AU3297099A - Inhibitors of phospholipase a2 - Google Patents

Inhibitors of phospholipase a2 Download PDF

Info

Publication number
AU3297099A
AU3297099A AU32970/99A AU3297099A AU3297099A AU 3297099 A AU3297099 A AU 3297099A AU 32970/99 A AU32970/99 A AU 32970/99A AU 3297099 A AU3297099 A AU 3297099A AU 3297099 A AU3297099 A AU 3297099A
Authority
AU
Australia
Prior art keywords
alkyl
cooh
compound
alkoxy
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU32970/99A
Inventor
Jean Bemis
Lihren Chen
Neelu Kaila
John Mckew
Jasbir S. Seehra
Yi Bin Xiang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genetics Institute LLC
Original Assignee
Genetics Institute LLC
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
Application filed by Genetics Institute LLC filed Critical Genetics Institute LLC
Publication of AU3297099A publication Critical patent/AU3297099A/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • 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
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Indole Compounds (AREA)

Description

WO 99/43672 PCT/US99/03388 INHIBITORS OF PHOSPHOLIPASE A2 This application is a continuation-in-part of application Ser. No. 08/918,400, filed August 26, 1997, which was a continuation of application Ser. No. 08/703,115, August 26, 1996. Background of the Invention The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A enzymes. Leukotrienes and prostaglandins are important mediators of inflammation. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli. Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the produciton of leukotrienes. Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A (hereinafter PLA 2 ). The reaction catalyzed by PLA. is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA. is of the phosphotidyl choline class with an ether linkage in the sn-I position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58 (1988)]. Most anti-inflammatory therapies have focussed on preventing production of either prostaglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin and indomethacin are all NSAIDs which inhibit the production of prostaglandins by WO 99/43672 PCT/US99/03388 COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathwasy of conversion of arachidonic acid to leukotrienes, witout affecting the production of prostaglandins. None of these widelt-used anti inflammatory agents affects the production of PAF. Consequently the direct inhibition of the activity of PLA has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)]. A family of PLA, enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLAs have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA~s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis. Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated. The primary structure of the first human non-pancreatic PLA has been determined. This non pancreatic PLA. is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLAis an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLAis regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme. A murine PLA, has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 pmols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase 2 WO 99/43672 PCT/US99/03388 enzymes, particularly PLA,. A cytosolic phospholipase A (hereinafter "cPLA,") has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli. Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are al desired. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states. 3 WO 99/43672 PCT/US99/03388 Summary of the Invention The present invention provides compounds having a chemical formula selected from the group consisting of: A RR f;1 ' B
R
4 aN> R N B R and RB or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH,- and -CH,-CH 2 -; B is independent of any other group and is selected from the group consisting of -(CH,).-, -(CH,0)n-, -(CHS),-, -(OCH,)n-, -(SCH,)n-, -(CH =CH).-, -(C=C),-,
-CON(R
6 )-, -N(R 6 )CO-, -0-, -S- and -N(R 6 )-; RI is independent of any other R group and is selected from the group consisting of -X-., -H. OH, halogen, -CN, -NO,, Cc-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl; R, is independent of any other R group and is selected from the group consisting of -H, -COOH,
-COR
5 , -CONR 5
R
6 , -(CH,)n-W-(CH,)m-Z-R5, -(CH1)n-W-R 5 , -Z-R 5 , C,-CI 0 alkyl, alkenyl and substituted aryl;
R
3 is independent of any other R group and is selected from the group consisting of -H, -COOH,
-COR
5 , -CONR 5
R
6 , -(CH,)n-W-(CH,)m-Z-R5, -(CH),-W-R 5 , -Z-R 5 , C,-Cie alkyl, alkenyl and substituted aryl;
R
4 is independent of any other R group and is selected from the group consisting of -H, -OH, OR, -SR6, -CN, -CORl, -NHR 6 , -COOH, -CONR 6
R
7 , -NO 2 , -CONHSO 2
R
8 , C,-C 5 alkyl, alkenyl and substituted aryl; 4 WO 99/43672 PCTIUS99/03388
R
5 is independent of any other R group and is selected from the group consisting of -H, -OH, O(CH,).R, -SR 6 , -CN, -COR 6 , -NHR 6 , -COOH, -NO, -COOH, -CONR 6
R
7 ,
-CONHSOR
8 , C,-C 5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CFi, -CFCF 3 and
R
9 R is independent of any other R group and is selected from the group consisting of -H, -C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R
7 is independent of any other R group and is selected from the group consisting of -H, q-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl; R, is independent of any other R group and is selected from the group consisting of -C 3 alkyl, aryl and substituted aryl;
R
9 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR, -COOH, -CONR 6
R
7 , tetrazole, -CONHSQR 8 , -COR 6 , -(CH2)nCH(OH)R 6 and -(CH,)nCHR 6
R
5 ; RIO is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR 6 , -COOH, -CONR6R 7 , tetrazole, -CONHSOR, -CO&1, -(CH2)aCH(OH)l6 and -(CH,)nCHR 6
R
5 ; W is, independently each time used including within the same compound, selected from the group consisting of -0-, -S-, -CI-, -CH=CH-, -C = C- and -N(R6)-; X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-; Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N(1&)-, -CO-, -CON(14)- and N(1 6 )CO-; m is, independently each time used including within the same compound, an integer from 0 to 4; and n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4. Preferably, the compounds of the invention have phospholipase enzyme inhibiting activity. Other 5 WO 99/43672 PCTIUS99/03388 preferrred embodiments include compounds having the following chemical formula: R, RB 4, compounds having the following chemical formula: R B RR50; and R I N 3 R 5 compounds having the following A chemical formula: In particularly preferred embodiments, A is -CH- and R, is
-(CH
2
),-W-(CH
2 )m-ZRs These preferred compounds includes those wherein n is 1, m is 1, W is -S- and Z is -CO-; those wherein 1 5 is -NHR 6 ; those wherein R 6 is a substituted aryl group and those wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -CF 3 ,
-CF
7
CF
3 , -(CH 2 ),COOH, -(CH 2
),CH
3 , -O(CH 2
),CH
3 , -(CH 2 ),OH, -(CH,),S(C 6
H
6 ),
-(CH
2 ),CONH, and -CHR,,COOH, wherein R, is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH 2 ),OH, and -O(CH 2
),CH
3 , and wherein p is an integer from 0 to 4. Other preferred comounds include those wherein I, is selected from the group consisting of -H and -OCH(C 6
H
6 ) and R 3 6 WO 99/43672 PCT/US99/03388 is -COR 5 , R 5 is -OCH 2
R
6 and R 6 is a substituted aryl group. In particularly preferred compounds, said aryl group is substituted with one or more substituents selected from the group consisting of -C, CF 2
CF
3 and
-C(CH
3
)
2
CH
2
CH
3 7 WO 99/43672 PCT/US99/03388 Among the compounds of this invention are those of the formula: R1 R3 R 1 R3 Rj. R4 Rj- R4 R2 R2 N N R5 or R5 wherein R, and RV are independently selected from C 1
-C
6 alkyl, -Z-C-C 6 alkyl, phenyl, -(CH 2 )n
Z-(CH
2 )n-phenyl, benzyl, -(CH 2 )n-Z-(CH 2 )n-benzyl, napthyl, -(CH 2 )n-Z-(CH 2 ),-napthyl, pyrimidinyl, -(CH 2 )n-Z-(CH 2 )n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-C 6 alkyl, Cl-C 6 alkoxy, -NO 2 , -NH 2 , -CN, -CF3, or -OH; Z is O or S; n is an integer from 0 to 3; R, is selected from H, halogen, -CF 3 , -OH, -C 1
-CI
0 alkyl, CI-Clo alkoxy, -CHO, -CN, NO 2 , -NH2, -NH-C-C6 alkyl, -N(C 1
-C
6 alkyl) 2 , -N-S0 2
-C,-C
6 alkyl, or -S0 2
-C-C
6 alkyl; R3 is selected from H, halogen, -CF3, -OH, -CI-C,, alkyl, C,-C 0 alkoxy, -CHO, C(O)CH 3 , -C(O)-(CH 2 )n-CF3, -CN, -NO 2 , -NH 2 , -NH-C,-C6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 C 1
-C
6 alkyl, -SO2,C alkyl or a moiety of the formula:
R
8 0Rg (CH2)n- 0- (CH2)n n in each appearance is independently selected as an integer selected from 0-3; -8- WO 99/43672 PCTIUS99/03388 R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ).-COOH, -(CH2).-C(O)-COOH, -CF3, -OH, -(CH2)n,-C(O)-COOH, -C,-C6 alkyl, -O-CI-C6 alkyl, -NH(C,
C
6 alkyl), or -N(C 1
-C
6 alkyl) 2 ;
R
4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: R 12 R 12 O R 12 N N N N S N or 0
NR
1 2 N S
R
2 is selected from H, -CF3, C,-C6 alkyl, -(CH 2 )n-C 3
-C
6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH 2 )-COOH, -(CH 2 )n-C(O)-COOH, -C,-C 6 alkyl, -O-C,
C
6 alkyl, -NH(C-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-O-, -(CH 2 )n-S-, -(CH 2 )n-O-(CH 2 )n-, -(CH 2 )n-S-(CH 2 )n-, -C(O)-O-, -C(O)-(CH 2 )n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M' is -COOH or a moiety selected from: -9- WO 99/43672 PCT/US99/03388 R8 R 8 Ri R
A
1 0 or 10
R
10 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, -CF3, -OH, (CH 2 ).-C(O)-COOH, -C -C 6 alkyl, -0-C-C 6 alkyl, R8 R8 R8 Z R9ZR (CH2)n R or R8 (CH2)n with a proviso that the moiety or combination of moieties comprising R 3 include an acidic group selected from carboxylic acid or a moiety of the formulae: R 12R 12 0 RA 12 N N N N S N 0 A 12 N or S -10- WO 99/43672 PCTIUS99/03388
R
5 is selected from: a) a moiety of the formula -L 2
-M
2 ;
L
2 is selected from a chemical bond or a bridging group selected from -(CH 2 )n-Z-,
-(CH
2 )n-Z-(CH 2 )n-, -C(O)-O-, -C(O)-(CH 2 ).-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M
2 is selected from -C 1
-C
6 alkyl, -0-C,-C 6 alkyl, R8 R8 R 8 /Nj /3 R9 Rg R or wherein R 8 and R 9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or b) a moiety of the formulae: R8 R8 /N, L3 or L wherein L 3 is a chemical bond or a group selected from -CH 2 , -CH-Z- , -C(0)- , -0-, -S- , or -(CH2)n,-Z-(CH2)n,
M
3 is selected from -(CH 2 )n-C 3
-C
5 cycloalkyl, furanyl, thienyl, pyrrolyl, -11- WO 99/43672 PCT/US99/03388 RS R 8 _-R9 N. or N S or a pharmaceutically acceptable salt thereof. Of the compounds in the group just defined, a preferred subset include those in which the core molecule is an indole. Within the indole group is another subset wherein R" and R 2 are hydrogen, and the moieties R 3 , R 4 , R', R', R 9 and R 10 , n, L', L 2 , M' and M 2 are as defined above. Within this subset is another preferred group wherein R 1 is in the indole 5-position. Also among the compounds of this invention are those of the formula: R, R3 R4 N R2 I R5 wherein R, is selected from -O-CI-C 6 alkyl, -S-C 1
-C
6 alkyl, -0-phenyl, -S-phenyl, -O-benzyl, -S benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-C 6 alkyl, C-C 6 alkoxy, -NO 2 , -NH 2 , -CN, -CF 3 , or -OH; -12- WO 99/43672 PCT/US99/03388
R
2 is selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, preferably -C 1
-C
6 alkyl, CI-C 0 alkoxy, preferably CI-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C-C 6 alkyl, -N(C 1
-C
6 alkyl) 2 , N-S0 2
-C,-C
6 alkyl, or -S0 2 -C-C alkyl;
R
3 is selected-from H, halogen, -CF3, -OH, -C -CI 0 alkyl, preferably -CI-C 6 alkyl, C 1 -Cl 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-CI-C 6 alkyl, -N(C,-C 6 alkyl) 2 , N-S0 2
-C-C
6 alkyl, -S0 2
-C-C
6 alkyl, or a moiety of the formula:
R
8 0 /0-R9
(CH
2 )~ 0- (CH2)n n in each appearance is independently selected as an integer selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH,
-(CH
2 ),-C(O)-COOH, -CF 3 , -OH, -(CH 2 )n-C(O)-COOH, -C,-C 6 alkyl, -O-CI-C 6 alkyl, -NH(C,
C
6 alkyl), or -N(C,-C 6 alkyl) 2 ;
R
4 is the moiety -L'-M' or O N H N R 0 0 S or S L' is selected from a chemical bond or a bridging group selected from -(CH 2 )n-O-, -(CH2),n-S-, -(CH'I)n-O-(CH2),,-, -(CH2)n-S-(CH2)n-, -C(O)-0-, -C(O)-(CH2,)n-O-, -C(O)-N-, or -(CH2)n-S-(CH,)n-C(O)-N-; -13- WO 99/43672 PCTIUS99/03388 M' is the moiety: R8 ..... Rg
R
10
R
1 4 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH, -C,-C 6 alkyl, -O-C-C 6 alkyl, R8 R8 R8
N-N
RgRg Rg9 Z Z (CH2)n R8
~-(CH
9 ),
-
with a proviso that the combination of moieties comprising R 4 include a carboxylic acid or a moiety of the formulae: -14- WO 99/43672 PCTIUS99/03388 0 OH R9 N N / 0 0 S or S
R
5 is a structure of the formula -L 2
-M
2
L
2 is selected from a chemical bond or a bridging group selected from -(CH 2 )n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n,-, -(CH2),,-S-(CH2),,-, -C(O)-O-, -C(O)-(CH2) ,-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M
2 is selected from -C,-C 6 alkyl, -0-C,-C 6 alkyl,
R
8 -Rg_ R9 10 or wherein R', R 9 and R 1 0 are as defined above; or a pharmaceutically acceptable salt thereof. Also preferred are compounds of the group above with the structure: -15- WO 99/43672 PCT/US99/03388 R3 R1 R4 N wherein R, is selected from -O-C-C 6 alkyl, -S-C-C 6 alkyl, -0-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-C
6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH2, -CN, -CF 3 , or -OH;
R
3 is selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, preferably -CI-CI 0 alkyl,
C
1
-CI
0 alkoxy, preferably C,-C 10 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-S0C2-C 6 alkyl, -S02C,-C 6 alkyl or a moiety of the formula: R8
(CH
2 )n- 0- (CH2)n wherein R 4 , R', R', R 9 and R' 0 are as defined above, or a pharmaceutically acceptable salt thereof. Also among the compounds of the present invention are those of the formulae: -16- WO 99/43672 PCTIUS99/03388 R1 R3 R1 R3 R1' R4 R1, R4 N N R2 IR2I R5 or R5 wherein RI and R. are independently selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, preferably -C 1
-C
6 alkyl, -S-C-CI 0 alkyl, preferably -S-C-C 6 alkyl, C 1 -Cl 0 alkoxy, preferably Cr
C
6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a -S-, -0- or -(CH 2 )n- bridge; a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C -C 10 alkyl, preferably C 1
-C
6 alkyl, CI-C 0 alkoxy, preferably C 1
-C
6 alkoxy, -NO 2 , -NH2, -CN, -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-CI
0 alkyl, preferably C-C 6 alkyl, C 1
-C
0 alkoxy, preferably 1
-C
6 alkoxy, -CHO, NO 2 , -NH 2 , -CN, -CF 3 or -OH; or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, -17- WO 99/43672 PCT/US99/03388 quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-CI
0 alkyl, preferably C1C alkyl,
C
1
-C
0 alkoxy, preferably CI-C 6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 or -OH; or d) a moiety of the formulae: R6
R
6 R R N N N O Rz O0 ,O
R
6 R7 z R7A 7 R 6 R 7 N or 0 0 ZisOorS;
R
6 is selected from the relevant members of the group H, -CF3, C-CI 0 alkyl, preferably
C,-C
6 alkyl, CI-C 1 0 alkoxy, preferably C,-C 6 alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -0 benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CeCi alkyl, preferably C-C alkyl, C -C 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF3, or -OH;
R
7 is selected from the relevant members of the group -OH, -CF 3 , C 1
CI
0 alkyl, preferably
C
1
C
6 alkyl, C,-C 0 alkoxy, preferably C-C 6 alkoxy, -NH 2 , -(CH 2 )n-NH 2 , -NH-(C-C 6 alkyl), -18- WO 99/43672 PCTIUS99/03388
N-(C-C
6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -(CH 2 )n-N-(C-C 6 alkyl) 2 , phenyl, -0-phenyl, benzyl, or -O-benzyl; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Cl 0 alkyl, preferably CI-C 6 alkyl, C 1 -Clo alkoxy, preferably CI-C 6 alkoxy, -NO 2 , -NH2, -CN, or -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C -C 0 alkyl, preferably C-C 6 alkyl, CI-C 0 alkoxy, preferably C1-C6 alkoxy, -CHO, NO 2 , -NH2, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen,
C
1
-CI
0 alkyl, preferably CC6 alkyl, C 1
-CI
0 alkoxy, preferably C C6 alkoxy, -CHO, -NO 2 , NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R
2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, CI-CI0 alkyl, preferably C,-C 6 alkyl, CgC,, alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C6 alkyl,
-N(C-C
6 alkyl) 2 , -N-SO 2 -C-C6 alkyl, or -S0 2 -C-C alkyl; -19- WO 99/43672 PCT/US99/03388
R
3 is selected from H, halogen, -CF 3 , -OH, -C 1
-CI
0 alkyl, CI-C 0 alkoxy, -CHO, C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(CI-C 6 alkyl) 2 , -N-SO 2 C,-C 6 alkyl, -So0 2
C,-C
6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl,
-C(O)
benzyl, -CH 2
-(C
3
-C
6 cycloalkyl), -C(O)-OH, C(O)-C-C 6 alkyl, -C(O)-O-C,-C alkyl, -C(O)
CF
3 , -(CH 2 )n-S-CH 2
-(C
3
-C
5 cycloalkyl), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C-C 6 alkyl, Ci-C 6 alkoxy, -N2, 3, C(O)-OH, or -OH; or a moiety of the formula: R8 0 CHA -R9
(CH
2 )n~ 0- 0CH2) n in each appearance is an integer independently selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH, -(CH2),n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -CI-C6 alkyl, -O-C -C6 alkyl, -NH(C,
C
6 alkyl), or -N(C 1
-C
6 alkyl) 2 ;
R
4 is selected from -COOH, -(CH 2 )n-COOH, -(CH,)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: 0 R 1 O R12 0 R12 N N N 0 0 0 N S N or N z 0 S -20- WO 99/43672 PCT/US99/03388
R
2 is selected from H, -CF3, C-C6 alkyl, -(CH 2 )n-C 3
-C
6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -C-C6 alkyl, -O-C,
C
6 alkyl, -NH(C,-C 6 alkyl), or -N(C-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2).,-O-(CH2)n,-, -(CH2)n,-S-(CH2)n,-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n,-O-(CH2)n-, -(CH2)n-S-(CH2)n-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R 6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, -C(Z)-NH-SO2-(CH2)n,-, -C(O)-(CH2)n-O-, -C(O) N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M' is -COOH or a moiety selected from: R8 R8 RR8 ~R9RR -N N R10 R10
R
9 0 S R 8 O N R 8 HNN R RP
R
9 0 01 10 0 01 S INS N (C 1
-C
6 lower alkyl N (C1-C6 lower haloalkyl 0 N S -21- WO 99/43672 PCTIUS99/03388 S ON o 0 0
OR
11 , OH or R., in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH, (CH 2 )n-C(O)-COOH, tetrazole, 00 0 O-P-OH S , or OH;
R
9 in each appearance is independently selected from H, halogen, -CF 3 , -OH, -COOH, (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH,
-C
1
-C
6 alkyl, -0-C,-C 6 alkyl, -NH(C-C 6 alkyl), or
-N(C-C
6 alkyl) 2 ;
R'
0 is selected from H, -COOH, -(CH2)-COOH,
-(CH
2 )n-C(O)-COOH,
-CF
3 , -OH, (CH 2 )n-C(O)-COOH,
-CI-C
6 alkyl, -0-C-C 6 alkyl, -22- WO 99/43672 PCT/US99/03388 R8 R8 R8 N-- RR
N
Z .....- Z (CH2)n -- ,H or R8 Rg 0 0 (CH2)n N (C1-C6 lower alkyl N N OR S R N (C-C6 lower haloalkyl,
R
1 is selected from H, C,-C 6 lower alkyl, C 1
-C
6 cycloalkyl, -CF 3 , -COOH, -(CH 2 )n COOH, -(CH 2 )n-C(O)-COOH,
R
8
R
8 N-R R - (CH 2 )n with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: 00 0 0 0 0-P-OH S 0 OH N -23- WO 99/43672 PCTIUS99/03388 0 /R12 0 ,R12 O R12 N N N 0 0 02 N ,S ;N N or S
R
5 is selected from CC6 lower alkyl, C 1
-C
6 lower alkoxy, -(CH 2 )n-C 3 -CI cycloalkyl,
-(CH
2 )n-S-(CH 2 )n-C 3
-C
0 cycloalkyl, -(CH 2
),-O-(CH
2 )n-C 3 -CI cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl,
-(CH
2 )n-phenyl-CH 2 -phenyl, -(CH 2 )a-O-phenyl-CH 2 phenyl, -(CH 2 )n-phenyl-(0-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: 0 0 " O y "(CH2), (CH2)rN S_ y 0
CH(CH
2 )H2) (CH2)N 0 (COH2) S (CH 2 )n (CH2)N - (CH 2 )n wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C, cycloalkyl or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, -24- WO 99/43672 PCT/US99/03388 isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-CI
0 alkyl, preferably Cl-C 6 alkyl, C 1 -Cl 0 alkoxy, preferably CI-C 6 alkoxy, -NO 2 , -NH2, -CN, or -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1
-CI
0 alkyl, preferably C 1
-C
6 alkyl, C,-C,, alkoxy, preferably CI-C 6 alkoxy, -CHO, NO 2 , -NH2, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen,
C
1
-CI
0 alkyl, preferably Cl-C 6 alkyl, CI-Cl 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO,, NH2, -CN, -CF3 or -OH; d) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 ),-O-A, wherein A is the moiety: D C B wherein D is H, CI-C 6 lower alkyl, 1
-C
6 lower alkoxy, -CF 3 or -(CH 2 )n-CF 3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF -OH, -C -C alkyl, C -C 6 alkoxy, -NH 2 or -NO 2 ; -25- WO 99/43672 PCTIUS99/03388 or a pharmaceutically acceptable salt thereof. Preferred compounds include those having the formula: R1 R3 R1 R3 R4 R4 N 1 N R2 2 R5 or R5 wherein R, is selected from H, halogen, -CF 3 , -OH, -C -C alkyl, preferably -C 1
-C
6 alkyl, -S-C, CIO alkyl, preferably -S-C 1
-C
6 alkyl, C 1 -CI alkoxy, preferably C 1
-C
6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a -S-, -0- or (CH 2 );- bridge; a) furan, pyrrole, or thiophene, being optionally substituted by from 1 to 3 substituents selected from halogen, C1CI alkyl, preferably C 1
-C
6 alkyl, CI-CIO alkoxy, preferably
C,-C
6 alkoxy, -NO 2 , -NH2, -CN, -CF 3 ; or b) pyridine, pyrimidine, piperidine, or morpholine, each being optionally substituted by from 1 to 3 substituents selected from halogen, C C alkyl, preferably C,-C 6 alkyl, C,-CIe alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NO2, -NH, -CN, -CF3 or -OH; or c) benzofuran, indole, napthalene, purine, or quinoline, each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI. alkyl, preferably C 1
-C
6 alkyl, C-CI alkoxy, preferably C 1
C
6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 or -OH; or d) a moiety of the formulae: -26- WO 99/43672 PCT/US99/03388 R6 6 R RI z R Z R7 R O R I-, 61 R7 ' R7 R N or 0 0 Z is O or S;
R
6 is selected from the relevant members of the group H, -CF3, C 1
-C
0 alkyl, preferably Cl-C 6 alkyl, CI-Cl 0 alkoxy, preferably C-C 6 alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -0 benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Clo alkyl, preferably C-C 6 alkyl, CI-Cl 0 alkoxy, preferably C-C 6 alkoxy, -CHO, -NO,, -NH 2 , -CN, -CF 3 , or -OH;
R
7 is selected from the relevant members of the group -OH, -CF 3 , C -C 0 alkyl, preferably
C
1
-C
6 alkyl, CI-CI 0 alkoxy, preferably C 1
-C
6 alkoxy, -NH 2 , -(CH 2 )n-NH 2 , -NH-(Cl-C 6 alkyl), N-(CI-C 6 alkyl) 2 , -(CH 2 )n-NH-(C-C 6 alkyl), -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , phenyl, -0-phenyl, benzyl, or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole, or morpholine the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 0 alkyl, preferably CI-C 6 alkyl, CI-C 0 alkoxy, preferably C 1
-C
6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF 3 or -OH; -27- WO 99/43672 PCT/US99/03388 n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R
2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, CI-CI0 alkyl, preferably C,-C 6 alkyl, CI-CI0 alkoxy, preferably CI-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C-C 6 alkyl,
-N(C,-C
6 alkyl) 2 , -N-S0 2
-CI-C
6 alkyl, or -S0 2
-C-C
6 alkyl;
R
3 is selected from H, halogen, -CF 3 , -OH, -CI-C 1 alkyl, CI-Cl 0 alkoxy, -CHO,
-C(O)CH
3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C C6 alkyl, -N(C-C 6 alkyl) 2 , -N-SO 2 C,-C 6 alkyl, -S0 2
-C-C
6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O) benzyl, -CH 2
-(C
3
-C
5 cycloalky), -C(O)-OH, C(O)-C-C 6 alkyl, -C(O)-O-C-C 6 alkyl, -C(O)-CF 3 , or -(CH 2 )n-S-CH 2
-(C
3
-C
5 cycloalky), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C1-C6 alkyl, C 1
-C
6 alkoxy, -NO 2 , -CF3, C(O)-OH, or -OH; or a moiety of the formula: R8 0R9 (CH2)n- 0- (CH2)n n in each appearance is independently selected as an integer selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH,
-(CH
2 ).-C(O)-COOH, -CF 3 , -OH, -(CH 2 )n-C(O)-COOH, -C1-C6 alkyl, -O-C,-C 6 alkyl, -NH(C, C6 alkyl), or -N(C 1
-C
6 alkyl) 2 ;
R
4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )a-tetrazole, the moiety -L 1 -M' or a moiety of the formulae: 0 R12 O R12 R12 N N N N S ; N or -28- WO 99/43672 PCTIUS99/03388 0 R N =0 S
R
2 is selected from H, -CF3, C -C 6 alkyl, -(CH 2 )n-C 3
-C
6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF 3 , -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -C6-C6 alkyl, -O-Cl
C
6 alkyl, -NH(C,-C 6 alkyl), or -N(C 1
-C
6 alkyl) 2 ; L' is selected from -(CH 2 )n-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n-O-(CH2)n-, -(CH2),,-S-(CH2)n-, -(CH2)n,-C(O)-(CH2)n-, -(CH2),,-O-(CH2),,-, -(CH2)n-S-(CH2)n-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-,
-C(O)-C(Z)-N(R
6
)-(CH
2 ),-, -C(Z)-NH-SO -, -C(Z)-NH-SO -(CH 2 )n-, -C(O)-(CH 2 )n-O-, -C(O) N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M' is -COOH or a moiety selected from:
R
8
R
8 / R8<1 _;R9 R9 R N N R10 R10
R
9 0
R
7 S R 8 8 N R 8 H7N R R9R9 -29- WO 99/43672 PCT/US99/03388 S 00 0 N I/0-P -OH NR11 0 -O S S .*g OH (C1-Ce loweralkyl N (C1-Ce lower haloalkyl: ~OHR N O g R 10 or
R
8 , in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2),-C(O)-COOH, tetrazole, 0 0 0 0-P-OH S 0 ,or OH
R
9 in each appearance is independently selected from H, halogen, -CF -OH, -COOH, (CH 2 )-COOH, -(CH 2 )n-C(O)-COOH, -CI-C 6 alkyl, -0-C-C 6 alkyl, -NH(C,-C 6 alkyl), or
-N(C-C
6 alkyl) 2 ;
R'
0 is selected from H, -COOH, -(CH 2 ),-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH, -C,-C 6 alkyl, -O-C6-C6 alkyl, -30- WO 99/43672 PCT/US99/03388
R
8
R
8
R
8 Z R- , (CH2)n Rg , or RR, -S N ~A (CH2)nNR 0 0 SS N (C1-C6 lower alkyl N (C1-C6 lower haloalkyl . with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: O O2 N 0 0 0 0~ -P-OH S -31 O 0~ DH N - N R 12 0A 12 N N 0 0 S N N 00 or S
R
5 is selected from C 1
-C
6 lower alkyl, Cl-C 6 lower alkoxy, -(CH 2
)II-C
3
-C
10 cycloalkyl, -31- WO 99/43672 PCT/US99/03388
-(CH
2 )n-S-(CH 2 )n-C 3 -CIe cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3 -CO cycloalkyl, -(CH2)n-phenyl-O phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D C B D is H, C-C 6 lower alkyl, CI-C 6 lower alkoxy, -CF 3 or -(CH 2 )n-CF 3 ; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C 1
-C
6 alkyl, CI-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof. Yet other preferred compounds include those having the formula: R3 R3 R4 R4 N N R2 IR2I R5 or R wherein R, is selected from H, halogen, -CF 3 , -OH, -C-C 0 alkyl, preferably -C,-C6 alkyl, -S-C, CIO alkyl, preferably -S-C 1
-C
6 alkyl, C,-CI0 alkoxy, preferably CI-C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -0- or -(CH 2 ),- bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substituted by from 1 to 3 substituents selected -32- WO 99/43672 PCT/US99/03388 from halogen, C 1
