WO1999062513A1 - Hiv integrase inhibitors - Google Patents

Hiv integrase inhibitors Download PDF

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Publication number
WO1999062513A1
WO1999062513A1 PCT/US1999/012095 US9912095W WO9962513A1 WO 1999062513 A1 WO1999062513 A1 WO 1999062513A1 US 9912095 W US9912095 W US 9912095W WO 9962513 A1 WO9962513 A1 WO 9962513A1
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WIPO (PCT)
Prior art keywords
alkyl
pyrrol
substituted
dioxobutyric acid
independently selected
Prior art date
Application number
PCT/US1999/012095
Other languages
French (fr)
Inventor
Harold G. Selnick
Daria Jean Hazuda
Melissa Egbertson
James P. Guare, Jr.
John S. Wai
Steven D. Young
David L. Clark
Julio C. Medina
Original Assignee
Merck & Co., Inc.
Tularik, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9814930.5A external-priority patent/GB9814930D0/en
Application filed by Merck & Co., Inc., Tularik, Inc. filed Critical Merck & Co., Inc.
Priority to EP99926096A priority Critical patent/EP1083897A4/en
Priority to JP2000551769A priority patent/JP2002516858A/en
Priority to AU42256/99A priority patent/AU756826C/en
Priority to CA002329134A priority patent/CA2329134A1/en
Publication of WO1999062513A1 publication Critical patent/WO1999062513A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells.
  • Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site.
  • the fourth step in the process, repair synthesis of the resultant gap may be accomplished by cellular enzymes.
  • Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)].
  • Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al, Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
  • 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).
  • 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:
  • A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R 1 ,R2 and R 8 ;
  • the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen- containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
  • R is selected from: (1) -H, (2) "C l-5 ' a ' lkyl,
  • R is selected from:
  • each R 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:
  • (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,
  • each R is independently sele
  • R7 is selected from:
  • R8 is selected from: (1) -H,
  • each n is independently selected from 0, 1 and 2.
  • Particular compounds of structural formula I include:
  • A is selected from:
  • A is imidazolyl
  • A is pyrrolyl
  • A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indol e.
  • Rl is selected from: (1) -H,
  • halo is selected from: -F, Cl, -Br, and -I;
  • halo is selected from: -F, -Cl, and -Br;
  • halo is selected from: -F, Cl, -Br, and -I;
  • R2 is selected from: (1) -H,
  • R2 is selected from:
  • R2 is selected from: (1) -H,
  • R2 is selected from:
  • R3 is selected from:
  • R4 is selected from:
  • R4 is selected from:
  • R4 is selected from: (1) -H, and
  • R5 is selected from: (1) -H, (2) -C ⁇ g alkyl,
  • R5 is selected from: (1) -H,
  • R7 is hydrogen
  • R7 is selected from:
  • R8 is selected from: (1) -H,
  • R8 is selected from: (1) -H, and
  • R ⁇ is selected from: (1) -H, and (2) Ci-6 alkyl.
  • compositions useful for inhibiting HIV integrase comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC.
  • the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from: (1) an AIDS antiviral agent,
  • 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.
  • 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 (la) and (lb):
  • any variable e.g., R3, R4 ; etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • 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.
  • 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.
  • the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • 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.
  • 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 pyrazoiyl 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.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate,
  • 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.
  • bases such as ammonia, ethylenediamine, N-methyl- glutamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminome
  • 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.
  • 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.
  • administering a 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.
  • a method of treating and a pharmaceutical composition for treating HIV infection and AIDS 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.
  • 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.
  • 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.
  • these compositions 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.
  • 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.
  • compositions 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.
  • 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.
  • compositions 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
  • 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.
  • the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams ofthe active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated.
  • 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.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
  • Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
  • HIV positive also in combination with
  • Ribavirin (Costa Mesa, CA) positive, LAS, ARC
  • Isethionate (IM & IV) (Rosemont, IL)
  • Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.
  • An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl.
  • a preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
  • Indinavir is generally administered at a dosage of 800 mg three times a day.
  • Other preferred protease inhibitors are nelfinavir and ritonavir.
  • 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, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV.
  • Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999.
  • Indinavir is generally administered at a dosage of 800 mg three times a day.
  • Ac represents acetyl
  • ACN is acetonitrile
  • Bn represents benzyl
  • DME is dimethoxy ethane
  • DMF is dimethyl formamide
  • DMSO is dimethyl sulfoxide
  • EDC represents l-(3- dimethylaminopropyl-3-ethyl carbodiimide
  • Et represents ethyl
  • HOBT represents 1-hydroxybenzotriazole
  • LiHMDS represents ; IPA is isopropyl alcohol; Me represents methyl; sat. is saturated; THF is tetrahydrofuran; TLC is thin layer (Si ⁇ 2) chromatography.
  • Step 1 l-[l-(4-fluorobenzyl)-lH -pyrrol-2-yl]ethanone AI-1-1
  • Step 2 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AI-2-1
  • Step 3 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid
  • AI-1-2 (1.35g, 0.0045 mole) was dissolved in 1:1 T ⁇ F / MeO ⁇ (20 mL) and treated with 1 N NaO ⁇ (22.5 mL, 0.0225 mole) and stirred overnight.
  • the reaction mixture was washed with dilute ether, then acidified to p ⁇ 2 with IN HCl and extracted three times with EtOAc.
  • the organic layers were combined, washed with 1 N HCl, dried over MgS ⁇ 4, filtered and evaporated to dryness. The residue was crystallized from CHCI3 to give AI-3-1 as bright orange-yellow crystals, mp 172°C decomposed (uncorrected).
  • Step 1 l-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]ethanone AI-1-3
  • Step 2 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-2
  • Step 3 4-[l-(4-methylbenzy ili.))--l--H ⁇ J.--pyyyri.r 1o uli--2__i--y.yl-.]j--2,4-dioxobutyric acid
  • AI-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 IH HCl (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et2 ⁇ / hexanes to afford AI-3-9 as a yellow solid, melting point 179-181°C (uncorrected).

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.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes. Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al, Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT. Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The applicants additionally demonstrate that inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro and integrase as a component of the preintegration complex in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication. The compounds of the present invention inhibit integrases of closely related lentiviruses such as HIV 2 and SIV, but not integrases from more distantly related retroviruses, for example RSV. These compounds do not inhibit binding or catalysis of other nucleic acid binding proteins, including enzymatic reactions such as those catalyzed by HIV reverse transcriptase, HIV Rnase H, Influenza transcriptase, Hepatitis C polymerase, Yeast DNA polymerase, DNase I, Eco RI endonuclease, or mammalian polymerase II.
Zhao et al., (J. Med Chem. vol. 40, pp. 937-941 and 1186- 1194 (1997)) describe hydrazide and arylamide HIV integrase inhibitors. Bis-catechols useful for inhibiting HIV integrase are described in LaFemina et al. (Antimicrobial Agents & Chemotherapy, vol. 39, no. 2, pp. 320-324, February 1995).
U.S. Patents 4,377,258; 4,336,397; and 4,423,063 as well as Williams and Rooney (J. Med. Chem. vol 26, pp. 1196-1200, 1983) disclose 2,4-dioxo-4-substituted-l-butanoic acid derivatives useful intreating urinary tract calcium oxalate lithiasis. 4-substituted 2,4- dioxobutanoic acid compounds useful for inhibiting an influenza virus endonuclease are described in Tomassini et al. (Antimicrobial Agents & Chemotherapy, vol. 38, no. 12, pp. 2827-2837, December, 1994). 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:
Figure imgf000005_0001
(I) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R 1 ,R2 and R 8 ; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen- containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
R is selected from: (1) -H, (2) "Cl-5 ' a ' lkyl,
(3) -CFg,
(4) -halo,
(5) -N02,
( (66)) --NN((RR44)(R5),
(7) -R6,
(8) -C2_5 alkenyl-R3,
(9) -C2.5 alkynyl-R3,
(10) -0-R6, (11) -O-Cl-6 alkyl, and
(12) -C(0)CH2C(0)C(0)OR7;
R is selected from:
(I) -H, (2) -R3,
(3) -C^ alkyl, g
(4) -Ci alkyl substituted with R ,
(5) -O-R6,
(6) -O-Cj.6 alkyl-OR6, (7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -Cπ.6 alkyl-N(R4)(R6) ,
(10) -C^g alkyl S(0)n-R6,
(II) -C^ alkyl C(0)-R6, (12) -Cl alkyl C(S)-R6,
(13)
Figure imgf000006_0001
alkyl NR4 C(0)-R6 , and
(14) -Cl alkyl-C(0)N(R4)(R5);
3 each R 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) C^e alkyl, (c) Cτ_6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(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 alkyl, (c) C .5 alkyloxy-,
(d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0, (h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4- d]imidazolyl with one or two substituents selected from: (a) oxo,
(b) halogen,
(0 Cl alkyl,
(d) C^g alkyloxy-,
(e) -CFg,
(f) -OCFg,
(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) -C-L.g alkyl,
(c) -Cl alkyloxy-
(d) -CFg,
(e) -OCFg,
(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 alkyl,
(c) C^g alkyloxy-, (d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0, (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 alkyl,
(c) Cτ_6 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =o,
(h) hydroxy;
4
. is independently selected
(1) -H,
(2) -C-L.3 alkyl,
(3) -CFg,
(4) -R3,
(5) "^2-3 alkenyl,
(6) -C^g alkyl-R3,
(7) "^2-3 alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
,5 . i is independently selectee
(1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C2.3 alkenyl, (6) -C^g alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently sele
(1) -0-^ g alkyl-R , ai
(2) -R3;
R7 is selected from:
(1) -H, and
(2) Ci-6 alkyl;
R8 is selected from: (1) -H,
(2) Cl-6 alkyl-oxy, and
(3) Cl-6 alkyl; and
each n is independently selected from 0, 1 and 2. Particular compounds of structural formula I include:
(1) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester,
(2) 4-[l-(4-fluorobenzyl)---H-pyrrol-2-yl]-2,4-dioxobutyric acid,
(3) 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester,
(4) 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid,
(5) 4-[l-(4-fluorobenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester,
(6) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester,
(7) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n- butyl ester, (8) 4-(l-benzyl-lH-pyrrol-2-yl)-2,4- dioxobutyric acid, (9) 4-(l-naphthalen-2-ylmethyl-lH- pyrrol-2-yl)-2,4-dioxobutyric acid,(10) 4-(l-biphenyl-4- ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid, (11) 4-(l-naphthalen-l-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid, (12) 2,4-dioxo-4-[l-(4-phenylbutyl)- IH-pyrrol -2-yl]- butyric acid, (13) 4-[l-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (14) 2,4-dioxo-4-(l-phenethyl-lH-pyrrol -2-yl)-butyric acid,
(15) 4-[l-(2-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(16) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (17) 4-[l-(4-bromobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (18) 4-[l-(2-bromobenzyl)-lH-pyrrol-2- yl]-2,4-dioxobutyric acid, (19) 4-[l-(3-bromobenzyl)-lH- pyrrol-2-yl]-2,4-dioxobutyric acid, (20) 4-[l-(3-chlorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (21) 4-[l-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(22) 4-[l-(2-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(23) 2,4-dioxo-4-( 1-hexyl- IH-pyrrol -2-yl)-butyric acid, (24) 4- (l-biphenyl-2-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid,
(25) 2,4-dioxo-4-[l-(4-phenoxybutyl)-lH -pyrrol-2-yl]-butyric acid, (26) 4-[l-(3-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(27) 4-[l-(2-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,(28) 4-[l-(4-fluorobenzyl)-4-iodo-lH-pyrrol-2-yl]-2,4- dioxobutyric acid (29) 4-[l-(4-methoxybenzyl)- IH-pyrrol - 2-yl]-2,4-dioxobutyric acid,.(30) 4-[l-(2,4,5-trifluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (31) 4-[l-(2,3- difluorobenzyl)-l_H-pyrrol-2-yl]-2,4-dioxobutyric acid,(32) 4- [l-(3,5-difluorobenzyD- lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (33) 4-[l-(2,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (34) 4-[l-(2,5,6-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (35) 4-[l-(2-fluorobenzyl)-lΗ-pyrrol-2-yl]-2,4- dioxobutyric acid, (36) 4-[l-(4-trifluoromethylbenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid, (37) 4-[l-(4-cyanobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (38) 4-[l-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid,
(39) 2-hydroxy-4-[l-(4-hydroxybenzyl)-lΗ-pyrrol-2-yl] -2,4- dioxobutyric acid, (40) 4-(l-cyclopentylmethyl-lH-pyrrol- 2-yl) -2,4-dioxobutyric acid,
(41) 4-{l-[3-(4-fluorophenyl)propyl]-lH-pyrrol-2-y}-2,4- dioxobutyric acid,
(42) 4-{l-[2-(4-fluoroρhenyl)ethyl]-lH-pyrrol-2-yl}-2,4-dioxobutyric acid, (43) 4-[l-(3-phenylpropyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(44) 4-(l-ethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid,
(45) 4-[l-(3-fluoro-benzyl)-l-H -pyrrol- 2-yl]- 2,4-dioxobutyric acid,
(46) 4-[l-(2-chloro-benzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid,
(47) 4-[l-(3-benzoylaminopropyl)-lΗ-pyrrol-3-yl] -2,4-dioxobutyric acid,
(48) 4-{l-[3-(4-fluorophenoxy)benzyl]-lH-pyrrol-2-yl}] -2,4- dioxobutyric acid,
(49) 4-(l-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester (50) 4-(l-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid,
(51) 4- [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl-2,4- dioxobutyric acid ethyl ester,
(52) 4- [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(53) 4-[l-(4-fluorobenzyl)-4-phenethyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester,
(54) 4-[l-(4-fluorobenzyl)-4-phenethyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (55) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid methyl ester,
(56) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(57) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid, (58) 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(59) 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(60) 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(61) 4-[5-(3-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutvric acid, (62) 4-[5-(4-fluorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(63) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-LΗ' -ρyrrol-2-yl]-2,4- dioxobutyric acid,
(64) 4-[5-(benzyl)-l-(4-fluorobenzyl)-lH -pyrrol- 2-yl] -2,4- dioxobutyric acid,
(65) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(66) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid, (67) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid,
(68) 4-[5-(benzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(69) 4-[5-(3-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl] -2,4- dioxobutyric acid, (70) 4-(5-benzyl-lff -pyrrol-3-yl)-2,4-dioxobutyric acid,
(71) 4-[2,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid,
(72) 4-[l-(4-Fluorobenzyl)-5-phenyl-lΗ-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (73) 4-[l-(4-Fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(74) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester,
(75) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(76) 4-[l-(4-Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(77) 4-[4-(Benzylamino)-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (78) 4-[5-Nitro-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutvric (79) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester,
(80) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(81) 4-[l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[l-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(83) 4-[l-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(84) 4-[2,4-dimethyl-l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (85) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(86) 4-[l-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(87) 4-[l-(4-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(88) 4-[l-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,. (89) 4-[l-(3,4-dichlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(90) 4-[l-(2-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,.
(91) 4-[l-(3-chlorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (92) 4-[l-(3-trifluoromethylbenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(93) 4-[l-(4-methylbenzyl)-lH-p rrol-3-yl]-2,4-dioxobutvric acid,
(94) 4-[l-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(95) 4-[l-(3-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,. (96) 4-{l-[3-(4-fluorophenyl)-propyl]-lΗ-pyrrol-3-yl}-2,4- dioxobutyric acid,
(97) 4-[l-(4-bromobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(98) 4-[l-(4-chlorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(99) 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lΗ-pyrrol-2-yl]- 2,4-dioxobutyric acid, ethyl ester,
(100) 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]- 2,4-dioxobutyric acid,
(101) 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (102) 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(103) 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric acid ethyl ester, (104) 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric acid,
(105) 4-[l-(4-Fluorobenzyl)-3-acetylamino-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(106) 4-[4-acetylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid,
(108) 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(109) 4-[l,4-bis-(4-fluorobenzyl)- lH -pyrrol-3-yl]-2,4-dioxobutyric acid, (110) 4-[5-(3-ethoxycarbonyl-3-oxopropionyl)-l-(4-fluorobenzyl)-lH- pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester,
(111) 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester,
(112) 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid, (113) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-3-yl] -2,4- dioxobutyric acid,
(114) 4-[l-(4-Fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]-2-hydroxy-4- oxobut-2-enoic acid,
(115) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid ethyl ester,
(116) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid,
(117) l-[l-(4-fluorobenzyl)-3-methyl- lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester,
(118) l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(119) 4-[3-methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester,
(120) 4-[3 -methyl-l-(3-chlorobenzyl)-lH-pvrazol-4-yl]-2,4- dioxobutyric acid, (121) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(122) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester, (123) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(124) 4-[l-(4-fluoro-benzyl)-lΗ-imidazol-2-yl]-2,4-dioxo-butyric acid,
(125) 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid ethyl ester,
(126) 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid,
(127) 4-(l-Benzyl-lH-imidazol-2-yl)-2,4-dioxobutyric acid,
(128) 4-[l-(4-fluorobenzyl)-lΗ-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester, (129) 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid,
(130) 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric acid methyl ester,
(131) 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric acid,
(132) 2-hydroxy-4-(l-methyl-l-H -indol-2-yl) -2,4-dioxobutyric acid, (133) 4-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid,
(134) l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid ethyl ester,
(135) l-[l-(4-fluorobenzyl)-iH-indol-3-yl]-2,4-dioxobutyric acid,(136) 4-[l-(3-fluorobenzyl)-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid,
(137) 4-[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric acid,
(138) 4-[4-(4-fluorobenzyl)-l-methyl-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(139) 4-[2,5-dimethyl-l-(4-fluorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxo- butyric acid,
(140) 4-[l-(3,5-dichlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(141) 4-[l-(3-thiophenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (142) 4-[l-2,4-dimethylbenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(143) 4-[l-(3-chloro-5-methyl-benzyl)-l-H-pyrrol-3-yl]-2,4-dioxo- butyric acid, (144) 4-[l-(l-naphthalenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(145) 4-[l-(2-thiophenemethyl)-l-Η-pyrrole-3-yl]-2,4-dioxobutyric acid, and
(146) 4-[4-(3-chlorobenzyl)-l-methyl-l-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:
R2 O O
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000017_0001
Still another embodiment of the present invention are compounds of structural formula:
Figure imgf000017_0002
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000018_0001
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000018_0002
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000018_0003
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000018_0004
Another embodiment of the present invention are compounds of structural formula:
Figure imgf000019_0001
In one class of compounds of the present invention, A is selected from:
(1) pyrrolyl, (2) imidazolyl,
(3) pyrazoiyl, 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 pyrazoiyl.
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 indol e.
In one class of compounds of the present invention, Rl is selected from: (1) -H,
(2) -CHg,
(3) -CFg,
(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) C^g alkyl,
(c) C-^g alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) "OCFg,
(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,
(9) phenyl C^.g alkyl-,
(10) substituted phenyl C^. alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C-^g alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C 6 alkyl,
(iii) -CF3, and
(iv) hydroxy, (11) -C2_5 alkenyl-R3,
(12) -C2_5 alkynyl-R3, and
(13) -C(0)CH2C(0)C(0)OR7.
In another class of compounds of the present invention, Rl cted from:
(1) -H,
(2) -CHg,
(3) -CFg,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) ssuubbssttiittuutteedd phenyl substituted with 1 or 2 substituents independently selected from: (a) halo,
(b) methyl, and
(c) methoxy,
(9) phenyl C^g alkyl-,
(10) substituted phenyl C^.g alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy, g
(11) -C2_5 alkenyl-R , and (12) -C(0)CH2C(0)C(0)OR7)
In yet another class of compounds of the present invention, selected from:
(1) -H,
(2) -Cj.5 alkyl, (3) -CF3,
(4) -halo,
(5) -N02, (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 C^g alkyl-,
(10) substituted phenyl C^.g alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy, g
(11) -C2_5 alkenyl-R , and (12) -C(0)CH2C(0)C(0)OR7.
In yet another class of compounds of the present invention, elected from:
(1) -H,
(2) -C^ alkyl, (3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02,
(6) -N(R4)(R5),
(7) -phenyl, (8) phenyl C^g alkyl-,
(9) substituted phenyl C^.g 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(0)CH2C(0)C(0)OR7.
In another class of compounds of the present invention, Rl cted from: (1) -H, (2) -Cj.5 alkyl,
(3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02, (6) -N(R4)(R5),
(7) -phenyl,
(8) phenyl C^ alkyl-,
(9) substituted phenyl C^g 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.
In one class of compounds of the present invention, R2 is selected from: (1) -H,
(2) -R3,
(3) -C^g alkyl, g
(4) -C]__6 alkyl substituted with R ,
(5) -O-R6, (6) -0-Ci.g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -C1.6 alkyl-N(R4)(R6) ,
(10) -C^g alkyl S(0)n-R6, (11) -C1 alkyl C(0)-R6,
(12) -Cj.6 alkyl C(S)-R6,
(13) -C1-6 alkyl NR4C(0)-R6, and
(14) -C1 alkyl-C(0)N(R4)(R5).
In another class of compounds of the present invention, R2 is selected from:
(1) -H, (2) -R3,
(3) -Ci.g alkyl,
(4) -C-^ alkyl substituted with E
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -C^g alkyl-N(R4)(R6) ,
(10) -C^g alkyl S(0)n-R6,
(11) -Cj.g alkyl NR4C(0)-R6, and
(12) -C^g alkyl-C(0)N(R4)(R5 ).
In yet another class of compounds of the present invention, R2 is selected from: (1) -H,
(2) -R3,
(3) -C1-6 alkyl, g
(4) -C^. alkyl substituted with R ,
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C-^g alkyl-N(R4)(R6) ,
(9) -C^g alkyl C(0)-R6,
(10) -C1 alkyl NR4C(0)-R6, and
(11) -C^g alkyl-C(0)N(R4)(R5).
In still another class of compounds of the present invention,
R2 is selected from:
(1) -H,
(2) -R3,
(3) -C 6 alkyl, g
(4) -Cι_ alkyl substituted with R ,
(5) -O-R6, (6) -0-Cj.g alkyl-OR6,
(7) -Cw alkyl (OR6 )(R4) ,
(8) -C^g alkyl-N(R4)(R6) ,
(9) -C^g alkyl C(0)-R6, and (10) -C^g alkyl NR4C(0)-R6.
In one 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) C^ alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cl 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 alkyl,
(c) C-^g alkyloxy-,
(d) phenyl, (e) -CFg,
(f) "OCFg,
(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;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one two substituents independently selected from:
(a) halogen,
(b) C-L.g alkyl,
(c) C-L.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(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;
(7) imidazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1 alkyl,
(c) C^ alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cl 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) C^g alkyl,
(0 C^g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(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; (11) pyrazoiyl;
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C1 alkyl,
(c) Cj. alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (g) -CN,
(h) hydroxy, (i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen,
(ii) C-L.6 alkyl, (iii) -CF3, and (iv) hydroxy; (13) Cg_6 cycloalkyl; (14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-, (d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0,
(h) hydroxy; (15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen, (b) Cτ_6 alkyl,
(0 C1 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(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) Cj.g alkyl,
(0 C-^g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0,
(h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen,
(b) -C1.6 alkyl,
(c) -C1 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(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 alkyl,
(c) -Cj.g alkyloxy-,
(d) -CFg,
(e) -OCFg, (f) -CN, and
(g) -hydroxy;
(23) Cg.g cycloalkyl fused with a phenyl ring;
(24) substituted Cg.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C-^g alkyl,
(0 C^g alkyloxy-,
(d) -CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy.
In another class of compounds of the present invention, R3 cted from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(c) C-L.g alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) -OCFg,
(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, (3) thienyl,
(4) pyridyl,
(5) imidazolyl, (6) pyrrolyl,
(7) pyrazoiyl,
(8) Cg.g cycloalkyl,
(9) substituted C3.g cycloalkyl with 1 or 2 substituents independently selected from: (a) halogen,
(b) Cj.6 alkyl,
(c) C^g alkyloxy-,
(d) -CF3,
(e) -OCFg, (f -CN,
(g) =0, and (h) hydroxy;
(10) piperidinyl,
(11) morpholinyl, (12) naphthyl,
(13) indolyl, and
(14) C3.g cycloalkyl fused with a phenyl ring.
In still another class of compounds of the present invention, elected from: (1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen, (b) C^ alkyl,
(c) C1 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(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) napl ithyl. In one class of compounds of the present invention, R4 is selected from:
(1) -H,
(2) -C1-θ alkyl, and
(3) -CFg. In another class of compounds of the present invention, R4 is selected from:
(1) -H,
(2) -Cj.3 alkyl,
(3) "CFg,
(4) -R3,
(5) -C2.3 alkenyl,
(6) -C1-θ alkyl-R3, (7) -C .g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3.
In still another class of compounds of the present invention, is selected from:
(1) -H,
(2) -C^g alkyl,
(3) "CFg,
(4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3.
In yet another class of compounds of the present invention, R4 is selected from: (1) -H, and
(2) -C^g alkyl.
In one class of compounds of the present invention, R5 is selected from: (1) -H, (2) -C^g alkyl,
Figure imgf000033_0001
(5) -C2-3 alkenyl,
(6) -C^g alkyl-R3, (7) -C2_g alkenyl-R3,
(8) -S(0)n-R3, and
(9) -C(0)-R3.
In another class of compounds of the present invention, R5 is selected from: (1) -H,
(2) -C^g alkyl, (3) -CFg, and
(4) -R3.
I Inn yyeett aannootthheerr class of compounds of the present invention, seleci ted from:
(1) -H,
(2) -C-L.3 alkyl,
(3) -CFg,
(4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3.
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) Ci-4 alkyl.
In one class of compounds of the present invention, R8 is selected from: (1) -H,
(2) -OCH3, and
(3) -CH3.
In another class of compounds of the present invention, R8 is selected from: (1) -H, and
(2) CH3.
In yet another class of compounds of the present invention, Rδ is selected from: (1) -H, and (2) Ci-6 alkyl.
Also included within the present invention are pharmaceutical compositions useful for inhibiting HIV integrase, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV integrase, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an AIDS treatment agent selected from: (1) an AIDS antiviral agent,
(2) an anti-infective agent, and
(3) an immunomodulator.
