NZ248177A

NZ248177A - Benzyl phenyl hydrazine derivatives

Info

Publication number: NZ248177A
Application number: NZ248177A
Authority: NZ
Inventors: Prasit Petpiboon; Rejean Fortin; John H Hutchinson; Michel L Belley; Serge Leger; John Gillard; Richard Frenette
Original assignee: Merck Frosst Canada Inc
Priority date: 1989-08-22
Filing date: 1990-08-13
Publication date: 1995-01-27

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £48177 2 8 1 Priority Date(s): ... .2-.?-.S8^ .: 7-9o CouipitJie Specification Filed: Placs; CP.ffi&fJlir, , Under tho , Provisions of R0{?u tat«3n 23 (i) !he 5 "* Spocificxuon hasten ~ to. "vw 19:^ rr* w~vu arco-dato* 9.0 -rk. 'nftiate Publication Date: P.O. Journal, No: 2 7 JAN IS95 ^ ^ PATENT QFFir:c 19 JUL 1993 .. <*.' .IS Ml ■ fj-j RECEIVED NEW ZEALAND PATENTS ACT, 1953 Divided from No. 234883 Date Filed: 13 August 1990 i COMPLETE SPECIFICATION BENZYL PHENYL HYDRAZINES We, MERCK FROSST CANADA INC., a corporation organized and existing under the laws of Canada, of 16711 Trans-Canada Highway, City of Kirkland, Quebec, Canada, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 2 - 24 BACKGROUND OF THE INVENTION European Patent Applications 166,591 and 275,667 disclose a series of indole-based compounds with activity as prostaglandin antagonists and inhibitors of leukotriene biosynthesis respectively. In EP 181,568 and EP 200,101 are disclosed a series of compounds, containing two aromatic nuclei, which "are'liescribed as possessing activity as lipoxygenase inhibitors. In EP 279,263 is disclosed a series of indoles, benzofurans and benzothiophenes which are described as possessing activity as lipoxygenase inhibitors. U.S. Patent 4,629,733 describes novel indolinones which are antithrombotic and inhibit both phosphodiesterase and tumor metastasis. The chemical preparation of quinolylindoles is referred to by Sheinkman, et al., Chem. Ab., Vol. 67, 54017 (1967), without mentioning any utility for such compounds. A number of N-acyl derivatives of indole-3-acetic acid are described as potential anti-inflammatory agents by Biniecki, et al., Chem. Ab. , Vol. 98, 197936 (1983), by Pakula, et al., Chem. Ab., Vol. 105, 190835 (1986), and in British Pat. Spec. 1,228,848. New Zealand Patent Specification No. 234883 relates to compounds having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to methods and pharmaceutical formulations for using these compounds in mammals (especially humans). Because of their activity as leukotriene biosynthesis inhibitors, the compounds of Specification No. 234883 are useful as anti-asthmatic, anti-allergic, and anti-inflammatory agents and are useful in treating allergic rhinitis and chronic bronchitis and for amelioration of skin diseases like psoriasis and atopic eczema. These compounds are also 24 8 1 useful to inhibit the pathologic actions of leukotrienes on the cardiovascular and vascular systems for example, actions such as result in angina or endotoxin shock. The compounds of the Specification No. 234883 are useful in the treatment of inflammatory and allergic diseases of the eye, including allergic conjuctivitis. The compounds are also useful as cytoprotective agents and for the treatment of migraine headache. Thus, the compounds of Specification No. 234883 may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions; hepatic ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCI4 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure. The compounds of Specification No. 234883 are inhibitors of the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETE and the leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease conditions such as asthma, psoriasis, pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesis of such compounds will alleviate these and other leukotriene-related disease states. New Zealand Patent Specification No. 234883 provides novel compounds of the formula I: 24 8 1 7? r1 7 r2 t r3 and R4 are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -N02, -N3, -C(0H)R11R11, -CO2R12, -SR14, -S(0)R14, -S(0)2R14, -S(0)2NR15R15, -OR15, -NR15R15, -C(0)R16 or -(CH2)tR21; R5 is hydrogen, -CH3, CF3, -C(0)H, Xx-R6 or X2-R7; R® is hydrogen or x3-r9; R^ and R^ are independently alkyl, alkenyl, -(CH2)uPh(R10)2 or -(CH2)uTh(R10)2; R7 is -CF3 or R^ as defined above; R1*"* is hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF , -CN, -NCL, -N , -C(OH)R11R11, -CO R12, -SR14, -S(0)R14, -S(O)2R14, -S(O)2NR15R15, -OR15, -NR15R15, -C(0)R16 or -(CH2)tR21; each R11 is independently hydrogen or lower alkyl, or two 11 R 's on the same carbon atom are joined to form, together with that carbon at cm, a cycloalkyl ring of 3 to 6 carbon atoms; R12 is hydrogen, lower alkyl or -CHoR^1; R1^ is lower alkyl or -(CH2)rR 21 24 8 1 7? - 5 - R14 is -CF3 or R^as defined above; is hydrogen, -C(0)R^, as defined above, or two R15,s on the same nitrogen may be joined to form, together with that nitrogen, 5 a monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 heteroatcms chosen from 0, S and N; r!6 is hydrogen, -CF3, lower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR^1; 10 R17 is -(CH2)s-C(R18R18)-(CH2)s-R19 or -CH2C(0)NR15R15 where R"''5 is as defined above; R1® is hydrogen or lower alkyl; 15 R1^ is a) a monocyclic or bicyclic heterocyclic ring containing from 3 to 9 nuclear carbon atoms and 1 or 2 nuclear hetero-atoms selected from N, S and 0 and with each ring in the heterocyclic radical being 20 formed of 5 or 6 atoms, or b) the radical W-R^O; R^O is alkyl or -C(0)R^; r21 is phenyl substituted with 1 or 2 groups; 25 r22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -NO2 or -N3; 30 r23 is alkyl, cycloalkyl, or a monocyclic monoheterocyclic ring; 248177 m is 0 to 1; n is 0 to 3; p is 1 to 3 when m is 1; p is 0 to 3 when m is 0; r is 0 to 2; s is 0 to 3; t is 0 to 2; u is 0 to 3; v is 0 or 1; i c 15 W is 0, S or NR-*--1 where R is as defined above; X1 is 0 or NR15 where R15 is as defined above; X2 is C(0), CR^R11 where R11 is as defined above, S, S(O) or S(0)2; X"^ is C(0), CR^R11 where R11 is as defined above, S(0)2 or a bond; Y is X1 as defined above or X2 as defined above; Q is -C02R12, -C(0)NHS(0)2R14, -NHS(0)2R14, -S(0)2NHR15, -C(0)NR15R15, -CO2R17, -C(0)NR18R24, -CH20H, or 1H- or 2H-tetrazol-5-yl,where R12, R14, r15, 7 18 r and R are as defined above; and R24 is the residual structure of a standard amino acid, or R18 and R24 attached to the same N can cyclize to form, together with that N, a proline residue; and the pharmaceutically acceptable salts thereof. A preferred embodiment of Formula I is that in which: R1, R2, R^ and R4 are hydrogen R5 is X2-R7 or -OR6; R7 is R6; R8 is R9; R^O is hydrogen or halogen; m i s 0 ; - 7 - Zk$ 1 n is 1 to 3; u is 0 in r6 and 1 in R9; vis 0; X2 is CR11R11 or S; Q is -CO2R12; and the remaining substituents are as defined for Formula I; and the pharmaceutically acceptable salts thereof. Definitions The following abbreviations have the indicated meanings: Me = methyl Et = ethyl Pr - propyl Bz = benzyl Ph = phenyl t-Bu = tert-butyl i-Pr = isopropyl c-C^H-q = cyclohexyl c-Pr = cyclopropyl c- = cyclo Ac = acetyl Tz = 5-tetrazolyl Th = 2- or 3- thienyl c-C5H9 = cyclopentyl 1-Ad = 1-adamantyl. Alkyl, alkenyl, and alkynyl are intended to include linear, branched, and cyclic structures and combinations thereof. As used herein, the term "alkyl" includes "lower alkyl" and extends to cover carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, norbornyl, undecyl, 10 30 2 4J R 1 - 8 - dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclododecyl, adamantyl, and the like. As used herein, the term "lower alkyl" denotes those alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, cyclopropylmethyl, and the like. The term "cycloalkyl" refers to a hydrocarbon ring having from 3 to 7 carbon atoms. Examples of cycloalkyl groups are cyclopropyl,"* cyclopentyl, cycloheptyl and the like. 15 "Lower alkenyl" groups denote those alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 2Q 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like. "Lower alkynyl" groups denote those alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 25 3-methyl-l-pentynyl, 2-heptynyl and the like. As used herein, the term "lower alkoxy" denotes those alkoxy groups of from 1 to 7 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. The term "monocyclic monoheterocyclic ring" in the definition of R^3 denotes those monocyclic groups of 2 4 - 9 - 5 to 7 members containing only 1 heteroatom selected from N, S or 0 in the ring. Examples include tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, tetrahydropyran, and the like. 5 Examples of the term "monocyclic or bicyclic heterocyclic ring" as defined for R19 include 2,5-dioxo-l-pyrrolidinyl, (3-pyridinylcarbonyl) amino, 1,3-dihydro-l,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl, ]_o 2,4-imidazolinedion-l-yl, 2 , 6-piper idinedion-l-yl, 2-imidazolyl, 2-oxo-l,3-dioxolen-4-yl, piperidin-l-yl, morpholin-l-yl, piperazin-l-yl and the like. The point of attachment of any heterocyclic 15 ring may be at any free valence of the ring. The term standard amino acid is employed, to include the following amino acids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamic acid, glutamine, glycine, histidine, 20 isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. (See F.H.C. Crick, Symposium of the Society for Experimental Biology, 1958 (12) p. 140.) 25 It is understood that R1 and R2 may be located at any of positions 3,4,5,6,7 or 8 of the quinoline ring. As used herein the term "lower alkylthio" denotes those alkylthio groups of from 1 to 7 carbon 30 atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the 248177 - 10 - \ ■ propylthio group signifies -SCH2CH2CH3. The terms PhCR1®^ and Th(R^)2 indicate a phenyl or thienyl group substituted with two R1® substituents. 5 Halogen includes F, CI, Br, and I. It is intended that the definitions of any substituent (e.g., R1, R2, R15, Ph(R10)2> etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, -Nr1^r15 represents 10 -NHH, -NHCH3, -NHC6H5, etc. The monocyclic heterocyclic rings formed when two R15 groups join through N include pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine, and N-methvlpiperazine rings. 15 The prodrug esters of Q (i.e., when Q = C02R17) are intended to include the esters such as are described by Saari et al.. J. Med. Chem., 21, No. 8, 746-753 (1978), Sakamoto et al.. Chem. Pharm. Bull., 3.2., No. 6, 2241-2248 (1984) and Bundgaard et 20 ah , J. Med. Chem., 10, No. 3, 451-454 (1987). Some of the compounds of Formula I contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The Formula I is meant to comprehend such possible 25 diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof. The pharmaceutical compositions of Patent Specification No. 234883 comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally 30 / / 24 - 11 - other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include" aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium andsodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N^-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, txipropylamine, tromethamine and the like. When the compound of the Formula I is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Compounds of the Formula I can be prepared according to the following methods. Temperatures are in degrees in Celsius. The starting methoxy phenylhydrazines IX are either commercially available or are described in the chemical literature as are the acetamidophenols XXVI. The benzyl phenylhydrazine starting materials III are prepared as described in EP 166,591 and the ketones IV and XXXI are prepared as . described in EP 166,591 and EP 275,667. The 2-(halomethyl)quinolines VII are available from literature methods described in "Quinolines" Parts I and II0 G. Jones (ED.), John Wiley &. Sons, Toronto, 1977 and 1982. The preparation of VII by halogenation of the corresponding 2-methylquinolines is also described in the Jones' volumes. The benzyl halides, (R11-1^ PhCE^-Hal, are readily prepared and many such compounds are described in the prior art, such as U.S. Patent 4,808,608. Hal in VII and (R^)2 PhCH2-Hal represents CI, Br or I. Many syntheses of indoles are well-known in the chemical literature: