INHIBITORS OF PHOSPHOLIPASE ENZYMES

Abstract: Compounds having a chemical formula selected from the group consisting of formulae (I), (II) and (III) or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH2- and -CH2-CH2-; B is independent of any other group and is selected from the group consisting of -(CH2)n-, -(CH2O)n-, -(CH2S)n-, -(OCH2)n-, -(SCH2)n-, -(CH=CH)n-, -(CC)n-, -CON(R6)-, -N(R6)CO-, -O-, -S- and -N(R6)-; R2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C1-C10 alkyl, alkenyl and substituted aryl; R3 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C1-C10 alkyl, alkenyl and substituted aryl; which inhibit the activity of phospholipase enzymes, particularly cytosolic phospholipase A2. Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.

Description: INHIBITORS OF PHOSPHOLIPASE ENZYMES 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. 227: 1 171-76 ( 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. Likewise arachidonic acid is not free in cells but is released from the sn-2 position of membrane phospholipids by phospholipase A : (hereinafter PLA 2 ). The reaction catalyzed by PLA 2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis. When the phospholipid substrate of PLA, is of the phosphotidyl choline class with an ether linkage in the sn- 1 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)]. 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 PLA,s 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 Biophvs 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 PLA 2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intraceliular proteins Moreover, there is evidence that PLA 2 is 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 intraceliular proteins It would be impossible for the non-pancreatic PLA 2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme A muπne PLA-, has been identified in the muπne macrophage cell line, designated RAW 264 7 A specific activity of 2 μmols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule However, this protein was not puπfied to homogeneity [See, C C Leslie et al, Biochem Biophvs Acta . 963 476-492 (1988)] The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA 2 A cytosolic phospholipase A 2 (hereinafter "cPLAi") 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 intraceliular PLA 2 enzyme, puπfied from its natural source or otherwise produced in puπfied form, which functions intraceilularly 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. However, there remains a need in the art for an identification of effective anti-inflammatory agents for therapeutic use in a vaπety of disease states Summary of the Invention The present invention provides compounds having a chemical formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH 2 - and -CH 2 -CH 2 -; B is independent of any other group and is selected from the group consisting of -(CH 2 ) n -, -(CH 2 0) n -, -(CH 2 S) n -, -(OCH 2 ) n -, -(SCH 2 ) n -, -(CH=CH) n -, -(C≡C) n -, -CON(R 6 )-, -N(R 6 )CO-, -0-, -S- and -N(R 6 )-; R, is independent of any other R group and is selected from the group consisting of -X-R 6 , -H. -OH, halogen, -CN, -N0 2 , C,-C, 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,, -CONR,R 6 , -(CH 2 ) n -W-(CH 2 ) m -Z-R„ -(CH 2 )„-W-R„ -Z-R„ C,-C, 0 alkyl, alkenyl and substituted aryl; R, is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR,R 6 , -(CH 2 ) n -W-(CH 2 ) m -Z-R s , (CH 2 ) n -W-R„ -Z-R„ C r C l0 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 6 , -CN, -COR 6 , -NHR 6 , -COOH, -CONR 6 R 7 , -N0 2 , -CONHS0 2 R R , 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, -0(CH 2 ) n R 6 , -SR 6 , -CN, -COR 6 , -NHR 6 , -COOH, -N0 2 , -COOH, -CONR ή R 7 , -CONHSO : R 8 , C r C, alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF„ -CF,CF, and R 6 is independent of any other R group and is selected from the group consisting of -H, C,-C 3 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,-C, alkyl, alkenyl, alkinyl, aryl and substituted aryl, R 8 is independent of any other R group and is selected from the group consisting of C,-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 6 , -COOH, -CONR 6 R 7 , tetrazole, -CONHS0 2 R 8 , -COR ή , -(CH 2 ) n CH(OH)R 6 and -(CH 2 ) n CHR 6 R„ R ι0 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR 6 , -COOH, -CONR 6 R 7 , tetrazole, -CONHS0 2 R 8 , -COR 6 , -(CH 2 )„CH(OH)R 6 and -(CH 2 ) n CHR 6 R 5 , W is, independently each time used including within the same compound, selected from the group consisting of -0-, -S-, -CH,-, -CH=CH-, -C ≡ C- and -N(R 6 )-, X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -O-, -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 2 -, -0-, -S-, -N(R 6 )-, - CO-, -CON(R 6 )- and -N(R„)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 preferrred embodiments include compounds having the following chemical formula compounds having the following chemical formula: compounds having the following chemical formula: In particularly preferred embodiments, A is -CH 2 - and R 2 is -(CH 2 ) n -W-(CH 2 ) m -ZR<j These preferred compounds includes those wherein n is 1 , is 1 , W is -S- and Z is -CO-; those wherein R 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 2 CF 3 , -(CH 2 ) p COOH, -(CH 2 ) p CH 3 , -0(CH 2 ) p CH„ -(CH 2 ) p OH, -(CH 2 ) p S(C 6 H 6 ), -(CH 2 ) p CONH 2 and -CHR M COOH, wherein R π is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH 2 ) p OH, and -0(CH 2 ) p CH 3 , and wherein p is an integer from 0 to 4. Other preferred comounds include those wherein R, is selected from the group consisting of -H and -OCH 2 (C 6 H 6 ) and R, is -COR , 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 -CF 3 , -CF 2 CF 3 and -C(CH,) 2 CH 2 CH 3 . 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 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 descπbed herein are also part of the present invention and may be used in practicing the compounds and methods disclosed herein. Bπef Description of the Figures Figs. 1 -13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are descπbed in further detail below. Detailed Descnption of Preferred Embodiments As used herein: "halogen" includes chloπne, fluorine, iodine and bromine; "alkyl", "alkenyl" and "alkinyl" include both straight chain and branched moieties; "aryl" includes single and multiple πng moieties; and "substituted" denotes the presence of one or more similar ot dissimilar substituent groups of any character. 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 descπbed 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 "IC 50 " value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay. Where no numeπcal IC 50 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 SUBSTITUTE SHEET (RULE 26) oo m fN rn CN oo CN rt o >n Λ rt rr fN co o Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure descπbed in Example 89 The results are reported in Table VII Table VII As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays descπbed in Example 88 below). A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA 2 ) in any available assay (preferably an assay descπbed below in Example 88 or Example 89) for enzyme activity In preferred embodiments, a compound has ( 1 ) an IC S0 value of less than about 25 μM, preferably less than about 6 μM, in the LysoPC assay, (2) an IC S0 value of less than about 50 μM in the vesicle assay; (3) an IC<;o value of less than about 1 μM in the PMN assay, (4) an IC 50 value of less than about 15 μM in the Coumaπne assay, and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction) in the rat carrageenan-induced footpad edema test Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA,) activity and, therefore, are useful in "treating" (I e., treating, preventing or ameliorating) inflammatory or inflammation-related conditions (e.g., rheumatoid arthπtis, psoπasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotπenes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis The present invention encompasses both pharmaceutical compositions and therapeutic 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 earner Such a composition may also contain (in addition to a compound or compounds of the present invention and a earner) diluents, fillers, salts, buffers, stabilizers, solubihzers, and other mateπals well known in the art The term "pharmaceutically acceptable" means a non-toxic mateπal that does not interfere with the effectiveness of the biological activity of the active ιngredιent(s) The characteπstics of the earner 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 effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention 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 earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution Suitable lipids for hposomal formulation include, without limitation, monoglyceπdes, diglyceπdes, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like Preparation of such hposomal 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 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, l e , treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention 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, seπally or simultaneously In practicing the method of treatment or use of the present invention, a 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 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), cytokιne(s), lymphokιne(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially If administered sequentially, the attending physician will decide on the appropπate sequence of ad inisteπng compounds of the present invention in combination with other anti- lnflammatory agent(s), cytokme(s), lymphokιne(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be earned out in a vanety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection 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 earner such as a gelatin or an adjuvant The tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention When administered in liquid form, a liquid earner 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 ethylene glycol, propylene glycol or polyethylene giycol. 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 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 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. 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. 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 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 μg to about 100 mg of compound of the present invention per kg body weight. 