The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as mixtures of stereoisomers or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
As is recognized by one of ordinary skill in the art, the diketo-acid/ester compounds of the present invention exist as tautomers, and thus by using the phrase "and tautomers thereof in describing compounds of structural formula (I), Applicants also intend the following tautomeric forms of the same compound (la) and (lb):
Figure imgf000035_0001
(lb) By naming or referring to compound (I) and tautomers thereof, it is understood for the purposes of the present application that the tautomers (la) and (lb) are also intended. Similarly, be referring to compound (la), it is understood for the purposes of the present application that the tautomers (I) and (lb) are also intended. The same holds true for references to tautomer (lb).
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 pyrazoiyl 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 Al
Figure imgf000037_0001
4-fluorobenzyl bromide
NaH
DMF
Figure imgf000037_0002
AI-1 -2 dimethyl oxalate
NaH
DME heat
Figure imgf000038_0001
ROH NaOH TsOH THF/ MeOH / H20
Figure imgf000038_0002
Scheme All
Figure imgf000039_0001
LiHMDS cyclohexanecarbonyl chloride THF
Figure imgf000039_0002
BH3-Me2S
THF heat
Figure imgf000039_0003
n -butyllithium
THF
N - methoxy- N- methylacetamide
Figure imgf000040_0001
dimethyl oxalate
NaH
DME heat
Figure imgf000040_0002
NaOH
THF / MeOH / H20
Figure imgf000040_0003
Scheme AIII
Figure imgf000041_0001
Figure imgf000042_0001
Scheme AIV
Figure imgf000043_0001
Mel
NaH
DMF
Figure imgf000043_0002
Figure imgf000044_0001
dimethyl oxylate
NaH
DME
1 N NaOH reflux THF cat. MeOH
Figure imgf000044_0002
Scheme AV
Figure imgf000044_0003
COOEt
J Boc20/Et3N/DMF
NH
4-DMAP / CHCIg O
AV-1-1
Figure imgf000045_0001
AV-2-1
Figure imgf000045_0002
AV-3-1
AV-4-1 MeONHMe»HCI
Figure imgf000046_0001
AV-5-1
Figure imgf000046_0002
AV-6-1
Figure imgf000046_0003
AV-7-1
Figure imgf000046_0004
AV-8-1
Figure imgf000047_0001
AV-9-1
Figure imgf000047_0002
AV-10-1
Scheme A-VI
Figure imgf000047_0003
AI-1-1
Figure imgf000048_0001
AVI-1-1
Figure imgf000048_0002
CH3I /DMF /Cs2C03
AVI-2-1
Figure imgf000048_0003
AVI-3-1
Figure imgf000049_0001
AVI-4-1
Figure imgf000049_0002
SCHEME AVII
bromide
Figure imgf000049_0003
Figure imgf000050_0001
dimethyl oxalate
NaH
DME heat
Figure imgf000050_0002
NaOH
THF / MeOH / H20
Figure imgf000050_0003
Scheme AVIII
Figure imgf000051_0001
AVI-2-1
Figure imgf000051_0002
AVIII-1-1
Figure imgf000051_0003
NaOEt/THF/RT
Figure imgf000051_0004
AVIII-2-1
Figure imgf000052_0001
AVIII-3-1
Figure imgf000052_0002
AVIII-4-1
Scheme AIX
Figure imgf000052_0003
AIII-1-1
Figure imgf000053_0001
AIX-1-1
Figure imgf000053_0002
Figure imgf000053_0003
AIX-3-1
SCHEME AX
Figure imgf000054_0001
methylsulfonylchloride TEA/CH2CI2
Figure imgf000054_0002
diethyloxalate NaOEt/THF
Figure imgf000054_0003
1 N NaOH CH3OH/THF
Figure imgf000055_0001
Scheme AXI
Figure imgf000055_0002
AICI3
CH2CI 4-fluorobenzoyl chloride
Figure imgf000055_0003
BH3-Me2S
THF heat
Figure imgf000056_0001
Si(i-Pr)3
AICI3 CH2CI2 acetyl chloride
Figure imgf000056_0002
[Bu]NF THF
Figure imgf000056_0003
1 ) dimethyl oxalate
NaH
DME heat
2) NaOH THF / MeOH / H20
Figure imgf000057_0001
Scheme AXI(b)
ide
Figure imgf000057_0002
1) dimethyl oxalate
NaH
DME heat
2) NaOH
THF / MeOH / H20
Figure imgf000058_0001
Scheme BI
Figure imgf000058_0002
TEA DMF
Figure imgf000058_0003
1N LiOH THF
Figure imgf000059_0001
MeLi THF
BI-4-1
Figure imgf000060_0001
oxalate
Figure imgf000060_0002
Scheme BI (cont.)
Figure imgf000060_0003
Figure imgf000061_0001
Scheme BII
Figure imgf000061_0002
NaH DMF
Figure imgf000061_0003
n-BuLi Et20
Figure imgf000062_0001
oxalate
Figure imgf000062_0002
Figure imgf000062_0003
1M NaOH MeOH
Figure imgf000062_0004
Scheme Bill
Figure imgf000063_0001
NaH DMF
Figure imgf000063_0002
Diethyl oxalate
NaOEt
THF
Figure imgf000064_0001
1 M NaOH THF
Figure imgf000064_0002
Figure imgf000064_0003
Figure imgf000065_0001
Diethyl oxalate
NaOEt
THF
Figure imgf000065_0002
1 M NaOH THF
Figure imgf000066_0001
Scheme BV
Figure imgf000066_0002
BIV-1-1
NaH
Figure imgf000066_0003
Figure imgf000067_0001
oxalate
Figure imgf000067_0002
Figure imgf000067_0003
1M NaOH
1M NaOH MeOH MeOH
Figure imgf000068_0001
Scheme Cl
N
H
4-F-benzylbromid1 TEA/ DMF
Figure imgf000068_0002
1) nBuLi/THF/-78°C 2) C02
Figure imgf000069_0001
Figure imgf000069_0002
CH3Li/THF/-78°(
Figure imgf000069_0003
diethyloxalate NaOEt/THF
Figure imgf000070_0001
1 N NaOH CH3OH/THF
Figure imgf000070_0002
Scheme CII
Figure imgf000070_0003
4-F-benzylbromid< Cs2C03/ DMF
Figure imgf000071_0001
CH3Li/THF -78°C
Figure imgf000071_0002
diethyloxalate NaOEt/THF
Figure imgf000071_0003
1 N NaOH CHgOH/THF
Figure imgf000072_0001
Scheme DI
Figure imgf000072_0002
MeLi Et20 reflux
Figure imgf000072_0003
Dl-1 -1
4-fluorobenzyl bromidi
NaH
DMF
Figure imgf000073_0001
dimethyl oxalate
NaH
DME heat
Figure imgf000073_0002
Figure imgf000073_0003
Scheme DII
Figure imgf000074_0001
NaH DMF
Figure imgf000074_0002
oxalate
Figure imgf000074_0003
Figure imgf000075_0001
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, 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, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams ofthe active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. The present invention is also directed to combinations of the
HIV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, imunomodulators, antiinfectives, or vaccines, such as those in the following table.
ANTIVIRALS
Druer Name Manufacturer Indication
097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor)
Amprenivir Glaxo Wellcome HIV infection,
141 W94 AIDS, ARC
GW 141 (protease inhibitor)
Abacavir (1592U89) Glaxo Wellcome HIV infection,
GW 1592 AIDS, ARC (RT inhibitor)
Acemannan Carrington Labs ARC (Irving, TX)
Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in combination with AZT
AD-439 Tanox Biosystems HIV infection, AIDS, ARC
AD-519 Tanox Biosystems HIV infection, AIDS, ARC
Adefovir dipivoxil Gilead Sciences HIV infection
AL-721 Ethigen ARC, PGL
(Los Angeles, CA) HIV positive, AIDS
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination w/Retrovir Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH) Erbamont (Stamford, CT)
Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD)
Interferon
AR177 Aronex Pharm HIV infection, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases
BMS-232623 Bristol-Myers Squibb/ HIV infection,
(CGP-73547) Novartis AIDS, ARC (protease inhibitor)
BMS-234475 Bristol-Myers Squibb/ HIV infection,
(CGP-61755) Novartis AIDS, ARC (protease inhibitor)
CI-1012 Warner-Lambert HIV-1 infection
Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
Curdlan sulfate AJI Pharma USA HIV infection
Cytomegalovirus Medlmmune CMV retinitis immune globin
Cytovene Syntex sight threatening
Ganciclovir CMV peripheral CMV retinitis
Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor)
Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
Ind. Ltd. (Osaka, positive asymptomatic
Japan) ddC Hoffman-La Roche HIV infection, AIDS,
Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T
DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor)
Efavirenz DuPont Merck HIV infection,
(DMP 266) AIDS, ARC
((-) 6-Chloro-4(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor)
4(S)-trifluoro- methyl -1,4- dihy dr o-
2H-3 , 1-benzoxazin-
2-one)
STOCRIN,
EL10 Elan Corp, PLC HIV infection (Gainesville, GA)
Famciclovir Smith Kline herpes zoster, herpes simplex
FTC Emory University HIV infection,
AIDS, ARC
(reverse transcriptase inhibitor)
GS 840 Gilead HIV infection,
AIDS, ARC
(reverse transcriptase inhibitor)
HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC
(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS,
ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS,
ARC, asymptomatic
HIV positive, also in combination with
AZT/ddl/ddC
ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection,
AIDS, ARC
(reverse transcriptase inhibitor); also with AZT
Lobucavir Bristol-Myers Squibb CMV infection Nelfϊnavir Agouron HIV infection,
Pharmaceuticals AIDS, ARC
(protease inhibitor)
Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC
(RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH)
Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence
Trisodium Astra Pharm. CMV retinitis, HIV
Phosphonoformate Products, Inc infection, other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor)
Probucol Vyrex HIV infection, AIDS
RBC-CD4 Sheffield Med. HIV infection,
Tech (Houston TX) AIDS, ARC
Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor)
Saquinavir Hoffmann- HIV infection,
LaRoche AIDS, ARC (protease inhibitor)
Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,
Didehydrodeoxy- ARC thymidine
Valaciclovir Glaxo Wellcome genital HSV & CMV infections
Virazole Viratek/ICN asymptomatic HIV
Ribavirin (Costa Mesa, CA) positive, LAS, ARC
VX-478 Vertex HIV infection, AIDS, ARC
Zalcitabine Hoffmann-La Roche HIV infection, AIDS, ARC, with AZT
Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies
IMMUNO-MODULATORS
Drug Name Manufacturer Indication
AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn advanced AIDS
Acemannan Carrington Labs, Inc. AIDS, ARC
(Irving, TX)
CL246,738 American Cyanamid AIDS, Kaposi's
Lederle Labs sarcoma
EL10 Elan Corp, PLC HIV infection (Gainesville, GA)
FP-21399 Fuki ImmunoPharm blocks HIV fusion with CD4+ cells
Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor)
Granulocyte Genetics Institute AIDS
Macrophage Colony Sandoz
Stimulating
Factor
Granulocyte Hoeschst-Roussel AIDS
Macrophage Colony Immunex
Stimulating
Factor
Granulocyte Schering-Plough AIDS, combination
Macrophage Colony w/AZT
Stimulating Factor
HIV Core Particle Rorer seropositive HIV
Immuno stimulant
IL-2 Cetus AIDS, in combination
Interleukin-2 w/AZT
IL-2 Hoffman-La Roche AIDS, ARC, HIV, in
Interleukin-2 Immunex combination w/AZT
IL-2 Chiron AIDS, increase in CD4
Interleukin-2 cell counts
(aldeslukin) Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
IMREG-2 Imreg AIDS, Kaposi's
(New Orleans, LA) sarcoma, ARC, PGL
Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate
Alpha-2 Schering Plough Kaposi's sarcoma
Interferon w/AZT, AIDS
Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL)
MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
Muramyl-Tripeptide
Granulocyte Amgen AIDS, in combination
Colony Stimulating w/AZT
Factor
Remune Immune Response immunotherapeutic
Corp. rCD4 Genentech AIDS, ARC
Recombinant
Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids
Recombinant Biogen AIDS, ARC
Soluble Human CD4
Interferon Hoffman-La Roche Kaposi's sarcoma
Alfa 2a AIDS, ARC, in combination w/AZT
SK&F106528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HrV infection Research Institute (Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination
Factor; TNF w/gamma Interferon
ANTI-INFECTIVES
Drug Name Manufacturer Indication
Clindamycin with Pharmacia Upjohn PCP
Primaquine
Fluconazole Pfizer cryptococcal meningitis, candidiasis
Pastille Squibb Corp. prevention of
Nystatin Pastille oral candidiasis
Ornidyl Merrell Dow PCP
Efl ornithine
Pentamidine LyphoMed PCP treatment
Isethionate (IM & IV) (Rosemont, IL)
Trimethoprim antibacterial
Trimethoprim/sulfa antibacterial
Piritrexim Burroughs Wellcome PCP treatment
Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation
Spiramycin Rhone-Poulenc cryptosporidial diarrhea
Intraconazole- Janssen Pharm. histoplasmosis;
R51211 cryptococcal meningitis
Trimetrexate Warner-Lambert PCP OTHER
Drug Name Manufacturer Indication Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin assoc. with AZT therapy
Recombinant Human Serono AIDS-related wasting, Growth Hormone cachexia Megestrol Acetate Bristol-Myers Squibb treatment of anorexia assoc. w/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir 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, ddl and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
Indinavir is an inhibitor of HIV protease and is the sulfate salt of N-(2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day.
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 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 l-(3- dimethylaminopropyl-3-ethyl carbodiimide; Et represents ethyl; HOBT represents 1-hydroxybenzotriazole; LiHMDS represents ; IPA is isopropyl alcohol; Me represents methyl; sat. is saturated; THF is tetrahydrofuran; TLC is thin layer (Siθ2) chromatography.
EXAMPLE 1 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid AI-3-1
Step 1: l-[l-(4-fluorobenzyl)-lH -pyrrol-2-yl]ethanone AI-1-1
Figure imgf000089_0001
A solution of 2-acetyl pyrrole (1.09g, 0.01 mole) in 20 mL of DMF was treated with sodium hydride (0.48g 60 % dispersion in oil, 0.012 mole) followed by 4-fluorobenzyl bromide (1.73g, 0.012 mole) and stirred overnight at room temperature. The solution was poured into 300 mL saturated NaΗCθ3 and extracted with EtOAc three times, the combined organic layers were washed with NaHCθ3 and dried over MgSθ4, filtered and evaporated to give a clear yellow oil that was taken on to the next step without further purification. Rf=0.58 (20% EtOAc/Hexanes). IH NMR (400 MHz, CDCI3) d 7.1 (m, 2H), 7.0 (m, 3H), 6.9 (m, IH), 6.2 (m, IH), 5.52 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester AI-2-1
Figure imgf000090_0001
A solution of l-[l-(4-fluorobenzyl)-lH -pyrrol-2-yl]ethanone (AI-1-1) (2.17g, 0.01 mole) in DME (20 mL) was treated with sodium hydride (0.48g, 60% dispersion in oil) followed by dimethyl oxalate (1.42g, 0.012 mole) and a drop of methanol and the solution was warmed to reflux overnight. The reaction mixture was poured into 300 mL saturated NaΗCθ3 and extracted with EtOAc three times, the combined organic layers were washed with NaHCθ3 and dried over MgSθ4, filtered and evaporated. The residue was crystallized with diethyl ether to give AI-2- 1 as yellow -orange crystals. Rf=0.39 (97:3:1 CHCI3 / MeOH / HOAc). lH NMR (400 MHz, CDCI3) δ 7.15, (dd, J = 1.65, 4.21 Hz, IH), 7.10 (m, 2H), 7.0 (m, 3H), 6.84 (s, IH), 6.28 (dd, J = 2.57, 4.11 Hz, IH), 5.6 (s, 2H), 3.9 (s, 3H).
Step 3: 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid
AI-3-1
Figure imgf000090_0002
A solution of AI-1-2 (1.35g, 0.0045 mole) was dissolved in 1:1 TΗF / MeOΗ (20 mL) and treated with 1 N NaOΗ (22.5 mL, 0.0225 mole) and stirred overnight. The reaction mixture was washed with dilute ether, then acidified to pΗ2 with IN HCl and extracted three times with EtOAc. The organic layers were combined, washed with 1 N HCl, dried over MgSθ4, filtered and evaporated to dryness. The residue was crystallized from CHCI3 to give AI-3-1 as bright orange-yellow crystals, mp 172°C decomposed (uncorrected). TLC Rf=0.37 (94:6:6 CHCI3 / MeOH / HOAc). IH NMR (400 MHz, CDCI3) δ 7.2 (dd,J = 1.65, 4.21 Hz,lH), 7.09 (m, 3H), 7.0 (m, 2H), 6.86 (s, IH), 6.3 (dd, J = 2.56, 4.21 Hz, IH), 5.58 (s, 2H). mass spec (FAB, m+1) 290.08
EXAMPLE 2 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-9
Step 1: l-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]ethanone AI-1-3
Figure imgf000091_0001
To a solution of 2-acetyl pyrrole (1.09g, 10 mmole) in acetone (5 mL) was added 10 N NaOΗ(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 Et2θ, washed with water, dried with MgS04, and the solvent evaporated. The residue was purified by preparative silica HPLC using 20% EtOAc/Hex to afford the product as a thick clear oil that solidified upon standing, melting point 52-53° C (uncorrected). IH NMR (400 MHz, CDCI3) δ 7.11 (d, J=7.8 Hz, 2H), 7.04 (d, J=7.72 Hz, 2H), 7.01 (m, IH), 6.18 (m,lH), 5.55 (s, 2H), 2.42 (s, 3H), 2.32 (s, 3H). mass spec (El, m z) 213 (M+), 105.
Step 2: 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-2
Figure imgf000092_0001
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 IM HCl (50 mL), filtered, and dried under vacuum. The product was further purified by crystallization from EtOAc / Hexanes / Et20 to obtain the product as a yellow powder, melting point 94-97°C (uncorrected). lH NMR (400 MHz, CDCI3) δ 7.15 (m, IH), 7.12 (d, J=8.04 Hz, 2H), 7.03 (d, J=8.08 Hz, 2H), 7.01 (m, IH), 6.85 (s, IH), 6.26 (dd, J=2.48, 4.08Hz, IH), 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 (El, m z) 331 (M+), 105.
Step 3: 4-[l-(4-methylbenzy ili.))--l--H±J.--pyyyri.r 1o uli--2__i--y.yl-.]j--2,4-dioxobutyric acid
Figure imgf000092_0002
A solution of AI-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 IH HCl (25 mL), the solid was filtered, dried under vacuum and the product purified by trituration with Et2θ / hexanes to afford AI-3-9 as a yellow solid, melting point 179-181°C (uncorrected). lH NMR (400 MHz, DMSO) δ 7.50 (s, IH), 7.41 (d, J=4.28 Hz, IH), 7.10(d, J=7.68 Hz, 2H), 6.98 (d, J=7.68 Hz, 2H), 6.83 (s, IH), 6.30 (dd, J=2.5, 4.1 Hz, IH), 5.58 (s, 2H), 2.24
(s, 3H). mass spec (FAB, m+1) 286
EXAMPLE 3 4-[l-(4-fluorobenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI- 2-3
Step 1: l-[l-(4-fluorobenzyl)-4-iodo-lH -pyrrol-2-yl]ethanone_AI-l-2
Figure imgf000093_0001
A solution of l-[l-(4-fluorobenzyl)-lH -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 NaΗC03 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). lH NMR (400 MHz, CDCI3) δ 7.15 (m, 2H), 7.08 (m, IH), 7.0 (m, 2H), 6.93 (m, IH), 5.5 (s, 2H), 2.4 (s, 3H).
Step 2: 4-[l-(4-fluorobenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AI-2-3
Figure imgf000093_0002
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). lH NMR (400 MHz, CDCI3) δ 7.15 (dd, J=1.6, 4.16 Hz, IH), 7.09 (m, 2H), 7.01-6.96 (m, 3H), 6.83 (s, IH), 6.27 (dd, J=2.52, 4.20 Hz, IH), 5.60 (s, 2H), 4.36 (q, J=7.16 Hz, 2H), 1.38 (t, J=7.16 Hz, 3H). mass spec (El, m z) 317 (M+), 109.
EXAMPLE 4 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester AI-2-4
Figure imgf000094_0001
To a solution of AI-2-3 (317mg, 1 mmole) in 2-propanol (anhydrous, 20 mL) was added p-toluenesulfonic acid (19mg, 0.1 mmole) and the mixture was set to reflux for 72 hours. The reaction mixture was then allowed to cool to ambient temperature, diluted with Et2θ, washed with a solution of saturated NaΗCθ3, the organic layer separated and dried with MgS04, the solvent evaporated and the crude was purified by preparative silica HPLC eluting with 30% EtOAc / hexanes to afford the product as yellow solid, melting point 87-88°C (uncorrected). lH NMR (400 MHz, CDCI3) δ 7.15-7.08 (m, 3H), 7.00-6.95 (m, 3H), 6.80 (s, IH), 6.27 (dd, J=2.52, 4.10 Hz, IH), 5.60 (s, 2H), 5.19 (m, IH), 1.36 (d, J=6.24 Hz, 6H). mass spec (FAB, m+1) 332
EXAMPLE 5 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n-butyl ester AI-2-5
Figure imgf000095_0001
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). lH NMR (400 MHz, CDCI3) δ 7.14-7.08 ( , 3H), 7.00-6.95 (m, 3H), 6.81 (s, IH), 6.26 (dd, J=2.52, 4.12 Hz, IH), 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
EXAMPLE 6
4-(l-benzyl-lH-pvrrol-2-yl)-2,4-dioxobutyric acid AI-3-2
Figure imgf000095_0002
In a manner similar to that described for AI-3-1, 2-acetyl pyrrole was treated with benzyl bromide and carried through the sequence to yield AI-3-2. mp 150-151°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 7.55 (s, IH), 7.41 (m, IH), 7.25 (m, 3H), 7.06 (m, 2H), 6.82 (s, IH), 6.3 (s, IH), 5.63 (s, 2H).
EXAMPLE 7 4-( l-naphthalen-2-ylmethyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid AI-3-3
Figure imgf000096_0001
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 2-bromomethylnapthylene and carried through the sequence to yield AI-3-3. mp 160-162°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 7.82 (m, 3H), 7.6 (s, IH), 7.45 (m, 4H), 7.3 (m, IH), 6.83 (s, IH), 6.38 (m, IH), 5.8 (s, 2H).
EXAMPLE 8 4-(l-biphenyl-4-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid A- 1-3-4
Figure imgf000096_0002
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 4-phenyl benzyl bromide and carried through the sequence to yield AI-3-4. mp 189-191°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 7.75 (m, 5H), 7.58 (m, 3H), 7.48 (m, IH), 7.3 (m, 2H), 7.0 (s, IH), 6.45 (m, IH), 5.8 (s, 2H).
EXAMPLE 9 4-(l-naphthalen-l-ylmethyl-lH-pyrrol -2-yl)-2,4-dioxobutyric acid AI-3-5
Figure imgf000097_0001
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 1-bromomethyl napthalene and carried through the sequence to yield AI-3-5. mp 172-174°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 8.1 (m, IH), 8.0 (m, IH), 7.83 (m, IH), 7.6 (m, 3H), 7.4 (m, 2H), 6.9 (s, IH), 6.5 (m, IH), 6.4 (m, IH), 6.18 (s 2H).
EXAMPLE 10 2,4-dioxo-4-[l-(4-phenylbutyl)- IH-pyrrol -2-yl]-butyric acid AI-3-6
Figure imgf000097_0002
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 4-phenyl butyl chloride and carried through the sequence to yield AI-3-6. mp 119-121°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 7.38 (s, IH), 7.36 (m, IH), 7.23 (m, 2H), 7.18 (m, 3H), 6.82 (s, IH), 6.22 (m, IH), 4.38 (m, 2H), 2.55 (m, 2H), 1.7 (m, 2H), 1.5 (m, 2H).
EXAMPLE 11 4-[l-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-7
Figure imgf000097_0003
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 4-chlorobenzyl bromide and carried through the sequence to yield AI-3-7. mp 182-184°C (uncorrected). lH NMR (300 MHz, DMSO) δ 7.55 (s, IH), 7.42 (m, IH), 7.4 (m, 2H), 7.1 (m, 2H), 6.82 (s, IH), 6.35 (m, IH), 5.6 (s, 2H),
EXAMPLE 12
2,4-dioxo-4-(l-phenethyl- IH-pyrrol -2-yl)-butyric acid AI-3-8
Figure imgf000098_0001
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 2-phenyl 1-bromoethane and carried through the sequence to yield AI-3-8. mp 168-170°C (uncorrected). lΗ NMR (300 MHz, DMSO) δ 7.35 (m, IH), 7.2 (m, 6H), 6.85 (s, IH), 6.18 (m, IH), 4.6 (m, 2H), 3.0 (m, 2H)
EXAMPLE 13 4-[l-(2-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-10
Figure imgf000098_0002
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 afford the product as a brownish-yellow solid, melting point 176-178°C (uncorrected). lΗ NMR (400 MHz, DMSO) δ 7.48 (dd, J=1.52, 4.2 Hz, IH), 7.36 (dd, J=1.96 Hz, IH), 7.21 (d, J=6.92 Hz, IH), 7.15 (dd, J=7.4, 7.4 Hz, IH), 7.07 (dd, J=7.4, 7.4 Hz, 1), 6.88 (s, IH), 6.37 (dd, J=2.44, 4.0 Hz, IH), 6.31, (d, J=7.32 Hz, IH), 5.64 (s, 2H), 2.31 (s, 3H). mass spec (FAB, m+1) 286.
