Patent Description:
Flaviviruses, which are transmitted by mosquitoes or ticks, cause life-threatening infections in man, such as encephalitis and hemorrhagic fever. Four distinct, but closely related serotypes of the flavivirus dengue are known, so-called DENV-<NUM>,-<NUM>, -<NUM>, and -<NUM>. Dengue is endemic in most tropical and sub-tropical regions around the world, predominantly in urban and semi-urban areas. According to the World Health Organization (WHO), <NUM> billion people of which <NUM> billion children are at risk of DENV infection (WHO, <NUM>). An estimated <NUM> to <NUM> million cases of dengue fever [DF], half a million cases of severe dengue disease (i.e. dengue hemorrhagic fever [DHF] and dengue shock syndrome [DSS]), and more than <NUM>,<NUM> deaths occur worldwide each year. DHF has become a leading cause of hospitalization and death amongst children in endemic regions. 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 have risen dramatically over the past years. Not only is the number of dengue cases increasing as the disease is spreading to new areas, but the outbreaks tend to be more severe.

Although progress is being made in the development of vaccines against dengue with the availability of the Dengvaxia® vaccine, many difficulties are encountered. These include the existence of a phenomenon referred to as antibody-dependent enhancement (ADE). Recovery from an infection by one serotype provides lifelong immunity against that serotype but confers only partial and transient protection against a subsequent infection by one of the other three serotypes. 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, resulting in uncontrolled virus replication and higher peak viral titers. In both primary and secondary infections, higher viral titers are associated with more severe dengue disease. Since maternal antibodies can easily pass on to infants by breast 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 as hyper endemic regions, 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 hemorrhagic 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 Prevention (CDC), both mosquitoes are currently omnipresent 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 considerable room for improvement due to limited efficacy, especially against DENV-<NUM> and -<NUM>, 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-naive 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, specific antiviral drugs for the treatment or prevention of dengue fever virus infection are not available. Clearly, there is still a great unmet medical need for therapeutics for the prevention or treatment of viral infections in animals, 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.

<CIT> discloses <NUM>-phenylpyrrolidine and indoline derivatives as cold menthol receptor antagonists for treatment of inflammatory and central diseases. <CIT> discloses indole and indoline derivatives for use in the treatment of dengue viral infections.

The present invention now provides compounds, substituted indole derivatives, which show high potent activity against all four (<NUM>) serotypes of the Dengue virus.

The present 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 present invention provides compounds which have been shown to possess potent antiviral activity against all four (<NUM>) serotypes currently known. The present invention furthermore demonstrates that these compounds efficiently inhibit proliferation of Dengue virus (DENV). Therefore, these compounds constitute a useful class of potent compounds that can be used in the treatment and/or prevention of viral infections in animals, mammals and humans, more specifically for the treatment and/or prevention of infections with Dengue viruses.

The present invention furthermore relates such compounds for use as a medicament and for use in treating and/or preventing viral infections, in particular with viruses belonging to the family of the Dengue viruses in animals or mammals, more in particular in humans. The invention also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount.

The present invention also relates to one or more such compounds or a pharmaceutically acceptable salt thereof optionally in combination with one or more other medicines, like another antiviral agent, for use in a method of treatment or prevention of dengue viral infections in humans to a patient in need thereof.

One aspect of the invention is the provision of compounds of formula (Ia or lb). Formula (Ia) is represented as follows:
<CHM>
a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:.

Formula (Ib) is represented by the following structure:
<CHM>
a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:.

Part of the invention are also the following three compounds having the structures (II), (III) and (IV) respectively:
<CHM>
<CHM>
<CHM>
or a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof.

In particular the compounds of the invention or their stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof are selected from the group:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Part of the current invention is also a pharmaceutical composition comprising a compound of formula (la, Ib, II, III or IV) or a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.

Pharmaceutically acceptable salts of the compounds of formula (la, Ib, II, III or IV) include the acid addition 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 non-toxic salts.

The compounds of the invention may also exist in un-solvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.

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 present 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 precipitation, 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 ingredient other than the compound(s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation 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 preparations such as suspensions, syrups, elixirs, emulsions, 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 employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms.

It 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 discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient 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 determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be from <NUM>/kg to <NUM>/kg body weight, more preferably from <NUM>/kg to <NUM>/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 <NUM> to <NUM>, and in particular <NUM> to <NUM> of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (la, Ib, II, III or IV) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the 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 present disclosure is also intended to include any isotopes of atoms present in the compounds of the invention. For example, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include C-<NUM> and C-<NUM>.

The present compounds used in the current invention may also exist in their stereochemically isomeric form, defining all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which are not interchangeable. Unless otherwise mentioned or indicated, the chemical designation of compounds encompasses the mixture of all possible stereochemically isomeric forms, which said compounds might possess.

Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds used in the present invention either in pure form or in admixture with each other are intended to be embraced within the scope of the present invention including any racemic mixtures or racemates.

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least <NUM>% (i. minimum <NUM>% of one isomer and maximum <NUM>% of the other possible isomers) up to a stereoisomeric excess of <NUM>% (i.e. <NUM>% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of <NUM>% up to <NUM>%, even more in particular having a stereoisomeric excess of <NUM>% up to <NUM>% and most in particular having a stereoisomeric excess of <NUM>% up to <NUM>%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of compounds and intermediates used in this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (Ia), (Ib), (II), (III) or (IV) of the present invention all have at least one chiral carbon atom as indicated in the figure below by the carbon atom labelled with * :
<CHM>
<CHM>
<CHM>.

Due to the presence of said chiral carbon atom, a "compound of formula (Ia), (Ib), (II), (III) or (IV)" 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 specific optical rotation of said particular enantiomer.

In an aspect the present invention relates to a first group of compound of formula (Ia), (Ib), (II), (III) and (IV) wherein the compounds of formula (Ia), (Ib), (II), (III) and (IV) have the (+) specific rotation.

In a further aspect the present invention relates to a second ground of compounds of formula (Ia), (Ib), (II), (III) and (IV) wherein the compounds of formula (Ia), (Ib), (II), (III) and (IV) have the (-) specific rotation.

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

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

Hereinafter, "SQD" means Single Quadrupole Detector, "MSD" Mass Selective Detector, "RT" room temperature, "BEH" bridged ethylsiloxane/silica hybrid, "DAD" Diode Array Detector, "HSS" High Strength silica.

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

The SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to <NUM> 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 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 temperature (T) in °C; Run time in minutes, Backpressure (BPR) in bars.

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

For a number of compounds, melting points were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a temperature gradient of <NUM>/minute. Maximum temperature was <NUM>.

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

[α]λT = (100α) / (/x c) : where / is the path length in dm and c is the concentration in g/<NUM> for a sample at a temperature T (°C) and a wavelength λ (in nm). If the wavelength of light used is <NUM> (the sodium D line), then the symbol D might be used instead. The sign of the rotation (+ or -) should always be given. When using this equation the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/<NUM>).

<NUM>-(<NUM>-Fluoro-<NUM>-methoxyphenyl)acetic acid [<NPL>] (<NUM>, <NUM> mmol) was added in small portions to thionyl chloride (<NUM>) and the resulting solution was stirred overnight at room temperature. The solvent was concentrated under reduced pressure and co-evaporated with toluene to give <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>) as an oily residue that was used without further purification in the next step.

A solution of <NUM>-chloro-<NUM>-methyl-<NUM>H-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise over <NUM> and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise over <NUM>. Stirring was continued at <NUM> for <NUM> and at room temperature for <NUM>. The reaction mixture was cooled again to <NUM> and the reaction was quenched by the slow addition of a solution of potassium sodium tartrate tetrahydrate (Rochelle salt) [<NPL>] (<NUM>, <NUM> mmol) in water (<NUM>). Stirring was continued at <NUM> for <NUM>. THF (<NUM>) was added and the mixture was allowed to warm to room temperature. Na<NUM>SO<NUM> (<NUM>) was added and after overnight stirring, the mixture was filtered over dicalite® and the filter cake was washed with THF (4x <NUM>). The filtrates were combined and evaporated under reduced pressure. The residue was stirred up in CH<NUM>CN (<NUM>) at <NUM> and the resulting precipitate was filtered off, washed with CH<NUM>CN (4x) and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 1a (<NUM>). The filtrate was concentrated under vacuum and co-evaporated with EtOAc. The residue was stirred up in CH<NUM>Cl<NUM> (<NUM>). The solids were isolated by filtration, washed with CH<NUM>Cl<NUM> (5x) and dried under vacuum at <NUM> to provide a second crop of 1a (<NUM>).

A stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 1a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. Phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) was added and the resulting suspension was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The solids were removed by filtration and washed with THF (2x). The combined filtrates were evaporated under reduced pressure to provide <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 1b (<NUM>), which was used without further purification in the next step.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 1b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [CAS <NUM>-<NUM>-<NUM>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was stirred at room temperature overnight. More diisopropylethylamine (<NUM>, <NUM> mmol) was added and the reaction mixture was heated at <NUM> for <NUM>. The reaction mixture was poured out into water (<NUM>) and the product was extracted with EtOAc (2x). The combined extracts were washed with brine, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: heptane/EtOAc/EtOH gradient <NUM>/<NUM>/<NUM> to <NUM>/<NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was further purified via preparative HPLC (Stationary phase: Uptisphere® C18 ODB - <NUM>, <NUM>, <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The desired fractions were combined and evaporated under reduced pressure. The residue was stirred up in MeOH (<NUM>) at <NUM>. The solids were filtered off, washed with MeOH (4x <NUM>) and dried under vacuum at <NUM> to give <NUM>-(<NUM>-chloro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture.

The enantiomers of Compound <NUM> (<NUM>) were separated via normal phase chiral separation (Stationary phase: (S,S)-Whelk-O1, Mobile phase: <NUM>% heptane, <NUM>% ethanol). The product fractions were combined and evaporated to provide Enantiomer 1A as the first eluted product and Enantiomer 1B as the second eluted product. Enantiomer 1A was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: heptane/EtOAc/EtOH gradient <NUM>/<NUM>/<NUM> to <NUM>/<NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was stirred up in heptane (<NUM>) and EtOAc (<NUM>) was added dropwise. The mixture was stirred for <NUM>, the solids were filtered off, washed (4x) with a mixture of heptane/EtOAc (<NUM>/<NUM>), and dried at under vacuum at <NUM> to provide Enantiomer 1A (<NUM>). Enantiomer 1B was crystallized from CH<NUM>Cl<NUM> (<NUM>). The solids were filtered off, washed (4x) with a small amount of CH<NUM>Cl<NUM>, and dried under vacuum at <NUM> to provide Enantiomer 1B (<NUM>).

A solution of <NUM>-chloro-<NUM>-methoxy-<NUM>-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise over <NUM> and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise over <NUM>. Stirring was continued at <NUM> for <NUM> min and at room temperature for <NUM>. The reaction mixture was cooled again to <NUM> and the reaction was quenched by the slow addition of a solution of potassium sodium tartrate tetrahydrate (Rochelle salt) [CAS <NUM>-<NUM>-<NUM>] (<NUM>, <NUM> mmol) in water (<NUM>). Stirring was continued at <NUM> for <NUM> and at room temperature for <NUM>. THF (<NUM>) and Na<NUM>SO<NUM> (<NUM>) were added and after overnight stirring, the mixture was filtered over dicalite® and the filter cake was washed with <NUM>-methyl-THF (5x <NUM>) and with THF (<NUM>). The THF filtrates were combined and evaporated under reduced pressure to a residual volume of <NUM>. The resulting precipitate was filtered off, washed with THF (2x <NUM>) and dried under vacuum at <NUM> to provide a first fraction of <NUM>-(<NUM>-chloro-<NUM>-methoxy-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 2a (<NUM>). The filtrate was combined with the earlier obtained <NUM>-methyl-THF filtrates and concentrated under reduced pressure. The residue (<NUM>) was stirred up in CH<NUM>Cl<NUM> (<NUM>). The resulting precipitate was filtered off, washed with CH<NUM>Cl<NUM> (4x <NUM>) and dried under vacuum at <NUM> to provide a second fraction of 2a (<NUM>).

A stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxy-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 2a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. Phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) was added and the resulting suspension was stirred at <NUM> for <NUM> and at room temperature for <NUM>. <NUM>-(<NUM>-Amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) was added and the solvents were evaporated under reduced pressure. The residue was dissolved in CH<NUM>CN (<NUM>), diisopropylethylamine (<NUM>, <NUM> mmol) was added and the reaction mixture was stirred at room temperature for <NUM> and at <NUM> for <NUM>. The reaction mixture was poured out into water (<NUM>) and the product was extracted with <NUM>-methyl-THF (2x). The combined extracts were washed with brine, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: CH<NUM>Cl<NUM>/MeOH gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined, evaporated under reduced pressure and co-evaporated with MeOH. The residue was further purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - <NUM>, <NUM> × <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, MeOH). The desired fractions were combined, evaporated under reduced pressure and co-evaporated with MeOH. The residue was further purified via preparative HPLC (Stationary phase: Uptisphere® C18 ODB - <NUM>, <NUM>, <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The desired fractions were combined, evaporated under reduced pressure and co-evaporated with MeOH. The residue was stirred up in MeOH (<NUM>) at <NUM>. The solids were filtered off, washed with MeOH (3x <NUM>) and dried under vacuum at <NUM> to give <NUM>-(<NUM>-chloro-<NUM>-methoxy-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture.

The enantiomers of Compound <NUM> (<NUM>) were separated via normal phase chiral separation (Stationary phase: (S,S)-Whelk-O1, Mobile phase: <NUM>% methanol). The product fractions were combined and evaporated to provide Enantiomer 2A as the first eluted product and Enantiomer 2B as the second eluted product. Enantiomer 2A was stirred up in MeOH at <NUM> (<NUM>), filtered off, washed (4x) with MeOH and dried at under vacuum at <NUM> to provide Enantiomer 2A (<NUM>). Enantiomer 2B was stirred up in MeOH at <NUM> (<NUM>), filtered off, washed (4x) with MeOH and dried at under vacuum at <NUM> to provide Enantiomer 2B (<NUM>).

Diethylaluminium chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise at <NUM> to a solution of <NUM>-fluoro-<NUM>-methyl-<NUM>H-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>). After <NUM> at <NUM>, <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol, synthesis: see Example <NUM>) in CH<NUM>Cl<NUM> (<NUM>) was added slowly at <NUM>. The reaction was stirred at <NUM> for <NUM> and then at room temperature for <NUM>. Ice-water was added. The precipitate was filtered off, washed with water and dried under vacuum to afford <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 3a (<NUM>).

At <NUM>, a solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise to a mixture of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 3a (<NUM>, <NUM> mmol) in THF (<NUM>). The mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up with EtOAc, washed with water, dried over MgSO<NUM>, filtered, and the solvent was evaporated under reduced pressure. The residue was taken up with a minimum amount of EtOAc. The precipitate was filtered off and dried under vacuum to give <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 3b (<NUM>). The filtrate was concentrated under reduced pressure to give a second batch of 3b (<NUM>). The two batches were used as such in the next step.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 3b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in THF (<NUM>) and CH<NUM>CN (<NUM>) was stirred at <NUM> for <NUM>. The solution was concentrated under reduced pressure. The residue was taken up with EtOAc. The organic layer was washed with water and HCl (1N) (twice), separated, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The crude residue (<NUM>) was combined with another batch of crude Compound <NUM> (<NUM> in total) and purified by column chromatography on silica gel (<NUM>-<NUM>, <NUM> in CH<NUM>Cl<NUM>/MeOH/NH<NUM>OH (<NUM>/<NUM>/<NUM>)). The fractions containing Compound <NUM> were combined and the solvent was evaporated under reduced pressure. The compound was crystallized from a solution in Et<NUM>O containing a few drops of CH<NUM>CN. The precipitate was filtered off and dried to give <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The Enantiomers of Compound <NUM> were separated via Preparative Chiral SFC (Stationary phase: Chiralpak® IA <NUM> <NUM> × <NUM>, Mobile phase: <NUM>% CO<NUM>, <NUM>% mixture of EtOH/iPrOH <NUM>/<NUM> (+ <NUM>% iPrNH<NUM>) to give <NUM> of the first eluted enantiomer and <NUM> of the second eluted enantiomer. The first eluted enantiomer was crystallized from Et<NUM>O to afford Enantiomer 3A (<NUM>). The second eluted enantiomer was crystallized from Et<NUM>O (with a few drops of CH<NUM>CN) to afford Enantiomer 3B (<NUM>).

To a mixture of <NUM>-iodo-<NUM>-methyl-<NUM>-(trifluoromethoxy)aniline [<NPL>] in DMF (<NUM>) under N<NUM>-flow at <NUM> was added copper(I) iodide (<NUM>, <NUM> mmol), triethyamine (<NUM>, <NUM> mmol), PdCl<NUM>(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol) and trimethylsilylacetylene (<NUM>, <NUM> mmol). The mixture was stirred at room temperature for <NUM> under N<NUM>-flow, poured into ice-water and extracted with EtOAc. The organic layer was dried over MgSO<NUM>, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (<NUM>-<NUM>, <NUM> in heptane/EtOAc <NUM>/<NUM>). The pure fractions were combined and evaporated under reduced pressure to give <NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>-((trimethylsilyl)ethynyl)aniline 4a (<NUM>).

