OA19489A

OA19489A - Substituted indoline derivatives as dengue viral replication inhibitors.

Info

Publication number: OA19489A
Application number: OA1201900446
Authority: OA
Inventors: Jean-François BONFANTI; Bart Rudolf Romanie Kesteleyn; Pierre Jean-Marie Bernard Raboisson; Dorothée Alice Marie-Eve BARDIOT; Arnaud Didier M MARCHAND; Erwin Coesemans; Benoît Christian Albert Ghislain DE BOECK
Original assignee: Janssen Pharmaceuticals, Inc.; Katholieke Universiteit Leuven
Priority date: 2017-05-22
Filing date: 2019-05-18
Publication date: 2020-10-23

Abstract

The present invention concerns substituted indoline derivatives, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of the compounds.

Description

The présent invention relates to substituted indoline dérivatives, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent dengue viral infections. The présent invention furthermore relates to pharmaceutical compositions or combination préparations of the compounds, to the compositions or préparations for use as a medicine, more ίο preferably for the prévention or treatment of dengue viral infections. The invention also relates to processes for préparation of the compounds.

BACKGROUND OF THE INVENTION

Flaviviruses, which are transmitted by mosquitoes orticks, cause life-threatening infections in man, such as encephalitis and hémorrhagie fever. Four distinct, but closely related serotypes ofthe flavivirus dengue are known, so-called DENV-1, -2, -3, and -4. Dengue is endemic in most tropical and sub-tropical régions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization (WHO), 2.5 billion people of which 1 billion children are at risk of DENV infection (WHO, 2002). An estimated 50 to 100 million cases of dengue fever [DF], half a million cases of severe dengue disease (i.e. dengue hémorrhagie fever [DHF] and dengue shock syndrome [DSS]), and more than 20,000 deaths occur worldwide each year. DHF has become a leading cause of hospitalization and death amongst children in endemic régions. Altogether, dengue represents the most common cause of arboviral disease. Because of recent large outbreaks in countries situated in Latin America, South-East Asia and the Western Pacific (including Brazil, Puerto Rico, Venezuela, Cambodia, Indonesia, Vietnam, Thailand), numbers of dengue cases hâve risen dramatically over the past years. Not only is the number of dengue cases increasing as the disease is spreading to 30 new areas, but the outbreaks tend to be more severe.

Following infection with another serotype, pre-existing heterologous antibodies form complexes with the newly infecting dengue virus serotype but do not neutralize the pathogen. Instead, virus entry into cells is believed to be facilitated, 35 resulting in uncontrolled virus réplication and higher peak viral titers. In both primary and secondary infections, higher viral titers are associated with more severe dengue disease. Since maternai antibodies can easily pass on to infants by | -2breast feeding, this might be one of the reasons that children are more affected by severe dengue disease than adults.

In locations with two or more serotypes circulating simultaneously, also referred to 5 as hyper endemic régions, the risk of serious dengue disease is significantly higher due to an increased risk of experiencing a secondary, more severe infection. Moreover, in a situation of hyper-endemicity, the probability of the emergence of more virulent strains is increased, which in turn augments the probability of dengue hémorrhagie fever (DHF) or dengue shock syndrome.

The mosquitoes that carry dengue, including Aedes aegypti and Aedes albopictus (tiger mosquito), are moving north on the globe. According to the United States (US) Centers for Disease Control and Prévention (CDC), both mosquitoes are currently omniprésent in Southern Texas. The spread north of dengue-carrying mosquitoes is not confined to the US, but has also been observed in Europe.

Dengvaxia®, the dengue vaccine produced by Sanofi Pasteur was first approved in Mexico and has received in the meantime approval in more countries.

Nevertheless, the vaccine leaves considérable room for improvement due to 20 limited efficacy, especially against DENV-1 and -2, low efficacy in flavivirus-naive subjects and the lengthy dosing schedule.

Despite these shortcomings, the vaccine is a game changer in endemic settings as it will offer protection to a large part of the population, but likely not to very young infants, who bear the largest burden of dengue. In addition, the dosing schedule and very limited efficacy in flavivirus-naïve subjects make it unsuitable and likely not worthwhile/cost-effective for travelers from non-endemic areas to dengue-endemic areas. The above mentioned shortcomings of the dengue vaccines are the reason why there is a need for a pre-exposure prophylactic dengue antiviral.

Furthermore, today, spécifie antiviral drugs for the treatment or prévention of dengue fever virus infection are not available. Clearly, there is still a great unmet medical need for therapeutics for the prévention or treatment of viral infections in 35 animais, more in particular in humans and especially for viral infections caused by flaviviruses, more in particular Dengue virus. Compounds with good anti-viral potency, no or low levels of side-effects, a broad spectrum activity against multiple Dengue virus serotypes, a low toxicity and/or good pharmacokinetic or -dynamic properties are highly needed.

- 3 WO-2010/021878 discloses 2-phenylpyrrolidine and indoline dérivatives as cold menthol receptor antagonists for treatment of inflammatory and central diseases. WO-2013/045516 discloses indole and indoline dérivatives for use in the treatment of dengue viral infections. WO 2014/154682 also discloses compounds for treating flavivirus, such as dengue virus. WO 2016/050841 discloses indole compounds as inhibitors of dengue virus réplication.

The présent invention now provides compounds, substituted indoline dérivatives, which show high potent activity against ail four (4) serotypes of the Dengue virus.

SUMMARY OF THE INVENTION

The présent invention is based on the unexpected finding that at least one of the above-mentioned problems can be solved by the current compounds of the invention.

The présent invention provides compounds which hâve been shown to possess potent antiviral activity against ail four (4) serotypes currently known. The présent invention furthermore demonstrates that these compounds efficiently inhibit prolifération of Dengue virus (DENV). Therefore, these compounds constitute a useful class of potent compounds that can be used in the treatment and/or prévention of viral infections in animais, mammals and humans, more specifically for the treatment and/or prévention of infections with Dengue viruses.

The présent invention furthermore relates to the use of such compounds as medicines and to their use for the manufacture of médicaments for treating and/or preventing viral infections, in particular with viruses belonging to the family of the Dengue viruses in animais or mammals, more in particular in humans. The invention also relates to methods for the préparation of ail such compounds and to pharmaceutical compositions comprising them in an effective amount.

The présent invention also relates to a method of treatment or prévention of dengue viral infections in humans by the administration an effective amount of one or more such compounds, or a pharmaceutically acceptable sait thereof optionally in combination with one or more other medicines, like another antiviral agent, to a patient in need thereof.

AMENDED SHEET

-4The présent invention concerns compounds of formula (I), including any stereochemically isomeric form thereof, :

wherein

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is pentafluorosulfanyl, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethyl, R⁵ is hydrogen, Z is carbon, and R⁶ is methyl; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethyl, R⁵ is fluoro, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵is hydrogen, Z is carbon, and R⁶ is methyl; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵is fluoro, Z is carbon, and R⁶ is hydrogen; or

R¹ is fluoro, R² is methoxy, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is hydrogen, R³ is deuterium, A is (a-1), R⁴ is trifluoromethoxy, R⁵is hydrogen, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is -OCH₂CH₂OH, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethyl, R⁵ is methoxy, Z is nitrogen, and R⁶ is absent; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-2), and R⁴ is trifluoromethyl; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethylthio, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen;

or a pharmaceutically acceptable sait, solvaté or polymorph thereof.

-5A first group of compounds of formula (I) are those compounds of formula (I) wherein radical A is (a-1).

A second group of compounds of formula (I) are those compounds of formula (I) 5 wherein radical A is (a-2).

In an alternative représentation, the présent invention relates to a compound

wherein the compound is selected from the group consisting of :

, or a pharmaceutically acceptable sait, solvaté or polymorph thereof.

Part ofthe current invention is also a pharmaceutical composition comprising a 5 compound mentioned above or a stereoisomeric form, a pharmaceutically acceptable sait, solvaté or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.

Pharmaceutically acceptable salts of said compounds include the acid addition îo and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Suitable base salts are formed from bases which form nontoxic salts.

The pharmaceutically acceptable acid salts as mentioned hereinabove are meant 15 to comprise the therapeutically active non-toxic acid addition sait forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, 20 phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic acid and the like acids.

-7The compounds ofthe invention may also exist in un-solvated and solvated forms. The term “solvaté” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molécules, for example, éthanol.

The term “polymorph” refers to the ability of the compound of the invention to exist in more than one form or crystal structure.

The compounds of the présent invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingrédient other than the compound(s) of the invention. The choice of excipient dépends largely on factors such as the particular mode of administration, the effect ofthe excipient on solubility and stability, and the nature of the dosage form.

The compounds of the présent invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited ail compositions usually employed for systemically administering drugs. To préparé the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of préparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral or rectal administration. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid préparations such as suspensions, syrups, élixirs, émulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form préparations that can be converted, shortly before use, to liquid forms.

-8It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrète units suitable as unitary dosages, each unit containing a predetermined quantity of active ingrédient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

Those of skill in the treatment of infectious diseases will be able to détermine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingrédient per unit dosage form.

The exact dosage and frequency of administration dépends on the particular compound ofthe invention used, the particular condition being treated, the severity ofthe condition being treated, the âge, weight and general physical condition of the particular patient as well as other médication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is évident that the effective amount may be lowered or increased depending on the response ofthe treated subject and/or depending on the évaluation of the physician prescribing the compounds ofthe instant invention. The effective amount ranges mentioned above are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.

The présent disclosure is also intended to include any isotopes of atoms présent in the compounds ofthe invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include C-13 and C-14.

As used herein, any Chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplâtes each possible stereoisomer, or mixture of two or more stereoisomers.

-9Hereinbefore and hereinafter, the terms “compound of formula (I)” and “intermediates of synthesis of formula (I)” are meant to include the stereoisomers thereof and the tautomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes ail stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable miror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images.

The term “stereoisomers” also includes any rotamers, also called conformational isomers, the compounds of formula (I) may form.

Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixtures thereof, whenever chemically possible.

The meaning of ail those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

When a spécifie stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1 %, of the other stereoisomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer.

-10Some of the compounds according to formula (I) may also exist in their tautomenc form. Such forms in so far as they may exist, although not explicitly indicated in the above formula (I) are intended to be included within the scope of the présent invention.

The compounds of formula (I) of the présent invention ail hâve at least one asymmetric carbon atom as indicated in the figure below by the carbon atom labelled with * :

Due to the presence ofsaid chiral center, a “compound of formula (1)” can be the (R)-enantiomer, the (S)-enantiomer, the racemic form, or any possible combination of the two individual enantiomers in any ratio. When the absolute (R)- or (S)configuration of an enantiomer is not known, this enantiomer can also be identified by indicating whether the enantiomer is dextrorotatory (+)- or levorotatory (-)- after measuring the spécifie optical rotation of said particular enantiomer.

In an aspect the présent invention relates to a first group of compound of formula (I) wherein the compounds of formula (I) hâve the (+) spécifie rotation.

In a further aspect the présent invention relates to a second ground of compounds of formula (I) wherein the compounds of formula (I) hâve the (-) spécifie rotation.

Examples

LC/MS methods

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound’s nominal

F -11monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental rétention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molécule) and/or [M-H]' (deprotonated molécule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]', etc...). For molécules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. Ail results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Sélective Detector, “RT” room température, “BEH” bridged ethylsiloxane/siiica hybrid, “DAD”

Diode Array Detector, ”HSS” High Strength silica.

LC/MS Method codes (Flow expressed in mL/min; column température (T) in °C; Run time in minutes).

Method code	Instrument	Column	Mobile phase	Gradient	Flow Col T	Run time (min)
LC-A	Waters: Acquity® UPLC® - DADQuattro Micro™	Waters: BEH® C18 (1.7 pm, 2.1 x 100 mm)	A: 95% CH3COONH4 7mM / 5% CH3CN, B: CH3CN	84.2% A for 0.49 min, to 10.5% A in 2.18 min, held for 1.94 min, back to 84.2% A in 0.73 min, held for 0.73 min.	0.343 mL/min 40°C	6.2
LC-B	Waters: Acquity® HClass - DAD and SQD2TM	Waters: BEH® C18 (1.7 pm, 2.1 x 100 mm)	A: 95% CH3COONH4 7mM15% CH3CN, B: CH3CN	84.2% A/15.8% B to 10.5% Ain 2.18 min, held for 1.96 min, back to 84.2% A/15.8% B in 0.73 min, held for 0.49 min.	0.343 mL/min 40°C	6.1
LC-C	Waters: Acquity® UPLC® -DADSQD	Waters: BEH C18 (1.7 pm, 2.1 x 50 mm)	A: 10mM CH3COONH4 in 95% H2O + 5% CH3CN B: CH3CN	From 95% A to 5% A in 1.3 min, held for 0.7 min.	0.8 mL/min 55°C	2

Method code	Instrument	Column	Mobile phase	Gradient	Flow Col T	Run time (min)
LC-D	Waters: Acquity® UPLC® -DADSQD	Waters: HSS T3 (1.8 pm, 2.1 x 100 mm)	A: 10mM CH3COONH4 in 95% H2O + 5% CH3CN B: CH3CN	From 100% A to 5% A in 2.10 min, to 0% A in 0.90 min, to 5% A in 0.5 min	0.7 mL/min 55°C	3.5

SFC/MS methods

The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon 5 dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the îo identification of the compound’s nominal monoisotopic molecular weight (MW).

Data acquisition was performed with appropriate software. Analytical SFC/MS Methods (Flow expressed in mL/min; column température (T) in °C; Run time in minutes, Backpressure (BPR) in bars.

Method	column	mobile phase	gradient	Flow	Run time
code	Col T	BPR
SFC-A	Daicel Chiralpak® AS3 column (3.0 pm, 150 x 4.6 mm)	A:CO₂ B: EtOH (+0.2% iPrNH₂+3% H₂O)	10%-50% B in 6 min, hold 3.5 min	2.5 40	9.5 110
SFC-B	Daicel Chiralpak® OD3 column (3.0 pm, 150 x 4.6 mm)	A:CO₂ B: EtOH (+0.2% iPrNH₂)	10%-50% B in 6 min, hold 3.5 min	2.5 40	9.5 110
SFC-C	Daicel Chiralpak® AS3 column (3.0 pm, 150 x 4.6 mm)	A:CO₂ B: EtOH (+0.2% iPrNH₂)	10%-50% B in 6 min, hold 3.5 min	2.5 40	9.5 110

Method code	column	mobile phase	gradient	Flow Col T	Run time
BPR
SFC-D	Daicel Chiralcel® OD-3 column (3 pm, 100 x 4.6 mm)	A:CO₂ B: iPrOH (+0.3% iPrNH₂)	40% B hold 3 min	3.5 35	3 105
SFC-E	Whelk®-O-(R,R) column (5.0 pm, 250 x 4.6 mm)	A:CO₂ B: EtOH (+0.2% iPrNH₂)	10%-50% B in 6 min, hold 3.5 min	2.5 40	9.5 110
SFC-F	Daicel Chiralpak® ID3 column (3.0 pm, 150 x 4.6 mm)	A:CO₂ B: EtOH (+0.2% IPrNH₂)	10%-50% B in 6 min, hold 3.5 min	2.5 40	9.5 110
SFC-G	Regis WhelkO1,S,S column (3 pm, 100 x 4.6 mm)	A:CO₂ B: MeOH	40% B hold 3 min,	3.5 35	3 103
SFC-H	Daicel Chiralcel® OD-3 column (3 pm, 100 x 4.6 mm)	A:CO₂ B: MeOH	40% B hold 3 min,	3.5 35	3 103
SFC-I	Daicel Chiralcel® OD-3 column (3 pm, 100 x 4.6 mm)	A:CO₂ B: MeOH	30% B hold 3 min,	3.5 35	3 103

Meltinq Points

Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method.

DSC823e (indicated as DSC)

For a number of compounds, melting points were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a température gradient of 10°C/minute. Maximum température was 300°C.

Optical Rotations:

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with a sodium lamp and reported as follows: [α]° (λ, c g/100ml, solvent, T°C).

-14[α]_λ ^τ = (100α) / (/ x c) : where I is the path length in dm and c is the concentration in g/100 ml for a sample at a température T (°C) and a wavelength λ (in nm). If the wavelength of light used is 589 nm (the sodium D line), then the symbol D might be used instead. The sign ofthe rotation (+ or -) should always be given. When using this équation the concentration and solvent are always provided in parenthèses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/100 ml).

Abbreviations used in experimental part

(M+H)⁺MH⁺	protonated molecular ion	iPrNH₂	isopropylamine
aq.......... Boc	aqueous ______ tert-butyloxycarbonyl	iPrOH K2CO3	2-propanol potassium carbonate
BOC2O	di-tert-butyl dicarbonate	kno₃	potassium nitrate
br	broad	UAIH4	lithium aluminium hydride
CH₃CN	acetonitrile	m/z	mass-to-charge ratio
CHCI3	chloroform	Me	methyl
CH2CI2	dichloromethane	MeOH	methanol
CH3OH	methanol	MgSO₄	magnésium sulfate
CO₂	carbon dioxide	min	minute(s)
CsCO₃	césium carbonate	MTBE	methyl-tert-butylether
d	doublet	N_?	nitrogen
DCM	dichloromethane	Na2CO₃	sodium carbonate
DIEA	diisopropylethylamine	Na2SO₄	sodium sulfate
DIPE	diisopropyl ether	NaBH₄	sodium borohydride
DMA	dimethylacetamide	NaCl	sodium chloride
DMAP	4-dimethylaminopyridine	i NaHCO₃	sodium bicarbonate
DME DMF	1,2-dimethoxyethane dimethylformamide	NaOH NH4CI	podium hydroxide___ ammonium chloride
DMSO	dimethyl sulfoxide	NH₄HCO₃	ammonium bicarbonate _
EDCI	1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide	NMP	N-methylpyrrolidon
eq. _	équivalent	q	quartet
Et₂O	diethyl ether	rt or RT	room température
Et₃N	triethylamine	SEMCI	2-(trimethylsilyl)ethoxymethyl chloride __________
EtOAc EtOH h₂HNO₃	ethyl acetate	s	singlet
éthanol hydrogen _______ nitric acid	t I tBuOK TEA __	triplet __________ potassium tert-butanolaat triethylamine

H₂O	water	TFA	trifluoroacetic acid
H₂SO₄	sulfuric acid	THF	tetrahydrofuran
HATU	O-(7-aza-1 H-benzotriazol-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate - CAS [148893-10-1]	2-Me-THF	2-methyltetrahydrofuran
HCl	hydrochloric acid	TMSCI	trimethylsilyl chloride
HPLC	high performance liquid chromatography	TMSCF₃	trifluoromethyltrimethylsilane

Example 1 : synthesis of 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-(pentafluoro-X⁶sulfanyl)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 1) and chiral séparation into Enantiomers 1A and 1B.