EXAMPLE 14 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-11
Figure imgf000099_0001
AI-3-11 was synthesized from 2-acetyl pyrrole and 3,4-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 145-148°C (uncorrected) lΗ NMR (400 MHz, DMSO) δ 7.56 (d, J=2.2 Hz, IH), 7.44 (dd, J=1.4, 4.12 Hz, IH), 7.39 (dd, J=8.6, 19.4 Hz, IH), 7.19 (ddd, J=2.12, 7.72, 9.96 Hz, IH), 6.92 (m, IH), 6.86 (s, IH), 6.35 (dd, J=2.48, 4.12 Hz, IH), 5.61 (s, 2H). mass spec (FAB, m+1) 308
EXAMPLE 15 4-[l-(4-bromobenzyl)-_LH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-12
Figure imgf000099_0002
AI-3-12 was synthesized from 2-acetyl pyrrole and 4-bromobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 184-185°C (uncorrected). lΗ NMR (400 MHz, DMSO) δ 7.54 (d, J=1.68 Hz, IH), 7.52 (d, J=8.4 Hz, 2H), 7.44 (dd, J=1.4, 4.12 Hz, IH), 7.04 (d, J=8.4 Hz, 2H), 6.65 (s, IH), 6.34 (dd, J=2.52, 4.16 Hz, IH), 5.61 (s, 2H). mass spec (FAB, m+1) 352, 350
EXAMPLE 16 4-[l-(2-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-13
Figure imgf000100_0001
AI-3-13 was synthesized from 2-acetyl pyrrole and 2-bromobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 176- 180°C
(uncorrected). lΗ NMR (400 MHz, DMSO) δ 7.66 (dd, J=1.28, 7.88 Hz, IH), 7.51 (dd, J=1.6, 4.24 Hz, IH), 7.47 (s, IH), 7.28 (dd, J=6.7, 6.7 Hz, IH), 7.21 (dd, J=7.4, 7.4 Hz, IH), 6.88 (s, IH), 6.40 (dd, J=2.56, 4.2 Hz, IH), 6.28 (dd, J=1.4, 7.72 Hz, IH), 5.68 (s, 2H). mass spec (FAB, m+1)
EXAMPLE 17 4-[l-(3-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-14
Figure imgf000100_0002
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). lΗ NMR (400 MHz, DMSO) δ 7.54 (broad s, IH), 7.43 (m, 2H), 7.28-7.24 (m, 2H), 7.05 (d, J=6.76 Hz, IH), 6.83 (s, IH), 6.33 (dd, J=2.56, 4.12 Hz, IH), 5.61 (s, 2H). mass spec (FAB, m+1) 352, 350.
EXAMPLE 18 4-[l-(3-chlorobenzyl)-lH-pyrrol-2-yll-2.4-dioxobutyric acid AI-3-15
Figure imgf000101_0001
AI-3-15 was synthesized from 2-acetyl pyrrole and 3-chlorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 159-161°C (uncorrected). lΗ NMR (400 MHz, DMSO) δ 7.56 (d, J=2.2 Hz, IH), 7.45 (dd, J=1.48, 4.24 Hz, IH), 7.38-7.30 (m, 2H), 7.12 (s, IH), 7.04 (d, J=7.28 Hz, IH), 6.86 (s, IH), 6.36 (dd, J=2.48, 4.2 Hz, IH), 5.65 (s, 2H). mass spec (FAB, m+1) 306
EXAMPLE 19 4-[l-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-16
Figure imgf000101_0002
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). lΗ NMR (400 MHz, DMSO) δ 7.50 (d, J=1.92 Hz, IH), 7.41 (dd, J=1.44, 4.12 Hz, IH), 7.20 (dd, J=7.64, 7.64 Hz, IH), 7.06 (d, J=7.6 Hz, IH), 6.93 (s, IH), 6.86 (m, 2H), 6.33 (dd, J=2.44, 4.12 Hz, IH), 5.61 (s, 2H) 2.56 (s, 3H). mass spec (FAB, m+1) 286
EXAMPLE 20 4-[l-(2-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-17
Figure imgf000102_0001
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 155- 156°C
(uncorrected). lΗ NMR (400 MHz, DMSO) δ 7,47 (m, 2H), 7.32 (dd, 5.4, 14.0, IH), 7.22 (dd, J=10.36, 10.36 Hz, IH), 7.12 (dd, J=8.44, 8.44Hz, IH), 6.86 (s, IH), 6.68 (dd, 7.68, 7.68, IH), 6.36 (dd, J=2.56, 4.12Hz, IH), 5.71 (s, 2H). mass spec (FAB, m+1) 290
EXAMPLE 21 2,4-dioxo-4-( 1-hexyl- IH-pyrrol -2-yl)-butyric acid AI-3-18
Figure imgf000102_0002
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 CΗCI3 / MeOH / HOAc) 99/62513
lH NMR (400 MHz, CDCI3) δ 7.15 (dd, IH, J=1.65 Hz, J=4.21 Hz), 7.01 (m,lH), 6.93 (s, IH), 6.35 (dd, IH, 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)
EXAMPLE 22
4-(l-biphenyl-2-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid
Figure imgf000103_0001
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with l-biphenyl-2-yl bromomethane and carried through the sequence to yield AI-3-19. mp 150-152°C (uncorrected). Η NMR (400 MHz, CDCI3) δ 7.4 (m, 9H), 6.8 (s, IH), 6.42 (m, IH), 6.3 (m, IH), 5.6 (s, 2H).
EXAMPLE 22 2,4-dioxo-4-[l-(4-phenoxybutyl)-lH -pyrrol-2-yl]-butyric acid AI-3-20
Figure imgf000103_0002
In a manner similar to that described for AI-3-1. 2-acetyl pyrrole was treated with 4-phenoxy-l-butyl bromide and carried through the sequence to yield AI-3-2. TLC Rf=0.63 (94:6:6 CΗCI3 / MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 7.29 (m, 2H), 7.16 (dd, J=1.65 Hz, 4.21 Hz, IH), 7.05 (m, IH), 6.94 (m, IH), 6.93 (s, IH), 6.87 (m, 2H), 6.25 (dd, J=2.56 Hz, 4.21 Hz IH) 4.45 (t, J=7.14, 2H), 3.98 (t, J=6.22, 2H), 2.01 (m, 2H), 1.80 (m, 2H). EXAMPLE 23 4-[l-(3-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-21
Figure imgf000104_0001
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). lΗ NMR (400 MHz, DMSO) δ 7.55 (s, IH), 7.45 (d, J=3.72 Hz, IH), 7.36(dd, J=7.72, 14.4 Hz, IH), 7.08 (ddd, J =2.2, 8.48, 8.48 Hz, IH), 6.92-6.86 (m, 3H), 6.35 (dd, J=2.48, 4.04 Hz, IH), 5.66 (s, 2H). mass spec (FAB, m+1) 290
EXAMPLE 24 4-ri-(2-chlorobenzyl)-lH-pyrrol-2-yll-2.4-dioxobutyric acid AI-3-22
Figure imgf000104_0002
AI-3-22 was synthesized from 2-acetyl pyrrole and 2- chlorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 179- 180° C (uncorrected). *Η NMR (400 MHz, DMSO) δ 7.52-7.47 (m, 3H), 7.30 (ddd, J=1.6, 7.44, 7.44 Hz, IH), 7.24 (ddd,J=1.32, 7.52, 7.52 Hz, IH), 6.88 (s, IH), 6.40 (dd, J=2.44, 4.12 Hz, IH), 6.35 (dd, J=1.48, 7.68 Hz, IH), 5.79 (s, 2H). mass spec (FAB, m+1) 306 EXAMPLE 25 4-[l-(4-fluorobenzyl)-4-iodo-lH-pyrrol-2-yl]-2,4-dioxo-butyric acid
Figure imgf000105_0001
In a manner similar to that described for AI-3-1. AI-3-23 was prepared from AI-1-2. mass spec (FAB, m+1) 416 . lΗ NMR (400 MHz, D6-DMSO) δ 7.7 (s, IH), 7.6 (s, IH), 7.2 (m, 4H), 6.85 (s, IH), 5.6 (s, 2H).
EXAMPLE 26 4-ri-(4-methoxybenzyl)-lH-pyrrol-2-yll-2.4-dioxobutyric acid AI-3-24
Figure imgf000105_0002
AI-3-24 was synthesized from 2-acetyl pyrrole and 4-methoxybenzyl chloride in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 167-168°C (uncorrected). lΗ NMR (400 MHz, DMSO) δ 7.50 (s, IH), 7.38 (d, J=3.16 Hz, IH), 7.09 (d, J=8.72 Hz, 2H), 6.86 (d, J=8.72 Hz, 2H), 6.83 (s, IH), 6.29 (dd, J=2.56, 4.08 Hz, IH), 5.55 (s, 2H), 3.70 (s, 3H). mass spec (FAB, m+1) 302
EXAMPLE 27
4-[l-(2,4,5-trifluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-25
Figure imgf000106_0001
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). lH NMR (400 MHz, DMSO) δ 7.6 (m, IH), 7.48 (m, 2H), 6.86 (s, IH), 6.78 (m, IH), 6.36 (dd, J=2.5, 4.1 Hz, IH), 5.66 (s, 2H).
EXAMPLE 28 4-ri-(2.3-difluorobenzyl)-lH-pyrrol-2-yll-2.4-dioxobutyric acid AI-3-26
Figure imgf000106_0002
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). lΗ NMR (400 MHz, DMSO) δ 7.51 (s, IH), 7.45 (m, IH), 7.35 (m, IH), 7.12 (m, IH), 6.86 (s, IH), 6.48 (m, IH), 3.38 (dd, J=2.5, 4.1 Hz, IH), 5.75 (s, 2H). mass spec (FAB, m+1) 308
EXAMPLE 29 4-[l-(3,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-26
Figure imgf000107_0001
AI-3-27 was synthesized from 2-acetyl pyrrole and 3,5-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 166-168°C (uncorrected); lH NMR (400 MHz, DMSO) δ 7.58 (s, IH), 7.48 (m, IH), 7.14 (m, IH), 6.88 (s, IH), 6.75 (m, 2H), 6.38 (dd, J=2.5, 4.0 Hz, IH), 5.67 (s, 2H). mass spec (FAB, m+1) 308
EXAMPLE 30 4-[l-(2,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-28
Figure imgf000107_0002
AI-3-28 was synthesized from 2-acetyl pyrrole and 2,5-difluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 142-146°C
(uncorrected); lΗ NMR (400 MHz, DMSO) δ 7.50 (m, 2H), 7.30 (m, IH), 7.17 ( m, IH), 6.86 (s, IH), 6.38 (m, 2H), 5.69 (s, 2H). mass spec (FAB, m+1) 308
EXAMPLE 31
4-[l-(2,5,6-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AI-3-29 9/62513
Figure imgf000108_0001
AI-3-29 was synthesized from 2-acetyl pyrrole and 2,3,6- trifluorobenzyl bromide in a manner similar to that described for AI-3-9 to afford the product as a brownish-yellow solid, melting point 131- 133° C (uncorrected). lH NMR (400 MHz, DMSO) δ 7.50 (m, IH), 7.40 (m, IH), 7.37 (s, IH), 7.15 (m, IH), 6.84 (s, IH), 6.29 (dd, J=2.5, 4.1 Hz, IH), 5.77 (s, 2H). mass spec (FAB, m+1) 326.
EXAMPLES 32-45 In a manner similar to that described for AI-3-1. the following compounds were prepared: 4-[l-(2-fluorobenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric acid
Figure imgf000108_0002
CHN Calc. 62.28, 4.18, 4.84; Fnd. 62.11, 4.37, 4.91. (32) 4-[l-(4-trifluoromethylbenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric acid:
Figure imgf000108_0003
CHN Calc. 56.64, 3.56, 4.12; Fnd. 56.89, 3.75, 4.36. (33) 4-[l-(4-cyanobenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric acid:
Figure imgf000109_0001
CHN Calc. 64.86, 4.08, 9.45; Fnd. 64.61, 4.32, 9.77. (34)
Figure imgf000109_0002
4-[l-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid CΗN Calc. 63.78, 5.02, 4.65; Fnd. 63.99,5.14, 4.60. (35)
Figure imgf000109_0003
2-hydroxy-4-[l-(4-hydroxybenzyl)-lΗ-pyrrol-2-yl] -2,4-dioxobutyric acid CHN Calc. (C15H13NO5 0.20 TFA) 59.65, 4.29, 4.52; Fnd. 59.50, 4.31, 4.68. (36)
Figure imgf000109_0004
4-(l-cyclopentylmethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 63.86, 6.51, 5.32; Fnd. 63.88, 6.27, 5.37 (37)
Figure imgf000110_0001
4-{l-[3-(4-fluorophenyl)propyl]-lH-pyrrol-2-y}-2,4-dioxobutyric acid CHN Calc.( C17H16NO4F 0.35 EtOAc) 63.47, 5.44, 4.02; 63.16, 5.12, 4.34. (38)
Figure imgf000110_0002
4-{l-[2-(4-fluorophenyl)ethyl]-lH-pyrrol-2-yl}-2,4-dioxobutyric acid CHN Calc. 63.36, 4.65, 4.62; Fnd. 63.16, 4.64, 4.50. (39)
Figure imgf000110_0003
4-[l-(3-phenylpropyl)-lH-pvrrol-2-yl]-2,4-dioxobutyric acid CHN
Calc.(Ci7Hi7Nθ4 0.1 H2O) 67.80, 5.76, 4.65; Fnd. 67.79, 5.67, 4.70. (40)
Figure imgf000111_0001
4-(l-ethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid CHN Calc. 57.41, 5.30, 6.70; Fnd. 57.13, 5.33, 6.70. (41)
H
Figure imgf000111_0002
4-[l-(3-fluoro-benzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CΗN Calc.(Ci5Ηi2 FNO4 0.35 H2O) 60.95, 4.33, 4.74; Fnd. 60.894.25, 4.78. (42)
Figure imgf000111_0003
4-[l-(2-chloro-benzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid CΗN Calc. (C15Η12NO4CI 0.15 H2θ)58.41, 4.02, 4.54; Fnd. 58.31, 3.94, 4.62 (43)
Figure imgf000111_0004
4-[l-(3-benzoylaminopropyl)-lH-pyrrol-3-yl] -2,4-dioxobutyric acid CHN Calc. ( C18H18N2O5 0.35 H2O 0.35 TFA ) 57.80, 4.94, 7.21; Fnd. 57.80, 4.88, 7.35. (44)
Figure imgf000112_0001
4-{l-[3-(4-fluorophenoxy)benzyl]-lH-pyrrol-2-yl}] -2,4-dioxobutyric acid CHN Calc. 66.14, 4.23, 3.67; Fnd. 66.37, 4.32, 3.69. (45)
EXAMPLE 46 4-(l-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid AII-5-1 Step 1: cyclohexyl-pyrrol-1-yl-methanone All- 1-1
Figure imgf000112_0002
A solution of pyrrole (2.00g, 0.0298 mole) in 30 mL TΗF was cooled to -78°C and treated with 1.0 M LiHMDS in hexanes (29.8 mL, 0.0298 mole) followed by dropwise addition of cyclopentanecarbonyl chloride (4.00 mL, 0.0298 mole). After five minutes the solution was allowed to warm to room temperature and stirred for four hours. The solution was poured into 200 mL saturated NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with NH4CI and dried over MgSθ4, 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 All- 1-1 as white crystals. TLC Rf=0.62 (5:95 EtOAc / Hexanes) lH NMR (400 MHz, CDCI3) δ 7.32 (m, 2H), 6.29 (m, 2H), 2.92 (m, IH), 1.85- 1.97 (m, 4H), 1.56-1.76 (m, 3H), 1.24-1.43 (m, 3H).
Step 2: 1-cyclohexylmethyl-l-H -pyrrole AII-2-1
Figure imgf000113_0001
A solution of AII-1-1 (3.45 g, 0.0195 mole) in 60 mL TΗF was treated with 1.0 M BΗ3-Me2S (58.5 L, 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 CH2CI2 three times. The combined organic layers were washed with water, dried over MgSθ4, 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) lH NMR (400 MHz, CDCI3) δ 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: l-( 1-cyclohexylmethyl-l-H -pyrrol-2-yl)-ethanone AII-3-1
Figure imgf000113_0002
A solution of AII-2-1 (1.32g, 0.0081 mole) in 20 mL TΗF was cooled to -78°C and treated with 2.5 M n -butyllithium (16.2 mL, 0.0405 mole) over five minutes and stirred overnight at room temperature under argon. The solution was then treated with N -methoxy-N - methylacetamide (4.18g, 0.0405 mole) and stirred three hours. The solution was poured into 200 mL saturated NH4CI solution and extracted with E 2θ three times. The combined organic layers were washed with NH4CI and dried over MgSθ4, 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) lH NMR (300 MHz, CDCI3) δ 6.95 (dd, J=1.65, 4.03 Hz, IH), 6.84 (m, IH), 6.11 (dd, J=2.65, 4.03 Hz, IH), 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-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester AII-4-1
Figure imgf000114_0001
In a manner similar to that described for AI-2-1. AII-3-1 was treated with NaΗ and dimethyloxalate to give AII-4-1. TLC Rf=0.62 (2.5:97.5 MeOΗ / CΗ2CI2) IH NMR (400 MHz, CDCI3) δ 7.10, (dd, J = 1.65, 4.21 Hz, IH), 6.92 (m, IH), 6.85(s, IH), 6.19 (dd, J = 2.57, 4.21 Hz, IH), 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-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid
All- 5-1
Figure imgf000115_0001
In a manner similar to that described for AI-3-1. AII-4-1 was treated with NaOH to give AII-5-1. TLC Rf=0.65 (94:6:6 CHCI3 / MeOH / HOAc) IH NMR (400 MHz, CDCI3) δ 7.15 (dd, J=1.65, 4.21 Hz, IH), 6.96 (m, IH), 6.93 (s, IH), 6.22 (dd, J=2.56, 4.21 Hz, IH), 4.18 (d, J=7.13 Hz, 2H), 1.57- 1.72 (m, 6H), 1.16-1.23 (m, 3H), 0.96 (m, 2H).
EXAMPLE 47 4-[l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AIII-3-1
Step 1: l-[l-(4-fluorobenzyl)-4-phenylethynyl-iH-pyrrol-2- yl]ethanone AIII- 1-1
Figure imgf000115_0002
A mixture of AI-1-2 (.49 g, 1.43 mmol), phenylacetylene (.218 g, .235 mis, 2.14 mmol), copper(I) iodide (.022 g, .116 mmol), tetrakis(triphenylphosphine)-palladium(0) (.1 g, .086 mmol) and triethylamine (5 ml) were combined in 2 mL acetonitrile and heated to reflux for 4 hrs. After cooling, the solvent was removed in vacuo and the residue partitioned between ethyl acetate/Η2θ and extracted. The combined organic extracts were washed with H2O, brine, dried over 9/62513
Na2S04, filtered and the solvent removed. The resulting brown oil was purified by radial disc chromatography twice, first using 2:1 hexane/ CH2CI2 followed by straight ethyl acetate, then straight CH2CI2 to afford the title compound. lH NMR (400 MHz, CDCI3) δ 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 (m, 3H), 7.45 - 7.48 (m, 2H)
Step 2: [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl-2,4- dioxobutyric acid ethyl ester AIII-2-1
Figure imgf000116_0001
A solution of AIII-1-1 (.264 g, .83 mmol) in 10 mL TΗF was treated with diethyl oxalate (.243 g, 1.66 mmol) and sodium ethoxide (.113 g, 1.66 mmol). After stirring for 1 hr, the reaction was poured into 20 mL 10% citric acid and extracted with ethyl acetate. The combined organic extracts were washed with Η2O, brine, dried over Na2Sθ4 filtered, and the solvent removed in vacuo to give the title compound as a yellow oil. IH NMR (400 MHz, CDCI3) δ 1.36 (t, 3H, J = 7.1 Hz), 4.34 (q, 2H, J = 7.2 Hz), 5.55 (s, 2H), 6.80 (s, IH), 6.99 (t, 2H, J = 8.7 Hz), 7.12 - 7.18 (m, 2H), 7.19 (d, IH, J = 1.65 Hz), 7.25 (d, IH, J = 1.65 Hz), 7.29 - 7.35 (m, 3H), 7.44 - 7.48 (m, 2H)
Step 3: [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid AIII-3-1
Figure imgf000117_0001
In a similar manner to AI-3-1. AIH-2-1 (.347 g, .83 mmol) was reacted with 1.66 mL IM LiOH in 5 mis THF to give the title compound as a yellow resin. lH NMR (400 MHz, CDCI3) δ 6.86 (s, IH), 7.01 (t, 2H, J = 8.6 Hz), 7.12 - 7.19 (m, 2H), 7.21 (d, IH, 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)
EXAMPLE 48
4-[l-(4-fluorobenzyl)-4-phenethyl-lH-pyrrol-2-yl]-2,4-dioxobutyric acid
Step 1: l-[l-(4-fluorobenzyl)-4-phenethyl-lH-pvrrol-2-yl]ethanone
AIII-4-1
Figure imgf000117_0002
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 with hydrogen (via balloon) and allowed to stir for 6 hr. The catalyst was filtered and the solvent removed in vacuo. NMR of this crude mixture showed about 20% starting material. The product was purified by radial disc chromatography (CH2CI2) to obtain the title compound as a resin. lH NMR (400 MHz, CDCI3) δ 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, IH, 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-[l-(4-fluorobenzyl)-4-phenethyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester AIII-5-1
Figure imgf000118_0001
In a similar manner to AIII-2-1. AIII-4-1 (.1 g, .31 mmol) was reacted with diethyl oxalate (.091 g, .084 ml, .62 mmol) and sodium ethoxide (.042 g, .62 mmol) in 5 mL TΗF to give the title compound, which was used in the next reaction without further purification. lΗ NMR (400 MHz, CDCI3) δ 1.37 (t, 3H, J = 7.14 Hz), 2.76 (t, IH, J = 7.7 Hz), 2.86 (t, IH, J = 7.7 Hz)4.35 (q, 2H, J = 7.14 Hz), 5.48 (s, 2H), 6.67 (s, IH), 6.77 (s, IH), 6.92 - 7.06 (m, 5H), 7.11 - 7.29 (m, 5H)
Step 3: 4-[l-(4-fluorobenzyl)-4-phenethyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid AIII-6-1 9/62513
Figure imgf000119_0001
In a manner similar to AI-3-1. AIH-5-1 was reacted with .5 ml IN NaOH in 3 mL THF for 2 hr to give the title compound as a yellow solid. MP = 135-137 °C; lH NMR (400 MHz, CDCI3) δ 2.75 - 2.82 (m, IH), 2.84 - 2.91 (m, IH), 5.47 (s, 2H), 6.71 (d, IH, J = 1.3 Hz), 6.86 (s, IH), 6.95 - 7.08 (m, 4H), 7.11 - 7.16 (m, 2H), 7.17 - 7.23 (m, IH), 7.24 - 7.32 (m, 3H)
EXAMPLE 49 4-[5-(4-fluorobenzyl)-l-methyl-l-H -pyrrol-2-yl]-2,4-dioxobutvric acid AIV- 5-1
Step 1: 2-(4-fluorobenzyl)-lH -pyrrole AIVl-1
Figure imgf000119_0002
MeMgCI (3N in TΗF, 43.8 mL, 0.131 mole) was added dropwise to a solution of 50:50 TΗF:CΗ2Cl2 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 NH4CI and extracted five times with Et2θ. The combined organic layers were dried over NaSθ4, filtered and evaporated to give a dark brown oil that was distilled under vacuum to give analytically pure AIV-1-1. IH NMR (400 MHz, CDCI3) δ 7.77 (broad s, IH), 7.17-7.13 (m, 2H), 7.00-6.95 (m, 2H), 6.67 (s, IH), 6.15-6.14 (d, IH, J=2.7 Hz), 5.97 (m, IH), 3.94 (s, 2H). Step 2: l-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]ethanone AIV-2-1
Figure imgf000120_0001
MeMgCI (2.95 mL, 0.0284 mole) was added dropwise to a solution of AIV- in TΗF (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 NΗ4CI and extracted three times with EtOAc. The combined organic layers were dried over NaSθ4, 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) lH NMR (400 MHz, CDCI3) δ 9.72 (broad s, IH), 7.18-7.14 (m, 2H), 7.00-6.95 m, 2H), 6.85-6.83 (m, IH), 6.01- 5.99 (m, IH), 3.97 (s, 2H), 2.37 (s, 2H)
Step 3: l-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]ethanone AIV-
3-1
Figure imgf000120_0002
NaΗ (.098g, 0.00244 mole) was added to a solution of AIV-2-1 in DMF (25 mL) at 0° C followed by subsequent addition of Mel (0.53g, 0.00244 mole). The ice bath was removed and the reaction was stirred for one hour. The solution was poured into NΗ4CI and extracted three times with EtOAc. The combined organic layers were dried over NaS04, filtered and evaporated to give AIV-3-1 as a brown oil. TLC: Rf=0.43 (80:20 Hexanes / EtOAc) lH NMR (400 MHz, CDCI3) δ 7.11-7.07 (m, 2H), 7.01- 9/62513
6.97 (m, 2H), 6.93-6.92 (m, IH), 5.90-5.89 (m, IH), 3.93 (s, 2H), 3.79 (s, 3H), 2.42 (s, 3H).
Step 4: 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid methyl ester AIV-4-1
Figure imgf000121_0001
A solution of AIV-3-1 (0.222g, 0.000961 mole) in DME (lOmL) was treated with sodium hydride (0.058g, 0.00144 mole) followed by dimethyl oxalate (0.113g, 0.000961 mole) and methanol (200mL) and the solution was warmed to reflux for 1.5 hours. The reaction was poured into 30 mL of 1 N ΗC1 and extracted three times with EtOAc. The combined organic layers were dried over NaSθ4, filtered and evaporated to give AIV-4-1 as a brown solid. TLC: Rf=0.39 (97:3:1 CΗ2CI2 / MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 7.12-7.07 (m, 3H), 7.04-6.99 (m, 2H), 6.83 (s, IH), 5.99- 5.98 (d, IH, j=4.21), 3.97 (s, 2H), 3.915 (s, 3H), 3.85 (s, 3H).
Step 5: 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid AIV-5-1
Figure imgf000121_0002
AIV-4-1 was dissolved in TΗF (15 mL) and 1 N NaOΗ (5 mL) was added. After two hours the reaction was acidified with 1 N ΗC1. This mixture was extracted three times with EtOAc, dried over NaSθ4, 99/62513
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 CHCLJ MeOH / HOAc) lH NMR (400 MHz, CDC13) δ 7.128-7.086 (m, 3H), 7.04-6.99 (t, 2H j=9), 6.90 (s, IH), 6.03- 6.02 (d, IH. j=4.39 Hz), 3.98 (s, 2H), 3.85 (s, 3H).
EXAMPLE 50 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV- 5-2
Figure imgf000122_0001
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 CHCI3/ MeOH / HOAc) lH NMR (400 MHz, DMSO) δ 7.39-7.29 (m, 4H), 7.18-7.16 (d, IH, j=6.7 Hz), 6.81 (s, IH), 6.04-6.03 (d, IH, j=4.2 Hz), 4.10 (s, IH), 3.82 (s, IH).