-CI
0 alkyl, preferably C 1
-C
6 alkyl, CI-C 0 alkoxy, preferably C-C 6 alkoxy, NO 2 , -NH2, -CN, -CF 3 ; or n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R
2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C 1
-C
0 alkyl, preferably
C
1
-C
6 alkyl, C 1 -Cl 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C6 alkyl,
-N(C,-C
6 alkyl) 2 , -N-S0 2
-CI-C
6 alkyl, or -S0 2
-CI-C
6 alkyl;
R
3 is selected from H, halogen, -CF 3 , -OH, -CI-CI 0 alkyl, CI-Cl 0 alkoxy, -CHO,
-C(O)CH
3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , 2 NH-CIC6 alkyl, -N(C-C 6 alkyl) 2 , -N-SO
C
1
-C
6 alkyl, -S0 2
-C,-C
6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl,
-C(O)
benzyl, -CH 2
-(C
3
-C
5 cycloalky), -C(O)-OH,
C(O)-C,-C
6 alkyl, -C(O)-O-C-C 6 alkyl, -C(O)-CF 3 , or -(CH 2 )n-S-CH 2
(C
3
-C
5 cycloalky), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C -C alkyl, C-C 6 alkoxy, -NO2, -CF3, C(O)-OH, or -OH; or a moiety of the formula: R8 0R9 '. (CH2)n- O-- (CH2)n _ \ n in each appearance is independently selected as an integer selected from 0-3;
R
8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ),-COOH, -(CH2)n,-C(O)-COOH, -CF3, -OH, -(CH2),,-C(O)-COOH, -CF-C6 alkyl, -O-CI-C6 alkyl, -NH(C,
C
6 alkyl), or -N(C 1
-C
6 alkyl) 2 ;
R
4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: -33- WO 99/43672 PCT/US99/03388 / R 12R1o R 12 N N N o 0 0 or N 00 S
R
2 is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 )n-C 3
-C
6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from I to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH)-COOH, -(CH,)-C(O)-COOH,
-C,-C
6 alkyl, -O-C 1 C 6 alkyl, -NH(C,-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; L' is selected from -(CH2).-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n,-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2) ,-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -(CH2)n,-S-(CH2-)n-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-,
-C(O)-C(Z)-N(R
6
)-(CH
2 )-, -C(Z)-NH-S0 2 -, -C(Z)-NH-SO,-(CH 2 )-, -C(O)-(CH 2 )n-O-, -C(O) N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M' is -COOH or a moiety selected from: R8 R8 RR8
R
9 -N N R10 R 1 0 -34- WO 99/43672 PCT/US99/03388
R
9 0 US
R
8 0 8NR HN N RO R9 R. R10 0 0S 0owerS al0 N (C1-C6 loweralkyl N (C1-C6 lower haloalkyl, O S N OORO O0 R11 /0-1-O1S O
R
8 N-->R or R, in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH, (CH 2 )n-C(O)-COOH, tetrazole, 0 0 0 II \e 0P-OH S 0 ,or OH;
R
9 in each appearance is independently selected from H, halogen, -CF, -OH, -COOH, (CH 2 )n-COOH, -(CH 2 ),-C(O)-COOH, -C,-C 6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), or
-N(C,-C
6 alkyl)2;
R'
0 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH,
-C
1
-C
6 alkyl, -0-C-C 6 alkyl, -35- WO 99/43672 PCT/US99/03388 R8 R8 R8 Z R9ZRg (CH2) or R9 R0.O N (CrC6 lower alkyl 0 S..O R9 0 00 SN O N (ClC6 lower haloalkyl' with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: N 0 0 0 0 o-P-OH S 0 0 " OH N 3- N 00 N N S 0 N 0 00 N 00 or S -36- WO 99/43672 PCT/US99/03388
R
5 is selected from CI-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 )n-C 3 -CO cycloalkyl,
-(CH
2 )n-S-(CH 2 )n-C 3 -CO cycloalkyl, -(CH 2
).-O-(CH
2
).-C
3 -CO cycloalkyl, -(CH 2 )n-phenyl-O phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: C B D is H, C-C6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH2)n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF, -OH, -C 1
-C
6 alkyl, C-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof. -37- WO 99/43672 PCT/US99/03388 The present invention also provides for a method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention. Methods of treating an inflammatory response or condition, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention are also provided. Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided. Pharmaceutically acceptable salts of the compounds of the compounds described herein are also part of the present invention and may be used in practicing the compounds and methods disclosed herein. Brief Description of the Figures Figs. 1-13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are described in further detail below. Detailed Description of Preferred Embodiments As used herein, the terms "aryl" and "substituted aryl" are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms. Among these aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties. The aryl and heteroaryl groups of this invention also include the following: a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine; or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms 38 WO 99/43672 PCT/US99/03388 selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine. The "substituted aryl" groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, Cl-C10 alkyl, preferably C1-C6 alkyl, Cl-C1O alkoxy, preferably C1-C6 alkoxy, -CHO, -COOH or esters thereof, -N02, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NH(CH3), etc. A preferred subset of these groups, optionally substituted as just described, include moieties formed from benzene, pyridine, napthylene or quinoline rings. A further preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings. A preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings. The alkyl, alkenyl and alkinyl groups referred to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched. Halogens herein are understood to include F, Cl, Br and I. Preferred compounds of the present invention are disclosed in Tables I-VI below. Methods for synthesis of the compounds listed in Tables I-VI are described below. Compound Nos. in the tables correspond to example numbers below describing synthesis of that particular compound. Tables I-VI also report data for the listed compounds in the "LysoPC" assay and the Coumarine assay (see Example 88 below). In the data columns of the tables, assay results are reported as an "IQ" value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay. Where no numerical IQ0 value appears, "NA" denotes that inhibitory activity was not detected from such compound in the corresponding assay and a blank box denotes that the compound was not tested in such assay as of the time of filing of the present application. 39 WO 99/43672 PCT/US99/03388 E 40- WO 99/43672 PCTIUS99/03388 <0 Z 54 WO 99/43672 PCTIUS99/03388 09~ 00 V)r - c 6 6 S S - 00 C4 WO 99/43672 PCT/US99103388 - - Ir~ 0 5 C U U 7 7 C U,.
Q o - Q = * U 5, C! / 43 WO 99/43672 PCT/US99/03388 0u C z 44 WO 99/43672 PCT/US99/03388 ocz u L C; 454 WO 99/43672 PCT/US99/03388 0llr 00 00 000 468 WO 99/43672 PCTIUS99/03388 1r~ tr~ 0 0 6 6 - -4 5 0 0 0 C C - C Q C Q 0 ___ / Wv 47 WO 99/43672 PCT/US99/03388 00 -c 00 8 - 48 WO 99/43672 PCTIUS99/03388 00 -~ (4 C 0 0 0 o (-) z /0 Q~ 0 U (4 Z 7 / V 49 WO 99/43672 PCTIUS99/03388 A 00 5 50 WO 99/43672 PCTIUS99/03388 00 Clr 51 WO 99/43672 PCTIUS99/03388 A A > z m 52 WO 99/43672 PCT[US99/03388 00 5 53 WO 99/43672 PCT/US99/03388 A 0 UU zz C5 WO 99/43672 PCTIUS99/03388 00 A ~ / \ /0\ 55 WO 99/43672 PCTIUS99/03388 A 56 WO 99/43672 PCTIUS99/03388 00 575 WO 99/43672 PCT/US99/03388 / \/ 58 WO 99/43672 PCTIUS99/03388 0 0 A A 6 6 00 59 WO 99/43672 PCT/US99/03388 06 60 WO 99/43672 PCT/US99/03388 A A S 0 0 0. 61 WO 99/43672 PCTIUS99/03388 110 C) 0 62 WO 99/43672 PCTIUS99/03388 UmA 00 UU 00 63 WO 99/43672 PCT/US99103388 - 0 N \ / S Z 4 C-) <I V N N N N N 64 WO 99/43672 PCT/US99/03388 Cf) Vr) 00 C) 00 0 / 65 WO 99/43672 PCTIUS99/03388 - A A A A 0r - 00 100 00 00 66 WO 99/43672 PCTIUS99/03388 00 0 S6 WO 99/43672 PCTIUS99/03388 Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure described in Example 89. The results are reported in Table VII. 5 Table VII Compound No. % inhibition of rat carrageenan-induced footpad edema 8 29 10 8.9 14 34.2 10 15 21.8 16 26.3 17 29.3 19 10.5 20 19.5 15 25 17.5 26 10.3 32 26.7 33 4.2 46 12.5 20 47 7.8 50 11.7 67 17.5 70 21.7 76 8.2 25 77 13.0 68 WO 99/43672 PCT/US99/03388 As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 88 below). A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA) in any available assay (preferably an assay 5 described below in Example 88 or Example 89) for enzyme activity. In preferred embodiments, a compound has (1) an IQO value of less than about 25 pM, preferably less than about 6 pM, in the LysoPC assay; (2) an Iq 0 value of less than about 50 ptM in the vesicle assay; (3) an IC value of less than about 1 pM in the PMN assay; (4) an IQo value of less than about 15 puM in the Coumarine assay; and/or (5) measurable activity (preferably 10 at least about 5 % reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15 %, most preferably about 20-30%) in the rat carrageenan-induced footpad edema test. Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA 2 ) activity and, therefore, are useful in "treating" (i.e., treating, preventing 15 or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis. The present invention encompasses both pharmaceutical compositions and therapeutic 20 methods of treatment or use which employ compounds of the present invention. Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the 25 art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic 30 effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention. 69 WO 99/43672 PCT/US99/03388 The pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in 5 aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incorporated herein 10 by reference. As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention 15 or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. In practicing the method of treatment or use of the present invention, a 20 therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other 25 anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of 30 the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors. 70 WO 99/43672 PCTIUS99/03388 Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection. 5 When a therapeutically effective amount of compounds of the present invention is administered orally, compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% compound of the 10 present invention, and preferably from about 25 to 90% compound of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as 15 ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention. When a therapeutically effective amount of compounds of the present invention is 20 administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition 25 to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art. 30 The amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. 71 WO 99/43672 PCT/US99/03388 Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger doses of compounds of the present invention may be administered until the 5 optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0. 1 pg to about 100 mg (preferably about .1 mg to about 50 mg, more preferably about 1mg to about 2 mg) of compound of the present invention per kg body weight. 10 The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending 15 physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention. Methods of Synthesis for Examples 1-87 Compounds of the present invention can be prepared according to the following 20 methods. Temperatures are in degrees Celsius. METHOD A Indol-2-carboxylic acid ethyl ester I is converted to aldehyde II in two steps: reduction with lithium aluminum hydride (LAH) or other hydride in a suitable solvent such as 25 tetrahydrofuran (THF) at 0 0 C, and then oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilyl amide (KHMDS) in THF, followed by reaction with a chloroformate in the presence of a base, such as triethyl amine, produces carbamate III. III is transformed into bromide IV in two steps: (1) reduction with sodium borohydride 3 0 in an alcoholic solution and (2) reaction withcarbon tetrabromide in the presence of a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane. Displacement of the bromine in IV with potassium phenoxide, prepared by reaction of a phenol with 72 WO 99/43672 PCTIUS99/03388 KHMDS, in a suitable solvent such as THF or DMF affords ether V. V can be converted to either trifluoromethyl ketone VII or to carboxylic acid IX in different procedures. Reaction of V with trifluoromethyl trimethylsilane (TMSCF3) in the presence oftetrabutylammonium fluoride gives trifluoromethyl alcohol, which is then oxidized with periodinane (Dess-Martin 5 reagent) in dichloromethane to afford ketone VI. In this stage the carbamate can be removed with either trifluoroacetic acid (TFA) or with a base such as sodium hydroxide. The indole nitrogen is then alkylated with a suitable alkyl bromide in the presence of a base such as sodium hydride to produce VII. Alternatively, V can be deprotected with TFA or aqueous base, and then reacted with alkyl bromide to give VIII, which is oxidized with sodium 10 chlorite in an aqueous THF to yield acid IX. METHOD B 15 2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give X. Hydrolysis of X with a aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropyl ethylcarbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide XI. XI is 20 hydrolyzed to corresponding acid XII in a aqueous base such as sodium hydroxide. METHOD C 25 Indole I can be brominated on the 3-position by reaction with a bromine or N bromosuccinimide in a suitable solvent such ascarbon tetrachloride or dichloromethane to yield bromide XIII. Reaction of XIII with a suitable alkyl bromide in the presence of a strong base such as NaH in THF or DMF affords indole XIV. Palladium mediated coupling of XIV with a suitable alkene in the presence of phosphine and a base such as triethyl amine 30 produces 3-substituted indole XV. XV can be converted to amide XVII in two step reactions: (1) hydrolysis with aqueous base such as NaOH and (2) coupling with an amine in the presence of carbodiimide such as EDCI. Ester XIV can be transformed to lithium salt XVIII 73 WO 99/43672 PCTIUS99/03388 by hydrolysis with aqueous base and then reaction with lithium hydroxide in a suitable solvent such as ether. Lithiation with n-butyl lithium in a suitable solvent such as THF, and then acylation with an acyl chloride in THF affords ketone XIX. Carbodiimide (EDCI) catalyzed coupling of XIX and a suitable amine gives amide XX. 5 METHOD D Indole I can be converted to XXI in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSCl) in a solvent such as 10 dichloromethane or DMF in the presence of a base such as imidazole. Treatment of XXI with Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -60C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF affords ketone XXII. The silyl group on 15 XXII is removed using tetrabutylammonium fluoride in a solvent such THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide XXIII. Displacement of the bromine of XXIII with a thiol compound in the presence of a base such as Cs'-C0 3 , or with an alcohol in the presence of a strong base such as NaH in DMF affords 20 XXIV (sulfide, or ether respectively). METHOD E 25 Aldehyde II, prepared by Method A, can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield XXV. XXV can be converted to an unsaturated acid XXVI by two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such 30 as THF and (2) Hydrolysis by aqueous sodium hydroxide. Coupling reaction of XXVI with an amine catalyzed by a diimide such as EDCI (dimethylaminopropyl ethylcarbodiimide 74 WO 99/43672 PCT/US99/03388 hydrochloride), followed by hydrolysis with aqueous base such as sodium hydroxide affords XXVII. METHOD F 5 Indole I is reduced with LAH in a solvent such as THF. A second reduction with sodium cyanoborohydride in a solvent such as acetic acid to yield alcohol XXVIII. Protection of the nitrogen of XXVIII with t-butoxycarbonyl (BOC) using di-t-butyldicarbonate ((BOC)O) in the presence of a base such as triethylamine affords carbamate XXIX. The hydroxyl group in 10 XXIX is mesylated using mesyl chloride and triethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as described in METHOD D to produce indoline XXX. Deprotection of XXX using trifluoroacetic acid affords XXXI, which is either acylated (acyl chloride, triethylamine, dichloromethane) or alkylated (alkyl halide, KC0 3 , DMF) to afford XXXII, or XXXIII respectively. 15 METHOD G Carboxylic acid XXXIV is converted to aldehyde XXXV in two steps: (1) reaction with N,O 20 dimethylhydroxy amine in the presence of EDCI in a solvent such as dichloromethane, and (2) reduction with diisobutyl aluminum hydride (DIBAL) in a solvent such as THF. Treatment of XXXV with trimethyl phosphonoacetate in the presence of a strong base such as KHMDS in a solvent such as THF results in the formation of ester XXXVI. Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inert solvent such 25 as toluene gives XXXVII. Alkylation on nitrogen of XXXVII under conditions described in METHOD F, and then hydrolysis of the ester with aqueous base such as NaOH affords acid XXXVIII. XXXVIII can be converted to an amide XXXIX by coupling with a suitable amine such as benzylamine in the presence of EDCI. 30 METHOD H 75 WO 99/43672 PCT/US99/03388 Aldehyde XXXV, prepared in METHOD G, is subjected to a Wittig reaction using methyl triphenylphosphonium iodide in the presence of a strong base such as KHMDS or NaH in a solvent such as THF to afford alkene XL. Reduction of the nitro group of XL with iron powder in an ammonium chloride solution, followed by treatment with benzyl chloroformate 5 in the presence of a base such as triethyl amine produces carbamate XLL XLI is treated with iodine in a basic solution such as aqueous NaHCQ in THF to yield iodide XLIL Displacement of the iodine on XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH affords alcohol XLIII. 10 METHOD I Indoline XXVIII, prepared in METHOD F or METHOD H, can be either acylated by reaction with an acyl chloride in the presence of a base such as triethyl amine or alkylated 15 using alkyl halide in the presence of KCO 3 in a solvent such as DMF to produce alcohol XLIV. Treatment of XLIV with mesyl chloride and triethyl amine in a solvent such as dichloromethane, followed by displacement with a thiol such as methyl mercaptoacetate in the presence of a base such as CsCO 3 in a solvent such as acetonitrile yields ester XLV. Hydrolysis of XLV with an aqueous base such as NaOH gives acid XLVI, which can be 20 coupled with an amine catalyzed by a diimide such as EDCI in a solvent such as dichloromethane to afford amide XLVII. XLVII can be alkylated on the amide nitrogen by treatment with alkyl halide and strong base such as NaH in DMF. Hydrolysis of the resulting amide with aqueous base such as NaOH gives acid XLIX. XLIV can also be directly hydrolyzed with NaOH to a carboxylic acid XLVIII. 25 METHOD J METHOD J illustrates the synthesis of alpha-substituted aminophenylacetic acid esters. Ester 30 L can be deprotonated with a strong base such as lithium diisobutylamide (LDA) in a solvent such as THF, and subsequently alkylated with an alkyl halide such as methyl iodide to give LI. Reduction of LI to amine LIII can be accomplished using hydrogenation catalyzed by 76 WO 99/43672 PCT/US99/03388 palladium in a solvent such as ethanol. L can be oxidized to alcohol LII using LDA and oxaziridine in a solvent such as THF. Alkylation of LII with a alkylating reagent such as methyl iodide in the presence of a strong base such as NaH in DMF, followed by catalytic hydrogenation in the presence of palladium produces amine LIV. 5 METHOD K METHOD K illustrates the synthesis of substituted aminobenzoic acid esters. Mono-acid LV 10 can be converted to amide LVI by the following steps: (1) reaction with oxalyl chloride in dichloromethane to form acid chloride and (2) treatment with a suitable amine such as dimethyl amine. Reduction of the nitro group to the amine is accomplished with hydrogenation catalyzed by palladium as described in METHOD J. LV can be reduced to alcohol LVIII with hydroborane-THF complex in THF. Protection of the hydroxy group as a 15 silyl ether using TBDMSCl in the presence of imidazole and subsequently, reduction of the nitro group (H. / Pd-C) to the amine affords LIX. LVIII can be converted to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent such as manganese dioxide (MnO,) in ethyl acetate and (2) addition of a desired Grignard reagent such as methyl magnesium bromide in THF. Oxidation of LX with MnO in THF and reduction of the nitro 2 0 group (H, / Pd-C) produces ketone LXIII Reduction of LVII (I- / Pd-C) yields LXI. METHOD L 25 Alcohol LXIV, prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon in a solvent such as ethanol. The resulting alcohol is treated with p methoxybenzyl chloride in the presence of KCO 3 in a solvent such as THF to afford LXV. Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures described in METHOD D. Deprotection of the p-methoxybenzyl group with TFA in a solvent such as 3 0 dichloromethane, and subsequent alkylation on oxygen with a suitable reagent such as 4 benzylbenzyl bromide in the presence of KCO 3 in a solvent such as THF affords LXVIL 77 WO 99/43672 PCT/US99/03388 EXPERIMENTAL SECTION The Examples which follow further illustrate the invention. All temperatures set forth in the Examples are in degrees Celsius. All the compounds were characterized by proton 5 magnetic resonance spectra taken on a Varian Gemini 300 spectrometer or equivalent instruments. EXAMPLE 1 10 2-(2-(1-Phenylmethoxvcarbonyl-5-phenylmethoxy)indolvl)methoxybenzoic acid Step 1: 2-(5-Phenylmethoxy)indolyl aldehyde 12.3 g (42 mmol) of ethyl 2-(5-phenylmethoxy)indolyl) carboxylate was dissolved in 15 100 mL of THF, to which was added 130 mL (130 mmol) of 1 M solution of lithium aluminum hydride in THF at 0 0 C. The reacton was stirred at this temperature for 2 hours and quenched by adding 65 mL of 6 N NaOH solution slowly. The product was extracted with ethyl acetate, and the organic phase was washed with aqueous ammonium chloride. Evaporation of the solvent afforded crude alcohol, which without further purification was 20 dissolved in 400 mL of THF, 52 g of manganese(IV) oxide was added, and the mixture was stirred at room temperature overnight. Removal of manganese oxide by filtration and flash chromatographic purification using 3:1 hexane:ethyl acetate yielded 8.15 g of the title compound. 25 Step 2: Benzyl (1-( 2 -formvl-5-phenylmethoxy)indolyllformate To a solution of 6.9 g (27.5 mmol) of the aldehyde of step lin 140 mL of THF was slowly added 61 mL (30.5 mmol) of 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene at 30 -35 0 C. After stirring at this temperature for 10 min, 4.4 mL (29.5 mmol) of benzyl chloroformate was added at -35 0 C, and the mixture was then warmed from -35 0 C to 0 0 C for 3.5 hours. The reaction was quenched by pouring into aqueous ammonium chloride. 78 WO 99/43672 PCT/US99/03388 Aqueous work up and flash chromatography using 12:1 toluene:ethyl acetate afforded 4.8 g of the title compound. Step 3: Benzyl (1-(2-hydroxymethyl-5-phenvlmethoxy)indolvl)formate 5 To a solution of 2.9 g (7.5 mmol) of the aldehyde of step 2 in 40 mL of THF and 20 mL of trifluoroethanol was added 760 mg (20 mmol) of sodium borohydride at (YC. The mixture was stirred at 0 0 C for 30 min and then quenched by adding aqueous ammonium chloride. Flash chromatography using 2:1 hexane-ethyl acetate afforded 2.2 g of the title 10 compound. Step 4: Benzyl (1-(2-bromomethyl-5-phenylmethoxy)indolyl)formate To a solution of 2.2 g (5.7 mmol) of the alcohol of step 3 and 2.05 g (5.0 mmol) of 15 1,3-bis(diphenylphosphino)propane in 60 mL of dichloromethane was added a solution of 2.0 g (6 mmol) of carbon tetrabromide in 4 mL of dichloromethane at 151C. The mixture was stirred at room temperature for 2 hours and 1 g (3 mmol) of 1,3 bis(diphenylphosphino)propane was added at room temperature. After 1 hour stirring, the reaction was quenched by adding aqueous ammonium chloride. Aqueous work up and flash 20 chromatography using 4:1 hexane:ethyl acetate afforded 1.7 g of the title compound. Step 5: Benzvl (1-( 2
-(