Enantiomers 1A and 1B

Synthesis of intermediate 1a:

To a mechanically stirred solution of tert-butyl 4-bromobutanoate [CAS 110661-911] (42.3 g, 0.19 mol) in DMF (600 mL) was added in portions a solid mixture of

3-amino-5-methoxyphenol [CAS 162155-27-3] (26.4 g, 0.19 mol) and CS2CO3 (123.6 g, 0.379 mol). The reaction was stirred at 60°C for 65 h, and allowed to reach room température. The mixture was poured out into H₂O (2.5 L). The product was extracted with Et₂O (2 times). The combined organic layers were washed with brine, dried over MgSO₄ and filtered. The solvent was evaporated under reduced pressure, and co-evaporated with toluene. The residue was purified ) -16via Normal Phase HPLC (Stationary phase: silica gel 60A 25-40 pm (Merck), mobile phase: gradient from 20% EtOAc, 80% heptane to 60% EtOAc, 40% heptane) yielding tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (27 g).

Synthesis of intermediate 1b:

At 0°C, BHs-Pyridine (1.46 mL, 14.5 mmol) was added slowly to a solution of 6-(pentafluoro-X⁶-sulfanyl)-1H-indole [CAS 1379811-84-3] (1.0 g, 4.11 mmol) in EtOH (8.5 mL). 5N HCl (7 mL) was slowly added. The mixture was stirred at 0°C for 2 h and allowed to gradually warm to room température while stirring overnight.

After cooling to 0°C (ice-bath), 50% NaOH (2 mL) was added dropwise and stirring was continued for 15 min. Water (50 mL) was added and the product was extracted with Et₂O/EtOAc 2/1. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (25 g) using a gradient of heptane/CH₂CI₂100/0 to 0/100. The product fractions were combined and evaporated under reduced pressure. The residue was dried under vacuum at 45°C to give 6-(pentafluoro-X⁶-sulfanyl)indoline 1b (328 mg).

Synthesis of intermediate 1c:

A mixture of give 6-(pentafluoro-l⁶-sulfanyl)indoline 1b (328 mg, 1.34 mmol), 2-(4chlorophenyl)acetic acid [CAS 1878-66-6] (228 mg, 1.34 mmol), HATU (778 mg, 2.0 mmol) and diisopropylethylamine (663 pL, 4.0 mmol) in CH3CN (15 mL) was stirred at room température for 65 h. The solvent was evaporated under reduced pressure. The residue was dissolved in 2-Me-THF (50 mL) and washed with 1N

HCl (25 mL) and brine. The organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (12 g) using a gradient of heptane/EtOAc 100/0 to 0/100. The desired fractions were combined and evaporated under reduced pressure. The product was crystallized from

CH₂Cl2/EtOAc, filtered off, washed (3x) with EtOAc, and dried under vacuum at 45°C to provide 2-(4-chlorophenyl)-1-(6-(pentafluoro-À⁶-sulfanyl)indolin-1-yl)ethanone 1c (209 mg). The filtrate was evaporated under reduced pressure. The residue was stirred up in Et₂O (2 mL), filtered off, washed (3x) with Et₂O, and dried at under vacuum at 45°C to provide a second crop of intermediate 1c (155 mg).

Synthesis of intermediate 1d:

At -70°C, under a N₂ flow, LiHMDS 1M in THF (1.78 mL, 1.78 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1-(6-(pentafluoro-À⁶-sulfanyl)indolin-1

F -17yl)ethanone 1c (354 mg, 0.89 mmol) in 2-Me-THF (35 mL) and the mixture was kept at -70°C for 30 min. TMSCI (182 pL, 1.42 mmol) was added dropwise. The mixture was stirred for 30 min at -70°C and a solution of /V-bromosuccinimide (198 mg, 1.11 mmol) in a solvent mixture of THF (1.5 mL) and 2-Me-THF (5 mL) was added dropwise. After stirring for 1 h at -78°C, the reaction was quenched with a saturated aqueous solution of NH4CI (50 mL). The cooling bath was removed and the reaction mixture was stirred for 50 min. Water (10 mL) was added and the organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1 -(διό (pentafluoro-À⁶-sulfanyl)indolin-1-yl)ethanone 1d (424 mg), which was used as such in the next step.

Synthesis of Compound 1 and chiral séparation into Enantiomers 1A and 1B:

A mixture of 2-bromo-2-(4-chlorophenyl)-1 -(6-(pentafluoro-À⁶-sulfanyl)indolin-1 yl)ethanone 1d (424 mg, 0.89 mmol), tert-butyl 4-(3-amino-5methoxyphenoxy)butanoate 1a (260 mg, 0.92 mmol) and diisopropylethylamine (306 pL, 1.78 mmol) in CH3CN (30 mL) was stirred at 60°C for 18 h. The reaction mixture was allowed to reach room température, and poured out into stirring water (150 mL). The product was extracted (2x) with Et20. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (40 g) using a gradient of heptane/EtOAc/EtOH 100/0/0 to 40/45/15). The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with dioxane.

The residue (602 mg, containing 58% of intermediate 1e) was mixed with 4M HCl in dioxane (4 mL) and the mixture was stirred at room température for 5 h. The solids were filtered off, washed with dioxane (3x) and Et₂O (2x), and dried under 30 vacuum at 45°C to provide crude 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6(pentafluoro-À⁶-sulfanyl)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 1, 309 mg). An analytical sample (60 mg) of racemic Compound 1 was further purified via préparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - 10 pm, 30 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The pure fractions were combined and the organic volatiles were evaporated under reduced pressure. The remaining aqueous solution was coevaporated under reduced pressure with o-xylene. The residue was dissolved in a solvent mixture of CH3CN and water, evaporated under reduced pressure and co19489

-18evaporated with dioxane. The residue was lyophilized from a solvent mixture of CH3CN (2 mL) and water (0.8 mL) to provide pure 4-(3-((1 -(4-chlorophenyl)-2-oxo2-(6-(pentafluoroy⁶-sulfanyl)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 1, 40 mg) as a powder.

The enantiomers of Compound 1 (249 mg) were separated via préparative chiral SFC (Stationary phase: Chiralpak® Diacel AD 20 x 250 mm, mobile phase: CO2, EtOH + 0.4% iPrNHs). The product fractions of the first eluted enantiomer were combined, evaporated under reduced pressure and co-evaporated with MeOH. The residue was stirred up in water (3.5 mL) and MeOH (1 mL), the solids were filtered off, washed (3x) with water/MeOH 4/1, and dried under vacuum at 45°C to provide Enantiomer 1A (41 mg). The product fractions of the second eluted enantiomer were combined, evaporated under reduced pressure and coevaporated with MeOH. The residue was stirred up in water (3 mL) and MeOH (0.6 mL), the solids were filtered off, washed (3x) with water/MeOH 4/1, and dried under vacuum at 45°C to provide Enantiomer 1B (48 mg).

Compound 1:

¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.86 (quin, 7=6.8 Hz, 2 H) 2.33 (t, 7=7.3 Hz, 2 H) 3.12 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, 7=6.5 Hz, 2 H) 3.99 - 4.13 (m, 1 H) 4.47 - 4.59 (m, 1 H) 5.57 (d, 7=8.6 Hz, 1 H) 5.76 (t, 7=2.1 Hz, 1 H) 5.91 - 5.96 (m, 2 H) 6.45 (d, 7=8.6 Hz, 1 H) 7.39 - 7.50 (m, 3 H) 7.51 - 7.62 (m, 3 H) 8.58 (d, 7=2.0 Hz, 1 H) 12.12 (brs, 1 H)

LC/MS (method LC-C): Rt 1.09 min, MH⁺ 621

Enantiomer 1A:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.85 (quin, 7=6.8 Hz, 2 H) 2.26 (brt, 7=6.8 Hz, 2 H) 3.15 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.84 (brt, 7=6.4 Hz, 2 H) 4.02 - 4.12 (m, 1 H) 4.48 - 4.60 (m, 1 H) 5.59 (d, 7=8.8 Hz, 1 H) 5.76 (t, 7=2.0 Hz, 1 H) 5.93 (t, 7=2.0 Hz, 1 H) 5.96 (t, 7=2.0 Hz, 1 H) 6.47 (d, 7=8.4 Hz, 1 H) 7.42 - 7.47 (m, 3 H) 7.53 - 7.59 (m, 3 H) 8.58 (d, 7=2.2 Hz, 1 H) LC/MS (method LC-D): Rt 1.99 min, MH⁺ 621 [a]D²⁰: .44 ₆° (_C 0.28, DMF)

Chiral SFC (method SFC-A): Rt 3.54 min, MH⁺ 621 chiral purity 97.9%.

Enantiomer 1 B:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.86 (quin, 7=6.8 Hz, 2 H) 2.33 (t, 7=7.3 Hz, 2 H) 3.14 - 3.29 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, 7=6.4 Hz, 2 H) 4.01 - 4.11 (m, 1 H) 4.48 - 4.58 (m, 1 H) 5.58 (d, 7=9.1 Hz, 1 H) 5.76 (t, 7=2.0 Hz, 1 H) 5.93 (t, 7=1.8

-19Hz, 1 H) 5.94 - 5.96 (m, 1 H) 6.48 (d, J=9A Hz, 1 H) 7.41 - 7.48 (m, 3 H) 7.52 -

7.61 (m, 3 H) 8.58 (d, J=2.2 Hz, 1 H) 12.13 (br s, 1 H)

LC/MS (method LC-D): Rt 1.98 min, MH⁺ 621 [a]_D ²⁰: +46.0° (c 0.265, DMF)

Chiral SFC (method SFC-A): R_t 3.82 min, MH⁺ 621 chiral purity 99.0%.

Example 2 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-(4-methyl-6(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 2) and chiral séparation into Enantiomers 2A and 2B.

Synthesis of intermediate 2a:

Pd/C (10%) (1.18 g) was added to a solution of 1-benzyl-4-methyl-6(trifluoromethyl)indoline [CAS 1156512-79-6] (11.8 g, 40.5 mmol) in AcOH (11.8 15 mL) and MeOH (118 mL). The reaction was stirred at room température for 12 h under H₂ atmosphère. The mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was taken up with CH₂CI₂, washed with water, brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel 20 (heptane/EtOAc 9/1 ). The pure fractions were combined and the solvent was evaporated to dryness to give 8.2 g of 4-methyl-6-(trifluoromethyl)indoline 2a.

b -20Synthesis of intermediate 2b:

tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (2.94 g, 10.5 mmol) was added to solution of methyl 2-bromo-2-(4-chlorophenyl)acetate [CAS 24091-92-7] (2.51 g, 9.53 mmol) in CH₃CN (200 mL). Diisopropylethylamine (2.46 mL, 14.3 mmol) was added and the reaction mixture was stirred at 80°C ovemight. The solvent was evaporated under reduced pressure. The residue was dissolved in CH2CI2 and washed with 1N HCl. The organic layer was washed with water, dried · over MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) using a gradient of EtOAc:EtOH (3:1 )/heptane 0/100 to 50/50. The product fractions were combined, and evaporated under reduced pressure and the residue was dried under vacuum at 50°C to provide tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-methoxy-2oxoethyl)amino)-5-methoxyphenoxy)butanoateas 2b (3.74 g) as a yellow oil.

Synthesis of intermediate 2c:

Lithium hydroxide (336 mg, 14.0 mmol) was added to a solution of tert-butyl 4-(3((1-(4-chlorophenyl)-2-methoxy-2-oxoethyl)amino)-5methoxyphenoxy)butanoateas 2b (3.74 g, 7.02 mmol) in a solvent mixture of water (25 mL), MeOH (25 mL) and THF (75 mL) and the reaction mixture was stirred at 20 room température for 5 h. Saturated aqueous NH4CI (50 mL) was added and the organic volatiles were evaporated under reduced pressure. The residual aqueous solution was acidified with 1N HCl to pH 2 and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was dried under vacuum at 50°C to give 2-((3-(425 (tert-butoxy)-4-oxobutoxy)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)acetic acid

2c (3.22 g) as a thick brown oil.

Synthesis of intermediate 2d:

A/,A/-Diisopropylethylamine (1.58 mL, 9.57 mmol) was added to a solution of 2-((330 (4-(terf-butoxy)-4-oxobutoxy)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)acetic acid 2c (1.44 g, 3.19) and 4-methyl-6-(trifluoromethyl)indoline 2a (953 mg, 3.51 mmol) in dry DMF (30 mL). HATU (1.82 g, 4.78 mmol) was added and the reaction mixture was stirred at room température for 2 h. The reaction mixture was poured out into water (400 mL) and the white suspension was extracted with EtOAc. The 35 aqueous layer was saturated by the addition of NaCl and extracted again with

EtOAc. The combined organic layers were washed with brine, water, dried over MgSÜ4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) using a gradient of EtOAc:EtOH

-21(3:1 )/heptane 0/100 to 60/40). The product fractions were combined and evaporated under reduced pressure. The residue (1.41 g) was purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - 10 pm, 50 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The product 5 fractions were combined and evaporated under reduced pressure to provide tertbutyl 4-(3-((1 -(4-chlorophenyl)-2-(4-methyl-6-(trifluoromethyl)indolin-1 -yl)-2oxoethyl)amino)-5-methoxyphenoxy)butanoate 2d (808 mg) as a white solid.

Synthesis of Compound 2 and chiral séparation into Enantiomers 2A and

2B:

Tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-(4-methyl-6-(trifluoromethyl)indolin-1-yl)-2oxoethyl)amino)-5-methoxyphenoxy)butanoate 2d (808 mg, 1.28 mmol) was mixed with 4M HCl in dioxane (9.6 mL) and the mixture was stirred at room température for 15 h. Nitrogen gas was bubbled through the reaction mixture for 15 30 min. The solvent was evaporated under reduced pressure to give 4-(3-((1-(4chlorophenyl)-2-(4-methyl-6-(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5methoxyphenoxy)butanoic acid (Compound 2, 735 mg) as a light brown solid. The enantiomers of Compound 2 (735 mg) were separated via preparative chiral SFC (Stationary phase: Chiralcel® Diacel OD 20 x 250 mm, mobile phase: CO₂, 20 EtOH + 0.4% iPrNH2). The product fractions were combined and evaporated under reduced pressure to give Enantiomer 2A as the first eluted product and Enantiomer 2B as the second eluted product. Both residues were mixed with EtOAc and water. The mixture was acidified to pH 1-2 with 1N HCl. The layers were separated and the aqueous layer was extracted twice with EtOAc. The 25 combined organic layers were washed with water, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was dried under vacuum at 50°C to give Enantiomer 2A (216 mg) and Enantiomer 2B (184 mg), respectively.

Compound 2:

Ή NMR (360 MHz, DMSO-cfe) δ ppm 1.87 (br quin, 7=6.9 Hz, 2 H) 2.25 (s, 3 H) 2.33 (br t, 7=7.1 Hz, 2 H) 3.07 - 3.20 (m, 2 H) 3.62 (s, 3 H) 3.84 (br t, 7=6.4 Hz, 2 H) 3.97 - 4.09 (m, 1 H) 4.48 - 4.60 (m, 1 H) 5.57 (br d, 7=8.8 Hz, 1 H) 5.76 (t, 7=1.8 Hz, 1 H) 5.90 - 5.99 (m, 2 H) 6.43 (br d, 7=8.8 Hz, 1 H) 7.25 (s, 1 H) 7.44 (d, 7=8.4 Hz, 2 H) 7.56 (br d, 7=8.4 Hz, 2 H) 8.22 (s, 1 H) 12.15 (br s, 1 H)

LC/MS (method LC-C): Rt 1.14 min, MH⁺ 577

Enantiomer 2A:

¹H NMR (360 MHz, DMSO-ofe) δ ppm 1.87 (quin, 7=6.8 Hz, 2 H) 2.25 (s, 3 H) 2.34 (t, 7=7.3 Hz, 2 H) 3.05 - 3.23 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, 7=6.4 Hz, 2 H) 4.03 (td,

-22J=) 0.2, 7.3 Hz, 1 H) 4.54 (td, J=10.2, 6.2 Hz, 1 H) 5.57 (d, J=8.8 Hz, 1 H) 5.76 (t, J=2.0 Hz, 1 H) 5.91 - 5.99 (m, 2 H) 6.42 (d, J=8.8 Hz, 1 H) 7.24 (s, 1 H) 7.44 (d, J=8.4 Hz, 2 H) 7.56 (d, J=8.8 Hz, 2 H) 8.22 (s, 1 H) 12.17 (br s, 1 H) LC/MS (method LC-C): Rt 1.26 min, MH⁺ 577

[a]_D ²⁰: -39.0° (c 0.438, DMF)

Chiral SFC (method SFC-B): Rt 5.11 min, MH⁺ 577 chiral purity 100%.