EXAMPLE 51 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-3
Figure imgf000122_0002
AIV-5-3 was prepared in a manner similar to that described for AIV-5- with the exception that the methylation step was omitted. TLC: Rf=0.28 (93:7:7 CHCI3/ MeOH / HOAc) lH NMR (400 MHz, DMSO) δ 12.19 (s, IH), 7.32-7.28 (m, 2H) 7.17 (s, IH), 7.14-7.10 (t, 2H, j=8.8 Hz), 6.79 (s, IH), 6.06-6.04 (m, IH) 3.97 (s, IH).
EXAMPLE 52 4-[5-(3-chlorobenzyl)-LH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-4
Figure imgf000123_0001
AIV-5-4 was prepared in a manner similar to that described for AIV-5- with the exception that the methylation step was omitted. TLC:
Rf=0.44 (93:7:7 CΗCI3/ MeOH / HOAc) lH NMR (400 MHz, DMSO) δ 12.21 (s, IH), 7.36-7.18 (m, 5H), 6.80 (s, IH), 6.10 (s, IH), 3.99 (s, IH).
EXAMPLE 53 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-5
Figure imgf000123_0002
AIV-5-5 was prepared in a manner similar to that described for AIV- 5- 1, with the exception that the methylation step was omitted. TLC: Rf=0.34 (93:7:7 CΗCI3/ MeOH / HOAc) lH NMR (400 MHz, DMSO) δ 12.20 (s, IH), 7.32-7.18 (m, 6H), 6.80 (s, IH), 6.05 (m, IH), 3.98 (s, 2H).
EXAMPLE 54 4-[5-(3-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-6
Figure imgf000124_0001
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 CHCI3/ MeOH / HOAc) lH NMR (400 MHz, DMSO) δ 12.21 (s, IH), 7.35-7.33 (dd, IH, j=8.1 Hz, 1.6 Hz), 7.19 (d, IH, j=2.2 Hz), 7.12-7.10 (d, 2H, j=6.6 Hz), 7.04 (m, IH), 6.80 (s, IH), 6.10-6.09 (dd, IH, j=3.8 Hz, 2.1 Hz), 4.00 (s, IH).
EXAMPLE 55
4-[5-(4-fluorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-7
Figure imgf000124_0002
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 CΗCI3/ MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 7.21-7.20 (d, IH, j=4.2 Hz) 7.049-6.96 (m, 6H), 6.93 (s, IH), 6.90-6.86 (dd, 2H j=8.4 Hz, 5.3 Hz), 6.07-6.06 (d, IH j=4.2 Hz), 5.60 (s, 2H), 3.85 (s, 2H).
EXAMPLE 56 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-8
Figure imgf000125_0001
AIV-5-8 was prepared in a manner similar to that described for AIV-5- L except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. lH NMR (400 MHz, DMSO) δ 7.46-7.45 (d, IH 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, IH), 6.14-6.13 (d, IH, j=4.2 Hz), 5.69 (s, 2H), 3.99 (s, 2H). mass spec: (FAB, m+1) 414.10
EXAMPLE 57
4-[5-(benzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV- 5-9
Figure imgf000125_0002
AIV-5-9 was prepared in a manner similar to that described for AIV- 5- 1, except that 4-fluorobenzyl bromide was substituted for methyl iodide in the N-alkyation step. lΗ NMR (400 MHz, CDCI3) δ 7.31-7.27 (m, 2H), 7.24 (m, IH), 7.22-7.21 (d, IH j=4.2 Hz), 7.08-7.06 (m, 2H), 7.00-6.96 (m, 2H), 6.92 (s, IH), 6.90-6.87 (m, 2H), 6.11-1.10 (d, IH, j=4.2 Hz), 5.60 (s, 2H), 3.88 (s, 2H). mass spec: (FAB, m+1) 380 EXAMPLE 58 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid AIV-5-10
Figure imgf000126_0001
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. lΗ NMR (400 MHz, CDCI3) δ 7.27 (m, IH), 7.25-7.24 (m, IH), 7.21-7.20 (d, IH, j=4.2 Hz), 7.01-6.95 (m, 4H), 6.93 (s, IH), 6.89- 6.85 (m, 2H), 6.08-6.07 (d, IH, j=4.2 Hz), 5.59 (s, 2H), 3.84 (s, 2H). mass spec: (FAB, m+1) 414
EXAMPLE 59 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV- 8-1
Step 1: l-[5-(4-fluorobenzyl)-l-methyl-l H -pyrrol-3-yl]ethanone
AIV-6-1
Figure imgf000126_0002
AIV-3-1 was dissolved in TFA 10 mL and was refluxed for two days. Cooled and removed TFA under reduced pressure. Dissolved brown oil in saturated NaΗC03 and extracted three times with EtOAc, dried over NaSθ4, filtered and evaporated to give AIV-6-l as a green oily solid. TLC: Rf=0.33 (60:40 Hexanes / EtOAc) lH NMR (400 MHz, CDCI3) δ 7.21-7.20 (d, IH, j=1.83 Hz), 7.12-7.09 (m, 2H), 7.01-6.96 (m, 2H), 6.33-6.22 (d, IH, j=1.8 Hz), 3.88 (s, 2H), 3.45 (s, 3H), 2.36 (s, 3H).
Step 2: 4-[5-(4-fluorobenzyl)-l-methyl-lH -pvrrol-3-yl]-2,4- dioxobutyric acid AIV-8-1
Figure imgf000127_0001
In a manner similar to that described for AIV-5-1. AIV-6-1 was treated with NaΗ and dimethyl oxalate followed by hydrolysis with NaOΗ to give AIV-8-1. lΗ NMR (400 MHz, CDCI3) δ 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, IH, j=1.7 Hz), 6.38 (s, IH), 3.91 (s, 2H), 3.51 (s, 3H). mass spec: (FAB, m+1) 304.19
EXAMPLE 60 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV- 8-2
Figure imgf000127_0002
In a manner similar to that described for AIV-8-1. pyrrole was alkylated with 3-chlorobenzyl bromide and carried through the sequence to give AIV-8-2. lΗ NMR (400 MHz, CDCI3) δ 7.43-7.42 (d, IH, j=1.8 Hz), 7.25-7.24 (m, 2H), 7.14 (s, IH), 7.04-7.03 (m, IH), 6.72 (s, IH), 6.42-6.41 (d, lH, j=l.lHz), 3.92 (s, 2H), 3.50 (s, 3H). mass spec: (FAB, m+1) 320.2
EXAMPLE 61 4-[5-(benzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV-8-3
Figure imgf000128_0001
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-8-3. lΗ NMR (400 MHz, CDCI3) δ 7.43-7.42 (d, IH, j=1.8), 7.34-7.30 (m, 2H), 7.27 (m, IH), (d, 2H, j=7.1 Hz), 6.72 (s, IH), 6.41-6.40 (d, IH, j=1.8), 3.94 (s, 2H), 3.50 (s, 3H). mass spec: (FAB, m+1) 286.3
EXAMPLE 62 4-[5-(3-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid AIV- 8-4
Figure imgf000128_0002
In a manner similar to that described for AIV-8-1. pyrrole was alkylated with 3-fluorobenzyl bromide and carried through the sequence to give AIV-8-4. lΗ NMR (400 MHz, CDCI3) δ 7.43 (d, IH, j=1.8 Hz), 7.32- 7.28 (m, IH), 6.98-6.93 (m, 2H), 6.86-6.83 (d, IH, j=9.5 Hz), 6.72 (s, IH), 6.43-6.42 (d, IH, j=1.3 Hz), 3.94 (s, 2H), 3.50 (S, 3H). mass spec: (FAB, m+1) 304.2
EXAMPLE 63 4-(5-benzyl-lH -pyrrol-3-yl)-2,4-dioxobutyric acid AIV-8-5
Figure imgf000129_0001
In a manner similar to that described for AIV-8-1. with the exception that the N-alkylation step was omitted, pyrrole was alkyated with benzyl bromide and carried through the sequence to give AIV-8-5. TLC: Rf=0.18 (93:7:7 CHCI3/ MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 8.43 (s, IH), 7.48 (dd, IH, j=3.1 Hz, 1.8 Hz), 7.41-7.18 (m, 5H), 6.78 (s, IH), 6.47 (d, IH, j=0.7 Hz), 3.98 (s, IH).
EXAMPLE 64
4-[2,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid ATV-8-6
Figure imgf000129_0002
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 AIV-8-6. TLC: Rf=0.42 (93:7:7 CHCI3/ MeOH / HOAc) 1H NMR (400 MHz, CDCI3) δ 9.10 (s, IH), 7.26-7.21 (m, 3H), 7.08-6.97 (m, 5H), 6.90 (d, IH, j=2.6 Hz), 6.77 (s, IH), 3.92 (s, 2H), 3.77 (s, 2H).
EXAMPLE 65 4-[l-(4-Fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AV- 10-1
Step 1: (+/-) 5-Oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1
Figure imgf000130_0001
To a 2L round bottomed flask with a stirring bar was added pyroglutamic acid (50g, 387.2 mmol) and IL 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 NaHCθ3 (2X) and brine. Drying (MgSθ4), 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. lH NMR (CDCI3) δ 1.30 (3H, t, j=7.3 Hz), 2.18 to 2.60 (4H, complex multiplet), 4.21 (3H, m), 3.37 (IH, br s).
Step 2: (+/-) 5-Oxo-pyrrolidine-l,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1
Figure imgf000130_0002
To a IL round bottomed flask with a stirring bar and an argon inlet was added gave 5-oxo-pyrrolidine-2-carboxylic acid ethyl ester AV-1-1 (18.6g, 118.34 mmol) CHCI3 (300 mL), di-te -butyldicarbonate (30.99g, 142.01 mmol), Et3N (16.5 mL, 118.34 mmol), and 4-dimethylaminopyridine (14.46g, 118.34 mmol). The mixture was stirred at ambient temperature 18h. The solvent was removed in vacuo and the residue was dissolved in 750 mL of EtOAc. The EtOAc solution was washed with 10% aqueous citric acid, aqueous NaHC03, H2O, and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 300g of silica gel using 1:1 EtOAc-hexane as eluant. There was obtained (+/-) 5-oxo-pyrrolidine-l,2-dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 as an oil. lH NMR (CDCI3) δ 1.27 (3H, t, j=7.3 Hz), 1.50 (9H, s), 2.08 (IH, m), 2.45 to 2.71 (3H, complex multiplet), 4.27 (2H, q, j=7.3 Hz), 4.60 (IH, dd, j=3, 9 Hz).
Step 3: (+/-) 2-Tert-butoxycarbonylamino-5-oxo-5-phenyl-pentanoic arid ethyl ester AV-3-1
Figure imgf000131_0001
To an oven dried 500 mL, three-necked round bottomed flask with a stirring bar, argon inlet and septum was added 5-oxo-pyrrolidine-l,2- dicarboxylic acid, 1-tert-butyl ester 2-ethyl ester AV-2-1 (6.50g, 25.25 mmol) and 100 mL of dry THF. This solution was cooled to -40°C and a solution of phenyl magnesium bromide (25.3 mL of a IM 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 NH4CI solution. This mixture was stirred 30m. The mixture was extracted with EtOAc. The organic extract was washed with brine, dried (MgSθ4), filtered and concentrated in vacuo to give 2-tert- butoxycarbonylamino-5-oxo-5-phenyl-pentanoic acid ethyl ester AV-3-1 which was used in the subsequent step without purification. Step 4: (+/-) 5-Phenyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-4-1
Figure imgf000132_0001
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 CH2CI2. 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 CHCI3 and concentrated a second time. The resulting residue was dissolved in 100 mL of CH2CI2 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 H2O and brine. Drying (MgSθ4), 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. IH NMR (CDCI3) δ 1.31 (3H, t, j=7.1 Hz), 2.22 (2H, m), 3.00 (IH, m),
3.17 (IH, m), 4.23 (2H, d, j=7.1), 4.92 (IH, m), 7.41 (3H, m), 7.89 (2H, dd, j= 2.7, 4.0).
Step 5: 5-Phenyl-lH-pyrrole-2-carboxylic acid AV-5-1
Figure imgf000132_0002
To a IL round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester AV-
44 (4.84g, 22.28 mmol), dry CH2CI2 (220 mL) and DDQ (5.06g, 22.28 mmol). This solution was stirred at ambient temperature lh. The solvent was removed in vacuo. Aqueous NaOH (10% w/v, 440 mL) was added and the mixture was heated at reflux 24h. The cooled, black solution was poured onto crushed ice and the mixture was acidified with cone HCl. This mixture was extracted with EtOAc (2X). The combined extracts were washed with brine, dried (MgSθ4), 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-lH- pyrrole-2-carboxylic acid AV-5-1 as an off white solid. lH NMR (CDCI3 ) δ 6.59 (IH, dd, j=2.7, 3.9 Hz), 7.13 (IH, dd, j= 2.7, 3.9 Hz), 7.34 (IH, m), 7.41 (2H, m), 7.59 (2H, m), 9.40 (IH, br s).
Step 6: 5-Phenyl-lH-pyrrole-2-carboxylic acid methoxymethylamide
AV-6-1
Figure imgf000133_0001
To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 5-phenyl-lH-pyrrole-2-carboxylic acid AV-5-1 (2.45g, 13.09 mmol), N,0-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 NaHCθ3 and EtOAc. The layers were separated and the organic phase was washed with H2O (2X) and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 35% EtOAc in hexane as eluant to give 5-phenyl-lH-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 as a solid. lH NMR (CDCI3) δ 3.36 (3H, s), 3.80 (3H, s), 6.58 (IH, dd, j=2.2, 4.0 Hz), 6.94 (IH, dd, j= 2.2, 4.0 Hz), 7.30 (IH, m), 7.41 (2H, m), 7.58 (2H, m), 9.63 (IH, br s).
Step 7: l-(4-Fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1
Figure imgf000134_0001
To a 100 mL round bottomed flask containing 5-phenyl-lH-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, 3.31 mmol) was added. This mixture was stirred 15 min at ambient temperature then 4-fluorobenzylbromide (0.41 mL, 3.31 mmol) was added. The resulting mixture was stirred 24h at ambient temperature. The mixture was diluted with EtOAc and the solution was washed with IN HCl, water and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 25% EtOAc in hexanes a eluant to give l-(4-fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1. lH NMR (CDCI3) δ 3.21 (3H, s), 3.47 (3H, s), 5.52 (2H, s), 6.24 (IH, d, j= 3.9 Hz), 6.75 to 6.90 (5H, m), 6.94 (IH, d, j= 3.9 Hz), 7.38 (4H, m).
Step 8: l-[l-(4-Fluorobenzyl)-5-phenyl-lH-pyττol-2-yl]ethanone AV-8-1
Figure imgf000134_0002
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added l-(4-fluorobenzyl)-5-phenyl-lH-pyrrole-2-carboxylic acid methoxy-methylamide AV-7-1 (0.726g, 2.16 mmol) and dry THF (20 mL). This solution was cooled to -78°C and methyllithium (3.39 mL of a 1.4 M solution in Et2θ, 4.75 mmol). The mixture was stirred 30 min at -78°C then the reaction was quenched with saturated aqueous NH4CI solution. The mixture was warmed to room temperature and stirred 2h. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried (MgSθ4), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give l-[l-(4- fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]ethanone AV-8-1 as an oil. lH NMR (CDCI3) δ 2.42 (3H, s), 5.59 (2H, s), 6.29 (IH, d, j= 4.2 Hz), 6.78 to 6.91 (4H, m), 7.12 (IH, d, j= 4.2 Hz), 7.29 (2H, m), 7.38 (3H, m).
Step 9: 4-[l-(4-Fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester AV-9-1
Figure imgf000135_0001
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added l-[l-(4-fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]ethanone AV-8-1 (0.628g, 2.14 mmol), dry THF (10 mL), diethyl oxalate (0.41 mL, 3.00 mmol) and NaOEt (0.204g, 3.00 mmol). The resulting mixture was stirred lh at ambient temperature. The mixture was diluted with EtOAc and washed with IN HCl, H2O (2X) and brine. Drying (MgS04) filtration and removal of the solvent in vacuo gave 4-[l-(4-fluorobenzyl)-5-phenyl- lH-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 as an oil. This material was used without further purification. lH NMR (CDCI3) δ 1.38 (3H, t, j=7.1 Hz), 4.38 (2H, q, j= 7.1 Hz), 5.65 (2H, s), 6.38 (IH, d, j= 4.1 Hz), 6.79 to 6.94 (4H, m), 7.29 (2H, m), 7.39 (3H, m).
Step 10: 4-[l-(4-Fluorobenzyl)-5-phenyl-lH-pvrrol-2-yl]-2,4- dioxobutyric acid AV-10-1
Figure imgf000136_0001
To a 200 mL round bottomed flask with a stirring bar and an argon inlet was added 4-[l-(4-fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester AV-9-1 (0.84g, 2.14 mmol) and MeOH (72 mL). To this solution was added aqueous NaOH (11 mL of a IN solution). The mixture was stirred at ambient temperature 18h. The organic solvents were removed in vacuo and the aqueous residue was washed with Et2θ then acidified with IN HCl. The mixture was extracted with Et2θ and the Et2θ extract was washed with brine, dried (MgSθ4), filtered and concentrated in vacuo. The crude solid was recrystallized from a mixture of EtOAc and hexane to give 4-[l-(4-fluorobenzyl)-5-phenyl-lH- pyrrol-2-yl]-2,4-dioxobutyric acid AV-10-1 as a white, crystalline solid. MP: 151-152°C (dec). lH NMR (CDCI3) δ 5.63 (2H, s), 6.42 (IH, d, j= 4.4 Hz), 6.80 (2H, m), 6.94 (3H, m), 7.29 (2H, m), 7.40 (2H, m).
EXAMPLE 66 4-[4-Diπιethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid A-VI-5-1
Step 1: l-[l-(4-Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]ethanone AVI-1-
1
Figure imgf000136_0002
To a 500 mL round bottomed flask with a stirring bar and a drying tube was added l-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone A J. (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 NaHCθ3 solution (2X) and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave a solid. This material was chromatographed on silica gel using 20% EtOAc in hexane as eluant. An impure yellow crystalline solid was obtained. This material was recrystallized from Et2θ/hexane to give white crystals of l-[l-(4-fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]ethanone AVI- 1-1. IH NMR (CDCI3) δ 2.55 (3H, s), 5.54 (2H, s), 7.06 (2H, m), 7.20 (2H, m), 7.47 (IH, d, j= 1.8 Hz), 7.63 (IH, d, j= 1.8 Hz).
Step 2: l-[4-Amino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone
AVI-2-1
Figure imgf000137_0001
To a IL round bottomed flask with a stirring bar and a balloon hydrogenation adapter was added l-[l-(4-fluorobenzyl)-4-nitro-lH-pyrrol- 2-yl]ethanone AVI- 1-1 (8.00g, 30.51 mmol) absolute EtOH (640 mL) and 10% Pd-C (2.24g, 2.11 mmol). This mixture was hydrogenated at ambient temperature 24h. The catalyst was removed by filtration and the EtOH was removed in vacuo. The semi-solid residue was chromatographed on silica gel using EtOAc as eluant to give l-[4-amino- l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVI-2-1 as a yellow crystalline solid. lH NMR (CDCI3) δ 2.34 (3H, s), 3.01 (2H, br s), 5.42 (2H, s), 6.46 (IH, d, j= 2.0 Hz), 6.50 (IH, d, j= 2.0 Hz), 6.98 (2H, m), 7.12 (2H, m). Step 3: l-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2- yl]ethanone AVI-3-1
Figure imgf000138_0001
To a 100 mL round bottomed flask with a stirring bar and a nitrogen inlet was added l-[4-amino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVI-2-1 (0.50g, 2.15 mmol), dry DMF (20 mL), finely powdered CS2CO3 (3.26g, 10 mmol) and Mel (0.31 mL, 5.00 mmol). The resulting mixture was stirred lh at ambient temperature. The solids were removed by filtration and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with water (3X) and brine. Drying
(MgSθ4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 50% EtOAc-hexanes as eluant to give l-[4-dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2- yl]ethanone AVI-3-1 as an oil. lH NMR (CDCI3) δ 2.36 (3H, s), 2.70 (6H, s), 5.46 (2H, s), 6.36 (IH, d, j= 2.0 Hz), 6.50 (IH, d, j= 2.0 Hz), 6.98 (2H, m), 7.11 (2H, m).
Step 4: 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester AVI-4-1
Figure imgf000138_0002
In a manner substantially similar to that described for Example AV-9- lΛl-[4-dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVI-3-1 was used to prepare 4-[4-dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2- yl]-2,4-dioxobutyric acid ethyl ester AVI-4-1 which was used in the next step without further purification.
Step 5: 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid AVI-5-1
Figure imgf000139_0001
In a manner substantially similar to that described for Example AV-10-1 4-[4-dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]- 2,4-dioxobutyric acid ethyl ester AVI-4-1 was used to prepare 4-[4- dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AVI-5-1. IH NMR (DMSO-d6-CDCl3 1:1) δ 3.12 (6H, s), 5.61 (2H, s), 7.06 (2H, m), 7.19 (2H, m), 7.60 (IH, br s), 7.68 (IH, br s).
EXAMPLES 67-69 The following compounds was prepared in a manner similar to that described for AVI-5-1:
4-[l-(4-Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]-2,4-dioxobutyric acid CΗN Calc. (Ci5ΗnFN2θ6'0.8Η2θ) 51.65, 3.64, 8.03; Fnd. 51.65, 3.42, 7.88. (67)
Figure imgf000139_0002
4-[4-(Benzylamino)-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid CΗN Calc. (C22Η19FN2O4 • 0.33 CHCI3) 61.83, 4.49, 6.45; Fnd. 62.07, 4.27, 5.74. (68)
Figure imgf000140_0001
4-[5-Nitro-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid CΗN Calc. 53.90, 3.32, 8.38; Fnd. 53.77, 3.24, 8.20. (69)
Figure imgf000140_0002
EXAMPLE 70 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1
Step 1: l-[l-benzyl-lH-pyrrol-3-yl]ethanone AVII-1-1
Figure imgf000140_0003
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 NaΗ (260 mg of a 60% suspension in mineral oil, 6.50 mmol). After stirring at 0 °C for 20 min and room temperature for 1 h, the reaction mixture was treated with sat. NH4CI (10 mL) and poured onto sat. NH4CI (50 mL). The resulting mixture was extracted with Et2θ (3 x 50 mL). The combined organic extracts were washed with sat. NaCl (50 mL) and dried (MgS04). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with 2:l/hexanes:EtOAc, afforded the product as a clear oil. lH NMR (400 MHz, CDCI3) δ 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 (El, M+) 199
Step 2: 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester
AVII-2-1
Figure imgf000141_0001
To a solution of AVII- 1-1 (900 mg, 4.52 mmol) in TΗF (10 mL) was added dimethyl oxalate (795 mg, 6.74 mmol) followed by NaΗ (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 ΗC1 (20 mL) was added and the mixture extracted with CΗ2CI2 (3 x 20 mL). The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgSθ4). Concentration followed by medium-pressure liquid chromatography on silica gel, eluting with
5:5:l/CH2Cl2:hexanes:EtOAc, afforded the product as a yellow solid. IH NMR (400 MHz, CDCI3) δ 7.44 (m, IH), 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-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-1
Figure imgf000142_0001
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 Et2θ (5 x 10 mL). The Et2θ extracts were discarded. The aqueous phase was treated with 3 N HCl (20 mL), extracted with CH2CI2 (3 x 20 mL) and the combined organic extracts dried (MgSθ4). 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) lH NMR (400 MHz, i6-DMSO) δ 8.04 (d, J = 1.6 Hz, IH), 7.40-7.25 (m, 5H), 7.01 (m, IH), 6.74 (s, IH), 6.62 (m, IH), 5.18 (s, 2H). mass spec (negative mode electrospray, M-H) 270.
EXAMPLES 71-85 In a manner similar to that described for AVII-3-1. the following compounds were prepared:
EXAMPLE 71 4-[l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-2 (71)
Figure imgf000142_0002
p 145-146 °C (uncorrected) lH NMR (400 MHz, ctø-DMSO) δ 8.04 (m, IH), 7.40-7.35 (m, 2H), 7.22-7.17 (m, 2H), 7.01 (m, IH), 6.73 (s, 1), 6.62 (m, IH), 5.17 (s, 2H). mass spec (negative mode electrospray, M-H) 288.
EXAMPLE 72 4-[l-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-3
Figure imgf000143_0001
mp 159-160 °C (uncorrected) lΗ NMR (400 MHz, dβ-ΩMSO) δ 8.07 (m, IH), 7.56-7.50 (m, 2H), 7.36-7.28 (m, 2H), 7.04 (m, IH), 6.74 (s, IH), 6.63 (m, IH), 5.18 (s, 2H). mass spec (negative mode electrospray, M-H) 348, 350.
EXAMPLE 73 4-[l-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII- 3-4
Figure imgf000143_0002
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) lΗ NMR (400 MHz, ctø.DMSO) δ 8.10 (m, IH), 7.37 (dd, J = 5.5, 7.6 Hz, 2H), 7.18 (dd, J = 7.6, 8.9 Hz, 2H), 6.77 (m, IH), 6.72 (s, IH), 5.10 (s, 2H), 2.20 (s, 3H). mass spec (negative mode electrospray, M-H) 302.
EXAMPLE 74 4-[2,4-dimethyl-l-(4-fluorobenzyl)--_H-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-5
Figure imgf000144_0001
AVII-3-5 was prepared in a manner similar to AVII-3-1. starting with 2,4-dimethyl-3-acetyl pyrrole, mp 184-185 °C (uncorrected) lΗ NMR (400 MHz, dβ-OMSO) δ 7.20-7.12 (m, 4H), 6.74 (s, IH), 6.62 (s, IH), 5.13 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H). mass spec (negative mode electrospray, M-H) 316.
EXAMPLE 75 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-6
Figure imgf000144_0002
mp 143-144 °C (uncorrected) lΗ NMR (400 MHz, dβ-OMSO) δ 8.05 (s, IH), 7.43 (m, 2H), 7.17 (m, IH), 7.03 (dd, J = 3.0, 1.8 Hz, IH), 6.73 (s, IH), 6.61 (dd, J = 3.0, 1.8 Hz, IH), 5.16 (s, 2H), 3.3 bs, IH). mass spec (negative mode electrospray, M-H) 306.
EXAMPLE 76 4-[l-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-7
Figure imgf000145_0001
mp 159-160 °C (uncorrected) lΗ NMR (400 MHz, dβ-OMSO) δ 8.07 (m, IH), 7.38 (m, 3H), 7.26 (m, IH), 7.04 (m, IH), 6.74 (s, IH), 6.63 (m, IH), 5.19 (s, IH). mass spec (negative mode electrospray, M-H) 304, 306.