see for example, "Heterocyclic compounds" Volume 25, Parts I, II, III, W.J. Houlihan (Ed.), Interscience, J. Wiley & Sons, N.Y. , 1979, and "The Chemist r;/ of Indoles" by R.J. Sundberg, Academic Press, N.Y., 1970. One of the most common syntheses is known as the Fischer Indole Synthesis, and is abbreviated in the following methods as "Fischer". The -CO2H and -C02R12 groups in the intermediates and final products in the various methods can be transformed to other representatives of 0 such as -C0NHS(0)2R14. -NHS(0)2R14, -CONR15R15, - 13 - 2 4 R n " w i; -CH2OH or tetrazol-5-yl by the methodology described in U.S. Patent 4,808,608. The preparation of the pro-drug forms (Q is -CC^R1') from the acids may be effected by the methodology of EP 104,885. It will be apparent to one skilled in the art that the various functional groups (R1, R2, Y, Q, etc.) must be chosen so as to be compatible with the chemistry being carried out. Such compatibility can often be achieved by protecting groups, or by specific variations in the sequence of the reactions. When R5 is S-R7, the corresponding sulfoxides and sulfones can be prepared by oxidation of the sulfides with one or two equivalents of an oxidizing agent such as m-chloroperbenzoic acid or monoperoxyphthalic acid or oxone (Trost, J. Org. Chem., 1988, pg.532). Many of the following methods involve a basic hydrolysis of an ester function to obtain the corresponding carboxylic acid. In all cases, the free acid is obtained by acidification of the reaction mixture with a suitable acid such as hydrochloric, sulfuric, acetic, trifluoroacetic acid, etc. Compounds VIII. XI, XV, XIX, XXXVI and their precursor esters are all examples of the Formula I compounds. Compounds III. XXIII and XXX are novel compounds which are intermediates in the preparation of the compounds of Formula I. The present invention relates to the novel Compounds III. XXIII and XXX. which are compounds of the formula 24 8 1 R4 wherein: Ra is methyl, t-butylcarbonyl or R1 R1, R2, R3, R4 and R10 are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -N02, -N3, -C(0H)R11R11, -CO2R12, -SR14, -S(0)R14, -S(0)2R14, -S(0)2NRI5R15, -OR15, -NR15R15, -C(0)R16 or -(CH2)tR21; each R11 is independently hydrogen or lower alkyl, or two Rll!s on the same carbon atom are joined to form, together with that carbon atcm, a cycloalkyl ring of 3 to 6 carbon atcms; 10 15 20 248177 - 15 - R12 is hydrogen, lower alkyl or -CH2R21 ; R13 is lower alkyl or -(CH2)rR21; R14 is CF3 or R13 as defined above; R15 is hydrogen, -C(0)R16, R13 as defined above, or two R15 's on the same nitrogen may be joined to form, together with that nitrogen, a pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine or N-methyl-piperazine ring; ^ ^ is hydrogen, -CF3, lower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR21; 21 R is phenyl substituted with 1 or 2 R22 groups; 22 R is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -N02 or -N3; r is 0 to 2; and t is 0 to 2. 25 30 $ Method 1 - 16 - 10 15 20 25 30 1)R'COCl/\lCl, c3h4ci2 2)NaOM»/M«OH -cc2h 1 ) K2CO,/TKP'~£I2_ ^ . hc-j+- ^~ni^' 23 LiOH -c02me C510D3-n R<' V1 24 a - 17 - Method 1 Intermediate V is prepared by a Fischer reaction between benzylphenylhydrazine III and ketone IV, followed by hydrolysis with an aqueous solution of an alkali hydroxide or other suitable hydroxide in mixture with a suitable water miscible organic solvent such as tetrahydrofuran (THF) or methanol (MeOH). The methoxy acid V is demethylated by heating with an alkali salt of an aliphatic thiol in a suitable solvent such as hexamethylphosphorictri-amide (HMPA) or N-methylpyrrolidone (NMP). The reaction mixture is acidified and the crude acid so obtained is converted to the methyl ester VI by-treatment with diazomethane. The phenol VI is coupled to the 2-halomethylquinoline VII. by stirring with a base (preferably an alkali hydride or carbonate) in a suitable solvent such as dimethyl formamide (DMF), NMP, acetone or the like. The resulting ester is hyarolysed by base to yield VIII, a compound of the present invention. When intermediate V contains a sulfide group attached to position 3, treatment with a Lewis acid, such as AICI3, and an aliphatic thiol, simultaneously effects demethylation ana removes the sulfide group. Suitable solvents for this reaction are methylene chloride, 1,2-dichloroethane, etc. The resulting acid is then converted to the methyl ester IX with diazomethane. A Friedel-Crafts reaction between IX and an acid chloride, R^COCl, simultaneously introduces the acyl substituent into the 3-position of the indole ring and onto the phenolic hydroxyl group. The acyl group is removed from the phenol by *<*3 1 - 18 - treatment with sodium methoxide in MeOH to yield acylphenol X. Phenol X is coupled with VII as described for the coupling of VI and VII above. In these coupling reactions, it is at times advantageous to add a catalyst such as potassium iodide or tetraethylammonium bromide, especially when Hal is chlorine. A final hydrolysis yields compound XI. 10 15 20 25 30 - 19 - METHOD 2 ii + iv 1 ) KHMD3/THF/- 78 C 25 HaHal ■r- h -cojh' tx)p r r xii 10 15 20 30 mso -c02r' R HO~H~ „h xiii a rM 1) LIOH 2) NaS-c-Bu/HMPA 3) CHJNJ r4 HO xiv •c02ma r r'1 |l) XJCOJ/DMF/VII 12) LIOH COjH R1 / xvx (x) R'1 R11 1 ) NaCSBH,/ZnI2 CjH.CI, 2) NaOMa/MaQH R7C02-£ 1) R COCl/NEC 3/THF 2) B'COCI/AICI, C,H.C1, COjR1 PO- 1 J NaOMB/M»OH 2) k3co3/DMF/VII 3) LIOH cor' R" XIXfI) >r OxOp fl 2 4 1 _ 20 _ Method 2 Intermediate XII is prepared by a Fischer reaction between methoxyphenyl hydrazine II and ketone IV, followed by alkylation of the indole 5 nitrogen, after deprotonation using potassium hexamethyldisilazane in an ether solvent such as tetrahydrofuran (THF), with an alkyl or aralkyl halide. The methoxy group in XIII is removed using ]_0 the conditions of Method 1. The corresponding phenol XIV is now coupled with the 2-halomethylquinoline VII by stirring with a base (preferably an alkali hydride or carbonate) in a suitable solvent such as DMF, NMP or the like. The resulting ester is hydrolysed using ]_5 base to yield XV a compound of the present invention. When intermediate XIII contains a sulfide at position 3, treatment with a Lewis acid such as AICI3 and an aliphatic thiol simultaneously effects demethylation and removes the sulfide group. 20 Suitable solvents for this reaction are . dichloromethane or dichloroethane. In a variation of Method 1, the phenolic hydroxyl in XVI is first acylated with the reagent R7C0C1 (XVII) in the presence of a weak base such as triethylamine. A 25 Friedel-Crafts reaction is then carried out on the 0-acylated intermediate, with an additional mole of XVII and AICI3, to yield the intermediate XVIII. Acyl ester XVIII may then be reduced to a 3-alkyl indole XIV using sodium cyanoborohydride in 30 dichloroethane using a zinc iodide catalyst. Acyl ester XVIII is cleaved to the indole phenol by hydrolysis with sodium methoxide in methanol and is coupled to 2-halomethyl quinoline VII 24 8 ^ 7/ - 21 - using a base such as an alkali hydride or carbonate in a solvent such as DMF or NMP. Hydrolysis of the resulting compound using base yields the compound XIX. method 3 10 15 (CH,)3CC0C1 -t-BuCOz—H- xx kj xxi xxii NEt 3/ButNBr/CHj Cl2 20 C-3uC02 XXIV C510)2 'Cx) nscHER/i v .co2r 12 t-BUC02 Ca'°>2 NH, xxiii NaOM»/M»OH as par Mechod 1 vi vine I) 30 22 Method 3 A suitably substituted aminophenol XX is protected on oxygen by the use of pivaloyl chloride dissolved in CH2CI2 using triethyl amine as base. The pivaloate ester XXI is then diazotized using hydrochloric acid and sodium nitrite in an aqueous solvent and the transient diazonium species reduced in situ to the hydrazine XXII using sodium hydrosulfite in water. Benzylation of the hydrazine is effected as described in Method 1. subjected to a Fischer indolization using the appropriate ketone IV to produce the indole XXJV. Cleavage of the 0-pivaloyl group using sodium 15 methoxide in methanol transforms the product into the phenolic indole VI which is converted to the products as described in Method 1. 20 METHOD 4 The O-pivaloyl-N-benzylhydrazine XXIII is 25 XXII + IV 1 ) khmds/thf 2) R - Ho 1 3) NaOMs /MeOH as par Mac.Mod 2 24 8 -23 - Method 4 The pivaloyloxyphenylhydrazine XXII is used directly in the Fischer indolization using ketone IV. N-Alkylation of the indole XXV. as described in Method 2, followed by removal of the pivaloyl group as described, yields the phenolic indole XIV which is converted as described in Method 2 to the products of Formula I. - 24 - Method 5 K3C03/t)MFZVTI_ y^TIKAc R\ 10 xxvi KOH/aq. EtOH/hoac 4 0 17 7 - 25 - Method 5 A suitable N-acetylated aminophenol XXVI is reacted with VII using an alkali hydride or carbonate, such as potassium carbonate as a base in a 5 polar solvent like DMF or NMP. The quinolinylmethoxy acetanilide XXVII is then de-acetylated using standard basic conditions, preferably using alcoholic potassium hydroxide under reflux to produce the quinolinylmethoxy aniline derivative XXVIII. 10 Conversion of the quinolinylmethoxy aniline derivative to the hydrazine analogue XXIX is effected through reduction of the intermediate diazonium salt using sodium hydrosulfite in an aqueous medium- The hydrazine XXIX is then N-benzylated 15 using a benzyl halide in an organic solvent such as methylene chloride containing an amine base such as diisopropylethylamine and preferably tetra-n-butylammonium bromide as catalyst. The hydrazine XXX is then processed using a 2Q Fischer indolization with ketone IV according to Methods 1, 2, 3 and 4 to produce compounds of Formula I. 30 - 26 - Method 6 10 15 20 77 1, 1) FISCHER/XXIX vc°2r =- vv" a / \ 2) KHMSS/THF/f? Ha 1 R11 R11 co2r" xxxi JL LiAlPL C^„ OH r1 . (Xn^° r3 1 Rn 8" XXXIII K XXXIV Ra R'1 R'1 r'1 1) NaH/THF/TCXXV 21 LdOH Hal"^ p"C02IM= XXXV R co2h xxxvi(i) 30 24 8 1 - 21 ~ Method 6 Hydrazine XXIX may also be transformed directly to unsubstituted indoles by a Fischer reaction with various ketones like XXXI. N-Alkylation of the indoles is effected using the conditions described in Method 2 to produce quinolinylmethoxyindole alkanoate esters XXXII. Such esters are transformed to ketones or carbinols via Grignard conditions using alkyl magnesium halides in ether solvents like diethyl ether or through the use of lithium aluminum hydride in ether solvents like THF. The carbinols XXXIV so produced may be further transformed into ester compounds of the present-invention by reacting with a-halo esters XXXV using sodium hydride as base in a suitable solvent like THF. Subsequent hydrolysis of the esters using Method 1 leads to acid compounds of Formula I. 25 30 2 4 8' - 28 - Method 7 10 xii aici3/ecsh CRs = S-R7) ,h HO xxxvii .CA> -co2r 1 2 h r'1 r11 vii k2co3/dmf 15 20 xxxix Ra-Hal/bas a 25 30 - 29 - METHOD 7 Phenol XXXVII is obtained by treatment of XII (R^ = S-R^) with a Lewis acid and a thiol, as in Method 1 for the conversion of V to IX. Compound XXXVIII is then obtained by reaction of XXXVII with VII in the presence of a base in a suitable solvent, as described for the conversion of V£ to VIII in Method 1. The introduction of R^ in XXXIX is conveniently effected by an electrophilic reaction between XXXVIII and R5-C1 (R5 not = X^R6). Such reactions are frequently catalysed by Lewis acids or proton acids such as AICI3, SnCl^., TiCl,^, BBrj^HCl, HBr and the like. They may be carria out in a variety of solvents, with a preference for non-protonic solvents such as dichloromethane, 1,2-dichloroethane, nitromethane, chlorobenzene and the like. It will be obvious to one skilled in the art, that the chlorine in R^-Cl, in this and the other Methods, may often be replaced by another halogen or by a hydroxy1 group, or R^-Cl may be replaced by an acid anhydride (R^CO^O. An alternative synthesis of XXXIX is to effect a Fischer reaction between compounds IV and XXIX. Introduction of R® into XXXIX. is accomplished by alkylation with R^-Hal and a base as described previously for Methods 2, 4 and 6. Finally, hydrolysis of the ester will yield XV. Alternatively, the ester group in XXXIX can be hydrolysed, and the corresponding free acid (R12 = H) alkylated on the indole nitrogen with R^-Hal and an aqueous base, such as NaOH, and a phase-transfer catalyst, such as methyltrioctylammonium chloride. Alkylation of the acid corresponding to XXXIX (R12 = H) can also be 2 4 - 30 - effected using a strong base such as sodium hydride in a solvent such as DMT. This latter procedure usually gives the ester of XV in which the carboxyl group has also been alkylated. The free acid XV can be obtained by standard hydrolysis procedures. If R® in XV or the ester precurson of XV is alkenyl, it can be reduced to alkyl using hydrogen gas, and a Pt or Pd catalyst in a suitable solvent, at atmospheric pressure. 