WO2010011147A1

WO2010011147A1 - Indole compounds

Info

Publication number: WO2010011147A1
Application number: PCT/NO2009/000270
Authority: WO
Inventors: Rolf Berge; Jon Skorve; Andrew David Miller; Michael R. JØRGENSEN; Yushma Bhurruth-Alcor; Therese RØST
Original assignee: Thia Medica As
Priority date: 2008-07-23
Filing date: 2009-07-23
Publication date: 2010-01-28
Also published as: NO20083270L

Abstract

Novel indole compounds which interact with peroxisome proliferator-activated receptors (PPARs) are disclosed. The compounds have an influence on metabolic diseases, obesity and diabetes.

Description

TITLE

Indole compounds

FIELD OF INVENTION

The present invention relates to novel indole compounds which interact with peroxisome proliferator-activated receptors (PPARs).

BACKGROUND OF THE INVENTION

Peroxisome proliferator-activated receptors (PPARs) have been shown to have a critical role in fatty acid oxidation, triglyceride synthesis and lipid metabolism, making them an important target in drug discovery. The present invention relates to a novel series of 2,5-substituted indoles as PPARα/y dual agonists. A key aspect of the synthesis focused on the selective introduction of an aryl group on the 2-position of the indole. The PPAR activation assay with the following known potent agonists WY14.643, BRL49653 and L165.041 as positive controls showed potency of the compounds of the present invention on PPARα, PPARγ and PPARδ.

Diabetes is a major and growing public health problem throughout the world. The disorder results from resistance to insulin action through inappropriate response from target tissues or from a deficiency in the production of insulin in response to increased blood glucose. It is a very serious chronic disease leading to the dysfunction and failure of organs and is also a major cause of blindness, kidney failure, amputation and cardiovascular disease.

The metabolic syndrome is a complex set of disorders including obesity, dyslipidaemia, insulin resistance, blood pressure elevation and coronary heart disease. People with the metabolic syndrome have a five-fold greater risk of developing diabetes type II. Peroxisome proliferator- activated receptors (PPARs) have been established as a prime target in drug discovery for the treatment of metabolic diseases because of their critical role in the regulation of lipid metabolism and fat cell differentiation. Indeed, these nuclear receptors are transcription factors which play an important role in the regulation of gene expression by binding to specific peroxisome proliferator response elements (PPREs) within promoters. There are 3 subtypes of PPARs: a, γ and δ. The main roles of the different PPARs are summarized (Table 1). Natural ligands of the PPARs include a wide variety of saturated and unsaturated fatty acids and eicosanoid derivatives.

The thiazolidinediones are a well-founded class of anti-diabetic drugs that act as PPARf agonists and thereby improve insulin sensitivity, decrease hepatic glucose output and improve nonglycemic effects. However, use of thiazolidinediones is known to have attendant side effects such as weight gain, oedema, and anaemia with possible liver dysfunction. Accordingly, there have been suggestions to develop dual or even pan PPAR agonists (targeted at PP ARa and δ subtypes as well) that might be expected to exert complementary and synergistic actions in increasing lipid homeostasis and insulin sensitivity with minimal attendant side-effects.

Table 1. Summary of locations and roles of PPARs a, γ and δ

PPAR Site of expression Role

Catabolically active tissues such as liver, Oxidation of fatty acids and a heart, kidneys and skeletal muscle lipoprotein metabolism

Broad range of metabolically active tissues Fat cell differentiation and triglyceride

Y such as skeletal muscle, kidneys, intestine synthesis and adipose tissue

Wide range of tissues and cells, high Regulation of lipid metabolism and expression in the brain cholesterol efflux

SUMMARY OF THE INVENTION

The present invention relates to novel compounds which have an effect on PPAR activity. A first aspect of the invention relates to compounds of the formula (I)

wherein

R₁ is selected from hydrogen, C₆-Ci₄ aryl, C₅-Ci₃ heteroaryl, linear or branched CpC₈ alkyl, C₂- C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

R₂ and R₃ are independently selected from hydrogen, linear or branched CpC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

A is linear or branched Ci-Cg alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

and wherein the indole moiety may be optionally substituted at any available carbon or nitrogen atom with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

or a prodrug or pharmaceutically acceptable salt thereof.

In a preferred embodiment is Ri selected from phenyl, benzyl, naphlhyl, naphtylmelhyl or anthracene each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl.

In a more preferred embodiment Ri is 2-naphthylmethyl.

hi a preferred embodiment is R₂ a halide substituted alkyl, alkene or alkyne. A further preferred embodiments relates to a compound wherein R2 is selected from -CF₃, CF₃, CH₃, -CH₂- CF_3, -CH₂-CCl₃, -CH₂- CH₃, -CH₂-CH₂-CF₃₁ -CH₂-CH₂-CCI₃, -CH₂-CH₂-CH₃, -CH₂- CH₂-CH₂-CF₃, -CH₂-CH₂-CH₂-CCl₃ or -CH₂-CH₂-CH₂-CH₃.

More preferred, R₂ is -CF₃.

The invention preferable relates to the specific compounds; wherein R₁ is H and R₂ is CH₃; wherein Ri is H and R₂ is CF₃; wherein Ri is benzyl and R₂ is CH₃; wherein R| is benzyl and R₂ is CF₃; wherein R₁ is naphthylmethyl and R₂ is CH₃; wherein R| is naphthylmethyl and R₂ is CF₃; wherein R₁ is 2-naphthylmethyl and R₂ is CH₃; and wherein Ri is 2-naphthylmethyl and R₂ is CF₃

A second aspect of the invention relates to a process for the synthesis of the compounds of the present invention comprising the steps of:

a) reduction of a compound of formula (II)

to yield a compound of formula (III)

and

b) saponification of a compound of formula (III)

to yield a compound of formula (I).

A third aspect of the invention relates to the intermediate compounds of formula (II)

wherein Ri is selected from hydrogen, C₆-Ci₄ aryl, C₅-C₁₃ heteroaryl, linear or branched C₁-C₈ alkyl, C₂- Cs alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

R₂ and R₃ are independently selected from hydrogen, linear or branched CpC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, C_rC₃ alkyl, hydroxyl and carboxyl;

A is linear or branched Ci-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

or a prodrug or pharmaceutically acceptable salt thereof.

A fourth aspect of the present invention relates to a pharmaceutical composition containing a compound of the present invention, and to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the prevention and/or treatment of various diseases or disorders.

A preferred embodiment relates to the use of a compound_of formula (I)

wherein

Ri is selected from hydrogen, Ca-Ci₄ aryl, C₅-Ci₃ heteroaryl, linear or branched CpC₈ alkyl, C₂- C₈ alkenyl or C₂-Cs alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, Ci-C₃ alkyl, hydroxyl and carboxyl;

R₂ and R₃ are independently selected from hydrogen, linear or branched Ci-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, Ci-C₃ alkyl, hydroxyl and carboxyl;

A is linear or branched Ci-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

and wherein the indole moiety may be optionally substituted at any available carbon or nitrogen atom with one or more of the groups selected from halide, oxo, C_rC₃ alkyl, hydroxyl and carboxyl;

or a prodrug or pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prevention and/or treatment of peroxisome proliferator-activated receptor (PPAR) related diseases.

Preferred embodiments relates to PPAR related disease such as metabolic syndrome.

A further embodiment relates to diseases such as obesity, dyslipidaemia, diabetes, insulin resistance, blood pressure elevation and coronary heart disease. A still further embodiment relates to indications such as inflammation, and diseases such as inflammatory brain diseases (Alzheimer's disease, multiple sclerosis) and cancer.

Definitions

As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-ρropyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylenyl" refers to a divalent linking alkenyl group.

As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent linking alkynyl group.

As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂CIs, and the like.

As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2 or 3 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl and the like.

As used herein, "heteroaryl" groups refer to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2 or 3 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. Compounds of the invention also include tautomeric forms, such as keto-enol tautomers. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds described herein. As used herein, "prodrugs" refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.

Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety. When employed as pharmaceuticals, the compounds of the present invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

ABBREVIATIONS

CDCl₃ deuterated chloroform d doublet

DCM dichloromethane

DMSO dimethylsulfoxide

EI electron ionisation

EtOAc ethyl acetate hr hour

IR infra-red

J coupling constant

LBD ligand binding domain m multiplet

MeOD deuterated methanol

MeOH methanol min minutes mmol millimole m/z mass-to-charge ratio

NaOH sodium hydroxide

NMR nuclear magnetic resonance

PPAR peroxisome proliferator-activated receptor

Rf retention time

RT room temperature

S singlet t triplet

TLC thin layer chromatography

DETAILED DESCRIPTION OF THE INVENTION

Novel compounds of the present invention were designed as potential PPAR άu&la/γ agonists. At the start of the design process, the crystal structure of a known potent PPAR^ agonist GI262570 (formula 47) complexed with PPAR^(PDB 1FM9) was studied.

The crystal structure elucidates a number of important interactions between the ligand and receptor including hydrogen bonding between the carboxylic acid moiety and residues HIS449, TYR473 and HIS323 of the AF-2 helix and an a hydrophobic phenoxy moiety interacting primarily through Van der Waals forces with residues TYR327, LEU330 and CYS284. Analysis of this LBD and also of the LBD of PPARα in PDB entry 1I7G enabled a hypothesis for a pharmacophore required to confer both PPARγ and PPARα agonism that could be used as an input to de novo design. Based on this we postulated that the target scaffold may consist of an indole core with different aromatic groups, R_b on the 2-position of the indole, possible with an alkoxy side chain at the 5- position. A racemic synthesis was first explored to test for the activity of the 2,5-indole compounds.

In accordance with the present invention, we have synthesized the molecules 1 to 6, with Ri = H, phenyl and naphthylmethyl groups as potent PPARγ/α modulators (Table 2).

The compounds 1 and 2 test the importance of the aryl group for the binding to the receptor in a hydrophobic site which in part is occupied by the methyl oxazole moiety of ligand 47

Table 2. Target 2,5-indole compounds 1 to 6

Compound Ri Rz

1 H CH₃

2 H CF₃

3 Benzyl CH₃

4 Benzyl CF₃

5 2-Naphthylmethyl CH₃

6 2-Naphthylmethyl CF₃

For indoles 1 and 2, where R₁ is a hydrogen atom, commercially available indole-5- carboxaldehyde 7 provided an ideal template from which the aryl substituents and PPAR-binding carboxylic acid moiety could be synthesised (Scheme 1). A Homer Wadsworth Emmons (HWE) coupling was carried out with the required phosphonoacetates 8 and 9 to give the Z and E isomers

10 to 13. The reduction of the double bond with magnesium turnings in dry methanol proceeded smoothly, as described by Lohray et al. (Lohray, B. B.; Lohray, V. B.; Bajji, A. C; Kalchar, S.; Ramanujam, R.; Chakrabarti, R. US patent 2000, 6,054,453). Finally, saponification of the methyl ester with potassium hydroxide in a 1:1 mixture of ethanol/water gave the desired target 1 and 2 in excellent yields (Zhang, W.; Cao, X. Y.; Zi, H.; Pei, J. Single-molecule nanosized polycyclic aromatics with alternant five- and six-membered rings: Synthesis and optical properties. Organic Letters 2005, 7, 959-962.).

8 R2 ~~ CH3 10-11 R₂ = CH₃

9 R₂ = CF₃ 12-13 R₂ = CF₃

14 R₂ = CH₃ 1 R₂ = CH₃ 15 R₂ = CF₃ 2 R₂ = CF₃

Scheme 1. Synthesis of indole leads 1-2 a) NaH, dry THF, 0 ⁰C to RT, 93-99% b) Mg turnings, dry MeOH, RT, 60-83% c) KOH, EtOH/H₂O, reflux, 92-93%

The HWE coupling reagents 8 and 9 were prepared as shown in Scheme 2 and Scheme 3 respectively. For R₂ being a methyl group, triethylphosphite 16 and commercially available 2- chloro-2-ethoxyacetic acid 17 were coupled using Arbuzov chemistry as described by Grell et al. (Grell, W.; Machleidt, H. PO-Aktivierte Alkoxyolefinierung. Annalen. Chemie. 1966, 699, 53- 67). This reaction proceeded smoothly, phosphonoacetate 8 was obtained in a quantitative yield of 92% and used without any purification.

Scheme 2. Preparation of the phosphonoacetate 8 a) Anhydrous DMF, reflux at 150 ⁰C, 15 hr, 92%

For the synthesis of the 2,2,2-trifluoro phosphonoacetate 9, the diazo transfer reagent, tosyl azide 20, was first prepared by coupling sodium azide and tosyl chloride (McElweewhite, L.; Goddard, W. A.; Dougherty, D. A. Theoretical-Studies on 1,4,6,9-Spiro 4.4 Nonatetrayl, an Organic Tetraradical. Journal of the American Chemical Society 1984, 106, 3461-3466). The diazo intermediate 22 was next synthesised from tosyl azide 20 and phosphonoacetate 21 using sodium hydride in dry THF as described by Moody et al. (Moody, C. J.; Sie, E.; Kulagowski, J. J. The Use of Diazophosphonates in the Synthesis of Cyclic Ethers. Tetrahedron 1992, 48, 3991 -4004; Regitz, M.; Anschutz, W.; Liedhegener, A. Synthese von alpha-Diazo-phosphonsaureestern. Chemische Berichte 1968, 101, 3734-3743). Finally, rhodium(II) acetate dimer was used to generate a carbenoid from the diazo compound 22 which was inserted into the O-H bond of 2,2,2- trifluoroethanol, Αsper Haigh et al. (Haigh, D.; Birrell, H. C; Cantelio, B. C. C; Hindley, R. M.; Ramaswamy, A. Non-thiazolidinedione antihyperglycaemic agents. Part 4: Synthesis of ( plus -)-, (R)-(+)- and (S)-(-)-enantiomers of 2-oxy-3-arylpropanoic acids. Tetrahedron-Asymmetry 1999, 10, 1335-1351).

NaN₃ ⁺ TsCI _ ⁵→K ₊ . _Eto^ I^ i _OEt — ^b)_ .

^{18 19} Tos ;yyll aa;zide

20

Scheme 3. Synthesis of 2,2,2-trifluorophosρhonoacetate 9 a) EtOH, acetone, RT, 23 hr, 96% b) NaH, dry THF, 0 ⁰C to RT, 5 hr, 70% c) 2,2,2-trifluoroethanol, [Rh(OAc)₂]₂, benzene, reflux, 63%

For indoles 3 to 6, where R| is a benzyl and a naphthylmethyl group, a suitably functionalised cyano indole 23 provided an ideal starting material. The first step was to protect the nitrogen of indole 23 with a benzene sulfonyl group using the phase transfer catalyst (»Bu)₄NBr. The protected indole 24 was purified by crystallisation from ethanol in a 96% yield. The benzene sulfonyl group was chosen as it allows chelation of lithium to the oxygen of the benzene sulfonyl group and enhances substitution on the C2 position due to the influence of the nitrogen atom. After treatment of indole 24 with M3uLi in dry THF at -45 ⁰C adapted from a method by Sundberg et al, the lithiated intermediate, without isolation, was treated with either benzyl bromide or 2-(bromomethyl)naphthalene. (Sundberg, R. J,; Russell, H. F. Syntheses with N- protected 2-lithioindoles, Journal of Organic Chemistry 1973, 38, 3324-3330). After chromatography on silica gel, crystallisation from hexane/DCM 20: 1 yielded shiny white crystals. X-ray crystal structures were carried out to confirm the selective introduction of the R₁ group on the 2-ρosition of the indole.