EXAMPLE 77 4-ri-(4-chlorobenzyl)-lH-pyrrol-3-yn-2.4-dioxobutyric acid AVII-3-8
Figure imgf000145_0002
mp 170-171 °C (uncorrected) lH NMR (400 MHz, cfø.DMSO) δ 8.03 (t, J = 1.8 Hz, IH), 7.43-7.40 (m, 2H), 7.34 (m, IH), 7.31 (m, IH), 7.00 (dd, J = 2.8, 1.8 Hz, IH), 6.72 (s, IH), 6.61 (dd, J = 2.8, 1.8 Hz, IH). mass spec (negative mode electrospray, M-H) 304. EXAMPLE 78 4-ri-(4-bromobenzyl)-lH-pyrrol-3-vn-2.4-dioxobutyric acid AVII-3-9
Figure imgf000146_0001
mp 184-185 °C (uncorrected) lH NMR (400 MHz, <fø.DMSO) δ 8.04 (t, J = 2.0 Hz, IH), 7.59-7.54 (m, 2H), 7.28-7.23 (m, 2H), 7.01 (dd, J = 2.0, 2.9 Hz, IH), 6.74 (s, IH), 6.62 (dd, J = 2.0, 2.9 Hz, IH), 5.17 (s, 2H). mass spec (negative mode electrospray, M-H) 348, 350.
EXAMPLE 79 4-ri-(3.4-dichlorobenzyl)-lH-pyrrol-3-yll-2.4-dioxobutyric acid AVII-3-10
Figure imgf000146_0002
mp 175-176 °C (uncorrected) lΗ NMR (400 MHz, dg.DMSO) δ 8.06 (t, J = 1.9 Hz, IH), 7.62 (d, J = 8.2 Hz, IH), 7.61 (s, IH), 7.28 (dd, J = 8.2, 2.0 Hz, IH), 7.04 (dd, J = 2.9, 1.9 Hz, IH), 6.73 (s, IH), 6.62 (dd, J = 2.9, 1.9 Hz, IH), 5.18 (s, 2H), 3.36-3.20 (bs, IH). mass spec (negative mode electrospray, M-H) 338, 340.
EXAMPLE 80 4-ri-(2-methylbenzyl)-lH-pyrrol-3-vn-2.4-dioxobutyric acid AVII-3-11
Figure imgf000147_0001
mp 119-120 °C (uncorrected) lΗ NMR (400 MHz, ffø.DMSO) δ 7.91 (t, J = 1.9 Hz, IH), 7.24-7.15 (m, 2H), 6.94 (d, J = 7.4 Hz, IH), 6.91 (dd, J = 2.9, 1.9 Hz, IH), 6.72 (s, IH), 6.64 (dd, J = 2.9, 1.9 Hz, IH), 5.21 (s, 2H), 3.45-3.21 (bs, IH), 2.25 (s, 3H). mass spec (negative mode electrospray, M-H) 284.
EXAMPLE 81
4-[l-(3-chlorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII- 3-12
Figure imgf000147_0002
AVII-3-12 was prepared in a manner similar to AVII-3-1. starting with 4-methyl-3-acetyl pyrrole. mp 148-149 °C (uncorrected) lH NMR (400 MHz, dg-DMSO) δ 8.09 (d, J = 2.2 Hz, IH), 7.41-7.35 (m, 2H), 7.26 (m, IH), 6.79 (dd, J = 2.1, 1.1 Hz, IH), 6.72 (s, IH), 5.09 (s, 2H), 3.40-3.30 (bs, IH), 2.19 (s, 3H). mass spec (negative mode electrospray, M-H) 318, 320.
EXAMPLE 82 4-[l-(3-trifluoromethylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid A VII- 3-13
Figure imgf000148_0001
mp 145-146 °C (uncorrected) lΗ NMR (400 MHz, cfø-DMSO) δ 8.09 (t, J = 1.9 Hz, IH), 7.70-7.66 (m, 2H), 7.63-7.58 (m, 2H), 7.06 (m, IH), 6.73 (s, IH), 6.63 (dd, J = 4.7, 1.7 Hz, IH), 5.28 (s, 2H), 3.40-3.20 (bs, IH). mass spec (negative mode electrospray, M-H) 338.
EXAMPLE 83 4-[l-(4-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-14
Figure imgf000148_0002
mp 164-165 °C (uncorrected) lH NMR (400 MHz, cfø.DMSO) δ 8.00 (t, J = 1.9 Hz, IH), 7.20-7.14 (m, 4H), 6.97 (dd, J = 2.9, 1.9 Hz, IH), 6.72 (s, IH), 6.59 (dd, J = 2.9, 1.9 Hz, IH), 5.11 (s, 2H), 3.37-3.27 (bs, IH), 2.26 (s, 3H). mass spec (negative mode electrospray, M-H) 284
EXAMPLE 84 4-[l-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid AVII-3-15
Figure imgf000149_0001
mp 137-138 °C (uncorrected) lΗ NMR (400 MHz, cfø.DMSO) δ 7.99 (t, J = 1.9 Hz, IH), 7.27-7.25 (m, 2H), 6.97 (dd, J = 2.9, 1.9 Hz, IH), 6.90 (m, 2H), 6.71 (s, IH), 6.58 (dd, J = 2.9, 1.9 Hz, IH), 5.08 (s, 2H). mass spec (negative mode electrospray, M-H) 300
EXAMPLE 85
4-ri-(3-methylbenzyl)-lH-ρyrrol-3-yll-2.4-dioxobutyric acid AVII-3-16
Figure imgf000149_0002
Rf =0.49 (94:6:1 CΗ2CI2 / MeOH / HOAc) Η NMR (400 MHz, CDCI3) δ 7.46 (s, IH), 7.25 (m, 2H), 7.15 (d, J=7.5 Hz, IH), 6.98 (m, 2H), 6.25 (s, IH), 6.23 (m, IH), 6.20 (m, IH), 5.05 (s, 2H),2.33 (s, 3H).
EXAMPLES 86-88 The following compounds were prepared in a manner similar to AVII- 3-1:
EXAMPLE 86 4-{l-[3-(4-fluorophenyl)-propyl]-lH-pyrrol-3-yl}-2,4-dioxobutyric acid
Figure imgf000150_0001
CHN Calc. (C17H16FNO4 0.2 water) 63.62, 5.15,4.36; Fnd. 63.54,5.07,4.00.
EXAMPLE 87 4-[l-(4-bromobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid
Figure imgf000150_0002
CHN Calc. 51.45, 3.45,4.00; Fnd. 51.53,3.50,3.92.
EXAMPLE 88 4-[l-(4-chlorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid 9/62513
Figure imgf000151_0001
CHN Calc. 58.93,3.96,4.58; Fnd. 58.79,4.04,4.47.
EXAMPLE 89 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid AVIII-4-1
Step 1: l-[4-Benzylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVIII- 1-1
Figure imgf000151_0002
AVIII- 1-1 To a 100 mL round bottomed flask with a stirring bar, addition funnel and an argon inlet was added l-[4-amino-l-(4-fluorobenzyl)-lH-pyrrol-2- yljethanone AVI-2-1 (l.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 add (0.246 mL, 4.31 mmol) in MeOH (20 mL). The acetic add 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 NaHCθ3 , aqueous sodium potassium tartrate and brine. Drying (MgSθ4), 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 l-[4-Benzylamino-l-(4-fluorobenzyl)-lH-pyrrol- 2-yl]ethanone AVIII- 1-1 as a crystalline solid. lH NMR (CDCI3) δ 2.34 (3H, s), 3.35 (IH, br s), 4.16 (2H, s), 5.41 (2H, s), 6.36 (IH, d, j= 2.2 Hz), 6.49 (IH, d, j=2.2 Hz), 6.93 (2H, m), 7.06 (2H, m), 7.30 to 7.37 (5H, complex multiplet).
Step 2: l-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2- yl]ethanone AVIII-2-1
Figure imgf000152_0001
AVIII-2-1
To a 100 mL round bottomed flask with a stirring bar and an addition funnel topped by an argon inlet was added l-[4-benzylamino-l-(4- fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVIII- 1-1 (0.472g, 1.46 mmol), MeOH (20 mL), formalin (1.19 mL of 37% aqueous solution, 14.64 mmol) and sodium cyanoborohydride (0.628g, 10.00 mmol). The addition funnel was charged with a solution of glacial acetic acid (0.57 mL, 10.0 mmol) in MeOH (20 mL). The acetic add 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 NaHCθ3, aqueous sodium potassium tartrate and brine. Drying (MgSθ4), 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 l-[4- benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone AVIII-2- 1 as a crystalline solid. lH NMR (CDCI3) δ 2.25 (3H, s), 2.36 (3H, s), 4.16 9/62513
(2H, s), 5.43 (2H, s), 6.33 (IH, d, j= 2.2 Hz), 6.53 (IH, 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-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]- 2,4-dioxobutyric acid ethyl ester A-VIII-3-1
Figure imgf000153_0001
In a manner substantially similar to that described for Example A-V-9-1 l-[4-benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]ethanone A- VIII-2-1 was used to prepare 4-[4-benzylmethylamino-l-(4-fluorobenzyl)- lH-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- l-(4-fluorobenzyl)- lH-pyrrol-2-yl]- 2,4-dioxobutyric acid AVI-5-1
Figure imgf000153_0002
AVIII-4-1
In a manner substantially similar to that described for Example AV-10-1 4-[4-benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric add ethyl ester AVIH-3-1 was used to prepare 4-[4- benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid AVIII-4-1. IH NMR (CDCI3) δ 2.79 (3H, s), 4.23 (2H, s), 5.48 (2H, s), 6.54 (IH, d, j=2.0 Hz), 6.74 (IH, d, j=2.0 Hz), 7.00 (4H, m), 7.28 (5H, m). EXAMPLE 90 4-[4-Din ethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid A-IX-3-1
Step 1: l-[l-(4-Fluorobenzyl)-4-phenyl-lH-pyrrol-2-yl]ethanone AIX-
1-1
Figure imgf000154_0001
To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added l-[l-(4-fluorobenzyl)-4-iodo-lH-pyrrol-2- yl]ethanone AIII-1-1 (l.OOg, 2.91 mmol), phenylboronic add (0.431g, 3.54 mmol), tetrakis(triphenylphosphine)palladium° (0.20g, 0.17 mmol), barium hydroxide (1.37g, 4.37 mmol), DME (40 mL), and H2O (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 H2O, IN HCl, H2O, and brine. Drying (MgSθ4), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give l-[l-(4-fluorobenzyl)-4-phenyl-lH-pyrrol-2-yl]ethanone AIX-1-1 as an oil. lH NMR (CDCI3) δ 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-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester AIX-2-1
Figure imgf000155_0001
In a manner substantially similar to that described for Example AV-9-1. l-ri-(4-fluorobenzvl)-4-phenvl-lH-pvrrol-2-vllethanone AIX-1-1 was used to prepare 4-[4-phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric add ethyl ester AIX-2-1 which was used in the next step without further purification.
Step 3: 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid AIX-3-1
Figure imgf000155_0002
In a manner substantially similar to that described for Example AV-10-1 4-[4-phenyl- l-(4-fluorobenzyl)- lH-pyrrol-2-yl]-2,4-dioxobutyric add ethyl ester AIX-2-1 was used to prepare 4-[4-phenyl-l-(4-fluorobenzyl)-lH- ρyrrol-2-yl]-2,4-dioxobutyric add AIX-3-1. lH NMR (DMSO-dβ) δ 5.66 (2H, s), 6.93 (IH, s), 7.05 (2H, m), 7.23 (3H, m), 7.36 (2H, m), 7.59 (3H, m), 7.65 (IH, d, j=1.7 Hz).
EXAMPLE 91 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3-yl]-2,4-dioxo- butyric add AX-3-1 Step 1: N-[4-acetyl-l-(4-fluorobenzyl)-lH-pyrrol-3-yl]- methanesulfonamide AX- 1-1
Figure imgf000156_0001
A solution of l-[4-amino-l-(4-fluoro-benzyl)-lH-pyrrol-3-yl]-ethanone AVI-2-1 (.5g, 2.15 mmole) in 10 ml of CH2CI2 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 CH2CI2 and washed with 10% ritric acid. Organic layer was dried over MgSθ4, filtered and concentrated in vacuo to afford a light pink semi-solid residue. This material was chromatographed on silica gel using 50% EtO Ac Hex as eluant to give AX-1-1 as a white crystalline solid. lH NMR (400 MHz, CDCI3) δ 7.12 (m, 2H), 6.96 (m, 2H), 6.94 (d, J=1.8Hz, IH), 6.85 (d, J=1.8Hz, IH ), 5.97 (s, b, IH), 5.49 (s, 2H), 2.97 (s, 3H), 2.39 (s, 3H).
Step 2: 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pvrrol-3- yl]-2,4-dioxo-butyric add ethyl ester AX-2-1
Figure imgf000156_0002
A solution of AX-1-1 (460 mg, 1.48 mmole) in 10ml dried THF was treated with diethyl oxalate (0.40 ml, 2.96 mmole) and sodium ethoxide (200 mg, 2.96 mmole) at room temperature over night under N2 atmosphere. The reaction mixture was poured into 20 ml of IN HCl solution and extracted twice with EtOAc. Combined extracts were washed with brine and dried over MgSθ4, filtered and evaporated to give a yellow brown residue that was flashed chromatographed using 100% EtOAc as eluant to give AX-2-1 as a yellow crystalline solid. lH NMR (400 MHz, CDCI3) δ 7.13 (m, 2H), 6.97 (m, 4H), 6.75 (s, IH), 5.92 (s, br, IH) , 5.56 (s, 2H), 4.34-4.40 (q, 2H), 2.97 (s, 3H), 1.39 (t, 3H).
Step 3: 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric acid AX-3-1
Figure imgf000157_0001
A solution of AX-2-1 (200 mg, 0.48 mmole) was dissolved in 6ml of CH3OH and 6ml of IN NaOH for 3 hours. The reaction mixture was washed with ether and aridified to pH 1-2 with IN HCl and extracted three times with EtOAc. Combined extracts were washed with brine, dried over MgSθ4, filtered and evaporated to give an oily residue that was triturated with 20% Et20/Hex to afford AX-3-1 as a yellow crystalline solid, m.p.: 160°C decomposed lH NMR (400 MHz, DMSO-dβ) δ 9.33 (s, IH), 7.39 (s, IH), 7.12-7.17 (m, 5H), 6.75 (s, IH), 5.58 (s, 2H), 2.92 (s, 3H).
EXAMPLES 92-94 The following compounds were prepared in a manner similar to that described for AX-3-1: EXAMPLE 92
4-[l-(4-Fluorobenzyl)-3-acetylamino-lH-pyrrol-2-yl]-2,4-dioxobutyric acid NHAc
COOH
O O
CHN Calc. 58.96, 4.37, 8.09; Fnd. 59.20, 4.30, 8.06.
EXAMPLE 93 4-[4-acetylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric acid
Figure imgf000158_0001
CHN Calc. (C17H15FN2O5 0.3 H2O) 58.05, 4.47, 7.97; Fnd. 58.09,4.40,8.06.
EXAMPLE 94 4-[l-(4-fluorobenzyl)-4-(2-oxo-piperidin-l-yl)-lH-pyrrol-2-yl] -2,4- dioxobutyric add
CHN Calc.( C20H19FN2O5 0.4 H2O) 61.03, 5.07, 7.12; Fnd. 60.96, 5.00, 7.22.
EXAMPLE 95 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxo-butyric acid AXI-5-1
Step 1: (4-fluorophenyl)-(l-triisopropylsilanyl-lH -pyrrol-3- yDmethanone AXI-1-1
Figure imgf000159_0001
A stirred slurry of AICI3 (99.99% anhydrous powder, 3.28g, 0.0246 mole) in anhydrous CΗ2CI2 (45 mL) was treated with 4-fluorobenxoyl chloride (2.64 mL, 0.0224 mole) added dropwise at 0°C. After 0.5 h, a solution of l-(triisopropylsilyl)pyrrole (5.55 mL, 0.0224 mole) in CH2CI2 (11 mL) was added. The mixture was stirred for 0.5 h at 0°C then 3 h at room temperature and then poured into 300 mL cold saturated NH4CI solution. The organic phase was separated and combined with two CH2CI2 extracts of the aqueous phase. The combined organic layers were washed with NH4CI 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 AXI-1-1 as a yellow oil. TLC Rf=0.54 (10:90 EtOAc / Hexanes) lH NMR (400 MHz, CDCI3) δ 7.87 (m, 2H), 7.32 (m, IH), 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)-l-triisopropylsilanyl-lH -pyrrole AXI-2-1
Figure imgf000159_0002
Si(i-Pr)3 AXI-2-1
In a similar manner to AII-2-1. AXI-1-1 (3.50 g, 0.0101 mole) was refluxed with 1.0 M BΗ3-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) lH NMR (400 MHz, CDCI3) δ 7.15 (m, 2H), 6.94 (m, 2H), 6.71 (t, J=2.38 Hz, IH), 6.50 (m, IH), 6.09 (m, IH), 3.82 (s, 2H), 1.41 (m, 3H), 1.08 (d, J=7.51, 18H).
Step 3: l-[4-(4-fluorobenzyl)-l-triisopropylsilanyl-lH -pyrrol-3- yljethanone AXI-3-1
Figure imgf000160_0001
Si(i-Pr)3 AXL3.!
In a similar manner to AXI-1-1. AXI-2-1 was acylated using freshly distilled acetyl chloride to give AXI-3-1 as a light yellow solid.
TLC Rf=0.41 (10:90 EtOAc / Hexanes) lH NMR (400 MHz, CDCI3) δ 7.31
(m, IH), 7.17 (m, 2H), 6.93 (m, 2H), 6.30 (t, J=1.10 Hz, IH), 4.08 (s, IH), 2.37 (s, 3H), 1.42 (m, 3H), 1.08 (d, J=7.51 Hz, 18H)
Step 4: l-[4-(4-fluorobenzyl)-lH -pyrrol-3-yl]ethanone AXI-4-1
Figure imgf000160_0002
A solution of AXI-3-1 (0.145g, 0.387 mmol) in dry TΗF (0.5 mL ) was treated with tetra-n-butylammonium fluoride (0.397 μL 1.0 M in TΗF, 0.387 mmol) at room temperature for one hour. The reaction was quenched with saturated NaΗCθ3, extracted with EtOAc, dried over MgSθ4, filtered and concentrated to give the product as a yellow solid. TLC Rf=0.15 (10:90 EtOAc / Hexanes) lH NMR (400 MHz, CDCI3) δ 8.2 (bs, IH), 7.38 (s, 1H),7.22 (m, 2H), 6.95 (m, 2H), 6.34 (s, IH), 4.1 (s, 2H), 2.4 (s, 3H). 9/62513
Step 5: l-[l,4-bis-(4-fluorobenzyl)-lH -pyrrol-3-yl]ethanone AXI-4-2
Figure imgf000161_0001
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) lH NMR (400 MHz, CDCI3) δ 7.17- 7.21 (m, 3H), 7.04-7.12 (m, 4H), 6.93 (m, 2H), 6.20 (s, IH), 4.94 (s, 2H), 4.06 (s, 2H), 2.34 (s, 3H).
Step 6: 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric add AXI-5-1
Figure imgf000161_0002
AXI-4-1 was carried on to the diketo add AXI-5-1 as described for AI-3-1. TLC Rf=0.41 (94:6:6 CΗCI3 / MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 8.4 (bs, IH), 7.4 (s, 1H),7.2 (m, 2H), 6.97 (m, 2H), 6.41 (s, IH), 4.1 (s, 2H).
EXAMPLE 96 4-[l,4-bis-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid AXI-5-2
Figure imgf000162_0001
AXI-4-2 was carried on to the diketo acid AXI-5-2 as described for AI-3-1. TLC Rf=0.66 (94:6:6 CHCI3 / MeOH / HOAc) lH NMR (400 MHz, CDCI3) δ 7.41 (s, IH), 7.04-7.19 (m, 6H), 6.96 (m, 2H), 6.70 (s, IH), 6.28 (s,lH), 4.97 (s, 2H), 4.07 (s, 2H).
EXAMPLE 97 4-[5-(3-carboxy-3-oxo-propionyl)-l-(4-fluorobenzyl)-lH-pyrazol-3-yl]-2,4- dioxobutyric acid BI-6-1
Step 1: l-(4-fluorobenzyl)-lH-pyrazol-3,5-dicarboxylic add diethyl ester BI-1-1
Figure imgf000162_0002
A mixture of lΗ-pyrrole-2,4-dicarboxylic add 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 dry 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 H2O, brine, dried over Na2S04, filtered and the solvent removed. TLC showed about 30% unreacted pyrrole. Further purification by column chromatography (2:1 hexane/ethyl acetate) gave .335 gr (50%) of the title compound as a colorless oil.
IH NMR (400 MHz, CDC13) 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, J = 7.14 Hz), 5.80 (s, 2H), 6.98 (t, 2H, J = 8.7 Hz), 7.29 (m, 2H), 7.36 (s, IH)
Step 2: l-(4-fluorobenzyl)-lH-pyrazol-3,5-dicarboxylic add dilithium salt BI-2-1
Figure imgf000163_0001
BI-1-1 (.2 g, .62 mmol) was dissolved in 2 ml TΗF, and to it was added LiOΗ (1.3 ml of a IM sohx). 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: l-(4-fluorobenzyl)-lH- pyrazol-2,4-dicarboxylic add bis-
(methoxymethylamide) BI-3-1
Figure imgf000163_0002
A mixture of BI-2-1 from the previous example, N,0- dimethylhydroxylamine hydrochloride (.121 g, 1.24 mmol), l-ethyl-3-(3- dimethylaminopropyDcarbodiimide hydrochloride (.238 g, 1.24 mmol), 1- hydroxybenzotriazole hydrate (.167 g, 1.24 mmol), and triethylamine (.125 g, .173 ml, 1.24 mmol) were combined in 3 ml DMF and stirred for 18 hr. The solvent was removed in vacuo and the residue partitioned between ethyl acetate H2θ and extracted. The combined organic extracts were washed with H2O, brine, dried over Na2Sθ4} filtered and the solvent removed. Further purification via radial disc chromatography (1:1 hexane/ethyl acetate) afforded the title compound as a colorless oil. IH NMR (400 MHz, CDCI3) δ 3.27 (s, 3H), 3.43 (s, 3H), 3.46 (s, 3H), 3.75 (s, 3H), 6.91 - 7.00 (m, 3H), 7.22 - 7.32 (m, 3H)
Step 4: l-[5-acetyl-l-(4-fluorobenzyl)-lH-pyrazol-3-yl]ethanone BI-4-1
Figure imgf000164_0001
BI-3-1 (.142 g, .41 mmol) was dissolved in 5 ml dry TΗF 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 10% aqueous ritric add solution.
After warming to room temperature, the mixture was poured into 10 ml Η2O and extracted with ethyl acetate. The combined organic extracts were washed with H2O, brine, dried over Na2Sθ4, filtered and the solvent removed to get the title compound as an oil. lH NMR (400 MHz, CDCI3) δ 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)-l-(4-fluorobenzyl)-lH- pyrazol-3-yl]-2,4-dioxobutyric add ethyl ester BI-5-1
Figure imgf000165_0001
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. lΗ NMR (400 MΗz, CDCI3) δ 1.38 (t, 3Η, J = 7.33 Hz), 1.42 (t, 3H, J = 7.14 Hz), 4.36 (q, 2H, J = 7.14 Hz), 4.41 (q, 2H, J = 7.14 Hz), 5.84 (s, 2H), 6.85 (s, IH), 7.00 (t, 2H, J = 2.0 Hz), 7.29 - 7.36 (m, 3H), 7.54 (s, IH)
Step 6: 4-[5-(3-carboxy-3-oxopropionyl)-l-(4-fluorobenzyl)-lH- pyrazol-3-yl]-2,4-dioxobutyric acid BI-6-1
Figure imgf000165_0002
In a similar manner to AI-3-1. BI-5-1 (.157 g, .35 mmol) was reacted with LiOΗ (.7 ml of a IM solution in Η2O) in 5 ml THF to give the title compound as a light tan solid. MP = 215 - 217 °C lH NMR (400 MHz, CDCI3) δ 5.84 (s, 2H), 7.00 (t, 2H, J = 8.7 Hz), 7.29 - 7.37 (m, 4H), 7.55 (s, IH); FAB MS: m z 405 (M+ + H)
EXAMPLE 98 9/62513
4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid BII-4-1
Step 1: 4-bromo-l-(4-fluorobenzyl)-lH-pyrazole BII-1-1
Figure imgf000166_0001
4-Bromopyrazole (.441 g, 3mmol) was added to a slurry of sodium hydride (.072 g, .12 gr of a 60% oil dispersion, 3 mmol) in 5 ml DMF and stirred for 15 min, after which 4-fluorobenzyl bromide (.568 g, .374 ml, 3 mmol) was added and the reaction was stirred for 18 hr. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate/Η2θ and extracted. The combined organic extracts were washed with H2O, brine, dried over Na2Sθ4, filtered and the solvent removed to afford title compound as a colorless oil. lH NMR (400 MHz, CDCI3) δ 5.23 (s, 2H), 7.04 (t, 2H, J = 8.6 Hz), 7.18 - 7.25 (m, 2H), 7.36 (s, IH), 7.49 (s, IH)
Step 2: l-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]ethanone BII-2-1
Figure imgf000166_0002
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) was added and the mixture allowed to warm to room temperature. After stirring for 2 hr, the reaction was quenched with 10% citric acid solution and extracted with H2O, brine, dried over Na2Sθ4, filtered and the solvent removed. Purification by radial disc chromatography (4:1 hexane/ethyl acetate) the title compound as a colorless oil.