24 8 17? - 32 - METHOD 8 Compound XL may be prepared either by the coupling of VI to VII (Method 1) or by a Fischer 5 reaction between IV and XXX (Method 5). Compound XL may be desulfurized by treatment with a Lewis acid such as AICI3, or by reduction with Raney nickel, to give compound XLI. A Friedel-Crafts reaction on XLI with the reagent R^COCl and a Lewis acid catalyst 10 such as AICI3 yields the 3-acyl derivative XLII, hydrolysis of which yields XI. In the Friedel-Crafts reaction, carbon monoxide may be lost and compound XLIII is formed; hydrolysis under standard conditions then yields XLIV. The formation of XLIII occurs when the cation R7 + is especially stable and when the ■ reagents R^COCl and the Lewis acid are mixed before adding XLI. If the Lewis acid is added last, the main product is usually the acylated compound XLII. If a milder Lewis acid such as TiCl^ is used, the 20 main product is also XLII. It will be obvious to one skilled in the art that the reagent R^COCl can often be replaced by R7CO-Hal (Hal = F, Br or I) or (R7C0)20. 25 Representative Compounds Table I and Table II illustrate compounds having the formulae la and lb respectively, "Attach point" is the position on the indole nucleus where the 30 quinolyImethoxy moiety is attached. -33 248177 TABLE I Ex R\R2 R3 ATTACH R3 R5 Y- -{CR1 ^R11)( No. POINT 1 H,H H 5 -CH2Ph-4-Cl -S-t-8u - C(Me)2 2 H,H H 5 _CH2Ph-4-C1 Me C f Me)2 3 H,H H 5 -CH0Ph-4_S-t-8u U -S-t-Bu C < Me) 2 4 H,H H 5 _CH2Ph-4-Cl -SPh C(Me)2 6 H,H H 5 -CH2Ph-4_Cl -S(0)2Ph C(Me)2 7 H,H H 5 -CH2Ph-4-Cl -S(0)Ph C(Me) ^ 8 H,H H 5 -CH2Ph-4-Cl H C(Me) 2 9 H,H H 5 _CH2Ph-4-Cl —C (0}Ph C(Me)2 10 H,H H 5 -CH2Ph-4-C1 -CH2Ph C(Me)2 11 H,H H 5 -CH2Ph-4-Cl -C(0)CH2-t-Bu C(Me)2 12 H, H H 5 -CH2Ph-4_Cl -S-t-8u ch2och2 13 H,H H 5 -CH2Ph-4-Cl -CH2CH2-t-8u C(Me)2 14 H,H H 5 -CH2Ph-4-Cl -S-t-8u CH(Me) 15 6-C1, 7-C1 H 5 -CH2Ph-4_Cl Me C(Me) 2 16 H, 7—CI H 5 _CH2Ph-4-Cl Me C(Me) 2 17 H,H 4-allyl 5 -CH2Ph-4-Cl -S-t-8u c(me)2 18 H, H 4-allyl 5 _CH2Ph-4_Cl H C(Me)2 30 Ex No 19 20 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 2 4 8 1 - 34 ~ table ii ch2-y-(cr1 1 r1 1 )p-c02k lb ATTACH POINT Y-(CR11R11). 6 -CH2Ph-4-Cl -S-t-Bi "C (Me ) 2 7 -CH2Ph-4-Cl -S-t-Bu C(Me)2 5 -CH2Ph-4-Cl -S-t-Bu CH20CH(Me) 4 -CH2Ph-4-Cl H C(Me)2 6 Me -C(0)Ph-4-Cl C(Me)2 6 Me -CH2Ph-4-Cl C(Me)2 5 -CH2Ph-4-CI -O-i-Px C(Me)2 5 -CH2Ph-4-Cl -S-t-Bu CH(St) 5 -CH2Ph-4-Cl -C(0)-CF3 C(Me)2 5 -CH2Ph-4-CI -C(0)CH2-t-Bu CH(Me) 5 H -C(0)CH2-t-Bu C(Me)2 5 -CH2Ph-4-CF3 -C(0)CH2-t-Bu C(Me)2 5 -CH2Ph -C(0)CH2-t-Bu C(Me)2 5 -CH2Ph-3-0Me -C(0)CH2-t-Bu C(Me)2 5 -CH7CHCH- Z. L. -C(0)CH2-t-Bu C(Me)2 5 -CH2Ph-4-0Me -C(0)CH2-t-Bu C(Me)2 5 Me -C(0)CH2-t-Bu C(Me)2 6 H -CH2Ph-4-Cl C(Me )2 6 -S(0)2Ph -CH2Ph-4-Cl C(Me)2 6 -CH2Ph -CH2Ph-4-Cl C(Me)2 5 -CH2Ph-4-Cl -S(0)2-t-Bu C(Me)2 5 -CH2Ph-4-Cl -S(0 )-t-Bu C(Me)2 6 -ch2chch2 -CH2Ph-4-Cl C(Me)2 - 35 -TABLE II (cont.) Ex ATTACH r8 r5 y- (cr11r11 ■) No. POINT 5 43 6 -(ch2)2ch3 -CH2Ph-4-Cl C (Me 2 44 6 -ch2ch3 -CH2Ph-4-Cl C(Me 2 45 5 -CH2Ph-4-Cl -C(0)Ph-4-t-Bu C(Me 2 46 5 -CH2Ph-4-Cl -C(0)Ph-4-Cl C(Me 2 47 5 -CH2Ph-4-Cl -t-Bu C(Me 2 10 48 5 -CH2Ph-4-Cl -C(0)Me C (Me 2 4-9 5 -CH2Ph-4-Cl -C(0)-c-Pr C (Me 2 50 5 -CH2Ph-4-Cl -C(0)CH2CH2-c-C5 H9 C(Me 2 51 5 -CH2Ph-4-Cl -C(0)CH2CH(Me)2 C (Me O L 52 5 -CH2Ph-4-Cl -C(0)Et C (Me 2 15 53 5 -CH2Ph-4-Cl -C(0)CH(Me)2 C (Me 2 54 5 -CH2Ph-4-Cl -C(0)C(Me)3 C (Me 2 55 5 -CH2Ph-4-Cl -C(0)CH2Ph C (Me 2 56 5 -CH2Ph-4-F -C(0)CH2-t-Bu C(Me 2 57 5 -CH2Ph-4-Br -C(0)CH2-t-Bu C(Me 2 20 58 5 -CH2Ph-4-I -C(0)CH2-t-Bu C(Me 2 59 5 -CH2Ph-4-Cl -C(Me)2Pr C (Me 2 60 5 -CH2Ph-4-Cl -C(Me)2Et C (Me 2 61 5 -CH2Ph-3-F -t-Bu C(Me 0 L. 62 5 -CH2Ph-4-Cl -CH(Me)2 C (Me 25 63 5 -CH2Ph-4-Cl -c-Pr C'(Me 2 64 5 -CH2Ph-4-Cl -(1-Me)-c-Pr C (Me 2 65 5 -CH2Ph-4-Cl — c—C ^Hq C(Me o i. 66 5 -CH2Ph-4-Cl -c-C6HH C(Me o L. 67 5 -CH2Ph-4-Cl -C(Me)2Ph C (Me 2 30 68 5 -CH2Ph-4-Cl -C(Me)2Ph-4-Cl C(Me C 69 5 -CH2Ph-4-Cl -1-Ad C (Me o L 70 5 -CH2Ph-4-Cl -CH2-1-Ad C (Me 2 71 6 -t-Bu -CH2Ph-4-Cl C(Me 2 72 6 -C(Me)2Et -CH2Ph-4-Cl C(Me 2 73 5 -CH2Ph-4-Cl -C(0)CH2-t-Bu C (Et 2 2 4 8 ? 7 7 The invention is further defined by-reference to the following examples, which are intended to be illustrative and not limiting. All temperatures are in degrees Celsius. Example 1 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethvlpropanoic acid Step A: 3-[N-p-Chlo.robenzyl-3-(t-butylthio)-5- methoxyindol-2-yl]-2,2-dimethylpropanoic acid methyl ester To a solution of 39 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in a mixture of 300 mL of toluene and 150 mL of glacial acetic acid was added 15 g of NaOAc and 50 g of l-(4-methoxyphenyl)-l-(p-chlorobenzvl)hydrazine hydrochloride. The reaction was maintained with stirring at room temperature for 3 days under argon in the dark. The mixture was poured into 3, L of H2O and extracted with 3 x 500 mL of EtOAc. The ethyl acetate was washed with 3 x 500 mL of water then solid NaHC03 was added. The mixture was filtered and the filtrate washed twice with water. The organic phase was dried over MgSO^ and evaporated to dryness to provide the title compound, m.p. 102-103° C. Step B: 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid The compound from Step A was hydrolysed using 325 mL of THF, 600 mL of MeOH and 325 mL of 1.0M LiOH. The solution was heated to 80° C for 3 h. The solution was acidified with IN HC1 and extracted with 3 x 200 mL of EtOAc. The organic 24 § | - 37 - phase was washed with water (2 x 150 mL) and dried over MgSC>4. The solution was evaporated to dryness to provide the title compound, m.p. 190-191° C. 5 Anal C, H, N: Calc. C 65.27; H 6.57; N 3.04, Found C 65.28; H 6.58; N 3.04 Step C: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-10 propanoate A solution of 61 mL of t-butylthiol in 650 mL of dry HMPA at 0° C was treated portionwise with 26 g of 50% NaH in mineral oil after removal of oil with hexane. The reaction was stirred at RT for 30 mins and 46 g of the compound from Step B was added. The reaction was then heated under N2 at 175° C for 5 hours. The solution was cooled, and poured onto crushed ice, after which it was treated 20 with 2 N HCl to pH 5 and extracted with EtOAc (3 x 500 mL). The organic phase was washed with H2O (3 x 200 mL) dried (MgSO^) and evaporated. The residue was dissolved in 300 mL of ether and ethereal diazomethane was added until all acid was consumed. 2=; The excess solvent was removed and the oily residue triturated with hexane to leave a crystalline mass which was recrystallized from EtOAc/hexane to provide the title compound as a white crystalline solid, m.p. 170-171° C. From the mother liquors was isolated 30 methyl 3-[N-(p-t-butylthiobenzyl)-5-hydroxy-3- (t-butylthio)indol-2-yl]-2,2-dimethvl propanoate which was used as such in Example 3. 2 4 - 38 - Step D: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethvlpropanoate . Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate (33.6 g) from Step C was dissolved in 500 mL of dry DMF and the solution was charged with 2.4 g of KI, 30.3 g of K2C03, 4.77 g of Cs2C03 and 23.5 g of 2-(chloromethyl)quinoline hydrochloride. The reaction was stirred at RT, under N2, for 72 hours then it was poured into water (1.5 L), acidified with IN HCl and extracted (3 x 200 mL) with CH2C12- The organic phase was washed with H20 (3 x 150 mL), dried and evaporated. The residue was dissolved in hot EtOAc and upon cooling crystallized to deposit 22.0 g of the title compound, m.p. 166-167° C.. Step E: 3-[N-(p-Chlorobenzy1)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethvlpropanoic acid Using the hydrolytic procedure of Step B but substituting the ester of Step D for the ester of Step A provided the title compound, which was recrystallized from 1:1 EtOAc/hexane. m.p. 208°C. Anal C, H, N: Calc. C 69.55; H 6.01; N 4.77, Found C 69.77; H 6.05; N 4.70 3-[N-(p-Chlorobenzy1)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2- dimethvlpropanoic acid 5 Step A: N-Acetvl-4-(quinolin-2-ylmethoxv)aniline A mixture containing 2-(chloromethyl)-quinoline hydrochloride (100.0 g), 4-acetamido-phenol (70.69 g) and milled anhydrous potassium 10 carbonate (194 g) was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous stirring. After the ice had melted, the solid "was filtered and rinsed thoroughly with water. It was 15 recrystallized from 95% ethanol and filtered to give the title compound in three crops. Step B: 4-(Ouinolin-2-vlmethoxv)aniline 20 A suspension of N-acetyl-4-(quinolin -2-ylmethoxy)aniline (Step A, 108.9 g) in 1 L of 95% ethanol containing 10 M KOH (120 mL) was heated at reflux under nitrogen in a heating mantle. When the hydrolysis was complete (approx. 36 h), the 25 30 24 - 40 - reaction mixture was cooled and ethanol was partially removed under vacuum. The mixture was then diluted with water (200 mL) and the fine off-white crystals were collected and thoroughly rinsed with water. The material, after air-drying, yielded the title compound which was used as such in the next step. Step C: 4-(0uinolin-2-vlmethoxv)phenvlhydrazine A quantitiy of 84 g of 4-.(quinolin-2-ylmethoxy)aniline from Step B was -suspended in 300 mL of deionized E^O and 84 mL of 12 M HCl. The suspension was stirred vigourously to obtain a'fine particle suspension. Then a preccooled solution (5 °C) of 23.88 g of sodium nitrite dissolved in 75 mL of deionized H2O was added dropwise to the suspension ax 5°C over 25 minutes. The solution was stirred at 5°<T for 60 min to obtain the diazonium salt as a clear brown solution. The presence of excess HNO2 was confirmed by Kl-starch paper, ana the pH of the solution was about 3.0. If a white suspension persisted after 1 h, the mixture was filtered through a glass wool plug, to give the diazonium salt in the filtrate. In the meantime a sodium hydrosulfite solution was prepared by dissolving 321 g of sodium hydrosulfite (approx. 85% purity) in 2 L of deionized: water, and cooled at 0° to 5°C. To this solution were added 15 mL of 2N NaOH and 2 L of ether. The biphasic solution was kept near 0°C by additon of crushed ice and was stirred vigorously. To this solution was added dropwise the diazonium salt 10 24 - 41 - A quantity of 10 g of 4-(quinolin-2- -ylmethoxy)phenylhydrazine from Step C was added to a solution of 10.5 mL of diisopropylethylamine and 150 mL of CH2CI2• To the yellow suspension was added 9.11 g of p-chlorobenzyl chloride followed by 3.64 g of Bu^NBr and 50 mL of CI^C^- The reaction was stirred for approximately 24 hours. When no starting 20 material remained, the reaction was diluted with H2O and extracted 3 times with CE^C^- The combined organic phase was washed once with water and dried (MgS04>, filtered and evaporated to dryness. The solid residue was dried under vacuum overnight prior 25 to being swished in ether/methanol 90/10 to give the title compound as a pale yellow solid, m.p. 130°C. Step £: 3-[N-(p-Chlorobenzy1)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-3q dimethvlpropanoic acid 1 7 7 solution with stirring maintained throughout. At the end of the addition an orange solid was formed and 600 mL of NaOH (2N) was added over 30 minutes. The reaction was finally stirred for 60 minutes at 25°C. The solid was collected, suspended in ether (1 L) and filtered. The process was repeated with 2 L of water to yield the title compound as a pale yellow solid after freeze-drying overnight, m.p. 73-85°C (dec). Step D: l-(p-Chlorobenzy1)-l-[4-(quinolin-2-yl-methoxv)phenyl1hydrazine The methyl ester of the title compound was prepared according to the method described .in Step A 15 20 25 - 42 _ 24 of Example 1 but using the phenylhydrazine from Step D of Example 1A as starting material. The title compound was prepared under the conditions described in Step B of Example 1. 