6.5 (in, 1H), 6.4 (mn, 1H), 6.18 (s 2H).
EXAMPLE 2+4dioxo-4-[1-(4-phenylbutyl). 1H-pyrrol -2-yl]-butyric acid AI-3-6 0 N OH Al-3-6 In a manmer similar to that described for AI1-3-1, 2-acetyl pyrrole was treated with 4-phenyl butyl chloride and carried through the sequence to yield _AI-3-6. mp 119-121TC (uncorrected). 1H NMVR (300 MHz, DMSO) 8 7.38 1H), 7.36 (mn, 1H), 7.23 (mn, 2H), 7.18 (mn, 3H), 6.82 1H), 6.22 (in, 1H), 4.38 (mn, 2H), 2.55 (mn, 2H), 1.7 (in, 2H), 1.5 (in, 2H).
EXAMPLE 11 l-(4-chlorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid AJ-3-7 0 N OH 0 0 C I AI-3-7 95 WO 99/62513 WO 9962513PCTJUS99/1 2095 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 4-chlorobenzyl bromide and carried through the sequence to Yield AJ-3-7. mp 182-184'C (uncorrected). 111 NMR (300 AMz, DMSO) 8 7.55 11H), 7.42 (in, 1H), 7.4 (in, 2H), 7.1 (in, 2H), 6.82 1H), 6.35 (mn, 1H), 5.6 2H), EXAMPLE 12 2,4-dioxo-4-( 1-phenethyl- 1H-pyrrol -2-yl)-butyric acid AI-3-8 0 N OH 0 0 AI-3-8 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 2-phenyl 1-bromoethane and carried through the sequence to yield A-3-8. mp 168-170'C (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.35 (mn, 1H), 7.2 (in, 6H), 6.85 1H), 6.18 (mn, 1H), 4.6 (mn, 2H), 3.0 (in, 2H) EXAMPLE 13 4-I -(2-methylbenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3- 0 N
OH
0N 0
CH
3 AI-3-10 AJ-3-10 was synthesized from 2-acetyl pyrrole and 2-methylbenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 176-178TC (uncorrected). 1H NAM (400 AMz, DMSO) 8 7.48 (dd, J=1.52, 4.2 Hz, 1H), 7.36 (dd, J=1.96 Hz, 1H), 7.21 (d J=6.92 Hz, 1H), 7.15 (dd, J=7.4, 7.4 Hz, 96 WO 99/62513 WO 9962513PCTIUS99/1 2095 1H), 7.07 (dd, J=7.4, 7.4 Hz, 6.88 1H), 6.37 (dd, J=2.44, 4.0 Hz, 1H), 6.31, J=7.32 Hz, 1H), 5.64 2H), 2.31 3H). mass spec (FAB, m+1) 286.
EXAMPLE 14 1-(3 ,4-difluorobenzyl)-.l-H-pyrrol-2-yl]-2,4-dioxobutyric acid AM-3- 11 N
OH
F 0 0 F Al-3-11I AI-3-11 was synthesized from 2-acetyl pyrrole and 3,4-difluorobenzyl bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid, melting point 145-148*C (uncorrected) 1H NMR (400 MHz, DMSO) 5 7.56 J=2.2 Hz, 1H), 7.44 (dd, J=1.4, 4.12 Hz, 1H), 7.39 (dd, J=8.6, 19.4 Hz, 1H), 7.19 (ddd, J=2.12, 7.72, 9.96 Hz, 1H), 6.92 (in, 1H), 6.86 1H), 6.35 (dd, J=2.48, 4.12 Hz, 1H), 5.61 2H).
mass spec (FAB, m+1) 308 EXAMPLE 4-[l1-(4-bromobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid AJ-3- 12 N OH 0 0 B r AJ-3-12 AJ-3-12 was synthesized from 2-acetyl pyrrole and 4-bromobenzyl bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid. melting point 184-185TC (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.54 J=1.68 Hz, 1H), 7.52 97 WO 99/62513 WO 9962513PCTIUS99/12095 J=8.4 Hz, 2H), 7.44 (dd, J=1.4, 4.12 Hz, 1H), 7.04 J=8.4 Hz, 2H), 6.65 1H), 6.34 (dd, J=2.52, 4.16 Hz, 1H), 5.61 2H). mass spec (FAiB, m+ 1) 352,350 EXAMPLE 16 4-[1-(2-bromobenzyl lH-pyrrol-2-yH-2,4-dioxobutyric acid AI-3- 13 0 N
OH
0 0 Br Al-3-13 Al-3-13 was synthesized from 2-acetyl pyrrole and 2-bromobenzyl bromide in a manner similar to that described for _A-3-9 to afford the product as a brownish-yellow solid, melting point 176-180'C (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.66 (dd, J=1.28, 7.88 Hz, 1H), 7.51 (dd, J= 1.6, 4.24 Hz, 1H), 7.47 1H), 7.28 (dd, J=6.7, 6.7 Hz, 1H), 7.21 (dd, J=7.4, 7.4 Hz, 1H), 6.88 1H), 6.40 (dd, J=2.56, 4.2 Hz, 1H), 6.28 (dd, J=1.4, 7.72 Hz, 1H), 5.68 2H).
mass spec (FAB, m+1) EXAMPLE 17 1-(3-bromobenzyl )-lI-pyrrol-2-yl]-2 ,4-dioxobutyric acid Al-3- 14 0 N
OH
Br 0 0 AI-3- 14 Al-3-14 was synthesized from 2-acetyl pyrrole and 3-bromobenzyl bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid. melting point 164-166TC (uncorrected). 1H NMR (400 M7Hz, DMSO) 5 7.54 (broad s, 1H), 7.43 (in, 98 WO 99/62513 WO 9962513PCTIUS99/1 2095 2H), 7.28-7.24 (in, 2H), 7.05 J=6.76 Hz, 1H), 6.83 1H), 6.33 (dd, J=2.56, 4.12 Hz, 1H), 5.61 2H.).
mass spec (FAB, mn-1) 352, 350.
EXAMPLE 18 4-F 1-(3-chlorobenzvl IH-DvrrolV2-yll-2,4-dioxobutyric acid AI-3- 0 N
OH
C1 0 0 AI-3- AI-3-15 was synthesized from 2-acetyl pyrrole and 3-chlorobenzvl bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid, melting point 159-161TC (uncorrected). 1H NMR (400 Mffz, DMSO) 6 7.56 J=2.2 Hz, 1H), 7.45 (dd, J= 1.48, 4.24 Hz, 1H), 7.38-7.30 (mn, 2H), 7.12 1H), 7.04 J=7.28 Hz, 1H), 6.86 1H), 6.36 (dd, J=2.48, 4.2 Hz, 1H), 5.65 2H). mass spec (FAB, m+1) 306 EXAMPLE 19 l-(3-methylbenzyl lH-pyrrol-2-yl]-2 ,4-dioxobutyric acid AI-3- 16 0 N
OH
H
3 C 0 0 AI-3-16 AJ-3-16 was synthesized from 2-acetyl pyrrole and 3-inethylbenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 140-141TC (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 J=1.92 Hz, 1H), 7.41 99 WO 99/62513 WO 9962513PCTIUS99/12095 (dd, J= 1.44, 4.12 Hz, 1H), 7.20 (dd, J=7.64, 7.64 1Hz, 1H), 7.06 J=7.6 Hz, 1H), 6.93 1H), 6.86 (in, 2H), 6.33 (dd, J=2.44, 4.12 Hz, 1H), 5.61 2H) 2.56 3H). mass spec (FAB, m±1) 286 EXAMPLE 1-(2-fluorobenzyl)- lH-pyrrol-2-yHl-2,4-dioxobutyric acid AJ-3- 17 N YOH 0 0 F AJ-3-17 Al-3-17 was synthesized from 2-acetyl pyrrole and 2-fluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 155-156'C (uncorrected). 1H NMR (400 MHz, DMSO) 8 7,47 (mn, 2H), 7.32 (dd, 5.4, 14.0, 1H), 7.22 (dd, J=10.36, 10.36 Hz, 1H), 7.12 (dd, J=8.44, 8.44Hz, 1H), 6.86 1H1), 6.68 (dd, 7.68, 7.68, 1H), 6.36 (dd, J=2.56, 4.12Hz, 1H), 5.71 (s, 2H). mass spec (FAB, m+1) 290 EXAMPLE 21 2 ,4-dioxo-4-( -hexyl- 1H-pyrro1 -2-yl)-butyric acid AI-3- 18 0 N OH AI-3-18 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated 1-bromo hexane and carried through the sequence to yield-A-3- 18.
mp 94.8'C (uncorrected). TLC Rf=O.68 (94:6: 6:6 CHC13 MeGH HOAc) 100- WO 99/62513 W099/2513PCT/US99/12095 1H NMR (400 MHz, CDCl3) 5 7.15 (dd, 1H, J=1.65 Hz, J=4.21 Hz), 7.01 6.93 1H), 6.35 (dd, 1H, J=2.56 Hz, J=4.21 Hz), 4.35 2H, J=7.33 Hz), 1.77 (mn, 2H), 1.28 (in, 6H), 0.88 3H, J=6.69 Hz) EXAMPLE 22 4- -biphenyl-2-ylinethyl- 1H-pyrroI -2-yl )-2,4-dioxobutyric acid 0 N OH 0 0 AJ-3- 19 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 1-biphenyl-2-yl bromoinethane and carried through the sequence to yield A-3-19. mp 150-152'C (uncorrected). 1H NMR (400 MHz, CDCl 3 6 7.4 (mn, 9H), 6.8 1H), 6.42 (mn, 1H), 6.3 (in, 1H), 5.6 (s, 2H).
EXAMPLE 22 2 ,4-dioxo-44 1-(4-phenoxybutyl 111 -pyrrol-2-yl]-butyric acid AI-3-20 0 N-
OH
0 OH AI-3-20 In a manner similar to that described for AI-3-, 2-acetyl pyrrole was treated with 4-phenoxy-1-butyl bromide and carried through the sequence to yield TLC Rf=0.63 (94:6:6 CHC1 3 MeOH HOAc) 1H NMR (400 MHz, CDC13) 8 7.29 (mn, 211), 7.16 (dd, J=1.65 Hz, 4.21 Hz, 1H), 7.05 (mn, 1H), 6.94 (mn, 1H), 6.93 1H), 6.87 (in, 2H), 6.25 (dd, J=2.56 Hz, 4.21 Hz 1H) 4.45 J=7.14, 2H), 3.98 J=6.22, 2H), 2.01 (mn, 2H), 1.80 (mn, 2H).
101 WO 99/62513 WO 9962513PCTIUS99/1 2095 EXAMPLE 23 4-[1-(3-fluorobenzyl )-1lH-pyrrol-2-yll-2,4-dioxobutyric acid Al-3-2 1 0 N OH 0 0 F AI-3-21 AI-3-21 was synthesized from 2-acetyl pyrrole and 3-fluorobenzyl bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid, melting point 147-149 0
C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.55 1H), 7.45 J=3.72 Hz, 1H), 7.36(dd, J=7.72, 14.4 Hz, 1H), 7.08 (ddd, J 8.48, 8.48 Hz, 1H), 6.92-6.86 (in, 3H), 6.35 (dd, J=2.48, 4.04 Hz, 1H), 5.66 2H). mass spec (FAB, m+1) 290 EXAMPLE 24 4-r 2-chlorobenzl 1H-pvrol-2-yll-2 .4-dioxobutvric acid A-3-22 0 N OH C I Al-3-22 AJ-3-22 was synthesized from 2-acetyl pyrrole and 2chlorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 179-180TC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.52-7.47 (mn, 3H), 7.30 (ddd, J=1.6, 7.44, 7.44 Hz, 1H), 7.24 (ddd,J=1.32, 7.52, 7.52 Hz, 1H), 6.88 1H), 6.40 (dd, J=2.44, 4.12 Hz, 1H), 6.35 (dd, J= 1.48, 7.68 Hz, 1H), 5.79 2H).
mass spec (FAB, m+1) 306 102 WO 99/62513 WO 9962513PCTIUS99/1 2095 EXAMPLE 4-I -(4-fluorobenzyl )-4-iodo- 1H-pyrrol-2-yl]-2 ,4-dioxo-butyric acid 0 N OH 0 0 AI-3-23 F& Al-3-23 In a manner similar to that described for AJ-3-1, Al-3-23 was prepared from AI-1-2. mass spec (FAB, m+1) 416. 1H NMR (400 MHz, D 6
-DMSO)
8 7.7 11H), 7.6 1H), 7.2 (in, 4H), 6.85 1H), 5.6 2H1).
EXAMPLE 26 4-[1-(4-methoxvbenzvl)- lH-pvrol-2-vll-2.4-dioxobutvric acid Al-3-24 N
OH
0 0 MeOjC Al-3-24 Al-3-24 was synthesized from 2-acetyl pyrrole and 4-methoxybenzyl chloride in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid, melting point 167-168TC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.50 1H), 7.38 J=3.16 Hz, 1H1), 7.09 J=8.72 Hz, 2H), 6.86 J=8.72 Hz, 2H), 6.83 1H), 6.29 (dd, J=2.56, 4.08 Hz, 1H), 5.55 2H), 3.70 3H). mass spec (FAB, mn-i1) 302 EXAMPLE 27 1-(2 ,4 ,5-trifluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid Al-3-25 103 WO 99/62513 WO 9962513PCTIUS99/1 2095 N _r OH F 0 0 F F AI-3-25 AJ-3-25 was synthesized from 2-acetyl pyrrole and 2,4,5trifluorobenzyl bromide in a manner similar to that described for Al-3-9 to afford the product as a brownish-yellow solid, melting point 154-156TC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.6 (in, 1H), 7.48 (in, 2H), 6.86 1H), 6.78 (in, 1H), 6.36 (dd, J=2.5, 4.1 Hz, 1H), 5.66 2H).
EXAMPLE 28 l-( 2 3 -difluorobenzvl)-IHvrrol2yll24-dioxobutvric acid A-3-26 0 N OH .0 0 qF F Al-3-26 Al-3-26 was synthesized from 2-acetyl pyrrole and 2,3difluorobenzyl bromide in a manner similar to that described for -AI-3-9 to afford the product as a brownish-yellow solid. melting point 154-156 0
C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.51 1H), 7.45 (mn, 1H), 7.35 (mn, 1H), 7.12 (mn, 1H), 6.86 1H), 6.48 (mn, 1H), 3.38 (dd, J=2.5, 4.1 Hz, 1H), 5.75 2H). mass spec (FAB, mn+1) 308 EXAMPLE 29 l-( 3 ,5-difluorobenzyl)-1FI-pyrrol2yl..2,4'dioxobutyric acid AI-3-26 -104- WO 99/62513 WO 9962513PCT/US99/1 2095 0 N
OH
F 0 0 F Al-3-27 Al-3-27 was synthesized from 2-acetyl pyrrole and 3 bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 166-168TC (uncorrected); IH NMR (400 MHz, DMSO) 6 7.58 1H), 7.48 (in, 1H), 7.14 (in, 1H), 6.88 1H), 6.75 (in, 2H), 6.38 (dd, J=2.5, 4.0 Hz, 1H), 5.67 (s, 2H). mass spec (FAB, m+1) 308 EXAMPLE 1-(2 ,5-difluorobenzyl lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-28 0 F N
OH
0 0 F AI-3-28 AI-3-28 was synthesized from 2-acetyl pyrrole and 2 bromide in a manner similar to that described for A-3-9 to afford the product as a brownish-yellow solid, melting point 142-146TC (uncorrected); lIE NMR (400 MHz, DMSO) 5 7.50 2H), 7.30 (in, 1H), 7.17 (in, 1H), 6.86 1H), 6.38 (in, 2H), 5.69 2H). mass spec (FAB, m+1) 308 EXAMPLE 31 1-(2,5 ,6-difluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid AI-3-29 105 WO 99/62513 WO 9962513PCTIUS99/12095 0 F N
OH
0 0
F
F AI-3-29 AI-3-29 was synthesized from 2-acetyl pyrrole and 2,3,6trifluorobenzyl bromide in a manner similar to that described 'for Al-3-9 to afford the product as a brownish-yellow solid, melting point 131-133 0
C
(uncorrected). 1H NMR (400 MHz, DM80) 8 7.50 (in, 1H), 7.40 (mn, 1H), 7.37 1H1), 7.15 (mn, 1H1), 6.84 1H), 6.29 (dd, J=2.5, 4.1 Hz. 1H), 5.77 (s, 2H). mass spec (FAB, m+1) 326.
EXAMPLES 32-45 In a manner similar to that described for AI-3-1, the following compounds were prepared: 1-(2-fluorobenzyl 1H-pyrrol-2-yl] -2,4-dioxobutyric acid N C0 2
H
0 OH CHIN Calc. 62.28, 4.18, 4.84; Fnd. 62.11, 4.3 7, 4.91. (32) l-( 4 -trifluoromethylbenzyl)- 1H-pyrrol-2-yl] -2,4-dioxobutyric acid: N C0 2
H
0 OH
F
3
C&
CHN Calc. 56.64, 3.56, 4.12; Fnd. 56.89, 3.75, 4.36. (33) 106- WO 99/62513 WO 9962513PCTIUS99/1 2095 44 1-(4-cyanobenzyl 1H-pyrrol-2-yl] -2,4-dioxobutyric acid: N C0 2
H
0 OH CHN Caic. 64.86, 4.08, 9.45; Fnd. 64.61, 4.32, 9.77. (34) 0 N OH 0 HO 3-methoxybenzyl 1H -pyrrol-2-yl] -2,4-dioxobutyric acid CHN Caic.
63.78, 5.02, 4.65; Fnd. 63.99,5.14, 4.60. N I
O
2 H 0 4y 0
OH
HO 0.20 TFA 2-hydroxy-4-[ l-(4-hydroxybenzyl)- 1H-pyrrol-2-yl] -2,4-dioxobutyric acid GuN Caic. (Cl5H13NO5 0.20 TFA) 59.65,4.29, 4.52; Fnd. 59.50, 4.31, 4.68. (36) C0 2
H
N'
0
OH
107 WO 99/62513 WO 9962513PCTIUS99/1 2095 l-cyclopentylmethyl. 1H-pyrrol-2-yl) -2,4-dioxobutyric acid CIHN Calc.
63.86, 6.51, 5.32; Fnd. 63.88, 6.27, 5.37 (37) N CO H O OH 0.35 EtOAc
F
4- 1- [3-(4-fluorophenyl )propyl]- 1H-pyrrol-2-y} -2 ,4-dioxobutyric acid CHN Cale.( C17H16N0 4 F 0.35 EtOAc) 63.47, 5.44, 4.02; 63.16, 5.12, 4.34. (38) N C0 2
H
O OH
F
4-f l-[2-(4-fluorophenyl)ethyl..lH-pyrrol-2-yl}-2,4-dioxobutyric acid CHN Cale. 63.36, 4.65, 4.62; Fnd. 63.16, 4.64, 4.50. (39)
N-
0 0H 3-phenyipropyl lH-pyrro-2-y1]-2,4-cjjoxobutyric acid CHN Calc.(C17Hl 7
NO
4 0.1 H20) 67.80, 5.76, 4.65; Fnd. 67.79, 5.67, 4.70. 108 WO 99/62513PCIS9125 PCTIUS99/12095 OHr-yICO 2
H
H
3 C 0
O
1-ethyl- 1H-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Cale. 57.41, 5.30, 6.70; End. 57.13, 5.33, 6.70. (41) N I CZ 2
H
N00
OH
F
4 -[1-3-fluoro-benzyl)- 1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN 2 FN0 4 0.35 H20) 60.95, 4.33, 4.74; End. 60.89 4.25, 4.78. (42) N N C0 2
H
IN
ci 2-chloro-benzy)- 1-H -pyrrol-2-yl]- 2 ,4-dioxobutyric acid CHN Caic.
(C15H12N0 4 C1 0.15 H20)58.41, 4.02, 4.54; Fnd. 58.31, 3.94, 4.62 (43) O OH rli 00 2
H
-109- WO 99/62513 PCT/US99/12095 4 -[l-(3-benzoylaminopropyl)-1H-pyrrol-3-yl] -2,4-dioxobutyric acid CHN Calc. (C18H18N20 5 0.35 H20 0.35 TFA )57.80, 4.94, 7.21; Fnd. 57.80, 4.88, 7.35.(44) 0 N OH 0 OH
FO
3 -(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}] -2,4-dioxobutyric acid CHN Calc. 66.14, 4.23, 3.67; Fnd. 66.37, 4.32, 3.69. EXAMPLE 46 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 Step 1: cyclohexyl-pyrrol-1-yl-methanone AII-1-1
N
All-I-1 A solution of pyrrole 2 .00g, 0.0298 mole) in 30 mL THF was cooled to -78 0 C and treated with 1.0 M LiHMDS in hexanes (29.8 mL, 0.0298 mole) followed by dropwise addition of cyclopentanecarbonyl chloride (4.00 mL, 0.0298 mole). After five minutes the solution was allowed to warm to room temperature and stirred for four hours. The solution was poured into 200 mL saturated NH4Cl solution and extracted with EtOAc three times. The combined organic layers were washed with NH4Cl and dried over MgSO4, filtered and evaporated to give a crude brown oil. Flash chromatography on silica gel of the crude -110- WO 99/62513 PCT/US99/12095 product, using a 2.5:97.5 EtOAc Hexane mixture as the eluting solvent, gave AII-I-1 as white crystals. TLC Rf=0.62 (5:95 EtOAc /Hexanes) 1H NMR (400 MHz, CDC13) 5 7.32 2H), 6.29 2H), 2.92 1H), 1.85- 1.97 4H), 1.56-1.76 3H), 1.24-1.43 3H).
Step 2: 1-cyclohexylmethyl-l-H -pyrrole AII-2-1 0
N
AIl-2-1 A solution of AII-1-1 (3.45 g, 0.0195 mole) in 60 mL THF was treated with 1.0 M BH3-Me2S (58.5 mL, 0.0585 mole) and warmed to reflux for three hours. The solution was cooled to 0°C, slowly poured into 300 mL ice cold water and extracted with CH2C12 three times. The combined organic layers were washed with water, dried over MgSO4, and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc Hexane mixture as the eluting solvent, gave AII-2-1 as a light yellow oil. TLC Rf=0.71 (5:95 EtOAc Hexanes) 1H NMR (400 MHz, CDC13) 8 6.60 J=2.01 Hz, 2H), 6.12 J=2.01 Hz, 2H), 3.67 2H), 1.58-1.72 6H), 1.15-1.22 (m, 3H), 0.92 2H).
Step 3: 1-(1-cyclohexylmethyl-l-H -pyrrol-2-yl)-ethanone AII-3-1
N
AII-3-1 A solution of AII-2-1 (1.32g, 0.0081 mole) in 20 mL THF was cooled to -78 0 C and treated with 2.5 M n -butyllithium (16.2 mL, 0.0405 -111- WO 99/62513 PCT/US99/12095 mole) over five minutes and stirred overnight at room temperature under argon. The solution was then treated with N -methoxy-N methylacetamide (4.18g, 0.0405 mole) and stirred three hours. The solution was poured into 200 mL saturated NH4C1 solution and extracted with Et20 three times. The combined organic layers were washed with NH4C1 and dried over MgS04, filtered and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc Hexane mixture as the eluting solvent, gave AII-3-1 as a yellow oil. TLC Rf=0.49 (5:95 EtOAc /Hexanes) 1H NMR (300 MHz, CDC1 3 5 6.95 (dd, J=1.65, 4.03 Hz, 1H), 6.84 1H), 6.11 (dd, J=2.65, 4.03 Hz, 1H), 4.13 J=7.32 Hz, 2H), 2.43 3H), 1.58-1.72 (m, 6H), 1.17-1.25 3H), 0.92 2H).
Step 4: 4-(1-cyclohexylmethyl-l-H -pyrrol- 2 -yl)-2,4-dioxo-butyric acid methyl ester AII-4-1 N OCH 3 All-4-1 In a manner similar to that described for AI-2-1, AII-3-1 was treated with NaH and dimethyloxalate to give AII-4-1. TLC Rf=0.62 (2.5:97.5 MeOH CH2C12) 1H NMR (400 MHz, CDC13) 5 7.10, (dd, J 1.65, 4.21 Hz, 1H), 6.92 1H), 6.85(s, 1H), 6.19 (dd, J 2.57, 4.21 Hz, 1H), 4.19 (d, J=7.14 Hz, 2H), 1.57-1.72 6H), 1.17-1.24 3H), 0.93 2H).
Step 5: 4-(1-cyclohexylmethyl- 1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 -112- WO 99/62513 WO 9962513PCTIUS99/12095 AIl-5-1I In a manner similar to that described for Al31 AlI-4- 1 was treated with NaOH to give AIJ-5-1. TLC Rf=0.65 (94:6:6 CHC13 MeOH HOAc) 1H NMR (400 MHz, CDCl3) 5 7.15 (dd, J=1.65, 4.21 Hz, 1H), 6.96 (in, 1H), 6.93 1H), 6.22 (dd, J=2.56, 4.21 Hz, 1H), 4.18 J=7.13 Hz, 2H1), 1.57- 1.72 (in, 6H), 1.16-1.23 (mn, 3H), 0.96 (mn, 2H).
