AU4225699A - Hiv integrase inhibitors - Google Patents
Hiv integrase inhibitors Download PDFInfo
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- AU4225699A AU4225699A AU42256/99A AU4225699A AU4225699A AU 4225699 A AU4225699 A AU 4225699A AU 42256/99 A AU42256/99 A AU 42256/99A AU 4225699 A AU4225699 A AU 4225699A AU 4225699 A AU4225699 A AU 4225699A
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- alkyl
- pyrrol
- substituted
- dioxobutyric acid
- independently selected
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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
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- 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
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- 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
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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
- C07D207/34—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
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- 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
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- 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
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- 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
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- Public Health (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
WO 99/62513 PCT/US99/12095 TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS 5 The present application claims priority of U.S. provisional application Serial No. 60/087,845, filed June 3, 1998. BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus 10 (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus 15 replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two 20 nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes. 25 Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., 30 Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV. It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of 35 AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants - I - 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 5 reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely 10 related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza 15 transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II. Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are 20 described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995). U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted- 1-butanoic acid derivatives useful 25 intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4 dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). 30 Applicants have discovered that certain 5-membered nitrogen containing heteroaromatic diketo acid derivatives are potent inhibitors of HIV integrase. These compounds are useful in the treatment of AIDS or HIV infection. 35 SUMMARY OF THE INVENTION - 2- WO 99/62513 PCT/US99/12095 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, 5 pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed. 10 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 15 by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows: R
AOR
7
R
8 0 0 (1) and tautomers and pharmaceutically acceptable salts thereof, 20 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 ; 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 25 nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
R
1 is selected from: (1) -H, -3- WO 99/62513 PCT/US99/12095 (2) -C 1
-
5 alkyl, (3)
-CF
3 , (4) -halo, (5)
-NO
2 , 5 (6) -N(R4)(R 5), (7) -R6, 3 (8) -C 2
-
5 alkenyl-R 3 3 (9) -C 2
.-
5 alkynyl-R 3 (10) -O-R6, 10 (11) -O-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7;
R
2 is selected from: (1) -H, 15 (2) -R 3 , (3) -C 1
-
6 alkyl, (4) -C 1
-
6 alkyl substituted with R (5) -O-R 6 6 (6) -0-C 1
-
6 alkyl-OR , 6 20 (7) -S(O)n-R (8) -C 1
.-
6 alkyl (OR )(R ), (9) -C 1
-
6 alkyl-N(R4 )(R6), (10) -C- 6 alkyl S(O)n-R 6 (11) -C 1
-
6 alkyl C(O)-R , 6 25 (12) -C 1
-
6 alkyl C(S)-R , (13) -C1- 6 alkyl NR4 C(O)-R 6 , and (14) -C 1
-
6 alkyl-C(O)N(R4
)(
R 5 ); each R 3 is independently selected from: 30 (1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, -4- 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: (a) halogen, (b) C1-6 alkyl, 5 (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 , (g) -CN, 10 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 15 (ii) C 1
.
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0 or 1 20 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from: (a) halogen, (b) C 1
.-
6 alkyl, 25 (c) C1- 6 alkyloxy-, (d) -CF3, (e)
-OCF
3 , (f) -CN, (g) =O, 30 (h) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: -5- WO 99/62513 PCT/US99/12095 (a) oxo, (b) halogen, (c) C 1
.-
6 alkyl, (d) C 1
-
6 alkyloxy-, 5 (e) -CF 3 , (f)
-OCF
3 , (g) -CN, and (h) hydroxy; 10 (4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: 15 (a) -halogen, (b) -C 1 l 6 alkyl, (c) -C 1
-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 , 20 (f) -CN, and (g) -hydroxy; (5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused 25 with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C 1
.-
6 alkyl, (c) C 1
-
6 alkyloxy-, 30 (d) -CF 3 , (e)
-OCF
3 , (f) -CN, (g) =O, -6- WO 99/62513 PCT/US99/12095 (h) hydroxy; and (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 5 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, 10 (d) -CF 3 , (e)
-OCF
3 , (f) -CN, (g) =0, (h) hydroxy; 15 each R 4 is independently selected from: (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , 3 20 (4) -R 3 (5) -C 2
-
3 alkenyl, 3 (6) -C1- 3 alkyl-R (7) -C 2
-
3 alkenyl-R 3 (8) -S(O)n-R 3 , and 3 25 (9) -C(0)-R each R 5 is independently selected from: (1) -H, (2) -C 1
-
3 alkyl, 30 (3) -CF3, (4) -R 3 , (5) -C 2
-
3 alkenyl, -7- WO 99/62513 PCT/US99/12095 3 (6) -C 1
-
3 alkyl-R 3 (7) -C 2
.-
3 alkenyl-R 3 (8) -S(O)n-R, and (9)
-C(O)-R
3 5 each R 6 is independently selected from: 3 (1) -C 1
.-
3 alkyl-R 3 , and 3 (2) -R; 10 R 7 is selected from: (1) -H, and (2) C1-6 alkyl;
R
8 is selected from: 15 (1) -H, (2) C1-6 alkyl-oxy, and (3) C1-6 alkyl; and each n is independently selected from 0, 1 and 2. 20 Particular compounds of structural formula I include: (1) 4-[ 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester, (2) 4-[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (3) 4-[l-(4-methylbenzyl)- l-H-pyrrol-2-yl]-2,4-dioxobutyric acid 25 ethyl ester, (4) 4-[1-(4-methylbenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid, (5) 4-[1-(4-fluorobenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (6) 4-[ 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid 30 isopropyl ester, (7) 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n butyl ester, (8) 4 -(1-benzyl-1H-pyrrol-2-yl)-2,4 dioxobutyric acid, (9) 4-(1-naphthalen-2-ylmethyl-lH -8- WO 99/62513 PCT/US99/12095 pyrrol-2-yl)-2,4-dioxobutyric acid,(10) 4-(1-biphenyl-4 ylmethyl-l1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (11) 4-(1-naphthalen-1-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid, (12) 2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl] 5 butyric acid, (13) 4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-. dioxobutyric acid, (14) 2
,
4 -dioxo-4-(1-phenethyl-lH-pyrrol -2-yl)-butyric acid, (15) 4 -[1-(2-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric 10 acid, (17) 4-[ 1-(4-bromobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (18) 4-[1-(2-bromobenzyl)-l1H-pyrrol-2 yl]-2,4-dioxobutyric acid, (19) 4-[1-(3-bromobenzyl)-lH pyrrol- 2 -yl]-2,4-dioxobutyric acid, (20) 4-[1-(3-chlorobenzyl) 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 15 (21) 4 -[1-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (22) 4-[1-(2-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (23) 2
,
4 -dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid, (24) 4 (1-biphenyl-2-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid, (25) 2,4-dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl]-butyric acid, 20 (26) 4-[1-(3-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (27) 4 -[1-( 2 -chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid,(28) 4-[ 1-(4-fluorobenzyl)-4-iodo- 1H-pyrrol-2-yll-2,4 dioxobutyric acid (29) 4-[1-(4-methoxybenzyl)-1H-pyrrol 2-yl]-2,4-dioxobutyric acid,_(30) 4-[1-(2,4,5-trifluorobenzyl) 25 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (31) 4-[1-(2,3 difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid,(32) 4 [1-(3,5-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (33) 4-[ 1-(2,5-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 30 (34) 4-[ 1-(2,5,6-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (35) 4 -[l1-( 2 -fluorobenzyl)-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (36) 4-[1-( 4 -trifluoromethylbenzyl)-lH-pyrrol-2-yl] -2,4 dioxobutyric acid, 35 (37) 4 -[1-(4-cyanobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, -9- WO 99/62513 PCT/US99/12095 (38) 4-[1-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid, (39) 2-hydroxy-4-[1-(4-hydroxybenzyl)-1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (40) 4-(1-cyclopentylmethyl- 1H-pyrrol 5 2-yl) -2,4-dioxobutyric acid, (41) 4-{ 1-[ 3 -(4-fluorophenyl)propyl]-1H-pyrrol-2-y}-2,4 dioxobutyric acid, (42) 4-{ 1-[2-(4-fluorophenyl)ethyl]- 1H-pyrrol-2-yl}-2,4-dioxobutyric acid, 10 (43) 4-[1-(3-phenylpropyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (44) 4-(1-ethyl- 1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (45) 4-[1-(3-fluoro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (46) 4-[1-(2-chloro-benzyl)-l1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (47) 4-[1-(3-benzoylaminopropyl)-l1H-pyrrol-3-yl] -2,4-dioxobutyric 15 acid, (48) 4- {1l-[ 3 -(4-fluorophenoxy)benzyl]-l1H-pyrrol-2-yl}] -2,4 dioxobutyric acid, (49) 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester 20 (50) 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid, (51) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-l1H-pyrrol-2-yl-2,4 dioxobutyric acid ethyl ester, (52) 4- [1-( 4 -fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4 25 dioxobutyric acid, (53) 4 -[1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester, (54) 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 30 (55) 4-[5-(4-fluorobenzyl)-l1-methyl-l1H -pyrrol-2-yl]-2,4 dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (57) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 35 dioxobutyric acid, - 10- WO 99/62513 PCT/US99/12095 (58) 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (59) 4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (60) 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (61) 4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, 5 (62) 4-[5-(4-fluorobenzyl)-l1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4 dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (64) 4-[5-(benzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 10 dioxobutyric acid, (65) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (66) 4-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 15 (67) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, (68) 4-[5-(benzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[5-(3-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 20 (70) 4-(5-benzyl-lH -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4-[2,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (72) 4-[ 1-(4-Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester, 25 (73) 4-[ 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, (75) 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 30 dioxobutyric acid, (76) 4-[ 1-(4-Fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 35 (78) 4-[5-Nitro- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric -11 - WO 99/62513 PCT/US99/12095 (79) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester, (80) 4-[1-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4 -[1-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 5 (82) 4-[1-(3-bromobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) 4-[ 1-( 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, 10 (85) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 4-[1-(4-chlorobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[1-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 15 (89) 4-[1-(3,4-dichlorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (90) 4-[1-(2-methylbenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (91) 4-[ 1-(3-chlorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, 20 (92) 4-[ 1-(3-trifluoromethylbenzyl)- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, (93) 4-[1-(4-methylbenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[1-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(3-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 25 (96) 4-{ 1-[ 3 -(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl}-2,4 dioxobutyric acid, (97) 4-[1-(4-bromobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (98) 4-[1-(4-chlorobenzyl)-l1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (99) 4 -[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 30 2,4-dioxobutyric acid, 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, -12- WO 99/62513 PCT/US99/12095 (102) 4-[4-Phenyl-l1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (103) 4-[ 1-(4-fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid ethyl ester, 5 (104) 4-[ 1-(4-fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid, (105) 4-[1-(4-Fluorobenzyl)-3-acetylamino-l1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (106) 4-[4-acetylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4 10 dioxobutyric acid, (108) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (109) 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, 15 (110) 4-[5-(3-ethoxycarbonyl-3-oxopropionyl)- 1-(4-fluorobenzyl)- 1H pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 4-[1-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4-[l1-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid, 20 (113) 4-[4-Dimethylamino-l1-(4-fluorobenzyl)-l1H-pyrrol-3-yl] -2,4 dioxobutyric acid, (114) 4-[ 1-(4-Fluorobenzyl)-5-methyl- 1H-pyrazol-4-yl]-2-hydroxy-4 oxobut-2-enoic acid, (115) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid 25 ethyl ester, (116) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid, (117) 1-[l1-(4-fluorobenzyl)-3-methyl-l1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester, (118) 1-[l-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 30 dioxobutyric acid, (119) 4-[3-methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester, (120) 4-[3 -methyl-l1-(3-chlorobenzyl)-l1H-pyrazol-4-yl]-2,4 dioxobutyric acid, -13- WO 99/62513 PCT/US99/12095 (121) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid, (122) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester, 5 (123) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid, (124) 4-[1-(4-fluoro-benzyl)-l1H-imidazol-2-yl]-2,4-dioxo-butyric acid, (125) 4-[1-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid 10 ethyl ester, (126) 4-[1-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid, (127) 4-(1-Benzyl-lH-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4-[ 1-(4-fluorobenzyl)- 1H-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester, 15 (129) 4-[ 1-(4-fluorobenzyl)- 1H-imidazol-4-yl]-2,4-dioxo-butyric acid, (130) 4-[1-(4-fluorobenzyl)- 1H -indol - 2 -yl]-2,4-dioxobutyric acid methyl ester, (131) 4-[1-(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, 20 (133) 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid, (134) 1-[1-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid ethyl ester, (135) 1-[ 1-(4-fluorobenzyl)- 1H-indol-3-yl]-2,4-dioxobutyric acid,(136) 4-[ 1-(3-fluorobenzyl)- 1-H-pyrrol-3-yl]-2,4 25 dioxobutyric acid, (137) 4-[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (138) 4 -[4-(4-fluorobenzyl)-l1-methyl-l1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (139) 4-[2,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-pyrrol-3-yl] -2,4-dioxo 30 butyric acid, (140) 4-[ 1-(3,5-dichlorobenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (141) 4- [ 1-(3-thiophenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, -14- WO 99/62513 PCT/US99/12095 (142) 4-[1-2,4-dimethylbenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (143) 4-[1-(3-chloro-5-methyl-benzyl)-l1-H-pyrrol-3-yl]-2,4-dioxo butyric acid, 5 (144) 4-[1-(1-naphthalenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (145) 4-[ 1-(2-thiophenemethyl)- 1-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and (146) 4-[4-(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yll-2,4 10 dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof. One embodiment of the present invention are compounds of structural formula:
R
1 :I R 8 0Q N OR 7
R
2 O O 15 Another embodiment of the present invention are compounds of structural formula:
R
1 0 N OH
R
2 O O Still another embodiment of the present invention are compounds of structural formula:
N
~ 0 20
R
2 -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 O
R
2 Another embodiment of the present invention are 5 compounds of structural formula: 0O
OR
7 N N O N
R
2 Another embodiment of the present invention are compounds of structural formula: 0 0
OR
7 R1 0 N R2 10 Another embodiment of the present invention are compounds of structural formula:
R
1 N 0 N OH
R
2 0 0 Another embodiment of the present invention are compounds of structural formula: -16- WO 99/62513 PCT/US99/12095 0 N OH
R
2 0 0 In one class of compounds of the present invention, A is selected from: (1) pyrrolyl, 5 (2) imidazolyl, (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I). 10 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, 15 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 20 selected from: (1) -H, (2)
-CH
3 , (3)
-CF
3 , (4) -halo, 25 (5) -NO 2 , (6) -N(R4)(R5) (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: 30 (a) halogen, -17- WO 99/62513 PCT/US99/12095 (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e) -CF 3 , 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy, 15 (9) phenyl C 1
-
3 alkyl-, (10) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1
.-
6 alkyl, 20 (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 , (g) -CN, 25 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy, - 18- WO 99/62513 PCT/US99/12095 (11) -C 2
.-
5 alkenyl-R3 (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 5 is selected from: (1) -H, (2)
-CH
3 , (3)
-CF
3 , (4) -halo, 10 (5) -NO 2 , (6) -N(R)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: 15 (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1
.-
3 alkyl-, (10) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 20 substituents independently selected from: (a) halo, (b) methyl, and (c) methoxy, 3 (11) -C 2
-
5 alkenyl-R 3 , and 25 (12) -C(O)CH2C(O)C()OR7 In yet another class of compounds of the present invention, R1 is selected from: (1) -H, (2) -C 1
-
5 alkyl, 30 (3) -CF 3 , (4) -halo, (5)
-NO
2 , - 19- WO 99/62513 PCT/US99/12095 (6) -N(R4)(R 5 (7) -phenyl, (8) substituted phenyl substituted with 1 substituent independently selected from: 5 (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1
-
3 alkyl-, (10) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 10 substituents independently selected from: (a) halo, (b) methyl, and (c) methoxy, 3 (11) -C 2
-
5 alkenyl-R 3 , and 15 (12) -C(O)CH2C(O)C(O)OR7 In yet another class of compounds of the present invention, R1 is selected from: (1) -H, (2) -C1- 5 alkyl, 20 (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5)
-NO
2 , (6) -N(R4)(R5) (7) -phenyl, 25 (8) phenyl C 1
-
3 alkyl-, (9) substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br; (10) -C 2
-
5 alkynyl-R 3 , and 30 (11) -C(O)CH2C(O)C(O)OR7 In another class of compounds of the present invention, R1 is selected from: (1) -H, - 20 - WO 99/62513 PCT/US99/12095 (2) -C 1
.-
5 alkyl, (3)
-CF
3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5)
-NO
2 , 5 (6) -N(R4)(R5), (7) -phenyl, (8) phenyl C 1
.-
3 alkyl-, (9) substituted phenyl C 1
-
3 alkyl- substituted with 1 or 2 substituents independently selected from: 10 (a) halo, wherein halo is selected from: -F, -Cl, and -Br, and 3 (10) -C 2
.-
5 alkynyl-R In one class of compounds of the present invention, R 2 is selected from: 15 (1) -H, 3 (2) -R 3 (3) -C 1
-
6 alkyl, (4) -C 1
-
6 alkyl substituted with R 6 (5) -O-R 6 20 (6) -0-C 1
.
6 alkyl-OR (7) -S(O)n-R 6 , (8) -C 1
-
6 alkyl (OR6 )(R4), (9) -C1- 6 alkyl-N(R 4 )(R 6 ), 6 (10) -C 1
-
6 alkyl S(O)n-R 6 25 (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 (14) -C 1
-
6 alkyl-C(O)N(R 4
)(R
5 ). In another class of compounds of the present invention, R 2 30 is selected from: (1) -H, -21 - WO 99/62513 PCT/US99/12095 3 (2) -R 3 (3) -C 1
-
6 alkyl, (4) -C 1
-
6 alkyl substituted with R 3 6 (5) -O-R 6 5 (6) -O-C 1
-
6 alkyl-OR 6 (7) -S(O)n-R (8) -C 1
-
6 alkyl (OR6 )(R4), (9) -C 1
-
6 alkyl-N(R4 )(R 6 ), (10) -C 1
-
6 alkyl S(O)n-R 6 , 10 (11) -C1- 6 alkyl NR4 C(O)-R 6 , and (12) -C 1
-
6 alkyl-C(O)N(R4 )(R 5 ). In yet another class of compounds of the present invention,
R
2 is selected from: (1) -H, 15 (2) -R 3 , (3) -C 1
.-
6 alkyl, (4) -C 1
.-
6 alkyl substituted with R 3 6 (5) -O-R , 6 (6) -0-C 1
-
6 alkyl-OR , 20 (7) -C 1
-
6 alkyl (OR6)(R4), (8) -C 1
-
6 alkyl-N(R4 )(R6), 6 (9) -C 1
-
6 alkyl C(O)-R 4 6 (10) -C 1
.-
6 alkyl NR4 C(O)-R 6 , and (11) -C 1
-
6 alkyl-C(O)N(R 4
)(R
5 ). 25 In still another class of compounds of the present invention, R2 is selected from: (1) -H, (2) -R 3 , (3) -C 1
-
6 alkyl, 30 (4) -C 1
.-
6 alkyl substituted with R 3 6 (5) -O-R - 22 - WO 99/62513 PCT/US99/12095 (6) -O-C 1
-
6 alkyl-OR6 (7) -C 1
-
6 alkyl (OR6 )(R4), (8) -C 1
.-
6 alkyl-N(R4)(R 6), (9) -C 1
-
6 alkyl C(O)-R 6 , and 4 6 5 (10) -C1- 6 alkyl NR4 C(O)-R 6 In one class of compounds of the present invention, R 3 is selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently 10 selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, 15 (e) -CF 3 , (f)
-OCF
3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 20 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
.-
6 alkyl, (iii) -CF 3 , and 25 (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 30 (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, - 23 - WO 99/62513 PCT/US99/12095 (e) -CF 3 , (f)
-OCF
3 , (g) -CN, (h) hydroxy, 5 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
-
6 alkyl, 10 (iii) -CF 3 , and (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: 15 (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
.-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , 20 (f)
-OCF
3 ' (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 25 selected from: (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 30 (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, - 24 - WO 99/62513 PCT/US99/12095 (b) C 1
.-
6 alkyl, (c) C 1
.-
6 alkyloxy-, (d) phenyl, (e) -CF 3 , 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 15 (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1
_
6 alkyl, 20 (c) C 1
.-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , (f)
-OCF
3 , (g) -CN, 25 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C 1
-
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: (a) halogen, 5 (b) C 1
.-
6 alkyl, (c) C 1
.-
6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f)
-OCF
3 , 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C 1
-
6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3
-
6 cycloalkyl; 20 (14) substituted C 3
-
6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
.-
6 alkyloxy-, 25 (d) -CF 3 , (e)
-OCF
3 , (f) -CN, (g) =O, (h) hydroxy; 30 (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, - 26 - WO 99/62513 PCT/US99/12095 (b) C1- 6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 , 5 (f) -CN, (g) =O, (h) hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen 10 atom with 1 or 2 independently selected from: (a) halogen, (b) C 1
-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d)
-CF
3 , 15 (e) -OCF 3 , (f) -CN, (g) =0, (h) hydroxy; (19) naphthyl; 20 (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) -halogen, (b) -C 1
.-
6 alkyl, (c) -C 1
.-
6 alkyloxy-, 25 (d) -CF 3 , (e)
-OCF
3 , (f) -CN, and (g) -hydroxy; (21) indolyl; 30 (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) -halogen, - 27 - WO 99/62513 PCT/US99/12095 (b) -C1- 6 alkyl, (c) -C 1
.-
6 alkyloxy-, (d)
-CF
3 , (e)
-OCF
3 , 5 (f) -CN, and (g) -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 10 independently selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1
-
6 alkyloxy-, (d) -CF 3 , 15 (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy. In another class of compounds of the present invention, R3 20 is selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 25 (b) C 1
.-
6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF3, (f)
-OCF
3 , 30 (g) -CN, (h) hydroxy, (i) phenyloxy, and - 28 - WO 99/62513 PCT/US99/12095 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1
.-
6 alkyl, 5 (iii) -CF 3 , and (iv) hydroxy, (3) thienyl, (4) pyridyl, (5) imidazolyl, 10 (6) pyrrolyl, (7) pyrazolyl, (8) C 3
.-
6 cycloalkyl, (9) substituted C 3
-
6 cycloalkyl with 1 or 2 substituents independently selected from: 15 (a) halogen, (b) C1- 6 alkyl, (c) C 1
.-
6 alkyloxy-, (d) -CF 3 , (e)
-OCF
3 , 20 (f) -CN, (g) =0O, and (h) hydroxy; (10) piperidinyl, (11) morpholinyl, 25 (12) naphthyl, (13) indolyl, and (14) C 3
-
6 cycloalkyl fused with a phenyl ring. In still another class of compounds of the present invention, R3 is selected from: 30 (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, - 29 - WO 99/62513 PCT/US99/12095 (b) C 1
.-
6 alkyl, (c) C 1
-
6 alkyloxy-, (d) phenyl, (e)
-CF
3 , 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, wherein halogen is selected from -F, C1, and Br, (ii) methyl, (iii) -CF 3 , and 15 (iv) hydroxy; (3) C 3
-
6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo; and (6) naphthyl. 20 In one class of compounds of the present invention, R4 is selected from: (1) -H, (2) -C 1
-
3 alkyl, and (3)
-CF
3 . 25 In another class of compounds of the present invention, R4 is selected from: (1) -H, (2) -C 1
.-
3 alkyl, (3)
-CF
3 , 3 30 (4) -R 3 (5) -C 2
-
3 alkenyl, 3 (6) -C 1
-
3 alkyl-R - 30 - WO 99/62513 PCT/US99/12095 (7) -C 2
-
3 alkenyl-R3 3 (8) -S(O)n-R 3 , and (9) -C(O)-R 3 In still another class of compounds of the present invention, 5 R4 is selected from: (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , 3 (4) -R 3 10 (5) -C1- 3 alkyl-R3 (6) -S(O)n-R 3 , and (7) -C(O)-R 3 . In yet another class of compounds of the present invention, R4 is selected from: 15 (1) -H, and (2) -C 1
-
3 alkyl. In one class of compounds of the present invention, R 5 is selected from: (1) -H, 20 (2) -C1- 3 alkyl, (3)
-CF
3 , (4) -R 3 (5) -C 2
-
3 alkenyl, (6) -C 1
-
3 alkyl-R 3 3 25 (7) -C 2
-
3 alkenyl-R 3 (8) -S(O)n-R 3 , and (9) -C(O)-R 3 In another class of compounds of the present invention, R5 is selected from: 30 (1) -H, (2) -CI- 3 alkyl, -31 - WO 99/62513 PCT/US99/12095 (3) -CF3, and (4) -R 3 In yet another class of compounds of the present invention, R5 is selected from: 5 (1) -H, (2) -C 1
-
3 alkyl, (3)
-CF
3 , 3 (4) -R 3 3 (5) -C 1
-
3 alkyl-R 10 (6) -S(O)n-R 3 , and (7) -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 15 is selected from: (1) -H, and (2) C1-4 alkyl. In one class of compounds of the present invention, R8 is selected from: 20 (1) -H, (2) -OCH3, and (3) -CH3. In another class of compounds of the present invention, R8 is selected from: 25 (1) -H, and (2) CH3. In yet another class of compounds of the present invention, R8 is selected from: (1) -H, and 30 (2) 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 5 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: 10 (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator. The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as 15 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, 20 and thus by using the phrase "and tautomers thereof' in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (Ia) and (Ib): R1
R
1 O RR R OR
OR
7 R2--O
OR
7
R
8 O O
R
8 O OH (I) (la) R R
OR
7
R
8 OH O (Ib) - 33 - WO 99/62513 PCT/US99/12095 By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (Ia) and (Ib) are also intended. Similarly, be referring to compound (Ia), it is understood for the purposes of the present application that the 5 tautomers (I) and (Ib) are also intended. The same holds true for references to tautomer (Ib). When any variable (e.g., R3, R 4 , etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, 10 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 15 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 20 invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. The compounds of this invention are useful in the preparation and execution of screening assays for antiviral 25 compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, 30 e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of 35 AIDS or ARC. - 34 - WO 99/62513 PCT/US99/12095 Compounds of structural formula (I) wherein A is pyrrolyl may be made according to the procedures in Schemes Al-AXI. Compounds of structural formula (I) wherein A is pyrazolyl may be prepared according to the procedures in Schemes BI-BV. Compounds of 5 structural formula (I) 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
OH
3 N
H
0 4-fluorobenzyl bromide NaH DMF 10 Y C H 3 I ' H 3 S NIS N Al-1-1 O o acetone F F AI-1-2 dimethyl oxalate NaH DME heat - 35 - WO 99/62513 PCT/US99/12095 0 N
OCH
3 Al-2-1 0 0 F& ROH Na0H RsOH THF /MeOH /H 2 0 0 N OH Al-3-1 0 0 -36- WO 99/62513 PCT/US99/12095 Scheme All N H LiHMDS cyclohexanecarbonyl chloride THF N AIl-1-1 O 0
BH
3 -Me 2 S THF heat N AII-2-1 n -butyllithium THF N- methoxy-N- methylacetamide - 37 - WO 99/62513 PCT/US99/12095 N AII-3-1 0 dimethyl oxalate NaH DME heat 0 N
OCH
3 AII-4-1 O 0 NaOH THF / MeOH/
H
2 0 0 N OH AII-5-1 0 0 - 38 - WO 99/62513 PCT/US99/12095 Scheme AIII N + 0 Al-1-2 Cul A112 Cul
[(C
6
H
5
)
3
P]
4 Pd TEA
CH
3 CN N O F 10% Pd/C EtOH AIII-1 -1 Diethyl oxalate NaOEt THF - 39 - WO 99/62513 PCT/US99/12095 AIII-4-1 0 N N OEt O 0 0 ° F AIII-2-1 Diethyl oxalate 1 N LiOH NaOEt THF THF AIII-5-1 0 AIII-3-1 N OEt 0 'N0 0 U0 /\o N OH F OO 0 1N NaOH FTHF 0 N OH 'N 0 AIII-6-1 F - 40 - WO 99/62513 PCT/US99/12095 Scheme AIV N H MeMgCI 50:50 THF:MeOH benzyl bromide F AIV-1-1 N H MeMgCI THF acetic anhydride AIV-2-1 -/? N yCH3 H 0 O Mel NaH DMF IF AIV-3-1 N CH3 H3C O - 41
-
WO 99/62513 PCT/US99/12095 dimethyl oxylate TFA NaH refux DME reflux reflux AIV-6-1 cat. MeOH F 0 O \ 0 AIV-4-1 CH3 N OCH 3 N
H
3 C o o H 3 C dimethyl oxylate NaH DME 1 N NaOH reflux THF cat. MeOH F O AIV-7-1 F AIV-5-1 OH N N OH HI H3C O O 1 N NaOH THF AIV-8-1 F O O OH N
H
3 C 5 Scheme AV COOH EtOH (abs) ~NH (+/-) NH SOC12 (cat) / RT O - 42 - WO 99/62513 PCT/US99/12095 COOEt Boc 2 0 / Et 3 N / DMF NH 4-DMAP / CHCI 3 O AV-1-1 COOEt O PhMgBr /THF N4 O -40 0 C / 30 min O AV-2-1 O Ph 1. TFA/ CH 2 C2 /RT O N COOEt H 2. Et 3 N /CH 2 CI/RT AV-3-1 1. DDQ / CH 2
CI
2 / RT N COOEt 2. NaOH / H 2 0 / reflux AV-4-1 - 43 - WO 99/62513 PCTIUS99/12095 MeONHMe-HCI - / \EDO*HCI N COGH H HOBt*H 2 0 DMF /Et 3 N AV-5-1 Y0H 3 F -a CH 2 Br N CH 3 H 0NaH/DMF AV-6-1 ?0H 3 /\ N', MeLi/THF /-78 0 C N CH 3 ___ _ 00 N10 F& AV--1 -440 WO 99/62513 PCT/US99/12095 0 S CH3 1 NaOH / MeOH/RT N 0 OH 3 _ _ _ _ _ _ _ O 0 F AV-9-1 0 N OH 0 0 F AV-10-1 5 Scheme A-VI /
HNO
3 / Ac 2 0 N F Al-1-1 - 45 - WO 99/62513 PCT/US99/12095
NO
2 NO10% Pd-C ON \ EtOH /H 2 (1Atm) F AVI-1-1
NH
2 0 F
CH
3 1 / DMF / Cs 2
CO
3 AVI-2-1 0
(CH
3
)
2 N EtO OEt OO ,
N
0 \ NaOEt / THF / RT F AVI-3-1 - 46 - WO 99/62513 PCT/US99/12095
(CH
3
)
2 NO N \OEt 0 0 "OO F AVI-4-1 (CH3)2 N 1N NaOH / MeOH/RT
(CH
3
)
2 N /N OH 0 0 F AVI-5-1 SCHEME AVII O
CH
3 N H 4-fluorobenzyl bromide NaH DMF 5 -47 - WO 99/62513 PCT/US99/12095 0 O N H 3 AVII-1-1 dimethyl oxalate NaH DME heat O 0
-OCH
3 0 N AVII-2-1 NaOH THF / MeOH / H 2 0 O O o0 OH O H AVII-3-1 N - 48 - WO 99/62513 PCT/US99/12095 Scheme AVIII
NH
2 N \ PhCHO / NaCNBH 3 N O MeOH /HOAc F AVI-2-1 NH / \H 2 CHO / NaCNBH 3 O MeOH / HOAc F AVIII-1-1
CH
3 0 N EtO OE t OEt 0 S ONaOEt / THF / RT F AVIII-2-1 -49 - WO 99/62513 PCT/US99/12095
CH
3 O 1N NaOH / MeOH/RT N OEt AVIII-3-1
CH
3 N OH 00 F AVIII-4-1 5 Scheme AIX / \ PhB(OH) 2 / Pd(Ph 3
P)
4 0 Et 3 N / DMF / 900C F AIII-1-1 - 50 - WO 99/62513 PCT/US99/12095 /o EtO oEt OEt O N 0 0 NaOEt / THF / RT F AIX-1-1 O 1 N NaOH / MeOH /RT N OEt F0 0 F 7N OH AIX-3-1 5 SCHEME AX -51- WO 99/62513 PCT/US99/12095
H
2 N
CH
3 O AVI-2-1 K0 F methylsulfonylchloride
TEA/CH
2 C 2 H
H
3 C,, N oo
\OCH
3 IN O AX-1-1 F diethyloxalate NaOEt/THF H H3Cs N O, S O
CO
2 Et IN 0 0 AX-2-1 F 1 N NaOH
CH
3 OH/THF - 52 - WO 99/62513 PCT/US99/12095 H
H
3 Cs N SO" o C0 2 H O O AX-3-1 F Scheme AXI N Si(i-Pr) 3
AICI
3
CH
2 CI2 4-fluorobenzoyl chloride O S\ AXI-1-1 I F N Si(i-Pr) 3
BH
3 -Me 2 S THF heat 5 -53 - WO 99/62513 PCT/US99/12095 F\AXI-2-1 F N I Si(i-Pr) 3 AICi 3
CH
2
CI
2 acetyl chloride O 0 / \ AXI-3-1 F N I Si(i-Pr) 3 [Bu]NF THF AXI-4-1 O F N H 1) dimethyl oxalate NaH DME heat 2) NaOH THF / MeOH / H 2 0 - 54- WO 99/62513 PCT/US99/12095 AXI-5-1 0 F OOO O OH F N H Scheme AXI(b) AXI-4-1 O DMF NaH 4-fluorobenzyl bromide F N 5 H O 0 F N AXI-4-2 F 1) dimethyl oxalate NaH DME heat 2) NaOH THF / MeOH / H 2 0 - 55 - WO 99/62513 PCT/US99/12095 0 0 0 H AXI-5-2 F N F Scheme BI 0 O OEt + Br EtO N' F H TEA DMF O 0 OEt EtO NN BI-1-1 F 1 N LiOH THF - 56- WO 99/62513 PCT/US99/12095 0 0O O / OLi LiO N N -BI-2-1 F MeO, NH.HCI EDC, HOBT, TEA DMF O ON OMe MeO-N N'N BI-3-1 F MeLi THF - 57 - WO 99/62513 PCT/US99/12095 O 0 ,N NI N F BI-4-1 F Diethyl oxalate NaOEt THF Scheme BI (cont.) 0 0 O OEt O EtO N N I BI-5-1 F 1 N LiOH THF -58 - WO 99/62513 PCT/US99/12095 O O H 0 HO N O BI-6-1 F Scheme BII Br N Br N'N\ F H NaH DMF Br N BII-1-1
I
F MeO O /N-- , n-BuLi 5 Et 2 0 - 59 - WO 99/62513 PCT/US99/12095 O N BII-2-1 F Diethyl oxalate NaOEt THF 00 OEt NN 0 N BII-3-1 F 1 M NaOH MeOH 0O OH N) O N \ BII-4-1 F& - 60 - WO 99/62513 PCT/US99/12095 Scheme Bill B r N% N + " B N F H 0 F NaH DMF N 0 F BIII-1-1 Diethyl oxalate NaOEt THF -61 - WO 99/62513 PCT/US99/12095 0 N OEt OO FBIII-2-1 1 M NaOH THF 0 NN OH 0 0 OJOO F BIII-3-1 Scheme BIV 0 N o¢.. 1 M NaOH 5 THF - 62 - WO 99/62513 PCT/US99/12095 O N BIV-1-1 H NaH/DMF 0 N \" BIV-2-1 F Diethyl oxalate NaOEt THF 0 0 OEt N\. 0 N BIV-3-1 F 1 M NaOH THF - 63 - WO 99/62513 PCT/US99/12095 O O OH N FBIV-4-1 Scheme BV 0 NBr N , N H Cl BIV-1-1 NaH DMF 5 - 64 - WO 99/62513 PCT/US99/12095 O O N N N Cl C .