Enantiomer 2B:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.88 (quin, J=6.9 Hz, 2 H) 2.25 (s, 3 H) 2.34 10 (t, J=7.3 Hz, 2 H) 3.06 - 3.24 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.4 Hz, 2 H) 3.97 4.11 (m, 1 H) 4.55 (td, J=) 0.3, 6.8 Hz, 1 H) 5.58 (d, J=8.4 Hz, 1 H) 5.77 (t, J=2.Q Hz, 1 H) 5.92 - 5.99 (m, 2 H) 6.43 (d, J=8.8 Hz, 1 H) 7.25 (s, 1 H) 7.41 - 7.50 (m, 2 H) 7.52 - 7.60 (m, 2 H) 8.23 (s, 1 H) 12.17 (br s, 1 H)

LC/MS (method LC-C): Rt 1.25 min, MH⁺ 577

[a]_D ²⁰: +47. Γ (c 0.384, DMF)

Chiral SFC (method SFC-B): Rt 8.00 min, MH⁺ 577 chiral purity 99.6%.

Example 3 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-(5-fluoro-6(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 3) and chiral séparation into Enantiomers 3A and 3B.

OMe

Cl

3c

(iPr)₂NEt

CH₃CN, 70°C 4h

Enantiomers 3A and 3B

Synthesis of intermediate 3a:

At 0°C, BHs-Pyridine (10.45 mL, 103.4 mmol) was added slowly to a solution of 25 5-fluoro-6-(trifluoromethyl)-1/-/-indole [CAS 1493800-10-4] (7.0 g, 34.5 mmol) in

EtOH (45 mL). 6N HCl (105 mL) was added dropwise while maintaining the température below 10°C. The mixture was stirred at 0°C for 3 h. Water was added

F -23and the mixture was basified to pH 8.5 with a concentrated solution of NaOH (température below 20°C). EtOAc was added. The organic layer was separated, washed with water, dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. Toluene was added and removed under reduced pressure (to eliminate traces of pyridine). The residue was purified by flash chromatography on silica gel (20-45 pm, 120 g, CH2Cl2/MeOH 98.5/1.5). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 5-fluoro-6-(trifluoromethyl)indoline 3a (3.5 g).

Synthesis of intermediate 3b:

A mixture of 5-fluoro-6-(trifluoromethyl)indoline 3a (500 mg, 2.44 mmol), 2-(4chlorophenyl)acetic acid [CAS 1878-66-6] (457 mg, 2.64 mmol), HATU (1.39 g, 3.66 mmol) and diisopropylethylamine (1.2 mL, 7.31 mmol) in DMF (10 mL) was stirred at room température for 12 h. The mixture was poured out into ice-water, 15 the precipitate was filtered off and taken up with CH2Cl2.The organic layer was dried over MgSO₄ and concentrated under reduced pressure. The compound was crystallized from CH3CN and dried to give 2-(4-chlorophenyl)-1-(5-fluoro-6(trifluoromethyl)indolin-1-yl)ethanone 3b (854 mg).

Synthesis of intermediate 3c:

At -78°C, under a N2 flow, LiHMDS 1M in THF (4.78 mL, 4.78 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1-(5-fluoro-6-(trifluoromethyl)indolin-1yl)ethanone 3b (854 mg, 2.39 mmol) in THF (7 mL). TMSCI (485 pL, 3.82 mmol) was added dropwise. The mixture was stirred for 15 min at -78°C and a solution of 25 /V-bromosuccinimide (510 mg, 2.87 mmol) in THF (7 mL) was added dropwise.

After stirring for 2 h at -78°C, the reaction was quenched with a saturated aqueous solution of NH₄CI. EtOAc was added and the organic layer was separated, dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 40 g, 30 CH2Cl2/heptane 50/50). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1-(5fluoro-6-(trifluoromethyl)indolin-1-yl)ethanone 3c (820 mg).

Synthesis of intermediate 3d:

A mixture of 2-bromo-2-(4-chlorophenyl)-1 -(5-fluoro-6-(trifluoromethyl)indolin-1 yl)ethanone 3c (820 mg, 1.88 mmol), tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (528 mg, 1.88 mmol) and diisopropylethylamine (388 pL, 2.25 mmol) in CH3CN (20 mL) was stirred at 70°C for 4 h. The reaction mixture was ’ -24concentrated under reduced pressure. The residue was taken up with EtOAc. The organic layer was washed twice with a 1N solution of HCl, water, dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 40 g,

CH2CI2 100%). The pure fractions were combined and the solvent was concentrated under reduced pressure to give tert-butyl 4-(3-((1-(4-chlorophenyl)-2(5-fluoro-6-(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoate 3d (1.07 g).

Synthesis of Compound 3 and chiral séparation into Enantiomers 3A and 3B:

A solution of tert-butyl 4-(3-((1-(4-chlorophenyl)-2-(5-fluoro-6(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoate 3d (1.07 g, 1.68 mmol) in HCl (4M in dioxane) (20 mL) was stirred at 5°C for 3 h and 15 at room température for 12 h. The precipitate was filtered off, washed with diisopropyl ether and dried. The residue was purified via reverse phase chromatography (Stationary phase: YMC-actus Triart-C18 10 pm 30 x 150 mm, mobile phase: gradient from 65% NH4HCO3 0.2%, 35% CH3CN to 25% NH4HCO3 0.2%, 75% CH3CN) to provide Compound 3 (540 mg). An analytical sample (30 mg) was further purified via reverse phase chromatography (Stationary phase: YMC-actus Triart-C18 10 pm 30 x 150mm, mobile phase: gradient from 65% NH4HCO3 0.2 35% CH₃CN to 25% NH4HCO3 0.2%, 75% CH3CN) to give 4-(3-((1(4-chlorophenyl)-2-(5-Îluoro-6-(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5methoxyphenoxy)butanoic acid (Compound 3, 30 mg, 0.16 H2O). The remaining amount of Compound 3 (510 mg) was used for chiral séparation of the enantiomers via Préparative Chiral SFC (Stationary phase: Whelk O1 S,S 5 pm 250 x 30 mm, mobile phase: 60% CO₂, 40% MeOH). The first eluted enantiomer (250 mg) was further purified by flash chromatography on silica gel (20-45 pm, 24 g, CH2Cl2/MeOH 98/2). The pure fractions were combined and the solvent was concentrated under reduced pressure to give, after solidification in heptane/diisopropyl ether, Enantiomer 3A (170 mg). The second eluted enantiomer (249 mg) was solidified in heptane/diisopropyl ether to give Enantiomer 3B (182 mg).

Compound 3:

¹H NMR (500 MHz, DMSO-7₆) δ ppm 1.78 - 1.92 (m, 2 H) 2.26 (br s, 2 H) 3.15 3.31 (m, 2 H) 3.61 (s, 3 H) 3.84 (br s, 2 H) 4.02 (br d, 7=7.88 Hz, 1 H) 4.54 (br d, J=5.99 Hz, 1 H) 5.58 (br d, 7=8.51 Hz, 1 H) 5.76 (br s, 1 H) 5.90 - 5.99 (m, 2 H)

-256.42 (br d, 7=8.51 Hz, 1 H) 7.44 (br d, 7=7.88 Hz, 3 H) 7.55 (br d, 7=7.88 Hz, 2 H)

8.38 (br d, 7=6.31 Hz, 1 H) 11.60 - 12.92 (m, 1 H)

LC/MS (method LC-A): Rt 2.94 min, MH⁺ 581

Melting point: 206°C

Enantiomer 3A:

¹H NMR (500 MHz, DMSO-cfe) δ ppm 1.87 (quin, 7=6.86 Hz, 2 H) 2.29 - 2.39 (m, 2 H) 3.18 - 3.30 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, 7=6.46 Hz, 2 H) 4.03 (td, 7=10.25, 7.25 Hz, 1 H) 4.54 (td, 7=10.17, 6.15 Hz, 1 H) 5.58 (d, 7=8.51 Hz, 1 H) 5.76 (s, 1 H) 5.95 (br d, 7=11.35 Hz, 2 H) 6.43 (d, 7=8.83 Hz, 1 H) 7.43 - 7.48 (m, 3 H) 7.55 (d, 7=8.51 Hz, 2 H) 8.39 (d, 7=6.31 Hz, 1 H) 12.08 - 12.27 (m, 1 H) LC/MS (method LC-A): Rt 2.95 min, MH⁺ 581

[a]_D ²⁰: -48.9° (c 0.315, DMF)

Chiral SFC (method SFC-G): Rt 1.65 min, MH⁺ 581 chiral purity 100%.

Enantiomer 3B:

¹H NMR (500 MHz, DMSO-cfe) δ ppm 1.87 (quin, 7=6.54 Hz, 2 H) 2.25 - 2.46 (m, 2 H) 3.15-3.31 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, 7=6.31 Hz, 2 H) 3.98 - 4.07 (m, 1 H) 4.50 - 4.59 (m, 1 H) 5.58 (br d, 7=8.83 Hz, 1 H) 5.76 (s, 1 H) 5.95 (br d, 7=12.30 Hz, 2 H) 6.43 (br d, 7=8.83 Hz, 1 H) 7.42 - 7.48 (m, 3 H) 7.56 (br d, 7=8.20 Hz, 2 H) 8.39 (br d, 7=6.31 Hz, 1 H) 11.40 - 12.54 (m, 1 H)

LC/MS (method LC-A): Rt 2.94 min, MH⁺ 581

[a]_D ²⁰: +47.8° (c 0.27, DMF)

Chiral SFC (method SFC-G): Rt 2.14 min, MH⁺ 581 chiral purity 99.43%.

-26Example 4 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-(4-methyl-6(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 4) and chiral séparation into Enantiomers 4A and 4B.

rt 1 h

TF AA Dioxane

HNO₃, Ac₂O

55°C overnight

F₃CO

no₂

NHCOCF3

4b

2M K₂CO₃MeOH

70°C overnight

) NaNO₂, H₂SO₄, H₂O CH₃COOH, rt 30 min

reflux, 40 min

Fe, NH₄CI

EtOH, H₂O

T rimethylsilylacetylene

Cul, PdCI₂(PPh₃)₂

Et₃N 65°C overnight

2) urea, H₂O, rt 10 min

3) Kl, H^, rt 30 min

BH₃-Pyridine

EtOH, 0°C 3h

Synthesis of intermediate 4a:

To a solution of 2-methyl-4-(trifluoromethoxy)aniline [CAS 86256-59-9] (10.0 g, 52.3 mmol) in dioxane (20 mL) was added trifluoroacetic anhydride (8 mL, 57.2 mmol). The reaction mixture was stirred at room température for 1 h. The reaction 10 mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and 1N HCl. The phases were separated. The organic phase was washed with a saturated solution of NaHCOs in water, H₂O and brine, dried over Na₂SO4, filtered and concentrated under reduced pressure to afford 14.7 g of 2,2,2-trifluoro-A/-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide 4a as a white 15 powder. The compound was used in the next step without further purification.

F -27Synthesis of intermediate 4c:

To acetic anhydride (11.4 mL, 61.1 mmol), cooled at 0°C was added dropwise 70% nitric acid (3.9 mL). 2,2,2-Trifluoro-/\/-(2-methyl-4-(trifluoromethoxy)phenyl)acetamide 4a (5 g, 17.4 mmol) was added portionwise and the reaction mixture 5 was heated at 55°C for 12 h. After cooling to room température, the reaction mixture was diluted with EtOAc and washed with Η₂Ο. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (46 mL). 2M K2CO3 (23 mL, 46 mmol) was added and the reaction mixture was heated at 70°C for 4 h. More 2M ίο K2CO3 (10 mL, 20 mmol) was added and the reaction mixture was heated at 70°C for 12 h. The reaction mixture was partially concentrated under reduced pressure to remove methanol. The residue was extracted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on 15 silica gel using a gradient of EtOAc (20% to 50%) in heptane to afford 3.6 g of 2-methyl-6-nitro-4-(trifluoromethoxy)aniline 4c as a yellow solid.

Synthesis of intermediate 4d:

To a solution of 2-methyl-6-nitro-4-(trifluoromethoxy)aniline 4c (1.8 g, 7.69 mmol) 20 in acetic acid (10.9 mL) was added dropwise a solution of sodium nitrite (0.806 g, 11.7 mmol) in H2SO4/H2O (2 mL, 1/1). The reaction mixture was stirred at room température for 30 min. H2O (22 mL) and urea (0.802 g, 13.4 mmol) were added. After 10 min at room température, a solution of potassium iodide (1.7 g, 10.2 mmol) in H2O (11 mL) was added dropwise. The reaction mixture was stirred at 25 room température for 30 min. The yellow solid was filtered off, washed with H2O and dried to give 2.4 g of 2-iodo-1-methyl-3-nitro-5-(trifluoromethoxy)benzene 4d.

Synthesis of intermediate 4e:

To a solution of 2-iodo-1-methyl-3-nitro-5-(trifluoromethoxy)benzene 4d (3.5 g, 30 10.0 mmol) in EtOH (30 mL) was added a solution of NH4CI (2.7 g, 49.9 mmol) in

H2O (30 mL). The reaction mixture was heated at 50°C. Iron (2.6 g, 46.9 mmol) was added and the reaction mixture was heated under reflux for 40 min. After cooling to room température, the reaction mixture was filtered through Celite®. The solids were washed with EtOH. The filtrate was partially concentrated under reduced pressure to remove EtOH. The residue was partitioned between EtOAc and a saturated solution of NaHCOs in water. The phases were separated. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash ’ -28chromatography on silica gel using a gradient of EtOAc (0% to 25%) in heptane to afford 2.9 g of 2-iodo-3-methyl-5-(trifluoromethoxy)aniline 4e as a yellow oil.

Synthesis of intermediate 4f:

A solution of 2-iodo-3-methyl-5-(trifluoromethoxy)aniline 4e (2.9 g, 9.1 mmol) in triethylamine (23 mL) was degassed with argon for 15 min.

Dichlorobis(triphenylphosphine)palladium(ll) (0.327 g, 0.47 mmol), copper(l) iodide (0.164 g, 0.86 mmol) and trimethylsilylacetylene (1.8 mL, 13.1 mmol) were added. The reaction mixture was heated at 65°C for 12 h. After cooling to room température, the reaction mixture was diluted with Η₂Ο and extracted with EtOAc (3x). The organic phases were combined, washed with H2O and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in heptane to afford 2.6 g of 3-methyl-5-(trifluoromethoxy)-215 ((trimethylsilyl)ethynyl)aniline 4f as an orange oil.

Synthesis of intermediate 4g:

To a solution of 3-methyl-5-(trifluoromethoxy)-2-((trimethylsilyl)ethynyl)aniline 4f (2.7 g, 9.3 mmol) in NMP (27 mL) was added tBuOK (3.1 g, 27.8 mmol). The 20 reaction mixture was heated at 80°C for 4 h. After cooling to room température, the reaction mixture was diluted with H₂O and extracted with EtOAc (2x). The organic phases were combined, washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc (0% to 20%) in 25 heptane to afford 1.7 g of 4-rnethyl-6-(trifluoromethoxy)-1 /7-indole 4g as an orange oil.

Synthesis of intermediate 4h:

At 0°C, BHs-Pyridine (1.2 mL, 11.6 mmol) was added dropwise to a solution of 430 methyl-6-(trifluoromethoxy)-1/7-indole 4g (0.5 g, 2.32 mmol) in EtOH (3 mL). 6N

HCl (6 mL) was slowly added dropwise while maintaining the reaction température below 10°C. The mixture was stirred at 0°C for 3 h. Water (12 mL) was added and the mixture was basified until pH 8-9 with a concentrated solution of NaOH in water (the reaction température was kept below 20°C). The mixture was extracted 35 with EtOAc. The organic layer was washed with water, dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. Toluene was added and the solution was concentrated under reduced pressure to give 450 mg of 4-methyl6-(trifluoromethoxy)indoline 4h.

-29Synthesis of intermediate 4i:

Λ/,/V-Diisopropylethylamine (1.58 mL, 9.57 mmol) was added to a solution of 2-((3(4-(fert-butoxy)-4-oxobutoxy)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)acetic acid 2c (1.44 g, 3.19) and 4-methyl-6-(trifluoromethoxy)indoline 4h (846 mg, 3.51 5 mmol) in dry DMF (30 mL). HATU (1.82 g, 4.78 mmol) was added and the reaction mixture was stirred at room température for 2 h. The reaction mixture was poured out into water (400 mL) and the white suspension was extracted with EtOAc. The aqueous layer was saturated by the addition of NaCl and extracted again with EtOAc. The combined organic layers were washed with brine, water, dried over io MgSO₄ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) using a gradient of EtOAc:EtOH (3:1)/heptane 0/100 to 60/40. The product fractions were combined and evaporated under reduced pressure. The residue (1.47 g) was purified via préparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - 10 pm, 50 x 15 150 mm, mobile phase: 0.25% NH₄HCO3 solution in water, CH3CN). The product fractions were combined and evaporated under reduced pressure to provide tertbutyl 4-(3-((1 -(4-chlorophenyl)-2-(4-methyl-6-(trifluoromethoxy)indolin-1 -yl)-2oxoethyl)amino)-5-methoxyphenoxy)butanoate 4i (821 mg) as a white solid.

