CA2329134A1 - Hiv integrase inhibitors - Google Patents
Hiv integrase inhibitors Download PDFInfo
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- CA2329134A1 CA2329134A1 CA002329134A CA2329134A CA2329134A1 CA 2329134 A1 CA2329134 A1 CA 2329134A1 CA 002329134 A CA002329134 A CA 002329134A CA 2329134 A CA2329134 A CA 2329134A CA 2329134 A1 CA2329134 A1 CA 2329134A1
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- alkyl
- pyrrol
- substituted
- dioxobutyric acid
- independently selected
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- MITHGUSEVJOZDH-UHFFFAOYSA-N CC(c1c[nH]nc1C)=O Chemical compound CC(c1c[nH]nc1C)=O MITHGUSEVJOZDH-UHFFFAOYSA-N 0.000 description 1
- GOJKMRXGLNNGSQ-UHFFFAOYSA-N Cc1n[n](Cc(cc2)ccc2F)cc1C(CC(C(O)=O)=O)=O Chemical compound Cc1n[n](Cc(cc2)ccc2F)cc1C(CC(C(O)=O)=O)=O GOJKMRXGLNNGSQ-UHFFFAOYSA-N 0.000 description 1
- LZIYAIRGDHSVED-UHFFFAOYSA-N Clc1cccc(CBr)c1 Chemical compound Clc1cccc(CBr)c1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Nitrogen-containing heteroaryl dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
Description
TITLE OF THE INVENTION
HIV INTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority of U.S. provisional application Serial No. 60/087,845, filed June 3, 1998.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS> and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three stepsa assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 35I (1987)].
All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV
replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV
infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents &
Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983 ) disclose 2,4-dioxo-4-substituted-1-butanoic ac,~id derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994).
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.
SUMMARY OF THE INVENTION
HIV INTEGRASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority of U.S. provisional application Serial No. 60/087,845, filed June 3, 1998.
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS> and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three stepsa assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV
protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 35I (1987)].
All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV
replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV
infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186-1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents &
Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983 ) disclose 2,4-dioxo-4-substituted-1-butanoic ac,~id derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4-dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994).
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.
SUMMARY OF THE INVENTION
Compounds of formula I, as herein defined, are disclosed.
These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV' and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
R~
~ O
R z~
\OR7 and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R1 ,R2 and R8; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
Rl is selected from:
(1) -H, (2> -C1-~ alkyl, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4)(R5), (7) -R6, (8) -C2-5 alkenyl-R3, (9) -C2_5 alkynyl-R3, (10) -O-R6, (11) -O-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7;
R2 is select ed from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-g alkyl substituted with R3, (5) -O-R6, (6 ) -O-C 1-6 alkyl-OR6 , (7) -S(O)n-R6, (8) -C 1-6 alkyl (OR6 )(R4 ) , (9) -C1-g alkyl-N(R4)(R6) , (10) -Cl-g alkyl S(O)n-R6, (11) -C1-g alkyl C(O)-R6, (12) -Cl-6 alkyl C(S)-R6, (13) -C1-g alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, -OCF3, (g> -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i> halogen, (ii) C~_g alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) CZ_6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f7 -CN, (g) -O, (h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, ( c ) C 1-g alkyl, (d) C~l_6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or f membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C~-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C~-6 alkyl, (c) C1-6 alkyloxy-, (d) -CFA, (e) -OCF3, (f) -CN, (g> =O, (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 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) Cl-g alkyl, (c) Cl-6 alkyloxy-, (d) -CF3, (e) -~CF3, (f) -CN, (g) -O, (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3 > -CF3 , (4) -R3, (5) -C2_3 alkenyl, (6 ) -C 1-3 alkyl-R3 , (7) -C2-3 alkenyl-R~, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R~ is independently selected from:
(1) -H, (2) -C1_3 alkyl, (3 ) -CF3 , (4) -R3 , (5) -C2-3 alkenyl, (6 ) -C 1_3 alkyl-R3 , (7) -C2_3 alkenyl-R'~, (8) -S(O)n-R3, and (9) -C(O)-R3;
each Rs is independently selected from:
( 1 ) -C 1-3 alkyl-R3 , and (2> -R3;
R7 is selected from:
( 1 ) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H, (2) C1_6 alkyl-oxy, and (3) C1-6 alkyl; and each n is independently selected from 0, 1 and 2.
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-[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, (6) 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester, (7) 4-[1-(4-fluorobenzyl)-1H-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-1H-pyrrol-2-yl)-2,4-dioxobutyric acid,(10) 4-(1-biphenyl-4-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (11) 4-(1-naphthalen-1-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, ( 12 > 2,4-dioxo-4-[ 1-(4-phenylbutyl )- IH-pyrrol -2-yl]-butyric acid, (13) 4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (14) 2,4-dioxo-4-(I-phenethyl-1H-pyrrol -2-yl)-butyric acid, (15) 4-[1-(2-methylbenzyl>-IH-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[1-(3,4-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutrvric acid, ( 17 ) 4-[ 1-(4-bromobenzyl )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (18> 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (19) 4-[I-(3-bromobenzyl>-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (20) 4-[1-(3-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (21) 4-[1-(3-methylbenzyl)-1~~-pyrrol-2-yl]-2,4-dioxobutyric acid, (22) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (23) 2,4-dioxo-4-(1-hexyl-1.H-pyrrol -2-yl)-butyric acid, (24) 4-(1-biphenyl-2-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (25) 2,4-dioxo-4-[1-(4-phenoxybutyl)-lIl -pyrrol-2-yl]-butyric acid, (26) 4-[I-(3-fluorobenzyl)-1H-pyrrol-2-yI]-2,4-dioxobutyric acid, (27) 4-[1-(2-chlorobenzyl)-IH-pyrrol-2-yl]-2,4-dioxobutyric acid,(28) 4-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (29) 4-[1-(4-methoxybenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (30) 4-[I-(2,4,5-trifluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (31) 4-[1-(2,3-difluorobenzyl)-IH-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 acid, (35) 4-[1-(2-fluorobenzyl)-1H-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)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (38) 4-[1-(3-methoxybenzyl)-lIl -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-2-yl ) -2,4-dioxobutyric acid, (41) 4-{1-[3-(4-fluorophenyl)prc>pyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid, (42> 4-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrrol-2-yl}-2,4-dioxobutyric acid, (43) 4-[1-(3-phenylpropyl)-1H-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)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (47) 4-[1-(3-benzoylarninopropyl)-1H-pyrrol-3-yl]
-2,4-dioxobutyric acid, (48) 4-{1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}]
-2,4-dioxobutyric acid, (49) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester (50) 4-(1-cyclohexylmethyl-1-Fi~ -pyrrol-2-yl)-2,4-dioxo-butyric aCld, (51) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl-2,4-dioxobutyric acid ethyl ester, (52) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4-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, (55) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (57) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (58) 4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobut-ic acid, (59) 4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobuty-ic acid, (60) 4-[5-(benzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid.
(61) 4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (62) 4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (64) 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutvric acid, (65) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (66) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (67) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (68) 4-[5-(benzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (70) 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4-[2,5-bis-(3-chlorobenzyl)-1-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, (73) 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (74) 4-[4-Dimethylamino-1-(4-fiuorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (75) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (76) 4-[1-(4-Fluorobenzyl)-4-vitro-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (78) 4-[5-Nitro-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric (79) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester, (80) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[1-(4-fluorobenzyl)-1H-pvrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutvric 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, (85) 4-[1-(3,4-difluorobenzyl)-11~-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(3-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 4-[1-(4-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[1-(4-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (89) 4-[1-(3,4-dichlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (90) 4-[1-(2-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(91) 4-[1-(3-chlorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (92) 4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (93) 4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(3-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(96) 4-(1-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-yl}-2,4-dioxobutyric acid, (97) 4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl)-2,4-dioxobutyric acid, (98) 4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (99) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-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, (102) 4-[4-Phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (103) 4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pvrrol-3-yl]-2,4-dioxo-butyric acid ethyl ester, (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-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]
-2,4-dioxobutyric acid, ( 108 ) 4-[4-( 4-fluorobenzyl )- 1H -pyrrol-3-yl]-2,4-dioxobutvric 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-pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-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 ethyl ester, (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, (119) 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (120) 4-[3 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (121) 4-[5 -methyl-l-(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, (123) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (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-ixnidazol-2-yl]-2,4-dioxo-butyric acid, (127) 4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4-[1-(4-fluorobenzyl>-1H-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)- lIl -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, (133) 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid, (134) 1-[1-(4-fluorobenzyl)-1H-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-dioxobutyric acid, (137) 4-[4-(3-chlorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (138) 4-[4-(4-fluorobenzyl)-1-methyl-1-H-pyrrol-3-yl]
-2,4-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)-1-H-pyrrol-3-yl]-2,4-dioxobutyric 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, (143) 4-[l-(3-chloro-5-methyl-benzyl>-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (14~) 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-yl]-2,4-dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention are compounds of structural formula:
R~
~I-~ Ra O
N ~ ~ ~OR~
Another embodiment of the present invention are compounds of structural formula:
R~
O
N ~ ~ ~OH
Still another embodiment of the present invention are compounds of structural formula:
Rg O
R~~~
~ ~'~~oR' O O
R z Another embodiment of the present invention are compounds of structural formula:
RB O
R~~ ~ OH
O O
Another embodiment of the present invention are compounds of structural formula:
O O
ORS
R~\ v ,N O
N
Another embodiment of the present invention are compounds of structural formula:
O O
N.N~ O
~2 R
Another embodiment of the present invention are compounds of structural formula:
R~. N O
N'~ O H
Another embodiment of the present invention are compounds of structural formula:
/ O
II !I \OH
Rz O O
In one class of compounds of the present invention, A is selected from:
(1) pyrrolyl, (2) imidazolyl, (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I).
In another class of compounds of the present invention, A is pyrazolyl.
In yet another class of compounds of the present invention, A is imidazolyl.
In still another class of compounds of the present invention, A is pyrrolyl.
In another class of compounds of the present invention, A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indole.
In one class of compounds of the present invention, R1 is selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4)(R5), ('7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halogen, (b) Cl_~ alkyl, (c) C1_6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, ( iii ) -CF3 , and (iv) hydroxy, (9) phenyl Cl_3 alkyl-, (10) subs tituted phenyl C1_3 alkyl- substituted With 1 or 2 subs tituents independently selected from:
(a) halogen, (b) (~1_6 alkyl, (c) Cl_6 alkyloxy-, (d) phenyl, (e) -CF3, (f7 -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF.~, and (iv) hydroxy, (11) -C2-5 alkenyl-R3, (12) -C2-J alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7.
In another class of compounds of the present invention, R1 is selected from:
(1) -H, (2 ) -CHI , (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4 )(R~), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
ta> halo, (b) methyl, and ( c) methoxy, (9) phenyl C1_3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, and (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, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4 )(R'5 ) >
(7) -phenyl, (8) substituted phenyl substituted with 1 substituent independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl Cl-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) rnethoxy, ( 11 ) -C2-5 alkenyl-R3 , and (12) -C(O)CH2C(O)C(O)OR7 In yet another class of compounds of the present invention, R~- is selected from:
(1) -H, (2) -C1_5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02, (6) -N(R4)(R5) , (7) -phenyl, (8) phenyl C1-3 alkyl-, (9) substituted phenyl Cl_3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br;
(10) -C2-5 alkynyl-R3, and (11) -C(O)CH2C(O)C(0>OR7 In another class of compounds of the present invention, R1 is selected from:
(1) -H, - 2(l -(2) -C1_5 alkyl, (3 ) -CF3 , (4) -halo, wherein halo is selected from: -F, C1, -Br, and -I;
(5) -N02, (6> -N(R4 >(R5 ), (7) -phenyl, (8) phenyl Cl_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, and ( 10) -C2_~ alkynyl-R3 .
In one class of compounds of the present invention, R2 is selected from:
(1) -H, (2 ) -R3 , (3) -C1_6 alkyl, (4) -C1-6 alkyl substituted with R3 , (5) -O-R6, (fi) -O-Cl-~ alkyl-OR6, (7) -S(O >n-R6, (8) -C1-6 alkyl (OR6)(R4) , (9) -C1_g alkyl-N(R4)(R6) , (10) -C1-6 alkyl S(O)n-R6, (11) -Cl-g alkyl C(O)-R6, (12) -C1_6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1_6 alkyl-C(O)N(R4)(R5).
In another class of compounds of the present invention, R2 is selected from:
(1) -H, (2) -R3, (3) -C1_6 alkyl, (4) -Cl_~ alkyl substituted with R3, (5) -O-R6, (6) -O-C1_6 alkyl-OR6, (7) -S(O)n-R6, (8) -Cl_6 alkyl (OR6 )(R4 ) , (9) -Cl_6 alkyl-N(R4)(R6) , (10) -Cl_6 alkyl S(O>n-R~, (11) -Cl_6 alkyl NR4C(0)-R6, and (12) -C1_6 alkyl-C(O)N(R4 )(R5 i.
In yet another class of compounds of the present invention, R2 is selected from:
(1) -H, (2) -R3, (3 ) -C 1_g alkyl, (4) -C1_6 alkyl substituted with R3, (5> -O-R6, (6) -O-Cl_6 alkyl-OR6, (7) -C1_6 alkyl (OR6)(R4) , (8 ) -C 1_g alkyl-N(R4 )(R6 ) , (9) -C1_6 alkyl C(O)-R6, (10) -C1_6 alkyl NR4C(O)-R~, and (11) -C1_6 alkyl-C(O)N(R4)(R~).
In still another class of compounds of the present invention, R2 is select ed from:
(1) -H, (2) -R3, (3) -Cl_6 alkyl, (4) -C1_6 alkyl substituted with R3, (5) -O-R6>
(6) -O-C1_6 alkyl-OR6, (7 ) -C 1_& alkyl (OR6 )(R4 > , (8) -Cl_g alkyl-N(R4)(R6) , (9) -C1_6 alkyl C(O)-R6, and (10) -C1_g alkyl NR4C(O)-R6.
In one class of compounds of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with l, 2, or 3 substituents independently selected from:
(a) halogen, ~~1-6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i ) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) Cl_6 alkyl, (iii ) -CF3 , and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF~, (g) -CN, (h) hydroxy, (i ) phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1~ alkyl, (iii ) -CF3, arid (iv> hydroxy;
(5) pyridyl;
(6 ) subs tituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii ) -CF3 , and (iv) hydroxy;
(7) imidazolyl;
($) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1_6 alkyl, ( c ) C1_fi alkyloxy-, (d) phenyl, (e) -CFA, (f7 -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, ( ii ) C 1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrr olyl;
(10) subs tituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C~_6 alkyl, ( c ) C 1-6 alkyloxy-, (d) phenyl, (e) -CF3, (fl -OCF3, (g) -CN, (h) bydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected fram:
(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, (c) C1_6 alkyloxy-, (d) phenyl, (e) -CF3, (f7 -OCF3, (g) _CN, (h) hydroxy, (i ) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_s alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3_6 cycloalkyl;
(14) substituted C3_6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1_g alkyl, (c) Cl_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy;
(I5) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, ( c ) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) -0, (h) hydroxy;
These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV' and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
This invention is concerned with compounds of formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV integrase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). Compounds of formula I are defined as follows:
R~
~ O
R z~
\OR7 and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R1 ,R2 and R8; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
Rl is selected from:
(1) -H, (2> -C1-~ alkyl, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4)(R5), (7) -R6, (8) -C2-5 alkenyl-R3, (9) -C2_5 alkynyl-R3, (10) -O-R6, (11) -O-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7;
R2 is select ed from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-g alkyl substituted with R3, (5) -O-R6, (6 ) -O-C 1-6 alkyl-OR6 , (7) -S(O)n-R6, (8) -C 1-6 alkyl (OR6 )(R4 ) , (9) -C1-g alkyl-N(R4)(R6) , (10) -Cl-g alkyl S(O)n-R6, (11) -C1-g alkyl C(O)-R6, (12) -Cl-6 alkyl C(S)-R6, (13) -C1-g alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, -OCF3, (g> -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i> halogen, (ii) C~_g alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) CZ_6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f7 -CN, (g) -O, (h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, ( c ) C 1-g alkyl, (d) C~l_6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or f membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C~-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C~-6 alkyl, (c) C1-6 alkyloxy-, (d) -CFA, (e) -OCF3, (f) -CN, (g> =O, (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 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) Cl-g alkyl, (c) Cl-6 alkyloxy-, (d) -CF3, (e) -~CF3, (f) -CN, (g) -O, (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3 > -CF3 , (4) -R3, (5) -C2_3 alkenyl, (6 ) -C 1-3 alkyl-R3 , (7) -C2-3 alkenyl-R~, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R~ is independently selected from:
(1) -H, (2) -C1_3 alkyl, (3 ) -CF3 , (4) -R3 , (5) -C2-3 alkenyl, (6 ) -C 1_3 alkyl-R3 , (7) -C2_3 alkenyl-R'~, (8) -S(O)n-R3, and (9) -C(O)-R3;
each Rs is independently selected from:
( 1 ) -C 1-3 alkyl-R3 , and (2> -R3;
R7 is selected from:
( 1 ) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H, (2) C1_6 alkyl-oxy, and (3) C1-6 alkyl; and each n is independently selected from 0, 1 and 2.
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-[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, (6) 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester, (7) 4-[1-(4-fluorobenzyl)-1H-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-1H-pyrrol-2-yl)-2,4-dioxobutyric acid,(10) 4-(1-biphenyl-4-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (11) 4-(1-naphthalen-1-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, ( 12 > 2,4-dioxo-4-[ 1-(4-phenylbutyl )- IH-pyrrol -2-yl]-butyric acid, (13) 4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (14) 2,4-dioxo-4-(I-phenethyl-1H-pyrrol -2-yl)-butyric acid, (15) 4-[1-(2-methylbenzyl>-IH-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[1-(3,4-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutrvric acid, ( 17 ) 4-[ 1-(4-bromobenzyl )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (18> 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (19) 4-[I-(3-bromobenzyl>-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (20) 4-[1-(3-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (21) 4-[1-(3-methylbenzyl)-1~~-pyrrol-2-yl]-2,4-dioxobutyric acid, (22) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (23) 2,4-dioxo-4-(1-hexyl-1.H-pyrrol -2-yl)-butyric acid, (24) 4-(1-biphenyl-2-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid, (25) 2,4-dioxo-4-[1-(4-phenoxybutyl)-lIl -pyrrol-2-yl]-butyric acid, (26) 4-[I-(3-fluorobenzyl)-1H-pyrrol-2-yI]-2,4-dioxobutyric acid, (27) 4-[1-(2-chlorobenzyl)-IH-pyrrol-2-yl]-2,4-dioxobutyric acid,(28) 4-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (29) 4-[1-(4-methoxybenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (30) 4-[I-(2,4,5-trifluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (31) 4-[1-(2,3-difluorobenzyl)-IH-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 acid, (35) 4-[1-(2-fluorobenzyl)-1H-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)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (38) 4-[1-(3-methoxybenzyl)-lIl -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-2-yl ) -2,4-dioxobutyric acid, (41) 4-{1-[3-(4-fluorophenyl)prc>pyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid, (42> 4-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrrol-2-yl}-2,4-dioxobutyric acid, (43) 4-[1-(3-phenylpropyl)-1H-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)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (47) 4-[1-(3-benzoylarninopropyl)-1H-pyrrol-3-yl]
-2,4-dioxobutyric acid, (48) 4-{1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}]
-2,4-dioxobutyric acid, (49) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester (50) 4-(1-cyclohexylmethyl-1-Fi~ -pyrrol-2-yl)-2,4-dioxo-butyric aCld, (51) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl-2,4-dioxobutyric acid ethyl ester, (52) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4-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, (55) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (57) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (58) 4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobut-ic acid, (59) 4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobuty-ic acid, (60) 4-[5-(benzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid.
(61) 4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (62) 4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (64) 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutvric acid, (65) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (66) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (67) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (68) 4-[5-(benzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (70) 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4-[2,5-bis-(3-chlorobenzyl)-1-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, (73) 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (74) 4-[4-Dimethylamino-1-(4-fiuorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (75) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (76) 4-[1-(4-Fluorobenzyl)-4-vitro-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (78) 4-[5-Nitro-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric (79) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester, (80) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[1-(4-fluorobenzyl)-1H-pvrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutvric 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, (85) 4-[1-(3,4-difluorobenzyl)-11~-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(3-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 4-[1-(4-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[1-(4-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (89) 4-[1-(3,4-dichlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (90) 4-[1-(2-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(91) 4-[1-(3-chlorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (92) 4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (93) 4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(3-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(96) 4-(1-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-yl}-2,4-dioxobutyric acid, (97) 4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl)-2,4-dioxobutyric acid, (98) 4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-yl] -2,4-dioxobutyric acid, (99) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-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, (102) 4-[4-Phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4 dioxobutyric acid, (103) 4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pvrrol-3-yl]-2,4-dioxo-butyric acid ethyl ester, (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-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]
-2,4-dioxobutyric acid, ( 108 ) 4-[4-( 4-fluorobenzyl )- 1H -pyrrol-3-yl]-2,4-dioxobutvric 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-pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-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 ethyl ester, (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, (119) 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (120) 4-[3 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (121) 4-[5 -methyl-l-(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, (123) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (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-ixnidazol-2-yl]-2,4-dioxo-butyric acid, (127) 4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4-[1-(4-fluorobenzyl>-1H-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)- lIl -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, (133) 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid, (134) 1-[1-(4-fluorobenzyl)-1H-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-dioxobutyric acid, (137) 4-[4-(3-chlorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (138) 4-[4-(4-fluorobenzyl)-1-methyl-1-H-pyrrol-3-yl]
-2,4-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)-1-H-pyrrol-3-yl]-2,4-dioxobutyric 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, (143) 4-[l-(3-chloro-5-methyl-benzyl>-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (14~) 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-yl]-2,4-dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof.
One embodiment of the present invention are compounds of structural formula:
R~
~I-~ Ra O
N ~ ~ ~OR~
Another embodiment of the present invention are compounds of structural formula:
R~
O
N ~ ~ ~OH
Still another embodiment of the present invention are compounds of structural formula:
Rg O
R~~~
~ ~'~~oR' O O
R z Another embodiment of the present invention are compounds of structural formula:
RB O
R~~ ~ OH
O O
Another embodiment of the present invention are compounds of structural formula:
O O
ORS
R~\ v ,N O
N
Another embodiment of the present invention are compounds of structural formula:
O O
N.N~ O
~2 R
Another embodiment of the present invention are compounds of structural formula:
R~. N O
N'~ O H
Another embodiment of the present invention are compounds of structural formula:
/ O
II !I \OH
Rz O O
In one class of compounds of the present invention, A is selected from:
(1) pyrrolyl, (2) imidazolyl, (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I).
In another class of compounds of the present invention, A is pyrazolyl.
In yet another class of compounds of the present invention, A is imidazolyl.
In still another class of compounds of the present invention, A is pyrrolyl.
In another class of compounds of the present invention, A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indole.
In one class of compounds of the present invention, R1 is selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4)(R5), ('7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halogen, (b) Cl_~ alkyl, (c) C1_6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, ( iii ) -CF3 , and (iv) hydroxy, (9) phenyl Cl_3 alkyl-, (10) subs tituted phenyl C1_3 alkyl- substituted With 1 or 2 subs tituents independently selected from:
(a) halogen, (b) (~1_6 alkyl, (c) Cl_6 alkyloxy-, (d) phenyl, (e) -CF3, (f7 -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF.~, and (iv) hydroxy, (11) -C2-5 alkenyl-R3, (12) -C2-J alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7.
In another class of compounds of the present invention, R1 is selected from:
(1) -H, (2 ) -CHI , (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4 )(R~), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
ta> halo, (b) methyl, and ( c) methoxy, (9) phenyl C1_3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, and (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, (3) -CF3, (4) -halo, (5) -N02, (6) -N(R4 )(R'5 ) >
(7) -phenyl, (8) substituted phenyl substituted with 1 substituent independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl Cl-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) rnethoxy, ( 11 ) -C2-5 alkenyl-R3 , and (12) -C(O)CH2C(O)C(O)OR7 In yet another class of compounds of the present invention, R~- is selected from:
(1) -H, (2) -C1_5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02, (6) -N(R4)(R5) , (7) -phenyl, (8) phenyl C1-3 alkyl-, (9) substituted phenyl Cl_3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br;
(10) -C2-5 alkynyl-R3, and (11) -C(O)CH2C(O)C(0>OR7 In another class of compounds of the present invention, R1 is selected from:
(1) -H, - 2(l -(2) -C1_5 alkyl, (3 ) -CF3 , (4) -halo, wherein halo is selected from: -F, C1, -Br, and -I;
(5) -N02, (6> -N(R4 >(R5 ), (7) -phenyl, (8) phenyl Cl_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, and ( 10) -C2_~ alkynyl-R3 .
In one class of compounds of the present invention, R2 is selected from:
(1) -H, (2 ) -R3 , (3) -C1_6 alkyl, (4) -C1-6 alkyl substituted with R3 , (5) -O-R6, (fi) -O-Cl-~ alkyl-OR6, (7) -S(O >n-R6, (8) -C1-6 alkyl (OR6)(R4) , (9) -C1_g alkyl-N(R4)(R6) , (10) -C1-6 alkyl S(O)n-R6, (11) -Cl-g alkyl C(O)-R6, (12) -C1_6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1_6 alkyl-C(O)N(R4)(R5).
In another class of compounds of the present invention, R2 is selected from:
(1) -H, (2) -R3, (3) -C1_6 alkyl, (4) -Cl_~ alkyl substituted with R3, (5) -O-R6, (6) -O-C1_6 alkyl-OR6, (7) -S(O)n-R6, (8) -Cl_6 alkyl (OR6 )(R4 ) , (9) -Cl_6 alkyl-N(R4)(R6) , (10) -Cl_6 alkyl S(O>n-R~, (11) -Cl_6 alkyl NR4C(0)-R6, and (12) -C1_6 alkyl-C(O)N(R4 )(R5 i.
In yet another class of compounds of the present invention, R2 is selected from:
(1) -H, (2) -R3, (3 ) -C 1_g alkyl, (4) -C1_6 alkyl substituted with R3, (5> -O-R6, (6) -O-Cl_6 alkyl-OR6, (7) -C1_6 alkyl (OR6)(R4) , (8 ) -C 1_g alkyl-N(R4 )(R6 ) , (9) -C1_6 alkyl C(O)-R6, (10) -C1_6 alkyl NR4C(O)-R~, and (11) -C1_6 alkyl-C(O)N(R4)(R~).
In still another class of compounds of the present invention, R2 is select ed from:
(1) -H, (2) -R3, (3) -Cl_6 alkyl, (4) -C1_6 alkyl substituted with R3, (5) -O-R6>
(6) -O-C1_6 alkyl-OR6, (7 ) -C 1_& alkyl (OR6 )(R4 > , (8) -Cl_g alkyl-N(R4)(R6) , (9) -C1_6 alkyl C(O)-R6, and (10) -C1_g alkyl NR4C(O)-R6.
In one class of compounds of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with l, 2, or 3 substituents independently selected from:
(a) halogen, ~~1-6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i ) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) Cl_6 alkyl, (iii ) -CF3 , and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF~, (g) -CN, (h) hydroxy, (i ) phenyloxy, and substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1~ alkyl, (iii ) -CF3, arid (iv> hydroxy;
(5) pyridyl;
(6 ) subs tituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) Cl-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii ) -CF3 , and (iv) hydroxy;
(7) imidazolyl;
($) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1_6 alkyl, ( c ) C1_fi alkyloxy-, (d) phenyl, (e) -CFA, (f7 -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j ) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, ( ii ) C 1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrr olyl;
(10) subs tituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C~_6 alkyl, ( c ) C 1-6 alkyloxy-, (d) phenyl, (e) -CF3, (fl -OCF3, (g) -CN, (h) bydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected fram:
(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, (c) C1_6 alkyloxy-, (d) phenyl, (e) -CF3, (f7 -OCF3, (g) _CN, (h) hydroxy, (i ) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_s alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3_6 cycloalkyl;
(14) substituted C3_6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1_g alkyl, (c) Cl_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy;
(I5) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cl_6 alkyl, ( c ) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) -0, (h) hydroxy;
(17) morpholinyl;
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from:
(a) halogen, (b) (;l-g alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy;
(a) halogen, (b) (;l-g alkyl, (c) C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(a) -halogen, (b) -C1-6 alkyl, (c) -C1_6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1_6 alkyl, (c) -Cl-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(a) -halogen, (b) -C1_6 alkyl, (c) -Cl-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b> Cl-~ alkyl, (c> C1_6 alkyloxy-, (d) -CF3, 1~ (e) -OCF3, -CN, (g) =O, and (h) hydroxy.
In another class of compounds of the present invention, R3 is selected from:
( 1 ) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, 2~ (b) C1-6 alkyl, (c) C1-s alkyloxy-, (d) phenyl, (e) -CF3, -OCF3 , (g) _CN, (h) hydroxy, (i) phenyloxy, and _2H_.
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy, (3) thienyl, (4) py~dyl, (5) imidazolyl, (6) pyrrolyl, (7) pyrazolyl, (8) C3_6 cycloalkyl, (9) substituted C3_6 cycloalkyl with 1 or 2 substituents independently selected from:
1~ (a) halogen, (b) Cl_6 alkyl, (c) C1_~ alkyloxy-, (d) -CFg, (e) -OCF3, (f7 -CN, ( g) =O, and (h) hydroxy;
(10) piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and (14) C3_~ cycloalkyl fused with a phenyl ring.
In still another class of compounds of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1_6 alkyl, (c) Cl_6 alkyloxy-, (d) phenyl, (e) -CF3, (I7 -OCF3, (g) -CN, (h) hydroxy, (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, (ii) methyl, (iii ) -CF3 , and (iv) hydroxy;
(3) C3_6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo;
and (6) naphthyl.
In one class of compounds of the present invention, R4 is selected from:
(1) -H, (2) -C1-3 alkyl, and (3) -CF3.
In another class of compounds of the present invention, R4 is selected from:
(1) -H, (2) -Cl_3 alkyl, (3) -CF3, (4) _R3, (5 ) -C2_3 alkenyl, (6) -Ct-3 alkyl-R3, _3O_ (7) -C2-3 alkenyl-R3, (8) -S(O)n-R'~, and (9) -C(O)-R~.
In still another class of compounds of the present invention , R4 is selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CFA, (4) -R3, (5 ) -C 1-~ alkyl-R3 , (6) -S(O)n-R3, and (7) -C(O)-R~.
In yet another class of compounds of the present invention , R4 is selected from:
(1) -H, and (2) -C1-3 alkyl.
In one class of compounds of the present invention, R5 is selected from:
(1) -H, (2) -C1-~ alkyl, (3 > -CF3 , (4) -R3 , (5) -C2-3 alkenyl, -C1-3 ~yl-R3>
(7) -C2-3 alkenyl-R3, (8) -S(O)ri R3, and (9) -C(O)-R'3 _ In another class of compounds of the present invention, is selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, and (4 ) -R3 .
In yet another class of compounds of the present invention, R 5 is selected from:
(1) -H, (2) -C1-3 alkyl, (.3) -CF3, (4) -R3, (5) -C1_3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R~.
In one class of compounds of the present invention, R7 is hydrogen.
In another class of compounds of the present invention, R7 is selected from:
(1) -H, and (2 ) C 1-4 alkyl.