5 Example 2 3-[N-(p-Chlorobenzy1)-3-methy1-5-(quinolin-2-yl-methoxv)indol-2-vl1-2.2-dimethvlpropanoic acid 10 The title compound was prepared according to the method of Example 1, but using methyl 2,2-dimethyl-4-oxohexanoate as starting material in Step A in place of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate. m.p. 215-217° C. Example 3 3-[N-(p-t-Butylthiobenzy1)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The methyl ester byproduct from Step C of Example 1 was reacted 2-(chloromethyl)quinoline according to the conditions of Steps D &. E of Example 1 to provide the title compound, m.p. 172-173° C. Example 4 3-[N-(p-Chlorobenzy1)-3-(phenylthio)-5-(auinolin-2-vlmethoxy)indol-2-vll-2.2-dimethvlpropanoic acid 30 The title compound was prepared according to the method described for Example 1, but substituting methyl-5-phenylthio-2,2-dimethyl-4-oxopentanoate for 77 10 - 43 - methyl 5-t-butylthio-2,2-dimethyl-4-oxopentonoate in Example 1 (Step A). Anal. C, H, N for sodium salt- 2 H£0: Calc. C 64.91; H 5.30; N 4.20 Found C 64.94; H 5.04; N 4.15 Example 5 3-[N-(p-Chlorobenzy1)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid. N-oxide Methyl 3-[N-(p-chlorobenzyl)-3-(phenylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-15 dimethyl propanoate (430 mg) from Step D of Example 4 was dissolved in 5 mL cold and treated with a solution of 448 mg of 807o m-chloroperbenzoic acid (MCPBA) in CH2CI2• After 24 hours, the solution was poured onto 10 mL of sat. aqueous NaHCC^ solution, 20 extracted with 3 x 10 mL of CH2CI2, washed with 2 x 10 mL of H2O, dried with magnesium sulfate and evaporated to dryness. The residue was crystallised from 2:1 CE^C^/EtOAc to yield 280 mg of the title compound as its methyl ester. Hydrolysis using the 2c conditions described in Example 1 (Step B) provided the title compound, m.p. 197° C (dec.) Anal. C, H, N: Calc. C 66.0; H 4.77; N 4.28 Found C 66.06; H 4.77; N 4.19. 30 _ 44 _ 2 4 Examples 6 and 7 3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid and 5 3-[N-(p-Chlorobenzy1)-3-(phenylsulfinyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid Methyl 3-[N-p-chlorobenzyl-3-(phenyl 1q thio)-5-(quinolin-2-methoxy)indol-2-yl]-2,2- dimethyl propanoate (430 mg) from Example 4 (Step D) was dissolved in 5 mL of cold methylene chloride and a solution of 150 mg of 807» (MCPBA) in methylene chloride was added. After 24 hours, the reaction ■[_- solution was poured onto 10 mL of saturated aqueous sodium bicarbonate solution and this mixture was extracted 3 times with 10 mL of methylene chloride. The combined organic phases were washed twice with 10 mL of water, dried with magnesium sulfate and 20 evaporated under vacuum. Chromatography over silica gel (2 hexane: 1 ethyl acetate) provided two compounds which were separately hydrolyzed using the procedure described in Example 1 (Step B). 2 c 3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2.2-dimethylpropanoic acid: Anal. C, H, N for sodium salt" B^O: Calc. C 63.57; H 4.89; N 4.12 Found C 63.28; H 4.77; N 3.90 30 24 8 1 - 45 - . 3-[N-(p-Chlorobenzyl)-3-(phenylsulfinyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid : Anal. C, H, N for sodium salt- H2O: 5 Calc. C 63.38; H 5.17; N 4.11 Found C 63.28; H 4.89; N 3.97 Examp1e 8 3-[N-(p-Chlorobenzyl)-5-(quinolin-2-ylmethoxy)- 10 indol-2-vl"l-2.2-dimethvlpropanoic acid Step A: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxyindol-2-vl~l-2 .2-dimethvlpropanoate A suspension of 1.0 g of 3-[N-(p-chloro-15 benzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2- dimethylpropanoic acid (from Example 1 Step B) in 50 mL of CH2CI2 was treated with 1.3 mL of ethanethiol and 3.47 g of AICI3 at 0°C under argon. After 40 min the mixture was poured onto 50 mL IN HCl, extracted 20 with 3 x 50 mL of CH2CI2 washed with 2 x 50 mL of H2O, dried with MgS04 and the solvent removed. The residue was dissolved in 10 mL ether and ethereal diazomethane added until all the acid was consumed. The excess solvent was removed and the residue 25 chromatographed on silica gel to afford the title compound. Step B: 3-[N-(p-Chlorobenzyl)-5-(auinolin-2-yl- methoxy)indol-2-yl]-2,2-dimethylpropanoic 3 0 acid The title compound was prepared by treating 24 - 46 - the ester from Step A with 2-(choromethyl)quinoline hydrochloride under the conditions of Step D and effecting hydrolysis under the conditions of Example 1 (Step B), m.p. 193-194'C. 5 Example 9 3-[N-(p-Chlorobenzy1)-3-benzoyl-5-(quinolin-2-yl-methoxv) indol-2-vl~l-2 . 2-dimethvlpropanoic acid Step A: Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-10 benzovloxvindol-2-vn-2.2-dimethvlpropanoate Methyl 3-[N-(p-chlorobenzy1)-5-hydroxy indol-2-yl]-2 , 2-dimethylpropanoate (609 mg) frcTm Example 8 (Step A) was dissolved in 10 mL of 15 1,2-dichloroethane and the solution charged with 0.5 mL of benzoyl chloride and 680 mg of AICI3. The reaction was heated to 80° C under argon for 1.5 h, then quenched with 20 mL of 0.5N Na, K tartrate solution, extracted with 3 x 20 mL of ether, washed 20 with 10 mL of H2O and dried (MgSO^.). Removal of solvent provided an oily residue which was chromatographed on silica gel to give the title compound .' 25 Step B: Methyl 3-[N-(p-chlorobenzyl)-3-benzovl-5-hvdroxyindol-2-yl~l-2 .2-dimethvlpropancate The compound from Step A (300 mg) was dissolved in 4 mL of MeOH and treated with 1 mL of a 30 1.4 M solution of NaOMe in MeOH under argon for 3 hrs. The mixture was poured onto 20 mL of NH4OAC (257„ solution), extracted with 3 x 15 mL of ether, 24 8 1 - 47 - washed with 10 mL of H20, dried over MgS04 and the solvent removed under vacuum. The resulting oil was purified by chromatography on silica gel to afford the title compound. 5 Step C: 3-[N-(p-Chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethyl-propanoic acid 10 The title compound was prepared using the conditions described in Step D and Step E of Example 1, but substituting the ester from Step B for the ester of Example 1 , Step C; m.p. 165-166°C. Example 10 3-[N-(p-Chlorobenzyl)-3-benzy1-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid Step A: Methyl 3-[N-(p-Chlorobenzyl)-3-benzyl-5-20 (benzoyloxy)indol-2-yl]-2,2-dimethyl- propanoate Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-(benzoyloxy)indol-2-yl]-2,2-dimethyl-,5 propanoate (360 mg) (prepared in Step A of Example 9), 800 mg of Znl2, and 500 mg of sodium cyanoborohydride were stirred in 5 mL of dichloroethane at RT under argon for 30 min. The temperature was then raised to 65° C for 3 hr. After jo the solution had cooled, it was poured onto 10 mL of NH^OAc (257. solution), extracted with 3 x 15 mL of ether, washed with 10 mL of H2O and dried (MgSO^). *) ' 24 8)7 - 48 - The solution was evaporated to dryness and the residue was chromatographed on silica gel to yield the title compound as a white foam. 5 Step B: 3-[N-(p-Chlorobenzyl)-3-benzyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The title compound was prepared under the 10 conditions described in Step B and Step C of Example 9 but substituting the ester from Example 10 (Step A) for the ester of Example 9 (Step A), m.p. 178°C. Example 11 3-[N-(p-Chlorobenzy 1 )-3-(3 , 3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethvlpropanoic acid The title compound was prepared according to 20 the method described in Example 9, but using t-butylacetylchloride in place of benzoyl chloride in Step A, m.p. 183-184°C. Examp1e 12 25 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin- 2-vlmethoxv)indol-2-vl1ethoxvethanoic acid Step A: Methyl 2-[N-(p-Chorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indcl-2-yl] ethanoate 30 The title compound was prepared according to the method outlined in Steps A-D of Example 1, but 24 a 1 77 - 49 - using methyl 4-t-butylthio-3-oxo-butanoate in Step A instead of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate. 5 Step B: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-vlmethoxv)indol-2-vl1ethanol The compound from Step A (192 mg) was dissolved in 3 mL of THF at RT under an argon 10 atmosphere and treated with 30 mg of lithium aluminum hydride. After 1 hr, the reaction was poured onto 10 mL of 0.5 N Na,K tartrate solution and extracted with 3 x 10 mL of EtOAc. The organic layer was washed with 10 mL of H2O, dried (MgSO^.) and evaporated to 15 dryness to yield the title compound. Step C: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxy-ethanoic acid 20 To 91 mg of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yi]ethanol from Step B in 2 mL THF at 0° C under an argon atmosphere was added 40 mg of 807. sodium 25 hydride over 30 min. Ethyl bromoacetate (0.3 ml) was added to the solution and the reaction stirred at RT overnight. The reaction was poured onto 10 mL of NH^OAc (257. solution), extracted with 3 x 10 mL of EtOAc, washed with 20 mL of H2O and dried over 30 MgSO^. Removal of the solvent followed by column chromatography on silica gel afforded the ethyl ester of title compound. Hydrolysis of this ester under 24 0 1 - 50 - the conditions described in Step B of Example 1 provided the title compound, m.p. 185°C (dec.). Example 13 5 3-[N-(p-Chlorobenzyl)-3-(3,3-dimethyl-l- butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2.2-dimethvlpropanoic acid The title compound was prepared according to 10 the method described in Example 10 but using methyl 3-[N-(p-chlorobenzyl)-3-(3,3-dimethy-l-oxo-l-butyl)-5-(t-butylacetyloxy)-indol-2-yl]-2,2-dimethylpropanoate (obtained as an intermediate"from Example 11) as starting material, m.p. 188°C (dec.). 15 Examp1e 14 3-[N-(p-Chlorobenzyl)-3-(t-butylthi.o)-5-(quinolin-2-vlmethoxv)indol-2-vll-2-methvlpropanoic acid 20 The title compound was prepared according to the method of Example 1 using methyl 5-t-butyl-thio-2-methyl-4-oxopentanoate as starting material in Step1 A in place of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate. 25 1H NMR (250 MHz, acetone-d6) S 1.05 (3H, d, J = 6Hz), 1.15 (9H, s), 2.7 (1H, m), 3.2 (2H. d. J = 7Hz), 5.4 (2H, s), 5.6 (2H, s), 6.9 (1H, dd), 7.0 (2H, d), 7.3 (4H, m), 7.6 (1H, td), 7.7 (1H, d), 7.8 (1H, td), 7.9 (1H, d), 8.1 (1H, d), 8.3 ppm (1H, d). 30 - 51 - Example 15 3-[N-(p-Chlorobenzyl)-3-methyl-5-(6,7-dichloro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-5 propanoic acid The title compound was prepared according to the method described in Example 1 but using methyl 2,2-dimethyl-4-oxohexanoate as starting material in 10 Step A and 2-(bromomethyl)-6,7-dichloroquinoline in Step D. Anal. C, H, N: Calc. C 63.21; H 4.74; N 4.91 ~ Found C 63.47; H 4.94; N 4.67 15 Example 16 3-[N-(p-Chlorobenzy1)-3-methyl-5-(7-chloroquino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid 20 The title compound was prepared according to the method described in Example 15 but using 2-(bromomethyl)-7-chloroquinoline instead of 2-(bromomethyl)-6,7-dichloroquinoline. m.p. 25 105-107"C. Anal. C, H, N: Calc. C 67.41; H 5.24; N 5.24 Found C 67.82; H 5.12; N 4.32 3 0 Examn1e 17 3-[N-(p-Chlorobenzy1)-4-allyl-5-(quinolin-2-yl-methoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid 24 - 52 - Step A: Methyl 3-{N-(p-chlorobenzyl)-5-allyloxy-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid 5 500 mg. of methyl 3-[N-(p-chlorobenzyl)-5- hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate from Step C of Example 1 was dissolved in 5 mL of DMF and 20 mg of K2CO3 and 150 mg of allyl bromide were added. The reaction was stirred for 16 10 hrs. Water was added and the organic phase extracted with. EtOAc (3 x 5mL). The organic phase was dried with MgS04 and evaporated to yield, after chromatography on silica gel (EtOAc:hexane 1:57, the title compound. 