BV-1-1 Cl N BV-2-1 Diethyl oxalate Diethyl oxalate NaOEt NaOEt THF THF O O O O 0 0 0 0 OEt O Et NN. 0 N 0 "N c I .
CI BV-3-1 BV-5-1 1 M NaOH MeOH M NaOH eMeOHH -65MeOH -65 - WO 99/62513 PCT/US99/12095 0O OH 0 0 SOH N N 0 N "l Cl BV-4-1 BV-6-1 Scheme Cl N [N H 4-F-benzylbromid, TEA/ DMF N N ICI-1-1 F 1) nBuLi/THF/-780C 2) C02 5 - 66 - WO 99/62513 PCT[US99/12095 N CI-2-1 IEDO/HOBT/TEA/DM~F N OCH 0 CI-3-1
SCH
3 Li/THF/-78oC N 0 CI-4-1 Idiethyloxalate NaOEt/TH F - 67 - WO 99/62513 PCTJUS99/12095 N CI-5-1 F&
ICH
3 OH/THF N NlI~ 00 2 OH N o 0 CI-6-1 F", Scheme Cli 5 N 0 2 H N H I4-F-benzylbromidi
CS
2 00 3 I DMF - 68 - WO 99/62513 PCT/US99/1 2095 0 0 0/F 0 N + F"' N p11-1-iCI-i-lb
ICH
3 Li/TH F -780C 0 O- H 3 N CII-2-1 F& diethytoxalate INaOEt/THF 0 0
-/-C
2 Et N CII-3-1 1 iN Na0H
CH
3 OH/THF - 69 - WO 99/62513 PCT/US99/12095 0O S C0 2 H CII-4-1 N F Scheme DI \I OH N H 0 MeLi Et 2 0 5 reflux \ NH
C
H
3 N H 0 DI-1-1 4-fluorobenzyl bromide NaH DMF - 70 - WO 99/62513 PCT/US99/12095 S"N
CH
3 N 0 S 0 DI-2-1 F dimethyl oxalate NaH DME heat 0 N
OCH
3 00 DI-3-1 NaOH THF / MeOH / H 2 0 a Z 0 N OH 0 0 F DI-4-1 -71- WO 99/62513 PCT/US99/12095 Scheme DII 0 F Br N H NaH DMF 0 N DII-1-1 F Diethyl oxalate NaOEt THF - 72 - WO 99/62513 PCT/US99/12095 0 O OEt N DII-2-1 F 1M LiOH THF 0 O OH /\o N F DII-3-1 The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The 5 term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, 10 chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, - 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 5 hydrolysis characteristics or can be used in sustained release or pro drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, 10 and from bases such as ammonia, ethylenediamine, N-methyl glutamine, lysine, arginine, ornithine, choline, N,N' dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium 15 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. 20 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. 25 For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically 30 acceptable carriers, adjuvants and vehicles. The terms "administration of' and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment. - 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 5 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 10 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. 15 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 20 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 25 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 30 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. -75- WO 99/62513 PCT/US99/12095 The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable 5 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 10 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 15 doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 20 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 25 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. 30 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 PCT/US99/12095 antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table. ANTIVIRALS 5 Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir - 77 - WO 99/62513 PCT/US99/12095 Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection, (CGP-73547) Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV peripheral CMV retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomatic Japan) -78- WO 99/62513 PCT/US99/12095 ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIV infection, (DMP 266) AIDS, ARC ((-) 6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro methyl-1,4-dihydro 2H-3,1-benzoxazin 2-one) STOCRIN, ELO0 Elan Corp, PLC HIV infection (Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC (reverse transcriptase inhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor) HBYO97 Hoechst Marion HIV infection, Roussel AIDS, ARC (non-nucleoside reverse transcriptase inhibitor) - 79 - WO 99/62513 PCT/US99/12095 Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddl/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc infection, other CMV infections - 80 - WO 99/62513 PCT/US99/12095 PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV infections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS -81 - WO 99/62513 PCT/US99/12095 Bropirimine Pharmacia Upjohn advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10 Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT Stimulating Factor HIV Core Particle Rorer seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts (aldeslukin) - 82 - WO 99/62513 PCT/US99/12095 Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT Factor Remune Immune Response immunotherapeutic Corp. rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 - 83 - WO 99/62513 PCT/US99/12095 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation Spiramycin Rhone-Poulenc cryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis; R51211 cryptococcal meningitis Trimetrexate Warner-Lambert PCP - 84 - WO 99/62513 PCT/US99/12095 OTHER Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS It will be understood that the scope of combinations of the 5 compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. Preferred combinations are simultaneous or alternating 10 treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is 15 the sulfate salt of N-( 2 (R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S) hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido) piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir 20 and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non - 85 - 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 5 include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and 10 lamivudine. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other 15 agent(s). It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical 20 composition useful for the treatment of AIDS. Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5 (1-( 4
-(
3 -pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl)) pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. 25 Indinavir is generally administered at a dosage of 800 mg three times a day. The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope 30 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 35 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 5 formamide; DMSO is dimethyl sulfoxide; EDC represents 1-(3 dimethylaminopropyl-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 (SiO2) chromatography. 10 EXAMPLE 1 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1 Step 1: 1-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone Al-1-1 S9
OCH
3 N 0 15 F Al-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 20 saturated NaHCO3 and extracted with EtOAc three times, the combined organic layers were washed with NaHCO 3 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, CDC1 3 ) d 7.1 (m, 2H), 7.0 (m, 3H), 6.9 (m, 1H), 6.2 (m, 25 1H), 5.52 (s, 2H), 2.4 (s, 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 0 N OCH 3 00 F AI-2-1 A solution of 1- [ 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 5 (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 10 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 (m, 2H), 7.0 (m, 3H), 6.84 (s, 1H), 6.28 (dd, J = 2.57, 4.11 Hz, 1H), 5.6 (s, 2H), 3.9 (s, 3H). 15 Step 3: 4-[l1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1 F Al-3-1 020 N OH 0 0 F A1-3-1 20 A solution of AI-1-2 (1.35g, 0.0045 mole) was dissolved in 1:1 THF / MeOH (20 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 25 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 CHCl3 to give Al-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 (m, 3H), 5 7.0 (m, 2H), 6.86 (s, 1H), 6.3 (dd, J = 2.56, 4.21 Hz, 1H), 5.58 (s, 2H). mass spec (FAB, m+1) 290.08 EXAMPLE 2 4-[1-(4-methylbenzyl)-l1-H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-9 10 Step 1: 1-[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]ethanone Al-1-3 N H3C 0
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, 10 15 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 52-53oC 20 (uncorrected). 1H NMR (400 MHz, CDC13) 5 7.11 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.72 Hz, 2H), 7.01 (m, 1H), 6.18 (m,1H), 5.55 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H). mass spec (EI, m/z) 213 (M+), 105. Step 2: 4-[1-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid 25 ethyl ester AI-2-2 - 89 - WO 99/62513 PCT/US99/12095 N OCH 2
CH
3 O 0
H
3 C AI-2-2 To a solution of Al-1-3 (639mg, 3 mmole) and diethyl oxalate (0.814 mL, 6 mmole) in THF (3 mL) was added in portions NaOEt ( 4 08mg, 6 mmole). The reaction was stirred at ambient temperature under a N2 5 atmosphere for 1.5 hours. The reaction was poured into hexanes (50 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 / Et 2 0 to obtain the product as a yellow powder. 10 melting point 94-97oC (uncorrected). 1H NMR (400 MHz, CDCl3) 5 7.15 (m, 1H), 7.12 (d, J=8.04 Hz, 2H), 7.03 (d, J=8.08 Hz, 2H), 7.01 (m, 1H), 6.85 (s, 1H), 6.26 (dd, J=2.48, 4.08Hz, 1H), 5.61 (s, 2H), 4.37 (q, J=7.12 Hz, 2H), 2.33 (s, 3H), 1.40 (t, J=7.12 Hz, 3H). mass spec (EI, m/z) 331 (M'), 105. 15 Step 3: 4 -[1-(4-methylbenzyl)-l1-H-pyrrol-2-yl]-2,4-dioxobutyric acid SOH AI-3-9 Na N ~ 0 Al-3-9 H 3 C AI-3-9 A solution of AI-2-2 (240mg, 1mmol) in 1,4-dioxane (3 mL) and 3N HC1 (3 mL) was heated in a sealed tube at 70oC overnight. The reaction was then allowed to cool to ambient temperature and poured into 1H HC1 (25 20 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 / hexanes to afford Al-3-9 as a yellow solid, melting point 179-181oC (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (s, 1H), 7.41 (d, J=4.28 Hz, 1H), 7.10(d, J=7.68 Hz, 2H), 6.98 (d, - 90 - WO 99/62513 PCT/US99/12095 J=7.68 Hz, 2H), 6.83 (s, 1H), 6.30 (dd, J=2.5, 4.1 Hz, 1H), 5.58 (s, 2H), 2.24 (s, 3H). mass spec (FAB, m+1) 286 5 EXAMPLE 3 4 -[1-( 4 -fluorobenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester Al 2-3 Step 1: 1-[1-(4-fluorobenzyl)-4-iodo-1H -pyrrol-2-yl]ethanoneAl-1-2 I CH 3 N 0 Al-1-2 10 A solution of 1-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone (Al-1-1) (3g, 13.8 mmole) in acetone (75 mL) was cooled to -78 0 C and treated with N iodosuccinimide (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 15 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). 1H NMR (400 MHz, CDC13) 5 7.15 (m, 2H), 7.08 (m, 1H), 7.0 (m, 2H), 6.93 (m, 1H), 5.5 (s, 2H), 2.4 (s, 3H). 20 Step 2: 4-[1-(4-fluorobenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-3 N OCH 2
CH
3 F 0 0 F AlI-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 87-90oC (uncorrected). 1H NMR (400 MHz, CDC13) 6 7.15 (dd, J=1.6, 4.16 Hz, 1H), 7.09 (m, 2H), 7.01-6.96 (mi, 3H), 6.83 (s, 1H), 6.27 (dd, J=2.52, 4.20 5 Hz, 1H), 5.60 (s, 2H), 4.36 (q, J=7.16 Hz, 2H), 1.38 (t, J=7.16 Hz, 3H). mass spec (EI, m/z) 317 (M*), 109. EXAMPLE 4 4-[l1-(4-fluorobenzyl)-liH-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester 10 AI-2-4 N 0
OJ
°
O F AI-2-4 To a solution of AI-2-3 (317mg, 1 mmole) in 2-propanol (anhydrous, 20 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 15 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 87-88oC (uncorrected). 1H NMR 20 (400 MHz, CDC13) 6 7.15-7.08 (m, 3H), 7.00-6.95 (m, 3H), 6.80 (s, 1H), 6.27 (dd, J=2.52, 4.10 Hz, 1H), 5.60 (s, 2H), 5.19 (m, 1H), 1.36 (d, J=6.24 Hz, 6H). mass spec (FAB, m+1) 332 EXAMPLE 5 25 4-[1-(4-fluorobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester AI-2-5 - 92 - WO 99/62513 PCT/US99/12095 N O(CH 2
)
3 0 H 3 S 0 0 F AI-2-5 AI-2-5 was synthesized from AI-2-3 by refluxing for 24 hours in n butanol in a manner similar to that described for the synthesis of AI-2-4 to afford the product as a yellow solid, melting point 64-65oC 5 (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.14-7.08 (m, 3H), 7.00-6.95 (m, 3H), 6.81 (s, 1H), 6.26 (dd, J=2.52, 4.12 Hz, 1H), 5.59 (s, 2H), 4.29 (t, J=6.76 Hz, 2H), 1.72 (m, 2H), 1.42 (m, 2H), 0.96 (t, J=7.52 Hz, 3H). mass spec (FAB, m+1) 346 10 EXAMPLE 6 4-(1-benzyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-2 0 N OH 0 0 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 15 AI-3-2. mp 150-151C (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.55 (s, 1H), 7.41 (m, 1H), 7.25 (m, 3H), 7.06 (m, 2H), 6.82 (s, 1H), 6.3 (s, 1H), 5.63 (s, 2H). EXAMPLE 7 - 93 - WO 99/62513 PCT/US99/12095 4-(1-naphthalen-2-ylmethyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-3 0 N OH 0 0 AI-3-3 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 2-bromomethylnapthylene and carried through the 5 sequence to yield AI-3-3. mp 160-162 0 C (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.82 (m, 3H), 7.6 (s, 1H), 7.45 (m, 4H), 7.3 (m, 1H), 6.83 (s, 1H), 6.38 (m, 1H), 5.8 (s, 2H). EXAMPLE 8 10 4-(1-biphenyl-4-ylmethyl-lH-pyrrol
-
2 -yl)-2,4-dioxobutyric acid A-I-3-4 0 N OH 0 0 AI-3-4 In a manner similar to that described for Al-3-1, 2-acetyl pyrrole was treated with 4-phenyl benzyl bromide and carried through the sequence to yield AI-3-4. mp 189-191 0 C (uncorrected). 1H NMR (300 MHz, DMSO) 15 5 7.75 (m, 5H), 7.58 (m, 3H), 7.48 (m, 1H), 7.3 (m, 2H), 7.0 (s, 1H), 6.45 (m, 1H), 5.8 (s, 2H). EXAMPLE 9 - 94 - WO 99/62513 PCT/US99/12095 4-(1-naphthalen-1-ylmethyl- 1H-pyrrol -2-yl)-2,4-dioxobutyric acid AI-3-5 0 N OH 00 AI-3-5 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 1-bromomethyl napthalene and carried through the 5 sequence to yield AI-3-5. mp 172-174C (uncorrected). 1H NMR (300 MHz, DMSO) 8 8.1 (m, 1H), 8.0 (m, 1H), 7.83 (m, 1H), 7.6 (m, 3H), 7.4 (m, 2H), 6.9 (s, 1H), 6.5 (m, 1H), 6.4 (m, 1H), 6.18 (s 2H). EXAMPLE 10 10 2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl]-butyric acid AI-3-6 0 -~ N OH 0 0 AI-3-6 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 4-phenyl butyl chloride and carried through the sequence to yield AI-3-6. mp 119-121oC (uncorrected). 1H NMR (300 MHz, DMSO) 6 15 7.38 (s, 1H), 7.36 (m, 1H), 7.23 (m, 2H), 7.18 (m, 3H), 6.82 (s, 1H), 6.22 (m, 1H), 4.38 (m, 2H), 2.55 (m, 2H), 1.7 (m, 2H), 1.5 (m, 2H). EXAMPLE 11 4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-7 0 N OH 0 0 20 CI AI-3-7 - 95 - WO 99/62513 PCT/US99/12095 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 AI-3-7. mp 182-184 0 C (uncorrected). 1H NMR (300 MHz, DMSO) 6 7.55 (s, 1H), 7.42 (m, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 6.82 (s, 1H), 6.35 (m, 5 1H), 5.6 (s, 2H), EXAMPLE 12 2,4-dioxo-4-(1-phenethyl-l1H-pyrrol -2-yl)-butyric acid AI-3-8 0 N OH 00 AI-3-8 10 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 AI-3-8. mp 168-170 0 C (uncorrected). 1H NMR (300 MHz, DMSO) 8 7.35 (m, 1H), 7.2 (m, 6H), 6.85 (s, 1H), 6.18 (m, 1H), 4.6 (m, 2H), 3.0 (m, 2H) 15 EXAMPLE 13 4-[1-(2-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid Al-3-10 0 N OH
CH
3 AI-3-10 AI-3-10 was synthesized from 2-acetyl pyrrole and 2-methylbenzyl 20 bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 176-178oC (uncorrected). 1H NMR (400 MHz, DMSO) 6 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 PCT/US99/12095 1H), 7.07 (dd, J=7.4, 7.4 Hz, 1), 6.88 (s, 1H), 6.37 (dd, J=2.44, 4.0 Hz, 1H), 6.31, (d, J=7.32 Hz, 1H), 5.64 (s, 2H), 2.31 (s, 3H). mass spec (FAB, m+1) 286. 5 EXAMPLE 14 4-[1-( 3
,
4 -difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-11 9N 1 _OH F 0 0 F AI-3-11 AI-3-11 was synthesized from 2-acetyl pyrrole and 3,4-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the 10 product as a brownish-yellow solid, melting point 145-148 0 C (uncorrected) 1H NMR (400 MHz, DMSO) 8 7.56 (d, 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 (m, 1H), 6.86 (s, 1H), 6.35 (dd, J=2.48, 4.12 Hz, 1H), 5.61 (s, 2H). 15 mass spec (FAB, m+1) 308 EXAMPLE 15 4-[1-(4-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid Al-3-12 0 N OH 0 0 Br AlI-3-12 20 Al-3-12 was synthesized from 2-acetyl pyrrole and 4-bromobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid. melting point 184-185oC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.54 (d, J=1.68 Hz, 1H), 7.52 - 97 - WO 99/62513 PCT/US99/12095 (d, J=8.4 Hz, 2H), 7.44 (dd, J=1.4, 4.12 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 6.34 (dd, J=2.52, 4.16 Hz, 1H), 5.61 (s, 2H). mass spec (FAB, m+1) 352,350 5 EXAMPLE 16 4-[1-(2-bromobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-13 0 N OH 0 0 Br AI-3-13 AI-3-13 was synthesized from 2-acetyl pyrrole and 2-bromobenzyl bromide in a manner similar to that described for AI-3-9 to afford the 10 product as a brownish-yellow solid, melting point 176-180C (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 (s, 1H), 7.28 (dd, J=6.7, 6.7 Hz, 1H), 7.21 (dd, J=7.4, 7.4 Hz, 1H), 6.88 (s, 1H), 6.40 (dd, J=2.56, 4.2 Hz, 1H), 6.28 (dd, J=1.4, 7.72 Hz, 1H), 5.68 (s, 2H). 15 mass spec (FAB, m+1) EXAMPLE 17 4-[1-(3-bromobenzyl)-1lH-pyrrol-2-yl]-2,4-dioxobutyric acid Al-3-14 0 N OH Br NO O Al-3-14 20 AI-3-14 was synthesized from 2-acetyl pyrrole and 3-bromobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 164-166o 0 (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.54 (broad s, 1H), 7.43 (m, - 98 - WO 99/62513 PCT/US99/12095 2H), 7.28-7.24 (m, 2H), 7.05 (d, J=6.76 Hz, 1H), 6.83 (s, 1H), 6.33 (dd, J=2.56, 4.12 Hz, 1H), 5.61 (s, 2H). mass spec (FAB, m+1) 352, 350. 5 EXAMPLE 18 4-[ 1-(3-chlorobenzvl)- 1H-pvrrol-2-vll1-2,4-dioxobutvric acid AI-3-15 0 N OH C1 0 0 AI-3-15 AI-3-15 was synthesized from 2-acetyl pyrrole and 3-chlorobenzyl 10 bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 159-161 0 C (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.56 (d, J=2.2 Hz, 1H), 7.45 (dd, J=1.48, 4.24 Hz, 1H), 7.38-7.30 (m, 2H), 7.12 (s, 1H), 7.04 (d, J=7.28 Hz, 1H), 6.86 (s, 1H), 6.36 (dd, J=2.48, 4.2 Hz, 1H), 5.65 (s, 2H). mass spec 15 (FAB, m+1) 306 EXAMPLE 19 4-[1-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-16 0 N OH
H
3 C 0 0 AI-3-16 20 Al-3-16 was synthesized from 2-acetyl pyrrole and 3-methylbenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 140-141oC (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (d, J=1.92 Hz, 1H), 7.41 - 99 - WO 99/62513 PCT/US99/12095 (dd, J=1.44, 4.12 Hz, 1H), 7.20 (dd, J=7.64, 7.64 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 6.86 (m, 2H), 6.33 (dd, J=2.44, 4.12 Hz, 1H), 5.61 (s, 2H) 2.56 (s, 3H). mass spec (FAB, m+1) 286 5 EXAMPLE 20 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-17 N OH N 0 0 F AI-3-17 AI-3-17 was synthesized from 2-acetyl pyrrole and 2-fluorobenzyl bromide in a manner similar to that described for Al-3-9 to afford the 10 product as a brownish-yellow solid, melting point 155-156oC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7,47 (m, 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 (s, 1H), 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 15 EXAMPLE 21 2,4-dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid AI-3-18 0 N OH Al-3-18 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was 20 treated 1-bromo hexane and carried through the sequence to yield AI-3 18. mp 94.8'C (uncorrected). TLC Rf=0.68 (94:6: 6:6 CHCl3 / MeOH / HOAc) - 100- WO 99/62513 PCT/US99/12095 1H NMR (400 MHz, CDC13) 6 7.15 (dd, 1H, J=1.65 Hz, J=4.21 Hz), 7.01 (m,1H), 6.93 (s, 1H), 6.35 (dd, 1H, J=2.56 Hz, J=4.21 Hz), 4.35 (t, 2H, J=7.33 Hz), 1.77 (m, 2H), 1.28 (m, 6H), 0.88 (t, 3H, J=6.69 Hz) 5 EXAMPLE 22 4-(1-biphenyl-2-ylmethyl-lH-pyrrol
-