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 physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention. Methods of Synthesis Compounds of the present invention can be prepared according to the following 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 tetrahydrofuran (THF) at 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. Ill is transformed into bromide IV in two steps: (1 ) reduction with sodium borohydride 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 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 (TMSCF 3 ) in the presence oftetrabutylammonium fluoride gives trifluoromethyl alcohol, which is then oxidized with periodinane (Dess-Martin 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 chlorite in an aqueous THF to yield acid IX. METHOD B 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 hydrochloπde (EDCI) in a suitable solvent such as dichloromethane affords amide XI XI is hydrolyzed to corresponding acid XII in a aqueous base such as sodium hydroxide METHOD C Indole I can be brominated on the 3-posιtιon by reaction with a bromine or N- bromosucciπimide in a suitable solvent such ascarbon tetrachloπde 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 tπethyl amine produces 3-substιtuted 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 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 chloπde in THF affords ketone XIX Carbodiimide (EDCI) catalyzed coupling of XIX and a suitable amine gives amide XX 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 chloπde (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole Treatment of XXI with Gπgnard reagent such as ethyl magnesium bromide m a solvent such as THF at -60 °C, acylation of the resulting magnesium salt with a suitable acyl chloπde such as acetyl chloπde 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 XXII is removed using tetrabutylammonium fluoπde in a solvent such THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bιs(dιphenylphosphιno)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 O,, or with an alcohol in the presence of a strong base such as NaH in DMF affords XXIV (sulfide, or ether respectively) METHOD E 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 hydnde 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 tπmethyl phosphonoacetate in the presence of a base such as sodium hydnde in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide Coupling reaction of XXVI with an amine catalyzed by a dnmide such as EDCI (dimethylaminopropyl ethylcarbodnmide hydrochloπde), followed by hydrolysis with aqueous base such as sodium hydroxide affords XXVII. METHOD F Indole I is reduced with LAH in a solvent such as THF A second reduction with sodium cyanoborohydπde 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) 3 0) in the presence of a base such as tnethylamine affords carbamate XXIX The hydroxyl group in XXIX is mesylated using mesyl chloπde and tnethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as descπbed in METHOD D to produce indohne XXX Deprotection of XXX using tπfluoroacetic acid affords XXXI, which is either acylated (acyl chloπde, tnethylamine, dichloromethane) or alkylated (alkyl ha de, K 2 CO DMF) to afford XXXII, or XXXIII respectively METHOD G Carboxylic acid XXXIV is converted to aldehyde XXXV in two steps ( 1) reaction with N.O-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 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. METHOD H 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 in the presence of a base such as triethyl amine produces carbamate XLI. XLI is treated with iodine in a basic solution such as aqueous NaHCO, in THF to yield iodide XLII. Displacement of the iodine on XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH affords alcohol XLIII. 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 using alkyl halide in the presence of K- j CO, 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 Cs 3 CO, 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 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 METHOD J METHOD J illustrates the synthesis of alpha-substituted aminophenylacetic acid esters Ester L can be deprotonated with a strong base such as lithium dnsobutylamide (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 palladium in a solvent such as ethanol L can be oxidized to alcohol LII using LDA and oxazindine 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 METHOD K METHOD K illustrates the synthesis of substituted aminobenzoic acid esters Mono-acid LV can be converted to amide LVI by the following steps' (1) reaction with oxalyl chloπde in dichloromethane to form acid chloπde 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 descπbed in METHOD J LV can be reduced to alcohol LVIII with hydroborane-THF complex in THF Protection of the hydroxy group as a silyl ether using TBDMSCI in the presence of lmidazole and subsequently, reduction of the nitro group (H 2 / Pd-C) to the amine affords LIX LVIII can be converted to the secondary alcohol LX in two steps. ( I ) oxidation with a suitable reagent such as manganese dioxide (Mn0 2 ) in ethyl acetate and (2) addition of a desired Gπgnard reagent such as methyl magnesium bromide in THF Oxidation of LX with MnO, in THF and reduction of the nitro group (H 2 / Pd-C) produces ketone LXIII. Reduction of LVII (H, / Pd-C) yields LXI. METHOD L Alcohol LXrV, 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 chloπde in the presence of K 2 C0 3 in a solvent such as THF to afford LXV Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures descπbed in METHOD D Deprotection of the p-methoxybenzyl group with TFA in a solvent such as dichloromethane, and subsequent alkylation on oxygen with a suitable reagent such as 4-benzylbenzyl bromide in the presence of K-.CO, in a solvent such as THF affords LXVII 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 characteπzed by proton magnetic resonance spectra taken on a Vanan Gemini 300 spectrometer or equivalent instruments EXAMPLE 1 2-(2-( 1 -Phenylmethoxycarbonyl-^-phenylmethoxy)ιndolyl)methoxybenzoιc acid Step 1 2-(5-Phenylmethoxy ιndolyl aldehyde 12.3 g (42 mmol) of ethyl 2-(5-phenylmethoxy)ιndo!yl) carboxylate was dissolved in 100 mL of THF, to which was added 130 mL (130 mmol) of 1 M solution of lithium aluminum hydnde in THF at 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 chloπde Evaporation of the solvent afforded crude alcohol, which without further puπfication was 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 punfication using 3 1 hexane ethyl acetate yielded 8 15 g of the title compound Step 2: Benzyl ( l -(2-foπrιyl-5-phenylmethoxy)indolyl)formate To a solution of 6.9 g (27.5 mmol) of the aldehyde of step 1 in 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 -35 °C. After stirring at this temperature for 10 min, 4.4 L (29.5 mmol) of benzyl chloroformate was added at -35 °C, and the mixture was then warmed from -35 °C to 0 °C for 3.5 hours. The reaction was quenched by pouring into aqueous ammonium chloride. Aqueous work up and flash chromatography using 12: 1 toluene:ethyl acetate afforded 4.8 g of the title compound. Step 3: Benzyl (l -(2-hvdroxymethyl-5-phenylmethoxy)indolyl)formate To a solution of 2.9 g (7.5 mmol) of the aldehyde of step 2 in 40 mL of THF and 20 L of trifluoroethanol was added 760 mg (20 mmol) of sodium borohydride at 0 °C. The mixture was stirred at 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 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 l ,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 15 °C. 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 chromatography using 4: 1 hexane:ethyl acetate afforded 1.7 g of the title compound. Step 5: Benzyl (l-(2-(2-formylphenoxy)methyl-5-phenylmethoxy)indolyl)formate To a solution of 439 mg (3.6 mmol) of methyl 2-hydroxybenzoate in 18 mL of THF was added 6 mL (3 mmol) of 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene at 0 °C. The solution was stirred at 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 0 U C The reaction was warmed to room temperature and stirred at this temperature for 2 hours After aqueous work up (NH^Cl / ethyl acetate), the organic solvent was collected, dned over sodium sulfate and evaporated The product was solidified and washed with ethyl acetate. hexane 1 1 Yield 690 mg (51 %) Step 6 120 mg (0 24 mmol) of the aldehyde of step 5 was dissolved in 1 1 mL of 5' 1.5 THF-acetonιtπle-2,2-dιmethylethanol To this solution was added a solution of 56 mg (0 5 mmol) of sodium chloπte in 0 5 mL water and 1 drop of aqueoues hydrogen peroxide solution After 4 hours, another 56 mg (0 5 mmol) of sodium chloπte was added The mixture was stirred at room temperature for three days Aqueous work up and flash chromatography using 2 5 1 0 05 hexane ethyl acetate-acteic acid afforded 1 10 mg of the title compound. EXAMPLE 2 4-(2-( 1 -Phenylmethoxycarbonyl-5-phenv!methoxy)ιndolyl)methoxybenzoιc acid The title compound was prepared according to the procedure descnbed in Example 1 , but using 4-hydroxybenzaldehyde EXAMPLE 3 3-(2-( 1 -Phenylmethoxycarbonyl-5-phenylmethoxy)ιndolyl)methoxybenzoιc acid The title compound was prepared according to the procedure descnbed in Example 1 , but using 3-hydroxybenzaldehyde EXAMPLE 4 Benzyl ( l -(2-(2-(1 -oxo-2,2.2-trifluoroethyl)phenoxy)methyl-5- phenylmethoxy)ιndolvπformate Step 1 : Benzyl ( l -(2-(2-(l -hvdroxy-2.2.2-tnfluoroethyl)phenoxy)methyl-5- phenylmethoχy)ιndolyl)-formate A solution of 0.4 g (0.8 mmol) of the aldehyde, prepared in step 1 of Example 1 , in 4 mL of THF was cooled to 0 °C. To this were added 0.24 mL ( 1.6 mmol) of tπfluoromethyl tπmethylsilane and 5 mg of tetrabutylammonium fluoride tπhydrate The reaction was stirred for 2.5 hpurs at 0 °C, and additional 0.2 mL (1.3 mmol) of tπfluoromethyl tπmethylsilane and 5 mg of tetrabutylammonium fluonde tπhydrate were added. After stireed at 0 °C for 2 hours, the reaction was worked up with aqueous ammonium chloride and ethyl acetate. Silica gel chromatographic punfication 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 Step 2: To a solution of 150 mg (0.27 mmol) of trifluoroethanol, prepared step 1 , in 5.5 mL of dichloromethane was added 255 mg (0.6 mmol) of the Dess-Martin's peπodinate. The mixture was stirred at room temperature for 1 hour, and then partitioned between aqueous NaHCO, and ethyl acetate. The organic phase was washed once with aqueous NaHC0 3 and puπfied with chromatography using 3: 1 hexane-ethyl acetate to yield 150 mg of the titled compound. EXAMPLE 5 3-(2-( 1 -Benzy -5-benzyloxy)indolecarboxamιdo)benzoιc acid Step 1. Ethyl 2-(l -benzyl-5-benzyloχy)ιndolecarboxylate To a solution of 1 g (3.4 mmol) of ethyl 5-beπzyloxyιndole-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 stmed for 30 minutes. Benzyl bromide (0.44 L, 3.73 mmol) was added at this time and the reaction stined 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 Step 2. 2-(l -Benzyl-5-benzyloxy)ιndolecarboxyιc 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 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts were dπed 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-( l -benzyl-5-beπzyloxy)ιndolecarboxamιdo)benzoate The acid (0.54 g, 1.5 mmol) of step 2, l -(3-dιmethylamιnopropyl)-3- ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-dιmethylamιnopyπdme (DMAP) (0.018 g, 0.15 mmol) and ethyl 3-amιnobenzoate (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 acetate and water, extracted with ethyl acetate (3X), dπed over magnesium sulfate and concentrated. The crude mateπal 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). Step 4 The ester (0 578 g, 1 15 mmol), prepared in step 3, was dissolved in THF (13 6 L), methanol ( 13 6 mL) and then I N NaOH (9 6 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 dned 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) The Examples 6. 