15 Step B: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-allyl-5-hydroxyindol-2-yl]-2,2-dimethyl-propanoate 500 mg of the ester of Step A was converted to the title compound by heating to 180° in m-xylene for 4 hours. Step C: 3-[N-(p-Chlorobenzy1)-4-ally1-5-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethvlpronanoic acid The title compound was prepared from the compound of Step B using the methodology of Example 1, (Steps D and E), m.p. 103-105°C. Anal. C, H, N: Calc. C 69.09; H 6.11; N 4.35 Found C 70.55; H 6.31; N 4.29 24-8 - 53 -Example 18 3-[N—(p-Chlorobenzy1)-4-allyl-5-(quinolin-2-yl-methoxv)indol-2-vll-2.2-dimethvlpronanoic acid The methyl ester of the title compound was prepared according to the method of Example 17 but substituting methyl 3-[N-(p-chlorobenzyl)-5-hyaroxyindol-2-yl]-2,2-dimethylpropanoate as starting material (obtained in Step A Example 8) for the ester in Example 17 (Step A). Hydrolysis was then effected according to the conditions of Step B of Example 1 to provide the title compound, m.p. 196-197°C (dec.). Example 19 3-[N-(p-Chlorobenzy1)-6-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared according to the conditions of Example 1, Steps A to E, but substituting l-(3-methoxyphenyl)-l-(p-chloro-benzyl)hydrazine hydrochloride for the starting material in Example 1 (Step A). Chromatographic separation of the desired regioisomer was achieved at Step A by isolating the most polar product, methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-6-methoxy-indol-2-yl]-2,2-dimethylpropanoate. The properties of the title compound were as follows: m.p. 165-167 °C. Anal C, H, N: Calc. C 69,54; H 6.01: N 4.77 Found C 69.46; H 6.18; N 4.96 20 24 8 1 7 7 - 54 - Example 20 3-[N-(p-Chlorobenzy1)-4-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid 5 Methyl 3-[N-(p-chlorobenzy1)-3-(t-butylthio)-4-methoxyindol-2-yl]-2,2-dimethylpropanoate was obtained as a by-product from Step A of Example 19 and isolated by chromatography as the less polar 10 product. The compound was used as starting material for the preparation of the title product using the methodology of Steps B to E of Example 1. Anal C, H, N: Calc. C 69.54; H 6.01; N 4.77; 15 Found C 69.80; H 6.24; N 4.86 Example 21 3-[N-(p-Chlorobenzy1)-3-(t-butylthio)-7-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid : The title product was prepared according to Steps A to E of Example 1 but substituting l-(2-methoxyphenyl)-l-(p-chlorobenzy1)hydrazine 25 hydrochloride for l-(4-methoxyphenyl)-l-(p- chlorobenzyl hydrazine hydrochloride in Example 1 (Step A), m.p. 206 °C . 30 Anal. C, H, N: Calc. C 69.54; H 6.01; N 4.77, Found C 69.40: H 5.88; N 4.65 _ 55 _ Example 22 2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quino-lin-2-ylmethoxy)indol-2-yl]ethoxy]propanoic acid sodium salt dihvdrate Step A: Methyl 2-[2-[N-(p-chlorobenzyl)-3-(t-butyl-thio)-5-quinolin-2-ylmethoxy)indol-2-yl]-ethoxvlpropanoate The title compound was prepared from 251 mg of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethanol (Step B of Example 12) under the conditions described in Step C of Example 12 using methyl D,L-2-bromopropanoate instead of ethyl bromoacetate. Step B: 2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxy]-propanoic acid sodium salt dihvdrate The acid corresponding to the title compound of Example 22 was prepared from the ester of Step A of Example 22 under the conditions described in Step B of Example 1. A quantity of 204 mg of the acid was suspended in 1.5 mL of EtOH and treated with 1 equiv. of IN aq. NaOH and freezed dried for 2 days to afford the title compound. Anal. C, H, N: Calc. C 61.25; H 5.61; N 4.33, Found C 61.75; H 5.70; N 3.97 24 - 56 - Example 23 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-ylmethoxy)-indol-2-yll-2.2-dimethvlpropanoic acid 5 Step A: Methyl 3-[N-(p-chlorobenzyl)-4- hvdroxyindol-2-vll-2.2-dimethvlpropanoate The title compound was prepared using methodology from Step A of Example 8 but substituting 10 3" [N-(p-chlorobenzy1)-3-(t-butylthio)-4-methoxy indol-2-yl]-2,2-dimethylpropanoic acid (Step B of Example 20) for the propanoic acid in Example 8 (Step A) . 15 Step B: 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-yl- methoxy)indol-2-yl]-2,2-dimethylpropanoic acid The title product was prepared according to 2q conditions described in Steps D and E of Example 1 substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy indol-2-yl]-2,2-dimethylpropanoate for the propanoate in Example 1 (Step D), m.p. 158-160°C. 25 Anal. C, H, N: Calc. C 72.20; H 5.45;' N 5.61 Found C 72.25; H 5.60; N 5.75 30 Example 24 3-[N-Methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-y1-methoxv)indol-2-vl1-2.2-dimethylpropanoic acid 24 - 57 - Step A: Methyl 3-[6-methoxy-3-(t-butylthio) indol-2-vll-2.2-dimethvlpropanoate A mixture of 4.2 g of 3-methoxyphenyl-5 hydrazine hydrochloride and 4.9 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in 100 mL of t-butanol was refluxed for 18 hours. The mixture was cooled to R.T., and evaporated to dryness. The residue was suspended in ether (150 ml) and stirred for 30 min. The salts were filtered and the filtrate evaporated to dryness to give a residue which was chromatographed on flash silica gel using as eluant ethyl acetate:toluene (1:99) to isolate the title compound as the most polar product; m.p. 133°C. 15 Step B: Methyl 3-[N-methyl-3-(t-butylthio)-6- methoxvindol-2-vl1-2.2-dimethvlpropanoate A solution of 1.75 g of the indole from Step 2Q A in 30 mL of THF and 3 mL HMPA was cooled to -78°C and to this solution was slowly added a solution of 0.54M KHMDS in toluene (10.2 mL). The mixture was stirred at this temperature for 15 min. and treated with 0.34 mL of iodomethane. The mixture was stirred 25 at -78°C for 5 h, quenched with IN HCl (100 mL), extracted with ethyl acetate, and the organic layer washed with H2O, dried over Na2S04 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as 20 eluant to afford the title compound as a solid; m.p. 97-98 °C. 24 - 58 - Step C: Methyl 3-[N-methyl-6-hydroxyindol-2-yl]-2.2-d imethvlpropanoat e To a cold solution of 940 mg of the indole 5 ester from Step B and 1.6 mL of ethanethiol in CH2CI2 (50 mL) was added portion-wise 4.3 g of AICI3. After complete addition, the mixture was stirred at R.T. for 2 h. The mixture was then cooled to 0°C and carefully quenched with a solution of 0.5 M Na,K 10 tartrate (200 mL) and extracted with CB^C^- The organic layer was dried over Na2SC>4 and evaporated to dryness to give a solid which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to afford the title compound; m.p. 15 125-126 °C. Step D: Methyl 3-[N-methyl-6-(p-chlorobenzoyloxy)-3-(p-chlorobenzoyl)indol-2-yl]-2,2-di-methvlpropanoate 20 To a cold solution of 393 mg of hydroxy indole from Step C in 5 mL of THF were added 0.31 mL of Et3N followed by 0.21 mL of p-chlorobenzoyl . chloride. The mixture was stirred at R.T for 15 min 25 and quenched with H2O. The mixture was extracted with ethyl acetate which was dried over Na2SC>4 and evaporated to dryness to give a solid which was dissolved in 10 mL of 1,2-dichloroethane. To this mixture were added successively at R.T. 0.38 mL of 3Q p-chlorobenzoyl chloride and 803 mg of AICI3. The mixture was heated at 80°C for 3 h, cooled to R.T. and quenched with 50 mL of 0.5 N HCl. The mixture was extracted with CH2C12, washed with ^0, 24 8 - 59 - dried over Na2S04 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as eluant to afford the title compound as a white solid, m.p. 138°C. 5 Step E: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-hvdroxvindol-2-vll-2.2-dimethvlpropanoate To a suspension of 270 mg of the p-chlorobenzoate 10 from Step D in 3 mL of MeOH was added 1.2 mL of a solution of 1.3M NaOMe in MeOH and the mixture was stirred at R.T. for 2 hr. The reaction mixture was poured onto 25% aq. NH^OAc and extracted with ethyl acetate. The organic extract was dried over Na2S04, 15 evaporated to dryness and the residue chromatographed on flash silica gel using ethyl acetate:hexane (40:60) as eluant to afford the title compound as a yellow foam. 20 Step F: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-ylmethoxy)indcl-2-yl]-2.2-dimethvlpror>anoate To a solution of 180 mg of the phenol from ?5 Step E in 5 mL of DMF were added 124 mg of milled K2CO3 followed by 150 mg of 2-(bromomethyl) quinoline. The mixture was stirred at R.T. for 18 h, poured onto 25% aq. NH4OAC and extracted with ethyl acetate. The extract was dried over Na2S04 and 50 evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam. 24 8 1 - 60 - Step G: 3-[N-Methy1-3-(p-chlorobenzoyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid 5 To a solution of 230 mg of ester from Step F in 1.5 mL of THF and 3 mL of MeOH was added 1M aq. LiOH and the mixture stirred at 80°C for 4 h. The mixture was cooled to R.T. and evaporated to dryness in vacuo. The residue was dissolved in a mixture of 10 20 mL of 257o aq. NH^OAc and 20 mL of ethyl acetate using vigourous stirring. The organic layer was separated, dried over Na2SC>4 and evaporated to dryness to give a yellow solid (216 mg). This-solid was swished for 2 h in 5 mL of a mixture of Et20:hexane (1:1). The solid was filtered and rinsed with a 1:2 mixture of Et20:hexane to give the title product as a yellow solid, m.p. 203-205°C. Anal. C, H, N: Calc. C 70.65; H 5.16; N 5.32; 20 Found C 70.42; H 5.25; N 5.40 Example 25 , 3-[N-Methy1-3-(p-chlorobenzyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid, 25 'sodium salt hemihvdrate Step A: Methyl 3-[N-methyl-3-(p-chlorobenzyl)-6- (p-chlorobenzoyloxv)indol-2-yl]-2,2-dimethyl-propanoate 30 To a solution of 500 mg of the benzoyl derivative from Step D of Example 24 in 10 mL of 24 8 1 4 ^ _ 61 _ 1,2-dichloroethane were added 1.19 g of Znl£ and 700 mg of NaBE^CN. The mixture was heated at 65°C for 5 hours and cooled to R.T. The mixture was quenched with IN aq. HCl and extracted with CH2CI2• The extracts were washed with brine, dried over Na2S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (15:85) as eluant to isolate the title compound as a white foam. Step B: Methyl 3-[N-methyl-3-(p-chlorobenzyl)- 6-hvdroxvindol-2-yll-2.2-dimethvlpropanoate To a suspension of 425 mg of p-chlorobenzoate from Step A in 3 mL of MeOH was added 1.9 mL of a solution of 1.3M NaOMe in MeOH. The mixture was stirred at R.T. for 1 h, poured into 20 mL of 257, aq. NH^OAc, and extracted with ethyl acetate. The organic extract was dried over Na2S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a white foam. Step C: Methyl 3-[N-methyl-3-(p-chlcrobenzyl)- 6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethvlpropanoate To a solution of 315 mg of the ester from Step B in 3 mL of DMF were added 225 mg of milled K2CO3 and 272 mg of 2-(bromomethyl)quinoline. The mixture was stirred at R.T. for 18 h, poured into 257, aq. NH^OAc, and extracted with ethyl 10 20 30 2 - 62 - acetate. The organic extract was dried over Na£S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam. Step D: 3-[N-Methy1-3-(p-chlorobenzy1)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid, sodium salt hemihvdrate To a solution of 367 mg of the ester from Step C in 3 mL of THF and 6 mL of MeOH was added 1 M aq. LiOH and the mixture was heated at 80°C for 2 h. The mixture was cooled to R.T. and evaporated to ■, 5 dryness. The residue was dissolved in a mixture of 20 mL of 25% aq. NH^OAc and 20 mL of ethyl acetate (vigourous stirring required). The organic layer was separated, dried over Na£S04 and evaporated to dryness to give a white solid (346 mg). The solid was swished at R.T. for 2 h with 10 mL of a mixture of Et20:hexane (1:1), filtered, rinsed with a mixture of (1:2) Et20:hexane and the solid collected to give the title compound as its free acid, a white solid: m.p. 185°C . The title compound was prepared by-dissolving the above acid in 1 mL of EtOH to which 0.63 mL of IN aq. NaOH was added. The mixture was freeze dried for 2 days to give the title product as a white solid. Anal. C, H, N: Calc. C 67.32; H 5.29; N 5.07; Found C 67.15; H 5 . 