In one class of compounds of the present invention, Rg is selected from:
( 1 ) -H, (2) -OCH3, and (3) -CH3.
In another class of compounds of the present invention, Rg is selected from:
(1) -H, and (2> CHg.
In yet another class of compounds of the present invention, R8 is selected from:
(1) -H, and (2) Cl_g 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/b2513 PCT/US99/12095 pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected fram:
(1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof' in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (Ia) and (Ib):
R O R~ O
R A R
ORS - ~ ORS
(la) R' ~ O
Rz ~~ ~ ~OR~
R$ OH O
(Ib) By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (Ia) and (Ibi are also intended. Similarly, be referring to compound (Ia), it is understood for the purposes of the present application that the tautomers (1) and (Ib) are also intended. The same holds true for references to tautomer (Ib>.
When any variable (e.g., R3, R4, etc. ) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV > and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS
related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
Compounds of structural formula (I) wherein A is pyrrolyl may be made according to the procedures in Schemes AI-AXI.
Compounds of structural formula (I) wherein A is pyrazolyl may be prepared according to the procedures in Schemes BI-BV. Compounds of 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
N
H O
4-fluorobenzyl bromide NaH
DMF
I
~CH3 ~ ~ CH
N NIS N~ ~ 3 A1-1-1 O - O
acetone dimethyl oxalate NaH
DME
heat N~ ~ ~ ~OCH3 AI-2-1 O O
F
ROH ~ NaOH
TsOH THF / MeOH / H20 O
N~ ~ ~ -OH I- -1 O O
F
-3f~-Scheme All / \
N
H
LiHMDS
cyclohexanecarbonyl chloride THF
/ \
N
w ~O
BH3-Me2S
THF
heat / \
N
n -butyllithium THF
N - methoxy-N - methylacetamide N ~ AI- I3-1 O
dimethyl oxalate NaH
DME
heat O
N~ ~ ~ OCH3 A1I-4-1 O O
NaOH
THF / MeOH / H20 O
N~ ~ ~ -OH II- -1 O O
WO 99/b2513 PCT/US99/12095 Scheme AIII
I
/ 1 w N 1~
O
I
F
AI-1-2 I Cul ~~C6H5)3P~4Pd TEA
~~ ~ ~N
O
I
F ~ ~ 10% Pd/C
EtOH
Diethyl oxalate NaOEt THF
_39_ N
OEt I ~ O
O O /
F
Diethyl oxalate 1 N LiOH NaOEt THF THF
/
O
N ~ ~ 'OEt O O
o I
F /
~OH
a v 1 N NaOH
I
F / THF
OH
O O
F
Scheme ArV
/ \
N
H
MeMgCI
50:50 THF:MeOH
benzyl bromide / \
N
H
MeMgCI
THF
acetic anhydride F
A_ TV-2-1 / \
~N~CH3 H O
Mel NaH
DMF
F
/ \
~N~C H3 HsC O
dimethyl oxylate TFA
NaH
D M E refl ux reflux AIV-6- I
cat. MeOH
F F O
Arv-~-~ \
N' ~ ~ ~OCH3 N
dimethyl oxylate NaH
DME
1 N NaOH reflux THF cat. MeOH
F ' F O O AIV-7-1 O AIV-S-1 ~ ~ / ' OH
Q
N OH
HsC O O H3C
1 N NaOH
THF
F O O
OH
/\
~--~ N J O
Scheme AV
COOH
EtOH (abs) (f/-) N H
I SOC12 (cat) / RT
O
COOEt Boc20 / Et3N / DMF
NH
O
COOEt PhMgBr /THF
N
O -40°C / 30 min O
O Ph 1. TFA / CH2C12 / RT
O H COOEt 2. Et3N / CH2C1 / RT
1. DDQ / CH2C12 / RT
~N~COOEt 2. NaOH / H20 I reflux MeON HMe~HCI
EDC~HCI
N~'COOH
H HOBt~ H20 DMF / Et3N
OCH F ~ ~ CH2Br N.
N '~ C H 3 H O NaH / DMF
N ~ C H MeLi / TH F / -78°C
N ~ s O
\
F
O
CH3 Et0 pEt N ~ O
O
I / NaOEt I THF l RT
F
O
O~ C H 1 N NaOH / MeOH /RT
N ~ ~ s O O
F /
O
N ~ ~ -OH
O O
F /
s Scheme A-VI
HN03 / Ac20 N II
O
F /
10% Pd-C
N II
O
EtOH ! H2 (lAtm) F
N II
O
F
CH31 / DMF / Cs2C03 VA lit-1 O
(C H3)2N Et0 OEt N~ O
O
NaOEt / THF / RT
F
AVI-3-1.
- 4fi --(CH3)2N O
N ~ ~ -OEt I\
F
(CH3)2N
O
1 N NaOH / MeOH /RT
N~ ~ ~ OH
O O
I
F
SCHEME AVII
O
N
H
4-fluorobenzyl bromide NaH
DMF
O
,\
dimethyl oxalate NaH
DME
heat O O
O
N II- -NaOH
THF / MeOH / H20 O O
OH
N
Scheme AVIII
PhCHO / NaCNBH3 N~
p MeOH / HOAc F
AV1~2-1 \ NH
H2CH0 / NaCNBH3 N
O MeOH / HOAc \
F
\ N Et0 ~OEt N~ O
O
\ NaOEt / THF / RT
F
N O
/ \ 1 N NaOH / MeOH /RT
N ~~OEt I\
F
N
O
N ~ ~ OH
O O
I \
F
Scheme AIX
I
/ ~ PhB(OH)2 / Pd(Ph3P)4 N
O Et3N I DMF I 90°C
I \
F
I IA ,I-1-1 - 5() _ O
Et0 OEt O
O
NaOEt / THF / RT
F
AIX-1-i 1 N NaOH / MeOH /RT
OEt O O
F
OH
O O
F
SCHEME AX
N
F
methylsulfonylchloride H
H3C~ ,N
~S~~
O O ~ ~ CH3 N
\ O X-1-1 F
diethyloxalate NaOEt/THF
H
H3C~ ,N
S
O~ ~~O ~ C02Et N
O O
F
1 N NaOH
H
H3C~ ,N
O S O ~ ~ C02H
N
O O AX-3-13_1 F /
Scheme AXI
N
I
Si(i-Pr)3 4-fluorobenzoyl chloride O
F ~ / / ~ AXI- I - I
N
I
Si(i-Pr)3 BH3-Me2S
THF
heat _ 53 ._ WO 99/b2S13 PCT/US99/12095 F N
I
Si(i-Pr)3 acetyl chloride O
OO
F N
I
Si(i-Pr)3 [Bu]NF
THF
A7fl_4_ I O
F N
H
1 ) dimethyf oxalate NaH
DME
heat 2) NaOH
THF I MeOH i H20 OH
/\
F N
H
Scheme AXI(b) NaH
4-fluorobenzyl bromide I~ r F N
H
O
I / / \
F N~ AXI-4-2 I
F
1 ) dimethyl oxalate NaH
DME
heat 2) NaOH
THF / MeOH / H20 O O
/ \ O H ~~-5-~
F / ~N~ O
F
Scheme BI
O /
v OEt I ~ Br Et0 N~N F
H
TEA
DMF
O
O OEt Et0 ~N
N
Bl-1-1 F /
1 N LiOH
THF
O
O OLi Li0 ~N
N
\
I~
F
MeO
NH.HCI
EDC, HOBT, TEA
DMF
O
O N~OMe / ~~ 1 Me0-; ~N
~ BI~3-1., F
MeLi THF
O
O
~~~ ~N
N
F
Diethyl oxalate NaOEt THF
Scheme B1 (cont.) OEt Et0 1 N LiOH
THF
O \
BI_ _1 F
O O
O OH
O
O
HO ~N~N
O
F
Scheme BII
Br Br / ~ +
N' N F
H
NaH
DMF
Br NON
/
F
Me0 O
'N
n-BuLi Et20 O
N~N
F
Diethyl oxalate NaOEt THF
O O
OEt N. O
N
F
1 M NaOH
MeOH
OH
N.N O
F
Scheme BIII
\ ~ ~ Br N\ H F
O
NaH
DMF
N
N
O
Diethyl oxalate NaOEt THF
O
N
N OEt O O
F
1 M NaOH
THF
O
N
~N O H
O O
F ~ BIII- -Scheme BIV
N~N
O' 1 M NaOH
THF
O
N~ N ~ BIV-1-1 H
Br F
NaH/DMF
O
i N~N
\ B1V-2-1 F
Diethyl oxalate NaOEt THF
O O
OEt i ~ II
N~ ~ O
N
Iv- -F
1 M NaOH
THF
_~3_ O O
OH
N~
.N O
~ BIV-4-i F
Scheme BV
\ ' Br N. /
N
H CI
NaH
DMF
O O
N/N~ N/ , v ~N
CI ~ V-1-1 CI
Diethyl oxalate Diethyl oxalate NaOEt NaOEt THF THF
OEt OEt N~ ~ II / ~ " n O N, O
N N
CI ~ CI
/ BV-3-1 ~ / BV-5-1 1 M NaOH 1 M NaOH
MeOH
MeOH
O O
OH O O
OH
N/N \\ O N/
,N O
CI
CI
i Scheme C1 CN
N
H
4-F-benzylbromid~
TEA/ DMF
r- N
N
F
1 ) nBuLi/THF/-78°C
2) C02 -6f~-N
C02'Li+
N
\ CI-2-1 F ~
N,O-dimethylhydroxylamine.HC
EDC/HOBT/TEA/DMF
~N OCH3 N~N~CH3 O
F
CH3Li/THF/-78°C
N
N
O
\ CI-4-1 F
diethyloxalate NaOEt/TH F
N
C02Et N
a o F
1 N NaOH
N
N
O O
F
Scheme CII
N co2H
N
H
4-F-benzylbromid~
Cs2C03/ DMF
-6H._ O "~ O
/ F ~ O , / F
+ F ~ N
CH3LiITHF
-78°C
O
N
N
F
diethyloxalate Na0 Et/TH F
O O
C02Et N
F
1 N NaOH
CH30HlTHF
O O
'C02H
N
N\ CII-4-1 F
Scheme DI
off N
H O
MeLi Et20 reflux N
H O
4-fluorobenzyl bromide NaH
DMF
-7~-\ ~ ~ C Hs N
O
F
dimethyl oxalate NaH
DME
heat O
N ~ ~ OCH3 O O
F
NaOH
THF / MeOH / H20 O
N ~ ~ OH
O O
F
Scheme DII
O
-' ' ~ ~ B r \ + F~i N
H
NaH
DMF
O
\
N
w DII-1-1 \ /
F
Diethyl oxalate NaOEt THF
O
O OEt ,- ~..
O
N
F
1 M LiOH
THF
O
O OH
w O
N
w The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt°' is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygaiacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, _73_ hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl>aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g.
acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment..
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15Ø 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS
- 7 fi -antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
ANTIVIRALS
Drub Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC
(non-nucleo side reverse transcriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC
GW 141 (protease inhibitor) Abacavir (1592U89)Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC
(RT inhibitor) Acemannan Carrington Labs ARC
(Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT
AD-439 Tanox Biosystems HIV infection, AIDS, ARC
AD-519 Tanox Biosystems HIV infection, AIDS, ARC
Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/R,etrovir _77_ Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC
neutralizes pH Concepts labile alpha aberrant,(Rockville, MI>) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC
beta-fluoro-ddA Nat'1 Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers ,Squibb/HIV infection, (CGP-73547) Novartis AIDS, ARC
(protease inhibitor) BMS-234475 Bristol-Myers Squibb/HIV infection, (CGP-61755) Novartis AIDS, ARC
(protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV
peripheral CMV
retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC
(RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive asymptomatic Japan) _78_ ddC Hoffman-La :ftoche HIV infection. AIDS, Dideoxycytidine AR C
ddI 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, EL10 Elan Corp, PhC HIV infection (Gainesville, GA) Famciclovir Smith HIine herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC
(reverse transcriptase inhibitor) GS MO Gilead HIV infection, AIDS, ARC
(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC
(non-nucleo side reverse transcriptase inhibitor) _79_ Hypericin VIMRx Pharm. HIV infection, AIDS, ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCS
Interferon alfa-n3Interferon SciencesARC, AIDS
Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC
ISIS 2922 ISIS PharmaceuticalsCMV retinitis KNI-272 Nat'1 Cancer InstituteHIV-assoc.
diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC
(reverse transcriptase inhibitor); also with AZT
Lobucavir Bristol-Myers SquibbCMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC
(protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC
(RT inhibitor) Novapren Novaferon Labs, HIV inhibitor Inc.
(Akron, OH) Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc infection, other CMV
infections WO 99/b2513 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, Di dehydrodeoxy- AR C
thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV
infections Virazole Viratek/ICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex H1V infection, AIDS, ARC
Zalcitabine Hoffrnann-La Roche HIV infection, AIDS, ARC, with AZT
Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies I_MMUNO-MODULATORS
Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS
_ H1 _ Brapirimine Pharmacia Upjohn advanced AIDS
Acemannan Carrington Labs, AIDS, ARC
Inc.
(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 ColanySandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS
Macrophage ColonyImmunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT
Stimulating Factor HIV Core ParticleRorer seropositive HIV
Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT
IL-2 Hoffman-La Rache AIDS, ARC, HIV, in interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in Interleukin-2 cell counts (aldeslukin) _g2_ 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) MT:P-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&F106~28 Smith Kline HIV infection Soluble T4 _g3_ Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVE~
Drug Name Manufacturer Indication Clindamycin withPharmacia Upjohn PCP
Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow pCp Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM (Rosemont, IL) & IV) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation 5piramycin Rhone-Poulenc cryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis;
851211 cryptococcal meningitis Trimetrexate Warner-Lambert PCp 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 Squibbtreatment 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 compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-(4-(3-pyridyl-methyl )-2(S )-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
The preparation of ddC, ddI and AZT are also described in EPO
0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following ( 1 ) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT andlor ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-( 4-(3-pyridyl-methyl )-2(S)-N'-(t-butylcarboxamido)-piperazinyl ) )-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
Indinavir is generally administered at a dosage of 800 mg three times a day.
The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed.
Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the ocmpounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variatioons of the conditions and processes of the following _g~,_ preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: Ac represents acetyl; ACN is acetonitrile;
Bn represents benzyl; DME is dimethoxy ethane; DMF is dimethyl formamide; DMSO is dimethyl sulfoxide; EDC represents 1-(3-dimethylaminopropyl-3-ethyl carbodiimide; Et represents ethyl; HOBT
represents L-hydroxybenzotriazole; LiHMDS represents '; IPA is isopropyl alcohol; Me represents methyl; sat. is saturated; THF is tetrahydrofuran; TLC is thin layer (Si02) chromatography.
EXAMPhE 1 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1 Step 1: I-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone AI-1-1 C
N
O
F
A solution of 2-acetyl pyrrole ( 1.09g, 0.01 mole) in 20 mL of DMF was treated with sodium hydride (0.488 60 % dispersion in oil, 0.012 mole) followed by 4-fluorobenzyl bromide ( 1.73g, 0.012 mole) and stirred overnight at room temperature. The solution was poured into 300 mL
saturated NaHC03 and extracted with EtOAc three times, the combined organic layers were washed with NaHC03 and dried over MgS04, filtered and evaporated to give a clear yellow oiI that was taken on to the next step without further purification. Rf--0.58 (20% EtOAclHexanes).
1H NMR (400 MHz, CDCl3) d 7.1 (m, 2H), 7.0 (m, 3H), 6.9 (m, 1H), 6.2 (m, 1H), 5.52 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AI-2-1 _g7_ '~ ~OCH3 O O
i~
F
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 (0.48g, 60°l° dispersion in oil) followed by dimethyl oxalate ( 1.42g, O.OI2 mole) and a drop of methanol and the solution was warmed to reflex overnight. The reaction mixture was poured into 300 mL saturated NaHC03 and extracted with EtOAc three times, the combined organic layers were washed with NaHC03 and dried over MgS04, filtered and evaporated. The residue was crystallizesd with diethyl ether to give AI-2-1 as yellow -orange crystals. Rf--0.39 (97:3:1 CHCl3 / MeOH / HOAc). 1H
NMR (400 MHz, CDC13) 8 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).
Step 3: 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid N OH
O O
F
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 HCl and extracted three times with EtC>Ac. The organic layers were combined, washed with 1 N HCI, dried over MgS04, _gg_ filtered and evaporated to dryness. The residue was crystallized from CHC13 to give AI-3-1 as bright orange-yellow crystals. mp 172°C
decomposed (uncorrected). TLC Rf-__0.37 (94:6:6 CHCl3 / MeOH / HOAc).
1H NMR (400 MHz, CDCl3) 8 7.2 (dd,J = 1.65, 4.21 Hz,lH), 7.09 (m, 3H), 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 4-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-9 Step 1: 1-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]ethanone AI-1-3 N ]'~
O
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 mmole ). The reaction was stirred at ambient temperature for 12 hours, then the mixture was diluted with Et2O, washed with water, dried with MgS04, and the solvent evaporated. The residue was purified by preparative silica HPLC using 20% EtOAcJHex to afford the product as a thick clear oil that solidified upon standing. melting point 52-53°C
(uncorrected). 1H NMR (400 MHz, CDCl3) 8 7.11 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.72 Hz, 2H), 7.01 (m, 1H), 6.18 (m,lH), 5.55 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H). mass spec (EI, m/z) 213 (M+), 105.
Step 2: 4-[I-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-2 _gc~_ N ~ ~ ~OCH2CH3 O O
To a solution of AI-1-3 (639mg, 3 mmole) and diethyl oxalate (0.814 mL, 6 mmole) in THF (3 mL) was added in portions NaOEt (408mg, 6 mmole>.
The reaction was stirred at ambient temperature under a N2 atmosphere for 1.5 hours. The reaction was poured into hexanes (50 mL) and the yellow precipitate was filtered and dried under vacuum.
The crude solid was triturated with 1M HCl (50 mL), filtered, and dried under vacuum. The product was further purified by crystallization from EtOAc / Hexanes / EtlO to obtain the product as a yellow powder.
melting point 94-97°C (uncorrected). 1H NMR (400 MHz, CDC13) b 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, 1.H), 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.
Step 3: 4-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid N ~ ~ -OH
O O
A solution of I-2-2 (240mg, lmmol) in 1,4-dioxane (3 mL) and 3N HCl (3 mL) was heated in a sealed tube at 70°C overnight. The reaction was then allowed to cool to ambient temperature and poured into 1H HCl (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 / hexanes to afford AI~3-9 as a yellow solid. melting point 179-181°C (uncorrected). 1H NMR (400 MHz, DMSO) b 7.50 (s, 1H), 7.41 (d, J=4.28 Hz, 1H), 7.1.0(d, J=7.68 Hz, 2H), 6.98 (d, _yp_ J=7.68 Hz, 2H), 6.83 (s, 1H), 6.30 (dd, ~1=2.5, 4.1 Hz, 1H), 5.58 (s, 2H), 2.24 ( s, 3H ).
mass spec (FA$, m+1) 286 4-[1-(4-fluorobenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-Step l: 1-[1-(4-fluorobenzyl)-4-iodo-1H -pyrrol-2-yl]ethanone AI-1-2 I
N
O
pI_I_~
A solution of 1-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone (AI-1-1) (3g, 13.8 mmole) in acetone (75 mL) was cooled to -78°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 NaHC03 solution and brine, dried over MgS04, 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, CDCl3) b 7.15 (m, 2H), 7.08 (m, 1H), 7.0 (m, 2H), 6.93 (m, 1H), 5.5 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-3 N ~'( ~ ~OCH2CH3 O O
F /
AI-2-3 was synthesized from AI-1-2 in a manner similar to that described for AI-2-2 to afford the product as a yellow solid. melting point 87-90°C (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.15 (dd, J=1.6, 4.16 Hz, 1H), 7.09 (m, 2H), 7.01-6.96 (m, 3H), 6.83 (s, 1H), 6.27 (dd, J=2.52, 4.20 Hz, 1H), 5.60 (s, 2H), 4.36 (q, J=7.I6 Hz, 2H), 1.38 (t, J=7.16 Hz, 3H).
mass spec (EI, m/z) 317 (M' ), 109.
4-[1-(4-fluorobenzyl)-lIl-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester N T( if _ o O O
F
To a solution of AI-2-3 (317mg, 1 mmole) in 2-propanol (anhydrous, 20 mL) was added p-toluenesulfonic acid (l9mg, 0.1 mmole) and the mixture was set to reflux for 72 hours. The reaction mixture was then allowed to cool to ambient temperature, diluted with Et20, washed with a solution of saturated NaHC03, the organic layer separated and dried with MgS04, the solvent evaporated and the crude was purified by preparative silica HPLC eluting with 30°~o EtOAc / hexanes to afford the product as yellow solid. melting point 87-88°C (uncorrected). 1H NMft (400 MHz, CDCl3) 8 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 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester _92_ N ~ ~ -O(CH2)sCHs O O
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 64-65°C
(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 4-(1-benzyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-2 O
N ~ ~ -O H
O O
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 I5 AI-3-2. mp 150-151°C (uncorrected). 1H NMR (300 MHz, DMSO) F~
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).
4-( 1-naphthalen-2-ylmethyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-3 O
N~ ~ ~ -O H
~ O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 2-bromomethylnapthylene and carried through the sequence to yield AI-3-3. mp 160-162°C (uncorrected). 1H NMR (300 MHz, DMSO) ~ 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).
4-(1-biphenyl-4-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid A-I-3-4 O
N ~ ~ OH
O O
In a manner similar to that described for AI-3-13-1, 2-acetyl pyrrole was treated with 4-phenyl benzyl bromide and carried through the sequence to yield AI;3-44. mp 189-191°C (uncorrected). 1H NMR (300 MHz, DMSO) S 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).
4-(1-naphthalen-1-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid AI-3-5 O
N OH
O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 1-bromomethyl napthalene and carried through the sequence to yield AI- -5, mp 172-174°C (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).
2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl]-butyric acid AI-3-6 O
N OH
O O
In a manner similar to that described for AI-3-13-1, 2-acetyl pyrrole was treated with 4-phenyl butyl chloride and carried through the sequence to yield AI-3-6. mp 119-121°C (uncorrected). 1H NMR (300 MHz, DMSO) 8 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).
4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-7 O
N~ ~ ~ O H
O O
CI
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 4-chlorobenzyl bromide and carried through the sequence to yield AI-3-7. mp 182-184°C (uncorrected). 1H NMR (300 MHz, DMSO) b 7.55 (s, 1H), 7.42 (m, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 6.82 (s, 1H), 6.35 (m, 1H), 5.6 (s, 2H), 2,4-dioxo-4-( 1-phenethyl-1H-pyrrol -2-yl)-butyric acid AI-3-8 O
N ~ ~ OH
O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 2-phenyl 1-bromoethane and carried through the sequence to yield AI-3-8. mp 168-170°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) i5 4-[1-(2-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-10 O
N 1'( ~ O H
O O
/
AI-3-10 was synthesized from 2-acetyl pyrrole and 2-methylbenzyl bromide in a manner similar to that described for AI-3-9 to a$'ord the product as a brownish-yellow solid. melting point 176-178°C
(uncorrected). 1H NMR (400 MHz, DMSO) b 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, 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.
4-[ 1-(3,4-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-11 N ~'( ~ ~ O H
F ~ O O
F
AI-3-11 was synthesized from 2-acetyl pyrrole and 3,4-difluorobenzyl bromide in a manner similar to that described for A_A_ I;3_99 to afford the product as a brownish-yellow solid. melting point 145-148°C
(uncorrected) 1H NMR (400 MHz, DMSO) b 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).
mass spec (FAB, m+1) 308 4-[1-(4-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-12 N ~'( ~ -O H
O O
Br AI-' -12 was synthesized from 2-acetyl pyrrole and 4-bromobenzyl bromide in a manner similar to that described for AI3-9 to afford the product as a brownish-yellow solid. melting point 184-185°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.54 (d, J=1.68 Hz, 1.H), 7.52 _97_ (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, IH), 6.34 (dd, J=2.52, 4.16 Hz, 1H), 5.61 (s, 2H). mass spec IFAB, m+1) 352, 350 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-13 O
N~ ~ ~ ~OH
O O
AI-3-13 was synthesized from 2-acetyl pyrrole and 2-bromobenzyl bromide in a manner similar to that described for AI3-9 to afford the product as a brownish-yellow solid. melting point 176-180°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 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).
mass spec (FAB, m+1) 4-[1-(3-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-14 O
N ~ ~ ~OH
Br ~ O O
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 164-166°C
(uncorrected ). 1H NMR (400 MHz, DMSO ) 8 7.54 (broad s, 1H ), 7.43 (m, 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.
4-f 1-(3-chlorobenzvl)-1H-nvrrol-2-vll-2 4-dioxobutvric acid AI 3 15 O
N I'( ~ ~ O H
C I ,~ O p AI-3-15 was synthesized from 2-acetyl pyrrole and 3-chlorobenzvl bromide in a manner similar to that described for AI'3-99 to afford the product as a brownish-yellow solid. melting point 159-161°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 (FAB, m+1) 306 4-[1-(3-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-16 O
N j'( ~ -O H
HsC \ O O
AI-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 140-141°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (d, J=1.92 Hz, 1H), 7.41 _c~c~_ (dd, J=1.44, 4.12 Hz, 1H), 7.20 (dd, J=7.64, ?.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 4-[L-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-17 N ~"( ~ O H
O O
AI-3-17 was synthesized from 2-acetyl pyrrole and 2-fluorobenzyl bromide in a manner similar to that described for AI'3-9 to afford the product as a brownish-yellow solid. melting point I55-156°C
(uncorrected). IH NMR (400 MHz, DMSO) 8 7,47 (m, 2H), 7.32 (dd, 5.4, 14.0, 1H), ?.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), 6.3Ei (dd, J=2.56, 4.12Hz, 1H), 5.71 (s, 2H). mass spec (FAB, m+1) 290 2,4-dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid AI-3-18 O
N ~ ~ -OH
O O
In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated 1-bromo hexane and carried through the sequence to yield AI-3-18.
mp 94.8°C (uncorrected). TLC Rf-__0.68 (94:6: 6:6 CHC13 / MeOH / HOAc) - 1 ()0 -1H NMR (400 MHz, CDC13) 8 7.15 (dd, 1H, J=1.65 Hz, J=4.21 Hz), 7.01 (m,lH), 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) 4-(1-biphenyl-2-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid O
N 1~ ~ -O H
O
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 sequence to yield AI-3-19. mp 150-152°C (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.4 (m, 9H), 6.8 (s, 1H), 6.42 (m, 1H), 6.3 (m, 1H), 5.6 (s, 2H).
2,4-dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl]-butyric acid AI-3-20 O
N~ ~ ~~ ~OH
O~V/~ O O H
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 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) b 7.29 (m, 2H), ?.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).
4-[1-(3-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-21 O
N T[ ~ ~ O H
O O
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 147-149°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 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), 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 4-fl-(2-chlorobenzvl)-1H-pvrrol-2-vll-2 4 dioxobutvric acid AI 3 22 O
N- ~ ~ -O H
O O
/ C ~ A-A_I-3-2222 AI-3-22 was synthesized from 2-acetyl pyrrole and 2-chlorobenzyl bromide in a manner similar to that described for A~ to afford the product as a brownish-yellow solid. melting point 179-180°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.52-7.47 (m, 3H), 7.30 (ddd, J=1.6, 7.44, 7.44 Hz, 1H), 7.24 (ddd,J=1.32, 7.52, 7.52 Hz, 1H), 6.88 (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 - I ()2 -4-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid I
O
N~ ~ ~ O H
O O
In a manner similar to that described for AI-3-1, AI-3-23 was prepared from AI-l-2. mass spec (FAB, m+1) 416 . 1H NMR (400 MHz, Dh-DMSC>) 8 7.7 (s, 1H), 7.6 (s, 1H>, 7.2 (m, 4H), 6.85 (s, 1H), 5.6 (s, 2H).
4-f 1-(4-methoxvbenzvl)-1H-nvrrol-2-vll-2 4 dioxobutvric acid AI 3 24 N ~'( ~ OH
O O
Me0 Al-3-24 AI-3-24 was synthesized from 2-acetyl pyrrole and 4-methoxybenzyl chloride in a manner similar to that described for Ah3-9 to afford the product as a brownish-yellow solid. melting point 167-168°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (s, 1H), ?.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) 4-[1-(2,4,5-trifluorobenzyl)-1H-pyrrol-2-~~l]-2,4-dioxobutyric acid AI-3-25 -O H
F ~ O O
i F ~ F
AI-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 154-156"C
(uncorrected). 1H NMR (400 MHz, DMSO) h 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).
4-f 1-(2,3-difluorobenzvl >-1H-pyrrol 2 yl ] 2 4 dioxobutyric acid AI 3 26 O
N ~ ~ ~OH
O O
i F
AI-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°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.51 (s, 1H), 7.45 (m, 1H), 7.35 (m, IH), 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 4-[1-(3,5-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-26 O
N ~ ~ ~OH
F ~ O O
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-I68°C
(uncorrected); 1H NMR (400 MHz, DMSO) 8 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 (FA~I, m+ I ) 308 4-[1-(2,5-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-28 O
F N~ ~ ~' ~OH
O O
A_ I-3-28 was synthesized from 2-acetyl pyrrole and 2,5-difluorobenzyl bromide in a manner similar to that described for AI-~~ to afford the product as a brownish-yellow solid. melting point 142-146°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 4-[1-(2,5,6-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-29 O
F N ~ ~ ~OH
O O
F
AI-~ 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 I31-133°C
(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.
In a manner similar to that described for AI-3-1, the following compounds were prepared:
4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid N
O OH
F
CHN Calc. 62.28, 4.18, 4.84; Fnd. 62.11, 4.37, 4.91. (32) 4-[1.-(4-trifluoromethylbenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid:
N
O OH
CHN Calc. 56.64, 3.56, 4.12; Fnd. 56.89, 3.75. 4.36. (33 ) 4-[1-(4-cyanobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid:
N
O OH
NC
CHN Calc. 64.86, 4.08, 9.45; Fnd. 64.61, 4.32, 9.77. (34) O
N~ ~~~~OH
O HO
,O
4-[l-(3-methoxybenzyl)-1H -pyrrol-2-yl] -2,4-dioxobutyric acid CHN Calc.
63.78, 5.02, 4.65; Fnd. 63.99,5.14, 4.60. (35) N
O OH
HO ~- 0.20 TFA
2-hydroxy-4-[1-(4-hydroxybenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid CHlrt Calc. (C15H13N05 0.20 TFA) 59.65, 4.29, 4.52; Fnd. 59.50, 4.31, 4.68. (36) y N
O OH
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) \ C02H
N
O OH
0.35 EtOAc F
4-il-[3-(4-fluorophenyl)propyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid CHN
Calc.( C17H16N04F 0.35 EtOAc) 63.47, 5.44, 4.02; 63.16, 5.12, 4.34. (38) ~ C02H
N
O OH
F
4-~1-[2-(4-fluorophenyl)ethyl]-1H-pyrrol-2-yl}-2,4-dioxobutyric acid CHN
Calc. 63.36, 4.65, 4.62; Fnd. 63.16, 4.64, 4.50. (39) N
O OH
4-[1-(3-phenylpropyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Cale.(C17H17N04 0.1 H20) 67.80, 5. 76, 4.65; 1''nd. 67.79, 5.67, 4.70. (40) N
O OH
H3~J
4-( 1-ethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 57.41, 5.30, 6. 7 0; Fnd. 57.13, 5.33, 6.70. (41) N
O OH
F
4-[ l-(3-fluoro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN
Calc.(C15H12 FN04 0.35 H20) 60.95, 4.33, 4.74; Fnd. 60.89 4.25, 4.78. (42) N
O OH
CI
4-[1-(2-chloro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN Calc.
