WO2023237732A1 - Rsv inhibiting triazolo bearing derivatives - Google Patents

Rsv inhibiting triazolo bearing derivatives Download PDF

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Publication number
WO2023237732A1
WO2023237732A1 PCT/EP2023/065475 EP2023065475W WO2023237732A1 WO 2023237732 A1 WO2023237732 A1 WO 2023237732A1 EP 2023065475 W EP2023065475 W EP 2023065475W WO 2023237732 A1 WO2023237732 A1 WO 2023237732A1
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Prior art keywords
compound
halo
mmol
alkyl
formula
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PCT/EP2023/065475
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French (fr)
Inventor
Sandrine Céline Grosse
Minh Thao TRAN
Serge Maria Aloysius Pieters
Eric Tan
Ferdinand Hermann LUTTER
Matthieu Dominique Jouffroy
Edgar Jacoby
Tim Hugo Maria Jonckers
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Janssen Sciences Ireland Unlimited Company
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Publication of WO2023237732A1 publication Critical patent/WO2023237732A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • 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.
  • 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 or is selected from the groups set forth below wherein each of the groups is optionally substituted with one, two or three substituents R 6 , R 7 and R 8 each independently selected from halo; hydroxy; C 1-4 alkyl; C 1-4 alkyloxy; C 3-6 cycloalkyl; C 3-6 cycloalkyloxy; polyhaloC 1-4 alkyl; polyhaloC 1-4 alkyloxy; C 1-4 alkyl substituted with hydroxy; C 3-6 cycloalkyl substituted with halo or hydroxy; amino; cyano; CH 3 -SO 2 -; CHO; and triazolyl; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl, imidazolyl, pyridinyl or benzothiophenyl,
  • W is N or CR 9 wherein R 9 is halo
  • R 1 is hydrogen, polyhaloC 1-4 alkyl, or C 3-6 cycloalkyl substituted with halo;
  • R 1 is OH or NH 2 ; or R 1 and R 1' may be taken together with the carbon to which they are attached to form carbonyl;
  • R 2 is hydrogen, halo, hydroxy, C 1-4 alkyl, or C 1-4 alkyloxy;
  • R 3 is C 1-4 alkyl substituted with one, two or three substituents each independently selected from hydrogen, halo, hydroxy, amino, C 1-4 alkyl-SO 2 -amino, or C 1-4 al kyl -carbonyl - amino;
  • R 4 is hydrogen, halo, hydroxy, C 1-4 alkyl, or C 1-4 alkyloxy;
  • - halo is generic to fluoro, chloro, bromo and iodo
  • - C 1-4 al kyl 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;
  • C 3-6 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • stereoisomers “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
  • 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 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.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • 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.
  • a compound of formula (I) is for instance specified as (R)
  • a compound of formula (I) is for instance specified as E
  • Z Z isomer
  • a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • compositions of formula (I) are meant to comprise the therapeutically active non-toxic addition salt forms that the compounds of formula (I) are able to form.
  • 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.
  • the compounds of formula (I) may exist in both unsolvated and solvated forms.
  • 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.
  • solvent molecules e.g. water or ethanol.
  • hydrate is used when said solvent is water.
  • compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms.
  • 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.
  • W is N
  • R 1 is hydrogen, polyhaloC 1-4 alkyl, or C 3-6 cycloalkyl substituted with halo;
  • R 1 is OH or NH 2 ; or R 1 and R 1' may be taken together with the carbon to which they are attached to form carbonyl;
  • R 2 is hydrogen;
  • R 3 is C 1-4 al kyl substituted with one substituent selected from hydroxy;
  • R 4 is halo
  • R 5 is hydrogen, halo or polyhaloC 1-4 alkyl; or a pharmaceutically acceptable addition salt thereof.
  • the compounds of formula (I) are defined as compounds of formula (II) : wherein ring B, R 1 , R 1' , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and W are as defined for compounds of formula (I).
  • the compounds of formula (I) are defined as compounds of formula (III) : wherein ring B, R 1 , R 1' , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and W are as defined for compounds of formula (I).
  • the compounds of formula (I) are defined as compounds of formula (IV) : wherein ring B, R 1 , R 1' , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and W are as defined for compounds of formula (I).
  • the compounds of formula (I) are defined as compounds of formula (V) : wherein ring B, R 1 , R 1' , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and W are as defined for compounds of formula (I).
  • interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply : a) B is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C 1-6 alkyl or polyhalo C 1-6 alkyl; or b) B is phenyl substituted with halo; or c) B is 4-fluorophenyl; or d) B is indolyl; or e) R 2 is hydrogen, R 3 is C 1-4 alkyl substituted with hydroxy, and R 4 is halo; f) R 5 is hydrogen; k) ring A is cinnoline optionally; and l) ring A is quinoline optionally substituted.
  • 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 R 6 , R 7 and R 8 each independently selected from halo; hydroxy; C 1-4 alkyl; C 1-4 alkyloxy; C 3-6 cycloalkyl; polyhaloC 1-4 alkyl; polyhaloC 1-4 alkyloxy; C 3-6 cycloalkyl substituted with halo; amino; cyano; CH 3 -SO 2 -; CHO; and triazolyl; is phenyl substituted with halo;
  • W is N
  • R 1 is hydrogen, polyhaloC 1-4 alkyl, or C 3-6 cycloalkyl substituted with halo;
  • R 1' is OH or NH 2 ; or R 1 and R 1' may be taken together with the carbon to which they are attached to form carbonyl;
  • R 3 is C 1-4 al kyl substituted with one substituent selected from hydroxy
  • 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
  • R 2 is hydrogen
  • R 3 is C(CH 3 ) 2 OH;
  • R 4 is fluoro;
  • 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).
  • 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.
  • compounds of the formula (I) wherein R 5 is hydrogen represented as compounds of formula (I-a), may be synthesized according to Scheme 1.
  • 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.
  • 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.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure 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).
  • RSV human and bovine respiratory syncytial virus
  • a number of the compounds of this invention moreover are active against mutated strains of RSV.
  • 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).
  • compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Dosage unit form 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.
  • 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.
  • 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 lauryl sulphate) 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).
  • suspending agents e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • 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 sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,r,6'-trichloro-4,r,6
  • Intense sweeteners are conveniently used in low concentrations.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 combination of another antiviral agent and a compound of formula (I) can be used as a medicine.
  • 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.
  • 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.
  • 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-1-[3-(methyl- sulfonyl)propyl]- 1H-benzimidazol-2-yl ⁇ methyl)-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one, 3-[[7-chloro-3-(2-ethylsulfonyl-ethyl)imidazo[ 1,2-a]pyridin-2-yl]methyl]-1- cyclopropyl-imidazo
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • Optical rotations were measured on a Perkin Elmer 341 polarimeter and reported as follow [ ⁇ ] ⁇ T .
  • ⁇ 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).
  • Compound 10 was prepared in an analogous following general procedure A.
  • 3-Fluoro-8-methoxyquinoline-6-carboxylic acid 200 mg, 0.9 mmol
  • DPPF Pd G3 83.6 mg, 0.09 mmol
  • l,3-bis(diphenylphosphino)propane 37.3 mg, 0.09 mmol
  • bis[(tetrabutylammonium iodide)copper(I) iodide] 50.6 mg, 0.05 mmol
  • the obtained residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield 6-ethynyl-3-fluoro-8-methoxyquinoline 19 (30 mg, 51%) as a light-yellow solid.
  • Manganese(IV) oxide (14.2 mg, 0.2 mmol) was added to a mixture of compound 25 (9.8 mg, 0.03 mmol) in DCM (0.3 mL). The resulting mixture was stirred at room temperature for 5 days. Celite was added to the reaction mixture, and the suspension was filtered onto a pad of Celite, eluted with DCM (5 mL), and the filtrate evaporated to dryness to yield compound 26 (7 mg, 96%) as a yellow paste.
  • Enantiomers were separated via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH-iPrOH (50-50) + 0.4% iPrNH 2 ) to yield compound 38a (1 g, 48%) and compound 38b (1 g, 50%), both as white solid.