To a mixture of <NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>-((trimethylsilyl)ethynyl)aniline 4a (<NUM>, <NUM> mmol) in N-methyl-pyrrolidone (<NUM>) under N<NUM>-flow, was added potassium tert-butoxide (<NUM>, <NUM> mmol) in one portion. The reaction was stirred at <NUM> for <NUM>, poured into ice-water, acidified with 3N HCl until pH <NUM>-<NUM> and extracted with EtOAc. The organic layer was washed <NUM> times with water, separated, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (<NUM>-<NUM>, <NUM> in heptane/EtOAc <NUM>/<NUM>). The pure fractions were combined and evaporated to under reduced pressure to give <NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>-indole 4b (<NUM>).

Diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise at <NUM> to a solution of <NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>H-indole 4b (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>). After <NUM> at <NUM>, <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol, synthesis: see Example <NUM>) in CH<NUM>Cl<NUM> (<NUM>) was added slowly at <NUM>. The reaction was stirred at <NUM> for <NUM>. Ice-water was added. The precipitate was filtered off, washed with water and dried under vacuum to afford <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>H-indol-<NUM>-yl)ethanone 4c (<NUM>).

At <NUM>, a solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise to a mixture of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(trif!uoromethoxy)-<NUM>H-indol-<NUM>-yl)ethanone 4c (<NUM>, <NUM> mmol) in THF (<NUM>). The mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up with EtOAc, washed with water, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure to give <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>H-indol-<NUM>-yl)ethanone 4d (<NUM>).

A mixture of <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>H-indol-<NUM>-yl)ethanone 4d (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in THF (<NUM>) and CH<NUM>CN (<NUM>) was stirred at <NUM> for <NUM>. The solution was concentrated under reduced pressure. The residue was taken up with EtOAc. The organic layer was washed with water and 1N HCl (twice). The organic layer was separated, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (<NUM>-<NUM>, <NUM> in CH<NUM>Cl<NUM>/MeOH <NUM>/<NUM>). The fractions containing Compound <NUM> were combined and the solvent was evaporated under reduced pressure. The residue was further purified by column chromatography on silica gel (irregular bare silica, <NUM> in CH<NUM>Cl<NUM>/MeOH/NH<NUM>OH <NUM>/<NUM>/<NUM>). The fractions containing Compound <NUM> were combined and the solvent was evaporated under reduced pressure to give <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)-<NUM>-(<NUM>-methyl-<NUM>-(trifluoromethoxy)-<NUM>-indol-<NUM>-yl)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The Enantiomers were separated via Preparative Chiral SFC (Stationary phase: Chiralcel® OD-H <NUM> <NUM> x30 mm, Mobile phase: <NUM>% CO<NUM>, <NUM>% iPrOH (+ <NUM>% iPrNH<NUM>) to give <NUM> of the first eluted enantiomer and <NUM> of the second eluted enantiomer. The first eluted enantiomer was solidified from diisopropyl ether/heptane to afford Enantiomer 4A (<NUM>). The second eluted enantiomer was solidified from diisopropyl ether/heptane to afford Enantiomer 4B (<NUM>).

A solution <NUM>-methyl-<NUM>-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to -<NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at -<NUM> for <NUM>. A solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The reaction mixture was poured out in a stirring ice/Rochelle salt solution. The mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with water, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>). The precipitate was filtered off, washed (2x) with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 5a (<NUM>).

A stirred solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 5a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was mixed with EtOAc (<NUM>). The solids were isolated by filtration, washed with a small amount of EtOAc and dried under vacuum at <NUM> to provide <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 5b (<NUM>).

A mixture of <NUM>-bromo-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 5b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN was stirred at room temperature for <NUM> days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM> (<NUM>), washed with 1N HCl (<NUM>) and brine (<NUM>), dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: EtOAc/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was further purified via preparative HPLC (Stationary phase: Uptisphere® C18 ODB - <NUM>, <NUM>, <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with EtOAc to a white powder. The solids were stirred up for <NUM> in a mixture of MeOH (<NUM>) and water (<NUM>) and filtered off to give <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)-<NUM>-(<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone (Compound <NUM>, <NUM>) as a racemic mixture.

The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Normal Phase Chiral separation (Stationary phase: AS <NUM>, Mobile phase: <NUM>% methanol). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 5A as the first eluted product and Enantiomer 5B as the second eluted product. Both enantiomers recrystallized from a solution in MeOH (<NUM>). The solids were isolated by filtration to provide Enantiomer 5A (<NUM>) and Enantiomer 5B (<NUM>) as white powders.

N-iodosuccinimide (<NUM>, <NUM> mmol) was added in one portion to a solution of <NUM>-ethoxy-<NUM>-methylaniline [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>), and the reaction mixture was stirred at room temperature for <NUM>. The solvent was evaporated. The black residue was purified by flash chromatography on silica gel using heptane/EtOAc <NUM>/<NUM> as the eluent. The product fractions were combined and evaporated under reduced pressure. The residue was triturated with heptane. The precipitate was filtered off, washed with a small amount of heptane and dried under vacuum at <NUM> to give <NUM>-ethoxy-<NUM>-iodo-<NUM>-methylaniline 6a (<NUM>) as a dark gray solid.

<NUM>-Ethoxy-<NUM>-iodo-<NUM>-methylaniline 6a (<NUM>, <NUM> mmol) was dissolved in DMF (<NUM>) and degassed with N<NUM>. Copper(I) iodide (<NUM>, <NUM> mmol), bis(triphenylphosphine)palladium(II) chloride (<NUM>, <NUM> mmol), triethylamine (<NUM>, <NUM> mmol) and trimethylsilylacetylene (<NUM>, <NUM> mmol) were added to the stirred solution, under nitrogen atmosphere, while cooling with a water bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured onto ice/water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra <NUM>, Mobile phase: EtOAc/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>) to give <NUM>-ethoxy-<NUM>-methyl-<NUM>-((trimethylsilyl)ethynyl)aniline 6b (<NUM>) as a black oil.

Potassium tert-butoxide (<NUM>, <NUM> mmol) was added in one portion to a solution of <NUM>-ethoxy-<NUM>-methyl-<NUM>-((trimethylsilyl)ethynyl)aniline 6b (<NUM>, <NUM> mmol) in NMP (<NUM>) at room temperature under N<NUM>-atmosphere. The reaction mixture was stirred at <NUM> for <NUM>. The reaction mixture was poured into ice/water and the mixture was extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of CH<NUM>Cl<NUM>/heptane <NUM>/<NUM> to <NUM>/<NUM>. The product fractions were combined, evaporated under reduced pressure and dried under vacuum at <NUM> to give <NUM>-ethoxy-<NUM>-methyl-<NUM>H-indole 6c (<NUM>) as a yellow solid.

Diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise, to a cooled (-<NUM>) solution of <NUM>-ethoxy-<NUM>-methyl-<NUM>H-indole 6c (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) under a N<NUM>-atmosphere. After stirring for <NUM> at -<NUM>, a solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol, synthesis: see Example <NUM>) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise to the reaction mixture. Stirring was continued at -<NUM> for <NUM> and the mixture was allowed to warm to room temperature while stirring for <NUM>. The reaction mixture was poured onto ice/water containing excess Rochelle salt. After warming to room temperature, the mixture was filtered on a short pad of dicalite® and the filter cake was rinsed several times with THF. The layers were separated. The organic layer was washed with brine, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>) and the solids were filtered off, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to give <NUM>-(<NUM>-ethoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 6d (<NUM>).

A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM> g, <NUM> mmol) in THF (<NUM>) was added dropwise to a cooled (<NUM>) solution of <NUM>-(<NUM>-ethoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 6d (<NUM>, <NUM> mmol) in THF (<NUM>), and the reaction mixture was allowed to warm to room temperature while stirring for <NUM>. The reaction mixture was filtered and the solids were washed with THF. The filtrate was evaporated under reduced pressure and dried under vacuum at <NUM> to provide <NUM>-bromo-<NUM>-(<NUM>-ethoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 6e (<NUM>) as a grey solid. The product was used without further purification in the next step.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-ethoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 6e (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>. The organic solution was washed with 1N HCl, water, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined and evaporated under reduced pressure. The residue was further purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD <NUM> <NUM> × <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The product fractions were combined and evaporated under reduced pressure. The residue was further purified via preparative achiral SFC (Stationary phase: PYR (Pyridine) 60A <NUM> <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined, evaporated under reduced pressure and dried under vacuum at <NUM> to provide racemic <NUM>-(<NUM>-ethoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as an off-white powder.