Synthesis of Compound 4 and chiral séparation into Enantiomers 4A and 4B:

Tert-butyl 4-(3-((1-(4-chlorophenyl)-2-(4-methyl-6-(trifluoromethoxy)indolin-1-yl)-2oxoethyl)amino)-5-methoxyphenoxy)butanoate 4i (821 mg, 1.27 mmol) was mixed with 4M HCl in dioxane (9.5 mL) and the mixture was stirred at room température 25 for 15 h. Nitrogen gas was bubbled through the reaction mixture for 30 min. The solvent was evaporated under reduced pressure to give 4-(3-((1-(4-chlorophenyl)2-(4-methyl-6-(trifluoromethyl)indolin-1-yl)-2-oxoethyl)amino)-5methoxyphenoxy)butanoic acid (Compound 4, 750 mg) as an off-white solid.

The enantiomers of Compound 4 (750 mg) were separated via préparative chiral 30 SFC (Stationary phase: Chiralcel® Diacel OD 20 x 250 mm, mobile phase: CO₂,

EtOH + 0.4% iPrNH₂). The product fractions were combined and evaporated under reduced pressure to give Enantiomer 4A as the first eluted product and Enantiomer 4B as the second eluted product. Both residues were mixed with EtOAc and water. The mixture was acidified to pH 1-2 with 1N HCl. The layers 35 were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, dried over MgSO₄, filtered, and evaporated under reduced pressure. The residue was dried under vacuum at 50°C to give Enantiomer 4A (213 mg) and Enantiomer 4B (194 mg) respectively.

) -30Compound 4:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=7.0 Hz, 2 H) 2.20 (s, 3 H) 2.33 (t, J=7A Hz, 2 H) 2.98 - 3.16 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, J=6.4 Hz, 2 H) 4.04 (td, 5 J=10.4, 7.0 Hz, 1 H) 4.53 (td, J=10.3, 6.4 Hz, 1 H) 5.56 (d, J=9.1 Hz, 1 H) 5.76 (t,

J=2.0 Hz, 1 H) 5.91 - 5.98 (m, 2 H) 6.45 (d, J=8.8 Hz, 1 H) 6.87 (s, 1 H) 7.38 - 7.47 (m, 2 H) 7.50 - 7.61 (m, 2 H) 7.89 (s, 1 H) 12.18 (br s, 1 H)

LC/MS (method LC-C): Rt 1.14 min, MH⁺ 593 io Enantiomer 4A:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.20 (s, 3 H) 2.34 (t, J=7.3 Hz, 2 H) 2.98 - 3.16 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.4 Hz, 2 H) 4.05 (td, J=WA, 7.0 Hz, 1 H) 4.53 (td, J=10.3, 6.4 Hz, 1 H) 5.56 (d, J=8.8 Hz, 1 H) 5.76 (t, J=) .8 Hz, 1 H) 5.91 - 5.99 (m, 2 H) 6.45 (d, J=8.8 Hz, 1 H) 6.88 (s, 1 H) 7.38 - 7.49 15 (m, 2 H) 7.51 -7.61 (m, 2 H) 7.89 (s, 1 H) 12.17 (br s, 1 H)

LC/MS (method LC-C): Rt 1.29 min, MH⁺ 593

[a]_D ²⁰: -39.6° (c 0.455, DMF)

Chiral SFC (method SFC-C): Rt 3.34 min, MH⁺ 593 chiral purity 100%.

Enantiomer 4B:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.88 (quin, J=6.9 Hz, 2 H) 2.20 (s, 3 H) 2.34 (t, J=7 Λ Hz, 2 H) 2.98 - 3.16 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=8A Hz, 2 H) 4.05 (td, J=10.3, 7.1 Hz, 1 H) 4.53 (td, J=10.2, 6.6 Hz, 1 H) 5.56 (d, J=8.8 Hz, 1 H) 5.76 (t, J=1.8 Hz, 1 H) 5.92 - 5.99 (m, 2 H) 6.46 (d, J=8.8 Hz, 1 H) 6.88 (s, 1 H) 7.38 - 7.49 25 (m, 2 H) 7.50 - 7.63 (m, 2 H) 7.89 (s, 1 H) 12.16 (brs, 1 H)

LC/MS (method LC-C): R_t 1.30 min, MH⁺ 593

[a]_D ²⁰: +43.7° (c 0.38, DMF)

Chiral SFC (method method SFC-C): Rt 3.16 min, MH⁺ 593 chiral purity 100%.

-31Example 5 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-(5-fluoro-6(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 5) and chiral séparation into Enantiomers 5A and 5B.

KNO_3i H2SO4

Fe, NH4CI iPrOH, water

60°C16h

5b

Pd(PPh₃)CI₂

Cul, Et₃N 90°C, 16h

0°C to 25°C, 16h

5a

EtOH, 6N HCl 0°C 2h

BH₃-Pyridine

OMe

(iPr)₂NEt

CH₃CN, 80°C 18h

Synthesis of intermediate 5a:

A solution of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene [CAS 105529-58-6] (98.7 g, 381.1 mmol) in concentrated H2SO4 (98%, 200 mL), was cooled to 0°C with an ice-bath. KNO3 (43.0 g, 425.3 mmol) was added in portions. After addition, 10 the ice-bath was removed and the mixture was stirred at room température for 16 h. The reaction mixture was poured out into ice-water (2 L) while stirring. The mixture was extracted with CH2CI2 (3x 500 mL). The combined organic layers were washed with a saturated aqueous NaHCOs solution (2x 500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 15 1 -bromo-5-fluoro-2-nitro-4-(trifluoromethoxy)benzene 5a (117.2 g), which was used in the next step without further purification.

Synthesis of intermediate 5b:

To a stirred suspension of 1-bromo-5-fluoro-2-nitro-4-(trifluoromethoxy)benzene 20 5a (70.0 g, 230 mmol) and NH₄CI (123.2 g, 2.30 mol) in iPrOH (1 L) and water (330 mL) was added reductive iron powder (64.3 g, 1.15 mol) under N219489

F -32atmosphere. The reaction mixture was stirred at 60°C for 16 h. The reaction mixture was diluted with EtOAc (1 L) and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (1 L) and water (800 mL). The layers were separated and the organic phase was washed with brine (1 L), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure (oil pump, b.p. 60~64°C). 2-Bromo-4-fluoro-5-(trifluoromethoxy)aniline 5b (47.3 g) was obtained as a yellow oil.

îo Synthesis of intermediate 5c:

To a mixture of 2-bromo-4-fluoro-5-(trifluoromethoxy)aniline 5b (18.4 g, 67.2 mmol) and ethynyl(trimethyl)silane (19.9 g, 202.4 mmol, 28.00 mL) in Et₃N (300 mL) was added Cul (1.28 g, 6.72 mmol) and Pd(PPh₃)2Cl2 (2.40 g, 3.42 mmol). The reaction mixture was heated under N2-atmosphere at 90°C for 16 h. After cooling to room température, the mixture was diluted with MTBE (300 mL) and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®, 220 g SepaFlash® Silica Flash Column, eluent: gradient of 0 to 5% EtOAc in petroleum ether @100mL/min). 4-Fluoro-5-(trifluoromethoxy)-2-((trimethylsilyl)ethynyl)aniline

5c (16.1 g, 90% purity) was obtained as a brown oil.

Synthesis of intermediate 5d:

A mixture of 4-fluoro-5-(trifluoromethoxy)-2-((trimethylsilyl)ethynyl)aniline 5c (16.1 g, 55.3 mmol) and tBuOK (18.6 g, 165.8 mmol) in NMP (220.00 mL) was heated at 25 90°C for 16 h under N2-atmosphere. After cooling to room température, the reaction mixture was poured out into ice-water (1 L) and extracted with MTBE (3x 300mL). The combined organic phases were washed with water (2x 200 mL), brine (300 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ISCO®, 30 120 g SepaFlash® Silica Flash Column, eluent: gradient of 0 to 5% EtOAc in

Petroleum ether @ 85 mL/min) to afford 5-fluoro-6-(trifluoromethoxy)-1/7-indole 5d (11 g) product as a dark-green oil. The residue was combined with another fraction (total amount = 17.2 g) and further purified by distillation under reduced pressure (oil pump, b.p. 60~64°C) to provide 5-fluoro-6-(trifluoromethoxy)-1/7-indole 5d 35 (14.7 g, 95% purity) as a colorless oil.

p -33Synthesis of intermediate 5e:

At 0°C, BHs-pyridine (13.8 mL, 136.9 mmol) was added dropwise to a solution of 5-fluoro-6-(trifluoromethoxy)-1/7-indole 5d (6 g, 27.4 mmol) in EtOH (40 mL). 6N HCl (90 mL) was added dropwise while maintaining the température below 10°C.

The mixture was stirred at 0°C for 2 h. Water (100 mL) was added and the mixture was basified to pH 8-9 with a concentrated solution of NaOH in water (the reaction température was kept below 20°C). The mixture was extracted with CH2CI2. The organic layer was washed with water, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. Toluene was added and the solution îc was concentrated under reduced pressure to give 5.52 g of 5-fluoro-6(trifluoromethoxy)indoline 5e. The compound was used in the next reaction step without further purification.

Synthesis of intermediate 5f:

To a mixture of 2-bromo-2-(4-chlorophenyl)acetic acid [CAS 3381-73-5] (0.61 g, 2.4 mmol), 5-fluoro-6-(trifluoromethoxy)indoline 5e (0.55 g , 2.2 mmol) and DMAP (0.027 g, 0.22 mmol) in CH2CI2 (14 mL) was added EDCI (0.51 g, 2.7 mmol). The mixture was stirred at room température for 18 h. The mixture was diluted with a 10% K2CO3 solution in water. The layers were decanted. The organic layer was washed with water, dried over MgSO4, filtered and the solvent was concentrated under reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1-(5-fluoro-6(trifluoromethoxy)indolin-1-yl)ethanone 5f (1.1 g, purple oil). The compound was used in the next step without further purification.

Synthesis of intermediate 5g:

A mixture of 2-bromo-2-(4-chlorophenyl)-1-(5-fluoro-6-(trifluoromethoxy)indolin-1yl)ethanone 5f (1.1 g, 2.2 mmol), tert-butyl 4-(3-amino-5methoxyphenoxy)butanoate 1a (1.0 g, 3.3 mmol) and diisopropylethylamine (1.5 mL, 8.7 mmol) in CH3CN (29 mL) was stirred at 80°C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30 pm, 40 g, heptane/EtOAc gradient 85/15 to 75/25). The fractions containing the expected compound were combined and the solvent was concentrated under reduced pressure to give tert-butyl 4-(3-((1-(4chlorophenyl)-2-(5-fluoro-6-(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)amino)-535 methoxyphenoxy)butanoate 5g (480 mg, 57% purity by LC/MS).

| -34Synthesis of Compound 5 and chiral séparation into Enantiomers 5A and 5B:

A mixture of tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-(5-fluoro-6(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoate 5g 5 (0.48 g, 0.42 mmol, 57% purity) in HCl (4M in dioxane) (4.6 mL) was stirred at room température for 18 h. The mixture was concentrated under reduced pressure, taken up in Et₃N (5 mL) and concentrated again in vacuo. The residue was purified by flash chromatography on silica gel (30 pm, 24 g, CH2CI2/ MeOH gradient 99/1 to 96/4). The pure fractions were combined and evaporated to dryness. The residue (150 mg) was further purified via Reverse Phase HPLC (Stationary phase: YMC-actus Triart-C18 10 pm 30 x 150mm, mobile phase: gradient from 65% NH₄HCO₃ 0.2%, 35% CH₃CN to 25% NH₄HCO₃ 0.2%, 75% CH₃CN) to give 4-(3-((1 -(4-chlorophenyl)-2-(5-fluoro-6-(trifluoromethoxy)indolin-1yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 5, 71 mg).

The enantiomers (55 mg) were separated via chiral SFC (Stationary phase: Chiralcel® OD-H 5 pm 250 x 20 mm, mobile phase: 55% CO2, 45% MeOH) to give, after freeze-drying from a solvent mixture of CH₃CN/water the first eluted Enantiomer 5A (25 mg, white solid) and the second eluted Enantiomer 5B (25 mg, white solid).

Compound 5:

¹H NMR (500 MHz, DMSO-cfe) δ ppm 1.86 (quin, 7=6.70 Hz, 2 H) 2.24 - 2.43 (m, 2 H) 3.06 - 3.25 (m, 2 H) 3.61 (s, 3H) 3.84 (br t, 7=6.31 Hz, 2 H) 3.94 - 4.13 (m, 1 H) 4.46 - 4.57 (m, 1 H) 5.56 (br d, 7=8.83 Hz, 1 H) 5.75 (s, 1 H) 5.93 (s, 1 H) 5.95 (s, 25 1 H) 6.45 (br d, 7=8.83 Hz, 1 H) 7.44 (br d, 7=8.20 Hz, 3 H) 7.54 (br d, 7=8.20 Hz,

H) 8.16 (brd, 7=6.62 Hz, 1 H) 12.12 (brs, 1 H) LC/MS (method LC-A): Rt 3.00 min, MH⁺ 597

Enantiomer 5A:

¹H NMR (500 MHz, DMSO-ofe) δ ppm 1.86 (quin, 7=6.94 Hz, 2 H) 2.25 - 2.44 (m, 2 H) 3.06 - 3.26 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, 7=6.46 Hz, 2 H) 4.05 (td, 7=10.32, 7.09 Hz, 1 H) 4.48 - 4.55 (m, 1 H) 5.56 (d, 7=8.83 Hz, 1 H) 5.76 (t, 7=1.89 Hz, 1 H) 5.94 (br d, 7=11.98 Hz, 2 H) 6.45 (d, 7=8.83 Hz, 1 H) 7.42 - 7.46 (m, 3 H) 7.54 (d, 7=8.20 Hz, 2 H) 8.16 (brd, 7=6.94 Hz, 1 H) 12.01 (brs, 1H)

LC/MS (method LC-A): Rt 3.00 min, MH⁺ 597

[a]_D ²⁰: -35.8° (c 0.257, DMF)

Chiral SFC (method SFC-H): Rt 1.34 min, MH⁺ 597 chiral purity 100%.

-35Enantiomer 5B:

¹H NMR (500 MHz, DMSO-c/₆) δ ppm 1.85 (quin, J=6.86 Hz, 2 H) 2.27 (t, J=7.25 Hz, 2 H) 3.10 - 3.31 (m, 2 H) 3.61 (s, 3 H) 3.78 - 3.90 (m, 2 H) 4.05 (td, J=10.40, 7.25 Hz, 1 H) 4.52 (td, J=10.32, 6.46 Hz, 1 H) 5.57 (d, J=8.83 Hz, 1 H) 5.75 (t, .89 Hz, 1 H) 5.94 (br d, J=16.39 Hz, 2 H) 6.45 (d, J=8.83 Hz, 1 H) 7.41 - 7.46 (m, 3 H) 7.55 (d, J=8.51 Hz, 2 H) 8.16 (brd, J=6.94 Hz, 1 H) LC/MS (method LC-A): Rt 3.00 min, MH⁺ 597 [a]_D ²⁰: +52.8° (c 0.231, DMF)

Chiral SFC (method SFC-H): Rt 3.14 min, MH⁺ 597 chiral purity 100%.

ic

Example 6 : synthesis of 4-(3-((1 -(4-fluoro-2-methoxyphenyl)-2-oxo-2-(6(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 6) and chiral séparation into Enantiomers 6A and 6B.

Synthesis of intermediate 6a:

A mixture of 6-(trifluoromethoxy)indoline [CAS 959235-95-1] (2 g, 9.84 mmol), 2(4-fluoro-2-methoxyphenyl)acetic acid [CAS 886498-61-9] (2.17 g, 10.8 mmol), HATU (5.62 g, 14.8 mmol) and diisopropylethylamine (4.9 mL, 29.5 mmol) in DMF 20 (20 mL) was stirred at room température for 3 h. Water and ice were added and the precipitate was filtered off and dried to give 2-(4-fluoro-2-methoxyphenyl)-1-(6(trifluoromethoxy)indolin-1-yl)ethanone 6a (3.44 g).

Synthesis of intermediate 6b:

At -78°C under a N₂ flow, LiHMDS (18.7 mL, 18.7 mmol) was added dropwise to a mixture of 2-(4-fluoro-2-methoxyphenyl)-1 -(6-(trifluoromethoxy)indolin-1 yl)ethanone 6a (3.44 g, 9.32 mmol) in THF (45 mL). TMSCI (1.42 mL, 11.2 mmol) was added dropwise. The mixture was stirred for 15 min at -78°C and Nbromosuccinimide (1.83 g, 10.2 mmol) in THF (35 mL) was added dropwise. After ’ -36stirring for 2 h at -78°C, the reaction was quenched with a saturated NH₄CI solution. The mixture was extracted with EtOAc, dried over MgSO₄, filtered and the solvent was concentrated under reduced pressure to give 2-bromo-2-(4-fluoro-2methoxyphenyl)-1-(6-(trifluoromethoxy)indolin-1-yl)ethanone 6b (4.48 g). The crude compound was used without further purification in the next step.

Synthesis of intermediate 6c:

A mixture of 2-bromo-2-(4-fluoro-2-methoxyphenyl)-1-(6-(trifluoromethoxy)indolin1-yl)ethanone 6b (2.0 g, 4.46 mmol), tert-butyl 4-(3-amino-510 methoxyphenoxy)butanoate 1a (1.26 g, 4.46 mmol) and diisopropylethylamine (1.15 mL, 6.69 mmol) in CH₃CN (45 mL) was stirred at 80°C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 40 g, heptane/EtOAc 85/15). The fractions containing expected compound were combined and the solvent was 15 concentrated under reduced pressure to give tert-butyl 4-(3-((1 -(4-fluoro-2methoxyphenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5methoxyphenoxy)butanoate 6c (1.6 g, 67% purity by LC/MS).