7. 8. 9. 10 and JJ. in Table I were prepared by the procedures of Example 5 using suitable amines and alkyl halides EXAMPLE 12 3-(2-(3-(2.4-bιs( 1.1 -dιmethypropyl)phenoxyacetyl)-5-methoxy- 1 -methyl )ιndoly I) methylthιoacetamιdo-4-methoxybenzoιc acid Step I 2-(5-Methoχy)ιndolylmethanol Ethyl 5-methoxy-2-ιndolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0° C and Lithium Aluminum Hydnde (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 0° 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 dned over MgSOj and concentrated to yield 24 8 g of alcohol, which was used for the next reaction directly Step 2 2-(5-methoxy)ιndolylmethoxy-tert-buthyldιmethylsιlane 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 lmidazole (5 5g, 81 5 mmol) and t- butyldimethylsilyl chloπde (5.4g, 35 8 mmol) The mixture was stmed at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate (3X) Organic layers were dned over magnesium sulfate and concentrated. The crude matenal was puπfied 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-butvdιmethylsιlyloxymethyl-5-methoxy)ιndolyl (2,4-bιs(l .l- dιmethypropyl)phenoxy)methyl ketone 2.32 g (7 95 mmol) of 2.4-Bιs-tert-amylphenoxyacetιc acid was dissolved in dichloromethane (21 mL), oxalyl chloπde (1.4 mL 16.1 mmol) was added, followed by dimethyl formamide (0.5 mL) at room temperature. After one hour the reaction is 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 -78 °C The reaction was stirred at -60°C for 2 hr. To this reaction solution, the above prepared acid chloπde in ether (4 L) was added slowly. The reaction was maintained between -50°C and -60 C C for another 2 hrs. The reaction was then quenched with saturated sodium bicarbonate. Extracted with ethyl acetate (3X) Organic layers were dned over magnesium sulfate and concentrated The crude matenal was punfied 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 acetate 19: 1 Step 4 3-(2-tert-butvdιmethylsιlyloxymethyl-5-methoxy- l -methyl)ιndolyl (2,4-bιs( l , l - dimethvpropyl)phenoxy)methyl ketone To the ketone ( 1.97g, 3.4 mmol) of in step 3 in 12 mi of DMF, sodium hydnde (0.163g, 60% oil dispersion, 4 07 mmol) was added at room temperature. The reaction was stirred for 30 minutes. Methyl iodide (0.23 mL, 3.73 mmol) was added at this time and the reaction stined for another hour. On completion of the reaction (monitored by TLC) it was quenched with water, extracted with ethyl acetate (3X) Organic layers were dπed over magnesium sulfate, concentrated and the crude product was used for the next step. Step 5: 3-(2-Hvdrσxymethyl-5-methoxy- l -methyl)indolyl (bis-2,4- (1.1.dimethylpropyDphenox v )methyl ketone A mixture of N-methyl indole, prepared in step 4, (2.01 g, 3.4 mmol) and tetra- butyl ammoniumfluoride (TBAF) (8.5 mL of a 1M solution in THF, 8.5 mmol) in THF ( 17.9 mL) were stined 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 hexaneethyl acetate). Step 6: Methyl 3-(2-(3-(2.4-bis(l ,l -dimethvpropyl)phenoxy)acetyl-5-methoxy-l - methylindolyl)methylthioacetamido)-4-methoxybenzoate The indole alcohol, prepared in step 5, (0.20 g, 0.43 mmol) was dissolved in dichloromethane (0.7 mL) and treated with tnethylamine (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. T e reaction was stined for a further 2 hour at 0°C, 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 degassed by bubbling nitrogen through for ten min. Cesium carbonate (0.25 g, 1.29 mmol) was added and then thiol (0.1 1 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 hexane:ethyl acetate 1 : 1 ). Step 7: The ester, prepared in step 6, (0.12 g, 0.17 mmol) was dissolved in THF ( 1.0 mL), methanol (1.0 L) and then IN 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 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts were dπed 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 using Ethyl 2-(5-benzyloxy)ιndolecarboxylate, acetyl chloπdes and suitable alkyl halides EXAMPLE 17 3-(2-(-5-benzyloxy-l -(2.4-bιs( 1.1 -dιmethv)propyπphenoxyacetvPιndolιnyl) methylthioacetamidobenzoic acid Step I 2-(5-Benzyloxy)ιndolιnylmethanol Ethyl 5-benzyloxy-2-ιndolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0° C, to which Lithium Aluminum Hydnde (LAH) (255 mL of a 1.0 M solution in THF) was added via addition funnel over 40 minutes The reaction was stmed a for 2 hours at 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 MgS0 and concentrated to yield 24.8 g. This crude matenal was then dissolved 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 stmed for 3 hours The reaction was quenched by pouπng slowly into 1.5 liters of nearly saturated NaHCO,, extracted with ethyl acetate (3X), dπed over MgS0 4 and concentrated to yield a orange solid (29.6 g). Step 2 tert-Butyl l-(5-benzyloxy-2-hvdroxymethv)lιndolιnylformate 25 g (85 mmol) of crude alcohol, prepared in step 1 , and 4-dιmethylamιno pyπdine (DMAP) ( 1.19 g, 9.78 mmol) were dissolved in dichloromethane ( 180 mL). The solution was cooled to 0 C C and then tnethylamine ( 13.6 mL, 98 mmol) was added to it. After 10 minutes of stirπng a solution of di-tert-butyl dicarbonate (21.3 mL, 98mmol) dissolved in dichloromethane (20 mL) was added via synnge pump over 2 hours After 1 hour of stirnng the reaction was quenched by the addition of 1/2 saturated NH 4 C1 solution and extracted with CH-C1, (3X), dned over MgS0 and concentrated to yield 36 3 g of a yellow oil, which was punfied 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%) Step 3 Ethyl 2-(5-benzyloxy-l -tert-butoxycarbonyl)ιndolιnylmethylthιoacetate The carbamate, prepared in step 2, ( 15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with tnethylamine (9.0 mL, 64 4 mmol). The solution was cooled to -10° C at which time mesyl chlonde (4.3 mL. 56 mmol) was added over 5 minutes The reaction was stined for a further 2 hour at -10 °C, it was then concentrated and used directly for the next displacement reaction The above prepared mesyiate was dissolved in DMF (85 mL, degassing the solvent is strongly reccomended) cesium carbonate (35 g, 107 3 mmol) was added and then ethyl thioacetate (4 70 mL, 42 9 mmol) was added The mixture was stined for 1 day, then poured into 1/2 sturated ammonium chlonde and extracted with ethyl acetate (3X), dned, concentrated and chromatographed (hexane. ethyl acetate gradient 10: 1 to 4 1 ) to yield 8.55 g of a yellow oily product. Step 4 2-(5-Benzyloxy-l -tert-butoxycarbonyl)ιndolιnylmethylthιoacetιc acid To a solution of the indoline ester, prepared in step 3, (5g, 1 1 mmol) in IM potassium hydroxide in methanol (100 mL), water (10 mL) was added. The reaction was stmed at room temperature for two hours at which time it was diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts were dπed over magnesium sulfate and concentrated to give the indoline acid ( 4.5g, 95.5%, TLC = 0.5 Rf in 2.1 hexane:ethyl acetate with 1 % acetic acid). The crude matenal was used for the next step directly Step 5 Ethyl 3-(2-(5-benzyloxy- l-tert- butoxycarbonvDindolinvDmethylthioacetamidobenzoate The acid (3g, 7 mmol), prepared in step 4, l-(3-dιmethylamιnopropyl)-3- ethylcarbodπmide (1.6g, 8.4 mmol), 4-dιmethylamιnopyπdιne (0.85g, 7 mmol) and ethyl 3-amιnobenzoate ( 1.27 g, 7.7 mmol) were stmed in tetrahydrofuran (43 mL) at room 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). 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 stined for 1 hour at 0°C. The reaction was quenched by the addition of water and the TFA neutralized by the addition of sodium bicarbonate, the aqueous layer was 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-f 2-f 5-benzyloxy- 1 -(2.4-bis( 1.1 - dimethyl)propyl)phenoxyacetyl)indolinvπ methylthioacetamidobenzoate The 2,4-bis( l , l -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 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) and then the above prepared acid chloride in dichloromethane (0.5mL) was added followed by the addition of tnethylamine (0.28mL, 1.95 mmol). The reaction was stined 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 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: The ester (0.231 g, 0.31 mmol) of step 7 was dissolved in THF (4.3 mL), methanol (4.3 L) and than IN NaOH (3.2 mL) was added. The reaction mixture was stined 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 dπed over magnesium sulfate and concentrated to give the titled product ( 0 207 g, 93 2 %, TLC = 0 3 Rf in 2 1 hexane ethyl acetate with 1 5 % acetic acid) EXAMPLE 18 3-(2-(-5-Benzyloxy-l -(2.4-bιs( l .l -dιmethv)propyl)phenoxyacetyl)ιndolιnvD methylthιoacetamιdo-4-methylbenzoιc acid Step 1 Ethyl 2-(5-benzyloxy)ιndolιnylmethylthιoacetate 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 0 °C To this reaction mixture tπfluoroacetic acid was added (35 mL) and the reaction was stired for 1 hour at 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 dned over magnesium sulfate and concentrated to an orange oil (1.85 g, 79%) that was used directly for the next step Step 2 Ethyl 2-(5-benzyloxy-l -(2.4-bιs(l , l -dιmethv)ρropyl)phenoxyacetyl)- indolinylmethylthioacetate 2,4-Bιs( 1 , 1 -dιmethy)propy Ophenoxyacetic acid (2 Og, 6 8 mmol), dichloromethane (15 mL), oxalyl chlonde (1 2 mL, 13 6 mmol), dimethylformamide (0 1 mL) were stmed at 0° C for 45 minutes at which time the reaction is concentrated and azeotroped with toluene (I X) and concentrated on the high vac for 2 hours before use The indoline ester (1 85g, 5.2 mmol), prepared in stepl , and 4-dιmethylammopyπdιne (008 g) were dissolved in dichloromethane ( 15 mL) and then the above generated acid chloπde in dichloromethane (5 mL) was added followed by the addition of tnethylamine (0 95 mL, 6 8 mmol) The reaction was stmed 16 hours at rt, worked up and concentrated (4 0 g, orange oil), chromatographed using a 9 1 to 6 1 gradient of hexaneethyl acetate to yield the product (2.5g, 75%) that was used for the next step without further puπfication Step 2-(5-Benzyloxy- 1 -f 2.4-bιsf 1.1 - dιmethv)propyl)phenoxyacetyl)ιndolιnylmethylthιoacetιc acid The ester (2 5 g, 3 9 mmol), prepared in step 2, was dissolved in THF (20 mL), methanol (6 mL) and then 1 N sodium hydroxide ( 12 mL) was added The resulting mixture was stmed 24 hours at which time it was concentrated, diluted with water, acidified to pH 4 with concentrated HCl and extracted with ethyl acetate (4X), the organic extracts were dπed over magnesium sulfate, concentrated, and punfied via chromatography (3 1 hexane ethyl acetate with 1 % acetic acid) to yield 1 17 g ( 50%) of the product as white solid Step 4 Methyl 3-(2-(5-benzyloxy- l -(2,4-bιs( 1.1- dιmethv)propyl)phenoxyacetvhιndolιnyl) methylthιoacetamιdo-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-amιno-4-hydroxy benzoate (0 06 g, 0 33 mmol) were dissolved in THF (3 mL) and refluxedlό hours Aqueous workup with ammonium chloπde and ethyl acetate and puπfication via silica gel chromatography (hexane ethyl acetate 3 1 ) yielded 0 13 g (52%) of the product as a white solid Step 5 The titled compound was prepared from ester, prepared in step 4, according to the procedure descπbed in step EXAMPLES 17 to 36 in Table 2 were prepared according to the procedurs descπbed in either Example 17 or Example 18 EXAMPLE 37 2-(5-Benzyloxy-l -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetic acid Step 1 : 2-(5-Benzyloxy- 1 -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol 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 CH 2 C1 2 (300 mL). 