Step 3: 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester BII-3-1
Figure imgf000167_0001
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. lΗ NMR (400 MHz, CDCI3) δ 1.40 (t, 3H, J = 7.14 Hz), 4.38 (q, 2H, J = 7.14 Hz), 5.31 (s, 2H), 6.66 (s, IH), 7.08 (t, 2H, J = 8.61 Hz), 7.24 - 7.31 (m, 2H), 7.94 (2, IH), 8.02 (s, IH)
Step 4: 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric add
BII-4-1
Figure imgf000167_0002
In a similar manner to AI-3-1. BII-3-1 (.17 g, .53 mmol) was reacted in 5 ml MeOH containing 2 ml IM NaOH to give a light tan solid after triturating the crude material with CH2CI2. MP = 191-192 °C
IH NMR (400 MHz, CDCI3) δ 5.31 (s, 2H), 6.71 (d, IH, J = .73 Hz), 7.08
(t, 2H, J = 8.6 Hz), 7.24 - 7.33 (m, 2H), 7.99 (s, IH), 8.03 (s, IH)
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:
EXAMPLE 99 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-3-yl] -2,4-dioxobutyric acid
Figure imgf000168_0001
CΗN Calc. (C16Η16N3O4F 0.5 EtOAc) 57.28, 5.34, 11.14; Fnd. 56.93, 5.01, 11.43.
EXAMPLE 100 4-[l-(4-Fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]-2-hydroxy-4-oxobut-2- enoic acid
Figure imgf000168_0002
CHN Calc. (C15H13N2O4F 0.4 MeOH) 58.33,4.64,8.84; Fnd 57.95, 4.40, 8.44.
EXAMPLE 101 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid BIII-3- 1
Step 1: l-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]ethanone BIII-l-l
Figure imgf000169_0001
l-(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, 6mmol). After stirring for 5 min, 4-fluorobenzyl bromide (.567 g, .374 ml, 3 mmol) was added and the reaction allowed to stir for 2 hr. It was then poured into 10 ml Η2O and extracted with ethyl acetate. The combined organic extracts were washed with H2O, brine, dried over Na2Sθ4, filtered and the solvent removed. Further purification by radial disc chromatography (3:1 hexane/ethyl acetate) yielded the title compound as a colorless oil. lH NMR (400 MHz, CDCI3) δ 2.58 (s, 3H), 5.33 (s, 2H), 6.80 (d, IH, J = 2.4 Hz), 7.05 (t, 2H, J = 8.6 Hz), 7.19 - 7.28 (m, 2H), 7.35 (d, IH, J = 2.4 Hz)
Step 2: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric add ethyl ester BIII-2-1
Figure imgf000169_0002
In a similar manner to AIII-2-1. Bill- 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. lH NMR (400 MHz, CDCI3) δ 1.38 (t, 3H, J = 7.14 Hz), 4.36 (q, 2H, J = 7.14 Hz), 5.36 (s, 2H), 6.90 (d, IH, J = 2.38 Hz), 7.06 (t, 2H, J = 8.61 Hz), 7.22 - 7.28 (m, 3H), 7.40 (d, IH, J = 2.38 Hz)
Step 3: 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid
BIII-3- 1
Figure imgf000170_0001
In a similar manner to AI-3-1. BIII-2-1 (crude from previous reaction) was reacted with IN NaOΗ (3ml) in 20 ml TΗF to yield the title compound as a light tan solid after trituration in diethyl ether. MP = 157 - 159 °C; 1Η NMR (400 MHz, CDCI3) δ 5.35 (s, 2H), 6.90 (d, IH, J = 2.57 Hz), 7.06 (t, 2H, J = 8.61 Hz), 7.22 - 7.31 (m, 3H), 7.42 (d, IH, J = 2.38 Hz) FAB MS: m/z 291 (M+ + H)
EXAMPLE 102 l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4-dioxobutyric add BIV- 3-1 Step 1: l-(3-methyl-lH-pyrazol-4-yl)ethanone BIV-1-1
O
N Η BIV-1-1 A mixture of l-(4-acetyl-5-methylpyrazol-l-yl)ethanone (1 g, 6 mmol, Maybridge) and 10 ml IN NaOH were dissolved in 40 ml THF and stirred 4 days. The solvent was removed in vacuo and the residue partitioned between ethyl acetate/ H2O and extracted. The combined organic extracts were washed with H2O, brine, dried over Na2Sθ4, filtered and the solvent removed to get the title compound. lH NMR (400 MHz, CDCI3) δ 2.43 (s, 3H), 2.60 (s, 3H), 7.96 (s, IH)
Step 2: l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]ethanone BIV-2-1
Figure imgf000171_0001
In a similar manner to Bill- 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 ΗPLC (Chiralcel OD 25x2, 75% hexane/1% diethylamine, 25% EtOΗ) yielded the title compound and 1-[1- (4-fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]ethanone as white solids. lΗ NMR (400 MHz, CDCI3) δ 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, IH)
Step 3: l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester BIV-3-1
Figure imgf000172_0001
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. IH NMR (400 MHz, CDCI3) δ 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, IH), 7.06 (t, 2H, J = 8.61 Hz), 7.21 - 7.32 (m, 2H), 7.89 (s, IH)
Step 4: l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid BIV-4-1
Figure imgf000172_0002
In a similar manner to AI-3-1. BIV-3-1 (.234 g, .68m mmol) was reacted with 2 ml NaOΗ in 10 ml TΗF to afford the title compound as a light tan solid. MP = 187-188 °C; lΗ NMR (400 MHz, CDCI3) δ 2.53 (s, 3H), 5.23 (s, 2H), 6.64 (2, IH), 7.08 (t, 2H, J = 8.61), 7.23 - 7.31 (m, 2H), 7.88 (s, IH)
EXAMPLE 103 4-[3-methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid BV- 4-1 Step 1: l-[l-(3-chlorobenzyl)-3-methyl-lH-pyrazol-4-yl]ethanone BV-
1-1 and l-[l-(3-chlorobenzyl)-5-methyl-lH-pyrazol-4- yl]ethanone BV-2-1
Figure imgf000173_0001
In a similar manner to BIV-2-1. BIV-1-1 (.271 g, 2.2 mmol) was reacted with 3-chlorobenzyl bromide (.493 g, .315 ml, 2.4 mmol) and sodium hydride (.063 g, .105 gr of a 60% oil dispersion, 2.6 mmol) in 5 ml TΗF for 2 hr and purified by preparative ΗPLC (Chiralpak AD 25x2, 75% hexane/1% diethylamine, 25% 2-propanol) to yield the faster eluting 1-[1- (3-chlorobenzyl)-3-methyl-lH-pyrazol-4-yl]ethanone and the slower eluting l-[l-(3-chlorobenzyl)-5-methyl-lH-pyrazol-4-yl]ethanone, both as clear oils. l-[l-(3-chlorobenzyl)-3-methyl-lH-pyrazol-4-yl]ethanone BV-1-1: lΗ NMR (400 MHz, CDCI3) δ 2.38 (s, 3H), 2.49 (s, 3H), 5.21 (s, 2H), 7.12 (dt, IH, J = 6.2, 2.2, 1.6 Hz), 7.22 (s, IH), 7.31 - 7.34 (m, 2H), 7.78 (s, IH) l-[l-(3-chlorobenzyl)-5-methyl-lH-pyrazol-4-yl]ethanone BV-2-1: lΗ NMR (400 MHz, CDCI3) δ 2.45 (s, 3H), 2.52 (s, 3H), 5.28 (s, 2H), 6.87 - 7.02 (m, IH), 7.10 (s, IH), 7.22 - 7.30 (m, 2H), 7.90 (s, IH)
Step 2: 4-[3-methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric add ethyl ester BV-3-1
Figure imgf000174_0001
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. lH NMR (400 MHz, CDCI3) δ 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, IH), 7.11 - 7.18 (m, IH), 7.23 (s, IH), 7.29 - 7.35 (m, 2H), 7.93 (s, IH)
Step 3: 4-[3 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric add BV-4-1
Figure imgf000174_0002
In a similar manner to AI-3-1. 4-[3 -methyl-l-(3-chlorobenzyl)-lH- pyrazol-4-yl]-2,4-dioxobutyric add ethyl ester (crude from above) was reacted with 5 ml IN NaOΗ in 20 ml methanol for two hours to give the title compound as a light tan solid. MP = 183 - 184 °C. lΗ NMR (400 MHz, CDCI3) δ 2.54 (s, 3H), 5.23 (s, 2H), 6.67 (s, IH), 7.12 - 7.18 (m, IH), 7.25 (s, IH), 7.31 - 7.36 (m, 2H), 7.97 (2, IH)
EXAMPLE 104 4-[5 -methyl- l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric add Step 1: 4-[5 -methyl- l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester BV-5-1
Figure imgf000175_0001
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. lΗ NMR (400 MHz, CDCI3) δ 1.40 (t, 3H, J = 7.14 Hz), 2.58 (s, 3H), 4.38 (q, 2H, J = 7.14 Hz), 5.31 (s, 2H), 6.75 (s, IH), 6.98 - 7.04 (m, IH), 7.12 (s, IH), 7.25 - 7.31 (m, 2H), 7.99 (s, IH)
Step 2: 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric add BV-6-1
Figure imgf000175_0002
In a similar manner to AI-3-1. BV-5-1 (crude from above) was reacted with 2 ml IN NaOΗ in 10 ml methanol for two hours to give the title compound as a white solid after ether trituration. MP(uncorrected)168 169 °C lΗ NMR (400 MHz, CDCI3) δ 2.53 (s, 3H), 5.23 (2, 2H), 6.67 (s, IH), 7.12 - 7.18 (m, IH), 7.25 (s, IH), 7.31 - 7.36 (m, 2H), 7.97 (s, IH) EXAMPLE 105 4-[l-(4-fluoro-benzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid CI-6-1 Step 1: l-(4-fluoro-benzyl)-lH-imidazole CI-1-1
Figure imgf000176_0001
To a solution of imidazole (lOg, 0.146 mole) in 80 ml of DMF at 0°C was added triethylamine ( 25.5 ml, 0.176 mole) followed by a solution of 4- Fluorobenzylbromide ( 22 ml, 0.176 mole) in 30ml of DMF added dropwise via addition funnel. The ice bath was removed and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure in vacuo. The residue was partitioned with H2O and CH2CI2. The organic layer was washed with saturated NaHC03, brine, dried over MgSθ4, 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. lH
NMR (400 MHz, CDCI3) δ 7.53 (s, IH), 7.09-7.15 (m, 5H), 6.88 (s, IH), 5.09 (s, 2H).
Step 2: l-(4-fluorobenzyl)-lH-imidazole-2-carboxylic lithium salt CI-
2-1
Figure imgf000176_0002
A solution of CI-1-1 (8.8 lg, O.Oδmole) in 120 ml dried THF at -78°C under N2 was added a solution of 2.5M nBuLi in Hexanes (21ml, .052 mole) dropwise via syringe over 40 minutes. This resulting mixture was aged 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 Cl -2-1 as a solid salt. lH NMR (400 MHz, DMSO-dβ) δ 7.34 (t, 2H), 7.22 (s, IH), 7.11 (t, 2H), 6.83 (s, IH), 5.74 (s, 2H).
Step 3: l-(4-fluorobenzyl)-lH-imidazole-2-carboxylic add methoxy- methyl-amide CI-3-1
Figure imgf000177_0001
A solution of CI -2-1 (7.0g, .031 mole) was treated with EDC.HC1 (6.5g, .034 mole), HOBT.H2O (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 vacuo. The residue was partitioned with saturated NaHCθ3 and extracted three times with EtOAc. Combined organics layers were washed with H2O and brine, dried over MgSθ4, filtered and evaporated to afford a yellow oil. This crude material was chromatographed on silica gel using 70-100% EtO Ac/Hex as eluant. Obtained Cl- 3-1 as an oil. lH NMR (400 MHz, CDCI3) δ 7.19- 7.23 (m, 2H), 7.09 (s, IH), 6.97-7.04 (m, 3H), 5.42 (s, 2H), 3.81 (s, 3H), 3.48 (s, 3H)
Step 4: l-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]ethanone CI-4-1
Figure imgf000178_0001
A solution of CI -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 Et2θ dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to 0°C for 2 hours. The reaction was quenched with 75ml of saturated NH4CI solution and extracted with three times EtOAc. Combined organics layers were washed with brine, dried over MgSθ4, filtered and evaporated to give an oil. This crude material was chromatographed on silica gel using 70% EtOAc/Hex as eluant. Obtained Cl- 4-1 as an oil. lH NMR (400 MHz, CDCI3) δ 7.16-7.20 (m , 3H), 7.06 (s, IH), 6.99-7.04 (t, 2H), 5.58 (s, 2H), 2.66 (s, 3H).
Step 5: 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric add ethyl ester CI-5-1
Figure imgf000178_0002
A solution of Cl- 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 MgSθ4, filtered and evaporated to give a crude residue. This crude material was chromatographed on silica gel using 50% EtOAc Hex as eluant. Obtained Cl- 5-1 as a beige solid. lH NMR (400 MHz, CDCI3) δ 7.19-7.23 (m, 3H), 7.13 (s, IH), 7.01 (t, 2H), 5.69 (s, 2H), 4.33-4.37 (q, 2H), 1.36 (t, 3H)
Step 6: 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric add
CI-6-1
Figure imgf000179_0001
A solution of Cl- 5-1 (0.3 g, 0.0009 mole) was dissolved in 7ml of CH3OH, 7 ml of THF and 3ml of IN NaOH and stirred for 3 hours. The reaction mixture was washed with ether and addified to pH 1-2 with IN HCl and extracted three times with EtOAc. The combined extracts were washed with brine, dried over MgSθ4, filtered and evaporated to give a crystalline solid, that was stirred in hot EtOAc and filtered to obtained Cl- 6-1 as a light beige solid. m.p.: 163-164°C. lH NMR (400 MHz, CDCI3) δ 7.20 (m, 3H), 7.13 (s, IH), 7.01 (t, 3H), 5.69 (s, 2H).
EXAMPLE 106 In a manner similar to that described for CI-6-1. the following compound was prepared:. 4-(l-Benzyl-lH-imidazol-2-yl)-2,4-dioxobutyric add
Figure imgf000179_0002
CΗN Calc. 61.76, 4.44, 10.29; Fnd. 61.80, 4.58, 10.17
EXAMPLE 107 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid CII-4-1 Step 1: l-(4-fluorobenzyl)-lH-imidazole-4-carboxylic acid 4-fluorobenzyl ester CII- 1- la; and
3-(4-fluorobenzyl)-3H-imidazole-4-carboxylic add 4-fluorobenzyl ester CII- 1-lb
Figure imgf000180_0001
A suspension of lH-imidazole-4-carboxylic acid (l.Og, 0.0089 mole) in 25 ml of DMF was treated with CS2CO3 (8.72g, .026 mole) followed by 4- fluorobenzyl bromide (3.33 ml, .026 mole) and stirred overnight at room temperature under N2 atmosphere. DMF was removed under reduced pressure in vacuo. The residue was partitioned with H2O and three times with EtOAc. Combined extracts were washed with brine, dried over MgSθ4)? filtered and evaporated to give a crude oil. This material was chromatographed on silica gel with 50% EtOAc/Hex as eluant to afford a 1 : 1 mixture of Cl I-l-la and Cl I- 1-lb . lH NMR (400 MHz, CDCI3) δ 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: l-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-ethanone CII-2-1
Figure imgf000180_0002
A solution of CI I- 1-1 (0.9g, .0027 mole) in 10 ml dried THF at -78°C was treated with a solution of 1.4M CH3Li (2.35 ml, .0032mole) in Et2θ dropwise via syringe under N2 atmosphere. The ice bath was removed after addition was completed and the reaction was warmed to room temperature over the weekend. The reaction was quenched with 10ml of IN HCl. The solution was basified with saturated NaHCθ3 and extracted with EtOAc three times. Combined organics layers were washed with brine, dried over MgSθ4, filtered and evaporated to give Cl 1-2-1 as a crystalline solid. lH NMR (400 MHz, CDCI3) δ 7.53 (d, 2H), 7.15 (m, 2H), 7.04 (m, 2H), 5.1 (s, 2H), 2.5 (s, 3H).
Step 3: 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester CII-3-1
Figure imgf000181_0001
A solution of Cl 1-2-1 (75 mg, 0.34 mmole) in 3ml dried THF was treated with diethyl oxalate (0.092 ml, 0.68 mmole) and sodium ethoxide (47 mg, 0.68 mmole) at room temperature over night under N2 atmosphere. The reaction mixture was poured into 10 ml of IN HCl solution and extracted twice with EtOAc. The combined extracts were washed with brine and dried over MgS04, filtered and evaporated to give Cl 1-3-1 as a bright yellow oil. Used as is without further purification. lH NMR (400 MHz, CDCI3) δ 7.78 (s, IH), 7.69 (s, IH), 7.22 (m, 2H), 7.10 (m, 3H), 5.19 (m, 2H), 4.35 (m, 2H), 1.4(m, 3H).
Step 4: 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric add
CII-4-1
Figure imgf000182_0001
A solution of CI I-3-1 (70 mg, 0.2 mmole) was dissolved in 3ml of CH3OH and 3ml of IN NaOH for 3 hours. The reaction mixture was washed with ether, acidified to pH 1-2 with IN HCl 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% Et2θ/Ηex to afford Cl 1-4-1 as a yellow crystalline solid. IH NMR (400 MHz, CDCI3) δ 8.24 (s, IH), 8.07 (s, IH), 7.44 (m, 2H),
7.19 (m, 2H), 6.92 (s, IH), 5.28 (s, 2H).
EXAMPLE 108 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric add DI-4-1 Step 1: 1-(1H -indol-2-yl)ethanone DI-1-1
Figure imgf000182_0002
A solution of 2-carboxy indole (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 predpitated. After addition was complete the reaction was warmed to reflux for two hours, quenched by pouring into ice water, and extracted with Et2θ. The organic layers were combined, washed with saturated sodium bicarbonate solution and brine, dried over MgSθ4, filtered and evaporated to give DI-1-1 as a white solid. Rf=0.53 (20% EtOAc/Ηexanes) lΗ NMR (400 MHz, CDCI3) δ 9.1 (bs, lh), 7.72 (d, J= 7.78 Hz, IH), 7.42 (d, J= 8.4 Hz, IH), 7.36 (m, IH), 7.2 (m, IH), 7.15 (m, IH), 2.6 (s, 3H).
Step 2: l-[l-(4-fluorobenzyl)- IH -indol -2-yl]ethanone DI-2-1
Figure imgf000183_0001
In a manner similar to that described for the preparation of AI-1-1. DI- 1-1 was treated with 4-fluorobenzyl bromide to give DI-2-1 as a yellow oil. Rf=0.67 (20% EtOAc/Ηexanes) lΗ NMR (400 MHz, CDCI3) δ 7.73(d, J = 8.06 Hz, IH), 7.36 (m, 3H), 7.18 (m, IH), 7.02 (m, 2H), 6.9 ( m, 2H), 5.8 (s, 2H), 2.6 (s, 3H).
Step 3: 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric add
Figure imgf000183_0002
In a manner similar to that described for the preparation of AI-2-1. DI- 2-1 was treated with dimethyl oxalate and sodium hydride to give DI-3-1 as a yellow solid. Rf=0.26 (97:3:1 CHCI3 / MeOH / HOAc). lH NMR (400 MHz, CDCI3) d 7.75 (d, J = 8.05 Hz, IH), 7.52 (s, IH), 7.38 (m, 2H), 7.2 (m, IH), 7.09 (s, IH), 7.05 (m, 2H), 6.95 (m, 2H), 3.95 (s, 3H).
Step 4: 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric add
DI-4-1
Figure imgf000184_0001
In a manner similar to that described for the preparation of A-I-3-1. D- 1-3-1 was treated with sodium hydroxide to give DI-4-1 as bright yellow crystals after crystallization from EtOAc. lH NMR (400 MHz, DMSO- D6) δ 7.90 (s, IH), 7.77 (d, J= 7.88 Hz, IH), 7.62 (d, J = 8.42 Hz, IH), 7.4 (m, IH), 7.2 (m, IH), 7.1 (m, 5H), 5.9 (s, 2H). mass spec (FAB, M+1) 340.03.
EXAMPLE 109 The following compound was prepared in a manner similar to that described for DI-4-1:
2-hydroxy-4-(l-methyl-l-H -indol-2-yl) -2,4-dioxobutyric acid
Figure imgf000184_0002
CHN Calc(Ci3HnN040.15 H2O) 62.97, 4.59, 5.65; Fnd. 63.05, 4.45, 5.80.
EXAMPLE 110 4-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric add DII-3-1 Step 1: l-[l-(4-fluorobenzyl)-lH-indol-3-yl]ethanone DII- 1-1
Figure imgf000185_0001
In a similar manner to Bill- 1-1. 3-acetylindole (.318 g, 2 mmol) was treated with 4-fluorobenzyl bromide (.378 g, .244 ml, 2 mmol) and sodium hydride (.048 g, .08 gr of a 60% oil dispersion, 2 mmol) in 2 ml DMF for one hour to give the title compound as a white solid. lH NMR (400 MHz, CDCI3) δ 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, IH), 8.39 (d, IH, J = 7.5 Hz)
Step 2: l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric add ethyl ester DII-2-1
Figure imgf000185_0002
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. IH NMR (400 MHz, CDCI3) δ 1.41 (t, 3H, J = 7.14 Hz), 4.39 (q, 2H, J = 7.14 Hz), 5.35 (s, 2H), 6.83 (s, IH), 7.05 (t, 2H, J = 8.6 Hz), 7.13 - 7.20 (m, 2H), 7.30 - 7.39 (m, 3H), 7.88 (s, IH), 8.40 (d, IH, J = 7.51 Hz)
Step 3: l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid DII-
3-1
Figure imgf000186_0001
In a similar manner to AI-3-1. DII-2-1 (.1 g, .27 mmol) was hydrolyzed using .54 ml IM LiOΗ (5.4 mmol) in 2 ml TΗF to give the title compound as a yellow solid. MP = 161 - 162 °C. lΗ NMR (400 MHz, CDCI3) δ 5.36 (s, 2H), 6.92 (s, IH), 7.07 (t, 2H, J = 8.61 Hz), 7.15 - 7.23 (m, 2H), 7.31 - 7.39 (m, 3H), 7.95 (s, IH), 8.30 (d, IH, J = 6.59 Hz)
EXAMPLE 111
HITV 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, CM. 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 ICδO's less than 1 micromolar. Further, representative compounds tested in the preintegration complex assay also demonstrated IC50's of less than 1 micromolar.
EXAMPLE 112 Assay for inhibition of HIV replication
Assays for the inhibition of acute HIV infection of 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 IC95S of less than 10 micromolar.
EXAMPLE 113 Oral Composition As a specific embodiment of an oral composition of a compound of this invention, 50 mg of a compound of the present invention is formatted with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the foregoing spedfication 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

WHAT IS CLAIMED:
1. A compound of structural formula (I):
Figure imgf000188_0001
(I) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen
1 2 8 atoms and substituted on carbon or nitrogen by R , R and R ; the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen- containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
R is selected from:
(1) -H,
(2) -C^ alkyl,
(3) -CF3,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5),
(7) -R6,
(8) -C2.5 alkenyl-R ,
(9) -C2_5 alkynyl-R ,
(10) -0-R6,
(11) -O-Ci-6 alkyl, and
(12) -C(0)CH2C(0)C(0)OR7;
R is selected from:
(1) -H,
(2) -R3, (3) -C^g alkyl,
3
(4) -C-^ alkyl substituted with R
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C1-6 alkyl (OR6)(R4) ,
(9) -C^g alkyl-N(R4)(R6) ,
(10) -C╬╣ fi alkyl S(0)n-R6,
(11) -C^g alkyl C(0)-R6, (12) -C1 alkyl C(S)-R6,
(13) -C-..Q alkyl NR4C(0)-R6, and
(14) -C╬╗.6 alkyl-C(0)N(R4)(R5);
3 each R 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) C^g alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCF3, is) -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) C1 alkyl, (c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, 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) Cl alkyloxy-,
(e) -CFg,
(f) -OCFg,
(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) -C-^g alkyloxy-,
(d) -CF3,
(e) -OCFg,
(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-^g alkyl,
(c) C^g alkyloxy-,
(d) -CF3,
(e) "OCFg,
(f) -CN,
(g) =0, 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) C-L.6 alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg, (f) -CN,
(g) =0, and (h) hydroxy; 4 each R is independently selected from:
(1) -H,
(2) -C-L.3 alkyl,
(3) "CFg,
(4) -R3,
(5) -C2.g alkenyl,
(6) -C^g alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently select.
(1) -H,
(2) -C-L.3 alkyl,
(3) "CFg,
(4) -R3,
(5) -C2.g alkenyl,
(6) -C^g alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently select<
(1) -Ci g alkyl-R , and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) Cl-6 alkyl; R8 is selected from:
(1) -H,
(2) Cl-6 alkyl-oxy, and
(3) Ci-6 alkyl; and
each n is independently selected from 0, 1 and 2.
2. The compound according to Claim 1, and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is selected from:
(1) pyrrolyl,
(2) imidazolyl, (3) pyrazoiyl, and
(4) indolyl, provided that the nitrogen- containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I); R is selected from: (1) -H,
(2) -CH3,
(3) -CFg,
(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) C^g alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (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,
(9) phenyl C1.3 alkyl-,
(10) substituted phenyl C^.g alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(c) C 6 alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) CI_Q alkyl,
(iii) -CF3, and
(iv) hydroxy,
(11) "C2-5 alkenyl-R , g
(12) _C2-5 alkynyl-R , and
(13) -C(0)CH2C(0)C(0)OR7;
selected from:
(1) -H, (2) -R3,
(3) -Ci.6 alkyl, g
(4) -C╬╣_g alkyl substituted with R ,
(5) -O-R6, (6) -0-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -C1 alkyl-N(R4)(R6) ,
(10) -C^g alkyl S(0)n-R6, (11) -C1 alkyl C(0)-R6,
(12) -C-L.g alkyl C(S)-R6,
(13) -C^g alkyl NR4C(0)-R6, and
(14) -C^g alkyl-C(0)N(R4)(R5); g each R is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, (b) C1 alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen,
(ii) C1 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) C^g alkyl,
(c) Cl alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 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) Cl alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and (j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C1 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) Ci_g alkyl,
(c) C1.6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cj.g 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) C╬╣_g alkyl,
(c) C-^g alkyloxy-,
(d) phenyl,
(e) "CFg,
Figure imgf000197_0001
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(11) pyrazoiyl;
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C╬╣_6 alkyl,
(c) C1.6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C -6 alky
(c) Cj. alkyloxy-, (d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, 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^g alkyl,
(c) C^g alkyloxy-,
(d) -CF3,
(e) "OCFg,
(f) -CN,
(g) =0, 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) C-^g alkyl,
(c) C^g alkyloxy-,
(d) "CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) -halogen,
(b) -C-L.g alkyl, (c) -C-L.6 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(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) -Cl alkyl,
(c) -C-L.g alkyloxy-,
(d) "CFg,
(e) "OCFg,
(f -CN, and
(g) -hydroxy;
(23) Cg-6 cycloalkyl fused with a phenyl ring;
(24) substituted C .fi cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: (a) halogen,
(b) C^Q alkyl,
(c) Cl alkyloxy-,
(d) "CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
4
. is independently selected
(1) -H,
(2) -C^g alkyl, and
(3) -CF3: > each R is independently selected from:
-Γûán ,
(2) -C-L.3 alkyl,
(3) -CFg,
(4) -R3,
(5) -C2_3 alkenyl,
(6) -Ci-3 alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from: (1) -C-L.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) pyrazoiyl, and (4) indolyl, provided that the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric moiety in structural formula (I);
R is selected from:
(1) -H,
(2) -CHg,
(3) "CFg,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) ssuubbssttiittuutteedd phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo, (b) methyl, and
(c) methoxy,
(9) phenyl C^g alkyl-,
(10) substituted phenyl C^. alkyl- substituted with 1 or 2 substituents independently selected from: (a) halo,
(b) methyl, and
(c) methoxy, g
(11) -C2_5 alkenyl-R , and
(12) -C(0)CH2C(0)C(0)0R7.