(C15H12N04C1 0.15 H20)58.41, 4.02, 4.54; Fnd. 58.31, 3.94, 4.62 (43) O OH
~N
O
4-[1-(3-benzoylaminopropyl)-1H-pyrrol-3-yI] -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) O
N~ ~ \~ OOH
O OH
\ O
F /
4-{ 1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}] -2,4-dioxobutyric acid CHN Calc. 66.14, 4.23, 3.67; Fnd. 66.37, 4.32, 3.69. (45 ) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 Step 1: cyclohexyl-pyrrol-1-yl-methanone AII-1-1 N
~O
AII-I-I
A solution of pyrrole (2.OOg, 0.0298 mole) in 30 mL THF was cooled to -78°C and treated with I.0 M LiHMDS in hexanes (29.8 mL, 0.0298 mole) followed by dropwise addition of cyclopentanecarbonyl chloride (4.00 mL, 0.0298 mole). After five minutes the solution was allowed to warm to room temperature and stirred for four hours. The solution was poured into 200 mL saturated NH4Cl solution and extracted with EtOAc three times. The combined organic layers were washed with NH4Cl and dried over MgS04, filtered and evaporated to give a crude brown 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-1-1 as white crystals. TLC Rf-__0.62 (5:95 EtOAc / Hexanes) IH
NMR (400 MHz, CDC13) b 7.32 (m, 2Hi, 6.29 (.m, 2H), 2.92 (m, lHl, 1.8W-1.97 (m, 4H), 1.56-1.76 (m, 3H), 1.24-1.43 (m, 3H).
Step 2: 1-cyclohexylmethyl-1-H -pyrrole AII-2-1 N
A solution of AII-1-1 (3.45 g, 0.0195 mole) in 60 mL THF was treated with 1.0 M BH3-Me2S (58.5 mL, 0.0585 mole) and warmed to reflux for three hours. The solution was cooled to 0°C, slowly poured into 300 mL ice cold water and extracted with CH2Cl2 three times. The combined organic layers were washed with water, dried over MgS04, and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc / Hexane mixture as the eluting solvent, gave AII-2-1 as a light yellow oil. TLC Rf-__0.71 (5:95 EtOAc / Hexanes ) 1H NMR (400 MHz, CDCl3) 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).
Step 3: 1-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-ethanone AII-3-1 N
a A solution of AII-2-1 (1.32g, 0.0081 mole) in 20 mL THF was cooled to -78°C and treated with 2.5 M n. -butyllithium ( 16.2 mL, 0.0405 WO 99162513 PCTlUS99/12095 mole) over five minutes and stirred overnight at room temperature under argon. The solution was then treated with N -methoxy-1V -methylacetamide (4.18g, 0.0405 mole) and stirred three hours. The solution was poured into 200 mL saturated NH4Cl solution and extracted with Et20 three times. The combined organic layers were washed with NH4Cl and dried over MgS04, filtered and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc / Hexane mixture as the eluting solvent, gave AII-3-1 as a yellow oil. TLC Rf-__0.49 ( 5:95 EtOAc / Hexanes) 1H NMR
(300 MHz, CDCl3) 8 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 methyl ester AII-4-1 O
O O
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 / CH2Cl2) 1H NMR (400 MHz, CDC13) 8 7.10, (dd, J = 1.65, 4.21 Hz, 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-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid O
-OH
O O
In a manner similar to that described for AI-3-1, AII-4-I was treated with NaOH to give AII-5-1. TLC Rf-__0.65 (94:6:6 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) 8 7.15 (dd, J=1.65, 4.21 Hz, 1H), 6.96 (m, 1H7, 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).
4-[1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid Step 1: 1-[1-(4-fluorobenzyl>-4-phenylethynyl-IH-pyrrol-2-yl]ethanone AIII-1-1 O
F
A mixture of AI-1-2 (.49 g, L43 mmol), phenylacetylene (.218 g, .235 mls, 2.14 mmol), copper(I) iodide (.022 g, .116 mmol), tetrakis(triphenylphosphine)-palladium(0) (.l g, .086 mrnol) and triethylamine (5 mI) were combined in 2 mL acetonitrile and heated to reflux for 4 hrs. After cooling, the solvent was removed irt uczcuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed. The resulting brov~~n oil was purified by radial disc chromatography twice, first using 2:1 hexane/
CH2Cl2 followed by straight ethyl acetate, then straight CH2Cl2 to afford the title compound. 1H NMR (400 MHz, CDCl3) ~ 2.42 (s, 3H), 5.52 (s, 2H), 6.99 (t, 2H, J = 8.7 Hz), 7.11 - 7.16 (m, 4H), 7.29 - 7.47 tm, 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 OEt O O
F
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 (.7.13 g, 1.66 mmol >. After stirring for 1 hr, the reaction was poured into 20 mL
109 citric acid and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2SO4 filtered, and the solvent removed in uacuo to give the title compound as a yellow oil.
1H NMR (400 MHz, CDC13) 8 1.36 (t, 3H, J = 7.1 Hz), 4.34 (q, 2H, ~1 = 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 -7.48 (m, 2H) Step 3: [ 1-(4-fluorobenz 1 )-4 hen leth Y -P Y YnYl-~-PYrrol-2-yl]-2,4-dioxobutyric acid AIII-3-1 OH
In a similar manner to AI-3-13-1, 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 yellow resin. 1H NMR (400 MHz, CDCl3) 8 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) 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 O
F
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 O O
F
with hydrogen (via balloon) and allowed to stir for 6 hr. The catalyst was filtered and the solvent removed in uacuo. NMR of this crude mixture showed about 20% starting material. The product was purified by radial disc chromatography (CH2Cl2 > to obtain the title compound as a resin.
1H NMR (400 MHz, CDCl3) 8 2.35 (s, 3H), 2.72 - 2.79 (m, 2H), 2.82 - 2.89 (m, 2H), 5.42 (s, 2H), 6.57 (d, iH, 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-dioxobutyric acid ethyl ester AIII-5-1 OEt In a similar manner to AIII-2-1, AIII-4-1 (.l g, .31 mmol) was reacted with diethyl oxalate (.091 g, .084 ml, .62 mmol) and sodium ethoxide (.042 g, .62 mmol) in 5 mL THF to give the title compound, which was used in the next reaction without further purification. 1H NMR, (400 MHz, CDCl3) 8 1.37 (t, 3H, .1 = 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) Step 3: 4-[ 1-(4-fluorobenzyl )-4-phenethyl-lIl-pyrrol-2-yl]-2,4-dioxobutyric acid AIII-6-1 - I lb O O
F
OH
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 °C; 1H NMR (400 MHz, CDC13) ~ 2.75 - 2.82 (m, 1H), 2.84 -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),. 7.1? - 7.23 (m, 1H), 7.24 - 7.32 (m, 3H) 4-[5-(4-fluorobenzyl)-1-methyl-1-II -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-Step 1: 2-(4-fluorobenzyl)-1H -pyrrole AIV1-1 F
N
MeMgCl (3N in THF, 43.8 mL, 0.131 mole) was added dropwise to a solution of 50:50 THF:CH2Cl2 and pyrrole (9.31g, 0.139 mole) at 0°C
followed by quick addition of 4-fluorobenzyl bromide and stirred at room temperature overnight. The solution was poured into 300 mL of saturated NH4C1 and extracted five times with Et20. The combined organic layers were dried over NaS04, filtered and evaporated to give a dark brown oil that was distilled under vacuum to give analytically pure AIV-1-1. 1H NMR (400 MHz, CDC13) 8 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, 1.H), 3.94 (s, 2H).
O O
F
Step 2: 1-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone AIV-2-1 F
~N~CH3 H
MeMgCI (2.95 mL, 0.0284 mole) was added dropwise to a solution ofAIV-l~l in THF (35 mL) at 0° 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 NH4Cl and extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give a brown oil, Silica gel chromatography using 85:15 Hexane/EtOAc gave AIV-2-1 as a light yellow powder.
TLC: Rf-__0.30 (80:20 Hexanes /EtOAc) 1H NMR (400 MHz, CDCh3) c~ 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) Step 3: 1-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]ethanone AIV-F
~N~CHs NaH (.0988, 0.00244 mole) was added to a solution ofAIV-2-1 in DMF (25 mL) at 0° C followed by subsequent addition of MeI (0.538, 0.00244 mole).
The ice bath was removed and the reaction was stirred for one hour.
The solution was poured into NH4Cl arid extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give AIV-~-1 as a brown oil. TLC: Rf--0.43 (80:20 Hexanes / EtOAc) 1H NMR (400 MHz, C'DCI~~) h 7.11-7.07 (m, 2H), 7.01-- 1 1 ~i -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).
Step 4: 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AIV-4-1 F
O
~N ~ ~ -OCH3 A solution of AIV-3-1 (0.2228, 0.000961 mole) in DME (lOmL) was treated with sodium hydride (0.0588, 0.00144 mole) followed by dimethyl oxalate (0.1138, 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 NaS04, filtered and evaporated to give AIV-4-1 as a brown solid. TLC: Rf--0.39 (97:3:1 CH2Cl2 / MeOH / HOAc) 1H NMR
(400 MHz, CDC13) 8 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)-1-methyl-lII -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-1 F /
O
~~ ~OH
AIV-4-1 was dissolved in THF (I5 mL) and 1 N NaOH (5 mL) was added. After two hours the reaction was acidified with 1 N HCI.
This mixture was extracted three times with EtOAc, dried over NaS04, 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 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, CDC13) 8 7.128-7.086 (m, 3H), 7.04-6.99 (t, 2H j=9), 6.90 (s, 1H). 6.03-6.02 (d, 1H. j=4.39 Hz), 3.98 (s, 2H), 3.85 (s, 3H).
4-[5-(3-chlorobenzyl)-1-methyl-1.H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-Ci \ ~ /
~~N OH
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 MHz, DMSO) 8 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).
4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-3 F
N OH
H O O
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.
12(>
TLC: Rf-__0.28 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, DMSO ) ~ 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).
4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-4 CI ~ I ~ ~ O
N OH
H O O
AIV-5-4 was prepared in a manner similar to that described for AIV-5-1 with the exception that the methylation step was omitted. TLC:
Rf--0.44 (93:7:7 CHCl3/ 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).
4-[5-(benzyl)-lIl -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-5 O
N OH
H O O
AIV-5-55-5 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) b 12.20 (s, 1H), 7.32-7.18 (m, 6H), 6.80 (s, 1H), 6.05 (m, 1H), 3.98 (s, 2H).
4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-6 i F ~ ~ /
N OH
H O O
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 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, DMSO) 8 12.21 (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).
4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl)-2,4-dioxobutyric acid AIV-5-7 F
O
N OH
O O
F
AIV-5-7 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-alkylation step. TLC: Rf=0.60 (93:7:7 CHCl3/ MeOH / HOAc> 1H
NMR (400 MHz, CDC13) 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).
4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl)-2,4-dioxobutyric acid AIV-5-8 CI v ~ ~N~ ~ ~ ~OH
O O
F
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) 8 7.46-7.45 (d, 1H j=4.2 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 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-O
N ~' ~ OH
O O
AIV-5-95-9 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 NMR (400 MHz, CDC13) 8 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 (s, 2H). mass spec.: (FAB, m+1) 380 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric;
acid AIV-5-10 CI
I ~ , O
N ~ ~ OH
I\
F
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, CDCl3) 8 7.27 (m, 1H), 7.25-7.24 (m, 1H), 7.21-?.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 spec.: (FAB, m+1) 414 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-Step l: 1-[5-(4-fluorobenzyl)-1-methyl-1 H -pyrrol-3-yl]ethanone F O
~CH3 N' A1V-fi-1 AIV-3-13-1 was dissolved in TFA 10 mL and was refluxed for two days.
Cooled and removed TFA under reduced. pressure. Dissolved brown oil in saturated NaHC03 and extracted three times with EtOAc, dried over NaS04, filtered and evaporated to give AIV-6-1 as a green oily solid.
TLC: Rf-__0.33 (60:40 Hexanes / EtOAc) 1H NMR (400 MHz, CDCl3) 8 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).
Step 2: 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-8-1 O O
/ OH
N
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 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 4-[5-(3-chlorobenzyl)-1-methyl-IH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-O O
OH
O
CI N
In a manner similar to that described for AIV-8-l, pyrrole was alkylated with 3-chlorobenzyl bromide and carried through the sequence to give AIV-8-2. 1H NMR (400 MHz, CT)C13) b 7.43-7.42 (d, 1H, j=1.8 Hz), 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=l.lHz), 3.92 (s, 2H), 3.50 (s, 3H). mass spec.: (FAB, m+1) 320.2 4-[5-(benzyl)-1-methyl-1X -pyrrol-3-yl]-'~,4-dioxobutyric acid AIV-8-3 O O
OH
O
N
In a manner similar to that described for AIV-8-1, pyrrole was alkylated with benzyl bromide and carried through the sequence to give AIV-8-38-3. 1H NMR, (400 MHz, CDCl3) 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), (i.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 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-O O
OH
F \ ~ ~ ~ O
N
In a manner similar to that described for AIV-8-18-1, pyrrole was alkylated with 3-fluorobenzyl bromide and carried through the sequence to give AIV-8-4. 1H NMR, (400 MHz, CDCl3) ~ 7.43 (d, 1H, j=1.8 Hz), 7.32-- 12b 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 4-(5-benzyl-1H -pyrrol-3-yl>-2,4-dioxobutyric acid AIV-8-5 O O
OH
/~
O
N
In a manner similar to that described for AIV-8-l, with the exception that the N-alkylation step was omitted, pyrrole was alkyated with benzyl 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, CDCl3) 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).
4-[2,5-bis-(3-chlorobenzyl)-1-H -pyrrol-3-yl~-2,4-dioxobutyric acid AIV-8-6 OH
CI
In a manner similar to that described for AIV-5-1 pyrrole was alkyated with 3-chlorobenzyl bromide and the minor 2,5-bis 3-chlorobenzyl alkylated product was isolated. Treatment with MeMgCI followed by acetic anyhydride as described for AIV-2-1 gave the 3-acylated product that was carried through the sequence to give AI_ V-8-6. TLC: Rf_-0.42 (93:7:7 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, CDCl3) 8 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>.
4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-Step 1: (+/-) 5-Oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 COOEt NH
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) 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 NaHC03 (2X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave 5-oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 as an oil which crystallized on standing. 1H NMR
(CDCl3) 8 1.30 (3H, t, j=7.3 Hz), 2.18 to 2.60 (4H, complex multiplet), 4.22 (3H, m), 3.37 (1H, br s).
Step 2: (+/-) 5-Oxo-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-I.
COOEt ,.O
~N
O
To a 1L round bottomed flask with a stirring bar and an argon inlet was added gave 5-oxo-pyrrolidine-2-carboxyli c acid ethyl ester AV- l -1 ( 18.68, 118.34 mmol) CHCl,3 (300 mL), di-tort-butyldicarbonate (30.998, 142.01 mmol), Et3N (16.5 mL, 118.34 mmol), and 4-dimethylaminopyridine (14.468, 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°~o aqueous citric acid, aqueous NaHC03, H20, and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 3008 of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained (+/-) 5-oxa-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 as an oil. 1H NMft (CDCl3 ) ~ 1.2 7 (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).
Step 3: (+/-) 2-Tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 O Ph O
O H COOEt To an oven dried 500 mL, three-necked round bottomed flask with a 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 (6.508, 25.25 mmol) and 100 mL of dry THF. This solution was cooled to -40°C and a solution of phenyl magnesium bromide (25.3 mL of a 1M solution in THF) was added slowly with a syringe. The mixture was aged 15m at -40°C, the cooling bath was removed and the mixture was warmed to 20°C. The reaction was quenched by the addition of 150 mL of saturated aqueous NH4Cl solution. This mixture was stirred 30m. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried (MgS04), filtered and concentrated in vacuo to give 2-tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-13-1 which was used in the subsequent step without purification.
- 12q -Step 4: (+/-) 5-Phenyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-4-1 r'COOEt 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 CH2Cl2. This solution was cooled in an ice bath and 100 mL of trifluoroacetic acid was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 24h. The solvents were removed in vacuo and the residue was redissolved in 300 mL of CHC13 and concentrated a second time. The resulting residue was dissolved in 100 mL of CH2Cl2 and this solution was cooled in an ice bath. Et3N (50 mL) was added and the mixture was stirred 3h. The solvents were removed in vacuo and the residue was dissolved in 300 mL of EtOAc. This solution was washed with H20 and brine. Drying (MgS04), 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 oil. 1H NMR (CDCl3) b 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, m), 7.89 (2H, dd, j=
2.7, 4.0).
Step 5: 5-Phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 ~COOH
H AV;S-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 ~V-4-1 (4.848, 22.28 mmol), dry CH2Cl2 (220 mL) and DDIa (5.06g, 22.28 mmol). This solution was stirred at ambient temperature 1h. The solvent was removed in vacuo. Aqueous NaOH (20% w/v, 440 mL) was added and the mixture was heated at reflux 24h. The cooled, black solution was poured onto crushed ice and the mixture was acidified with conc. HCl. This mixture was extracted with EtOAc (2X). The combined extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 2.5~% MeOH in EtOAc as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 as an off white solid. 1H NMR (CDC13 ) 8 6.59 (1H, dd, j=2.7, 3.9 Hz), 7.13 (1H, dd, j= 2.7, 3.9 Hz), 7.34 (l.H, m), ?.41 (2H, m), 7.59 (2H, rn), 9.40 (1H, br s).
Step 6: 5-Phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide N N.CHs Fi O 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-5-15-1 (2.45g, 13.09 mmol), N,O-dimethylhydroxylamine hydrochloride (1.40g, 14.40 mmol), N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride (2.76g, 14.40 mmol), hydroxybenztriazole hydrate (1.94g, 14.40 mmol) and dry, degassed DMF (25 mL). This well stirred mixture was warmed gently until all of the solids dissolved. Et3N (5.6 mL, 40.00 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo at +80°C. The residue was partitioned between saturated aqueous NaHC03 and EtOAc. The layers were separated and the organic phase was washed with H20 (2X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 35~~o EtOAc in hexane as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. 1H NMR (CDCl3) F~ 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).
Step 7: 1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1 N
N ~ CHI
O
F
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 added and, when all of the solids had dissolved, NaH-oil suspension (0.132g of a 60% w/w suspension, 3.3I mmol) was added. This mixture was stirred 15 min at ambient temperature then 4-fluorobenzylbromide (0.41 mL, 3.31 mmol) was added. The resulting mixture was stirred 24h at ambient temperature. The mixture was diluted with EtOAc and the solution was washed with 1N HC1, water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oiI. This material was chromatographed on silica gel using 25% EtOAc in hexanes a eluant to give 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1. 1H NMR (CDCl3) 8 3.21 (3H, s), 3.47 (3H, 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 N
O
F
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methylamide -7-1 (0.726g, 2.16 mmol) and dry THF' (20 mL).
This solution was cooled to -78°C and methyllithium (3.39 mL of a 1.4 M
solution in Et20, 4.75 mmol). The mixture was stirred 30 min at -78°C', then the reaction was quenched with saturated aqueous NH4C1 solution.
The mixture was warmed to room temperature and stirred 2h. The layers were separated and the aqueous phase was extracted with EtOAc.
The combined organic fractions were dried (MgS04 ), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 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).
Step 9: 4-[ 1-(4-Fluorobenzyl )-5-phenyl-1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AV-9-1 O
~O~C H3 O O
F
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-1H-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 1h at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HCl, H20 (2X) and brine. Drying (MgS04) filtration 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-9-19-1 as an oil. This material was used without further purification. 1H NMR (CDCl3) 8 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).
Step 10: 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 O
N OH
O O
F
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 (0.848, 2.14 mmol) and MeOH (72 mL). To this solution was added aqueous NaOH ( 11 mL of a 1N solution). The mixture was stirred at ambient temperature 18h. The organic solvents were removed in vacuo and the aqueous residue was washed with Et2O
then acidified with 1N HCI. The mixture was extracted with Et;20 and the Et2O extract was washed with brine, dried (MgS04), filtered and concentrated in vacuo. The crude solid was recrystallized from a mixture of EtOAc and hexane to give 4-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 as a white, crystalline solid.
MP: 151-152°C (dec). 1H NMR (CDCl3) 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).
4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-VI-5-1 Step 1: 1-[1-(4-Fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-N II
O
F
To a 500 mL round bottomed flask with a stirring bar and a drying tube was added 1-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AI-1-1 (11.64g, 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to -78°C and concentrated nitric acid (3.7 mL of 15.9 N solution, 58.24_ mmol) was added with a pipette. The cooling bath was allowed to expire and the mixture warmed to 0°C over 7h. The acetic anhydride was removed in vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHC;03 solution (2X) and brine.
Drying (MgS04), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 20°~0 EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et20/hexane to give white crystals of 1-[1-(4-fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDCl3) 8 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).
Step 2: 1-[4-Amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone N II
O
F
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-2-yl]ethanone AVI-1-1 (8.OOg, 30.51 mmol) absolute EtOH (640 mL) and 10°~o Pd-C (2.248, 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-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).
Step 3: 1-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 (~Hs)2N
N II
O
F
To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yI]ethanone AVI-2-1 (0.50g, 2.15 mmol), dry DMF (20 mL), finely powdered Cs2C03 (3.26g, 10 mmol) and MeI (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 dissolved in EtOAc and washed with water (3X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50°h EtOAc-hexanes as eluant to give 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yI]ethanone AVI-3-1 as an oil. 1H NMR (CDCl3) 8 2.36 (3H, s), 2.70 (6H, 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), 7.1.1 (2H, m).
Step 4: 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AVI-4-1 (CH3)2N O
N ~ ~ -OEt O O
F
In a manner substantially similar to that described for Example AV-9-1 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 was used to prepare 4-[4-dimethylarnino-1-(4-fluorobenzyl)-1H-pyrrol-2--13f-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-dioxobutyric acid AVI-5-1 (CHs)2N
O
N ~ ~ -OH
O O
F
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 A I-4-1 was used to prepare 4-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVI-5-1. 1H NMR (DMSO-d6-CDC13 1:1) 8 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).
The following compounds was prepared in a manner similar to that described for AVI-5-1:
4-[1-(4-Fluorobenzyl)-4-vitro-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Calc. (C15H11FN206~0.8H20) 51.65, 3.64, 8.03; Fnd. 51.65, 3.42, 7.88. (67) COOH
N II II
O O
F
4-[4-(Benzylamino)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN Calc. (C22H1gFN204 ~ 0.33 CHCl3) 61.83, 4.49, 6.45; Fnd.
62.07, 4.27, 5.74. (68) BnHN
COOH
N
O O
F /
4-[5-Nitro-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Calc. 53.90, 3.32, 8.38; Fnd. 53.77, 3.24, 8.20. (69) O O
COOH
F /
4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 Step 1: 1-[1-benzyl-1H-pyrrol-3-yl]ethanone AVII-1-1 O
N
(\
To a solution of 3-acetylpyrrole ( 545 mg, 5.00 mmol) in DMF ( 10 mL) at 0 °C was added benzyl bromide (0.60 mL, 5.05 mmol) followed by NaH (260 mg of a 60°~o suspension in mineral oil, 6.50 mmol). After stirring at °C for 20 min and room temperature for 1 h, the reaction mixture was treated with sat. NH4C1 ( 10 mL) and poured onto sat. NH4C1 (50 mL).
The resulting mixture was extracted with Et20 (3 x 50 mL). The 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).
mass spec (EI, M+ ) 199 Step 2: 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester O
I I
N O
To a solution of A I-1-1 (900 mg, 4.52 mmol) in THF (10 mL) was added dimethyl oxalate (795 mg, 6.74 mmol) followed by NaH (270 mg of a 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 CH2Cl2 (3 x 20 mL). The combined organic extracts were washed with sat. NaCI (20 mL) and dried (MgS04). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 5:5:1/CH2C12:hexanes:EtOAc, afforded the product as a yellow solid.
1H NMR (400 MHz, CDCl3) 8 7.44 (m, 1H), 7.40-7.32 (m, 3H), 7.19-7.15 (m, 2H), 6.72-6.68 (m, 3H), 5.09 (s, 2H), 3.91 (s, 3H).
Step 3: 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 O
OH
I I
N O
To a solution ofAVII-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 Et2O (5 x 10 mL). The Et20 extracts were discarded. The aqueous phase was treated with 3 N HCl (20 mL), extracted with CH2C12 (3 x 20 mL) and the combined organic extracts dried (MgS04). Concentration provided a yellow solid which was recrystallized from benzene to afford the desired product as a light yellow solid. mp 151-152 °C (uncorrected) 1H NMR
(400 MHz, d6-DMSO) F~ 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.
In a manner similar to that described for AVII-3-1, the following compounds were prepared:
4-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-2 (71) OH
I I
N O
- 14(~
mp 145-146 °C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 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.
EXAMPhE 72 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-3 O
OH
I I
N O
Br AVM
mp 159-160 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 8.07 (m, 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.
4-[1-(4-fluorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-,~ I.
N O
AVII-3-4 was prepared in a manner similar to AVII-3-1, starting with 4-methyl-3-acetyl pyrrole. mp 162-163 °C (uncorrected) 1H NMR (400 MHz, ds-DMSO) 8 8.10 (m, 1H), 7.37 (dd, J = 5.5, 7.6 Hz, 2H), 7.18 (dd, J =
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.
4-[2,4-dimethyl-1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid H3~ OH
il N ~H3 O
/ F
A VII-3-~
AVII-3-5 was prepared in a manner similar to AV- II-3-1, starting with 2,4-dimethyl-3-acetyl pyrrole. mp 7.84-185 °C (uncorrected) 1H NMR (400 MHz, dg-DMSO) 8 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.
4-[1-(3,4-difluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-6 OH
I I
N O
\ F
mp 143-144 °C (uncorrected) 1H NMR, (400 MHz, dg_DMSO) 8 8.05 (s, IH), 7.43 (m, 2H), 7.17 (m, 1H), 7.03 (dd, J = 3.0, 1.8 Hz, 1H), 6.73 (s, 1H), 6.61 (dd, J = 3.0, 1.8 Hz, 1H), 5.16 (s, 2H), 3.3 bs, 1H). mass spec (negative mode electrospray, M-H) 306.
4-[1-(3-chlorobenzyl>-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-7 OH
I I
N O
\ CI
mp 159-160 °C (uncorrected) 1H NMR (400 MHz, ds-DMSO) 8 8.07 (m, 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.
_4-f l.-(4-chlorobenzyl)-1H-pyrrol-3-yll-2 4-dioxobutyric acid AVII 3 8 O O
OH
N O
mp 170-171 °C (uncorrected) 1H NMR (400 MHz, dg-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 (negative mode electrospray, M-H) 304.
4-fl-(4-bromobenzvl>-1H-nvrrol-3-vll-2 4 dioxobutvric acid AVII 3 9 O
OH
I I
N O
i~
/
Br AVII-3-9 mp 184-185 °C (uncorrected) 1H NMR (400 MHz, dg_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), 5.1? (s, 2H). mass spec (negative mode electrospray, M-H) 348, 350.
4-fl-(3,4-dichlorobenwl)-1H-pvrrol-3-vll 2 4 dioxobutvric acid AVII 3 10 OH
I I
N O
CI
C I A-n-3-10 mp 175-176 °C (uncorrected) 1H NMR (400 MHz, dg_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, 1H), 5.18 (s, 2H), 3.36-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338, 340.
4-fl-(2-methvlbenzvl)-1H-nvrrol-3-yll-2 4-dioxobutyric acid AVII 3 11 O O
OH
I I
N O
mp 119-120 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 ?.91 (t, J =
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, LH), 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.
4-[1-(3-chlorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-O
,~ II
N O
CI
AVII-3-12 was prepared in a manner similar to AVII-3-l, starting with 4-methyl-3-acetyl pyrrole.
mp 148-149 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 8.09 (d, ~1 =
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.
4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-O O
,O H
I I
N O
C F:3 mp 145-146 °C (uncorrected) 1H NMR (:400 MHz, ds-DMSO) 8 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.
4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-14 O O
.OH
I I
N O
C H i AVII-3-14 - 146 .-WO 99/62513 PCTlUS99/12095 mp 164-165 °C (uncorrected) 1H NMR (400 MHz, dg_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
1.
mass spec (negative mode electrospray, M-H) 284 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-15 O O
OH
I I
N O
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 4-f 1-(3-methvlbenzvl >-1H-nvrrnl-~Yl~-2 4 dioxobutvric ac,~i~d AVII 3 16 OH
I I
N O
Rf =0.49 (94:6:1 CH2C12 / MeOH / HOAc) 'H NMR (400 MHz, CDCl3) b 7.46 (s, 1H), 7.25 (m, 2H), 7.15 (d, ~1=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).
The following compounds were prepared in a manner similar to AVII-3-l 4-Il-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-yl)-2,4-dioxobutyric acid CHN Calc. (C17H16FN04 0.2 water) 63.62, 5.15,4.36; Fnd. 63.54,5.07,4.00.
4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid O OH
'~ ~C02H
N
Br CHN Calc. 51.45, 3.45,4.00; Fnd. 51.53,3.50,3.92.
4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-yl] -2.4-dioxobutyric acid O OH
N
CI
CHN Calc. 58.93,3.96,4.58; Fnd. 58.79,4.04,4.47.
4-[4-Benzylmethylamino-1-(4-fluorobenzyl )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVIV-4-~
Step 1: 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIV-1.-1 \ I
NH
N II
O
F
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)-1H-pyrrol-2-yl]ethanone AVI-2-1 (I.OOg, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHC03 , aqueous sodium potassium tartrate and brine. Drying - 14~ --(MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30°~o EtOAc in hexanes as eluant to give 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl)ethanone AVIV-1-1 as a crystalline solid. 1H NMR (CDCl3) 8 2.34 (3I-i, 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-yl]ethanone AVIII-2-1 N
N I
O
F
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)-1H-pyrrol-2-yl]ethanone AVIV-1-1 (0.472g, 1.46 mmol), MeOH (20 mL), formalin ( 1.19 mL of 37% aqueous solution, 14.64 mmol) and sodium cyanoborohydride (0.628g, 10.00 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.57 mL, 10.0 mmol}
in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHC03, aqueous sodium potassium tartrate and brine. Drying (MgS04), 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-benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl)ethanone AVIV-2-1 as a crystalline solid. 1H NMR (CDCI,g) 8 2.25 (3H, s), 2.36 (3H, s), 4.16 (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]-2,4-dioxobutyric acid ethyl ester A-VIII-3-I
N
O
N ''~ ~ -OEt O O
F /
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-1-(4-fluorobenzyl)-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-I-(4-fluorobenzyl)-1H-pyrrol-2-yl;]-2,4-dioxobutyric acid AVI-5-1 N
N ~ ~ ~OH
O O
F /
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 AVIV-3-1 was used to prepare 4-[4-benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVIV-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, rn), 7.28 (5H, m).
- I51 ~-4-[4-Dimethylamino-1-(4-fluorobenzy) )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-IX-3-1 Step 1: 1-[1-(4-Fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-O
F
To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 1-[1-(4-tluorobenzyl)-4-iodo-1H-pyrrol-2-yl)ethanone AIII-1-1 (I.OOg, 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 was cooled to 20°C and diluted with EtOAc. This solution was washed with H20, 1N HCl, H20, and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using I5~o EtOAc in hexanes as eluant to give 1-[ 1-(4-fluorobenzyl )-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 as an oil. 1H NMR (CDCl3) 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 Et O O
F
In a manner substantially similar to that described for Example AV-9-1.