2 -yl)-2,4-dioxobutyric acid 0 N OH 00 Al-3-19 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 1-biphenyl-2-yl bromomethane and carried through the 10 sequence to yield A-3-19. mp 150-152 0 C (uncorrected). 1H NMR (400 MHz, CDC13) 6 7.4 (m, 9H), 6.8 (s, 1H), 6.42 (m, 1H), 6.3 (m, 1H), 5.6 (s, 2H). EXAMPLE 22 15 2,4-dioxo-4-[1-(4-phenoxybutyl)-lH -pyrrol-2-yl]-butyric acid AI-3-20 0 N N OH 0 0 OH AI-3-20 In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with 4-phenoxy-1-butyl bromide and carried through the sequence to yield AI-3-2. TLC Rf=0.63 (94:6:6 CHC13 / MeOH / HOAc) 20 1H NMR (400 MHIz, CDC13) 6 7.29 (m, 2H), 7.16 (dd, J=1.65 Hz, 4.21 Hz, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.93 (s, 1H), 6.87 (m, 2H), 6.25 (dd, J=2.56 Hz, 4.21 Hz 1H) 4.45 (t, J=7.14, 2H), 3.98 (t, J=6.22, 2H), 2.01 (m, 2H), 1.80 (m, 2H). - 101 - WO 99/62513 PCT/US99/12095 EXAMPLE 23 4-[1-(3-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-21 0 N OH °OO F~ F AI-3-21 5 AI-3-21 was synthesized from 2-acetyl pyrrole and 3-fluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 147-149oC (uncorrected). 1H NMR (400 MHz, DMSO) 6 7.55 (s, 1H), 7.45 (d, J=3.72 Hz, 1H), 7.36(dd, J=7.72, 14.4 Hz, 1H), 7.08 (ddd, J =2.2, 8.48, 8.48 Hz, 1H), 10 6.92-6.86 (m, 3H), 6.35 (dd, J=2.48, 4.04 Hz, 1H), 5.66 (s, 2H). mass spec (FAB, m+1) 290 EXAMPLE 24 4-1-(2-chlorobenzv1)-1H-pvrrol-2-yll-2,4-dioxobutvric acid AI-3-22 0 N OH 15 CI AI-3-22 Al-3-22 was synthesized from 2-acetyl pyrrole and 2 chlorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 179-180oC (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.52-7.47 (m, 3H), 7.30 (ddd, 20 J=1.6, 7.44, 7.44 Hz, 1H), 7.24 (ddd,J=1.32, 7.52, 7.52 Hz, 1H), 6.88 (s, 1H), 6.40 (dd, J=2.44, 4.12 Hz, 1H), 6.35 (dd, J=1.48, 7.68 Hz, 1H), 5.79 (s, 2H). mass spec (FAB, m+1) 306 -102- WO 99/62513 PCT/US99/12095 EXAMPLE 25 4-[1-(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 5 In a manner similar to that described for AI-3-1, AI-3-23 was prepared from AI-1-2. mass spec (FAB, m+1) 416. 1H NMR (400 MHz, D 6 -DMSO) 8 7.7 (s, 1H), 7.6 (s, 1H), 7.2 (m, 4H), 6.85 (s, 1H), 5.6 (s, 2H). EXAMPLE 26 10 4-[1-(4-methoxvbenzvl)-l1H-pvrrol-2-yll-2,4-dioxobutvric acid Al-3-24 N OH 0 0 MeO AI-3-24 AI-3-24 was synthesized from 2-acetyl pyrrole and 4-methoxybenzyl chloride in a manner similar to that described for Al-3-9 to afford the product as a brownish-yellow solid, melting point 167-168oC 15 (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (s, 1H), 7.38 (d, J=3.16 Hz, 1H), 7.09 (d, J=8.72 Hz, 2H), 6.86 (d, J=8.72 Hz, 2H), 6.83 (s, 1H), 6.29 (dd, J=2.56, 4.08 Hz, 1H), 5.55 (s, 2H), 3.70 (s, 3H). mass spec (FAB, m+1) 302 20 EXAMPLE 27 4-[1-(2,4,5-trifluorobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-25 - 103 - WO 99/62513 PCT/US99/12095 N OH F 0 0 F F AI-3-25 Al-3-25 was synthesized from 2-acetyl pyrrole and 2,4,5 trifluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 154-156oC 5 (uncorrected). 1H NMR (400 MHz, DMSO) 5 7.6 (m, 1H), 7.48 (m, 2H), 6.86 (s, 1H), 6.78 (m, 1H), 6.36 (dd, J=2.5, 4.1 Hz, 1H), 5.66 (s, 2H). EXAMPLE 28 4-1-(2,3-difluorobenzyl)-1H-pyrrol-2-vl1-2,4-dioxobutvric acid Al-3-26 0 N OH 0 0 F 10 F AI-3-26 Al-3-26 was synthesized from 2-acetyl pyrrole and 2,3 difluorobenzyl 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 (s, 1H), 7.45 (m, 1H), 15 7.35 (m, 1H), 7.12 (m, 1H), 6.86 (s, 1H), 6.48 (m, 1H), 3.38 (dd, J=2.5, 4.1 Hz, 1H), 5.75 (s, 2H). mass spec (FAB, m+1) 308 EXAMPLE 29 4-[1-(3,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-26 -104- WO 99/62513 PCT/US99/12095 0 N O H F 0 0 F AI-3-27 AI-3-27 was synthesized from 2-acetyl pyrrole and 3,5-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 166-168 0 C 5 (uncorrected); 1H NMR (400 MHz, DMSO) 6 7.58 (s, 1H), 7.48 (m, 1H), 7.14 (m, 1H), 6.88 (s, 1H), 6.75 (m, 2H), 6.38 (dd, J=2.5, 4.0 Hz, 1H), 5.67 (s, 2H). mass spec (FAB, m+1) 308 EXAMPLE 30 10 4-[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 2,5-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the 15 product as a brownish-yellow solid, melting point 142-146 0 C (uncorrected); 1H NMR (400 MHz, DMSO) 8 7.50 (m, 2H), 7.30 (m, 1H), 7.17 ( m, 1H), 6.86 (s, 1H), 6.38 (m, 2H), 5.69 (s, 2H). mass spec (FAB, m+1) 308 20 EXAMPLE 31 4-[1-(2,5,6-difluorobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-29 - 105 - WO 99/62513 PCT/US99/12095 0 F N OH 0 0 F F AI-3-29 AI-3-29 was synthesized from 2-acetyl pyrrole and 2,3,6 trifluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 131-133oC 5 (uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (m, 1H), 7.40 (m, 1H), 7.37 (s, 1H), 7.15 (m, 1H), 6.84 (s, 1H), 6.29 (dd, J=2.5, 4.1 Hz, 1H), 5.77 (s, 2H). mass spec (FAB, m+1) 326. EXAMPLES 32-45 10 In a manner similar to that described for AI-3-1, the following compounds were prepared: 4-[1-(2-fluorobenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid NCO 2 H 0 OH F CHN Calc. 62.28, 4.18, 4.84; Fnd. 62.11, 4.37, 4.91. (32) 15 4 -[1-(4-trifluoromethylbenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid: NN CO 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 PCT/US99/12095 4-[1-(4-cyanobenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid: NC0 2 H 0 OH NC CHN Calc. 64.86, 4.08, 9.45; Fnd. 64.61, 4.32, 9.77. (34) 0 N ~ OH O HO .110 ,O 5 4-[1-(3-methoxybenzyl)-l1H -pyrrol-2-yl] -2,4-dioxobutyric acid CHN Calc. 63.78, 5.02, 4.65; Fnd. 63.99,5.14, 4.60. (35) N CO 2 H O OH HO 0.20 TFA 2-hydroxy-4-[1-(4-hydroxybenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid 10 CHN Calc. (C15H13NO5 0.20 TFA) 59.65, 4.29, 4.52; Fnd. 59.50, 4.31, 4.68. (36) C0 2 H N O H - 107 - WO 99/62513 PCT/US99/12095 4-(1-cyclopentylmethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 63.86, 6.51, 5.32; Fnd. 63.88, 6.27, 5.37 (37)
NCO
2 H O OH / 0.35 EtOAc F 4- {1-[3-(4-fluorophenyl)propyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid CHN 5 Calc.( C17H16NO4F 0.35 EtOAc) 63.47, 5.44, 4.02; 63.16, 5.12, 4.34. (38)
CO
2 H O OH F 4-{1l-[2-(4-fluorophenyl)ethyl]-lH-pyrrol-2-yl}-2,4-dioxobutyric acid CHN Calc. 63.36, 4.65, 4.62; Fnd. 63.16, 4.64, 4.50. (39) CO2H N 0 OH 10 4-[1-(3-phenylpropyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN Calc.(C17H1 7
NO
4 0.1 H20) 67.80, 5.76, 4.65; Fnd. 67.79, 5.67, 4.70. (40) - 108- WO 99/62513 PCT/US99/12095 9,N. CO 2 H S OH H3 C 4-(1-ethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 57.41, 5.30, 6.70; Fnd. 57.13, 5.33, 6.70. (41) C02H N 0 OH 5 F 4-[1-(3-fluoro-benzyl)- 1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN Calc.(C15H12 FNO4 0.35 H20) 60.95, 4.33, 4.74; Fnd. 60.89 4.25, 4.78. (42) N -. ,r C O2 H 0 OH CI 4-[1-(2-chloro-benzyl)-l1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN Calc. 10 (C15H12NO4C1 0.15 H20)58.41, 4.02, 4.54; Fnd. 58.31, 3.94, 4.62 (43) O OH
/CO
2 H N N H - 109- WO 99/62513 PCT/US99/12095 4-[1-(3-benzoylaminopropyl)-l1H-pyrrol-3-yl] -2,4-dioxobutyric acid CHN Calc. (C18H18N205 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 5 4- {1-[3-(4-fluorophenoxy)benzyl]-l1H-pyrrol-2-yl}] -2,4-dioxobutyric acid CHN Calc. 66.14, 4.23, 3.67; Fnd. 66.37, 4.32, 3.69. (45) EXAMPLE 46 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 10 Step 1: cyclohexyl-pyrrol-1-yl-methanone AII-1-1 0 N AII-1-1 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 15 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 NH4C1 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 20 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- 1-1 as white crystals. TLC Rf=0.62 (5:95 EtOAc / Hexanes) 1H NMR (400 MHz, CDC1 3 ) 5 7.32 (m, 2H), 6.29 (m, 2H), 2.92 (m, 1H), 1.85 1.97 (m, 4H), 1.56-1.76 (m, 3H), 1.24-1.43 (m, 3H). 5 Step 2: 1-cyclohexylmethyl-l1-H -pyrrole AII-2-1 0 N AIIl-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 10 reflux for three hours. The solution was cooled to 0oC, 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 15 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 (t, J=2.01 Hz, 2H), 6.12 (t, J=2.01 Hz, 2H), 3.67 (m, 2H), 1.58-1.72 (m, 6H), 1.15-1.22 (m, 3H), 0.92 (m, 2H). 20 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 5 with Et20 three times. The combined organic layers were washed with NH4C1 and dried over MgSO4, 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 10 (300 MHz, CDC1 3 ) 6 6.95 (dd, J=1.65, 4.03 Hz, 1H), 6.84 (m, 1H), 6.11 (dd, J=2.65, 4.03 Hz, 1H), 4.13 (d, J=7.32 Hz, 2H), 2.43 (s, 3H), ), 1.58-1.72 (m, 6H), 1.17-1.25 (m, 3H), 0.92 (m, 2H). Step 4: 4-( 1-cyclohexylmethyl- 1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid 15 methyl ester AII-4-1 0 N OCH 3 OJOO AII-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, CDC1 3 ) 8 7.10, (dd, J = 1.65, 4.21 Hz, 20 1H), 6.92 (m, 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 (m, 6H), 1.17-1.24 (m, 3H), 0.93 (m, 2H). Step 5: 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 25 -112- WO 99/62513 PCT/US99/12095 0 N OH AII-5-1 In a manner similar to that described for AI-3-1, AII-4-1 was treated with NaOH to give AII-5-1. TLC Rf=0.65 (94:6:6 CHC13 / MeOH / HOAc) 1H NMR (400 MHz, CDC1 3 ) 5 7.15 (dd, J=1.65, 4.21 Hz, 1H), 6.96 (m, 1H), 5 6.93 (s, 1H), 6.22 (dd, J=2.56, 4.21 Hz, 1H), 4.18 (d, J=7.13 Hz, 2H), 1.57 1.72 (m, 6H), 1.16-1.23 (m, 3H), 0.96 (m, 2H). EXAMPLE 47 4-[ 1-(4-fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid 10 AIII-3-1 Step 1: 1-[ 1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2 yl]ethanone AIII-1-1 AIII-1-1 K0 A mixture of AI-1-2 (.49 g, 1.43 mmol), phenylacetylene (.218 15 g, .235 mls, 2.14 mmol), copper(I) iodide (.022 g, .116 mmol), tetrakis(triphenylphosphine)-palladium(0) (.1 g, .086 mmol) and triethylamine (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 20 combined organic extracts were washed with H20, brine, dried over -113- WO 99/62513 PCT/US99/12095 Na2SO4, filtered and the solvent removed. The resulting brown oil was purified by radial disc chromatography twice, first using 2:1 hexane/ CH2Cl 2 followed by straight ethyl acetate, then straight CH2Cl 2 to afford the title compound. 1H NMR (400 MHz, CDCl 3 ) 6 2.42 (s, 3H), 5.52 5 (s, 2H), 6.99 (t, 2H, J = 8.7 Hz), 7.11 - 7.16 (m, 4H), 7.29 - 7.47 (m, 3H), 7.45 - 7.48 (m, 2H) Step 2: [1-(4-fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yl-2,4 dioxobutyric acid ethyl ester AIII-2-1 /\ o N OEt 0 0 10 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 10% citric acid and extracted with ethyl acetate. The combined organic 15 extracts were washed with H20, brine, dried over Na2SO4 filtered, and the solvent removed in vacuo to give the title compound as a yellow oil. 1H NMR (400 MHz, CDC13) 5 1.36 (t, 3H, J = 7.1 Hz), 4.34 (q, 2H, J = 7.2 Hz), 5.55 (s, 2H), 6.80 (s, 1H), 6.99 (t, 2H, J = 8.7 Hz), 7.12 - 7.18 (m, 2H), 7.19 (d, 1H, J = 1.65 Hz), 7.25 (d, 1H, J = 1.65 Hz), 7.29 - 7.35 (m, 3H), 7.44 20 7.48 (m, 2H) Step 3: [1-(4-fluorobenzyl)-4-phenylethynyl- 1H-pyrrol-2-yll-2,4 dioxobutyric acid AIII-3-1 -114- WO 99/62513 PCT/US99/12095 0 N OH OJOO 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 LiOH in 5 mls THF to give the title compound as a 5 yellow resin. 1H NMR (400 MHz, CDC13) 6 6.86 (s, 1H), 7.01 (t, 2H, J = 8.6 Hz), 7.12 - 7.19 (m, 2H), 7.21 (d, 1H, J = 1.65 Hz), 7.28 (d, 2H, J = 1.65 Hz), 7.30 - 7.36 (m, 4H), 7.43 - 7.50 (m, 2H) FAB MS: m/z 390 (M' + H) 10 EXAMPLE 48 4 -[1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid Step 1: 1-[1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]ethanone AIII-4-1 N 15 AMII-4-1 AIII-1-1 (.15 g, .47 mmol) was dissolved in 10 ml absolute ethanol, and to it was added 10% Pd/C (.03 g, 20 wt-%). 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. 5 1H NMR (400 MHz, CDC1 3 ) 6 2.35 (s, 3H), 2.72 - 2.79 (m, 2H), 2.82 - 2.89 (m, 2H), 5.42 (s, 2H), 6.57 (d, 1H, J = 1.8 Hz), 6.79 (d, 1H, J = 1.8 Hz), 6.94 (t, 2H, J = 8.7 Hz), 7.00 - 7.07 (m, 2H), 7.12 - 7.30 (m, 5H) Step 2: 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 10 dioxobutyric acid ethyl ester AIII-5-1 0 N OEt 0 0 F AIIU-5-1 In a similar manner to AIII-2-1, AIII-4-1 (.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 15 the next reaction without further purification. 1H NMR (400 MHz, CDC13) 6 1.37 (t, 3H, J = 7.14 Hz), 2.76 (t, 1H, J = 7.7 Hz), 2.86 (t, 1H, J = 7.7 Hz)4.35 (q, 2H, J = 7.14 Hz), 5.48 (s, 2H), 6.67 (s, 1H), 6.77 (s, 1H), 6.92 7.06 (m, 5H), 7.11 - 7.29 (m, 5H) 20 Step 3: 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid AIII-6-1 -116- WO 99/62513 PCT/US99/12095 0 N OH 0 0 F AB-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, CDC1 3 ) 6 2.75 - 2.82 (m, 1H), 2.84 5 2.91 (m, 1H), 5.47 (s, 2H), 6.71 (d, 1H, J = 1.3 Hz), 6.86 (s, 1H), 6.95 - 7.08 (m, 4H), 7.11 - 7.16 (m, 2H), 7.17 - 7.23 (m, 1H), 7.24 - 7.32 (m, 3H) EXAMPLE 49 4-[5-(4-fluorobenzyl)- 1-methyl- 1-H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV 10 5-1 Step 1: 2-(4-fluorobenzyl)-1H -pyrrole AIV1-1 F N'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:CH2C1 2 and pyrrole (9.31g, 0.139 mole) at 0 0 C 15 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 20 AIV-1-1. 1H NMR (400 MHz, CDC13) 6 7.77 (broad s, 1H), 7.17-7.13 (m, 2H), 7.00-6.95 (m, 2H), 6.67 (s, 1H), 6.15-6.14 (d, 1H, J=2.7 Hz), 5.97 (m, 1H), 3.94 (s, 2H). -117- WO 99/62513 PCT/US99/12095 Step 2: 1-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]ethanone AIV-2-1 F
C
H
3 N 0 AIV-2-1 MeMgCl (2.95 mL, 0.0284 mole) was added dropwise to a solution of AIV 5 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 10 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, CDCl3) 8 9.72 (broad s, 1H), 7.18-7.14 (m, 2H), 7.00-6.95 m, 2H), 6.85-6.83 (m, 1H), 6.01 5.99 (m, 1H), 3.97 (s, 2H), 2.37 (s, 2H) 15 Step 3: 1-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]ethanone
AIV
3-1 F /FN CH3 H3C O 3 AIV-3-1 NaH (.098g, 0.00244 mole) was added to a solution of AIV-2-1 in DMF (25 mL) at 00 C followed by subsequent addition of Mel (0.53g, 0.00244 mole). 20 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) 8 7.11-7.07 (m, 2H), 7.01 -118- WO 99/62513 PCT/US99/12095 6.97 (m, 2H), 6.93-6.92 (m, 1H), 5.90-5.89 (m, 1H), 3.93 (s, 2H), 3.79 (s, 3H), 2.42 (s, 3H). 5 Step 4: 4 -[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 dioxobutyric acid methyl ester AIV-4-1 F \ O N OCH3 H3C O O AIV-4-1 A solution of AIV-3-1 (0.222g, 0.000961 mole) in DME (O10mL) was treated with sodium hydride (0.058g, 0.00144 mole) followed by dimethyl oxalate 10 (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 NaSO4, filtered and evaporated to give AIV-4-1 as a brown solid. TLC: Rf=0.39 (97:3:1 CH2C1 2 / MeOH / HOAc) 1H NMR 15 (400 MHz, CDC13) 5 7.12-7.07 (m, 3H), 7.04-6.99 (m, 2H), 6.83 (s, 1H), 5.99 5.98 (d, 1H, j=4.21), 3.97 (s, 2H), 3.915 (s, 3H), 3.85 (s, 3H). Step 5: 4 -[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 20 dioxobutyric acid AIV-5-1 F0 N OH
CH
3 0 OH AWV-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 PCT/US99/12095 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 AIV-5-1 as a yellow solid. TLC Rf=0.52 (93:7:7 CHCl,/ MeOH / HOAc) 1H NMR (400 MHz, CDC1 3 ) 6 7.128-7.086 (m, 3H), 7.04-6.99 (t, 2H j=9), 6.90 (s, 1H), 6.03 5 6.02 (d, 1H. j=4.39 Hz), 3.98 (s, 2H), 3.85 (s, 3H). EXAMPLE 50 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV 5-2 10 0 N OH H3C O O
H
3 0 0 AIV-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 AIV-5-2. TLC: Rf=0.52 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 15 MHz, DMSO) 5 7.39-7.29 (m, 4H), 7.18-7.16 (d, 1H, j=6.7 Hz), 6.81 (s, 1H), 6.04-6.03 (d, 1H, j=4.2 Hz), 4.10 (s, 1H), 3.82 (s, 1H). EXAMPLE 51 20 4 -[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-3 F N OH O O AIV-5-3 AIV-5-3 was prepared in a manner similar to that described for AIV-5 1 with the exception that the methylation step was omitted. -120- WO 99/62513 PCT/US99/12095 TLC: Rf=0.28 (93:7:7 CHC1 3 / MeOH / HOAc) 1H NMR (400 MHz, DMSO) 6 12.19 (s, 1H), 7.32-7.28 (m, 2H) 7.17 (s, 1H), 7.14-7.10 (t, 2H, j=8.8 Hz), 6.79 (s, 1H), 6.06-6.04 (m, 1H) 3.97 (s, 1H). 5 EXAMPLE 52 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-4 ci 0 CI \ 0 N OH O O AIV-5-4 AIV-5-4 was prepared in a manner similar to that described for AIV-5 10 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 (s, 1H), 7.36-7.18 (m, 5H), 6.80 (s, 1H), 6.10 (s, 1H), 3.99 (s, 1H). EXAMPLE 53 15 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-5 0 N OH O O AIV-5-5 AIV-5-5 was prepared in a manner similar to that described for AIV-5 1, with the exception that the methylation step was omitted. TLC: 20 Rf=0.34 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, DMSO) 8 12.20 (s, 1H), 7.32-7.18 (m, 6H), 6.80 (s, 1H), 6.05 (m, 1H), 3.98 (s, 2H). EXAMPLE 54 4-[5-(3-fluorobenzyl)-l1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-6 25 - 121 - WO 99/62513 PCT/US99/12095 0 N OH O O AIV-5-6 AIV-5-6 was prepared in a manner similar to that described for AIV-5 1, with the exception that the methylation step was omitted. TLC: Rf=0.34 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, DMSO) 8 12.21 5 (s, 1H), 7.35-7.33 (dd, 1H, j=8.1 Hz, 1.6 Hz), 7.19 (d, 1H, j=2.2 Hz), 7.12-7.10 (d, 2H, j=6.6 Hz), 7.04 (m, 1H), 6.80 (s, 1H), 6.10-6.09 (dd, 1H, j=3.8 Hz, 2.1 Hz), 4.00 (s, 1H). 10 EXAMPLE 55 4-[5-(4-fluorobenzyl)-l1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-7 F N O H F AIV-5-7 AIV-5-7 was prepared in a manner similar to that described for AIV-5 15 1, except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkylation step. TLC: Rf=0.60 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, CDCl3) 8 7.21-7.20 (d, 1H, j=4.2 Hz) 7.049-6.96 (m, 6H), 6.93 (s, 1H), 6.90-6.86 (dd, 2H j=8.4 Hz, 5.3 Hz), 6.07-6.06 (d, 1H j=4.2 Hz), 5.60 (s, 2H), 3.85 (s, 2H). 20 EXAMPLE 56 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- 1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-8 - 122 - WO 99/62513 PCT/US99/12095 0 CI N OH 0 0 OJOO F AIV-5-8 AIV-5-8 was prepared in a manner similar to that described for AIV-5 1 except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NMR (400 MHz, DMSO) 6 7.46-7.45 (d, 1H j=4.2 5 Hz), 7.28-7.22 (m, 2H), 7.12-7.04 (m, 4H), 6.92-6.88 (m, 2H), 6.85 (s, 1H), 6.14-6.13 (d, 1H, j=4.2 Hz), 5.69 (s, 2H), 3.99 (s, 2H). mass spec.: (FAB, m+1) 414.10 10 EXAMPLE 57 4-[5-(benzyl)- 1-(4-fluorobenzyl)- 1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV 5-9 0 N OH 0 0 F AIV-5-9 15 AIV-5-9 was prepared in a manner similar to that described for AIV-5 1 except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NIMR (400 MHz, CDC13) 6 7.31-7.27 (m, 2H), 7.24 (m, 1H), 7.22-7.21 (d, 1H j=4.2 Hz), 7.08-7.06 (m, 2H), 7.00-6.96 (m, 2H), 6.92 (s, 1H), 6.90-6.87 (m, 2H), 6.11-1.10 (d, 1H, j=4.2 Hz), 5.60 (s, 2H), 3.88 20 (s, 2H). mass spec.: (FAB, m+1) 380 - 123 - WO 99/62513 PCT/US99/12095 EXAMPLE 58 4-[5-(3-chlorobenzyl)- 1-(4-fluorobenzyl)- 1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-10 CI 0 N OH 00 F AIV-5-10 5 AIV-5-10 was prepared in a manner similar to that described for AIV-5 1 except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. 1H NMR (400 MHz, CDCl 3 ) 6 7.27 (m, 1H), 7.25-7.24 (m, 1H), 7.21-7.20 (d, 1H, j=4.2 Hz), 7.01-6.95 (m, 4H), 6.93 (s, 1H), 6.89 6.85 (m, 2H), 6.08-6.07 (d, 1H, j=4.2 Hz), 5.59 (s, 2H), 3.84 (s, 2H). mass 10 spec.: (FAB, m+1) 414 EXAMPLE 59 4-[5-(4-fluorobenzyl)- 1-methyl-1lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV 8-1 15 Step 1: 1-[5-(4-fluorobenzyl)-l1-methyl-1 H -pyrrol-3-yl]ethanone AIV-6-1 F 0
HCH
3
H
3 C AIV-6-1 AIV-3-1 was dissolved in TFA 10 mL and was refluxed for two days. 20 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 PCT/US99/12095 TLC: Rf=0.33 (60:40 Hexanes / EtOAc) 1H NMR (400 MHz, CDC13) 5 7.21-7.20 (d, 1H, j=1.83 Hz), 7.12-7.09 (m, 2H), 7.01-6.96 (m, 2H), 6.33-6.22 (d, 1H, j=1.8 Hz), 3.88 (s, 2H), 3.45 (s, 3H), 2.36 (s, 3H). 5 Step 2: 4-[5-(4-fluorobenzyl)- 1-methyl-llH -pyrrol-3-yl]-2,4 dioxobutyric acid AIV-8-1 0O F OH \ 0 N I
CH
3 AIV-8-1 In a manner similar to that described for AIV-5-1, AIV-6-1 was treated with NaH and dimethyl oxalate followed by hydrolysis with NaOH to give 10 AIV-8-1. 1H NMR (400 MHz, CDC13) 8 7.42 (d, 2H, j=1.8 Hz), 7.13-7.10 (m, 2H), 7.04-6.99 (m, 2H), 6.72-6.71 (d, 1H, j=1.7 Hz), 6.38 (s, 1H), 3.91 (s, 2H), 3.51 (s, 3H). mass spec.: (FAB, m+1) 304.19 EXAMPLE 60 15 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV 8-2 0O OH 0 CI O Cl N I
CH
3 AIV-8-2 In a manner similar to that described for AIV-8-1, pyrrole was 20 alkylated with 3-chlorobenzyl bromide and carried through the sequence to give AIV-8-2. 1H NMR (400 MHz, CDC13) 5 7.43-7.42 (d, 1H, j=1.8 Hz), - 125 - WO 99/62513 PCT/US99/12095 7.25-7.24 (m, 2H), 7.14 (s, 1H), 7.04-7.03 (m, 1H), 6.72 (s, 1H), 6.42-6.41 (d, 1H, j=1.lHz), 3.92 (s, 2H), 3.50 (s, 3H). mass spec.: (FAB, m+1) 320.2 5 EXAMPLE 61 4-[5-(benzyl)-l1-methyl-l1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-8-3 0O OH \ 0 N 1
CH
3 AIV-8-3 In a manner similar to that described for AIV-8-1, pyrrole was 10 alkylated with benzyl bromide and carried through the sequence to give AIV-8-3. 1H NMR (400 MHz, CDC13) 8 7.43-7.42 (d, 1H, j=1.8), 7.34-7.30 (m, 2H), 7.27 (m, 1H), (d, 2H, j=7.1 Hz), 6.72 (s, 1H), 6.41-6.40 (d, 1H, j=1.8), 3.94 (s, 2H), 3.50 (s, 3H). mass spec.: (FAB, m+1) 286.3 15 EXAMPLE 62 4-[5-(3-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV 8-4 0O OH \ 0 FC N 20
CH
3 AIV-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 AIV-8-4. 1H NMR (400 MHz, CDC13) 8 7.43 (d, 1H, j=1.8 Hz), 7.32 - 126 - WO 99/62513 PCT/US99/12095 7.28 (m, 1H), 6.98-6.93 (m, 2H), 6.86-6.83 (d, 1H, j=9.5 Hz), 6.72 (s, 1H), 6.43-6.42 (d, 1H, j=1.3 Hz), 3.94 (s, 2H), 3.50 (S, 3H). mass spec.: (FAB, m+1) 304.2 5 EXAMPLE 63 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid AIV-8-5 O O OH 0 N H AIV-8-5 In a manner similar to that described for AIV-8-1, with the exception that the N-alkylation step was omitted, pyrrole was alkyated with benzyl 10 bromide and carried through the sequence to give AIV-8-5. TLC: Rf=0.18 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, CDC13) 8 8.43 (s, 1H), 7.48 (dd, 1H, j=3.1 Hz, 1.8 Hz), 7.41-7.18 (m, 5H), 6.78 (s, 1H), 6.47 (d, 1H, j=0.7 Hz), 3.98 (s, 1H). 15 EXAMPLE 64 4-[2,5-bis-(3-chlorobenzyl)-1-H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-8-6 OO OH N H C AIV-8-6 In a manner similar to that described for AIV-5-1 pyrrole was alkyated 20 with 3-chlorobenzyl bromide and the minor 2,5-bis 3-chlorobenzyl alkylated product was isolated. Treatment with MeMgC1 followed by acetic anyhydride as described for AIV-2-1 gave the 3-acylated product - 127 - WO 99/62513 PCT/US99/12095 that was carried through the sequence to give AIV-8-6. TLC: Rf=0.42 (93:7:7 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, CDC1 3 ) 6 9.10 (s, 1H), 7.26-7.21 (m, 3H), 7.08-6.97 (m, 5H), 6.90 (d, 1H, j=2.6 Hz), 6.77 (s, 1H), 3.92 (s, 2H), 3.77 (s, 2H). 5 EXAMPLE 65 4-[1-(4-Fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AV 10-1 10 Step 1: (+/-) 5-Oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 COOEt NH 0 AV-1-1 To a 2L round bottomed flask with a stirring bar was added pyroglutamic acid (50g, 387.2 mmol) and 1L of absolute ethanol. To this well stirred mixture was added thionyl chloride (10.0 mL, 137.1 mmol) 15 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 20 ethyl ester AV-1-1 as an oil which crystallized on standing. 1H NMR (CDC13) 8 1.30 (3H, t, j=7.3 Hz), 2.18 to 2.60 (4H, complex multiplet), 4.21 (3H, m), 3.37 (1H, br s). Step 2: (+/-) 5-Oxo-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl 25 ester 2-ethyl ester AV-2-1 COOEt NO 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) CHC1 3 (300 mL), di-tert-butyldicarbonate
(
3 0.99g, 142.01 mmol), Et3N (16.5 mL, 118.34 mmol), and 4 -dimethylaminopyridine 5 (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 (MgSO 4 ), filtration and removal of the solvent in vacuo gave an oil. This material 10 was chromatographed on 300g of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained (+/-) 5-oxo-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 as an oil. 1H NMR (CDC1 3 ) 6 1.27 (3H, t, j=7.3 Hz), 1.50 (9H, s), 2.08 (1H, m), 2.45 to 2.71 (3H, complex multiplet), 4.27 (2H, q, j=7.3 Hz), 4.60 (1H, dd, j=3, 9 Hz). 15 Step 3: (+/-) 2 -Tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 0 Ph 0 N COOEt H AV-3-1 To an oven dried 500 mL, three-necked round bottomed flask with a 20 stirring bar, argon inlet and septum was added 5-oxo-pyrrolidine-1,2 dicarboxylic 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 0 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 25 40oC, the cooling bath was removed and the mixture was warmed to 20 0 C. 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-tert 30 butoxycarbonylamino-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 S/ ' COOEt AV-4-1 5 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 10 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 15 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-2H pyrrole-2-carboxylic acid ethyl ester AV-4-1 was obtained as a colorless 20 oil. 1H NMR (CDCl3) 5 1.31 (3H, t, j=7.1 Hz), 2.22 (2H, m), 3.00 (1H, m), 3.17 (1H, m), 4.23 (2H, d, j=7.1), 4.92 (1H, m), 7.41 (3H, min), 7.89 (2H, dd, j= 2.7, 4.0). Step 5: 5-Phenyl-lH-pyrrole-2-carboxylic acid AV-5-1 N COOH 25 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 30 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 conc. HCI. This mixture was extracted with EtOAc (2X). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed on 5 silica gel using 2.5% MeOH in EtOAc as eluant to give 5-phenyl-1H pyrrole-2-carboxylic acid AV-5-1 as an off white solid. 1H NMR (CDC1 3 ) 5 6.59 (1H, dd, j=2.7, 3.9 Hz), 7.13 (1H, dd, j= 2.7, 3.9 Hz), 7.34 (1H, m), 7.41 (2H, m), 7.59 (2H, m), 9.40 (1H, br s). 10 Step 6: 5-Phenyl-l1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1