  • the reaction was stirred at 50°C for 16 h.
  • the reaction was treated with Silicycle Imidazole (100 mg) for 4 h and extracted with DCM (3 x 1.2 mL) and filtered. 3 mL of DMSO was added and DCM was evaporated overnight in Genevac.
  • the sample was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to yield compound 59 (7.1 mg, 11%).
  • a VLT tube was charged with compound 105 (281 mg, 0.8 mmol) and compound 8 (163.1 mg, 0.8 mmol) in MeOH (5 mL) and THF (3.6 mL). To this mixture was added copper (II) sulfate pentahydrate (20 mg, 0.08 mmol) solution and sodium ascorbate (40 mg, 0.2 mmol) solution (in that order). The mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo and the residue was treated with NH4OH solution. The precipitate was filtered off and boiled in methanol. The precipitated product was filtered off and dried under vacuum to become compound 106 (280 mg, 64%) as a white solid.
  • the reaction was then cooled to 0°C. A solution of NaOH (0.7 g, 16.3 mmol) in water (5 mL) was added to the reaction mixture. The resulting solution was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction mixture was evaporated to dryness. The paste obtained was dissolved in EtOAc (50 mL) and water (50 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (50 mL), dried (Na 2 SO 4 ), filtered, and the solvent evaporated to dryness.
  • the dark yellow oil obtained was purified by column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield 2-[3-fluoro-2-(4-fluorophenyl)-6- (oxiran-2-yl)-4-pyridyl]propan-2-ol 108 (1.4 g, 89%) as an off-white solid.
  • reaction mixture was allowed to cool to room temperature and the solvent was evaporated to dryness (water bath set at 35°C to see if dimer formation could be suppressed) to yield 2-[6-(2- amino-1-hydroxy-ethyl)-3-fluoro-2-(4-fluorophenyl)-4-pyridyl]propan-2-ol 109 (1.5 g, 76%, a mixture of 78% product and 12% dimer) as an off-white solid.
  • the reaction was quenched at 0°C with a sat aq. NaHCO 3 solution and extracted with DCM. The organic layer was dried over MgSO 4 , filtered and concentrate in vacuo. The crude product was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 05:95).
  • the resulting product was repurified by FCC reverse phase (Gemini C18 100 x 30 mm, 5 pm) (from 50% [0.1% HCOOH] - 50% [ACN:MeOH 1 : 1] to 25% [0.1% HCOOH] - 75% [ACN: MeOH 1 : 1]).
  • Fraction 1 was separated by SFC (column: Lux i-Cellulose-1, 250 x 30 mm, 5 ⁇ m; Isocratic 50% [i-PrOH + 0.1% DEA]). The desired fractions were combined and dried in vacuo to compound 117 (20 mg, 7%) as a white solid and compound 118 (10 mg, 4%) as a white solid. Other fractions were discarded.
  • the desired fractions were combined and the solvent was removed in vacuo to yield a mixture of compounds 121 and 122 (45 mg, 20%) as a yellow solid and starting material 39 (70 mg, 67%) as a colourless oil.
  • the mixture of compounds 121 and 122 was purified by reverse phase chromatography (Phenomenex, Gemini C18, 100 x 30 mm, 5 pm; from 59% [0.1% HCOOH in water] - 41% [ACN: MeOH 1 : 1] to 17% [0.1% HCOOH in water] - 83% [ACN: MeOH 1 :1]).
  • the desired fractions were collected and diluted with aqueous sat. solution of NaHCO 3 and the aqueous layer was extracted with DCM (x3).
  • the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo to yield compound 121 (24 mg, 13%) as a white solid and compound 122 (3 mg, 2%) as a colourless oil.
  • the desired fractions were combined and the solvent was removed.
  • the product was further purified by reverse phase (Phenomenex Gemini C18 30 x 100 mm 5pm Column; from 59% [25 mM NH 4 HCO 3 ] - 41% [ACN:MeOH (1 : 1)] to 17% [25 mM NH 4 HCO 3 ] - 83% [ACN:MeOH (1 : 1)]).
  • the desired fractions were collected and concentrated to yield compound 124 (33 mg, 48%) as a beige solid.
  • Black 384-well clear-bottom microtiter plates (Coming, 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 ⁇ L 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).
  • 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.
  • 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.
  • 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.

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.

Description

RSV INHIBITING TRIAZOLO 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-2014/031784, WO-2015/026792, WO-2016/138158, WO-2021/066922 and WO-2021/214136. Detailed description of the Invention
The present invention relates to compounds of formula (I)
Figure imgf000004_0001
including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000004_0002
Figure imgf000004_0003
or is selected from the groups set forth below
Figure imgf000005_0001
Figure imgf000005_0002
wherein each of the groups is optionally substituted with one, two or three substituents
Figure imgf000005_0003
R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; C3-6cycloalkyloxy; polyhaloC1-4alkyl; polyhaloC1-4alkyloxy; C1-4alkyl substituted with hydroxy; C3-6cycloalkyl substituted with halo or hydroxy; amino; cyano; CH3-SO2-; CHO; and triazolyl; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl,
Figure imgf000005_0004
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 polyhaloC 1-6alkyl;
W is N or CR9 wherein R9 is halo;
R1 is hydrogen, polyhaloC1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1 is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkyloxy;
R3 is C1-4alkyl substituted with one, two or three substituents each independently selected from hydrogen, halo, hydroxy, amino, C1-4alkyl-SO2-amino, or C1-4al kyl -carbonyl - amino;
R4 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkyloxy;
R5 is hydrogen, halo, C1-4al kyl or polyhaloC1-4alkyl; or a pharmaceutically acceptable addition salt thereof. As used in the foregoing definitions :
- halo is generic to fluoro, chloro, bromo and iodo;
- C1-4al kyl 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
- polyhaloC1-4alkyl is defined as polyhalosubstituted C1-4alkyl, in particular C1-4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like
- C3-6cycloalkyl 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 transconfiguration; 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, 13C, 14C, 14N, 15O or the like.
In an embodiment the present invention relates to compounds of formula (I)
Figure imgf000008_0001
including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000009_0001
Figure imgf000009_0002
is selected from the groups set forth below
Figure imgf000009_0003
Figure imgf000009_0004
wherein each of the groups is optionally substituted with one, two or three substituents
Figure imgf000009_0005
R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; polyhaloC1-4alkyl; polyhaloC1-4alkyloxy; C3-6cycloalkyl substituted with halo; amino; cyano; CH3-SO2-; CHO; and triazolyl; is a aromatic mono- or bicyclic ring selected from phenyl or indolyl, wherein the
Figure imgf000009_0006
aromatic mono- or bicyclic ring is substituted with one substituent selected from halo;
W is N;
R1 is hydrogen, polyhaloC1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1 is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen; R3 is C1-4al kyl substituted with one substituent selected from hydroxy;
R4 is halo;
R5 is hydrogen, halo or polyhaloC1-4alkyl; 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) :
Figure imgf000010_0001
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined for compounds of formula (I).
In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (III) :
Figure imgf000010_0002
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined for compounds of formula (I). In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (IV) :
Figure imgf000011_0001
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined for compounds of formula (I).
In another embodiment of the present invention the compounds of formula (I) are defined as compounds of formula (V) :
Figure imgf000011_0002
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined for compounds of formula (I).
Interesting groups of compounds are compounds of formula (I), (II), (III), (IV), or (V), wherein ring B is phenyl and said ring B is substituted halo.