2 -formylphenoxy)methyl-5-phenylmethoxy)indolvl)formate To a solution of 439 mg (3.6 mmol) of methyl 2-hydroxybenzoate in 18 mL of THF 25 was added 6 mL (3 mmol) of 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene at 0 0 C. The solution was stirred at 0 0 C for 10 min, to which was added a solution of 1.25 g (2.8 mmol) of the bromide, prepared in step 4, in THF at OOC. The reaction was warmed to room temperature and stirred at this temperature for 2 hours. After aqueous work up (NaLCl / ethyl acetate), the organic solvent was collected, dried over sodium sulfate and evaporated. 3 0 The product was solidified and washed with ethyl acetate:hexane 1:1. Yield 690 mg (51%). Step 6: 79 WO 99/43672 PCT/US99/03388 120 mg (0.24 mmol) of the aldehyde of step 5 was dissolved in 11 mL of 5:1:5 THF acetonitrile-2,2-dimethylethanol. To this solution was added a solution of 56 mg (0.5 mmol) of sodium chlorite in 0.5 mL water and 1 drop of aqueoues hydrogen peroxide solution. After 4 hours, another 56 mg (0.5 mmol) of sodium chlorite was added. The mixture was stirred at 5 room temperature for three days. Aqueous work up and flash chromatography using 2.5:1:0.05 hexane:ethyl acetate-acteic acid afforded 110 mg of the title compound. EXAMPLE 2 10 4-(2-(I-Phenylmethoxycarbonyl-5-phenvlmethoxy)indolyl)methoxvbenzoic acid The title compound was prepared according to the procedure described in Example 1, but using 4-hydroxybenzaldehyde. 15 EXAMPLE 3 3-(2-(1-Phenvlmethoxvcarbonyl-5-phenvlmethoxy)indolvl)methoxvbenzoic acid 20 The title compound was prepared according to the procedure described in Example 1, but using 3-hydroxybenzaldehyde. 25 80 WO 99/43672 PCTIUS99/03388 EXAMPLE 4 Benzyl (1-(2-(2-(1-oxo-2.2.2-trifluoroethyl)phenoxy)methyl-5 phenvlmethoxy)indolyl)formate 5 Step 1: Benzyl (1-(2-(2-(1-hydroxy-2.2.2-trifluoroethyl)phenoxy)methyl-5 phenvlmethoxy)indolvl)-formate A solution of 0.4 g (0.8 mmol) of the aldehyde, prepared in step 1 of Example 1, in 10 4 mL of THF was cooled to 0 0 C. To this were added 0.24 mL (1.6 mmol) of trifluoromethyl trimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate. The reaction was stirred for 2.5 hpurs at 0 0 C, and additional 0.2 mL (1.3 mmol) of trifluoromethyl trimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate were added. After stireed at 0 0 C for 2 hours, the reaction was worked up with aqueous 15 ammonium chloride and ethyl acetate. Silica gel chromatographic purification using 4:1 hexane-ethyl acetate afforded corresponding TMS ether. Treatment of TMS ether with 1.3 mL of IN Hcl solution at room temperature, aqueous woukup using brine and ethyl acetate and chromatographic purification using 3:1 hexane-ethyl acetate gave 230 mg of the titled compound. 20 Step 2: To a solution of 150 mg (0.27 mmol) of trifluoroethanol, prepared in step 1, in 5.5 mL of dichloromethane was added 255 mg (0.6 mmol) of the Dess-Martin's periodinate. The 25 mixture was stirred at room temperature for 1 hour, and then partitioned between aqueous NaHCO 3 and ethyl acetate. The organic phase was washed once with aqueous NaHCQand purified with chromatography using 3:1 hexane-ethyl acetate to yield 150 mg of the titled compound. 30 81 WO 99/43672 PCT/US99/03388 EXAMPLE 5 3-(2-(I-Benzyl-5-benzyloxyindolecarboxamido)benzoic acid 5 Step 1: Ethyl 2-(1-benzyl-5-benzyloxy)indolecarboxylate To a solution of 1 g (3.4 mmol) of ethyl 5-benzyloxyindole-2-carboxylate in 12 ml of DMF, sodium hydride (0. 163g, 60% oil dispersion, 4.07 mmol) was added at room temperature. The reaction was stirred for 30 minutes. Benzyl bromide (0.44 mL, 3.73 10 mmol) was added at this time and the reaction stirred for another hour. On completion of the reaction (monitored by TLC = 0.5 Rf in 3:1 Hexane:Ethyl acetate) it was quenched with water, extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate, concentrated and used for the next step. 15 Step 2: 2-(1-Benzvl-5-benzyloxy)indolecarboxvic acid The ester (3.4 mmol), prepared in step 2, was dissolved in THF (20 mL), methanol (20 mL) and then IN NaOH (15 mL) was added. The reaction mixture was stirred at room temperature over night at which time it was concenterated, diluted with water, acidified to pH 20 5 with 10% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the indole acid ( 1.14 g, 94.2 %, TLC = 0.5 Rf in 1:1 Hexane:Ethyl acetate with 1 % acetic acid). Step 3: Ethyl 3-(2-(1-benzvl-5-benzyloxy)indolecarboxamido)benzoate 25 The acid (0.54 g, 1.5 mmol) of step 2, 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0.018 g, 0.15 mmol) and ethyl 3-aminobenzoate (0.27 g, 1.66 mmol) were stirred in tetrahydrofuran (9 mL) at room temperature overnight. The next day the reaction was diluted with ethyl 30 acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 3:1 hexane:ethyl acetate to give pure amide (0.578 g, 76%, TLC = 0.4 Rf in 3:1 Hexane:Ethyl acetate). 82 WO 99/43672 PCT/US99/03388 Step 4: The ester (0.578 g, 1.15 mmol), prepared in step 3, was dissolved in THF (13.6 mL), methanol (13.6 mL) and then IN NaOH (9.6 mL) was added. The reaction mixture was 5 stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the titled compound (0.437 g, 80 %, TLC = 0.5 Rf in 3:1 hexane:ethyl acetate with 1 % acetic acid). 10 The Examples 6. 7. 8. 9, 10 and 11 in Table I were prepared by the procedures of Example 5 using suitable amines and alkyl halides. 15 EXAMPLE 12 3-(2-(3-(2,4-bis(1,1-dimethypropyl)phenoxyacetyl)-5-methoxy-1-methyl)indolyl) methylthioacetamido-4-methoxybenzoic acid 20 Step 1: 2-(5-Methoxy)indolylmethanol Ethyl 5-methoxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to (' C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours 25 at 04 C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO 4 and concentrated to yield 24.8 g of alcohol, which was used for the next reaction directly. 30 Step 2: 2-(5-methoxy)indolylmethoxy-tert-buthyldimethylsilane 83 WO 99/43672 PCT/US99/03388 The crude indole alcohol prepared in step 1(6.2 g, 32.6 mmol) was dissolved in DMF (10.5 mL). To this solution was added imidazole (5.5g, 81.5 mmol) and t butyldimethylsilyl chloride (5.4g, 35.8 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate (3X). Organic 5 layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19:1 hexane:ethyl acetate to give pure product (9.5g, 31 mmol, 94 % yield, TLC: 0.8 Rf in toluene:ethyl acetate 2:1) Step 3: 3-(2-tert-butydimethylsilyloxymethyl-5-methoxy)indolyl (2,4-bis(1.1 10 dimethypropvl)phenoxy)methyl ketone 2.32 g (7.95 mmol) of 2.4-Bis-tert-amylphenoxyacetic acid was dissolved in dichloromethane (21 mL), oxalyl chloride (1.4 mL 16.1 mmol) was added, followed by dimethyl formamide (0.5 mL) at room temperature. After one hour the reaction is 15 concentrated and azeotroped with toluene and left on the high vacuum for two hours. In another reaction vessel, a solution of the silyl protected indole, prepared in step 2, (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethyl magnesium bromide (2.4 mL of a 3M solution in ether, 7.2 mmol) in ether (10 ml), the latter maintained at -78oC. The reaction was stirred at -60'C for 2 hr. To this reaction solution, the above prepared acid 20 chloride in ether (4 mL) was added slowly. The reaction was maintained between -56C and -60'C for another 2 hrs. The reaction was then quenched with saturated sodium bicarbonate. Extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19:1 Hexane:Ethyl acetate to give pure product (2.36 g, 50%, TLC: 0.15 Rf in hexane:ethyl 25 acetate 19:1. Step 4: 3 -(2-tert-butydimethylsilyloxymethyl-5-methoxv-1-methyl)indolvl (2,4-bis(1.1 dimethvpropyl)phenoxv)methyl ketone 30 To the ketone (1.97g, 3.4 mmol) of in step 3 in 12 ml of DMF, sodium hydride (0.163g, 60% oil dispersion, 4.07 mmol) was added at room temperature. The reaction was 84 WO 99/43672 PCTIUS99/03388 stirred for 30 minutes. Methyl iodide (0.23 mL, 3.73 mmol) was added at this time and the reaction stirred for another hour. On completion of the reaction (monitored by TLC) it was quenched with water, extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate, concentrated and the crude product was used for the next step. 5 Step 5: 3-(2-Hydroxymethyl-5-methoxy-1-methyl)indolyl (bis-2.4 (1,1,.dimethylpropyl)phenoxy)methyl ketone A mixture of N-methyl indole, prepared in step 4, (2.01 g, 3.4 mmol) and tetra-butyl 10 ammoniumfluoride (TBAF) (8.5 mL of a IM solution in THF, 8.5 mmol) in THF (17.9 mL) were stirred at room temperature for one hour. At this time the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using hexane:ethyl acetate 2:1 to yield pure alcohol (0.82 g, 60 %, TLC: 0.3 Rf in 2:1 hexane:ethyl acetate). 15 Step 6: Methyl 3-(2-(3-(2.4-bis( 1,1-dimethypropyl)phenoxy)acetyl-5-methoxy-1 methylindolyl)methylthioacetamido)-4-methoxybenzoate The indole alcohol, prepared in step 5, (0.20 g, 0.43 mmol) was dissolved in 20 dichloromethane (0.7 mL) and treated with triethylamine (0. 1 mL, 0.64 mmol) and cooled to 0" C at which time mesyl chloride (0.04 mL 0.52 mmol) was added over 5 minutes, followed by addition of two drops of DMF. The reaction was stirred for a further 2 hour at OC, it was then concentrated and used directly for the next reaction. The above prepared mesylate was dissolved in DMF (0.8 mL). The solution was 25 degassed by bubbling nitrogen through for ten min. Cesium carbonate (0.25 g, 1.29 mmol) was added and then thiol (0.11 g, 0.43 mmol), prepared in Intermediate 1, was added. The mixture was stirred overnight, then poured into saturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated. The crude material was purified on a silica gel column using hexane:ethyl = 2:1 acetate to give pure product (0.12 g, 40%, TLC: 0.3 Rf in 30 hexane:ethyl acetate 1:1). Step 7: 85 WO 99/43672 PCT/US99/03388 The ester, prepared in step 6, (0.12 g, 0.17 mmol) was dissolved in THF (1.0 mL), methanol (1.0 mL) and then 1N NaOH (0.4 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 withlO% HCl and extracted with ethyl acetate (3X), the organic extracts 5 were dried over magnesium sulfate and concentrated to give the titled compound (85 mg, 72 %, TLC = 0.3 Rf in 1:1 Hexane:Ethyl acetate with 1 % acetic acid). EXAMPLES 13, 14, 15 and 16 in Table I were prepared by the procedures of Example 12 10 using Ethyl 2-(5-benzyloxy)indolecarboxylate, acetyl chlorides and suitable alkyl halides. EXAMPLE 17 15 3-(2-(-5-benzyloxv- 1-(2,4-bis( 1.1 -dimethy)ropyl)phenoxvacetyl)indolinvl) methylthioacetamidobenzoic acid Step 1: 2-(5-Benzyloxy)indolinylmethanol Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF 20 and cooled to 01 C, to which Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) was added via addition funnel over 40 minutes. The reaction was stirred a for 2 hours at 0 0 C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3X400 mL), the filtrates were combined, dried over MgSO 4 and concentrated to yield 24.8 g. This crude material was then dissolved 25 in glacial acetic acid (260 mL) and the resulting yellow solution was cooled to 15 C, sodium cyanoborohydride (18.5 g, 294 mmol) was added portionwise over 10 minutes, and the resulting mixture was stirred for 3 hours. The reaction was quenched by pouring slowly into 1.5 liters of nearly saturated NaHCq, extracted with ethyl acetate (3X), dried over MgSQ and concentrated to yield a orange solid (29.6 g). 30 Step 2: tert-Butvl 1-(5-benzyloxy-2-hydroxymethy)lindolinlformate 86 WO 99/43672 PCTIUS99/03388 25 g (85 mmol) of crude alcohol, prepared in step 1, and 4-dimethylamino pyridine (DMAP) (1.19 g, 9.78 mmol) were dissolved in dichloromethane (180 mL). The solution was cooled to O' C and then triethylamine (13.6 mL, 98 mmol) was added to it. After 10 minutes of stirring a solution of di-tert-butyl dicarbonate (21.3 mL, 98mmol) dissolved in 5 dichloromethane (20 mL) was added via syringe pump over 2 hours. After 1 hour of stirring the reaction was quenched by the addition of 1/2 saturated NIJCl solution and extracted with CHCl 2 (3X), dried over MgSO 4 and concentrated to yield 36.3 g of a yellow oil, which was purified by column chromatography using a hexane:ethyl acetate gradient of 9:1 to 4:1 to 1:1 to deliver the product (15.25 g, 44%). 10 Step 3: Ethyl 2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinylmethylthioacetate The carbamate, prepared in step 2, (15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with triethylamine (9.0 mL, 64.4 mmol). The solution 15 was cooled to -10' C at which time mesyl chloride (4.3 mL. 56 mmol) was added over 5 minutes. The reaction was stirred for a further 2 hour at -10"C, it was then concentrated and used directly for the next displacement reaction. The above prepared mesylate was dissolved in DMF (85 mL, degassing the solvent is strongly reccomended) cesium carbonate (35 g, 107.3 mmol) was added and then ethyl 20 thioacetate (4.70 mL, 42.9 mmol) was added. The mixture was stirred for 1 day, then poured into 1/2 sturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (hexane:ethyl acetate gradient 10:1 to 4:1) to yield 8.55 g of a yellow oily product. 25 Step 4: 2-(5-Benzyloxy-1-tert-butoxycarbonyl)indolinylmethylthioacetic acid To a solution of the indoline ester, prepared in step 3, (5g, 11 mmol) in IM potassium hydroxide in methanol (100 mL), water (10 mL) was added. The reaction was stirred at room temperature for two hours at which time it was diluted with water, acidified to 30 pH 5 with10% HCl and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the indoline acid ( 4.5g, 95.5%, TLC = 0.5 87 WO 99/43672 PCTIUS99/03388 Rf in 2:1 hexane:ethyl acetate with 1 % acetic acid). The crude material was used for the next step directly. Step 5: Ethyl 3-(2-(5-benzyloxy-1-tert 5 butoxycarbonyl)indolinvl)methylthioacetamidobenzoate The acid (3g, 7 mmol), prepared in step 4, 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide (1.6g, 8.4 mmol), 4-dimethylaminopyridine (0.85g, 7 mmol) and ethyl 3 aminobenzoate (1.27 g, 7.7 mmol) were stirred in tetrahydrofuran (43 mL) at room 10 temperature overnight. On next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 3:1 hexane:ethyl acetate to give the product (3.4g, 85%, TLC = 0.3 Rf in 3:1 hexane:ethyl acetate). 15 Step 6: Ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate To the indoline (3.4g, 5.9 mmol) of step 5, trifluoroacetic acid (24 mL) was added and the reaction stirred for 1 hour at G'C. The reaction was quenched by the addition of water and the TFA neutralized by the addition of sodium bicarbonate, the aqueous layer was 20 extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2:1 hexane:ethyl acetate to yield product (2.7 g, 96 %, TLC = 0.3 Rf in 2:1 hexane:ethyl acetate). Step 7: Ethyl 3-(2-(5-benzyloxy-1-(2.4-bis(1,1-dimethyllpropyl)phenoxyacetyl)indolinyl) 25 methylthioacetamidobenzoate The 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid (0.228 g, 0.78 mmol) was dissolved in dichloromethane (2 mL), to which oxalyl chloride (0.14 mL 1.6 mmol) was added followed by dimethyl formamide (0.1 mL) at room temperature. After one hour the 30 reaction is concentrated and azeotroped with toluene and left on the high vacuum for two hours. The indoline ester (0.308 g, 0.65 mmol), prepared in step 6, and 4 dimethylaminopyridine (0.008 g, 0.066 mmol) were dissolved in dichloromethane (1.2 mL) 88 WO 99/43672 PCT/US99/03388 and then the above prepared acid chloride in dichloromethane (0.5mL) was added followed by the addition of triethylamine (0.28mL, 1.95 mmol). The reaction was stirred at room temperature overnight, and then diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was 5 purified on silica gel using 2:1 hexane:ethyl acetate to yield product (0.291 g, 60 %, TLC = 0.4 Rf in 2:1 hexane:ethyl acetate). Step 8: 10 The ester (0.231 g, 0.31 mmol) of step 7 was dissolved in THF (4.3 mL), methanol (4.3 mL) and than IN NaOH (3.2 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the titled product ( 0.207 g, 93.2 %, TLC = 0.3 15 Rf in 2:1 hexane:ethyl acetate with 1.5 % acetic acid). EXAMPLE 18 20 3-(2-(-5-Benzyloxv-1-(2,4-bis(1.1-dimethy)propyl)phenoxvacetyl)indolinvl) methylthioacetamido-4-methylbenzoic acid Step 1: Ethyl 2-(5-benzyloxy)indolinylmethylthioacetate 25 The N-tert-butoxycarbonyl indoline (3.0 g, 6.6 mmol), prepared in step 3 of Example 17, was added to a flask and cooled to 01C. To this reaction mixture trifluoroacetic acid was added (35 mL) and the reaction was stired for 1 hour at 0 0 C and then 1 hour at rt. The reaction was quenched by the addition of water, and the TFA was neutralized by the addition of solid sodium bicarbonate, the aqueous layer was extracted with ethyl acetate (4X) and 30 dried over magnesium sulfate and concentrated to an orange oil (1.85 g, 79%) that was used directly for the next step. 89 WO 99/43672 PCT/US99/03388 Step 2: Ethyl 2-(5-benzyloxy-1-(2.4-bis(1,1-dimethy)propyl)phenoxyacetyl) indolinylmethylthioacetate 2,4-Bis(1, 1-dimethy)propyl)phenoxyacetic acid (2.0g, 6.8 mmol), dichloromethane 5 (15 mL), oxalyl chloride (1.2 mL, 13.6 mmol), dimethylformamide (0.1 mL) were stirred at 00 C for 45 minutes at which time the reaction is concentrated and azeotroped with toluene (1X) and concentrated on the high vac for 2 hours before use. The indoline ester (1.85g, 5.2 mmol), prepared in step, and 4-dimethylaminopyridine (0.08 g) were dissolved in dichloromethane (15 mL) and then the above generated acid chloride in dichloromethane (5 10 mL) was added followed by the addition of triethylamine (0.95 mL, 6.8 mmol). The reaction was stirred 16 hours at rt, worked up and concentrated (4.0 g, orange oil), chromatographed using a 9:1 to 6:1 gradient of hexane:ethyl acetate to yield the product (2.5g, 75%) that was used for the next step without further purification. 15 Step 3: 2-(5-Benzyloxy-1-(2,4-bis(1.1 dimethy)propyl)phenoxyacetyl)indolinylmethylthioacetic acid The ester (2.5 g, 3.9 mmol), prepared in step 2, was dissolved in THF (20 mL), methanol (6 mL) and then 1N sodium hydroxide (12 mL) was added. The resulting mixture 20 was stirred 24 hours at which time it was concentrated, diluted with water, acidified to pH 4 with concentrated HCI and extracted with ethyl acetate (4X), the organic extracts were dried over magnesium sulfate, concentrated, and purified via chromatography (3:1 hexane:ethyl acetate with I % acetic acid) to yield 1.17 g ( 50%) of the product as white solid. 25 Step 4: Methyl 3-(2-(5-benzyloxy-1-(2.4-bis(1,1-dimethy)propvl)phenoxvacetyl)indolinvl) methylthioacetamido-4-methylbenzoate The acid (0.20 g, 0.33 mmol), prepared in step 3, EDCI (0.08 g, 0.43 mmol), DMAP (4 mg, 0.03 mmol) and methyl 3-amino-4-hydroxy benzoate (0.06 g, 0.33 mmol) 30 were dissolved in THF (3 mL) and refluxed16 hours. Aqueous workup with ammonium chloride and ethyl acetate and purification via silica gel chromatography (hexane:ethyl acetate 3:1) yielded 0.13 g (52%) of the product as a white solid. 90 WO 99/43672 PCT/US99/03388 Step 5: The titled compound was prepared from ester, prepared in step 4, according to the procedure described in step 3. 5 EXAMPLES 17 to 36 in Table 2 were prepared according to the procedurs described in either Example 17 or Example 18. 10 91 WO 99/43672 PCT/US99/03388 EXAMPLE 37 2-(5-Benzyloxy-1-(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetic acid 5 Step 1: 2-(5-Benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methano A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and equalizing dropping funnel was charged with 17.0 g ( 59 mmol) of 3,5 bis(trifluoromethyl)phenoxyacetic aci, DMF (5 drops) and anhydrous CICl, (300 mL). 10 Oxalyl chloride (23 mL, 263 mmol) was added dropwise over 10 min. After stirring for 2.5 h at room temperature solvent, excess oxalyl chloride were removed in vacuo to afford acid chloride as a white solid. This was used immediately in the next reaction. A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and equalizing dropping funnel was charged with 15.3 g (60 mmol) of 2-(5 15 Benzyloxy)indolinylmethanol, prepared in step of Example 17, DMAP (0.73 g, 6 mmol) and anhydrous CHRCl, (300 mL). After cooling to 0 C, a solution of above prepared acid chloride (59 mmol) in anhydrous CRCI, (100 mL) was added dropwise, followed by NE; (9 mL, 64.7 mmol). After stirring for 1 h at 0"C the reaction mixture was washed with saturated NaHCO solution (100 mL), 1 N HCI solution (100 mL) and HO (100 mL), dried 20 over NaSO 4 and filtered. The solvent was removed in vacuo. Purification by column chromatography in silica gel using 25-40% AcOEt in hexane afforded product as a light yellow solid. Yield 22.0 g (71 %). Step 2: Ethyl 2-(5-benzyloxy-1-(3.5-bis(trifluoromethvl)phenoxyacetyl)indolinyl) 25 methylthioacetate A 500-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (19.0 g, 36.15 mimol), prepared in step 1, anhydrous CHCI (300 mL), and NEt 3 (7.5 mL, 54.23 mmol). MsCl was added dropwise over 2 min and the reaction 30 mixture was stirred at room temperature for 10 min. The solution was diluted with CHCl 2 (500 mL) and washed with IN HCl solution (100 mL) and saturated NaHCQ solution (100 92 WO 99/43672 PCTIUS99/03388 mL). The CH 2 Cl 2 solution was dried over NaS0 4 and filtered. The solvent was removed and the mesylate was used in the next step without further purification. A 500-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ethyl thioacetate (4.2 mL, 38.5 mmol), and anhydrous THF (75 mL). After 5 cooling in a dry ice/acetone bath NaN(SiM9)2 (1 M solution in THF, 50 mL, 50 mmol) was added. After 15 min a solution of above prepared mesylate (21 g, 35 mmol) in anhydrous THF (60 mL) was added. After 15 min the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 100 min the reaction was heated at reflux for 4 h. The solution was allowed to cool to room temperature. It was diluted with CHC1 3 10 (500 mL), washed with saturated NaCO 3 solution (200 mL) and IN HCl solution (200 mL). The organic solution was dried over NaSO 4 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel using15% AcOEt in hexane to afford 13.8 g (63%) of product. 15 Step 3: A 250-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (12.45 g, 19.8 mmol), prepared in step 2, THF (100 mL), MeOH (33 mL) and HO (33 mL). LiOH-HO (1.08 g, 25.7 mmol) was added and the reaction mixture was stirred at 20 room temperature for 3 h. The solvents were removed in vacuo. The residue was taken into IN HCl solution (200 mL) and extracted with AcOEt (2 x 400 mL). The combined extracts were washed with 1 N HCl solution (100 mL), dried over NaSO 4 and filtered. The solvent was removed in vacuo to afford the titled compound. Yield 11.9 g (100%). 25 93 WO 99/43672 PCT/US99/03388 EXAMPLE 38 5-(2-(-5-Benzyloxy- 1 -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinvl)methylthioacetamido) 5 benzene-1.3-dicarboxylic acid Step 1: 5-(2-(-5-Benzyloxy-1-(3.5-bis(trifluoromethyl)phenoxvacetyl)indolinvl) methylthioacetamido)benzene-1.3-dicarboxylate 10 A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with acid (1.2 g, 2 mmol), prepared in step 3 of Example 37, anhydrous THF (40 mL), EDCI (0.544 g, 2.8 mmol), DMAP (0.024 g, 0.2 mmol), and 5-amino-1,3 benzenedicarboxylic acid (0.46 g, 2.2 mniml). The reaction mixture was heated at reflux until no change was detected by TLC. The solvent was removed in vacuo. The residue was 15 dissolved in CHCl, (200 mL), washed with 1 N HCl solution (25 mL), dried over NaSO 4 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel using 1-2% MeOH in CHClI 2 to afford 1.2 g (77%) of product. Step 2: 20 A 25-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (0.6 g, 0.76 mmol), prepared in step, THF (7.5 mL), MeOH (2.5 mL) and H20 (2.5 mL). LiOH-HO (0.084 g, 2 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h. The solvents were removed in vacuo. The residue was taken into 1N 25 HCI solution (10 mL) and extracted with AcOEt (2 x 50 mL). The combined extracts were dried over Na2SO4 and filtered and removed in vacuo. The crude material was purified by column chromatography on silica gel (eluant: 5% MeOH in CHCi3 + 0.5-0.7% AcOH) to yield 0.28 g (46%) of the titled compound. 30 EXAMPLES 39, 40, 43 in Table 3 were prepared according to the procedurs described in either Example 38. 94 WO 99/43672 PCT/US99/03388 EXAMPLE 41 5 -2--5-Benzlox--(3.-bstrifluoromethv)phenoxvacetlindolinvlmethlthioacetamido) 3 -hydroxvmethylbenzoic acid Step 1: Methyl 5-(2-(-5-benzyloxy-1-(3.5-bis(trifluoromethyl)henoxvacetyl)indolinvl) methylthioacetamido)-3-tert-butvidimethylsilxymethylbenzoate 10 This compound was prepared according to the procedure described in step 1 of Example 38. Step 2: Methyl 5-(2-(-5-benzvloxy 1 -(3. S-bis(trifluoromethyl)phenoxvacetyllindolinyl) 15 methylthioacetamido)-3-hvdroxymethylbenzoate A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with silyl propected ester (1.32 g, 1.5 mmol), prepared in step 1, anhydrous THF (10 mL), and TBAF (1 M solution in THF, 2.5 mol equiv.). The reaction mixture was 20 stirred at room temperature for 3 hours. The solvent was removed in vacuo. The oily residue was purified by column chromatography on silica gel using 0-30% AcO~t in CI,1 to afford 0.94 g (92%) of desired product. Step 3: 25 The titled compound was prepared according to the procedure described in step 2 of Example 38. 30 EXAMPLE 42 in table 3 was prepared according to the procedures described in Example 41. 95 WO 99/43672 PCT/US99/03388 EXAMPLE 44 5-(2-(-5-Hydroxy- 1 -(3.5-bis(trifluoromethyl)phenoxvacetyl)indolinvl)methylthioacetamdo) benzene-1.3-dicarboxylic acid 5 Step 1: 2-(5-Hydroxy-1-(3.5-bis(trifluoromethyl)phenoxvacetyl)indolinyl)methanol A 500-mL Parr Hydrogenation bottle was charged with 2-(5-Benzyloxy-1-(3,5 bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol (10 g, 19.1 mmol), prepared in step 1 10 of Example 37, 5% Pd on carbon (1.0 g), AcOEt (150 mL) and MeOH (100 mL) and subsequently hydrogenated at 50 psi for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to afford crude product. This was used in the next step reaction without further purification. 15 Step 2: 2-(5-(4-Methoxy)benzyloxy-1-(3.5 bis(trifluoromethyl)phenoxvacetyl)indolinvl)methanol A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with alcohol (8.56 g, 19.7 mmol), prepared in step, 200 mesh 20 K 2 C0 3 (6.53 g, 47.2 mmol), KI (3.91 g, 23.6 mmol) and finally the p-methoxy benzyl chloride (3.2 mL, 23.6 mmol) in 450 mL of anhydrous acetonitrile. The reaction mixture was heated at reflux for 4 h. The reaction mixture was partitioned between AcOEt (500 mL) and HO (200 mL). The aqueous layer was extracted with AcOE(3 x 500 mL). The combined AcOEt extracts were washed with brine (500 mL), dried over NaSO 4 and filtered. 25 The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 40% AcOEt in hexane) afforded desired product. Yield 8.7 g (83%). Step 3: Methyl 5-(2-(-5-(4-methoxylbenzyloxv-1-(3.5-bis(trifluoromethyl)phenoxvacetyl) indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate 30 A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (3.2 g, 5.77 mmol), prepared in step 2, and anhydrous CHEl, (44 mL). 96 WO 99/43672 PCTIUS99/03388 The reaction mixture was cooled to OOC and added anhydrous EtN (1.2 mL, 8.61 mmol) followed by MsCl (0.53 mL, 6.84 mmol). The reaction mixture was stirred at O'C for 5 min. The reaction mixture was partitioned between CHCI 2 (100 mL) and HO (50 mL). The aqueous layer was extracted with ClICl (3 x 100 mL). The combined CRIC 2 extracts 5 were washed with 1 N HCI solution (100 mL), saturated NaHCQ solution (100 mL), HLO (100 mL), brine (100 mL), dried over NaSO 4 and filtered. The solvents were removed in vacuo to afford mesylate. This was used in the next step reaction without further purification. A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar 10 and reflux condenser was charged with above prepared mesylate (3.60 g, 5.70 mmol), anhydrous CS-C0 3 (5.19 g, 15.9 mmol) and anhydrous DMF (20 mL). The reaction solution was passed through N for 15 min. Methyl 5-thioacetamido-1,3-benzenedicarboxylate, prepared in Intermediate 2, was added in one portion and the reaction mixture was heated at 50 0 C for 18 h. The reaction mixture was partitioned between AcOEt (500 mL) and HO 15 (200 mL). The aqueous layer was extracted with AcOEt(3 x 100 mL). The combined AcOEt extracts were washed with saturated NaCO 3 solution (100 mL), H0 (100 mL), brine (500 mL), dried over NaS0 4 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 5 % AcOEt in CHIl 2 ) afforded product. Yield 2.5 g (53%). 20 Step 4: Methyl 5-(2-(-5-Hydroxv-1-(3.5-bis(trifluoromethyl)phenoxyacetyl) indolinyl)methylthioacetamido)benzene- 13-dicarboxylate A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was 25 charged with ester (2.60 g, 3.17 mmol), prepared in step 3, and anhydrous CHCl, (30 mL). To the reaction mixture was added TFA (25 mL) in several portions over 1 min. The reaction mixture was poured onto 500 mL saturated NaHCQ solution and extracted with CHCl (3 x 100 mL). The combined CHCl, extracts were washed with saturated NaCO 3 solution (200 mL), HO (200 mL), brine (500 mL), dried over NaSO 4 and filtered. The 30 solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 12.5% - 20% AcOEt in CIICl ) afforded the product. Yield 1.5 g (68%). 