-OCH
3 N N'C H 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-1H-pyrrole-2-carboxylic acid AV-5-1 (2.45g, 13.09 15 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 20 one portion. The resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo at +80oC. 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 25 gave a solid. This material was chromatographed on silica gel using 35% EtOAc in hexane as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. 1H NMR (CDC13) 5 3.36 (3H, s), 3.80 (3H, s), 6.58 (1H, dd, j=2.2, 4.0 Hz), 6.94 (1H, dd, j= 2.2, 4.0 Hz), 7.30 (1H, m), 7.41 (2H, m), 7.58 (2H, m), 9.63 (1H, br s). 30 Step 7: 1-( 4 -Fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1 - 131 - WO 99/62513 PCT/US99/12095 OC H 3 N N.C H3 0 F AV-7-1 To a 100 mL round bottomed flask containing 5-phenyl-1H-pyrrole-2 carboxylic 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 5 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 10 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 INMR (CDC13) 6 3.21 (3H, s), 3.47 (3H, 15 s), 5.52 (2H, s), 6.24 (1H, d, j= 3.9 Hz), 6.75 to 6.90 (5H, m), 6.94 (1H, d, j= 3.9 Hz), 7.38 (4H, m). Step 8: 1-[ 1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1
YCH
3 N 0 20 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 (0.726g, 2.16 mmol) and dry THF (20 mL). This solution was cooled to -78oC and methyllithium (3.39 mL of a 1.4 M 25 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 NH4CI 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 (MgSO4), filtered and 5 concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-(4 fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]ethanone AV-8-1 as an oil. 1H NMR (CDC13) 8 2.42 (3H, s), 5.59 (2H, s), 6.29 (1H, d, j= 4.2 Hz), 6.78 to 6.91 (4H, m), 7.12 (1H, d, j= 4.2 Hz), 7.29 (2H, m), 7.38 (3H, m). 10 Step 9: 4-[ 1-( 4 -Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AV-9-1 O N 0 C H 3 0 0 F AV-9-1 To a 100 mL round bottomed flask with a stirring bar and an argon inlet 15 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 20 and removal of the solvent in vacuo gave 4 -[1-( 4 -fluorobenzyl)-5-phenyl 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) 5 1.38 (3H, t, j=7.1 Hz), 4.38 (2H, q,j= 7.1 Hz), 5.65 (2H, s), 6.38 (1H, d,j= 4.1 Hz), 6.79 to 6.94 (4H, m), 7.29 (2H, m), 7.39 (3H, m). 25 Step 10: 4-[ 1-( 4 -Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid AV-10-1 - 133 - WO 99/62513 PCT/US99/12095 N OH 0 0 F AV-10-1 To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 4-[ 1-(4-fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 (0.84g, 2.14 mmol) and MeOH (72 mL). To this 5 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 Et20 then acidified with 1N HC1. The mixture was extracted with Et20 and the Et20 extract was washed with brine, dried (MgSO4), filtered and 10 concentrated in vacuo. The crude solid was recrystallized from a mixture of EtOAc and hexane to give 4 -[1-( 4 -fluorobenzyl)-5-phenyl-lH pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 as a white, crystalline solid. MP: 151-152oC (dec). 1H NMR (CDC13) 8 5.63 (2H, s), 6.42 (1H, d, j= 4.4 Hz), 6.80 (2H, m), 6.94 (3H, m), 7.29 (2H, m), 7.40 (2H, m). 15 EXAMPLE 66 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-VI-5-1 20 Step 1: 1-[1-( 4 -Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]ethanone AVI-1 1
NO
2 N 0 F AVI-1-1 To a 500 mL round bottomed flask with a stirring bar and a drying tube was added 1-[ l-(4-fluorobenzyl)- 1H-pyrrol-2-yl]ethanone Al-1-1 (11.64g, -134- WO 99/62513 PCT/US99/12095 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to 78oC 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 0oC over 7h. The acetic anhydride was removed in 5 vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHCO3 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 20% EtOAc in hexane as eluant. An impure yellow crystalline solid was 10 obtained. This material was recrystallized from Et20/hexane to give white crystals of 1-[ 1-(4-fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDC1 3 ) 5 2.55 (3H, s), 5.54 (2H, s), 7.06 (2H, m), 7.20 (2H, m), 7.47 (1H, d,j= 1.8 Hz), 7.63 (1H, d,j= 1.8 Hz). 15 Step 2: 1-[4-Amino-l1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]ethanone AVI-2-1
NH
2 N 0 F AVI-2-1 To a 1L round bottomed flask with a stirring bar and a balloon hydrogenation adapter was added 1-[1-( 4 -fluorobenzyl)-4-nitro-1H-pyrrol 20 2-yl]ethanone AVI-1-1 (8.00g, 30.51 mmol) absolute EtOH (640 mL) and 10% 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-amino 25 1-( 4 -fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 as a yellow crystalline solid. 1H NMR (CDC13) 8 2.34 (3H, s), 3.01 (2H, br s), 5.42 (2H, s), 6.46 (1H, d, j= 2.0 Hz), 6.50 (1H, d, j= 2.0 Hz), 6.98 (2H, m), 7.12 (2H, m). - 135 - WO 99/62513 PCT/US99/12095 Step 3: 1-[ 4 -Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2 yl]ethanone AVI-3-1
(CH
3
)
2 N N 0 'N F AVI-3-1 To a 100 mL round bottomed flask with a stirring bar and a nitrogen 5 inlet was added 1-[4-amino-l1-(4-fluorobenzyl)-l1H-pyrrol-2-yl]ethanone AVI-2-1 (0.50g, 2.15 mmol), dry DMF (20 mL), finely powdered Cs2CO 3 (3.26g, 10 mmol) and Mel (0.31 mL, 5.00 mmol). The resulting mixture was stirred lh at ambient temperature. The solids were removed by filtration and the solvent was removed in vacuo. The residue was 10 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 1-[4-dimethylamino-l1-(4-fluorobenzyl)-l1H-pyrrol-2 yl]ethanone AVI-3-1 as an oil. 1H NMR (CDC13) 6 2.36 (3H, s), 2.70 (6H, 15 s), 5.46 (2H, s), 6.36 (1H, d, j= 2.0 Hz), 6.50 (1H, d, j= 2.0 Hz), 6.98 (2H, m), 7.11 (2H, m). Step 4: 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AVI-4-1
(CH
3
)
2 N 0 N OEt 0 0 20 F AVI-4-1 In a manner substantially similar to that described for Example AV-9 1.l-[4-dimethylamino-l1-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVI-3-1 was used to prepare 4 -[4-dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2 -136- WO 99/62513 PCT/US99/12095 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- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 5 dioxobutyric acid AVI-5-1
(CH
3
)
2 N N OH 0 0 OO F AVI-5-1 In a manner substantially similar to that described for Example AV-10-1 4-[4-dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 2,4-dioxobutyric acid ethyl ester AVI-4-1 was used to prepare 4-[4 10 dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVI-5-1. 1H NMR (DMSO-d6-CDC1 3 1:1) 5 3.12 (6H, s), 5.61 (2H, s), 7.06 (2H, m), 7.19 (2H, m), 7.60 (1H, br s), 7.68 (1H, br s). EXAMPLES 67-69 15 The following compounds was prepared in a manner similar to that described for AVI-5-1: 4-[1-(4-Fluorobenzyl)-4-nitro-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN Calc. (C15H11FN206*0.8H 2 0) 51.65, 3.64, 8.03; Fnd. 51.65, 3.42, 7.88. (67)
NO
2 COOH N 0 0 20 F 4 -[4-(Benzylamino)- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN Calc. (C22H19FN20 4 * 0.33 CHC13) 61.83, 4.49, 6.45; Fnd. 62.07, 4.27, 5.74. (68) - 137 - WO 99/62513 PCT/US99/12095 BnHN COOH N 0 0 F 4-[5-Nitro-l1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid CHN 5 Calc. 53.90, 3.32, 8.38; Fnd. 53.77, 3.24, 8.20. (69) C O O H 00 0 2 N N K F EXAMPLE 70 4-[ 1-benzyl- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 10 Step 1: 1-[1-benzyl-1H-pyrrol-3-yl]ethanone AVII-1-1 O
CH
3 N AVII-1-1 To a solution of 3-acetylpyrrole ( 545 mg, 5.00 mmol) in DMF (10 mL) at 0 oC was 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 oC for 20 min and room temperature for 1 h, the reaction mixture was treated with sat. NH4Cl (10 mL) and poured onto sat. NH4Cl (50 mL). The resulting mixture was extracted with Et20 (3 x 50 mL). The 5 combined organic extracts were washed with sat. NaCl (50 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 2:1/hexanes:EtOAc, afforded the product as a clear oil. 1H NMR (400 MHz, CDC13) 8 7.35-7.29 (m, 4H), 7.13-7.27 (m, 2H), 6.66-6.61 (m, 2H), 5.07 (s, 2H), 2.38 (s, 3H). 10 mass spec (EI, M') 199 Step 2: 4-[1-benzyl-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester AVII-2-1 0 [IOCH 3 N AVII-2-1 15 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 NaHl (270 mg of a 60% 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 (20 mL) was added and the mixture extracted with CH2C12 (3 x 20 mL). The 20 combined organic extracts were washed with sat. NaC1 (20 mL) and dried (MgSO4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 5:5:l/CH2C12:hexanes:EtOAc, afforded the product as a yellow solid. 1H NMR (400 MHz, CDC13) 8 7.44 (m, 1H), 7.40-7.32 (m, 3H), 7.19-7.15 (m, 25 2H), 6.72-6.68 (m, 3H), 5.09 (s, 2H), 3.91 (s, 3H). Step 3: 4-[l1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 - 139- WO 99/62513 PCT/US99/12095 0 OH 0 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 5 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 oC (uncorrected) 1H NMR 10 (400 MHz, d6-DMSO) 5 8.04 (d, J = 1.6 Hz, 1H), 7.40-7.25 (m, 5H), 7.01 (m, 1H), 6.74 (s, 1H), 6.62 (m, 1H), 5.18 (s, 2H). mass spec (negative mode electrospray, M-H) 270. EXAMPLES 71-85 15 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) 00 OH N 20 F A-VII-3-2 -140- WO 99/62513 PCT/US99/12095 mp 145-146 C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 6 8.04 (m, 1H), 7.40-7.35 (m, 2H), 7.22-7.17 (m, 2H), 7.01 (m, 1H), 6.73 (s, 1), 6.62 (m, 1H), 5.17 (s, 2H). mass spec (negative mode electrospray, M-H) 288. 5 EXAMPLE 72 4-[1-(3-bromobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-3 00 OH 0 N Br AVII-3-3 mp 159-160 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 6 8.07 (m, 10 1H), 7.56-7.50 (m, 2H), 7.36-7.28 (m, 2H), 7.04 (m, 1H), 6.74 (s, 1H), 6.63 (m, 1H), 5.18 (s, 2H). mass spec (negative mode electrospray, M-H) 348, 350. EXAMPLE 73 15 4-[1-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII 3-4 O 0
H
3 Cb OH N N F AVII-3-4 AVII-3-4 was prepared in a manner similar to AVII-3-1, starting with 4-methyl-3-acetyl pyrrole. mp 162-163 oC (uncorrected) 1H NMR (400 20 MHz, d6-DMSO) 5 8.10 (m, 1H), 7.37 (dd, J = 5.5, 7.6 Hz, 2H), 7.18 (dd, J = - 141 - WO 99/62513 PCT/US99/12095 7.6, 8.9 Hz, 2H), 6.77 (m, 1H), 6.72 (s, 1H), 5.10 (s, 2H), 2.20 (s, 3H). mass spec (negative mode electrospray, M-H) 302. EXAMPLE 74 5 4-[2,4-dimethyl- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-5
H
3 C OH N CH 3 F AVII-3-5 AVII-3-5 was prepared in a manner similar to AVII-3-1, starting with 2,4-dimethyl-3-acetyl pyrrole. mp 184-185 C (uncorrected) 1H NMR (400 10 MHz, d6-DMSO) 5 7.20-7.12 (m, 4H), 6.74 (s, 1H), 6.62 (s, 1H), 5.13 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H). mass spec (negative mode electrospray, M-H) 316. EXAMPLE 75 15 4-[1-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-6 OH N F F AVII-3-6 mp 143-144 oC (uncorrected) 1H NIMR (400 MHz, d6-DMSO) 5 8.05 (s, 1H), 7.43 (m, 2H), 7.17 (m, 1H), 7.03 (dd, J = 3.0, 1.8 Hz, 1H), 6.73 (s, 1H), 6.61 - 142 - WO 99/62513 PCT/US99/12095 (dd, J = 3.0, 1.8 Hz, 1H), 5.16 (s, 2H), 3.3 bs, 1H). mass spec (negative mode electrospray, M-H) 306. 5 EXAMPLE 76 4-[1-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-7 OH N0 N Cl AVfII-3-7 mp 159-160 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 6 8.07 (m, 10 1H), 7.38 (m, 3H), 7.26 (m, 1H), 7.04 (m, 1H), 6.74 (s, 1H), 6.63 (m, 1H), 5.19 (s, 1H). mass spec (negative mode electrospray, M-H) 304, 306. EXAMPLE 77 4-[1-(4-chlorobenzvl)-l1H-pyrrol-3-vl]-2,.4-dioxobutvric acid AVII-3-8 15 O O OH N Cl A-VII-3-8 mp 170-171 C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 8.03 (t, J = 1.8 Hz, 1H), 7.43-7.40 (m, 2H), 7.34 (m, 1H), 7.31 (m, 1H), 7.00 (dd, J = 2.8, 1.8 Hz, 1H), 6.72 (s, 1H), 6.61 (dd, J = 2.8, 1.8 Hz, 1H). mass spec 20 (negative mode electrospray, M-H) 304. - 143 - WO 99/62513 PCT/US99/12095 EXAMPLE 78 4-[1-(4-bromobenzvl1)-lH-pyrrol-3-vll-2,4-dioxobutgric acid AVII-3-9 5 O OH N Br AVII-3-9 mp 184-185 oC (uncorrected) 1H NMR (400 MHz, d6.DMSO) 8 8.04 (t, J = 2.0 Hz, 1H), 7.59-7.54 (m, 2H), 7.28-7.23 (m, 2H), 7.01 (dd, J = 2.0, 2.9 Hz, 1H), 6.74 (s, 1H), 6.62 (dd, J = 2.0, 2.9 Hz, 1H), 5.17 (s, 2H). mass spec 10 (negative mode electrospray, M-H) 348, 350. EXAMPLE 79 4-l[1-(3,4-dichlorobenzvl)-lH-pvrrol-3-vl1-2,4-dioxobutvric acid AVII-3-10 15 OH o N ClI CI A-II-3-10 mp 175-176 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 8.06 (t, J = 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.04 (dd, J = 2.9, 1.9 Hz, 1H), 6.73 (s, 1H), 6.62 (dd, J = 2.9, 1.9 Hz, -144- WO 99/62513 PCT/US99/12095 1H), 5.18 (s, 2H), 3.36-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338, 340. 5 EXAMPLE 80 4-[1-(2-methylbenzvl)-lH-pvrrol-3-yll-2,.4-dioxobutyric acid AVII-3-11 0O OH 0 N H3 C
H
3 C AVII-3-11 mp 119-120 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 7.91 (t, J = 10 1.9 Hz, 1H), 7.24-7.15 (m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.91 (dd, J = 2.9, 1.9 Hz, 1H), 6.72 (s, 1H), 6.64 (dd, J = 2.9, 1.9 Hz, 1H), 5.21 (s, 2H), 3.45-3.21 (bs, 1H), 2.25 (s, 3H). mass spec (negative mode electrospray, M-H) 284. 15 EXAMPLE 81 4-[1-(3-chlorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII 3-12 0
H
3 C OH 0 N CI1 AVII-3-12 AVII-3-12 was prepared in a manner similar to AVII-3-1, starting with 20 4-methyl-3-acetyl pyrrole. - 145 - WO 99/62513 PCT/US99/12095 mp 148-149 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 6 8.09 (d, J = 2.2 Hz, 1H), 7.41-7.35 (m, 2H), 7.26 (m, 1H), 6.79 (dd, J = 2.1, 1.1 Hz, 1H), 6.72 (s, 1H), 5.09 (s, 2H), 3.40-3.30 (bs, 1H), 2.19 (s, 3H). mass spec (negative mode electrospray, M-H) 318, 320. 5 EXAMPLE 82 4-[l-(3-trifluoromethylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII 3-13 0 0 OH 0 N
CF
3 AVII-3-13 10 mp 145-146 C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 6 8.09 (t, J = 1.9 Hz, 1H), 7.70-7.66 (m, 2H), 7.63-7.58 (m, 2H), 7.06 (m, 1H), 6.73 (s, 1H), 6.63 (dd, J = 4.7, 1.7 Hz, 1H), 5.28 (s, 2H), 3.40-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338. 15 EXAMPLE 83 4- [ 1-(4-methylbenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-14 0 0 OH 0 N
CH
3
H
3 AVII-3-14 - 146 - WO 99/62513 PCT/US99/12095 mp 164-165 oC (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 8.00 (t, J = 1.9 Hz, 1H), 7.20-7.14 (m, 4H), 6.97 (dd, J = 2.9, 1.9 Hz, 1H), 6.72 (s, 1H), 6.59 (dd, J = 2.9, 1.9 Hz, 1H), 5.11 (s, 2H), 3.37-3.27 (bs, 1H), 2.26 (s, 3H). mass spec (negative mode electrospray, M-H) 284 5 EXAMPLE 84 4-[ 1-(4-methoxybenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-15 0 0 OH 0 N
OCH
3
OCH
3 AVII-3-15 10 mp 137-138 C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 7.99 (t, J = 1.9 Hz, 1H), 7.27-7.25 (m, 2H), 6.97 (dd, J = 2.9, 1.9 Hz, 1H), 6.90 (m, 2H), 6.71 (s, 1H), 6.58 (dd, J = 2.9, 1.9 Hz, 1H), 5.08 (s, 2H). mass spec (negative mode electrospray, M-H) 300 15 EXAMPLE 85 4-[r1-(3-methylbenzvl)-lH-pyrrol-3-yll-2.4-dioxobutyric acid AVII-3-16 OH N
SCH
3 AVII-3-16 Rf =0.49 (94:6:1 CH2C1 2 / MeOH / HOAc) - 147 - WO 99/62513 PCT/US99/12095 1 H NMR (400 MHz, CDC13) 8 7.46 (s, 1H), 7.25 (m, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.98 (m, 2H), 6.25 (s, 1H), 6.23 (m, 1H), 6.20 (m, 1H), 5.05 (s, 2H),2.33 (s, 3H). 5 EXAMPLES 86-88 The following compounds were prepared in a manner similar to AVII 3-1: EXAMPLE 86 10 4-{1-[3-(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl}-2,4-dioxobutyric acid O OH
/\CO
2 H N F CHN Calc. (C17H16FNO 4 0.2 water) 63.62, 5.15,4.36; Fnd. 63.54,5.07,4.00. EXAMPLE 87 15 4-[ 1-(4-bromobenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid O OH A CO 2 H N Br CHN Calc. 51.45, 3.45,4.00; Fnd. 51.53,3.50,3.92. EXAMPLE 88 20 4 -[1-(4-chlorobenzyl)-l1-H-pyrrol-3-yl] -2,4-dioxobutyric acid - 148 - WO 99/62513 PCT/US99/12095 O OH
CO
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]-2,4 5 dioxobutyric acid AVIII-4-1 Step 1: 1-[4-Benzylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] ethanone AVIII-1-1 S NH N 0 F AVIII-1-1 10 To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added 1-[ 4 -amino-1-(4-fluorobenzyl)-lH-pyrrol-2 yl]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 15 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 20 separated and the organic phase was washed with saturated aqueous NaHCO 3 , 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-l1-(4-fluorobenzyl)-l1H-pyrrol 2-yl]ethanone AVIII-1-1 as a crystalline solid. 1H NMR (CDC1 3 ) 6 2.34 5 (3H, s), 3.35 (1H, br s), 4.16 (2H, s), 5.41 (2H, s), 6.36 (1H, d,j= 2.2 Hz), 6.49 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.30 to 7.37 (5H, complex multiplet). Step 2: 1-[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2 10 yl]ethanone AVIII-2-1 H3 N 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-1-(4 fluorobenzyl)-l1H-pyrrol-2-yl]ethanone AVIII-1-1 (0.472g, 1.46 mmol), 15 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 20 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 25 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 benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]ethanone AVIII-2 1 as a crystalline solid. 1H NMR (CDC13) 8 2.25 (3H, s), 2.36 (3H, s), 4.16 - 150 - WO 99/62513 PCT/US99/12095 (2H, s), 5.43 (2H, s), 6.33 (1H, d, j= 2.2 Hz), 6.53 (1H, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.27 to 7.32 (5H, complex multiplet). Step 3: 4 -[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 5 2,4-dioxobutyric acid ethyl ester A-VIII-3-1 CH3 N N 0 N OEt 0 0 F A-VIII-3-1 In a manner substantially similar to that described for Example A-V-9-1 1-[4-benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] ethanone A VIII-2-1 was used to prepare 4 -[4-benzylmethylamino-l-(4-fluorobenzyl) 10 1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester A-VIII-3-1 which was used in the next step without further purification. Step 4: 4
-[
4 -Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 2,4-dioxobutyric acid AVI-5-1 CH3 N 0 N OH 0 0 15 F AVIII-4-1 In a manner substantially similar to that described for Example AV-10-1 4
-[
4 -benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AVIII-3-1 was used to prepare 4-[4 benzylmethylamino- 1-( 4 -fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric 20 acid AVIII-4-1. 1H NMR (CDC13) 8 2.79 (3H, s), 4.23 (2H, s), 5.48 (2H, s), 6.54 (1H, d, j=2.0 Hz), 6.74 (1H, d, j=2.0 Hz), 7.00 (4H, m), 7.28 (5H, m). - 151 - WO 99/62513 PCT/US99/12095 EXAMPLE 90 4-[4-Dimethylamino-l1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-IX-3-1 5 Step 1: 1-[l1-(4-Fluorobenzyl)-4-phenyl-lH-pyrrol-2-yl]ethanone
AIX
1-1 N 0 F AIX-1-1 To a 100 mL round bottomed flask with a stirring bar, reflux condenser 10 and an argon inlet was added 1-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2 yl]ethanone AIII-1-1 (1.00g, 2.91 mmol), phenylboronic acid (0.431g, 3.54 mmol), tetrakis(triphenylphosphine)palladiumo (0.20g, 0.17 mmol), 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 15 was cooled to 20oC and diluted with EtOAc. This solution was washed with H20, 1N HC1, H20, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-( 4 -fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone 20 AIX-1-1 as an oil. 1H NMR (CDC13) 8 2.47 (3H, s), 5.57 (2H, s), 6.98 (2H, m), 7.13 to 7.28 (5H, complex multiplet), 7.36 (2H, m), 7.51 (2H, m). Step 2: 4-[4-Phenyl- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AIX-2-1 - 152- WO 99/62513 PCT/US99/12095 KO N OEt O OOO F AIX-2-1 In a manner substantially similar to that described for Example AV-9-1, 1-[l-(4-fluorobenzyl)-4-phenyl- 1H-pyrrol-2-yl]ethanone AIX-1-1 was used to prepare 4-[4-phenyl-l1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric 5 acid ethyl ester AIX-2-1 which was used in the next step without further purification. Step 3: 4-[4-Phenyl- l-(4-fluorobenzyl)- 1H-pyrrol-2-yl] -2,4 dioxobutyric acid AIX-3-1 N O H OO O 10 F AIX-3-1 In a manner substantially similar to that described for Example AV-10-1 4-[4-phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-1 was used to prepare 4
-[
4 -phenyl-l-(4-fluorobenzyl)-lH pyrrol-2-yl]-2,4-dioxobutyric acid AIX-3-1. 1H NMR (DMSO-d 6 ) 8 5.66 15 (2H, s), 6.93 (1H, s), 7.05 (2H, m), 7.23 (3H, m), 7.36 (2H, m), 7.59 (3H, m), 7.65 (1H, d, j= 1.7 Hz). EXAMPLE 91 4-[ 1-( 4 -fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3-yl]-2,4-dioxo 20 butyric acid AX-3-1 - 153- WO 99/62513 PCT/US99/12095 Step 1: N-[4-acetyl- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl] methanesulfonamide AX-1-1 H
H
3 Cs N O S O CH 3 IN 0 F AX-1-1 A solution of 1-[4-amino- 1-(4-fluoro-benzyl)-1H-pyrrol-3-yl]-ethanone 5 AVI-2-1 (.5g, 2.15 mmole) in 10 ml of CH2C12 was cooled to 0 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 MgSO4, 10 filtered and concentrated in vacuo to afford a light pink semi-solid residue. This material was chromatographed on silica gel using 50% EtOAc/Hex as eluant to give AX-1-1 as a white crystalline solid. 1H NMR (400 MHz, CDC13) 8 7.12 (m, 2H), 6.96 (m, 2H), 6.94 (d, J=1.8Hz, 1H), 6.85 (d, J=1.8Hz, 1H ), 5.97 (s, b, 1H), 5.49 (s, 2H), 2.97 (s, 3H), 2.39 (s, 15 3H). Step 2: 4-[ 1-( 4 -fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid ethyl ester AX-2-1 H
H
3 Cs., N O, S O1 CO02Et 0 0 F AX-2-1 20 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 N2 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) 6 7.13 (m, 2H), 6.97 (m, 4H), 6.75 (s, 1H), 5.92 (s, br, 1H) 5 ,5.56 (s, 2H), 4.34-4.40 (q, 2H), 2.97 (s, 3H), 1.39 (t, 3H). Step 3: 4-[1-(4-fluorobenzyl)- 4 -methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid AX-3-1 H
