WO2023237730A1

WO2023237730A1 - Rsv inhibiting triazolo and spiro bearing derivatives

Info

Publication number: WO2023237730A1
Application number: PCT/EP2023/065473
Authority: WO
Inventors: Sandrine Céline Grosse; Minh Thao TRAN; Eric Tan; Edgar Jacoby; Ferdinand Hermann LUTTER; Manuel Jesús Alcázar Vaca; Tim Hugo Maria Jonckers
Original assignee: Janssen Sciences Ireland Unlimited Company
Priority date: 2022-06-10
Filing date: 2023-06-09
Publication date: 2023-12-14

Abstract

The invention concerns compounds having antiviral activity, in particular having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment or prevention of respiratory syncytial virus infection (I).

Description

RSV INHIBITING TRIAZOLO AND SPIRO BEARING DERIVATIVES

Field of the Invention

The invention concerns compounds having antiviral activity, in particular having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment or prevention of respiratory syncytial virus infection.

Background

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Pneumoviridae, genus Orthopneumovirus together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.

Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.

Today only two drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue that provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. Synagis® (palivizumab a monoclonal antibody, is used for passive immunoprophylaxis. Although the benefit of Synagis® has been demonstrated, the treatment is expensive, requires parenteral administration and is restricted to children at risk for developing severe pathology.

Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. It would be particularly preferred to provide drugs against RSV replication that could be administered perorally. Compounds that exhibit anti-RSV activity are disclosed in WO-2021/214136, WO-2014/031784, WO-2015/026792, WO-2016/138158 and WO2021/066922.

Detailed description of the Invention The present invention relates to compounds of formula (I)

including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom

wherein each of the groups is optionally substituted with one, two or three substituents R⁶, R⁷ and R⁸ each independently selected from halo; hydroxy; C^alkyl; C^alkyloxy; C_3-6cycloalkyl; C_3-6cycloalkyloxy; polyhaloC_1-4alkyl; polyhaloC_1-4alkyloxy; C_1-4alkyl substituted with hydroxy; or C_3-6cycloalkyl substituted with halo or hydroxy; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl, imidazolyl,

pyridinyl or benzothiophenyl, wherein the aromatic mono- or bicyclic ring is substituted with one, two or three substituents each independently selected from hydrogen, halo, C_1-6alkyl or p^olyhaloC _1-6 ^alkyl; W is N or CR⁹ wherein R⁹ is halo; R¹ is C_1-4alkyl, halo, hydroxy, amino, C_1-4alkyloxy, polyhaloC_1-4alkyloxy, C_1-4alkyl-carbonyl- a^{mino, C} _1-4 ^alkyl-oxy-C _1-4 ^{alkyl, C} _1-4 ^{alkylamino, polyhaloC} _1-4 ^alkylamino, isoindolinedionyl, or C_1-4alkyl substituted with amino or mono-or di(C_1-4alkyl)amino; X is O, C(=O), or CR¹⁰R¹¹ wherein R¹⁰ and R¹¹ are each independently hydrogen, C_1-4alkyl, halo, hydroxy; or alternatively R⁹ and R¹⁰ are taken together to form C_3-6cycloalkyl; Y is CH₂ or C(=O); Z is CH₂; when n = 1 then the -Y-Z- radical may form R² is hydrogen, halo, hydroxy, C_1-4alkyl, or

R³ is C_1-4alkyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, hydroxy, amino, C_1-4alkyl-SO₂-amino, or C_1-4alkyl-carbonyl-amino; R⁴ is hydrogen, halo, hydroxy, C_1-4alkyl, or C_1-4alkyloxy; R⁵ is hydrogen or C_1-4alkyl; or a pharmaceutically acceptable addition salt thereof. As used in the foregoing definitions : - halo is generic to fluoro, chloro, bromo and iodo; - C_1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl- propyl and the like; and - polyhaloC_1-4alkyl is defined as polyhalosubstituted C_1-4alkyl, in particular C_1-4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like - C_3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; - -(C=O) or (CO) means carbonyl. The term “compounds of the invention” as used herein, is meant to include the compounds of formula (I), and the salts and solvates thereof.

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

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

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

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example, if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

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

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

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

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

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

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

It follows that a single compound may exist in both stereoisomeric and tautomeric form.

Atropisomers (or atropoisomers) are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.

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

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol. The term ‘hydrate’ is used when said solvent is water. For the avoidance of doubt, compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound. Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such _{as deuterium,} ¹³ _C, ¹⁴ _C, ¹⁴ _N, ¹⁵ _{O or the like.} In an embodiment the present invention relates to compounds of formula (I)

including any stereochemically isomeric form thereof, wherein is selected from the group set forth below by removal of a hydrogen atom

and is optionally substituted with one, two or three substituents R⁶, R⁷ and R⁸ each i^{ndependently selected from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^cycloalkyl, ^C _3-6 ^{cycloalkyloxy, polyhaloC} _1-4 ^{alkyl, polyhaloC} _1-4 ^{alkyloxy, or C} _3-6 ^{cycloalkyl substituted} with halo; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic monocyclic ring selected from phenyl substituted with one substituent

selected from hydrogen or halo; W is N or CR⁹ wherein R⁹ is halo; R¹ is C_1-4alkyl, halo, hydroxy, amino, or polyhaloC_1-4alkyloxy; _{X is CR} ¹⁰ _R ¹¹ _{wherein R} ¹⁰ _{and R} ¹¹ _{are hydrogen;} Y is CH₂; Z is CH₂; R² is hydrogen; R³ is C_1-4alkyl substituted with 1 substituent selected from hydroxy; _R ⁴ _{is halo;} R⁵ is hydrogen; or a pharmaceutically acceptable addition salt thereof. In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (II) :

wherein ring B, R¹, R², R³, R⁴, R⁵, W, X, Y Z, n and m are as defined for compounds of formula (I) and R⁶ is selected from halo, C_1-4alkyl, C_1-4alkyloxy, C_3-6cycloalkyl, C_3-6cycloalkyloxy, polyhaloC_1-4alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo. In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (III) :

- 8 - wherein ring B, R², R³, R⁴ and W are as defined for compounds of formula (I) and R⁶ is selected ^{from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^{cycloalkyl, C} _3-6 ^{cycloalkyloxy, polyhaloC} _1-4 ^alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo. In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (IV) :

wherein ring B, R², R³, R⁴ and W are as defined for compounds of formula (I) and R⁶ is selected ^{from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^{cycloalkyl, C} _3-6 ^{cycloalkyloxy, polyhaloC} _1-4 ^alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo. In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (V) :

wherein ring B, R², R³, R⁴ and W are as defined for compounds of formula (I) and R⁶ is selected ^{from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^{cycloalkyl, C} _3-6 ^{cycloalkyloxy, polyhaloC} _1-4 ^alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo. In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (VI) :

that is substituted with one substituent R⁶ selected from C_1-4alkyloxy; is phenyl substituted with halo; _{X is CR} ¹⁰ _R ¹¹ _{wherein R} ¹⁰ _{and R} ¹¹ _{are hydrogen;} Y is CH₂; Z is CH₂; W is N; n is integer 0, 1 or 2: R² is hydrogen; R³ is C_1-4alkyl substituted with 1 substituent selected from hydroxy; R⁴ is halo; and R⁵ is hydrogen; or a pharmaceutically acceptable addition salt thereof. Particular compounds of formula (VI) are those compounds of formula (VI) wherein is 8-methoxyquinolin-6-yl;