A suspension of <NUM>-nitro-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-amine [<NPL>] (<NUM>, <NUM> mmol) in concentrated HCl (<NUM>) was heated to <NUM> for <NUM>. The solution was cooled to <NUM>. A solution of NaNO<NUM> (<NUM>, <NUM> mmol) in H<NUM>O (<NUM>) was added dropwise. The reaction mixture was stirred for <NUM> at <NUM>. The reaction mixture was added slowly to a cooled (<NUM>) solution of KI (<NUM>, <NUM> mol) in H<NUM>O (<NUM>). The resulting mixture was heated to <NUM> for <NUM>. After cooling to room temperature, H<NUM>O (<NUM>) was added and the crude product was extracted with EtOAc (<NUM>× <NUM>). The combined organic phases were washed with aqueous HCl (<NUM>%, <NUM>), aqueous NaOH (<NUM> N, <NUM>), a saturated aqueous Na<NUM>SO<NUM> solution (<NUM>) and brine (<NUM>). After drying over MgSC<NUM>, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc <NUM>/<NUM>) to give <NUM>-iodo-<NUM>-nitro-<NUM>,<NUM>-dihydrobenzofuran 7a (<NUM>) as a pale yellow solid.

To a solution of FeCl<NUM>. <NUM><NUM>O (<NUM>, <NUM> mmol) in MeOH (<NUM>) were added <NUM>-iodo-<NUM>-nitro-<NUM>,<NUM>-dihydrobenzofuran 7a (<NUM>, <NUM> mmol) and active carbon (<NUM>). The mixture was heated under reflux and hydrazine hydrate (<NUM>, <NUM> mmol) was added dropwise. The mixture was stirred at <NUM> for <NUM>. The mixture was filtered and the filtrate was concentrated under reduced pressure. The solid residue was washed with MeOH (<NUM>) to give <NUM>-iodo-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-amine 7b (<NUM>) as a pale yellow solid.

A stirred suspension of <NUM>-iodo-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-amine 7b (<NUM>, <NUM> mmol), Cul (<NUM>, <NUM> mmol) and Pd(PPh<NUM>)<NUM>Cl<NUM> (<NUM>, <NUM> mmol) in triethylamine (<NUM>) was degassed with N<NUM> and evacuated/backfilled with N<NUM> (<NUM> cycles). The reaction mixture was stirred at <NUM> for <NUM> minutes. After addition of ethynyl(trimethyl)silane (<NUM>, <NUM> mmol) the suspension was stirred for <NUM> hours at <NUM> under N<NUM> atmosphere. The reaction mixture was diluted with water (<NUM>) and extracted with EtOAc (2x <NUM>). The combined organic phases were washed with brine (<NUM>) and dried over MgSO<NUM>. Removal of the solvent under reduced pressure gave the crude product as brown solid. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc <NUM>/<NUM>) to provide <NUM>-(<NUM>-trimethylsilylethynyl)-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-amine 7c (<NUM>) as a pale yellow solid.

A mixture of <NUM>-(<NUM>-trimethylsilylethynyl)-<NUM>,<NUM>-dihydrobenzofuran-<NUM>-amine 7c (<NUM>, <NUM> mmol) and t-BuOK (<NUM>, <NUM> mmol) in NMP (<NUM>) was stirred at <NUM> for <NUM>. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc <NUM>/<NUM>) to give <NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indole 7d (<NUM>) as a pale yellow solid.

A solution <NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-f]indole 7d (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled on an ice-bath under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. Stirring was continued at <NUM> for <NUM>. The ice-bath was removed and the reaction mixture was stirred at room temperature for <NUM>. The reaction mixture was poured out into a stirring ice/Rochelle salt solution. After the ice had melted, the mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with brine and water. The combined aqueous layers were extracted with THF and the combined organic layers were dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>). The precipitate was filtered off, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide <NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 7e (<NUM>) as a white solid.

A stirred solution of <NUM>-(<NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 7e (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was triturated with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solids were isolated by filtration and washed with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>) to provide <NUM>-bromo-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 7f (<NUM>) as a yellow powder.

A mixture of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 7f (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>, washed with 1N HCl and water, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was dried under vacuum at <NUM> to provide <NUM>-(<NUM>,<NUM>-dihydro-<NUM>/-/-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Preparative SFC (Stationary phase: Chiralpak® Diacel AS <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 7A as the first eluted product and Enantiomer 7B as the second eluted product. Both enantiomers were further purified via Preparative SFC (Stationary phase: Chiralpak® Diacel AD <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>) and subsequently by column chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). Enantiomer 7A was crystallized from MeOH (<NUM>). The solid was isolated by filtration, washed with a small amount of MeOH and dried under vacuum at <NUM> to provide Enantiomer 7A (<NUM>) as a white powder. Enantiomer 7B was crystallized from a mixture of MeOH (<NUM>) and water (<NUM> drops). The solid was isolated by filtration, washed with a small amount of MeOH and dried under vacuum at <NUM> to provide Enantiomer 7B (<NUM>) as a white powder.

A solution <NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to -<NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at -<NUM> for <NUM>. A solution of <NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)acetyl chloride 1a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. The reaction mixture was stirred at -<NUM> for <NUM>, and subsequently at room temperature for <NUM>. The reaction mixture was poured out into a stirring ice/Rochelle salt solution. After the ice had melted, the mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with brine and water. The combined aqueous layers were extracted with THF and the combined organic layers were dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>). The precipitate was filtered off, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide <NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 8a (<NUM>).

A stirred solution of <NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 8a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was triturated with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solids were isolated by filtration and washed with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>) to provide <NUM>-bromo-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 8b (<NUM>) as a yellow solid.

A mixture of <NUM>-bromo-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)ethanone 8b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>, washed with 1N HCl and water, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was dried under vacuum at <NUM> to provide <NUM>-(<NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Preparative SFC (Stationary phase: Chiralpak® Diacel AS <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 8A as the first eluted product and Enantiomer 8B as the second eluted product. Enantiomer 8A was stirred up in CH<NUM>Cl<NUM> (<NUM>). The solid was isolated by filtration, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide Enantiomer 8A (<NUM>) as a white powder. Enantiomer 8B was purified by Preparative SFC (Stationary phase: Chiralpak® Diacel AD <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure. Enantiomer 8B was stirred up in CH<NUM>Cl<NUM> (<NUM>). The solid was isolated by filtration, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide Enantiomer 8B (<NUM>) as a white powder.

<NUM>-(<NUM>-Chloro-<NUM>-methoxyphenyl)acetic acid [<NPL>] (<NUM>, <NUM> mmol) was added in small portions to thionyl chloride (<NUM>) and the resulting solution was stirred overnight at <NUM>. The solvent was concentrated under reduced pressure and co-evaporated with toluene to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-acetyl chloride 9a' (<NUM>) as an oily residue that was used without further purification in the next step.

A solution of <NUM>-fluoro-<NUM>-methyl-<NUM>H-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. Stirring was continued at <NUM> for <NUM> and the reaction mixture was subsequently stirred at room temperature for <NUM>. The reaction mixture was poured out into a stirring ice/Rochelle salt solution. After the ice had melted, the mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with brine, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>) and the precipitate was filtered off and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 9a (<NUM>).

A stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 9a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at <NUM> for <NUM> and subsequently at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was mixed with EtOAc (<NUM>). The solids were isolated by filtration, washed with a small amount of EtOAc and dried under vacuum at <NUM> to provide <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 9b (<NUM>) as a white solid, which was used without further purification in the next step.

A mixture <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 9b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in CH<NUM>CN (<NUM>) was stirred at room temperature overnight and subsequently at <NUM> for <NUM>. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM> (<NUM>), washed with 1N HCl (<NUM>) and water (<NUM>), dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residual solid was precipitated from CH<NUM>Cl<NUM>/heptane. The precipitate was filtered off and washed with CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solid (<NUM>) was further purified via preparative HPLC (Stationary phase: Uptisphere® C18 ODB - <NUM>, <NUM>, <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The desired fractions were combined, evaporated under reduced pressure, and co-evaporated with EtOAc (<NUM>) to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Normal Phase Chiral separation (Stationary phase: (S,S)-Whelk-O1, Mobile phase: <NUM>% ethanol). The product fractions were combined and evaporated to provide Enantiomer 9A as the first eluted product and Enantiomer 9B as the second eluted product.

Enantiomer 9A (<NUM>) was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: heptane/EtOAc/EtOH gradient <NUM>/<NUM>/<NUM> to <NUM>/<NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was triturated with H<NUM>O (<NUM>) and MeOH (<NUM>). After stirring for <NUM>, the solids were filtered off, washed (3x) with a mixture of H<NUM>O/MeOH <NUM>/<NUM>, and dried at under vacuum at <NUM> to provide Enantiomer 9A (<NUM>).