Synthesis of Compound 6 and chiral séparation into Enantiomers 6A and

6B:

A solution of tert-butyl 4-(3-((1 -(4-fluoro-2-methoxyphenyl)-2-oxo-2-(6(thfluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 6c (1.5 g, 2.31 mmol) in HCl (4M in dioxane) (15 mL) was stirred at 5°C for 2 h and at room température for 3 h. The solvent was concentrated under reduced pressure and 25 3N NaOH were added until neutral pH was obtained. The solution was extracted with EtOAc. The organic layer was dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20-45 pm, 40 g, CH2Cl2/MeOH gradient 99.5/0.5 to 95/5). The pure fractions were combined and the solvent was concentrated under reduced pressure to provide Compound 6 (646 mg). A small fraction was crystallized from CH₃CN/diisopropyl ether to give 4-(3-((1 -(4-fluoro-2-methoxyphenyl)-2-oxo-2-(6(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 6, 35 mg). The remaining amount (600 mg) was used for chiral séparation of the enantiomers via chiral SFC (Stationary phase: Chiralcel® OD-H 5 35 pm 250 x 20 mm, mobile phase: 60% CO₂, 40% MeOH). To provide Enantiomer 6A as the first eluted product and Enantiomer 6B as the second eluted product. Both enantiomers were further purified by flash chromatography on silica gel (2045 pm, 12 g, CH₂CI₂/MeOH gradient 100/0 to 95/5). The pure fractions were ) -37combined and the solvent was concentrated under reduced pressure to give, after solidification in diisopropyl ether/pentane (+ a few drops of CH3CN), Enantiomer 6A(108 mg) and Enantiomer 6B (108 mg), respectively.

Compound 6:

¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=6.82 Hz, 2 H) 2.33 (t, J=7.33 Hz, 2 H) 3.08 - 3.27 (m, 2 H) 3.61 (s, 3 H) 3.78 - 3.91 (m, 5 H) 3.92 - 4.02 (m, 1 H) 4.33 - 4.42 (m, 1 H) 5.59 (d, J=8.59 Hz, 1 H) 5.75 (s, 1 H) 5.87 (br d, J=7.07 Hz, 2 H) 6.39 (brd, J=8.59 Hz, 1 H) 6.78 (td, J=8.46, 2.27 Hz, 1 H) 6.94 - 7.02 (m, 2 H)

7.29 - 7.35 (m, 2 H) 8.03 (s, 1 H) 12.14 (br s, 1 H)

LC/MS (method LC-B): Rt 2.76 min, MH⁺ 593 Melting point: 164°C

Enantiomer 6A:

¹H NMR (500 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=6.78 Hz, 2 H) 2.31 - 2.47 (m, 2 H) 3.10 - 3.28 (m, 2 H) 3.62 (s, 3 H) 3.80 - 3.93 (m, 5 H) 3.93 - 4.06 (m, 1 H) 4.33 4.44 (m, 1 H) 5.59 (br d, J=8.51 Hz, 1 H) 5.76 (s, 1 H) 5.88 (br d, J=8.83 Hz, 2 H) 6.39 (br d, J=8.83 Hz, 1 H) 6.79 (td, J=8.43, 2.05 Hz, 1 H) 6.95 - 7.04 (m, 2 H) 7.30 - 7.37 (m, 2 H) 8.03 (s, 1 H) 12.16 (br s, 1 H)

LC/MS (method LC-A): Rt 2.86 min, MH⁺ 593

[a]_D ²⁰: -37.3° (c 0.255, DMF)

Chiral SFC (method SFC-I): Rt 1.03 min, MH⁺ 593 chiral purity 100%.

Enantiomer 6B:

Ή NMR (500 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=6.86 Hz, 2 H) 2.30 - 2.45 (m, 2 H) 3.09 - 3.26 (m, 2 H) 3.62 (s, 3 H) 3.80 - 3.93 (m, 5 H) 3.93 - 4.06 (m, 1 H) 4.33 4.44 (m, 1 H) 5.59 (br d, J=8.51 Hz, 1 H) 5.76 (s, 1 H) 5.88 (br d, J=8.83 Hz, 2 H) 6.39 (br d, J=8.51 Hz, 1 H) 6.79 (td, J=8.43, 2.05 Hz, 1 H) 6.95 - 7.04 (m, 2 H) 7.30-7.37 (m, 2 H) 8.03 (br s, 1 H), 12.18 (brs, 1H)

LC/MS (method LC-A): Rt 2.88 min, MH⁺ 593

[a]_D ²⁰: +32.7° (c 0.294, DMF)

Chiral SFC (method SFC-I): Rt 1.82 min, MH⁺ 593 chiral purity 99.56%.

-38Example 7 : synthesis of 4-(3-((1-(4-chlorophenyl)-1-deuterio-2-oxo-2-(6(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 7-D) and chiral séparation into Enantiomers 7A-D and 7B-D

NaCNBD₃

Chiral séparation

AcOH, MeOH rt 62h

Enantiomer 7A-D + Enantiomer 7B-D

O

The abolute stereochemistry of the chiral center (*) of Enantiomer 7A has not been determined

Synthesis of intermediate 7a:

A mixture of 6-(trifluoromethoxy)indoline [CAS 959235-95-1] (2 g, 9.84 mmol), 2-(4-chlorophenyl)acetic acid [CAS 1878-66-6] (1.85 g, 10.8 mmol), HATU (5.6 g, 14.8 mmol) and diisopropylethylamine (4.9 mL, 29.5 mmol) in DMF (40 mL) was io stirred at room température for 12 h. Water was added and the precipitate was filtered off. The residue was taken up with EtOAc. The organic solution was washed with a 10% aqueous solution of K2CO3, brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (15-40 pm, 80 g, heptane/EtOAc gradient 90/10 to 15 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-(4-chlorophenyl)-1-(6-(trifluoromethoxy)indolin-1yl)ethanone 7a (3 g).

I -39Synthesis of intermediate 7b:

At -78°C, under N2 flow, LiHMDS 1.5 M in THF (11.2 mL, 16.9 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1-(6-(trifluoromethoxy)indolin-15 yl)ethanone 7a (3 g, 8.43 mmol) in THF (50 mL). The mixture was stirred for min at -78°C and a solution of /V-bromosuccinimide (1.65 g, 9.3 mmol) in THF (30 mL) was added dropwise. After stirring for 2 h at -78°C, the reaction was quenched with a saturated solution of NH4CL The mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 2-bromo-2-(4chlorophenyl)-1-(6-(trifluoromethoxy)indolin-1-yl)ethanorïe 7b (3.6 g). The compound was used as such in the next step.

Synthesis of intermediate 7c:

A mixture of 2-bromo-2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 yl)ethanone 7b (3.6 g, 8.3 mmol), tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 1a (2.3 g, 8.3 mmol) and diisopropylethylamine (1.7 mL, 9.94 mmol) in CH3CN (80 mL) was stirred at 70°C for 4 h. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with 1N HCl and water. The organic phase was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The compound was purified by flash chromatography on silica gel (15-40 pm, 120 g, heptane/EtOAc 80/20). The pure fractions were combined and evaporated to dryness to give, after crystallization from diisopropyl ether, tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoro25 methoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 7c (2.6 g).

Synthesis of Compound 7 and chiral séparation into Enantiomers 7A and 7B:

A solution of tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)30 indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 7c (2.4 g, 3.8 mmol) in HCl (4M in dioxane) (24 mL) was stirred at 5°C for 3 h and at room température for 3h. The precipitate was filtered off and dried to afford 4-(3-((1 -(4-chlorophenyl)-2-oxo2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid as an HCl sait (Compound 7, 2 g, 0.8 equiv. HCl, 0.07 equiv. H₂O). Compound 7 (2 g, HCl sait) was neutralized prior to chiral séparation by treatment of a solution of Compound 7 (HCl sait) with 1N NaOH and évaporation of the organic layer under reduced pressure. The enantiomers were separated via Préparative Chiral SFC (Stationary phase: Chiralcel® OD-H 5 pm 250 x 30 mm, mobile phase: 50%

I -40CO₂, 50% iPrOH (+ 0.3% iPrNH2)) and further purified via Préparative achiral SFC (Stationary phase: Cyano® 6 pm 150 x 21.2 mm, mobile phase: 80% CO2, 20% MeOH (+ 0.3% iPrNH2)). The product fractions were combined and evaporated under reduced pressure. The two enantiomers were taken up with EtOAc and washed with 1N HCl. The organic layers were separated, dried over MgSO₄, filtered and the solvent was evaporated under reduced pressure. The first eluted enantiomer was solidified from ether/diisopropyl ether to give Enantiomer 7A (616 mg). The second eluted enantiomer was solidified from ether/diisopropyl ether to give Enantiomer 7B (715 mg).

Compound 7:

¹H NMR (500 MHz, DMSO-c/6) δ ppm 1.87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.07 - 3.28 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.04 (td, J=) 0.5, 7.1 Hz, 1 H) 4.52 (td, J=10.3, 6.5 Hz, 1 H) 5.57 (s, 1 H) 5.76 (t, J=2.2 Hz, 1 H) 5.90 15 6.00 (m, 2 H) 7.01 (dd, J=8.2, 1.6 Hz, 1 H) 7.33 (d, J=8.2 Hz, 1 H) 7.41 - 7.48 (m,

H) 7.55 (d, J=8.5 Hz, 2 H) 8.03 (s, 1 H) LC/MS (method LC-B): Rt 2.70 min, MH⁺ 579 Melting point: 150°C

Enantiomer 7A:

¹H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (quin, J=6.7 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.08 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.3 Hz, 2 H) 3.99 - 4.11 (m, 1 H) 4.47 - 4.57 (m, 1 H) 5.57 (br s, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.6 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, 25 J=8.5 Hz, 2 H) 7.55 (brd, J=8.2 Hz, 2 H) 8.04 (brs, 1 H) 12.12 (brs, 1 H)

LC/MS (method LC-A): R_t 2.95 min, MH⁺ 579

[a]_D ²⁰: -48.5° (c 0.27, DMF)

Chiral SFC (method SFC-D): Rt 1.13 min, MH⁺ 579, chiral purity 100%.

Enantiomer 7B:

¹H NMR (500 MHz, DMSO-d6) δ ppm 1.87 (br t, J=6.8 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.09 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6A Hz, 2 H) 3.99 - 4.10 (m, 1 H) 4.46 - 4.59 (m, 1 H) 5.57 (s, 1 H) 5.76 (br s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.9 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, 35 J=8.2 Hz, 2 H) 7.55 (br d, J=8.2 Hz, 2 H) 8.04 (br s, 1 H) 12.12 (br s, 1 H)

LC/MS (method LC-A): R_t 2.94 min, MH⁺ 579

[ct]_D ²⁰: +42.9° (c 0.28, DMF)

Chiral SFC (method SFC-D): Rt 2.13 min, MH⁺ 579, chiral purity 100%.

r -41Synthesis of deuterated Compound 7-D and chiral séparation into Enantiomers 7A-D and 7B-D:

Copper(ll) acetate (241 mg, 1.33 mmol) was added in one portion to a solution of Enantiomer 7A (384 mg, 0.663 mmol) in CH₃CN (15 mL) at room température.

The reaction mixture was heated in a sealed tube under microwave irradiation at 130°C for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was taken up with CH2CI2 and water. The layers were separated. The aqueous layer was extracted again with CH2Cl2.The combined organic layers were washed with brine and water, dried over MgSO4, filtered, and 10 evaporated under reduced pressure. The residue, containing crude intermediate 7d was dissolved in MeOH (20 mL). Sodium cyanoborodeuteride (349 mg, 5.31 mmol) and two drops of acetic acid were added and the reaction mixture was stirred at room température for 55 h. Additional sodium cyanoborodeuteride (48 mg, 0.663 mmol) and a few drops of acetic acid were added and the reaction 15 mixture was stirred for 7 h at room température. The solvent was evaporated under reduced pressure. The residue was mixed with water and Et20. The biphasic system was acidified to pH 1-2 by the addition of 1N HCl. The layers were separated. The aqueous layer was extracted again with Et2O. The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at 50°C to give racemic 4-(3-((1-(4-_chlorophenyl)-Tdeuterio-2-oxo-2-(6-(trifluoromethoxy)indolin-T yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 7-D, 242 mg) as a white solid.

The enantiomers of Compound 7-D (242 mg) were separated via préparative SFC (Stationary phase: Kromasil (R,R) Whelk-O1 10/100, mobile phase: CO2, EtOH + 0.4% iPrNH2). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 7A-D as the first eluted product and Enantiomer 7B-D as the second eluted product. Both enantiomers were mixed with in Et₂O and water. The mixture was acidified to pH 1-2 with 1N HCl. The layers were separated and the aqueous layer was extracted twice with Et2O. The combined organic layers were washed with water, dried over MgSO4, filtered, evaporated under reduced pressure and dried under vacuum at 50°C to give Enantiomer 7A-D (85 mg, 92% deuterated according to ¹H HMR) and Enantiomer

7B-D (77 mg, 92% deuterated according to ¹H HMR) as off-white solids.

-42Enantiomer 7A-D:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.87 (quin, 7=7.0 Hz, 2 H) 2.34 (t, 7=7.1 Hz, 2 H) 3.07 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, 7=6.4 Hz, 2 H) 4.05 (td, 7=10.3, 7.1 Hz, 1 H) 4.52 (td, 7=10.3, 6.4 Hz, 1 H) 5.76 (t, 7=2.0 Hz, 1 H) 5.92 - 5.98 (m, 2 H) 6.45 (s, 1 H) 7.01 (dd, 7=8.1, 1.5 Hz, 1 H) 7.33 (d, 7=8.1 Hz, 1 H) 7.39 - 7.49 (m, 2 H) 7.51 - 7.60 (m, 2 H) 8.03 (s, 1 H) 12.17 (br s, 1 H)

LC/MS (method LC-C): Rt 1.13 min, MH⁺ 580

[a]_D ²⁰: +54.2° (c0.41, DMF)

Chiral SFC (method SFC-E): Rt 5.51 min, MH⁺ 580, chiral purity 100%.

Enantiomer 7B-D:

¹H NMR (360 MHz, DMSO-afe) δ ppm 1.87 (quin, 7=6.9 Hz, 2 H) 2.34 (t, 7=7.3 Hz, 2 H) 3.07 - 3.25 (m, 2 H) 3.61 (s, 3 H) 3.84 (t, 7=6.6 Hz, 2 H) 4.05 (td, 7=10.4, 7.3 Hz, 1 H) 4.52 (td, 7=10.3, 6.4 Hz, 1 H) 5.76 (t, 7=2.0 Hz, 1 H) 5.92 - 5.98 (m, 2 H) 6.45 (s, 1 H) 7.01 (dd, 7=8.1, 1.5 Hz, 1 H) 7.33 (d, 7=8.1 Hz, 1 H) 7.40 - 7.49 (m, 2 H) 7.51 -7.62 (m, 2 H) 8.03 (s, 1 H) 12.16 (brs, 1 H)

LC/MS (method LC-C): Rt 1.10 min, MH⁺ 580

[a]_D ²⁰: -50.1° (c 0.459, DMF)

Chiral SFC (method SFC-E): Rt 6.10 min, MH⁺ 580, chiral purity 100%.

-43Example 8 : synthesis of 4-(3-((1-(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 8).

1)1NLiHMDS in THF THF, -70°C 1h

2)CISiMe₃, -70°C 15 min 3) NBS,-70°Cto-55”C 2h

Synthesis of intermediate 8a:

To a mixture of ethyl 2-(4-chloro-2-hydroxyphenyl)acetate [CAS 1261826-30-5] (5.2 g, 24.2 mmol) and césium carbonate (15.8 g, 48.5 mmol) in DMF (90 mL) at 10°C was added (2-bromoethoxy)(tert-butyl)dimethylsilane [CAS 86864-60-0] îo (6.26 mL, 29.1 mmol). The reaction mixture was stirred at room température overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 80 g, heptane/EtOAc 80/20). The pure fractions were combined and the 15 solvent was removed under reduced pressure to give ethyl 2-(2-(2-((fert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)acetate 8a (7.8 g).

| -44Synthesis of intermediate 8b:

To a cooled (-70°C) solution of 1M lithium bis(trimethylsilyl)amide in THF (41.8 mL, 41.8 mmol) was added a solution of ethyl 2-(2-(2-((tert-butyldimethylsilyl)oxy)5 ethoxy)-4-chlorophenyl)acetate 8a (7.8 g, 20.9 mmol) in THF (45 mL). After stirring for 1 h at -70°C, chlorotrimethylsilane (4.24 mL, 33.5 mmol) was added. The reaction mixture was stirred at -70°C for 15 min. A/-Bromosuccinimide (4.46 g, 25.1 mmol) in THF (45 mL) was added and stirring was continued at -55°C for 2 h. The reaction mixture was poured out into H₂O and extracted twice with EtOAc. The 10 organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 2-bromo-2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)acetate 8b (10.1 g), which was used in the next step without further purification.

Synthesis of intermediate 8c:

A mixture of ethyl 2-bromo-2-(2-(2-((terf-butyldimethylsilyl)oxy)ethoxy)-4chlorophenyl)acetate 8b (2.0 g, 4.429 mmol), tert-butyl 4-(3-amino-5methoxyphenoxy)butanoate 1a (1.62 g, 5.76 mmol) and diisopropylethylamine (1.53 mL, 8.86 mmol) in CH3CN (40 mL) was stirred at 50°C for 12 h. The reaction 20 mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 80 g, heptane/EtOAc gradient 85/15 to 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give tert-butyl 4-(3-((1 -(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)-2-ethoxy-2-oxoethyl)amino)-5-methoxyphenoxy)25 butanoate 8c (1.1 g).