97 WO 99/43672 PCT/US99/03388 98 WO 99/43672 PCT/US99/03388 Step 5: A 25-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (270 mg, 0.40 mmol), prepared in step 4, UOH hydrate (3.3 equiv.), THF (3.6 mL), 5 MeOH (1.2 mL) and 1O (1.2 mL). The reaction mixture was heterogeneous with white solid suspended in the solution. After stirring for 4 h, more solvents were added in 3 : 1 : 1 = THF : MeOH : H,0 to make a clear solution. The reaction mixture was stirred at room temperature for 18 h and monitored by TLC. The reaction mixture was acidified with 1 N HCl solution to pH = 2 or with acetic acid to pH = 4 and then partitioned between AcOEt 10 (20 mL) and H20 (20 mL). The aqueous layer was extracted with AcOE(3 x 20 mL). The combined AcOEt extracts were washed with HO (20 mL), brine (20 mL), dried over NaSO 4 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel followed by recrystallization from acetone / hexane afforded 130 mg of the titled compound (50%). 15 EXAMPLE 45 5-(2-(5-(3.5-Dibromo)benzyloxy- 1-(3,5-bis(trifluoromethyl)phenoxvacetyl)indolinyl) 20 methylthioacetamido)benzene-1,3-dicarboxylic acid Step l: Methyl 5-(2-(5-(3.5-Dibromo)benzyloxy-1-(3.5-bis(trifluoromethyl)phenoxYacetyl) indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate 25 A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with methyl 5-(2-(-5-Hydroxy-1-(3,5 bis(trifluoromethyl)phenoxyacetyl) indolinyl)methylthioacetamido)benzene-1,3-dicarboxylate (0. 19 g, 0.27 mmol), prepared in step 4 of Example 4, 200 mesh KCO 3 (2.4 equiv.) and 3,5 dibromobenzyl bromide (1.2 equiv.) in 7.5 mL of anhydrous acetonitrile. The reaction 30 mixture was heated at 70'C for 2 h. The reaction mixture was partitioned between AcOEt (30 mL) and H20 (20 mL). The aqueous layer was extracted with AcOEt(3 x 30 mL). The combined AcOEt extracts were washed with brine (50 mL), dried over NaSO 4 and filtered. 99 WO 99/43672 PCT/US99/03388 The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel using 15% EtOAc in dichloromethane afforded 0.20 g of the product (77%). Step 2: 5 The titled compound was prepared from the ester, prepared in step 1, according to the procedure described in step 5 of Example 44. 10 EXAMPLES 46 to 50 in table 4 were prepared according to the procedures described in Example 44, but using corresponding alkylating reagent. EXAMPLE 51 15 Methyl 3-(2-(5-benzyloxy-1-(4-benzylbenzoyl)indolinyl)methylthioacetamido)benzoate 4-Benzylbenzoic acid (0. 19g, 0.91 mmol) was dissolved in dichloromethane (2.3 ml), next oxalyl chloride (0.16 mL, 1.82 mmol) was added followed by dimethylformamide 20 (0.5 mL) at room temperature. After one hour the reaction was concentrated and azeotroped with toluene and left on high vaccum for two hours. Ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.308 g, 0.65 mmol), prepared in step 6 of Examle 17, and 4-dimethylaminopyridine (8 mg, 0.066 mmol) were dissolved in dichloromethane (1.2 mL) and then the above prepared acid chloride in 25 dichloromethane (0.5 mL) was added followed by the addition of triethylamine (0.28 mL, 1.95 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2:1 hexane:ethyl acetate to yield 0.354 g of the titled product (81.7%, TLC = 0.4 Rf in 2:1 30 hexane:ethyl acetate). 100 WO 99/43672 PCT/US99/03388 101 WO 99/43672 PCT/US99/03388 EXAMPLE 52 3-(2-(5-Benzyloxy-1-(4-benzylbenzoyl)indolinyl)methylthioacetamido)benzoic acid 5 The ester (0.354 g, 0.53 mmol), prepared in Example 51, was dissolved in THF (5.6 mL), methanol (5.6 mL) and than IN NaOH (4.2 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concentrated, diluted with water, acidified to pH 5 withlO% HCl and extracted with ethyl acetate (3X). The organic extracts were dried over magnesium sulfate and concentrated to give the titled product (0.32 g, 94.4 10 %, TLC = 0.3 Rf in 2:lhexane:ethyl acetate with 1.5 % acetic acid). EXAMPLES 53 to 58 in Table 5 were prepared according to the procedures described in Example 51 and 52. 15 EXAMPLE 59 3-(2-(5-Benzyloxy-1-(2-naphthoxyacetyl)indolinyl)methylthioacetamido)-4-methoxybenzoic 20 acid Step 1: Methyl 3-(2-(5-benzyloxyindolinyl)methylthioacetamido)-4-methoxybenzoate This compound was prepared according to the procedures described in step 6 of 25 Example 17, but with methyl 4-methoxybenzoate. Step 2: Methyl 3-(2-(5-benzyloxy-1-(2-naphthoxyacetyl)indolinyl)methylthioacetamido)- 4 methoxybenzoate 30 The indole ester (0.22 g, 0.45 mmol), prepared in step 1, 2-naphthoxyacetic acid (0.11 g, 0.53 mmol), EDCI (0.10 g, 0.53 mmol) and DMAP (5 mg, 0.04 mmol) were weighed into a flask that was equipped with a condenser, flushed with nitrogen, and then 102 WO 99/43672 PCT/US99/03388 tetrahydrofuran (5 mL) was added and the reaction was brought to reflux for 18 hours; the reaction was diluted with 1/2 saturated ammonium chloride and ethyl acetate, extracted 3X with ethyl acetate, dried over magnesium sulfate, concentrated to yield (0.30 g, 100% crude) a white solid that was used without purification. 5 Step 3: The ester ( 0.12 g, 0.20 mmol), prepared in step 2, was dissolved in THF/ methanol and then 1N sodium hydroxide (0.8 mL) was added and the resulting mixture was stirred 16 10 hours at RT and a further 5 hours at 45'C, workup yielded 0.12 g of a yellow solid that was purified via preparative TLC (1:1 hexane:ethyl acetate with 1% acetic acid) to yield 0.12 g of the titled product (95%). 15 EXAMPLES 60 to 63 in Table 5 were prepared according to the procedures described either in Example 59 or in Examples 51 and 52. EXAMPLE 64 20 3-(2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinyl)methylsulfonvlacetamidobenzoic acid Step 1: Ethyl 3-(2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinyl)methylsulfonyl acetamidobenzoate 25 To a solution of Ethyl 3-(2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinyl)methy lthioacetamidobenzoate (0.05g, 0.09 mmol), prepared in step 5 of Example 17, in dichloromethane (0. 1 mL) at room temperature, m-chloroperbenzoic acid (0.06g of 60% m cPBA, 0.21 mmol) was added and the reaction stirred overnight. Next day the reaction was 3 0 quenched with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude sulfone (0.52g, 98%, TLC = 0.3 Rf in 1:1 hexane:ethyl acetate) was used for the next reaction directly. 103 WO 99/43672 PCT/US99/03388 104 WO 99/43672 PCT/US99/03388 Step 2: The titled compound was prepared according to the procedure described in step 3 of Example 59. 5 EXAMPLES 66 and 65 were prepared according to the procedures described in Example 18. 10 EXAMPLE 67 2-(2-(-5-Benzyloxy-1-(2.4-bis(1.1-dimethy)propyl)phenoxvacetyl)indolinvl)methvlthiobenzoic acid 15 Step 1: 5-Benzyloxv-1-(2.4-bis(1.1-dimethy)ropyl)phenoxyacetyl)-2-hvdroxymethylindoline The diisopropylethylamine (3.5 mL, 20.5 mmol), DMAP(0.25 g, 2.05 mmol) and the indoline alcohol (4.53 g, 17.7 mmol), prepared in step I of Example 17, were weighed into a flask which was flushed with nitrogen and cooled to 0 C at which time a 0' C solution of di 20 tert-amylphenoxyacetyl chloride (20.5 mmol) in CHCI 2 (50 mL) was added via cannula. The resulting solution was left to warm to room temperature overnight and then quenched by the addition of 1/2 saturated ammonium chloride and CHClI, the solution was extracted with CHCl (3X), the combined layers were dried over magnesium sulfate and concentrated to yield (10.4 g) of a yellow foam that was purified via chromatography using a gradient 25 (hexane:ethyl acetate 7:1 to 3:1 to 1:1) to yield 3.62 g of the product. Step 2: 2-(5-Benzyloxy-1-(2.4-bis(1.1-dimethy)propyl)phenoxvacetyl)indolinvlmethyl _ methylsulfonate 30 To a solution of alcohol (1.2 g, 2.26 umol) in CHClI (15 mL), prepared in step 1, is added triethylamine (0.44 mL, 3.16 mmol). The solution is brought to -50'C and then mesyl chloride (0.23 mL, 2.93 mmol) is added. The mixture is stirred 2 h at -50'C, 105 WO 99/43672 PCT/US99/03388 quenched with saturated ammonium chloride and allowed to come to rt. The mixture is taken up in CHC1 3 (50 mL), washed with saturated sodium bicarbonate (1 X 10 mL), brine (1 X 10 mL), dried (MgSO4), filtered and concentrated to afford the product (1.19 g, 86%). 5 Step 3: Methyl 2-(2-(-5-benzyloxy-1-(2.4-bis(1,1-dimethy)propyl)phenoxyacetyl) indolinyl)methylthiobenzoate To a solution of mesylate (0.54 g, 0.89 mmol), prepared in step 2, in degassed DMF (2 mL) is added CsCO 3 (0.724 g, 2.22 mmol) and methyl thiosalicylate (0.134 mL, 0.98 10 mmol). The mixture is stirred 4 h, taken up in ethyl acetate (20 mL), washed with brine (3 X 3 mL), dried (MgSO 4 ), filtered and concentrated. Chromatography (gradient, hexane:ethyl acetate 15:1 to 4:1) afforded 0.53 (86%) of the title compound as a yellow oil. Step 4: 15 The titled compound was prepared according to the procedure described in step 3 of Example 59. 20 EXAMPLE 68 was prepared according to the procedures described in Example 67. EXAMPLE 69 25 3-(N-(2-(-5-Benzvloxy-1-(2.4-bis(1, 1 -dimethy)propylphenoxvacetyl)indolinvl) methylthioethyl)aminobenzoic acid The titled product was prepared according to the procedures described in step 3 of Example 59, but using Intermediate 15. 30 106 WO 99/43672 PCT/US99/03388 EXAMPLE 70 3-N-Methvl-(2-(-5-Benzyloxv-l-(2.4-bis(1 1-dimethy)propyl)phenoxyacetyl)indolinyl) methylthioacetamido-4-methoxvbenzoic acid 5 An oven-dried 100 mL, 3-neck round bottom flask, equipped with a stir bar and nitrogen inlet, was charged with methyl 3-(2-(-5-Benzyloxy-1-(2,4-bis(1,1-dimethy)propyl) phenoxyacetyl)indolinyl)methylthioacetamido-4-methoxybenzate (581 mg, 0.757 mmol), prepared in the synthesis of Example 20 using the procedures described in Example 18, and 10 10 mL of THF was added via syringe. To the resulting yellow solution was added NaH (60% suspension in mineral oil, 39 mg, 0.975 mmol). The reaction mixture was stirred at 25 'C for 1.5 h to afford a pale suspension. Methyl iodide (161 mg, 1.14 mmol) was added, and the reaction mixture was stirred at 25 'C for 2 days. After chilling to 0 'C, water was added (10 mL), followed by 50 mL of half saturated ammonium chloride, and 100 mL of EtOAc. 15 The layers were separated, and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were dried (sodium sulfate), filtered, and concentrated to afford 0.6 g of crude product as an orange oil. This material was dissolved in 15 mL of THF and 10 mL of methanol, and 7 mL of IN NaOH solution was added, under nitrogen. After being stirred for 2 h at 25 'C, the reaction mixture was concentrated to dryness on the rotary, and 20 100 mL of IN HCl, and 100 mL of EtOAc were added. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered, and concentrated. The crude material obtained (0.565 g) was purified by column chromatography on silica gel (eluant: chloroform to 3% MeOH in chloroform) to afford the titled compound (0.415 g, 70% yield). 25 EXAMPLE 71 was prepared according to the procedures described in Example 70, but using allyl bromide. 30 107 WO 99/43672 PCT/US99/03388 EXAMPLE 72 3-(2-(5-benzyloxy-1-( 2
-(
4 -pyridinyl))ethyl)indolinyl)methylthioacetamidobenzoic acid 5 Step 1: Ethyl 3-(2-(5-benzyloxy-1-(2-(4 pyridinyl)ethyl)indolinvl)methylthioacetamidobenzoate To a solution of ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.30 g, 0.63 mmol), prepared in step 6 of Example 17, in dichloromethane (3.0 mL) and 10 acetic acid (2.0 mL), 4-vinylpyridine (0.08 mL, 0.75 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was quenched with half saturated sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using a gradient of 2:1 hexane:ethyl acetate to 100% ethyl acetate to yield 0.023 g of product (25 %, TLC = 0.7 Rf 15 in ethyl acetate). Step 2: The titled compound was prepared according to the procedure described in step 3 of 20 Example 59. EXAMPLE 73 25 3-(2-(5-benzyloxy-1-( 2 -naphthyl)methy)indolinyl)methylthioacetamidobenzoic acid Step 1: Ethyl 3-(2-(5-benzyloxy-1-(2-naphthyl)methy)indolinvl)methylthioacetamidobenzoate A mixture of 3
-(
2 -(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.2g, 0.42 3 0 mmol), prepared in step 6 of Example 17, 2-(bromomethyl)naphthalene (0. 1 g, 0.42 mmol) and potassium carbonate (0.17 g, 1.26 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. Next the reaction was diluted with ethyl acetate and water, 108 WO 99/43672 PCTIUS99/03388 extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2:1 hexane:ethyl acetate to yield 0.22 g of product (85 %, TLC = 0.5 Rf in 2:1 hexane:ethyl acetate). 5 Step 2: The titled compound was prepared according to the procedure described in step 3 of Example 59. 10 EXAMPLES 74 and 75 in Table 6 were prepared according to the procedures described in Example 73. 15 EXAMPLE 76 2
-(
2 -(-5-Benzyloxy-1-(2-naphthyl)methvl)indolinyllmethylthiobenzoic acid Step 1: 2-(2-(-5-Benzyloxy-1-(1,1-dimethyl)ethoxycarbonyl)indolinvl)methyl 20 methylsulfonate tert-Butyl 1-(5-benzyloxy-2-hydroxymethy)lindolinylformate (6.72 g, 19 mmol), prepared in step 2 of Example 17, was dissolved in CHCl, (80 mL, dried over MgSO 4 before use). The clear yellow solution was cooled in a dry-ice bath. EJN (4.0 mL) was then 25 added followed by methanesulfonyl chloride (2.0 mL). The reaction mixture was stirred for 2 h at -40 OC then quenched with H{O. It was washed with satuarated NaHCQ (300 mL) and the aqueous layer extracted twice with CI-Cl,. The combined CHCl 1 layers were dried over MgSO 4 , filtered and evaporated to dryness to give the product (7.30 g, 89.1 % yield), which was used for the next reaction directly. 30 Step 2: Methyl 2-(2-(5-Benzyloxy-1-(1.1-dimethyl)ethoxvcarbonyl)indolinvl)methylthio benzoate 109 WO 99/43672 PCTIUS99/03388 Mesylate (7.2 g, 1.8 mmol), prepared in step 1, was dissolved in DMF (50 mL). The clear light brown solution was degassed by vigorously bubbling with Ar for 30 min. Cesium carbonate (13.8 g) was added followed by methyl thiosalicylate (2.4 mL). The solution changed to a bright yellow and the suspension was stirred overnight. Methyl 5 thiosalicylate (0. 15 mL) was added to complete the reaction and the mixture was stirred overnight. The reaction was then quenched by the addition of saturated NaHCQ(400 mL). The mixture was extracted with ClCI, (3 x) and the combined CHCI, solution was back washed with H20 (200 mL). The organic layer was dried over MgSQ, filtered and evaporated to dryness to give the product (9.71 g, 99%). 10 Step 3: Methyl 2
-(
2 -(5-Benzyloxy)indolinvl)methylthiobenzoate Ethyl acetate (75 mL, dried over MgSO4 before use) was charged in a 500 mL round bottom flask. HCl gas was bubbled through and the EtOAc/HCI solution was cooled in an 15 ice bath. Methyl ester (8.4 g), prepared in step 2, was dissolved in EtOAc (25 mL, dried over MgSO4 before use). This solution was transferred to the HCl/EtOAc solution by syringe. The solution turned to red and was stirred in an ice bath. A white precipitate appeared in I h and the solution was stirred overnight to complete the reaction. The solid was collected by filtration, washed with dry EtOAc, suspended in saturated NaHCQ(175 20 mL) and stirred with EtOAc (400 mL). The milky emulsion gradually dissolved and the mixture changed to a clear solution. The layers were separated and the aqueous layer was extracted (2 x) with EtOAC, while the combined EtOAC layers were dried over MgSO4, filtered and evaporated to dryness to give the product (6.06 g, 90 % yield). 25 Step 4: Methyl 2-(2-(5-Benzyloxy-1-(4-benzyl)benzyl)indolinvl)methy'lthiobenzoate In a 50 mL round bottom flask, ester (1 g), prepared in step 3, was dissolved in DMF (6 mL). p-Benzylbenzyl bromide was added (1 eq) followed by KCO 3 (1 eq). The reaction mixture was stirred overnight at room temperature. To complete the reaction 30 additional p-benzylbenzyl bromide (0.5 eq) was added and the reaction was stirred for another 2 hours. After its completion, the reaction was diluted with HO and extracted with EtOAc (2 x). The organic layers were combined and dried over MgSQ. The MgSO 4 was 110 WO 99/43672 PCTIUS99/03388 filtered and the solvent was evaporated to give an oily material which was dried overnight on high vacuum to give the product (1.59 g, 109 % yield). 111 WO 99/43672 PCT/US99/03388 Step 5: The ester (1.52 g), prepared in step 4, was dissolved in THF (10 mL) in a 50 mL round bottom flask. To it was added NaOH (1 eq, 2N) followed by MeOH (3 mL) and the 5 reaction mixture was stirred overnight. Additional NaOH (0.3 eq) was added to complete the reaction and the mixture was stirred throughout the weekend. Then it was acidified and diluted with H0 and extracted with EtOAc (2 x). The organic layers were combined and dried over MgSO 4 . The MgSO 4 was filtered and the solvent was evaporated and dried on high vacuum to give a crude reddish solid. This solid was dissolved in EtOAc and hexane 10 was added to precipitated the product. The resulting solid was filtered and the impure filter cake was combined with the filtrate and evaporated to dryness. This material was treated with EtOAc and EtOH. The resulting solid was filtered then suspended in EtOH, with stirring and heating at a low temperature. Then it was allowed to cool to room temperature. The suspension was filtered and washed with EtOH to give the titled product (280 mg, 19 % 15 yield). EXAMPLES 77, 78 and 79 in Table 6 were prepared according to the procedures described in Example 76. 20 EXAMPLE 80 4-(1-(5-Benzvloxy-2-(bis-2,4-trifluoromethyl)benzyloxvmethyl)indolinvl)methylbenzoic acid 25 Step 1: Methyl 1-(5-Benzyloxy-2-(hydroxymethyl)indolinvl)methylbenzoate 2-(5-Benzyloxy)indolinylmethanol (3.21 g, 12.6 mmol), prepared in DMF (20 mL), methyl 4-(bromomethyl)benzoate (2.88 g, 14.5 mmol) and potassium carbonate (1.77 g, 30 heated to 125 OC before use) were mixed and stirred at room temperature for 2 h. The reaction was diluted with 100 mL of HO and extracted three times with EtOAc. The combined EtOAc layers were evaporated to dryness to give the crude product (5.66 g). The 112 WO 99/43672 PCT/US99/03388 crude material was purified on a silica gel column using hexane:ethyl acetate 3:1 to 2:1. The appropriate fractions were combined, evaporated to dryness and further dried on high vacuum to the product (3.00 g, 64%). 5 Step 2: Methyl 4-(1-(5-Benzyloxy-2-(bis-2,4-trifluoromethyl)benzyloxymethyl)indolinyl) methylbenzoate Ester (700 mg), prepared in step 1, and bis-(2,4-trifluoromethyl)benzyl bromide (0.35 mL) were dissolved in DMF (5 mL). The resulting clear yellow solution was cooled in 10 an ice bath and then NaH (85 mg) was added in small portions over a period of 5 minutes. The suspension was stirred at 0 0 C for 4 h. To complete the reaction, another 0.35 mL of 2,4-bis(trifluoromethyl)-benzyl bromide was added and the stirring was continued for another 3 h 40 min. The reaction was then diluted with HO and extracted three times with EtOAc. The combined EtOAc layers were evaporated to give a crude product which was then purifed 15 on a silica gel columnusing hexane:ethyl acetate 8:1. The appropriate fractions were combined and evaporated to dryness to give the product (0.417 g, 38.2 % yield). Step 3: 20 The titled compound was prepared according to the prodedure described in step 5 of Example 76. EXAMPLES 81 and 82 in Table 6 were prepared according to the procedures described in 25 Example 80. 113 WO 99/43672 PCT/US99/03388 EXAMPLE 83 5-(2-(1-(2,4-Bis(trifluoromethyl)benzyl)indolinyl)carboxamido-1 .3-benzenedicarboxylic acid 5 Step 1: 2-(1-(2,4-Bis(trifluoromethyl)benzyl)indolinyl)carboxylic acid 2-Indolinylcarboxylic acid (0.43 g, 2.6 mmol) was dissolved in DMF (5 mL), placed under N 2 , and cooled to O' C, the sodium hydride (0.26 g of a 60 % dispersion, 6.5 mmol) was added and stirring was continued for 1 hour at this temperature. 2,4 10 Bis(trifluoromethyl)benzyl bromide (1.22 mL, 6.5 mmol) was next added and the reaction was warmed to room temperature overnight. The reaction was then diluted with 1/2 saturated ammonium chloride/ethyl acetate, the aqueous layer was extracted with ethyl acetate (3X), the organic layers were dried over magnesium sulfate and concentrated. The crude product was purified via chromatography (hexane:ethyl acetate 9:1) to yield 0.96 g of the 15 ester. The resulting ester (0.87 g, 0.1.41 mmol) was dissolved in THF/ methanol and then IN sodium hydroxide (4.21 mL) was added and the resulting mixture was stirred 2 hours at RT, workup and purification via Chromatography (7:1 hexane:ethyl acetate with 1 % acetic acid) yielded 0.58 g of the product. 20 Step 2: The acid (0.25 g, 0.64 mmol), prepared in step 1, EDCI (0.16 g, 0.83 mmol), DMAP (7 mg, 0.06 mmol) and dimethyl 5-aminoisophthalate (0. 16 g, 0.77 mmol) were dissolved in THF (2 mL) and refluxed 16 hours which yielded after aqueous workup 0.33 g 25 of a crude product. The ester (0.29 g, 0.50 mmol) was dissolved in THF/ methanol and then IN sodium hydroxide (1.5 mL) was added and the resulting mixture was stirred 16 hours at RT, workup and purification via Chromatography (1:1 hexane:ethyl acetate with 1 % acetic acid) yielded 0.22 g of the titled compound. 30 EXAMPLE 84 114 WO 99/43672 PCTIUS99/03388 N-Methylsulfonyl-2-(1-(2.
4 -bis(trifluoromethyl)benzyl)indolinv1)carboxamide The acid (0. 13g, 0.32 mmol), prepared in step 1 of Example 83, EDCI (0.07 g, 0.39 mmol), DMAP (4 mg, 0.03 mmol) and methylsulfonanilide (0.04 g, 0.39 mmol) were 5 dissolved in THF (5 mL) and refluxed 16 hours which yielded after workup (0.16 g), purification via Chromatography (98:2 dichloromethane:methanol) yielded 0.04 g of the titled compound (29%). 10 EXAMPLE 85 N-Phenvlsulfonyl-2-(1-(bis-2,4-trifluoromethyl)benzyl)indolinyl)carboxamide The titled compound was prepared according to the prodedure described in Example 15 84, but using phenylsulfonylamide. EXAMPLE 86 20 5-(2-(5-Methoxybenzyloxy-1-(2.4 bis(trifluoromethyl)benzyl)indolinvl)methylaminocarboxamido-1.3-benzenedicarboxylic acid Step 1: 2-Trimethylsilvlethyl 1-(5-benzyloxy-2-hydroxymethvl)indolinvlformate 25 An oven-dried 1 L round bottom flask, equipped with a stir bar was charged with 2 (5-benzyloxy)indolinylmethanol (33.2 g, 130 mmol), prepared in step of Example 17, 2 (trimethylsilyl)ethyl p-nitrophenyl carbonate 36.8 g, 130 mmol), NEj (38 ml, 273 mmol), and 300 mL of anhydrous DMF. The reaction mixture was stirred at 6(PC for 28 hours and at room temperature overnight. The resulting solution was concentrated to dryness in vacuo, 30 and 1 L of CHC 3 and 200 mL of saturated NaHCQ solution were added. The layers were separated, and the organic phase was dried (NaSO 4 ), filtered, and concentrated. The crude 115 WO 99/43672 PCTIUS99/03388 material obtained (55.7 g) was purified by column chromatography on silica gel (eluant: 0-5 % MeOH in dichloromethane) to afford product (33.5 g, 60% yield). Step 2: 2-Trimethylsilylethyl 1-(5-hydroxy-2-hydroxymethyl)indolinylformate 5 An oven-dried 500 mL Parr pressure flask was charged with the alcohol (30 g, 75 mmol), prepared in step 1, Pd/C (10 %, 2.2 g), 100 mL of MeOH, and 300 mL of EtOAc. After being shaken overnight in a Parr apparatus under H atmosphere (50 psi), the reaction mixture was filtered through Florisil. The filtrate was concentrated to dryness on the rotary. 10 The crude material obtained (24 g) was purified by column chromatography on silica gel (eluant: 0-3 % MeOH in dichloromethane) to afford product (20.9 g, 90% yield). Step 3: 2-Trimethylsilvlethyl 1-(5-(4-methoxv)benzyloxy-2-hydroxymethyl)indolinvlformate 15 An oven-dried 1 L round bottom flask, equipped with a stir bar was charged with the diol (27.1 g, 87.7 mmol), prepared in step 2, 4-methoxybenzyl chloride (Aldrich, 15 mL, 110 mmol), K,C0 3 (200 mesh, 30.4 g, 220 mmol), KI (Aldrich, 18.3 g, 110 mmol), and 800 mL of anhydrous acetonitrile. The reaction mixture was heated at reflux for 4 h. The solution was allowed to cool to room temperature and water (800 mL) and CHC(1.5 L) 20 were added. The layers were separated, and the aqueous phase was extracted with CHQl (800 mL). The combined extracts were washed with water (200 mL), dried (NaSO 4 ), filtered, and concentrated. The crude material obtained (45 g) was purified by column chromatography on silica gel (eluant: 20-25 % EtOAc in hexane), and recrystallization from EtOAc/Hexane to afford product (22.2 g, 59% yield). 25 Step 4: 2-Trimethylsilvlethyl 1-(5-(4-methoxv)benzyloxy-2-bromomethyl)indolinvlformate To a solution of 3.0 g (6.4 mmol) of the alcohol, prepared in step 3, in 30 mL of dichloromethane was added 2.53 g (7.6 mmol) of carbon tetrabromide and 3.15 g (7.6 mmol) 30 of 1,3-bis(diphenylphosphino)propane. The reaction was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NHC1, and the product was extracted with dichloromethane. The combined organic extracts were washed with brine and dried 116 WO 99/43672 PCT/US99/03388 over MgSO 4 . The crude product was purified by flash chromatography using hexane:ethyl acetate 3:2 to afford 1.51 g of the product. Step 5: 2-Trimethylsilylethyl 1-(5-(4-methoxy)benzyloxy-2-azidomethyl)indolinylformate 5 To a solution of 1.4 g (2.6 mmol) of the bromide, prepared in step 4, in 15 mL of dimethylformamide was added 0.51 g (7.9 mmol) of sodium azide. The reaction was heated to 75 "C, and was stirred for 18 h. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, 10 brine and dried over MgSO 4 . The crude product was purified by flash chromatography using hexane:ethyl acetate 4:1 to afford 1.08 g of the product. Step 6: 2-Trimethylsilylethyl 1-(5-(4-methoxy)benzyloxy-2-aminomethyl)indolinylformate 15 To a solution of 0.88 g (1.9 mmol) of the azide, prepared in step 5, in 20 mL of ethanol was added 90 mg (10%/wt) of Pd/CaCQ. The mixture was placed under atmospheric hydrogen, and was stirred for 18 h. The reaction was then filtered through a pad of celite and the organic phase was concentrated. The crude product was purified by flash chromatography using 10% MeOH/CHCl, to afford 0.717 g of the product. 20 Step 7: Methyl 5-(2-(5-Methoxvbenzyloxy-1-(2-trimethylsilyloxy)ethoxycarbony)lindolinvl) methylaminocarboxamido-1,3-benzenedicarboxylate To a solution of 0.164 g (0.6 mmol) of triphosgene in 5 mL of dichloromethane was 25 added a solution of 0.31 g (1.5 mmol) of dimethyl-5-aminoisophthalate and 0.39 g (3.0 mmol) of diisopropylethylamine in 20 mL of dichloromethane over a 30 minute period via a syringe pump. The reaction was stirred for 1 h at room temperature following the addition, and then a solution of 0.64 g (1.5 mmol) of the amino, prepared in step 6, in 5 mL of dichloromethane was added in one portion. The reaction was stirred for 2 h, and then 30 quenched with water. The product was extracted with ethyl acetate, and the combined organic layers were washed with water, saturated aqueous NaHCQ, brine and dried over 117 WO 99/43672 PCTIUS99/03388 MgSO 4 . The crude product was purified by flash chromatography using 10% MeOH/CHCl 2 to afford 0.78 g of the product. Step 8: -Methyl 5-(2-(5-Methoxybenzyloxy)indolinyllmethylaminocarboxamido-1.3 5 benzenedicarboxylate To a solution of 0.485 g (0.7 mmol) of the ester, prepared in step 7, in 20 mL of acetonitrile was added 2.2 mL (2.2 mmol) of a 1.0 M tetrabutylammonium fluoride solution in THF. The reaction was stirred at room temperature for 18 h. The reaction was quenched 10 with brine, and the product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NUJCl, brine and dried over MgSO 4 . The crude product was purified by flash chromatography using 5% MeOH/CHCl 2 to afford 0.342 g of the product. 