Enantiomer 9B (<NUM>) was purified by flash chromatography (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: heptane/EtOAc/EtOH gradient <NUM>/<NUM>/<NUM> to <NUM>/<NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was triturated with H<NUM>O (<NUM>) and MeOH (<NUM>). After stirring for <NUM>, the solids were filtered off, washed (3x) with a mixture of H<NUM>O/MeOH <NUM>/<NUM>, and dried at under vacuum at <NUM> to provide Enantiomer 9B (<NUM>).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ ppm <NUM> (d, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> (q, J=<NUM>, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (s, <NUM>) <NUM> (t, J=<NUM>, <NUM>) <NUM> (t, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (dd, J=<NUM>, <NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (d, J=<NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> (br s, <NUM>) LC/MS (method LC-B): Rt <NUM>, MH+ <NUM>.

A solution <NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-f]indole 7d (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled on an ice-bath under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. Stirring was continued at <NUM> for <NUM>. The ice-bath was removed and the reaction mixture was stirred at room temperature for <NUM>. The reaction mixture was poured out into a stirring ice/Rochelle salt solution. After the ice had melted, the mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with brine and water. The combined aqueous layers were extracted with THF and the combined organic layers were dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>). The precipitate was filtered off, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>/-/-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)ethanone 10a (<NUM>) as a white solid.

A stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)ethanone 10a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was triturated with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solids were isolated by filtration, washed with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>) and dried under vacuum at <NUM> to provide <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)ethanone 10b (<NUM>) as a yellow powder.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)ethanone 10b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)-ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>, washed with 1N HCl and water, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-f]indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture.

The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Preparative SFC (Stationary phase: Chiralcel® Diacel OD <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 10A as the first eluted product and Enantiomer 10B as the second eluted product. Both enantiomers were further purified via Preparative SFC (Stationary phase: Chiralcel® Diacel AD <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure. Both enantiomers were crystallized from a mixture of MeOH (<NUM>) and water (<NUM>). The solids were isolated by filtration, washed with a small amount of MeOH/water (<NUM>/<NUM>) and dried under vacuum at <NUM> to provide Enantiomer 10A (<NUM>) and Enantiomer 10B (<NUM>) as white powders.

A solution <NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-g]indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was cooled to <NUM> under N<NUM>-atmosphere. A solution of diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise and the resulting mixture was kept at <NUM> for <NUM>. A solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise. The reaction mixture was stirred at <NUM> for <NUM>, and subsequently at room temperature for <NUM>. The reaction mixture was poured out into a stirring ice/Rochelle salt solution. After the ice had melted, the mixture was filtered over dicalite® and the filter cake was washed several times with THF. The filtrates were combined. The layers were separated and the organic layer was washed with brine and water. The combined aqueous layers were extracted with THF and the combined organic layers were dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>). The precipitate was filtered off, washed with a small amount of CH<NUM>Cl<NUM> and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)ethanone 11a (<NUM>).

A stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)ethanone 11a (<NUM>, <NUM> mmol) in THF (<NUM>) was cooled to <NUM>. A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise. The reaction mixture was stirred at room temperature for <NUM>. The solids were removed by filtration and washed with THF. The combined filtrates were evaporated under reduced pressure. The residue was triturated with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solids were isolated by filtration, washed with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>) and dried under vacuum at <NUM> to provide <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)ethanone 11b (<NUM>) as a solid.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>/-/-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)ethanone 11b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>, washed with 1N HCl and water, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was dried under vacuum at <NUM> to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>,<NUM>-dihydro-<NUM>H-furo[<NUM>,<NUM>-g]indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture.

The chiral separation of the enantiomers of Compound <NUM> (<NUM>) was performed via Preparative SFC (Stationary phase: Chiralpak® Diacel AS <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 11A as the first eluted product and Enantiomer 11B as the second eluted product. Enantiomer 11A was further purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: EtOAc:EtOH (<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined and evaporated under reduced pressure. The solid residue was dried under vacuum at <NUM> to provide Enantiomer 11A (<NUM>). Enantiomer 11B was purified by Preparative SFC (Stationary phase: Chiralpak® Diacel AD <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure. The residue was further purified by column chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase:
EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined and evaporated under reduced pressure. The solid residue was washed with MeOH and dried under vacuum at <NUM> to provide Enantiomer 11B (<NUM>) as a white powder.

N-iodosuccinimide (<NUM>, <NUM> mmol) was added to a cooled (<NUM>) solution of <NUM>-fluoro-<NUM>-methoxy-<NUM>-methylaniline [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>), and the reaction mixture was stirred at <NUM> for <NUM>. The reaction mixture was diluted with EtOAc (<NUM>), washed with water (<NUM>) and brine (<NUM>), dried over MgSO<NUM>, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient <NUM> to <NUM>% EtOAc in petroleum ether) to provide <NUM>-fluoro-<NUM>-iodo-<NUM>-methoxy-<NUM>-methylaniline 12a (<NUM>) as a gray solid.

A mixture of <NUM>-fluoro-<NUM>-iodo-<NUM>-methoxy-<NUM>-methylaniline 12a (<NUM>, <NUM> mmol), Copper(I) iodide (<NUM>, <NUM> mmol), bis(triphenylphosphine)palladium(II) chloride (<NUM>, <NUM> mmol) and trimethylsilylacetylene (<NUM>, <NUM> mmol) in triethylamine (<NUM>) was heated at <NUM> for <NUM> under N<NUM>-atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was suspended in water (<NUM>) and extracted with EtOAc (2x <NUM>). The combined organic layers were washed with brine (2x <NUM>), dried over MgSO<NUM>, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: <NUM> to <NUM>% EtOAc in petroleum ether) to provide <NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>-((trimethylsilyl)ethynyl)aniline 12b (<NUM>) as gray solid.

Potassium tert-butoxide (<NUM>, <NUM> mmol) was added to a solution of <NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>-((trimethylsilyl)ethynyl)aniline 12b (<NUM>, <NUM> mmol) in NMP (<NUM>) at room temperature. The reaction mixture was stirred at <NUM> for <NUM>. The reaction was diluted with H<NUM>O (<NUM>) and extracted with EtOAc (2x <NUM>). The combined organic layers were washed with brine (3x <NUM>), dried over MgSO<NUM>, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: <NUM> to <NUM>% EtOAc in petroleum ether) to give <NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>/-/-indole 12c (<NUM>) as a yellow solid.

Diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise, to a cooled (<NUM>) solution of <NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>H-indole 12c (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) under a N<NUM>-atmosphere. After stirring for <NUM> at <NUM>, a solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added dropwise to the reaction mixture. Stirring was continued at <NUM> for <NUM> and the mixture was allowed to warm to room temperature while stirring for <NUM>. The reaction mixture was poured out into ice-water containing excess Rochelle salt. After warming to room temperature, the mixture was filtered on a short pad of dicalite® and the filter cake was rinsed several times with THF. The layers were separated. The organic layer was washed with brine and water, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The solid residue was suspended in CH<NUM>Cl<NUM> (<NUM>) and the solids were filtered off, washed with a small amount of CH<NUM>CI<NUM> and dried under vacuum at <NUM> to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 12d (<NUM>).

A solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise to a cooled (<NUM>) solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 12d (<NUM>, <NUM> mmol) in THF (<NUM>), and the reaction mixture was allowed to warm to room temperature while stirring for <NUM>. The reaction mixture was filtered and the solids were washed with THF. The filtrate was evaporated under reduced pressure. The residual brown solid was triturated with a small amount of CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>). The solids were filtered off and washed with CH<NUM>Cl<NUM>/heptane (<NUM>/<NUM>) to give <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 12e (<NUM>) as a white solid. The product was used without further purification in the next step.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 12e (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>µL, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated under reflux overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in CH<NUM>Cl<NUM>. The organic solution was washed with 1N HCl, water, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (Stationary phase: Biotage® SNAP Ultra <NUM>, Mobile phase: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined and evaporated under reduced pressure. The residue (<NUM>) was further purified via Preparative HPLC (Stationary phase: Uptisphere® C18 ODB - <NUM>, <NUM>, <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The product fractions were combined and evaporated under reduced pressure to provide racemic2-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>).

The enantiomers of Compound <NUM> (<NUM>) were separated via Preparative SFC (Stationary phase: Chiralcel® Diacel OD <NUM> × <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 12A as the first eluted product and Enantiomer 12B as the second eluted product. Both enantiomers were further purified by column chromatography (Biotage® SNAP Ultra silica <NUM>, eluent: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined and evaporated under reduced pressure. The solid residues were dried under vacuum at <NUM> to provide Enantiomer 12A (<NUM>) and Enantiomer 12B (<NUM>) as a white powders.