35 ; N 5.17 7 77 63 - EXAMPLE 26 3-[N-(4-Chlorobenzy1)-3-i-propoxy-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid 5 The title compound is prepared according to the method of Example 1, but using methyl 5-i-propoxy-2,2-dimethyl-4-oxopentanoate as starting material in Step A in place of methyl 5-t-butylthio-2,2-dimethyl-10 4-oxopentanoate. EXAMPLE 27 3-[N-(4-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-15 vlmethoxv)indol-2-vll-2-ethvlpropanoic acid Step A: Methvl 4-chloro-2-ethvl-4-pentenoate A 2L 3-necked flask equipped with a mechanical stirrer, pressure equalizing addition funnel, and nitrogen inlet was charged with diisopropylamine (28 mL, 200 mmol) and dry THF (400 mL). The mixture was cooled to 0°C and a 1.6 M solution of butyl lithium in hexane (125 mL, 200 mmol) was then added over a 15 minute period and stirring was continued for an additional 45 minutes. The resultant solution of lithium diisopropylamide (200 mmol) was cooled to -78°C and then butyric acid (9.1 mL, 100 mmol) was added over a 15 minute period. The reaction was allowed to warm to room temperature (1 hour) and then heated at 55°C for 3.5 hours. The resultant gel was cooled to -78°C and then treated 2,3-dichloro-l-propene (10.1 mL, 110 mmol) over a 15 minute period. The mixture was then 20 30 2 - 64 - allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with Et20 (400 mL), extracted with H2O (400 mL) and with NaOH 5 IN (300 mL). The aqueous layers were combined, acidified with HCl (2N, until pH 1-2) and the product was extracted with EtOAc (2 x 300 mL). The organic layers were combined, washed with brine (200 mL) and dried over MgSO4. Filtration and concentration gave 10 a yellow oil which was dissolved in dry MeOH (150 mL) and acetyl chloride (1 mL) was added dropwise. The resultant solution was gently refluxed for 20 hours. The reaction was allowed to cool to room temperature and it was concentrated'. The resultant residue was diluted with Et20 (600 mL), washed with NaHCC^ sat. (200 mL), washed with brine (200 mL), and dried over MgSO^. Filtration and concentration gave a yellow oil which was purified by Kugelrohr distilation (bp 110°C at 0.2 mm Hg) to give pure (250 MHz NMR) methyl 20 4-chloro-2-ethyl-4-pentenoate. Step B: Methvl 5-bromo-2-ethvl-4-oxopentanoate To a cold (08C) solution of methyl 4-chloro-2-ethyl-4-pentenoate from Step 2 (1.67 g, 25 9.5 mmol) in MeOH (31 ml) and H20 (16 ml) was added Br2 dropwise (0.60 mL, 11.6 mmol). The resulting yellow solution was stirred at room temperature for 1 hour. EtOAc (300 mL) and H2O (200 mL) were added. The organic layer was separated, washed with H2O, IN 20 NaOH, H2O, brine and dried over MgS04. Filtration and concentration gave a yellow liquid which was purified by flash chromatography (EtOAc/Hexane (1:9)) to give pure (NMR 250 MHz) methyl 5-bromo-2-ethyl-4-oxopentanoate. 2 d _ 65 _ Step C: Methyl 5-(t-butylthio)-2-ethyl-4- oxopentanoate To a cold (0°C) stirred solution of the bromoketone from Step 2 (490 mg, 2.07 mmol), in 10 mL 5 of dry THF, were sequentially added 2-methyl-2-propyl thiol (0.30 mL) and triethylamine (0.40 mL, 2.9 mmol). The reaction mixture was then allowed to warm to room temperature. After 18 hours the white solid was removed by filtration and the filtrate was 10 concentrated. The resulting yellow residue was purified by flash chromatography (Et20/Hexane C9:50)) to give the pure title compound (250 MHz NMR). Step D: 3-[N-(4-Chlorobenzyl)-3-(t-butylthio)-15 5-(quinolin-2-yl-methoxy)indol-2-yl]- 2-ethvlpropanoic acid. The title compound was prepared according to the method of Example 1, but using methyl 5-t-butylthio-2-ethyl-4-oxopentanoate as starting 20 material in Step A in place of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate. Anal. C, H, N, for sodium salt • 2^0: Calc. C 63.30; H 5.94; N 4.34 Found. C 63.29; H 5.87; N 4.37 The sodium salt of the title compound in this and other Examples was prepared by the method of Example 25. 25 30 24 8 1 - 66 - EXAMPLE 28 3-[N-(4-Chlorobenzyl)-3-trifluoroacetyl-5-(quinolin-2-vlmethoxv) indol-2-vl~l-2.2-dimethvlpronanoic acid Step A: Methyl 3-[N-(4-chlorobenzyl)-3-trifluoroacetyl-5-hydroxyindol-2-yl]- 2.2-dimethvlpropanoate Methyl 3-[N-(4-chlorobenzyl)-5-hydroxy indol-2-yl]-2,2-dimethylpropanoate (310 mg) from Example 8 (Step A) was dissolved in 3 ml of 1,2-dichloroethane and the solution charged with 0.6 ml of trifluoroacetic anhydride and 500 mg of AICI3. The reaction was stirred at RT, under argon for 4'n, then quenched with 20 mL of 0.5 N Na, K tartrate solution* extracted with 3x20 ml of Et20, washed with 10 mL of .H2O and dried over MgSO^. Removal of solvent provided an oily residue which was chromatographed on silica gel to give the title compound. Step B: 3-[N-(4-Chlorobenzyl)-3-trifluoroacetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- propanoic acid. The title compound was prepared using the conditions described in Step D and Step E of Example 1, but substituting the ester from Step A for the ester of Example 1, Step C. 30 Anal. C, H, N. for sodium salt • 7H2O Calc. C 51.72; H 5.29; N 3.76 Found. C 51.81; H 5.19; N 3.73 24 - 67 - EXAMPLE 29 3-[N-(4-Chlorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2-methylpropanoic acid 5 Step A: Methyl 5-(t-butylthio)-2-methyl-4- oxopentanoate The title compound was prepared according to the method described in Example 27, but using 10 propionic acid as starting material in Step A in place of butyric acid. Step B: 3-[N-(4-Chlorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl ) -5- (qui noli n-2-ylmethoxy) indo 1-2- vll-2-methvlpropanoic acid The title compound was prepared according to the method described in Example 11, but substituting 5-t-butylthio-2-methyl-4-oxopentanoate as starting material in Example 1 Step A in place of methyl 2Q 5-t-butylthio-2,2-d imethyl-4-oxopentanoate. Anal. C, H, N, for sodium salt • 1.5 0 Calc. C 66.50; H 5.90; N 4.43 Found. C 66.58; H 5.87; N 4.40 25 EXAMPLE 30 3—[3—(3,3-Dimethyl-l-oxo-l-butyl-5-(quinolin-2-ylmethoxv)indol-2-vll-2.2-dimethvlpropanoic acid 30 Step A: Methyl 3-[3-(t-butylthio)-5-methoxy indol-2-vl1-2.2-dimethvlpropanoate 2 4 8 1 - 68 - A mixture containing 4-methoxyphenyl hydrazine'HCl (70.66 g, 0.405 mol) and methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate (99.54 g, 0.405 mol) in tBuOH (400 ml) was heated at a 5 gentle reflux for 48 hours. The mixture was allowed to cool to RT and the precipitated NH^Cl was removed by filtration. The residue was concentrated and fractionated on a plug of silica using EtOAc/hexane (1:3) as eluent. Evaporation of the appropriate 10 fraction gave an orange-brown solid which was crystallized from EtOH (100 ml). Yield from two crops afforded 55.6g of the title compound. 1H NMR (CD3COCD3): 5 1. 20(s, 6H); 1.25 (s, 9H) 3.33 15 (s, 2H); 3.62 (s, 3H); 3.81 ppm (s, 3H); in addition to aromatic protons. Step B: Methyl 3-[5-hydroxyindol-2-yl]- 2.2-dimethvlpropanoate 20 To a solution of the compound from step A (25.50 g, 73 mmol) in CH2CI2 (250 ml) at 0°C was added AICI3 (87.70 g, 9 mol ea.) portion-wise. When the addition was complete, the ice-bath was removed and the mixture was stirred at RT for 3 hours. EtSH 25 (27 ml, 5 mol eq.) was added and the resulting mixture was stirred for a further 5 hours. It was then slowly poured onto an ice-cold 1M solution of Na, K tartrate. The product was extracted into CH2CI2 (x2) and the organic phase was washed with aq. 30 NaCl (x3). Conventional work-up followed chromatography on silica gel using EtOAc/hexane 1:5 - 69 - to 3:2 afforded 13.60 g of the title compound, 75% yield. 1H NMR (CDC13): 5 1.26 (s, 6H); 2.95 (s, 2H); 3.72 (s, 3H); 6.11 (s, 1H); 6.71 (bd, 1H); 6.95 (s, 1H); 7.16 (d, 1H); 7.26 ppm (s, 1H) Step C: Methyl 3-[5-(quinolin-2-ylmethoxy)- indol-2-vll-2.2-dimethvlpropanoate . A mixture of the phenol from step B (13.62 g, 55.14 mmol) and 2-bromomethylquinoline (12.85 g, 1.05 mol eq.) and anhydrous K2CO3 (15.22 g, 2 mol. eq.) in DMF (40 ml) was stirred at RT for 48 hours. The mixture was then poured onto ice/water and after all the ice had melted, the brown solid was collected and air-dried. The dried material was passed through a plug of silica (using EtOAc/hexane (1:3) as eluent) to remove the color; yield: 19 g, 88%. Recrystallization from EtOH afforded 14.17g of pure title compound, m.p. 131-132°C. Step D: Methyl 3—[3 — (3,3-dimethyl-l-oxo-l-butyl) 5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- ropanoate To a suspension of A1C13 (5.7 g, 42 mmol) in CH2CI2 (30 mL) at 0°C was added 3,3-dimethylbutanoyl chloride (2.4 mL. 17 mmol). After 15 minutes at 0°C, a solution of the ester from step C (3.0 g, 7.7 mmol) in CH2Cl2 (10 mL) was added by double-tipped needle. The mixture was stirred a further 20 minutes, at which point it was poured into a mixture of 0.5 M _ 70 _ Na, K tartrate (150 mL) and ice (100 g). The product was extracted with EtOAc, and the organic layer was washed successively with 0.5 M NaK tartrate, H2O, and brine. The solvent was then removed and 5 yellow/orange oil (3.5 g) was used without purification in the following step. Step E: 3 — [3 — (3,3-Dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2- ]_0 dimethvlpropanoic acid The crude ester from step D was dissolved in a mixture of MeOH (20 mL), THF (20 mL), and H2O (5 mL). To this was added 10 M NaOH (2.3 mL, 23 mmol). After stirring for 3 hours, the solution was cooled to 0°C, and HOAc (1.5 mL) was added dropwise. The solution was partly concentrated to remove the THF and MeOH, and the product was then extracted into EtOAc. The organic layer was washed with H20 and brine. After drying (MgSO^), the solution was 20 filtered and evaporated to give a pale orange solid. The product was stirred vigourously with a mixture of isopropanol (30 mL) and H2O (3 mL) to give the title compound as an off-white amourphous solid (2.6 g). mp= 193-196°C (dec) 25 EXAMPLE 31 methvlpropanoic acid The product from Example 30 (100 mg, 0.21 - 71 - mmol) and 4-trifluoromethylbenzyl bromide (98 mg, 0.41 mmol), and methyltrioctylammonium chloride (83 mg, 0.21 mmol) were dissolved in a mixture of 50% NaOH (2 mL) and benzene (0.5 mL). After vigourous 5 stirring for 3.5 hours, the reaction mixture was cooled to 0°C and was acidified with HOAc (2 mL). The product was extracted with EtOAc, and the organic layer was washed with H2O and brine. Following evaporation of the solvent; the residue was purified 10 by flash chromatography on silica gel, eluting with 1:5 EtOAc/hexane containing VL HOAc. The resulting yellow foam was triturated with 1:4 Et20/hexane to give the title compound as a pale yellow solid -(37 mg , 287o). 15 1H NMR (CDCI3) 5 8.22 (1H, d, J=8.5 Hz), 8.13 (1H, d, J = 8.5 Hz), 7.87-7.70 (3H, m), 7.62-7.45 (4H, m) , 7.00-6.85 (4H, m), 5.45 (4H, s), 3.58 (2H, brs), 2.87 (2H, s), 1.3 0 (6H, s), 1.03 ppm (9H, s). 20 EXAMPLE 32 3-[N-Benzyl-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy )indol-2-yl]-2,2-dimethyl- propanoic acid 2q Following the method of Example 31, with benzyl bromide as the alkylating agent, the title compound was obtained as an off-white solid (mp=180-183 °C (dec)) . 30 10 24B177 -12 - EXAMPLE 33 3-[N-(3-Methoxybenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2 ,2- dimethvlpropanoic acid Following the method of example 31, with 3-methoxybenzyl bromide as the alkylating agent, the title compound was obtained as an off-white solid. (mp=173-175 °C (dec)). EXAMPLE 3 4 3-[N-Allyl-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-vlmethoxv) indol-2-vl~l-2 . 2-dimethvlpropanoic-acid Step A: Allyl 3-[N-allyl-3-(3,3-dimethyl-l-oxo-l-butyl )-5-(quinolin-2-ylmethoxy)indol-2-yl]- 2.2-dimethylpropanoate To a solution of the product from Example 30 (100 mg, 0.21 mmol) in dry DMF (2 mL) was added 80% 20 NaH (14 mg, 0.47 mmol), followed 15 minutes later by allyl bromide (0.35 mL, 4 mmol). After 2 1/2 hours, saturated NH^Cl solution was added, and the product was extracted with EtoAC. The organic layer was washed with H2O and brine, dried over MgSO^, filtered 25 and was then evaporated to give the title compound as a yellow oil which was used as such in the next step. methvlpropanoic acid The crude ester from step 1 was treated as 24 8 - 73 - in the method of Example 30, Step 2 to give the title compound as an off-white solid (mp=146-148°C (dec)). EXAMPLE 35 3-[N-(4-Methoxybenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- propanoic acid Following the method of Example 34, with 4 methoxybenzyl chloride as the alkylating agent, the title compound was obtained as a white solid. lE NMR (250 MHz, acetone-d6) 5 1.05 (9H, s), 1.27 (6H, s) 2.38 (2H, s), 3.73(3H, s), 3.78 (2H, s) 5.46(2H, s), 5.48(2H, s), 6.70-8.40 ppm (13H, aromatics). EXAMPLE 36 3-[N-Methyl-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- propanoic acid Following the method of Example 34, with' methyl iodide as the alkylating agent, the title compound was obtained as a white solid. Anal. C, H, N for sodium salt . 