EXAMPLE 47 1-(4-fluorobenzyl )-4-phenylethynyb 1-H-pyrrol-2-yl]-2 ,4-dioxobutyric acid AIII-3-1 Step 1: 1-(4-fluorobenzyl )-4-phenylethynyl-1H-pyrrol-2.
yllethanone AIII- 1-1 K 0 A mixture of Al-1-2 (.49 g, 1.43 inmol), phenylacetylene (.218 g, .235 mals, 2.14 minol), copper(J) iodide (.022 g, .116 mmol), terkstihnlhshn)plaimO g, .086 minol) and triethylarnine (5 ml) were combined in 2 mL acetonitrile and heated to reflux for 4 hrs. After cooling, the solvent was removed in vacuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over 113- WO 99/62513 PCT/US99/12095 Na2SO 4 filtered and the solvent removed. The resulting brown oil was purified by radial disc chromatography twice, first using 2:1 hexane/ CH2C12 followed by straight ethyl acetate, then straight CH2C12 to afford the title compound. 1H NMR (400 MHz, CDC13) 5 2.42 3H), 5.52 2H), 6.99 2H, J 8.7 Hz), 7.11 7.16 4H), 7.29 7.47 3H), 7.45 7.48 2H) Step 2: [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl-2,4dioxobutyric acid ethyl ester AIII-2-1 0 NN
OE
F AIII-2-1 A solution of AIII-1-1 (.264 g, .83 mmol) in 10 mL THF was treated with diethyl oxalate (.243 g, 1.66 mmol) and sodium ethoxide (.113 g, 1.66 mmol). After stirring for 1 hr, the reaction was poured into 20 mL citric acid and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2SO 4 filtered, and the solvent removed in vacuo to give the title compound as a yellow oil.
1H NMR (400 MHz, CDC13) 8 1.36 3H, J 7.1 Hz), 4.34 2H, J 7.2 Hz), 5.55 2H), 6.80 1H), 6.99 2H, J 8.7 Hz), 7.12 7.18 2H), 7.19 1H, J 1.65 Hz), 7.25 1H, J 1.65 Hz), 7.29 7.35 3H), 7.44 7.48 2H) Step 3: [1-(4-fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl]-2,4dioxobutyric acid AIII-3-1 -114- WO 99/62513 WO 9962513PCT/1US99/1 2095 0 0 AIII-3- 1 In a similar manner to AI-3-1, AIII-2-1 (.347 g, .83 mmol) was reacted with 1.66 mL 1M LiOR in 5 mis THF to give the title compound as- a yellow resin. 1H NMR (400 MHz, CDCl3) 6 6.86 1H), 7.01 2H,. J 8.6 Hz), 7.12 7.19 (in, 2H), 7.21 1H, J 1.65 Hz), 7.28 2H, J 1.65 Hz), 7.30 7.36 (in, 4H), 7.43 7.50 (mn, 2H) FAB MS: m/z 390 H) .0 EXAMPLE 48 4-II-(4-fluorobenzyl )-4-phenethyl- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid Step 1: 1-[1-(4-fluorobenzyl )-4-phenethyl- lH-pyrrol-2-yl]ethanone AIII-4- 1 Am-4-1 AIJI-l- 1 (.15 g, .47 inmol) was dissolved in 10 ml absolute ethanol, and to it was added 10% Pd/C (.03 g, 20 The reaction vessel was purged -115- WO 99/62513 PCT/US99/12095 with hydrogen (via balloon) and allowed to stir for 6 hr. The catalyst was filtered and the solvent removed in vacuo. NMR of this crude mixture showed about 20% starting material. The product was purified by radial disc chromatography (CH2C1 2 to obtain the title compound as a resin.
1H NMR (400 MHz, CDC13) 6 2.35 3H), 2.72 2.79 2H), 2.82 2.89 2H), 5.42 2H), 6.57 1H, J 1.8 Hz), 6.79 1H, J 1.8 Hz), 6.94 2H, J 8.7 Hz), 7.00 7.07 2H), 7.12 7.30 Step 2: 4-[1-(4-fluorobenzyl)-4-phenethyl-1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester AIII-5-1 0 NN OEt
F
Am-5-1 In a similar manner to AIII-2-1, AIII-4-1 g, .31 mmol) was reacted with diethyl oxalate (.091 g, .084 ml, .62 mmol) and sodium ethoxide (.042 g, .62 mmol) in 5 mL THF to give the title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, CDC13) 6 1.37 3H, J 7.14 Hz), 2.76 1H, J 7.7 Hz), 2.86 1H, J 7.7 Hz)4.35 2H, J 7.14 Hz), 5.48 2H), 6.67 1H), 6.77 1H), 6.92 7.06 5H), 7.11 7.29 Step 3: 4-[1-(4-fluorobenzyl)-4-phenethyl- 1-pyrrol-2-yl]-2,4dioxobutyric acid AIII-6-1 -116-
L
WO 99/62513 PCT/US99/12095 N-
OH
Am-6-1 In a manner similar to AI-3-1, AIII-5-1 was reacted with .5 ml 1N NaOH in 3 mL THF for 2 hr to give the title compound as a yellow solid.
MP 135-137 oC; 1H NMR (400 MHz, CDC13) 6 2.75 2.82 1H), 2.84 2.91 1H), 5.47 2H), 6.71 1H, J 1.3 Hz), 6.86 1H), 6.95 7.08 4H), 7.11 7.16 2H), 7.17 7.23 1H), 7.24 7.32 3H) EXAMPLE 49 4-[5-(4-fluorobenzyl)- -methyl-l-H -pyrrol-2-yl]- 2 ,4-dioxobutyric acid AIV- 5-1 Step 1: 2-(4-fluorobenzyl)-1H -pyrrole AIVl-1
N
H AIV-1-1 MeMgC1 (3N in THF, 43.8 mL, 0.131 mole) was added dropwise to a solution of 50:50 THF:CH2C12 and pyrrole (9.31g, 0.139 mole) at 0 C followed by quick addition of 4-fluorobenzyl bromide and stirred at room temperature overnight. The solution was poured into 300 mL of saturated NH4C1 and extracted five times with Et20. The combined organic layers were dried over NaSO4, filtered and evaporated to give a dark brown oil that was distilled under vacuum to give analytically pure AIV-1-1. 1H NMR (400 MHz, CDC13) 6 7.77 (broad s, 1H), 7.17-7.13 (m, 2H), 7.00-6.95 2H), 6.67 1H), 6.15-6.14 1H, J=2.7 Hz), 5.97 (m, 1H), 3.94 2H).
-117- WO 99/62513 PCT/US99/12095 Step 2: 4 -fluorobenzyl)-LH -pyrrol-2-yl]ethanone AIV-2-1
F
N
CH
H
0 ATV-2-1 MeMgCl (2.95 mL, 0.0284 mole) was added dropwise to a solution of AIV- 1-1 in THF (35 mL) at 00 C. After ten minutes acetic anhydride (2.95 mL, 0.0312 mole) was added and the reaction was stirred for 1 hour. The solution was poured into saturated NH4C1 and extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give a brown oil. Silica gel chromatography using 85:15 Hexane/EtOAc gave AIV-2-1 as a light yellow powder.
TLC: Rf=0.30 (80:20 Hexanes EtOAc) 1H NMR (400 MHz, CDC13) 5 9.72 (broad s, 1H), 7.18-7.14 2H), 7.00-6.95 m, 2H), 6.85-6.83 1H), 6.01- 5.99 1H), 3.97 2H), 2.37 2H) Step 3: 4 -fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]ethanone
AIV-
3-1
F
H/C O 3 AIV-3-1 NaH (.098g, 0.00244 mole) was added to a solution of AIV-2-1 in DMF mL) at 00 C followed by subsequent addition of Mel (0.53g, 0.00244 mole).
The ice bath was removed and the reaction was stirred for one hour.
The solution was poured into NH4C1 and extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give AIV-3-1 as a brown oil. TLC: Rf=0.43 (80:20 Hexanes EtOAc) 1H NMR (400 MHz, CDC13) 5 7.11-7.07 2H), 7.01- -118- WO 99/62513 PCT/US99/12095 6.97 2H), 6.93-6.92 1H), 5.90-5.89 1H), 3.93 2H), 3.79 3H), 2.42 3H).
Step 4: 4 5 4 -fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4dioxobutyric acid methyl ester AIV-4-1
F
N OCH3 H3C O O 3 AIV-4-1 A solution of AIV-3-1 (0.222g, 0.000961 mole) in DME (10mL) was treated with sodium hydride (0.058g, 0.00144 mole) followed by dimethyl oxalate (0.113g, 0.000961 mole) and methanol (200mL) and the solution was warmed to reflux for 1.5 hours. The reaction was poured into 30 mL of 1 N HC1 and extracted three times with EtOAc. The combined organic layers were dried over NaSO 4 filtered and evaporated to give AIV-4-1 as a brown solid. TLC: Rf=0.39 (97:3:1 CH2C12 MeOH HOAc) 1H NMR (400 MHz, CDC13) 5 7.12-7.07 3H), 7.04-6.99 2H), 6.83 1H), 5.99- 5.98 1H, j=4.21), 3.97 2H), 3.915 3H), 3.85 3H).
Step 5: 4-[5-(4-fluorobenzyl)-l-methyl-l H -pyrrol-2-yl]-2,4dioxobutyric acid AIV-5-1
F
0 N OH
CH
3 0
OH
AIV-5-1 AIV-4-1 was dissolved in THF (15 mL) and 1 N NaOH (5 mL) was added. After two hours the reaction was acidified with 1 N HC1.
This mixture was extracted three times with EtOAc, dried over NaSO4, -119- WO 99/62513 WO 9962513PCTIUS99/1 2095 filtered and evaporated to give a brown solid. Prepped on HPLC using a gradient of 5:95 -95:5 CH3CN/water over 45 minutes to give AJV-5-i as a yellow solid. TLC Rf=0.52 (93:7:7 CHCl 3 MeOH /HOAc) 1H NMR (400 MHz, CDC1.) 5 7.128-7.086 (in, 3H), 7.04-6.99 2H 6.90 1H1), 6.03- 6.02 1H. j=4.39 Hz), 3.98 2H), 3.85 3H).
EXAMPLE 4 -[5-(3-chilorobenzyl)- 1-methyl-ll -pyrrol-2-yl]-2 ,4-dioxobutyric acid ATV- 5-2 0 C 1 N OH
H
3 C 0 0 AJV-5-2 In a manner similar to that described for AIV- 5- 1, pyrrole was alkylated with 3-chlorobenzyl bromide and carried through the sequence to give AJV-5-2. TLC: Rf=0.52 (93:7:7 CHCl3/ MeOH HOAc) 1H NMR (400 MHz, DMSO) 567.39-7.29 (in, 4H), 7.18-7.16 1H, j=6.7 Hz), 6.81 1H), 6.04-6.03 1H, j =4.2 Hz), 4. 10 1H), 3.82 1H).
EXAMPLE 51 4 -15-(4-fluorobenzyl)- 11 -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-3 0 0 AIV-5-3 AIFV-5-3 was prepared in a manner similar to that described for .1 with the exception that the methylation step was omitted.
-120- WO 99/62513 WO 9962513PCTIUS99/1 2095 TLC: Rf=O.28 (93:7:7 CHC1 3 MeOH HOAc) 1H NMR (400 MHz, DMSO) 6 12.19 1H),.7.32-7.28 (in, 2H) 7.17 1H), 7. 14-7.10 2H, j=8.8 Hz), 6.79 1H), 6.06-6.04 (mn, 1H) 3.97 1H).
EXAMPLE 52 4-[5-(3-chlorobenzyl 11 -pyrrol-2-yl]-2,4-dioxobutyric acid AJV-5-4 0 N OH H 0 ATV-5-4 AIV-5-4 was prepared in a manner similar to that described for .1 with the exception that the methylation step was omitted. TLC: Rf=0.44 (93:7:7 CHC13/ MeOH HOAc) 1H NMR (400 MHz, DMSO) 8 12.21 1H), 7.36-7.18 (mn, 5H), 6.80 1H), 6.10 1H), 3.99 1H).
EXAMPLE 53 4-[5-(benzyl)- 1H -pyrrol-2-yl]-2 ,4-dioxobutyric acid 0 N O H H 0 0 was prepared in a manner similar to that described for .1 with the exception that the inethylation step was omitted. TLC: Rf=0.34 (93:7:7 CHCl3/ MeOH HOAc) 1H NMR (400 MHz, IJMSO) 5 12.20 1H), 7.32-7.18 (in, 6H), 6.80 1H), 6.05 (mn, 1H), 3.98 2H).
EXAMPLE 54 4-[5-(3-fluorobenzyl)- 11 -pyrrol-2-yl] -2,4-dioxobutyric adid AJV-5-6 121 WO 99/62513 WO 9962513PCTJUS99/1 2095 0 0 AJV-5-6 AIV-5-6 was prepared in a manner similar to that described for 1 with the exception that the methylation step was omitted. TLC: Rf=0.34 (93:7:7 CHC13/ MeOH HOAc) 1H NAM (400 MHz, DMSO) 5 12.21 1H), 7.35-7.33 (dd, 1H, j=8.1 Hz, 1.6 Hz), 7.19 1H, j=2.2 Hz), 7.12-7. 2H, j=6.6 Hz), 7.04 (mn, 1H), 6.80 1H), 6.10-6.09 (dd, 1H, j=3.8 Hz, 2.1 Hz), 4.00 1H).
EXAMPLE 4-[5-(4-fluorobenzyl 1-(4-fluorobenzyl )-il -pyrrol- 2 -ylil-2,4-dioxobutyric acid AIV-5-7
F
F" ATV-5-7 AIV-5-7 was prepared in a manner similar to that described for 1 except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkylation step. TLC: Rf=0.60 (93:7:7 CHCl3/ MeOH HOAc) 1H NMR (400 MHz, CDCl 3 5 7.21-7.20 1H, j=4.2 Hz) 7.049-6.96 (mn, 6H1), 6.93 1H1), 6.90-6.86 (dd, 2H j=8.4 Hz, 5.3 Hz), 6.07-6.06 1H j=4.2 Hz), 5.60 211), 3.85 2H).
EXAMPLE 56 4 -[5-(3-chlorobenzyl l-(4-fluorobenzyl 11 -pyrrol-2-yl]-2 ,4-dioxobutyric acid AJV-5-8 122 WO 99/62513 WO 9962513PCTIUS99/1 2095 UF I N" Y} Y( -OH 0 0 FAiIV-5-8 AIV-5-8 was prepared in a manner similar to that described for 1 except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NMR (400 MHz, DMSO) 5 7.46-7.45 1H j=4.2 Hz), 7.28-7.22 (in, 2H), 7.12-7.04 (in, 4H), 6.92-6.88 (in, 2H), 6.85 1H), 6.14-6.13 1H, j=4.2 Hz), 5.69 2H), 3.99 2H). mass spec.: (FAB, m+1) 414.10 EXAMPLE 57 1-(4-fluorobenzyl 1F -pyrrol-2-yl]-2 ,4-dioxobutyric acid AJTV- 5-9 0 N OH 0 0 F" AIV-5-9 ATV-5-9 was prepared in a manner similar to that described for except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NMR (400 MHz, CDC13) 8 7.31-7.27 (mn, 2H), 7.24 (mn, 1H), 7.22-7.21 1H j=4.2 Hz), 7.08-7.06 (mn, 2H), 7.00-6.96 (in, 2H), 6.92 1H), 6.90-6.87 (in, 2H), 6. 11- 1. 10 1H, j=4.2 Hz), 5.60 2H), 3.88 2H). mass spec.: (FAB, m+ 1) 380 123 WO 99/62513 WO 9962513PCTIUS99/12095 EXAMPLE 58 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- 1H -pyrrol- 2 -yl]-2,4-dioxobutyric acid AIV-5-10 0 0 AIV-5-10 was prepared in a manner similar to that described for I~ except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NMR (400 MHz, CDCI 3 8 7.27 (in, 1H), 7.25-7.24 (mn, 1H), 7.21-7.20 1H, j=4.2 Hz), 7.01-6.95 (in, 4H), 6.93 1H), 6.89- 6.85 (mn, 2H), 6.08-6.07 1H, j=4.2 Hz), 5.59 2H), 3.84 2H). mass spec.: (FAB, mn+1) 414 EXAMPLE 59 4 -[5-(4-fluorobenzyl 1-methyl-ill -pyrrol-3-yl]-2 ,4-dioxobutyric acid A- 8-1 Step 1: 1-15-(4-fluorobenzyl).1-methyl-i H -pyrrol-3-yllethanone AIV-6- 1
-CH
3 AIV-6-1I
H
3
C
AIV-3-1 was dissolved in TFA 10 mL and was refluxed for two days.
Cooled and removed TFA under reduced pressure. Dissolved brown oil in saturated NaHCO3 and extracted three times with EtOAc, dried over NaSO4, filtered and evaporated to give AIV-6-1 as a green oily solid.
-124- WO 99/62513 WO 9962513PCT/US99/12095 TLC: Rf=0.33 (60:40 Hexanes EtOAc) 1H NMR (400 MHz, CDC1 3 7.21-7.20 1H, j=1.83 Hz), 7.12-7.09 (in, 2H), 7.01-6.96 (in, 2H), 6.33-6.22 1H, j=1.8 Hz), 3.88 2H), 3.45 2.36 3H).
Step 2: 4-15-(4-fluorobenzyl 1-methyl- 1H -pyrrol-3-yl]-2,4dioxobutyric acid AIV-8-1
L;H
3 AIV-8-1 In a manner similar to that described for ATV-5-1, AIV-6-1 was treated with NaH and dimethyl oxalate followed by hydrolysis with NaOH to give AIV-8-1. 1H NMR (400 Mz, CDC13)867.42 2H, j=1.8 Hz), 7.13-7.10 (in, 2H1), 7.04-6.99 (in, 2H), 6.72-6.71 1H, j=1.7 Hz), 6.38 1H), 3.91 (s, 2H), 3.51 3H). mass spec.: (FAB, m+1) 304.19 EXAMPLE 4-115-( 3-chlorobenzyl 1-methyl-Ill -pyrrol-3-yl]-2 ,4-dioxobutyric acid AJV- 8-2
OH
OH
3 AIV-8-2 In a manner similar to that described for ATV-8-1, pyrrole was alkylated with 3-chlorobenzyl bromide and carried through the sequence to give ATV-8-2. 1H N1\R (400 MHz, CDCl3) 6 7.43-7.42 1H, j=1.8 Hz), 125- WO 99/62513PCIS/129 PCTfUS99/12095 7.25-7.24 (in, 2H), 7.14 1H), 7.04-7.03 (in, 1H), 6.72 1H), 6.42-6.41 (d, 1H, j=l.lHz), 3.92 2H), 3.50 3H). mass spec.: (FAB, m±1) 320.2 EXAMPLE 61 4 -[5-(benzyl)-1-methyl-1-H -pyrrol- 3 -yI]-2,4-dioxobutyric acid ATV-8-3
.OH
AIV-8-3
OH
3 In a manner similar to that described for AJ-V-8- 1, pyrrole was alkylated with benzyl bromide and carried through the sequence to give AJV-8-3. 1H NV1R (400 MIHz, CDCl3) 867.43-7.42 1H, 7.34-7.30 (mn, 2H), 7.27 (mn, 1H), 2H, j=7.1 Hz), 6.72 1H), 6.41-6.40 1H, 3.94 2H), 3.50 3H). mass spec.: (FAB, m+1) 286.3 EXAMPLE 62 4 -[5-(3-fluorobenzyl 1-methyl- 1F -pyrrol-3-yl]-2 ,4-dioxobutyric acid AJTV- 8-4
OH
3 AJV-8-4 In a manner similar to that described for AIV-8- 1, pyrrole was alkylated with 3-fluorobenzyl bromide and carried through the sequence to give AJV-8-4. 1H NMR (400 MHz, CDC13) 8 7.43 1H, j=1.8 Hz), 7.32- -126- WO 99/62513 WO 9962513PCTIUS99/1 2095 7.28 (in, 1H), 6.98-6.93 (in, 2H), 6.86-6.83 1H, j=9.5 Hz), 6.72 1H), 6.43-6.42 1H, j=1.3 liz), 3.94 2H), 3.50 3H). mass spec.: (FAB, m+1) 304.2 EXAMPLE 63 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid In a manner similar to that described for AJV-8-i, with the exception that the N-alkylation step was omitted, pyrrole was alkyated with benzyl bromide and carried through the sequence to give ATIV-8-5. TLC: Rf=0.18 (93:7:7 CHC13/ MeOH HOAc) 1H NMR (400 MHz, CDCl3) 8 8.43 1H), 7.48 (dd, 1H, j=3.1 Hz, 1.8 Hz), 7.41-7. 18 (mn, 5H), 6.78 1H), 6.47 1H, j=0.7 Hz), 3.98 1H).
EXAMPLE 64 4-[2 ,5-bis-(3-chlorobenzyl)-l -H -pyrrol-3-yl]-2,4-dioxobutyric acid ATrV-8-6
.OH
ATV-8-6 In a manner similar to that described for AIV-5-1 pyrrole was alkyated with 3-chlorobenzyl bromide and the minor 2,5-his 3-chlorobenzyl alkylated product was isolated. Treatment with MeMgCl followed by acetic anyhydride as described for ATIV-2-1 gave the 3-acylated product 127 WO 99/62513 WO 9962513PCTIUS99/1 2095 that was carried through the sequence to give AIV-8-6. TLC: Rf=0.42 (93:7:7 CHCl3/ MeOH HOAc) I NMR (400 MHz, CDCl 3 5 9.10 1H), 7.26-7.21 (in, 3H), 7.08-6.97 (in, 5H), 6.90 1H, j=2.6 Hz), 6.77 1H), 3.92 2H), 3.77 2H).
EXAMPLE 1-(4-Fluorobenzyl )-5-phenyl- lH-pyrrol-2-yl]-2,4-dioxobutyic acid AV- 10-1 Step 1: S-Oxo-pyrroli dine- 2- carboxyli c acid ethyl ester AV-1-1 COQEt ~NH 0 AV-1-1 To a 2L round bottomed flask with a stirring bar was added pyroglutamic acid (50g, 387.2 inmol) and 1L of absolute ethanol. To this well stirred mixture was added thionyl chloride (10.0 mL, 137.1 mmol) dropwise over 15 minutes. The resulting mixture was stirred at ambient temperature 24h. The resulting solution was concentrated in vacuo to give a colorless oil. This material was dissolved in EtOAc and washed with aqueous NaHCO3 (2X) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave 5-oxo-pyrrolidine-2-carboxylic acid ethyl ester AV- 1-1 as an oil which crystallized on standing. 1H NMR (CDCl3) 5 1.30 (3H, t, j=7.3 Hz), 2.18 to 2.60 (4H, complex multiplet), 4.21 (3H, mn), 3.37 (1H, br s).
Step 2: 5-Oxo-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 COQEt 0 AV-2-1 128- WO 99/62513 PCT/US99/12095 To a 1L round bottomed flask with a stirring bar and an argon inlet was added gave 5-oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 (18.6g, 118.34 mmol) CHC13 (300 mL), di-tert-butyldicarbonate (30.99g, 142.01 mmol), Et3N (16.5 mL, 118.34 mmol), and 4 -dimethylaminopyridine (14.46g, 118.34 mmol). The mixture was stirred at ambient temperature 18h. The solvent was removed in vacuo and the residue was dissolved in 750 mL of EtOAc. The EtOAc solution was washed with 10% aqueous citric acid, aqueous NaHCO 3 H20, and brine. Drying (MgS0 4 filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 300g of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained 5-oxo-pyrrolidine-l,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 as an oil. 1H NMR (CDC13) 5 1.27 (3H, t, j=7.3 Hz), 1.50 (9H, 2.08 (1H, 2.45 to 2.71 (3H, complex multiplet), 4.27 (2H, q, j=7.3 Hz), 4.60 (1H, dd, j=3, 9 Hz).
Step 3: 2 acid ethyl ester AV-3-1 O Ph O N COOEt H AV-3-1 To an oven dried 500 mL, three-necked round bottomed flask with a stirring bar, argon inlet and septum was added 5-oxo-pyrrolidine-l,2dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 6 .50g, 25.25 mmol) and 100 mL of dry THF. This solution was cooled to -40°C and a solution of phenyl magnesium bromide (25.3 mL of a 1M solution in THF) was added slowly with a syringe. The mixture was aged 15m at 40°C, the cooling bath was removed and the mixture was warmed to The reaction was quenched by the addition of 150 mL of saturated aqueous NH4C1 solution. This mixture was stirred 30m. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 2-tertbutoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 which was used in the subsequent step without purification.