is 4-fluorophenyl; and R³ is C(CH₃)₂OH. - 10 -

Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply : a) ring A is quinoline substituted with C^alkyloxy; b) ring B is phenyl substituted with halo; or c) ring B is 4-fluorophenyl; or e) R² is hydrogen, R³ is C^alkyl substituted with hydroxy, and R⁴ is halo; f) R⁵ is hydrogen; g) X is CR¹⁰Rⁿ wherein R¹⁰ and R¹¹ are hydrogen, Y is CH₂, n is integer 0, and m is integer 0; h) X is CR¹⁰Rⁿ wherein R¹⁰ and R¹¹ are hydrogen, Y is CH₂, Z is CH₂, n is integer 1, and m is integer 0; and i) X is CR¹⁰Rⁿ wherein R¹⁰ and R¹¹ are hydrogen, Y is CH₂, Z is CH₂, n is integer 2, and m is integer 0.

General synthetic methods

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein. Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

In some embodiments, compounds of the formula (I) wherein R⁵ is hydrogen, represented as compounds of formula (La), may be synthesized according to Scheme 1.

In Scheme 1, the ring A, ring B, and substituents R¹, R², R³, R⁴, R⁵, W, X, Y Z, and integers n and m are as defined for compounds of formula (I), or any variation thereof as described above.

The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

Other synthetic pathways for preparing compounds of formula (I) have been described in the experimental party as general methods of preparation and specific working examples.

The starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. 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.

Particular examples are provided in the Example section below. It is understood that the schemes above may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials.

The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. in Antiviral Research, 38, p. 31 - 42 (1998).

Additionally the present invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of formula (I), and another antiviral agent, in particular a RSV inhibiting compound.

In order to prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or addition salt form, as the active ingredient is combined in intimate admixture with at least one 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, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection.

For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection compositions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient. Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment. Addition salts of the compounds of formula (I), due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

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

For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e.g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,r,6'-trichloro-4,r,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the said concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation. The bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results. In the high- dosage formulations, stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like. Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume).

Combinations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intra-muscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.

In general it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder 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 said effective daily 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 daily amount ranges mentioned hereinabove are therefore only guidelines.

Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections. Other antiviral compounds (b) to be combined with a compound of formula (I) for use in the treatment of RSV are RSV fusion inhibitors or RSV polymerase inhibitors. Specific antiviral compounds for combination with any of the compounds of formula (I) that are useful in the treatment of RSV are the RSV inhibiting compounds selected from ribavirin, sisunatovir, ziresovir, lumicitabine, presatovir, ALX-0171, MDT-637, BTA-9881, BMS-433771, YM-543403, A-60444, TMC-353121, RFI-641, CL-387626, MBX-300, 3-({5-chloro-l-[3-(methyl-sulfonyl)propyl]-U/-benzimidazol-2- yl}methyl)-l-cyclopropyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, 3-[[7-chloro-3-(2- ethylsulfonyl-ethyl)imidazo[l,2-a]pyridin-2-yl]methyl]-l-cyclopropyl-imidazo[4,5-c]pyridin-2- one, and 3-({ 5-chloro- l -[3-(methyl-sulfonyl)propyl]- l7/-indol-2-yl J methyl)-! -(2,2,2- trifluoroethyl)-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

Experimental part

General Information

NMR analysis

¹ H NMR spectra were recorded on 1) a Bruker Avance DRX 400 spectrometer or Bruker Advance III 400 spectrometer or 2) a Bruker Avance 500 MHz spectrometer and NMR spectra were recorded at ambient temperature unless otherwise stated. Data are reported as follow: chemical shift in parts per million (ppm) relative to TMS (5 = 0 ppm) on the scale, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintuplet, sex = sextuplet, m = multiplet, b = broad, or a combination of these), coupling constant(s) J in Hertz (Hz).

HPLC and LC-MS

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 15 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 20 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 25 compound was not directly ionizable the type of adduct is specified (i.e. [MUNHt]+, [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 30 Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica. LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes)

Description of SFC Methods

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 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SEC -MS Methods (Flow expressed in mL/min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. “IPrNEh” means isopropylamine, “iPrOH means 2-propanol, “EtOH” means ethanol, min means minutes.

Optical rotation

Optical rotations were measured on a Perkin Elmer 341 polarimeter and reported as follow [a]%^T. X is the wavelength of light used in nm (if the wavelength of light used is 589 nm, the sodium D line, then the symbol D is used) and T is the temperature in degree Celsius. The sign (+ or -) of the rotation is given. The concentration and the solvent of the sample are provided in brackets after the rotation. The rotation is reported in degrees and no units of concentration are given (it is assumed to be g/100 mL).

Stereochemical configuration

The stereochemical configuration for some compounds has been designated as R or S (or *R or *S) when the absolute stereochemistry is undetermined (even if the bonds are drawn stereospecifically) although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. This means that the absolute stereoconfiguration of the stereocentre indicated by * is undetermined (even if the bonds are drawn stereospecifically) although the compound is enantiomerically pure at the indicated centre.

Abbreviations

Synthesis of fluorosulfuryl azide 1

MTBE MeCN

Behind a blast shield, a solution of sodium azide (240 mg, 3.7 mmol) in water (7.4 mL) and tertbutyl methyl ether (7.4 mL) was stirred at room temperature in a loosely sealed plastic tube at 0°C. A solution of l-(fluorosulfonyl)-2,3-dimethyl-lH-imidazol-3-ium trifluoromethanesulfonate (1.45 g, 4.4 mmol) in MeCN (0.4 mL) was added to the plastic tube. The vial that contained l-(fluorosulfonyl)-2,3-dimethyl-lH-imidazol-3-ium trifluoromethanesulfonate was rinsed with extra MeCN (0.37 mL) and added to the plastic tube. The reaction mixture was stirred vigorously at 0°C for 10 minutes, before being poured into a separating funnel. The mixture was rested in the separating funnel at room temperature for 30 minutes until phase separation was observed. The layers were partitioned, and the organic layer containing the product was diluted with DMF (7.4 mL) to yield compound 1 as a 0.2 M solution. The resulting solution was kept in a loosely sealed plastic bottle away from light and was used immediately in subsequent chemistry without further purification. Complete conversion was assumed.

Synthesis of 8-methoxy-6-((trimethylsilyl)ethynyl)quinoline 3

6-Bromo-8 -methoxy quinoline (20 g, 84 mmol), copper(I) iodide (3.2 g, 16.8 mmol), and triethylamine (170 mL) were added to a three-necked round-bottomed flask equipped with a condenser, and the resulting mixture was bubbled through with nitrogen for 30 minutes. TMS- acetylene (35.4 mL, 252 mmol) and PdfPPhs^Ch (11.8 g, 16.8 mmol) were added to the reaction vessel. The resulting mixture was heated to reflux at 78 °C for 16 hours. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and filtered on a pad of Celite, eluting with EtOAc (20 mL). The filtrate was washed with water (50 mL) and brine (50 mL). The organic layer was dried (MgSCU), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (gradient EtOAc/heptane 0: 100 to 100:0) to yield compound 2 as a viscous brown oil, which solidified upon standing (20.2 g, 91%).