15 Step 9: Methyl 5-(2-(5-Methoxybenzyloxy-1-(bis-2.4-trifluoromethvl)benzyl)indolinvl) methylaminocarboxamido-1.3-benzenedicarboxylate To a solution of 0.15 g (0.3 mmol) of the indoline diester, prepared in step 8, in 5 mL of dimethylformamide was added 0.097 g (0.3 mmol) of 2,4-bis(trifluoromethyl)benzyl 20 bromide and 0. 12 g (0.9 mmol) of potassium carbonate. The reaction was stirred at room temperature for 18 h. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over MgSO 4 . The crude product was purified by flash chromatography using hexane:ethyl acetate 1:1 to afford 0.066 g of the product. 25 Step 10: To a solution of 0.063 g (0. 1 mmol) of the diester, prepared in step 9, in 5 mL of tetrahydrofuran was added 0.8 mL (0.8 mmol) of a 1.0 N NaOH solution and 0.5 mL of 30 methanol. The reaction was stirred at room temperature for 18 h. The organic solvents were evaporated, and the resulting solid was suspended in water and acidified to pH 3 with 10% HCL. The product was extracted with ethyl acetate, and the combined organic extracts were 118 WO 99/43672 PCT/US99/03388 washed with water, brine and dried over MgSQ. The crude product was purified by flash chromatography using 5% MeOH/CIIC2 to afford 0.049 g of the titled compound. 5 EXAMPLE 87 was prepared according to the prodedure described in Example 86, but using 4-(3,5-bis(trifluoromethyl)phenoxymethyl)benzyl bromide. 10 INTERMEDIATE 1 Methyl 4-methoxy-3-thioacetamidobenzoate 15 Step 1: Bis(methyl 4-methoxy-3-dithioacetamidobenzoate) A 2-L oven-dried round bottom flask fitted with a magnetic stirring bar was charged with Dithioacetic acid (10.2-15.5 g, 56-85 mmol) and anhydrous CHCI, (50 mL). Oxalyl 20 chloride (2.1 mol equiv.) was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 4-5 h. Methyl 4-methoxy-3-amidobenzoate (2.1 mol equiv.) in anhydrous CH.Cl, (300-500 mL) and DMAP (0. 1 mol equiv.) were added at room temperature. NEt 3 (4.2 mol equiv.) was added dropwise over 30 min. After stirring overnight at room temperature the reaction mixture was washed with 1 N HCl solution (2 x 25 300 mL), dried over Na.SO 4 and filtered. The solvent was removed in vacuo. Purification of the residue by column chromatography on silica gel using hexane:ethyl acetate = 5:1 afford desired product in 56% yield. Step 2: 30 A 1-L round bottom flask fitted with a magnetic stirring bar was charged with disulfide, prepared in step 1, (15.7-26.3 g, 36.6-57.5 mmol) and PPg (1.1 mol equiv.). The 119 WO 99/43672 PCTIUS99/03388 reactants were suspended in dioxane/H-O (4/1, 375-500 mL) and concentrated HCl solution (5 drops) was added. The reaction mixture was heated at 40"C until all disulfide was consumed. Solvents were removed in vacuo. The residue was purified immediately by column chromatography on silica gel using hexane : ethyl acetate 2:1 to afford the titled 5 product in 89% yield. INTERMEDIATE 2 10 Methyl 5-thioacetamido-1.3-benzenedicarboxylate The titled compound was synthesized according to the procedures described in Intermediate 1 using 5-amino-1,3-benzenedicarboxylate. 15 UINTERMEDIATE 3 Methyl 2-(3-amino-4-methoxyphenvl)-2-methoxyacetate 20 Step 1: Methyl 2-(3-nitro-4-methoxyphenyl)acetate An oven-dried 2-L, 3-neck round bottom flask, equipped with a mechanical stir motor, a low-temperature thermometer and an equalizing dropping funnel, was charged with acetic anhydride (631 mL) and subsequently cooled to -78 0 C. Fuming nitric acid (Baker, 25 90%, 27 mL) was added dropwise via the dropping funnel protected with a drying tube filled with CaC 2 . After addition was completed, the reaction temperature was allowed to warm to 20 0 C over 1 h. The reaction mixture was cooled to -78C again and added 4 methoxyphenylacetic acid (50 g, 0.28 mol) dropwise via the dropping funnel. After stirring at -50 0 C for 1 h., the reaction mixture was allowed to warm to -30 0 C over 20 min. and then 3 0 cooled to -50 0 C again. The reaction mixture was quenched with HO (500 mL) at -50 0 C and warmed up to room temperature and stirred for 0.5 h. The reaction mixture was partitioned between CHCl (500 mL) and HO. The aqueous layer was extracted with CHClI 2 (3 x 500 120 WO 99/43672 PCT/US99/03388 mL). The combined CHRCl, extracts were concentrated in vacuo to give a yellow oil. This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0 0 C and stirred at room temperature overnight. The reaction mixture was partitioned between CHCl 2 (500 mL) and
H
2 0. The aqueous layer was extracted with CHCI, (3 x 500 mL). The combined C1{Cl 5 extracts were stirred with 2 M NaOH solution (1 L) for 1 h. The layers were separated and the organic layer was washed with HLO (500 mL), brine (500 mL), dried over NaSO 4 and filtered. The solvents were removed in vacuo to afford crude product as a light yellow solid (56 g). Purification by recrystallization from MeOH (600 mL) gave product. Yield 48 g (77%). 10 Step 2: Methyl 2
-(
3 -nitro-4-methoxyphenvl)-2-hydroxvacetate A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ester (2.3 g, 10 mmol), prepared in step 1, and anhydrous THF (100 mL). The 15 reaction mixture was cooled to -78'C and a solution of NaN(SiMe)2 (1.0 M in THF, 12 mL, 12 mmol) was added dropwise over 10 min. After stirring at -78 0 C for 30 min., the deep purple solution was added dropwise a solution of racemic camphor sulfonyloxaziridine (3.4 g, 15 mmol), prepared by mixing the commercially available (1S)-(+)-(10 camphorsulfonyl)oxaziridine (1.7 g) and (lR)-(-)-(10-camphorsulfonyl)oxaziridine (1.7 g) in 20 50 mL THF. After stirring at -78 0 C for 30 min., the reaction mixture was quenched with sat. NH 4 Cl solution (45 mL) at -78 C and then allowed to warm to room temperature. The reaction mixture was partitioned between ether (250 mL) and HO (50 mL). The aqueous layer was extracted with ether(3 x 250 mL). The combined ether extracts were washed with brine (250 mL), dried over NaSO 4 and filtered. The solvents were removed in vacuo. 25 Purification by column chromatography on silica gel (eluant: 50% AcOEt in hexane) afforded desired product. Yield 2.2 g (88%). Step 3: Methyl 2
-(
3 -nitro-4-methoxyphenvl)-2-methoxvacetate 30 A 10-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2, AgO (0.68 g, 3.0 mmol) and toluene (3 mL). To this was added CqlI (0.36 g, 5.75 mmol) dropwise. The reaction flask 121 WO 99/43672 PCT/US99/03388 was capped tightly and placed into a sonication chamber. The reaction mixture was sonicated for 18 h while stirring at room temperature. The reaction mixture was filtered through Celite and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel (eluant: 30% AcOEt in hexane) to afford desired product. Yield 0.26 g (82%). 5 Step 4: A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar and a three way adapter, connecting to a hydrogen balloon and a water aspirator was charged with 10 nitro compound (0.7 g, 2.6 mmol), 5% Pd on Carbon (10% by weight) and MeOH (20 mL). The reaction flask was placed under vacuum via the water aspirator and subsequently filled with H 2 . This was repeated three times. The reaction mixture was stirred for 18 hours under positive H, pressure until all starting material was reacted. The reaction mixture was filtered through Celite and concentrated in vacuo to dryness. The residue was purified by column 15 chromatography on silica gel using 10% ethyl acetate in dichloromethane to afford the titled compound (0.57 g, 97%) INTEMEDIATE 4 20 Methyl 2-(3-amino-4-methoxyphenyl)-2-tert-butyldimethylsilyloxvacetate A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2 of Intermediate 3 and 25 anhydrous CHCl, (10 mL). The reaction mixture was cooled to 0 0 C and added 2,6-lutidine (dried over NaOH pellet, 0.36 mL, 3.11 mmol) followed by addition ofBuMeSiOTf (0.43 mL, 1.87 mmol) dropwise. After stirring at 0"C for 30 min., the reaction mixture was partitioned between CI-Cl, (20 mL) and HO (15 mL). The aqueous layer was extracted with CHCl,(3 x 20 mL). The combined CHCl, extracts were washed with brine (20 mL), 3 0 dried over NaS0 4 and filtered. The solvents were removed in vacuo. Purification by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded desired product. Yield 0.42 g (95%). 122 WO 99/43672 PCT/US99/03388 Step 2: The titled compound was prepared from nitro compound of step 1 according to the procedure described in step 4 of Intermediate 3. 5 INTERMEDIATE 5 Methyl 2-(3-amino-4-methoxyphenyl)acetate 10 The titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure described in step 4 of Intermediate 3. 15 INTERMEDIATE 6 Methyl 2-(3-amino-4-methoxyphenyl)-2-methylacetate Step 1: Methyl 2-(3-nitro-4-methoxyphenyl)-2-methylacetate 20 A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with redistilled diisopropylamine (0.84 mL, 6.0 mmol) and anhydrous THF (10 mL) and cooled to 0 0 C. A solution of n-BuLi (2.5 M in hexane, 2.4 mL, 6.0 mmol) was added dropwise over 5 min. After stirring at 0 0 C for 15 min., the reaction temperature was 25 allowed to cool to -78'C and added a solution of easter (1.13 g, 5.0 mmol), prepared in step 1 of Intermediate 3, in 10 mL THF dropwise. After stirring at -78 0 C for 45 min., dimethylsulfate (1.60 g, 12.5 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between CI-Cl, (50 mL) and HO (50 mL). The aqueous layer was extracted with 30 CH 2 Cl, (3 x 50 mL). The combined CHCI, extracts were washed with brine (50 mL), dried over NaSO 4 and filtered. The solvents were removed in vacuo. Purification by column 123 WO 99/43672 PCTIUS99/03388 chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded 0.7 g of product (58%). Step 2: 5 The titled compound was prepared from nitro compound, prepared in step 1, according tothe procedure described in step 4 of Intermediate 3. 10 124 WO 99/43672 PCT/US99/03388 INTERMEDIATE 7 Methyl 2
-(
3 -amino-4-methoxyphenyl)-2-allvlacetate 5 Step 1: Methyl 2
-(
3 -nitro-4-methoxyphenvl)-2-allvlacetate This compound was synthesized form ester, prepared in step lof Intermediate 3, according to the procedure described in step 1 of Intermediate 6, but using allyl bromide. 10 Step 2: A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ester (0.30 g, 1.13 mmol), prepared in step 1, SnCl 2H.0 (1.28 g, 5.66 mmol) and EtOH (5 mL). The reaction mixture was heated at 70'C for 30 min. The reaction 15 mixture was cooled to room temperature and poured onto ice/water (20 mL) and basified with saturated NaC0 3 solution to pH = 8. AcOEt (50 mL) was added. The resulting emulsion was filtered through Celite. The filtrate was partitioned between AcOEt (20 mL) and HO (15 mL). The aqueous layer was extracted with AcOEt(3 x 50 mL). The combined AcOEt extracts were washed with brine (50 mL), dried over NaSO 4 and filtered. The solvents were 20 removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 10% AcOEt in CHRCI,) afforded the titled compound. Yield 0.16 g (60%). INTERMEDIATE 8 25 2,4-Bis(l. 1-dimethypropvl)phenoxvacetic acid The 2 ,4-bis(1,1-dimethy)propylphenol (12 g, 51.2 mmol) in dimethylformamide (100 mL) was cooled to -30' C, treated with solid potassium bis(trimethylsilyl)amide (12.3g, 61.5 30 mmol), stirred for 30 minutes and then methyl bromoacetate (5.7 mL, 61.5 mmol) was added, the reaction was stirred 1 hour at this temperature and five hours after removal of the cooling bath, workup yielded (16.6g, ~100%) a yellow oil. The oil was dissolved in 125 WO 99/43672 PCT/US99/03388 THF/methanol and treated with IN sodium hydroxide (155 mL) and stirred for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 4 with concentrated HCl, extracted with ethyl acetate (4X), dried over magnesium sulfate and concentrated. Crystalization from ethyl acetate and hexane yielded 12.85 g of the titled compound. (86%). 5 INTERMEDIATE 9 4-Benzylphenoxvacetic acid 10 The titled compound was prepared from 4-benzylphenol according to the procedure described in of Intermediate 8. 15 INTERMEDIATE 10 2-Naphthoxvacetic acid The titled compound was prepared from 2-naphthol according to the procedure described in of Intermediate 8. 20 INTERMEDIATE 11 3,5-Bis(trifluoromethyl)phenoxvacetic acid 25 The titled compound was prepared from 3,5-bis(trifluoromethyl)phenol according to the procedure described in of Intermediate 8. 30 INTERMEDIATE 12 Methyl 5-amino-3-(NN-dimethyl)carbamovlbenzoate 126 WO 99/43672 PCT/US99/03388 Step 1: Methyl 5-nitro-3-(N.N-dimethyl)carbamovlbenzoate A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with 5-nitro-3-methoxycarbonylbenzoic acid (3.15 g, 10 mmol), DMF (1 drop), 5 anhydrous CHCl, (70 mL), and oxalyl chloride (3.7 mL, 42.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to afford acid chloride as a white solid. This was used immediately in the next step without further purification. An oven-dried round bottom flask fitted with a magnetic stirring bar was charged 10 with above prepared acid chloride (14 mmol), anhydrous CHC 2 (50 mL), and dimethylamine hydrochloride (70 mmol). NEt (2 mL, 144 mmol) was added dropwise. After stirring at room temperature for 30-60 min excess NE (1 mL, 72 nmol) was added and stirring was continued. After 30-60 min the solution was washed with saturated NaCO 3 solution (2 x 20 mL), dried over NaS0 4 and filtered. The solvent was removed in vacuo to afford 3.3 g of 15 product. This was used in the next step without further purification. Step 2: The titled compound was prepared from nitro compound, prepared in step 1, 20 according to the procedure described in step 4 of Intermediate 3. INTERMEDIATE 13 25 Methyl 5-amino-3-acetylbenzoate Step 1: Methyl 5-nitro-3-acetylbenzoate A 250-mL oven-dried round bottom flask fitted with a magnetic stirring bar was 3 0 charged with di-tert-butyl malonate (2.16 g, 10 mmol), anhydrous toluene (50 mL), and NaH (60% suspension in mineral oil, 0.88 g, 22 mmol). The reaction mixture was heated at 80'C for I h. A solution of methyl 5-nitro-3-chloroformylbenzoate (10 mmol), prepared in step 1 127 WO 99/43672 PCTIUS99/03388 of Intermediate 12, in anhydrous toluene (20 mL) was added and heating was continued for 2 h. The reaction mixture was cooled to room temperature and p-toluenesulfonic acid (0.21 g, 1.2 mmol) was added. The resulting mixture was filtered and the oily residue was washed with toluene until a white solid was left. The filtrates were combined and the solvent was 5 removed in vacuo. The resulting oil was dissolved in anhydrous toluene (50 mL) and p toluenesulfonic acid (0.3 g, 1.74 mmol) was added. After heating to reflux for 18 h the reaction mixture was allowed to cool to room temperature, washed with saturated N CO 3 solution (2 x 25 mL), dried over NaSO 4 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel (eluant: CIl 2 ) to 10 afford product. Yield 1.06 g (50%). Step 2: The titled compound was prepared from nitro compound, prepared in step 1, 15 according to the procedure described in step 4 of Intermediate 3. INTERMEDIATE 14 20 Methyl 5-amino-3-(1-tert-butyldimethylsilyloxy)ethylbenzoate Step 1: Methyl 5-nitro-3-(1-hydroxy)ethylbenzoate An oven-dried round bottom flask fitted with a magnetic stirring bar was charged 25 with compound methyl 5-nitro-3-acetylbenzoate (0,5 g), prepared in step 1 of Intermediate 13, BH 3 THF (1 M solution in THF, 5 mol equiv.), and anhydrous THE. After stirring at room temperature for 24 h, HO (20 mL) was added and the solution was concentrated in vacuo. The residue was taken in HO (20 mL) and extracted with CHCl (3 x 100 mL). The combined CHC 3 extracts were washed with saturated NaCO 3 solution (20 mL), dried over 3 0 NaSO 4 and filtered. The solvent was removed in vacuo to afford product. This was used in the next step without further purification. 128 WO 99/43672 PCT/US99/03388 Step 2: Methyl 5nitro-3-(1-tert-butvldimethylsilyloxy)ethylbenzoate An oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.5g, 5 mmol), prepared in step 1, tert-BuMgSiCl (1.3 mol equiv.), imidazole 5 (2.15 mol equiv.), and anhydrous THF. After stirring at room temperature for 28 hours the solvent was removed in vacuo. The residue was taken in HO (50 mL) and extracted with CHCl 3 (2 x 100 mL). The combined CHCt extracts were washed with H1O (50 mL), dried over Na 2
SO
4 and filtered. The solvent was removed in vacuo. The crude material was purified on silica gel using 25 %-50% dicloromethane in hexane to afford the product (0.69 g, 91%). 10 Step 3: The titled compound was prepared from nitro compound, prepared in step 2, according to the procedure described in step 4 of Intermediate 3. 15 INTERMEDIATE 15 Methyl 4-methoxy-3-(2-thioethyl)aminobenzoate 20 Step 1: Bis(2-bromoethyl)disulfide The dithioethanol (0.79 mL, 6.48 mmol), carbon tetrabromide (4.3 g, 13.0 mmol) and 1,3 bis(diphenylphosphino)propane (5.34 g, 13.0 mmol) were weighed into a flask and 25 flushed with nitrogen and then taken up in CHCl, (15 mL) and stirred for 16 hours, workup consisted of pouring into 1/2 saturated ammonium chloride and extracted with CH'l 2 (3X) dry magnesium sulfate and concentrated to yield (9.0 g) of a crude product that was chromatographed (Hexane:Ethyl acetate9: 1) to yield 1.49 g of product. 30 Step 2: Bis-(methvl 4-methoxy-3-(2-dithioethyl)aminobenzoate 129 WO 99/43672 PCT/US99/03388 Bromide (0.39 mg, 1.387 mmol), prepared in step 1, and methyl 3-amino-4-methoxy benzoate (1.00 g, 5.51 mmol) were added into a flask, flush with nitrogen and take up in DMF (5 mL) and then heat to 600 C for 24 hours at which time the reaction was diluted with ethyl acetate and quenched into water, extracted with ethyl acetate (3X), the combined 5 organic layers were washed with water (3X), dried and concentrated to yield 1.27 g of a product that was purified by chromatography (hexane:ethyl acetate 5:1 to 3:1) to yield 0.15 g of the desired product. Step 3: 10 The disulfide (0.15 g, 0.24 mmol), prepared in step 2, and the triphenylphoshpine (0.14 g, 0.53 mmol) were taken up in THF (3 mL). IjO (0.3 mL) and two drops of conc. HCl were added and the resulting mixture was stirred at 400 C for 2 hours, the reaction was diluted with water and ethyl acetate, extracted with ethyl acetate (3 X) and dried over 15 magnesium sulfate to yield 0.27 g of a crude product that was purified by chromatography (hexane:ethyl acetate 9:1 to 6:1) to yield 0.11 g of the titled compound. 130 WO 99/43672 PCT/US99/03388 Methods of Synthesis for Examples 88-135 Additional compounds of the invention can be made according to the following methods. Specific examples of synthesis of compounds pursuant to these methods are also disclosed below. Method A The aldehyde is reacted with the alpha-carbon of a heterocycle such at 2,4-thiazolidinedione or rhodanine or 2-thiohydantoin in the presence of a base such a potassium carbonate or potassium hydroxide in a solvent system such a water:ethanol or ethanol. The resulting product may then be N-alkylated with a base such a sodium hydride in a solvent such a DMF or DMSO. The final acid may then be realized by cleavage of the ester with hydrogen fluoride in a solvent such as acetonitrile. Method B Indole-2-carboxylic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh 3
)
4 as a catalyst in a mixed solvent (ethanol-benzene water) at elevated temperature to give the 1-alkyl-5-substituted indole. Method C The starting material for the inhibitors in this class, 2-Ethoxycarbonyl-5-benzyloxyindole I, was deprotonated with a suitable base such as sodium hydride and alkylated on the nitrogen atom with selected electrophiles such as alkyl or benzyl halides to provide compounds II. Saponification of the ester functionality with a base such as aqueous sodium hydroxide in miscible solvents such as tetrahydrofuran and methanol gave inhibitors III. Further extensions at the 2-position were carried out through aide formation of the acid functionality via acid chloride formation with a suitable reagent such as oxalyl chloride and reaction with an amino-ester in the presence of a base such as pyridine in a suitable solvent such as methylene chloride. Saponification provided the chain extended acid moiety V. 131 WO 99/43672 PCT/US99/03388 Method D Acid isosteres such as tetrazole were prepared from the carboxylic acids I via the nitriles III Conversion to the nitriles was accomplished through primary amide formation of the acid functionality via the acid chloride with a suitable reagent such as oxalyl chloride and reaction with ammonia followed by a dehydration sequence using a suitable reagent such as oxalyl chloride and a base such as pyridine. The nitriles such as III could be converted to the tetrazoles by reaction with an azide source such as sodium azide in an appropriate high boiling point solvent such as N-methyl pyrrolidinone to give compounds such as IV. Method E Other acid isosteres such as the thiazolidinedione group with longer carbon atom bridges were prepared through a sequence involving the unsaturated aldehyde moiety at the 2-position such as compound IV. Partial reduction of the ester group in I with a suitable reagent such as diisobutyl aluminum hydride or reduction to a hydroxy group with a suitable reagent such as lithium aluminum hydride followed by oxidation to the aldehyde with a suitable oxidizing agent gave the aldehyde II. A Homer-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran gave the unsaturated ester III which was converted to the aldehyde IV under the conditions described for II. The aldehyde could then be transformed to the thiazolidinedione V using a base such as piperdine and isolated with an acid such as acetic acid. Method F 2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give VI. Hydrolysis of VI witha aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethyl carbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide VII. Amide VII is hydrolyzed to corresponding acid VIII in a aqueous base such as sodium hydroxide. Method G 132 WO 99/43672 PCTIUS99/03388 Aldehyde IX is prepared from Indol-2-carboxylic acid ethyl ester I in two steps: (1) Reduction with lithium aluminium hydride or other hydride in a suitable solvent such as THF at 0 0 C and (2) oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Aldehyde IX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield indole X . Indole X can be converted to an unsaturated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide. Method H Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of II with Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -60'C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF affords ketone III. The silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide IV. Displacement of the bromine of IV with a thiol compound in the presence of a base such as cesium carbonate, or with an alcohol in the presence of a strong base such as NaH in DMF affords V (sulfide or ether respectively). 133 WO 99/43672 PCTIUS99/03388 Method A 0 R5 N R 5
K
2 C0 3 a0 N 'N DMFN 1HH R5 R A5 Brj HF
CH
3 CN0 Ri R 2 R R4 R 5 -lO alkl lyl N. S alkyl OHsN al aryl rR5 134 WO 99/43672 PCT/US99/03388 Method B Br Br COOH RBr COOH R'B(OH) 2 R COOH iPr 2 NEt N (C 6
H
5
)
4 Pd 1 R Na 2
CO
3 m 5
R
5 Rl CD F
OCH
3 CCl Brr
CH
3 COHN 135 WO 99/43672 PCT[US99/03388 Method C N 0E NaHl I ~'CO 2 E I ~ CO 2 Et DMF N H RX R I [ 0 2 Et NaOH. TlHF-MeOH H - c
)(COCI)
2 ~~'c /) / Pyriine R 1-12N C0 2 Et N 0 IV N c I R LiOH. THF-H,O
F
3 a CF 3 CO,H SN 0 RN
CF
3 V CF 3 136 WO 99/43672 PCT/US99/03388 Method D 020 1)(COCI)2 0OH -~N2) NI-4OH- - N R R II I )(COCI) 2 , DMF, CH 3 CN 2) Pyridine N 0 NaN 3 0 N _____ ~ N Et N-HCI C NN N 3 N R R Ror NCF 3
F
3 a CF 3
CF
3 137 WO 99/43672 PCT/US99/03388 Method E 0
CO
2 Et 1)LiAIH 4 O CHO ~ N2) Mn0 2 N
F
3 a CF 3 F 3
CF
3 III trimethoxyphosphonoacetate 1)DIBAL-H 0 O 0 2) M n0 2 e IV F 3
CF
3 F 3
CF
3 III piperdine 0 HOAc O 00 NN N-H 0 F3 a CF 3 V 138 WO 99/43672 PCT/US99/03388 METHOD F R COOEt R'X (Br, 1), NaH R COOEt H R' v 1) NaOH, THF/MeOH 2) EDCl, DMAP HH =R" NH NH - COOCH 3 R O COOCH3 R' V i NaOH, THF/MeOH H N OCOOH R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO 2 , alkyl or aryl R' Vill R'= alkyl, benzyl, alkenyl, alkynyl R"= halogen, CN, alkyl, alkoxy, alkoxycarbonyl, amido, acyl, H, OH 139 WO 99/43672 PCT/US99/03388 Method G N 1)LiAIH 4 , THF OQ 2t)MnO2, THF 10-CHO R COOEt RCH NN H H Ix R'X (Br, 1), NaH 1)(MeO) 2
POCH
2 COOM / COOH NaH Ri CHO N ' N 2)NaOH, THF/MeOH R' XI X R' R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO2, alkyl or aryl R'= alkyl, aryl 140 WO 99/43672 PCT/US99/03388 Method H 1) LiAIH 4 , THF 2) TBDMSCI, Imidazole, DMF OTBDMS RCOEt R N N H H 1) EtMgBr, THF 2) R'COCl/(R'CO) 2 0, ether 3) R"Br(I), NaH o 0 FR' 1) TBAF, THF R' 2) Ph 2
PCH
2
CH