1-[1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 was used to prepare 4-[4-phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-I which was used in the next step without further purification.
Step 3: 4-[4-Phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AIX-3-1 OH
O O
F
In a manner substantially similar to that described for Example AV-10-1 4-[4-phenyl-L-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-1 was used to prepare 4-[4-phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid IX- -1. 1H NMR (DMSO-dg) 8 5.66 (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).
4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pyrrol-3-yl]-2,4-dioxo-butyric acid AX-3-1 Step 1: N-[4-acetyl-1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-methanesulfonamide AX-1-1 H
H3C~ ,N
O S.O I
~CH3 N
O
A solution of 1-[4-amino-1-(4-fluoro-benzyl)-1H-pyrrol-3-yl]-ethanone AVI-2-1 (.5g, 2.15 mmole) in 10 ml of CH2C12 was cooled to 0°C and treated with triethylamine (.25 mL, 3.22 mmole) followed by methane sulfonylchloride ( .45 mL, 3.22 mmole) dropwise via syringe. The reaction was completed in two hours and was diluted with CH2C12 and washed with 10% citric acid. Organic layer was dried over MgS04, filtered and concentrated in uacuo to afford a light pink semi-solid residue. This material was chromatographed on silica gel using 50%
EtOAcIHex as eluant to give AX-1-1 as a white crystalline solid. 1H
NMR (400 MHz, CDCl3) 8 7.12 (m, 2H), 6.96 (m, 2H), 6.94 (d, J=l.BHz, 1H), 6.85 (d, J=l.BHz, 1H ), 5.97 (s, b, 1H), 5.49 (s, 2H), 2.97 (s, 3H), 2.39 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pyrrol-3 yl]-2,4-dioxo-butyric acid ethyl ester AX-2-1 H
H3C~ ,N
O S.O
CO~Et N
O O
A solution of AX-1-1 (460 mg, 1.48 mmole) in lOml 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 HCl solution and extracted twice with EtOAc. Combined extracts were washed with brine and dried over MgSO4, filtered and evaporated to give a yellow brown residue that was flashed chromatographed using 100°h EtOAc as eluant to give AX-2-1. as a yellow crystalline solid. 1H NMR
(400 MHz, CDCl3) b 7.13 (m, 2H), 6.97 (m, 4H), 6.75 (s, 1H), 5.92 (s, br, lH) , 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
H3C~ ,N
N
O O
F
A solution of AX-2-1 (200 mg, 0.48 mmole) was dissolved in 6ml of CH~30H and 6m1 of 1N NaOH for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HCl and extracted three times with EtOAc. Combined extracts were washed with brine, I5 dried over MgS04, filtered and evaporated to give an oily residue that was triturated with 20% EtlO/Hex to afford AX-3-1 as a yellow crystalline solid.
m.p.: 160°C decomposed 1H NMR (400 MHz, DMSO-d6) 8 9.33 (s, 1H), 7.39 (s, 1H), 7.12-7.17 (m, 5H), 6.75 (s, 1H), 5.58 (s, 2H), 2.92 (s, 3H ).
The following compounds were prepared in a manner similar to that described for AX-3-1:
4-[1-(4-Fluorobenzyl)-3-acetylamino-1H-pyrrol-2-yl]-2,4-dioxobutyric acid NHAc COOH
N
O O
F
CHN Calc. 58.96, 4.37, 8.09; Fnd. 59.20, 4.30, 8.06.
4-[4-acetylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid H
~N
O / t C02H
N
\ O OH
F
CHN Calc. (C17H15FN2O5 0.3 H20) 58.05, 4.47, 7.97; Fnd. 58.09,4.40,8.06.
4-[1-(4-fluorobenzyl)-4-(2-oxo-piperidin-1-yl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid O
N
N \ CO2H
\ O OH
F
CHN Calc.( C2pH1gFN205 0.4 H20) 61.03, 5.07, 7.12; Fnd. 60.96, 5.00, 7.22.
4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxo-butyric acid AXI-5-1 Step l: (4-fluorophenyl)-(1-triisopropylsilanyl-1H -pyrrol-3-yl)methanone AXI-1-1 O
/ \
I
Si(i-Pr)3 pXl-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 added. The mixture was stirred for 0.5 h at O°C then 3 h at room temperature and then poured into 300 mL cold saturated NH4C1 solution. The organic phase was separated and combined with two CH2C12 extracts of the aqueous phase. The combined organic layers were washed with NH4Cl solution and dried over MgS04, filtered and evaporated to give a crude brown oil. Flash chromatography on silica gel of the crude product, using a 5:95 EtOAc / Hexane mixture as the eluting solvent, gave I-1-1 as a yellow oil. TLC Rf-__0.54 ( 10:90 EtOAc /
Hexanes) 1H NMR, (400 MHz, CDCl3) 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).
Step 2: 3-(4-fluorobenzyl)-1-triisopropylsilanyl-1H -pyrrole AXI-2-1 /\
I
Si(i-Pr)3 AXI-2-1 In a similar manner to AII-2-1, AXI-1-l (3.50 g, 0.0101 mole) was refluxed with 1.0 M BH3-Me2S (30.3, 0.0303 mole) in 100 mL anhydrous THF to give AXI-2-1 as a light yellow solid. TLC Rf-__0.57 (5:95 EtOAc /
Hexanes) 1H NMR (400 MHz, CDCl3) 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).
Step 3: 1-[4-(4-fluorobenzyl)-1-triisopropylsilanyl-1H -pyrrol-3-yl]ethanone AXI-3-1 O
F N
I
Si(i-Pr)3 pXI-3-I
In a similar manner to AXI-1-l, AXI-2-1 was acylated using freshly distilled acetyl chloride to give AXI-3-1 as a light yellow solid.
TLC Rf--0.41 ( 10:90 EtOAc / Hexanes) I H NMR (400 MHz, CDC13 ) 8 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) Step 4: 1-[4-(4-fluorobenzyl)-1H -pyrrol-3-yl]ethanone AXI-4-1 O
F N
A solution of AXI-3-1 (0.1458, 0.387 mmol) in dry THF (0.5 mL ) was treated with tetra-n-butylammonium fluoride (0.397 ~tL 1.0 M in THF, 0.387 mmol) at room temperature for one hour. The reaction was quenched with saturated NaHC03, extracted with EtOAc, dried over MgS04, filtered and concentrated to give the product as a yellow solid.
TLC Rf--0.15 ( 10:90 EtOAc / Hexanes) 1:H NMR (400 MHz, CDCl3 ) 8 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).
Step 5: 1-[1,4-bis-(4-fluorobenzyl)-1H -pyrrol-3-yl]ethanone AXI-4-2 O
/ \
In a similar manner to AIV-3-1, AXI-4-1 was alkylated using 4-fluorobenzyl bromide to give AXI-4-2 as a light brown oil.
TLC Rf-__0.69 (40:60 EtOAc / Hexanes ) 1 H NMR (400 MHz, CDC13 ) 8 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).
Step 6: 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid O O
OH
/\
NJ O
H AXI-S- l 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 CHCl3 / MeOH / HC>Ac) 1H NMR (400 MHz, CDCl3) 8 8.4 (bs, IH), 7.4 (s, 1H),7.2 (m, 2H), 6.97 (m, 2H), 6.41 (s, 1H), 4.1 (s, 2H).
4-[1,4-bis-(4-fluorobenzyl)- 1H -pyi-rol-3-yl]-2,4-dioxobutyric acid AXI-5-2 O O
off ~ ~ \ ~ o F N
I\
s AXI-4-2 was carried on to the diketo acid AXI-5-2 as described for AI-3-1.
ThC Rf--0.66 (94:6:6 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) b 7.41 (s, 1H), 7.04-7.19 (m, 6H), 6.96 (m, 2H), 6.70 (s, 1H), 6.28 (s,lH), 4.97 (s, 2H), 4.07 (s, 2H).
EXAMPhE 97 4-[5-(3-carboxy-3-oxo-propionyl )-1-(4-fluorobenzyl )-1H-pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 Step 1: 1-(4-fluorobenzyl)-1H-pyrazol-3,5-dicarboxylic acid diethyl ester BI-1-1 O
° oEt Et0 N~N
I
F
A mixture of 1H-pyrrole-2,4-dicarboxylic acid diethyl ester (.424 g, 2 mmol), 4-fluorobenzyl bromide (.378 g, .25 ml, 2 mmol) and triethylamine (.303 g, .417 ml, 3 mmol ) was dissolved in 5 ml drv DMF
and stirred for 18 hr.. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate/ H2O and extracted.
The combined organics were washed with H20, brine, dried over Na2SU4, filtered and the solvent removed. TLC showed about 309 unreacted pyrrole. Further purification by column chromatography (2:1 hexane/ethyl acetate) gave .335 gr (5010) of the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3) d 1.34 (t, 3H, J = 7.14), 1.41 (t, 3H, J = 7.14 Hz , 4.32 (q, 2H, J = 7.14 Hz), 4.42 (q, 2H, ~I = 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)-1H-pyrazol-3,5-dicarboxylic acid dilithium salt BI-2-1 O
O OLi \1 Li0 ~N
F
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 purification.
Step 3: 1-(4-fluorobenzyl)-1H- pyrazol-2,4-dicarboxylic acid bis-(methoxymethylamide) BI-3-1 O
O OMe ~N
MeO~N / N
N' '~
F
- 161 _ A mixture of BI-2-1 from the previous example, N,O-dimethylhydroxylamine hydrochloride (.121 g, I.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (.238 g, 1.24 mmol), 1-hydroxybenzotriazole hydrate (.7.67 g, 1.24 mmol), and triethylamine (.125 g, .173 ml, 1.24 mmol) were combined in 3 ml DMF and stirred for 18 hr. The solvent was removed in uacuo and the residue partitioned between ethyl acetate~H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04 filtered and the solvent removed. Further purification via radial disc chromatography (l:l hexane/ethyl acetate) afforded the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3) b 3.27 (s, 3F1), 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)-lH-pyrazol-3-yl]ethanone BI-4-1 O
O
N~N
BI-3-13-1 (.I42 g, .41 mmol) was dissolved in 5 ml dry THF and cooled to -78°C. To this was added methyl lithium (1.158 ml of a 1.4M solution in diethyl ether, 1.64 mmol). The mixture was stirred for 1 hr, then quenched by the addition of excess l0~lo aqueous citric acid solution.
After warming to room temperature, the mixture was poured into 10 ml H2O and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to get the title compound as an oil.
1H NMR (400 MHz, CDCl3) 8 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) Step 5: 4-[5-(3-ethoxycarbonyl-3-oxopropionyl)-1-(4-fluorobenzyl)-lH-pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester BI-5-1 O O
O OEt O ~ \ v O
Et0 ~ N~N
O \
F
Bl-5-1 In a similar manner to AIII-2-1, BI-4-1 (.094 g, .36 mmol) was reacted with diethyl oxalate (.212 g, .196 ml, 1.44 mmol) and sodium ethoxide (.096 g, 1.44 mmol) to give the title compound as a yellow solid.
1H NMR (400 MHz, CDC13) 8 1.38 (t, 3H, J = 7.33 Hz), 1.42 (t, 3H, J = 7.:14 Hz),4.36(q,2H,J=7.14Hz),4.41(q,2H,J=7.14Hz),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) Step 6: 4-[5-(3-carboxy-3-oxopropionyl)-1-(4-fluorobenzyl)-1H
pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 O O
O OH
O ~ 1 v O
HO ~N~N
O \
F
In a similar manner to AI-3-1, BI-5-1 (.157 g, .35 mmol) was reacted with LiOH (.7 ml of a 1M solution in H20) in 5 m1 THF to give the title compound as a light tan solid. MP = 215 - 217 °C
1H NMR (400 MHz, CDCl3) 8 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) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 Step 1: 4-bromo-1-(4-fluorobenzyl)-1H-pyrazole BII-1-1 Br N~N
F
Bn-I-~
4-Bromopyrazole (.441 g, 3mmol) was added to a slurry of sodium hydride (.072 g, .12 gr of a 60°l0 oil dispersion, 3 mmol ) in 5 ml DMF
and stirred for 15 min, after which 4-fluorobenzyl bromide (.568 g, .374 ml, 3 mmol) was added and the reaction was stirred for 18 hr. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to afford title compound as a colorless oil. 1H NMR (400 MHz, CDC13) cS 5.23 (s, 2H), 7.04 (t, 2H, J = $.6 Hz), 7.18 - 7.25 (m, 2H), 7.36 (s, 1H), 7.49 (s, 1H) Step 2: 1-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]ethanone BII-2-1 O
N/
F
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 which time N-methoxy-N-methyl-acetamide (.33 g, .33 ml, 3.22 mmol) - 1 f~4 -was added and the mixture allowed to warm to room temperature. After stirring for 2 hr, the reaction was quenched with l0~lo citric acid solution and extracted with H20, brine, dried over Na2S04, filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexane/ethyl acetate ) the title compound as a colorless oil.
Step 3: 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BII-3-1 O O
OEt O
N~N
F /
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) 8 I.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), ?.94 (2, 1H), 8.02 (s, 1H) Step 4: 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid O O
OH
O
N~N
F /
In a similar manner to AI-3-1, BII-3-13-1 (.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 °C
1H NMR (400 MHz, CDCl3) 8 5.31 (s, 2H), 6.71 (d, 1H, J = .73 Hz), 7.08 (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 described for BII-4-1:
4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-3-yl] -2,4-dioxobutyric acid / O OH
N / OH
/ ~ ll N~ O
N
F
CHN Calc. (C1gH16N3O4F 0.5 EtOAc) 57.28, 5.34, 11.14; Fnd. 56.93, 5.01, 11.43.
E~:AMPLE 100 4-[ 1-(4-Fluorobenzyl)-5-methyl-1H-pyrazol-4-yl~-2-hydroxy-4-oxobut-2-enoic acid OH
/ OH
I I
N~ O
N
F
CHN Calc. (C15H13N204F 0.4 MeOH) 58.33,4.64,8.84; Fnd 57.95, 4.40, 8.44.
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/
N
O
F
1-(2H-Pyrazol-3-yl)ethanone hydrochloride (.44 g, 3 mmol) was dissolved in 8 ml DMF, and to it was added sodium hydride (.144 g, .24 g of a 60%:
oil dispersion, 6mmo1). 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 Na2S04, filtered and the solvent removed. Further purification by radial disc chromatography (3:1 hexane/ethyl acetate) yielded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) 8 2.58 (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) Step 2: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid ethyl ester BIII-2-1 O
N, N OEt O O
F
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, CDCl3) b 1.38 (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 O
N, N OH
O O
F
In a similar manner to AI-3-l, BIII-2-1 (crude from previous reaction) was reacted with 1N NaOH (3m1) in 20 ml THF to yield the title compound as a light tan solid after trituration in diethyl ether. MP = 157 - 159 °C; 1H NMR (400 MHz, CDCl3) S 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) 1-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BIV-Step 1: 1-(3-methyl-1H-pyrazol-4-yl)ethanone BIV-1-1 O
N~ N
BIV-I-I
A mixture of 1-(4-acetyl-5-methylpyrazol-1-yl)ethanone (1 g, 6 mmol, Maybridge) and 10 ml 1N NaOH were dissolved in 40 ml THF and stirred 4 days. The solvent was removed in Uc~cuo and the residue partitioned between ethyl acetate/ H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to get the title compound. 1H NMR (400 MHz, CDCl3) 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 O
N~ N
F
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 work-up and purification by preparative HPLC (Chiralcel OD 25x2, 75°l0 hexane/1% diethylamine, 25% EtOH) yielded the title compound and 1-[1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]ethanone as white solids.
1H NMR (400 MHz, CDC13) 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) Step 3: 1-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester BIV-3-1 O O
OEt O
N~N
\
F
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 solid. 1H NMR (400 MHz, CDCl3) 8 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-dioxobutyric acid BIV-4-1 OH
N
O
N
F
In a similar manner to AI-3-13-1, BIV-3-1 (.234 g, .68m mmol) was reacted with 2 ml NaOH in lU ml THF to afford the title compound as a light tan solid. MP = 187-188 °C; 1H NMR (400 MHz, CDC13) b 2.53 (s, 3H), 5.23 (s, 2H), 6.64 (2, 1H), 7.08 (t, 2H, J = 8.61), 7.23 - 7.31 (m, 2H), 7.88 (s, 1H) 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-Step 1: 1-[1-(3-chlorobenzyl)-3-methyl-1H-pyrazol-4-yl]ethanone BV-1-1 and 1-[1-(3-chlorobenzyl)-5-methyl-1H-pyrazol-4-yl]ethanone BV-2-1 O O
N, ~ N /
N ' \
CI ~ CI
/ /
In a similar manner to BIV-2-l, 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°~0 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-(3-chlorobenzyl)-3-methyl-1H-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-l:
1H NMR (400 MHz, CDC13) b 2.38 (s, 3H), 2.49 (s, 3H), 5.21 (s, 2H), 7.12 (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) b 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) Step 2: 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BV-3-1 O O
OEt N, / , O
CI
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 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-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-4-1 O O
OH
/ ~ II
N~ O
N
CI
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 title compound as a light tan solid. MP - 183 - 184 °C. 1H NMR (400 MHz, CDC13) b 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) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid Step 1: 4-[5 -methyl-1-{3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BV- 5-1 O O
OEt i ~ II
N.~ O
CI
In a similar manner to AIII-2-1, BV-2-1 {.158 g, .64 mmol) was reacted with diethyl oxalate (.199 g, .185 ml, 1.36 mmol) and sodium ethoxide (.092 g, 1.36 mmol) to give the title compound, which was used without further purification. 1H NMR (400 MHz, CDC13) S 1.401'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) Step 2: 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-6-1 O O
OH
i ~ II
N~ O
N
CI
In a similar manner to AI-3-1, BV-5-1 (crude from above) was reacted 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 °C
1H NMR (400 MHz, CDCl3) 8 2.53 (s, 3H), 5.23 (2, 2H), 6.67 (s, 1HO, 7.12 -7.18 (m, 1H), 7.25 (s, 1H), 7.31 - 7.36 (m, 2H), 7.97 (s, 1H) 4-[1-(4-fluoro-benzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 Step 1: 1-(4-fluoro-benzyl)-1H-imidazole CI-1-1 r-- N
J
N
\
F
To a solution of imidazole (10g, 0.146 mole) in 80 ml of DMF at 0°C was added triethylamine ( 25.5 ml, 0.176 mole) followed by a solution of 4-Fluorobenzylbromide ( 22 ml, 0.176 mole) in 30m1 of DMF added dropwise via addition funnel. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure in uctcuo. The residue was partitioned with H20 and CH2C12. The organic layer was washed with saturated NaHC03, brine, dried over MgS04, filtered and evaporated to afford a crude oil. This material was chromatographed on silica gel using 50-100% EtOAc,/Hex as eluant. Obtained CI-1-1 as an oil. 1H
NMR (400 MHz, CDCl3) 8 7.53 (s, 1H), 7.09-7.I5 (m, 5H), 6.88 (s, 1H), 5.09 (s, 2H).
Step 2: 1-(4-fluorobenzyl)-1H-imidazole-2-carboxylic lithium salt CI-N 1_2_1 ~C02-Li+
N
F
A solution of I-1-1 (8.81g, 0.05mole) in 120 ml dried THF at -78°C
under N2 was added a solution of 2.5M nBuLi in Hexanes (2lml, .052 mole) dropwise via syringe over 40 minutes. 'this resulting mixture was aged for 1 hour at -78°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 obtain I -2-1 as a solid salt. 1H NMR (400 MHz, DMSO-dg) 8 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)-1H-imidazole-2-carboxylic acid methoxy-methyl-amide CI-3-1 r---N O C H 3 W
N~N~CH3 F
A solution of I -2-1 (7.Og, .031 mole) was treated with EDC.HCI (6.5g, .034 mole), HOBT.H20 (4.6g, .034 mole), N,0- dimethylhydroxy-amine.HCl (3.31g, .034 mole), and triethylamine (12.9 ml, .092 mole) in 60 ml of DMF and stirred over the weekend under N2 . The DMF was removed under reduced pressure in vocuo. The residue was partitioned with saturated NaHC03 and extracted three times with EtOAc.
Combined organics layers were washed with H20 and brine, dried over MgS04, filtered and evaporated to afford a yellow oil. This crude material was chromatographed on silica gel using 70-100% EtOAcIHex as eluant. Obtained CI-3-13-1 as an oil. 1I NMR (400 MHz, CDC13) s 7.19-7.23 (m, 2H), 7.09 (s, 1H), 6.97-?.04 (m, 3H), 5.42 (s, 2H), 3.81 (s, 3H), 3.48 (s, 3H) Step 4: 1-[1-(4-fluorobenzyl)-1H-imidazol-2-yl)ethanone CI-4-1 N
CHI
N
O I_4-F
A solution of ,I -3-1 (2.0g, .0076 mole) in 60 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (6.5 ml, .0091 mole) in Et20 drnpwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to 0°C for 2 hours. The reaction was quenched with 75m1 of saturated NH4C1 solution and extracted with three times EtOAc. Combined organics layers were washed with brine, dried over MgS04, filtered and evaporated to give an oil. This crude material was chromatographed on silica gel using 70% EtOAc/Hex as eluant. Obtained I- 4-1 as an oil. 1H
NMR (400 MHz, CDCl3) b ?.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 ethyl ester CI-5-1 N
C02Et N
F
A solution of I- 4-1 (0.5g, 0.0023 mole) in 8ml dried THF was treated with diethyl oxalate (0.62 ml, 0.0046 mole) and sodium ethoxide (.31g, 0.0046 mmole) at room temperature over night under N2 atmosphere.
The reaction mixture was poured into 10 ml of .5 N HCl solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgS04, filtered and evaporated to give a crude residue. This crude material was chromatographed on silica gel using 50% EtOAcIHex as eluant. Obtained CI- 5-1 as a beige solid. 1H NMR
(400 MHz, CDCl3) 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) Step 6: 4-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid N
N
O O
\ CI- -1 F /
A solution of CCIiS-11 {0.3 g, 0.0009 mole) was dissolved in 7ml of CH30H, 7 ml of THF and 3ml of 1N NaOH and stirred for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HCl and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgS04, filtered and evaporated to give a crystalline solid, that was stirred in hot EtOAc and filtered to obtained I- -1 as a light beige solid. m.p.: 163-164°C. 1H NMR (400 MHz, CDC13) 8 7.20 (m, 3H), 7.13 (s, 1H), ?.O1 (t, 3H), 5.69 (s, 2H).
In a manner similar to that described for I- -1, the following compound was prepared:-4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid ~N
~N '~'~ ~ _OH
O O
[\
CHN Calc. 61.76, 4.44, 10.29; Fnd. 61.80, 4.58, 10.17 4-[1-(4-fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 Step 1: 1-(4-fluorobenzyl)-1H-imidazole-4-carboxylic acid 4-fluoro-benzyl ester CII-1-la; and 3-(4-fluorobenzyl )-3H-imidazole-4-carboxylic acid 4-fluoro-benzyl ester CII-1-lb O ~. O _ N O 1 / F \ N O 1 / F
L~ I
N + F N
I \ ~II_1;1a H X11_1_ F
A suspension of 1H-imidazole-4-carboxylic acid ( l.Og, 0.0089 mole ) in 25 ml of DMF was treated with Cs2C03 (8.728, .026 mole) followed by 4-fluorobenzyl bromide (3.33 ml, .026 mole) and stirred overnight at room temperature under N2 atmosphere. DMF was removed under reduced pressure in Uaccuo. The residue was partitioned with H20 and three times with EtOAc. Combined extracts were washed with brine, dried over MgS04~, filtered and evaporated to give a crude oil. This material was chromatographed on silica gel with 50% EtOAc/Hex as eluant to afford a l:l mixture of I I-1-la and I I- 1-1 1H NMR (400 MHz, CDCl3) 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)-1H-imidazol-4-yl]-ethanone CII-2-1 O
'CH3 N
'N
F
A solution of CI I-1-1 (0.9g, .0027 mole) in 10 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (2.35 ml, .0032mo1e) in Et2O
dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to room temperature over the weekend. The reaction was quenched with l0ml of 1N HCl. The solution was basified with saturated NaHC03 and extracted with EtOAc three times. Combined organics layers were washed with brine, dried over MgS04, filtered and evaporated to give CI I-2-1 as a crystalline solid. 1H NMR (400 MHz, CDCl3) 8 7.53 (d, 2H), 7.15 (m, 2H), 7.04 (m, 2H), 5.1 (s, 2H), 2.5 (s, 3H).
Step 3: 4-[1-(4-fluorobenzyl)-LH-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester CII-3-1 O O
C02Et N
N
F
A solution of I I-2-1 (75 mg, 0.34 mmole) in 3ml dried THF was treated with diethyl oxalate (U.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 HCl solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgS04, filtered and evaporated to give I I-3-1 as a bright yellow oil. Used as is without further purification. 1H NMR (400 MHz, CDCl3) b 7.78 (s, 1H), 7.69 (s, 1H), ?.22 (m, 2H), 7.10 (m, 3H), 5.19 (m, 2H), 4.35 (m, 2H), 1.4(m, 3H).
Step 4: 4-[1-(4-fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid O O
N
N
F
A solution of CI I-3-1 (70 mg, 0.2 mmole) was dissolved in 3ml of CH3OH
and 3ml of 1N NaOH for 3 hours. The reaction mixture was washed with ether, acidified to pH 1-2 with 1N HC1 and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgS04, 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) 8 8.24 (s, 1H), 8.07 (s, 1H), 7.44 (m, 2H), 7.19 (m, 2H), 6.92 (s, 1H), 5.28 (s, 2H).
4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid DI-4-1 Step l: 1-(1H -indol-2-yl)ethanone DI-1-1 N
H
A solution of 2-carboxy indoie (3g, 16.9 mmol) in anhydrous ether (50 mL) was cooled to 0°C and treated with Methyl Lithium (1.4 M, 48.3 mL) A white solid precipitated. After addition was complete the reaction was warmed to reflux for two hours, quenched by pouring into ice water, and extracted with Et2O. The organic layers were combined, washed with saturated sodium bicarbonate solution and brine, dried over MgS04, filtered and evaporated to give DI-1-1 as a white solid. Rf-__0.53 (20%
EtOAc/Hexanes ) 1H NMR (400 MHz, CDC13) 8 9.1 (bs, lh), 7.72 (d, J= 7.78 Hz, 1H), 7.42 - I HO -(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-[l-(4-fluorobenzyl)- 1H -indol -2-yl]ethanone DI-2-1 \ ~ ~ CHs N
O
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 (20r1o EtOAc/Hexanes> 1H NMR (400 MHz, CDC13) 8 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).
Step 3: 4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid \
O
N ~ ~ -OCH3 O O
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-3-13-1 as a yellow solid. Rf--0.26 (97:3:1 CHC13 / MeOH / HOAc). 1H NMR (400 MHz, CDCl3 ) 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 O
-OH
O O
F
Df-4-1 In a manner similar to that described for the preparation of A-I-3-1, I-I-3-11 was treated with sodium hydroxide to give DI-4-1 as bright yellow crystals after crystallization from EtOAc. 1H NMR (400 MHz, DMSO-D6) 8 7.90 (s, 1H), 7.77 (d, J= 7.88 Hz, 1.H), 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.
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 N
CHN Calc.(C13H11N04 0.15 H20) 62.97, 4.59, 5.65; Fnd. 63.05, 4.45, 5.80.
4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid DII-3-1 Step 1: 1-[1-(4-fluorobenzyl)-1H-indol-3-yl]ethanone DII-1-1 WO 99!62513 PCT/US99/12095 O
\~ O
N
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°~0 oil dispersion, 2 mmol) in 2 ml DMF
for 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)-1H-indol-3-yl]-2,4-dioxobutyric acid ethyl ester DII-2-1 O
OEt v \ ~ ~ O
N
w F
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 g, 2 mmol) to yield the title compound as a yellow solid after trituration in diethyl ether.
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, 2I~, J = 8.6 Hz), 7.13 - 7.20 fm, 2H), 7.30 - 7.39 (m, 3H), 7.88 (s, 1H), 8.40 (d, 1H, J = 7.51 Hz) Step 3: 1-[1-(4-fluorobenzyl)-1H-indol-3-yl)-2,4-dioxobutyric acid DII-O
O OH
O
F
In a similar manner to AI-3-1, DII-2-1 (.1 g, .27 mmol) was hydrolyzed using .54 m1 1M LiOH (5.4 mmol) in 2 m1 THF to give the title compound as a yellow solid. MP = 161- 162 °C. 1H NMR, (400 MHz, CDCl3) 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) HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, C.M. and Bushman F.D. (1997) Cell; 88, 483 for recombinant integrase and preintegration complexes, respectively, hereby incorporated by reference for these purposes.
Representative compounds tested in the integrase assay demonstrated IC50's less than 1 micromolar. Further, representative compounds tested in the preintegration complex assay also demonstrated IC50's of less than 1 micromolar.
Assay 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.
Representative compounds tested in the present assay demonstrated ICgSs of less than 10 micromolar.
Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as come within the scope of the following claims and their equivalents.
(a) halogen, (b> Cl-~ alkyl, (c> C1_6 alkyloxy-, (d) -CF3, 1~ (e) -OCF3, -CN, (g) =O, and (h) hydroxy.
In another class of compounds of the present invention, R3 is selected from:
( 1 ) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, 2~ (b) C1-6 alkyl, (c) C1-s alkyloxy-, (d) phenyl, (e) -CF3, -OCF3 , (g) _CN, (h) hydroxy, (i) phenyloxy, and _2H_.
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1_6 alkyl, (iii) -CF3, and (iv) hydroxy, (3) thienyl, (4) py~dyl, (5) imidazolyl, (6) pyrrolyl, (7) pyrazolyl, (8) C3_6 cycloalkyl, (9) substituted C3_6 cycloalkyl with 1 or 2 substituents independently selected from:
1~ (a) halogen, (b) Cl_6 alkyl, (c) C1_~ alkyloxy-, (d) -CFg, (e) -OCF3, (f7 -CN, ( g) =O, and (h) hydroxy;
(10) piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and (14) C3_~ cycloalkyl fused with a phenyl ring.
In still another class of compounds of the present invention, R3 is selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1_6 alkyl, (c) Cl_6 alkyloxy-, (d) phenyl, (e) -CF3, (I7 -OCF3, (g) -CN, (h) hydroxy, (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, (ii) methyl, (iii ) -CF3 , and (iv) hydroxy;
(3) C3_6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo;
and (6) naphthyl.
In one class of compounds of the present invention, R4 is selected from:
(1) -H, (2) -C1-3 alkyl, and (3) -CF3.
In another class of compounds of the present invention, R4 is selected from:
(1) -H, (2) -Cl_3 alkyl, (3) -CF3, (4) _R3, (5 ) -C2_3 alkenyl, (6) -Ct-3 alkyl-R3, _3O_ (7) -C2-3 alkenyl-R3, (8) -S(O)n-R'~, and (9) -C(O)-R~.
In still another class of compounds of the present invention , R4 is selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CFA, (4) -R3, (5 ) -C 1-~ alkyl-R3 , (6) -S(O)n-R3, and (7) -C(O)-R~.