In a round bottomed flask equipped with a dropping funnel was added a solution of compound 2 (29.1 g, 113.9 mmol) in dry THF (292 mL). TBAF (1 M in THF, 171 mL, 170.9 mmol) was cannulated into the dropping funnel under nitrogen, and was then added dropwise to the reaction vessel at room temperature. The resulting black solution was stirred at room temperature for 1 hour. The reaction was quenched by dropwise addition of saturated aqueous NaHCCL solution (100 mL). The resulting mixture was diluted with EtOAc (100 mL) and transferred to a separating funnel. The layers were partitioned. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (100 mL), dried (MgSO4), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (gradient EtOAc/heptane 0: 100 to 100:0) to yield compound 3 as a dark red solid (13.9 g, 60%, 90% purity). Synthesis of 2-(3-fluoro-2-(4-fluorophenyl)-6-(2-((4-(8-methoxyquinolin-6-yl)-lH-L2,3-triazol-

1 -yl (methyl )oxetan-2-yl (pyri di n-4-yl )propan-2-ol 6

A VLT tube was charged with [2734049-13-7] (500 mg, 1.4 mmol) in DMSO (4 mL). Sodium azide (266.1 mg, 4.1 mmol) was added at room temperature and the mixture was stirred for 30 minutes at room temperature. The mixture was poured into water and extracted with EtOAc (x 2). The combined organic layers were washed with brine, dried (MgSO4), filtered, and the solvent evaporated to dryness. The residue was purified by column chromatography (gradient EtOAc/heptane 0: 100 to 50:50) to yield compound 4 as a white solid (281 mg, 63%).

A VLT tube was charged with compound 4 (281 mg, 0.8 mmol) and compound 3 (163.1 mg, 0.8 mmol, 95% purity) in MeOH (5 mL) and THF (3.6 mL). To this mixture was added copper (II) sulfate pentahydrate (0.5 M aqueous solution, 0.2 mL, 0.08 mmol) followed by sodium ascorbate (1 M aqueous solution, 0.2 mL, 0.2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was treated with NH4OH solution. The precipitate was filtered off and refluxed in methanol. The precipitate was filtered off and dried under vacuum to yield compound 5 as a white solid (280 mg, 64%).

Trimethyl sulfoxonium iodide (95.1 mg, 0.4 mmol) was added to a microwave vial and purged with positive nitrogen pressure for 15 minutes. To the microwave vial was added dry DMSO (346 μL) and potassium tert-butoxide in THF (1 M, 432 μL, 0.4 mmol). The resulting suspension was stirred at room temperature for 15 minutes, after which the suspension turned into a colorless solution. Compound 5 (89.1 mg, 0.2 mmol) was charged to a second vial and was purged with positive nitrogen pressure for 15 minutes. Dry DMSO (1 mL) and dry THF (1 mL) were then added to the second vial to form a yellow solution, which was cooled to 0ºC. The solution from the microwave vial was added to the second vial at 0ºC, and the resulting red solution was stirred at this temperature for 20 minutes, before being warmed to room temperature. The resulting mixture was stirred at this temperature for 2 hours. The mixture was further warmed to 55ºC and was stirred at this temperature for 24 hours. To the reaction mixture was added water (1 mL) and EtOAc (1 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layers were washed with water (10 mL), brine (5 mL), dried (Na₂SO₄), and the solvent evaporated to dryness. The obtained residue was purified by flash chromatography (gradient MeOH/DCM 0:100 to 10:90). The obtained product was further purified by Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂) to yield compound 6a as a light-yellow foam (13 mg, 14%) and compound 6b as a light yellow foam (13 mg, 14%).

compound 6a 1H NMR (400 MHz, CHLOROFORM-d, 27 ºC) ^ ppm 1.66 - 1.74 (m, 6 H) 1.99 - 2.09 (m, 1 H) 2.79 - 2.90 (m, 1 H) 2.94 - 3.05 (m, 1 H) 4.14 - 4.21 (m, 3 H) 4.22 - 4.30 (m, 1 H) 4.54 - 4.64 (m, 1 H) 4.68 - 4.76 (m, 1 H) 5.27 - 5.37 (m, 1 H) 7.14 - 7.23 (m, 2 H) 7.41 - 7.49 (m, 1 H) 7.63 - 7.71 (m, 1 H) 7.80 - 7.86 (m, 1 H) 7.88 - 7.94 (m, 1 H) 7.96 - 8.03 (m, 2 H) 8.13 - 8.19 (m, 1 H) 8.23 - 8.31 (m, 1 H) 8.88 - 8.95 (m, 1 H) SFC Rt 4.06 min, 100.00%, MW: 543.21, Method SFC_A LCMS Rt 1.92, 100%, MW: 543.20, 544 [M+H]+, 542 [M-H]-, Method A

compound 6b 1H NMR (400 MHz, CHLOROFORM-d, 27 ºC) ^ ppm 1.65 - 1.76 (m, 6 H) 2.02 - 2.12 (m, 1 H) 2.77 - 2.92 (m, 1 H) 2.94 - 3.05 (m, 1 H) 4.17 - 4.21 (m, 3 H) 4.23 - 4.32 (m, 1 H) 4.54 - 4.63 (m, 1 H) 4.69 - 4.76 (m, 1 H) 5.27 - 5.36 (m, 1 H) 7.15 - 7.22 (m, 2 H) 7.42 - 7.49 (m, 1 H) 7.65 - 7.71 (m, 1 H) 7.80 - 7.86 (m, 1 H) 7.87 - 7.94 (m, 1 H) 7.96 - 8.05 (m, 2 H) 8.11 - 8.20 (m, 1 H) 8.25 - 8.31 (m, 1 H) 8.86 - 8.95 (m, 1 H) SFC Rt 4.06 min, 100.00%, MW: 543.21, Method SFC_A LCMS Rt 1.93, 100%, MW: 543.20, 544 [M+H]+, 542 [M-H]-, Method A Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloro-3-fluoro-6-iodopyridine 9

[17282-04-1]

The three batches were launched in parallel. To a solution of compound [17282-04-1] (2.0 kg, 15.2 mol) in 2-MeTHF (16 L), was added LDA (2.0 M, 7.6 L) dropwise at -78°C under N2. After 1 h, acetone (1.8 kg, 30.4 mol) was added to the reaction. The brown mixture was stirred at -78°C for 2 h. The reaction mixture was warmed to 0°C. The mixture was slowly quenched with sat NH4Cl aq. (10.0 L) keeping the temperature at 0-5°C. Then the reaction mixture was warmed to room temperature, and the layers were separated. The aqueous phase was extracted once more with EtOAc (8.00 L). The combined organic phases were washed with H2O (20.0 L). Then the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure at 40°C. The crude product 7 (6.2 kg, 54%, 76% purity) was used into the next step without further purification. The reaction was done in two batches in parallel. A mixture of compound 7 (3.1 kg, 13.1 mol, 80.0 % purity) and 2-MeTHF (10.3 L) was cooled to 5°C. TBDMS-OTf (5.2 kg, 19.6 mol) was added keeping the temperature between 5-25°C in a N₂ atm. Then 2,6-dimethylpyridine (2.8 kg, 26.2 mol) was added slowly and keeping the reaction temperature between 5-25°C. The brown mixture was heated to 50°C and stirred for 10 h. The mixture was cooled to 25°C and then slowly quenched with water (10.0 L) while keeping the temperature below 30°C. Then the reaction was acidified with HC1 to pH 2-5, and the 2 layers were separated. The organic layer was washed with 10% NaHCCh aq. solution (8 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc, gradient from 100:0 to 0: 100) to yield compound 8 (5.5 kg, 67%) as a yellow oil.