Synthesis of intermediate 8d:

Lithium hydroxide monohydrate (142 mg, 3.37 mmol) in water (7.5 mL) was added dropwise to a solution of tert-butyl 4-(3-((1 -(2-(2-((tert-butyldimethylsilyl)oxy)30 ethoxy)-4-chlorophenyl)-2-ethoxy-2-oxoethyl)amino)-5-methoxyphenoxy)butanoate 8c (1.1 g, 1.69 mmol) in THF/CH3OH (1/1) (15 mL) at 10°C. The reaction was stirred at room température for 5 h, diluted with water and cooled to 0°C. The solution was slowly acidified to pH 6-7 with 0.5N HCl, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent was concentrated under reduced pressure to give 2-((3-(4-(tert-butoxy)-4-oxobutoxy)-5methoxyphenyl)amino)-2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4chlorophenyl)acetic acid 8d (675 mg). The compound was used without further purification in the next step.

) -45Synthesis of intermediate 8e:

To a solution of 2-((3-(4-(tert-butoxy)-4-oxobutoxy)-5-methoxyphenyl)amino)-2-(2(2-((fert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)acetic acid 8d (675 mg, 1.08 mmol) in DMF (6 mL) were added HATU (617 mg, 1.62 mmol), diisopropylethylamine (536 pL, 3.24 mmol) and 6-(trifluoromethoxy)indoline [CAS 959235-95-1] (220 mg, 1.08 mmol). The reaction mixture was stirred at room température for 7 days. The reaction mixture was diluted with water. The precipitate was filtered off, washed with water and taken up with EtOAc. The organic layer was washed with a 10% solution of K2CO3 snd water, dried over MgSO₄, filtered and the solvent was concentrated under reduced pressure to give tert-butyl 4-(3-((1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)-2-oxo2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 8e (385 mg). The compound was used without further purification in the next reaction 15 step.

Synthesis of intermediate 8f:

Under N₂ flow at 5°C, HCl (4M in dioxane) (1.19 mL, 4.76 mmol) was added dropwise to a solution of tert-butyl 4-(3-((1-(2-(2-((fert-butyldimethylsilyl)oxy)20 ethoxy)-4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5methoxyphenoxy)butanoate 8e (385 mg, 0.476 mmol) in MeOH (5 mL). The reaction was stirred at room température for 1 h. The mixture was cooled to 0°C, basified with a 10% aqueous solution of K2CO3 and extracted with EtOAc. The organic phase was separated, dried over MgSO₄, filtered and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (15-40 pm, 24 g, CH2Cl2/MeOH 99/1). The pure fractions were combined and the solvent was removed under reduced pressure to give methyl 4-(3-((1 -(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2-(6(trifluoromethoxy)indolin-l -yl)ethyl)amino)-5-methoxyphenoxy)butanoate 8f (99 mg).

Synthesis of Compound 8:

Lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (2.5 mL) was added dropwise to a solution of methyl 4-(3-((1 -(4-chloro-2-(2-hydroxyethoxy)phenyl)-235 oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 8f (99 mg, 0.152 mmol) in THF (2.5 mL) at 10°C. The reaction was stirred at room température for 18 h, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20-45 pm, 12 g, CH2Cl2/MeOH

F -46gradient 99/1 to 90/10). The fractions containing expected compound were combined and the solvent was removed under reduced pressure. A second purification was performed via Reverse phase HPLC (Stationary phase: YMCactus Triart-C18 10 pm 30 x 150mm, mobile phase: gradient from 65% NH4HCO3 5 0.2%, 35% CH3CN to 25% NH4HCO3 0.2%, 75% CH3CN) to give, after freeze drying from a mixture of water/CHsCN (8/2), 4-(3-((1 -(4-chloro-2-(2hydroxyethoxy)phenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5methoxyphenoxy)butanoic acid (Compound 8, 16 mg).

Compound 8:

Ή NMR (500 MHz, DMSO-cfe) δ ppm 1.86 (quin, J=6.86 Hz, 2 H) 2.28 - 2.47 (m, 2 H) 3.10 - 3.27 (m, 2 H) 3.61 (s, 3 H) 3.68 - 3.88 (m, 4 H) 4.06 - 4.23 (m, 3 H) 4.39 (td, J=10.09, 6.62 Hz, 1 H) 5.70 - 5.76 (m, 2 H) 5.91 (brd, J=9.14 Hz, 2 H) 6.44 (d, J=8.83 Hz, 1 H) 6.99 - 7.03 (m, 2 H) 7.12 (d, J=) .89 Hz, 1 H) 7.34 (d, J=8.20 Hz, 2 15 H) 8.02 (s, 1 H)

LC/MS (method LC-B): Rt 2.65 min, MH⁺ 639

-47Example 9 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-(5-methoxy-6(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)amino)-5methoxyphenoxy)butanoic acid (Compound 9).

9a hno₃ h₂so₄

50°C 60h

9b

DMF-DMA

DMF

120°C 4h

Fe

SiO₂, acetic acid toluene, 90°C 2h

NaOMe

MeOH rt60h

9d

Boc₂O

DMAP, CH₂CI₂

F î Boc

Pd/C (10%) N

H₂, EtOH 50°C, 12h „ rt, 1h

TFA, CH₂CI₂

rt 30 min g_e

9g

Synthesis of intermediate 9a:

A suspension of 2-chloro-6-methyl-3-(trifluoromethyl)pyridine [CAS 1099597-74-6] (4.8 g, 24.6 mmol in sodium methoxide (25% in MeOH) (24 mL, 105 mmol) was stirred at room température for 60 h. The mixture was poured out into ice-water îo and extracted twice with Et2O. The combined organic layers were dried over

Na₂SO4, filtered and concentrated under reduced pressure to give 2-methoxy-6methyl-3-(trifluoromethyl)pyridine 9a (4.69 g). The product was used as such in the next step.

Synthesis of intermediate 9b:

HNO3 (2.32 mL, 49.1 mmol) was added dropwise to a cooled (0°C) solution of 2-methoxy-6-methyl-3-(trifluoromethyl)pyridine 9a (4.69 g, 24.5 mmol) in H₂SO4 (63.3 mL, 1.128 mol). The reaction mixture was stirred at 50°C for 60 h. the reaction mixture was poured out carefully into ice-water and the mixture was

-48stirred at OC for 30 min. The solid was filtered off and washed with water to give 2-methoxy-6-methyl-5-nitro-3-(trifluoromethyl)pyridine 9b (4.38 g) as a white solid.

Synthesis of intermediate 9c:

2-methoxy-6-methyl-5-nitro-3-(trifluoromethyl)pyridine 9b (4.38 g, 18.5 mmol) was dissolved in dry DMF (84 mL) under N₂ atmosphère. DMF-DMA (12.2 mL, 91.5 mmol) was added and the reaction mixture was heated at 120°C for 4 h. After cooling to room température, the mixture was concentrated under reduced pressure and the solid residue was purified by column chromatography on silica gel (120 g) using a gradient of petroleum ether/EtOAc from 100/0 to 60/40). The pure fractions were combined and the solvent was removed under reduced pressure to give (E)-2-(6-methoxy-3-nitro-5-(trifluoromethyl)pyridin-2-yl)-/V,/Vdimethylethenamine 9c (4.5 g) as a red solid.

Synthesis of intermediate 9d:

(E)-2-(6-methoxy-3-nitro-5-(trifluoromethyl)pyridin-2-yl)-/V,/\/-dimethylethenamine 9c (4.5 g, 15.5 mmol) was dissolved in toluene (87 mL) under N₂ atmosphère. Silica gel (4.64 g), iron powder (8.63 g, 154.5 mmol) and acetic acid (35.4 mL) were added and the reaction mixture was stirred at 90°C for 2 h. The reaction mixture was filtered over Celite® and the solid was rinsed several times with EtOAc. The combined filtrâtes were evaporated and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc gradient 100/0 to 65/35) to give 5-methoxy-6-(trifluoromethyl)-1H-pyrrolo[3,2-jb]pyridine 9d (3.1 g) as a yellow solid.

Synthesis of intermediate 9e:

5-methoxy-6-(trifluoromethyl)-1/7-pyrrolo[3,2-b]pyridine 9d (2.04 g, 9.44 mmol) was dissolved in dry CH₂CI₂ (90 mL) under N₂ atmosphère. DMAP (123 mg, 1.01 mmol) and Boc₂O (2.49 g, 11.4 mmol) were added. The reaction mixture was stirred for 30 min at room température, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc gradient 100/0 to 96/4) to give tert-butyl 5-methoxy-6(trifluoromethyl)-1/7-pyrrolo[3,2-b]pyridine-1-carboxylate 9e (2.95 g) as a white solid.

Synthesis of intermediate 9f:

tert-butyl 5-methoxy-6-(trifluoromethyl)-1 /7-pyrrolo[3,2-£>]pyridine-1-carboxylate 9e (1.45 g, 4.59 mmol) was dissolved in EtOH (30 mL) and the reaction was purged with nitrogen. Pd/C (10%) (976 mg, 0.917 mmol) was added to the reaction

-49mixture was hydrogenated overnight at 50°C. The reaction mixture was cooled down to room température and filtered over Celite®. The filter cake was washed with EtOH and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc gradient 100/0 to 95/5) to give tert-butyl 5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1/7pyrrolo[3,2-b]pyridine-1 -carboxylate 9f (1.2 g) as a white solid.

Synthesis of intermediate 9g:

A solution of tert-butyl 5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2b]pyridine-1-carboxylate 9f (1.2 g, 3.77 mmol) in TFA/CH2CI2 (1/1) (19 mL) was stirred at room température for 1 h. The reaction mixture was diluted with CH2CI2 (60 mL), washed with a saturated aqueous Na₂COs solution (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, petroleum ether/EtOAc gradient 80/20 to 40/60) to give 5-methoxy6-(trifluoromethyl)-2,3-dihydro-1/7-pyrrolo[3,2-b]pyridine 9g (745 mg) as a yellow solid.

Synthesis of intermediate 9h:

5-methoxy-6-(tnfluoromethyl)-2,3-dihydro-1/7-pyrrolo[3,2-b]pyridine 9g (350 mg, 1.60 mmol) was dissolved in dry CH2CI2 (6.5 mL) under N₂ atmosphère. DMAP (28 mg, 0.229 mmol) and 2-bromo-2-(4-chlorophenyl)acetic acid [CAS 3381-73-5] (460 mg, 1.84 mmol) were added. EDCI (383 mg, 1.998 mmol) was added and the reaction mixture was stirred at room température for 1 h. The reaction mixture was diluted with CH₂CI₂, cooled to 0°C and a saturated aqueous solution of K₂CO3 was added. The layers were separated and the organic layer was washed with brine, dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, petroleum ether/EtOAc gradient 100/0 to 60/40). A second purification was performed on silica gel (40 g, toluene/Et₂O gradient 100/0 to 90/10). A third purification was performed (12 g, toluene/Et₂O gradient 98/2 to 97/3). The pure fractions were combined and concentrated under reduced pressure to give 2-bromo-2-(4chlorophenyl)-1-(5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1/7-pyrrolo[3,2b]pyridin-1-yl)ethanone 9h (407 mg) as pale green foam.

Synthesis of intermediate 9i:

2-bromo-2-(4-chlorophenyl)-1-(5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)ethanone 9h (400 mg, 0.89 mmol) and tert-butyl 4-(319489 amino-5-methoxyphenoxy)butanoate 1a (300 mg, 1.07 mmol) were dissolved in dry CH3CN (40 mL) under N₂ atmosphère. Diisopropylethylamine (232 pL, 1.33 mmol) was added and the reaction mixture was heated to 70°C for 36 h. The reaction mixture was diluted with 20 mL of EtOAc, and washed with 1M HCl and brine. The organic layer was dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, toluene/EtOAc gradient 100/0 to 94/6). A second purification was performed by column chromatography on silica gel (2x12 g, petroleum ether/acetone gradient 100/0 to 95/5). The pure fractions were combined and concentrated under reduced pressure to give tert-butyl 4-(3-((1-(4-chlorophenyl)-2(5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2oxoethyi)amino)-5-methoxyphenoxy)butanoate 9i (341 mg) as white foam.

Synthesis of Compound 9:

Tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-(5-methoxy-6-(trifluoromethyl)-2,3-dihydro1/7-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoate 9i (341 mg, 0.525 mmol) was dissolved under N₂ atmosphère in HCl (4M in dioxane) (6.62 mL). The reaction was stirred at room température for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, toluene/EtOAc/AcOH gradient 99/0/1 to 50/49/1). A second purification was performed on silica gel (2x12 g, CH₂CI₂/MeOH/AcOH gradient 99/0/1 to 96/3/1). A third purification was performed on silica gel (12 g, CH₂CI₂/MeOH/AcOH gradient 98/1/1 to 96.5/2.5/1). The pure fractions were combined and concentrated under reduced pressure to give 4-(325 ((1 -(4-chlorophenyl)-2-(5-methoxy-6-(trifluoromethyl)-2,3-dihydro-1 /7-pyrrolo[3,2b]pyridin-1-yl)-2-oxoethyl)amino)-5-methoxyphenoxy)butanoic acid (compound 9, 72 mg) as white solid.

Compound 9:

¹H NMR (500 MHz, DMSO-cfe) δ ppm 1.84 - 1.91 (m, 2 H) 2.30 - 2.37 (m, 2 H) 3.21 - 3.30 (m, 2 H) 3.62 (s, 3 H) 3.80 - 3.89 (m, 2 H) 3.94 (s, 3 H) 3.98 - 4.12 (m, 1 H) 4.56 (td, J=10.64, 6.15 Hz, 1 H) 5.58 (d, J=8.83 Hz, 1 H) 5.76 (t, J=1.89 Hz, 1 H) 5.95 (br d, J=10.72 Hz, 2 H) 6.40 (d, J=8.83 Hz, 1 H) 7.44 (d, J=8.51 Hz, 2 H) 7.56 (d, J=8.51 Hz, 2 H) 8.53 (s, 1 H) 12.06 - 12.26 (m, 1 H)

LC/MS (method LC-A): Rt 2.87 min, MH⁺ 594

-51Example 10 : synthesis of 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(2-(trifluoromethyl)5,6-dihydro-4/-/-thieno[3,2-b]pyrrol-4-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 10) and chiral séparation into Enantiomers 10A and 10B.

rt 20h

HCl (4M in dioxane)

Chiral séparation

Enantiomers

10A and 10B

Synthesis of intermediate 10a:

A solution of ethyl 2-(3-amino-5-(trifluoromethyl)thiophen-2-yl)acetate ([CAS 860398-39-6] (1.49 g, 5.88 mmol) in CH3CN (40 mL) was stirred at room température under N2-atmosphere. NaHCOs (0.544 g, 6.47 mmol) and 2-(410 chlorophenyl)acetyl chloride ([CAS 25026-34-0] (861 pL, 5.88 mmol) were added, and the reaction mixture was stirred at room température for 100 min. The mixture was poured out into stirring H2O (200 mL) and extracted with Et₂O (2x 100 mL). The combined organic layers were washed with brine, dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (50 g) using a gradient of heptane/EtOAc 100/0 to 80/20. The desired fractions were combined, evaporated under reduced pressure and co-evaporated with toluene to provide ethyl 2-(3-(2-(4chlorophenyl)acetamido)-5-(trifluoromethyl)thiophen-2-yl)acetate 10a (1.15 g).

Synthesis of intermediate 10b:

A solution of LiBH₄ 2M in THF (2.59 mL, 5.18 mmol) was added slowly to a stirring solution of ethyl 2-(3-(2-(4-chlorophenyl)acetamido)-5-(trifluoromethyl)thiophen-2yl)acetate 10a (1.05 g, 2.59 mmol) in 2-Me-THF (20 mL). The reaction mixture was stirred at room température for 18 h. The mixture was poured out into a stirring

I -52mixture of H₂O (100 mL) and Et₂O (100 mL). 1N HCl (10 mL) was added dropwise (foaming), and after stirring for 15 minutes, the layers were separated. The organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel 5 (25 g) using a gradient of heptane/iPrOH 100/0 to 50/50. The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with toluene. The residue was stirred up in toluene (6 mL) at 45°C for 15 minutes, filtered off at room température, washed with toluene (3x), and dried under vacuum at 50°C to provide 2-(4-chlorophenyl)-A/-(2-(2-hydroxyethyl)-510 (trifluoromethyl)thiophen-3-yl)acetamide 10b (1.15 g).

Synthesis of intermediate 10c:

Triphenylphosphine (1.02 g, 3.85 mmol) was added to a stirring solution of 2-(4chlorophenyl)-A/-(2-(2-hydroxyethyl)-5-(trifluoromethyl)thiophen-3-yl)acetamide

10b (1.0 g, 2.75 mmol) in THF (20 mL) under N₂-atmosphere. Di-tert-butyl azodicarboxylate (0.71 g, 3.02 mmol) was added and the resulting solution was stirred at room température for 20 h. The volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (25 g) using a gradient of CH^I^heptane 0/100 to 100/0. The desired fractions were combined and concentrated under reduced pressure to a residual volume of 15 mL. The product was allowed to crystallize over a period of 4 days. The solids were filtered off, washed with heptane (4x) and dried under vacuum at 50°C to provide 2-(4-chlorophenyl)-1-(2-(trifluoromethyl)-5,6-dihydro-4H-thieno[3,2b]pyrrol-4-yl)ethanone 10c (0.75 g).