1 H2O Calc. C 68.42; H 6.70; N 5.32 Found. C 68.36; H 6.81; N 5.44 10 30 248177 - 74 - EXAMPLE 37 3-[3-(4-Chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-vll-2.2-dimethvlpropanoic acid Step A: 3-(Quinolin-2-vlmethoxv')phenylhydrazine The title compound was prepared using the conditions described in Step A, Step B and Step C of Example 1A, but replacing the phenol in Step A with 3-acetamidophenol; m.p. 55-70°C (dec). Step B: Ethvl (4-chlorobenzene)propanoate A solution of 4-chlorobenzaldehyde (28 g) and (carboethoxymethylene)triphenylphosphorane (73-g) in toluene (500 mL) was refluxed for 2 hours. The reaction was cooled to room temperature and concentrated under vacuum to a total volume of 150 mL. Then pure hexane (500 mL) was added and the mixture was left for 18 hours at room temperature. The solid (triphexylphosphine oxide) was filtered, 20 rinsed with hexane and the filtrate evaporated to give crude product which was distilled at 0.5 mm Eg, and the fraction boiling at 130°C was collected to give ethyl 4-chlorocinnamate, which was reduced as follows: the cinnamate (21 g) was hydrogenated in 25 EtoAc (300 mL) in the presence of 5°L Pd on C (2 g) for 3 hours at atmospheric pressure. After completion, the reaction mixture was filtered through a celite pad, rinsed with EtOAc and the filtrate evaporated to dryness to give the title product as an oil. Step C: Methyl 6-(4-chlorophenyl)-2,2-dimethvl-4-oxohexanoate kA - 75 - To a solution of ethyl (4-chlorobenzene)-propanoate (Step B, 10 g) in dry THF (500 mL) at -78°C was added 0.58M potassium hexamethyldisilazane in toluene (243 mL). The mixture was stirred at -60°C for one hour. Then a solution of 2,2-dimethylsuccinic anhydride (6 g) in THF (100 mL) was added slowly and the mixture was slowly warmed to room temperature and finally stirred for 18 hours. Water (1000 mL) was added and the organic layer separated. The aqueous layer was washed with EtOAc (3 x 250 ml) and acidified with IN HCl. The aqueous layer was extracted with EtOAc, the extract was dried (Na2S04) and evaporated to give a residue which was dissolved in THF (LOO mL) and MeOH (200 mL) and treated at reflux with IN LiOH (100 mL) for 4 hours. The mixture was cooled to room temperature and concentrated under vacuum until H20 distilled off. Water (500 mL) was added, the mixture acidified with IN aq. HCl, extracted with EtOAc, the extract was dried (Na2S04) and evaporated to give the title product as its carboxylic acid. The compound was treated with diazomethane in ether, evaporated to dryness and chromatographed over silica gel, eluting with EtOAc-hexane (10:90) to give the title product as a white solid; m.p. 52-54°C. Step D: Methyl 3-[3-(4-chlorobenzyl)-6-(quinolin- 2-vlmethoxv)indol-2-vll-2,2-dimethvlpropanoate To a solution of methyl 6-(4-chlorophenvl) -2,2-dimethyl-4-oxohexanoate (Step C, 2.8 g) in toluene (30 mL) and glacial HOAc (15 mL) was added portion-wise solid 3-(quinolin-2-ylmethoxy)-phenylhydrazine (Step A, 3.2 g) and stirred at room 10 15 20 25 24 8 1 77 - 76 - temperature for 2 hours. The reaction mixture was diluted with Et20 (200 mL), washed with IN NaOH, H20, dried (Na2S04.) and evaporated to give crude hydrazone which was immediately treated as follows: the crude hydrazone was dissolved in a mixture of PPE(15 mL) and 1,2-dichloroethane (30 mL) and stirred at 40°C for 18 hours. The reaction mixture was cooled to 0°C and carefully treated with IN NaOH to bring to pH 9. The mixture was then extracted with ether, the extract was washed with H2O, dried (Na2S04.) an(^ evaporated to give a residue, which was chromatographed in a column of flash silica gel (eluting with EtOAc-hexane 25:75) and isolating the most polar component as the title., product as a foam. Step- E: 3-[3-(4-Chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared using the conditions described in Step B of Example 1, but substituting the ester from Step D for the ester of Example 1, Step A. Anal. C, H, N for sodium salt • 1 1/2 H2O Calc. C 65.75; H 5.33; N 5.11 Found. C 66.08; H 5.31; N 5.08 30 3 2 EXAMPLE 38 -[N-(Phenylsulfonyl)-3-(4-chlorobenzyl)-6-(quinolin--vlmethoxv)indol-2-yll-2.2-dimethvlpropanoic acid 20 24 8 1 7 7 - 77 - Step A: Methyl 3-[N-(phenylsulfonyl)-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2 -vll-2,2-dimethvlpropanoate To a solution of methyl 3-[3-(4-5 chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-d imethylpropanoate (Step D, Example 37) (208 mg) in dry THF (5 mL) and HMPA (0.5 mL) at -78°C was added 0.58M potassium hexamethyldisilazane in toluene (0.77 mL) and the solution then stirred at -78°C for 15 10 minutes. Then freshly distilled benzenesulfonyl chloride (0.062 mL) was added and stirred at -78°C for 2.5 hours. The reaction mixture was quenched with 25% aq. NH^OAc, extracted with EtOAc, dried over Na£S0^ and evaporated to give crude product. Chromatography of the residue in a column of flash silica gel (eluting with EtOAc-hexane 25:75) afforded the title product as an oil. Step B: 3-[N-Phenylsulfonyl)-(3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid The title compound was prepared under the conditions described in Step B of Example 1, but substituting the ester from Step A for the ester of Example 1, Step A. Anal. C, H, N for sodium salt Calc. C 67.65; H 4.89; N 4.38 Found. C 68.07; H 5.18; N 4.32 30 - 78 - 2 4 8 1 EXAMPLE 39 3-[N-Benzyl-3-(4-chlorobenzyl)-6-(quinolin-2-vlmethoxv)indol-2-vl1-2.2-dimethvlpropanoic acid The title compound was prepared under the 5 conditions described in Step A and Step B of Example 38, but substituting benzyl chloride for the benzenesulfonyl chloride from Example 38 (Step A). Anal. C, H, N for sodium salt • 1/2 E^O Calc. C 71.66; H 5.36; N 4.52 10 Found. C 71.65; H 5.49; N 4.44 EXAMPLE 40 AND 41 3-[N-(4-Chlorobenzyl)-3-(t-butylsulfonyl)-5-(quinolin-_ 1S 2-vlmethoxv)indol-2-yl~l-2. 2-dimethylpropanoic acid and 3-[N-(4-chlorobenzy1)-3-(t-butylsulfinyl)-5-(quinolin- 2-vlmethoxv) indol-2-yl~l-2 . 2-dimethvlpropanoic acid The title compounds were prepared using the conditions described for Examples 6 and 7, but 2Q substituting the ester of Example 4 (Step D) for the ester of Example 1 (Step D). 3t[N-(4-chlorobenzy1)-3-(t-butylsulfonyl)-5-(quinolin-2 -ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid: 25 Anal. C, H, N for sodium salt • 1 1/2 H^O Calc. C 61.12; H 5.58; N 4:19 Found C 61.31; H 5.39; N 4.19 3 0 3-[N-(4-chlorbenzyl)-3-(t-butylsulfinyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid: 2 4 8 1 - 79 - Anal. C, H, N for sodium salt • 2 H2O Calc. C 61.76; H 5.79; N 4.24 Found C 61.44; H 5.68; N 4.19 EXAMPLE 42 3-[N-Allyl-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)- indol-2-vll-2. 2-dimethvlprotianoic acid The title compound was prepared under the 10 conditions described in Step A and Step B of Example 38, but substituting allyl bromide for the benzenesulfonyl chloride from Example. 38 (Step A). Anal. C, H, N for sodium salt ■ 2 H2O L5 Calc. C 66.38; H 5.74; N 4,69 Found C 66.57; H 5.75; N 4.73 20 30 EXAMPLE 43 3-[N-(n-Propy1)-3-(4-chlorobenzyl)-6-(quinoline-2-vlmethoxv)indol-2-vll-2.2-dimethvlpropanoic acid A solution of methyl 3-[N-allyl-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (Example 42, methyl ester) (190 mg) was hydrogenated in EtOAc (4 mL) in the presence of 57, Pd on charcoal at atmospheric pressure for 1 hour. Filtration on Celite pad and evaporation of liquors afforded the methyl ester of the title product. Hydrolysis of this ester under the conditions described in Step B of Example 1 provided the title compound. - 80 - 24 8 1 Anal. C, H, N for sodium salt • 1 1/2 H£0 Calc. C 67.17; H 5.98; N 4.75 Found C 67.38; H 5.44; N 4.85 EXAMPLE 44 3-[N-Ethyl-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)- indol-2-vll-2.2-dimethvlpropanoic acid The title product was prepared under the 10 conditions described in Step A and Step B of Example 38, but substituting iodoethane for the benzenesulfonyl chloride from Example 38 (Step A). Anal. C, H, N for sodium salt . 2 H2O 15 Calc. C 65.69; H 5.86 N 4.79 Found C 65.81; H 5.21; N 4.77 EXAMPLE 45 20 3-[N-(4-Chlo robenzyl)-3-(4-t-buty.lbenzoyl )-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2- dimethvlpropanoic acid The, title compound was prepared according to the method described in Example 9, but using 25 4-t-butylbenzoyl chloride in place of benzoyl chloride in Step A. 30 Anal. C, H, N, for sodium salt Calc. C 67.81; H 5.97; N 3.86 Found. C 67.91; H 6.01; N 3.64 2 1/2 H20 24 8 1 EXAMPLE 46 3-[N-(4-chlorobenzyl)-3-(4-chlorobenzoyl)-5-(quinolin- 2-vlmethoxv)indol-2-v^-2 .2-dimethvlpropanoic acid The title compound was prepared according to 5 the method described in Example 9, but using 4-chlorobenzoyl chloride in place of benzoyl chloride in Step A. Anal. C, H, N.for sodium salt . 2 H2O 10 Calc. C 63.89; H 4.78; N 4.03 Found C 64.20; H 4.61; N 3.99 EXAMPLE 47 3-[N-(4-Chlorobenzyl)-3-(1,1-dimethyiethyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid Step A: Methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-20 2-ylmethoxv)indol-2-vl1-2.2-dimethvlpropanoate Methyl 3-[N-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (3.77 g, 6.27 mmol) from Step D of Example 1, was dissolved in 75 mL of dry CH2CI2 and 2q the solution was charged with 6.27 g (47.0 mmol) of AICI3 and the mixture was stirred at RT, under Ar, for 1.75 hours. The reaction was then quenched by the addition of 0.5N Na, K tartrate (150 mL) and the resulting mixture was extracted with EtOAc (3x). The 30 organic extracts were washed with 0.5N Na, K tartrate (lx) and with brine (lx). and dried (MgSO^.). - 82 - Filtration and removal of solvents provided a brown oily residue which was chromatographed on silica gel using EtOAc-hexane (1:3) to give the title compound. Step B: Methyl 3-[N-(4-chlorobenzyl)-3- (1,1-dimethylethyl)-5-(quinolin-2-ylmethoxy)- indol-2-vl~l-2.2-dimethylpropanoate Trimethylacetyl chloride (4.23 g, 4.32 mL, 35.09 mmol) was added to a cold suspension (0°C) of AICI3 (11.7 g, 87.7 mmol) in dry CH2CI2 (60 mL) under Ar. The yellow mixture was stirred at 0°C for 15 minutes, and a solution of 9.00 g (17.54 mmol) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A) in CH2CI2 (40 mL) was added dropwise (over 10 minutes) at 0°C. The reaction mixture was stirred for 10 minutes and slowly poured onto an ice-cold and vigourously stirred mixture of 0.5M aqueous Na, K tartrate (500 mL) and EtOAc (400 mL). After 20 minutes, the aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with H20 (2x), with IN aqueous NaOH (2x), with H2O (2x) and dried (MgSO^). Filtration and removal of solvents provided a yellow oily residue which was chromatographed on silica gel using EtOAc-hexane (1:4) to give the title compound. 2.2-dimethvlpropanoic acid The title compound was prepared according to 248177 - 83 - the conditions described in Step B of Example 1, but substituting the ester from Step B for the ester of Example 1. The title compound was recrystallized from EtOAc-EtOH; m.p. 201-202°C. Anal. Calc. C 73.57 H 6.36 N 5.05 Found C 73.75 H 6.37 N 5.03 EXAMPLE 48 3-[N-(4-Chlorobenzyl)-3-acety1-5-(quinolin-2-vlmethoxv) indol-2-vl~l-2 . 2-dimethylpropanoic acid The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47) but using acetyl chloride in place of trimethylacetyl chloride in Step B. 1H NMR (CD3COCD3) 5 1.20 (6H, s)-, 2.64 (3H,s), 3.62 (2H, br s), 5.47 (2H, s) 5.57 (2H, s), 6.90-6.99 (3H, m), 7.28-7.37 (3H, m) , 7.56-7.83 (4H, m), 7.97 (1H, d) 8.05 (1H, d), 8.39 ppm (lH,d). EXAMPLE 49 propanoic acid The title compound was prepared according to 24 8 1 7 -84 - the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using cyclopropanecarbonyl chloride in place of trimethylacetyl chloride in Step B. Anal. C, H, N for sodium salt • 1 H2O: Calc. C 67.27; H 5.31; N 4.61 Found C 67.27; H 5.16; N. 4.58 EXAMPLE 50 3-[N-(4-Chlorobenzyl)-3-(3-cyclopentylpropanoyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2- dimethvlpropanoic acid ' The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoate (prepared in Step A of Example 47), but using 3-cyclopentylpropanoyl chloride in place of trimethylacetyl chloride in Step B. NMR (CD3COCD3) 5 1.09 (2H, m) 1.22 (6H, s), 1.40-1.91 (9H, m), 2.94 (2H, t), 3.68 (2H, br s), 5.46(2H, s), 5.58 (2H, s), 6.91-6.99 (3H, m), 7.30(3H, m), 7.53-7.63 (2H, m) 7.72-7.82 (2H, m), 7.96 (1H, d), 8.06 (1H, d), 8.34 ppm, (lh, d). 