To a solution of TMPMgCl.LiCl (1 M in THF, 1.8 L, 1.8 mol) was added a solution of compound 8 (140 g, 460 mmol) in THF (280 mL) at 40°C under N2. After 1 h, a solution of I2 (350 g, 1.4 mol) in THF (1.2 L) was added at 0°C and stirred for 1 h. The mixture was stirred at rt for 30 min. The reaction mixture was quenched by addition of sat. Na2SOs aq. solution (500 mL) while keeping the temperature below 25°C, then filtered and the mother liquid was diluted with H2O (1 L) and extracted with EtOAc (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate, gradient from 100:0 to 100:0) to yield compound 9 (173 g, 42%) as a yellow solid.

Synthesis of (2-(4-(2-((TerLbutyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4- fluorophenyDpyri din-2 -yl)-tetrahydro-2H-pyran-2-yl)methanamine 18

Isopropylmagnesium chloride lithium chloride complex solution (1.3 M, 8.9 mL, 11.6 mmol) was added dropwise to a stirred solution of compound 9 (2.0 g, 4.7 mmol) in dry THF (20 mL) at -30°C under nitrogen. A solution of 5-chloro-A-methoxy-A-methylpentanamide [138344-21-5] (1.7 g, 9.3 mmol) in dry THF (4 mL) was added to the mixture under nitrogen at -30°C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water. 10% aqueous H2SO4 solution was added until pH = 3. The mixture was extracted with EtOAc (3 x 150 mL). The organic layers were separated, combined, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by reverse phase (Phenom enex Gemini Cl 8 30 x 100 mm 5 pm column; from 25% [25 mM NH4HCO3] - 75% MeCN to 0% [25 mM NH4HCO3] - 100% MeCN) to yield compound 10 as a colourless oil (1.07 g, 54%).

Vinylmagnesium bromide solution (1 M in THF, 3.0 mL, 3.0 mmol) was added to a stirred solution of compound 10 (1.1 g, 2.5 mmol) in dry THF (17 mL) at -30°C under nitrogen. The reaction was stirred for 3 h with an increase of the temperature from -30°C to 0°C. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 30:70) to yield compound 11 as a colorless oil (983 mg, 86%).

Potassium bis(trimethylsilyl)amide solution (1 M in THF, 2.2 mL, 2.2 mmol) was added to a stirred solution of compound 11 (980 mg, 2.2 mmol) in dry THF (32 mL) at 0°C under nitrogen. The reaction was stirred for 30 minutes. The mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 20:80) to yield compound 12 as a colorless oil (866 mg, 95%).

A solution of cesium carbonate (2.0 g, 6.2 mmol) in degassed water (3 mL) was added to a stirred solution of compound 12 (861 mg, 2.1 mmol) and (4-fluorophenyl)boronic acid (349 mg, 2.5 mmol) in degassed 1,4-dioxane (10 mL) at room temperature while nitrogen was bubbling. The mixture was stirred at room temperature for 5 minutes while nitrogen was bubbling. [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (170.2 mg, 0.2 mmol) was added and the mixture was stirred in a sealed tube at 100°C for 18 h. The mixture was allowed to cool to room temperature. The mixture was diluted with saturated aqueous NaHCCh solution and extracted with EtOAc (x 3). The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 13 as a yellowish oil (780 mg, 78%).

Osmium tetroxide (4% in water, 589 μL, 0.1 mmol) was added to a stirred solution of compound 13 (776 mg, 1.6 mmol), 2,6-lutidine (558 μL, 0.92 g/mL, 4.8 mmol) and 4-methylmorpholine N- oxide (451 mg, 3.9 mmol) in acetone/water (10: 1, v/v, 24 mL) at room temperature. The mixture was stirred for 3 days at room temperature. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 12:88) to yield compound 14 as a viscous yellowish oil (764 mg, 94%).

Sodium periodate (384.2 mg, 1.8 mmol) was added to a stirred mixture of compound 14 (760 mg, 1.5 mmol) in THF (6 mL) and water (3 mL) at room temperature, and the mixture was stirred for 3 h. The organic solvent was evaporated in vacuo and the aqueous phase was extracted with EtOAc (x 3). The organic layers were separated, combined, washed with water and brine, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield compound 15 as a yellow oil (408 mg, 69%). The crude product was used in the next step without further purification.

Sodium borohydride (58.5 mg, 1.5 mmol) was added to a solution compound 15 (736 mg, 1.5 mmol) in methanol (8 mL) at 0°C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCCh solution and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 16 as a white solid (624 mg, 84%). DIAD (383 μL, 1.03 g/mL, 1.9 mmol) was added dropwise to a stirred solution of compound 16 (619 mg, 1.3 mmol), phthalimide (210 mg, 1.4 mmol) and triphenylphosphine (510 mg, 1.9 mmol) in dry THF (2 mL) under nitrogen at 50°C. The mixture was stirred at 50°C for 4 h. The solvents were evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 5:95) to yield compound 17 as an off-white solid (736 mg, 84%).

Hydrazine hydrate (134 μL, 1.03 g/mL, 2.4 mmol) was added to stirred solution of compound 17 (360 mg, 0.6 mmol) in ethanol (9 mL) at room temperature. The mixture was stirred at 40°C for 16 h. The mixture was diluted with 0.2 M aqueous solution NaOH (10 mL) and extracted with DCM (x 3). The organic layer was separated, combined, dried (MgSCU), filtered and the solvents evaporated in vacuo to yield compound 18 as a sticky transparent oil (270 mg, 96%). The crude product was used in the next step without further purification.

Synthesis of 2-(3-fluoro-2-(4-fluorophenyl)-6-(2-((4-(8-methoxyquinolin-6-yl)-lH-L2,3-triazol- l-yl)methyl)tetrahydro-2H-pyran-2-yl)pyridin-4-yl)propan-2-ol 21

Compound 18 (55 mg, 0.1 mmol) was dissolved in DMF (0.51 mL). Then, compound 1 (0.25 M solution, 508 μL, 0.1 mmol) was added followed by a solution of KHCO3 (46.2 mg, 0.5 mmol) in water (155 μL) at room temperature. The reaction mixture was stirred for 16 hours at room temperature. TLC showed complete and clean conversion. The mixture was dissolved in water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried (MgSCU), filtered and the solvents evaporated in vacuo to yield compound 19 as sticky white oil (54 mg, 93%). Compound 3 (9.1 mg, 0.05 mmol) was added to a solution of compound 19 (25 mg, 0.05 mmol) in /c/7-Butanol (0.3 mL). (+)-Sodium L-ascorbate (3.5 mg, 0.02 mmol) in water (0.3 mL) was added to the mixture at room temperature. Copper(II) sulfate pentahydrate (2.5 mg, 0.01 mmol) was added to the mixture at room temperature. The mixture was stirred at 40°C for 16 hours. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 70:30) to yield compound 20 as a white solid (26 mg, 76%).