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 1 .3 g (60 mmol) of 2-(5- Benzyloxy)indolinylmethanol, prepared in stepl of Example 17, DMAP (0.73 g, 6 mmol) and anhydrous CH,CI 2 (300 L). After cooling to 0 °C, a solution of above prepared acid chloride (59 mmol) in anhydrous CH 2 C1 2 (100 mL) was added dropwise, followed by NEt 3 (9 mL, 64.7 mmol). After stirring for 1 h at 0 °C the reaction mixture was washed with saturated NaHC0 3 solution (100 mL), 1 N HCl solution (100 mL) and H,0 (100 mL), dried over Na,S0 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-l -(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl) methylthioacetate A 500-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (19.0 g, 36.15 mmol), prepared in step 1 , anhydrous CH,CI 2 (300 mL), and NEt 3 (7.5 mL, 54.23 mmol). MsCl was added dropwise over 2 min and the reaction mixture was stined at room temperature for 10 min. The solution was diluted with CH,Cl 2 (500 mL) and washed with IN HCl solution ( 100 L) and saturated NaHC0 3 solution ( 100 mL). The CH 2 C1, solution was dried over Na 2 S0 4 and filtered. The solvent was removed and the mesylate was used in the next step without further purification. A 500-mL oven-dπed round bottom flask fitted with a magnetic stimng bar was charged with ethyl thioacetate (4 2 mL, 38 5 mmol), and anhydrous THF (75 mL) After cooling in a dry ice/acetone bath NaN(SιMe 3 ) 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 stimng 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 (500 mL), washed with saturated Na,C0 3 solution (200 mL) and IN HCl solution (200 mL) The organic solution was dned over Na 2 S0 4 and filtered The solvent was removed in vacuo The crude matenal was punfied by column chromatography on silica gel using 15% AcOEt in hexane to afford 13 8 g (63%) of product Step 3 A 250-mL round bottom flask fitted with a magnetic stimng bar was charged with ester ( 12 45 g, 19 8 mmol), prepared in step 2, THF (100 mL), MeOH (33 mL) and H 2 0 (33 mL). LiOH H 2 0 ( 1.08 g, 25 7 mmol) was added and the reaction mixture was stmed at 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), dned over Na,S0 4 and filtered The solvent was removed in vacuo to afford the titled compound Yield 1 1 9 g ( 100%) EXAMPLE 38 -f2-(-5-Benzyloxy-l -(3.5- bιs(tnfluoromethyl)phenoxyacetyl)ιndolιnyl)methylthιoacetamιdo) benzene- 1.3- dicarboxylic acid Step 1 5-(2-(-5-Benzyloxy- 1 -(3.5-bιs(tnfluoromethyl)phenoxyacetyl)ιndolιnyl) methylthιoacetamιdo)benzene- 1.3-dιcarboxylate A 100-mL oven-dπed round bottom flask fitted with a magnetic stimng 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-amιno- 1 ,3- benzenedicarboxyiic acid (0 46 g, 2 2 ml) The reaction mixture was heated at reflux until no change was detected by TLC The solvent was removed in vacuo The residue was dissolved in CH (200 L), washed with 1 N HCl solution (25 mL), dπed over Na 2 S0 4 and filtered The solvent was removed in vacuo The crude matenal was puπfied by column chromatography on silica gel using 1 -2% MeOH in CH,C1 2 to afford I 2 g (77%) of product Step 2 A 25-mL round bottom flask fitted with a magnetic stirπng bar was charged with ester (0 6 g, 0 76 mmol), prepared in stepl , THF (7 5 mL), MeOH (2 5 mL) and H20 (2 5 mL) LiOH H 2 0 (0084 g, 2 mmol) was added, and the reaction mixture was st ed at room temperature for 6 h The solvents were removed in vacuo The residue was taken into IN HCl solution (10 mL) and extracted with AcOEt (2 x 50 mL) The combined extracts were dπed over Na2SO4 and filtered and removed in vacuo The crude matenal was puπfied by column chromatography on silica gel (eluant 5% MeOH in CHCB + 0 5- 0 7% AcOH) to yield 0 28 g (46%) of the titled compound EXAMPLES 39. 40. 43 in Table 3 were prepared according to the procedurs descπbed in either Example 38 EXAMPLE 41 5-(2-(-5-Benzyloxy-l -(3.5- bιs(tnfluoromethyl)phenoxyacetyl)ιndolιnyl)methylthιoacetamιdo)-3- hvdroxymethylbenzoic acid Step 1 Methyl 5-(2-(-5-ben7yloxy-l -(3.5-bιs(tnfluoromethyl)phenoxyacetyl)ιndolιnyl) methylthιoacetamιdo)-3-tert-butyldιmethylsιlyloxymethylbenzoate This compound was prepared according to the procedure descπbed in step 1 of Example 38 Step 2 Methyl 5-(2-(-5-benzyloχy- l -(3.5-bιs(trifluoromethyl)phenoxyacetyl)ιndolιnyl) methylthioacetamidoVl-hvdroxymethylbenzoate A 25-mL oven-dπed round bottom flask fitted with a magnetic stirnng 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 stined at room temperature for 3 hours The solvent was removed in vacuo The oily residue was puπfied by column chromatography on silica gel using 0-30% AcOEt in CH 2 C1 2 to afford 0 94 g (92%) of desired product Step 3 The titled compound was prepared according to the procedure descπbed in step 2 of Example 38 EXAMPLE 42 in table 3 was prepared according to the procedures descπbed in Example 41 EXAMPLE 44 5-(2-(-5-Hvdroxy- l -(3.5- bis(trifluoromethyl)phenoxyacetvDindolinyl)methylthioacetamido) benzene- 1.3- dicarboxylic acid Step 1 : 2-(5-Hvdroxy- 1 -(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol A 500-mL Pan Hydrogenation bottle was charged with 2-(5-Benzyloxy-l-(3,5- bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol (10 g, 19.1 mmol), prepared in step 1 of Example 37, 5% Pd on carbon ( 1.0 g), AcOEt ( 150 L) 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. Step 2: 2-(5-(4-Methoxy)benzyloxy-l -(3.5- bis(trifluoromethyl)phenoxyacetvπindolinyl)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 stepl , 200 mesh K,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 H 2 0 (200 mL). The aqueous layer was extracted with AcOEt (3 x 500 mL). The combined AcOEt extracts were washed with brine (500 mL), dried over Na 2 S0 and filtered. 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-methoxy)benzyloxy- l -(3.5-bis(trifluoromethyl)phenoxyacetyl) indolinyl)methylthioacetamido)benzene- 1.3-dicarboxylate 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 CH 2 C (44 mL) The reaction mixture was cooled to 0"C and added anhydrous Et,N (1 2 mL. 8 61 mmol) followed by MsCl (0.53 mL, 6 84 mmol) The reaction mixture was stined at 0 °C for 5 min. The reaction mixture was partitioned between CH,C1 2 (100 mL) and H,0 (50 mL) The aqueous layer was extracted with CH 2 C1 2 (3 x 100 mL). The combined CH,CI 2 extracts were washed with 1 N HCl solution ( 100 mL), saturated NaHCO, solution ( 100 mL), H 2 0 ( 100 mL), bπne ( 100 mL), dπed over Na,S0 and filtered. The solvents were removed in vacuo to afford mesylate This was used in the next step reaction without further punfication. A 100-mL oven-dned round bottom flask fitted with a magnetic stimng bar 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 2 for 15 mm. Methyl 5-thιoacetamιdo-l ,3- benzenedicarboxylate, prepared in Intermediate 2, was added in one portion and the reaction mixture was heated at 50 °C for 18 h The reaction mixture was partitioned between AcOEt (500 mL) and H 2 0 (200 mL) The aqueous layer was extracted with AcOEt (3 x 100 mL) The combined AcOEt extracts were washed with saturated Na,C0 3 solution (100 mL), H,0 (100 mL), bπne (500 mL), dned over Na 2 S0 4 and filtered. The solvents were removed in vacuo Punfication of the residue by column chromatography on silica gel (eluant. 5% AcOEt in CH,C1 2 ) afforded product Yield 2 5 g (53%) Step 4- Methyl 5-(2-(-5-Hvdroxy-l -(3.5-bιs(trifluoromethyl)phenoxyacetyl) ιndolιnyl)methylthιoacetamιdo)benzene- 1 ,3-dιcarboxylate A 100-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with ester (2.60 g, 3.17 mmol), prepared in step 3, and anhydrous CH 2 C1 2 (30 mL) To the reaction mixture was added TFA (25 mL) in several portions over 1 m The reaction mixture was poured onto 500 L saturated NaHCO, solution and extracted with CH 2 CL (3 x 100 mL) The combined CH 2 C1 2 extracts were washed with saturated Na 2 C0 3 solution (200 mL), H 2 0 (200 mL), bπne (500 mL), dπed over Na,S0 and filtered The solvents were removed in vacuo. Punfication of the residue by column chromatography on silica gel (eluant 12.5% - 20% AcOEt CH 2 C1 2 ) afforded the product Yield 1.5 g (68%) Step 5 A 25-mL round bottom flask fitted with a magnetic stirnng bar was charged with ester (270 mg, 0 40 mmol), prepared in step 4, LiOH hydrate (3 3 equiv ), THF (3.6 mL), MeOH ( 1.2 mL) and H 2 0 ( 1.2 mL). The reaction mixture was heterogeneous with white solid suspended in the solution After stimng for 4 h, more solvents were added in 3 1 : 1 = THF ' MeOH . H 2 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 (20 mL) and H 2 0 (20 mL) The aqueous layer was extracted with AcOEt (3 x 20 mL) The combined AcOEt extracts were washed with H,0 (20 mL), bnne (20 mL), dπed over Na,S0 4 and filtered. The solvents were removed in vacuo Punfication of the residue by column chromatography on silica gel followed by recrystallization from acetone / hexane afforded 130 mg of the titled compound (50%) EXAMPLE 45 5-(2-(5-(3.5-Dιbromo)benzyloxy- l -(3.5-bιs(tπfluoromethyl)phenoxyacetyl)indolιnyl) methylthιoacetamιdo)benzene- 1 ,3-dicarboxyiιc acid Stepl Methyl 5-(2-(5-(3.5-Dιbromo)benzyloxy- l-(3.5- bιs(tπfluoromethyl)phenoxyacetyl) ιndolιnvPmethylthιoacetamιdo)benzene-l ,3- dicarboxylate A 25-mL oven-dned round bottom flask fitted with a magnetic stimng bar and reflux condenser was charged with methyl 5-(2-(-5-Hydroxy- l -(3,5- bιs(tπfluoromethyl)phenoxyacetyl) ιndo!ιnyl)methylthιoacetamιdo)benzene- 1 ,3- dicarboxylate (0.19 g, 0.27 mmol), prepared in step 4 of Example 4. 