129- WO 99/62513 PCT/US99/12095 Step 4: 5-Phenyl-3, 4 -dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-4-1 N COOEt S/-COQEt AV-4-1 To a 500 mL round bottomed flask with a stirring bar and a nitrogen inlet was added tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 (8.09g, 22.76 mmol) and 100 mL of CH2C12. This solution was cooled in an ice bath and 100 mL of trifluoroacetic acid was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 24h. The solvents were removed in vacuo and the residue was redissolved in 300 mL of CHC13 and concentrated a second time. The resulting residue was dissolved in 100 mL of CH2C12 and this solution was cooled in an ice bath. Et3N (50 mL) was added and the mixture was stirred 3h. The solvents were removed in vacuo and the residue was dissolved in 300 mL of EtOAc. This solution was washed with H20 and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 1:4 EtOAc-hexane as eluant. 5-Phenyl-3,4-dihydro-2Hpyrrole-2-carboxylic acid ethyl ester AV-4-1 was obtained as a colorless oil. 1H NMR (CDC13) 5 1.31 (3H, t, j=7.1 Hz), 2.22 (2H, 3.00 (1H, m), 3.17 (1H, 4.23 (2H, d, 4.92 (1H, 7.41 (3H, 7.89 (2H, dd, j= 2.7, Step 5: 5-Phenyl-1H-pyrrole-2-carboxylic acid AV-5-1
N/COOH
H AV-5-1 To a 1L round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl- 3 ,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV- 4-1 (4.84g, 22.28 mmol), dry CH2C12 (220 mL) and DDQ (5.06g, 22.28 mmol). This solution was stirred at ambient temperature lh. The solvent was removed in vacuo. Aqueous NaOH (10% w/v, 440 mL) was added and the mixture was heated at reflux 24h. The cooled, black -130- WO 99/62513 PCT/US99/12095 solution was poured onto crushed ice and the mixture was acidified with cone. HC1. This mixture was extracted with EtOAc The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 2.5% MeOH in EtOAc as eluant to give 5-phenyl-1Hpyrrole-2-carboxylic acid AV-5-1 as an off white solid. 1H NMR (CDC1 3 8 6.59 (1H, dd, j=2.7, 3.9 Hz), 7.13 (1H, dd, j= 2.7, 3.9 Hz), 7.34 (1H, 7.41 (2H, 7.59 (2H, 9.40 (1H, br s).
Step 6: 5-Phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1
SOCH
3 N N'CH 3 H 0 AV-6-1 To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl-lH-pyrrole-2-carboxylic acid AV-5-1 (2.45g, 13.09 mmol), N,O-dimethylhydroxylamine hydrochloride (1.40g, 14.40 mmol), N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride (2.76g, 14.40 mmol), hydroxybenztriazole hydrate (1.94g, 14.40 mmol) and dry, degassed DMF (25 mL). This well stirred mixture was warmed gently until all of the solids dissolved. Et3N (5.6 mL, 40.00 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo at +80C. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated and the organic phase was washed with H20 (2X) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using EtOAc in hexane as eluant to give 5-phenyl-lH-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. 1H NMR (CDC13) 5 3.36 (3H, 3.80 (3H, 6.58 (1H, dd, j=2.2, 4.0 Hz), 6.94 (1H, dd, j= 2.2, Hz), 7.30 (1H, 7.41 (2H, 7.58 (2H, 9.63 (1H, br s).
Step 7: l-( 4 -Fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1 131 WO 99/62513 PCT/US99/12095 AV-7-1 To a 100 mL round bottomed flask containing 5-phenyl-lH-pyrrole-2carboxylic acid methoxymethylamide AV-6-1 (0.692g, 3.01 mmol) was added a stirring bar and an argon inlet was attached. THF (15 mL) was added and, when all of the solids had dissolved, NaH-oil suspension (0.132g of a 60% w/w suspension, 3.31 mmol) was added. This mixture was stirred 15 min at ambient temperature then 4 -fluorobenzylbromide (0.41 mL, 3.31 mmol) was added. The resulting mixture was stirred 24h at ambient temperature. The mixture was diluted with EtOAc and the solution was washed with 1N HC1, water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 25% EtOAc in hexanes a eluant to give 1-(4-fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1. 1H NMR (CDC13) 5 3.21 (3H, 3.47 (3H, 5.52 (2H, 6.24 (1H, d, j= 3.9 Hz), 6.75 to 6.90 (5H, 6.94 (1H, d, j= 3.9 Hz), 7.38 (4H, m).
Step 8: 1-[-(4-Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]ethanone AV-8-1 N
CH
3
N
I-
F AV-8-1 To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-(4-fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methylamide AV-7-1 (0.
7 26g, 2.16 mmol) and dry THF (20 mL).
This solution was cooled to -78 0 C and methyllithium (3.39 mL of a 1.4 M solution in Et20, 4.75 mmol). The mixture was stirred 30 min at -78°C 132- WO 99/62513 PCT/US99/12095 then the reaction was quenched with saturated aqueous NH4C1 solution.
The mixture was warmed to room temperature and stirred 2h. The layers were separated and the aqueous phase was extracted with EtOAc.
The combined organic fractions were dried (MgS04), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]ethanone AV-8-1 as an oil. 1H NMR (CDC1 3 5 2.42 (3H, 5.59 (2H, 6.29 (1H, d, j= 4.2 Hz), 6.78 to 6.91 (4H, 7.12 (1H, d, j= 4.2 Hz), 7.29 (2H, 7.38 (3H, m).
Step 9: 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester AV-9-1
O
N 0 CH 3 F AV-9-1 To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]ethanone AV-8-1 (0.628g, 2.14 mmol), dry THF (10 mL), diethyl oxalate (0.41 mL, 3.00 mmol) and NaOEt (0.204g, 3.00 mmol). The resulting mixture was stirred lh at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HC1, H20 (2X) and brine. Drying (MgSO4) filtration and removal of the solvent in vacuo gave 4 4 1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 as an oil. This material was used without further purification. 1H NMR (CDC13) 6 1.38 (3H, t,j=7.1 Hz), 4.38 (2H, q,j= 7.1 Hz), 5.65 (2H, 6.38 (1H, d,j= 4.1 Hz), 6.79 to 6.94 (4H, 7.29 (2H, 7.39 (3H, m).
Step 10: 4 4 -Fluorobenzyl)-5-phenyl- H-pyrrol-2-yl]-2,4dioxobutyric acid AV-10-1 133- WO 99/62513 WO 9962513PCT/US99/1 2095 Y '0H 0 0 F AV-10-1 To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 4- [l-(4-fluorobenzyl)-5-phenyl- lH-pyrrol-2-yl]-2,4-dioxobutyic acid ethyl ester AV-9-1 (0.84g, 2.14 mmol) and MeGH (72 mL). To this solution was added aqueous NaOH (11 mL of a 1N solution). The mixture was stirred at ambient temperature 18h. The organic solvents were removed in vacuo and the aqueous residue was washed with Et2O then acidified with 1N HCl. The mixture was extracted with Et2O and the Et2O extract was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude solid was recrystallized from a mixture of EtOAc and hexane to give 4 4 pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 as a white, crystalline solid.
MP: 151-152'C (dec). 1H NMR (CDCl3) 6 5.63 (2H, 6.42 (1H, d, j= 4.4 Hz), 6.80 (2H, in), 6.94 (3H, in), 7.29 (2H, in), 7.40 (2H, in).
EXAMPLE 66 4-[4-Diinethylamino- 1-(4-fluorobenzyl lH-pyrrol-2-ylJ-2 ,4-dioxobutyric acid A-VI-5-1 Step 1: 1-[Il-(4-Fluorobenzyl)-4-nitro- lH-pyrrol-2-yljethanone AVI- 1- 1 N0 2
N
0 To a 500 mL round bottomed flask with a stirring bar and a drying tube was added l-( 4 -fluorobenzyi lH-pyrrol-2-yllethanone AI-1-1 (11 .64g, -134- WO 99/62513 PCT/US99/12095 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to 78°C and concentrated nitric acid (3.7 mL of 15.9 N solution, 58.24 mmol) was added with a pipette. The cooling bath was allowed to expire and the mixture warmed to 0°C over 7h. The acetic anhydride was removed in vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHCO 3 solution (2X) and brine.
Drying (MgSO4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et20/hexane to give white crystals of 1-[l-(4-fluorobenzyl)-4-nitro- H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDC13) 2.55 (3H, 5.54 (2H, 7.06 (2H, 7.20 (2H, 7.47 (1H, d,j= 1.8 Hz), 7.63 (1H, d,j= 1.8 Hz).
Step 2: 1-[4-Amino-l-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1
NH
2 F AVI-2-1 To a 1L round bottomed flask with a stirring bar and a balloon hydrogenation adapter was added 4 -fluorobenzyl)-4-nitro- 1H-pyrrol- 2 -yl]ethanone AVI-1-1 (8.00g, 30.51 mmol) absolute EtOH (640 mL) and Pd-C (2.24g, 2.11 mmol). This mixture was hydrogenated at ambient temperature 24h. The catalyst was removed by filtration and the EtOH was removed in vacuo. The semi-solid residue was chromatographed on silica gel using EtOAc as eluant to give 1-[4-aminol-( 4 -fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 as a yellow crystalline solid. 1H NMR (CDC13) 6 2.34 (3H, 3.01 (2H, br 5.42 (2H, 6.46 (1H, d, j= 2.0 Hz), 6.50 (1H, d, j= 2.0 Hz), 6.98 (2H, 7.12 (2H, m).
135- WO 99/62513 WO 9962513PCTIUS99/12095 Step 3: l-[4-Dimethylamino- 4-fluorobenzyl)- 1H-pyrrol-2yllethanone AVI-3- 1
(CH
3 2
N
N
0 F, AVI-3-1 To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added i-IA-amino- 1-(4-fluorobenzyl lH-pyrrol-2-yllethanone AVI-2-1 (0.50g, 2.15 mmol), dry DMF (20 inL), finely powdered Cs2C03 (3.26g, 10 mmol) and Mel (0.31 mL, 5.00 mmol). The resulting mixture was stirred 1h at ambient temperature. The solids were removed by filtration and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with water (3X) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50% EtOAc-hexanes as eluant to give l-[ 4 -dimethylamino-l-(4-fluorobenzyl)..1H.pyrol.2 yl]ethanone AVI-3-1 as an oil. 1H NMR (CDCl3) 8 2.36 (3H, 2.70 (6H, 5.46 (2H, 6.36 (1H, d, j= 2.0 Hz), 6.50 (1H, d, j= 2.0 Hz), 6.98 (2H1, in), 7.11 (2H, in).
Step 4: 4-[4-Dimethylairno- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2,4dioxobutyric acid ethyl ester AVI-4-1
(CH
3 2 N 0 N 0Et 0 0 FAVJ-4- 1 In a manmer substantially similar to that described for Example AV-9- ,1-[-dimethylamino- 1-(4-fluorobenzyl)- lH-pyrrol-2-yllethanone AVI-3 -1 was used to prepare 4-[4-dimethylaniino- 1-( 4 -fluorobenzyl)- 1H-pyrrol-2- -136- WO 99/62513 PTU9/29 PCTIUS99/12095 yl]-2,4-dioxobutyric acid ethyl ester AVI-4-1 which was used in the next step without further purification.
Step 5: 4- [4-Dimethylamino- l-(4-fluorobenzyl 1H-pyrrol-2-yl]-2,4.
dioxobutyric acid AVI-5-1
(CH
3 2N N O H 0 0 F AVI-5-1 In a manner substantially similar to that described for Example AV- 10-1 4-[4-cimethylamino- 1-(4-fluorohenzyl 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid ethyl ester AVJ-4- 1 was used to prepare 4-[4dimethylamino- 1-(4-fluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid AVJ-5-1. 1H NMR (DMSO-d6-CDCl 3 1:1) 6 3.12 (6H, 5.61 (2H, 7.06 (2H, in), 7.19 (2H, in), 7.60 (1H, hr 7.68 (1H, hr s).
EXAMPLES 67-69 The following compounds was prepared in a manner similar to that described for AVI-5-1: l-( 4 -Fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl].2 ,4-dioxobutyric acid CHN Caic. (C15Hj1FN20 6 *0.8H 2 0) 51.65, 3.64, 8.03; Fnd. 51.65, 3.42, 7.88. (67)
NO
2
COOH
N
0 0 4 -[4-(Benzylamino)- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid CHN Caic. (C22H19FN204 9 0.33 CHCl 3 61.83, 4.49, 6.45; Fnd.
62.07, 4.27, 5.74. (68) 137- WO 99/62513 WO 9962513PCT/US99/12095 BnHN
COOH
N
1J 0 0 4- [5 -Nitro- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]- 2,4-dioxobutyri c acid CHN Caic. 53.90, 3.32, 8.38; Fnd. 53.77, 3.24, 8.20. (69)
COOH
EXAMPLE 1-benzyl- lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3- 1 Step 1: 1-benzyl- lH-pyrrol-3-yllethanone AVII- 1-1 0 0 H 3
N
AVII-1-1 To a solution of 3 -acetylpyrrole 545 mg, 5.00 mmol) in DMF (10 mL) at 0 'Cwas added benzyl bromide (0.60 mL, 5.05 mmol) followed by NaH (260 138 WO 99/62513 PCT/US99/12095 mg of a 60% suspension in mineral oil, 6.50 mmol). After stirring at 0 'C for 20 min and room temperature for 1 h, the reaction mixture was treated with sat. NH4C1 (10 mL) and poured onto sat. NH4CI (50 mL).
The resulting mixture was extracted with Et20 (3 x 50 mL). The combined organic extracts were washed with sat. NaCI (50 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 2:l/hexanes:EtOAc, afforded the product as a clear oil. 1H NMR (400 MHz, CDC13) 7.35-7.29 4H), 7.13-7.27 2H), 6.66-6.61 2H), 5.07 2H), 2.38 3H).
mass spec (EI, 199 Step 2: 4-[l-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester AVII-2-1
O
OCH
3 0
N
AVII-2-1 To a solution of AVII-1-1 (900 mg, 4.52 mmol) in THF (10 mL) was added dimethyl oxalate (795 mg, 6.74 mmol) followed by NaH (270 mg of a suspension in mineral oil, 6.76 mmol). Methanol (2 drops) was added and the reaction mixture was heated to reflux. After 1 h, 1 N HC1 mL) was added and the mixture extracted with CH2C12 (3 x 20 mL). The combined organic extracts were washed with sat. NaCI (20 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 5:5:1/CH2C12:hexanes:EtOAc, afforded the product as a yellow solid.
1H NMR (400 MHz, CDC13) 5 7.44 1H), 7.40-7.32 3H), 7.19-7.15 (m, 2H), 6.72-6.68 3H), 5.09 2H), 3.91 3H).
Step 3: 4-[1-benzyl-lH-pyrrol-3-yl]-2, 4 -dioxobutyric acid AVII-3-1 139- WO 99/62513 PCTIUS99/12095
OH
N
AVII-3-1 To a solution of AVII-2-1 (450 mg, 1.58 mmol) in THF (3.2 mL) was added 1 N NaOH (2.4 mL). After stirring 14 h at room temperature, the mixture was poured onto 1 N NaOH (10 mL) and extracted with Et20 (5 x 10 mL). The Et20 extracts were discarded. The aqueous phase was treated with 3 N HC1 (20 mL), extracted with CH2C12 (3 x 20 mL) and the combined organic extracts dried (MgSO4). Concentration provided a yellow solid which was recrystallized from benzene to afford the desired product as a light yellow solid. mp 151-152 °C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 8.04 J 1.6 Hz, 1H), 7.40-7.25 5H), 7.01 (m, 1H), 6.74 1H), 6.62 1H), 5.18 2H). mass spec (negative mode electrospray, M-H) 270.
EXAMPLES 71-85 In a manner similar to that described for AVII-3-1, the following compounds were prepared: EXAMPLE 71 4-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-2 (71)
OOH
O
N
F A-VII-3-2 -140- WO 99/62513 WO 9962513PCTIUS99/12095 mp 145-146 'C (uncorrected) 1H NMR (400 MHz, d6..DMSO) 5 8.04 (in, 1H), 7.40-7.35 (in, 2H), 7.22-7.17 (in, 2H), 7.01 (in, 1H), 6.73 6.62 (in, 1H), 5.17 2H). mass spec (negative mode electrospray, M-H) 288.
EXAMPLE 72 3-bromobenzyl lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-3 AVHI-3-3 mp 159-160 TC (uncorrected) 1H NMR (400 MHz, d6..DMSO) 5 8.07 (in, 1H), 7.56-7.50 (mn, 2H), 7.36-7.28 (in, 2H), 7.04 1H), 6.74 1H), 6.63 (in, 1H), 5.18 2H). mass spec (negative mode electrospray, M-H) 348, 350.
EXAMPLE 73 l-(4-fluorobenzyl )-4-methyl- 1H-pyrrol-3-yI]-2 ,4-dioxobutyric acid AVII- 3-4
H
3
C,
AVII-3-4 AVII-3-4 was prepared in a manner similar to AVJJ-3-1, starting with 4-methyl-3-acetyl pyrrole. mp 162-163 TC (uncorrected) 1H NMR (400 M4Hz, d6..DMSO)868.10 (mn, 1H1), 7.37 (dd, d 5.5, 7.6 Hz, 2H), 7.18 (dd, J= 141 WO 99/62513 WO 9962513PCT/US99/12095 7.6, 8.9 Hz, 2H), 6.77 (in, 1H), 6.72 1H), 5. 10 2H), 2.20 3H). mass spec (negative mode electrospray, M-H) 302.
EXAMPLE 74 4- [2 ,4-dimethyl- l-(4-fluorobenzyl lH-pyrrol-3-yl-2,4-clioxobutyric acid AVII1-3-5 was prepared in a manner similar to AVJI-3-1, starting with 2,4-dimethyl-3-acetyl pyrrole. mp 184-185 IC (uncorrected) 1H NMR (400 M7Hz, d6.DMSO) 8 7.20-7.12 (in, 4H), 6.74 1H), 6.62 1H), 5.13 2H), 2.41 3H), 2.19 3H). mass spec (negative mode electrospray,
M-H)
316.
EXAMPLE 1-(3 ,4-difluorobenzyl lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-6
OH
AVIII-3-6 mp 143-144 0 C (uncorrected) 1H NIMR (400 MHz, d6..DMSO) 5 8.05 1H), 7.43 (in, 2H), 7.17 (in, 1H), 7.03 (dd, J 1.8 Hz, 1H), 6.73 1H), 6.61 -142- WO 99/62513 WO 9962513PCTIUS99/I 2095 (dd, J 3.0, 1.8 Hz, 1H), 5.16 2H), 3.3 bs, 1H). mass spec (negative mode electrospray, M-H) 306.
EXAMPLE 76 44 1-(3-chlorobenzyl)- lH-pyrrol-3-yll-2,4-dioxobutyric acid AVII-3-7 jy
OH
N
CI
AVII-3-7 mp 159-160 TC (uncorrected) 1H NMR (400 MHz, d6..DMSO) 8 8.07 (in, 1H), 7.38 (in, 3H), 7.26 (in, 1H), 7.04 (mn, 1H), 6.74 1H1), 6.63 (in, 1H), 5.19 1H). mass spec (negative mode electrospray, M-H) 304, 306.
EXAMPLE 77 4-r 1-(4-chlorobenzyl 1H-pvrrol-3-vl]-2 .4-dioxobutvric acid AVII-3-8 0 0 -11 yooOH
N
A-VII-3-8 mp 170-171 TC (uncorrected) 1H NMR (400 1MHz, d6-DMSO) 8 8.03 J 1.8 Hz, 1H), 7.43-7.40 (in, 2H), 7.34 (mn, 1H), 7.31 (in, 1H), 7.00 (dd, J 2.8, 1.8 Hz, 1H), 6.72 1H), 6.61 (dd, J 2.8, 1.8 Hz, 1H). mass spec (negative mode electrospray, M-H) 304.
-143- WO 99/62513 WO 9962513PCTIUS99/12095 EXAMPLE 78 1-(4-bromobenzvl 1H-nvrrol-3-yl 1-2 .4-di oxobutvric acid AVIJ-3- 9
.OH
AVII-3-9 mp 184-185 'C (uncorrected) 1H NAM (400 MHz, d6..DMSO) 568.04 J Hz, 1H), 7.59-7.54 (in, 2H), 7.28-7.23 (in, 2H), 7.01 (dd, J 2.0, 2.9 Hz, 1H), 6.74 1H), 6.62 (dd, J 2.0, 2.9 Hz, 1H), 5.17 2H). mass spec (negative mode electrospray, M-H) 348, 350.
EXAMPLE 79 .4-dichlorobenzvl)- IR-Dvrrol-3-vfl-2 .4-dioxobutvric acid AVII-3-
OH
A-U-3-10 mp 175-176 TC (uncorrected) 1H NMR (400 MHz, d6..DMSO) 5 8.06 J 1.9 Hz, 1H), 7.62 J 8.2 Hz, 1H1), 7.61 1H), 7.28 (dd, J 8.2, 2.0 Hz, 1H), 7.04 (dd, J 2.9, 1.9 Hz, 1H), 6.73 1H), 6.62 (dd, J 2.9, 1.9 Hz, -144- WO 99/62513 WO 9962513PCT/US99/12095 1H), 5.18 2H), 3.36-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338, 340.
EXAMPLE 4-[1-(2-methvlbenzvl 1H-nvrrol-3-vl]-2 .4-dioxobutyric acid AVII-3- 11 0 0 11 00OH
N
H
3 0' AVII-3-11I mp 119-120 TC (uncorrected) 1H NMR (400 MHz, d6.DMSO) 8 7.91 J 1.9 Hz, 1H), 7.24-7.15 (in, 2H), 6.94 J 7.4 Hz, 1H), 6.91 (dd, J 2.9, 1.9 Hz, 1H), 6.72 111), 6.64 (dd, J 2.9, 1.9 Hz, 1H), 5.21 2H), 3.45-3.2 1 (bs, 1H), 2.25 3H). mass spec (negative mode electrospray, M-H) 284.
EXAMPLE 81 1-(3-chlorobenzyl )-4-methyl- 1tI-pyrrol-3-yl]-2 ,4-dioxobutyric acid AVII- 3-12 0
H
3 C
OH
N 0
N
C I AVII-3-12 AVII-3-12 was prepared in a manner similar to AVII-3-1, starting with 4-methyl-3-acetyl pyrrole.
145 WO 99/62513 WO 9962513PCTIUS99/1 2095 mp 148-149 TC (uncorrected) 1H NMR (400 MHz, d6..DMSO) 8 8.09 J 2.2 Hz, 1H), 7.41-7.35 (in, 2H), 7.26 (in, 1H), 6.79 (dd, J 2.1, 1.1 Hz, 1H), 6.72 1H), 5.09 2H), 3.40-3.30 (bs, 1H), 2.19 3H). mass spec (negative mode electrospray, M-H) 318, 320.
EXAMPLE 82 l-(3-trifluoromethylbenzyl lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII- 3-13 o 0
OH
C ~0
N
SCF
3 AVII-3- 13 mp 145-146 TC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 5 8.09 J= 1.9 Hz, 1H), 7.70-7.66 (in, 2H), 7.63-7.58 (mn, 2H), 7.06 (in, 1H), 6.73 1H), 6.63 (dd, J 4.7, 1.7 Hz, 1H), 5.28 2H), 3.40-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338.
EXAMPLE 83 l-(4-inethylbenzyl lH-pyrrol-3-yl]-2,4-dioxobutyic acid AVII-3- 14 0 0
OH
N0
N
OH
3 AVIJ-3-14 146- WO 99/62513 WO 9962513PCTIUS99/1 2095 mp 164-165 TC (uncorrected) 1H NMR (400 MHz, d6.DMSO) 568.00 J 1.9 Hz, 1H), 7.20-7.14 (in, 4H), 6.97 (dd, J 2.9, 1.9 Hz, 1H), 6.72 1H), 6.59 (dd, J 2.9, 1.9 Hz, 1H), 5. 11 2H), 3.37-3.27 (bs, 1H), 2.26 3H).
mass spec (negative mode electrospray, M-H) 284 EXAMPLE 84 l-(4-methoxybenzyl )-l1I-pyrrol-3-yl]-2 ,4-dioxobutyric acid AVII-3-
,OH
00CH 3 AVTI-3-15 mp 137-138 0 C (uncorrected) 1H NMR (400 MHz, d6..DMSO) 8 7.99 J 1.9 Hz, 1H), 7.27-7.25 (in, 2H), 6.97 (dd, J 2.9, 1.9 Hz, 111), 6.90 (in, 2H), 6.71 1H), 6.58 (dd, J 2.9, 1.9 Hz, 1H), 5.08 2H). mass spec (negative mode electrospray, M-H) 300 EXAMPLE 4-r 1-(3-methylbenzyl 1EI-pvrrol-3-ylL-2 .4-dioxobutyric acid AVJ-3 16
,OH
AVII-3-16 Rf =0.49 (94:6:1 CH2C1 2 MeOll HOAc) 147 WO 99/62513 WO 9962513PCTIUS99/1 2095 'H NMR (400 MHz, CDCL3) 5 7.46 1H), 7.25 (in, 2H), 7.15 J=7.5 Hz, 1H), 6.98 (in, 2H), 6.25 1H), 6.23 (in, 1H), 6.20 (in, 1H), 5.05 2H),2.33 3H).
EXAMPLES 86-88 The following compounds were prepared in a manner similar to AVII- 3-1: EXAMPLE 86 4- -[3-(4-fluorophenyl )-propyl]- 1H-pyrrol-3-yl ,4-dioxobutyric acid O OH
CO
2
H
N
F
CHN Caic. (C17H16FNO 4 0.2 water) 63.62, 5.15,4.36; Fnd. 63.54,5.07,4.00.