<NUM> HCl in dioxane (<NUM>, <NUM> mmol) was added dropwise to a stirred solution of <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) in dioxane (<NUM>) under N<NUM>-atmosphere. The resulting white mixture was vigorously stirred for <NUM> minutes. Phosphorous oxychloride (<NUM>, <NUM> mmol) was added slowly, and the reaction mixture was stirred at room temperature for <NUM> days. The reaction mixture was poured out into ice-water (<NUM>). After stirring for <NUM>, the solvent was concentrated under reduced pressure to a residual volume of ~<NUM>. Et<NUM>O (<NUM>) was added, causing precipitation. The solids were removed by filtration, washed with water and discarded. The filtrate was purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - <NUM>, <NUM> × <NUM>, Mobile phase: water, CH<NUM>CN). The fractions containing product 13a were combined. Evaporation of the organic volatiles under reduced pressure caused precipitation of the product in multiple consecutive crops. The solids were isolated by filtration and dried at <NUM> under vacuum to provide <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethyl dihydrogen phosphate 13a (total amount (<NUM> crops): <NUM>).

Diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise at <NUM> to a solution of <NUM>-fluoro-<NUM>H-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>). After stirring for <NUM> at <NUM>, a solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added slowly at <NUM>. The reaction was stirred at <NUM> for <NUM>. Ice-water was added and the precipitate was filtered off, washed with water and a small amount of CH<NUM>Cl<NUM>. The solids were dried under vacuum at <NUM> overnight to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13b (<NUM>).

At <NUM>, phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) was added in portions to a stirred solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13b (<NUM>, <NUM> mmol) in THF (<NUM>). The reaction mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with THF (2x). The combined filtrated were added to a solution of diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) and DMF (<NUM>). 13a (<NUM>, <NUM> mmol) was added and the reaction mixture was stirred at room temperature for <NUM> and at <NUM> for <NUM> days. The volatiles were evaporated under reduced pressure. The residue was purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD - <NUM>, <NUM> x <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The product fractions were combined and co-evaporated with xylene under reduced pressure. The residue was dried under vacuum at <NUM> for <NUM> hours, stirred up in CH<NUM>CN, filtered off, washed with CH<NUM>CN (3x), and dried under vacuum at <NUM> to provide <NUM>-(<NUM>-((<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)-<NUM>-oxoethyl)amino)-<NUM>-methoxyphenoxy)ethyl dihydrogen phosphate (Compound <NUM>-P, <NUM>) as a racemic mixture.

The enantiomers of Compound <NUM>-P were separated via Chiral SFC (Stationary phase: Chiralpak® Daicel ID <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The fractions containing product were combined and evaporated under reduced pressure to provide 13A-P as the first eluted enantiomer and 13B-P as the second eluted enantiomer. The first eluted enantiomer was further purified via preparative SFC (Stationary phase: Chiralpak® Daicel ID <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The desired fractions were combined, evaporated under reduced pressure and co-evaporated with EtOAc. The residual solid was dried under vacuum at <NUM> to provide Enantiomer 13A-P (<NUM>, iPrNH<NUM>-salt). The second eluted enantiomer was taken up with DIPE/EtOAc (<NUM>/<NUM>). The solids were filtered off, washed with DIPE (5x) and dried under vacuum at <NUM> to give Enantiomer 13B-P (<NUM>, iPrNH<NUM>-salt).

At <NUM>, a solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise to a mixture of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13b (<NUM>, <NUM> mmol) in THF (<NUM>). The mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with EtOAc. The combined filtrates were concentrated under reduced pressure. The residue was taken up with EtOAc and washed with water. A precipitate appeared in the organic layer and was filtered off and dried to provide a first batch of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13c (<NUM>). The organic layer was separated, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc. The precipitate was filtered off, washed with Et<NUM>O and dried under vacuum to provide a second fraction of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13c (<NUM>).

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)ethanone 13c (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and triethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was heated in a sealed tube at <NUM> for <NUM> using a microwave Biotage® Initiator EXP <NUM> with a power output ranging from <NUM> to <NUM> W (fixed hold time). The reaction was diluted with CH<NUM>Cl<NUM> and the organic layer was washed with water, dried over MgSO<NUM>, filtered and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (<NUM>-<NUM>, <NUM>) using a heptane/EtOAc gradient of <NUM>/<NUM> to <NUM>/<NUM>. The pure fractions were combined and concentrated to give <NUM> of Compound <NUM>. This fraction was combined with another batch of <NUM> of Compound <NUM> and subsequently purified via achiral SFC (Stationary phase: CYANO <NUM> <NUM> x <NUM>, Mobile phase: <NUM>% CO<NUM>, <NUM>% MeOH) to provide <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-fluoro-<NUM>H-indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>, <NUM>) as a racemic mixture. The enantiomers of Compound <NUM> (<NUM>) were separated via Chiral SFC (Stationary phase: Chiralcel® OJ <NUM> x <NUM>, Mobile phase: <NUM>% CO<NUM>, <NUM>% MeOH) yielding <NUM> of the first eluted enantiomer and <NUM> of the second eluted enantiomer. The first eluted enantiomer was taken up with CH<NUM>CN/diisopropyl ether/heptane. The precipitate was filtered off and dried to give Enantiomer 13A (<NUM>) as an amorphous powder. The second eluted enantiomer was taken up with CH<NUM>CN/diisopropyl ether/heptane. The precipitate was filtered off and dried to give Enantiomer 13B (<NUM>) as an amorphous powder.

A stirring solution of Enantiomer 13A (<NUM>, <NUM> mmol) in dioxane (<NUM>), under N<NUM>-atmosphere, was cooled on an ice-bath. <NUM> HCl in dioxane (<NUM>µL, <NUM> mmol) was added, followed by phosphorous oxychloride (<NUM>µL, <NUM> mmol). The ice-bath was removed, and the reaction mixture was stirred for <NUM> minutes. Extra phosphorous oxychloride (<NUM>µL) was added and the reaction mixture was stirred at room temperature for <NUM>. The reaction mixture was quenched by the addition of crushed ice (<NUM>). After stirring for <NUM>, the organic volatiles were evaporated under reduced pressure until a residual volume of ~<NUM>. The aqueous solution was purified via preparative HPLC (Stationary phase: RP XBridge® Prep C18 OBD-<NUM>, <NUM> x <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, CH<NUM>CN). The fractions containing product were combined and the organic volatiles were evaporated under reduced pressure. The remaining aqueous solution was co-evaporated with xylene to dryness. The residue was dissolved in CH<NUM>CN and evaporated under reduced pressure to dryness. The residue was triturated with Et<NUM>O. The solids were filtered off, washed with Et<NUM>O (2x), and dried under vacuum at <NUM> to provide Enantiomer 13A-P (<NUM>).

Copper(II) acetate (<NUM>, <NUM> mmol) was added to a stirring solution of Enantiomer 13A (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) at room temperature. The reaction mixture was heated at <NUM> for <NUM>. The reaction mixture was evaporated to dryness under reduced pressure and the black residue was taken up with CH<NUM>Cl<NUM> and water. The layers were separated. The aqueous layer was extracted again with CH<NUM>Cl<NUM>. The combined organic layers were dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue, containing crude intermediate 13d was dissolved in MeOH (<NUM>). Sodium cyanoborodeuteride (<NUM>, <NUM> mmol) and acetic acid (<NUM>µL, <NUM> mmol) were added, and the reaction mixture was stirred at room temperature overnight under N<NUM>-atmosphere. The solvent was evaporated under reduced pressure. Water, aqueous NaHCOs and CH<NUM>Cl<NUM> were added and the layers were separated. The aqueous layer was extracted again with CH<NUM>Cl<NUM>. The combined organic layers were dried over MgSC<NUM> and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage® SNAP Ultra <NUM>, eluent:
EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined, concentrated under reduced pressure and dried under vacuum at <NUM> to give racemic <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-deuterio-<NUM>-(<NUM>-fluoro-<NUM>-indol-<NUM>-yl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)ethanone (Compound <NUM>-D, <NUM>) as a white solid.

The enantiomers of Compound <NUM>-D (<NUM>) were separated via preparative SFC (Stationary phase: Chiralpak® Diacel AD <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 13A-D as the first eluted product and Enantiomer 13B-D as the second eluted product. Both enantiomers were further purified by column chromatography (Biotage® SNAP Ultra silica <NUM>, eluent: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined, evaporated under reduced pressure and dried under vacuum at <NUM> to give Enantiomer 13A-D (<NUM>, <NUM>% deuterated according to <NUM>H HMR) and Enantiomer 13B-D (<NUM>, <NUM>% deuterated according to <NUM>H HMR) as white solids.