Compound 20 (25 mg, 0.04 mmol) was dissolved in THF (0.2 mL). TBAF (1 M in THF, 0.1 mL, 0.1 mmol) was added at room temperature and the mixture was stirred at room temperature for 24 hours. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography ((MeOH/DCM (1 :9))/DCM, gradient from 0: 100 to 70:30) to yield compound 21 as a white powder (17 mg, 81%).

’H NMR (400 MHz, DMSO-tL, 25°C) 5 8.81 (dd, J = 4.1, 1.6 Hz, 1H), 8.42 (s, 1H), 8.31 (dd, J = 8.4, 1.6 Hz, 1H), 8.00 - 7.90 (m, 3H), 7.60 (d, J = 1.3 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.32 (t, J = 8.9 Hz, 2H), 5.40 (s, 1H), 4.71 (dd, J = 42.3, 14.2 Hz, 2H), 4.02 (s, 3H), 4.01 - 3.95 (m, 1H), 3.67 - 3.52 (m, 1H), 2.68 - 2.61 (m, 1H), 1.81 - 1.67 (m, 2H), 1.62 - 1.31 (m, 9H) SFC Rt Pl : 7.248 min; P2: 7.712 min, Area % (P1/P2): 55:45, Method: 5 to 60% [2Prop+0.1 %DEA]Lux- Amylose- 1 -2 -Prop

LCMS Rt 3.365 min, 99%, MW: 571.2, 572.2 [M+H]⁺, Method B HRMS Rt 4.405 min, 572.2559 [M+H]⁺, Method D m.p. 208.2°C (Mettler Toledo MP50)

Synthesis of l-(4-(2-((7erCbutyldimethylsilyl)oxy)propan-2-yl)-6-chloro-5-fluoropyridin-2-yl)-

4-chlorobutan-l-one 22

9 [64214-66-0] 22 A solution of compound 9 (21.5 g, 50.0 mmol) in THF (900 mL) was stirred at -40°C under a nitrogen flow. Isopropylmagnesiumchloride-lithium chloride complex (1.3 M in THF, 77 mL, 100 mmol) was added dropwise and stirring was continued for 30 minutes. A solution of 4- chloro-A-methoxy-A-methyl-butanamide (12.4 g, 74.9 mmol) in THF (100 mL) was added dropwise at -40°C and stirring was continued for one hour at room temperature. Ice was added to the stirring solution and the mixture was extracted with 2-methyl-THF twice. The organic layer was washed with brine, dried (MgSCU), filtered and the solvents evaporated in vacuo to yield compound 22 as an off-white solid (20.1 g, 98%).

Synthesis of 2- Aminomethyl )tetrahydrofuran-2-yl )-3 -fluoro-2-(4-fluorophenyl)pyridin-4-

yl)propan-2-ol 26

Compound 22 (2.5 g, 6.1 mmol), KCN (600.3 mg, 9.2 mmol) and MeOH (13 mL) were cooled to 0°C for 40 h. The mixture was diluted in water and extracted with DCM (x 3). The combined organic layers were dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 15:85) to yield compound 23 as a colourless oil which solidified upon standing under high vacuum (1.1 g, 44%).

Nickel Raney (500 mg, 8.52 mmol) was added to solution of compound 23 (2.16 g, 5.41 mmol) in ethanol under nitrogen. The nitrogen was replaced by H2 and the mixture was stirred at rt for 16 hours. The mixture was filtered over a pad of celite and solvent concentrated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95). The desired fractions were collected and concentrated in vacuo to yield compound 24 as a colorless oil (1.5 g, 68%). Compound 24 (600 mg, 1.5 mmol) was dissolved in 1,4-dioxane (15 mL) and water (4 mL) in a sealed tube. 4-fluorophenylboronic acid (250 mg, 1.8 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were added and the mixture was degassed with nitrogen stream for 5 minutes. Pd(PPh₃)₂Cl₂ (104.5 mg, 0.1 mmol) and Xantphos (172.3 mg, 0.3 mmol) were added under nitrogen atmosphere and the mixture was heated at 100°C for 16 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 5:95) to yield compound 25 a white foam (429 mg, 62%).

Compound 25 (425 mg, 0.9 mmol) was dissolved in THF (9 mL). TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added at room temperature and the mixture was stirred at room temperature for 20 h. Extra TBAF (1 M in THF, 1.4 mL, 1.4 mmol) was added. The mixture was stirred for 4 h. The reaction was diluted with EtOAc and washed with a saturated aqueous NaHCOs solution and brine. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0:100 to 10:90) to yield compound 26 as a colorless oil (230 mg, 68%).

Synthesis of 2-(3-fluoro-2-(4-fluorophenyl)-6-(2-((4-(8-methoxyquinolin-6-yl)-l H- l .2.3-triazol-

1 -yl)methyl)tetrahy drofuran-2-yl)pyridin-4-yl)propan-2-ol 28

Compound 26 (95 mg, 0.273 mmol) was dissolved in DMF (1.2 mL). Then, compound 1 (0.25 M solution, 1.2 mL, 0.300 mmol) was added followed by potassium bicarbonate (109 mg, 1.089 mmol) in water (0.360 mL) (solution 3.0 M) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The mixture was dissolved in water and extracted with EtOAc (x 2). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 90: 10). The desired fractions were collected and concentrated in vacuo to yield compound 27 as yellow solid (75 mg, 73%). Compound 3 (36 mg, 0.197 mmol) was added to a solution of compound 271 (74 mg, 0.198 mmol) in tert-Butanol (0.5 mL). (+)-Sodium L-ascorbate (14 mg, 0.079 mmol) in water (0.5 mL) was added to the mixture at room temperature. Copper(II) sulfate pentahydrate (10 mg, 0.040 mmol) was added to the mixture at room temperature. The mixture was stirred at 40°C for 16 hours. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 28 as a white solid (65 mg, 59%).

’H NMR (400 MHz, DMSO-tL, 25°C) 5 8.81 (dd, J = 4.1, 1.7 Hz, 1H), 8.61 (s, 1H), 8.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.99 (q, J = 5.7 Hz, 3H), 7.74 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.55 (dd, J = 8.3, 4.1 Hz, 1H), 7.36 (t, J = 8.9 Hz, 2H), 5.52 (s, 1H), 4.90 (s, 2H), 4.04 (s, 3H), 4.01 - 3.94 (m, 2H), 2.42 - 2.34 (m, 1H), 2.28 - 2.19 (m, 1H), 1.80 - 1.65 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H)

LCMS Rt 0.96 min, 93%, MW: 557.2, 558.2 [M+H]⁺, Method C

The enantiomers of compound 28 (87 mg, 0.14 mmol) were separated by SFC (Phenomenex;

Lux Cellulose-1 250x30 mm 5 um; Isocratic 25% [ACN-2-Prop + 0.1% DEA]) to yield compound 28a as a white solid (30 mg, 34%) and compound 28b as a white solid (29 mg, 33%).