The next step required deprotection of the benzene sulfonyl group in basic conditions. Cyano indoles 27-28 were subsequently reduced to the corresponding aldehydes 29-30 using DIBAL. Next, a Horner Wadsworth Emmons coupling with the two different phosphonoacetates 8 and 9 respectively yielded the Z and E isomers 31 to 38. The reduction of the double bond with magnesium turnings in dry methanol proceeded to give indole precursors 39 to 42. The final step was saponification of the methyl ester by refluxing with potassium hydroxide in ethanol/water to yield the desired indole leads 3 to 6.

Scheme 4. a) 1. (W-C₄Hg)₄NBr, NaOH(aq), toluene, H₂O 2. PhSO₂Cl, RT, 96% b) 1. /-BuLi, -45 0C, 55 min 2. BnBr, -45 ⁰C to RT, 15 hr, 30-51% c) NaOH(aq), MeOH, 99% d) DIBAL, dry DCM, 80-86% e) NaH, dry THF, 0 ⁰C to RT, 78-90% f) Mg turnings, dry MeOH, RT, 73-80% g) KOH, EtOH/H₂O, reflux, 93-99%

The six indole leads 1 to 6 were thus successfully synthesised. The purity of the compounds was an important aspect, prior to their testing in vitro. A minimum of 97% purity of the indoles was achieved by careful purification of all the intermediates, followed by crystallisation wherever possible.

EXPERIMENTAL SECTION

Chemistry. All reactions were carried out under an atmosphere of nitrogen or argon, in oven- dried glassware, unless otherwise stated. CH₂Cl₂ was distilled over P₂O₅, and other solvents were bought and pre-dried as required. All chemicals were purchased from Sigma- Al drich, Lancaster and Merck Biosciences. Flash column chromatography was performed on silica gel 60 (Merck Kieselgel 60 F₂₅₄ 230-240 mesh). TLC refers to thin layer chromatography performed on pre- coated Merck silica gel (0.2 mm, 60 F₂₅₄) aluminium-backed plates, and visualised with a UV lamp (254 nm) and/or stained with acidic ammonium molybdate (IV), basic potassium manganate (VII; KMnO₄), iodine and phosphomolybdic acid. Special chromatography solvent mixture A is as follows: CH₂Cl₂/MeOH/H₂O 65:25:4. Melting points were measured on a Stuart Scientific SMP3 apparatus and are reported without correction. Infra red spectra (IR) were measured on a JASCO FT/IR-620 spectrometer. ¹HNMR, '³CNMR and ³¹P NMR spectra were recorded on Bruker Avance 400. ¹H NMR was recorded at 400 MHz and chemical shifts, <5H are quoted in parts per million (ppm), using residual isotopic solvent as internal reference (CDCl₃, S_H - 7.27 ppm; CD₃OD, S^ = 3.30 ppm). Data is reported as follows: (integration; br = broad; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet; coupling constant(s) Jin Hz; assignment). Peaks split by the presence of a phosphorus atom are indicated with a superscript p. ¹³C NMR spectra were recorded at 100 MHz and chemical shifts, δ_c are quoted in parts per million (ppm), using residual isotopic solvent as internal reference (CDCl₃, S₀ = 77.00 ppm; CD₃OD, δc = 49.05 ppm). Data is reported as follows: (C, CH, CH₂, CH₃; d = doublet, q = quadruplet; coupling constant(s) J in Hz). Peaks split by the presence of a phosphorus atom are indicated with a superscript p. Mass spectra were recorded using VG Platform II, VG-070B, Joel SX- 102 or Bruker Esquire 3000 ESI instruments. Mass accuracy is indicated to the nearest 0. lppm. Elemental analysis was carried out using a Perkin Elmer 2400 CHN elemental analyser at the Science Technical Support unit, London Metropolitan University.

Example 1

Preparation of 2-Ethoxy-3-dH-indol-5-yl)proρanoic acid 1

Ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetatβ 8

To a colourless solution of 2-chloro-2-ethoxyacetic acid ethyl ester (1.41 g, 8.49 mmol, 1.00 eq) in anhydrous DMF (10 ml) was added triethylphosphite (1.46 ml, 8.49 mmol, 1.00 eq) and the reaction mixture was refluxed at 145 ⁰C for 15 hr and at 152 ⁰C for 30 min. The solution which had turned yellow was allowed to cool down to RT and water (40 ml) was poured onto the reaction mixture. The aqueous phase was extracted with DCM (3x40 ml). After drying the organic phase over MgSCM, concentration in vacuo yielded 2.11 g of 8 as a yellowish oil (92%) which was used as such for the HWE couplings: R_f 0.25 [hexane/EtOAc 1: 1]; v_mm (filmycm^"1 1746, 1265, 1145, 1039; 4 (CDCl₃) 4.24-4.09 (5H, m, 4xH7, 2xH5), 3.68-3.61 (IH, m, H3), 3.54-3.47 (IH, m, H3), 1.29-1.21 (9H, m, 6xH8, 3xH4 or 3xH6), 1.19-1.16 (3H, m, 3xH4 or 3xH6); δ_c (CDCl₃) 167.34-167.32" (C, /2.0), 77.34-75.77" (CH, / 157.0), 68.35-68.23" (CH₂, J 12.0), 63.46-63.39" (CH₂, J7.0), 63.37-63.30 (CH₂, J7.0), 61.45 (CH₂), 16.15-16.09" (CH₃, J 6.0), 14.70 (CH₃), 13.88 (CH₃); m/z (EI⁺) 269 ([M+H]⁺, 10), 224 ([M-ethyl etherf, 81), 197 ([M- (ether+ester)]⁺, 90), 167 (85), 152 (70), 139 (75), 111 (100), 103 (55), 75 (62), 65 (71); found [M+H]⁺, 268.1302, C₁₀H₂AP requires [M+H]⁺, 268.1076; Found: C, 44.6; H, 7.9. Required: C, 44.8; H, 7.9; Δ = 8.4 ppm.

(Z)-EtHyI 2-ethoxy-3-(lH-indol-5-yl)acrylate 10 and (E)-ethyl 2-ethoxy-3-(lH-indol-5-yl)acrylate 11

To a milky suspension of sodium hydride, 60% in oil (310 mg, 7.75 mmol, 2.23 eq) and molecular sieves 4A in anhydrous THF (40 ml) at 0 ⁰C, under a constant flow of N₂, was added dropwise via syringe pump, phosphonoacetate 8 (1.87 g, 6.97 mmol, 2.00 eq) in THF (2.0 ml) over 29 min. The suspension turned into a clear pale yellow solution. The latter was stirred at 0 ⁰C for 1 hr before the dropwise addition of 5-indole-carbaldehyde 7 (506 mg, 3.48 mmol, 1.00 eq) in dry THF (4.0 ml) via syringe pump over 38 min. The solution turned orange, it was stirred at 0 ⁰C for 1 hr and at RT for 44 lirs. The reddish solution was concentrated in vacuo, then re- dissolved in EtOAc (40 ml) and washed with water (2x45 ml). Some NaCl was added to aid the separation of the two phases. The aqueous phase was extracted with EtOAc (4x90 ml). After drying the organic phase over MgSO,), concentration in vacuo of the organic phase gave a brown liquid which was purified by flash column chromatography on silica gel (hexane/EtOAc 20:1, 15: 1, 10:1, 9: 1, 8:2) to yield 844 mg (93%) of the product. Ratio Z:£ = 63:37. Zisomer 10: amorphous white powder; mp 77.5-78.5 ⁰C (hexane/DCM 20: 1); R_f 0.35 [hexane/EtOAc 6:4]; v_ιmx (nujoiycnϊ¹ 3267, 2923-2850, 1731, 1687, 1550, 1378; 4 (CDCl₃) 8.32 (IH, br, Hl), 8.13 (IH, s, H4), 7.74-7.72 (IH, dd, /8.4, / 1.6, H6), 7.40-7.38 (IH, d, J8.8, H7), 7.23-7.22 (IH, t, / 2.8, H2), 7.20 (IH, s, Hl'), 6.60-6.58 (IH, m, H3), 4.35-4.30 (2H, q, 714.4, /7.2, H3¹), 4.06- 4.00 (2H, q, / 14.2, /7.0, H6'), 1.44-1.38 (6H, m, H4', H7'); δ_c (CDCl₃) 165.30 (C), 142.56, 136.03, 127.98 (3xC), 126.19 (CH), 125.60 (C), 124.90 (CH), 124.56 (CH), 123.46 (CH), 111.00 (CH), 103.36 (CH), 67.46 (CH₂), 60.92 (CH₂), 15.55, 14.35 (CH₃); m/z (EI⁺) 259 ([M]⁺, 100), 202 ([M-CH₂CH₃-CH₂CH₃]^'1', 39), 157 (75), 129 (51), 118 ([Indole]', 13); found [M+H]⁺, 259.1199, C₁₅H₁₇NO₃ requires [M+H]⁺, 259.1208; Found: C, 69.6; H, 6.7; N, 5.3. Required: C, 69.5; H, 6.6; N, 5.4; Δ = -3.5 ppm. E isomer 11: amorphous white powder; mp 98.5-100.5 ⁰C (hexane/DCM 20: 1); R_f 0.28 [hexane/EtOAc 6:4]; v_mm (nujol)/cm-' 3330, 2923-2850, 1702, 1621, 1379, 1227, 1176; ^ (CDCl₃) 8.23 (IH, br, Hl), 7.51-7.50 (IH, d, /0.4, H4), 7.30-7.28 (IH, d, / 8.4, H7), 7.17-7.16 (IH, t, /2.8, H2), 7.08-7.06 (IH, dd, / 8.4, / 1.6, H6), 6.50-6.49 (IH, m, H3), 6.32 (IH, s, Hl '), 4.18-4.13 (2H, q, / 14.2, /7.0, H3'), 3.99-3.94 (2H, q, / 14.0, /6.8, H6'), 1.45- 1.42 (3H, t, /6.8, H7'), 1.09-1.06 (3H, /7.0, H4'); δ_c (CDCl₃) 165.24 (C), 146.23, 134.93, 127.82, 126.17 (4xC), 124.54 (CH), 122.99 (CH), 120.54 (CH), 111.47 (CH), 110.58 (CH), 102.57 (CH), 64.62 (CH₂), 61.07 (CH₂), 14.53 (CH₃), 13.68 (CH₃); m/z (EI⁺) 259 ([M]⁺, 100), 202 ([M-CH₂CH₃-CH₂CH₃]⁺, 37), 157 (68), 129 (49); found [M+H]⁺, 259.1199, Ci₅Hi₇NO₃ requires [M+H]⁺,259.1208; Found: C, 69.6; H, 6.5; N, 5.5. Required: C, 69.5; H, 6.6; N, 5.4; Δ = -3.5 ppm.

Methyl 2-ethoxy-3-(lH-indol-5-yl)propanoate 14

To a yellow solution of the starting material 10 (380 mg, 1.47 mmol, 1.00 eq) in anhydrous methanol (13.0 ml) at RT, under a constant flow of N₂, were added the magnesium turnings (648 mg, 26.7 mmol, 18.2 eq) in one portion and the reaction mixture was stirred at RT for 3 hr. Effervescence was seen as hydrogen gas was evolved. The reaction mixture was poured onto water (60 ml) and the two phases were separated. The aqueous phase was extracted with DCM (4x60 ml) and the organic extracts were washed with brine (60 ml). After extraction with DCM (4x60 ml) and drying over MgSO,}, concentration in vacuo gave a brownish oil which was purified by flash column chromatography on silica gel (hexane/EtOAc 9: 1, 8:2, EtOAc) to yield 300 mg (83%) of the product as a yellow oil: R_f 0.20 [hexane/EtOAc 7.5:2.5]; v_inax (film)/cm^"' 3408, 2977-2850, 1741, 1444, 1209, 1110; 4 (CDCl₃) 8.25 (IH, br, Hl), 7.51 (IH, s, H4), 7.32- 7.30 (IH, d, J 8.0, H7), 7.18-7.17 (IH, t, /2.8, H2), 7.11-7.08 (IH, dd, J8.4, / 1.6, H6), 6.51- 6.50 (IH, m, H3), 4.14-4.11 (IH, dd, /7.6, / 1.6, H2'), 3.71 (3H, s, H4"), 3.65-3.58 (IH, m, H3'), 3.42-3.35 (IH, m, H3'), 3.15 (IH, s, Hl'), 3.13-3.12 (IH, d, /2.8, Hl'), 1.20-1.16 (3H, t, H4'); & (CDCl₃) 173.30 (C), 134.80 (C), 128.19 (C), 127.98 (C), 124.38 (CH), 123.54 (CH), 121.04 (CH), 110.74 (CH), 102.23 (CH), 80.98 (CH), 66.21 (CH₂), 51.73 (CH₃), 39.51 (CH₂), 15.02 (CH₃); m/z (EI⁺) 247 ([M]⁺, 16), 130 (100), 117 (3); found [M+H]⁺, 247.1205, C₁₄H_nNO₃ requires [M+H]⁺, 247.1208; Found: C, 68.2; H, 6.9; N, 5.8. Required: C, 68.0; H, 6.9; N, 5.7; Δ = -1.2 ppm.

2-Ethoxy-3-(lH-indol-5-yl)propanoic acid 1

To a pale yellow solution of the starting material 14 (53.4 mg, 0.216 mmol, 1.00 eq) in a mixture of ethanol/water 1: 1 (1.6 ml), were added the potassium hydroxide pellets (15.1 mg, 0.269 mmol, 1.25 eq) and the solution was stiiτed at 78 ⁰C for 15 hr. The yellow solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~8 drops) until a pH of 1 was reached. The desired acid crashed out as a brown ppt. It was dissolved in DCM and washed with water (2x30 ml). The aqueous phase was extracted with DCM (4x50 ml). After drying over MgSO₄, concentration in vacuo gave 46.2 mg (92%) of the product as a pale yellow oil: R_f 0.45 [Solvent A]; v_mm (DCM filmycin ¹ 3411, 2978-2929, 1724, 1265, 1105; 4 (CDCl₃) 10.8 (IH, br, OH), 8.47 (IH, br, Hl), 7.57 (IH, s, H4), 7.30-7.28 (IH, d, /8.4, H7), 7.15-7.13 (2H, m, H2, H6), 6.52 (IH, br, H3), 4.23-4.20 (IH, dd, /7.8, /4.6, H2'). 3.70-3.62 (IH, m, lxH3'), 3.49-3.41 (IH, m, lxH3'), 3.31-3.26 (IH, dd, / 14.2, /4.2, Hl '), 3.21-3.16 (IH, dd, / 14.0, /7.6, Hl '), 1.21-1.17 (3H, t, /7.0, H4'); S₀ (CDCl₃) 177.33 (C), 134.76 (C), 127.84 (C), 127.49 (C), 124.63 (CH), 123.25 (CH), 120.95 (CH), 110.93 (CH), 101.80 (CH), 80.27 (CH), 66.52 (CH₂), 38.91 (CH₂), 14.82 (CH₃); Wz (EI⁺) 233 ([M]⁺, 22), 130 (M-(ethoxypropanoic acid side chain)]⁺, 100); found [M+H]⁺, 233.1047, C₁₃H₁₅NO₃ requires [M+H]⁺, 233.1052; Found: C, 67.0; H, 6.4; N, 5.9. Required: C, 66.9; H, 6.5; N, 6.0; Δ = -2.1 ppm.