EXAMPLE 87 1-(4-bromobenzyl 1-H-pyrrol-3-yl]-2 ,4-dioxobutyric acid O OH C0 2
H
N
Br"" CHN Caic. 51.45, 3.45,4.00; Fnd. 51.53,3.50,3.92.
EXAMPLE 88 l-(4-cblorobenzyl l-H-pyrrol-3-ylI -2,4-dioxobutyric acid 148 WO 99/62513 PCT/US99/12095 S -'C0 2
H
N
CI
CHN Calc. 58.93,3.96,4.58; Fnd. 58.79,4.04,4.47.
EXAMPLE 89 4-[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4dioxobutyric acid AVIII-4-1 Step 1: 1-[4-Benzylamino- -(4-fluorobenzyl)- H-pyrrol-2-yl]ethanone AVIII-1-1
NH
N
F AVIII-1-1 To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added l-[ 4 -amino-l-(4-fluorobenzyl)-lH-pyrrol-2yl]ethanone AVI-2-1 (1.00g, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 aqueous sodium potassium tartrate and brine. Drying 149- WO 99/62513 PCT/US99/12095 (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4-Benzylamino-l-(4-fluorobenzyl)-lH-pyrrol- 2-yl]ethanone AVIII-1-1 as a crystalline solid. 1H NMR (CDC1 3 2.34 (3H, 3.35 (1H, br 4.16 (2H, 5.41 (2H, 6.36 (1H, d, j= 2.2 Hz), 6.49 (1H, d, j=2.2 Hz), 6.93 (2H, 7.06 (2H, 7.30 to 7.37 (5H, complex multiplet).
Step 2: 1-[4-Benzylmethylamino- -(4-fluorobenzyl)-lH-pyrrol-2yl]ethanone AVIII-2-1
S
C H3
N
0 F AVIII-2-1 To a 100 mL round bottomed flask with a stirring bar and an addition funnel topped by an argon inlet was added 1-[4-benzylamino-l-(4fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVIII-1-1 (0.472g, 1.46 mmol), MeOH (20 mL), formalin (1.19 mL of 37% aqueous solution, 14.64 mmol) and sodium cyanoborohydride (0.628g, 10.00 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.57 mL, 10.0 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, aqueous sodium potassium tartrate and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexanes as eluant to give 1-[4benzylmethylamino- l-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIII-2- 1 as a crystalline solid. 1H NMR (CDC13) 8 2.25 (3H, 2.36 (3H, 4.16 -150- WO 99/62513 WO 9962513PCTIUS99/1 2095 (2H, 5.43 (2H, 6.33 (1H, d, j= 2.2 Hz), 6.53 (1H, d, j=2.2 Hz), 6.93 (2H, in), 7.06 (2H, mn), 7.27 to 7.32 (5H, complex inultiplet).
Step 3: 4 -[4-Benzylmethylamino- l-(4-fiuorobenzyl 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid ethyl ester A-VIII-3-1 N 0 N OEt 0 0 F A-VIIT-3- 1 In a manner substantially similar to that described for Example A-V-9-1 l-[4-benzylmethylainino- 1-(4-fluorobenzyl 1H-pyrrol-2-yl] ethanone A VTII- 2-1 was used to prepare 4 -[4-benzylmethylamino- l-(4-fluorobenzyl lH-pyrrol-2-yl-2,4-dioxobutyric acid ethyl ester L-_VIJI-3-1 which was used in the next step without further purification.
Step 4: 4 4 -Benzylmethylainino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid AVI-5-1 N 0 N O H 0 0 F& AVIII-4- 1 In a manner substantially similar to that described for Example AV-10-1 4 4 -benzylmethylamiino- l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2 ,4dioxobutyric acid ethyl ester AVITI-3-1 was used to prepare 4-114benzylmethylamino- l-(4-fluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acidAVII-4-1. 1H NMR (CDCl 3 8 2.79 (3H1, 4.23 (2H1, 5.48 (2H, s), 6.54 (1H, d, j=2.0 Hz), 6.74 (1H, d, j=2.0 Hz), 7.00 (4H, in), 7.28 (5H, in).
151 WO 99/62513 WO 9962513PCT/US99/12095 EXAMPLE 4- [4-Dimethylam-ino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid A-IX-3-1 Step 1: 1-[l1-(4-Fluorobenzyl )-4-phenyl- iH-pyrrol-2-yllethanone
AIX-
1-1
N
0 F AIX-i-i To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added i-[i-(4-fluorobenzyl)-4-iodo.1Hpyrol.2 yl]ethanone AIII-1-1 (1.00g, 2.91 minol), phenylboronic acid (0.431g, 3.54 mmol), tetrakis(triphenylphosphine)palladiamo (0.20g, 0.17 nimol), barium hydroxide (1.37g, 4.37 mmol), DME (40 mL), and H20 (5 mL).
This well stirred mixture was heated at reflux 4h. The reaction mixture was cooled to 20'C and diluted with EtOAc. This solution was washed with H20, iN HCl, H20, and brine. Drying (MgSO4), filtration and removal of the solvent in vacua gave an amorphous material. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-l(-looezl--hny-Hpro--lehnn AIX-i-i as an oil. 1H N7MR (CDCl3) 8 2.47 (3H, 5.57 (2H, 6.98 (2H, in), 7.13 to 7.28 (5H, complex multiplet), 7.36 (2H, in), 7.51 (2H, in).
Step 2: 4-[4-Phenyl- l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4dioxobuty-ric acid ethyl ester AJX-2-1 -152- WO 99/62513 WO 9962513PCTJLJS99/12095 0 0 r AIX-2- 1 In a manner substantially similar to that described for Example AV-9-1, 4 -fluorobenzyl)-4-phenyl- 1H-pyrrol-2-yllethanone AIX-i-i1 was used to prepare 4-[4-phenyl- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid ethyl ester AIX-2-1 which was used in the next step without further purification.
Step 3: 4 -[4-Phenyl-1-(4-fluorobenzyl). H-pyrrol-2-yl]-2,4dioxobutyric acid AIX-3-1 FAIX-3-1 In a manner substantially similar to that described for Example AV-10-1 4-[4-phenyl- 1-(4-fluorobenzyl lH-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-1 was used to prepare 4 4 -phenyl-1-(4-fluorobenzyl)1Hpyrrol- 2 -yl]-2,4..dioxobutyric acid AIX-3-1. 1H NIMR (DMSO-d 6 5 5.66 (2H, 6.93 (1H, 7.05 (2H, in), 7.23 (3H, in), 7.36 (2H, in), 7.59 (3H, in), 7.65 (1H, d, j= 1.7 Hz).
EXAMPLE 91 l-( 4 -fluorobenzyl)-4-methanesulfonylamjno..lH-pyrrol-3-yl]-2,4-dioxo.
butyric acid AX-3-1 -153- WO 99/62513 PCT/US99/12095 Step 1: N-[4-acetyl- -(4-fluorobenzyl)- H-pyrrol-3-yl]methanesulfonamide AX-1-1
H
H
3
N
O0 SO
CH
3 F AX-1-1 A solution of 1-[4-amino-1-(4-fluoro-benzyl)-lH-pyrrol-3-yl]-ethanone AVI-2-1 2.15 mmole) in 10 ml of CH2C12 was cooled to 0°C and treated with triethylamine (.25 mL, 3.22 mmole) followed by methane sulfonylchloride .45 mL, 3.22 mmole) dropwise via syringe. The reaction was completed in two hours and was diluted with CH2C12 and washed with 10% citric acid. Organic layer was dried over MgS04, filtered and concentrated in vacuo to afford a light pink semi-solid residue. This material was chromatographed on silica gel using EtOAc/Hex as eluant to give AX-1-1 as a white crystalline solid. 1H NMR (400 MHz, CDC13) 5 7.12 2H), 6.96 2H), 6.94 J=1.8Hz, 1H), 6.85 J=1.8Hz, 1H 5.97 b, 1H), 5.49 2H), 2.97 3H), 2.39 (s, 3H).
Step 2: 4 -fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3yl]-2,4-dioxo-butyric acid ethyl ester AX-2-1
H
H
3 C.s. N S O C02Et
IN,
0 0 AX-2-1 A solution of AX-1-1 (460 mg, 1.48 mmole) in 10ml dried THF was treated with diethyl oxalate (0.40 ml, 2.96 mmole) and sodium ethoxide (200 mg, 2.96 mmole) at room temperature over night under N 2 atmosphere. The reaction mixture was poured into 20 ml of 1N HC1 solution and extracted twice with EtOAc. Combined extracts were 154- WO 99/62513 PCT/US99/12095 washed with brine and dried over MgSO4, filtered and evaporated to give a yellow brown residue that was flashed chromatographed using 100% EtOAc as eluant to give AX-2-1 as a yellow crystalline solid. 1H NMR (400 MHz, CDC13) 5 7.13 2H), 6.97 4H), 6.75 1H), 5.92 br, 1H) 5.56 2H), 4.34-4.40 2H), 2.97 3H), 1.39 3H).
Step 3: -(4-fluorobenzyl)- 4 -methanesulfonylamino- 1H-pyrrol-3yl]- 2 4 -dioxo-butyric acid AX-3-1
H
H
3 C- N O"S OI
CO
2
H
N
0 0 F AX-3-1 A solution of AX-2-1 (200 mg, 0.48 mmole) was dissolved in 6ml of and 6ml of 1N NaOH for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HC1 and extracted three times with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and evaporated to give an oily residue that was triturated with 20% EtO2/Hex to afford AX-3-1 as a yellow crystalline solid.
160 0 C decomposed 1H NMR (400 MHz, DMSO-d 6 8 9.33 1H), 7.39 1H), 7.12-7.17 (m, 5H), 6.75 1H), 5.58 2H), 2.92 3H).
EXAMPLES 92-94 The following compounds were prepared in a manner similar to that described for AX-3-1: EXAMPLE 92 4 -Fluorobenzyl)-3-acetylamino-1H-pyrrol-2-yl]-2, 4 -dioxobutyric acid -155- WO 99/62513 WO 9962513PCTIUS99/1 2095 NHAc NF -I
COOH
N
CHN Caic. 58.96, 4.37, 8.09; Fnd. 59.20, 4.30, 8.06.
EXAMPLE 93 acetyl amino- 1- (4-fluorobenzyl)- 1H-pyrrol- 2-yl] -2,4-dioxobutyric acid N C0 2
H
0 OH CHN Caic. (C 17H 15FN 2 05 0.3 H20) 58.05, 4.47, 7.97; Fnd. 58.09,4.40,8.06.
EXAMPLE 94 4-l -(4-fluorobenzyl 2-oxo-piperidin- l-yl)- 1H-pyrrol-2-yl] -2,4dioxobutyric acid cxiN .00 2
H
0 OH CHN Calc. C2OH19FN2OS 0.4 1H20) 61.03, 5.07, 7.12; Fnd. 60.96, 5.00, 7.22.
EXAMPLE -156- WO 99/62513 PCT/US99/12095 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxo-butyric acid AXI-5-1 Step 1: (4-fluorophenyl)-(l-triisopropylsilanyl-1H -pyrrol-3yl)methanone AXI-1-1
O
F
N
Si(i-Pr) 3 AXI-1-1 A stirred slurry of A1C13 (99.99% anhydrous powder, 3 2 8g, 0.0246 mole) in anhydrous CH2Cl2 (45 mL) was treated with 4-fluorobenxoyl chloride (2.64 mL, 0.0224 mole) added dropwise at OC. After 0.5 h, a solution of l-(triisopropylsilyl)pyrrole (5.55 mL, 0.0224 mole) in CH2C12 (11 mL) was added. The mixture was stirred for 0.5 h at O°C then 3 h at room temperature and then poured into 300 mL cold saturated NH4C1 solution. The organic phase was separated and combined with two CH2Cl2 extracts of the aqueous phase. The combined organic layers were washed with NH4Cl solution and dried over MgSO4, filtered and evaporated to give a crude brown oil. Flash chromatography on silica gel of the crude product, using a 5:95 EtOAc Hexane mixture as the eluting solvent, gave AXI-1-1 as a yellow oil. TLC Rf=0.54 (10:90 EtOAc Hexanes) 1H NMR (400 MHz, CDC13) 5 7.87 2H), 7.32 1H), 7.13 2H), 6.78 2H), 1.48 3H), 1.12 J=7.51 Hz, 18H).
Step 2: 3 -(4-fluorobenzyl)-l-triisopropylsilanyl-lH -pyrrole AXI-2-1 F
N
Si(i-Pr) 3 AXI-2-1 In a similar manner to AII-2-1, AXI-1-1 (3.50 g, 0.0101 mole) was refluxed with 1.0 M BH3-Me2S (30.3, 0.0303 mole) in 100 mL anhydrous 157- WO 99/62513 WO 9962513PCTIUS99/1 2095 THF to give AXJ-2-1 as a light yellow solid. TLC Rf=0.57 (5:95 EtOAc Hexanes) 1H NMR (400 MHz, CDCl3) 5 7.15 (in, 2H), 6.94 (in, 2H), 6.71 (t, J=2.38 Hz, 1H), 6.50 (in, 1H), 6.09 (in, 1H), 3.82 211), 1.41 (in, 3H), 1.08 Ad J=7.51, 1811).
Step 3: l-[ 4 -(4-fluorobenzyl)- l-triisopropylsilanyl-I11 -pyr-rol-3yllethanone AXI-3-1 0 FD N\ Si(i-Pr) 3 AXI-3-1 In a similar manner to AXJ-1-1, AXI-2-1 was acylated using freshly distilled acetyl chloride to give AXI-3-1 as a light yellow solid.
TLC Rf=0.41 (10:90 EtOAc Hexanes) 1H NMR (400 MHz, CDCl 3 6 7.31 (in, 1H), 7.17 (in, 2H), 6.93 (in, 2H1), 6.30 J=1.10 Hz, 111), 4.08 1H1), 2.37 311), 1.42 (in, 3H), 1.08 J=7.51 Hz, 18H) Step 4: l- 4 -(4-fluorobenzyl)-1H -pyr-rol-3-yllethanone AXI-4-1 0 Fj
N
H AXI-4-1 A solution of AXI-3- 1 (0.1l 4 5g, 0.387 inmol) in dry THF (0.5 mL was treated with tetra-n-butyla mmoniuin fluoride (0.397 iL 1.0 M in THF, 0.387 inmol) at room temperature for one hour. The reaction was quenched with saturated NaHCO3, extracted with EtOAc, dried over MgSO4, filtered and concentrated to give the product as a yellow solid.
TLC Rf=0.i15 (10:90 EtOAc Hexanes) 111 NMR (400 MHz, CDCl3) 6 8.2 (bs, 1H), 7.38 1H),7.22 (mn, 211), 6.95 (in, 211), 6.34 111), 4.1 211), 2.4 311).
158- WO 99/62513 WO 9962513PCT/US99/I 2095 Step 5: 1,4-bis-(4-fluorobenzyl Il -pyrrol-3-yllethanone AXI-4-2 F AXI-4-2 In a similar manner to AIV-3-1, AXI-4-1 was alkylated using 4fluorobenzyl bromide to give AXI-4-2 as a light brown oil.
TLC Rf=0.69 (40:60 EtOAc Hexanes) 1H NMR (400 MHz, CDCl3) 5 7.17- 7.21 (in, 3H), 7.04-7.12 (in, 4H), 6.93 (in, 2H), 6.20 1H), 4.94 2H), 4.06 2H), 2.34 3H).
Step 6: 4-[4-(4-fluorobenzyl)- 1Hf -pyrrol-3-yl]-2,4-dioxobutyric acid AXI-5-1 0 0 O H I 0 H AXI-5-1 AXI-4-1 was carried on to the diketo acid AXI-5-1 as described for AJ-3-1.
TLC Rf=0.41 (94:6:6 CHC1 3 MeGH HOAc) 1H1 NMR (400 MHz, CDC1 3 8 8.4 (bs, 1H), 7.4 1H),7.2 (in, 2H), 6.97 (mn, 2H), 6.41 111), 4.1 2H).
EXAMPLE 96 4-11,4-bis-(4-fluorobenzyl)- 1W -pyrrol- 3 -yl]-2,4-dioxobutyric acid AXI-5-2 -159- WO 99/62513 WO 9962513PCTIUS99/1 2095
OH
FD
N\
F AXI-5-2 AXI-4-2 was carried on to the diketo acid AXI-5-2 as described for AJ-3-1.
TLC Rf=0.66 (94:6:6 CHC13 MeOH HOAc) 1H NMR (400 MHz, CDC13) 7.41 1H), 7.04-7.19 (in, 6H), 6.96 (mn, 2H), 6.70 1H), 6.28 4.97 2H), 4.07 2H).
EXAMPLE 97 4 3 -carboxy-3-oxo-propionyl 1-(4-fluorobenzyl 1H-pyrazol-3-yl]-2 ,4dioxobutyric acid BI-6-1 Step 1: 1-(4-fluorobenzyl lH-pyrazol-3,5-dicarboxylic acid diethyl ester BI-1-1 0 0 t BI-1-1 A mixture of lH-pyrrole-2,4-dicarboxylic acid diethyl ester (.424 g, 2 minol), 4-fluorobenzyl bromide (.378 g, .25 ml, 2 mmol) and triethylamnine (.303 g, .417 ml, 3 inmol) was dissolved in 5 ml dry DMF and stirred for 18 hr.. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate! H 2 0 and extracted.
The combined organics were washed with H 2 0, brine, dried over Na 2
SO
4 filtered and the solvent removed. TLC showed about 160 WO 99/62513 PCT/US99/12095 unreacted pyrrole. Further purification by column chromatography (2:1 hexane/ethyl acetate) gave .335 gr of the title compound as a colorless oil.
1H NMR (400 MHz, CDC13) d 1.34 3H, J 7.14), 1.41 3H, J 7.14 Hz 4.32 2H, J 7.14 Hz), 4.42 2H, J 7.14 Hz), 5.80 2H), 6.98 2H, J 8.7 Hz), 7.29 2H), 7.36 1H) Step 2: 1-(4-fluorobenzyl)-1H-pyrazol-3,5-dicarboxylic acid dilithium salt BI-2-1
O
0 0 LiO N BI-2-1 BI-1-1 g, .62 mmol) was dissolved in 2 ml THF, and to it was added LiOH (1.3 ml of a 1M soln.). After stirring 18 hr, the solvent was removed in vacuo and 3x5 ml toluene added and removed to eliminate water. The crude material was used in the next reaction without further purification.
Step 3: 1-(4-fluorobenzyl)-1H- pyrazol-2,4-dicarboxylic acid bis- (methoxymethylamide) BI-3-1 0 0 N ,OMe MeON N BI-3-1 161 WO 99/62513 PCT/US99/12095 A mixture of BI-2-1 from the previous example, N,Odimethylhydroxylamine hydrochloride (.121 g, 1.24 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (.238 g, 1.24 mmol), 1hydroxybenzotriazole hydrate (.167 g, 1.24 mmol), and triethylamine (.125 g, .173 ml, 1.24 mmol) were combined in 3 ml DMF and stirred for 18 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed. Further purification via radial disc chromatography (1:1 hexane/ethyl acetate) afforded the title compound as a colorless oil.
1H NMR (400 MHz, CDC1 3 6 3.27 3H), 3.43 3H), 3.46 3H), 3.75 (s, 3H), 6.91 7.00 3H), 7.22 7.32 3H) Step 4: 1-[5-acetyl-l-(4-fluorobenzyl)-lH-pyrazol-3-yl]ethanone BI-4-1
O
NN
BI-4-1 BI-3-1 (.142 g, .41 mmol) was dissolved in 5 ml dry THF and cooled to 78 0 C. To this was added methyl lithium (1.158 ml of a 1.4M solution in diethyl ether, 1.64 mmol). The mixture was stirred for 1 hr, then quenched by the addition of excess 10% aqueous citric acid solution.
After warming to room temperature, the mixture was poured into 10 ml and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2SO4, filtered and the solvent removed to get the title compound as an oil.
1H NMR (400 MHz, CDC13) 2.50 3H), 2.63 3H), 5.74 2H), 6.99 2H, J 8.8 Hz), 7.28 7.37 3H) 162- WO 99/62513 WO 9962513PCTJUS99/1 2095 Step 5: 4 3 -ethoxycarbonyl-3-oxopropionyl). l-( 4 -fluorobenzyl i1pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester BI-5-1 BI-5-1 In a similar marnner to AIJ-2-1, BI-4-1 (.094 g, .36 mmol) was reacted with diethyl oxalate (.212 g, .196 ml, 1.44 mmol) and sodium ethoxide (.096 g, 1.44 mmol) to give the title compound as a yellow solid.
1H NMR (400 MHz, CDCl3) 8 1.38 3H, J 7.33 Hz), 1.42 3H, J 7.14 Hz), 4.36 2H, J 7.14 Hz), 4.41 2H, J 7.14 Hz), 5.84 211), 6.85 1H), 7.00 2H, J 2.0 Hz), 7.29 7.36 (in, 3H), 7.54 1H) Step 6: 4 3 -carboxy-3-oxopropionyl)- 1-(4-fluorobenzyl 1Hpyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 In a similar manner to AI-3- 1, BI-5-1 (.157 g, .35 minol) was reacted with LiOH ml of a 1M solution in H20) in 5 ml THF to give the title compound as a light tan solid. MP 215 217 'C 1H NMR (400 MHz, CDC13) 5 5.84 2H), 7.00 2H, J 8.7 Hz), 7.29 7.37 (mn, 4H), 7.55 1H); FAB MS: m/z 405 H) EXAMPLE 98 163 WO 99/62513 PCT/US99/12095 4-[l-(4-fluorobenzyl)-LH-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 Step 1: 4 -bromo-l-(4-fluorobenzyl)-lH-pyrazole BII-I-1 Br
N
BDI-1-1 4-Bromopyrazole (.441 g, 3mmol) was added to a slurry of sodium hydride (.072 g, .12 gr of a 60% oil dispersion, 3 mmol) in 5 ml DMF and stirred for 15 min, after which 4-fluorobenzyl bromide (.568 g, .374 ml, 3 mmol) was added and the reaction was stirred for 18 hr. The solvent was then removed in vacuo 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 to afford title compound as a colorless oil. 1H NMR (400 MHz, CDC13) 5 5.23 2H), 7.04 2H, J 8.6 Hz), 7.18 7.25 2H), 7.36 1H), 7.49 1H) Step 2: l-[1-(4-fluorobenzyl)-LH-pyrazol-4-yl]ethanone BII-2-1 0 O
N,
F
BII-2-1 BII-1-1 (.686 g, 2.7 mmol) was dissolved in 8 ml diethyl ether and cooled to -78 0 C. To this was added butyllithium (1.85 ml of a 1.6M solution in hexane, 2.95 mmol) and the reaction was allowed to stir for 1 hr, after which time N-methoxy-N-methyl-acetamide (.33 g, .33 ml, 3.22 mmol) -164- WO 99/62513 PCT/US99/12095 was added and the mixture allowed to warm to room temperature. After stirring for 2 hr, the reaction was quenched with 10% citric acid solution and extracted with H20, brine, dried over Na2S0 4 filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexane/ethyl acetate) the title compound as a colorless oil.
Step 3: 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BII-3-1 00 OO OEt Ns N 0
N
BII-3-1 In a manner analogous to AIII-2-1, BII-2-1 was reacted with diethyl oxalate (.152 g, .142 ml. 1.04 mmol) and sodium ethoxide (.071 g, 1.04 mmol) to yield the title compound as a white solid.
1H NMR (400 MHz, CDC13) 5 1.40 3H, J 7.14 Hz), 4.38 2H, J 7.14 Hz), 5.31 2H), 6.66 1H), 7.08 2H, J 8.61 Hz), 7.24 7.31 2H), 7.94 1H), 8.02 1H) Step 4: 4-[l-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 S0
OH
N, O
N
FB
BII-4-1 165- WO 99/62513 WO 9962513PCTIUS99/1 2095 1n a similar manner to AI-3-1, BII-3-1 (.17 g, .53 mmol) was reacted in ml MeGH containing 2 ml IM NaOH to give a light tan solid after triturating the crude material with CH2Cl2. MP 191-192 0
C
1H NMR (400 MHz, CDCl 3 5 5.31 2H), 6.71 1H, J .73 Hz), 7.08 2H, J 8.6 Hz), 7.24 7.33 (in, 2H), 7.99 1H), 8.03 1H) FAB MS: mjz291
+H)
EXAMPLES 99 100 The following compound were prepared in a manner similar to that described for BII-4-1: EXAMPLE 99 4-[4-Dimethylamino- 1-(4-fluorobenzyl 1H-pyrrol-3-yl] -2 ,4-dioxobutyric acid 0OOH -N
OH
N
F,
CHN Caic. (C16Hl6N304F 0.5 EtOAc) 57.28, 5.34, 11.14; Fnd. 56.93, 5.01, 11.43.
EXAMPLE 100 l-( 4 -Fluorobenzyl)-5-methyl- l--pyrazol-4-yl-2-hydroxy4-oxobut.2 enoic acid O0H
OH
N, 0
N
FV
-166- WO 99/62513 WO 9962513PCT/US99/12095 CHN CaIc. (C15H13N20 4 F 0.4 MeOH) 58.33,4.64,8.84; Fnd 57.95, 4.40, 8.44.