Interesting compounds of formula (I) are those compounds of formula (I) wherein one or more of the following restrictions apply : a) B is phenyl substituted with one, two or three substituents each independently selected from hydrogen, halo, C1-6alkyl or polyhalo C1-6alkyl; or b) B is phenyl substituted with halo; or c) B is 4-fluorophenyl; or d) B is indolyl; or e) R2 is hydrogen, R3 is C1-4alkyl substituted with hydroxy, and R4 is halo; f) R5 is hydrogen; k) ring A is cinnoline optionally; and l) ring A is quinoline optionally substituted. In a further embodiment the present invention relates to compounds of formula (I)
Figure imgf000012_0001
including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
Figure imgf000012_0005
Figure imgf000013_0001
wherein each of the groups is optionally substituted with one, two or three substituents
Figure imgf000013_0002
R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; polyhaloC1-4alkyl; polyhaloC1-4alkyloxy; C3-6cycloalkyl substituted with halo; amino; cyano; CH3-SO2-; CHO; and triazolyl; is phenyl substituted with halo;
Figure imgf000013_0003
W is N;
R1 is hydrogen, polyhaloC1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1' is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen;
R3 is C1-4al kyl substituted with one substituent selected from hydroxy;
R4 is halo;
R5 is hydrogen, halo or polyhaloC1-4alkyl; or a pharmaceutically acceptable addition salt thereof.
In yet a further embodiment the present invention relates to compounds of formula (I)
Figure imgf000013_0004
including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
wherein each of the groups is optionally substituted with one, two or three substituents
Figure imgf000014_0004
R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; ppolyhaloC1-4alky;l polyhaloC1-4alkyloxy; C3-6cycloalkyl substituted with halo; amino; cyano; CH3-SO2-; CHO; and triazolyl; is 4-fluorophenyl;
Figure imgf000014_0005
W is N;
R1 is hydrogen, polyhaloC1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1' is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen;
R3 is C(CH3)2OH; R4 is fluoro;
R5 is hydrogen, halo or polyhaloC1-4alkyl; or a pharmaceutically acceptable addition salt thereof.
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 (I-a), may be synthesized according to Scheme 1.
Scheme 1
Figure imgf000015_0001
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 lauryl sulphate) 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-1-[3-(methyl- sulfonyl)propyl]- 1H-benzimidazol-2-yl}methyl)-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5- c]pyridin-2-one, 3-[[7-chloro-3-(2-ethylsulfonyl-ethyl)imidazo[ 1,2-a]pyridin-2-yl]methyl]-1- cyclopropyl-imidazo[4,5-c]pyridin-2-one, and 3-({5-chloro-1-[3-(methyl-sulfonyl)propyl]- 1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-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 (δ = 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 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+NH4] , [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. LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes).
Figure imgf000021_0001
Abbreviations
Figure imgf000022_0001
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 [α]λ T. λ 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.
Synthesis of trifluoromethanesulfonyl azide 2
Figure imgf000023_0001
To an ice-cooled suspension of sodium azide (115.9 mg, 1.8 mmol) in dry acetonitrile (3 mL) was carefully and slowly added triflic anhydride (250 μL, 1.7 g/mL, 1.5 mmol). The mixture was stirred at 0°C for 2 hours. The solids were allowed to settle and the supernatant containing compound 2 was used further. Complete conversion was assumed. Product was used as solution 0.5 M. Synthesis of compound 6
Figure imgf000024_0001
Sodium hydride (323.9 mg, 8.1 mmol) was suspended on THF (14 mL) under N2 atmosphere, and the mixture was cooled at 0°C. 5-Methoxy-6-azaindole (1 g, 6.7 mmol) dissolved in THF (6 mL) was slowly added to the mixture at 0°C. It was stirred for 30 minutes, then, p- toluenesulfonyl chloride (1.4 g, 7.4 mmol) was slowly added at 0°C, and the mixture was stirred at rt for 3 hours. Water was added carefully at 0°C. The mixture was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo to yield compound 3 (2.1 g, yield quant.) as a brown solid. Diisopropylamine (2.8 mL, 0.7 g/mL, 20.2 mmol) was dissolved in THF (10 mL) and the solution was cooled at -30°C. n-Butyllithium solution (8.1 mL, 2.5 M, 20.2 mmol) was added slowly at -30°C and the mixture was stirred for 1 hour at -30°C. On the other hand, compound 3 (3.4 g, 11.2 mmol) and N,N,N',N'-tetramethylethylenediamine (1.9 mL, 0.8 g/mL, 12.4 mmol) were dissolved in THF (110 mL) and the first solution was added dropwise at -78°C and it was stirred 30 minutes at -30°C. A solution of iodine (6.3 g, 24.7 mmol) in THF (50 mL) was added and the mixture was stirred at -78°C for 30 minutes. The mixture was dissolved in water and the mixture was extracted with EtOAc (x3). The combined organic layers were washed with aq. sat. solution of Na2S2O3, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0: 100 to 100:0). The desired fractions were combined, and the solvent was removed in vacuo to yield compound 4 (1.5 g, 30%) as a brown foam.
Compound 4 (1.5 g, 3.5 mmol) was dissolved in 1,4-dioxane (54 mL) and sodium tert- butoxide (511 mg, 5.3 mmol) was added. The mixture was stirred at 80°C for 3 hours. The mixture was diluted in water and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0:100 to 100:0). The desired fractions were combined to yield compound 5 (525 mg, 53%) as a beige solid.
Compound 5 (740 mg, 2.7 mmol) was dissolved in dry DCM (7 mL). TEA (564.5 μL, 0.7 g/mL, 4.1 mmol) and DMAP (16.5 mg, 0.1 mmol) were added. Then di- tert-butyl dicarbonate (744.4 μL, 1 g/mL, 3.2 mmol) was added and the mixture was stirred at rt for 16 hours. The reaction mixture was diluted with water and DCM was added. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to yield compound 6 (992 mg, 96%) as a brown solid.
General procedure A: 8-methoxy-6-((trimethylsilyl)ethynyl)quinoline 8
Figure imgf000025_0001
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, 0.69 g/mL, 252 mmol) and Pd(PPh3)2Cl2 (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 (MgSO4), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 7 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 7 (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 NaHCO3 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 (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield compound 8 as a dark red solid (13.9 g, 60%, 90% purity).
Synthesis of 3-(4-ethynylphenyl)- 1H-L2,4-triazole 9
Compound 9 was obtained in an analogous manner following general procedure A.
Figure imgf000026_0001
Synthesis of tert-butyl 2-ethynyl-5-methoxy- 1H-pyrrolo[2,3-c]pyridine-1-carboxylate 10
Compound 10 was prepared in an analogous following general procedure A.
Figure imgf000026_0002
General procedure B: 4-ethynyl- 1,2-dimethoxybenzene 12
Figure imgf000026_0003
Copper(I) iodide [7681-65-4] (175.5 mg, 0.9 mmol) was added to a stirred solution of 4- bromo-1,2-dimethoxybenzene [2859-78-1] (662.7 μL, 1.5 g/mL, 4.6 mmol) in TEA (5 mL). The mixture was bubbled with nitrogen for 7 min. TMS-acetylene [1066-54-2] (6.4 mL, 0.7 g/mL, 46.1 mmol) was added to the mixture at room temperature. The mixture was bubbled with nitrogen for 3 min. Pd(PPh3)2Cl2 [13965-03-2] (646.7 mg, 0.9 mmol) was added to the mixture and the reaction was stirred at 80°C for 16 h. The crude was extracted with EtOAc and water. The organic layer was dried over MgSO4, filtered and concentrated under vacuum The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0: 100 to 2:98). The desired fractions were joined and evaporated to dryness to yield ((3,4-dimethoxyphenyl)ethynyl)trimethylsilane 11 (964 mg, 88%) as a yellow oil. ((3,4-Dimethoxyphenyl)ethynyl)trimethylsilane (964 mg, 4.1 mmol) was dissolved in THF (12 mL). TBAF solution (1 M in THF) [429-41-4] (4.9 mL, 4.9 mmol) was added at room temperature and the mixture was stirred at for 2 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0:100 to 30:70). The desired fractions were concentrated in vacuo to yield 4-ethynyl-1,2- dimethoxybenzene 12 (577 mg, 86%) as a white solid.