R is selected from:
(1) -H,
(2) -R3,
(3) -C╬╣.( alkyl, (4) -C^g alkyl substituted with R3,
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6, (8) -C^e alkyl (OR6)(R4) ,
(9) -C^g alkyl-N(R4)(R6) ,
(10) -ClJ6 alkyl S(0)n-R6,
(11) -C^g alkyl NR4C(0)-R6, and (12) -C1 alkyl-C(0)N(R4)(R5); g each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(c) C^ alkyloxy-,
(d) phenyl, (e) -CF3,
(f) -OCFg,
(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,
(3) thienyl,
(4) pyridyl,
(5) imidazolyl,
(6) pyrrolyl, (7) pyrazoiyl,
(8) C3.6 cycloalkyl, (9) substituted C3_g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C^g alkyl, (c) C^g alkyloxy-,
(d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0, and (h) hydroxy;
(10) piperidinyl,
(11) morpholinyl,
(12) naphthyl,
(13) indolyl, and (14) Cg.g cycloalkyl fused with a phenyl ring;
4 each R is independently selected from:
(1) -H,
(2) -C^g alkyl, and (3) -CF3;
5 each R is independently selected from:
(1) -H,
(2) -C^g alkyl, (3) -CFg, and
(4) -R3, : each R is independently selected from: (1) -C^g 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:
Figure imgf000205_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R is selected from:
(1) -H,
(2) -C .5 alkyl
(3) -CFg,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5)
(7) -phenyl,
(8) ssuubbssttiittuutteedd phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and (c) methoxy,
(9) phenyl C^g alkyl-,
(10) substituted phenyl C^g 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(0)CH2C(0)C(0)OR7
2 R is selected from:
(1) -H,
(2) -R3,
(3) -C^g alkyl, (4) -C-L.6 alkyl substituted with R3,
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) , (9) -C-L.6 alkyl-N(R4)(R6) ,
(10) -C^g alkyl S(0)n-R6,
(11) -C^g alkyl C(0)-R6,
(12) -C1 alkyl C(S)-R6,
(13) -C^g alkyl NR4C(0)-R6, and (14) -C1 alkyl-C(0)N(R4)(R5); g each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(c) C╬╗_6 alkyloxy-,
(d) phenyl, (e) -CF3,
(f) -OCFg,
(g) -CN, (h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 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) C-L.6 alkyl,
(c) C-L.6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Ci_Q 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) C1J6 alkyl,
(c) C-^ alkyloxy-,
(d) phenyl, (e) "CFg,
(f) "OCFg,
(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,
(7) imidazolyl,
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C-^g alkyl,
(c) C^ 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) C^g 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) C^g alkyl,
(c) C1 alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) "OCFg,
(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,
(11) pyrazoiyl,
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(c) C-L. alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) -OCFg,
(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, (13) Cg-6 cycloalkyl,
(14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C-^g alkyl,
(c) Cj.g alkyloxy-,
(d) -CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy,
(15) piperidinyl,
(16) substituted piperidinyl substituted on a carbon atom with one i or two substituents independently selected from:
(a) halogen,
(b) Cj.g alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, 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) C╬╣_g alkyl,
(c) C^ alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and (h) hydroxy,
(19) naphthyl,
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from: (a) halogen,
(b) Cl alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg, (f) -CN,
(g) =0, and (h) hydroxy,
(21) indolyl,
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) Cl alkyl,
(c) C^g alkyloxy-,
(d) -CFg, (e) -OCFg,
(f) -CN,
(g) =0, and (h) hydroxy,
(23) C3.g cycloalkyl fused with a phenyl ring, (24) substituted Cg.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) Ci.6 alkyl, (c) C 6 alkyloxy-,
(d) -CFg,
(e) -OCFg, (f) -CN,
(g) =0, and (h) hydroxy;
each R is independently selected from:
(1) -H,
(2) -C^g alkyl,
(3) -CF3,
(4) -R3, (5) -C2_g alkenyl,
(6) -C^g alkyl-R3,
(7) -C2_g alkenyl-R3,
(8) -S(0)n-R3, and
(9) -C(0)-RL
each R is independently selected from:
(1) -H,
(2) -C-L.3 alkyl,
(3) -CFg,
(4) -R3,
(5) -C2.3 alkenyl,
(6) -C^g alkyl-R3,
(7) -C2_3 alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from:
(1) -C╬╗_3 alkyl-R3, and
(2) -R3;
R7 is selected from: (1) -H, and
(2) Cl-6 alkyl;
R8 is selected from: (1) -H, and
(2) Cl-6 alkyl; and
each n is independently selected from 0, 1 and 2.
5. The compound according to Claim 4 of structural formula:
Figure imgf000213_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R is selected from:
(1) -H,
(2) -C-L.5 alkyl,
(3) "CFg,
(4) -halo,
(5) -N02,
(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 C^g alkyl-, (10) substituted phenyl C-j^ alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy,
(ID -C2.g alkenyl-R , and
(12) -C(0)CH2C(0)C(0)OR7;
R is selected from:
(1) -H,
(2) -R3,
(3) -C1.g alkyl,
3
(4) -C^.g alkyl substituted with R ,
(5) -O-R6,
(6) -O-Ci.6 alkyl-OR6,
(7) -C1 alkyl (OR6)(R4) ,
(8) -C^g alkyl-N(R4)(R6) ,
(9) -C^g alkyl C(0)-R6,
(10) -Cχ.6 alkyl NR4C(0)-R6, and
(11) -C^g alkyl-C(0)N(R4XR5);
each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (g) -CN, (h) hydroxy, (i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C╬╗.2 alkyl,
(iii) -CF3, and
(iv) hydroxy; (3) thienyl,
(4) pyridyl,
(5) imidazolyl,
(6) pyrrolyl,
(7) pyrazoiyl, (8) C3.6 cycloalkyl,
(10) piperidinyl,
(11) morpholinyl,
(12) substituted morpholinyl substituted with a substituent selected from: (a) halogen,
(b) .6 alkyl,
(c) C^g alkyloxy-,
(d) -CF3,
(e) -OCFg, (f) -CN,
(g) =0,
(h) hydroxy;
(12) naphthyl,
(13) indolyl, and (14) Cg_6 cycloalkyl fused with a phenyl ring;
4 each R is independently selected from:
(1) -H, (2) -C^g alkyl,
(3) -CF 3'
(4) -R"
(5) -C-L.3 alkyl-R ,3
(6) -S(0)n-R3, and
(7) -C(0)-R3;
5 each R is independently selected from:
(1) -H,
(2) -C-t.g alkyl,
(3) -CFg,
(4) -R3,
(5) -Cj.3 alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3;
each R is independently selected from:
(1) -C-L.3 alkyl-R3, and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) Ci-4 alkyl;
R8 is selected from:
(1) -H, and
(2) -CH3; and
each n is independently selected from 0, 1 and 2.
6. The compound according to Claim 5 of structural formula:
Figure imgf000217_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R is selected from: (1) -H,
(2) -C^ alkyl,
(3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02, (6) -N(R4)(R5),
(7) -phenyl,
(8) phenyl C^g alkyl-,
(9) substituted phenyl C^.g 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(0)CH2C(0)C(0)OR7.
.2 R is selected from:
(1) -H,
(2) -R3,
(3) -C-^ alkyl, g
(4) -C╬╣_6 alkyl substituted with R ,
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -C1 alkyl (OR6)(R4) ,
(8) -Cχ.6 alkyl-N(R4)(R6) , (9) -C^g alkyl C(0)-R , and
(10) -C^g alkyl NR4C(0)-R6;
each R is independently selected from:
(1) pher ╬╣yi;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) Ci-6 alkyl,
(c) Cl alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) "OCFg,
(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) Cg_6 cycloalkyl, (4) morpholinyl,
(5) substituted morpholinyl substituted with oxo; and
(6) naphthyl;
4 each R is independently selected from: (1) -H, and
(2) -C^g alkyl, 5 each R is independently selected from:
(1) -H,
(2) -Ci.3 alkyl,
(3) -CFg, (4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3;
each R is independently select*
(1) -C]_ 3 alkyl-R , 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:
Figure imgf000219_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R1 is selected from:
(1) -H,
(2) -C-L.5 alkyl, (3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02,
(6) -N(R4)(R5), (7) -phenyl,
(8) phenyl C-^.g alkyl-,
(9) substituted phenyl C-^.g 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-R ;
2 R is selected from:
(1) -H,
(2) -R3,
(3) -C-L.g alkyl, g
(4) -C-j__6 alkyl substituted with R ,
(5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C^g alkyl-N(R4)(R6) ,
(9) -Ci.g alkyl C(0)-R6, and
(10) -C1 alkyl NR4C(0)-R6;
each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) Cl alkyl,
(c) C^g alkyloxy-,
(d) phenyl, (e) -CF3,
(f) -OCFg,
(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) Cg.6 cycloalkyl,
(4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and
(6) naphthyl;
4 each R is independently selected from:
(1) -H, and (2) -Ci.3 alkyl;
each R is independently selected from:
(1) -H,
(2) -C^g alkyl,
(3) "CFg, (4) -R3,
(5) -C^g alkyl-Rd,
(6) -S(0)n-R3, and
(7) -C(0)-R3; g each R is independently selected from:
(1) -C^g 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:
Figure imgf000222_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from:
(1) -H,
(2) -C-,_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 C^g alkyl-,
(9) substituted phenyl C^.g 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-R ;
2 R is selected from:
(1) -H,
(2) -R3,
(3) -C-L.g alkyl,
(4) -C╬╣_6 alkyl substi
(5) -O-R6, (6) -O-Cj.6 alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C1 alkyl-N(R4)(R6) ,
(9) -C- g alkyl C(0)-R6, and
(10) -C^g alkyl NR4C(0)-R6;
each R is independently selected from:
(1) pher ╬╣yi,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C-^g alkyl,
(c) Cx.g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(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;
4 each R is independently selected from: (1) -H, and (2) '1-3 alkyl;
5 each R is independently selected from:
(1) -H,
(2) -C-L.3 alkyl,
(3) -CFg,
(4) -R3,
(5) -Cj.3 alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3;
each R is independently selected from: (1) -Cj-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:
Figure imgf000224_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from:
(1) -H,
(2) -Cχ.5 alkyl,
(3) -CFg,
(4) -halo, (5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) substituted phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo,
Ob) methyl, and
(c) methoxy,
(9) phenyl C-^. alkyl-,
(10) substituted phenyl Cj.g alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
Oo) methyl, and
(c) methoxy,
(11) -C2.g alkenyl-R ,
(12) -C2.g alkynyl-R , and
(13) -C(0)CH2C(0)C(0)OR7;
elected from:
(1) -H,
(2) -R3,
(3) -C-L.g alkyl, g
(4) -C]__╬▓ alkyl substituted with R
(5) -O-R6,
(6) - -C^Q alkyl-OR6,
(7) -S(0)n-R6,
(8) -Cχ.6 alkyl (OR6)(R4) ,
(9) -C1 alkyl-N(R4)(R6) ,
(10) -C1 alkyl S(0)n-R6,
(11) -Cχ.6 alkyl C(0)-R6,
(12) -C^g alkyl C(S)-R6,
(13) -C╬╣ fi alkyl NR4C(0)-R6, and (14) -C^g alkyl-C(0)N(R4)(R5);
each R is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C-^ alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 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) C^g alkyl,
(0 C^g alkyloxy-,
(d) phenyl,
(e) -CFg,
( ) "OCFg,
(g) -CN,
(h) hydroxy, (i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Ci.g 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) Ci-6 alkyl,
(c) C1 alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(7) imi( iazolyl;
(8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) Ci-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) -CF 3' (f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cl 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,
Ob) Cj.g alkyl,
(0 C1.g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) "OCFg,
(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;
(11) pyrazoiyl;
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C1 alkyl, (c) Cj.g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C╬╗_6 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted Cg_g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) "OCFg,
(f) -CN,
(g) =0, 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 alkyl,
(0 C^g alkyloxy-,
(d) -CFg,
Figure imgf000229_0001
(f) -CN,
(g) =0, and (h) hydroxy;
(17) mo╬╖ pholinyl;
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C1 alkyloxy-,
(d) -CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-,
(d) -CF3,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) ClJ╬▓ alkyl,
(0 C1.g alkyloxy-,
(d) -CF3,
(e) "OCFg, (f) -CN,
(g) =0, and (h) hydroxy;
(23) Cg.g cycloalkyl fused with a phenyl ring; (24) substituted Cg.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) Cw alkyl, (c) C-╬╣_g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and (h) hydroxy;
4 each R is independently selected from:
(1) -H,
(2) -C^g alkyl, (3) -CF3,
(4) -R3,
(5) -C2_3 alkenyl,
(6) -C1-╬╕ alkyl-R3,
(7) -C2_g alkenyl-R3, (8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from: (1) -H, (2) -C^g alkyl,
(3) -CFg,
(4) -R3, (5) -C2_3 alkenyl,
(6) -Cj.3 alkyl-R3,
(7) -C2_g alkenyl-R3,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from:
(1) -C^g alkyl-R3, and
(2) -R3;
R7 is selected from:
(1) -H, and
(2) Ci-6 alkyl;
R8 is selected from:
(1) -H, and
(2) Ci-6 alkyl; and
each n is independently selected from 0, 1 and 2.
10. The compound according to Claim 9 of structural formula:
Figure imgf000232_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein:
R is selected from:
(1) -H,
(2) -Cχ_5 alkyl, (3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I;
(5) -N02,
(6) -N(R4)(R5), (7) -phenyl,
(8) phenyl C^g alkyl-,
(9) substituted phenyl C-^.g 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-R ;
R is selected from:
(1) -H,
(2) -R3,
(3) -C1 alkyl, g
(4) -C]__g alkyl substituted with R ,
(5) -O-R6,
(6) -0-Ci.g alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C1 alkyl-N(R4)(R6) ,
(9) -C-^g alkyl C(0)-R6, and
(10) -C1 alkyl NR4C(0)-R6;
each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or selected from: (a) halogen, (b) C^g alkyl,
(c) C1 alkyloxy-,
(d) phenyl, (e) -CFg,
(f) -OCFg,
(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) Cg_6 cycloalkyl,
(4) morpholinyl, (5) substituted morpholinyl substituted with oxo; and
(6) naphthyl;
4 each R is independently selected from:
(1) -H, and (2) -C^g alkyl;
each R is independently selected from:
(1) -H,
(2) -Cχ.3 alkyl,
(3) -CF 3' (4) -R"
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3;
each R is independently selected from: (1) -Cj-g alkyl-R3, and (2) -ΕC
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:
Figure imgf000235_0001
(I) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is pyrazoiyl;
, is selected from:
(1) -H,
(2) -C-L.5 alkyl,
(3) "CFg,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) ssuubbssttiittuutteedd phenyl substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy, (9) phenyl C-^g alkyl-, (10) substituted phenyl C-^. 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(0)CH2C(0)C(0)OR7;
R is selected from:
Figure imgf000236_0001
(3) -C1 alkyl, g
(4) -C^.g alkyl substituted with R , (5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C1 alkyl (OR6)(R4) ,
(9) -C^g alkyl-N(R4)(R6) , (10) -Cl alkyl S(0)n-R6,
(11) -Cl alkyl C(0)-R6,
(12) -Cl alkyl C(S)-R6,
(13) -Cl alkyl NR4 C(0)-R6 , and
(14) -C^g alkyl-C(0)N(R4)(R5); g each R is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from: (a) halogen,
(b) C1 alkyl,
(c) C-L.g alkyloxy-, (d) phenyl,
(e) "CFg,
(f) "OCFg,
(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;
(3) thienyl;
(4) substituted thienyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CFg,
( ) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 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) Ci_6 alkyl,
(c) Cl alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cχ.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) C^e alkyl,
(c) C-L.6 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg, (g) -CN,
(h) hydroxy, (i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen,
(ii) Cχ.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) ClJ╬▓ alkyl,
(c) Cl alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 alkyl,
(iii) -CF3, and
(iv) hydroxy;
(ID pyrazoiyl;
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
G) substituted phenyloxy with 1, 2, or 3 substituents selected from: (i) halogen, (ii) C^g alkyl, (iii) -CF3, and (iv) hydroxy;
(13) C3_6 cycloalkyl;
(14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) Cj.g alkyl,
(c) C1 alkyloxy-,
(d) "CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(15) piperidinyl;
(16) substituted piperidinyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
Ob) C1.6 alkyl,
(c) C╬╗_6 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(17) mor pholinyl;
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C-^ alkyloxy-,
(d) -CFg, (e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C-..6 alkyl,
(c) C1 alkyloxy-,
(d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0, 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 alkyl,
(0 Cj.6 alkyloxy-,
(d) "CFg,
(e) "OCFg, ω -CN,
(g) =0, and
(h) hydroxy;
(23) C3-6 cycloalkyl fused with a phenyl ring;
(24) substituted C .fi 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) C- 6 alkyloxy-,
(d) "CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
,4 each R is independently selected from: (1) -H, (2) -C-L.3 alkyl,
(3) -CF 3' (4) -R"
(5) -C2_3 alkenyl,
(6) ΓûáCW alkyl-R3,
(7) -C .g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3; g each R is independently selected from: (1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C2.g alkenyl, (6) -C^g alkyl-R3,
(7) -C2_g alkenyl-R3,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from: (1) -C^g alkyl-R3, and (2) -Ε
R7 is selected from: (1) -H, and (2) Cl-6 alkyl;
R╬┤ is selected from:
(1) -H, and
(2) Cl-6 alkyl; and
each n is independently selected from 0, 1 and 2.
12. The compound according to Claim 11 wherein: R is selected from: (1) -H,
(2)
Figure imgf000243_0001
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 C-^g alkyl-,
(9) substituted phenyl C^.g 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-R ;
R2 is selected from:
(1) -H,
(2) -R3,
(3) -Ci.6 alkyl, g
(4) -C╬╣_6 alkyl substituted with R , (5) -0-Ru,
(6) -O-C^g alkyl-OR6,
(7) -Ci.6 alkyl (OR6)(R4) ,
(8) -Cχ.6 alkyl-N(R4)(R6) ,
(9) -C-t.Q alkyl C(0)-R6, and
(10) -C^g alkyl NR4C(0)-R6; g each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) ClJ╬▓ alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) "OCFg,
(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) Cg.g cycloalkyl,
(4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and
(6) naphthyl; 4 each R is independently selected from:
(1) -H, and
(2) -C^g alkyl;
5 each R is independently selected from:
(1) -H,
(2) -Cχ.3 alkyl,
(3) "CFg,
(4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3;
each R is independently selected from:
(1) -Cj alkyl-R , 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 tautomers and pharmaceutically acceptable salts thereof.
13. The compound according to Claim 12 of structural formula:
Figure imgf000246_0001
and tautomers and pharmaceutically acceptable salts thereof.
14. The compound according to Claim 12 of structural formula:
Figure imgf000246_0002
and tautomers and pharmaceutically acceptable salts thereof.
15. The compound according to Claim 1 of structural formula:
Figure imgf000246_0003
(I) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is imidazolyl;
R is selected from:
(1) -H,
(2) -C^g alkyl,
(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) halo,
(b) methyl, and
(c) methoxy,
(9) phenyl C1.3 alkyl-,
(10) substituted phenyl C^. alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
(c) methoxy,
(11) -C2_5 alkenyl-R , g
(12) -C _ alkynyl-R , and
(13) -C(0)CH2C(0)C(0)OR7;
elected from:
(1) -H, (2) -R3,
(3) -C1 alkyl, g
(4) -C╬╣_ alkyl substituted with R , (5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -C1 alkyl-N(R4)(R6) , (10) -C1 alkyl S(0)n-R6,
(11) -C1 alkyl C(0)-R6,
(12) -C1 alkyl C(S)-R6, (13) -C^ alkyl NR4C(0)-R6, and
(14) -C1 alkyl-C(0)N(R4)(R5); g each R is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1 alkyl,
(0 C-L.6 alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cl 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 alkyl,
(c) C-L.6 alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN, (h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C^e 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) Cj. alkyl,
(c) C-L.6 alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1 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) ClJ╬▓ alkyl,
(c) C1.6 alkyloxy-,
(d) phenyl, (e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) .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) C^g alkyl,
(c) C-^g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(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;
(11) pyrazoiyl
(12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) Cj.g alkyl,
(0 C^g alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
CD substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cw alkyl,
(iii) -CF3, and
(iv) hydroxy;
(13) C3-6 cycloalkyl;
(14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b) C -g alkyl,
(c) C^ alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, 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!_g alkyl,
(c) C^g alkyloxy-,
(d) -CFg, (e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(17) mor pholinyl,
(18) substituted morpholinyl substituted at a carbon or nitrogen atom with 1 or 2 independently selected from:
(a) halogen,
(b) Cj.g alkyl,
(c) C1.g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
Ob) C-..6 alkyl,
(c) C-L.g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C 6 alkyloxy-, (d) -CFg,
(e) -OCFg,
( ) -CN,
(g) =0, and (h) hydroxy;
(23) Cg.g cycloalkyl fused with a phenyl ring;
(24) substituted Cg.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from: (a) halogen,
(b) C1 alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
_ is independently selected
(1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C .g alkenyl,
(6) -C^g alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from:
(1) -H, (2) -C-^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C2.3 alkenyl,
(6) -C^g alkyl-R3,
(7) -C2.g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from:
(1) -C^g alkyl-R3, and
(2) -R3;
R7 is selected from: (1) -H, and
(2) Cl-6 alkyl;
R8 is selected from: (1) -H, and (2) Cl-6 alkyl; and
each n is independently selected from 0, 1 and 2.
16. The compound according to Claim 15 of structural formula:
Figure imgf000254_0001
and tautomers and pharmaceutically acceptable salts thereof, wherein: R is selected from: (1) -H,
(2) -Ci.5 alkyl,
(3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I; (5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) phenyl C^ alkyl-,
(9) substituted phenyl C^.g 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;
R is selected from:
(1) -H, (2) -R3,
(3) -C^g alkyl, g (4) -C╬╣_ alkyl substituted with R , (5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C^g alkyl-N(R )(R6) ,
(9) -ClJ6 alkyl C(0)-R6, and (10) -Ci.g alkyl NR4C(0)-R6; g each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C^g alkyl, (c) C-L.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (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) Cg_g cycloalkyl,
(4) morpholinyl,
(5) substituted morpholinyl substituted with oxo, and
(6) naphthyl;
4 each R is independently selected from:
(1) -H, and
(2) -C^g alkyl;
each R is independently selected from: (1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C^g alkyl-R3, (6) -S(0)n-R3, and
(7) -C(0)-R3; each R is independently selected from:
(1) -C^g 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:
Figure imgf000257_0001
(I) and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is indolyl and the dioxobutyric acid/ester moeity is attached to the nitrogen containing ring of the indole;
R is selected from:
(1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -halo,
(5) -N02,
(6) -N(R4)(R5),
(7) -phenyl,
(8) ssuubbssttiittuutteedd phenyl substituted with 1 or 2 substituents independently selected from: (a) halo,
(b) methyl, and
(c) methoxy, (9) phenyl C^ alkyl-, (10) substituted phenyl C^.g alkyl- substituted with 1 or 2 substituents independently selected from:
(a) halo,
(b) methyl, and
5 (c) methoxy,
(11) -C2.g alkenyl-R , g
(12) -C2_5 alkynyl-R , and
(13) -C(0)CH2C(0)C(0)OR7;
2
10 R is selected from:
(1) -H,
(2) -R3,
(3) -C^ alkyl, g
(4) -C^g alkyl substituted with R ,
15 (5) -O-R6,
(6) -O-C^g alkyl-OR6,
(7) -S(0)n-R6,
(8) -C^g alkyl (OR6)(R4) ,
(9) -C-^g alkyl-N(R4XR6) ,
20 (10) -C^g alkyl S(0)n-R6,
(11) -C^g alkyl C(0)-R6,
(12) -C^g alkyl C(S)-R6,
(13) -C^g alkyl NR4C(0)-R6, and
(14) -C╬╗.6 alkyl-C(0)N(R4)(R5);
each R is independently selected from:
(1) phenyl;
(2) substituted phenyl with 1, 2, or 3 substituents indep< selected from: 30 (a) halogen,
(b) C1 alkyl,
(c) C^g alkyloxy-, (d) phenyl,
(e) "CFg,
(f) -OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Cl 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 alkyl,
(c) C1 alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(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;
(5) pyridyl;
(6) substituted pyridyl substituted on a carbon atom with one or two substituents independently selected from: (a) halogen,
(b) Ci-6 alkyl,
(c) Cj.g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg,
(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;
(7) imidazolyl; (8) substituted imidazolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) Ci. alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) "CFg, ω "OCFg,
(g) -CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) Ci.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) Cl alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (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;
(11) pyrazoiyl; (12) substituted pyrazoiyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C^g alkyl,
(c) C^g alkyloxy-, (d) phenyl,
(e) -CF3,
(f) "OCFg,
(g) -CN, (h) hydroxy, (i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen, (ii) C1 alkyl, (iii) -CF3, and (iv) hydroxy; (13) Cg_6 cycloalkyl, (14) substituted Cg.g cycloalkyl with 1 or 2 substituents independently selected from:
(a) halogen,
(b)
Figure imgf000262_0001
alkyl,
(c) C^g alkyloxy-, (d) -CF3,
(e) -OCFg,
(f) -CN,
(g) =0, 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 alkyl, (c) C1 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN,
(g) =0, 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 alkyl,
(c) C^g alkyloxy-,
(d) -CFg, (e) -OCFg,
(f) -CN,
(g) =0, and (h) hydroxy; (19) naphthyl;
(20) substituted naphthyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1 alkyl, (c) C1 alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f -CN,
(g) =0, and (h) hydroxy;
(21) indolyl;
(22) substituted indolyl substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen, (b) C^g alkyl,
(c) C^g alkyloxy-,
(d) -CFg,
(e) -OCFg,
(f) -CN, (g) =0, and
(h) hydroxy;
(23) Cg.g cycloalkyl fused with a phenyl ring;
(24) substituted Cg.g cycloalkyl fused with a phenyl ring substituted on a carbon atom with one or two substituents independently selected from:
(a) halogen,
(b) C^g alkyl, (0 C1.g alkyloxy-,
(d) -CFg,
(e) "OCFg,
(f) -CN,
(g) =0, and
(h) hydroxy;
-4 each R is independently selected from:
(1) ΓûáH,
(2) -C1.3 alkyl,
(3) -CFg,
(4) -R3,
(5) -C2_g alkenyl,
(6) -C^g alkyl-R3 ,
(7) -C .g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
,5 . i is independently sele
(1) -H,
(2) -C;._g alkyl,
(3) -CFg,
(4) -R3,
(5) -C2.3 alkenyl,
(6) -C^g alkyl-R3,
(7) -C .g alkenyl-R ,
(8) -S(0)n-R3, and
(9) -C(0)-R3;
each R is independently selected from: (1) -Cj-g alkyl-R3, and (2) -R┬░
R7 is selected from: (1) -H, and (2) Cl-6 alkyl;
R8 is selected from:
(1) -H, and
(2) Cl-6 alkyl; and
each n is independently selected from 0, 1 and 2.