200 mesh K 2 CO, (2.4 equiv ) and 3,5-dιbromobenzyl bromide (1 2 equiv.) in 7.5 mL of anhydrous acetonitnle. The reaction mixture was heated at 70 °C for 2 h. The reaction mixture was partitioned between AcOEt (30 mL) and H 2 0 (20 mL) The aqueous layer was extracted with AcOEt (3 x 30 mL). The combined AcOEt extracts were washed with bπne (50 mL), dπed over Na 2 S0 and filtered. The solvents were removed in vacuo. Punfication of the residue by column chromatography on silica gel using 15% EtOAc in dichloromethane afforded 0 20 g of the product (77%) Step 2 The titled compound was prepared from the ester, prepared in step 1 , according to the procedure descπbed in step 5 of Example 44 EXAMPLES 46 to 50 in table 4 were prepared according to the procedures descnbed in Example 44, but using conesponding alkylating reagent EXAMPLE 51 Methyl l-(2-(5-benzyloxy-l -(4-benzylbenzovPιndolιnvPmethylthιoacetamιdo)benzoate 4-Benzylbenzoιc acid (0 19g, 0 91 mmol) was dissolved in dichloromethane (2 3 ml), next oxalyl chloπde (0 16 mL, 1.82 mmol) was added followed by dimethylformamide (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)ιndolιnyl)methylthιoacetamιdobenzoate (0 308 g, 0 65 mmol), prepared in step 6 of Examle 17, and 4-dιmethylamιnopyπdιne (8 mg, 0 066 mmol) were dissolved in dichloromethane (1 2 mL) and then the above prepared acid chloπde in dichloromethane (0 5 mL) was added followed by the addition of tnethylamine (0.28 mL, 1 95 mmol) The reaction was stined at room temperature overnight The reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dπed over magnesium sulfate and concentrated The crude material was puπfied on silica gel using 2 1 hexane:ethyl acetate to yield 0 354 g of the titled product (81 7%, TLC = 04 Rf in 2.1 hexaneethyl acetate) EXAMPLE 52 3-(2-(5-Benzyloxy- 1 -(4-beπzylbenzovPindolinvPmethylthioacetamido)benzoic acid The ester (0.354 g, 0.53 mmol), prepared in Example 51 , was dissolved in THF (5.6 mL), methanol (5.6 L) and than IN NaOH (4.2 mL) was added. The reaction mixture was stined at room temperature overnight at which time it was concentrated, diluted with water, acidified to pH 5 withl 0% 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 %, TLC = 0.3 Rf in 2: l hexane: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. EXAMPLE 59 3-(2-(5-Benzyloxy-l -(2-naphthoxyacetvPindolinvPmethylthioacetamido)-4- methoxybenzoic acid Step 1 : Methyl 3-(2-(5-benzyloxyindolinvPmethylthioacetamido)-4-methoxybenzoate This compound was prepared according to the procedures described in step 6 of Example 17. but with methyl 4-methoxybenzoate. Step 2: Methyl 3-(2-(5-benzyloxy-l -(2-naphthoxyacetvPindolinvPmethylthioacetarnido)- 4-methoxybenzoate The indole ester (0.22 g, 0.45 mmol), prepared in step 1 , 2-naphthoxyacetic acid (0.1 1 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 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 Step 3 The ester ( 0 12 g, 0.20 mmol), prepared in step 2, was dissolved in THF7 methanol and then I N sodium hydroxide (0 8 mL) was added and the resulting mixture was stmed 16 hours at RT and a further 5 hours at 45°C, workup yielded 0.12 g of a yellow solid that was puπfied via preparative TLC ( 1 1 hexane ethyl acetate with 1 % acetic acid) to yield 0 12 g of the titled product (95%) EXAMPLES 60 to 63 in Table 5 were prepared according to the procedures descπbed either in Example 59 or in Examples 51 and 52 EXAMPLE 64 3-(2-(5-benzyloχy-l -tert-butoxycarbonvPιndolιnvPmethylsulfonylacetamιdobenzoιc acid Step 1 Ethyl 3-(2-(5-benzyloxy- l -tert-butoxycarbonyl)ιndolιnyl)methylsulfonyl acetamidobenzoate To a solution of Ethyl 3-(2-(5-benzy loxy- 1 -tert-butoxycarbonyl)ιndolιnyl)methy Ithioacetamidobenzoate (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 stmed overnight Next day the reactton was quenched with an aqueous solution of sodium bicarbonate, extracted with eth l acetate (3X), dπed 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 Step 2. The titled compound was prepared according to the procedure descπbed in step 3 of Example 59 EXAMPLES 66 and 65 were prepared according to the procedures descπbed in Example 18. EXAMPLE 67 2-(2-(-5-Benzyloxy- 1 -( 2.4-bιsf 1.1 - dιmethv)propyPphenoxyacetvPιndolιnvPmethylthιoben7θic acid Step 1 • 5-Benzyloxy- 1 -(2.4-bιs( 1 , 1 -dιmethv)propy PphenoxyacetvP-2- hvdroxymethylindohne The dnsopropylethylamine (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 1 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-tert-amylphenoxyacetyl chlonde (20.5 mmol) in CH,C1, (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 CH 2 C1 2 , the solution was extracted with CH 2 CI 2 (3X), the combined layers were dπed over magnesium sulfate and concentrated to yield ( 10.4 g) of a yellow foam that was punfied via chromatography using a gradient (hexanexthyl 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-bιs( 1.1 -dιmethv)propyPphenoxyacetvPιndolιnylmethyl methylsulfonate To a solution of alcohol ( 1.2 g, 2.26 mmol) in CH,C1 2 ( 15 mL), prepared in step 1 , is added tnethylamine (0.44 mL, 3.16 mmol). The solution is brought to -50 °C and then mesyl chloπde (0.23 mL, 2 93 mmol) is added The mixture is stmed 2 h at -50 °C, quenched with saturated ammonium chloride and allowed to come to rt The mixture is taken up in CHCl, (50 mL), washed with saturated sodium bicarbonate ( 1 X 10 mL), bπne ( 1 X 10 mL), dπed (MgS04), filtered and concentrated to afford the product ( 1 19 g, 86%) Step 3 Methyl 2-(2-(-5-benzyloxy- l-(2.4-bιs( l . l -dιmethv)propyl)phenoxyacetvP indolinvPmethylthiobenzoate To a solution of mesylate (0 54 g, 0.89 mmol), prepared in step 2, in degassed DMF (2 mL) is added CsCO, (0 724 g, 2.22 mmol) and methyl thiosahcylate (0.134 mL, 0 98 mmol) The mixture is stmed 4 h, taken up in ethyl acetate (20 mL), washed with bnne (3 X 3 mL), dried (MgS0 ), filtered and concentrated Chromatography (gradient, hexane:ethyl acetate 15.1 to 4 I ) afforded 0.53 (86%) of the title compound as a yellow oil Step 4 The titled compound was prepared according to the procedure descπbed in step 3 of Example 59. EXAMPLE 68 was prepared according to the procedures descπbed in Example 67 EXAMPLE 69 3-(N-(2-(-5-Benzyloxy- l-(2.4-bιs( l .l -dιmethv)propyPphenoxyacetyl)ιndolιnvP rnethylthioethvPaminobenzoic acid The titled product was prepared according to the procedures described in step 3 of Example 59, but using Intermediate 15. EXAMPLE 70 3-N-Methyl-(2-(-5-Benzyloxy- 1 -(2.4-bιs( 1.1 -dιmethv)propyPphenoxyacetyl)ιndolinyl) methylthιoacetamιdo-4-methoxybenzoιc acid An oven-dned 100 mL, 3-neck round bottom flask, equipped with a stir bar and nitrogen inlet, was charged with methyl 3-(2-(-5-Benzyloxy-l -(2,4-bιs(l ,l- dιmethy)propyl)-phenoxyacetyl)ιndoiιnyl)methylthιoacetamido-4-methoxybenzate (581 mg, 0.757 mmol), prepared in the synthesis of Example 20 using the procedures descnbed in Example 18, and 10 mL of THF was added via synnge To the resulting yelllow solution was added NaH (60% suspension in mineral oil, 39 mg, 0.975 mmol). The reaction mixture was st ed 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 stined at 25 °C for 2 days. After chilling to 0 °C, water was added ( 10 mL), followed by 50 L of half saturated ammonium chlonde, and 100 mL of EtOAc. The layers were separated, and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were dπed (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 1 N NaOH solution was added, under nitrogen. After being stmed for 2 h at 25 °C, the reaction mixture was concentrated to dryness on the rotary, and 100 mL of IN HCl, and 100 mL of EtOAc were added. The layers were separated, and the organic phase was dπed (magnesium sulfate), filtered, and concentrated. The crude matenal obtained (0.565 g) was puπfied by column chromatography on silica gel (eluant: chloroform to 3% MeOH in chloroform) to afford the titled compound (0 415 g, 70% yield) EXAMPLE 71 was prepared according to the procedures descπbed in Example 70. but using allyl bromide. EXAMPLE 72 3-(2-(5-benzylox v- 1 -(2-(4-pyndιn vPkthvPmdolinvPmethylthioacetamidobenzoic acid Step l - Ethyl 3-(2-(5-benzyloxy- l-(2-(4- pyndinypethvPindolinvPmethylthioacetamidobenzoate To a solution of ethyl 3-(2-(5-benzyloxy)ιndolιnyl)methylthιoacetamιdobenzoate (0.30 g, 0.63 mmol), prepared in step 6 of Example 17, in dichloromethane (3.0 mL) and acetic acid (2.0 mL), 4-vmyIpyπdιne (0 08 mL, 0 75 mmol) was added The reaction was st ed at room temperature overnight The reaction was quenched with half saturated sodium bicarbonate, extracted with ethyl acetate (3X), dπed over magnesium sulfate and concentrated. The crude matenal was punfied on silica gel using a gradient of 2.1 hexane:ethyi acetate to 100% ethyl acetate to yield 0.023 g of product (25 %, TLC = 0 7 Rf in ethyl acetate). Step 2 The titled compound was prepared according to the procedure descnbed in step 3 of Example 59. EXAMPLE 73 3-(2-(5-benzyloxy-l -(2-naphthyl)methy)ιndolιnvPmethylthιoacetamιdobenzoιc acid Step 1 - Ethyl 3-(2-(5-benzyloxy-l -(2- naphthvPmethv)ιndolιnyl)methylthιoacetamιdobenzoate A mixture of 3-(2-(5-benzyloxy)ιndoiιnyl)methylthιoacetamιdobenzoate (0 2g, 0 42 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-dιmethylformamιde (2 mL) was st ed at room temperature overnight Next the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dπed 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). Step The titled compound was prepared according to the procedure described in step 3 of Example 59. EXAMPLES 74 and 75 in Table 6 were prepared according to the procedures described in Example 73. EXAMPLE 76 2-(2-(-5-Benzyloxy- 1 -(2-naphthyl)methvPindolinvPmethylthiobenzoic acid Step 1 : 2-(2-(-5-Benzyloxy- 1 -( 1.1 -dimethvPethoxycarbonvPindolinyl )methyl methylsulfonate tert-Butyl l -(5-benzyloxy-2-hydroxymethy)lindolinylformate (6.72 g, 19 mmol), prepared in step 2 of Example 17, was dissolved in CH 2 C1 (80 mL, dried over MgS0 4 before use). The clear yellow solution was cooled in a dry-ice bath. Et,N (4.0 mL) was then added followed by methanesulfonyl chloride (2.0 mL). The reaction mixture was stined for 2 h at -40 °C then quenched with H 2 0. It was washed with satuarated NaHC0 3 (300 mL) and the aqueous layer extracted twice with CH 2 C1 2 . The combined CH 2 CI 2 layers were dried over MgS0 4 , filtered and evaporated to dryness to give the product (7.30 g, 89.1 % yield), which was used for the next reaction directly. Step 2: Methyl 2-(2-(5-Benzyloxy-l-(l .l-dimethyl)ethoxycarbonvPindolinvPmethylthio benzoate 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 L). The solution changed to a bright yellow and the suspension was stined overnight. Methyl thiosalicylate (0.15 mL) was added to complete the reaction and the mixture was stined overnight. The reaction was then quenched by the addition of saturated NaHCO, (400 mL). The mixture was extracted with CH 2 C1 2 (3 x) and the combined CH TK solution was back-washed with H 2 0 (200 L). The organic layer was dried over MgS0 , filtered and evaporated to dryness to give the product (9.71 g, 99%). Step 3: Methyl 2-(2-(5-Benzγloxy)indolinyl)methylthiobeπzoate Ethyl acetate (75 mL, dried over MgS04 before use) was charged in a 500 mL round bottom flask. HCl gas was bubbled through and the EtOAc/HCl solution was cooled in an ice bath. Methyl ester (8.4 g), prepared in step 2, was dissolved in EtOAc (25 mL, dried over MgS04 before use). This solution was transfened to the HCl/EtOAc solution by syringe. The solution turned to red and was stined in an ice bath. A white precipitate appeared in 1 h and the solution was stined overnight to complete the reaction. The solid was collected by filtration, washed with dry EtOAc, suspended in saturated NaHCϋ 3 ( 175 mL) and stined 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 MgS04, filtered and evaporated to dryness to give the product (6.06 g, 90 % yield). Step 4: Methyl 2-(2-(5-Benzyloxy- l -(4-benzvPbenzvPindolinyl)methylthiobenzoate 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 ( I eq) followed by K 2 CO, ( 1 eq). The reaction mixture was stined overnight at room temperature. To complete the reaction additional p-benzylbenzyl bromide (0.5 eq) was added and the reaction was stined for another 2 hours. After its completion, the reaction was diluted with H 2 0 and extracted with EtOAc (2 x). The organic layers were combined and dried over MgS0 4 . The MgS0 4 was 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). 