compound 28a

’H NMR (400 MHz, DMSO-t/e, 25°C) 5 8.81 (dd, J = 4.1, 1.7 Hz, 1H), 8.61 (s, 1H), 8.33 (dd, J = 8.4, 1.7 Hz, 1H), 8.02 - 7.94 (m, 3H), 7.74 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.55 (dd, J = 8.3, 4.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 5.52 (s, 1H), 4.90 (s, 2H), 4.04 (s, 3H), 4.02 - 3.91 (m, 2H), 2.43 - 2.34 (m, 1H), 2.28 - 2.18 (m, 1H), 1.83 - 1.62 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H)

SFC Rt 5.675 min, 99%, Method: 5 to 60% [ACN-2-Prop+0.1% DEA] UV-Cellulose-l-ACN-2- Prop

LCMS Rt 3.220 min, 99%, MW: 557.2, 558.2 [M+H]⁺, Method B HRMS Rt 3.20 min, 558.2906 [M+H]⁺, Method D OR +157.1° (589 nm, c 0.1000 w/v, MeOH, 23°C) m.p. 138.0°C (Mettler Toledo MP50)

compound 28b

’H NMR (400 MHz, DMSO-t/e, 25°C) 5 8.81 (dd, J = 4.1, 1.7 Hz, 1H), 8.61 (s, 1H), 8.33 (dd, J = 8.4, 1.6 Hz, 1H), 8.03 - 7.92 (m, 3H), 7.74 (d, J = 5.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.55 (dd, J = 8.3, 4.1 Hz, 1H), 7.41 - 7.31 (m, 2H), 5.52 (s, 1H), 4.90 (s, 2H), 4.04 (s, 3H), 4.01 - 3.91 (m, 2H), 2.42 - 2.34 (m, 1H), 2.28 - 2.18 (m, 1H), 1.85 - 1.63 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H)

SFC Rt 5.842 min, 99%, Method: 5 to 60% [ACN-2-Prop+0.1% DEA] UV-Cellulose-l-ACN-2- Prop

LCMS Rt 3.219 min, 99%, MW: 557.2, 558.2 [M+H]⁺, Method B

HRMS Rt 3.21 min, 558.2795 [M+H]⁺, Method D OR -184.0° (589 nm, c 0.0933 w/v, MeOH, 23°C) m.p. 144.7°C (Mettler Toledo MP50)

Synthesis of 2-(5-(2-(aminomethyl)tetrahydrofuran-2-yl)-2,4\6-trifluoro-[E l'-biphenyl1-3- yl)propan-2-ol 35

[1891438-87-1] 29 30

Chlorotrimethylsilane (39.1 mL, 0.86 g/mL, 307.8 mmol) was added to a solution of 2-(3-chloro- 2,4-difluorophenyl)propan-2-ol [1891438-87-1] (21.2 g, 102.6 mmol) and triethylamine (42.9 mL, 0.73 g/mL, 307.8 mmol) in DCM (250 mL). The resulting mixture was stirred at 45°C for 16 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCCL solution. The organic layer was dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 10:90) to yield compound 29 as a colorless oil (17.4 g, 60%).

//BuLi in hexanes (2.5 M, 41.6 mL, 104 mmol) was added dropwise at 0°C to a solution of diisopropylamine (14.6 mL, 0.72 g/mL, 104 mmol) in anhydrous THF (50 mL). The reaction was stirred for 60 minutes at 0°C. Then, the solution was added dropwise to a solution of compound 29 (11.6 g, 41.6 mmol) in anhydrous THF (100 mL) at -78°C (the solution turned yellow/orange). The reaction was stirred at -78°C for another 30 minutes. Then, the mixture was allowed to slowly warm at -40°C for 3 h (the solution turned red). After that, iodine (15.8 g, 62.4 mmol) in anhydrous THF (20 mL) was added to the mixture at -78°C. The reaction medium was allowed to slowly warm to room temperature and stirred for 16 h (the solution turned yellow). TLC and LCMS showed total consumption of starting material. The mixture was diluted with a saturated aqueous Na2S20s solution and extracted with DCM. The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (EtOAc/heptane, gradient from 0:100 to 20:80) to yield compound 30 as a colorless oil (15.3 g, 86%).

Into a round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 30 (8.0 g, 19.8 mmol) and copper (I) bromide (567.1 mg, 4.0 mmol) in dry THF (55 mL). This was followed by the dropwise addition of isopropylmagnesium chloride lithium chloride complex solution in THF (1.3 M, 22.8 mL, 29.7 mmol) at -15°C. To this solution was added 4-chlorobutyryl chloride (2.7 mL, 1.26 g/mL, 23.7 mmol) in dry THF (32 mL) dropwise at -15°C. The resulting solution was agitated for 45 minutes at -10°C. The mixture was allowed to reach 0°C and then was quenched with saturated aqueous NH4CI solution. The resulting mixture was further agitated at room temperature for 20 minutes. Afterwards, the solution was extracted with EtOAc. The combined organic phase was dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 40:60) to yield compound 31 as a colorless oil (4.3 g, 56%).

Potassium cyanide (343.2 mg, 5.3 mmol) was added portion wise to a solution of compound 31 (1.3 g, 3.5 mmol) in MeOH (8 mL) at 0°C. After the addition, the reaction medium was allowed to slowly warm to room temperature and stirred at this temperature for 16 h. TLC (stained with phosphomolybdic acid) confirmed reaction's completion. The mixture was diluted in water and extracted with DCM (x 3). The combined organic layers were dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography (DCM/heptane, gradient from 0: 100 to 30:70) to yield compound 32 as a colorless oil (465 mg, 35%).

Raney Nickel (39.3 mg, 0.7 mmol) was added to solution of compound 32 (159 mg, 0.4 mmol) in EtOH (3 mL) at room temperature under nitrogen atmosphere. The nitrogen was replaced by hydrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of celite and the mother liquors were concentrated in vacuo to yield compound 33 as a colorless oil (159 mg, 99%) which was used as such in the next step.

A solution of K3PO4 (267.9 mg, 1.3 mmol) in water (0.7 mL) was added to a stirred solution of compound 33 (159 mg, 0.4 mmol) and 4-fhiorobenzeneboronic acid (88.3 mg, 0.6 mmol) in 1,4- dioxane (3 mL). The mixture was bubbled with nitrogen for 10 min, x-Phos (40.1 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (48.6 mg, 0.04 mmol) were sequentially added at room temperature. The reaction mixture was heated at 100°C under nitrogen atmosphere for 16 h. The crude was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo to yield compound 34 as a brownish oil (182.3 mg, 99%) which were used as such in the next step.

Compound 34 (182 mg, 0.42 mmol) was dissolved in THF. TBAF (1.25 mL, 1.25 mmol, 1 M in THF) was added at rt and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with water. Upon addition of ethyl acetate the organic layer was separated. The organic layer was washed with sat. aqueous NaHCOs, dried over MgSO4, filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography ((DCM/MeOH (9: 1))/DCM, gradient from 0:100 to 100:0). The desired fractions were combined and the solvent was removed in vacuo to yield compound 35 a brownish foam (138 mg, 91%).