Example 2

Preparation of 3-(lH-indol-5-yl^')-2-(2.2,2-trifiuoiOethoxy)proρanoic acid 2 4-Methyl-ben∑enesulfonyl azide 20

To a solution of sodium azide (5.10 g, 78.4 mmol, 1.00 eq) in ethanol (25 ml) was added a colourless solution of/>-toluene sulfonyl chloride (14.9 g, 78.2 mmol, 1.00 eq) in acetone (70 ml). A precipitate of NaCl formed immediately. The reaction mixture was stirred at RT for 17 hr. It was then filtered and the acetone was removed by rotary evaporation. The organic phase was diluted with DCM (40 ml), and washed with water (3x40 ml). The aqueous phase was extracted with DCM (4x90 ml). After drying the organic phase over Na₂SO₄, concentration in vacuo yielded 15.1 g of 20 as a colourless liquid (98%): R_f 0.40 [hexane/EtOAc 8:2]; v_mΛX (film)/cm^" ' 2129, 1369, 1171; * (CDCl₃) 7.85-7.83 (2H, m, H2), 7.42-7.40 (2H, m, H3), 2.48 (3H, br, Hl'); S₀ (CDCl₃) 146.17 (C), 135.42 (C), 130.21 (CH), 127.43 (CH), 21.65 (CH₃); tn/z (EI⁺) 197 ([M]⁺, 8), 155 ([M-azide]⁺, 70), 91 ([methylbenzenef, 100); found [M+H]⁺, 197.0256, C₇H₇N₃O₂S requires [M+H]^1', 197.0259; Found: C, 42.7; H, 3.6; N, 21.3. Required: C, 42.6; H, 3.6; N, 21.3; Δ = -1.5 ppm.

Ethyl 2-diazo-2-(diethoxyphosphoryl)acetate 22

To a suspension of sodium hydride (157 mg, 3.92 mmol, 1.23 eq) in dry THF (8.00 ml) under nitrogen at 0 ⁰C, was added dropwise, over 3 min, triethylphosphonoacetate (0.63 ml, 3.20 mmol, 1.00 eq). The suspension turned into a clear colourless solution. After stirring at 0 ⁰C for 47 min, was added a solution of tosyl azide 20 (630 mg, 3.20 mmol, 1.00 eq) in dry THF (2x1.00 ml). The reaction mixture turned yellow, it was left to stir in the ice bath overnight. Ether (14.0 ml) and water (14.0 ml) were added and the 2 layers were separated. The aqueous phase was extracted with ether (4x20.0 ml). The combined ethereal extracts were washed with aq NaOH 0.5M (50.0 ml), water (90.0 ml) and brine (80.0 ml). The aqueous phases were extracted with ether respectively (4x50 ml, 3x80 ml, 2x100 ml). After drying the organic phase over MgSO₄, concentration in vacuo yielded a colourless liquid which was purified by flash column chromatography on silica gel (hexane, hexane/EtOAc 8:2, 6:4) to yield 586 mg (73%) of the product as a pale yellow liquid: R_f 0.20 [hexane/EtOAc 1:1]; v_mm (film)/cm^'' 2987, 2131, 1707, 1284, 1026; 4(CDCl₃) 4.28-4.22 (2H, q, / 14.4, /7.2, 2xH5), 4.23-4.10 (4H, m, 2xH3), 1.36- 1.33 (6H, dt, /7.1, /0.7, 2xH4), 1.30-1.27 (3H, /7.2, H6); S₀ (CDCl₃) 163.40-163.28" (C, d, J 12.0), 129.48-126.32^P (C, d, /316.0), 63.59-63.53" (CH₂, d, J6.0), 61.61 (CH₂), 16.09-16.02 (CH₃, d, /7.0), 14.25 (CH₃); ra/z (EI⁺) 250 ([M]⁺, 16), 121 (100), 109 (98), 93 (73), 81 (68), 65 (87); found [M+H]⁺, 250.0711, C₈H₁₅N₂O₅P requires [M+H]⁺, 250.0719; Found: C, 38.5; H, 6.0; N, 11.1. Required: C, 38.4; H, 6.0; N, 11.2; Δ = -3.2 ppm. Ethyl 2-(diethoxyphosphoiγl)-2-(2,2,2-trifluoroethoxy)acetate 9

A mixture of diazo ester 22 (586 mg, 2.34 mmol, 1.00 eq), trifluoroethanol (0.340 ml, 4.68 mmol, 2.00 eq) and Rh(II) acetate dimer (10.5 mg, 0.024 mmol, 0.01 eq) in benzene (7.00 ml) was heated at 85 ⁰C for 22 hr. The green solution was concentrated in vacuo to give a greenish oil which was purified by flash column chromatography on silica gel (IiEtOAc 8:2, 7:3, 6:4, 1:1) to yield 474 mg (63%) of the product as a colourless liquid: R_f 0.20 [hexane/EtOAc 4:6]; M_nax (film)/cm^"' 1743, 1265, 1041; ό\ (CDCl₃) 4.52-4.47^p (IH, d, J 14.4, H2), 4.37-4.08 (7H, m, 2xH5, H7, lxH3), 3.98-3.89 (IH, m, lxH3), 1.36-1.30 (9H, m, 2xH6, H8); S₀ (CDCl₃) 166.09 (C), 127.51-119.19 (C, q, /277.5), 77.89-76.33" (CH, d, J 156.0), 69.09-67.94" (CH₂, dq, /35.0, / 11.5), 64.05-63.93" (CH₂, t, J 6.0), 62.21 (CH₂), 16.26-16.20" (CH₃, d, /6.0), 13.99 (CH₃); m/z (EI⁺) 322 ([M]⁺, 1), 249 ([M-ethyl]⁺, 20), 183 ([M-(trifluoroether + 2 ethyl groups)]⁺, 61), 155 ([M-(trifluoroether + 3 ethyl groups)]⁺, 100), 65 (64); found [M+H]⁺, 322.0787, C₁₀Hi₈F₃O₆P requires [M+H]⁺, 322.0793; Found: C, 37.3; H, 5.6. Required: C, 37.3; H, 5.6; Δ = -1.9 ppm.

(Z)-Ethyl 3-(lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy)acrylate 12 and (E)-ethyl 3-(lH-indol-5-yl)- 2-(2,2,2-triflιιoroethoxy)acrylate 13

To a milky suspension of sodium hydride (9.80 mg, 0.245 mmol, 1.40 eq) in anhydrous THF (0.800 ml) at 0 ⁰C, was added dropwise via syringe pump, phosphonoacetate 9 (60.0 mg, 0.186 mmol, 1.06 eq) in THF (0.600 ml) over 7 min, under a constant flow OfN₂. The suspension turned into a clear pale yellow solution. The latter was stirred at 0 ⁰C for 24 min before the dropwise addition of 5-indole-carbaldehyde (25.4 mg, 0.175 mmol, 1.00 eq) in dry THF (0.900 ml) via syringe pump over 34 min. The solution which had turned orange was left stirring in the ice bath over 15 hr, and then at RT for 25.5 hr. The yellowish solution was concentrated in vacuo, re-dissolved in EtOAc (15.0 ml) and washed with water (15.0 ml). The aqueous phase was extracted with EtOAc (4x15.0 ml) and the organic extracts were washed with brine (50.0 ml). The aqueous phase was extracted with EtOAc (4x50.0 ml). After drying the organic phase over MgSθ4, concentration in vacuo of the organic phase gave a yellowish slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 20:1, 15:1, 10: 1, 8:2) to yield 54.3 mg (99%) of the products. Ratio ZE= 59:41. Z isomer: amorphous white powder; mp 98.0-99.0 ⁰C (hexane/DCM); R_f 0.20 [hexane/EtOAc 7.5:2.5]; v_ιmx (nujol)/cm^"' 3343, 2977-2850, 1691, 1459, 1371, 1261, 1056; 4 (CDCl₃) 8.26 (IH, br, Hl), 8.11 (IH, s, H4), 7.70-7.67 (IH, dd, /8.6, / 1.4, H6), 7.42-7.40 (IH, d, /8.8, H7), 7.27 (IH, br, Hl'), 7.25-7.24 (IH, t, /2.8, H2), 6.61-6.60 (IH, m, H3), 4.41-4.31 (4H, m, H3', H6'), 1.42-1.38 (3H, t, /7.2, H7'); & (CDCl₃) 164.05 (C), 140.54 (C), 136.37 (C), 128.08 (C), 127.58-119.27 (C, q, /277.0), 127.34 (CH), 125.06 (CH), 124.84 (CH), 124.84 (C), 124.19 (CH), 111.16 (CH), 103.62 (CH), 68.38-67.34 (CH₂, q, /34.5), 61.34 (CH₂), 14.29 (CH₃); m/z (EI⁺) 313 ([M]⁺, 100), 230 ([M-CH₂CF₃]⁺,6), 202 ([M-CH₂CH₃- CH₂CF₃J⁺, 39), 157 (33), 129 (44), 118 ([Indolef, 13); found [M+H]⁺, 313.0925, C₁₅Hi₄F₃NO₃ requires [M+H]⁺, 313.0926; Found: C, 57.6; H, 4.6; N, 4.5. Required: C, 57.7; H, 4.5; N, 4.5; Δ = -0.3 ppm. E isomer: amorphous pale yellow powder; mp 88.0-89.0 ⁰C (hexane/DCM); R_f 0.15 [hexane/EtOAc 7.5:2.5]; v_mm (mojoO/αn ¹ 3372, 2950-2850, 1711, 1461, 1378, 1269, 1157; & (CDCl₃) 8.19 (IH, br, Hl), 7.63-7.62 (IH, d, /0.8, H4), 7.35-7.33 (IH, d, / 8.4, H7), 7.22-7.21 (IH, t, /2.8, H2), 7.18-7.15 (IH, dd, /8.4, / 1.6, H6), 6.74 (IH, s, Hl '), 6.55-6.53 (IH, m, H3), 4.31-4.25 (2H, q, / 16.4, /8.4, H3'), 4.23-4.17 (2H, q, / 14.0, /7.2, H6'), 1.16-1.12 (3H, t, /7.2, H7'); S₀ (CDCl₃) 163.51(C), 143.55 (C), 135.52 (C), 127.76 (C), 124.77 (CH), 124.54 (C), 123.42 (CH), 127.40-119.08 (C, q, /277.0), 121.67 (CH), 121.56 (CH), 110.62 (CH), 103,00 (CH), 68.19-67.14 (CH₂, q, /35.0), 61.29 (CH₂), 13.75 (CH₃); m/z (EI⁺) 313 ([M]⁺, 100), 230 ([M-CH₂CF₃]⁺,6), 202 ([M-CH₂CH₃-CH₂CF₃]⁺, 38), 157 (34), 129 (48), 118 ([Indolef, 15); found [M+H]⁺, 313.0926, C₁₅H₁₄F₃NO₃ requires [M+H]⁺, 313.0926; Found: C, 57.8; H, 4.6; N, 4.4. Required: C, 57.7; H, 4.5; N, 4.5; Δ = 0.0 ppm.

Methyl 3-(lH-indol-5-yl)-2-(2, 2, 2-tήfluoroethoxy)propanoate 15

To a mixture of the starting material 12 and 13 (1.12 g, 3.59 mmol, 1.00 eq) and the magnesium turnings (1.31 g, 53.8 mmol, 15.0 eq) at 0 ⁰C, under a constant flow OfN₂, was added the anhydrous methanol (15.0 ml). Effervescence was seen after a few mins and the RM turned darker yellow. The reaction mixture was left in the ice bath for 14.5 hr. A white agglomerate was seen, some dry methanol (10.0 ml) was added and the reaction mixture was stirred at RT for another 45 min. The RM was cooled to 0 °C and water (22.0 ml) was added, followed by 2M HCl (14.0 ml). The mixture was filtered and brine (100 ml) was added. The 2 phases were separated and the aqueous phase was extracted with DCM (3x100, 1x150 ml). After drying over MgSO₄, concentration in vacuo gave an almost colourless oil which was purified by flash column chromatography on silica gel (hexane/EtOAc 20: 1, 10:1, 9:1, 8:2) to yield 653 mg (60%) of the product as a pale yellow oil: R_f 0.20 [hexane/EtOAc 7.5:2.5]; v_maκ (DCM film)/cm^'' 3377, 2933, 1741, 1513, 1278, 1164; 4 (CDCl₃) 8.13 (IH, br, Hl), 7.51 (IH, s, H4), 7.34-7.32 (IH, d, /8.4, H7), 7.21-7.20 (IH, t, /2.8, H2), 7.10-7.08 (IH, dd, /8.4, / 1.6, H6), 6.52-6.51 (IH, m, H3), 4.28-4.25 (IH, dd, /7.6, /4.8, H2'), 4.02-3.93 (IH, m, H3'), 3.75 (3H, s, H6'), 3.73-3.66 (IH, m, H3'), 3.26-3.21 (IH, dd, / 14.0, /4.8, Hl '), 3.19-3.14 (IH, dd, / 14.2, /7.8, Hl'); Sc (CDCl₃) 171.50 (C), 134.91 (Q, 128.05 (C), 127.72-119.40 (C, q, /277.0), 127.42 (C), 124.43 (CH), 123.62 (CH), 121.25 (CH), 110.84 (CH)₁ 102.47 (CH), 82.02 (CH), 68.40-67.38 (CH₂, q, /34.0), 52.11 (CH₂), 39.17 (CH₂); m/z (EI⁺) 301 ([M]⁺, 100), 242 (65), 201 ([M-CH₂CH₃-CH₂CF₃J⁺, 39), 131 (80); found [M+H]\ 301.0923, C₁₄H₁₄F₃NO₃ requires [M+H]⁺, 301.0926; Found: C, 55.9; H, 4.7; N, 4.6. Required: C, 55.8; H, 4.7; N, 4.7; Δ = -1.0 ppm.