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 ( I eq, 2N) followed by MeOH (3 mL) and the reaction mixture was st ed overnight Additional NaOH (0 3 eq) was added to complete the reaction and the mixture was stined throughout the weekend Then it was acidified and diluted with H 2 0 and extracted with EtOAc (2 x) The organic layers were combined and dned over MgS0 The MgS0 was filtered and the solvent was evaporated and dπed on high vacuum to give a crude reddish solid. This solid was dissolved in EtOAc and hexane 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 matenal was treated with EtOAc and EtOH The resulting solid was filtered then suspended in EtOH, with stimng 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 % yield) EXAMPLES 77. 78 and 79 in Table 6 were prepared according to the procedures descπbed in Example 76 EXAMPLE 80 4-( l -(5-Benzyloχy-2-(bιs-2.4-tπfluoromethyl)benzyloxymethvPιndolιnvPmethylbenzoιc Step 1 Methyl l -(5-Benzyloxy-2-(hvdroxymethvPιndolιnyl)methylbenzoate 2-(5-Benzyloxy)ιndolιnylmethanol (3 21 g, 126 mmol), prepared in DMF (20 mL), methyl 4-(bromomethyI)benzoate (2.88 g, 14 5 mmol) and potassium carbonate ( 1 77 g, heated to 125 °C before use) were mixed and stined at room temperature for 2 h The reaction was diluted with 100 mL of H,0 and extracted three times with EtOAc The combined EtOAc layers were evaporated to dryness to give the crude product (5 66 g) The crude matenal was punfied on a silica gel column using hexane ethyl acetate 3 I to 2 1 The appropπate fractions were combined, evaporated to dryness and further dried on high vacuum to the product (3 00 g, 64%) Step 2 Methyl 4-( l -(5-Benzyloxy-2-(bιs-2,4-tnfluoromethyl)ben7yloxymethyl)ιndolιnyl) methylbenzoate Ester (700 mg), prepared in step 1 , and bιs-(2,4-tπfluoromethyl)benzyl bromide (0 35 mL) were dissolved in DMF (5 mL) The resulting clear yellow solution was cooled in an ice bath and then NaH (85 mg) was added in small portions over a peπod of 5 minutes The suspension was st ed at 0 υ C for 4 h To complete the reaction, another 0 35 mL of 2,4-bιs(tπfluoromethyl)-benzyi bromide was added and the stimng was continued for another 3 h 40 mm The reaction was then diluted with H 2 0 and extracted three times with EtOAc The combined EtOAc layers were evaporated to give a crude product which was then puπfed on a silica gel columnusing hexane ethyl acetate 8 1 The appropnate fractions were combined and evaporated to dryness to give the product (0 417 g, 38 2 % yield) Step 3 The titled compound was prepared according to the prodedure descπbed in step 5 of Example 76 EXAMPLES 81 and 82 in Table 6 were prepared according to the procedures descπbed in Example 80 EXAMPLE 83 5-(2-(l -(2.4-Bis(trifluoromethyl)benzyPindolinyl)carboxamido-1.3-benzenedicarboxylic acid Step 1 : 2-(l -(2.4-Bis(trifluoromethvPbenzyl)indolinyl)carboxylic acid 2-Indolinylcarboxylic acid (0.43 g, 2.6 mmol) was dissolved in DMF (5 mL), placed under N,, and cooled to 0° 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- Bis(trifluoromethyI)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 ester. The resulting ester (0.87 g, 0.1.41 mmol) was dissolved in THF/ methanol and then I N sodium hydroxide (4.21 L) was added and the resulting mixture was stmed 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. 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-aminoιsophthalate (0.16 g, 0.77 mmol) were dissolved in THF (2 mL) and refluxed 16 hours which yielded after aqueous workup 0.33 g 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 stined 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. EXAMPLE 84 N-Methylsulfonyl-2-(l -(2.4-bis(trifluoromethvPbenzvPindolιnyl)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 methylsuifonanihde (004 g, 0 39 mmol) were dissolved THF (5 mL) and refluxed 16 hours which yielded after workup (0 16 g), punfication via Chromatography (98 2 dichloromethane methanol) yielded 0 04 g of the titled compound (29%) EXAMPLE 85 N-Phenylsulfonyl-2-( l-(bιs-2.4-trιfluoromethyl)benzvPιndolιnyl)carboxamιde The titled compound was prepared according to the prodedure descπbed in Example 84, but using phenylsulfonylamide EXAMPLE 86 5-(2-(5-Methoxybenzyloxy- 1 -(2.4- bιs(tπfluoromethvPbenzyl)ιndolιnyl)methylamιnocarboxamιdo-1.3-benzenedιcarboxylιc acid Step 1 2-Tπmethylsιlylethyl l -(5-benzyloxy-2-hvdroxymethvPιndolιnylformate An oven-dned 1 L round bottom flask, equipped with a stir bar was charged with 2-(5-benzyloxy)ιndoIιnylmethanol (33.2 g, 130 mmol), prepared in stepl of Example 17. 2-(tnmethylsιlyI)ethyl p-nitrophenyl carbonate 36 8 g, 130 mmol), NEt, (38 ml, 273 mmol), and 300 mL of anhydrous DMF The reaction mixture was st ed at 60 °C for 28 hours and at room temperature overnight The resulting solution was concentrated to dryness in vacuo, and 1 L of CHCl, and 200 mL of saturated NaHCO, solution were added The layers were separated, and the organic phase was dπed (Na,S0 ), filtered, and concentrated The crude matenal obtained (55 7 g) was punfied by column chromatography on silica gel (eluant 0-5 % MeOH in dichloromethane) to afford product (33.5 g, 60% yield) Step 2: 2-Trimethylsilylethyl l-(5-hvdroxy-2-hvdroxymethyl)indolinylformate An oven-dried 500 mL Pan pressure flask was charged with the alcohol (30 g, 75 mmol), prepared in step 1, Pd/C (10 %, 2.2 g), 100 L of MeOH, and 300 mL of EtOAc. After being shaken overnight in a Parr apparatus under H 2 atmosphere (50 psi), the reaction mixture was filtered through Florisil. The filtrate was concentrated to dryness on the rotary. 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-Trimethylsilylethyl l -(5-(4-methoxy)benzyloxy-2- hvdroxymethvPindolinylformate 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, 1 mL, 1 10 mmol), K 2 C0 3 (200 mesh, 30.4 g, 220 mmol), KI (Aldrich, 18.3 g, 1 10 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 L) and CHCl, (1.5 L) were added. The layers were separated, and the aqueous phase was extracted with CHC1 3 (800 L). The combined extracts were washed with water (200 mL), dried (Na 2 S0 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). Step 4: 2-Trimethylsilylethyl l -(5-(4-methoxy)benzyloxy-2- bromomethvPindolinylformate 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) of 1 ,3-bis(diphenylphosphino)propane. The reaction was stined at room temperature for 18 h. The reaction was quenched with saturated aqueous NH C1, and the product was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over MgS0 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 l-(5-(4-methoxy)benzyloxy-2- azidomethvPindolinylfoπnate 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 stined 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, brine and dried over MgS0 . 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 l -(5-(4-methoxy)benzyloxy-2- aminomethvDindolinylformate 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 CaCO,. The mixture was placed under atmospheric hydrogen, and was stined 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/CH 2 Cl 2 to afford 0.717 g of the product. Step 7: Methyl 5-(2-(5-Methoxybenzyloxy- l -(2- trimethylsilyloxy)ethoxycarbonv)lindolinyl) methylaminocarboxamido-1.3- benzenedicarboxylate To a solution of 0.164 g (0.6 mmol) of triphosgene in 5 mL of dichloromethane was 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 stined 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 stined for 2 h, and then quenched with water. The product was extracted with ethyl acetate, and the combined organic layers were washed with water, saturated aqueous NaHCO,, brine and dried over MgS0 . The crude product was purified by flash chromatography using 10% MeOH/CH 2 Cl 2 to afford 0.78 g of the product. Step 8 Methyl 5-(2-(5-Methoxybenzyloxy)ιndolιnyl)methylamιnocarboxamιdo-1.3- benzenedicarboxylate To a solution of 0 485 g (0 7 mmol) of the ester, prepared in step 7, in 20 mL of acetonitπle was added 2 2 mL (2.2 mmol) of a 1.0 M tetrabutylammonium fluoπde solution in THF The reaction was stined at room temperature for 18 h The reaction was quenched with bπne, and the product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NH 4 C1, bπne and dπed over MgS0 4 The crude product was punfied by flash chromatography using 5% MeOH/CH,Cl 2 to afford 0.342 g of the product Step 9 Methyl 5-(2-(5-Methoxybenzyloxy- l -(bιs-2.4-tnfluoromethyl)benzvPιndolιnvP eth ylaminocarboxamido- 1.3-benzenedιcarboxylate 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- bιs(trifluoromethyl)benzyl bromide and 0.12 g (0.9 mmol) of potassium carbonate The reaction was stmed 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, bπne and dπed over MgS0 4 The crude product was punfied by flash chromatography using hexane:ethyl acetate 1 : 1 to afford 0.066 g of the product. 