H
3 C- N O'O 2 H N 0 0 10 F AX-3-1 A solution of AX-2-1 (200 mg, 0.48 mmole) was dissolved in 6ml of CH3OH 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, 15 dried over MgSO4, filtered and evaporated to give an oily residue that was triturated with 20% Et 2 0/Hex to afford AX-3-1 as a yellow crystalline solid. m.p.: 160 0 C decomposed 1H NMR (400 MHz, DMSO-d 6 ) 8 9.33 (s, 1H), 7.39 (s, 1H), 7.12-7.17 (m, 20 5H), 6.75 (s, 1H), 5.58 (s, 2H), 2.92 (s, 3H). EXAMPLES 92-94 The following compounds were prepared in a manner similar to that described for AX-3-1: 25 EXAMPLE 92 4-[ 1-( 4 -Fluorobenzyl)-3-acetylamino- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid - 155 - WO 99/62513 PCT/US99/12095 NHAc /",,C COO H COH N 0 0 CHN Calc. 58.96, 4.37, 8.09; Fnd. 59.20, 4.30, 8.06. EXAMPLE 93 5 4-[4-acetylamino-l-(4-fluorobenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid H N o /\ N
CO
2 H 0 OH F CHN Calc. (C17H15FN 2 05 0.3 H20) 58.05, 4.47, 7.97; Fnd. 58.09,4.40,8.06. EXAMPLE 94 10 4-[ 1-(4-fluorobenzyl)- 4
-(
2 -oxo-piperidin-1-yl)- 1H-pyrrol-2-yl] -2,4 dioxobutyric acid N C0 2 H O 0O OH F CHN Calc.( C20H19FN20 5 0.4 H20) 61.03, 5.07, 7.12; Fnd. 60.96, 5.00, 7.22. 15 EXAMPLE 95 -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)-(1-triisopropylsilanyl-l1H -pyrrol-3 yl)methanone AXI-1-1 O F N 5 Si(i-Pr) 3 AXI-1-1 A stirred slurry of A1C13 (99.99% anhydrous powder, 3 .28g, 0.0246 mole) in anhydrous CH2C12 (45 mL) was treated with 4-fluorobenxoyl chloride (2.64 mL, 0.0224 mole) added dropwise at O'C. After 0.5 h, a solution of 1-(triisopropylsilyl)pyrrole (5.55 mL, 0.0224 mole) in CH2C12 (11 mL) was 10 added. The mixture was stirred for 0.5 h at OoC 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 CH2C12 extracts of the aqueous phase. The combined organic layers were washed with NH4C1 solution and dried over MgSO4, filtered and 15 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) 8 7.87 (m, 2H), 7.32 (m, 1H), 7.13 (m, 2H), 6.78 (m, 2H), 1.48 (m, 3H), 1.12 (d, J=7.51 Hz, 18H). 20 Step 2: 3-(4-fluorobenzyl)-l-triisopropylsilanyl-l1H -pyrrole AXI-2-1 FN I 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 PCT/US99/12095 THF to give AXI-2-1 as a light yellow solid. TLC Rf=0.57 (5:95 EtOAc / Hexanes) 1H NMR (400 MHz, CDC1 3 ) 8 7.15 (m, 2H), 6.94 (m, 2H), 6.71 (t, J=2.38 Hz, 1H), 6.50 (m, 1H), 6.09 (m, 1H), 3.82 (s, 2H), 1.41 (m, 3H), 1.08 (d, J=7.51, 18H). 5 Step 3: 1-[4-(4-fluorobenzyl)- 1-triisopropylsilanyl-l1H -pyrrol-3 yl]ethanone AXI-3-1 0 F N Si(i-Pr) 3 AXI-3-1 In a similar manner to AXI-1-1, AXI-2-1 was acylated using freshly 10 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, CDC1 3 ) 6 7.31 (m, 1H), 7.17 (m, 2H), 6.93 (m, 2H), 6.30 (t, J=1.10 Hz, 1H), 4.08 (s, 1H), 2.37 (s, 3H), 1.42 (m, 3H), 1.08 (d, J=7.51 Hz, 18H) 15 Step 4: 1-[4-(4-fluorobenzyl)-lH -pyrrol-3-yl]ethanone AXI-4-1 O F N H AXI-4-1 A solution of AXI-3-1 (0.145g, 0.387 mmol) in dry THF (0.5 mL ) was treated with tetra-n-butylammonium fluoride (0.397 gtL 1.0 M in THF, 0.387 mmol) at room temperature for one hour. The reaction was 20 quenched with saturated NaHCO3, extracted with EtOAc, dried over MgSO4, filtered and concentrated to give the product as a yellow solid. TLC Rf=0.15 (10:90 EtOAc / Hexanes) 1H NMR (400 MHz, CDC13) 6 8.2 (bs, 1H), 7.38 (s, 1H),7.22 (m, 2H), 6.95 (m, 2H), 6.34 (s, 1H), 4.1 (s, 2H), 2.4 (s, 3H). - 158- WO 99/62513 PCT/US99/12095 Step 5: 1-[1,4-bis-(4-fluorobenzyl)-IH -pyrrol-3-yl]ethanone AXI-4-2 O F N F AXI-4-2 In a similar manner to AIV-3-1, AXI-4-1 was alkylated using 4 5 fluorobenzyl bromide to give AXI-4-2 as a light brown oil. TLC Rf=0.69 (40:60 EtOAc / Hexanes) 1H NMR (400 MHz, CDC13) 5 7.17 7.21 (m, 3H), 7.04-7.12 (m, 4H), 6.93 (m, 2H), 6.20 (s, 1H), 4.94 (s, 2H), 4.06 (s, 2H), 2.34 (s, 3H). 10 Step 6: 4-[4-(4-fluorobenzyl)- 11 -pyrrol-3-yl]-2,4-dioxobutyric acid AXI-5-1 0 0 OH / 0 F N H AXI-5-1 AXI-4-1 was carried on to the diketo acid AXI-5-1 as described for AI-3-1. TLC Rf=0.41 (94:6:6 CHC1 3 / MeOH / HOAc) 1H NMR (400 MHz, CDC1 3 ) 8 15 8.4 (bs, 1H), 7.4 (s, 1H),7.2 (m, 2H), 6.97 (m, 2H), 6.41 (s, 1H), 4.1 (s, 2H). EXAMPLE 96 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid AXI-5-2 -159- WO 99/62513 PCT/US99/12095 0 0 F O OO O OH F N F AXI-5-2 AXI-4-2 was carried on to the diketo acid AXI-5-2 as described for AI-3-1. TLC Rf=0.66 (94:6:6 CHC13 / MeOH / HOAc) 1H NMR (400 MHz, CDC13) 6 7.41 (s, 1H), 7.04-7.19 (m, 6H), 6.96 (m, 2H), 6.70 (s, 1H), 6.28 (s,1H), 4.97 5 (s, 2H), 4.07 (s, 2H). EXAMPLE 97 4 -[5-( 3 -carboxy-3-oxo-propionyl)- 1-(4-fluorobenzyl)- 1H-pyrazol-3-yl]-2,4 dioxobutyric acid BI-6-1 10 Step 1: 1-(4-fluorobenzyl)-lH-pyrazol-3,5-dicarboxylic acid diethyl ester BI-1-1 O O0 OEt EtO N'N F BI-1-1 A mixture of 1H-pyrrole-2,4-dicarboxylic acid diethyl ester (.424 g, 2 15 mmol), 4-fluorobenzyl bromide (.378 g, .25 ml, 2 mmol) and triethylamine (.303 g, .417 ml, 3 mmol) 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 20 Na 2
SO
4 , filtered and the solvent removed. TLC showed about 30% - 160- WO 99/62513 PCT/US99/12095 unreacted pyrrole. Further purification by column chromatography (2:1 hexane/ethyl acetate) gave .335 gr (50%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDC1 3 ) d 1.34 (t, 3H, J = 7.14), 1.41 (t, 3H, J = 7.14 Hz 5 ,4.32 (q, 2H, J = 7.14 Hz), 4.42 (q, 2H, J = 7.14 Hz), 5.80 (s, 2H), 6.98 (t, 2H, J = 8.7 Hz), 7.29 (m, 2H), 7.36 (s, 1H) Step 2: 1-(4-fluorobenzyl)-l1H-pyrazol-3,5-dicarboxylic acid dilithium salt BI-2-1 0 0~OU O/ OLi LiO N 10 BI-2-1 BI-1-1 (.2 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 15 purification. Step 3: 1-(4-fluorobenzyl)-1H- pyrazol-2,4-dicarboxylic acid bis (methoxymethylamide) BI-3-1 0 OO 0 NOMe N Me(.sN N' F BI-3-1 - 161 - WO 99/62513 PCT/US99/12095 A mixture of BI-2-1 from the previous example, N,O dimethylhydroxylamine hydrochloride (.121 g, 1.24 mmol), 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide hydrochloride (.238 g, 1.24 mmol), 1 hydroxybenzotriazole hydrate (.167 g, 1.24 mmol), and triethylamine 5 (.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 Na2SO4, filtered and the solvent removed. Further purification via radial disc chromatography 10 (1:1 hexane/ethyl acetate) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDC1 3 ) 8 3.27 (s, 3H), 3.43 (s, 3H), 3.46 (s, 3H), 3.75 (s, 3H), 6.91 - 7.00 (m, 3H), 7.22 - 7.32 (m, 3H) Step 4: 1-[5-acetyl- 1-(4-fluorobenzyl)- 1H-pyrazol-3-yl]ethanone BI-4-1 0 0 N' N N 15 FBI-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 20 quenched by the addition of excess 10% aqueous citric acid solution. After warming to room temperature, the mixture was poured into 10 ml H20 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. 25 1H NMR (400 MHz, CDC13) 6 2.50 (s, 3H), 2.63 (s, 3H), 5.74 (s, 2H), 6.99 (t, 2H, J = 8.8 Hz), 7.28 - 7.37 (m, 3H) - 162- WO 99/62513 PCT/US99/12095 Step 5: 4 -[5-(3-ethoxycarbonyl-3-oxopropionyl)- 1-(4-fluorobenzyl)- 1H pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester BI-5-1 o o ,OEt 0 Eto N; ( F BI-5-1 In a similar manner to AIII-2-1, BI-4-1 (.094 g, .36 mmol) was reacted 5 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, CDC13) 6 1.38 (t, 3H, J = 7.33 Hz), 1.42 (t, 3H, J = 7.14 Hz), 4.36 (q, 2H, J = 7.14 Hz), 4.41 (q, 2H, J = 7.14 Hz), 5.84 (s, 2H), 6.85 (s, 1H), 7.00 (t, 2H, J = 2.0 Hz), 7.29 - 7.36 (m, 3H), 7.54 (s, 1H) 10 Step 6: 4 -[5-(3-carboxy-3-oxopropionyl)- 1-(4-fluorobenzyl)- 1H pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 °OO F In a similar manner to AI-3-1, BI-5-1 (.157 g, .35 mmol) was reacted 15 with LiOH (.7 ml of a 1M solution in H20) in 5 ml THF to give the title compound as a light tan solid. MP = 215 - 217 oC 1H NMR (400 MHz, CDC13) 5 5.84 (s, 2H), 7.00 (t, 2H, J = 8.7 Hz), 7.29 7.37 (m, 4H), 7.55 (s, 1H); FAB MS: m/z 405 (M' + H) 20 EXAMPLE 98 - 163- WO 99/62513 PCT/US99/12095 4-[1-(4-fluorobenzyl)-IH-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 Step 1: 4-bromo-l1-(4-fluorobenzyl)-lH-pyrazole BII-1-1 Br N N F BII-1-1 5 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 10 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) 8 5.23 (s, 2H), 7.04 (t, 2H, J = 8.6 Hz), 7.18 - 7.25 (m, 2H), 7.36 (s, 1H), 7.49 (s, 1H) 15 Step 2: 1-[1-(4-fluorobenzyl)-l1H-pyrazol-4-yl]ethanone BII-2-1 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'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 20 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 Na2SO4, filtered and the solvent removed. Purification by radial disc chromatography (4:1 5 hexane/ethyl acetate) the title compound as a colorless oil. Step 3: 4-[1-(4-fluorobenzyl)-l1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BII-3-1 0 0
O
Et NN, 0 N F F BII-3-1 10 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 (t, 3H, J = 7.14 Hz), 4.38 (q, 2H, J = 7.14 Hz), 5.31 (s, 2H), 6.66 (s, 1H), 7.08 (t, 2H, J = 8.61 Hz), 7.24 - 7.31 (m, 2H), 15 7.94 (2, 1H), 8.02 (s, 1H) Step 4: 4-[1-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 0O OH N BII-4-1 - 165 - WO 99/62513 PCT/US99/12095 In a similar manner to AI-3-1, BII-3-1 (.17 g, .53 mmol) was reacted in 5 ml MeOH containing 2 ml 1M NaOH to give a light tan solid after triturating the crude material with CH2C12. MP = 191-192 oC 1H NMR (400 MHz, CDC1 3 ) 5 5.31 (s, 2H), 6.71 (d, 1H, J = .73 Hz), 7.08 5 (t, 2H, J = 8.6 Hz), 7.24 - 7.33 (m, 2H), 7.99 (s, 1H), 8.03 (s, 1H) FAB MS: m/z 291 (M' + H) EXAMPLES 99 & 100 The following compound were prepared in a manner similar to that 10 described for BII-4-1: EXAMPLE 99 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl] -2,4-dioxobutyric acid / 0 O H -N / / OH N, 1"0 N F 15 CHN Calc. (C16H16N304F 0.5 EtOAc) 57.28, 5.34, 11.14; Fnd. 56.93, 5.01, 11.43. EXAMPLE 100 4-[1-( 4 -Fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]-2-hydroxy-4-oxobut-2 enoic acid OH / OH N 20 F - 166- WO 99/62513 PCT/US99/12095 CHN Calc. (C15H13N20 4 F 0.4 MeOH) 58.33,4.64,8.84; Fnd 57.95, 4.40, 8.44. EXAMPLE 101 5 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid BIII-3-1 Step 1: 1-[ 2
-(
4 -fluorobenzyl)-2H-pyrazol-3-yl]ethanone BIII-1-1 N 0 BIII-1-1 1-(2H-Pyrazol-3-yl)ethanone hydrochloride (.44 g, 3 mmol) was dissolved 10 in 8 ml DMF, and to it was added sodium hydride (.144 g, .24 g of a 60% 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 15 Na2SO4, 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, CDC13) 8 2.58 (s, 3H), 5.33 (s, 2H), 6.80 (d, 1H, J = 2.4 Hz), 7.05 (t, 2H, J = 8.6 Hz), 7.19 - 7.28 (m, 2H), 7.35 (d, 1H, J = 2.4 Hz) 20 Step 2: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid ethyl ester BIII-2-1 0 N, N OEt F BIII-2-1 - 167 - WO 99/62513 PCT/US99/12095 In a similar manner to AIII-2-1, BIII-1-1 (.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, CDC1 3 ) 6 1.38 5 (t, 3H, J = 7.14 Hz), 4.36 (q, 2H, J = 7.14 Hz), 5.36 (s, 2H), 6.90 (d, 1H, J = 2.38 Hz), 7.06 (t, 2H, J = 8.61 Hz), 7.22 - 7.28 (m, 3H), 7.40 (d, 1H, J = 2.38 Hz) Step 3: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid 10 BIII-3-1 0 N N N OH OO© BIII-3-1 In a similar manner to AI-3-1, BIII-2-1 (crude from previous reaction) was reacted with 1N NaOH (3ml) in 20 ml THF to yield the title compound as a light tan solid after trituration in diethyl ether. MP = 157 15 - 159 oC; 1H NMR (400 MHz, CDC13) 6 5.35 (s, 2H), 6.90 (d, 1H, J = 2.57 Hz), 7.06 (t, 2H, J = 8.61 Hz), 7.22 - 7.31 (m, 3H), 7.42 (d, 1H, J = 2.38 Hz) FAB MS: m/z 291 (M' + H) EXAMPLE 102 20 1-[l-(4-fluorobenzyl)-3-methyl-l1H-pyrazol-4-yl]-2,4-dioxobutyric acid BIV 3-1 Step 1: 1-(3-methyl-l1H-pyrazol-4-yl)ethanone BIV-1-1 O N.. NN H H BIV-1-1 - 168 - WO 99/62513 PCT/US99/12095 A mixture of 1-( 4 -acetyl-5-methylpyrazol-1-yl)ethanone (1 g, 6 mmol, Maybridge) and 10 ml IN NaOH 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 5 extracts were washed with H20, brine, dried over Na2SO 4 , filtered and the solvent removed to get the title compound. 1H NMR (400 MHz, CDC1 3 ) 8 2.43 (s, 3H), 2.60 (s, 3H), 7.96 (s, 1H) Step 2: 1-[1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl] ethanone 10 BIV-2-1 0 N, N F BIV-2-1 In a similar manner to BIII-1-1, 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 mmol) for 2 hr. Subsequent 15 work-up and purification by preparative HPLC (Chiralcel OD 25x2, 75% hexane/1% diethylamine, 25% EtOH) yielded the title compound and 1-[1 (4-fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]ethanone as white solids. 1H NMR (400 MHz, CDC1 3 ) 8 2.36 (s, 3H), 2.49 (s, 3H), 5.21 (s, 2H), 7.07 (t, 2H, J = 8.4 Hz), 7.24 (dd, 2H, J = 8.4, 4.9 Hz), 7.73 (s, 1H) 20 Step 3: 1-[ 1-( 4 -fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester BIV-3-1 - 169- WO 99/62513 PCT/US99/12095 0 0 OEt Ns N F BIV-3-1 In a similar manner to AIII-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 5 solid. 1H NMR (400 MHz, CDC13) 5 1.37 (t, 3H, J = 7.14 Hz), 2.52 (s, 3H), 4.35 (q, 2H, J = 7.14 Hz), 5.23 (s, 2H), 6.61 (s, 1H), 7.06 (t, 2H, J = 8.61 Hz), 7.21 - 7.32 (m, 2H), 7.89 (s, 1H) Step 4: 1-[1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 10 dioxobutyric acid BIV-4-1 0O OH N, O N F BIV-4-1 In a similar manner to AI-3-1, BIV-3-1 (.234 g, .68m mmol) was reacted with 2 ml NaOH in 10 ml THF to afford the title compound as a light tan solid. MP = 187-188 oC; 1H NMR (400 MHz, CDC13) 8 2.53 (s, 3H), 5.23 (s, 15 2H), 6.64 (2, 1H), 7.08 (t, 2H, J = 8.61), 7.23 - 7.31 (m, 2H), 7.88 (s, 1H) EXAMPLE 103 4-[3-methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV 4-1 20 - 170 - WO 99/62513 PCT/US99/12095 Step 1: 1-[1-(3-chlorobenzyl)-3-methyl-l1H-pyrazol-4-yl]ethanone
BV
1-1 and 1-[1-(3-chlorobenzyl)-5-methyl-lH-pyrazol-4 yl]ethanone BV-2-1 0 0 N, N N Cl CI BV-1-1 BV-2-1 5 In a similar manner to BIV-2-1, BIV-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 ml THF for 2 hr and purified by preparative HPLC (Chiralpak AD 25x2, 75% hexane/1% diethylamine, 25% 2-propanol) to yield the faster eluting 1-[1 10 ( 3 -chlorobenzyl)-3-methyl-lH-pyrazol-4-yl]ethanone and the slower eluting 1-[ 1-(3-chlorobenzyl)-5-methyl- 1H-pyrazol-4-yl]ethanone, both as clear oils. 1-[ 1-(3-chlorobenzyl)-3-methyl- 1H-pyrazol-4-yl]ethanone BV-1-1: 1H NMVIR (400 MHz, CDC13) 8 2.38 (s, 3H), 2.49 (s, 3H), 5.21 (s, 2H), 7.12 15 (dt, 1H, J = 6.2, 2.2, 1.6 Hz), 7.22 (s, 1H), 7.31 - 7.34 (m, 2H), 7.78 (s, 1H) 1-[1-( 3 -chlorobenzyl)-5-methyl- 1H-pyrazol-4-yl]ethanone BV-2-1: 1H NMR (400 MHz, CDC13) 8 2.45 (s, 3H), 2.52 (s, 3H), 5.28 (s, 2H), 6.87 7.02 (m, 1H), 7.10 (s, 1H), 7.22 - 7.30 (m, 2H), 7.90 (s, 1H) 20 Step 2: 4-[3-methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester BV-3-1 - 171 - WO 99/62513 PCT/US99/12095 0 0 OEt NO 0 CI BV-3-1 In a similar manner to AIII-2-1, BV-1-1 (.255 g, 1 mmol) was reacted with diethyl oxalate (.321 g, .298 ml, 2.2 mmol) and sodium ethoxide (.15 g, 2.2 mmol) to give the title compound, which was used without further 5 purification. 1H NMR (400 MHz, CDC13) 8 1.38 (t, 3H, J = 7.14 Hz), 2.53 (s, 3H), 4.35 (q, 2H, J = 7.14 Hz), 5.24 (s, 2H), 6.63 (s, 1H), 7.11 - 7.18 (m, 1H), 7.23 (s, 1H), 7.29 - 7.35 (m, 2H), 7.93 (s, 1H) Step 3: 4-[3 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4 10 dioxobutyric acid BV-4-1 0O OH N CI BV-4-1 In a similar manner to AI-3-1, 4-[3 -methyl-1-(3-chlorobenzyl)-1H pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester (crude from above) was reacted with 5 ml 1N NaOH in 20 ml methanol for two hours to give the 15 title compound as a light tan solid. MP = 183 - 184 oC. 1H NMR (400 MHz, CDC13) 8 2.54 (s, 3H), 5.23 (s, 2H), 6.67 (s, 1H), 7.12 - 7.18 (m, 1H), 7.25 (s, 1H), 7.31 - 7.36 (m, 2H), 7.97 (2, 1H) EXAMPLE 104 20 4-[5 -methyl-l1-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid - 172- WO 99/62513 PCT/US99/12095 Step 1: 4-[5 -methyl-l1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester BV-5-1 0 0 OEt N, 0 N0 CI BV-5-1 In a similar manner to AIII-2-1, BV-2-1 (.158 g, .64 mmol) was reacted 5 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, CDC13) 6 1.40 (t, 3H, J = 7.14 Hz), 2.58 (s, 3H), 4.38 (q, 2H, J = 7.14 Hz), 5.31 (s, 2H), 6.75 (s, 1H), 6.98 7.04 (m, 1H), 7.12 (s, 1H), 7.25 - 7.31 (m, 2H), 7.99 (s, 1H) 10 Step 2: 4-[5 -methyl-l1-(3-chlorobenzyl)-l1H-pyrazol-4-yl]-2,4 dioxobutyric acid BV-6-1 0O OH N, O N CI BV-6-1 In a similar manner to AI-3-1, BV-5-1 (crude from above) was reacted 15 with 2 ml 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 oC 1H NMR (400 MHz, CDC13) 5 2.53 (s, 3H), 5.23 (2, 2H), 6.67 (s, 1H), 7.12 7.18 (m, 1H), 7.25 (s, 1H), 7.31 - 7.36 (m, 2H), 7.97 (s, 1H) - 173- WO 99/62513 PCT/US99/12095 EXAMPLE 105 4-[1-(4-fluoro-benzyl)- 1H-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 Step 1: 1-(4-fluoro-benzyl)-l1H-imidazole CI-1-1 N CI-1-1 5 F To a solution of imidazole (10g, 0.146 mole) in 80 ml of DMF at 0 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 10 was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure in vacuo. The residue was partitioned with H20 and CH2C1 2 . 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 15 using 50-100% EtOAc/Hex as eluant. Obtained CI-1-1 as an oil. 1H NMR (400 MHz, CDC13) 8 7.53 (s, 1H), 7.09-7.15 (m, 5H), 6.88 (s, 1H), 5.09 (s, 2H). Step 2: 1-(4-fluorobenzyl)-lH-imidazole-2-carboxylic lithium salt CI 20 2-1 N CO2Li CI-2-1 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 of 2.5M nBuLi in Hexanes (21ml, .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, .15 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 5 obtain CI -2-1 as a solid salt. 1H NMR (400 MHz, DMSO-d 6 ) 6 7.34 (t, 2H), 7.22 (s, 1H), 7.11 (t, 2H), 6.83 (s, 1H), 5.74 (s, 2H). Step 3: 1-(4-fluorobenzyl)-l1H-imidazole-2-carboxylic acid methoxy methyl-amide CI-3-1 IN OCHz N OCH 3 O CI-3-1 10 F A solution of CI -2-1 (7.0g, .031 mole) was treated with EDC.HC1 (6.5g, .034 mole), HOBT.H20 (4.6g, .034 mole), N,O- dimethylhydroxy amine.HC1 (3.31g, .034 mole), and triethylamine (12.9 ml, .092 mole) in 60 ml of DMF and stirred over the weekend under N 2 . The DMF was 15 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 20 as eluant. Obtained CI- 3-1 as an oil. 1H NMR (400 MHz, CDC13) 8 7.19 7.23 (m, 2H), 7.09 (s, 1H), 6.97-7.04 (m, 3H), 5.42 (s, 2H), 3.81 (s, 3H), 3.48 (s, 3H) Step 4: 1-[1-(4-fluorobenzyl)-lH-imidazol-2-yl]ethanone CI-4-1 - 175 - WO 99/62513 PCT/US99/12095 N N CH3 CI-4-1 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 Et20 dropwise via syringe under N2 atmosphere. The ice bath was removed 5 after addition was completed and the reaction was warmed to 0oC 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 10 silica gel using 70% EtOAc/Hex as eluant. Obtained CI- 4-1 as an oil. 1H NMR (400 MHz, CDC13) 5 7.16-7.20 (m, 3H), 7.06 (s, 1H), 6.99-7.04 (t, 2H), 5.58 (s, 2H), 2.66 (s, 3H). Step 5: 4-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid 15 ethyl ester CI-5-1 \N
CO
2 Et N O 0 01-5-1 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. 20 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 50% EtOAc/Hex as eluant. Obtained CI- 5-1 as a beige solid. 1H NMR (400 MHz, CDC13) 8 7.19-7.23 (m, 3H), 7.13 (s, 1H), 7.01 (t, 2H), 5.69 (s, 2H), 4.33-4.37 (q, 2H), 1.36 (t, 3H) 5 Step 6: 4-[1-(4-fluorobenzyl)-l1H-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 N CN C2 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 3m1 of 1N NaOH and stirred for 3 hours. The reaction 10 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. m.p.: 163-164 0 C. 1H NMR (400 MHz, 15 CDC13) 8 7.20 (m, 3H), 7.13 (s, 1H), 7.01 (t, 3H), 5.69 (s, 2H). EXAMPLE 106 In a manner similar to that described for CI-6-1, the following compound was prepared: 20 4-(1-Benzyl- 1H-imidazol-2-yl)-2,4-dioxobutyric acid CN 0 N -OH 0 0 CHN Calc. 61.76, 4.44, 10.29; Fnd. 61.80, 4.58, 10.17 25 EXAMPLE 107 - 177 - WO 99/62513 PCT/US99/12095 4-[ 1-(4-fluorobenzyl)- 1H-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 Step 1: 1-(4-fluorobenzyl)-l1H-imidazole-4-carboxylic acid 4-fluoro benzyl ester CII-1-la; and 3-(4-fluorobenzyl)-3H-imidazole-4-carboxylic acid 4-fluoro 5 benzyl ester CII-1-1b 0 .~0 O O N 0 N + F N QII-1 1 aH QII-1-1b FH A suspension of 1H-imidazole-4-carboxylic acid (1.0g, 0.0089 mole) in 25 ml of DMF was treated with Cs2CO3 (8.72g, .026 mole) followed by 4 fluorobenzyl bromide (3.33 ml, .026 mole) and stirred overnight at room 10 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 15 afford a 1:1 mixture of CI I-1-la and CI I- 1-1b. 1H NMR (400 MHz, CDC13) 8 7.54-7.57 (d, J= 9.7Hz, 2H), 7.40 (m, 2H), 7.14 (m, 2H), 6.99 (m, 4H), 5.28 (s, 2H), 5.09 (s, 2H). Step 2: 1-[1-(4-fluorobenzyl)-lH-imidazol-4-yl]-ethanone CII-2-1 O N CH 3 N 20 F CII-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 0 C was treated with a solution of 1.4M CH3Li (2.35 ml, .0032mole) in Et20 dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to room 5 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 MgSO4, filtered and evaporated to give CI I-2-1 as a crystalline solid. 1H NMR (400 MHz, CDC1 3 ) 5 7.53 (d, 2H), 7.15 (m, 2H), 10 7.04 (m, 2H), 5.1 (s, 2H), 2.5 (s, 3H). Step 3: 4-[1-(4-fluorobenzyl)-l1H-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester CII-3-1 00
CO
2 Et N N F CII-3-1 15 A solution of CI I-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 1N HC1 solution and 20 extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgSO4, filtered and evaporated to give CI I-3-1 as a bright yellow oil. Used as is without further purification. 1H NMR (400 MHz, CDC13) 8 7.78 (s, 1H), 7.69 (s, 1H), 7.22 (m, 2H), 7.10 (m, 3H), 5.19 (m, 2H), 4.35 (m, 2H), 1.4(m, 3H). 25 Step 4: 4-[1-(4-fluorobenzyl)-l1H-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 - 179- WO 99/62513 PCT/US99/12095 0O0
CO
2 H N N F CII-4-1 A solution of CI I-3-1 (70 mg, 0.2 mmnole) was dissolved in 3ml of CH3OH and 3ml of IN NaOH for 3 hours. The reaction mixture was washed with ether, acidified to pH 1-2 with 1N HC1 and extracted three times with 5 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, CDCl3) 5 8.24 (s, 1H), 8.07 (s, 1H), 7.44 (m, 2H), 7.19 (m, 2H), 6.92 (s, 1H), 5.28 (s, 2H). 10 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 N\ \