In yet another class of compounds of the present invention , R4 is selected from:
(1) -H, and (2) -C1-3 alkyl.
In one class of compounds of the present invention, R5 is selected from:
(1) -H, (2) -C1-~ alkyl, (3 > -CF3 , (4) -R3 , (5) -C2-3 alkenyl, -C1-3 ~yl-R3>
(7) -C2-3 alkenyl-R3, (8) -S(O)ri R3, and (9) -C(O)-R'3 _ In another class of compounds of the present invention, is selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, and (4 ) -R3 .
In yet another class of compounds of the present invention, R 5 is selected from:
(1) -H, (2) -C1-3 alkyl, (.3) -CF3, (4) -R3, (5) -C1_3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R~.
In one class of compounds of the present invention, R7 is hydrogen.
In another class of compounds of the present invention, R7 is selected from:
(1) -H, and (2 ) C 1-4 alkyl.
In one class of compounds of the present invention, Rg is selected from:
( 1 ) -H, (2) -OCH3, and (3) -CH3.
In another class of compounds of the present invention, Rg is selected from:
(1) -H, and (2> CHg.
In yet another class of compounds of the present invention, R8 is selected from:
(1) -H, and (2) Cl_g 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/b2513 PCT/US99/12095 pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected fram:
(1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof' in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (Ia) and (Ib):
R O R~ O
R A R
ORS - ~ ORS
(la) R' ~ O
Rz ~~ ~ ~OR~
R$ OH O
(Ib) By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (Ia) and (Ibi are also intended. Similarly, be referring to compound (Ia), it is understood for the purposes of the present application that the tautomers (1) and (Ib) are also intended. The same holds true for references to tautomer (Ib>.
When any variable (e.g., R3, R4, etc. ) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The compounds of the present inventions are useful in the inhibition of HIV integrase, the prevention or treatment of infection by human immunodeficiency virus (HIV > and the treatment of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS
related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.
The present invention also provides for the use of a compound of structural formula (I) to make a pharmaceutical composition useful for inhibiting HIV integrase and in the treatment of AIDS or ARC.
Compounds of structural formula (I) wherein A is pyrrolyl may be made according to the procedures in Schemes AI-AXI.
Compounds of structural formula (I) wherein A is pyrazolyl may be prepared according to the procedures in Schemes BI-BV. Compounds of 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
N
H O
4-fluorobenzyl bromide NaH
DMF
I
~CH3 ~ ~ CH
N NIS N~ ~ 3 A1-1-1 O - O
acetone dimethyl oxalate NaH
DME
heat N~ ~ ~ ~OCH3 AI-2-1 O O
F
ROH ~ NaOH
TsOH THF / MeOH / H20 O
N~ ~ ~ -OH I- -1 O O
F
-3f~-Scheme All / \
N
H
LiHMDS
cyclohexanecarbonyl chloride THF
/ \
N
w ~O
BH3-Me2S
THF
heat / \
N
n -butyllithium THF
N - methoxy-N - methylacetamide N ~ AI- I3-1 O
dimethyl oxalate NaH
DME
heat O
N~ ~ ~ OCH3 A1I-4-1 O O
NaOH
THF / MeOH / H20 O
N~ ~ ~ -OH II- -1 O O
WO 99/b2513 PCT/US99/12095 Scheme AIII
I
/ 1 w N 1~
O
I
F
AI-1-2 I Cul ~~C6H5)3P~4Pd TEA
~~ ~ ~N
O
I
F ~ ~ 10% Pd/C
EtOH
Diethyl oxalate NaOEt THF
_39_ N
OEt I ~ O
O O /
F
Diethyl oxalate 1 N LiOH NaOEt THF THF
/
O
N ~ ~ 'OEt O O
o I
F /
~OH
a v 1 N NaOH
I
F / THF
OH
O O
F
Scheme ArV
/ \
N
H
MeMgCI
50:50 THF:MeOH
benzyl bromide / \
N
H
MeMgCI
THF
acetic anhydride F
A_ TV-2-1 / \
~N~CH3 H O
Mel NaH
DMF
F
/ \
~N~C H3 HsC O
dimethyl oxylate TFA
NaH
D M E refl ux reflux AIV-6- I
cat. MeOH
F F O
Arv-~-~ \
N' ~ ~ ~OCH3 N
dimethyl oxylate NaH
DME
1 N NaOH reflux THF cat. MeOH
F ' F O O AIV-7-1 O AIV-S-1 ~ ~ / ' OH
Q
N OH
HsC O O H3C
1 N NaOH
THF
F O O
OH
/\
~--~ N J O
Scheme AV
COOH
EtOH (abs) (f/-) N H
I SOC12 (cat) / RT
O
COOEt Boc20 / Et3N / DMF
NH
O
COOEt PhMgBr /THF
N
O -40°C / 30 min O
O Ph 1. TFA / CH2C12 / RT
O H COOEt 2. Et3N / CH2C1 / RT
1. DDQ / CH2C12 / RT
~N~COOEt 2. NaOH / H20 I reflux MeON HMe~HCI
EDC~HCI
N~'COOH
H HOBt~ H20 DMF / Et3N
OCH F ~ ~ CH2Br N.
N '~ C H 3 H O NaH / DMF
N ~ C H MeLi / TH F / -78°C
N ~ s O
\
F
O
CH3 Et0 pEt N ~ O
O
I / NaOEt I THF l RT
F
O
O~ C H 1 N NaOH / MeOH /RT
N ~ ~ s O O
F /
O
N ~ ~ -OH
O O
F /
s Scheme A-VI
HN03 / Ac20 N II
O
F /
10% Pd-C
N II
O
EtOH ! H2 (lAtm) F
N II
O
F
CH31 / DMF / Cs2C03 VA lit-1 O
(C H3)2N Et0 OEt N~ O
O
NaOEt / THF / RT
F
AVI-3-1.
- 4fi --(CH3)2N O
N ~ ~ -OEt I\
F
(CH3)2N
O
1 N NaOH / MeOH /RT
N~ ~ ~ OH
O O
I
F
SCHEME AVII
O
N
H
4-fluorobenzyl bromide NaH
DMF
O
,\
dimethyl oxalate NaH
DME
heat O O
O
N II- -NaOH
THF / MeOH / H20 O O
OH
N
Scheme AVIII
PhCHO / NaCNBH3 N~
p MeOH / HOAc F
AV1~2-1 \ NH
H2CH0 / NaCNBH3 N
O MeOH / HOAc \
F
\ N Et0 ~OEt N~ O
O
\ NaOEt / THF / RT
F
N O
/ \ 1 N NaOH / MeOH /RT
N ~~OEt I\
F
N
O
N ~ ~ OH
O O
I \
F
Scheme AIX
I
/ ~ PhB(OH)2 / Pd(Ph3P)4 N
O Et3N I DMF I 90°C
I \
F
I IA ,I-1-1 - 5() _ O
Et0 OEt O
O
NaOEt / THF / RT
F
AIX-1-i 1 N NaOH / MeOH /RT
OEt O O
F
OH
O O
F
SCHEME AX
N
F
methylsulfonylchloride H
H3C~ ,N
~S~~
O O ~ ~ CH3 N
\ O X-1-1 F
diethyloxalate NaOEt/THF
H
H3C~ ,N
S
O~ ~~O ~ C02Et N
O O
F
1 N NaOH
H
H3C~ ,N
O S O ~ ~ C02H
N
O O AX-3-13_1 F /
Scheme AXI
N
I
Si(i-Pr)3 4-fluorobenzoyl chloride O
F ~ / / ~ AXI- I - I
N
I
Si(i-Pr)3 BH3-Me2S
THF
heat _ 53 ._ WO 99/b2S13 PCT/US99/12095 F N
I
Si(i-Pr)3 acetyl chloride O
OO
F N
I
Si(i-Pr)3 [Bu]NF
THF
A7fl_4_ I O
F N
H
1 ) dimethyf oxalate NaH
DME
heat 2) NaOH
THF I MeOH i H20 OH
/\
F N
H
Scheme AXI(b) NaH
4-fluorobenzyl bromide I~ r F N
H
O
I / / \
F N~ AXI-4-2 I
F
1 ) dimethyl oxalate NaH
DME
heat 2) NaOH
THF / MeOH / H20 O O
/ \ O H ~~-5-~
F / ~N~ O
F
Scheme BI
O /
v OEt I ~ Br Et0 N~N F
H
TEA
DMF
O
O OEt Et0 ~N
N
Bl-1-1 F /
1 N LiOH
THF
O
O OLi Li0 ~N
N
\
I~
F
MeO
NH.HCI
EDC, HOBT, TEA
DMF
O
O N~OMe / ~~ 1 Me0-; ~N
~ BI~3-1., F
MeLi THF
O
O
~~~ ~N
N
F
Diethyl oxalate NaOEt THF
Scheme B1 (cont.) OEt Et0 1 N LiOH
THF
O \
BI_ _1 F
O O
O OH
O
O
HO ~N~N
O
F
Scheme BII
Br Br / ~ +
N' N F
H
NaH
DMF
Br NON
/
F
Me0 O
'N
n-BuLi Et20 O
N~N
F
Diethyl oxalate NaOEt THF
O O
OEt N. O
N
F
1 M NaOH
MeOH
OH
N.N O
F
Scheme BIII
\ ~ ~ Br N\ H F
O
NaH
DMF
N
N
O
Diethyl oxalate NaOEt THF
O
N
N OEt O O
F
1 M NaOH
THF
O
N
~N O H
O O
F ~ BIII- -Scheme BIV
N~N
O' 1 M NaOH
THF
O
N~ N ~ BIV-1-1 H
Br F
NaH/DMF
O
i N~N
\ B1V-2-1 F
Diethyl oxalate NaOEt THF
O O
OEt i ~ II
N~ ~ O
N
Iv- -F
1 M NaOH
THF
_~3_ O O
OH
N~
.N O
~ BIV-4-i F
Scheme BV
\ ' Br N. /
N
H CI
NaH
DMF
O O
N/N~ N/ , v ~N
CI ~ V-1-1 CI
Diethyl oxalate Diethyl oxalate NaOEt NaOEt THF THF
OEt OEt N~ ~ II / ~ " n O N, O
N N
CI ~ CI
/ BV-3-1 ~ / BV-5-1 1 M NaOH 1 M NaOH
MeOH
MeOH
O O
OH O O
OH
N/N \\ O N/
,N O
CI
CI
i Scheme C1 CN
N
H
4-F-benzylbromid~
TEA/ DMF
r- N
N
F
1 ) nBuLi/THF/-78°C
2) C02 -6f~-N
C02'Li+
N
\ CI-2-1 F ~
N,O-dimethylhydroxylamine.HC
EDC/HOBT/TEA/DMF
~N OCH3 N~N~CH3 O
F
CH3Li/THF/-78°C
N
N
O
\ CI-4-1 F
diethyloxalate NaOEt/TH F
N
C02Et N
a o F
1 N NaOH
N
N
O O
F
Scheme CII
N co2H
N
H
4-F-benzylbromid~
Cs2C03/ DMF
-6H._ O "~ O
/ F ~ O , / F
+ F ~ N
CH3LiITHF
-78°C
O
N
N
F
diethyloxalate Na0 Et/TH F
O O
C02Et N
F
1 N NaOH
CH30HlTHF
O O
'C02H
N
N\ CII-4-1 F
Scheme DI
off N
H O
MeLi Et20 reflux N
H O
4-fluorobenzyl bromide NaH
DMF
-7~-\ ~ ~ C Hs N
O
F
dimethyl oxalate NaH
DME
heat O
N ~ ~ OCH3 O O
F
NaOH
THF / MeOH / H20 O
N ~ ~ OH
O O
F
Scheme DII
O
-' ' ~ ~ B r \ + F~i N
H
NaH
DMF
O
\
N
w DII-1-1 \ /
F
Diethyl oxalate NaOEt THF
O
O OEt ,- ~..
O
N
F
1 M LiOH
THF
O
O OH
w O
N
w The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt°' is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygaiacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, _73_ hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl>aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed, e.g.
acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
The terms "administration of and or "administering a"
compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment..
Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectible preparations, for example, as sterile injectible aqueous or oleagenous suspensions or suppositories.
When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The injectible solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug The compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 200 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.5 to 100 mg/kg body weight orally in divided doses. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15Ø 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
The present invention is also directed to combinations of the HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS
- 7 fi -antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
ANTIVIRALS
Drub Name Manufacturer Indication 097 Hoechst/Bayer HIV infection, AIDS, ARC
(non-nucleo side reverse transcriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC
GW 141 (protease inhibitor) Abacavir (1592U89)Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC
(RT inhibitor) Acemannan Carrington Labs ARC
(Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT
AD-439 Tanox Biosystems HIV infection, AIDS, ARC
AD-519 Tanox Biosystems HIV infection, AIDS, ARC
Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/R,etrovir _77_ Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced Biotherapy AIDS, ARC
neutralizes pH Concepts labile alpha aberrant,(Rockville, MI>) Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC
beta-fluoro-ddA Nat'1 Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers ,Squibb/HIV infection, (CGP-73547) Novartis AIDS, ARC
(protease inhibitor) BMS-234475 Bristol-Myers Squibb/HIV infection, (CGP-61755) Novartis AIDS, ARC
(protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus MedImmune CMV retinitis immune globin Cytovene Syntex sight threatening Ganciclovir CMV
peripheral CMV
retinitis Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC
(RT inhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive asymptomatic Japan) _78_ ddC Hoffman-La :ftoche HIV infection. AIDS, Dideoxycytidine AR C
ddI 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, EL10 Elan Corp, PhC HIV infection (Gainesville, GA) Famciclovir Smith HIine herpes zoster, herpes simplex FTC Emory University HIV infection, AIDS, ARC
(reverse transcriptase inhibitor) GS MO Gilead HIV infection, AIDS, ARC
(reverse transcriptase inhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC
(non-nucleo side reverse transcriptase inhibitor) _79_ Hypericin VIMRx Pharm. HIV infection, AIDS, ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARCS
Interferon alfa-n3Interferon SciencesARC, AIDS
Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC
ISIS 2922 ISIS PharmaceuticalsCMV retinitis KNI-272 Nat'1 Cancer InstituteHIV-assoc.
diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC
(reverse transcriptase inhibitor); also with AZT
Lobucavir Bristol-Myers SquibbCMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC
(protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC
(RT inhibitor) Novapren Novaferon Labs, HIV inhibitor Inc.
(Akron, OH) Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc infection, other CMV
infections WO 99/b2513 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, Di dehydrodeoxy- AR C
thymidine Valaciclovir Glaxo Wellcome genital HSV & CMV
infections Virazole Viratek/ICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex H1V infection, AIDS, ARC
Zalcitabine Hoffrnann-La Roche HIV infection, AIDS, ARC, with AZT
Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies I_MMUNO-MODULATORS
Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst AIDS
_ H1 _ Brapirimine Pharmacia Upjohn advanced AIDS
Acemannan Carrington Labs, AIDS, ARC
Inc.
(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 ColanySandoz Stimulating Factor Granulocyte Hoeschst-Roussel AIDS
Macrophage ColonyImmunex Stimulating Factor Granulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZT
Stimulating Factor HIV Core ParticleRorer seropositive HIV
Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT
IL-2 Hoffman-La Rache AIDS, ARC, HIV, in interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in Interleukin-2 cell counts (aldeslukin) _g2_ 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) MT:P-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&F106~28 Smith Kline HIV infection Soluble T4 _g3_ Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVE~
Drug Name Manufacturer Indication Clindamycin withPharmacia Upjohn PCP
Primaquine Fluconazole Pfizer cryptococcal meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille oral candidiasis Ornidyl Merrell Dow pCp Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM (Rosemont, IL) & IV) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation 5piramycin Rhone-Poulenc cryptosporidial diarrhea Intraconazole- Janssen Pharm. histoplasmosis;
851211 cryptococcal meningitis Trimetrexate Warner-Lambert PCp 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 Squibbtreatment 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 compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-(4-(3-pyridyl-methyl )-2(S )-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz.
The preparation of ddC, ddI and AZT are also described in EPO
0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following ( 1 ) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT andlor ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1-( 4-(3-pyridyl-methyl )-2(S)-N'-(t-butylcarboxamido)-piperazinyl ) )-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
Indinavir is generally administered at a dosage of 800 mg three times a day.
The following examples are provided to further illustrate details for the preparation and use of the compounds of the present invention. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed.
Furthermore, the compounds described in the following examples are not to be construed as forming the only genus that is considered as the invention, and any combination of the ocmpounds or their moieties may itself form a genus. Those skilled in the art will readily understand that known variatioons of the conditions and processes of the following _g~,_ preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless noted otherwise.
Abbreviations: Ac represents acetyl; ACN is acetonitrile;
Bn represents benzyl; DME is dimethoxy ethane; DMF is dimethyl formamide; DMSO is dimethyl sulfoxide; EDC represents 1-(3-dimethylaminopropyl-3-ethyl carbodiimide; Et represents ethyl; HOBT
represents L-hydroxybenzotriazole; LiHMDS represents '; IPA is isopropyl alcohol; Me represents methyl; sat. is saturated; THF is tetrahydrofuran; TLC is thin layer (Si02) chromatography.
EXAMPhE 1 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1 Step 1: I-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone AI-1-1 C
N
O
F
A solution of 2-acetyl pyrrole ( 1.09g, 0.01 mole) in 20 mL of DMF was treated with sodium hydride (0.488 60 % dispersion in oil, 0.012 mole) followed by 4-fluorobenzyl bromide ( 1.73g, 0.012 mole) and stirred overnight at room temperature. The solution was poured into 300 mL
saturated NaHC03 and extracted with EtOAc three times, the combined organic layers were washed with NaHC03 and dried over MgS04, filtered and evaporated to give a clear yellow oiI that was taken on to the next step without further purification. Rf--0.58 (20% EtOAclHexanes).
1H NMR (400 MHz, CDCl3) d 7.1 (m, 2H), 7.0 (m, 3H), 6.9 (m, 1H), 6.2 (m, 1H), 5.52 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AI-2-1 _g7_ '~ ~OCH3 O O
i~
F
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 (0.48g, 60°l° dispersion in oil) followed by dimethyl oxalate ( 1.42g, O.OI2 mole) and a drop of methanol and the solution was warmed to reflex overnight. The reaction mixture was poured into 300 mL saturated NaHC03 and extracted with EtOAc three times, the combined organic layers were washed with NaHC03 and dried over MgS04, filtered and evaporated. The residue was crystallizesd with diethyl ether to give AI-2-1 as yellow -orange crystals. Rf--0.39 (97:3:1 CHCl3 / MeOH / HOAc). 1H
NMR (400 MHz, CDC13) 8 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).
Step 3: 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid N OH
O O
F
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 HCl and extracted three times with EtC>Ac. The organic layers were combined, washed with 1 N HCI, dried over MgS04, _gg_ filtered and evaporated to dryness. The residue was crystallized from CHC13 to give AI-3-1 as bright orange-yellow crystals. mp 172°C
decomposed (uncorrected). TLC Rf-__0.37 (94:6:6 CHCl3 / MeOH / HOAc).
1H NMR (400 MHz, CDCl3) 8 7.2 (dd,J = 1.65, 4.21 Hz,lH), 7.09 (m, 3H), 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 4-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-9 Step 1: 1-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]ethanone AI-1-3 N ]'~
O
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 mmole ). The reaction was stirred at ambient temperature for 12 hours, then the mixture was diluted with Et2O, washed with water, dried with MgS04, and the solvent evaporated. The residue was purified by preparative silica HPLC using 20% EtOAcJHex to afford the product as a thick clear oil that solidified upon standing. melting point 52-53°C
(uncorrected). 1H NMR (400 MHz, CDCl3) 8 7.11 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.72 Hz, 2H), 7.01 (m, 1H), 6.18 (m,lH), 5.55 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H). mass spec (EI, m/z) 213 (M+), 105.
Step 2: 4-[I-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-2 _gc~_ N ~ ~ ~OCH2CH3 O O
To a solution of AI-1-3 (639mg, 3 mmole) and diethyl oxalate (0.814 mL, 6 mmole) in THF (3 mL) was added in portions NaOEt (408mg, 6 mmole>.
The reaction was stirred at ambient temperature under a N2 atmosphere for 1.5 hours. The reaction was poured into hexanes (50 mL) and the yellow precipitate was filtered and dried under vacuum.
The crude solid was triturated with 1M HCl (50 mL), filtered, and dried under vacuum. The product was further purified by crystallization from EtOAc / Hexanes / EtlO to obtain the product as a yellow powder.
melting point 94-97°C (uncorrected). 1H NMR (400 MHz, CDC13) b 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, 1.H), 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.
Step 3: 4-[1-(4-methylbenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid N ~ ~ -OH
O O
A solution of I-2-2 (240mg, lmmol) in 1,4-dioxane (3 mL) and 3N HCl (3 mL) was heated in a sealed tube at 70°C overnight. The reaction was then allowed to cool to ambient temperature and poured into 1H HCl (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et20 / hexanes to afford AI~3-9 as a yellow solid. melting point 179-181°C (uncorrected). 1H NMR (400 MHz, DMSO) b 7.50 (s, 1H), 7.41 (d, J=4.28 Hz, 1H), 7.1.0(d, J=7.68 Hz, 2H), 6.98 (d, _yp_ J=7.68 Hz, 2H), 6.83 (s, 1H), 6.30 (dd, ~1=2.5, 4.1 Hz, 1H), 5.58 (s, 2H), 2.24 ( s, 3H ).
mass spec (FA$, m+1) 286 4-[1-(4-fluorobenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-Step l: 1-[1-(4-fluorobenzyl)-4-iodo-1H -pyrrol-2-yl]ethanone AI-1-2 I
N
O
pI_I_~
A solution of 1-[1-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone (AI-1-1) (3g, 13.8 mmole) in acetone (75 mL) was cooled to -78°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 NaHC03 solution and brine, dried over MgS04, 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, CDCl3) b 7.15 (m, 2H), 7.08 (m, 1H), 7.0 (m, 2H), 6.93 (m, 1H), 5.5 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-1-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-3 N ~'( ~ ~OCH2CH3 O O
F /
AI-2-3 was synthesized from AI-1-2 in a manner similar to that described for AI-2-2 to afford the product as a yellow solid. melting point 87-90°C (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.15 (dd, J=1.6, 4.16 Hz, 1H), 7.09 (m, 2H), 7.01-6.96 (m, 3H), 6.83 (s, 1H), 6.27 (dd, J=2.52, 4.20 Hz, 1H), 5.60 (s, 2H), 4.36 (q, J=7.I6 Hz, 2H), 1.38 (t, J=7.16 Hz, 3H).
mass spec (EI, m/z) 317 (M' ), 109.
4-[1-(4-fluorobenzyl)-lIl-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester N T( if _ o O O
F
To a solution of AI-2-3 (317mg, 1 mmole) in 2-propanol (anhydrous, 20 mL) was added p-toluenesulfonic acid (l9mg, 0.1 mmole) and the mixture was set to reflux for 72 hours. The reaction mixture was then allowed to cool to ambient temperature, diluted with Et20, washed with a solution of saturated NaHC03, the organic layer separated and dried with MgS04, the solvent evaporated and the crude was purified by preparative silica HPLC eluting with 30°~o EtOAc / hexanes to afford the product as yellow solid. melting point 87-88°C (uncorrected). 1H NMft (400 MHz, CDCl3) 8 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 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester _92_ N ~ ~ -O(CH2)sCHs O O
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 64-65°C
(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 4-(1-benzyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-2 O
N ~ ~ -O H
O O
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 I5 AI-3-2. mp 150-151°C (uncorrected). 1H NMR (300 MHz, DMSO) F~
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).
4-( 1-naphthalen-2-ylmethyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-3 O
N~ ~ ~ -O H
~ O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 2-bromomethylnapthylene and carried through the sequence to yield AI-3-3. mp 160-162°C (uncorrected). 1H NMR (300 MHz, DMSO) ~ 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).
4-(1-biphenyl-4-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid A-I-3-4 O
N ~ ~ OH
O O
In a manner similar to that described for AI-3-13-1, 2-acetyl pyrrole was treated with 4-phenyl benzyl bromide and carried through the sequence to yield AI;3-44. mp 189-191°C (uncorrected). 1H NMR (300 MHz, DMSO) S 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).
4-(1-naphthalen-1-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid AI-3-5 O
N OH
O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 1-bromomethyl napthalene and carried through the sequence to yield AI- -5, mp 172-174°C (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).
2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrrol -2-yl]-butyric acid AI-3-6 O
N OH
O O
In a manner similar to that described for AI-3-13-1, 2-acetyl pyrrole was treated with 4-phenyl butyl chloride and carried through the sequence to yield AI-3-6. mp 119-121°C (uncorrected). 1H NMR (300 MHz, DMSO) 8 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).
4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-7 O
N~ ~ ~ O H
O O
CI
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 4-chlorobenzyl bromide and carried through the sequence to yield AI-3-7. mp 182-184°C (uncorrected). 1H NMR (300 MHz, DMSO) b 7.55 (s, 1H), 7.42 (m, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 6.82 (s, 1H), 6.35 (m, 1H), 5.6 (s, 2H), 2,4-dioxo-4-( 1-phenethyl-1H-pyrrol -2-yl)-butyric acid AI-3-8 O
N ~ ~ OH
O O
In a manner similar to that described for AI-3-l, 2-acetyl pyrrole was treated with 2-phenyl 1-bromoethane and carried through the sequence to yield AI-3-8. mp 168-170°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) i5 4-[1-(2-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-10 O
N 1'( ~ O H
O O
/
AI-3-10 was synthesized from 2-acetyl pyrrole and 2-methylbenzyl bromide in a manner similar to that described for AI-3-9 to a$'ord the product as a brownish-yellow solid. melting point 176-178°C
(uncorrected). 1H NMR (400 MHz, DMSO) b 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, 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.
4-[ 1-(3,4-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-11 N ~'( ~ ~ O H
F ~ O O
F
AI-3-11 was synthesized from 2-acetyl pyrrole and 3,4-difluorobenzyl bromide in a manner similar to that described for A_A_ I;3_99 to afford the product as a brownish-yellow solid. melting point 145-148°C
(uncorrected) 1H NMR (400 MHz, DMSO) b 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).
mass spec (FAB, m+1) 308 4-[1-(4-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-12 N ~'( ~ -O H
O O
Br AI-' -12 was synthesized from 2-acetyl pyrrole and 4-bromobenzyl bromide in a manner similar to that described for AI3-9 to afford the product as a brownish-yellow solid. melting point 184-185°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.54 (d, J=1.68 Hz, 1.H), 7.52 _97_ (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, IH), 6.34 (dd, J=2.52, 4.16 Hz, 1H), 5.61 (s, 2H). mass spec IFAB, m+1) 352, 350 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-13 O
N~ ~ ~ ~OH
O O
AI-3-13 was synthesized from 2-acetyl pyrrole and 2-bromobenzyl bromide in a manner similar to that described for AI3-9 to afford the product as a brownish-yellow solid. melting point 176-180°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 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).
mass spec (FAB, m+1) 4-[1-(3-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-14 O
N ~ ~ ~OH
Br ~ O O
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 164-166°C
(uncorrected ). 1H NMR (400 MHz, DMSO ) 8 7.54 (broad s, 1H ), 7.43 (m, 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.
4-f 1-(3-chlorobenzvl)-1H-nvrrol-2-vll-2 4-dioxobutvric acid AI 3 15 O
N I'( ~ ~ O H
C I ,~ O p AI-3-15 was synthesized from 2-acetyl pyrrole and 3-chlorobenzvl bromide in a manner similar to that described for AI'3-99 to afford the product as a brownish-yellow solid. melting point 159-161°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 (FAB, m+1) 306 4-[1-(3-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-16 O
N j'( ~ -O H
HsC \ O O
AI-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 140-141°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (d, J=1.92 Hz, 1H), 7.41 _c~c~_ (dd, J=1.44, 4.12 Hz, 1H), 7.20 (dd, J=7.64, ?.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 4-[L-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-17 N ~"( ~ O H
O O
AI-3-17 was synthesized from 2-acetyl pyrrole and 2-fluorobenzyl bromide in a manner similar to that described for AI'3-9 to afford the product as a brownish-yellow solid. melting point I55-156°C
(uncorrected). IH NMR (400 MHz, DMSO) 8 7,47 (m, 2H), 7.32 (dd, 5.4, 14.0, 1H), ?.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), 6.3Ei (dd, J=2.56, 4.12Hz, 1H), 5.71 (s, 2H). mass spec (FAB, m+1) 290 2,4-dioxo-4-(1-hexyl-1H-pyrrol -2-yl)-butyric acid AI-3-18 O
N ~ ~ -OH
O O
In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated 1-bromo hexane and carried through the sequence to yield AI-3-18.
mp 94.8°C (uncorrected). TLC Rf-__0.68 (94:6: 6:6 CHC13 / MeOH / HOAc) - 1 ()0 -1H NMR (400 MHz, CDC13) 8 7.15 (dd, 1H, J=1.65 Hz, J=4.21 Hz), 7.01 (m,lH), 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) 4-(1-biphenyl-2-ylmethyl-1H-pyrrol -2-yl)-2,4-dioxobutyric acid O
N 1~ ~ -O H
O
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 sequence to yield AI-3-19. mp 150-152°C (uncorrected). 1H NMR (400 MHz, CDC13) 8 7.4 (m, 9H), 6.8 (s, 1H), 6.42 (m, 1H), 6.3 (m, 1H), 5.6 (s, 2H).
2,4-dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl]-butyric acid AI-3-20 O
N~ ~ ~~ ~OH
O~V/~ O O H
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 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) b 7.29 (m, 2H), ?.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).
4-[1-(3-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-21 O
N T[ ~ ~ O H
O O
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 147-149°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 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), 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 4-fl-(2-chlorobenzvl)-1H-pvrrol-2-vll-2 4 dioxobutvric acid AI 3 22 O
N- ~ ~ -O H
O O
/ C ~ A-A_I-3-2222 AI-3-22 was synthesized from 2-acetyl pyrrole and 2-chlorobenzyl bromide in a manner similar to that described for A~ to afford the product as a brownish-yellow solid. melting point 179-180°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.52-7.47 (m, 3H), 7.30 (ddd, J=1.6, 7.44, 7.44 Hz, 1H), 7.24 (ddd,J=1.32, 7.52, 7.52 Hz, 1H), 6.88 (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 - I ()2 -4-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]-2,4-dioxo-butyric acid I
O
N~ ~ ~ O H
O O
In a manner similar to that described for AI-3-1, AI-3-23 was prepared from AI-l-2. mass spec (FAB, m+1) 416 . 1H NMR (400 MHz, Dh-DMSC>) 8 7.7 (s, 1H), 7.6 (s, 1H>, 7.2 (m, 4H), 6.85 (s, 1H), 5.6 (s, 2H).
4-f 1-(4-methoxvbenzvl)-1H-nvrrol-2-vll-2 4 dioxobutvric acid AI 3 24 N ~'( ~ OH
O O
Me0 Al-3-24 AI-3-24 was synthesized from 2-acetyl pyrrole and 4-methoxybenzyl chloride in a manner similar to that described for Ah3-9 to afford the product as a brownish-yellow solid. melting point 167-168°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.50 (s, 1H), ?.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) 4-[1-(2,4,5-trifluorobenzyl)-1H-pyrrol-2-~~l]-2,4-dioxobutyric acid AI-3-25 -O H
F ~ O O
i F ~ F
AI-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 154-156"C
(uncorrected). 1H NMR (400 MHz, DMSO) h 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).