2 PPh 2 CBr 4 / y MsCl, Et 3 N OTBDMS R R~i N N R IV R" III SR"'SH, CsCO 3 \ R"'OH, NaH or K 2 CO3 0 R' X-R'" N R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO 2 , alkyl or aryl R'= alkyl, aryl V R" = alkyl, benzyl, alkenyl, alkynyl R= alkyl, aryl X = os Y = halogen, mesylate EXAMPLE 88 4-[(5-{(E)-[5-(benzvloxv)-1 -(4-{F3.5 bis(trifluoromethyl)phenoxylmethyllbenzyl)-1H-indol-2-vllmethvlidenel-2.4 dioxo-1,3-thiazolan-3-vl)methvllbenzoic acid Step 1 - The aldehyde from Example 124, (5.2 g) was suspended in ethanol (150 mL). To the thick slurry was added 2,4-thiazolidinedione (1.28g) and potassium carbonate (6.1 g). The 141 WO 99/43672 PCT/US99/03388 mixture was heated in a bath at 60 'C (later dropped to 45 C). After 1 h TLC showed no reaction. Sodium hydroxide (2.1 g) was added and the mixture was heated at 58 'C. After 45 minutes the TLC showed reaction progress. Additional 2,4-thiazolidinedione (0.1 g) was added. The mixture was stirred overnight at room temperature. The mixture was poured into water (500 mL) and acidified to pH 2 with 6 N HCl, extracted with ethyl acetate, dried (MgSO4) and filtered. Trituration from ethanol afforded an orange solid which was filtered and washed with ethanol to give the desired product (5.74 g, 94%) as an orange solid. Step 2 - To the material prepared in step 1 (1.1 g) in DMF (15 mL) at 0 'C was added sodium hydride (0.08 g. 60% dispersion in mineral oil). The suspension was stirred for 30 minutes. To the reaction mixture was added the benzyl bromide (0.54 g) and the reaction was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated. Column chromatography (1:6 ethyl acetate:hexane to 1:4 ethyl acetate:hexane) afforded the desired product (1.18 g, 75%) as a yellow solid. Step 3 - To the material prepared in step 2 (0.34 g) in acetonitrile (15 mL) was added HF (48% aqueous, 3.7 mL) via syringe. The reaction was stirred overnight. The reaction was not complete by TLC therefore THF was added to dissolve the starting material and additional HF (0.6 mL) was added. The reaction was stirred for 2 h after which the TLC showed reaction completion. Water was added which resulted in the formation of a yellow solid. The yellow solid was dissolved in ethyl acetate, washed with brine, dried over MgSO 4 and concentrated. The resulting crude solid was suspended in ethanol and stirred for 30 min, filtered and dried to afford the title compound (140 mg, 48%) as a yellow solid. EXAMPLE 89 5-r(E)-(5-(benzvloxv)-1-13-r3,5-bis(trifluoromethyl)phenoxvlpropvl}-1H-indol 2-yllmethvlidenel-1,3-thiazolane-2.4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 90 142 WO 99/43672 PCT/US99/03388 5-((E)-15-(benzyloxv)-1-[2,4-bis(trifluoromethyl)benzyll-1H-indol-2 Vl Imethylidene)- 1.3-thiazolane-2.4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 91 5-{(E)-r5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-vllmethylidenel-1.3 thiazolane-2,4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 92 5-f(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-vllmethvlideneL-1 3 thiazolane-2,4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 93 5-{(E)-r1-(4-benzylbenzyl)-5-(benzyloxy)-1H-indol-2-vllmethlidene}-13 thiazolane-2,4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 94 5-{(E)-[5-(benzvloxv)-1-(4-chlorobenzvl)-1H-indol-2-vllmethvlidene-1.3 thiazolane-2,4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 95 5-((E)-{5-(benzvloxv)-1-[2,4-bis(trifluoromethvl)benzyll-1H-indol-2 Vllmethvlidene)-1,3-thiazolane-2,4-dione 143 WO 99/43672 PCT/US99/03388 The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. EXAMPLE 96 2-(5-{(E)-[5-(benzyloxy)-1-(4-{[3.5 bis(trifluoromethyl)phenoxylmethyllbenzyl)-1H-indol-2-yllmethvlidenel-2.4 dioxo-1.3-thiazolan-3-vl)acetic acid Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. EXAMPLE 97 4-[(5-f (E)-[5-(benzvloxv)-1 -(4-chlorobenzvl)-1H-indol-2-vllmethvlidene}1-2.4 dioxo-1,3-thiazolan-3-vl)methvllbenzoic acid Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. EXAMPLE 98 2 -(5-{(E)-[5-(benzyloxv)-1-(2-naphthylmethvl)-1H-indol-2vllmethylidenel-2,4 dioxo-1,3-thiazoan-3-vlacetic acid 144 WO 99/43672 PCT/US99/03388 Step 1- The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. EXAMPLE 99 4-[(5-f (E)-[5-(benzyloxv)-1-(2-naphthylmethyl)-1H-indol-2-yllmethylidenel-2,4 dioxo-1,3-thiazolan-3-yl)methyllbenzoic acid Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. EXAMPLE 100 2-(5-{(E)-r5-(benzvloxv)-1-(4-chlorobenzyl)-1H-indol-2-yllmethvlidenel-2,4 dioxo-1,3-thiazolan-3-vI)acetic acid Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. 145 WO 99/43672 PCT/US99/03388 The compounds of the following Examples 101-106 were prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine. EXAMPLE 101 5-((E)-{5-(benzyloxy)-1-[2.4-bis(trifluoromethyl)benzyll-1H-indol-2 yllmethylidene)-2-thioxo-1.3-thiazolan-4-one EXAMPLE 102 5- (E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-vllmethylidenel-2 thioxo- 1,3-thiazolan-4-one EXAMPLE 103 5-r(E)-(5-(benzvloxv)-1-{3-[3,5-bis(trifluoromethvl)phenoxylpropyl}-1H-indol 2-v1)methylidenel-2-thioxo- 1,3-thiazolan-4-one EXAMPLE 104 5-{(E)-5-(benzyloxv)-1-(4-chlorobenzvl)-1H-indol-2-vllmethvlidene}-2-thioxo 1,3-thiazolan-4-one GI 1418 EXAMPLE 105 5-1(E)-[1-(4-benzvlbenzvl)-5-(benzvloxv)-1IH-indol-2-vllmethvlidene}-2-thioxo 1,3-thiazolan-4-one EXAMPLE 106 5-1(E)-[5-(benzvloxy)-1-(4-{F3,5-bis(trifluoromethvl)phenoxylmethyl benzyl) 1H-indol-2-vllmethvlidenel-2-thioxo-1,3-thiazolan-4-one EXAMPLE 107 4-{[5-((E)-{5-(benzvloxy)-1-[2,4-bis(trifluoromethvl)benzyll-1H-indol-2 Vllmethvlidene)-4-oxo-2-thioxo-1.3-thiazolan-3-vIlmethvllbenzoic acid 146 WO 99/43672 PCT/US99/03388 Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine. Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. EXAMPLE 108 5-((E)-15-(benzvloxy)-1-[2,4-bis(trifluoromethyl)benzyll-1H-indol-2 Vllmethylidene)-2-thioxotetrahydro-4H-imidazol-4-one The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and 2-thiohydantoin EXAMPLE 109 1-benzyl-5-(2-thienvl)-1H-indole-2-carboxvlic acid To a sealed tube containing 2-[5-bromo-l-benzyl-1H-indole-2carboxylic acid (100 mg, 0.303 mmol) and 2-thiopheneboronic acid (116 mg, 0.909 mmol), (C 6
H
5
)
4 Pd (42 mg, 0.036 mmol), Na 2
CO
3 (2.42 mmol) in a mixture of benzene-ethanol-H 2 0 (5/1/2=v/v, 4.5 mL) was heated at 100 'C for 23 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer was washed with NaH 2
PO
4 , dried over MgSO 4 and evaporated to give the crude product which was purified on silica gel column ( 15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product. EXAMPLE 110 5-(1-benzofuran-2-vl)-1-benzvl-1IH-indole-2-carboxvlic acid The title compound was prepared according to the procedure described in Example 109 except that benzo[blfran-2-boronic acid was used. EXAMPLE 111 1-benzvl-5-(4-fluorophenvl)-1H-indole-2-carboxylic acid 147 WO 99/43672 PCT/US99/03388 The title compound was prepared according to the procedure described in Example 109 except that 4-fluorophenylboronic acid was used. EXAMPLE 112 1-benzyl-5-(3-methoxyphenyl)-1H-indole-2-carboxylic acid The title compound was prepared according to the procedure described in Example 109 except that 3-methoxyphenylboronic acid was used. EXAMPLE 113 1-benzyl-5-phenyl-1H-indole-2-carboxvlic acid The title compound was prepared according to the procedure described in Example 109 except that phenylboronic acid was used. EXAMPLE 114 1-benzhvdrvl-5-bromo-1H-indole-2-carboxvlic acid To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in 1-methyl-2-pyrrolidinone (13 mL) at 0 'C were added 'Pr 2 NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated at 50 'C for 21 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH 2
PO
4 , dried over MgSO 4 and evaporated to dryness. Purification on silica gel column ( 15% EtOAc in hexane) yielded 1.51 g (87 % yield) of the product. EXAMPLE 115 5-[3-(acetylaminolphenvll-benzhydrvl-1H-indole-2-carboxylic acid The title compound was prepared according to the procedure described in Example 109 except that 3-acetamidobenzeneboronic acid and 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid were used. EXAMPLE 116 1-benzhvdrvl-5-(2-thienvl)-1H-indole-2-carboxvlic acid 148 WO 99/43672 PCT/US99/03388 The title compound was prepared according to the procedure described in Example 109 except that 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid and 2-thiopheneboronic acid were used. EXAMPLE 117A 5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indole-2-carboxylic acid Step 1 To an ice-cold (0"C) solution of 2-ethoxycarbonyl-5-benzyloxyindole (5.0g, 16.9mmol) in dimethylformamide (50ml) was added sodium hydride (0.62g, 18.6mmol). The ice bath was removed after 10min and the reaction was stirred at rt for an addition 30min at which time bis(trifluoromethyl)benzyl bromide (3.8ml, 20.3mmol) was added dropwise. The green mixture was stirred at rt for 4h, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated. The product was recrystallized from EtOAc/Hex to afford 6.87g (81%) of the desired intermediate as an off-white powder. Step 2 To a solution of the above intermediate (1.3g, 2.5mmol) in THF (50ml) was added IN NaOH (5ml) and MeOH (6ml). The mixture was stirred overnight at rt and then concentrated. The residue was suspended in water and acidified with HOAc. The product was extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO 4 and concentrated to afford a quantitative yield of the title compound as an off-white solid. EXAMPLE 117B 5-[({5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2 yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid Step 1 To a solution of the title compound above (0.4g, 0.8mmol) in CH 2 Cl 2 (5ml) and a few drops of DMF was added oxalyl chloride (0.2ml, 2.4mmol). The reaction was stirred for 1.5h and concentrated. The resulting yellow residue was dissolved in CH 2 Cl 2 (2ml) and added to a solution of the pyridyl aminobenzoate ether (0.24g, 0.8mmol) and pyridine (0.1ml, 0.9mmol) in CH 2 Cl2 (8ml). The reaction was stirred overnight at rt, water was added and the product was extracted with CH 2 Cl 2 . The combined organic layers were washed with saturated aqueous NH 4 Cl, water, 149 WO 99/43672 PCTIUS99/03388 brine and dried over MgSO 4. Concentration and flash chromatography (Hex/EtOAc, 3/2) afforded 0.182g (51%) of the desired intermediate as a tan solid. Step 2 To a solution of the above intermediate (0. 136g, 0.2mmol) in THF (3ml), was added LiOH (0.022g, 0.5mmol) and water (0.5m1). The mixture was stirred overnight at rt, concentrated and the resulting residue was suspended in water and acidified with HOAc. The product was extracted with EtOAc, the combined organic layers were washed with water, brine and dried over MgSO 4 . Concentration gave 0. 122g of the title compound (94%) as a white crystalline solid. EXAMPLE 117C 5-(benzyloxy)-1-(4-{[ 3 ,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H indole-2-carboxylic acid The procedure in EXAMPLE 117A steps I and 2 were followed using 2-ethoxycarbonyl-5 benzyloxyindole (2.0g, 3.2mmol) and the appropriate alkylating reagent to afford 1.7g (41% for 2 steps) of the title compound as a yellow solid. EXAMPLE 117D 5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-iH indole-2-carboxylic acid The procedure in EXAMPLE 117A steps I and 2 were followed using 2-ethoxycarbonyl-5 benzyloxyindole (2.0g, 3.2mmol) and the appropriate alkylating reagent to afford 1.7g (41% for 2 steps) of the title compound as a yellow solid. EXAMPLE 118 5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-2-(1H-1,2,3,4-tetraazol-5-yl) 1H-indole Step 1 To a suspension of the acid prepared in Example 117A (1.5g, 3.Ommol) in CH 2 Cl 2 (20ml) was added oxalyl chloride (0.8ml, 9.1mmol) and three drops of DMF. The mixture became homogeneous and was stirred for lh at rt. The reaction was concentrated and redissolved in
CH
2
CI
2 (5ml) and NH 4 0H (2.Oml) was added. The biphasic mixture was stirred for 24h and concentrated. The remaining aqueous residue was extracted with CH,Cl, and the combined 150 WO 99/43672 PCT/US99/03388 organic layers washed with brine, dried and concentrated to give 1.4g (95%) of the desired intermediate as a yellow powder. Step 2 To an ice-cold solution of DMF (0.23 ml, 3.Ommol) in CH 3 CN (10ml) was added oxalyl chloride (0.24ml, 0.28mmol). A white precipitate formed immediately and the solution was stirred for an additional 5 min. A solution of the above intermediate (1.2g, 2.5mmol) in CH 3 CN (5ml) was added. The resulting yellow-orange solution was stirred for 10 min and pyridine (0.44ml, 5.5mmol) was added. After 5 min the red mixture was partitioned between 10% aqueous HC and EtOAc. The organic layer was dried and concentrated to give 1.Og (84%) of the desired intermediate as a yellow powder. Step 3 GI 1563 5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxyJmethyl}benzyl)-1H-indole-2-carboxylic acid To a solution of the above intermediate (0.94g,2.0mmol) in N-methyl-2-pyrrolidinone (10ml) was added sodium azide (0.39g, 5.9mmol). The mixture was heated at reflux for 2h. The reaction was allowed to cool to rt and poured into 50ml of ice water. The resulting solution was adjusted to pH=2 with 10% aqueous HCI and a tan precipitate formed. The mixture was filtered and washed with EtOAc. Flash chromatography (CH 2 Cl 2 /MeOH, 10:1) gave 0.78g (78%) of the title compound as a white powder. EXAMPLE 119 benzyl 1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-2-(lH-1,2,3,4-tetraazol-5-yl)-1H indol-5-yl ether acid was prepared in an analogous manner to Example 118 according to steps 1-3 starting from the acid prepared in EXAMPLE 117C. EXAMPLE 120 4-{ [5-((E)-{5-(benzvloxv)-1-[2,4-bis(trifluoromethvl)benzvll-1H-indol-2 Vllmethylidene)-4-oxo-2-thioxo-1,3-thiazolan-3-vllmethyllbenzoic acid 151 WO 99/43672 PCTIUS99/03388 Step 1 The thiasolidinedione prepared in Example 101 (0. lg, 0.2mmol), was alkylated by treatment with sodium hydride (0.006g, 0.22mmol), and the bromomethyl SEM ester (0.058g, 0.2mmol) in DMF (2ml). Flash chromatography (Hex/EtOAc, 4/1) gave 0.073g (50%) of the desired intermediate as a thick oil. Step 2 To a solution of the above intermediate (0.07g, 0.Immol) in CH 3 CN (5ml) was added aqueous 48% HF (2ml). After 2h water was added and the product was extracted with EtOAc, the combined organic layers were washed with water, brine and dried over MgS04. Concentration gave 0.025g of the title compound (42%) as an orange powder. Example 121 5-((Z,2E)-3-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}-2 propenylidene)-1,3-thiazolane-2,4-dione Step 1 A solution of the intermediate prepared in EXAMPLE 117A, step 1 (4.4g, 8.4mmol) in THF (30ml) was cooled to 0 0 C and a solution of lithium aluminum hydride in THF (1.OM, 8.4ml) was added dropwise with vigorous stirring. After lh at 0 0 C the reaction was carefully quenched with a saturated solution of NH 4 Cl. The salts were filtered and washed with EtOAc. Concentration of the solvents afforded 3.9g (96%) of the alcohol as a yellow foam. The alcohol (1.6g, 3.3mmol) was dissolved in THF (50ml) and MnO2 (2.91g, 33.4mmol) was added. The reaction was stirred for 12h and filtered through a pad of Celite. Concentration of the filtrate gave 1.47g (92%) of the desired intermediate as a thick clear oil. Step 2 To an ice-cold solution of trimethylphosphonoacetate (0.5ml, 3.1mmol) in DMF (10ml) was added sodium hydride (0.1 4 g, 3.4mmol) and the reaction was stirred for 20min. A solution of the above intermediate (1.47g, 3.1mmol) in DMF (3ml) was added, the ice bath was removed and the reaction was allowed to stir overnight at rt. Water was added and the aqueous phase was extracted with EtOAc. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated. Flash chromatography (Hex/EtOAc, 3/2) provided 1.5g (93%) of the desired intermediate as a yellow solid. 152 WO 99/43672 PCT/US99/03388 Step 3 The above intermediate (0.5g, 0.9mmol) was dissolved in CH 2 Cl 2 (10ml) and the solution was cooled to -20 0 C. A solution of diisobutylaluminium hydride (1.OM in toluene, 1.9ml) was added dropwise, and the reaction was allowed to stir at rt overnight. Water was added, and the mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc, washed with water and the combined organic layers washed with brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 3/2) gave 0.49g (75%) of an orange solid. This material was dissolved in THF (12ml) and MnO 2 (1.lg, 12.3mmol) was added. The mixture was stirred overnight and filtered through a pad of Celite. Concentration of the solvent afforded 0.4g (65%) of the desired intermediate as a thick tan oil. Step 4 The above intermediate (0.lg, 0.2mmol) was dissolved in toluene (lml), followed by piperidine (6jil, 0.1mmol) acetic acid (1.2 Ll) and 2,4-thiazolidinedione (0.023g, 0.2mmol). The mixture was heated to reflux for 2h. The reaction was allowed to cool to rt, water was added and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 3/2) gave 0.056g (47%) of the title compound as a red powder. EXAMPLE 122 5-(benzyloxv)-1-(4-{[3.5-bis(trifluoromethyl)phenoxylmethyl benzyl)-1H indole-2-carboxylic acid Step 1: To ethyl 5-benzyloxy-2-indolcarboxylate (1 g, 3.4 mmol) in 12 ml of DMF, sodium hydride (0. 163g, 60% oil dispersion, 4.07 mmol) is added at room temperature. The reaction is stirred for 30 minutes. a-Bromo-a'-[3,5-bis(trifluoromethyl)phenoxyll-p-xylene (1.54 g, 3.73 mmol) is added at this time and the reaction stirred overnight. On completion of the reaction (monitored by TLC) it is quenched with water, extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate, concentrated and used for the next step. Step 2: The ester ( 2.1 g, 3.39 mmol) is dissolved in 40 mL of 1/1 THF/ methanol and then 1N sodium hydroxide (15 mL) is added and the resulting mixture is stirred for 16 hours at RT, workup gave crude product that is purified via chromatography (1:1 Hexane:Ethyl acetate with 1% acetic acid) to yield (1.73 g, 85%) of solid. 153 WO 99/43672 PCTIUS99/03388 EXAMPLE 123 5 -({[1-benzyl-5-(benzyloxy)-1H-indol-2-vllcarbonyllamino)isophthalic acid Step 1: This intermediate was prepared according to the procedure described in Example 122, but using benzyl bromide. Step 2: The acid (0.27 g, 0.75 mmol) prepared in step 1, EDCI (0.18 g, 0.97 mmol), DMAP (3 mg, 0.02 mmol) and dimethyl-5 aminoisophthalate (0.18g, 0.75 mmol) were dissolved in THF (8.8 mL) and refluxed for 16 hours, after workup and purification (Hexane:Ethyl Acetate 3:1) yielded (0.25 g, 60%) of pure product. Step 3: The title compound was prepared from ester, prepared in step 2 above, according to the procedure described in step 2, Example 122. EXAMPLE 124
(E)-
3 -[5-(benzyloxy)-1-(2-naphthylmethvi)-1H-indol-2-vll-2-propenoic acid Step 1: Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0' C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 00 C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO 4 and concentrated to yield 24.8 g (96%). Step 2: Indole alcohol (26.1 g, 103 mmol) from step 1 is dissolved in THF (900 ml). Manganese dioxide (106.6 g) is added and the mixture is stirred for 2h at room temperature. After the reaction is complete the mixture is filtered through celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, dried to give the desired aldehyde (22.9 g, 89%). Step 3: This intermediate was prepared from indole, prepared in step 2 above and 2 (bromomethyl)naphthalene, according to the procedure described in step 1, Example 122. Step 4: To sodium hydride (0.025 g, 60% oil dispersion, 0.63 mmol) in 7.5 mL of THF is added trimethyl phosphonoacetate (0.1 mL, 0.62 mmol) in 2.5 mL of THF at room temperature. The reaction is stirred for 10 minutes. Next the aldehyde (0.24 g, 0.62 mmol) prepared in step 3 above in 2.5 mL THF is added dropwise at room temperature. Reaction is stirred for another 30 minutes 154 WO 99/43672 PCTIUS99/03388 NOT FURNISHED UPON FILING 155 WO 99/43672 PCT/US99/03388 NOT FURNISHED UPON FILING 156 WO 99/43672 PCT/US99/03388 NOT FURNISHED UPON FILING 157 WO 99/43672 PCTIUS99/03388 NOT FURNISHED UPON FILING 158 WO 99/43672 PCT/US99/03388 EXAMPLE 133 2-( f 3 -acetv-l-r4-(1.3-benzothiazol-2-vcarbonyl)benzyll-5-(benzvioxy)-1H indol-2-vllmethyllsulfanvl)acetic acid Step 1 p-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCI (1.1 eq) dissolved in methylene chloride at 0*C over 20 min. The reaction was allowed to warm to 25"C. After stirring at 25'C for 1 day, workup with methylene chloride and water afforded crude product in ca. 100% yield. Step 2 Under anhydrous conditions benzothiazole was dissolved in THF (0.35 M). At -78 *C added BuLi (1.1 eq). After 1 h at -78'C, added the aide from step 1 in THF, over 15 min. The reaction was allowed to warm to 25*C. After stirring at 25*C for 1 day, workup with ethyl acetate and water and chromatography afforded pure tolyl ketone product (52%). Step 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0. 19M), and NBS (1.2 eq) and AIBN (0.11 eq) were added. After 1 d at 60"C, about 1:1 of starting material and product were present. Resubmission under the same conditions, followed by filtration and recrystallization from ethyl acetate afforded pure bromobenzyl ketone product (28%). Step 4 The intermediate from step 3, Example 131 was dissolved in dry DMF (0.1 M), followed by NaH (1.2 eq). After 1.5 h at 25 C, added the bromobenzyl ketone from step 3 and stirred for 1 d at 25*C. Workup (ethyl acetate/hexanes) and trituration (ethyl acetate/hexanes) afforded the product in 46% yield. Step 5: The product from step 4 was dissolved in methylene chloride and 1 N HCI (ca. 0.04 M) and stirred at 25'C for 1 h. Workup (sodium bicarbonate), and trituration with ether afforded the product alcohol (89%). Step 6: The alcohol from step 5 was dissolved in dry methylene chloride (0.014 M), treated with thionyl chloride (1.2 eq) and stirred at 25'C for 1 d. Concentration and trituration with ethyl acetate/hexanes afforded the product chloride (100%). 159 WO 99/43672 PCTIUS99/03388 NOT FURNISHED UPON FILING 160 WO 99/43672 PCT/US99/03388 Activity data for the compounds of Examples 88-135 are reported in Table VIII (assay described in Example 136) and Table IX (assay of Example 137). Example 136 Activity Assays (a) Vesicle Assay 1-palmitoyl-2-[1 4 C] arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 pM) and 1,2-dioleyolglycerol (final concentration 3 IM) were mixed and dried under a stream of nitrogen. To the lipids was added 50 mM Hepes pH 7.5 (2x final concentration of lipids) and the suspension was sonicated for 3 min. at 4"C. To the suspension was added 50 mM Hepes pH 7.5, 300 mM NaCl, 2 mM DTT, 2 mM CaClb and 2 mg/ml bovine serum albumin (BSA) (Sigma A7511) (1.2x final concentration of lipids). A typical assay consisted of the lipid mixture (85 Il) to which was added consecutively, the inhibitor (5 ptl in DMSO) and cPLA., 10 ng for an automated system or 1 ng for a manual assay, in 1Opl of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below. (b) Soluble Substrate Assay (LysoPC) 1-["C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 IM) was dried under a stream of nitrogen. The lipid was resuspended by vortexing 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consisted of lipid suspension (85 pl) to which was added consecutively the inhibitor ( 5 ptl in DMSO) and cPLA, 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA. This assay was conducted by either the manual assay or automated assay protocol described below. 161 WO 99/43672 PCTIUS99/03388 NOT FURNISHED UPON FILING 162 WO 99/43672 PCT/US99/03388 (f) RBL Assay RBL-2H3 cells were routinely cultured as 37C in a 5 % CO 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded into spinner flasks at 3 x 10 cells/ml and 100 ng/ml DNP specific-IgE was added. After 20 hrs, the cells were harvested by centrifugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 cells/ml in serum free media. The cells were then preincubated with either inhibitor in DMSO (1 % v/v) or DMSO (1 % v/v) for 15 min at 37C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGD content in accordance with known methods. (g) Coumarine Assay 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). Inhibitors were mixed with 200pL assay buffer (80mM Hepes, pH 7.5, 1 mM EDTA) containing 60 pM 7-hydroxycoumarinyl 6 heptenoate. The reaction was initiated by adding 4 pg cPLA2 in 50pAL assay buffer. Hydrolysis of the 7-hydroxycoumarinyl 6-heptenoate ester was monitored in a fluorometer by exciting at 360 nm and monitoring emission at 460 nm. Enzyme activity is proportional to the increasein emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less. Example 137 Rat Carrageenan-Induced Footpad Edema Test Each compound was suspended in 0.3ml absolute ethanol, 0.1 ml Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0. Iml IN NaOH was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All comounds remained in solution. Compounds were administered i.v. in a volumne of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1 % Type IV carrageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan. 163 WO 99/43672 PCT/US99/03388 Table Vill Example Structure PERCENT CONCENTR INHIBITION ATION @ !(micromolar) 88 0 68 6.25 OH oo F F F 0 F FF 88 50! 3 89 50. 22 0 0~ N 0 F F F FP 89 50 24 89 - -- -- -7 90 50 30 F F 90 50 23 9 50 37 90 N50 2 90 50 381 164 WO 99/43672 PCT/US99/03388 Table Vill 91 50 18 0 S N /ci 91 _ ____50: 25 N 92 50 22 93 50 12.5 0 93 55 12.5 96 0 57 6.25 OH 96 0 50 5ro -165 'N F 0 F F F 96 50 - 165 WO 99/43672 PCT/US99/03388 Table VIII 97 56 6.25 OH 0N N 0 Oci 97 50 4.5 98 50 37 OH 0/ S N 98 50 45 98 50 42 98 50 25 98 50 33 98 50 37 99 050 9 OH O O 99 50 12 100 50. 7 OH c 1 66 N 166 WO 99/43672 PCT/US99/03388 Table VIII 100 50 9 101 50 9.5 0 Ns N S F F F F 101 501 10 101 50 12.5 101 50 14 101 -- - -50 17 101 50 22 101 50; 10 102 50 16 0s 102 50 18 102 50 25 103 50 15 FF 103 50 16 103 50 22 167 WO 99/43672 PCT/US99/03388 Table VIII 104 50i 17 0 s N / c5 104 50 20 104 50 12 104 50 12 104 50 14 104 50 18 105 s 18 N 105 50 16 106 N 50 9 0"0 N F F F F F F 106 50 12.5 107 50 3.8 OH ON N F F F F 107 67 6.2 168 WO 99/43672 PCT/US99/03388 Table VIII 108 50i 32 0N N N F F F 108 501 39 109 50; 50 0 N OH 109 501 .55 110 50 50 OH N 110 50' 50 111 50 13 F O OH N 169 WO 99/43672 PCT/US99/03388 Table VIi 112 50 12.5 0
H
3 C11 0
'
0OH N 112 32 -25 112 4650 1-12-0 50 113 38: 100 0 1 N OH 113 50' 170 114 50 40 N OH 114 50 42 115 50. 30 N Q H 3 0 P 00 OH 115 50 35 170 WO 99/43672 PCT/US99/03388 Table ViII 116' 501 60 0 N OH 116 50 70 117A 50 28 0 O 0 OH FN F 117A . 39 50 117B 50 34 OO 7 OH N 0 F F F FE 117B 50 34 117B 50 43 117B 50 43 171 WO 99/43672 PCT/US99/03388 Table VIII 117C 50! 9 0 OH N F F O F F F 117C 50 4 1170 50 8.5 118 50 12 O N N N F N F F F F 118 50 15 119 50 5 O NN FF F F N F F F 119 50 4 119 50 172 WO 99/43672 PCT/US99/03388 Table Vill 120 501 3.8 OH ON 0 N N F FF F 120 67 6.2 120 50 3.8 120 67 6.2 50 18.5 O 0 FF F I F F F F -50 20 122 50 3.75 0 SOH FFF F 0 F F 122 50 10 123 31, 50 OOH N O 0 FHO 123 25 50 173 WO 99/43672 PCT/US99/03388 Table VIII 124 50 12.5 0 N OH C '~ 0 124 50i 15 125 50 23 - 0 OH 0 F F F FF 126 50, 17 OH N 126 50: 18 127 50 28 OH FFFN FF F F 127 50 86 174 WO 99/43672 PCTIUS99/03388 Table ViII 128 501 5 NON OH FF 0 -eC F N~ C N,.. cl F F 128 501 6 128 50 8.5 128 52 12.5 128 50 44 129 ~ 50 2.5 N F F F N 0 OH F F 129 50 4 129 50 3.5 129 50 3.8 129 95 12.5 129 _50 30 130 50 12 N N N F N 0 0 0O F F F 130 50 80 130 50 10 130 50 16 130 50 32 130 50 44 130 50; 50 175 WO 99/43672 PCTIUS99/03388 Table VIII 131 501 7 0 CH 3 N 0 OH 131 50 46 132A 50 9 No 1 F 0 FF N -F O K - t OH 0 132A- ___ __ 50i 17 132A 50 30 13 3 50 19 IH o F 7 N0 F = / HO F F F F 1 32B 50 20 133 50, 8.5 ON 0 0 CH, N O 0 NO 176 WO 99/43672 PCT/US99/03388 Table VIII 134 OH 50i 3.5
SH
3 __ 0 ",- 0 " , N 0 N ~ N CH, 0 7 0 OH N 177 WO 99/43672 PCTIUS99/03388 All patent and literature references cited herein are incorporated as if fully set forht herein. 178