EXAMPLE 101 4-[2-(4-fluorobenzyl 2 H-pyrazol-3-yl]-2,4..dioxo-butyijc acid BIII-3- 1 Step 1: l4[ 2 4 -fluorobenzyl 2 H-pyrazol-3-yl]ethanone BIJII-1-1
N
0 l-( 2 H-Pyrazol-3-yl)ethanone hydrochloride (.44 g, 3 mmol) was dissolved in 8 ml DMF and to it was added sodium hydride 144 g, .24 g of a oil dispersion, 6mmol). After stirring for 5 min, 4-fluorobenzyl bromide (.567 g, .374 ml, 3 mmol) was added and the reaction allowed to stir for 2 hr. It was then poured into 10 ml H20 and extracted with ethyl acetate.
The combined organic extracts were washed with H20, brine, dried over Na2SO 4 filtered and the solvent removed. Further purification by radial disc chromatography (3:1 hexane/ethyl acetate) yielded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) 8 2.58 3H), 5.33 2H), 6.80 1H, J 2.4 Hz), 7.05 2H, J 8.6 Hz), 7.19 7.28 (in, 2H), 7.35 1H, J 2.4 Hz) Step 2: 4 2 -(4-fluorobenzyl 2 H-pyrazol.3.yl]..2,4..dioxo..butyric acid ethyl ester BIII-2-1 0
NG~
0 0 FjBII-2- 1 167 WO 99/62513 WO 9962513PCTIUS99/1 2095 In a similar manner to AJJJ-2-1, BIII-i-i1 (.474 g, 2.2 mmol) was reacted with diethyl oxalate (.635 g, .59 ml, 4.4 mmol) and sodium ethoxide (.295 g, 4.4 mmol) to give the title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl 3 6 1.38 3H, J 7.14 Hz), 4.36 2H, J 7.14 Hz), 5.36 2H), 6.90 1H, J 2.38 Hz), 7.06 2H, J 8.61 Hz), 7.22 7.28 (in, 3H), 7.40 1H, J 2.38 Hz) Step 3: 4-12-(4-fluorobenzyl )-2H-pyrazol-3-yl]-2 4 -dioxo-butyric acid BIII-3-1 0 NN
OH
0 0 F BII-3- 1 In a similar manner to AI-3-1, BIII-2-1 (crude from previous reaction) was reacted with 1N NaOH (3m1) in 20 ml THF to yield the title compound as a light tan solid after trituration in diethyl ether. M? 157 159 0 C; 1H NMR (400 MHz, CDCl3) 565.35 2H), 6.90 1H, J 2.57 Hz), 7.06 2H, J 8.61 Hz), 7.22 7.31 (in, 3H), 7.42 1H, J 2.38 Hz) FAB MS: m/z291 (M H) EXAMIPLE 102 l-(4-fluorobenzyl )-3-methyl- lH-pyrazol-4-yl-2,4-dioxobutyr.ic acid BlV- 3-1 Step 1: 1-(3-methyl- lH-pyrazol-4-yl)ethanone BIV- 1-1 0
NN
H BTV-1-1 168- WO 99/62513 WO 9962513PCTIUS99/1 2095 A mixture of i-( 4 -acetyl-5-methylpyrazo1-.yl)ethanone (1 g, 6 mxnol, Maybridge) and 10 ml 1N NaGH were dissolved in 40 ml THF and stirred 4 days. The solvent was removed in vacuo and the residue partitioned between ethyl acetate! H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2SO 4 filtered and the solvent removed to get the title compound. 1H NMR (400 MHz, CDC13) 5 2.43 3H), 2.60 3H), 7.96 1H) Step 2: 1-[Il-(4-fluorobenzyl )-3-methyl- 1H-pyrazol-4-yl] ethanone BIV-2-1 0
N,
N
Fj: BIV-2-1I In a similar manner to BIII-i-i, BIV-1-1 (.248 g, 2 mmol) was reacted with sodium hydride (.096 g, .16 gr of a 60% oil dispersion, 4 mmol) and 4-fluorobenzyl bromide (.378 g, .249 ml, 2 nimol) for 2 hr. Subsequent work-up and purification by preparative HPLC (Chiralcel GD 25x2, hexane/1% diethylamine, 25% EtOH) yielded the title compound and 1-[i- (4-fluorobenzyl )-5-methyl- lH-pyrazol-4-yllethanone as white solids.
1H NMR (400 MHz, CDCl3) 8 2.36 3H), 2.49 3H), 5.21 2H), 7.07 2H, J 8.4 Hz), 7.24 (dd, 2H, J 4.9 Hz), 7.73 1H) Step 3: l-I[l-( 4 -fluorobenzyl)-3-methyl. H-pyrazol-4-yl]-2,4dioxobutyric acid ethyl ester BIV-3-1 169- WO 99/62513 WO 9962513PCT/US99/12095 0 0
N
BIV-3-1I In a similar manner to AJJI-2- 1, BIV-2-1 (.168 g, .72 mmol) was reacted with diethyl oxalate (.211 g, .196 ml, 1.44 mmol) and sodium ethoxide (.098 g, 1.44 mmol) in 5 ml THF to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) 5 1.37 3H, J 7.14 Hz), 2.52 3H), 4.35 2H, J 7.14 Hz), 5.23 2H), 6.61 1H), 7.06 2H, J 8.61 Hz), 7.21 7.32 (in, 2H), 7.89 1H) Step 4: l-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4dioxobutyric acid BIV-4-1 0 0 O0H 0
N
F BIV-4-1 In a similar manner to AI-3-1, BJV-3- 1 (.234 g, .68m inmol) was reacted with 2 ml NaOH in 10 ml THF to afford the title compound as a light tan solid. MAP 187-188 1H NMR (400 MHz, CDCl3) 862.53 3H), 5.23 (s, 2H), 6.64 1H), 7.08 2H, J 8.61), 7.23 7.31 (in, 2H), 7.88 1H) EXAMPLE 103 4-[3-methyl- l-(3-chlorobenzyl)- lH-pyrazol-4-yl]-2,4-dioxobutyric acid BV- 4-1 170 WO 99/62513 WO 9962513PCTIUS99/1 2095 Step 1: 3-chlorobenzyl )-3-methyl- 1H-pyrazol-4-yl] ethanone By- 171 and 1-(3-chlorobenzyl )-5-methyl- 1H-pyrazol-4yllethanone BV-2- 1 0 0 N N
N
BV-1-I BV-2-1I In a similar manner to BIV-2-1, BJV-1-1 (.271 g, 2.2 mmol) was reacted with 3-chlorobenzyl bromide (.493 g, .315 ml, 2.4 mmol) and sodium hydride (.063 g, .105 gr of a 60% oil dispersion, 2.6 mmol) in 5 nil THF for 2 hr and purified by preparative HPLC (Chiralpak AD 25x2, hexane/1% diethylamine, 25% 2-propanol) to yield the faster eluting 1-[1- 3 -chlorobenzyl)-3-methyl- 1H-pyrazol-4-yl] ethanone and the slower eluting l-(3-chlorobenzyl)-5-methyl.lH-pyrazol-4-yllethanone, both as clear oils.
l-(3-chlorobenzyl)-3-methyl- lH-pyrazol-4-yllethanone By- 1-1: 1H NMVR (400 MIHz, CDCl3) 862.38 3H), 2.49 3H), 5.21 2H), 7.12 (dt, 1H, J 6.2, 2.2, 1.6 Hz), 7.22 1H), 7.31 7.34 (in, 2H), 7.78 1H) lH-pyrazol-4-yljethanone BV-2- 1: 1H NMR (400 MHz, CDCl3) 8 2.45 3H), 2.52 3H), 5.28 2H), 6.87 7.02 (mn, 1H1), 7.10 1H), 7.22 7.30 (mn, 2H), 7.90 1H) Step 2: 4-[3-methyl- l-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2 ,4dioxobutyric acid ethyl ester BV-3-i 171 WO 99/62513 WO 9962513PCT/US99/1 2095 BV-3-1I In a similar manner to AIJ-2-1, RV-- (.255 g, 1 mmol) was reacted with diethyl oxalate 321 g, .298 ml, 2.2 mmol) and sodium ethoxide g, 2.2 inmol) to give the title compound, which was used without further purification. 1H NMR (400 MHz, CDCl3) 5 1.38 3H, J 7.14 Hz), 2.53 3H), 4.35 2H, J 7.14 Hz), 5.24 2H), 6.63 1H), 7.11 7.18 (in, 1H), 7.23 1H), 7.29 7.35 (mn, 2H), 7.93 1H) Step 3: 44[3 -methyl-1-(3-ch~orobenzy)..1-pyazol4yl..2,4.
dioxobutyric acid BV-4-1 0 0 O
H
0
N
C1 BV-4-1 In a similar manner to AI-3-1, 4-43 -inethyl-1-(3-chlorobenzyl)4IH pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester (crude from above) was reacted with 5 ml 1N NaGH in 20 ml methanol for two hours to give the title compound as a light tan solid. MP 183 184 0 C. 1H NMR (400 MHz, CDCl3) 5 2.54 3H), 5.23 2H), 6.67 1H), 7.12 7.18 (mn, 1H1), 7.25 1H), 7.31 7.36 (mn, 2H), 7.97 1H) EXAMVPLE 104 4-[5 -methyl- 1-(3-chlorobenzyl)- lFI-pyrazol-4-yl]-2,4-dioxobutyric acid 172 WO 99/62513 WO 9962513PCTIUS99/12095 Step 1: 4-[5 -methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl]-2,4.
dioxobutyric acid ethyl ester BV-5- 1 BV-5-1I In a similar manner to AIJI-2-1, BV-2-1 (.158 g, .64 inmol) was reacted with diethyl oxalate (.199 g, .185 ml, 1.36 mmol) and sodium ethoxide (.092 g, 1.36 mmol) to give the title compound, which was used without further purification. 1H NMR (400 MHz, CDCl3) 8 1.40 3H, J 7.14 Hz), 2.58 3H), 4.38 2H, J 7.14 Hz), 5.31 2H), 6.75 1H), 6.98 7.04 (in, 1H), 7.12 1H), 7.25 7.31 (in, 2H), 7.99 1H) Step 2: 4-[5 -methyl-1-(3-chlorobenzyl 1H-pyrazol-4-yl]-2,4dioxobutyric acid BV-6-1 BV-6-1 In a similar manmer to AI-31, BV-5-1 (crude from above) was reacted with 2 nml 1N NaOH in 10 ml methanol for two hours to give the title compound as a white solid after ether trituration. MP(uncorrected)168 169 0
C
1H NMR (400 MHz, CDCl3) 8 2.53 3H), 5.23 2H), 6.67 1H), 7.12 7.18 (in, 1H), 7.25 1H), 7.31 7.36 (in, 2H), 7.97 1H) 173 WO 99/62513 PCT/US99/12095 EXAMPLE 105 -(4-fluoro-benzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 Step 1: l-( 4 -fluoro-benzyl)-lH-imidazole CI-1-1
N
CNCl-1-1
F
To a solution ofimidazole (10g, 0.146 mole) in 80 ml of DMF at 0°C was added triethylamine 25.5 ml, 0.176 mole) followed by a solution of 4- Fluorobenzylbromide 22 ml, 0.176 mole) in 30ml of DMF added dropwise via addition funnel. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure in vacuo. The residue was partitioned with H20 and CH2C12. The organic layer was washed with saturated NaHCO 3 brine, dried over MgSO4, filtered and evaporated to afford a crude oil. This material was chromatographed on silica gel using 50-100% EtOAc/Hex as eluant. Obtained CI-1-1 as an oil. 1H NMR (400 MHz, CDC13) 8 7.53 1H), 7.09-7.15 5H), 6.88 1H), 5.09 2H).
Step 2: 1-(4-fluorobenzyl)-lH-imidazole-2-carboxylic lithium salt CI- 2-1 CO2LiCI-2-1 CO 2Li+
F&
A solution of CI-1-1 (8.81g, 0.05mole) in 120 ml dried THF at -78 0 C under N2 was added a solution of2.5M nBuLi in Hexanes 2 1ml, .052 mole) dropwise via syringe over 40 minutes. This resulting mixture was aged -174- WO 99/62513 PCT/US99/12095 for 1 hour at -78 0 C and small chunks of dried ice were added 6.6g, mole). The ice bath was removed and the reaction warmed to ambient temperature for 4 hours. The homogeneous solution was concentrated in vacuo to give a gummy foam which was triturated with ether to obtain CI -2-1 as a solid salt. 1H NMR (400 MHz, DMSO-d 6 6 7.34 2H), 7.22 1H), 7.11 2H), 6.83 1H), 5.74 2H).
Step 3: 1-( 4 -fluorobenzyl)-lH-imidazole-2-carboxylic acid methoxymethyl-amide CI-3-1 IN OCHz
N,
N CH 3 0 CI-3-1
F
A solution of CI -2-1 (7.0g, .031 mole) was treated with EDC.HC1 .034 mole), HOBT.H20 (4.6g, .034 mole), N,O- dimethylhydroxyamine.HC1 (3.31g, .034 mole), and triethylamine (12.9 ml, .092 mole) in ml of DMF and stirred over the weekend under N 2 The DMF was removed under reduced pressure in vacuo. The residue was partitioned with saturated NaHCO3 and extracted three times with EtOAc.
Combined organics layers were washed with H20 and brine, dried over MgSO4, filtered and evaporated to afford a yellow oil. This crude material was chromatographed on silica gel using 70-100% EtOAc/Hex as eluant. Obtained CI- 3-1 as an oil. 1H NMR (400 MHz, CDC13) 7.19- 7.23 2H), 7.09 1H), 6.97-7.04 3H), 5.42 2H), 3.81 3H), 3.48 3H) Step 4: 1-[1-(4-fluorobenzyl)-lH-imidazol-2-yl]ethanone CI-4-1 -175- WO 99/62513 PCT/US99/12095 6 C1-4-1 o
F"&
A solution of CI -3-1 (2.0g, .0076 mole) in 60 ml dried THF at -78 0 C was treated with a solution of 1.4M CH3Li (6.5 ml, .0091 mole) in dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to 0°C for 2 hours. The reaction was quenched with 75ml of saturated NH4C1 solution and extracted with three times EtOAc. Combined organics layers were washed with brine, dried over MgSO4, filtered and evaporated to give an oil. This crude material was chromatographed on silica gel using 70% EtOAc/Hex as eluant. Obtained CI- 4-1 as an oil. 1H NMR (400 MHz, CDC13) 6 7.16-7.20 3H), 7.06 1H), 6.99-7.04 2H), 5.58 2H), 2.66 3H).
Step 5: 4 -[1-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid ethyl ester CI-5-1
CCO
0 2 Et 0 0CI-5-1
F"
A solution of CI- 4-1 (0.5g, 0.0023 mole) in 8ml dried THF was treated with diethyl oxalate (0.62 ml, 0.0046 mole) and sodium ethoxide (.31g, 0.0046 mmole) at room temperature over night under N2 atmosphere.
The reaction mixture was poured into 10 ml of .5 N HC1 solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgSO4, filtered and evaporated to give a crude residue. This crude material was chromatographed on silica gel using -176- WO 99/62513 PCT/US99/12095 EtOAc/Hex as eluant. Obtained CI- 5-1 as a beige solid. 1H NMR (400 MHz, CDC13) 6 7.19-7.23 3H), 7.13 1H), 7.01 2H), 5.69 2H), 4.33-4.37 2H), 1.36 3H) Step 6: 4 -fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1
N
0
CO
2
H
0 CI-6-1
F&
A solution of CI- 5-1 (0.3 g, 0.0009 mole) was dissolved in 7ml of CH3OH, 7 ml of THF and 3ml of 1N NaOH and stirred for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HC1 and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated to give a crystalline solid, that was stirred in hot EtOAc and filtered to obtained CI- 6-1 as a light beige solid. 163-164 0 C. 1H NMR (400 MHz, CDC13) 6 7.20 3H), 7.13 1H), 7.01 3H), 5.69 2H).
EXAMPLE 106 In a manner similar to that described for CI-6-1, the following compound was prepared:.
4-(1-Benzyl- H-imidazol-2-yl)-2,4-dioxobutyric acid N 0OH 0 0 CHN Calc. 61.76, 4.44, 10.29; Fnd. 61.80, 4.58, 10.17 EXAMPLE 107 177- WO 99/62513 WO 9962513PCTIUS99/1 2095 4-[1-(4-fluorobenzyl lH-imidazol-4-yl-2,4-dioxo.butyic acid CI-4- 1 Step 1: 1-(4-fluorobenzyl lH-imidazole-4-carboxylic acid 4-fluorobenzyl ester CUI-i-la; and 3-(4-fluorobenzyl )-3H-imidazole-4-carboxylic acid 4-fluorobenzyl ester CuI-i-lb 0 0 N 0
F
F.
A suspension of lH-imidazole-4-carboxylic acid (1.0g, 0.0089 mole) in ml of DMF was treated with Cs2CO3 (8.72g, .026 mole) followed by 4fluorobenzyl bromide (3.33 ml, .026 mole) and stirred overnight at room temperature under N2 atmosphere. DMF was removed under reduced pressure in vacuo. The residue was partitioned with H20 and three times with EtOAc. Combined extracts were washed with brine, dried over MgSO4,, filtered and evaporated to give a crude oil. This material was chromatographed on silica gel with 50% EtOAc/Hex as eluant to afford a 1:1 mixture of CI I-i-la and CII- 1b. 1H NMR (400 MHz, CDCI3) 8 7.54-7.57 J= 9.7Hz, 2H), 7.40 (in, 2H), 7.14 (in, 2H), 6.99 (in, 4H), 5.28 2H), 5.09 2H).
Step 2: 1-(4-fluorobenzyl lH-imidazol-4-yl]-ethanone CII-2- 1 0 N- CH 3
N
FCII-2- 1 178 WO 99/62513 PCT/US99/12095 A solution of CI I-1-1 (0.9g, .0027 mole) in 10 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (2.35 ml, .0032mole) in dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to room temperature over the weekend. The reaction was quenched with 10ml of 1N HC1. The solution was basified with saturated NaHCO 3 and extracted with EtOAc three times. Combined organics layers were washed with brine, dried over MgS04, filtered and evaporated to give CI I-2-1 as a crystalline solid. 1H NMR (400 MHz, CDC13) 8 7.53 2H), 7.15 2H), 7.04 2H), 5.1 2H), 2.5 3H).
Step 3: 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester CII-3-1
CO
2 Et N0 c
N
F CII-3-1 A solution of CI 1-2-1 (75 mg, 0.34 mmole) in 3ml dried THF was treated with diethyl oxalate (0.092 ml, 0.68 mmole) and sodium ethoxide (47 mg, 0.68 mmole) at room temperature over night under N2 atmosphere. The reaction mixture was poured into 10 ml of IN HCI solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgSO4, filtered and evaporated to give CI 1-3-1 as a bright yellow oil. Used as is without further purification. 1H NMR (400 MHz, CDC13) 8 7.78 1H), 7.69 1H), 7.22 2H), 7.10 3H), 5.19 2H), 4.35 2H), 1.4(m, 3H).
Step 4: 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 -179- WO 99/62513 PCT/US99/12095 N-r 0NC 2
H
N
F CII-4-1 A solution of CI I-3-1 (70 mg, 0.2 mmole) was dissolved in 3ml of CH3OH and 3ml of 1N NaOH for 3 hours. The reaction mixture was washed with ether, acidified to pH 1-2 with 1N HC1 and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgSO 4 filtered and evaporated to give an oily residue that was triturated with 20% Et20/Hex to afford CI I-4-1 as a yellow crystalline solid. 1H NMR (400 MHz, CDC13) 5 8.24 1H), 8.07 1H), 7.44 2H), 7.19 2H), 6.92 1H), 5.28 2H).
EXAMPLE 108 4-[1-(4-fluorobenzyl)- 1H -indol 2 -yl]-2,4-dioxobutyric acid DI-4-1 Step 1: 1-(1H -indol-2-yl)ethanone DI-1-1 S CH 3
N
H
H DI-1-1 A solution of 2-carboxy indole (3g, 16.9 mmol) in anhydrous ether mL) was cooled to 0°C and treated with Methyl Lithium (1.4 M, 48.3 mL) A white solid precipitated. After addition was complete the reaction was warmed to reflux for two hours, quenched by pouring into ice water, and extracted with Et20. The organic layers were combined, washed with saturated sodium bicarbonate solution and brine, dried over MgS04, filtered and evaporated to give DI-1-1 as a white solid. Rf=0.53 EtOAc/Hexanes) 1H NMR (400 MHz, CDC1 3 5 9.1 (bs, Ih), 7.72 J= 7.78 Hz, 1H), 7.42 180- WO 99/62513 WO 9962513PCTIUS99/12095 J= 8.4 Hz, 1H), 7.36 (in, 1H), 7.2 (mn, 1H), 7.15 (in, 1H), 2.6 3H).
Step 2: 1-[l1-(4-fluorobenzyl W1 -indol -2-yflethanone DI-2- 1
,.CH
3 DI-2-1 In a manner similar to that described for the preparation of DL- 1-1 was treated with 4-fluorobenzyl bromide to give DI-2-1 as a yellow oil.
Rf=0.67 (20% EtOAc/Hexanes) 1H NMR (400 MHz, CDCl3) 5 7.73(d, J 8.06 Hz, 1H), 7.36 (mn, 3H), 7.18 (in, 1H), 7.02 (mn, 2H), 6.9 m. 2H), 5.8 2H), 2.6 3H).
Step 3: 4-[ll-(4-fluorobenzyl). W -indol 2 -yl]-2,4-dioxobutyric acid 00H 3 methyl ester DI-3-1 F DI-3- 1 In a manner similar to that described for the preparation of ALI-21 DI- 2-1 was treated with liinethyl oxalate and sodium hydride to give DI-3-1 as a yellow solid. Rf=0.26 (97:3:1 CHC13 MeOH HOAc). 1H NMR (400 MHz, CDCl3) d 7.75 J 8.05 Hz, 1H), 7.52 1H), 7.38 (mn, 2H), 7.2 (mn, 1H), 7.09 1H), 7.05 (mn, 2H), 6.95 (in, 2H), 3.95 311).
Step 4: l-( 4 -fluorobenzyl 1H -indol 2 -yl]-2,4-dioxobutyric acid DI-4- 1 181 WO 99/62513 WO 9962513PCTIUS99/1 2095 rT-H 0 0 F DI-.4-1 In a manner similar to that described for the preparation of A.-11
D-
1-3-1 was treated with sodium hydroxide to give DI-4-1 as bright yellow crystals after crystallization from EtOAc. 1H NAMR (400 MHz, DMSO- D6) 5 7.90 11H), 7.77 J= 7.88 Hz, 1H), 7.62 J 8.42 Hz, 1H), 7.4 (in, 1H), 7.2 (mn, 1H), 7.1 (in, 5H), 5.9 2H).
mass spec (FAB, M+1) 340.03.
EXAMPLE 109 The following compound was prepared in a manner similar to that described for DJ-4-1: 2-hydroxy-4-(1-methyl- 1-H -indol-2-yl) -2,4-dioxobutyric acid N C2 6H 3 O0 OH CHN Calc.(C13H1N0 4 0.15 H20) 62.97, 4.59, 5.65; Fnd. 63.05, 4.45, 5.80.
EXAMPLE 110 4 -[l-(4-fluorobenzyl).JI-indol-3-yl]-2 ,4-dioxobutyric acid DII-3- 1 Step 1: l-(4-fluorobenzyl lH-indol-3-yllethanone DII- 1-1 -182- WO 99/62513 WO 9962513PCTJUS99/1 2095 In a similar manner to BIIl-i-i, 3-acetylindole (.318 g, 2 mmol) was treated with 4-fluorobenzyl bromide (.378 g, .244 ml, 2 mmol) and sodium hydride (.048 g, .08 gr of a 60% oil dispersion, 2 mmol) in 2 ml DMF for one hour to give the title compound as a white solid. 1H NMR (400 Affz, CDCl3) 8 2.52 3H)5.33 2H), 7.03 2H1, J 8.61 Hz), 7.11 7.18 (in, 2H), 7.24 7.35 (in, 2H), 7.74 1H), 8.39 1H, J 7.5 Hz) Step 2: 1-(4-fluorobenzyl)- lF-indol-3-yl]-2,4-dioxobutyric acid ethyl ester DII-2-1 DII-2- 1 In a similar manner to AJJJ-2-1, DII-i (.267 g, 1 mmol) was reacted with diethyl oxalate (.292 g, .271 ml, 2 mmol) and sodium ethoxide (.136 g, 2 minol) to yield the title compound as a yellow solid after trituration in diethyl ether.