Synthesis of intermediate 10d:

At -75°C, under a N₂ flow, LiHMDS 1M in THF (4.34 mL, 4.34 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1-(2-(trifluoromethyl)-5,6-dihydro-4/7thieno[3,2-b]pyrrol-4-yl)ethanone 10c (750 mg, 2.17 mmol) in 2-Me-THF (30 mL) 30 and the mixture was kept at -75°C for 20 min. TMSCI (444 pL, 3.47 mmol) was added dropwise. The mixture was stirred for 20 min at -75°C and a solution of Nbromosuccinimide (502 mg, 2.82 mmol) in THF (5 mL) was added dropwise. After stirring for 20 min at -75°C, the reaction was quenched with a saturated aqueous solution of NH₄CI (25 mL). The cooling bath was removed and the reaction mixture 35 was stirred until the reaction température reached -15°C. Water (25 mL) and DIPE (25 mL) were added and the mixture was stirred for 10 min. The organic layer was separated and the aqueous phase was extracted with Et₂O. The combined organic layers were dried over MgSO₄, filtered and the solvent was evaporated under

P -53reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1-(2-(trifluoromethyl)-5,6dihydro-4H-thieno[3,2-b]pyrrol-4-yl)ethanone 10d (921 mg), which was used as such in the next step.

Synthesis of intermediate 10e:

A mixture of 2-bromo-2-(4-chlorophenyl)-1-(2-(trifluoromethyl)-5,6-dihydro-4/7thieno[3,2-b]pyrrol-4-yl)ethanone 10d (921 mg, 2.17 mmol), tert-butyl 4-(3-amino5-methoxyphenoxy)butanoate 1a (1.22 g, 4.34 mmol) and diisopropylethylamine (747 pL, 4.34 mmol) in 2-butanol (15 mL) was stirred at 45°C for 2 h. The reaction îo mixture was allowed to reach room température, and poured out into stirring water (50 mL). The product was extracted (2x) with Et20. Trie combined organic layers were dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure and co-evaporated with dioxane (2x). The residue was purified by flash chromatography on silica gel (40 g) using a gradient of heptane/EtOAc/EtOH 15 100/0/0 to 40/45/15. The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with dioxane (2x) to provide tert-butyl 4-(3((1-(4-chlorophenyl)-2-oxo-2-(2-(trifluoromethyl)-5,6-dihydro-4/7-thieno[3,2bJpyrrol-4-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 10e (1.36 g), which was used as such in the next step.

Synthesis of Compound 10 and chiral séparation into Enantiomers 10A and 10B:

tert-Butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(2-(trifluoromethyl)-5,6-dihydro-4/7thieno[3,2-bJpyrrol-4-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 10e (1.36 g, 25 2.17 mmol), was mixed with 4M HCl in dioxane (15 mL) and the mixture was stirred at room température for 20 h. The solids were filtered off, washed with dioxane (3x), and dried under vacuum at 50°C. The residue (1.4 g) was purified via préparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - 10 pm, 50 x 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN). The desired 30 fractions were combined and the organic volatiles were evaporated under reduced pressure. The remaining aqueous solution was extracted (2x) with a solvent mixture of Et2O/2-Me-THF (2/1). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure to provide crude 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(2-(trifluoromethyl)-5,6-dihydro35 4/7-thieno[3,2-b]pyrrol-4-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 10, 0.54 g). An analytical sample (40 mg) was dissolved in stirring Et₂O (1 mL) and 4M HCl in dioxane (250 pL) was added. After stirring for 2 min, ) -54the product was filtered off, washed (3x) with Et2O/dioxane (4/1), and dried under vacuum at 50°C to provide Compound 10 (20 mg).

The enantiomers of Compound 10 (500 mg) were separated via préparative chiral SFC (Stationary phase: Chiralpak® Diacel IC 20 x 250 mm, mobile phase: CO₂, 5 EtOH). The product fractions of the first eluted enantiomer were combined, evaporated under reduced pressure and purified by flash chromatography on silica gel (12g) using a gradient of heptane/EtOAc:EtOH:AcOH 100/0:0:0 to 60/30:9.8:0.2. The desired fractions were combined, evaporated under reduced pressure and co-evaporated with DCM. The residue was dried under vacuum at 10 50°C to provide Enantiomer 10A (164 mg). The product fractions of the second eluted enantiomer were combined, evaporated under reduced pressure and purified by flash chromatography on silica gel (12g) using a gradient of heptane/EtOAc:EtOH:AcOH 100/0:0:0 to 60/30:9.8:0.2. The desired fractions were combined, evaporated under reduced pressure and co-evaporated with DCM. The 15 residue was dried under vacuum at 50°C to provide Enantiomer 10B (167 mg).

Compound 10:

¹H NMR (360 MHz, DMSO-d ) δ ppm 1.87 (t, J=6.8 Hz, 2 H), 2.31 - 2.37 (m, 2 H), 3.26 - 3.38 (m, 2 H), 3.62 (s, 3 H), 3.84 (br t, J=6.4 Hz, 2 H), 4.29 (td, J=10.5, 6.8 20 Hz, 1 H), 4.79 (td, J=10.2, 6.2 Hz, 1 H), 5.49 (s, 1 H), 5.76 (t, J=2.0 Hz, 1 H), 5.91

- 5.97 (m, 2 H), 7.44 (d, J=8.4 Hz, 2 H), 7.54 (d, J=8.8 Hz, 2 H), 7.76 (s, 1 H) LC/MS (method LC-D): Rt 1.93 min, MH⁺ 569

Enantiomer 10A:

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.83 -1.91 (m, 2 H), 2.30 - 2.36 (m, 2 H), 3.23 - 3.30 (m, 2 H), 3.62 (br s, 3 H), 3.85 (br s, 2 H), 4.30 (m, J=9.5 Hz, 1 H), 4.79 (m, J=6.8 Hz, 1 H), 5.48 (br d, J=8.8 Hz, 1 H), 5.76 (br s, 1 H), 5.94 (br d, J=9.0 Hz, 2 H), 6.35 (br d, J=8.1 Hz, 1 H), 7.43 (br d, J=7.3 Hz, 2 H), 7.54 (br d, J=8.1 Hz, 2 H), 7.76 (br s, 1 H), 12.10 (br s, 1 H)

LC/MS (method LC-C): Rt 1.03 min, MH⁺ 569

[a]_D ²⁰: +36.9° (c 0.4445, DMF)

Chiral SFC (method SFC-F): R_t 5.52 min, MH⁺ 569 chiral purity 100%.

Enantiomer 10B:

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.83 - 1.91 (m, 2 H), 2.34 (br t, J=6.8 Hz, 2 H), 3.23 - 3.30 (m, 2 H), 3.62 (s, 3 H), 3.85 (br t, J=5.9 Hz, 2 H), 4.25 - 4.35 (m, 1 H), 4.75 - 4.83 (m, 1 H), 5.48 (br d, J=8.4 Hz, 1 H), 5.76 (br s, 1 H), 5.94 (br d,

-55J=8.8 Hz, 2 H), 6.35 (br d, J=8.4 Hz, 1 H), 7.43 (br d, J=7.7 Hz, 2 H), 7.54 (br d,

J=7.9 Hz, 2 H), 7.76 (s, 1 H), 12.11 (br s, 1 H)

LC/MS (method LC-C): Rt 1.03 min, MH⁺ 569 [a]_D ²⁰: -39.1 ° (c 0.437, DMF)

Chiral SFC (method SFC-F): Rt 6.98 min, MH⁺ 569 chiral purity 97%.

Example 11 : synthesis of 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6((trifluoromethyl)thio)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 11)

SEMCI

NaH

dioxane, 100°C, 5h 11b

THF, 15^CC 16h

NalO₄

NH₄OAc ------------------1» acetone, water rt, 16h

Synthesis of intermediate 11a:

To the suspension of NaH (26.5 g, 663 mmol, 60% in oil) in THF (100 mL) at 0°C was added 6-bromo-1H-indole [CAS 52415-29-9] (100 g, 510 mmol) in portions.

The reaction was stirred for 30 min at 15°C. After cooling to 0°C, SEMCI (93.6 g, 561 mmol, 99.5 mL) was added. The reaction mixture was stirred for 16 h at 15°C and poured out into a saturated aqueous ammonium chloride solution (200 mL). The mixture was diluted with ethyl acetate (300 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x 200 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column ) -56chromatography on silica gel using petroleum ether. The product fractions were combined and evaporated under reduced pressure to afford 6-bromo-1-((2(trimethylsilyl)ethoxy)methyl)-1/7-indole 11a (134 g) as a yellow oil.

Synthesis of intermediate 11b:

A mixture of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1/7-indole 11a (134 g, 411 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (158.5 g, 624 mmol), Pd(dppf)CI₂ (15.02 g, 20.5 mmol) and KOAc (161.2 g, 1.64 mol) in 1,4dioxane (1.5 L) was stirred at 100°C for 5 h under N₂-atmosphere. The reaction 10 was cooled to 25°C and filtered through a pad of Celite®. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate gradient 100/0 to 50/1 ). The product fractions were combined and evaporated under reduced pressure to afford 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((215 (trimethylsilyl)ethoxy)methyl)-1H-indole 11b (104 g) as a light yellow oil.

Synthesis of intermediate 11c:

To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-indole 11b (52 g, 139 mmol) in acetone (2.4 L) 20 and H₂O (2.4 L) were added NalO4 (119 g, 557 mmol) and NH₄OAc (53.7 g, 696 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction was duplicated at the same scale (52 g of compound 11b) and the reaction mixtures of both reactions were combined for the work-up. The precipitate was filtered off and the solvent (acetone) was removed under reduced pressure. Ethyl acetate (5 L) 25 was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3x 5 L). The combined organic layers were dried over Na₂SO4, filtered and concentrated in vacuo to afford (1-((2-(trimethylsilyl)ethoxy)methyl)1H-indol-6-yl)boronic acid 11c (85 g) as a black brown solid which was used into the next step without further purification.

Synthesis of intermediate 11 d:

A mixture of TMSCF3 (207.5 g, 1.46 mol), CuSCN (10.7 g, 87.6 mmol), S₈ (224.6 g, 875.6 mmol), (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-6-yl)boronic acid 11c (85 g, 292 mmol), Ag₂CO₃ (161 g, 584 mmol), K3PO4 (186 g, 876 mmol), 1,1035 phenanthroline (31.6 g, 175 mmol) and 4Â molecular sieves (85 g) in DMF (1 L) was stirred at 25°C for 16 hours under N₂-atmosphere. The reaction mixture was filtered through a pad Celite®. The filtrate was diluted with MTBE (1 L), washed with water (3x 500 mL), dried over Na₂SO₄, filtered and concentrated under f -57reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 100/1). The product fractions were combined and evaporated under reduced pressure to afford 6-((trifluoromethyl)thio)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-indole 11d (38 g) as an light yellow oil.

Synthesis of intermediate 11e:

To the solution of 6-((trifluoromethyl)thio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1Hindole 11 d (38 g, 109 mmol) in THF (1.5 L) were added TBAF.3H2O (345 g, 1.09 mol) and ethane-1,2-diamine (131.45 g, 2.19 mol). The reaction mixture was 10 stirred at 70°C for 16 h. The reaction mixture was cooled to 25°C and poured out into saturated aqueous NaHCOs (3 L). The aqueous mixture was extracted with ethyl acetate (3x 1 L). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250 x 50mm 10 pm, mobile 15 phase: water (0.05% ammonia hydroxide v/v), CH3CN) to give 6((trifluoromethyl)thio)-1H-indole 11e (10.1 g) as an off-white solid.

Synthesis of intermediate 11f:

A mixture of 6-((trifluoromethyl)thio)-1 H-indole 11e (1.0 g, 4.6 mmol) and borane 20 dimethyl sulfide complex (7 mL) was heated in a sealed tube at 75°C for 5 h. The reaction mixture was allowed to reach room température and added dropwise to stirring MeOH (30 mL) (exothermic). After addition, the resulting solution was heated under reflux for 3 h. The solvent were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (25 g) using a 25 gradient of heptane/CH₂Cl2 100/0 to 40/60. The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with dioxane. The product was dried under vacuum at 50°C to provide 6-((trifluoromethyl)thio)indoline 11f (0.79 g).

Synthesis of intermediate 11g:

A solution of 6-((trifluoromethyl)thio)indoline 11f (0.79 g, 3.6 mmol) in CH₃CN (30 mL) was stirred under N2-atmosphere. NaHCO₃ (0.333 g, 3.96 mmol) was added and the reaction mixture was cooled on an ice-bath. A solution of 2-(4chlorophenyl)acetyl chloride ([CAS 25026-34-0] (0.852 g, 4.51 mmol) in CH₃CN 35 (20 mL) was added, and the reaction mixture was stirred at room température for

h. The mixture was poured out into stirring H2O (100 mL). The precipitate was filtered off and washed with water (4x 10 mL). The solids were stirred up in Et₂O/heptane (3/2) (20 mL), filtered off, washed with Et₂O/heptane (3/2) (2x 10

-58mL) and dried under vacuum at 50 C to provide 2-(4-chlorophenyl)-1-(6((trifluoromethyl)thio)indolin-1-yl)ethanone 11g (1.033 g).

Synthesis of intermediate 11 h:

At -78°C, under a N₂ flow, LiHMDS 1M in THF (5.56 mL, 5.56 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1-(6-((trifluoromethyl)thio)indolin-1yl)ethanone 11g (1.033 mg, 2.78 mmol) in 2-Me-THF (40 mL) and the mixture was kept at -78°C for 20 min. TMSCI (568 pL, 4.45 mmol) was added dropwise. The mixture was stirred for 35 min at -78°C and a solution of /V-bromosuccinimide (643 mg, 3.61 mmol) in THF (8 mL) was added dropwise. After stirring for 35 min at 78°C, the reaction was quenched with a saturated aqueous solution of NH4CI (30 mL). The cooling bath was removed and the reaction mixture was stirred until the reaction reached room température. Water (30 mL) and DIRE (30 mL) were added and the mixture was stirred for 20 min. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1-(6((trifluoromethyl)thio)indolin-1-yl)ethanone 11h (1.25 g), which was used as such in the next step.

Synthesis of intermediate 11 i:

A mixture of 2-bromo-2-(4-chlorophenyl)-1-(6-((trifluoromethyl)thio)indolin-1yl)ethanone 11h (1.25 mg, 2.78 mmol), tert-butyl 4-(3-amino-5methoxyphenoxy)butanoate 1a (1.56 g, 5.56 mmol) and diisopropylethylamine (957 pL, 5.56 mmol) in 2-butanol (25 mL) was stirred at 45°C for 16 h. The reaction mixture was allowed to reach room température, and poured out into stirring water (100 mL). The product was extracted (2x) with CH₂CI₂. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (40 g) using a gradient of heptane/EtOAc/EtOH 100/0/0 to 70/20/10. The desired fractions were combined and evaporated under reduced pressure to provide tert-butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6((trifluoromethyl)thio)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 11 i (2.0 g), which was used as such in the next step.

Synthesis of Compound 11 :

tert-Butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-((trifluoromethyl)thio)indolin-1yl)ethyl)amino)-5-methoxyphenoxy)butanoate 11 i (1.81 g, 2.78 mmol), was mixed with 4M HCl in dioxane (20 mL) and the mixture was stirred at room température f -59for 3.5 h. The solids were filtered off, washed with dioxane (3x) and Et2O (20mL). The solid was dissolved in CH2CI2 (100 mL) and mixed with water (50mL) and saturated aqueous Na2CO3 (30mL). After stirring for 15 min, the layers were separated. The organic layer was washed with brine, dried over MgSO₄, filtered and evaporated under reduced pressure. The residue was purified via préparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD- 10 pm, 30 x 150 mm, mobile phase: 0.25% NH₄HCO3 solution in water, CH3CN). CH3CN was evaporated and the residual aqueous solution was acidified to pH 3 with 1N HCl. The product was extracted with EtOAc (100mL). The organic layer was washed with brine (50mL), dried over MgSO₄, filtered, evaporated under reduced pressure and co-evaporated with CH2CI2 to give 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6((trifluoromethyl)thio)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 11, 164 mg).