Claims (76)

1. A compound having a chemical formula selected from the group consisting of: AR2 B R N> Ri and B 4 R, 3 R5 or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH,- and -CH,-CH,-; B is independent of any other group and is selected from the group consisting of -(CH,),,-, -(CHO),-, -(CHS).-, -(OCH,),,-, -(SCH,),,-, -(CH = CH) ,-, -(C =C)-, -CON(R 6 )-, -N(R)CO-, -0-, -S- and -N(14)-; R, is independent of any other R group and is selected from the group consisting of -X-, -H. OH, halogen, -CN, -Na, C,-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl; R 2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR R 6 , -(CH1)n-W-(CH,)m-Z-R5, -(CH,).-W-R 5 , -Z-R 5 , C-C, 0 alkyl, alkenyl and substituted aryl; R 3 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR 5 R,, -(CH,),-W-(CH,)m-Z-R5, -(CH),-W-R 5 , -Z-R 5 , C,-Co alkyl, alkenyl and substituted aryl; R 4 is independent of any other R group and is selected from the group consisting of -H, -OH, OR 6 , -SR,, -CN, -COR, -NHR1, -COOH, -CONR6R 7 , -NO 2 , -CONHSOR 8 , C-C 5 alkyl, alkenyl and substituted aryl; R, is independent of any other R group and is selected from the group consisting of -H, -OH, 179 WO 99/43672 PCT/US99/03388 O(CH 2 ),R 6 , -SR 6 , -CN, -COR 6 , -NHI&, -COOH, -NO 2 , -COOH, -CONR 6 R 7 , -CONHSO 2 R 8 , C-C 5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF3, -CF 2 CF 3 and R9 -- aR 1 0 R 6 is independent of any other R group and is selected from the group consisting of -H, qC 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl; R 7 is independent of any other R group and is selected from the group consisting of -H, -C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl; R, is independent of any other R group and is selected from the group consisting of -C 3 alkyl, aryl and substituted aryl; R is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR, -COOH, -CONRIR 7 , tetrazole, -CONHSOR 8 , -COR 6 , -(CH 2 ),CH(OH)R 6 and (CH,).CH 6 R 5 ; RIO is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR 6 , -COOH, -CONR6R 7 , tetrazole, -CONHSOR 8 , -COR 6 , -(CH 2 )nCH(OH)R 6 and -(CH),CHR 6 R 5 ; W is, independently each time used including within the same compound, selected from the group consisting of -0-, -S-, -C-L-, -CH =CH-, -C = C- and -N(R6)-; X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-; Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N(R)-, -CO-, -CON(IR)- and -N(R6)CO-; m is, independently each time used including within the same compound, an integer from 0 to 4; and n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4.
2. The compound of claim 1 having phospholipase enzyme inhibiting activity. 180 WO 99/43672 PCT/US99/03388
3. The compound of claim 1 wherein said compound has the following chemical formula: -- A R(2 V 3
4. The compound of claim 1 wherein said compound has the following chemical formula: R, RB R4
5. The compound of claim 1 wherein compound has the following chemical formula: N B R5
6. The compound of claim 1 wherein A is -CH- and R, is -(CH 2 )n-W-(CH 2 )m-ZRs
7. The compound of claim 6 wherein n is 1, m is 1, W is -S- and Z is -CO-.
8. The compound of claim 7 wherein g% is -NHIR.
9. The compound of claim 8 wherein 1R is a substituted aryl group. 181 WO 99/43672 PCTIUS99/03388
10. The compound of claim 9 wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -CF, -CFCF 3 , -(CH,),COOH, -(CH 2 ),CH 3 , -O(CH 2 ),CH 3 , -(CH 2 ),OH, -(CH 2 ),S(C 6 H 6 ), -(CH 2 ),CONH, and -CHR 11 COOH, wherein R, is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH 2 ),OH, and -O(CH 2 ),CH 3 , and wherein p is an integer from 0 to 4.
11. The compound of claim 6 wherein 1A is selected from the group consisting of -H and OCH 2 (C 6 H 6 ).
12. The compound of claim 6 wherein Ig is -COR 5 , R 5 is -OCHR 6 and R 6 is a substituted aryl group.
13. The compound of claim 12 wherein said aryl group is substituted with one or more substituents selected from the group consisting of -CF 3 , -CF 2 CF 3 and -C(CH 3 )2CHCH 3 .
14. A method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of claim 1.
15. A method of treating an inflammatory condition, comprising administering to a mammalian subject a therapeutically effective amount of a compound of claim 1.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 182 WO 99/43672 PCTIUS99/03388
17. A compound of the formula: R1 R3 R1 R3 Rj- R4 R1, R4 N N R2 1R2I R5 or R 5 wherein R, and RI. are independently selected from C 1 -C 6 alkyl, -Z-C-C 6 alkyl, phenyl, -(CH 2 )n Z-(CH2)n-phenyl, benzyl, -(CH 2 )n-Z-(CH 2 )n-benzvl, napthyl, -(CH 2 )n-Z-(CH 2 )n-napthyl, pyrimidinyl, -(CH 2 ).-Z-(CH 2 )n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C-C 6 alkoxy, -NO2, -NH2, -CN, -CF3, or -OH; Z is O or S; n is an integer from 0 to 3; R 2 is selected from H, halogen, -CF, -OH, -C -CIO alkyl, CI-CI 0 alkoxy, -CHO, -CN, NO 2 , -NH 2 , -NH-C-C6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, or -S0 2 _C,-C 6 alkyl; R 3 is selected from H, halogen, -CF 3 , -OH, -C CIe alkyl, C 1 -CIO alkoxy, -CHO, C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C-C6 alkyl, -N(C-C 6 alkyl) 2 , -N-S02 C 1 -C 6 alkyl, -S0 2 -C-C 6 alkyl or a moiety of the formula: R8 0 (CH2)n- O- (CH2)n () n in each appearance is independently selected as an integer selected from 0-3; -183- WO 99/43672 PCTIUS99/03388 R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ),-COOH, -(CH2)n,-C(O)-COOH, -CF3, -OH, -(CH2)n,-C(O)-COOH, -C,-C6 alkyl, -O-C -C6 alkyl, -NH(C, C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 ; R 4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: R 12 R 12 R 12 N N N 0 0 0 N S ; N or 0 R1 N 0 S R 12 is selected from H, -CF 3 , C 1 -C 6 alkyl, -(CH 2 )n-C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH 2 )n-C(O)-COOH, -CI-C 6 alkyl, -0-C, C 6 alkyl, -NH(C-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n-O-(CH 2 )n-, -(CH 2 )n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH 2 ),-O-, -C(O)-N-, or -(CH2),-S-(CH2)n-C(O)-N-; M' is -COOH or a moiety selected from: -184- WO 99/43672 PCT/US99/03388 R 8 R8 R9 R9 10o or 10 R 0 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF 3 , -OH, (CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C-C 6 alkyl, R8 R8 R 8 Z R Rg z z -(C H 2 n or R8 (CH2)n with a proviso that the moiety or combination of moieties comprising R 3 include an acidic group selected from carboxylic acid or a moiety of the formulae: 0 R 12 R1 0 1 N N N o 0 N ,S ;N N 0 or S -185- WO 99/43672 PCT/US99/03388 R 5 is selected from: a) a moiety of the formula -L 2 -M 2 ; L 2 is selected from a chemical bond or a bridging group selected from -(CH 2 )n-Z-, -(CH 2 ),-Z-(CH2),-, -C(O)-O-, -C(O)-(CH 2 )n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M 2 is selected from -C 1 -C 6 alkyl, -O-C-C 6 alkyl, R 8 R 8 R8 / NJ .- R 9 RR9 R9 or wherein R' and R 9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or b) a moiety of the formulae: R 8 R8 N L 3-m3 or L3-m3. wherein L 3 is a chemical bond or a group selected from -CH 2 - , -CH 2 -Z- , -C(O)- , -0-, -S- , or -(CH2)n,-Z-(CH2)n-; M 3 is selected from -(CH 2 )n-C 3 -C 5 cycloalkyl, furanyl, thienyl, pyrrolyl, -186- WO 99/43672 PCT/US99/03388 R8 R 8 / RN or N or a pharmaceutically acceptable salt thereof.
18. A compound of Claim 17 of the formula: R R3 Rj- R4 N R2 R5 wherein R" and R 2 are hydrogen, and the moieties R 3 , R 4 , R', R', R 9 and R', n, L', L 2 , MI and M2 are as defined in Claim 17, or a pharmaceutically acceptable salt thereof.
19. A compound of the formula: -187- WO 99/43672 PCTIUS99/03388 R R3 R4 N R2 R5 wherein R, is selected from -O-C-C 6 alkyl, -S-C 1 -C 6 alkyl, -0-phenyl, -S-phenyl, -O-benzyl, -S benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH2, -CN, -CF3, or -OH; R 2 is selected from H, halogen, -CF3, -OH, -C 1 -CI 0 alkyl, preferably -C 1 -C 6 alkyl, C,-C 10 alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -CN, -NO 2 , -NH., -NH-C,-C 6 alkyl, -N(C-C 6 alkyl) 2 , N-S0 2 -C,-C 6 alkyl, or -S0 2 -C-C 6 alkyl; R 3 is selected from H, halogen, -CF 3 , -OH, -CI-CI 0 alkyl, preferably -C 1 -C 6 alkyl, CI-Clo alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C-C 6 alkyl, -N(C-C 6 alkyl) 2 , N-S0 2 -C-C 6 alkyl, -S0 2 -C,-C 6 alkyl, or a moiety of the formula: R8 0 (CH2)n- O- (CH2)n n in each appearance is independently selected as an integer selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF 3 , -OH, -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C,-C 6 alkyl, -NH(Cl C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; R 4 is the moiety -L'-M' or -188- WO 99/43672 PCTIUS99/03388 R 8 0 N/H0 R 0 0 S or S L' is selected from a chemical bond or a bridging group selected from -(CH 2 ),,-O-, or -(CH2)n-S-(CH2)n-C(O)-N-; M' is the moiety: R8 ORg R' 0 is selected from H, -COOH, -(CH2),-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -0-C-C 6 alkyl, R8 R8 R8 R9 J R, Z RZRg (CH -189- WO 99/43672 PCT/US99/03388 R 8 'Rg (CH2)n -- with a proviso that the combination of moieties comprising R 4 include a carboxylic acid or a moiety of the formulae: o HO R 9 N /- N 0 - , =0 S or S R 5 is a structure of the formula -L 2 -M 2 ; L 2 is selected from a chemical bond or a bridging group selected from -(CH 2 )n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-; M 2 is selected from -C,-C 6 alkyl, -0-C,-C 6 alkyl, R 8 R9 10 or wherein R', R 9 and R' 0 are as defined above; -190- WO 99/43672 PCT/US99/03388 or a pharmaceutically acceptable salt thereof.
20. A compound of Claim 19 of the formula: R3 R1 R4 N R5 wherein RI is selected from -O-C-C 6 alkyl, -S-C-C 6 alkyl, -0-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C-C6 alkoxy, -NO 2 , -NH2, -CN, -CF3, or -OH; R 3 is selected from H, halogen, -CF3, -OH, -CI-CI0 alkyl, preferably -C 1 -Cl 0 alkyl, CI-CI 0 alkoxy, preferably CI-Cl 0 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-S0 2 -CIC 6 alkyl, -SO2-C 6 alkyl or a moiety of the formula: R 8 0Rg (CH2)n- 0- (CH 2 )n wherein R 4 , R', R', R 9 and R' 0 are as defined in Claim 19, or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. -191- WO 99/43672 PCT/US99/03388
22. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
23. A compound of the formula: R1 R3 R1 R3 RI, R4 R1, R4 N N R2 IR2I R5 or R5 wherein R, and R 1 . are independently selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, preferably -C 1 -C 6 alkyl, -S-CI-CIO alkyl, preferably -S-C,-C 6 alkyl, CI-CIe alkoxy, preferably C, C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a -S-, -0- or -(CH 2 )n- bridge; a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-CIO alkyl, preferably C 1 -C 6 alkyl, CI-CIO alkoxy, preferably C 1 -C 6 alkoxy, -NO 2 , -NH2, -CN, -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six -192- WO 99/43672 PCT/US99/03388 membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -CI 0 alkyl, preferably C 1 -C 6 alkyl, CI-CI 0 alkoxy, preferably CI-C 6 alkoxy, -CHO, NO 2 , -NH2, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 0 alkyl, preferably C,-C 6 alkyl, C 1 -C 0 alkoxy, preferably CI-C 6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 or -OH; or d) a moiety of the formulae: R6 R 6 R Z R7 OS Z , R R7 NR7R7 R 6 z 0 0 R 6 R R N or 0 O Zis O or S; R 6 is selected from the relevant members of the group H, -CF3, CI-CI0 alkyl, preferably Ci-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -0 -193- WO 99/43672 PCTIUS99/03388 benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-CI 0 alkyl, preferably C 1 -C 6 alkyl, C 1 -C 0 alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 , or -OH; R 7 is selected from the relevant members of the group -OH, -CF3, C 1 -CI 0 alkyl, preferably C-C 6 alkyl, CI-C 0 alkoxy, preferably C 1 -C 6 alkoxy, -NH 2 , -(CH2)-NH 2 , -NH-(C-C 6 alkyl), N-(C-C 6 alkyl) 2 , -(CH 2 ),-NH-(C 1 -c 6 alkyl), -(CH 2 )n-N-(C 1 -C 6 alkyl) 2 , phenyl, -0-phenyl, benzyl, or -O-benzyl; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C,, alkyl, preferably C 1 -C 6 alkyl, C 1 -C 0 alkoxy, preferably C-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CC0 alkyl, preferably C 1 -C 6 alkyl, C 1 -CI 0 alkoxy, preferably C 1 -C 6 alkoxy, -CHO, NO 2 , -NH 2 , -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -CI 0 alkyl, preferably C 1 -C 6 alkyl, -C, 1 alkoxy, preferably C-C 6 alkoxy, -CHO, -NO 2 , NH 2 , -CN, -CF 3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2; -194- WO 99/43672 PCTIUS99/03388 R 2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C 1 -C 0 alkyl, preferably C 1 -C 6 alkyl, CI-CI 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -N-SO 2 -C-C 6 alkyl, or -S0 2 -C-C 6 alkyl; R 3 is selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, C,-CI, alkoxy, -CHO, C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH2, -NH-C-C 6 alkyl, -N(C-C 6 alkyl) 2 , -N-SO 2 C 1 -C 6 alkyl, -S0 2 -C-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O) benzyl, -CH 2 -(C 3 -C 6 cycloalkyl), -C(O)-OH, C(O)-C-C 6 alkyl, -C(O)-O-C,-C 6 alkyl, -C(O) CF 3 , -(CH 2 )n-S-CH 2 -(C 3 -C 5 cycloalkyl), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , C(O)-OH, or -OH; or a moiety of the formula: R 8 (CH2)n- 0 - (CH2)n n in each appearance is an integer independently selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF 3 , -OH, -(CH 2 )n-C(O)-COOH, -CI-C6 alkyl, -O-C,-C 6 alkyl, -NH(C, C 6 alkyl), or -N(C-C 6 alkyl) 2 ; R 4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: 0- R 120R12 0R 12 N N N 0 0 0 N S ; N or -195- WO 99/43672 PCTIUS99/03388 0R N =0 S R 2 is selected from H, -CF 3 , C 1 -C 6 alkyl, -(CH2)n-C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CI-C 6 alkyl, -O-C C 6 alkyl, -NH(C 1 -C 6 alkyl), or -N(C-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)"-, -(CH2)n,-S-(CH2)n,-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2,)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R 6 )-(CH 2 )n-, -C(Z)-NH-S0 2 -, -C(Z)-NH-SO 2 -(CH 2 )n-, -C(O)-(CH 2 )n-O-, -C(O) N-, or -(CH 2 ),-S-(CH 2 )n-C(O)-N-; M' is -COOH or a moiety selected from: R8 R8 R RR8 R9 / -N N R10 R1O R 9 S R 8 O R 8 N R 8 R8 1/ \ HN N R9 R 9 \Rg 10O R10 R 10 -196- WO 99/43672 PCTIUS99/03388 S S. N (C1-Ce lower alkyl N (C 1 -C 6 lower haloalkyl' 0 0 '.0R S' S R8 O S R9 0 0, 0 N R11 --- OH , Ho R10 0 OH or R 8 , in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH, (CH 2 )a-C(O)-COOH, tetrazole, 0 0 0 0-P-OH S 0 ,or OH; R 9 in each appearance is independently selected from H, halogen, -CF, -OH, -COOH, (CH 2 ),-COOH, -(CH 2 )n-C(O)-COOH, -C-C 6 alkyl, -O-C-C 6 alkyl, -NH(CI-C 6 alkyl), or -N(C-C 6 alkyl) 2 ; R' 0 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C-C 6 alkyl, -197- WO 99/43672 PCT/US99/03388 R8 R8 R8 N- R, E N- R Z \..-Z (CH2) R 8 CR9 ~00 (CH 2 ) - N (C1-C6 lower alkyl 0 O ~ 0N R S. N (C1-C6 lower haloalkyl RH is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ). COOH, -(CH 2 )n-C(O)-COOH, R8 R8 N- -\RqR | R9 R -(CH2) with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: 0 0 00 P-OH S O 0 1H N 98 -198- WO 99/43672 PCT/US99/03388 O R12 /R12 O R12 O 0 N S N R12 N 0 or S R 5 is selected from C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, -(CH 2 )n-C 3 -CI cycloalkyl, -(CH2).-S-(CH2).-C3_CIO cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3 -C 0 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-0-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o O (CH2) (CH2) S 0 (H2)CH 2 )H2) CH2)N 0 (CH2) n (CH 2 )n (CH2)N 0 (CH 2 ) wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C 5 cycloalkyl or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole. pyrazole, -199- WO 99/43672 PCT/US99/03388 isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -CI 0 alkyl, preferably CI-C6 alkyl, CI-C 0 alkoxy, preferably CI-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF3; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Cl 0 alkyl, preferably C 1 -C 6 alkyl, CI-Clo alkoxy, preferably CI-C 6 alkoxy, -CHO, NO 2 , -NH2, -CN, -CF 3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 0 alkyl, preferably C 1 -C 6 alkyl, CI-Cie alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -NO 2 , NH 2 , -CN, -CF 3 or -OH; d) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D C B wherein D is H, C 1 -C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH2)n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 , -OH, -C -C 6 alkyl, CI-C 6 alkoxy, -NH, or -NO 2 ; -200- WO 99/43672 PCT/US99/03388 or a pharmaceutically acceptable salt thereof.
24. A compound of Claim 23 having the formula: R1 R3 R1 R3 R4 R4 N N R2 R2 R5 or R5 wherein R, is selected from H, halogen, -CF 3 , -OH, -C-CIO alkyl, preferably -C 1 -C 6 alkyl, -S-Cs CIO alkyl, preferably -S-C,-C 6 alkyl, CI-CI alkoxy, preferably C 1 -C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a -S-, -0- or (CH 2 )n- bridge; a) furan, pyrrole, or thiophene, being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 0 alkyl, preferably C-C 6 alkyl, C 1 -CO alkoxy, preferably C,-C6 alkoxy, -NO 2 , -NH 2 , -CN, -CF 3 ; or b) pyridine, pyrimidine, piperidine, or morpholine, each being optionally substituted by from 1 to 3 substituents selected from halogen, C-C 1 O alkyl, preferably C,-C 6 alkyl, CI-CIO alkoxy, preferably CI-C 6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF3 or -OH; or c) benzofuran, indole, napthalene, purine, or quinoline, each being optionally substituted by from 1 to 3 substituents selected from halogen, CI-CIO alkyl, preferably C,-C 6 alkyl, C,-CO alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH; or d) a moiety of the formulae: -201- WO 99/43672 PCT/US99/03388 R6 R6 RI Z O7 OS Z z R7R7' R6 z N7 % I Nj R7 R7 N6 R7 R6 R N R 7 -_ ~ N or 0 0 Z is O or S; R 6 is selected from the relevant members of the group H, -CF3, C 1 -CI 0 alkyl, preferably Ci-C 6 alkyl, C 1 -CI 0 alkoxy, preferably CI-C 6 alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -0 benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Cie alkyl, preferably C-C 6 alkyl, C 1 -Co alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 , or -OH; R 7 is selected from the relevant members of the group -OH, -CF3, CCI 0 alkyl, preferably C 1 -C 6 alkyl, CI-CI 0 alkoxy, preferably C 1 -C 6 alkoxy, -NH 2 , -(CH 2 )n-NH 2 , -NH-(Cl-C 6 alkyl), N-(C,-C 6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , phenyl, -0-phenyl, benzyl, or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole, or morpholine the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CI-CI 0 alkyl, preferably CI-C 6 alkyl, CI-Cl 0 alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 or -OH; -202- WO 99/43672 PCT/US99/03388 n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2; R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C 1 -CI 0 alkyl, preferably C 1 -C 6 alkyl, C 1 -CI 0 alkoxy, preferably C-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-S0 2 -CI-C 6 alkyl, or -SO 2 C,-C 6 alkyl; R 3 is selected from H, halogen, -CF 3 , -OH, -CCI 0 alkyl, C 1 -CI 0 alkoxy, -CHO, -C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 CI-C 6 alkyl, -S0 2 -C-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O) benzyl, -CH 2 -(C 3 -C 5 cycloalky), -C(O)-OH, C(O)-C-C 6 alkyl, -C(O)-O-C-C 6 alkyl, -C(O)-CF 3 , or -(CH 2 )n-S-CH 2 -(C 3 -C 5 cycloalky), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C-C 6 alkyl, C-C 6 alkoxy, -NO 2 , CF3, C(O)-OH, or -OH; or a moiety of the formula: R 8 0 7R (CH2)n- 0- (CH 2 )n n in each appearance is independently selected as an integer selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF 3 , -OH, -(CH 2 )n-C(O)-COOH, -C6-C6 alkyl, -O-C,-C 6 alkyl, -NH(C, C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; R 4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L'-M' or a moiety of the formulae: 0R 120 R 12 R 12 N N N 0 0z 0 N S N or -203- WO 99/43672 PCT/US99/03388 0 R N 0 S R 2 is selected from H, -CF3, C-C6 alkyl, -(CH 2 )n-C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CI-C6 alkyl, -O-Cl C 6 alkyl, -NH(C-C 6 alkyl), or -N(CI-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n,-O-(CH2)n-, -(CH2)n-S-(CH2)- -(CH2)-()(H)- -(CH2)--C2n -(CH2)n-S-(CH2)n-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n,-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n,-, -C(Z)-NH-SO2-, -C(Z)-NH-SO, (CH2)n-, -C(O)-(CH2),,-O-, -C(O) N-, or -(CH2)n-S-(CH2)n-C(0)-N-; M' is -COOH or a moiety selected from: R R8R 9 _- Rg R9 -N N R1O R10 R 9 0 N R R N R 8 HN N R9 -2 R9 --- CR9 -204- WO 99/43672 PCTIUS99/03388 S O N R1 - -OH 0 R10 0 0 0or 0- - O ,0 HQ S S I % R, in each appearance, is independently selected from Hao, -CFGH, -OH,)-COOH, (C 2)-C OH, -C 2NCO-O H CI-C oe alkyl -O-C-Ce alylw-N (Ch-Coalkyl),o (CH 2 )n-C(O)-COOH, tetral,-OCC ak, 0 025 0 ,oror Rv in each appearance, is independently selected from H ao, -C E, -OCH), -GOGH, (H)O(CH2) CH)-C(O)-COOH, -C- 6 lyltO- 1 C 6 aky,-N( 1 - 6 aly),o R9 nec aaac is inendtl selected from H, -GOGHe, -(CH 2 )1-COH, -(H)CCO)C OH, -H (CH 2 ),,-C(O)-COOH, -C 1 -C 6 alkyl, -0-C 1 -C 6 alkyl, -205- WO 99/43672 PCT/US99/03388 R 8 R8 R8 Z Z (CH 2 )n or 7ROO (CHN R9 O 0 010 0 00 S S' N (C1-C6 lower alkyl N (C1-C6 lower haloalkyl. with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: N 0 0 00 O-P-OH S OH O OH N N 0 R 12 0R1 N N S N N 0 or S R 5 is selected from C 1 -C 6 lower alkyl, C-C 6 lower alkoxy, -(CH 2 )n-C 3 -CO cycloalkyl, -206- WO 99/43672 PCT/US99/03388 -(CH 2 )n-S-(CH 2 ).-C 3 -CI cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3 -CO cycloalkyl, -(CH 2 )n-phenyl-O phenyl, -(CH 2 ) 1 -phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: DC B D is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, -CF 3 or -(CH2)n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
25. A compound of Claim 24 having the formula: R1 R3 R1 R3 R4 R4 N N R2 IR2I R5 or R 5 wherein RI is selected from H, halogen, -CF3, -OH, -CI-C , alkyl, preferably -CI-C 6 alkyl, -S-C, CIO alkyl, preferably -S-C-C 6 alkyl, CI-CO alkoxy, preferably C 1 -C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -0- or -(CH 2 ),- bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substituted by from 1 to 3 substituents selected -207- WO 99/43672 PCTIUS99/03388 from halogen, CI-CI 0 alkyl, preferably C 1 -C 6 alkyl, C 1 -CI 0 alkoxy, preferably C,-C 6 alkoxy, NO 2 , -NH2, -CN, -CF 3 ; or n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2; R 2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, CI-CI0 alkyl, preferably C 1 -C 6 alkyl, C 1 -C 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C6 alkyl, -N(C-C 6 alkyl) 2 , -N-S0 2 C,-C 6 alkyl, or -S0 2 -C-C 6 alkyl; R 3 is selected from H, halogen, -CF3, -OH, -CI-CI 0 alkyl, CI-CI0 alkoxy, -CHO, -C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH2, -NH-C,-C6 alkyl, -N(C-C 6 alkyl) 2 , -N-SO 2 Ci-C 6 alkyl, -S0 2 -C-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O) benzyl, -CH 2 -(C 3 -C, cycloalky), -C(O)-OH, C(O)-C-C 6 alkyl, -C(O)-O-C-C 6 alkyl, -C(O)-CF 3 , or -(CH 2 )n-S-CH 2 -(C 3 -C 5 cycloalky), the rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C, -C alkyl, C 1 -C 6 alkoxy, -N2 -CF3, C(O)-OH, or -OH; or a moiety of the formula: R8 0 (CH2)n- 0- (CH2)n n in each appearance is independently selected as an integer selected from 0-3; R' and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 )a-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, -(CH 2 )a-C(O)-COOH, -C,-C6 alkyl, -O-C,-C 6 alkyl, -NH(C, C 6 alkyl), or -N(C -C 6 alkyl) 2 ; R 4 is selected from -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH 2 )n-tetrazole, the moiety -L 1 -M' or a moiety of the formulae: -208- WO 99/43672 PCT/US99/03388 Oo 0 0 R12 0 1 1 N S N or N 20 S R 2 is selected from H, -CF3, C 1 -C 6 alkyl, -(CH 2 )n-C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C 1 C 6 alkyl, -NH(CI-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ; L' is selected from -(CH 2 )n-, -S-, -0-, -C(O)-, -C(O)-O-,-(CH 2 )n-O-, -(CH 2 )n-S-, -(CH2)n,-O-(CH2)n-, -(CH2)n-S-(CH2,)n-, -(CH2)n,-C(O)-(CH2)n-, -(CH2),,-O-(CH2)n-, -(CH2),,-S-(CH,,),-,-C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n,-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n,-, -C(Z)-NH-SO2-, -C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2).-O-, -C(O) N-, or -(CH2)n-S-(CH2)-C(O)-N-; M' is -COOH or a moiety selected from: R8 R8 -~i' R 8 ~f .--- 9..---R9 R9 -N N R10 R10 -209- WO 99/43672 PCT/US99/03388 R 8 \ S R 8 0 8 N R 8 HN R 9 R9 R 10 R 10 R1o 0 O 0 %S' S N (C1-C6 lower alkyl N (C1-C6 lower haloalkyl O S N R9 O N R1 0--OH S O R8 N-- R9 R1o or R8, in each appearance, is independently selected from H, -COOH, -(CH2),-COOH, (CH 2 )n-C(O)-COOH, tetrazole, 0 0 0 0-P-OH S 0 ,or OH ; R 9 in each appearance is independently selected from H, halogen, -CF -OH, -COOH, (CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C,-C 6 alkyl, -NH(C-C 6 alkyl), or -N(C-C 6 alkyl) 2 ; R' is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -CF3, -OH, (CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -0-C-C 6 alkyl, -210- WO 99/43672 PCT/US99/03388 R8 R8 R8 Z Z R (CH2)n R or IRS 0 0 0 (CH 2 )n R S. N 1-C6 lower alkyl O O , N .ORg S. N C1-C6 lower haloalkyl, with a proviso that the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae: N 00 0 0 0 X--211 0 0 OH N~ - N R1 R 12 N N 0 R1 N 0 or S -211- WO 99/43672 PCT/US99/03388 R 5 is selected from C,-C 6 lower alkyl, CI-C 6 lower alkoxy, -(CH 2 )n-C 3 -C 0 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3 -C 0 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3 -CI 0 cycloalkyl, -(CH 2 )n-phenyl-O phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D B D is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, -CF 3 or -(CH2)n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
26. A compound of Claim 1 which is 4 -[(5-{(E)-[5-(benzyloxy)-1-(4-{[3,5-bis (trifluoromethyl)phenoxy]methyl benzyl)-1H-indol-2-yl]methylidene}-2,4-dioxo-1,3-thiazolan-3 yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
27. A compound of Claim 1 which is 5-[(E)-(5-(benzyloxy)-1-{3-[3,5-bis (trifluoromethyl)phenoxy]propyl }-1 H-indol-2-yl)methylidene]- 1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
28. A compound of Claim I which is 5-((E)-{5-(benzyloxy)-l-[2,4-bis (trifluoromethyl)benzyl- 1 H-indol-2-yl I methylidene)- 1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof. -212- WO 99/43672 PCT/US99/03388
29. A compound of Claim 1 which is 5-{ (E)-[5-(benzyloxy)- 1 -(4-chlorobenzyl)- 1 H indol-2-yl]methylidene}-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
30. A compound of Claim 1 which is 5-{ (E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H indol-2-yl]methylidene }-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
31. A compound of Claim 1 which is 5-{(E)-[1-(4-benzylbenzyl)-5-(benzyloxy)-1H indol-2-yl]methylidene }-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
32. A compound of Claim 1 which is 5-{ (E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H indol-2-yl]methylidene}-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
33. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl methylidene)-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
34. A compound of Claim 1 which is 2-(5-{(E)-[5-(benzyloxy)-1-(4-{[3,5 bis(trifluoromethyl)phenoxy]methyl} benzyl)- 1 H-indol-2-yl]methylidene }-2,4-dioxo- 1,3 thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
35. A compound of Claim 1 which is 4-[(5-{ (E)-[5-(benzyloxy)-1-(4-chlorobenzyl) 1H-indol-2-yl]methylidene}-2,4-dioxo-1,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
36. A compound of Claim 1 which is 2-(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl) 1H-indol-2yl]methylidene }-2,4-dioxo- 1,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
37. A compound of Claim 1 which is 4-[(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl) 1H-indol-2-yl]methylidene} -2,4-dioxo- 1,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. -213- WO 99/43672 PCT/US99/03388
38. A compound of Claim 1 which is 2-(5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H indol-2-yl]methylidene} -2,4-dioxo- 1,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
39. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene)-2-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
40. A compound of Claim 1 which is 5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-lH indol-2-yl]methylidene}-2-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
41. A compound of Claim 1 which is 5-[(E)-(5-(benzyloxy)-l-{3-[3,5- bis(trifluoromethyl)phenoxy]propyl } -1 H-indol-2-yl)methylidene]-2-thioxo- 1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
42. A compound of Claim 1 which is 5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H indol-2-yl]methylidene}-2-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
43. A compound of Claim 1 which is 5-{ (E)-[1-(4-benzylbenzyl)-5-(benzyloxy)-lH indol-2-yl]methylidene}-2-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
44. A compound of Claim 1 which is 5-{(E)-[5-(benzyloxy)-1-(4-{[3,5 bis(trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indol-2-yl]methylidene }-2-thioxo- 1,3-thiazolan 4-one or a pharmaceutically acceptable salt thereof.
45. A compound of Claim I which is 4-{ [5-((E)-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]- 1 H-indol-2-yl } methylidene)-4-oxo-2-thioxo- 1,3-thiazolan-3 yl]methyl }benzoic acid or a pharmaceutically acceptable salt thereof.
46. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene)-2-thioxotetrahydro-4H-imidazol-4-one or a pharmaceutically acceptable salt thereof. -214- WO 99/43672 PCT/US99/03388
47. A compound of Claim 1 which is 1-benzyl-5-(2-thienyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
48. A compound of Claim 1 which is 5-(1-benzofuran-2-yl)-1-benzyl-1H-indole-2 carboxylic acid or a pharmaceutically acceptable salt thereof.
49. A compound of Claim 1 which is 1-benzyl-5-(4-fluorophenyl)-1H-indole-2 carboxylic acid or a pharmaceutically acceptable salt thereof.
50. A compound of Claim 1 which is 1-benzyl-5-(3-methoxyphenyl)-1H-indole-2 carboxylic acid or a pharmaceutically acceptable salt thereof.
51. A compound of Claim 1 which is 1-benzyl-5-phenyl- 1 H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
52. A compound of Claim 1 which is 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
53. A compound of Claim 1 which is 5-[3-(acetylamino)phenyl]-l-benzhydryl-1H indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
54. A compound of Claim 1 which is 1-benzhydryl-5-(2-thienyl)-1H-indole-2 carboxylic acid or a pharmaceutically acceptable salt thereof.
55. A compound of Claim 1 which is 5-[({5-(benzyloxy)-l-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof. -215- WO 99/43672 PCT/US99/03388
56. A compound of Claim 1 which is 5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
57. A compound of Claim 1 which is 5-(benzyloxy)-1-(4-{ [3,5 bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
58. A compound of Claim 1 which is 5-[({5-(benzyloxy)-l-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof.
59. A compound of Claim 1 which is 5-(benzyloxy)-1-(4-{[3,5 bis(trifluoromethyl)phenoxylmethyl } benzyl)- 1 H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
60. A compound of Claim 1 which is 4-{[5-((E)-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene)-4-oxo-2-thioxo-1,3-thiazolan-3 yl]methylIbenzoic acid or a pharmaceutically acceptable salt thereof.
61. A compound of Claim 1 which is 5-((Z,2E)-3-{5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}-2-propenylidene)-1,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
62. A compound of Claim 1 which is 5-(benzyloxy)-1-(4-{ [3,5 bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
63. A compound of Claim 1 which is 5-({[1-benzyl-5-(benzyloxy)-1H-indol-2 yl]carbonyl } amino)isophthalic acid or a pharmaceutically acceptable salt thereof. -216- WO 99/43672 PCTIUS99/03388
64. A compound of Claim 1 which is (E)-3-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H indol-2-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof.
65. A compound of Claim 1 which is (E)-3-{5-(benzyloxy)-l-[2,4 bis(trifluoromethyl)benzyl]-1H-indol-2-yl}-2-propenoic acid or a pharmaceutically acceptable salt thereof.
66. A compound of Claim 1 which is (E)-3-[5-(benzyloxy)-1-(4-chlorobenzyl)-lH indol-2-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof.
67. A compound of Claim 1 which is 1-(4-{[3,5 bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
68. A compound of Claim 1 which is 5-({[5-(benzyloxy)-1-(4-{[3,5 bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indol-2-yl]carbonyl amino)-2-[(5-chloro-3 pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof.
69. A compound of Claim 1 which is 3-({[1-(4-f[3,5 bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indol-2-yl]carbonyl i amino)benzoic acid or a pharmaceutically acceptable salt thereof.
70. A compound of Claim 1 which is 2-[4-({[1-(4-{[3,5 bis(trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indol-2-yl]carbonyl I amino)phenyl]acetic acid or a pharmaceutically acceptable salt thereof.
71. A compound of Claim 1 which is 3-{[3-acetyl-5-(benzyloxy)-1-(2 naphthylmethyl)-1H-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof. -217- WO 99/43672 PCT/US99/03388
72. A compound of Claim 1 which is 4-{[ 5 -(benzyloxy)-1-(2-naphthylmethyl)-3 ( 2 , 2 , 2 -trifluoroacetyl)-1H-indol-2-yl]methoxylbenzoic acid or a pharmaceutically acceptable salt thereof.
73. A compound of Claim 1 which is 3-{[5-(benzyloxy)-1-[2,4 bis(trifluoromethyl)benzyl]-3-(2,2,2-trifluoroacetyl)-1H-indol-2-yl]methoxy benzoic acid or a pharmaceutically acceptable salt thereof.
74. A compound of Claim 1 which is 2-({[3-acetyl-1-[4-(1,3-benzothiazol-2 ylcarbonyl)benzyl]-5-(benzyloxy)-1H-indol-2-yl]methyl}sulfanyl)acetic acid or a pharmaceutically acceptable salt thereof.
75. A compound of Claim 1 which is 2 -({[3-acetyl-l-[4-(1,3-benzothiazol-2 ylcarbonyl)benzyl]-5-(benzyloxy)- 1H-indol-2-yl]methyl} sulfanyl)benzoic acid or a pharmaceutically acceptable salt thereof.
76. A compound of Claim 1 which is 4- { [3-acetyl- 1-[4-(1,3-benzothiazol-2 ylcarbonyl)benzyl]-5-(benzyloxy)- 1 H-indol-2-yl]methoxy } benzoic acid or a pharmaceutically acceptable salt thereof. -218-
AU32970/99A 1998-02-25 1999-02-17 Inhibitors of phospholipase a2 Abandoned AU3297099A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US3010298A 1998-02-25 1998-02-25
US09030102 1998-02-25
PCT/US1999/003388 WO1999043672A1 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2