183- WO 99/62513 PCT/US99/12095 1H NMR (400 MHz, CDC13) 6 1.41 3H, J 7.14 Hz), 4.39 2H, J 7.14 Hz), 5.35 2H), 6.83 1H), 7.05 2H, J 8.6 Hz), 7.13 7.20 2H), 7.30 7.39 3H), 7.88 1H), 8.40 1H, J 7.51 Hz) Step 3: 4 -fluorobenzyl)-IH-indol-3-yl]-2,4-dioxobutyric acid DII- 3-1
O
o DD-3-1 In a similar manner to AI-3-1, DII-2-1 g, .27 mmol) was hydrolyzed using .54 ml 1M LiOH (5.4 mmol) in 2 ml THF to give the title compound as a yellow solid. MP 161 162 oC. 1H NMR (400 MHz, CDC13) 5 5.36 2H), 6.92 1H), 7.07 2H, J 8.61 Hz), 7.15 7.23 2H), 7.31 7.39 3H), 7.95 1H), 8.30 1H, J 6.59 Hz) EXAMPLE 111 HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, C.M. and Bushman F.D. (1997) Cell; 88, 483 for recombinant integrase and preintegration complexes, respectively, hereby incorporated by reference for these purposes.
Representative compounds tested in the integrase assay demonstrated IC50's less than 1 micromolar. Further, representative 184- WO 99/62513 PCT/US99/12095 compounds tested in the preintegration complex assay also demonstrated IC50's of less than 1 micromolar.
EXAMPLE 112 Assay for inhibition of HIV replication Assays for the inhibition of acute HIV infection of Tlymphoid cells was conducted according to Vacca, J.P.et al., (1994), Proc. Natl. Acad. Sci. USA 91, 4906, herein incorporated by reference for these purposes.
Representative compounds tested in the present assay demonstrated IC95s of less than 10 micromolar.
EXAMPLE 113 Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as come within the scope of the following claims and their equivalents.
185-
Claims (7)
1. A compound of structural formula R 1 oR 7 R 8 O O (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R, R 2 and R8; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety; R 1 is selected from: -H, -C 1 5 alkyl, -CF 3 -halo, -NO 2 -R6, -C 2 5 alkenyl-R 3 -C 2 5 alkynyl-R 3 -O-R 6 (11) -O-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7; R 2 is selected from: -H, -R 3 -186- WO 99/62513 WO 9962513PCTIUS99/1 2095 (3) (4) (6) (7) (8) (9) (11) (12) (13) (14) -C 1 6 alkyl, -C 1 6 alkyl substituted with R, 66 -0-C 1 6 alkyl-OR, -C 1 6 alkyl (OR 6 -C 1 6 alkyl-N(R 4 6 -C 1 6 alkyl S(0)n-R6 -C 1 6 alkyl C(0)-R6 6 -C 1 6 alkyl C(S)-R -C 1 6 alkyl NR C(0)-R 6 and -C 1 6 alkyl-C(0)N(R )(XR each R 3 is (1) independently selected from: 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: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 Mf -OCF 3 -CN, hyifroxy, (i phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, -187- WO 99/62513 PCT/US99/12095 (iii) -CF 3 and (iv) hydroxy; 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: halogen, C 1 -6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; unsubstituted or substituted hexahydrothieno[3,4- d]imidazolyl with one or two substituents selected from: oxo, halogen, C1- 6 alkyl, C 1 .6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: -halogen,
188- WO 99/62513 PCT/US99/12095 -C 1 -6 alkyl, -C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; and 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: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; -189- WO 99/62513 WO 9962513PCTIUS99/1 2095 each R 4is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R 3 each R 5is independently selected from: -H, -C 1 3 alkyl, -CE 3 -R 3 -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R ,and each R 6is independently selected from: -C 1 3 alkyl-R and -R 3 R7 is selected from: and C1.6 alkyl; -190- 20234Y PCLtrr?~ IPE~' Ai 72CS R 8 is selected from: -H, C1-6 alkyl-oxy, and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. 2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: pyrrolyl, imidazolyl, pyrazolyl, and indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula Sis R is selected (1) (2) (3) (4) (6) (7) (8) from: -H, -CH3, -CF3, -halo, -N02, -phenyl, substituted phenyl subst selected from: halogen, C1-6 alkyl, C1-6 alkyloxy-, phenyl, -CF3, -OCF3, :ituted with 1 or 2 substituents independently
191- <Rr- WO 99/62513 WO 9962513PCTIUS99/1 2095 -CN, hydroxy, Wi phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, phenyl C 1 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and U) substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, 3 (11) -C 2 5 alkenyl-R 3 (12) -C 2 5 alkynyl-R and (13) -C(O)C}{2C(O)C(O)0R7; R is selected from: -H,
192- WO 99/62513 WO 99/25 13PCT/US99/1 2095 (2) (3) (4) (6) (7) (8) (9) (11) (12) (13) (14) 3 -C 1 6 alkyl, -C 1 6 alkyl substituted withR 6 6 -0-C 1 6 alkyl-OR 46 -C 1 6 alkyl(R -C 1 6 alkyl S(OR X 6 -C 1 6 alkyl C(O)-R 6 -C 1 6 alkyl C(S)-R -C 1 6 alkyl NR4 C(O)-R 6 and -C 1 6 alkyl-C(O)N(R each R 3 is (1) (2) independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, 193 WO 99/62513 PCT/US99/12095 (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1. 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI_6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF3, -OCF 3 -CN, hydroxy, phenyloxy, and -194- WO 99/62513 PCT/US99/12095 substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1. 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF3, -OCF 3
195- WO 99/62513 PCT/US99/12095 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1. 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 -6 cycloalkyl; (14) substituted C 3 -6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-,
196- WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, and hydroxy; piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C1. 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (19) naphthyl; substituted naphthyl with 1, 2, or 3 substituents independently selected from: -halogen, -C1. 6 alkyl, -197- WO 99/62513 PCT/US99/12095 -C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: -halogen, -CI-6 alkyl, -C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and -hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring; (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; each R 4 is independently selected from: -H, -C1- 3 alkyl, and -CF 3
198- WO 99/62513 PCT/US99/12095 each R 5 is independently selected from: -H, -C1- 3 alkyl, -CF 3 -R 3 -C 2 3 alkenyl, -C 1 3 alkyl-R 3 -C 2 .3 alkenyl-R 3 -S(O)n-R 3 and -C(O)-R3 each R is independently selected from: -C 1 -3 alkyl-R 3 and -R3 R7 is H; R8 is selected from: -H, -OCH3, and -CH3; and each n is independently selected from 0, 1 and 2. 3. The compound according to Claim 2 and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: pyrrolyl, imidazolyl, pyrazolyl, and -199- WO 99/62513 PCT/US99/12095 indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula R is selected from: -H, -CH 3 -CF 3 -halo, -NO 2 -N(R4 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, (11) -C 2 5 alkenyl-R 3 and (12) -C(O)CH2C(O)C(O)OR7. R 2 is selected from: -H, -R 3 -C1- 6 alkyl, -C 1 -6 alkyl substituted with R 3 -O-R 6 -O-C 1 -6 alkyl-OR 6 -S(O)n-R, -200- WO 99/62513 WO 9962513PCT/US99/1 2095 -C 1 6 alkyl (OR 6)(R4), -C 1 6 alkyl-N(R )(XR 6, 6 -C 1 6 alkyl S(O)n-R (11) -C 1 6 alk~yl NR C(O)-R 6, and (12) -C 1 6 alkYl-C(O)N(R each R 3 is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, Wi phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, 201 WO 99/62513 PCT/US99/12095 substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and (14) C 3 -6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: -H, -C1- 3 alkyl, and -CF 3 each R 5 is independently selected from: -H, -C1- 3 alkyl, -CF 3 and -R 3 each R is independently selected from: -C1- 3 alkyl-R 3 and -R 3 R7 is H; and -202- WO 99/62513 PCT/US99/12095 R8 is selected from: and CH3; and each n is independently selected from 0, 1 and 2. 4. The compound according to Claim 1 of structural formula: 'I R 8 0 N OR 7 R 2 0 0 and tautomers and pharmaceutically wherein: R 1 is selected from: -H, -C1- 5 alkyl, -CF 3 -halo, -NO 2 acceptable salts thereof, (7) (8) -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and (9) -203- WO 99/62513 WO 9962513PCTIJS99/1 2095 (11) (12) (13) methoxy, 3 -C 2 5 alkenyl-R 3 -C 2 5 alkynyl-R and -C(O)CH2C(O)C(O)0R7 R is selected from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted withR 6 -O-R -0-Cl 1 6 alkyl-0R 6 6 -S(O)n-R -C 1 6 alkyl (R 6 )(R 4 46 -C 1 6 alkyl S(O)n-R 6 6 (11) -C 1 6 alkyl C(O)-R 6 (12) -C 1 6 alkyl C(S)-R 4 6 (13) -C 1 6 alkyl NR 4C(O)-R ,and (14) -C 1 6 alkyl-C(O)N(R each R 3 is (1) (2) independently selected from: phenyl, substituted phenyl. with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, 204 WO 99/62513 PCT/US99/12095 hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy, thienyl, substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl, substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, phenyl, -205- WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF3, and (iv) hydroxy, imidazolyl, substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C1-6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF3, and (iv) hydroxy; pyrrolyl, substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, -206- WO 99/62513 WO 9962513PCT/US99/1 2095 C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, (11) pyrazolyl, (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CE' 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: Wi halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy, 207 WO 99/62513 PCT/US99/12095 (13) C 3 6 cycloalkyl, (14) substituted C3- 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy, piperidinyl, (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy, (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C 1 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and -208- WO 99/62513 PCT/US99/12095 hydroxy, (19) naphthyl, substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy, (21) indolyl, (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy, (23) C 3 -6 cycloalkyl fused with a phenyl ring, (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -209- WO 99/62513 WO 9962513PCT/US99/1 2095 -CN, and hydroxy; each R 4 is (1) (2) (3) (4) -o (5) (6) (7) (8) (9) independently selected from: -H, -Cl 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -C(0)-R3 independently selected from: -H, -C 1 3 alkyl, -CF 3 -R 3 -C 2 3 alkenyl, 3 -C 1 3 alkyl-R -C 2 3 alkenyl-R3 -S(O)n-R 3, and -()R3 each R 5 is (1) (2) (3) (4) (6) (7) (8) (9) each R 6is independently selected from: 3 -C 1 3 alkyl-R and _R 3 R 7 is selected from: -210- 20234Y PCT4 0 9 and C1-6 alkyl; R 8 is selected from: and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. The compound according to Claim 4 of structural formula: R 1 N OR 7 R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from: -H, -C1-5 alkyl, -CF3, -halo, -NO 2 -phenyl, substituted phenyl substituted with 1 substituent independently selected from: halo, methyl, and methoxy, phenyl C1-3 alkyl-, -211 WO 99/62513 WO 9962513PCT/1JS99/1 2095 substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, 3 (11) -C 2 5 alkenyl-R and (12) -C(O)CH2C(0)C(0)0R7- R 2 is selected from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted with R, 66 -C 1 akl O )R) 46 -C 1 6 alkyl-N(R 6 -C 1 6 alkyl C(O)-R (10) -C 1 6 alkyl NR C(O)-R 6, and (11) -Cl. 6 alkyl-C(O)N(R 4 eachR 3 is (1) (2) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 Mf -OCF 3 -212- WO 99/62513 PCT/US99/12095 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1. 2 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, C 3 6 cycloalkyl, piperidinyl, (11) morpholinyl, (12) substituted morpholinyl substituted with a substituent selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, =0, hydroxy; (12) naphthyl, (13) indolyl, and (14) C 3 -6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: -H, -213- 20234Y PCT/US 99/120 -C1-3 alkyl, -CF3, 3 -R 3 -C1-3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R3; each R is independently selected from: -H, -C1-3 alkyl, -CF3, 3 -R, -C1-3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R3 each R 6 is independently selected from: -C1-3 alkyl-R 3 and -R3; R 7 is selected from: and C1-4 alkyl; R 8 is selected from: and -CH3; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-4 alkyl, then R 2 is not -H or -C1-6 alkyl. 6. The compound according to Claim 5 of structural formula: -214- WO 99/62513 WO 9962513PCT/US99/1 2095 I-D N OR 7 R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R1is selected from: -H, -C 1 5 alkyl, -CF 3 -halo, wherein halo is selected from: Cl, -Br, and -I; -NO 2 -N(R 4 -phenyl, phenyl C 1 3 alkyl-, substituted phenyl C 1 -D alkvl- substituited with1 1 or9 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br; 3 -C 2 5 alkynyl-R and -C(O)CH2C(O)C(O)0R7; (11) R 2 is selected from: -H, -R 3 -Cl 1 6 alkyl, -C 1 6 alkyl substituted withR 66 -0-C 1 l. 6 alkyl-OR6 -C 1 6 alkyl (OR 6)(R4), -C 1 6 alkyl-N(R 4 )(R 6 -215 WO 99/62513 PCT/US99/12095 -C 1 6 alkyl C(O)-R 6 and -C1- 6 alkyl NR4C(O)-R6 each R 3 is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, CI. 6 alkyl, C1-6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy; C 3 -6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo; and naphthyl; each R is independently selected from: and -C1- 3 alkyl, -216- WO 99/62513 PCT/US99/12095 each R 5 is (1) (2) (3) (4) independently selected from: -H, -C 1 3 alkyl, -CF3, -R 3 -C 1 -3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R3 each R is independently selected from: -C 1 -3 alkyl-R 3 and -R 3 R7 is -H; R8 is selected from: and -CH3; and each n is independently selected from 0, 1 and 2. 7. The compound according to Claim 6 of structural formula: R' 0 N OH R 2 O 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: -H, -C 1 -5 alkyl, -217- mi WO 99/62513 PCT/US99/12095 -CF 3 -halo, wherein halo is selected from: C1, -Br, and -I; -NO 2 -N(R 4 (R 5 -phenyl, phenyl C1- 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C 2 5 alkynyl-R 3 R 2 is selected from: -H, -R 3 -C 1 6 alkyl, -C 1 -6 alkyl substituted with R 3 -O-R 6 -O-CI-6 alkyl-OR 6 -C 1 6 alkyl (OR 6 )(R 4 -C 1 -6 alkyl-N(R 4 )(R 6 -C 1 -6 alkyl C(O)-R 6 and -C1- 6 alkyl NR4C(O)-R6; each R 3 is (1) (2) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl, C1-6 alkyloxy-, phenyl, -218- WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and naphthyl; each R is independently selected from: and -C 1 -3 alkyl; each R 5 is independently selected from: -H, -C1. 3 alkyl, -CF 3 -R 3 -C1-3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R 3 each R 6 is independently selected from: -C1- 3 alkyl-R 3 and -219- WO 99/62513 PCT/US99/12095 -R 3 and each n is independently selected from 0, 1 and 2. 8. The compound according to Claim 6 of structural formula: 0 N OH R 2 O O and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: -H, -C1- 5 alkyl, -CF 3 -halo, wherein halo is selected from: Cl, -Br, and -I; -NO 2 -phenyl, phenyl C 1 -3 alkyl-, substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C 2 -5 alkynyl-R3; R 2 is selected from: -H, -R 3 -C 1 6 alkyl, -C 1 6 alkyl substituted with R 3 -O-R 6 -220- WO 99/62513 PCT/US99/12095 (6) (7) (8) (9) (10) -O-C 1 6 alkyl-OR 6 -C 1 6 alkyl (OR 6 )(R 4 -C 1 .6 alkyl-N(R 4 -C 1 -6 alkyl C(O)-R 6 and -C1- 6 alkyl NR 4 C(O)-R6 each R 3 is (1) (2) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and naphthyl; each R 4 is independently selected from: -221 WO 99/62513 PCT/US99/12095 and -C1-3 alkyl; each R 5 is independently selected from: -H, -CI- 3 alkyl, -CF 3 -R 3 -C1- 3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R 3 each R is independently selected from: -C1- 3 alkyl-R 3 and -R3; each n is independently selected from 0, 1 and 2. formula: 9. The compound according to Claim 1 of structural R 8 0 R 2 O R 2 and tautomers and pharmaceutically wherein: R 1 is selected from: -H, -C 1 5 alkyl, -CF 3 -halo, acceptable salts thereof, -222- WO 99/62513 WO 9962513PCTIUS99/1 2095 -NO 2 -N(R 4 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, (10) substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, 3 (11) -C 2 5 alkenyl-R 3 (12) -C 2 5 alkynyl-R and (13) -C(O)CH2C(O)C(O)0R7; R2 is selected from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted with R, 64 25(8) -0C 6 alkyl OR )R 46 -C 1 6 alkyl-N(R -C 1 6 alkyl S(O)n-R6 (11) -C 1 6 alkyl C(O)-R 6 (12) -C 1 6 alkyl C(S)-R? (13) -C 1 6 alkyl NR4 C(O)-R 6 and -223- WO 99/62513 PCT/US99/12095 (14) -C 1 -6 alkyl-C(O)N(R 4 )(R 5 each R 3 is (1) (2) independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1-6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1-6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, -224- 225 phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, 9 (iii) -CF 3 and (iv) hydroxy; pyrazolyl; substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, BH]01990.doc:sxc phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; C 3 6 cycloalkyl; substituted C3- 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 ,5 -CN, and hydroxy; (11) piperidinyl; (12) substituted piperidinyl substituted on a carbon atom with one or two f 20 substituents independently selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (13) morpholinyl; (14) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, T C 1 6 alkyl, C1- 6 alkyloxy-, 227 -CF 3 -OCF 3 -CN, and hydroxy; naphthyl; (16) substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) indolyl; (18) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, S(C) C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (19) C 3 6 cycloalkyl fused with a phenyl ring; substituted C 3 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, ~Tf -CF 3 -OCF 3 [I:\DayLib\LflBH]01990.doc:sxc 228 -CN, and hydroxy; each R4 is independently selected from: -H, -C 1 3 alkyl, -CF 3 -R -C 2 3 alkenyl,' -C 1 3 alkyl-R -C 2 3 alkenyl-R 3 and 3 each R 5 is independently selected from: 15 -H, -C 1 3 alkyl, -CF 3 -R 3 S S S S 555 5 S. S 0* S S SSSS S S S 555*55 S S 55* 55 S 0 5* S S S 55 [1:\DayLib\LIBH]O I 990.doc:sxc 229 THIS PAGE HAS BEEN INTENTIONALLY LEFT BLANK 0* [1:\DayLib\LIBH]O I 990.doc:sxc 20234Y PCT/l0 99 12095 .j 2000 -C2-3 alkenyl, -C1-3 alkyl-R 3 -C2-3 alkenyl-R 3 -S(O)n-R 3 and -C(O)-R3 each R 6 is independently selected from: -C1-3 alkyl-R 3 and -R3 R 7 is selected from: and C1-6 alkyl; R 8 is selected from: and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. The compound according to Claim 9 of structural formula: R 8 0 R 1 OH R 2 and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from: -H, -C1-5 alkyl, R- 230- R4 O/j WO 99/62513 PCT/US99/12095 R 2 is -CF 3 -halo, wherein halo is selected from: Cl, -Br, and -I; -NO 2 -phenyl, phenyl C 1 -3 alkyl-, substituted phenyl C 1 -3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C 2 5 alkynyl-R3; selected from: -H, -R 3 -C1- 6 alkyl, -C 1 -6 alkyl substituted with R 3 -O-R 6 -O-C1-6 alkyl-OR 6 -C 1 -6 alkyl (OR6)(R4), -C 1 6 alkyl-N(R4)(R6), -C 1 6 alkyl C(O)-R 6 and -C1- 6 alkyl NR4C(O)-R6 each R 3 is (1) (2) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 .6 alkyl, C 1 6 alkyloxy-, phenyl, -231 WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo; and naphthyl; each R is independently selected from: and -C1- 3 alkyl; each R 5 is independently selected from: -H, -C 1 3 alkyl, -CF 3 -R 3 -C1- 3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R 3 each R 6 is independently selected from: -C 1 3 alkyl-R 3 and -232- WO 99/62513 PCT/US99/12095 -R3; R 8 is selected from: and CH3; and each n is independently selected from 0, 1 and 2. 11. The compound according to Claim 1 of structural formula: /Y'R 1 0 R O OR 7 R 8 0 0 (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is pyrazolyl; R 1 is selected from: -H, -C1- 5 alkyl, -CF 3 -halo, -NO 2 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 -3 alkyl-, -233- WO 99/62513 WO 9962513PCTIUS99/1 2095 substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, (11) -C 2 5 alkenyl-R3 3 (12) -C 2 5 alkynyl-R ,and (13) -C(O)CH2C(O)C(O)0R7; R is each selec (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) R is (1) (2) ted from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted with R, 66 6 -0(~-CR6aklO 64 -C 1 6 alkyl (OR 6)(R -C 1 6 allkyl-N(R 6), 6 -C 1 6 alkyl S(O)n-R 6 -C 1 6 alkyl C(O)-R -C 1 6 alkyl C(S)-R6 -C 1 6 alkyl NR4 CO)-R 6 and -C 1 6 alkyl-C(O)N(R 4 5 independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, 234 WO 99/62513 PCT/US99/12095 phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: -235- WO 99/62513 WO 9962513PCT/US99/1 2095 hallogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; 236 WO 99/62513 PCT/US99/12095 pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, -237- H-u WO 99/62513 PCT/US99/12095 (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 -6 cycloalkyl; (14) substituted C3- 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 238 I WO 99/62513 PCT/US99/12095 -OCF 3 -CN, and hydroxy; (19) naphthyl; substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring; (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, -239- WO 99/62513 WO 9962513PCTIUS99/1 2095 C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; each R4is independently selected from: -H, -C 1 3 alkyl, -CF 3 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R ,and COR eachR is (1) (2) (3) (4) (6) (7) (8) (9) each R 6is (1) independently selected from: -H, -C 1 3 alkyl, -C3, 3 -R, -C 2 3 alkenyl, 3 -C 1 3 alkyl-R 3 -C 2 3 alkenyl-R -S(O)n-R 3, anld independently selected from: -C 1 3 alkyl-R 3 and 240 20234Y PCTIUS 9 0 9 IF nn -R3; R 7 is selected from: and C1-6 alkyl; R 8 is selected from: and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. 