General procedure C: 6-ethynyl-8-methoxy-3-methylquinoline 15
Figure imgf000027_0001
LAH 2.4 M solution in THF [16853-85-3] (1.8 mL, 4.4 mmol) was added to a solution of methyl 8-methoxy-3-methylquinoline-6-carboxylate (481 mg, 2.1 mmol) in dry THF (16.7 mL) at 0°C. The reaction was stirred at this temperature for 1 hour. The reaction was quenched at 0°C with water (15 mL) and was diluted with EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL), washed with brine (5 mL), dried (Na2SO4), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (MeOH/DCM, gradient from 0:100 to 10:90) to yield (8-methoxy-3- methylquinolin-6-yl) methanol 13 (304 mg, 66%) as a colorless paste.
Pyridinium chlorochromate [26299-14-9] (0.9 g, 4.1 mmol) was added to a solution of (8- m ethoxy-3 -methylquinolin-6-yl) methanol (304 mg, 1.4 mmol) in DCM (13.5 mL). The resulting mixture was stirred at room temperature for 2.5 hours. The black suspension was filtered through a pad of Celite, eluted with DCM (10 mL), and the solvent evaporated to dryness. The crude residue was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 10:90) to yield 8-methoxy-3-methylquinoline-6-carbaldehyde 14 (175 mg, 61%) as a black viscous oil.
8-Methoxy-3-methylquinoline-6-carbaldehyde (175 mg, 0.8 mmol) and K2CO3 [584-08-7] (233.2 mg, 1.7 mmol) were added to a reaction vial and was purged with positive pressure of nitrogen for 15 minutes. Dry MeOH (2.4 mL), and dimethyl (l-diazo-2-oxopropyl) phosphonate [90965-06-3] (253.2 μL, 1.3 g/mL, 1.7 mmol) were then added to the reaction vial. The resulting brown mixture was stirred at room temperature for 40 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and was diluted with DCM (2 mL). The aqueous layer was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine (3 mL), dried (MgSO4), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (EtOAc/n-heptane, gradient from 0:100 to 100:0) to yield 6-ethynyl-8-methoxy-3-methylquinoline 15 (60 mg, 36%) as a white solid.
Synthesis 6-ethynyl-2-( 1 -fluorocyclopropyl )-8-methoxyimidazo[ 1,2-a]pyridine 16
Compound 16 was obtained in an analogous manner following general procedure C.
Figure imgf000028_0001
Synthesis of 2-cyclopropyl-6-ethynyl-4-methoxybenzo[d|oxazole 17
Compound 17 was obtained in an analogous manner following general procedure C.
Figure imgf000028_0002
General procedure D: 3-fluoro-8-methoxy-6-((triisopropylsilyl)ethynyl)quinoline 19
Figure imgf000028_0003
3-Fluoro-8-methoxyquinoline-6-carboxylic acid (200 mg, 0.9 mmol), DPPF Pd G3 (83.6 mg, 0.09 mmol), l,3-bis(diphenylphosphino)propane (37.3 mg, 0.09 mmol), and bis[(tetrabutylammonium iodide)copper(I) iodide] (50.6 mg, 0.05 mmol) were added to a microwave vial. The vial was sealed and flushed with positive nitrogen pressure for 15 minutes.
To the vial was added dry 1,4-dioxane (9 mL), trimethylacetic anhydride (183.5 μL, 0.9 g/mL, 0.9 mmol), (triisopropylsilyl)acetylene (402.2 μL, 0.8 g/mL, 1.8 mmol), and 1- methylimidazole (93.7 μL, 1 g/mL, 1.2 mmol). The resulting mixture was warmed to 100°C and was stirred at this temperature for 4 hours. The reaction was allowed to cool to room temperature and was poured onto water (10 mL) and diluted with EtOAc (5 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), filtered, and the solvent evaporated to dryness. The obtained residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield 3- fluoro-8-methoxy-6-((triisopropylsilyl)ethynyl)quinoline 18 (111 mg, 32%) as a dark-yellow paste.
Tetrabutylammonium fluoride 1 M in THF (581.8 μL, 0.6 mmol) was added to a solution of compound 18 (111 mg, 0.3 mmol) in dry THF (2.9 mL) at room temperature. The resulting mixture was stirred for 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 solution (3 mL), and the layers were partitioned. The aqueous layer was extracted with DCM (3 x 3 mL). The combined organic layers were washed with water (5 mL), dried (MgSO4), filtered, and the solvent evaporated to dryness.
The obtained residue was purified by flash column chromatography (EtOAc/heptane, gradient from 0: 100 to 100:0) to yield 6-ethynyl-3-fluoro-8-methoxyquinoline 19 (30 mg, 51%) as a light-yellow solid.
Synthesis of 3-chloro-6-ethynyl-8-methoxyquinoline 20
Compound 20 was obtained in an analogous manner following general procedure D.
Figure imgf000029_0001
Synthesis of 6-ethynyl-2-fluoro-8-methoxy-3 -methylquinoline 21
Compound 21 was obtained in an analogous manner following general procedure D.
Figure imgf000029_0002
Synthesis of 6-ethynyl-8-methoxy-3-methylcinnoline 22
Figure imgf000030_0001
Compound 22 was obtained in an analogous manner following general procedure D. TMS deprotection was performed using silver (II) fluoride (1.5 eq) in dry methanol.
Synthesis of 6-(3, 3 -difluoroprop- 1-yn- 1-yl)-8 -methoxy quinoline 23
Figure imgf000030_0002
Compound 8 (400 mg, 2.2 mmol) and potassium tert-butoxide (490 mg, 4.4 mmol) were purged with N2. Dry toluene (8.8 mL) was added and the mixture was stirred at 0°C for 10 min. (Bromodifluoromethyl)trimethylsilane (679 μL, 1.3 g/mL, 4.4 mmol) was added and the mixture was stirred at 0°C for 30 min. TBAF solution in THF (4.4 mL, 1 M, 4.4 mmol) was added and the mixture was stirred at rt for 1 h. Silver nitrate (1.5 g, 8.7 mmol) and, lastly, ammonia solution 25% (22 mL) were added and the mixture was stirred at rt for 16 h. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0: 100 to 70:30). The desired fractions were combined and the solvent was removed in vacuo to yield compound 23 (243 mg, 41%) as an orange solid.
Synthesis of 6-(chloroethynyl)-8-methoxyquinoline 24
Figure imgf000030_0003
To a stirred mixture of compound 8 (200 mg, 1.1 mmol) in dry acetone (1.2 mL) was added N-chlorosuccinimide (175 mg, 1.3 mmol) and silver acetate (18.2 mg, 0.1 mmol) and the solution was heated at reflux for 16 hours. The residue was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0: 100 to 10:90). The desired fractions were combined and the solvent was removed in vacuo to yield compound 24 (155 mg, 62%) as an orange solid.
Synthesis of 8-ethoxy-6-ethynyl-3-methylcinnoline 26
Figure imgf000031_0001
During TMS deprotection as described in general procedure D the alkyne was obtained as a mixture of desired compound and reduced compound 25.
Manganese(IV) oxide (14.2 mg, 0.2 mmol) was added to a mixture of compound 25 (9.8 mg, 0.03 mmol) in DCM (0.3 mL). The resulting mixture was stirred at room temperature for 5 days. Celite was added to the reaction mixture, and the suspension was filtered onto a pad of Celite, eluted with DCM (5 mL), and the filtrate evaporated to dryness to yield compound 26 (7 mg, 96%) as a yellow paste.
Synthesis of (S)-3-amino- 1 ,1, 1 -trifluoro-2-( 5-fluoro-6-( 7-fluoro- 1H-indol-2-yl )-4-(2- hydroxypropan-2-yl)pyridin-2-yl)propan-2-ol 27
Figure imgf000031_0002
A solution of Cs2CO3 (4.5 g, 33.2 mmol) in water (28 mL) was added to a stirred solution of (S)-3 -amino-2-(6-chl oro-5 -fluoro-4-(2-hydroxypropan-2-yl)pyri din-2 -yl)- 1,1,1- trifluoropropan-2-ol (3.5 g, 11.1 mmol) and 7-fluoro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-indole (3.5 g, 13.3 mmol) in dioxane (112 mL). The mixture was bubbled with nitrogen for 10 min, PdCl2(dppf) (902.6 mg, 1.1 mmol) was added at r.t. The reaction mixture was heated at 100°C and stirred under nitrogen atmosphere for 16 h. The mixture was diluted with EtOAc and the organic layer was washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 90: 10). The desired fractions were combined and concentrated in vacuo to yield compound 27 (4 g, 83%) as a brown solid.