3-(lH-indol-5-yl)-2-(2,2,2-triflιιoroethoxy)propanoic acid 2

To a very pale yellow solution of the starting material 15 (40.4 mg, 0.134 mmol, 1.00 eq) in a mixture of ethanol/water 1:1 (1.60 ml), were added the potassium hydroxide pellets (9.60 mg, 0.171 mmol, 1.30 eq) and the solution was stirred at 78 °C for 15 hr. The solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~5 drops) until a pH of 1 was reached. The desired acid crashed out. It was dissolved in DCM and washed with water (2x30.0 ml). The aqueous phase was extracted with DCM/MeOH 99:1 (4x50.0 ml). After drying over MgSO₄ and filtration, concentration in vacuo gave 38.1 mg (93%) of the product as a pale yellow oil: R_f 0.25 [Solvent A]; v_mm (DCM film)/cm^"' 3415, 2933, 1726, 1279, 1167; & (CDCl₃/MeOD 2:1) 9.85 (IH, br, OH), 7.45 (IH, s, H4), 7.29-7.27 (IH, d, / 8.0, H7), 7.14-7.13 (IH, m, H2), 7.04-7.01 (IH, dd, J8.4, / 1.6, H6), 6.38-6.37 (IH, m, H3), 4.20-4.17 (IH, dd, /8.4, /4.0, H2'), 3.97-3.87 (IH, m, lxH3'), 3.70-3.60 (IH, m, lxH3'), 3.21-3.16 (IH, dd, / 14.2, /4.2, Hl '), 3.09-3.04 (IH, dd, / 14.2, / 8.2, Hl '); S₀ (CDCl₃/MeOD 2: 1) 173.97 (C), 135.68 (C), 128.53 (C), 128.33-120.02 (C, q, /277.0), 127.67 (CH), 125.20 (CH), 123.52 (CH), 121.31 (CH), 111.40 (CH), 101.73 (CH), 82.44 (CH), 68.69-67.66 (CH₂, q, / 68.5, /34.5), 39.63 (CH₂); m/z (EI⁺) 287 ([M]⁺, 18), 130 ([M-(ethoxypropanoic acid side chain)]*, 100); found [M+H]⁺, 287.0763, C₁₃H₁₂NO₃F₃ requires [M+H]⁺, 287.0769; Found: C, 54.7; H, 4.2; N, 4.8. Required: C, 54.4; H, 4.2; N, 4.9; Δ = -2.0 ppm.

Example 3

Preparation of 3-(2-Benzyl- lH-indol-5-yl)-2-ethoxy-proDanoic acid 3

l-Benzenesulfonyl-lH-indole-5-carbonitrile 24 To a vigorously stirred mixture of indole-5-carbonitrile 23 (864 mg, 6.08 mmol, 1.00 eq) and n- tetrabutylammonium bromide (197 mg, 0.609 mmol, 0.10 eq) in 50% aqueous NaOH (5.90 ml), toluene (5.00 ml) and water (9.00 ml) was added dropwise, over 30 min, benzenesulfonyl chloride (0.850 ml, 0.688 mmol, 1.10 eq) in toluene (4.00 ml) via a syringe pump. The reaction flask was covered with aluminium foil and the mixture stirred at RT for 25 hr. The solution was yellow. After removal of the aqueous phase, the organic phase was washed with 0.1 M NaHCO₃ (20.0 ml), water (75.0 ml) and saturated brine (75.0 ml). After extractions with EtOAc (3x70.0 ml), the organic phase was dried over MgSO₄ and concentrated in vacuo to give an off-white powder (1.69 g) which was purified by crystallisation from hexane/DCM 20:1 to yield 1.65 g (96%) of the product as white needles: mp 131.0-133.5 ⁰C (hexane/DCM 20:1); R_f 0.35

[hexane/EtOAc 6:4]; v;_mx (nujoiycm ¹ 2222, 1458, 1375, 1080, 721; 4 (CDCl₃) 8.10-8.08 (IH, d, /8.4, lxH2'), 7.90-7.89 (3H, m, lxH2\ H4, W), 7.71-7.70 (IH, d, /3.6, H2), 7.62-7.56 (2H, m, 2xH3'), 7.51-7.47 (2H, t, /7.8, H4', H6), 6.74-6.73 (IH, d, J 3.6, H3); S₀ (CDCl₃) 137.73 (C), 136.43 (C), 134.42 (CH), 130.65 (C), 129.54 (CH), 128.37 (CH), 127.59 (CH), 126.77 (CH), 126.36 (CH), 119.18 (C), 114.27 (CH), 108.65 (CH), 107.03 (Q; m/z (EI⁺) 282 ([M]', 50), 141 ([M-BzSulfonyl group]^"1", 66), 114 ([unsubstituted indole]^"1", 12), 77 (100); found [M+H]⁺, 282.0474, Ci₅H₁₀N₂O₂S requires [M+Hf, 282.0463; Found: C, 63.7; H, 3.5; N, 9.9. Required: C, 63.8; H, 3.6; N, 9.9; Δ = 3.9 ppm.

2-Benzyl-l-(phenylsulfonyl)-lH-indole-5-carbonitrile 25

To a pale yellow solution of benzenesulfonyl indole 24 (210 mg, 0.743 mmol, 1,00 eq) in anhydrous THF (2.10 ml), was added dropwise a 1.7M /-BuLi solution in pentane (0.520 ml, 0.891 mmol, 1.20 eq) over 8 min, at -45 ⁰C, under a constant flow of N₂. The solution which had turned dark yellow, then dark green was stirred at -45 ⁰C to -30 ⁰C over 55 min, cooled down to - 45 ⁰C before the dropwise addition of benzyl bromide (108 μL, 0.906 mmol, 1.22 eq) diluted in dry THF (1.50 ml) over 8 min. The reaction mixture was allowed to warm up to -10 ⁰C over 55 min. The reaction mixture turned brown and finally orange. It was put in an ice bath for 55 min, before being allowed to warm up to RT over 15 hr. The reddish brown reaction mixture was poured over 5% citric acid (30.0 ml) and the organic phase was washed with water (30.0 ml). The aqueous phase was extracted with DCM (4x30.0 ml). The organic phase was dried over MgSO₄ and concentrated in vacuo to give an off-white solid (1.02 g) which was purified by flash column chromatography on silica gel (hexane/EtOAc 20:1, 15:1, 10: 1) to yield 55.0 mg (51%) of the product as a yellow oil. Crystallisation from hexane/DCM 20:1 yielded the product as white needles: mp 130.5-131.5 ⁰C (hexane/DCM 20:1); R_f 0.20 [hexane/EtOAc 8:2]; v_mm (nujol)/cm^'' 2220, 1460, 1371, 1053; 4 (CDCl₃) 8.29-8.27 (IH, d, J 8.8, H7), 7.71 (IH, s, H4), 7.67-7.65 (2H, d, J 7.6, H2'), 7.60-7.56 (IH, t, /7.6, H4'), 7.55-7.53 (IH, dd, /8.8, / 1.2, H6), 7.44-7.40 (2H, t, /8.8, H3'), 7.34-7.29 (3H, m, H8\ H9'), 7.20-7.18 (2H, m, H7'), 6.16 (IH, s, H3), 4.37 (2H, s, 2x1-15'); δc (CDCl₃) 143.63 (C), 138.98 (C), 138.59 (C), 136.99 (C), 134.19 (CH), 129.46 (CH), 129.38 (C), 129.33 (CH), 128.69 (CH), 127.18 (CH), 127.03 (CH), 126.39 (CH), 125.04 (CH), 119.32 (C), 115.35 (CH), 110.07 (CH), 107.10 (C), 35.12 (CH₂); m/z (EI⁺) 372 ([M]⁺, 57), 284 ([M-Bn group]⁺, 30), 230 ([M-Bzsulfonyl group]*, 100), 141 (11), 115 ([indole]*, 5), 91 (12), 77 (47); found [M+H]⁺, 372.0934, C₂₂H₁₆N₂O₂S requires [M+H]⁺, 372.0932; Found: C, 71.0; H, 4.2; N, 7.6. Required: C, 71.0; H, 4.3; N, 7.5; Δ = 0.5 pprn. Crystal data for 25: C₂₂H₁₆N₂O₂S, M= 372.43, monoclinic, Pl₁In (no. 14), a = 10.8591(3), b = 10.0425(3), c = 17.0542(4) A, β =

100.888(3)°, F= 1826.32(9) A³, Z= 4, D₀ = 1.354 g cm^"3, μ(Mo-Kα) = 0.197 mm^"1, T= 173 K, colourless blocks, Oxford Diffraction Xcalibur 3 diffractometer; 4231 independent measured reflections, F² refinement, R_\ = 0.044, wR₂ = 0.101, 2710 independent observed absorption- corrected reflections [|F₀| > 4σ(|F₀|), 2θ_mm = 58°], 245 parameters. CCDC 667594.

2-Benzyl-lH-indole-5-carbonitrile 27To a solution of MeOH/NaOH 2M 5:1 (25.0 ml) was added the 2-benzyl indole 25 (141 mg, 0.379 mmol, 1.00 eq) and the reaction mixture was refluxed at 110 ⁰C for 18 hr. After allowing the reaction mixture to cool down to RT, it was treated with 0.1M HCl to a pH of 2 and the aqueous phase was extracted with DCM (4x25.0 ml). Concentration in vacuo of the organic phase gave a greenish oil (96.0 mg) which was purified by flash column chromatography on silica gel (hexane, hexane/EtO Ac 10: 1, 9:1, 8:2) to yield 87.0 mg (99%) of the product as an off-white solid: mp 119.5-120.5 ⁰C (hexane/DCM 20:1); R_f 0.25 [hexane/EtOAc 7:3]; v_ιmx (nujol)/cin ' 3300, 3056-2850, 2229, 1373, 1056, 740; S_n (CDCl₃) 8.12 (IH, br, Hl), 7.88 (IH, s, H4), 7.38-7.25 (6H, m, H4', H7, H5', H6, H3'), 6.41 (IH, s, H3), 4.16 (2H, s, H5'); S₀ (CDCl₃) 140.38 (C), 137.94 (C), 137.53 (C), 128.94 (2xCH), 128.82 (2xCH), 128.49 (C), 127.10 (CH), 125.40 (CH), 124.49 (CH), 120.82 (C), 111.26 (CH), 102.84 (C), 101.66 (CH), 34.59 (CH₂); m/z (EI⁺) 232 ([M]⁺, 100), 231 (64), 155 (71), 91 (16), 84 (21), 49 (23), 43 (25); found [M+H]⁺, 232.1002, C₁₆H,₂N₂ requires [M+H]⁺, 232.1000; Found: C, 82.9; H, 5.1; N, 11.9. Required: C, 82.7; H, 5.2; N, 12.1; Δ = 0.9 ppm.

2-Ben∑yl-lH-indole-5-carbaldehyde 29

To a clear colourless solution of 2-Benzyl-li7-indole-5-carbonitrile 27 (411 mg, 1.77 mmol, 1.00 eq) in anhydrous DCM (8.00 ml) under a constant flow of N₂, at 0 ⁰C, was added dropwise the DIBAL-H solution, 1.0M in DCM (2.20 ml, 2.20 mmol, 1.24 eq) over 7 min. The reaction mixture which turned pale yellow was allowed to warm up to RT over 16 hrs. To the bright yellowish orange solution was added 1.0M Rochelle solution (17.0 ml) at 0 °C. Caution: evolution of gas. The reaction mixture was stirred at RT for 4.5 hr. The two phases were separated and the aqueous phase extracted with DCM (4x20.0 ml). The solvent was removed in vacuo, and the orange slurry was dissolved in DCM (10.0 ml) and stirred with IM HCl (2,90 ml) at RT for 1 hr 40 min. Water (13.0 ml) was added, and the pH adjusted to 14 using 2M NaOH (2.90 ml). The produce was extracted with DCM (4x20.0 ml) and the organic phase was washed with water (60.0 ml) and brine (60.0ml). After extraction of the aqueous phase with DCM (4x60.0 ml), drying over MgSO₄ and concentration in vacuo, an orange powder was obtained. The crude was purified by flash column chromatography on silica gel (hexane/EtOAc 10: 1, 9: 1) to yield 332 mg (80%) of the product as a pale orange amorphous powder: mp 126.5-127.5 ⁰C (hexane/DCM 20:1); R_f 0.20 [hexane/EtOAc 7.5:2.5]; v_mκ (nujol)/cm^'' 3324, 3056-2850, 1671, 1373, 1056, 739; 4 (CDCl₃) 10.01 (IH, s, Hl"), 8.08 (2H, br, Hl, H4), 7.71-7.69 (IH, dd, /8.6, / 1.4, H6), 7.38-7.28 (6H, m, 2xH4', H7, H5', 2xH3'), 6.49 (IH, br, H3), 4.17 (2H, s, H5'); S_c (CDCl₃) 192.47 (CH), 139.95 (C), 139.88 (C), 137.76 (C), 129.67 (CH), 128.87 (2xCH), 128.81 (2xCH), 128.54 (C), 127.00 (CH), 125.05 (CH), 122.10 (CH), 111.04 (CH), 102.58 (CH), 34.65 (CH₂); m/z (EI⁺) 235 ([M]⁺, 100), 206 ([M-aldehyde]⁺, 27), 167 (30), 158 (42), 149 (30), 91 (14); found [M+H]⁺, 235.0997, Ci₆Hi₃NO requires [M+H]\ 235.0997; Found: C, 81.6; H, 5.5; N, 5.9. Required: C, 81.7; H, 5.6; N, 6.0; Δ = 0.0 ppm.

(Z)-EtHyI 3-(2-benzyl-lH-indol-5-yl)-2-ethoxyacrylate 31 and (E)-ethyl 3-(2-ben∑yl-lH-indol-5- yl)-2-ethoxyacrylate 32

To a milky suspension of sodium hydride (19.5 mg, 0.488 mmol, 2.31 eq) in anhydrous THF (0.400 ml) at 0 ⁰C, was added dropwise, phosphonoacetate 8 (123 mg, 0.459 mmol, 2.17 eq) in THF (1.00 ml) over 10 min, under a constant flow of N₂. The pale yellowish solution was stirred at 0 ⁰C for 40 min before the dropwise addition of aldehyde 29 (49.7 mg, 0.211 mmol, 1.00 eq) in dry THF (1.00 ml) via syringe pump over 37 min. The solution which had turned orange was left stirring in the ice bath over 42 hr. The dark yellow solution was concentrated in vacuo, then dissolved in EtOAc (30.0 ml) and washed with water (35.0 ml). An emulsion was observed, thus some NaCl was added. The aqueous phase was extracted with EtOAc (4x45.0 ml). After drying the organic extract over MgSO₄, concentration in vacuo of the organic phase gave a deep orange slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 15: 1, 12: 1) to yield 66.0 mg (90%) of the product. Ratio Z:E = 63:37. Z isomer 31: colourless oil: R_f 0.20 [hexane/EtOAc 8:2]; v_mκ (DCM film)/cm-' 3441, 3055, 1743, 1646, 1051, 740; 4 (CDCl₃) 8.03 (IH, br, H4), 7.89 (IH, br, Hl), 7.65-7.62 (IH, dd, /8.4, J 1.6, H6), 7.37-7.33 (2H, m, H4'), 7.30-7.22 (4H, m, H3', H7, H5'), 7.17 (IH, s, Hl"), 6.36-6.35 (IH, d, J0.8, H3), 4.34-4.29 (2H, q, / 14.4, /7.2, H6"), 4.14 (2H, s, Hl'), 4.04-3.98 (2H, q, / 14.2, /7.1, H3"), 1.42-1.37 (6H, m, H7", H4"); δ_c (CDCl₃) 165.31 (C), 142.43 (C), 138.67 (C), 138.21 (C), 136.56 (C), 128.81 (2xCH), 128.77 (2xCH), 126.82 (CH), 126.30 (CH), 125.53 (2xC), 124.08 (CH), 122.71 (CH), 110.43 (CH), 101.73 (CH), 67.41 (CH₂), 60.87 (CH₂), 34.69 (CH₂), 15.56 (CH₃), 14.36 (CH₃); m/z (EI⁺) 349 ([M]⁺, 100), 292 ([M-ethyI]⁺, 17), 292 (32), 247 (36), 219 (26), 91 (50); found [M+H]⁺, 349.1672, C₂₂H₂₃NO₃ requires [M+H]⁺, 349.1678; Found: C, 75.6; H, 6.5; N, 3.9. Required: C, 75.6; H, 6.6; N, 4.0; Δ = -1.7 ppm. £ isomer 32: pale yellow oil: R_f 0.15 [hexane/EtOAc 8:2]; v_max (DCM filmycm-' 3441, 3055-2850, 1725, 1644, 1548, 1266, 1043, 738; A (CDCl₃) 7.75 (IH, br, Hl), 7.40 (IH, s, H4), 7.36-7.32 (2H, m, 2xH4'), 7.28-7.25 (3H, m, 2xH3', H5'), 7.16-7.14 (IH, d, J8.4, H7), 7.00-6.97 (IH, dd, /8.4, J 1.2, H6), 6.29 (IH, s, Hl"), 6.27 (IH, br, H3), 4.18-4.12 (4H, m, 2xH6", 2xHl '), 3.98-3.93 (2H, q, J 13.8, J 6.9, 2xH3"), 1.44-1.41 (3H, t, ./7.0, 3xH4"), 1.11-1.08 (3H, t, J7.0, 3xH7"); S₀ (CDCl₃) 165.20 (C), 146.16 (C), 138.41 (CJ, 138.16 (C), 135.44 (C), 128.81 (2xCH), 128.74 (2xCH), 126.76 (CH), 126.26 (2xC), 122.40 (CH), 119.96 (CH), 111.60 (CH), 110.00 (CH), 101.20 (CH), 64.63 (CH₂), 61.05 (CH₂), 34.73 (CH₂), 14.58 (CH₃), 13.77 (CH₃); m/z (EI⁺) 349 ([M]⁺, 16), 232 ([M- (benzyl+ethyl)]⁺, 100), 155 (77), 84 (42), 49 (56); found [M+H]⁺, 349.1671, C₂₂H₂₃NO₃ requires [M+H]⁺, 349.1678; Found: C, 75.7; H, 6.8; N, 3.9. Required: C, 75.6; H, 6.6; N, 4.0; Δ = -2.0 ppm.