2 4 8 17 7 - 85 - 3-[N-(4-Chlorobenzyl)-3-(3-methylbutanoyl)-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethyl- propanoic acid 5 The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoate (prepared in Step A of Example 47), but 10 using 3-methylbutanoyl chloride in place of trimethylacetyl chloride in Step B. 1H NMR (CD3COCD3) : 5 0.98 (6H, d), 1.24 (6H, s)-, 2.30 (1H, m), 2.85 (2H, d), 3.70 (2H, br s), 5.46 (2H, s), 15 5.58 (2H, s), 6.96 (3H, m), 7.30 (3H, m), 7.55-7.63 (2H, m), 7.73-7.82 (2H, m), 7.95 (1H, d), 8.07 (1H, d), 8.36 ppm (1H, d). 20 EXAMPLE 52 3-[N-(4-Chlorobenzyl)-3-propanoyl-5-(quinolin-2-vlmethoxv)indol-2-vl1-2.2-dimethvlpropanoic acid The title compound was prepared according to the conditions described in Step B and Step C of 25 Example 47, from methyl 3-[N-(4-chlorobenzyl)- 5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using propanoyl chloride in place of trimethylacetyl chloride in Step B. 30 Anal. C, H, N for sodium salt IH2O Calc. C 66.61; H 5.^2; N 4.71 Found C 66.87; H 5.^5; N 4.69 24 8 177 _ 86 _ EXAMPLE 53 3-[N-(4-Chlorobenzyl)-3-(2-inethylpropanoyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- propanoic acid 5 The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoat e (prepared in Step A of Example 47), but using 10 2-methylpropanoyl chloride in place of trimethylacetyl chloride in Step B. 1H-NMR (CD3COCD3): 5 1.07 (6H, d), 1.16 (6H, s>, 3.34 (1H, m), 3.64 (2H, br s), 5.46 (2H, s), 5.57 (2H, s), 15 6.95 (3H, m), 7.32 (3h, m), 7.45 (1H, br s), 7.60 (1H, br t), 7.71-7.83 (2H, m), 7.97 (1H, d), 8.07 (1H, d), 8.36 ppm (1H, d). EXAMPLE 54 20 3-[N-(4-Chlorobenzyl)-3-tr ime thy lac ety 1-5.-(qui noli n-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid, sodium salt Step A: Methyl 3-[N-(4-chlorobenzyl)-3-trimethyl-25 acetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]- 2.2-dimethvlpropanoate Method A: The indole from Example 47, Step A (2.00 g, 3.9 mmol) and trimethylacetyl chloride (0.86 g, 7.1 mmol) were dissolved in sieve-dried CH2CI2 (15 30 mL). The mixture was cooled to -25°C and AICI3 (1.64 g, 12.3 mmol) was added in two portions 5 minutes apart. After 10 minutes at -20 to -25'C, 7 mL of 2.5 M aqueous HOAc was added to the mixture such that the temperature stayed below -20°C. The mixture was 8 17? 10 _ 87 _ then warmed to RT and the layers were separated. The organic layer was washed with H2O, saturated aqueous NaHCC^, and H2O, and then evaporated to dryness. The resulting oil was crystalized from MeOH (20 mL) to give 1.4 g (607.) of the title compound. Method B: A solution of TiCl4 (6 mL of a 1.0 M solution in CH2CI2, 6.0 mmol) and trimethylacetyl chloride (0.491 g, 4.1 mmol) was cooled to -5°C. To the cooled solution was added a solution of the indole from Example 47, Step A (1.025 g, 2.0 mmol) in 2 mL of CH2CI2 over a 5 minute period. After 30 minutes, the reaction was quenched by the addition of 3 mL o-f 2.5 M aqueous HOAc. The mixture was warmed to RT and the 15 layers separated. The organic layer was washed with H2O, saturated aqueous NaHC03, and H20, and then evaporated to dryness. The residual oil was crystallized from 10 mL of MeOH to give 625 mg (537.) of the title compound. 20 XH-NMR (CDCI3) 5 1.22 (6H, s), 1.30 (9H, s), 3.29 (2H, s), 3.61 (3H, s), 5.28 (2H, s), 5.47 (2H, s), 6.7-8.2 ppm (13H, m) 2s IR(Nujol mull) 1636, 1730 cm-1 Step B: 3-[N-(4-Chlorobenzyl)-3-trimethylacetyl-5-(quinolin-2-ylmethoxy)indol-2-yl]- 2.2-dimethvlpropanoic acid, sodium salt 3q The acylated methyl ester from Step A (401 mg, 0.67 mmol), absolute EtOH (1.62 g), and NaOH (64.2 mg of a 50.9% aq. solution, 0.82 mmol) were refluxed 42 10 248 17 7 _ 88 _ hours. During the latter stages of the reaction, product crystallized. At the end of the reflux, the product was filtered and washed with EtOH to give 288 mg (747o) orange solid. The material was slurried in 3 mL EtOH for 8 hours at RT to give 190 mg of the title compound as a pale orange solid. 1H-NMR ('CD3OD) 5 1.08 (6H, s), 1.15 (9H, s), 3.23 (2H, s), 5.40 (2H, s), 5.55 (2H, s), 6.7-8.2 ppm (13H, m). IR (Nujol mull) 1680, 1575 cm-1. EXAMPLE 55 15 3-[N-(4-Chlorobenzyl)-3-phenylacetyl-5-(quinolin-2-yl methoxv)indol-2-vl1-2.2-dimethvlpropanoic acid The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 20 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-y l]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using phenylacetyl chloride in place of trimethylacetyl chloride in Step B. 25 Anal. C, H, N for sodium salt . IH2O Calc. C 69.46; H 5.22; N 4.26 Found C 69.71; H 5.25; N 4 . 11 30 24 8 1 - 89 - EXAMPLE 56 3-[N-(4-Fluorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid Using the procedure of Example 31, but replacing 4-trifluoromethylbenzyl bromide with 4-fluorobenzyl bromide, the title compound is obtained EXAMPLE 57 3-[N-(4-Bromobenzyl)—3—(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid - Using the procedure of Example 31, but replacing 4-trifluoromethylbenzyl bromide with 4-bromobenzyl bromide, the title compound is obtained. EXAMPLE 58 20 3-[N-(4-Iodobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl- propanoic acid Using the procedure of Example; 31, but replacing 4-trifluoromethylbenzyl bromide with 25 4-iodobenzyl bromide, the title compound is obtained. 30 24 8 1 7 7 _ 90 _ EXAMPLES 59-70 Operating as described in the previous examples, the following compounds are prepared 10 ch2o ch2- y-cch1 1 r1 1) p-c02k 15 20 25 30 Ex ATTACH R8 R5 Y- (CR11R11)p No . POINT 59 5 -CH2Ph-4-Cl -C(Me)2Pr C(Me)2 60 5 -CH2Ph-4-Cl -C(Me)2Et C(Me)2 61 5 -CH2Ph-3-F -C.(Me)3 C(Me)2 62 5 -CH2Ph-4-Cl -CH(Me)2 C(Me)2 63 5 -CH2Ph-4-Cl -c-Pr C(Me)2 64 5 -CH2Ph-4-Cl -(1-Me)-c-Pr C(Me)2 65 5 -CH2Ph-4-Cl —c —C^Hq C(Me)2 66 5 -CH2Ph-4-Cl -c-C6Hh C(Me)2 67 5 -CH2Ph-4-Cl -C(Me)2Ph C(Me)2 68 5 -CH2Ph-4-Cl -C(Me)2Ph-4-Cl C(Me)2 69 5 -CH2Ph-4-Cl -1-Ad ' C(Me)2 70 5 -CH2Ph-4-Cl -CH2-1-Ad C(Me)2 71 6 -t-Bu -CH2Ph-4-Cl C(Me)2 72 6 -C(Me)2Et -CH2Ph-4-Cl C(Me)2 24 8 17 1 - 91 - EXAMPLE 73 3-[N-(4-Chlorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-diethyl-propanoic acid 5 Step A: Methvl 4-chloro-2.2-di ethvl-4-pentenoate To a cold solution (0°C) of diisopropylamine (0.80 mL, 5.7 mmol) in THF (5 mL) was added a 1.6 M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) 10 over a 5 minute period and stirring was continued for an additional 45 min. Then a solution of methyl 4-chloro-2-ethyl-4-pentenoate (800 mg, 5 mmol) from Example 27, Step A, in THF (2 mL) was added and"the reaction was stirred at 0°C for another 30 minutes. 15 Then ethyl iodide (440 (iL, 5.5 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with NH^OAc buffer (50 mL of 257. w/v) and extracted with EtOAc. The organic layer was separated, dried 20 over MgSO^ filtered and concentrated. The crude product was purified by Kugelrohr distillation (b.p. 120°C at 0.1 mm Hg) to give the title compound. Step B: Methyl 5-(t-Butylthio)-2,2-diethyl- 25 4-oxopentanoate The title compound was prepared according to the method of Example 27, Step B and Step C, but using methyl 4-chloro-2,2-diethyl-4-pentenoate as starting material in Step B in place of methyl 30 4-chloro-2-ethyl-4-pentenoate. 24 8 1 - 92 - Step C: Methyl 3-[N-(4-chlorobenzyl)-3- (t-butylthio)-5-(quinolin-2-ylmethoxy) indol-2-vll-2.2-diethvlpropanoate. To a mixture of l-(4-chlorobenzyl)-l-[4-(quinolin-2-ylmethoxy)phenyl]hydrazine from Example 1A, Step D, (660 mg, 1.7 mmol) and anhydrous NaOAc (160 mg, 1.95 mmol) in toluene (3 mL) was added glacial HOAc (1.5 mL). After 30 minutes, a solution containing methyl 5-(t-butylthio)-2,2-diethyl-4-oxopentanoate from Step B (402 mg, 1.47 mmol) in toluene (1 mL) was added and the reaction mixture stirred for 24 hours at room temperature and for 48 hours at 65°C. The reaction was then diluted w-ith EtOAc, washed with NH^OAc buffer (25% w/v) and dried over MgSO^.. Filtration and concentration gave a viscous oil which was purified by flash chromatography on silica gel (eluant: EtOAc-hexane 15:85) to give the title compound. XH NMR (250 MHz acetone-d ); 5 0.85 (6H, t), 1.1 (9H, 6 s), 1.7 (4H, q), 3.2 (2H, s), 3.6 (3H, s), 5.4 (2H, s), 5.5 (2H, s) 6.9 (3H, m), 7.3 (4H, m), 7.6 (1H, dd) 7.7 (1H, d) 7.8 (1H, td),. 7.9 (1H, d), 8.1 (1H, d) 8.3 ppm (1H, d). Step D: Methyl 3-[N-(4-chlorobenzyl)- 5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2- diethvlpropanoate The title compound was prepared according to the method of Example 47, Step A, but using methyl 3-[N-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2- 4 8 1 _ 93 _ ylmethoxy)indol-2-yl]-2,2-diethylpropanoate from Step C in place of methyl 3-[N-(4-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate. Step E: Methyl 3-[N-(4-chlorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2- diethvlpropanoate To a cold solution (0°C) of methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-diethylpropanoate (from Step D) (177 mg, 0.33 mmol) in CH2CI2 (3 mL) was added AICI3 (220 mg,-1.65 mmol) followed by t-butylacetyl chloride (82 |xL, 0.66 mmol). The reaction was stirred at 0°C for 20 minutes and then quenched with 30 mL of 0.5 N Na,K tartrate solution, and extracted with 3 x 30 mL of EtOAC. The organic layers was combined and dried over MgS04. Filtration and concentration gave an oily residue which was purified by flash chromatography (eluent EtOAc-hexane (17:83)) to give the title compound. Step F: 3-[N-(4-Chlorobenzyl)-3-(3,3-dimethyl-l-oxo-l-butyl ) -5- (quinol in-2-ylmethoxy) -indol-2-vl1-2.2-diethvlpropanoic acid The compound from Step E was hyarolysed using THF (2.5 mL), MeOH (0.6 mL) and NaOH (IN, 1.5 mL). The solution was heated at 70°C for 2 weeks. The reaction was neutralized by addition of Na^Ac buffer (20 mL of 257, w/v) and extracted with EtOAc (3 x 30 mL) . The organic la;/ers were combined, dried </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 10 20 25 30 24 8 1 ? ? - 94 _ over MgSC>4, filtered and concentrated. The resulting residue was purified by flash chromatography (eluent: EtOAc-hexane-HOAc (250:750:1)) to give the title compound. Anal. C, H, N for sodium salt • 11/2 H£0; Calc. C 67.70; H6.43; N 4.15 Found C 67.67; H6.31; N 4.06 EXAMPLE 74 Methyl 3-[N-(4-chlorobenzyl)-3,6-bis(acetyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2 dimethylpropanoate 15 The title compound was isolated in Step B of Example 48 from a chromatography on silica gel (EtOAc-Hexane 2:3). lE NMR (CD3COCD3): 5 1.22 (6H, s), 2.63 (3H, s), 2.66 (3H, s), 3.58 (3E, s), 3.65 (2H, s), 5.61 (2H, s), '5.65 (2H, s), 6.95 (2H, d), 7.31 (2H, d), 7.62 (1H, br t), 7.71-7.85 (4H, m), 7.97 (1H, d), 8.08 (1H, d) 8.40 ppm (1H, d). EXAMPLE 75 Methyl 3-[N-(4-chlorobensyl)-3,6-bis (cyclopropanecarbonyl)-5-(quinolin-2-ylmethoxy)indol- 2-vl1-2.2-dimethvlpropanoate The title compound was isolated in Step B of Example 49 from a chromatography on silica gel (EtOAc-hexane 3:7) and was recrystallized from EtOAc-EtOH; m.p. 166-167°C. - 95 - WHAT WE CLAIM IS: 2481

1. A compound of the formula: 10 15 wherein: Ra is methyl, t-butylcarbonyl or 20 25 CH, R1, R2, R3, R4 and R1® are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -N02, -N3, -C(0H)R11R11, -CO2R12, -SR14, -S(0)R14, -S(0)2R14, -S(0)ZNR15R15, -OR15, -NR15R15, -C(0)R16 or -(CH2)tR21; 30 each R11 is independently hydrogen or lower alkyl, or two R^^'s on the same carbon atom are joined to form, together with that carbon atom, a cycloalkyl ring of 3 to 6 carbon atoms; " 2 7 APK; >94- 248177 R12 is hydrogen, lower alkyl or -CH2R21; R13 is lower alkyl or -(CH2)rR21; R14 is CF3 or R13 as defined above; R15 is hydrogen, -C(0)R16, R13 as defined above, or two R1^ 's on the same nitrogen may be joined to form, together with that nitrogen, a pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine or N-methyl— piperazine ring; R16 is hydrogen, -CF3, lower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR21; R21 is phenyl substituted with 1 or 2 R22 groups; R22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -N02 or - N3; r is 0 to 2; and t is 0 to 2.

2 . A compound according to Claim 1 wherein Ra is R1 and the other substituents are as described in Claim 1. •# 24 8 1 7 7 97 -

3. The compound according to Claim 2 which is l-(p-chlorobenzyl)-l-[4-(<iuinolin-2-yl-methoxy)phenyl]hydrazine and has the structure: 10 15 DATED THIS If DAY OF 19^3 A. J. PARK & SON PER AGENTS FOR THE APPLICANTS 20 25 N.Z. PATENT ©FBQE 119 JUL $83 RECilViS 30 </div>