Synthesi s of (*R)-2-(6-(2-amino- 1 -( 1 -fluorocyclopropyl)- 1 -hy droxy ethyl)-3 -fluoro-2-(7 - fluoro- 1H-indol -2 -yl)pyridin-4-yl)propan-2-ol 28 Compound 28 was obtained in an analogous manner
Figure imgf000032_0001
Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloro-3-fluoro-6-iodopyridine
31
Figure imgf000032_0002
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 in THF, 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 NH4CI 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 29 (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 29 (3.1 kg, 13.1 mol, 80.0% purity) and 2 -Me THF (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% NaHCO3 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 100:0) to yield compound 30 (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 30 (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: 1) to yield compound 31 (173 g, 42%) as a yellow solid.
Synthesis of 1-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4- fluorophenyl)pyridin-2-yl)-2,2,2-trifluoroethan-1-one 33
Figure imgf000033_0001
To the mixture of 4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-2-chloro-3-fluoro-6- iodopyridine 31 (4 g, 9.285 mmol) and anhydrous ethyl trifluoroacetate (5.277 g, 37.141 mmol) in THF (50 mL) was added isopropylmagnesium chloride (2.39 g, 23.3 mmol) at 0°C under N2 atmosphere and stirred for 30 min. The mixture was quenched by aq. NH4CI (150 mL) and extracted by EtOAc (100 mL x 3). The mixture was concentrated under reduced pressure. The crude product was purified with flash column chromatography (PE/EA, isocratic eluent of 10:1) to get 1-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-5- fluoropyridin-2-yl)-2,2,2-trifluoroethan-1-one 32 (3.1 g, 66%) as a yellow oil.
A mixture of 1- (4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-6-chloro-5-fluoropyridin-2- yl)-2,2,2-trifluoroethan-1-one 32 (800 mg, 2.0 mmol), 4-fluorobenzeneboronic acid (420 mg, 3.0 mmol), potassium carbonate (554 mg, 4.0 mmol) and tetrakis(triphenylphosphine) palladium (231.6 mg, 0.200 mmol) in DME (11 mL) and H2O (3.7 mL) was heated under microwave conditions at 160°C for 5 min. The solid was filtered out. The mixture was extracted by EtOAc (50 mL x 3) and the organic layer was concentrated under reduced pressure. The crude product was purified with flash column chromatography (PEZEA, isocratic eluent of 10:1) to get 1-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6- (4-fluorophenyl)pyridin-2-yl)-2,2,2-trifluoroethan-1-one 33 (430 mg, 48%) as a yellow solid.
Synthesis of (EZ)-4-(2-((tert-butyldimethyl silyl )oxy )propan-2-yl )-3 -fluoro-2-(4- fluorophenyl)-6-(3 ,3,3 -trifluoro- 1 -nitroprop- 1 -en-2-yl)pyridine 35
Figure imgf000034_0001
A solution of1- [4-[1-[tert-butyl(dirnethyl)silyl]o1x-y- rnethyl-ethyl]-5-fluoro-6-(4- fluorophenyl)-2-pyridyl]-2,2,2-trifluoro-ethanone 33 (9.2 g, 20 mmol) and triethylamine (6.0 mL, 0.73 g/mL, 43.5 mmol) in nitromethane (26.8 mL, 1.14 g/mL, 500 mmol) was stirred at rt for 2 h. Water and EtOAc were added and the pH was adjusted to pH = 6 with acetic acid (2.5 mL). The organic layer was separated, washed with water, dried over MgSO4, filtered off and evaporated to afford 2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4- fluorophenyl)pyri din-2 -yl)-1, 1,1 -trifluoro-3-nitropropan-2-ol 34 (10.4 g, quant.).
To a solution of (2S)-2-[4-[ 1-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-fluoro-6-(4- fluorophenyl)-2-pyridyl]-1, 1, 1-trifluoro-3-nitro-propan-2-ol 34 (10 g, 19.2 mmol) in toluene (67 mL) was added pyridine (4.6 mL, 1 g/mL, 57.6 mmol) at 0°C. The solution was stirred at 0°C for 5 min. Then SOCl2 (3.9 mL, 1.6 g/mL, 53.8 mmol) was added at 0°C and stirred for 30 min. The cooling bath was removed and the reaction mixture was stirred at rt for 1 h. The reaction was diluted with EtOAc (100 mL) and water (50 mL). The pH was adjusted to pH 4 with a saturated aqueous solution of NaHCO3. The aqueous layer was separated and extracted once more with EtOAc (100 mL). The combined organic layers were dried over MgSO4, filtered off and evaporated in vacuo to give crude (EZ)-4-(2-((tert- butyldimethyl sily l)oxy)propan-2-yl)-3 -fluoro-2-(4-fluorophenyl)-6-(3 ,3,3 -trifluoro- 1 - nitroprop- l-en-2-yl)pyri dine 35 (10.8 g, 90%) as a red oil.
Synthesis of 2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4- fluorophenyl)pyridin-2-yl)-3,3,3-trifluoropropane-L2-diamine 37
Figure imgf000035_0001
A solution of compound 35 (12.1 g, 19.2 mmol) in THF (90 mL) was cooled to -60°C and then NH3 (25% in H2O) (13.1 mL, 0.9 g/mL, 172.8 mmol) was added. The reaction mixture was stirred between -60°C to -40°C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 times 100 mL). The organic layers were combined and evaporated to dry and the crude was purified via silica (heptane/EtOAc, gradient from 100:0 to 85: 15) to obtain crude oil. This was further purified flash column chromatography (heptane/EtOAc, isocratic 90: 10) to yield crude compound 36 (8 g) as a brown oil, which was used as such in the next step.
To a heated suspension of compound 36 (8 g, 15.5 mmol) and iron (8.9 g, 0.2 mol) in EtOH (120 mL) and water (12 mL) was added ammonium chloride (3.3 g, 0.06 mol) at 80°C. The reaction mixture was heated at 85°C for 20 min. The reaction was cooled to rt, then DCM (200 mL) and sat. Na2CO3 (50 mL) were added. The mixture was dried over Na2SO4 as such. The solids were filtered off and the filtrate was evaporated to dry. The crude oil was purified via flash column chromatography (DCM/EtOAc, gradient of 100:0 to 0: 100). After evaporation of the fractions compound 37 (3 g, 39%) was obtained as a yellow oil.
Synthesis of compound 38a and 38b
Figure imgf000035_0002
Compound 37 (2.9 g, 5.4 mmol) was dissolved in HC1 (6 M in iPrOH) (75 mL, 450 mmol) and the solution was heated at 50°C for 16 h. Solvent was evaporated and the residue was coevaporated with EtOH and di-ethyl ether. The yellowish foam was triturated in ether and 4 mL iPrOH was added, but all went into solution. The product was evaporated to dry again (now we have powder, not a foam). Ether was added and the suspension was stirred at rt for 20 h. The white solid was filtered off, washed with ether and dried in vacuo to obtain a white powder. Enantiomers were separated via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH-iPrOH (50-50) + 0.4% iPrNH2) to yield compound 38a (1 g, 48%) and compound 38b (1 g, 50%), both as white solid.