4-f 1-(2,3-difluorobenzvl >-1H-pyrrol 2 yl ] 2 4 dioxobutyric acid AI 3 26 O
N ~ ~ ~OH
O O
i F
AI-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°C
(uncorrected). 1H NMR (400 MHz, DMSO) 8 7.51 (s, 1H), 7.45 (m, 1H), 7.35 (m, IH), 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 4-[1-(3,5-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-26 O
N ~ ~ ~OH
F ~ O O
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-I68°C
(uncorrected); 1H NMR (400 MHz, DMSO) 8 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 (FA~I, m+ I ) 308 4-[1-(2,5-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-28 O
F N~ ~ ~' ~OH
O O
A_ I-3-28 was synthesized from 2-acetyl pyrrole and 2,5-difluorobenzyl bromide in a manner similar to that described for AI-~~ to afford the product as a brownish-yellow solid. melting point 142-146°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 4-[1-(2,5,6-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-29 O
F N ~ ~ ~OH
O O
F
AI-~ 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 I31-133°C
(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.
In a manner similar to that described for AI-3-1, the following compounds were prepared:
4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid N
O OH
F
CHN Calc. 62.28, 4.18, 4.84; Fnd. 62.11, 4.37, 4.91. (32) 4-[1.-(4-trifluoromethylbenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid:
N
O OH
CHN Calc. 56.64, 3.56, 4.12; Fnd. 56.89, 3.75. 4.36. (33 ) 4-[1-(4-cyanobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid:
N
O OH
NC
CHN Calc. 64.86, 4.08, 9.45; Fnd. 64.61, 4.32, 9.77. (34) O
N~ ~~~~OH
O HO
,O
4-[l-(3-methoxybenzyl)-1H -pyrrol-2-yl] -2,4-dioxobutyric acid CHN Calc.
63.78, 5.02, 4.65; Fnd. 63.99,5.14, 4.60. (35) N
O OH
HO ~- 0.20 TFA
2-hydroxy-4-[1-(4-hydroxybenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid CHlrt Calc. (C15H13N05 0.20 TFA) 59.65, 4.29, 4.52; Fnd. 59.50, 4.31, 4.68. (36) y N
O OH
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) \ C02H
N
O OH
0.35 EtOAc F
4-il-[3-(4-fluorophenyl)propyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid CHN
Calc.( C17H16N04F 0.35 EtOAc) 63.47, 5.44, 4.02; 63.16, 5.12, 4.34. (38) ~ C02H
N
O OH
F
4-~1-[2-(4-fluorophenyl)ethyl]-1H-pyrrol-2-yl}-2,4-dioxobutyric acid CHN
Calc. 63.36, 4.65, 4.62; Fnd. 63.16, 4.64, 4.50. (39) N
O OH
4-[1-(3-phenylpropyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Cale.(C17H17N04 0.1 H20) 67.80, 5. 76, 4.65; 1''nd. 67.79, 5.67, 4.70. (40) N
O OH
H3~J
4-( 1-ethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 57.41, 5.30, 6. 7 0; Fnd. 57.13, 5.33, 6.70. (41) N
O OH
F
4-[ l-(3-fluoro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN
Calc.(C15H12 FN04 0.35 H20) 60.95, 4.33, 4.74; Fnd. 60.89 4.25, 4.78. (42) N
O OH
CI
4-[1-(2-chloro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CHN Calc.
(C15H12N04C1 0.15 H20)58.41, 4.02, 4.54; Fnd. 58.31, 3.94, 4.62 (43) O OH
~N
O
4-[1-(3-benzoylaminopropyl)-1H-pyrrol-3-yI] -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) O
N~ ~ \~ OOH
O OH
\ O
F /
4-{ 1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}] -2,4-dioxobutyric acid CHN Calc. 66.14, 4.23, 3.67; Fnd. 66.37, 4.32, 3.69. (45 ) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 Step 1: cyclohexyl-pyrrol-1-yl-methanone AII-1-1 N
~O
AII-I-I
A solution of pyrrole (2.OOg, 0.0298 mole) in 30 mL THF was cooled to -78°C and treated with I.0 M LiHMDS in hexanes (29.8 mL, 0.0298 mole) followed by dropwise addition of cyclopentanecarbonyl chloride (4.00 mL, 0.0298 mole). After five minutes the solution was allowed to warm to room temperature and stirred for four hours. The solution was poured into 200 mL saturated NH4Cl solution and extracted with EtOAc three times. The combined organic layers were washed with NH4Cl and dried over MgS04, filtered and evaporated to give a crude brown 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-1-1 as white crystals. TLC Rf-__0.62 (5:95 EtOAc / Hexanes) IH
NMR (400 MHz, CDC13) b 7.32 (m, 2Hi, 6.29 (.m, 2H), 2.92 (m, lHl, 1.8W-1.97 (m, 4H), 1.56-1.76 (m, 3H), 1.24-1.43 (m, 3H).
Step 2: 1-cyclohexylmethyl-1-H -pyrrole AII-2-1 N
A solution of AII-1-1 (3.45 g, 0.0195 mole) in 60 mL THF was treated with 1.0 M BH3-Me2S (58.5 mL, 0.0585 mole) and warmed to reflux for three hours. The solution was cooled to 0°C, slowly poured into 300 mL ice cold water and extracted with CH2Cl2 three times. The combined organic layers were washed with water, dried over MgS04, and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc / Hexane mixture as the eluting solvent, gave AII-2-1 as a light yellow oil. TLC Rf-__0.71 (5:95 EtOAc / Hexanes ) 1H NMR (400 MHz, CDCl3) 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).
Step 3: 1-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-ethanone AII-3-1 N
a A solution of AII-2-1 (1.32g, 0.0081 mole) in 20 mL THF was cooled to -78°C and treated with 2.5 M n. -butyllithium ( 16.2 mL, 0.0405 WO 99162513 PCTlUS99/12095 mole) over five minutes and stirred overnight at room temperature under argon. The solution was then treated with N -methoxy-1V -methylacetamide (4.18g, 0.0405 mole) and stirred three hours. The solution was poured into 200 mL saturated NH4Cl solution and extracted with Et20 three times. The combined organic layers were washed with NH4Cl and dried over MgS04, filtered and evaporated to give a crude yellow oil. Flash chromatography on silica gel of the crude product, using a 2.5:97.5 EtOAc / Hexane mixture as the eluting solvent, gave AII-3-1 as a yellow oil. TLC Rf-__0.49 ( 5:95 EtOAc / Hexanes) 1H NMR
(300 MHz, CDCl3) 8 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 methyl ester AII-4-1 O
O O
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 / CH2Cl2) 1H NMR (400 MHz, CDC13) 8 7.10, (dd, J = 1.65, 4.21 Hz, 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-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid O
-OH
O O
In a manner similar to that described for AI-3-1, AII-4-I was treated with NaOH to give AII-5-1. TLC Rf-__0.65 (94:6:6 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) 8 7.15 (dd, J=1.65, 4.21 Hz, 1H), 6.96 (m, 1H7, 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).
4-[1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid Step 1: 1-[1-(4-fluorobenzyl>-4-phenylethynyl-IH-pyrrol-2-yl]ethanone AIII-1-1 O
F
A mixture of AI-1-2 (.49 g, L43 mmol), phenylacetylene (.218 g, .235 mls, 2.14 mmol), copper(I) iodide (.022 g, .116 mmol), tetrakis(triphenylphosphine)-palladium(0) (.l g, .086 mrnol) and triethylamine (5 mI) were combined in 2 mL acetonitrile and heated to reflux for 4 hrs. After cooling, the solvent was removed irt uczcuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed. The resulting brov~~n oil was purified by radial disc chromatography twice, first using 2:1 hexane/
CH2Cl2 followed by straight ethyl acetate, then straight CH2Cl2 to afford the title compound. 1H NMR (400 MHz, CDCl3) ~ 2.42 (s, 3H), 5.52 (s, 2H), 6.99 (t, 2H, J = 8.7 Hz), 7.11 - 7.16 (m, 4H), 7.29 - 7.47 tm, 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 OEt O O
F
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 (.7.13 g, 1.66 mmol >. After stirring for 1 hr, the reaction was poured into 20 mL
109 citric acid and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2SO4 filtered, and the solvent removed in uacuo to give the title compound as a yellow oil.
1H NMR (400 MHz, CDC13) 8 1.36 (t, 3H, J = 7.1 Hz), 4.34 (q, 2H, ~1 = 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 -7.48 (m, 2H) Step 3: [ 1-(4-fluorobenz 1 )-4 hen leth Y -P Y YnYl-~-PYrrol-2-yl]-2,4-dioxobutyric acid AIII-3-1 OH
In a similar manner to AI-3-13-1, 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 yellow resin. 1H NMR (400 MHz, CDCl3) 8 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) 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 O
F
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 O O
F
with hydrogen (via balloon) and allowed to stir for 6 hr. The catalyst was filtered and the solvent removed in uacuo. NMR of this crude mixture showed about 20% starting material. The product was purified by radial disc chromatography (CH2Cl2 > to obtain the title compound as a resin.
1H NMR (400 MHz, CDCl3) 8 2.35 (s, 3H), 2.72 - 2.79 (m, 2H), 2.82 - 2.89 (m, 2H), 5.42 (s, 2H), 6.57 (d, iH, 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-dioxobutyric acid ethyl ester AIII-5-1 OEt In a similar manner to AIII-2-1, AIII-4-1 (.l g, .31 mmol) was reacted with diethyl oxalate (.091 g, .084 ml, .62 mmol) and sodium ethoxide (.042 g, .62 mmol) in 5 mL THF to give the title compound, which was used in the next reaction without further purification. 1H NMR, (400 MHz, CDCl3) 8 1.37 (t, 3H, .1 = 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) Step 3: 4-[ 1-(4-fluorobenzyl )-4-phenethyl-lIl-pyrrol-2-yl]-2,4-dioxobutyric acid AIII-6-1 - I lb O O
F
OH
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 °C; 1H NMR (400 MHz, CDC13) ~ 2.75 - 2.82 (m, 1H), 2.84 -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),. 7.1? - 7.23 (m, 1H), 7.24 - 7.32 (m, 3H) 4-[5-(4-fluorobenzyl)-1-methyl-1-II -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-Step 1: 2-(4-fluorobenzyl)-1H -pyrrole AIV1-1 F
N
MeMgCl (3N in THF, 43.8 mL, 0.131 mole) was added dropwise to a solution of 50:50 THF:CH2Cl2 and pyrrole (9.31g, 0.139 mole) at 0°C
followed by quick addition of 4-fluorobenzyl bromide and stirred at room temperature overnight. The solution was poured into 300 mL of saturated NH4C1 and extracted five times with Et20. The combined organic layers were dried over NaS04, filtered and evaporated to give a dark brown oil that was distilled under vacuum to give analytically pure AIV-1-1. 1H NMR (400 MHz, CDC13) 8 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, 1.H), 3.94 (s, 2H).
O O
F
Step 2: 1-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]ethanone AIV-2-1 F
~N~CH3 H
MeMgCI (2.95 mL, 0.0284 mole) was added dropwise to a solution ofAIV-l~l in THF (35 mL) at 0° 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 NH4Cl and extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give a brown oil, Silica gel chromatography using 85:15 Hexane/EtOAc gave AIV-2-1 as a light yellow powder.
TLC: Rf-__0.30 (80:20 Hexanes /EtOAc) 1H NMR (400 MHz, CDCh3) c~ 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) Step 3: 1-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]ethanone AIV-F
~N~CHs NaH (.0988, 0.00244 mole) was added to a solution ofAIV-2-1 in DMF (25 mL) at 0° C followed by subsequent addition of MeI (0.538, 0.00244 mole).
The ice bath was removed and the reaction was stirred for one hour.
The solution was poured into NH4Cl arid extracted three times with EtOAc. The combined organic layers were dried over NaSO4, filtered and evaporated to give AIV-~-1 as a brown oil. TLC: Rf--0.43 (80:20 Hexanes / EtOAc) 1H NMR (400 MHz, C'DCI~~) h 7.11-7.07 (m, 2H), 7.01-- 1 1 ~i -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).
Step 4: 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AIV-4-1 F
O
~N ~ ~ -OCH3 A solution of AIV-3-1 (0.2228, 0.000961 mole) in DME (lOmL) was treated with sodium hydride (0.0588, 0.00144 mole) followed by dimethyl oxalate (0.1138, 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 NaS04, filtered and evaporated to give AIV-4-1 as a brown solid. TLC: Rf--0.39 (97:3:1 CH2Cl2 / MeOH / HOAc) 1H NMR
(400 MHz, CDC13) 8 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)-1-methyl-lII -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-1 F /
O
~~ ~OH
AIV-4-1 was dissolved in THF (I5 mL) and 1 N NaOH (5 mL) was added. After two hours the reaction was acidified with 1 N HCI.
This mixture was extracted three times with EtOAc, dried over NaS04, 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 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, CDC13) 8 7.128-7.086 (m, 3H), 7.04-6.99 (t, 2H j=9), 6.90 (s, 1H). 6.03-6.02 (d, 1H. j=4.39 Hz), 3.98 (s, 2H), 3.85 (s, 3H).
4-[5-(3-chlorobenzyl)-1-methyl-1.H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-Ci \ ~ /
~~N OH
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 MHz, DMSO) 8 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).
4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-3 F
N OH
H O O
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.
12(>
TLC: Rf-__0.28 (93:7:7 CHC13/ MeOH / HOAc) 1H NMR (400 MHz, DMSO ) ~ 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).
4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-4 CI ~ I ~ ~ O
N OH
H O O
AIV-5-4 was prepared in a manner similar to that described for AIV-5-1 with the exception that the methylation step was omitted. TLC:
Rf--0.44 (93:7:7 CHCl3/ 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).
4-[5-(benzyl)-lIl -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-5 O
N OH
H O O
AIV-5-55-5 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) b 12.20 (s, 1H), 7.32-7.18 (m, 6H), 6.80 (s, 1H), 6.05 (m, 1H), 3.98 (s, 2H).
4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-6 i F ~ ~ /
N OH
H O O
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 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, DMSO) 8 12.21 (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).
4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl)-2,4-dioxobutyric acid AIV-5-7 F
O
N OH
O O
F
AIV-5-7 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-alkylation step. TLC: Rf=0.60 (93:7:7 CHCl3/ MeOH / HOAc> 1H
NMR (400 MHz, CDC13) 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).
4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl)-2,4-dioxobutyric acid AIV-5-8 CI v ~ ~N~ ~ ~ ~OH
O O
F
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) 8 7.46-7.45 (d, 1H j=4.2 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 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-O
N ~' ~ OH
O O
AIV-5-95-9 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 NMR (400 MHz, CDC13) 8 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 (s, 2H). mass spec.: (FAB, m+1) 380 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric;
acid AIV-5-10 CI
I ~ , O
N ~ ~ OH
I\
F
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, CDCl3) 8 7.27 (m, 1H), 7.25-7.24 (m, 1H), 7.21-?.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 spec.: (FAB, m+1) 414 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-Step l: 1-[5-(4-fluorobenzyl)-1-methyl-1 H -pyrrol-3-yl]ethanone F O
~CH3 N' A1V-fi-1 AIV-3-13-1 was dissolved in TFA 10 mL and was refluxed for two days.
Cooled and removed TFA under reduced. pressure. Dissolved brown oil in saturated NaHC03 and extracted three times with EtOAc, dried over NaS04, filtered and evaporated to give AIV-6-1 as a green oily solid.
TLC: Rf-__0.33 (60:40 Hexanes / EtOAc) 1H NMR (400 MHz, CDCl3) 8 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).
Step 2: 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-8-1 O O
/ OH
N
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 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 4-[5-(3-chlorobenzyl)-1-methyl-IH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-O O
OH
O
CI N
In a manner similar to that described for AIV-8-l, pyrrole was alkylated with 3-chlorobenzyl bromide and carried through the sequence to give AIV-8-2. 1H NMR (400 MHz, CT)C13) b 7.43-7.42 (d, 1H, j=1.8 Hz), 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=l.lHz), 3.92 (s, 2H), 3.50 (s, 3H). mass spec.: (FAB, m+1) 320.2 4-[5-(benzyl)-1-methyl-1X -pyrrol-3-yl]-'~,4-dioxobutyric acid AIV-8-3 O O
OH
O
N
In a manner similar to that described for AIV-8-1, pyrrole was alkylated with benzyl bromide and carried through the sequence to give AIV-8-38-3. 1H NMR, (400 MHz, CDCl3) 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), (i.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 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-O O
OH
F \ ~ ~ ~ O
N
In a manner similar to that described for AIV-8-18-1, pyrrole was alkylated with 3-fluorobenzyl bromide and carried through the sequence to give AIV-8-4. 1H NMR, (400 MHz, CDCl3) ~ 7.43 (d, 1H, j=1.8 Hz), 7.32-- 12b 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 4-(5-benzyl-1H -pyrrol-3-yl>-2,4-dioxobutyric acid AIV-8-5 O O
OH
/~
O
N
In a manner similar to that described for AIV-8-l, with the exception that the N-alkylation step was omitted, pyrrole was alkyated with benzyl 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, CDCl3) 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).
4-[2,5-bis-(3-chlorobenzyl)-1-H -pyrrol-3-yl~-2,4-dioxobutyric acid AIV-8-6 OH
CI
In a manner similar to that described for AIV-5-1 pyrrole was alkyated with 3-chlorobenzyl bromide and the minor 2,5-bis 3-chlorobenzyl alkylated product was isolated. Treatment with MeMgCI followed by acetic anyhydride as described for AIV-2-1 gave the 3-acylated product that was carried through the sequence to give AI_ V-8-6. TLC: Rf_-0.42 (93:7:7 CHCl3/ MeOH / HOAc) 1H NMR (400 MHz, CDCl3) 8 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>.
4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-Step 1: (+/-) 5-Oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 COOEt NH
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) 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 NaHC03 (2X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave 5-oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 as an oil which crystallized on standing. 1H NMR
(CDCl3) 8 1.30 (3H, t, j=7.3 Hz), 2.18 to 2.60 (4H, complex multiplet), 4.22 (3H, m), 3.37 (1H, br s).
Step 2: (+/-) 5-Oxo-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-I.
COOEt ,.O
~N
O
To a 1L round bottomed flask with a stirring bar and an argon inlet was added gave 5-oxo-pyrrolidine-2-carboxyli c acid ethyl ester AV- l -1 ( 18.68, 118.34 mmol) CHCl,3 (300 mL), di-tort-butyldicarbonate (30.998, 142.01 mmol), Et3N (16.5 mL, 118.34 mmol), and 4-dimethylaminopyridine (14.468, 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°~o aqueous citric acid, aqueous NaHC03, H20, and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 3008 of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained (+/-) 5-oxa-pyrrolidine-1,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 as an oil. 1H NMft (CDCl3 ) ~ 1.2 7 (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).
Step 3: (+/-) 2-Tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 O Ph O
O H COOEt To an oven dried 500 mL, three-necked round bottomed flask with a 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 (6.508, 25.25 mmol) and 100 mL of dry THF. This solution was cooled to -40°C and a solution of phenyl magnesium bromide (25.3 mL of a 1M solution in THF) was added slowly with a syringe. The mixture was aged 15m at -40°C, the cooling bath was removed and the mixture was warmed to 20°C. The reaction was quenched by the addition of 150 mL of saturated aqueous NH4Cl solution. This mixture was stirred 30m. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried (MgS04), filtered and concentrated in vacuo to give 2-tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-13-1 which was used in the subsequent step without purification.
- 12q -Step 4: (+/-) 5-Phenyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-4-1 r'COOEt 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 CH2Cl2. This solution was cooled in an ice bath and 100 mL of trifluoroacetic acid was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 24h. The solvents were removed in vacuo and the residue was redissolved in 300 mL of CHC13 and concentrated a second time. The resulting residue was dissolved in 100 mL of CH2Cl2 and this solution was cooled in an ice bath. Et3N (50 mL) was added and the mixture was stirred 3h. The solvents were removed in vacuo and the residue was dissolved in 300 mL of EtOAc. This solution was washed with H20 and brine. Drying (MgS04), 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 oil. 1H NMR (CDCl3) b 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, m), 7.89 (2H, dd, j=
2.7, 4.0).
Step 5: 5-Phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 ~COOH
H AV;S-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 ~V-4-1 (4.848, 22.28 mmol), dry CH2Cl2 (220 mL) and DDIa (5.06g, 22.28 mmol). This solution was stirred at ambient temperature 1h. The solvent was removed in vacuo. Aqueous NaOH (20% w/v, 440 mL) was added and the mixture was heated at reflux 24h. The cooled, black solution was poured onto crushed ice and the mixture was acidified with conc. HCl. This mixture was extracted with EtOAc (2X). The combined extracts were washed with brine, dried (MgS04), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 2.5~% MeOH in EtOAc as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid AV-5-1 as an off white solid. 1H NMR (CDC13 ) 8 6.59 (1H, dd, j=2.7, 3.9 Hz), 7.13 (1H, dd, j= 2.7, 3.9 Hz), 7.34 (l.H, m), ?.41 (2H, m), 7.59 (2H, rn), 9.40 (1H, br s).
Step 6: 5-Phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide N N.CHs Fi O 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-5-15-1 (2.45g, 13.09 mmol), N,O-dimethylhydroxylamine hydrochloride (1.40g, 14.40 mmol), N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride (2.76g, 14.40 mmol), hydroxybenztriazole hydrate (1.94g, 14.40 mmol) and dry, degassed DMF (25 mL). This well stirred mixture was warmed gently until all of the solids dissolved. Et3N (5.6 mL, 40.00 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo at +80°C. The residue was partitioned between saturated aqueous NaHC03 and EtOAc. The layers were separated and the organic phase was washed with H20 (2X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 35~~o EtOAc in hexane as eluant to give 5-phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. 1H NMR (CDCl3) F~ 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).
Step 7: 1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1 N
N ~ CHI
O
F
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 added and, when all of the solids had dissolved, NaH-oil suspension (0.132g of a 60% w/w suspension, 3.3I mmol) was added. This mixture was stirred 15 min at ambient temperature then 4-fluorobenzylbromide (0.41 mL, 3.31 mmol) was added. The resulting mixture was stirred 24h at ambient temperature. The mixture was diluted with EtOAc and the solution was washed with 1N HC1, water and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oiI. This material was chromatographed on silica gel using 25% EtOAc in hexanes a eluant to give 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1. 1H NMR (CDCl3) 8 3.21 (3H, s), 3.47 (3H, 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 N
O
F
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methylamide -7-1 (0.726g, 2.16 mmol) and dry THF' (20 mL).
This solution was cooled to -78°C and methyllithium (3.39 mL of a 1.4 M
solution in Et20, 4.75 mmol). The mixture was stirred 30 min at -78°C', then the reaction was quenched with saturated aqueous NH4C1 solution.
The mixture was warmed to room temperature and stirred 2h. The layers were separated and the aqueous phase was extracted with EtOAc.
The combined organic fractions were dried (MgS04 ), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 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).
Step 9: 4-[ 1-(4-Fluorobenzyl )-5-phenyl-1H-pyrrol-2-yl]-2,4 dioxobutyric acid ethyl ester AV-9-1 O
~O~C H3 O O
F
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 1-[1-(4-fluorobenzyl)-5-phenyl-1H-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 1h at ambient temperature. The mixture was diluted with EtOAc and washed with 1N HCl, H20 (2X) and brine. Drying (MgS04) filtration 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-9-19-1 as an oil. This material was used without further purification. 1H NMR (CDCl3) 8 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).
Step 10: 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 O
N OH
O O
F
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 (0.848, 2.14 mmol) and MeOH (72 mL). To this solution was added aqueous NaOH ( 11 mL of a 1N solution). The mixture was stirred at ambient temperature 18h. The organic solvents were removed in vacuo and the aqueous residue was washed with Et2O
then acidified with 1N HCI. The mixture was extracted with Et;20 and the Et2O extract was washed with brine, dried (MgS04), filtered and concentrated in vacuo. The crude solid was recrystallized from a mixture of EtOAc and hexane to give 4-[1-(4-fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 as a white, crystalline solid.
MP: 151-152°C (dec). 1H NMR (CDCl3) 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).
4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-VI-5-1 Step 1: 1-[1-(4-Fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-N II
O
F
To a 500 mL round bottomed flask with a stirring bar and a drying tube was added 1-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AI-1-1 (11.64g, 53.58 mmol) and acetic anhydride (230 mL). This solution was cooled to -78°C and concentrated nitric acid (3.7 mL of 15.9 N solution, 58.24_ mmol) was added with a pipette. The cooling bath was allowed to expire and the mixture warmed to 0°C over 7h. The acetic anhydride was removed in vacuo and the residue was taken up in EtOAc (500 mL). This solution was washed with saturated aqueous NaHC;03 solution (2X) and brine.
Drying (MgS04), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 20°~0 EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et20/hexane to give white crystals of 1-[1-(4-fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-1. 1H NMR (CDCl3) 8 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).
Step 2: 1-[4-Amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone N II
O
F
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-2-yl]ethanone AVI-1-1 (8.OOg, 30.51 mmol) absolute EtOH (640 mL) and 10°~o Pd-C (2.248, 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-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).
Step 3: 1-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 (~Hs)2N
N II
O
F
To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yI]ethanone AVI-2-1 (0.50g, 2.15 mmol), dry DMF (20 mL), finely powdered Cs2C03 (3.26g, 10 mmol) and MeI (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 dissolved in EtOAc and washed with water (3X) and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50°h EtOAc-hexanes as eluant to give 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yI]ethanone AVI-3-1 as an oil. 1H NMR (CDCl3) 8 2.36 (3H, s), 2.70 (6H, 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), 7.1.1 (2H, m).
Step 4: 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AVI-4-1 (CH3)2N O
N ~ ~ -OEt O O
F
In a manner substantially similar to that described for Example AV-9-1 1-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-3-1 was used to prepare 4-[4-dimethylarnino-1-(4-fluorobenzyl)-1H-pyrrol-2--13f-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-dioxobutyric acid AVI-5-1 (CHs)2N
O
N ~ ~ -OH
O O
F
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 A I-4-1 was used to prepare 4-[4-dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVI-5-1. 1H NMR (DMSO-d6-CDC13 1:1) 8 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).
The following compounds was prepared in a manner similar to that described for AVI-5-1:
4-[1-(4-Fluorobenzyl)-4-vitro-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Calc. (C15H11FN206~0.8H20) 51.65, 3.64, 8.03; Fnd. 51.65, 3.42, 7.88. (67) COOH
N II II
O O
F
4-[4-(Benzylamino)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN Calc. (C22H1gFN204 ~ 0.33 CHCl3) 61.83, 4.49, 6.45; Fnd.
62.07, 4.27, 5.74. (68) BnHN
COOH
N
O O
F /
4-[5-Nitro-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid CHN
Calc. 53.90, 3.32, 8.38; Fnd. 53.77, 3.24, 8.20. (69) O O
COOH
F /
4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 Step 1: 1-[1-benzyl-1H-pyrrol-3-yl]ethanone AVII-1-1 O
N
(\
To a solution of 3-acetylpyrrole ( 545 mg, 5.00 mmol) in DMF ( 10 mL) at 0 °C was added benzyl bromide (0.60 mL, 5.05 mmol) followed by NaH (260 mg of a 60°~o suspension in mineral oil, 6.50 mmol). After stirring at °C for 20 min and room temperature for 1 h, the reaction mixture was treated with sat. NH4C1 ( 10 mL) and poured onto sat. NH4C1 (50 mL).
The resulting mixture was extracted with Et20 (3 x 50 mL). The 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).
mass spec (EI, M+ ) 199 Step 2: 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester O
I I
N O
To a solution of A I-1-1 (900 mg, 4.52 mmol) in THF (10 mL) was added dimethyl oxalate (795 mg, 6.74 mmol) followed by NaH (270 mg of a 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 CH2Cl2 (3 x 20 mL). The combined organic extracts were washed with sat. NaCI (20 mL) and dried (MgS04). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 5:5:1/CH2C12:hexanes:EtOAc, afforded the product as a yellow solid.
1H NMR (400 MHz, CDCl3) 8 7.44 (m, 1H), 7.40-7.32 (m, 3H), 7.19-7.15 (m, 2H), 6.72-6.68 (m, 3H), 5.09 (s, 2H), 3.91 (s, 3H).
Step 3: 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1 O
OH
I I
N O
To a solution ofAVII-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 Et2O (5 x 10 mL). The Et20 extracts were discarded. The aqueous phase was treated with 3 N HCl (20 mL), extracted with CH2C12 (3 x 20 mL) and the combined organic extracts dried (MgS04). Concentration provided a yellow solid which was recrystallized from benzene to afford the desired product as a light yellow solid. mp 151-152 °C (uncorrected) 1H NMR
(400 MHz, d6-DMSO) F~ 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.
In a manner similar to that described for AVII-3-1, the following compounds were prepared:
4-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-2 (71) OH
I I
N O
- 14(~
mp 145-146 °C (uncorrected) 1H NMR (400 MHz, d6-DMSO) 8 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.
EXAMPhE 72 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-3 O
OH
I I
N O
Br AVM
mp 159-160 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 8.07 (m, 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.
4-[1-(4-fluorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-,~ I.
N O
AVII-3-4 was prepared in a manner similar to AVII-3-1, starting with 4-methyl-3-acetyl pyrrole. mp 162-163 °C (uncorrected) 1H NMR (400 MHz, ds-DMSO) 8 8.10 (m, 1H), 7.37 (dd, J = 5.5, 7.6 Hz, 2H), 7.18 (dd, J =
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.
4-[2,4-dimethyl-1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid H3~ OH
il N ~H3 O
/ F
A VII-3-~
AVII-3-5 was prepared in a manner similar to AV- II-3-1, starting with 2,4-dimethyl-3-acetyl pyrrole. mp 7.84-185 °C (uncorrected) 1H NMR (400 MHz, dg-DMSO) 8 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.
4-[1-(3,4-difluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-6 OH
I I
N O
\ F
mp 143-144 °C (uncorrected) 1H NMR, (400 MHz, dg_DMSO) 8 8.05 (s, IH), 7.43 (m, 2H), 7.17 (m, 1H), 7.03 (dd, J = 3.0, 1.8 Hz, 1H), 6.73 (s, 1H), 6.61 (dd, J = 3.0, 1.8 Hz, 1H), 5.16 (s, 2H), 3.3 bs, 1H). mass spec (negative mode electrospray, M-H) 306.
4-[1-(3-chlorobenzyl>-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-7 OH
I I
N O
\ CI
mp 159-160 °C (uncorrected) 1H NMR (400 MHz, ds-DMSO) 8 8.07 (m, 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.
_4-f l.-(4-chlorobenzyl)-1H-pyrrol-3-yll-2 4-dioxobutyric acid AVII 3 8 O O
OH
N O
mp 170-171 °C (uncorrected) 1H NMR (400 MHz, dg-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 (negative mode electrospray, M-H) 304.
4-fl-(4-bromobenzvl>-1H-nvrrol-3-vll-2 4 dioxobutvric acid AVII 3 9 O
OH
I I
N O
i~
/
Br AVII-3-9 mp 184-185 °C (uncorrected) 1H NMR (400 MHz, dg_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), 5.1? (s, 2H). mass spec (negative mode electrospray, M-H) 348, 350.
4-fl-(3,4-dichlorobenwl)-1H-pvrrol-3-vll 2 4 dioxobutvric acid AVII 3 10 OH
I I
N O
CI
C I A-n-3-10 mp 175-176 °C (uncorrected) 1H NMR (400 MHz, dg_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, 1H), 5.18 (s, 2H), 3.36-3.20 (bs, 1H). mass spec (negative mode electrospray, M-H) 338, 340.