12. The compound according to Claim 11 wherein: R is selected from: -H, -C1-5 alkyl, -CF 3 -halo, wherein halo is selected from: Cl, -Br, and -I; -NO 2 -phenyl, phenyl C1-3 alkyl-, substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C 2 -5 alkynyl-R3 2 R is selected from: -H, -R 3 -C1- 6 alkyl, S(4) -C1- 6 alkyl substituted with R3 S-241 WO 99/62513 WO 9962513PCTIUS99/1 2095 (6) (7) (8) (9) 6 -0-CR. lkl0 6 64 -Cl- 6 alkyl (OR 6)(R -C 1 6 alkyl-N(R )(XR 6 -C 1 6 alkyl C(O)-R and -C 1 6 alkyl NR C(O)-R6 each R 3 is (1) (2) (3) (4) (6) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and Ci) substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from -F, Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and nap hthyl; 242 20234Y PCT/ 0 9 iF- 2000 4 each R is independently selected from: and -C1-3 alkyl; each R is independently selected from: -H, -C1-3 alkyl, -CF3, 3 -R, -C1-3 alkyl-R 3 3 -S(O)n-R 3 and -C(O)-R3; each R 6 is independently selected from: -C1-3 alkyl-R 3 and -R3; each R 7 is independently selected from: -H, -CH2CH3, and -CH3; and R 8 is selected from: and -CH3; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is -CH2CH3 or -CH3, then R 2 is not -H or -C1-6 alkyl; and tautomers and pharmaceutically acceptable salts thereof. 13. The compound according to Claim 12 of structural formula: -243- WO 99/62513 PCT/US99/12095 00 OR 7 NIN 0 R 2 and tautomers and pharmaceutically acceptable salts thereof. 14. The compound according to Claim 12 of structural formula: 00 OR 7 R' R2 and tautomers and pharmaceutically acceptable salts thereof. The compound according to Claim 1 of structural formula: R 1 OR 7 R 8 0 0 (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is imidazolyl; R 1 is selected from: -H, -C1- 5 alkyl, -CF 3 -244- WO 99/62513 WO 9962513PCTIUS99/1 2095 (9) -halo, -NO 2 -N(R -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C 1 3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, 3 -C 2 5 alkenyl-R 3 -C 2 5 alkynyl-R and -C(O)CH2C(O)C(O)0R7; (11) (12) (13) R 2 is selected from: -H, 3 -R, -C 1 6 alkyl, -C 1 6 alkyl substituted with R, 6 -0-R 6 -0-C 1 6 alkyl-OR S(O)n-R, -C 1 6 alkyl (O 6 )(R 4 -C 1 6 alkyl-N(R 4 6 (10)-C 1 6 lky S(~n- 6 (11) -C 1 6 alkyl C(O)-R 6 (12) -C 1 6 alkyl C(S)-R 245 WO 99/62513 PCT/US99/12095 (13) -C 1 -6 alkyl NR 4 C(O)-R 6 and (14) -CI-6 alkyl-C(O)N(R 4 )(R 5 each R is independently selected from: phenyl; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 -6 alkyl, C1- 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1-6 alkyl, C1-6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, -246- WO 99/62513 PCT/US99/12095 hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) CI. 6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C1 6 alkyloxy-, phenyl, 247 WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1. 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, -248- WO 99/62513 WO 9962513PCT/1JS99/1 2095 C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, WI phenyloxy, and Ci) substituted phenyloxy with 1, 2, or 3 substituents selected from: Wi halogen, (ii) C 1 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 6 cycloalkyl; (14) substituted C 3 6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 249 WO 99/62513 PCT/US99/12095 -OCF 3 -CN, and hydroxy; (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (19) naphthyl; substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, -250- WO 99/62513 PCT/US99/12095 -CF 3 -OCF 3 -CN, and hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring; (24) substituted C3- 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; each R is independently selected from: -H, -C1- 3 alkyl, -CF 3 -R 3 -C2- 3 alkenyl, -C1- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R 3 and -C(0)-R 3 each R 5 is independently selected from: -H, -251- 20234Y PC 1 0 9 L J 2000 -C1-3 alkyl, -CF3, 3 -R 3 -C2- 3 alkenyl, -C1- 3 alkyl-R 3 -C2- 3 alkenyl-R 3 3 -S(O)n-R 3 and -C(O)-R3; each R is independently selected from: -C1-3 alkyl-R 3 and -R3; R 7 is selected from: and C1-6 alkyl; R 8 is selected from: and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. 16. The compound according to Claim 15 of structural formula: R 1 N 0 LN OH R2 O O and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: -252- WO 99/62513 PCT/US99/12095 -H, -C1- 5 alkyl, -CF 3 -halo, wherein halo is selected from: Cl, -Br, and -I; -NO 2 -N(R 4 -phenyl, phenyl C 1 -3 alkyl-, substituted phenyl C 1 3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C 2 -5 alkynyl-R3 R 2 is selected from: -H, -R 3 -C 1 6 alkyl, -C1 6 alkyl substituted with R 3 -O-R 6 -0-C 1 -6 alkyl-OR 6 -C1- 6 alkyl (OR -C 1 -6 alkyl-N(R4)(R) -C 1 6 alkyl C(O)-R 6 and (10) -C 1 -6 alkyl NR4C(O)-R6; each R 3 is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C1. 6 alkyl, -253- WO 99/62513 PCT/US99/12095 C 1 6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from C1, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and naphthyl; each R 4 is independently selected from: and -C1. 3 alkyl; each R 5 is (1) (2) (3) (4) (6) (7) independently selected from: -H, -C1. 3 alkyl, -CF 3 -R 3 -C1-3 alkyl-R 3 -S(O)n-R 3 and -C(0)-R3; -254- WO 99/62513 PCT/US99/12095 each R 6 is (1) (2) independently selected from: -C1- 3 alkyl-R 3 and -R3; and each n is independently selected from 0, 1 and 2. 17. The compound according to Claim 1 of structural formula: RF A OR 7 R 8 O O (I) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indole; R 1 is selected from: -H, -C1- 5 alkyl, -CF 3 -halo, -NO 2 -phenyl, substituted phenyl substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, phenyl C13 alkyl-, -255- WO 99/62513 WO 9962513PCTIUS99/1 2095 substituted phenyl C 1 3 alkyl.- substituted with 1 or 2 substituents independently selected from: halo, methyl, and methoxy, 3 (11) -C 2 5 alkenyl-R (12) -C 2 5 alkynyl-R 3, and (13) -C(O)CH2C(O)C(O)0R7; R is selected from: -H, -C 1 6 alkyl, -C 1 6 alkyl. substituted with R, 66 -0-C 16 alkyl-OR6 64 -C 1 6 alkyl (OR 6)(R 46 (10) -C 1 6 alkyl. S(O)n-R 6 (11) -C 1 6 alkyl. C(O)-R 6 6 (12) -C 1 6 alkyl C(S)-R (13) -C 1 6 alkyl. NR C(O)-R 6 and (14) -C 1 6 alkyl-C(O)N(R each R 3is (1) (2) independently selected from: phenyl.; substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, 256 WO 99/62513 PCT/US99/12095 phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; thienyl; substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; pyridyl; substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: -257- WO 99/62513 PCT/US99/12095 halogen, C1. 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; imidazolyl; substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C 1 .6 alkyl, (iii) -CF 3 and (iv) hydroxy; -258- WO 99/62513 PCT/US99/12095 pyrrolyl; substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, (ii) C1- 6 alkyl, (iii) -CF 3 and (iv) hydroxy; (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, -259- WO 99/62513 PCT/US99/12095 (ii) C 1 -6 alkyl, (iii) -CF 3 and (iv) hydroxy; (13) C 3 -6 cycloalkyl, (14) substituted C 3 -6 cycloalkyl with 1 or 2 substituents independently selected from: halogen, C1. 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C 1 -6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: halogen, C1- 6 alkyl, C 1 -6 alkyloxy-, -CF 3 -260- WO 99/62513 PCT/US99/12095 -OCF 3 -CN, and hydroxy; (19) naphthyl; substituted naphthyl with 1, 2, or 3 substituents independently selected from: halogen, C1- 6 alkyl, C1-6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 .6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; (23) C 3 -6 cycloalkyl fused with a phenyl ring; (24) substituted C 3 -6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: halogen, C 1 -6 alkyl, -261 WO 99/62513 WO 9962513PCTIUS99/1 2095 C 1 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; each R 4is independently selected from: -H, -Cl 1 3 alkyl, -CF 3 -R, -C 2 3 alkenyl, 3 -Cl. 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(0)n-R ,and each R5is (1) (2) (3) (4) (6) (7) (8) (9) independently selected from: -H, -CF 3 -R 3 -C 2 3 alkenyl, 3 -C1-. 3 alkyl-R 3 and 3 each R 6is independently selected from: -C 1 3 alkyl-R and 262 PCTI/US 99/ 12095 IPEA'l:C' JUL 3 -R; R 7 is selected from: and C1-6 alkyl; R 8 is selected from: and C1-6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1-6 alkyl, then R 2 is not -H or -C1-6 alkyl. 18. The compound according to Claim 17 of structural formula: R 1 N OH R2 0 0 or a tautomer or a pharmaceutically acceptable salt thereof, wherein: 1 R is selected from: -H, -C1-5 alkyl, -CF3, -halo, wherein halo is selected from: Cl, -Br, and -I; -N02, -phenyl, phenyl C1-3 alkyl-, substituted phenyl C 1 -3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -263- WO 99/62513 PCT/US99/12095 R 2 is -C 2 5 alkynyl-R3; selected from: -H, -R 3 -C1- 6 alkyl, -C 1 -6 alkyl substituted with R 3 -O-R 6 -O-C 1 -6 alkyl-OR 6 -C1- 6 alkyl (OR -C 1 -6 alkyl-N(R4)(R6), -C1- 6 alkyl C(O)-R 6 and -C1- 6 alkyl NR4C(O)-R6 each R 3 is (1) (2) independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C-. 6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, -264- WO 99/62513 PCT/US99/12095 (3) (4) (6) (iii) -CF 3 and (iv) hydroxy, C 3 -6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and naphthyl; each R 4 is independently and -C1- 3 alkyl; selected from: each I rc Z is independently se -H, -C 1 3 alkyl, -CF 3 -R 3 -C 1 -3 alkyl-R 3 -S(O)n-R 3 and -C(O)-R3 lected from: each R 6 is independently selected from: -C1- 3 alkyl-R 3 and -R 3 and each n is independently selected from 0, 1 and 2. 19. The compound according to Claim 17 of structural formula: -265- 20234Y PCTA.Jl qo,, 0 9 or a tautomer or a pharmaceutically acceptable salt thereof, wherein: R is selected from: -H, -CI-5 alkyl, -CF3, -halo, wherein halo is selected from: Cl, -Br, and -I, -N02, -phenyl, phenyl C 1 -3 alkyl-, substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from: halo, wherein halo is selected from: -Cl, and -Br, and -C2-5 alkynyl-R3; R 2 is selected from: -H, -R 3 -C1-6 alkyl, 3 -C1-6 alkyl substituted with R 3 -O-R 6 -0-C1-6 alkyl-OR 6 -C1-6 alkyl (OR6)(R4), -C1-6 alkyl-N(R4)(R6), -266- c WO 99/62513 PCT/US99/12095 -C1-6 alkyl C(O)-R 6 and -C 1 -6 alkyl NR 4 C(O)-R 6 each R 3 is independently selected from: phenyl, substituted phenyl with 1, 2, or 3 substituents independently selected from: halogen, C 1 -6 alkyl, C 1 -6 alkyloxy-, phenyl, -CF 3 -OCF 3 -CN, hydroxy, phenyloxy, and substituted phenvloxv with 1. 2. or 3 suhstit.lnts selected from: halogen, wherein halogen is selected from Cl, and Br, (ii) methyl, (iii) -CF 3 and (iv) hydroxy, C 3 -6 cycloalkyl, morpholinyl, substituted morpholinyl substituted with oxo, and naphthyl; (3) (4) (6) each R 4 is (1) (2) independently selected from: and -C 1 3 alkyl; -267- WO 99/62513 WO 9962513PCTIUS99/1 2095 each R5is independently selected from: -H, -C 1 3 alkyl, -CF 3 -R 3 -C 1 3 alkyl-R 3 -S(O)n-R ,and each R 6is independently selected from: -C 1 3 alkyl-R 3 and -R 3 and each n is independently selected from 0, 1 and 2. The compound according to Claim 1 selected from: 4-[1-(4-fluorobenzyl)- lH-pyrrol-2-yl]-2,4.dioxobutyric acid methyl ester, 1-(4-fluorobenzyl)-l1F-pyrrol-2-yl]-2 ,4-dioxobutyric acid, 1-(4-methylbenzyl)- l-H-pyrrol-2-yl..2,4..dioxobutyric acid ethyl ester, 4-II-(4-methylbenzyl)- 1-H-pyrrol-2-yl] -2,4-dioxobutyric acid, 4- -(4-fluorobenzyl)- l-H-pyrrol-2-yl]-2,4.dioxobutyric acid ethyl ester, 1-(4-fluorobenzyl)- lF-pyrrol-2-yl]-2,4..dioxobutyric acid isopropyl ester, 1-(4-fluorobenzyl)- lJ-pyrrol-2-yl]-2,4-dioxobutyric acid n- butyl ester, 1-benzyl- lH-pyrrol-2-yl)-2,4-dioxobutyric acid, 2 1-naphthalen-2-ylmethyl- 1H-pyrrol-2-yl)-2 ,4-dioxobutyric acid, 1-biphenyl-4-ylmethyl- 1H-pyrrol 2-yl )-2,4-dioxobutyric acid, 268 20234Y PCT -L "2o (11) 1-naphthalen- 1-ylmethyl- 1H-pyrrol 2 -yl)- 2 ,4-dioxobutyric acid, (12) 2,4-dioxo-4-[ 1-(4-phenylbutyl). 1H-pyrrol -2-yII-butyric acid, (13) 1-(4-chlorobenzyl). H-pyrroI-2-y1]-2,4dioxobutyric acid, (14) 2,4-dioxo-4-( 1-phenethyl- 1H-pyrroI -2-yl)-butyric acid, 1-( 2 -methylbenzyl)- lH-pyrroI-2-y1]-2,4dioxobutyric acid, (16) 1-(3 ,4-difluorobenzyl)- lH-pyrroI-2-yI]-2,4-dioxobutyric acid, (17) 1-(4-bromobenzyl)- 1H-pyrrol-2-yl] 2 ,4-dioxobutyric acid, (18) 1-( 2 -bromobenzyl)- 1H-pyrrol-2-yl] 2 ,4-dioxobutyric acid, (19) 4- [1-(3-bromobenzyl)- lH-pyrrol-2-yI]-2,4-dioxobutyiic acid, I-(3-chlorobenzyl)- lH-pyrroI-2-yI]-2,4-dioxobutyric acid, (21) 1-(3-methylbenzyl)- 1H-pyrrol-2-yI] 2 ,4-dioxobutyric acid, (22) 1-(2-fluorobenzyl)- lH-pyr-rol-2-yIJ-2,4-dioxobutyric acid, (23) 2,4-dioxo-4-( 1-hexyl- 1H-pyrrol 2 -yI)-butyric acid, (24) I-biphenyl-2-ylmethyl 1H-pyrrol 2 -yl)- 2 ,4-dioxobutyric acid, 2,4-dioxo-4-[ 1-(4-phenoxybutyl)- 1H -pyrrol-2-ylJ-butyric acid, (26) 4- [1-(3-fluorobenzyl)- lH-pyrrol-2-yI]-2,4-dioxobutytic acid, (27) 4-[1 -(2-chlorobenzyl)- lH-pyrroI- 2 -yI]-2,4-dioxobutyric acid, (28) 1-(4-fluorobenzyl)-4-iodo I-pyrrol- 2 -yI]-2,4-dioxo-butyric acid, (29) 4-11 -(4-methoxybenzyl)- lH-pyrrol-2-yI] 2 ,4-dioxobutyric acid, I-( 2 4 ,5-trifluorobenzy1)- lH-pyrrol-2-yI]-2,4-dioxobutyic acid, (31) 1-( 2 ,3-difluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutynic acid, (32) 1-(3 ,5-difluorobenzyl)-lH-pyrol-2-y]-2,4-dioxobutyic acid, (33) 1-( 2 ,5-difluorobenzyl)- lH-pyrrol-2-yI]-2,4-dioxobutyic acid, (34) 1-( 2 ,5,6-difluorobenzyl)- IH-pyrrol-2-yI]-2,4-dioxobuty-ic acid, 4- [1-(2-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (36) 1-( 4 -trifluoromethylbenzyly 1 H-pyrrol-2-yl] -2,4-dioxobutyric acid, (37) 4-[1 -(4-cyanobenzyl)- 1H-pyrrol-2-yl] 2 ,4-dioxobutyric acid, 269 WO 99/62513 WO 9962513PCT/US99/1 2095 (38) 1-(3-methoxybenzyl 111 -pyrrol-2-yl] -2 ,4-dioxobutyric acid, (39) 2-hydroxy-4-[ 1-(4-hydroxybenzyl 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, (40) 4 -(l-cyclopentylmethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (41) 4 3 -(4-fluorophenyl)propyl-H-pyrrol2y.2,4. dioxobutyric acid, (42) 4-11- [2-(4-fluorophenyl)ethyl]- 1H-pyrrol-2-yl) -2 ,4-dioxobutyric acid, (43) 4-[1-(3-phenylpropyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (44) 44-( 1ethyl- 1H-pyrrol- 2-yl) -2,4-dioxobutyric acid, 4-[1-3-fluorobenzyl)- 1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (46) 4-lI1-(2-chlorobenzyl)- 1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (47) l-( 3 -benzoylaminopropyl)- 1H-pyrrol-3-yl] -2 ,4-dioxobutyric acid, (48) 4-1 l-[ 3 -(4-fluorophenoxy)benzyl]- 1H-pyrrol-2-yl}] -2,4- dioxobutyric acid, (49) 1-cyclohexylmethyl- 1-H -pyrrol-2-yl ,4-dioxo-butyric acid methyl. ester (50) 1-cyclohexylmethyl- 1-H -pyrrol-2-yl ,4-dioxo-butyric acid, (51) 4- 4 -fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl-2 ,4- dioxobutyric acid ethyl ester, (52) 4- 4 -fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (53) 1-(4-fluorobenzyl )-4-phenethyl- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (54) l-( 4 -fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (55) 4-[5-(4-fluorobenzyl)- 1-methyl-ll -pyrrol-2-yl]-2,4- dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)- 1-methyl-llH -pyrrol-2-yl]-2 ,4- dioxobutyric acid, (57) 4-15-(3-chlorobenzyl)- 1-methyl-lH -pyrrol-2-yl]-2 ,4- dioxobutyric acid, 270 WO 99/62513 WO 9962513PCT/US99/1 2095 (58) 4 -[5-(4-fluorobenzyl)- 1H -pyrrol- 2 -yl]-2,4-dioxobutyric acid, (59) 4-[5-(3-chlorobenzyl)- 11 -pyrrol-2-yl]-2,4-dioxobutyric acid, 4-[5-(benzyl)- 1-H -pyrrol-2-yl]-2,4-dioxobutyric acid, (61) 4-[54(3-fluorobenzybl H -pyrrol-2-yl]-2 ,4-dioxobutyric acid, (62) 4 -[5-(4-fluorobenzyl 1-(4-fluorobenzyl)- 11 -pyrrol-2-yl] -2,4- dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)-I11 -pyrrol-2-yl]-2,4- dioxobutyric acid, (64) 4-[5-(benzyl)- 1-(4-fluorobenzyl 1H -pyrrol-2-yl] -2,4- dioxobutyric acid, 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- 111 -pyrrol-2-yl] -2,4- dioxobutyric acid, (66) 4 -[5-(4-fluorobenzyl 1-methyl-ll -pyrrol-3-yl]-2 ,4- dioxobutyric acid, (67) 4 -[5-(3-chlorobenzyl)- 1-methyl- 1H -pyrrol-3-yl]-2,4- dioxobutyric acid, (68) 4-[5-(benzyl)- 1-methyl-llH -pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4 -[5-(3-fluorobenzyl)- 1-methyl-l! -pyrrol-3-yl]-2 ,4- dioxobutyric acid, (70) 4-(5-benzyl- 11 -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4 -E 2 ,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (72) 1-(4-Fluorobenzyl )-5-phenyl- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (73) 1-(4-Fluorobenzyl )-5-phenyl- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (74) 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, 4-[4-Dimethylamino. -(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2 ,4- dioxobutyric acid, (76) l-( 4 -Fluorobenzyl 4 -nitro-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4 -1 4 -(Benzylamino)- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2 ,4- dioxobutyric acid, (78) 4-[5-Nitro- l-(4-fluorobenzyl)- l-I-pyrrol-2-yl]-2,4-dioxobutyric -271 WO 99/62513 WO 9962513PCTIUS99/1 2095 (79) 4 -[l-benzyl-1H-pyrrol-3-yl]-2,4.dioxobutyr-jc acid methyl ester, 4 -[l-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 1-(4-fluorobenzyl 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (82) 4-[1-(3-bromobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) l-(4-fluorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4- dioxobutyric acid, (84) 4-[2 ,4-dimethyl- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl]-2 ,4- dioxobutyric acid, (85) 1-(3 ,4-clifluorobenzyl 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (86) 4 3 -chlorobenzyl)-iH-pyrrol-3-yl]-2,4.cdioxobutrc acid, (87) 4-l -(4-chlorobenzyl lII-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 1-(4-bromobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (89) ,4-dichlorobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, i-(2-methylbenzyl)- 1H-pyrrol-3-yl] -2 ,4-dioxobutyr.ic acid,_ (91) 1-(3-chlorobenzyl )-4-methyl- 1H-pyrrol-3-yl]-2,4- dioxobutyric acid, (92) l- 3 -trifluoromethylbenzyl 1I-pyrrol-3-yl]-2,4- dioxobutyric acid, (93) 4- -(4-methylbenzyl)- 1JI-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (94) 4-ri -(4-methoxybenzyl)- lH-pyrrol-3-yfl-2,4-dioxobutyric acid, 4-[1-(3-methylbenzyl)- lF-pyrrol-3-yl]-2 ,4-dioxobutylric acid,_ (96) 4-f l-[ 3 -(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl) -2,4- dioxobutyric acid, (97) 4- -(4-bromobenzyl)- 1-H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (98) 1-(4-chlorobenzyl)- 1-H-pyrrol-3-yl] -2 ,4-dioxobutyric acid, (99) 4 -14-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]- 2,4-dioxobutyric, ethyl ester (100) 4- [4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid, (101) 4-[4-Phenyl- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, 272 WO 99/62513 WO 9962513PCT/US99/1 2095 (102) 4-E4-Phenyl- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (103) l- 4 -fluorobenzyl )-4-methanesulfonylamino. 1H-pyrrol-3- yl]-2,4-dioxo-butyric acid ethyl ester, (104) 4-El -(4-fluorobenzyl )-4-methanesulfonylamino- 1H-pyrrol-3- yl]-2,4-dioxo-butyric acid, (105) 4 4 -Fluorobenzyl)-3-acetylamino-lIH-pyrrol-2-yl]-2 ,4- dioxobutyric acid, (106) 4-[4-acetylamino- 1-(4-fluorobenzyl 1H-pyrrol-2-ylI -2,4- dioxobutyric acid, (108) 4- [4-(4-fluorobenzyl)- I -pyrrol-3-yl]-2,4-dioxobutyric acid, (109) 1,4-bis-(4-fluorobenzyl)- 1H1 -pyrrol-3-yl]-2,4-clioxobutyric acid, (110) 4 -E5-(3-ethoxycarbonyl-3-oxopropionyl 1-(4-fluorobenzyl)- 1H- pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 1-(4-fluorobenzyl)- 1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4 -El-( 4 -fluorobenzyl)-1JI-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino- 1-(4-fluorobenzyl lJI-pyrrol-3-yl] -2,4- dioxobutyric acid, (114) 1-(4-Fluorobenzyl )-5-methyl-l1F-pyrazol-4-yl]-2-hydroxy-4- oxobut-2-enoic acid, (115) 4 2 -(4-fluorobenzyl)-2H-pyrazol-3-yl]-2 ,4-dioxo-butyric acid ethyl ester, (116) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl.2 ,4-dioxo-butyric acid, (117) 1-E 1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2 ,4- dioxobutyric acid ethyl ester, (118) l-E1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4- dioxobutyric acid, (119) 4-E3-methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl]-2 ,4- dioxobutyric acid ethyl ester, (120) 4-[3 -methyl- 1-(3-chlorobenzyl)- 1JI-pyrazol-4-yl]-2,4- dioxobutyric acid, (121) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1FI-pyrazol-4-yl] -2,4- dioxobutyric acid, 273 WO 99/62513 WO 9962513PCT/US99/1 2095 (122) 445 -methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl] -2,4- dioxobutyric acid ethyl este,r (123) 4-45 -methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl] -2,4- dioxobutyric acid, (124) 4 -[1-(4-fluoro-benzyl)- lH-imidazol-2-yl]-2,4-dioxo-butyric acid, (125) 1-(4-fluorobenzyl 1H-imidazol-2-yl]-2 ,4-dioxo-butyric acid ethyl ester, (126) 1-(4-fluorobenzyl lH-imidazol-2-yll-2,4-dioxo-butyric acid, (127) 1-Benzyl- lH-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4 4 -fluorobenzyl)-1H-imidazol-4-yl].2,4-dioxo..butyric acid ethyl ester, (129) 4 4 -fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid, (130) 1-(4-fluorobenzyl 1H -indol 2 -yl]-2,4-dioxobutyric acid methyl ester, (131) 4-[1-(4-fluorobenzyl)- 111 -indol 2 -yl)-2,4-dioxobutyric acid, (132) 2-hydroxy-4-( 1-methyl- 1-H -indol-2-yl) -2,4-dioxobutyric acid, (133) 4-[1-(4-fluorobenzyl)- 1H-indol-3-yl]-2 ,4-dioxobutyric acid, (134) 1-I1-(4-fluorobenzyl lH-indol-3-yl]-2,4-dioxobutyric acdd ethyl ester, (135) 1-(4-fluorobenzyl 1H-indol-3-yl]-2 ,4-dioxobutyric acid,( 136) 1-(3-fluorobenzyl)- 1-H-p yrrol-3-yl]-2 ,4- dioxobutyric acid, (137) 4-4(-hooezl---yro--l-,-ix-uyi acid, (138) 4-[4-(4-fluorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl] -2,4-dioxo- butyric acid, (139) 4-12 ,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-p yrrol-3-yl] -2,4-dioxo- butyric acid, (140) 4- [1-(3,5-dichlorobenzyl)- 1-H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (141) 4-11-(3-thiophenemethyl)- l-H-pyrrol-3-yll-2,4-dioxobutyric acid, (142) 4-[1 2 4 -dimethylbenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, 274 WO 99/62513 WO 9962513PCTJUS99/1 2095 (143) 4 -Iil-(3-chloro-5-methyl-benzyl)- 1-H-pyrrol-3-yl]-2,4-clioxo- butyric acid, (144). 