General procedure E: Synthesis of (S)-3-(4-(3.4-dimethoxyphenyl )- 1H- 1.2.3-triazol- yl )-1-
1, 1, 1 -trifluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2 -hydroxypropan-2-yl)pyri din-2 -yl)propan-
Figure imgf000036_0001
To a solution of (S)-3-amino-1, 1, 1-trifluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)propan-2-ol (160 mg, 0.4 mmol) and NaHCO3 [144-55-8] (142.9 mg, 1.7 mmol) in MeOH/H2O (2: 1) (3.5 mL) was added a freshly solution of trifluoromethanesulfonyl azide 2 (2.6 mL, 0.5 M in CH3CN, 1.3 mmol) at 0°C. The reaction was stirred at room temperature for 20 h. The mixture was dissolved in water and extracted with EtOAc three times. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (EtOAc/Heptane, gradient from 0: 100 to 30:70). The desired fractions were collected and concentrated in vacuo to yield (2S)-3-azido-1, 1, 1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4- (l-hydroxy-1-methyl-ethyl)-2-pyridyl]propan-2-ol 39 (105 mg, 61%) as a clear oil. 4-Ethynyl-1,2-dimethoxybenzene 12 (16 mg, 0.1 mmol) was added to a solution of compound 39 (36 mg, 0.09 mmol) in tert-BuOH (1 mL). (+)-Sodium L-ascorbate [134-03-2] (6.3 mg, 0.04 mmol) in water (1 mL) was added to the mixture at room temperature. Then copper(II) sulfate pentahydrate [7758-99-8] (4.5 mg, 0.02 mmol) was added at room temperature. The mixture was heated at 40°C for 4 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (EtOAc/Heptane, gradient from 0:100 to 100:0). The desired fractions were combined, and the solvent was removed in vacuo to yield (2S)-3-[4-(3,4-dimethoxyphenyl)triazol-1-yl]-1, 1, 1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)- 4-(l -hydroxy- l-methyl-ethyl)-2-pyridyl]propan-2-ol 40 (40 mg, 71%) as a white solid.
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
General procedure F: synthesis of (S)- 1, 1, 1-trifluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)-3-(4-(pyridin-2-yl)- 1H- 1,2,3-triazol-1-yl)propan-2-ol 59
Figure imgf000042_0001
To a solution of sodium azide [26628-22-8] (13.1 mg, 0.2 mmol) in water (1,5 mL) was added tert-butyl methyl ether (0.3 mL) followed by a solution of 2,3-dimethylimidazol-1-ium-1- sulfonyl fluoride trifluoromethanesulfonate [2179072-33-2] (65.7 mg, 0.2 mmol) in ACN (0.3 mL). The reaction was stirred at room temperature for 30 min. The reaction mixture was then left for separation of the 2 layers. The aqueous phase was removed by pipette. To the organic layer was added a solution of (S)-3 -amino- 1, 1,1 -trifluoro-2-(5-fluoro-6-(4-fluorophenyl)-4-(2- hydroxypropan-2-yl)pyridin-2-yl)propan-2-ol (75.3 mg, 0.2 mmol) in DMSO (0,5 mL) followed by a solution of KHCO3 (80.1 mg, 0.8 mmol) in water (0.5 mL). The reaction was stirred for 3 days at room temperature and the reaction solution was used as such in the next step.
To a solution of sodium ascorbate [134-03-2] (128.8 mg, 0.7 mmol), sodium phosphate dibasic [7558-79-4] (369.1 mg, 2.6 mmol), citric acid [77-92-9] (249.8 mg, 1.3 mmol), copper(ii) sulfate pentahydrate [7758-99-8] (0.3 mg, 0.001 mmol) and tris(3-hydroxypropyl-triazolylmethyl)amine [760952-88-3] (0.6 mg, 0.001 mmol) in water (1 mL) and DMSO (1 mL) was added 2- ethynylpyridine [1945-84-2] (26.8 mg, 0.3 mmol) and (S)-3-azido-1, 1, 1-trifluoro-2-(5-fluoro-6- (4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyridin-2-yl)propan-2-ol 39 (52.3 mg, 0.1 mmol). The reaction was stirred at 50°C for 16 h. The reaction was treated with Silicycle Imidazole (100 mg) for 4 h and extracted with DCM (3 x 1.2 mL) and filtered. 3 mL of DMSO was added and DCM was evaporated overnight in Genevac. The sample was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to yield compound 59 (7.1 mg, 11%).
Compound 59-102 described in the table below were made in a similar manner following general procedure F.
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0002
Synthesis of 1 -(5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyri din-2 -yl)-2-(4-(8- m ethoxy quinolin-6-yl)- 1H-1,2,3 -tri azol- 1 -yl)ethan- 1 -one 106
Figure imgf000049_0001
Figure imgf000050_0001
Into a 250 mL round bottom flask sparged with nitrogen and equipped with a magnetic stir bar was placed tributyl(l -ethoxy vinyl)stannane (12.7 mL, 1.1 g/mL, 38.8 mmol) and 2-(6-chl oro-3 - fluoro-2-(4-fluorophenyl)pyridin-4-yl)propan-2-ol (10 g, 35.2 mmol) in 1,4-di oxane (52 mL). Then, bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.8 mmol) was added and the reaction was stirred for 2 h at 100°C. The reaction mixture was filtered through packed celite, the solvent of the filtrate was removed under reduced pressure. Heptane was added and the white precipitate was isolated by filtration to afford compound 103 (10.2 g, 91%).
Into a 250 mL round bottom flask with a magnetic stir bar was placed compound 103 (10.2 g, 31.9 mmol) in THF (65 mL) and water (5 mL). At 0°C, NBS (6.3 g, 35.1 mmol) was added. The reaction mixture was allowed to reach rt and stirred for 5 h. The mixture was quenched with sat. aq. NaHCO3 and the product was extracted with Me-THF. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (heptane/EtOAc, gradient from 100:0 to 50:50). The product fractions were collected and concentrated in vacuo to become compound 104 (8.3 g, 70%) as a white solid.
A VLT was charged with compound 104 (500 mg, 1.4 mmol) in DMSO (4 mL). Sodium azide (266.1 mg, 4.1 mmol) was added at r.t. and the mixture was stirred for 30 min at r.t., the mixture was poured out in water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/heptane, gradient from 0:100 to 50:50). The product fractions were collected and concentrated in vacuo to become compound 105 (281 mg, 63%) as a white solid.
A VLT tube was charged with compound 105 (281 mg, 0.8 mmol) and compound 8 (163.1 mg, 0.8 mmol) in MeOH (5 mL) and THF (3.6 mL). To this mixture was added copper (II) sulfate pentahydrate (20 mg, 0.08 mmol) solution and sodium ascorbate (40 mg, 0.2 mmol) solution (in that order). The mixture was stirred at rt for 16 h. The mixture was concentrated in vacuo and the residue was treated with NH4OH solution. The precipitate was filtered off and boiled in methanol. The precipitated product was filtered off and dried under vacuum to become compound 106 (280 mg, 64%) as a white solid.
LCMS : Rt: 1.04 min, 100%, 516 [M+H]+, 514 [M-H]’, Method E
1H NMR (400 MHz, DMSO-d6, 27°C) δ ppm 1.59 (s, 6 H) 4.07 (s, 3 H) 5.84 (s, 1 H) 6.43 (s, 2 H) 7.43 (t, J=8.9 Hz, 2 H) 7.57 (dd, J=8.1, 4.2 Hz, 1 H) 7.69 (d, J=1.5 Hz, 1 H) 8.04 (d, J=1.5 Hz, 1 H) 8.15 (dd, J=7.4, 5.6 Hz, 2 H) 8.32 (d, J=5.5 Hz, 1 H) 8.38 (dd, J=8.5, 1.7 Hz, 1 H) 8.75 (s, 1 H) 8.83 (dd, J=4.1, 1.7 Hz, 1 H).