Synthesis of 2-(2,4\6-trifluoro-5-(2-((4-(8-methoxyquinolin-6-yl)-lH-L2,3-triazol-l- yl)methyl)tetrahy drofuran-2-yl)-[ 1 , 1 '-biphenyl]-3 -yl)propan-2-ol 38

Pd(PPh )

A solution of K3PO4 (978.9 mg, 4.6 mmol) in water (2.6 mL) was added to a stirred solution of compound 35 (470 mg, 1.5 mmol) and 4-fluorobenzeneboronic acid (322.6 mg, 2.3 mmol) in 1,4-dioxane (10.4 mL). The mixture was bubbled with nitrogen for 10 minutes. x-Phos (146.6 mg, 0.3 mmol) and Tetrakis(triphenylphosphine)palladium(0) (177.6 mg, 0.2 mmol) were sequentially added at room temperature. The reaction mixture was heated at 100°C under nitrogen atmosphere for 16 hours. The crude was diluted with water and extracted with EtOAc. The organic layer was dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography ((DCM/MeOH (9: 1))/DCM, gradient from 0: 100 to 100:0) to yield compound 36 as a brownish foam (503 mg, 90%).

Compound 36 (300 mg, 0.8 mmol) was dissolved in DMF (3.6 mL). Then, compound 1 (0.25 M solution, 3.6 mL, 0.9 mmol) was added followed by a solution of KHCO3 (328.8 mg, 3.3 mmol) in water (1.1 mL) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. The mixture was dissolved in water and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield compound 37 as a colorless oil (237 mg, 74%). Compound 3 (93.6 mg, 0.5 mmol) was added to a solution of compound 37 (200 mg, 0.5 mmol) in tert-butanol (3 mL) followed by addition of (+)-sodium L-ascorbate (36 mg, 0.2 mmol) in water (3 mL). Finally, copper(II) sulfate pentahydrate (25.5 mg, 0.1 mmol) was added at room temperature and the mixture was stirred at 40ºC for 16 hours. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO₄), filtered and the solvents evaporated in vacuo. The crude was purified by flash column chromatography ((DCM/MeOH (9:1))/DCM, gradient from 0:100 to 70:30) to yield compound 38 as a yellowish powder (222 mg, 75%). 1H NMR (400 MHz, DMSO-d₆, 25°C) ^ 8.81 (d, J = 2.6 Hz, 1H), 8.64 (s, 1H), 8.40 – 8.24 (m, 1H), 8.00 (s, 1H), 7.78 (t, J = 9.3 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.61 – 7.48 (m, 3H), 7.35 (t, J = 8.9 Hz, 2H), 5.31 (s, 1H), 4.82 (d, J = 14.3 Hz, 1H), 4.71 (d, J = 14.3 Hz, 1H), 4.05 (s, 3H), 4.01 – 3.94 (m, 1H), 3.88 (q, J = 7.0 Hz, 1H), 2.44 – 2.34 (m, 1H), 2.27 – 2.16 (m, 1H), 1.86 – 1.69 (m, 1H), 1.64 – 1.51 (m, 1H), 1.46 (s, 3H), 1.36 (s, 3H) SFC Rt P1: 8.305 min; P2: 8.717 min, 50:50%, Method: 5 to 60% [2PrOH+0.1% DEA] Lux- Amylose-1-2PrOH LCMS Rt 3.257 min, 99%, MW : 574.2, 575.2 [M+H]+, Method B HRMS 3.294 min, 575.2036 [M+H]+, Method D m.p.208.2°C (Mettler Toledo MP50) The enantiomers of compound 38 (143.5 mg, 0.2 mmol) were separated by SFC (column: Phenomenex Lux Amylose-1250x30 mm 5 um; Isocratic 35% [2PrOH + 0.1% DEA]) to yield compound 38a as a yellowish powder (64 mg, 44%) and compound 38b as a yellowish powder (74 mg, 51%).

compound 38a 1H NMR (400 MHz, DMSO-d₆25°C) ^ 8.82 (dd, J = 4.1, 1.5 Hz, 1H), 8.64 (s, 1H), 8.39 – 8.29 (m, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.78 (t, J = 9.3 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.60 – 7.50 (m, 3H), 7.35 (t, J = 8.9 Hz, 2H), 5.31 (s, 1H), 4.82 (d, J = 14.3 Hz, 1H), 4.71 (d, J = 14.3 Hz, 1H), 4.05 (s, 3H), 3.97 (dd, J = 13.4, 7.6 Hz, 1H), 3.88 (dd, J = 15.1, 7.1 Hz, 1H), 2.43 – 2.34 (m, 1H), 2.26 – 2.17 (m, 1H), 1.82 – 1.72 (m, 1H), 1.62 – 1.51 (m, 1H), 1.46 (s, 3H), 1.36 (s, 3H) SFC Rt 8.305 min, 99%, Method: 5 to 60% [2PrOH+0.1% DEA] Lux-Amylose-1-2PrOH LCMS Rt 3.256 min, 99%, MW : 574.2, 575.2 [M+H]+, Method B HRMS Rt 3.314 min, 575.2822 [M+H]+, Method D OR +99° (589 nm, c 0.1667 w/v, DMSO, 23°C) m.p.165.3°C (Mettler Toledo MP50)

compound 38b 1H NMR (400 MHz, DMSO-d₆, 25°C) ^ 8.84 (d, J = 3.0 Hz, 1H), 8.66 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.78 (t, J = 9.3 Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J = 8.2, 4.2 Hz, 1H), 7.56 – 7.49 (m, 2H), 7.35 (t, J = 8.9 Hz, 2H), 5.31 (brs, 1H), 4.83 (d, J = 14.3 Hz, 1H), 4.72 (d, J = 14.3 Hz, 1H), 4.07 (s, 3H), 3.98 (dd, J = 13.4, 7.5 Hz, 1H), 3.89 (dd, J = 15.1, 7.1 Hz, 1H), 2.44 – 2.33 (m, 1H), 2.27 – 2.16 (m, 1H), 1.83 – 1.71 (m, 1H), 1.63 – 1.51 (m, 1H), 1.46 (s, 3H), 1.35 (s, 3H) SFC Rt 8.705 min, 98%, Method: 5 to 60% [2PrOH + 0.1% DEA] Lux-Amylose-1-2PrOH LCMS Rt 3.258 min, 98%, MW : 574.2, 575.2 [M+H]+, Method B HRMS 3.321 min, 575.2794 [M+H]+, Method D OR -107° (589 nm, c 0.1733 w/v, DMSO, 23°C) m.p.208.3°C (Mettler Toledo MP50) Biological Assays Antiviral Activity Black 384-well clear-bottom microtiter plates (Corning, Amsterdam, The Netherlands) were filled via acoustic drop ejection using the echo liquid handler (Labcyte, Sunnyvale, California). 200 nL of compound stock solutions (100% DMSO) were transferred to the assay plates. 9 serial 4-fold dilutions of compound were made, creating per quadrant the same compound concentration. The assay was initiated by adding 10 µL of culture medium to each well (RPMI medium without phenol red, 10% FBS-heat inactivated, 0.04% gentamycin (50 mg/mL). All addition steps are done by using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium). Next, rgRSV224 virus (MOI = 1) diluted in culture medium was added to the plates. rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak LK, Spillmann D, Collins PL, Peeples ME. Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection; Journal of virology (2000), 74(22), 10508-13) and was in-licensed from the NIH (Bethesda, MD, USA). Finally, 20 μL of a HeLa cell suspension (3,000 cells/well) were plated. Medium, virus- and mock-infected controls were included in each test. The wells contain 0.05% DMSO per volume. Cells were incubated at 37°C in a 5% CO2 atmosphere. Three days post-virus exposure, viral replication was quantified by measuring GFP expression in the cells by an in house developed MSM laser microscope (Tibotec, Beerse, Belgium). The EC50 was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 384-well microtiter plates (Coming) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (Perkin Elmer, Zaventem, Belgium) according to the manufacturer’s instructions. The CC50 was defined as the 50% concentration for cytotoxicity.