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 methanol. The reaction was stmed 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 washed with water, brine and dned over MgS0 4 . The crude product was puπfied by flash chromatography using 5% MeOH CH 2 Cl 2 to afford 0.049 g of the titled compound. EXAMPLE 87 was prepared according to the prodedure descπbed in Example 86. but using 4-(3,5-bιs(tnfluoromethyl)phenoxymethyl)benzyl bromide. INTERMEDIATE 1 Methyl 4-methoxy-3-thιoacetamιdobenzoate Step 1 : Bιs(methyl 4-methoxy-3-dιthιoacetamιdobenzoate) A 2-L oven-dned round bottom flask fitted with a magnetic sti ng bar was charged with Dithioacetic acid ( 10.2- 15 5 g, 56-85 mmol) and anhydrous CH,C1 2 (50 mL) Oxalyl chlonde (2.1 mol equiv.) was added dropwise over 10 min. The reaction mixture was stmed at room temperature for 4-5 h Methyl 4-methoxy-3-amιdobenzoate (2.1 mol equiv.) in anhydrous CH 2 C1 2 (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 stirnng overnight at room temperature the reaction mixture was washed with 1 N HCl solution (2 x 300 mL), dπed over Na 2 S0 4 and filtered. The solvent was removed in vacuo Punfication of the residue by column chromatography on silica gel using hexane:ethyl acetate = 5 1 afford desired product in 56% yield Step 2: A 1-L round bottom flask fitted with a magnetic stimng bar was charged with disulfide, prepared in step 1 , ( 15.7-26.3 g, 36.6-57.5 mmol) and PPh, (1.1 mol equiv.). The reactants were suspended in dιoxane/H,0 (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 punfied immediately by column chromatography on silica gel using hexane • ethyl acetate 2.1 to afford the titled product in 89% yield. INTERMEDIATE 2 Methyl 5-thιoacetamιdo-l ,3-benzenedιcarboxylate The titled compound was synthesized according to the procedures descπbed in Intermediate 1 using 5-amιno-l ,3-benzenedιcarboxylate UINTERMEDIATE 3 Methyl 2-(3-amιno-4-methoxyphenyl)-2-methoxyacetate Step 1 Methyl 2-(3-nιtro-4-methoxyphenvPacetate An oven-dned 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 anhydnde (631 mL) and subsequently cooled to -78 °C Fuming nitπc acid (Baker, 90%, 27 mL) was added dropwise via the dropping funnel protected with a drying tube filled with CaCl, After addition was completed, the reaction temperature was allowed to warm to 20 °C over 1 h. The reaction mixture was cooled to -78°C again and added 4-methoxyphenylacetιc acid (50 g, 0.28 mol) dropwise via the dropping funnel After stirnng at -50 °C for 1 h., the reaction mixture was allowed to warm to -30 °C over 20 min and then cooled to -50 °C again The reaction mixture was quenched with H 2 0 (500 mL) at -50 °C and warmed up to room temperature and stmed for 0 5 h The reaction mixture was partitioned between CH 2 C1 2 (500 mL) and H,0 The aqueous layer was extracted with CH,CI, (3 x 500 mL) The combined CH 2 C1 2 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 °C and stined at room temperature overnight The reaction mixture was partitioned between CH 2 CL (500 mL) and H 2 0 The aqueous layer was extracted with CH 2 C1, (3 x 500 mL) The combined CH 2 C1 2 extracts were stmed with 2 M NaOH solution (1 L) for 1 h. The layers were separated and the organic layer was washed with H 2 0 (500 mL), bπne (500 mL), dπed over Na,S0 and filtered. The solvents were removed in vacuo to afford crude product as a light yellow solid (56 g) Punfication by recrystalhzation from MeOH (600 L) gave product. Yield 48 g (77%). Step 2 Methyl 2-(3-nιtro-4-methoxyphenvP-2-hvdroxyacetate A 25-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with ester (2.3 g, 10 mmol), prepared in step 1 , and anhydrous THF ( 100 mL) The reaction mixture was cooled to -78 "C and a solution of NaN(SiMe 3 ) 2 (1.0 M in THF, 12 mL, 12 mmol) was added dropwise over 10 mm. After stimng at -78 °C for 30 m ., the deep purple solution was added dropwise a solution of racemic camphor sulfonyloxaziπdine (3 4 g, 15 mmol), prepared by mixing the commercially available ( 1S)- (+)-(10-camphorsulfonyl)oxazιπdιne ( 1 7 g) and ( lR)-(-)-( 10-camphorsulfonyl)oxazιπdιne ( 1.7 g) in 50 L THF After stimng at -78 °C for 30 min., the reaction mixture was quenched with sat. NH 4 C1 solution (45 mL) at -78 °C and then allowed to warm to room temperature. The reaction mixture was partitioned between ether (250 mL) and H 2 0 (50 mL) The aqueous layer was extracted with ether (3 x 250 mL). The combined ether extracts were washed with bπne (250 mL), dπed over Na,S0 4 and filtered The solvents were removed in vacuo. Punfication by column chromatography on silica gel (eluant: 50% AcOEt in hexane) afforded desired product. Yield 2.2 g (88%). Step 3. Methyl 2-(3-nιtro-4-methoxyphenvP-2-methoxyacetate A 10-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2, Ag 2 0 (0 68 g, 3.0 mmol) and toluene (3 mL). To this was added CH,I (0.36 g, 5 75 mmol) dropwise. The reaction flask was capped tightly and placed into a sonication chamber. The reaction mixture was sonicated for 18 h while stirnng at room temperature. The reaction mixture was filtered through Celite and concentrated in vacuo to dryness The residue was puπfied by column chromatography on silica gel (eluant: 30% AcOEt in hexane) to afford desired product Yield 0.26 g (82%). Step 4 A 100-mL oven-dned round bottom flask fitted with a magnetic stimng bar and a three way adapter, connecting to a hydrogen balloon and a water aspirator was charged with 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 stmed for 18 hours under positive H 2 pressure until all starting matenal was reacted The reaction mixture was filtered through Cehte and concentrated in vacuo to dryness The residue was punfied by column chromatography on silica gel using 10% ethyl acetate in dichloromethane to afford the titled compound (0.57 g, 97%) INTEMEDIATE 4 Methyl 2-(3-amιno-4-methoxyphenvP-2-tert-butyldιmethylsilyloxyacetate A 25-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with alcohol (0 30 g, 1.24 mmol), prepared in step 2 of Intermediate 3 and anhydrous CH,CI 2 ( 10 mL) The reaction mixture was cooled to 0 °C and added 2,6- lutidme (dπed over NaOH pellet, 0.36 mL, 3.1 1 mmol) followed by addition of 'BuMe 2 SιOTf (0.43 mL, 1.87 mmol) dropwise After stimng at 0 °C for 30 mm., the reaction mixture was partitioned between CH,C1, (20 mL) and H 2 0 (15 mL). The aqueous layer was extracted with CH 2 C1 2 (3 x 20 mL). The combined CH 2 C1 2 extracts were washed with bnne (20 mL), dried over Na,S0 4 and filtered. The solvents were removed in vacuo Punfication by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded desired product Yield 0.42 g (95%) Step 2- The titled compound was prepared from nitro compound of step 1 according to the procedure descπbed in step 4 of Intermediate 3 INTERMEDIATE 5 Methyl 2-(3-amιno-4-methoxyphenvPacetate The titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure descπbed in step 4 of Intermediate 3 INTERMEDIATE 6 Methyl 2-(3-amιno-4-methoxyphenyl)-2-methylacetate Step 1 Methyl 2-(3-nιtro-4-rnethoxyprtenyl)-2-methylacetate A 25-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with redistilled dnsopropyiamine (0 84 mL, 6.0 mmol) and anhydrous THF (10 mL) and cooled to 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 stimng at 0 °C for 15 min., the reaction temperature was 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 stimng at -78 °C for 45 mm., dimethylsulfate ( 1.60 g, 12.5 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stmed overnight. The reaction mixture was partitioned between CH 2 C1 2 (50 L) and H 2 0 (50 mL) The aqueous layer was extracted with CH 2 C1, (3 x 50 mL). The combined CH 2 C1 2 extracts were washed with bπne (50 mL), dπed over Na 2 S0 4 and filtered. The solvents were removed in vacuo. Punfication by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded 0 7 g of product (58%). Step 2 The titled compound was prepared from nitro compound, prepared in step 1 , according tothe procedure descnbed in step 4 of Intermediate 3. INTERMEDIATE 7 Methyl 2-(3-amιno-4-methoxyphenvP-2-allylacetate Step 1 Methyl 2-f3-nιtro-4-methoxyphenvP-2-allylacetate This compound was synthesized form ester, prepared in step 1 of Intermediate 3, according to the procedure descnbed in step 1 of Intermediate 6, but using allyl bromide. Step 2 A 25-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with ester (0 30 g, 1 13 mmol), prepared in step 1 , SnCI, 2H 2 0 ( 1 28 g, 5.66 mmol) and EtOH (5 mL) The reaction mixture was heated at 70 °C for 30 min The reaction mixture was cooled to room temperature and poured onto ice/water (20 mL) and basified with saturated Na 2 CO, 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 H,0 ( 15 mL) The aqueous layer was extracted with AcOEt (3 x 50 mL) The combined AcOEt extracts were washed with bπne (50 mL), dned over Na 2 S0 4 and filtered The solvents were removed in vacuo Punfication of the residue by column chromatography on silica gel (eluant. 10% AcOEt in CH,C1,) afforded the titled compound Yield 0 16 g (60%) INTERMEDIATE 8 2.4-Bιs(l .l -dιmethvpropyPphenoxyacetιc acid The 2,4-bιs(l ,l-dιmethy)propylphenol ( 12 g, 51 2 mmol) in dimethylformamide (100 mL) was cooled to -30° C, treated with solid potassium bιs(tπmethylsιlyl)amιde (12.3g, 61 5 mmol), stmed for 30 minutes and then methyl bromoacetate (5 7 mL, 61 5 mmol) was added, the reaction was stmed 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 THF/methanol and treated with IN sodium hydroxide (155 mL) and stmed for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 4 with concentrated HCl, extracted with ethyl acetate (4X), dπed over magnesium sulfate and concentrated. Crystaiization from ethyl acetate and hexane yielded 12.85 g of the titled compound (86%). INTERMEDIATE 9 4-Benzylphenoxyacetιc acid The titled compound was prepared from 4-benzylphenol according to the procedure descnbed in of Intermediate 8. INTERMEDIATE 10 2-Naphthoxyacetιc acid The titled compound was prepared from 2-naphthol according to the procedure descπbed in of Intermediate 8. INTERMEDIATE 1 1 3,5-Bιs(trifluoromethyl)phenoxyacetιc acid The titled compound was prepared from 3,5-bιs(tπfluoromethyl)phenol according to the procedure descπbed in of Intermediate 8. INTERMEDIATE 12 Methyl 5-amιno-3-(N.N-dιmethvPcarbamoylbenzoate Step 1 Methyl 5-nιtro-3-(N.N-dιmethvPcarbamoylbenzoate A 100-mL oven-dned round bottom flask fitted with a magnetic stimng bar was charged with 5-mtro-3-methoxycarbonylbenzoιc acid (3.15 g, 10 mmol), DMF ( 1 drop), anhydrous CH 2 C1 2 (70 L), and oxalyl chlonde (3.7 mL, 42.3 mmol). The reaction mixture was stined at room temperature for 2 h. The solvent was removed in vacuo to afford acid chloπde as a white solid. This was used immediately in the next step without further punfication. An oven-dned round bottom flask fitted with a magnetic stimng bar was charged with above prepared acid chloπde (14 mmol), anhydrous CH 2 C1 2 (50 mL), and dimethyiamine hydrochlonde (70 mmol). NEt 3 (2 mL, 144 mmol) was added dropwise. After stimng at room temperature for 30-60 min excess NEt, (1 mL, 72 mmol) was added and stirring was continued. After 30-60 min the solution was washed with saturated Na 2 C0 3 solution (2 x 20 mL), dried over Na^O j and filtered. The solvent was removed in vacuo to afford 3.3 g of product. This was used in the next step without further punfication. Step 2- The titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure descπbed in step 4 of Intermediate 3. INTERMEDIATE 13 Methyl 5-amιno-3-acetylbenzoate Step 1 - Methyl 5-nitro-3-acetylbenzoate A 250-mL oven-dried round bottom flask fitted with a magnetic stimng bar was 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 1 h. A solution of methyl 5-nitro-3-chIoroformylbenzoate ( 10 mmol), prepared in step 1 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 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 Na ^ CO j solution (2 x 25 mL), dned over Na 2 S0 4 and filtered. The solvent was removed in vacuo The crude matenal was punfied by column chromatography on silica gel (eluant. CH 2 C1 2 ) to afford product Yield 1.06 g (50%) Step 2 The titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure descπbed in step 4 of Intermediate 3 INTERMEDIATE 14 Methyl 5-amιno- (1 -tert-butyldιmethylsιlyloxy ethylbenzoate Step I Methyl 5-nιtro-3-( l -hydroxy)ethylbenzoate An oven-dned round bottom flask