Mp: 264.4°C (DSC: From 30 to 400°C at 10°C/min 50 ml)
Synthesis of compound 112 and 113
Figure imgf000051_0001
A flask was charged with 2-[6-chl oro-3 -fluoro-2-(4-fluorophenyl)-4-pyridyl]propan-2-ol (1 g, 3.525 mmol), potassium vinyltrifluoroborate [13682-77-4] (0.614 g, 4.582 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) [72287-26-4] (52 mg, 0.07 mmol). Dry triethylamine [121-44-8] (0.64 mL, 0.726 g/mL, 4.582 mmol) and dry EtOH (20.298 mL, 0.8 g/mL, 352.479 mmol) were added to the reaction vessel. The resulting mixture was heated to reflux at 80°C and stirred for 3 hours. The reaction was concentrated in vacuo. The residue was washed with water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50). The product fractions were collected and concentrated in vacuo to yield 2-[3-fluoro-2-(4-fluorophenyl)-6-vinyl-4-pyridyl]propan-2-ol 107 (869 mg, 90%) as a white solid. A-Bromosuccinimide (1 g, 5.7 mmol) was added to a suspension of 2-[3-fluoro-2-(4- fluorophenyl)-6-vinyl-4-pyridyl]propan-2-ol 107 (2 g, 5.4 mmol) in water (19 mL) and tBuOH (19.2 mL). The resulting suspension was warmed to an internal temperature of 40°C and stirred for 1.5 hours. The reaction was then cooled to 0°C. A solution of NaOH (0.7 g, 16.3 mmol) in water (5 mL) was added to the reaction mixture. The resulting solution was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction mixture was evaporated to dryness. The paste obtained was dissolved in EtOAc (50 mL) and water (50 mL). The layers were partitioned. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (50 mL), dried (Na2SO4), filtered, and the solvent evaporated to dryness. The dark yellow oil obtained was purified by column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield 2-[3-fluoro-2-(4-fluorophenyl)-6- (oxiran-2-yl)-4-pyridyl]propan-2-ol 108 (1.4 g, 89%) as an off-white solid.
A mixture of 2-[3-fluoro-2-(4-fluorophenyl)-6-(oxiran-2-yl)-4-pyridyl]propan-2-ol 108 (1.4 g, 4.9 mmol) and ammonia in MeOH (69.4 mL, 7 M, 486 mmol) was warmed to 40°C and was stirred at this temperature for 18 hours. After this time, extra ammonia in MeOH [7664-41-7] (10.4 mL, 7 M, 72.9 mmol) was added to the reaction and was stirred at 42°C for 3 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated to dryness (water bath set at 35°C to see if dimer formation could be suppressed) to yield 2-[6-(2- amino-1-hydroxy-ethyl)-3-fluoro-2-(4-fluorophenyl)-4-pyridyl]propan-2-ol 109 (1.5 g, 76%, a mixture of 78% product and 12% dimer) as an off-white solid.
A solution of 2-[6-(2-amino-1-hydroxy-ethyl)-3-fluoro-2-(4-fluorophenyl)-4-pyridyl]propan-2-ol 109 (200 mg, 0.5 mmol) and NaHCO3 (170 mg, 2 mmol) in MeOH/H20 (2: 1 v/v) (4 mL) was cooled to 0°C. To the cooled reaction vial was added a freshly prepared solution of compound 2 (3 mL, 0.5 M in CH3CN, 1.5 mmol) at 0°C behind a blast shield. The reaction was allowed to warm to room temperature and was stirred for 18 hours behind a blast shield. The reaction was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4), filtered, and the solvent evaporated to dryness. The crude residue was purified by column chromatography (EtOAc/heptane, gradient from 0: 100 to 50:50) to yield 2-[6-(2-azido-1-hydroxy-ethyl)-3-fluoro-2-(4-fluorophenyl)-4-pyridyl]propan- 2-ol 110 (151 mg, 88%) as a colorless oil.
Final compound 111 obtained using second step of general procedure E. Enantiomers 112 and 113 were obtained after purification via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2)
Figure imgf000053_0001
Synthesis of compound 117 and 118
Figure imgf000054_0001
Tert-butyldimethylsilyl trifluoromethanesulfonate (364 μL, 1.2 g/mL, 1.6 mmol) was added to solution of (2S)-1, 1, 1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4-( 1-hydroxy-1-methyl-ethyl)-2- pyridyl]-3-[4-(8-methoxy-6-quinolyl)triazol-1-yl]propan-2-ol 41 (375 mg, 0.6 mmol) and triethylamine (123.7 μL, 0.7 g/mL, 0.9 mmol) in anhydrous DCM (3.5mL) and the mixture was stirred at 45°C for 16 hours. The reaction was quenched at 0°C with a sat aq. NaHCO3 solution and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrate in vacuo. The crude product was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 05:95). The desired fractions were collected and concentrated in vacuo to yield (S)-2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4-fluorophenyl) pyridin-2-yl)- 1, 1, 1-trifluoro-3-(4-(8-methoxyquinolin-6-yl)- 1H-1,2,3-triazol-1-yl)propan-2-ol 114 (285 mg, 64%).
To a solution of (S)-2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4- fluorophenyl)pyridin-2-yl)-1, 1, 1-trifluoro-3-(4-(8-methoxyquinolin-6-yl)- 1H-1,2,3-triazol-1- yl)propan-2-ol 114 (125 mg, 0.2 mmol) in DCM anhydrous (2 mL) was added DAST (70.8 μL, 1.2 g/mL, 0.5 mmol) at -10°C. Once the addition was completed, the mixture was stirred at 0°C for 16 h. LCMS didn't show consumption of starting material. DAST (70.8 μL, 1.2 g/mL, 0.5 mmol) was added to the mixture and it was stirred at r.t. for 4 h. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo to yield 6-( 1-(2-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6- (4-fluorophenyl)pyridin-2-yl)-2,3,3,3-tetrafluoropropyl)- 1H-1,2,3-triazol-4-yl)-8- methoxy quinoline 115 which was used as such in the next step.
6-( 1-(2-(4-(2-(( Tert-butyldimethylsilyl)oxy)propan-2-yl)-5-fluoro-6-(4-fluorophenyl)pyridin-2- yl)-2,3,3,3-tetrafluoropropyl)- 1H-1,2,3-triazol-4-yl)-8-methoxyquinoline 115 (125 mg, 0.2 mmol) was dissolved in THF (2 mL). TBAF solution 1 M in THF (0.6 mL, 0.6 mmol) was added at rt and the mixture was stirred at rt for 72 h. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 05:95). The desired fractions were combined, and the solvent was removed in vacuo to afford compound 116.
The resulting product was repurified by FCC reverse phase (Gemini C18 100 x 30 mm, 5 pm) (from 50% [0.1% HCOOH] - 50% [ACN:MeOH 1 : 1] to 25% [0.1% HCOOH] - 75% [ACN: MeOH 1 : 1]). The desired fractions were combined, neutralized to pH=7 with a sat. aq. NaHCO3 solution, extracted with DCM and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to yield five different fractions.
Fraction 1 was separated by SFC (column: Lux i-Cellulose-1, 250 x 30 mm, 5 μm; Isocratic 50% [i-PrOH + 0.1% DEA]). The desired fractions were combined and dried in vacuo to compound 117 (20 mg, 7%) as a white solid and compound 118 (10 mg, 4%) as a white solid. Other fractions were discarded.
Figure imgf000055_0001
Figure imgf000056_0002
Synthesis of compounds 119 and 120
Figure imgf000056_0001
Compound 23 (240 mg, 1.0 mmol) was added to a solution of compound 39 (296 mg, 0.7 mmol) in dry toluene (3 mL) and the mixture was stirred at 140°C for 16 h in microwave. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 03:97). The desired fractions were combined and the solvent was removed in vacuo to yield compound 119 (203 mg, 41%) and compound 120 (217 mg, 41%) as a white solids.
Figure imgf000056_0003
Figure imgf000057_0002
Synthesis of compounds 121 and 122
Figure imgf000057_0001
Compound 24 (60 mg, 0.3 mmol) was added to a solution of compound 39 (92.4 mg, 0.2 mmol) in dry toluene (800 μL) and the mixture was stirred at 140°C for 16 h in microwave. The mixture was diluted with water and EtOAc. The aqueous layer was separated and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (MeOH/DCM, gradient from 0: 100 to 03:97). The desired fractions were combined and the solvent was removed in vacuo to yield a mixture of compounds 121 and 122 (45 mg, 20%) as a yellow solid and starting material 39 (70 mg, 67%) as a colourless oil. The mixture of compounds 121 and 122 was purified by reverse phase chromatography (Phenomenex, Gemini C18, 100 x 30 mm, 5 pm; from 59% [0.1% HCOOH in water] - 41% [ACN: MeOH 1 : 1] to 17% [0.1% HCOOH in water] - 83% [ACN: MeOH 1 :1]). The desired fractions were collected and diluted with aqueous sat. solution of NaHCO3 and the aqueous layer was extracted with DCM (x3). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield compound 121 (24 mg, 13%) as a white solid and compound 122 (3 mg, 2%) as a colourless oil.