Methyl 3-(2-benzyl-lH-indol-5-yl)-2-ethoxypropanoate 39

To a yellow solution of the starting material 31 and 32 (55.2 mg, 0.158 mmol, 1.00 eq) in anhydrous methanol (2.00 ml) at RT, under a constant flow of N₂, were added the magnesium turnings (20.6 mg, 0.847 mmol, 5.36 eq) in one portion and the reaction mixture was stirred at RT for 7 hr. A few more magnesium turnings were added as well as some dry methanol (1.00 ml) and the reaction mixture was stirred at RT for another 12 hr before being poured onto water (35.0 ml). The aqueous phase was extracted with DCM (4x30.0 ml) and the organic extracts were washed with brine (70.0 ml). After extraction with DCM (4x100 ml) and drying over MgSO₄, concentration in vacuo gave a yellowish oil which was purified by flash column chromatography on silica gel (hexane/ElOAc 15: 1, 10:1) to yield 40.6 mg (76%) of the product as a pale yellow oil: R_f 0.25 [hexane/EtOAc 7.5:2.5]; v_am (DCM film)/cm-' 3392, 3027-2900, 1741, 1644, 1446, 1115, 705; & (CDCl₃) 7.77 (IH, br, Hl), 7.41 (IH, br, H4), 7.36-7.32 (2H, m, H4'), 7.29-7.26 (3H, m, H3\ H5'), 7.17-7.15 (IH, d, J 8.4, H7), 7.02-7.00 (IH, dd, J 8,4, H6), 6.28 (IH, s, H3), 4.12 (2I-I, s, Hl'), 4.11-4.07 (IH, t, J6.6, H2"), 3.71 (3H, s, 3xH6"), 3.64-3.56 (IH, m, lxH3"), 3.41-3.34 (IH, m, lxH3"), 3.11-3.09 (2H, m, 2xHl"), 1.20-1.16 (3H, t, /6.8, H6"); <3fc (CDCl₃) 173.28 (C), 138.51 (C), 138.03 (C), 135.28 (C), 128.83 (C), 128.80 (2xCH), 128.68 (2xCH), 128.24 (C), 126.69 (CH), 122.91 (CH), 120.44 (CH), 110.16 (CH), 100.86 (CH), 81.04 (CH), 66.19 (CH₂), 51.73 (CH₂), 39.55 (CH₂), 34.72 (CH₂), 15.06 (CH₃); m/z (EI⁺) 337 ([M]⁺, 37), 234 ([M-(benzyl + methyl groups)]⁺, 81), 220 ([M-(benzyl+2 methyl groups)]^4", 100), 91 (29); found [M+H]⁺, 337.1664, C₂₁H₂₃NO₃ requires [M+H]⁺, 337.1678; Found: C, 79.9; H, 5.2.; N, 4.2. Required: C, 74.8; H, 6.9; N, 4.2; Δ = -4. L ppm.

3-(2-Benzyl-lH-indol-5-yl)-2-ethoxy-propanoic acid 3

To a yellow solution of the starting material 39 (33.4 mg, 0.099 mmol, 1.00 eq) in a mixture of ethanol/water 1:1 (1.0 ml), were added the potassium hydroxide pellets (10.0 mg, 0.178 mmol, 1.80 eq) and the yellow solution was stirred at 82 ⁰C for 14 hr. The yellow solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~10 drops) until a pH of 1 was reached. The desired acid crashed out as a brown ppt. It was dissolved in DCM and washed with water (35.0 ml). The aqueous phase was extracted with DCM (4x30.0 ml). After drying over MgSCU, concentration in vacuo gave 29.8 mg (93%) of the product as a yellowish oil: R_f 0.20 [hexane/EtOAc 1:1]; v_mm (DCM film)/cm^"1 3620, 3398, 1710, 1646, 1461, 1108; S_n (CDCl₃) 7.77 (IH, br, Hl), 7.42 (IH, s, H4), 7.36-7.32 (2H, m, H4'), 7.29- 7.25 (3H, m, H3\ H5'), 7.18-7.16 (IH, d, J 8.4, H7), 7.03-7.00 (IH, dd, ./8.2, J 1.4, H6), 6.28 (IH, s, H3), 4.14-4.12 (3H, m, lxH2", 2xHl'), 3.63-3.56 (IH, m, lxH3"), 3.49-3.42 (IH, m, lxH3"), 3.25-3.20 (IH, dd, J 14.2, J4.2, Hl"), 3.11-3.09 (IH, dd, J 14.2, /7.8, Hl "), 1.20-1.16 (3H, t, J7.0, H4"); & (CDCl₃) 175.40 (C), 138.45 (C), 138.15 (C), 135.35 (C), 128.86 (C), 128.81 and 128.70 (2xCH each), 127.69 (Q, 126.71 (CH), 122.95 (CH), 120.63 (CH), 110.27 (CH), 100.89 (CH), 80.36 (CH), 66.82 (CH₂), 38.85 (CH₂), 34.71 (CH₂), 15.05 (CH₂); m/z (EI⁺) 323 ([M]⁺, 16), 220 ([M-(benzyl+methyl group)]⁺, 88), 199 (29), 171 (M-(benzyl + ether side chain + OH)]⁺, 100), 127 (51), 57 (53); found [M+H]⁺, 323.1520, C₂₀H₂₁NO₃ requires [M+H]⁺, 323.1521; Found: C, 74.2; H, 6.5; N, 4.4. Required: C, 74.3; H, 6.6; N, 4.3; Δ = -0.3 ppm.

Example 4

Preparation of 3-(2-Benzyl-lH-indol-5-yl')-2-(2.2,2-trifluoroethoxy^')proρanoic acid 4

(Z)-Ethyl 3-(2-benzyl-lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy)acrylate 33 and (E)-ethyl 3-(2- benzyl-lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy)acrylate 34

To a milky suspension of sodium hydride (17.0 mg, 0.425 mmol, 1.37 eq) and molecular sieves 4A in anhydrous THF (1.40 ml) at 0 ⁰C, under a constant flow OfN₂, was added dropwise via syringe pump, phosphonoacetate 9 (112 mg, 0.347 mmol, 1.12 eq) in THF (1.20 ml) over 12 min. The suspension turned into a clear pale yellow solution. The latter was stirred at 0 ⁰C for 29 min before the dropwise addition of aldehyde 29 (73.0 mg, 0.310 mmol, 1.00 eq) in dry THF (1.60 ml) via syringe pump over 38 min. The solution turned dark yellow. It was left to stir in the ice bath over 24 hr and at RT for another 16 lir, before being concentrated in vacuo. It was re- dissolved in EtOAc (30.0 ml) and washed with water (35.0 ml). Some NaCl was added. The 2 phases were separated and the aqueous phase was extracted with EtOAc (4x50.0 ml). After drying the organic extracts over MgSO₄, concentration in vacuo of the organic phase gave a yellowish slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 15:1, 10:1) to yield 107 mg (85%) of the product. Ratio Z:E= 39:61. Z isomer 33: yellow amorphous powder; mp 120.5-121.5 ⁰C (hexane/DCM 20: 1); R_f 0.30 [hexane/EtOAc 7.5:2.5]; v_im (DCM film)/crn ^l 3441, 1743, 1548, 1371, 1265, 1055; 4(CDCl₃) 8.02 (IH, s, H4), 7.90 (IH, br, Hl), 7.60-7.58 (IH, dd, 78.6, / 1.4, H6), 7.37-7.34 (2H, m, 2xH4'), 7.30-7.24 (5H, m, 2xH3', H5', Hl", H7), 6.38-6.37 (IH, d, 71.2, H3), 4.40-4.30 (4H, m, 2xH3", 2xH6"), 4.14 (2H, s, 2xHl'), 1.42-1.38 (3H, t, 77.0, 3xH7"); S₀ (CDCl₃) 164.08 (C), 140.33 (C), 138.91 (C), 138.10 (C), 136.91 (C), 128.88 (C), 128.81 (2xCH), 128.80 (2xCH), 127.57-119.27 (C, q, 7

277.0), 127.52 (CH), 126.87 (CH), 124.33 (CH), 124.24 (C), 123.36 (CH), 110.61 (CH), 101.85 (CH), 68.32-67.28 (CH₂, q, 7 35.0), 61.30 (CH₂), 34.66 (CH₂), 14.28 (CH₃); m/z (EI⁺) 403 ([M]¹, 45), 252 (25), 221 ([M-propanoic acid side chainf, 100), 91 (27); found [M+H]⁺, 403.1392, C₂₂H₂₀F₃NO₃ requires [M+H]⁺, 403.1395; Found: C, 65.4; H, 4.9; N, 3.5. Required: C, 65.5; H, 5.0; N, 3.5; Δ = -0.7 ppm. E isomer 34: pale yellow oil: R_f 0.25 [hexane/EtOAc 7.5:2.5]; i/_mnx (DCM filmycrn ¹ 3441, 1743, 1548, 1265, 1053; 4(CDCl₃) 7.84 (IH, br, Hl), 7.53 (IH, s, H4), 7.37-7.33 (2H, m, 2xH3')_; 7.30-7.25 (3H, m, 2xH4', H5'), 7.19-7.16 (IH, d, 78.4, H7), 7.10-7.07 (IH, dd, 78.4, 7 1.6, H6), 6.71 (IH, s, Hl"), 3.61 (IH, br, H3), 4.30-4.23 (2H, q, 7 16.8, 78.4, 2xH3"), 4.23-4.18 (2H, q, 714.4, 7 7.2, 2xH6"), 4.12 (2H, s, 2xHl'), 1.18-1.15 (3H, t, 77.0, 3xH7"); δ_c (CDCl₃) 163.53 (C), 143.28 (C), 138.55 (C), 138.26 (C), 136.03 (C), 128.79 (2xCH), 128.74 (2xCH), 128.54 (C), 127.38-119.08 (C, q, 7277.0), 126.79 (CH), 124.31 (C), 122.75 (CH), 121.76 (CH), 120.95 (CH), 110.08 (CH), 101.32 (CH), 68.16-67.11 (CH₂, q, 735.0), 61.26 (CH₂), 34.65 (CH₂), 13.78 (CH₃); m/z (EI⁺) 403 ([M]⁺, 45), 252 (25), 221 ([M-propanoic acid side chainf, 100), 91 (27); found [M+H]⁺, 403.1392, C₂₂H₂₀F₃NO₃ requires [M+H]⁺, 403.1395; Found: C, 65.5; H, 5.0; N, 3.4. Required: C, 65.5; H, 5.0; N, 3.5; Δ = -0.7 ppm.

Methyl 3-(2-benzyl-lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy)propanoate 40

To a mixture of the starting material 33 and 34 (67.6 mg, 0.168 mmol, 1.00 eq) and the magnesium turnings (61.9 mg, 2.55 mmol, 15.2 eq) at RT, under a constant flow OfN₂, was added the anhydrous methanol (2.50 ml). After stirring at RT for 4 hr, the yellowish orange solution turned into a pale yellowish slurry. It was poured onto water (20.0 ml). The 2 phases were separated and the aqueous phase was extracted with DCM (4x25.0 ml). The organic extracts were washed with brine (80.0 ml). The aqueous phase was extracted with DCM (4x65.0 ml). After drying over MgSO₄, concentration in vacuo gave an orangish slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 15: 1, 10:1, 9:1, 8:2) to yield 48.0 mg (73%) of the product as a very pale yellow oil: R_f 0.15 [hexane/EtOAc 8:2]; v_max (DCM film)/cm^" ¹ 3361, 2920-2846, 1741, 1448, 1275, 1157, 790; 4(CDCl₃) 7.76 (IH, br, Hl), 7.40 (IH, s, H4), 7.36-7.32 (2H, m, 2xH4'), 7.28-7.25 (3H, m, 2xH3', H5'), 7.18-7.16 (IH, d, J8.4, H7), 7.01-6.98 (IH, dd, J8.2, J 1.4, H6), 6.28 (IH, br, H3), 4.26-4.23 (IH, m, H2"), 4.128 (2H, s, 2xHl'), 3.99- 3.93 (IH, m, H3"), 3.74-3.66 (4H, m, 3xH6", H3"), 3.21-3.11 (2H, m, 2xHl"); S₀ (CDCl₃) 171.50 (C), 138.43 (C), 138.16 (C), 135.37 (C), 128.86 (C), 128.81 (2xCH), 128.70 (2xCH), 128.08-119.39 (C, q, J278.0), 127.28 (C), 126.72 (CH), 122.85 (CH), 120.54 (CH), 110.29 (CH), 100.88 (CH), 82.02 (CH), 68.36-67.34 (CH₂, q, /34.5), 52.08 (CH₃), 39.17 (CH₂), 34.69 (CH₂); m/z (EI⁺) 391 ([M]⁺, 27), 220 ([M-propanoic acid side chainf, 100), 49 (23); found [M+H]⁺,

391.1394, C_2IH₂₀F₃NO₃ requires [M+H]⁺, 391.1395; Found: C, 64.5; H, 5.1; N, 3.5. Required: C, 64.4; H, 5.2; N, 3.6; Δ = -0.3 ppm.