18. The compound according to Claim 17 of structural formula:
Figure imgf000265_0001
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R is selected from: (1) -H, (2) -C^g 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 C^g alkyl-,
(9) substituted phenyl C-i _g 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;
R is selected from:
(1) -H, (2) -R3,
(3) -C1 alkyl, g
(4) -C╬╣_g alkyl substituted with R ,
(5) -O-R6,
(6) -0-Cj.g alkyl-OR6, (7) -C^g alkyl (OR6 )(R4) ,
(8) -C^g alkyl-N(R4)(R6) ,
(9) -C^g alkyl C(0)-R6, and
(10) -C^g alkyl NR4C(0)-R6; g each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen, Ob) Cj.6 alkyl,
(c) C^g alkyloxy-,
(d) phenyl,
(e) -CF3,
(f) -OCFg, (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) -CFg, and (iv) hydroxy,
(3) C3.g cycloalkyl,
(4) morpholinyl, (5) substituted morpholinyl substituted with oxo, and
(6) naphthyl;
4 each R is independently selected from:
(1) -H, and (2) -C^g alkyl;
each R is independently selected from:
(1) -H,
(2) -C^g alkyl, (3) -CFg,
(4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3; fi each R is independently selected from:
Figure imgf000267_0001
each n is independently selected from 0, 1 and 2.
19. The compound according to Claim 17 of structural formula:
Figure imgf000268_0001
or a tautomer or a pharmaceutically acceptable salt thereof, wherein:
R is selected from: (1) -H,
(2) -Ci.5 alkyl,
(3) -CFg,
(4) -halo, wherein halo is selected from: -F, Cl, -Br, and -I,
(5) -N02, (6) -N(R4)(R5),
(7) -phenyl,
(8) phenyl C^g alkyl-,
(9) substituted phenyl C-i _g 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;
R is selected from: (1) -H,
(2) -R3,
(3) -C1 alkyl, g
(4) -C]__6 alkyl substituted with R ,
(5) -O-R6, (6) -0-Cj.g alkyl-OR6,
(7) -C^g alkyl (OR6)(R4) ,
(8) -C^g alkyl-N(R4)(R6) , (9) -C^g alkyl C(0)-R┬░, and
(10) -C^g alkyl NR4C(0)-Re
each R is independently selected from:
(1) phenyl,
(2) substituted phenyl with 1, 2, or 3 substituents independently selected from:
(a) halogen,
(b) C1J6 alkyl,
(c) C-,_6 alkyloxy-,
(d) phenyl,
(e) "CFg,
(f) -OCFg,
(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) Cg.6 cycloalkyl, (4) morpholinyl,
(5) substituted morpholinyl substituted with oxo, and
(6) naphthyl;
4 each R is independently selected from:
(1) -H, and
(2) -C^g alkyl; 5 each R is independently selected from:
(1) -H,
(2) -C^g alkyl,
(3) -CFg,
(4) -R3,
(5) -C^g alkyl-R3,
(6) -S(0)n-R3, and
(7) -C(0)-R3; fi each R is independently selected from:
(1) -C^g 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-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid methyl ester,
(2) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (3) 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester,
(4) 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid,
(5) 4-[l-(4-fluorobenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid ethyl ester, (6) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid isopropyl ester,
(7) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid n- butyl ester,
(8) 4-(l-benzyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid, 2 (9) 4-(l-naphthalen-2-ylmethyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid, (10) 4-(l-biphenyl-4-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid, (11) 4-(l-naphthalen-l-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid,
(12) 2,4-dioxo-4-[l-(4-phenylbutyl)- IH-pyrrol -2-yl] -butyric acid,
(13) 4-[l-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutvric acid, (14) 2,4-dioxo-4-(l-phenethyl- IH-pyrrol -2-yl)-butyric acid,
(15) 4-[l-(2-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(16) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(17) 4-[l-(4-bromobenzyl)-lH-pyrroT2-yl]-2,4-dioxobutyric acid, (18) 4-[l-(2-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(19) 4-[l-(3-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(20) 4-[l-(3-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(21) 4-[l-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(22) 4-[l-(2-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (23) 2,4-dioxo-4-( 1-hexyl- IH-pyrrol -2-yl)-butyric acid,
(24) 4-(l-biphenyl-2-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid, (25) 2,4-dioxo-4-[l-(4-phenoxybutyl)-lH -pyrrol-2-yl]- butyric acid, (26) 4-[l-(3-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (27) 4-[l-(2-chlorobenzyl)-lH-pyrrol-2- yl]-2,4-dioxobutyric acid,(28) 4-[l-(4-fluorobenzyl)-4-iodo- lH-pyrrol-2-yl]-2,4-dioxo-butyric acid,(29) 4-[l-(4- methoxybenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,_(30)
4-[l-(2,4,5-trifluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (31) 4-[l-(2,3-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,(32) 4-[l-(3,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (33) 4-[l-(2,5-difluorobenzyl)-lH-pyrrol- 2-yl]-2,4-dioxobutyric acid, (34) 4-[l-(2,5,6-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (35) 4-[l-(2-fluorobenzyl)-lΗ-pyrrol-2-yl] -2,4- dioxobutyric acid,
(36) 4-[l-(4-trifluoromethylbenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid,
(37) 4-[l-(4-cyanobenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric acid, (38) 4-[l-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid,
(39) 2-hydroxy-4-[l-(4-hydroxybenzyl)-lΗ-pyrrol-2-yl] -2,4- dioxobutyric acid, (40) 4-(l-cyclopentylmethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid,
(41) 4-{l-[3-(4-fluorophenyl)propyl]-lH-pvrrol-2-y}-2,4- dioxobutyric acid,
(42) 4-{l-[2-(4-fluorophenyl)ethyl]-lH-pyrrol-2-yl}-2,4-dioxobutyric acid, (43) 4-[l-(3-phenylpropyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(44) 4-(l-ethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid,
(45) 4-[l-(3-fluorobenzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid,
(46) 4-[l-(2-chlorobenzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid,
(47) 4-[l-(3-benzoylaminopropyl)-lΗ-pyrrol-3-yl] -2,4-dioxobutyric acid,
(48) 4-{l-[3-(4-fluorophenoxy)benzyl]-lH-pyrrol-2-yl}] -2,4- dioxobutyric acid,
(49) 4-( 1-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid methyl ester (50) 4-( 1-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid,
(51) 4- [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl-2,4- dioxobutyric acid ethyl ester,
(52) 4- [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(53) 4-[l-(4-fluorobenzyl)-4-phenethyl-lH-pvrrol-2-yl]-2,4- dioxobutyric acid ethyl ester,
(54) 4-[l-(4-fluorobenzyl)-4-phenethyl- lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (55) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid methyl ester,
(56) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(57) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid, (58) 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(59) 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid,
(60) 4-[5-(benzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(61) 4-[5-(3-fluorobenzyl)-lH -pvrrol-2-yl]-2,4-dioxobutyric acid, (62) 4-[5-(4-fluorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl] -2,4- dioxobutyric acid,
(63) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(64) 4-[5-(benzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(65) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(66) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid, (67) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid,
(68) 4-[5-(benzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(69) 4-[5-(3-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid, (70) 4-(5-benzyl-lH -pyrrol-3-yl)-2,4-dioxobutyric acid,
(71) 4-[2,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid,
(72) 4-[l-(4-Fluorobenzyl)-5-phenyl-lΗ-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (73) 4-[l-(4-Fluorobenzyl)-5-phenyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(74) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester,
(75) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(76) 4-[l-(4-Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(77) 4-[4-(Benzylamino)-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (78) 4-[5-Nitro-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric (79) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid methyl ester,
(80) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(81) 4-[l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid, (82) 4-[l-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(83) 4-[l-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(84) 4-[2,4-dimethyl-l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (85) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(86) 4-[l-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(87) 4-[l-(4-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(88) 4-[l-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,. (89) 4-[l-(3,4-dichlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(90) 4-[l-(2-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,.
(91) 4-[l-(3-chlorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (92) 4-[l-(3-trifluoromethylbenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(93) 4-[l-(4-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(94) 4-[l-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(95) 4-[l-(3-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_ (96) 4-{l-[3-(4-fluorophenyl)-propyl]-lΗ-pyrrol-3-yl}-2,4- dioxobutyric acid,
(97) 4-[l-(4-bromobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(98) 4-[l-(4-chlorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(99) 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lΗ-pyrrol-2-yl]- 2,4-dioxobutyric , ethyl ester
(100) 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]- 2,4-dioxobutyric acid,
(101) 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid ethyl ester, (102) 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(103) 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric acid ethyl ester, (104) 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric acid,
(105) 4-[l-(4-Fluorobenzyl)-3-acetylamino-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(106) 4-[4-acetylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid,
(108) 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(109) 4-[l,4-bis-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(110) 4-[5-(3-ethoxycarbonyl-3-oxopropionyl)-l-(4-fluorobenzyl)-lH- pyrazol-3-yl]-2,4-dioxobutyric acid ethyl ester,
(111) 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid ethyl ester,
(112) 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid,
(113) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-3-yl] -2,4- dioxobutyric acid,
(114) 4-[l-(4-Fluorobenzyl)-5-methyl-lH-pyrazol-4-yl]-2-hydroxy-4- oxobut-2-enoic acid,
(115) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid ethyl ester, (116) 4-[2-(4-fluorobenzyl)-2H-pyrazol-3-yl]-2,4-dioxo-butyric acid,
(117) l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester,
(118) l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid, (119) 4-[3-methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl ester,
(120) 4-[3 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(121) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid, (122) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid ethyl este,r
(123) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid, (124) 4-[l-(4-fluoro-benzyl)-lΗ-imidazol-2-yl]-2,4-dioxo-butyric acid,
(125) 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid ethyl ester,
(126) 4-[l-(4-fluorobenzyl)-lH-imidazol-2-yl]-2,4-dioxo-butyric acid, (127) 4-(l-Benzyl-lH-imidazol-2-yl)-2,4-dioxobutyric acid,
(128) 4-[l-(4-fluorobenzyl)-lΗ-imidazol-4-yl]-2,4-dioxo-butyric acid ethyl ester,
(129) 4-[l-(4-fluorobenzyl)-lH-imidazol-4-yl]-2,4-dioxo-butyric acid,
(130) 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric acid methyl ester,
(131) 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric acid,
(132) 2-hydroxy-4-(l-methyl-l-H -indol-2-yl) -2,4-dioxobutyric acid,
(133) 4-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid,
(134) l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid ethyl ester,
(135) l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid,(136) 4-[l-(3-fluorobenzyl)-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid,
(137) 4-[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric acid, (138) 4-[4-(4-fluorobenzyl)-l-methyl-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(139) 4-[2,5-dimethyl-l-(4-fluorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(140) 4-[l-(3,5-dichlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(141) 4-[l-(3-thiophenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(142) 4-[l-2,4-dimethylbenzyl)-l-Η-pyrrol-3-yl]-2,4-dioxobutyric acid, (143) 4-[l-(3-chloro-5-methyl-benzyl)-l-H-pyrrol-3-yl]-2,4-dioxo- butyric acid,
(144) 4-[l-(l-naphthalenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (145) 4-[l-(2-thiophenemethyl)-l-Η-pyrrole-3-yl]-2,4-dioxobutyric acid, and (146) 4-[4-(3-chlorobenzyl)-l-methyl-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid, or a tautomer or a pharmaceutically acceptable salt thereof.
21. The compound according to Claim 1 selected from:
(1) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(2) 4-[l-(4-methylbenzyl)-l-H-pyrrol-2-yl]-2,4-dioxobutyric acid,
(3) 4-(l-benzyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid, (4) 4-(l-naphthalen-2-ylmethyl-lH-pyrrol-2-yl)-2,4-dioxobutyric acid,
(5) 4-(l-biphenyl-4-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid,
(6) 4-(l-naphthalen-l-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid,
(7) 2,4-dioxo-4-[l-(4-phenylbutyl)- IH-pyrrol -2-yl] -butyric acid,
(8) 4-[l-(4-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (9)
2,4-dioxo-4-(l-phenethyl- IH-pyrrol -2-yl)-butyric acid, (10) 4-[l-(2-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (11) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(12) 4-[l-(4-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(13) 4-[l-(2-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(14) 4-[l-(3-bromobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (15) 4-[l-(3-chlorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(16) 4-[l-(3-methylbenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(17) 4-[l-(2-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(18) 2,4-dioxo-4-(l-hexyl- IH-pyrrol -2-yl)-butyric acid,
(19) 4-(l-biphenyl-2-ylmethyl- IH-pyrrol -2-yl)-2,4-dioxobutyric acid,(20) 2,4-dioxo-4-[l-(4-phenoxybutyl)-lH -pyrrol-2-yl]- butyric acid, (21) 4-[l-(3-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (22) 4-[l-(2-chlorobenzyl)-lH-pyrrol-2- yl]-2,4-dioxobutyric acid,(23) 4-[l-(4-fluorobenzyl)-4-iodo- lH-pyrrol-2-yl]-2,4-dioxo-butyric acid, (24) 4-[l-(4- methoxybenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,_(25)
4-[l-(2,4,5-trifluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (26) 4-[l-(2,3-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,(27) 4-[l-(3,5-difluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (28) 4-[l-(2,5-difluorobenzyl)-lH-pyrrol-
2-yl]-2,4-dioxobutyric add, (29) 4-[l-(2,5,6-difluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (30) 4-[l-(2-fluorobenzyl)-lΗ-pyrrol-2-yl] -2,4- dioxobutyric acid, (31) 4-[l-(4-trifluoromethylbenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid,
(32) 4-[l-(4-cyanobenzyl)-lH-pyrrol-2-yl] -2,4-dioxobutyric add,
(33) 4-[l-(3-methoxybenzyl)-lH -pyrrol-2-yl] -2,4-dioxobutyric acid, (34) 2-hydroxy-4-[l-(4-hydroxybenzyl)-lΗ-pyrrol-2-yl] -2,4- dioxobutyric acid,
(35) 4-(l-cyclopentylmethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid,
(36) 4-{l-[3-(4-fluorophenyl)propyl]-lH-pyrrol-2-y}-2,4- dioxobutyric acid, (37) 4-{l-[2-(4-fluorophenyl)ethyl]-lH-pyrrol-2-yl}-2,4-dioxobutyric acid,
(38) 4-[l-(3-phenylpropyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(39) 4-(l-ethyl-lH-pyrrol-2-yl) -2,4-dioxobutyric acid,
(40) 4-[l-(3-fluoro-benzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid, (41) 4-[l-(2-chloro-benzyl)-l-H -pyrrol-2-yl]- 2,4-dioxobutyric acid,
(42) 4-[l-(3-benzoylaminopropyl)-lΗ-pyrrol-3-yl] -2,4-dioxobutyric acid,
(43) 4-{l-[3-(4-fluorophenoxy)benzyl]-lH-pyrrol-2-yl}] -2,4- dioxobutyric acid, (44) 4-( 1-cyclohexylmethyl-l-H -pyrrol-2-yl)-2,4-dioxo-butyric acid,
(45) 4- [l-(4-fluorobenzyl)-4-phenylethynyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (46) 4-[l-(4-fluorobenzyl)-4-ρhenethyl-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(47) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(48) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(49) 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(50) 4-[5-(3-chlorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(51) 4-[5-(benzyl)-lH -pyτrol-2-yl]-2,4-dioxobutyric acid,
(52) 4-[5-(3-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid, (53) 4-[5-(4-fluorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(54) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(55) 4-[5-(benzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(56) 4-[5-(3-chlorobenzyl)-l-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4- dioxobutyric acid,
(57) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl] -2,4- dioxobutyric acid, (58) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid,
(59) 4-[5-(benzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(60) 4-[5-(3-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl] -2,4- dioxobutyric acid, (61) 4-(5-benzyl-lH -pyrrol-3-yl)-2,4-dioxobutyric acid,
(62) 4-[2,5-bis-(3-chlorobenzyl)-l-H -pyrrol-3-yl]-2,4-dioxobutyric acid, (63) 4-[l-(4-Fluorobenzyl)-5-phenyl-lΗ-pyτrol-2-yl]-2,4- dioxobutyric acid, (64) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(65) 4-[l-(4-Fluorobenzyl)-4-nitro-lH-pyrrol-2-yl]-2,4-dioxobutyric acid, (66) 4-[4-(Benzylamino)-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(67) 4-[5-Nitro-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric
(68) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(69) 4-[l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric add, (70) 4-[l-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(71) 4-[l-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(72) 4-[2,4-dimethyl-l-(4-fluorobenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (73) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(74) 4-[l-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(75) 4-[l-(4-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(76) 4-[l-(4-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric add,_ (77) 4-[l-(3,4-dichlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,.
(78) 4-[l-(2-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_
(79) 4-[l-(3-chlorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid, (80) 4-[l-(3-trifluoromethylbenzyl)-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(81) 4-[l-(4-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(82) 4-[l-(4-methoxybenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(83) 4-[l-(3-methylbenzyl)-lΗ-pyrrol-3-yl]-2,4-dioxobutyric add,_ (84) 4-{l-[3-(4-fluorophenyl)-propyl]-lH-pyrrol-3-yl}-2,4- dioxobutyric acid,
(85) 4-[l-(4-bromobenzyl)-l-H-pyτrol-3-yl]-2,4-dioxobutyric acid,
(86) 4-[l-(4-chlorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric add,
(87) 4-[4-Benzylmethylamino-l-(4-fluorobenzyl)-lΗ-pyrrol-2-yl]- 2,4-dioxobutyric acid, (88) 4-[4-Phenyl-l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4- dioxobutyric acid,
(89) 4-[l-(4-fluorobenzyl)-4-methanesulfonylamino-lH-pyrrol-3- yl]-2,4-dioxo-butyric add, (90) 4-[l-(4-Fluorobenzyl)-3-acetylamino-lH-pyrrol-2-yl]-2,4- dioxobutyric acid, (91) 4-[4-acetylamino-l-(4-fluorobenzyl)-lH-pyrrol-2-yl] -2,4- dioxobutyric acid, (93) 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid, (94) 4-[l,4-bis-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(95) 4-[l-(4-fluorobenzyl)-lH-pyrazol-4-yl]-2,4-dioxobutyric acid,
(96) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lH-pyrrol-3-yl] -2,4- dioxobutyric acid, (97) 4-[l-(4-Fluorobenzyl)-5-methyl-lH-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) l-[l-(4-fluorobenzyl)-3-methyl-lH-pyrazol-4-yl]-2,4- dioxobutyric acid, (100) 4-[3 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(101) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(102) 4-[5 -methyl-l-(3-chlorobenzyl)-lH-pyrazol-4-yl]-2,4- dioxobutyric acid,
(103) 4-[l-(4-fluoro-benzyl)-lΗ-imidazol-2-yl]-2,4-dioxo-butyric acid,
(104) 4-[l-(4-fluorobenzyl)-lH-iπύdazol-2-yl]-2,4-dioxo-butyric acid,
(105) 4-(l-Benzyl-lH-imidazol-2-yl)-2,4-dioxobutyric acid, (106) 4-[l-(4-fluorobenzyl)-lΗ-imidazol-4-yl]-2,4-dioxo-butyric acid,
(107) 4-[l-(4-fluorobenzyl)- IH -indol -2-yl]-2,4-dioxobutyric acid,
(108) 2-hydroxy-4-(l-methyl-l-H -indol-2-yl) -2,4-dioxobutyric acid,
(109) 4-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric add,
(110) l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric add, ethyl ester, (111) l-[l-(4-fluorobenzyl)-lH-indol-3-yl]-2,4-dioxobutyric acid,(112) 4-[l-(3-fluorobenzyl)-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid,
(113) 4-[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric add, (114) 4-[4-(4-fluorobenzyl)-l-methyl-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(115) 4-[2,5-dimethyl-l-(4-fluorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(116) 4-[l-(3,5-dichlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(117) 4-[l-(3-thiophenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(118) 4-[l-2,4-dimethylbenzyl)-l-Η-pyrrol-3-yl]-2,4-dioxobutyric acid, (119) 4-[l-(3-chloro-5-methyl-benzyl)-l-H-pyrrol-3-yl]-2,4-dioxo- butyric acid,
(120) 4-[l-(l-naphthalenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(121) 4-[l-(2-thiophenemethyl)-l-Η-pyτrole-3-yl]-2,4-dioxobutyric acid, and
(122) 4-[4-(3-chlorobenzyl)-l-methyl-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid, utomer or a pharmaceutically acceptable salt thereof.
22. The compound according to Claim 21 selected from:
(1) 4-[l-(2-thiophenemethyl)-l-H-pyrrole-3-yl]-2,4-dioxobutyric acid, and
(2) 4-[4-(3-chlorobenzyl)-l-methyl-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid, (3) 4-[l-(4-fluorobenzyl)-lH-pyrrol-2-yl]-2,4-dioxobutyric acid,
(4) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-2-yl] -2,4- dioxobutyric acid,
(5) 4-[5-(4-fluorobenzyl)-lH -pyrrol-2-yl]-2,4-dioxobutyric acid,
(6) 4-[5-(4-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid, (7) 4-[5-(3-chlorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid,
(8) 4-[5-(benzyl)-l-methyl-lH -pyrrol-3-yl]-2,4-dioxobutyric acid,
(9) 4-[5-(3-fluorobenzyl)-l-methyl-lH -pyrrol-3-yl]-2,4- dioxobutyric acid,
(10) 4-[4-Dimethylamino-l-(4-fluorobenzyl)-lΗ-pyrrol-2-yl]-2,4- dioxobutyric acid,
(11) 4-[l-benzyl-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(12) 4-[l-(3-bromobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric add, (13) 4-[l-(4-fluorobenzyl)-4-methyl-lH-pyrrol-3-yl]-2,4- dioxobutyric acid,
(14) 4-[l-(3,4-difluorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,
(15) 4-[l-(3-chlorobenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric add, (16) 4-[l-(2-methylbenzyl)-lH-pvrrol-3-yl]-2,4-dioxobutyric acid,.
(17) 4-[l-(3-methylbenzyl)-lH-pyrrol-3-yl]-2,4-dioxobutyric acid,_
(18) 4-[4-Benzylmethylamino- l-(4-fluorobenzyl)- lΗ-pyrrol-2-yl]- 2,4-dioxobutyric acid,
(19) 4-[4-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric add, (20) 4-[l,4-bis-(4-fluorobenzyl)- IH -pyrrol-3-yl]-2,4-dioxobutyric acid, (21) 4-[l-(3-fluorobenzyl)-l-H-pyrrol-3-yl]-2,4- dioxobutyric acid,
(22) 4-[4-(3-chlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxo-butyric acid,
(23) 4-[4-(4-fluorobenzyl)-l-methyl-l-H-pyrrol-3-yl] -2,4-dioxo- butyric acid,
(24) 4-[2,5-dimethyl-l-(4-fluorobenzyl)-l-H-pyrrol-3-yl] -2,4-dioxobutyric acid,
(25) 4-[l-(3,5-dichlorobenzyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid, (26) 4-[l-(3-thiophenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid,
(27) 4-[l-2,4-dimethylbenzyl)-l-Η-pyrrol-3-yl]-2,4-dioxobutyric acid,
(28) 4-[l-(3-chloro-5-methyl-benzyl)-l-H-pyrrol-3-yl]-2,4-dioxo- butyric add, and (29) 4-[l-(l-naphthalenemethyl)-l-H-pyrrol-3-yl]-2,4-dioxobutyric acid; or a tautomer or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition useful for inhibiting
ΗIV 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 ΗIV, 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 ΗIV protease inhibitor.
27. The composition of Claim 26 wherein the ΗIV protease inhibitor is N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl- 4(S)-hydroxy-5-(l-(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.
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HOWARTH T. T., ET AL.: "PYRROLES AND RELATED COMPOUNDS. PART XXVI. PYRROLE BETA-KETO-ESTERS", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1974 (1974-01-01), LETCHWORTH; GB, pages 490 - 501., XP002923831, ISSN: 0368-1769 *
See also references of EP1083897A4 *

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US7745459B2 (en) 2004-09-21 2010-06-29 Japan Tobacco Inc. Quinolizinone compound and use thereof as HIV integrase inhibitor
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AU756826C (en) 2003-08-21
AU756826B2 (en) 2003-01-23
AU4225699A (en) 1999-12-20
EP1083897A4 (en) 2003-01-02
EP1083897A1 (en) 2001-03-21
JP2002516858A (en) 2002-06-11
CA2329134A1 (en) 1999-12-09

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