Figure imgf000058_0002
Synthesis of compound 124
Figure imgf000058_0001
Compound 123 was obtained following general procedure A and E starting from compound 6. Compound 123 (80 mg, 0.1 mmol) was dissolved in dichloromethane (6 mL). Hydrogen chloride (1.6 mL, 4 M in dioxane, 6.4 mmol) was added slowly at 0°C. The mixture was stirred at rt for 16 hours. The mixture was diluted in DCM and aq. sat. solution of NaHCO3 were added to pH 7- 8. The mixture was extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (EtOAc/Heptane, gradient from 0: 100 to 100:0). The desired fractions were combined and the solvent was removed. The product was further purified by reverse phase (Phenomenex Gemini C18 30 x 100 mm 5pm Column; from 59% [25 mM NH4HCO3] - 41% [ACN:MeOH (1 : 1)] to 17% [25 mM NH4HCO3] - 83% [ACN:MeOH (1 : 1)]). The desired fractions were collected and concentrated to yield compound 124 (33 mg, 48%) as a beige solid.
LCMS: Rt: 2.88 min, 99%, 565 [M+H]+, Method A
SFC: Rt: 6.26 min, 99%, Method: 5 to 60% [EtOH + 0.1% DEA] UV-2-Cellulose-1-EtOH) 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.04 (dd, J = 7.6, 5.7 Hz, 2H), 7.99 (d, J = 5.3 Hz, 1H), 7.37 (t, J = 8.9 Hz, 2H), 6.82 (s, 1H), 6.70 (s, 1H), 6.51 (s, 1H), 5.63 (s, 1H), 5.34 (d, J = 14.3 Hz, 1H), 5.21 (d, J = 14.2 Hz, 1H), 3.83 (s, 3H), 1.56 (s, 3H), 1.51 (s, 3H), 1.03 - 0.69 (m, 3H), 0.63 - 0.46 (m, 1H).
Mp: 189.9°C
Biological Assays Antiviral Activity
Black 384-well clear-bottom microtiter plates (Coming, 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: antiviral data (averaged data of several repeat experiments)
Figure imgf000060_0001
Figure imgf000061_0001
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 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.

Claims

Claims
1. A compound of formula (I)
Figure imgf000063_0001
including any stereochemically isomeric form thereof, wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000063_0002
Figure imgf000063_0003
or is selected from the groups set forth below
Figure imgf000064_0001
Figure imgf000064_0002
wherein each of the groups is optionally substituted with one, two or three
Figure imgf000064_0003
substituents R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; C3-6cycloalkyloxy; polyhaloC1-4alkyl; polyhaloC1-4alkyloxy; C1-4al kyl substituted with hydroxy; C3-6cycloalkyl substituted with halo or hydroxy; amino; cyano; CH3-SO2-; CHO; and triazolyl; is a aromatic mono- or bicyclic ring selected from phenyl, indolyl, pyrazolyl, imidazolyl,
Figure imgf000064_0004
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 polyhaloC1-6alkyl;
W is N or CR9 wherein R9 is halo;
R1 is hydrogen, polyhaloC 1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1' is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkyloxy;
R3 is C1-4al ky 1 substituted with one, two or three substituents each independently selected from hydrogen, halo, hydroxy, amino, C1-4alkyl-SO2-amino, or C1-4al kyl -carbonyl - amino;
R4 is hydrogen, halo, hydroxy, C1-4alkyl, or C1-4alkyloxy;
R5 is hydrogen, halo, C1-4al kyl or polyhaloC1-4alkyl; or a pharmaceutically acceptable addition salt thereof.
2. The compound as claimed in claim 1 wherein is selected from the groups set forth below by removal of a hydrogen atom
Figure imgf000065_0001
Figure imgf000065_0002
or is selected from the groups set forth below
Figure imgf000065_0003
Figure imgf000065_0004
wherein each of the groups is optionally substituted with one, two or three
Figure imgf000065_0005
substituents R6, R7 and R8 each independently selected from halo; hydroxy; C1-4alkyl; C1-4alkyloxy; C3-6cycloalkyl; polyhaloC1-4alkyl; polyhaloC1-4alkyloxy; C3-6cycloalkyl substituted with halo; amino; cyano; CH3-SO2-; CHO; and triazolyl; is a aromatic mono- or bicyclic ring selected from phenyl or indolyl, wherein the
Figure imgf000065_0006
aromatic mono- or bicyclic ring is substituted with one substituent selected from halo;
W is N;
R1 is hydrogen, polyhaloC1-4alkyl, or C3-6cycloalkyl substituted with halo; and
R1' is OH or NH2; or R1 and R1' may be taken together with the carbon to which they are attached to form carbonyl;
R2 is hydrogen;
R3 is C1-4al kyl substituted with one substituent selected from hydroxy;
R4 is halo;
R5 is hydrogen, halo or polyhaloC1-4 alkyl; or a pharmaceutically acceptable addition salt thereof.
3. The compound as claimed in claim 2 wherein B is phenyl substituted with halo.
4. The compound as claimed in claim 3 wherein B is 4-fluorophenyl, R3 is C(CH3)2OH and R4 is fluoro.
5. The compound as claimed in any one of claims 1, 2 or 3 wherein the compound of formula (I) is defined as a compound of formula (II)
Figure imgf000066_0001
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined in any one of claims 1, 2 or 3.
6. The compound as claimed in any one of claims 1, 2 or 3 wherein the compound of formula (I) is defined as a compound of formula (III)
Figure imgf000066_0002
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined in any one of claims 1, 2 or 3.
7. The compound as claimed in any one of claims 1, 2 or 3 wherein the compound of formula (I) is defined as a compound of formula (IV)
Figure imgf000067_0001
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined in any one of claims 1, 2 or 3.
8. The compound as claimed in any one of claims 1, 2 or 3 wherein the compound of formula
(I) is defined as a compound of formula (V)
Figure imgf000067_0002
wherein ring B, R1, R1' , R2, R3, R4, R5, R6, R7, R8 and W are as defined in any one of claims 1, 2 or 3.
9. 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 8.
10. The pharmaceutical composition according to claim 9, which further comprises another antiviral agent.
11. The pharmaceutical composition according to claim 9, wherein the other antiviral agent is a RSV inhibiting compound.
12. A process for preparing a pharmaceutical composition as claimed in any one of claims 9 to 11 wherein a therapeutically active amount of a compound as claimed in any one of claims 1 to 8 is intimately mixed with a pharmaceutically acceptable carrier.
13. A compound as claimed in any one of claims 1 to 8 for use as a medicine.
14. A compound as claimed in any one of claims 1 to 8, or a pharmaceutical composition as claimed in any one of claims 9 to 11, for use in the treatment of a respiratory syncytial virus infection.
PCT/EP2023/065475 2022-06-10 2023-06-09 Rsv inhibiting triazolo bearing derivatives WO2023237732A1 (en)

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WO2014031784A1 (en) 2012-08-23 2014-02-27 Alios Biopharma, Inc. Compounds for the treatment of paramoxyvirus viral infections
WO2015026792A1 (en) 2013-08-21 2015-02-26 Alios Biopharma, Inc. Antiviral compounds
WO2016138158A1 (en) 2015-02-25 2016-09-01 Alios Biopharma, Inc. Antiviral compounds
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WO2021214136A1 (en) 2020-04-21 2021-10-28 Janssen Sciences Ireland Unlimited Company Rsv inhibiting 3-substituted quinoline and cinnoline derivatives

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Title
HALLAK LKSPILLMANN DCOLLINS PLPEEPLES ME: "Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection", JOURNAL OF VIROLOGY, vol. 74, no. 22, 2000, pages 10508 - 13
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