3-(2-Benzyl-lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy)propanoic acid 4 Indole 40 (14.6 mg, 0.037 mmol, 1.00 eq) was refluxed with potassium hydroxide pellets (4.90 mg, 0.087 mmol, 2.34 eq) in a mixture of ethanol/water 1:1 (1.60 ml) at 82 ⁰C for 15 hr. The pale yellow solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~5 drops) until a pH of 1 was reached. The desired acid crashed out as a brown ppt. DCM was added and the 2 phases were separated. The aqueous phase was extracted with DCM (4x20.0 ml). After drying over MgSO₄, concentration in vacuo gave 14.0 mg (99%) of the product as a pale yellow oil: R_f 0.20 [hexane/EtOAc 1:9]; κ_max (DCM filmVcm^"1 3289, 2950-2850, 1702, 1651, 1425, 1053; 4 (CDCl₃) 7.76 (IH, br, Hl), 7.43 (IH, s, H4), 7.34-7.32 (2H, m, 2xH4'), 7.28-7.25 (3H, m, 2xH3', H5'), 7.19-7.17 (IH, d, /8.4, H7), 7.03-7.01 (IH, dd_; J8.2, J 1.4, H6), 6.29 (IH, d, J0.8, H3), 4.31-4.27 (IH, dd, 78.0, J4.4, H2"), 4.13 (2H, s, 2xHl'), 3.96-3.87 (IH, m, lxH3"), 3.77-3.70 (IH, m, lxH3"), 3.30-3.26 (IH, J 14.2, ,/4.2, IxHl"), 3.18-3.13 (IH, J 14.0, ./ 8.0, IxHl"); S₀ (CDCl₃) 174.74 (C), 138.37 (C), 138.31 (C), 135.46 (C), 128.93 (C), 128.83 (2xCH), 128.74 (2xCH), 127.57-119.26 (C, q, J 277.0), 126.92 (C),, 126.77 (CH), 122.86 (CH), 120.67 (CH), 110.43 (CH), 100.93 (CH), 81.63 (CH), 68.64-67.61 (CH₂, q, J 34.5), 38.98 (CH₂), 34.72 (CH₂); m/z (EI⁺) 377 ([M]⁺, 30), 220 ([M- propanoic acid side chain]*, 100), 142 (9), 91 (12); found [M+H]⁺, 377.1244, C₂₀Hi₈F₃NO₃ requires [M+H]⁺, 377.1239; Found: C, 63.5; H, 4.7; N, 3.7. Required: C, 63.7; H, 4.8; N, 3.7; Δ = 1.3 ppm.

Example 5

Preparation of 2-Ethoxy-3-(2-diaphthalen-2-ylmethyl)-lH-indol-5-yl^')propanoic acid 5

2-(Naphthalen-2-ylmethyl)-l-(phenylsulfonyl)-lH-indole-5-carbonitrile 26 To a very pale yellow solution of indole-carbonitrile 24 (905 mg, 3.20 mmol, 1.00 eq) in anhydrous THF (10.0 ml), was added dropwise a 1.7M f-BuLi solution in pentane (2.30 ml, 3.91 mmol, 1.22 eq) over 8 min, at - 48 to -45 ⁰C, under a constant flow of N₂. The solution which had turned dark yellow, then dark green was stirred at -45 ⁰C to -30 ⁰C over 55 min, cooled down to -45 ⁰C before the dropwise addition of 2-(bromomethyl)naphthalene (887 mg, 4.01 mmol, 1.25 eq) diluted in dry THF (2.00 ml) over 7 min. The reaction mixture was allowed to warm up to -10 ⁰C over 50 min whereupon it turned brown. It was next put in an ice bath for 50 min, before being allowed to warm up to RT over 25 hr. The brown reaction mixture was poured over 5% citric acid (10.0 ml) and the organic phase was washed with brine (50.0 ml). The aqueous phase was extracted with DCM (4x50.0 ml). The organic phase was dried over anhydrous K₂CO₃ and concentrated in vacuo to give a brown oil (1,73 g) which was purified by flash column chromatography on silica gel (hexane/EtOAc 25: 1, 20: 1 , 15: 1) to yield 406 mg (30%) of the product as a yellow oil. Crystallisation from hexane/DCM 20:1 afforded shiny white needles: mp 142.0-143.0 ⁰C (hexane/DCM 20:1); R_f 0.30 [hexane/EtOAc 7:3]; v_maκ (nujoiycrn ¹ 2950-2850, 2222, 1651, 1548, 1379, 1055; 4 (CDCl₃) 8.32-8.30 (IH, d, /8.8_; HT), 7.86-7.83 (IH, m), 7.81-7.87 (IH, d, J8.4), 7.73-7.71 (2H, m), 7.64- 7.62 (2H, dd, J 8.6, / 1.0), 7.59 (IH, br, H4), 7.57-7.54 (IH, dd, J 8.8, J 1.6, H6), 7.50-7.46 (3H, m, 2xH3'), 7.32-7.28 (3H, m), 6.21 (IH, br, H3), 4.53 (2H, s, 2xH5'); S₀ (CDCl₃) 143.41 (C), 139.07 (C), 138.57 (C), 134.41 (C), 134.09 (CH), 133.47 (C), 132.44 (C), 129.34 (CH), 128.36 and 127.95 (2xCH), 127.65, 127.61, 127.45, 127.25, 126.29, 126.25, 125.92, 125.08 (8xCH), 119.32 (C), 115.38 (CH), 110.30 (CH), 107.14 (C), 35.24 (CH₂); m/z (EI⁺) 422 ([M]⁺, 61), 280 ([M-methyl naphthyl groupf, 100), 141 (34), 77 (34); found [M+H]⁺, 422.1087, C₂₆Hi₈N₂O₂S requires [M+H]⁺, 422.1089; Found: C, 74.0; H, 4.2; N, 6.6. Required: C, 73.9; H, 4.3; N, 6.6; Δ = -0.5 ppm. Crystal data for 26: C₂₆Hi₈N₂O₂S, M= 422.48, monoclinic, Pl_xIn (no. 14), a = 18.0309(4), b = 5.88641(15), c = 19.5220(4) A, β = 98.636(2)°, F= 2048.52(19) A³, Z= 4, D_c = 1.370 g cm^"3, μ(Cu-Kα) = 1.615 mm^"1, T= 173 K, colourless needles, Oxford Diffraction Xcalibur PX Ultra diffractometer; 3230 independent measured reflections, F² refinement, R_x = 0.040, wR₂ = 0.076, 1894 independent observed absorption-corrected reflections [\F₀\ > 4σ(|F₀|), 2θ_max = 126°], 280 parameters. CCDC 667595.

2-(Naphthalen-2-ylmethyl)-lH-indole-5-carbonitrile 28 To a solution of MeOH (65.0 ml), NaOH 2M (12.5 ml) was added the indole 26 (503 mg, 1.19 mmol, 1.00 eq) and the reaction mixture was refluxed at 76 ^°C for 17 hr. After allowing the reaction mixture to cool down to RT, the clear colourless solution was poured onto 2M HCl (14.0 ml) to a pH of 3 and the aqueous phase was extracted with DCM (5x70.0 ml). Concentration in vacuo of the organic phase gave a white solid which was washed with water. Concentration in vacuo yielded 335 mg (99%) of the product as an amorphous white powder: mp 152.0-153.0 ⁰C (hexane/DCM 20:1); R_f 0.25 [hexane/EtOAc 7:3]; v_ma* (nujoiycm^'1 3206, 2980-2850, 2215, 1461, 1371, 1053; 4 (CDCl₃) 8.13 (IH, br, Hl), 7.89 (IH, s), 7.86-7.80 (3H, m), 7.73 (IH, s, H4), 7.54-7.47 (2H, m), 7.37-7.34 (2H, m, H6), 7.28-7.26 (IH, d, J8.4, H7), 6.46 (IH, d, 70.8, H3), 4.33 (2H, s, Hl'); S₀ (CDCl₃) 140.25 (C), 137.95 (C), 134.96 (C), 133.54 (C), 132.47 (C), 128.76 (CH), 128.51 (C), 127.74, 127.54, 127.30, 127.23, 126.99, 126.47, 125.99, 125.44, 124.53 (1 IxCH), 120.81 (C), 111.28 (CH), 102.88 (C), 101.77 (CH), 34.79 (CH₂); m/z (EI⁺) 282 ([M]⁺, 100), 155 (52); found [M+H]⁺, 282.1142, C₂₀H₁₄N₂ requires [M+H]⁺, 282.1157; Found: C, 85.1; H, 4.9; N, 9.9. Required: C, 85.1; H, 5.0; N, 9.9; Δ = -5.3 ppm.

2-(Naphthalen-2-ylmethyl)-lH-indole-5-carbaldehyde 30

To a clear colourless solution of indole 28 (312 mg, 1.10 mmol, 1.00 eq) in anhydrous DCM (5.50 ml) under a constant flow OfN₂, at 0 ⁰C, was added dropwise the DIBAL-H solution, 1.0M in DCM (1.50 ml, 1.50 mmol, 1.36 eq). The reaction mixture turned pale yellow, it was allowed to warm up to RT over 14 hr. To the bright yellow solution was added a 1.0M Rochelle solution (10.2 ml) at 0 °C. Caution: evolution of gas. The reaction mixture was stirred at RT for 5 hr. The two phases were separated and the aqueous phase extracted with DCM (4x25.0 ml). The solvent was removed in vacuo, and the yellowish orange slurry was dissolved in DCM (10.0 ml) and stirred with IM HCl (1.70 ml) at RT for 2 hr 20 min. Water (7.70 ml) was added, and the pH adjusted to 13 using 2M NaOH (1.10 ml). The two phases were extracted with separated, the aqueous phase was extracted with DCM (4x20.0 ml) and the organic extracts washed with water (40.0 ml) and brine (40.0 ml). After extraction of the aqueous phase with DCM (4x40.0 ml), drying over MgSU₄ and concentration in vacuo, the off-white solid isolated was purified by flash column chromatography on silica gel (hexane/EtOAc 12:1, 10:1, 9:1, 7:3) to yield 272 mg (86%) of the product as an amorphous pale yellow powder: mp 162.5-163.5 ⁰C (hexane/DCM 20:1); R_r 0.20 [hexane/EtOAc 7.5:2.5]; v_mm (nujol)/cm^"1 3221, 2980-2850, 1660, 1306, 796; & (CDCVMeOD 1:2) 9.86 (IH, s, Hl"), 8.00 (IH, s, H4), 7.78-7.73 (3H, m), 7.69 (IH, s, Hl), 7.61-7.59 (IH, d, / 8.4, H6), 7.44-7.33 (4H, m, H7), 6.36 (IH, br, H3), 4.25 (2H, s, 2xHl'); & (CDCl₃/MeOD 1 :2) 194.21 (CH), 141.47 (C), 141.20 (C), 136.49 (C), 134.11 (Q, 132.84 (C), 129.29 (C), 129.08 (C), 128.65, 128.03, 127.96, 127.63, 127.51, 126.54, 126.02 (7xCH), 125.93 (CH), 121.94 (CH), 111.83 (CH), 102.50 (CH), 35.13 (CH₂); m/z (EI⁺) 285 ([M]⁺, 100), 254 ([M-aldehyde]⁺, 38), 158 (50), 158 (42); found [M+H]⁺, 285.1146, C₂₀Hi₅NO requires [M+H]⁺, 285.1154; Found: C, 84.1; H, 5.3; N, 4.9. Required: C, 84.2; H, 5.3; N, 4.9; Δ = -2.8 ppm.

(Z)-EtHyI 2-ethoxy-3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)acrylate 35 and (E)-ethyl 2- ethoxy-3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)acrylate 36

To a milky suspension of sodium hydride, 60% in oil (31.0 mg, 0.775 mmol, 2.18 eq) and molecular sieves 4A in anhydrous THF (4.00 ml) at 0 °C, under a constant flow of N₂, was added dropwise, phosphonoacetate 8 (173 mg, 0.644 mmol, 1.81 eq) in THF (1.20 ml) over 12 min. The pale yellowish solution was stirred at 0 ⁰C for 52 min before the dropwise addition of aldehyde 30 (102 mg, 0.356 mmol, 1.00 eq) in dry THF (2.00 ml) via syringe pump over 58 min. The solution which turned dark yellow was left to stir in the ice bath over 42 hr. The yellowish orange solution was concentrated in vacuo, re-dissolved in EtOAc (25.0 ml) and washed with water (30.0 ml). An emulsion was observed, thus some NaCl was added. The aqueous phase was extracted with EtOAc (4x40.0 ml). After drying the organic extracts over MgSO₄, concentration in vacuo of the organic phase gave an orange slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 12: 1, 9:1, 8:2, EtOAc) to yield 112 mg (79%) of the product. Ratio Z:E = 63:37. Z isomer 35: colourless oil: R_f 0.30 [hexane/EtOAc 7:3]; M_nax (DCM fϊlm)/cm^"' 3352, 3053-2900, 1701, 1620, 1252, 1095, 740; & (CDCl₃) 8.06 (IH, s, H4), 7.98 (IH, br, Hl), 7.86-7.78 (3H, m), 7.72 (IH, s), 7.66-7.64 (IH, dd, J 8.6, / 1.0, H6), 1.52-1 Al (2H, m), 7.39-7.37 (IH, dd, /8.4, / 1.2), 7.23-7.21 (IH, d, /8.4, H7), 7.19 (IH, s), 6.41 (IH, br, H3), 4.34-4.29 (4H, m, 2xH6", 2xHl '), 4.05-4.00 (2H, q, / 14.2, /7.0, 2xH3"), 1.43-1.37 (6H, m, 3xH4", 3xH7"); <5fc (CDCl₃) 165.32 (C), 142.39, 138.60, 136.60, 135.70, 133.52, 132.36, 128.81 (7xC), 128.45, 127.67, 127.53, 127.16, 127.12, 126.34, 126.26, 125.74 (8xCH), 125.48 (C), 124.07 (CH), 122.70 (CH), 110.50 (CH), 101.81 (CH), 67.40 (CH₂), 60.87 (CH₂), 34.83 (CH₂), 15.54 (CH₃), 14.32 (CH₃); m/z (EI⁺) 399 ([M]⁺, 78), 342 ([M-both ethyl groups]^4", 25), 297 (24), 141 (100); found [M+H]⁺, 399.1830, C₂₆H₂₅NO₃ requires [M+H]⁺, 399.1834; Found: C, 78.3; H, 6.2; N, 3.6. Required: C, 78.2; H, 6.3; N, 3.5; Δ = -1.0 ppm. E isomer 36: colourless oil: R_f 0.30 [hexane/EtOAc 7:3]; v_mm (DCM filmVcm^"1 3392, 3050-2900, 1712, 1635, 1228, 1153, 740;^ (CDCl₃) 7.85-7.79 (4H, m), 7.71 (IH, s), 7.52-7.45 (2H, m), 7.42 (IH, s, H4), 7.38-7.36 (IH, dd, /8.4, J 1.6), 7.14-7.12 (IH, d, J 8.4, H7), 7.00-6.98 (IH, dd, J 8.4, J 1.6, H6), 6.33-6.32 (IH, d, J 0.8, H3), 6.29 (IH, s, Hl"), 4.28 (2H, s, Hl '), 4.18-4.11 (2H, q, J 14.4, J7.2, 2xH6"), 3.98-3.93 (2H, q, J 13.8, J7.0, 2xH3"), 1.44-1.41 (3H, t, J6.8, 3xH4"), 1.11-1.08 (3H, t, 3xH7"); S₀ (CDCl₃) 165.19 (C), 146.09, 138.06, 135.90, 135.46, 133.52, 132.33, 128.67 (7xC), 128.39, 127.66, 127.52, 127.19, 127.07, 126.23 (6xCH), 126.20 (C), 125.69 (CH), 122.37 (CH), 119.92 (CH), 111.61 (CH), 110.05 (CH), 101.25 (CH), 64.60 (CH₂), 61.04 (CH₂), 34.70 (CH₂), 14.53 (CH₃), 13.73 (CH₃); m/z (EI⁴) 399 ([M] ^1", 72), 342 ([M-both ethyl groupsf, 24), 282 (34), 141 (100); found [M+H]⁺, 399.1832, C₂₆H₂₅NO₃ requires [M+H]⁺, 399.1834; Found: C, 78.3; H, 6.2; N, 3.6. Required: C, 78.2; H, 6.3; N, 3.5; Δ = -0.5 ppm.