fitted with a magnetic stimng bar was charged with compound methyl 5-nιtro-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 THF After stimng at room temperature for 24 h, H 2 0 (20 mL) was added and the solution was concentrated in vacuo The residue was taken in H 2 0 (20 mL) and extracted with CHCI 3 (3 x 100 mL) The combined CHCl, extracts were washed with saturated Na 2 C0 3 solution (20 mL), dned over Na 2 S0 4 and filtered. The solvent was removed in vacuo to afford product This was used in the next step without further punfication. Step 2 Methyl 5nιtro-3-(l -tert-butyldιmethylsιlyloxy)ethylbenzoate An oven-dned round bottom flask fitted with a magnetic stimng bar was charged with alcohol (0 5g, 5 mmol), prepared in step 1 , tert-BuMe 2 SιCl ( 1 3 mol equiv ), lmidazole (2.1 mol equiv.), and anhydrous THF After stirnng at room temperature for 28 hours the solvent was removed in vacuo. The residue was taken H : 0 (50 mL) and extracted with CHC1 3 (2 x 100 mL). The combined CHCl, extracts were washed with H 2 0 (50 mL), dπed over Na,S0 4 and filtered. The solvent was removed in vacuo. The crude matenal was punfied on silica gel using 25%-50% dicloromethane in hexane to afford the product (0.69 g, 91 %) 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. INTERMEDIATE 15 Methyl 4-methoχy-3-(2-thιoethyl)amιnobenzoate Step 1. Bιs(2-bromoethvPdisulfide The dithioethanol (0 79 mL, 6.48 mmol), carbon tetrabromide (4.3 g, 13.0 mmol) and 1 ,3 bιs(dιphenylphosphιno)propane (5.34 g, 13.0 mmol) were weighed into a flask and flushed with nitrogen and then taken up in CH 2 C1 2 (15 mL) and stmed for 16 hours, workup consisted of pouπng into 1/2 saturated ammonium chloπde and extracted with CH 2 C1 2 (3X) dry magnesium sulfate and concentrated to yield (90 g) of a crude product that was chromatographed (Hexane:Ethyl acetate9.1 ) to yield I 49 g of product. Step 2: Bιs-( methyl 4-methoxy-3-(2-dithιoethyl)amιnobenzoate 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 60 ° 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 organic layers were washed with water (3X), dπed 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: 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). H 2 0 (0.3 mL) and two drops of cone. HCl were added and the resulting mixture was stined at 40 " C for 2 hours, the reaction was diluted with water and ethyl acetate, extracted with ethyl acetate (3 X) and dried over magnesium sulfate to yield 0.27 g of a crude product that was purified by chromatography (hexane:ethy 1 acetate 9: 1 to 6: 1 ) to yield 0.1 1 g of the titled compound. Example 88 Activity Assays (a) Vesicle Assay l-palmitoyl-2-[ , C] arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 μM) and 1 ,2-dioleyolglycerol (final concentration 3 μM) 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 CaCl 2 and 2 mg/ml bovine serum albumin (BSA) (Sigma A751 1 ) ( 1.2x final concentration of lipids). A typical assay consisted of the lipid mixture (85 μl) to which was added consecutively, the inhibitor (5 μl in DMSO) and cPLA 2 , 10 ng for an automated system or 1 ng for a manual assay, in lOμl of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below. (b) Soluble Substrate Assay (LvsoPO l -[' C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 μM) 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 μl) to which was added consecutively the inhibitor (5μl in DMSO) and cPLA 2 , 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. (c) Automated Assay The lipid suspension and inhibitor were pre-incubated for 7 min. at 37°C. Enzyme was added and the incubation was continued for a further 30 mins. The reaction was then quenched by the addition of decane: isopropanol: trifluoroacetic acid (192:8: 1 w/v, 150 μl). A portion of the quench layer (50 μl) was passed through a Rainin Spheric-5 silica column (5μ, 30 x 2.1 mm) eluting with heptane:methanol:TFA (97:3:0.1 v/v). The level of [ l C]- arachidonic acid was analyzed by an in-line Radiomatic Flo-One/Beta counter (Packard). (d) Manual Assay The lipid, inhibitor and enzyme mixture were incubated at 37°C for 30 min. The reaction was quenched by the addition of heptane:isopropanol:0.5M sulfuric acid ( 105:20: 1 v/v, 200 μl). Half of the quench layer was applied to a dispoable silica gel column (Whatman SIL, 1 ml) in a vacuum manifold positioned over a scintillation vial. Free [ l C]- arachidonic acid was eluted by the addition of ethyl ether ( 1 ml). The level of radioactivity was measured by liquid scintillation counter. (e) PMN Assay PMNs were isolated using Ficoll-Hypaque according to the manufacturers directions. Red blood cells contaminating the PMNs were removed by hypotonic lysis, and the PMN pellet was washed once, and resuspended in Hanks buffered saline at a concentration of 2 x 10 6 cells/ml. The cells were preincubated with inhibitors for 15 min at 37 °C and then stimulated with 2 uM A23187. When monitoring LTB 4 production as a measure of cPLA 2 inhibition, the reaction was quenched with an equal volume of ice cold phosphate buffered saline. Cells were removed by centrifugation, and the LTB 4 present in the cell supernatant was measured using the LTB scintillation proximity assay provided by Amersham according to the manufacturers directions. In the assays reported in the Tables above, LTB 4 was measured. When monitoring arachidonic acid production, the reaction was quenched with methanol containing D8-arachidonic acid as an internal reference. The lipids were extracted by the method of Bligh et al. ((1959) Can. J. Biochem. Physiol., 37, 91 1-917), and the fatty acid was converted to the pentafluorobenzyl ester and analyzed by GC-MS in a manner similar to that reported by Ramesha and Taylor ((1991 ) Anal. Biochem. 192, 173-180). (c) Coumaπne (PGE, Production) Assay RBL-2H3 cells were routinely cultured as 37°C in a 5% C0 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum The day before the expenment, cells were seeded into spinner flasks at 3 x \ 0 cells/ml and 100 ng/ml DNP specific-IgE was added After 20 hrs, the cells were harvested by centnfugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 6 ceils/ml in serum free media The cells were then premcubated with either inhibitor in DMSO (1 % v/v) or DMSO ( 1 % v/v) for 15 min at 37°C followed by stimulation with DNP-BSA (300 ng/ml) After 6 min, the cells were removed by centnfugation, and the supernatant was assayed for PGD 2 content in accordance with known methods Example 89 Rat Canageenan-Induced Footpad Edema Test Each compound was suspended in 0.3ml absolute ethanol, 0 I ml Tween-80 and 2 0 ml Dulbecco s PBS (without calcium or magnesium). To this mixture, 0 1 ml I N NaOH was added After solution was complete, additional amounts of PBS were added to adjust the concentration to I 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 canageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan. All patent and literature references cited herein are incorporated as if fully set forht herein

Claims: What is claimed is 1 A compound having a chemical formula selected from the group consisting of 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 2 -CH 2 -, B is independent of any other group and is selected from the group consisting of -(CH 2 )„-, -(CH 2 0) n -, -(CH 2 S)„-, -(OCH 2 ) n -, -(SCH 2 ),-. -(CH=CH)„-, -(C=C) n -, -CON(R 6 )-, -N(R 5 )CO-, -0-, -S- and -N(R 6 )-, R, is independent of any other R group and is selected from the group consisting of -X-R 6 , -H -OH, halogen, -CN, -NO,, C,-C, 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,, -CONR,R 6 , -(CH 2 ) n -W-(CH 2 ) m -Z-R s , -(CH 2 ) n -W-R„ -Z-R„ C,-C l0 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 2 )„-W-(CH 2 ) ra -Z-R„ (CH 2 ) r -W-R„ -Z-R„ C,-C l0 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 6 , -CN, -COR 6 , -NHR 6 , -COOH, -CONR 6 R 7 , -NO,, -CONHSO R 8 , C,- G, alkyl, alkenyl and substituted aryl, R 5 is independent of any other R group and is selected from the group consisting of -H, -OH, -0(CH,) n R„ -SR ft , -CN, -COR 6 , -NHR 6 , -COOH, -NO,, -COOH, -CONR 6 R 7 , -CONHSO,R s , C,-C 3 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF„ -CF,CF, and R 6 is independent of any other R group and is selected from the group consisting of -H, C,-C, 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,-C, alkyl, alkenyl, alkinyl, aryl and substituted aryl, R 8 is independent of any other R group and is selected from the group consisting of C r 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 6 , -COOH, -CONR„R 7 , tetrazole, -CONHSO,R K , -COR 6 , - (CH,) n CH(OH)R 6 and -(CH 2 ) n CHR 6 R s , Rι 0 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR 6 , -COOH. -CONR 5 R 7 , tetrazole, -CONHS0 2 R 8 , -COR 6 , -(CH,) n CH(OH)R 6 and -(CH 2 ) n CHR 6 R„ W is, independently each time used including within the same compound, selected from the group consisting of -0-, -S-, -CH,-, -CH=CH-, -C = C- and -N(R 6 )-, X is independent of any other group and is, independently each time used including with the same compound, selected from the group consisting of -O-, -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,-, -O-, -S-, -N(R 6 )-, -CO-, -CON(R 6 )- and -N(R b )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 3. The compound of claim 1 wherein said compound has the following chemical formula. 4. The compound of claim 1 wherein said compound has the following chemical formula: The compound of claim 1 wherein compound has the following chemical formula: 6. The compound of claim 1 wherein A is -CH,- and R, is -(CH,) n -W-(CH,) m -ZR, 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 R, is -NHR 6 . 9. The compound of claim 8 wherein R 6 is a substituted aryl group 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,, -CF 2 CF„ -(CH 2 ) p COOH, -(CH 2 ) p CH„ -0(CH,)„CH„ -(CH 2 ) p OH, -(CH,) p S(C 6 H 6 ), -(CH 2 ),,CONH 2 and -CHR π COOH, wherein R n is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH,) p OH, and -0(CH,) P CH,, and wherein p is an integer from 0 to 4 1 1 The compound of claim 6 wherein R, is selected from the group consisting of -H and -OCH,(C 6 H ή ) 12. The compound of claim 6 wherein R, is -COR,, R, is -OCH,R 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„ -CF,CF, and -C(CH,),CH,CH, 14 A method of inhibiting the phospholipase enzyme activity of an enzyme, compπsing admimstenng to a mammalian subject a therapeutically effective amount of a compound of claim 1 15 A method of treating an inflammatory condition, compnsing admi stenng to a mammalian subject a therapeutically effective amount of a compound of claim 1 16 A pharmaceutical composition compnsing a compound of claim 1 and a pharmaceutically acceptable earner

Inventors: BEMIS JEAN, KAILA NEELU, MCKEW JOHN, XIANG YIBIN, BEMIS, JEAN, KAILA, NEELU, MCKEW, JOHN, XIANG, YIBIN
Applicants: GENETICS INST, GENETICS INSTITUTE, INC.
Application year: 1997
Main classification: C07D209
IPC codes: A61K31, A61P29, A61P43, C07D209, C07D401, C07D405