4-fl-(2-methvlbenzvl)-1H-nvrrol-3-yll-2 4-dioxobutyric acid AVII 3 11 O O
OH
I I
N O
mp 119-120 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 ?.91 (t, J =
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, LH), 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.
4-[1-(3-chlorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-O
,~ II
N O
CI
AVII-3-12 was prepared in a manner similar to AVII-3-l, starting with 4-methyl-3-acetyl pyrrole.
mp 148-149 °C (uncorrected) 1H NMR (400 MHz, dg_DMSO) 8 8.09 (d, ~1 =
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.
4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-O O
,O H
I I
N O
C F:3 mp 145-146 °C (uncorrected) 1H NMR (:400 MHz, ds-DMSO) 8 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.
4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-14 O O
.OH
I I
N O
C H i AVII-3-14 - 146 .-WO 99/62513 PCTlUS99/12095 mp 164-165 °C (uncorrected) 1H NMR (400 MHz, dg_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
1.
mass spec (negative mode electrospray, M-H) 284 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-15 O O
OH
I I
N O
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 4-f 1-(3-methvlbenzvl >-1H-nvrrnl-~Yl~-2 4 dioxobutvric ac,~i~d AVII 3 16 OH
I I
N O
Rf =0.49 (94:6:1 CH2C12 / MeOH / HOAc) 'H NMR (400 MHz, CDCl3) b 7.46 (s, 1H), 7.25 (m, 2H), 7.15 (d, ~1=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).
The following compounds were prepared in a manner similar to AVII-3-l 4-Il-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-yl)-2,4-dioxobutyric acid CHN Calc. (C17H16FN04 0.2 water) 63.62, 5.15,4.36; Fnd. 63.54,5.07,4.00.
4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid O OH
'~ ~C02H
N
Br CHN Calc. 51.45, 3.45,4.00; Fnd. 51.53,3.50,3.92.
4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-yl] -2.4-dioxobutyric acid O OH
N
CI
CHN Calc. 58.93,3.96,4.58; Fnd. 58.79,4.04,4.47.
4-[4-Benzylmethylamino-1-(4-fluorobenzyl )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVIV-4-~
Step 1: 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVIV-1.-1 \ I
NH
N II
O
F
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)-1H-pyrrol-2-yl]ethanone AVI-2-1 (I.OOg, 4.31 mmol), MeOH (20 mL), benzaldehyde (0.875 mL, 8.61 mmol) and sodium cyanoborohydride (0.541g, 8.61 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHC03 , aqueous sodium potassium tartrate and brine. Drying - 14~ --(MgS04), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30°~o EtOAc in hexanes as eluant to give 1-[4-Benzylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl)ethanone AVIV-1-1 as a crystalline solid. 1H NMR (CDCl3) 8 2.34 (3I-i, 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-yl]ethanone AVIII-2-1 N
N I
O
F
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)-1H-pyrrol-2-yl]ethanone AVIV-1-1 (0.472g, 1.46 mmol), MeOH (20 mL), formalin ( 1.19 mL of 37% aqueous solution, 14.64 mmol) and sodium cyanoborohydride (0.628g, 10.00 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.57 mL, 10.0 mmol}
in MeOH (20 mL). The acetic acid solution was added dropwise to the reaction mixture over 1.5h. When the addition was complete, the resulting mixture was stirred at ambient temperature 18h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water. The layers were separated and the organic phase was washed with saturated aqueous NaHC03, aqueous sodium potassium tartrate and brine. Drying (MgS04), 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-benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl)ethanone AVIV-2-1 as a crystalline solid. 1H NMR (CDCI,g) 8 2.25 (3H, s), 2.36 (3H, s), 4.16 (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]-2,4-dioxobutyric acid ethyl ester A-VIII-3-I
N
O
N ''~ ~ -OEt O O
F /
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-1-(4-fluorobenzyl)-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-I-(4-fluorobenzyl)-1H-pyrrol-2-yl;]-2,4-dioxobutyric acid AVI-5-1 N
N ~ ~ ~OH
O O
F /
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 AVIV-3-1 was used to prepare 4-[4-benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AVIV-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, rn), 7.28 (5H, m).
- I51 ~-4-[4-Dimethylamino-1-(4-fluorobenzy) )-1H-pyrrol-2-yl]-2,4-dioxobutyric acid A-IX-3-1 Step 1: 1-[1-(4-Fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-O
F
To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 1-[1-(4-tluorobenzyl)-4-iodo-1H-pyrrol-2-yl)ethanone AIII-1-1 (I.OOg, 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 was cooled to 20°C and diluted with EtOAc. This solution was washed with H20, 1N HCl, H20, and brine. Drying (MgS04), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using I5~o EtOAc in hexanes as eluant to give 1-[ 1-(4-fluorobenzyl )-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 as an oil. 1H NMR (CDCl3) 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 Et O O
F
In a manner substantially similar to that described for Example AV-9-1.
1-[1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 was used to prepare 4-[4-phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-I which was used in the next step without further purification.
Step 3: 4-[4-Phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid AIX-3-1 OH
O O
F
In a manner substantially similar to that described for Example AV-10-1 4-[4-phenyl-L-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AIX-2-1 was used to prepare 4-[4-phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid IX- -1. 1H NMR (DMSO-dg) 8 5.66 (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).
4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pyrrol-3-yl]-2,4-dioxo-butyric acid AX-3-1 Step 1: N-[4-acetyl-1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-methanesulfonamide AX-1-1 H
H3C~ ,N
O S.O I
~CH3 N
O
A solution of 1-[4-amino-1-(4-fluoro-benzyl)-1H-pyrrol-3-yl]-ethanone AVI-2-1 (.5g, 2.15 mmole) in 10 ml of CH2C12 was cooled to 0°C and treated with triethylamine (.25 mL, 3.22 mmole) followed by methane sulfonylchloride ( .45 mL, 3.22 mmole) dropwise via syringe. The reaction was completed in two hours and was diluted with CH2C12 and washed with 10% citric acid. Organic layer was dried over MgS04, filtered and concentrated in uacuo to afford a light pink semi-solid residue. This material was chromatographed on silica gel using 50%
EtOAcIHex as eluant to give AX-1-1 as a white crystalline solid. 1H
NMR (400 MHz, CDCl3) 8 7.12 (m, 2H), 6.96 (m, 2H), 6.94 (d, J=l.BHz, 1H), 6.85 (d, J=l.BHz, 1H ), 5.97 (s, b, 1H), 5.49 (s, 2H), 2.97 (s, 3H), 2.39 (s, 3H).
Step 2: 4-[1-(4-fluorobenzyl)-4-methanesulfonylamino-1H-pyrrol-3 yl]-2,4-dioxo-butyric acid ethyl ester AX-2-1 H
H3C~ ,N
O S.O
CO~Et N
O O
A solution of AX-1-1 (460 mg, 1.48 mmole) in lOml 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 HCl solution and extracted twice with EtOAc. Combined extracts were washed with brine and dried over MgSO4, filtered and evaporated to give a yellow brown residue that was flashed chromatographed using 100°h EtOAc as eluant to give AX-2-1. as a yellow crystalline solid. 1H NMR
(400 MHz, CDCl3) b 7.13 (m, 2H), 6.97 (m, 4H), 6.75 (s, 1H), 5.92 (s, br, lH) , 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
H3C~ ,N
N
O O
F
A solution of AX-2-1 (200 mg, 0.48 mmole) was dissolved in 6ml of CH~30H and 6m1 of 1N NaOH for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HCl and extracted three times with EtOAc. Combined extracts were washed with brine, I5 dried over MgS04, filtered and evaporated to give an oily residue that was triturated with 20% EtlO/Hex to afford AX-3-1 as a yellow crystalline solid.
m.p.: 160°C decomposed 1H NMR (400 MHz, DMSO-d6) 8 9.33 (s, 1H), 7.39 (s, 1H), 7.12-7.17 (m, 5H), 6.75 (s, 1H), 5.58 (s, 2H), 2.92 (s, 3H ).
The following compounds were prepared in a manner similar to that described for AX-3-1:
4-[1-(4-Fluorobenzyl)-3-acetylamino-1H-pyrrol-2-yl]-2,4-dioxobutyric acid NHAc COOH
N
O O
F
CHN Calc. 58.96, 4.37, 8.09; Fnd. 59.20, 4.30, 8.06.
4-[4-acetylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid H
~N
O / t C02H
N
\ O OH
F
CHN Calc. (C17H15FN2O5 0.3 H20) 58.05, 4.47, 7.97; Fnd. 58.09,4.40,8.06.
4-[1-(4-fluorobenzyl)-4-(2-oxo-piperidin-1-yl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid O
N
N \ CO2H
\ O OH
F
CHN Calc.( C2pH1gFN205 0.4 H20) 61.03, 5.07, 7.12; Fnd. 60.96, 5.00, 7.22.
4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxo-butyric acid AXI-5-1 Step l: (4-fluorophenyl)-(1-triisopropylsilanyl-1H -pyrrol-3-yl)methanone AXI-1-1 O
/ \
I
Si(i-Pr)3 pXl-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 added. The mixture was stirred for 0.5 h at O°C then 3 h at room temperature and then poured into 300 mL cold saturated NH4C1 solution. The organic phase was separated and combined with two CH2C12 extracts of the aqueous phase. The combined organic layers were washed with NH4Cl solution and dried over MgS04, filtered and evaporated to give a crude brown oil. Flash chromatography on silica gel of the crude product, using a 5:95 EtOAc / Hexane mixture as the eluting solvent, gave I-1-1 as a yellow oil. TLC Rf-__0.54 ( 10:90 EtOAc /
Hexanes) 1H NMR, (400 MHz, CDCl3) 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).
Step 2: 3-(4-fluorobenzyl)-1-triisopropylsilanyl-1H -pyrrole AXI-2-1 /\
I
Si(i-Pr)3 AXI-2-1 In a similar manner to AII-2-1, AXI-1-l (3.50 g, 0.0101 mole) was refluxed with 1.0 M BH3-Me2S (30.3, 0.0303 mole) in 100 mL anhydrous THF to give AXI-2-1 as a light yellow solid. TLC Rf-__0.57 (5:95 EtOAc /
Hexanes) 1H NMR (400 MHz, CDCl3) 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).
Step 3: 1-[4-(4-fluorobenzyl)-1-triisopropylsilanyl-1H -pyrrol-3-yl]ethanone AXI-3-1 O
F N
I
Si(i-Pr)3 pXI-3-I
In a similar manner to AXI-1-l, AXI-2-1 was acylated using freshly distilled acetyl chloride to give AXI-3-1 as a light yellow solid.
TLC Rf--0.41 ( 10:90 EtOAc / Hexanes) I H NMR (400 MHz, CDC13 ) 8 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) Step 4: 1-[4-(4-fluorobenzyl)-1H -pyrrol-3-yl]ethanone AXI-4-1 O
F N
A solution of AXI-3-1 (0.1458, 0.387 mmol) in dry THF (0.5 mL ) was treated with tetra-n-butylammonium fluoride (0.397 ~tL 1.0 M in THF, 0.387 mmol) at room temperature for one hour. The reaction was quenched with saturated NaHC03, extracted with EtOAc, dried over MgS04, filtered and concentrated to give the product as a yellow solid.
TLC Rf--0.15 ( 10:90 EtOAc / Hexanes) 1:H NMR (400 MHz, CDCl3 ) 8 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).
Step 5: 1-[1,4-bis-(4-fluorobenzyl)-1H -pyrrol-3-yl]ethanone AXI-4-2 O
/ \
In a similar manner to AIV-3-1, AXI-4-1 was alkylated using 4-fluorobenzyl bromide to give AXI-4-2 as a light brown oil.
TLC Rf-__0.69 (40:60 EtOAc / Hexanes ) 1 H NMR (400 MHz, CDC13 ) 8 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).
Step 6: 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid O O
OH
/\
NJ O
H AXI-S- l 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 CHCl3 / MeOH / HC>Ac) 1H NMR (400 MHz, CDCl3) 8 8.4 (bs, IH), 7.4 (s, 1H),7.2 (m, 2H), 6.97 (m, 2H), 6.41 (s, 1H), 4.1 (s, 2H).
4-[1,4-bis-(4-fluorobenzyl)- 1H -pyi-rol-3-yl]-2,4-dioxobutyric acid AXI-5-2 O O
off ~ ~ \ ~ o F N
I\
s AXI-4-2 was carried on to the diketo acid AXI-5-2 as described for AI-3-1.
ThC Rf--0.66 (94:6:6 CHCl3 / MeOH / HOAc) 1H NMR (400 MHz, CDCl3) b 7.41 (s, 1H), 7.04-7.19 (m, 6H), 6.96 (m, 2H), 6.70 (s, 1H), 6.28 (s,lH), 4.97 (s, 2H), 4.07 (s, 2H).
EXAMPhE 97 4-[5-(3-carboxy-3-oxo-propionyl )-1-(4-fluorobenzyl )-1H-pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 Step 1: 1-(4-fluorobenzyl)-1H-pyrazol-3,5-dicarboxylic acid diethyl ester BI-1-1 O
° oEt Et0 N~N
I
F
A mixture of 1H-pyrrole-2,4-dicarboxylic acid diethyl ester (.424 g, 2 mmol), 4-fluorobenzyl bromide (.378 g, .25 ml, 2 mmol) and triethylamine (.303 g, .417 ml, 3 mmol ) was dissolved in 5 ml drv DMF
and stirred for 18 hr.. The solvent was removed in vacuo and the resulting residue partitioned between ethyl acetate/ H2O and extracted.
The combined organics were washed with H20, brine, dried over Na2SU4, filtered and the solvent removed. TLC showed about 309 unreacted pyrrole. Further purification by column chromatography (2:1 hexane/ethyl acetate) gave .335 gr (5010) of the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3) d 1.34 (t, 3H, J = 7.14), 1.41 (t, 3H, J = 7.14 Hz , 4.32 (q, 2H, J = 7.14 Hz), 4.42 (q, 2H, ~I = 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)-1H-pyrazol-3,5-dicarboxylic acid dilithium salt BI-2-1 O
O OLi \1 Li0 ~N
F
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 purification.
Step 3: 1-(4-fluorobenzyl)-1H- pyrazol-2,4-dicarboxylic acid bis-(methoxymethylamide) BI-3-1 O
O OMe ~N
MeO~N / N
N' '~
F
- 161 _ A mixture of BI-2-1 from the previous example, N,O-dimethylhydroxylamine hydrochloride (.121 g, I.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (.238 g, 1.24 mmol), 1-hydroxybenzotriazole hydrate (.7.67 g, 1.24 mmol), and triethylamine (.125 g, .173 ml, 1.24 mmol) were combined in 3 ml DMF and stirred for 18 hr. The solvent was removed in uacuo and the residue partitioned between ethyl acetate~H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04 filtered and the solvent removed. Further purification via radial disc chromatography (l:l hexane/ethyl acetate) afforded the title compound as a colorless oil.
1H NMR (400 MHz, CDCl3) b 3.27 (s, 3F1), 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)-lH-pyrazol-3-yl]ethanone BI-4-1 O
O
N~N
BI-3-13-1 (.I42 g, .41 mmol) was dissolved in 5 ml dry THF and cooled to -78°C. To this was added methyl lithium (1.158 ml of a 1.4M solution in diethyl ether, 1.64 mmol). The mixture was stirred for 1 hr, then quenched by the addition of excess l0~lo aqueous citric acid solution.
After warming to room temperature, the mixture was poured into 10 ml H2O and extracted with ethyl acetate. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to get the title compound as an oil.
1H NMR (400 MHz, CDCl3) 8 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) Step 5: 4-[5-(3-ethoxycarbonyl-3-oxopropionyl)-1-(4-fluorobenzyl)-lH-pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester BI-5-1 O O
O OEt O ~ \ v O
Et0 ~ N~N
O \
F
Bl-5-1 In a similar manner to AIII-2-1, BI-4-1 (.094 g, .36 mmol) was reacted with diethyl oxalate (.212 g, .196 ml, 1.44 mmol) and sodium ethoxide (.096 g, 1.44 mmol) to give the title compound as a yellow solid.
1H NMR (400 MHz, CDC13) 8 1.38 (t, 3H, J = 7.33 Hz), 1.42 (t, 3H, J = 7.:14 Hz),4.36(q,2H,J=7.14Hz),4.41(q,2H,J=7.14Hz),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) Step 6: 4-[5-(3-carboxy-3-oxopropionyl)-1-(4-fluorobenzyl)-1H
pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1 O O
O OH
O ~ 1 v O
HO ~N~N
O \
F
In a similar manner to AI-3-1, BI-5-1 (.157 g, .35 mmol) was reacted with LiOH (.7 ml of a 1M solution in H20) in 5 m1 THF to give the title compound as a light tan solid. MP = 215 - 217 °C
1H NMR (400 MHz, CDCl3) 8 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) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1 Step 1: 4-bromo-1-(4-fluorobenzyl)-1H-pyrazole BII-1-1 Br N~N
F
Bn-I-~
4-Bromopyrazole (.441 g, 3mmol) was added to a slurry of sodium hydride (.072 g, .12 gr of a 60°l0 oil dispersion, 3 mmol ) in 5 ml DMF
and stirred for 15 min, after which 4-fluorobenzyl bromide (.568 g, .374 ml, 3 mmol) was added and the reaction was stirred for 18 hr. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate/H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to afford title compound as a colorless oil. 1H NMR (400 MHz, CDC13) cS 5.23 (s, 2H), 7.04 (t, 2H, J = $.6 Hz), 7.18 - 7.25 (m, 2H), 7.36 (s, 1H), 7.49 (s, 1H) Step 2: 1-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]ethanone BII-2-1 O
N/
F
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 which time N-methoxy-N-methyl-acetamide (.33 g, .33 ml, 3.22 mmol) - 1 f~4 -was added and the mixture allowed to warm to room temperature. After stirring for 2 hr, the reaction was quenched with l0~lo citric acid solution and extracted with H20, brine, dried over Na2S04, filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexane/ethyl acetate ) the title compound as a colorless oil.
Step 3: 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BII-3-1 O O
OEt O
N~N
F /
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) 8 I.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), ?.94 (2, 1H), 8.02 (s, 1H) Step 4: 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid O O
OH
O
N~N
F /
In a similar manner to AI-3-1, BII-3-13-1 (.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 °C
1H NMR (400 MHz, CDCl3) 8 5.31 (s, 2H), 6.71 (d, 1H, J = .73 Hz), 7.08 (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 described for BII-4-1:
4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-3-yl] -2,4-dioxobutyric acid / O OH
N / OH
/ ~ ll N~ O
N
F
CHN Calc. (C1gH16N3O4F 0.5 EtOAc) 57.28, 5.34, 11.14; Fnd. 56.93, 5.01, 11.43.
E~:AMPLE 100 4-[ 1-(4-Fluorobenzyl)-5-methyl-1H-pyrazol-4-yl~-2-hydroxy-4-oxobut-2-enoic acid OH
/ OH
I I
N~ O
N
F
CHN Calc. (C15H13N204F 0.4 MeOH) 58.33,4.64,8.84; Fnd 57.95, 4.40, 8.44.
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/
N
O
F
1-(2H-Pyrazol-3-yl)ethanone hydrochloride (.44 g, 3 mmol) was dissolved in 8 ml DMF, and to it was added sodium hydride (.144 g, .24 g of a 60%:
oil dispersion, 6mmo1). 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 Na2S04, filtered and the solvent removed. Further purification by radial disc chromatography (3:1 hexane/ethyl acetate) yielded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) 8 2.58 (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) Step 2: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid ethyl ester BIII-2-1 O
N, N OEt O O
F
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, CDCl3) b 1.38 (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 O
N, N OH
O O
F
In a similar manner to AI-3-l, BIII-2-1 (crude from previous reaction) was reacted with 1N NaOH (3m1) in 20 ml THF to yield the title compound as a light tan solid after trituration in diethyl ether. MP = 157 - 159 °C; 1H NMR (400 MHz, CDCl3) S 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) 1-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BIV-Step 1: 1-(3-methyl-1H-pyrazol-4-yl)ethanone BIV-1-1 O
N~ N
BIV-I-I
A mixture of 1-(4-acetyl-5-methylpyrazol-1-yl)ethanone (1 g, 6 mmol, Maybridge) and 10 ml 1N NaOH were dissolved in 40 ml THF and stirred 4 days. The solvent was removed in Uc~cuo and the residue partitioned between ethyl acetate/ H20 and extracted. The combined organic extracts were washed with H20, brine, dried over Na2S04, filtered and the solvent removed to get the title compound. 1H NMR (400 MHz, CDCl3) 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 O
N~ N
F
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 work-up and purification by preparative HPLC (Chiralcel OD 25x2, 75°l0 hexane/1% diethylamine, 25% EtOH) yielded the title compound and 1-[1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]ethanone as white solids.
1H NMR (400 MHz, CDC13) 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) Step 3: 1-[1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl]-2,4 dioxobutyric acid ethyl ester BIV-3-1 O O
OEt O
N~N
\
F
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 solid. 1H NMR (400 MHz, CDCl3) 8 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-dioxobutyric acid BIV-4-1 OH
N
O
N
F
In a similar manner to AI-3-13-1, BIV-3-1 (.234 g, .68m mmol) was reacted with 2 ml NaOH in lU ml THF to afford the title compound as a light tan solid. MP = 187-188 °C; 1H NMR (400 MHz, CDC13) b 2.53 (s, 3H), 5.23 (s, 2H), 6.64 (2, 1H), 7.08 (t, 2H, J = 8.61), 7.23 - 7.31 (m, 2H), 7.88 (s, 1H) 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-Step 1: 1-[1-(3-chlorobenzyl)-3-methyl-1H-pyrazol-4-yl]ethanone BV-1-1 and 1-[1-(3-chlorobenzyl)-5-methyl-1H-pyrazol-4-yl]ethanone BV-2-1 O O
N, ~ N /
N ' \
CI ~ CI
/ /
In a similar manner to BIV-2-l, 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°~0 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-(3-chlorobenzyl)-3-methyl-1H-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-l:
1H NMR (400 MHz, CDC13) b 2.38 (s, 3H), 2.49 (s, 3H), 5.21 (s, 2H), 7.12 (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) b 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) Step 2: 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BV-3-1 O O
OEt N, / , O
CI
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 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-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-4-1 O O
OH
/ ~ II
N~ O
N
CI
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 title compound as a light tan solid. MP - 183 - 184 °C. 1H NMR (400 MHz, CDC13) b 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) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid Step 1: 4-[5 -methyl-1-{3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BV- 5-1 O O
OEt i ~ II
N.~ O
CI
In a similar manner to AIII-2-1, BV-2-1 {.158 g, .64 mmol) was reacted with diethyl oxalate (.199 g, .185 ml, 1.36 mmol) and sodium ethoxide (.092 g, 1.36 mmol) to give the title compound, which was used without further purification. 1H NMR (400 MHz, CDC13) S 1.401'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) Step 2: 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid BV-6-1 O O
OH
i ~ II
N~ O
N
CI
In a similar manner to AI-3-1, BV-5-1 (crude from above) was reacted 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 °C
1H NMR (400 MHz, CDCl3) 8 2.53 (s, 3H), 5.23 (2, 2H), 6.67 (s, 1HO, 7.12 -7.18 (m, 1H), 7.25 (s, 1H), 7.31 - 7.36 (m, 2H), 7.97 (s, 1H) 4-[1-(4-fluoro-benzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 Step 1: 1-(4-fluoro-benzyl)-1H-imidazole CI-1-1 r-- N
J
N
\
F
To a solution of imidazole (10g, 0.146 mole) in 80 ml of DMF at 0°C was added triethylamine ( 25.5 ml, 0.176 mole) followed by a solution of 4-Fluorobenzylbromide ( 22 ml, 0.176 mole) in 30m1 of DMF added dropwise via addition funnel. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure in uctcuo. The residue was partitioned with H20 and CH2C12. The organic layer was washed with saturated NaHC03, brine, dried over MgS04, filtered and evaporated to afford a crude oil. This material was chromatographed on silica gel using 50-100% EtOAc,/Hex as eluant. Obtained CI-1-1 as an oil. 1H
NMR (400 MHz, CDCl3) 8 7.53 (s, 1H), 7.09-7.I5 (m, 5H), 6.88 (s, 1H), 5.09 (s, 2H).
Step 2: 1-(4-fluorobenzyl)-1H-imidazole-2-carboxylic lithium salt CI-N 1_2_1 ~C02-Li+
N
F
A solution of I-1-1 (8.81g, 0.05mole) in 120 ml dried THF at -78°C
under N2 was added a solution of 2.5M nBuLi in Hexanes (2lml, .052 mole) dropwise via syringe over 40 minutes. 'this resulting mixture was aged for 1 hour at -78°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 obtain I -2-1 as a solid salt. 1H NMR (400 MHz, DMSO-dg) 8 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)-1H-imidazole-2-carboxylic acid methoxy-methyl-amide CI-3-1 r---N O C H 3 W
N~N~CH3 F
A solution of I -2-1 (7.Og, .031 mole) was treated with EDC.HCI (6.5g, .034 mole), HOBT.H20 (4.6g, .034 mole), N,0- dimethylhydroxy-amine.HCl (3.31g, .034 mole), and triethylamine (12.9 ml, .092 mole) in 60 ml of DMF and stirred over the weekend under N2 . The DMF was removed under reduced pressure in vocuo. The residue was partitioned with saturated NaHC03 and extracted three times with EtOAc.
Combined organics layers were washed with H20 and brine, dried over MgS04, filtered and evaporated to afford a yellow oil. This crude material was chromatographed on silica gel using 70-100% EtOAcIHex as eluant. Obtained CI-3-13-1 as an oil. 1I NMR (400 MHz, CDC13) s 7.19-7.23 (m, 2H), 7.09 (s, 1H), 6.97-?.04 (m, 3H), 5.42 (s, 2H), 3.81 (s, 3H), 3.48 (s, 3H) Step 4: 1-[1-(4-fluorobenzyl)-1H-imidazol-2-yl)ethanone CI-4-1 N
CHI
N
O I_4-F
A solution of ,I -3-1 (2.0g, .0076 mole) in 60 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (6.5 ml, .0091 mole) in Et20 drnpwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to 0°C for 2 hours. The reaction was quenched with 75m1 of saturated NH4C1 solution and extracted with three times EtOAc. Combined organics layers were washed with brine, dried over MgS04, filtered and evaporated to give an oil. This crude material was chromatographed on silica gel using 70% EtOAc/Hex as eluant. Obtained I- 4-1 as an oil. 1H
NMR (400 MHz, CDCl3) b ?.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 ethyl ester CI-5-1 N
C02Et N
F
A solution of I- 4-1 (0.5g, 0.0023 mole) in 8ml dried THF was treated with diethyl oxalate (0.62 ml, 0.0046 mole) and sodium ethoxide (.31g, 0.0046 mmole) at room temperature over night under N2 atmosphere.
The reaction mixture was poured into 10 ml of .5 N HCl solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgS04, filtered and evaporated to give a crude residue. This crude material was chromatographed on silica gel using 50% EtOAcIHex as eluant. Obtained CI- 5-1 as a beige solid. 1H NMR
(400 MHz, CDCl3) 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) Step 6: 4-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid N
N
O O
\ CI- -1 F /
A solution of CCIiS-11 {0.3 g, 0.0009 mole) was dissolved in 7ml of CH30H, 7 ml of THF and 3ml of 1N NaOH and stirred for 3 hours. The reaction mixture was washed with ether and acidified to pH 1-2 with 1N HCl and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgS04, filtered and evaporated to give a crystalline solid, that was stirred in hot EtOAc and filtered to obtained I- -1 as a light beige solid. m.p.: 163-164°C. 1H NMR (400 MHz, CDC13) 8 7.20 (m, 3H), 7.13 (s, 1H), ?.O1 (t, 3H), 5.69 (s, 2H).
In a manner similar to that described for I- -1, the following compound was prepared:-4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid ~N
~N '~'~ ~ _OH
O O
[\
CHN Calc. 61.76, 4.44, 10.29; Fnd. 61.80, 4.58, 10.17 4-[1-(4-fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 Step 1: 1-(4-fluorobenzyl)-1H-imidazole-4-carboxylic acid 4-fluoro-benzyl ester CII-1-la; and 3-(4-fluorobenzyl )-3H-imidazole-4-carboxylic acid 4-fluoro-benzyl ester CII-1-lb O ~. O _ N O 1 / F \ N O 1 / F
L~ I
N + F N
I \ ~II_1;1a H X11_1_ F
A suspension of 1H-imidazole-4-carboxylic acid ( l.Og, 0.0089 mole ) in 25 ml of DMF was treated with Cs2C03 (8.728, .026 mole) followed by 4-fluorobenzyl bromide (3.33 ml, .026 mole) and stirred overnight at room temperature under N2 atmosphere. DMF was removed under reduced pressure in Uaccuo. The residue was partitioned with H20 and three times with EtOAc. Combined extracts were washed with brine, dried over MgS04~, filtered and evaporated to give a crude oil. This material was chromatographed on silica gel with 50% EtOAc/Hex as eluant to afford a l:l mixture of I I-1-la and I I- 1-1 1H NMR (400 MHz, CDCl3) 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)-1H-imidazol-4-yl]-ethanone CII-2-1 O
'CH3 N
'N
F
A solution of CI I-1-1 (0.9g, .0027 mole) in 10 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (2.35 ml, .0032mo1e) in Et2O
dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to room temperature over the weekend. The reaction was quenched with l0ml of 1N HCl. The solution was basified with saturated NaHC03 and extracted with EtOAc three times. Combined organics layers were washed with brine, dried over MgS04, filtered and evaporated to give CI I-2-1 as a crystalline solid. 1H NMR (400 MHz, CDCl3) 8 7.53 (d, 2H), 7.15 (m, 2H), 7.04 (m, 2H), 5.1 (s, 2H), 2.5 (s, 3H).
Step 3: 4-[1-(4-fluorobenzyl)-LH-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester CII-3-1 O O
C02Et N
N
F
A solution of I I-2-1 (75 mg, 0.34 mmole) in 3ml dried THF was treated with diethyl oxalate (U.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 HCl solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgS04, filtered and evaporated to give I I-3-1 as a bright yellow oil. Used as is without further purification. 1H NMR (400 MHz, CDCl3) b 7.78 (s, 1H), 7.69 (s, 1H), ?.22 (m, 2H), 7.10 (m, 3H), 5.19 (m, 2H), 4.35 (m, 2H), 1.4(m, 3H).
Step 4: 4-[1-(4-fluorobenzyl)-1H-imidazol-4-yl]-2,4-dioxo-butyric acid O O
N
N
F
A solution of CI I-3-1 (70 mg, 0.2 mmole) was dissolved in 3ml of CH3OH
and 3ml of 1N NaOH for 3 hours. The reaction mixture was washed with ether, acidified to pH 1-2 with 1N HC1 and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgS04, 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) 8 8.24 (s, 1H), 8.07 (s, 1H), 7.44 (m, 2H), 7.19 (m, 2H), 6.92 (s, 1H), 5.28 (s, 2H).