Methyl 2-ethoxy-3-(2-(naphthalen-2-ylmethyl)~lH-indol-5-yl)propanoate 41

To a clear orange-brown solution of the starting material 35 and 36 (110 mg, 0.275 mraol, 1.00 eq) in anhydrous methanol (4.00ml) at RT, under a constant flow OfN₂, were added the magnesium turnings (68.5 mg, 2.82 mmol, 10.3 eq) in one portion. After stirring at RT for 4.5 hr, some starting material was still seen by MS. Therefore, were added, more magnesium turnings (46.7 mg, 1.92 mmol, 7.00 eq) and the reaction mixture was stirred for another 18 hr. The pale orangish suspension was poured onto water (30.01). The 2 phases were separated and the aqueous phase was extracted with DCM (4x25.0 ml). The organic extracts were washed with brine (50.0 ml). The aqueous phase was extracted with DCM (4x45.0 ml). After drying over MgSO₄, concentration in vacuo gave a pale yellow oil which was purified by flash column chromatography on silica gel (hexane/EtOAc 10: 1, 9:1, 8:2) to yield 85.0 mg (80%) of the product as a yellowish oil: R_f 0.15 [hexane/EtOAc 8:2]; v_mm (DCM filmycm^"1 3392, 3050-2900, 1741, 1643, 1273, 1 114, 740; 4 (CDCl₃) 7.84-7.79 (4H, m), 7.71 (IH, s, Hl), 7.51-7.45 (2H, m), 7.42 (IH, s, H4), 7.39-7.36 (IH, dd, J8.4, J 1.6), 7.16-7.13 (IH, d, J8.4, H7), 7.01-6.99 (IH, dd, ./8.0, / 1.6, H6), 6.33-6.32 (IH, d, / 1.2, H3), 4.28 (2H, s, Hl '), 4.10-4.07 (IH, dd, J7.2, J6.0, 2xH2"), 3.71 (3H, s, H6"), 3.63-3.58 (IH, m, lxH3"), 3.40-3.33 (IH, m, lxH3"), 3.11 (IH, s, IxHl"), 3.09-3.08 (IH, d, J 1.6, IxHl"), 1.19-1.16 (3H, t, J6.8, 3xH4"); £_c (CDCl₃) 173.30 (Q, 137.89, 135.97, 135.30, 133.53, 133.18, 132.33, 128.90 (7xC), 128.41 (CH), 128.26 (C), 127.72, 127.52, 127.24, 127.09, 126.35, 125.69 (6xCH), 122.95 (CH), 120.47 (CH), 110.19 (CH), 101.02 (CH), 81.02 (CH), 66.20 (CH₂), 51.77 (CH₃), 39.53 (CH₂), 34.92 (CH₂), 15.07 (CH₃); m/z (EI¹) 387 ([M]^1-, 27), 270 ([M-side chain on 5-positionf, 100), 146 (67); found [M+H]⁺, 387.1835, C₂₅H₂₅NO₃ requires [M+H]⁺, 387.1834; Found: C, 77.5; H, 6.4; N, 3.7. Required: C, 77.5; H, 6.5; N, 3.6; Δ = 0.3 ppm.

2-Ethoxy-3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)propanoic acid 5 The starting material 41 (62.1 mg, 0.160 mmol, 1.00 eq) was refluxed with potassium hydroxide pellets (18.0 mg, 0.321 mmol, 2.00 eq) in a mixture of ethanol/water 1:1 (1.60 ml) at 75 ⁰C for 15 hr and at 90 ⁰C for a further 2.5 hr. Some stalling material was still seen by MS, thus more potassium hydroxide (31.0 mg, 0.552 mmol, 3.40 eq) was added and the RM was stirred for a further 4 hr. The light orange solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~30 drops) until a pH of 1 was reached. The desired acid crashed out as an off-white ppt. DCM was added and the 2 phases were separated. The aqueous phase was extracted with DCM (4x10 ml). The extracts were washed with water (2x25.0 ml). The aqueous phase was extracted with DCM (4x45.0 ml, 3x20.0 ml, 2x50.0 ml). After drying over MgSO₄, concentration in vacuo gave 58.5 mg (98%) of the product as a yellowish oil: R_f 0.25 [hexane/EtOAc 1:9]; v_inax (DCM film)/cm ' 3403, 3053-2900, 1720, 1644, 1267, 1110, 739; 4 (CDCl₃) 7.85-7.79 (4H, m), 7.71 (IH, s), 7.51-7.45 (2H, m), 7.43 (IH, s, H4), 7.39-7.36 (IH, dd, /8.4, / 1.6), 7.16-7.14 (IH, d, /8.4, H7), 7.02-7.00 (IH, dd, /8.2, / 1.4, H6), 6.34 (IH, br, H3), 4.28 (2H, s, Hl '), 4.14-4.11 (IH, dd, /7.6, /4.4, 2xH2"), 3.62-3.54 (IH, m, lxH3"), 3.50-3.42 (IH, m, lxH3"), 3.25-3.21 (IH, dd, / 14.2, /4.2, IxHl"), 3.11-3.06 (IH, dd, / 14.2, /7.8, IxHl"), 1.19-1.16 (3H, t, /7.0, 3xH4"); <5fe (CDCl₃) 174.59 (C), 138.03, 135.90, 135.39, 133.53, 132.35, 128.87 (6xC), 128.44 (CH), 127.68 (CH), 127.65 (C), 127.53, 127.24, 127.12, 126.25, 125.72 (5xCH), 123.01 (CH), 120.69 (CH), 110.32 (CH), 101.04 (CH), 80.31 (CH), 66.89 (CH₂), 38.75 (CH₂), 34.93 (CH₂), 15.07 (CH₃); m/z (EI⁺) 373 ([M]⁺, 33), 270 ([M- side chain on 5-position]⁺, 100), 142 (36); found [M+H]⁺, 373.1676, C₂₄H₂₃NO₃ requires [M+H]\ 373.1678; Found: C, 73.2; H, 6.2; N, 3.0. Required: C, 77.2; H, 6.2; N, 3.8; Δ = 0.9 ppm.

Example 6

Preparation of 3-(2-(Naphthalen-2-ylmethyl)-lH-indol-5-yl)-2-(2,2,2-trifluoroethoxy^')propanoic acid 6

(Z)-EtHyI 3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)-2-(2, 2, 2-trifluoroethoxy)acrylate 37 and (E)-ethyl 3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)-2-(2, 2, 2-trifluoro-ethoxy)-acrylate 38 To a milky suspension of sodium hydride, 60% in oil (29.4 mg, 0.735 mmol, 1.41 eq) and molecular sieves 4A in anhydrous THF (3.60 ml) at 0 ⁰C, under a constant flow of N₂, was added dropwise, phosphonoacetate 9 (180 mg, 0.560 mmol, 1.08 eq) in THF (1.20 ml) over 12 min. The pale yellowish solution was stirred at 0 ⁰C for 35 min before the dropwise addition of aldehyde 30 (148 mg, 0.520 mmol, 1.00 eq) in dry THF (1.60 ml) via syringe pump over 42 min. The solution which had turned bright yellow was left to stir in the ice bath over 39 hr. The light yellow solution was concentrated in vacuo, re-dissolved in EtOAc (30 ml) and washed with water (30 ml). An emulsion was observed, thus some NaCl was added. The aqueous phase was extracted with EtOAc (4x30 ml). After drying the organic extracts over MgSθ₄, concentration in vacuo of the organic phase gave a very pale orangish slurry which was purified by flash column chromatography on silica gel (hexane/EtOAc 10: 1) to yield 183 mg (78%) of the product. Ratio Z:E = 38:62. Z isomer 37: almost colourless oil: R_f 0.35 [hexane/EtOAc 7:3]; i-w (DCM film)/cm^"' 3408, 2975, 1702, 1620, 1263, 1167, 742; 4 (CDCl₃) 8.06 (IH, s, H4), 7.93 (IH, br, Hl), 7.88-7.82 (3H, m), 7.75 (IH, s), 7.62-7.60 (IH, dd, J 8.6, / 1.4, H6), 7.56-7.48 (2H, m), 7.48-7.38 (IH, dd, /8.4, / 1.6), 7.29 (IH, s, Hl"), 7.25-7.23 (IH, d, /8.4, H7), 6.45-6.44 (IH, d, /0.8, H3), 4.42-4.34 (4H, m, 2xH3", 2xH6"), 4.32 (2H, s, 2xHl '), 1.43-1.40 (3H, t, 77.2, 3xH7"); δc (CDCl₃) 164.08 (C), 140.38, 138.80, 136.95, 135.56, 133.56, 132.42, 128.93 (7xC), 128.58 (CH), 127.71 (CH), 127.59-119.28 (C₁ q, .7277.0), 127.55, 127.48, 127.18, 127.15 126.34, 125.82 (6xCH), 124.38 (CH), 124.30 (C), 123.39 (CH), 110.64 (CH), 102.00 (CH), 68.34-67.30 (CH₂, q, J35.0), 61.30 (CH₂), 34.88 (CH₂), 14.28 (CH₃); m/z (EI⁺) 453 ([M]⁺, 100), 342 (17), 141 (93); found [M+H]⁺, 453.1553, C₂₆H₂₂F₃NO₃ requires [M+H] ', 453.1552; Found: C, 68.8; H, 4.8; N, 2.9. Required: C, 68.9; H, 4.9; N, 3.1; Δ = 0.2 ppm. E isomer 38: off-white powder: mp 123.0- 124.5 ⁰C (hexane/DCM 20:1); R_f 0.30 [hexane/EtOAc 7:3]; M_n3x (DCM film)/cm⁴ 3441, 2970- 2850, 1709, 1645, 1267, 1132, 740; ή, (CDCl₃) 7.86-7.79 (4H, m), 7.71 (IH, s, Hl), 7.55 (IH, s, H4), 7.53-7.49 (2H, m), 7.38-7.34 (IH, dd, /8.4, / 1.6), 7.17-7.15 (IH, d, /8.4, H7), 7.10-7.08 (IH, dd, /8.4, / 1.6), 6.72 (IH, s, Hl"), 6.36 (IH, d, /= 0.8, H3), 4.30-4.23 (4H, m, 2xH3", 2xHl'), 4.23-4.18 (2H, q, / 14.0, /7.2, 2xH6"), 1.18-1.15 (3H, t, /7.2, 3xH7"); & (CDCl₃) 163.51 (C), 143.33, 138.42, 136.08, 135.73, 133.54, 132.38, 128.58 (7xC), 128.49, 127.70, 127.53 (3xCH), 127.40-119.09 (CH₂, q, /277.0), 127.16, 127.13, 126.31, 125.78 (4xCH), 124.37 (C), 122.82 (CH), 121.82 (CH), 121.00 (CH), 110.11 (CH), 101.49 (CH), 68.20-67.15 (CH₂, q, / 35.0), 61.26 (CH₂), 34.87 (CH₂), 13.79 (CH₃); m/z (EI⁺) 453 ([M]⁺, 61), 342 (10), 210 (100), 141 (46), 105 (69); found [M+H]⁺, 453.1548, C₂₆H₂₂F₃NO₃ requires [M+H]⁺, 453.1552 Found: C, 69.0; H, 5.0; N, 3.0. Required: C, 68.9; H, 4.9; N, 3.1; Δ = -0.9 ppm.

Methyl 3-(2-(naphthalen-2-ylmethyl)-lH-indol-5-yl)-2-(2, 2, 2-trifluoroethoxy)propanoate 42 To a mixture of the starting material 37 and 38 (14.7 mg, 0.032 mmol, 1.00 eq) and the magnesium turnings (19.2 mg, 0.790 mmol, 24.3 eq) at RT, under a constant flow of N_∑, was added the anhydrous methanol (1.50 ml). A white slurry was observed, it was stirred at RT for 14 hr before being poured onto water (25.0 ml) and the aqueous phase was acidified with IM HCl (2.00 ml). The 2 phases were separated and the aqueous phase was extracted with DCM (4x25.0 ml). After drying over MgSO₄, concentration in vacuo gave a pale yellow oil which was purified by flash column chromatography on silica gel (hexane/EtOAc 9:1, 8:2) to yield 11.3 mg (79%) of the product as a colourless oil: R_f 0.25 [hexane/EtOAc 7.5:2.5]; v_mM (DCM film)/cm^"' 3403, 3054-2850, 1743, 1645, 1279, 1165, 739; & (CDCl₃) 7.85-7.79 (3H, m), 7.77 (IH, br, Hl), 7.72 (IH, s), 7.52-7.46 (2H₁ m), 7.42 (IH, s, H4), 7.39-7.37 (IH, dd, /8.6, / 1.8), 7.17-7.15 (IH, d, / 8.0, H7), 7.00-6.98 (IH, dd, /8.4, / 1.6, H6), 6.34 (IH, m, H3), 4.29 (2H, s, 2xHP), 4.27-4.24 (IH, dd, /7.6, /4.8, H2"), 4.01-3.92 (IH, m, lxH3"), 3.74 (3H, s, 3xH6"), 3.74-3.66 (IH, m, lxH3"), 3.23-3.18 (IH, m, IxHl"), 3.17-3.12 (IH, m, IxHl"); δ_c (CDCl₃) 171.49 (C), 138.05, 135.90, 135.44, 133.56, 132.38, 128.92 (7xC), 128.46 (CH), 127.74-119.42 (C, q, / 277.0), 127.69 (CH), 127.55 (CH), 127.36 (C), 127.24, 127.13, 126.26, 125.73 (4xCH), 122.93 (CH), 120.60 (CH), 110.33 (CH), 101.07 (CH), 82.04 (CH), 68.40-67.37 (CH₂, q, / 34.5), 52.09 (CH₃), 39.18 (CH₂), 34.94 (CH₂); m/z (EI⁺) 441 ([M]⁺, 56), 270 ([M-propanoate side chainf, 100); found [M+Hf, 441.1548, C₂₅H₂₂F₃NO₃ requires [M+H]⁺, 441.1552; Found: C, 72.7; H, 4.9; N, 3.8. Required: C, 68.2; H, 5.0; N, 3.2; Δ = 0.9 ppm.