C
H
3 N H 0 DI-1-1 15 A solution of 2-carboxy indole (3g, 16.9 mmol) in anhydrous ether (50 mL) was cooled to 0OC 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 20 saturated sodium bicarbonate solution and brine, dried over MgSO4, filtered and evaporated to give DI-1-1 as a white solid. Rf=0.53 (20% EtOAc/Hexanes) 1H NMR (400 MHz, CDC13) 6 9.1 (bs, 1h), 7.72 (d, J= 7.78 Hz, 1H), 7.42 - 180- WO 99/62513 PCT/US99/12095 (d, J= 8.4 Hz, 1H), 7.36 (m, 1H), 7.2 (m, 1H), 7.15 (m, 1H), 2.6 (s, 3H). Step 2: 1-[l1-(4-fluorobenzyl)- 1H -indol -2-yl]ethanone DI-2-1 N CH 3 N 0 DI-2-1 5 In a manner similar to that described for the preparation of AI-1-1. DI 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, CDC1 3 ) 5 7.73(d, J = 8.06 Hz, 1H), 7.36 (m, 3H), 7.18 (m, 1H), 7.02 (m, 2H), 6.9 ( m, 2H), 5.8 (s, 2H), 2.6 (s, 3H). 10 Step 3: 4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid N OCH 3 00 OJOO methyl ester DI-3-1 F DI-3-1 In a manner similar to that described for the preparation of AI-2-1, DI 2-1 was treated with dimethyl oxalate and sodium hydride to give DI-3-1 15 as a yellow solid. Rf=0.26 (97:3:1 CHC13 / MeOH / HOAc). 1H NMR (400 MHz, CDC13) d 7.75 (d, J = 8.05 Hz, 1H), 7.52 (s, 1H), 7.38 (m, 2H), 7.2 (m, 1H), 7.09 (s, 1H), 7.05 (m, 2H), 6.95 (m, 2H), 3.95 (s, 3H). Step 4: 4 -[1-(4-fluorobenzyl)- 1H -indol - 2 -yl]-2,4-dioxobutyric acid 20 DI-4-1 - 181 - WO 99/62513 PCT/US99/12095 0 N OH 00 F DI-4-1 In a manner similar to that described for the preparation of A-I-3-1, D I-3-1 was treated with sodium hydroxide to give DI-4-1 as bright yellow crystals after crystallization from EtOAc. 1H NMR (400 MHz, DMSO 5 D6) 5 7.90 (s, 1H), 7.77 (d, J= 7.88 Hz, 1H), 7.62 (d, J = 8.42 Hz, 1H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (m, 5H), 5.9 (s, 2H). mass spec (FAB, M+1) 340.03. EXAMPLE 109 10 The following compound was prepared in a manner similar to that described for DI-4-1: 2-hydroxy-4-(1-methyl- 1-H -indol-2-yl) -2,4-dioxobutyric acid S\C02H N
CH
3 0 OH 15 CHN Calc.(C13H11NO4 0.15 H20) 62.97, 4.59, 5.65; Fnd. 63.05, 4.45, 5.80. EXAMPLE 110 4 -[1-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid DII-3-1 Step 1: 1-[1-(4-fluorobenzyl)-l1H-indol-3-yl]ethanone DII-1-1 - 182- WO 99/62513 PCT/US99/12095 0 N F DII-1-1 In a similar manner to BIII-1-1, 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 5 one hour to give the title compound as a white solid. 1H NMR (400 MHz, CDC13) 8 2.52 (s, 3H)5.33 (s, 2H), 7.03 (t, 2H, J = 8.61 Hz), 7.11 - 7.18 (m, 2H), 7.24 - 7.35 (m, 2H), 7.74 (s, 1H), 8.39 (d, 1H, J = 7.5 Hz) Step 2: 1-[1-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid 10 ethyl ester DII-2-1 O O OEt /\0 o N F DII-2-1 In a similar manner to AIII-2-1, DII-1-1 (.267 g, 1 mmol) was reacted with diethyl oxalate (.292 g, .271 ml, 2 mmol) and sodium ethoxide (.136 15 g, 2 mmol) 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) 8 1.41 (t, 3H, J = 7.14 Hz), 4.39 (q, 2H, J = 7.14 Hz), 5.35 (s, 2H), 6.83 (s, 1H), 7.05 (t, 2H, J = 8.6 Hz), 7.13 - 7.20 (m, 2H), 7.30 - 7.39 (m, 3H), 7.88 (s, 1H), 8.40 (d, 1H, J = 7.51 Hz) 5 Step 3: 1-[1-( 4 -fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid DII 3-1 0 0 OH F DII-3-1 In a similar manner to AI-3-1, DII-2-1 (.1 g, .27 mmol) was hydrolyzed 10 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) 8 5.36 (s, 2H), 6.92 (s, 1H), 7.07 (t, 2H, J = 8.61 Hz), 7.15 - 7.23 (m, 2H), 7.31 - 7.39 (m, 3H), 7.95 (s, 1H), 8.30 (d, 1H, J = 6.59 Hz) 15 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 20 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 5 Assay for inhibition of HIV replication Assays for the inhibition of acute HIV infection of T lymphoid cells was conducted according to Vacca, J.P.et al., (1994), Proc. Natl. Acad. Sci. USA 91, 4906, herein incorporated by reference for these purposes. 10 Representative compounds tested in the present assay demonstrated IC95s of less than 10 micromolar. EXAMPLE 113 Oral Composition 15 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. 20 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. 25 - 185-
Claims (31)
1. A compound of structural formula (I): R 1 R2 OR 7 R 8 0 0 (i) and tautomers and pharmaceutically acceptable salts thereof, 5 wherein: A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen 1 2 8 atoms and substituted on carbon or nitrogen by R , R and R ; 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 10 nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety; R 1 is selected from: (1) -H, 15 (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, (5) -NO 2 , (6) -N(R4 )(R5 20 (7) -R 6 , 3 (8) -C 2 - 5 alkenyl-R 3 3 (9) -C 2 . 5 alkynyl-R 3 (10) -O-R 6 , (11) -O-C1-6 alkyl, and 25 (12) -C(O)CH2C(O)C(O)OR7; 2 R is selected from: (1) -H, (2) -R3 -186- WO 99/62513 PCT/US99/12095 (3) -C 1 .- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R 6 (6) -O-C 1 - 6 alkyl-OR 64 5 (7) -S(O)n-R 6 (8) -C 1 .- 6 alkyl (OR6 )(R4), (9) -C 1 - 6 alkyl-N(R4 )(R6), (10) -C1- 6 alkyl S(O)n-R6 (11) -C 1 - 6 alkyl C(O)-R 6 6 10 (12) -C 1 - 6 alkyl C(S)-R (13) -C1- 6 alkyl NR4 C(O)-R 6 , and (14) -C 1 - 6 alkyl-C(O)N(R4 )(R5); each R 3 is independently selected from: 15 (1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from: (a) halogen, 20 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1 - 6 alkyl, - 187- WO 99/62513 PCT/US99/12095 (iii) -CF 3 , and (iv) hydroxy; (2) a 3 to 6 membered saturated ring containing 0 or 1 5 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from: (a) halogen, (b) C 1 .- 6 alkyl, 10 (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and 15 (h) hydroxy; (3) unsubstituted or substituted hexahydrothieno[3,4 d]imidazolyl with one or two substituents selected from: (a) oxo, 20 (b) halogen, (c) C 1 - 6 alkyl, (d) C1- 6 alkyloxy-, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, and (h) hydroxy; (4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, 30 nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from: (a) -halogen, - 188 - WO 99/62513 PCT/US99/12095 (b) -C 1 - 6 alkyl, (c) -C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 5 (f) -CN, and (g) -hydroxy; (5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused 10 with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from: (a) halogen, (b) C1- 6 alkyl, (c) C1- 6 alkyloxy-, 15 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy; and 20 (6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from: 25 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 30 (f) -CN, (g) =0, and (h) hydroxy; - 189- WO 99/62513 PCT/US99/12095 each R 4 is independently selected from: (1) -H, (2) -C1- 3 alkyl, 5 (3) -CF3, 3 (4) -R 3 (5) -C 2 .- 3 alkenyl, 3 (6) -C1- 3 alkyl-R (7) -C 2 - 3 alkenyl-R3 10 (8) -S(O)n-R , and (9) -C(O)-R each R 5 is independently selected from: (1) -H, 15 (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R 3 (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R 20 (7) -C 2 - 3 alkenyl-R 3 3 (8) -S(O)n-R 3 , and (9) -C(O)-R 3 ; each R 6 is independently selected from: 25 (1) -C 1 - 3 alkyl-R 3 , and 3 (2) -R3 R 7 is selected from: (1) -H, and 30 (2) C1-6 alkyl; - 190- WO 99/62513 PCT/US99/12095 R8 is selected from: (1) -H, (2) C1-6 alkyl-oxy, and (3) C1-6 alkyl; and 5 each n is independently selected from 0, 1 and 2.
2. The compound according to Claim 1, and tautomers 10 and pharmaceutically acceptable salts thereof, wherein: A is selected from: (1) pyrrolyl, (2) imidazolyl, 15 (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I); R is selected from: 20 (1) -H, (2) -CH 3 , (3) -CF 3 , (4) -halo, (5) -NO 2 , 25 (6) -N(R 4 )(R5 (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halogen, 30 (b) C 1 .- 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , - 191 - WO 99/62513 PCT/US99/12095 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 5 selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy, 10 (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 15 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 20 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 25 (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 3 , and 30 (13) -C(O)CH2C(O)C(O)OR7; 2 R is selected from: (1) -H, - 192 - WO 99/62513 PCT/US99/12095 3 (2) -R 3 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R (5) -O-R 6 5 (6) -O-C 1 - 6 alkyl-OR (7) -S(O)n-R 6 (8) -C 1 - 6 alkyl (OR6)(R 4 ), (9) -C 1 - 6 alkyl-N(R 4 )(R 6 ), 6 (10) -C 1 - 6 alkyl S(O)n-R 10 (11) -C 6 alkyl C()-R 6 6 10 (12) -C 1 - 6 alkyl C(S)-R 6 (12) -C 1 - 6 alkyl C(S)-R (13) -C1- 6 alkyl NR4 C(O)-R 6 , and (14) -C 1 .- 6 alkyl-C(O)N(R4)(R 5); 15 each R 3 is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 20 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1 .- 6 alkyl, - 193 - WO 99/62513 PCT/US99/12095 (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or 5 two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 10 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 15 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 20 (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 25 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF 3 , 30 (g) -CN, (h) hydroxy, (i) phenyloxy, and -194- WO 99/62513 PCT/US99/12095 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 .- 6 alkyl, 5 (iii) -CF 3 , and (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: 10 (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , 15 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 20 selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 25 (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 30 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , - 195 - WO 99/62513 PCT/US99/12095 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 5 selected from: (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 10 (11) pyrazolyl; (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 15 (c) C 1 .- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 20 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 25 (ii) CI- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3 - 6 cycloalkyl; (14) substituted C 3 .- 6 cycloalkyl with 1 or 2 substituents 30 independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, - 196- WO 99/62513 PCT/US99/12095 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 5 (h) hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 10 (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 15 (g) =0O, and (h) hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: 20 (a) halogen, (b) C1- 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 25 (f) -CN, (g) =0O, and (h) hydroxy; (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents 30 independently selected from: (a) -halogen, (b) -C 1 - 6 alkyl, - 197 - WO 99/62513 PCT/US99/12095 (c) -C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, and 5 (g) -hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) -halogen, 10 (b) -C 1 .- 6 alkyl, (c) -C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, and 15 (g) -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: 20 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 25 (f) -CN, (g) =0O, and (h) hydroxy; each R 4 is independently selected from: 30 (1) -H, (2) -C 1 - 3 alkyl, and (3) -CF 3 ; - 198 - WO 99/62513 PCT/US99/12095 each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 5 (3) -CF 3 , 3 (4) -R 3 (5) -C 2 - 3 alkenyl, 3 (6) -C1- 3 alkyl-R 3 (7) -C 2 .- 3 alkenyl-R 3 10 (8) -S(O)n-R 3 , and (9) -C(O)-R each R 6 is independently selected from: 3 (1) -C 1 - 3 alkyl-R 3 , and 15 (2) -R3; R7 is H; R8 is selected from: 20 (1) -H, (2) -OCH3, and (3) -CH3; and each n is independently selected from 0, 1 and 2. 25
3. The compound according to Claim 2 , and tautomers and pharmaceutically acceptable salts thereof, wherein: A is selected from: 30 (1) pyrrolyl, (2) imidazolyl, (3) pyrazolyl, and - 199- WO 99/62513 PCT/US99/12095 (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I); R is selected from: 5 (1) -H, (2) -CH 3 , (3) -CF3, (4) -halo, (5) -NO 2 , 10 (6) -N(R4 )(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halo, 15 (b) methyl, and (c) methoxy, (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: 20 (a) halo, (b) methyl, and (c) methoxy, 3 (11) -C 2 .- 5 alkenyl-R 3 , and (12) -C(O)CH2C(O)C(O)OR7; 25 2 R is selected from: (1) -H, 3 (2) -R 3 (3) -C 1 .- 6 alkyl, 30 (4) -C 1 - 6 alkyl substituted with R 6 (5) -O-R (6) -O-C 1 - 6 alkyl-OR 6 6 (7) -S(O)n-R - 200 - WO 99/62513 PCT/US99/12095 (8) -C 1 .- 6 alkyl (OR6 R 4 ), (9) -C 1 - 6 alkyl-N(R4 )(R6), 6 (10) -C 1 - 6 alkyl S(O)n-R (11) -C1- 6 alkyl NR4 C(O)-R 6 , and 5 (12) -C 1 - 6 alkyl-C(O)N(R4 )(R 5); each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently 10 selected from: (a) halogen, (b) C1-. 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 15 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 20 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1- 6 alkyl, (iii) -CF 3 , and 25 (iv) hydroxy, (3) thienyl, (4) pyridyl, (5) imidazolyl, (6) pyrrolyl, 30 (7) pyrazolyl, (8) C 3 - 6 cycloalkyl, - 201 - WO 99/62513 PCT/US99/12095 (9) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 5 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 10 (h) hydroxy; (10) piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and 15 (14) C 3 - 6 cycloalkyl fused with a phenyl ring; each R is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, and 20 (3) -CF 3 ; each R 5 is independently selected from: (1) -H, (2) -C1- 3 alkyl, 25 (3) -CF 3 , and 3 (4) -R 3 each R is independently selected from: (1) -C1- 3 alkyl-R 3 , and 30 (2) -R3 R7 is H; and - 202 - WO 99/62513 PCT/US99/12095 R8 is selected from: (1) -H, and (2) CH3; and 5 each n is independently selected from 0, 1 and 2.
4. The compound according to Claim 1 of structural formula: R 1 1--3- RS O N OR 7 10 R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: (1) -H, 15 (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, (5) -NO 2 , (6) -N(R4)(R5), 20 (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 25 (c) methoxy, (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C 1 .- 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, 30 (b) methyl, and - 203 - WO 99/62513 PCT/US99/12095 (c) methoxy, 3 (11) -C 2 - 5 alkenyl-R 3 (12) -C 2 - 5 alkynyl-R 3 , and (13) -C(O)CH2C(O)C(O)OR7 5 2 R is selected from: (1) -H, 3 (2) -R 3 (3) -C1- 6 alkyl, 10 (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R 6 (6) -O-C 1 - 6 alkyl-OR 6 (7) -S(O)n-R (8) -C 1 .- 6 alkyl (OR6 )(R4), 15 (9) -C 1 - 6 alkyl-N(R4)(R 6), (10) -C16 6 alkyl S()n-R 6 (11) -C 1 - 6 alkyl C(O)-R 6 (12) -C 1 .- 6 alkyl C(S)-R 6 (12) -C 1 .. 6 alkyl C(S)-R (13) -C1- 6 alkyl NR4 C(O)-R 6 , and 20 (14) -C 1 - 6 alkyl-C(O)N(R4)(R 5); each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently 25 selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 30 (e) -CF 3 , (f) -OCF 3 , (g) -CN, - 204 - WO 99/62513 PCT/US99/12095 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 5 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy, (3) thienyl, 10 (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, 15 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 20 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1- 6 alkyl, 25 (iii) -CF 3 , and (iv) hydroxy; (5) pyridyl, (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: 30 (a) halogen, (b) C1- 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) phenyl, - 205 - WO 99/62513 PCT/US99/12095 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 5 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1- 6 alkyl, 10 (iii) -CF 3 , and (iv) hydroxy, (7) imidazolyl, (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: 15 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , 20 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 25 selected from: (i) halogen, (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 30 (9) pyrrolyl, (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, - 206 - WO 99/62513 PCT/US99/12095 (b) C1- 6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy, 15 (11) pyrazolyl, (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 20 (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 25 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 30 (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy, - 207 - WO 99/62513 PCT/US99/12095 (13) C 3 - 6 cycloalkyl, (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, 5 (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 10 (g) =0O, and (h) hydroxy, (15) piperidinyl, (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: 15 (a) halogen, (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 20 (f) -CN, (g) =0O, and (h) hydroxy, (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen 25 atom with 1 or 2 independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , 30 (e) -OCF 3 , (f) -CN, (g) =0, and - 208 - WO 99/62513 PCT/US99/12095 (h) hydroxy, (19) naphthyl, (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: 5 (a) halogen, (b) C 1 .- 6 alkyl, (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 10 (f) -CN, (g) =0O, and (h) hydroxy, (21) indolyl, (22) substituted indolyl substituted on a carbon atom with one or 15 two substituents independently selected from: (a) halogen, (b) C1-. 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , 20 (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy, (23) C 3 - 6 cycloalkyl fused with a phenyl ring, 25 (24) substituted C 3 - 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 _ 6 alkyl, 30 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , - 209 - WO 99/62513 PCT/US99/12095 (f) -CN, (g) =0O, and (h) hydroxy; 5 each R 4 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R 3 10 (5) -C 2 - 3 alkenyl, 3 (6) -C 1 .- 3 alkyl-R (7) -C 2 - 3 alkenyl-R3 3 (8) -S(O)n-R , and (9) -C(O)-R3 15 each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 20 (4) -R 3 , (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R (7) -C 2 - 3 alkenyl-R 3 3 (8) -S(O)n-R 3 , and 3 25 (9) -C(0)-R each R 6 is independently selected from: (1) -C 1 .- 3 alkyl-R 3 , and (2) -R 30 R 7 is selected from: -210- WO 99/62513 PCT/US99/12095 (1) -H, and (2) C1-6 alkyl; R8 is selected from: 5 (1) -H, and (2) C1-6 alkyl; and each n is independently selected from 0, 1 and 2. 10
5. The compound according to Claim 4 of structural formula: R 1 N OR 7 R 2 O O and tautomers and pharmaceutically acceptable salts thereof, wherein: 15 R 1 is selected from: (1) -H, (2) -C1- 5 alkyl, (3) -CF 3 , (4) -halo, 20 (5) -NO 2 , (6) -N(R 4 )(R 5 ), (7) -phenyl, (8) substituted phenyl substituted with 1 substituent independently selected from: 25 (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1 - 3 alkyl-, -211- WO 99/62513 PCT/US99/12095 (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 5 (c) methoxy, 3 (11) -C 2 - 5 alkenyl-R 3 , and (12) -C(0)CH2C(0)C(0)ORT7; 10 R 2 is selected from: (1) -H, 3 (2) -R 3 (3) -C1- 6 alkyl, (4) -C 1 .- 6 alkyl substituted with R 15 (5) -O-R 6 , 6 (6) -O-C 1 - 6 alkyl-OR (7) -C 1 - 6 alkyl (OR6 (R 4 ), (8) -C 1 - 6 alkyl-N(R4)(R 6), 6 (9) -C 1 - 6 alkyl C(0)-R 20 (10) -C 1 - 6 alkyl NR4C(0)-R 6 , and (11) -C 1 - 6 alkyl-C(0)N(R4 )(R5); each R 3 is independently selected from: (1) phenyl, 25 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, 30 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , -212- WO 99/62513 PCT/US99/12095 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 5 selected from: (i) halogen, (ii) C 1 .- 2 alkyl, (iii) -CF 3 , and (iv) hydroxy; 10 (3) thienyl, (4) pyridyl, (5) imidazolyl, (6) pyrrolyl, (7) pyrazolyl, 15 (8) C 3 - 6 cycloalkyl, (10) piperidinyl, (11) morpholinyl, (12) substituted morpholinyl substituted with a substituent selected from: 20 (a) halogen, (b) C1- 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF3, (e) -OCF 3 , 25 (f) -CN, (g) =0, (h) hydroxy; (12) naphthyl, (13) indolyl, and 30 (14) C 3 - 6 cycloalkyl fused with a phenyl ring; each R 4 is independently selected from: (1) -H, -213- WO 99/62513 PCT/US99/12095 (2) -C 1 - 3 alkyl, (3) -CF3, (4) -R 3 , 3 (5) -C 1 .- 3 alkyl-R 3 5 (6) -S(O)n-R 3 , and (7) -C(O)-R 3 each R 5 is independently selected from: (1) -H, 10 (2) -C 1 .- 3 alkyl, (3) -CF3, (4) -R 3 , 3 (5) -C 1 - 3 alkyl-R , 3 (6) -S(O)n-R 3 , and 15 (7) -C(O)-R each R 6 is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and 3 (2) -R3 20 R7 is selected from: (1) -H, and (2) C1-4 alkyl; 25 R8 is selected from: (1) -H, and (2) -CH3; and each n is independently selected from 0, 1 and 2. 30
6. The compound according to Claim 5 of structural formula: -214- WO 99/62513 PCT/US99/12095 R 1 1-- R8 0 N OR 7 R 2 0 O and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: 5 (1) -H, (2) -C 1 .- 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5) -NO 2 , 10 (6) -N(R)(R5), (7) -phenyl, (8) phenyl C 1 - 3 alkyl-, (9) substituted phenyl C 1 _ 3 alkyl- substituted with 1 or 2 substituents independently selected from: 15 (a) halo, wherein halo is selected from: -F, -Cl, and -Br; 3 (10) -C 2 - 5 alkynyl-R 3 , and (11) -C(O)CH2C(O)C(O)OR7; 20 R 2 is selected from: (1) -H, (2) -R 3 , (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 25 (5) -O-R , (6) -O-C 1 - 6 alkyl-OR 6 (7) -C 1 - 6 alkyl (OR6 )(R 4 ), (8) -C 1 - 6 alkyl-N(R4 )(R6), -215- WO 99/62513 PCT/US99/12095 (9) -C1. 6 alkyl C(O)-R 6 , and (10) -C1- 6 alkyl NR4 C(O)-R ; each R 3 is independently selected from: 5 (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 10 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 15 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, 20 C1, and Br, (ii) methyl, (iii) -CF 3 , and (iv) hydroxy; (3) C 3 - 6 cycloalkyl, 25 (4) morpholinyl, (5) substituted morpholinyl substituted with oxo; and (6) naphthyl; each R 4 is independently selected from: 30 (1) -H, and (2) -C1- 3 alkyl, -216- WO 99/62513 PCT/US99/12095 each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 5 (4) -R 3 3 (5) -C 1 - 3 alkyl-R 3 (6) -S(O)n-R , and (7) -C(O)-R 3 10 each R 6 is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and 3 (2) -R3 R7 is -H; 15 R8 is selected from: (1) -H, and (2) -CH3; and 20 each n is independently selected from 0, 1 and 2.