Diethylaluminum chloride <NUM> in hexane (<NUM>, <NUM> mmol) was added dropwise at <NUM> to a solution of <NUM>-methoxy-<NUM>-methyl-<NUM>-indole [<NPL>] (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>). After <NUM> at <NUM>, a solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>Cl<NUM> (<NUM>) was added slowly at <NUM>. The reaction was stirred at <NUM> for <NUM>. Ice-water was added and the precipitate was filtered off and washed with water. The solid was dried under vacuum to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 14a (<NUM>).

At <NUM>, a solution of phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) in THF (<NUM>) was added dropwise to a mixture of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 14a (<NUM>, <NUM> mmol) in THF (<NUM>). The mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was taken up with the minimum of diisopropyl ether. The precipitate was filtered off and dried under vacuum to give <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>-indol-<NUM>-yl)ethanone 14b (<NUM>).

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone 14b (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN/THF (<NUM>/<NUM>) (<NUM>) was stirred at <NUM> for <NUM>. The mixture was concentrated under reduced pressure. The residue was diluted with CH<NUM>Cl<NUM>, washed with 1N HCl and water. The organic layer was separated, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography on silica gel (<NUM>-<NUM>, <NUM> in CH<NUM>Cl<NUM>/MeOH <NUM>/<NUM>). A small amount was crystallized from Et<NUM>O/CH<NUM>CN to give an analytical sample of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>/-/-indol-<NUM>-yl)ethanone (Compound <NUM>) as a racemic mixture. The remaining amount of crude Compound <NUM> (<NUM>) was mixed with another batch (total amount <NUM>) and was further purified twice via preparative LC (Stationary phase: irregular bare silica <NUM>, Mobile phase: CH<NUM>Cl<NUM>/MeOH (<NUM>/<NUM>), and then toluene/iPrOH (<NUM>/<NUM>), prior to chiral separation.

The Enantiomers of Compound <NUM> (<NUM>) were separated via Preparative Chiral SFC (Stationary phase: Chiralpak® IC <NUM> <NUM> x <NUM>, Mobile phase: <NUM>% CO<NUM>, <NUM>% MeOH) to give <NUM> of the first eluted enantiomer and <NUM> of the second eluted enantiomer. The first eluted enantiomer was solidified from CH<NUM>CN/Et<NUM>O to afford Enantiomer 14A (<NUM>) as an amorphous white powder. The second eluted enantiomer was solidified from CH<NUM>CN/Et<NUM>O to afford Enantiomer 14B (<NUM>,) as an amorphous white powder.

Copper(II) acetate (<NUM>, <NUM> mmol) was added to a stirring solution of Enantiomer 14B (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) at room temperature. The reaction mixture was heated at <NUM> for <NUM>, and was subsequently kept at room temperature overnight. The reaction mixture was evaporated to dryness and the black residue was taken up with CH<NUM>Cl<NUM> and water. The layers were separated. The aqueous layer was extracted again with CH<NUM>Cl<NUM>. The combined organic layers were washed with water, dried over MgSO<NUM>, filtered, and evaporated under reduced pressure. The residue, containing crude intermediate 14c was dissolved in MeOH (<NUM>) and the solution was degassed with N<NUM> for <NUM>. Sodium cyanoborodeuteride (<NUM>, <NUM> mmol) and acetic acid (<NUM>µL, <NUM> mmol) were added and the reaction mixture was stirred at room temperature under N<NUM>-atmosphere for <NUM>. Aqueous NaHCOs and EtOAc were added and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layers were dried over MgSO<NUM> and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage® SNAP Ultra silica <NUM>, eluent: EtOAc:EtOH(<NUM>:<NUM>)/heptane gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined, evaporated under reduced pressure and dried under vacuum at <NUM> to give racemic <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-deuterio-<NUM>-((<NUM>-(<NUM>-hydroxyethoxy)-<NUM>-methoxyphenyl)amino)-<NUM>-(<NUM>-methoxy-<NUM>-methyl-<NUM>H-indol-<NUM>-yl)ethanone (Compound <NUM>-D, <NUM>) as a yellow solid.

The enantiomers of Compound <NUM>-D (<NUM>) were separated via preparative SFC (Stationary phase: Chiralpak® Diacel AD <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 14A-D as the first eluted product and Enantiomer 14B-D as the second eluted product. Both enantiomers were dissolved in MeOH (<NUM>) and water was added dropwise until the solution became cloudy. The mixtures were then stirred until a white solid appeared. The white solids were filtered off, washed with a small amount of MeOH/water (<NUM>/<NUM>) and dried under vacuum at <NUM> to provide Enantiomer 14A-D (<NUM>, <NUM>% deuterated according to <NUM> H NMR) and Enantiomer 14B-D (<NUM>, <NUM>% deuterated according to <NUM> H NMR) as white solids.

At <NUM>, under a N<NUM> flow, sodium hydride (<NUM>% in oil, <NUM>, <NUM> mmol) was added portionwise to a mixture <NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>H-indole [<NPL>] (<NUM>, <NUM> mmol) in DMF (<NUM>). The mixture was stirred at <NUM> for <NUM>. A solution of tosyl chloride (<NUM>, <NUM> mmol) in DMF (<NUM>) was added dropwise. The ice-bath was removed and the mixture was stirred at room temperature for <NUM>. The mixture was poured out in ice-water (<NUM>) and vigorously stirred for <NUM>. The precipitate was filtered off, washed with water (4x) and dried at <NUM> under vacuum to give <NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>-tosyl-<NUM>H-indole 15a (<NUM>).

Titanium(IV) chloride (<NUM>µL, <NUM> mmol) was added dropwise at room temperature to a stirred solution of <NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>-tosyl-<NUM>H-indole 15a (<NUM>, <NUM> mmol) and <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)acetyl chloride 9a' (<NUM>, <NUM> mmol) in CH<NUM>CH<NUM> (<NUM>). The reaction was stirred at room temperature for <NUM>. Crushed ice (<NUM>) was added, and after stirring for <NUM>, the layers were separated. The organic layer was dried over MgSO<NUM>, filtered, and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Stationary phase: Grace Reveleris® silica <NUM>, Mobile phase: heptane/CH<NUM>Cl<NUM> gradient <NUM>/<NUM> to <NUM>/<NUM>). The product fractions were combined. The solvent was evaporated under reduced pressure and co-evaporated with dioxane. The residue was dried under vacuum at <NUM> to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>-tosyl-<NUM>H-indol-<NUM>-yl)ethanone 15b (<NUM>).

Potassium hydroxide (<NUM>, <NUM> mmol) was added to a solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>-tosyl-<NUM>H-indol-<NUM>-yl)ethanone 15b (<NUM>, <NUM> mmol) in dioxane (<NUM>) and water (<NUM>). The mixture was stirred at room temperature for <NUM>. Ice-water (<NUM>) and 1N HCl (<NUM>) were added and the product was extracted with <NUM>-Me-THF (2x). The combined organic layers were washed with brine, dried over MgSO<NUM>, filtered and the solvent was evaporated under reduced pressure. The solid residue was stirred up with in CH<NUM>Cl<NUM>. The precipitate was filtered off, washed with CH<NUM>Cl<NUM> (4x <NUM>) and dried to give <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>H-indol-<NUM>-yl)ethanone 15c (<NUM>).

At <NUM>, phenyltrimethylammonium tribromide [<NPL>] (<NUM>, <NUM> mmol) was added to a solution of <NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>H-indol-<NUM>-yl)ethanone 15c (<NUM>, <NUM> mmol) in THF (<NUM>). The mixture was stirred at <NUM> for <NUM> and at room temperature for <NUM>. The precipitate was filtered off and washed with THF (2x). The combined filtrates were concentrated under reduced pressure to provide <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>H-indol-<NUM>-yl)ethanone 15d (<NUM>) which was without further purification in the next step.

A mixture of <NUM>-bromo-<NUM>-(<NUM>-chloro-<NUM>-methoxyphenyl)-<NUM>-(<NUM>-(pentafluoro-λ<NUM>-sulfanyl)-<NUM>H-indol-<NUM>-yl)ethanone 15d (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino-<NUM>-methoxyphenoxy)ethanol [<NPL>] (<NUM>, <NUM> mmol) and diisopropylethylamine (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was stirred at room temperature for <NUM>. Water (<NUM>) was added and the product was extracted with Et<NUM>O (2x). The combined organic layers were washed with brine, dried over MgSO<NUM>, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Stationary phase: Biotage® SNAP Ultra silica <NUM>, Mobile phase: heptane/EtOAc/EtOH gradient <NUM>/<NUM>/<NUM> to <NUM>/<NUM>/<NUM>). The desired fractions were combined and evaporated under reduced pressure. The residue was further purified by preparative HPLC (Stationary phase: RP XBridge® Prep C18 ODB - <NUM>, <NUM> x <NUM>, Mobile phase: <NUM>% NH<NUM>HCO<NUM> solution in water, MeOH). The product fractions were combined and concentrated under reduced pressure to give racemic Compound <NUM> (<NUM>). The enantiomers were separated via Preparative Chiral SFC (Stationary phase: Chiralpak® Diacel AS <NUM> x <NUM>, Mobile phase: CO<NUM>, EtOH + <NUM>% iPrNH<NUM>). The product fractions were combined and evaporated under reduced pressure to provide Enantiomer 15A as the first eluted product and Enantiomer 15B as the second eluted product. Both enantiomers were solidified by precipitation from a solvent mixture of MeOH and water. The solids were filtered off and dried at <NUM> under vacuum to provide Enantiomer 15A (<NUM>) and Enantiomer 15B (<NUM>).