Compound 11:

¹H NMR (360 MHz, DMSO-cfe) δ ppm 1.87 (quin, J=7A Hz, 2 H) 2.25 - 2.38 (m, 2 H) 3.16 - 3.27 (m, 2 H) 3.62 (s, 3 H) 3.81 - 3.87 (m, 2 H) 3.95 - 4.08 (m, 1 H) 4.44 4.56 (m, 1 H) 5.57 (br d, 7=8.8 Hz, 1 H) 5.74 - 5.77 (m, 1 H) 5.90 - 5.98 (m, 2 H) 6.47 (br d, 7=8.8 Hz, 1 H) 7.34 - 7.40 (m, 2 H) 7.41 - 7.48 (m, 2 H) 7.51 - 7.59 (m, 20 2 H) 8.39 (s, 1 H) 12.16 (brs, 1 H)

LC/MS (method LC-C): Rt 1.12 min, MH⁺ 595

Compound	Structure	Optical rotation
IB	Cl Y? OMe A f vCô °^o HO	[a]_D ²⁰ = +46.0°
2	F¹ XI OMe Tx>	racemic
2A	~o / \ o ¹ A O^Z ω 7 o	[a]_D ²⁰ = -39.0°
2B	Cl Q Y OMe _F rS X-Q^ _o τ⁷ «Γ	[a]_D2° = +47. T
3	Cl OMe O. / /A. F Y _Λ // FxJ 1 N'A J F 11 S x X-Y/ ff^OH F^^ J	racemic
3A	T O ^ko ® O Ο-Υ^Λ k/ T	[a]_D ²⁰ = -48.9°
3B	F¹ OMe _F °yAx) F\l ' N'A 7 Αγγ H °^x Il J_~_/ î^^oh F^ &	[a]_D ²⁰ = +47.8°

Compound	Structure	Optical rotation
4	Cl OMe ^f f y™ 1 °	racemic
4A	Cl MX ^0MevAA ^{F F} ^/r~^0H 1 o	[a]_D ²⁰ = -39.6°
4B	Cl vJ ^OMe°VU ih ^F\ CL 4 ⁿAa ΛΎΎ \ ^H ^{F F} LA? \^^OH T θ	[a]_D ²⁰ = +43.7°
5	o L ® Z° oXy ^ΑΑγ²¹ χ A·	racemic
5A	Cl V OMe vArS ^F F Λ \s=o ^F HO	[a]_D ²⁰ = -35.8°
5B	Cl ^OMe°vx> /A MxvM.-x ^F f JL V^Q ^F HO	[a]_D ²⁰ = +52.8°
6	F A MeO-AX P^Me^xo A^ HO	racemic

Compound	Structure	Optical rotation
6A	F MeoÆj P^Me HO	[a]_D ²⁰ = -37.3°
6B	F MeoXj f^Me Ji) HO	[a]_D ²⁰ = +32.7° 1
7A-D	Cl J) ^0Me 1 F-___H —v-x X UO ^r^OH o'	[a]_D ²⁰ = +54.2°
7B-D	Π ^1 O y O^Z Q o I	[a]_D ²⁰ = -50.1°
8	Cl HO A OMe Vo^AA «ΑΧ _pa Ύία °X-χ ^{F F} /Τ'^01-1 o	racemic
9	Cl Xy OMe ^fy/ /yx-’^N H V^x ^FI X> MeO N _ΗΓ	racemic
10	Cl J OMe o.-. / γΆ, Ή—«CH/ ^{F S} HO	racemic

ANTIVIRAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION

DENV-2 antiviral assay

The antiviral activity of ail the compounds of the invention was tested against the 5 DENV-2 16681 strain which was labeled with enhanced green fluorescent protein (eGPF). The culture medium consists of minimal essential medium supplemented with 2% of heat-inactivated fêtai calf sérum, 0.04% gentamycin (50mg/mL) and 2mM of L-glutamine. Vero cells, obtained from ECACC, were suspended in culture medium and 25pL was added to 384-well plates (2500 cells/well), which already îo contain the antiviral compounds. Typically, these plates contain a 5-fold serial dilution of 9 dilution steps of the test compound at 200 times the final concentration in 100% DMSO (200nL). In addition, each compound concentration is tested in quadruplicate (final concentration range: 25μΜ - 0.000064pM or 2.5μΜ - 0.0000064pM for the most active compounds). Finally, each plate contains wells which are assigned as virus Controls (containing cells and virus in the absence of compound), cell Controls (containing cells in the absence of virus and compound) and medium Controls (containing medium in the absence of cells, virus and compounds). To the wells assigned as medium control, 25pL of culture medium was added instead of Vero cells. Once the cells are added to the plates, 20 the plates were incubated for 30 minutes at room température to allow the cells to distribute evenly within the wells. Next, the plates were incubated in a fully humidified incubator (37°C, 5% CO2) until the next day. Then, DENV-2 strain

F -6416681, labeled with eGFP, was added at a multiplicity of infection (MOI) of 0.5. Therefore, 15pL of virus suspension was added to ail the wells containing test compound and to the wells assigned as virus control. In parallel, 15pL of culture medium was added to the medium and cell contrais. Next, the plates were incubated for 3 days in a fully humidified incubator (37°C, 5% CO2). At the day of the read out, the eGFP fluorescence was measured using an automated fluorescence microscope at 488 nm (blue laser). Using an in-house LIMS system, inhibition dose response curves for each compound were calculated and the half maximal effective concentration (EC50) was determined. Therefore, the percent 10 inhibition (I) for every test concentration is calculated using the following formula: I = 100*(St-Scc)/(Svc-Scc); St, Sec and Svc are the amount of eGFP signal in the test compound, cell control and virus control wells, respectively. The EC50 represents the concentration of a compound at which the virus réplication is inhibited with 50%, as measured by a 50% réduction ofthe eGFP fluorescent intensity compared to the virus control. The EC50 is calculated using linear interpolation (Table 1).

In parallel, the toxicity ofthe compounds was assessed on the same plates. Once the read-out for the eGFP signal was done, 40pL of ATPIite, a cell viability stain, was added to ail wells ofthe 384-well plates. ATP is présent in ail metabolically 20 active cells and the concentration déclinés very rapidly when the cells undergo necrosis or apoptosis, The ATPLite assay system is based on the production of light caused by the reaction of ATP with added luciferase and D-luciferin. The plates were incubated for 10 minutes at room température. Next, the plates were measured on a ViewLux. The half maximal cytotoxic concentration (CC50) was 25 also determined, defined as the concentration required to reduce the luminescent signal by 50% compared to that ofthe cell control wells. Finally, the selectivity index (SI) was determined for the compounds, which was calculated as followed: SI = CC50/EC50·

-65Table 1 : ECso, CCso, and SI for the compounds of the invention in the DENV-2 antiviral assay

compound#	ECso(pM)	N	CCso (pM)	N	SI	N
1	0.00064	3	13	4	19800	3
1A	0.0013	3	12	3	9200	3
1B	0.00011	3	13	4	104092	3
2	0.00038	3	12	4	32100	3
2A	0.015	3	12	3	799	3
2B	0.000078	4	14	4	166670	4
3	0.00056	3	13	3	22700	3
3A	0.036	3	12	3	346	3
3B	0.00012	3	13	3	91000	3
4	0.00011	4	12	4	96000	4
4A	0.011	3	13	3	1180	3
4B	0.000057	4	13	4	186421	4
5	0.00011	3	10	3	90900	3
5A	0.0023	6	10	9	4440	6
5B	0.00012	4	12	4	>54214	4
6	0.00063	3	12	3	19500	3
6A	0.25	3	11	3	46	3
6B	0.00039	3	15	4	39700	3
7A-D	0.000100	3	12	3	118813	3
7B-D	0.016	3	9.6	3	584	3
8	0.00015	3	13	4	86800	3
9	0.00099	4	12	4	12600	4
10	0.00052	3	19	3	40900	3
10A	0.00030	3	14	3	58900	3
10B	0.037	3	12	3	330	3
11	0.00028	3	13	3	43300	3

N= the number of independent experiments in which the compounds were tested.

Tetravalent reverse transcriptase quantitative-PCR (RT-qPCR) assay

The antiviral activity ofthe compounds ofthe invention was tested against DENV-1 strain TC974#666 (NCPV), DENV-2 strain 16681, DENV-3 strain H87 (NCPV) and DENV-4 strain H241 (NCPV) in a RT-qPCR assay. Therefore, Vero cells were io infected with either DENV-1, or -2, or -3, or -4 in the presence or absence of test compounds. At day 3 post-infection, the cells were lysed and cell lysâtes were used to préparé cDNA of both a viral target (the 3’UTR of DENV; Table 2) and a

cellular reference gene (β-actin, Table 2). Subsequently, a duplex real time PCR was performed on a Lightcycler480 instrument. The generated Cp value is inversely proportional to the amount of RNA expression of these targets. Inhibition of DENV réplication by a test compound results in a shift of Cp’s for the 3’UTR gene. On the other hand, if a test compound is toxic to the cells, a similar effect on β-actin expression will be observed. The comparative ΔΔΟρ method is used to calculate ECso, which is based on the relative gene expression ofthe target gene (3’UTR) normalized with the cellular housekeeping gene (β-actin). In addition, CCso values are determined based on the C_p values acquired for the housekeeping gene β-actin.

Table 2: Primers and probes used for the real-time, quantitative RT-PCR .

Primer/probe	Target	Sequence³·^b
F3utr258	DENV 3’- UTR	5'-CGGTTAGAGGAGACCCCTC-3'
R3utr425	DENV 3’- UTR	5'-GAGACAGCAGGATCTCTGGTC-3'
P3utr343	DENV 3’- UTR	FAM-5'-AAGGACTAG-ZEN- AGGTTAGAGGAGACCCCCC-3'-lABkFQ
Factin743	β-actin	5'-GGCCAGGTCATCACCATT-3'
Ractin876	β-actin	5'-ATGTCCACGTCACACTTCATG-3'
Pactin773	β-actin	HEX-5'-TTCCGCTGC-ZE/V-CCTGAGGCTCTC-3'lABkFQ

^a Reporter dyes (FAM, HEX) and quenchers (ZEN and lABkFQ) éléments are indicated in bold and italics.

^b The nucléotide sequence of the primers and probes were selected from the conserved région in the 3’UTR région of the dengue virus genome, based on the alignment of 300 nucléotide sequences ofthe four dengue serotypes deposited in Genbank (Gong et al., 2013, Methods Mol Biol, Chapter 16).

The culture medium consisted of minimal essential medium supplemented with 2% of heat-inactivated fêtai calf sérum, 0.04% gentamycin (50mg/mL) and 2mM of L-glutamine. Vero cells, obtained from ECACC, were suspended in culture medium and 75pL/well was added in 96-well plates (10000 cells/well), which f -67already contain the antiviral compounds. Typically, these plates contain a 5-fold serial dilution of 9 dilution steps of the test compound at 200 times the final concentration in 100% DMSO (500nL; final concentration range: 25μΜ 0.000064μΜ or 2.5μΜ - 0.0000064μΜ for the most active compounds). In addition, each plate contains wells which are assigned as virus Controls (containing cells and virus in the absence of compound) and cell Controls (containing cells in the absence of virus and compound). Once the cells were added in the plates, the plates were incubated in a fully humidified incubator (37°C, 5% CO2) until the next day. Dengue viruses serotype-1,2, 3 and 4 were 10 diluted in order to obtain a Cp of -22-24 in the assay. Therefore, 25μL of virus suspension was added to ail the wells containing test compound and to the wells assigned as virus control. In parallel, 25μ1_ of culture medium was added to the cell Controls. Next, the plates were incubated for 3 days in a fully humidified incubator (37°C, 5% CO2). After 3 days, the supematant was removed from the wells and the cells were washed twice with ice-cold PBS (~100pL). The cell pellets within the 96-well plates were stored at -80°C for at least 1 day. Next, RNA was extracted using the Cells-to-CT™ lysis kit, according to the manufacturer’s guideline (Life Technologies). The cell lysâtes can be stored at -80°C or immediately used in the reverse transcription step.

In préparation of the reverse transcription step, mix A (table 3A) was prepared and 7.57pL/well was dispensed in a 96-well plate. After addition of 5pL of the cell lysâtes, a five minute dénaturation step at 75°C was performed (table 3B). Afterwards, 7.43pL of mix B was added (table 3C) and the reverse transcription step was initiated (table 3D) to generate cDNA.

Finally, a RT-qPCR mix was prepared, mix C (table 4A), and 22.02 pL/well was dispensed in 96-well LightCycler qPCR plates to which 3pL of cDNA was added and the qPCR was performed according to the conditions in table 4B on a LightCycler 480.

Using the LightCycler software and an in-house LIMS system, dose response 30 curves for each compound were calculated and the half maximal effective concentration (EC50) and the half maximal cytotoxic concentration (CC50) were determined (Tables 5-8).

-68Table 3: cDNA synthesis using Mix A, dénaturation, Mix B and reverse transcription.

Mix A

Plates	8
Samples	828		Reaction Vol. (mD	20
Mix Item	Concentration	Volume for (pl)
Unit	Stock	Final	1 sample	x samples
Milli-Q H₂0				7.27	6019.56
R3utr425	μΜ	20	0.27	0.15	124.20
Ractin876	μΜ	20	0.27	0.15	124.20
	Volume mix/well (pl)	7.57
Cell lysâtes	5.00

B Dénaturation step:

Step	Temp	Time
Dénaturation	75°C	5'
Hold	4°C	hold

C Mix B

Samples	864
Mix Item	Concentration	Volume for (pl)
Unit	Stock Final	1 sample	x samples
Expand HIFI buffer 2	X	10.00	1.00	2.00	1728.0
MgCI₂	mM	25.00	3.50	2.80	2419.2
dNTPs	mM	10.00	1.00	2.00	1728.0
Rnase inhibitor	U/pl	40.00	1.00	0.50	432.0
Expand RT	U/pl	50.00	0.33	0.13	112.3
	Total Volume Mix (Pl)	7.43

D Protocol cDNA synthesis

Step	Temp	Time
Rev transe	42°C	30'
Dénaturation	99°C	5'
Hold	4°C	hold

Table 4: qPCR mix and protocol.

A Mix c

Samples	833		Reaction Vol. (PO	25
Mix Item	Concentration	Volume for (μΙ)
Unit	Stock	Final	1 sample	x samples
H2O PCR grade Roche				7.74	6447.42
Roche 2xMM mix	X	2	1	12.50	10412.50
F3utr258	μΜ	20	0.3	0.38	316.54
R3utr425	μΜ	20	0.3	0.38	316.54
P3utr343	μΜ	20	0.1	0.13	108.29
Factin743	μΜ	20	0.3	0.38	316.54
Ractin876	μΜ	20	0.3	0.38	316.54
Pactin773	μΜ	20	0.1	0.13	108.29
	Volume Mix / Tube (μΙ)	22.02
cDNA	3.00

B Protocol qPCR3

Step	Temp	Time	Ramp rate
preincub/denat	95°C	10 min	4.4
Dénaturation	95°C	10 sec	4.4	40 cycles
annealing	58°C	1 min	2.2
Elongation	72°C	1 sec	4.4
Cooling	40°C	10 sec	1.5

Table 5: ECso, CCso, and SI for the compounds against serotype 1 in the RT-qPCR assays

	RT-qPCR serotype	1 TC974#666
compound#	EC50 (μΜ)	N	CC50 (μΜ)	N	SI	N
1B	0.000096	4	>2.5	4	>79500	4
2B	0.000091	5	>1.0	5	>33100	5
3B	0.00010	3	>2.5	3	>54200	3
4B	0.00011	4	>1.0	4	>45200	4
5B	0.00033	3	>1.0	3	>5910	3
6B	0.00064	4	13	4	20500	4

	RT-qPCR serotype	1 TC974#666
compound#	ECso (μΜ)	N	CC50 (μΜ)	N	SI	N
7A-D	0.00024	3	>1.0	3	>6180	3
10A	0.00022	5	13	5	56000	5

N= the number of independent experiments in which the compounds were tested.

Table 6: EC₅q, CC₅q, and SI for the compounds against serotype 2 in the RT-qPCR assays

	RT-	qPCR serotype 2 16681
compound#	EC50 (μΜ)	N	CC50 (μΜ)	N	SI	N
1B	0.00018	4	>2.5	4	>11700	4
2B	0.000061	4	>1.0	4	>36300	4
3B	0.000096	3	>2.5	3	>46900	3
4B	0.000067	4	>1.0	4	>39400	4
5B	0.00029	3	>1.0	3	>5770	3
6B	0.00041	3	15	4	28100	3
7A-D	0.00016	3	>1.0	3	>9330	3
10A	0.00011	6	15	5	131977	5

N= the number of independent experiments in which the compounds were tested.

Table 7: EC₅q, CCso, and SI for the compounds against serotype 3 in the RT-gPCR assays

	RT-qPCR serotype 3 H87
compound#	EC50 (μΜ)	N	CC50 (μΜ)	N	SI	N
1B	0.0019	4	>2.5	4	>1590	4
2B	0.00085	4	>1.0	4	>2050	4
3B	0.0015	3	>2.5	3	>3870	3
4B	0.00092	4	>1.0	4	>2360	4
5B	0.0026	3	>1.0	3	>719	3
6B	0.0056	4	13	4	2520	4
7A-D	0.0024	3	>1.0	3	>574	3
10A	0.0042	5	15	5	6210	5

N= the number of independent experiments in which the compounds were tested.

-71Table 8: EC₅q, CCso, and SI for the compounds against serotype 4 in the RTqPCR assays

	RT-q	PCR serotype 4	4241
compound#	ECso (μΜ)	N	CC50 (μΜ)	N	SI	N
1B	0.0096	4	8.8	4	2980	4
2B	0.010	4	4.1	4	1020	4
3B	0.014	3	3.6	1	333	1
4B	0.012	3	6.8	2	563	2
5B	0.020	3	8.4	3	613	3
6B	0.029	4	9.7	3	317	3
7A-D	0.013	3	8.2	3	1000	3
10A	0.030	5	3.2	5	105	5

N= the number of independent experiments in which the compounds were tested.

Claims

1. A compound of formula (I), including any stereochemically isomeric form thereof,

wherein

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵ is hydrogen, Z is carbon, and R⁶ is methyl; or

R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethoxy, R⁵ is fluoro, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is hydrogen, R³ is deuterium, A is (a-1), R⁴ is trifluoromethoxy, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or

R¹ is chloro, R² is -OCH₂CH₂OH, R³ is hydrogen, A is (a-1 ), R⁴ is trifluoromethoxy, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or

-73R¹ is chloro, R² is hydrogen, R³ is hydrogen, A is (a-1), R⁴ is trifluoromethylthio, R⁵ is hydrogen, Z is carbon, and R⁶ is hydrogen; or a pharmaceutically acceptable sait, solvaté or polymorph thereof.

5

2. The compound as claimed in claim 1 wherein A is (a-1 ).

3. The compound as claimed in claim 1 wherein A is (a-2).

4. The compound according to any one of claims 1 to 3 wherein said compound îo has the (+) spécifie rotation.

5. The compound according to claim 1 wherein said compound is selected from :

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 together with one or more pharmaceutically acceptable excipients, diluents or carriers.

-747. The pharmaceutical composition according to claim 6 which comprises a second or further active ingrédient.

8. The pharmaceutical composition according to claim 7 wherein the second or further active ingrédient is an antiviral agent.

9. A compound of formula (I) according to any one of claims 1 to 5 for use as a medicine.

10. A compound of formula (I) according to any one of claims 1 to 5 for use in the treatment of Dengue viral infection and for the prévention or treatment of disease associated with Dengue viral infection.

11. A compound of formula (I) for use according to claim 10 wherein the Dengue viral infection is an infection by viruses ofthe DENV-1, DENV-2, DENV-3 or DENV-4 strain.