7. The compound according to Claim 6 of structural formula: R 1 /\ 0 N OH R 2 0 0 25 and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: (1) -H, (2) -C 1 - 5 alkyl, -217- WO 99/62513 PCT/US99/12095 (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, C1, -Br, and -I; (5) -NO 2 , (6) -N(R4 )(R5), 5 (7) -phenyl, (8) phenyl C 1 - 3 alkyl-, (9) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br, 10 and (10) -C 2 .- 5 alkynyl-R3 R 2 is selected from: (1) -H, 15 (2) -R (3) -C1- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R 6 (6) -O-C 1 - 6 alkyl-OR , 20 (7) -C 1 - 6 alkyl (OR6 )(R4), (8) -C 1 - 6 alkyl-N(R4 )(R6), (9) -C 1 .- 6 alkyl C(O)-R 6 , and (10) -C1- 6 alkyl NR4C(O)-R6 25 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 30 (b) C 1 _ 6 alkyl, (c) CI- 6 alkyloxy-, (d) phenyl, -218- WO 99/62513 PCT/US99/12095 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 5 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, Cl, and Br, 10 (ii) methyl, (iii) -CF 3 , and (iv) hydroxy, (3) C 3 - 6 cycloalkyl, (4) morpholinyl, 15 (5) substituted morpholinyl substituted with oxo, and (6) naphthyl; each R 4 is independently selected from: (1) -H, and 20 (2) -C1- 3 alkyl; each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 25 (3) -CF3, (4) -R 3 , 3 (5) -C 1 - 3 alkyl-R 3 (6) -S(O)n-R 3 , and (7) -C(O)-R 30 each R is independently selected from: (1) -C1- 3 alkyl-R 3 , and - 219- WO 99/62513 PCT/US99/12095 (2) -R3; and each n is independently selected from 0, 1 and 2. 5
8. The compound according to Claim 6 of structural formula: 0 R1 OH R 2 0 0 and tautomers and pharmaceutically acceptable salts thereof, wherein: 10 R 1 is selected from: (1) -H, (2) -C 1 .- 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; 15 (5) -NO 2 , (6) -N(R )(R5), (7) -phenyl, (8) phenyl C 1 - 3 alkyl-, (9) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 20 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C 2 - 5 alkynyl-R3 25 R 2 is selected from: (1) -H, (2) -R 3 , (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 6 30 (5) -O-R - 220 - WO 99/62513 PCT/US99/12095 (6) -O-C 1 .- 6 alkyl-OR6 (7) -Cl- 6 alkyl (OR 6 )(R 4 ), 46 (8) -C 1 . 6 alkyl-N(R4 )(R6), (9) -C 1 - 6 alkyl C(0)-R 6 , and 5 (10) -C1- 6 alkyl NR4 C(0)-R6 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently 10 selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 15 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 20 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, Cl, and Br, (ii) methyl, 25 (iii) -CF 3 , and (iv) hydroxy, (3) C 3 - 6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and 30 (6) naphthyl; each R is independently selected from: - 221 - WO 99/62513 PCT/US99/12095 (1) -H, and (2) -C 1 3 alkyl; each R 5 is independently selected from: 5 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R 3 (5) -C1- 3 alkyl-R3 10 (6) -S(O)n-R 3 , and (7) -C(O)-R 3 each R 6 is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and 15 (2) -R3 each n is independently selected from 0, 1 and 2. 20
9. The compound according to Claim 1 of structural formula: R s O OR 7 N co R 2 and tautomers and pharmaceutically acceptable salts thereof, wherein: 25 R 1 is selected from: (1) -H, (2) -C1- 5 alkyl, (3) -CF 3 , (4) -halo, - 222 - WO 99/62513 PCT/US99/12095 (5) -NO 2 , (6) -N(R4 )(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents 5 independently selected from: (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1- 3 alkyl-, 10 (10) substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and (c) methoxy, 3 15 (11) -C 2 .- 5 alkenyl-R 3 3 (12) -C 2 - 5 alkynyl-R 3 , and (13) -C(O)CH2C(O)C(O)OR7; 2 R is selected from: 20 (1) -H, 33 (2) -R3 (3) -C1- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 (5) -O-R 6 6 25 (6) -O-C 1 - 6 alkyl-OR 6 (7) -S(O)n-R (8) -C 1 .- 6 alkyl (OR6)(R4), (9) -C 1 - 6 alkyl-N(R 4 )(R 6 ), (10) -C 1 - 6 alkyl S(O)n-R 6 , 30 (11) -C1 6 alkyl C()-R 6 6 30 (12) -C 1 - 6 alkyl C(S)-R 6 (12) -C 1 .. 6 alkyl C(S)-R (13) -C1- 6 alkyl NR4 C(O)-R 6 , and - 223 - WO 99/62513 PCT/US99/12095 (14) -C 1 - 6 alkyl-C(O)N(R4)(R 5); each R 3 is independently selected from: (1) phenyl; 5 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, 10 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 15 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1.-6 alkyl, 20 (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from: 25 (a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF 3 , 30 (f) -OCF 3 , (g) -CN, (h) hydroxy, - 224 - WO 99/62513 PCTIUS99/12095 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 5 (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or 10 two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 15 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 20 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 25 (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 30 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , - 225 - WO 99/62513 PCT/US99/12095 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 5(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF3, and 10 (iv) hydroxy; (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 15 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 20 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 25 (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (11) pyrazolyl; 30 (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, - 226 - WO 99/62513 PCT/US99/12095 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 5 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 10 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3 .- 6 cycloalkyl; 15 (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, 20 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 25 (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 30 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , - 227 - WO 99/62513 PCT/US99/12095 (f) -CN, (g) =0O, and (h) hydroxy; (17) morpholinyl; 5 (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 10 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 15 (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 20 (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 25 (h) hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 30 (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , - 228 - WO 99/62513 PCT/US99/12095 (f) -CN, (g) =0, and (h) hydroxy; (23) C 3 - 6 cycloalkyl fused with a phenyl ring; 5 (24) substituted C 3 - 6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 10 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and 15 (h) hydroxy; each R 4 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 20 (3) -CF 3 , (4) -R 3 (5) -C 2 .- 3 alkenyl, (6) -C1- 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R 3 25 (8) -S(O)n-R 3 , and (9) -C(O)-R each R 5 is independently selected from: (1) -H, 30 (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R 3 - 229 - WO 99/62513 PCT/US99/12095 (5) -C 2 - 3 alkenyl, 3 (6) -C 1 - 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R 3 (8) -S(O)n-R 3 , and 5 (9) -C(O)-R 3 each R 6 is independently selected from: 3 (1) -C 1 - 3 alkyl-R 3 , and 3 (2) -R3 10 R7 is selected from: (1) -H, and (2) C1-6 alkyl; 15 R8 is selected from: (1) -H, and (2) C1-6 alkyl; and each n is independently selected from 0, 1 and 2. 20
10. The compound according to Claim 9 of structural formula: R 8 0 R 1 OH R 0 U 1 -H N 0O0 R 2 and tautomers and pharmaceutically acceptable salts thereof, 25 wherein: R 1 is selected from: (1) -H, (2) -C1- 5 alkyl, - 230 - WO 99/62513 PCT/US99/12095 (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5) -NO 2 , (6) -N(R )(R5), 5 (7) -phenyl, (8) phenyl C 1 - 3 alkyl-, (9) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br, 10 and (10) -C 2 -. 5 alkynyl-R3 R 2 is selected from: (1) -H, 33 15 (2) -R 3 , (3) -C1- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R , 6 (6) -O-C 1 - 6 alkyl-OR 20 (7) -C 1 - 6 alkyl (OR )(R4), (8) -C 1 - 6 alkyl-N(R4)(R6), 6 (9) -C 1 - 6 alkyl C(O)-R , and (10) -C1- 6 alkyl NR4 C(O)-R6 25 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 30 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, - 231 - WO 99/62513 PCT/US99/12095 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 5 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, Cl, and Br, 10 (ii) methyl, (iii) -CF 3 , and (iv) hydroxy, (3) C 3 - 6 cycloalkyl, (4) morpholinyl, 15 (5) substituted morpholinyl substituted with oxo; and (6) naphthyl; each R 4 is independently selected from: (1) -H, and 20 (2) -C 1 - 3 alkyl; each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 25 (3) -CF3, (4) -R 3 , 3 (5) -C 1 - 3 alkyl-R (6) -S(O)n-R 3 , and (7) -C(O)-R 3 30 each R is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and -232- WO 99/62513 PCT/US99/12095 (2) -R3 R 8 is selected from: (1) -H, and 5 (2) CH3; and each n is independently selected from 0, 1 and 2.
11. The compound according to Claim 1 of structural 10 formula: SR 1 OR 7 R 8 0 0 (i) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is pyrazolyl; 15 R 1 is selected from: (1) -H, (2) -C 1 - 5 alkyl, (3) -CF 3 , 20 (4) -halo, (5) -NO 2 , (6) -N(R4 )(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents 25 independently selected from: (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1 - 3 alkyl-, - 233 - WO 99/62513 PCT/US99/12095 (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 5 (c) methoxy, (11) -C2- 5 alkenyl-R3 3 (12) -C 2 - 5 alkynyl-R 3 , and (13) -C(O)CH2C(O)C(O)OR7; 10 R 2 is selected from: (1) -H, (2) -R 3 , (3) -C 1 .- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 6 15 (5) -O-R , 6 (6) -O-C 1 - 6 alkyl-OR 6 (7) -S(O)n-R 6 (8) -C 1 - 6 alkyl (OR6)(R4), (9) -C 1 - 6 alkyl-N(R4)(R 6), 6 20 (10) -C 1 - 6 alkyl S(O)n-R (11) -C16 6 alkyl C()-R 6 (12) -C 1 - 6 alkyl C(S)-R 6 (12) -C 1 .. 6 alkyl C(S)-R (13) -C1- 6 alkyl NR4 C(O)-R 6 , and (14) -C 1 - 6 alkyl-C(O)N(R 4 )(R 5 ); 25 each R 3 is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: 30 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, - 234- WO 99/62513 PCT/US99/12095 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 5 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 10 (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or 15 two substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, 20 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 25 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 30 (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: - 235 - WO 99/62513 PCT/US99/12095 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) phenyl, 5 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 10 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1- 6 alkyl, (iii) -CF 3 , and 15 (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 20 (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; - 236 - WO 99/62513 PCT/US99/12095 (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 5 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (11) pyrazolyl; 20 (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, 25 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 30 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, - 237 - WO 99/62513 PCT/US99/12095 (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3 - 6 cycloalkyl; 5 (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, 10 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 15 (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, 20 (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 25 (h) hydroxy; (17) morpholinyl; (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, 30 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , - 238 - WO 99/62513 PCT/US99/12095 (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 5 (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, 10 (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and 15 (h) hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 20 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 25 (g) =0, and (h) 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 30 independently selected from: (a) halogen, (b) C 1 - 6 alkyl, - 239 - WO 99/62513 PCT/US99/12095 (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 5 (g) =0O, and (h) hydroxy; each R 4 is independently selected from: (1) -H, 10 (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R 3 (5) -C 2 - 3 alkenyl, (6) -C 1 - 3 alkyl-R 3 3 15 (7) -C 2 .- 3 alkenyl-R (8) -S(O)n-R 3 , and (9) -C(O)-R each R 5 is independently selected from: 20 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R 3 (5) -C 2 - 3 alkenyl, 3 25 (6) -C 1 - 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R 3 (8) -S(O)n-R 3 , and (9) -C(0)-R 3 30 each R 6 is independently selected from: (1) -C1- 3 alkyl-R 3 , and - 240 - WO 99/62513 PCT/US99/12095 (2) -R3 R 7 is selected from: (1) -H, and 5 (2) C1-6 alkyl; R 8 is selected from: (1) -H, and (2) C1-6 alkyl; and 10 each n is independently selected from 0, 1 and 2.
12. The compound according to Claim 11 wherein: R is selected from: 15 (1) -H, (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5) -NO 2 , 20 (6) -N(R 4 )(R 5 ) , (7) -phenyl, (8) phenyl C 1 .- 3 alkyl-, (9) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: 25 (a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C 2 - 5 alkynyl-R3 2 R is selected from: 30 (1) -H, (2) -R 3 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R - 241 - WO 99/62513 PCT/US99/12095 (5) -O-R (6) -0-C 1 - 6 alkyl-OR 6 (7) -C 1 - 6 alkyl (OR6 )(R4), (8) -C 1 .- 6 alkyl-N(R4 )(R6), 5 (9) -C 1 - 6 alkyl C(O)-R 6 , and (10) -C1- 6 alkyl NR4 C(O)-R6 each R 3 is independently selected from: (1) phenyl, 10 (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, 15 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 20 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, Cl, and Br, 25 (ii) methyl, (iii) -CF 3 , and (iv) hydroxy, (3) C 3 .- 6 cycloalkyl, (4) morpholinyl, 30 (5) substituted morpholinyl substituted with oxo, and (6) naphthyl; - 242 - WO 99/62513 PCT/US99/12095 each R 4 is independently selected from: (1) -H, and (2) -C 1 .- 3 alkyl; 5 each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R 3 3 10 (5) -C 1 - 3 alkyl-R 3 (6) -S(O)n-R 3 , and (7) -C(O)-R each R 6 is independently selected from: 3 15 (1) -C 1 _ 3 alkyl-R 3 , and 3 (2) -R3 each R 7 is independently selected from: (1) -H, 20 (2) -CH2CH3, and (3) -CH3; and R 8 is selected from: (1) -H, and 25 (2) -CH3; and each n is independently selected from 0, 1 and 2; and tautomers and pharmaceutically acceptable salts thereof. 30
13. The compound according to Claim 12 of structural formula: - 243 - WO 99/62513 PCT/US99/12095 0 0 O O R RK OR R IN O N R 2 and tautomers and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 12 of structural 5 formula: 0 0 OR 7 R2 N R2 and tautomers and pharmaceutically acceptable salts thereof.
15. The compound according to Claim 1 of structural 10 formula: SR 1 OR 7 R 8 O O (i) and tautomers and pharmaceutically acceptable salts thereof, wherein: A is imidazolyl; 15 R 1 is selected from: (1) -H, (2) -C1- 5 alkyl, (3) -CF 3 , - 244- WO 99/62513 PCT/US99/12095 (4) -halo, (5) -NO 2 , (6) -N(R4)(R5), (7) -phenyl, 5 (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and (c) methoxy, 10 (9) phenyl C 1 - 3 alkyl-, (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 15 (c) methoxy, 3 (11) -C 2 - 5 alkenyl-R 3 3 (12) -C 2 - 5 alkynyl-R 3 , and (13) -C(O)CH2C(O)C(O)OR7; 20 R 2 is selected from: (1) -H, (2) -R 3 (3) -C 1 - 6 alkyl, (4) -C 1 .- 6 alkyl substituted with R 3 25 (5) -O-R 6 6 (6) -O-C 1 - 6 alkyl-OR (7) -S(O)n-R 6 (8) -C 1 - 6 alkyl (OR6 )(R4), (9) -C 1 - 6 alkyl-N(R 4 )(R 6 ) , 6 30 (10) -C 1 - 6 alkyl S(O)n-R (11) -C6 6 alkyl C()-R , (12) -C 1 - 6 alkyl C(S)-R , -245 (12) -C 1 .. 6 alkyl C(S)-R _ 245 - WO 99/62513 PCTIUS99/12095 (13) -C1- 6 alkyl NR 4 C(O)-R 6 , and (14) -C 1 - 6 alkyl-C(O)N(R4 )(R5); each R 3 is independently selected from: 5 (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 _ 6 alkyl, 10 (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 15 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 20 (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or 25 two substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, 30 (e) -CF 3 , (f) -OCF 3 , (g) -CN, - 246 - WO 99/62513 PCT/US99/12095 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 5 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (5) pyridyl; 10 (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 15 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 20 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 _ 6 alkyl, 25 (iii) -CF 3 , and (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: 30 (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, - 247 - WO 99/62513 PCT/US99/12095 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 5 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1- 6 alkyl, 10 (iii) -CF 3 , and (iv) hydroxy; (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: 15 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , 20 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 25 selected from: (i) halogen, (ii) C 1 _ 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 30 (11) pyrazolyl (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, - 248 - WO 99/62513 PCT/US99/12095 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , 5 (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents 10 selected from: (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; 15 (13) C 3 .- 6 cycloalkyl; (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 20 (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and 25 (h) hydroxy; (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 30 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , -249 - WO 99/62513 PCT/US99/12095 (e) -OCF 3 , (f) -CN, (g) =0, and (h) hydroxy; 5 (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, (b) C1- 6 alkyl, 10 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0, and 15 (h) hydroxy; (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 20 (b) C1- 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 25 (g) =0, and (h) hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: 30 (a) halogen, (b) C1- 6 alkyl, (c) C 1 - 6 alkyloxy-, - 250 - WO 99/62513 PCT/US99/12095 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 5 (h) 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: 10 (a) halogen, (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , 15 (f) -CN, (g) =0O, and (h) hydroxy; each R 4 is independently selected from: 20 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , 3 (4) -R 3 (5) -C 2 - 3 alkenyl, 3 25 (6) -C 1 - 3 alkyl-R (7) -C 2 - 3 alkenyl-R 3 (8) -S(O)n-R , and (9) -C(O)-R 30 each R 5 is independently selected from: (1) -H, - 251 - WO 99/62513 PCT/US99/12095 (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R (5) -C 2 .- 3 alkenyl, 3 5 (6) -C 1 .- 3 alkyl-R 3 (7) -C 2 - 3 alkenyl-R 3 (8) -S(O)n-R 3 , and (9) -C(O)-R 3 10 each R 6 is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and 3 (2) -R3 R 7 is selected from: 15 (1) -H, and (2) C1-6 alkyl; R 8 is selected from: (1) -H, and 20 (2) C1-6 alkyl; and each n is independently selected from 0, 1 and 2.
16. The compound according to Claim 15 of structural 25 formula: R 1 N 0 N OH 'R20 O and tautomers and pharmaceutically acceptable salts thereof, wherein: R 1 is selected from: - 252 - WO 99/62513 PCT/US99/12095 (1) -H, (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, C1, -Br, and -I; 5 (5) -NO 2 , (6) -N(R4)(R5), (7) -phenyl, (8) phenyl C1- 3 alkyl-, (9) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 10 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C 2 - 5 alkynyl-R 3 15 R 2 is selected from: (1) -H, (2) -R3, (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 20 (5) -O-R 6 (6) -O-C 1 - 6 alkyl-OR , (7) -C 1 - 6 alkyl (OR )(R4), (8) -C 1 - 6 alkyl-N(R )(R ), (9) -C 1 - 6 alkyl C(O)-R 6 , and 4 6 25 (10) -C1- 6 alkyl NR4 C(O)-R6 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently 30 selected from: (a) halogen, (b) C 1 - 6 alkyl, - 253 - WO 99/62513 PCT/US99/12095 (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 5 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 10 (i) halogen, wherein halogen is selected from -F, Cl, and Br, (ii) methyl, (iii) -CF 3 , and (iv) hydroxy, 15 (3) C 3 - 6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl; 20 each R 4 is independently selected from: (1) -H, and (2) -C1- 3 alkyl; each R 5 is independently selected from: 25 (1) -H, (2) -C 1 - 3 alkyl, (3) -CF 3 , (4) -R 3 , 3 (5) -C 1 - 3 alkyl-R 3 30 (6) -S(O)n-R 3 , and 3O3 (7) -C(O)-R; - 254- WO 99/62513 PCT/US99/12095 each R 6 is independently selected from: (1) -C1- 3 alkyl-R 3 , and (2) -R3; and 5 each n is independently selected from 0, 1 and 2.
17. The compound according to Claim 1 of structural formula: R OR 7 R 8 0 0 (i) 10 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; 15 R 1 is selected from: (1) -H, (2) -C1- 5 alkyl, (3) -CF 3 , (4) -halo, 20 (5) -NO 2 , (6) -N(R4)(R5 (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from: 25 (a) halo, (b) methyl, and (c) methoxy, (9) phenyl C 1 3 alkyl-, - 255 - WO 99/62513 PCT/US99/12095 (10) substituted phenyl C 1 - 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, (b) methyl, and 5 (c) methoxy, 3 (11) -C 2 - 5 alkenyl-R 3 (12) -C 2 - 5 alkynyl-R 3 , and (13) -C(0)CH2C(0)C(0)OR7; 10 R 2 is selected from: (1) -H, 3 (2) -R 3 (3) -C 1 - 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 15 (5) -O-R , (6) -O-C 1 - 6 alkyl-OR 6 6 (7) -S(0)n-R (8) -C1- 6 alkyl (OR6)(R 4 ), (9) -C 1 .- 6 alkyl-N(R4)(R 6), 6 20 (10) -C 1 - 6 alkyl S(0)n-R (11) -C1- 6 alkyl C(O)-R6 6 (12) -C 1 - 6 alkyl C(S)-R (13) -C 1 .- 6 alkyl NR4C(0)-R 6 , and (14) -C 1 - 6 alkyl-C(0)N(R4)(R 5); 25 each R 3 is independently selected from: (1) phenyl; (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: 30 (a) halogen, (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, - 256 - WO 99/62513 PCT/US99/12095 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 5 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, 10 (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (3) thienyl; (4) substituted thienyl substituted on a carbon atom with one or 15 two substituents independently selected from: (a) halogen, (b) CI_ 6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, 20 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 25 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and 30 (iv) hydroxy; (5) pyridyl; (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: - 257 - WO 99/62513 PCT/US99/12095 (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 .- 6 alkyloxy-, (d) phenyl, 5 (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and 10 (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and 15 (iv) hydroxy; (7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 20 (b) C 1 .- 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, (ii) C 1 - 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; - 258 - WO 99/62513 PCT/US99/12095 (9) pyrrolyl; (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 5 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 10 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 15 (i) halogen, (ii) C1- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (11) pyrazolyl; 20 (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, 25 (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, (h) hydroxy, 30 (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, - 259 - WO 99/62513 PCT/US99/12095 (ii) C 1 .- 6 alkyl, (iii) -CF 3 , and (iv) hydroxy; (13) C 3 - 6 cycloalkyl, 5 (14) substituted C 3 - 6 cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen, (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, 10 (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 15 (15) piperidinyl; (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, 20 (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 25 (h) hydroxy; (17) morpholinyl, (18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from: (a) halogen, 30 (b) C 1 - 6 alkyl, (c) C 1 - 6 alkyloxy-, (d) -CF 3 , - 260 - WO 99/62513 PCT/US99/12095 (e) -OCF 3 , (f) -CN, (g) =0O, and (h) hydroxy; 5 (19) naphthyl; (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C1- 6 alkyl, 10 (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, (g) =0O, and 15 (h) hydroxy; (21) indolyl; (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, 20 (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 25 (g) =0O, and (h) 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 30 independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, - 261 - WO 99/62513 PCT/US99/12095 (c) C 1 .- 6 alkyloxy-, (d) -CF 3 , (e) -OCF 3 , (f) -CN, 5 (g) =0, and (h) hydroxy; each R 4 is independently selected from: (1) -H, 10 (2) -C1- 3 alkyl, (3) -CF 3 , 3 (4) -R 3 (5) -C 2 - 3 alkenyl, 3 (6) -C1- 3 alkyl-R 3 15 (7) -C 2 - 3 alkenyl-R 3 (8) -S(O)n-R 3 , and (9) -C(O)-R each R 5 is independently selected from: 20 (1) -H, (2) -C1- 3 alkyl, (3) -CF 3 , (4) -R 3 , (5) -C 2 - 3 alkenyl, 3 25 (6) -C 1 .- 3 alkyl-R (7) -C 2 - 3 alkenyl-R 3 3 (8) -S(O)n-R 3 , and (9) -C(0)-R 3 30 each R 6 is independently selected from: 3 (1) -C1- 3 alkyl-R 3 , and - 262 - WO 99/62513 PCT/US99/12095 3 (2) -R3 R 7 is selected from: (1) -H, and 5 (2) C1-6 alkyl; R 8 is selected from: (1) -H, and (2) C1-6 alkyl; and 10 each n is independently selected from 0, 1 and 2.