The antiviral activity of all the compounds of the invention was tested against the DENV-<NUM><NUM> strain which was labeled with enhanced green fluorescent protein (eGPF). The culture medium consists of minimal essential medium supplemented with <NUM>% of heat-inactivated fetal calf serum, <NUM>% gentamycin (<NUM>/mL) and <NUM> of L-glutamine. Vero cells, obtained from ECACC, were suspended in culture medium and <NUM>µL was added to <NUM>-well plates (<NUM> cells/well), which already contain the antiviral compounds. Typically, these plates contain a <NUM>-fold serial dilution of <NUM> dilution steps of the test compound at <NUM> times the final concentration in <NUM>% DMSO (<NUM> nL). In addition, each compound concentration is tested in quadruplicate (final concentration range: <NUM> - <NUM> or <NUM> - <NUM> 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, <NUM>µL of culture medium was added instead of Vero cells. Once the cells were added to the plates, the plates were incubated for <NUM> minutes at room temperature to allow the cells to distribute evenly within the wells. Next, the plates were incubated in a fully humidified incubator (<NUM>, <NUM>% CO<NUM>) until the next day. Then, DENV-<NUM> strain <NUM>, labeled with eGFP, was added at a multiplicity of infection (MOI) of <NUM>. Therefore, <NUM>µL of virus suspension was added to all the wells containing test compound and to the wells assigned as virus control. In parallel, <NUM>µL of culture medium was added to the medium and cell controls. Next, the plates were incubated for <NUM> days in a fully humidified incubator (<NUM>, <NUM>% CO<NUM>). At the day of the read out, the eGFP fluorescence was measured using an automated fluorescence microscope at <NUM> (blue laser). Using an in-house LIMS system, inhibition dose response curves for each compound were calculated and the half maximal effective concentration (EC<NUM>) was determined. Therefore, the percent inhibition (I) for every test concentration is calculated using the following formula: I = <NUM>*(ST-SCC)/(SVC-SCC); ST, See and Svc are the amount of eGFP signal in the test compound, cell control and virus control wells, respectively. The EC<NUM> represents the concentration of a compound at which the virus replication is inhibited with <NUM>%, as measured by a <NUM>% reduction of the eGFP fluorescent intensity compared to the virus control. The EC<NUM> is calculated using linear interpolation (Table <NUM>).

In parallel, the toxicity of the compounds was assessed on the same plates. Once the read-out for the eGFP signal was done, <NUM>µL of ATPlite, a cell viability stain, was added to all wells of the <NUM>-well plates. ATP is present in all metabolically active cells and the concentration declines 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 <NUM> minutes at room temperature. Next, the plates were measured on a ViewLux. The half maximal cytotoxic concentration (CC<NUM>) was also determined, defined as the concentration required to reduce the luminescent signal by <NUM>% compared to that of the cell control wells. Finally, the selectivity index (SI) was determined for the compounds, which was calculated as followed: SI = CC<NUM>/EC<NUM>.

The antiviral activity of the compounds of the invention was tested against DENV-<NUM> strain TC974#<NUM> (NCPV), DENV-<NUM> strain <NUM>, DENV-<NUM> strain H87 (NCPV) and DENV-<NUM> strain H241 (NCPV) in a RT-qPCR assay. Therefore, Vero cells were infected with either DENV-<NUM>, or -<NUM>, or -<NUM>, or -<NUM> in the presence or absence of test compounds. At day <NUM> post-infection, the cells were lysed and cell lysates were used to prepare cDNA of both a viral target (the <NUM>'UTR of DENV; Table <NUM>) and a cellular reference gene (β-actin, Table <NUM>). 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 replication by a test compound result in a shift of Cp's for the <NUM>'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 ΔΔCp method is used to calculate EC<NUM>, which is based on the relative gene expression of the target gene (<NUM>'UTR) normalized with the cellular housekeeping gene (β-actin). In addition, CC<NUM> values are determined based on the Cp values acquired for the housekeeping gene β-actin.

The culture medium consisted of minimal essential medium supplemented with <NUM>% of heat-inactivated fetal calf serum, <NUM>% gentamycin (<NUM>/mL) and <NUM> of L-glutamine. Vero cells, obtained from ECACC, were suspended in culture medium and 75µL/well was added in <NUM>-well plates (<NUM> cells/well), which already contain the antiviral compounds. Typically, these plates contain a <NUM>-fold serial dilution of <NUM> dilution steps of the test compound at <NUM> times the final concentration in <NUM>% DMSO (<NUM> nL; final concentration range: <NUM> - <NUM> or <NUM> - <NUM> 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 (<NUM>, <NUM>% CO<NUM>) until the next day. Dengue viruses serotype-<NUM>, <NUM>, <NUM> and <NUM> were diluted in order to obtain a Cp of ~<NUM>-<NUM> in the assay. Therefore, <NUM>µL of virus suspension was added to all the wells containing test compound and to the wells assigned as virus control. In parallel, <NUM>µL of culture medium was added to the cell controls. Next, the plates were incubated for <NUM> days in a fully humidified incubator (<NUM>, <NUM>% CO<NUM>). After <NUM> days, the supernatant was removed from the wells and the cells were washed twice with ice-cold PBS (~100µL). The cell pellets within the <NUM>-well plates were stored at -<NUM> for at least <NUM> day. Next, RNA was extracted using the Cells-to-CT™ lysis kit, according to the manufacturer's guideline (Life Technologies). The cell lysates can be stored at -<NUM> or immediately used in the reverse transcription step.

In preparation of the reverse transcription step, mix A (table 3A) was prepared and <NUM>µL/well was dispensed in a <NUM>-well plate. After addition of <NUM>µL of the cell lysates, a five minute denaturation step at <NUM> was performed (table 3B). Afterwards, <NUM>µL 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 <NUM>µL/well was dispensed in <NUM>-well LightCycler qPCR plates to which <NUM>µL of cDNA was added and the qPCR was performed according to the conditions in table 4B on a LightCycler <NUM>.

Using the LightCycler software and an in-house LIMS system, dose response curves for each compound were calculated and the half maximal effective concentration (EC<NUM>) and the half maximal cytotoxic concentration (CC<NUM>) were determined (Tables <NUM>-<NUM>).

Compound (<NUM>) disclosed in <CIT> has been tested in an analogous DENV-<NUM> antiviral assay as the compounds of the present invention and their reported activity is listed below.

Claim 1:
A compound of formula (la, Ib, II, III or IV), wherein formula (Ia) is represented by:
<CHM>
a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:
R<NUM> is Cl, R<NUM> is H, R<NUM> is CH<NUM>;
R<NUM> is Cl, R<NUM> is OCH<NUM>, R<NUM> is H;
R<NUM> is CH<NUM>, R<NUM> is F or OCF<NUM> or H or OCH<NUM>CH<NUM> and R<NUM> is H;
R<NUM> and R<NUM> are connected forming a heterocycle of <NUM> members having one oxygen atom, R<NUM> is H;
R<NUM> and R<NUM> are connected forming a heterocycle of <NUM> members having one oxygen atom, R<NUM> is H;
or wherein formula (Ib) is represented by:
<CHM>
a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof; said compound is selected from the group wherein:
R<NUM> is CH<NUM>, R<NUM> is F, R<NUM> and R<NUM> are both H;
R<NUM> is CH<NUM>, R<NUM> is OCH<NUM>, R<NUM> is H, R<NUM> is F;
R<NUM> is SF<NUM>, R<NUM> = R<NUM> = R<NUM> are all H;
R<NUM> and R<NUM> are connected forming a heterocycle of <NUM> members having one oxygen atom, R<NUM> and R<NUM> are both H;
R<NUM> and R<NUM> are connected forming a heterocycle of <NUM> members having one oxygen atom, R<NUM> and R<NUM> are both H;
and wherein compounds (II, III and IV) respectively are represented by:
<CHM>
<CHM>
<CHM>
or a stereoisomeric form, a pharmaceutically acceptable salt, solvate or polymorph thereof.