4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid DI-4-1 Step l: 1-(1H -indol-2-yl)ethanone DI-1-1 N
H
A solution of 2-carboxy indoie (3g, 16.9 mmol) in anhydrous ether (50 mL) was cooled to 0°C and treated with Methyl Lithium (1.4 M, 48.3 mL) A white solid precipitated. After addition was complete the reaction was warmed to reflux for two hours, quenched by pouring into ice water, and extracted with Et2O. The organic layers were combined, washed with saturated sodium bicarbonate solution and brine, dried over MgS04, filtered and evaporated to give DI-1-1 as a white solid. Rf-__0.53 (20%
EtOAc/Hexanes ) 1H NMR (400 MHz, CDC13) 8 9.1 (bs, lh), 7.72 (d, J= 7.78 Hz, 1H), 7.42 - I HO -(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-[l-(4-fluorobenzyl)- 1H -indol -2-yl]ethanone DI-2-1 \ ~ ~ CHs N
O
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 (20r1o EtOAc/Hexanes> 1H NMR (400 MHz, CDC13) 8 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).
Step 3: 4-[1-(4-fluorobenzyl)- 1H -indol -2-yl]-2,4-dioxobutyric acid \
O
N ~ ~ -OCH3 O O
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-3-13-1 as a yellow solid. Rf--0.26 (97:3:1 CHC13 / MeOH / HOAc). 1H NMR (400 MHz, CDCl3 ) 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 O
-OH
O O
F
Df-4-1 In a manner similar to that described for the preparation of A-I-3-1, I-I-3-11 was treated with sodium hydroxide to give DI-4-1 as bright yellow crystals after crystallization from EtOAc. 1H NMR (400 MHz, DMSO-D6) 8 7.90 (s, 1H), 7.77 (d, J= 7.88 Hz, 1.H), 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.
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 N
CHN Calc.(C13H11N04 0.15 H20) 62.97, 4.59, 5.65; Fnd. 63.05, 4.45, 5.80.
4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid DII-3-1 Step 1: 1-[1-(4-fluorobenzyl)-1H-indol-3-yl]ethanone DII-1-1 WO 99!62513 PCT/US99/12095 O
\~ O
N
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°~0 oil dispersion, 2 mmol) in 2 ml DMF
for 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)-1H-indol-3-yl]-2,4-dioxobutyric acid ethyl ester DII-2-1 O
OEt v \ ~ ~ O
N
w F
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 g, 2 mmol) to yield the title compound as a yellow solid after trituration in diethyl ether.
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, 2I~, J = 8.6 Hz), 7.13 - 7.20 fm, 2H), 7.30 - 7.39 (m, 3H), 7.88 (s, 1H), 8.40 (d, 1H, J = 7.51 Hz) Step 3: 1-[1-(4-fluorobenzyl)-1H-indol-3-yl)-2,4-dioxobutyric acid DII-O
O OH
O
F
In a similar manner to AI-3-1, DII-2-1 (.1 g, .27 mmol) was hydrolyzed using .54 m1 1M LiOH (5.4 mmol) in 2 m1 THF to give the title compound as a yellow solid. MP = 161- 162 °C. 1H NMR, (400 MHz, CDCl3) 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) HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase and Preintegration Complexes Assays for the strand transfer activity of integrase were conducted according to Wolfe, A.L. et al., J. Virol. 70, 1424 (1996), and Farnet, C.M. and Bushman F.D. (1997) Cell; 88, 483 for recombinant integrase and preintegration complexes, respectively, hereby incorporated by reference for these purposes.
Representative compounds tested in the integrase assay demonstrated IC50's less than 1 micromolar. Further, representative compounds tested in the preintegration complex assay also demonstrated IC50's of less than 1 micromolar.
Assay 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.
Representative compounds tested in the present assay demonstrated ICgSs of less than 10 micromolar.
Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adoptions, or modifications, as come within the scope of the following claims and their equivalents.
Claims
1. A compound of structural formula (I):
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R1, R2 and R8; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -R6, (8) -C2-5 alkenyl-R3, (9) -C2-5 alkynyl-R3, (10) -O-R6, (11) -O-C1-6 alkyl, and (12) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4), (9) -C1-6 alkyl-N(R4)(R6), (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo, (b) halogen, (c) C1-6 alkyl, (d) C1-6 alkyloxy-, (e) -CF3, (f) -OCF3, (g) -CN, and (h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring; wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (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 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3 , and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H, (2) C1-6 alkyl-oxy, and (3) C1-6 alkyl; and each n is independently selected from 0, 1 and 2;
and further provided that when R7 is C1-6 alkyl, then R2 is not -H or -C1-6 alkyl.
2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) pyrrolyl, (2) imidazolyl, (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I);
R1 is selected from:
(1) -H.
(2) -CH3, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) suhstituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -UCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl-substituted with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6 (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4), (9) -C1-6 alkyl-N(R4)(R6), (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) bydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) -halogen, (b) -C1-6 alkyl, (c) -C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, and (g) -hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, and (3) -CF3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
R7 is H;
R8 is selected from:
(1) -H, (2) -OCH3, and (3) -CH3; and each n is independently selected from 0, 1 and 2.
3. The compound according to Claim 2 , and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) pyrrolyl, (2) imidazolyl, (3) pyrazolyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I);
R1 is selected from:
(1) -H, (2) -CH3, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, and (12) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4), (9) -C1-6 alkyl-N(R4)(R6), (10) -C1-6 alkyl S(O)n-Rf, (11) -C1-6 alkyl NR4C(O)-R6, and (12) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (3) thienyl, (4) pyridyl, (5) imidazolyl, (6) pyrrolyl, (7) pyrazolyl, (8) C3-6 cycloalkyl, (9) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(10) piperidinyl, (11) morpholinyl, (12) naphthyl, (13) indolyl, and (14) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, and (3) -CF3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, and (4) -R3, each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
R7 is H; and R8 is selected from:
(1) -H, and (2) CH3; and each n is independently selected from 0, 1 and 2.
4. The compound according to Claim 1 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7 R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4), (9) -C1-6 alkyl-N(R4)(R6), (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (3) thienyl, (4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl, (6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF 3, and (iv) hydroxy, (7) imidazolyl, (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl, (10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (11) pyrazolyl, (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy, (13) C3-6 cycloalkyl, (14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy, (15) piperidinyl, (16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy, (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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy, (19) naphthyl, (20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy, (21) indolyl, (22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy, (23) C3-6 cycloalkyl fused with a phenyl ring, (24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (fl -CN, (g) =O, and {h) hydroxy;
each R4 is independently selected from:
(i) -H, (2) -C1_3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -Cl_3 alkyl-R3, (7) -C2-~ alkenyl-R3, (8) -S(O)n-R'3, and (9) -C(O)-R~;
each R5 is independently selected from:
(1) -H, (2) -Cl_3 alkyl, (3) -CF3, (5) -C2_~ alkenyl, (6 ) -C 1-3 alkyl-R3 , (7) -C2-3 alkenyl-R3, (8) -S(O)n R3, and (9) -C(O)-R3;
each R6 is independently selected from:
-C1-~ alkyl-R~, and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H, and (2) C1-6 alkyl: and each n is independently selected from 0, 1 and 2;
and further provided that when R7 is C1-6 alkyl, then R2 is not -H or -C1 -6 alkyl.
5. The compound according to Claim 4 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H.
(2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 substituent independently selected from:
(a) halo.
(b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, and (12) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3 (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, (10) -C1-6 alkyl NR4C(O)-R6, and (11) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-2 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl, (4) pyridyl, (5) imidazolyl, (6) pyrrolyl, (7) pyrazolyl, (8) C3-6 cycloalkyl, (10) piperidinyl, (11) morpholinyl, (12) substituted morpholinyl substituted with a substituent selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, (h) hydroxy;
(12) naphthyl, (13) indolyl, and (14) C3-6 cycloalkyl fused with a phenyl ring;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R3;
each R5 is in dependently selected from:
(1) -H, (2) -C1-3 alkyl.
(3) -CF3, (4) -R3, (5) -C1-3 alkyl-R-3, (6) -S(O)n-R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3 and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-4 alkyl;
R8 is selected from:
(1) -H, and (2) -CH3; and each n is independently selected from 0, 1 and 2:
and further provided that when R7 is C1-4 alkyl, then R2 is not -H or -C1-6 alkyl.
6. The compound according to Claim 5 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -NO2, (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:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br;
(10) -C2-5 alkynyl-R3, and (11) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, - Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy;
(3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo; and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl, each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
R7 is -H;
R8 is selected from:
(1) -H, and (2) -CH3; and each n is independently selected from 0, 1 and 2.
7. The compound according to Claim 6 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -NO2, (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:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R 3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, -Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3 (5) -C1-3 alkyl-R3, (6) -S(O)n -R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3; and each n is independently selected from 0, 1 and 2.
8. The compound according to Claim 6 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -NO2, (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:
(a) halo, wherein halo is selected from: -F,-Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, -Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n -R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
each n is independently selected from 0, 1 and 2.
9. The compound according to Claim 1 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4, (9) -C1-6 alkyl-N(R4)(R6), (10)-C1-6 alkyl S(O)n-R6, (11)-C1-6 alkyl C(O)-R6, (12)-C1-6 alkyl C(S)-R6, (13)-C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituent independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -(CN, (g) =O, and (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n -R3, and (9) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n -R3, and (9) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl:
R8 is selected from:
(1) -H, and (2) C1-6 alkyl: and each n is independently selected from 0, 1 and 2:
and further provided that when R7 is C1-6 alkyl, then R2 is not -H or -C1-6 alkyl.
10. The compound according to Claim 9 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -NO2, (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:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4 C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, -Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo; and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n -R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3;
R8 is selected from:
(1) -H, and (2) CH3; and each n is independently selected from 0, 1 and 2.
11. The compound according to Claim 1 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is pyrazolyl;
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, ( 12) -C2-5 alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4) , (9) -C1-6 alkyl-N(R4)(R6) , (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with l, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii ) -CF3, and (iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h ) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with l, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, C1-6 alkyl, (c)C1-6 alkyloxy-, (d)-CF3, (e)-OCF3, (f) -CN, (g)=O, and (h)hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n R3, and (9) -C(O)-R3;
each R 5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n R3, and (9) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3 , and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H, and (2) C1-6 alkyl; and each n is independently selected from 0, 1 and 2;
and further provided that when R7 is C1-6 alkyl, then R2 is not -H or-C1-6 alkyl.
12. The compound according to Claim 11 wherein:
R1 is selected from;
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F,Cl,-Br, and-I
(5) -NO2, (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:
(a) halo, wherein halo is selected from: -F,-Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1)-H, (2) -R3.
(3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4) , (8) -C1-6 alkyl-N(R4)(R6) , (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with l, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F,-Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4 ) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O))-R3;
each R6 is independently selected from:
( 1 ) -C1-3 alkyl-R3, and (2) -R3;
each R7 is independently selected from:
(1) -H.
(2) -CH2CH3, and (3) -CH3: and R8 is selected from:
(1) -H. and (2) -CH3; and each n is independently selected from 0, 1 and 2; and further provided that when R7 is -CH2CH3 or -CH3, then R2 is not -H or-C1-6 alkyl;
and tautomers and pharmaceutically acceptable salts thereof.
13. The compound according to Claim 12 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 12 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof.
15. The compound according to Claim 1 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is imidazolyl;
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, (12) -C2-5 alkynyl-R3, and (13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O)n-R6, (8) -C1-6 alkyl (OR6)(R4) , (9) -C1-6 alkyl-N(R4)(R6) , (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f)-OCF3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl (12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii)C1-6 alkyl (iii ) -CF3, and (iv) hydroxy;
(13) C3-6cycloalkyl;
(14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from;
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) C3-6cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3 , (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n-R3, and (9) -C(O)-R3 each R6 is independently selected from:
(1) -C 1 -3 alkyl-R3, and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl;
R8 is selected from:
(1) -H and (2) C1-6 alkyl; and each n is independently selected from 0, 1 and 2;
and further provided that when R7 is C1-6 alkyl, then R2 is not-H or-C1-6 alkyl.
16. The compound according to Claim 15 of structural formula:
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, C1 -Br, and -I;
(5) -NO2, (6) -N(R4)(R5), (f) -phenyl, (8) phenyl C1-3 alkyl-, (9) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, wherein halo is selected from: -F, -C1, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4) , (8) -C1-6 alkyl-N(R4)(R6) , (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3;
(g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, Cl, and Br (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo,and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from (1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n- R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3; and each n is independently selected from 0, 1 and 2.
17. The compound according to Claim 1 of structural formula:
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;
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, (5) -NO2, (6) -N(R4)(R5), (7) -phenyl, (8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (9) phenyl C1-3 alkyl-, (10) substituted phenyl C1-3 alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and (c) methoxy, (11) -C2-5 alkenyl-R3, ( 12 ) -C2-5 alkynyl-R3 , and (13) -C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -S(O )n-R6, (8) -C1-6 alkyl (OR6)(R4) , (9) -C1-6 alkyl-N(R4 )(R6 ) , (10) -C1-6 alkyl S(O)n-R6, (11) -C1-6 alkyl C(O)-R6, (12) -C1-6 alkyl C(S)-R6, (13) -C1-6 alkyl NR4C(O)-R6, and (14) -C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from;
(a) halogen, (b) C1-6 alkyl, (c) C1-6alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i} phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(9) pyrrolyl;
(10) substituted pyrrolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(11) pyrazolyl;
(12) substituted pyrazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3 , (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1-6 alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3-6 cycloalkyl, (14) substituted C3-6 cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(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, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C3-6 cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) -CF3, (e) -OCF3, (f) -CN, (g) =O, and (h) hydroxy;
each R4 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n -R3, and (9) -C(O)-R3;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C2-3 alkenyl, (6) -C1-3 alkyl-R3, (7) -C2-3 alkenyl-R3, (8) -S(O)n -R3, and (9) -C(O)-R3;
each R6 is independently selected from:
1) -C1-3 alkyl-R3, and (2) -R3;
R7 is selected from:
(1) -H, and (2) C1-6 alkyl:
R8 is selected from:
(1) -H, and (2) C1-6 alkyl: and each n is independently selected from 0, 1 and 2:
and further provided that when R7 is C1-6 alkyl, then R2 is not -H or -C1-6 alkyl.
18. The compound according to Claim 17 of structural formula:
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from:
(1) -H.
(2) -C1-5 alkyl.
(3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -NO2.
(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:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3, (3) -C1-6 alkyl, (4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4), (8) -C1-6 alkyl-N(R4)(R6), (9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f) -OCF3, (g) -CN, (h) hydroxy, (i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, wherein halogen is selected from -F, -Cl, and Br, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3, (5) -C1-3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(l) -C1-3 alkyl-R3, and (2) -R3; and each n is independently selected from 0, 1 and 2.
19. The compound according to Claim 17 of structural formula:
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from:
(1) -H, (2) -C1-5 alkyl, (3) -CF3, (4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I, (5) -NO2, (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:
(a) halo, wherein halo is selected from: -F, -Cl, and -Br, and (10) -C2-5 alkynyl-R3;
R2 is selected from:
(1) -H, (2) -R3.
(3) -C1-6 alkyl.
(4) -C1-6 alkyl substituted with R3, (5) -O-R6, (6) -O-C1-6 alkyl-OR6, (7) -C1-6 alkyl (OR6)(R4).
(8) -C1-6 alkyl-N(R4)(R6).
(9) -C1-6 alkyl C(O)-R6, and (10) -C1-6 alkyl NR4C(O)-R6;
each R3 is independently selected from:
(1) phenyl, (2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1-6 alkyl, (c) C1-6 alkyloxy-, (d) phenyl, (e) -CF3, (f7 -OCF3, (g) -CN, (h) hydroxy, (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, (ii) methyl, (iii) -CF3, and (iv) hydroxy, (3) C3-6 cycloalkyl, (4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and (6) naphthyl;
each R4 is independently selected from:
(1) -H, and (2) -C1-3 alkyl;
each R5 is independently selected from:
(1) -H, (2) -C1-3 alkyl, (3) -CF3, (4) -R3 (5) -C1-3 alkyl-R3, (6) -S(O)n-R3, and (7) -C(O)-R3;
each R6 is independently selected from:
(1) -C1-3 alkyl-R3, and (2) -R3; and each n is independently selected from 0, 1 and 2.
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, (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, (6) 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester, (7) 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester, (8) 4-(1-benzyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid, 2 (9) 4-(1-naphthalen-2-ylmethyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid, (10) 4-(1-biphenyl-4-ylmethyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid, (11) 4-(1-naphthalen-1-ylmethyl-1H-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)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (14) 2,4-dioxo-4-(1-phenethyl-1H-pyrrol-2-yl)-butyric acid, (15) 4-[1-(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)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (18) 4-[1-(2-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (19) 4-[1-(3-bromobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (20) 4-[1-(3-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (21) 4-[1-(3-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (22) 4-[1-(2-fluorobenzyl)-1H-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-1H-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-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)-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, (34) 4-[1-(2,5,6-difluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (35) 4-[1-(2-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid.
(36) 4-[1-(4-trifluoromethylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (37) 4-[1-(4-cyanobenzyll-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (38) 4-[1-(3-methoxybenzyl)-1H-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-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, (43) 4-[1-(3-phenylpropyl)-1H-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)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (48) 4-{1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}]-2,4-dioxobutyric acid, (49) 4-(1-cyclohexylmethyl-1-H-pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester (50) 4-(1-cyclohexylmethyl-1-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-1H-pyrrol-2-yl]-2,4-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, (55) 4-[5-(4-fluorobenzyl)-1-methyl-1H-pyrrol-2-yl)-2,4-dioxobutyric acid methyl ester, (56) 4-[5-(4-fluorobenzyl)-1-methyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (57) 4-[5-(3-chlorobenzyl)-1-methyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (58) 4-[5-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (59) 4-[5-(3-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (60) 4-[5-(benzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (61) 4-[5-(3-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (62) 4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4 dioxobutyric acid, (63) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (64) 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (65) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (66) 4-[5-(4-fluorobenzyl)-1-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (67) 4-[5-(3-chlorobenzyl)-1-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (68) 4-[5-(benzyl)-1-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (69) 4-[5-(3-fluorobenzyl)-1-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (70) 4-(5-benzyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid, (71) 4-[2,5-bis-(3-chlorobenzyl)-1-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, (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-dioxobutyric acid, (76) 4-[1-(4-Fluorobenzyl)-4-vitro-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (77) 4-[4-(Benzylamino)-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (78) 4-[5-Nitro-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric (79) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester, (80) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[1-(4-fluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (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, (85) 4-[1-(3,4-difluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(3-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (87) 4-[1-(4-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (88) 4-[1-(4-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (89) 4-[1-(3,4-dichlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (90) 4-[1-(2-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (91) 4-[1-(3-chlorobenzyl)-4-methyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (92) 4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (93) 4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(3-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (96) 4-{1-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-yl}-2,4-dioxobutyric acid, (97) 4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (98) 4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (99) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric, ethyl ester (100) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (101) 4-[4-Phenyl-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (102) 4-[4-Phenyl-1-(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, (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-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-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-pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester, (111) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (112) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-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 ethyl ester, (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, (119) 4-[3-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester, (120) 4-[3 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (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 (123) 4-[5-methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (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, (127) 4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid, (128) 4-[1-(4-fluorobenzyl)-1H-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 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, (133) 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2,4-dioxobutyric acid, (134) 1-[1-(4-fluorobenzyl)-1H-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-dioxobutyric acid, (137) 4-[4-(3-chlorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (138) 4-[4-(4-fluorobenzyl)-1-methyl-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (139) 4-[2,5-dimethyl-1-(4-fluorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (140) 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, (142) 4-[1-2,4-dimethylbenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (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, (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, a tautomer or a pharmaceutically acceptable salt thereof.
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-y1)-2,4-dioxobutyric acid, (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 acid, (7) 2,4-dioxo-4-[1-(4-phenylbutyl)- 1H-pyrral -2-yl]-butyric acid, (8) 4-[1-(4-chlorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (9) 2,4-dioxo-4-(1-phenethyl-1H-pyrrol -2-yl)-butyric acid, (10) 4-[1-(2-methylbenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (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)-1H-pyrrol-2-yl]-2,4-diaxobutyric acid, (15) 4-[1-(3-chlorobenzyl)-7H-pyrrol-2-yl]-2,4-dioxobutyric acid, (16) 4-[1-(3-methylbenzyl)-1H-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-1H-pyrrol -2-yl)-2,4-dioxobutyric acid,(20) 2,4-dioxo-4-[1-(4-phenoxybutyl)-1H -pyrrol-2-yl]-butyric acid, (21) 4-[1-(3-fluorobenzyl)-1H-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-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-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, (31) 4-[1-(4-trifluoromethylbenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (32) 4-[1-(4-cyanobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (33) 4-[1-(3-methoxybenzyl)-1H -pyrrol-2-yl] -2,4-dioxobutyric acid, (34) 2-hydroxy-4-[1-(4-hydroxybenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (35) 4-(1-cyclopentylmethyl-1H-pyrrol-2-yl) -2,4-dioxobutyric acid, (36) 4-{1-[3-(4-fluorophenyl)propyl]-1H-pyrrol-2-y}-2,4-dioxobutyric acid, (37) 4-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrrol-2-yl}-2,4-dioxobutyric acid, (38) 4-[1-(3-phenylpropyl)-1H-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)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (41) 4-[1-(2-chloro-benzyl)-1-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (42) 4-[1-(3-benzoylaminopropyl)-1H-pyrrol-3-yl] -2,4-dioxobutyric acid, (43) 4-{1-[3-(4-fluorophenoxy)benzyl]-1H-pyrrol-2-yl}] -2,4-dioxobutyric acid, (44) 4-(1-cyclohexylmethyl-1-H -pyrrol-2-yl)-2,4-dioxo-butyric acid, (45) 4- [1-(4-fluorobenzyl)-4-phenylethynyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (46) 4-[ 1-(4-fluorobenzyl)-4-phenethyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (47) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (48) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (49) 4-[5-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (50) 4-[5-(3-chlorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (51) 4-[5-(benzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (52) 4-[5-(3-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (53) 4-[5-(4-fluorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4 dioxobutyric acid, (54) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (55) 4-[5-(benzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (56) 4-[5-(3-chlorobenzyl)-1-(4-fluorobenzyl)-1H -pyrrol-2-yl]-2,4-dioxobutyric acid, (57) 4-[5-(4-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (58) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (59) 4-[5-(benzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (60) 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl)-2,4-dioxobutyric acid, (61) 4-(5-benzyl-1H -pyrrol-3-yl )-2,4-dioxobutyric acid, (s2) 4-[2,5-bis-(3-chlorobenzyl)-1-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (63) 4-[1-(4-Fluorobenzyl)-5-phenyl-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (64) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (65) 4-[1-(4-Fluorobenzyl)-4-vitro-1.H-pyrrol-2-yl]-2,4-dioxobutyric acid, (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, (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, (73) 4-[1-(3,4-difluorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (74) 4-[1-(3-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (75) 4-[1-(4-chlorobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (76) 4-[1-(4-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (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, (80) 4-[1-(3-trifluoromethylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (81) 4-[1-(4-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[1-(4-methoxybenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (83) 4-[1-(3-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (84) 4-(1-[3-(4-fluorophenyl)-propyl]-1H-pyrrol-3-y1)-2,4-dioxobutyric acid, (85) 4-[1-(4-bromobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (86) 4-[1-(4-chlorobenzyl)-1-H-pyrrol-3-y1] -2,4-dioxobutyric acid, (87) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]
2,4-dioxobutyric acid, (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, (90) 4-[1-(4-Fluorobenzyl)-3-acetylamino-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (91) 4-[4-acetylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl] -2,4-dioxobutyric acid, (93) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[1,4-bis-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (95) 4-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (96) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-3-yl] -2,4 dioxobutyric acid, (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, (100) 4-[3 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (101) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (102) 4-[5 -methyl-1-(3-chlorobenzyl)-1H-pyrazol-4-yl]-2,4-dioxobutyric acid, (103) 4-[1-(4-fluoro-benzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid, (104) 4-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2,4-dioxo-butyric acid, (105) 4-(1-Benzyl-1H-imidazol-2-yl)-2,4-dioxobutyric acid, (106) 4-[1-(4-fluorobenzyl)-1H-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)-1H-indol-3-yl]-2,4-dioxobutyric acid, ethyl ester, (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)-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (114) 4-[4-(4-fluorobenzyl)-1-methyl-1-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 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, (119) 4-[1-(3-chloro-5-methyl-benzyl)-1-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 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.
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, (3) 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (4) 4-[5-(3-chlorobenzyl)-1-methyl-1H -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-dioxobutyric acid, (7) 4-[5-(3-chlorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (8) 4-[5-(benzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (9) 4-[5-(3-fluorobenzyl)-1-methyl-1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (10) 4-[4-Dimethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (11) 4-[1-benzyl-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (12) 4-[1-(3-bromobenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid, (13) 4-[1-(4-fluorobenzyl)-4-methyl-1H-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, (16) 4-[1-(2-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(17) 4-[1-(3-methylbenzyl)-1H-pyrrol-3-yl]-2,4-dioxobutyric acid,-(18) 4-[4-Benzylmethylamino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid, (19) 4-[4-(4-fluorobenzyl)- 1H -pyrrol-3-yl]-2,4-dioxobutyric acid, (20) 4-[1,4-his-(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)-1-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (23) 4-[4-(4-fluorobenzyl)-1-methyl-1-H-pyrrol-3-yl] -2,4-dioxo-butyric acid, (24) 4-[2,5-dimethyl-1-(4-fluorobenzyl)-1-H-pyrrol-3-yl] -2,4-dioxo-butyric acid, (25) 4-[1-(3,5-dichlorobenzyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (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-butyric acid, and (29) 4-[1-(1-naphthalenemethyl)-1-H-pyrrol-3-yl]-2,4-dioxobutyric acid;
or a tautomer or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition useful for inhibiting HIV integrase, comprising an effective amount of a compound according to Claim 1 and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of Claim 23, useful for treating infection by HIV, or for treating AIDS or ARC.
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
treatment agent selected from (1) an AIDS antiviral agent, (2) an anti-infective agent, and (3) an immunomodulator.
26. The composition of Claim 25 wherein the antiviral agent is an HIV protease inhibitor.
27. The composition of Claim 26 wherein the HIV
protease inhibitor is N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition made by combining the compound of Claim 1 and a pharmaceutically acceptable carrier.
29. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.
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.
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.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8784598P | 1998-06-03 | 1998-06-03 | |
| US60/087,845 | 1998-06-03 | ||
| GBGB9814930.5A GB9814930D0 (en) | 1998-07-09 | 1998-07-09 | HIV integrase inhibitors |
| GB9814930.5 | 1998-07-09 | ||
| PCT/US1999/012095 WO1999062513A1 (en) | 1998-06-03 | 1999-06-01 | Hiv integrase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2329134A1 true CA2329134A1 (en) | 1999-12-09 |
Family
ID=26314003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002329134A Abandoned CA2329134A1 (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 |
|---|---|---|---|---|
| US6333323B1 (en) | 1998-03-26 | 2001-12-25 | Shionogi & Co., Ltd. | 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 |
| JP3929244B2 (en) | 1998-12-25 | 2007-06-13 | 塩野義製薬株式会社 | Aromatic heterocyclic derivatives having HIV integrase inhibitory activity |
| AU5880600A (en) * | 1999-06-25 | 2001-01-31 | Merck & Co., Inc. | 1-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof |
| KR20030078958A (en) | 2001-03-01 | 2003-10-08 | 시오노기세이야쿠가부시키가이샤 | Nitrogen-containing heteroaryl compounds having hiv integrase inhibitory activity |
| DE10178132T1 (en) | 2001-08-10 | 2016-06-23 | Shionogi & Co., Ltd. | Antiviral agent |
| WO2003077850A2 (en) | 2002-03-15 | 2003-09-25 | Merck & Co., Inc. | N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7- carboxamides useful as hiv integrase inhibitors |
| ATE404537T1 (en) | 2002-08-13 | 2008-08-15 | Shionogi & Co | HETEROCYCLIC COMPOUNDS HAVING HIV-INTEGRASE-INHIBITING EFFECT |
| WO2004035577A2 (en) | 2002-10-16 | 2004-04-29 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
| DE602004021611D1 (en) | 2003-09-19 | 2009-07-30 | Gilead Sciences Inc | AZACHINOLINOL PHOSPHONATE COMPOUNDS AS INTEGRASE INHIBITORS |
| US7776883B2 (en) | 2004-03-10 | 2010-08-17 | The United States Of America As Represented By The Department Of Health And Human Services | Quinolin-4-ones as inhibitors of 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 |
| US7741315B2 (en) * | 2005-05-10 | 2010-06-22 | Merck Sharp & Dohme Corp. | HIV integrase inhibitors |
| NZ572367A (en) | 2006-05-16 | 2011-09-30 | Gilead Sciences Inc | Fused cyclic compounds as integrase inhibitors |
| US7888375B2 (en) | 2006-07-19 | 2011-02-15 | The University Of Georgia Research Foundation, Inc | Pyridinone diketo acids: inhibitors of HIV replication |
| EP2254582B1 (en) | 2008-01-25 | 2016-01-20 | Chimerix, Inc. | Methods of treating viral infections |
| US8664255B2 (en) | 2008-10-20 | 2014-03-04 | The Texas A&M University System | Inhibitors of mycobacterium tuberculosis malate synthase, methods of making and uses thereof |
| 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 |
| HUE032860T2 (en) | 2010-02-12 | 2017-11-28 | Chimerix Inc | Methods of treating viral infection |
| CN103420894A (en) * | 2012-05-22 | 2013-12-04 | 中国科学院上海药物研究所 | 2- butane-1,4-diketone compounds, preparation method and applications |
| MX2022005187A (en) * | 2019-10-28 | 2022-07-27 | Shanghai Inst Materia Medica Cas | Five-membered heterocyclic oxocarboxylic acid compound and medical use thereof. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS554334A (en) * | 1978-06-24 | 1980-01-12 | Yoshitomi Pharmaceut Ind Ltd | Pyranopyrazole derivative |
| JPS5535066A (en) * | 1978-09-05 | 1980-03-11 | Yoshitomi Pharmaceut Ind Ltd | Novel pyrazole derivative |
| JPS56100784A (en) * | 1980-01-16 | 1981-08-12 | Yoshitomi Pharmaceut Ind Ltd | Indolizine derivative |
| JPS61164346A (en) * | 1985-01-17 | 1986-07-25 | Matsushita Electric Ind Co Ltd | Echo canceller |
| SU1373708A1 (en) * | 1986-08-04 | 1988-02-15 | Пермский фармацевтический институт | Method of producing 5,6-diaryl-2-carboxy-4,7-dioxo-5h-pyrrolo (3.4-b) pyrans |
| US5192773A (en) * | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| AU4917397A (en) * | 1996-10-31 | 1998-05-22 | Merck & Co., Inc. | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
-
1999
- 1999-06-01 JP JP2000551769A patent/JP2002516858A/en not_active Withdrawn
- 1999-06-01 AU AU42256/99A patent/AU756826C/en not_active Ceased
- 1999-06-01 EP EP99926096A patent/EP1083897A4/en not_active Withdrawn
- 1999-06-01 CA CA002329134A patent/CA2329134A1/en not_active Abandoned
- 1999-06-01 WO PCT/US1999/012095 patent/WO1999062513A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU4225699A (en) | 1999-12-20 |
| WO1999062513A1 (en) | 1999-12-09 |
| AU756826B2 (en) | 2003-01-23 |
| JP2002516858A (en) | 2002-06-11 |
| EP1083897A1 (en) | 2001-03-21 |
| EP1083897A4 (en) | 2003-01-02 |
| AU756826C (en) | 2003-08-21 |
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