18. The compound according to Claim 17 of structural formula: 0 N OH 15 R 2 0 0 or a tautomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from: (1) -H, 20 (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5) -NO 2 , (6) -N(R4)(R5) 25 (7) -phenyl, (8) phenyl C 1 - 3 alkyl-, (9) substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo, wherein halo is selected from: -F, -Cl, and -Br, 30 and - 263 - WO 99/62513 PCT/US99/12095 (10) -C 2 - 5 alkynyl-R3 R 2 is selected from: (1) -H, 3 5 (2) -R 3 (3) -CI- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R 6 (6) -O-C 1 - 6 alkyl-OR 10 (7) -C 1 - 6 alkyl (OR6 )(R4), (8) -C 1 .- 6 alkyl-N(R4 )(R6), 6 (9) -C 1 - 6 alkyl C(O)-R 6 , and (10) -C1- 6 alkyl NR4 C(O)-R6 15 each R 3 is independently selected from: (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, 20 (b) C 1 - 6 alkyl, (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , 25 (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: 30 (i) halogen, wherein halogen is selected from -F, Cl, and Br, (ii) methyl, - 264 - WO 99/62513 PCT/US99/12095 (iii) -CF 3 , and (iv) hydroxy, (3) C 3 - 6 cycloalkyl, (4) morpholinyl, 5 (5) substituted morpholinyl substituted with oxo, and (6) naphthyl; each R 4 is independently selected from: (1) -H, and 10 (2) -C 1 - 3 alkyl; each R 5 is independently selected from: (1) -H, (2) -C 1 - 3 alkyl, 15 (3) -CF 3 , (4) -R 3 3 (5) -C1- 3 alkyl-R 3 (6) -S(O)n-R 3 , and (7) -C(O)-R 20 each R 6 is independently selected from: (1) -C1- 3 alkyl-R 3 , and (2) -R 3 ; and 25 each n is independently selected from 0, 1 and 2.
19. The compound according to Claim 17 of structural formula: - 265 - WO 99/62513 PCT/US99/12095 0 0 OH I0 N R 2 or a tautomer or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from: 5 (1) -H, (2) -C 1 - 5 alkyl, (3) -CF 3 , (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I, (5) -NO 2 , 10 (6) -N(R4)(R5), (7) -phenyl, (8) phenyl C1- 3 alkyl-, (9) substituted phenyl C1- 3 alkyl- substituted with 1 or 2 substituents independently selected from: 15 (a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C 2 - 5 alkynyl-R3 2 R is selected from: 20 (1) -H, (2) -R 3 , (3) -C 1 .- 6 alkyl, (4) -C 1 - 6 alkyl substituted with R 3 6 (5) -O-R , 6 25 (6) -0-C 1 - 6 alkyl-OR (7) -C 1 - 6 alkyl (OR6 )(R4) (8) -C 1 - 6 alkyl-N(R4 )(R6), - 266 - WO 99/62513 PCT/US99/12095 (9) -C 1 - 6 alkyl C(O)-R 6 , and (10) -C1- 6 alkyl NR4C(O)-R6 each R 3 is independently selected from: 5 (1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C 1 .- 6 alkyl, 10 (c) C1- 6 alkyloxy-, (d) phenyl, (e) -CF 3 , (f) -OCF 3 , (g) -CN, 15 (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, wherein halogen is selected from -F, 20 Cl, and Br, (ii) methyl, (iii) -CF 3 , and (iv) hydroxy, (3) C 3 - 6 cycloalkyl, 25 (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl; each R is independently selected from: 30 (1) -H, and (2) -C 1 - 3 alkyl; - 267 - WO 99/62513 PCT/US99/12095 each R 5 is independently selected from: (1) -H, (2) -C 1 .- 3 alkyl, (3) -CF 3 , 3 5 (4) -R 3 3 (5) -C1- 3 alkyl-R 3 3 (6) -S(O)n-R 3 , and (7) -C(0)-R 3 10 each R 6 is independently selected from: (1) -C 1 - 3 alkyl-R 3 , and (2) -R 3 ; and each n is independently selected from 0, 1 and 2. 15
20. The compound according to Claim 1 selected from: (1) 4-[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester, (2) 4-[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 20 (3) 4-[1-(4-methylbenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (4) 4-[1-(4-methylbenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid, (5) 4- [ 1-(4-fluorobenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, 25 (6) 4-[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester, (7) 4-[1-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n butyl ester, (8) 4-(1-benzyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid, 2 30 (9) 4-(1-naphthalen-2-ylmethyl- 1H-pyrrol-2-yl)-2,4-dioxobutyric acid, (10) 4-(1-biphenyl-4-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid, - 268 - WO 99/62513 PCT/US99/12095 (11) 4-(1-naphthalen-1-ylmethyl-l1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (12) 2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl]-butyric acid, (13) 4-[1-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, 5 (14) 2,4-dioxo-4-(1-phenethyl-l1H-pyrrol -2-yl)-butyric acid, (15) 4 -[l1-( 2 -methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (17) 4-[1-(4-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, 10 (18) 4-[1-(2-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (19) 4-[1-(3-bromobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (20) 4-[1-(3-chlorobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (21) 4-[1-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (22) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 15 (23) 2,4-dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid, (24) 4-(1-biphenyl-2-ylmethyl-l1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (25) 2,4-dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl] butyric acid, (26) 4-[1-(3-fluorobenzyl)-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (27) 4-[1-(2-chlorobenzyl)-1H-pyrrol-2 20 yl]-2,4-dioxobutyric acid,(28) 4-[1-(4-fluorobenzyl)-4-iodo 1H-pyrrol-2-yl]-2,4-dioxo-butyric acid,(29) 4-[1-(4 methoxybenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid,_(30) 4-[1-(2,4,5-trifluorobenzyl)-l1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 25 (31) 4-[ 1-(2,3-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid,(32) 4-[ 1-(3,5-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (33) 4-[1-(2,5-difluorobenzyl)-1H-pyrrol 2-yl]-2,4-dioxobutyric acid, (34) 4-[ 1-(2,5,6-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric 30 acid, (35) 4-[1-(2-fluorobenzyl)-l1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (36) 4-[1-(4-trifluoromethylbenzyl)-1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (37) 4-[1-(4-cyanobenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid, - 269 - WO 99/62513 PCT/US99/12095 (38) 4-[1-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid, (39) 2-hydroxy-4-[ 1-(4-hydroxybenzyl)- 1H-pyrrol-2-yl] -2,4 dioxobutyric acid, 5 (40) 4-(1-cyclopentylmethyl-l1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (41) 4-{ 1-[3-(4-fluorophenyl)propyl]- 1H-pyrrol-2-y}-2,4 dioxobutyric acid, (42) 4-{ 1-[2-(4-fluorophenyl)ethyl]- 1H-pyrrol-2-yl}-2,4-dioxobutyric acid, 10 (43) 4-[1-(3-phenylpropyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (44) 4-(1-ethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (45) 4-[1-(3-fluorobenzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (46) 4-[1-(2-chlorobenzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (47) 4-[1-(3-benzoylaminopropyl)-l1H-pyrrol-3-yl] -2,4-dioxobutyric 15 acid, (48) 4-{1-[3-(4-fluorophenoxy)benzyl]-l1H-pyrrol-2-yl}] -2,4 dioxobutyric acid, (49) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester 20 (50) 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid, (51) 4- [1-( 4 -fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl-2,4 dioxobutyric acid ethyl ester, (52) 4- [1-( 4 -fluorobenzyl)-4-phenylethynyl-l1H-pyrrol-2-yl]-2,4 25 dioxobutyric acid, (53) 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester, (54) 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 30 (55) 4-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)-l1-methyl-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (57) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 35 dioxobutyric acid, - 270 - WO 99/62513 PCT/US99/12095 (58) 4-[5-(4-fluorobenzyl)-l1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (59) 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (60) 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (61) 4-[5-(3-fluorobenzyl)-l1H -pyrrol-2-yl]-2,4-dioxobutyric acid, 5 (62) 4-[5-(4-fluorobenzyl)-l1-(4-fluorobenzyl)-l1H -pyrrol-2-yl]-2,4 dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (64) 4-[5-(benzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 10 dioxobutyric acid, (65) 4-[5-(3-chlorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (66) 4 -[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 15 (67) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, (68) 4-[5-(benzyl)-l1-methyl-iH -pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[5-(3-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 20 (70) 4-(5-benzyl-lH -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4-[2,5-bis-(3-chlorobenzyl)-l1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (72) 4-[ 1-(4-Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester, 25 (73) 4-[ 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, (75) 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 30 dioxobutyric acid, (76) 4-[ 1-(4-Fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 35 (78) 4-[5-Nitro- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric -271 - WO 99/62513 PCT/US99/12095 (79) 4-[1-benzyl-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester, (80) 4-[1-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[l1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, 5 (82) 4-[1-(3-bromobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) 4-[l1-(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, 10 (85) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[l1-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 4-[l-(4-chlorobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[l-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 15 (89) 4-[1-(3,4-dichlorobenzyl)- IH-pyrrol-3-yl]-2,4-dioxobutyric acid, (90) 4-[l1-(2-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (91) 4-[ l-(3-chlorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, 20 (92) 4-[ l-(3-trifluoromethylbenzyl)- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, (93) 4-[l1-(4-methylbenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[l-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(3-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 25 (96) 4-{ l-[3-(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl}-2,4 dioxobutyric acid, (97) 4-[l-(4-bromobenzyl)-l1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (98) 4-[l1-(4-chlorobenzyl)-l1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (99) 4-[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 30 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 PCT/US99/12095 (102) 4-[4-Phenyl-l1-(4-fluorobenzyl)-l1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (103) 4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-l1H-pyrrol-3 yl]-2,4-dioxo-butyric acid ethyl ester, 5 (104) 4-[ 1-( 4 -fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid, (105) 4- [ 1-(4-Fluorobenzyl)-3-acetylamino- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (106) 4-[4-acetylamino-l1-(4-fluorobenzyl)-l1H-pyrrol-2-yl] -2,4 10 dioxobutyric acid, (108) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (109) 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (110) 4 -[5-(3-ethoxycarbonyl-3-oxopropionyl)- 1-(4-fluorobenzyl)- 1H 15 pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 4-[1-(4-fluorobenzyl)-l1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4-[1-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl] -2,4 20 dioxobutyric acid, (114) 4-[ 1-(4-Fluorobenzyl)-5-methyl- 1H-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, 25 (116) 4 -[ 2 -( 4 -fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid, (117) 1-[ 1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester, (118) 1-[ 1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid, 30 (119) 4-[3-methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester, (120) 4-[3 -methyl-l1-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4 dioxobutyric acid, (121) 4-[5 -methyl-l1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4 35 dioxobutyric acid, - 273 - WO 99/62513 PCT/US99/12095 (122) 4-[5 -methyl-l1-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl este,r (123) 4-[5 -methyl-l1-(3-chlorobenzyl)-l1H-pyrazol-4-yl]-2,4 dioxobutyric acid, 5 (124) 4-[1-(4-fluoro-benzyl)- 1H-imidazol-2-yl]-2,4-dioxo-butyric acid, (125) 4-[1-(4-fluorobenzyl)- 1H-imidazol-2-yl]-2,4-dioxo-butyric acid ethyl ester, (126) 4-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid, 10 (127) 4-(1-Benzyl-l1H-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4-[1-(4-fluorobenzyl)-l1H-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester, (129) 4 -[1-( 4 -fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid, (130) 4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid 15 methyl ester, (131) 4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid, (132) 2-hydroxy-4-(1-methyl-l1-H -indol-2-yl) -2,4-dioxobutyric acid, (133) 4-[1-(4-fluorobenzyl)-l1H-indol-3-yl]-2,4-dioxobutyric acid, (134) 1-[1-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid 20 ethyl ester, (135) 1-[ 1-(4-fluorobenzyl)- 1H-indol-3-yl]-2,4-dioxobutyric acid,(136) 4-[ 1-(3-fluorobenzyl)- 1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, (137) 4-[4-(3-chlorobenzyl)-l1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, 25 (138) 4-[4-(4-fluorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (139) 4-[2,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (140) 4-[1-(3,5-dichlorobenzyl)-l1-H-pyrrol-3-yl]-2,4-dioxobutyric 30 acid, (141) 4-[1-(3-thiophenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (142) 4-[1-2,4-dimethylbenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, - 274 - WO 99/62513 PCT/US99/12095 (143) 4 -[1-(3-chloro-5-methyl-benzyl)- 1-H-pyrrol-3-yl]-2,4-dioxo butyric acid, (144) 4-[ 1-(1-naphthalenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, 5 (145) 4-[ 1-(2-thiophenemethyl)- 1-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and (146) 4-[4-(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof. 10
21. The compound according to Claim 1 selected from: (1) 4-[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (2) 4-[ 1-(4-methylbenzyl)- 1-H-pyrrol-2-yl]-2,4-dioxobutyric acid, (3) 4-(1-benzyl- 1H-pyrrol-2-yl)-2,4-dioxobutyric acid, 15 (4) 4-(1-naphthalen-2-ylmethyl- 1H-pyrrol-2-yl)-2,4-dioxobutyric acid, (5) 4-(1-biphenyl-4-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (6) 4-(1-naphthalen-1-ylmethyl- 1H-pyrrol -2-yl)-2,4-dioxobutyric 20 acid, (7) 2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl]-butyric acid, (8) 4-[1-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (9) 2,4-dioxo-4-(1-phenethyl-lH-pyrrol -2-yl)-butyric acid, (10) 4-[1-(2-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 25 (11) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (12) 4-[1-(4-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (13) 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (14) 4-[1-(3-bromobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 30 (15) 4-[1-(3-chlorobenzyl)-l1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[1-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (17) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (18) 2,4-dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid, (19) 4-(1-biphenyl-2-ylmethyl-l1H-pyrrol -2-yl)-2,4-dioxobutyric 35 acid,(20) 2,4-dioxo-4-[1-(4-phenoxybutyl)- 1H -pyrrol-2-yl] - 275 - WO 99/62513 PCT/US99/12095 butyric acid, (21) 4-[1-(3-fluorobenzyl)-l1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (22) 4-[1-(2-chlorobenzyl)-1H-pyrrol-2 yl]-2,4-dioxobutyric acid,(23) 4-[ 1-(4-fluorobenzyl)-4-iodo 1H-pyrrol-2-yl]-2,4-dioxo-butyric acid, (24) 4-[1-(4 5 methoxybenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid,_(25) 4-[ 1-(2,4,5-trifluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (26) 4-[ 1-(2,3-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid,(27) 4-[1-(3,5-difluorobenzyl)-1H-pyrrol-2-yl]-2,4 10 dioxobutyric acid, (28) 4-[1-(2,5-difluorobenzyl)-1H-pyrrol 2-yl]-2,4-dioxobutyric acid, (29) 4-[ 1-(2,5,6-difluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (30) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl] -2,4 dioxobutyric acid, 15 (31) 4-[1-(4-trifluoromethylbenzyl)-l1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (32) 4-[1-(4-cyanobenzyl)-l1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (33) 4-[1-(3-methoxybenzyl)-1H -pyrrol-2-yl] -2,4-dioxobutyric acid, 20 (34) 2-hydroxy-4-[1-(4-hydroxybenzyl)-l1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (35) 4-(1-cyclopentylmethyl-l1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (36) 4-{ 1-[3-(4-fluorophenyl)propyl]- 1H-pyrrol-2-y}-2,4 dioxobutyric acid, 25 (37) 4-{ 1-[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-(1-ethyl- 1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (40) 4-[1-(3-fluoro-benzyl)-l1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, 30 (41) 4-[1-(2-chloro-benzyl)-l1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (42) 4 -[1-(3-benzoylaminopropyl)-l1H-pyrrol-3-yl] -2,4-dioxobutyric acid, (43) 4-{1-[3-(4-fluorophenoxy)benzyl]-l1H-pyrrol-2-yl}] -2,4 dioxobutyric acid, - 276 - WO 99/62513 PCT/US99/12095 (44) 4-(1-cyclohexylmethyl-l1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid, (45) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, 5 (46) 4-[ 1-(4-fluorobenzyl)-4-phenethyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (47) 4-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (48) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-2-yl]-2,4 10 dioxobutyric acid, (49) 4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (50) 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (51) 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (52) 4-[5-(3-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, 15 (53) 4-[5-(4-fluorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (54) 4-[5-(3-chlorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (55) 4-[5-(benzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 20 dioxobutyric acid, (56) 4-[5-(3-chlorobenzyl)-l1-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4 dioxobutyric acid, (57) 4-[5-(4-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 25 (58) 4-[5-(3-chlorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, (59) 4-[5-(benzyl)-l1-methyl-iH -pyrrol-3-yl]-2,4-dioxobutyric acid, (60) 4-[5-(3-fluorobenzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, 30 (61) 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid, (62) 4 -[2,5-bis-(3-chlorobenzyl)-l1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (63) 4-[ 1-(4-Fluorobenzyl)-5-phenyl- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, - 277 - WO 99/62513 PCT/US99/12095 (64) 4-[4-Dimethylamino-l1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (65) 4-[ 1-(4-Fluorobenzyl)-4-nitro- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, 5 (66) 4-[4-(Benzylamino)- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (67) 4-[5-Nitro- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric (68) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, 10 (70) 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (71) 4-[ 1-(4-fluorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, (72) 4-[2,4-dimethyl- 1-(4-fluorobenzyl)- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, 15 (73) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (74) 4-[1-(3-chlorobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (75) 4-[1-(4-chlorobenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (76) 4-[1-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 20 (77) 4-[1-(3,4-dichlorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (78) 4-[1-(2-methylbenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (79) 4-[ 1-(3-chlorobenzyl)-4-methyl- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, 25 (80) 4-[ 1-(3-trifluoromethylbenzyl)- 1H-pyrrol-3-yl]-2,4 dioxobutyric acid, (81) 4-[1-(4-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[1-(4-methoxybenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) 4-[1-(3-methylbenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, 30 (84) 4-{ 1-[3-(4-fluorophenyl)-propyl]- 1H-pyrrol-3-yl}-2,4 dioxobutyric acid, (85) 4-[1-(4-bromobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(4-chlorobenzyl)-l1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (87) 4-[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 35 2,4-dioxobutyric acid, - 278 - WO 99/62513 PCT/US99/12095 (88) 4-[4-Phenyl- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (89) 4-[ 1-( 4 -fluorobenzyl)-4-methanesulfonylamino- 1H-pyrrol-3 yl]-2,4-dioxo-butyric acid, 5 (90) 4- [ 1-(4-Fluorobenzyl)-3-acetylamino- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (91) 4-[4-acetylamino-l1-(4-fluorobenzyl)-l1H-pyrrol-2-yl] -2,4 dioxobutyric acid, (93) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, 10 (94) 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid, (96) 4-[4-Dimethylamino-l1-(4-fluorobenzyl)-1H-pyrrol-3-yl] -2,4 dioxobutyric acid, 15 (97) 4-[ 1-(4-Fluorobenzyl)-5-methyl- 1H-pyrazol-4-yl]-2-hydroxy-4 oxobut-2-enoic acid, (98) 4 -[ 2 -( 4 -fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid, (99) 1-[ 1-(4-fluorobenzyl)-3-methyl- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid, 20 (100) 4-[3 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 dioxobutyric acid, (101) 4-[5 -methyl-l-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4 dioxobutyric acid, (102) 4-[5 -methyl- 1-(3-chlorobenzyl)- 1H-pyrazol-4-yl]-2,4 25 dioxobutyric acid, (103) 4-[ 1-(4-fluoro-benzyl)- 1H-imidazol-2-yl]-2,4-dioxo-butyric acid, (104) 4-[1-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid, (105) 4-(1-Benzyl-l1H-imidazol-2-yl)-2,4-dioxobutyric acid, 30 (106) 4-[1-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid, (107) 4-[1-(4-fluorobenzyl)- 1H -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)-l1H-indol-3-yl]-2,4-dioxobutyric acid, 35 ethyl ester, -279- WO 99/62513 PCT/US99/12095 (111) 1-[ 1-(4-fluorobenzyl)- 1H-indol-3-yl]-2,4-dioxobutyric acid,(112) 4-[ 1-(3-fluorobenzyl)-1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, (113) 4 -[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, 5 (114) 4-[4-(4-fluorobenzyl)-l1-methyl-l1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (115) 4-[2,5-dimethyl- 1-(4-fluorobenzyl)- 1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (116) 4-[1-(3,5-dichlorobenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric 10 acid, (117) 4-[ 1-(3-thiophenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (118) 4 -[1- 2 , 4 -dimethylbenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, 15 (119) 4 -[1-(3-chloro-5-methyl-benzyl)-l1-H-pyrrol-3-yl]-2,4-dioxo butyric acid, (120) 4-[ 1-(1-naphthalenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (121) 4-[1-(2-thiophenemethyl)- 1-H-pyrrole-3-yl]-2,4-dioxobutyric 20 acid, and (122) 4 -[4-(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof. 25
22. The compound according to Claim 21 selected from: (1) 4 -[1-(2-thiophenemethyl)- 1-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and (2) 4-[4-(3-chlorobenzyl)- 1-methyl- 1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, 30 (3) 4 -[1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (4) 4-[5-(3-chlorobenzyl)- 1-methyl-l1H -pyrrol-2-yl]-2,4 dioxobutyric acid, (5) 4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (6) 4 -[5-(4-fluorobenzyl)- 1-methyl- 1H -pyrrol-3-yl]-2,4 35 dioxobutyric acid, - 280 - WO 99/62513 PCT/US99/12095 (7) 4-[5-(3-chlorobenzyl)- 1-methyl-lH -pyrrol-3-yl]-2,4 dioxobutyric acid, (8) 4-[5-(benzyl)-l1-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid, (9) 4-[5-(3-fluorobenzyl)- 1-methyl- 1H -pyrrol-3-yl]-2,4 5 dioxobutyric acid, (10) 4-[4-Dimethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (11) 4-[1-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (12) 4-[1-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, 10 (13) 4-[1-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4 dioxobutyric acid, (14) 4-[ 1-(3,4-difluorobenzyl)- 1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (15) 4 -[1-( 3 -chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, 15 (16) 4-[1-(2-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (17) 4-[1-(3-methylbenzyl)-l1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (18) 4-[4-Benzylmethylamino- 1-(4-fluorobenzyl)- 1H-pyrrol-2-yl] 2,4-dioxobutyric acid, (19) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, 20 (20) 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (21) 4-[ 1-(3-fluorobenzyl)- 1-H-pyrrol-3-yl]-2,4 dioxobutyric acid, (22) 4-[4-(3-chlorobenzyl)-l1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (23) 4-[4-(4-fluorobenzyl)-l1-methyl-l1-H-pyrrol-3-yl] -2,4-dioxo 25 butyric acid, (24) 4-[2,5-dimethyl-l1-(4-fluorobenzyl)-l1-H-pyrrol-3-yl] -2,4-dioxo butyric acid, (25) 4-[ 1-(3,5-dichlorobenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, 30 (26) 4- [ 1-(3-thiophenemethyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (27) 4-[1-2,4-dimethylbenzyl)- 1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (28) 4 -[1-(3-chloro-5-methyl-benzyl)- 1-H-pyrrol-3-yl]-2,4-dioxo 35 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. 5
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 10 for treating infection by HIV, or for treating AIDS or ARC.
25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a therapeutically effective amount of an AIDS 15 treatment agent selected from (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator. 20
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 25 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 30 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. 35 -282- WO 99/62513 PCT/US99/12095
30. 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. 5
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. - 283 -
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8784598P | 1998-06-03 | 1998-06-03 | |
| US60/087845 | 1998-06-03 | ||
| GB9814930 | 1998-07-09 | ||
| GBGB9814930.5A GB9814930D0 (en) | 1998-07-09 | 1998-07-09 | HIV integrase inhibitors |
| PCT/US1999/012095 WO1999062513A1 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU4225699A true AU4225699A (en) | 1999-12-20 |
| AU756826B2 AU756826B2 (en) | 2003-01-23 |
| AU756826C AU756826C (en) | 2003-08-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU42256/99A Ceased AU756826C (en) | 1998-06-03 | 1999-06-01 | HIV integrase inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1083897A4 (en) |
| JP (1) | JP2002516858A (en) |
| AU (1) | AU756826C (en) |
| CA (1) | CA2329134A1 (en) |
| WO (1) | WO1999062513A1 (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL343249A1 (en) | 1998-03-26 | 2001-07-30 | Shionogi & Co | Indole derivatives with antiviral activity |
| 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 |
| DE69939749D1 (en) | 1998-12-25 | 2008-11-27 | Shionogi & Co | AROMATIC HETEROCYCLES WITH HIV INTEGRASE INHIBITING PROPERTIES |
| EP1196384A4 (en) * | 1999-06-25 | 2002-10-23 | Merck & Co Inc | 1-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof |
| ATE411292T1 (en) | 2001-03-01 | 2008-10-15 | Shionogi & Co | NITROGEN-CONTAINING HETEROARYL COMPOUNDS WITH HIV INTEGRASE INHIBITING EFFECT |
| EP3042894A1 (en) | 2001-08-10 | 2016-07-13 | Shionogi & Co., Ltd. | Antiviral agent |
| US7323460B2 (en) | 2002-03-15 | 2008-01-29 | Merck & Co., Inc. | N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors |
| US7358249B2 (en) | 2002-08-13 | 2008-04-15 | Shionogi & Co., Ltd. | Heterocyclic compounds having inhibitory activity against HIV integrase |
| AU2003301439A1 (en) | 2002-10-16 | 2004-05-04 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
| CA2537325A1 (en) | 2003-09-19 | 2005-03-31 | Gilead Sciences, Inc. | Aza-quinolinol phosphonate integrase inhibitor compounds |
| DE602005023717D1 (en) * | 2004-03-10 | 2010-11-04 | Usa | CHINOLIN-4-ONE AS INHIBITORS OF THE RETROVIRAL INTEGRASE FOR THE TREATMENT OF HIV, AIDS AND AIDS-RELATED COMPLEX (ARC) |
| 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 |
| CA2657034A1 (en) | 2006-07-19 | 2008-01-24 | University Of Georgia Research Foundation, Inc. | Pyridinone diketo acids: inhibitors of hiv replication in combination therapy |
| 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 |
| US8703801B2 (en) | 2009-12-07 | 2014-04-22 | University Of Georgia Research Foundation, Inc. | Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications |
| US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
| 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 |
| KR20220100607A (en) * | 2019-10-28 | 2022-07-15 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | 5-membered heterocyclic oxocarboxylic acid compound and its medicinal use |
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 |
| WO1998018473A1 (en) * | 1996-10-31 | 1998-05-07 | 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 EP EP99926096A patent/EP1083897A4/en not_active Withdrawn
- 1999-06-01 JP JP2000551769A patent/JP2002516858A/en not_active Withdrawn
- 1999-06-01 CA CA002329134A patent/CA2329134A1/en not_active Abandoned
- 1999-06-01 AU AU42256/99A patent/AU756826C/en not_active Ceased
Also Published As
| Publication number | Publication date |
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| AU756826B2 (en) | 2003-01-23 |
| EP1083897A1 (en) | 2001-03-21 |
| EP1083897A4 (en) | 2003-01-02 |
| CA2329134A1 (en) | 1999-12-09 |
| WO1999062513A1 (en) | 1999-12-09 |
| AU756826C (en) | 2003-08-21 |
| JP2002516858A (en) | 2002-06-11 |
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