1-naphthalenemethyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (145) 4-[1-(2-thiophenemethyl)- l-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and (146) 4 4 -(3-chlorobenzyl)-1-methyl--H-pyrrol.3yll2,4. dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof. 21. The compound according to Claim 1 selected from: 4-[1-(4-fluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, 1-(4-methylbenzyl)- 1-H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, 1-benzyl- 1H-pyrrol-2-yl )-2,4-dioxobutyric acid, 1-naphthalen-2-ylmethyl- 1tH-pyrrol-2-yl ,4-dioxobutyric acid, 1-biphenyl-4-ylmethyl- 1H-pyrroI -2-yl)-2,4-.dioxobutyric acid, 1-naphthalen- 1-ylmethyl- 1H-pyrrol -2-yl)-2,4-dioxobutyric acid, 2 ,4-dioxo-4-[ 1-(4-phenylbutyl 1II-pyrrol 2 yl] -butyric acid, 1-(4-chlorobenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, (9) 2,4-dioxo-4-( 1-phenethyl-lHJ-pyrrol -2-yl)-butyric acid, 4-[1-(2-methylbenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, (11) 1-(3 ,4-difluorobenzyl)- IF-pyrrol-2-yl]-2,4-dioxobutyric acid, (12) 1-(4-bromobenzyl)- l-I-pyrrol-2-yl]-2,4-dioxobutyric acid, (13) 4- -(2-bromobenzyl)- lf-pyrrol-2-yl]-2,4-dioxobutyric acid, (14) 1-(3-bromobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (15) 44 1-(3-chlorobenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid, (16) 1-(3-methylbenzyl)- lU-pyrrol-2-yl]-2 ,4-dioxobutyric acid, (17) 1-(2-fluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (18) 2,4-dioxo-4-( 1-hexyl-lII-pyrrol -2-yl)-butyric acid, (19) 1-biphenyl-2-ylmethyl. 1H-pyrrol -2-yl )-2,4-dioxobutyric acid,(20) 2 4 -dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl]- 275 WO 99/62513 WO 9962513PCTIUS99/1 2095 butyric acid, (21) 1-(3-fluorobenzyl)-1H-pyrrol-2yl].2,4. dioxobutyric acid, (22) 1-(2-chlorobenzyl)-1H-pyrrol-2. yl]-2 ,4-dioxobutyric acid,(23) 1-(4-fluorobenzyl)-4-iodo- lFI-pyrrol-2-yl]-2,4-dioxo-butyric acid, (24) 4-[l methoxybenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric 1-(2,4,5-trifluorobenzyl)- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (26) 1-(2,3-cifluorobenzyl)- 1H-pyrrol-2-yl]-2 ,4-dioxobutyric acid,(27) 4-I1-(3,5-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (28) 4-I[l-(2,5-difluorobenzyl). 1H-pyrrol- 2-yl]-2,4-dioxobutyric acid, (29) 1-(2 ,5 ,6-difluorobenzyl lII-pyrrol-2-yl]-2,4-dioxobutyric acid, (30) 1-(2-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, (31) l-(4-trifluoromethylbenzyl)- 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, (32) 4-[1-(4-cyanobenzyl)- 1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (33) 1-(3-methoxybenzyl)- 111 -pyrrol-2-yl] -2,4-dioxobutyric acid, (34) 2-hydroxy-4-[ 1-(4-hyclroxybenzyl 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, 1-cyclopentylmethyl- 1H-pyrrol-2-yl) -2 ,4-dioxobutyric acid, (36) 4-f l-[3-(4-fluorophenyl)propyl] H-pyrrol-2-yl-2 ,4- dioxobutyric acid, (37) l-[2-(4-fluorophenyl)ethyl]- 1H-pyrrol-2-yl)-2 ,4-dioxobutyric acid, (38) 4-[1-(3-phenylpropyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (39) 4-(l 1-ethyl- 1H-pyrrol- 2-yl) -2,4-dioxobutyric acid, 4-[1-(3-fluoro-benzyl)- 1-H -pyrrol-2-yl i- 2 ,4-dioxobutyric acid, (41) 4-I11-2-chloro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (42) l-(3-benzoylaminopropyl)- 1H-pyrrol-3-yl] -2,4-dioxobutyric acid, (43) 4-f i-[3-(4-fluorophenoxy)benzyl]- 1H-pyrrol-2-yl}] -2,4- dioxobutyric acid, -276- WO 99/62513 WO 9962513PCTJUS99/1 2095 (44) 1-cyclohexylmethyl- 1-H -pyrrol-2-yl)-2 ,4-dioxo-butyric acid, 4- [1-(4-fluorobenzyl )-4-phenylethynyl- 1H-pyrrol-2-yl]-2 ,4- dioxobutyric acid, (46) 4-[Il-(4-fluorobenzyl)-4-phenethyl- 1tI-pyrrol-2-yl]- 2,4- dioxobutyric acid, (47) 4-15-(4-fluorobenzyl)- 1-methyl-llH -pyrrol-2-yl]-2 ,4- dioxobutyric acid, (48) 4 -[5-(3-chlorobenzyl)- 1-methyl- Il -pyrrol-2-yl]-2 ,4- dioxobutyric acid, (49) 4-[5-4-fluorobenzyl)- 11 -pyrrol-2-yl]-2,4-dioxobutyric acid, 4-[5-(3-chlorobenzyl )-ll -pyrrol-2-yl]-2,4-dioxobutyric acid, (51) 4- [5-(benzyl )-ll -pyrrol-2-yl]-2 ,4-dioxobutyric acid, (52) 4-[5-(3-fluorobenzyl)-ll -pyrrol-2-yl]-2,4-dioxobutyric acid, (53) 4-15-(4-fluorobenzyl)- 1-(4-fluorobenzyl)- 11 -pyrrol-2-yl]-2,4- dioxobutyric acid, (54) 4-15-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- il -pyrrol-2-yl]-2,4- dioxobutyric acid, 4-15-(benzyl)- 1-(4-fluorobenzyl Il -pyrrol-2-yl]-2 ,4- dioxobutyric acid, (56) 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- Il -pyrrol-2-yl]-2,4- dioxobutyric acid, (57) 4-[5-(4-fluorobenzyl)- 1-methyl-llH -pyrrol-3-yl]-2 ,4- dioxobutyric acid, (58) 4-15-(3-chlorobenzyl)- 1-methyl-llH -pyrrol-3-yl]-2,4- dioxobutyric acid, (59) 4-15-(benzyl)- 1-methyl-ill -pyrrol-3-yl]-2,4-dioxobutyric acid, 4 -15-(3-fluorobenzyl)- 1-methyl-llH -pyrrol-3-yl]-2,4- clioxobutyric acid, (61) 4-(5-benzyl-ll -pyrrol-3-yl)-2,4-dioxobutyric acid, (62) 4 2 ,5-bis-(3-chlorobenzyl)- 1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (63) l-( 4 -Fluorobenzyl)-5-phenyl- 1H-pyr-rol-2-yl]-2,4- dioxobutyric acid, 277 WO 99/62513 WO 9962513PCTIUS99/1 2095 (64) 4-[4-Dimethylamino- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2 ,4- dioxobutyric acid, l-(4-Fluorobenzyl)-4-nitro- lfI-pyrrol-2-yl]-2,4-dioxobutyric acid, (66) 4- [4-(Benzylamino)- 1-(4-fluorobenzyl 1H-pyrrolb2-yl]-2 ,4- dioxobutyric acid, (67) 4-[5-Nitro- 1-(4-fluorobenzyl)- l-H-pyrrol-2-yl]-2,4-clioxobutyric (68) 4 -[l-benzyl-lHk-pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4 4 -fluorobenzyl)-iTI-pyrrol-3-yl]-2,4-dioxobutyric acid, (70) 4 -[1-(3-bromobenzyl)-1I-pyrrol-3-yl]-2,4-dioxobutyric acid, (71) l-(4-fluorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4- dioxobutyric acid, (72) 4-[2 ,4-dimethyl- 1-(4-fluorobenzyl)-l1F-pyrrol-3-yl]-2 ,4- dioxobutyric acid, (73) 4-[l ,4-difluorobenzyl)- 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, (74) 1-(3-chlorobenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 1-(4-chlorobenzyl)- lFI-pyrrol-3-yl]-2,4-dioxobutyric acid, (76) 1-(4-bromobenzyl)- lFI-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (77) ,4-dichlorobenzyl)- lfI-pyrrol-3-yHl-2,4-dioxobutyric acid,_ (78) 4-[1-(2-methylbenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric, acid,_ (79) l-(3-chlorobenzyl)-4-methyl- 1H-pyrrol-3-yfl-2,4- dioxobutyric acid, (80) l-(3-trifluoromethylbenzyl)-1Fi-pyrrolb3yl]-2,4. dioxobutyric acid, (81) 4-I1-(4-methylbenzyl)-lIF-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-I1-(4-methoxybenzyl)- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) 4-1 -(3-methylbenzyl)- 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid,_ (84) 4- -[3-(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl} -2,4- dioxobutyric acid, 4-[1-(4-bromobenzyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 1-(4-chlorobenzyl 1-H-pyrrol-3-yl] 2 ,4-dioxobutyric acid, (87) 4- [4-Benzylmethylamino- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid, 278 WO 99/62513 WO 9962513PCTJUS99/1 2095 (88) 4-[4-Phenyl- 1-(4-fluorobenzyl 1H-pyrrol-2-yl]-2,4- dioxobutyric acid, (89) 4-[l1-( 4 -fluorobenzyl)-4-methanesulfonylamino. H-pyrrol-3- yl]-2,4-dioxo-butyric acid, (90) 4-l -(4-Fluorobenzyl )-3-acetylamino- 1H-pyrrol-2-yl]-2 ,4- dioxobutyric acid, (91) 4-[4-acetylamino- 1-(4-fluorobenzyl 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, (93) 4-[4-(4-fluorobenzyl 1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-El ,4-bis-(4-fluorobenzyl)- 1H -pyrroll-3-yl]-2,4-dioxobutyric acid, 4-[1-(4-fluorobenzyl)- 1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (96) 4-[4-Dimethylamino- l-(4-fluorobenzyl)-l11-pyrrol-3-yl] -2,4- dioxobutyric acid, (97) 1-(4-Fluorobenzyl )-5-methyl- lH-pyrazol-4-y]-2-hydroxy-4- oxobut-2-enoic acid, (98) 4 2 4 -fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid, (99) 1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4- dioxobutyric acid, (100) 4-[3 -methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl]-2,4- dioxobutyric acid, (101) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4- dioxobutyric acid, (102) 4-[5 -methyl- 1-(3-chlorobenzyl 1H-pyrazol-4-yl]-2,4- dioxobutyric acid, (103) 4-[1-(4-fluoro-benzyl)- 1H-imidazol-2-yl] -2,4-dioxo-butyric acid, (104) 1-(4-fluorobenzyl)- lH-imidazol-2-yl]-2,4-dioxo-butyric acid, (105) 1-Benzyl- 1FI-imidazol-2-yl)-2 ,4-dioxobutyric acid, (106) 4-[l-(4-fluorobenzyl)- lH-imidazol-4-yl]-2,4-dioxo..butyric acid, (107) 4-l -(4-fluorobenzyl)- 1.H -indol -2-yl] -2,4-dioxobutyric acid, (108) 2-hydroxy-4-( 1-methyl- 1-H -indol-2-yl) -2,4-dioxobutyric acid, (109) 4-[1-(4-fluorobenzyl)- 1H-indol-3-yl]-2,4-dioxobutyric acid, (110) 1- [1-(4-fluorobenzyl)- 1H-indol-3-yH]-2,4-dioxobutyric acid, ethyl ester, -279- WO 99/62513 WO 9962513PCTJUS99/1 2095 (111) l-[l-(4-fluorobenzyl).lH-indol-3-yl]-2,4-dioxobutyric acid,( 12) 4 -[l-(3-fluorobenzyl)-1-H-pyrrol3yl..2,4. dioxobutyric acid, (113) 4 -[4-(3-chlorobenzyl)- l-H-pyrrol-3-yl]-2,4-dioxo..butyric acid, (114) 4 -14-(4-fluorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl] -2,4-dioxo- butyric acid, (115) 4-[2 ,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-p yrrol-3-yl] -2 ,4-dioxo- butyric acid, (116) 4 -Iil-( 3 ,5-dichlorobenzyl)- 1-H-p yrrol -3-yl]-2 ,4-dioxobutyric acid, (117) 4 -[l-(3-thiophenemethyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (118) 4 2 4 -dimethylbenzyl)-1-H-pyrro13.y1}-2,4-ioxobutyric acid, (119) 3 -chloro-5-methyl-benzyl 1-H-pyrrol-3-yl]-2,4-dioxo. butyric acid, (120) l-naphthalenemethyl)- 1-H-p yrrol-3-yl]-2 ,4-dioxobutyric acid, (121) 4 -[l-(2-thiophenemethyl l-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and (1-22) 4 -[4-(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl]-2 ,4- dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof. 22. The compound according to Claim 21 selected from: 4 -[l-(2-thiophenemethyl)- l-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and 4 4 -(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl]-2,4- dioxobutyric acid, 4 -I[l-(4-fluorobenzyl)- lU-pyrrol-2-yl]-2,4-dioxobutyric acid, 4 3 -chlorobenzyl)- 1-methyl-llH -pyrrol-2-yl]-2,4- dioxobutyric acid, 4 4 -fluorobenzyl)- il -pyrrol-2-yl]-2 ,4-dioxobutyric acid, 4 -[5-(4-fluorobenzyl)-l -methyl-lUH -pyrrol-3-yl]-2,4- dioxobutyric acid, 280 WO 99/62513PC/S9125 PCT/7JS99/12095 4-[5-(3-chlorobenzy)- 1-methyl-ll -pyrrol-3-yl]-2 ,4- dioxobutyric acid, 4- [5-(benzyl)- 1-methyl-llH -pyrrol- 3-yl]-2 ,4-dioxobutyric acid, 4-15-(3-fluorobenzyl)- 1-methyl- llH -pyrrol-3-yl]-2,4- dioxobutyric acid, 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4- dioxobutyric acid, (11) 4-II1-benzyl- lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (12) 4 -[1-(3-bromobenzyl)- lF-pyrrol-3-yl]-2,4-dioxobutyric acid, (13) l-(4-fluorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4- dioxobutyric acid, (14) 1-(3 ,4-difluorobenzyl 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid, 1-(3-chlorobenzyl)- IJ-pyrrol-3-yl]-2,4-dioxobutyric acid, (16) 1-(2-methylbenzyl)- lH-pyrrol-3-yll-2,4-dioxobutyric acid,_ (17) 4-[1-(3-methylbenzyl)- 1H-pyrrol-3-yl]-2 ,4-dioxobutyric acid,_ (18) 4 -[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]- 2,4-dioxobutyric acid, (19) 4-14-(4-fluorobenzyl)- 1-H -pyrrol-3-yl]-2,4-dioxobutyrjc acid, (20) 1, 4 -bis-(4-fluorobenzyl)- 1-H -pyrrol-3-yl]-2 ,4-dioxobutyric acid, (21) 4-l -(3-fluorobenzyl)- 1-H-p yrrol-3-yl]-2 ,4- dioxobutyric acid, (22) 4-[4-(3-chlorobenzyl)- l-H-pyrrol-3-yl-2,4-dioxo-butyric acid, (23) 4-[4-(4-fluorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl] -2,4-clioxo- butyric acid, (24) 4-[2 ,S-dimethyl-1-(4-fluorobenzyl)-. -H-p yrrol-3-yl] -2,4-dioxo- butyric acid, l-(3,5-dichlorobenzyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (26) 1-(3-thiophenemethyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyriic acid, (27) l-2,4-dimethylbenzyl)- l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (28) 4 3 -chloro-5-methyl-benzyl)- l-H-pyrrol-3-yl]-2,4-dioxo- butyric acid, and 281 WO 99/62513 PCT/US99/12095 (29) 4-[1-(1-naphthalenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid; or a tautomer or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition useful for inhibiting HIV integrase, comprising an effective amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier. 24. The pharmaceutical composition of Claim 23, useful for treating infection by HIV, or for treating AIDS or ARC. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a therapeutically effective amount of an AIDS treatment agent selected from an AIDS antiviral agent, an anti-infective agent, and an immunomodulator. 26. The composition of Claim 25 wherein the antiviral agent is an HIV protease inhibitor. 27. The composition of Claim 26 wherein the HIV protease inhibitor is N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl- 4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier. 29. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier. -282- 283 A method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 31. A method of treating infection by HIV, or of treating AIDS or ARC, comprising the administration to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 32. A pharmaceutical composition when prepared by the process of Claim 29. 33. Use of a therapeutically effective amount of a compound according to Claim 1 for the manufacture of a medicament for inhibiting HIV integrase in a mammal in need of such treatment. 34. Use of a therapeutically effective amount of a compound according to Claim 1 for the manufacture of a medicament for treating infection by HIV, or of treating AIDS or ARC in a mammal in need of such treatment. o35. A therapeutically effective amount of a compound according to Claim 1 when 15 used for inhibiting HIV integrase in a mammal in need of such treatment. 36. A therapeutically effective amount of a compound according to Claim 1 when used for treating infection by HIV, or for treating AIDS or ARC in a mammal in need of such treatment. 37. A process for preparing a compound of formula I, said process being 20 substantially as hereinbefore described with reference to any one of the examples. 38. A compound of formula I, *R 0 R 2 A .000 4) II O O (I) and tautomers and pharmaceutically acceptable salts thereof, wherein A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R 1 R 2 and R 8 the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety; [I:\DayLib\LIBHO 1990.doc:sxc 284 R' is selected from: -H, -CI- 5 alkyl, -CF 3 -halo, -NO 2 6 -N(R 4 )(R 5 -R -C 2 5 alkenyl-R -C 2 5 alkynyl-R 6 (10) -0-R (11) -0-CI- 6 alkyl, and (12) -C(O)CH 2 C(O)C(O)0R 7 R 2is selected from: 0 -H, 0es 0,0 15 -R 3 0.60 .0. %504 0. [I:\DayLib\LIBH]O1 990.doc:sxc 285 (3) (4) (6) (7) (8) (9) (11) (12) (13) (14) each R 3 is (1) -C 1 6 alkyl, -CI-. 6 alkyl substituted withR 6 6 -0-CI-. 6 alkyl-OR, 6 -S(O)n-R -C 1 6 alkyl (R 6 )(R 4 46 -C 1 6 alkyl S(O)n-R, 6 -C 1 6 alkyl C(O)-R -C 1 6 alkyl C(S)-R6 4 6 -C1-.6 alkyl NR C(O)-R ,and -Cl 1 6 alkyl-C(O)N(R )(XR independently selected from: a 5 or 6 membered aromatic or hetero aromatic 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: halogen, C 1 6 alkyl, C 1 6 alkyloxy-, phenyl, -C3 Mf -OCF 3 -CN, hydroxy, (i phenyloxy, and 0) substituted phenyloxy with 1, 2, or 3 substituents selected from: Wi halogen, (ii) C 1 6 alkyl, 0 000..: 0:*00: 0 0 0 0 0 286 (iii) -CF 3 and (iv) hydroxy; 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: halogen, C 1 -6 alkyl, C1- 6 alkyloxy-, -CF3, -OCF 3 -CN, and 15 hydroxy; unsubstituted or substituted hexahydrothieno[3,4- d]imidazolyl with one or two substituents selected from: oxo, 20 halogen, C1- 6 alkyl, C 1 .6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: -halogen, 287 -C 1 -6 alkyl, -C 1 -6 alkyloxy-, -CF3, -OCF 3 -CN, and -hydroxy; a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 )substituents selected from: halogen, C1-6 alkyl, C1-6 alkyloxy-, 15 -CF3, -OCF 3 -CN, and hydroxy; and a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 :0 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: halogen, C1- 6 alkyl, C1- 6 alkyloxy-, -CF 3 -OCF 3 -CN, and hydroxy; 288 each R 4 isindependently selected from: -H, -C 1 3 alkyl, -CF 3 -R, -C 2 3 alkenyl, -C 13 alkyl-R3 3 -S(O)n-R 3 and COR each] R 5 is independently selected from: -H, -CI- 3 alkyl, -CF 3 -R 3, -C 2 3 alkenyl, 3 -CI- 3 alkyl-R 3 -C 2 3 alkenyl-R 3 -S(O)n-R ,and each R 6 is (1) (2) independently selected from: 3 -C 1 3 alkyl-R and -R3 R 7 is selected from: and C1-6 alkyl; 289 R 8 is selected from: -H, C 1 6 alkyl-oxy, and C 1 -6 alkyl; and each n is independently selected from 0, 1 and 2; and further provided that when R 7 is C1- 6 alkyl, then R 2 is not -H or -C1- 6 alkyl, said compound of formula I being substantially as hereinbefore described with reference to any one of the examples. Dated 20 November, 2002 1o Merck Co., Inc. Tularik, Inc. Patent Attorneys for the Applicants/Nominated Persons SPRUSON FERGUSON [L:\DayLib\LBH]01990.dc:sxc
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| US8784598P | 1998-06-03 | 1998-06-03 | |
| US60/087845 | 1998-06-03 | ||
| GBGB9814930.5A GB9814930D0 (en) | 1998-07-09 | 1998-07-09 | HIV integrase inhibitors |
| GB9814930 | 1998-07-09 | ||
| PCT/US1999/012095 WO1999062513A1 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
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| EP (1) | EP1083897A4 (en) |
| JP (1) | JP2002516858A (en) |
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| DE69925918T2 (en) | 1998-07-27 | 2006-05-11 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | DIKETIC ACID DERIVATIVES AS POLYMERASES INHIBITORS |
| BR9916583A (en) | 1998-12-25 | 2001-09-25 | Shionogi & Co | Heteroaromatic derivatives having an inhibitory activity against hiv integrase |
| AU5880600A (en) * | 1999-06-25 | 2001-01-31 | Merck & Co., Inc. | 1-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof |
| EP2033952B1 (en) | 2001-03-01 | 2012-08-29 | Shionogi&Co., Ltd. | Nitrogen-containing Heteroaryl compounds having HIV Integrase Inhibitory Activity |
| BR0211750A (en) | 2001-08-10 | 2004-10-13 | Shionogi & Co | Antiviral agent |
| DE60323743D1 (en) | 2002-03-15 | 2008-11-06 | Merck & Co Inc | N-(substituierte benzyl)-8-hydroxy-1,6-naphthyridin-7- carbonsäureamide als hiv-integrase-hemmer |
| WO2004024693A1 (en) | 2002-08-13 | 2004-03-25 | Shionogi & Co., Ltd. | Heterocyclic compound having hiv integrase inhibitory activity |
| WO2004035577A2 (en) | 2002-10-16 | 2004-04-29 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
| AU2004274493A1 (en) | 2003-09-19 | 2005-03-31 | Gilead Sciences, Inc. | Aza-quinolinol phosphonate integrase inhibitor compounds |
| ATE482208T1 (en) * | 2004-03-10 | 2010-10-15 | Us Of America Represented By T | QUINOLIN-4-ONE AS RETROVIRAL INTEGRASE INHIBITORS FOR THE TREATMENT OF HIV, AIDS AND AIDS-RELATED COMPLEX (ARC) |
| US7745459B2 (en) | 2004-09-21 | 2010-06-29 | Japan Tobacco Inc. | Quinolizinone compound and use thereof as HIV integrase inhibitor |
| EP1881825B1 (en) * | 2005-05-10 | 2013-07-24 | Merck Sharp & Dohme Corp. | Hiv integrase inhibitors |
| WO2007136714A2 (en) | 2006-05-16 | 2007-11-29 | Gilead Sciences, Inc. | Integrase inhibitors |
| US7888375B2 (en) | 2006-07-19 | 2011-02-15 | The University Of Georgia Research Foundation, Inc | Pyridinone diketo acids: inhibitors of HIV replication |
| US8993542B2 (en) | 2008-01-25 | 2015-03-31 | Chimerix Inc. | Methods of treating viral infections |
| WO2010047774A2 (en) * | 2008-10-20 | 2010-04-29 | The Texas A & M University System | Inhibitors of mycobacterium tuberculosis malate synthase, methods of marking and uses thereof |
| EA201270651A1 (en) | 2009-12-07 | 2013-01-30 | Юниверсити Оф Джорджия Рисерч Фаундейшн, Инк. | CARBOXAMIDES PYRIDINON HYDROXYCLOPENTILA: HIV INHIBITORS INTEGRASES AND AREAS OF THERAPEUTIC APPLICATION |
| US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
| US9006218B2 (en) | 2010-02-12 | 2015-04-14 | Chimerix Inc. | Nucleoside phosphonate salts |
| CN103420894A (en) * | 2012-05-22 | 2013-12-04 | 中国科学院上海药物研究所 | 2- butane-1,4-diketone compounds, preparation method and applications |
| AU2020373913B2 (en) * | 2019-10-28 | 2024-04-18 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Five-membered heterocyclic oxocarboxylic acid compound and medical use thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS554334A (en) * | 1978-06-24 | 1980-01-12 | Yoshitomi Pharmaceut Ind Ltd | Pyranopyrazole derivative |
| JPS5535066A (en) * | 1978-09-05 | 1980-03-11 | Yoshitomi Pharmaceut Ind Ltd | Novel pyrazole derivative |
| JPS56100784A (en) * | 1980-01-16 | 1981-08-12 | Yoshitomi Pharmaceut Ind Ltd | Indolizine derivative |
| JPS61164346A (en) * | 1985-01-17 | 1986-07-25 | Matsushita Electric Ind Co Ltd | Echo canceller |
| SU1373708A1 (en) * | 1986-08-04 | 1988-02-15 | Пермский фармацевтический институт | Method of producing 5,6-diaryl-2-carboxy-4,7-dioxo-5h-pyrrolo (3.4-b) pyrans |
| US5192773A (en) * | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| EP0949926A4 (en) * | 1996-10-31 | 2001-01-17 | Merck & Co Inc | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
-
1999
- 1999-06-01 WO PCT/US1999/012095 patent/WO1999062513A1/en not_active Application Discontinuation
- 1999-06-01 AU AU42256/99A patent/AU756826C/en not_active Ceased
- 1999-06-01 CA CA002329134A patent/CA2329134A1/en not_active Abandoned
- 1999-06-01 EP EP99926096A patent/EP1083897A4/en not_active Withdrawn
- 1999-06-01 JP JP2000551769A patent/JP2002516858A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU756826C (en) | 2003-08-21 |
| JP2002516858A (en) | 2002-06-11 |
| WO1999062513A1 (en) | 1999-12-09 |
| EP1083897A1 (en) | 2001-03-21 |
| AU4225699A (en) | 1999-12-20 |
| EP1083897A4 (en) | 2003-01-02 |
| CA2329134A1 (en) | 1999-12-09 |
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