Table of Biological Activity

Table : antiviral data (averaged data of several repeat experiments)

Prophetic composition examples

“Active ingredient” as used throughout these examples relates to a final compound of Formula (I), the pharmaceutically acceptable salts thereof, the solvates and the stereochemically isomeric forms and the tautomers thereof. Typical examples of recipes for the formulation of the invention are as follows:

Tablets

Active ingredient 5 to 50 mg

Di calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Suspension

An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

Injectable

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol in water.

Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g

Water ad 100 g

Claims

1. A compound of formula (I)

wherein each of the groups is optionally substituted with one, two or three substituents R⁶, R⁷ and R⁸ each independently selected from halo; hydroxy; C^alkyl; C^alkyloxy;

C_3.6cycloalkyl; C_3.6cycloalkyloxy; polyhaloC^alkyl; polyhaloC^alkyloxy; C ^alkyl substituted with hydroxy; or C_3.6cycloalkyl substituted with halo or hydroxy; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl,

imidazolyl, pyridinyl or benzothiophenyl, wherein the aromatic mono- or bicyclic ring is substituted with one, two or three substituents each independently selected from h^{ydrogen, halo, C} _1-6 ^{alkyl or polyhaloC} _1-6 ^alkyl; W is N or CR⁹ wherein R⁹ is halo; R^{1 is C} _1-4 ^{alkyl, halo, hydroxy, amino, C} _1-4 ^{alkyloxy, polyhaloC} _1-4 ^{alkyloxy, C} _1-4 ^alkyl- ^{carbonyl-amino, C} _1-4 ^alkyl-oxy-C _1-4 ^{alkyl, C} _1-4 ^{alkylamino, polyhaloC} _1-4 ^alkylamino, isoindolinedionyl, or C_1-4alkyl substituted with amino or mono-or di(C_1-4alkyl)amino; X_{is O, C(=O), or CR} ¹⁰ _R ¹¹ _{wherein R} ¹⁰ _{and R} ¹¹ _{are each independently hydrogen,} C_1-4alkyl, halo, hydroxy; or alternatively R⁹ and R¹⁰ are taken together to form C_3-6 ^cycloalkyl; Y is CH₂ or C(=O); Z is CH₂; when n = 1 then the -Y-Z- radical may form R² is hydrogen, halo, hydroxy, C_1-4alkyl, or

R³ is C_1-4alkyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, hydroxy, amino, C_1-4alkyl-SO₂-amino, or C_1-4alkyl-carbonyl-amino; R⁴ is hydrogen, halo, hydroxy, C_1-4alkyl, or C_1-4alkyloxy; R⁵ is hydrogen or C_1-4alkyl; or a pharmaceutically acceptable addition salt thereof.

2. The compound as claimed in claim 1 wherein is selected from the group set forth below by removal of a hydrogen atom

and is optionally substituted with one, two or three substituents R⁶, R⁷ and R⁸ each i^{ndependently selected from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^cycloalkyl, C_3-6cycloalkyloxy, polyhaloC_1-4alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo; n is integer 0, 1 or 2: m is integer 0, 1 or 2; is a aromatic monocyclic ring selected from phenyl substituted with one substituent

selected from hydrogen or halo; W is N or CR⁹ wherein R⁹ is halo; R¹ is C_1-4alkyl, halo, hydroxy, amino, or polyhaloC_1-4alkyloxy; X_{is CR} ¹⁰ _R ¹¹ _{wherein R} ¹⁰ _{and R} ¹¹ _{are hydrogen;} Y is CH₂; Z is CH₂; R² is hydrogen; R³ is C_1-4alkyl substituted with 1 substituent selected from hydroxy; R⁴ _{is halo;} R⁵ is hydrogen; or a pharmaceutically acceptable addition salt thereof.

3. The compound as claimed in claim 1 or claim 2 wherein the compound of formula (I) is defined as a compound of formula (II)

wherein ring B, R¹, R², R³, R⁴, R⁵, W, X, Y Z, n and m are as defined in claim 1 or claim 2 a^{nd R6 is selected from halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^{cycloalkyl, C} _3-6 ^{cycloalkyloxy,} polyhaloC_1-4alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo.

4. The compound as claimed in claim 1 or claim 2 wherein the compound of formula (I) is defined as a compound of formula (III)

wherein ring B, R², R³, R⁴ and W are as defined in claim 1 or claim 2 and R⁶ is selected f^{rom halo, C} _1-4 ^{alkyl, C} _1-4 ^{alkyloxy, C} _3-6 ^{cycloalkyl, C} _3-6 ^{cycloalkyloxy, polyhaloC} _1-4 ^alkyl, polyhaloC_1-4alkyloxy, or C_3-6cycloalkyl substituted with halo.

5. The compound as claimed in claim 1 or claim 2 wherein the compound of formula (I) is defined as a compound of formula (IV)

6. The compound as claimed in claim 1 or claim 2 wherein the compound of formula (I) is defined as a compound of formula (V)

7. The compound as claimed in claim 1 wherein the compound of formula (I) is defined as a compound of formula (VI)

wherein is selected from the group set forth below by removal of a hydrogen atom

that is substituted with one substituent R⁶ selected from C_1-4alkyloxy; is phenyl substituted with halo;

X_{is CR} ¹⁰ _R ¹¹ _{wherein R} ¹⁰ _{and R} ¹¹ _{are hydrogen;} Y is CH₂; Z is CH₂; W is N; n is integer 0, 1 or 2: R² is hydrogen; R³ is C_1-4alkyl substituted with 1 substituent selected from hydroxy; R⁴ _{is halo;} R⁵ is hydrogen; and or a pharmaceutically acceptable addition salt thereof.

8. The compound as claimed in claim 6 wherein is 8-methoxyquinolin-6-yl;

is 4-fluorophenyl; and

R³ is C(CH₃)₂OH.

9. The compound as claimed in any one of claims 1, 7 or 8 wherein the compound is selected from

and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in any one of claims 1 to 9.

11. The pharmaceutical composition according to claim 10, which further comprises another antiviral agent.

12. The pharmaceutical composition according to claim 10, wherein the other antiviral agent is a RSV inhibiting compound.

13. A process for preparing a pharmaceutical composition as claimed in any one of claims 10 to 12 wherein a therapeutically active amount of a compound as claimed in any one of claims 1 to 9 is intimately mixed with a pharmaceutically acceptable carrier.

14. A compound as claimed in any one of claims 1 to 9 for use as a medicine.

15. A compound as claimed in any one of claims 1 to 9, or a pharmaceutical composition as claimed in any one of claims 10 to 12, for use in the treatment of a respiratory syncytial virus infection.