Publications (1)

Publication Number Publication Date
AU3297099A true AU3297099A (en) 1999-09-15

Family

ID=21852517

Family Applications (1)

Application Number Title Priority Date Filing Date
AU32970/99A Abandoned AU3297099A (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2

Country Status (19)

Country Link
EP (1) EP1062216A1 (en)
JP (1) JP2002504551A (en)
KR (1) KR20010041346A (en)
CN (1) CN1298404A (en)
AU (1) AU3297099A (en)
BG (1) BG104781A (en)
BR (1) BR9909242A (en)
CA (1) CA2322163A1 (en)
EA (1) EA200000873A1 (en)
EE (1) EE200000522A (en)
HR (1) HRP20000513A2 (en)
HU (1) HUP0100156A3 (en)
ID (1) ID26123A (en)
IL (1) IL137540A0 (en)
NO (1) NO20004217L (en)
PL (1) PL342516A1 (en)
SK (1) SK12782000A3 (en)
TR (1) TR200002445T2 (en)
WO (1) WO1999043672A1 (en)

Families Citing this family (124)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2299879C2 (en) * 2000-01-17 2007-05-27 Байер Акциенгезелльшафт Substituted arylketones
WO2002000620A1 (en) * 2000-06-27 2002-01-03 Smithkline Beecham Corporation Fatty acid synthase inhibitors
EP1303262A2 (en) * 2000-07-14 2003-04-23 Eli Lilly And Company Use of a spla2 inhibitor for the treatment of sepsis
EP1305285B1 (en) 2000-07-25 2007-05-16 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
RU2290403C2 (en) * 2000-12-28 2006-12-27 Дайити Фармасьютикал Ко., Лтд. Vla-4 inhibitors
AU2002302248B2 (en) * 2001-05-23 2008-03-06 Merck Frosst Canada Ltd. Dihydropyrrolo[1,2-A]indole and tetrahydropyrido[1,2-A]-indole derivatives as prostaglandin D2 receptor antagonists
US7291639B2 (en) 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
TWI224101B (en) 2001-06-20 2004-11-21 Wyeth Corp Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
DE60203529T2 (en) 2001-09-27 2006-03-16 F. Hoffmann-La Roche Ag INDOIND DERIVATIVES AS COX-II INHIBITORS
US7101875B2 (en) 2001-12-03 2006-09-05 Wyeth Methods for treating arthritic disorders
US6984735B2 (en) 2001-12-03 2006-01-10 Wyeth Process for making an aldehyde
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions
US6635771B2 (en) 2001-12-03 2003-10-21 Wyeth N-benzhydryl indole compounds
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US6797708B2 (en) 2001-12-03 2004-09-28 Wyeth Inhibitors of cytosolic phospholipase A2
AUPS282602A0 (en) 2002-06-07 2002-06-27 Garvan Institute Of Medical Research Method of inhibiting cell proliferation
US7247741B2 (en) * 2005-01-21 2007-07-24 Ptc Therapeutics, Inc. Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
EP1532119A2 (en) 2002-07-31 2005-05-25 Euro-Celtique S.A. Aryl substituted benzimidazoles and their use as sodium channel blockers
CA2495915A1 (en) 2002-08-29 2004-03-11 Merck & Co., Inc. Indoles having anti-diabetic activity
RU2328483C2 (en) 2002-08-29 2008-07-10 Мерк Энд Ко., Инк. Indoles with antidiabetic activity
KR20050072812A (en) 2002-11-07 2005-07-12 악조 노벨 엔.브이. Indoless useful in the treatment of androgen-receptor related diseases
EP1569901B1 (en) 2002-12-10 2008-10-15 Wyeth ARYL, ARYLOXY, AND ALKYLOXY SUBSTITUTED i 1H /i -INDOL-3-YL GLYOXYLIC ACID DERIVATIVES AS INHIBITORS OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
DE60306548T2 (en) 2002-12-10 2007-06-21 Wyeth SUBSTITUTED 3-CARBONYL-1-YL-ACETIC DERIVATIVES AS PLASMINOGEN ACTIVATOR INHIBITOR (PAI-1) INHIBITORS
UA80453C2 (en) 2002-12-10 2007-09-25 Derivatives of substituted dyhydropyranoindol-3,4-dion as inhibitors of plasminogen activator inhibitor-1 (pai-1)
DE60306547T2 (en) 2002-12-10 2007-06-28 Wyeth SUBSTITUTED 3-ALKYL AND 3-ARYL ALKYL-1H-INDOL-1-YL-ACETIC ACID DERIVATIVES AS PLASMINOGEN ACTIVATOR
DE60327550D1 (en) 2002-12-10 2009-06-18 Wyeth Corp SUBSTITUTED INDOLOXOACETYLAMINOACETIC ACID DERIVATIVES AS INHIBITORS OF PLASMINOGENACTIVATOR INHIBITOR-1 (PAI-1)
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
US7129264B2 (en) * 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
JP5001650B2 (en) * 2003-07-11 2012-08-15 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Benzimidazole carboxamide
CA2770493A1 (en) 2003-07-24 2005-02-03 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
AU2004261628B2 (en) * 2003-07-28 2011-05-12 Janssen Pharmaceutica N.V. Benzimidazole, benzthiazole and benzoxazole derivatives and their use as LTA4H modulators
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7119214B2 (en) * 2004-04-13 2006-10-10 Cephalon France Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives
TW200602317A (en) 2004-04-23 2006-01-16 Akzo Nobel Nv Novel androgens
US20050244367A1 (en) * 2004-05-03 2005-11-03 Ilypsa, Inc. Phospholipase inhibitors localized in the gastrointestinal lumen
CA2570363A1 (en) 2004-06-18 2005-12-29 Biolipox Ab Indoles useful in the treatment of inflammation
KR20070055563A (en) 2004-08-23 2007-05-30 와이어쓰 Oxazolo-naphthyl acids as plasminogen activator inhibitor type-1(pai-1) modulators useful in the treatment of thrombosis and cardiovascular diseases
MX2007003335A (en) * 2004-09-21 2007-06-05 Athersys Inc Benzimidazole acetic acids exhibiting crth2 receptor antagonism and uses thereof.
AU2005302706B2 (en) 2004-10-27 2011-12-15 Janssen Pharmaceutica N.V. Indole derivatives useful as progesterone receptor modulators
DE602005007765D1 (en) * 2004-10-27 2008-08-07 Hoffmann La Roche NEW INDOL OR BENZIMIDAZOLE DERIVATIVES
WO2006077367A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflamation
US20080249091A1 (en) * 2005-01-19 2008-10-09 Benjamin Pelcman Indoles Useful in the Treatment of Inflammation
US20090042949A1 (en) * 2005-01-19 2009-02-12 Benjamin Pelcman Indoles Useful in the Treatment of Inflammation
US8097623B2 (en) * 2005-01-19 2012-01-17 Biolipox Ab Indoles useful in the treatment of inflammation
WO2006109633A1 (en) * 2005-04-07 2006-10-19 Daiichi Sankyo Company, Limited Substituted indole compound
GT200600228A (en) 2005-05-27 2006-12-26 INHIBITORS OF PHOSPHOLIPASE A2 CITOSOLICA
CN101263115A (en) 2005-08-17 2008-09-10 惠氏公司 Substituted indoles and use thereof
AR056690A1 (en) 2005-10-14 2007-10-17 Athersys Inc INDOL DERIVATIVES AS INDOL INHIBITORS AS INHIBITORS OF HISTAMINE RECEIVER 3 FOR THE PARKING OF SUENO DISORDERS AND COGNITIVES OBESITY AND OTHER SNC DISORDERS
EP1779848A1 (en) * 2005-10-28 2007-05-02 Nikem Research S.R.L. V-ATPase inhibitors for the treatment of inflammatory and autoimmune diseases
MX2008005666A (en) 2005-11-03 2009-03-02 Ilypsa Inc Multivalent indole compounds and use thereof as phospholipase-a2 inhibitors.
GB2431927B (en) 2005-11-04 2010-03-17 Amira Pharmaceuticals Inc 5-Lipoxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
WO2008009924A2 (en) * 2006-07-18 2008-01-24 Biolipox Ab Indoles useful in the treatment of inflammation
WO2008019357A2 (en) 2006-08-07 2008-02-14 Ironwood Pharmaceuticals, Inc. Indole compounds
CA2712854C (en) 2008-01-31 2016-02-23 Sanofi-Aventis Cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals
KR20160129109A (en) 2008-05-23 2016-11-08 아미라 파마슈티칼스 인코포레이티드 5-lipoxygenase-activating protein inhibitor
MX2011003239A (en) 2008-09-26 2011-04-28 Merck Sharp & Dohme Novel cyclic benzimidazole derivatives useful anti-diabetic agents.
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
JP2012507530A (en) 2008-10-29 2012-03-29 メルク・シャープ・エンド・ドーム・コーポレイション Novel cyclic benzimidazole derivatives that are useful anti-diabetic agents
JP5557845B2 (en) 2008-10-31 2014-07-23 メルク・シャープ・アンド・ドーム・コーポレーション Novel cyclic benzimidazole derivatives useful as antidiabetic agents
PE20120493A1 (en) 2009-06-29 2012-05-20 Incyte Corp PYRIMIDINONES AS PI3K INHIBITORS
US8759359B2 (en) 2009-12-18 2014-06-24 Incyte Corporation Substituted heteroaryl fused derivatives as PI3K inhibitors
BR112012018631A8 (en) 2010-01-28 2017-12-19 President And Fellows Of Harvard Colege compositions and methods for enhancing proteasome activity
EP2538784B1 (en) 2010-02-25 2015-09-09 Merck Sharp & Dohme Corp. Benzimidazole derivatives useful anti-diabetic agents
BR112012024380A2 (en) 2010-03-25 2015-09-15 Glaxosmithkline Llc chemical compounds
CA2796311A1 (en) 2010-04-14 2011-10-20 Incyte Corporation Fused derivatives as pi3k.delta. inhibitors
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9617197B2 (en) * 2010-08-04 2017-04-11 University Of Virginia Patent Foundation Compositions and methods for treating inflammatory diseases
US9000025B2 (en) 2010-08-20 2015-04-07 Amira Pharmaceuticals, Inc. Autotaxin inhibitors and uses thereof
AR084366A1 (en) 2010-12-20 2013-05-08 Incyte Corp N- (1- (REPLACED PHENYL) ETIL) -9H-PURIN-6-AMINAS AS PI3K INHIBITORS
AR084433A1 (en) 2010-12-22 2013-05-15 Ironwood Pharmaceuticals Inc FAAH INHIBITORS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2012125629A1 (en) 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors
DK2707101T3 (en) 2011-05-12 2019-05-13 Proteostasis Therapeutics Inc PROTEOSTASE REGULATORS
EP2714680B1 (en) 2011-05-27 2015-11-25 Amira Pharmaceuticals, Inc. Heterocyclic autotaxin inhibitors and uses thereof
KR101982475B1 (en) 2011-09-02 2019-05-27 인사이트 홀딩스 코포레이션 Heterocyclylamines as pi3k inhibitors
ES2790358T3 (en) 2011-12-28 2020-10-27 Global Blood Therapeutics Inc Substituted Heteroaryl Aldehyde Compounds and Methods for Their Use in Increasing Tissue Oxygenation
PL3738434T3 (en) 2011-12-28 2024-03-04 Global Blood Therapeutics, Inc. Intermediates to obtain substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
AR090548A1 (en) 2012-04-02 2014-11-19 Incyte Corp BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS
WO2014036016A1 (en) 2012-08-31 2014-03-06 Principia Biopharma Inc. Benzimidazole derivatives as itk inhibitors
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US20140274961A1 (en) 2013-03-15 2014-09-18 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
WO2014145040A1 (en) 2013-03-15 2014-09-18 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
CA2902711C (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Substituted pyridinyl-6-methoxy-2-hydroxybenzaldehyde derivatives and pharmaceutical compositions thereof useful for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
KR20190041548A (en) 2013-03-15 2019-04-22 글로벌 블러드 테라퓨틱스, 인크. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN105073728A (en) 2013-03-15 2015-11-18 全球血液疗法股份有限公司 Compounds and uses thereof for the modulation of hemoglobin
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds
WO2015073528A1 (en) 2013-11-12 2015-05-21 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
EP3071205B1 (en) 2013-11-18 2020-02-05 Forma Therapeutics, Inc. Benzopiperazine compositions as bet bromodomain inhibitors
EA202092627A1 (en) 2013-11-18 2021-09-30 Глобал Блад Терапьютикс, Инк. COMPOUNDS AND THEIR APPLICATIONS FOR HEMOGLOBIN MODULATION
PL3071203T3 (en) 2013-11-18 2021-08-23 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
PE20160179A1 (en) 2014-02-07 2016-05-20 Global Blood Therapeutics Inc CRYSTALLINE POLYMORPHES FROM THE FREE BASE OF 2-HYDROXY-6 - ((2- (1-ISOPROPYL-1H-PYRAZOL-5-IL) PYRIDIN-3-IL) METOXY) BENZALDEHYDE
WO2015191677A1 (en) 2014-06-11 2015-12-17 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as pi3k inhibitors
MY187502A (en) 2015-02-27 2021-09-24 Incyte Corp Salts of pi3k inhibitor and processes for their preparation
MA41841A (en) 2015-03-30 2018-02-06 Global Blood Therapeutics Inc ALDEHYDE COMPOUNDS FOR THE TREATMENT OF PULMONARY FIBROSIS, HYPOXIA, AND AUTOIMMUNE AND CONNECTIVE TISSUE DISEASES
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
TW201731509A (en) 2015-12-04 2017-09-16 全球血液治療公司 Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
AU2016374294B2 (en) 2015-12-15 2019-06-27 Astrazeneca Ab Isoindole compounds
AR108435A1 (en) 2016-05-12 2018-08-22 Global Blood Therapeutics Inc PROCESS TO SYNTHETIZE 2-HYDROXI-6 - ((2- (1-ISOPROPIL-1H-PIRAZOL-5-IL) -PIRIDIN-3-IL) METOXI) BENZALDEHYDE
TWI778983B (en) 2016-10-12 2022-10-01 美商全球血液治療公司 Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
EP3638661A1 (en) 2017-06-14 2020-04-22 Astrazeneca AB 2,3-dihydroisoindole-1-carboxamides useful as ror-gamma modulators
WO2020072377A1 (en) 2018-10-01 2020-04-09 Global Blood Therapeutics, Inc. Modulators of hemoglobin for the treatment of sickle cell disease
PL3860998T3 (en) 2018-10-05 2024-06-17 Annapurna Bio Inc. Compounds and compositions for treating conditions associated with apj receptor activity

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL109311A0 (en) * 1993-04-16 1994-07-31 Lilly Co Eli 1H-indole-3-acetamide sPla2 inhibitors
DE4338770A1 (en) * 1993-11-12 1995-05-18 Matthias Dr Lehr Indole-2-alkanoic acids and their derivatives as inhibitors of phospholipase A¶2¶
DK0848004T3 (en) * 1995-07-31 2003-07-21 Shionogi & Co Pyrrolidine derivatives with inhibitory activity against phospholipase A2
EP0923546B1 (en) * 1996-08-01 2003-11-26 Merckle GmbH Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a2
WO1998008818A1 (en) * 1996-08-26 1998-03-05 Genetics Institute, Inc. Inhibitors of phospholipase enzymes

Also Published As

Publication number Publication date
BR9909242A (en) 2000-11-14
NO20004217L (en) 2000-10-23
CN1298404A (en) 2001-06-06
KR20010041346A (en) 2001-05-15
HUP0100156A2 (en) 2001-07-30
WO1999043672A1 (en) 1999-09-02
HRP20000513A2 (en) 2001-12-31
JP2002504551A (en) 2002-02-12
NO20004217D0 (en) 2000-08-23
EP1062216A1 (en) 2000-12-27
IL137540A0 (en) 2001-07-24
TR200002445T2 (en) 2000-12-21
HUP0100156A3 (en) 2002-12-28
BG104781A (en) 2001-10-31
WO1999043672A9 (en) 2000-05-04
PL342516A1 (en) 2001-06-18
SK12782000A3 (en) 2001-04-09
ID26123A (en) 2000-11-23
EA200000873A1 (en) 2001-04-23
CA2322163A1 (en) 1999-09-02
EE200000522A (en) 2002-02-15

Similar Documents

Publication Publication Date Title
AU3297099A (en) Inhibitors of phospholipase a2
US6630496B1 (en) Inhibitors of phospholipase enzymes
AU2782599A (en) Inhibitors of phospholipase enzymes
US6828344B1 (en) Inhibitors of phospholipase enzymes
AU717430B2 (en) Inhibitors of phospholipase enzymes
AU2782699A (en) Inhibitors of phospholipase enzymes
EP0275667B1 (en) 3-hetero-substituted-n-benzyl-indoles
US6916841B2 (en) Inhibitors of phospholipase enzymes
CZ89394A3 (en) Derivative of +h-indole-3-acetamide, process of its preparation, and pharmaceutical preparation in which it is comprised
JPH0680666A (en) Angiotensin ii antagonist
JP2006510673A (en) Aryl, aryloxy and alkyloxy substituted 1H-indol-3-ylglyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor 1 (PAI-1)
JPH05345778A (en) Pharmaceutical composition
JP2006511562A (en) Use of substituted 2,5-diamidindoles for the treatment of urological diseases
MXPA00008294A (en) Inhibitors of phospholipase a2
CZ20003117A3 (en) Phospholipase inhibitors
MXPA00008292A (en) Inhibitors of phospholipase enzymes
MXPA99001864A (en) Inhibitors of phospholipase enzymes
MXPA00008295A (en) Inhibitors of phospholipase enzymes
CZ20003113A3 (en) Phospholipase inhibitors
CZ20003115A3 (en) Phospholipase inhibitors

Legal Events

Date Code Title Description
MK5 Application lapsed section 142(2)(e) - patent request and compl. specification not accepted