3-(2-(Naphthalen-2-ylmethyl)-lH-indol-5-yl)-2-(2, 2, 2-trifluoroethoxy)propanoic acid 6 The starting material 42 (5.90 mg, 0.013 mmol, 1.00 eq) was refluxed with potassium hydroxide pellets (1.50 mg, 0.027 mmol, 2.00 eq) in a mixture of ethanol/water 1:1 (1.00 ml) at 78 ⁰C for 15 hr. The light yellow solution was allowed to cool down to RT and concentrated in vacuo. With vigorous stirring in ice, was added IM HCl (~2 drops) until a pH of 1 was reached. The desired acid crashed out as an off-white ppt. DCM was added and the 2 phases were separated. The aqueous phase was extracted with DCM (4x20.0 ml). The extracts were washed with water (25.0 ml). The aqueous phase was extracted with DCM (4x25.0 ml). After drying over MgSO,}, concentration in vacuo gave 5.60 mg (98%) of the product as a pale yellow oil: R_f 0.40 [Solvent A]; v_max (DCM filmycm^"1 3441, 3000-2700, 1706, 1646, 1267, 1049, 740; ό\ (CDCl₃/MeOD 2: 1) 9.53 (IH, br, H6"), 7.76-7.71 (3H, m), 7.65 (IH, s), 7.51 (IH, s, H4), 7.42-7.38 (2H, m), 7.35- 7.32 (IH, dd, / 8.4, / 1.2), 7.17-7.15 (IH, d, / 8.4, H7), 7.09-7.07 (IH, m, H6), 6.59 (IH, s, Hl"), 6.18 (IH, br, H3), 4.26-4.20 (4H, m, 2xH3", 2xHl'); δc (CDCl₃) 174.21 (C), 138.19, 135.85, 135.50, 133.55, 132.38, 128.96 (7xC), 128.48, 127.69 (2xCH), 127.58-119.27 (C, q, /277.0), 127,54, 127.23, 127.14 (3xCH), 126.98 (C), 126.27, 125.74 (2xCH), 122.91 (CH), 120.70 (CH), 110.46 (CH), 101.07 (CH), 81.65 (CH), 68.64-67.61 (CH₂, q, /34.5), 38.98 (CH₂), 34.93 (CH₂); m/z (EI⁺) 427 ([M]⁺, 47), 270 (100), 141 (53); found [M+H]⁺, 427.1389, C₂₄H₂₀F₃NO₃ requires [M+H]⁺, 427.1395; Found: C, 67.3; H, 4.6; N, 3.2. Required: C, 67.4; H, 4.7; N, 3.3; Δ = 0.9 ppm.

Biological studies

The activation of the three PPAR subtypes by the indole compounds 1 to 6 of the present invention was studied in vitro using a luciferase reporter gene assay. Specifically, a plasmid containing genes encoding for each subtype of PPARs, as well as a luciferase reporter gene which has peroxisome proliferator response elements (PPREs) in the promoter region of the gene was transfected into human breast cancer MCF-7 cells. The firefly luciferase catalyses the bioluminescent oxidation of luciferin in the presence of ATP, magnesium and oxygen. The luciferase protein complexes with the luciferin substrate to form a luciferyl-adenylate complex in the presence of magnesium ions and ATP. In the presence of oxygen, this complex is oxidised to oxyluciferin with the release of carbon dioxide and adenosine as well as a light emission with a wavelength of 560 nm. The measurement of the amount of luciferase protein expressed can be detected on a luminometer and is expressed in relative light units (RLU), which can be used to quantify the efficiency of the PPAR activation. The advantages of the luciferase assay are the high sensitivity, the absence of luciferase activity inside most of the cell types, the wide dynamic range, rapidity and low costs.

Example 7

Human MCF-7 breast cancer cells were seeded at a density of 85,000 cells per well of a 12-well pate. The following day, they were transiently transfected using a PPRE-luciferase reporter plasmid and DNA with the three subtypes of PPARs. The total amount of plasmid was kept constant at 2.65 μg by compensating with pCMV-5 which is an empty expression plasmid. 24 hours after transfection, the cells were treated with the indoles. After another 48 hours, the cells were washed once with PBS, lysed and the cell extracts were used for luciferase determination on a LUCY-I luminometer. The luciferase assay was performed in accordance with the protocol of the Luciferase Assay Kit (BIO Thema AB, Sweden). First of all, cells used for the PPAR assays were checked for any endogenous PPAR activity by performing transfection in the absence of the PPAR DNA. Under these conditions, no significant luciferase expression was detected. For each of the experiments, negative controls were done by carrying out the assay on cells in the absence of the compounds. Positive controls were performed with the following selective potent PPAR agonists at concentrations of 1 μM or 30 μM: WY14.643 43 for PPARor, BRL49653 44 (rosiglitazone) for PPAR^, and L165.041 45 for PPARS

WY 14.643 BRL49653 Rosiglitazone 43 44

Selective PPAR agonists used as positive controls and TTA 46

Different concentrations of TTA 46, a known PPAR agonist (1 μM, 30 μM and 75 μM) were also run in parallel. Five different concentrations between 1 μM and 75 μM of the indole compounds 1 to 6 of the present invention in DMSO were prepared and used to obtain a preliminary indication of their effects on the activation. The lowest concentration which gave activity as well as a higher concentration relative to the first were selected. These experiments were performed three times in triplicate at these optimum concentrations. All results were normalised relative to the negative control and the standard deviation was calculated from the variability of the readings obtained for one compound at a particular concentration. If there is PPAR activation, a high expression of Luciferase relative to the control is expected. A high activity relative to the control at low concentrations indicates good potency. The lower the concentration, the better the compound since this means that a small dose of compound would be enough to activate the PPARs. This would reduce any toxicity problems or side-effects.

PPAR activation assay: results and discussion

Normalised PPAR activation results are shown in Figure 1. A dose-dependent PPARo; response was observed with administration of all the compounds of the present invention. In general, the compounds 1 and 2 were less potent than the other four targets. This supports the fact that the aryl group on the 2-position of the indole is important for binding and thus activation of the receptor. With the indole compound 3, the activation of PP ARa at 5 μM was comparable to that of WY14.643 at 30 μM, showing that it is a potent activator. Indole compound 4 was also a strong activator although a higher concentration was needed to see a comparable effect to target 3. Indole compound 5 was a very potent activator of PP ARa, in fact, the best activator out of the series. Activity at a low concentration of 1 μM was already slightly better than that of WY 14.643 at 30 μM. The effects of indole compound 6 were also very significant at low concentrations of 10 and 30 μM. If we compare indoles 3 and 5 to indoles 4 and 6, data indicated that the ethyl ether gives slightly better activation than the 2,2,2-trifluoro ether. Comparison of the indole compounds 3 and 4 with the compounds 5 and 6 indicated that the last two compounds with a 2- naphthylmethyl group activated PPARα better than the first two leads 3 and 4 with a 2-benzyl group.

A large variability was seen in positive control response with PPARf. As with PP ARa, dose dependency was seen with all the indoles. Again, the compounds 1 and 2 activated PPARf the least, confirming that the aryl group on the 2-position of the indole is important for strong activation of the receptor. Indole 3 was a potent activator of PPARf at low concentrations of 1 to 10 μM. Indole 4 was as effective as indole 3, although its activation was slightly less strong. Indoles 5 and 6 were both very potent agonists, with indole 5 being very potent at a low concentration of 1 μM. From the comparison of the compounds 1, 3 and 5 to the compounds 2, 4 and 6, the ethyl ether gave better activation of PPARf than the 2,2,2-trifluoroethyl ether.

Comparison between the compounds 3 and 4 and the compounds 5 and 6 indicates that the 2- naphthylmethyl group is favoured for PP AR/ activation. In general, the six compounds were not found to be as strong activators of PPAR(JaS L165.041. Indeed, the compounds of the present invention had been designed to be dual PP AKa/γ agonists and the data obtained seemed to confirm that they were potent activators of PP ARa and PPAR^ but less effective on PPAR<5. Indole 3, at concentrations of 1 and 5 μM, gave comparable activity to that of TTA at 30 μM whereas a much higher concentration of indole 4 was needed to observe similar activity to that of TTA at 75 μM. The activation with indole 5 was higher than with TTA at a concentration of 30 μM, indicating that this compound may be a more potent agonist than TTA. Indole 6 was also potent, however at high concentrations of 75 μM. In the case of PP ARJ, it was not possible to conclude on whether the 2,2,2-trifmoro ether was better than the ethyl ether as there was no pattern in the data observed. Indole 3 seemed to show the best activation of PPAR δ at low concentrations. Activation levels at low concentrations of 1 and 5 μM were comparable to the effects of TTA at 30 and 75 μM which has been proven to be a potent PPAR5 agonist.

Considering the activation results of the three PPAR subtypes, the indoles activated the PPARs in the following order in human MCF-7 cells: γ> a> δ. In terms of structure-activity relationship, indoles 1 and 2 were found to be much less potent in general, confirming the presence of the benzyl or methyl-napthyl group on the 2-position of the indole is important for the interaction in the hydrophobic site at the entrance. Out of the four most potent indoles, leads 5 and 6 were found to be slightly better PPARo// dual agonists than indoles 3 and 4. Indole 3 was found to be a potent activator of PPAR5

Claims

1. A compound of formula (I)

wherein

Ri is selected from hydrogen, Cβ-Cu aryl, G₅-Ci₃ heteroaryl, linear or branched C]-C₈ alkyl, C₂- Cg alkenyl or C2-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, Ci-C₃ alkyl, hydroxyl and carboxyl;

R₂ and R3 is independently selected from hydrogen, linear or branched Ci-C₃ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

A is linear or branched Ci-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

and wherein the indole moiety may be optionally substituted at any available carbon or nitrogen atom with one or more of the groups selected from halide, oxo, C, -C₃ alkyl, hydroxyl and carboxyl;

or a prodrug or pharmaceutically acceptable salt thereof.

2. Compound in accordance with claim 1, wherein R) is selected from phenyl, benzyl, naphtyl, naphtylmethyl or anthracene each optionally substituted with one or more of the groups selected from halide, oxo, Ci-C₃ alkyl, hydroxyl and carboxyl.

3. Compound in accordance with claim 1 , wherein Ri is hydrogen.

4. Compound in accordance with claim 1, wherein Ri is benzyl, phenylethyl, phenylpropyl or phenylbutyl.

5. Compound in accordance with claim 1, wherein Ri is naphthylmethyl, naphthylethyl, naphthylproply or naphthylbutyl.

6. Compound in accordance with claim 1, wherein Ri is 2-naphthylmethyl.

7. Compound in accordance with claim 1, wherein Ri is anthracylmethyl, anthracylethyl, anthracylproply or anthracylbutyl.

8. Compound in accordance with claim 1, wherein R₂ is Ci-C₈ alkyl, a halide subtituted alkyl, alkene or alkyne, preferable a halide subtituted CpC₈ alkyl.

9. Compound in accordance with claim 1, wherein R₂ is selected from -CF₃, CF₃, CH₃, - CH₂- CF₃, -CH₂-CCl₃, -CH₂- CH₃, -CH₂-CH₂-CF₃, -CH₂-CH₂-CCl₃, -CH₂-CH₂-CH₃, -CH₂-CH₂- CH₂-CF₃₁ -CH₂-CH₂-CH₂-CCI₃ or -CH₂-CH₂-CH₂-CH₃.

10. Compound in accordance with claim 9, wherein R₂ is -CF₃.

11. Compound in accordance with claim 1 , wherein A is a linear or branched C i-C₈ alkyl, preferable -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂- or -CH₂-CH₂-CH₂-CH₂-

12. Compound in accordance with claim 1, wherein wherein R, is selected from phenyl, benzyl, naphtyl, anthracene or phenantrene each optionally substituted with one or more of the groups selected from halide, oxo, C_rC₃ alkyl, hydroxyl and carboxyl and wherein R₂ is selected from -CF₃, CCl₃, CI-I₃, -CH₂- CF_3, -CH₂-CCl₃, -CH₂- CH₃, -CH₂-CH₂-CF₃,-CH₂-CH₂-CC1₃, -CH₂- CH₂-CH₃, -CH₂-CH₂-CH₂-CF₃, -CH₂-CH₂-CH₂-CCl₃ or -CH₂-CH₂-CH₂-CH₃.

13. Compound in accordance with claim 1, wherein R| is H and R₂ is CH₃

14. Compound in accordance with claim 1, wherein Ri is H and R₂ is CF₃

15. Compound in accordance with claim 1, wherein R₁ is benzyl and R₂ is CH₃

16. Compound in accordance with claim 1 , wherein Ri is benzyl and R₂ is CF₃

17. Compound in accordance with claim 1, wherein Ri is naphthylmethyl and R₂ is CH₃

18. Compound in accordance with claim 1, wherein R] is naphthylmethyl and R₂ is CF₃

19. Compound in accordance with claim 1, wherein Ri is 2-naphthylmethyl and R₂ is CH₃

20. Compound in accordance with claim 1, wherein R₁ is 2-naphthylmethyl and R₂ is CF₃

21. A process for preparation of a compound according to claim 1 comprising the steps of:

a) reduction of a compound of formula (II)

to yield a compound of formula (III)

and

b) saponification of a compound of formula (III)

to yield a compound of formula (I).

22. Process in accordance with claim 20, wherein the reduction of step a) is conducted with magnesium turnings in methanol at elevated temperature and/or the saponification in step b) is conducted with KOH in ethanol and water at elevated temperature.

23. A compound of formula (II)

wherein

Ri is selected from hydrogen, C₆-Ci₄ aryl, C₅-Ci₃ heteroaryl, linear or branched Ci-C₈ alkyl, C₂- Cs alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, Ci-C₃ alkyl, hydroxyl and carboxyl;

R₂ and R3 is independently selected from hydrogen, linear or branched Ci-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, CpC₃ alkyl, hydroxyl and carboxyl;

A is linear or branched C_rC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

or a prodrug or pharmaceutically acceptable salt thereof.

24. Use of a compound_of formula (I)

wherein

Ri is selected from hydrogen, Ce-Ci₄ aryl, C₅-C₁₃ heteroaryl, linear or branched Ci-C₈ alkyl, C₂- C₈ alkenyl or C₂-C₈ alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, C₁-C₃ alkyl, hydroxyl and carboxyl;

R2 and R3 is independently selected from hydrogen, linear or branched C₁-Cs alkyl, C₂-Cg alkenyl or C₂-Cg alkynyl, each optionally substituted with one or more of the groups selected from halide, oxo, C₁-C₃ alkylj hydroxyl and carboxyl;

A is linear or branched C_rC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl;

and wherein the indole moiety may be optionally substituted at any available carbon or nitrogen atom with one or more of the groups selected from halide, oxo, C₁-C₃ alkyl, hydroxyl and carboxyl;

25. Use in accordance with claim 24, wherein the PPAR related disease is metabolic syndrome.

26. Use in accordance with claim 24, wherein said disease is obesity, dyslipidaemia, insulin resistance, blood pressure elevation and coronary heart disease

27. Use in accordance with claim 24, wherein said disease is diabetes.

28. Use in accordance with claim 24, wherein said disease is cancer, inflammation, inflammatory brain diseases such as Alzheimer's disease and multiple sclerosis.